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World Health Organization Classification of Tumours
LeBoit P. E., Burg G., Weedon D., Kurman R.J., Carcangiu M.L., El-Naggar A. K., Chan J.K.C.,
Sarasin A. (Eds): World Health Herrington C.S., Young R.H. (Eds): Gradis J.R., Takata T., Slootweg P.J.
Organization Classification of WHO Classification of Tumours (Eds): WHO Classification of Head
Tumours. Pathology and Genetics of Female Reproductive and Neck Tumours (4th edition).
of Skin Tumours (3rd edition). Organs (4th edition). IARC: Lyon 2014. IARC: Lyon 2017.
IARC Press: Lyon 2006. ISBN 978-92-832-2435-8 ISBN 978-92-832-2438-9
ISBN 978-92-832-2414-0
Bosman F.T., Carneiro F., Travis W. D., Brambilla E., Burke A. P., Lloyd R.V., Osamura R.Y., Kloppel G.,
Hruban R. H., Theise N. D. (Eds): Marx A., Nicholson A. G. (Eds): Rosai J. (Eds): WHO Classification of
WHO Classification of Tumours of WHO Classification of Tumours of Tumours of Endocrine Organs
the Digestive System (4th edition). the Lung, Pleura, Thymus and Heart (4th edition). IARC: Lyon 2017.
IARC: Lyon 2010. (4th edition). IARC: Lyon 2015. ISBN 978-92-832-4493-6
ISBN 978-92-832-2432-7 ISBN 978-92-832-2436-5
Lakhani S.R., Ellis I.O., Schnitt S. J., Moch H., Humphrey P. A., Swerdlow S. H., Campo E., Harris N. L.,
Tan P. H., van de Vijver M.J. (Eds): Ulbright T.M., Reuter V.E. (Eds): Jaffe E.S., Pileri S.A., Stein H.,
WHO Classification of Tumours of the WHO Classification of Tumours of the Thiele J. (Eds): WHO Classification of
Breast (4th edition). IARC: Lyon 2012. Urinary System and Male Genital Tumours of Haematopoietic and Lym
ISBN 978-92-832-2433-4 Organs (4th edition). IARC: Lyon 2016. phoid Tissues (Revised 4th edition).
ISBN 978-92-832-2437-2 IARC: Lyon 2017.
ISBN 978-92-832-4494-3
Fletcher C. D. M., Bridge J.A., Louis D. N., Ohgaki H., Wiestler O.D.,
Hogendoorn P.C.W., Mertens F. (Eds): Cavenee W. K. (Eds):
WHO Classification of Tumours WHO Classification of Tumours of
of Soft Tissue and Bone (4th edition). the Central Nervous System (Revised
IARC: Lyon 2013. 4th edition). IARC: Lyon 2016.
ISBN 978-92-832-2434-1 ISBN 978-92-832-4492-9
This book and all other volumes of the series can be purchased:
WHO OMS
Edited by
Steven H. Swerdlow
Elias Campo
Nancy Lee Harris
Elaine S. Jaffe
Stefano A. Pileri
Harald Stein
Jurgen Thiele
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The authors alone are responsible for the views expressed in this publication.
WHO classification of tumours of haematopoietic and lymphoid tissues / edited by Steven H. Swerdlow, Elias Campo,
Nancy Lee Harris, Elaine S. Jaffe, Stefano A. Pileri, Harald Stein, Jurgen Thiele. - Revised 4th edition.
10 WHO classification
Blastic plasmacytoid dendritic cell neoplasm 9727/3 Alpha heavy chain disease 9762/3
Plasma cell neoplasms
Acute leukaemias of ambiguous lineage Non-IgM monoclonal gammopathy of
Acute undifferentiated leukaemia 9801/3 undetermined significance 9765/1
Mixed-phenotype acute leukaemia with Plasma cell myeloma 9732/3
t(9;22)(q34.1;q11.2); BCR-ABL1 9806/3 Solitary plasmacytoma of bone 9731/3
Mixed-phenotype acute leukaemia with Extraosseous plasmacytoma 9734/3
t(v;11q23.3); KMT2A-rearranged 9807/3 Monoclonal immunoglobulin deposition diseases
Mixed-phenotype acute leukaemia, Primary amyloidosis 9769/1
B/myeloid, NOS 9808/3 Light chain and heavy chain
Mixed-phenotype acute leukaemia, deposition diseases 9769/1
T/myeloid, NOS 9809/3 Extranodal marginal zone lymphoma of mucosa-
Mixed-phenotype acute leukaemia, NOS, associated lymphoid tissue (MALT lymphoma) 9699/3
rare types Nodal marginal zone lymphoma 9699/3
Acute leukaemias of ambiguous lineage, NOS Paediatric nodal marginal zone lymphoma 9699/3
Follicular lymphoma 9690/3
Precursor lymphoid neoplasms In situ follicular neoplasia 9695/1*
B-lymphoblastic leukaemia/lymphoma, NOS 9811/3 Duodenal-type follicular lymphoma 9695/3
B-lymphoblastic leukaemia/lymphoma with Testicular follicular lymphoma 9690/3
t(9;22)(q34.1;q11.2); BCR-ABL1 9812/3 Paediatric-type follicular lymphoma 9690/3
B-lymphoblastic leukaemia/lymphoma with Large B-cell lymphoma with IRF4 rearrangement 9698/3
t(v;11q23.3); KMT2A-rearranged 9813/3 Primary cutaneous follicle centre lymphoma 9597/3
B-lymphoblastic leukaemia/lymphoma Mantle cell lymphoma 9673/3
with t(12;21)(p13.2;q22.1); ETV6-RUNX1 9814/3 In situ mantle cell neoplasia 9673/1*
B-lymphoblastic leukaemia/lymphoma Diffuse large B-cell lymphoma (DLBCL), NOS 9680/3
with hyperdiploidy 9815/3 Germinal centre B-cell subtype 9680/3
B-lymphoblastic leukaemia/lymphoma Activated B-cell subtype 9680/3
with hypodiploidy (hypodiploid ALL) 9816/3 T-cell/histiocyte-rich large B-cell lymphoma 9688/3
B-lymphoblastic leukaemia/lymphoma Primary DLBCL of the CNS 9680/3
with t(5;14)(q31.1;q32.1); IGH/IL3 9817/3 Primary cutaneous DLBCL, leg type 9680/3
B-lymphoblastic leukaemia/lymphoma EBV-positive DLBCL, NOS 9680/3
with t(1;19)(q23;p13.3); TCF3-PBX1 9818/3 EBV-positive mucocutaneous ulcer 9680/1*
B-lymphoblastic leukaemia/lymphoma, DLBCL associated with chronic inflammation 9680/3
BCR-ABL 1―like 9819/3* Fibrin-associated diffuse large B-cell
B-lymphoblastic leukaemia/lymphoma with lymphoma
iAMP21 9811/3 Lymphomatoid granulomatosis, grade 1,2 9766/1
T-lymphoblastic leukaemia/lymphoma 9837/3 Lymphomatoid granulomatosis, grade 3 9766/3*
Early T-cell precursor lymphoblastic Primary mediastinal (thymic) large
leukaemia 9837/3 B-cell lymphoma 9679/3
NK-lymphoblastic leukaemia/lymphoma Intravascular large B-cell lymphoma 9712/3
ALK-positive large B-cell lymphoma 9737/3
Mature B-cell neoplasms Plasmablastic lymphoma 9735/3
Chronic lymphocytic leukaemia (CLL)/ Primary effusion lymphoma 9678/3
small lymphocytic lymphoma 9823/3 Multicentric Castleman disease
Monoclonal B-cell lymphocytosis, CLL-type 9823/1* HHV8-positive DLBCL, NOS 9738/3
Monoclonal B-cell lymphocytosis, non-CLL-type 9591/1* HHV8-positive germinotropic lymphoproliferative
B-cell prolymphocytic leukaemia 9833/3 disorder 9738/1*
Splenic marginal zone lymphoma 9689/3 Burkitt lymphoma 9687/3
Hairy cell leukaemia 9940/3 Burkitt-like lymphoma with 11q aberration 9687/3*
Splenic B-cell lymphoma/leukaemia, unclassifiable 9591/3 High-grade B-cell lymphoma
Splenic diffuse red pulp small B-cell lymphoma 9591/3 High-grade B-cell lymphoma with MYC
Hairy cell leukaemia variant 9591/3 and BCL2 and/or BCL6 rearrangements 9680/3
Lymphoplasmacytic lymphoma 9671/3 High-grade B-cell lymphoma, NOS 9680/3
Waldentrom macroglobulinemia 9761/3 B-cell lymphoma, unclassifiable, with features
IgM monoclonal gammopathy of undetermined intermediate between DLBCL and classic
significance 9761/1* Hodgkin lymphoma 9596/3
Heavy chain diseases
Mu heavy chain disease 9762/3
Gamma heavy chain disease 9762/3
WHO classification 11
Mature T- and NK-cell neoplasms Hodgkin lymphomas
T-cell prolymphocytic leukaemia 9834/3 Nodular lymphocyte predominant Hodgkin
T-cell large granular lymphocytic leukaemia 9831/3 lymphoma 9659/3
Chronic lymphoproliferative disorder of NK cells 9831/3 Classic Hodgkin lymphoma 9650/3
Aggressive NK-cell leukaemia 9948/3 Nodular sclerosis classic Hodgkin lymphoma 9663/3
Systemic EBV-positive T-cell lymphoma Lymphocyte-rich classic Hodgkin lymphoma 9651/3
of childhood 9724/3 Mixed cellularity classic Hodgkin lymphoma 9652/3
Chronic active EBV infection of Lymphocyte-depleted classic Hodgkin
T- and NK-cell type, systemic form lymphoma 9653/3
Hydroa vacciniforme-like lymphoproliferative
disorder 9725/1* Immunodeficiency-associated
Severe mosquito bite allergy lymphoproliferative disorders
Adult T-cell leukaemia/lymphoma 9827/3 Post-transplant lymphoproliferative disorders (PTLD)
Extranodal NK/T-cell lymphoma, nasal type 9719/3 Non-destructive PTLD
Enteropathy-associated T-cell lymphoma 9717/3 Plasmacytic hyperplasia PTLD
Monomorphic epitheliotropic intestinal Infectious mononucleosis PTLD
T-cell lymphoma 9717/3 Florid follicular hyperplasia
Intestinal T-cell lymphoma, NOS 9717/3 Polymorphic PTLD 9971/1
Indolent T-cell lymphoproliferative disorder Monomorphic PTLD
of the gastrointestinal tract 9702/1* Classic Hodgkin Lymphoma PTLD 9650/3
Hepatosplenic T-cell lymphoma 9716/3 Other iatrogenic immunodeficiency-
Subcutaneous panniculitis-like T-cell lymphoma 9708/3 associated lymphoproliferative disorders
Mycosis fungoides 9700/3
Sezary syndrome 9701/3 Histiocytic and dendritic cell neoplasms
Primary cutaneous CD30-positive T-cell Histiocytic sarcoma 9755/3
lymphoproliferative disorders Langerhans cell histiocytosis, NOS 9751/1
Lymphomatoid papulosis 9718/1* Langerhans cell histiocytosis, monostotic 9751/1
Primary cutaneous anaplastic Langerhans cell histiocytosis, polystotic 9751/1
large cell lymphoma 9718/3 Langerhans cell histiocytosis, disseminated 9751/3
Primary cutaneous gamma delta T-cell Langerhans cell sarcoma 9756/3
lymphoma 9726/3 Indeterminate dendritic cell tumour 9757/3
Primary cutaneous CD8-positive aggressive Interdigitating dendritic cell sarcoma 9757/3
epidermotropic cytotoxic T-cell lymphoma 9709/3 Follicular dendritic cell sarcoma 9758/3
Primary cutaneous acral CD8-positive Fibroblastic reticular cell tumour 9759/3
T-cell lymphoma 9709/3* Disseminated juvenile xanthogranuloma
Primary cutaneous CD4-positive small/medium Erdheim-Chester disease 9749/3
T-cell lymphoproliferative disorder 9709/1
Peripheral T-cell lymphoma, NOS 9702/3 The morphology codes are from the International Classification of Diseases
for Oncology (ICD-O) {1257A}. Behaviour is coded /0 for benign tumours;
Angioimmunoblastic T-cell lymphoma 9705/3 /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in
Follicular T-cell lymphoma 9702/3 situ and grade III intraepithelial neoplasia; and /3 for malignant tumours.
Nodal peripheral T-cell lymphoma with The classification is modified from the previous WHO classification, taking
into account changes in our understanding of these lesions.
T follicular helper phenotype 9702/3
Anaplastic large cell lymphoma, ALK-positive 9714/3 * These new codes were approved by the IARC/WHO Committee for
Anaplastic large cell lymphoma, ALK-negative 9715/3* ICD-O.
** These lesions are classified according to the lymphoma to which they
Breast implant-associated anaplastic
correspond, and are assigned the respective ICD-O code.
large cell lymphoma 9715/3*
Italics: Provisional tumour entities.
12 WHO classification
Introduction to the WHO classification of Harris N.L.
Arber D.A.
Pileri S.A.
Stein H.
tumours of haematopoietic and lymphoid Campo E.
Hasserjian R.P.
Swerdlow S.H.
Thiele J.
tissues Jaffe E.S. Vardiman J.W.
Orazi A.
Why classify? Classification is the language 130 pathologists and haematologists from The first component is the recognition that
of medicine; diseases must be described, around the world were involved in writing the underlying causes of these neoplasms
defined, and named before they can be the chapters. are often unknown and may vary. There
diagnosed, treated, and studied. A con It has now been more than 8 years since fore, the WHO approach to classification
sensus on definitions and terminology is the publication of the 4th edition, and nu incorporates all available information ―
essential for both clinical practice and in merous basic and clinical investigations morphology, immunophenotype, genetic
vestigation. A classification should contain have since led to many advances in the features, and clinical features ― to define
diseases that are clearly defined, clinically field that warrant an update to the clas the diseases. The relative importance of
distinctive, and non-overlapping (i.e. mutu sification. Important contributions have each of these features varies by disease,
ally exclusive), and that together constitute been made through the application of depending on the current state of know
all known entities (i.e. are collectively ex high-throughput genetic technologies ledge; there is no single gold standard by
haustive). A classification should provide such as gene expression profiling and which all diseases are defined.
a basis for future investigation and should next-generation sequencing. These tech The second important component of this
be able to incorporate new information as it nologies have led to new diagnostic tools classification process is the recognition
becomes available. Disease classification and have revealed new mechanisms of that the complexity of the field makes it
involves two distinct processes: class dis tumorigenesis and new potential therapeu impossible for any single expert or small
covery (the process of identifying catego tic targets. Because the 4th edition of the group of experts to be completely au
ries of diseases) and class prediction (the WHO classification of tumours series is not thoritative; for a classification to be widely
process of determining to which category yet complete (with several volumes yet to accepted, broad agreement is necessary.
individual cases belong). The work of pa be released), the 5th edition cannot yet be Therefore, the WHO approach to clas
thologists is essential for both processes. started, so the editors and authors have in sification relies on building a consensus
The 2008 WHO classification of tumours stead undertaken a major update to the ex on the definitions and nomenclature of
of the haematopoietic and lymphoid tis isting 4th edition of the WHO classification the diseases among as many experts as
sues (4th edition) {3848} was a collabora of tumours of the haematopoietic and lym possible. We recognize that compromise is
tive project of the European Association phoid tissues. This process has involved essential for establishing a consensus, but
for Haematopathology and the Society for many of the original editors as well as an we believe that even an imperfect single
Hematopathology. It was a revision and additional three senior advisors special classification is better than multiple com
update of the 3rd edition {1820}, which izing in myeloid neoplasms and two senior peting classifications.
was the first true worldwide consensus advisors with expertise in molecular and The final important component of this clas
classification of haematological malignan cytogenetic issues. Clinical advisory com sification process is the understanding that
cies. The 4th edition had an eight-member mittee meetings were held regarding both although pathologists must take primary
steering committee composed of members myeloid and lymphoid neoplasms, as was responsibility for developing a classifica
of both societies. Through a series of meet done for prior editions. The key features of tion, the involvement of clinicians is also
ings and discussions, with input from both this revision have been summarized in re essential, to ensure the classification’s
societies, the steering committee agreed cent review articles {129A.3848A}. usefulness and acceptance in daily prac
on a proposed list of diseases and chap The WHO classification of tumours of hae tice {1556}. When the 3rd edition of the
ters and chose authors. As was done for matopoietic and lymphoid tissues is based WHO classification was published, pre
the 3rd edition, the advice of clinical hae- on the principles initially defined in the Re vious proponents of other classifications of
matologists and oncologists was obtained vised European-American classification of haematological neoplasms agreed to ac
to ensure that the classification would be lymphoid neoplasms (REAL), proposed by cept and use the new classification, end
clinically useful {1556}. Two clinical advi the International Lymphoma Study Group ing decades of controversy over the clas
sory committees were convened: one for (ILSG) {1557}. In the WHO classification, sification of these tumours {338A,339,340,
myeloid neoplasms and other acute leu these principles have also been applied to 1165,1330A, 1643A, 2412A,2836,3310A}.
kaemias and one for lymphoid neoplasms. the classification of myeloid and histiocytic As stated above, there is no single gold
The meetings were organized around a se neoplasms. The guiding principle of both standard by which all diseases are defined
ries of questions, which addressed topics the REAL and the WHO classification is in the WHO classification. Morphology is al
such as disease definitions, nomenclature, the importance of defining ‘real’ diseases ways important; many diseases have char
grading, and clinical relevance. The com that can be recognized by pathologists acteristic or even diagnostic morphological
mittees were able to reach consensus on using the available techniques, and that features. Immunophenotype and genetic
most of the questions posed, and much of appear to be distinct clinical entities. There features are also important aspects of the
the input from the committees was incor are three important components of this definition of tumours of haematopoietic and
porated into the classification. More than process. lymphoid tissues, and the availability of this
Introduction and
overview of the
classification of the
Myeloid neoplasms
Introduction and overview of the Arber D.A.
Orazi A.
Tefferi A.
Levine R.
classification of myeloid neoplasms Hasserjian R.P.
Brunning R.D.
Bloomfield C.D.
Cazzola M.
Le Beau M.M. Thiele J.
Porwit A.
The 2001 WHO Classification of Tumours: current revision explicitly acknowledges decision-making and that also provides a
Pathology and Genetics of Tumours of that recurrent genetic abnormalities not flexible framework for integration of new
Haematopoietic and Lymphoid Tissues only provide objective criteria for rec data.
(3rd edition) reflected a paradigm shift in ognition of specific entities but are also
the approach to the classification of my vital for the identification of abnormal
eloid neoplasms {1820}. For the first time, gene products and pathways that are Prerequisites for the
genetic information was incorporated into potential therapeutic targets. Several classification of myeloid
diagnostic algorithms provided for the disease subgroups and sets of defining
various entities. The publication was pref criteria have been expanded to include
neoplasms by WHO criteria
aced with a comment predicting future not only neoplasms associated with chro The WHO classification of myeloid neo
revisions necessitated by rapidly emerg mosomal abnormalities recognizable by plasms relies on the morphological, cy-
ing genetic information relevant to the di conventional karyotyping, but also those tochemical, and immunophenotypic fea
agnosis and classification of myeloid ma with gene mutations with or without a cy tures of the neoplastic cells to establish
lignancies. The 4th edition (published in togenetic correlate. However, the impor their lineage and degree of maturation,
2008) and the current 4th edition revision tance of careful clinical, morphological, and to determine whether the cellular
reflect the significant new molecular in and immunophenotypic characterization appearance is cytologically normal, dys-
sights that have become available since of every myeloid neoplasm, and correla plastic, or otherwise morphologically ab
the publication of the 2001 edition. tion with the genetic findings, cannot be normal. The classification is based on cri
The first entity described in this volume, overemphasized. The discoveries of acti teria applied strictly to initial specimens
chronic myeloid leukaemia, remains the vating JAK2 mutations and mutations in obtained prior to any therapy. Blast per
prototype for the identification and clas CALR and MPL have revolutionized the centages in the peripheral blood, bone
sification of myeloid neoplasms. This leu diagnostic approach to myeloprolifera marrow, and other involved tissues re
kaemia is recognized by its clinical and tive neoplasms (MPNs) {299,1831,2014, main of practical importance for catego
morphological features, and its natural 2037,2099,2290,2823}. However, these rizing myeloid neoplasms and determin
progression is characterized by an in mutations are not specific for any single ing their progression. Cytogenetic and
crease in blasts of myeloid, lymphoid, or clinical or morphological MPN pheno molecular genetic studies are required at
mixed myeloid-lymphoid immunophe- type, and some are also reported in cer the time of diagnosis not only for recogni
notype. It is always associated with the tain cases of myelodysplastic syndromes tion of specific genetically defined enti
BCR―ABL1 fusion gene, which results in (MDSs), myelodysplastic/myeloprolifera- ties, but also for establishing a baseline
the production of an abnormal protein ty tive neoplasms (MDS/MPNs), and acute against which follow-up studies can be
rosine kinase with enhanced enzymatic myeloid leukaemia (AML). Therefore, an interpreted to assess disease progres
activity. This oncoprotein is sufficient to integrated, multimodality approach is sion. Given the integrated, multimodality
cause the disease and is also a target for necessary for the classification of all my approach required for diagnosing and
protein tyrosine kinase inhibitor therapy, eloid neoplasms. It is also critical to eluci classifying these neoplasms, it is recom
which has prolonged the lives of thou date how molecular testing can be used mended that the various diagnostic stud
sands of patients with this previously fatal to inform the diagnosis and treatment of ies be correlated with the clinical findings
illness {1040}. This successful integration myeloid malignancies, and to articulate and communicated in a single integrated
of clinical, morphological, and genetic in how these tests should be incorporated report. If a definitive classification cannot
formation embodies the goal of the WHO into clinical practice, on the basis of cur be determined, the report should indicate
classification scheme. rent and evolving scientific evidence. why and provide guidance for additional
In this revision, the combination of clini With so much yet to be learned, there studies that may clarify the diagnosis.
cal, morphological, immunophenotypic, may be some missteps as traditional For the purpose of achieving consist
and genetic features continues to be approaches to categorization are fused ency, the following guidelines are recom
used in an attempt to define disease enti with more molecularly oriented classifi mended for the evaluation of specimens
ties, such as chronic myeloid leukaemia, cation schemes. But the authors, senior when a myeloid neoplasm is suspected.
that are biologically homogeneous and advisors and editors of this revision of In this context, a standardized approach
clinically relevant ― the same approach the WHO classification, as well as the to the processing, documentation, and
used in the 3rd and 4th editions of the clinicians who served as members of reporting of bone marrow findings is
classification. The previous classifica its clinical advisory committees, have emphasized {2253}. It is assumed that
tion schemes opened the door to includ worked diligently to develop an updated, the evaluation will be performed with full
ing genetic abnormalities as criteria for evidence-based classification that can knowledge of the clinical history and per
classifying myeloid neoplasms, and the be used in daily practice for therapeutic tinent laboratory data.
Blasts
The percentage of myeloid blasts is very
important for the diagnosis and classi
fication of myeloid neoplasms. In the
peripheral blood, the blast percentage
should be determined from a 200-cell
leukocyte differential count and in the
bone marrow, from a 500-cell count using
cellular bone marrow aspirate smears as
described above. The blast percentage
Fig. 1.01 Myelodysplastic syndrome. Bone marrow biopsies should be well fixed, and thin (3―4 pm) sections should determined from the bone marrow aspi
be stained with H&E and/or Giemsa stain to enable optimal evaluation of histological details. rate should correlate with an estimate of
blasts may have focal punctate activity marily stains cells of the neutrophil line calcified) as well as on peripheral blood
with NSEs. but neutrophils are usually age and mast cells, enables identification or bone marrow aspirate smears. In pure
negative. Megakaryoblasts and erythroid of monocytes and immature and mature erythroid leucaemia, periodic acid-Schiff
blasts may have some multifocal, punc neutrophils simultaneously. Some cells, (PAS) staining may be helpful because
tate alpha-naphthyl acetate positivity, but particularly in myelomonocytic leukae the cytoplasm of the leukaemic pro
the reactivity is partially resistant to sodi mias. may exhibit simultaneous activity erythroblasts may show large globu es of
um fluoride inhibition, whereas monocyte with NSEs and CAE. Although normal eo PAS positivity. Well-controlled iron stains
reactivity is totally inhibited by sodium sinophils lack CAE. it may be expressed should always be performed on the bone
fluoride. The combined use of an NSE by neoplastic eosinophils. CAE staining marrow aspirate to detect iron stores, nor
and the specific esterase naphthol AS-D can be performed on tissue sections mal sideroblasts. and ring sideroblasts;
chloroacetate esterase (CAE), which pri (providing the sections are not acid de ring sideroblasts are defined as erythroid
≥ 50% ≥ 20% no yes n/a AML with recurrent AML with recurrent genetic
genetic abnormality abnormality
> 80% immature erythroid < 20% no no a n/a AML, NOS; AML, NOS;
precursors with acute erythroid leukaemia pure erythroid leukaemia
> 30% proerythroblasts (pure erythroid subtype)
AML, acute myeloid leukaemia; BM, bone marrow; MDS, myelodysplastic syndrome; n/a, not applicable; NOS, not otherwise specified; PB, peripheral blood.
a Cases of AML with t(8;21)(q22;q22.1) resulting in the RUNX1-RUNX1T1 fusion protein, AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22) resulting in the CBFB-MYH11
fusion protein, or acute promyelocytic leukaemia with the PML-RARA fusion protein may rarely occur in this setting with < 20% blasts, and those diagnoses take
precedence over the diagnosis of either AML, NOS or MDS.
b Classify according to the myeloblast percentage of all BM cells and PB leukocytes, along with other MDS criteria.
proper classification to guide the clini fied: single lineage versus multilineage this revision that affects MDS diagnosis
cal approach. The general features of dysplasia, ring sideroblasts, excess is in the diagnostic criteria for myeloid
MDS, as well as specific guidelines for blasts, or the defining del(5q) cytogenet neoplasms in which ≥ 50% of the bone
their diagnosis and classification, are ic abnormality. No new disease entities marrow cells are erythroid precursors. In
outlined in Chapter 6, Myeiodyspiastic have been introduced, but the diagnostic the original 4th edition WHO classifica
syndromes: Overview (p. 98). criteria for some entities have been re tion, erythroid/myeloid-type acute eryth
In this revised WHO classification, new fined, as detailed in Table 6.01 (p. 101) in roid leukaemia (erythroleukaemia) was
terminology has been introduced. In the the Myeiodyspiastic syndromes chapter diagnosed if blasts accounted for ≥ 20%
original 4th edition, MDS disease names and in the sections on each MDS entity. of the non-erythroid cells in the bone
included references to cytopenia or spe MDS cases with multilineage dysplasia, marrow; if blasts accounted for < 20%
cific types of cytopenia (e.g. refractory ring sideroblasts, and no excess of blasts of the non-erythroid cells, the case was
anaemia). Although cytopenia is a sine or isolated del(5q) cytogenetic abnormal considered to be MDS and subclassified
qua non of any MDS diagnosis, the WHO ity are now categorized as a subgroup of on the basis of the blast count among all
classification relies mainly on the degree MDS with ring sideroblasts rather than nucleated bone marrow cells. Due to the
of dysplasia and blast percentages for being grouped with MDS with multiline apparent close biological relationship of
MDS classification; specific cytopenias age dysplasia lacking ring sideroblasts erythroleukaemia to MDS and the poor
have only a minor impact on classifica as in the original 4th edition. MDS in chil reproducibility and potential lability of
tion. Moreover, the lineage(s) manifesting dren has features that differ from those of non-erythroid blast counts, and in an at
significant morphological dysplasia often most MDS in adults, and the provisional tempt to achieve consistency in express
do not correlate with the specific cytope entity refractory cytopenia of childhood ing blast percentages across all myeloid
nias seen in individual MDS cases. For remains in this updated classification. neoplasms, non-erythroid blast counting
these reasons, the updated MDS names Although this entity is still provisional, its has been eliminated from the diagnostic
do not refer to cytopenia. All diagnostic morphological features and distinction criteria for all myeloid neoplasms. For
entity names start with ‘myeiodyspiastic from severe aplastic anaemia are now all cases (even those with ≥ 50% bone
syndrome’, with further qualifiers speci better defined. An important change in marrow erythroid cells), the bone mar
Analysis Cytogenetic and molecular Next-generation sequencing The Cancer Genome Atlas (TCGA) project {545}
genetic analysis approaches
Class I
Class 2 - Nucleophosmin 1
Activated signalling
NPM1 mutations
Class I e.g. FLT3, KIT, and RAS
Activated signalling mutations
Class 3 - Tumour suppressor genes
e.g. FLT3, KIT, RAS mutations
e.g. TP53 and PHF6 mutations
Class II
Class 7 - Myeloid transcription factor genes
Transcription and differentiation
e.g. CEBPA, RUNX1 mutations
e.g. t(8;21), inv(16), t(15;17),
and CEBPA mutations Epigenetic modifiers
(so-called ‘Class III’) Class 8 - Cohesin complex genes
e.g. TET2, DNMT3A, and ASXL1 e.g. STAG2, RAD21, SMC1, SMC2 mutations
mutations
Class 9 - Spliceosome-complex genes
e.g. SRSF2, U2AF1, ZRSR2 mutations
used in the 4th edition proved flexible studies have shown no difference in de assigned to this category if they evolve
enough to incorporate the new entities novo cases with and without this find from previously documented MDS, have
proposed by members of the WHO and ing {211,975,1145}. Lastly, the provisional specific myelodysplasia-related cytoge
clinical advisory committees. The origi category of AML with mutated RUNX1 netic abnormalities, or exhibit morpho
nal entities described in the subgroup has been added for de novo cases with logical multilineage dysplasia. However,
‘acute myeloid leukaemia with recurrent this mutation that are not associated with these features do not supersede therapy-
genetic abnormalities’ remain (with only MDS-related cytogenetic abnormalities. related disease or the defined cytoge
minor modifications), and two provisional This provisional category appears to rep netic categories of AML. As mentioned
entities have been added. A new provi resent a biologically distinct form of AML above, de novo cases with NPM1 or bi
sional category, AML with BCR-ABL1, {1274,2627,3576,3897}. AML with mu allelic CEBPA mutation with no MDS-re
has been added to recognize these rare tated FLT3 is not included as a separate lated cytogenetic abnormalities, but with
de novo cases {2082,2801,3740}, which entity, because FLT3 mutation occurs multilineage dysplasia, are now classi
may benefit from tyrosine kinase inhibi across multiple AML subtypes; however, fied as either AML with mutated NPM1
tor therapy and must be distinguished the significance of this mutation should or AML with biallelic mutation of CEBPA.
from blast transformation of chronic my not be underestimated, and it should be The cytogenetic abnormalities that de
eloid leukaemia. AMLs with mutated tested for in essentially all cases, includ fine MDS-associated disease have also
NPM1 and CEBPA are now full entities, ing those with NPM1 or CEBPA mutation been modified: del(9q), which does not
but a biallelic mutation is required for the or other recurrent genetic abnormali appear to have prognostic significance
revised category now known as AML ties. Broader gene panels are becom in the setting of NPM1 or biallelic CEBPA
with biallelic mutation of CEBPA. Addi ing increasingly available and are prob mutation, has been removed from the list
tionally, multilineage dysplasia alone no ably indicated in most, if not all, types {1511,3562}, as has monosomy 5; del(5q)
longer supersedes a diagnosis of AML of AML. Modifications have been made and unbalanced translocation involving
with mutated NPM1 or AML with bial to the AML with myelodysplasia-related 5q remain {1559,4209}.
lelic mutation of CEBPA, because recent changes subgroup. Cases should still be
Myeloproliferative neoplasms 29
Chronic myeloid leukaemia, BCR-ABL1-positive 30
Chronic neutrophilic leukaemia 37
Polycythaemia vera 39
Primary myelofibrosis 44
Prefibrotic/early primary myelofibrosis 46
Overt primary myelofibrosis 48
Essential thrombocythaemia 50
Chronic eosinophilic leukaemia, NOS 54
Myeloproliferative neoplasm, unclassifiable 57
Chronic myeloid leukaemia, Vardiman J.W.
Melo J.V.
BCR-ABL1―positive Baccarani M.
Radich J.P
Kvasnicka H.M.
30 Myeloproliferative neoplasms
Microscopy
Chronic phase
In CP, the peripheral blood shows leu
kocytosis (12―1000 x 109/L, median:
~ 80 x 109/L) due to neutrophils in vari
ous stages of maturation, with peaks in
the proportions of myelocytes and seg
mented neutrophils {1662,3534,3753};
children often have higher WBC counts
than adults (median: ~ 250 x 109/L)
{1374,2665,3836}. Significant granulo
cytic dysplasia is absent. Blasts typically
account for < 2% of the WBCs. Absolute
basophilia and eosinophilia are com
mon {1662,3753}. Absolute monocytosis
may be present, but the proportion of
monocytes is usually < 3% {339}, except
in rare cases with the p190 BCR-ABL1
isoform, which often mimic chronic mye-
lomonocytic leukaemia {2623}. Plate
let counts are normal or increased to
≥ 1000 x 109/L; marked thrombocytope Fig. 2.02 Chronic myeloid leukaemia (CML), BCR-ABL1-positive (chronic phase). A Peripheral blood smear
nia is uncommon in CP {1662}. showing leukocytosis and neutrophilic cells at various stages of maturation; basophilia is prominent; no dysplasia is
Most cases of CML can be diagnosed present. B Bone marrow biopsy showing marked hypercellularity due to granulocytic proliferation. C The megakar
on the basis of peripheral blood findings yocytes in CML are characteristically smaller than normal megakaryocytes. D Bone marrow aspirate smear shows
expansion and maturation of the neutrophil lineage, increased basophils and a small ‘dwarf megakaryocyte, which is
combined with detection of the Ph chro
smaller than a normal megakaryocyte but larger than the micromegakaryocytes seen in myelodysplastic syndromes,
mosome and/or BCR-ABL1 by cytoge although micromegakaryocytes are sometimes seen in CML in the accelerated or myeloid blast phase.
netic and molecular genetic techniques.
However, bone marrow aspiration is es
sential to ensure sufficient material for
a complete karyotype and for morpho
logical evaluation to confirm the phase
of disease. Bone marrow biopsy is not
required to diagnose CML in most cases,
but should be done if the findings in the
peripheral blood are atypical or if a cel
lular aspirate cannot be obtained {1662,
2911}.
In CP, bone marrow specimens are hyper-
cellular, with marked granulocytic prolif
eration and a maturation pattern similar
to that in the blood, including expansion
at the myelocyte stage {822}. There is
no significant dysplasia. Blasts usually
account for < 5% of the marrow cells;
≥ 10% suggests advanced disease {817}.
The proportion of erythroid precursors is
usually significantly decreased. Mega
karyocytes may be normal or slightly
decreased in number, but 40―50% of
cases exhibit moderate to marked mega-
karyocytic proliferation {495,3976,3982}.
In CP, the megakaryocytes are smaller
than normal and have hyposegmented
nuclei; they are referred to as ‘dwarf’
megakaryocytes, but are not true micro
megakaryocytes such as those seen in
myelodysplastic syndromes {853,3982}. cher cells are common. These features cytes (5―10 cells in thickness) is common
Eosinophils and basophils are usually are mirrored in marrow biopsy sections, around the bone trabeculae, in contrast
increased in number, and pseudo-Gau in which a layer of immature granulo to the normal thickness of 2―3 cells {853}.
Moderate to marked reticulin fibrosis, Disease phases disease that develops during TKI therapy
which correlates with increased numbers Disease progression: has a poor outcome. Furthermore, gene
of megakaryocytes and may be associ Accelerated phase and blast phase expression studies of CP, AP, and BP
ated with an enlarged spleen, has been Recognition of disease progression is suggest that progression of CP to AP
reported in 30―40% of biopsies at diag important for treatment and prognostic and/or BP is more consistent with a two-
nosis {490,495,1329,3982}. Although the purposes, but the clinical and morpho step process, with new gene expression
presence of fibrosis at the time of diag logical boundaries between CP, AP, and profiles occurring early in AP (or late in
nosis was reported to be associated with BP are not always sharp, and the param CP), before the accumulation of blasts
a worse outcome in the pre-TKI era, it eters used to define them differ between and other features often used to define
reportedly has no substantial impact on investigators. These categories were of AP {3277}. BP continues to have a very
prognosis in patients treated with TKIs substantial prognostic importance in the poor outcome, even with TKI therapy
{926,1932}. pre-TKI era, when effective treatment {1601}. Death occurs due to bleeding or
Splenic enlargement in CP is due to in without allogeneic transplant was not infectious complications, as normal hae-
filtration of the red pulp cords by mature available, but the effectiveness of TKIs matopoiesis is increasingly disrupted by
and immature granulocytes. A similar has further blurred the lines between the malignant cells. In BP, the increase
infiltrate can be seen in hepatic sinuses these phases of CML. For example, in blasts not only indicates a loss of re
and portal areas. some studies show that newly diagnosed sponse to therapy, but also signifies that
patients who initially present in AP may the disease has acquired characteristics
have similar outcomes, when treated with of acute leukaemia.
TKIs, as those of patients with newly dia
gnosed CP {2939,3324}. In contrast, AP Accelerated phase
In the original 4th edition of the classifi
cation, it was recommended that the
diagnosis of AP be made if any of the
following parameters were present:
(1) a persistent or increasing high WBC
count (> 10 x 109/L) and/or persistent or
increasing splenomegaly, unresponsive
to therapy; (2) persistent thrombocyto
sis (> 1000 x 109/L), unresponsive to
therapy; (3) persistent thrombocytopenia
(< 100 x 109/L), unrelated to therapy; (4)
evidence of clonal cytogenetic evolu
tion, defined by cells harbouring the Ph
chromosome and additional cytogenetic
changes; (5) ≥ 20% basophils in the pe
ripheral blood; and (6) 10―19% blasts in
the peripheral blood and/or bone mar
row. In addition, large clusters or sheets
of small, abnormal megakaryocytes as
sociated with marked reticulin or colla
gen fibrosis were considered to be pre
sumptive evidence of AP, particularly if
Fig. 2.05 Chronic myeloid leukaemia, BCR-ABL1-positive, myeloid blast phase. A Peripheral blood smear; most accompanied by any of the haematologi-
of the white blood cells are blasts. B and C Sheets of blasts in the bone marrow biopsy. D Myeloperoxidase (MPO) cal parameters listed above. Although
immunohistochemistry proving the myeloid origin of the blasts. other defining criteria for AP have been
32 Myeloproliferative neoplasms
suggested {817}, these clinical, haema Table 2.01 Defining criteria for the accelerated phase (AP) of chronic myeloid leukaemia (CML)
tological, morphological, and genetic CML―AP is defined by the presence of ≥ 1 of the following haematological/cytogenetic criteria or provisional
parameters are evidence of disease pro criteria concerning response to tyrosine kinase inhibitor (TKI) therapy
gression (Table 2.01).
Haematological/cytogenetic criteria a
When defined as above, however, AP
includes a very heterogeneous group of - Persistent or increasing high white blood cell count (> 10 x 109/L), unresponsive to therapy
- Persistent or increasing splenomegaly, unresponsive to therapy
cases, so these parameters alone are in
- Persistent thrombocytosis (> 1000 x 109/L), unresponsive to therapy
sufficient for prognostic purposes. How - Persistent thrombocytopenia (< 100 x 109/L), unrelated to therapy
ever, their utility may be increased by the - ≥ 20% basophils in the peripheral blood
consideration of additional response- - 10―19% blasts in the peripheral blood and/or bone marrow b,c
defined parameters {1535}. Response - Additional clonal chromosomal abnormalities in Philadelphia (Ph) chromosome-positive (Ph+) cells at
to therapy (e.g. TKIs or allogeneic trans diagnosis, including so―called major route abnormalities (a second Ph chromosome, trisomy 8,
plant) is linked to the phase of disease. isochromosome 17q, trisomy 19), complex karyotype, and abnormalities of 3q26.2
- Any new clonal chromosomal abnormality in Ph+ cells that occurs during therapy
For example, the rare cases defined at
diagnosis as AP solely on the basis of Provisional response―to―TKI criteria
additional cytogenetic changes {1124} - Haematological resistance (or failure to achieve a complete haematological response d) to the first TKI
but who do not have an increase in - Any haematological, cytogenetic, or molecular indications of resistance to two sequential TKIs
blasts respond to therapy similar to pa - Occurrence of two or more mutations in the BCR-ABL1 fusion gene during TKI therapy
tients with CP disease, whereas patients a Large clusters or sheets of small, abnormal megakaryocytes associated with marked reticulin or collagen
with newly diagnosed AP disease with fibrosis in biopsy specimens may be considered presumptive evidence of AP, although these findings are
additional cytogenetic abnormalities and usually associated with one or more of the criteria listed above.
increased blasts do appreciably worse b The finding of bona fide lymphoblasts in the peripheral blood or bone marrow (even if < 10%) should prompt
{3324}. Moreover, cases in clinical and concern that lymphoblastic transformation may be imminent, and warrants further clinical and genetic
morphological CP that develop resistant investigation.
c ≥ 20% blasts in the peripheral blood or bone marrow, or an infiltrative proliferation of blasts in an
BCR-ABL1 mutations have gene expres
extramedullary site, is diagnostic of the blast phase of CML.
sion patterns similar to those seen in d Complete haematological response is defined as white blood cell count < 10 x 109/L, platelet count
advanced disease {2605,3277}. There < 450 x 109/L, no immature granulocytes in the differential, and spleen not palpable.
fore, response―to―therapy parameters
are now included as provisional crite
ria for AP, pending verification of their present and may be associated with sig Blast phase
validity. According to these provisional nificant reticulin and/or collagen fibrosis, The criteria for BP include (1) ≥ 20%
criteria, CP cases can be considered to which is best assessed in biopsy sec blasts in the blood or bone marrow or (2)
be functionally in AP (with poor rates of tions. The increased proportion of blasts the presence of an extramedullary prolif
long―term, progression―free survival) if in AP (10―19%) may be highlighted with eration of blasts. Some investigators and
there is (1) haematological resistance to immunohistochemical staining for CD34 clinical trials have instead used a thresh
the first TKI, (2) any grade of resistance {2989,3960}. In most cases, the blasts old of ≥ 30% blasts in the blood and/or
to two sequential TKIs, or (3) occurrence have a myeloid phenotype {1131}. bone marrow to define BP, but most pa
of two or more BCR-ABL1 mutations Lymphoid blasts may be seen, but some tients in BP have a very poor prognosis
(Table 2.01). data suggest that the finding of any bona regardless of which cut―off point is used
In AP, bone marrow specimens are often fide lymphoblasts in the blood and/or {817,1601}.
hypercellular, and dysplastic changes bone marrow in CP or AP should raise In most BP cases, the blast lineage is
may be seen in any of the myeloid lin concern that a lymphoblastic crisis may myeloid, and may include neutrophilic,
eages {2776,4395}. Clusters of small be imminent, because lymphoblastic BP monocytic, megakaryocytic, basophilic,
megakaryocytes (including true micro is reported to sometimes have an abrupt eosinophilic, or erythroid blasts, or any
megakaryocytes similar to those seen onset, without a preceding AP {66,619, combination thereof {1131,1601,1997,
in myelodysplastic syndromes) may be 1087,1931}. 2806}. In approximately 20―30% of BP
34 Myeloproliferative neoplasms
Genetic profile
At diagnosis, 90―95% of cases of
CML have the characteristic t(9;22)
(q34.1 ;q11.2) reciprocal translocation that
results in the Ph chromosome, der(22)
t(9;22) {3433}. This translocation fuses
sequences of the BCR gene on chromo
some 22 with regions of ABL1 on chro
mosome 9 {282}. The remaining cases
have either variant translocations that
involve a third or even a fourth chromo
some in addition to chromosomes 9 and
22, or a cryptic translocation of 9q34.1
and 22q11.2 that cannot be identified by
routine cytogenetic analysis. In such cas
es, the BCR-ABL1 fusion gene is present
and can be detected by FISH analysis
and/or RT-PCR {2619}.
The site of the breakpoint in chromo
some 22 may influence the phenotype
of the disease {2619}. In CML, the break Fig. 2.09 Chronic myeloid leukaemia, BCR-ABL1-positive (chronic phase): incidence of reported mutations within
point cluster region (BCR) is almost al the kinase domain by percentage of the total. The seven most frequent mutations are depicted in red and the next
ways in the major BCR (M-BCR), span eight in blue. The mutations shown in green have been reported in < 2% of clinical resistance cases. Specific regions
ning exons 12―16 (previously known as of the kinase domain are indicated as a P-loop or ATP-binding site (P), an imatinib-binding site (B), a catalytic domain
b1―b5) and an abnormal fusion protein, (C), and an activation loop (A). The contact regions with SH2 and SH3 domain-containing proteins are also shown.
Based on data from Apperley JF {122} and Soverini S et al. {3743A}.
p210, is formed, which has increased ty
rosine kinase activity. Rarely, the break
point in the BCR gene occurs in the short fusion proteins (p190) and is most monocytes, which can resemble chronic
p―BCR region, spanning exons 17―20 frequently associated with Ph chromo myelomonocytic leukaemia {2623}.
(previously known as c1―c4), and a larger some-positive ALL, small amounts of the It is generally accepted that the increa
fusion protein, p230, is encoded. Patients p190 transcript can be detected in more sed tyrosine kinase activity of BCR-ABL1
with this fusion may demonstrate promi than 90% of patients with CML as well, is necessary and sufficient to cause
nent neutrophilic maturation and/or con due to alternative splicing of the BCR CML-CP through the constitutive activa
spicuous thrombocytosis {2619,3048}. gene (4140). However, this breakpoint tion of proteins in several signal trans
Although breaks in the minor breakpoint may also be seen in rare cases of CML duction pathways. Among the many
region, m―BCR (exons 1―2) lead to a associated with increased numbers of pathways affected are the JAK/STAT
Fig. 2.10 Chronic myeloid leukaemia, BCR-ABL1-positive. A Schematic representation of the t(9;22) chromosomal translocation, the fusion mRNA transcripts encoded by
the BCR-ABL1 fusion gene generated in the changed chromosome 22 and the Philadelphia (Ph) chromosome, and the translated BCR-ABL1 fusion protein (p210) - whose
oncogenic properties are due primarily to its constitutively activated tyrosine kinase, encoded by the SH1 domain (indicated in red). Some of the other important functional domains
contributed by the BCR and ABL1 portions of the oncoprotein are also shown: the dimerization domain (DD); Y177, which is the autophosphorylation site crucial for binding to
GRB2; the phospho-serine/threonine (P―S/T) SH2―binding domain; a region homologous to Rho guanine nucleotide exchange factors (rho-GEF); the ABL1 regulatory SH3 and
SH2 domains; Y412, which is the major site of autophosphorylation within the SH1 kinase domain; nuclear localization signals (NLS); and the DNA-binding and actin-binding
domains. B Mechanism of action of BCR-ABL1 tyrosine kinase inhibitors. The physiological binding of ATP to its pocket allows BCR-ABL1 to phosphorylate selected tyrosine
residues on its substrates (left panel); a synthetic ATP mimic such as imatinib fits the pocket (right panel), but does not provide the essential phosphate group to be transferred
to the substrate. The downstream chain of reactions is then halted because, with its tyrosines in the unphosphorylated form, the substrate does not assume the necessary
conformation to ensure association with its effector.
36 Myeloproliferative neoplasms
Chronic neutrophilic leukaemia Bain B.J.
Brunning R.D.
Orazi A.
Thiele J.
Definition kaemia {391,2845}, but there is no reason present as well {4441,4501}. There may
Chronic neutrophilic leukaemia is a rare to postulate a relationship between the be bruising and purpura. A history of
myeloproliferative neoplasm character two conditions. Acute myeloid leukaemia bleeding from mucocutaneous surfaces
ized by sustained peripheral blood neu has supervened in 3 cases of a chronic or from the gastrointestinal tract is re
trophilia, bone marrow hypercellularity neutrophilic leukaemia―like condition as ported in 25―30% of cases {1588,4501}.
due to neutrophilic granulocyte prolifera sociated with a plasma cell neoplasm, Gout and pruritus are other possible fea
tion, and hepatosplenomegaly. There but all 3 patients had been exposed to tures {4501}. Serum vitamin B12 and uric
is no Philadelphia (Ph) chromosome or leukaemogenic drugs before the emer acid are often elevated.
BCR-ABL1 fusion gene. The diagnosis gence of acute myeloid leukaemia {995,
requires exclusion of reactive neutrophilia 2294,4079}. The association of a con Imaging
and other myeloproliferative and myelo- dition resembling chronic neutrophilic Imaging may show enlargement of the
dysplastic/myeloproliferative neoplasms leukaemia with other neoplasms is also liver or spleen.
(Table 2.02, p.38). likely to reflect a leukaemoid reaction.
Microscopy
ICD-O code 9963/3 Localization The peripheral blood shows neutrophilia,
The peripheral blood and bone marrow with a white blood cell count ≥ 25 x 109/L.
Epidemiology are always involved, and the spleen and The neutrophils are usually segmented,
The true incidence of chronic neutro liver usually show leukaemic infiltrates. but there may also be a substantial in
philic leukaemia is unknown; > 200 cas However, any tissue can be infiltrated crease in band forms. In almost all cases,
es have been reported, but only about {4035,4441,4501}. neutrophil precursors (promyelocytes,
150 of these meet the current diagnostic myelocytes, and metamyelocytes) ac
criteria {231}. In one study of 660 cases Clinical features count for < 5% of the white blood cells,
of chronic leukaemias of myeloid origin, The most constant clinical feature re but occasionally they may account for
not a single case of chronic neutrophilic ported is splenomegaly, which may be as much as 10% {515,1094,1096A,1588,
leukaemia was observed {3642}. Chronic symptomatic. Hepatomegaly is usually 4441,4501}. Myeloblasts are almost
neutrophilic leukaemia generally affects
older adults, but has also been reported
rarely in adolescents and young adults
{1588,4441,4501}. In 116 patients whose
age and sex were reported, the median
age at presentation was 66 years and the
male―to―female ratio was 1.6:1 {231}.
Etiology
The cause of chronic neutrophilic leukae
mia is unknown. Some cases have fol
lowed cytotoxic chemotherapy {1095}.
Its occurrence in a father and son has
been reported {2072}. In about a quarter
of reported cases of chronic neutrophilic
leukaemia or an apparently similar con
dition, the neutrophilia was associated
with an underlying neoplasm, most often
multiple myeloma or monoclonal gam-
mopathy of undetermined significance.
The majority of such cases constitute a
neutrophilic leukaemoid reaction result
ing from synthesis of granulocyte colony-
stimulating factor by neoplastic plasma
cells. A very small number of patients ap
pear to have had both a plasma cell neo
plasm and true chronic neutrophilic leu
38 Myeloproliferative neoplasms
Polycythaemia vera Thiele J.
Kvasnicka H.M.
Orazi A.
Tefferi A.
Birgegard G.
Barbui T.
Polycythaemia vera 39
Fig. 2.13 Polycythaemia vera, so-called masked/prodromal presentation. A Mildly hypercellular bone marrow showing a predominance of large megakaryocytes in the bone
marrow biopsy section. B Many large and giant hypersegmented (essential thrombocythaemia-like) megakaryocytes in a case clinically mimicking ET, because of a platelet
count > 1000 x 109/L). Note the only mildly increased granulo- and erythropoiesis (panmyelosis), better demonstrated by naphthol-AS-D-chloroacetate esterase (CAE) reaction.
Fig. 2.14 Polycythaemia vera, overt polycythaemic presentation. A Bone marrow biopsy shows a characteristically hypercellular marrow characterizing the overt polycythaemic
presentation (panmyelosis). B Megakaryocytes revealing different sizes are always a prominent feature. The cells are more easily evaluated by using the periodic acid-Schiff
(PAS) staining reaction. C Panmyelosis (trilineage proliferation) as demonstrated by the naphthol-ASD-chloroacetate (CAE) stain which, by accurately identifying the granulocytic
cells (red reaction product), helps in the assessment of the relative proportion of the two major marrow lineages (erythropoietic and granulopoietic). D At this disease stage, the
megakaryocytes show increased pleomorphism, with significant differences in size but no relevant maturation defects such as nuclear or cytoplasmic differentiation, as shown
with PAS staining.
>15 g/dL in women associated with normal predicted value, but with haemo the diagnostic criteria for PV proposed
a sustained increase of ≥ 2 g/dL from globin levels and haematocrit below the in the 2007 British Committee for Stand
baseline that cannot be attributed to cor cut―off points {2602,3677,3758}. For this ards in Haematology (BCSH) guidelines
rection of iron deficiency, or RBC mass reason, the term ‘masked PV’ was intro {248,2603}. Cut―off points were deter
> 25% above the mean normal predicted duced {82,251} for JAK2-mutated cases mined to be the optimal thresholds for
value {3931}. However, it has been ar in patients with latent (initial, occult pre- distinguishing JAK2-mutated essential
gued that the application of these crite polycythaemic) disease manifestations thrombocythaemia from PV {249,252}.
ria may result in the underdiagnosis of who have persistently elevated haemo Consequently, these values have been
PV due to exclusion of patients with an globin concentrations (>16.5 g/dL in included in the revised WHO criteria
actual RBC mass > 25% above the mean men; >16.0 g/dL in women) or that fulfil {3932} (see Table 2.03, p. 39).
40 Myeloproliferative neoplasms
Fig. 2 .15 Acute leukaemia in polycythaemia vera. Blood Fig.2.16 Polycythaemia vera, post-polycythaemic myelofibrosis (post-PV MF) and myeloid metaplasia stage.
smear from a patient with a long-standing history of PV. A Peripheral blood smear demonstrates leukoerythroblastosis with numerous teardrop-shaped red blood cells
The patient had been treated with alkylating agents (dacryocytes). B Bone marrow biopsy shows conspicuously abnormal megakaryocytic proliferation and depletion of
during the polycythaemic stage. The blasts expressed the erythroid and granulocytic cells. C Immunostaining for CD61 illustrates the atypia in the megakaryocytic popula
CD13, CD33, CD117 and CD34, and had a complex tion, including a population of small immature megakaryocytes. D Overt reticulin fibrosis that is invariably present in
karyotype. post-PV MF with myeloid metaplasia.
Clinical laboratory studies that facilitate lineages; i.e. there is a panmyelosis. cially noteworthy in the subcortical mar
the diagnosis of PV include detection of The peripheral blood shows a mild to row space, which is normally hypocellular
JAK2 V617F or functionally similar mu overt excess of normochromic, normo- {1329,3964}. Panmyelosis accounts for
tations (e.g. JAK2 exon 12 mutations) cytic RBCs. If there is iron deficiency the increased haematopoietic cellularity,
{2603,3056,3929,3931,3932} and sub due to bleeding, the RBCs may be hy but increased numbers of erythroid pre
normal erythropoietin levels {251,2602, pochromic and microcytic. Neutrophilia cursors and megakaryocytes are often
2760,3677,3929}. Endogenous erythroid and rarely basophilia may be present. most prominent {1098,1329,3964,3978}.
colony growth is no longer included as Occasional immature granulocytes may Using standardized prominent bone mar
a minor diagnostic criterion, due to its be detectable, but circulating blasts are row features {3969,3973}, several groups
limited practicality {3932}; it is time-con generally not observed. have succeeded in identifying histo
suming, unstandardized, restricted to Bone marrow cellularity is usually in logical patterns that are characteristic
specialized institutions, and costly. creased {3975}. Hypercellularity is espe of WHO-defined PV, including so-called
Some cases (in particular cases in
JAK2 V617F-mutated patients with pro
minent thrombocytosis and initially low
haemoglobin levels and/or haematocrit)
can clinically mimic essential thrombo
cythaemia at onset {249}, despite show
ing bone marrow histopathology char
acteristic of PV and later increases in
the RBC parameters {1364,2152,3972}.
Therefore, determination of JAK2 and
CALR mutation status alone (without mor
phological examination) is not sufficient
to differentiate PV from JAK2-mutated
essential thrombocythaemia {3920}.
Microscopy
In PV, the major features in the periph
eral blood and bone marrow are attribut
able to effective proliferation in the eryth
roid, granulocytic, and megakaryocytic
Polycythaemia vera 41
Table 2.04 Relative incidence of discriminating features according to standardized WHO morphological criteria generating histological patterns in initially performed bone marrow
biopsy specimens. Modified and adapted from Thiele J. and Kvasnicka H.M. {3969}
Bone marrow morphology features Relative frequency of features
PV ET Pre-PMF Overt PMF
Cellularity Age-related increase > 80% 10―19% > 80% 10―19%
masked PV {251,1361,1364,3677,3964, with a minor increase in reticulin {3964}. myelofibrosis, underscoring the value of
3972,3978,3983}. Erythropoiesis is usu Marrow sinuses are dilated and often bone marrow biopsy {11,253}. Reactive
ally normoblastic, erythroid precursors densely filled by erythrocytes. It is usually nodular lymphoid aggregates are found
form large islets or sheets, and granu possible to distinguish PV from essential in as many as 20% of cases {3964,3969}.
lopoiesis is morphologically normal. thrombocythaemia, primary myelofi In > 95% of cases, stainable iron is ab
The proportion of myeloblasts is not in brosis, and reactive erythrocytosis and sent in bone marrow aspirate and biopsy
creased. Megakaryocytes are increased thrombocytosis {1361,1380,2147,2433, specimens {1098,3978,3983}.
in number (particularly in cases with an 3964,3983} on the basis of the char
excess of platelets) and frequently dis acteristic histological pattern of PV Spent phase and post-polycythaemic
play hypersegmented nuclei. Cases with (Table 2.04) {3969}. Therefore, WHO has myelofibrosis (post-PV MF)
high platelet counts and low haemoglo adopted bone marrow morphology as During the later phases of PV, erythro
bin or haematocrit values may mimic es one of the major diagnostic criteria for poiesis progressively decreases. As a re
sential thrombocythaemia at onset {1364, PV {257,3932}. Reticulin staining reveals sult, the RBC mass normalizes and then
2152,3972}. Megakaryocytes tend to form a normal reticulin fibre network in about decreases, and the spleen further en
loose clusters or lie close to the bone tra 80% of cases, but the remainder may larges. Persistent leukocytosis occurring
beculae, and often show a significant de display increased reticulin and even mild at or around the time of progression to
gree of pleomorphism, resulting in a mix to moderate collagen fibrosis {11,253, post-PV MF has been reported to be as
ture of sizes. Most of the megakaryocytes 496,1329,2105,3964,3983}, depending sociated with an overall more aggressive
exhibit normally folded or deeply lobed on the stage of disease at initial diag course of disease {405}. These changes
nuclei, and they usually lack significant nosis. Even a minor increase in reticulin are usually accompanied by correspond
atypia, although a minority may show fibres (reticulin grade 1) {3975} at initial ing bone marrow alterations {407,1098,
bulbous nuclei and other nuclear abnor presentation of PV has been associated 3511,3758}. The most common pattern
malities, particularly when associated with a more rapid progression to post-PV of disease progression is post-PV MF
42 Myeloproliferative neoplasms
Table 2.05 Diagnostic criteria for post-polycythaemia vera (PV) myelofibrosis {265} 3056,3604}. Mutations similar to those
Required criteria described in MPNs {3915} have also
1. Documentation of a previous diagnosis of WHO―defined PV been found at very low frequencies in el
2. Bone marrow fibrosis of: derly patients with no haematological ma
grade 2 ― 3 on a 0 ― 3 scale {3975} or lignancy {1326,1830,4386}. At diagnosis,
grade 3 ― 4 on a 0 ― 4 scale {2146} cytogenetic abnormalities are detectable
Additional criteria (2 are required)
in as many as 20% of cases {3920}. The
most common recurrent abnormalities
1. Anaemia (i.e. below the reference range given age, sex, and altitude considerations) or
sustained loss of requirement of either phlebotomy (in the absence of cytoreductive therapy) or are gain of chromosome 8 or 9, del(20q),
cytoreductive treatment for erythrocytosis del(13q), and del(9p); gains of chromo
2. Leukoerythroblastosis somes 8 and 9 are sometimes found
3. Increasing splenomegaly, defined as either an increase in palpable splenomegaly of
together {102,4307}. There is no Phila
> 5 cm from baseline (distance from the left costal margin) or delphia (Ph) chromosome or BCR-ABL1
the development of a newly palpable splenomegaly fusion. The frequency of chromosomal
4. Development of any 2 (or all 3) of the following constitutional symptoms: abnormalities increases with disease pro
> 10% weight loss in 6 months, night sweats, unexplained fever (> 37.5 °C) gression; they are seen in nearly 80―90%
of cases of post-PV myelofibrosis {102}.
Reprinted by permission from Macmillan Publishers Ltd: Leukemia. Barosi G, Mesa RA, Thiele J, Cervantes
F, Campbell PJ, Verstovsek S, et al. Proposed criteria for the diagnosis of post-polycythemia vera and post Cases that progress to the accelerated
essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for phase or blast phase often have cytoge
Myelofibrosis Research and Treatment. Leukemia. 2008;22:437―8. Copyright 2008. netic abnormalities, including those com
monly observed in therapy-related myelo
dysplastic syndrome and acute myeloid
accompanied by myeloid metaplasia, in the number of immature cells may be leukaemia (see Acute myeloid leukaemia
which is characterized by a leukoeryth- observed in these stages, but the finding and related precursor neoplasms, p. 129).
roblastic peripheral blood smear, poikil- of ≥10% blasts in the peripheral blood
ocytosis with teardrop―shaped RBCs, or bone marrow or the presence of sub Genetic susceptibility
and splenomegaly due to extramedul stantial myelodysplasia is unusual, and A genetic predisposition has been re
lary haematopoiesis, as defined in Ta most likely indicates transformation to ported in some families {1411,1677,3457}.
ble 2.05, p.38 {265}. In two large series an accelerated phase. Cases with ≥ 20%
of patients with WHO-defined myelofibro blasts are considered to be blast-phase Prognosis and predictive factors
sis, post-PV MF was found to account for post-PV MF, formerly called acute leu With currently available treatment, me
about 20% of the cases {3920}. The mor kaemia {3089,3758,3964}. dian survival times >10 years are com
phological hallmark of this disease stage monly reported {2150,3090,3209,3758}.
is overt reticulin {3983} and collagen fi Cell of origin Recent studies using WHO criteria have
brosis {407,1098,3511,3964} of the bone The postulated cell of origin is a haemato found median survivals of >13 years over
marrow. Cellularity varies in this terminal poietic stem cell. all and about 24 years in patients aged
stage, but hypocellular specimens are < 60 years {3920,3929}. Prognostic fac
common. Clusters of megakaryocytes, Genetic profile tors other than older age remain contro
often with hyperchromatic and very dys The most common genetic abnormality versial {2150,2500,3090}. It has been
morphic nuclei, are prominent; however, in PV is the somatic gain-of-function mu shown that survival is adversely affected
cases retaining PV―like features have tation JAK2 V617F {2099}. Although this by leukocytosis and abnormal karyotype
also been described {407}. Erythropoie mutation occurs in > 95% of patients with {405,3929}. Most patients die from throm
sis and granulopoiesis are decreased in PV {3915,3929}, it is not specific for this botic complications or second malignan
quantity; RBCs, granulocytes, and meg entity; it is found in other MPNs {3915, cies, but as many as 20% succumb to my
akaryocytes are sometimes found lying 3920} and is also seen in a small subset elodysplastic syndrome or blast phase /
within dilated marrow sinusoids {3511, (< 5%) of cases of acute myeloid leukae acute myeloid leukaemia {2500,3209,
3964}. Bone marrow fibrosis is usually of mia, myelodysplastic syndromes, chronic 3758}. In large series of cases defined
grade 2―3 on a 0―3 scale {2148,3975} myelomonocytic leukaemia, and other per the WHO criteria, 3―7% of cases were
or grade 3―4 on a 0―4 scale {2146}. myeloid malignancies {3775}. Rare cases found to be in the blast phase {3920}.
Osteosclerosis may occur {1098,3511}. of JAK2-mutant PV acquire a BCR-ABL1 The factors that predict the risk of throm
There is disagreement about the degree rearrangement; however, the clinical sig bosis or haemorrhage are not well defined,
to which advanced post-PV MF resem nificance of this is uncertain. Due to this but age and previous thrombosis have
bles overt primary myelofibrosis in terms additional phenotypic mutation, a mor been shown to indicate a higher throm
of clinical and morphological features phological and haematological shift ca botic risk {247,2500,2501,3087,3758}.
{407,3511}. The splenic enlargement is a pable of producing a chronic myeloid leu The incidence of myelodysplastic syn
consequence of extramedullary haema kaemia-like evolution may occur {1740, drome and the blast phase is only 2―3%
topoiesis, which is characterized by the 3190}. Functionally similar mutations in in patients who have not been treated with
presence of erythroid, granulocytic, and exon 12 of JAK2 are found in about 3% of cytotoxic agents, but increases to ≥ 10%
megakaryocytic elements in the splenic cases, which generally show a predomi following certain types of chemotherapy
sinuses and cords of Billroth. An increase nant erythroid haematopoiesis {2194, {1216,2500,3087,3089,3758,3929}.
Polycythaemia vera 43
Primary myelofibrosis Thiele J.
Kvasnicka H.M.
Barbui T.
Barosi G.
Orazi A. Tefferi A.
Gianelli U.
Definition Table 2.06 Diagnostic criteria for primary myelofibrosis, prefibrotic/early stage
Primary myelofibrosis (PMF) is a clon The diagnosis of prefibrotic/early primary myelofibrosis requires that all 3 major criteria and
al myeloproliferative neoplasm (MPN) at least 1 minor criterion are met.
characterized by a proliferation of pre
dominantly abnormal megakaryocytes Major criteria
and granulocytes in the bone marrow, 1. Megakaryocytic proliferation and atypia, without reticulin fibrosis grade > 1a, accompanied by
increased age―adjusted bone marrow cellularity, granulocytic proliferation, and (often) decreased
which in fully developed disease is asso
erythropoiesis
ciated with reactive deposition of fibrous
2. WHO criteria for BCR-ABL1—positive chronic myeloid leukaemia, polycythaemia vera,
connective tissue and with extramedul
essential thrombocythaemia, myelodysplastic syndromes, or other myeloid neoplasms are not met
lary haematopoiesis.
3. JAK2, CALR, or MPL mutation
There is a stepwise evolution from an
or
initial prefibrotic/early stage, character
Presence of another clonal marker b
ized by hypercellular bone marrow with
or
absent or minimal reticulin fibrosis, to Absence of minor reactive bone marrow reticulin fibrosis c
an overt fibrotic stage with marked re
ticulin or collagen fibrosis in the bone Minor criteria
marrow, and often osteosclerosis. The Presence of at least one of the following, confirmed in 2 consecutive determinations:
fibrotic stage of PMF is clinically char - Anaemia not attributed to a comorbid condition
acterized by leukoerythroblastosis in the - Leukocytosis ≥ 11 x 109/L
- Palpable splenomegaly
blood (with teardrop―shaped red blood
- Lactate dehydrogenase level above the upper limit of the institutional reference range
cells), hepatomegaly, and splenomega
ly. The diagnostic criteria for prefibrotic/ a See Table 2.09 (p. 47).
early PMF (pre―PMF) are summarized in b In the absence of any of the 3 major clonal mutations, a search for other mutations associated with myeloid
Table 2.06 and those of overt (classic) neoplasms (e.g. ASXL1, EZH2, TET2, IDH1, IDH2, SRSF2, and SF3B1 mutations) may be of help in determin
PMF in Table 2.07. ing the clonal nature of the disease.
c Minor (grade 1) reticulin fibrosis secondary to infection, autoimmune disorder or other chronic inflammatory
ICD-O codes conditions, hairy cell leukaemia or another lymphoid neoplasm, metastatic malignancy, or toxic (chronic)
myelopathies.
Primary myelofibrosis 9961/3
Primary myelofibrosis,
prefibrotic/early stage 9961/3
Primary myelofibrosis, lence of PMF is probably increasing, due familial predisposition to PMF {617,3418}.
overt fibrotic stage 9961/3 to earlier diagnosis (i.e. of pre―PMF) and
prolonged survival {615}. PMF affects Localization
Synonyms men and women nearly equally {3916}. The blood and bone marrow are al
Chronic idiopathic myelofibrosis; myelofi- It occurs most commonly in the sixth to ways involved. In the later stages of the
brosis/sclerosis with myeloid metaplasia; seventh decades of life, and only about disease, extramedullary haematopoie
agnogenic myeloid metaplasia; mega 10% of overt PMF cases are diagnosed sis (also known as myeloid metaplasia)
karyocytic myelosclerosis; idiopathic in patients aged < 40 years {614}. Chil becomes prominent, particularly in the
myelofibrosis; myelofibrosis with myeloid dren are rarely affected {81,614}. spleen {267}, which harbours neoplastic
metaplasia; myelofibrosis as a result of stem cells {4255}. In the initial stages, the
myeloproliferative disease Etiology number of randomly distributed CD34+
Exposure to benzene or ionizing radiation progenitors is slightly increased in the
Epidemiology has been documented in some cases bone marrow, but not in the peripheral
The estimated annual incidence of overt {998}. Rare familial cases of bone mar blood. The frequency of bone marrow
PMF is 0.5―1.5 cases per 100 000 popu row fibrosis in young children have been CD34+ cells is inversely related to the
lation {2613,2764,3916,4010}. Valid data reported; how many of these constitute number of circulating CD34+ cells {2864,
on the incidence of pre―PMF are not MPNs is unknown, but at least some 3971}; only in the later stages do they ap
available, but data from reference cen cases appear to constitute an autosomal pear in large numbers in the peripheral
tres suggest that the prefibrotic/early recessive inherited condition {3457}. In blood. This increase in the number of cir
stage accounts for 30―50% of all PMF other families, with a somewhat older pa culating CD34+ cells is a phenomenon
cases. There are few reliable estimates tient age at onset, the features have been largely restricted to overt PMF; it is not
of prevalence {2764,4010}. The preva consistent with an MPN, suggesting a seen in non―fibrotic polycythaemia vera
44 Myeloproliferative neoplasms
or essential thrombocythaemia {101,268, Table 2.07 Diagnostic criteria for primary myelofibrosis, overt fibrotic stage
3091}. It has been postulated that ex The diagnosis of overt primary myelofibrosis requires that all 3 major criteria and
tramedullary haematopoiesis is a conse at least 1 minor criterion are met.
quence of the unique ability of the spleen
Major criteria
to sequester the numerous circulating
CD34+ cells {3970,4255}. Other possible 1. Megakaryocytic proliferation and atypia, accompanied by reticulin and/or collagen fibrosis grades 2 or 3 a
sites of extramedullary haematopoiesis 2. WHO criteria for essential thrombocythaemia, polycythaemia vera, BCR-ABL1—positive chronic
myeloid leukaemia, myelodysplastic syndrome, or other myeloid neoplasmsb are not met
are the liver, lymph nodes, kidneys, ad
renal glands, dura mater, gastrointestinal 3. JAK2, CALR, or MPL mutation
tract, lungs and pleura, breasts, skin, and or
Presence of another clonal marker c
soft tissue {3916}.
or
Absence of reactive myelofibrosis d
Clinical features
As many as 30% of cases are asymp Minor criteria
tomatic at the time of diagnosis and are Presence of at least one of the following, confirmed in 2 consecutive determinations:
discovered by detection of splenomegaly - Anaemia not attributed to a comorbid condition
during a routine physical examination or - Leukocytosis ≥ 11 x 109/L
when a routine blood count reveals anae - Palpable splenomegaly
- Lactate dehydrogenase level above the upper limit of the institutional reference range
mia, leukocytosis, and/or thrombocyto
- Leukoerythroblastosis
sis. Less commonly, the diagnosis results
from discovery of unexplained leuko a See Table 2.09 (p.47).
erythroblastosis or an increased lactate b Myeloproliferative neoplasms can be associated with monocytosis or they can develop it during the course of
dehydrogenase level {613,3916,3931}. the disease; these cases may mimic chronic myelomonocytic leukaemia (CMML); in these rare instances,
In the initial prefibrotic stage of PMF, the a history of MPN excludes CMML, whereas the presence of MPN features in the bone marrow and/or
only finding may be marked thrombocy MPN-associated mutations (in JAK2, CALR, or MPL) tend to support the diagnosis of MPN with monocytosis
tosis mimicking essential thrombocythae rather than CMML.
c In the absence of any of the 3 major clonal mutations, a search for other mutations associated with myeloid
mia, because the other clinical features
neoplasms (e.g. ASXL1, EZH2, TET2, IDH1, IDH2, SRSF2, and SF3B1 mutations) may be of help in
may be either within the normal range or determining the clonal nature of the disease.
only borderline abnormal {254,266,3931, d Bone marrow fibrosis secondary to infection, autoimmune disorder or another chronic inflammatory condition,
3962,3966,3977}. Therefore, neither sus hairy cell leukaemia or another lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathy.
tained thrombocytosis nor positive muta
tion status alone can distinguish prefibrot
ic PMF from essential thrombocythaemia; Although these mutations are helpful in Microscopy
careful analysis of bone marrow morphol distinguishing PMF from reactive condi The classic picture of overt (advanced)
ogy is necessary (see Table 2.04, p.42, tions that can result in bone marrow fibro PMF includes a peripheral blood smear
and Table 2.08, p. 47) {254,257,263,1366, sis, they are not specific for PMF; muta that shows leukoerythroblastosis and an-
1380,3933,3965}. tions in these genes can also be found isopoikilocytosis (typically with teardrop
More than 50% of patients with PMF in essential thrombocythaemia, and shaped red blood cells) associated with
experience constitutional symptoms, in JAK2 V617F can be found in polycythae a hypocellular bone marrow with marked
cluding fatigue, dyspnoea, weight loss, mia vera {3920}. reticulin and/or collagen fibrosis and or
night sweats, low―grade fever, and ca ganomegaly caused by extramedullary
chexia {2643}. These symptoms, which
reflect the biological activity of the dis
ease, compromise quality of life and are
associated with prognosis {616}. Gouty
arthritis and renal stones due to hyperuri-
caemia can also occur. Splenomegaly of
various degrees is detected in as many
as 90% of patients, and can be massive.
Nearly 50% of patients have hepatomeg
aly, depending on the stage of disease
{264,613,614,3916}.
In WHO-defined PMF, JAK2 V617F muta
tion is found in 50―60% of early―stage
cases {254} (as well as in advanced
stages); CALR mutations are found in
about 24% of PMF cases and MPL mu
tations in 8%. About 12% of cases are
triple―negative for mutations in JAK2,
CALR, and MPL {3920,3932,3933}.
Primary myelofibrosis 45
Fig.2.19 Primary myelofibrosis (PMF). A Bone marrow biopsy in this prefibrotic/early-stage case shows megakaryocytic and granulocytic proliferation. Naphthol AS-D chloro-
acetate esterase (CAE) staining identifies the granulocytic component (red reaction product); megakaryocytes show extensive clustering and condensed nuclei with conspicu
ously clumped chromatin and abnormal nucleancytoplasmic ratios (N:C). B Megakaryocytic abnormalities are the key finding in diagnosing PMF and in its distinction from other
myeloproliferative and reactive disorders; in this prefibrotic/early-stage case, note the abnormalities of megakaryopoiesis, including anisocytosis, abnormal N:C ratios, abnormal
chromatin clumping with hyperchromatic nuclei, plump lobation of some nuclei (cloud-like nuclei), and clustering. C Immunohistochemistry for CD61 highlights abnormal mega
karyocytes, including small forms.
Fig.2.20 Primary myelofibrosis: bone marrow fibrosis (MF) grading in silver-stained bone marrow biopsy sections. A MF-0, with no increase in reticulin. B MF-1, with a very
loose network of reticulin fibres. C MF-2, showing a more diffuse and dense increase in reticulin fibres and some coarse collagen fibres. D MF-3, with coarse bundles of collagen
fibres intermingled with dense reticulin, accompanied by initial osteosclerosis.
haematopoiesis. However, the morpholog marrow fibrosis is important. A simplified, Prefibrotic/early primary myelofibrosis
ical and clinical findings can vary signifi semiquantitative grading system (recently No registry―based prevalence or inci
cantly at diagnosis, depending on whether slightly modified), is presented in Ta dence data are available for this prodro
the case is first encountered during the ble 2.09 {2148,3975}. For cases present mal stage of PMF, but series from refer
prefibrotic/early stage or the overt fibrotic ing with higher fibre grades (2 and 3), and ence centres show that 30―50% of PMF
stage {254,264,266,613,3931,3977}. Be particularly for clinical studies, an addition cases are first detected in the prefibrotic/
cause the progressive accumulation of al trichrome stain is recommended, to es early stage {263,496,3963,3965}, with no
fibrous tissue (including reticulin and col tablish the grade of collagen (Table 2.10) significant increase in reticulin and/or col
lagen) and the development of osteoscle {2148}. In this context, a corresponding lagen fibres (i.e. fibrosis grades 0 and 1)
rosis parallel disease progression {3967}, grading system for osteosclerosis may {2148,3975}. In these cases, the bone
reproducible, sequential grading of bone also be useful (Table 2.11) {2148}. marrow biopsy usually shows hypercel-
46 Myeloproliferative neoplasms
lularity, with an increase in the number Table 2.08 Morphological features helpful in distinguishing essential thrombocythaemia (ET)
of neutrophils and atypical megakaryo fromprefibrotic/early primary myelofibrosis (pre-PMF)a
cytes. There may be a minor left shift Morphological feature ET Pre―PMF
in granulopoiesis, but metamyelocytes,
bands, and segmented neutrophils usu Cellularity (age―adjusted) Normal Increased
ally predominate. Myeloblasts are not in Myeloid―to―erythroid ratio Normal Increased
creased in percentage, and conspicuous
clusters of blasts are not observed; how
Dense megakaryocyte clusters Rare Frequent
ever, the number of randomly distributed
CD34+ progenitors is slightly increased Megakaryocyte size Large/giant Variable
{3965,3971}. In most cases, erythropoie
sis is reduced but the erythrocytes show Megakaryocyte nuclear lobulation Hyperlobulated Bulbous/hypolobulated
no dysplastic features {3963,3965}. The
Reticulin fibrosis, grade 1 b Very rare More frequent
megakaryocytes are markedly abnor
mal, and their morphological atypia and
a On the basis of a representative, artifact―free bone marrow biopsy (> 1.5 cm) taken at a right angle (90°)
topographical distribution within the bone
from the cortical bone.
marrow are critical for the recognition of b According to WHO grading {3975}: see Table 2.09.
pre―PMF. The megakaryocytes often form
dense clusters, which are frequently adja
cent to the bone marrow vascular sinuses Table 2.09 Semiquantitative bone marrow fibrosis (MF) grading system proposed by Thiele J et al. {3975},
and bone trabeculae {496,2147,2152, with minor modifications concerning collagen and osteosclerosis a
3965,3969,3978}. Most megakaryocytes
Grade Definition
are enlarged, but small megakaryocytes
may also be seen; their detection is fa MF―0 Scattered linear reticulin with no intersections (cross―overs), corresponding to normal bone marrow
cilitated by immunohistochemistry with MF―1 Loose network of reticulin with many intersections, especially in perivascular areas
antibodies reactive with megakaryo MF-2 Diffuse and dense increase in reticulin with extensive intersections, occasionally with focal bundles
cytic antigens {3962,3965}. Deviations of thick fibres mostly consistent with collagen and/or associated with focal osteosclerosisb
from the normal N:C ratio (an indication MF―3 Diffuse and dense increase in reticulin with extensive intersections and coarse bundles of thick
of defective maturation), abnormal pat fibres consistent with collagen, usually associated with osteosclerosis b
terns of chromatin clumping (includ
ing hyperchromatic forms and bulbous, a Fibre density should be assessed only in haematopoietic areas; if the pattern is heterogeneous,
cloud―like, or balloon―shaped nuclei), the final grade is determined by the highest grade present in ≥ 30% of the marrow area.
and the frequent occurrence of bare (na b In grades MF-2 and MF-3, an additional trichrome stain is recommended (Table 2.10).
ked) megakaryocytic nuclei are typical
findings. Overall, in pre―PMF, the mega Table 2.10 Semiquantitative grading of collagen3
karyocytes are more atypical than in any
Grade Definition
other type of MPN (Table 2.04, p.42, and
Table 2.08). Vascular proliferation is only 0 Perivascular collagen only (normal)
mildly increased in the bone marrow, with 1 Focal paratrabecular or central collagen deposition with no connecting meshwork
no gross abnormalities of vessel shape 2 Paratrabecular or central deposition of collagen with focally connecting meshwork or
{2149}. Lymphoid nodules are found in as generalized paratrabecular apposition of collagen
many as 20% of cases {3962,3965}. 3 Diffuse (complete) connecting meshwork of collagen in ≥ 30% of marrow spaces
Careful morphological examination of the
bone marrow is particularly crucial for a If the pattern is heterogeneous, the final grade is determined by the highest grade
distinguishing pre―PMF with accompany present in ≥ 30% of the marrow area.
ing thrombocytosis from essential throm
bocythaemia, as has been demonstrated
by a number of groups {254, 1227, 1361, Table 2.11 Semiquantitative grading of osteosclerosis a,b
1366, 1379, 1380, 2105, 2147, 2433, 3962, Grade Definition
3966,3977}. No single morphological
0 Regular bone trabeculae (distinct paratrabecular borders)
feature is pathognomonic of a specific
subtype, but the identification of charac 1 Focal budding, hooks, spikes, or paratrabecular apposition of new bone
teristic morphological patterns is key for 2 Diffuse paratrabecular formation of new bone with thickening of trabeculae,
the differential diagnosis between pre- occasionally with focal interconnections
PMF and essential thrombocythaemia 3 Extensive interconnecting meshwork of new bone with overall effacement of marrow spaces
(Table 2.04, p.42, and Table 2.08). Most
a If the pattern is heterogeneous, the final grade is determined by the highest grade
cases of pre―PMF eventually transform
into overt fibrotic/sclerotic myelofibrosis present in ≥ 30% of the marrow area.
b Bone marrow core biopsy of sufficient length, taken at a right angle (90°) from the cortical bone,
associated with extramedullary haemat
without fragmentation, is mandatory for the grading of osteosclerosis.
opoiesis {494,2105,2152,3965,3980}.
Primary myelofibrosis 47
Fig. 2.21 Primary myelofibrosis, overt fibrotic stage, with extramedullary haematopoiesis in the liver. A In the liver, the sinusoids are prominently involved by trilineage proliferation.
B Abnormal megakaryocytes are the hallmark of abnormal intrasinusoidal haematopoiesis.
Fig. 2.22 Primary myelofibrosis (PMF), overt fibrotic stage. A Bone marrow biopsy specimen showing hypocellularity, markedly dilated sinuses, and severe marrow fibrosis with
osteosclerosis, findings typical of advanced-stage PMF. B PMF with osteomyelosclerosis characterized by broad, irregular bone trabeculae, which can occupy as much as 50%
of the marrow space; fibrosis, cellular depletion, sinusoidal dilatation, and megakaryocytic proliferation are prominent in the intertrabecular areas.
Overt primary myelofibrosis matopoietic cells, showing mainly dense reported that interferon {744,3204} and
Most cases of PMF are initially diagnosed reticulin or collagen fibrosis, with small is JAK1/JAK2 inhibitor {1563A,1798,1800,
in the overt fibrotic stage {264,613,3916}. lands of haematopoietic precursors situ 1833,2543A,4316} therapy may delay or
In this stage, the bone marrow biopsy ated mostly within the vascular sinuses. even reverse bone marrow fibrosis pro
shows clear―cut reticulin or collagen fi Associated with the development of my gression across all aspects of the fibrotic
brosis (i.e. fibrosis grades 2 and 3) {2148, elofibrosis is a significant proliferation of process (i.e. reticulin fibrosis, collagen
3975}, often associated with various de vessels showing marked tortuosity and deposition, and osteosclerosis).
grees of collagen fibrosis and osteo luminal distension, often also associated The development of monocytosis in PMF
sclerosis (see Table 2.10 and Table 2.11, with conspicuous intrasinusoidal haema may indicate disease progression {404}.
p.47). The bone marrow may still be fo- topoiesis {438,2149,2642,2863}. Osteoid In patients with a previously established
cally hypercellular, but is more often nor- seams or appositional new bone forma diagnosis of PMF, the finding of 10―19%
mocellular or hypocellular, with patches tion in bud―like endophytic plaques may blasts in the peripheral blood and/or bone
of active haematopoiesis alternating with be observed {3965}. In this osteosclerotic marrow and the detection by immunohis-
hypocellular regions of loose connective phase, the bone may form broad, irregu tochemistry of an increased number of
tissue and/or fat. Foci of immature cells lar trabeculae that can occupy > 50% of CD34+ cells with cluster formation and/
may be more prominent, although my the bone marrow space. or an abnormal endosteal location in the
eloblasts account for < 10% of the bone The development of overt fibrosis in PMF bone marrow {3965,3971} indicate an ac
marrow cells {3965}. Atypical mega is related to disease progression {494, celerated phase of the disease, whereas
karyocytes are often the most conspicu 3979,3980}, and is not significantly in the finding of ≥ 20% blasts is diagnostic
ous finding; they occur in large clusters fluenced by standard cytoreductive of blast transformation. Patients with PMF
or sheets, often within dilated vascular treatment modalities (with the exception may rarely present initially in the acceler
sinuses {494,3965}. In some cases, the of allogeneic stem cell transplantation ated phase or blast phase.
bone marrow is almost devoid of hae {2125,2864,3974}). Flowever, it has been
48 Myeloproliferative neoplasms
pact on survival {3920,3924,3934}, in
contrast to the negative prognostic value
of the triple―negative mutation status (i.e.
JAK2, CALR, and MPL wild-type) {3920,
3924} and other, less frequent mutations
{1486,3921,4149}. Mutations similar to
those described in MPNs {3915} have
also been found at very low frequencies
in elderly patients with no haematologi
cal malignancy {1326,1830,4386}. Very
rarely, cases of PMF acquire a BCR-
ABL1 rearrangement; however, the clini
cal significance of this is uncertain. Due
to this additional phenotypic mutation, a
morphological and haematological shift
capable of producing a chronic mye
loid leukaemia―like evolution may occur
{1740}. Cytogenetic abnormalities occur
in as many as 30% of cases {3920}. There
is no Philadelphia (Ph) chromosome or
BCR-ABL1 fusion gene. The presence of
Fig.2,23 Primary myelofibrosis (PMF), overt fibrotic stage. A Peripheral blood smear showing dacryocytes, either del(13)(q12-22) or der(6)t(1;6)(q21-
occasional nucleated red blood cells, and immature granulocytes (leukoerythroblastosis). B Dilated sinus containing 23;p21.3) is strongly suggestive (but not
immature haematopoietic elements, most notably megakaryocytes, as demonstrated by periodic acid―Schiff diagnostic) of PMF {996}. The most com
(PAS) staining. This intrasinusoidal haematopoiesis together with vascular proliferation is characteristic (but not
diagnostic) of PMF with myeloid metaplasia. C Megakaryocytes are often the most conspicuous haematopoietic
mon recurrent abnormalities are del(20q)
element in the marrow; the cells often appear to stream through the marrow, due to the underlying fibrosis. and partial trisomy 1q; gains of chromo
D Silver staining highlights the marked reticulin and collagen fibrosis associated with a stream-like arrangement of somes 9 and/or 8 have also been report
megakaryocytes and initial osteosclerosis. ed {3336,3926}. Deletions affecting the
long arms of chromosomes 7 and 5 oc
Extramedullary haematopoiesis Cell of origin cur as well, but may be associated with
The most common site of extramedul The postulated cell of origin is a haemato prior cytotoxic therapy used to treat the
lary haematopoiesis is the spleen, fol poietic stem cell. myeloproliferative process.
lowed by the liver. The spleen shows an
expansion of the red pulp by erythroid, Genetic profile Prognosis and predictive factors
granulocytic, and megakaryocytic cells No genetic defect specific for PMF has The time of survival with PMF ranges
{3232}. The identification of these cells been identified. Approximately 50―60% from months to decades. Overall prog
can be facilitated by immunohistochem- of WHO―defined PMF cases carry nosis depends on the stage at which the
istry {2918,3959}, which also facilitates JAK2 V617F or a functionally similar mu neoplasm is initially diagnosed {2150,
the identification of neoangiogenesis tation, about 30% of cases have a muta 3965} and the corresponding risk status,
{267}. Megakaryocytes are often the tion in CALR and 8% in MPL, and about which can be determined using several
most conspicuous component of the 12% of cases are triple-negative for these prognostic scoring systems {616,1290,
extramedullary haematopoiesis. Occa mutations {3915,3920,3933}. A subset of 3086,3923}. The median overall survival
sionally, large aggregates of megakaryo triple-negative cases have been found time for patients diagnosed in the overt
cytes growing cohesively can produce to have gain―of―function mutations (e.g. fibrotic stage (myelofibrosis with myeloid
macroscopically evident tumoural le MPL S204P and MPL Y591N) through metaplasia) is approximately 3―7 years
sions. In the presence of nodular lesions whole-exome sequencing or other sen {264,613,3914}, whereas diagnosis in
and in any advanced―stage disease with sitive molecular techniques {2666}. This the prefibrotic/early stage is associated
large amounts of extramedullary haema finding is consistent with the assump with 10-year and 15-year relative survival
topoiesis in general, the possibility of a tion that JAK2/CALR/MPL-wild-type PMF rates of 72% and 59%, respectively {254,
myeloid sarcoma should be considered is not a homogeneous entity and that 2150,3965,3967,4173}. The widely used
and carefully excluded through immu- cases with polyclonal haematopoiesis refined Dynamic International Prognostic
nohistochemical studies with CD34 and probably constitute a hereditary disor Scoring System (DIPSS Plus) includes
KIT (CD117) {3970,4255}. The red pulp der {2666}. Although the presence of eight predictors of inferior survival: patient
cords may exhibit fibrosis and pooling the JAK2 mutation confirms the clonal age > 65 years, haemoglobin concentra
of platelets. Hepatic sinuses also show ity of the proliferation, the mutation is tion < 10 g/dL, leukocytes > 25 x 109/L,
prominent extramedullary haematopoie also found in polycythaemia vera and circulating blasts ≥ 1%, constitutional
sis, and cirrhosis of the liver may occur essential thrombocythaemia, and there symptoms, red blood cell transfusion de
{3916}. fore does not distinguish PMF from these pendency, platelet count < 100 x 109/L,
MPNs {3920,3933}. CALR mutation has and unfavourable karyotype (i.e. a com
been reported to have a favourable im plex karyotype or 1―2 of the following
Primary myelofibrosis 49
abnormalities: gain of chromosome 8, {1486,3920,3921,3924}. In the context of mortality are bone marrow failure (infec
loss of chromosome 7/7q, isochro these risk models, the prognostic value tion, haemorrhage), thromboembolic
mosome 17q, inv(3), loss of chromo of bone marrow fibrosis reflecting the events, portal hypertension, cardiac fail
some 5/5q or 12p, or 11q23 rearrange stage of disease (pre-PMF vs overt PMF) ure, and blast-phase disease (i.e. sec
ment). Risk status is defined by the is emphasized {2150,3923,3967,4173}. ondary acute myeloid leukaemia). The
number of adverse prognostic factors The findings of a study investigating the reported frequency of the blast phase
present: 0 (low risk), 1 (intermediate-1 relationship between DIPSS score {3086} is 5―30% {264,613,3914,3916,3920}.
risk), 2 or 3 (intermediate-2 risk), or ≥ 4 and marrow fibrosis grading {3975} in Although some blast―phase cases are
(high risk), with respective median sur patients with PMF suggested that better related to prior cytotoxic therapy, many
vival times of approximately 15.4, 6.5, prognostication could be achieved by have been reported in patients who have
2.9, and 1.3 years {1290,3916}. High-risk considering morphological parameters never been treated, confirming that blast
disease is also defined by a CALR-neg in addition to clinical and mutation data transformation is part of the natural his
ative and ASXL1-positive mutation status {1365}. Major causes of morbidity and tory of PMF.
50 Myeloproliferative neoplasms
JAK2 and mutations of the gelsolin gene leukocytosis and erythrocytosis were normal platelet counts (adjusted for sex
(GSN) were recently reported in several unusual findings, as was an increased and race) {2265,3452,3469,3931}. This
pedigrees of hereditary thrombocytosis serum level of lactate dehydrogenase; threshold value has also been adopted
{1677,3457}. leukoerythroblastosis and poikilocytosis by the British Committee for Standards
were absent {254,3933,3977}. in Haematology (BCSH) {1562}. Although
Localization Previously, the platelet count threshold this lowered threshold will encompass
The bone marrow and blood are the prin for the diagnosis of ET was ≥ 600 x 109/L more cases of ET, it will also include
cipal sites of involvement. The spleen {2791}. However, given that some patients more cases of conditions that mimic
does not show significant extramedullary experience haemorrhagic or thrombotic ET {257,1380}; therefore, it is essential
haematopoiesis at the time of onset, but events at lower platelet counts {2265, that all diagnostic criteria for ET (see
is a sequestration site for platelets {1217, 3331,3469}, several investigators have Table 2.12) are met in order to exclude oth
1563}. convincingly argued for a lower platelet er neoplastic and non-neoplastic causes
count threshold for the diagnosis of ET, in of thrombocytosis {1380,3931,3932}.
Clinical features order to avoid compromising the diagno Bone marrow biopsy is particularly help
More than half of all cases are asymp sis in such cases. As a result, WHO has ful in excluding other myeloid neoplasms
tomatic at the time of diagnosis, dis adopted the recommendation of a plate associated with high platelet counts,
covered incidentally when an elevated let count threshold of ≥ 450 x 109/L, a such as myelodysplastic syndromes as
platelet count is found on a routine pe value that exceeds the 95th percentile for sociated with isolated del(5q), myelodys-
ripheral blood count {254,1217,1378,
1563}. The other half present with some
manifestation of vascular occlusion or
haemorrhage {566,1096,1215,3088,
3933}. Microvascular occlusion can lead
to transient ischaemic attacks, digital
ischaemia with paraesthesias, and gan
grene {566,3088}. Thrombosis of major
arteries and veins can also occur, and
ET can be a cause of splenic or hepatic
vein thrombosis as seen in Budd-Chiari
syndrome {1022,2012,3703}. Bleeding
occurs most commonly from mucosal
surfaces, such as in the gastrointestinal
tract and upper airway passages {1096,
1215,1378}. In PVSG-defined ET, mild
splenomegaly is present in approximate
ly 50% of cases at diagnosis and hepa
tomegaly in 15―20% {1563,2791,3927}.
When the WHO criteria, which exclude
cases with thrombocytosis associated
with prefibrotic/early primary myelofibro
Fig. 2.25 Essential thrombocythaemia, bone marrow biopsy. A Normocellular bone marrow with an increased number
sis (pre―PMF), are used, minor palpable
of large to giant megakaryocytes. B There is no significant increase in erythropoiesis or granulopoiesis, as demonstrated
splenomegaly is seen in only 15―20% of by naphthol AS-D chloroacetate esterase (CAE) staining: granulocytic cells are stained red by the reaction product.
ET cases {254,3917,3933,3977}. In three C With periodic acid—Schiff (PAS) staining, the enlarged megakaryocytes demonstrate abundant amounts of mature
studies including almost 1500 WHO-de cytoplasm and deeply lobulated and hyperlobulated (staghorn-like) nuclei. D The large to giant megakaryocytes may
fined cases of ET from various centres, be arranged in small, loose clusters.
Essential thrombocythaemia 51
plastic/myeloproliferative neoplasm with predominance of large to giant forms The morphological findings, i.e. the char
ring sideroblasts and thrombocytosis, displaying abundant, mature cytoplasm acteristic histological patterns in the
and in particular pre―PMF. Although most and deeply lobed and hypersegmented bone marrow biopsy (Table 2.04, p.42),
WHO-defined ET cases harbour a phe (staghorn-like) nuclei. The megakaryo are essential for distinguishing ET from
notypic driver mutation in JAK2 (present cytes are typically dispersed throughout other MPNs {1380} and myeloid disor
in 50―60% of cases), CALR (in ~30%), or the bone marrow, but may occur in loose ders or reactive conditions that present
MPL (in ~3%), about 12% of cases are clusters. Unlike in pre-PMF and overt with sustained thrombocytosis. The find
triple-negative for these mutations. None primary myelofibrosis, bizarre, highly ing of even a low degree of combined
of these mutations is specific for ET, but atypical megakaryocytes or large dense granulocytic and erythroid proliferation
their presence does exclude reactive clusters are very rarely found in ET; if they should raise suspicion of the prodromal
thrombocytosis {3920,3933}. Similarly, in are present, the diagnosis of ET should stage of polycythaemia vera {1364,2152,
vitro endogenous erythroid and/or mega be reconsidered {1227,1366,3961,3966, 3972}, and the finding of granulocytic
karyocytic colony formation, although not 3977}. Proliferation of erythroid precur proliferation associated with bizarre,
specific for ET, also excludes reactive sors is seen in some cases (most com highly atypical megakaryocytes should
thrombocytosis {1011}. monly when the patient has experienced raise suspicion of pre-PMF {1227,1366,
recurrent major haemorrhages or has 2147,3962,3984}. Significant dyserythro-
Microscopy been pretreated with hydroxycarbamide), poiesis or dysgranulopoiesis suggests a
The major abnormality seen in the pe but granulocytic proliferation is highly diagnosis of myelodysplastic syndrome
ripheral blood is marked thrombocytosis. unusual; if present, the increase in granu rather than ET. The large megakaryo
The platelets often display anisocytosis, lopoiesis is usually only slight. There is no cytes with hypersegmented nuclei seen
ranging from tiny forms to atypical large increase in myeloblasts and no myelod in ET contrast with the medium-sized
or giant platelets. Bizarre shapes, pseu ysplasia. The network of reticulin fibres is non-lobated megakaryocytes seen in
dopods, and agranular platelets may usually normal, or is very rarely (in <5% myelodysplastic syndrome with isolated
be seen, but are not common. In WHO- of cases) minimally increased (but never del(5q) and with the small, dysplastic
defined ET, the white blood cell count to more than WHO grade 1 {3975}) {254, megakaryocytes seen in acute myeloid
and leukocyte differential count are usu 2105,3981}; infrequently, reticulin fibrosis leukaemia or myelodysplastic syndrome
ally normal, although a borderline eleva may increase in sequential bone marrow with inv(3)(q21q26.2) or t(3;3)(q21;q26.2).
tion in the white blood cell count may oc biopsy examinations {2105,3981}. The Some cases of chronic myeloid leukae
cur {254,1378,3920,3933,3977}. The red finding of significant reticulin fibrosis or mia initially present with thrombocytosis
blood cells are usually normocytic and any collagen fibrosis at presentation ex without leukocytosis, and can mimic ET
normochromic, unless recurrent haem cludes the diagnosis of ET {1227,1329, clinically. The large megakaryocytes of
orrhage has caused iron deficiency, in 1366,2105,3933,3966,3969}. Bone mar ET can be easily distinguished from the
which case they may be microcytic and row aspirate smears also reveal markedly small (dwarf) megakaryocytes of chronic
hypochromic. Leukoerythroblastosis and increased numbers of large megakaryo myeloid leukaemia, but cytogenetic and/
teardrop-shaped red blood cells are not cytes with hyperlobulated nuclei, as well or molecular genetic analysis to exclude
seen in ET {254,3977}. as large sheets of platelets in the back BCR-ABL1 fusion is recommended for all
Haematopoietic cellularity is normal in ground. Emperipolesis of bone marrow patients in whom the diagnosis of ET is
most cases {3975}, but a small propor elements is frequently observed in ET, considered {3350}.
tion of cases show a hypercellular mar but is not a specific finding. Stainable iron
row (Table 2.04, p.42) {3969,3972}. The may be present in aspirated bone marrow Cell of origin
most striking abnormality is a marked specimens at diagnosis {2791}. The postulated cell of origin is a haemato
proliferation of megakaryocytes, with a poietic stem cell.
52 Myeloproliferative neoplasms
Genetic profile Table 2.13 Diagnostic criteria for post―essential thrombocythaemia (ET) myelofibrosis {265}
No molecular genetic or cytogenetic Required criteria
abnormality specific for ET is known. Ap 1. Documentation of a previous diagnosis of WHO―defined ET
proximately 50―60% of WHO-defined 2. Bone marrow fibrosis of grade 2―3 on a
ET cases carry JAK2 V617F or a func 0―3 scale {3975} or grade 3―4 on a
tionally similar mutation, about 30% of 0―4 scale {2146}
cases have a mutation in CALR and 3%
Additional criteria (2 are required)
MPL, and about 12 % of cases are triple
1. Anaemia (i.e. below the reference range given age, sex, and altitude considerations) and a
negative for these mutations {3915,3920, > 2 g/dL decrease from baseline haemoglobin concentration
3933,3935}. A subset of triple-negative
2. Leukoerythroblastosis
cases have been found to have gain-
3. Increasing splenomegaly, defined as either an increase in palpable splenomegaly of
of-function mutations (e.g. MPL S204P > 5 cm from baseline (distance from the left costal margin) or the development
and MPL Y591N) through whole-exome of a newly palpable splenomegaly
sequencing or other sensitive molecu 4. Elevated lactate dehydrogenase level (above the reference range)
lar techniques {517,2666}. This finding
5. Development of any 2 (or all 3) of the following constitutional symptoms:
is consistent with the assumptions that > 10% weight loss in 6 months, night sweats, unexplained fever (>37.5 °C)
JAK2/CALR/MPL-wildtype ET is not a
homogeneous entity and that cases Reprinted by permission from Macmillan Publishers Ltd: Leukemia. Barosi G, Mesa RA, Thiele J, Cervantes
with polyclonal haematopoiesis prob F, Campbell PJ, Verstovsek S, et al. Proposed criteria for the diagnosis of post-polycythemia vera and post
essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for
ably constitute a hereditary disorder Myelofibrosis Research and Treatment. Leukemia. 2008;22:437―8. Copyright 2008.
{2666}. These mutations are not specific
for ET; they are found in polycythaemia
vera and primary myelofibrosis as well. or grade 3―4 on a 0―4 scale {2146}, as thrombocytosis and ET according to the
But none of these mutations have been sociated with myeloid metaplasia (ex current WHO classification {263}. A sub
reported in cases of reactive thrombo tramedullary haematopoiesis), but such stantial difference in overall prognosis
cytosis {3920,3933}. Mutations similar progression is uncommon {254,612,717, has been reported depending on which
to those described in MPNs {3915} have 1217,1377,1378,1380,3511,3927}, occur classification system is applied {2150}.
also been found at very low frequencies ring in only about 10% of cases in large, For patients with strictly WHO-defined
in elderly patients with no haematologi strictly WHO-defined cohorts {3920}. The ET, the observed and relative survival
cal malignancy {1326,1830,4386}. Very diagnostic criteria for post-ET myelofibro was similar to that of the general Euro
rarely, cases of ET acquire a BCR-ABL1 sis are listed in Table 2.13. Strict adher pean population {254,2150}, and trans
rearrangement; however, the clinical sig ence to these and other WHO criteria formation to overt myelofibrosis and the
nificance of this is uncertain. Due to this {265,3931,3932} is necessary to avoid blast phase appeared to be relatively
additional phenotypic mutation, a mor diagnostic confusion associated with rare {254,3933}. In contrast, the survival
phological and haematological shift ca pre―PMF accompanied by thrombocy of patients with WHO―defined ET was
pable of producing a chronic myeloid leu- tosis {263,1380}. Clear―cut differentiation found to be inferior to that of a sex― and
kaemia-like evolution may occur {1740}. of ET from pre―PMF is crucial, because age―matched United States population at
An abnormal karyotype is found in only these entities differ significantly in terms one centre {3920}, whereas the observed
5―10% of ET cases diagnosed according of complications and survival {11,254, rates of fibrotic and blast transformation
to the previous PVSG criteria {2791} and 1086,1380,2150,3961,3977}. In large se were comparable with those found in a
in 7.7% of WHO-defined cases {3920}. ries of WHO―defined cases, the relative previous Italian study {254}. The rates of
There is no consistent abnormality, but incidence rates of post―ET myelofibrosis conversion of ET to overt polycythaemia
reported abnormalities include gain of were found to be approximately half the vera in JAK2―mutated cases reported
chromosome 8, abnormalities 9q, and rates of post―polycythaemia vera my in some studies {540,3458} depend on
del(20q) {1641,3045}. Isolated instances elofibrosis {254,3920}. Transformation of the diagnostic criteria applied; when the
of del(5q) have also been reported in ET, ET to the blast phase (i.e. acute myeloid WHO criteria are used, the incidence of
and careful morphological examination is leukaemia) or myelodysplastic syndrome transformation appears to be < 5% {250}.
needed to distinguish such cases from occurs in < 5% of cases, and is likely re
myelodysplastic syndromes associated lated to previous cytotoxic therapy {1217,
with this abnormality {3045}. 1563}; the risk of transformation is lower
among strictly WHO―defined cases {254,
Prognosis and predictive factors 1378,3920}. Median survival times of
ET is an indolent disorder characterized 10―15 years are commonly reported. Be
by long symptom-free intervals interrupt cause ET usually occurs late in middle
ed by occasional life-threatening throm age, life expectancy is near normal for
boembolic or haemorrhagic events {566, many patients {254,717,1377,2150,3090,
1096,1215,1217,1378,1563,2791,3088, 4348}. However, most clinical studies
3927}. After many years, a few patients are based on older diagnostic guidelines
with ET develop bone marrow fibrosis of {2791}, which fail to differentiate clearly
grade 2―3 on a 0―3 scale {2148,3975} between pre―PMF with accompanying
Essential thrombocythaemia 53
Chronic eosinophilic leukaemia, NOS Bain B.J.
Horny H.-P.
Hasserjian R.P.
Orazi A.
Definition Table 2.14 Diagnostic criteria for chronic eosinophilic leukaemia, NOS
Chronic eosinophilic leukaemia (CEL)
1. Eosinophilia (eosinophil count ≥ 1.5 x 109/L)
not otherwise specified (NOS), is a mye
loproliferative neoplasm (MPN) in which 2. WHO criteria for BCR-ABL1-positive chronic myeloid leukaemia, polycythaemia vera,
essential thrombocythaemia, primary myelofibrosis, chronic neutrophilic leukaemia, chronic
an autonomous, clonal proliferation of eo
myelomonocytic leukaemia and BCR-ABL1-negative atypical chronic myeloid leukaemia are not met
sinophil precursors results in persistently
3. No rearrangement of PDGFRA, PDGFRB or FGFR1, and no PCM1-JAK2,
increased numbers of eosinophils in the
ETV6-JAK2, or BCR-JAK2 fusion
peripheral blood, bone marrow, and pe
ripheral tissues, with eosinophilia being 4. Blast cells constitute < 20% of the cells in the peripheral blood and bone marrow, and inv(16)(p13.1q22),
t(16;16)(p13.1;q22), t(8;21)(q22;q22.1), and other diagnostic features of acute myeloid leukaemia are
the dominant haematological abnormal
absent
ity. Organ damage occurs as a result of
5. There is a clonal cytogenetic or molecular genetic abnormality a
leukaemic infiltration or of the release of
or
cytokines, enzymes, or other proteins by Blast cells account for ≥ 2% of cells in the peripheral blood or ≥ 5% in the bone marrow
the eosinophils.
CEL, NOS excludes cases with a Phil a Because some clonal molecular genetic abnormalities (e.g. mutations in TET2, ASXL1, and DNMT3A) can
adelphia (Ph) chromosome; BCR-ABL1 occur in a minority of elderly people in the absence of any apparent haematological abnormality, it is essential
fusion; rearrangement of PDGFRA, to exclude all possible causes of reactive eosinophilia before making this diagnosis solely on the basis of a
PDGFRB, or FGFR1; or PCM1―JAK2, molecular genetic abnormality in an elderly person.
ETV6―JAK2, or BCR―JAK2 fusion.
In CEL, NOS the eosinophil count is
≥ 1.5 x 109/L in the blood, and there are Table 2.15 Diagnostic criteria for myeloproliferative neoplasm (MPN), unclassifiable.
< 20% blasts in the peripheral blood and
The diagnosis of myeloproliferative neoplasm (MPN), unclassifiable, requires that either all 3 criteria are met.
bone marrow. For a diagnosis of CEL,
NOS to be made, there should be evi 1. Features of an MPN are present
dence for clonality of myeloid cells or an 2. WHO criteria for any other MPN, myelodysplastic syndrome a, myelodysplastic/
increase in myeloblasts in the peripheral myeloproliferative a neoplasm, or BCR-ABL1-pos\{m chronic myeloid leukaemia are not met
blood or bone marrow. However, in many
3. JAK2, CALR, or MPL mutation characteristically associated with MPN
cases it is impossible to prove clonal
or
ity; in such cases, providing there is no
Presence of another clonal marker b
increase in blast cells, the diagnosis of
or
idiopathic hypereosinophilic syndrome Absence of a cause of reactive fibrosis c
(HES) is made. It is clinically important
to clearly distinguish between CEL, NOS a Effects of any previous treatment, severe comorbidity, and changes during the natural progression of the
and idiopathic HES. Idiopathic HES is disease process must be excluded.
defined as eosinophilia (eosinophil count b In the absence of any of the 3 major clonal mutations, a search for other mutations associated with
≥ 1.5 x 109/L) persisting for ≥ 6 months myeloid neoplasms (e.g. ASXL1, EZH2, TET2, IDH1, IDH2, SRSF2, and SF3B1 mutations) may be of help
for which no underlying cause can be in confirming the clonal nature of a suspected MPN, unclassifiable.
c Bone marrow fibrosis secondary to infection, autoimmune disorder or another chronic inflammatory condition,
found, associated with signs of organ
involvement and dysfunction {759,4291}; hairy cell leukaemia or another lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathy.
there is no evidence of eosinophil clon
ality. It is a diagnosis of exclusion, and
may include some cases of true eosino 2.14, diagnosis of CEL, NOS requires common in men, with a reported median
philic leukaemia that cannot currently be integration of clinical, laboratory, and mo age of occurrence in the seventh decade
recognized, as well as cases of cytokine- lecular features. of life {4249B,1606}. The epidemiologi
driven eosinophilia due to the abnormal cal features of idiopathic cases of HES
release of eosinophil growth factors (e.g. ICD-O code 9964/3 remain undefined.
IL2, IL3, and IL5) for unknown reasons
{226,759,3581,3759,4291}. If there is a Epidemiology Localization
similar unexplained hypereosinophilia Due to the previous difficulty in distin CEL, NOS is a multisystemic disorder.
but with no evidence of tissue damage, guishing CEL from idiopathic HES, the The peripheral blood and bone marrow
the designation ‘idiopathic hypereosino true incidence of these rare diseases is are always involved. Tissue infiltration by
philia’ is appropriate. As outlined in Table unknown. CEL, NOS appears to be more eosinophils and the release of cytokines
54 Myeloproliferative neoplasms
and humoral factors from the eosinophil tion, and rheumatological findings are {4249B}. Neutrophilia often accompanies
granules lead to tissue damage in a num frequent manifestations {1606}. the eosinophilia, and some cases show
ber of organs; the heart, lungs, central mild monocytosis, but do not meet all
nervous system (CNS), skin, and gastro Microscopy the criteria for chronic myelomonocytic
intestinal tract are commonly involved. In CEL, NOS the most striking feature leukaemia. Mild basophilia has been re
Splenic and hepatic involvement is also in the peripheral blood is eosinophilia, ported. Blast cells may be present but
common {1606}. mainly of mature eosinophils, with only account for < 20% of the cells.
small numbers of eosinophilic myelo The bone marrow is hypercellular, due
Clinical features cytes and promyelocytes {2127}. There in part to eosinophilic proliferation {481,
Eosinophilia is sometimes detected in may be a range of eosinophil abnormali 1606,2127}. In most cases, eosinophil
cidentally in patients who are otherwise ties, including sparse granulation (with maturation is orderly (i.e. without a dis
asymptomatic. In other cases, patients clear areas of cytoplasm), cytoplasmic proportionate increase in myeloblasts).
experience constitutional symptoms vacuolation, nuclear hypersegmentation Charcot―Leyden crystals are often pres
such as weight loss, night sweats, fever, or hyposegmentation, and increased ent. Erythropoiesis and megakaryocy-
fatigue, cough, angio―oedema, muscle size. Because these changes can be topoiesis are usually normal. Increased
pain, pruritus, and diarrhoea. The most seen in both reactive and neoplastic proportions of myeloblasts (≥ 2% in pe
serious clinical findings relate to endomy eosinophilia, they are not very helpful in ripheral blood or 5―19% in bone marrow)
ocardial fibrosis, with ensuing restrictive determining whether a case is likely to support the diagnosis of CEL, NOS, as
cardiomegaly. Scarring of the mitral and be CEL, NOS {226}. Occasional patients do dysplastic features in other cell line
tricuspid valves leads to valvular regur with CEL, NOS have cytologically normal ages {4249B}. Marrow fibrosis is seen in
gitation and the formation of intracardiac eosinophils, but the absence of eosino about one third of cases, although severe
thrombi, which can embolize to the brain phil dysplasia generally favours reactive fibrosis is rare {481.4249B}.
or elsewhere. Cardiac failure can occur. eosinophilia {4249B}. Significant dys Any tissue can show eosinophilic infiltra
Peripheral neuropathy, CNS dysfunction, plasia in cells of other myeloid lineages tion, and Charcot―Leyden crystals are of
pulmonary symptoms due to lung infiltra supports the diagnosis of CEL, NOS ten present. Fibrosis is common, caused
56 Myeloproliferative neoplasms
Myeloproliferative neoplasm, Kvasnicka H.M.
Thiele J.
unclassifiable Orazi A.
Horny H.-P.
Bain B.J.
Definition 3. Cases with convincing evidence of an lar to those of other MPNs. In early un
The designation of myeloproliferative neo MPN in which a coexisting neoplastic or classifiable disease, organomegaly may
plasm, unclassifiable (MPN-U) should be inflammatory disorder obscures some of be minimal or absent, but splenomegaly
applied only to cases that have definite the usual diagnostic clinical and/or mor and hepatomegaly can be massive in
clinical, laboratory, molecular, and mor phological features {2147}. advanced cases in which bone marrow
phological features of a myeloproliferative specimens are characterized by marked
neoplasm (MPN) but fail to meet the diag ICD-O code 9975/3 myelofibrosis and/or increased numbers
nostic criteria for any of the specific MPN of blasts {3978,3983}. The haematologi
entities, or that present with features that Epidemiology cal values are also variable, ranging from
overlap between two or more of the MPN The exact incidence of MPN―U is un mild leukocytosis to moderate or marked
categories (Table 2.15, p.54). Most cases known, but some reports indicate that thrombocytosis, with or without accom
of MPN-U fall into one of three groups: unclassifiable cases account for as many panying anaemia. Prominent cytope-
1. A subset of cases with so―called as 10―15% of all MPNs {3983}. The rela nia or myelodysplastic features should
masked/pre―polycythaemic presentation tive frequency varies significantly ac always prompt the definitive exclusion
of polycythaemia vera, prefibrotic/early cording to the experience of the diag of MDS/MPN and myelodysplastic syn
primary myelofibrosis, or early―phase nostician and the specific classification drome (MDS) {257,2147}. Discrepancies
essential thrombocythaemia in which the system and criteria used {1361,1361 A, between morphological and clinical fea
characteristic features are not yet fully 1362,1363,2151,2348A,3978}. Careful tures are particularly common in cases
developed {1380,2147,2152} ― a propor evaluation of clinical, morphological, and presenting with otherwise unexplained
tion of cases presenting with portal or molecular features reduces the frequen portal or splanchnic vein thrombosis
splanchnic vein thrombosis that fail to cy of unclassifiable cases to < 5% {257, {1103,1362}.
meet the diagnostic criteria for any of the 1086,1361A,1799A,2147,2433}.
specific MPN entities may also be con Exclusionary criteria
sidered to belong in this group {1103, Localization The presence of BCR-ABL1 fusion; re
1362}; The blood and bone marrow are the ma arrangement of PDGFRA, PDGFRB, or
2. Advanced―stage MPN, in which pro jor sites of involvement, but in advanced FGFRt, or PCM1-JAK2 fusion excludes
nounced myelofibrosis, osteosclerosis, stages the spleen and liver (i.e. the major the diagnosis of MPN-U. This diagnosis is
or transformation to a more aggressive sites of extramedullary haematopoiesis) also inappropriate if clinical data sufficient
stage with increased blast counts and/or may be also affected. for proper classification are not available,
myelodysplastic changes obscures the if the bone marrow specimen is of inad
underlying disorder {404,405,2151,3968, Clinical features equate quality or size for accurate evalua
3978,3983}; or The clinical features of MPN―U are simi tion {2147,2151,2152,3978,3983}, or if the
58 Myeloproliferative neoplasms
{1261,2986}. Although chronic myeloid features may appear during the natural Prognosis and predictive factors
leukaemia may also be accompanied progression of an MPN even without prior In patients with MPNs that are initially
by marked myelofibrosis, the small size cytoreductive therapy {404}. However, if unclassifiable, follow―up studies per
of the megakaryocytes indicates the cor an initial, untreated case demonstrates formed at intervals of 6―12 months can
rect diagnosis {3978,3983}, and cytoge significant myelodysplasia, the diagnos often provide sufficient information for
netic and molecular genetic demonstra tic alternatives of MDS/MPN or MDS, un a more precise classification {257,2147,
tion of the Philadelphia (Ph) chromosome classifiable, should be considered {225, 2152,3978,3983}. In the early stages of
or BCR-ABL1 fusion confirms the diagno 994,1520,1748,2987,3919,3930}. In such disease, such patients have a prognosis
sis of chronic myeloid leukaemia. cases, additional molecular testing and similar to patients with the neoplasms into
The presence of ≥10% blasts in the pe cytogenetic analysis may be necessary which their disease eventually evolves
ripheral blood or bone marrow and/or for better diagnostic characterization {2150}. Patients with advanced disease
the finding of significant myelodyspla {1517,3930,4502}. in whom the initial process is no longer
sia generally indicate a transition to a recognizable due to bone marrow fibro
more aggressive, often terminal phase Cell of origin sis or blastic infiltration are expected to
of the disease {404,405}. Cases initially The postulated cell of origin is a haema have a poor prognosis {404,405}. Se
diagnosed as MPN―U in which 10―19% topoietic stem cell. lective JAK1/JAK2 inhibitor therapy has
blasts are found in the peripheral blood been shown to rapidly reduce spleno
or bone marrow are considered to be in Genetic profile megaly, markedly improve myelofibro
the accelerated phase. Blast percent There is no cytogenetic or molecular ge sis―associated symptoms, and prolong
ages of ≥ 20% in the peripheral blood or netic finding specific for this group. There overall survival in primary and secondary
bone marrow indicate the blast phase is no BCR―ABL1 fusion; no rearrange myelofibrosis (i.e. primary myelofibrosis,
(i.e. acute leukaemic transformation) of ment of PDGFRA, PDGFRB, or FGFR1, post―polycythaemia vera myelofibrosis,
previously diagnosed MPN―U. In most and no PCM1―JAK2 fusion. The pres and post―essential thrombocythaemia
of these advanced―stage cases, fibrosis ence of a phenotypic driver mutation in myelofibrosis) {1798,1833,4316}. Howev
can cause dilution of bone marrow as JAK2, CALR, or MPL supports the diag er, the same therapeutic approach was
pirates; therefore, immunohistochemical nosis of an MPN. Cases that do not meet not found to be effective in MDS/MPN or
staining of the bone marrow biopsy sec the clinical and/or morphological criteria MDS associated with bone marrow fibro
tions for CD34 provides diagnostic value for a specific MPN subtype or any other sis. Therefore, the identification of MPNs
by demonstrating increased numbers specific disease category are best cat {1261,2962}, even if they are unclassifia
and/or clusters or aggregates of blasts egorized as MPN―U. ble, is of importance for clinical decision
{3978,3983}. Prominent myelodysplastic making and overall prognosis {941,942}.
Mastocytosis
Cutaneous mastocytosis 65
61
Systemic mastocytosis 66
Mast cell sarcoma 69
Mastocytosis Horny H.-P.
Akin C.
Metcalfe D.D.
Bennett J.M.
Arber D.A. Bain B.J.
Peterson L.C. Escribano L.
Tefferi A. Valent P.
62 Mastocytosis
Table 3.02 Diagnostic criteria for cutaneous and systemic mastocytosis setting of systemic mastocytosis but also
Cutaneous mastocytosis in patients with other disorders, includ
Skin lesions demonstrating the typical findings of urticaria pigmentosa/maculopapular cutaneous ing IgE-dependent allergic reactions. In
mastocytosis, diffuse cutaneous mastocytosis or solitary mastocytoma, and typical histological some patients with MCAS, the diagnos
infiltrates of mast cells in a multifocal or diffuse pattern in an adequate skin biopsya. tic criteria for systemic mastocytosis are
In addition, features/criteria sufficient to establish the diagnosis of systemic mastocytosis must be not fulfilled but clonal mast cells with the
absent {1567,4105,4107}. There are three variants of cutaneous mastocytosis (see Table 3.01).
KIT D816V mutation or aberrant surface
Systemic mastocytosis CD25 are found; these patients are diag
The diagnosis of systemic mastocytosis can be made when the major criterion and at least 1 minor nosed with monoclonal MCAS. Patients
criterion are present, or when ≥ 3 minor criteria are present. with monoclonal MCAS and those with
Major criterion mediator-related symptoms and systemic
Multifocal dense infiltrates of mast cells (≥ 15 mast cells in aggregates) detected in sections of bone mastocytosis are collectively designated
marrow and/or other extracutaneous organ(s) as having primary (clonal) MCAS {4104}.
The additional diagnosis of MCAS in the
Minor criteria
1. In biopsy sections of bone marrow or other extracutaneous organs,
setting of systemic mastocytosis has
> 25% of the mast cells in the infiltrate are spindle-shaped or have atypical morphology or clinical and therapeutic implications,
> 25% of all mast cells in bone marrow aspirate smears are immature or atypical. and should therefore be included in the
2. Detection of an activating point mutation at codon 816 of KIT in the bone marrow, blood or another medical record in the same way as the
extracutaneous organ presence or absence of B symptoms (i.e.
3. Mast cells in bone marrow, blood or another extracutaneous organ express CD25, with or without CD2, fever, night sweats and weight loss) are
in addition to normal mast cell markersb.
documented in lymphomas.
4. Serum total tryptase is persistently > 20 ng/mL, unless there is an associated myeloid neoplasm,
in which case this parameter is not valid.
The haematological abnormalities as
sociated with systemic mastocytosis
a This criterion applies to both the dense focal and the diffuse mast cell infiltrates in the biopsy. include anaemia, leukocytosis, eosino-
b CD25 is the more sensitive marker, by both flow cytometry and immunohistochemistry. philia (a common finding), neutropenia
and thrombocytopenia {228,1694,2094,
3064}. Bone marrow failure occurs only
to life-threatening. Symptoms related to with indolent systemic mastocytosis as a in patients with aggressive or leukaemic
organ impairment (due to mast cell infil result of extensive generation and release disease variants. Significant numbers of
trates) can also occur, in particular in of biochemical mediators such as hista circulating mast cells are rarely observed
patients with high-grade systemic mas mine, eicosanoids, proteases and hepa in systemic mastocytosis; when present,
tocytosis, including aggressive systemic rin. For example, gastrointestinal mani they suggest mast cell leukaemia {4107}.
mastocytosis and mast cell leukaemia festations such as peptic ulcer disease In as many as 30% of systemic masto
(Tables 3.03 and 3.04). and diarrhoea are more commonly attrib cytosis cases, an associated haemato
The physical findings at diagnosis of sys uted to the release of biologically active logical neoplasm is diagnosed before,
temic mastocytosis may include spleno mediators than to infiltration of the gastro simultaneously with, or after systemic
megaly (often minimal); lymphadeno- intestinal tract by excessive numbers of mastocytosis. In principle, any defined
pathy and hepatomegaly are present abnormal mast cells {1033,1853}. Patients myeloid or lymphoid malignancy can
less often {1690,1692,1695,2647}. Orga with severe mediator-related symptoms occur as an associated haematological
nomegaly is often absent in indolent occurring in temporal association with neoplasm, but myeloid neoplasms pre
systemic mastocytosis but is usually substantially increased serum tryptase dominate, with chronic myelomonocytic
present (along with impaired organ func levels may be diagnosed with mast cell leukaemia and myelodysplastic/myelo-
tion) in advanced systemic mastocytosis, activation syndrome (MCAS) {43,4103, proliferative neoplasm, unclassifiable
including aggressive systemic masto 4104}. However, MCAS is not considered being most common {1694,1696,1697,
cytosis and mast cell leukaemia. Severe a subset of systemic mastocytosis. This 3735,3751,3793}. In patients with syste
systemic symptoms can occur in patients is because MCAS occurs not only in the mic mastocytosis with an associated
Fig. 3.01 Cutaneous mastocytosis. A Numerous typical macular and maculopapular pigmented lesions of urticaria pigmentosa in a young child. B The skin lesions of all forms of
cutaneous mastocytosis may urticate when stroked (Darier’s sign). A palpable wheal appears a few moments after the physical stimulation, due to the release of histamine from the
mast cells. C Thickened, reddish, peau chagrine lesions characteristic of diffuse cutaneous mastocytosis, which occur almost exclusively in children.
Mastocytosis 63
Fig. 3.02 Mastocytoma of skin. A In this isolated lesion from the wrist of an infant, the papillary dermis and reticular dermis are filled with mast cells. B At high magnification,
the bland appearance of the mast ceil infiltrate is apparent.
haematological neoplasm, the clinical diffuse infiltration pattern, it is therefore In high-grade mastocytosis lesions, cyto
symptoms, disease course and progno impossible to es.ablish the diagnosis of logical atypia is pronounced, and the
sis relate both to systemic mastocytosis mastocytosis without additional studies, occurrence of metachromatic blast cells
and to the associated haematological including the demonstration of an aber is a typical feature of mast cell leukaemia
disorder {2329,3751,4107}; in many cas rant immunophenotype and/or detec {4107,4108}. The finding of frequent mast
es. the clinical outcome is determined tion of an activating point mutation in KIT cells with bilobated or multilobated nuclei
primarily by the associated haematologi {1698,1699,2122,3735,3736}. In contrast, (called promastocytes) usually indicates
cal neoplasm {570,3928}. Therefore, both the presence of multifocal compact mast an aggressive mast cell proliferation,
the type of systemic mastocytosis and cell infiltrates or a diffuse-compact mast although these cells may also be seen
the type ot associated haematological cell infiltration pattern is highly compat at lower frequency in other subtypes of
neoplasm should be classified according ible with the diagnosis of mastocytosis. the disease. Mitotic figures do occur in
to the WHO criteria in all cases. However, additional irrmunohistochemi- mast cells, but are infrequent even in the
Serum tryptase levels are used in the cal and molecular studies are strongly aggressive and leukaemic variants of
evaluation and monitoring of patients with recommended even in these cases. systemic mastocytosis. In a few patients
mastocytosis. Serum total tryptase per In tissue sections stained with haemato- with systemic mastocytosis, the mast
sistently > 20 ng/mL suggests systemic xylin and eosin. normal/reactive mast cells are mature and well granulated,
mastocytosis, and is a minor criterion for cells are usually loosely scattered without atypia or aberrant CD25 expres
diagnosis (unless there is an associated throughout the sample and display round sion; such cases have been referred to
myeloid neoplasm, in which case this to oval nuclei with clumped chromatin, a as well-differentiated systemic masto
parameter is not valid). In most patients low nuclear:cytoolasmic ratio, and ab cytosis. In most of these cases, no KIT
with cutaneous mastocytosis, serum sent or indistinct nucleoli. The mast cell mutation at codon 816 is found, and the
tryptase levels are normal to slightly el cytoplasm is abundant and usually filled mast cells usually respond to KIT tyrosine
evated {3591,4107}. with small, faintly visible granules. Dense kinase inhibitors, including imatinib {42.
aggregates of mast cells are only very 83}. However, well-differentiated morph
Microscopy exceptionally detected in reactive states ology of mast cells can be present in any
The diagnosis of mastocytosis is usually {2268,3074,4107}. variant of systemic mastocytosis. There
based on the demonstration of multifocal In smear preparations, mast celis are fore, well-differentiated systemic masto
clusters or cohesive aggregates/infiltrates readily visible with Romanowsky staining cytosis is not considered a distinct cate
of mast cells in adequate biopsy speci as medium-sized round or oval cells with gory of systemic mastocytosis.
mens (Table 3.02, p.63). The histological plentiful cytoplasm, containing densely The number of mast cells can be as
pattern of the mast cell infiltrate can vary packed metachromatic granules and sessed by conventional staining proce
depending on the tissue sampled {1568, round or oval nuclei. In normal/reactive dures, using Giemsa or toluidine blue
1698,4107}. A diffuse interstitial infiltration states, mast cells are easily distinguished staining to detect the metachromatic mast
pattern is defined as loosely scattered from basophils, which have segmented cell granules; CAE is also helpful {1698}.
mast cells in the absence of compact nuclei and larger and fewer granules. However, the most specific methods for
aggregates. However, this pattern is also Enzyme cytochemistry shows that mast identifying immature or atypical mast cells
observed in reactive mas: cell hyperpla cells react strongly with naphthol AS-D in tissue sections involve immunohisto-
sia and in some myeloproliferative neo chloroacetate esterase (CAE) but do not chemical staining for tryptase/chymase
plasms, including cases in which elevat express myeloperoxidase. In mastocyto and KIT (CD117), and, for identifying neo
ed numbers of immature atypical mast sis, the cytology of mast cells varies, but plastic mast cells, CD25 or less common
cells are found but the criteria for system abnormal cytological features (including ly CD2. In a subset of cases, mast cells
ic mastocytosis or mast cell leukaemia marked spindling and hypogranularity) also express CD30 {2729,3734}. Aberrant
are not met {1696}. In patients with the are almost always present {3750.4107}. expression of surface markers, including
64 Mastocytosis
CD2 and CD25, can also be detected by
flow cytometry {1114}. The morphological
and clinical features of the common forms
of mastocytosis are described in the fol
lowing sections on each variant
Cutaneous mastocytosis
Definition
The diagnosis of cutaneous mastocytosis
(CM) requires the demonstration of typi
cal clinical findings and histological proof
of abnormal mast cell infiltration of the
dermis. In cutaneous mastocytosis, there
is no evidence of systemic involvement Fig. 3.03 Urticaria pigmentosa. In this typical skin lesion in a child, aggregates of mast cells fill the papillary dermis
in the bone marrow or any other organ. and extend as sheets into the reticular dermis.
In addition, the diagnostic criteria for
systemic mastocytosis are not fulfilled. In adults, the lesons are disseminated mon than urticaria pigmentosa and pre
However, patients with cutaneous masto and they tend to be red or brownish red sents almost exclusively in childhood.
cytosis may present with one or two of and macular or maculopapular. Histopa The skin is diffusely thickened and may
the minor diagnostic criteria for systemic thology of urticaria pigmentosa in adults have a grain leather (peau chagrine) or
mastocytosis, such as an elevated se typically reveals fewer mast cells than orange peel (peau d'orange) appear
rum tryptase level or abnormal morphol are seen in children. However, as men ance. There are no individual lesions.
ogy of mast cells in the bone marrow tioned above, cutaneous mastocytosis is In patients with clinically less obvious
(Table 3.02, p.63). very rare in adults; upon thorough bone infiltration of the skin, the biopsy usu
Three major variants of cutaneous masto marrow examination, most adult patients ally shows a band-like infiltrate of mast
cytosis are recognized: urticaria pigmen with skin lesions are found to have syste cells in the papillary and upper reticular
tosa/maculopapular cutaneous masto mic mastocytosis. The number of lesio- dermis. In massively infiltrated skin, the
cytosis, diffuse cutaneous mastocytosis nal mast cells can sometimes overlap histology may be the same as that seen
and mastocytoma of skin {4105,4107). with the upper range of mast cell counts in mastocytoma of skin {1568,4353}.
found in normal or inflamed skin. In some
ICD-O code 9740/1 cases, examination of multiple biopsies Mastocytoma of skin
and immunohistochemical analysis may This variant typically occurs as a single
Synonyms be necessary to establish the diagnosis lesion, almost exclusively in children, and
Maculopapular cutaneous mastocytosis; of cutaneous mastocytosis {4105,4353}. without predilection for site {576,4353}. In
diffuse cutaneous mastocytosis; Various KIT mutations, including D816V, some cases, two or three lesions occur.
solitary mastocytoma of skin; urticaria have been detected in lesional skin in Histology shows sheets of mature-look
pigmentosa childhood cutaneous mastocytosis. ing. highly metachromatic mast cells with
abundant cytoplasm, which densely in
Urticaria pigmentosa/maculopapular Diffuse cutaneous mastocytosis filtrate the papillary and reticular dermis.
cutaneous mastocytosis This clinically remarkable variant of cuta These mast cell infiltrates may extend into
This is the most common form of cuta neous mastocytosis is much less com the subcutaneous tissues. Cytological
neous mastocytosis. In children, the le
sions of urticaria pigmentosa tend to be
larger, fewer, and more papular than the
skin lesions seen in adults with systemic
mastocytosis. Recent data suggest that
monomorphic small lesions detected in
early childhood are more likely to persist
into adulthood than are larger polymor
phic lesions {569,1567}. Histopathology
typically reveals aggregates of spindle-
shaped mast cells filling the papillary
dermis and extending as sheets and
aggregates into the reticular dermis, often Fig. 3.04 Systemic mastocytosis, bone marrow biopsy A One region of this photomicrograph (left side) is
occupied by mast cells with fibrosis, whereas the adjacent area is hypercelluiar. with panmyelosis, in cases like
in perivascular and periadnexal distribu this, it is important to consider the diagnosis of systemic mastocytosis with an associated haematological neoplasm.
tion {4353}. A subset of cases, usually B Mast cells usually demonstrate metachromatic granules on Giemsa or toluidine blue staining. However, the most
occurring in young children, present as specific methods for identifying mast cells in tissue sections are immunohistochemical staining for tryptase/chymase
non-pigmented plaque-forming lesions. and KIT (CD117) and for identifying neoplastic mast cells, CD2 and CD25.
Cutaneous mastocytosis 65
Table 3.03 Diagnostic criteria for the variants of systemic mastocytosis atypia is absent, which enables the dis
Indolent systemic mastocytosis tinction of mastocytoma from an extreme
Meets the general criteria for systemic mastocytosis ly rare mast cell sarcoma of the skin.
No C findings a
No evidence of an associated haematological neoplasm
Low mast cell burden Systemic mastocytosis
Skin lesions are almost invariably present
Bone marrow mastocytosis
Definition
As above (indolent systemic mastocytosis), but with bone marrow involvement and no skin lesions Consensus criteria for the diagnosis of
systemic mastocytosis have been estab
Smouldering systemic mastocytosis lished (Table 3.02, p.63), and five vari
Meets the general criteria for systemic mastocytosis ants are recognized: indolent systemic
≥ 2 B findings; no C findingsa mastocytosis, smouldering systemic
No evidence of an associated haematological neoplasm mastocytosis, systemic mastocytosis
High mast cell burden with an associated haematological neo
Does not meet the criteria for mast cell leukaemia
plasm, aggressive systemic mastocyto
Systemic mastocytosis with an associated haematological neoplasm sis and mast cell leukaemia.
Meets the general criteria for systemic mastocytosis Table 3.03 summarizes the specific diag
Meets the criteria for an associated haematological neoplasm (i.e. a myelodysplastic syndrome, nostic criteria for each variant of systemic
myeloproliferative neoplasm, acute myeloid leukaemia, lymphoma or another haematological neoplasm mastocytosis.
classified as a distinct entity in the WHO classification)
C findings
1. Bone marrow dysfunction caused by neoplastic mast cell infiltration,
manifested by ≥ 1 cytopenia: absolute neutrophil count < 1.0 x 109/L, haemoglobin level < 10 g/dL,
and/or platelet count < 100 x 109/L
2. Palpable hepatomegaly with impairment of liver function, ascites and/or portal hypertension
3. Skeletal involvement, with large osteolytic lesions with or without pathological fractures (pathological
fractures caused by osteoporosis do not qualify as a C finding)
4. Palpable splenomegaly with hypersplenism
5. Malabsorption with weight loss due to gastrointestinal mast cell infiltrates
66 Mastocytosis
Fig. 3.06 Systemic mastocytosis, spleen. A Macroscopic view of this spleen from a patient with systemic mastocytosis. B Aggregates of mast cells may be seen in the red or
white pulp, or in both. In this case, the mast cells have prominent, lightly stained cytoplasm and are seen in a perifollicular location.
Fig. 3.07 Systemic mastocytosis, bone marrow biopsy. A The lesions often consist of a central core of lymphocytes surrounded by polygonal mast cells with pale, faintly granular
cytoplasm, and with reactive eosinophils at the outer margin of the lesion. B The lesions are often well circumscribed; they may occur in paratrabecular or perivascular locations,
or may be randomly distributed within the intertrabecular regions.
Fig. 3.08 Systemic mastocytosis, bone marrow biopsy. A Densely packed, spindled mast cells along a bone trabecula in paratrabecular infiltration of marrow. B The monomorphic,
spindled mast cells are often accompanied by fibrosis and may replace large areas of the bone marrow biopsy specimen. Osteosclerosis often accompanies such lesions.
Bone marrow mastocytosis Smouldering systemic mastocytosis can occur. Skin lesions are found in most
In the bone marrow mastocytosis sub- In smouldering systemic mastocytosis, patients and the KIT D816V mutation is
type of indolent systemic mastocytosis, the mast cell burden is high, organo almost invariably present; unlike in typi
the burden of neoplastic mast cells is megaly is often found, and multilineage cal indolent systemic mastocytosis, the
usually low, and serum tryptase levels involvement is typically present. Although mutation is usually detectable in several
are often normal or nearly normal. the clinical course is often stable for many myeloid lineages and sometimes even
years, progression to aggressive system in lymphocytes, reflecting multilineage
ic mastocytosis or mast cell leukaemia involvement by the neoplastic process
Systemic mastocytosis 67
Fig. 3.09 Systemic mastocytosis, lymph node biopsy. A This biopsy is diffusely infiltrated by neoplastic mast cells; only a remnant of a normal follicle can be seen. B The infiltrate
is often parafollicular in distribution; it is seen here as a monotonous population of cells with abundant, lightly staining cytoplasm. C Immunohistochemical staining for mast cell
tryptase highlights the parafollicular distribution of the mast cell infiltrate.
despite a lack of morphological evi as a myelodysplastic syndrome, myelo mastocytosis with an AHN, and in many
dence of an associated haematological proliferative neoplasm, myelodysplastic/ cases is detectable not only in the sys
neoplasm. myeloproliferative neoplasm or acute temic mastocytosis compartment but
myeloid leukaemia {4107}. The AHN also in the AHN cells (e.g. acute myeloid
Systemic mastocytosis with an should usually be considered a second leukaemia blasts or chronic myelomono
associated haematological neoplasm ary neoplasm with clinical and prognos cytic leukaemia monocytes). Depending
Systemic mastocytosis with an associa tic implications. The most commonly de on the type of AHN, additional mutations
ted haematological neoplasm (AHN) tected AHN is chronic myelomonocytic in other genes (e.g. TET2, SRSF2, ASXL1,
fulfils the general criteria for systemic leukaemia. Lymphoid neoplasms, such CBL, RUNX1 and the RAS family of onco
mastocytosis as well as the criteria for an as multiple myeloma and lymphoma, genes) may also be detected, and the
AHN. In most cases, a myeloid disease of are rare. The activating KIT D816V muta accumulation of such mutations appears
non-mast cell lineage is detected, such tion is found in most cases of systemic to be of prognostic significance.
Fig. 3.10 Mast cell leukaemia. A Immunohistochemical staining for of the bone marrow biopsy mast cell tryptase. B Peripheral blood; note the bilobated nuclei and granulated
cytoplasm often seen in this aggressive form of mastocytosis. C This image demonstrates the so-called clear-cell appearance and the folded, somewhat monocytoid nuclei that
are typical of immature mast cells in mast cell leukaemia. D The bone marrow biopsy is diffusely infiltrated by the neoplastic mast cells.
68 Mastocytosis
Fig. 3.11 Mast cell sarcoma. A This tumour is composed of poorly differentiated neoplastic cells that show no cytological evidence of mast cell differentiation. B On immunohisto-
chemistry, the neoplastic cells stain for mast cell tryptase, which confirms the tumour’s mast cell origin.
PCM1-JAK2
Cytochemistry
The eosinophils, neutrophils and mono
cytes show the cytochermical reactions
expected for cells of these lineages.
Immunophenotype
Immunophenotypic analysis of the mast
cells has shown expression of CD2 and
CD25, which is also found in most cases
of mast cell disease {4236}.
Cell of origin
The postulated cell of origin is a pluri-
potent haematopoietic stem cell that
can give rise to neutrophils, mono
cytes, eosinophils, probably mast cells
and (in some patients) B-cell lineage
lymphoblasts.
Genetic profile
Fig.4.04 Myeloid neoplasm with eosinophilia and rearrangement of PDGFRB. A Bone marrow trephine biopsy Cytogenetic analysis usually shows
section from a patient with t(5;12) shows a marked increase in eosinophils. B Peripheral blood smear from a patient t(5;12)(q32;p13.2), with the translocation
with t(5;12) shows numerous abnormal eosinophils, at lower (B) and higher (C) magnification. Eosinophils accounted resulting in ETV6-PDGFRB gene fusion
for 40% of the leukocytes. {1398} (previously called TEL-PDGFRB).
In one patient, ETV6-PDGFRB fusion
is not indicated when no 5q31-33 break cases. Tissue infiltration by eosinophils resulted from a four-way translocation:
point is found by conventional cytoge and the release of cytokines, humoral t(1;12;5;12)(p36;p13.2;q32;q24) {835};
netic analysis, because almost all cases factors or granule contents by eosino in another, the fusion occurred in asso
reported to date in which 20 metaphases phils can contribute to tissue damage in ciation with ins(2;12)(p21;q13;q22) {883}.
were available for examination have had several organs. The 5q breakpoint is sometimes as
a cytogenetically detectable abnormality. signed to 5q31 and sometimes to 5q33,
Clinical features although the gene map locus of PDGFRB
ICD-O code 9966/3 Most patients have splenomegaly and is 5q32.
some have hepatomegaly. Some patients Not all translocations characterized
Synonyms have skin infiltration and some have car as t(5;12)(q31-33;p12) lead to ETV6-
Chronic myelomonocytic leukaemia with diac damage leading to cardiac failure. PDGFRB fusion. Cases without a fusion
eosinophilia associated with t(5;12); mye Serum tryptase may be mildly or moder gene are not assigned to this category
loid neoplasms with PDGFRB rearrange ately elevated. The vast majority of pa of MPN and, importantly, are not likely
ment; myeloid neoplasms associated tients who have been treated with imatin to respond to imatinib; in such cases,
with PDGFRB rearrangement ib have been found to be responsive. an alternative leukaemogenic mecha
nism is upregulation of interleukin 3
Epidemiology Microscopy (IL3) {799}. Therefore, RT-PCR using
This neoplasm is considerably more The white blood cell count is increased. primers suitable for all known break
common in men than in women (male-to- There may be anaemia and thrombocy points is recommended for confirma
female ratio: 2:1) and occurs over a wide topenia. There is a variable increase in tion of ETV6-PDGFRB {850}, but if mo
age range (8―72 years), with peak inci neutrophils, eosinophils, monocytes and lecular analysis is not available, a trial
dence in middle-aged adults and a me eosinophil and neutrophil precursors. of imatinib is justified in patients with an
dian age of onset in the late 40s {3776}. Rarely, there is a marked increase in ba MPN associated with t(5;12). Due to the
sophils {4236}. large number of potential partner genes,
Localization The bone marrow is hypercellular as a re molecular analysis to demonstrate variant
MPN associated with t(5;12)(q32;p13.2) sult of active granulopoiesis (neutrophilic fusion genes is only feasible after a trans
is a multisystem disorder. The periph and eosinophilic). Bone marrow trephine location has been shown by cytogenetic
eral blood and bone marrow are always biopsy may show an increase in mast analysis. If subsequent monitoring of
involved. The spleen is enlarged in most cells, which may be spindle-shaped treatment response is planned, the fusion
Myelodysplastic/myeloproliferative neoplasms 81
Chronic myelomonocytic leukaemia 82
Atypical CML, BCR-ABL1-negative 87
Juvenile myelomonocytic leukaemia 89
MDS/MPN with ring sideroblasts and thrombocytosis 93
MDS/MPN, unclassifiable 95
Chronic myelomonocytic leukaemia Orazi A.
Bennett J.M.
Bain B.J.
Cazzola M
Germing U. Foucar K.
Brunning R.D. Thiele J.
a Myeloproliferative neoplasms (MPN) can be associated with monocytosis or it can develop during the course
Synonyms
of the disease; such cases can mimic CMML. In these rare instances, a documented history of MPN excludes
Chronic myelomonocytic leukaemia, type I;
CMML, whereas the presence of MPN features in the bone marrow and/or MPN-associated mutations (in
chronic myelomonocytic leukaemia, type JAK2, CALR orMPL) tends to support MPN with monocytosis rather than CMML.
II; chronic myelomonocytic leukaemia in b Blasts and blast equivalents include myeloblasts, monoblasts and promonocytes. Promonocytes are monocytic
transformation (obsolete); chronic myelo precursors with abundant light-grey or slightly basophilic cytoplasm with a few scattered fine lilac-coloured
monocytic leukaemia, NOS granules, finely distributed stippled nuclear chromatin, variably prominent nucleoli and delicate nuclear folding
or creasing. Abnormal monocytes, which can be present in both the peripheral blood and the bone marrow,
Epidemiology are excluded from the blast count (see Introduction and overview of the classification of myeloid neoplasms,
Fig. 1.04, p. 18).
There are few reliable incidence data for c In the appropriate clinical context, mutations in genes often associated with CMML (e.g. TET2, SRSF2,
CMML; in some epidemiological surveys, ASXL1 and SETBP1) support the diagnosis. However, some of these mutations can be age-related or present
CMML has been grouped with chronic in other neoplasms; therefore, these genetic findings must be interpreted with caution.
myeloid leukaemias and in others it has
82 Myelodysplastic/myeloproliferative neoplasms
Fig. 5.01 Chronic myelomonocytic leukaemia-1. A With Wright-Giemsa staining in this bone marrow aspirate smear, the dysplastic granulocytic component is obvious, but the
monocytic component is more difficult to identify. B The monocytic component can be highlighted with special staining: naphthol AS-D chloroacetate esterase (CAE) reaction
combined with alpha-naphthyl butyrate esterase stains monocytes brown, neutrophils blue and myelomonocytic cells a mixture of blue and brown. C CD163 immunostaining of
a bone marrow biopsy section shows positivity in scattered monocytic cells and strong staining of the bone marrow macrophages. Immunohistochemistry can be used to identify
monocytes in tissue sections, but is less sensitive than cytochemistry applied to bone marrow aspirate smears.
Microscopy
Peripheral blood monocytosis is the
hallmark of CMML. By definition, the
monocyte count is always ≥ 1 x 109/L;
it is usually 2―5 x109/L, but can ex
ceed 80 x 109/L {2517,2653}. Mono
cytes should account for ≥ 10% of the
leukocytes {339}. In general, the mono
cytes are mature and have unremark
able morphology, but they can exhibit
unusual nuclear segmentation or chro
matin patterns and abnormal granulation
{2092}. Those with abnormal granulation
are best termed abnormal monocytes,
a designation used to describe mono
cytes that are immature but have denser
chromatin, more nuclear convolutions
and folds, and more abundant grey
ish cytoplasm than do promonocytes
and monoblasts (see Introduction and Fig. 5.03 Chronic myelomonocytic leukaemia-1. The degree of leukocytosis, neutrophilia and dysplasia is
variable. A The white blood cell count in this case is elevated, with minimal dysplasia in the neutrophil series.
overview of the classification of myeloid
B The white blood cell count in this case is normal, with absolute monocytosis, neutropenia and dysgranulopoie-
neoplasms, Fig. 1.04, p. 18). Blasts and sis. C In this biopsy section, monocytes (with their characteristic folded nuclei and delicate nuclear chromatin) can
promonocytes may also be seen, but if be seen among the granulocytes. D Bone marrow biopsy section immunostain shows that the monocytic cells in this
they account for ≥ 20% of the leukocytes, case are strongly positive for CD14.
the diagnosis is acute myeloid leukaemia may have complications related to the biopsy or on marrow aspirate smears.
(AML; acute myelomonocytic leukaemia degranulation of the eosinophils. These Cytochemical and immunohistochemi-
or acute monocytic leukaemia) rather hypereosinophilic cases of CMML can cal studies that facilitate the identifica
than CMML. Other changes in the blood closely resemble cases of myeloid neo tion of monocytes and their precursors
are variable. The WBC count may be plasms with eosinophilia associated with are strongly recommended when the
normal or slightly decreased with neu specific genetic abnormalities, which diagnosis of CMML is suspected {2985,
tropenia, but in half or more of all cases are classified and discussed separately 2987}. Dysgranulopoiesis, similar to
it is increased due to both monocytosis from CMML (see Myeloid/lymphoid neo that in the blood, is present in the bone
and neutrophilia {1334,2517,2978}. Neu plasms with PDGFRB rearrangement, marrow of most patients with CMML.
trophil precursors (promyelocytes and p.75). Mild anaemia, often normocytic Dyserythropoiesis (e.g. megaloblastoid
myelocytes) usually account for < 10% of but sometimes macrocytic, is common. changes, other abnormal nuclear fea
the leukocytes {339}. Dysgranulopoiesis, Platelet counts vary, but moderate throm tures and ring sideroblasts) may also be
including the formation of neutrophils with bocytopenia is often present. Atypical, observed, but is usually mild {1334,2517,
hyposegmented or abnormally segment large platelets and nucleated red blood 2653}. Micromegakaryocytes and/or
ed nuclei or abnormal cytoplasmic gran cell precursors may be seen {1338,2517}. megakaryocytes with hyposegmented
ulation, is present in most cases, but may The bone marrow is hypercellular in nuclei are found in as many as 80% of
be less prominent in patients with leuko >7 5% of cases, but normocellular speci cases {1338,2517,2653}.
cytosis than in those with a normal or low mens are also seen {2653,2985,3805}. Unlike in chronic myeloid leukaemia,
WBC count {2092,2517}. In some cases, Hypocellularity is very rare. One recent pseudo-Gaucher cells are usually ab
it may be difficult to distinguish between study on the histological assessment of sent. A mild to moderate increase in the
hypogranular neutrophils and dysplastic marrow found that < 5% of CMML cases number of reticulin fibres is seen in the
monocytes. Mild basophilia is sometimes were hypocellular and 84% were hyper bone marrow in nearly 30% of cases
present. Eosinophils are usually normal or cellular {3554}. {2538}. Careful attention to morphologi
slightly increased in number, but in some Granulocytic proliferation is often the cal features and other disease-specific
cases eosinophilia is striking. CMML with most striking finding in the bone marrow, clinicopathological findings may be
eosinophilia can be diagnosed when the but an increase in erythroid precursors needed to distinguish CMML from MPN
criteria for CMML are met and the eo may also be seen {339,2653}. Mono associated with monocytosis {404,1097}.
sinophil count in the peripheral blood is cytic proliferation is invariably present, The presence of one of the characteristic
≥ 1.5 x 109/L. Patients with this diagnosis but can be difficult to recognize in the MPN driver mutations (in JAK2, CALR or
Fig. 5.05 Chronic myelomonocytic leukaemia. A Some degree of fibrosis may be seen in as many as 30% of cases; this bone marrow biopsy specimen shows streaming of cells
suggestive of underlying reticulin fibrosis, the presence of which was confirmed by reticulin silver staining (B).
84 Myelodysplastic/myeloproliferative neoplasms
MPL) is helpful for identifying MPN asso used category of CMML-1 (defined by 2482,3640,4364}. The blood and mar
ciated with monocytosis. blasts including promonocytes account row monocytes often have aberrant
Nodules composed of mature plasma- ing for <5% of the leukocytes in the pe phenotypes, with two or more aberrant
cytoid dendritic cells in the bone mar ripheral blood and < 10% in the bone features shown by flow cytometric analy
row biopsy have been reported in 20% marrow) has now been split into two sis {4396}. Decreased CD14 expression
of cases {2985}. The cells have round new categories: CMML-0 and CMML-1. may reflect relative monocyte immaturity
nuclei, finely dispersed chromatin, incon It is currently recommended {2978,3587, {3618}. Other aberrant characteristics in
spicuous nucleoli, and a rim of eosino 3805} that CMML be subdivided into clude: overexpression of CD56; aberr
philic cytoplasm. The cytoplasmic mem three categories, defined by the percent ant expression of CD2; and decreased
brane is usually distinct with well-defined age of blasts and promonocytes in the expression of HLA-DR, CD13, CD11c,
cytoplasmic borders, imparting a cohe peripheral blood and bone marrow: CD15, CD16, CD64 and CD36 {2554,
sive appearance to the infiltrating cells. CMML-0: < 2% blasts in the blood and 3618,3714,4396}. An increased propor
Apoptotic bodies, often within starry-sky < 5% in the bone marrow; no Auer rods. tion of CD14+/CD16― monocytes has
histiocytes, are frequently present. The CMML-1: 2―4% blasts in the blood or recently been described {3618}. Matur
relationship of the plasmacytoid dendritic 5-9% in the bone marrow; <5% blasts in ing myeloid cells may also have aberrant
cell proliferation to the leukaemic cells the blood, < 10% blasts in the bone mar immunophenotypic features, and neutro
was previously uncertain {216,1127,1555, row, and no Auer rods. phils may show aberrant light-scattering
1691}, but there is now evidence that the CMML-2: 5―19% blasts in the blood, 10- properties. An increased proportion of
proliferation is neoplastic in nature and is 19% in the bone marrow or Auer rods are CD34+ cells and an emerging blast
clonally related to the associated CMML present; < 20% blasts in the bone marrow population with an aberrant immunophe
{1126}. and blood. notype have been associated with early
The splenic enlargement seen in CMML transformation to acute leukaemia {1063,
is usually due to infiltration of the red pulp Cytochemistry 4365,4396}.
by leukaemic cells. Lymphadenopathy Cytochemical studies are strongly rec For the identification of monocytic cells,
is uncommon, but when it occurs it may ommended whenever the diagnosis of immunohistochemistry on tissue sections
indicate transformation to a more acute CMML is considered {2985}. Alpha-naph is less sensitive than cytochemistry or
phase, and the lymph node may show thyl butyrate esterase or alpha-naphthyl flow cytometry. The most reliable marker
diffuse infiltration by myeloid blasts. acetate esterase (with fluoride inhibition) is CD14 {3257}. CD68R and CD163 can
There is sometimes lymph node (and staining of blood and bone marrow as also be helpful {2985}. Lysozyme used in
less commonly splenic) involvement by pirate smears, alone or in combination conjunction with cytochemistry for CAE
a diffuse infiltration of plasmacytoid den with naphthol AS-D chloroacetate ester can facilitate the identification of mono
dritic cells. In some cases, generalized ase (CAE) staining, is extremely useful cytic cells, which are lysozyme posi
lymphadenopathy due to tumoural pro for assessing the monocytic component, tive but CAE negative (in contrast to the
liferations of plasmacytoid dendritic cells and in some cases may facilitate distin granulocyte precursor cells, which are
is the presenting manifestation of CMML. guishing monocytes from monoblasts positive for both). An increased propor
Blast cells and promonocytes usually and promonocytes (blast equivalents) tion of CD34+ cells detected by immu
account for < 5% of the peripheral blood and from non-monocytic cells. nohistochemistry has been associated
leukocytes and < 10% of the nucleated with transformation to acute leukaemia
marrow cells at the time of diagnosis. Immunophenotype {2985}.
A higher proportion may indicate poor The blood and marrow cells usually ex The mature plasmacytoid dendritic cells
prognosis or higher risk of rapid trans press typical myelomonocytic antigens associated with CMML have a charac
formation to acute leukaemia {1180,1339, (e.g. CD33 and CD13) and variably ex teristic immunophenotype. They are
1442,3805,3922,4365}. The previously press CD14, CD68 and CD64 {1993, positive for antigens normally expressed
Fig. 5.06 Chronic myelomonocytic leukaemia-1. A Nodules composed of mature plasmacytoid dendritic cells in the bone marrow biopsy section. B Immunostaining shows that
these cells strongly express CD123.
86 Myelodysplastic/myeloproliferative neoplasms
Atypical chronic myeloid leukaemia, Orazi A.
Bennett J.M.
BCR―ABL1―negative Bain B.J.
Brunning R.D.
Thiele J.
Definition Table 5.02 Diagnostic criteria for atypical chronic myeloid leukaemia, BCR―ABL1-negative (aCML)
Atypical chronic myeloid leukaemia,
- Peripheral blood leukocytosis ≥ 13 x 109/L, due to increased numbers of neutrophils and their precursors
BCR-ABL1-negative (aCML) is a leukae (i.e. promyelocytes, myelocytes and metamyelocytes), with neutrophil precursors constituting
mic disorder with myelodysplastic as well ≥ 10% of the leukocytes
as myeloproliferative features present at -Dysgranulopoiesis, which may include abnormal chromatin clumping
the time of initial diagnosis (Table 5.02). It -No or minimal absolute basophilia; basophils constitute < 2% of the peripheral blood leukocytes
is characterized by principal involvement -No or minimal absolute monocytosis; monocytes constitute < 10% of the peripheral blood leukocytes
of the neutrophil lineage, with leukocyto -Hypercellular bone marrow with granulocytic proliferation and granulocytic dysplasia,
sis resulting from an increase of morpho with or without dysplasia in the erythroid and megakaryocytic lineages
logically dysplastic neutrophils and their - < 20% blasts in the blood and bone marrow
precursors. However, multilineage dys - No evidence of PDGFRA, PDGFRB or FGFR1 rearrangement, or of PCM1-JAK2
plasia is common, and reflects the stem - WHO criteria for BCR-ABL1-positive chronic myeloid leukaemia, primary myelofibrosis, polycythaemia vera,
cell origin of this entity. The neoplastic or essential thrombocythaemiaa are not met
cells do not have BCR―ABL1 fusion;
a Myeloproliferative neoplasms (MPNs), in particular those in accelerated phase and/or in post-polycythaemia
rearrangement of PDGFRA, PDGFRB or
FGFR1, or PCM1-JAK2. Therapy-related vera or post-essential thrombocythaemia myelofibrosis, if neutrophilic, may simulate aCML. A history of
cases with features of aCML are dis MPN, the presence of MPN features in the bone marrow, and/or MPN-associated mutations (in JAK2, CALR
or MPL) tend to exclude the diagnosis of aCML; conversely, the diagnosis is supported by the presence of
cussed separately (see Therapy-related SETBP1 and/or ETNK1 mutations. CSF3R mutation is uncommon and, if detected, should prompt careful
myeloid neoplasms, p. 153). morphological review to exclude an alternative diagnosis of chronic neutrophilic leukaemia or another
myeloid neoplasm.
ICD-O code 9876/3
Synonyms been reported in teenagers {447,1621, times to thrombocytopenia; for other pa
Atypical chronic myeloid leukaemia, Phil 2143,2517,4248}. The reported male-to- tients, the primary symptoms are related
adelphia chromosome―negative (Ph1-); female ratio varies, but in larger series it to splenomegaly {447,1621,2143,2517}.
atypical chronic myeloid leukaemia, is approximately 1:1 {447,1621,2143,2517,
BCR/ABL1―negative 4248}. Microscopy
The white blood cell count is always
Epidemiology Localization ≥ 13 x 109/L {339}, but median values
The exact incidence of aCML is unknown, The peripheral blood and bone marrow of 24―96 x 109/L have been reported,
but it is estimated that there are only are always involved; splenic and hepatic and some patients have white blood cell
1-2 aCML cases for every 100 cases of involvement is also common. counts of > 300 x 109/L {447,1621,2143,
BCR-ABL1-positive chronic myeloid leu 2517,4248}. Blasts are usually < 5% and
kaemia {2987,4248}. Patients with aCML always < 20% of peripheral blood leuko
tend to be elderly. In the few series re Clinical features cytes. Neutrophil precursors (promye
ported to date, the median patient age at There are only a few reports of the clinical locytes, myelocytes, and metamyelo
diagnosis is in the seventh or eighth dec features of aCML. Patients usually have cytes) constitute ≥10% of the leukocytes.
ade of life, although the disease has also symptoms related to anaemia or some The absolute monocyte count may be
Fig. 5.07 Atypical chronic myeloid leukaemia, BCR-ABL1-negai\ve. A The diagnosis requires ≥10% circulating neutrophil precursors; three myelocytes are apparent in this
peripheral blood microscopic field. B The white blood cell count is elevated, with dysplastic neutrophils. C Marked granulocytic dysplasia and immature granulocytes. Cytogenetic
studies revealed a gain of chromosome 8, but no Philadelphia (Ph) chromosome. No BCR-ABL1 fusion gene was detected by FISH.
Cytochemistry
No specific cytochemical abnormalities
have been reported to date, although
the use of esterase stains or immuno-
histochemistry to exclude a significant
monocytic component can facilitate the
exclusion of chronic myelomonocytic leu
kaemia. Neutrophil alkaline phosphatase
scoring is rarely done; the scores can be
low, normal, or high, and are therefore not
useful for distinguishing this entity from
BCR-ABL1-positive chronic myeloid leu
kaemia {2143,2517}.
Immunophenotype
No specific immunophenotypic charac
teristics have been reported to date. Like
esterase cytochemistry, immunohisto-
chemistry for CD14 or CD68R on biopsy
sections may facilitate the identification
of monocytes; the finding of significant
Fig. 5.08 Atypical chronic myeloid leukaemia, BCR-ABL1-negative. A The bone marrow biopsy shows hyper- marrow monocytosis should call into
cellularity, due to granulocytic proliferation. B Note the increased number of megakaryocytes, with small, abnormal question a diagnosis of aCML. In some
forms. From the biopsy alone, the morphology would be difficult to differentiate from that of BCR-ABL1-positive cases with decreased megakaryocytes,
chronic myeloid leukaemia. C Dysplasia in the granulocytic and megakaryocytic lineages is evident on the bone CD61 or CD42b immunohistochemistry
marrow aspirate smear.
may facilitate the identification of dys-
increased, but the percentage of periph cursors. The myeloid―to―erythroid ratio is megakaryopoiesis. CD34 can facilitate
eral blood monocytes is < 10%. Basophil usually > 10:1, reflecting the increased the identification of blasts.
ia may be observed but is not prominent granulopoiesis and the decreased eryth-
{339,447,1621,2517,4248}. One of the ropoiesis, but in some cases erythroid Cell of origin
major features that characterize aCML precursors account for > 30% of the mar A bone marrow haematopoietic stem cell
is dysgranulopoiesis, which may be pro row cells. Dyserythropoiesis is present
nounced. Acquired Pelger―Huët anom in about 40% of cases {339,447,4248}. Genetic profile
aly or other nuclear abnormalities, such Dysgranulopoiesis is invariably present, Karyotypic abnormalities are reported
as hypersegmentation with abnormally and the changes in the neutrophil lineage in as many as 80% of cases. The most
clumped nuclear chromatin or bizarrely observed in the bone marrow are similar common abnormalities are gain of chro
segmented nuclei, abnormal cytoplas to those in the blood. Megakaryopoie- mosome 8 and del(20q), but abnormali
mic granularity (usually hypogranularity) sis is usually quantitatively normal or in ties of chromosomes 13, 14, 17, 19 and 12
and multiple nuclear projections, may creased, but is sometimes decreased; are also common {447,1621,2517}. Rare
be observed in the neutrophils. Mod there is often evidence of dysmegakary- ly, cases is which the neoplastic cells
erate anaemia is common, and the red opoiesis, including micromegakaryo have an isolated isochromosome 17q
blood cells may show changes indica cytes and small megakaryocytes with have features of aCML, although most
tive of dyserythropoiesis. The platelet hypolobated nuclei {447,1621}. Blasts fulfil the criteria for chronic myelomono
count is variable, but thrombocytopenia may be moderately increased in number, cytic leukaemia {2594}. There is no BCR-
is common {339,1621,2517}. Careful mor but are always < 20%; large sheets or ABL1 fusion. Cases with rearrangement
phological examination of the peripheral clusters of blasts are not present. Mar of PDGFRA, PDGFRB or FGFR1, or with
blood is crucial for distinguishing this en row fibrosis (usually mild) is seen in some PCM1―JAK2, are also specifically ex
tity from chronic neutrophilic leukaemia cases at the time of diagnosis; in others, it cluded. In the past, some cases of t(8;9)
{4248}, which lacks dysplastic features in appears later in the course of the disease. (p22;p24) with PCM1―JAK2 fusion were
the neutrophils and has < 10% circulating diagnosed as aCML {436,3337}, but
immature myeloid cells. There are also Variant such cases are now grouped with other
differences in the frequency of associ Most cases reported as the syndrome of eosinophilic neoplasms associated with
ated mutations (see Genetic profile). abnormal chromatin clumping can in fact specific chromosomal rearrangements,
The bone marrow is hypercellular due to be considered a variant of aCML {460, and are discussed separately (see Mye-
an increase of neutrophils and their pre 1178,1766}. These cases are character loid/lymphoid neoplasms with PCM1-
88 Myelodysplastic/myeloproliferative neoplasms
JAK2, p. 78). JAK2 V617F mutation has larger proportion of chronic neutrophilic thrombocytopenia and haemoglobin
only rarely been reported in patients with leukaemia cases {1414,2588,3057,3918}, level < 10 g/dL have been reported to
aCML {1184,2288,4248}; therefore, the it is helpful in distinguishing between the be adverse prognostic findings {447,
typical myeloproliferative neoplasm-as two neoplasms. 1621}. However, patients who receive
sociated mutations (in JAK2, CALR and a bone marrow transplant may have an
MPL) tend to exclude the diagnosis of Prognosis and predictive factors improved outcome {2077}. In 30―40% of
aCML {1184}. Recent data indicate that Patients with aCML fare poorly. Among patients, aCML evolves to acute myeloid
SETBP1 and ETNK1 mutations are rela the small numbers of patients included leukaemia {4248}; most of the remaining
tively common in aCML {1286,2610,2779, in reported series to date, the median patients die of marrow failure {447,2143}.
3167}, whereas CSF3R mutation is pres survival time is 14―29 months {447,1621,
ent in <10% of cases {2779}. Because 2143,4248}. Age > 65 years, female sex,
this mutation is found in a considerably white blood cell count > 50 x 109/L,
Definition as girls. Approximately 15% of cases twins {3093}. The association between
Juvenile myelomonocytic leukaemia occur in infants with Noonan syndrome NF1 and JMML has long been estab
(JMML) is a clonal haematopoietic dis like disorder (which is caused by a CBL lished {581,2872,3804}. In children with
order of childhood characterized by a mutation) {2381}, and 10% occur in chil NF1 (unlike in adults with the disorder),
proliferation principally of the granulo dren with neurofibromatosis type 1 (NF1) the risk of developing myeloid malig
cytic and monocytic lineages. Blasts {2872}. nancy (mainly JMML) is reported to be
and promonocytes account for < 20% 200―500 times that in the general pae
of the white blood cells in the peripheral Etiology diatric population {2872}. Occasionally,
blood and bone marrow. Erythroid and The cause of JMML is unknown. Rare infants with Noonan syndrome develop
megakaryocytic abnormalities are often cases have been reported in identical a JMML―like disorder, which resolves
present {88,507,2662}. BCR-ABL1 fusion
is absent, whereas mutations involving Table 5.03 Diagnostic criteria for juvenile myelomonocytic leukaemia; modified from Locatelli F and Niemeyer CM {2377}
genes of the RAS pathway are character Clinical and haematological criteria (all 4 criteria are required)
istic. The diagnostic criteria are listed in
- Peripheral blood monocyte count ≥ 1 x 109/L
Table 5.03. - Blast percentage in peripheral blood and bone marrow of < 20%
- Splenomegaly
ICD-O code 9946/3 - No Philadelphia (Ph) chromosome or BCR-ABL1 fusion
Genetic criteria (any 1 criterion is sufficient)
Synonym - Somatic mutationa in PTPN11, KRAS or NRAS
Juvenile chronic myelomonocytic - Clinical diagnosis of neurofibromatosis type 1 or NF1 mutation
leukaemia - Germline CBL mutation and loss of heterozygosity of CBLb
Other criteria
Epidemiology Cases that do not meet any of the genetic criteria above must meet the following criteria
The annual incidence of JMML is estima in addition to the clinical and haematological criteria above:
ted to be approximately 0.13 cases per - Monosomy 7 or any other chromosomal abnormality
100 000 children aged 0―14 years. It or
accounts for < 2―3% of all leukaemias - ≥ 2 of the following:
in children, but for 20―30% of all cases - Increased haemoglobin Fforage
of myelodysplastic and myeloprolifera - Myeloid or erythroid precursors on peripheral blood smear
tive diseases in patients aged < 14 years - Granulocyte-macrophage colony-stimulating factor (also called CSF2) hypersensitivity in colony assay
- Hyperphosphorylation of STAT5
{1585,3092}. Patient age at diagnosis
ranges from 1 month to early adoles a If a mutation is found in PTPN11, KRAS or NRAS it is essential to consider that it might be a germline
cence, but 75% of cases occur in chil mutation and the diagnosis of transient abnormal myelopoiesis of Noonan syndrome must be considered.
dren aged < 3 years {2415,2872}. Boys b Occasional cases have heterozygous splice-site mutations.
are affected nearly twice as frequently
Localization
The peripheral blood and bone marrow
always show evidence of myelomono
cytic proliferation. Leukaemic infiltration Fig. 5.09 Juvenile myelomonocytic leukaemia. A The bone marrow aspirate smear usually reflects the changes
of the liver and spleen is found in virtually noted in the blood, but the monocyte component may be difficult to distinguish from other marrow cells in Wright-
all cases. The lymph nodes, skin, respira Giemsa-stained preparations. B Combined alpha-naphthyl butyrate esterase and naphthol AS-D chloroacetate
tory system, and gut are other common esterase (CAE) reaction identifies the granulocytic (blue) and monocytic (brown) components; a few cells contain
sites of involvement, although any tissue both blue and brown reaction products.
can be infiltrated {2415,2872}.
normal karyotype {2872}. Other features cytosis consists mainly of neutrophils,
Clinical features include polyclonal hypergammaglob- with some immature cells (e.g. promye
Most patients present with constitutional ulinaemia and the presence of autoan locytes and myelocytes) and monocytes.
symptoms or evidence of infection {2415, tibodies {2872}. In vitro hypersensitivity Blasts (including promonocytes) usu
2872}. There is generally marked hepato- of JMML myeloid progenitors to granu ally account for < 5% of the white blood
splenomegaly. Occasionally, spleen size locyte―macrophage colony―stimulating cells, and always < 20%. Eosinophilia
is normal at diagnosis but rapidly increas factor (also called CSF2) {1100} is a and basophilia are observed in a minor
es thereafter. About half of all patients hallmark of the disease, and served as ity of cases. Nucleated red blood cells
have lymphadenopathy, and leukaemic an important diagnostic tool before the are often seen. Red blood cell changes
infiltrates may give rise to markedly en discovery of the five canonical RAS path include macrocytosis (particularly in pa
larged tonsils. Dry cough, tachypnoea way mutations (in PTPN11, NRAS, KRAS, tients with monosomy 7), but normocytic
and interstitial infiltrates on chest X―ray NF1 and CBL), which now allow molecu red blood cells are more common; micro
are signs of pulmonary infiltration. Gut lar diagnosis in approximately 85% of cytosis due to iron deficiency or acquired
infiltration may predispose patients to all JMML cases, greatly facilitating the thalassaemia phenotype {1680} may be
diarrhoea and gastrointestinal infections. diagnosis. In RAS pathway mutation seen as well. Platelet counts vary, but
Signs of bleeding are common, and negative cases, disorders with a clinical thrombocytopenia is typical and may be
about a quarter of all patients have skin and haematological picture mimicking severe {2415,2872,3093}.
rashes (eczematous eruptions or indura that of JMML, such as infection {2481}, Bone marrow findings alone are not diag
tions with central clearing). Cafe―au―lait Wiskott―Aldrich syndrome (eczema- nostic. The bone marrow aspirate and bi
spots might be indicative of an underly thrombocytopenia―immunodeficiency opsy are hypercellular with granulocytic
ing germline condition such as NF1 or syndrome) {4436} and malignant infantile proliferation, although in some patients
Noonan syndrome―like disorder {2528, osteopetrosis {3811}, must be excluded. erythroid precursors may predominate
2874}. JMML rarely involves the central {2872,3093}. Monocytes in the bone
nervous system (CNS), although a small Microscopy marrow are often less prominent than in
number of patients with CNS myeloid The peripheral blood is the most impor the peripheral blood, generally account
sarcoma and ocular infiltrates have been tant specimen for diagnosis. It typically ing for 5―10% of the bone marrow cells.
described {2872}. shows leukocytosis and thrombocyto Blasts (including promonocytes) account
A notable feature of many JMML cases penia, and often anaemia {2415,2872}. for < 20% of the bone marrow cells, and
is markedly increased synthesis of hae The median reported white blood cell Auer rods are never present. Dysplasia
moglobin F, particularly in cases with a counts are 25―30 x 109/L. The leuko is usually minimal; however, dysgranu-
Fig. 5.10 Juvenile myelomonocytic leukaemia. Peri Fig. 5.11 Juvenile myelomonocytic leukaemia. A The bone marrow biopsy specimen is hypercellular, with granu
pheral blood smear showing abnormal monocytes with locytic proliferation and a decreased number of megakaryocytes. B Although the megakaryocytes in this specific
cytoplasmic vacuoles and two normoblasts. case are reduced in number, they appear morphologically normal; blasts are not substantially increased in number.
90 Myelodysplastic/myeloproliferative neoplasms
lopoiesis (including pseudo―Pelger―Huët
neutrophils and hypogranularity) may be
noted in some cases, and erythroid pre
cursors may be enlarged. Megakaryo
cytes are often reduced in number, but
marked megakaryocytic dysplasia is
unusual {2872,3093}.
Leukaemic infiltrates are common in the
skin, where myelomonocytic cells infil
trate the papillary and reticular dermis. In
the lung, leukaemic cells spread from the
capillaries of the alveolar septa into al
veoli; in the spleen, they infiltrate the red
pulp and have a predilection for trabecu
lar and central arteries; in the liver, the
sinusoids and portal tracts are infiltrated.
Fig. 5.12 Juvenile myelomonocytic leukaemia (JMML): molecular lesions in RAS signalling proteins. Granulocyte-
macrophage colony-stimulating factor (GM-CSF; also called CSF2) normally binds to its receptor, induces
Cytochemistry heterodimerization, and assembles a complex of signalling molecules and adapters that include SHC1 and GRB2.
No specific cytochemical abnormalities These proteins, in turn, recruit GAB2, SHP2 (encoded by PTPN11) and SOS1, which catalyse guanine nucleotide
have been reported. In bone marrow exchange on RAS and increase intracellular levels of GTP-bound RAS (RAS-GTP). Once activated, RAS-GTP
aspirate smears, cytochemical staining interacts with several downstream effectors. The GTPase-activating protein RASA1 (also called p120GAP) and
for alpha―naphthyl acetate esterase or neurofibromin bind to RAS-GTP and accelerate its conversion to RAS-GDP. Hypersensitivity to GM-CSF is a
cellular hallmark of JMML that results from a number of distinct mechanisms. Mutations in PTPN11 increase SHP2
alpha―naphthyl butyrate esterase, alone
phosphatase activity and increase RAS signalling. Similarly, cancer-associated amino acid substitutions in KRAS
or in combination with staining for naph- and NRAS result in mutant RAS proteins that accumulate in the active, GTP-bound conformation. Inactivation of
thol AS―D chloroacetate esterase (CAE), the NF1 tumour suppressor gene deregulates RAS signalling through loss of neurofibromin (reviewed by Niemeyer
may be helpful in identifying the mono CM {2871}). Finally, CBL acts as a GM-CSF receptor responsive protein that targets SRC for ubiquitin-mediated
cytic component. Neutrophil alkaline destruction upon GM-CSF stimulation. Loss of negative regulation by SRC results in hyperactive GM-CSF {497}.
phosphatase scores are reported to be Modified from Niemeyer CM {2871}.
elevated in about 50% of cases, but this
test is not helpful in establishing the diag aberrant signal transduction of the RAS the normal NF1 allele in leukaemic cells
nosis {2415}. signalling pathway. As many as 85% of is associated with RAS hyperactivity.
patients harbour driving molecular al Despite the central role of RAS pathway
Immunophenotype teration in one of five particular genes mutation, a small subset (approximately
No specific immunophenotypic abnor cPTPN11, NRAS, KRAS, CBL and NF1), 15%) of cases remain RAS pathway mu
malities have been reported in JMML. which encode proteins that when mu tation negative {3484,3801}. JMML is
In extramedullary tissues, the monocytic tated are predicted to activate RAS ef characterized by a paucity of additional
component is best identified using immu- fector pathways. Heterozygous somatic genetic abnormalities {3484}. Secondary
nohistochemical techniques that detect gain-of-function mutations in PTPN11 are abnormalities (in addition to the canoni
lysozyme and CD68R. However, individ the most frequent alterations, occurring cal RAS pathway mutation) are present in
ual cases may show infiltration almost ex in approximately 35% of patients {2382, fewer than half of all cases, and include
clusively by MPO―positive granulopoietic 3906}. Typical oncogenic heterozygous second hits in one of the other RAS path
precursor cells. Flow cytometry, which somatic NRAS and KRAS mutations in way genes (so―called RAS double mu
enables simultaneous analysis of cell codons 12, 13, and 61 account for 20― tants) as well as mutations in SETBP1,
phenotype and cell signalling, shows that 25% of JMML cases {3484,3801,3906}. JAK3, SFI2B3, the genes of the poly
JMML cells exhibit an aberrant response Approximately 15% of children with JMML comb repressor complex, and ASXL1
of phospho―STAT5A to subsaturating harbour germline CBL mutations {2874, {587,3484,3801}. Secondary mutations
doses of granulocyte―macrophage colo 3131}, commonly missense alterations are often subclonal and may be involved
ny―stimulating factor {1578,2090}. in the linker region or ring finger domain in disease progression rather than initia
(exons 8 and 9), with JMML cells showing tion of leukaemia {587,3484,3802}.
Cell of origin duplication of the mutant CBL through
A haematopoietic stem cell acquired uniparental disomy {587,2381, Genetic susceptibility
2788}. Occasionally, heterozygous ger The RASopathies constitute a class of
Genetic profile mline splice―site CBL mutations are not autosomal dominant developmental dis
Karyotyping studies reveal monosomy 7 ed in CBL-associated JMML {2381,2528, orders caused by germline mutations in
in about 25% of patients, other abnormal 3817}. Germline mutations in NF1 are genes that encode components of the
ities in 10% and a normal karyotype in present in approximately 10% of children RAS pathway. These disorders’ major
65% {2872}. The Philadelphia (Ph) chro with JMML {587,2872,3484}. Because features include facial dysmorphism,
mosome and the BCR―ABL1 fusion gene the NF1 gene product (neurofibromin) cardiac defects, reduced growth, vari
are absent. is a negative modulator of RAS function, able cognitive deficits, ectodermal and
JMML occurs, at least in part, due to loss of heterozygosity (LOH) with loss of skeletal anomalies, and susceptibility to
malignancies (including JMML) {2102, heart defects, and a variety of abnormali haemoglobin F levels at diagnosis are the
2871,3316}. ties in other organs. Heterozygous ger main clinical predictors of short survival
NF1, the first syndrome found to be as mline mutations in PTPN11, SOS1, RAF1, {2872,3093}.
sociated with a germline mutation in KRAS, NRAS and other components of JMML with KRAS or NRAS mutation gen
the RAS pathway, can manifest in early the RAS pathway {811} are recognized, erally has an aggressive course, with
childhood with cafe-au-lait spots, JMML, with PTPN11 mutations accounting for early haematopoietic stem cell trans
plexiform neurofibromas, optic pathway about half of the cases {3317}. As many plantation needed. In a few infants with
tumours, and bone lesions {3314}. In as 10% of children with Noonan syn KRAS or NRAS alterations, long―term
children with NF1, the risk of developing drome develop a transient myelopro survival in the absence of therapy has
JMML is estimated to be 200―350 times liferative disorder in early infancy {217, been observed; these children had low
the risk in children without the syndrome 2871}. The vast majority of patients with haemoglobin F levels, normal or moder
{3804}. For about half of the patients with Noonan syndrome/myeloproliferative ately decreased platelet counts, and no
JMML and NF1, a positive family history disorder harbour germline PTPN11 mu subclonal mutations {2377,3801}. There
is known. In most affected children, the tations predicted to result in a weaker are similarities between JMML with KRAS
clinical diagnosis of NF1 can be made gain-of-function effect than the somatic or NRAS mutation and RAS―associated
at the time of leukaemic presentation; PTPN11 mutations found in children with autoimmune leukoproliferative disorder
JMML may be the first manifestation of JMML {2103}. The abnormal myelopoie- (RALD) {530}. JMML and RALD show
NF1 in some of these infants {3801}. Pa sis in Noonan syndrome/myeloprolifera overlapping clinical and laboratory fea
tients with Noonan syndrome―like disor tive disorder is benign in most infants, tures (with the exception of the leukope
der exhibit a variable Noonan syndrome but about 10% of these children acquire nia seen in RALD). However, long―term
like phenotype, with a high frequency clonal chromosomal abnormalities and follow―up suggests that RALD has an in
of neurological features and pigmented develop JMML {217,2871}. dolent clinical course, unlike most cases
skin lesions {2528,2874,3817}. Suscepti of JMML with RAS mutations {530}.
bility for JMML in children with germline Prognosis and predictive factors Most children with JMML and germline
CBL mutation is high, although the small JMML with somatic PTPN11 mutation CBL mutations experience spontaneous
number of patients precludes more pre or occurring in children with NF1 is in regression of JMML with persistence of
cise risk estimation {2528}. variably rapidly fatal if left untreated. The uniparental disomy of the CBL locus in
Noonan syndrome is the most common median survival time without allogeneic haematopoietic cells. Occasionally, sec
RASopathy, with an incidence of 1 case haematopoietic stem cell transplantation ondary genetic alterations occur that re
per 1000―2500 births {3317}. It is char is about 1 year. Low platelet count, pa sult in an aggressive clinical course.
acterized by a typical facial appearance, tient age > 2 years at diagnosis and high
92 Myeiodysplastic/myeloproliferative neoplasms
Myelodysplastic / myeloproliferative Orazi A.
Hasserjian R.P.
neoplasm with ring sideroblasts and Cazzola M.
Thiele J.
thrombocytosis Malcovati L.
Definition Table 5.04 Diagnostic criteria for myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis
Myelodysplastic/myeloproliferative neo - Anaemia associated with erythroid-lineage dysplasia, with or without multilineage dysplasia;
plasm (MDS/MPN) with ring sideroblasts ≥15% ring sideroblastsa, < 1% blasts in the peripheral blood and < 5% blasts in the bone marrow
and thrombocytosis (MDS/MPN―RS―T) - Persistent thrombocytosis, with platelet count ≥ 450 x 109/L
is a subtype of MDS/MPN character
- SF3B1 mutation or, in the absence of SF3B1 mutation, no history of recent cytotoxic or growth factor therapy
ized by the presence of thrombocytosis that could explain the myelodysplastic/myeloproliferative featuresb
(≥ 450 x 109/L) and < 1% blasts in the
- No BCR-ABL1 fusion; no rearrangement of PDGFRA, PDGFRB or FGFR1; no PCM1-JAK2
peripheral blood and associated with and no t(3;3)(q21.3;q26.2), inv(3)(q21.3q26.2), or del(5q)c
ring sideroblasts accounting for ≥15%
- No history of myeloproliferative neoplasm, myelodysplastic syndrome (except myelodysplastic syndrome
of erythroblasts, dyserythropoiesis and with ring sideroblasts), or other myelodysplastic/myeloproliferative neoplasm
< 5% blasts in the bone marrow (1499,
1890,3104,3862}. a ≥15% ring sideroblasts is a required criterion even if SF3B1 mutation is detected.
In the original 4th edition of the WHO b The diagnosis of myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis is
classification, refractory anaemia with strongly supported by the presence of SF3B1 mutation together with a JAK2 V617F, CALR or MPL mutation.
ring sideroblasts associated with marked c In a case that otherwise meets the diagnostic criteria for myelodysplastic syndrome with isolated del(5q).
thrombocytosis (RARS―T) was proposed
as a provisional entity to encompass
cases with the clinical and morpho tions. By convention, these cases would Clinical features
logical features of myelodysplastic syn be considered to constitute disease pro The clinical features of MDS/MPN―RS―T
drome with ring sideroblasts (MDS―RS) gression of MDS, and would therefore be greatly overlap those seen in MDS―RS
but also with thrombocytosis associated excluded from the MDS/MPN category and the BCR―ABL1―negative MPN cat
with abnormal megakaryocytes similar to (see Table 5.04); however, given the lack egories, in particular essential thrombo-
those seen in BCR―ABL1―negative my of prognostic difference, it might be most cythaemia. Anaemia is always present,
eloproliferative neoplasms {1499,1890}. appropriate to group these cases with but at the time of clinical presentation, pa
More recently, MDS/MPN―RS-T has the rest of the cases of MDS/MPN-RS- tients with MDS/MPN-RS-T tend to have
become a well―characterized, distinct T. Therapy―related cases with features higher haemoglobin levels, white blood
MDS/MPN overlap entity, particularly of MDS/MPN―RS―T are diagnosed as cell (WBC) counts, and platelet counts
following the discovery of a strong asso therapy―related myeloid neoplasms and than do patients with MDS-RS, with simi
ciation with SF3B1 mutations, which are are discussed separately (see Therapy- lar mean corpuscular volumes. In con
often concurrent with the JAK2 V617F related myeloid neoplasms, p. 153). trast, patients with MDS/MPN-RS-T have
mutation and less commonly with MPL lower haemoglobin levels, WBC counts,
or CALR mutation (409,594,1310,2461, ICD-O code 9982/3 and platelet counts, but higher mean cor
2464,3103,3339,3344,3569,3575,3773, puscular volumes than do patients with
3862,4249}. Synonym essential thrombocythaemia {463}.
Cases that fulfil the diagnostic criteria for Refractory anaemia with ring sideroblasts
MDS with isolated del(5q) or that have associated with marked thrombocytosis Microscopy
t(3;3)(q21.3;q26.2) or inv(3)(q21.3;q26.2) The peripheral blood typically shows
cytogenetic abnormalities are excluded Epidemiology normochromic macrocytic or normo―
from this category, as are cases with a A median patient age at the time of dia cytic anaemia. The red blood cells in
BCR-ABL1 fusion gene. If there has been gnosis of 74 years has been reported, the blood smear may show anisocytosis,
a prior diagnosis of an MPN without ring which is higher than that observed in often with a dimorphic pattern. Circulat
sideroblasts, or if there is evidence that MPN such as essential thrombocythae- ing blasts are absent or rare (accounting
the ring sideroblasts might be a conse mia. A slight female prevalence has been for < 1% of the cells). Thrombocytosis
quence of therapy or might reflect dis consistently reported across studies (≥ 450 x 109/L) is one of the defining fea
ease progression of a case that meets {462,463}. tures. The platelets often display anisocy
the criteria for another well―defined MPN, tosis, ranging from tiny forms to atypical
this designation should not be used. It is Localization large or giant platelets. Bizarrely shaped
unclear how to best categorize the rare The peripheral blood and bone marrow or agranular platelets may be seen, but
cases that initially present as MDS-RS are always involved. Splenomegaly has are uncommon. The WBC count and leu
and later evolve to MDS/MPN-RS-T upon been reported in about 40% of cases, kocyte differential count are usually nor
acquisition of a JAK2 V617F mutation and hepatomegaly can also occur {3861}. mal, although a borderline elevation in
{2461} or other MPN―associated muta the WBC count can occur.
The bone marrow shows increased roblasts. The SF3B1 mutation is often (in MDS/MPN―RS―T is significantly shorter
erythropoiesis due to ineffective eryth > 60% of cases) found in association with than that of patients with essential throm-
roid proliferation, with megaloblastoid the JAK2 V617F mutation, and much less bocythaemia, but longer than that of pa
and/or other dyserythropoietic features of commonly (in < 10% of cases) in associa tients with MDS―RS and single lineage
the erythroid precursors associated with tion with the CALR or MPL W515 muta dysplasia (P < 0.001) {463,4249}.
≥15% ring sideroblasts present on iron tion. The presence of these MPN―asso- Patient age, JAK2 V617F and SF3B1 mu
staining. Multilineage dysplasia, similar ciated mutations may account for the tation have been reported as independ
to that seen in MDS-RS and multilineage proliferative aspects of MDS/MPN―RS-T ent prognostic factors. In one study of
dysplasia, occurs in some cases {3569, and would seem to confirm its true hy MDS/MPN―RS―T, SF3B1 mutation was
3570}. Megakaryocytes are increased brid nature {2461,2464,3103,3570,4202}. associated with a significantly longer
and usually have morphological features Therefore, although studies for SF3B1, median overall survival (6.9 years with
similar to those observed in the BCR- JAK2 V617F, CALR and MPL W515 muta SF3B1 mutation vs 3.3 years with SF3B1
ABL1-negative MPN. A proportion of pa tions are not required for the diagnosis of wildtype, P= 0.003); JAK2M617F muta
tients have marrow fibrosis {3569,3570}. MDS/MPN―RS―T, the presence of these tion was also associated with a more fa
mutations supports the diagnosis and vourable outcome compared with JAK2
Cell of origin appears to have prognostic significance. wildtype (P= 0.019) {462}.
A haematopoietic stem cell The existing scientific literature does not
Prognosis and predictive factors support any therapy specific for patients
Genetic profile A median overall survival of 76―128 with MDS/MPN―RS-T; the treatments
Cytogenetic abnormalities have been re months has been reported in patients available for MDS and MPN are typically
ported in about 10% of patients {2461}. with MDS/MPN―RS―T {462,463}. A ret adopted for these patients, depending
Many cases (60―90%) harbour the rospective study including a total of on the clinical picture {2460}.
SF3B1 mutation {2460}. The mutant al 200 cases from 16 centres in six Europe
lele burden is comparable to that seen an countries showed that sex― and age―
in other WHO categories with ring side standardized survival in patients with
94 Myelodysplastic/myeloproliferative neoplasms
Myelodysplastic / myeloproliferative Orazi A.
Bennett J.M.
Thiele J.
Bueso-Ramos C.
neoplasm, unclassifiable Bain B.J.
Baumann i.
Malcovati L.
Genetic profile
There are no cytogenetic or molecular
genetic findings specific for this group.
The Philadelphia (Ph) chromosome
and the BCR―ABL1 fusion gene should
always be excluded prior to making the
diagnosis of MDS/MPN-U. Cases with re
arrangements of PDGFRA, PDGFRB, or
FGFR1 or with PCM1-JAK2, are excluded
from this category as well.
The appropriate categorization of cases
associated with isolated isochromo
some 17q is uncertain. A proportion of
cases meet the criteria for chronic myelo
monocytic leukaemia, BCR―ABL1―nega
tive atypical chronic myeloid leukaemia,
MPN in accelerated or blast phase, MDS
or acute myeloid leukaemia, but other
cases may be appropriately categorized
as MDS/MPN―U {1220,1912,2594}.
Relatively high frequencies of TET2,
NRAS, RUNX1, CBL, SETBP1 and ASXL1
mutations have been reported in several Fig. 5.15 Myelodysplastic/myeloproliferative neoplasm, unclassifiable. A case associated with isolated isochromo
studies {2610,4248,4502}. In diagnosti some 17q. A Bone marrow core biopsy showing hypercellularity with increased dysplastic megakaryocytes and
cally difficult cases, the presence of one increased immature cells. B Bone marrow aspirate smear showing increased blasts and dysplastic granulocytes
or more of these mutations in the appro with pseudo-Pelger-Huët nuclei (Wright-Giemsa). C Bone marrow aspirate showing dysplastic non-lobated mega
karyocytes (Wright-Giemsa).
priate clinicopathological context may
help to confirm a suspected diagnosis.
SF3B1 mutation should prompt careful tation be classified as MDS with isolated had a median overall survival of 21.8
exclusion of MDS/MPN―RS―T, includ del(5q) rather than included in the MDS/ months and leukaemia―free survival of
ing rare instances of disease progres MPN―U category. 18.9 months {4248}. Prognosis is vari
sion from MDS with ring sideroblasts. Cases with MDS/MPN features that har able, with its uncertainty further com
Although cases that meet the criteria for bour one of the types of driver mutations pounded by inadequate representation
MDS with isolated del(5q) are excluded, seen in classic MPN (i.e. JAK2, MPL or of the subgroup in commonly used prog
a small proportion of such cases with a CALR mutations) most likely constitute nostic scoring systems, including the
combined del(5q) and JAK2 V617F muta MPN with features of disease progres International Prognostic Scoring System
tion have been reported to have prolifera sion. However, if a chronic phase has not (IPSS) and Revised IPSS (IPSS-R) {4011}.
tive features in the bone marrow associ been previously detected or cannot be As with other MDS/MPN overlap disor
ated with higher median platelet counts documented and therefore the underly ders, the treatment for patients with MDS/
{1759}. However, it is unclear whether ing MPN cannot be confirmed, then the MPN―U is based on therapies used for
their clinical presentation or progno designation of MDS/MPN―U is justified. MDS or MPN and is guided by symptoms
sis is any different from that of the MDS and/or cytopenias {4011}. Growth factors
with isolated del(5q) and wildtype JAK2 Prognosis and predictive factors (erythropoiesis- and granulopoiesis-stim
{3101,3717}. Until more evidence is pub There is very limited information avail ulating agents) can alleviate cytopenias,
lished, it is recommended that cases with able about this rare subgroup. In a re whereas leukocytosis can be managed
combined del(5q) and JAK2 V617F mu cent study, patients with MDS/MPN―U with cytoreductive therapies.
96 Myelodysplastic/myeloproliferative neoplasms
ﻧﻌﻢ راﺑﻄﺔأﻃﺒﺎء
اﻟﺒﺎﺛﻮﻟﻮﺟﻴﺎ ﻟﻘﺎﻧﻮن
اﻟﻤﻌﺎﻣﻞ
اﻟﺠﺪﻳـﺪ اﻹﻛﻠﻴﻨﻴﻜﻴﺔ
واﻟﻜﻴﻤﻴﺎﺋﻴﺔ
Special Edition
CHAPTER
Myelodysplastic Syndromes 97
Overview 98
MDS with single lineage dysplasia 106
MDS with ring sideroblasts 109
MDS with multilineage dysplasia 111
MDS with excess blasts 113
MDS with excess blasts and erythroid predominance 114
MDS with excess blasts and fibrosis 114
MDS with isolated del(5q) 115
MDS, unclassifiable 116
Childhood MDS 116
Refractory cytopenia of childhood 117
Myelodysplastic syndromes: Hasserjian R.P.
Orazi A.
Baumann I.
Hellstrom-
Overview Brunning R.D.
Germing U.
Lindberg E,
List A.F.
Le Beau M.M. Cazzola M.
Porwit A. Foucar K.
Definition
The myelodysplastic syndromes (MDS)
are a group of clonal haematopoietic
stem cell diseases characterized by cy
topenia, dysplasia in one or more of the
major myeloid lineages, ineffective hae-
matopoiesis, recurrent genetic abnor
malities and increased risk of developing
acute myeloid leukaemia (AML) {340,
592,4151}. There is an increased degree
of apoptosis within the bone marrow pro
genitors, which contributes to the cyto-
penias {439}. Cytopenia in at least one
haematopoietic lineage is required for a
diagnosis of MDS. The recommended The morphological hallmark of MDS is the number of cytopenias at presentation,
thresholds for cytopenias established dysplasia in one or more myeloid line the number of myeloid lineages manifest
in the original International Prognostic ages. Dysplasia may be accompanied by ing dysplasia, the presence of ring side-
Scoring System (IPSS) for risk stratifica an increase in myeloblasts in the periph roblasts, and the blast percentages in
tion (haemoglobin concentration < 10 g/ eral blood and/or bone marrow, but the the blood and bone marrow. In the cur
dL, platelet count < 100 x 109/L, and blast percentage is always < 20%, which rent classification, only one cytogenetic
absolute neutrophil count < 1.8 x 109/L is the requisite threshold recommended abnormality, del(5q), is used in the defini
{1442,1442A}), have traditionally been for the diagnosis of AML. It is important tion of a specific MDS subtype. Mutation
used to define cytopenias for MDS di to recognize that the threshold of 20% of one gene, SF3B1, is closely associ
agnosis and most MDS patients will blasts distinguishing AML from MDS ated with MDS with ring sideroblasts as
have a cytopenia below at least one of does not reflect a therapeutic mandate well as with one of the MDS/MPN sub-
these thresholds. However, a diagnosis to treat cases with ≥ 20% blasts as acute types: MDS/MPN with ring sideroblasts
of MDS may still be made in patients leukaemia. Recurrent cytogenetic abnor and thrombocytosis.
with milder degrees of anaemia (haemo malities are present in 40―50% of cases, Although progression to AML is the nat
globin < 13 g/dL in men or < 12 g/dL in whereas acquired somatic gene muta ural course in many cases of MDS, the
w omen) or thrombocytopenia (platelets tions are seen in the vast majority of MDS percentage of patients who progress
< 150 x 109/L) if definitive morphologic cases at diagnosis. varies substantially across the subtypes,
and/or cytogenetic findings are present The MDS category encompasses several with a higher probability of progression
{1444A,4179}. In determining whether distinct subtypes, which are defined by in subtypes with increased myeloblasts
a patient is cytopenic, it is important to
be cognizant of each laboratory’s lower
reference range and to take into account
conditional variants of these values, such
as due to ethnicity and sex. These are
particularly important considerations in
patients with a borderline low neutro
phil count {229}. Persistent neutrophilia,
monocytosis, erythrocytosis or thrombo
cytosis in a patient with cytopenias and
dysplastic morphology generally war
rants classification as a myelodysplastic/
myeloproliferative neoplasm (MDS/MPN)
or myeloproliferative neoplasm rather
than MDS. However, thrombocytosis
(platelet count ≥ 450 x 109/L) is allowed
in MDS with isolated del(5q) or with inv(3) Fig. 6.03 Antifolate chemotherapy effect. Bone marrow smear from a 57-year-old woman who received several
(q21.3q26.2) or t(3;3)(q21.3;q26.2). chemotherapeutic agents for breast carcinoma, including folic acid antagonists, showing transient marked
dyserythropoiesis and megaloblastic changes.
98 Myelodysplastic syndromes
ricultural chemicals or solvents, and fam in ~13% of MDS cases) appear to have
ily history of haematopoietic neoplasms more aggressive disease {89}. The blast
{3815}. Some inherited haematological count in myeloid neoplasms is expressed
disorders, such as Fanconi anaemia, as a percentage of all nucleated cells (al
dyskeratosis congenita, Shwachman―Di― ways including nucleated erythroid cells)
amond syndrome and Diamond―Black― in the bone marrow and as a percentage
fan anaemia, are also associated with of the leukocytes (excluding nucleated
an increased risk of MDS; familial syn erythroid cells) in the peripheral blood.
dromes predisposing to MDS and AML The number of dysplastic lineages (i.e.
are discussed separately (see Myeloid single lineage vs multilineage dysplasia)
neoplasms with germline predisposition, is relevant for distinguishing between the
p. 121). Acquired aplastic anaemia is also types of MDS (see Table 6.01, p. 101) and
associated with increased risk of devel may be important for predicting disease
{1340,2467}. Most subtypes are charac opment of MDS {222}. behaviour {947,4179}. Assessment of the
terized by progressive bone marrow fail degree of dysplasia may be problematic,
ure, but the biological course of some Clinical features depending on the quality of the smear
subtypes is prolonged and indolent, with The majority of patients present with preparations and the stain. Poor―quality
a very low incidence of evolution to AML symptoms related to cytopenia. Most pa smears may result in misinterpretation of
{2462,4179}. tients are anaemic, whereas neutropenia the presence or absence of dysplasia,
and/or thrombocytopenia are less com particularly in assessing neutrophil gran
Epidemiology mon; about one third of patients are de ulation. Given the critical importance of
MDS occurs principally in older adults pendent on red blood cell transfusions at recognizing dysplasia, the need for high-
(median patient age: 70 years), with a diagnosis {1444,2511}. Organomegaly is quality slide preparations for the diagno
male predominance. The annual inci infrequently observed. sis of MDS cannot be overemphasized.
dence is 3―5 cases per 100 000 popu Slides for the assessment of dysplasia
lation overall (non―age―corrected) and is Microscopy should be made from freshly obtained
at least 20 cases per 100 000 individuals The morphological classification of MDS specimens; specimens exposed to anti
aged > 70 years. Due to underreporting is principally based on the percentage of coagulants for > 2 hours are unsatisfac
of MDS in most cancer registries, the blasts in the bone marrow and peripheral tory. It should be noted that the determi
true annual incidence in patients aged blood, the type and degree of dysplasia, nation of whether significant dysplasia
> 65 years may be closer to 75 cases per and the percentage of ring sideroblasts is present (particularly in the erythroid
100 000 population {199,777,1342}. Ap (Table 6.01, p. 101). The myeloid lineages lineage) and the distinction between sin
proximately 10 000 new cases of MDS are affected by cytopenias are not necessar gle lineage and multilineage dysplasia
diagnosed annually in the USA, accord ily those that manifest dysplasia {1338, have been found in some studies to be
ing to 2003―2004 data from the Surveil 2423,4179}. To determine blast percent subject to significant interobserver vari
lance, Epidemiology, and End Results age in the bone marrow and blood, a ability {1233,3622}. This interobserver
(SEER) Program and the North American 500―cell differential count of all nucleated variability is more problematic for cases
Association of Central Cancer Regis cells in a smear or trephine biopsy imprint in which the degree of dysplasia is near
tries (NAACCR), but estimates based on is recommended for the bone marrow the requisite 10% threshold, and some
Medicare claims for the same time period and a 200―leukocyte differential count for authors have reported individual lineage
are as high as 45 000 cases diagnosed the peripheral blood. In patients with se dysplasia exceeding the 10% threshold
in individuals aged > 65 years annually vere cytopenia, buffy coat smears of pe in non―cytopenic controls {947,3067,
{1394,2421,3397}. Therapy―related mye ripheral blood may facilitate the differen 3297}; consequently, it is essential to
loid neoplasms are discussed separately tial count. An accurate blast count in the apply strict criteria for dysplasia and to
(see Therapy-related myeloid neoplasms, peripheral blood is important, because evaluate high―quality and well―stained
p. 153). MDS affecting children is rare and patients with higher blast percentages in material.
has unique characteristics and diagnos the blood than in the bone marrow (seen
tic criteria that differ from those of MDS
in adults; therefore, childhood cases are
also discussed separately (p. 116).
Etiology
Primary or de novo MDS occurs without a
known history of chemotherapy or radia
tion exposure. Possible etiologies for pri
mary MDS include benzene exposure (at
levels well above the minimum allowed
by most government agencies), cigarette
smoking (at least in part also due to ben Fig. 6.05 Granulocyte colony-stimulating factor (G-CSF) therapy effect. A Blood smear from a patient on G-CSF,
zene in cigarette smoke), exposure to ag showing a neutrophil with a bilobed nucleus and increased azurophilic granulation and a myeloblast (B).
Characteristics of dysplasia
Dyserythropoiesis manifests principally
as nuclear alterations, including budding,
internuclear bridging, karyorrhexis and
multinuclearity. Megaloblastoid changes
are often present in MDS, but alone they
are insufficiently specific to firmly estab
lish dyserythropoiesis. Cytoplasmic
features include formation of ring side
roblasts, vacuolization and aberrant pe
As a general precaution, no patient nosed with MDS either; this condition has riodic acid―Schiff (PAS) positivity (either
should be diagnosed with MDS if the been termed ‘clonal haematopoiesis of diffuse or granular). Dysgranulopoiesis
clinical and drug history is unknown, indeterminate potential’ {3772}. is characterized primarily by nuclear hy-
and no case of MDS should be reclassi Cases of MDS without an increase in posegmentation (pseudo―Pelger―Huët
fied while the patient is on growth factor blasts are recognized as manifesting ei anomaly) or hypersegmentation, cyto
therapy, including erythropoietin. Certain ther single lineage dysplasia or multilin plasmic hypogranularity, pseudo―Ché-
drugs, infections, metabolic deficiencies eage dysplasia. In most cases of MDS diak-Higashi granules and small size
and immune disorders can cause both with single lineage dysplasia, the dyspla {1387}. Megakaryocyte dysplasia is
cytopenias and morphological dyspla sia is confined to the erythroid lineage. characterized by micromegakaryocytes,
sia; these possible secondary etiolo Single lineage dysplasia can also affect non-lobated nuclei in megakaryocytes
gies must be carefully considered prior the granulocytic lineage or megakaryo of all sizes, and multiple widely sepa
to rendering a diagnosis of MDS (see cytes, but this is much less common rated nuclei {1388}; however, the finding
Differential diagnosis). Unexplained, than dysplasia isolated to erythroid cells of multiple widely separated nuclei is of
persistent cytopenia in the absence of {450,2423}. In MDS with multilineage limited specificity for MDS, unless the
dysplasia should not be interpreted as dysplasia, significant dysplastic features nuclei are rounded and roughly similar in
MDS unless certain specific cytogenetic are recognized in two or more lineages. size. Megakaryocytic dysplasia is read
abnormalities are present (see Genetic The recommended requisite percent ily apparent in bone marrow sections,
profile below and Table 6.03, p. 104). age of erythroid and granulocytic cells and both biopsy and aspirate specimens
Persistent cytopenia without dysplasia manifesting dysplasia to be considered should be evaluated. The morphological
and without one of the specific cytoge significant is ≥ 10% {3404}. Significant manifestations of dysplasia in each line
netic abnormalities should be diagnosed megakaryocyte dysplasia is defined as age are summarized in Table 6.02. Auer
as idiopathic cytopenia of undetermined ≥ 10% dysplastic megakaryocytes based rods are considered to be evidence of
significance, and the patient’s haemato- on evaluation of ≥ 30 megakaryocytes in MDS with excess blasts regardless of
logical and cytogenetic status should be smears or sections; however, some stud the blast percentage. Cases of MDS with
carefully monitored {4106,4336}. Patients ies suggest that a 30―40% threshold for < 5% blasts in the bone marrow and < 1%
with MDS―associated clonal gene muta megakaryocyte dysplasia may provide in the peripheral blood may rarely have
tions identified in haematopoietic cells greater specificity {947,1309,2567}. Mi Auer rods, and such cases are associ
but without significant dysplasia on bone cromegakaryocytes and multinucleated ated with an adverse prognosis {4328}.
marrow examination should not be diag megakaryocytes with separated nuclei
MDS-MLD 2―3 1―3 < 15% / < 5% b BM < 5%, Any, unless fulfils all criteria for
PB < 1%, MDS with isolated del(5q)
no Auer rods
MDS-RS
MDS-RS-SLD 1 1―2 ≥ 15% / ≥ 5% b BM < 5%, Any, unless fulfils all criteria for
PB < 1%, MDS with isolated del(5q)
no Auer rods
2―3 1―3 ≥ 15% / ≥ 5% b BM < 5%, Any, unless fulfils all criteria for
MDS-RS-MLD
PB < 1%, MDS with isolated del(5q)
no Auer rods
MDS with isolated del(5q) 1―3 1―2 None or any BM < 5%, del(5q) alone or with
PB < 1%, 1 additional abnormality, except
no Auer rods loss of chromosome 7 or del(7q)
MDS-EB
MDS-EB-1 1―3 1-3 None or any BM 5-9% or PB 2―4%, Any
BM < 10% and PB < 5%,
no Auer rods
MDS-EB-2 1―3 1―3 None or any BM 10-19% or PB 5-19% Any
or Auer rods,
BM and PB < 20%
MDS-U
with 1% blood blasts 1―3 1―3 None or any BM < 5%, Any
PB = 1% c,
no Auer rods
with SLD and pancytopenia 1 3 None or any BM < 5%, Any
PB < 1%,
no Auer rods
based on defining 0 1―3 < 15% d BM < 5%, MDS-defining abnormality e
cytogenetic abnormality PB < 1%,
no Auer rods
MDS-EB, MDS with excess blasts; MDS-MLD, MDS with multilineage dysplasia; MDS-RS, MDS with ring sideroblasts; MDS-RS-MLD, MDS with ring sideroblasts and
multilineage dysplasia; MDS-RS-SLD, MDS with ring sideroblasts and single lineage dysplasia; MDS-SLD, MDS with single lineage dysplasia; MDS-U,
MDS, unclassifiable; SLD, single lineage dysplasia.
a Cytopenias defined as haemoglobin concentration < 10 g/dL, platelet count < 100 x 109/L and absolute neutrophil count < 1.8 x 109/L, although
MDS can present with mild anaemia or thrombocytopenia above these levels; PB monocytes must be < 1 x 109/L.
b If SF3B1 mutation is present.
c 1% PB blasts must be recorded on ≥ 2 separate occasions.
d Cases with ≥ 15% ring sideroblasts by definition have significant erythroid dysplasia and are classified as MDS-RS-SLD.
e See Table 6.03, p. 104.
Differential diagnosis and other factors can also cause myelo tation causes ring sideroblast formation.
A major difficulty in the diagnosis of MDS dysplastic changes in any of the haema The antibiotic cotrimoxazole and the im
is the determination of whether the pres topoietic lineages. These factors include munosuppressants tacrolimus and my-
ence of morphological dysplasia and vitamin B12 and folic acid deficiency, cophenolate mofetil can cause marked
cytopenia is due to a clonal disorder or essential element deficiencies (such as neutrophil hyposegmentation, often in
is the result of another factor. Dysplasia, copper deficiency), exposure to heavy distinguishable from the changes seen in
even if prominent, is not in itself defini metals (in particular arsenic, lead and MDS. In some patients on multiple drugs
tive evidence of a clonal process. Some toxic levels of zinc) and exposure to sev or with multiple comorbidities, it may be
dysplastic features, such as micromega eral commonly used drugs and biologi difficult to identify the cause of dysplastic
karyocytes, are strongly associated with cal agents {439}. Isoniazole treatment in changes {1991,3867}. Dysplastic chang
MDS {947}, but several nutritional, toxic the absence of vitamin B6 supplemen es can also be encountered in otherwise
Immunophenotype
The immunophenotypic abnormalities
that have been described in MDS hae
matopoietic cells compared with normal
haematopoiesis are abnormal quantity
and aberrant phenotypes of progenitor
cells; aberrant immunophenotypic pro
files of maturing granulocytic, erythroid
and monocytic cells; and a decrease
of haematogones {63,1856,2555,2935,
3895}. Abnormal myeloid maturation
patterns include asynchrony of CD15
in some cases of aplastic anaemia) are and CD16 on granulocytes; altered ex screening panels have also been applied
helpful in this distinction {342,945,947}. pression of CD13 in relation to CD11b or {4,259,945,1856,2933,3287}, but may
MDS―associated somatic mutations have CD16; and aberrant expression of CD56 be less sensitive and less specific than
been reported to occur in as many as one and/or CD7 on progenitors, granulocytes larger panels.
third of patients with aplastic anaemia or monocytes. Decreased side―scatter of
{4440}. Immunosuppressive therapies granulocytes can also be seen. In eryth Cell of origin
used to treat aplastic anaemia have been roid cells, an increased coefficient of vari The postulated cell of origin is a haema
used with some degree of success in this ation and decreased intensity of CD71 or topoietic stem cell.
MDS subgroup {439,2334,3698,4447, CD36 expression are highly associated
4448}. When considering the diagnosis with MDS {2563}. There is generally good Genetic profile
of hypoplastic MDS, it is important to ex correlation between the percentage of Cytogenetic studies play a major role in
clude acute marrow injury due to a toxin, blasts as determined by morphological the evaluation of patients with MDS in re
infection or an autoimmune disorder. examination of the bone marrow aspi gard to prognosis, determination of clon-
rate smear or touch imprint, immunohis- ality {1442,3551,2971} and recognition of
Myelodysplastic syndrome with fibrosis tochemistry of the bone marrow biopsy cytogenetic correlates with morphological
Significant degrees of myelofibrosis (i.e. section and flow cytometry (CD34+ cells) and clinical features. MDS with isolated
corresponding to grade 2 or 3 of the {1994}. However, in some cases there del(5q), i.e. either with a del(5q) alone or
WHO grading scheme) {3975} are ob may be significant discordance due to with one additional abnormality other than
served in 10―15% of MDS cases, and marrow fibrosis or haemodiluted sam loss of chromosome 7 or del(7q), is a spe
these cases have been referred to as ples; therefore, percentages of CD34+ cific MDS subtype in this classification. It
MDS with fibrosis (MDS―F) {2201}. Sig cells as determined by flow cytometry occurs more often in women and is char
nificant fibrosis does not define a spe cannot replace the morphological differ acterized by megakaryocytes with non-lo-
cific MDS subtype in this classification. ential count. Nevertheless, the finding of bated or hypolobated nuclei, macrocytic
However, many of the cases with fibrosis CD34+ myeloid progenitors accounting anaemia, normal or increased platelet
have an excess of blasts, and significant for > 2% of nucleated cells has been re count, and a favourable clinical course.
fibrosis is associated with an aggressive ported to be of adverse prognostic sig Loss of 17p is associated with MDS or
clinical course in MDS, independent of nificance in MDS {2555A.2556}. AML with pseudo―Pelger―Huët anomaly,
the blast count {942,1261}. MDS―F cases Flow cytometry findings alone are not small vacuolated neutrophils, TP53 muta
with excess blasts may erroneously be sufficient to establish a primary diagnosis tion and an unfavourable clinical course;
diagnosed as low―grade MDS based of MDS in the absence of definitive mor it is most common in therapy―related MDS
only on the blast count determined from phological and/or cytogenetic findings. A {2187}. Complex karyotypes (≥ 3 abnor
the bone marrow aspirate, which is usu series of consensus guidelines has been malities) typically include abnormalities of
ally diluted with peripheral blood. In this published by the European LeukemiaNet chromosomes 5 and/or 7, such as del(5q),
fibrotic group, as in other cases of MDS (ELN) MDS working group regarding the loss of 5q, loss of chromosome 7 and
with inadequate aspirates, accurate blast use of flow cytometry in the diagnos del(7q); these are generally associated
determination requires a bone marrow bi tic work―up of patients with MDS {3223, with an unfavourable clinical course. Sev
opsy, and immunohistochemical studies 4117,4118,4305}, including a summary of eral other cytogenetic findings appear to
for CD34 may prove invaluable. Unlike the reported aberrations associated with be associated with characteristic morpho
the myeloproliferative neoplasm entity MDS and how to report the results {2463, logical abnormalities; for example, isolat
primary myelofibrosis, MDS―F is usually 3223,4119}. Aberrant findings in at least ed del(20q) is associated with dysmega-
not associated with splenomegaly, leu- three tested features and at least two karyopoiesis and thrombocytopenia, and
koerythroblastosis or intrasinusoidal hae- cell compartments have been reported inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)
matopoiesis and typically exhibits MDS- to be highly associated with an MDS or is associated with abnormal megakaryo
type megakaryocyte morphology (i.e. MDS/MPN diagnosis in several stud cytes and may be associated with throm
micromegakaryocytes), other dysplastic ies {3221,3223,4063,4119}. More limited bocytosis. {446,1500,2142,3392}.
bone marrow blast percentage in all survival prediction in the IPSS-R {1444}. lower―risk cases and at time points after
MDS diagnoses, so that the IPSS―R can Another risk―stratification scheme used the initial diagnosis {2462}.
be applied. Five IPSS―R risk groups are to predict outcome in MDS is the WHO Accumulating data indicate that both
defined, on the basis of the total score Classification―based Prognostic Scoring number and type of individual gene
of the parameters listed in Table 6.06: System (WPSS), which incorporates ad mutations are strongly associated with
very low, low, intermediate, high and very ditional variables of transfusion require disease outcome in MDS. The addi
high. The IPSS-R is significantly better at ment and morphological dysplasia (sin tion of mutation data improves the abil
predicting survival and evolution to AML gle lineage vs multilineage) that are not ity of existing risk―stratification schemes
than the original IPSS {4219}. Consid included in the IPSS―R. The WPSS may such as the IPSS to predict prognosis in
eration of patient age further improves be particularly useful when applied to MDS {311,312}. Many commonly mutated
Fig. 6.12 Myelodysplastic syndrome with fibrosis (MDS-F). A Bone marrow biopsy from a case of MDS with excess blasts and fibrosis shows several micromegakaryocytes.
B Reticulin of a marrow biopsy from a case of MDS with fibrosis reveals a marked increase in reticulin fibres.
Myelodysplastic syndromes
Myelodysplastic syndrome with MDS―SLD was called refractory cytope agnostic conclusion. The defining feature
single lineage dysplasia nia with unilineage dysplasia, and was of this type of MDS is ≥ 10% dysplastic
divided into three subtypes: refractory cells in one myeloid lineage. Cases with
Brunning R.D. Thiele J. anaemia, refractory neutropenia and re erythroid dysplasia only and ≥ 15% ring
Hasserjian R.P. Hellstrom- fractory thrombocytopenia. This subclas sideroblasts (or ≥ 5% ring sideroblasts
Porwit A. Lindberg E. sification has been controversial; some in the presence of SF3B1 mutation) are
Bennett J.M. List A.F. studies have demonstrated no clear cor classified as MDS with ring sideroblasts
Orazi A. relation between lineage cytopenia and and single lineage dysplasia (MDS―RS-
lineage dysplasia and no significant dif SLD). If SF3B1 mutation status is un
ferences in survival between the three known, it is recommended that cases
Definition subtypes {1503,2423,2568,4179}. How with 5―14% ring sideroblasts and single
The category of myelodysplastic syn ever, other studies have found some sur lineage dysplasia be classified as MDS-
drome (MDS) with single lineage dyspla vival differences {449,2511}. Given these SLD. As in the 2008 classification, it is
sia (MDS―SLD) encompasses the MDS conflicting findings and the inconsisten recommended that cases with single
cases that present with unexplained cies between lineage cytopenia and line lineage dysplasia and pancytopenia be
cytopenia or bicytopenia, with ≥10% age dysplasia, we recommend that cas categorized as MDS, unclassifiable.
dysplastic cells in one myeloid lineage. es of MDS presenting with single lineage As noted in the Overview section (p.98),
Most patients present with persistent un cytopenia or bicytopenia and unilineage the recommended thresholds for de
explained anaemia or bicytopenia; some dysplasia be classified as MDS―SLD, fining cytopenias are haemoglobin
present with persistent unexplained neu without additional subclassification. concentration < 10 g/dL, absolute neu
tropenia or thrombocytopenia {2423}. The presenting lineage dysplasia and trophil count < 1.8 x 109/L and plate
In the 2008 edition of this classification, cytopenias(s) should be noted in the di let count < 100 x 109/L, as per the risk
stained aspirate smears, ≥ 15% (or ≥ 5% if Cell of origin roid cells provided an SF3B1 mutation is
SF3B1 mutation has been documented) A haematopoietic stem cell present. Cases of MDS―RS with < 15%
of the red blood cell precursors are ring ring sideroblasts tend to have a lower
sideroblasts, as defined by ≥ 5 iron gran Genetic profile SF3B1 mutant allele burden than do cas
ules encircling one third or more of the Mutation in the spliceosome gene SF3B1 is es with ≥ 15% ring sideroblasts, but they
nucleus {2778}. The bone marrow biopsy frequent in MDS―RS, being present in 80- appear to have a similar prognosis {2466,
specimen is normocellular to markedly hy- 90% of MDS-RS-SLD cases and 30―70% 3099}.
percellular, usually with marked erythroid of MDS-RS-MLD cases {593,2464,3104}. Clonal chromosomal abnormalities are
proliferation. Megakaryocytes are normal Mutations in other splicing factor genes seen in 5―20% of cases of MDS―RS-
in number and morphology. In MDS-RS- (e.g. SRSF2, U2AF1 and ZRSR2) are pres SLD; when present, they typically involve
MLD, in addition to ring sideroblasts and ent in < 10% of MDS―RS cases and are a single chromosome {448,1333,1335}.
erythroid lineage dysplasia, there is signif mutually exclusive with the SF3B1 muta Cytogenetic abnormalities are seen in
icant dysplasia (≥ 10% dysplastic forms) in tion {2464,4433}. Additional mutations in about half of MDS―RS―MLD cases and
one or two non―erythroid lineages. Aside TET2 and DNMT3A, genes affecting DNA more often include high―risk abnorm
from the presence of ring sideroblasts, the methylation, are associated with SF3B1 alities such as loss of chromosome 7
morphological features of MDS―RS―MLD mutation and are more frequent in MDS- {1341,2467,2940}.
are generally similar to those of MDS with RS-MLD than in MDS-RS-SLD {2464}. In
multilineage dysplasia. cases with multiple mutations, SF3B1 mu Prognosis and predictive factors
Ring sideroblasts are often observed tation tends to be present at the highest Approximately 1―2% of cases of MDS-
in other types of MDS and can also be allele burden and is stable during disease RS-SLD evolve to acute myeloid leukae
seen in other myeloid neoplasms, in progression, suggesting that it is an early mia. The reported median overall survival
cluding acute myeloid leukaemia {1333, event in the disease pathogenesis {593, is 69 to 108 months {943,1335}. Overall
1891}. For example, cases of MDS with 1513,2337,4354}. survival is 28 months in MDS―RS―MLD
ring sideroblasts that have excess blasts A diagnosis of MDS―RS can be made if (similar to that in MDS with multilineage
in the peripheral blood or bone marrow ring sideroblasts constitute ≥ 5% of eryth dysplasia), and approximately 8% of cas-
are classified as MDS with excess blasts,
and cases that fulfil the criteria for MDS
with isolated del(5q) should be classified
as such, even if ring sideroblasts and/or
SF3B1 mutation are present.
Non―neoplastic causes of ring sidero
blasts, including alcohol, toxins (e.g. lead
and benzene), drugs (e.g. isoniazid), cop
per deficiency (which may be induced
by zinc administration), and congenital
sideroblastic anaemia must be excluded
{55}. Unlike in MDS―RS, patients with
congenital sideroblastic anaemia tend to
present at a much younger age and with
microcytic (rather than macrocytic) anae
mia {2940}.
Fig. 6.17 Myelodysplastic syndrome with ring sideroblasts (MDS-RS). Survival curves based on long-term follow-up
Immunophenotype of 167 patients with MDS-RS with single lineage dysplasia and ≥15% ring sideroblasts (formerly called refractory
In MDS―RS, aberrant immunophenotypic anaemia with ring sideroblasts, RARS) and 318 patients with MDS-RS with multilineage dysplasia (formerly called
features of erythropoietic precursors may refractory cytopenia with multilineage dysplasia, RCMD) with ≥ 15% ring sideroblasts (RS), showing inferior survival
be found by flow cytometry analysis {944}. of patients with MDS-RS with multilineage dysplasia (P = 0.00005); data from the Dusseldorf MDS registry.
Synonym
Refractory cytopenia with multilineage
dysplasia
Microscopy
Peripheral blood smears frequently show
Fig. 6.21 Myelodysplastic syndrome with isolated del(5q). A Bone marrow section showing numerous megakaryocytes of various sizes, several with non-lobated nuclei. B Bone
marrow aspirate smear showing two megakaryocytes with non-lobated, rounded nuclei.
Fig. 6.24 Aplastic anaemia. Bone marrow biopsy shows Fig. 6.25 Refractory cytopenia of childhood (RCC). A Bone marrow aspirate smear showing abnormal nuclear
adipocytosis of bone marrow spaces; the few scattered segmentation of an erythropoietic precursor cell and a small megakaryocyte with a bilobed nucleus. B Bone marrow
cells are mainly lymphocytes, plasma cells, macrophages, biopsy showing a cluster of proerythroblasts without maturation.
mast cells and occasional mature myeloid cells.
amegakaryocytic thrombocytopenia or megakaryocytes does not rule out refractory cytopenia of childhood.
pancytopenia with radioulnar synostosis)
as well as some DNA repair deficiency
disorders (e.g. LIG4 syndrome) show Table 6.08 Comparison of the morphological criteria for hypoplastic refractory cytopenia of childhood and
morphological features overlapping those aplastic anaemia in children
of RCC {1942,4437,4481}. These entities Refractory cytopenia of childhood Aplastic anaemia in children
must be excluded by medical history,
Bone marrow Bone marrow Bone marrow Bone marrow
physical examination and the appropriate Criterion biopsy aspirate cytology biopsy aspirate cytology
laboratory and molecular studies before
a definite diagnosis of RCC can be made. Erythropoiesis Patchy distribution Nuclear segmentation Absent or single Absent or very
The clinical picture of paroxysmal noctur small focus; few cells, without
Left shift Multinuclearity
< 10 cells with dysplasia or
nal haemoglobinuria is rare in childhood,
Increased mitosis Megaloblastoid maturation megaloblastoid
although paroxysmal nocturnal haemo change
changes
globinuria clones in the absence of hae
molysis or thrombosis may be observed Granulopoiesis Marked decrease Pseudo-Pelger-Huët Absent or Few maturing
in children with RCC {5}. The association anomaly markedly cells, with no
Left shift
between RCC with two or more dysplas decreased, with dysplasia
Agranularity of
very few small foci
tic lineages and MDS with multilineage cytoplasm
with maturation
dysplasia has not been fully investigated Hypogranularity of
{4418}. It is currently recommended that cytoplasm
cases that would otherwise fulfil the cri
Nuclear-cytoplasmic
teria for MDS with multilineage dysplasia
maturation defects
be considered as RCC until further stud
ies clarify whether the number of lineages Megakaryo Marked decrease or Micromegakaryocytes Absent or very Absent or few
involved is an important prognostic dis poiesis aplasia few non-dysplastic non-dysplastic
Multiple separated
criminator in childhood MDS. megakaryocytes megakaryocytes
Dysplastic changes nuclei
Micromegakaryocytes Small round nuclei
Immunophenotype
Micromegakaryocytes can easily be Lymphocytes May be increased May be increased May be increased May be increased
missed in H&E―stained bone marrow focally or dispersed focally or
trephine biopsy sections, but are more dispersed
readily apparent with immunostaining CD34+ No increase No increase
for platelet glycoproteins such as CD61 precursor cells
(also called glycoprotein Ilia), CD41 (also
called glycoprotein llb/llla) or von Wille- KIT+ (CD117+) No increase No increase
brand factor. Myeloblasts are < 5% of precursor cells
the bone marrow cells; detection of ≥ 5% KIT+ (CD117+) Slightly increased Slightly increased
blast cells that are positive for mye mast cells
loperoxidase (MPO), lysozyme, and/or
Definition are generally considered to be rare, but failed stem cell engraftment, poor graft
Myelodysplastic syndromes (MDSs) and as recognition grows, they may be found function, and donor―derived leukaemias.
acute myeloid leukaemia (AML) present to be more common than is currently re Therefore, it is critical to distinguish mye
primarily as sporadic diseases and typi alized. Because the hereditary basis for loid neoplasms that arise as a conse
cally occur in older adults. However, it these neoplasms is only beginning to be quence of germline predisposition from
has become increasingly apparent that understood, it is likely that more disor those that arise spontaneously or are
some cases of myeloid neoplasms, in ders will be identified and that many of secondary to environmental or chemical
particular MDS and AML, occur in asso the currently recognized disorders will exposures.
ciation with inherited or de novo germline become more clearly defined. This chapter discusses the major mye
mutations characterized by specific The recognition and diagnosis of myeloid loid neoplasms with germline predisposi
genetic and clinical findings. The most malignancies that arise from a germline tion. The discussion focuses on myeloid
established of these disorders are those mutation is critical for the proper clinical neoplasms, but lymphoid neoplasms
that occur in the setting of well―defined management and long―term follow-up of and solid tumours also occasionally
inherited syndromes that exhibit add affected individuals. Even if a patient has occur in these same pedigrees, and are
itional non―haematological findings and not developed malignancy, the presence mentioned when relevant. There is in
often present in childhood, such as the of additional organ dysfunction and ab creasing evidence to support germline
bone marrow failure syndromes (includ normalities in platelet number and func mutations with predisposition to lympho
ing Fanconi anaemia) and the telomere tion warrant clinical management. For blastic leukaemia {1734,3134,3630}; this
biology disorders (e.g. dyskeratosis example, patients with germline RUNX1, is discussed in the sections on T- and B-
congenita, see Table 7.01) {2866,3613, ANKRD26, or ETV6 mutations can bleed lymphoblastic leukaemias/ lymphomas.
3800}. However, we have become in out of proportion to their platelet counts The familial myeloid neoplasms included
creasingly aware of additional autosomal and may require anticipatory transfusion in this chapter are categorized into three
dominant disorders with predisposition of normal platelets prior to invasive pro groups (Table 7.01). The first group in
to MDS/AML. Some patients with these cedures or childbirth. Individuals in these cludes myeloid neoplasms associated
disorders initially present with a myeloid families benefit greatly from genetic with germline mutations of CEBPA or
neoplasm, whereas others have a pre counselling from counsellors with train DDX41, with a clinical picture dominat
existing disorder or organ dysfunction. ing in familial haematopoietic disorders. ed by either MDS or AML and with no
Some of the first cases to be described Because the clinical management of pa other significant organ dysfunction or
were AML with germline-mutated CEBPA tients with malignant myeloid disorders pre―existing disorder. The second group
and MDS/AML with germline mutations often involves allogeneic haematopoietic consists of myeloid neoplasms associ
in RUNX1 and a pre―existing familial stem cell transplantation, careful donor ated with germline mutations of RUNX1,
platelet disorder, but the list of these dis selection is critical in these families, to ANKRD26, or ETV6 in which affected pa
orders is expanding (Table 7.01) {854, avoid re―introduction of the deleterious tients have a pre―existing platelet disor
1390,3015,4301}. Myeloid neoplasms mutation. Inadvertent use of affected der. The third category includes myeloid
associated with predisposing mutations donor stem cells has resulted in poor or neoplasms with predisposing mutations
Myeloid neoplasms with germline predisposition and pre-existing platelet disorders 125
Myeloid neoplasms with germ line
predisposition associated with
other organ dysfunction
Myeloid neoplasms with germline
GATA2 mutation
Germline GATA2 gene mutations were
originally identified as four separate
syndromes:
- MonoMAC syndrome, characterized by
monocytopenia and non―tuberculous
mycobacterial infection {1715,4197}
- Dendritic cell, monocyte, B- and NK-
lymphoid (DCML) deficiency with vul
nerability to viral infections {375,977,
1518}
- Familial MDS/AML {1293,1518}
- Emberger syndrome, characterized
by primary lymphoedema, warts
and a predisposition to MDS/AML
{2490,3002}
Severe congenital AD: MDS, AML 21―40% HAXT: Gene sequencing for relevant
neutropenia ELANE, CSF3R, GFI1 neurodevelopmental mutations
AR: G6PC3:
HAX1, G6PC3 cardiac and other
XLR:
WAS
Shwachman-Diamond AR: MDS, AML, ALL 5―24% Preceding isolated Gene sequencing for SBDS
syndrome SBDS neutropenia, mutations
pancreatic insufficiency,
short stature,
skeletal abnormalities
including metaphyseal
dysostosis
Diamond-Blackfan AD: MDS, AML, ALL 5% Small stature, Screening:
anaemia RPS19, RPS17, RPS24, congenital anomalies elevated erythrocyte adenosine
RPL35A, RPL5, RPL11, (e.g. craniofacial, cardiac, deaminase and haemoglobin F
RPS7, RPS26, RPS10 skeletal, genitourinary) Gene sequencing for relevant
XLR: mutations
GATA1
Telomere biology XLR: MDS, AML 2―30% Nail dystrophy, Telomere length measurement by
disorders DKC1 abnormal skin and flow-FISH
including dyskeratosis AD: pigmentation, If abnormal, gene sequencing
congenita and TERT, TERC, TINF2, oral leukoplakia, for relevant mutations
syndromes RTEL1 pulmonary fibrosis,
due to TERC or TERT hepatic fibrosis,
mutation AR: squamous cell carcinoma
NOP10, NHP2, WRAP53,
RTEL1, TERT, CTC1
AD, autosomal dominant; AlL, lymphoblastic leukaemia/lymphoma; AML, acute myeloid leukaemia; AR, autosomal recessive; CMML, cnronic myelomonocytic leukaemia;
MDS, myelodysplastic syndrome; XLR, X-linked recessive.
a Because phenotypes are variable, some cases may show additional features or lack the key features listed.
patients develop MDS with a high risk B cells, and NK cells; lymphoedema; and peak incidence in adolescence. In
of evolution to AML or development of and/or other clinical manifestations of most children with germline GATA2 muta
CMML {3755}. Concurrent ASXL1 mu GATA2 mutation may point to the dia tion, MDS appears to be sporadic, with
tations have been reported in many gnosis. However, some patients with out a family history of myeloid leukaemia
patients with monosomy 7, some of germline GATA2 mutation present with or other GA7A2-related symptoms {4342}.
whom have a germline GATA2 mutation MDS/AML without these clues. In MDS in GATA2-mutant MDS can be heralded by
{514,2656,4303}. MDS/AML develops in children and adolescents, GATA2 muta anaemia, neutropenia, or thrombocy
approximately 70% of affected individu tion accounts for 15% of advanced MDS topenia. Characteristic morphological
als, at a median patient age of 29 years cases and 7% of all MDS cases {4342}. features are bone marrow hypocellu-
{2656}. It is highly prevalent among patients with larity and multilineage dysplasia (most
The clinical history of immunodeficiency monosomy 7, with 37% of such patients prominent in the megakaryocyte line
associated with reduced monocytes, harbouring GATA2 germline mutations, age), including micromegakaryocytes
Myeloid neoplasms with germline predisposition associated with other organ dysfunction 127
and megakaryocytes with separated and these disorders are listed in Table 7.03 spectrum of inherited bone marrow fail
peripheralized nuclear lobes. Increased (p. 127), and the reader is referred to ex ure syndromes are the telomere biology
reticulin fibrosis is also a feature. Flow cellent reviews of this topic {1390,2866, disorders associated with abnormal tel
cytometric immunophenotyping shows 3613,3800}. It should be noted that the omere maintenance and predisposition
abnormal granulocytic maturation, mono phenotypes of these disorders are highly to MDS and AML. Dyskeratosis congen
cytopenia, and reduced numbers of variable; in some cases key findings may ita is a prototypical disorder in this group,
bone marrow NK cells and B cells. Plas be absent, and patients may not be diag with the classic triad of nail dystrophy,
ma cells are present, but are often abnor nosed until adulthood {3658}. The inher abnormal reticular skin pigmentation,
mal (e.g. CD56+). Increased T―cell large ited bone marrow failure syndromes are and oral leukoplakia, and a high risk of
granular lymphocyte populations are a heterogeneous group of disorders in developing MDS/AML. Telomere biology
common {531}. The most common cyto cluding Fanconi anaemia, Shwachman- disorders result from mutations in one
genetic abnormalities are monosomy 7 Diamond syndrome, Diamond-Blackfan of several genes, and inheritance pat
and trisomy 8. Based on the limited num anaemia, and severe congenital neu terns are diverse (Table 7.03, p. 127). The
bers of cases reported in the literature, tropenia {1390,3613}. Although lympho clinical presentations of telomere biology
affected patients appear to have a poor blastic leukaemias have been described disorders are heterogeneous, and not all
prognosis. However, improved clinical in these syndromes, MDS and AML are patients exhibit the classic features. The
outcomes have been reported with hae the most common haematological neo involvement of at least two genes {TERC,
matopoietic stem cell transplantation in plasms {2471}. Patients are typically diag which encodes the telomerase RNA
patients with MDS {4303}. nosed in childhood due to bone marrow components, and TERT, which encodes
failure or systemic manifestations such the telomerase reverse transcriptase
as limb abnormalities in Fanconi anae component) can cause clinical presen
Myeloid neoplasms with germ line mia or pancreatic dysfunction in Shwach tations that completely lack the charac
predisposition associated with man―Diamond syndrome, but some teristic mucocutaneous findings. These
inherited bone failure syndromes cases may not be recognized until adult disorders predispose patients not only to
and telomere biology disorders hood {3658}. One of the classic disorders MDS/AML, but also to a variety of solid
in this group, Fanconi anaemia, lacks the tumours {1390}.
The remaining cases of familial characteristic physical features of short
MDS/AML associated with other organ stature and radial anomalies in about
dysfunction include the well-known clas 25% of cases. Because there is a 600―
sic disorders often diagnosed in child to 800―fold increased risk of MDS/AML,
hood and known as the inherited bone development of a haematological ma
marrow failure syndromes and telomere lignancy may be the presenting feature
biology disorders. The main features of of the disease {4301}. Also within the
Introduction tion of 200 AML cases found an average with a high rate of complete remission
of 13 mutations per case of AML, with and favourable long―term outcome.
Acute myeloid leukaemia with balanced at least 23 recurrent mutations identi
translocations/inversions fied {545}. These discoveries and others ICD-O code 9896/3
The recurrent genetic abnormalities in have identified at least eight distinct cat
acute myeloid leukaemia (AML) are as egories of mutations in AML, which are Synonyms
sociated with distinctive clinicopatho- discussed in more detail in Chapter 1 Acute myeloid leukaemia, t(8;21)
logical features and have prognostic (Introduction and overview of the classi (q22;q22); acute myeloid leukaemia,
significance. Those most commonly fication of the myeloid neoplasms, p. 15). AML1 (CBF―alpha)/ETO; acute mye
identified are balanced abnormalities: The current WHO classification recog loid leukaemia with t(8;21)(q22;q22),
t(8;21)(q22;q22.1), inv(16)(p13.1q22) or nizes AML with mutated NPM1 and RUNX1―RUNX1T1
t(16;16)(p13.1;q22),t(15;17)(q24.1;q21.2), AML with biallelic mutation of CEBPA as
and t(9;11)(p21.3;q23.3) {511,1236,1465, specific AML classification categories Epidemiology
1466,3701}. Most of these structural (entities), and AML with mutated RUNX1 The t(8;21)(q22;q22.1) is found in 1–5%
chromosomal rearrangements create a as a provisional entity. However, many of cases of AML, usually in younger pa
fusion gene encoding a chimeric protein other mutations also occur in AML, and tients and in cases with features of AML
that is required, but usually not sufficient, some that have prognostic significance, with granulocytic maturation.
for leukaemogenesis {3746}. Many of such as FLT3 internal tandem duplication
these disease groups have characteristic (FLT3―ITD) and KIT mutations, may be Clinical features
morphological and immunophenotypic mutated in specific AML types. Tumour manifestations, such as myeloid
features {126}. Many other balanced Next―generation sequencing panels sarcoma, may be present at presenta
translocations and inversions also recur are now available to screen for a large tion. In such cases the initial bone mar
in AML, but are uncommon. Several of number of mutations in AML. Table 8.02 row aspiration may show a low number
these occur more commonly in paedi (p. 146) summarizes the more common of blast cells.
atric patients, and are summarized in gene mutations in AML. It is beyond the
Table 8.01. scope of this classification to discuss Microscopy
AML with t(8;21)(q22;q22.1), AML with each prognostically significant mutation The common morphological features in
inv(16)(p13.1q22) or t(16;16)(p13.1 ;q22), in AML individually, and the significance clude the presence of large blasts with
and acute promyelocytic leukaemia of some mutations is still unclear. Some abundant basophilic cytoplasm, often
with PML-RARA are considered to be combinations of gene mutations (e.g. containing numerous azurophilic gran
acute leukaemias without regard to blast NPM1 mutation and FLT3-ITD in normal- ules and perinuclear clearing (hofs). In
cell count. It is controversial whether all karyotype AML) appear to cluster within many cases, a few blasts show very large
cases with t(9;11)(p21.3;q23.3), t(6;9) certain disease categories {9,545}; the granules (pseudo-Chédiak-Higashi gran
(p23;q34.1), inv(3)(q21.3q26.2), t(3;3) prognostic significance of these muta ules), suggesting abnormal fusion. Auer
(q21.3;q26.2), or t(1;22)(p13.3;q13.1) as tions and combinations of mutations is rods are frequently found and appear as
well as AML with the BCR-ABL1 fusion discussed within the various sections a single long and sharp rod with tapered
should be categorized as AML when the throughout this volume. ends; they may be detected in mature
blast cell count is < 20%. Therapy-related neutrophils. In addition to the large blast
myeloid neoplasms may also have the cells, some smaller blasts, predominant
balanced translocations and inversions Acute myeloid leukaemia ly in the peripheral blood, may be found.
described in this section, but these with t(8;21)(q22;q22.1); Promyelocytes, myelocytes, and mature
should be diagnosed as therapy-related neutrophils with variable dysplasia are
RUNX1―RUNX1T1
myeloid neoplasms, with the associated present in the bone marrow. These cells
genetic abnormality noted. Definition may show abnormal nuclear segmenta
Acute myeloid leukaemia (AML) with tion (e.g. pseudo―Pelger―Huët nuclei)
Acute myeloid leukaemia with t(8;21)(q22;q22.1) resulting in RUNX1- and/or cytoplasmic staining abnormali
gene mutations RUNX1T1 is an AML showing predomi ties, including homogeneous pink cyto
It is now understood that, in addition to nantly neutrophilic maturation. The bone plasm in neutrophils. However, dysplasia
translocations and inversions, gene mu marrow and peripheral blood show large of other cell lines is uncommon; erythro-
tations are also common in AML {9,545, myeloblasts with abundant basophilic blasts and megakaryocytes usually have
1074,3095,3651}. The Cancer Genome cytoplasm, often containing azurophilic normal morphology. A monocytic compo
Atlas (TCGA) Research Network evalua granules. This type of AML is associated nent is usually minimal or absent. Eosino-
phil precursors are frequently increased, is reported in some cases; mast cell infil Immunophenotype
but they do not exhibit the cytological trates may be masked by the acute leu Most cases of AML with t(8;21) display
or cytochemical abnormalities charac kaemia infiltration of the bone marrow at a characteristic immunophenotype, with
teristic of AML with inv(16)(p13.1q22) diagnosis {1868}. Rare cases with a bone a subpopulation of blast cells showing
or t(16;16)(p13.1 ;q22); basophils and/or marrow blast percentage < 20% occur; high―intensity expression of CD34, HLA-
mast cells are sometimes present in ex these should be classified as AML rather DR, MPO, and CD13, but relatively weak
cess. Concurrent systemic mastocytosis than myelodysplastic syndrome. expression of CD33 {2002,3224}. There
Epidemiology
Either inv(16)(p13.1q22) or t(16;16)
(p13.1;q22) is found in 5–8% of younger
patients with AML; the frequency is lower
in older adults.
Clinical features
Myeloid sarcoma may be present at
initial diagnosis or at relapse and may
are usually signs of neutrophilic differen More than 70% of cases show additional constitute the only evidence of relapse
tiation, with subpopulations of cells show chromosome abnormalities, such as loss in some patients. The white blood cell
ing neutrophilic maturation demonstrated of a sex chromosome or del(9q) with loss count at diagnosis is significantly higher
by CD15 and/or CD65 expression. Pop of 9q22. KIT mutations occur in 20–30% in AML with inv(16)(p13.1q22) or t(16;16)
ulations of blasts showing maturation of cases {3078}. Secondary cooperating (p13.1;q22) than in cases with t(8;21)
asynchrony (e.g. coexpressing CD34 mutations of KRAS or NRAS are com (q22;q22.1) {2502,3559}.
and CD15) are sometimes present. mon, occurring in 30% of paediatric and
These leukaemias frequently express the 10―20% of adult CBF―associated leu Microscopy
lymphoid markers CD19 and PAX5, and kaemias {1392,3077}. ASXL1 mutations In AML with inv(16)(p13.1q22) or t(16;16)
may express cytoplasmic CD79a {1738, occur in approximately 10% of patients, (p13.1;q22), in addition to the usual
2034,3996}. In t(8;21) AML, PAX5 is not mostly adults; ASXL2 mutations occur in morphological features of acute myelo-
directly activated by RUNX1―RUNX1T1, 20―25% of patients of all ages {2657}. monocytic leukaemia, the bone marrow
but expression requires constitutive shows a variable number of eosinophils
MAPK signalling {3322}. Some cases Prognosis and predictive factors (usually increased, but sometimes < 5%)
are TdT―positive, but TdT expression is AML with t(8;21)(q22;q22.1) is usually at all stages of maturation, without sig
generally weak. CD56 is expressed in a associated with a high rate of complete nificant maturation arrest. The most strik
fraction of cases and may have adverse remission and long―term disease―free ing abnormalities involve the immature
prognostic significance {221,1777}. The survival when treated with intensive con eosinophilic granules, mainly evident
adverse prognostic significance of CD56 solidation therapy (e.g. high―dose cytara- at the late promyelocyte and myelocyte
may be due to higher CD56 expression in bine) {393,1466}. Some factors appear to stages. The abnormalities are usually
cases with KIT mutations {894}. adversely affect prognosis, including the not present at later stages of eosinophil
presence of KIT mutations in adults and maturation. The eosinophilic granules are
Postulated normal counterpart CD56 expression {221,3078}. Therapeu often larger than those normally present
A haematopoietic progenitor cell with the tic trials investigating mutant KIT in this in immature eosinophils, are purple―violet
potential to differentiate along granulo AML type are under way. in colour, and in some cells are so dense
cytic and monocytic lineages that they obscure the cell morphology.
The mature eosinophils occasionally
Genetic profile Acute myeloid leukaemia with show nuclear hyposegmentation. Auer
The genes for both heterodimeric com inv(16)(p13.1q22) or t(16;16) rods may be observed in myeloblasts.
ponents of core―binding factor (CBF), Neutrophils in the bone marrow are usu
(p13.1;q22); CBFB―MYH11
RUNX1 (also called AML1 and CBFA) ally sparse, with a decreased number of
and CBFB, are involved in rearrange Definition
ments associated with acute leukaemias Acute myeloid leukaemia (AML) with
{3746}. The t(8;21)(q22;q22.1) involves inv(16)(p13.1 q22) or t(16;16)(p13.1;q22)
RUNX1, which encodes the alpha subunit resulting in CBFB-MYH11 is an AML that
of CBF, and RUNX1T1 (ETO) {1032,2321, usually shows monocytic and granulo
3149}. The RUNX1-RUNX1T1 fusion tran cytic differentiation and characteristically
script is consistently detected in patients an abnormal eosinophil component in
with t(8;21)(q22;q22.1) AML. The CBF the bone marrow {2236,2513,3746}.
transcription factor is essential for hae-
matopoiesis; transformation by RUNX1- ICD-O code 9871/3
RUNX1T1 likely results from transcrip
tional repression of normal RUNX1 target Synonyms
genes via aberrant recruitment of nuclear Acute myeloid leukaemia, t(16;16)
transcriptional co―repressor complexes. (p13;q11); acute myeloid leukaemia,
mature neutrophils. The peripheral blood granulocytic lineage (positive for CD13, tions are suboptimal. Therefore FISH and
is not different from that in other cases CD33, CD15, CD65, and MPO) and the RT―PCR methods may be necessary at
of acute myelomonocytic leukaemia; eo monocytic lineage (positive for CD14, diagnosis to document the genetic al
sinophils are not usually increased, but CD4, CD11b, CD11c, CD64, CD36, and teration. Secondary cytogenetic abnor
an occasional case has been reported lysozyme). Maturation asynchrony is malities occur in approximately 40% of
with abnormal and increased eosinophils often seen. Coexpression of CD2 with cases, with gains of chromosomes 22
in the peripheral blood. Most cases with myeloid markers has been frequently and 8 (each occurring in 10―15% of cas
inv(16)(p13.1q22) have abnormal eosino documented, but it is not specific for this es), del(7q), and gain of chromosome 21
phils, but in some cases they are rare diagnosis. (in ~ 5% of cases) most commonly ob
and difficult to find. Occasional cases served {2502}. Trisomy 22 is fairly spe
with this genetic abnormality lack eosino- Postulated normal counterpart cific for inv(16)(p13.1q22) cases, being
philia, show only granulocytic matura A haematopoietic progenitor cell with the rarely detected with other primary aber
tion without a monocytic component, or potential to differentiate along granulo rations in AML, whereas gain of chromo
show only monocytic differentiation. In cytic and monocytic lineages some 8 is commonly seen in patients with
some cases, the blast percentage is at other primary aberrations. Rare cases
the 20% threshold or occasionally lower. Genetic profile of AML and chronic myeloid leukaemia
Cases with inv(16)(p13.1q22) or t(16;16) The inv(16)(p13.1q22) found in the vast with both inv(16)(p13.1q22) and t(9;22)
(p13.1;q22) and < 20% bone marrow majority of this subtype and the less (q34.1;q11.2) have been reported, and
blasts should be diagnosed as AML. common t(16;16)(p13.1;q22) both result this finding in chronic myeloid leukaemia
in the fusion of CBFB at 16q22 to MYH11 is usually associated with the accelerat
Cytochemistry at 16p13.1 {3650}. MYH11 codes for a ed or blast phase of the disease {4379}.
The naphthol AS―D chloroacetate ester smooth muscle myosin heavy chain {871}. Secondary gene mutations are very com
ase (CAE) reaction, which is normally CBFB codes for the beta subunit of core mon in this AML type; present in > 90% of
negative in eosinophils, is characteristi binding factor (CBFB), a heterodimeric cases. Mutations of KIT (most commonly
cally faintly positive in the abnormal eosin transcription factor known to bind the en in exons 8 and 17) occur in 30―40% of
ophils. Such a reaction is not seen in eo hancers of the T―cell receptor, cytokine cases {3078}. Mutations of NRAS (in 45%
sinophils of AML with t(8;21)(q22;q22.1). genes, and other genes. The CBFB subu of cases), KRAS (in 13%), and FLT3 (in
At least 3% of the blasts show MPO re nit heterodimerizes with RUNX1 (CBFA2), 14%) have also been reported {3076}.
activity. The monoblasts and promono the gene product of RUNX1, which is one ASXL2 mutations, although common in
cytes usually show non―specific esterase of the genes involved in AML with t(8;21) AML with t(8;21), are uncommon in AML
reactivity, although it may be weaker than (q22;q22.1). Occasionally, cytological with inv(16) or t(16;16) {2657}.
expected or even absent in some cases. features of AML with abnormal eosino
phils may be present without karyotypic Prognosis and predictive factors
Immunophenotype evidence of a chromosome 16 abnor Like AML with t(8;21)(q22;q22.1),
Most of these leukaemias are charac mality, but with CBFB―MYH11 neverthe AML with inv(16)(p13.1q22) or t(16;16)
terized by a complex immunopheno less demonstrated by molecular genetic (p13.1;q22) is associated with a high rate
type, with the presence of multiple blast studies {2775,3432}. By conventional of complete remission and favourable
populations: immature blasts with high cytogenetic analysis, inv(16)(p13.1 q22) overall survival when treated with inten
CD34 and KIT (CD117) expression and is a subtle rearrangement that may be sive consolidation therapy (e.g. high-
populations differentiating towards the overlooked when metaphase prepara dose cytarabine) {1466,2772}.
Clinical features
Both hypergranular and microgranular
APL are frequently associated with dis
seminated intravascular coagulation and
increased fibrinolysis {454,3519}. Co
Fig. 8.05 Acute promyelocytic leukaemia. A Hypergranular type; in bone marrow smear, there are several abnormal
agulopathy is associated with significant
promyelocytes, with intense azurophilic granulation; bundles of numerous Auer rods are seen in some of the
early death rates in APL patients {3282}. promyelocytes. B Microgranular variant; in peripheral blood smear, there are several abnormal promyelocytes with
In microgranular APL, unlike hypergranu lobed, almost cerebriform nuclei; the cytoplasm contains numerous small azurophilic granules; other cells appear
sparsely granular.
Epidemiology
The t(1;22)(p13.3;q13.1) is an uncommon
abnormality in AML, occurring in < 1%
of all cases. It occurs most commonly
in infants without trisomy 21 (Down syn
drome), with a female predominance.
Some cases are congenital {232}. Fig. 8.13 Acute myeloid leukaemia (megakaryoblastic) with t(1;22)(p13.3;q13.1). A Bone marrow section from
a 3.5-month-old child shows extensive replacement of marrow by blast cells in areas arranged into clusters and
aggregates surrounded by fibrotic stroma. B Bone marrow smear contains a heteromorphic population of blasts.
Clinical features C High magnification of the specimen shows blasts without differentiating features.
Most of the balanced translocations and
inversions discussed in this chapter are medium-sized to large blasts (12―18 pm) Immunophenotype
more common in adult AML than in pae with a round, slightly irregular, or indent The megakaryoblasts express one or
diatric cases. However, AML with t(1;22) ed nucleus with fine reticular chromatin more of the platelet glycoproteins: CD41
(p13.3;q13.1) is a de novo AML restrict and 1―3 nucleoli. The cytoplasm is ba (glycoprotein llb/llla), CD61 (glycopro
ed to infants and young children (aged sophilic, often agranular, and may show tein IlIa), and CD42b (glycoprotein lb).
≤ 3 years), with most cases occurring in distinct blebs or pseudopod formation. The myeloid―associated markers CD13
the first 6 months of life (median patient Micromegakaryocytes are common, but and CD33 may also be positive. CD34,
age: 4 months). The vast majority of cas dysplastic features of granulocytic and CD45, and HLA―DR are often negative;
es present with marked organomegaly, erythroid cells are not usually present. CD36 is characteristically positive but not
most commonly hepatosplenomegaly. The bone marrow is usually normocel- specific. Blasts are negative with MPO
Patients also have anaemia and usually lular to hypercellular, with reticulin and antibodies. Lymphoid markers and TdT
have thrombocytopenia and a moderate collagenous fibrosis usually present. Due are not expressed. Cytoplasmic expres
ly elevated white blood cell count. to the often dense fibrosis, the pattern of sion of CD41 or CD61 is more specific
bone marrow infiltration may mimic that of and sensitive than is surface staining.
Microscopy a metastatic tumour {357,567}. The pres
The peripheral blood and bone marrow ence of fibrosis may cause difficulties in Postulated normal counterpart
blasts of AML with t(1;22)(p13.3;q13.1) establishing the presence of ≥ 20% blast A myeloid progenitor cell with predomi
are similar to those of acute megakaryo cells in the bone marrow based on the nant megakaryocytic differentiation
blastic leukaemia (one of the subtypes aspirate; correlation with bone marrow
of AML, NOS). Small and large mega- biopsy findings may be crucial. Genetic profile
karyoblasts may be present and they Cases should show karyotypic evidence
may be admixed with more morpholog Cytochemistry of t(1;22)(p13.3;q13.1) or molecular ge
ically undifferentiated blast cells with Cytochemical staining for Sudan Black B netic evidence of RBM15―MKL1 fusion.
a high N:C ratio, resembling lympho and MPO is consistently negative in the In most cases, t(1;22)(p13.3;q13.1) is the
blasts. The megakaryoblasts are usually megakaryoblasts. sole karyotypic abnormality. This translo
Synonym
Acute myeloid leukaemia with cytoplas
mic nucleophosmin Fig. 8.14 Acute myeloid leukaemia with mutated NPM1 and myelomonocytic features. A Bone marrow biopsy shows
complete replacement by large blasts with abundant cytoplasm and folded nuclei. B and C Leukaemic cells are
Epidemiology CD34-negative (B) and show aberrant cytoplasmic expression of NPM1 (C). D Expression of nucleolin (also called
C23) is restricted to the nucleus.
NPM1 mutation is one of the most com
mon recurrent genetic lesions in AML both acute myelomonocytic and acute mia. Multilineage dysplasia, as seen in
{470,1075,1149,1150,3958,4185}, and is monocytic leukaemia and NPM1 mu many cases of AML with myelodyspla
relatively specific for AML; it occurs in tation {1149,1150}; notably, 80–90% sia―related changes (AML-MRC), is ob
2―8% of childhood cases and 27―35% of acute monocytic leukaemias show served in almost a quarter of cases of
of adult cases overall, as well as in NPM1 mutation. However, NPM1 muta de novo AML with mutated NPM1. These
45―64% of adult cases with a normal kar tions are also detected in AML with and cases usually have a normal karyotype,
yotype {470,590,749,1149,3958,4185}. without maturation and in pure erythroid and the blast cells are CD34―negative.
There is a female predominance. leukaemia. The bone marrow is usually markedly hy-
The diagnosis relies on the identifica percellular. In the setting of NPM1 muta
Clinical features tion of the genetic lesion by molecular tion, this type of dysplasia does not result
Patients with AML with mutated NPM1 techniques and/or immunohistochemical in a worse prognosis, and its presence
often have anaemia and thrombocyto detection in paraffin sections of aberrant does not eliminate a diagnosis of AML
penia, and often have higher white blood cytoplasmic expression of NPM1 {1150}. with mutated NPM1 {975,1145}.
cell and platelet counts than seen with Immunostaining with anti-NPM1 antibod
other AML types {1075}. Cases may show ies reveals involvement of two or more Immunophenotype
extramedullary involvement; the most fre bone marrow lineages (myeloid, mono AML with mutated NPM1 is character
quently affected sites are gingiva, lymph cytic, erythroid, megakaryocytic) in the ized by high CD33 expression and vari
nodes, and skin. vast majority of cases {3083}. The vari able (often low) CD13 expression. KIT
ability of bone marrow cell types show (CD117), CD123, and CD110 expres
Microscopy ing NPM1 mutation accounts for the wide sion are common {2889}. HLA―DR is
There is a strong association between morphological spectrum of this leukae often negative. Two major subgroups of
Fig. 8.15 Multilineage involvement in acute myeloid leukaemia with mutated NPM1. A Bone marrow biopsy shows massive replacement by myeloid blasts with maturation; there
are also megakaryocytes and occasional immature erythroid cells (arrow). B Bone marrow biopsy of a minimally differentiated case shows occasional immature glycophorin-
positive erythroid cells. C Myeloid blasts and immature erythroid cells (arrow) show cytoplasmic expression of NPM1.
Clinical features
AML with biallelic mutation of CEBPA
tends to be associated with higher hae
moglobin levels, lower platelet counts,
and lower lactate dehydrogenase levels
than does CEBPA―wildtype AML {1052,
1705,3908}. It may also be associated
with a lower frequency of lymphadenopa-
thy and myeloid sarcoma {372,1260}. The
diagnosis of AML with biallelic mutation
of CEBPA (especially in younger patients)
should raise concern and prompt inves
tigation for the possibility of a germline
mutation with predisposition to develop
AML (see Myeloid neoplasms with germ-
line predisposition, p. 121).
Microscopy
AML with biallelic mutation of CEBPA has
no distinctive morphological features, but
the vast majority of cases have features
of AML either with or without maturation
{1052,1429,1668}.
Multilineage dysplasia is reportedly pres
ent in 26% of cases of de novo AML with
mutated CEBPA (similar to in AML with
mutated NPM1), with no adverse prog
nostic significance {211}. Therefore, in
the setting of biallelic CEBPA mutations,
this type of dysplasia no longer excludes
a case from this category.
Immunophenotype
In earlier studies that did not distinguish
between single and double mutations in
CEBPA, leukaemic blasts were reported
to usually express one or more of the
myeloid―associated antigens (CD13,
CD33, CD65, CD11b, and CD15). There
was usually expression of HLA―DR and
CD34 by most blasts. CD7 was present
in 50–73% of cases, whereas expression
of CD56 or other lymphoid antigens was
uncommon {372,1776,2341}. In contrast,
cases with biallelic mutation of CEBPA
are reported to have a higher frequency
of HLA―DR, CD7, and CD15 expression
and a lower frequency of CD56 expres
sion than are cases with a single mutation
{1705,2341}. Monocytic markers such as
CD14 and CD64 are usually absent.
KIT mutation inv(16)(p13.1q22)/t(16;16)(p13.1;q22) In most studies, no significant difference in Rl {523A}, RFS {408A}, PFS {1876A}, EFS
{408A}, or OS {408A,523A,1876A,3076,3095} between patients with and without KIT
mutation, or in EFS {2016A} or OS {2016A} between patients with and without KIT mutation
in exon 17 at codon D816
In single studies, shorter RFS {3076} for patients with KIT mutation (especially in exon 8),
higher RR {564A} for patients with exon 8 KIT mutation, and higher CIR and shorter OS
{3078} for patients with exon 17 KIT mutation than for patients with wildtype KIT
In paediatric studies, no significant difference in CRR {3207A}, DFS {3207A}, EFS {3653A},
RR {3207A,3653A}, or OS {3207A.3653A} between patients with and without KIT mutation
FLT3-ITD Normal karyotype Significantly shorter DFS {372,4307A,4307C}, CRD {345A,1259A}, and OS
{345A,372,1259A,4307C} for patients with FLT3-ITD than for patients without FLT3-ITD
No significant difference in CRR between patients with and without FLT3-ITD
{345A,372,4307A,4307C}
FLT3-ITD with no expression Normal karyotype Significantly shorter DFS and OS for patients with FLT3-ITD and no expression of
of wildtype FLT3 wildtype FLT3 than for patients without FLT3-ITD {4307A}
FLT3-ITD Various abnormal and normal Among younger patients (aged < 60 years), significantly shorter OS for patients with
karyotypes combined FLT3-ITD than for patients without FLT3-ITD {3095}
FLT3-ITD mutant level Various abnormal and normal Increasingly worse RR and OS (but not CRR) with increasing FLT3-ITD mutant level (i.e.
karyotypes combined the proportion of total FLT3 alleles accounted for by FLT3-ITD) in a comparison of mutant
levels in 4 subsets of patients: without FLT3-ITD, with low (1–24%) FLT3-ITD mutant level,
with intermediate (25–50%) mutant level, and with high (> 50%) mutant level {1278}
Biallelic CEBPA mutation Normal karyotype Significantly higher CRR {3908} and DFS {1705} and longer RFS {3908}, EFS {3908},
and OS {1052,1705,3908} for patients with double CEBPA mutation than for patients with
wildtype CEBPA
Biallelic CEBPA mutation Various abnormal and normal Significantly longer DFS {1705,3022}, EFS {4368}, and OS {1429,1705,3022,4368} for
karyotypes combined patients with double CEBPA mutation than for patients with wildtype CEBPA or
single CEBPA mutation
Single CEBPA mutation Normal karyotype Significantly lower CRR {3908} and shorter DFS {1705} and OS {1705} for patients with
single CEBPA mutation than for patients with double CEBPA mutation
NPM1 mutation Normal karyotype In some studies, significantly higher CRR {3577} and longer DFS {3958}, RFS {1075}, and
EFS {3577} for patients with NPM1 mutation than for patients with wildtype NPMT, in other
studies, no significant difference in CRR {258A,408C}, RFS {258A,408C,3577}, or EFS
{258A,408C} between patients with and without NPM1 mutation
No consistently observed significant difference in OS between patients with and
without NPM1 mutation {258A,408C,1075,3577,3958}
Among older patients (aged ≥ 60 years), significantly better CRR, DFS, and OS for patients
with NPM1 mutation than for patients with wildtype NPM1 {310}
NPM1 mutation & FLT3-ITD Normal karyotype Significantly better CRR {3560}, EFS {3577}, RFS {1075,3560}, DFS {3958}, and OS
{1075,3560,3577,3958} for patients with NPM1 mutation without FLT3-ITD than for patients
with NPM1 mutation and FLT3-ITD or with wildtype NPM1 with or without FLT3-ITD
RUNX1 mutation Normal karyotype Significantly lower CRR {2627}; higher resistant disease rate {1274}; and shorter DFS
{2627,3897}, EFS {1274,2627,3576}, and OS {2627,3576,3897} for patients with RUNX1
mutation than for patients with wildtype RUNX1
RUNX1 mutation Non-complex karyotype (i.e. 1 Significantly shorter EFS and OS for patients with RUNX1 mutation than for patients with
or 2 abnormalities and a normal wildtype RUNX1 {3576}
karyotype combined)
KMT2A-PTD Normal karyotype No difference in CRR, DFS, or OS between patients with and without KMT2A-PTD,
either among younger patients (aged < 60 years) receiving intensive treatment including
autologous stem cell transplantation {4307D} or among older patients (aged ≥ 60 years)
{4307B}
In earlier studies, significantly worse CRD (but not CRR or OS) {526A,1075A} and
higher RR or risk of death during CR {3560} for patients with KMT2A-PJD than for patients
without KMT2A-P TD
KMT2A-PTD Various abnormal and normal Among younger patients (aged < 60 years), significantly shorter OS for patients with
karyotypes combined KMT2A-PTD than for patients without KMT2A-PTD {3095}
WT1 mutation Normal karyotype Significantly lower CRR {4197A}; higher resistant disease rates {4197A}, RR {3343B}, and
CIR {4197A}; and shorter DFS {3078A}, RFS {4197A}, EFS {2104B}, and OS {3078A} for
patients with WT1 mutation than for patients with wildtype WT1
Among younger patients (aged ≤ 60 years), significantly worse CRR, RFS, and OS for
patients with WT1 mutation and FLT3-ITD than for patients with WT1 mutation
without FLT3-ITD {1274B}
In studies in Europe {1668B} and the USA {1646A}, significantly worse CRR {1668B}, EFS
{1646A,1668B}, and OS {1646A,1668B} for paediatric patients with WT1 mutation than for
those with wildtype WT1] in a Japanese study {3513A}, no significant difference in
DFS or OS
WT1 mutation Various abnormal and normal Significantly worse RR and OS for patients with WT1 mutation than for patients with
karyotypes combined wildtype WT1 {3343B}; no significant difference in EFS {2104B}
In studies in Europe {1668B} and the USA {1646A}, significantly worse resistant disease
rates {1668B}, CIR {1668B}, EFS {1646A.1668B}, and OS {1646A,1668B} for paediatric
patients with WT1 mutation than for those with wildtype WT1\ in a Japanese study {3513A},
no significant difference in DFS or OS
TET2 mutation Normal karyotype No significant difference in CRR {864A,1274A,2648C}, DFS {2648C}, RFS {864A.1274A},
EFS {1274A,2648C}, or OS {864A,1274A,2648C,4290A} between patients with and without
TET2 mutation
Significantly worse CRR {2648C}, DFS {2648C}, RR {4290A}, EFS {2648C,4290A}, and OS
{2648C} for patients with TET2 mutations classified in the ELN favourable genetic groupc
(but not those in the intermediate-l groupc) than for patients with wildtype TET2\ one study
{1274A}, reported higher CRR for younger patients (aged ≤ 60 years) with TET2 mutations
classified in the ELN intermediate-l genetic groupc (but not those in the favourable groupc)
than for those with wildtype TET2
Significantly worse RR {4290A}, EFS {4290A}, and OS {3998A} for patients with TET2 and
NPM1 mutation without FLT3-ITD than for patients with wildtype TET2; similarly, TET2
mutation was associated with shorter RFS and OS in younger patients (aged ≤ 60 years)
with FIT3-ITD {864A} and with shorter OS in patients with NPM1 mutation {3998A}
TET2 mutation Various abnormal and normal Among younger patients (aged ≤ 60 years), no significant difference in CRR, RFS, EFS,
karyotypes combined or OS between patients with and without TET2 mutation {1274A}
ASXL1 mutation Normal karyotype Significantly worse CRR {2648A}, DFS {2648A}, EFS {2648A,3576A}, and OS
{2648A,3576A} for patients with ASXL1 mutation than for patients with wildtype ASXL1
Among older patients (aged ≥ 60 years), significantly worse CRR, DFS, EFS, and OS for
patients with ASXL1 mutation classified in the ELN favourable genetic groupc (but not those
in the intermediate-l genetic groupc) than for patients with wildtype ASXL1 {2648A}
ASXL1 mutation Various abnormal and normal Significantly worse CRR {748A,3079,3232A}, RFS {3079}, and OS {748A,3079,
karyotypes combined 3095,3232A} for patients with ASXL1 mutation than for patients with wildtype ASXL1
ASXL1 mutation Intermediate-risk karyotypeb Significantly shorter EFS and OS for patients with ASXL1 mutation than for patients with
wildtype ASXL1 {3576A}
DNMT3A R882 mutation Normal karyotype Among older patients (aged ≥ 60 years), significantly shorter DFS and OS for patients with
DNMT3A R882 mutation than for patients with wildtype DNMT3A {2501E}
Non-R882 DNMT3A mutation Normal karyotype Among younger patients (aged < 60 years), significantly shorter DFS for patients with
non-R882 DNMT3A mutation than for patients with wildtype DNMT3A {2501E}
DNMT3A mutation Various abnormal and normal Among younger patients (aged ≤ 60 years), significantly higher CRR but no significant
karyotypes combined difference in RFS, EFS, or OS for patients with DNMT3A mutation (R882 and non-R882
combined) than for patients with wildtype DNMT3A {1274C}
IDH1 mutation Normal karyotype No significant difference in CRR {408B,2501D}, DFS {2501D}, RR {408B}, or OS {408B,2501D}
between patients with IDH1 mutation and patients with wildtype IDH1 and IDH2
IDH1 R132 mutation Normal karyotype Among patients with NPM1 mutation without FLT3-ITD, significantly shorter DFS for patients
with IDH1 R132 mutation than for patients with wildtype IDH1 and IDH2 {2501D}
Among patients with NPM1 or CEBPA mutation without F/.73-ITD, significantly higher RR and
shorter OS for patients with IDH1 R132 mutation than for patients with wildtype IDH1 {408B}
IDH2 mutation Normal karyotype No significant difference in CRR, RFS, or OS between patients with and without IDH2 mutation
(mostly R140); this was also true in a subset of patients with NPM1 mutation without
FLT3- ITD {3987B}
IDH2 R172 mutation Normal karyotype Significantly worse CRR {408B,2501D}, RR {408B}, and OS {408B} for patients with IDH2 R172
mutation than for patients with wildtype IDH2
IDH2 R140 mutation Normal karyotype No significant difference in CRR, DFS, or OS between patients with IDH2 R140 mutation and
patients with wildtype IDH1 and IDH2 {2501D}
IDH2 R140Q mutation Various abnormal and normal Among younger patients (aged < 60 years), significantly longer OS for patients with IDH2
karyotypes combined R140Q mutation than for patients with wildtype IDH2 {3095}
IDH1 and IDH2 mutations Normal karyotype Significantly shorter DFS and OS for patients with IDH1 or IDH2 mutation than for patients with
combined wildtype IDH1 and IDH2 {2889A}
Among younger patients (aged ≤ 60 years), no significant difference in CRR, RFS, or OS
between patients with IDH1 or IDH2 mutation and patients with wildtype IDH1 and IDH2; but
in a subset of patients with NPM1 mutation without FLT3-ITD, significantly shorter RFS for
patients with IDH1 or IDH2 mutation than for patients with wildtype IDH1 and IDH2 {3078B}
IDH1 and IDH2 mutations Various abnormal and normal Among younger patients (aged ≤ 60 years), no significant difference in CRR, RFS, or OS
combined karyotypes combined between patients with IDH1 mutation or with either IDH1 or IDH2 mutation and patients with
wildtype IDH1 and IDH2{3078B}
TP53 alteration (mutation or loss) Complex karyotype Significantly shorter RFS, EFS, and OS for patients with TP53 alteration than for patients with
(≥ 3 abnormalities)d wildtype TP53{3462A}
TP53 mutation Complex karyotype No significant difference in CRR, DFS, or OS between patients with and without TP53 mutation
(≥ 5 abnormalities) {439A}
TP53 mutation Abnormalities of chromosome 5, Significantly shorter OS for patients with TP53 mutation than for patients with wildtype TP53
7, or 17 and/or complex karyotype {439A}
(≥ 5 abnormalities)
BAALC expression Various abnormal and normal No significant difference in CIR {1620A}, EFS {1620A}, or OS {1620A.3763A} between
karyotypes combined paediatric patients with high and low BAALC expression; in one study {3763A},
high expression was associated with significantly shorter EFS
ERG expression Normal karyotype Significantly worse CRR {2501C,2648B}, DFS {2648B}, EFS {2501C}, CIR {2501 A}, and
OS {2501 A,2648B,3594C} for patients with high ERG expression in blood {2501A,2501C}
or bone marrow {2648B} than for patients with low expression
No significant difference in CIR, EFS, or OS between paediatric patients with high and low
ERG expression {1620A}
ERG expression Various abnormal and normal No significant difference in CIR, EFS, or OS between paediatric patients with high and low
karyotypes combined ERG expression {1620A}
MN1 expression Normal karyotype Significantly lower CRR {2217A,3594B}; higher RR {1631 A}; and shorter RFS {1631A},
EFS {3594B}, and OS {1631 A,2217A} for patients with high MN1 expression than for
patients with low expression
DNMT3B expression Normal karyotype Among older patients (aged ≥ 60 years), significantly lower CRR and shorter DFS and OS
for patients with high DNMT3B expression than for patients with low expression {2870A}
SPARC expression Normal karyotype Among younger patients (aged ≤ 60 years), significantly lower CRR and shorter DFS and
OS for patients with high SPARC expression than for patients with low expression {50A}
MECOM expression Normal karyotype Among younger patients (aged ≤ 60 years), significantly shorter EFS for patients with high
MECOM (EVI1) expression than for patients with low expression {1479A}
MECOM expression Various abnormal and normal Among younger patients (aged ≤ 60 years), significantly lower CRR and shorter RFS and
karyotypes combined EFS for patients with high MECOM (EVI1) expression than for patients with low expression
{1479A}
MECOM expression Intermediate-risk karyotypeb Among younger patients (aged ≤ 60 years), significantly shorter RFS and EFS for patients
with high MECOM (EVI1) expression than for patients with low expression {1479A}
MIR181A expression Normal karyotype Among younger patients (aged < 60 years), significantly better CRR and OS for patients
with high MIR181A expression than for patients with low expression {3594A}
MIR3151 expression Normal karyotype Among older patients (aged ≥ 60 years), significantly shorter DFS and OS for patients with
high MIR3151 expression than for patients with low expression {1085A}
MIR3151 expression Intermediate-risk karyotypeb Significantly shorter DFS and OS and higher CIR for patients with high MIR3151 expression
than for patients with low expression {974B}
MIR155 expression Normal karyotype Significantly lower CRR and shorter DFS and OS for patients with high MIR155 expression
than for patients with low expression {2501B}
CIR, cumulative incidence of relapse; CR, complete remission; CRD, complete remission duration; CRR, complete remission rate; DFS, disease―free survival; EFS,
event-free survival; ELN, European LeukemiaNet; FLT3-ITD, FLT3 internal tandem duplication; KMT2A-PJD, KMT2A (MLL) partial tandem duplication; OS, overall survival;
PFS, progression-free survival; RFS, relapse-free survival; Rl, relapse incidence; RR, risk of relapse.
in the intermediate-l genetic group have wildtype CEBPA and either wildtype NPM1 (with or without FLT3-ITD) or mutated NPM1 with FLT3-ITD.
d Complex karyotype is defined by ELN as ≥ 3 chromosome abnormalities in the absence of the WHO-designated recurring translocations or inversions, i.e. t(8;21), inv(16)
or t(16;16), t(15;17), t(9;11), t(v;11)(v;q23.3), t(6;9), inv(3), or t(3;3). Table prepared by Krzysztof Mrozek.
Definition Table 8.03 Diagnostic criteria for acute myeloid leukaemia with myelodysplasia-related changes (AML-MRC)
Acute myeloid leukaemia with myelodys The diagnosis of AML-MRC requires that the following 3 criteria are met.
plasia-related changes (AML-MRC) is an
acute leukaemia with ≥ 20% peripheral 1 ≥ 20% blood or marrow blasts
blood or bone marrow blasts with mor 2 Any of the following:
phological features of myelodysplasia, or - History of myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm
occurring in patients with a prior history - Myelodysplastic syndrome-related cytogenetic abnormality (Table 8.04)
of a myelodysplastic syndrome (MDS) or - Multilineage dysplasiaa
myelodysplastic/myeloproliferative neo
plasm (MDS/MPN), with MDS-related 3 Absence of both of the following:
cytogenetic abnormalities; the specific - Prior cytotoxic or radiation therapy for an unrelated disease
- Recurrent cytogenetic abnormality as described in Acute myeloid leukaemia with recurrent
genetic abnormalities characteristic of
genetic abnormalities (p. 130)
acute myeloid leukaemia (AML) with re
current genetic abnormalities are absent. a Multilineage dysplasia alone is insufficient for a diagnosis of AML-MRC in a de novo case of AML with
Patients should not have a history of prior mutated NPM1 or biallelic mutation of CEBPA (see text for details).
cytotoxic or radiation therapy for an unre
lated disease. Therefore, there are three
possible reasons for classifying a case transformation, and may have clinical be Microscopy
as this subtype (Table 8.03): AML arising haviour more similar to that of MDS than Most cases in this category of AML have
from previous MDS or MDS/MPN, AML that of AML {1590}. Some authors rec morphological evidence of multilineage
with an MDS―related cytogenetic abnor ommended categorizing such cases as dysplasia, which must be assessed on
mality and AML with multilineage dyspla a favourable prognostic subtype of AML well―stained smears of peripheral blood
sia. A given case may be classified as {1590}. However, this recommendation is and bone marrow. For an AML to be clas
this subtype for one, two or all three of controversial. The National Comprehen sified as having myelodysplasia―related
these reasons. sive Cancer Network (NCCN) Clinical changes based on morphology, dyspla
Practice Guidelines for Myelodysplas sia must be present in ≥ 50% of the cells
ICD-O code 9895/3 tic Syndromes, which endorse using in at least two haematopoietic cell lines.
the WHO classification system, recom Dysgranulopoiesis is characterized by
Synonyms mend that cases with 20―29% marrow neutrophils with hypogranular cytoplasm,
Acute myeloid leukaemia with multiline blasts and a stable clinical course for hyposegmented nuclei (pseudo―Pelger-
age dysplasia; acute myeloid leukaemia ≥ 2 months be considered as either MDS Huët anomaly) or bizarrely segmented
with prior myelodysplastic syndrome or AML, in order for such cases to be eli nuclei. In some cases, these features
gible for treatment as either entity {1443}. can be more readily identified on periph
Epidemiology Several important findings support this eral blood than bone marrow smears.
AML―MRC occurs mainly in elderly pa recommendation: (1) patients with 20- Dyserythropoiesis is characterized by
tients, and is rare in children {1595,2261}. 29% marrow blasts have previously been megaloblastosis, karyorrhexis, and nu
Although the definitions of multilineage included in and benefited from major clear irregularity, fragmentation or multi-
dysplasia in the literature vary, this cat therapeutic trials for MDS {1183,1796}; (2) nucleation. Ring sideroblasts, cytoplas
egory appears to account for 24 to 35% survival and disease evolution were simi mic vacuoles and periodic acid―Schiff
of all cases of AML {132,885,1514,2682, lar in the MDS patient groups with 10- (PAS) positivity are additional features of
4276,4416}. 19% and 20―29% marrow blasts {1444}; dyserythropoiesis. Dysmegakaryopoie-
and (3) molecular and cytogenetic fea sis is characterized by micromegakaryo
Clinical features tures have been reported to be similar cytes and normal―sized or large mega
AML―MRC often presents with severe between these two patient groups {210}. karyocytes with non―lobated or multiple
pancytopenia. Some cases with 20―29% Molecular genetic factors (rather than nuclei. Dysplastic megakaryocytes may
blasts, especially cases arising from strictly morphological or historical fac be more readily appreciated in sections
MDS or in childhood, may be slowly pro tors) have helped refine the diagnosis of than on smears {132,1270}.
gressive. Such cases, with relatively sta MDS―type AML; a set of gene mutations Some cases lack sufficient non―blast
ble peripheral blood counts for weeks or defines a subset of de novo AML cases, bone marrow elements to adequately
months, are categorized by the French- including those that evolved from MDS, assess for multilineage dysplasia; oth
American―British (FAB) classification as with clinical features and therapeutic re ers have sufficient non-blast cells but do
refractory anaemia with excess blasts in sponses highly specific for MDS {2351}. not meet the criteria described above for
Clinical features
Two subsets of t―MNs are generally
recognized clinically {1976,2221,3119,
3435,3709}. The more common occurs
5―10 years after exposure to alkylating
agents and/or ionizing radiation. These
cases often present with an MDS with
marrow failure and one or more cytope-
nias, although a minority present with
t―MDS/MPN or overt t―AML. This subset
is commonly associated with unbalanced
loss of genetic material, often involving
chromosomes 5 and/or 7, as well as com acute leukaemia associated with multi may be designated as t―MDS or t―AML
plex karyotypes and mutations or loss of lineage dysplasia {130,2654,3709,4154, depending on the blast percentage, but
TP53. The second t―MN subset accounts 4479}. There is commonly an elicited whether the percentage of blasts is prog-
for 20―30% of cases, has a shorter latent history of prior therapy with alkylating nostically significant in this group with
period (1―5 years), and follows treatment agents and/or radiation therapy, and MDS―related features is unclear {208,
with agents that interact with DNA topoi cytogenetic studies often reveal abnor 1211,2124,3686,4479}. About half of the
somerase II (topoisomerase II inhibitors). malities of chromosomes 5 and/or 7 or cases that present with a myelodysplas
Most cases in this subset do not have a complex karyotype, often associated tic phase have < 5% bone marrow blasts,
a myelodysplastic phase but present with mutated TP53 {2351,3253,3652}. but they often exhibit poor-risk cytogenet
with overt acute leukaemia, often as The peripheral blood shows one or more ics {2654,3686}. The diagnosis of t-MDS,
sociated with a balanced chromosomal cytopenias. Anaemia is almost always t-AML, or t-MDS/MPN should include the
translocation. Although it may be useful present and red blood cell morphology associated cytogenetic abnormalities.
to consider t―MN cases as being either is usually characterized by macrocytosis In 20―30% of cases, the first manifesta
alkylating agent/radiation―related or and poikilocytosis. Dysplastic changes tion of a t―MN is overt acute leukaemia
topoisomerase II inhibitor―related, many in the neutrophils include abnormal nu without a preceding myelodysplastic
patients have received multiple types of clear segmentation and hypogranular phase {2654,3435,3709}. These cases
therapy, and the boundaries between cytoplasm. Basophilia is frequently pre often occur following topoisomerase II in
these two categories are therefore not sent. The bone marrow may be hypercel- hibitor therapy, and most are associated
always clear {1976}. Most cases of t―MN lular, normocellular, or hypocellular, and with recurrent balanced chromosomal
present within 10 years of the most recent reticulin fibrosis is common {852,2654}. translocations, which frequently involve
exposure, and the origin of AML in cases Dysgranulopoiesis and dyserythropoie 11q23 (KMT2A, previously called MLL)
with very long latent periods may be un sis are usually present. Most cases show or 21q22.1 (RUNX1) and have a morphol
related to therapy {1420}. dysplastic megakaryocytes with non- ogy resembling that of de novo acute
lobated or hypolobated nuclei or widely leukaemia associated with these same
Microscopy separated nuclear lobes. Cases present chromosomal abnormalities, although
Most patients present with an MDS or ing with myelodysplasia and cytopenias a few such cases present as MDS or
Fig. 8.23 Therapy-related myelodysplastic syndrome/acute myeloid leukaemia. This 42-year-old man was treated with ABVD chemotherapy (i.e. doxorubicin, bleomycin, vin
blastine, and dacarbazine) for classic Hodgkin lymphoma, then relapsed 16 months later and was given salvage chemotherapy and radiotherapy; 2 years later, he presented with
pancytopenia in the peripheral blood (A) and a bone marrow aspirate (B) and bone marrow biopsy (C) showed increased blasts and multilineage dysplasia. The karyotype was
complex and included loss of chromosomes 5 and 7.
Fig. 8.27 Acute myeloid leukaemia with maturation. A Bone marrow biopsy reveals myeloblasts with abundant cytoplasm and azurophilic granules; occasional blasts contain an
Auer rod and scattered eosinophils are present. There are numerous blasts with intense MPO activity (B) and lysozyme positivity (C).
Fig. 8.28 Acute myelomonocytic leukaemia. A Blood smear shows a myeloblast, a monoblast, and promonocytes. B Bone marrow smear shows myeloblasts and several more-
mature monocytes, including promonocytes. C Non-specific esterase reaction on a bone marrow smear reveals several positive cells; the non-reacting cells are predominantly
myeloblasts and neutrophil precursors.
Cell of origin
The postulated cell of origin is a haemato
poietic stem cell. any of the previously described groups; obviously granulated, with occasional
i.e. acute myeloid leukaemia (AML) with large azurophilic granules and vacu
Genetic profile recurrent genetic abnormalities, AML oles. Auer rods are rare; when present,
Myeloid–associated, non–specific cyto with myelodysplasia-related changes, or they are usually in cells identifiable as
genetic abnormalities (e.g. gain of chro therapy-related AML. myeloblasts. Haemophagocytosis (eryth-
mosome 8) are present in most cases. rophagocytosis) may be observed and is
ICD-O code 9891/3 often associated with t(8;16)(p11.2;p13.3)
{972,1512,3768}. Haemophagocytosis
Acute monoblastic and Synonyms with associated t(8;16)(p11.2;p13.3) may
monocytic leukaemia Acute monocytic leukaemia; acute also be observed in acute myelomono
monoblastic leukaemia; French―Ameri cytic leukaemia and some cases of
Definition can―British (FAB) classification M5; AML with maturation. The bone marrow
Acute monoblastic leukaemia and acute monoblastic leukaemia, NOS in acute monoblastic leukaemia is usu
monocytic leukaemia are myeloid leu ally hypercellular, with a predominant
kaemias in which the peripheral blood or Epidemiology population of large, poorly differentiated
bone marrow has ≥ 20% blasts (including Acute monoblastic leukaemia accounts blasts with abundant cytoplasm. Nucleoli
promonocytes) and in which ≥ 80% of the for < 5% of cases of AML. It can occur at may be prominent. The promonocytes in
leukaemic cells are of monocytic lineage, any age, but is most common in young acute monocytic leukaemia show nu
including monoblasts, promonocytes, individuals. Extramedullary lesions can clear segmentation. The extramedullary
and monocytes; a minor neutrophil com occur. lesion may be composed predominantly
ponent (< 20%) may be present. Acute Acute monocytic leukaemia accounts for of monoblasts or promonocytes or an
monoblastic leukaemia and acute mono < 5% of cases of AML. It is more com admixture of two cell types.
cytic leukaemia are distinguished by the mon in adults; the median patient age is
relative proportions of monoblasts and 49 years {3766}. The male–to–female ratio Cytochemistry
promonocytes. In acute monoblastic leu is 1.8:1. In most cases, the monoblasts and
kaemia, most (≥ 80%) of the monocytic promonocytes show intense non―specific
cells are monoblasts. In acute monocytic Clinical features esterase activity. In as many as 10―20%
leukaemia, most of the monocytic cells Patients commonly present with bleeding of cases of acute monoblastic leukae
are promonocytes or monocytes. Acute disorders. Extramedullary masses, cuta mia, the non―specific esterase reaction
monoblastic and monocytic leukaemia neous and gingival infiltration, and CNS is negative or only very weakly positive.
does not fulfil the criteria for inclusion in involvement are common. In cases in which non―specific esterase
is negative, immunophenotyping may
Microscopy be necessary for establishing monocytic
The monoblasts are large cells with differentiation. Monoblasts are typically
abundant cytoplasm that can be mod MPO―negative; promonocytes may show
erately to intensely basophilic and may some scattered MPO positivity.
show pseudopod formation. Scattered
fine azurophilic granules and vacuoles Differential diagnosis
may be present. The monoblasts usu The major differential diagnoses of acute
ally have round nuclei with delicate lacy monoblastic leukaemia include AML with
chromatin and one or more large promi out maturation, AML with minimal differ
nent nucleoli. Promonocytes have a more entiation, AML with t(9;11)(p21.3;q23.3),
irregular and delicately convoluted nu and acute megakaryoblastic leukaemia.
clear configuration; the cytoplasm is usu Extramedullary myeloid (monoblastic)
ally less basophilic and sometimes more sarcoma may be confused with malig-
Fig. 8.31 Acute monocytic leukaemia, testicular infiltration. A and B The monocytic cells have relatively abundant
Epidemiology
cytoplasm and very dispersed chromatin. Pure erythroid leukaemia is extremely
rare. It can occur at any age, including in
nant lymphoma or soft tissue sarcomas. Cell of origin childhood. It can occur de novo, but more
Occasional cases resemble prolympho- The postulated cell of origin is a haemato often occurs as progression of a prior
cytic leukaemia; they are readily distin poietic stem cell. myelodysplastic syndrome or as therapy-
guished by immunophenotyping and related disease {2371,4247}. Therapy-
cytochemistry. The major differential dia Genetic profile related cases should be diagnosed as
gnoses of acute monocytic leukaemia Myeloid―associated, non―specific cyto therapy―related myeloid neoplasms.
include chronic myelomonocytic leukae genetic abnormalities are present in
mia, acute myelomonocytic leukaemia, most cases. The t(8;16)(p11.2;p13.3) Clinical features
and microgranular acute promyelocytic can be associated with acute monocytic The clinical features are not unique,
leukaemia. These can be distinguished leukaemia or acute myelomonocytic leu but profound anaemia and circulating
by careful examination of well―stained kaemia and in most cases is associated erythroblasts are common.
smears. The differential diagnosis with with haemophagocytosis (in particular
chronic myelomonocytic leukaemia is erythrophagocytosis) by leukaemic cells Microscopy
critical; it relies on the proper identifica and with coagulopathy {972,3768}. Pure erythroid leukaemia is character
tion of promonocytes and their inclusion ized by the presence of medium―sized
as blast equivalents. The abnormal pro to large erythroblasts, usually with round
myelocytes in acute promyelocytic leu Pure erythroid leukaemia nuclei, fine chromatin, and one or more
kaemia show intense MPO and naphthol nucleoli (proerythroblasts); the cyto
AS–D chloroacetate esterase (CAE) posi Definition plasm is deeply basophilic and agranular
tivity, whereas the monocytes are weakly Pure erythroid leukaemia is a neoplas and frequently contains vacuoles, which
reactive or negative. tic proliferation of immature cells (undif often give a positive periodic acid-Schiff
ferentiated or proerythroblastic in ap (PAS) reaction. Occasionally, the blasts
Immunophenotype pearance) committed exclusively to the are smaller, with scanty cytoplasm, and
Flow cytometry shows that these leukae erythroid lineage (>80% of the bone can resemble the lymphoblasts of lymph
mias variably express the myeloid antigens marrow cells are erythroid, with ≥ 30% oblastic leukaemia. The cells are nega
CD13, CD33 (often very bright), CD15, and proerythroblasts), with no evidence of tive for MPO and Sudan Black B staining;
CD65. There is generally expression of at a significant myeloblastic component they show reactivity with alpha―naphthyl
least two markers characteristic of mono {2095,2281,2371}. acetate esterase, acid phosphatase, and
cytic differentiation, such as CD14, CD4, Cases previously classified as erythro- PAS (with PAS, usually in a block―like
CD11b, CD11c, CD64 (bright), CD68, leukaemia (erythroid/myeloid type) on staining pattern). In bone marrow biopsy
CD36 (bright), and lysozyme. CD34 is the basis of counting myeloblasts as a sections of pure erythroid leukaemia,
positive in only 30% of cases, whereas percentage of non―erythroid cells when the cells appear undifferentiated and
KIT (CD117) is more often expressed. erythroid precursor cells constituted
Most cases are positive for HLA–DR. ≥ 50% of the marrow cells are now clas
MPO can be expressed in acute mono sified on the basis of the total bone mar
cytic leukaemia and less often in mono row or peripheral blood blast cell count.
blastic leukaemia. Aberrant expression Such cases are classified as myelodys
of CD7 and/or CD56 is found in 25–40% plastic syndrome with excess blasts if
of cases. By immunohistochemistry in blasts constitute < 20% of all marrow or
paraffin–embedded bone marrow biopsy blood cells, and usually as acute myeloid
specimens and in extramedullary myeloid leukaemia (AML) with myelodysplasia-re
(monoblastic) sarcomas, MPO and CAE lated changes if blasts constitute ≥ 20%
are typically negative but can be weakly of the cells, irrespective of the erythroid
positive. Lysozyme is often positive, but is precursor cell count.
also expressed in AML lacking monocytic
differentiation. CD68 (PGM1) and CD163 ICD-O code 9840/3
are often positive.
Epidemiology
Acute megakaryoblastic leukaemia is an
uncommon disease, accounting for < 5%
of cases of AML. It occurs in both adults
and children.
Clinical features
Fig. 8.34 Pure erythroid leukaemia. A Bone marrow smear shows four abnormal proerythroblasts; the erythroblasts Patients present with cytopenias (often
are large, with finely dispersed chromatin, prominent nucleoli, and cytoplasmic vacuoles, some of which are thrombocytopenia), although some may
coalescent. B The cytoplasm of the proerythroblasts shows intense globular periodic acid-Schiff (PAS) staining. have thrombocytosis. Dysplastic features
Microscopy
The megakaryoblasts are usually medi
um―sized to large blasts (12―18 pm) with Fig. 8.36 Acute megakaryoblastic leukaemia. Bone marrow smear (A) and bone marrow section (B) from a
a round, slightly irregular, or indented 22-month-old child, with complete replacement by poorly differentiated blasts.
nucleus with fine reticular chromatin and
1–3 nucleoli. The cytoplasm is basophilic,
often agranular, and may show distinct
blebs or pseudopod formation. In some
cases, the blasts are predominantly small
with a high N:C ratio, resembling lympho
blasts; large and small blasts may be
present in the same patient. Occasional
ly, the blasts occur in small clusters. Cir
culating micromegakaryocytes, mega-
karyoblast fragments, dysplastic large
platelets, and hypogranular neutrophils Fig. 8.37 Acute megakaryoblastic leukaemia A Bone marrow smear shows two megakaryoblasts, which are large
may be present. Micromegakaryocytes cells with cytoplasmic pseudopod formation; portions of the cytoplasm are zoned, with granular basophilic areas and
should not be counted as blasts. In some clear cytoplasm; nucleoli are unusually prominent. B The cytoplasm of the megakaryoblasts is intensely reactive with
patients, because of extensive bone mar antibody to CD61 (platelet glycoprotein Ilia).
row fibrosis resulting in so-called dry tap,
the percentage of bone marrow blasts is esterase (CAE), and MPO is consistent megakaryoblastic leukaemia, acute pan
estimated from the bone marrow biopsy. ly negative in the megakaryoblasts; the myelosis with fibrosis, and AML-MRC can
Imprints of the biopsy may also be useful. blasts may give a positive periodic acid- be problematic. In such cases, careful
Although acute megakaryoblastic leu Schiff (PAS) reaction, show reactivity for immunohistochemical analysis of bone
kaemia can be associated with extensive acid phosphatase, and show punctate or marrow biopsy can be particularly help
fibrosis, this is not an invariable finding. focal non―specific esterase reactivity. ful {2991}.
The histopathology of the biopsy speci
men varies; some cases have a uniform Differential diagnosis Immunophenotype
population of poorly differentiated blasts The differential diagnosis includes mini The megakaryoblasts express one or
and others have a mixture of poorly dif mally differentiated AML, AML―MRC, more of the platelet glycoproteins: CD41
ferentiated blasts and maturing dysplas acute panmyelosis with myelofibrosis, (glycoprotein llb/llla), CD61 (glycopro
tic megakaryocytes. Various degrees of lymphoblastic leukaemia, pure eryth tein Ilia), and CD42b (glycoprotein lb).
reticulin fibrosis can be present. roid leukaemia, blastic transformation The myeloid―associated markers CD13
of chronic myeloid leukaemia, and the and CD33 may be positive. CD34, the
Cytochemistry blast phase of any other myeloprolifera panleukocyte marker CD45, and HLA-
Cytochemical staining with/for Sudan tive neoplasm. In blastic transformation DR are often negative, especially in chil
Black B, naphthol AS–D chloroacetate of chronic myeloid leukaemia and the dren; CD36 is characteristically positive
blast phase of any other myeloprolifera but not specific. Blasts are negative with
tive neoplasm, there is usually a history MPO antibody and with other markers
of a chronic phase, and splenomegaly is of granulocytic differentiation. Lymphoid
an almost invariable finding. Some meta markers and TdT are not expressed,
static tumours in the bone marrow, in but there may be aberrant expression of
particular in children (e.g. alveolar rhab CD7. Cytoplasmic expression of CD41 or
domyosarcoma), may resemble acute CD61 is more specific and sensitive than
megakaryoblastic leukaemia. In general, is surface staining, due to possible ad
acute megakaryoblastic leukaemia con herence of platelets to blast cells, which
stitutes a proliferation predominantly of can be misinterpreted as positive staining
megakaryoblasts, whereas acute pan on flow cytometry. In cases with fibrosis,
myelosis is characterized by a trilineage immunophenotyping on bone marrow
Fig. 8.35 Acute megakaryoblastic leukaemia. Bone
marrow biopsy section showing virtually complete proliferation of granulocytes, megakaryo trephine biopsy sections is particularly
replacement by a population of blasts; one micromega cytes, and erythroid precursors. In some important for diagnosis. Megakaryocytes
karyocyte can be seen. cases, the distinction between acute (and in some cases megakaryoblasts)
can be recognized by a positive reac Acute basophilic leukaemia may be vacuolation of the cytoplasm.
tion with antibodies to von Willebrand Immature forms can be seen, but mature
factor, the platelet glycoproteins (CD61 Definition basophils are usually sparse. Dysplastic
and CD42b), and LAT; the detection of Acute basophilic leukaemia is an acute features in the erythroid precursors may
platelet glycoproteins is most lineage- myeloid leukaemia (AML) in which the be present. Electron microscopy shows
specific, but detection is highly depend primary differentiation is to basophils. that the granules have features charac
ent on the procedures used for fixation Acute basophilic leukaemia does not fulfil teristic of basophil precursors; they con
and decalcification. the criteria for inclusion in any of the pre tain an electron―dense particulate sub
viously described groups (i.e. AML with stance, are internally bisected (e.g. have
Cell of origin recurrent genetic abnormalities, AML a theta character), or contain crystalline
The postulated cell of origin is a with myelodysplasia―related changes, or material arranged in a pattern of scrolls
haematopoietic stem cell. therapy–related AML). or lamellae (which is more typical of mast
cells) {3148}. The most characteristic
Genetic profile ICD-O code 9870/3 cytochemical reaction is metachromatic
There is no unique chromosomal abnor staining with toluidine blue. The blasts
mality associated with acute megakary Synonym usually show a diffuse pattern of staining
oblastic leukaemia in adults. Complex Basophilic leukaemia (no longer used) with acid phosphatase, and in some cas
karyotypes typical of myelodysplastic es show periodic acid―Schiff (PAS) pos
syndrome, inv(3)(q21.3q26.2), and t(3;3) Epidemiology itivity in large blocks; the blasts are often
(q21.3q26.2) can all be associated with Acute basophilic leukaemia is a very rare negative for naphthol AS―D chloroacetate
megakaryoblastic/ megakaryocytic dif disease, with a relatively small number esterase (CAE), Sudan Black B staining,
ferentiation {873,2964}, but such cases of reported cases. It accounts for < 1% of MPO, and non―specific esterase. The
should be assigned to other categories of cases of AML. lack of CAE reactivity can be helpful in
AML (see Acute myeloid leukaemia with distinguishing blasts of acute basophilic
recurrent genetic abnormalities, p. 130). Clinical features leukaemia from mast cells {1360}. Bone
In young males with mediastinal germ As with other acute leukaemias, patients marrow biopsy shows diffuse replace
cell tumours and acute megakaryoblas present with features related to bone ment by blast cells.
tic leukaemia, several cytogenetic abnor marrow failure and may or may not have
malities have been observed; of these, circulating blasts. Cutaneous involve Differential diagnosis
isochromosome 12p is particularly char ment, organomegaly, lytic lesions, and The differential diagnosis includes the
acteristic {633,2990}. symptoms related to hyperhistaminaemia blast phase of a myeloproliferative
may be present. neoplasm; other AML subtypes with
Prognosis and predictive factors basophilia, such as AML with t(6;9)
The prognosis of this category of acute Microscopy (p23;q34.1); AML with BCR―ABL1; mast
megakaryoblastic leukaemia is usually The circulating peripheral blood and cell leukaemia; and (more rarely) a sub-
poorer than that of other AML types, bone marrow blasts are medium―sized, type of lymphoblastic leukaemia with
AML (megakaryoblastic) with t(1;22) with a high N:C ratio; an oval, round, or prominent coarse granules. The clinical
(p13.3;q13.1) {1050,2964}, and acute irregular nucleus characterized by dis features and cytogenetic pattern distin
megakaryoblastic leukaemia in Down persed chromatin, and 1―3 prominent nu guish cases presenting de novo from
syndrome. cleoli. The cytoplasm is moderately baso those resulting from transformation of
philic and contains a variable number of chronic myeloid leukaemia and from oth
coarse basophilic granules that are pos er AML subtypes with basophilia. Immu
itive with metachromatic staining; there nological markers distinguish between
Immunophenotype
Leukaemic blasts express myeloid mark
ers such as CD13 and CD33; are usually
positive for CD123, CD203c, and CD11b;
and are negative for other monocytic
markers and KIT (CD117) {3761}. Blasts
may express CD34. Unlike normal baso
phils, they may be positive for HLA-DR
but are negative for KIT. Immunopheno-
typic detection of abnormal mast cells
expressing KIT, mast cell tryptase, and
CD25 distinguishes mast cell leukaemia
from acute basophilic leukaemia. Blasts
usually express CD9. Some cases are
positive for membrane CD22 and/or
TdT. Other membrane and cytoplasmic
lymphoid―associated markers are usually
negative {2322,3762}.
Genetic profile
No consistent chromosomal abnormal
ity has been identified, but a recurrent
t(X;6)(p11.2;q23.3) resulting in MYB-
GATA1 appears to occur in male infants
with acute basophilic leukaemia {872,
3260}. Other cytogenetic abnormalities Fig. 8.39 Acute panmyelosis with myelofibrosis. A Marrow trephine imprint shows several megakaryocytes with hy-
reported in acute basophilic leukaemia posegmented nuclei and blast forms. B The marrow is markedly hypercellular, with increased fibrosis and a hetero
include t(3;6)(q21;p21) and abnormalities geneous mixture of cells that include numerous dysplastic megakaryocytes. C Reticulin staining shows marked
involving 12p {1710,1711}. AML with t(6;9) marrow fibrosis. D Immunohistochemistry for CD34 shows an increase in blast cells.
(p23;q34.1) is specifically excluded, as
are cases associated with BCR-ABL1. changes, or therapy―related acute mye only minimal splenomegaly. The clinical
loid leukaemia. evolution is usually rapidly progressive
Prognosis and predictive factors {3986}.
There is little information on survival with ICD-O code 9931/3
this rare type of acute leukaemia. The Microscopy
cases observed have generally been as Synonyms The peripheral blood shows pancyto
sociated with a poor prognosis. Acute panmyelosis, NOS; acute (malig penia, which is usually marked. The
nant) myelofibrosis; acute (malignant) red blood cells show no or minimal an-
myelosclerosis, NOS; malignant myelo isopoikilocytosis and variable macrocy-
Acute panmyelosis with sclerosis; acute myelofibrosis; acute my tosis; rare erythroblasts can be seen, but
myelofibrosis elosclerosis, NOS teardrop–shaped cells (dacryocytes) are
not observed. Occasional neutrophil pre
Definition Epidemiology cursors, including blasts, may be seen.
Acute panmyelosis with myelofibrosis APMF is a very rare form of AML. It oc Dysplastic changes in myeloid cells are
(APMF) is an acute panmyeloid prolifera curs de novo and is primarily a disease frequent, but the criteria for AML with
tion with increased blasts (≥ 20% of cells of adults, but has also been reported in myelodysplasia―related changes are not
in the bone marrow or peripheral blood) children. met. Abnormal platelets may be noted.
and accompanying fibrosis of the bone Bone marrow aspiration is frequently un
marrow {307,2991,3831}. APMF does not Clinical features successful; either no bone marrow can
fulfil the criteria for inclusion in any of the Patients are acutely sick at presentation, be obtained or the specimen is subopti-
previously described groups; i.e. acute with severe constitutional symptoms in mal. Bone marrow biopsy supplemented
myeloid leukaemia (AML) with recurrent cluding weakness and fatigue. Fever and with immunohistochemistry is required
genetic abnormalities, acute myeloid bone pain are also common. Pancyto for diagnosis {3837,3986}. The bone mar
leukaemia with myelodysplasia―related penia is always present. There is no or row is hypercellular and shows, within a
Localization
Almost any site in the body can be in
volved; the most frequently affected are
the skin, lymph nodes, gastrointestinal
tract, bone, soft tissue, and testes {1144,
3177}. In <10% of cases, myeloid sarco
ma presents at multiple anatomical sites
{1144,3177}.
Fig. 8.40 Myeloid sarcoma. The tumour consists of blasts with scant cytoplasm and round-oval nuclei with finely
Clinical features dispersed chromatin and minute but distinct nucleoli. Mitotic figures are numerous. Neoplastic cells strongly express
Myeloid sarcoma occurs in the absence MPO (inset).
Blastic
plasmacytoid
dendritic cell
neoplasm
Blastic plasmacytoid dendritic Facchetti F.
Petrella T.
cell neoplasm Pileri S.A.
Etiology
There are currently no clues to the etiolo
gy of BPDCN, but its association with my-
elodysplastic syndrome (MDS) in some
cases may suggest a related pathogen
esis. There is no association with EBV.
Localization
The disease tends to involve multiple
sites, most commonly the skin (involved
in 64―100% of cases), followed by the
bone marrow and peripheral blood (in
60―90%) and lymph node (in 40―50%)
{2525,3151}.
Clinical features
Skin manifestations are the most frequent
clinical presentation of typical cases of
BPDCN, and the diagnosis is made on
skin biopsy. Patients usually present with
asymptomatic solitary or multiple lesions.
Three types of presentation are most
Microscopy
BPDCN is characterized by a diffuse,
monomorphous infiltrate of medium
sized blast cells resembling either lymph
oblasts or myeloblasts. Nuclei have ir
regular contours, fine chromatin, and one
to several small nucleoli. The cytoplasm
is usually scant and appears greyish-
blue and agranular on Giemsa staining.
Mitoses are variable in number, and the
Ki–67 proliferation index is 20―80%; an-
gioinvasion and coagulative necrosis are
absent {820,1887,2004,3182}.
In cutaneous infiltrates, the dermis is usu
ally massively involved, with extension to
the subcutaneous fat; the epidermis and
adnexa are spared, with rare exceptions
{820}. Lymph nodes are diffusely involved
in the interfollicular areas and medulla,
whereas B cell follicles are often spared.
Bone marrow biopsy shows either a mild
interstitial infiltrate (detectable only by im-
munophenotyping) or massive replace
ment; residual haematopoietic tissue may
exhibit dysplastic features, especially in
megakaryocytes {3151}. On peripheral
blood and bone marrow smears, tumour
cells may show cytoplasmic microvacu
oles localized along the cell membrane does not rule out the diagnosis if other
and pseudopodia; granules and crystals PDC―associated antigens (in particular
are absent {1209}. CD123, TCL1A, or CD303) are expressed
{53,406,1887}. Tumours that have some
Cytochemistry immunophenotypic features of BPDCN
The neoplastic cells in BPDCN are may be better classified as one of the
negative with alpha―naphthyl butyrate subtypes of acute leukaemia of ambigu
esterase, naphthol AS―D chloroacetate ous lineage. CD68 (an antigen typically
esterase (CAE), and MPO cytochemical expressed strongly on normal PDCs) is
reactions {300,1209,2004,3332}. detected in 50―80% of cases, in the form
of small cytoplasmic dots {3151,3157}. Of
Immunophenotype the lymphoid and myeloid―associated
The tumour cells express CD4, CD43, antigens, CD7 and CD33 are relatively
CD45RA, and CD56, as well as the PDC- commonly expressed; some cases
associated antigens CD123 (IL3 alpha- show expression of CD2, CD5, CD36, may also express other antigens that are
chain receptor), CD303, TCL1A, CD2AP, CD38, and CD79a, whereas CD3, CD13, usually negative in normal PDCs, such
and SPIB and the type I interferon―de CD16, CD19, CD20, LAT, lysozyme, and as BCL6, IRF4, and BCL2 {820} (with
pendent molecule MX1 {107,406,1618, MPO are negative. Granzyme B, which BCL2 potentially acting against tumour
1887,2497,2702,3151,3152,3157,3182, is found in normal PDCs, has also been cell apoptosis {3520}). In addition, S100
3248,3332}. Recently, the TCF4 (E2-2) demonstrated on flow cytometry im- protein is expressed in 25―30% of all
transcription factor, which is essential munophenotyping and mRNA analysis cases {1887}, and even more frequently
to drive PDCs development, was found in BPDCN {663,1410}, but it is typically in paediatric cases {1847,1849}; the zonal
to represent a faithful diagnostic mark negative on tissue sections, as are oth distribution of this antigen and its vari
er for BPDCN {605B}. In about 8% of er cytotoxic molecules such as perforin able expression in tumour cells may re
cases, CD4 or CD56 is negative, which and TIA1. In addition to CD56, BPDCN flect divergent subclones with maturation
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اﻟﺒﺎﺛﻮﻟﻮﺟﻴﺎ
اﻹﻛﻠﻴﻨﻴﻜﻴﺔ
واﻟﻜﻴﻤﻴﺎﺋﻴﺔ
ﻧﻌﻢ_ﻟﻘﺎﻧﻮن_اﻟﻤﻌﺎﻣﻞ_اﻟﺠﺪﯾﺪ#
CHAPTER
Acute leukaemias of
ambiguous lineage 179
Acute undifferentiated leukaemia 182
Mixed-phenotype AL with t(9;22)(q34.1;q11.2); BCR-ABL1 182
Mixed-phenotype AL with t(v;11q23.3); KMT2A-rearranged 183
Mixed-phenotype acute leukaemia, B/myeloid, NOS 184
Mixed-phenotype acute leukaemia, T/myeloid, NOS 185
Mixed-phenotype acute leukaemia, NOS, rare types 186
Acute leukaemias of ambiguous lineage, NOS 187
Acute leukaemias of ambiguous lineage Borowitz M.J.
Bene M.-C.
Harris N.L.
Porwit A.
Matutes E.
Arber D.A.
Definition ‘acute bilineage (or bilineal) leukaemia’ specified, irrespective of whether one
Acute leukaemias of ambiguous line has been applied to MPALs containing or more than one population of blasts is
age are leukaemias that show no clear separate populations of blasts of more seen.
evidence of differentiation along a single than one lineage. The term ‘biphenotypic Some well-defined myeloid leukaemia
lineage. They include acute undifferenti leukaemia’ has typically been reserved entities have immunophenotypic features
ated leukaemias, which show no lineage- for MPALs containing a single population that might suggest that they be classified
specific antigens, and mixed-phenotype of blasts coexpressing antigens of more as B/myeloid or T/myeloid leukaemia.
acute leukaemias (MPALs), which have than one lineage {1539,2257,2578,3830}, However, the MPAL group, as defined
blasts that express antigens of more than but is sometimes used more broadly to in this volume, excludes cases that can
one lineage to such a degree that it is not also encompass bilineage leukaemias. be classified (either by genetic or clini
possible to assign the leukaemia to any In this volume, the term ‘mixed-pheno cal features) in another category, such
one lineage with certainty. MPALs can type acute leukaemia’ is applied to this as cases with the recurrent genetic ab
contain distinct blast populations each group in general; the more specific terms normalities t(8;21), inv(16), or PML-RARA
of a different lineage, one population with ‘B/myeloid leukaemia’ and ‘T/myeloid fusion, which are associated with acute
multiple antigens of different lineages on leukaemia’, as defined below, refer to myeloid leukaemia (AML); cases with
the same cells, or a combination. The leukaemias containing the two lineages t(8;21) express multiple B-cell markers
ambiguity of antigen expression most of
ten involves myeloid antigens coexisting
with either T-cell or B-cell antigens, but
rare cases of ambiguity of assignment
between B-cell and T-cell lineages also
occur. Leukaemia with well-defined line
age engagement but expressing one or
more antigens associated with a different
lineage should be considered acute leu
kaemia with aberrant antigen expression
rather than MPAL.
Epidemiology
Ambiguous-lineage leukaemias are rare,
accounting for < 4% of all acute leukae
mia cases. Many cases that have been
reported as undifferentiated leukaemia
can in fact be demonstrated to be leu
kaemias of unusual lineages, and many
cases that have been reported as biphe-
notypic acute leukaemias may in fact be
acute lymphoid or myeloid leukaemias
with cross-lineage antigen expression;
therefore, the true frequency of ambig
uous-lineage leukaemias may be even
lower than reported. These leukaemias
occur in both children and adults, but
more frequently in adults, although some
subtypes of MPAL may be more common
in children {2013,3013}.
Terminology
Historically, there has been confusion re
garding the terminology and definitions
of all ambiguous-lineage leukaemias
and in particular the MPALs. The term
Epidemiology
This rare leukaemia is more common
in children than in adults. Like ALL and
acute myeloid leukaemia with KMT2A re
arrangements, this leukaemia is relatively
more common in infancy {2013,3013}.
Clinical features
Patients present similarly to other pa
tients with acute leukaemia. As with other
Fig. 10.02 B/myeloid mixed-phenotype acute leukaemia with t(9;22)(q34.1;q11.2). The blasts vary from small
acute leukaemias with KMT2A transloca
lymphoid-appearing blasts to large blasts with dispersed chromatin, prominent nucleoli, and a moderate amount of
pale cytoplasm. tions, high white blood cell counts are
common.
blood cell counts, similar to patients with mixed blast crisis should be considered
Philadelphia (Ph) chromosome-positive in the differential diagnosis, especially if Microscopy
lymphoblastic leukaemia. there are two distinct lymphoid and mye These leukaemias typically show a dimor
loid blast populations. Many cases have phic blast population, with some blasts
Microscopy additional cytogenetic abnormalities, clearly resembling monoblasts and oth
Many cases show a dimorphic blast and complex karyotypes are common. ers resembling lymphoblasts. However,
population, with some blasts resembling some cases have no distinguishing fea
lymphoblasts and others myeloblasts, Prognosis and predictive factors tures and appear only as undifferenti
although other cases have no distin This type of leukaemia has a poor prog ated blast cells. Cases in which the entire
guishing features. Cases generally do nosis, which appears to be worse than blast population appears monoblastic
not show significant myeloid maturation; that of other MPALs {2013}, in particular are more likely to be acute myeloid leu
caution should be exercised when mak in adults {2583}. kaemia with a KMT2A translocation, but
ing this diagnosis in a case of myeloid It is unclear whether the prognosis is this diagnosis requires flow cytometry to
leukaemia with maturation that also ex worse than that of Ph chromosome-pos exclude the presence of a small lympho
presses lymphoid markers, because itive lymphoblastic leukaemia. Some blastic population.
such a pattern can also be seen in the data suggest that treatment with tyrosine
blast phase of CML. kinase inhibitors may improve outcome Immunophenotype
as is seen in lymphoblastic leukaemia In most cases, it is possible to recognize
Immunophenotype with BCR-ABL1 {1973,3659}. There are a lymphoblast population with a CD19+,
The great majority of cases have blasts no known biological factors that predict CD10–, pro-B (B-cell precursor, B–1) im
that meet the criteria for B–cell and whether patients with this leukaemia will munophenotype, frequently positive for
myeloid lineage, as described above, do better or worse with therapy. CD15. Expression of other B-cell mark
although some cases have T–cell and ers, such as CD22 and CD79a, is often
myeloid blasts. Triphenotypic cases have weak. Cases also fulfil the criteria for
also rarely been reported. Mixed-phenotype acute myeloid lineage as defined above, most
leukaemia with t(v;11q23.3); commonly via demonstration of a sepa
Postulated normal counterpart rate population of myeloid (usually mono
KMT2A-rearranged
The postulated normal counterpart is a blastic) leukaemic cells {3013,4279}. Co
multipotent haematopoietic stem cell. Definition expression of MPO on lymphoid blasts
There is no evidence that this leukaemia Mixed-phenotype acute leukaemia is rare. Because KMT2A translocations
derives from a different cell than do other (MPAL) with t(v;11q23.3) fulfils the criteria can also produce T-ALL, it is theoretically
cases of Ph chromosome-positive acute for MPAL and has blasts with a transloca possible that T/myeloid leukaemias with
leukaemia. tion involving KMT2A (previously called t(v;11q23.3) could occur, although no
MLL). Many cases of lymphoblastic leu such cases have been reported.
Genetic profile kaemia (ALL) with KMT2A translocations
All cases have either t(9;22) detected by express myeloid-associated antigens, Genetic profile
conventional karyotyping or the BCR- but such cases should not be considered All cases have rearrangements of
ABL1 translocation detected by FISH or MPAL unless they fulfil the specific crite KMT2A, with the most common part
PCR. The p190 fusion transcript is more ria noted above. ner gene being AFF1 (AF4) on chromo
common than the p210 transcript {4256}. some 4 band q21.3 {560,3013}. Trans
If the p210 transcript is present, CML in a ICD-O code 9807/3 locations t(9;11) and t(11;19) have also
Mixed-phenotype acute
leukaemia, B/myeloid,
not otherwise specified
Definition
B/myeloid mixed-phenotype acute leu
kaemia (MPAL), not otherwise specified
(NOS), fulfils the criteria for B/myeloid Fig. 10.03 B/myeloid mixed-phenotype acute leukaemia, NOS: flow cytometry histograms. A Side scatter (SSC)
leukaemia as described above, but does versus CD45 histogram showing a major population of dim CD45+ blasts; B-cell lymphoblasts are blue, residual
normal B-cells red, and MPO+ cells (both blasts and residual normal cells) green. B and C The B-cell markers CD19
not fulfil the criteria for any of the geneti and CD22 are strongly expressed on the B-cell lymphoid blasts, at levels comparable to those seen on the residual
cally defined subgroups. normal B-cells (in red). D Most of the B-cell blasts lack MPO and many of the non-B-cell blasts are MPO+; there is
also a small population of blasts coexpressing CD19 and MPO.
ICD-O code 9808/3
commonly when a separate population of malities including near-tetraploidy {560,
Epidemiology B-cell lineage blasts is present {4279}. 3013}. Complex karyotypes are common
This is a rare leukaemia, probably ac {2487,2583}. Gene expression profile
counting for about 1% of all leukaemia Postulated normal counterpart studies suggest a signature intermedi
cases. It occurs in both children and The postulated normal counterpart is a ate between that of ALL and that of acute
adults, but more commonly in adults. multipotent haematopoietic stem cell. myeloid leukaemia in most cases {3447}.
There is growing evidence of a possible Mutations frequently found in either acute
Microscopy relationship between B-cell and myeloid myeloid or ALLs have also been reported
Most cases either have blasts with no development, suggesting the involve in MPAL, including mutations of ASXL1,
distinguishing features — morphologically ment of either a common precursor or a TET1/2, IDH1, IDH2, DNMT3A, NOTCH1,
resembling lymphoblastic leukaemia precursor of one lineage that has reacti and ETV6, and deletion of IKZF1 {4414}.
(ALL) — or have a dimorphic population vated a differentiation programme of the There are as yet insufficient data in the lit
with some blasts resembling lympho other {1974,2193}. erature and too few reported cases to de
blasts and others myeloblasts. termine whether any genetic entities can
Genetic profile be defined other than those discussed
Immunophenotype Most cases have clonal cytogenetic ab above, involving BCR-ABL1 and KMT2A.
The blasts meet the criteria for both B- normalities. Many different lesions have
cell and myeloid lineage assignment as been demonstrated, although none com Prognosis and predictive factors
listed above. MPO-positive myeloblasts monly enough to suggest specificity for B/myeloid MPAL, NOS, is generally
and monoblasts commonly also express this group of leukaemias. The lesions that considered a poor-prognosis leukae
other myeloid-associated markers, in have been seen in more than a single mia, although data on outcome of these
cluding CD13, CD33, and KIT (CD117). case include del(6p), 12p11.2 abnormali cases versus other MPALs are limited.
Expression of more mature B-cell mark ties, del (5q), structural abnormalities of In children, outcome is worse than that
ers, such as CD20, is rare, occurring most chromosome 7, and numerical abnor of ALL {923,1343,2402,3447}; in adults,
Fig. 10.04 T/myeloid mixed-phenotype acute leukaemia, NOS, infiltrating a lymph node. A and B Diffuse replacement of node by a population of cells with high nucleancytoplasmic
ratios and fine chromatin, histologically indistinguishable from lymphoblastic leukaemia/lymphoma. C Immunoperoxidase staining for CD3 stains most of the blast cells. D Immuno-
peroxidase staining for MPO shows distinct staining of a subpopulation of cells with round nuclei; this indicates that they are part of the neoplasm rather than infiltrating granulocytes.
Mixed-phenotype acute
leukaemia, not otherwise
specified, rare types
Definition
In some documented cases of leukae
mia, the leukaemic blasts show clear-cut
evidence of both T-cell and B-cell line
age commitment as defined above. This
is a very rare phenomenon, with a fre
quency that is likely even lower than has
typically been reported in the literature
{2583}. As strictly applied, the European
Group for the Immunological Characteri
zation of Leukemias (EGIL) criteria for bi
phenotypic leukaemia (i.e. scores > 2 in
more than one lineage), which assign a
2–point value to CD79a expression {331,
332} may overestimate the incidence of
B-/T-leukaemia, because CD79a can
be detected in T-lymphoblastic leukae
mia with some antibodies {1584}. For
the purpose of assigning B-cell lineage
to a case of T-lymphoblastic leukaemia,
CD79a and CD10 should not be consid
ered evidence of B-cell differentiation.
There have also been a few cases with
evidence of trilineage (B-cell, T-cell, and
myeloid lineage) assignment. Overall,
there are too few cases with these char
acteristics for any specific statements to
be made about clinical features, genetic
lesions, or prognosis.
To date, there have been no reports of
Fig. 10.06 T/myeloid mixed-phenotype acute leukaemia, NOS: flow cytometry in several cases, with gating on all mixed B- or T-cell and megakaryocytic or
cells (A,C,E) and on blasts (B,D,F), and with normal T-cells superimposed in violet. A and B So-called bilineage mixed B- or T-cell and erythroid leukae
leukaemia, with two separate populations of T-cell (blue) and myeloid (green) blasts; the side scatter (SSC) mias. It has been postulated that eryth
versus CD45 histogram shows that (A) the myeloid and T-cell populations have distinct light-scattering profiles. roid and megakaryocytic lineages are
B The cCD3 expression on the T-cell blasts is comparable in intensity to that on the residual normal T-cells.
the earliest to branch off from the pluri-
C and D So-called biphenotypic leukaemia, with a single population of blasts (red) coexpressing cCD3 and MPO;
there is a wide range of cCD3 expression intensity, but the brightest blasts are about as bright as the normal T-cells. potent haematopoietic stem cell, leaving
E and F Leukaemia in which both coexpression (red) and separate populations of T-cell (blue) and myeloid (green) progenitor cells with T-cell, B-cell, and
blasts can be seen; neither the term ‘biphenotypic’ nor the term ‘bilineage’ readily fits this case. myeloid potential {1803}; therefore, neo-
Introduction and
overview of the
classification of the
Lymphoid neoplasms
Introduction and overview of the Jaffe E.S.
Campo E.
classification of lymphoid neoplasms Harris N.L.
Pileri S.A.
Stein H.
Swerdlow S.H.
scribed germinal centre markers include of the late primary or secondary immune correspond to proliferating cells and are
LMO2 and HGAL. LMO2 is expressed in response {2428}. BCL6 also undergoes clinically aggressive tumours.
haematopoietic precursors in the bone somatic mutation in the germinal centre, Centroblasts mature to centrocytes,
marrow, but appears to be specific for but at a lower frequency than do the IG and these cells are seen predominantly
germinal centre B cells in normal reac genes {3084}. Ongoing IGV gene mu in the light zone of the germinal centre.
tive lymphoid tissues {2840}; it lacks this tation with intraclonal diversity is a hall Centrocytes express slg that has an al
specificity in lymphoid neoplasms {35}. mark of germinal centre cells, and both tered antibody-combining site compared
HGAL (also called GCET2) rs expressed IGV gene and BCL6 mutations serve as with that of their progenitors, due to both
in germinal centre B cells and germinal markers of cells that have been through somatic mutations and heavy-chain
centre-derived malignancies {3043}. the germinal centre. Most diffuse large class switching. Centrocytes with muta
In the germinal centre, somatic hyper B-cell lymphomas (DLBCLs) are com tions that result in increased affinity are
mutation occurs in the IGV genes; these posed of cells that at least in part resem rescued from apoptosis and re-express
mutations can result in a non-functional ble centroblasts and have mutated IGV BCL2 {2427}. Through interaction with
gene or a gene that produces antibody genes, consistent with a derivation from surface molecules on follicular dendritic
with lower or higher affinity for antigen. cells that have been exposed to the ger cells and T cells (e.g. CD23 and CD40
Also in the germinal centre, some cells minal centre. Burkitt lymphoma cells are ligand), centrocytes switch off BCL6
switch from IgM production to IgG or IgA BCL6-positive and have mutated IGH expression {584,3199} and differenti
production. Through these mechanisms, genes, and are therefore also thought ate into either memory B cells or plasma
the germinal centre reaction gives rise to to correspond to a germinal centre blast cells {2427}. BCL6 and IRF4 (also called
the higher-affinity IgG or IgA antibodies cell. Both Burkitt lymphoma and DLBCL MUM1) are reciprocally expressed, with
T-cell lymphomas:
Lymphocyte differentiation and function
T lymphocytes arise from a bone mar
row precursor that undergoes maturation
and acquisition of function in the thymus
gland. Antigen-specific T cells mature in
the thymic cortex. T cells recognizing self
peptides are eliminated via apoptosis, in
a process mediated by cortical epithe
lial cells and thymic nurse cells. Corti
cal thymocytes have an immature T-cell
phenotype and express TdT, CD1a, CD3,
CD5, and CD7. CD3 is first expressed in
the cytoplasm, prior to complete T-cell
receptor (TR) gene rearrangement and
export to the cell membrane. Cortical thy
mocytes are initially double-negative for
CD4 and CD8. These antigens are coex
pressed in maturing thymocytes; more-
Fig. 11.03 B-cell differentiation. B cells go through various stages of differentiation as they mature from pro-B cells mature T cells express only CD4 or CD8.
to plasma cells. The antigen-dependent phase of differentiation usually begins in the germinal centre, where B cells
encounter antigen. Red bar in nucleus indicates heavy chain gene rearrangement; blue bar indicates light chain re
These various stages of T-cell maturation
arrangement; black boxes connote somatic hypermutation. Cells coloured in yellow have not encountered antigen, as are reflected in T-lymphoblastic leukae-
opposed to antigen-dependent stages shown in violet. Modified from Swerdlow SH et al. {3848}. mia/lymphoma.
BCR, B-cell receptor; D, surface IgD; M, surface IgM; SHM, somatic hypermutation. Medullary thymocytes have a phenotype
similar to that of mature T cells of the pe
IRF4 being positive in late centrocytes Post-germinal centre memory B cells ripheral lymphoid organs. There are two
and plasma cells {1141,3483}. IRF4 plays circulate in the peripheral blood and classes of T cells: alpha beta T cells and
a critical role in downregulating BCL6 account for at least some of the cells in gamma delta T cells {3850}. This distinc
expression {3483}. Recent studies indi the follicular marginal zones of lymph tion is based on the structure of the T-cell
cate that MYC plays an important role in nodes, spleen, and mucosa-associated receptor. The alpha beta and gamma
germinal centre formation {1020}. MYC lymphoid tissue (MALT). Marginal-zone delta chains are each composed of a
is upregulated upon interaction of naive B cells of this compartment typically ex variable portion and a constant portion.
B cells with antigen and T cells by the press pan-B-cell antigens and surface They are both associated with the CD3
action of BCL6, and is essential for ger IgM (with only low levels of IgD), and lack complex, which contains gamma, delta,
minal centre formation. In normal reactive both CD5 and CD10 {3749,4124}. Plasma and epsilon chains. NK cells do not have
lymph nodes, staining for MYC highlights cells produced in the germinal centre en a complete T-cell receptor complex; ac
a population of centrocytes in the light ter the peripheral blood and home to the tivated NK cells express the epsilon and
zone of the germinal centre, and is re bone marrow. They contain predominant zeta chains of CD3 in the cytoplasm.
pressed in the dark zone. However, MYC ly IgG or IgA; they lack slg and CD20 but They express CD2, CD7, and sometimes
is re-induced in a subset of light-zone B express IRF4, CD79a, CD38, and CD138. CD8, but not surface CD3. They also typ
cells (centrocyes), allowing re-entry into Both memory B cells and long-lived plas ically express CD16 and CD56, variably
the dark zone and maintenance of the ma cells have mutated IGV genes, but do express CD57, and contain cytoplasmic
germinal centre reaction {1020}. Follicu not continue to undergo mutation. Post- cytotoxic granule proteins. NK cells kill
lar lymphomas are tumours of germinal germinal centre B cells retain the ability their targets through antibody-dependent
centre B cells (centrocytes and centro- to home to tissues in which they have cell-mediated cytotoxicity or a second
blasts) in which the germinal centre cells undergone antigen stimulation, probably mechanism involving killer activation re
fail to undergo apoptosis, in most cases through surface integrin expression, so ceptors and inhibitory killer-cell immuno
due to a chromosomal rearrangement, that B cells that arise in MALT tend to re globulin-like receptors. Because NK cells
t(14;18), that prevents the normal switch turn there, whereas B cells that arise in do not rearrange the TR genes, antibod
ing off of BCL2 expression. Centrocytes the lymph nodes home to nodal sites and ies to the various killer-cell immunoglobu-
usually predominate over centroblasts, bone marrow {508}. Marginal zone lym lin-like receptors can be used for analysis
and these neoplasms tend to be indolent. phomas of the MALT type, splenic type, of clonality in NK-cell proliferations.
MCL +, – + – – + – – – + –
DLBCL +/–, –/+ –c –/+ d n/a –/+ n/a +/–d +/– e – –
a The plasma cell components of LPL and MALT lymphoma are IRF4+.
b Some grade 3A and 3B FLs are IRF4+.
c Some DLBCLs are CD5+. Other B-cell neoplasms can sometimes be CD5+, including LPL, MALT and FL.
d DLBCLs of germinal centre B-cell type express CD10 and BCL6.
e DLBCLs of activated B-cell type are typically IRF4 +
1815,2199}. Hepatosplenic T-cell lym Principles of classification classic Hodgkin lymphoma (CHL). Simi
phoma of gamma delta origin has muta The classification of lymphoid neoplasms larly, CD56 is a characteristic feature of
tions in STAT5B in approximately 35% of is based on all available information to nasal NK/T-cell lymphoma, but it can
cases {2869}, and the same mutation is define disease entities {1557}. Having also be found in other T-cell lymphomas,
recurrent in gamma delta T-cell lympho sufficient tissue for this multiparameter in plasma cell neoplasms, and in non
mas involving the gastrointestinal tract approach is critical. Great caution is ad lymphoid cells such as blastic plasmacy-
and skin {2160}. The JAK/STAT path vised when core needle biopsies are used toid dendritic cell neoplasms. {173,315,
way is implicated in many forms of T-cell for the primary diagnosis of lymphoma; 746,987,4357}. Within a given disease
lymphoma, including anaplastic large fine-needle aspiration is generally inad entity, variation in immunophenotypic
cell lymphoma (both ALK-positive and equate for this purpose. Morphology and features can be seen. For example, most
ALK-negative) and monomorphic epithe- immunophenotype are sufficient for the hepatosplenic T-cell lymphomas are of
liotropic intestinal T-cell lymphoma {836, diagnosis of most lymphoid neoplasms. the gamma delta T-cell phenotype, but
2807}. However, no one antigenic marker is spe some cases are of alpha beta T-cell
Other genetic tools have also been ap cific for any neoplasm, and a combination derivation. Likewise, some follicular lym
plied in the study of mature lymphoid of morphological features and a panel of phomas are CD10-negative. An aberrant
neoplasms. These include comparative antigenic markers are necessary for cor immunophenotype may suggest or help
genomic hybridization and more sensitive rect diagnosis. Most B-cell lymphomas to confirm a diagnosis of malignancy
techniques of array-based copy-number have characteristic immunophenotypic {1815}.
profiling, both of which can identify areas profiles that are very helpful in diagnosis. Although lineage is a defining feature of
of deletion or amplification within the However, immune profiling is somewhat most lymphoid malignancies, in recent
genome. Gene expression microarrays less helpful in the subclassification of T- years there has been an increasing ap
can interrogate the expression of thou cell lymphomas. preciation of lineage plasticity within the
sands of genes at the RNA level, helping Although certain antigens are commonly haematopoietic system. Lineage switch
to elucidate pathways of activation and associated with specific disease enti or demonstration of multiple lineages
transformation {877,878,884,1208,1775, ties, these associations are not entirely is most often encountered in immature
2719,3409,3538}. Most recently, studies disease-specific. For example, CD30 is a haematolymphoid neoplasms, but also
have begun to explore changes at the universal feature of anaplastic large cell can be seen rarely in mature lymphomas
epigenetic level that control the expres lymphoma, but can also be expressed in {772,1172,1536}.
sion of multiple genes {2352, 3528}. other T-cell and B-cell lymphomas and in
Definition lymphoma with recurrent genetic abnor 6000 per year {1603}, with approximately
B-lymphoblastic leukaemia/lymphoma malities (p. 203). 80–85% being of precursor B-cell pheno
(B-ALL/LBL) is a neoplasm of precur type {1501,3358}.
sor lymphoid cells committed to the B- ICD-O code 9811/3 B-LBL constitutes about 10% of lympho
cell lineage, typically composed of small blastic lymphomas (LBLs); the remainder
to medium-sized blast cells with scant Synonyms are of T-cell lineage {419}. In one literature
cytoplasm, moderately condensed to Pro-B lymphoblastic leukaemia; com review, approximately 64% of 98 reported
dispersed chromatin, and inconspicu mon precursor B-lymphoblastic leukae cases were in patients aged < 18 years
ous nucleoli, involving bone marrow and mia; pre-B lymphoblastic leukaemia; {2448}. One report indicated a male pre
blood (B-ALL) and occasionally present pre-pre-B lymphoblastic leukaemia; dominance {2345}.
ing with primary involvement of nodal or common lymphoblastic leukaemia; pre
extranodal sites (B-LBL). By convention, cursor B-cell lymphoblastic lymphoma; Etiology
the term lymphoma is used when the pro precursor B-cell lymphoblastic leukae The etiology of B-ALL/LBL is unknown.
cess is confined to a mass lesion with no mia, NOS; B-cell acute lymphoblastic There is an increased risk of B-ALL in
or minimal evidence of blood and mar leukaemia children with Down syndrome and other
row involvement. With extensive marrow constitutional genetic disorders {4494}.
and blood involvement, the appropriate Epidemiology Genome-wide association studies have
term is B-ALL. If a patient presents with ALL is primarily a disease of children; 75% shown increased risk of B-ALL associ
a mass lesion and lymphoblasts in the of cases occur in children aged < 6 years. ated with certain single nucleotide poly
marrow, the distinction between leukae The estimated annual incidence world morphisms (SNPs) of genes including
mia and lymphoma is arbitrary {2792}. wide is 1–4.75 cases per 100 000 popu GATA3, ARID5B, IKZF1, CEBPE, and
In many treatment protocols, a value of lation {3327}. The estimated number of CDKN2A/B {3051,3133}. However, true
> 25% marrow blasts is used to define new cases in the USA is approximately familial ALL is rare, with some kindreds
leukaemia. Unlike with myeloid leukae
mias, there is no agreed-upon lower limit
for the proportion of blasts required to
establish a diagnosis of lymphoblastic
leukaemia (ALL). In general, the diag
nosis should be avoided when there are
< 20% blasts. Presentations of ALL with
low blast counts are uncommon; there
is no compelling evidence that failure to
treat a patient when there are < 20% mar
row lymphoblasts has an adverse effect
on outcome. Fig. 12.01 B-lymphoblastic leukaemia. A Bone marrow smears showing several lymphoblasts with a high
nucleancytoplasmic ratio and variably condensed nuclear chromatin. B B-cell lymphoblasts containing numerous
Exclusionary criteria coarse azurophilic granules.
The term B-ALL should not be used to
indicate Burkitt leukaemia/lymphoma.
Furthermore, some cases of B-ALL/LBL
have specific recurrent genetic abnor
malities that are associated with distinc
tive clinical and phenotypic properties,
have important prognostic implications,
or demonstrate other evidence that they
are mutually exclusive of other entities.
These cases should not be classified
as B-ALL/LBL, NOS, but rather accord
Fig. 12.02 Benign B-cell precursors (haematogones) in bone marrow. A Increased haematogones in bone marrow
ing to their genetic abnormalities. There
biopsy section may resemble lymphoblasts. B Bone marrow aspirate smear with increased haematogones, from an
are currently nine genetically defined B- 8-year-old boy, shows lymphoid cells with a high nucleancytoplasmic ratio and homogeneous nuclear chromatin;
ALL/LBLs, which are further described nucleoli are not observed or are indistinct. These cells resemble the lymphoblasts in lymphoblastic leukaemia of
in section B-lymphoblastic leukaemia/ childhood.
described having mutations in PAX5 children. Marrow and blood involvement Cytochemistry
{3630}, ETV6 {4435}, and TP53 {3226}. may be present, but by definition the pro Cytochemistry seldom contributes to the
TP53 mutation, as discussed below, portion of lymphoblasts in the marrow is diagnosis of ALL. Lymphoblasts are nega
shows a specific association with low < 25% {2345,2448}. tive for MPO. Granules, if present, may
hypodiploid B-ALL {1929}. Some translo stain light grey with Sudan Black B but are
cations associated with ALL have been Microscopy less intense than myeloblasts. Lympho
detected in neonatal specimens long In smear and imprint preparations, the blasts may show periodic acid-Schiff
before the onset of leukaemia, and mo lymphoblasts in B-ALL/LBL vary from (PAS) positivity, usually in the form of
nozygotic twins with concordant leukae small blasts with scant cytoplasm, con coarse granules. They may react with non
mia frequently share genetic abnormali densed nuclear chromatin, and indis specific esterase, with a multifocal punc
ties {1428,2731}. However, these findings tinct nucleoli to larger cells with moder tate or Golgi region pattern that shows
are thought to reflect somatic mutations ate amounts of light-blue to bluish-grey variable inhibition with sodium fluoride.
occurring in one twin and shared via in cytoplasm (occasionally vacuolated),
utero circulation rather than constitutional dispersed nuclear chromatin, and mul Immunophenotype
genetic lesions. tiple variably prominent nucleoli. The The lymphoblasts in B-ALL/LBL are
nuclei are round or show convolutions. almost always positive for the B-cell
Localization Coarse azurophilic granules are pres markers CD19, cCD79a, and cCD22;
By definition, the bone marrow is involved ent in some lymphoblasts in approxi although none of these by itself is spe
in all cases classified as B-ALL, and mately 10% of cases. In some cases, the cific, their positivity in combination or at
the peripheral blood is usually involved. lymphoblasts have cytoplasmic pseudo high intensity strongly supports the diag
Extramedullary involvement is common, pods (hand-mirror cells). Normal B-cell nosis. The lymphoblasts are positive for
with particular predilection for the cen precursors (haematogones) can mimic CD10, surface CD22, CD24, PAX5, and
tral nervous system (CNS), lymph nodes, lymphoblasts, but they typically have TdT in most cases, whereas CD20 and
spleen, liver, and testes. The most frequent even higher nuclear:cytoplasmic ratios, CD34 expression is variable; CD45 may
sites of involvement in B-LBL are the skin, more-homogeneous chromatin, and no be absent and if present is nearly always
soft tissue, bone, and lymph nodes {354, discernible nucleoli. more dimly expressed than on mature
2345,2448}. Mediastinal masses are un In bone marrow biopsies, the lympho B cells. The myeloid-associated antigens
common {354,2448,3506}. blasts in B-ALL are relatively uniform CD13 and CD33 may be expressed and
in appearance, with round to oval, in the presence of these myeloid markers
Clinical features dented, or convoluted nuclei. Nucleoli
Most patients with B-ALL present with range from inconspicuous to prominent.
evidence and consequences of bone The chromatin is finely dispersed. The
marrow failure: thrombocytopenia, anae number of mitotic figures varies. LBL is
mia, and/or neutropenia. The leukocyte generally characterized by a diffuse or
count may be decreased, normal, or (less commonly) paracortical pattern of
markedly elevated. Lymphadenopathy, involvement of lymph node. A single-file
hepatomegaly, and splenomegaly are pattern of infiltration of soft tissue is com
frequent. Bone pain and arthralgias may mon. Mitotic figures are usually numer
be prominent symptoms. Patients pre ous, and in some cases there may be a
senting with B-LBL are usually asymp focal so-called starry-sky pattern. The
tomatic, and most have limited-stage morphological features of B-lymphoblas
disease. Head and neck presentations tic and T-lymphoblastic proliferations are
are particularly common, especially in indistinguishable.
Fig. 12.07 B-lymphoblastic leukaemia/lymphoma with t(v;11q23.3); K/Wr2/A-rearranged. FISH study using a break-
apart probe for KMT2A (previously called MLL); the normal KMT2A gene [MLL(11q23)] appears as juxtaposed red B-lymphoblastic
and green signals or sometimes a yellow signal; the translocation is demonstrated by separation of the red and green leukaemia/lymphoma with
probes (MLLsp). t(12;21)(p13.2;q22.1);
Synonym blastic populations, a finding that can be ETV6-RUNX1
B-lymphoblastic leukaemia/lymphoma confirmed by immunophenotyping; such
with t(v;11q23); MLL-rearranged cases should be considered B/myeloid Definition
leukaemias. B-lymphoblastic leukaemia/lymphoma
Epidemiology (B-ALL/LBL) with t(12;21 )(p13.2;q22.1)
B-ALL with KMT2A rearrangement is the Immunophenotype is a neoplasm of lymphoblasts commit
most common leukaemia in infants aged Cases of B-ALL with KMT2A rearrange ted to the B-cell lineage in which the
< 1 year. It is less common in older child ments, especially t(4;11), typically have a blasts harbour a translocation between
ren and then becomes increasingly com CD19+, CD10-, CD24-, pro-B immuno ETV6 (also called TEL) on chromo
mon with age into adulthood. phenotype, and are also positive for some 12 and RUNX1 (also called AML1)
CD15 {1712,3066}. The NG2 homologue on chromosome 21.
Etiology encoded by CSPG4 is also characteris
Although the specific etiology of leukae tically expressed and is relatively specific. ICD-O code 9814/3
mia with KMT2A translocations is un
known, this rearrangement may occur Genetic profile Synonym
in utero, with a short latency between The KMT2A gene on chromo B acute lymphoblastic leukaemia/
the translocation and development of some 11q23.3 is a promiscuous onco lymphoma with t(12;21 )(p13;q22),
disease. Evidence for this includes the gene, with >100 fusion partners. Trans TEL/AML1 (ETV6-RUNX1)
fact that these leukaemias are frequent locations involving this gene can be
in very young infants, as well as the fact detected by standard karyotyping stud Epidemiology
that this translocation has been identified ies or by FISH with a break-apart probe This leukaemia is not seen in infants, but
in neonatal blood spots of patients who directed against the KMT2A gene. PCR is common in children, accounting for
subsequently develop leukaemia {1277}. can be used to identify major transloca about 25% of cases of B-ALL in that age
tion partners, but a negative PCR result group. It decreases in frequency with age
Clinical features cannot exclude an alternative fusion part to the point that it is rare in adulthood.
Patients with this leukaemia typically ner. The most common partner gene is
present with very high white blood cell AFF1 (AF4) on chromosome 4q21. Other Clinical features
counts: frequently >100 x 109/L. There common partner genes include MLLT1 The presenting features are generally
is also a high frequency of CNS involve (ENL) on chromosome 19p13 and MLLT3 similar to those seen in patients with
ment at diagnosis. Although organ in (AF9) on chromosome 9p21.3. KMT2A- other ALLs.
volvement may be seen, pure lymphoma- MLLT1 fusions are also common in T-
tous presentations are not typical. ALL, whereas fusions between KMT2A Microscopy
and MLLT3 are more typically associ There are no unique morphological or cy
Microscopy ated with acute myeloid leukaemia. Leu tochemical features that distinguish this
There are no unique morphological or kaemias with KMT2A rearrangement are entity from other types of ALL.
cytochemical features that distinguish frequently associated with overexpres
this entity from other types of ALL. In sion of FLT3 {149}. In contrast to nearly Immunophenotype
some cases of leukaemias with KMT2A all other categories of B-ALL, B-ALL with Blasts have a CD19+, CD10+ phenotype
rearrangement, it may be possible to rec KMT2A rearrangement in infants has very and are most often CD34 positive; other
ognize distinct lymphoblastic and mono- few associated additional mutations, with phenotypic features, including near or
Fig. 12.08 B-lymphoblastic leukaemia/lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1. FISH study using
B-lymphoblastic
probes against RUNX1 (AML1) (red) and ETV6 (TEL) (green). The normal genes appear as isolated red or green leukaemia/lymphoma with
signals, and the fusion gene (arrows) appears as a yellow signal. hyperdiploidy
complete absence of CD9, CD20, and expression signature {4423}. The ETV6-
CD66c {421,914,1712}, are relatively spe RUNX1 translocation is considered to be Definition
cific. Myeloid-associated antigens, es an early lesion in leukaemogenesis, as B-lymphoblastic leukaemia/lymphoma
pecially CD13, are frequently expressed evidenced by studies of neonatal blood (B-ALL/LBL) with hyperdiploidy is a
{283}. spots that have shown the presence neoplasm of lymphoblasts committed
of the translocation in children who de to the B-cell lineage whose blasts con
Cell of origin velop leukaemia many years later {4311}. tain > 50 chromosomes (usually <66),
This leukaemia appears to derive from a There is evidence that the translocation is typically without translocations or other
B-cell progenitor rather than a haemato necessary but not sufficient for the devel structural alterations. There is contro
poietic stem cell {580}. opment of leukaemia {4311}. versy as to whether the specific chromo
somal additions, rather than the specific
Genetic profile Prognosis and predictive factors number of chromosomes, should be part
The ETV6-RUNX1 translocation results B-ALL with the ETV6-RUNX1 transloca of the definition {1554,3284,3835}.
in the production of a fusion protein that tion has a very favourable prognosis, with
probably acts in a dominant negative cure seen in >90% of children, especially ICD-O code 9815/3
fashion to interfere with normal function of if they have other favourable risk factors.
the transcription factor RUNX1. This leu Relapses often occur much later than do Synonyms
kaemia appears to have a unique gene those of other types of ALL. Because this Hyperdiploid acute lymphoblastic leu
kaemia; high hyperdiploid acute lympho
blastic leukaemia; acute lymphoblastic
leukaemia with favourable trisomies
Epidemiology
This leukaemia is common in children,
accounting for about 25% of cases of
B-ALL in this age group. It is not seen
in infants, and decreases in frequency
among older children. It is uncommon in
adulthood, accounting for about 7-8% of
cases of B-ALL in adults {2771}.
Clinical features
The presenting features are generally
similar to those seen in patients with oth
er ALLs.
Microscopy
There are no unique morphological or cy-
tochemical features that distinguish this
Fig. 12.09 B-lymphoblastic leukaemia with hyperdiploidy. G-banded karyotype showing 55 chromosomes, including entity from other types of ALL.
trisomies of chromosomes 4,10, and 17 and tetrasomy 21. There are no structural abnormalities.
Genetic profile
The TCF3-PBX1 translocation results in
the production of a fusion protein that
has an oncogenic role as a transcrip
tional activator, and also likely interferes
with the normal function of the transcrip
tion factors coded by TCF3 and PBX1
{2243}. The functional fusion gene re
sides on chromosome 19, and there may
be loss of the derivative chromosome 1 in
some cases, resulting in an unbalanced
Fig. 12.10 B-lymphoblastic leukaemia with t(5;14)(q31.1;q32.1); IGH//L3. Bone marrow smear showing a population
translocation. Gene expression profil
of typical lymphoblasts along with numerous mature eosinophils. The granule distribution in some of the eosinophils ing studies have identified a signature
is unusual, but this is not a consistent factor. unique to this lesion {4423}. An alterna
tive TCF3 translocation, t(17;19), occurs
Microscopy B-lymphoblastic in rare cases of ALL involving the HLF
Blasts in this neoplasm have the typi leukaemia/lymphoma with gene on chromosome 17 and is associ
cal morphology of lymphoblasts, but the ated with a dismal prognosis. Therefore,
t(1;19)(q23;p13.3);
striking finding is an increase in circulat demonstration of a TCF3 rearrangement
ing eosinophils. This is a reactive popula TCF3-PBX1 by itself is not a diagnostic criterion for
tion and not part of the leukaemic clone. this leukaemia.
Definition A subset of B-ALL cases, most common
Immunophenotype B-lymphoblastic leukaemia/lymphoma ly hyperdiploid B-ALLs, have a karyotypi-
Blasts have a CD19+, CD10+ pheno (B-ALL/LBL) with t(1;19)(q23;p13.3) is a cally identical t(1;19) that involves neither
type. The finding of even small numbers neoplasm of lymphoblasts committed to TCF3 nor PBX1, and should not be con
of blasts with this phenotype in a patient the B-cell lineage in which the blasts har fused with this entity.
with eosinophilia strongly suggests this bour a translocation between TCF3 (also
diagnosis. known as E2A) on chromosome 19 and Prognosis and predictive factors
PBX1 on chromosome 1. In early studies, B-ALL with TCF3-PBX1
Genetic profile was associated with a poor prognosis,
The unique characteristics of this neo ICD-O code 9818/3 but this is now readily overcome with
plasm derive from a functional re modern intensive therapy. However,
arrangement between the IL3 gene on Epidemiology there may be an increased relative risk
chromosome 5 and an IGH gene on This leukaemia is relatively common in of CNS relapse in these patients {1850}.
chromosome 14, resulting in constitu children, accounting for about 6% of cas Many treatment protocols no longer re
tive overexpression of IL3 {1463}. Other es of B-ALL. It is less common in adults. quire identification of this genetic lesion;
than eosinophilia, the functional con the importance of identifying it as a dis
sequences of this rearrangement are Clinical features tinct entity is controversial, although the
not well understood. The abnormality is The presenting features are generally findings of unique immunophenotypic
typically detected by conventional karyo similar to those seen in patients with and genetic features support its inclusion
typing; it can also be detected by FISH, other ALLs. as a distinct entity.
although appropriate probes are not
widely available. Microscopy
There are no unique morphological or
Prognosis and predictive factors cytochemical features that distinguish
The prognosis is not considered to be this entity from other types of ALL.
different from that of other types of ALL,
although there are too few cases to be Immunophenotype
certain. Blast percentage at diagnosis is Blasts typically have a pre-B phenotype,
not known to be a predictive factor. with positivity for CD19, CD10, and cy
toplasmic mu heavy chain, although not
all cases of pre-B ALL have the t(1;19).
Fig. 12.11 T-lymphoblastic leukaemia. A Blood smear. The lymphoblasts vary in size from large cells to small cells with a very high N:C ratio. B Bone marrow biopsy section
showing mitotic activity in the lymphoblasts.
Etiology small lymphoblasts with very condensed abnormality involving the FGFR1 gene
One study reported a set of T-ALL cas nuclear chromatin and no evident nucle (see Myeloid/lymphoid neoplasms with
es in monozygotic twins that shared the oli to larger blasts with finely dispersed FGFR1 rearrangement, p. 77) {15,1760}.
same TR gene rearrangement {1235}, chromatin and relatively prominent nucle
suggesting an in utero origin of the ear oli. Nuclei range from round to irregular to Cytochemistry
liest genetic lesions. convoluted. Cytoplasmic vacuoles may T-lymphoblasts frequently show focal
be present. Occasionally, blasts of T-ALL acid phosphatase activity in smear and
Localization may resemble more mature lymphocytes; imprint preparations, although this is not
The bone marrow is involved in all cases in such cases, immunophenotypic stud specific.
of T-ALL. Unlike in B-ALL, aleukaemic ies may be required to distinguish this
presentations in the setting of bone mar disease from a mature (peripheral) T-cell Immunophenotype
row replacement are uncommon. T-LBL leukaemia. The lymphoblasts in T-ALL/LBL are usu
frequently shows mediastinal (thymic) In bone marrow sections, the lympho ally TdT-positive and variably express
involvement, although it may involve any blasts have a high N:C ratio, a thin nucle CD1a, CD2, CD3, CD4, CD5, CD7, and
lymph node or extranodal site. The skin, ar membrane, finely stippled chromatin, CD8. Of these markers, CD7 and CD3
tonsils, liver, spleen, CNS, and testes and inconspicuous nucleoli. The number (cytoplasmic) are most often positive,
may be involved, although presentation of mitotic figures is reported to be higher but only CD3 is considered lineage
at these sites without nodal or mediasti in T-ALL than in B-ALL. In T-LBL, the specific. CD4 and CD8 are frequently
nal involvement is uncommon. lymph node generally shows complete coexpressed on the blasts, and CD10
effacement of architecture and involve may be positive; however, these immu-
Clinical features ment of the capsule. Partial involvement nophenotypes are not specific for T-ALL,
T-ALL typically presents with a high leu in a paracortical location with sparing of because CD4 and CD8 double positivity
kocyte count, and often with a large me germinal centres may occur. Sometimes, can also be seen in T-cell prolymphocytic
diastinal mass or other tissue mass. Lym- a multinodular pattern is produced due leukaemia and CD10 positivity in periph
phadenopathy and hepatosplenomegaly to stretching of the fibrous framework, eral T-cell lymphomas (most commonly
are common. For a given leukocyte count mimicking follicular lymphoma. A starry- angioimmunoblastic T-cell lymphoma).
and tumour burden, T-ALL often shows sky effect may be present, sometimes In addition to TdT and CD34, CD1a and
relative sparing of normal bone marrow mimicking Burkitt lymphoma, although CD99 may help to indicate the precur
haematopoiesis compared to B-ALL. the nucleoli and cytoplasm are typically sor nature of T-lymphoblasts {3373}. In
T-LBL frequently presents with a mass in less prominent in T-LBL. The blasts can 29-48% of cases, there is nuclear stain
the anterior mediastinum, often exhibiting have round or convoluted nuclei. Mitotic ing for TAL1, but this does not necessar
rapid growth and sometimes presenting figures are often numerous. In the thy ily correlate with presence of TAL1 gene
as a respiratory emergency. Pleural effu mus, there is extensive replacement of alteration {695,931}.
sions are common. the thymic parenchyma and permeative CD79a positivity has been observed in
infiltration of the surrounding fibroadi- approximately 10% of cases {3188}. One
Microscopy pose tissue. or both of the myeloid-associated an
The lymphoblasts in T-ALL/LBL are mor Cases with histological findings of T-LBL tigens CD13 and CD33 are expressed
phologically indistinguishable from those with a significant infiltrate of eosinophils in 19–32% of cases {1998,4088}. KIT
of B-ALL/LBL. In smears, the cells are of among the lymphoma cells may be as (CD117) is positive in occasional cases;
medium size with a high N:C ratio; there sociated with eosinophilia, myeloid hy such cases have been associated with
may be a considerable size range, from perplasia, and an 8p11.2 cytogenetic activating mutations of FLT3 {3027}. The
presence of myeloid markers does not (TR) genes, and there is simultaneous as a result of a cryptic interstitial deletion
exclude the diagnosis of T-ALL/LBL, nor presence of IGH gene rearrangements in at chromosome 1p32 {467,1596,1837}.
does it indicate T/myeloid mixed-pheno approximately 20% of cases {3187,3860}. Aberrant TAL1 expression interferes with
type acute leukaemia. differentiation and proliferation by inhib
Many markers characteristic of immature Cytogenetic abnormalities and iting the transcriptional activity of TCF3
T cells, such as CD7, CD2, and even CD5 oncogenes (also called E47) and TCF12 (also called
and cCD3-epsilon, may also be seen in An abnormal karyotype is found in HEB) {2919}. Other important transloca
NK-cell precursors. Therefore, it can be 50–70% of cases of T-ALL/LBL {1426, tions in T-ALL include t(10;11 )(p13;q14),
very difficult to distinguish the rare true 1534}. The most common recurrent cy which results in PICALM-MLLT10 (also
NK-cell ALL/LBL from T-ALL that ex togenetic abnormality involves the al called CALM-AF10) and is found in 10%
presses only immature markers. CD56 pha and delta TR loci at 14q11.2, the of cases, and translocations involving
expression, although characteristic of beta locus at 7q35, and the gamma lo KMT2A (also called MLL), which occur in
NK cells, does not exclude T-cell leu cus at 7p14-15, with a variety of partner 8% of cases, most often with the partner
kaemia. T-ALL/LBL has previously been genes {1426,1534}. In most cases, these MLLT1 (also called ENL) at 19p13 {1426};
stratified into four stages of intrathymic translocations lead to a dysregulation of both result in activation of HOXA genes
differentiation according to the antigens transcription of the partner gene by jux {2614}. It has been proposed that T-ALL
expressed {332}: (1) pro-T/T-l, (2) pre- taposition with the regulatory region of be divided into four distinct, non-overlap
T/T-ll, (3) cortical T/T-lll, and (4) medul one of the TR loci. The most commonly ping genetic subgroups based on spe
lary T/T-IV. Many cases previously clas involved genes include the transcrip cific translocations that lead to aberrant
sified as pro-T or pre-T would now meet tion factors TLX1 (also called HOX11) expression of (1) TAL or LMO genes, (2)
the criteria for early T-cell precursor ALL at 10q24, which is involved in 7% of TLX1, (3) TLX3, and (4) HOXA genes, re
(see next section). Like normal thymo childhood and 30% of adult cases, and sulting in arrest of T-cell maturation at dis
cytes, T-ALL of the cortical T stage often TLX3 (also called HOX11L2) at 5q35, tinct stages of thymocyte development
has a double-positive (CD4+, CD8+) im- which is involved in 20% of childhood {2614,4143}. The TLX1 group appears
munophenotype together with CD1a posi and 10–15% of adult cases {1426}. Other to have a relatively favourable prognosis
tivity, whereas the medullary T stage ex transcription factors that may be involved {1189}. Another group, characterized by
presses either CD4 or CD8. Some studies in translocations include MYC at 8q24.1, overexpression of LYL1, may correspond
have shown a correlation between the TAL1 at 1p32, LM01 (also called RBTN1) more closely to early T-cell precursor
stages of T-cell differentiation and surviv at 11 p15, LM02 (also called RBTN2) at ALL {2614}.
al. T-ALL tends to have a more immature 11 p13, and LYL1 at 19p13 {897,1426}. Deletions also occur in T-ALL. The most
immunophenotype than does T-LBL, but The cytoplasmic tyrosine kinase LCK important is del(9p), resulting in loss of
the groups overlap {4287}. at 1p34.3–35 can also be involved in a the tumour suppressor gene CDKN2A
translocation. In many cases, transloca (an inhibitor of the cyclin-dependent ki
Postulated normal counterpart tions are not detected by karyotyping nase CDK4), which occurs at a frequen
A T-cell progenitor (T-ALL) or a thymic but only by molecular genetic studies. cy of about 30% by cytogenetics, and a
lymphocyte (T-LBL) For example, the TAL1 locus is altered greater frequency by molecular testing.
by translocation in about 20–30% of This leads to loss of G1 control of the
Genetic profile cases of T-ALL, but a t(1;14)(p32;q11) cell cycle.
Antigen receptor genes translocation can be detected in only About 50% of cases have activating muta
T-ALL/LBL almost always shows clonal about 3% of cases. Much more often, tions involving the extracellular heterodi
rearrangements of the T-cell receptor TAL1 is fused to STIL (also called SIL) merization domain and/or the C-terminal
Definition Early in their development, NK-cell pro wider availability of more specific NK-cell
NK-lymphoblastic leukaemia/lymphoma genitors express no specific markers markers, including panels of antibodies
has been very difficult to define, and {1255}, or express markers that overlap against killer-cell immunoglobulin-like re
there is considerable confusion in the with those seen in T-ALL, including CD7, ceptors, will help clarify this disease, but
literature. Contributing to this confusion CD2, and even CD5 and cCD3-epsilon until then, NK-ALL/LBL is best consid
is the fact that many cases reported as {3757}; therefore, distinguishing between ered a provisional entity. The diagnosis
NK-leukaemia due to expression of CD56 T-ALL and NK-cell tumours can be dif of precursor NK-ALL/LBL may be con
(NCAM) are now recognized to in fact be ficult. More-mature but more-specific sidered in a case that expresses CD56
blastic plasmacytoid dendritic cell neo markers such as CD16 are rarely ex along with immature T-associated mark
plasms {3151,3152}. Similarly, the entity pressed in any acute leukaemia; some ers such as CD7 and CD2, and even
known as myeloid/NK acute leukaemia markers that might be considered rela including cCD3, provided that the case
{3599,3841}, which has been suggested tively specific but that are still expressed lacks B-cell and myeloid markers, TCR
to be of precursor NK-cell origin {3000}, on NK-cell progenitors (e.g. CD94 and IG genes are in the germline con
has a primitive immunophenotype indis and CD161 {1255}) are not commonly figuration {1975,2070,3000}, and blastic
tinguishable from that of acute myeloid tested. Some well-characterized cases plasmacytoid dendritic cell neoplasm
leukaemia with minimal differentiation. of NK precursor tumours with lympho- has been excluded.
Until further evidence emerges, these matous presentations that expressed
should be considered as cases of acute NK-specific CD94 1A transcripts have
myeloid leukaemia. been described {2338}. It is hoped that
broader than a 20x field or becoming 4006}. The former are associated with a Monoclonal B―cell
confluent. Although data are limited, median survival time of < 1 year, whereas lymphocytosis
cases may also belong in this category the prognosis of the latter is identical to
when the Ki―67 proliferation index is that of a de novo DLBCL {3058}. DLBCL Definition
> 40% or there are > 2.4 mitoses in the transformation is associated with TP53 Monoclonal B―cell lymphocytosis (MBL)
proliferation centres {760,1373}. These and NOTCH1 mutations, CDKN2A de is defined by a monoclonal B-cell count
cases are reported to have an outcome letions, and MYC translocations {712, < 5 x109/L in the peripheral blood in
intermediate between those of typical 1125,3245}. The vast majority of Hodgkin subjects who have no associated lym-
CLL and classic Richter syndrome (dif lymphoma cases occur in mutated CLL, phadenopathy, organomegaly, other ex
fuse large B―cell lymphoma; DLBCL) are EBV―positive, and are unrelated to tramedullary involvement, or any other
{760,1373}. An increasing proportion of the CLL clone {2492}. The diagnosis of feature of a B―cell lymphoproliferative
prolymphocytes in the blood may also be Hodgkin lymphoma in the setting of CLL disorder {2516}. MBL is classified into
seen (prolymphocytoid transformation). requires classic Reed―Sternberg cells in three categories on the basis of pheno
However, progression of CLL into B―cell an appropriate background. The pres type: (1) chronic lymphocytic leukaemia
prolymphocytic leukaemia does not oc ence of scattered EBV―positive or some (CLL)―type, (2) atypical CLL―type, and (3)
cur, by definition. Approximately 2―8% of times EBV―negative Reed―Sternberg non―CLL―type. Caution is advised, be
patients with CLL develop DLBCL, and cells in the background of CLL does cause many small B―cell lymphomas/leu-
< 1% develop classic Hodgkin lymphoma not fulfil the criteria for the diagnosis of kaemias have low―level peripheral blood
{453,2492,4006}. Most cases of DLBCL- Hodgkin lymphoma. EBV―associated involvement.
type Richter syndrome are clonally relat lymphoproliferative disorders, including MBL with a CLL―type phenotype is the
ed to the previous CLL, i.e. they express Hodgkin lymphoma―type proliferations, most common, accounting for as many
the same immunoglobulin gene rear may occur in patients with CLL following as 75% of all cases. It is characterized by
rangement, and are IGHV―unmutated, immunosuppressive therapy {16,3993}. coexpression of CD19, CD5, CD23, and
whereas clonally unrelated cases usu CD20 (dim). The B cells show light chain
ally occur in IGHV―mutated CLL {2492, class restriction or ≥ 25% lack surface
Definition Localization
Splenic marginal zone lymphoma (SMZL) The tumour involves the spleen and
is a B―cell neoplasm composed of small splenic hilar lymph nodes, the bone mar
lymphocytes that surround and replace row, and often the peripheral blood. The
the splenic white pulp germinal centres, liver may also be involved. Peripheral
efface the follicle mantle, and merge with lymph nodes are not typically involved
a peripheral (marginal) zone of larger {347,2691}.
cells, including scattered transformed
blasts; both small and larger cells infiltrate Clinical features
the red pulp. Splenic hilar lymph nodes Patients present with splenomegaly,
and bone marrow are often involved; lym sometimes accompanied by autoim
phoma cells are frequently found in the mune thrombocytopenia or anaemia and
peripheral blood as villous lymphocytes. a variable presence of peripheral blood
villous lymphocytes. The bone mar
ICD-O code 9689/3 row is regularly involved, but peripheral
lymphadenopathy and extranodal infil protein, but marked hyperviscosity and
Synonyms tration are extremely uncommon. About hypergammaglobulinaemia are uncom
Splenic B―cell marginal zone lymphoma; one third of patients have a small para- mon {347,2691}. An association with
splenic lymphoma with villous lympho hepatitis C virus has been described in
cytes; splenic lymphoma with circulating southern Europe {135,1620}.
villous lymphocytes (no longer used)
Macroscopy
Epidemiology Gross examination of the spleen reveals
SMZL is a rare disorder, accounting for marked expansion of the white pulp and
< 2% of lymphoid neoplasms {148}, but it infiltration of the red pulp.
may account for most cases of otherwise
unclassifiable chronic lymphocytic leu Microscopy
kaemias that are CD5―negative. Most pa In the splenic white pulp, a central zone
tients are aged > 50 years, with a median of small round lymphocytes surrounds or,
age of 67―68 years. The incidence rates more commonly, replaces reactive ger
among males and females are equal {347, minal centres, with effacement of the nor
1999,4388}. mal follicle mantle {1783,2691}. This zone
merges with a peripheral zone of small to are a helpful feature, although they are however, such a specimen is often not
medium―sized cells with more dispersed sometimes observed in other lymphomas available.
chromatin and abundant pale cytoplasm, {1242}. When lymphoma cells are present
which resemble marginal zone cells, and in the peripheral blood, they are usually Immunophenotype
interspersed transformed blasts. The characterized by short polar villi. Some Tumour cells express surface IgM and
red pulp is always infiltrated, with small may appear plasmacytoid {2622}. usually IgD. They are positive for CD20
nodules of the larger cells and sheets of and CD79a and negative for CD5, CD10,
the small lymphocytes, which often in Differential diagnosis CD23, CD43, and annexin A1 {1783,
vade sinuses. Epithelioid histiocytes may The differential diagnosis includes other 2579}. CD103 is usually negative, and
be present in the lymphoid aggregates. small B―cell lymphomas/leukaemias, in cyclin D1 is absent {3540}. Ki―67 staining
Some cases have a markedly predomi cluding chronic lymphocytic leukaemia shows a distinctive targetoid pattern due
nant population of the larger marginal (CLL), hairy cell leukaemia (HCL), mantle to an increased growth fraction in both
zone―like cells {1532,1793}. Plasmacytic cell lymphoma, follicular lymphoma, and the germinal centre, if present, and the
differentiation may occur, and in rare cas lymphoplasmacytic lymphoma. It is also marginal zone. The absence of cyclin D1
es, clusters of plasma cells are present important to recognize that many small B- and LEF1 is useful in excluding mantle
in the centres of the white pulp nodules. cell lymphomas (other than HCL, which cell lymphoma and CLL, respectively.
In splenic hilar lymph nodes, the sinuses diffusely involves the red pulp) can have The absence of annexin A1 excludes
are dilated and lymphoma surrounds and slightly larger cells with pale cytoplasm HCL, and lack of CD10 and BCL6 helps
replaces germinal centres, but the two when they involve the splenic marginal to exclude follicular lymphoma {3540}. A
cell types, small lymphocytes and mar zone, mimicking SMZL {3197}. The nodu group of CD5+ SMZL cases has been
ginal zone cells, are often more intimately lar pattern on bone marrow biopsy ex described, distinguished by a higher
admixed, without the formation of a dis cludes HCL, but the morphological fea lymphocytosis and diffuse bone marrow
tinct so―called marginal zone. In the bone tures on bone marrow examination may infiltration {285}.
marrow, there is a nodular interstitial in not be sufficient to distinguish between
filtrate cytologically similar to that in the the other small B―cell neoplasms. Immu- Postulated normal counterpart
lymph nodes. Occasionally, neoplastic nophenotypic and molecular/cytogenetic A marginal―zone B cell that may or may
cells surround reactive follicles. Intrasinu- findings may also be very helpful, but the not demonstrate evidence of antigen
soidal lymphoma cells, which are more diagnosis can be rendered most con exposure
apparent after CD20 immunostaining, fidently from a splenectomy specimen;
Genetic profile
Antigen receptor genes
IG heavy and light chain genes have
clonal rearrangements, and approxi
mately half of the cases have somatic hy
permutation. Bias in IGHV1―2*04 usage
has been found in 30% of SMZL cases,
suggesting that this tumour derives from
a highly selected B―cell population {62,
378}. Stereotyped HCDR3 sequences,
specific for SMZL, support a potential
role of antigen selection in the pathogen
esis of these lymphomas {4493}.
Cytogenetic abnormalities and NOTCH2 is one of the most frequently Prognosis and predictive factors
oncogenes mutated genes in SMZL, mutated in ap The clinical course is indolent, with a 10
SMZL lacks recurrent chromosomal proximately 10―25% of cases {771,2006, year survival probability from 67% to 95%
translocations, including transloca 2532,3070,3203,3419}. Although dia {135,347,2266,2781,3956,3957,3768A}.
tions that are typical of other lymphoma gnostically useful, NOTCH2 mutations Response to chemotherapy of the type
types, such as the t(14;18)(q32;q21) are also seen in infrequent other small that is typically effective in other small B-
translocation affecting BCL2 in follicular B―cell lymphomas {305,1945,2006, cell neoplasms is often poor, but patients
lymphoma; the t(11;14)(q13;q32) trans 3419}. KLF2 is somatically mutated in generally have haematological responses
location affecting CCND1 in mantle cell approximately 10―40% of SMZLs {771, to splenectomy and/or rituximab, with
lymphoma; and the t(11;18)(q21;q21), 3070,3203}, but these mutations are long―term survival {2266,3139A,3768A}.
t(14;18)(q32;q21), and t(1;14)(p22;q32) also found in some other small B―cell Transformation to large B―cell lymphoma
translocations resulting in BIRC3/MALT1, neoplasms {3203}. Mutations in both of occurs in 10―15% of cases {4388}, and
IGHIMALT1, and IGH/BCL10 juxtaposi these genes have been associated with is usually associated with a shorter time
tion, respectively, in extranodal marginal SMZLs that have deletion in 7q. MYD88 to progression {2266,2781}. Hepatitis C
zone lymphoma of mucosa―associated mutations are rare in SMZL, and may virus―positive cases have been reported
lymphoid tissue (MALT lymphoma). The therefore be a useful biomarker for the to respond to antiviral treatment using in
absence of these abnormalities helps differentiation of SMZL from lymphop- terferon gamma, with or without ribavirin
distinguish SMZL from some of the lym lasmacytic lymphoma in pathologically {1620,3955}. Adverse clinical prognostic
phomas that can mimic it. A small num challenging cases with evidence of plas- factors include a large tumour mass and
ber of SMZLs carry a recurrent t(2;7) macytic differentiation {2534,3070}. The poor general health status {627}. A clinical
(p12;q21) translocation, which activates fact that the most frequently mutated scoring system has been proposed that
the CDK6 gene through juxtaposition genes in SMZL (i.e. NOTCH2 and KLF2) incorporates haemoglobin concentration,
with the IGK locus {810}. Approximately are physiologically involved in prolifera platelet count, lactate dehydrogenase
30% of SMZLs show a heterozygous tion and commitment of mature B cells level, and presence of extrahilar lym-
deletion in 7q, which is rarely found in to the marginal zone, points to homing phadenopathy {2696}. Although data are
other lymphoma subtypes {3362,3497}. to the spleen compartment and marginal limited, NOTCH2, KLF2, and in particular
The gene(s) targeted by the 7q deletion zone differentiation as the major pro TP53 mutations have been reported to be
remain unknown, despite the combined grammes deregulated in this lymphoma. adverse prognostic indicators {3070}.
investigation of genomic and transcrip- Congruently, SMZL has an expression
tomic profiles and mutation analysis of a signature characterized by the upregula-
number of candidate genes {1254,3376, tion of genes belonging to the marginal
4268}. Gain of 3q is present in a consid zone differentiation programme {3455,
erable subset of cases. 4064}.
Genetic profile
Antigen receptor genes
Although exceptions have been report
ed, the majority (> 85%) of cases of HCL
demonstrate IGHV genes with somatic
hypermutation indicative of a post―ger
minal centre stage of maturation {152,
Fig. 13.22 Hairy cell leukaemia (HCL), A Hypocellular HCL with interstitial infiltrates in bone marrow biopsy. 586,3994). A unique feature of HCL is the
B CD20 immunohistochemical staining highlights the subtle leukaemic infiltrate in this case. C Spleen shows red pulp common coexpression of multiple clon
infiltration with numerous red blood cell lakes. D There is both portal and sinusoidal infiltration in the liver. ally related immunoglobulin isotypes,
suggesting arrest at some point during
isotype switching {3994}.
Epidemiology
Splenic diffuse red pulp small SDRPL is a rare disorder, account
B―cell lymphoma ing for < 1% of non―Hodgkin lympho
mas. It accounts for about 10% of the
Definition B―cell lymphomas diagnosed in sple
Splenic diffuse red pulp small B―cell lym nectomy specimens. Most patients are
phoma (SDRPL) is an uncommon lympho aged > 40 years, and there is no sex
ma with a diffuse pattern of involvement predilection.
of the splenic red pulp by small mono
morphous B lymphocytes. The neoplasm Localization
also involves bone marrow sinusoids and All cases are diagnosed at clinical
peripheral blood, commonly with a vil stage IV, with spleen, bone marrow, and
lous cytology {1921,4043,4044}. This is a peripheral blood involvement. Peripheral
provisional entity that requires additional lymph node involvement is only rarely
molecular studies for defining its main reported.
features and diagnostic markers. This
Genetic profile
Antigen receptor genes
IG genes are rearranged, usually with
variable regions that show somatic
hypermutation but lack ongoing muta
tions {4226}. There may be biased IGHV
gene usage {1801,2114}. Clonal cytotoxic
T―cell populations may be present, at
least in the peripheral blood {2299}.
Definition Table 13.03 Diagnostic criteria for IgM monoclonal may be required to identify the clonal
IgM monoclonal gammopathy of unde gammopathy of undetermined significance; adapted population within the background of be
termined significance (MGUS) is defined from the International Myeloma Working Group (IMWG) nign polytypic B cells {2924,3032,3034}.
by a serum IgM paraprotein concen updated criteria for the diagnosis of multiple myeloma When present, the clonal B―cell popula
From: Rajkumar SV, et al. {3290}.
tration < 30 g/L; bone marrow lympho tion shows a non―specific phenotype
plasmacytic infiltration of < 10%; and • Serum IgM monoclonal protein similar to that of LPL (CD19+, CD20+,
no evidence of anaemia, constitutional concentration < 30 g/L CD5―, CD10―, and CD103―). The plas
symptoms, hyperviscosity, lymphadeno- • Bone marrow lymphoplasmacytic infiltration ma cells in IgM MGUS lack expression of
pathy, hepatosplenomegaly, or other of < 10% CD56 {3034}.
end―organ damage that can be attribut • No evidence of anaemia,
ed to the underlying lymphoproliferative constitutional symptoms, hyperviscosity, Postulated normal counterpart
disorder {3290}. IgM MGUS is a precur lymphadenopathy, hepatosplenomegaly, B cells with somatic hypermutation of the
sor condition that may progress to overt or other end-organ damage that IGHV genes but without class switching
can be attributed to the underlying
lymphoma or primary amyloidosis. {2177}
lymphoproliferative disorder
Localization
The spleen, liver, bone marrow, and pe
ripheral blood may be involved; periph
eral lymphadenopathy is usually absent.
Clinical features
Most patients present with a slowly pro
gressive disease resembling CLL. Mu
HCD differs from most cases of CLL in
the high frequency of hepatospleno
megaly and the absence of peripheral
lymphadenopathy. Routine serum protein
electrophoresis is frequently normal. Im
munoelectrophoresis reveals reactivity
to anti―mu in polymers of diverse sizes.
Although mu chain is not found in the
urine, Bence Jones light chains (particu
larly kappa chains) are common (found in
the urine in 50% of cases). Light chains,
although still produced in mu HCD, are
not assembled into a complete immuno
globulin protein, due to IGH gene aber-
rancies leading to truncated forms {242,
4229,4230}.
Microscopy
The bone marrow contains vacuolated
plasma cells, which are typically admixed
with small, round lymphocytes similar to
CLL cells.
Localization
The tumour may involve the lymph nodes,
Waldeyer ring, gastrointestinal tract and
other extranodal sites, bone marrow,
liver, spleen, and peripheral blood.
Synonym
Franklin disease
Immunophenotype
The cells express CD79a and cytoplasmic
gamma chain and are negative for CD5
and CD10. CD20 is found on the lympho
cytic component and CD138 on the plas
ma cell component. Kappa and lambda
light chains are typically not expressed,
but a minority of cases show staining for
monotypic light chains by immunohisto-
chemistry or in situ hybridization, despite
the absence of light chains on immuno-
fixation studies {370,371,4230}.
Genetic profile
IG genes are clonally rearranged and
contain high levels of somatic hypermu
tation. Deletions in the IGHG gene are
present that result in expression of an
abnormally truncated heavy chain pro
tein that cannot bind light chain to form istic of lymphoplasmacytic lymphoma is phoplasmacytic infiltrates appear to re
a complete immunoglobulin molecule. absent in gamma HCD {1526}. spond to non―anthracycline―containing
These deletions involve IGHV and vari chemotherapy, and responses to rituxi
able proportions of the CH1 domain, and Prognosis and predictive factors mab and other single agents have also
there may be insertions of large amounts The clinical course is highly variable, been reported {370,4230}.
of DNA of unknown origin {57,370,1132, ranging from indolent to rapidly progres
1243,1249,4230}. sive. One study of 23 cases reported a
Abnormal karyotypes have been found median survival time of 7.4 years, with
in about half of the reported cases, but more than half of the deaths unrelated to
no specific or recurrent genetic abnor the lymphoproliferative disorder {4231}.
mality has been reported {371,4231}. The There is no standardized therapy. Most
MYD88 L265P mutation that is character patients with low-grade-appearing lym
Synonyms
Mediterranean lymphoma; immunoprolif Fig. 13.37 Alpha heavy chain disease (also known as immunoproliferative small intestinal disease). A Partially
erative small intestinal disease colonized reactive follicle centre is present just above the muscularis mucosae at the right. Clusters of pale-staining
marginal zone cells are present adjacent to the follicle and elsewhere in the biopsy. The lamina propria and small
intestinal villi are expanded by plasma cells. B A lymphoepithelial lesion in a case of alpha heavy chain disease
Epidemiology
showing destruction of intestinal crypts by marginal zone cells, with surrounding plasma cells.
Alpha HCD is the most common of the
HCDs. Unlike the other HCDs, alpha
HCD involves a young age group, with phoresis, or immunoselection techniques and the CH1 domain, and there may be
a peak incidence rate in the second and {370,4230}. insertions of DNA of unknown origin {48,
third decades; it is rare in young children 4230}. Cytogenetic abnormalities have
and older adults, and there is an equal in Microscopy been reported in rare single cases. The
cidence in males and females. It is most The lamina propria of the bowel is heav t(11;18)(q21;q21) (BIRC3/MALT1) trans
common in areas bordering the Mediter ily infiltrated with plasma cells and ad location associated with gastric and pul
ranean Sea, including northern Africa, mixed small lymphocytes; marginal zone monary MALT lymphomas has not been
Israel and Saudi Arabia. It is associated B cells may be present, with formation of described {4421}.
with factors linked to low socioeconomic lymphoepithelial lesions. The lymphop
status, including poor hygiene, malnu lasmacytic infiltrate separates the crypts, Prognosis and predictive factors
trition, and frequent intestinal infections and villous atrophy may be present {1781, In the early phase, alpha HCD may com
{48,3298,3617,4230}. 3239,3298}. Sheets of large plasmacyt pletely remit with antibiotic therapy. In
oid cells and immunoblasts that form sol patients with more advanced disease,
Etiology id, destructive aggregates with ulceration multiagent chemotherapy is typically
Chronic intestinal infection, in some cas characterize progression to diffuse large required. Treatment with anthracycline-
es with Campylobacter jejuni, is believed B-cell lymphoma {370,4230}. containing regimens has been reported
to result in chronic inflammation, a set to result in remission and long-term sur
ting in which neoplastic transformation Immunophenotype vival in 67% of patients {48,3295,4230}.
of a clone of abnormal B cells develops The plasma cells and marginal zone cells
{2248,3072}. express monoclonal cytoplasmic alpha
chain without light chains. Marginal zone
Localization cells express CD20 and are negative for
Alpha HCD involves the gastrointestinal CD5 and CD10; plasma cells are typi
tract (mainly the small intestine) and mes cally CD20-negative and CD138-positive
enteric lymph nodes. The gastric and {1781}.
colonic mucosa may also be involved.
The bone marrow and other organs are Postulated normal counterpart
usually not involved, although respiratory A post-germinal centre B cell that can
tract and thyroid involvement has been differentiate into a plasma cell, with an
described in rare cases {3617,4040}. abnormal IGHA gene
Plasma cell neoplasms result from ex Table 13.04 Plasma cell neoplasms
pansion of a clone of immunoglobulin-
secreting, heavy chain class-switched, Non-IgM (plasma cell) monoclonal gammopathy Clinical variants
of undetermined significance (precursor lesion)
terminally differentiated B cells that
typically secrete a single homogeneous Plasma cell myeloma Smouldering (asymptomatic) plasma cell myeloma
monoclonal immunoglobulin called an Non-secretory myeloma
M protein; the presence of such a pro Plasma cell leukaemia
tein is called monoclonal gammopathy.
Plasmacytoma Solitary plasmacytoma of bone
The plasma cell neoplasms discussed
Extraosseous (extramedullary) plasmacytoma
in this section include plasma cell my
eloma, plasmacytoma, disorders defined Monoclonal immunoglobulin Primary amyloidosis
by tissue immunoglobulin deposition deposition diseases Systemic light and heavy chain deposition diseases
(primary amyloidosis and light and heavy
Plasma cell neoplasms with associated POEMS syndrome
chain deposition diseases), and clonal paraneoplastic syndrome TEMPI syndrome (provisional)
plasma cell proliferations with an associ
ated paraneoplastic syndrome (POEMS
syndrome and TEMPI syndrome) (see are detailed in the section on lymphop Synonym
Table 13.04). Non―IgM monoclonal gam lasmacytic lymphoma and will not be dis Monoclonal gammopathy, NOS
mopathy of undetermined significance, cussed further in this section.
a precursor lesion with the potential to Non―IgM (plasma cell) MGUS is defined Epidemiology
evolve to a malignant plasma cell neo as the presence in the serum of an IgG, MGUS is uncommon in patients aged
plasm, is also included. Other immuno IgA, or (rarely) IgD M protein at a con < 40 years but is found in approximately
globulin―secreting disorders that consist centration < 30 g/L; clonal bone marrow 3―4% of individuals aged > 50 years and
of both clonal lymphocytes and plasma plasma cells < 10%; and absence of end- in > 5% of individuals aged > 70 years;
cells, including lymphoplasmacytic lym organ damage such as hypercalcaemia, 80―85% of cases are non―IgM MGUS
phoma, the heavy chain diseases, and renal insufficiency, anaemia, and bone {2175, 2176}. Approximately 60% of pa
IgM monoclonal gammopathy of unde lesions (CRAB) and amyloidosis attrib tients with non-IgM MGUS are men, and
termined significance, are discussed in utable to the plasma cell proliferative it is nearly twice as frequent in Black pop
other sections. disorder (Table 13.05) {3290}. The risk ulations as in White populations {2171,
of progression to plasma cell myeloma, 2210,2211,3685}.
light-chain amyloidosis, or a related dis
Non-IgM monoclonal order is 1% per year. Light-chain MGUS Etiology
gammopathy of undetermined consists only of monoclonal light chains. No cause of MGUS has been identified,
It is defined by an abnormal free light but there is an increased prevalence in
significance
chain ratio and an increase of involved families with members with a lymphoid or
Definition light chain with complete loss of heavy plasma cell proliferative disorder {1441,
There are two major types of monoclo chain expression. The urinary light chain 2212}. Transient oligoclonal and mono
nal gammopathy of undetermined sig excretion must be < 0.5 g/24 hour. The clonal gammopathies may occur in solid
nificance (MGUS): plasma cell and lym- plasma cell content is < 10%, and there organ and bone marrow / stem cell trans
phoid/lymphoplasmacytic, which have is no end-organ damage attributable to plant recipients {2171,2679,3330}.
different genetic bases and different the plasma cell disorder {1004,2167}.
outcomes in terms of malignant progres The rate of progression of light-chain Localization
sion. Plasma cell MGUS and lymphoid/ MGUS is approximately 0.3% per year The clonal plasma cells producing non-
lymphoplasmacytic MGUS can usually (Table 13.06). Although the M protein IgM MGUS are in the bone marrow.
be distinguished by morphology, but this reflects the presence of an expanded
analysis is not always precise. Instead, clone of immunoglobulin―secreting Clinical features
MGUS is classified as IgM MGUS, which plasma cells, non―IgM MGUS is consid Patients exhibit no symptoms or physi
is mostly lymphoid/lymphoplasmacytic, ered a premalignant neoplasm, which in cal findings related to non-IgM MGUS,
or non-IgM MGUS, which is mostly plas most cases does not progress to overt and the typical laboratory and radio-
ma cell, although about 1% of plasma malignancy. graphical abnormalities associated with
cell MGUS cases actually produce an plasma cell myeloma are lacking. The
IgM M protein. Features of IgM MGUS ICD-O code 9765/1 M protein is often identified in the course
PCM
Prognosis and predictive factors Clonal bone marrow plasma cell percentage ≥ 10% or biopsy-proven plasmacytoma and
In most cases, the clinical course of MGUS ≥ 1 of the following myeloma-defining events:
is stable, with no increase in M protein or End-organ damage attributable to the plasma cell proliferative disorder:
other evidence of progression, but in a - Hypercalcaemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the upper limit of normal or
substantial minority, there is evolution to > 2.75 mmol/L (> 11 mg/dL)
an active plasma cell myeloma, solitary - Renal insufficiency:
plasmacytoma, or amyloidosis {1762, creatinine clearance < 40 mL/minute or serum creatinine > 177 μmol/L (> 2 mg/dL)
- Anaemia: a haemoglobin value of > 20 g/L below the lower limit of normal or a
2171}. The risk of progression is about 1%
haemoglobin value < 100 g/L
per year (0.3% for light-chain MGUS) and - Bone lesions: ≥ 1 osteolytic lesion on skeletal radiography, CT, or PET/CT
indefinite, persisting even after 30 years
≥ 1 of the following biomarkers of malignancy:
{2171,2176}. The size and type of M pro - Clonal bone marrow plasma cell percentage ≥ 60%
tein and serum free light chain ratio are - An involved-to-uninvolved serum free light chain ratio ≥100
significant prognostic indicators {1762, - > 1 focal lesion on MRI
2172,2176,3080,4078}. The risk of pro Smouldering (asymptomatic) PCM
gression for patients with an M protein Both criteria must be met:
concentration of 25 g/L is > 4 times that - Serum M protein (IgG or IgA) ≥ 30 g/L or urinary M protein ≥ 500 mg/24 hours and/or
of patients with a concentration < 5 g/L. clonal bone marrow plasma cell percentage of 10-60%
Patients with IgA MGUS are at greater - Absence of myeloma―defining events or amyloidosis
risk of progression (~1.5% per year) to a
malignant disorder than are patients with
IgG or light-chain MGUS {2171}. Patients based on a combination of clinical, mor radiation has been associated with an in
with IgG or IgA MGUS with an abnormal phological, immunological, and radiologi creased incidence of PCM {2292,2353}.
serum free light chain ratio at diagnosis cal features. The diagnostic criteria for An antigenic stimulus giving rise to mul
are at higher risk of progression than are PCM are listed in Table 13.07. tiple benign clones could be followed by
patients with a normal ratio {2171,3292}. a mutagenic event initiating malignant
Individuals with marked predominance ICD-O code 9732/3 transformation {1522}. Most patients have
of aberrant plasma cells (> 90%) on flow
cytometry have a significantly higher risk Synonyms
of progression to myeloma {2974,3138}. Multiple myeloma; medullary plasmacy
DNA aneuploidy and subnormal levels of toma; myelomatosis; Kahler disease (no
polyclonal immunoglobulin appear to be longer used); myeloma, NOS
additional clinical risk factors {3138}. An
evolving clinical phenotype also predicts Epidemiology
an increased probability of progression PCM accounts for about 1% of malig
to myeloma {3137}. Several risk stratifica nant tumours, 10―15% of haematopoi
tion models identify subgroups of cases etic neoplasms, and 20% of deaths from
of non-IgM MGUS that progress to mye haematological malignancies {1851,
loma at rates ranging from approximately 2164,3357}. In the USA in 2015, an es
0.3% to 12% per year {2167,3137,3138, timated 26 000 cases were diagnosed
3292,4496}. and > 11 000 patients died of PCM
{3673}. PCM is more common in men
than in women, with a male-to-female ra
Plasma cell myeloma tio of 1.1:1. It is nearly twice as frequent
in Black populations as in White popula
Definition tions {2164,3357,3673}. PCM is almost
Plasma cell myeloma (PCM) is a bone never found in children and very infre
marrow-based, multifocal neoplastic pro quently in adults aged < 30 years {840,
liferation of plasma cells, usually associat 390}; the incidence increases progres
ed with an M protein in serum and/or urine sively with patient age thereafter, with
and evidence of organ damage related to about 90% of cases occurring in patients
the plasma cell neoplasm. Bone marrow aged > 50 years (median patient age at
is the site of origin of nearly all PCMs, and diagnosis: ~70 years).
in most cases there is disseminated bone
marrow involvement. Other organs may Etiology
be secondarily involved. The disease Chronic antigenic stimulation from in Fig. 13.38 Plasma cell myeloma. Radiographs of skull
spans a clinical spectrum from asympto fection or other chronic disease and ex (A) and femoral head (B) demonstrate multiple lytic
matic to highly aggressive. Diagnosis is posure to specific toxic substances or bone lesions.
Imaging
Bone lesions are found on radiographical
skeletal survey in about 70% of cases of
PCM, and even more frequently by MRI
and PET/CT {988,2164,3348,4455}. Lytic
lesions are most common (accounting
for ~70% of the bone lesions found), but
abnormalities also include osteoporo
sis (accounting for 10―15% of bone le
sions), pathological fractures, and ver
tebral compression fractures. The most
frequent sites of lesions, in decreasing
order, are the vertebrae, ribs, skull, shoul
ders, pelvis, and long bones {4455}.
Macroscopy
The bone defects apparent on gross ex
amination are filled with soft, gelatinous,
fish-flesh haemorrhagic tissue.
Microscopy
Bone marrow biopsy
Monoclonal plasma cells may be scat
tered interstitially, in small clusters, in
focal nodules, or in diffuse sheets {281,
480,3330}. There is often bone marrow
sparing and preservation of normal hae
matopoiesis, with interstitial and focal
patterns of involvement. With diffuse in
volvement, expansive areas of the bone
marrow are replaced and haematopoie
sis may be markedly decreased. There is
typically progression from interstitial and
focal disease in early PCM to diffuse in
volvement in advanced stages of disease
{281}. Generally, when 30% of the bone
marrow volume is composed of plasma
cells, a diagnosis of myeloma is likely,
although rare cases of reactive plasma-
cytosis can reach that level. A tumoural
Genetic profile
Antigen receptor genes
IG heavy and light chain genes are clon
ally rearranged. There is a high load of
IGHV gene somatic hypermutation with
out ongoing mutations, consistent with
derivation from a post-germinal centre,
antigen-driven B cell {237}.
Proportion of
Genetic category cases
Hyperdiploid 45%
Non-hyperdiploid 40%
Cyclin D translocation 18%
t(11;14)(q13;q32) 16%
t(6;14)(p25;q32) 2%
t(12;14)(p13;q32) <1%
trisomies and whole or partial chromo patterns of translocations and cyclin D NSD2
(also called MMSET)
some deletions and translocations; expression (TC groups), non-IgM MGUS
translocation 15%
complex cytogenetic abnormalities are and PCM can be classified into groups
common. A molecular cytogenetic classi that are based mostly on early patho t(4;14)(p16;q32) 15%
fication of PCM proposed by the Interna genic events (Table 13.10). Some or all MAF translocation 8%
tional Myeloma Working Group (IMWG) of these groups may represent distinct t(14;16)(q32;q23) 5%
is shown in Table 13.08 {1232}. The ge disease entities that require different t(14;20)(q32;q11) 2%
netic categories are major indicators therapeutic strategies {2128,3798}. Two t(8;14)(q24;q32) 1%
of prognosis and form the basis for risk other molecular classifications based on
stratification of PCM (see Prognosis and unsupervised clustering of tumours by Unclassified (other) 15%
predictive factors). The IMWG consensus gene expression profiles are similar to
recommendations on genetic testing are the TC groups {473,4474}. However, they Table 13.09 The International Myeloma Working Group
are not generally applicable for non-IgM (IMWG) consensus recommendations on genetic test
listed in Table 13.09 {1232}.
ing. Adapted from Fonseca R, et al. {1232}
The most frequent chromosome trans MGUS, because some of the groups are
locations involve IGH on chromo based on progression events not found in FISH (on cell-sorted samples or cytoplasmic
some 14q32 and are present in 55―70% MGUS (e.g. proliferation) {2128}. immunoglobulin FISH)
of PCMs {202,1231}. Seven recurrent on Monosomy or partial deletion of chromo Minimal panel:
cogenes are involved in 14q32 transloca some 13 (13q14) is found by FISH in near t(4;14)(p16;q32),
tions: CCND1 on 11q13 (involved in 16% ly half of PCMs. It is sometimes an early t(14;16)(q32;q23),
of cases), MAFon 16q23 (in 5%), FGFR3/ event (present in about 35% of non-IgM del(17p13)
NSD2 (also called FGFR3/MMSET) on MGUSs) but can also be a progression
More comprehensive panel:
4p16.3 (in 15%), CCND3 on 6p21 (in event, particularly in PCM with t(11;14) t(11;14)(q13;q32),
2%), MAFB on 20q11 (in 2%), MAFA on {711,1231}. MYC (and rarely MYCN) locus del 13,
8q24 (in < 1%), and CCND2 on 12p13 (in rearrangements are present in nearly half ploidy category,
< 1%) (see Table 13.08 and Table 13.10) of PCM tumours. These reposition MYC chromosome 1 abnormalities
{200,1232,2128}. Together these seven near a promiscuous array of plasma
Clinical trials should incorporate gene expression
translocations are found in about 40% of cell-specific super-enhancers (includ profiling
cases of PCM, most of which are non-hy ing IGH, IGK, and IGL super-enhancers).
perdiploid (i.e. with < 48 or > 75 chromo The MYC rearrangements may some
somes). The remaining PCMs are mostly times contribute to the progression from DIS3 {109,1232,2128,2383}. Epigenetic
hyperdiploid (usually with gains in three non-IgM MGUS to PCM, but can also changes manifested by DNA methy-
or more of the odd-numbered chromo occur at later stages of PCM progres lation are also associated with tumour
somes 3, 5, 7, 9, 11, 15, 19, and 21) and sion {26}. Mutually exclusive activating progression.
only infrequently have one of the seven mutations of KRAS, NRAS, or BRAF are Myeloma tumour cells from individual pa
recurrent IGH translocations listed above present in about 40% of PCMs and are tients often have heterogeneous somatic
{728,729,1231}. candidates for mediating the transition of genetic abnormalities reflecting the pres
IGH translocations and hyperdiploidy ap non-IgM MGUS to myeloma in some pa ence of multiple subclones. Tumour sub
pear to be early events in the genesis of tients {2383,3312,4496}. clones can have activating mutations of
plasma cell neoplasms, unified by asso Other recurrent genetic changes asso NRAS, KRAS, or BRAF; although each
ciated upregulation of one of the cyclin D ciated with disease progression include subclone can have only one of these mu
genes (CCND1, CCND2, or CCND3) secondary IGH or IGL translocations; tations. This has important therapeutic
{351,2128}. Gene expression profiling deletion and/or mutation of TP53( 17p13); implications, because a specific thera
can determine the expression levels of gains of chromosome 1q and loss of 1p; peutic regimen may target one or more
CCND1, CCND2, and CCND3 RNA and mutations of genes that result in activation specific subclones but have little or no
identify tumours that overexpress onco of the NF―kappaB pathway; mutations of effect on other subclones {1979, 2383}.
genes dysregulated by the seven recur FGFR3 in tumours with t(4;14); and inac Although genetic events appear to play
rent IGH translocations. On the basis of tivation of CDKN2C, RB1, FAM46C, and the key role in initiation and progression
N >H 15 MS
Prognosis and predictive factors
NSD2e TLC 4p16 NSD2, FGFR3 MS
(CCND2) For most patients, PCM is an incurable
progressive disease, but newer thera
MAF TLC 16q23 MAF (CCND2) N 5 MF MF peutic approaches have significantly
20q12 MAFB (CCND2) N 2 MF MF improved quality of life and survival
8q24 MAFA (CCND2) N <1 MF MF {2723}. Survival ranges from < 6 months
No primary D1 CCND1 H 33 HY Y, CD1, NFKB, CTA, PRL3 to > 10 years (median: ~ 5.5 years) {666}.
TLC D1 +D2 CCND1, CCND2 H 7 PR PR, CTA Patients aged > 70 years and those with
D2 CCND2 H, NH 18 PR, LB LB, CTA, PRL3 significant comorbidities and poor per
Nonef No cyclin D genes N 2 PR PR, CTA formance status have a less favourable
prognosis. The International Staging Sys
H, mostly hyperdiploid; HOVON-GMMG, Dutch-Belgian Cooperative Trial Group for Hematology-Oncology and tem (ISS) for PCM, based on pretreat
German Multiple Myeloma Group classification; N, mostly non-hyperdiploid; PR, proliferation; ment serum beta-2 microglobulin and al
TC, translocations and cyclin D classification; TLC, IGH translocation; UAMS, University of Arkansas for
bumin levels, provides a strong predictor
Medical Science classification.
of survival (Table 13.11) {1456}. Treatment
a The TC classification is generally valid for monoclonal gammopathy of undetermined significance (MGUS) response as measured by minimal resid
and multiple myeloma. The UAMS and HOVON-GMMG classifications include plasma cell myeloma ual disease detection by flow cytometry
progression events and are probably not generally valid for MGUS. is a significant predictor of both progres
b 11q13 and 6p21 are combined into one TC group; 12p13 is rarely identified and thus usually in the D2 group.
sion-free and overall survival, especially
c TLC target and/or cyclin D upregulated
d The percentage of patients with plasma cell myeloma in each group. e NSD2 is also known as MMSET.
following autologous stem cell transplan
f None refers to a group of patients with no cyclin D expression. tation {3035,3036}.
Genetics is a powerful predictor of prog
Table 13.11 International Staging System (ISS) for plasma cell myeloma. From Greipp PR, et al. {1456} nosis and has been combined with the
ISS (R―ISS) to provide improved risk
Stage Criteria Median survival (months) stratification {3041}. Genetic risk stratifi
I Serum beta-2 microglobulin < 3.5 g/dL 62 cation based primarily on FISH analysis
Serum albumin ≥ 3.5g/dL stratifies cases into standard-risk, inter
mediate―risk, and high―risk categories
II Not stage I or IIIa 44
{690,1232,2661}. The most important ge
III Serum beta-2 microglobulin ≥ 5.5 mg/L 29 netic indicators of high-risk myeloma are
deletion of 17pITP53 sequences and the
a There are two categories for stage II:
MAF translocations t(14;16) and t(14;20)
(1) serum beta-2 microglobulin < 3.5 mg/L but serum albumin < 3.5 g/dL and (Table 13.12). Several high-risk molecular
(2) serum beta-2 microglobulin of 3.5 to < 5.5 mg/L, irrespective of the serum albumin level.
signatures, based on gene expression
profiling using various panels of genes,
Table 13.12 Mayo Stratification of Myeloma and Risk-Adapted Therapy. Adapted from Chesi M and Bergsagel PL {690} serve as prognostic indicators for PCM.
Standard risk (60%) Intermediate risk (20%) High risk (20%) Increased expression of genes associ
ated with proliferation is an important
t(11;14) t(4;14) Del 17p component of these prognostic signa
t(6;14) Del 13 t(14;16) tures. The UAMS―70 and related UAMS-
17 prognostic scores {3639} and the
Hyperdiploid Hypodiploid t(14;20) EMC-92-gene signature {2129} appear to
All others GEP high-risk signature be the most robust prognostic gene sig
nature models when applied to cohorts
OS: 8-10 years OS: 4-5 years OS: 3 years of PCMs from various institutions. Other
reported indicators of less favourable risk
GEP, gene expression profiling; OS, overall survival.
include reduced polyclonal (uninvolved)
serum Igs, elevated lactate dehydroge
of PCM, the bone marrow microenviron of the bone marrow stromal cells with nase, high C-reactive protein, increased
ment is also important in pathogenesis neoplastic plasma cells are major con plasma cell proliferative activity, a high
and progression {97}. Extracellular matrix stituents that influence the pathophysiol degree of bone marrow replacement,
proteins, secreted cytokines and growth ogy of PCM {2677}. plasmablastic morphology, and elevated
factors (including IL6), and/or the func serum soluble receptor for IL6 {281,289,
tional consequences of direct interaction 290,1454,1455,2164,3291}.
Location Any site, Predominantly extranodal, 80% in head and neck region,
with or without leukaemic peripheral oral cavity, gastrointestinal tract, mostly extranodal
blood involvement skin, and lymph nodes;
50% in immunocompetent patients
Disease stage Usually in advanced-stage PCM > 90% either stage I or IV Mostly stage IE–IIE
Molecular alterations PCM cytogenetics, with PCM-type translocations absent t(11;14) translocation and
50–70% IG translocations 50% MYC rearrangement MYC rearrangement absent
MYC rearrangement frequent with
PB morphology
Immunophenotype
LCDD has a high prevalence of kappa
light chains (80%), with overrepresen
tation of the V kappa IV variable region
{510,3230}. Immunohistochemistry on
bone marrow sections may reveal an ab
errant kappa/lambda ratio {4349}.
Definition Epidemiology
Extranodal marginal zone lymphoma MALT lymphoma accounts for 7―8% of
of mucosa―associated lymphoid tissue all B-cell lymphomas {1} and for as many
(MALT lymphoma) is an extranodal lym as 50% of primary gastric lymphomas
phoma composed of morphologically {1016,3275}. Most cases occur in adults,
heterogeneous small B cells including with a median patient age in the sev
marginal zone (centrocyte―like) cells, enth decade of life. Men and women are
cells resembling monocytoid cells, small about equally affected, although there
lymphocytes, and scattered immuno- are site-specific sex differences, with a
blasts and centroblast―like cells. There female predominance reported for cas
is plasmacytic differentiation in some es in the thyroid and salivary glands {1,
cases. The neoplastic cells reside in 1999}. There is geographical variability,
the marginal zones of reactive B-cell fol with a higher incidence of gastric MALT
licles and extend into the interfollicular lymphoma reported in north-eastern Italy
region as well as into the follicles (follicu {1016}, and a special subtype called al
lar colonization). In epithelial tissues, the pha heavy chain disease (also known
neoplastic cells typically infiltrate the epi as immunoproliferative small intesti
thelium, forming lymphoepithelial lesions nal disease) occurs in the Middle East
{1044,1782}. Thus, MALT lymphomas {48,4230}, the Cape region of South Af
variably recapitulate Peyer’s patch-type rica {3239}, and a variety of other tropi
lymphoid tissue, the prototypical nor cal and subtropical locations (see Alpha
mal mucosa-associated lymphoid tissue heavy chain disease, p. 240).
(MALT). MALT lymphomas arising at any
anatomical site share many characteris Etiology
tics, but there are also site-specific differ In many MALT lymphoma cases, there is
ences with respect to etiology, morpho a history of a chronic inflammatory disor lymphoma {1199,3954}. The continued
logical features, molecular cytogenetic der that results in accumulation of extran proliferation of gastric MALT lymphoma
abnormalities, and clinical course {502, odal lymphoid tissue (called acquired cells from patients infected with H. py
1044,2140}. MALT). The chronic inflammation may be lori depends on the presence of T cells
the result of infection, autoimmunity, or specifically activated by H. pylori anti
ICD-O code 9699/3 unknown other stimuli. gens and/or direct oncogenic effects of
The link between infection and MALT H.pylori proteins on B cells {1741,2137}.
lymphoma is most clearly established The importance of this stimulation in vivo
for Helicobacter pylori and gastric MALT has been clearly demonstrated by the
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) 259
induction of remissions in gastric MALT ocular adnexal MALT lymphoma and cu with primary Sjogren syndrome have an
lymphomas with antibiotic therapy to taneous MALT lymphoma, respectively estimated risk of lymphoma 14―19 times
eradicate H.pylori {4366}. In the first {611,1199,1201}. There is great variation that of the general population {2319,
study in which the association of gastric in the strength of these associations, 4497}; most lymphomas in patients with
MALT lymphoma with H. pylori infection which might relate in part to geographi Sjogren syndrome are MALT lymphomas.
was examined, the organism was present cal diversity {658,2296,3454}. A similar In patients with Hashimoto thyroiditis, the
in > 90% of cases {4367}. More recent role has been proposed for Campylobac risk of developing lymphoma is 3 times
studies, in the era of antibiotic eradica ter infection in patients with alpha heavy that in the general population, and the
tion therapy for H. pylori gastritis, suggest chain disease. risk of thyroid lymphoma 70 times that
that the overall incidence of gastric MALT In other cases, acquired MALT second in the general population, for an overall
lymphoma is decreasing, and that a ary to autoimmune disease may serve lymphoma risk of 0.5―1.5% {117,1671,
much smaller proportion of cases (32%) as the substrate for lymphoma develop 1959}. Approximately 90% of thyroid lym
are now associated with H. pylori at dia ment {1779}. Autoimmune-based chronic phomas have evidence of lymphocytic
gnosis {2414, 3621}. inflammation in the form of Sjogren syn thyroiditis {957,4265}.
A role for antigenic stimulation by Chla drome and Hashimoto thyroiditis is known
mydia psittaci and Borrelia burgdorferi to precede salivary gland and thyroid Localization
has been proposed for some cases of MALT lymphomas, respectively. Patients The stomach is the most common site of
MALT lymphoma, affected in 35% of all
cases. Other common sites include the
eyes and ocular adnexa (affected in 13%
of cases), skin (9%), lungs (9%), salivary
glands (8%), breasts (3%), and thyroid
(2%) {1999}.
Clinical features
Most patients present with stage I or II
disease, but 23―40% have involve
ment of multiple extranodal sites {1905,
2140}. Staging in patients with multiple
extranodal lesions may be challenging,
because at least some cases constitute
multiple clonally unrelated proliferations
rather than truly disseminated disease
{2081}. Making this distinction may not
be possible in routine practice. A minori
ty of patients (2―20%) have bone marrow
involvement {148,3276,3953}. The fre
quency of bone marrow involvement and
involvement of multiple extranodal sites
is higher in non-gastric MALT lymphoma
than in gastric cases. Generalized nodal
involvement is rare (reported in < 10% of
cases) {1905,2140,3952}. Plasmacytic
Microscopy
The characteristic marginal zone B cells
have small to medium-sized, slightly ir
regular nuclei with moderately dispersed
chromatin and inconspicuous nucleoli,
resembling those of centrocytes, and
relatively abundant, pale cytoplasm. The
accumulation of even more pale-staining
cytoplasm may lead to a monocytoid ap
pearance, which is especially common in amples, this can lead to a close resem should not be applied to a DLBCL even if
salivary gland MALT lymphomas. Alterna blance to follicular lymphoma. Lymphoe- it has arisen in a MALT site or is associ
tively, the marginal zone cells may more pithelial lesions, defined as aggregates ated with lymphoepithelial lesions.
closely resemble small lymphocytes. of ≥ 3 marginal zone cells with distortion
Plasmacytic differentiation is present in or destruction of the epithelium, may be Immunophenotype
approximately one third of gastric MALT seen in glandular tissues, often together The neoplastic cells of MALT lymphoma
lymphomas, is frequently found in cutane with eosinophilic degeneration (oxyphilic are CD20+, CD79a+, CD5–, CD10–,
ous MALT lymphomas, and is a constant change) of epithelial cells. CD23–, CD43+/–, and CD11c+/– (weak).
and often striking feature in thyroid MALT In lymph nodes, MALT lymphoma in Infrequent cases are CD5+, and very rare
lymphomas. In some MALT lymphomas, vades the marginal zone, with subse cases are CD10+ but BCL6– {2140,3954}.
there is a marked predominance of plas quent interfollicular expansion. Discrete Staining for CD21, CD23, and CD35 typi
ma cells, resulting in resemblance to an aggregates of monocytoid-like B cells cally reveals expanded meshworks of
extramedullary plasmacytoma. Cutane may be present in a parafollicular and follicular dendritic cells, corresponding
ous plasmacytomas are diagnosed as perisinusoidal distribution. Cytological to colonized follicles. The demonstration
MALT lymphoma. Amyloid deposition is heterogeneity is still present, and both of light chain restriction is helpful in the
seen in some cases. Large cells resem plasmacytic differentiation and follicular differential diagnosis with reactive hyper
bling centroblasts or immunoblasts are colonization may be seen. plasia. Recent reports have highlighted
usually present, but are in the minority. MALT lymphoma, by definition, is a lym IRTA1 as a possible specific marker for
The lymphoma cells infiltrate around re phoma composed predominantly of small marginal zone lymphomas, including
active B-cell follicles external to a pre cells. Transformed centroblast-like or MALT lymphoma, although IRTA1 anti
served mantle in a marginal zone dis immunoblast-like cells may be present bodies are not yet widely available {1137,
tribution, and spread out to form larger in variable numbers, but when solid or 1154}. MNDA staining may facilitate the
confluent areas that eventually replace sheet-like proliferations of transformed differential diagnosis of MALT lymphoma
some or most of the follicles, often leav cells are present, the tumour should be versus follicular lymphoma, because this
ing small remnants of germinal centres, diagnosed as diffuse large B-cell lympho nuclear antigen is expressed in 61-75%
which can be highlighted by negativ ma (DLBCL) and the presence of accom of MALT lymphomas but < 10% of follicu
ity for BCL2 {1784,1785}. The lymphoma panying MALT lymphoma noted. The term lar lymphomas {1922,2645}.
cells sometimes specifically colonize ‘high-grade MALT lymphoma’ should not The tumour cells of MALT lymphoma typi
reactive germinal centres; in extreme ex be used, and the term ‘MALT lymphoma’ cally express IgM heavy chains, and less
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) 261
(q21;q21), t(1;14)(p22;q32), t(14;18) years, may involve other extranodal sites
(q32;q21), and t(3;14)(p14.1;q32), result and occur more often in patients with ex-
ing in the production of a chimeric protein tragastric MALT lymphomas than in pa
(BIRC3-MALT1) and in transcriptional de tients with primary gastric disease {3276}.
regulation of BCL10, MALT1, and FOXP1, Cutaneous marginal zone lymphomas
respectively {1044,3813}. Trisomy of have a particularly indolent course, with
chromosome 3 or 18 (or less commonly 5-year survival rates approaching 100%
of other chromosomes) is a non-specific {4320}. MALT lymphomas are sensitive
but also not infrequent finding in MALT to radiation therapy, and local treatment
lymphomas. The frequencies at which may be followed by prolonged disease-
Fig. 13.64 MALT lymphoma. Immunohistochemistry the translocations or trisomies occur vary free intervals. Involvement of multiple
for CD21 highlights expanded and distorted follicular markedly with the primary site of disease. extranodal sites and even bone marrow
dendritic cell meshworks in this salivary gland MALT The t(11;18)(q21;q21) translocation is involvement do not appear to confer a
lymphoma with follicular colonization. mainly detected in pulmonary and gas worse prognosis {3953,3954}.
tric tumours; t(14;18)(q32;q21) in ocular Protracted remissions may be induced in
often IgA or IgG. A notable exception is adnexa, orbit, and salivary gland lesions; FI. pylori-associated gastric MALT lym
cutaneous marginal zone lymphoma, of and t(3;14)(p14.1;q32) in MALT lympho phoma by antibiotic therapy for FI. pylori
which two subsets have been described: mas arising in the thyroid, ocular adnexa, {2853,4366}. The presence or absence
a more common class-switched subset orbit, and skin (Table 13.16). Similarly, of FI. pylori should be investigated in both
(accounting for 75―85% of cases) with geographical variability in incidence and gastric MALT lymphoma and gastric
IgG (including many lgG4+ cases) or anatomical site specificity of the translo DLBCL, because some primary gastric
IgA expression and usually a T-cell-pre- cations has been noted, suggesting dif DLBCLs may also respond to antibiotic
dominant background, and a less com ferent environmental influences, such as eradication therapy alone {676,1200}.
mon (15―25% of cases) lgM+ subset that infectious and other etiological factors Cases with t(11;18)(q21;q21) appear to be
tends to be B-cell-predominant {455, {3340,3813}. resistant to FI. pylori eradication therapy
1080,4137}. Abnormalities of TNFAIP3 on chromo {2366}. Antibiotics have also been used
some 6q23, which may include deletions, to successfully treat selected other MALT
Postulated normal counterpart mutations, and promoter methylation, oc lymphomas. Transformation to DLBCL
A post-germinal centre marginal-zone cur in 15―30% of cases, most frequently may occur but is uncommon (reported in
B cell cases lacking specific translocations < 10% of cases) {3953,3954}.
{657,1045,2898}. However, TNFAIP3
Genetic profile abnormalities are not specific for MALT
IG heavy and light chain genes are lymphoma, and can be found in many
rearranged and show somatic hypermu types of non-Hodgkin lymphoma {1681}.
tation of variable regions {1043,3254}. MYD88 L265P mutation has been report
There is biased usage of certain IGHV ed in 6―9% of MALT lymphomas {1267,
gene families at different anatomical 2315,2860}.
sites, suggesting antigen-induced clonal
expansion during the process of lympho- Prognosis and predictive factors
magenesis {1905,3954}. MALT lymphomas have an indolent natu
Chromosomal translocations associated ral course and are slow to disseminate.
with MALT lymphomas include t(11;18) Recurrences, which can occur after many
Table 13.16 Anatomical site distribution and frequency of chromosomal translocations and trisomies 3 and 18 in MALT lymphomas.
Data summarized according to Streubel B et al. {3812} and Remstein ED et al. {3340}
Frequency (%)
Definition and occasionally the peripheral blood nant monocytoid B-cell population are
Nodal marginal zone lymphoma (NMZL) {106,347,2834,4123}. uncommon. Plasma cell differentiation
is a primary nodal B-cell neoplasm that may be prominent, and the differential
morphologically resembles lymph nodes Clinical features diagnosis with lymphoplasmacytic lym
involved by marginal zone lymphoma Most patients present with asympto phoma or even nodal plasmacytoma may
(MZL) of the extranodal or splenic types, matic, localized, or generalized periph be difficult. The presence of remnants of
but without evidence of extranodal or eral lymphadenopathy {137,347}. The follicular dendritic cell meshworks sug
splenic disease. head and neck lymph nodes are more gestive of colonized follicles favours the
frequently involved {4123}. B symptoms diagnosis of NMZL. Prominent eosino-
ICD-O code 9699/3 are present in 10―20% of patients. Bone philia may be present. Some cases have
marrow infiltration is seen in one third of more-numerous large transformed cells
Synonyms patients {4123}. The presence of a pri (sometimes > 20%). However, these cells
Monocytoid B-cell lymphoma; mary extranodal MZL should be ruled are usually mixed with small cells and
parafollicular B-cell lymphoma (obsolete) out, because approximately one third of may be more common in the colonized
cases presenting as NMZL in fact con germinal centres {2834,4046}. Some
Epidemiology stitute nodal dissemination of a MALT cases mimic splenic MZL, with the neo
NMZL accounts for only 1.5―1.8% of all lymphoma, which is particularly common plastic cells being small to medium-sized
lymphoid neoplasms, and has an annual in patients with Hashimoto thyroiditis or lymphocytes with pale cytoplasm and
incidence of 0.8 cases per 100 000 adults Sjogren syndrome {542}. occasional transformed cells growing in
{106,347,2834}. Most cases occur in side an attenuated mantle zone and often
adults, with a median age of ~ 60 years, Microscopy around a residual germinal centre {542}.
and the proportion of males and females Lymph nodes demonstrate a small-cell Composite NMZL and Hodgkin lympho
affected is similar {106,4123}. This lym lymphoid proliferation that surrounds re ma have been reported {4473}.
phoma can also occur in children, and is active follicles and expands into the in- Bone marrow involvement is usually inter
then separately designated as paediatric terfollicular areas. Follicular colonization stitial or nodular, with an intertrabecular
NMZL {3866}. A significantly increased may be present. In cases with a diffuse or paratrabecular distribution. An intrasi-
incidence has been observed among fe pattern, follicle remnants may be de nusoidal infiltration may be seen but is
males with autoimmune disorders {442}. tected with immunohistochemical stains less common {437,1757}.
A relationship to hepatitis C virus infec for follicular dendritic cells and germinal
tion has been detected in some studies centre markers. The neoplastic cells are Immunophenotype
{137,4503}, but not in others {442,4046}. composed of variable numbers of mar Most NMZLs express pan-B-cell mark
ginal zone (centrocyte-like and monocy ers, with CD43 coexpression in 20―75%
Localization toid) B cells, plasma cells in some cases, of cases {3486}. CD23 is usually nega
NMZL involves peripheral lymph nodes, and scattered transformed B cells {533, tive, but may be expressed in as many
but can also involve the bone marrow 2834,2884,4046}. Cases with a predomi as 29% of cases {4123}. CD5 expression
Definition Etiology
Follicular lymphoma (FL) is a neoplasm Individuals with a high environmental
composed of follicle centre (germinal cen exposure to pesticides and herbicides
tre) B cells (typically both centrocytes and have increased numbers of cells carrying
centroblasts/large transformed cells), t(14;18)(q32;q21) (IGH/BCL2) in the pe
which usually has at least a partially fol ripheral blood {33}. This may help explain
licular pattern. Lymphomas composed of the reported increased risk of FL among
centrocytes and centroblasts with an en such individuals.
tirely diffuse pattern in the sampled tissue
may be included in this category, but are Localization
relatively rare at presentation. Progression FL predominantly involves the lymph
in cytological grade is common during the nodes, but also involves the spleen, bone
natural history of the disease. A diffuse marrow, peripheral blood, and less com
lymphoma composed of centroblasts is monly Waldeyer ring. Any nodal group
considered evidence of progression to can be involved, but most patients pre
diffuse large B-cell lymphoma (DLBCL). sent with peripheral lymphadenopathy.
Four variants of FL are recognized: (1) in Pure extranodal presentations are un
situ follicular neoplasia, formerly called FL common. The most commonly affected
in situ; (2) duodenal-type FL; (3) testicular extranodal sites include the gastrointes
FL; and (4) the diffuse variant of FL. tinal tract (often in association with mes
Primary cutaneous follicle centre lym enteric lymph node involvement), soft
phomas are separately classified {2242, tissue, breast, and ocular adnexa. FL
3848}. FL is nearly exclusively a disease arising in the small intestine, in particular
of adults, and very rarely occurs in pa the duodenum, has distinctive features
tients aged < 18 years. Paediatric-type (duodenal-type FL).
FL, which is a nodal lymphoma that oc FLs can occur in almost any extranodal
curs in children and young adults, is con site {1203}. In some cases, the morphol
sidered a separate entity. ogy, phenotype, and genetics are similar gree of lymphadenopathy and extent of
to those of nodal FL. However, many FLs disease. FDG-PET is less useful in as
ICD-O codes in extranodal sites tend to be of higher sessing disease than in more aggressive
Follicular lymphoma 9690/3 grade (grade 3), and may lack BCL2 pro lymphomas. However, the detection of
Grade 1 9695/3 tein and the BCL2 translocation {3021, PET-avid disease may be useful in iden
Grade 2 9691/3 4148}. tifying patients with higher risk for pro
Grade 3A 9698/3 gression {112}.
Grade 3B 9698/3 Clinical features
Most patients have widespread disease at Staging
Epidemiology diagnosis, including peripheral and cen The stage of the disease is now deter
FL accounts for about 20% of all lympho tral (abdominal and thoracic) lymphad mined using the Lugano classification,
mas. The highest incidence rates are re enopathy and splenomegaly. The bone a modification of the Ann Arbor staging
ported in the USA and western Europe. marrow is involved in 40―70% of cases. system {691}. Assessment of bone mar
In eastern Europe, Asia, and developing Only 15―25% of cases are stage I or II row involvement should be accomplished
countries, the incidence is much lower at the time of diagnosis {1632}. Despite with bone marrow biopsy. Bone marrow
{95}. It affects predominantly adults, with widespread disease, patients are usually aspiration has a lower yield, due to the
a median age in the sixth decade of life otherwise asymptomatic. B symptoms difficulty is aspirating cells from the para-
and a male-to-female ratio of 1:1.7 {1}. FL such as fever and weight loss are uncom trabecular lymphoid aggregates. The
is 2-3 times as common in White popula mon. Waxing and waning of the disease designation of a case as A or B (asymp
tions as in Black populations {1477}. Un without therapy is common. The disease tomatic or symptomatic) is no longer re
like paediatric-type FL, usual FL rarely follows a chronic relapsing clinical course. quired for non-Hodgkin lymphoma sub-
occurs in individuals aged < 18 years. types, according to the Lugano system.
Agricultural exposure to pesticides and Imaging
herbicides has been associated with an Conventional imaging tools such as CT Macroscopy
increased risk {33,1257,3678}. and MRI are useful in assessing the de The cut surface of lymph nodes involved
Microscopy
Pattern
Most cases of FL have a predominantly
follicular pattern, with closely packed
follicles that efface the nodal architec
ture. Neoplastic follicles are often poorly
defined and usually have attenuated or
absent mantle zones. Unlike in reactive
germinal centres, where the proportion
of centroblasts and centrocytes var
ies in different zones (polarization), in
FL the two types of cells are randomly
distributed. Similarly, tingible body mac
rophages, characteristic of reactive ger
minal centres, are usually absent in FL.
In some cases, follicles may be irregular
and serpiginous, but this growth pattern
does not constitute progression to a dif
fuse growth pattern. Staining for follicular
dendritic cell (FDC) markers (CD21 and/
or CD23) can be helpful in highlighting
the follicular pattern. Interfollicular in
filtration by neoplastic cells is common
and does not constitute a diffuse pat
tern. The interfollicular neoplastic cells
are often centrocytes that are smaller
than those in the germinal centres, with
a less irregular nuclear contour, and
they may show immunophenotypic dif
ferences from the cells in the germinal
centres {1015}. Infrequent cases have a
so-called floral growth pattern that re
sembles progressively transformed ger
minal centres {4004}.
Spread beyond the lymph node cap
sule is often associated with sclerosis,
particularly in mesenteric and retroperi
toneal locations. With limited sampling
in small biopsies, it may be difficult to
appreciate a follicular pattern. A diffuse
area is defined as an area of the tissue of follicular and diffuse areas be noted in diagnosis of DLBCL should be made
completely lacking follicles as evidenced the pathology report as follicular (> 75% {1556} (see Grading).
by the absence of CD21+/CD23+ FDCs. follicular), follicular and diffuse (25―75% Some cases have the morphology and
The distinction between an extensive follicular), or focally follicular / predomi immunophenotype of FL but with no evi
interfollicular component and a diffuse nantly diffuse (< 25% follicular) {1556}. dence of a follicular growth pattern. This
component is sometimes arbitrary. Dif However, the presence of diffuse areas phenomenon is usually seen in small bi
fuse areas composed predominantly of composed entirely or predominantly of opsy specimens, and likely constitutes
centrocytes are not thought to be clini large centroblasts (that would fulfil the a diffuse area in an FL that was not ad
cally significant. Nevertheless, it is rec criteria for grade 3 FL) in FL of any grade equately sampled. A repeat biopsy in the
ommended that the relative proportions is equivalent to DLBCL, and a separate same or another site may reveal a follicu-
immunostaining in germinal centre cells cases have a proliferation index > 20%, Grading
requires caution, because T cells, pri although there is considerable variation FL is graded by counting or estimat
mary follicles, and mantle zones normally among studies, probably due to techni ing the absolute number of centroblasts
express this protein. cal differences in immunostaining {2088, (large or small) in 10 neoplastic follicles,
In addition to FDCs, neoplastic follicles 2520,3008,4250}. A subgroup of mor expressed per high-power (40x mag
contain numerous other non-neoplastic phologically low-grade FLs with a high nification, 0.159 mm2) microscopic
cells normally found in germinal centres, proliferation index has been described field (HPF) {1820,2485,2835}. At least
including follicular T cells (CD3+, CD4+, {2088,4250}; these cases behaved 10 HPFs within different follicles must be
CD57+, PD1/CD279+, CXCL13+) and more aggressively than did those with evaluated; these should be representa
varying numbers of histiocytes. Consist a low proliferation index, and similarly to tive follicles, not those with the most nu
ent with the germinal centre phenotype of grade 3 FL {4250}. Therefore, Ki-67 stain merous large cells.
the neoplastic cells, most cases are neg ing should be considered as an adjunct Grade 1―2 cases have a marked pre
ative for IRF4/MUM1. However, a subset to histological grading, and its use is dominance of centrocytes, with few
of FLs negative for CD10 are positive clinically justified, although not formally centroblasts (grade 1: 0―5 centroblasts
for IRF4/MUM1 {1944}. Such tumours required at this time. per HPF; grade 2: 6―15 centroblasts
typically lack the BCL2 translocation but per HPF). As recommended in the 2008
show amplification of BCL6 {1950}. They Postulated normal counterpart WHO classification, the combined des
tend to occur in elderly patients and cy- The postulated normal counterpart is ignation of grade 1―2 is preferred, due
tologically are of higher grade (3A or 3B). a germinal centre B cell. In cases with to the lack of clinically significant differ
These cases must be distinguished t(14;18)(q32;q21), the IGH/BCL2 trans ences between grades 1 and 2, the con
from large B-cell lymphoma with IRF4 location occurs in bone marrow pre- siderable interobserver variation in grad
rearrangement, which often has at least B cells; fully malignant transformation of ing, and variations in grade within a given
a partially follicular growth pattern {2369, these t(14;18)-positive primed cells oc biopsy.
3491}. curs during (re)entry into the germinal Grade 3 cases have > 15 centroblasts
The Ki-67 proliferation index in FL gen centres in secondary lymphoid organs per HPF. Grade 3 is further subdivided
erally correlates with histological grade; {3425,3426}. on the basis of the presence or absence
most grade 1―2 cases have a prolifera of centrocytes. In grade 3A, centrocytes
tion index < 20%, whereas most grade 3 are still present, whereas grade 3B
FL is rare, with most cases containing at c If the biopsy specimen is small, a note should be added that the absence of follicles may reflect sampling error.
Microscopy
ISFN is generally not apparent in rou
tine H&E-stained sections {789}. Lymph
nodes contain reactive follicles with well-
formed germinal centres. The affected
follicles are similar in size and shape to
adjacent uninvolved follicles, although
on close inspection closely packed cen
trocytes may be appreciated. The lesion
can also be seen in reactive follicles in
extranodal sites, i.e. any location where
reactive follicles are identified. ISFN is
distinct from partial involvement by FL,
Fig. 13.82 Duodenal-type follicular lymphoma. Large nodules of lymphoid cells are present in the mucosa (A). The follicles are uniformly positive for BCL2 (B) and positive for
CD10 (C).
Definition
Large B-cell lymphoma (LBCL) with IRF4
rearrangement is an uncommon subtype
of LBCL that can be entirely diffuse, fol
licular and diffuse, or entirely follicular.
It is characterized by strong expression
of IRF4/MUM1, usually with IRF4 re
arrangement. It occurs primarily in chil
dren and young adults, with predomi
nantly Waldeyer ring or head and neck
lymph node involvement {2369,3491}.
Despite its common occurrence in the
paediatric age group, it is distinct from
paediatric-type follicular lymphomas,
even when purely follicular {2369,2400}.
Epidemiology
LBCL with IRF4 rearrangement is rare,
accounting for just 0.05% of diffuse
LBCLs. The patient age range at presen
tation is 4―79 years, with a median age
of 12 years and an equal sex distribution.
This entity is significantly more frequent
in children (individuals aged < 18 years)
than in adults (P< 0.001) {3491}.
Localization
Most patients present with enlarged
lymph nodes of the head and neck re
gion. The Waldeyer ring is also a frequent
site of disease. Another reported site of
involvement is the gastrointestinal tract
{898,2369,3491}.
Clinical features
Most patients present with isolated lymph
node or tonsillar enlargement (stage l-ll) pattern. Unlike in paediatric-type follicu rate is usually high, with no evidence of
{3491}. lar lymphoma, the follicles generally lack polarization in the neoplastic follicles. In
a serpiginous configuration and starry- the appropriate clinical context, cases
Microscopy sky pattern. with coexpression of CD10, BCL6, and
The neoplastic cells are medium-sized to IRF4/MUM1 should be screened for IRF4
large, with chromatin which is more open Immunophenotype rearrangements.
than typically seen in centrocytes and The atypical cells have a mature B-cell
small, basophilic nucleoli. Mitotic figures phenotype and are positive for CD20, Postulated normal counterpart
are infrequent, and a starry-sky pattern is CD79a, and PAX5. IRF4/MUM1 is typi Germinal centre B cell with IRF4
absent. When a follicular pattern is pres cally strongly expressed, and BCL6 is rearrangement resulting in IRF4/MUM1
ent, the neoplastic follicles are large, with positive, whereas PRDM1 (also known expression
a back-to-back growth pattern and ab as BLIMP1) is usually negative. CD10
sent or attenuated mantle zones. Many and BCL2 expression is observed in Genetic profile
cases have an entirely diffuse growth 66% of cases {3491}. The proliferation Immunoglobulin genes are clonally re-
Definition Synonyms the legs, and 15% with multifocal skin le
Primary cutaneous follicle centre lym Reticulohistiocytoma of the dorsum; sions {2062,3623,4499}.
phoma (PCFCL) is a tumour of neoplastic Crosti lymphoma
follicle centre cells, including centrocytes Clinical features
and variable numbers of centroblasts, Epidemiology The clinical presentation consists of firm
with a follicular, follicular and diffuse, or PCFCL accounts for approximately 50% erythematous to violaceous plaques,
diffuse growth pattern. It generally pre of primary cutaneous B-cell lymphomas. nodules, or tumours of variable size.
sents on the head or trunk {4320}. Lym It mainly affects middle-aged adults, with Particularly on the trunk, tumours may
phomas with a diffuse growth pattern a male-to-female ratio of approximately be surrounded by erythematous pap
and a monotonous proliferation of centro 1.5:1 {1530,3623,4499}. ules and slightly infiltrated, sometimes
blasts and immunoblasts are classified, figurate plaques, which may precede
irrespective of site, as primary cutaneous Localization the development of tumorous lesions by
diffuse large B-cell lymphoma, leg type PCFCL characteristically presents with months or years {358,3517,4322}. PCFCL
{4320}. solitary or localized skin lesions on the with this typical presentation on the back
scalp, forehead, or trunk. Approximately was formerly referred to as reticulohis
ICD-O code 9597/3 5% of cases present with skin lesions on tiocytoma of the dorsum or Crosti lym-
Microscopy
PCFCL shows perivascular and periad-
nexal to diffuse infiltrates, with almost
invariable sparing of the epidermis. The
infiltrates show a spectrum of growth pat
terns, with a morphological continuum
from follicular to follicular and diffuse to
diffuse {3517,4320,4322}. Cases with a
follicular growth pattern show nodular in
filtrates throughout the entire dermis, often
extending into the subcutis. Unlike in cuta
neous follicular hyperplasias, the follicles
in PCFCL may be poorly defined, show a
monotonous proliferation of BCL6+ follicle
centre cells enmeshed in a meshwork of
CD21+/CD35+ follicular dendritic cells,
lack tingible body macrophages, gener
ally have an attenuated or absent mantle
zone, and show a low proliferation rate
{606,1408}. Reactive T cells may be nu
merous, and a prominent stromal compo
nent is usually present. with a diffuse growth pattern {903,1409, matic hypermutation are present, but
Cases with a diffuse growth pattern usu 1654,2016,2062,2674,3623}. Most cases may not be detectable by PCR {6,1325}.
ally show a monotonous population of either do not express BCL2 or only show
large centrocytes, some of which may faint BCL2 staining (weaker than in ad Cytogenetic abnormalities and
have a multilobated appearance, and mixed T cells) in a minority of neoplastic oncogenes
variable numbers of admixed centro- B cells {606,610,715,1318,1654,2062, In many studies, PCFCLs, including
blasts {358,1421,3517,4322}. In rare cas 3623}. However, several studies have re cases with a follicular growth pattern,
es, the large centrocytes may be spindle- ported BCL2 expression in a substantial do not show (or rarely show) BCL2
shaped {607,1406}. In some cases, foci proportion of PCFCLs with at least a par rearrangements {10,610,715,1318,1408,
of CD21+/CD35+ follicular dendritic cells tially follicular growth pattern {37,1409, 1409,1494,1524,1525,3164,4183}. How
may still be present; in other cases, they 2016,2674,3164}. Strong expression of ever, other studies using PCR and/or
may be totally absent {1494}. The prolif both BCL2 and CD10 by the neoplastic FISH report BCL2 rearrangements in
erative fraction in these diffuse PCFCLs B cells should always raise suspicion of about 10-40% of PCFCLs with a follicu
is generally high. a nodal follicular lymphoma involving the lar growth pattern, as well as in some to
skin secondarily. Staining for IRF4/MUM1 tally diffuse cases {37,2016,2674,3859}.
Immunophenotype and FOXP1 is negative in most cases; PCFCLs have the same gene expression
The neoplastic cells express CD20 and staining for CD5 and CD43 is always profile as germinal centre B-cell-sub-
CD79a, but are usually immunoglobulin negative {2062,3623}. type diffuse large B-cell lymphomas,
negative by immunohistochemistry. Flow and often show amplification of REL {6,
cytometric studies are reported to dem Postulated normal counterpart 986,1653}. Deletion of chromosome
onstrate restricted light chain expression A mature germinal centre B cell 14q32.33 has been reported {986}. Un
in almost 3/4 of cases {3549A}. PCFCLs like in primary cutaneous diffuse large
consistently express BCL6. CD10 may be Genetic profile B-cell lymphoma, leg type, inactivation
positive in cases with a follicular growth Antigen receptor genes of CDKN2A and CDKN2B gene loci on
pattern, but is generally negative in cases Clonally rearranged IG genes with so chromosome 9p21.3 by deletion or pro
ICD-0 codes
Mantle cell lymphoma 9673/3
In situ mantle cell neoplasia 9673/1
Synonyms
Mantle zone lymphoma (obsolete); malig
nant lymphoma, lymphocytic, intermedi
ate differentiation, diffuse (obsolete); ma
lignant lymphoma, centrocytic (obsolete);
malignant lymphomatous polyposis; in
situ mantle cell lymphoma (for in situ
mantle cell neoplasia)
Epidemiology
Mantle cell lymphoma accounts for to-female ratio of ≥ 2:1 {139,423,543, ment, are also important sites of disease
approximately 3―10% of non-Hodgkin 2219,3849,3854}. {139,423,2896,3849}. Other extranodal
lymphomas {1}. It occurs in middle-aged sites are also frequently involved, includ
to older individuals, with a median age Localization ing the gastrointestinal tract (where in
of about 60 years. There is a variably Lymph nodes are the most commonly in filtration may be subclinical), Waldeyer
marked male predominance, with a male- volved site. The spleen and bone marrow, ring, lungs, and pleura {1324,3487}. An
with or without peripheral blood involve uncommon but distinctive presentation is
Fig. 13.94 Mantle cell lymphoma, peripheral blood, cytological variation. A This typical mantle cell lymphoma demonstrates relatively small lymphoid cells with clumped
chromatin and prominent nuclear clefts. B In contrast, the cells in this blastoid mantle cell lymphoma are larger and have prominent nucleoli. C This mantle cell lymphoma could
easily be confused morphologically with chronic lymphocytic leukaemia.
Clinical features
Most patients present with stage III or,
usually, stage IV disease with lymphade-
nopathy, hepatosplenomegaly, and bone
marrow involvement {423,543,2896,
3854}. Extranodal involvement, usually
in the presence of extensive lymphad-
enopathy, is common. Peripheral blood
involvement is also common, and can
be identified by flow cytometry in almost
all patients {1192}. Some patients have a
marked lymphocytosis, which can close
ly mimic prolymphocytic leukaemia {139,
423,2896}, an acute leukaemia {4204},
or chronic lymphocytic leukaemia. Some
patients present with leukaemic non-nod-
al disease, sometimes with splenomega
ly. These cases constitute a different vari
ant of the disease (see below).
Macroscopy
Most cases of multiple lymphoma
tous polyposis constitute mantle cell
lymphoma.
Microscopy
Classic mantle cell lymphoma is a mono-
morphic lymphoid proliferation with a
vaguely nodular, diffuse, mantle zone, or
rarely follicular growth pattern {245,2219,
2269,3849,4018}. Mantle cell lymphoma
with a mantle zone growth pattern should
be distinguished from in situ mantle cell
neoplasia (see discussion below). Most
cases are composed of small to medium
sized lymphoid cells with slightly to mark
edly irregular nuclear contours, most
closely resembling centrocytes. The nu
clei have at least somewhat dispersed
chromatin but inconspicuous nucleoli.
Neoplastic transformed cells resembling {1187}, and the marginal zone-like vari positive nuclei) is critical because of its
centroblasts, immunoblasts, or paraim- ant is of greatest interest because of its prognostic impact.
munoblasts and proliferation centres are potential confusion with marginal zone Hyalinized small vessels are commonly
absent; however, foci mimicking prolifera lymphomas. Mantle cell lymphoma in seen. Many cases have scattered single
tion centres may be present {3855A}, and the peripheral blood or in bone marrow epithelioid histiocytes, which in occasion
a spectrum of morphological variants is aspirates shows the same cytological al blastoid or pleomorphic cases can cre
recognized, which can also cause dia spectrum that is seen in tissue sections; ate a so-called starry-sky appearance.
gnostic confusion (Table 13.21, p.285). however, nucleoli are sometimes more Non-neoplastic plasma cells may be
The blastoid and pleomorphic variants prominent, even in cases of classic type. present, but true plasmacytic differentia
are considered to be of important clini Although mantle cell lymphoma is not tion, which can be very marked, is seen
cal significance. The small-cell variant graded, evaluation of the proliferative only rarely {2645,3347,3851,4444,4445}.
is overrepresented among cases of leu fraction (either by counting mitotic figures Splenic involvement, characterized by
kaemic, non-nodal mantle cell lymphoma or estimating the proportion of Ki-67- white pulp and variable red pulp infiltra-
Genetic profile
Antigen receptor genes
IG genes are clonally rearranged. IGV
genes are unmutated or minimally mu
tated in most cases, but in 15―40% of
cases, IG genes show somatic hyper
mutation, although the load of mutations
is usually lower than in mutated chronic
Fig. 13.96 Mantle cell lymphoma (MCL). Cell-cycle and DNA damage repair pathways altered in MCL. The cyclin D1 /
CDK4/6 complex promotes phosphorylation of RB (also called RB1). This leads to release of the E2F transcription
lymphocytic leukaemia {534,2008,2992,
factors, which then lead to progression of the cell cycle into the S phase. The cyclin D1 / CDK4/6 complex is inhibited 3950}. A biased use of the IGHV genes
by p16 (also called CDKN2A). BMI1 is a transcriptional repressor of the CDKN2AIARF locus. Abnormalities in MCL has been reported, suggesting that man
that lead to progression of cells from G1 to S phase include increased cyclin D1 in almost all cases, as well as loss tle cell lymphoma may originate from
of p16, RB1 deletions, increased CDK4, and increased BMI1 in a minority of cases, especially those that are more specific subsets of B cells {534,2008,
aggressive. Deregulated E2F also induces ARF transcription. ARF leads to stabilization of p53 by inhibiting the 2992,3950}. Together with other obser
activity of MDM2, which leads to the degradation of p53. The tumour suppressor p53 leads to increased expression
vations, this finding suggests that at least
of p21 (also called CDKN1A) and to cell-cycle arrest or apoptosis. ATM is required for activation of p53 after DNA
damage. Many MCLs have ATM abnormalities, and some patients have germline mutations of this gene. Some MCLs a substantial proportion of mantle cell
have loss or transcriptional repression of the CDKN2AIARF locus (lacking p16/ARF), loss or mutation of TP53, or lymphomas show evidence of antigenic
high levels of MDM2. Finally, cyclin E / CDK2 complexes also lead to cell-cycle progression, and are inhibited by drive {1509,4391}.
p21 and p27 (also called CDKN1B). In MCL, increased levels of cyclin D1 lead to sequestration of these cell-cycle
inhibitors, and they may also increase p27 degradation {1843}. Cytogenetic abnormalities and
oncogenes
tion, can mimic a splenic marginal zone CD23 is negative or weakly positive. Nu The t(11;14)(q13;q32) translocation be
lymphoma, with smaller cells with lit clear cyclin D1 is expressed by > 95% tween an IGH gene and CCND1 (encod
tle cytoplasm centrally in the white pulp of mantle cell lymphomas, including the ing cyclin D1) is present in > 95% of cases
nodules and a peripheral zone where minority of cases that are CD5-nega- and is considered to be the primary ge
the neoplastic cells more closely resem tive {700,3855,4026}. SOX11 is positive netic event {2301,3408,4095,4146,4323,
ble marginal zone cells, being some with the most sensitive monoclonal an 4324}. Variant CCND1 translocations with
what larger and with more abundant tibody in > 90% of mantle cell lympho the IG light chains have also been report
cytoplasm. mas, including cyclin D1-negative and ed but are very uncommon. The translo
Histological transformation to a typical blastoid cases {2769,2816,3721}. Cau cation results in deregulated overexpres
diffuse large B-cell lymphoma does not tion is advised, because the specificity sion of CCND1 mRNA and protein {422,
occur; however, loss of a mantle zone and sensitivity of SOX11 antibodies vary 889,3627}. Some mantle cell lymphomas
growth pattern, increase in nuclear size, widely. Aberrant phenotypes have been express aberrant transcripts, resulting
pleomorphism and chromatin dispersal, described (sometimes in association in an increased half-life of cyclin D1. Tu
and increase in mitotic activity and Ki-67 with blastoid or pleomorphic variants), mours with these truncated transcripts
proliferation index can be seen in some including absence of CD5 and expres have very high levels of cyclin D1 expres
cases at relapse {139,2219,2896,3849, sion of CD10 and BCL6 {41,535,1294, sion {422,889,3627}, high proliferation
4208}. Some such cases fulfil the criteria 2737,4425}. Rare cases express other rates, and more-aggressive clinical be
for a blastoid or pleomorphic mantle cell antigens more typically associated with haviour {3413}. Deregulated expression
lymphoma (see below). Cases that are chronic lymphocytic leukaemia, such of cyclin D1 is assumed to overcome the
blastoid at diagnosis may relapse with as LEF1 or CD200, with LEF1 more like cell cycle suppressive effect of RB and
classic morphology {4208}. ly to be seen in blastoid or pleomorphic p27 in addition to other effects, leading to
mantle cell lymphoma and CD200 in the the development of mantle cell lymphoma
Immunophenotype leukaemic non-nodal variant {636,1115, {1841,3264}. Nevertheless, it is not suffi
The cells express relatively intense sur 1157,2633,3505}. Immunohistochemical cient by itself to lead to mantle cell lym
face IgM/lgD, more frequently with lamb staining often reveals loose meshworks phoma, as demonstrated both with animal
da than kappa restriction {543,3849, of follicular dendritic cells. models and by observations related to
4018}. They are uniformly BCL2-positive CCA/DArearranged clonal populations in
{3853}; usually positive for CD5, FMC7, Postulated normal counterpart the peripheral blood of healthy individuals
and CD43; sometimes positive for IRF4/ The postulated normal counterpart is a {2247}. In addition to the molecular cy
MUM1; and negative forCDIOand BCL6. peripheral B cell of the inner mantle zone; togenetic abnormalities described below,
Definition Table 13.22 Large B-cell lymphomas; italics indicate that an entity is provisional
Diffuse large B-cell lymphoma (DLBCL) Diffuse large B-cell lymphoma, NOS
is a neoplasm of medium or large B lym Morphological variants
phoid cells whose nuclei are the same Centroblastic
size as, or larger than, those of normal Immunoblastic
macrophages, or more than twice the Anaplastic
size of those of normal lymphocytes, with Other rare variants
Molecular subtypes
a diffuse growth pattern.
Germinal centre B-cell subtype
Morphological, biological, and clinical Activated B-cell subtype
studies have subdivided DLBCLs into
morphological variants, molecular sub- Other lymphomas of large B cells
types, and distinct disease entities (Ta T-cell/histiocyte-rich large B-cell lymphoma
ble 13.22). However, there remain many Primary diffuse large B-cell lymphoma of the CNS
cases that may be biologically heteroge Primary cutaneous diffuse large B-cell lymphoma, leg type
EBV-positive diffuse large B-cell lymphoma, NOS
neous, but for which there are no clear
Diffuse large B-cell lymphoma associated with chronic inflammation
and accepted criteria for subdivision. Lymphomatoid granulomatosis
These cases are classified as DLBCL, Large B-cell lymphoma with IRF4 rearrangement
NOS, which encompasses all cases that Primary mediastinal (thymic) large B-cell lymphoma
do not belong to a specific diagnostic Intravascular large B-cell lymphoma
category listed in Table 13.22. DLBCL, ALK-positive large B-cell lymphoma
NOS can be subdivided into germi Plasmablastic lymphoma
HHV8-positive diffuse large B-cell lymphoma
nal centre B-cell (GCB) subtype and
Primary effusion lymphoma
activated B-cell (ABC) subtype. Focal
involvement of follicular structures in High-grade B-cell lymphoma
DLBCL, which can be highlighted by im- High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements
munohistochemical staining for follicular High-grade B-cell lymphoma, NOS
dendritic cells, does not require the ad B-cell lymphoma, unclassifiable
ditional diagnosis of a grade 3B follicular B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and
lymphoma. classic Hodgkin lymphoma
ICD-O codes
Diffuse large B-cell lymphoma, NOS aggressive lymphoma (referred to as DLBCL associated with chronic inflam
9680/3 secondary), such as chronic lympho mation or lymphomatoid granulomatosis).
Germinal centre B-cell subtype 9680/3 cytic leukaemia/small lymphocytic lym
Activated B-cell subtype 9680/3 phoma, follicular lymphoma, marginal Localization
zone lymphoma, or nodular lymphocyte Patients may present with nodal or ex
Epidemiology predominant Hodgkin lymphoma. Un tranodal disease; as many as 40% of
DLBCL, NOS, constitutes 25―35% of derlying immunodeficiency is a signifi cases are confined to extranodal sites
adult non-Hodgkin lymphomas in devel cant risk factor. DLBCLs, NOS, occurring at least initially {1,95}. The most common
oped countries, and a higher percentage in the setting of immunodeficiency are
in developing countries. It is more com more often EBV-positive than sporadic
mon in elderly individuals. The median cases. In DLBCL cases without an overt
patient age is in the seventh decade of immunodeficiency, the EBV infection rate
life, but it can also occur in children and varies from 3% in western populations
young adults. It is slightly more common to approximately 10% in Asian and Latin
in males than in females {1,95}. American populations, and the lympho
ma is typically of the ABC subtype {325,
Etiology 1017,1367,1655,2701,2956,3696}. Impor
The etiology of DLBCL, NOS, remains tantly, EBV positivity in most tumour cells
unknown. These tumours usually arise should lead to a diagnosis of either EBV-
de novo (referred to as primary) but can positive DLBCL, NOS, or another spe
also represent transformation of a less cific type of EBV-positive lymphoma (e.g.
Genetic susceptibility
Recent case control studies have identi
fied genetic loci that may predispose in
dividuals to the development of DLBCL
{602,2135,3691,3704}. Some of the find
ings in European studies have been rep
licated in eastern Asian populations, sug
gesting a common risk {286,3888}. The
identities of the candidate genes in these
loci suggest that immune recognition and
immune function may underlie the patho
genesis of DLBCL {602}.
Definition
T-cell/histiocyte-rich large B-cell lym
phoma (THRLBCL) is characterized by a
limited number of scattered, large B cells
embedded in a background of abundant
T cells and histiocytes. THRLBCL may
arise de novo; however, more recent data
suggest the possibility of a closer rela
tionship with progression forms of nodular
lymphocyte predominant Hodgkin lym
phoma (NLPHL) than previously thought,
indicating that NLPHL may proceed to or
contain areas indistinguishable from THR
LBCL. In small biopsies in particular, dif
ferentiating between a progression form
of NLPHL (i.e. NLPHL with THRLBCL-like
transformation) and de novo THRLBCL
may be difficult, if not impossible.
Synonyms
T-cell―rich B-cell lymphoma; B-cell lym
phoma rich in T cells and simulating Hodg
kin disease; histiocyte-rich/T-cell―rich
large B-cell lymphoma; T-cell―rich large
B-cell lymphoma; T-cell―rich/histiocyte-
rich large B-cell lymphoma; histiocyte-
rich large B-cell lymphoma
Epidemiology
THRLBCL mainly affects middle-aged diagnosis with NLPHL, clinical staging (LP) cells of NLPHL, but usually show
men. It accounts for <10% of all DLBCLs. procedures (including imaging analyses) greater variation in size and, in some cas
are important. NLPHL usually affects one es, may resemble centroblasts or more
Localization or two regions, whereas THRLBCL fre pleomorphic cells, mimicking Reed-
THRLBCL mainly affects the lymph quently manifests as systemic disease. Sternberg or Hodgkin cells {19,3299}.
nodes, but bone marrow, liver, and Because THRLBCL is more PET-avid They are typically found within clusters of
spleen involvement is frequently found at than is NLPHL, staging procedures such bland-looking non-epithelioid histiocytes
diagnosis. as FDG-PET and CT may facilitate the that may not be obvious on conventional
differential diagnosis {246}. examination. These histiocytes are a main
Clinical features and distinctive component of THRLBCL
Patients present with fever, malaise, Microscopy and are useful for the diagnosis {1448}.
splenomegaly, and/or hepatomegaly. THRLBCL has a diffuse or less common Nearly all of the background lymphocytes
At diagnosis, almost half of cases are at ly vaguely nodular growth pattern replac are of T-cell lineage, with typically only
an advanced Ann Arbor stage, with an ing most of the normal lymph node pa very few scattered B cells. Meshworks of
intermediate-risk to high-risk International renchyma. It is composed of scattered, follicular dendritic cells are absent. Eo
Prognostic Index (IPI) score (Table 13.24). single large B cells embedded in a back sinophils and plasma cells are not found.
The disease is often refractory to the ground of small T cells and variable num De novo THRLBCLs are usually diffuse
chemotherapy regimens currently in use. bers of histiocytes. The tumour cells are and do not show the typical small B-cell
always dispersed and do not form aggre background of NLPHL. However, there
Imaging gates or sheets. These cells may mimic are cases of NLPHL in which the small
Because of the important differential the neoplastic lymphocyte predominant B cells are diminished in number, and in
Definition
Primary diffuse large B-cell lymphoma
(DLBCL) of the CNS is defined as DLBCL
arising within the brain, spinal cord, lep-
tomeninges or eye. Excluded are lym
phomas of the dura, intravascular large
B-cell lymphomas, lymphomas with evi
dence of systemic disease or secondary
lymphomas, and all immunodeficiency-
associated lymphomas.
Synonyms
Primary CNS lymphoma; primary intraoc
ular lymphoma; lymphomatosis cerebri
(no longer recommended)
Epidemioiogy
CNS DLBCL accounts for < 1% of all
non-Hodgkin lymphomas and 2.4―3%
of all brain tumours {3556}. The overall
annual incidence rate of CNS DLBCL cells may also contribute to organ restric supratentorial space, including the frontal
is 0.47 cases per 100 000 population tion {2710}. Upon relapse, CNS DLBCLs lobe (affected in 15% of cases), temporal
{4196}. This lymphoma can affect pa show a restricted homing to the main im lobe (in 8%), parietal lobe (in 7%), occipi
tients of any age, with a peak incidence mune sanctuaries (i.e. the brain, eyes, tal lobe (in 3%), basal ganglia and perive
in the fifth to seventh decade of life, a and testes) {416,1552,1828,3289}, and ntricular brain parenchyma (in 10%), and
median patient age of 56 years, and a primary testicular and intraocular lym corpus callosum (in 5%). Less frequently
male-to-female ratio of 3:2. In the past phomas frequently spread to the CNS affected sites include the posterior fossa
two decades, an increased incidence {4205}, suggesting that the tumour cells (affected in 13% of cases) and spinal cord
has been reported among patients aged need to hide in an immune sanctuary. (in 1%) {919}. A single tumour is present
> 60 years {821,4196}. Many DLBCLs of the CNS and testis in 60―70% of cases, with the remainder
show decreased or absent expression of presenting as multifocal disease {919}.
Etiology HLA class I and II proteins, allowing the The leptomeninges may be involved, but
In immunocompetent individuals, the eti tumour cells to further escape from im exclusive meningeal manifestation is unu
ological factors are unknown. Viruses, in mune attack {415,3355}. sual. Approximately 20% of patients pre
cluding EBV, HHV6 {3114}, HHV8 {2708}, sent with or develop intraocular lesions,
and the polyomaviruses SV40 and Localization and 80-90% of patients with intraocular
BK virus {2705,2795}, do not play a role. About 60% of CNS DLBCLs involve the DLBCL develop contralateral tumours
Pathogenically, expression or absence of
chemokines and chemokine receptors or
cytokines may contribute to the specific
localization {3706}. Tumour cells and en
dothelial cells may interact via activation
of IL4 to create a favourable microenvi
ronment for tumour growth {3443}.
Tumour cells of CNS DLBCL recognize
proteins present in the CNS via their
poly-reactive B-cell receptor, and thus
have the capacity to stimulate B-cell
receptor signalling. This interaction be
tween CNS antigens and the lymphoma
Clinical features
The clinical features at presentation are
variable {1017,1663,2867,3018,3019}.
More than half of the patients have a high
or high-intermediate International Prog
nostic Index (IPI) score. Most patients
have detectable EBV DNA in serum or
whole blood, but this can also be seen
in patients with EBV-negative DLBCL
{2316,2961}.
Microscopy
The histological features overlap with
those of other EBV-related lymphoid pro
liferations, including EBV-positive classic
Hodgkin lymphoma. The neoplastic com
ponent most often consists of a variable
number of large transformed cells/immu-
noblasts and Hodgkin/Reed-Sternberg-
like cells. There is a variable component
of reactive elements, including small
lymphocytes, plasma cells, histiocytes,
and epithelioid cells. The rich back
ground of small lymphocytes and histio
cytes may resemble T-cell/histiocyte-rich for the pan-B-cell antigens CD19, CD20, tumour cells often express PDL1 and
large B-cell lymphoma, also referred to CD22, CD79a, and PAX5, and have an PDL2, providing a mechanism for im
as the polymorphic pattern in some stud activated-B-cell immunophenotype, be mune escape {668,2867,4431}.
ies {2867,4087}. This is the most common ing positive for IRF4/MUM1 and nega In situ hybridization for EBV-encoded
pattern in young patients. Other cases tive for CD10 and commonly BCL6 {1017, small RNA (EBER) is mandatory for the
are more monomorphic, and may be dif 2867,3018,3019}. CD30 is frequently diagnosis of EBV-positive DLBCL, NOS.
ficult to distinguish from EBV-negative positive and CD15 is sometimes coex With EBER in situ hybridization, more
DLBCL without ancillary studies {165, pressed, but other phenotypic features than 80% of the atypical cells are posi
780,1017,1018,2701,3018,3019}. Large typical of classic Hodgkin lymphoma tive. Small numbers of EBER-positive
areas of geographical necrosis and an- are usually lacking {668,1017,2867}. cells may be present as bystander B-
gioinvasion are other characteristic find Light chain restriction may be difficult to cells in EBV-negative B-cell or T-cell lym
ings, but they are not always present. demonstrate. EBNA2 and LMP1 are ex phomas {2867,2960,3821}.
pressed in 7―36% and > 90% of cases,
Immunophenotype respectively, indicating type III and (more Postulated normal counterpart
The neoplastic cells are usually positive often) type II EBV latency {2867}. The A mature B cell, transformed by EBV
EBV-positive diffuse large B-cell lymphoma, not otherwise specified (NOS) 305
Genetic profile and MYD88, which are often found in immunochemotherapy {1017,3019,3527,
Clonality of the IG genes and EBV can the activated B-cell type of DLBCL, are 3820}, but younger patients appear to
usually be detected by molecular tech absent {1316}. Chromosomal gains at have an excellent prognosis, with long
niques, and is helpful for distinguishing 9p24.1 may contribute to increased ex term complete remission in > 80% {2867,
polymorphous cases from reactive hy pression of PDL1 and PDL2 {4431}. Gene 4087}. Cases with the T-cell/histiocyte-
perplasia and infectious mononucleo expression profiling shows activation of rich large B-cell lymphoma-like or poly
sis {2867,3018,3019}. Restricted/clonal the JAK/STAT and NF-kappaB pathways morphic pattern appears to have a better
T-cell receptor responses can be seen {1958,2956}. prognosis than do monomorphic EBV-
in some cases {1018,2867}, but can positive DLBCL in young patients {1017,
also be present in other EBV-associated Prognosis and predictive factors 1018,2867}. Positivity for CD30 {2956}
lymphoproliferations such as infectious With an age cut-off point of 45 years, the and EBNA2 {3820} may have an adverse
mononucleosis {2447}. IG translocations prognosis of EBV-positive DLBCL differs prognostic impact. In elderly patients,
are uncommon (seen in ~ 15% of cases). significantly between elderly and young B symptoms and age > 70 years appear
The presence of an IGH/MVC transloca patients (P < 0.0001) {1017,2867,3019}. to be adverse prognostic factors {3019};
tion or variants should suggest a diag The disease is aggressive, with a median patients with neither, one, or both of these
nosis of plasmablastic lymphoma {2365, survival of about 2 years in elderly pa factors have median overall survival times
4110}. Mutations in CD79B, CARD11, tients, even when treated with rituximab of 56, 25, and 9 months, respectively.
Immunophenotype
The large transformed immunoblasts and
Hodgkin/Reed-Sternberg-like cells are
B cells that in most cases have CD20
expression ranging from strong to weak
and heterogeneous. These cells are
positive for PAX5 and OCT2, with vari
able expression of BOB1. They have an
activated-B-cell phenotype, being nega
tive for CD10 and BCL6 and positive for
IRF4/MUM1, and are CD30-positive.
CD15 is expressed in about half of the
cases. CD79a is often positive. EBV is Postulated normal counterpart immunosuppressive therapy. In patients
consistently positive, with transformed An EBV-transformed post-germinal cen in whom immunosuppression cannot
cells commonly positive for LMP1. Posi tre B cell be reversed, responses to rituximab, lo
tivity for EBV-encoded small RNA (EBER) cal radiation, and chemotherapy have
parallels expression of most B-cell anti Genetic profile been observed. Spread to distant sites is
gens, and is found in a range of cell sizes, Fewer than half of all EBVMCUs show rare, but local progression may be seen.
from small lymphocytes to immunoblasts clonal IG gene rearrangements. Studies The outcome is superior to that to other
and cells with Hodgkin/Reed-Sternberg of TR gene rearrangement often reveal immunodeficiency-associated EBV-driv-
cell morphology. The background con an oligoclonal or restricted pattern by en lymphoproliferative disorders {1017,
sists mainly of T cells, with numerous PCR {971,1017,1018}. 1565,2597,3852,4408}. However, rare
CD8+ T cells. A dense rim of CD3+ lym cases of relapses or progression to more
phocytes is present between the lesion Prognosis and predictive factors widespread disease {2721} have been
and adjacent soft tissue. Case reports and series suggest a be reported.
nign natural history, with nearly all re
ported cases responding to reduction of
Definition
Diffuse large B-cell lymphoma (DLBCL)
associated with chronic inflammation is a
lymphoid neoplasm occurring in the set
ting of longstanding chronic inflammation
and showing association with EBV. Most
cases involve body cavities or narrow
spaces. Pyothorax-associated lympho
ma (PAL) is the prototypical form, devel
oping in the pleural cavity of patients with
longstanding pyothorax.
Synonym
Pyothorax-associated lymphoma
Epidemiology
PAL develops in patients with a 20 to 64-
year (median: 37-year) history of pyotho type III EBV latency) {1264,2949,3150, are the pleural cavity (PAL), bone (espe
rax resulting from artificial pneumothorax 3525,3873,3874}. Chronic inflammation cially femur), joints, and periarticular soft
for treatment of pulmonary or pleural at the local site probably plays a role tissue {696}. In more than half of all PAL
tuberculosis {121,1797,2818,2827,3150}. in the proliferation of EBV-transformed cases, the tumour mass is > 10 cm {121}.
Patient age at diagnosis ranges from B cells by enabling them to escape from There is direct invasion of adjacent struc
the fifth to eighth decade of life (median: the host immune surveillance through tures, but the tumour is often confined to
65―70 years) {2818,2827}. The male-to- production of IL10 (an immunosuppres the thoracic cavity at the time of diagno
female ratio is 12:1 versus nearly equal in sive cytokine) and by providing autocrine sis, with about 70% of patients presenting
chronic pyothorax, suggesting that males to paracrine growth via IL6 and IL6R with clinical stage I or II disease {2818}.
are more susceptible to this type of lym {1925,1928}. PAL differs from primary effusion lympho
phoma than are females {1797}. Although DLBCLs associated with chronic inflam ma, which is characterized by lympho
most cases of PAL have been reported mation that occur in other settings simi matous serous effusions in the absence
in Japan, this lymphoma has also been larly harbour EBV, likely facilitated by so- of tumour mass formation and is HHV8+.
described in the west {166,2518,3150}. called local immunodeficiency resulting
For DLBCLs arising in other settings of from longstanding chronic suppuration or Clinical features
chronic suppuration or inflammation, inflammation in a confined space {696, Patients with PAL present with chest
such as chronic osteomyelitis, metallic 804}. pain, back pain, fever, or tumorous swell
implant insertion, surgical mesh implan ing in the chest wall, or with respiratory
tation, and chronic skin venous ulcer, Localization symptoms such as productive cough,
the interval between the predisposing The most common sites of involvement haemoptysis, and dyspnoea. Radiologi-
event and malignant lymphoma is usually
>10 years (range: 1.2―57 years) {696,
804,1263}.
Etiology
Artificial pneumothorax, used in the past
as a form of surgical therapy for pulmo
nary tuberculosis, is the only significant
risk factor for development of PAL among
patients with chronic pyothorax {120,
1679}. PAL is strongly associated with
EBV, with expression of EBNA2 and/or
LMP1 together with EBNA1 (i.e. usually
Microscopy
The morphological features are the same
as those of DLBCL, NOS. Most cases
show centroblastic or immunoblastic
morphology, with round nuclei and large
single or multiple nucleoli. Massive ne
crosis and angiocentric growth may be
present.
Immunophenotype
Most cases express CD20 and CD79a.
However, a proportion of cases may show
plasmacytic differentiation, with loss of
CD20 and/or CD79a, and expression of Genetic profile differentially expressed genes is IFI27,
IRF4/MUM1 and CD138. The lymphoma IG genes are clonally rearranged and hy- which is known to be induced in B lym
has an activated B-cell phenotype. CD30 permutated, but lack ongoing mutations phocytes by stimulation of interferon al
can be expressed. Occasional cases {2680,3875}. TP53 mutations are found pha, consistent with the role of chronic
also express one or more T-cell markers in about 70% of cases, usually involving inflammation in this condition. Downreg-
(CD2, CD3, CD4, and/or CD7), causing dipyrimidine sites, which are known to ulation of HLA class I expression, which
problems in lineage assignment {2734, be susceptible to mutagenesis induced is essential for efficient induction of host
2818,3150,4022}. by ionizing radiation {1679}. MYC gene cytotoxic T lymphocytes, and mutations
In situ hybridization for EBV-encoded amplification is common {4412}, and of cytotoxic T-lymphocyte epitopes in
small RNA (EBER) shows positive la TNFAIP3 (also called A20) is deleted in EBNA3B, an immunodominant antigen
belling of the lymphoma cells. Type III a proportion of cases {100}. Cytogenetic for cytotoxic T-lymphocyte responses,
EBV latency (i.e. positivity for LMP1 and studies show complex karyotypes with might also contribute to escape of PAL
EBNA2) is characteristic {1263,3150}. numerous numerical and structural ab cells from host cytotoxic T lymphocytes
normalities {3874}. The gene expression {1926,1927}.
Postulated normal counterpart profile of PAL is distinct from that of nodal
An EBV-transformed post-germinal DLBCL, which may be attributable to the
centre B cell presence of EBV {2882}. One of the most
Epidemiology Macroscopy
LYG is a rare condition. It usually presents LYG most commonly presents as pulmo
in adulthood, but may be seen in chil nary nodules that vary in size. The lesions
dren with immunodeficiency disorders. are most often bilateral in distribution, in
It affects males more often than females, volving the mid- and lower lung fields.
with a male-to-female ratio of ≥ 2:1 {1965, Larger nodules frequently exhibit central
3726}. It appears to be more common in necrosis and may cavitate. Nodular le
western countries than in Asia. sions are found in the kidneys and brain,
usually associated with central necrosis
Etiology {1966,3726}. Skin lesions are extremely
LYG is an EBV-driven lymphoprolifera diverse in appearance. Nodular lesions
tive disorder. Individuals with underlying are found in the subcutaneous tissue.
immunodeficiency are at increased risk Dermal involvement may also be seen,
{1490,1544}. Predisposing conditions in sometimes with necrosis and ulceration.
clude allogeneic organ transplantation, Cutaneous plaques or a maculopapular
Wiskott-Aldrich syndrome (eczema- rash are less common cutaneous mani
thrombocytopenia-immunodeficiency festations {309,1823,1965,2604}.
syndrome), HIV infection, and X-linked
lymphoproliferative syndrome. Patients Microscopy
presenting without evidence of under LYG is characterized by an angiocen
lying immunodeficiency usually manifest tric and angiodestructive polymorphous
reduced immune function on careful clini lymphoid infiltrate {1965,1966,2087,
cal or laboratory analysis {3733,4332}. 3726}. Lymphocytes predominate and
are admixed with plasma cells, immu
Localization noblasts, and histiocytes. Neutrophils background {1490,1966,1967}. The EBV-
Pulmonary involvement occurs in >90% and eosinophils are usually inconspicu positive cells usually show some atypia.
of patients and is usually present at ini ous. The background small lymphocytes They may resemble immunoblasts or less
tial diagnosis. Other common sites of may show some atypia or irregularity, but commonly have a more pleomorphic ap
involvement include the brain, kidneys, do not appear overtly neoplastic. LYG pearance reminiscent of Hodgkin cells.
liver, and skin. Involvement of the upper is composed of a variable but usual Multi nucleated forms may be seen. Clas
respiratory tract or gastrointestinal tract ly small number of EBV-positive B cells sic Reed-Sternberg cells are generally
is relatively uncommon {841,1966,3726}. admixed with a prominent inflammatory not present; if seen, they should raise the
Grading
The grading of LYG relates to the propor
tion of EBV-positive B cells relative to the
reactive lymphocyte background {1491,
1966,2357,3726}. It is most important to
distinguish grade 3 from grade 1 or 2. A
uniform population of large atypical EBV-
positive B cells without a polymorphous
background should be classified as EBV-
positive, diffuse large B-cell lymphoma,
NOS and is beyond the spectrum of LYG
as currently defined.
Grade 1 lesions contain a polymorphous
lymphoid infiltrate without cytological
atypia. Large transformed lymphoid
cells are absent or rare, and are better
appreciated by immunohistochemistry.
When present, necrosis is usually focal.
Genetic profile
Antigen receptor genes
Immunoglobulin genes are rearranged
and may be class switched, with a high
load of somatic hypermutations without
ongoing mutation activity {2262}.
Immunophenotype
PMBL expresses B-cell-lineage antigens
such as CD19, CD20, CD22, and CD79a,
but commonly lacks immunoglobulin de
spite a functional IG gene rearrangement
and expression of the transcription fac
tors PAX5, BOB1, OCT2, and PU1 {1915,
2379,3179,4274}. Flow cytometric studies
may demonstrate surface IG in a sub
set of cases {4274}. CD30 is present in
> 80% of cases; however, staining is usu
ally weak and heterogeneous compared
to that in CHL {1633,3179}. CD15 may be
expressed in a minority of cases {2800}.
EBV is almost always absent {589}. The
neoplastic cells are frequently positive
for IRF4/MUM1; present in 75% of cases,
Definition
Intravascular large B-cell lymphoma is a
rare type of extranodal large B-cell lym
phoma characterized by the selective
growth of lymphoma cells within the lu-
mina of vessels, in particular capillaries,
and with the exception of larger arteries
and veins.
Synonyms
Malignant angioendotheliomatosis;
angioendotheliomatosis proliferans
syndrome; intravascular lymphomatosis;
angioendotheliotropic lymphoma
(all obsolete)
Epidemiology
This tumour occurs in adults, with a medi
an age of 67 years (range: 13―85 years)
and a male-to-female ratio of 1.1:1. The in western females; it is characterized by Microscopy
frequency and clinical presentation differ restriction of the tumour to the skin and is The neoplastic lymphoid cells are mainly
according to patients’ geographical ori associated with a better prognosis {1193, lodged in the lumina of small or interme
gin (West vs Far East) {1196,2789,3214, 3214}. Conventional staging procedures diate sized vessels in many organs. Fi
3215,3655}. are generally associated with a high pro brin thrombi, haemorrhage, and necrosis
portion of false negatives due to the lack may be observed in some cases. The tu
Localization of detectable tumour masses. A random mour cells are large, with prominent nu
This lymphoma is usually widely dissemi skin biopsy of normal-appearing skin and cleoli and frequent mitotic figures. Rare
nated in extranodal sites, including the transbronchial lung biopsy are often help cases have cells with anaplastic features
bone marrow, and may present in virtual ful to make the diagnosis. Tumour cells or smaller size {3215}. Minimal extravas-
ly any organ. However, the lymph nodes are often seen in subcutaneous tissue cular location of neoplastic cells may
are usually spared. irrespective of the absence of skin erup be seen. In the CNS, recurrences may
tion, even in the haemophagocytic syn be associated with extravascular brain
Clinical features drome-associated form {2569}. masses {1642,3657}. Sinusoidal involve
Two major patterns of clinical presenta ment occurs in the liver, spleen, and bone
tion have been recognized: a so-called marrow. Malignant cells are occasionally
classic form (mostly present in western detected in peripheral blood {3215}.
countries) characterized by symptoms re
lated to the main organ involved, predom Immunophenotype
inantly neurological or cutaneous, and a Tumour cells express mature B-cell—
haemophagocytic syndrome-associated associated antigens. CD5 and CD10
form, originally documented as an Asian coexpression is seen in 38% and 13%
variant, in which patients present with of the cases, respectively. Almost all
multiorgan failure, hepatosplenomegaly, CD10-negative cases are positive for
and pancytopenia {1196,2789,3214,3215, IRF4/MUM1. An increasing number of
3655}. Exceptions to these geographical intravascular NK/T-cell lymphomas with
distributions may occur. B symptoms, in EBV-positive tumour cells {1317,4241}
particular fever, are very common, occur and rarely intralymphatic anaplastic large
ring in 55―76% of patients, in both types cell lymphomas, ALK-negative {2644,
of presentation. An isolated cutaneous 3871}, have been reported, but they
variant has also been identified, invariably should be considered different entities.
Definition 1307}. Atypical multinucleated neoplastic acteristically strongly express EMA and
ALK-positive large B-cell lymphoma giant cells may be seen. plasma cell markers such as CD138,
(LBCL) is an aggressive neoplasm of VS38, PRDM1 (also known as BLIMP1),
ALK-positive monomorphic large immu- Immunophenotype and XBP1, and are negative or only
noblast-like B cells, which usually have a Lymphoma cells are strongly positive for positive in occasional cells for B-cell line
plasma cell phenotype. the ALK protein, with most demonstrat age-associated antigens (CD20, CD79a,
ing a restricted granular cytoplasmic and PAX5). IRF4/MUM1 is also positive
ICD-O code 9737/3 staining pattern highly indicative of the {951,3763,4111}. CD45 is weak or nega
expression of the CLTC-ALK fusion pro tive {951,1307,2230}. CD30 is negative
Synonyms tein. Few cases show cytoplasmic, nu {951}, although focal and weak staining
Large B-cell lymphoma expressing the clear, and nucleolar ALK staining associ has been reported in a few cases {3763}.
ALK kinase and lacking the t(2;5) translo ated with the NPM1-ALK fusion protein. Most tumours express cytoplasmic im
cation; ALK-positive plasmablastic B-cell ALK translocations with other partners munoglobulin (usually IgA, more rarely
lymphoma (both obsolete) may be associated with a cytoplasmic IgG) with light chain restriction {951}. As
staining pattern. The tumours also char described in some plasma cell tumours,
Epidemiology
This lymphoma is very rare, accounting
for < 1% of diffuse LBCLs. It seems to oc
cur more frequently in young men, with a
male-to-female ratio of 5:1, but spans all
age groups, with a patient age range of
9―85 years (median: 43 years). One third
of cases occur in the paediatric age
group {2230,3333}. There is no associa
tion with immunosuppression.
Localization
The tumour mainly involves lymph nodes
{22,951,1307,1790,3333,3763} or pre
sents as a mediastinal mass {907,1348}.
Extranodal involvement has also been re
ported, at sites such as the nasopharynx
{2976}, tongue {907}, stomach {2601},
bone {2976}, soft tissue {713}, liver,
spleen, and skin {2230}.
Clinical features
Most patients present with generalized
lymphadenopathy, and 60% present in
advanced stage lll/IV. Bone marrow is
infiltrated in 25% of cases {2230}.
Microscopy
The lymph nodes show a marked dif
fuse infiltrate, frequently with a sinusoidal
growth pattern. The infiltrate is composed
of monomorphic large immunoblast-like
cells with round pale nuclei containing
a large central nucleolus and abundant
amphophilic cytoplasm. Some cases
show plasmablastic differentiation {951,
Genetic profile
The IG genes are clonally rearranged
{713,1307}. The key oncogenic factor of
this tumour is ALK overexpression due
to the fusion protein generated by the locations are typically detected in the con Prognosis and predictive factors
translocation of the ALK locus on chro text of complex karyotypes {713,907,1307, In one study, the reported median overall
mosome 2. The most frequent abnormal 1348,1790,2230,2601,3333,3763,4111}. survival of patients with stage lll/IV dis
ity is t(2;17)(p23;q23), responsible for a ALK protein oncogenic mechanisms in ease was 11 months {3333}. Longer sur
CLTC-ALK fusion protein. Few cases clude activation of the STAT3 pathway; vival (> 156 months) has been reported in
are associated with the t(2;5)(p23;q35) concordantly, ALK-positive LBCLs ex children {951,2976}. These tumours are
translocation, as described in ALK-pos press high phospho-STAT3 {4111}. MYC usually negative for CD20 antigen, and
itive anaplastic large cell lymphoma {22, is also expressed in the absence of MYC are thus unlikely to be sensitive to rituxi
2976}. A cryptic insertion of three ALK translocations or amplifications, prob mab. Patients presenting with localized
gene sequences into chromosome 4q22- ably due to transcriptional activation disease (stage l-ll) have been found to
24 has also been reported. ALK may also downstream of STAT3 {4111}. Oncogenic have significantly longer survival {2230}.
be fused to SQSTM1, SEC31A, or other Aik activation in murine B cells gener
uncommon fusion partners. These trans ates plasmablastic B-cell tumours {709}.
Definition PBL also occurs in children with immu (IPI) score. CT and PET show disseminat
Plasmablastic lymphoma (PBL) is a very nodeficiency, mainly due to HIV infection ed bone involvement in 30% of patients
aggressive lymphoma with a diffuse pro {417,578,785,936,2365}. {3942}. A paraprotein may be detected
liferation of large neoplastic cells, most in some cases {3865}. Tumours with fea
of which resemble B immunoblasts or Etiology tures of PBL may occur in patients with
plasmablasts, that have a CD20-nega- Immunodeficiency, due to various caus prior plasma cell neoplasms, including
tive plasmacytic phenotype. It was origi es, predisposes individuals to the de plasma cell myeloma. Such cases should
nally described in the oral cavity and velopment of PBL. The tumour cells are be considered plasmablastic transforma
frequently occurs in association with HIV EBV-infected in most patients {417,785, tion of myeloma and distinguished from
infection, but it may also occur in other 936,1023}. primary PBL.
sites, predominantly extranodal, and in
association with other causes of immu Localization Microscopy
nodeficiency {785,936}. Some cases, PBL most frequently presents as a mass PBLs show a morphological spectrum
particularly in the oral cavity (i.e. the oral in extranodal regions of the head and varying from a diffuse and cohesive pro
mucosa type), look most like a diffuse neck, in particular the oral cavity, with the liferation of cells resembling immunob
large B-cell lymphoma (LBCL); other gastrointestinal tract being the next most lasts to cells with more obvious plasma
cases have morphologically recogniz common site. Other extranodal localiza cytic differentiation, which may resemble
able plasmacytic differentiation. Other tions reported in > 1% of cases include cases of plasmablastic plasma cell
subtypes of LBCLs with a plasmablas the skin, bone, genitourinary tract, nasal myeloma. Mitotic figures are frequent.
tic immunophenotype (e.g. ALK-positive cavity and paranasal sinuses, CNS, liver, Apoptotic cells and tingible body mac
LBCL and HHV8-associated lymphopro lungs, and orbits. Nodal involvement is rophages may be present. Cases with
liferative disorders) are not included in found in < 10% of cases overall, but in monomorphic plasmablastic cytology
this category. 30% of post-transplant cases {578,785, are most commonly seen in the setting
936,1023}. of HIV infection and in the oral, nasal,
ICD-O code 9735/3 and paranasal sinus areas (i.e. the oral
Clinical features mucosal type). Conversely, cases with
Epidemiology Disseminated stage lll/IV disease, includ plasmacytic differentiation tend to occur
This lymphoma occurs predominantly ing bone marrow involvement, is found more commonly in other extranodal sites,
in adults with immunodeficiency, most at presentation in 75% of HIV-positive as well as in lymph nodes {785,936}.
commonly due to HIV infection but also patients and 50% of post-transplant pa The differential diagnosis of cases with
in the setting of iatrogenic immunosup tients, but in only 25% of patients without plasmacytic differentiation may include
pression (transplantation and autoim apparent immunodeficiency {578}. Most anaplastic or plasmablastic plasma
mune diseases) and in elderly patients patients have an intermediate-risk or cell myeloma. A history of immune de
with presumptive immunosenescence. high-risk International Prognostic Index ficiency and the presence of EBV by in
Fig. 13.143 Plasmablastic lymphoma (PBL). A PBL of the oral mucosa with a monomorphic proliferation of large, immunoblastic cells with prominent nucleoli. B PBL with
plasmacytic differentiation. Many of the tumour cells are large, with round nuclei and variably prominent nucleoli and showing coarse chromatin. Smaller cells with plasmacytic
differentiation are also present.
Immunophenotype
The neoplastic cells express a plasma
cell phenotype, including positivity for
CD138, CD38, VS38c, IRF4/MUM1,
PRDM1 (also called BLIMP1), and XBP1.
CD45, CD20, and PAX5 are either nega
tive or sometimes weakly positive in a
minority of cells. CD79a is positive in
approximately 40% of cases {578,2699, In situ hybridization for EBER is posi has been identified in approximately 50%
4111}. Cytoplasmic immunoglobulin is tive in 60―75% of cases, but LMP1 is of cases, more frequently in EBV-positive
commonly expressed, most frequently rarely expressed. PBL is more frequently tumours (74%) than in EBV-negative tu
IgG and either kappa or lambda light EBV-positive in HIV-positive and post mours (43%), and it is associated with
chain. CD56 is detected in 25% of cas transplant patients than in HIV-negative MYC protein expression {400,3865,4110,
es. It is usually negative in the oral mu patients {578,2755}. HHV8 is consistently 4111}. The rearrangement usually occurs
cosal type, but may be seen in cases absent. with IG genes {4110}.
with plasmacytic differentiation. EMA
and CD30 are frequently expressed. The Postulated normal counterpart Prognosis and predictive factors
Ki-67 proliferation index is usually very A plasmablast (i.e. a blastic proliferat The prognosis is generally poor; more
high (> 90%). BCL2 and BCL6 expres ing B cell that has switched its pheno than three quarters of patients die of
sion is usually absent, whereas CD10 is type to the plasma cell gene expression the disease, with a median survival of
expressed in 20% of cases. Cyclin D1 programme) 6―11 months {578,2755}. Newer thera
is negative. Some cases express the pies and better treatment of HIV infection
T-cell associated markers CD43 and Genetic profile may be associated with a better prog
CD45RO {578,785,936,1023,4164}. Re Clonal IGH rearrangement is demon nosis, but the results are not consistent
active infiltrating T cells are usually very strable, even when immunoglobulin ex across studies {578}. Evaluation of prog
scarce. Some LBCLs may have marked pression is not detectable, and IGHV nostic parameters has not yielded con
morphological plasmablastic features may have somatic hypermutation or be sistent results. However, MYC transloca
but strongly express CD20, CD79a, and unmutated with a germline configuration tion has been associated with a worse
PAX5 {3682}. These cases should not be {1273}. outcome in two studies {578,2755}.
considered PBL and are better classified Genetic studies have revealed frequent
as diffuse LBCL, NOS. complex karyotypes. MYC translocation
Definition most cases of PEL are EBV-positive, lack Multicentric Castleman disease
In addition to causing Kaposi sarcoma, cytoplasmic immunoglobulins, express
which may involve the lymph nodes, the activation and plasma cell-associated Definition
human herpesvirus HHV8 (also called Ka antigens, including CD30, CD38, CD138, Multicentric Castleman disease (MCD) is
posi sarcoma-associated herpesvirus) is and EMA, and arise from a terminally dif a clinicopathological entity that encom
responsible for a spectrum of lymphopro ferentiated rather than a naive B cell. passes a group of systemic polyclonal
liferative disorders. These include HHV8- Rare cases of other HHV8-positive lym lymphoproliferative disorders in which
positive multicentric Castleman disease phomas have been described, including there is a proliferation of morphologi
(MCD); HHV8-positive diffuse large 13- a case with a Hodgkin-like appearance cally benign lymphocytes, plasma cells,
cell lymphoma (DLBCL), NOS, which fre in an immunocompetent patient and cas and vessels, due to excessive produc
quently arises in the background of MCD; es resembling intravascular large B-cell tion of cytokines, in particular IL6 {556,
and germinotropic lymphoproliferative lymphoma {834,1206}. Node-based 1133}. Activation of the IL6R signalling
disorder (GLPD). Except for GLPD, these HHV8-positive B-cell lymphomas with pathway by the virus plays a key role in
disorders are most commonly seen in anaplastic large cell morphology have the development of HHV8-infected B-
the setting of HIV infection and in HHV8- also been reported, and may constitute cell lymphoproliferative lesions, including
endemic areas, but they can also occur an anaplastic variant of HHV8-positive MCD {1048}. In patients with HIV, MCD
in other immunosuppressed states, in DLBCL, NOS {558,1721}. is almost always HHV8-related. In the
cluding following transplantation {2238}. absence of HIV, MCD is HHV8-related in
GLPD is most commonly seen in immu as many as 50% of cases, and usually
nocompetent individuals. Primary effu occurs in HHV8-endemic areas {1029}.
sion lymphoma (PEL) and extracavitary
PEL are also caused by HHV8, but are Table 13.25 Key features of HHV8-positive multicentric Castleman disease (MCD); diffuse large B-cell lymphoma
discussed elsewhere (see Primary effu (DLBCL), NOS; and germinotropic lymphoproliferative disorder (GLPD)
sion lymphoma, p.323). HHV8-positive
Feature HHV8-positive MCD DLBCL, NOS HHV8-positive GLPD
Associated conditions Clinical Generalized Large lymph node Localized or sometimes
Kaposi sarcoma is frequently present in presentation lymphadenopathy Splenic mass multifocal lymph node
patients with MCD and HHV8-positive Splenomegaly involvement
Extranodal sites
DLBCL, NOS, arising in MCD. PEL and Constitutional symptoms Peripheral blood
its extracavitary counterpart may compli
cate HHV8-positive MCD. Microscopy Abnormal follicles Sheets of large Retention of architecture
Plasmablasts predominantly plasmablastic cells with germinal centres
containing variable numbers
Other HHV8-positive lymphoproliferative in mantle zones
of plasmablasts sometimes
disorders Interfollicular plasma cell replacing follicles
Although most cases of HHV8-positive hyperplasia
lymphoproliferative disorders fall within Phenotype B-cell antigens +/- B-cell antigens +/- B-cell antigens-
the spectrum defined above, individual clgM lambda + clgM lambda + Monotypic kappa or lambda
cases have been reported in which there
IRF4a + IRF4a + Any heavy chain
are overlapping features. For example,
CD138- CD138- CD138-
cases arising in the background of MCD
intermediate between HHV8-positive CD30 +/-
DLBCL and GLPD have been reported Clonality Polyclonal Monoclonal Polyclonal or oligoclonal
in HIV-positive and HIV-negative patients HHV8 LANA1 + + +
{1404A}. They may resemble HHV8-
EBER - - +
positive DLBCL, NOS, but are also posi
tive for EBV-encoded small RNA (EBER) HIV status +/- +/- -
{3052,3616}. Although GLPD tends not to Poor but improved with
Prognosis Poor Usually responds to treatment
progress, one reported case evolved to a new therapies
high-grade HHV8-positive, EBV-positive
EBER, EBV-encoded small RNA.
lymphoma {826}. The differential between
HHV8-positive DLBCL, NOS, and extra a Also known as MUM1.
cavitary PEL may be problematic, but
Epidemiology
HHV8-positive MCD occurs worldwide
in immunosuppressed patients, particu
larly in association with HIV/AIDS. It may
also affect immunocompetent individuals
in HHV8-endemic areas (e.g. sub-Saha
ran Africa and Mediterranean countries)
{425}. In HIV-infected patients, there is
a strong association with sexual trans
mission, and men are predominantly
affected.
Etiology
MCD is a heterogeneous group of dis
orders thought to arise from excessive
hypercytokinaemia, most notably of IL6
{1133}. In HHV8-positive MCD, the plas-
mablastic cells are infected with HHV8,
which produces viral IL6. In addition,
HHV8-encoded proteins and microRNAs
provide proliferative and anti-apoptotic
signals contributing to the pathogenesis.
These include LANA1, LANA2, IL10,
vFLIP, and miR-K1 {116,156,172,1895,
4090}. HHV8-encoded vGPCR induces
expression of proinflammatory and an
giogenic factors contributing to the in
flammatory and hyperproliferative nature
of the lesions, and also constitutively
activates the nuclear factor of activated
T cells {3097}.
Localization
HHV8-positive MCD usually presents
with generalized lymphadenopathy and
splenomegaly.
Clinical features
Patients with HHV8-positive MCD pre
sent with constitutional symptoms, en
larging lymph nodes, and splenomegaly.
Constitutional symptoms include fever,
night sweats, fatigue, weight loss, and
respiratory symptoms {440}. Kaposi sar
coma is commonly also present {1064,
2968}. In addition to lymphadenopathy,
patients may have hepatosplenomegaly
and a skin rash {556}. Laboratory find
MCD is idiopathic in HHV8-negative germinal centres {1132A,3475A,4450A}. ings include anaemia, thrombocytope
and HIV-negative patients. Idiopathic The diagnosis requires exclusion of in nia, hypoalbuminaemia, hypergamma-
HIV― and HHV8―negative multicentric fectious, neoplastic, and autoimmune globulinaemia, and elevated C-reactive
Castleman disease (iMCD) is a systemic diseases that may have similar clinical protein {556}.
disease with constitutional symptoms, presentations. In this syndrome, the
laboratory abnormalities, and multicen hypercytokinaemia may be driven by Microscopy
tric lymphadenopathy characterized by inflammatory disease or inflammatory The B-cell follicles of lymph nodes and
polytypic plasmacytosis and variably gene mutations, autoantibodies, ectopic spleen show varied degrees of involution
prominent hypervascular or regressed cytokine secretion, as seen in paraneo and hyalinization of their germinal cen
Genetic profile
Despite the constant expression of mono-
typic IgM lambda by the plasmablasts in
HHV8-positive MCD, careful molecular
studies have shown that they constitute
a polyclonal population {1048}. The plas
mablastic aggregates that can develop
during the progression of MCD may be
monoclonal or oligoclonal.
Definition
Burkitt lymphoma (BL) is a highly aggres
sive but curable lymphoma that often pre
sents in extranodal sites or as an acute
leukaemia. It is composed of monomor
phic medium-sized B cells with baso
philic cytoplasm and numerous mitotic
figures, usually with a demonstrable MYC
gene translocation to an IG locus. The
frequency of EBV infection varies accord
ing to the epidemiological subtype of BL.
No single parameter, such as morphol
ogy, genetic analysis, or immunopheno-
typing, can be used as the gold standard
for diagnosis of BL; a combination of sev
eral diagnostic techniques is necessary.
Synonyms
Burkitt tumour (obsolete); malignant lym
phoma, undifferentiated, Burkitt type (ob
solete); malignant lymphoma, small non- South America and northern Africa), the Etiology
cleaved, Burkitt type (obsolete); Burkitt incidence of BL is intermediate between In all patients with endemic BL, the EBV
cell leukaemia (9826/3) that of sporadic BL in developed coun genome is present in > 95% of the neo
tries and endemic BL {2441,3258}. plastic cells. There is also a strong epide
Epidemiology Immunodeficiency-associated BL is more miological link with holoendemic malaria.
Three epidemiological variants of BL common in the setting of HIV infection Therefore, EBV and Plasmodium falcipa
are recognized, which mainly differ in than in other forms of immunosuppres rum are thought to be responsible for en
their geographical distribution, clinical sion. In HIV-infected patients, BL appears demic BL {915,1870}. Recent data have
presentation, subtle morphological as early in the progression of the disease, provided new insight into how these two
pects, molecular genetics, and biologi when CD4+ T-cell counts are still high human pathogens interact to cause the
cal features. {2332,3309}. The increased risk of devel disease, supporting the emerging con
Endemic BL occurs in equatorial Africa oping BL seems to have persisted among cepts of polymicrobial disease patho
and in Papua New Guinea, with a dis HIV-infected patients over time, across genesis {688,2692,2937,3285,3368}.
tribution that overlaps with regions en the pre- and post-HAART eras {1370}. Malaria and EBV are ubiquitous within
demic for malaria. In these areas, BL is the lymphoma belt of Africa, suggesting
the most common childhood malignancy, that other etiological agents may also be
with an incidence peak among children involved, including arboviruses, schis
aged 4―7 years and a male-to-female ra tosomiasis, and plant tumour promoters
tio of 2:1 {503,4369}. {4121,4122,2486}. A recent study using
Sporadic BL is seen throughout the world, RNA sequencing found herpesviruses
mainly in children and young adults. The in 12 of 20 cases (60%) of endemic BL,
incidence is low, accounting for only in particular HHV5 and HHV8, and con
1―2% of all lymphomas in western Eu firmed their presence by immunohisto-
rope and in the USA. In these countries, chemistry in the adjacent non-neoplastic
BL accounts for approximately 30-50% tissue {8}. The polymicrobial nature of en
of all childhood lymphomas. The median demic BL is further supported by the sta
age of the adult patients is 30 years, but tus of B-cell receptor, which carries the
there is also an incidence peak in elderly signs of antigen selection due to chronic
patients {2590}. The male-to-female ratio antigen stimulation {84,3171}.
is 2―3:1. In some parts of the world (e.g. In sporadic BL, EBV can be detected in
Fig. 13.158 Burkitt lymphoma. In one case, Giemsa (A) and H&E (B) staining highlights uniform tumour cells with multiple small nucleoli and finely dispersed chromatin. In another
case, Giemsa (C) and H&E (D) staining highlights greater nuclear irregularity.
Definition
Burkitt-like lymphoma with 11q aberra
tion is a subset of lymphomas identified
by several recent studies that resem
ble Burkitt lymphoma (BL) morphologi
cally, to a large extent phenotypically,
and in terms of microRNAs and gene
expression profile, but that lack MYC
rearrangements. Instead, they have a
chromosome 11q alteration character
ized by proximal gains and telomeric
losses: specifically, interstitial gains
including a minimal region of gain in
11q23.2―23.3 and losses of 11q24.1-ter
{195,3175,3490}. These lymphomas lack
the 1q gain frequently seen in BL and
have more-complex karyotypes than BL.
They also have a certain degree of cy-
tological pleomorphism, occasionally a
follicular pattern, and frequently a nodal
presentation {3490,4454}. The clinical
course seems to be similar to that of BL,
but only a limited number of cases have
been reported. Very similar cases have
also been reported in the post-transplant
setting {1191}.
Definition some rare follicular lymphomas and B- classifiable, with features intermediate
High-grade B-cell lymphoma (HGBL) lymphoblastic leukaemia/lymphomas) between DLBCL and BL). Less com
is a group of aggressive, mature B-cell that have a MYC (8q24) rearrangement monly, they have a blastoid appearance,
lymphomas that for biological and clini in combination with a BCL2 (18q21) and/ morphologically mimicking lymphoblas
cal reasons should not be classified as or a BCL6(3q27) rearrangement, i.e. the tic lymphoma or the blastoid variant of
diffuse large B-cell lymphoma (DLBCL), so-called double-hit and triple-hit lym mantle cell lymphoma.
NOS, or as Burkitt lymphoma (BL). There phomas. Morphologically, these cases The second category, HGBL, NOS, en
are two categories of HGBL {1547,3846}. typically either resemble DLBCL, NOS, compasses cases that either have fea
The first category, HGBL with MYC and or can have features of both BL and tures intermediate between DLBCL and
BCL2 and/or BCL6 rearrangements, en DLBCL (referred to in the 2008 WHO BL or appear blastoid, but by definition
compasses all B-cell lymphomas (except classification as B-cell lymphoma, un do not harbour a genetic double hit as
defined above. This category excludes
cases with the morphology of DLBCL,
which should be diagnosed as such,
even if they have a high proliferative
fraction.
Synonym
B-cell lymphoma, unclassifiable, with
features intermediate between diffuse
large B-cell lymphoma and Burkitt lym
phoma (no longer recommended)
Localization
More than half of all patients present with
widespread disease, including involve
ment of the lymph nodes. There can also
be involvement of more than one extra
nodal site (occurring in 30―88% of cas
es), the bone marrow (in 59―94%), and
even the CNS (in as many as 45%) {2350,
3158,3523}.
Clinical features
Most patients (70―100%) present with
advanced disease (stage IV according
to the Ann Arbor classification), more
than one extranodal localization, a high
International Prognostic Index (IPI), and
elevated lactate dehydrogenase levels
{2350,3158,3523,3846}. Extranodal lo
calizations include the bone marrow and
CNS. Double-hit HGBLs are particu
larly enriched in patients diagnosed with
DLBCL who do not respond well to induc
tion therapy with the CHOP chemothera
py regimen plus rituximab (R-CHOP) or
who have early relapses after complete
remission {843}.
Microscopy
Double-hit HGBLs have variable morphol
ogy. The specific morphological appear
ance should be stated in a diagnostic
comment. Although the incidence differs
between studies, most authors conclude liferation index (see below). Therefore, a Because these lymphomas can be indis
that approximately half of the cases have low proliferation rate does not exclude this tinguishable from other DLBCL, a double
the morphology of a DLBCL, NOS {193, type of lymphoma. The nuclei have a vari hit status should be investigated in all
194,1820,1865,2304,3158,3523,3712}. able size and contour, with some cases DLBCLs, NOS, using cytogenetic or mo
This is due to the fact that DLBCL is by showing nuclei that are 3―4 times the size lecular cytogenetic studies. Some pathol
far the most frequent lymphoma subtype, of normal lymphocytes (much larger than ogists may prefer to look for evidence of
and approximately 4―8% of all DLBCLs BL cells). The cytoplasm is usually more a double-hit only after immunohistochemi
are double-hit lymphomas. In a recent abundant and less basophilic than in BL. cal or other pre-selection (see below).
study, 69% of the MYC and BCL2 double
hit lymphomas and 85% of the MYC and
BCL6 double-hit lymphomas had DLBCL
morphology {2304}. The differences be
tween individual studies may be due to re
ferral bias, inclusion bias, and the variable
morphological criteria {2720A.3712}. The
growth pattern is completely diffuse, of
ten with relatively few small lymphocytes.
Some fibrosis may be present. Starry-sky
macrophages may be present, sometimes
only focally. The numbers of mitotic figures
and apoptotic figures are highly variable,
with some cases having a low number of
mitotic figures and also a low Ki-67 pro
Definition ported rarely in children {2995}. Medias and shows less of a male predominance
B-cell lymphoma, unclassifiable, with tinal presentations are infrequent among {1077,1121}. Cases of composite CHL
features intermediate between diffuse elderly patients {1077,1121}. Most cases and PMBL and cases of sequential de
large B-cell lymphoma (DLBCL) and have been reported from western coun velopment of CHL and PMBL in the same
classic Hodgkin lymphoma (CHL) is a tries. Like CHL, these tumours are less patient are not strictly accepted as ex
B-cell-lineage lymphoma that demon common in Black and Asian populations. amples of MGZL, but are thought to be
strates overlapping clinical, morphologi biologically related phenomena {1402,
cal, and/or immunophenotypic features Etiology 3140}. When seen sequentially, CHL is
between CHL and DLBCL, especially The etiology is unknown, but gene ex more often the initial presentation, fol
primary mediastinal (thymic) large B-cell pression profiling studies and genetic lowed by PMBL {4463}.
lymphoma (PMBL). These lymphomas studies have revealed close links to
are most commonly associated with me PMBL and CHL {1059}. Microscopy
diastinal disease, but similar cases have A characteristic feature is the broad
been reported in peripheral lymph node Localization spectrum of cytological appearances
groups as the primary site. Mediastinal The most common presentation is with within a given tumour; some areas more
cases are often referred to as medias a large anterior mediastinal mass, with closely resemble CHL and others resem
tinal grey-zone lymphoma (MGZL) and or without involvement of supraclavicu ble PMBL. There is also variation across
non-mediastinal cases as grey-zone lym lar lymph nodes {1297,4047}. Peripheral different cases, with some examples be
phoma (GZL), avoiding the cumbersome and intra-abdominal lymph nodes are ing more Hodgkin-like and others more
nomenclature of the official diagnosis. less commonly involved. There may be closely resembling either PMBL or dif
spread to lung by direct extension, as fuse large cell lymphoma. As discussed
ICD-O code 9596/3 well as spread to liver, spleen, and bone below (see Immunophenotype), discord
marrow. Non-lymphoid organs are rarely ance between the cytological appear
Synonyms involved, unlike in PMBL. ance and the immunophenotype is com
Mediastinal grey-zone lymphoma; Hodg mon. Tumour cell density is high, often
kin-like anaplastic large cell lymphoma Clinical features with sheet-like growth of pleomorphic
(obsolete) Most patients have bulky mediastinal tumour cells in a diffusely fibrotic stroma
masses, sometimes leading to supe {1297,4047}. Focal fibrous bands may be
Epidemiology rior vena cava syndrome or respiratory seen in some cases. The cells are larger
MGZL is most common in young men, distress. Supraclavicular lymph nodes and more pleomorphic than is typical in
usually presenting in patients aged may be involved. Non-mediastinal GZL PMBL, although some centroblast-like
20―40 years {1297,4047}. It has been re more often presents in older patients, cells may be present. There is usually a
Genetic profile
Clonal rearrangement of the IG genes is
positive by PCR in most cases, presum
ably due to the high content of tumour
cells in comparison with CHL. Many of
the genetic aberrations identified by
FISH are similar to those observed in
PMBL {1077}. Gains and amplification
of the JAK2 and PDCD1LG2 (also called
PDL2) loci at 9p24.1 are common, seen
in > 50% of cases. Increased expression
of CD274 (PD-L1) may occur as a result.
Also frequent are gains/amplification at
2p16.1 involving REL. Breaks in the CIITA
locus at 16p13.13 have been reported in Fig. 13.179 B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classic HL. A Sheets
approximately one third of cases {1077}. of tumour cells resembling lacunar cells are present, with a minimal inflammatory background. B In the same case,
Gains in MYC have been observed the tumour cells are strongly positive for CD20. C CD79a is uniformly positive. D CD15 is positive, but the sheet-like
growth and strong staining for CD20 and CD79a favour mediastinal grey-zone lymphoma.
in 20―30% of cases. The aberrations
above are seen in both mediastinal and
non-mediastinal cases, although gains/
amplification at 9p24.1 are more com
mon in patients with mediastinal than
non-mediastinal presentations, occurring
in 61% and 38% of such cases, respec
tively {1077}.
Etiology
The underlying pathophysiological mech
anisms of T―LGLL are not well under
stood, and this disorder is fairly unique
in that the clonal T―cell LGLs (T―LGLs)
retain many phenotypic and functional
properties of normal cytotoxic T lympho
cyte effector memory cells {377}. One
theory is that T―LGLL arises in a setting
of sustained immune stimulation. The fre
quent association of T-LGLL with autoim
mune disorders supports this hypothesis
{377,4343}. The absence of homeostatic
apoptosis is also a feature of the T-LGLs;
these cells express high levels of FAS
and FASL, leading investigators to pro
pose activation of prosurvival pathways
in T―LGLs, which prevents activation-
induced cell death {1112,3549}. FASL
levels are elevated in the sera of many
patients, and this elevation is postulat
ed to be important in the pathogenesis Fig. 14.05 T-cell large granular lymphocytic leukaemia. The various morphological variants of large granular lympho
of neutropenia {2368}. Other pathways cyte in the peripheral blood (Wright stain).
Fig. 14.07 T-cell large granular lymphocytic leukaemia. Bone marrow findings. A Neoplastic cells infiltrate interstitially, as demonstrated by staining for TIA1.
B,C Reactive lymphoid aggregates. Lymphoid nodules in the bone marrow immunostained with anti-CD20 (B) and anti-CD3 (C). B cells in the nodule are admixed with CD3+
T cells that predominate at the periphery.
Etiology
A transient increase in circulating NK cells
can be encountered in many conditions,
such as autoimmune disorders and viral
infections {2204,3274}. NK-cell activation
due to an unknown stimulus, presum
ably viral, is postulated to play a role in
the early pathogenesis of CLPD―NKs by
selecting and expanding NK―cell clones,
although no evidence of direct NK―cell
infection has been observed {1113,2336,
2398,3274,3605,4456,4457}. The tyros
ine kinase inhibitor dasatinib produces a
sustained increase in NK cells that can
be monoclonal {2113,2796}. One third of Fig. 14.09 Chronic lymphoproliferative disorder of NK cells (CLPD-NK). Peripheral-blood flow-cytometric immuno
phenotyping reveals an increase in CD16+/CD3- NK cells (upper panel, red arrow). Selective gating on these cells
cases have activating mutations in the
reveals that they uniformly express the killer-cell immunoglobulin-like receptor isoform CD158a (lower-left panel,
STAT3 SH2 domain {1163,1854}. orange arrow) and lack expression of the isoforms CD158b and CD158e (lower-right panel, orange arrow). This
restricted pattern of killer-cell immunoglobulin-like receptor expression by NK cells is abnormal and supports the
diagnosis of CLPD-NK.
Genetic susceptibility
A genetic susceptibility may be linked to
haplotypes containing higher numbers of
activating KIR genes {1113,3605,4456}.
Definition
Aggressive NK―cell leukaemia is a sys
temic neoplastic proliferation of NK cells
frequently associated with EBV and an
aggressive clinical course.
Synonym
Aggressive NK―cell leukaemia/lymphoma
Epidemiology
This rare form of leukaemia is much more
prevalent among Asians than in other
ethnic populations {3460}. Patients are
most commonly young to middle―aged
adults, with a median age of 40 years
and two incidence peaks, in the third and
fifth decades of life {1786,2297,3062,
3728,3840}. There is no definite sex pre
dilection {640,647,1756,2155,2157,2297,
2999,3460,3462,3728,3840}. Fig. 14.11 Aggressive NK-cell leukaemia. A In this blood smear, the neoplastic cells are very similar to normal large
granular lymphocytes. B In the peripheral blood, the neoplastic cells in this case have basophilic cytoplasm and
nuclei with more open chromatin and distinct nucleoli. Azurophilic granules can be seen in the cytoplasm. C The
Etiology
neoplastic cells are negative for surface CD3, whereas the normal T lymphocytes are stained. D Neoplastic cells
Little is known about the etiology of ag show strong immunoreactivity for CD56.
gressive NK―cell leukaemia, but the
strong association with EBV suggests a
pathogenetic role of the virus. In younger There can be overlap with extranodal stitutional symptoms, and a leukaemic
patients, the leukaemia may evolve from NK/T―cell lymphoma showing multiorgan blood picture. The number of circulating
chronic active EBV infection {1788,1789, involvement; it is unclear whether aggres leukaemic cells may be low or high (a
3062}. sive NK―cell leukaemia is the leukaemic few per cent to > 80% of all leukocytes);
counterpart of extranodal NK/T―cell lym anaemia, neutropenia, and thrombocyto
Localization phoma {640}. penia are common. Serum lactate dehy
The most commonly involved sites are the drogenase levels are often markedly ele
peripheral blood, bone marrow, liver, and Clinical features vated. Hepatosplenomegaly is common,
spleen, but any organ can be involved. Patients usually present with fever, con sometimes accompanied by lymphade-
Fig. 14.12 Aggressive NK-cell leukaemia. In situ hybrid Fig. 14.13 Aggressive NK-cell leukaemia complicated Fig. 14.14 Aggressive NK-cell leukaemia. The neoplas
ization for EBV-encoded small RNA (EBER) highlights by haemophagocytic syndrome. The marrow biopsy tic cells in this marrow aspirate smear show substantial
the neoplastic cells in the bone marrow biopsy. The nu shows neoplastic cells with substantial nuclear pleo- nuclear pleomorphism. Histiocytes with phagocytosed
clear atypia in this example is striking. morphism and irregular nuclear foldings. There are red blood cells are apparent.
admixed histiocytes with phagocytosed red blood cells.
Fig. 14.16 Aggressive NK-cell leukaemia. Bone marrow biopsy. A Patchy involvement by neoplastic cells with sub
stantial nuclear pleomorphism. B Immunostaining for CD3 highlights the neoplastic population and accentuates
the nuclear irregularities. C Extensive bone marrow involvement by a monotonous population of uniform-looking
cells. D The neoplastic cells stain positively for CD56.
EBV―associated T―cell and NK-cell lym- Table 14.01 Classification of EBV-positive T-cell and NK-cell proliferations
phoproliferative disorders in the paediat Diagnosis Usual patient age group(s)
ric age group can be categorized into two
major groups: systemic EBV―positive T- EBV-positive haemophagocytic lymphohistiocytosis Paediatric, adolescent
cell lymphoma of childhood and chronic (benign, may be self-limited)
active EBV infection. Both occur with in Systemic CAEBV Paediatric, adolescent
creased frequency in Asians and in Native
Americans from Central and South Amer Cutaneous CAEBV, hydroa vacciniforme-like lymphoproliferative disorder Paediatric, adolescent
ica and Mexico. Systemic EBV―positive
Cutaneous CAEBV, severe mosquito bite allergy Paediatric, adolescent
T―cell lymphoma of childhood has a very
fulminant clinical course, usually associ Systemic EBV-positive T-cell lymphoma Paediatric, adolescent
ated with a haemophagocytic syndrome.
Chronic active EBV infection of T- and NK- Aggressive NK-cell leukaemia Adult
cell type shows a broad range of clinical Extranodal NK/T-cell lymphoma, nasal type Adult
manifestations, from indolent, localized
forms such as hydroa vacciniforme―like Nodal peripheral T-cell lymphoma, EBV-positivea Adult
lymphoproliferative disorder and severe
mosquito bite allergy to more systemic CAEBV, chronic active EBV infection.
disease characterized by fever, hepatos- a Included within the category of peripheral T-cell lymphoma, NOS.
plenomegaly, and lymphadenopathy, with
or without cutaneous manifestations dis
eases. Additionally, significant overlap in scribed using a variety of terms, including order, and is therefore now considered
the morphological features of the follow fulminant EBV-positive T-cell lymphopro equivalent to systemic EBV-positive T-cell
ing conditions is present. Therefore, cor liferative disorder of childhood {3269}, lymphoma of childhood {3269}. The term
relation with clinical features is critical for sporadic fatal infectious mononucleosis, CAEBV was coined to describe an in
accurate diagnosis. fulminant haemophagocytic syndrome fectious mononucleosis―like syndrome
in children (in Taiwan, China) {3822}; fa persisting for at least 6 months and as
tal EBV―associated haemophagocytic sociated with high titres of IgG antibod
Systemic EBV-positive T-cell syndrome (in Japan) {2011}; and severe ies against EBV viral capsid antigen and
lymphoma of childhood CAEBV {2025,2963,3838}. The term ful early antigen, with no association with
minant or fatal haemophagocytic syn malignancy, autoimmune diseases, or
Definition drome was used to describe a systemic immunodeficiency {3809}. Because the
Systemic EBV―positive T―cell lymphoma disease secondary to acute primary EBV earliest described cases, which were
of childhood is a life-threatening illness of infection affecting previously healthy chil found in western populations, showed
children and young adults, characterized dren, but the disease has since been EBV predominantly in B cells {779,3809},
by a clonal proliferation of EBV―infected shown to be a monoclonal CD8+ T―cell CAEBV was originally thought to be a
T cells with an activated cytotoxic phe EBV―associated lymphoproliferative dis- disorder affecting B cells, but has since
notype. It can occur shortly after primary been shown to affect primarily T cells and
acute EBV infection or in the setting of NK cells {780,2025,2026}. Progression
chronic active EBV infection (CAEBV). to EBV―positive T-cell lymphoma is not
It has rapid progression, with multior unusual {1877,1918,2026,3269}. A more
gan failure, sepsis, and death, usually severe form of CAEBV, characterized by
within a timeframe of days to weeks. A high fever, hepatosplenomegaly, exten
haemophagocytic syndrome is nearly al sive lymphadenopathy, haemophago
ways present. This entity has some clin- cytic syndrome, and pancytopenia, has
icopathological features overlapping with been described in patients in Japan
those of aggressive NK―cell leukaemia. {2025,2028,3838}. These patients had
higher viral copy numbers in peripheral
ICD-O code 9724/3 blood, as well as monoclonal expan
Fig. 14.17 Systemic EBV-positive T-cell lymphoma of
childhood. PCR for TR gamma rearrangement dem sion of EBV―infected T cells or NK cells.
Synonyms and historical terminology onstrates an identical T-cell clone in liver, spleen, and Severe CAEBV with monoclonal EBV-
Historically, this process has been de lymph nodes. positive T-cell proliferation is part of the
spectrum of systemic EBV―positive T-cell EBV infection and its racial predisposi show pancytopenia, abnormal liver func
lymphoma of childhood {2951,3269}; to tion strongly suggest a genetic defect in tion, and often abnormal EBV serology,
avoid confusion, it should not be referred the host immune response to EBV {2011, with low or absent IgM antibodies against
to as CAEBV. 2025,3269,3822,3838}. viral capsid antigen. The disease is usual
ly complicated by haemophagocytic syn
Epidemiology Localization drome, coagulopathy, multiorgan failure,
Systemic EBV―positive T―cell lymphoma This is a systemic disease. The most and sepsis {3269}. Some cases occur in
of childhood is most prevalent in Asia, pri commonly involved sites are the liver and patients with a well―documented history
marily in Japan and Taiwan, China {2011, spleen, followed by the lymph nodes, of CAEBV {1877,1918}. A disorder that
2025,3822,3838}. It has been reported in bone marrow, skin, and lungs {2011,2025, is probably related but presents mainly
Mexico and in Central and South America, 3269,3822,3838}. with lymphadenopathy and high lactate
and is reported rarely in non―indigenous dehydrogenase levels has recently been
populations in western countries {3269}. It Clinical features reported in children from Peru {3388}.
occurs most often in children and young Previously healthy patients present with
adults. There is no sex predilection. acute onset of fever and general malaise Spread
suggestive of an acute viral respiratory ill The disease is systemic, with the poten
Etiology ness. Within a period of weeks to months, tial to involve all organ systems. How
Although the etiology of systemic EBV- patients develop hepatosplenomegaly ever, involvement of the CNS is less often
positive T―cell lymphoma of childhood and liver failure, sometimes accompanied seen.
is unknown, its association with primary by lymphadenopathy. Laboratory tests
Fig. 14.19 Systemic EBV-positive T-cell lymphoma of childhood. Lymph node. A The lymph node shows partial preservation of the architecture with residual regres
sive follicles and expanded interfollicular area. Inset: The interfollicular infiltrate is polymorphic with some relatively large cells with irregular nuclei and prominent nucleoli.
B The infiltrating lymphocytes are CD8-positive. Inset: The atypical cells are CD8-positive C Many cells are positive for EBV-encoded small RNA (EBER). Inset: Double staining
demonstrates that the EBER positive cells (black) are positive for CD8 (brown).
Fig. 14.21 Systemic EBV-positive T-cell lymphoma of childhood. A The spleen shows depletion of the white pulp and prominent sinusoidal and nodular lymphoid infiltrates.
The nodules are composed predominantly of CD4+ cells. B In situ hybridization for EBV-encoded small RNA (EBER) shows that the CD4+ cells are also positive for EBV RNA.
Chronic active EB infection Synonym genes related to the EBV immune response
of T- and NK-cell type, Systemic chronic active EBV infection of are responsible for the development of this
T―cell and NK―cell type disease {780,2023}. EBV―specific cyto
systemic form
toxic T lymphocyte activity is impaired in
Definition Epidemiology patients with CAEBV {780,3829,4071}.
Chronic active EBV infection (CAEBV) of Systemic CAEBV of T― and NK―cell type
T-cell or NK-cell type is a systemic EBV- has a strong racial predisposition, with Localization
positive polyclonal, oligoclonal, or (often) most cases reported from Asia, primar This is a systemic disease. The most
monoclonal lymphoproliferative disorder ily in Japan {1954,2025,2026,2951, commonly involved sites are the liver,
characterized by fever, persistent hepa 3838}; the Republic of Korea {1676}; and spleen, lymph nodes, bone marrow, and
titis, hepatosplenomegaly, and lymphad- Taiwan, China {4244}. It has also been skin. The lungs, kidneys, heart, CNS, and
enopathy, which shows varying degrees reported in Latin America and rarely in gastrointestinal tract can also be involved
of clinical severity depending on the host western {3422,3592,3730} and African {2025,2026,3062}.
immune response and the EBV viral load. populations {3353}. It occurs most often
The revised diagnostic criteria for CAEBV in children and adolescents. Adult―onset Clinical features
include infectious mon onucleosis―like disease is rare and appears to be rapidly Approximately 50% of patients present
symptoms persisting for > 3 months, in progressive and more aggressive {124, with infectious mononucleosis―like ill
creased EBV DNA (>10 2.5 copies/mg) in 1792}. There is no sex predilection. ness, including fever, hepatospleno
peripheral blood, histological evidence of megaly, and lymphadenopathy. Accom
organ disease, and demonstration of EBV Etiology panying symptoms include skin rash
RNA or viral protein in affected tissues in Although the etiology is unknown, the (occurring in 26% of cases), severe mos
patients without known immunodeficien strong racial predisposition for the devel quito bite allergy (in 33%), hydroa vaccini-
cy, malignancy, or autoimmune disorders. opment of CAEBV of T- and NK-cell type forme―like eruptions (in 10%), diarrhoea
in immunocompetent individuals strongly (in 6%), and uveitis (in 5%). Laboratory
suggests that genetic polymorphisms in tests reveal pancytopenia and abnormal
Fig. 14.23 Chronic active EBV infection in skin. A Skin biopsy shows a discrete lymphoid infiltrate without atypia in the dermis surrounding blood vessels, extending to the
epidermis. B The lymphoid cells are positive for CD8. C The relatively discrete lymphoid infiltrate is positive for EBV as demonstrated by in situ hybridization for EBV-encoded
small RNA (EBER).
liver function. In most patients, EBV se include haemophagocytic syndrome Immunophenotype
rology reveals high titres of IgG antibod (which occurs in 24% of cases), coronary The immunophenotype of the EBV-infect-
ies against EBV viral capsid antigen and artery aneurism (in 9%), hepatic failure (in ed cells varies; it includes T cells in 59%
early antigen. All patients have increased 15%), interstitial pneumonia (in 5%), CNS of cases, NK cells in 41%, and both T and
levels of EBV DNA (>102.5 copies/mg) involvement (in 7%), gastrointestinal per NK cells in 4%. CAEBV of B-cell pheno
in the peripheral blood. The clinical foration (in 11%), and myocarditis (in 4%). type is seen in only 2% of cases. Unlike
course varies but is usually protracted, Due to the variety of the clinical pres the T cells in systemic EBV-positive T-cell
with some patients surviving for many entations, diagnosis is often delayed. lymphoma of childhood, the T cells in
years without disease progression. The Progression to NK/T―cell lymphoma or CAEBV are predominantly CD4―positive,
severity of CAEBV is probably related aggressive NK―cell leukaemia occurs in and less often show a cytotoxic CD8+
to the immunological response of the 16% of cases {1676,2026,2028,2951}. phenotype {780,2026}. EBV―encoded
individual and to the EBV viral load. The small RNA (EBER) is positive.
clinical course also varies depending on Microscopy
the predominant infected cell type in the The infiltrating cells do not show changes Cell of origin
peripheral blood {2024,2025}. Patients suggestive of a neoplastic lymphopro- The postulated cells of origin are CD4+
with T―cell CAEBV have a shorter survival liferation. The liver shows sinusoidal T cells, NK cells, cytotoxic CD8+ lympho
time than patients with NK―cell disease. and portal infiltration suggestive of vi cytes, and (rarely) gamma delta T cells.
Patients with T―cell CAEBV often present ral hepatitis. The spleen shows atrophy
with prominent systemic symptoms and of the white pulp with congestion of the Genetic profile
high titres of EBV-specific antibodies and red pulp. The lymph nodes exhibit vari Chromosomal aberrations are detected
have rapid disease progression. In con able morphology, including paracortical in a minority of cases {2026}. One se
trast, patients with NK-cell disease, in ad and follicular hyperplasia, focal necrosis, ries reported monoclonally rearranged
dition to mild systemic symptoms, often and small epithelioid granulomas. Bone TR genes in 84% of cases, oligoclonally
have severe mosquito bite allergy, rash, marrow biopsies usually appear normal. rearranged TR genes in 11%, and poly
and high levels of IgE, and do not always In cases complicated by haemophago clonal TR genes in only 5% of cases
have elevated EBV―specific antibody cytic syndrome, sinus histiocytosis with {2026}. However, this report includes
titres. Life―threatening complications erythrophagocytosis is present {2026}. cases of ‘severe CAEBV’, which might be
Fig. 14.25 Chronic active EBV infection in lymph node. A The lymph node shows follicular and paracortical hyperplasia. B At high magnification, the interfollicular areas show a
polymorphic infiltrate lacking cytological atypia. C In situ hybridization for EBV-encoded small RNA (EBER) shows scattered positive cells. Inset: Double staining shows that the
EBER+ cells (black) are CD4-positive (brown).
liferative disorder has been proposed, to sentation varies between patients, with varies. The neoplastic cells are generally
encompass the various manifestations of a broad spectrum. Some cases present small to medium-sized, without significant
the EBV―associated HV―like skin lesions with a very indolent course, with local atypia. In severe cases, the overlying epi
{3271}. In the past, this disease has also ized skin lesions in sun―exposed areas dermis is frequently ulcerated {3271}.
been referred to as oedematous, scarring and no systemic symptoms (classic HV).
vasculitic panniculitis {3456}; angiocen- Spontaneous remission and clearing af Immunophenotype
tric cutaneous T―cell lymphoma of child ter photoprotection can occur, but most The cells have a cytotoxic T-cell pheno
hood {2440}; hydroa-like cutaneous T-cell cases show a long clinical course, with type, mostly CD8-positive, with few cas
lymphoma {274}; and severe HV {1806}. remissions and recurrences that may fi es being CD4-positive. One third of the
nally progress to more―severe disease cases show an NK-cell phenotype, with
Epidemiology {732}. There is seasonal variation, with expression of CD56 {1919,4484,2026,
This condition is seen mainly in children increased recurrences in spring and 3271,3389}. Clonal expansion of gamma
and adolescents from Asia {731,1805, summer. In more―severe cases, in addi delta T cells has been documented in the
1806,2883,4397}, and in Native Ameri tion to extensive skin lesions, systemic peripheral blood in most cases {1639,
cans from Central {1012} and South {274, symptoms (including fever, wasting, lym- 2026,4224}, but only in rare cases in the
3389,3512} America and Mexico {2439, phadenopathy, and hepatosplenomeg- infiltrating lymphocytes in the skin {2439,
3271}. The median patient age at diag aly) may be present, in particular late in 3271,4224}. CCR4 is expressed in the
nosis is 8 years (range: 1―15 years). The the course of the disease {1806,2026, gamma delta T cells {1917}. CD30 is often
male-to-female ratio is slightly elevated 3271,3512}. Some patients develop se expressed in the infiltrating EBV-positive
(2.3:1). It is rare in adults {731,3512}. vere mosquito bite allergy {1639,3271}. T cells. LMP1 is usually negative {3271}.
A rare clinical presentation with primarily
Etiology periorbital swelling has been reported in Postulated normal counterpart
The etiology is unknown. The geographi children from Bolivia {3206}. The postulated normal counterpart is a
cal and ethnic distribution indicate that, skin-homing cytotoxic T cell or NK cell.
like in other EBV―positive T-cell and NK- Macroscopy Gamma delta T cells have been hypoth
cell lymphomas, genetic predisposition In addition to prominent swelling of the esized to play a central role in the forma
plays a major role. face, lips, and eyelids, multiple vesiculo- tion of HV―like eruptions {1972}.
papules with umbilication and crust are
Localization characteristic. Genetic profile
This is a cutaneous condition that affects Most cases have clonal rearrange
sun―exposed and non―exposed skin ar Microscopy ments of the TR genes. Some cases of
eas. In the early phases, it affects mainly The characteristic histological feature NK―cell derivation do not show TR gene
the face, dorsal surface of the hands, of HV is epidermal reticular degenera rearrangement {2026,3271}. In situ hy
and earlobes; in advanced stages, it can tion leading to intraepidermal spongiotic bridization for EBV―encoded small RNA
be generalized {3271}. vesiculation. The lymphoid infiltrate pre (EBER) is positive, but the number of pos
dominates in the dermis but may extend itive cells varies from case to case. EBV is
Clinical features deep into the subcutaneous tissue. The monoclonal by terminal repeat analysis.
It is characterized by a papulovesicu infiltrate is mainly located around adnexa Although LMP1 is negative by immuno-
lar eruption that generally proceeds to and blood vessels, often with angiode- histochemistry, it can be detected in most
ulceration and scarring. The severity structive features. The intensity of the cases by PCR in peripheral blood, indi
of the skin lesions and the clinical pre infiltrate and atypia of the lymphocytes cating type II EBV latency {1804}.
Fig. 14.30 Severe mosquito bite allergy. A Skin biopsy with a subepidermal bulla with a dense infiltrate in the dermis, mainly surrounding blood vessels. B Higher magnification.
The infiltrate is polymorphic but mainly composed of relatively large cells with bland nuclei, inconspicuous nucleoli, and abundant cytoplasm.
Postulated normal counterpart {2025}. Chromosomal alterations are rare course, with an increased risk of de
Mature activated NK cell ly identified {2026}. In situ hybridization veloping haemophagocytic syndrome
for EBV―encoded small RNA (EBER) is and aggressive NK―cell leukaemia after
Genetic profile positive in a fraction of the NK cells. LMP1 2―17 years (median: 12 years). Patients
NK cells are infected with monoclonal is detected by PCR in peripheral blood, with chromosomal aberrations appear
EBV as demonstrated by terminal repeat indicating type II EBV latency {1804}. to have a higher risk of developing lym-
analysis, indicating clonal expansion of phoma/leukaemia {2026,4015}.
NK cells. Rarely, monoclonal TR gene Prognosis and predictive factors
rearrangement has been documented Patients usually have a long clinical
Definition an average patient age of 58 years. The Table 14.02 Clinical spectrum of
Adult T-cell leukaemia/lymphoma (ATLL) male-to-female ratio is 1.5:1. ATLL is a HTLV-1-associated diseases
is a mature T―cell neoplasm most often systemic disease, and the prognosis is Neoplastic disorders
composed of highly pleomorphic lym poor (Fig. 14.45, p.367). Adult T-cell leukaemia/lymphoma
phoid cells. The disease is usually widely Smouldering
disseminated and is caused by the hu ICD-O code 9827/3 Chronic
Acute
man retrovirus HTLV―1. Most ATLL pa
Lymphomatous
tients present with widespread lymph Synonyms
node involvement as well as involvement Adult T―cell lymphoma/leukaemia; Non-neoplastic disorders {2521}
of peripheral blood. The histology shows adult T―cell leukaemia - HTLV-1-associated myelopathy
remarkable pleomorphism, with several (tropical spastic paraparesis)
morphological variants having been de Epidemiology - HTLV-1-associated infective dermatitis
scribed. The leukaemic cells often show ATLL is endemic in several regions of the - Other HTLV-1 inflammatory disorders
a multilobed appearance of so―called world, in particular south―western Japan, Uveitis
flower cells. Neoplastic cells show mon the Caribbean basin, and parts of central Thyroiditis
oclonal integration of HTLV―1 and ex Africa. The distribution of the disease is Pneumonitis
press T―cell―associated antigens (CD2, closely linked to the prevalence of HTLV- Myositis
CD3, CD5), but usually lack CD7. Most 1 in the population.
cases are CD4―positive and CD8―nega- The disease has a long latency, and af
tive. ATLL most often occurs in regions fected individuals are usually exposed to and blood products. The cumulative in
endemic for HTLV―1, and the frequency the virus very early in life. The virus may cidence of ATLL is estimated to be 2.5%
is estimated to be 2.5% among HTLV―1 be transmitted in breast milk, as well as among HTLV―1 carriers in Japan {3869}.
carriers. ATLL occurs only in adults, with through exposure to peripheral blood Sporadic cases have been described,
Clinical features
Several clinical variants have been identi
fied: acute, lymphomatous, chronic, and
smouldering (see Table 14.03) {3660}.
Fig. 14.32 Adult T-cell leukaemia/lymphoma. Macroscopic findings of cutaneous lesions have been classified as The acute variant is most common and
A erythema, B papules, and C nodules. is characterized by a leukaemic phase,
often with a markedly elevated white
but the affected patients often derive from factor (HBZ) is thought to be important blood cell (WBC) count, skin rash, and
an endemic region of the world. ATLL oc for T―cell proliferation and oncogenesis generalized lymphadenopathy. Hyper-
curs only in adults, and the patient age {3532}. However, additional genetic alter calcaemia, with or without lytic bone
at onset ranges from the third to the ninth nations acquired over time may result in lesions, is a common feature. Patients
decade of life, with an average patient the development of a malignancy. Hyper- with acute ATLL have systemic disease
age of 58 years. The male-to-female ratio methylation is associated with disease accompanied by hepatosplenomegaly,
is 1.5:1 {4405}. progression {3528}. HTLV-1 can also indi constitutional symptoms, and elevated
rectly cause other diseases (Table 14.02), lactate dehydrogenase. Leukocytosis
Etiology such as HTLV―1―associated myelopathy/ and eosinophilia are common. Many pa
HTLV―1 is causally linked to ATLL, but tropical spastic paraparesis {3880}. tients have an associated T-cell immuno
HTLV―1 infection alone is not sufficient to deficiency, with frequent opportunistic
result in neoplastic transformation of in Localization infections such as Pneumocystis jirovecii
fected cells. HTLV―1 enters cells mainly Most patients present with widespread pneumonia and strongyloidiasis.
through cell―to―cell contact via three lymph node involvement and involvement The lymphomatous variant is character
cellular molecules: heparan sulfate pro of the peripheral blood. The number of ized by prominent lymphadenopathy but
teoglycan, neuropilin 1, and the glucose circulating neoplastic cells does not cor without peripheral blood involvement.
transporter GLUT1 {1352}. Neuropilin 1 relate with the degree of bone marrow Most patients present with advanced-
appears to function as the viral receptor. involvement. This suggests that circulat stage disease similar to the acute form,
The p40 tax viral protein leads to tran ing cells are recruited from other organs, although hypercalcaemia is seen less
scriptional activation of many genes in such as the skin, which is the most com often.
HTLV―1-infected lymphocytes {1241}. In mon extralymphatic site of involvement Cutaneous lesions are common in both
addition, the HTLV-1 basic leucine zipper (involved in > 50% of cases). the acute and the lymphomatous forms
Fig. 14.33 Adult T-cell leukaemia/lymphoma. Southern Fig. 14.34 Adult T-cell leukaemia/lymphoma. Fig. 14.35 Adult T-cell leukaemia/lymphoma.
blot analysis. Lanes 2-4 each display a single proviral A radiograph shows extensive lytic bone lesions. Bone marrow infiltrate is sparse. Osteoclastic activity
HTLV-1 DNA band. The difference in band sizes (differ surrounding the bone trabeculae is prominent.
ent cases) illustrates the difference in integration sites.
Fig. 14.36 Adult T-cell leukaemia/lymphoma (ATLL). Peripheral blood films. A In the acute variant, the leukaemic Fig. 14.37 Adult T-cell leukaemia/lymphoma cells fre
cells are medium-sized to large lymphoid cells with irregular nuclei and basophilic cytoplasm. The characteristic ATLL quently express FOXP3. The coexpression of FOXP3
cells have been described as ‘flower cells’, with many nuclear convolutions and lobes. B ATLL cells in the chronic and CD25 is characteristic of T regulatory (Treg) cells.
variant are generally small, with slight nuclear abnormalities such as notching and indentations.
Immunophenotype
Tumour cells express T―cell―associated
antigens (CD2, CD3, CD5), but usually
lack CD7. Most cases are CD4―positive
and CD8―negative, but a few are CD4-
Fig. 14.39 Adult T-cell leukaemia/lymphoma (ATLL). A The lymph nodes in Hodgkin-like ATLL show Reed-Stern- negative and CD8―positive or double
berg-like giant cells of B-cell (not T-cell) lineage, which (B) react with CD30 antibody and are EBV-positive (not positive for CD4 and CD8. CD25 is
shown). strongly expressed in nearly all cases.
The large transformed cells may be posi
tive for CD30, but are negative for ALK
{3882} and cytotoxic molecules. Tumour
cells frequently express the chemokine
receptor CCR4. FOXP3, a feature of
T regulatory (Treg) cells, is expressed in
a subset of cases {1948,3398}, but often
only in a subset of the neoplastic cells.
Grading
There is no formal grading system for
ATLL. However, the four clinical vari
ants — acute (leukaemic), lymphomatous,
chronic, and smouldering — vary in their
clinical course and cytological atypia
{3660}. In the chronic and smoulder
ing forms the neoplastic cells are small,
and can have minimal cytological atypia.
Pronounced cytological atypia is seen in
the acute and lymphomatous forms.
Genetic profile
Antigen receptor genes
Fig. 14.42 Adult T-cell leukaemia/lymphoma (ATLL). HTLV-1 proviral DNA integration and clinical subtypes. TR genes are clonally rearranged {2952}.
Oncogenes and other molecular of which are involved in T―cell receptor Prognosis and predictive factors
changes signalling. This study also confirmed a Clinical subtype, patient age, perfor
Neoplastic cells show monoclonal inte high incidence of CCR4 mutations and mance status, and serum calcium and
gration of HTLV―1. No clonal integration identified mutations in CCR7 in some lactate dehydrogenase levels are major
is present in healthy carriers {4075}. Tax, other cases. The additional mutations prognostic factors {4410}. The survival
encoded by the HTLV―1 pX region, is a identified affect the NF―kappaB pathway time for the acute and lymphomatous
critical non―structural protein that plays and genes involved in T―cell signalling. variants ranges from 2 weeks to > 1 year.
a key role in leukaemogenesis and acti Whole-genome sequencing identified in Death is often caused by infectious com
vates a variety of cellular genes {3126}. tragenic deletions involving TP73, a hom- plications, including P. jirovecii pneumo
Enhancement of cAMP response ele ologue of TP53. These deletions resulted nia, cryptococcal meningitis, disseminat
ment―binding transcription factor (CREB) in mutant p73, lacking the transactiva ed herpes zoster, and hypercalcaemia
phosphorylation by Tax appears to play tion domain (TAD). Recurrent splice-site {3660}. The chronic and smouldering
a role in leukaemogenesis {2022}. CREB mutations were found in GATA3, HNRN- forms have a more protracted clinical
is highly phosphorylated in a panel of PA2B1, and FAS. course and better survival, but can pro
HTLV―1-infected human T-cell lines, and ATLL genomes demonstrated prominent gress to an acute phase with an aggres
Tax is responsible for promoting elevated CpG island DNA hypermethyiation, lead sive course in approximately 25% of
levels of CREB phosphorylation. Howev ing to transcriptome silencing of many patients {1961,2954}.
er, Tax is not critical to sustained tumour genes, including genes encoding major
cell growth and is inactivated in a high histocompatibility complex (MHC) class I,
proportion of cases of ATLL {1957}. HBZ death receptors, and immune check
also appears to play a critical role in tu- points, providing a mechanism for im
morigenesis {4487}. HBZ is the only gene mune escape of the tumour cells {1957}.
that is consistently expressed in all ATLL
cases; it modulates a variety of cellular
signalling pathways that are related to
cell growth, immune response, and T-cell
differentiation. In whole―transcriptome
sequencing, CCR4 mutations have been
detected in one quarter of cases, and are
associated with gain of function and in
creased PI3K signalling {2808}.
A recent study ({1957}, reviewed in {4193})
provided an integrated genomic and tran-
scriptomic analysis of > 400 ATLL cases.
The authors identified a single viral inte
gration site in most cases of ATLL, con
firming the clonal nature of the disease.
Transcriptome analysis confirmed the
critical role of HBZ, which is expressed
at high levels in all cases. ATLL showed
considerable genomic instability, with a
high number of structural variations per
case. A total of 50 genes were recurrently
mutated. Among the most frequently mu Fig. 14.45 Adult T-cell leukaemia/lymphoma. Overall survival (OS) of 1665 patients diagnosed between 2000 and
tated genes were PLCG1, PRKCB, VAV1, 2009 in Japan. A total of 227 patients underwent allogeneic bone marrow transplantation; 25% of those patients had
IRF4, FYN, CARD11, and STAT3, some long survival. MST, median survival time. Data from Katsuya H et al. {1961}.
Definition
Extranodal NK/T―cell lymphoma, nasal
type, is a predominantly extranodal lym
phoma of NK-cell or T-cell lineage, char
acterized by vascular damage and de
struction, prominent necrosis, cytotoxic
phenotype, and association with EBV.
It is designated an NK/T―cell lymphoma
because although most cases appear
to be genuine NK―cell neoplasms, some
cases are of cytotoxic T―cell lineage.
Synonyms
Angiocentric T-cell lymphoma (obsolete);
malignant reticulosis, NOS (obsolete);
malignant midline reticulosis (obsolete);
polymorphic reticulosis (obsolete); lethal
midline granuloma (obsolete);
T/NK―cell lymphoma Fig. 14.47 Extranodal NK/T-cell lymphoma of the skin. Fig. 14.48 Extranodal NK/T-cell lymphoma of the skin,
The lymphomatous infiltrate involves the epidermis, intravascular variant. Neoplastic cells are confined to
Epidemiology dermis, and subcutaneous tissue. Necrosis is prominent vascular spaces. Note the uninvolved hair follicle and
Extranodal NK/T―cell lymphoma is more in the dermal component. glandular structures.
prevalent in Asians and the indigenous
populations of Mexico, Central and South mal form {133,649,1091,1646,1916,2607, sion, including following transplantation
America {187,640,2232,3266,3949}. It 3266,3842,4133} with type II latency {1702,2156}.
occurs most often in adults, with a report (EBNA1+, EBNA2―, LMP1+), and com
ed median patient age of 44―54 years monly shows a 30 bp deletion in the LMP1 Localization
{189,647,704,1484,1858,2305,3062, gene {708,1000,1091,2139,3868}. Most Extranodal NK/T―cell lymphoma almost
3210}. It is more common in males than studies show that the EBV is almost al always has an extranodal presentation.
in females. ways of subtype A {275,1091,1484,3120, The upper aerodigestive tract (nasal cav
3842,4023}. The disease activity can be ity, nasopharynx, paranasal sinuses, and
Etiology monitored by measuring circulating EBV palate) is most commonly involved, with
The very strong association with EBV, DNA; a high titre is correlated with ex the nasal cavity being the prototypical site
irrespective of the ethnic origin of the tensive disease, unfavourable response of involvement. Preferential sites of extra
patients, suggests a pathogenic role of to therapy, and poor survival {188,4257}. nasal involvement include the skin, soft
the virus {133,647,649,1091,1916,3266, Extranodal NK/T―cell lymphomas can tissue, gastrointestinal tract, and testes.
4133}. EBV is present in a clonal episo- occur in the setting of immunosuppres Some cases may be accompanied by
secondary lymph node involvement {640,
647,1996,2154,3154,4023}. Rare cases
with features of intravascular lymphoma
have been reported, involving sites such
as the skin and CNS {2138,2372,2810,
4385}.
Primary EBV-positive nodal T-cell or NK-
cell lymphomas have been reported {178,
718, 1901}. These usually have a mono-
morphic pattern of infiltration and lack
the angiodestruction and necrosis seen
Fig. 14.46 Extranodal NK/T-cell lymphoma, nasal type. A Expansion of the nasal bridge. B CT. The tumour in the in extranodal NK/T-cell lymphoma. They
nasal cavity extends upwards into the orbit, resulting in proptosis. are more common in elderly patients, or
in the setting of immune deficiency. They tract (often referred to as extranasal NK/ nodes can be involved as part of dissem
are considered a variant of peripheral T-cell lymphomas) have variable presen inated disease. Marrow and peripheral
T―cell lymphoma, NOS, and seem dis tations, depending on the major site of blood involvement can occur, and such
tinct from cases with primary extranodal involvement. Skin lesions are commonly cases may overlap with aggressive NK-
presentations. nodular, often with ulceration. Intestinal cell leukaemia.
lesions often manifest as perforation or
Clinical features gastrointestinal bleeding. Other involved Microscopy
Patients with nasal involvement present sites present as mass lesions. The pa The histological features of extranodal
with symptoms of nasal obstruction or tients commonly have high stage disease NK/T-cell lymphoma are similar irrespec
epistaxis due to the presence of a mass at presentation, with involvement of multi tive of the site of involvement. Mucosal
lesion, or with extensive destructive mid ple extranodal sites. Systemic symptoms sites often show extensive ulceration.
facial lesions (lethal midline granuloma). such as fever, malaise, and weight loss The lymphomatous infiltrate is diffuse
The lymphoma can extend to adjacent can be present {647,1996,4357}. Lymph and permeative. Mucosal glands often
tissues, such as the nasopharynx, para
nasal sinuses, orbits, oral cavity, palate,
and oropharynx. The disease is often lo
calized to the upper aerodigestive tract at
presentation, and bone marrow involve
ment is uncommon {4356}. The disease
may disseminate to various sites (e.g. the
skin, gastrointestinal tract, testes, and
cervical lymph nodes) during the clinical
course. Some cases may be complicat
ed by haemophagocytic syndrome {704,
2154}. Fig. 14.50 Extranodal NK/T-cell lymphoma, nasal type. A The lymphomatous infiltrate shows infiltration and destruc
Extranodal NK/T―cell lymphomas occur tion of an artery. B In this case involving the skin, the lymphomatous infiltrate has an angiocentric angiodestructive
ring outside of the upper aerodigestive quality.
become widely spaced or are lost. An an- phocytes, plasma cells, histiocytes, and variably expressed. Other T―cell―associ-
giocentric and angiodestructive growth eosinophils), may mimic an inflammatory ated and NK―cell―associated antigens,
pattern is frequently present, and fibri process {640,1591}. The lymphoma can including CD4, CD8, CD16, and CD57,
noid changes can be seen in the blood sometimes be accompanied by florid are usually negative. The subset of cases
vessels even in the absence of angioinva- pseudoepitheliomatous hyperplasia of of cytotoxic T―cell lineage may express
sion. Coagulative necrosis and admixed the overlying epithelium {2355}. CD5, CD8, and T―cell receptor (gamma
apoptotic bodies are common findings. delta or alpha beta) {1858,3210,4407}.
These have been attributed to vascular Immunophenotype Cytotoxic molecules (e.g. granzyme B,
occlusion by lymphoma cells, but other The most typical immunophenotype TIA1, and perforin) are positive {1091}.
factors (e.g. chemokines and cytokines) of extranodal NK/T―cell lymphoma is: HLA―DR, CD25, FAS (also known as
have also been implicated {3943}. CD2+, CD5―, CD56+, surface CD3― (as CD95), and FASL are commonly ex
The cytological spectrum is very broad. demonstrated on fresh or frozen tissue), pressed {2858,2955}. CD30 is positive
Cells may be small, medium-sized, large, and cCD3―epsilon+ (as demonstrated on in about 30% of cases {189,1484,2021,
or anaplastic. In most cases, the lympho fresh, frozen, or fixed tissues) {640,648, 2139,2305}. Nuclear expression of mega
ma is composed of medium―sized cells 1814,1819,3266,4069}. CD56, although a karyocyte―associated tyrosine kinase
or a mixture of small and large cells. The highly useful marker for NK cells, is not (MATK) is common {3210,3890}.
cells often have irregularly folded nuclei, specific for extranodal NK/T―cell lym Lymphomas that demonstrate a CD3―
which can be elongated. The chromatin phoma, and can be expressed in some epsilon+, CD56― immunophenotype are
is granular, except in the very large cells, peripheral T―cell lymphomas. CD43 and also classified as extranodal NK/T―cell
which may have vesicular nuclei. Nucle CD45RO are often positive, and CD7 is lymphomas if both cytotoxic molecules
oli are generally inconspicuous or small.
The cytoplasm is moderate in amount
and often pale to clear. Mitotic figures
are easily found, even in small cell―pre
dominant lesions. On Giemsa―stained
touch preparations, azurophilic granules
are commonly detected. UItrastructurally,
electron―dense membrane―bound gran
ules are present.
Extranodal NK/T―cell lymphomas, par
ticularly those in which small―cell or
mixed―cell populations predominate, Fig. 14.53 Extranodal NK/T-cell lymphoma, nasal type. A This example is difficult to diagnose because the neo
and those accompanied by a heavy ad plastic cells are practically indistinguishable from normal small lymphocytes. There are many admixed plasma
mixture of inflammatory cells (small lym cells. B The presence of large numbers of cells staining for CD56 supports a diagnosis of lymphoma.
Introduction Table 14.04 Comparison of enteropathy-associated T-cell lymphoma (EATL) and monomorphic epitheliotropic
intestinal T-cell lymphoma (MEITL)
Jaffe E.S. Bhagat G. Feature EATL MEITL
Chott A. Tan S.Y.
Stein H. Ethnicity (excess incidence) Northern European Asian, Hispanic
OttG.
Chan J.K.C. Isaacson P.G. Risk factors Coeliac disease, HLA–DQ2/DQ8 None recognized
Staging mesenteric lymph nodes are commonly many as 40% of cases exhibit predomi
The Ann Arbor staging system, with or involved. Occasionally, lymph node in nant large cell or anaplastic cytomor-
without the modification proposed by Ro- filtration by EATL occurs in the absence phology {2456}. Angiocentricity and an-
hatiner et al. {3394}, is frequently used for of macroscopic evidence of intestinal gioinvasion, as well as extensive areas of
staging EATL. High stage disease is de disease. necrosis, are frequently observed. Most
tected in 43―90% of patients at diagnosis tumours have an admixture of inflam
{932,1276,2456,3675}. Microscopy matory cells, including large numbers of
The neoplastic lymphocytes exhibit a histiocytes and eosinophils, which may
Macroscopy wide range of cytological appearances obscure the relatively small number of
The tumour may form ulcerating nodules, {2456,4370}. Most lymphomas show neoplastic cells in some cases. Intra
plaques, strictures, or (less commonly) pleomorphic medium―sized to large cells epithelial spread of tumour cells may be
a large exophytic mass. The uninvolved with round or angulated vesicular nu striking, but sometimes only single scat
mucosa can be thin and can show loss clei, prominent nucleoli, and moderate tered atypical lymphocytes are observed
of mucosal folds. The mesentery and to abundant pale―staining cytoplasm. As in the epithelium. The intestinal mucosa
Fig. 14.59 Adjacent uninvolved mucosa in enteropathy-associated T-cell lymphoma. Increased numbers of intraepithelial lymphocytes (A) are CD3-positive (B), CD8-negative
(C), and CD56-negative (D).
Genetic profile
TRB or TRG genes are clonally re
arranged in virtually all cases {169,2456,
2794}. Unlike primary nodal peripheral
T―cell lymphoma, most EATLs (~80%)
either display gains of the 9q34 region,
which harbours known proto―oncogenes
(e.g. NOTCH1, ABL1, and VAV2) or, alter
natively, show deletions of 16q12.1 {297,
596,937,4471}. Similar changes are also
observed in monomorphic epitheliotrop-
ic intestinal T―cell lymphoma. However,
Fig. 14.61 Enteropathy-associated T-cell lymphoma (EATL). A Capillary gel electrophoresis showing a clonal TRB EATLs frequently display chromosomal
gene rearrangement product (dominant peak on the right) in a duodenal biopsy sample from an individual with type 2 gains of chromosomes 1q and 5q, which
refractory coeliac disease. B Capillary gel electrophoresis showing a similar clonal TRB gene rearrangement in an are less common in monomorphic epi-
EATL that arose in the stomach a couple of years later. theliotropic intestinal T―cell lymphoma
{937,4471}.
villous atrophy is usually severe (subtotal EATL {3571,3864}. Disruption of intestinal Losses at 9p are detected in 18% of
or total). The intraepithelial lymphocytes immune homeostasis by deregulated ex EATLs; however, LOH at 9p21, targeting
lack significant cytological atypia, but pression of IL15 contributes to disease the cell-cycle inhibitor CDKN2A/B is ob
they can be widely distributed through pathogenesis {7,1747,2635,2639}. IL15 served in 56% of cases, accompanied
out the gastrointestinal tract {599,2454, also increases survival of the aberrant by loss of p16 protein expression {2923,
4186}. Small aggregates of lymphocytes intraepithelial lymphocytes {2457}, which 4471}. Loss of the 17p12―13.2 region,
are seen in the lamina propria in approxi can facilitate genomic instability and ac containing the TP53 tumour suppressor
mately half of the cases {4178}. Some quisition of genetic abnormalities. gene, is noted in 23% of EATLs, but aber
cases exhibit ulcerated mucosa associ Recurrent gains of chromosome 1q22―44 rant nuclear p53 expression can be seen
ated with variable degrees of chronic are detected in type 2 refractory coeliac in 75% of cases {937,2923}. Recent stud
inflammation and a relative paucity of disease in common with EATL {297,937, ies have reported recurrent mutations in
intraepithelial lymphocytes (ulcerative je- 2454,4187,4471}. This finding suggests constituents of the JAK―STAT signalling
junitis) {169,223,599}. early acquisition of chromosome 1q ab pathway in EATL {2869A}. Additionally,
The identification of TCR gene rearrange normalities in the evolution of EATL. Loss the detection of JAK1 and STAT3 muta
ments of similar size in biopsies exhibit of p16 protein, in the absence of LOH at tions in type 2 refractory coeliac disease
ing features of type 2 refractory coeliac chromosome 9p21, is observed in 40% implicates deregulation of JAK―STAT sig
disease and concurrent or subsequent of type 2 refractory coeliac disease cas nalling to be an early event in disease
EATL helped establish that the aberrant es exhibiting features of ulcerative jejuni- pathogenesis {1116A}.
intraepithelial lymphocytes are precur tis, and aberrant nuclear p53 expression
sors of EATL in a proportion of cases and can be detected in 57% of cases in the Genetic susceptibility
that they constitute a neoplastic popula absence of molecular lesions of TP53 Coeliac disease, or gluten―sensitive
tion (low―grade lymphoma of intraepithe {2923}. enteropathy, predisposes to EATL. Coe
lial T lymphocytes, EATL in situ, or cryptic Most patients have severe symptoms liac disease is a polygenic disorder with
EATL) {169,223,562,599,4371}. and they usually have profound malnour- various risk loci associated, including the
In most cases, the aberrant intraepithe ishment (body mass index < 18) due to HLA locus. EATL is associated with the
lial lymphocytes are considered to be of protein―losing enteropathy {1755,2454, HLA―DQA1*0501 and HLA―DQB1*0201
alpha beta TCR lineage. However, recent 3445}. Large ulcers or stenotic areas genotypes {49}. More than 90% of EATL
studies have suggested that some cas are frequently observed on endoscopy patients carry HLA―DQ2.5 heterodimers
es might derive from gamma delta TCR {2454}. As systemic dissemination of ab encoded by HLA―DQA1*05 and HLA-
T cells or possibly immature T/NK―cell errant intraepithelial lymphocytes occurs DQB1*02 alleles, either in cis or trans
precursors (innate immune cells), and in a high proportion of cases (44―60%), configuration {1708}.
that the maturational state of the cell of patients may present with extraintestinal
origin could impact the risk of extraintes- symptoms or disorders (e.g. skin lesions)
tinal dissemination and transformation to {2454,4178,4186}. The 5―year survival
Indolent T-cell Fig. 14.68 Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract, duodenum. Infiltrate fills the lami
lymphoproliferative disorder of na propria and focally extends beyond the muscularis mucosae. However, glands are largely intact.
the gastrointestinal tract
Jaffe E.S. Bhagat G. Clinical features clinical course. A subset of patients are
Chott A. Tan S.Y. Presenting symptoms include abdominal at risk for disease progression and more
OttG. Stein H. pain, diarrhoea, vomiting, dyspepsia, and widespread disease, usually after many
Chan J.K.C. Isaacson P.G. weight loss {561,3145}. The clinical course years {561,2506}.
is chronic, but progression to disseminat
ed disease has been reported infrequent Macroscopy
Definition ly. Peripheral lymphadenopathy is not The mucosa of affected sites in the gas
Indolent T―cell lymphoproliferative disor present, but a subset of patients exhibit trointestinal tract is thickened, with promi
der of the gastrointestinal tract is a clonal mesenteric lymphadenopathy {2506}. nent folds or nodularity. In some cases,
T―cell lymphoproliferative disorder that the infiltrate produces intestinal polyps
can involve the mucosa in all sites of the Spread resembling lymphomatous polyposis
gastrointestinal tract, but is most com Multiple sites in the gastrointestinal tract {1640,1794}. The mucosal surface can
mon in the small intestine and colon. The are involved, with a chronic relapsing be hyperaemic, with superficial erosions.
lymphoid cells infiltrate the lamina pro
pria but usually do not show invasion of Microscopy
the epithelium. The clinical course is in The lamina propria is expanded by a
dolent, but most patients do not respond dense, non―destructive lymphoid infil
to conventional chemotherapy. A sub trate {3145}. Infiltration of the muscularis
set of cases progress to a higher―grade mucosae and submucosa may be seen
T―cell lymphoma with spread beyond the focally. The mucosal glands are dis
gastrointestinal tract. placed by the infiltrate but not destroyed.
However, epitheliotropism is occasionally
ICD-O code 9702/1 seen. The infiltrate is monotonous, com
posed of small, round, mature―appearing
Epidemiology lymphocytes. Admixed inflammatory
Fig. 14.69 Indolent T-cell lymphoproliferative disorder
The disease presents in adulthood, more of the gastrointestinal tract. Small polypoid lesions are cells are rare, but epithelioid granulo
frequently in men than in women. Rare hyperaemic. Reprinted from Perry AM et al. {3145}. mas may be focally present {563,2506}.
cases have been reported in children. No Some of the histological changes may re
ethnic or genetic factors have been iden semble those of Crohn disease; whether
tified for increased risk. However, some some of these patients truly have preced
patients have a history of Crohn disease ing inflammatory bowel disease remains
{3145}. uncertain.
Localization Immunophenotype
Most patients present with disease af The cells have a mature T―cell pheno
fecting the small bowel or colon {3145, type, positive for CD3. Most reported
3305}. However, all sites in the gastroin cases have been positive for CD8 {3145},
testinal tract can be involved, including but CD4 has been expressed in a sig
the oral cavity and oesophagus {1082}. Fig. 14.70 Indolent T-cell lymphoproliferative disorder nificant number {561,2506,3305}. The
The bone marrow and peripheral blood of the gastrointestinal tract. The mucosa displays mul CD8+ cases express TIA1, but gran-
are usually not involved. tiple small polyps (arrows). From Perry AM et al. {3145}. zyme B is generally negative. Other
Fig. 14.71 Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract, ileum. The lamina propria is Cell of origin
diffusely infiltrated by small lymphoid cells. The postulated cell of origin is a mature
peripheral T cell
Genetic profile
All reported cases have had clonal re
arrangements of TR genes, either TRG or
TRB {2506,3145}. Recurrent mutations or
translocations have not been identified.
In limited studies, activating mutations of
STAT3 were absent. In situ hybridization
for EBV-encoded small RNA (EBER) was
negative in all cases studied.
Fig. 14.73 Indolent T-cell lymphoproliferative disorder Fig. 14.74 Indolent T-cell lymphoproliferative disorder
of the gastrointestinal tract. The Ki-67 proliferation in of the gastrointestinal tract. CD8, duodenal biopsy.
dex is extremely low. Glands are largely intact, but some epitheliotropism is
seen.
Definition T-cell lymphomas {904,4217}. Peak inci 3414}. Rare cases have been reported
Hepatosplenic T―cell lymphoma (HSTL) dence occurs in adolescents and young in patients with psoriasis or rheumatoid
is an aggressive subtype of extranodal adults (median patient age at diagnosis: arthritis receiving tumour necrosis factor
lymphoma characterized by a hepato ~35 years), with a male predominance inhibitors and immunomodulators {3825}.
splenic presentation without lymphad- {178,319,797}.
enopathy and a poor outcome. The Localization
neoplasm results from a proliferation of Etiology Patients present with marked spleno
cytotoxic T cells, usually of gamma delta As many as 20% of HSTLs arise in the megaly and usually hepatomegaly, but
T―cell receptor type. It is usually com setting of chronic immune suppression, without lymphadenopathy. The bone
posed of medium―sized lymphoid cells, most commonly during long―term immu marrow is almost always involved {178,
demonstrating marked sinusoidal infiltra nosuppressive therapy for solid organ 319,797,4166}.
tion of spleen, liver, and bone marrow. transplantation or prolonged antigenic
stimulation {319,4168,4375}. In this set Clinical features
ICD-O code 9716/3 ting, HSTL is regarded as a late―onset HSTL typically presents with hepatos-
post―transplant lymphoproliferative disor plenomegaly and systemic symptoms.
Epidemiology der of host origin. A number of HSTL cas Patients usually manifest marked throm
HSTL is a rare form of lymphoma, report es have been reported in patients (espe bocytopenia, often with anaemia and
ed in both western and Asian countries. cially children) treated with azathioprine leukopenia. Peripheral blood involvement
It accounts for 1―2% of all peripheral and infliximab for Crohn disease {922, is uncommon at presentation but may
Fig. 14.75 Hepatosplenic T-cell lymphoma. A Cords and sinusoids of the spleen are infiltrated by a monotonous population of neoplastic lymphoid cells with medium-sized nuclei
and a moderate rim of pale cytoplasm. B The neoplastic cells diffusely infiltrate the hepatic sinusoids. C The bone marrow is usually hypercellular, with neoplastic cells infiltrating
sinusoids. D Neoplastic cells in the bone marrow are highlighted with immunohistochemistry for CD3.
Fig. 14.80 Subcutaneous panniculitis-like T-cell lym Fig. 14.81 Subcutaneous panniculitis-like T-cell lym Fig. 14.82 Subcutaneous panniculitis-like T-cell lym
phoma. CD4 is negative in tumour cells but positive in phoma. The neoplastic cells stain for beta F1, indicative phoma. Tumour cells have a cytotoxic phenotype and ex
macrophages, which may be abundant. of origin from alpha beta T cells. press granzyme B as well as other cytotoxic molecules.
Definition lifestyle factors have also been associ tracted period. Extracutaneous dissemi
Mycosis fungoides is an epidermotro- ated with increased risk: obesity and nation may occur in advanced stages,
pic, primary cutaneous T―cell lymphoma a smoking history of ≥ 40 years {167}. It mainly to the lymph nodes, liver, spleen,
characterized by infiltrates of small to me has been speculated that mycosis fun lungs, and blood {892}. Involvement of
dium―sized T lymphocytes with cerebri- goides might be associated with certain the bone marrow is rare {4320}.
form nuclei. The term mycosis fungoides retroviruses, but no such association has
should be used only for classic cases, been identified through high―throughput Clinical features
characterized by the evolution of patch sequencing {956}. Mycosis fungoides has an indolent
es, plaques, and tumours, or for variants clinical course, with slow progression
with a similar clinical course. Localization over years or sometimes decades from
The disease is generally limited to the patches to more―infiltrated plaques and
ICD-O code 9700/3 skin, with variable distribution, for a pro eventually tumours. In early stages, the
Epidemiology
Mycosis fungoides is the most common
type of cutaneous T―cell lymphoma and
accounts for almost 50% of all primary
cutaneous lymphomas {4320}. Most pa
tients are adults/elderly, but the disease
can also be observed in children and
adolescents {395,1218}. The male―to-
female ratio is 2:1 {4320}. Worldwide, the
incidence is about 10 cases per one mil
lion population, with marked regional
variation {2085} and a higher incidence
in Black populations {1636}. An elevated
risk of mycosis fungoides has been as
sociated with several professions, includ
ing crop and vegetable farming, painting,
woodworking, and carpentry. These find
ings suggest possible environmental co
factors in the pathogenesis of the disease
{167}. Studies have shown increased risk
for individuals in the petrochemical, tex
tile, and metal industries {776}. Certain
Fig. 14.89 Early mycosis fungoides. A case showing epidermotropic lymphocytes Fig. 14.90 Early mycosis fungoides. Neoplastic cells can be seen lining up in the basal
aligned along the basal layer of the epidermis. layer, referred to as a string-of-pearls pattern (CD3 stain).
T1 Limited patchesa, papules, and/or plaquesb covering < 10% of the skin surface. May further stratify into T1a (patch only) vs T1b (plaque ± patch)
T2 Patches, papules, or plaques covering >10% of the skin surface. May further stratify into T2a (patch only) vs T2b (plaque ± patch)
T3 ≥ 1 turnoutc (≥ 1 cm in diameter)
Lymph nodes
N1 Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 1 or NCI LN0-2
N1a: Clone-negativee
N1b: Clone-positivee
N2 Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 2 or NCI LN3
N2a: Clone-negativee
N2b: Clone-positivee
N3 Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 3―4 or NCI LN4; clone-positive or clone-negative
Viscera
M0 No visceral organ involvement
M1 Visceral organ involvement (must have pathology confirmationf organ involved should be specified)
Blood
B0 Absence of significant blood involvement:
≤ 5% of peripheral blood lymphocytes are atypical (Sézary) cellsg
B0a: Clone-negativee
B0b: Clone-positivee
B1 Low blood tumour burden: > 5% of peripheral blood lymphocytes are atypical (Sézary) cells, but criteria for B2 are not met
B1a: Clone-negativee
B1b: Clone-positivee
Stage
IA T1, N0, M0, B0―1 IB T2, N0, M0, B0―1
III T4, N0―2, M0, B0―1 III A T4, N0―2, M0, B0 III B T4, N0―2, M0, B1
IVA1 T1―4, N0―2, M0, B2 IVA2 T1―4, N3, M0, B0―2 IV B T1―4, N0-3, M1, B0―2
a For skin, the term *patch+ means a skin lesion of any size without significant elevation or induration; the presence or absence of hypo– or hyperpigmentation, scale,
crusting, and/or poikiloderma should be noted.
b For skin, the term *plaque+ means a skin lesion of any size that is elevated or indurated; the presence or absence of scale, crusting, and/or poikiloderma should be noted;
histological features such as folliculotropism and large-cell transformation (> 25% large cells), CD30 positivity or negativity, and clinical features such as ulceration are
important to document.
c For skin, the term *tumour+ means a solid or nodular lesion ≥ 1 cm in diameter with evidence of depth and/or vertical growth; note the total number of lesions, total
volume of lesions, largest size of lesion, and region of body involved; also note whether there is histological evidence of large–cell transformation; phenotyping for CD30 is
recommended.
d For nodes, the term *abnormal peripheral lymph node+ means any palpable peripheral node that on physical examination is firm, irregular, clustered, fixed, or
≥1.5 cm in diameter; node groups examined on physical examination include cervical, supraclavicular, epitrochlear, axillary, and inguinal; central nodes, which are not
generally amenable to pathological assessment, are not considered in the nodal classification unless used to establish N3 histopathologically.
e A T-cell clone is defined by PCR or Southern blot analysis of the TR gene.
f Spleen and liver involvement can be diagnosed on the basis of imaging criteria.
9 Sézary cells are defined as lymphocytes with hyperconvoluted cerebriform nuclei; if Sézary cells cannot be used to determine tumour burden for B2, then one of the
following modified ISCL criteria along with a positive clonal rearrangement of the TR gene can be used instead:
(1) expanded CD4+ T cells with a CD4:CD8 ratio of ≥ 10, (2) expanded CD4+ T cells with abnormal immunophenotype including loss of CD7 or CD26.
{2972}. Recognition of the early infiltrates localization of the neoplastic infiltrate, cal cells have medium―sized or large
can be difficult and can be facilitated by folliculotropic mycosis fungoides is less cerebriform nuclei and either a CD4―/
PCR for clonal TR rearrangement analy accessible to skin―targeted therapies. CD8+ phenotype or (less commonly) a
sis {2972}. N3 lymph nodes may simulate The 5―year disease-specific survival rate CD4+/CD8― phenotype. CD30 is often
peripheral T―cell lymphoma, NOS, or is approximately 70―80%, which is sig expressed. Unlike with classic mycosis
Hodgkin lymphoma. nificantly worse than that seen in classic fungoides, neither extracutaneous dis
plaque-stage mycosis fungoides {4131}. semination nor disease―related deaths
Variants have ever been reported {4320}.
Folliculotropic mycosis fungoides Pagetoid reticulosis
Folliculotropic mycosis fungoides is char Pagetoid reticulosis is characterized by Granulomatous slack skin
acterized by infiltrates of atypical (cere- patches or plaques with an intraepider Granulomatous slack skin is an extreme
briform) CD4+ T lymphocytes involving mal proliferation of neoplastic T cells ly rare subtype of cutaneous T-cell lym
hair follicles, often with sparing of the {1516}. The term should only be used phoma characterized clinically by the
epidermis {608}. Many cases show muci for the localized type (Woringer―Kolopp development of bulky, pendulous skin
nous degeneration of the hair follicles (fol type) and not for the disseminated type folds in the flexural areas (axillae, groin),
licular mucinosis), but mucin deposition (Ketron―Goodman type), because most and histologically by a granulomatous
can be absent {1222,4131}. The lesions cases corresponding to the latter cat infiltrate within the dermis and subcuta
preferentially involve the head and neck egory would instead be classified as ag neous tissues, with clonal CD4+ T cells,
area and often present with grouped fol gressive epidermotropic CD8+ cytotoxic abundant macrophages with many multi-
licular papules and plaques associated T―cell lymphoma or cutaneous gamma nucleated giant cells, and loss of elastic
with alopecia {4131}. Due to the deep delta T-cell lymphoma {4320}. The atypi fibres {1989,2241}. Most reported cases
Fig. 14.93 Folliculotropic mycosis fungoides. Hyperplastic hair follicles surrounded Fig. 14.94 Folliculotropic mycosis fungoides. Colloidal iron staining shows marked
and infiltrated by lymphocytes. deposition of mucin in all follicles.
Immunophenotype
The typical phenotype is CD2+, CD3+,
TCR beta+, CD5+, CD4+, CD8―, TCR
gamma―. Cases with a cytotoxic phe
Fig. 14.96 Folliculotropic mycosis fungoides.
notype (CD8+ and/or TCR gamma+) are
Staining for CD5 highlights intraepithelial lymphocytes.
well recognized {2547,3390}. Such cases
have the same clinical behaviour and
prognosis as CD4+ cases, and should
not be considered a separate entity
{2547}. A CD8+ phenotype has been re
ported more commonly in paediatric my
cosis fungoides. Expression of CD56 has
been observed in otherwise conventional
mycosis fungoides. A lack of CD7 is fre
quent in all stages of the disease. Cu
taneous lymphocyte antigen (CLA), as
sociated with lymphocyte homing to the Fig. 14.95 Pagetoid reticulosis. Hyperplastic epidermis Fig. 14.97 Granulomatous slack skin.
skin, is expressed in most cases. Other infiltrated by numerous lymphocytes. Diffuse lymphoid infiltrates admixed with histiocytes and
alterations in the expression of T-cell an with several large, multinucleated giant cells.
tigens may be seen, but mainly occur in
the advanced (tumour) stages. Partial variants constitute the vast majority of cutaneous and extracutaneous disease,
expression of CD30 by neoplastic cells all driver mutations, including mutations as reflected by the clinical stage. Patients
may be found in all stages, in particular in multiple components of the TCR and with limited disease generally have an ex
in plaques and tumours of the disease. IL2 signalling pathways, in genes that cellent prognosis, with a similar survival
Cytotoxic granule―associated proteins drive T helper 2 (Th2) cell differentiation, as the general population {27,958,3256,
are uncommonly expressed in the early in genes that facilitate escape from TGF- 4132}. Large Pautrier microabscesses
patch/plaque lesions, but may be posi beta―mediated growth suppression, and dermal atypical lymphocytes in early
tive in neoplastic cells in more―advanced and in genes that confer resistance to lesions have been associated with pro
lesions {4188}. tumour necrosis factor receptor super gression to advanced stage {4212}. In
family (TNFRSF)―mediated apoptosis advanced stages, the prognosis is poor,
Cell of origin {736,2598,4039,4091,4134}. Constitutive in particular in patients with skin tumours
A mature skin―homing CD4+ T cell activation of STAT3 and inactivation of and/or extracutaneous dissemination
CDKN2A (also called p16INK4a) and {337,4132}. Failure to achieve complete
Genetic profile PTEN have been identified and may be remission after the first treatment, pa
TR genes are found to be clonally re associated with disease progression tient age > 60 years, and elevated lactate
arranged in most cases when sensitive {3547}. dehydrogenase are adverse prognostic
techniques (e.g. BIOMED―2) are used parameters {27,973}, as is histological
{3211}. Complex karyotypes are present Prognosis and predictive factors transformation with increase in blast cells
in many patients, in particular in the ad The single most important prognostic fac (> 25%) {155,609}.
vanced stages. Somatic copy―number tor in mycosis fungoides is the extent of
Definition Table 14.07 Histopathological staging for clinically abnormal lymph nodes (> 1.5 cm) in mycosis fungoides and
Sézary syndrome (SS) is defined by Sézary syndrome
the triad of erythroderma, generalized
ISCL/EORTC
lymphadenopathy, and the presence of {2972} Dutch system {3552A} NCI classification {3532A}
clonally related neoplastic T cells with
cerebriform nuclei (Sézary cells) in skin, N1 Category 1: LN0:
lymph nodes, and peripheral blood. In DL, no atypical CMCs No atypical lymphocytes
addition, one or more of the following LN1:
criteria are required: an absolute Sézary Occasional, isolated atypical lymphocytes
cell count ≥ 1000/μL, an expanded CD4+ LN2:
T-cell population resulting in a CD4:CD8 Clusters (3―6 cells) of atypical lymphocytes
ratio of ≥10, and loss of one or more
N2a Category 2: LN3:
T―cell antigens. SS and mycosis fungoi-
DL with early involvement and Aggregates of atypical lymphocytes, but
des are closely related neoplasms, but scattered atypical CMCs architecture preserved
are considered separate entities on the
basis of differences in clinical behaviour N3 Category 3: LN4:
Partial effacement of architecture, Partial or complete effacement of architecture,
and cell of origin {4211}.
with many CMCs with many atypical lymphocytes
Immunophenotype
The neoplastic T cells have a CD3+,
CD4+, CD8― phenotype; characteristi
cally lack CD7 and CD26; and express
PD1 (also known as CD279) in almost all
cases {625}. Sézary cells express cuta
neous lymphocyte antigen (CLA) and
the skin―homing receptor CCR4 {1213},
as well as CCR7 {2825}. Flow cytometry
analysis of peripheral blood lymphocytes
shows a CD4+/CD7― (> 30%) or CD4+/
Fig. 14.99 Sézary syndrome. Skin infiltrates with epidermotropic infiltrates of atypical, cerebriform lymphocytes.
CD26― (> 40%) T―cell population {356,
3718}.
Fig. 14.102 Lymphomatoid papulosis type A. A Mixed inflammatory infiltrate with scattered large atypical cells. B Staining for CD30 shows scattered large atypical cells.
C Scattered large anaplastic cells expressing CD30.
lesions disappear within 3―12 weeks and sheets of large CD30+ T cells with rela times pagetoid infiltrate of atypical small
may leave behind superficial scars. The tively few admixed inflammatory cells, to medium―sized CD8+, CD30+ pleo
duration of the disease may vary from very similar to cutaneous anaplastic morphic T cells, mimicking primary cuta
several months to > 40 years. In as many large cell lymphoma {314}. neous aggressive epidermotropic CD8+
as 20% of patients, LyP may be pre LyP, Type D lesions (< 5%) are character cytotoxic T―cell lymphoma {3473}.
ceded by, associated with, or followed ized by a strongly epidermotropic, some
by another type of malignant lymphoma,
generally mycosis fungoides, cutaneous
anaplastic large cell lymphoma, or Hodg
kin lymphoma {314,910}.
Microscopy
The histological picture of LyP is ex
tremely variable, and in part correlates
with the age of the biopsied skin lesion.
Several histological subtypes of LyP have
been described.
Type A LyP is the most common type
(> 80%) and is characterized by scat
tered or small clusters of large atypical
(sometimes multinucleated or Reed-
Sternberg―like) CD30+ cells intermingled
with numerous inflammatory cells, includ
ing small lymphocytes, neutrophils, and/
or eosinophils {314}.
LyP, Type B is uncommon (< 5%) and is
characterized by a predominantly epi-
dermotropic infiltrate of small atypical
CD30+ or CD30― cells with cerebriform
nuclei, histologically simulating early-
stage mycosis fungoides {314}. Fig. 14.105 Lymphomatoid papulosis type D. A Marked epidermotropism of CD8+ pleomorphic T cells mimicking
LyP, Type C lesions (~10%) demonstrate cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma. B Extensive epidermotropism of small to
a monotonous population or cohesive medium-sized pleomorphic T cells.
Some of these cases may have a gamma locus on 6p25.3 {1938}. Patients are sions, and a single LyP lesion may show
delta T―cell phenotype {3390}. older adults and often present with local histological features of multiple subtypes.
Type E LyP (< 5%) is characterized by angi- ized skin lesions. Histologically, skin le Recognition of these different subtypes
ocentric and angiodestructive infiltrates of sions show extensive epidermotropism of LyP is important, to avoid misdiag
small to medium-sized CD8+, CD30+ ple by weakly CD30+ small to medium nosis of other, often more aggressive,
omorphic T cells {1988}. Vascular occlu sized T cells with cerebriform nuclei and types of cutaneous T-cell lymphoma (see
sion, haemorrhages, extensive necrosis, strongly CD30+ medium―sized to large Table 14.08). However, the subtypes have
and ulceration may be present. Clinically, blast cells in the dermis, simulating trans no therapeutic or prognostic implications.
patients present with a few papulonodular formed mycosis fungoides.
lesions that rapidly ulcerate and evolve into Other rare histological variants have also Immunophenotype
large necrotic eschar―like lesions. been described, including folliculotropic, The large atypical cells in the lesions of
LyP with 6p25.3 rearrangement (< 5%) syringotropic, and granulomatous LyP type A and type C LyP have the same
is characterized by chromosomal re {1986,1987}. Different subtypes of LyP phenotype as the tumour cells in cutane
arrangements involving the DUSP22-IRF4 may occur in separate but concurrent le ous anaplastic large cell lymphoma.
Fig. 14.108 Lymphomatoid papulosis with DUSP22-IRF4 rearrangement. A Diffuse dermal infiltrate of medium-sized to large atypical lymphocytes. Intraepidermal infiltrate of
small atypical lymphocytes with hyperchromatic nuclei. B Diffuse dermal infiltrate of medium-sized to large atypical lymphocytes. Expression of CD8 by both intraepidermal and
dermal atypical T cells. C Diffuse dermal infiltrate of medium-sized to large atypical lymphocytes. CD30 expression by both intraepidermal and dermal atypical lymphocytes.
Fig. 14.112 Primary cutaneous anaplastic large cell Fig. 14.113 Primary cutaneous anaplastic large cell Fig. 14.114 Primary cutaneous anaplastic large cell
lymphoma with confluent sheets of large cells with lymphoma with cohesive sheets of CD30+ anaplastic lymphoma with a diffuse proliferation of medium-sized
anaplastic morphology. cells. pleomorphic cells.
Definition
Primary cutaneous gamma delta T―cell
lymphoma (PCGD―TCL) is a lymphoma,
involving primarily the skin, composed of
a clonal proliferation of mature, activated
gamma delta T cells with a cytotoxic phe
notype. This group includes cases previ
ously called subcutaneous panniculitis
like T-cell lymphoma with a gamma delta Fig. 14.116 Primary cutaneous gamma delta T-cell lymphoma. Lesions are clinically diverse, and consist of plaques,
phenotype. Gamma delta T―cell lympho without ulceration (A) or with ulceration (B), or tumours (C). The lesion may consist of an indurated plaque with
mas presenting primarily in mucosal sites subcutaneous infiltration (D).
Imaging
Abnormal PET and/or CT findings are
common in sites of active disease {1493}.
Microscopy
Three major histological patterns of
involvement can be present in the skin:
epidermotropic, dermal, and subcuta
neous. Often more than one histological
pattern is present in the same patient in
different biopsy specimens or within a
single biopsy specimen {359,4031,4321}.
Epidermal infiltration may occur as mild
epidermotropism to marked pagetoid re
ticulosis―like infiltrates {359}. Subcutane
ous cases may show rimming of fat cells,
similar to subcutaneous panniculitis―like
T-cell lymphoma of alpha beta origin, but
usually show dermal and/or epidermal
involvement in addition {4031,4321}. The
neoplastic cells are generally medium
sized to large, with coarsely clumped
chromatin {4031}. Large blastic cells with
vesicular nuclei and prominent nucleoli
are infrequent. Apoptosis and necrosis
are common, often with angioinvasion
{4031,4321}.
Immunophenotype
The tumour cells characteristically have
a gamma delta TCR―positive, beta F1-
negative, CD3+, CD2+, CD5―, CD7+/―,
CD56+ phenotype with strong expres
sion of cytotoxic proteins, including
granzyme B, perforin, and TIA1 {1821,
3495,4031,4321}. Most cases lack both
Fig. 14.118 Primary cutaneous gamma delta T-cell lymphoma. Histological patterns are diverse. A Dermal CD4 and CD8, although CD8 may be
infiltration is usually present, and, as seen in B, the infiltrate may extend from the epidermis to the subcutis. expressed in some cases {4031,4321}.
C,D Panniculitis-like pattern may be seen. The gamma delta T-cell phenotype (TCR
Definition
This provisional entity is a cutaneous
T-cell lymphoma characterized by prolif
eration of epidermotropic CD8+ cytotoxic
gamma―positive, beta F1―negative) can T cells and aggressive clinical behaviour.
now be assessed on formalin-fixed, par Differentiation from other types of cuta
affin―embedded tissue sections in most neous T―cell lymphomas with a CD8+
instances {1299,3850}. Coexpression of cytotoxic T―cell phenotype is based on
TCR gamma and beta F1 has been re the clinical presentation, clinical behav
ported in some cases {1310A,3390}. iour, and certain histological features,
such as marked epidermotropism with
Postulated normal counterpart epidermal necrosis.
Functionally mature and activated cyto
toxic gamma delta T cells of the innate ICD-O code 9709/3 other visceral sites (lungs, testes, CNS,
immune system oral mucosa), but lymph nodes are often
Epidemiology spared {361,2535,3267,3377}.
Genetic profile This disease is rare, accounting for < 1%
The cells show clonal rearrangement of all cutaneous T―cell lymphomas {30, Microscopy
of the TRG and TRD genes. TRB may 361,4320}. It occurs mainly in adults. The histological appearance is very vari
be rearranged or deleted, but is not ex There are no known predisposing factors. able, ranging from a lichenoid pattern
pressed. PCGD―TCLs usually express with marked, pagetoid epidermotropism
V delta 2, consistent with the prevalence Localization and subepidermal oedema (dissemi
of V delta 2 gamma delta T cells resid Most patients present with generalized nated variant) to deeper, more―nodular
ing in the skin {3243}. EBV is negative skin lesions. and less―epidermotropic infiltrates (lo
{150,3850,4031}. In common with other calized variant). The epidermis may be
tumours of gamma delta T―cell origin, Clinical features acanthotic or atrophic, often with necro
some cases have activating mutations in Clinically, these lymphomas are charac sis, ulceration, and blister formation {30,
STAT5B and rarely in STAT3. terized by localized ulcerated nodules, 361,3377}. Invasion and destruction of
Activation of the JAK/STAT pathway is tumours, or plaques, or (more common adnexal skin structures are commonly
common to many cytotoxic T―cell malig ly) by disseminated eruptive papules, seen. Angiocentricity and angioinvasion
nancies {2160}. nodules, and tumours showing central may be present {2546,3377}. Tumour
ulceration and necrosis {361,3377,3518}. cells are small-medium or medium-large,
Prognosis and predictive factors These lymphomas may disseminate to with pleomorphic or blastic nuclei {361}.
PCGD―TCLs are usually resistant to
multiagent chemotherapy and/or radiation
and have a poor prognosis, with a me
dian survival of approximately 15 months
{4031,4321}. Patients with subcutaneous
fat involvement tend to have a more unfa
vourable prognosis than do patients with
epidermal or dermal disease only {4031}.
However, rare cases with an indolent clin
ical course have been reported {178,1104,
1493,3267}. In one recent large series,
median survival was 31 months {1493}.
Definition
Primary cutaneous acral CD8+ T―cell
lymphoma is a rare cutaneous tumour
characterized by skin infiltration of clonal
atypical medium―sized cytotoxic lym
phocytes {3156}. The tumour is clinically
characterized by preferential involvement
of acral sites (in particular the ears) and Fig. 14.124 Primary cutaneous acral CD8+ T-cell lymphoma. A Nodule of the right helix. B Nodule of the nose. C
by a good prognosis. Nodule/plaque of the left foot.
Fig. 14.128 Primary cutaneous acral CD8+ T-cell Fig. 14.129 Primary cutaneous acral CD8+ T-cell lym Fig. 14.130 Primary cutaneous acral CD8+ T-cell
lymphoma. Fewer than 10% of the tumour cells are phoma. Several atypical cells show Golgi dot-like stain lymphoma. Infiltration of cutaneous fat tissue and nasal
positive for Ki-67. ing for CD68 (PGM1), besides normally stained reactive ala muscle.
histiocytes.
phils, and eosinophils are absent or very CD8+ cutaneous lymphomas should to other organs or lymphoid tissue. No
rare. The epidermis is most often spared, be carefully considered {3377}. Staining chemotherapy is needed. It is impor
with a grenz zone. Occasionally, minimal for B-cell markers (CD20, CD79a) might tant to recognize this disease to avoid
insignificant epidermotropism may be reveal reactive B-cell aggregates or folli overtreatment.
seen {1446,1515}. Skin appendages are cles. LMP1 and EBV-encoded small RNA
always spared, and angiotropism, an- (EBER) are negative.
giodestruction, and necrosis are never Primary cutaneous CD4+
seen. The proliferation frequently involves Postulated normal counterpart small/medium T―cell
the underlying fat tissue. The postulated normal counterpart is
lymphoproliferative disorder
a skin―homing CD8+ T cell. However,
Immunophenotype cases that are very similar in terms of Gaulard P.
The tumoural infiltrate is composed of morphology, phenotype, and clinical out Berti E.
T cells that express CD3, CD8, TIA1, come have also been recently described Willemze R.
and beta F1. TIA1 displays Golgi dot―like in the gastrointestinal tract {3145} and Petrella T.
staining. CD4 is always negative. CD2, genital tract {3863}, suggesting a new Jaffe E.S.
CD5, and CD7 are regularly positive but lymphoma entity arising from tissue-resi
one or more of them can be lost or weak. dent CD8+ memory T cells.
Granzyme B and perforin are generally Definition
negative but may occasionally be posi Genetic profile Primary cutaneous CD4+ small/medium
tive. CD56, CD57, CD30, and TdT are The neoplastic T cells show clonal TRG T-cell lymphoproliferative disorder is char
always negative, as are the T follicular gene rearrangements. Specific genetic acterized by a predominance of small to
helper (TFH) cell markers (CD10, BCL6, abnormalities have not yet been de medium-sized CD4+ pleomorphic T cells,
PD1, and CXCL13) {1446}. CD68 is fre scribed. EBV is negative. and by presentation with a solitary skin le
quently positive, displaying as does TIA1, sion in almost all cases, without evidence
Golgi dot―like staining {4345}. In the vast Prognosis and predictive factors of the patches and plaques typical of my
majority of cases, the Ki―67 proliferation The tumour has a very good prognosis. cosis fungoides. Because these cases
index is very low (<10%). A few typical Complete remission after surgical exci have the same clinicopathological features
cases with a high proliferation index have sion or radiotherapy is the rule. Local and benign clinical course as cutaneous
been reported {4468}; however, when or extra―site skin recurrence may occur. pseudo-T-cell lymphomas with a nodular
the proliferation index is > 50%, other There is no evidence of dissemination growth pattern {323,626,3267}, the term
Clinical features
Patients are asymptomatic; a single slow-
growing skin lesion is the sole manifes
tation of disease. In rare cases, multiple
lesions are present {323,626}. By defini
tion, there should be no patches typical
of mycosis fungoides.
Fig. 14.131 Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder. A Typical presentation as a
solitary lesion on the scalp. B The lesion is usually a single raised erythematous nodule. Microscopy
These lymphomas show dense, diffuse,
or nodular infiltrates within the dermis,
with a tendency to infiltrate the subcutis.
Epidermotropism may be present focal-
ly, but if epidermotropism is conspicu
ous, the diagnosis of mycosis fungoides
should be considered. There is a pre
dominance of small/medium―sized pleo
morphic T cells {317,323,626,1298,1471,
1832,3267,3391}. A small proportion
(< 30%) of large pleomorphic cells may
be present {320}. In almost all cases, the
atypical CD4+ T cells are admixed with
small reactive CD8+ T cells, B cells, plas
ma cells, and histiocytes (including multi-
nucleated giant cells) {323,626,3391}.
Immunophenotype
By definition, these proliferations have a
CD3+, CD4+, CD8―, CD30― phenotype.
Loss of pan―T―cell antigens (except for
CD7) is uncommon, and cytotoxic pro
teins are not expressed {323,626,1471,
3391}. Atypical CD4+ T cells express
PD1, BCL6 (variable), and CXCL13, sug
gesting T follicular helper (TFH) cell deri
vation {626,3391}. CD10 is usually nega
tive. The Ki―67 proliferation index is low
(typically 5%, and at most 20%).
Genetic profile
‘primary cutaneous CD4+ small/medium ICD-O code 9709/1 TR genes are clonally rearranged in most
T―cell lymphoproliferative disorder’ is pre cases {626,3391}. Specific genetic ab
ferred, rather than ‘primary cutaneous Synonym normalities have not been described.
CD4+ small/medium T―cell lymphoma’. Primary cutaneous CD4+ small/medium EBV is negative.
Rare cases presenting with widespread T―cell lymphoma (no longer used)
skin lesions, large rapidly growing tu Prognosis and predictive factors
mours, > 30% large pleomorphic T cells, Epidemiology Patients have an excellent prognosis. In-
and/or a high proliferative fraction do not This is a rare disease, accounting for 2% tralesional steroids, surgical excision, and
belong to this group {1298,1471}. Such of all cutaneous T-cell lymphomas {4320}. radiotherapy are preferred modes of treat
cases usually have a more aggressive ment {323,626,1471}. Spontaneous remis
clinical behaviour and are better classified Localization sion after biopsy has been reported {626,
as peripheral T―cell lymphoma, NOS. These lesions usually present as a soli 1471,1832}. Local recurrences are rare.
tary plaque or nodule, most commonly
Definition Table 14.09 Differential diagnosis of nodal peripheral T-cell lymphoma, NOS
Peripheral T―cell lymphoma (PTCL), Disease Immunophenotypic features
NOS, is a heterogeneous category of
nodal and extranodal mature T-cell lym Peripheral T-cell lymphoma, NOS CD4 > CD8; antigen loss frequent (CD7, CD5, CD4/CD8, CD52);
GATA3–/+; TBX21–/+; cytotoxic granules–/+; CD30―/+; CD56–/+;
phomas that do not correspond to any of
rare cases EBV+
the specifically defined entities of mature
T―cell lymphoma in the current classifi Angioimmunoblastic T-cell CD4+; expression of at least two (preferably three) of the following
cation (Table 14.09). Excluded from this lymphoma TFH-cell markers: CD10, BCL6, PD1, CXCL13, CXCR5, ICOS, SAP;
category are tumours with a T follicular hyperplasia of FDCs (CD21+) and HEVs (MECA79+);
EBV+ CD20+ B blasts
helper (TFH) cell phenotype, as defined
by the expression of at least two (ideally Nodal peripheral T-cell lymphoma Expression of at least two (preferably three) of the following
three) of the following markers: CD10, with TFH phenotype TFH-cell markers: CD10, BCL6, PD1, CXCL13, CXCR5, ICOS, SAP;
BCL6, PD1, CXCL13, CXCR5, ICOS, and no hyperplasia of FDCs or HEVs
SAP {34,2231,2496}. PTCL, NOS, nearly Adult T-cell leukaemia/lymphoma CD4+; CD25+; CD7–; CD30–/+; CD15–/+; FOXP3–/+
always presents in adults, and has an
ALK+ anaplastic large cell lymphoma CD30+; ALK+; EMA+; CD25+; cytotoxic granules+/–, CD4+/–;
aggressive clinical course. CD3–/+; CD43+
ICD-O code 9702/3 ALK– anaplastic large cell lymphoma CD30+; EMA+; CD25+; cytotoxic granules+/–; CD4+/–; CD3–/+;
CD43+; PAX5/BSAP–
Synonyms T-cell/histiocyte-rich large B-cell Large CD20+ blasts in background of reactive T cells with
T―cell lymphoma, NOS; peripheral T-cell lymphoma complete phenotypic profile
lymphoma, pleomorphic small cell; peri T-zone hyperplasia Expansion of T cells with complete phenotypic profile and
pheral T―cell lymphoma, pleomorphic mixed CD4/CD8, variable CD25 and CD30; scattered CD20+ B cells
medium and large cell; peripheral T―cell
lymphoma, large cell; lymphoepithelioid +, nearly always positive; +/–, majority positive; –/+, minority positive; –, negative
FDC, follicular dendritic cell; HEV: high endothelial venule; TFH, T follicular helper
lymphoma; Lennert lymphoma
Epidemiology
These tumours account for approxima EBV may be found in background B cells. Extranodal presentations can occur, most
tely 30% of PTCLs in western countries commonly in the skin and gastrointestinal
{3365}. Most patients are adults. These Localization tract {3365}. In this setting, the diagnosis
lymphomas are very rare in children. The Most patients present with peripheral of PTCL, NOS, should be made only after
male―to―female ratio is 2:1. lymph node involvement, but any site can more specific entities have been exclud
be affected. Advanced―stage disease is ed. Other less frequently involved sites
Etiology common, with secondary involvement of include the lungs and CNS {2632}.
The infection of neoplastic cells by EBV the bone marrow, liver, spleen, and ex
is reported in a small number of cases, in tranodal tissues {3365}. The peripheral Clinical features
which the virus plays a pathogenetic role blood is sometimes involved, but leukae- Patients most often present with lymph
{178,1068,1505,4298}. More commonly, mic presentation is uncommon {3365}. node enlargement, and most have
Fig. 14.133 Peripheral T-cell lymphoma, NOS, with prominent clear-cell features (A,B) or large lymphoid cells with vesicular, immunoblast-like nuclei (C).
Variants
Lymphoepithelioid lymphoma
This variant, also known as Lennert lym
phoma, shows diffuse or (less common
ly) interfollicular growth. Cytologically,
it consists predominantly of small cells
with slight nuclear irregularities; numer
ous and sometimes confluent clusters of
epithelioid histiocytes; and some larger,
more atypical, proliferating blasts. There
can be admixed inflammatory cells and
Fig. 14.134 Peripheral T-cell lymphoma, NOS. A Diffuse infiltrates of large lymphoid cells with pleomorphic, irregular scattered Reed―Sternberg―like B cells
nuclei and prominent nucleoli. B Between the neoplastic cells, there are scattered eosinophils and numerous (usually EBV―positive). High endothelial
vessels. C Nuclei are markedly pleomorphic and multilobed. D In some cases, nuclei are round and monomorphic venules are not prominent. In most cases,
in appearance. the neoplastic cells are CD8―positive and
have a cytotoxic profile {34,1321,1569,
advanced disease with B symptoms dominance of small lymphoid cells with 4411}. This variant may have a somewhat
{3365}. Paraneoplastic features such atypical, irregular nuclei. Hyperplasia of better prognosis than do other forms of
as eosinophilia, pruritus, or (rarely) hae- high endothelial venules and/or follicu PTCL, NOS.
mophagocytic syndrome may be seen lar dendritic cells and the open marginal
{3365}. sinuses characteristic of angioimmuno- Other variants
blastic T―cell lymphoma (AITL) are not The follicular variant included within the
Microscopy usually seen {1557,1816}. An inflammato PTCL, NOS, category in the 2008 edi
In the lymph node, these lymphomas ry background is often present, including tion of the WHO classification has been
show paracortical or diffuse infiltrates with small lymphocytes, eosinophils, plasma moved to the category of AITL and other
effacement of the normal architecture. cells, large B cells (which may be clonal nodal lymphomas of T follicular helper
The cytological spectrum is extremely irrespective of EBV infection) {4258}, and cell origin in this update.
broad, from polymorphous to monomor- clusters of epithelioid histiocytes. Epithe The same is true for a proportion of cases
phic. Most cases consist of numerous lioid histiocytes are particularly numerous previously designated as the T-zone vari
medium―sized and/or large cells with ir in the lymphoepithelioid variant. Extran- ant, because they usually have a TFH-
regular, pleomorphic, hyperchromatic, or odal involvement takes the form of dif cell phenotype {34}. Thus, the growth of
vesicular nuclei; prominent nucleoli; and fuse infiltrates composed of similar cells. atypical small T lymphocytes around flor
many mitotic figures {1557,1816}. Clear In the skin, the lymphomatous population id reactive germinal centres {3463,4258}
cells and Reed-Sternberg―like cells can tends to infiltrate the dermis and subcu is no longer considered to be a variant
also be seen. Rare cases have a pre tis, often producing nodules, which may of PTCL, NOS, but rather a non-specific
Fig. 14.135 Peripheral T-cell lymphoma, NOS. Fig. 14.136 Peripheral T-cell lymphoma, NOS. Fig. 14.137 Peripheral T-cell lymphoma, NOS.
Neoplastic cells express CD3. Neoplastic cells express T-cell receptor beta as asses Neoplastic cells lack CD5 expression. Note the
sed by beta F1 monoclonal antibody staining. presence of some reactive T lymphocytes, which serve
as an internal control.
Immunophenotype
PTCL, NOS, is usually characterized by
an aberrant T―cell phenotype with fre
quent downregulation of CD5 and CD7
{4298} (see Table 14.09, p. 403). A CD4+/
CD8― phenotype predominates in nodal
cases. CD4/CD8 double―positivity or
double―negativity is sometimes seen, Fig. 14.139 Peripheral T-cell lymphoma, NOS. Fig. 14.140 Peripheral T-cell lymphoma, NOS. Neo
as is CD8, CD56, and cytotoxic granule Neoplastic cells express the cytotoxic marker TIA1. plastic cells show partial and variable expression of
expression (e.g. TIA1, granzyme B, and CD30.
perforin) {4298}. T―cell receptor beta
(beta F1) is usually expressed, facilitat
ing the distinction from gamma delta T-
cell lymphomas and NK―cell lymphomas.
CD15 may be positive, and may be coex
pressed with CD30 in rare cases {277}.
Such cases may show features overlap
ping with those of ALK―negative (ALK―)
anaplastic large cell lymphoma (ALCL),
but are classified as PTCL, NOS, under
the current guidelines. CD15 expression
is associated with an adverse prognosis Fig. 14.141 Peripheral T-cell lymphoma, NOS. Most Fig. 14.142 Peripheral T-cell lymphoma, NOS. Most
{4298}. neoplastic cells express TBX21. neoplastic cells express GATA3.
Fig. 14.143 Peripheral T-cell lymphoma (PTCL), NOS. Gene expression profiling identifies two main subgroups of PTCL, NOS, characterized by overexpression of TBX21 and
GATA3, respectively. The former is associated with a more favourable clinical course, with longer overall survival (OS).
Angioimmunoblastic T-cell lymphoma and other nodal lymphomas of TFH-cell origin 407
below. For these reasons, in this update, Etiology matoid factor, and anti―smooth muscle
they have been included under the The strong association with EBV infec antibodies.
broader category of nodal lymphomas of tion suggests a possible role for the virus Patients exhibit immunodeficiency sec
TFH-cell origin with angioimmunoblastic in the etiology, possibly through antigen ondary to the neoplastic process. In most
T―cell lymphoma, but are summarized drive {1061}. However, the neoplastic cases (75%), expansion of EBV―positive
separately. Cutaneous T―cell lymphomas T cells are EBV―negative. B cells is seen, which is thought to be a
and lymphoproliferative disorders ex consequence of underlying immune dys
pressing TFH-cell markers are excluded Localization function {92,938,4288}.
from this group of neoplasms. The primary site of disease is the lymph
node, and virtually all patients present Microscopy
with generalized lymphadenopathy. The AITL is characterized by partial or total
Angioimmunoblastic T―cell spleen, liver, skin, and bone marrow are effacement of the lymph node architec
lymphoma also frequently involved {901,1013,1169, ture, often with perinodal infiltration but
2767}. sparing of the peripheral cortical sinus
Definition es. Cytologically, the neoplastic T cells of
Angioimmunoblastic T―cell lymphoma Clinical features AITL are small to medium―sized lympho
(AITL) is a neoplasm of mature T folli AITL typically presents with advanced- cytes, with clear to pale cytoplasm, dis
cular helper (TFH) cells characterized by stage disease, generalized lymphade tinct cell membranes, and minimal cyto-
systemic disease and a polymorphous nopathy, hepatosplenomegaly, systemic logical atypia. They frequently form small
infiltrate involving lymph nodes, with a symptoms, and polyclonal hypergam- clusters, often adjacent to HEVs. Vascu
prominent proliferation of high endo maglobulinaemia {1013,2181,2767,3674}. larity is often prominent, with arborization
thelial venules (HEVs) and follicular den Skin rash, often with pruritus, is frequent of HEVs in the paracortex. The neoplastic
dritic cells (FDCs). EBV-positive B cells ly present. Other common findings are cells are present in a polymorphous in
are nearly always present, and in some pleural effusion, arthritis, and ascites. flammatory background containing vari
cases constitute a significant part of the Laboratory findings include circulating able numbers of reactive lymphocytes,
cellular infiltrate. Recent studies using immune complexes, cold agglutinins histiocytes, plasma cells, and eosino
next-generation sequencing have identi with haemolytic anaemia, positive rheu phils. The cellular density varies, and in
fied recurrent mutations that help to unify
AITL with other T-cell neoplasms derived
from TFH cells. The disease is clinically
aggressive and seen mainly in older
adults.
Epidemiology
AITL occurs in middle-aged and elderly
individuals, with a higher incidence in
males than in females {901}. It is one of
the most common specific subtypes of
PTCL, accounting for 15―30% of non- Fig. 14.147 Histological patterns of angioimmunoblastic T-cell lymphoma (AITL). A Early involvement by AITL
characterized by bare, hyperplastic follicles with paracortical expansion and marked vascular proliferation
cutaneous T-cell lymphomas and 1―2%
associated with perifollicular or atypical lymphoid cells (pattern 1). B Case with depleted/atrophic follicles reminiscent
of all non―Hodgkin lymphomas {904, of Castleman disease and marked perifollicular expansion of clear cells (pattern 2). C Classic morphology with
3464,4217}. effacement of normal architecture and marked vascular proliferation associated with aggregates of atypical lymphoid
cells (pattern 3).
some cases there is amorphous intersti Variable numbers of B immunoblasts are linked to the functional properties of the
tial precipitate, producing a hypocellular usually present in the paracortex, which neoplastic TFH cells {1061}.
appearance. may be positive or negative for EBV by in
Three overlapping patterns are recog situ hybridization for EBV-encoded small Immunophenotype
nized {177}. In pattern 1, the neoplastic RNA (EBER). EBV―positive B cells are The neoplastic T cells express most
cells surround hyperplastic follicles with present in 80―95% of cases. They range pan-T―cell antigens (e.g. CD3, CD2, and
well―formed germinal centres, but often in size, and expansion of B immunob CD5) and in the vast majority of cases
lacking well―defined mantle cuffs {3328}. lasts may be prominent {4288,4470}. The are positive for CD4. Surface CD3 may
Pattern 1 is difficult to distinguish from EBV―positive B immunoblastic prolifera be reduced or absent by flow cytometry
reactive follicular hyperplasia, and immu- tion may progress, either composite with {679,3684}. Variable numbers of reactive
nohistochemical stains are necessary to AITL or at relapse, to EBV―positive dif CD8+ T cells are present. Characteristi
highlight the neoplastic T cells with their fuse large B―cell lymphoma {182,4470}. cally, the tumour cells show the immuno
characteristic TFH―cell phenotype. In EBV-positive Reed―Sternberg―like cells phenotype of normal TFH cells, express
pattern 2, remnants of follicles remain but of B―cell lineage may be present and ing CD10, CXCL13, ICOS, BCL6, and
show regressive changes. The neoplastic may simulate classic Hodgkin lymphoma PD1 (CD279) in 60―100% of cases {177,
cells are more readily identified in the ex {178,3265}. In rare cases, EBV―negative 905,1026,1470,3399}. This phenotype is
panded paracortex. In pattern 3, the ar Reed―Sternberg―like cells of B-cell line helpful in distinguishing AITL from atypi
chitecture is totally or subtotally effaced; age may be present {2868}. Plasma cells cal paracortical hyperplasia and other
remnants of regressed follicles may be may be very abundant, in rare cases PTCLs {1067,1469}, as well as in diag
seen in the outer cortex, displaced by obscuring the neoplastic T cells {238A, nosing extranodal dissemination {180,
the expanded paracortex. Progression 1736A}. The plasma cells are usually pol 284,2993}. None of these markers is TFH
from pattern 1 to pattern 3 in consecutive yclonal, but may be monoclonal in some cell―specific, and conversely, although
biopsies has been reported {3387}. cases. The expansion of normal B cells several TFH―cell markers can usually
In advanced cases, the inflammatory and plasma cells in the lesions has been be detected in the neoplastic cells, both
component may be diminished, and the
proportion of clear cells and large cells
may increase (so-called tumour cell-rich
AITL), which may simulate a PTCL, NOS.
In such cases, demonstration of a TFH-
cell immunophenotype and the presence
of expanded FDC meshworks are helpful
in diagnosis {178}. In some cases, there
may be a prominent infiltrate of reac
tive epithelioid histiocytes, mimicking a
granulomatous reaction and resembling
lymphoepithelioid lymphoma {34,178}.
The polymorphic infiltrate is frequently
associated with increased extrafollicular
FDC meshworks, which are most promi
nent around the HEVs. The neoplastic
cells are often arranged in clusters, sur Fig. 14.149 Angioimmunoblastic T-cell lymphoma, Fig. 14.150 Angioimmunoblastic T-cell lymphoma,
rounded by dendritic processes and pattern 1. CD10 staining highlights neoplastic T cells pattern 3, expressing PD1.
highlighted by CD21. surrounding the hyperplastic germinal centres.
Angioimmunoblastic T-cell lymphoma and other nodal lymphomas of TFH-cell origin 409
Fig. 14.151 Angioimmunoblastic T-cell lymphoma (AITL). A Multinucleated cells resembling Reed-Sternberg cells. B Low-power view of CD21 immunostaining highlighting
marked follicular dendritic cell proliferation entrapping high endothelial venules (pattern 3). C-E The characteristic phenotype of tumour cells expressing CD3 (C), CD10 (D), and
CXCL13 (E) (pattern 3). F EBV-positive B-cell proliferation in AITL double stained for CD79a (brown, cytoplasmic staining) and EBV-encoded small RNA (EBER) (blue, nuclear
staining).
the extent and the intensity of stain At the gene expression level, the mo in a Gly17Val-mutant, dominant-negative
ing are variable. An inverse correlation lecular profile of AITL is dominated by a variant of the enzyme {3485,4429}. Sev
tends to be observed between sensitiv strong microenvironment imprint, includ eral genes encoding components of the
ity and specificity of individual markers, ing overexpression of B―cell―related and T―cell receptor signalling pathway, such
with CXCL13 and CD10 being among FDC―related genes, chemokines and as FYN, PLCG1, and CD28, have been
the most specific and PD1 and ICOS chemokine receptors, and genes related found to be mutated in 5―10% of the cas
being more sensitive. B immunoblasts to extracellular matrix and vascular biol es {2254,2488}. Moreover, fusion genes
and plasma cells are polytypic; however, ogy. The signature contributed by the encoding a CTLA4―CD28 hybrid protein
secondary EBV―positive B―cell prolif neoplastic cells, although quantitatively consisting of the extracellular domain of
erations, including diffuse large B―cell minor, shows features of normal TFH CTLA4 and the cytoplasmic region of
lymphoma, classic Hodgkin lymphoma, cells {905,1010A}. CD28, likely capable of transforming in
and plasmacytoma, may be seen {182, By conventional cytogenetic analysis, hibitory signals into stimulatory signals for
901,3887}. FDC meshworks expressing clonal aberrations (most commonly triso- T―cell activation, have been identified in
CD21, CD23, and CD35 are expanded mies of chromosomes 3, 5, and 21; gain > 50% of AITLs, and other PTCLs as well
with an extrafollicular pattern, usually sur of X; and loss of 6q) have been reported {4428}. Rare cases carry t(5;9)(q33;q22),
rounding the HEVs. in as many as 90% of cases {1013,3558}. which results in ITK―SYK gene fusion, an
Comparative genetic hybridization has alteration initially recognized in associa
Postulated normal counterpart shown recurrent gains of 22q, 19, and tion with follicular PTCL {181,3814}.
A CD4+ TFH cell 11q13 and losses of 13q, whereas triso-
mies 3 and 5 were identified in only a Prognosis and predictive factors
Genetic profile small number of cases {3992}. The course of AITL is variable, but overall
TR genes show clonal rearrangements in Classic and more recently next―genera the prognosis is poor, with a median sur
75―90% of cases {179,901,3887}. Clonal tion sequencing studies have identified vival of < 3 years in most studies, even
IG gene rearrangements are found in frequent mutations of genes encoding when treated aggressively {2767,4217}.
about 25―30% of cases {179,3887} and epigenetic modifiers such as IDH2 (20- No well―defined prognostic factors have
correlate with expanded EBV―positive 30%), TET2 (50―80%), and DNMT3A been identified. The International Pro
B cells. Most EBV―infected B cells show (20―30%), as well as the small GT- gnostic Index (IPI) and Prognostic Index
ongoing mutation activity while carrying Pase RHOA (60―70%) {523,2264,2928, for T―cell Lymphoma (PIT) are of limited
hypermutated IG genes with destructive 3040,3485,4238,4429}. Among these, value {901}. Histological features and
mutations, suggesting that in AITL, alter IDH2 R172 mutations appear to be spe genetic findings have not been shown
native pathways operate to allow the sur cific for AITL, but the others can be seen to affect clinical course. In multivariate
vival of these mutating so-called ‘forbid in other PTCLs, in particular those with analysis, only male sex, mediastinal lym-
den’ (immunoglobulin―deficient) B cells. a TFH-cell—like immunophenotype. The phadenopathy, and anaemia adversely
hotspot RHOA mutation in AITL results affected overall survival {2767}.
Fig. 14.154 Follicular T-cell lymphoma, cytological features. The lymph node contains Fig. 14.155 Follicular T-cell lymphoma with a progressive transformation of germinal
an infiltrate of monotonous lymphoid cells with round nuclei and pale, so-called centres (PTGC)-like growth pattern showing nodules with nests of neoplastic cells
*monocytoid+ cytoplasm. reminiscent of follicle centre B cells in PTGCs.
Angioimmunoblastic T-cell lymphoma and other nodal lymphomas of TFH-cell origin 411
Fig. 14.156 Follicular T-cell lymphoma with a progres Fig. 14.157 Follicular T-cell lymphoma with a follicular Fig. 14.158 Follicular T-cell lymphoma with a
sive transformation of germinal centres-like growth pat lymphoma-like growth pattern. The neoplastic cells progressive transformation of germinal centres-like
tern. CD3 staining highlights nests of neoplastic T cells express PD1. growth pattern. IgD staining highlights mantle zone
surrounded by mantle zone B cells. B cells surrounding the nests of neoplastic T cells.
In a limited number of cases in which Genetic profile CD4, PD1, CD10, BCL6, CXCL13, and
consecutive biopsies from different time FTCLs show clonal TR gene rearrange ICOS) and some pathological features
points were studied, change of morphol ments in most cases. About 20% of cas of angioimmunoblastic T―cell lymphoma
ogy from FTCL to typical AITL or vice es carry a t(5;9)(q33;q22) translocation, (AITL). The minimum criteria for assign
versa has been observed, suggesting leading to ITK―SYK fusion {1729,3814}. ment of TFH―cell phenotype is not very
that these two entities may constitute dif This translocation appears to be specific well established, but the detection of at
ferent morphological representations of for FTCL; it has not been seen in other least two (ideally three) of the TFH―cell
the same biological process {1729}. peripheral T―cell lymphomas, except in markers in addition to CD4 is suggest
a rare case of AITL {181}. Comprehen ed to assign a TFH―cell phenotype to
Immunophenotype sive genomic profiling of FTCL cases a nodal CD4+ T―cell lymphoma. These
The neoplastic T cells express the pan- has not been specifically performed, but neoplasms frequently show a diffuse
T-cell antigens CD2, CD3, and CD5 (with it is likely that some cases of peripheral infiltration pattern without a prominent
frequent loss of CD7) and have a CD4+ T―cell lymphoma with TFH-cell—like im polymorphic inflammatory background,
T helper (Th) cell phenotype. Consist munophenotype showing mutations of vascular proliferation, or expansion of fol
ent with a TFH―cell origin, multiple TFH- TET2, RHOA, and DNMT3A are FTCLs licular dendritic cell meshworks. In some
cell markers (e.g. PD1, CXCL13, BCL6, {2264}. cases, a so―called T―zone pattern may
CD10, and ICOS) are expressed {1729}. be evident {34}. Genetic studies show
Like in AITL, interfollicular CD20+ B im- Prognosis and predictive factors that these cases share some of the ge
munoblasts, often with EBV reactivity, are The clinical course is not well character netic alterations seen in AITL, including
present in half of the cases. When Hodg- ized, due to the rarity of the lesion and mutations of TET2, DNMT3A, and RHOA
kin/Reed―Sternberg―like large cells the retrospective nature of most studies. {2264,3485}. These phenotypic and ge
are present, they may show phenotypic The disease appears to have an aggres netic characteristics suggest that such
features of classic Hodgkin lymphoma, sive course, with half of the patients dying cases may be related to AITL and may
expressing CD30, CD15, PAX5 (weakly), within 24 months of diagnosis {1729}. constitute a tumour cell―rich variant of
and frequently EBV, but lacking other B- AITL {178}. However, until further evi
cell markers {2868}. Such cells should dence showing that they are biologically
not be diagnosed as classic Hodgkin Nodal peripheral T―cell and clinically within the spectrum of AITL,
lymphoma in the absence of a typical lymphoma with T follicular it is recommended that such cases are
classic Hodgkin lymphoma background. classified as peripheral T―cell lymphoma
helper phenotype
CD21, CD23, and CD35 staining often with a TFH―cell phenotype.
reveals a retained follicular dendritic Definition
cell meshwork structure underlying the It has been recognized that a subset of ICD-O code 9702/3
follicular lymphoma―like or progressive the peripheral T―cell lymphomas clas
transformation of germinal centres―like sified as NOS have a T follicular helper
nodular growth pattern. (TFH) cell phenotype (i.e. positive for
Definition
ALK―positive (ALK+) anaplastic large
cell lymphoma (ALCL) is a T―cell lym
phoma consisting of lymphoid cells
that are usually large and have abun
dant cytoplasm and pleomorphic, often
horseshoe―shaped nuclei, with a chro
mosomal translocation involving the ALK
gene and expression of ALK protein
and CD30. ALCL with comparable mor
phological and phenotypic features, but
lacking ALK rearrangement and the ALK
protein, is considered to be a separate
category: ALK―negative (ALK―) ALCL.
ALK+ ALCL must also be distinguished
from primary cutaneous ALCL and from
other subtypes of T-cell or B-cell lympho
ma with anaplastic features and/or CD30
expression. A few cases of indolent ALK+ ALCL re (75%) have B symptoms, especially
stricted to the skin have been reported high fever {475,1151}. Rare cases of skin
ICD-O code 9714/3 {2996}. Clinical history and staging are and satellite lymph node involvement by
required to distinguish such lesions from ALK+ ALCL following insect bites have
Synonym the aggressive, poor―prognosis second been reported {2200}. The significance
Ki―1 lymphoma (obsolete) ary cutaneous involvement by systemic remains unclear. Possibly, ALK+ ALCL
ALK+ ALCL. cells home to these sites of inflammation.
Epidemiology
ALK+ ALCL accounts for approximately Clinical features Microscopy
3% of adult non―Hodgkin lymphomas Most patients (70%) present with ad ALK+ ALCLs show a broad morphologi
and 10―20% of childhood lymphomas vanced (stage III—IV) disease with pe cal spectrum {335,643,949,1138,2031,
{3782}. ALK+ ALCL is most frequent in ripheral and/or abdominal lymphadeno- 3181}. However, all cases contain a vari
the first three decades of life {335,1151} pathy, often associated with extranodal able proportion of cells with eccentric,
and shows a male predominance, with a infiltrates and involvement of the bone horseshoe―shaped, or kidney―shaped
male―to―female ratio of 1.5:1. marrow {475,1151,1543}. Most patients nuclei, often with an eosinophilic region
Localization
ALK+ ALCL frequently involves both
lymph nodes and extranodal sites. The
most commonly involved extranodal
sites include the skin, bone, soft tissue,
lungs, and liver {475,1151,1543,3782}.
Involvement of the gut or CNS is rare.
Mediastinal disease is less frequent than
in classic Hodgkin lymphoma. The esti
mated incidence of bone marrow involve
ment is approximately 10% when inves
tigated using H&E staining, but higher
(30%) when immunohistochemical stains
are used {1239}, because bone marrow
involvement is often subtle. The small
cell variant of ALK+ ALCL may have a
leukaemic presentation with peripheral Fig. 14.160 Anaplastic large cell lymphoma (ALCL), ALK-positive. General features of ALCL, common type. The
blood involvement {301,2031,3752}. lymph node architecture is obliterated by malignant cells, and intrasinusoidal cells are observed.
Immunophenotype
The tumour cells are positive for CD30 on
Fig. 14.162 Anaplastic large cell lymphoma, lymphohistiocytic pattern. A Large cells (hallmark cells) are admixed the cell membrane and in the Golgi re
with a predominant population of non-neoplastic cells, including histiocytes and plasma cells. B Malignant cells are gion {3787}. The strongest immunostain
highlighted by CD30 staining. ing is seen in the large cells. Smaller
Fig. 14.166 Anaplastic large cell lymphoma, ALK-positive. Different ALK staining patterns. A Nuclear, nucleolar, and cytoplasmic staining associated with the t(2;5) translocation
(expression of the NPM1-ALK fusion protein). B Strong membranous and cytoplasmic staining sparing the nucleus in a case associated with the t(1;2) translocation (expression
of the TPM3-ALK fusion protein). C Finely granular cytoplasmic staining associated with the t(2;17) translocation (expression of the CLTC-ALK fusion protein).
{1138}, inflammatory myofibroblastic tu clonal rearrangement of the TR genes 4059,4339}. FISH using an ALK break-
mours {1459}, and neural tumours {2512}, irrespective of whether they express apart probe or karyotyping is not manda
can be positive for ALK but are morpho T―cell antigens. The remainder show no tory in routine practice if ALK staining is
logically distinguishable from ALCL and rearrangement of TR or IG genes {1237}. positive {1138,3201}. RT-PCR is usually
are negative for CD30. ALK+ ALCL must reserved for detection of minimal residual
also be distinguished from a rare form of Cytogenetic abnormalities and disease in blood or bone marrow {865}.
ALK+ systemic histiocytosis occurring in oncogenes All of these translocations result in upreg-
early infancy {646}. ALK+ histiocytosis is The genes fused with ALK in various chro ulation and aberrant expression of ALK,
characterized by a proliferation of large mosomal translocations and the subcel- but the subcellular distribution of ALK
histiocytes that look morphologically lular distribution of NPM1―ALK and ALK staining varies depending on the translo
different from ALCL cells, are CD30- variant chimeric proteins are shown in Ta cation partner {1147}.
negative, and express the CD68 antigen ble 14.10. The most frequent genetic al The ALK gene encodes a tyrosine kinase
{646}. teration is a translocation, t(2;5)(p23;q35), receptor belonging to the insulin recep
between the ALK gene on chromosome 2 tor superfamily, which is normally silent
Postulated normal counterpart and the NPM1 gene on chromosome 5 in lymphoid cells {2753}. In the t(2;5)
An activated mature cytotoxic T cell {2199,2541,2753}. Variant translocations (p23;q35) translocation, NPM1 (a house
involving ALK and other partner genes on keeping gene encoding a nucleolar pro
Genetic profile chromosomes 1, 2, 3, 17, 19, 22, and X tein) fuses with ALK to produce a chimer
Antigen receptor genes also occur {801,1152,1177,1623,2195, ic protein in which the N-terminal portion
Approximately 90% of ALK+ ALCLs show 2197,2542,2608,3410,3782,4033,4037, of NPM1 is linked to the intracytoplasmic
Fig. 14.167 Anaplastic large cell lymphoma showing Fig. 14.168 A Hypocellular anaplastic large cell lymphoma. B Malignant cells are highlighted by ALK staining.
sarcomatous features.
Differential diagnosis
The principal differential diagnosis of
ALK― ALCL is with PTCL, NOS, and
CHL. Most cases referred to historically
as Hodgkin―like ALCL are now consid
ered to be tumour cell―rich forms of
CHL. With complete immunophenotypic
Fig. 14.173 Anaplastic large cell lymphoma, ALK-negative, with DUSP22 rearrangement. A Densely packed
monomorphic large cells. B Strong, uniform staining for CD30.
and genetic studies, ALK― ALCL can
be distinguished from CHL in virtually
These markers tend to be absent in cases should raise suspicion for CHL. How all cases. In contrast, the distinction be
bearing DUSP22 rearrangements {3069}; ever, CD15 may be expressed in some tween PTCL, NOS, and ALK― ALCL is
therefore, although desirable, their ex cases of PTCL, NOS, and such cases are not always clear―cut, and even experts
pression is not an absolute requirement generally strongly CD30―positive {277}. may disagree on this subject. In gen
for the diagnosis of ALK― ALCL. About Whether peripheral T-cell neoplasms ex eral, the WHO classification advocates
43% of cases are positive for EMA, on pressing both CD30 and CD15 should a conservative approach, recommend
at least a proportion of malignant cells, be classified as ALK― ALCL or PTCL, ing the diagnosis of ALK― ALCL only if
a marker that is almost always seen in NOS, remains to be determined. Notably, both the morphology and phenotype
ALK+ ALCL but only occasionally in these cases have a very poor prognosis, are very close to those of ALK+ cases,
PTCL, NOS {3536}. Nuclear phospho- clinically more closely resembling PTCL, with the only distinction being the pres
STAT3 is expressed in about 43% of NOS. ALK― ALCLs are consistently neg ence or absence of ALK. ALK― ALCL
cases {836}. ative for EBV, i.e. for EBV-encoded small must also be distinguished from primary
In cases that lack all T―cell/cytotoxic RNA (EBER) and LMP1, and the expres C―ALCL, which can have a similar phe
markers, CHL rich in neoplastic cells and sion of these markers should strongly notype and morphology. Clinical correla
other large cell malignancies (e.g. em suggest the possibility of CHL. tion with staging is of paramount impor
bryonal carcinoma) should be ruled out. ALK― ALCL and ALK+ ALCL lack T-cell tance in this differential. Primary C―ALCL
In this regard, staining for PAX5 is useful, receptor proteins, and in this respect has a much better prognosis than does
because CHL reveals weak expression of tend to differ from PTCL, NOS {413,1322}. ALK― ALCL.
PAX5 in most cases; however, rare cases Clusterin is also commonly expressed in
of ALCL (ALK― or ALK+) may express both ALK― and ALK+ ALCL, but rarely in Postulated normal counterpart
PAX5 {1175}. The demonstration of CD15 PTCL, NOS {2183,2830,3470}; this mark An activated mature cytotoxic T cell
Genetic profile
Most cases show clonal rearrangement of
the TR genes, whether or not they express
T―cell antigens.
A constellation of genetic findings, nota
bly recurrent activating mutations of JAK1
and/or STAT3, has been shown to lead to
constitutive activation of the JAK/STAT3
pathway in ALK― ALCL {836}. Translo
cations involving tyrosine kinase genes
other than ALK also lead to STAT3 activa
tion in a small subset of systemic and cu
taneous ALK― ALCLs {836,4171}. These
genetic events in ALK― ALCL partially
explain the biological and pathological
similarities to ALK+ ALCL, in which ALK
fusion proteins lead to constitutive STAT3
activation {710}, and may have therapeu
tic implications.
DUSP22 rearrangements, i.e. chromo
somal rearrangements in or near the
DUSP22―IRF4 locus on 6p25.3, occur in
Fig. 14.174 Anaplastic large cell lymphoma, ALK-negative. A Some of the features raise a differential diagnosis
with PTCL, NOS, expressing CD30, such as absence of hallmark cells. B CD30 is strongly expressed in all tumour about 30% of cases {3069}. These are
cells. C Lymphoma cells express CD3. Note a vessel surrounded by normal, small CD3+ T cells. D Tumour cells associated with decreased expression of
express CD4. the DUSP22 dual-specificity phosphatase
Definition studies have not identified an increased lymphoma diagnosis is 10.9 years, but
This provisional entity is a T-cell lympho risk of lymphoma in women with breast the interval varies greatly. No association
ma with morphological and immunophe- implants {895,2220,2358,2672}. with the type of implant (silicone vs saline,
notypic features indistinguishable from textured vs smooth) or with breast cancer
those of ALK―negative anaplastic large Localization history has been established.
cell lymphoma (ALCL), arising primarily The tumour cells may be localized to the
in association with a breast implant. seroma cavity or may involve the peri- Microscopy
capsular fibrous tissue, sometimes form The tumour cells may be identified initial
ICD-O code 9715/3 ing a mass. Locoregional lymph nodes ly in cytology specimens from aspirated
may be involved. effusion fluid. At capsulectomy, the tu
Synonym mour cells often line the capsule and may
Seroma―associated anaplastic large cell Clinical features show varying degrees of capsular infiltra
lymphoma The mean patient age is 50 years {2235, tion. In some cases, they extend beyond
2672,3382}. Most patients present with the capsule to form a mass, which may
Epidemiology stage I disease, usually with a peri-implant be palpable in the specimen at the time
Breast implant―associated ALCL is very effusion and less frequently with a mass. of gross evaluation {51}. The tumour cells
rare, with an estimated incidence of As many as 29% of patients have axillary are typically large and pleomorphic, and
1 case per 500 000 to 3 million women lymphadenopathy, but not all biopsied the so-called hallmark cells seen in other
with implants {461}. Although a possible nodes are positive for tumour. Rare cases forms of ALCL can usually be identified.
etiological relationship between implants present with disseminated disease. The
and ALCL has been suggested, large mean interval from implant placement to
Fig. 14.176 Breast implant-associated anaplastic large cell lymphoma. A The tumour cells have pleomorphic nuclear features. This case had invasion of the capsule and
underlying breast, shown in B and C. B Some tumours may show invasion of the breast, which is associated with a more aggressive clinical course. C Neoplastic cells with
strong staining for CD30 surround a duct in the breast.
EBV―positive {125,276,1190,2276,4277, have localized disease (stage I or II). Mediastinal involvement is most frequent
4278}. However, there are differences Approximately 60% of patients, most with ly seen in the nodular sclerosis subtype,
between urban and rural areas. For ex NSCHL, have mediastinal involvement. whereas abdominal involvement and
ample, NSCHL is more common in urban Splenic involvement is common (20%) splenic involvement are more common in
areas, whereas EBV―positive MCCHL is and is associated with an increased risk mixed cellularity cases. B symptoms con
more common in rural regions {1092}. of extranodal dissemination. Bone mar sisting of fever, drenching night sweats,
Delayed exposure to childhood infec row involvement is much less common and significant body weight loss are
tions has been postulated to play a role (5%). Because the bone marrow lacks present in as many as 40% of patients.
{1383}. It is possible that EBV infection of lymphatics, bone marrow infiltration in Most patients with NLPHL are asympto
a B cell replaces one of the genetic al dicates vascular dissemination of the matic and present with enlargement of
terations necessary for the development disease (stage IV). The anatomical dis peripheral lymph nodes; B symptoms are
of CHL. NLPHL is only rarely positive for tribution varies between the histological rare.
EBV (< 5% of cases) {1736}. subtypes of CHL {3654}. NLPHL tends
to spare axial lymph node groups, and Macroscopy
Localization is more common in peripheral lymph Lymph nodes are enlarged and encap
CHL most often involves lymph nodes of nodes. The mediastinum is uncommon sulated, and show a fish―flesh tumour on
the cervical region (75% of cases), fol ly involved, but mesenteric lymph node cut section. In NSCHL, there is prominent
lowed by the mediastinal, axillary, and involvement may be seen. nodularity, dense fibrotic bands, and a
para―aortic regions. Non―axial lymph thickened capsule. Splenic involvement
node groups, such as mesenteric and Clinical features usually shows scattered nodules within
epitrochlear lymph nodes, are rarely Patients with CHL usually present with the white pulp. Very large masses are
involved. Primary extranodal involve peripheral lymphadenopathy, localized sometime seen; these can demonstrate
ment is rare. More than 60% of patients to one or two lymph node―bearing areas. fibrous bands in the nodular sclerosis
Fig. 15.04 Age distribution of classic Hodgkin lymphoma (CHL) subtypes. Individuals with a history of infectious Fig. 15.05 Hodgkin lymphoma. This classic Reed-
mononucleosis have a higher risk for the development of CHL. LDCHL, lymphocyte-depleted CHL; LRCHL, Sternberg cell is binucleated, with prominent eosinophilic
lymphocyte-rich CHL; MCCHL, mixed cellularity CHL; NSCHL, nodular sclerosis CHL. nucleoli, producing the so-called owl’s eye appearance.
From: Mueller NE and Grufferman S {2777}.
Immunophenotype
The HRS cells of CHL are positive for
CD30 in nearly all cases {3590,3783,
3787} and for CD15 {1716,3787,3788}
in the majority (75―85%). They are usu
ally negative for CD45 and are consist
ently negative for J chain, CD75, and
macrophage―specific markers such as
the PGM1 epitope of the CD68 molecule
{724,1143} (Table 15.01). Both CD30 and
CD15 are typically present in a mem
brane pattern, with accentuation in the
Golgi area of the cytoplasm; CD15 may
subtype. CHL in the thymus can be as with a rich inflammatory background. be expressed by only a minority of the
sociated with cystic degeneration and Classic diagnostic Reed―Sternberg neoplastic cells and may be restricted
epithelial hyperplasia {2349}. Rare cases cells are large, have abundant slightly to the Golgi region. In 30―40% of cases,
can be confined to the thymus. basophilic cytoplasm, and have at least CD20 may be detectable but is usually
two nuclear lobes or nuclei. The nuclei of varied intensity and usually present
Microscopy are large and often rounded in contour, only on a minority of the neoplastic cells
In CHL, the lymph node architecture is with a prominent, often irregular, nuclear {3565,4504}. The B―cell―associated an
effaced by variable numbers of Hodgkin/ membrane; pale chromatin; and usually tigen CD79a is less often expressed.
Reed―Sternberg (HRS) cells admixed one prominent eosinophilic nucleolus, The B―cell nature of HRS cells is further
demonstrable in approximately 95% of ment in the HRS cells, so that the expres The LP cells are positive for CD20,
cases by their expression of the B―cell- sion of T―cell antigens is either aberrant CD79a, PAX5, OCT2, and BOB1. EMA
specific activator protein PAX5 (also or artefactual {3614,4176}. Expression of is sometimes positive, but often only in a
called BSAP) {1238}. The immunostain- EMA is rare and usually weak if present. fraction of the LP cells. IgD (but not IgM)
ing of HRS cells for PAX5 is usually A further characteristic finding is the ab is expressed in LP cells in a subset of
weaker than that of reactive B cells, a sence of the transcription factor OCT2 cases, most commonly in young males
feature that makes the PAX5+ HRS cells (also known as POU2F2) in up to 90% of {3231}. However, stains for immuno
easily identifiable. The transcription fac cases in some reports and the absence globulin light chains are generally nega
tor IRF4/MUM1 is consistently positive in of its coactivator BOB1 (also known as tive. CD30 may be weakly expressed in
HRS cells, usually at high intensity. In one POU2AF1) in the same proportion {2379}. some cases, but CD15 is nearly always
study, PRDM1 (also known as BLIMP1), The transcription factor PU1 is consist negative.
the key regulator of plasma cell differ ently absent from HRS cells {2379,4027}.
entiation, was expressed in only a small Most HRS cells express the proliferation- Cytokines and chemokines
proportion of HRS cells in 25% of CHLs associated nuclear antigen Ki―67 {1332}. CHL is associated with overexpression
{492}. The plasma cell―associated ad CHL cases rich in neoplastic cells may and an abnormal pattern of cytokines
hesion molecule CD138 is consistently resemble anaplastic large cell lymphoma and chemokines and/or their receptors
absent {492}. EBV-infected HRS cells ex (ALCL), a T―cell neoplasm. Their identi in HRS cells {1613,1751,1897,1899,1937,
press LMP1 and EBNA1 without EBNA2, fication as CHL is facilitated by demon 4120}, which likely explains the abundant
a pattern characteristic of type II EBV strating positivity for PAX5 and absence admixture of inflammatory cells {1876,
latency {950}. EBV―encoded LMP1 has of EMA and ALK protein {1238,3782}. The 3944}, the fibrosis {1897}, and the pre
strong transforming and antiapoptotic detection of EBV―encoded small RNA dominance of T helper 2 (Th2) cells in the
potential. (EBER) or LMP1 favours CHL over ALCL infiltrating T―cell population {4120}.
Membranous and less often globular cy {1731}. The most difficult differential di
toplasmic expression of one or more T- agnosis is with diffuse large B―cell lym Postulated normal counterpart
cell antigens by a minority of HRS cells phoma displaying anaplastic morphology Classic Hodgkin lymphoma (CHL)
may be encountered in some cases and expressing CD30. There may be The cellular origin of HRS was unknown
{862,4176}. However, this is often difficult a true biological overlap between such for many years, because the cells lack
to assess because of the T cells that usu cases and CHL, especially in cases with the morphology and immunophenotype
ally surround the HRS cells. Most T-cell mediastinal disease. of any normal counterpart. However,
antigen―positive CHL cases have both Unlike CHL, NLPHL generally shows IG gene rearrangement studies have
PAX5 expression and IG gene rearrange preservation of the B―cell programme. provided convincing evidence that HRS
Fig. 15.07 Classic Hodgkin lymphoma. A The immunostaining for PAX5 labels the nuclei of the Hodgkin/Reed-Sternberg (HRS) cells weakly and those of the non-neoplastic by
stander B cells strongly. B Immunostaining for BOB1 (the coactivator of the octamer-binding transcription factors OCT1 and 0CT2) fails to stain the HRS cells in most instances.
This is in contrast to the non-neoplastic bystander B cells and plasma cells, which show a moderately strong to strong labelling of their nuclei and in part of their cytoplasm. C Im
munostaining for the octamer-binding transcription factor OCT2 is negative in the HRS cells, whereas the non-neoplastic bystander B cells show a nuclear positivity.
cells are clonal and derived from germi also showed that LP cells are clonal ex CHL
nal centre B cells despite the frequent ab pansions of B cells with genotypic fea HRS cells contain clonal immunoglobulin
sence of B-cell markers other than PAX5. tures of GCBs, indicating that LP cells gene rearrangements in more than 98%
Thus, HRS cells are one of the most ex constitute a neoplasm of this B-cell type. of cases. The rearranged IGHV genes
treme examples of discordance between harbour a high load of somatic hyper
genotype and phenotype {1934,2495}. Genetic profile mutations in the variable (V) region, usu
The HRS cells of rare CHL cases have Antigen receptor genes ally without signs of ongoing mutations.
been reported to harbour clonally re Rearrangement studies of antigen recep However, the B―cell program is down-
arranged TR genes, indicating that ex tor genes of LP or HRS cells usually pro regulated in CHL, and HRS cells do not
ceptional cases with morphological fea vide only reliable results for these cells express immunoglobulin transcripts.
tures of CHL may be derived from T cells when DNA of isolated single LP and HRS Experimental data from several studies
{2798,3614}. Because the neoplastic cells is investigated and not whole tissue partially explain this defect. In approxi
cells in some cases of peripheral T―cell DNA. mately 25% of cases of CHL nonsense
lymphoma can have an appearance mutations in the V region genes were
similar to that of HRS cells, the differen NLPHL identified, which were proposed to result
tial diagnosis is challenging. Addition In all cases LP cells harbour a clonal im in the failure of Ig secretion {1934}. A ma
ally, some peripheral T―cell lymphomas munoglobulin gene rearrangement with a jor contributory factor is the absent or de
express CD30 and CD15, making their high load of somatic mutations and signs creased expression in most cases of CHL
distinction from CHL even more difficult of ongoing mutations in the variable (V) of the transcription factors (OCT2, BOB1)
{277}. region. The rearrangements are usually that regulate Ig expression {3785}. Final
functional and IG mRNA transcripts are ly, there is evidence of hypermethylation
Nodular lymphocyte predominant detectable in the LP cells. Consistent of multiple genes and pathways in CHL,
Hodgkin lymphoma (NLPHL) with this finding, the transcription factor which may further contribute to the dam
Due to their expression of B-cell markers, OCT2 and its coactivator BOB1, which age to the B―cell programme {2180A}.
LP cells were more readily identified as are dominantly involved in the regulation These findings, in conjunction with the
B―cell derived {783,3192,3193}, and this of the expression of IG mRNA, are con study of composite lymphomas consist
origin was confirmed by rearrangement sistently expressed {3785}. ing of CHL and follicular non―Hodgkin
studies of the IGH gene. These studies lymphoma, support the assumption that
Fig. 15.09 Classic Hodgkin lymphoma. A EBV-infected Hodgkin/Reed-Sternberg cells strongly express the EBV-encoded latent membrane protein LMP1. B EBV-infected
Hodgkin/Reed-Sternberg cells consistently show a strong expression of EBV-encoded small RNA (EBER) in their nuclei as revealed by non-radioactive in situ hybridization.
Epidemiology
NLPHL accounts for approximately 10%
of all Hodgkin lymphoma {2230A}. Pa
tients are predominantly male and most
are aged 30―50 years.
Localization
NLPHL usually involves cervical, axillary,
or inguinal lymph nodes. Mediastinal
involvement is rare. Mesenteric lymph
node involvement can be seen, unlike in
classic Hodgkin lymphoma (CHL). Pa
tients with advanced disease may have
involvement of the spleen and bone mar
row. Rare cases may have destructive le
sions involving bone.
Fig. 15.11 Nodular lymphocyte predominant Hodgkin lymphoma. A The nodules, which are usually larger than those
in follicular lymphoma and follicular hyperplasia, lack mantle zones. B Three lymphocyte predominant (LP) cells
Clinical features (arrows), also called popcorn cells, with the typically lobed nuclei, are visible in a background of small lymphoid
Most patients present with localized pe cells and a few histiocytes. C CD20 staining reveals that the nodules consist predominantly of B cells. D At higher
ripheral lymphadenopathy (stage I or II). magnification, the strong membrane staining of the LP cells for CD20 is apparent.
cells favour primary THRLBCL. Strongly are similar to the cells of THRLBCL and
stained LP cells in association with weak CHL {477}. They show partial loss of their
ly stained B cells are best identified by B―cell phenotype, and deregulation of
OCT2 or PAX5 immunostaining. many apoptosis regulators and putative
oncogenes. The only investigations that
Postulated normal counterpart point to distinct pathogeneses of NLPHL
A germinal centre B cell at the centro- and primary THRLBCL are two com
blastic stage of differentiation parative genomic hybridization studies
in which more and different genomic ab
Genetic profile errations were identified in NLPHL than
LP cells harbour clonally rearranged IG in THRLBCL {1246,1247}. Such different
(IGHV) genes {2493,2947}. The clonal genetic patterns were not found in the
rearrangements are usually not detect gene expression profiling study of micro-
able in whole―tissue DNA but only in the dissected tumour cells of typical cases
DNA of isolated single LP cells. The IGHV of NLPHL and THRLBCL {1570,1571}.
genes carry a high load of somatic muta These studies revealed, in addition to
tions, and also show signs of ongoing mu a common expression of BCL6, CD75,
tations. The rearrangements are usually EMA, J chain, and PU1, an identical ex
functional, and IG mRNA transcripts are pression of BAG6 (also called BATS),
detectable in the LP cells of most cases HIGD1A, and UBD (also called FAT10)
{2493}. EBV infection detected by EBV- in the tumour cells of cases with a nodu
encoded small RNA (EBER) may be found lar, a nodular and diffuse, and a diffuse
in the LP cells in 3―5% of cases in both growth in NLPHL and primary THRLBCL,
children and adults {1736}. EBV positivity suggesting the possibility that THRLBCL
might be higher in Asia {653}. EBV may may represent a variant or extension of
also be present in bystander lymphocytes NLPHL. This speculation is supported
{91}. BCL6 rearrangements (involving IG by the observation that NLPHL can show Fig. 15.17 Immunoarchitectural patterns in nodular
genes, IKAROS family genes, ABR, and a THRLBCL―like transformation, which lymphocyte predominant Hodgkin lymphoma {1159}.
other partner genes) are present in about is indistinguishable from primary THR In this schematic illustration, the X’s represent lym
phocyte predominant (LP) cells, the grey background
half of NLPHLs {174,3343,4341}. Aber LBCL. It is likely that the distinction be
a B-cell-rich background, and the white background
rant somatic hypermutations were found tween NLPHL and THRLBCL does not a T-cell—rich background. Pattern A So-called clas
in 80% of NLPHL cases, most frequently lie in different genomic alterations and sic B-cell-rich nodular pattern. Pattern B Serpiginous
in PAX5, but also in PIM1, RHOH (also the immunophenotype of the tumour nodular pattern. Pattern C Nodular pattern with many
called TTF), and MYC {2359}. Mutations cells, but rather in the different cellular extranodular LP cells (formerly called L&H cells). Pat
of SGK1, DUSP2, and JUNB are also re composition of the microenvironment as tern D T-cell—rich nodular pattern. Pattern E Diffuse,
ported in about half of NLPHLs {1575}. described above. T-cell—rich (TCRBCL-like) pattern. Pattern F (Diffuse),
moth-eaten (B-cell-rich) pattern.
DLBCL, diffuse large B-cell lymphoma; TCRBCL,
Relationship between NLPHL and Genetic susceptibility T-cell/histiocyte-rich large B-cell lymphoma.
THRLBCL An increased familial risk of NLPHL has From: Fan Z, Natkunam Y, Bair E, Tibshirani R, Warnke
LP cells by gene expression profiling been noted in some families {3466}. RA. Am J Surg Pathol (2003) {1159}.
However, the specific genetic factors Prognosis and predictive factors tion of the affected lymph node {3125}.
have not been identified. NLPHL has also NLPHL in its nodular and its nodular Histopathological variants characterized
been identified in patients with Herman- and diffuse forms develops slowly, with by LP cells outside B-cell nodules, B-cell
sky―Pudlak syndrome type 2 {2391}. fairly frequent relapses. It usually re depletion of the microenvironment, or
The affected patients in that study ex mains responsive to therapy and thus is THRLBCL―like transformation (patterns
hibited NK―cell and T―cell defects. An rarely fatal. The prognosis of patients with C, D, E and F as described by Fan et al.,
increased risk is also seen in patients stage I or II disease is very good, with a Figure 15.17) are associated more often
with autoimmune lymphoproliferative 10―year overall survival rate > 80% {980, with advanced disease and a higher
syndrome with mutations in FAS {3810}, 2888}. It is not yet clear whether immedi relapse rate compared with that of typi
which may also be linked to defective ate therapy is necessary to achieve this cal NLPHL {1572}. Therefore, it is use
immune surveillance. favourable prognosis; in some countries ful to note these variant features in the
(e.g. France), stage I disease (especially diagnostic report. Clinically recognized
in children) is not treated after the resec- advanced stages have an unfavourable
prognosis {980}. Progression to diffuse
large B―cell lymphoma has been re
ported in approximately 3―5% of cases
{723,1538,2660}. The neoplastic cells in
such cases may resemble LP cells or
may have centroblastic or immunoblastic
features. However, they keep their typi
cal immunophenotype (strong coexpres
sion of CD20, OCT2, and CD75). In some
cases, diffuse large B―cell lymphoma
was found to precede NLPHL {1159}.
The large B―cell lymphomas associated
Fig. 15.19 Nodular lymphocyte predominant Hodgkin lymphoma. A Immunostaining for the transcription factor
OCT2, which is involved in the regulation of immunoglobulin expression, produces strong nuclear staining of the
with NLPHL, if localized, generally have a
lymphocyte predominant (LP) cells (also called popcorn cells), and weaker labelling of the bystander B cells; thus, good prognosis {1538}. A clonal relation
OCT2 often highlights the presence and the nuclear atypia of LP cells. B Higher magnification. ship between NLPHL and the associated
diffuse large B―cell lymphoma has been
demonstrated {1452,1575,4310}. Bone
marrow involvement is rare in NLPHL
and raises the possibility of THRLBCL, or
THRLBCL―like transformation, in particu
lar if the characteristic microenvironment
is absent. Cases of NLPHL with bone
marrow involvement are clinically aggres
sive {2003}. Advanced―stage NLPHL
responds poorly to the chemotherapy
regimens traditionally used for CHL, but
responds better to the CHOP chemother
Fig. 15.20 Hodgkin lymphoma (HD)-specific survivals associated with the nodular lymphocyte predominant (LP),
apy regimen plus rituximab (R-CHOP), or
nodular sclerosis (NS), and mixed cellularity (MC) subtypes of classic Hodgkin lymphoma. A Failure-free survival regimens used for aggressive B-cell lym
(FFS). B Overall survival (SV). German Hodgkin Study Group (GHSG) phomas {4387}.
ICD-O code
Classic Hodgkin lymphoma 9650/3
Fig. 15.21 Nodular sclerosis classic Hodgkin lymphoma. A CT shows a large anterior mediastinal mass. B Chest
X-ray of the same patient shows a mediastinal mass exceeding one third of the chest diameter.
Fig. 15.24 Thymic cyst arising with thymic involvement Fig. 15.25 Nodular sderosis classic Hodgkin Fig. 15.26 Nodular sclerosis classic Hodgkin
by Hodgkin lymphoma. Cystic degeneration of the lymphoma, grade 2. Capsular fibrosis is present. Central lymphoma, grade 2. Lacunar Hodgkin/Reed-Sternberg
thymus gland is common with involvement by nodular areas of necrosis are noted in the nodular infiltrate. cells palisade around central necrotic area containing
sclerosis classic Hodgkin lymphoma. numerous neutrophils.
Fig. 15.27 Nodular sclerosis classic Hodgkin lymphoma Fig. 15.28 Nodular sclerosis classic Hodgkin lymphoma. Fig. 15.29 Nodular sclerosis classic Hodgkin
with aberrant CD3. The neoplastic cells are positive for This case had aberrant expression of CD2, a finding lymphoma. Lacunar cells show artificial retraction of the
CD3. Expression of PAX5 (not shown) and negative usually seen in grade 2 disease. In this case, the CD2 cytoplasm upon fixation. The nucleoli are often smaller
studies for TR gene rearrangement helped to confirm antigen appears to be partially expressed on the outer than those seen in classic Reed-Sternberg cells.
the diagnosis. surface of the cell membrane, suggestive of adsorption.
Definition
Lymphocyte―rich classic Hodgkin lym
phoma (LRCHL) is a subtype of classic
Hodgkin lymphoma (CHL) characterized
by scattered Hodgkin/Reed―Sternberg
(HRS) cells and a nodular or (less often)
diffuse cellular background consisting of
small lymphocytes, with an absence of
neutrophils and eosinophils.
Synonyms
Hodgkin disease, lymphocytic―histio
cytic predominance (obsolete); Hodgkin
disease, lymphocyte predominance, dif
fuse (obsolete); Hodgkin disease, lym
phocyte predominance, NOS (obsolete)
Epidemiology
LRCHL accounts for approximately 5% of
all CHLs, occurring at a frequency slightly
less than that of nodular lymphocyte pre
dominant Hodgkin lymphoma (NLPHL).
The median patient age is similar to that
of NLPHL and significantly older than
seen in other subtypes of CHL {980}. The
male―to―female ratio is 2:1 {3654}.
Localization
Peripheral lymph nodes are typically
involved. Mediastinal involvement and
bulky disease are uncommon {980,3654}.
Clinical features
Most patients present with stage I or II
disease. B symptoms are rare. The clini
cal features are similar to those of NLPHL,
with the exception that multiple relapses
seem to occur less frequently {980}.
Patients are also older than those with
NLPHL or the nodular sclerosis subtype.
Microscopy
There are two growth patterns: the com
mon nodular pattern {91} and the rare
diffuse pattern {91}. The nodules of the
nodular variant encompass most of the in
volved tissue, so that the T-zone is attenu
ated. The nodules are composed of small
lymphocytes and may harbour germinal sclerosis CHL might be more appropri bouring cases) as the HRS cells in the oth
centres, which are usually eccentrically ate. In some cases, sequential biopsies er subtypes of CHL. Thus, the distinction of
located and relatively small or regressed. have shown nodular sclerosis CHL, im LRCHL from NLPHL is possible by immu-
The HRS cells are predominantly found plying a possible relationship between nophenotyping in nearly all instances {91}.
within the nodules, but consistently out the two subtypes of CHL; this is further The expression of B-cell transcription fac
side of the germinal centres. A proportion inferred by the finding of HRS cells within tors such as OCT2, BOB1, and BCL6 has
of the HRS cells may resemble lympho expanded follicular mantle zones in some been found to be more frequent in LRCHL
cyte predominant (LP) cells or mono cases of nodular sclerosis CHL {1780}. than in the other CHL subtypes {2821}.
nuclear lacunar cells. This subtype can Coexistence of LRCHL and mixed cellu- Rosettes with a T follicular helper (TFH)
easily be confused with NLPHL. In the larity CHL occurs but is rare. cell immunophenotype (PD1/CD279+,
past, approximately 30% of cases initially In diffuse LRCHL cases, the small lym CD57―/+) surrounding the neoplastic cells
diagnosed as NLPHL were later found to phocytes of the cellular background may are present in as many as 50% of cases
be LRCHL {91}. The demonstration of an be admixed with histiocytes with or with {2821}. The small lymphocytes in the nod
immunophenotype typical of classic HRS out epithelioid features. ules have the features of mantle cells (i.e.
cells is essential in making this distinc positivity for IgM and IgD). Thus, the nod
tion. Eosinophils and/or neutrophils are Immunophenotype ules predominantly constitute expanded
absent from the nodules, or if present, The immunophenotype of the neoplastic mantle zones. At least some of them con
are located in the interfollicular zones and cells and their microenvironment display a tain eccentrically located, usually small,
are few in number. In rare instances, the mixture of features of NLPHL and CHL. The germinal centres, which are highlighted
LRCHL-typical nodules may be surround atypical cells in LRCHL show the same im by a dense meshwork of CD21+ follicu
ed by fibrous bands associated with ran munophenotype (CD30+, CD15+/―, IRF4/ lar dendritic cells. Because intact germi
domly distributed HRS cells in T―cell-rich MUM1+, PAX5+/―, CD20―/+, J chain―, nal centres are infrequent in NLPHL, this
zones. Typing of these cases as nodular CD75―, PU1―, EBV/LMP1+ for EBV―har- feature is helpful in differential diagnosis.
Fig. 15.42 Lymphocyte-rich classic Hodgkin lymphoma, nodular variant. A Immunostaining for CD20 shows that the nodules predominantly consist of small B cells.
HRS cells, evident as holes in the B-cell rich background are negative. B Immunostaining for CD21 reveals that the nodules contain a meshwork of follicular dendritic cells, and
demonstrates that they predominantly constitute follicular mantles, with occasional (usually regressed) germinal centres. The follicular dendritic cell meshwork is denser and more
sharply defined in the germinal centres.
Fig. 15.43 Mixed cellularity classic Hodgkin lymphoma. A The mixed cellular infiltrate does not contain fibrotic
bands. B A typical binucleated Reed-Sternberg cell in a mixed cellular infiltrate with lymphocytes, macrophages,
and eosinophils is visible.
Synonyms
Hodgkin lymphoma disease, lympho
cyte depletion, NOS; classic Hodgkin
lymphoma, lymphocyte depletion, NOS;
Hodgkin lymphoma, lymphocyte deple
tion, diffuse fibrosis (9654/3); Hodgkin
Fig. 15.46 Lymphocyte-depleted classic Hodgkin Fig. 15.47 Lymphocyte-depleted classic Hodgkin
lymphoma, lymphocyte depletion, reticu lymphoma. Hodgkin/Reed-Sternberg cells are readily lymphoma. CD30 immunostaining.
lar (9655/3) seen in a background rich in histiocytes and some small
lymphocytes.
Immunodeficiency-associated
lymphoproliferative disorders 443
LPDs associated with primary immune disorders 444
Lymphomas associated with HIV infection 449
Post-transplant lymphoproliferative disorders (PTLD) 453
Non-destructive PTLD 456
Polymorphic PTLD 457
Monomorphic PTLD (B- and T/NK-cell types) 459
Monomorphic B-cell PTLD 459
Monomorphic T/NK-cell PTLD 461
Classic Hodgkin lymphoma PTLD 462
Other iatrogenic immunodeficiency-associated LPDs 462
Lymphoproliferative diseases van Krieken J.H.
Onciu M.
associated with primary immune Elenitoba-Johnson K.S.J.
Jaffe E.S.
disorders
Definition
Lymphoproliferative diseases associated
with primary immune disorders (PIDs) are
lymphoid proliferations that arise in the
setting of immune deficiency due to a pri
mary immunodeficiency or immunoregu-
latory disorder. Because the pathol
ogy and pathogenesis of the > 60 PIDs
are heterogeneous, the manifestations
of these lymphoproliferative diseases
are highly variable. The PIDs most fre
quently associated with lymphoprolif
erative disorder are ataxia-telangiectasia
(AT), Wiskott―Aldrich syndrome (WAS),
common variable immunodeficiency
(CVID), severe combined immunodefi
ciency (SCID), X-linked lymphoprolifera
tive disease (XLP), Nijmegen breakage
syndrome (NBS), hyper―IgM syndrome
(HlgM), and autoimmune lymphoprolif T―cell immune surveillance to EBV is mutations are associated with lympho
erative syndrome (ALPS). believed to be the primary mechanism mas in the absence of immune abnor
{1628,3073,3251}. The absence of T-cell malities {1483}.
Epidemiology control may be complete (resulting in fa In AT, an abnormal DNA repair mecha
Patients with PIDs have an increased in tal infectious mononucleosis) or partial nism due to mutations of ATM can contrib
cidence of lymphomas {1878,3635}. Age- (resulting in other lymphoproliferative dis ute to the development of lymphoma, leu
specific mortality rates for all neoplasms orders) {1823}. kaemia, and other neoplasms {1090}. In
in patients with PIDs are 10―200 times WAS is a complex immune disorder, with these cases, non-leukaemic T-cell clones
the expected rates for the general popu defects in function of T cells, B cells, that have translocations involving the TR
lation. However, given that PIDs are rare, neutrophils, and macrophages. T―cell genes similar to those seen in overt leu
the overall occurrence of PID―associated dysfunction is significant, and tends to kaemias can be detected in the peripher
lymphoproliferative disorder is low, ac increase in severity during the course of al blood. B―cell non-Hodgkin lymphoma,
counting for 2.4% of all paediatric lym the disease. Hodgkin lymphoma, and lymphoblastic
phoma cases {144}. With the exception HlgM results from mutations in the gene leukaemia occur at a high rate and ear
of CVID, these diseases present primar for CD40 or CD40 ligand, which affect lier age than do carcinomas in AT. T-cell
ily in the paediatric age group. They are interactions between T cells and B cells prolymphocytic leukaemias are rarer than
more common in males than in females, and impair effective differentiation of initially reported. Prognosis is poor, but
primarily because several of the primary B cells into class―switched plasma cells patients may benefit from treatment, with
genetic abnormalities are X―linked, for {1767}. an improved survival {3823}.
example, XLP, SCID, and HlgM {1871}. It In ALPS, mutations in FAS or FASLG (and NBS also results from defects in DNA re
should be kept in mind that children can rarely other abnormalities) may contrib pair due to mutations in the NBN gene
present with a lymphoproliferation with ute directly to lymphoid proliferations, (also called NBS1), resulting in many
out the underlying immunodeficiency be through the accumulation of lymphoid chromosomal breaks and translocations,
ing known. Especially in polymorphous cells that fail to undergo apoptosis, re including in antigen receptor genes.
lesions, detection of EBV may indicate an sulting in the accumulation of CD4― and In patients with NBS, lymphoproliferative
underlying immune deficiency. CD8― cells in the peripheral blood and disorder is the most common neoplasm
lymphoid tissues {2331,3711}. In ALPS, {565,2880,4158}. In patients with CVID,
Etiology the severity of the apoptotic defect cor marked lymphoid hyperplasia may oc
The cause of the lymphoproliferative dis relates directly with the risk of develop cur in the lungs and gastrointestinal tract
order is related to the underlying primary ment of lymphoproliferative disorder {3507}, a setting in which more aggres-
immune defect {2897}. EBV is involved {1822}. The importance of FAS mutations sive―lymphoproliferative disorder or overt
in most PID-associated lymphoid prolif in causing lymphoproliferative disorder is lymphoma may develop {959}.
erations {4136}. In these cases, defective supported by the fact that sporadic FAS
Severe combined 1–5% Gamma chain of IL2R, IL4R, IL7R, Recurrent severe bacterial, fungal, EBV-associated lesions, fatal IM
immunodeficiency IL9R, IL15R, IL21R; JAK3 kinase; and viral infections, including (nearly 100%)
IL7R, CD45, CD3-delta or CD3- opportunistic infections; skin rash
epsilon; RAG1/2, Artemis, ADA
CD40 ligand and 1–2% CD40 ligand (CD40L, CD154) Neutropenia, thrombocytopenia, EBV-associated lesions
CD40 deficiencies or CD40 haemolytic anaemia, biliary tract and (DLBCL, Hodgkin lymphoma),
(hyper-IgM syndrome) liver disease, opportunistic infections large granular lymphocytic leukaemia
Wiskott-Aldrich syndrome 1–3% WAS (also called WASP) Thrombocytopenia, small platelets, EBV-associated lesions
eczema, autoimmune disease, (DLBCL, Hodgkin lymphoma,
bacterial infections lymphomatoid granulomatosis)
(3–9%)
Nijmegen breakage syndrome 1–2% NBN (nibrin, also called NBS1) Microcephaly, progressive mental DLBCL, PTCL, T-ALL/LBL,
retardation, sensitivity to ionizing Hodgkin lymphoma
radiation, predisposition to cancer (28–36%)
Autoimmune < 1% FAS (type 1a), Defective lymphocyte apoptosis, NLPHL, CHL, DLBCL, BL, PTCL (rare)
lymphoproliferative syndrome FAS LG (type 1b), splenomegaly, adenopathy, (CHL, DLBCL, and BL may be
(Canale-Smith syndrome) CASP10 (caspase 10; type 2a), or autoimmune cytopenias, EBV+ or EBV–)
CASP8 (caspase 8; type 2b) recurrent infections (3–10%)
ADA, adenosine deaminase; AFP, alpha-fetoprotein; BL, Burkitt lymphoma; CHL, classic Hodgkin lymphoma; DLBCL, diffuse large B-cell lymphoma;
IM, infectious mononucleosis; NLPHL, nodular lymphocyte predominant Hodgkin lymphoma; PTCL, peripheral T-cell lymphoma; T-ALL, T-lymphoblastic leukaemia;
T-ALL/LBL, T-lymphoblastic leukaemia/lymphoma; T-PLL, T-cell prolymphocytic leukaemia.
Fig. 16.03 Lymphomas in autoimmune lymphoproliferative syndrome. A Burkitt lymphoma. B Classic Hodgkin lymphoma, mixed-cellularity subtype.
C T-cell/histiocyte-rich large B-cell lymphoma. Histologically, these lymphoma subtypes resemble those occurring sporadically, without predisposing immune abnormalities.
seen in patients with ALPS {3146,3810}. by an increasing dominant clonal popu PID are of B―cell lineage, and thus ex
Both T-lymphoblastic leukaemia/lympho- lation: from clearly polyclonal, to oligo- press B―cell antigens corresponding
ma and T-cell prolymphocytic leukaemia clonal, to monoclonal. However, mono to their differentiation stage. EBV infec
have been reported in PIDs. clonal expansions, particularly if they are tion of B cells often leads to downregu-
minor clones, do not necessarily pro lation of B―cell antigens. Thus, CD20,
Hodgkin lymphoma gress to major persistent clonal lesions CD19, and CD79a may be negative or
Hodgkin lymphoma―like lymphoprolif- {2227}. Nevertheless, the detection of a expressed on only some of the neoplas
erations resembling those seen in the dominant clone indicates a more aggres tic cells in EBV―positive lymphoprolifera
setting of methotrexate therapy, as well sive disease {4128}. tive disorder. Similarly, EBV leads to the
as lymphoproliferative disorder with all expression of CD30 in most cases. In
morphological and phenotypic features Immunophenotype patients with EBV―positive lymphoprolif
of classic Hodgkin lymphoma, has been Non―neoplastic proliferations erative disorder resulting from defective
reported in patients with WAS or AT In ALPS, there is expansion of a distinc immune surveillance, the latency genes
{1090,3476}. In ALPS, nodular lympho tive CD3+, CD4―, CD8―, CD45RA+, including LMP1 may be expressed. In
cyte predominant Hodgkin lymphoma, CD45RO― naive T―cell population in the cases showing evidence of plasmacytoid
classic Hodgkin lymphoma, and T―cell/ peripheral blood and bone marrow. The differentiation, monotypic cytoplasmic
histiocyte―rich large B―cell lymphoma T cells may express CD57 but not CD25. immunoglobulin may be identified. The
have been described {2331}. Increased numbers of CD5+ polyclonal immunophenotypes of the specific B-cell
B cells may also be seen {2331}. HlgM is and T-cell lymphomas in PIDs do not dif
Precursor lesions characterized by peripheral blood B cells fer from those of the same lymphomas in
The underlying PID is the principal pre that bear only IgM and IgD. immunocompetent patients.
cursor lesion leading to the development
of lymphoproliferative disorder. This mor Neoplasms
phological spectrum is accompanied Most of the lymphomas in patients with
Fig. 16.05 Reactive lymph node from a patient with autoimmune lymphoproliferative syndrome. A There is prominent paracortical expansion. B Reactive germinal centres are
present and the paracortex is expanded. C The cells are slightly larger than normal small lymphocytes, with dispersed chromatin.
Genetic profile the TR genes on chromosomes 7 and 14 phoproliferative disorders, the prognosis
Antigen receptor genes are common. Consequently, these often must be evaluated in each case individu
Because lymphoproliferative disorder in show breakpoints at 14q11, 7q35, 7p13 ally, although clonality testing may be of
PID is a spectrum from reactive to ag and chromosomal rearrangements/trans- additional value {4128}. In patients with
gressive lymphoproliferations, the prolif locations including inv(7)(p13q35), t(7;7) EBV―driven infectious mononucleosis,
erations can be polyclonal, oligoclonal, (p13;q35), and t(7;14)(p13;q11), as well a haemophagocytic syndrome may be
or monoclonal. Fatal infectious mono as t(14;14)(q11;q32), which can involve the primary cause of death, usually as
nucleosis is generally polyclonal; overt the IGH gene locus {3910}. Such translo sociated with marked pancytopenia, liver
lymphomas such as diffuse large B―cell cations may also involve the TCL1A gene dysfunction, coagulopathy, and further
lymphoma and Burkitt lymphoma have in 14q32.1 and other oncogenes leading infectious complications.
clonal IG heavy and light chain gene re to T―cell lymphoproliferative diseases, Treatment is determined on the basis of
arrangement {1090,2227,3507}. There is including T―cell prolymphocytic leukae both the nature of the neoplastic pro
only limited experience with T-cell clonal- mia and pre―T lymphoblastic leukaemia/ cess and the underlying genetic defect.
ity tests in the setting of PIDs. lymphoma. In general, less―aggressive therapy is
needed than in patients without PID. Allo
Cytogenetic abnormalities and Prognosis and predictive factors geneic bone marrow transplantation has
oncogenes The prognosis is related to both the un been used in patients with WAS, SCID,
Genetic alterations may be directly re derlying PID and the type of lymphopro and HlgM {1066,1508}. Because the
lated to the primary immune defect, such liferative disorder. The immunological EBV―driven B―cell expansion in lympho-
as FAS mutation in patients with ALPS, status of the host is an important risk matoid granulomatosis is often not auton
mutations of the SH2D1A gene encod factor {547}. The lymphoid proliferations omous, it may respond to immunoregu-
ing for SAP/SLAM in XLP, and many in ALPS are often self―limiting. Lymphoid latory therapy using interferon alfa 2b
chromosomal breaks in NBS {1371, hyperplasias in CVID may be indolent. {4332}; however, like in post―transplant
3898}. Other abnormalities may occur Most of the other lymphoproliferative dis lymphoproliferative disorder, anti―CD20
in the course of lymphoproliferative dis orders in patients with PID are aggres directed therapy is more important.
order. In AT, in addition to mutations of sive. However, given the wide variety of
ATM, inversions and translocations of underlying conditions and ensuing lym
Definition
Lymphomas that develop in HIV―positive
patients are predominantly aggressive 13-
cell lymphomas. In a proportion of cases,
they are considered AIDS―defining con
ditions and are the initial manifestation of
AIDS. These disorders are heterogene
ous and include lymphomas usually dia
gnosed in immunocompetent patients,
as well as lymphomas seen much more
often in the setting of HIV infection. The
most common HIV―associated lympho
mas include Burkitt lymphoma, diffuse
large B―cell lymphoma (DLBCL; often
involving the CNS), primary effusion
lymphoma (PEL), and plasmablastic
lymphoma. Classic Hodgkin lymphoma
(CHL) is also increased in the setting of
HIV infection. those with moderate immune defect, phoid proliferations suggests a multistep
the relatively increased CHL incidence lymphomagenesis. B-cell stimulation, hy-
Epidemiology could be related to improvements in CD4 pergammaglobulinaemia, and persistent
The incidence of all subtypes of non- counts {374,770}. Lymphocyte predomi generalized lymphadenopathy preced
Hodgkin lymphoma is increased 60- nant Hodgkin lymphoma can occur in ing the development of these lymphomas
200 times in HIV―positive patients. Before HIV-infected individuals, but there is no probably reflect the role of chronic anti
combination antiretroviral therapy (cART) known association. genic stimulation and impaired immune
was available, primary CNS lymphoma response. Disruption of the cytokine net
and Burkitt lymphoma were increased Etiology work, leading to high serum levels of IL6
approximately 1000 times in compari Lymphomas in HIV―infected patients and IL10, is a feature of HIV-related lym
son with the general population {345, are heterogeneous, reflecting several phomas associated with EBV or HHV8.
2285}. Since the introduction of cART, pathogenetic mechanisms: chronic an EBV is identified in the neoplastic cells
the incidence of non―Hodgkin lymphoma tigen stimulation, genetic abnormalities, of approximately 40% of HIV-related lym
has decreased by 50%, mainly due to cytokine deregulation, and the role of phomas, but the detection of EBV varies
decreased CNS lymphoma and the im- EBV and HHV8 {555,557}. HIV―related considerably with the site of presentation
munoblastic histological subtype {1107}. lymphomas are consistently monoclonal and the histological subtype. EBV infec
Moreover, the decreased incidence of and are characterized by a number of tion is found in 80―100% of primary CNS
most AIDS―associated non―Hodgkin common genetic abnormalities of MYC lymphomas {536} and PELs, in 80% of
lymphomas after cART introduction is and BCL6, as well as tumour suppressor DLBCLs with immunoblastic features,
consistent with improved CD4 counts genes {1272,4096}. The polyclonal or oli- and in 30―50% of Burkitt lymphomas
{363,373}. cART is also associated with goclonal nature of some HIV-related lym {1531}. Nearly all CHL cases in the set
increased survival (with a 75% decrease ting of HIV infection are associated with
in mortality), although lymphomas now EBV {191,3754}. HHV8 is specifically as
account for a higher proportion of first sociated with PEL, which usually occurs
AIDS―defining illnesses {974,1107}. In in the late stages of the disease, in the
contrast, the risk of HIV―associated CHL setting of profound immunosuppression
has remained stable, and burden of dis {623}.
ease has increased. The incidence of
CHL is about 50 cases per 100 000 per Prevention
son―years among HIV-infected individu Despite the therapeutic advances with
als, 5―20 times the incidence in the gen cART, there is still no effective immuni
eral population {3649}. Because CHL zation or cure for HIV infection. Diversity
incidence is lower among patients with caused by circulating recombinant viral
severe immunosuppression than among forms is a major challenge, which has
Fig. 16.12 HIV-associated diffuse large B-cell lymphoma (DLBCL). A Primary CNS DLBCL. B DLBCL, immunoblastic variant. The cells have prominent central nucleoli. C The
cells exhibit marked plasmacytoid differentiation on touch imprint.
lack a starry-sky pattern. Immunoblastic Plasmablastic lymphoma cavity type. Other sites of involvement in
lymphomas consist of larger cells with Plasmablastic lymphoma accounts for clude the gastrointestinal tract, skin, ab
deeply basophilic or amphophilic cyto about 2% of all HIV―related lymphomas domen, retroperitoneum, and soft tissue
plasm, and may appear plasmacytoid {554}. The blastoid morphology and im- of the extremities {578}. Patients do not
with a perinuclear hof. The nuclei contain munophenotype suggest that these usually have a monoclonal gammopathy,
a prominent central nucleolus. Primary cells retain the blastoid appearance of but may have advanced clinical stage,
CNS lymphomas are usually of the im immunoblasts or centroblasts, but have with B symptoms and bone marrow in
munoblastic type {536}. They are intrac acquired the antigen profile of plasma volvement. Histologically, plasmablastic
ranial parenchymal tumours that may be cells. They may occur at all ages but are lymphoma is characterized by sheet―like
deep―seated in the brain or may be mul rare in paediatric patients. The median proliferation of large cells with immuno
tifocal. In addition to the cerebrum, they patient age at presentation is 38 years blastic or plasmablastic appearance,
may be located in the basal ganglia and {577}. The cell or origin is considered to including central round or oval nuclei
brain stem, and may involve the menin be an activated B cell after somatic hy with prominent nucleoli and moderately
ges. Lymphomas tend to follow vascular permutation and class―switch recombi abundant amphophilic cytoplasm. The
channels as perivascular cuffs, and there nation. About 60―70% of cases are posi nuclei may be eccentrically located with
may be admixed small lymphocytes and tive for EBER in the absence of EBNA2 a perinuclear clearing or so-called hof. In
glial cells. AIDS―related DLBCLs ex (compared with about 50% in immuno the oral cavity, the cells may have a more
press B―cell―lineage antigens including competent patients with plasmablastic centroblastic appearance but retain the
CD19 and CD20, and have phenotypes lymphoma) {2755}. There is expression plasmablastic phenotype {936}. There
similar to those of DLBCLs in the general of MYC in about 50% of cases, which are frequent apoptotic cells, but a starry-
population. Most have IG heavy and light correlates with MYC translocation or sky pattern is rare. The neoplastic cells
chain gene rearrangements, and several sometimes amplification. There are no are negative or weakly positive for CD45
proto―oncogenes may be involved in the translocations involving BCL2, BCL6, and usually negative for B―cell markers,
pathogenesis, including MYC, BCL2, MALT1, or PAX5. EBV LMP1 is usually including CD19, CD20, and PAX5, but
and BCL6. EBV infection is associated negative (type I EBV latency), although most cases are positive for CD79a, IRF4
with expression of several tumour mark type III latency has been recorded {578}. (also called MUM1), PRDM1 (also called
ers that are involved in the NF―kappaB Extranodal presentation is most frequent BLIMP1), CD38, and CD138. Intracyto-
pathway {659}. particularly in the oral cavity or jaw. For plasmic IgG may be detected in some
this reason, it is sometimes referred to patients. There may be aberrant expres
as plasmablastic lymphoma of the oral sion of T-cell markers, including CD2 and
CD4. The Ki-67 (MIB1) proliferation index type NK/T―cell lymphoma {159,365,501, Prognosis and predictive factors
is almost 100%. 546,1266,1492,1667,1857,4008}. There is Before the cART era, the outcome of
also an increased risk of lymphoplasma- patients with lymphoma and HIV infec
Hodgkin lymphoma cytic lymphoma and lymphoblastic leu tion was closely related to the severity
The incidence ofCHLmay have increased kaemia {1370}. of immunodeficiency {430}. HIV―directed
since the introduction of cART, suggest therapy can now reduce the impact of
ing that a threshold of CD4+ cells may Lymphomas occurring more HIV―related prognostic factors and allow
be required for the pathogenesis, and specifically in HIV―positive patients curative therapy for most patients with
that cART does not provide protection PEL, plasmablastic lymphoma, and aggressive lymphoma {278,2333,3580}.
from developing CHL {1657,2218}. In the HHV8-positive DLBCL, NOS, occur more The achievement of complete remission
era before cART, most cases were of the specifically in HIV-positive patients. is the most important prognostic factor
mixed―cellularity or lymphocyte―depleted with respect to survival {4351}. Expres
subtypes. Likely due to improved immu Lymphomas occurring in other sion of MYC in DLBCL from HIV―positive
nity with anti-HIV therapy, nodular sclero immunodeficient states patients is associated with increased
sis CHL now accounts for nearly 50% of Polymorphic lymphoid proliferations re 2―year mortality {660}. In HIV―associat
cases {3649}. HIV―associated CHL may sembling post―transplant lymphoprolif- ed DLBCL, the stromal immune reac
have an atypical clinical presentation with erative disorder may be seen in adults tion may also influence patient survival
advanced―stage bone marrow or liver and also in children, but are much less {661}. Patients with HIV have reduced
involvement, as well as non―contiguous common than in the post―transplant set stromal CD4+ and FOXP3+ T cells, and
spread to multiple nodal groups. In HIV- ting, accounting for < 5% of HlV―associ- increased density of stromal macrophag
related Hodgkin lymphoma, the Hodg- ated lymphomas. The mean patient age es. A higher density of infiltrating CD8+
kin/Reed―Sternberg cells are positive at presentation is 38 years, similar to T cells may be associated with reduced
for EBER in 80―100% of cases; the cells those of other HIV―related non―Hodgkin mortality from lymphoma {661}. Plasmab
express a type II EBV latency pattern in lymphomas. They may present in lymph lastic lymphoma is associated with early
which expression of EBV-encoded genes nodes as well as extranodal sites. These relapses, and chemotherapy resistance
is limited to EBNA1 and latent membrane conform to the criteria of polymorphic B- with an inferior overall survival compared
proteins (LMP1 and LMP2) {1624}. Both cell post―transplant lymphoproliferative with DLBCL and Burkitt lymphoma {278,
these proteins have oncogenic potential, disorder. The infiltrates contain a range 578}. In Burkitt lymphoma, use of modi
including the activation of the NF-kappaB of lymphoid cells, from small cells (often fied CODOX―M (cyclophosphamide,
pathway. In HIV―related CHL, there may with plasmacytoid features) to immuno- vincristine, doxorubicin, and high―dose
be decreased nodal CD4+ T cells and blasts, with scattered large bizarre cells methotrexate) regimens results in survival
lack of CD4+ rosetting around Hodgkin/ expressing CD30. EBV is often present, rates similar to those seen in studies that
Reed―Sternberg cells {1574}. but some cases are EBV-negative {2030, excluded HIV―positive patients {2906}.
2519,2804,3901}. A clonal B―cell popula On the other hand, PEL usually has a very
Other lymphomas tion is present in most cases, and there poor prognosis, with a low complete re
Cases of marginal zone lymphoma and may be an oligoclonal background, sug mission rate. CHL should be treated with
lymphoma of mucosa―associated lym gesting variable numbers of clonal cells curative intent, and has outcomes com
phoid tissue have been described in both within a polymorphic background. Clonal parable to those in the non―HIV popula
paediatric and adult patients with HIV in EBV infection has been demonstrated. tion {4089}. There is a need for increased
fection {1376,2593,3945}. Rare cases of They generally lack structural alterations supportive care and coincident cART in
NK/T-cell lymphomas have been report in MYC, BCL6, the RAS family of genes, the HIV―infected population {791}.
ed, including mycosis fungoides, ana and TP53 {2804}.
plastic large cell lymphoma, and nasal-
Infectious mononucleosis Absent Admixed small Pcl B cells and Pcl or very small Simple cytogenetic
lymphocytes, plasma admixed T cells; mcl B-cell population(s); abnormalities
cells, and immunoblasts EBV+ may have clonal/ rarely present
oligoclonal TR genes
Florid follicular hyperplasia Absent Prominent hyperplastic Pcl B cells and Pcl or very small mcl Non-specific
germinal centres admixed T cells; B-cell population(s) simple cytogenetic
EBV± abnormalities
rarely present
Polymorphic Present Full spectrum of Pcl ± mcl B cells and Mcl B cells, Some have BCL6
lymphoid maturation admixed T cells; non-clonal T cells somatic hypermutations
seen, not fulfilling criteria most EBV+
for NHL
Monomorphic Usually present Fulfils criteria for an Varies based on Clonal B cells Variably present
NHL (other than one type of neoplasm they and/or T cells (see text)
of the indolent B-cell resemble; (except for rare NK-cell
neoplasmsa) or plasma EBV more variable than cases)
cell neoplasm in other categories
CHL Present Fulfils criteria for CHL Similar to other CHL; IGH not easily Unknown
EBV+ demonstrated
CHL, classic Hodgkin lymphoma; NHL, non-Hodgkin lymphoma; mcl, monoclonal; pcl, polyclonal.
Monoclonality and polyclonality are only inferred when finding monotypic or polytypic light chain expression.
a EBV-positive MALT lymphomas at least of skin/subcutaneous tissues should be considered a type of PTLD.
is less sensitive. Most EBV-positive cases ences in the regulation of BCL2 family and frequently involve the allograft {147,
exhibit a type III EBV latency pattern, but a proteins between EBV―positive and EBV- 632,2225,3756,4290}. In contrast, most
moderate number show a type II pattern, negative PTLD have also been reported PTLDs in stem cell allograft recipients are
and fewer show a type I pattern, although {1354}. HHV8―associated PTLDs have of donor origin, as would be expected,
not all of the cells in a given case show been reported, including post―transplant given that successful engraftment results
the same pattern {1405,3011}. Evidence primary effusion lymphoma {1030,1935, in an immune system that is nearly exclu
of lytic EBV infection can also be docu 2571}; however, the etiology of the vast sively of donor origin {4507}.
mented in more than half of the cases and majority of EBV―negative PTLDs is un
has been associated with plasmacytic known. Some may be due to EBV that is Localization
differentiation {1405}. About 20―40% of no longer detectable {3760}, some due to Involvement of lymph node, gastrointes
PTLDs are EBV-negative, with some se other unknown viruses, and some due to tinal tract, lungs, and liver is common,
ries reporting an even higher proportion chronic antigenic stimulation, including but disease can occur at almost any site
of cases. Approximately two thirds of the by the transplant itself {385}. Two gene in the body {1205,2819,3130,4271}. The
T―cell PTLDs are EBV-negative {47,385, expression profiling studies support a CNS is involved uncommonly, either as
1205,2239,2756,2848,3845}. Further non―viral etiology for the EBV―negative the only site of disease or in association
more, the proportion of EBV―negative cases, although other studies have failed with multiorgan involvement {575,1119}.
PTLDs has increased since PTLDs were to find differences between EBV―positive In solid organ transplant recipients, PTLD
first being reported {2848}. EBV―negative and EBV―negative PTLDs {832,2754, can involve the allograft, which can cause
PTLDs are more common in adults, tend 4100}. The EBV―negative cases are still diagnostic confusion because rejection
to occur later after transplantation, and considered to represent PTLD, and some and infection can result in a similar clini
are more likely to be monomorphic com may respond to decreased immunosup cal picture. Allograft involvement appears
pared with EBV―positive cases {1355, pression {2848}. more frequently in early-onset, EBV-posi
2848}. Although data are limited, EBV- The majority (> 90%) of PTLDs in solid tive disease and is most common in lung
negative cases appear to have a gene organ recipients are of host origin, and and intestinal transplant recipients {236,
expression profile similar to that of dif only a minority of donor origin. Donor- 1355,2980,3296}. The non―destructive
fuse large B―cell lymphoma occurring in origin PTLDs appear to be most com PTLDs often present with tonsil and/or
immunocompetent hosts {2754}. Differ mon in liver and lung allograft recipients, adenoid involvement but can also occur
Clinical features
The clinical features of PTLD are highly
variable and correlate to some extent with
the type of allograft and morphologically
defined categories. PTLD frequently pre
sents in the first year after transplantation,
especially in EBV―seronegative recipients
who acquire early post―transplant EBV
infection, often from the donor. This pat
tern of presentation is particularly com
mon in children. However, the median
time to PTLD in some studies, especial
ly those of adult populations, is several
years, and as many as 15―25% of cas Fig. 16.14 Infectious mononucleosis post-transplant lymphoproliferative disorder in the tonsil of an 11-year-old renal
es occur > 10 years after the transplant allograft recipient. A There is preservation of overlying epithelium and crypts, but normal follicles are absent, and
{981,1122,2819,3130}. There is some ev there is a diffuse lymphoid proliferation. B Polymorphic proliferation of immunoblasts, small lymphoid cells, and
idence for an increase in prevalence of plasma cells. C CD20 staining showing scattered B cells. D In contrast, a stain for CD79a shows more-numerous
positive cells, indicating plasmacytoid differentiation. E In situ hybridization identifies EBV-encoded small RNA
late―onset disease {720}, although this
(EBER) expression in most of the cells.
may in part reflect the ever―expanding
population of patients at risk as the num
ber of long―term survivors of transplanta es, often at extranodal sites, sometimes However, some infectious mononucleo
tion increases. EBV―negative PTLD and with organ―specific dysfunction and sis―like PTLDs can be fatal. P―PTLDs
T/NK-cell PTLD tend to present later (with occasionally with widely disseminated and even a significant minority of M-
median times to occurrence of 4―5 years disease. A viral septic shock―like picture PTLDs may also regress with reduction in
and ~ 6 years, respectively), although is another rare presentation. immune suppression {3346,3769,4271}.
T―cell PTLDs following haematopoietic Some factors that have been reported to
stem cell or bone marrow transplanta Prognosis and predictive factors be associated with a lack of response to
tion occur significantly earlier {851,1625, Although overall mortality rates of decreased immunosuppression include
2239,2848,3845,3999}. 25―60% are still quoted {2756}, newer elevated lactate dehydrogenase, organ
PTLD presentations vary greatly. Some therapeutic strategies appear to be as dysfunction, multiorgan involvement, ad
PTLDs are found incidentally, some sociated with a better overall outcome. vanced stage, bulky disease, and older
present with very vague non―specific The non―destructive PTLDs (previously patient age {3346,4066}. Clinical caution
symptoms such as fever and malaise, termed early lesions) tend to regress is required because rebound acute or
and some present with infectious mono- with reduction in immune suppression; if chronic rejection is frequently observed
nucleosis―like findings. Others present this can be accomplished without graft during reduction of immunosuppression
with tonsil or adenoid enlargement, rejection, the prognosis is excellent, par and can lead to graft loss and death
lymphadenopathy or tumorous mass ticularly in children {2385,2849,4462}. {4271}. A proportion of P―PTLDs and
more-numerous M―PTLDs fail to regress, greatly across studies. Some of the re often used to help predict the risk for
and require additional therapies such as ported factors that have been associ PTLD and the onset of PTLD, as well as
monoclonal antibodies directed against ated with an adverse prognosis include to follow PTLD, including to guide pre
B―cell antigens (most commonly anti- multiple sites of disease (perhaps not in emptive therapy in some patients. Its use
CD20), sometimes together with chemo children), advanced stage, involvement appears most helpful in solid organ trans
therapy {741,742,1099,1404,1474}. The of the CNS, bone marrow and serous ef plant recipients who are seronegative at
anti―CD30 antibody brentuximab vedotin fusions, older patient age at diagnosis, transplantation, particularly children.
has also been used, with mixed results elevated lactate dehydrogenase, and However, it should be noted that EBV-
{47,1634}. Surgical excision or some hypoalbuminaemia {522,741,981,1099, positive PTLD can develop in the ab
times radiation therapy are other impor 1120,1356,2240,2435,4061,4271}. The sence of high viral loads, high viral loads
tant therapeutic modalities in localized combination of lytic EBV infection and are not predictive in all settings, and a
cases. Adoptive T―cell immunotherapy type III EBV latency has also been as fall in load may not always predict treat
is another therapeutic approach {1031, sociated with an adverse prognosis, as ment response. A rapid fall in EBV viral
1545,1629}. Although no comparative well as with early onset {1405}. Although load is almost invariable when anti-B cell
clinical trials have been reported for Bur EBV negativity in PTLD, and even among monoclonal antibodies are given as part
kitt lymphoma PTLDs, cessation of im the T/NK-cell PTLDs, has been reported of the treatment regimen, irrespective of
munosuppression and immediate use of to be an adverse prognostic indicator, long-term PTLD response {72,3451}. The
multidrug (immuno)chemotherapy likely not all studies document a survival dif lack of standardization of techniques and
offer the best outcomes for this aggres ference {741,3845}. PTLD of donor origin results for assessment of circulating viral
sive PTLD {3168,4495}. Plasmacytoma in solid organ transplant recipients and load has been an additional complicat
like PTLDs have a variable outcome, but the overlapping group of PTLD localized ing factor, although there is now an inter
many do well, sometimes with very lim to the allograft have better than average national WHO standard for determining
ited therapy {981,3142,3205,3352,4042}. prognoses, although in T-cell PTLD, graft EBV load {3451}.
The myelomatous lesions and cases with involvement has been reported to be
osteolytic bone lesions are not expected an adverse prognostic indicator {3999}.
to regress with decreased immunosup PTLDs with oncogene abnormalities are Non-destructive post-transplant
pression and have a poor prognosis, also considered to be more aggressive. lymphoproliferative disorders
although they may respond to myelo Whether P―PTLD does better than M-
ma―type therapy {2053,4042}. T/NK―cell PTLD is controversial. Overall, the mor Definition
PTLDs are also typically aggressive, par tality of PTLD is much greater in bone Non―destructive post―transplant lym
ticularly those of hepatosplenic type, with marrow allograft recipients than in solid phoproliferative disorders are defined
the exception of those of large granular organ allograft recipients. It should also as lymphoid proliferations in an allograft
lymphocyte type, which typically do very be remembered that, although uncom recipient characterized by architectural
well {3845,3999}. Nevertheless, some T- mon, there may be progression from preservation of the involved tissue and
cell PTLDs do respond to reconstitution non―destructive to polymorphic and from an absence of features that would be
of the patient’s immune system. Classic polymorphic to monomorphic PTLD, diagnostic of a malignant lymphoma.
Hodgkin lymphoma PTLDs are generally sometimes with documented additional In most cases, they form mass lesions.
treated with conventional classic Hodg molecular abnormalities {3168,4377}. These PTLDs must be distinguished from
kin lymphoma therapeutic regimens, Serial monitoring of EBV DNA levels in lymphoid proliferations with other known
with good results. whole blood, peripheral blood mono explanations and from other non―specific
Risk factors for adverse outcome vary nuclear cell preparations, or plasma is chronic inflammatory processes.
Clinical features
The reported frequency of P-PTLDs var
ies widely, but they account for a minor
ity of PTLDs in most studies. However, in
children P-PTLD is generally more com
mon and frequently follows post-trans
plantation primary EBV infection {4271}.
The clinical presentation of P-PTLDs is
Fig. 16.16 Plasmacytic hyperplasia. A The normal architecture of the lymph node is intact. B Numerous plasma not distinguishable from that of PTLDs
cells are present. in general, although they have been
Immunophenotype
Immunophenotypic studies demonstrate
B cells and a variable proportion of het
erogeneous T cells that are usually mod
erately numerous and sometimes pre
dominate {1062,2819}. Light chain class
restriction does not exclude the diag
nosis and, when present, may be focal,
or with the presence of different clonal
populations in the same or different sites
{2819}. The presence of clear―cut light
chain class restriction must be noted in
the diagnostic report, because some of
these cases could also be classified as
monomorphic diffuse large B―cell lym
phoma PTLD with plasmacytic differen
tiation or as plasma cell neoplasm with
increased transformed cells. Prominent
CD30 expression is common, but unlike
in most cases of classic Hodgkin lym
Fig. 16.17 Polymorphic post-transplant lymphoproliferative disorder. A Architectural effacement with large area of phoma, the CD30+ Reed―Sternberg―like
geographical necrosis. B Note the variably sized and shaped lymphoid cells, with one very large cell resembling a cells are CD20+ and CD15― {694,4159}.
Reed-Sternberg variant. C Numerous CD30+ cells are also present. Most cases of P―PTLD contain numer
ous cells positive for EBV―encoded small
reported to occur earlier than M―PTLD. which represent the typically prominent RNA (EBER). Detection of EBV by in situ
Reduction in immunosuppression leads T―cell component. There may be areas hybridization for EBER is a useful tool in
to regression in a variable proportion of of geographical necrosis and scattered the differential diagnosis of PTLD versus
cases; others may progress and require large, bizarre cells that not infrequently rejection in allografts.
treatment for lymphoma {2053,2819, resemble Reed―Sternberg cells (atypi
3769,4271}. cal immunoblasts). Numerous mitoses Genetic profile
may be present. Some cases have areas P―PTLDs are expected to demonstrate
Microscopy that appear more monomorphic in the clonally rearranged IG genes, although
Unlike the three types of non―destructive same or other tissues; thus, there may be the clones are less predominant than
PTLD lesions, P―PTLDs show efface a continuous spectrum between these in M―PTLD {766,1936,2053,2378}. EBV
ment of the underlying tissue architec lesions and M―PTLD. Other P―PTLDs terminal repeat analysis is the most sen
ture {1258,1541}. However, unlike many have features that more closely resem sitive method for demonstrating clonal
lymphomas, they show the full range ble those of Hodgkin lymphoma. Some populations in the EBV―positive cases,
of B―cell maturation, from immuno of these cases were previously referred but is not generally performed. In some
blasts to plasma cells, with small and to as Hodgkin―like. Variably sized, but reported cases, tumours at different sites
medium―sized lymphocytes and cells usually small, lymphoid aggregates with in the same patient may be clonally dis
with irregular nuclear contours, some of or without plasma cell clusters are seen tinct {628}. About 75% of P―PTLDs are
reported to have mutated IGV genes
without ongoing mutations, and the re
mainder are unmutated {550}. Significant
T-cell clones are not expected. Clonal cy
togenetic abnormalities may be present
although less commonly detected than in
B-cell M―PTLD {1010,4101}. Comparative
genomic hybridization studies also dem
onstrate abnormalities in some P―PTLDs,
including some recurrent abnormalities
also seen in M―PTLD {3207}. BCL6 so
Fig. 16.18 Polymorphic post-transplant lymphoproliferative disorder, EBV-positive. There are (A) numerous variably matic hypermutations are present in a
sized CD20+ B cells as well as (B) many mostly small CD3+ T cells. subset of cases, as is aberrant promoter
Fig. 16.22 Classic Hodgkin lymphoma post-transplant lymphoproliferative disorder in a 52-year-oid man following renal transplant. The Reed-Sternberg cells were EBV-
positive. A Reed-Sternberg cell surrounded by small lymphocytes and some eosinophils. B,C Reed-Sternberg cells with CD30 expression (B) and Golgi-type CD15 positivity (C).
Fig. 16.23 Polymorphic lymphoproliferative disorder with Hodgkin lymphoma-like features in a patient with rheumatoid arthritis treated with methotrexate. A Note the
polymorphous infiltrate, with lymphocytes, histiocytes, and Reed-Sternberg-like cells. B In situ hybridization for EBV-encoded small RNA (EBER) showing numerous positive
large cells as well as many positive small lymphocytes.
Localization
Of the cases reported in patients receiv
ing methotrexate, 40―50% have been
extranodal, occurring at sites such as
the gastrointestinal tract, skin, liver and
spleen, lung, kidney and adrenal gland,
thyroid gland, bone marrow, CNS,
gingiva, and soft tissue {74,1703,1787,
2065,2945,3498}. As is the case for
HSTL in other settings, the spleen, liver,
and bone marrow are the most common Fig. 16.24 EBV-positive large B-cell lymphoproliferation in a patient with rheumatoid arthritis treated with
sites of involvement of HSTL in patients methotrexate. This lesion regressed following cessation of therapy.
with Crohn disease receiving immuno-
modulators {2426,3414}. ing the recently recognized EBV―positive Prognosis and predictive factors
mucocutaneous ulcer {1018} and others A significant proportion of patients with
Clinical features more closely resembling a polymorphic methotrexate-associated lymphopro
The clinical features are the same as PTLD. HSTL in patients who have been liferative disorder have shown at least
those seen in immunocompetent patients treated with infliximab is indistinguish partial regression in response to drug
with similar―appearing lymphomas. able from HSTL arising in immunocom withdrawal (Table 16.04). Although most
petent or post―transplant patients. responses have occurred in EBV-positive
Microscopy cases {1703,1752,1764,2387,3498,4403},
The distribution of histological types of Immunophenotype a proportion of EBV-negative cases also
iatrogenic lymphoproliferations in non The immunophenotype of the lym- respond {1752,2065}. A variable propor
transplantation settings appears to differ phoproliferative disorder does not ap tion of DLBCLs (as many as ~ 40%) have
from that seen in other immunodeficiency pear to differ from that of the lymphomas regressed, while most require cytotoxic
settings, with a probable increase in the in non―immunosuppressed hosts, which therapy. The proportion of polymorphic
frequency of Hodgkin lymphoma and they resemble. Among methotrexate- lymphoproliferative disorder patients with
lymphoid proliferations with Hodgkin―like associated DLBCLs, the majority have regression after withdrawal is higher. In
features, such as EBV―positive mucocu an activated―B―cell immunophenotype, recent studies of methotrexate-asso
taneous ulcer. Among patients treated especially EBV-positive cases. EBV-pos ciated lymphoproliferative disorder in
with methotrexate, the reported cases itive methotrexate―associated DLBCLs rheumatoid arthritis patients, the 5-year
are most commonly DLBCL (35―60%) commonly express CD30 {2065,4403}. overall survival rate was > 70%. Spon
and CHL (12―25%), with less frequent Immunophenotype is a useful tool in the taneous regression following methotrex
cases of follicular lymphoma (3―10%), distinction from lymphoproliferative disor ate withdrawal has been associated with
Burkitt lymphoma, extranodal marginal ders that may have some Hodgkin lym EBV positivity and a non-DLBCL type
zone lymphoma of mucosa―associated phoma―like features, but which should of lymphoproliferative disorder, whereas
lymphoid tissue (MALT lymphoma), and not be considered to represent CHL, the patient age > 70 years and DLBCL type
peripheral T―cell lymphoma {1703,1752, large cells most typically being CD20+/ are predictive of a shorter survival {1752,
1908,2387,2509,3498}. Polymorphic or CD30+/CD15― and CD20―/CD30+/ 4014}. Early lymphocyte recovery after
lymphoplasmacytic infiltrates resembling CD15+, respectively. EBV is variably methotrexate withdrawal may be predic
polymorphic PTLD have been described positive, with type II latency (LMP1―posi- tive of good response {1764}. A moderate
in as many as 20% of cases in this setting tive and EBNA2―negative) more common number of patients whose lymphoprolif
{1752}. Peripheral T―cell lymphomas oc than type III (LMP1-positive, EBNA2-pos- erative disorder initially regresses after
curring in this setting seem to have a com itive) {1752,4403}. discontinuation of methotrexate later re
mon extranodal presentation, a cytotoxic lapse and then require chemotherapy
profile, and may include extranodal NK/ Postulated normal counterpart {1703,1752}. Regression after discon
T―cell lymphomas {2079,3870}. Among The postulated normal counterpart varies tinuation of drug seldom occurs in pa
CHLs, the mixed―cellularity subtype is depending on the specific type of lym tients who develop lymphoproliferative
more frequent than nodular sclerosis, phoproliferative disorder. disorder following the administration of
with a significant proportion that cannot TNF blockers. Like in individuals without
be further classified {2387}. Lesions con Genetic profile overt immunodeficiency, cases of HSTL
taining Reed―Sternberg―like cells but The genotype of these immunodeficien in patients treated with infliximab plus
not fulfilling the criteria for Hodgkin lym cy―associated lymphoproliferative disor thiopurine have a very aggressive clinical
phoma, which in the past were referred ders does not appear to differ from those course, with most survivors treated with
to as Hodgkin―like lesions, have been re of lymphomas of similar histological types allogeneic bone marrow transplantation
ported {1911}, with some likely constitut not associated with immunosuppression. {2426,3414}.
Introduction teristics of terminally differentiated ele circumstances, they carry the same TR
ments. In line with this, blastic plasma- or IG rearrangements and chromosomal
Pileri S.A. Jones D.M. cytoid dendritic cell (PDC) neoplasm is aberrations as lymphoid neoplasms,
Jaffe R. Jaffe E.S. excluded from this section on histiocytic consistent with transdifferentiation {678,
Facchetti F. and dendritic cell neoplasms, and is dis 859,860,1172,3313,3633}. The histiocytic
cussed after the acute myeloid leukae and lymphoid neoplasm may share a
mias and related precursor neoplasms, common progenitor {479}, but one that
Definition because it stems from a cell that ac has already undergone IG rearrange
Histiocytic neoplasms are derived from quires terminal differentiation and den ment. To date, neither comprehensive
mononuclear phagocytes (macrophages dritic appearance following activation gene expression profiling nor next―gen
and dendritic cells) or histiocytes. Den (see Chapter 9, Blastic plasmacytoid eration sequencing studies have been
dritic cell tumours are related to several dendritic cell neoplasm, p. 173). carried out, with the exception of studies
lineages of accessory antigen―present Intriguingly, during the past few years, based on canine models {399} and small
ing cells (dendritic cells) that have a role several publications have highlighted the series of follicular dendritic cell (FDC)
in phagocytosis, processing, and pre fact that, irrespective of their supposed sarcomas {1460,1569A,2184A, 2383A}.
sentation of antigen to lymphoid cells. normal counterparts (myeloid―derived A next generation sequencing study of
macrophages or myeloid―derived den 13 FDC sarcomas revealed recurrent
Epidemiology dritic cells), some of these neoplasms loss―of―function alterations in tumour
Tumours of histiocytes are among the are associated with or preceded by a suppressor genes involved in the nega
rarest tumours affecting lymphoid tis malignant lymphoma (e.g. follicular lym tive regulation of NF―kappaB activation
sues, probably accounting for < 1% of tu phoma, chronic lymphocytic leukaemia, (38% of cases) and cell―cycle progres
mours presenting in the lymph nodes or B―lymphoblastic leukaemia/lymphoma or sion (31% of cases) {1460}. The possible
soft tissue {1165,3180}. Because several T―lymphoblastic leukaemia/lymphoma, occurrence of BRAF V600E mutation has
of these tumour types were poorly recog and peripheral T―cell lymphoma) {678, been reported in the setting of histiocytic
nized until recently, their true incidence 859,860,1172,3313,3633}. Under these sarcoma, Langerhans cell histiocytosis,
remains to be determined. Historically,
some large cell lymphomas of B―cell or
T―cell type were thought to be histiocyt
ic or reticulum cell sarcomas on purely
morphological grounds, but only a small
number have proven to be of true mac
rophage or dendritic cell origin. Some of
the regulatory disorders, such as mac
rophage activation and haemophagocyt-
ic syndromes, can have large numbers of
histiocytes, but these are non-neoplastic.
No sex, racial, or geographical predilec
tion has been described (Table 17.01).
Histogenesis
The cellular counterparts of this group
of neoplasms consist of myeloid-derived
macrophages, myeloid―derived dendritic
cells, and stromal-derived dendritic cells.
The myeloid―derived macrophages and
dendritic cells constitute divergent lines
of differentiation from bone marrow pre
cursors, although transdifferentiation or
hybrid differentiation states likely occur.
Histiocytic and dendritic cell neoplasms
tend to reproduce the morphological,
phenotypic, and ultrastructural charac
Introduction 467
states of activation, and no single marker Prognosis and predictive factors Histiocytic sarcoma
identifies all dendritic cell subsets {244, Because there are few phenotypic mark
3303,3790}. Langerhans cells are spe ers unique for dendritic or macrophage Weiss L.M.
cialized dendritic cells in mucosal sites histiocytes, investigators should use a Pileri S.A.
and skin that upon activation become panel appropriate to the cell in ques Chan J.K.C.
specialized for antigen presentation to tion (Table 17.02, p.467) and rigorously Fletcher C.D.M.
T cells, and then migrate to the lymph exclude other cell lineages (i.e. T-cell, B-
node through lymphatics. Lymph nodes cell, and NK-cell lineages, but also stro
also contain a paracortical dendritic cell mal, melanocytic, and epithelial lineages) Definition
type, the interdigitating dendritic cell, by immunophenotypic and molecular Histiocytic sarcoma is a malignant pro
which may be derived in part from the means. It is also worth mentioning that liferation of cells showing morphological
Langerhans cell {1323}. This classic den some leukaemias and anaplastic large and immunophenotypic features of ma
dritic cell lineage is believed to give rise cell lymphomas can be accompanied in ture tissue histiocytes. Neoplastic prolif
to Langerhans cell histiocytosis/sarcoma lymph nodes by an exuberant histiocytic erations associated with acute monocytic
and to interdigitating dendritic cell sarco response that may obscure the neoplas leukaemia are excluded.
ma. A third, poorly defined subset of den tic cells.
dritic cells, dermal/interstitial dendritic Consistent with their rarity, the treatment ICD-O code 9755/3
cells, are found in the soft tissue, dermis, of histiocytic and dendritic cell neo
and most organs, and can be increased plasms is extremely variable, no specific Synonym
in some inflammatory states {244}. trials being available {859,860,1021}. Ex- True histiocytic lymphoma (obsolete)
PDCs (also known as plasmacytoid cisional biopsies should be performed
monocytes) are a distinct lineage of den whenever possible, needle aspirates be Epidemiology
dritic cells, which are believed to give rise ing indeed proscribed. Accurate staging Histiocytic sarcoma is a rare neoplasm,
to the blastic PDC neoplasm {1615}. The is mandatory, because the distinction with only limited numbers of reported se
histogenetic origins of PDCs are contro between localized and systemic forms ries of bona fide cases {806,860,1540,
versial but are likely of myelomonocytic impacts therapeutic decisions. Localized 1688,1909,3180,4216}. There is a wide
lineage. Interferon alpha―producing PDC forms are usually surgically resected; patient age range, from infancy to old age;
precursors, which only acquire a den the utility of radiotherapy and/or chemo however, most cases occur in adults (me
dritic appearance in cell culture, circulate therapy as adjuvant is debated {859,860, dian patient age: 52 years) {1688,3180,
in the peripheral blood and have the ca 1021}. The prognosis is relatively favour 4216}. A male predilection is found in
pacity to enter lymph nodes and tissue able, even in cases of relapse, which has some studies {3180,4216} but not others
through high endothelial venules {2373}. been reported in at least one quarter {1688}. Some cases are associated with
of patients {859,860,1021}. In contrast, prior or metachronous low―grade lympho
Stromal―derived dendritic cell types widespread disease requires chemo ma, usually follicular lymphoma, but also
FDCs, which are resident within primary therapy and has a poor prognosis overall chronic lymphocytic leukaemia/small
and secondary B―cell follicles, trap and {859,860,1021}. lymphocytic lymphoma {1172,3633}.
present antigen to B cells. FDCs can
store antigen on the cell surface as im
mune complexes for long periods of time
{4139}. FDCs appear to be closely re
lated to bone marrow stromal progenitors
with features of myofibroblasts {2436}.
They are a non―migrating population
that forms a stable meshwork within the
follicle via cell―to―cell attachments and
desmosomes.
Fibroblastic reticular cells are involved in
maintenance of lymphoid integrity and
in production and transport of cytokines
and other mediators. In lymph nodes,
they ensheath the postcapillary venules
{1955,4165}. They are of mesenchymal
origin and express SMA. Plyperplasia
of fibroblastic reticular cells (i.e. stromal
overgrowth) may be seen in Castleman
disease {1808,2342}, and tumours of fi
broblastic reticular cells arise in lymph
nodes and have features of myofibro-
blastic tumours and closely related neo
plasms {104}.
Localization
Most cases present in extranodal sites
{1688,3180,4216}, most commonly the in
testinal tract, skin, and soft tissue. Others
present with lymphadenopathy. Rare pa
tients have a systemic presentation, with
multiple sites of involvement, sometimes Fig. 17.03 Histiocytic sarcoma. A Histiocytic sarcoma involving the bowel. B Note the abundant cytoplasm, which
referred to as malignant histiocytosis stains strongly for CD68 (C) and lysozyme (D).
{585,3180,4331}.
cells are usually large and round to oval feature is particularly common in histio
Clinical features in shape; however, focal areas of spin cytic sarcoma involving the CNS {699}.
Patients may present with a solitary mass, dling (sarcomatoid areas) may be ob
but systemic symptoms, such as fever served. The cytoplasm is usually abun Ultrastructure
and weight loss, are relatively common dant and eosinophilic, often with some The neoplastic cells show abundant
{1688,3180,4216}. Skin manifestations fine vacuoles. Haemophagocytosis oc cytoplasm with numerous lysosomes.
may range from a benign―appearing rash curs occasionally in the neoplastic cells. Birbeck granules and cellular junctions
to solitary lesions to innumerable tumours The nuclei are generally large, round to are not seen.
on the trunk and extremities. Patients with oval or irregularly folded, and often ec
intestinal lesions often present with intes centrically placed; large multinucleated Immunophenotype
tinal obstruction. Hepatosplenomegaly forms are commonly seen. The chroma By definition, there is expression of one
and associated pancytopenia may occur. tin pattern is usually vesicular, and atypia or more histiocytic markers, including
The bone may show lytic lesions {1688, varies from mild to marked. Immunostain- CD163, CD68 (KP1 and PGM1), and
3180,4216}. ing is essential for distinction from other lysozyme, with typical absence of Langer-
large cell neoplasms, such as large cell hans cell (CD1a, langerin), follicular den
Microscopy lymphoma, melanoma, and carcinoma. dritic cell (CD21, CD35), and myeloid cell
The tumour consists of a diffuse non- A variable number of reactive cells may (CD13, MPO) markers {1688,3180,4216}.
cohesive proliferation of large cells be seen, including small lymphocytes, Both CD68 and lysozyme show granular
(>20 pm), but a sinusoidal distribution plasma cells, benign histiocytes, and cytoplasmic staining. The lysozyme stain
may be seen in the lymph nodes, liver, eosinophils. Sometimes the neoplastic ing is accentuated in the Golgi region.
and spleen. The proliferating cells may cells are obscured by a heavy inflamma CD163 staining is in the cell membrane
be monomorphic or (more commonly) tory infiltrate including many neutrophils, and/or cytoplasm. Rarely, weak expres
pleomorphic. The individual neoplastic mimicking an inflammatory lesion; this sion of CD15 occurs {3180}. In addition,
Fig. 17.04 Histiocytic sarcoma. A Note the multinucleated tumour cell. B The cytoplasm is relatively abundant, but the neoplasm is difficult to distinguish from a large B-cell
lymphoma without immunohistochemical studies. C Diffuse staining for the lysosomal marker CD68.
Localization
The disease can be localized to a single
site, can occur in multiple sites within a
single system (usually bone), or can be
more disseminated and multisystem
{2668,4009}. The dominant sites of in
volvement in the solitary form are bone
and adjacent soft tissue (skull, femur,
vertebra, pelvic bones, and ribs) and,
less commonly, lymph node, skin, and and T―lymphoblastic leukaemia, with predominate, along with eosinophils and
lung. Multifocal lesions are largely con the leukaemia―associated TR gene re neutrophils. In late lesions, the LCH cells
fined to bone and adjacent soft tissue. In arrangement present in the LCH cells; are decreased in number, with increased
multisystem disease, the skin, bone, liver, this has been considered a transdifferen foamy macrophages and fibrosis.
spleen, and bone marrow are the prefer tiation phenomenon {1173}. Involved lymph nodes have a sinus pat
ential sites of involvement. The gonads tern with secondary infiltration of the
and kidney appear to be spared even in Microscopy paracortex. Spleen shows nodular red
disseminated cases. The key feature is the LCH cells. These pulp involvement. Liver involvement has
are oval; about 10―15 pm; and recog strong preference for intrahepatic biliary
Clinical features nized by their grooved, folded, indented, involvement with progressive sclerosing
Patients with unifocal disease are usu or lobed nuclei with fine chromatin, in cholangitis. Bone marrow biopsy is pre
ally older children or adults who most conspicuous nucleoli, and thin nuclear ferred to aspiration for documentation of
commonly present with a lytic bone le membranes. Nuclear atypia is minimal, bone marrow involvement {2670}.
sion eroding the cortex. Solitary lesions but mitotic activity is variable and can Large clusters or sheets of LCH cells ac
at other sites present as mass lesions be high without atypical forms. The cy companied by eosinophils can be found
or enlarged lymph nodes. Patients with toplasm is moderately abundant and within other lesions (lymphomas and
unisystem multifocal disease are usually slightly eosinophilic. Unlike epidermal sarcomas). It remains to be determined
young children who present with multiple Langerhans cells or dermal perivascular whether these constitute a local reac
or sequential destructive bone lesions, cells, LCH cells are oval in shape and tive phenomenon or a transdifferentiation
often associated with adjacent soft tissue devoid of dendritic cell processes. The process {752}.
masses. Skull and mandibular involve characteristic milieu includes a variable
ment is common. Diabetes insipidus fol number of eosinophils, histiocytes (both Ultrastructure
lows cranial involvement. Patients with multinucleated LCH forms and osteo- The ultrastructural hallmark is the cyto
multisystem involvement are infants who clast-type cells, especially in bone), neu plasmic Birbeck granules, whose pres
present with fever, cytopenias, skin and trophils, and small lymphocytes. Plasma ence can be confirmed by langerin
bone lesions, and hepatosplenomegaly cells are usually sparse. Occasionally, expression. The Birbeck granule has a
{142,2669}. Pulmonary disease in child eosinophilic abscesses with central ne tennis-racket shape, and is 200―400 nm
hood is clinically variable {2927}. crosis, rich in Charcot―Leyden crystals, long and 33 nm wide, with a zipper-like
There is an association between LCH may be found. In early lesions, LCH cells appearance.
Fig. 17.08 Langerhans cell histiocytosis, at a later stage of evolution than the case illustrated in Fig 17.07. A This bony lesion shows a greater number of foamy macrophages and
lymphocytes. B A greater number of foamy macrophages and lymphocytes are present, although nuclei with typical grooves are still discernible.
Fig. 17.10 Langerhans cell histiocytosis. A Contrast the bland nuclear morphology with that of the sarcoma (see
Figs. 17.11 and 17.12). B Staining is both nuclear and cytoplasmic with S100. C CD1a uniformly stains the cell
surface, with a perinuclear dot. D Langerin staining is more granular and cytoplasmic.
Epidemiology
LC sarcoma is rare {327,401,3180}, and
almost all reported cases are in adults.
The median patient age is 41 years
(range: 10―72 years). Rare cases may
be associated with follicular lymphoma
{4302}.
Etiology
Merkel cell polyomavirus sequences
have been identified in a subset of cases
{2786}. Fig. 17.11 Langerhans cell (LC) sarcoma. A Nuclear pleomorphism is not a feature of LC histiocytosis (LCH), but
should raise the possibility of malignancy. B S100 is widely represented, nuclear and cytoplasmic, but variable in
Localization intensity. C Lesional cells express surface CD1a more variable than in LCH. D Langerin is demonstrable, though not
as much as in LCH in this example.
The skin and underlying soft tissue are
the most common sites of involvement.
Multiorgan involvement can affect the Chromatin is clumped and nucleoli are Postulated normal counterpart
lymph nodes, lung, liver, spleen, and conspicuous. Some cells may have the A mature Langerhans cell
bone {401,1202,3180}. complex grooves of the LC histiocytosis
cell, a key clue to the diagnosis. The mi Genetic profile
Clinical features totic rate is high, usually > 50 mitoses per At least one case has been found to har
Most cases are extranodal (involving skin 10 high―power fields. Rare eosinophils bour the BRAF V600E mutation {678}.
and bone) and multifocal; high-stage (III- may be admixed.
IV) disease is seen in 44%. Only 22% of Prognosis and predictive factors
cases are primarily nodal. Hepatospleno- Ultrastructure LC sarcoma is an aggressive, high-grade
megaly is noted in 22% and pancytope Birbeck granules are present, whereas malignancy, with > 50% mortality from
nia in 11%. desmosomes/junctional specializations progressive disease.
are absent {3180}.
Microscopy
The most prominent feature is the overtly Immunophenotype
malignant cytology of a pleomorphic tu The immunophenotype is identical to that
mour, and only the phenotype and/or of LC histiocytosis, although staining for
ultrastructure reveal the LC derivation. individual markers can be focal.
Fig. 17.12 Langerhans cell sarcoma. A Tonsillar lesion in a 31-year-old man. The nuclear features and abundant cytoplasm point to a histiocytic lesion. Nuclear pleomorphism
and atypical mitoses indicate high-grade disease. B The Ki-67 proliferation index is high.
Definition
Indeterminate dendritic cell tumour, also
known as indeterminate cell histiocytosis,
is a neoplastic proliferation of spindled to
ovoid cells with phenotypic features simi
lar to those of normal indeterminate cells,
the alleged precursor cells of Langer-
hans cells. These neoplasms are ex Fig. 17.13 Indeterminate dendritic cell tumour. The lesion is positive for CD1a (A) and S100 protein (B).
traordinarily rare {104,360,412,651,2076,
3407,3672,4160,4174,4363,4374}. There and usually eosinophilic. Multinucleated Cell of origin
may be an association with low―grade giant cells may be present. In some cas Normal indeterminate cells, the postul
B―cell lymphoma {4160}. es, there may be spindling of the cells. ated precursors of Langerhans cells
The mitotic rate varies widely from case
ICD-O code 9757/3 to case. An accompanying eosinophilic Genetic profile
infiltrate is usually not present. One case has been shown to be clonal
Localization by human androgen receptor gene assay
Patients typically present with one or Ultrastructure {4374}. One case has been shown to har
(more commonly) multiple generalized By definition, these cells lack Birbeck bour BRAFV600E mutation {2916}.
papules, nodules, or plaques on the skin. granules on ultrastructural examination.
Less often, primary lymph node or splen There can be complex interdigitating cell Prognosis and predictive factors
ic disease has been reported. processes, but desmosomes are lacking. The clinical course has been highly vari
able, ranging from spontaneous regres
Clinical features Immunophenotype sion to rapid progression. There are no
Systemic symptoms are usually The proliferating cells consistently ex known prognostic factors. One case
not present. press S100 protein and CD1a. Langerin was associated with the development of
is negative. They are negative for spe acute myeloid leukaemia {4174}.
Microscopy cific B-cell and T-cell markers, CD30, the
The lesions are usually based in the histiocytic marker CD163, and the folli
dermis, but may extend into the subcu cular dendritic cell markers CD21, CD23,
taneous fat. The infiltrate is diffuse, con and CD35. They are variably positive for
sisting of cells resembling Langerhans CD45, CD68, lysozyme, and CD4. The
cells, with irregular nuclear grooves and Ki-67 proliferation index is highly variable.
clefts. Cytoplasm is typically abundant
Fig. 17.14 Indeterminate dendritic cell tumour. A This is a histiocytic-appearing neoplasm. A multinucleated cell can be seen. B Ultrastructure showing complex interdigitating
processes, but no Birbeck granules.
Definition
Interdigitating dendritic cell (IDC) sarco
ma is a neoplastic proliferation of spindle
to ovoid cells with phenotypic features
similar to those of IDCs.
Fig. 17.15 Interdigitating dendritic cell sarcoma. The tumour is vaguely lobular in lymph node and firm in consistency.
ICD-O code 9757/3
to ovoid, and may show indentations; Immunophenotype
Synonym occasional multinucleated cells may be The neoplastic cells consistently express
Interdigitating dendritic cell tumour seen. The chromatin is often vesicular, S100 protein and vimentin, with CD1a
with small to large, distinct nucleoli. Cy- and langerin being negative. They are
Epidemiology tological atypia varies from case to case, usually positive for fascin and (variably)
IDC sarcoma is an extremely rare neo although the mitotic rate is usually low weakly positive for CD68, lysozyme,
plasm, with most studies constituting sin (< 5 mitoses per 10 high―power fields). and CD45. Strong nuclear staining for
gle case reports or very small series {104, Necrosis is usually not present. There are p53 may be present. They are negative
1179,2411,2659,2812,2813,3180,3431, often numerous admixed lymphocytes, for markers of follicular dendritic cells
4286}. The largest series to date have and less commonly, plasma cells. The (CD21, CD23, and CD35), MPO, CD34,
consisted of 4 cases {1269,3180,3186}. histological appearance is sometimes specific B-cell-associated and T-cell—
The reported cases have occurred pre indistinguishable from that of a follicular associated antigens, CD30, EMA, and
dominantly in adults, although one pae dendritic cell sarcoma, and phenotyping cytokeratins. The Ki―67 proliferation in
diatric series has been reported {3186}. is necessary for precise diagnosis. dex is usually 10―20% (median: 11%)
There is a slight male predominance. {1179}. The admixed small lymphocytes
Occasional cases have been associated Ultrastructure are almost always of T-cell lineage, with
with low―grade B―cell lymphoma, and The neoplastic cells show complex inter near absence of B cells.
rare cases have been associated with digitating cell processes, but well-formed
T―cell lymphoma {1172,1269}. desmosomes are not present. Scattered Postulated normal counterpart
lysosomes may be present, but Birbeck Interdigitating dendritic cell (IDC)
Localization granules are not seen.
The presentation can vary widely. Soli
tary lymph node involvement is most
common, but extranodal presentations,
in particular in the skin and soft tissue,
have also been reported.
Clinical features
Patients usually present with an asymp
tomatic mass, although systemic symp
toms, such as fatigue, fever, and night
sweats, have been reported. Rarely,
there may be generalized lymphadeno-
pathy, splenomegaly, or hepatomegaly.
Microscopy
The lesional tissue in lymph nodes is
present in a paracortical distribution with
residual follicles. The neoplastic prolifer
ation usually forms fascicles, a storiform
pattern, and whorls of spindled to ovoid
cells. Sheets of round cells are occasion
ally found. The cytoplasm of the neoplas
tic cells is usually abundant and slightly Fig. 17.16 Interdigitating dendritic cell sarcoma. A The tumour infiltrates the paracortex. Note the residual lymphoid
eosinophilic, and often has an indistinct tissue in one corner. B Sheets of spindled cells with a whorled pattern. C The cells show marked cytological
border. The nuclei also appear spindled atypia. D Staining for S100 protein is focally positive.
Synonyms
Dendritic reticulum cell tumour (no longer
recommended); follicular dendritic cell
tumour
Epidemiology
FDC sarcoma is a rare neoplasm {104,
645,2695,3135,3180,4286}. There is a
wide patient age range, with an adult
predominance (median patient age:
50 years) {3180,3543}. The sex distribu
tion is about equal {3180}.
Etiology
A proportion of cases appear to arise in
the setting of hyaline-vascular Castleman
disease, sometimes with a recognizable
intermediary phase of FDC proliferation
outside the follicles {638,645}. The Cas
Fig. 17.17 Interdigitating dendritic cell sarcoma. A Note the paracortical pattern of tumour growth in the lymph tleman disease lesion may be found con
node. B There are scattered small lymphocytes throughout the lesion. C The CD21 stain is negative on the tumour current with the FDC sarcoma, or may
cells, but labels follicular dendritic cells in residual follicles. D In contrast, the stain for S100 protein is strongly precede the latter by several years.
positive in the tumour cells.
Localization
FDC sarcoma presents with lymph node
disease in 31% of cases, extranodal
disease in 58%, and both nodal and ex
tranodal disease in 10% {3543}. Nodal
disease most often affects the cervical
nodes. A wide variety of extranodal sites
can be affected, most commonly tonsil,
gastrointestinal tract, soft tissue, medi
astinum, retroperitoneum, omentum, and
lung {1670,3543}. Common sites for me
Fig. 17.18 Interdigitating dendritic cell sarcoma. A The cells are rounded, and the nuclei are relatively bland, but (B)
have a vesicular chromatin pattern and a single medium-sized nucleolus. tastasis include lymph nodes, lung, and
liver {737}.
Genetic profile kidney, and lung. Stage may be an im Clinical features
A subset of cases of I DC sarcoma have portant prognostic factor; however, histo Patients most often present with a slow-
clonal IG rearrangements, particularly logical features have not been correlated growing, painless mass lesion, although
when there is an association with low- with clinical outcome. patients with abdominal disease may
grade B―cell lymphoma, most likely present with abdominal pain. The tu
constituting examples of transdifferen mours are often large, with a mean size
tiation {680,1172}. In cases associated Follicular dendritic cell of 7 cm {3543}. Most patients have local
with t(14;18)―positive follicular lympho sarcoma ized disease at presentation {3543}. Sys
ma, identical chromosomal breakpoints temic symptoms are uncommon. Rare
affecting the BCL2 locus are present in Chan J.K.C. patients have paraneoplastic pemphigus
both neoplasms {1172}. The TR genes Pileri S.A. {2250,2536,4240}.
are in a germline configuration {4286}. Fletcher C.D.M.
At least one case has been shown to Weiss L.M. Microscopy
harbour somatic BRAF V600E mutation Grogg K.L. The neoplasm consists of spindled to
{2916}. ovoid cells forming fascicles, storiform
arrays, whorls (sometimes reminiscent
Prognosis and predictive factors Definition of the 360° pattern observed in meningi
The clinical course is generally aggres Follicular dendritic cell (FDC) sarcoma is oma), diffuse sheets, or vague nodules.
sive, with about half of all patients dy a neoplastic proliferation of spindled to The individual neoplastic cells generally
ing of the disease. Commonly affected ovoid cells showing morphological and show indistinct cell borders and a moder
visceral organs include the liver, spleen, immunophenotypic features of FDCs. ate amount of eosinophilic cytoplasm. The
nuclei are oval or elongated, with vesicu es, often connected by scattered, mature T cells, or mixed B cells and T cells {645,
lar or granular finely dispersed chromatin, desmosomes. Birbeck granules and nu 3180}. Rarely, there are abundant im
small but distinct nucleoli, and a delicate merous lysosomes are not seen. mature TdT+ T cells {2020,2944}, which
nuclear membrane. The nuclei tend to may be associated with paraneoplastic
be unevenly spaced, with areas showing Immunophenotype pemphigus.
clustering. Nuclear pseudoinclusions are FDC sarcoma is positive for one or more
common. Binucleated and multinucleated of the FDC markers, such as CD21, Postulated normal counterpart
tumour cells are often seen. Although the CD35, and CD23 {2862}. CXCL13 and Follicular dendritic cell (FDC) of the lym
cytological features are usually relatively podoplanin (D2―40) are commonly posi phoid follicle
bland, significant cytological atypia may tive, but are not entirely specific {4192,
be found in some cases. The mitotic rate 4450}. Clusterin is often strongly positive, Genetic profile
is usually 0―10 mitoses per 10 high―pow- whereas this marker is usually negative or In one study, 3 of 8 cases of FDC sarco
er fields, although the more pleomorphic only weakly positive in other dendritic cell ma showed clonal rearrangements of the
cases can show much higher mitotic tumours {1472,1473}. The tumour is usual IG genes {680}, and thus the presence
rates (> 30 mitoses per 10 high―power ly positive for desmoplakin, vimentin, fas- of antigen receptor gene rearrangements
fields), easily found atypical mitoses, and cin, EGFR, and HLA-DR {642,3833}, and does not exclude a diagnosis of FDC
coagulative necrosis. variably positive for EM A, S100 protein, sarcoma.
The tumour is typically lightly infiltrated and CD68. Staining for cytokeratin, CD1a, The limited cytogenetic data show com
by small lymphocytes, which can some lysozyme, MPO, CD34, CD3, CD79a, plex karyotypes {3144}. A targeted next-
times be aggregated around the blood and HMB45 is negative. The Ki-67 pro generation sequencing study revealed
vessels as well {642}. Less common liferation index is 1―25% (mean: 13%). recurrent loss-of-function alterations in tu
morphological features include epithe Positivity for the FDC secreted protein mour suppressor genes involved in neg
lioid tumour cells with hyaline cytoplasm, (FDCSP), serglycin (SRGN) and PD-L1 ative regulation of NF-kappaB and cell-
clear cells, oncocytic cells, myxoid has recently been reported in FDC sar cycle progression {1460}. BRAF V600E
stroma, fluid―filled cystic spaces, promi coma {2184A.2383A}. mutation, a common genetic alteration in
nent fibrovascular septa, and admixed The admixed small lymphocytes can be Langerhans cell histiocytosis, is reported
osteoclastic giant cells {642,645,3135, predominantly B cells, predominantly in 0―19% of cases {1386,1460}.
3136}. Uncommonly, there is a nodular
growth pattern, with the large neoplastic
cells scattered in a background of small
B lymphocytes {2390}. Rare cases may
also show jigsaw puzzle―like lobulation
and perivascular spaces, mimicking thy
moma or carcinoma showing thymus-like
element {737}.
Ultrastructure
The neoplastic cells have elongated
nuclei, often with cytoplasmic invagina Fig. 17.22 Follicular dendritic cell sarcoma. This exam Fig. 17.23 Follicular dendritic cell sarcoma. Positive
tions. There are characteristically numer ple shows significant nuclear atypia and pleomorphism. cell membrane staining for CD21 with an anastomosing
ous long, slender cytoplasmic process pattern.
Inflammatory pseudotumour―like
follicular/fibroblastic dendritic
cell sarcoma
Inflammatory pseudotumour―like follicu
lar/fibroblastic dendritic cell (FDC/FRC)
sarcoma occurs predominantly in young
to middle―aged adults, with a marked
female predilection {697}. It typically in
volves the liver or spleen, but both sites
may be simultaneously involved {134,697,
3619}. Rarely, it selectively involves the
gastrointestinal tract in the form of a poly
poid lesion {3042}. Patients are asympto
matic or present with abdominal disten
sion or pain, sometimes accompanied by
systemic symptoms {683,697,733}.
Histologically, the neoplastic spindled
Fig. 17.24 Follicular dendritic cell sarcoma. A Spindle cell proliferation. B A 360° whorl is seen. Note the occasional cells are dispersed within a prominent
multinucleated cells. C In this example, the small lymphocytes are aggregated around the blood vessels. lymphoplasmacytic infiltrate. The nuclei
usually show a vesicular chromatin pat
Two studies examining the transcriptional Prognosis and predictive factors tern and small but distinct nucleoli. Nu
profile of FDC sarcoma have revealed: 1) FDC sarcoma is usually treated by com clear atypia is highly variable; usually
a peculiar immunological microenviron plete surgical excision, with or without most cells are bland―looking, but some
ment enriched in TFH and Treg popula adjuvant radiotherapy or chemotherapy. cells with enlarged, irregularly folded or
tions, with special reference to the inhibi A pooled analysis of the literature showed hyperchromatic nuclei are almost always
tory immune receptor PD1 and its ligands local recurrence and distant metasta found. Some tumour cells may even re
PD-L1 and PD-L2, and 2) the highly spe sis rates of 28% and 27%, respectively semble Reed―Sternberg cells {3619}.
cific expression of the genes encoding {3543}, but the true figures are likely to Necrosis and haemorrhage are often
for FDCSP and SRGN {1460B,1460C}. be higher, because these adverse events present, and may be associated with a
Conventional FDC sarcomas are nega are sometimes delayed many years. The histiocytic or granulomatous reaction.
tive for EBV, whereas the inflammatory 2―year survival rates for early, locally ad The blood vessels frequently show fibri
pseudotumour―like variant consistently vanced, and distant metastatic diseases noid deposits in the walls. In occasional
shows EBV in the neoplastic cells {697}. are 82%, 80%, and 42%, respectively cases, the tumour may be masked by
{3543}. Some patients may die from re massive infiltrates of eosinophils or nu
fractory paraneoplastic pemphigus. merous epithelioid granulomas {2310}.
The neoplastic cells are often positive for
follicular dendritic cell markers, such as
CD21 and CD35, with the staining rang
ing from extensive to very focal. Howev
er, in some cases, they may be negative
for follicular dendritic cell markers but
express SMA, raising the possibility of
fibroblastic reticular cell differentiation.
Still other cases are positive for all these
markers or lack these markers {129,697,
733,1399,2293}. Both FDC and FRC
share a common mesenchymal origin,
with plasticity in the immunophenotype.
The neoplastic cells are consistently as
sociated with EBV {134,697}, which is
Fig. 17.25 Follicular dendritic cell sarcoma. This electron micrograph shows numerous cytoplasmic processes, with present in a monoclonal episomal form
one well-formed desmosome present in the centre. {3619}.Outcome data are limited, but
Fig. 17.29 Splenic inflammatory pseudotumour-like Fig. 17.30 Inflammatory pseudotumour-like follicular Fig. 17.31 Inflammatory pseudotumour-like follicular
follicular dendritic cell sarcoma. Spindle cells with dendritic cell sarcoma. In situ hybridization for EBV- dendritic cell sarcoma. The atypical spindle cells focally
vesicular nuclei and distinct nucleoli are dispersed in encoded small RNA (EBER) highlights the neoplastic exhibit immunoreactivity for CD21.
a background of chronic inflammatory cells. They show spindle cells. Nuclear atypia in some neoplastic cells
minimal to mild atypia. becomes easier to appreciate.
the tumour appears to be indolent, with Localization digitating dendritic cell sarcoma, but
a tendency to develop repeated intra This tumour can occur in the lymph lacks the immunophenotypic profile of
abdominal recurrences over many years nodes, spleen, or soft tissue {104,639, these tumour types. There are often inter
{683,697}. 1415,1874}. spersed delicate collagen fibres.
Microscopy Ultrastructure
Fibroblastic reticular cell The tumour is histologically similar to Ultrastructurally, the spindle cells show
tumour follicular dendritic cell sarcoma or inter- delicate cytoplasmic extensions and fea
tures similar to those of myofibroblasts
Weiss L.M. (i.e. filaments with occasional fusiform
Chan J.K.C. densities, well―developed desmosomal
Fletcher C.D.M. attachments, rough endoplasmic reticu
lum, and basal lamina―like material).
Definition Immunophenotype
Fibroblastic reticular cell tumour is very The tumour cells are variably immunore-
rare. Tumours diagnosed as cytokeratin- active for SMA, desmin, cytokeratin (in a
positive interstitial reticulum cell tumours dendritic pattern), and CD68.
probably constitute the same entity {104,
639}. Prognosis and predictive factors
Available data regarding outcome are
ICD-O code 9759/3 extremely limited. The clinical outcome
is variable. Some patients die of the
Fig. 17.32 Fibroblastic reticular cell tumour.
Synonyms This neoplasm features blunt spindle cells arranged in
disease.
Cytokeratin―positive interstitial reticulum poorly formed whorls, with moderate cytological atypia.
cell tumour; fibroblastic dendritic cell Stains for follicular and interdigitating dendritic cells were
tumour negative.
Definition
Disseminated juvenile xanthogranuloma
(JXG) is characterized by a proliferation
of histiocytes similar to those of the der
mal JXG, commonly having a foamy (xan
thomatous) component with Touton―type
giant cells. There is evidence for clonal- Fig. 17.33 Systemic juvenile xanthogranuloma involving liver. A The infiltrate is portal in nature but spares the bile
ity in some instances. Erdheim―Chester duct. Few Touton cells are present. B There is diffuse factor XII la staining of the portal histiocytes.
disease is distinguished from JXG in the
current classification of histiocytic neo bone marrow. Retroperitoneal and peri pattern, and stabilin―1 (MS―1 antigen).
plasms {1101}. aortic involvement is principally noted Factor XII la staining is common but not
in Erdheim―Chester disease {925,1256, universal. Fascin stains the cell cyto
Synonyms 1836}. plasm and S100 is positive in < 20% of
Benign cephalic histiocytosis; progres the cases. However, none of these mark
sive nodular histiocytosis; generalized Clinical features ers is specific for JXG. CDIaand langerin
(non―lipidaemic) eruptive histiocytosis Skin lesions other than the common pap are negative {654,2104,3513,4465}.
(skin); xanthoma disseminatum (skin ular solitary form are small (1―2 mm) and
plus mucosa lesions); Erdheim―Chester multiple. Soft tissue lesions can be large, Cell of origin
disease (adult form with bone and lung and the lesions present as mass effect. The cell of origin is uncertain. Despite
involvement) Optic lesions can cause glaucoma. Like their macrophage phenotype, the cells of
in LCH, CNS and pituitary lesions can disseminated JXG have been postulated
Epidemiology cause diabetes insipidus, seizures, hy (on the basis of shared factor XII la and
Solitary dermal JXG is vastly more com drocephalus, and mental status chang fascin immunostaining) to originate from
mon than other forms and does not pro es {925,1256,1836}. Unlike in LCH, liver a dermal/interstitial dendritic cell, but
gress to more-disseminated forms {925}. involvement does not target the biliary these characteristics have limited spec
Most deep, visceral, and disseminated system or lead to sclerosing cholangitis ificity {2104}.
forms occur by the age of 10 years, half {1826}. There is some capacity for le
within the first year of life {1836}. sions to slowly regress. JXG appears Genetic profile
to be benign, but a concomitant mac No consistent cytogenetic or molecular
Etiology rophage activation syndrome can lead genetic change has been identified. IG
There is a known association with neu to cytopenias, liver damage, and (in the and TR rearrangements are germline.
rofibromatosis type 1; patients with both systemic forms) death. There is evidence for clonality in some in
are at slightly higher risk of juvenile my- stances {1835}. Unlike in Erdheim―Ches
elomonocytic leukaemia {4508}. Patients Microscopy ter disease, there are no reported cases
with both Langerhans cell disease (i.e. The JXG cell is small and oval, some of JXG bearing BRAF mutations {634,
Langerhans cell histiocytosis; LCH) and times slightly spindled with a bland round 1553}.
JXG are also encountered. To date, no to oval nucleus without grooves and with
cases of JXG bearing mutations of BRAF pink cytoplasm. Touton cells are less Genetic susceptibility
or other genes involved in the MAPK path common at non―dermal sites. The cells An association with neurofibromatosis
way have been described {634,1553}. become progressively lipidized (xan type 1 is known in some cases.
thomatous). A mixed inflammatory com
Localization ponent is invariable. Variants include epi Prognosis and predictive factors
The skin and soft tissues are affected thelioid cells with glassy cytoplasm. The All clinical forms are benign, although
most commonly. Disseminated forms ultrastructural features are histiocytic, multiple lesions in brain, dura, or pituitary
commonly affect the mucosal surfaces, without distinguishing features {4465}. can cause local consequences and even
in particular within the upper aerodiges- death. Systemic forms that involve liver
tive tract. When skin is involved, there Immunophenotype and bone marrow have been treated with
seems to be a predilection for the head In common with macrophages, cells LCH―type therapy.
and neck region {925}. The CNS, dura, express vimentin, surface CD14, CD68
and pituitary stalk can be affected, as (PGM1) in a coarse granular pattern,
can eye, liver, lung, lymph node, and CD163 in a surface and cytoplasmic
Definition
Erdheim―Chester disease (ECD) is a
clonal systemic proliferation of histio Fig. 17.35 Retroperitoneal Erdheim-Chester disease.
cytes, commonly having a foamy (xan The infiltrate is made up of foamy histiocytes and Touton
thomatous) component, and containing cells admixed with scattered small lymphocytes in a fi
Touton giant cells (considered to be a brous tissue.
non―Langerhans cell histiocytosis). It
was first described as lipoid granuloma loventricular groove and diffuse pleural
tosis in 1930 {693}. The name Erdheim- thickening. The clinical consequences
Chester disease was coined in 1972 to are usually not severe, except for reno
recognize the contribution to the dis vascular hypertension in a small number
covery of the condition by Erdheim, who of cases, which may require stenting.
was Chester’s mentor {693}. Diagnosis of Pericardial involvement can cause peri
ECD is based on clinical features, imag carditis, effusion, or even tamponade.
ing, and histology {693,1101}. Orbital infiltration, often bilateral, produc
es exophthalmos, pain, oculomotor nerve
ICD-O code 9749/3 palsies, or blindness. Xanthelasmata of
the eyelids or periorbital tissue are further
Synonyms ocular manifestations. Pituitary gland in
Lipogranulomatosis; lipoid granuloma filtration causes diabetes insipidus and
tosis; lipid (cholesterol) granulomatosis; (less frequently) hyperprolactinaemia,
polyostotic sclerosing histiocytosis gonadotropin insufficiency, and hypotes-
tosteronism. CNS involvement produces
Epidemiology variable symptoms (cerebellar and py
ECD is a rare condition. To date, ramidal syndromes, seizures, headache,
< 1000 cases have been reported. The neuropsychiatric symptoms, cognitive
mean patient age at diagnosis is 55- impairment, sensory disturbances, and
60 years, but rare paediatric cases (i.e. in cranial nerve paralysis). The most seri
patients aged < 15 years) have also been ous neurological complication is neuro-
reported. The male-to-female ratio is 3:1. degenerative cerebellar disease, which
is present in 15―20% of patients with
Localization ECD. In particular, CNS involvement is a
Virtually any organ or tissue can be in major prognostic factor in ECD, constitut
filtrated by ECD. Skeletal involvement ing an independent predictor of death at
occurs in > 95% of cases. Cardiovas Clinical features survival analysis.
cular involvement probably occurs in The clinical course of ECD depends on
at least half of all patients, but is likely the extent and distribution of the dis Imaging
underdiagnosed. One third of patients ease. Some cases, with lesions limited Characteristic features on imaging stud
have retroperitoneal involvement. CNS to the bone, are asymptomatic; others, ies are bilateral and symmetrical corti
involvement, diabetes insipidus, and/or with multisystemic disease, may follow cal osteosclerosis of the diaphyseal and
exophthalmos occur in 20―30% of pa an aggressive, rapid clinical course. In metaphyseal parts of the long bones on
tients. CNS involvement may occur due one third of patients, bone involvement X―ray and/or symmetrical and abnormal
to tissue infiltration by histiocytes or de may cause mild pain that starts at any ly intense labelling of the distal ends of
generative alterations typically affecting time during the course of the disease the long bones of the legs (and in some
the cerebellum, with involvement due and usually affects the distal limbs. Car cases, arms) on 99Tc bone scintigraphy.
to degenerative alterations being much diovascular involvement may be asymp These findings are highly suggestive of
more difficult to treat. Xanthelasma, gen tomatic and detected incidentally by MRI ECD. Occasionally, osteolytic lesions are
erally involving the eyelids or periorbital or CT. The most common cardiovascular also seen. PET/CT has a high specificity
spaces, is the most common cutaneous alteration corresponds to circumferen for the diagnosis of bone involvement by
manifestation. tial soft tissue sheathing of the thoracic ECD. Cardiovascular involvement mani
and abdominal aorta and large arteries, fests as circumferential sheathing of the
infiltration of the right atrium or auricu- thoracic or abdominal aorta (so-called
coated aorta) and large arteries, pericar S100, CD1a, and langerin, which are all tial diagnosis with juvenile xanthogranu
dial effusion (sometimes leading to tam markers of Langerhans cells. However, loma and some nonspecific inflammatory
ponade), infiltration of the right atrium or cases focally positive for S100 have been lesions challenging {71}. Molecular analy
auriculoventricular groove, and diffuse reported {1101}. The characteristic immu sis of such cases may be useful, because
pleural thickening. Retroperitoneal in nophenotype is shared by all members characteristic genetic aberrations favour
volvement may be prominent around the of the xanthogranuloma family of histio the diagnosis of ECD {1101}. Immunohis
renal capsule (producing the character cytoses. As many as 20% of patients with tochemistry may be a useful diagnostic
istic so―called hairy kidney appearance) ECD also have Langerhans cell histiocy tool for the detection of mutated BRAF, in
and ureters. tosis lesions, and infiltration by ECD and lieu of genetic studies.
Langerhans cell histiocytosis may be
Microscopy present within the same biopsies {1101}. Prognosis and predictive factors
There is tissue infiltration by histiocytes, Cases of ECD with mutated BRAF are ECD is a chronic disease. The disease
generally with single small nuclei and positive by immunohistochemistry with outcome correlates with sites of in
foamy (xanthomatous) cytoplasm. Other the VE1 monoclonal antibody to mutated volvement; patients with CNS disease
histiocytes, with compact eosinophilic BRAF protein {1101}. or multisystemic disease have a worse
cytoplasm, may also be present. A few outcome {149A,974A}. Disease activ
multinucleated histiocytes with a central Cell of origin ity is assessed by clinical examination,
ring of nuclei (Touton cells) are frequent The postulated cell of origin is an inter imaging, and C―reactive protein values,
ly observed. Fibrosis is present in most stitial dendritic cell, but this is the subject but no disease activity score has been
cases and is sometimes abundant. Re of some debate. established. PET scans are very useful
active small lymphocytes, plasma cells, for assessments of ECD activity {149C}.
and neutrophils are also frequently pres Genetic profile Histology is not predictive of evolution.
ent. The infiltrate may easily be misdiag In several cases, clonality has been ECD may respond to therapy with inter
nosed as a reactive process. identified by classic cytogenetics and feron alpha, but many cases are refrac
other techniques. Activating mutations tory, especially those with CNS and car
Immunophenotype in MAPK pathway genes, most notably diovascular involvement {544A.1552A}.
ECD histiocytes express three mol BRAF V600E (reported in > 50% of cas Vemurafenib, an inhibitor of BRAF that
ecules common to macrophages: CD14 es), as well as NRAS mutation (recorded is approved for treating patients with
(a monocyte or macrophage receptor in ~ 4% of cases), can be detected in metastatic melanoma and BRAF V600
that binds lipopolysaccharide), CD68 ECD {71,1553}. Recurrent mutations in mutations, has recently been used, with
(a largely lysosomal macrosialin), and the PI3KCA pathway gene have also promising results {544A,1552A,1553A}.
CD163 (a haemoglobin― and hapto been described (in ~11% of cases) {71}. The reported 5―year overall survival rate
globin―scavenging receptor). In addition, of patients treated with interferon therapy
the cells express factor XII la (a tissue Molecular tests and differential is 68% {149B}. Older series, perhaps with
transglutaminase) and fascin (an actin- diagnosis less―effective therapy, reported 43% of
bundling protein), both of which are typi Some cases of ECD may have dominant patients alive after an average follow―up
cal of interstitial and interdigitating den cutaneous manifestations, without other of 32 months {4192A}.
dritic cells. The abnormal histiocytes lack organ involvement, making the differen
484 Contributors
Dr Clara D. BLOOMFIELD Dr Daniel CATOVSKY Dr Wing Chung CHAN#
Comprehensive Cancer Center Division of Molecular Pathology Department of Pathology
Ohio State University Institute of Cancer Research City of Hope National Medical Center
C933 James Cancer Hospital 15 Cotswold Road, Brookes Lawley Building 1500 East Duarte Road
460 West 10th Avenue Sutton, Surrey SM2 5NG Familian Science Building, Room 1215
Columbus OH 43210 UNITED KINGDOM Duarte CA 91010
USA Tel. +44 20 8722 4114 USA
Tel. +1 614 293 7518 Fax +44 20 7795 0310 Tel. +1 626 218 9158
Fax +1 614 293 3132 daniel.catovsky@icr.ac.uk Fax +1 626 218 9450
clara.bloomfield@osumc.edu jochan@coh.org
Contributors 485
Dr Laurence DE LEVAL Dr Lyn M. DUNCAN Dr Falko FEND#
Institut Universitaire de Pathologie Dermatopathology Unit Institute of Pathology,
de Lausanne Massachusetts General Hospital University Hospital UKT
25 Rue du Bugnon 55 Fruit Street, Warren 820 Eberhard Karls Universitat Tubingen
CH-1005 Lausanne Boston MA 02114 Liebermeisterstrasse 8
SWITZERLAND USA 72076 Tubingen
Tel. +41 21 314 7194 Tel. +1 617 726 8890 GERMANY
laurence.deleval@chuv.ch Fax +1 617 726 8711 Tel. +49 707 1298 2266
duncan@helix.mgh.harvard.edu Fax +49 707 1292 258
falko.fend@med.uni-tuebingen.de
486 Contributors
Dr Philippe GAULARD Dr Peter L. GREENBERG Dr Eva HELLSTROM-LINDBERG#
Department of Pathology Hematology Division Division of Hematology, Dep. of Medicine
Henri Mondor Hospital, INSERM U841 Stanford University Cancer Center Karolinska Univ. Hospital, Huddinge
51, Ave du Marechal de Lattre de Tassigny 875 Blake Wilbur Drive, Room 2335 Karolinska Institutet
94010 Creteil Stanford CA 94305-5821 SE-141 86 Stockholm
FRANCE USA SWEDEN
Tel. +33 1 49 81 27 43 Tel. +1 650 725 8355 Tel. +46 8 585 860 36
Fax +33 1 49 81 27 33 Fax +1 650 723 1269 Fax +46 8 585 836 05
philippe.gaulard@hmn.aphp.fr peterg@stanford.edu eva.hellstrom-lindberg@ki.se
Contributors 487
Dr Daniel M. JONES# Dr Alla M. KOVRIGINA# Dr Richard A. LARSON
Department of Pathology Department of Pathology Department of Medicine
Nichols Institute National Research Center for Hematology University of Chicago
14225 Newbrook Drive Ministry of Healthcare of Russian Federation Cancer Research Center
Chantilly VA 20153 Novy Zykovskij proezd 4, Moscow 5841 South Maryland Avenue
USA 125167, RUSSIAN FEDERATION MC2115 Chicago IL 60637
Tel. +1 703 802 7257 Tel. +7 495 612 62 12 USA
Fax +1 703 802 7113 Fax +7 495 612 49 60 Tel. +1 773 702 6783
dan.jones@questdiagnostics.com kovrigina.alla@gmail.com Fax +1 773 702 3002
dajones@mdanderson.org rlarson@medicine.bsd.uchicago.edu
488 Contributors
Dr William R. MACON# Dr Manuela MOLLEJO Dr Bharat N. NATHWANI
Department of Laboratory Department of Pathology Director of Pathology Consultation Services
Medicine and Pathology Hospital Virgen de la Salud City of Hope National Medical Center
Mayo Clinic Avenida de Barber 30 1500 East Duarte Road, Room 2287B
200 First Street South-west 45004 Toledo Duarte CA 91010
Rochester MN 55905 SPAIN USA
USA Tel. +34 925 269 245 Tel. +1 626 359 8111 ext. 64101
Tel. +1 507 284 1198 Fax +34 925 253 613 Fax +1 626 218 9020
Fax +1 507 284 5115 mmollejov@sescam.jccm.es bharat.nathwani@gmail.com
macon.william@mayo.edu
Contributors 489
Dr Marco PAULLI Dr Stefania PITTALUGA Dr Andreas ROSENWALD
Pathology Unit, Department of Molecular Laboratory of Pathology Institute of Pathology
Medicine, University of Pavia Center for Cancer Research, NCI, NIH University of Wurzburg
Fondazione IRCCS Policlinico San Matteo 10 Center Drive, MSC-1500 Josef-Schneider-Strasse 2
Via Forlanini 14 Building 10, Room 2S 235 97080 Wurzburg
27100 Pavia Bethesda MD 20892-1500 GERMANY
ITALY USA Tel. +49 931 31 81199
Tel. +39 38 250 1241; +39 38 250 2953 Tel. +1 301 480 8465 Fax +49 931 31 81224
Fax +39 38 252 5866 Fax +1 301 480 8089 rosenwald@mail.uni-wuerzburg.de
m.paulli@smatteo.pv.it stefpitt@mail.nih.gov
490 Contributors
Dr Reiner SIEBERT# Dr Christer SUNDSTR0M Dr Peter VALENT
Institute of Human Genetics Department of Pathology Medical University of Vienna
University Hospital of Ulm Uppsala University Hospital Waehringer Guertel 18-20
Albert-Einstein-Allee 11 SE-751 85 Uppsala A-1090 Vienna
D-89081 Ulm SWEDEN AUSTRIA
GERMANY Tel. +46 18 611 3806 Tel. +43 1 404 006085
Tel. +49 731 500 654 00 Fax +46 18 611 2665 Fax +43 1 404 004030
Fax +49 731 500 654 02 christer.sundstrom@akademiska.se peter.valent@meduniwien.ac.at
reiner.siebert@uni-ulm.de
Contributors 491
Dr Dennis D. WEISENBURGER Dr Rein WILLEMZE Dr Sean J. WHITTAKER#
Department of Pathology Department of Dermatology Skin Cancer Unit, Division of Genetics &
City of Hope National Medical Center Leiden University Medical Center Molecular Medicine, KCL, St John’s Institute
1500 East Duarte Road PO Box 9600, B1-Q-93 of Dermatology, St Thomas’ Hospital
Duarte CA 91010-3600 2300 RC Leiden Westminster Bridge Road
USA THE NETHERLANDS London SE1 7EH
Tel. +1 626 256 4673 ext. 63584 Tel. +31 71 526 2421 UNITED KINGDOM
Fax +1 626 301 8842 Fax +31 71 524 8106 Tel. +44 20 7188 8076
dweisenburger@coh.org rein.willemze@planet.nl Fax +44 20 7188 8050
sean.whittaker@kcl.ac.uk
492 Contributors
Declaration of interests
Dr Akin reports receiving personal consulting Dr Feldman reports owning intellectual prop Dr Kyle reports being on monitoring commit
fees from Novartis. erty rights in United States patents (held by tees or boards for Celgene, Novartis, Mer
Mayo Clinic) on reducing IRF4, DUSP22, or ck, Bristol-Myers Squibb, Aeterna Zentaris
Dr Arber reports having received personal FLJ43663 polypeptide expression and on de (Keryx), Onyx Pharmaceuticals (Amgen), and
consulting fees from United States Diagnostic tecting TBL1XR1 and TP63 translocations. Pharmacyclics. He reports receiving personal
Standards. consulting fees from Binding Site.
Dr Fend reports having received travel sup
Dr Baccarani reports receiving personal con port from Roche and Janssen Pharmaceuti Dr List reports receiving personal consult
sulting and speaking fees from Ariad, Bristol- cals. ing fees from Cell Therapeutics and Celgene.
Myers Squibb, Novartis, and Pfizer. He reports having received research support
Dr Gascoyne reports receiving personal from Celgene.
Dr B6n6 reports having received travel and speaking fees and research support from Se
lodging support from Celgene, Beckman attle Genetics. He reports receiving personal Dr Macon reports receiving personal consult
Coulter, Mundipharma, Roche and Chugai. consulting fees from Celgene, Seattle Genet ing fees from Seattle Genetics.
She participated in COST EuGESMA, which ics, Genentech, Roche, and Janssen Pharma
covered travel and lodging expenses. She has ceuticals. Dr Niemeyer reports that the University of
received personal consulting fees from Beck Freiburg receives fees from Celgene for her
man Coulter, and as head of the Harmonemia Dr Gatterman reports receiving personal consulting services.
project also received travel and lodging sup consulting fees and research support from
port from Beckman Coulter. Novartis and Celgene. He reports receiving Dr Orazi reports receiving personal consult
personal speaking fees and travel support ing fees from Incyte and speaking fees from
Dr Bennett reports receiving personal con from Novartis. Incyte and Novartis. He reports that the De
sulting fees from Celgene and providing unre partment of Pathology and Laboratory Medi
munerated consulting services to GlaxoSmith Dr Germing reports that the MDS Registry, cine at Weill Cornell Medical College has a
Kline, Onconova Therapeutics, and Amgen. through the University of Dusseldorf, has re contract with GlaxoSmithKline to review his
ceived funding from Novartis, Celgene, Chu tology slides from patients with chronic idi
Dr Birgeg&rd reports that the Department of gai, Amgen, and Johnson & Johnson. He re opathic thrombocytopenic purpura who have
Medical Sciences at Uppsala University has ports receiving personal speaking fees from received long-term recombinant thrombopoi-
received research funding from Shire. He also Celgene and Johnson & Johnson. etin therapy.
reports having received speaking fees from
Shire and Renapharma AB, and consulting Dr Ghia reports receiving personal consulting Dr Piris reports receiving personal speaking
fees from Shire. fees from Gilead Sciences, Pharmacyclics, fees from Takeda.
Merck, Medlmmune, Roche, and AbbVie. He
Dr Borowitz reports receiving research sup reports receiving personal speaking fees from Dr Porwit reports receiving meeting travel
port from Bristol-Myers Squibb, Amgen, and Gilead Sciences and research support from support from Beckman Coulter and personal
Medlmmune, and having received research Roche and GlaxoSmithKline. speaking fees from Novartis.
support from Beckman Coulter. He reports
receiving non-financial research support from Dr Hasserjian reports having received per Dr Radich reports receiving honoraria from
Becton, Dickinson and Company. sonal consulting fees from Sanofi and Incyte. Novartis, Bristol-Myers Squibb, Ariad, and
Pfizer. He reports that the Fred Hutchinson
Dr Brousse reports having received personal Dr HellstrOm-Lindberg reports receiving un Cancer Research Center receives non-finan
speaking fees from Roche, Kephren, and Acuitude. restricted research support from Celgene. cial research support from Novartis.
Dr Chadburn reports receiving personal con Dr Inghirami reports having received person Dr Siebert reports receiving non-financial re
sulting fees from Clarient. al consulting fees from Menarini Diagnostics, search support from Abbott.
Celgene, and Seattle Genetics.
Dr Wing Chung Chan reports owning intel Dr Stein reports receiving technical research
lectual property rights in a patent (held by the Dr Elaine S. Jaffe reports receiving personal support from HistoGene.
United States National Cancer Institute) on the speaking fees from the French and Australa
classification of B-cell lymphoma using gene sian Divisions of the International Academy of Dr Swerdlow reports having received person
expression signatures. Pathology. al consulting fees from Centocor R&D, Travel
Destinations Management Group, and John
Dr Cook reports having received personal con Dr Ronald Jaffe reports receiving personal son & Johnson.
sulting fees from Medical Marketing Economics. consulting fees from GlaxoSmithKline.
Dr Thiele reports having received personal
Dr de Jong reports receiving personal con Dr Jones reports that he is a director and consulting fees from Sanofi, Incyte and
sulting fees from Millennium Pharmaceuticals shareholder at Quest Diagnostics. Novartis.
and Celgene.
Dr Kadin reports receiving personal consult DrVardiman reports that his department at
Dr Dogan reports receiving personal consult ing fees from Allergan. the University of Chicago has received fees
ing fees from Janssen Pharmaceuticals. from Celgene for his consulting services.
Dr Kinney reports that the University of Texas
Dr Escribano reports receiving travel support Health Science Center at San Antonio has re Dr Whittaker reports that his research unit at
from Thermo Fisher Scientific Brazil. ceived fees from Seattle Genetics for her con St John’s Institute of Dermatology receives
sulting services. fees from Actelion, Yaupon Therapeutics, and
Dr Falini reports having applied for a patent ProStrakan for his consulting services. He re
on the clinical use of nucleophosmin protein Dr Kovrigina reports receiving travel support ports that his unit has also received fees for his
(NPM1) mutants. and personal consulting fees from Novartis. consulting services from Johnson & Johnson.
A meeting with members of the Clinical Advisory Committees took place at the Gleacher Center, University of Chicago, 31 March to 1 April, 2014.
# Co-chair
# Co-chair
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576 References
Subject index
A note on gene and protein nomenclature: Throughout this volume, we have used the Human Genome Organisation (HUGO) Gene Nomencla
ture Committee (HGNC) Guidelines (http://www.genenames.org/) for citing genes and proteins. For immunoglobulin (IG) and T-cell receptor (TR)
alleles, we have used the nomenclature assigned by the ImMunoGeneTics (IMGT) Nomenclature Committee (http://www.imgt.org/), as recom
mended by HGNC.
WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues is a Revised 4th Edition Volume of the WHO
series on histological and genetic typing of human tumours. This authoritative, concise reference book provides an
international standard for oncologists and pathologists and will serve as an indispensable guide for use in the design of
studies monitoring response to therapy and clinical outcome.
Diagnostic criteria, pathological features, and associated genetic alterations are described in a strictly disease-oriented
manner. Sections on all recognized neoplasms and their variants further include new ICD-0 codes, epidemiology, clinical
features, macroscopy, prognosis and predictive factors.
This classification, prepared by 132 authors from 23 countries, contains about 1300 colour images and tables, and more
than 4500 references.
Special Edition
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ISBN 978-92-832-4494-3