Beruflich Dokumente
Kultur Dokumente
Classification of Tumours ,
Patholog y and Genetics of Tumours
Organization Classification of
Tumours. Pathology and Genetics of
Head and Neck Tumours (3I"d edition) .
IARC Press : lyon 2005
ISBN 92 832 24 17 5
Organization Classification 01
Tumours. Patho logy and Genetics 01
Tumours of Soft Tissue and Bone
(3rd edition).
IARC Press : lyon 2002
ISBN 92 832 2413 2
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-.I
I
WH O
OMS
4th Edition
Layout
Sebastien Antoni
Marlen Grassinger
Pascale Collard
Printed by
Publisher
Participe Present
69250 Neuville s/SaOne, France
International Agency for
Research on Cance r (IARC)
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concerning the legal status 01 any country , territory. city . or area or 01 its authonltes , or concerning the
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The mootion ol scecac companies or 01 certain manufacturers' products does not imply that they are
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The authors alone are responsible fOf the views expressed in this pubhcatlQfl.
The copyright of figures and charts remains with the authors
(see source 01 charts and photographs. page 376--379)
Contents
WHO Classifjcatioo
Summary table
Introduction to the classification of tumours of
haematopoietic and lymphoid tissues
Introduction and overview of the classification of
the myeloid neoplasms
2 Myeloproliferative neoplasms
10
14
17
31
38
40
44
48
51
54
57
58
61
61
61
64
PDGFRB Of FGFRl
67
4 MyelodysplasticJmyeloproliferative neoplasms
75
Chronic mveiomonocync leukaemia
76
Atypical ctYonic myeloid leukaEmia. BCR-ABL 1 negative 80
Juvenile myelomonocytic leuk aemia
MyelodysplastiC/myeloproliferali ve neoplasm ,
urclasaifiable
5 Myelodysplastic syndromes
Myelodysplastic synd romes/n eo plasms , overview
Refractory cytope nia with unilineage dysplasia
Refractory anaemia with ring side rob lasts
Refractory cytopenia with multilineage dysplasia
Refractory anaemia with exc ess b lasts
Myelodysp lastic synd rome with isolated de l(5q)
Myelodysp lastic synd rome, uncrasslttabte
Childhood mye lodysp lastic synd rome
Refractory c ytopenia of c hild hood
82
85
87
88
94
96
98
100
102
103
104
104
109
11 0
11 0
11 1
11 2
114
115
116
117
120
122
124
127
130
130
131
131
132
133
134
136
137
138
140
142
142
143
145
149
151
15 1
152
152
153
154
t 55
155
157
167
168
171
171
171
172
173
174
174
175
176
10 Mature B-ceUneoplasms
Chronic lymphocytic leukaemia Ismail
Iympt'locytic lymphoma :f
s-een prolyrTlhocytic leukaemia
Splenic B-cell marginal zone lymphoma
Hairy cell leukaemia
Splenic B-cell Iymphomalleukaemia, unclassiliable
Splenic diffuse red pulp small B-ceil lymphoma
Hairy cenleckaeme-....anent
lymphoplasmacytic lymphoma
Heavy chain diseases
Gamma heavy chain disease
Mu heavy chain disease
Alpha heavy chain disease
Plasma cell neoplasms
Monoc lonal gammop athy 01 undetermined
significance (MGUS)
Plasma ce ll myeloma
Solitary plasmacytoma of bone
Extraosseous plasmacytoma
Monoclonal immunoglobulin deposition diseases
Extranodat marginal zone lymphoma of mucosaassocia ted lymphoid tissue (MALT lymphoma)
Nodal marg inal zone lymphoma
Follicular lymphoma
Primary cutaneous follicle centre lymphoma
Mantle cell lymphoma
Diffuse large B-celllymphoma (DLBCl), NOS
T celilhi stiocyte-rich large B-ce ll lymphoma
Primary DlBCL of the CNS
Primary cutaneous DlBCl . leg type
EBV positive DLBCl of the elderly
DLBCL assoc iated with chronic inflammation
Lymphomatoid granulomatosis
Primary med iastinal (thymic) large B-celilymphoma
Intrav escurer large B-celi lymphoma
ALK positive large Been lymphoma
Plasmablastic lymphoma
large a-ceu lymphoma arising in HHV8-associated
multicent ric Castleman disease
Primary effusion lymphoma
Burkitllymp homa
B-cel1lymphoma, unclassiliab le, with features
intermediate between DLBCL and
Burkitllymphoma
B-ceillymphoma, unctessmebie. with features
intermediate between OLBCl and
clas sica l Hodgkin lymphoma
11 Mature T- and NK-cell neoplasms
r-cea prolymphocytic leukaemia
t- een large granular lymphocytic leukaemia
Chronic Iymphoproliferative disorder of NK cells
Aggressive NK cell leukaemia
Epstein-Barr virus (EBV) positive t-een
Iymphoprol ilerative diseases of ch ildhood
Systemic EBV+ t-een Iymphoproliferalive
disease of childhood
Hydroa vacclnrtorrne-uk e lymphoma
Adull T-ceil leukaemia/lymphoma
Extranodal NK/T-cell lymphoma. nasal type
179
180
183
185
188
191
191
192
194
196
196
197
198
200
200
202
289
292
294
296
299
300
302
302
303
304
306
309
312
317
208
208
209
214
218
220
227
229
233
238
240
242
243
245
247
250
252
254
256
258
260
262
265
267
269
270
272
274
276
278
278
280
281
285
32 1
322
323
326
330
331
332
334
Contributors
Clinical advi sory oorrrnittee
Source of Charts and photographs
References
Subject index
NOS, no! otherwise specifi ed
353
354
3S6
358
3S8
360
36 1
363
365
366
369
374
376
300
429
WHO Classification
4th Edition
-.,.e"
/
,
...,...,...
-~
/,f
~~
_....i?
~.,.~
MYELODYSPLASTIC SYNDROMES
987513
996 3/3
Polycythaemia vera
995 0/3
Primary myelofibrosis
996 1/3
Essential thrombocythaemia
996213
9964 /3
Mastocytosis
Cutaneous mastocytosis
9 74011
Systemic mastocytosis
9 74 1/3
974 213
974 0/3
Extracutaneous mastocytoma
974 0/1
Refractory anaemia
9980/3
Refractory neutropenia
999 1/3
Refractory thrombocytopenia
9992/3
9962/3
9965/3
9983/3
MyelodysplasUc syndrome
associated with isolated del(Sq)
Myelodysplasticsyndrome, uncJassifiable
9966/3
9969/3
996513
9975/3
9696/3
9671/3
9666/3
9697/3
986513
MYELODYSPLASTIC/MYELOPROLIFERAnVE
NEOPLASMS
9869/3
9945/3
AML (megakaryoblastic)
with t(I ;22)(p I 3;q I 3); RBMI5-MKLI
9911/3
967613
986 1/3
9946/3
9661/3
9965/3
9966/3
9967/3
Myelodysplasticlmyeloproliferative neoplasm.
unclassifiable
9975/3
Refractory anaemia with ring sideroblasts
associated WIth marked thrombocytosis
10
WHO ctassrtceton
99 6213
99 2013
9861/3
987213
9873/3
9874 /3
9867 /3
984013
99 10/3
987013
9931 13
Myeloid sarcoma
993013
989811
Myeloid leukaemia
associated with Down syndrome
9898/3
9727/3
B lymphoblastic leukaemia/lymphoma
with recurrent genetic abnormalities
B lymphoblastic leukaemiaflymphoma
with 1(9;22)(q 34;q l 1.2); BCR-ABU
9812/3
981Y3
9814/3
B lymphoblastic leukaemiallymphoma
w ith hyperdiploidy
981513
B lymphoblastic leukaemiallymphoma
with hypod iploidy (hypod iploid ALL)
981613
B lymphoblastic leukaemiallymphoma
with t(5;14 Xq31 ;q32 ); IL3-IGH
9817/3
(TCF3-PBX1)
9818/3
T lymphoblastic leukaemia/lymphoma
9837/3
980 1/3
980613
9807/3
9808/3
983313
968913
9940/3
9591/3
Hairy eel/leukaemia-variant
959 1/3
9671/3
Lymphoplasmacytic lymphoma
9809/3
waldenstrom macroglobulinemia
Heavy chain diseases
982313
98 11/3
9761/3
9762/3
9762/3
9762/3
9762/3
9732/3
9731/3
Extraosseous plasmacytoma
9734/3
WHO classification
11
~l..
9699/3
972513
9699/3
9827/3
9699/3
9719 /3
9690/3
9717/3
9690/3
971613
959713
967313
Subcutaneous panniculitis-like
T-cell lymphoma
970813
Mycosis fungoides
970013
Sezary syndrome
970113
Follicular lymphoma
Paediatric folliculaf lymphoma
9688/3
968013
9680/3
9680/3
9766 /1
9679/3
971213
9737/3
Plasmablastic lymphoma
973 5/3
l arge Bccell lymp homa arising in HHV8associated multicentric Castleman disease 9738/3
Primary effusio n lymphoma
9678/3
968 7/3
9834/3
983 1/3
983113
9948/3
WHO
ciassitcenon
lymphomatoid papulosis
9718/1
9718/3
r -ceuivmpncma
12
9726/3
9709/3
9709/3
970213
970513
970213
HODGKIN LYMPHOMA
Nodular lymphocyte predomi nant
Hodgkin lymp homa
9659/3
9650/3
9663/3
l ymphocyte-rich classica l
Hodgkin lymphoma
965113
965213
l ymphocyte-depleted classical
Hodgkin lymphoma
965313
Histiocytic sarcoma
9755 /3
975 1/3
9756/3
9757/3
975813
9759/3
9757/3
P1asmacytic hyperplasia
9971/1
9971 /1
Polymorphic PTLO
9971/3
subjectto changes.
The italicized histologi c type s are provisional enti ties , for
which the WHO Working Group fe ll the re was insufficient
evidence to recognize as distinct diseases at this time.
"These lesions are classi fied according to the leukaemia
or
WHO classification
13
.. .
NL Harris
E. Campo
E.S. Jaffe
SA Pileri
II should serve as a ba sis lor future investigation . and should be able to incorporate
new information as it becomes ava ilab le.
Classification has two aspects: clas s discovery - the proces s of identifying categories of diseases, and class pre diction
- the process of determining which cere-
gory an individual case belongs to. Pamerogi sts are critical to both processes .
The World Hea lth Org anizati on (WHO)
Classi fication of Tumours of the Haematopoietic and Lymp hOid Tissues (4th Edition ) was a coll aborative project of the
European Association for Haematopathology and the Society lor Hematopatholog y.
It is a revision and update of the 3rd Edition 11039 }. which was the first true
worldwide consensus c lassific ation of
baematoiocic malignancies. The update,
which began in 2006, had an a-me mbe r
steering committee composed of membe rs
of both societies, The Steering Comminee,
in a series of meetings and discussions,
agreed on a proposed list of diseases
and chapters and selec ted authors. with
input from both soc ieties. As with the
WHO 3fd ed ition 189 71. the advice of clin ical haematologists and oncologists was
obtained . in order to ensure that the classifica tion will be clinica lly useful. Two Clinic al Adv isory Committee s (CAG). one for
myeloid neoplasm s and other acut e
leukaemias and one for lym phoid neoplasms. were convened, The mee tings
were org anized aroun d a ser ies of
questions, inc luding disease definitions,
nomenclature, grading. and clinical relevance. The committ ees were able to
reach consensus on mos t of the questions po sed . and muc h of the inp ut of the
14
H. Stein
S.H. Swerdlow
J Thiele
J w. Vardiman
15
CHAPTER 1
Introduction and Overview
of the Classification
of the Myeloid Neoplasms
-,
"
..
J.w. Vardiman
A.D. Brunning
D.A . Arter
M.M.Le Beau
.-"""'"
Table 1.01 Themyeloid neoplasms' major sul:9'OUJlS and d\al;U::i tstic features at ~
0.....
MPN
MyeIoidIIymphoid
neoplasmswith
eosinophilia and abriof
malilies of PDGFRA.
8M ctllularity
Usually increased.
often normalin ET
tbmaJ or sIighlIy
increased: <10% in
dI'onic phase
Increased
Normal or $IigM~
increased: <20% irl
cnronc phase
Present
Nom1al or increased:
Preserlt
..........,
--
HatrnatopOitsit
G,,,''''''',
En-.
Relatively normal
Elfectrve
relabYe/y normal,
"""""""",
"""""'"
A. Porwit
A . retten
C.D. Bloomfield
J. Thiele
.... """"
VanabIe; 008 or
"""..-
IifIeage usually
irullallyincreased
Eosinophilia
Co<m>oo
Com~
j~t 5x10ir1.)
PDGFRB Of FGFRI
MOS
"''''as."
=-
~aror
M''''''PN
"""""'
"""'..."
"""" .......
""'.
~lasia
inoreor
-,,- --_""
incl'eased;<20'10
"""'"
Usually oneormae
......
rrft'!lal cIyspIaSIa
_>2ll%.
some cases of
erylhroIeukaemia
Inel!&Cti'Ie
Cytopenia(s)
U_
......
..--
\IariabIe. WBC
Co<m>oo
......,
-......
"",",
-...
""""""'"
dyspIaslai'loneor
Moy""Y ......
WllC_
........ ........
or e"ect1ve
.........
"""'-
Mf)N, myeloproliferative neoplasms: MDS, myelod)'spla:slic syndromes; MDSlMf)N, myeIodysplasbcJmyeloprolifefalive neoplasms: AMl, ICIJIe myeloid leukaemia; ET, esseflIlaj
Ihfombocylhaemia, JMML. ju&nile myelomonocytic leukaemia, wec. wniIe bloocI e&II$.
18
'
Introduction and overview of the c lassif ication of the mye loid neoplasms
is based on cr iteria applied 10 initial specimen s obtained prior to any definitive therapy, includ ing growth lactor therapy, for the
myeloid neoplasm. The blast percentage in
the per ip her al b lood , bone ma rrow an d
other involved tissues remains of p ractica l
impo rtance to categorize myeloid neoplas ms and to judge their progression .
Cytogenetic and molecular genetic studies are requ ired at the time of d iag nosis
not only for recoq r nton 01 specific genetically d efined entities, but for establiShing
a baseline against which futu re studies
can be judged to assess disease progression. Beca use of the multidisciplinary
approach req uired to diagnose and classify myeloid neoplasms it is recomnended
thaI the various diagnostic studies be
correlated with the clinical findings and
reported in a single, integ rated report. If
a definitive classification cannot be
reached the report should indicate the
reasons why and provide guidelines for
additional studies that may clarify the
diagnosis.
To obtain consistency, the following
guidelines are recommended for the evaluation of specimens when a myeloid neoplasm is suspected to be present. It is
assu me d tha t this evalua tion will be pe rformed with full knowled ge of the clinical
history and pertinent laboratory data.
Morphology
Periphera l blood: A perip heral b lood (PB)
smea r sho uld be exa mined and co rrelate d with result s of a co mple te b loo d
c ount. Freshly mad e smea rs shou ld be
sta ined with May-Gnmwald -Giernsa or
Wright-G iemsa and examined for wh ite
bloo d ce ll (WBC) , red b lood ce ll (AB C)
and plate let abnormal ities It is impo rtant
to ascerta in that the smears are we llstained, Evaluation of neutrophil g ranularity
is imp ortant when a myelo id d isor der is
suspected; de signat ion of neut rophils as
abnormal b ased o n hypog ranular cytoplasm alo ne shoul d not be conside red
unless the stain is well-controlled . Manual
2OO-cell leukocyte di fferentials of PB
smea rs are recommended in patients with
a myeloid neoplasm when the WBC count
permits.
Bone manowaspirate: Bone marrow (BM)
as pi rate smears should also be stained
with May-G rQnwald-G iemsa or WrightGie msa for optimal visua lization of cytoplas mic g ranules and nuclear chromatin.
Because the WHO Classification relies on
percentages of blasts and other specific
Introduction and overview of the
456
F'S!. 1.01 Bone marrow tIeI:Me biopsy, Bone marfOW
b'ephinebiopsies should be alleast 1.5 em in length and
ollt<w1ed at right angles10 the cortical bone.
cells to categorize some eoutes. it is recommended that 500 nucleated BM cells
be counted on cellular aspirate smears in
an area as close to the particle and as
undiluted with blood as possible. Countll"lQ
from multiple smears may reduce sampling error due to irregular distribution of
cells. The cells to be counted include
blasts and promonocytes (see definition
below) . pronveocvtes. myelocytes, metamyelocytes, band neutrophils, segmented
neutrophils, eosiropnns. basophils, fTlQIlOcytes , lymphocytes. plasma cells , erythrOid
precursors and mas t cells. Megakaryocvtes. including dysplastic forms. are not
inc lude d. If a concomitant non-mye loid
neoplasm is present, such as p lasma ceu
myeloma, it is reasonable to exclude
tho se neo plastic cells from the coun t
used to evaluate the myeloid neop lasm. If
an aspirate ca nnot be obta ined du e to
fibrosis Of ce llular packing, touch preparatio ns of the b iop sy may yield valuable
c yto log ic informa tion, but d ifferential
co unts from touc h preparations may not
be repr esentative . The d ifferential co unts
obta ined from marrow aspi rate s should
be compared to an estimate of the p ropo rtions of cells o bserved in avai lab le
biop sy sections,
Bone marrow trephine biopsy: The contribut ion of adequate 8M bio psy sections in
the diagnosis of myeloi d neoplasms cannot be overstated. The tre phine biopsy
provides information rega rdin g overall
cellularity and the to pog raphy, propo rtion
and maturation of baematopolenc cells ,
and allows evalu ation of 8M stroma. The
biopsy also provid es material for immunohistochemical studies th at may have
diagnostic and prognostic importance. A
biopsy is essential whenever there is
myelofibrosis, and the classification of sore
entities , partiCularly MPN, relies heavily on
trephine sections, The specimen must be
19
They are usually strongly positive for n0nspecific esterase(NSE) but have no or only
weak myeloperoxidase (MPO) activity,
Promonocytes are considered as ' rroooblast equivalents " when the requisite percentage 01 blasts is tallied for the
diagnosis of acute monoblastic . acute
monoc ytic and acute myerorronocync
leukaemia. Promonoc vtes have a delicately convoluted. folded or grooved
nucleus with finely dispersed chromatin,
a small , indistinct or absent nucleolus,
and finely granulated cytoplasm (Fig 1.04
C, 0), Most promonocytes express NSE
and are likely to have MPO activ ity. The
distinct ion between mono brasts and
prornonocvte s is often difficu lt. but
because the two cell types are summated
...
.,
20
-~
~
.
Fig. 1.04 Monoblasts, promonocytes and abnormal mcnccytea from a case of acute monocytic laukaemia.
A, B Monoblastsarelarge with abundant cylOlJlasm that ma y contain a few vacuoles Of fine granules and have roullCl
nuclei withlacy chroma~n and one Of more variably prominent nucleoli. C, D Prornor.ocytes have more irregular ancl
delicately folded n~ withfine chroma~n, small indistinct nucleoli and finely granulated cytoplasm. E, F Abnormal
monocytes appear immature, yet have more condensed nuclear chroma tin, con'o'Q/uled Of fdded nuclai, and more
cylopIasmiC granulaboo (Courtesy of Or. J. Goasguen).
21
<--U II 7+
C U 1I7+
c m l 7-
lib-
llb-I+
C D.l6-
' fh+
C DJ6 -
CD l 6 -
CDIJ ~'-
Cll1J~.-
C D235. -
C U,J. C O lJ5.prvQ')"lbn>bla. 1
b ....p bllk:
tory l b rub l.,.
"'"
pc.ol ycbrvm.lk
toryl h ruh l 1
C U lM-
C I)l63+
C IU+
C OU +
+
C IUJ+
C O IS+
C IU J +
C D36-+
C I)6" +
HL-\ -DR +
C O ll b+
C D I 4+
C O}4...
C IU +
C D U'"
C O l5-+-
COll ++
mon.. hl . ~1
p rumo"ucy'\'
,------''-,
r'----,
C O Il 7 +1C ll1 J+
C D 33 +
MPO+
C:0 6 5+
C D I5+/
C IH J d lm
C IU J +
MPO+
C ))65+
C D I5 +
C U ll b+'_
C D 3.. +-+
1I1.A.-UR
C D .\N+-+
m nmx: yl f'
em sC lU J '"
M''O+
C D6 5+
C U15+
C D I I II+
C1U 5tlim
e m s-
Un _
C D J .....
C IH M+
C D U JC1U5R A+
_n_
C D3.. +
ClHM _
C D IlJ-.
C1 U 5 HA TI'O -R+
22
C UJ4+I.
C DJ M., _
C D61+
C I).&I+
ce-e-
C DJ4
C DJ8+
C 06 1+
C 04I +
C04 l +I
C U"' l+
C DJ ....
C OM+
IH...A-O R +
C O l lb++
C O l -t-t
J
the utility o f in,s:livid ual markers in identify-
cvto-
"""'" _ _ (PM~
ESSoElI'IUl ~ (ET)
Oworic eosnophic Ieukaer'ru. NOS lea NOS)
"'-
MyelqiltMaabYeneoplasm,loI'ldasslJable (UPN,U)
23
ABU
CML
Myeloid neoplasms
with eosinoph ilia
PV
PDGFRA,PDGFRB,FGFR1
PMF
ET
Mastocytosis
KITD816V
Fig. ' .06 Myeloprololerative neoplasms (t.4PN)and oIhet myeloid neoplasms associated W11t1 mutaliOnlrearrangement of tyrosine kinase genes.
[
j
BCR-ABL1 fusion gene in CMl . are essocia ted with consistent clinical, laboratcry
and morp hologic find ing s that allow them
to be utilized as major criteria for classfication, whereas others provide proof that
the myeloid prolifera tion is neoplastic
rather than reactive.
Ac quired somat ic mutations of JAK2. at
chromosome 9p24. have been shown);)
playa p ivotal role in the pathogenesis d
many cases of BCR-ABL 1 negative MPH
11 04 4, 1163, 1186, 1287A , 12881. The
most comm on mutation , JAK2 V6 17F, results in a constitutively active cytoplasmic
JAK2 that activates signal transducer and
ac tivator of transcription (STAT), mitogen
activated p rotein kinase (MAPK) and
phospholidyllnositol a-kmase (P13K) sigo
naling pathways to prorote transforma1Ol
and proliferation of baemaroooenc pro.
g enitors (Fig. 1.07). The JAK2V617Fmutation is found In almost all patients wit~
polycythaemia vera (PV) and in n ear~
one-half of those with primary myelofil:Jrosis
~
I
I
Akt
TO
""FoxO
'-.,
(0
I
E0
I
~0
I
@jJ
or
Fig. 1.07 MecRanism activatiOn aI JA1<2 kinase actMty by rn.rtaIiOns in the JAK2 Signalirg pathway. It. Cytokile
ligallds normaHy bind cytokine recepIors, .tlich results in JaI'llS ki\ase 2 (JAK2) pIlosphoryIatio, recruilmenI aIsq.at
\rcInsduc:er and actrvator allJansaipbon (Stal) signaling protelns and pIlospholyIation alld activatiOn of downstream
SigRaIing pathways ind\.I:lIng SIal ~ lactor&,lT\IlogefIlIdMlled proIeIn U1ase(MAPK) sigMWlg proteins , arIl
the phosphotidyinos 3-kinase (Pl3K)--Akt pathway B The JAK2 Vfi17F alld JAK2 ewn 121Tl11anl kilases bind
cytokine recepIors, are phosphorylated il the absence alligand and lead to ~ activation aI 0JwIn.
streamsignaing palhways. C Bycontrast, MPl. W515lA( rrUal'lllhiOi'~ recepb$ are able 10 phospI1Oi'y\ale
ri1-Iype JAK2lithe absence 01 hanbopoleIi., and red II tle aetwabon of signaling paltrways <townstream 01 IN<2.
Negative regulation 01 JAX2 sigNIng is nonnaIy medIaIed by suwessor of cytome s9laIilg (Socs) proWls, most
notably SOCSl alld SOCS3; recent dala i'ldic3Ie Ihalthe JAK2 V617F aIeIe night escape negatiYe IeectIacll by
SOCS3. Repro:U;:ed from {1287AI
25
rearrangemeot
Myeloid aoo IylTVIOid neoplasms wiltl
FGFRf abnormallbes
TableU4
~neopIasms
(MDSlMPN).
MyekldysplastcIMyeloproliferative neoplasm,
undassdiable (MDSlMPN ,U)
Provisional entity: Refractory anaemia wittl Mrlg
sideroblasts and ltJramt>ocytasis (RARS-n
should not be categorized as MDS/MPN.
and in contras t to the criteria used in the
3rd edition of the WHO classification,
cases of CMML with PDGFRB rearrangements are also excluded
Rationale for diagnosis and classification
of MDSlMPN
This diagnostic ca tegory was introduced
in the 3rd edition amidst controversy as to
wl1ether some entities, particularly CMML,
would be better categorized as either
MDS or MPN depend ing on the extent of
mye loprol iferation as evidenced by the
WBC cou nt. Some cases of CMML have
low neutroph il co unts and only modestly
elevated monocyte co unts and resemble
MDS clinically and morphologically
whereas others have markedly elevated
WBC counts and org anomegaly more in
keep ing with MPN. yet criteria that clearly
distinguish biologiCally relevant subtypes
of CMML remain to be defined .
To date, a lew cases of CMML and atypical chronic myeloid leukaemia, BCR-ABL1
neg ative (aCML) have been reported to
demonstrate JAK2mutations that characterize BCR-ABL 1 negative MPN, but the
prol iferative aspec ts of most cases of
MPD/MPN are related to aberrancies in
the AAS/MAPK signaling p athways. In juvenile myelQmonocytic leukaemia (JMML)
nearly 80% of patients demonstrate
mutually exclusive mutations 01 PTNPN1',
NRAS or KRAS, or NFl 11329. 2096,
21621. all of wl1ich encode signaling proteins in AAS dependent pathways, and
approximately 30- 40% of cases of CMML
and aCML exhibit NRAS mutations {1686,
231 1, 24171. In view of the lack of any
spec ific genetic abno rmality 10 suggest
that these entities should be relocat ed 10
another myeloid subgroup, they remainin
this "mixed" category which acknowledges
the overlap that may occ ur between MDS
and MPN. Casesof CMML with eosinophilia
associated with PfX3FRB rearrangements
are excluded , but rare cases of CMML
by mixed MOS and MPN features associated with pro minent pseuoo-Percer-Hoet
anomaly of me neutroot urs. low 8M blast
count, and a rap id ly p rog ressive clinical
course. Most c ases rep or ted have a
prominent monoc ytic component and
meet the c riteria lor CMML, b ut in some,
the PB monocyte coun t may not reach the
low er threshold fo r that dia gnosis 1708,
14371 In cases that do not fu" ill the c riteria
lor CMML or another well de fined myeloid
category. desig nation as MOSIMPN. unclassifiable. with isolated isochromosome
17q abnormality, is most ap propriate.
50% of the BM ce lls are erythroid precutan d for which ac ute eryt hroid
leukaemia is co nsidered a po ssible dia gnosis. In such cas es. if blasts acc ount for
fewer than 20% of WBC in the PB and 01
all nucleated 8 M cells, and for less than
20% of the non-erythroid c ells in the BM
(lym phocytes, plasma c ells, etc. are also
excluded in this latter calculation), the
case is considered as MOS. In this scenario. there is lac k of consens us among
mem ber s of the WHO committee as to
whether the MOS should then be classified according to !he b last perceotace of
all nucleated 8 M cells or according 10the
blast percentage of all non-erythroid BM
cells. but the majority recommend s that
the MOS be classified using the blast percentage of all marrow nucleated cells.
Many cases of refractory anaemia with
ring sioerobrests as well as refrac tory
anaemia have marked eryth roid proliferation and using the b last percentage of the
non-erythroid cells lo r classification of
such cases might c ause these to be
placed in an unnecessarily high-risk category. On the other hand , if there is
severe multiline age dysplasia, very bizarre
erythroid morphology. and/o r minimal or
no maturation to segmented neut roobus.
and the btast percentage of total 8 M cells
is not sufficienl to place the c ase into a
hig h-g rade MOS c ategory, the case
shoul d be flag ged tor clin ical co rrelation
an d discussion, with ca refu l follow- up
(Tab le 1.06 ). More stud ies are needed
however to cla rify this controversial issue.
sors.
C*hood ~ syrw:lrome
Pn:MsicnaI nty Refra:t:ry ~ ~ d*hlod
(ROC)
27
... . -
Table 1.06 PMSib1e d~ when erythroid precursors ~50'10 of bone marrow nucleatedcells.
- -_."""""-
% Erythroid ~
Blocdhnarrow findirlgl.
0ltIer f1odlng&
DIagnosis
~ blasts in blood or
of all nucleatedmarrow
inmatln IJyIIwid
>5011
' 50'
blasts <m d II
"""""
"""'"' """""-
related changes
_01"
"""""'
Miwnall <Wly
fIm.>MiKi1I
~celsll
.."
"""""
... """""
~roid' cells
-,-.......
MDS: classifyMDS
acx:oroing 10 number of
blasts in blood and blasts
as pen:entIge d II
"""""" """""-
all myeloid lineages. Worldw ide the incidence is app roximately 2.5-3 cases per
100,000 popu lation per year, and is
reportedly highest in Australia. Western
Europe and the United States. The median age at diagnosis is 65 years, with a
slight male predominance in most c ountries. In Children less than 15 years of age,
AML com prises 15- 20% of all c ases of
acute leukaemia, with a peak incidence in
the first 3-4 years of lite 1559A, 2463AI.
The requisite blast perce ntage for a diag
rosrs of AML is 20% or more mveiobtasts
and/or monoblastslpromonocytes and/or
meg akaryo blasts in the P8 or BM. The di agnosis of myeloid sarcoma is synonymous with AML rega rdless of the numb er
of blasts in the PB or BM, unless the
patient has a prior history of MPN
or MDS/MPN, in wh ich c ase myeloid
sarcoma is evidence of acute transformation . The d iagnosis of AML can also
be mad e when the blast percentage in
the PB and/or BM is less than 20% if
there is an associated t(8;21XQ22;Q22),
inv(16)(p 13.1Q22), t(16:16XP13.1;Q22) or
t(15;17)(Q22:q 12) chromoso mal abnormality, and in some c ases of acute erythroid IeuI<aemia when eryttvoid precursors
ac count for more than SO% of the BM
ce lls and blasts account for more
than 20% of the non-erythroid marrow
ce lls (See Chapter on acute myeloid
leukaemia, NOS).
Although the diagnosis of AML using the
above guidelines is ope rationally useful to
indica te an unde rlying defec t in myeloid
28
IntroductIOn and
matur ation, the d iagnosis doe s not necessar ily translate into a mandate to treat
the pa tient for AML; c linical factors. including the pace of prog ression of the
dise ase, most atways be taken into consloerenon when deciding therapy.
Rationa le for the WHO diagnosis and
classification of AML
The 3rd edition 01 the WHO ctassrncatoo
ushered in the era of formal incorporati on
of gene tic abnormalities in the diagnostic
algor ithms for the diagnosis of AML. The
abnormalities included were mainly ch romosomal transiocenoee involVing transcription fac tors and associated with
charac teristic cl inical , morpholog ic and
immunophenotypic features Ihat formed
a clinico-pathologic-genelic entity. As
know ledge regarding leukaemogenes is
has increased, so has the acceptance
that the genetic abnormal ities leading to
leukaemia are not only heterogeneous,
but complex, and multiple aber rations
often coo perate in a multistep proce ss to
initiate the co mple te leukaemia phenotyp e. Expe rimental evide nce suggests
mat in many ca ses, although rearrangement of genes such as RUNX1, CBFB or
RARA that enc ode transcncuon factors
impair myeloid differentiation, a sec ond
genetic abnormality is necessa ry to promote proliferation or survival of the neoplastic clone (Fig . 1.08) 11135A I. Often.
the additional abnormalities are mutations
01genes such as FLT30 r KITthat encode
proteins that act ivate signal transduct ion
Class I mutations
Class II mutations
FLT3-ITD
FLT3-TKO
KIT
RAS
PTPN11
JAK2
PML-RARA
RUNX1-RUNX1Tl
CBFB-MYH11
MLL fusions
CEBPA
NPM11
Proliferation and/or
survival advantage; not
affecting differentiation
Impaired haematopoietic
differentiation and
HqUent .poptos~
.ub-
29
30
Introduction and ove rview of the classification of the myeloid neo plasms
/~
Definition
ICD-O code
9875/3
J W _Vard iman
J ,V. Melo
M . Bacc arani
J . Thiele
Synonyms
Ch ronic gr anulocytic leukaemia ; ch ronic
myeloid leukaemia
Epid emiology
CM L has a wo rldwi de annual inci dence of
1- 2 cases per 100 ,000 po pul ation. The
cens
32
Myelop",lile"tive neoplasms
Morphology
Chronic phase (CP)
In CP the peri pheral blood (PB) shows
leukocytosis (12-1 000x 1()lI1L. median
- 1OQx1CPIL) d ue to neutrop hils in different
stages of maturation wit h peaks in the
pe rcent of mye locyt es and seg mented
neutrophils 1486, 755, 1164, 1942, 20671 .
There is no significant dysplasia 11 89 ,
2458 }. Blasts usua lly account tor less than
2% of the wac 1189, 206 7l. Ab solute
basoph ilia is invariab ly pr esent and
eosinop hilia is common (2067l. Ab solut e
monocytosis may be p resent but the frac tion of rnonocvtes is usua lly <3% (189 1.
except in rare c ases assoc iated with the
p 190 BCA -A8 L 1 tsoto rm. in whi ch case
monoc ytosis is nearly always present and
con fusion with c hronic myelom onocytic
leukaemia is possib le 114581 The platelet
co unt usually rang es tram normal to
gre ater than 1000 x1()91L and thrombocytopeni a is uncommon 119421. The 8 M cellular ity is incr eased due to g ranulocytic
proliferation with a maturation pattern similar to that in the blood 1486, 1534 1. In
biopsy sections the paratrabecutar Cuff of
imma ture neutrophile is often 5- 10 cells
thick in contrast to the normal 2-3 cell
layer and 1he mallie neutroph~s are situated
in the intert rabecutar areas. Eosinophils
may be prominent. Blasts usually account
Fig. 2.04 CUL dVonicphase, "Pseudo-GaiI:: eels in CML.. A Pseucb-Gauchef cells In COITIllOl'Ily obsenoed i'l
the marTOW aspIate$ aI pabents WIth CML. B They Ina)' also be ~ as loamy or strialed eels in ITIlI"I'OW
biopsy sedions. TheseI'listo:)"es are seaJndary " increased celllm::Ner. <We del'ived from the neopIaslic dln and
easily ~ from the &mal rnagakaryoc:yte tt-" rn8f9I").
33
Fi9. 2.05 Splenomegaly 11 CML A The gross appearara of Itle spleen is solid and uniIonnIy deep red, although areas of inlartt IlI8)' appear as IlghIer aIloured regions, 8 TIll
red pljp disbibubon of!tie infiltrate usually (XIll1lfesse5 alldobhlefates lhe while pulp. C The leukaemiC cells are present in!he SInuses as wei asin!he spleniccools of lhe red pulp.
34
Myeloproliferative neoplasms
v- --
0 0
II
Irrm.oopheootyp
F"tg. 2.08 0r.I... myeloid bla ~ ptlase. A ~ l:tlodofl pllientWllh myeIoidbllst phase . Tht ma;onty oftle "'*
l:tlod oats<n blasts. B.C Sheetsof ~ in' " bin! ITWTtM bqIsy. D Myeloperolidase del8cllId Imu'oo
tvmchei,U1. pIWng ee myetoid lineage of hi blasl P'~lIlul.
35
Fig. 2.10 0Al.. myeloid bIasI phase , in 8Ile~ site . A,8 l~ node biopsy obtained from iI pabent with a tIiStor'y 01 CML lor 3 ~_ The lymph node d1iteclln is
Iatgely eIIaoad by a proIrfefatlon 01 medir.Jmkllarge Sized cells. C l~ im~ confirms the myeloid lineage ollhe blasts,
of origin
36
been repor ted to involve the g ranulOcytemac rop hage prog enitor pool rather than
the naerroooletc stem cell pool 114741.
Whether the same applies to lymphoid BP
is not know n,
L-
\m t?9;22)(q34 ;q11.2)
---.J
BCR.ABL1
813a2
.1402
p210
A
rig. 2.1 2 ... SC1lemabc representabDn of !he U:9:22) chromosomallranslocabon, me fusion mRNA ~ encoded by !he BCR..-&.1 tl)trid gene geoeqted in !he 22q. or
F'IlIacletiIlia (PIli chi OliiOJmll , and hi nnslated BCR-ABL1 kl5ion protOO, ...nose oncogenic ptqlllrties I'e/y pl'lIl'IiIdy' on ts conslllUOVely actrvaled tyrosne U1ase en:xlded bytie
s..:~ I ISH1)domain i'llicatedby ltle red Orde. Some of It1e oltlef ~ UlcWlaI don'IaI'S CQ'1tnlluted by tie BCR andABLl pcnons oIlhe Oi iCClPi oceifl n sI'lowfl.
These n 1Ile dMnensaliOn domain (00): Vl n wtlich is !tie allloptlosphoryllion s<1e crucial lor binding to 008-2; the ptIospho-Ser and -Thr SH-binding dorr'I<Wl; a region
turdogaIs tI Rho guarlIdne ru:Ieoticle exet.ange laclots (Rho-GE.F): ee ABll regoJa1o"y SH3 and SH2 domains; Y412 as !he map Slt8 r:I ~ wiltlillhe StU
IrNse dcrnarI; ru::i8ar kx:att:alitw, J9IaIs (tt.S) and lhe DNA- and adn-I:imng danains.. B Mectllnsm 01 adIion 01 acR-A8I..l \yrtliW1e kNse ~ 'M1ereas h physdogicaI
tning rJATP III its poDelllbn BCR-ABLllO phosphorylate seIeded tyrosWle residues onrts SI.tIslrales (left <iagam). a synlheIicATP rrmc such lIS inalinlb fits t1ls poct.et
Iiaopm),lluliXles nol prOYide Ihe esseoIiaI phosphate ~ lO be transfem!d k11he SI.tIslraIe Thedownstream d1aIn 01 reactions is lhenhaAed because,lfII'iltI irs tyrosines i'llhe
~ form. ee subslrate does not assume the necessary ronJoonabon 10erlSlH associabon WIlh itS efleclor.
t,..
6151
37
B.J . Bain
Definition
Chronic neutrophilic leuk aemia (CNL) is a
rare myeloproliferative disease . cha racterized by susta ined peripheral bloOd (PB)
neut rop hilia. bone marrow (8M) hypercellulanty d ue to neutrophilic granu locyte proliferation. and hepatosplenomegaly. There
996313
Epidem iolog y
The true incidence 01 CNL is unknown ,
Etiology
The cause of CNL is not known. In up to
20% of reported c ases, the neutrophilia
wa s associated with an und er ly ing neoplasm , most usua lly multiple my e loma
1355, 58 4, 20761. To dale, no cases of
CNL as sociated with myeloma have been
rep orted in wh ich a clonal c hromosomal
abnormal ity o r evid enc e of cronauty by
molecular tec hniques has been co nvinc ingly d emons trated in the neutroonns
120771. II is thus likely that most cases of
CNL associated w ith mye lom a are not
autonomous prolif erations of the neuuophi ls , but are secondary to abnorma l
cvtokme release from the neoplastic
plasma cells or othe r cells regulated by
the plasma cell population . The same
may be true of C NL associated with other
neoplasms. However, it should be noted
that evolution to acute myeloid leukaemia
(A ML) occurred in one pat ien t with CNL
associated with multip le my eloma {5841 .
Sites of involvement
The PB and BM are always involved, and
the splee n and liver usually show leukaemic
38
..
. :t
Fig. 2.13 Ovtnc newophIc ~ _ A The neutrophiia dIatac:IeristIc oIltie ~ t*:xx1 il CNL B The. .
granUatiolllXlr!JTllldy obset'o'ed. Reproduced from Anastasi and ~ (3SAJ. C The bone rnatfOW asprDt SI!W
der!lcmIrates neutrophil proWerabOn from myebcytes to ~ forms 'Mlh toO: granu/abOn, 1M no olIW"
s9'ificant abnormaibes. D The bone marrow biopsy specimen is hyperceWar, showing a markedly eIevMld
myeIoicI:erylM:lid ratio WI!h increased IIJrmers of nNrophk, partK:tarly maturesegmented bms.
--
Cy\ll(:hen>stry
The neutrophil alkaline phosphatase score
IS usually norma l or inc reased. but no
OCher cvtocoencarabl"l()(mahty has been
fepor1ed
"""""'"
Table 2.01 Diagnostc criteria lor chronic neu troph~ iC Ieu ~aemia.
Peripheral blood leukocytosis, wac <:25xW/L
5e9meflted neutrophils andband folms Bftl >80% of wtlite bloodceas
ImmatlKEl granu~es (promyelocytes, myebcytes, metamyelocytes) <10%ofwtllte bloodcells
Myeiotllasts<1 %of I't11ite blood cells
2.
3.
Hepatosplenomegaly
No ideflt!f.able caJ5e lorptrysioIogic neutrophika or. if presanl, denw:lnslration 01 donaIiIy ofmyeloid eels
by cytogenelic or molllo.I* studies
Noinfecbous or J1lIarnmaIory JlItlC8SS
6.
7.
8.
1909. 2504 1.
No_.. . .
39
Polycythaemia vera
Definition
Poiycvtbaemra vera (PV) is a chronic
myeloproliferative neoplasm (MPN) characterized by increased red blood cell
production independent of the mechanisms
that normally regu late erythropoiesis.
Virtually all pat ients carry the somatic
ga in-ol-lunction mutation 01 lhe Janus 2
kinase gene, JAK2 V617F or anothe r
functionally similar JAK2 mutation thai
results in proliferation not only 01 the
erythroid lineage but of the granulocytes
and megakaryocytes as well , t.e "panmyelosi s". Three phase s 01 PV may
be recognized : (1) a prOdromal, prepo lycythaemic phase c harac terized by
borderline to only mild erythrocytosis; (2)
an overt poIycythaemic phase. associated
with a significantly increased red cell mass ;
and (3 ) a "spent" or post-oo'vcvtnaemic
myelofibrosis phase (post-Pv MF) in
which cvtooeruas. including anaemia . are
associated with ineffective haematobone marrow (8M) fibrosis. extramedullary haematoooesrs (EMH) . and
hypersplenism, The natural progression
of PV also includes a low incidence of
evolution to a myelodysplastic/preleukaemic phase and/or to acute leukaemia
(AML). All causes of secondary eryth rocytosis, inheritab le po lycythaemia and
othe r MPN mus t be excluded. The d iagnosis requires integration of c linica l, laboratory and 8M histolog ica l features as
outlined in Tab le 2,02 .
J. Thiele
H ,M , Kvasnicka
A,Orazi
A TeHeri
G , 8irgegard
Evolution _
...10"Jl,,;15'Mi
....21 Idl!!!9-U-
Manifestation
- - - - - - - Transformation
Post -polycythaemc
myeIokl metaplasia
(post-PV MF)
1
t
. - -_ _ 20 %
~.Iy
L.._ < 10 %
definite increase In
red cell mass
I
Post-PV MF WIth
biasbc transformation
11
II
Tennin.J1 sage
poese.
ICD-Ocode
9950/3
Synonym
Polycythaemia rubr a vera,
Epidem iology
The reported annual incidence of PV
increases with advanced age and varies
from 0.710 2.6 per 100 000 inhabitants in
Europe and North America. but is much
Iavver in Japan 110591. Most reports indicate
a slig ht male predominance, with the M :F
ratio rang ing from 1- 2:1 ISO. 1389 1. The
median age at d iag nosis is 60 years . and
p atients you ng er than 20 years old are
only rarely reported 117001.
40
Myeloproliferative neoplasms
Etiolog y
The underlying cause is unknown in most
cases. A genetic predisposition has been
reported in some famil ies 11778 , 20321.
Ionizing rad iation and occupational
expo sure to toxins have been suggested
as po ssib le causes in occasional pa tients
1312}.
Table 2,02 Diagnosticcriteria lor poI~emia vera (PV). Diagnosis requires the presence 01 bottl major criteria and
onemM criteriOn or \he presence of the firstmajor cri tel'\orl togeth&r with two minor criteria.
Majorcriteria
Minor criteria
t . Bone marrow biopsy shoWing hypercellularily lor ageWIth lJirIeage growttl (panmyelosis) wiltl prrITWIefll
erytIvoid, granulocytic aodmegakaryocytJc proMerabon
Clinical features
The major symptoms of PV are related to
hypertension or vascular abnormalities
causedby the increased red cell mass, In
nearly 20% of patients an episode of
venous or arterial thrombosis, such as
deep vein thrombosis, myocardial ischaemia or stroke, is documented in the
medical history lSOI and may be the first
manifestation of Pl/lSO, 197, 1389.20711.
Mesenteric, portal or splenic vein thrombosis and the Budd-Chiari syndrome
should always lead to coosideration of PI/
asanIJlderlying cause and may precede
the onset 01 an overt polycythaemic
phase ISO, 2701. Headache, dizziness.
visual disturbances and paraesmeses
are major complaints, and pruntus. erythromelalgia and gout ere also common.
In the full-blown polycythaemic stage
physical findings usually include plethora
and palpable splenomegaly in 70% and
hepatomegaly in 40% 01 patients 11445,
20711.
Clinical laboratory studies that aid in
confirmation 01 the diagnosis of PV
include subnormal erythropoietin (EPO)
levels [223. 15271. endogenous erythroid
c:oklny (EEC) formation 15951. and oetectoo
at the JAK2 V617F or functionally similar
mutations, e.q. JAK2exon 12 mutations
11 981,2168. 21771.
Occasionally. patients may present with
clinical symptoms suggestive of PV b ut
WIth a haemoglobin level and/or red cell
volume not sufficiently e levated to substantiate the d iagnosis. Such patients
may be in the pre-oo'vcvtbaemrc phase,
wtlich was previously refe rred to by some
authors as "latent PV' or as ' p ure id iopathic erythrocytosis" 1197,1559, 1715,
1697,2224), The detection of a sub normal
EPO level, a JAK2V617F or funct ionally
similar mutation andlor abnormal EEC
lcmaton. in combination with the typ ical
morphologic features described below,
will allow the diagnosis of this phase of
PV; these features are not found in
secondary or spurious polycythaemia.
The ore-ooivcvtnaemc phase may be
expected to become overtly poIycythaemic
at a later time.
Maphology
The morphological lind lngs in BM biopsy
specimens at patients with PV must always be correlated with other clinical and
taboratory fmd ings in order to firmly establish the diagnosis 121771. However,
eYen n the earty pre-po/ycyttlaemi stage
PoIycythaemia vera
41
eeeseee
.......
MyeloproliferatIve neoplasms
1641, 22221 .
Required criteria
1. Documentation ofa previous diagnosis of'MiQ.defined PV
2,
Bone mallOlll1ibl"os4s grade 2-3 (000-3 $C8Ie) orgr-ade 3-4 (000- 4 scale)
2,
3.
Incteasll1g spIenornegllIy defIOlld as .rther aninaeasein palpable SPleoomegaIy of >S an from baseIint
ldistanee from the left costal marg.n) Of Iht 1pp&afaflC8 of newly palpable spleoomegaly
cnsoerec
""""phenotype
No abnormal phenotype has been reo
"",eo
Go'o'"
The mosf frequent genetic ab normality in
PV is the somatic qam-ot-tuncnon mut atoo JAK2 V617F. Altho ug h il occurs in
>95%of patients with PV, it is not specific
and is found in other MPN as well. but in
splerJedoi"r
coos
iower freq uencvltea. 1044 ,1 186 , 12881.
The mutation occurs in a haematopoielic
stem cell , and is found in all of the
myeloid lineages. Hence cells that utilize
JAK2 kinase in the intr acellular signaling
path way may be hyp ersen sitive to g rowth
fa ct ors a nd other cvtokmes. inc lud ing
EPO . A fun ct ionally similar mutat io n in
exon 12 of JAK2 has also been reported
11981/. so that virtually all patient s with PV
have a JAK2 aber ration , St ill, no ge ne tic
defect enti rely specif ic to PV has been
ide ntified . At diagnosis, c yto ge ne tic
ab normal ities are detectab le in ab out
20% of pa t ients. The mo st c ommon
rec urring abnormalities inc lude +8, +9,
del(20Q), de l( 13q) and de l{9p) : sometimes +8 and +9 are found tog ether 142,
2394/. There is no Philade lphi a c hromosome or BCR-ABL 1 fusi on g ene . The se
c hromosomal ab normalities are seen with
increasi ng frequency with d isea se progression and in near ly 80-90% of those
w ith post-PV MF 1421, Almost 100 % o f
those wh o develop MDS or AMl have
cyt ogenetic abnormalities. inclu ding those
commonly o bserved in the rapy-related
MD S and AMl (See Chapter 6 ).
PoIycythaemlCl vera
43
Primary myelofibrosis
J . Thiele
H M . Kvasnicka
A. Tefferi
G. Barosi
A. Orazi
JW. Vardi man
ICD-O code
Definition
Primary myelofibrosis (PMF) 11464 1 is a
clonal myeloproliferative neoplasm (MPN)
characterized by a proliferation of predominantly megakaryocytes and granulocytes in the bone marrow (8M) that in fully
developed d isease is associated with
reactive deposition of fibrous connec tive
tissue and with extramedul lary haematopoiesis (EM H) . There is a step wise evolution from an initial prefibrotic phase
121771 cha rac terized b y a hypercell ular
BM wit h absent or minimal reticulin fibrosis
to a fibrotic phase with marked reticulin
9961 /3
Synonyms
Chronic idiopathic myelofibros is (CIMF);
Agnogenic myeloid metaplasia (A MM);
Myelofib rosiS/scl erosis with myeloid metaplasia (MMM) ; Id iopathic myelofibrosis .
Epidemiology
The overt fibrotic pha se is estimated to
oc cur at 0.5- 1,5 per 100 000 persons per
year {1060,21671. It occur s most C()fTV'TK)ll1y
in the sixth 10 seventh decade of life, and
both sexes are nearty equally affected
121671. Children are rarely affected 136n
Etiology
Exposure to benzene or ionizing radi ation
has been documented in some cases
{5881 Rare familial c ases of 8 M fibrosis
Table 2.114 Diagnos1ic crilefialor primary myelofibrosis: <iagnosis requires meeting all 3 mator and2 miroof crileria
MaiOI' eritltria
t . Presence d
~ ........... 1
'"
nile absenat d sig1Icat /W)Jin Iibrosi:s, tle ~ chat'gesIl'LISI be llCClJI'llliDed by a'l 1lcJeaged
bone ITI8fTOWcelIularrty characlenzlld by granuIol:yIic pn:jferabDn and often deaea:Sed erythn;lpooesis
~ e. p!VftlroIic ceItEr-pllase disease ).
2. Not meeting WHO Criteria lor poIy<:ythaemia~. BCRABLt+ chronic myeIogeoous leukaemia'.
myelodysplaslic syndrome'.fJ( other myejoid neoplasms
oee-
Sites of involveme nt
Blood and BM are always invo lved. In the
later stages of the d isease , EMH (also
kno wn as myeloid metaplasia) becomes
prominent, in particular in the spleen
117731. In the initial stages. randomly distnbcted C034+ prOlJenitors are slightly increased in the 8 M. but not in the
pe ripheral b lood {PBl Only in the tate
stag es they ap pear in large numbers periphe rally (1592, 22091 This increase of
CD3 4 + ce lls in the PB is a ph enomenon
large ly restric ted to overt PMF and is not
seen in non-fib rotic po lycythaemia vera
(PV) or essential thrombocythaemia (ETl
141 ,1 45,17031 . It has been postulated
that EMH is a consequence ot me peculiar ability of the spleen to sequestrate the
numerous ci rculating CD34+ cells 122081.
Liver. lymph nodes. kidney ad renal gland.
dura mater, gastrointestinal tract, lung
and ple ura. b reast skin and sott tissues
are other possible sites of EMH 1216n
'"
in the absence 01 a clonal marker. 00 evidence lhatlhe bone marrow fibrosis et otherc:Nlnges aresecondary
kl mecoon.autorr1rrone dison:ler r:K0lIlerchronic I1ftarnnatory t'a'llIIJon hairyC8lI ~ et OCher IyrnJ:tMjd
neoplasm, metasta1ic mal9'ancy. et klxiC (etvonic) myeIopaltlies"
Minor aiteril
1 .l~ '
,
I
S""""""",,
Small to largemegakaryocyteswith an aberrant nuclearlcytoplasmic ratiO and hyperchromatic, bulbous, or
irregularly loIded nuclei and dense clustering
Requires !he lailure 01 ironrnpiacemenllherap)'to increasehaemoglobin level 10 tile potycythaem~ vera
range in the presence 01 decfeased serum fembn. ExckJsion of poIycylhaemia vera is based on haemoglobin
and haematocrit levels.n red eel massmeasurement is not required,
44
Evolution _
Manifestation - - - - - Transformation
initiat
Biage
GJ
~
CD
e;,.",d
~_I
MF-O
MFo I
11
Mf.2
Mf.]
45
08$criptlon'
MF 0
MF- 1
MF- 2
Diffuse arr:l dense increase In rebaJlin wrtll eJ:tenSlYe intersedtons. occasionally 'frilh local
burr:lles 01 coIagen and/or local OSleosderosis
MF- 3
0l1fuse and dense II"lCl'eaSe IIIreticulin 'M!tl extensive II'IIer$edIons ilIICl coarse bundles of
collagen, often associated 'frilh ~
coese
46
Myeloproliferative neoplasms
~~~) ..
Fig. 2.23 Primary myelofibrosis, fibrotic stage, WlIIl ellrameduallary haemalopoiesis in Iivet. A In the Mr, tie
sirtUSOids are prominenUy involved by bilineage prolilerallOll. B Megakaryotyles are the hallrnart. 01 abnonnll
irltrasinusoidal haematopoiesis.
Extramedullary baenatoooleeta
The most common site of EMH is the
spleen , followed by the liver 117731. The
spleen shows an expansion of the red
pulp by erythroid, granulocytic an d
megakaryocytic cells. Their identification
can be aided by immunohistochemistry
[ 16 13, 2 1991. which also allows an appreciation of an increase in neoanqioqenesis / 144\ . Megakaryocytes are often the
most conspicuous component of the
EMH. Occasionally large aggregates of
rreqakeryocytes. growing COhesively. can
ooocce macroscopically evident tt.mOUral
lesions. In the presence of nodular lesions
and , in general. in any advanced stage
disease with large amounts of EMH, the
PQS&bility 01 a myebd sarcoma should be
c:onsidefed and carefully excluded by perlaming irrmunohistological studies with
CD34 117731. The red pu lp cords may
exhibit fibrosis as well as pooling 01
platelets. Hepatic sinuses also show pr0minent EMH. and cirrhosis of the liver may
occur /21671.
Immunophenotype
No abnor mal phenotypic fea tures have
been reported .
Fig.2.24 PrWncwy myeIoIilrosis. 6brollc stage . A ThIs penrtIerBl bloodsme<I" shows dac:ryotytes. occasionalnu::MaIed
red bloodeels <n:I irrrnalJ..nI grarUocytes ~l . BA dilaIed sinus corrtans inmaIIft tIaerrI.1qloiet
elements, most notably megakaryocytes (p,f,$ stain) . ThiS intrasinusoidal haematopoiesi$ together oMth VilSClAr
pn:iIeralJon is charadetisbcbutnot liagl'105bC of PMF WIth myeloid rneIapIa:sia. C Megakaryocytes are ol\en the IOO5t
conspicuous haemalopoielic element il the marrow Often !he cells appear to "'s1ream"1I'rough themarrow due 10 the
In:lerI)tlg fitrosis. 0 Mcrled retJctjn and o:tagen Mln:lsII aSD:iated witha srreanHke arrargemenI of megakMyocytes
arld initial osteosclerosis is $hoIrm (slYerstaIn).
Genetics
No ge netic d efec t specific for PMF has
been ide ntified 11832AJ. Ap proximately
50% of pat ients with PMF exhibit the JAK2
V617Fmutation. Althou gh the presence of
the mutation confi rms the croneltty of the
proliferation, it is a lso found in PV and ET
and thus does not dis tingu ish PMF from
these MPN {163 , 1044 , 1064, 1186, 1288J.
A funct iona lly similar ga in-o f-f unc tio n
mutation of MPL (MPL W5 15K/l ) has
been repo rted in up to 5% at PMF cases.
but in occasional cases of ET as
/16891. Cytoge netic abno rmalities occur in
up to 30% of patients (630, 1832, 21 741.
There is no Philadelp hia chromosome or
BCRABL 1 fusion gene. The presence of
either del( 13)(q 12-22 ) or der(6) t( 1;6)
(q21-23 ;p2 1.3 ) is strongly suggestive b ut
not diagnoslic of PMF [5861. The most
common rec urring abnormalilies inc lude
del (2Oq), and partial trisomy 1q , allhough
+9 and/or +8 are also reported {63O.
1832A, 21741. Deletions aNeeting the long
arms of ch romosomes 7 and 5 occur as
'Nell. but may be associated with prior cytotoxic therapy used to treat the myeloproliferative p rocess.
wen
47
Essential thrombocythaemia
Defin ition
Essen tial thrombocythaern ia (Ell is a
other typ es of haematopoietic and nonhaemat opo ielic neop lasms. The presence
of a BCR- ABL 1 fusion gene exc ludes the
diagnosis of El
IC[).() code
9962/3
3. Not meetlng WHO atSerialor poIycyIIlaema vera, P'JI'Nf'Y myelofIbrosI$.< BCR-ABL f posiWe ct.ror.:
myeIogenouIlMaetnia' ormyeIodysplaslic syndrtml" Of oIher myeklid ~
4. Demonstration 01 JAK2V617F orolher donal maricer. or in !tie absenteofJAK2V617F, no e-.1dence lor
reeceve thrombocy1osls'
48
H M. Kvasnicka
A.Orazi
A. Tefleri
H. Gisslinger
Epidemiology
The true inc idenc e of ET is unk now n, bu t
when di ag no sed according to the g uidelines of the Polycythaemia Vera Stu dy
Group (PVSG)115491. it is estimated 10 be
06-2.5 per 100 000 persons per year
{1055. 10591. Most cases occur in patients
50-60 yea rs 01 age , with no major sex
predil ect ion. How ever, a second peak in
frequ ency, pa rtic ularly in women , oc c urs
at about 30 years 01age 1705. 902 . 10551.
ET can also be seen in ch ild ren , albeit infrequently 118151, but must be distinguished from rare cases 01 hereditary
thrombocytosis 1585. 24011.
Synonyms
Primary thrombocytosis: id iopathic mrom -
J . Thiele
a normocel lular or moderately hypercellular 8 M {775, 22161. The most striking abnormality is a marked proliferation of
megakaryocytes with a predominance of
large to giant forms displaying abundant,
mature cytoplasm. and deeply lobulated
and hyperlobu lated (stag- horn like) nuclei. The rnegakaryocytes are usually dispersed throughout the BM but may occur
in loose clusters. Bizarre, high ly atypical
megakaryocytes, such as those observed
in PMF, are not found in ET and if present.
the diagnos is of ET should be ques tioned
1712, 796 , 2200 , 22051. Proliferation of
erythroid precursors may be found in a
few cases, p articularly if the pat ient has
exper ienced haemorrhages. but granuloc ytic proliferation is highly unusual; If
f ig. 2.27 Essential ttwombocylhaerma, bone marrow aspl'ate smear. AAll increase in the nurrtler and size of the
megailaryocyles. B NoIe the deeply Iobutaledmegaka'yocytic ~, as well astarge pools01 pla te~_ Note that the
aspirate smears fail to reveal the overall marrow archilecture anddistribution of the rnegar.aryocytes thatcan be (Illy
seen in the biopsy,
Mo'phology
The major abnormality seen in the PB is
marked thrombocytosis, The plate lets
often display anisocytosis, rang ing from
tiny torms to atyp ica l large, g iant
platelets. Bizarre shapes, pseudopods
and agranular platelets may be seen, but
are rot common. The white bloo d ce ll
(WEq count and Ieueocyte differential
~e usually normal, although a borderline
eevaton in the WBC count may occur
(705,802.902, 21751. Basophilia is usuaMy absent or minimal 115491 _ The red
blOOd cells are usually normocytic and
rcerccnrcnc unless recurrent haerrormage has caused iron deficiency, in
W"Mch case they may be hypochromic
and microcytic. Leckoervtnrobleetosts
d teardrop-shaped red blood cells are
IQ seen I'l ET 121751.
~ rrosl cases, the BM core biopsy shows
Essential thrombocythaemia
49
rroecuer
Immunophenoty pe
Table 2.07 WHO diagnosbc cnleria lor posl~ssenlial thrombocythaemia myelofibrosis (postET MF),
R.quired criteria
1. Documenlatiol'l of a prevklus diagnosis of WHQ-defined essential ttlrombocythaemia
2. Bonfl marrow fibrosis grade 2-3 (011 0-3 scale) or grade 3-4 (oo 0-4 scale )
50
MyeloproliferatIVe neoplasms
01 eosinophil precursors results In perSistently increased numbers of eosiroptliIs in the peripheral blood (PS), bone
matrON
eoSKlOPh~ia
ico-oeeee
9964/3
Synonym
Hypereosinophilic synd rome (not recommend ed) .
Ep idemiology
Due 10 the p revious dilfic ulty in d istingu ishing CEL f rom idiopat hic HES. the
true inc id enc e of these di seases is
unknown, althou g h th ey are rare . Many
patients wh o wou ld until rec ently have
bee n c lassified as hav ing idiopathic HES
ca n now be show n to have C El assoc iated w ith a FJPtL 1-PDGFRA fusion gene
{466 1. Since this co ndition oc cur s mainl y
in ad ult me n, the male dominanc e and the
peak inc ide nce in the four th decad e
prev iously descr ibed in "HES" {443 , 1971 ,
2072, 2382 ) are now exp lained , at least in
BJ. Bain
D.G. Gi lliland
J W , Vardiman
H .-P. Horny
Sites of involvement
eEl
eos.roonns.
Clinical features
Sometimes eosinophilia is detected
inc identally in patients who are otherwise
asymptoma tic . In othe r pa tients, co nstitutiona l symp toms , such as fever, fatigue ,
cough, ang ioed ema . musc le pa ins, pr uritus and d iarr hoea are found . The mo st
serious clinical findings relate to endomyoc ardi al fibrosis . with ensu ing restrictive
ca rdiomeg aly. Scarring 01the mitralltricu spid valves leads to valvula r regurgitation
and formation of intrac ard iac thro mbi,
w hich may embouze to the brain or elsew here, Perip heral ne urop athy, cen tra l
nervou s syste m dy sfu nction, pulmonary
symptoms due to lung infiltration, and
51
rheoma toroptcar findings are other frequ ent ma nifestations (443, 1971 , 2072 ,
2382 1
Fig. 2.31 Ch ron ic~oop/l i l ic ~uk.aem ia . Peripheral blood smear from a patient With ahistory ofpersjstent eosi1c?*
Immatureaswell as mature eosinophilsarepresent CyloQenebc arlalysis showed trisomy of chromosome 10,
t-een
Differential diagnosis
D iag nosis re qu ires posi tiv e evidence of
the leukaemic nat ure of the co ncnton and
exclusion of cases of MPN with rearrangement 01 PDGFRA. POGFRB or
FGFR1. The diagnostic process often
starts wi th exclusion of reactive eosinophil ia. A d eta iled histor y, physical exam ina tion, b loo d count an d blood film ar e
essential. Conditions to be excluded
include parasitic otectoo. allergies, pulmonary d iseases such as Loetner's syndrome. cyclical eosinophilia. skin diseases
such as anqictymphoid hy perplasia, colla gen vascular d isorders and Kimu ra 's
52
Myeloproliferative neoplasms
,.
e
tiC
1m
Nc
m,
G.
No
"'"
;d
a,
Fa
lu
ca
wit
GEl
con
maO
as
e,tlchemstry
Cytochemical stains c an be used to
identify eosinophils bu t they a re no t
essential for diagnosis , Partial degranulaeco can lead to eosinop hils ha ving
reduced peroxidase con tent.
Geretics
No single or spec ific cytogenetic or
molecular genetic ab normality has been
identified in CEl. NOS . Cases with rearrangement of PDGFRA, PDGFRB or
FGFRI are spec ific ally excluded , The
detectOO d a Ph cbrcroscre or BCR-ABL 1
fusion gene ind icates one of the rare
cases of chronic myelogenous leukaemia
wnh dominant eos inoph ilia . rather than
eEL. Ellen when eosinophilia occurs in
conjunction with a ch romosomal abnormality that is usually mye loid neoplasmassociated, it may be difficult to decide
_.-
53
Mastocytosis
Definition
Mastocytosis is due to a c lonal, neoplastic
prolife ration of mast cells thai accumulate
Synonym
Mast cell d isease .
IC[)..() codes
Cutaneo us mastocytosis
(urtica ria pigmentosa)
Diffuse c utaneous
mastocytosis
9740/1
9740/ 1
54
MyeloproliferatIVe neoplasms
9740/1
974 1/ 1
97 41/3
97 41/3
97 4213
974013
974011
C. Akfl
L Escribaro
P. Valert
Epidemiology
Mastoc ytosis may occur at any age Cutaneous mastocytosis is most common in
c hil dren and may be present at birth.
About 50% of afflic ted chil dren develop
typical skin lesions before 6 months of age .
In adults. CM is less frequently diagnosed
than in ch ildre n 12055 . 2436 1. A slight
male predominance has been rep orted in
C M. SM is generally di ag nosed after the
second decade of life ; the ma le to female
ratio has been report ed to va ry from 1:1
to 1:31 181, 1465, 1694).
Sites of involvement
Approximately 80% of patients with mas toc ytosis have evid ence of skin involvement
{16871 . In SM the bone marrow (BM) is almost alwa ys involved, so morp hological
and molecula r anal ysis of a BM b iop sy
specimen is stron gly rec ommend ed 10
con firm or exclude the diagnosis [287.
290, 971, 12751. Rare ly. the pe riphe ral
blood (PB) shows leukaemia due 10 significant numbe rs of circulating mast ce lls
{972. 14841. Other organs that may be involved in SM inclu de the sp leen. lymph
nodes, liver and gastro intest inal tract mucosa, b ut any t issue may be affected
am:..
CIricaI features
Cutaneous mastocyt osis includes several
cetrct cmco- nistocettoicqcar en tities.
l esions of all form s 01 CM may urticate
when stroked ("Darier's sign 4 ) and most
snow intraepidermal accumulation of
melanin pigment. The term 'wtcana
4
ptgmentosa mac roscop ically describes
two clinical features. Blister ing
("b.bJs mastocytosis") does n:lI represent
a separate subtype but rather an exaqgeralion 01 urticaria. Blistering is usually
seen IrIpatients less than 3 years of age.
m may be assoc iated with all forms of
CM 11 68 7, 2055, 24361.
Symptoms in SM at presentation have
beefl grouped into 4 c ategor ies: 1) conSbtUtIOO8! symptoms (fat igue, weight loss,
Mr, diaphoresis). 2) skin manifestations
(prurituS, urticaria, dermatographism).
31mediator-related systemic events (abdcminal pain. gastrointestinal d istress ,
Dushing. syncope, headache. nvpoienson.
tachycardia. respira tory symptoms) and
4) musculoskeletal complaints (bone
pain. oeteoceora'osteoporoers. frac tu res,
<JltIralgias, myalgias) {181, 22901 . These
symptoms range from m ild in many
pabents to severe, life-threatening med iatorrelated events in othe rs, Sym ptoms ma y
also be related to orga n impa irme nt (du e
10 mast cell infiltrates), pa rticularly In
patients with high-grade ag g ress ive or
eukaernic disease variants,
Physical findings in SM at d iagn osis m ay
InClude splenomegal y (o ften minimal).
\lltile~dooopalhy and hepatome galy
are foond at signif ica ntly lower trequencies !966,968, 973. 1275, 1466 1. Organornegaly is often absent in the m ost
rormon variant. indolent systemic mastocytOSis(ISM). but is usuall y p resen t, alo ng
w impaired organ function, in aqq resSNesystemic mastocytosis (AS M) an d in
leukaemic variants. Severe systemic
~s may occ ur in patients w ith ISM
bbwIg eceosve release and generatIOn
rJ bcctemcar mediators including tustaI'!'f'e. eicosanoids. poteases and heparin.
For example, gastrointestinal symptoms
S\.d1 aspeptic ulcer disease Of diarrhoea
n more corrmonly attributed to release
rJ biologiCally active mediators than to
mast eels.
sese
ceeoanc
Fig. 2.38 Indolent systel'lic mastoeylOSis. A loo5eIy scattered spmd\Hhaped tlypograrlular mast cells WJlhooI
tendency III awegate. Diagnosis is lacihlatedI'fhen addibonal imrrI.rnostaHWI and moIeaJIar analysis n performed.
B IrrITlIA'lOSlain withCD25 shows an atypical ~ 01 mast eels with rnentlralle assooated reactivity.
Fig. 2.39 Systemic mastocytosis, Skeletal lesions ate common in systemic masloc,1OSiS. This X-ray shows paldty
osteosclerosis, osteoporosls WId multiple IyIiclesions mille lemur,
infiltration of the g astrointestinal trac t by
excessive numbers of abnormal m ast
cells P8 1. 1334 , 2288 1.
Ha ema tologica l abnormalities in 8 M
include an aemia , leukocytosis, blood
eosinophilia (a frequent f inding). neutropenia . and thrombocytopenia 1130,
287.7 13.971 , 1162 , 16871. Bone ma rrow
55
T~ble
The diagnosis 01 SM CBl be made when the IIIaJOI' critenon and one IIIir'Ia criterion or at least Ihnle mnor
crrteIia are prMel'll
lIIajor crilerion;
t.UlrfocaI, dense rliIlrates rJ mast eels (::!:15 mast celI$ n ~) deleded i1 sections of bone I'IllIITOW
and/or OCher eltraaAaneous organ(s)
Minor criIW:
1. In biopsy sedJons rJ bone nwrow orOlIlItel1raCUlaneOuS organs, :>25%ollhe mast eels r11he
infihle are ~ orhaveatypocaIlll(llllI1CJIog or, d aI mas! eels n bone m.arrtM'asprate
smeaR, :>25% aremnalln oratypical.
.........
2. Deleclion of an ICtiYaII'lg poI"It rnuta\lI:Wl at c:odor1816 of KIT~ bone manow. blocdor anolher eJ:lraCula.
3. MastOBIs itI bone marrow. blocdor oItler eJhcutaneous organs express CO2 and'orC025 in adl;1itlOII ~
nonnat mast 011 maR-eB.
<t 5enJm tolaI tryptase pet1istetllly exceeds 20l'lgIml(unless!here is an associated daIaI myeloid dIsordar, it
wtictI caselhisparamet9f 1$ not valid).
simultaneously with. or after the diagnosis of SM. In princi ple, any defined
myeloid or lymp hatic malig nancy may
occur as the AHNMD. but myeloid neoplasms predominate, and chronic myelomonocy tic leukaemia (CMML) is most
common 197 1, 9 75. 2056, 2066, 2095,
22901. In patient s with SM-AHNMO, clinical sympt oms and disease course relate
both to the associated baematoioqrcat disorder and to SM 11977, 2290).
Serum tryptase levels are used in the
evaluation and monitoring of patients with
mastocytos is, The finding of a pers istently
elevated serum total trypta se > 20 ng/mL
is suggestive of SM and is used as a
"minor" criterion for diagnosis, unless there
56
Myeloprol!ferative neoplasms
1. ~ pioJnenIosa (UP V~
1.
~dk19nosis of
1atIIe 2111122861.
IndolentsystemicmlStoeytosis(ISM)
Meets arteria b" SM. No"C" findings (see below). No evldence of afl associated non.roastc:elli'leage cJonaj
I1aematOOgicaI mali\1laflc.yldlsonlel" (AHNMOI In !hisvanant. !he mast cellMOefllS low and skin
lesions areaWnosI i'lVaria ~ present
2. Sptemie mastocytosis with n soeiBted clonal hMmaI~ norHnUt c:.Illl. . . . disease (SMAHNMO)
Meets CriIeria torSU and cntenalor an assoaaled. donIlIl'IIemaloklgicI flOIloITIaII eel lineage disorder.
AHNMO !MOS, MPN .AJ.IL,~ . oc ott. ~ neopasm tIal meets !he aliena b" a
disbnd~ " tie WHO cIasslticaIm).
3.
......
Meets c:nena b SM. <n oc IOOf8 "'C" Indings. No ll"o'lci8rOI of maslceI-..aema. UsuaIy ri'1oU: sm
6.
Extl'illcutaneous mastocytoma
UnilocaJ mast cell ltl'TlOU', Noevidence 01 SM. Noskin lesions. NoOOestruetiYe !1owth pattern, Low-grade
-8" findings
1.
Bone marrow biopsy showing >30% infinratkin bymast cells (focal, ceose aggregates) andlor serumlolal
lryptase level >20 nglmL.
2. Signs of dysplasia or myeloproliferation. in ten-mast ceil lineage(s). but insufficient criteria for definitive
diagnosis of a haematopoietic neoplasm(AHNMD), with nonnal or only slightly abnormal bloodcooors
57
Rg. 2.43 A Booe marrow smear of a patJenI WIth indolent systemiC masUytosi$. The eel is atypical. witIlan indenled nucleus in an eccentric Iocabon, and cytoplasm ... ....
an ~ emson WIt1 ~ dIslr1buIim of ~ 8 Sysl8rlIc rnastlc)tlsIs. The eels may haw bland ru:lel WIIIl moderate ~ of 1* tyqllasm , spinIed _ _ ..
I'MeITtlle fibroblasts. or IctllAated nuclei WIth ab.nln dear C)'kIpIasrn The Ialler eels mayresermle rnonoc:ytes or his/ioq'Ies. and ant more oommooly seenin aggnssift
"' .....
fewer mast cells than observed in children. The numb er of lesoner mast cells
may sometimes ove rlap with the up per
range of mast cell number s found in normal or inflamed skin. In some cases,
examination of multiple biopsi es and
immunohistochemical analysis may be
necessary to establi sh the diagnosis of
e M 12286, 2436).
n
s
Cl
Systemicmastocytosis (SM)
sa
di,
He
Fig. 2.45 SystemiC mastocytosis, booe marrow bklpsy. A The local lesions01 mast cellschenconsist of a central core
ol lymp/lOCyles, surrourldlld by polygonal mast cells with pa~ . faintly lJ"iJrlUlarcyIOplasm. WIth reactive eosinophils at
the outer margirl ol lhe lesion. 8 The lesiOns are often well-circumscribed. and may OCCIJ" irl parauabecular or
perivascular Iocabons, but may be I'lV'ldorTWy dislnbuted in the interll'abeclAar regionsas wei.
58
Myeloprol!terative neoplasms
Bone marrow
In most cases of SM, multifocal . sllar~
demarcated compact infiltrates 01 rna;
cells are the most common and easily ce
tect able feature in the BM bio psy. The
infiltrates are found pred ominantly If
paratrabecutar and/o r perivascular locations 1290, 965, 971, 977, 978. 11981. The
focal lesions are co mprised 01 varyiOj
numbers of mast ce lls. intermingled w
varying numbers of lymphocytes , eoere
phils , tusnocytes. and fibrob lasts. These
diagnostic "mixed" infiltr ates are o/tell
ex
era
fr
of
s
my
pl.
my
00<
d isl
0'
qUE
148
'he
Fig. 2.46 Systen'ic masb;ylosls, spleen, A Sl)Ieen tom a pa\letIt 'lII'i01 systen'ic maslIXylosls. B Aggregates rJmast
eels may be seen II \tie red orwliIe pulp, orbolh. ~ his case, mast eels ate seen II a penloIi::IJNlocation.
'l'IyflIOId eokaene.
CaretlJ inspec tion of the 8M no t
at!ected by mastoc ytosis is of crucial
ecctarce. Often, the una ffected 8M is
II1remarkable with a normal distribution of
tal cells and haematopoenc p rec ursors .
Such cases usually eithe r belong to ISM
o\'lthinvOvemen! of skin and 8M , or re preSMt isolated mastoc ytosis of the 8M ,
However, in othe r c ases th e 8M not
drectly infiltrated by mast cel ls may be
extremely hypercellular due to the prolifescoof cells of non-mast cell lineages,
tduding neutrophils, rnonocytes. or less
frequently, eosoopbns or b last cells. DePQ"Ong on the type of proliferating cells,
lindlngs may be reactive (myeloid
~ ), or may indica te the presence
d acoexisting naematoooeuc neoplasm
ll.d! as acute myeloid leukaemia , a
~ollferatiYe neoplasm, a myelodyssyndrome or myelodysplasliC/
~ferati ve neoplasm, Of chronic
...""llc ~. Lymphoproliferahve
diseases, such as plasma cell myeloma
~ malignant lymphoma. are less Ire(JJllfl\Iyseen 1110, 969 , 971, 975.1 147 ,
1484 2056,2066, 20951. In all such cases,
~ associated naematoroorc d isea se
eese
I
t
e
9
~
Fig. 2.43 SM-AHNUD (acutemyeloid Iel.Jkaemia). A The streaming, spindled eels of a largemast eel aggregate can
be seen on one side rJ lhe booy lrabecUkJm (arrow), weeeas a rTlCIllOIonoUs J)Opljabon of blast cellsis seen onlhlI
opposite side . B The spiodledcells of mastcell disease abut on a large aggregale of blasts.
59
...C
Liver
Liver involvement in SM usually presen
With disseminated small granulomat
foci of mast cells within the periportal
tracts and as loosely scattered mast eels
within the sousoos . Severe liver i~
rrent is only rarely seen in SM. WiderWg
and fibrosis 0 1 periportal areas is cctmonly found . but fully developed cirrhosis
is rare 1966, 14661.
f~ 2,49 SystemicmastlcyloliswiltI associ8led hl*yt:ell Waerria. A Bone marrow aspi'a'B smear Wllh hairycels
and al)1liCal mast eels B The spirded mast cells M pteSel11 adjacentto the hairy eel i'lfiItJate il lhe intersbbaI
regions oI1he IT\il'I'OW Although hairycelleubemia may occasioRaIy assume a spindledlTW)IJlIlology, in Ihis case lhe
mast eel tryplase lustrated in (e ) dearly demonslrales !he masl eel origin 01 ltle spindled tens. alll! an
imuIostaIn for C020 idenlifles ltle IIaify eels in (D).
60
Myeloproliferative neoplasms
exceptlOl'l3l cases exhibit a diffuse compact infiltration of the lamina p ropf"ia mu cosae by atypical mast cells , and this
'f'B1 reseroe inlIanTnatory bowel disease
r:1 malignanl lymphomaat first glance . AIklgelher, lour patterns of involveme nt of
theGI tractmucosa by mastocytosis can
be dlscnminaled 1171 1: 1) Loosely scattered mast cellswithout dense ag gregates
W wrth an atypical immunophenotype
and an activating point mutation of KIT,
usual~ in the settinq 01 SM of some duraioo and involving the 8M, 2) Slight increase in loosely-scattered mast c ells
withoccasional dense aggreg ates and an
atypical rrmoopterotvce with expression
ct CD25. usually associated with an actr~ating point mutation of KIT, 3) Diffuse
Cl:lmpaCI infill ralion 01 the mucosa by
atypiCal mast cells, resembling the ag~ive variant of SM in other tissu es
171 1and 4) Localized mast cell sarcoma
(based on one published case with in'OteTlerC oIlhe ascending colon) 111761.
_ 1esK>ns
llO'I
Extracutaneous mastocytoma
This localized tumour consists of an
ac cumulation of mature-appearing granulated strongly metachromati c mast cells ,
in contrast to the hig hly atyp ica l mast
cell s observe d in a mast c ell sarcom a.
Extra cutaneous mastocytoma is exception ally ra re, and the reported cases
involved the lung {3981.
Irrm.mopheooIype
Mast cells co-express COO, CD33, CD45 ,
CD68 and CD 117 but lack severa l
rnyelomonOCytic ant9S"S, including CD14,
CD15 and CD16, as well as most T- and
B-eell related antigens 1974, 977 , 978 ,
1073, 1292, 1687, 22901, Virtually an mast
cells , irrespective of stage of maturation
or neoptasnc state , react with antibodies
against trvp tase . a cell not expressing
tryp tase ca nnot be id entified as a mast
cell immunohistoc hemically. Chymase is
Mastocvtose
61
.. ." .
~
. e
205n
1141.
Genetics
Mastocytosis is frequently associated with
somatic activating point mutations within
K IT 121761. In most cases, co don 816
mutations in the tyrosine kinase domain
are detectab le. Rare familial cases with
qecmune mutations of KIT have bee n
repo rted [ 14,15, 1331,1332, 1333, 1557,
21761. In patients with SM-AHNMO additional genetic de fects are det ec ted,
depending on the type of AHNMO,
Somatic point mutations of the KIT protQoncogene that encodes the tyrosine
kinase recept or for SCF are de tected as
recurring abnormalities in mastocytosis
11 4,15, 1331, 1332, 1333, 1557, 1656,
21761 _ The most commonly observed
mutation shows substitution 01 Val for Asp
at codon B16 (D816V). This mutation
results in ligand-independent activation 01
KIT tyrosine kinase and provides relative
resistance to the prototypical tyrosine
kinase inhibitor imatinib 1995, 15571.
62
Myeloproliferative neoplasms
Fig. 2.53 Mast celleull.aem&a A ~ blood smear. Note lhe biIobed ru:tel and relatively ~
cytoplasmoften seen in Itll5 awessive form of rnastIcykIIas. B Theborle marrow biopsy is li1IuseIy inIiIlr.*ldby
~slJC mastcells, C derronslriIles !he 'dear aIr appearance !hat is due ~ !he poorgratlJIalion of the
ltIatis typical of inmature mast eels ofmast eelleukaernia. 0 All irmI.JnohisD::h slainbr masteel ~
""""' .......
Postulated C~ II of oriQin
Haematopoietic stem cells.
Prognosis and predictive factors
In children, CM usually has a favourable
outcome and may regress spontaneously
before or during puberty. In adul ts, cu taneous lesions generally do not regress
and are. in contrast to a previous belief,
oI1en associated with SM, usually the
ocoient variant. One study identified
predictors of a poorer prognosis as rate
onset of symptoms , absence of CM.
ttrembocytopenia. elevated lactate dehyciogenase (lOH). anaemia. 8 M hypercelk81ty. qualitative PB smear aboorrehtes.
elevated alkaline phosphatase and hepatosplenomegaly. The perce ntage and morphology of mast cells in 8M smears have
been ide ntified as additional important
and independent pred ictors of survival in
mastocytosis 122901Currently, there is no cure lor SM. and the
prognosisdepends on eediseasecategory
1228 7, 22881. Patients with high-grade
(agg ressive) disease inclUding mast cell
leukaemia may survive only a few months,
whereas those with indolent SM usually
have a normal life expectancy 12287.
22881. SM patien ts with cutaneous
invotvement usually also follow an indolent
course, whereas patients With aggr essive
MastocytosiS
63
Myeloproliferative neoplasm,
unclassifiable
Definition
The designation. myeloproliferative ne0plasm. unctassmaore (MPN . U) should be
applied only 10 cases that have definite
cl inical, labora tory and mor pholo gical
fea tures of an MPN but that fai l 10 meel
the criteria for any of the specific MPN
entities, or that present with featu res that
overlap two or more of the MPN ca tegories. Most cases 01 MPN. U, will tall into
one of three groups: 1) Early stages of
poIycythaemia vera (PV), primary myelofibrosis (PMF) or essootial thrcmbocythaemia
(El) in which the c harac teris tic featur es
are not vet fully d eveloped: 2) Advanced
stage MPN, in wh ic h p ronounc ed myelofib rosis. osteosclerosis. or transformation
to a more aggressive stage (r.e . increased
blasts and/or dysplasia) obscures the
underlying disorder 1775, 1216, 2206,
22 16,22221 : or, 3) Patients with convincing
evi de nce of an MPN in whom a coexisting
neoplastic o r inflammator y d isord er obscures some of th e diagnostic c linic a l
and/or morp hological featur es , The presence of a Philadelphia (Ph) ch romosome,
BCR-ABL 1fusion gene or rearrang eme nt
of POGFRA, POGFRB or FGFR 1 genes
excludes the diagnosis of MPN ,U.
The diagnosis MPN,U shou ld not be used
64
Myeloproliferative neoplasms
H.M. Kvasnicka
B.J . Bain
J , Thiele
A. Orazi
H.P. Horny
JW , vardiman
997 513
Epidem iolog y
The exact incidence of MPN, U is ur*~
but some reports indicate that the pelcentage of unclassifiable cases ecccn
for as many as 1~ 15% of all cases Ii
MPN 1775, 2222 1, The frequency varies
ElOOgy
The cause is unknown.
Sites 01 W1voIvement
5mlar to the other MPN
cncaJ leatures
Iil<pI<JI<lgy
'krrtcases that are diagnosed as MPN. U
tJemQ to very early stage disease in
iI'tlCJ the differentiation between ET, the
p"elibrOlic stage of PMF, and the preJ:dycythaemic stages of PV is difficult
11216, 2223, 22241. Often, the PB smear in
li.dI cases shows thromboc ytosis and
Ia'iatlle neutrophilia. The haemog lob in
concentration may be normal, mildly d eeeasec or borderline incr eased . The 8M
bqJsy specimen frequently shows hyperterlJiarityand often prominent megakaryoClI'= proliferation, with variable amounts of
Q'a1\Jlocytic and erythroi d prol iferation
12216,2223,22241, If the guid elines suqgested in the previous sections for each
specdic MPN are carefully applied wi th
ti:lSe attention paid 10 the megakaryocy' morpholog y and histotopography,
'lOSt cases can be accurately assigned
1I 8spedic subtype; but if not. the des."a1OO ot MPN, U is preferable until
follow-up data or adomonar lebo'By studies provide evidence leading
1)8 precise diagnosis.
lJe-stage disease. the BM specimens
-eseal dense fib rosis and/or os teo~, indicating a terminal or
...m<lA stage, and distinction between
oost-polycylhaemic stage of PV
a myelod ysplaslictmyeloproliferative reoplasm, incl uding the provisional entity, refractory anaemia with ring sidercblasts
and thrombocytosis, should be considered
11 27,1 29,865.1 245,1406.2082,2169/.
Inwrunophenotype
No abnormal phenotype has been
ported for this group of patien ts.
re-
Genetics
There is no cvtcqenetc or molecular
genetic finding specific for this group.
There is no Philadelphia chromosome,
BCRABL 1fusion gene , or rearrangement
of PDGFRA. PDGFRB or FGFR1. Some
cases with a mutation of JAK2 as a sole
genetic abnormal ity do not meet the criteria for a specific MPN or any other speci fic disease ca tegory, and are thus best
ca tego rized as MPN, U.
Postulated ce ll of origin
Haematop oietic stem ce ll.
Prognosis and predi ctiv e factors
In patients with the initial stages of an
MPN that is urctassmabie. follow-up studies performed at intervals of 4-6 mon ths
wilt etten provide sufficient information for
a more precise classification {2216, 2222/.
Such patients in the early stages of disease will have a prognosis similar to those
of the group into which their disease
eventually evolves. Patients with advanced
disease in whom the initial proc ess is no
k>nger recognizable due to 8M fibrosis or
bla stic infiltration wou ld be expected to
have a poor prognosis.
65
PDGFRA,PDGFRBorFGFR1
Myeloproliferative and lymphoid neoplasms
associated with rearrangernenl of PDGFRA.
B,J . Bain
D,G Gilli land
H.-P. Horny
JW. Vardiman
..
4,,
.'. ..
. '.'
and neen ercoocer features are also influenc ed by the partn er g ene involved . In
the c ase of PDG FRA-related disord ers,
prese ntation is usua lly as c hronic eo sinop hilic le ukae mia (CEl) with promi nent
involve ment of the mast cell linea ge and
sometimes of the neutr oph il lineage. l ess
often , pr esent ation is as ac ute my eloid
leuka emia (AMl ) or precur sor-T lymp hoblastic lymphoma (T-LBL), in both instances
with ac companying eos ino philia , In the
c ase of PDGFRB-related disea se, the features of the MPN are more va riab le but are
often those of c hronic myelomonocytic
leukaemia (CMML) with eosinophil ia, Proliferation of aberrant mast c ells can again
be a feature. Acute tran sformations that
have been d escribed to date have been
myeloid . In the case of FGFR r-reteteo disease, a lymphoma tous presentation is COOlmon, pa rticularly T-18L with accompanying
T~" 3.01
""
f ig. 3.01 FIP1L 1-PDGFRA-ffllaled etvonic ~leu kaerlia. A PenpheraI blood IilmstIOlWIg Ihree rrlllder*f
degranulated eosinopl'lils. Romanowsky stain. B Trephine biopsy section. Abundanl eosinophils and eosI'q)lli
precursors, Giemsa stain. C Trephine biopsy S&ClIOO. Abundalll mast cells. many of wI\it:tI are spindle-shaped,
Iormingsmalloose dosleB, Masteel tryp\lIS8 staining, 0 Trephinebiopsy section. CD25expression in tilemast CIk
AND
Presence of a FIPILl-PDGFRA fusion gene'
Definition
68
Myeloid and lymphoid neoplasms with eosinophilia and abnormalities 01 PDGFRA . PDGFRB Of FGFRI
roo _ a
The provisional code proposed for the
fourth edition of IGOoO is 996513
---
~".
~opi . .. . ,
1',...... eEL_
_c:,.........,
nptIine
---, --I
I~"!.-
-=Iya&.
b60CIaY Met
1n,"tiglClonb
Synonyms
~~
I
Epidemiology
The FIP1Ll PDGFRA syndrome is rare. It
is considerably more common in men
than women; the M:F ratio is - 17:1. Its
peak incidence is bet ween 25 and 55
years (median age of onset in late 40s)
with reported cases ranging in age from 7
10 77 years 1131).
Etiology
The cause is unknown, althoug h several
cases have been reported following c ytotoxic chemotherapy 11 625, 2157) and a
case of chronic myeloid leukaemia with a
BCRPDGFRA fusion gene also followed
combination chemotherapy 119061 .
Sites of involvement
GEL associated with FIP1L1-PDGFRA is
a multisystem disorder, The PB and 8 M
are always involved , Tissue infiltration by
eosinophils. and release ot c v tokmes and
humoral factors from the eosinophil granuleslead to tissue damage in a number of
organs, but the heart, lungs , central and
peripheral nervoussystem. skin and gastrointestinal tract are commonly involved .
The spleen is enlarged in the majority of
patients.
Cinical features
Patients usually present With fatigue or
pruritus, or with resp iratory. cardiac or
eel
~~~
.,
t,G
--_.......... @ e
--,
r.::==:=:::'::-l
~
(lncludiog
f _ I ...u..tI.1(11 nut
....
Hoi
~\I.
....
idiopathic HES
Fig. 3.02 Flow diagram showing the diagnostic process in hypereosinophilia, e EL, chronic eosinophilic leukaem ia
The definitivediagnosis is shown within blue circles/ovals,
markedly elevated (2309). FIP1L 1-PDGFRAassociated GEL is very responsive to imatinib , the gene prod uct being 100-fold
more sensitive than BCR-ABl 1 1466J.
MorphOlogy
The most striking feature in the PB is
eosinophilia. the eosinophils being mainly
mature with only small numbers of eosinophil mveiocvtes or promyelocytes . There
may be a range 01 eosinophil abnormalities,
inclUding sparse granulation with clear
areas " cytoplasm, cytop4asmc vacuolation,
smalle r than norm al granules , immature
granules that are purplish on a
Romanowsky stain . nuclear hypersegmentat ion or hyposegmentation and
increased eos inophil size 1466, 23091.
69
cozs-coense
70
Fig. ] .03 Myeloid neoplasm with eosinophilia associated WIlt! PDGFRB rearrangement Penpheral blood lWn d
a palienl 'MIh 1(5;12) showing numerous abnoImaleosiIlOphis; eosmphis were 40% cIleukoc)1eS.
Genetics
Usually cytogenetic ana lysis is normal,
with the FIPIL I-PDGFRA fusion gene
resu lting from a cryptic del(4)(q12).
Occasionally there is a chromosomal
rearrangement with a 4q12 breakpoint
such as t(1:4Xq44:q12) 14661 or 1(4;10)
(q12;p1 1) /21631. In other patients there
is an unrelated cytogenetic abnormality.
e.g. trisomy 8, which is likely to represent
disease evolution. The fusion gene can
be detected by AT-PCA, nested ATPeR
often being required 14661 The causative
deletion can also be detected by fluorescence in situ hybridization (FISH) analysis,
often using a probe lor the CHIC2 gene.
which is uniformly deleted , or using a
b reak -apa rt probe that encompasses
FlP tL 1 and PDGFRA. Since the maiontv of
patients do not have an increase of blast
cells or any abnor mality on conventional
cytogenetic analysis, it is usually the detection of the F/P 1LI -PDGFRA fusion gene
that per mits the definitive d iag nosis of a
myeloid neop lasm . Cytoge netic ab no rma lities ap pear to be more com mon when
evolut ion to AML has occurred (1469 1
Postulated cell of origin
The c ell of origi n appe ars to be a p luripotent haemopoietic stem cell able to give
rise to eosmophtts and in some pa tients
neutrophils. rronocytes, mast cells. T cells
and B cells {18541 . The detection 01 the
fusion gene in a lineage does not necessarily correla te with morphological evidence 01 involvement 0 1 that lineage .
lymphocytosis. for example . is not usual,
even in those with apparent involvement
of the B or the T lineage 118541. In
chronic phase disease, involvement is
predominantly of eosinophils and to a
lesser extent mast cells and neutrophils.
Acute phase disease may be myelOid or
T lymphoblastic 11469}.
Myeloid and Iymphotd neoplasms With eosinophilia and etoomannes of PDGFRA. PDGFRB 0' FGFR 7
,
(
E
T
n
"
rr
/:
Table 3 02 Diagnostc criteria of MPNaSsoclated witll ETV5-POGFRB tusioo gene oroItIer rearrangement of PDGFRB
fn:I ecreeres witt1 ~ orflUlX)'tlsis
AND
f'ntsence of 1(5:12)(q31""Q33;pt2)or a variant translocatiOn' or,demonstrabor1 of an ETV6-PDGFRB fusion
gene or of reBlfBngememof PDGFRB
A~~ , often -MIl ~eosilqlhIa
, Because t(5;ll)(q3t""Q33;p12) does IIOl always INd 10 an ETV6-PDGFRB fusion gene, rnoIei::uIM conlirmation
is ~ (lesjrable If I'lJClIe(Uar ana/ySiS is not avaiable. Ihis dtagnosJs sho\j:j be suspected if there IS a f'Il.
negative MPN asscrialed wi1tI eosirqIhiIiIlnd witha ~sIocaborl Wllh I 5q31-33 brealqloint.
Table 3 03 f.Aljecu1ar variants of MPN associated WIth ETVU'DGFRB Modified from It31)
FUIlon V&I1t
Definition
A distinctive type of myeloid neoplasm
occurs in association with rearrangement
~ PCXiFRBat 5q31-33 (Table 3 .02) . UsuaIy there is t(5 ; 12XQ31 - 33 ;p 12) with formalion of an ETV6-PDGFRB fusion gene
1812. 11341. In l/OCOITITlOfl variants. other
"ansIocations with a 5q31-33 breakpoint
lead to the formation of other fusion genes,
incorporating part of PrX;FRB (Table
3.03). In cases with t(5 ;12) . and in the
variant rransiocatcne. there is synthesis
~ an aber rant, consti tutively activated ty!OSine kinase. The haematological features
are most often those of CM ML (usually
With eosinophilia) but some patients have
been charac terized as atypical ch ronic
myeloid leukaemias (aC ML) (usually with
eosinophilia), CEL and MPN w ith eosinophilia 1131. 20851; Single cases have
been reported of AML. probably superimposed on ch ronic idiopathic my elofibrosis
12245). and of juve nile my elomon oc ytic
eukaemia 115 13J, the latter associated
/jith a variant fusion gene . Eosino philia is
usual but not inva riab le 12085 1 Acute
sensiorrnaton ca n occur, ofte n in a relatively short period of tim e . MPN with
PDGFRB rearra ng eme nt is sensi tive to
tyrosine kinase inhibitors such as imatinib
sse
t(1;3:5)(p36J)21;q33)
WDR48-POGFRB
ca
d8r(1lll1 ;5)(p34:q33).
dert5)1(1:5)(p34:ql5).
der(11 )ils(11;5Xp12:ql5q33)
GPfAP1-PDGRFB
ca
1(1:5)(q21;q33)
TPMJ.POGFRS
ca
1(1:5)(q23:q33)
POE4DII'POGFRS
l(4;5;5)(q23:q31;q33)
PRKG2-PDGFRB
l(3;5)(pll25;q3t-35)
GOtGA4-POGFRB
l(5:7)(q33;q1t .2)
HIP1.pf)GFRB
l(5:10l(q33:q21)
CClJC6.PDGFRB
t(5;ll)(q31.J3;q24)
GIT1.p()GFRB
eEl
l(5;14)(q33:q24)
NIN.PDGFRB
t(5;t4)(q33;q32)
KlAA1S09-POGFRB
1(5;15){q33:q22)
TP53BP1-PDGFRB
t(5:16)(q33:p1J)
NDE1-PDGFRB
CMML
t(5:17)(q33:pt 3)
RABEP1 -PDGFRB
CMML
t(5;17}(q33: pl1.2)
SPECC1 -PDGFRB
JMML
;64).
ICD-O code
The provisional code pro posed for the
foorth editio n of ICO- O is 996613.
Syronym
Chronic mvetomonocvnc leukaemia with
!IOSinophilia associated with t(5 ;12) .
-"'ogy
00lS1.
rl
Fig. 3.04 Myeloid neoplasm wI\tI ~ associa1ed wilh PDGFRB ~ Trephine biopsy sedion In:lm
a pa\llll'It WIth 1(5;12) showing a mar1o.ed increase in eosWlclphiII.
Myeloid and lymphoid neoplasms associated
W Ith
PDGFRB rearrangement
71
M<Kphology
The white cell count is increased . There
may be anaemia and thrombocytopenia
There is a ....anabre increase of neutrophils . eosooonne. rrooocvtes and eosinophil and neutrophil precursors. Rare ly.
there is a marked increase in basophils
{23551. The 8M is hype rcellu lar as a result
of active granulopoiesis (neutrophilic and
eosinophilic). Bone marrow trephine b iopsy
may show, in ad d ition , an increase 0 1 mast
cells and these may be spindle-shaped
1503,23551. Bo ne mar row reticulin may
be inc reased 123551. In c hro nic p hase
di sease, the blast cell co unt is less than
20% in the PB and 8 M.
Cytochemistry
The eos inop hils, neut rophile a nd mono c ytes show the expecte d c ytoc hem ical
reacti ons for ce lls of these lineages,
Immunoph enotype
Immunop henotypic analysis of the mast
cells has show n exp ression of C02 and
C025, as is also obse rved in the majori ty
of cases of ma st cell disease [23551.
Geneti c s
Cytog enetic analysis usually shows t(5;12)
(q 31-33 ;p 12 ) with the translocation
result ing in formatio n of an ETV6-PDGFRB
fusion gen e {8 12/ (p re viously known as
TEL-PDG FRB), In one patient ETV6
PDG FRB resulted from a four-way translocation, t( 1; 12;5 ; 12 )(p 36 ;p 13;q33;q24)
{489J, and in anomer occurred in
association with ins(2 ; 12)(p21;q?13q?22)
15121. The 5q breakpoint is sometimes
assigned to 5q3 1 and sometimes to
5q33, although the gene map loc us of
PDGFRBgene is 5q3132.
Not all translocations characterized as
t(5 ;12)(q31 ;p13) lead to ETV6-PDGFRB
fusion . Cases without a fusion gene are
not assigned to this category of MPN and.
importantly. are not likely to respond to
imatinib; in such cases an alternative
Ieukaemogenic mechan ism is upregulation
of mterleukin 3 (IL3) 146 71. AT-PeA. using
primers suitable for all known breakpoints, is therefo re rec om me nd ed to
confirm ETV6PDGFRB {498 / but if
molecular analysis is not available a Irial
of imatinib is justi fied in patients with an
MPN assoc iated with 1(5; 12).
Variants
A number of molecular variants of MPN
with ETV6-PDGFRB fusion have been
reported 1131, 20851. In addition, a patie!t
who acquired eosinophilia at relapse (j
AML was found to have acquired 1(5:14
(q33;q22) with a TRIPl1-PDGFRBf
gene. A number of other patients ha",
rearrangement of PDGFRB but With
second gene involved being unl<.novo1l.
Complex rearrangements appear to be
common (e .g. a small inversion as~.
translocation) 120851. Because of the
apeutic impl ication s, FISH (break~
FISH with a PDGFRB probe) is indicaled
in all patients with a presunptive
of MPN who have a 5q31-33 break
particularly. but not only. if there ,
eosinophilia. However, FISH analysis
not always demonstrate rearrangemercd
PDGFRB, even when it is detectable
Southern Blot analysis 120851. MoIect.iJ
analysis is not indicated if there is
5q31-33 breakpoint on classical
genetic analysis since all cases re
to date have had a cytogenetically delectable abnormality.
Table 3.04 Diagnosbc 0'Itetia of MPNor actIIe leuk.aerria associated withFGFRf rearrangement
A myeIoproIlleralive neoplasm lMlh promIfIent eosmpI1E and sometines withneutrophilia or rTW:IAClC)'Iosi
OR
AND
Preseoce r:A .8;13)(P11;q12) or. v;nnl\Jallsb..aboil!eadlng kl FGFRf~ delrorkStJaIed in
ITI)'8Ioid eels, ~sts or boItl
72
Definition
Haematoroqrce! neo plasms with FGFRJ
rea rrangemen t are hetero geneous.They
are de rived from a pluripote nt baemaio
poietic stem ce ll, altho ug h in differet'l
patients or at d ifferent stages of the disease
the neop lastic ce lls may be precursa
cells or mature ce lls. Presentation call be
as an MPN or, in tra nsfor mation, as AML
T or 8 lineage lymphoblastic lympt'loo'lQl
leukaemia or mi xed p heno type acute
leukaemia (MPAL) (Tabl e 3.04).
ICD-O code
The provisional code proposed fOf tl"E
fourth enuon of ICO-o is 996713.
Synonyms
8p 11 myeloproliferative syndrome, 8p11
stem cell syndrome, 8p1 1 stem eel
leukaemiallymphoma syndrome.
EpklemKllogy
This neoplasm occurs across a wide age
range (3-84 years) but most patients are
young . with a median age of onset iJi
Myeloid and lymphoid neoplasms With eosooobne and abnormalities 01 PDGFRA. PDGFRB Of FGFRI
Sites of involvement
Tissues primarily involved are 8M , PB,
lymph nodes, liver and spl een. lymphadenopathy is the result of infiltration
byeither Iymphoblasts or myeloid c ells.
Clinical features
Some patients present as lymphoma with
mainly lymph node involvement . while
others present with myeloproliferative
leatures. such as splenomegaly and
hypermetabolism. and yet others wilh
features of AML or myeloid sarcoma 13.
1006. 13541. Systemic symptoms such as
fever. weight loss and night sweats are
otten present 11311.
~
Presen tation may be as CEL, AML,
T-LBL or. least often. precursor B lymphoblastic leukaemiallymphoma . Cases 01
acute leukaemia/lymphoblastic lymphoma
may be of mixed phenotype . In patients
who present with CEL. there may be subsequent transformation to AML (including
myeloid sarcoma), T or B lineage lymphoblastic leukaemiall ymphoma or MPAL.
Lymphoblastic lymphoma ap pea rs to be
rrore common in patients with t(8;13) than
in those with variant transiocatons 113541.
Patients who present in chronic phase
usually have eosinophil ia and neutrophilia
and, occasionally. mono cyto sis. Those
who present in tran sformation are often
also found to have eosinop hilia, Ove rall,
about 90% of pat ients have PB Or BM
eosinophilia (1354). The eosinophils belong to the neop lastic clone, as do the
Cytochemistry
Neutrop hil alkaline phosphatase score is
often low, but cytochemistry is not important in the diag nosis.
Immunophenotype
Immuno phenolypic analysis is not useful
in chronic phase disease, but is importa nt
to demonstrate the T or B lineage 01
precursor Been or pr ec ursor
leukaemiallym phoma.
r-ceu
Genetics
A var iety of transloca tions with an 8p 1 t
breakpoint ca n underli e this syndrome,
Secondary cytogene tic abn ormalities
occu r, among wh ich trisomy 2 1 is most
often obser ved. Dependi ng on the partner
chromoso me, a variety of fusion gene s
inco rpo rating part of FGFR1 are formed .
All fusion genes encode an abe rrant tyrosine kinase (Tab le 3,05)
Cytogeoetica
M~laf
geoetic:s
ZNFI98-FGFR'
t(8:9Kp11 ;q33)
CEPf1O-FGFR1
t(6:8l(q27:pl1-12)
FGFRIOP1.FGFR1
1(822l(pl1;ql1)
BCR-FGFR1
(l' .8l(q34:pl1 )
TRJN2.f.FGFRJ
1(8.11)(pl1:Q23)
lrlY018A-FGFR1
1(8:19)(pl2;q13.3)
HERVK-fGFR1
n(12:8)(p11;pl1p22)
FGFR10P1-FGFRf
N'
"
73
CHAPTER 4
Myelodysplastic/Myeloproliferative
Neoplasms
Chronic mye lomonocytic leukaemia
Atypical chronic myeloid leukaemia. BCR-ABL 1 negative
Jwenile myelomonocytic leukaemia
Myelodysplasticlmyeloproliferative neoplasm. unclassifiable
A. Orazi
J. M. Bennett
U. Germi ng
A.D. Brunning
B.J. Bam
J . Thiele
Definition
CIvLric~ IeU<aenia (CMML)
is a clonal baematopoletrc mal ignancy
that is characterized by features of both a
myeloproliferative neoplasm and a mye lodysplastic syndrome. It is characterized
by : 1) persistent monocytosis >1x 1()9/L in
the peripheral blood (PBl; 2) absence of
a Philadelphia (Ph) ch romosome and
BCR-ABL 1 fusion gene; 3) no rearrangement of POGFRA or PDGFRB (should be
specifically exclude d in cases with
eosinophilia); 4) lewer than 20% blasts
76
2.
3,
5.
Dysplasia In oneor more myeloid lineages. If myelodys~asia is absent or minimal. the diagnosis of CMM,.
may stil l be made iflhe other requirements aremet. and'
anacquired, ctooa l cylogenelic or moleculargenetic abnoonality is present in thehaemopoietic cells. r:r
the monocytosis hasp&rSisted forat east 3 months and
aijother causes 0( monocytosis have been e~duded
Blasts irl<:IWe myeloblasts. monobIasts and prornotlOC)'le5. Promonocytes owe monocytic precursors WI1Il
ab\.IIdallt light grey or sIif1Iliy besophilic cytoplasmwitha lew scattered. h liIac-<::oIoIJ-ed p1UIes. finelydislrtluled. sWied nudear etwomabn. variably prominent nudeoIi. WId delicale nud8arloIding oroeasilg. rd
in tIIisdassilicaliorl are equivalenl lO~. AbnormaIITIClI'IOCy1eS wnen can be present baCh ti the ~
blood and bone marrow are excluded from lhe blastCCUIIl
ICD-Ocode
9945/3
Epidemiology
There are no reliab le inc id enc e data for
CMML. because in some epidemiolog ica l
surveys CMML is grouped with chronic
myeloid rewaemras and in others is
rega rded as a myeioovsptasnc syndrome
(M OS) \108] In one stud y in which CMML
accounted for 31% of the cases of MOS.
the incidence of MOS was estimated to
be approximately 12,8 cases per 100 ()(X)
pe rsons per year (2414). The median age
Myelodysplastic/myeloproliferative neoplasms
Clinical features
Inthe majority of patients, the white blood
cell (WBC) count is increased at the time
of diagnosis. and the disease appears as
an atypical myeloproliferative neoplasm.
Inother patients, however, the WBC is normal or slightly decreased with variable
neutropenia and the di sease resembles
MOS. The incidence of the most common
presenting comp laints of fatigu e, weight
css. fever and night sweats is similar in
re two groups 01pa tients. as is the rate of
otectooand of b leed ing due to thrombocytopenia 148, 683 , 777, 2047 , 2 1021. AI
ilough splenomegaly and hepatomegaly
rn'irf be present in either gr oup, they are
more frequent (up to 50%) in patients with
leukocytosis 177n
wac
f1. U 2 Chn:nc myeIomonocytic IeukaenU-l. The degree of ~s, neutrr.optMia and dysploIsia is YiWiabIe .. CUt.4L. A The ..... bIoocI eel Cl:Ullis eIINaIed wiIh rnirImaI
~
in !he ~ series. B A noonaI wtJIe bIoocI eel axn WIth absokJte monocytOSis. ~ and dysgrarUopoiesls. C A bone marrow biopsy splDnen Inlm a
CJM..1. Oftsn, " grarUoqIlc WI.-u"" ~ is mosl obYil::lIJs lin se biopsy ~, iW'llI monocyI8S may nol be rNliIy appreoaIed. D The tllded ru:IeIlnl dek:aIe
.... c:t'ttInRn em..... iiIic fA monocyI8S CM be appreciated IIIIO'IQ 1he~.
..,.. .
77
CMML- 1
Blasts (including promonocytes) <5% r:
ee PS , <10% in the BM ;
CMML2
Blasts (incl uding promonocytes) 5-1 9\
in the PB or 10- 19% in the 8M . ex I'tte1
Auer rod s are present irrespective of the
b last p lus p romonocyte cou nt.
The value of this approach has been recently con firmed 17801.
Cytoc hemic al or immunop henotypic studies are strongly recommended whenever
the d iagnosis of CMML is c onsidered
When performed on P8 and 8M aspirate
smears. alpha naphthyl acetate esterase
or alpha naphthyl butyrate esterase, used
alone or in combination with naphtt'dASD-chloroacetate esterase (cbioroacetae
I
A;. 4.03 Chronic myelomonocytlc teokaemia-2. A Blood smear from a newly ~ patient. 0C:casi0naI bl9:sls W8f1l noled.,!he perVleIaI blood smear. B Bilpsy~ ..
same palJefW. The Im\aIJ.ny of !he ba1e fllamlW BIemenIs c:ar1 be rea:iIy appreciated. C BIasts.-.d pI'Ofl'IOf'IOC) ICCOU'IC lor 12".110 of !he I'fllIm)fr eels (~ ~
78
Myelodysplasticlmyeloproliferative neoplasms
rceaseo
F"tg.4.04 Onncmyelomooocylic leukaemia, Some dl9'8801fibrosrsmay beseen in upb3O"1i 01 cases. A,8 These
pl1oklmicrographs 1ustra1e retiaJIin fibnls$ in a mafTllW blopsy specimen 01 a pabefIl WIIt1 CMML.
an
,8
Fig, U 5 CI.-onic myelornonocytIc leukaemia ANodI.*s COfl'IPOMd 01 pIastr1ac:ybd tter'01tiC eels in the bone R'IiIrrow 01 a patient WIIt1 CMML. B com is posilMIin pIasmaqtid dendriIic eels
Genetics
Cb'lal cytogenetic abnormalities are found
in 20-40% of pat ie nts w ith CMML, but
rme is specific 148, 683 , 684 , 777 ,867,
2102, 2170, 2260 1_ The most frequent re:urng abnormalities include +8. -7/deI(7q)
ind structural abnormalities of 12p. As
many as 40% of patients exhibit point
79
Def inition
Atypical chronic myeloid leukaemia.
BCR-ABL 1negative (aCMl) is a leukaemic
disorder with myelodysplastic as well as
myeloproliferative features at the lime of
initial diagnosis. It is characterized by
principal involvement of the neutrophil lineage with leukocytosis resulting from an
increase 01 tnOfphologically dysplastic
neutrophils and their precursors. However,
mullilineage dysplasia is common and
reflects the stem cell origin 01 aCML. The
neoplastic cells do not have a BCRABL 1
fusion gene.
ICD-<l code
Synonym
987613
Epid emiology
The exact incidence of aCMl is not krlOWn,
but is reported to be only 1- 2 cases for
every 100 cases of BCRABL 1 positive
C ML 1200 31. Patients with aCMl tend to
be elderly. In the few series repo rted to
dat e, the med ian age at di agnosis is the
seve nth or eighth d ec ad e of life bu t th e
d isea se has been reported in teen ag ers
as we t11266 , 928, 1208, 1396,20031 , The
report ed maie.temare ra tio var ies , b ut
based on the larger series reported , is
approximately 1:1 1266 ,928 , 1208,1 3961.
Sites of involvem ent
The pe riph eral blood (PB) and bone ma rrow (BM) are alwa ys invol ved: sp lenic and
hep atic invo lvement are also common.
Table 02 Dl3QOOSoc critenalor at)1Ial dlronic myeloid leuUemIa, BCR-ItBL nega!lYe (acML).
~ t*;lod
pi" . '
~arbone mafTtM'wiII~
and ~~. W!ltl or wrtloul
dysplasia n h etyflroict and megakaryocyIc Irl9Iges
Cl inic al features
There are only a lew reports of the clinical
featu res of pa tien ts with aC ML. Most patients have symptoms related 10 anaemia or
some times 10 thrombocytopenia. whereas in
others the chief complaint is rela ted to
JW, Vardiman
J.M. Bennett
B,J, Bain
R D , Brunning
J , Thiele
MyekldysplasticJrnyeloproliferative neoplasms
.
-,
.
- .....
~
Fog. ' .07 Atypical chrOIlIt myeloid leukaemia. A Bone IT\lIITOIfI'biopsy shows 1Iypetc:eIIWnty. 0Je to~ proMerabon B NcJ(e anncrease "' Ihe l1JITtler of rnegak.afyocytes,
... smal abnonnallorms From the biopsy alone. !he fT'OlIhology wWd be dlfliQjt to tjft'erentlale from BCR-ABl. po5IbYe chronic myelogenous leukaen'ia C Bone marrow
. . smear. Oysplasia in !he ~ and the megakaryo:;ybC lineages is eWlenI.
coesnon.
Genetics
Karyotypic abnormalities are reported in
up to 80% 01 patients with aCML. The most
CCfTITlOlI abnormalities are +8and del(2Oq) ,
but abnor malities of chromosomes 13, 14,
17,19 and 12 are corrvnonly repor ted as
'Nell 1266, 928.13961. Rarely, patients whose
neoplastic c ells have an iso lated isochromosome 17q may have features of aC ML
although most will fulfill the cr iter ia for
CMML 11437f.
There is no BCRABL 1 fusion gene.
Cases with rearran gement of PDGFRA or
PQGFRB gen es are also specifica lly
excl ude d. The ac tiva ting JAK2 V617F
mutation has been reported in some c ases
of aCML {1064, 12871. Approx imately 30%
of cases are ass ociated with acquired
mutat ions of NRASor KRAS1 2311 1,
Some c ases of t(8; 9)(p22;p 24 ) with the
PCM1..JAK2 fusio n gene have bee n
reported as "aCML" 1259, 18331 but d ata
cu rrently ava ilable suggest they hav e
eosinophilia and lack mye lody sp lasia and
may be better regarded as chronic eosinoph ilic leukaemia. Meticulous description of
the morpholog y of atypical mye loid proutera tions associated with var ious geneti c
defects will be necessary to assign them
to appropriate ca teg orie s,
81
Definition
Juvenilemyel:m:>nocyt<; ""-'<aemia (JMMLI
is a clonal haematoocietrc disorder of
childhood characterized by proliferation
p rinci pally of the gr anulocytic and m0nocytic lineages. Blasts pius promonocytes
account for <20% of cells in peripheral
blood (PB) and bone marrow (8 M). Erythroid and megakaryocytic abnomaunes
are frequently present 132. 303, 14771.
BCRA8L , is absent, whereas rrctato-s involving genes althe RASIMAPK pathway
are cha rac teristic .
ICD-Ocode
994613
Epidemiology
The inci dence of JMMl is estimated to be
approximately 1.3 per millio n ch ildren
0- 14 years of age per year. It accounts
for less than 2-3 % of altleukaemias in
chi ldren, but for 20-30% of all cases 01
mye lody splasl ic and mye loproliferative
disease in patients < 14 years of age 1907.
Etiology
The c ause of J MML is not known . Rare
c ases have b een repo rted in identical
twins \17051. The association between NF 1
and JMML has long been established 1345.
1595 , 2 1011. In contrast to adults who
hav e NFl . children with NFl are reported
to have a 2OQ. to 5(X).fold increased risk
of developing myeloid malignancy, mainly
J MML 115951.Occasionally young infants
with Noonan syndrome develop a JMML-like
disorder, which resolves without treatment
in some cases and behaves more aggressively in others 11211 , These children carry
germhne motanons in PTPN11,lt1e gene
encocting the protein tyrosine phosphatase
SHP2121621 or in KRAS 119741 .
Sites of involvement
The PB and BM always show evidence of
myerononccvnc p roliferation. Leukaemic
in filtra tion of the liver and spleen is found
in virtually all cases, Although any tissue
may be infilt rated, lymph node, skin an d
t he resp iratory t rac t are other co mmon
sites of invo lvem ent 1345, 134 6 , 15951.
Clinical features
Most patients p resent w ith constitutio na l
sym ptoms o r ev idence of inf ect ion \34 5 ,
1346, 1595l . There is generally ma rked
hepatosplenomegaly, Oc casionally sp leen
size is no rm a l at di agn osis but rap id ly
inc reases thereafter, About half the patient s
82
Myelodysplastic/myeloproliferative neoplasms
I Ba umann
J ,M. Benn ett
C.M. Niem ey er
J , Thiele
K , Shannon
<)
.~
FIg.4.111
oae-
Fig. U t Juvenile myeIomooocytlc leukaemia, A The bone marrow- aspole &IM3f usuaty refIecls thed\afIge$ noted
in the blood. buI !he monocyle ~ lllIlI is dmft10 appreciate, 8 ACOlTiw'oed alpha naplhyI acela1e eslefase and
naptl~ esterase ' eaclion idenblies the vanulocytlt (blue reaction product) and the ITIOflOCYlIC
component (brown feacbon product). A lew eels contain bolh pnxIuct$
Fig. 4.10 Juvenile ~ lOCytJc leukaemia, A The b<:Jre marrow is ~ wrlh g~pn:lilefabon.
B The megakalyocytes are reduced in IlUfTlbef, but appear rTlOIphologlcally IlOffIIII in Ihe biopsy Blasts are not
substantially ineteased in rvnber.
foC~
eoo
- type
Fig. 4.11 JU'.'OOile rnyeIofnoncq1ic leukaemia. The leukae ~ infiltrate in the Iivef isin the portalregiOns (AI as wei as
in !he hepalic sinusoids (8) , C The leukaemicI1filtrale in !he red pulp of !he spleen encroadles ~ !he gemiIIaI ten.
Int. 0 The infiltJale is compfised mainly of immalufltand maluflt neutrophils and fTIOflOCY\es.
Gene tics
Karyotyping studies show monosomy 7 in
about 25% of patients, other abnormalities in 10%. and a normal karyotype in
65% 115951. Philadephia chromosorneand
the BCR-ABL I fusion gene are absent.
JlIVenile myebnonocytic leukaemia
83
GM~SF
SO~
She
G, b2
Ga b2!
SHP-2 - -
R a s -GDP
~ --.......r-,
Neurofibforrin
.-I
"..,""'"""~
GM~SFR
PTPNU Mutation
(-35%)
oee
irr.IoeI.D"leYeIs d Ras-GTP.
aetvaaed, Ras-GTP ~ ..... rurtJerd ~ elfectIrs, The Gw.
lIdMI\log proB1s pt2OGN' and net.6OIibn:mn brld kIRas-GTP and aoc:eIerate lXlfI'o'eIWn d Ras-GTP kI Ras-W'
~ kI GM-CSf is a ceIlW haImart. d JtAt. ltIal resulls from a rurtJer d lisln::l genetic ~
t.lJtaIioI1s in PTPNfl increaseSHP2 phosphatase acIYlty a'lderNIce Ras SigrlafrIg. SiTI1arIy. cancer-associaled . . .
acid Slbsl.iluIiCI'I in NRAS or KRAS2 red in /TJJlarIl: Ras prol8in:s IIaIlICO.Il1Jiate " ee acINe. GTP-b:u1d c:onbmalion. FnaIy. inacIivaIiorI ofllle NF l ~ ~gene ~ Rassigoahng ItlrtXJgh loss ofneurofib'orm
s
(
s
ti
T
o
84
MyelOdysplasticJmyeloprolilerative neoplasms
Myelodysplastic/myeloproliferative
neoplasm, unclassifiable
JW. Vardiman
J.M . Bennett
B.J, Bam
I. Baumann
J , Thiele
A. Orazt
Definition
Myelodysplastic/myeloprohferative neopIasm. lI'lClassifiabie. (MDWPN. U) meets
!he criteria lor the MDSIMPN category in
lhat, at the time of irntial presentation ,
eee are clinical, laboralOf'y and rrceprobgicaI features that overlap both MOO and
MIh myelodysplasticfeatures. If the under~ MPN c annot be identified . the desigration of MDS/MPN , U is appropriate. If
there has bee n any rece nt cytotoxic or
arowth fact or therapy, follow-up clinical
and laboratory observations are esse ntia l
kl demonstrate that the peripheral b lood
(PS) and bone marrow (BM) c hanges are
'lOt due to the treatm ent.
ICD-O code
9975/3
Synonyms
\lIXed myeloc routerawe/myelocysptastc
syndrome , unctasstnebre : "overlap" synacme, unclassilia ble .
&las of involvement
The BM and PB are always involved:
spleen, liver and other extramedullary
':ISSUeS may be involved.
The case has dirucaI, laboratory and ~ IN!ufes rJ onerJ !he ca1egories rJ MDS (reifacklry
~ WIItl unineage: dysplaSIa, relraalryaJla&mia WI\IlI'IIgSiCIerObIasIs. reIracIory tyqlenia 'MIhIlUbIileage ~. relradory anaemia -.ilh elC8SS 01 blasts) and <20"4 blasts in the blood and bone marrow
""
no ""
The palienlhas de rICM) disease WI\tl nned myeIoprolilnlrt'8 and myelodyspIastIc features IIfId eatnlt
be assigned to i1It'/ olhercategory rJMOS, MPNrJMDSIMPN.
IrrmJnophenotype
Genetics
Definition
85
AARS, bu l who also have marked thrombocytosis assoc iated with abnormal
megakaryocytes similar to those observed
in the BCR-ABL 1 nega tive MPN, such as
ET or eartv-staqe primary myelofibrosis
(PMF) 1865,1077,21091. However, some
investigators have suggested that MAS- T
is not a unique entity but instead rep resents cases of other subtypes of MDS or
well-defined MPN that have acquired ring
sidercbtasts as a secondary form of
dysplasia 119661. It is not clear whether
AAAS-T is a distinct entity, one end of the
spectrum of AAAS . a progression of
AAAS due to an addrtiooat acquired
genetic abnormality. or less likely. Ihe
occurrence of two rare diseases in the
same patient. Therefore . until these questions are more ctearly answered . AAAS-T
remains a provisional entity
In support of a myeloproliferative component to this neoplasm, the majority of
cases reooeted as RAAS- T have shown
the JAK2 V617F mutation, or much less
commonly. the MPL W515KIL mutation
1234. 354 , 762, 1835. 1839. 1969. 2081 ,
2 139. 2358 1_ On the other hand. the few
reported cases with this mutation that
have been studied for endogenous colony
form ation in vitro have demonstrated a
pattern mo re akin to that of MDS 1234.
18351 . Thus it may be that the provisional
design ation of an MDS/MPN accurately
reflects the underlying biology in a substantia l pr oportion of the p atients 1762J;
more stud y is neede d to further ctarify this
diso rder.
Cases with isolated del(SQ),t(3;3)(q21;q26)
or inv(3)q 2 1q26) are exc lude d from this
ca teg ory, as are cases with a BCRABL 1
fusion gene, In ad dition, if there has been
a prior d iagno sis of an MPN without ring
sioerc otasts. or there is evide nce that the
ring stoerotsasts might be a consequence
of therapy or represent disease prog ression in a patient wi th features tha t meet
the crite ria of another well-de fined MPN,
this designation should not be used.
IC().() code
9982/3
Morphology
These cases have features of AAAS
(anaemia With no blasts in the PB and
dysplastic , ineffective erythroid prolif8fation
often with megaloblastoid features, ring
sideroorasts :2:- 15 % 01 the erythroid precursors. and <5% blasts in the BM) and
thrombocytosis With a platelet count
:2:- 450x1CJ1Il associated with proliferation
86
..
Fig.' .13 Refractory eneema WIth ring SideI'Ob~s andlhfombocylosis This sequence of rnitrophotogriljtls AtsIr3lt
blood and bone marrow 01 a 62-year-old man who presenled with severe anaemia anda plateletcount oI85lb:10"l
A Abnormal red cells and Ihrontlocylosis. B El)'lhroid proliferation and abnormal megakaryocylll$ reserrtIing megNyccytes seen in ET. C Mild dyserythropote$is. 0 The majority01 erythroid pIlICllfSOrS were ring sicleroblasts.
Genetics
The recent discovery that up 10 60% of
pa tients with AARS-T harb our the JAK2
V617F mutation (an inc idence similar to
that found in ET and PMF) or less cornmon ly, the M PL W515KjL mutation, not
only elucidates the reason for the proliferative aspect of AARS-T but also woold
seem to move it closer to the MPN catego)
1234, 354. 762. 1835, 1839, 1969,2081,
2139, 23581. Thus. studies for JAK2V617F,
and. if ind icated, for the MPL W515M
mutation should always be performed in
such cases .
CHAPTER 5
Myelodysplastic Syndromes
Myelodysplastic syndromes/neoplasms,
overview
Definition
The mve'oovsptasnc syndromes CMOS)
are a group of clonal haematopoienc
A.D. Brunning
A.Orazi
U. Germing
M .M . Le Beau
APOfWit
I. Baumam
J .W. Vardiman
E. Hellstrom-Lindberg
Myelodysplastic syndromes
:.
.It
Ep ide miology
Myetodysplastic syndromes occur princ ipally in olde r adu lts with a median age of
70 years . with a non-age corrected annual
incidenc e of 3-5/100 000 p ersons bu t
rising to >20/ 100 000 amo ng tho se ove r
the age of 70 years {109, 7831. App roximately 10 300 inciden t cases of MOS
were d iagnosed in 2003 in the USA
{1351 1. There is a male predominance .
Thera py-related mveioovsptasuc syndromes are discussed in Chapter 6.
Cli nic al featu res
The major ity of patients present with
symptoms related to cvtooentats): most of
the patients are anaemic and transfusiondependent. less frequent are neutropenia
and/or thrombocytopenia. Organomegaly
is infrequ ently observed.
Etiology
Prima ry or de novo MOS oc cu rs without a
know n history of c hemotherapy or race
expos ure. Possible etiolog ies for pre
ma ry MOS Include benzene exposure at
levels well abo ve the m inima allowed by
most government age nc ies. cigarette
smoking, exposure to agricultural cherricats or solvents an d family history ci
heematoootenc neoplasms 121131. Some
inherited haematolog ic al d isorders. SUCll
as Fanconi anaemia. dyskeratosis Cl)f\o
geni ta. Shwachmann-Diamond evnocre
and Diamond-Brackten syndrome are
also associated with an increased risk
MOS.
non
M"",hoIogy
The morphological classitication 01 MOO
is principally based 00 the percent
blasts in the 8M and PB. the type an:!
_ _ IRT)
8100dMdinp
~ or bicytopenia'
tI or rareblasts 1%)1
No "''''
Cylopenia(s)
No or fare blasts 1'10)2
NoAlIeI'rods
<'~10"11. monocytes
<5%_
Cytopenia{s)
<5%blasts'
NoAutlr rod s
< 1 ~1O"fl mooocytes
Cytope nia(s)
5-19% blasts
Auerrods t 1
<1~10'J1. mooocytes
Cytopeflias
5:1% blasts '
"""""
UsuaRy J'M)n1I3I or
we.ased pIaIeIet COUI1l
Noor rareblasts ,%)
tJwoIobated fIUdei
<5% blasts
Isolated _
del{5q) cytogenetic al:inl:lrmlliTy
No_
8q'qlenIa may 0CCiI5i0naIy be obseMld cases Wl1l'I pancytopenia should be classified as t.I05--U.
myeloblast perc:entBge is <5% bul1tlEWe ere 2--4% myeIoblasls nee blood, ee liagnosticdass1Iic:aticrl is RAEB 1. Cases 01 RCUO and RCMDIIo'ilh I %Il)'IlIoblasts IIIlhll blood shoUlIbe dassifled as MOS, U
I . . . JIlafl'DW
Cases W1111wfII rods nI <5% myetlbIasls III 'lie blood arw3 0(10% inee I'!llll1tIW sInJId be d8s$lIied ... RAEB 2.
,--
--""
-.
Fig. 5.05 A Blood smear from a pa\J8I"It on grarUocyte COOny sbmulating!acttJr. A neutrophil W'IIh a bIlobed nucleus
and naeased azuror:I* grClruabon. B The same SI)Itinen as (A) showing a myeloblast.
Tab le 5.02 Summary of cytopenias anddysplasia characteristics in MOS without an illCfease of marrow blasts.
Cytopenia(s)
Oysplasla
Categories
Unicytopenia
Bicytopenia
Unilineage
p- -"---...
Biq10penia
UflIinelIge and
""","",
"'"'-
90
2:15"" ringSideroblasts
Myelodysplastic Syndromes
(RCMO)
118641.
Ch.aracteristics of dysplasia
Dyserythropoiesis is manilest prine
by alterations in the nucleus ine
budding, internuclear bridging , karyCIrhexis , mu/tinuclarity and megalobla
changes; cytoplasmic features .
ring siderobIasls. vacooIisalion and penxk
acrd-Sctnf positivity. either diffuse (I
granular (Table 5.03). Dysgranu!opoiesl
is characterized primarily by nudelJ
hypolobation (pseudo Pelqer-Hoetj a~
hypersegmentation. cytoplasmic hypogranularity. pseudo Chediak-HigaS'J
granules and small size. MegakaryocytP
dysplasia is characterized by micromegakaryocytes with hypolobated nuclEi,
non-lobated nuclei in megakaryocytes Ii
all sizes, and multiple, wrderv-seoaraiea
nuclei, Megakaryocytic dysplasia maytlt
more readily app recia ted in 8M secncs
than smears and both types 01 specimers
should be eva luated
The cha racteristics of the dysplasia maj
be relevan t in pred icti ng biology of a
mveicoysorastc d isorder and the relatcoship to specific cy toge netic abnormalities,
ego Sq-syndrome {2327}, Unilineagedysptaaia is o bserved in RCUD and RARS
Multilineage dysplasia involving two c.
three of the myeloid ce ll lines is rTlOfe
frequently observed in the high-graClt
MDS an d is used to distinguish ReM!)
from ACUD 118641. Similarly, the presence
01 multilineage dysplasia is used
separate RARS from RCMD with n
sroerobtasts. the latte r of which has a
similar clinical course to RCMD_
increased number of ring sioerotnasa
occasionally> 15% of the erythroid precursors. may be observed in refract
anaemia with excess blasts (RAEB). TIt
defining criteria of RAEB- l or RAEB-2
dictate the classification in such cases
:-
--
A.
...
91
Fig. $.12 A Bone marrow bI:lpsy from a case of MDS (RAfB) WIth /I'I)'eIOfb'osi 5everaI ~ iIIe
presenl B Retio.anstain ona marrow bclpsy from a case of MDS wilh myelofibrosis. There is a marked inaease II
retia.Wl MIres.
Noclear budding
Int&rTll.lClear bridging
Karyorrtlexis
Mll ~inuclearity
Nuclear hyperlobation
Megaloblastic changes
Cytoplasmic
Ring sideroblasts
~izaliOn
.... """
--
~l)'ocytopoiIs ls
NudNt hypoklbllJon
~ (normaI .,..katytq1es in
I.lI'W'IJl:illI wilh kltdaled nudeI)
92
Myekxtysplaslic syndromes
no
1l1VTlUnophenotyping
Published studies on immunophenotyprg
by flow cytometry in MOS have focused CI'l
several stra tegies, including determrwg
the size and immunophenotype of ee
blast population and assessing the maturation pattern 0I1he myeloid cell popUatol
More specifically. these studies included
immunophenotyp ing of CD34+ cells, ap.
plication of SCOfing systems, and pattern
recognition strategies uSing muttiCOO
analysis and comparison with norrn;iI
reactive PB and 8M.
There is generally good correlation between the percentage of blasts as ceremined by morphologic examination iJ
fOJtine smearor irr'pV'ltor ~
preparations and percentage of CD34.
cells determined by flow cytometry ( FC~
However. in some cases there may be
significant discordance due to signilicart
myelofibrosis and haemodilute samples
As a result, Fe percentages 01 CD34+ eels
cannot replace differential counts 00
smears, However, Fe may be informal1Ye~
abnormal phenotypes of C034+ cells are
detected: this could be additional evidence
dysplasia. In addition, an emerging
athological population of CD34 IJ
01 17 cells in low-grade MDS could Sl.I9"
gest evolution of the d isease 116221.
Ma tu rat io n pa tte rns of erythropoie tic
g ranuloc ytic, and monocytic difterentiatcn
in the normal/reac tive 8 M, as well as the
immuno phenoty pe of the mature cells in
PB have been thorough ly desc ribed using
fou r-co lor FC. Erythroid abnorm alities as
de termined by the pattern of exoressce
of H-ferritin , CD7 1 and C010S in gly
cophorin A (GPA) posi tive nucleated cells
reportedly ca n pred ic t morphological erythroid dysplasia with 98% sensitivity [5501,
A be rran t maturation patterns in granulopoiesis could pred ict morphological
dysplasia and abnormal cytogenetics in
ap proximately 90% of cases 112121. ThJs
flow cytorretrv results co rreiate well with
morphology and cytogenetics in MDS
However, in cases with borderline dys.
plasia by morphology and no cytogenetic
abnormalities. FC results are highly suggestive for MOS only if there are three IJ
more aberrant features in erymropoietc.
g ranulocytic or monocytic maturation;
single aberrant features by FC are na
f:
Genetics
Cytogenetic and molecular studies have
a major role in the evaluation of patients
with MOS in regard to prognosis, determnaton of clonality {833, 16411, and the
'ecognltion of cytogenetic , morphologic ,
m clinical cor relates . Clonal cytogenetic
abnormalities are observed in - 50% of
I,()S cases. Myekxtysptastic syndromes
associated with an isol ated del(5q) occur
orinarity in women, are c ha racterized by
megakaryocy1es with roo-ocetec Of hypoklbated nuclei, refractory macrocytic
anaemia, normal or increased platelet
Cl:lOO t, and a favourable clinic al c ou rse,
and are recccneec as a scecinc type of
MDS in this c lassification , The oc c urrence
(j 17p loss is assoc iated wi th MOS or
AML with pseudo Pelger-Hu6t anomaly.
small vacuol ated neutroohlrs. TP53 mutation and unfavourable c linical course: it is
rest common in therapy-related MOS
(12371 Complex karyotypes (2:3 abnormalities) typically include chromosomes 5
andfOf 7 [-S/del(5q), -7/del(7q )), and are
generally assoc iated with an unfavourable
clinical course . Several olher cytogenetic
lindings ap pear to be assoc iated with
characteristic morp hologic abnormalities
such as isolated del(20q) w ith involve ment of eryt hroid ce lls and meg akaryocvies. and abnormalities of c hromosome
3 (irw (3)(q2 1q 26 ,2) or t( 3 ~ 3)( q 21 :q26,2 )].
which are associated with MOS and AML
withincreased abno rma l meg akaryoc ytes
1289, 866, 1207j.
Some clonal cytogene tic abnor mal ities
occuring in MOS are not definitive evidence for this disorde r in the absence of
morpholog ic al crtterte. e.q . -Y, +8 or
ool(2Oq) as the sale abnormali ty, The
other abnormalities listed in Tab le 504 in
presence of a refractory c ytope nia ,
but no morphologic evidence of dysplasia,
are considered presumptive ev idence for
MOS. It is recommended tha i tnese pallefllS be followed caretcuv lor emerging
roorphologi c al evidence of MOS. FISH
tJOVides increased senSitivity in monitoring
Sl.Ch pateots.once a recurring abnormality
res been identified ,
ee
A_"
MO'
""""""""
' 0%
' 0%
' 0%
' S'
1 or del(7Q)
-5 or del(Sq)
. ..
- ,'
.r
S%
. S%
~ 17Q)
or l(17p)
.13 or del(13Q)
del(11Q)
del(12p)Of 1(12p)
-,
,-110,
""'
""'
'"'"
'"
' .2%
' .2%
dc(X)(Q13)
...
.
1( 11;16)(q23,p13.3)
1(32 1)(q262;q22.1)
1(1;3)(p36.3:~1.2)
1(2;1l)(p21:Q231
~3)(q21 q26.2)
1(6:9)(p23;q34)
'"
2%
15321.
Table 5.05 International Prognostic SC:or1'1g System(IPSSllor MDS (833,833Af. See Prognosis and pt'edidive faclQrs
lor interpretation,
,,~
Prognostic variables
" bone marrow blasts
Karyotype"
C~s -
<5.
5-1 0%
.-,
Intermediate
Good
,.s
11 - 19"110
20-30%'
Poot
2-3
Hgb<1llgk1.
NeutropIiIs <1.8xlll'11.
93
Definition
Refractory cytopenia with unilineage dysplasia (RCUD) is intended to encompass
those myelodysplastic syndromes (MDS)
which present with a refractory cytopenia
with unilineage dysplasia and includes
refractory anaemia (RA) , refractory neutropenia (RN) and refractory thrombocytopenia (AT) . Although refractory anaemia
with ring sioercoiasts is also characterized
by unilineage dysplasia. it is considered
as a distinct entity of its own . Refractory
bicytopenia may be inCluded in the AGUD
category il accompanied by unilineage
dysplasia. It is recomnet ICIed that refractory
pancytopenia with unilineagEl dysplasia be
placed in the category 01 rnyelodysplastic
synd rome. unctassrnaore (MDSU). The
recommended level lor dysplasia is ~ 1 0%
in the cell lineag e affected. The recommen ded levels for defining cytopenias are
haemoglobin <10g/dL. absolute neutrophil count (ANG) < 1.8x1Ql1IL and platelet
count <100x1(19/l1833, 833AJ. However,
values above these levels do not exclude
MDS if definitive morphologic and/or cytoge netic ev idence of MOS is p resent. The
typ e of c ytopenia in the majo rity of cases
w ill cor respon d to the type of unilineage
dy spl asia , e.q. anaemia and eryth roid
A.D. Brunning
A.P. Hasserjian
A . Porwit
J.M. Bennett
A. Orazr
J. Thiele
E. Heustrorn -Ltndberq
Synonym
Refractory anaemia.
Epidemiology
Refractory cytopenia with unilineage
dysplasia comprises 10-20% of all cases
of MOS 1782, 1371/. It is primarily a dsease of older adults; the median age is
around 65-70 yea rs There is no signifi
cant sex pred ilection , The vast majorityo!
RCUD c ases are RA. Refractor y neutropen ia and refr actory thrombocyt openia
are rare an d extreme c aution should be
used in making either of these d iagnoses.
Sites of involvement
The P8 and 8 M are the p rinci pal sites 01
involvement,
Clinical feature s
In RCUO. the presenting symptoms are
related to the type of cytopenia, The cytoper nas are refracto ry to haernauruc therapy, but may be respo nsive 10 growth
factors 19831.
Mo<phology
Refractory anaemia
code 998013)
In the PB in RA, the red blood cells are
usually normochrcmic, normocytic or normoctYomic, macrocytic. Unusually, there is
anisochromasia or dimorphism with a
oco-o
Fig. 5.13 Refradory WIlIeIT'Iia, This bone IIWTt7W smear speomen shows dyspIasbc Jeatures criy in !he8f)1tVOld
preo.nors; octaSiOnaI erythrobIasl$ sI'lClW vacu:lIat8d c:ytopIasm Mel ~ megakXVst*! 1'oldBi.
94
Myelodysplastic syndromes
AS
Fif!. 5.14 A Refraclory neuuopel'lIa Bklod smear m a 56-year-old male;!tiel'lIllAJq)hI in lhe bwer IeflIS normal aweamg with weI-grarIJIated cytJpIa$ITI and a namaIy M!1I'*'*I
1IJdIus. The A8IA"ophI inltle l4lP8l'
is dysplastic wiIh ~ ~ cyq:.Ia$mWld oc:casionaI 0CHe bode&. The I1.JdM; shows retarded MglIl8lI!alJOll. ApprounaleIy
IlIIf01 fie nMropI'Iis 'III'8l1l dyspIaslic. Cytogenetic S!I..des showed .. extra toP'I d cnomosome 8 lWld perlOlft'lc rNer1ion d ctvornosare 12. B A tIyspIastic megakaI)uyte in a
~ ItTl8al' from a ll-year-okl male WIlIl a two year hISlory oIrelradory II1rtlmbocyk:Jp Theie is ~ Ikdearcylopiastllc dewelopll.,1 '/IIllh a ~
~ and 8 norHobated mnaltn nucleus. CytIgeoelic slldIes ' I this !line stoNed a missing Y chromosome. There was SlbsequenC evokIIIon at which lime ~
-.oes shcMoed a rrWsSlI'lg Y, addltIonaI9 and deletion 13.
rv-
10%).
present
The erythroid precursors in the 8M in RA
vary from decreased to rnatkedty increased ;
<tyseryltYopoie variestrern slight to mode ere. unequivocal evidence of dysp lasia
met be present in 10% or more erythroid
precursors. Dyserythropoiesis is manifest
Refractory neutropenia
(lCD-O code 999 1/3)
Refractor y neutropeni a is ch aracterized
by~ 1 0% dysplastic neutrophils in the PB or
3M; the dysplasia is principally manifesl as
ru:::1ear hypoIobation and hypogranulation.
--
Refractory thrombocytopenia
(ICD-O code 9992iJ)
Refra ct ory thrombocytope nia is characterized by 2': 10% d ysplastic megakaryocv tee of at lea st 30 megakaryocytes
eva luated : hypolcbate megakaryocytes,
b inucleate and multinucleate megakaryecytes and mrcromeqakarvocvtes are the
most reliab le and reproduci ble featu res
of mega karyocyte dysp lasia , Dyspl astic
megaka ryocyles may be more eviden t in
sections than smea rs and usually well
exceed the 10 % threshold . The megakarvocvtes may be increased or decreased . The other myeloid ce ll lines do
not show sign ificant dysplasia (<10%).
Distinction frem chronic autoinvnune
thrombocytopenia is cntc at and may be
extremely difficult clinica lly and morphologi ca lly. Cytogenetic studies may be of
consi derable aid in this distinclion 18661.
Immunophenotype
In refractory anae mia abe rrant immuneph enotyp ic features of erythropo ietic
precursors can be found by flow cytometry
ana lysis 15501. There are no d ata on RN
and RT.
Genetic s
Cytogenetic abnormalities may be observed in up to 50% of ca ses of refractory
anaemia 1782J Several difterent acquired
clonal chromosomal abnormalities may
be observed. and although useful for
establishing a diagnosis of RA, they are
not specific. The abnormalities generally
associated with RA include del(2OQ), .8
and abnormalities of 5 aod/Of 7. The number 01 reported case s of AN and
is 100
low to allow for generalizations, although
del(2Oq ) has been reported in AT 1866.
19381.
95
R.P. Hasserjian
N. Gatterman n
J.M. Bennett
A.D. Brunning
J . Thiele
Detinitioo
Refractory anaemia with nng stderoorasts
(RARS) is a myelodysp lastic syndrome
(MDS) cha racterized by anaemia. morpho-
ICD-O cod e
998213
Epidemiology
RARS accounts for 3-11% of MDS cases.
It occurs p rimarily in older indivi dua ls with
1267.782. 13711.
EIOOgy
Ring sideroblasls represent erythroid pre-
""""hology
Patients typically p resent with norrTll'>
ch rom ic macrocytic or normochromic
normocytic anaemia. The red blood eels
in the PB smear may manifest a d imorphic pattern with a major population 01
normochromic red bkxxt cells and a
minor population 01 hypochromic cells
Blasts are not present in the PB. The 8M
aspirate smear shows an inc rease in erythroid precursors with erythroid lineage
dysplasia. inc ludi ng nuclear lobation and
megaloblastoid fea tures . G ranulocytes
and megakaryocytes show no significant
dysplasia 10% dyspl astic forms).
Haemo sid erin-Iaden macrophages are
often abundant. Myelob lasts are less mao
5% of the nucleated 8 M cells. On an ironstained aspirate smea r, 15% or more of
the red cell prec ursors are ring srceroblasts, as defined by 5 or more iron g ranules enci rcli ng one thi rd or more of the
nuc leus. The 8 M biopsy is norrnocellularto
markedly hyperceIlular. usually witha marked
erythroid proliferation. Meqakaryocytes are
normal in number and morphology.
Ring sid eroblast s are frequen tly observed
in other types 01MDS 1776, 10781. For examp le , c ases with ring sideroblasts that
hav e exc ess blas ts in the PB or 8M are
cl assifi ed as refractory anaemi a with
excess of blasts (RAEB). When ring stoero
bl asts a re 15% o r more of the eryth roid
precur sors but there are 10% or more dyspl astic cells in any non-erythroid lineage.
Fig. 5.15 RefratQy..aema WItl'l rtog siderobIasts. A Blood smear wilh dmorphic red bklod eels and macrocyIeS (WrJItII-Giemsa). B 8lnI 1l\WfOlf aspt'aIe smear stlowIWlg I
marked 8l)'ttlroid proIiferallon with a d)'5!JIBstlc Mderate bm (WrVrt-Giecnsa). C Ironslain d bone Il\WfOlf iISpQI8 sIll:JrMng I'U"I'letOUS ring sdetoblasts.
96
Myelodysplas!iC svnorores
1201.
Irrrnunopheootyp
In refractory anaemia with ring stderooests . aberrant immunophenotypic tealures of erythropoietic precursors can be
lound by flow cytometry analysis 15501.
100
eo
0;
.~ 60
---1....-
"~
~RARS
40
Q.
20
0
0
100
200
300
Months
Genetics
Clonal chromosomal abnormalities are
seen in 5-20% of c ases of AARS and,
when presen t. typic ally involve a single
FIg. 5.16 Stn;vaI Ctro'eS aller long-lenn ~oI' 161 patients WIth RARS and 318 RCMO patients WIltJ 2'15%mg
siderotlIasts (RSI. showing i'ltenor survival lor lIIe pallents WIth mg sideroblasts and nUtiIineage dysplasia
(p:O.ClCIOOS)(Datafrom ltIe Dusseldorf UDS regislry),
soercoiests
97
Definition
Refractory cytopenia with multilineage
d ysp lasia (ACMD) is a type 01 myelodysplastic syndrome (MOS) with one or more
cytopenias and dysplastic changes in t'NO
or rrore of the myeloid lineages: erythroid .
9mnulocytic. n-egaka<yocytjc 118641. rtere
are < 1 % blasts in the peripheral blood
(PS) and <5% in the bOne marrow (8M) ;
Auer rods ere not present and the mono-
98
Myek:!dYSplastlC syndromes
R D. Brunning
J ,M . Bennett
E. Matures
A. Orazi
J.w. Vardiman
J. Thiele
998513
Epid emiology
Refractory cytopenia With multilineage
dysplasia occurs in older ind ividuals: the
median age is approximately 70 years.
There is a sligh t predominance of males.
The peak incidence for males is 70-74
years, for fema les 75-79 years (7821. It
accounts for -30% of cases of MDS 1782.
137 11 .
Sites of involv ement
Blood and bone ma rrow
Clinical features
Most patients present with evidence 01
BM failure with cy topenia 01two or more
myeloid cell lines.
Morphology
The BM is usually hypercellular. Neu trophil dy splasia is cha racte rized b y
.......
Fig. 5.1' Refractooy ~ withrn.J~~
Bone marrow smear shows eviOenCe 01 dyspasia...bl:tl
ee erythroidprecursors andthe neutropnils. The maI\tt
neutrophils aresmall andMvallypolobulated rn.cIeI.
Immunophenotype
See Chapter on mye lod ysplastic synoromesrneo otasms. overview.
Genetics
Clonal cytog enetic abnormalities including
trisomy 8, monosomy 7, del(7q). monosomy 5, del(5q ), and del(2Oq), as well as
com plex karyotyp es, may be found in up
to 50% of patients with RCMD {782, 8331.
Postulated cell of origin
Haematopoietic stem cell .
99
A.Orazi
R D. Brunning
R P. Hasserjian
U. Germing
J. Thiele
Definition
Refractory anaemia with excess blasts
(RAEB) is a myelodysplastic syndrome
(MDS) with 5-19% myeloblasts in the
bone marrow (BM) or 2-19% blasts in the
peripheral blood (PB) Because of differences in survival and inc idence of evolution to acute myeloid leukaemia (AML).
two categories of RAEB are recognized:
AAEB-l, defined by 5-9% blasts in the
BMor 2 -4% blasts in the PB, and RAEB-2 ,
defined by 10-19% blasts in the 8M or
5-19% blasts in the PB 18331. The pres-
998313
Ep;demkllogy
This disease affec ts primarily individuals
over 50 years 01 age . It accounts lor approximately 40% of all patients with MOS.
Etiology
The etiology is unknown. Exposure to environmenta l toxins, including pesticides,
pet roleum derivatives and some heavy
metals inc reases risk, as d oe s cigarette
smok ing 12113AI.
Sites of Involve me nt
Blood and bone marrow ,
Clinical features
Most p atients initially present w ith symptoms rela ted to BM fail ure , includ ing
anaemia, thrombocytopenia and neutrope nia.
"'"""",Iogy
The PB sme ar freq uently shows abnormali ties in all th ree myeloid cell lines.
including red cell anisopoikilocytosis.
large, giant or hypogranular platelets and
abnormal cytoplasmic granUlarity and
nuclear segmentation of the neutrophils.
Blasts are commonly present. The BM is
usually hyperceHular. The degree of dysplasia may vary. Erythropoiesis may be
increased with macrocyticlmegaloblastoid
changes . The erythroid precursors may
100
FIg. 5.19 Relractoryanaemia Wl1tJ excess b1asts-1(RAEB-1J. Bone rnatrOWsmear. The malJ.l'e ~ I'Ihsc.
show nuclear hypolobulabon (pseudo Pelger-Hll8I nuclei) and cytoplasmic hypograrnunty.
MyelOdysplastiC syndromes
Irrmunoph enotype
Flow cytometry in RAEB often shows
increased numbers 01 cells pos itive for
precursor ce ll assoc iated antigens CD34
and/or C0 117. These cell s are usually
positive for C038. HLA-DR and myeloidassoc iated antigens CD13 and/or CD33 .
Asynchronous expression of granulocytic
maturation antigens CD1S, C011b and/or
COOS can be seen in the blast population.
Aberrant expression 01C07 on blast cells
is seen in 20% 01 cases and C056 is
present in 10% of cases . while exp ression
of other lymphoid markers is rare {1210.
1623J,
In tiss ue sec tions, C034 immunoh istochemistry may be used to co nfirm the
presence of an increased number of
blasts; it allows the apprec iation of their
arrangement into clusters or agg regates,
a cha rac teristic finding seen in most of
the cases of RAEB 120501. Antibodies
such as C061 or C042b can aid in the
identification of micromegakaryocytes
and other small dysplastic forms. wh ich
are particu larly numerous in cases of
RAEB-F 11246, 22261_
Genetics
A variable percentage of cases of RAEB
(30- 50%) have clonal c ytogenetic abnormal ities, including +8 , -5, de l(5q ). -7.
del(7q) and del(2Oq). Complex karyotypes may also be observed 17821.
tOl
,.
,
Definition
Mveiccvsoiasnc syndrome with isolated
del(Sq) is a myelodysplastic syndrome
(MDS) cnaractertzeo by anaemia with or
without other cvtopenrasand/or thrombocytos is and in which the sole cytogenetic
abnormality is del(Sq), Myeloblasts conprise <5% of nucleated bone marrow (8M)
cells and < 1% 01 pe ripheral blood (PSI
leukocytes and Auer rods are absent.
Synonym
MyeIodyspIastic syndrome with 5Q deletion
(Sq- syndrome) .
EpidemK>logy
MDS with isolated del(Sq) occurs more
oflen In women, with a median age 0167
years.
Etiology
Pres umed loss of a tumou r suppressor
ge ne in the d eleted regioo . Possible ca ndi dates include the early g rowth respo nse
1 (EGR 1) and c -ceterm (CTNNA I) genes
and as-vet-untcennted genets) in 5q32
1256, 1075, 1324). The RPS14 gene that
encodes a ribosomal protein has been
propo sed as a can didate in the Sq- syndrome, raising the possib ility that a defect
in ribosomal p rotein func tion ca uses that
di sorder 1256. 635 , 1075. 1324 1.
Sites of involvement
Blood and bone ma rrow,
Clinicalleatures
The most common symptoms are usually
related to anaemia. whic h is often severe
and usually macrocytic. Thromboc ytosis is
present in one third 10 one half of patients.
while rnromcoocytopenle is uncommon
{794, 14171.
110051.
Mo<phology
The BM is usually hypercellular or normacellular and frequently exhibits erythroid
hypoplasia 123621. Meg akaryoc ytes are
increased in number and are normal to
sfil.:t1tIy decreased in size withconspicuwsIy
102
MyelodysplastJc Syndromes
139.2191.
Prognosis and predictive fact ors
13201
Myelodysplastic syndrome,
unclassifiable
Definition
Myelodysplastic syndrome. unclassifiable
(MDS-U ) is a subtype 01 MDS which init~1y lacks findings appropriate for classi-
9989/3
A.Orazi
AD Brunning
I. Baumann
R.P. Hasserpan
--
Genetics
Sjrooym
Uyelodysplastic syndrome, NOS.
EpOdemk>logy
The incidence of mvetodvscrasuc 5YO-
syndromes.
11 1651.
t03
% Incidence'
79
38.5
AU
AMl1
915
115
11
5.4
"lOS'
38
Myebd leuk.aemia of OS
19
1.8
0.9
JMMl
25
1,2
0,6
13
'VIET
Unclassified
o
o
0.1
0.1
1031
100
48.1
CMl
T","
104
Myelodysplastic syndromes
I. Bau mann
C,M. Niemeyer
J .M , Bennett
K. Shannon
~IQ .
5J l
Relractory~dd'ikhxld(RCC~_
actenzeo
ICD-{) code
998513
Synonym
Refractory anaemia of childhood.
Epidemkllogy
<
f
..
.,
./
. I ....~
'~
..
1-'
Stes of involvement
Blood and 8 M are alw ays affected. Gen efally. spleen. liver and lymph nod es are
rot sites of initial ma nifestation .
Clinical features
The most common symptoms are malaise,
bleeding , fever and infection /1109). lym-
Morphology
The classica l p ictu re of RCC is a PB
sme ar that shows red blood cell
antsopolknocytosts and macrocytosis.
Anisochromia may be present. Platelets
often di splay anisocytosis and occasionally g iant p late lets can be de tected.
Neutrope nia wit h pseudc -Pelg er-t-luet
nuclei and/or hypogranularity of neutrophil
11 1091.
Etiology
The etiology is unknown in most cases.
Bone marrow
aspirate
Bone marrow
biopsy
Erythropoiesis
Granulopoiesis
Megakaryopoiesis
Dysplasbc changes" in at
18ast 10%of granulocytic
Unequivocal
micromegakaryocytes,
othefdysplasticchangesl
in variable numbers
UnequiYocal
micromegakaryocytes:
irnrl'lJnohistoctlemistry is
obIigab')' (COOl , CD41 ).
oltlerdysplasti: cIIange5t
ill variable I1lSI1bers
increased numbers of
1''''0'''''''''''
lncmased I1UIT'tlers of mitoses.
Peripheral blood
Dysplastic changes'
nat I8ast10%of neutrophis;
""
....
IlI,dei.Theabsence of megakyIX:yIes
"not
105
bbl, 5.08
Comparison Of rnlIIphologicaI cnlefiaaI hypoplastic refracby cytopeoiaof childhood and aplasticanaemia inchildhood
R,1ractofy cytopenil of childhood
--- -_d_
Pattry dcstrtluIion
lell shift
.......,..."
~-
Agranuiabon ofcytoplasm
Ni.dear<ytoplasmlc malurabondefects
Marked dea8ase
Dysplastic manges
Miaomegakaryocytes
M~
Lymphocytes
May be increased
C034+ cells
Noincrease
MulI ~e
separated nuclei
--
I.JIc:UIg or ~ decrease,
Y8IY lewsmalloci 'NIth maturation
-""
C034+ cells
No increase
May be increased
Myelodysplastic syndromes
establis hing the diagnosis, Multiple sections prepared from the biopsy may be
helpful in roermtcanoo of abnormal rneqakarvocytes and immunohistochemistry to
identify mictomegakaryocytes is obligatory.
Fatty tissue between the areas of haematopoiesis can mimic aplastic anaemia
(Table 5.08). Thereforeat least two biopsies
at least two weeks apart are recommended to facil itate the detection of
representative 8M spaces containing foci
of erythropoiesis.
Differential di agnosi s
In children, a variety 01 non-haematological
d isord ers such as viral mtecuons. nutritional deficiencies and metabolic diseases
can give rise to secondary myelodysplasia,
Genetics
The genetic changes predisposing to
!.lOS in childhood remain largely obscure.
The presumed underlying mechanism
may also give rise 10 subtle phenotypic
abnormalihes noted in many children with
MOS. Monosomy 7 is the most common
cytogenetic abnormality /1 109, 1704,
17841 . Other cytogenetic abnormalities
IlChJding complex karyotypes may also
be observed. Most cases of ACC show a
rnmal karyotype irrespective 01 8M eelltarrty. There is no difference in morpholOgy between cases with Of without
-oonosomy 7.
PtlstuIated cell of origin
saematopoenc stem celt with multihneage potential ,
Prognosis and pred ictiv e factors
(aryotype is the most important factor
'or progression 10 advanced MOS. Patents with monosomy 7 have a sign ificantly higher probability of progression
f an patients with other chromosomal abrcmannes or normal karyotype 111091.
Table 5.09
Dfsofders which maypresent witll morp hoj ogic.a lleal~ res indisbnguishable from refractory cytopenia ofct1ildhood,
Sedtel syndrome)
P~nochrnaI ~ (PM-I)
~ apIasbc anaemia
dlmg haemalologicall'llCOYllfy
107
CHAPTER 6
Acute Myeloid Leukaemia and
Related Precursor Neoplasms
creates a fusion gene encoding a chimaeric protein that is required. but usually
ICD-Ocode
110
9896/3
D .A, Arber
R D , Brunning
M .M. le Beau
B , Falini
J.w.
Vard ima~
A. POrNIt
J. Thiele
CD. Bloomfield
Epidemiology
The t(8 ;2 1)(q 22;q 22 ) is found in -5% of
cases of AMl and in 10% 01 the prior acute
myeloblast ic le ukaemia with matu ration
(M2) c ategory of the French -AmericanBritish cl assification. It occurs predominantly in younger pat ients .
Cli nical featu res
Tumour manifestations , such as myeloid
sarconas. may be present at presentation .
In such cases the initial bone marrow (BM)
aspiration may show a mis leading low
number of b last cells. but should be
diagnosed as AMl despite a b last percentage in the BM of <20,
Morphology and cytochemistry
The co mmon morphological features inc lude th e presenc e of large blasts with
abundant basophilic cytoplasm, often
containing nume rous azuroph ilic granules
and perinuclear clearing or bots . A few
b lasts in many cases show ve ry large
gra nules (pseu do-Chedrak-Hiqashi gran ules), sug gestin g abnormal fusion . Auer
rods are freq uently found and appear as a
sing le long and sharp rod with tap ered
e nds; they may be de tect ed in mature
neutrophns. In addition to the large bla st
c ells , some smalle r bla sts, pred om inantly
in the peripheral blood (PBj, may be found.
Promyeroc vtes, myeiocytes and mature
neutroph ils with var iab le dy sp lasia are
present in the BM. These ce lls may show
abnormal nuc lea r seg mentation (e.q.
pse uoo-Pelqer-Hoet nuc lei) and/or cy toplas mic staining ab nor malities, including
homogeneous pink colo ured c ytoplas m in
neutrophil s. Dyspl asia of othe r Cell lines,
however, is uncommon. Eosinoph il precutsees are frequently increased. but they do not
exhibit the cytological or cytoc hemical ab normalities charac teristic of AMl associated
with ab nor ma lities of c hromosome 16:
basop hils and/or mast cells are sometimes
present in exce ss. A monocytiC component
is usually minimal or absent. Erythrob lasts
and meg akaryocytes are morphologically
normal. Rare c ases with a BM blast percentage <20 occur, These should be
cl assifi ed as AMl and not as MOS.
.........
eosinoph~
Immunop henotype
Most cases of AMl with the (8;21 )(q22;q22)
transloc ation d isp lay a characteristc
imm uno phenotype with a subpopulatioo
of blas t cells show ing hig h intensity expression of CD 34, together with HLA-DR,
myercoeroxidase (MPO) and CD13. bJ
relatively weak expression of CD33j114Q,
17751. There are usually sig ns of granulocyt ic differen tiation with subpopuianonsd
cells showing granulocytic rnaiuranco
demonstrated b y CD15 and/or COO
expression . Sometimes po pulations cI
blasts showing matu ration asynchrony
are present (e .g . co-expressing COOt
and CD15 ). These leukaemias frequen
express the lymphoid marke rs CD19 and
PAX5, and may express cvtoptasrre
CD79a 1996, 1155. 2236} . Some cases
are terminal deoxynucleotidyf transferase
(TdT) posi tive ; however, TdT exoresscoe
The genes for both reteroosreoc components of core bindll)Q lactor (CBF), RUNX I
(atso known as AML 1or CBFA) aOO CBFB
ere involved in rearrangements associated
WIth acute reukaemes {20631. The t(8 ;21)
(Q22;q 22 ) involves the RUNXI gene, which
encodes core- bi ndin g factor subunit
alpha and the RUNX 1T1(ETO) gene {608,
1294, 17331. The RUNX1 -RUNX1T1 fusion transcri p t is consistently detected in
patients with 1(8;21)(q 22;q 22) AML. The
CBF transcripti on factor is essential for
baematopolests. and tr ansformation by
RUNX 1-RUNX 1T1 likely results from transcriptional repression of normal RUNX1
target genes via abe rrant recr uitm ent of
nuclear transcription al co- repressor complexes. Over 70% 01pati ents show aooiIIQll3I chromosome abnormalities: e.q. loss
rJa sex chromosome or d el(9q ) with loss
rJ 9Q22. Secondary cooperating mutations
rJ KRAS or NRAS are common (30%) in
caedtamc CBFassociated leukaemias
~l. Mutations of KIT occur in 20-25%
01 cases (16961.
Postulated nor mal cout erpart
Myeloid stem cell wilh predominant reunophil differentiation.
Prognosis and predictive factors
Acu te myelo id leukaemia with t(8;21)
(q22;q22) is usually associated with a
16
inv(16)(pI3.1q22) or
t(16;16)(pI3.1;q22); CBFB
MYH11
Definition
Ac ute myeloid leu kaemia with inv(16)
(p1 3.1q22) or t(16: 16)(p13,1:q22); CBFBMYH11 is an AML that usually shows
monocytic and gra nuloc ytic differentiation
and characteristically abnormal eosinophil
component in the BM {1258. 1393, 20631.
ICD-O code
9871/3
Synonym
Acute myeloid leukaemia with abnormal
marrow-eosoconns .
Epidemiology
Either inv(1 6)(p 13.1q22) or t(16 ;16)
(p13. 1;q22) is found in 5-8% of all cases
of AM L. They can occur in all age grou ps
but are found predom inantl y in younger
patients.
Clinical features
Myeloid sarco mas may be p resent at
initial diagnosis or at relapse and may
c onstitute the only evidence of relapse in
some patient s.
Morpholog y and cytochemistry
In these cases. in addition to the usual
morphological featu res of acute myelomonocytic leukaemia, the 8M shows a
variable number of eosinophils (usually increased. but soretrres <5%) at all stages
01 rretoratco without significant maturation
arrest. The mos t striking aboomantee involve the immature eosinophilic granules.
mainly evident at the promyelocyte and
myelocyte stages . The abnormalities are
usually not p resent at later stages of
eosi nophil maturation . The eosinophilic
granules are often larger than mose normally pr esent in immature eosmocnus.
p urp le-violet in colo ur, and in some cells
are so dense that they obscure the cell
inv(16)
--<>
--<>
XI
16
inv (16)
:~:>:
Fig. 1.03 Acute myeloid leukaemia with inv(16)(pt 3.1q22). A The inversion 16 results from breakage and rejoining of bands 16p13.1 and 1&;22. G-banded normal (nI)
linrTIosome 16 and irW(16) are shown. B Dual rolor ftUOfllSC6OC6 in situhybridizalion: !he 5' regll)llof CBFB is labeled in red; !he3' regionin pen Anonnal ettromosome 16 has
~ 5'and 3' regions ~ 10 e<lch otherresultiog in a siogle yellowOf oveOappiog IlldIgreen signals, The invefsion 16splits theCBFB locus resulting in separale red andgreen
sigla/$. 80Itl interphase ooIIs have one normal 16etvomosome andoneinv(16),
11 1
Immunophenotype
Most of these leukaemias are c haracte rized by a complex immunop henotype with
the presenc e of multiple b last populations:
immature b lasts with high CD34 and
CD l 17 expression and pop ulations d ifferentiating toward s gran ulocytic (CD13,
CD33. CD l5. CD65. MPO positive) and
monocytic (CD 14. CD4. CDl 1b.
CD64. CD36 and lysozyme positive) lineages Mat urat ion async hron y is often
seen. Co-expression 01CD2 with myeloid
mark ers has been frequently documented
but It is not specmc for this di agnosis.
cone.
Genetics
The inv( 16)( p 13, 1q22) foun d in the vas t
major ity of this subtype and the less common t(16; 16)(p13, 1:q22) both resu lt in the
112
986613
Synonym
AM l with 1( 15;17)(q22;qt2).
Epidemiology
Ac ute promyeloc yte leukaemia comprises
5-8% of AMl {20 78 1. The disease can
occur at any age b ut pati ents are predom inantly adul ts in mid-life.
Clin ical featur es
Typical and rricrograrlAar API.. are lrequerty
associated with disseminated inlravasoJa'
coagulation (DIG) . In microgranular API..
unlike typical API.., the leukocyte COlJ'lt IS
very high, with a rapid doubling time
~
B
Fig. '.05 Acute promyeIocybc leukaema. A ~
~ type n bone marrow smear. Theft we IM'i
abnormal prornyelocyles wilhITIense amq:hIc,.....
lam. Sewr1lI ollhe promyeIocyles oontaillUl-.all
Auef rods(Iaggot oeIs). B M~ vWrt. 1'1 Ptripheral bloocI smear. There are several abnclmll
promyelocy!es 'Mthlobl,Jlaled. almostc:eretlnbm ru:Il
The cytoplasm coolains numerous small alI.tllPl*
granules: other ~Is appear sparsely ganlMr.
nl
15
d .~15 )
15
17
II
A
1(15 ;17XQ22;Q12)
~ U16 AcuIe prorll)'8locybc Ieuilaen'U WIIh 1(15;11Mq22;q12), A The D'lslocabon 15;11 t'&SUts from br9akage a'ld r-.nion of bands 15q22 a'ld 11q12. G-bMded normallnl) 15
111 17 dY\::Jnc:lsanes (Ieft.l a'ldthe derivatNe ldetl 151n:l11 reslAng from ee IransIocation are sIlOWl'I on hi fil1C. BOuaIlDorl'unscence" sill hybtidiZ.alion M1h probes Pf.C.
l'~ iIl'lll RARA(17ql2) derroostrate the presence of a Pl.UWtA.lusion ~ from the 15;11 transIoca1o'l. Eactlof hi fw'ee IlBphase eels has one sep;nte red (PK)
J9W. (W'II sepataIe ween (RARA) sigIaI, In:l one \'dOw or~ ~greet1 si!r.aI ronsislenl..,1Il1tle pttl5etIC8 of a PMJRARA gene Iusioo.
The nuclear size and shape in the aboorrrel promyelocytes of hypergranular APL
ere irregular and greatly variable; they are
::tten kidney-shaped or bilobed . The cytoplasm is marked by densely-packed or
even coalescent large granules, staining
:Yight pink, red or purple in Romanowsky
stains. The cytoplasmic granules may be
solarge andior numerous that they totally
rescore the nuclear cytoplasmic margin .
In some cells. the cytoplasm is filled with
Ire dust-like granules. Characteristic cells
containing bundles of Auer rods ("faggot
cells") randomly dis tributed in the cytoplasm are present in most cases, Myeloblasts with sing le Auer rod s may also be
Observed, A uer rod s in hyper gr anu lar
APL are usually large r than in other types
rJ. AML and they may have a c haracteristic
rrorpholog y at the ultras truct ural leve l
'.vith a hexagonal arrangement of tubular
structures with a specific period ici ty of
aeoroxrnaterv 250 mm in contrast to the
6-20 lamina r periodicity of Auer rods in
erertypes of AML. The MPO reaction is
always strongly positive in all the
exaernc oromyeiocvtes . with the reaction product covering the entire cytoplasm
l"Id often the nucleus . The non -specific
esterase reaction is weakly positive in ao;>rQximately 25% of cases. Only occaSJOnaI obvious leukaemic prooweiocvtes
may be observed in the PB.
Cases of rracrcqranurar (hypogranular)
A.PI. arecharacterized by distinct morphoQJicaI features such as apparent paucity
CJ absence of granules. and predomiI'lafltly bilobed nuclear shape 18111.
113
ICD-O code
Cunicalteatures
Patients may pr esent with d isseminaled
intravascular coagulation. They mayhave
extramedullary myeloid (monocytic) serco
mas and/or tissue infiltration (gingiva, skn~
Morphology and cylochem;Sby
There is a strong association between
acute monocytic and myelomooocytlc
leukaemias and t(9; 11)(p22;q23). altho.ql
occasionally the t(9 ;11) is detected i'l At.(
with Of without maturation. MonobIaSlS
and promonocytes typically predominale
Monoblasts are large cells . with abt.r1ci<rf
cytoplasm which can be moderately to.,.
tensely basophilic and may shcwt
pod lormabon. Scattered fine azurophilo:
granules and vacuoles may be preset
The rrooobasts usually have round BJCIl'i
With del icate lacy chromatin, and one f1
more large prominen t nucleoli. Prorcoo
cvtes have a more irregular and delicat~
convoluted nuclear configuration; the evtr
plasm is usually less basop hilic ana
sometimes more obviously granulated,
with occasional large azurophilic grarUe!
and vacuoles. Monoblasts and proro-o
cvtes usually show strong positive f'lCJl'
specific esterase reactions. The rrcocoass
ofte n lack MPO reactivity.
osecco
Immu nophenotype
Cases 01 AML with the t(9: 11)(p22;q23) ir1
c hild ren are associated with strong
exp ression 0 1 CD33, CD65 , CD4 and
HLA-DA, while exp ression at CD 13, CD34
and CD 14 is usually low /491 1.
Most AML c ases w ith 11q23 abnormalities
express the NG2 homologue (encoded by
CSPG4j, a c hond roitin sulfate molecule
reacting with the Mab 7.1124561. MostacU:
AM l case s w ith 11q 23 ab normalities
exp ress some marke rs 01 monocac
differentiation including CD14, CD4, COlle
CO l lc. CD64. CD36 and lysozyme, v.tIire
variable expression of imma ture markers
suc h as CD34 and CD1 17 and of CD56
has been reported {154 11.
9897/3
Genetics
Synonym
Ac ute myeloid leukaem ia . 11q23 abnorma lities.
Ep;demk>logy
The t(9;11)(p22;q23) may occur at any
age. but is morecomnor I in child ren. being
ootennar.
Prognosis and pred ictive factors
Acute myeloid leukaemia with the
. 9:11XP22;Q23) has an intermediate sur.....aI and one that is supefior to AML with
e:tner l1Q23 translocations 11531. 18911.
Cases with the t(9: 11) and <20% blasts
II'IJSt be monitored closely fOf development of more definite evidence of AML.
'fi1riant MLL translocations
in acute leukaemia
C>ief 80 different translocalions involving
MLL are now described in adult and
paediatric acute leukaemia, with over 50
eensiccato n partner genes now cnaraclenzed 11 470. 20081. rrensiccetcoe involving MLLT2(AF4). resuitmq predominantly
n acute lymphoblastic leukaemia (ALL).
end MLLT3(AF9). resuhing predominan tly
n AML, are the most common. Other MLL
eensccauons that commonly result in AML
rcuoe the MLLT1(ENL). MLLTIO (AF1O),
MLLT4 (AF6) and ELL as partner genes,
Other than the ML L-ELL fusion resulting
Irom the t(1 1:19)(q23:p13,1), which is
res often associated with only AML,
these fusions occ ur pr edom inantly in
AML, but may be seen in ALL as well. Up
10 one third of MLL transiocauons in AML
ee not detectable on co nventional karyotype analysis , and FISH or other
molecular stud ies may be necessary to
dentify these variant translocations 120081.
AML with these fusions usually have
myelomonocytic or monoblastic rro rpnobgic and immunophenotypic features
While in the p ast all of these translocali:lns were encompassed by the category
rj AML with 11q23 abnormalities. the diagnosis should now specify the specific
abnormality and should be limited to
cases with 11q23 balanced translocations
fI'o'OIving MLL. For example. a case of
AMl with an MLL-ENL fusion would be
dl8gnosed as acute myeloid leukaemia
dh ~11 ,19)(q23;p13.3): MLL-ENL.
40Jte myeloid leukaemia with cytogenetic
B
Fig. 6.09 AML (monoblaslic) WIth t(9;1'Xp22;q23). Bone marrow smears A 5evefall'l'lOl'lllblasts. some WIth very
allur'l<Ia1l cytoplasm and h myelopeloxidase,..1iYe azurophilic granules are present B Non-speciflc esterllse
reacbon showing I1lensely poslIiYe IrOlOblasts,
'"
..
Fig. 6.'0 Mt. (1TIOI'I:ltyIic) \Mlh 1(9;11)(p22;q23}. Bone tJWI(M ~ A ThenlarelilMlt8llfOIObIasts and ~
with very pale cytor*lsm containing numerous fine anrophiic ~_ The promonocyles have delicate rudear lolds.
B Noo-speci1ic esterase S\aII"I_ The pn::monocytes are intensely reactive.
Clinical features
Acute myeloid leukaemia with t(6:9)
(p23 ;Q34) usually presents with anaemia
and thrombocytopenia, and often with
pancytopenia, In adults, the presen ting
white blood cell count is gener ally lower
than other AML types with a median white
blood cell count of 12x1()9/L 120351,
Definition
Acu te myeloid leukaemia with the 1(6 :9)
(p23:q34); DEK-NUP214 is an AML with
or without monocytic features that is often
associated with basophilia and multilineage dysplasia {17 14, 20351 .
ICD-Ocode
The provisional code proposed for the
fourth edition of IGO-D is 986513.
Epidemiology
The t(6:9Xp23;q34) is detected in 0.7-1 .8%
of AML, and occurs in both children and
adul ts with a median age 01 13 years in
childhood and 35 years in adults 1306.
2035,20361.
115
a re presen t in a subset of cases, The per-
Clinical features
Patients most co mmonly present with
anaemia and a normal preteret count .
although marked thrombocythaemia
occurs in 7-22% of patients 1845.19831.
Patients may present de novo or have a
prior MOS. A subset of patients present
with hepalosptencmegaty. but "",,",,deropathy is UllCOI' llllOlI11983. 2C04, 21891.
116
30
Immunophenotype
Immunophenotypic studies of AML with
inv(3)(q21q26.2) or t(3:3}(q21:q26.2) are
limited. The blast cells generally express
C0 13. C033. HLA-OR. CD34 and C03S
Blast cells of some cases also abe rranf
express C07 and a subset may express
meg akaryocytic markers such as CQ4t
and C06 1. Abe rrant expr ession of lym.
photo markers other than C07 appears
uncommon [20041.
Genetics
A variety of abnoemauties of the long arm
of chromosome 3 occur in myeloid rnalo(t
nances. with inv(3)(q21q26.2) and t(3:31
(q21 ;q26.2) being the most common. The
abnormalities involve the oncogene EVIl
at 3q26.2 . or its longer form MOS1-EV!
and RPN7 at 3Q21 APN1 may act as <WI
enhancer of EVIl expression resulting
increased cell proliferation , and impaireo
ICD-O code
The p rovisional cod e prop o sed fo r the
fourth edition of ICD-D is 991 1/3,
Epidemiology
The t(1; 22)( p13:q 13) is an uncommon
abnormality in A Ml, repr esenting < 1% of
all c ases. It most commonty occurs in
infants without Down syn d rome, with a
female pred ominance .
Clinical features
Acute mye lo id leukaemia with t( 1;22 )
(p13;q13) is a de novo AMl restricted to
inf ants and young chi ldren (3 yea rs or
less) with most cases occurring in the first
6 months of life (median, 4 months). The
'last rnajonty of cases present with
marked organomegaly, especially hepatosplenomegaly. Patients alsohaveanaemia,
and usually have throm bocytope nia and
a moderat ely eleva ted white blood cell
count.
Morphology and cytochemistry
The PB and BM blasts 01AML with t( 1;22 )
(p13;q 13) are similar to those of acute
megakaryoblastic leukaemia of AM l, NOS.
Small and large megakaryo blasts may be
p resent and they may be admixed with
more mor ph olo gically und iffe rent iated
b last ce lls with a high nuclear-cytoplasmic
ratio resembling ivmorobrasts. The megakarvobtasts are usually of medium 10 large
size ( 12- 18 urn) with a round, sligh tly irrequrar Of indented nucleus with fine reticular ch romatin and one to three nucl eoli.
The cytopl asm is ba sophilic , often ag ranular, and may show d istinct ble b s o r
pseudopod formati on. Mic romeg akaryocvtes are common , but d yspl astic features of gra nu locytic and eryth roid c ells
are not usually p resent The 8 M biopsy is
usually normocellular to hyperce llular with
retic ulin and co llage nou s fib rosis usually
presen t. Cases may show a stromal pattern o f BM infiltration mimicking a metastatic tumour 120 5, 341 1. Cy toc hemical
stains for Sudan black B (SBB) and MPO
are cons istently negative in the megakaryob lasts. A subset of cases will have less
then 20% BM bla sts. but a low blast cell
count due to difficu lties aspira ting BM secon dary to fibrosis sho uld be excluded .
Fig. 6.12 AML WIth irlV(J)(Q21 q26.2). Bone marrowaspAte wrlhincreased blasts and atypica, rncnJIobaIed
cvtometrv
Genetics
Patients sho uld have karyotypic evidence
of t(1 ;22)(p1 3 ;q13) or molecul ar genetic
evidence of a RBMI5-MKL 1fusion, In most
cases, t( 1:22)(p 13;q 13) occurs as the sole
karyotyp ic ab normality, This trans locat ion
resu lts in a fusion of RNA-b inding motif
protem-rs (RBM1S) (also known as OTT)
and megakaryoc yte Ieukaemia- t (MKL 1)
(also known as MAL) (1352 ). RBMIS enco des RNA recognition motifs and aspen
par alog and ortholog C-terminal (SPOC)
domain , whi le MKL 1 encodes a DNAbin d ing motif involved in chromatin organization. The fusion gene may modul ate
chromatin orga nization . HD X-ind uced differenti ation and extrace llular sig naling
pathways 11461}.
Postu lated normal counterpart
Myeloid stem cell with predominant megakaryocytic d ifferentiation .
Defi1ition
,' cute myeloid leukaemia with t( 1;22)
(p13;q 13); RBM15-MKL 1 is an AMl genEJaJy showing maturation in the megakaryocyte lineage.
IrrmJnophenotype
117
"
E
re
p
Tillie &.01
Moleculaf geneticalteratioos allectlrtg dir1ical outcome of AML patients in specific qtogeoeUc groups.
Geoetics
Cytogenatiu
KiT mutabon$
t(8:21)(q22;q22)
Prognosticslgnillcance
Signlfocann~'~"""'
~~-:"'''',,~uenls
wiId-~
OFS andRFS
Wlth KITmutatons (especially ecse ill 8loo17) lXIIf4)8red 'Mtt1
KlTpalients
{233A., 2Q09A,
CIRandRI Slgoificantly higher fof peteots wilh KITmutaloons compared Wlth patients with wild.fype KIT{310A, 1696}
EfS signlf!canny shorter forpabents with KITmutatons (especialy eese n e.oo 17) ~red IIIilh pall8/1ts with w~ KIT(233A.
1969Aj
OS si!1liflCalltly shortef I'tlr patents WIth KITmuta!lorls (espec:iaIyIhOs8 ill elOfl 17)compared wrltJ pabents wr01 wiId-4ype KlT{233A..
31QA. 1969A. 2009A}
No Slgf1fflcanl dllJerence 111 0$ bereeen patients IIIilh -"' wilhOul KITmutatl(lllS {1696}
<IT_
FiJ><TD
ilw(16)(p131q22)1 RR'IIIOfSe lor patients wrltJ KlTmutatioos 111 el M 8 COIf4lilred WIlt1 patients \\'III'l wid-type KrTf33Ml
t(16.16)(p13,1;q22) CIR hIglMlI' and OS '/II'OIWfor pabents WIth KIT rrotations 11 elOfll1 c:unpared wr01 PI1ients with wid-typeKIT{1696}
No Sigr*ant dillereooe in EfS , RI, RFS and OS between pabentS withand 'Mlhoul KJTrnuIatols (2~ 31 0A)
Normar
......... .
CRa and DFS ~ shor1erfor pabenl$ WIth Fl.T3-lTD comparedwith palienls 'IIIClOlIl A.TJ.lTD {193A., 216. 736A 2394A)
EfS SiglWanty sI'o18r lor patents WIth fLT3-fTO comperedwotll palienl$ 'IlIltI'loIA A.TJ.lTD (2338)
OS~, sIlcrterlor patlents wotll A.T3-ITO c:unpared withpalients wrlholA FLTJ.lTD {193A. 216. 736Ai
No SIgI'ificart dIIetence in OS b8t'ween palietn WI!! a'ld witlCUfLT3-lTD(2338, ~
OfS .-.:I OS sqv6c:llIy shorter b patients Wlth FlT3-lTO and no 8~ rJno-l)1:Ie FlTJaIele ~ 'MiD'! ~ W!IhOut
FlTJ.lTD (m4A)
RJJ.m)MII t'1)
t,peRTJaWe
""00
w.-P1D
e_
::lflAli mutabCW'lS
.."".
OFS sagnficantty shorter for patienls wit! FLT3-TKD ll'I'IPB!t:Id Mlh petlenls WIth wild-type FlTJ*'es (23961
"""'"
"""'"
CRD (but not OS) SignlfIcal1Uy srorter for patletlts WIlt1 AILL-PTD compnd with peli8nlsWIVlout ULL-PTD (313. 603)
Noli&renoe in OFS cnl
between patlenIswiIhand ntW AoIl-PTD recero'rlg I'IS8nSre treamenllIW*1g a**lgous SCT {2395l
N,,,,,,,
kaizalion 01
NPM
os
CRD and OS ~ longer or patients WIll1 CEBPA mulabalsa:mpared wrlh patients with~ CEBFl4. genes {216, 731}
NoSigMIcant diIIereoce in OSbetweeI'l patienls 'lWilh and withOut CEBFl4. mulalions f233B}
EFSsignlflcanUy shorter forpatJeflts with CEBPA rnutaliolls compared Willi patients 'IIIIh wid-type CEBPA genes f2338}
CRrate of pabellts WIth cytopIaSlTic Iocaizaboll of NPM not 19'1ifical'lUy I)/Ieren! from CRrateof pabenls WJ\ll nudearIocaJiZatiOn of
NPM in l,I'Iivariable analysis. Cyloplasri; IocaIzabon 01 NPM wasan intIepen(lenllaYOUr3ble prognosbc Iador for CR achievement in
mulbvBl1a!e Iogislic-regres&Oll model inckIding WBC. age, NPM localizatIOn and FLTJ mutations {666}
N'''''''
CRrate Sigoificantly betterlor patents wrtI1 NPM1 mulatiOns lhal'llor palienls W1lh wi:l-type NPMl geoes {1970}
~ Sigl'lilical'll dillerel1C8 il'lCRrates between patiarllswith arid witt10ut NPMI mutations {139A. 233B}
DFSaodRFS sigl1lfical'l~y lorIQeffor peeems willi NPM1 mlllabor1$ compared wtlhpatients W1lh wild.fype NPMl genes {602, 219l1}
~ sigMicaol diflerel1C8 fnRFS between pabenls withandWithout NPM1 mutatiorls {139A. 2338. 1970}
EFSsigniflCilnlty ooget' 101' patients with NPM1 mlltatforls compared withpatients with wild-twa NPMl genes {1970}
~ Significam dillerel'lC8 in EFSbetween patents withandwitr.out NPMl mutatiOflS {139A, 233B}
Nosignificant dillerence in OSteween patients withandwithout NPM l rl'llItations {139A, 233B. 602, 1970, 2198}
Normal
CRrales, EfS, RFS, DfS andOSsignificantly better lot patients with NPMf mutations wholackFLT3-ITD compared withpatients wittl
NPMl mu tations andFLTJ-iTD or thosewith wildtype NPMI gelleS withor without FLTJ-ITD NPMl mutations do notseem to significantly alleet poorprognosis of patients with FLTJ-ITO {B02, 1970, 2198)
Nosignificant dillereoces in EFSand 05 between patents with NPMl mutations andnoFLTJ-ITD compared with patients with NPMf
mutations andFLTJ-ITD arid those with wild-type NPMl genes with or without FLTJ-ITD {139A/
IfTlmulations
Normal
Failureto achieve a CRwith standard induction chemotherapy lor patients With WTl mutations andFLTJ-ITD {2120Ai,
OFS andOSsignificantly shorter forpati$nts with WTl mutallons compared With pabents Wltt'l wiIdtype WTI alleles {1696A}
BAAle
i'bmaI
CRrateandrate01 primary resistant disease significantly WOfSelor patients withhigh e~pression oflhe BAALC gene in blood
compared willi patients withlow eJqlreSSiOn of the BAALC gene{1358}
No significant diflereooe in CRratesbe\Weel'I patieols withhigh aodpaLenls With lowe.pressiOn 01 the BAALCgeoe {l 35A, 216}
DFS, EFS. RR and OSsignificat1Uy WOfSeaooCIR significantly htgher for patients With high elpression of lhe BAALCgeoe 11 blood
compared 'Mth pabents withIoYt eqJre'SSlon oIth8 BAALCgeoe {1J5A.. 1356, 216}
Normal
CRrates, EFS, CIA, andOS SIgnificantly worse lor PlltJents widllligtl e~ioo oIlhe ERG gene in blood compared withpalieols wrlt1
lowe~oflt18 ERG gene{1J9OA, 139OB}
Normal
OS and RFS significantly shorter and RR higher for pallenl$ WIth high e~ of the MN f genecompared WIth pabents withIoYt
elp(8SSion altha ",NI gene (9J7A)
'ftIl mutations
""e...,
lblIiIcI by[) Mn\z8k from MrOzek and Bloomtiekl {1531A).-.d MrOzek et Ill, {1532} WIth pemlI$SiDn.
EFS ...... SUl\'lYII: RFS, ralapse-frM Sl.fVival: OS, ova-aI surYi'IaI; CIA, eurnulative inl:icIence of relapse, RI. relapse inQdence: OFS, d1seas&4ree SUI'YMl; RR.fisk of
. . .. FL1J.ITO .,.,. tandem duplalllOll of the FLngene, FLT.HKD,1IkJtlOOns 11 the tyrOSII18 kinase domiIIo offhll FLDgene, CRO. compIeIe remission dIntioo ; AIU.n ,pnal llwldemduplicabon of118 AIU gene: SCT. stem cellrWlsplanta1ior CR. ~ I'eITissIon; ". NMnal kar)'otype,
11 9
ICDGeode
9861/3
Synonym
Fig. 6.101 Acute myeloid leukaemia with NPAlt mutations and myelomonocytic features. A Bone marrow biopsy
showing complete teplacemel'l1 by large blaSCs With abuooanl cytoplasm and IoIded nuclei. B l elillaemic cells are
CD34-negalive. C l eukaeJTllC eels show aberrant cyloplasrric expression of rkJdeopilosrr'Wfl (NPM). D EXpt"ession of
C231nodeolin is restricted to Itle nucleus.
CEB~ +5 _ ~
CEBPA+lo\C.L-PTD+ 1.2%
Fl T3-lTO+IMLlP"TO+ 2."%
FlT3-lTO+ 8 .1%
NPM'+lFLJ'3.TKD+/ } O "
CEBPA +/KL-PTD+
"
NPM'+tf:;Un;::;: }o.,,%
NPMl+IFLT.J-TKD+/ } , _
CEBAI'+
-" ,.
FLJ'3.TKD+
NPM1+.<:ESPJIl,+ 3. ~
Fig. 6.15 Pie dlaf\ based on 2"6 pabent$ analyZed tor Itle Ilf99l!I'lC8 01 mutations in Itle NPUI and CEBPA genes.
FLT3-ITD. FLT3-TKD and AIU.-PTD. E.actI seclof nIc3les the peI'C8flIllge 01 pabenIs harbotmg one Of ITOOl 0I1he
ab'emenliOlllld muIabons. WT rocates pabef\tS WlIh only ~ alleles01 genes tes1ed. FromIkozek (If 11I.(1532)
lnlltdapled!ram 00IVlllf (If Ill. (602}.
120
Epidemiology
,,
However, N.PM1 mutations are also detected in AML with and without ma turation
and in acute erythroid leukaemia. A subset
01 cases shows multilineage dysplasia.
These cases usually have a norm al
~aryotype and the blast cells are CD34
negative. The 8 M biopsy is usually
markedly nvcerceuutar. Bone ma rrow
blast percentages are generally higher in
AML with muta ted NPM1 than in other
acute myeloid reukaermes with a normal
karjOlype
16021.
Fig. 6.16 W*eage IMIlvement in AAlt. WItl'l NPM1 mutabons. A Bone m<mlW biopsy. Massive replac:eITetlt by
myeloid blasts wittl maturalJon; !here are also megakaryocyles and occasional irTIrn<I~ erylhnlid eels (iIfl'OIW).
8 The same case as (A). Myeloid blasts (double arrtIlltS). rnegakarrocyles and mnaIu'e er)1tWOiCI eels (iIfl'OIW) sI'lOW
abemml cytr;lpIasri: po$l ~vity lor NPt.I (blue ). Immature erythroid eels (arrow) Ill! doubIe--slained lor gIytophonn
(brown) andNPM(bkJe~ C Bone marrow biopsy. UinmaIydilIenlnbaled llaIte myeIold leukaemia wrlh NPM1 rllIlaborls,
occasional immature g~ erythroid cells are present 0 The same caseas (C). Myeloid bIasls and
imrnatIR erythroid eels (amlW) showcytoplasmic eKl)feSSion of NPM.
-c
, 2
NPM1 gMfe ~
..!
11
89
.)]"12
.. -iF .. -..::::::JI
NPOI '
'u...,r"
.. . \ . _' '''.
N "
N "
"
NU H
N. . .,
c ' . t t
,
eu
.aoc U
'. eOT
............. . ....... c .C<. e ~
.............,
04
' c
co
'
u.u ,
E _ 8ognol (NEll)
.......
_ . . - - . s . - lNt-'i
protein
M ur.redNPM
.
04 .
..-----.-=- -....,
WI~ryp. NPM
tc'.'
" ." 04" .' .'
c '
_
' . .
co CTe'TT""ee ' . '
=_
04
'c
...,,
leul<aemle protein
COOH
, II I
. T. _
Genelies
Acute myeloid leukaemia with NPMl
ITkrtation is usually associated with a normal karyotype . however. 5- 15% of AML
W!ttl NPMt mutation show chromosomal
aberrations 1666, 667J, inc lud ing +8 and
de/(9q) 121961. NPMt m..rtabons are usually
Fig. 6.17 AclJte myebd leukaerria with NPM1 "'-IlaIions. Mutations usualy 0lXIS at exon 12 of tlle NPAlI gene. The
irs! i:lenlified NPU1rIlIlabons (A" F)Ill! shown (666}. MiDtIon A1$fie most hqI.Jenl acaulbng lcr 70-80'10 01 cases.
AI rn.Jtabllns feSUIt in a:mnon changes at fie e.tllmwu (COOH) 01 fie WlJd.type NPM protein. These dlanges (asl!lnst
in the NPM nwtated proIeIn) c:onsisl of replacement of ~s) aI posibon 288 and 290 and aeation d I ~
export sqJaI (NES) motil. whiCtllre boIh responsible lor the inc:reased nuclear eJPl and abemIrlt t')'lcIpliIsrrC
aca.oTUabon of !he NPM 1TlJIlwits.
121
~-
POCO 000 1
l-
.._..
1-
NPMt-IFl r:J.fI'D-I
I:
~_.
.-.
_
T_
P-O.71
l-
Donor
CESPA-
No-Donor
, r_ _
.-.
C NPM""'/FL T34TD-o
.\-
P<o.OO(U
l_
CE8I'A -
favou rab le prog nosis to AML with a chromosomal aberration or with multilineage
d ysp lasia.
,
T_
_,
0 _
",
P-O.OO3
!: -
ICD-Ocode
-i-j-
122
9861 /3
Epidemiology
Donor
No-Oonor
,
T_ _
Fig. 6.18 Prcq10sis ofAML paltents. A,B ThegenotypesNPM' -JFL1J-lTlY'" and CEBA<I'" arelaYCUable progllOSOC
markers. C.DUnivariate donor IWSUSno-donof analysis onreepse-rree survival 01 AML with normal karyolype in fi~
compleIe remission. acttII'ding III g&IlOtype. The donor group ....as defifled by !he availability01 a HLA-maIched larrily
donor comprising a maId'! in toe loci HlA-A, HLAB and HLA-DR C Results in AML with li!VOUfab~ genotype
NPMf"'lFlTJ-lTO""; (0) !he results in AMl wilt! adverse gerotypes FLT3-/1D"" and NPI,/1"ICEBPA"JFLTJ.lTO"";
OnIyAML withactYerse gel'lOtypes (0) benefit from allogeneic stem celIlransptanlalion. From Sd1lenk RF 1:/1aI. {1962AJ
Definition
Acute myeloid leuk aemi a with rnctaiec
CEBPA usually meets criteria for AML
maturat ion or AML without maturation, bul
some cases may sho w myel ornonocyliC
or monobtastic features. This leekaema
usually presents de novo.
The WHO Working Group ass igned ~
lesion 10 a group of provisional entities
7371.
Morphology and cyt ochemistry
There are no distinctive morpholog ic leatures ot AML with normal karyotype an~
CEBPA mutations. but the vast majority d
cases have features of either AML withoJ
Of with maturation Less commonl y. cases
have monocytic o r mveromonocvtc leatures. Three percent or more of the blasts
are myelope roxid ase or Sud an black B
positive, and most cases are non-specific
este rase neg ative.
Immu nophenotype
Leukaemic blasts usually express one (J
more of the myeloid-associated antigens.
CD13. CD33, CD65, C01 1b , and COIS
There is usually ex pression of HLA[)A
and CD34 on the majority of blasts
Monoc ytic markers such as C014 anc
C064 are usu ally absent. C07 is preset
in 50-73% of cases, while expression It
Genetics
Seventy percent of A ML with CEBPA
mutation have a normal karyotype .
Fl.T3-lTD mutations occur in 22-33% of
Prognosis
Acu te myeloid leukaem ia with a normal
karyotype and CEBPA mutation is associated with a favourab le prognosis. similar
to that of A ML with inv(16)(p13.1q22)
cases.
123
DA ArOOr
R D . Brunning
A .Orazi
Definition
Acute myeloid leukaemia (AML) with
myelo dysplasia-rela ted changes is an
acute leukaemia with 20% or more periphe ral blood (PB) or bone marrow (8M)
blasts with morphological features of
myelodysplasia or a prior history 01 a
myelodysplastic synd rome (MDS) or
myelodysplastic/myeloproliferative neoplasm (MDSlMPN), or MOS-related cvtogenetic abnormalities, and absence of
the specific genetic abnormalities of AMl
with recurrent genetic abnormalities. Patients should not have a history of prior
cytotoxic or radiation ther apy tor an unrelated d isease . Therefore , there are three
possible reasons for assig ning cases to
this subtype: AML arising from previous
MDS or MO S/M PN ; A ML w ith an MOSrelated cytogenetic abnormality; and AMl
with multilineage dysplasia. A given case
may be assig ned to this subtype for one,
two or alt three reasons (Table 6.02).
ICD-O code
989513
Synonym
Acute myeloid leukaemia with multilineage
dysplasia.
Epi d emiology
This ca tegory of AML with mveiccysptasiarelated cha nges occurs mainly in elderly
pat ients an d is rare in chi ld ren 1913,
12691. Although the d efinition 01 rnultitineage dysplasia is variable in the literature ,
this category appears to represent
24-35% 01 all cases of AML 169, 869 ,
1493 , 2465).
Clinical leatures
Patients with AML with myeiooysprasiarelated changes often present with severe
pancytopenia. Some cases with 20-29%
blasts, especially those arising from MDS
or in ch ildhood , may be slowly progressive.
These cases, w ith relative ly sta b le PB
co unts for weeks or months, co nsidered
refrac to ry anaemia with exc ess b lasts in
transformation in the Frenc h-A mer icanBritish Cooperative Group ctassmcauon.
may behave clinically in a manner more
similar 10 MDS than 10 A Ml.
BJ. Barn
sore
A.P<xw<
JW VardllTal
MoM. LeBeau
P.L Greertlefg
rcoees
Fig. 6.19 Acute myeloid le~~ with myelodysptasia-felated changes (murtilillllage dysplasia). The marrow aspirate shows numefOlJS I9"8nulaf blasts as wei as actIuII:
hypogrardar neutrophiIs with dul1lled nucleardWomatin and erytt'ftid preanors \MttI irreQlAar nuclear am..n. AA small. l'lypoIobated rnegakaryotyIe is IQS80I al lhe txb.
BAIigher magOOicaIion 01 anoltl8fcase showing rl'ICIre irregIJar nuclearfeatures 01 eryIhroi:I l)"eanors and ~ wiIhcbnped IIUd&ar etwomatn
124
Immunophenotype
Immunophenotyping results are variable
dueto the heterogenei ty of the underlying
genetic changes, In cases with aberralions
01 chromosomes5 and 7. a high incidence
oICD34, terminal deoxynucleotidyl trans!erase (Td T), and CD7 expression has
been reported 123241. In cases with anieceoent MOS. CD34+ cells frequently
const itute only a suboopuraton of blasts
m may have a stem-cell related immunopheootype with low expression of CD38
M"dkx HLA-DA. Blasts often exp ress pan myeloid markers (CD13. CD33). The re is
'Tequently aberrant expression 01 CD56
and CD7 116231. The maturing myeloid
cells may show patterns of antigen excesson differing from thOSe seen in nQ{mal myeloid development, and there may
ee alterations in the light scatter properDeS of maturing cells, particularly neutrotfWs, There is an increased incidence of
'TUlKinJg resistanceglycoprOlein (MOO-1)
expressiOn in the blast cells 11206, 1268,
12691.
123561.
Genetics
Chromosome abnormalities are similar to
AND
Anyof !tie Ioi:lwing
PreW:lus hislDry of myeIodysplaslic syndrome
MyeIodysj::QsbC syndrome--relaled L)'IogenetIc
abnormalrty (seeTable6.03)
Mullilineaga dysplasia
AND
......."bdh
Table 6.03
('.oorpe. ~ '
UnbtIIItdd aMoonaiilies
llde(7ql
.-5qJ
~ l1q)'l l1p)
131de1(13q)
del(t1q)
del(12pj/l(l2p)
"'l9q1
idic(X)(q13)
&tI1l11Ud abnoonaiities
t1:11 ;t 6)(q23;p13,3)"
t1:311 )(q26.2;q22.1)"'
t1:1:3)(p36.3:q2t ,1)
t{2:11)(p21:q23)"o
1(5;t2)(q33:p12)
t(5;1)(q33:qtl .2)
t(5;11)(q33;p13)
t(5;10){q33;q21)
t(3;5){q25:q34)
should be excluded before u~ng these abnormalilin asevidence lor a diagnosjs of AML with
myeiodysplaSlB-related features.
125
126
,!
--t_
4...
,
v.... ,,""' .......
Fig. 6.20 Survival curve lor cases of acu te myeloidleukae mia with adverse cytogenetic find ings in the "tRC-AMl IO
trial Reproduced from Grimwade Det al. {MB}.
MOS without assoc iated dysplasia idl!f$the lime 01 AMl diagnosis woUd
be considered ~ AMl with myelodysplasaarelated changes (following prevos
MOSt; and a case with prior MOS. dysplastic features and monosomy 7 WCllil
be considered "AMl with rnyeIoctyspIase
related Changes (fotleJ'oNing previous Ml.li
MDS-associated cytogenetic a~
and muttilineage dysplasia). Cases
NPM1, CEPBA and/or FLT3 mutatll)'lS
should also indicate the mutation hndrYJ
(r.e. "AMl with mverocvsotasta-reraiec
changes (multilineage dysplasia) aM
NPM1 mutation"). Finally, because ollhe
possible cli nical heterogeneity of cases
with low blast cell cou nts (20-29%), tt:E
b last count should be cl early stated in t~
repo rt.
ueo at
I""
Therapy -related myeloid neoplasms
Definition
Inis category include s therapy -rela ted
acute mye loid le ukaemia (IAML). rnyelodysplastic synd rome (I -M DS ) and m yelodysplastic/myelop ro life rative neoplasm s
(t-MDS/MPN) occurring as late compliea'ons 01 cytotoxic chemotherapy an d/or
-adtatlOn therapy adminis tered lor a pr ior
'lPIastic or non-neoplastic disorder. AIh:lu'Jh some patients may be d iagnosed
nnpt'dogicatty as 1-"'-105, t-MDS/MPN ()(
~AML according to the number 01b lasts
present. all of these therap y-related neoplasms are bes t considered together as a
IIlJque clinical syn d rome . Exc luded fro m
mig categor y is tran sfor mati on of MPN
srce it is etten no t possible to determine
if !his is disease evolution or therap yrelated.
992013
&,nlnym
Therapy-related acute myeloid
ielJ:.aemia. NOS.
-k>Iogy
Therapy-related t-AMl.../t-MDS and t-AMLJ
l.MDS!MPN ac count fo r 10 - 20% of a ll
cases of AML, MDS and MDS/M PN 11278,
1433, 1536 1. The incidence among paieras treated w ith c ytotoxic agents varie s
ElC cording to the underlying di sease and
fe treatment strategy. Any ag e group
rray be affected b ut the risk associated
lIllh alkylating agent or rad iation therapy
jjerlefally increases with age whereas the
rsillor those treated with topoisornerase II
II'hbIlors is similar ac ross all ages 1651,
12781,
E"*'lJy
Therapy-related neoplasms are thou ght to
bethe conseq uence of mutational eve nts
mceo by cytotoxic ther apy, Som e indiOOualsmay have a heritable predis position
due topolymorphism s in genes that affect
drug metabolism or DNA -repair rnecha ~sms. but for most cases the und erlying
08thOgenesis rema ins uncertain 11899 1.
Cy1oIoxic agents commonly imp licated
ire istec in the Table 6.04 . Although other
JW. Vardiman
DA Arber
RD. Bruming
RA Larson
E. Malutes
I. Baumann
J Thiele
Sites of involvement
Peripheral b lood (PB) and bone ma rrow
(BM) are the princip le sites of involvement .
Clinical features
Near ly an equal number of patient s give a
history of treatment fo r a p revious baematologi cal ma lignancy as for a non -haematolog ical solid tumo ur. How ever. 5 - 20 % of
patients are reported to have rece ived cytotoxic therapy lor a rco-oecoasrc disease.
A smlar num ber develop a therapy-related
myeloid neoplasm afte r high dose
chemotherapy and autologous haematoporenc stem cell transplant for a prev i.
ously treated malignancy 11 433. 20411 .
Two subsets of t-AMlIt-MDS and t-A MU
t-MDS/MPN are generally recognized ,
The most common occurs 5- 10 years
afte r exposure to alkylating agents an d/or
ioniz ing rad iation. Patien ts often pr esent
with t-MDS and ev idence of 8 M failure
with one or mul tiple cyto penias, although
a minority will present with tMDS/MPN or
with overt t-AML This c ate go ry is com mon ly associated with unbalanced loss of
genetic material . often in volv ing chromosomes 5 and/or 7 . The second category
of t-A ML/t-MDS and t-A ML/t-MDSIMPN
encompasses 20-30% of patients. has a
latency period of about 1- 5 years, and
follows neannent with agents thai inte ract
With DNA tcoosorerase II (topoisornerase
II inhibitors). Most patient s in this subset
do not have a mveioovsotasnc p hase bu t
pre sen t initia lly with ove rt acute leukaem ia
tha t is ofte n assoc iated with a bal anced
cororoscrat translocation 1651, 1716, 20411,
A lthough it may b e useful to c onsid er
t-A MlIt- MDS and t-A MU t-MDSIMPN
as being alkylating agent and/or rad iationrelated or as top:lisctnerase II irtlibitor-related.
t.1o<pIloIogy
The majority of patients present WIth
t-AMlIt-MDS associated with multllineage
dysplasia . Commonly, but not invariably
in such c ases, a history of p rior therapy
with alkylat ing agents and /or rad iation
therapy is elic ited and cytog enetic studies rev eal abno rmal ities of c hromosomes
5 and/or 7, o r a comp lex karyotype , Nevert heless, dysplasia may be seen in some
c ases wit h balanced tran siocauons as
well. The P8 shows one or more cvtopemas . Anaemia is almost always present
and red cell morphology is cha racterized
in most cases by macrocytosis and poikik::x:ytosis, Dysplastic changes in the neutn>
p hils include abnormal nuclear lobation,
particularly hypolobatoo, and cytoplasmic
hypogranulation . Baso philia is freq uently
present 11 4721. The 8M may be hyper.
ce llul ar, no rmcceuurar or twpoc euuiar.
and slight to mark ed 8M fibrosis occurs
in approximately 15% of c ases. Dysgranulcpoiesis and dy serythropo iesis are pre sent in mos t patients , Ring siderobla sts are
rep orted in up to 60% of cases and in
some c ases exceed 15% of the erythroid
precu rsors. Meg akaryoc ytes ....ary in nurnTherapy-related myeloid neoplasms
127
00
000
00 O __
000 0 00 00.p~ . _
o 0000000 &0 , _
000 00 0
10.Q 0 0 000
~ 00 0
00
00
00 .
00
0
0 00
0
00 0 1
A O OO. O O O_O..~O!?C .
Fig.6.22 Thefapy-relaled MDSlAML This 42-year-old man was lrealed withABVD therapy lor dassical Hodglin IymJ:tloma but retapsed 161T1OflthS laterandwas!Jven 9vage
chemolt1erapy and radiolt1erapy, Two years later he presented W11t1 pancytopenia in l!le PB(A), a BM asprate (8) and BM tMopsy (C) st'lowtld ilCteased bass and mullili1eaile
dysplaSia. A complex karyotype Jnduded lossof d1romosomes 5 and7.
....kylating agents
Melphalan. cydophosphamide , nitrogen mustard, cI*lrafnbldl. MuIIM, carboplalin. eisplabn ,
aMIl inhibiton
""""
docetaxel
128
2034 .20411 .
It shou ld be noted that occ asional patients assigned to the category of therapyrelated myeloid neoplasms represent
coincidental disease and would be expected to behave like other de novo
disease.
129
130
D.A. Arber
R D. Brunning
A.Orazi
L. Peterson
J. Thiele
M.M. Le Beau
A. Porwil
9872/3
Epidemiology
These cases comprise <5% of cases of
AML. The disease may occur at any age,
bu t most patients are ei ther intants or
older adul ts.
Clinical features
Patients wiltl AML, minimally differentiated
usually present with evidence of BM failure
With anaemia, ltl rombocytopenia and neutropenia. There may be leukoc ytosis with
a mark edly inc reased number of b lasts,
Morphology and cytoc hemistry
The blasts are usually of medium size with
dispersed nucl ear chromatin, round or
slightly ind ented nuc lei with one or two
nucl eoli . The cytoplasm is agranular with
..
a varying degree of basophilia Less frequently, the blasts are small with more
cond ensed chroma tin, inconspicuous
nucleoli and sca nty cytoplasm resemb ling lymp hoblasts. The c ytochemical
reactions for myeloperoxid ase (MPO),
Sudan Black B (SBB) and naphthol-ASDctnoroacetete esterase (CAE) are neqetive 3% positive blasts): a naphthyl
acetate and butyrate es terases are negative or may sbow a noo-specmc weak C1
local reaction distinct from that 01 rT"IOOl>
cvtrc cells 1186, 1084, 1880 1. In some
unusual cases of AML with minimal ditter
ennanon there may be a residual norma
population of maturing neutroo nue. These
c ases ma y resemb le AML with maturenon. but are distingui shed by the absence
of MPO or SBB positivity in the b lasts and
the abse nce of Auer rods, The BM sections are usually markedly hvoerceuuie
with poorly differentiated blasts. With sensitive ultrastructural studies, MPO, CAE
ac tivity may be demonstrated in sma
1",,,,,,,OP" 011Otype
Most cases express earty, heernetoooetcassociated antigens (such as CD34,
CD38 and HLA-DR) and lack antigens
associated with myeloid and monocyti c
maturation. such as CD 11b. C01S , CD14,
CD64 and CD65 Biasi ce lls usually express CD13 and/or CO l 17 while expression of CD33 is found in approximately
60% of cases, Blasts are negative tor Band T-assoc iated cytoplasmic lymphoid
markers cCD3, cCD79a and cCD22 .
MPO is neg ative by cytochemistry. but
may be positive in a fraction 01 blasts by
flow cytometry Of immunohistochemistry.
Nuclear terminal oeoxvnocieonoyttransterase (Td T) is positive in approximately
oons
Acute myeloid leukaemia
without maturation
Definition
Acute myeloid leukaem ia without maturation is characterized by a high percentage o! 8M b la.''-.ts l~I,~\1 $~":li~ic.5\'71
evidence of maturation to more matur e
neutrophils. Blasts constitute ~% of the
roo-erythroi d cells. The myeloid nature of
Fill.6.2" Acute myeloid leukaem ia without maturation. Bone marrow smear. AThecellsarepredominanlty myelobIasts:
OCC3S;onal myeloblasts contain azllrophilic grarlules or Aller rods. There is rIO e'o'i Oenc41 01 maturation beyornllhe
myeloblast stage. B Myeloperoxidase reaction showing OOmertlUSmyeIoblasls with strong peroxidase reactivity. There
areseYeraI peroxidase negative tfYlhroid precursors ifl the centre.
9873/3
Epidem iology
Acu te myeloid leukaemia without maturation comprises 5- 10% of cases of AML. It
may occu r at any age but the majority of
patients are ad ults; the median age is approximately 46 years.
Clinical features
The patients usually present with evidence of 8M failure with anaemia, thrombocytopenia and neutropenia, There may be
a leukocytosis with marke dly increased
blasts.
Morphology and cytochemistry
Some cases of AML without maturation
are characterized by obv cos mveicorasts.
some of which have azurophilic granulation
and/or unequivocal Auer rods. In other
cases, the blasts resemble Iymphob lasts
and lack azurophilic granules: MPO and
SBB positi vity are present in a varia ble
number of bl asts , but always in at least
3% . The 8M biopsy sections are usually
markedly nvperceuutar although rormocellular or nvooceuuiar cases may occur.
Immunophenotype
Acute myeloid leukaemia without maturation usually presents with a popu lation of
blasts expressing MPO and one Of more
of myel oid -associated antigens suc h as
C0 13, C033 and C0 117. C0 34 and HLAOR are positive in approximately 70% of
cases.
9874/3
~~iilblbm'
131
O inical features
Patients often present with symp toms r
elated to anaemia, thrombocytopenia and
neutropeni a. The white blood cell coun t is
variable as is the number of blasts.
_ o g y and cytochemisOy
Blasts with and without azurophilic granu
larion are present. Auer rods are frequently
present. Promyelocytes , mveiocvtes and
mature neutroph ils com prise at least 10%
of the BM cells; variable degre es of d ysplasia are frequently present. Eosinophil
precur sors are frequ ently increased but
do not exhibit the c ytolo gical or cytochemic al abnormalities ch aracteristic of
the eosinophils in acute myelomonocyti c
leukaemia. associated with inv(16)(p13,l q22).
Basophils and/or mast ce lls are some times increased . The BM biopsy is usually
hyoe rceuular.
Immunophenotyp e
l eukaemic blasts in AML with maturation
usually express one or more of the
myeloid-associated antigens, C0 13,C033,
C065, C0 11b and C01 S. There is often
132
Genetics
There is no demonstrated association between AM L with maturation and specific
recurrent chromosomal abnormalities.
Differential diagnosis
The differential diagnosis includes retractOf'y anaemia with excess blasts in cases
with a low bl ast percentage, AML withOut
maturation when the percentage of blasts
is high, and acute myelomonocytiC
leukaemia in cases with increased monocvtes.
Acute myelomonocytic
leukaemia
Definition
Acute myelomonocytic leukaemia is an
acu te leukaemia characterized by the
proliferation of both neutrophil and monocyte precu rsors, The PB or BM has ~20%
blasts (including prorronocvtes): neutrophils and their precu rsors and monocytes
and their precur sors eac h comprise at
least 20% of BM cells, This arbitrary minimal limit of 20% monocyt es and their
precu rsors disting uishes acute myelomonoc ytic leukaemia from cases of AML
with or without maturation in which some
monocyte s may be present. A high number (usually ~5x 1 09/L) of monocytic cells
may be present in the PB,
ICD-O code
9867/3
Ep id em iology
Acute myelomonocytic leukaemia c0mprises 5- 10% of cases of AML. uoccca n
all age groups but is more corrrnoo in ddEJ
individuals; the median age is 50 years,
There is a maleJemaIe ratio of 1.4:1 120781.
Clinical features
Patients typically present with anaerre
and thrombocytopenia, fever and fatigue
The white blood cell coun t may be high
with numerous blasts and promonocytes
--~7"
f'll. 6..27 Acute myeIomonocytIe 1eI*aen'ia.
A BIoocI smear. myeloblast monoblast al'ld prormnocytes. B Bone marrow smeaf. MyelobIas1s.1ld smnIlOOre mallJ'e mooocyte5
rdudir9 prornonocytes, C Nm-specific esterase reactionon bone marrow smear. 5eYetaI NSE positi'Ie eels819 presert. The l'ICIl'Hll8dII1 eels 8111 ~ myeIcitlIasls
m~ preaJ ~.
!rrmunophenotype
These ieusaemras generally show several
populations of blasts variably expressing
myeloid antigens C013. CD33, COO5 and
CD15, One of the b last populatio ns is
usually also positive for some markers
Genetics
Myeloid-assoc iated , non-s oecrnc cytogenetic abnormalities, e.g. +8, are present in the majority of the cases.
Differential diagn osis
The major d iffe renti al d iagnoses inc lude
AML with matu ration , acut e mo noc ytic
leukaemia and c hronic mvelomonocync
leukaemia. The distinction from the other
Mi L types is based on the cytochemical
n;. 6.21
9891/3
A Acute monoblaslic leukaemia, Bone marrow biopsy showing complete replacement by a ~lation of
llrge blasts wilh abundant cytoplasm. The nuclei aregeneraly rOI.Ild to oval: occasional nuclei are di&lol1ed
<TIO'lOCytiC leukaemia Bone marrow sedion . The nudea!'IoIds in the promonocyles arepfOmineol.
8 Acute
Ep idem io log y
Acut e monob lastic leukaemia com prises
<5% of cases of AML. 11 may oc cur at any
age bu t is most co mmon in young individuals, Extramed uliary lesions may occur.
Acute mo noc ytic leu kaemi a comprises
<5% of cases 01 AML : the mare.ternare
ratio is 1.8:1. It is more common in ad ults
(median. 49 years) 120781.
Clinical features
Bleed ing d isorders are common presenting featu res . Extramedullary masses .
cutaneous and gingival inlit1ration. and
c entral nervous system (eNS) involvement are common.
Morphology and cytochemistry
Monoblasts are large cells , with abundant
cytop lasm which c an be moderately 10
intensely baso philic an d may show
pseudop od formation. Scattered fine
az urop hilic g ranules and va cuo les may
be present. The monob lasts usually have
round nuc lei with delicate lacy c hromatin,
and one o r more large prom inent nucl eoli , Promonocytes have a more irregular
and delicately con voluted nuc lear con fig uration; the cytoplas m is usually less ba sophilic and sometimes more obv iously
g ranulated , with occasional large azurep hilic g ranules an d vacuoles. Auer rod s
are rare in acute mono blastic leukaemia
and. when present, are usu ally in ce lls
ident ifiable as myeloblasts. Haemophagocytosis (eryttrophagocytosis) may be 0bserved and suggests an associated
t(8;16)(p11 .2:P13.3) chromosomal abnormali ty 120 791. Haemoph agocytosis wilh
an associated t(8 :16)(pll.2:p 13.3) may
also be observed in AML with maturation .
The monobtasts and p rornonoc ytes usually show intense non-sp eci fic este rase
activity in mos t cas es, In up to 10-20% of
ca ses of acute monooasnc leukaemia, the
133
134
Genetics
Myeloid-assoc iated, non-specif ic cytoge netic abno rmalities are present in the majority of the cases. The t(8;16)(p 11.2;p13.3)
may be associated with acute monocyt ic
leukaemia or acute myelomonocytic
leukaemia and , in the majority of cases, is
associated with haemophagocytosis by
leukaemic cells, particularly erythrophagocytos is and coagulopathy 12079).
Differential diagnosis
The major differential diagnosis of acute
moncorastrc leukaemia incl udes AML
without maturation , AML minimally differentiated and acute megakaryoblastic
leukaemia. Extramedullary myeloid (monablastic) sarcomas may be confused with
malignant lymphoma or soft tissue sarcomas. Occasi onal cases resemble prolvmphocytic leukaemia; they are readi ly
distinguished by immunophenotypic analysis and cytoch emistry. The major differential diagnosis of acute monocytic
leukaemia inc ludes ch ronic mvelomonocytic leukaemia, acu te myelomonocytic
leukaemia and microgranu lar acute
promyelocyt ic leukaemia (APL). These
9840/3
Epidemiology
Erytnroleukaernia (erythroid/mye loid) is
predominantly a disease of adults (20781.
It compr ises <5% of cases of AML. Pure
erythroid leukaemia is extremely rare and
can occ ur at any age, including childhood
.'
Fig. 6.30 Acute erythrcleukaemia. erythroid/myeloid. BOlle marrow smear. A Myeloblasls and erythroid precursors
with dyserythropoietic changes are present. B Bone marrow smear Perocc acid-Schiff reaction. There are se~eraI
erythroid precu rsors atvaryingstagesof maturation wilh PAS-positi~ cytoplasm. The more immature precursors Mile
a coarsely granu laril10bular reaction; thelater stage precursors havea diffuse cytoplasmic positi~Fty.
"
,... .
Clinical features
The clinica l features of the eryth roid
leukaemias are not unique but profound
anaemia and circulating erythrob lasts
are common, Erythroreukaernia (erythroid!
myeloid) may present de novo or evolve
from MDS or, less common ly, from chronic
myeloproliferative neop lasms (MPN),
Morphology and c ytoc hemistry
Erythroleukaemia (erythroid/myeloid)
All maturation stages of the erythroid precursors may be present, frequently with a
shift to immatu rity. The erythroid precursors are dy splastic with meparobras torc
nuclei and/or bi- or multinucleated forms ;
the cytoplasm in the more immature ce lls
frequently contains poo rly dema rcated
vacuoles, which may coa lesce , Large
multinucleated erythroid cells may be
present. The rnveioorasta are of med ium
size, often con taining a few cytoplasmic
granules and occasionally Auer rods and
aresimilar to the mveiobrasts in AML with
and without maturation. Dysplastic changes
of maturing neutrophils and megakaryocytes are common, The iron stain may
show ring siderob lasts and the perio dic
acid-8ch iff (PAS) stain may be positive in
re erythroid precursors either in a globular or diffuse p attern. The MPO, CAE and
SBS stains may be positive in the myeloblasts. The 8 M biop sy in erythroid!
myeloid leukaemia is usually hypercelluar. There may be prominent mega karyocytic dysplasia.
Pure erythroid leukaemia
The undifferentiated form of pure erythroid leukaemia is usually ch aracterized
by the presence 01 medium to large size
erythroblasts usua lly with round nucl ei,
fine chromatin and one or more nuc leoli
Immunoph enotype
Erythrole ukaemia (erythroid/myeloid)
The erythroblas ts in ervtbroieokaemia
generally lack myeloid-assoc iated markers and are negativ e with anti-MPO; they
react with antibodies to haemog lobin A
and glycophorin, but the more immature
ce lls may be negative. An aberrantly low
expression of CD71 may be present. The
immunophenotype of the myeloid population usually co rresponds to that 01 AML
without differentiation or AML with minimal
differentiation.
coalesce,
Fig.6.33 Pure erythroid leukaemia,Bone marrow section, A Apredominant population of veryimmature erythroid precursors , some of which aremuRilobated (arrow). B The immature erythroid precursors and mrtotic figures showpositivity fof glycophorin A.
Fig.6.34 Pure erythroid leukaemia. A Bone marrow smear shows fourabnormal ptcerythrcblasts. The erythroblasts
are large withfinely dispersed chromatin. prominent nucleoliand cytoplasmic vacuoles, some ofwhfch are coalescent.
B The cytoplasm of the proerythroblasts shows intenseglobular PAS staining.
135
expressed ..by mo-ocvtes and mega karyocvtes. Antigens associated with me gakaryocytes (CD41 and CD6 1) are typically
negative, b ut may be partially expresse d
in some cases . Immunohistoc hemistry to
haemoglobin A or glycophorin may be
helpf ul in establishing cell origin in biopsy
specimens.
Genetics
There is no specific chromosome abnormality described in this type of AML.
Complex karyotypes with multiple structural abnormalities are com mo n, with
-5/del(Sq), -7/del(7q) and +8 the most
corrvnon 112821. However, cases with
-5/del(Sq), -7/del(7q) and/()( complex
chromosomal aonomaunes should be
classified as AML with myelodysplasiarelated changes if the other requirements
f()( that category are satisfied.
Acute megakaryoblastic
leukaemia
Definition
Acute megakaryoblastic leukaemia is an
acute leukaemia with 20% ()( more blasts
of which at least 50% are of megakaryocyte line age; however, this category
excludes cases of AML with myelodysplasia-related changes, AML with
t(1;22)(p13;q 13), inv(3)(q21q26.2), t(3;3)
(q21 ;q26.2) and Down syndrome-related
cases.
ICD-O code
99 10/3
Ep idemiology
Ac ute meg akaryo bl astic leukaemia occ urs in bo th adults an d children. This is
an unc ommon d isease compris ing <5%
of ca ses of AML .
Clinica l features
Patients present with cyto pe nias. often
thromb ocytop enia, although some may
have thrombocytosis. Dysplastic features
in th e neutroph ils, er ythroid precu rsors,
p late lets and me ga karyocytes may be
pres en t. Hep atosplenomeg aly is intre-
meqekarvonrasnc leukaemia and mediastinal germ cell tumours has been ocserved in young adul t males 115941.
_ B
:.til
fig.6.36 ACVle mega~ 1eI.*aenia. A Bone marrow smear. The two megaka-yoblasts are large ceHs with
GytlpIasmic pseudopod lonnatiOn: portIOnS of the cytqllasm are "zoned" with granular basoplliliC areas and dear
~_ Nucleoli cwelAl$lJ3ly ptCIII1nerL B Bone marrow smear reac:t8d wrth alllilOOy to CD61 (pIal9lel: gIycopro.., II). The eyklpIasm of the ITlI!9lkalyoblasls is in&enSeIy reactJYe
0rm.n0phen0Iype
The meqakarvobtests express one or
'!'(Jfa of the platelet glycoproteins: CD41
19yooprotein 1Ib/llla). and/Of COOl (glycoprotein ilia). The more mature plateletassociated marker CD42 (glycoprotein Ib)
s less frequently present The myeloidassociated markers, CD13 and CD33.
'fay be positive. C034. lhe pan-Ieukocyte
marker CD45. and HLA-OR are often negalIVe. especially in children; CD36 is characteristically positive. Blasts are negative
with !he anti- MPO antibody and with other
markers 01 g ranulocytic differentia tion.
Genetics
There is no unique chromosomal aonorTe'rty associated with acute meqakarvoblastic leukaemia in adults . Complex
r.aryofypes typical of MD S, inv(3)
!:321(126.2) and t(3;3Xq21q26.2) can all
be associated with megakaryoblasticl
n!gak.aryOcytic differentiation 1507, 16371
sopnns.
ICD-O cod e
987013
Epidem iology
This is a very rare disease with a relatively
small number of reported c ases, comprising < 1% 01 all cases of AML.
Clinical fea tures
As in other acute reokaemras. patients
present with featu res related to 8 M failure
and mayor may not have c irculating
bl asts, In addition, cutaneous involvement, organomegaly, lytic les ions and
symptoms related to hy perhistam inemia
ma y be present.
Morphology and cytochemistry
The circulating PB and 8 M bla sts are of
medi um size with a high nuclear-eytoplasmic
ra tio, an oval, round or b ilobed nucleus
c harac terize d by disperse d chromatin
an d one to three p rom inent nucleo li. The
cytoplasm is moderately basophilic and
contains a varia ble numbe r of coarse basophilic granules wh ic h ar e positive in
me tachromatic stains; vacuolation of the
cytoplasm may be present. M ature basephi ls are usually sparse. Dysplastic tealures in the erythroid precursors may be
present. Electron microscopy shows that
the granules contain structures characteristic of basophil precursors; they contain
an electron-dense particulate substance,
are internally-bisected, e .g. have a theta
character, or contain crystalline ma terial
arranged in a pattern of scrolls or lamellae , the latter finding is more typical of
137
F"Ii- 6.38 Acute ~ 1eINema . Bone marrow smear. A Blasts and irrmature basophiIs. The bascJpIj pUIs
vary from large roarsegraUes III smaI8rpUBs. B Bone marrow trepl1n8 biopsy. The bIa:sls /we pco1y~
Clinica l features
Patients pre sent acutel y with severe constitutional sympt oms including weakne ss
and fatigue ; fever and bone pain are also
frequently ob served. Pancytopenia is
alwa ys p resent. There is no or minimal
sp lenomeg aly. The clinical evolution is
usually rapidly progressive 122251.
Immunophenotype
If sufficient 8 M specimen is obtained!o'
immunologic markers or circulating bIas:s
are p resent in the P8 . the c ells sh:)w
phenot yp ic heterogen eity, with va~
d egrees of expression of myeloid-aSSOCIated antigens . The blasts usually express
Genetic s
There is no consistent chromosomal
abnormality identified in these cases.
AML with t(6:9)(p23;q 34) is speci fic ally
excluded as are cases associ ated with a
BCR-ABL 1 fusion gene.
Differential diagnosis
The d ifferential d iagnosis inc lud es bl ast
ph ase of MPN, other AML subtypes with
ba sophilia suc h as AML with t(6;9)
(p23:q 34), mast c ell leukaemia and , more
rare ly, a subtype of ALL with prominent
coarse granules. The clinical features and
cytogenetic pattern will distinguish cases
p resenting de novo from those resulting
'rom transformation of chronic my elogenous leukaemia and from other AML subtypes With basophilia. Immunologica l
markers will distinguish between granulated AlL and acute basophilic leukaemia
and light microsc op ic c ytochemist ry lo r
myelope roxidase and elect ron mlcroscopy will distinguish acute basophilic
leukaem ia from other leukaemias.
138
993 1/3
Synonyms
Acute (malignant) myelofibros is, acute
(malignant) myelosclerosis.
Epidem iology
Acute panmyelosrs with myelofib rosis is a
very rare form of AML APMF oc curs de
novo. It is primar ily a disease of adu lts but
has also been reported in children.
GeneIics
If sufficient specimen for cytogenetic
analysis is obt ained , me results are usually abnormal. The d etec tion of a com plex
karyotype, frequ ently Involving ch romosomes 5 and/or 7 [-51del(5q), -7/d el{7q)]
122251, means that the case is assigned
to AML with my elodysp lasia-related
changes, not to ac ute panmyelosis.
Differential diagnosis
The major di fferential diagnosis of APMF
includes other type s of AML with associated BM fibrosis including acute megakaryoblastic leukaem ia 116511. Usual ly
ess problematic is the di stinction from
primary myelofib rosis (PMF), po st-p olycythaemia vera myelofibrosis, post-essen~ a l lh rom boc yt h ae m i a myelofibrosis, and
eon other neopla sms that c an be encountered in a myelofib rotic BM such as
metastatic malig nancies with a de srnoplastlc stromal reaction . The distinction between AML. particularly c ases of AML with
myekxiysplasia-related changes with multi~neage dysplasia and myelofibrosis and
acute megakaryoblastic leukaemia with
myelofibrosis, and APMF may be difficu lt,
Il(){
139
Myeloid sarcoma
SA Pileri
A. Orazi
B. Falini
Definition
A myeloid sarcoma is a tumour mass consisting of myeloid blasts with or without
maturation occurring at an anatomical site
other than the bone marrow (BM) . Infiltrates of any site of the body by myeloid
blasts in leukaem ic patient s are rot cl as-
Sites of involvement
Almost every site of the body c an be involved , the skin, lymph node, ga strointestinal tract, bone, soft tissue and testis
be ing more frequently attectec 1663.
1742 1. In less than 10% of ca ses . myeloid
sarcoma presents at multiple anatomical
sites 1663, 17421.
proportion of c ases, it d isp lays rnyelomonocytic or pure monoblastic morphology 1663. 17421. Tumours with trilineage
haematopoies is Of predom inantly erythroid precursors or megakaryoblasts are
rare and may occu r in c onj unction W1tt1
transformation of MPN 117421.
ICD-Ocode
Synonyms
Extramedullary myeloid tumour; granulo-
Etiology
The same as for acute myeloid leukaemia
(AMl) and myelop roliferative neop lasm s
(MPN).
140
Cytochemistry
Morphology
A myeloid sarcoma most c ommonly consists of myelobl asts with or w ithout features of promyeloc ytic or neut rophilic
maturation that pa rtially o r totally efface
the tissue arch itecture. In a sig nific ant
Immunophenotype
On immunohistoc hemistry in paraffin sections, C D68 /KP1 is the most c ommonly
expressed marker, followed in decreasing
frequency by MPO , CD t 17, CD99 . CD6&'
PG-M t , lysozyme , CD34 , termin al deoxvnucreoncvt trans ferase (TdT ), CD56,
CD6t/lAT/von Willeb rand antigen, CD30,
ones.
Geneti cs
By FISH andlor c ytog enetics, c hromosomal aberrations are detec ted in ab out
55% of cases. They incl ud e rnonosomy 7,
trisomy 8, MLL-rear rangement. inv( 16).
trisomy 4, monosomy 16, 16q-,
2Oqand trisomy 11 {17421. About 16% of
cases carry evidence of NPM 1 mutations
as shown by aberrant cytopl asmic NPM
expre ssion 1663. 666/. The t(8;2 1Xq22;q22)
observed in paed iatric series seem s to be
less frequent in adu lthood 1' 742 , 19 781.
sc-.
MyelOId sarcoma
141
I. Baum ann
C M, Niemeyer
AD. Brunning
O.A. Arber
A, Porwit
Transient abnormal
myelopoiesis
Definition
Transient abnormal myelopoiesis (TAM) is
a unique d isord er of Down syndrome (OS)
newborns that presents with clinical and
mo rphologic find ing s indistinguishable
from AML. The blasts have morphologic
and irrrnunologic features of megakaryocytic lineage.
ICD-Ocode
The provisiona l code proposed for the
fourth edition ofICO-O is 9898/1.
Synonym
Transient mye lopro liferative d isord er.
Epide miolog y
Trans ient abnormal myelopoi es is occurs
in approximately 10% of OS newborn s: it
uncommonly occ urs in phenotyp ica lly
normal neonates with trisomy 21 mosaic ism,
Clinical fe atures
At presen tation , thrombocytopenia is most
commo n; other c ytopeni as are less freq uently encoun tered, There may be a
ma rked leukoc ytosis and the pe rcentag e
of blasts in the per ipher al blood (PB ) may
exceed the blast pe rce ntage in the bon e
ma rrow (BM ). Hepatospl enomeg aly may
be present. Rarely, cl inical complications
incl ude ca rd iopulmonary failure. hyper.
viscosity. spl enic necrosis and p rogressive hepa tic fibrosis 15921. The proc ess in
the major ity of patients undergoes spontaneous remission Within the first three
months of life; a few chil dren experience
life th reaten ing or even fatal clinical complications.
.-
FIg. 6.42 UyeIoid 1eukaerr'U associaled wilh Down syrdome in a two year-dd d*l. A Bone marrow smear. ThePB and8M smearsc:ontarled ITIJIbpIe blasts as ~_ loWry
ollie bIasls contained runetOUS coarse basoIlI*CI:lIcAnd gJarUes . wtidl were myeloperoxidase ~_ Cy!OgenetJC sludy et 1M bme showed trisomy 8 in ali:lIbDn kllrJsomy
21. B Bone marrow trephrle biopsy !rom !he same pabenl There aft! I'II.I'flef'OI. blasts and occasional megakaryocyles induding one with a IIOIHobated IllJl::llM. C An irTmJnl>
IJst*9C readJon WIth CD-61 antibody. There are r...metOUS readJng eels indtdng otMous megakatyocyles and sevetaI smaIer eels .
Fig. 1.'3 SedicI'I d iWI atldl:ri'III ~ node In:lm eNd wrltl Ck:Jr,yrJ syncmne lnl ac:uIe megakar'yobl9sbc Ieo..*aerTia
The I'lXIe is ~ ~ by b8sls wifl occasicI'laI ~. sane d.n::n ae dyscllasIc.
Sites of involvement
Blood and BM are the princip le sites of involvement . Extramedul lary involvement,
mainly of sp leen and liver, is almost always present.
Clinical features
The disorder manifests predominantly in
the first 3 years of life, The clinic al course
in children with tess than 20% blast cells
in the 8M appears to be relatively indolent and presents initially with a period of
thrombocytopenia. A preteokaemc phase
comparable to refractory cytopenia of
ch ildhood (RCG)generally preceeds MOS
with excess blasts or overt leukaemia.
Morphology
In the pre-leukaemic phase. which can
last for several months, the disease has
the features of RCC (See Chapter 5) lacking a significant increase of blasts. Erythroid cells are macrocytic. Dysplastic
features may be more pronounced than in
primary refractory cytopen ia.
In cases of AML, blasts and occasionally
erythroid precursors are usually present
in the PB. Erythrocytes often show
con siderable anrscooikllocytoele. sometimes dacryocytes. The platelet count is
usually decreased and giant platelets
may be observed,
In the 8M aspirate, the morphology of the
leukaemic blasts shows particu lar features with round to slightly irregular nuclei
and a moderate amount of basophilic
143
144
Immunophenotype
Leukaemic blasts in acute megakaryocytic
leukaemia of OS display a similar immunoph enotype to blasts in TAM /125 11. In
mos t cases, the blasts are posi tive for
CD 11?, CD 13, CD33 , CD? , CD4 , CD42 .
TPO-R, IL-3R. CD36, CD4 1, CD61, CD7 1.
and are negative for myeloperoxidase,
C0 15. CD1 4 and glycophorin A. However, in con trast 10 TAM, CD34 is
neg ative in 50% of cases and approximately 30% of cases are negative for
CD56 and CD4 1. Leukaemic blasts in
other types of AML in OS display phenotypes corresponding to the particular
AML category
Antibodies to C041 and C061 may be
particularly useful in identIfying c ells of
megakaryocytic lineage in irrvnunohistologic preparations.
Genetics
In addition to trisomy 21, senate rmtatcos
01 the ge ne encoding the transc npnon
factor GATA1 are considered pathognomonic of transient ab normal mveicooeeis
corceec
Definition
Blastic plasmacytoid dend ritic cell (BPDC)
recoesm is a clinically agg ressive tumour
defived from the precursors of otasrnacvklid dendritic cells (also known as pro tesSlOnaI type 1 interferon producing cells or
plasmacytoid morocvtes). with a high trecuencv of cut aneous and bo ne marrow
(8M) involvement and leukaemic d issemination.
ro<l code
9727/3
Sjoonyms
Blasbc NK-celilymphoma 11039/. aqraniJaf CD4. natural kille r cell leukaemia
12771. blastic natural killer leukaemia/lympt'(ma \576 J, aaranurar CD4 +CD56+
19201
Epidemiology
This is a rare form of haem atologic neoplasm. without any known racial or ethnic
predilection. It has a male/fema le rano of
33:1; most patients are elderly, w ith a
eererecnan age at diagnosis of 61-67
years. but it can occ ur at any age , inCkldlngchildhood 1702. 920 ,1031 1.
Ebology
There are c urrently no cl ues to the etrobgy 01 BPDC , bu t its association w ith
myelodysplasia in some cases may suqgeS! a related pathogenesis. There is no
association with Epstein-Ba rr virus (EBV) .
F. Pacchem
D.M. Jone s
T. Petrella
Sites of involvement
The d isease tends to involve mul tiple
sites . w ith a p redi lection for skin (almost
100% of cases). followed by 8 M and peripheral blood (PB) (60-90%). and lymph
nodes (40 -50%) 1920, 17351 .
Clinica l features
The pat ients usua lly present with asymptomatic solitary or multip le skin les ions
that c an be nod ules, pl aque s. o r b ruiselike areas, Reg ional lympha denopathy at
presentation is c ommon (20%); PB and
BM involvement can be minimal at pre sentation . but invaria bly develops w ith
progression of d isease . Cytopenias (especia lly thrombocytopenia) can occur at d iag nosis, and in a minority of cases can be
seve re, indic ating BM failure 1702, 920 1.
Follo wing initial respo nse to chemotherapy , re lapses invariab ly oc c ur, involv ing
skin alone. or skin associated with othe r
sites . includ ing soft tiss ues and the centrat nervous system. In most cases a fulminant leukaemic phase ult imately
develop s 1702 1.
About 10-20% of cases of BPOC are associated with or develop into a mveromonocytic leukaemia or acu te myeloid
leukaemia 1702, 920, 924 , 1142 . 1735 ,
18301 . Thes e second teukaermas can
evo lve from underl ying mye lodysplasia,
or appea r sud de nly upon prog ression or
relapse 1702, 924 ,1 1421
BPDC must be d istinguished from the
occasional association of a myeloid neoplasia (especially chronic myeIornonOCylic
leukaemia) with massive nod al or extranodal localization of plasmacytoid dendritic cells, in which the plasmacytoid
cells are rrnphoIogica/ly mature
and C056 negative 123351.
oeoouc
Morpho<ogy
BPDC is usually characterize d by a dif fuse, monomorphous infiltrate of mediumsized blast ce lls with irreg ular nuclei, fine
c hromatin an d one to seve ral small nucleoli . The cytoplasm is usually scant and
appears grey-blue and ag ranu lar on
Giemsa stain . Mitoses are variable in
number. but rarely prominent; angiOlnvasion and coagulative necrosis are absent.
In cutaneous inlihrates, tumour c ells predominantly occupy the dermis, sparing
the ep ide rmis , but eventually extending to
subcutaneous lat. l ymp h nodes are diffusely involved in the interfollic ular areas
and medulla, with a leukaemic pa ttern of
infiltratio n .
Bo ne marrow b iop sy may show either a
mild interstitial infihrate only delectable by
immunophenotyping , or massive infiltration ; residual haeroatcooetc tissue may
exh ib it dysplast ic features, especially in
megakaryocytes 11735}. On PB and BM
smears tumour cells may show cytoplasmic
rmcrovacuoles localized along the cell
memb rane and p seudop od ia.
Cytochem istry
BPDC tumour cells are non-reactive lor
naphthol-butyrate esterase and perox idase cytochemic al react ions .
"' '\;I''~CIoJii.
A Ski'I tI.I'I'lWfand plaques. B The inIiIlrate diftu$ety imoIYes !he demis andedends tl subc:Wnews fat. but spares lIle
1Pde!fM, CThe neoplasbc eels are mediI.m-sized. wiIh lineetwomatin and scanly cytoplasm. reminiscentof undlf!erentiated blasts,
145
Immunophenotype
Tumour cells express CD4, CD43, CD45RA
and CD56, as we ll as the plas mac ytoid
dendritic cell-assoc iated antigens CD123
(interleukin-3 a-chain receptor), BDCA-2/
CD303, TCU , CLA (cutaneous lymphocyte-associated antigen) and the interferon-a dependent molecu le MxA (92,
920,924 , 1735-1737, 1739, 1747, 1830,
22791. Rarely, the C056 antigen can be
negat ive, which does not rule out the diagnos is if CD4, CD123 and TCl 1 are
present. Tumours that share some but not
all immunophenotypic features of BPDC
may be better class ified as "acute
leukaemia of ambig uous lineage".
C068 (an antigen typical ly found on normal plasmacytoid dend ritic ce lls) is expressed in 50% of cases , in the form of
small cytoplasmic dots (1735 , 1739J.
Among lymphoid and myeloid-associa ted
antigens, CD7 and C033 are relatively
common ; and some cases have shown
expression of C02, CD36 and CD38 ,
while CD3 , CDS, CD13, CD16, CD19 ,
CD20, CD79a, LAT (linker for act ivation of
T cells) , lysozyme and myeloperoxioase
are regularly negative , Granzyme B,
which is reg ularly found in norma l plasmacytoid de ndritic cells , has bee n
demonstrated on flow immunophenotyping and mRNA analysis in BPDC [395 ,
820\. but it is most ly negative on tissue
sec tions, similarly to other cytoto xic
molecules such as oertonn and TIA 1,
Terminal deoxynucleotidyl transferase (TdT)
is expressed in about one third of cases ,
with pos itivity rang ing between 10% and
80% of cells; CD34 and CD117 are negative. EBV antigens or EBV-encoded small
nuclea r RNA (EBER) are not found.
Except for CD56 and TdT, the immunophenotype of BPOC largely overlaps with
that of plasmac yto id dendritic cells occu rring in reactive lymph nodes and tonsils [654}. Because other heematotoqic
neop lasms (such as acute myeloid
leukaemia, extranodal NK/T-eeil lymphoma,
nasal type and mature T-cell lymphomas),
with or without skin involvement, may express CD56 with or without CD4, an
extensive immunohistochemical and/or
genetic analysis is manda tory before a
definitive diagnosis of BPDC is made (92,
173,386,920, 1386).
Genetics
J-ceu and a-cen receptor ge nes are usually ge rmline {92, 1735, 1830}, except for
a few cases that showed T-cell receptor
146
192.920, 17351
147
CHAPTER 7
Acute Leukaemias of Ambiguous Lineage
150
M ,J Borowitz
M ,-e , Bene
Nt.. Harris
A. Porwit
E. Mat ures
Table 7.01 RllQuiremefils for assigrlingmore than onelineage toa Single ~asl populaton.
Myeloid lineage
~xidas.e (fbw cylomeIfy,
immunohislOChemistry or cytoChemistry)
"
Mi:Inocy1icdifterentiaticl'l (al least2 of lhe kllIowrng: NSE. CDlle , C014, CD64 ,~)
Tlineage
Cytoplasmic COO (!kM' cytomeIry wi1l'l antibodies 10COO epsilon etIatn: irnn~nolliStoehemistry USIIIg polydonaI
<W1b-C03 <W1tbody maydeled CD3zeta chain, wt\id'I is not T<:eII spec::ific)
"
Strong C019 wiltl a1ieas11 oftnefclowing strr.Tf/'I e~ . CD79a. C)1OpIasrrMc C022. COlO
"
Weak CD19withill least 2 oIlhe IoIowilg 5IfOn!lIY exp!&S:Sed: C079a, cyqMsmic C022.CD10
T-cell antibodies used in immunohistochemistry also reac t with the zeta (~)
Chain of the
receptor present in the
cytoplasm of NK-c ells , an d are thus not
absolutely
specific .
In contrast to w hat is d esc rib ed above
with mye loid and t -een lineages, no single marker is sufficie ntly specific to indicate B-cell differentiation with ce rtainty, so
that a constellation of find ing s is needed.
Been diffe rentiation can be recognized
v.tIen there is a distinct subpopulation of
cells that by itself meets criteria for B-ALL
When only one population of cells is present. then B-lineage assignment requi res
either 1) strong Co 19 exp ression coupled
with strong exp ression of at least one of
the follow ing antige ns : C01O, Co79a or
cCD22; or 2) weak CO 19 exp ression co upled with strong ex pression of at least two
of the following : C01O, Co79a and
cCD22. Rarely, a case may be ass igned
as B lineage even If C0 19 is negative,
though care must be taken when doing
this because of the relative lack of speci!iclty of C010 and Co79a.
Cases of MPAL based on one cri terion at
diagnosis (e.g. 'biph enotypi c leukaemia ")
may c hange ove r tim e or at relap se to the
other (" bilineage leuk aem ia"), o r vic e
versa. Also, following therapy, per sistent
disease or relap se may occur as eithe r
pure ALL o r AML. Some cases of wh at
'as been termed "lineage switch" 11684,
18251may reflect this phenomenon
Ambiguou s lineage leukaemias are rare
and account for less than 4% of atl cases
ol acute leukaemia. Many cases of w hat
have been rep o rted as undiffe rentiated
'eukaemia ca n b e d emon str ated to be
eokaemtas of un usua l lineag es, and
'TIany ca ses of what have been reported
as biphenotypic acu te leukaemias may in
tact represent acute lymphoid or myeloid
letJkaemias With cross-lineage ant igen
expression , so that the actual frequency
may even be lower, The se leukaerruas
occur both in children and adults but
-rore frequent ly in the latter, although
some su btypes of MPAL may be more
common in c hild ren 11145, 16711 .
Avariety of genetic lesions hav e been reported in am bigu ous lineage leukaemi as,
especially MPAL. Two of these , the t(9 :22 )
(Q34;q 1l ) BCR-ABL 7 translocation, and
sansrocanons associated with the MLL
gene occur frequently enough and are
associated with distinctive features that
lhey are considered as sep arate entities.
t-een
t-een
Acute undifferentiated
leukaemia
Genetics
There are too few case s des cnbed to
know whether any consistent ge netic
lesions occur.
Definition
Ac ute undifferentiated leukaemia expresses no markers co nsidered specific
for e ithe r lym pho id or myeloid line ag e .
Before categorizing a leukaemia as undif ferentiated, it is necessary to perform irnmunophenotyp ing w ith a comprehensive
panel of monoclonal antibodies in order
to exclude leukaemias of unusual lineage s, such as those derived from myeloi d
Of p lasmac ytoid dendritic cell p rec ursors,
NK-c ell precursors, basophils or even
non-baernatocoietrc tumo urs
ICD-O c od e
(q34;q11.2); BCR-ABL1
980 1/3
Synonyms
Acute leukaemia, NOS; stem c ell acute
leu kaemia.
Epidemiology
These leukaemfas are very rare , and
nothing subs tantial is known about the ir
frequency.
Sites of involvement
Bon e ma rrow and b loo d . There a re too
few cases to know wh ether the re is a
predilect ion for othe r sites.
Clinical featu res
There are no features that distinguish this
from other ac ute ieukaemias.
Morphology
The b lasts have no morp holog ic feature s
of myeloid d ifferentiation .
Cytochemistry
The blasts are negative for nweicoe ro xlcase and esterase.
Immunophenotype
These reukaemas typ ically express no
more than one membrane ma rker of any
given lineage. By definition , they lack the
T or my eloid lineag e specif ic ma rkers
cC 03 and MPO and do not expr ess Bce ll specific ma rkers such as cCD22,
cC079a or strong C0 19. They also lac k
specific features 01other lineages such
as megakaryocytes or p lasmacytoid denontrc ce lls. Blasts otten express HLA-oR.
CD34 , and/or C038 and may be posi tive
for terminal d eoxynuc leoti dyltransferase .
Epidem iology
Althoug h this is the most common recurrent genetic abnormality seen in mixed
p henotyp e ac ute leukae mia. it is a rare
leukaemia , prob ably accountin g for less
than 1% of ac ute leukaemias. It occurs in
bot h children an d ad ults , b ut is more
common in ad ults 1338 ,11 451.
Clinica l featu res
Patients present with features similar to
those of other patients with ac ute
leukaemia. Though there are not enough
da ta to be ce rtain , it is likely that they
present with high white b lood cell counts ,
similar to patients with Ph-s ALL.
Mof'phology
Many cases show a dimorphi c blast
population , one resembling Iymphoblasts
and the OIher nwecotasrs. although some
cases have no d ist inguishing features
Cases generally do not show significant
myeloid maturation ; care shoold be taken
abou t making this diagnosis in a case of
151
Mixed phenotype acute
leukaemia with t(V;11q23);
MLL rearranged
Immunop henotype
In the majority of cases it is possib le 10
rec og nize a lymp hoblast popula tion With
a CD 19-positive , CDlO-negative B prec ursor (p ro-B) irnmuncphenotype , frequently positive for CD15. Expression 01
other B markers such as CD22 and
CD79a is often we ak. In addition to this,
cases also fulfi l criteria lor myel oid lineage as defined above, most comrnonly
via demonstration of a separate papUa.
tion of myeloid. and usually monobIaSIJC
leukaemic ce lls 1167 1. 237 11. Coexpessian of myeloperoxi d ase on Iymphold
blasts is rare. MLL translocations can also
produce T.ALL, so that it is thOOfeticaly
possible that T/myeloid Ieukaemias
oc cur, although these have not been
reported .
Definition
Genetics
Fig.1 .01 ElJrnyeIoid I8ulalInN with 1(9.22Nq34;q11 2). Theblasts vary from smaI ~ iIppeWVlg bIasIs kl ~
blasts WIlh dispersed c:lVl:lmaIin, prorninefJl nudeoIi and a Il'llXlefllte ann.n of pale ~.
Genetic s
All cases have either the 1(9;22) detect ed
by classical karyotyp ing . or the BCR-ABL1
transloc ation d etect ed by FISH or PCR.
Many c ases have addit ional c ytogenetic
abno rmalities, and of ten have comp lex
kary olypes.
152
Acute
ewa
Morphology
Most commonl y these leukaemias display
a d imorph ic blast population , with one
population clearly resembling monoblasts
and the ot her resembling Iymphob lasts .
However. in other cases they may have no
d istinguishing features and appear only
as undiffe rentiated b last cells. Cases in
whi ch the e ntire blast po pulation is
monobtasnc are more likely to be A ML
with an MLL translocation.
mantes.
ICD-O cod e _
The provisiona l code propo sed for the
ftxmh edition of ICD-O is 9808/3
Epidemiology
This is a rare leukae mia , p rob abl y ac counting for ab out 1% 01 leukaemi as
overall. It can be seen bo th in ch ildre n
and adul ts bu t it is mo re common in
adults.
Clinical features
""""""'"
Most
--.f""""C"
5: .~"( -..
,
Genetics
Most cases of B!myeloi d leukaemia have
c lonal c ytogenetic abnormalities. Ma ny
d ifferent lesions have been demonstrated. thou g h none is of such frequency
to sug g est specifici ty for this g roup of
leukaemias. lesions that have been seen
in more than a single case include de l(6p) ,
-- _ .
Sf"
.'-,j"-""
;: ..~ -.
'
..::<:-'...
;. '
' I' :"'.: .
..
. ,
Mixedphenotype acute
leukaemia, T/myeloid, NOS
Def inition
This leukaemia meets c riteria for assign ment to both T and mye loid lineage as desc ribed above , but in which the blasts
lack the above men tioned genetic abnormalitie s.
COlO m e
ICD-O code
The provi siona l code proposed for the
fourth ed ition of ICD-O is 9809/3.
,, ;.
.
...'
I"
.:,~.;
. :.~..
: C
FITe
Fig. 1.D2 FkIw L)'IOmetty in EIJmyeIoid 1euUemia. A C045 'IS Side scatter display ShoWlIlQa ma,a popuIaIlon of din
COt5+ !:*lsts. B ~ 1111 bloe. residual normal B cells red and rnyeIoperoxidas posIbYe c:eIls (ndudong boIh
tesls and I1ISiduaI nonnaI ceh)~ . aeTheIk:et ~ CD19 and C022 areslrOI9Y expressed on !he B Iym~ blasts. II"" CXlll1lIlable b!hal seen WIII'I residual nonnaI Ek:eIs (in red). 0 t.b;t of !he B-ceI blasts IaciMPO
..., many hJu!1l nol aI of !he ~ blasts are MPO posiIi'Ie. There is a smaIpopUabonof blasts eoexpmsing
1I1l9 rei MPO.
Epidemiolog y
This is a rare leukaem ia, probab ly ac co unting for less than 1% of leukaemias
overall. It can be seen both in c hildren
and ad ults . It may be relatively more Irequent in c hildren than is 8/myeloid acute
leuka emia .
C linical features
There are no unique clinica l features.
153
""""""Most cases have blasts with no cnstmguishing features. morphologically resembling ALL, or have dimorphic
populations. with one resembling lympboblasts and the other resembling myeio-
t-een
fied 123711.
b lasts.
lmmunophenotype
Blasts meet the criteria for both T-lymphoid
and myeloid lineage assig nment listed
above. My eloper oxid ase-p ositiv e mvero-
Genetics
Most cases have clonal chromosomal abnor ma lities , although no ne is of such frequency to sug gest specific ity fo r this
g roup ofleukaemias. There are insufficient
data in the literature to sug gest tha t B/MY
and T/ MY le uka emi as hav e d ifferent freque nc ies of d ifferent ge netic lesions, once
Fig. 7.001 ThnyeIoid 1euIlaenU. ThIn ill . dimlrphicpop.MtionaI blasts wilh many smaI~ ; larger blasts
alsoMoe high ~sm 1'lIlio. h manatin arid inalnspicuous rndeoL
154
_.-
, '.
-.. .. -
."
B
-'j'-'<':;;;,;,......:
. .~.. _, , ...., . .. ,. ,
CVTOPlo\SMlC f1"O
coe """"
rrrc
r-cen-soecmc
.,',',- C
.;:
., ,....,
. . ..,.,
"Ii, ,..,.,
SS L..
~phom.
..
'
cf'FOFlTC
...
.'
,
.. .'
~.
. ,.~
. ..' .-
,.
t-een
155
CHAPTER 8
immunopheno typic and functional properties with T cells , these two classes of
neoplasms are considered together.
B-cell and T-cell neopla sms in many re-
E.S. Jaffe
N.L. Ha rris
H. Stein
E. Campo
SA Piler i
S.H. Swerdlow
yl T - . _ _
T_._--.
Agopeafic
-'''''
on B + T cells
Ag presentation to
T cells in
context of MHC
Immunological defense
cha racterized by specificity and memory
Fill, 1.01 There are I\lIO mainarms of tile immur.e system. the innate immur.e system, and the adaptive immuroe
system, Diagram shows respective roles 01 lymphocyte sutlpopulations in the innate and adaptive immuneresponses
NKcells, N K~ike Tcells, and yfo Tcellsfunction with othercell types including granulocytesand macropha ges asa first
Hna of defense. These cells havecytotoxicgran ules (shown in red) oontainingperIorin andgranzymes The inna teimmuoe system lacks specilidty and memory. In the adaptive invnuoe system, B 00115 andToeIIs r&COgnize anligeos (Ag)
lhrough specific rec:e~ , immunoglobulin (Ig) and !he T-eeII recepD" rompIex (TCR) respediwly, Antigen presenta,
tion to T eels must take pIac:e via anligen-presenling cells (APe) in lhe conlell of Ihe appropnale majorhlstoa::lmpatibihly c:omplex (MHC) ClassIIantigens. FiglIe R'I()Ijfied from {1035}.
158
Na...
Follicular
area
Perifollicular
area
B<e<1.
Progenitor
.... AG
B<e<1
.......
Memory B-cells
Marginal zone
ExtrafotJiCular
Pre-Ekell
(@f~
4
Immature
B-<ell
c:
--
I
/
/
/
-------
8-<011
Pre-GC neoplasm
Mantle cell lymphoma
GC neoplasms
Follicular lymphoma
Burkill lymphoma
OLBGC. (some)
Hodgkin lymphoma
Post-GC neoplasms
cursu:
ory/marginal zone B-cells. Most B-cells areactivatedwithin the GC, butT-cell independent activation can take place ootsideof thegerminal centreandalsoprobably leads to memory type B-cells. Monocytoid B-cells, many of which lack somatic hyperm utatioo, are not illustrated.
Dl.BCl, diffuse large Bcell 'Ymphoma; CLUSll, chronic lymphocytic leukaemia/sma ll 'Ymphocytic lymphoma; MAlT, meccsa-essccated lymphoid tissue; AG. antigen; FDC, fojlic
u1W Oeooriticceli. Red bar. irmnurKlglobulinheavy cha in gene (IGH@) rearrangement;bluebar,immunoglobulinlightchaingene(IGl)rearrarJgem&nt; b1ad1 insertions in thered and
blue tersindK:ite !WI'Iatic hypermutation.
late primary or secondary immune response 11 356 A I. The BCL6 gene also undergoes somatic mutation in the g erminal
cen tre, however, at a lower freq uency
than is seen in the IG genes l 1698A 1. Ongoing IGVregion gene mutation with intraclona l diversity is a hallmark of germinal
cent re cells. and bo th IGV reg ion gene
mutation and BCL6 mutation serve as
markers of cells that have been through
the germinal c entre. Most dilfuse large
B-cell neoplasms (DLBCL) are composed
01cells that at least in part resemble cantrobtasts and that have mutated IGV
159
Neoplasm
slg;
C05
C0 10
C023
CQ.t3
C0103
BCL6
c~
CWSL l
IRF.....
CyeUn
MUMI
D1
ANXA1
(+PCI
LPl
+/.,+
HCl
."
;.
.,.
','
MALT lymphoma
Iym_.
f ollicubr
. t,
.,
. ;.
MCl
' ,'
IIrge
8-cIll lymphoma
. /.;.
/.
811ttitl
. ;-
--
."
01-
....
NA
,.
NA
.,
NA
.'~
. /-"
, >90% 01 cases -: . /., >50% 01 cases -: 01., <50% 01 cases e:-, <l<ni. 01 cases IRF4IMUM1, inletfeton regu3a
and 311; - , DLBCl oIgerTTlInaI centre 8<eI type (GCB) elqlAlSS COlOand BCl6; " . DlBQ. 01 aclro'aIed 8<eI
type (ABC) aretypically posllMt lor IRF41MUM1; "'. some Dl8Cl are C05. ; NA. not applc:able; lPl,1yrnptooo
Iabng Iacb' 4:ANXA1 , AnneXll"lAl; PC, praIileratIon celllreS: " plasma eel c:ornponent po$IllYe;', some grades
P~B
Pre-8
Immature
Mature
Gemlinal
naive 8
eeoee B
Antigen Independent
Memory B
(Marginal zooe)
Plasma cell
Antigen Dependent
I,-,--~==~=
I CD79A
[PAX5
[ CD20
n nnours.
Centrobrasts ma ture to centrocstes. and
these cene are seen predomina ntly in the
light zone of the ge rminal cen tre. Centrocvtes express slg that has an altered antibody combini ng site as compared WIth
that 01 their oroqenrtors. based both on
somatic mutations and hea vy chain class
Swit ching Cen trocytes with mutations thai
result in increased affini ty are rescued
from eocotose and they re-express Bel2
protein 11355A1. Throug h inleraction"";tn
surface molecules on FDC 's and t-cees.
such as CD23 and CD40 ligancL centrocytes swilch off BCL6 p rotein expression
1346, 17601. and oitterennate into either
memory B-eetts Of p lasma
1t 355AJ.
BCL6 and IAF4/M UM 1 are rec iprocally
exp ress ed , w ith IAF4/MU M l being positive in late cer nrocytes and plasma cells
166 1. t 9t4AI. IRF4/MUM 1 plays a critical
role in down-regulating BCL6 expresser
11914AI, Follicu lar lymphomas are 1lJTlCU'S
of g er minal c entre B-c etts (centrocytes
and centrobiasts) in wh ich the germinal
c entre celts fail 10 undergo apcorosts. in
most cases du e to a chromosomal rearran gement. t{14 :18), that prevent s the
normal switc hing off 01 BCL2 proten
expression, Centrccvtes usua lly preooninate ove r cen t roblas ts , and these neoplasms tend to be ind olent.
Post-germinal ce ntre memory Bccells cir
cu lat e in the PB and comprise at least
in the follic ular marginal
some of the
zone s of lymph nodes, spleen and mucos a-assoc iated lymphoid tissue (MALT).
Marginal zone e-cens of this co-roanmen t typ ica lly express pan-B antigens,
surfac e Ig M w ith only low level IgO and
lac k both COS and COlO 12064 A. 2293Bl.
produced in the ge rminal
Plasma
c entre enter the PB and home 10 the bone
marrow (BM). They conran predom inantlY
IgG or IgA ; they lac k slg and CD20, bI.C
exp ress IRF4/ MUM 1, C D79a , C03B and
CD 138. Both memory B-eetl s and long.
lived p lasma cens have mutated IGV
reg ion genes , bu t d o not continue 10
undergo mutation . Posl-germinal centre
Beene reta in the ab ility to home to tissues
in wh ic h they have undergone antigen
cens
cens
ceus
fig.I.O] SChematic diagram showing pherlotype 0/8 ~ at ~ stages of mah.ra1ion. TOT is II feature of
earty Iyn1)hOid preanors, irdIclIng boIh Band T IyrrfJhobIasts. as wei as!he blasts in some cases of acu1ll myeloid
leukaemia. C079A and PAX5 appNI' allhe bme of heavy etlan ger-.e rearral'lQelTlelll. COlO is I'IOt e~ IA'ltIIIhe
stage of inIrrI.JllOgIobuIirlliljll chain gene (/GLJ I'8aITllflQE!I' TOT, Iermml ~ IransJerase; SHM, soma1lc~ ; Red t .,/GH@ ~ll blue bar./GL rearrarJgelTleflt; Pre-8CR. pre-8<eI receplor ~
sisIi1g 01 a IG heavy thaI'l and !he IIWfOgale io,tJl chail (YItIch is ~ d two lri;ed smaI pepIides VpreB llf'Id
45, represenled in ~J; BCR. B celIl'llOfII*;Irol rnetln 8 eels : Redbar and blue bar wiItl bladti'lser1DJs, fNIfIIIglId
IGH@ and IGl. QeIleS WIth somabc h~.
160
stimulation, probably through su rface integrin exp ression, so that B-cells that
arise in MA LT tend to return the re, while
those that arise in lymph nodes will home
to nodal sues and BM p03AI . Marg inal
zone lymphomas of MALT. splenic . and
nodal types correspond to post germinal
centre, merTIOfY B cells of marginal zone
type thaI derive from and proliferate
specifically in extranoctal, splen ic or nodal
Bone
ryi.i;;~:"
.. ... .....
,
t-een
.
Skin
""W
T
T-binI , . . "
c;ell
~ ~f ~, -,------+-------?~ffl'
AG
L~ ZT~'
Thymus
T tvmphoblastic
Iymphomaneukaemia
FDC
Follicle
Peripheral (mature) T-cell and NK-cell tymphomaslleukaemlas
Fig. ' .0<& Diagrammatic representation d T-cel drflerenbabal. T-<.:eI neopIastnscorrespond lCI dJflerent stages 01 mabntion. Lymphoid progenilClfs enteree thymus wherePfflCU'sorT-cees deYeIop intovaried typeS 01 naive T-ceis. The~ rnauationaI palhd natural kiIer cells andy6 T<.efls is not filly ~tood. Thea~ T<:eIsleave1he1l'Iyrrus where
\.p)n expl)Sl.Q 10 anligen they mayUI'ld9rgo b1asllranslormabon and developfurther intoC04+andCD8+ elledor andmemory T<ets, T regulalory eels en 1hemajortype 01 COol
eIIector T<ells. AnoIhllf speciIic type 01 eIJedor T<eIls is the IoIliculaf helperT-eel that is found in gernjnal centres. Upon anligetjc stimulabal, T-cel teSj)(Ilses may OCW" irJd&.
pendenl ollhe gemWoal ceoue. or in 1hecontext 01 a germinal centre reaction. FDC. Follicular dendritic cells: AG. antiQen.
Introduction and overview of the classifica tion of the lymp hoid neoplasms
161
r-ceus.
(3
88~~e~"
a-cens.
CD1a
CD2ICDS
C0 3
Cytoplasmic
Surface
CD4 +
CD4/CD8
Double +
CD8+
I
I~T~-ce=':Iym=P:h:"':":':bc=lou:k:.:om=_
===m:':(:T-Al
=:lIl:B:l~)IIPeripheral T-eell lymphomas
I
I
TOT
Fig.8.05 Schematic diagram of T-<:ell maturation illustrating changes inantigenic expression. Tccell receptor (TCR)
genes (TRA@, TRB@, TRG@,TRD@) are shown schematicallywith solid red bars indicating absence ofrearrangement, and rearrangement ofrelevant TCR genes as additional black segments.The TRG@generearranges first, followed by TRB@ and TRD@ . up T cells delete the TRD@ gene during TRA@ gene rearrangement, as TRD@is
contained within the TRA@ locuson14q11.2. HOIVevef, yO Tcells may haverearranged TRB@genes,withoutassembly
ofa complete up TCR Productive rearrangement gives rise to two mainT-<:ell populations. ul3and yO. wiltlexpression ofltle relevantTCR complex on the cell membrane (shown as double red bars).
162
Table a.o2
Imm~typic
Neoplasm.
CD)
CD4
CDS
CD7
COS
C02
TlA1
GrB
CDJO
CD2S
C056
C016
COS7
BCl6
COlO
EaV
EMA
PM
teu
T.lGl
Ani.
Ao'l"
ENKIT, Maul typt
EATL
.,
.,
"ISS
AITl
AlCl,ALK+
AlCl,AlK
.,
.,.,.,-
.,-
-.
<
"
HSTL
SPTCl
.,-
.,-
<.,
,'- .,- ,
.,- .,- .,- .,-
.,-
-,.
.. ..
.. ..
.,-
.,
-'
-'
-'
--
..
c, cytopla~ C03(01)'. restricled to C03&: " T<eII receptor 'l'6: 'IIi, a rJIfIOriIy of cases expresses the o;fI T-ceHreceptor. " cose is exprMSed in Iha moIlO1'lOI"phic t)1Itt of
EAR 0( Type II: " , EBVis Ibsenl in neoplastic cess. but is nearly always present in a subpopuIabon of backgrourld 8-ceIs; . , PTCl. OOS is 001 a Slrg\e disease, buI a hettrOgenttOUS group, andItlefelore, a vanety of imml.flOPhenotypic proftles canbe seen. A, a subset of PTC,l. NOS Ire 0&riVed !rom loIicuIar helper T-eels FH), and often express CDS7, COlO and BCl6: TPLl , T~ proIymphocytic leukaemia; T-LGl, T<eIIlarge gra1u!af lymphocyllC leukaemla; ATLl, adiJft T-<;8" leukaemia/lymphoma: AggNK,
aggressive NK-cel leukaemia, ENKIT-nasaltype. Mranodal NKfr-telllymphoma, nasa~lype; EATL, enteropathy-associated T-eelIlymphoma; HSTl. hepatosplenic T-ceH
lyrrloma: SPTCL, subcutanlC!JS panl'licu~tis-li ke T-een Iymptloma; MFISS, mycosis tungoides and sezary syndrome: primary cutaneous COJO+ lPD, primary cutaneous
CD30+ T-<;elI lymphoproll!erative disease, including primary cutaneousanaplasticT-cell lymphoma: AlLY. ang'oimmunoblestic T-ce~ lymphoma: PTLC, NOS, periphlfa! T-cell
lymphomas, nototherwise specified: ALCL, anaplastic large cel lymphoma. 00, granzyme B; Per, perforin,
rr
play an imp ortant role in preven ting autoimmunity. Tregs exp ress high den sity
CD25, and the tran scription fact or
FOXP3, in com binatio n w ith C04, Adul t
T-cell leukaem ia/lymphoma (ATLL), ha s
been linked to Treg ce lls b ased on expression of both C025 and FoxP3 , and
this finding helps to explain the marked
m munosuppression associated with ATLL
11862A1
Recent studi es have tried to relate the
pathological or c linical manifestati ons of
t -een lym phom as to c vtokme or onemokine expre ssion by the neoplastic cells, or
accompanying ac cessory cells w ithin the
lymph nod e . For exa mple. the hypercalcemia assoc iated with ATLL has be en
linked to sec retion of fact ors with osteoClast-activating ac tivity 1664, 13581. The
haemophagocytic synd rome seen in scme
T-cell and NK-celt ma ligna nc ies has bee n
associated wit h sec retion of both cy tokines and c herno kmes . in the selt ing
d efect ive cytolytic function (737 , 12761.
Geneti cs
Seve ral ma ture B-cell neopla sms have
characteristic genetic abn ormalities tha t
are impo rtant in determining their biologi c
features and can be useful in d ifferential
d iagnos is . These includ e the t( 11:14) in
mantle c etl lymphoma, t(14 :18) in follicu lar
lymphoma, 1(8 :14) and var iant s in Burkttt
Iymphana, and 1(11:18) in MALT lymphoma
1515 ,1 104, 12851. The 1(11;14) is seen in
both mantle c ell lymphoma and a fraction
of c ases of pla sma cell myeloma, but
mino r differences in the tra nslocation
exist , invol ving d ifferent portions of the
irnrronoglobu lin heavy chain gene (IGHO)
(1991. The most common paradig m tor
trans locations involving the IGHtlon 14q ,
r-cea
163
.CLLlSLL 12%
Primarymed large B-cell 3"A:
High Grade B. NOS 2.5%
Burkitt 0.8%
but also can be seen rarely in mature lymphomas l451A, 675A, 88DAI.
Genetic features are playing an increasing ly impo rtant role in the classification of
lymphoid malignancies, and for manyofth:l
small 8-celllymphomas and leukaemias,
recurren t genetic alterations have been
identi fied. However, the molecular pathogenes is of most T-cell and NK-ceillymphomas remains unknown,Genetic studies,
in pa rticu lar PCR stud ies of IGH@and
Teen recep tor (TCR) gene rearrangements and fluorescence insituhybridization
(FISH), are valuable diagnostic tools,both
for determinat ion of clonantv in 8-ce ll and
T-cell proliferations (aiding in the ditteren.
tial diagnosis with reactive hype rplasia),
and in identifying translocations associated with some disease entities,
The WHO class ification emphas izes the
impor tance of knowledge of clinical leateres, both for accu rate diagnosis, as well
as for the definition of some diseases,
such as margina l zone lymphoma of
MALT type versus noda l or splenic marginal zone lymp homa, mediastinal large
B-celilymphoma versus DLBCL, and roost
mature T-cell and NK-ce ll neoplasms.
Diagnosis of lymphoid neoplasms should
not take place in a vacuum , but in the
context of a complete cl inical btstorv
Lymphoid malignancies range in their
cl inical behaviour from low grade to high
grade, Howeve r, within anyone entity a
range in clin ical behaviour can be seen
Moreover, histological or clin ical proqressian is often encountered during a patient's clin ical co urse. For these reasons,
the WHO class ification does not attempt
to stratify lymphoid malignancies in terms
of grade . Both morphology and immunephenotype often change over time, asthe
lymphoid neoplasm unde rgoes clonal
evolution with the ecqutstion of additional
genetic changes , In addition, evolution
over time does not necessar ily lead tothe
develop ment of a more aggress ive lymphoma, For example, patients with DLBCL
can relapse with a more indo lent clonaity
related follicular lymphoma, Some of these
clonal evolutions can be unexpected and
not obv iously connected, such as the development of a plasmacytoma in a patient
with CHl [1042B).
Traditionally,classical Hodgkin lymphomas
(CHL) have been considered separately
from so-called "non-Hodgkin lymphomas'
However, with the recognition that CHL is
of B-cell lineage, grea ter overlap has
been app reciated between CHL and
lym~ AlK .
55",
allog raft rejection or graft versus host d isease (GVHD) and primary immun e defic ienc ies. Some autoimmune diseases are
also assoc iated with an inc reased risk of
lymphoma, pa rticu larly B-ce illymp homas
in patients with lympboepithelial sraraoentis or Hashimoto thyroiditis 11114, 11161.
Mutations in genes con trolling lymphoc yte epo ptosfs have been linked to a risk
for both autoimmu ne d isease and lymphoma (ma inly B-cell types). Patients with
the autoimmu ne Iymp hop roliferative syndrome. wh ich usua lly is ca used by
ge rmline muta tions in FAS, have an inc reased risk for a-cer lymp homas and
Hod gk in lymp homas 12108). Somatica lly
acquired FAS gene mutations also have
bee n reported in some spo rad ic B-cell
lymp homas, most co mmo nly marg inal
zone lymphomas 1855). Recen t stud ies
employing mo lecula r epidemiology have
identified pol ymorp hisms in a number of
immun ore g ulator y genes that appear to
impa ct both risk of lymphoma and prognosis within a patient cohort l359A.
1248A , 2358C) . Molec ular ep idemiology
is a relatively rec ent area of investigation
and more data will be accumulated in the
com ing yea rs. For example , a recent
stu dy foun d incre ased risk associated
with polymorph isms in certain drug
metabol izing enzymes 116A}.
Mature T-c ell and NK-c eil neoplasms are
Introd uction and overv iew of the c lassificat ion of the lymp hoid neoplasms
165
a-cens.
Conclusion
The multipa rameter app roach to classification adopted by the WHO classification
has been validated in international studies as being high ly reproducible, and enhancing the interpretation of clinical and
translational studies. In addition, accurate
and precise class ification of diseaseentities facilitates the discovery of the molecular basis of lymphoid neoplasms in the
basic science laboratory151, 1034, 1525A1.
I
I
i
I
I
l
B lymphoblastic leukaemia/lymphoma,
not otherwise specified
Definiti on
B lymphoblastic leukaemia/lymphoblastic
lymphoma is a neoplasm of precursor
cells (lymphoblasts) corrmined to the Bcea
lineage. typically composed of small to
medium-sized blast cells with scant cytoplasm. moderately condensed to dispersed
chromatin and inconspicuous nucleoli,
involVing bone marrow (BM) and blood
(8 acute lymphoblastic leukaemia/ALL)
and occasionally presenting with primary
involvement 01 nodal or extranodal sites
M .J, Borowi tz
J ,K ,C. Chan
Sites of involvement
By definition, BM is involved in all cases
c lassi fied as B-AL L, and PB is usually
invol ved. Extramed ullary invo lvement is
frequent. with parti c ular pred ilect ion for
the c entral nervous system , lymph nod es,
spleen. liver and testis in males. The most
frequent sites of involvement in BL BL are
th e skin, soft tissue, bo ne and lymph
nodes 1202, 1310, 13671- Med iastinal
mass es are infreq uent {202, 1367, 19281.
Clinical features
Most patie nts with B-ALL presen t with
evidence and consequences of BM failure: throm bocytopenia and/or anaemia
and/or neutropenia, The leukocyte count
may be decr eased , norma l or markedly
elevated, Lymphadenopathy, hepatcmegaly
and splenomegaly a re frequent. Bone
pain and arIt1ralgias may be prominent. Patients with B-LB L without leukaemia are
usually asymptomatic , and most have limited stage disease. Head and neck presentations are particularly common,
especially in children. Marrow and PB involvement may be present . but the
Genetics
Antigen recep tor genes
Near ly all cases of B-ALL have clonal OJ
rearrang eme nts of the IGH@gene. In ad d itio n, t-een recepto r gene rearr angeme nts may be see n in a sig nifican t
proportion of c ases (up to 70%) 122941so
that these rear rangements are not helpful
for lineag e assignmen t.
Ft;. 9.03 B~sbc lymphoma, A Skin, The ~Iic cells diffusely infiltrate the dermis -Mlh sparing of theepidermis. B Samecase aI h p magnification shows ~
SI.mU'ldW'9 a blood vessel.
169
:
B
..
Fig. 9.04 IrIcnIased haemalcJlp'le$ A Bone marrow sedJon . B Bone marrow smear In::m an et;;rt year.Qd male.
showing tympnoid eels with I high nucIeaIlcyqJlasmicratio and hcm:lgeneou$ nudear dlromaW1; nucleoli . . not
observed or areindl$1lllCl These cells resemble!he ~ in All 01 dtilood.
170
r~
113671.
B lymphoblastic leukaemiallymphoma
with recurrent genetic abnormalities
BLymphoblastic
leukaemiallymphoma with
~9;22)(q34;q 11 2); BCRABLt
Oefrlition
Aneoplasm of Iyrnphoblasts corrmitted to
lhe e -cen lineage in whic h the blasts
harbour a trans location be tween the BCR
gene on ch romosome 22 and the ABL 1
oncogene on ch romosome 9
ICD-O code
The provis ional co de prop osed for the
fourth ed ition of ICO-O is 98 12/3.
Epidemiology and cl inical features
Presenting features are generally similar
to those of other pat ient s w ith B-All.
BCR-ABL 1 associated ("Ph . -) All is
relatively more common in adults than
Children, accounting for about 25% of
adult All but only 2-4% of childhood
All. Most chil dren with Ph. B-All woul d
be consid ered "hig h risk " b y sta nd ard
age and white b lood ce ll (WBC) feat ures,
but there are otherwise no cha racteristic
docalf indings Though patients with t(9;22)
BAl l may have organ invo lvement. lymphomatous presentations are rare
and cytochemistry
MoJ. Borowitz
J.K.C. Chan
B Lymphoblastic
leukaemiallymphoma with
t(v;11q23); MLL reafT8t1ged
Definition
A neoplasm ol lymphoblasts ccmm ined to
the B lineage that harbours a transl oca tion between the MLL g ene at band
t 1q23 and anyone 01 a large number of
differe nt fus ion pa rtne rs. Patien ts with
leukaemias that have dele tions of 11q23
w ithout MLL rear rangemen ts are not incl ud ed in trns group ,
ICD-O code
The p rovis iona l code proposed for the
fourt h ed ition
is 981313
Etiology
Wh ile the specific et iology of leukaemia
with MLL transJocations is unknown . this
translocation may occur in utero. with a
sho rt latency between the transloca tion
and dev elopment of d isease , Evidence
for this inc lud es the fact that these
leu kaemias are frequ ent in very young
infants, as well as the fact that this translocation has been identified in neonatal
b lood spots of patients who subsequently
develop leukaemia {7451.
oucn-o
171
Genetics
Fig, 9.07 B tymphoblasbc le ukaemia~ym phom a with MLL reerrarqement FISHstudy usingan MLL breekapa rt probe.
The normal MU gene"MLL(11q23)"appears as ajuxtaposed red and green, Of sometirnas yellow signal, The trensJocatioo is demonstrated by separation of theredandgreen probes r MLLsp") (Cocrtesy of Or AJ carroll)
B Lymphoblastic
laukaemlaJlymphoma with
1(12;21)(p13;q22);TEL-AML 1
(ETV6-RUNX1)
Flg.9 .08 B tymphoblastic leukaemialtymphoma with1(12;21) (p13:q22); TEUAML 1 (ETV&-RUNX1) FISH study using
a red probe against RUNX1 and a green probe against ETV6. The normal genes appear as isolated red or green
signals, wMe evcerce of the fusion gene (arrows) appears asa yelklwsignal, (Coortesy of Or. AJ carroll).
Definition
A neoplasm of Iymphoblasts committed to
the B lineage with a translocation between
the TEL (ETV6) gene on chromosome 12
with the A ML 1 (RUNX 1)gene on ctecrcsome 12.
ICD-O code
The provisional code proposed for the
fourth edition ol lCD-O is 98 14/3.
Epidemiology and clinical features
This leukaemia is common in chiklren
accounting lor abou t 25% of cases ~
B-ALL It is not seen in infants and
decreases in frequency in older children
to the point that it is rare in adulthood.
Presenting features are generally similar
to those of other patients with ALL
.'
..
Imrru1ophenoIyp
Basts have a C019+ , C010+ phenotype
and are most often CD34+; other phenotypic features. includ ing near or complete
absence of COO, C020 and CD66c 1245,
533,9851. are relatively but not absolutely
specific. Myeloid-associated an tigens.
especially CD13, are frequently expressed,
but this does not indicate mixed phenotype acute leukaemia 11551.
Genetics
The t(12;21)(p13;q22): ETV6-RUNX1 translocation results in the p rodu c tio n of a
fusion prote in that likely ac ts in a dominant negative fashion to interfere with
normal func tion of the transcri ption
factor RUNX1. This leukaemia appears to
possess a unique gene expression
signature 12469 1. The E1Y6-RUNX1 translOCahon is co nsid ered to be an ea rly
lesion in leukaemog enesis, as evidenced
by studies of neonatal blood spots that
have shown the presence of the translocation Il'l child ren who develop leukaemia
many years later 124001. There is evioeoce that the translocation is necessary
but not suHicient for the development of
leukaemia 12400 1.
Postulated normal counterpart
This leukaemia appears to d erive from a
Been progeni tor rather than from a
naematoooetrc stem cell 13441
Prognosis and predictive factors
B-Al l with the TELAML 1 transloc ation
hasa V8fY favourab le prog nosis with c ures
seen in >90% of c hildren, espec ially if they
have other favo ura ble risk factors. Relapses often occur muc h late r than those
at other types of ALL. Beca use this
translocation appears to occur as an early
event, it has been sug gested that some
laterelapses in fact de rive from pe rsistent
"preleukaemic clones that ha rbour the
lI'ansIocalion and unde rgo ad ditional
genetic events afte r the first leukaemic
cICIIe has been eliminated 17191 Ch ildren
"MIh this leukaem ia who also harbour adverse prognostic factors . such as ag e
ewer 10 years or high white count d o not
have as good a prognosis, b ut may still
lare better as a g roup than other
patients with these same adverse fac tors .
"
"
"
... ..
"
..
..
. .~
"
,>4
"
!!'
r'
f,
"
Fig. U9 Hyperdiploid ALL. G banded karyotwe stlowlng 55d'll'omosomes. indudlng trisomies of 4. 10 and 17and
kltrasomy 2t. Thefe are nostruc:llnl abnor'malitJes. (Courtesy of Dr. AJ carrol).
B Lymphoblastic leukaemia!
lymphoma with hyperdiploidy
Defi nition
A neoplasm of Iymphoblasts comm itted to
the B lineage whose b last s c ontain >50
and usually <66 c hromosomes, typically
withou t uansiocanons or other struc tural
a lterations . There is controversy as to
whet her specific c hromos omal ad ditions.
rather than the specific numbe r of c hromosom es. should be part of the def inition
1894. 1806,21231.
ICO-D code
The p rovisional co de pr op osed for the
fourth edit ion ofICDD is 981513.
Synonyms
Hype rdi ploi d ALL; high hyp erd iploid ALL :
ALL with favo urable trisom ies.
Epkl_
Irrm.mophenotype
Blasts are C0 19 +, C01O+ . and expre ss
other markers typi cal of B-ALL Most
c ases are C 0 34 + and C045 is often
ab sent 19851. Patients with T-ALL with
hyperdiploidy should not be considered
part of this group, though most such
patients have near tetrap loid karyotypes.
Genet ics
Hyperd iploid B-Al L contains a numerical
increase in chromosomes. usually without
struc tural abnormal ities . Extra co p ies of
c hromosomes a re non random. with
ch romosomes 21, X, 14 and 4 being the
most co mmo n and ch romosomes 1. 2
and 3 being the least of ten seen 19151.
Hyperd iploid B-AlL may be detec ted by
standard karyotyp ing , FISH or flow cvtomet ric DNA ind ex 11 40 11. Some ca ses
that appear as hyperdiploid ALL by standard karyotyping may in fact represent
hypodiploid ALL that has undergone
enooreouoncetco. doubling the number
of chromosomes. Specific chromosomes
that appear as trisomies may be more impo rtant to prognosis than the actual
number of chromosomes, with simultaneous trisomies 014. 10 and 17 carrying the
best prognosis 121231.
173
B Lymphoblastic
leukaemiallymphoma with
hypodiploidy (HypodiploidALL)
Definition
A neop lasm of Iymp hob lasts committed to
the B lineag e whose blasts co ntain <46
chromosomes. A stricter definition of <45
chromosomes , and possib ly even <44
chromosomes , more accurately reflects
the clinic al pa thologic entity 115541.
ICD-O code
The provisional code p roposed for the
fourth edi tion ofICD-O is 981613.
Epidemiolog y and clinic al features
Hyp odiplo id ALL accounts for about 5%
of ALL overall, but if the d efinition is
restric ted to those with <45 chromosom es
the figure is close r to 1%. It is seen in both
chil dren and ad ults. although near haploid ALL (23-29 chromosomes) appe ars
limited to ch ildhood . Presenting teamre s
are gene rally similar to those of other pa tents with ALL
B Lymphoblastic
leukaemiallymphoma with
t(5;14)(q31;q32); 1l.3-IGH
Definition
A neoplasm of IymphOblasts comnitted 10
the B line age in which the blasts harbour
Fig. I .10 B IymphoblastJc ~ with l(5;14MQ31:Q32j. Bone manow smear sl'kMng a jXlIl\AbCrId
typicaIlymphobIasls along Wlth I'U'l'l9fOO$ mature eosinophil$. Thegrar.J1e Iislnbubon in some 01 the ~ illJIusual, bullhisis not a consisIenl lactor.
Genetics
The unique characte ristics of this
neoplasm de rive from a functional rearrangement between the fL3 gene on
chromosome 5 and the IGH@ gene on
chromosome 14, resulting in constitu tive
overexoresson of the IL3 gene 18461.
Functional consequences of this rearrangement other than eosinophilia . if
any. are not well understood. The abnormality is typically detected by standard
karyotypi ng ; it can also be detected by
FISH. though app ropriate probes are not
widelyavailable.
Prognosis and predictive features
The prognosis is no! considered to be ditlerent from other cases of ALL. though
there are too few cases 10 be ce rtain .
Blast percentage at diagnosis is not
known to be a pred ictive tacror.
B Lymphoblastic leukaemia!
lymphoma with 1(1;19)
(q23;p I3.3); E2APBXl
(feF3-PBX1)
Definition
This is a neoplasm of lympho blasts committed to the B lineage with a t( 1;19)
uaosrocatron between the E2A(TCF3)
gene on chr omosome 19 and the PBX 1
gene on chromo some 1.
ICD.Q code
The provisiona l co de proposed for the
fourth edition of ICD-O is 981813.
Epidemiology and clinica l features
This leukaemia is relatively common in
chil dren, accounting for abo ut 6% of
cases of B-ALL. It is also seen in adults .
but not at as high a frequency. Presenting
features are genera lly similar to those of
other patients with ALL.
logy
and cylochem;stry
There are no unique morphologic or cytochemical features that d isting uish this
from other types of ALL.
Immunophenotype
Blasts typically have a CD19 +.CD10+
cytoplasmic u (ctJ) heavy chain-positive
ore- e-ceu phenotype. although not all
cas es of preB-ALl have the t( 1:19). This
leukaemia can be suspected even when
cu is not determined as these teukaemias
typ ically show strong exp ression of COO
and lack CD34 , or show very limited
CD34 expression on only a minor subset
of leukaemic cells 12441 .
Genetics
The E2A-PBX1 translocation results in the
production of a fusion protein that has an
onco ge nic role as a transcri ptional activator, and also likely interferes with the
normal function of the transcription factors
175
T lymphoblastic leukaemia/lymphoma
Definition
T lymphoblastic leukaemia/ lym pho b lastic
lymphoma is a neoplasm of Iymphoblasts
committed 10 the t-een lineage . typ ically
composed of sma ll 10medium-sized blast
cells with scant c ytopl asm . moderately
con de nse d to d isper sed c hrom atin an d
inco nspicuous nucleoli, involving bone
marrow (8M) and b lood (T-acu te lymp hob lastic leukaemia, T-AL L) or p resenting
w ith primary involvement of thym us, nod al
or exlranodal sites (T-ac ute lympho blastic lymphoma, T-LBL). By co nvention. the
term lymphoma is used when the process
is confined to a mass lesion with no or
minimal evidence of peripheral blood
(PBl and 8 M invo lvement. With extens ive
8M and PB invo lvement, lym phobl asti c
leu kaemi a is the appropriate term . It the
patient p resen ts w ith a mass lesion and
Iymphoblasts in the 8M. the d istinction between leuk aemia an d lym phoma is arbitrary. Fo r many treatment p rotocols . a
figu re 01 >25% 8 M blasts is used as lhe
threshold lor defining leukaem ia, In contrast to myeloid leukaemi as. mere is no
agr eed -upon lowe r limit lo r the pe rcentag e 01 blasts req uired to estab lish a d iag nosis 01 ALL In genera l, the d iag nosis
should be avoided wh en there a re <20%
bla sts,
ICD -D cod e
The p rovisional co d e p ropo sed l or the
fourth ed ition of ICD -Q is 983713.
Epidemiology
T-ALl comprises abou t 15% 01 c hild hood
ALL; it is mo re common in adolescents
than in younger c hild ren and mo re
common in ma les than in females . T-ALl
comprises ap prox imat ely 25% of cases
of ad ult ALL T-l Bl comp rises approximat ely 85-90% of all lymphoblastic
lymphOmas; similar to its leukaemic counterpart , it is mos t freq uent in ad olesc ent
males but may be seen in any ag e group.
Etiolog y
One study repo rted T-ALL in monozygotic
twins that share the same
rece ptor
ge ne rearra ngement 17201. sug gesting
t-een
176
on
M .J. Borcwttz
J.K.C. Chan
_~",1
Fig. 9.11 T-lymphoblasticleukaemia, A Blood smear. The Iymphobla sts varyinsize from large cells tosmall cells with
a very highnuclear/cytoplasmic ratio, B Bone marrow section.
Mar_
The Iymphoblasts in T-AlL..A..8 L are morp hologi cally ind isting uishab le from those
of 8 -AlLJL8 L. In sme ars, the c ells are
of med ium size with a high nuclearl
cytopl asmic ratio; there may be a co nsid erable size range from small !ymphoblasts
occa-
FlO- ' .12 T/ynllI'lObIaStic 1'fnllhOma. A low ~tion 01 a tyn'4lh rode ~ ~ repIac:ement by ~ 1ympI'loma. Nwerous IrIgibIe 00dy rnacropnages ll(ll
scauered fYoul1IOul the rode. B H9'I rnagM:atlorl ol lhe specimen lin (A) s/'JcJwWlg ~ WIltI I'llUI"d tooval to ~-s/'Iaped nudei withdisperse(l etvorna!Jn a"d lisra bul nollllUSUaly PfOIl'W*'Il ru:W. 5eYeraI nvloIic ligIns en preset'(
T lymphoblastic leukaelTllaJlymphoma
177
lowmagriflcabon
178
__________________________----'1
-. - &
'
~.
C HAPTER 10
Mature Bcell Neoplasms
,"
.....
Bur1<itt Iymphome
B-ceillymphoma. unclassifiable, with features intermediate between
DLBCL and Bur1<itt lymphoma
B-celllymphoma. unclassifiable. with features Intermed iate between
DLBCL end classical Hodgkin lymphoma
H.K. Muller-Hermelink
E. Montserrat
D. Catovsky
E.Campo
NL Harr is
H. Stein
Defi nition
Chronic lym phocytic leukaemia/s mall lymphocytic lymphoma (C Ll/SLL) is a neop lasm com posed of monomorphic small,
round to slightly irregular B lym phocytes
in (he peripheral blood (PS) , bone marrow
(8 M), spleen and lymph nodes. admixed
with pro lymphocytes and parammunoblasts forming proliferation centres in
tissue infiltrates.The CLUSlL ceus usually
coexpress COS and CD23. In lhe absence of extramedullary tissue involvement. there must be ~5x l ()91l monoclonal
lymphocytes with a ell phenotype in the
PB. The intemanoret Workshop on Chronic
Lymphocytic Leukemia (IWell) report
requ ires that the lymphocytosis be p resent for at least 3 months and also allows
for the d iagnosis of eLL to be made with
lower lymphoc yte counts in patien ts with
cytopenias or disease-related symptoms
1873AI. Whethe r patients who would have
fulfilled the Criteria In the past for Cll but
who luHili the criteria only for monoclonal
B lymphocytosis (MBl) are better considered 10 have low stage Cll or MBl
remains to be determined. Some may
prefe r to sun consider many of these
cases more like Cll.
The term Sll is used for non- leukaemic
cases with the tissue mor phology and
immunophenotype of Cll. The IWCl l definition of Sll requi res lym phad enopathy,
no cytopen ias due to BM infiltration by
Cll./Sll and <5x 1CP/l PB e-ceus [873AI .
ICD-O code
9823/3
Epklemiology
Cll is the most common leukaemia of
adults in Western countries . The incidence
rate is abon 2-6 cases per 100,OCO person
per year, increasing with age reaching
12.81 100,000 at age 65 , the mean age at
diagnosis 11888]. It is now diagnosed more
often in younger ind ividuals 15251. e l l has
a male:fema le ratio of 1,5- 2: 1. CLUSll
accounts for 6.7% of non-Hodg kin lymphomas in biopsies (5 11. It is very rare in
far Eastern countries. This low incidence is
maintained in migrant populations speaking in favou r of a genetic predisposition.
180
Etiology
B-ce ll recep tor s (BCR) of Cll ce lls
demonstrate high ly selected immun og lobulin heavy c hain variab le (lGH V) gene
usag e or even very simila r entire antigenb ind ing sites, coded by both heavy and
lig ht chain genes, and thus d iffer from the
much b roa d er diversity found in normal
B lymphocytes. These findings argue in
favour of a limited set of (auto-)antigens
promoting div ision of precursor cells and
clonal evolution 1423, 1153,22431 .
Sites of involvement
Peripheral blood and BM are usually
involved, lymph nodes, liver and spleen
are also typ ically infiltrated, and other exiranoda l sites may occasionally be involved.
Rarely, patients with ClllSLl present with
aleu kaemic tissue involvement, but usually develop BM and PB involvement during the evolution 01 the disease.
Clinical feature s
Clinical features are very variable including
presentation, co urse and outcome. Most
p atients a re asym ptoma tic, bu t some
presen t with fatigue, autoimmune haemolytic anaemia , infections, sple nomegaly,
hepatomegaly, lymphadenopathy or extranodal infilt rates 1221 , 18051. A small
M-eomponent may be found in some patients .
~.
"""'" .
". C'
'\30''''''
~......
s l
..
~.'"
Fig. 10.01 AALymph node in'o'Olved bydllooic ~ leukaemja, showing regulartyspacedproliferation centres
in a dar1l background (Giemsa stain). B High mllQflilicatiorl ilIustrabng a mixture of small lymphocytes with sen
C'r'JPIasrn <r'ld clrrl>ed dYomattn. SOOlasIig1Iy larger ~ wiIIllTO'e disper$ed cMmabn and small ~
and single paralnwnunoblasts (arrows), lIIrtlidl are larger cells WIth I'OIJnd to oval nudei, dispersed chromalJn and a
""""-
-logy
18l 3AI
lmmunophenotype
Using flow cytometry, the tumou r cells exp ress dim surface IgM/ lgD, C020, C022,
COS, C019, C079a, C023, C043 and
Co 11c (wea k). COlO is negative and
FMC7 and CD79b are usually neg ative or
weakly expresse d in typical CLL. The immunop henolype of PB lymphoc ytes has
been integ rated into a scoring system that
helps in the differential diagnosis between
CLL and other B-c ell leukaemias 1t 430,
151 11 , In tissue sections. cy toplasmic Ig
may be detectable, and cvcun 01 is negative 12508 1; howeve r cvcnn 0 1 has been
detected in cells of the proliferation centres 116141. Some cases may have an
atyp ical immunep henotype (e.g COS- or
C023-, FMC7+ or C01 1c+, strong slg , or
C079b+) 1492 ,14291 .
Genetic susceptibility
CLL has the highest genet ic pred isposition of all haernatologic recotases. A family predisposition can be documented in
5- 10% of patents with CLL based on finding 2 or more cases in the same family.
The overall risk is 2-7 times increased in
181
Genetics
Antigen receptor g enes
IG genes are rearranged with 40- 50% of
Unmutated VH
80'10
65"4
84'4
50"4
26'Il.
iTriSOmy 12
11qdeleIIon'
15"4
4%
19"4
271i.
17p~'
3%
7"4
10"4
35'4
Abemtion
cmaI aberTMon&
~ 3q ~.
Isolaled 13qdeleIO'l'
17por 11qdelebon'
n:168 (56'1l.)
(8'Il.
182
Fig. 10.05 Aow t)'1omeIJy detection of ZANO in ClL. The left pIol shows \tie selecbon of the ~
subpopWbons ac:etlIding to the ~ (T-<:eIs in dar1l blue. NK<eIII iI'llight blue. CI..L cells iI'lllf'llllge and resdJaI
normal B-cells n grey). The CLl cellsate C05+ (see n left plot) arw:l CD19+ (seen II otherpIols). The plotin !he centrll shows a CLl wilh noIN'70 expression (2".4 positive CI..L cells) and the plot on the right a CI..L with t9 ZAP70
e.pression (65% positive CLlcelli). CLl cases with mote than 20% ZAp70 e~ are usuallyconsidered as
positi ve.
B-cell prolymphocytic leukaemia
Definition
B-cell prolymphocytic leukaemia (B-PLl)
is a neoplasm of B prolymphocytes affecting the pe ripheral b lood (PS ), bone
marrow (8 M) and spleen, Prolymphocytes
must exceed 55% of lymphoid cells in the
PB, Cases 01 tran sformed ch ron ic lymphocytic leukaemia (ell). ell with in
creased p rolymphocytes and lymphoid
prQifefationS with rela~ smlar m0rphology bu t carrying the t( 11;14)(q13:Q32)
translocation are ex cluded.
IC().() code
983313
Epidemiology
B-PLl is an extremely rare disease, com prising approximately 1% 01 lym p hocytic
leukaemias. Mos t pa tients are over 60year-old . with a median age of 65-69 and
similar male.temale distribution 11456 1.
Sites of involvement
The leukaemic cells are found in the PB,
8M and sple en .
Clinical features
Most pat ients present with B symptoms,
massive sp lenomeg aly wi th abs ent or
minimal per ipher al lymp had eno pathy,
and a rapid ly rising lymphoc yte count,
{11941.
Mo<phology
Peripheraf biood and bone marrow
The majority ( >55% and usually >90%) of
the circulating cells are prolymphocytes
-medium-sized cells (twice the size of a
lymphocyte) with a round nucleus, moderately condensed nuclear chromatin. a
prominent central nucleolus and a rela tively small amount of faintly basophilic
cytoplasm 1750 . 1456 1. Although the nucleus is typically round . there may be
some ind entation in some cases. The 8 M
shows an interstitial or nodu lar infiltrate of
nocieotateo cells with an intertrabe c ula r
d istribution.
Tissues other than bone marrow
The morpho logy of B-Pl l in tissues is not
we ll know n since pr evious histolog ic al
studies have inc lude d cases with the
t(11; 14) transloc ation that co rrespon d to
leu kaemic variants of mantle cell lymphoma (MC l ) 11892.1963). The sp leen
shows expanded white pulp nodul es and
red pu lp infiltrat ion by intermediate to
large ce lls with abu ndan t c ytoplasm and
irregu lar or round nuclei with the presence
E. Campo
0 , Catovsky
E. Montserrat
H ,K , Muller-Hermelink
N.L. Harris
H . Stein
15421
Ge netic s
Antigen receptor genes
Immuno g lo bulin genes are c lonally rearranged with an unm utated heavy chain
ge ne in ab out half of the c ases. All B--PLL
--
'
.~
183
the progressive course and relative treatment resistance of B-PLL. FISH analysis
detects deletions at 13q14 in 27% of the
cases 15421. Trisomy 12 is unconvnon
15421.
164
Definition
Splenic marginal zone lymphOma (SMZl)
is a Been neoplasm composed of small
lymphocytes which surrCM.Jnd and replace
the splenic white pulp germinal cen tres ,
efface the follicle mantle and merge with
a peripheral (marginal) zone of larger
ceus includ ing scattered transformed
blasts: both small and larger celts infiltrate
the red pulp . Splenic tater lymph nodes
and bone marrow (8M) are often invotved :
lymp homa cells may be found in the peripheral blood (PSI as villous lymphocytes
ICD-Ocode
9689/3
Synonym
Splenic lymphoma with circulating villous
lymphoCyte s (SLVL).
Epidemiology
SMll is a rare disor der, comprising less
than2% of lymphoid neoplasms 179}. but
it may accoun ttor most cases of otherwise unclassifiable ch ronic lympho id
J'-
P. G. Isaacson
M .A Piris
F. Berger
S,H. Swerdlow
C, Thieblemont
S, Pillaluga
NL Harris
........._
~~~_
185
Irrrounophenotyp
1231. Other
Cytogenetic abnormalities
Allelic loss 01 ch romoso me 7q3132 has
been de sc ribed in up to 40 % of SMZL
11 416 1. Oysregulalion of the CDK6 gene
located at 7q21 has been report ed in several cases of SlVL wilh translocations involving this region 14741. Trisomy 3q and
a number 01 other cytogenetic abnorma lities have been described 1319, 766, 859,
929 , 1669llNhile BCl2rearrangement and
t(14 ;18) are absent. CCNDl rearrangement , t(11 ;14) and cyclin 01 express ion
have been reported in a small propoton
01 the cases; however, the possibility that
these cases represent examples of mantle
cell lymphoma has not been excluded,
since c ycnn 0 1 exp ression is absent Irom
weu-cbaractere ec cases of SMZl119451 .
Transloc ation t(1 1; 18), common in extranodal marg inal zone lymphoma of mucosaassociated lymphoid tissue (MALT) type.
is not a leature of SMZL 1575, 18371.
Splenic marginal zone lymphoma has a
specific transcnptooat profile compared
with other B-eell , especially small B-eell
lymphomas. This specific molecular signature includes genes involved in the
signaling cascade of the AKT1 pathway
and B-eell receptor signaling {374. 21971.
Postulated norma l counterp art
B-ce ll of unknown di fferentiation stage,
The prese nce 01 IG gene somatic hypermutations in 50% of ca ses suggests
fig. 10.11 Splenic margI'IaI ZOfIll~ . .. SpIeric!*lr Iymj:tII"IJde s/'loIWIg a nodlNr infillra1e
C High ~ shows a rrU1ured smaI ~ and larger cells.
include a large tumour mass or poor general health status 13741. A clinical scoring
system has been proposed 1721 and
cases with mutated TP53 may show an
aggressive course 18581. The presence of
7q dele tion and unmutated IGHV genes
may be associated with an unfavourable
outcome 123, 22631.
(
Splenic B-eefl marginal zone lymphoma
187
Definition
Hairy ce ll leukaemia (HCL) is an indolent
neoplasm of small mature B lymphoid
ce lls with oval nuclei and abundant c ytoplasm with "hairy" projections invo lving
per ipheral blood (PBl and diffu sely infiltrating the bone marrow (8 M) and splenic
red pulp.
ICD-O code
994013
EpidemOOgy
Hairy ce ll leukaemia is a rare disease.
comprising 2% of lymphoid leukaemias .
Patients are predominantly midd le-aged
to elderly adults with a median age of 50
years ; HCl has been di agn osed rarely in
patients in their 20's, but is exceptionally
unc ommo n in children , The male.ternare
rali o is 5:11642/ .
Etiology
Sitesof involvement
Tumour c ells are found predom inantly in
the 8M and spleen . Typically a small number of c irc ulating c ells are noted. Tumour
infiltrate s may occu r in the liver and lymph
nodes, and oc c asionally also in the skin .
Rare pat ients demonstrate prom inent abdom inal lymphadenopathy, whi ch is associ ated w ith large ha iry cells; this may
rep resent a form of transformation 119991.
.-smears.
K. Foucar
8 . Falini
D. Calovsky
H. Stein
Mor phology
Peripheral blood and bone marrow
Ha iry ce lls a re sma ll to med ium-sized
lympho id cells w ith an oval or indent ed
(b ean -shaped ) nucl eus w ith hom og eneou s, spon gy. g rou nd- gl ass c hromatin
that is slig htly less c lumpe d than that of a
normallyrnphoCyte . Nuc leol i are typicall y
absent or inconspicuous. The c ytoplasm
is abundant and pa le blue , with circumferent ia l "h airy" p rojections on smears
1212, 19991. Occasionally the cytoplasm
contains d iscrete vacuoles or rod-s haped
inclusions that rep resent the ribosom e
lamellar complexes that have be en identified by electron micr oscopy 11999J.
The d iagnosis is be st made on 8M
biopsy. The exte nt of 8 M effacement in
HCl is variab le . The pr imary pattern is interstitialor pa tc hy with some preservation
of fat and naematoporetrc elements . The
infiltrate is c haract erized by wideIy...gpaced
lymphoid ce lls with oval or indented nuclei.
A,B Note 1helyf:icaI ~ fealuresoiciroJlatWlg hairycels ~ the range in nuclear morphology. C There isstrong~
188
Proposed pathogeneticmechanism(s)
Derived fmm I'Nlture memory B-cell. Leukaemic llairy eels diller from
fIOITIIal memory B.oeIls because of altenldeJqll"ession of c:hemolOO8
and adhesiOn I"8ClIJlkn
Inlluenced byo'<'enlllpreSSiDn and consbtuIive ~ of members
of Rho lamit)' of smaI GTPases and ~ oflhe ~ eresspetlfJcmolecule Gas7.
W<aema
~tobMemamlW . ~~
actovaIed integrin ~ and over expres:siDn cJ matIJ-mecaIDpr'oIeinasfI mitIikn.. Down ~ 01 dWll,()Q18 rec:epkn Sl..Id1 as
CCR7 iIl'ldCXCR5e~ absence 01 ~ node ~
"",.""""
Pseudosinus bmalion
Cytochem;SUy
The only cytoc hemical stain utilize d in the
diagnosis is tartrate-resistant ac id phosphatase(TRAP), and this techn ica lly chal lenging cytoc hemic al stain has be en
largely supplanted by immunophenotypic/
immunohistoc hemica l tech niques. If appropriate air-dried unf ixed slide p reparations are ava ilable , vi rtually all cases of
HCL will contain at least some ce lls w ith
strong , granu lar cytoplasm ic TRAP positivity, while wea k staining is not of d iagnostic utility (212, 1999 1.
(hypocelllW Hell
References {157, 348,2235}.
""'-
(TGF~ )
by
Immunophenotype
189
~"
F-'g, 10.16 Huy cellel.taenN. A.S Bone marrow biopsy. Hypoc:eljar ha-y cel leuk.aerlia lIIilhsublIe netsbtIaI ....
lillrcIles(A). lrmuIoperoxidas lor C020 ~ sublIe Ieukaenic: in6Itrates in hypocelUar HCl (B). C Spleen.Red
pulp i1iIlraticI'I lIIilhrunerous red bkxxlcel lal<es, 0 LiwM". Bo8l portal iI1d SinJ5CidaI irI6Ilr.3lion by ~ eelsis presert
Gene tics
Antigen recep tor genes
Although exceptions have been reported .
the majority (>85%) of cases of HCl
demonstrate VHgenes with somatic hypermutation indic ative of a post germinal centre stage of maturation 183. 348, 22351. A
unique feature of HCl is the comm on c oexpression of multiple cronauv related 19isotypes. sug gesting arrest at some point
during lsotype switching (22351.
Cytogenetic abnormalities
No c ytogenetic abnormal ity is specific for
HCl: numerical abnormalities of chromosomes 5 and 7 hav e been de scribed, but
transl ocations are distinctly uncommon
13481
Fig.10.17 Hairy cel leukae!l"ia, iml'T'l.J~ features. A,B,C Bone malfOWbiopsy. AD8A44 positivityothai'y
eels accef1luat nghairy projedlons. B com ~tYity ot hairy cells C Hairy cees express Annexin 11'ttli1e eryttwoid
prew-scn arenegaUve. 0 Uver. Sinusoidal inFiltration byAn!lexinA1-pClSjbve leukaemichairycells.
190
HCl diagnosis 1940 1- Hodgkin and nonHod gkin lymphomas as well as thyroid
cancer pr edominate in these long term
survivors 19401.
M . Piris
K. Fouca r
M . Mollejo
E. Campo
B . Falini
Synonyms
Splenic ma rginal zone lymphoma (SMZL)diffuse variant {1496 1, lym phocytiC lymphoma simulatin g hairy cell leukaemia
116811, splenic B-c eil lymphoma with villous lymphocytes (also used for SMZl
and HCl-vatiant), splenic red pulp lymphoma With numerous basophilic villous
lymphocytes 122621-
fCD-OCOde
959113
Epide miology
Splenic d iffuse red pulp small B-cell
lymphoma is a rare disorder, accounting
lor < 1% of non -Hodgkin lymphomas. It
rep resents about 10% of the B-c eil lymphomas diagnosed in splenectomy spec imens. Most patients are over 40 and
there is no gender bias .
Sites of involvement
All c ases are diagnosed at clinical stage
IV, with spleen, 8M and PB involvement.
Periphe ral lymph node involvemen t is
only rarely repo rted.
Clinical features
Sp lenic diff use red p ulp smal l B-ce Ulymphoma is a leukaemic neoplasm , usually
w ith a relativ e ly low lymphoc ytos is. Almos t all patients have, frequently massive,
sp lenomeg aly. Altho ugh not consistent
among all stud ies, thromboc ytopenia and
leukop enia a re frequently pres ent. while
anaemia has been reported more rarely,
B symptoms are infreq uent. A sma ll group
of these patients show cutaneous infiltration
.". .
_ .. ao
flll.10,18 Sj:IIehc do1luse red pulp smaI fk:elI~. A Peripheral blood cyloIogy wrItl YiIous eel. B Reticulin stairIIog oullinn!he mixed lllfillTation 01 bolh red Pl4I
CllI\'Wl8I'IlS: cordsarwj SinIsOidS. C BentITWTtIW innsilusoidal ldillratlon hiQt6lt4edby C020 Ulrlg
191
192
Definition
The de sig nat ion HCL v encompasses
c ases 01 B c hronic lym phop roliferallYe
d isord ers that resemble cl assic HCl but
exhibit variant "cvroneematotoqc" features (i.e. leukocytosis. pre sence 01
morocytes. cells with prominent nucl~,
c elts with bla stic or convoluted nuclei
andJor absence of ci rcumlerential shaggy
co ntou rs). var iant immunophenotype (i.e.
ab sence of C025, anne xin-A 1, or TRAP)
and resistance 10 conventional HCl ther
apy (r.e . lac k of dramatic respo nse to
claonbme). These cases are no longer
considered to be biologically related 10
HCL
ICD-Q code
959 1/3
Cytochemistry
Tartrate-resistant acid prosoatase (TRAP)
staining is not p resent.
Synony m
Prolymphoc ytic variant of HCL.
Immunophenotyp e
The ch arac teris tic profile is CD20+,
DBA44+, IgG+, Ig D-, Annexin A1-, C025- ,
COS-, C0103-, CD123-, C0 11c-, C01O- ,
C023- P 429 A, 1496, 19221. Ig O+ c ases
can be seen with similar featu res. Others
have rep o rted c ases with IgM+ lgG,
CD103+ an d COt t c- with infreq uent
CDS and C0123 exp ression 122621.
Ep idemiology
Cases of HCL-v account for about 10% of
HCL with an inc idence of approxrrnately
0.03 per l 00 ,CXXl persons per year 118501.
Middle-aged to elderly patients are attecteo and there is a slight male predominance 11431 1. Cases of HCL-v have been
des cr ibed in Asian patients where HCl -v
may be more comroon than HCL 114311.
Genetics
Most c ases seem to harbour a relatively
low load of somatic hypermutation in the
JGHV genes. No bias lor VH1.2 gene has
been seen , as in SMZl. Overrep resentstton of VH3-23 and VH4-34 . as in HCl,
has been reported 122621.
Complex cytogenetic alterations, including
Sites of involvement
Sp lee n. 8M and PB are involved but
hepatomegaly and lym phadenopathyare
relatively uncommon / 143 11. Involvemert
01other solid tissues is rare.
Clinical features
Patient s with HCL-v typically mamfesl
..
""-y
Cytochemistry
Unlike classic HCL, cytoc hemica l staining
for tartrate-resistant acid pnospetase
(TRAP) is weak to negat ive in HCl -v (541.
1431, 18501.
Immunophenotype
Cas es of HClv sha re man y immunop henot yp ic and immunohistochemical
(IHe) features with HCl , although HClv
cells characteristica lly lac k several key
HCl antigens usually includ ing C025.
Anne xin A 1, TRAP-IHC. C0123 and HC2
1670, 1431, 18501. Positive "markers" in
HCLv includ e DBA .44. pan-B-cell antigens. COlle. br ight monotypic surface
imm unoglob ulin (more frequently Ig G ),
CD 103 and FMC711423. 14311.
Genetics
There are no known specific genetic
changes. Some cases demonstrate complex cytogenetic abnormalities involving
t 4q32 or 8Q24 and TP53 deletions
114311.
Postulated norma l counterpart
Activated Been at late stage of maturation.
Prognosis and predictive factors
These patients have an indolent cou rse
with a long survival l ime, even though
patien ts with HCl -v do not typ ic ally
respond to either IFN-a or pu rine nucleoside analogs (oeoxvcotormvcln and
cladrib ine ) !l 850 ). Recent p reliminary
studies sug gest that monoclonal antibody
therapy (rituximab and anti-C022 immunoto xin ) is highly ellective 11850 1 In add ition. good clinical responses have been
achieved with resolution of cytopenias
after sple nec tomy 118501.
193
Lymphoplasmacytic lymphoma
SH. Swerdlow
F. Berger
SA Pilen
N.L Harr is
E.S. Jaffe
H. Stein
..
Definition
lymphopl asmac yt ic lymp homa (LPL) is a
neoplasm of small 8 lymphocytes, plasmacy toid lymp hocytes, and plasma cells.
usually involving bone marrow (8 M) and
sometimes lymph nodes and spleen ,
which does not fulfill the c riter ia for any of
the other small Bccell lymphoid neoplasms that may also have ptasmacytlc
differentiatiOn. Because the distinction be-
tween lPL and one of mese other lymphomas. especially some marginal zone
lymphomas (MZL), is not always clear-cut.
some cases may need 10 be diagnosed
as a small Bceujvmoboma with plasmacvtrc di fferentia tion and a d ifferential diagnosisprovided. Although often associated
with a paraprotein usually of IgM type, it is
not required for the diagnosis, Waldenstr6m
macroglobulinemia (WM) is found in a
significant subset of patients with LPL and
is defined as LPL with 8M involvement
and an IgM monoclonal gammopalhy 01
any concentration (16731.
ICD-{) code
967113
Epldem k>logy
LPL occurs in adults with a median age in
the 60s and a slight male predominance
1581,23371.
Etiology
A familial predispo sition may exist in up to
20% of pa tients with WM {29, 2267f.
These pa tients are diagnosed at a
younger age and with greater 8M involvement .
194
_..
-.
fl9- 10.22 lym~ ~ A Bone marrow biopsy shows a ~ infiltrate """ a PASpo5Itrve Ouk::her body (8fTOW). B The ~smaq1ic I1fi1lrale is alsoseen in ee asptalesme.
Hepatitis C virus (HCY) is associated with
type II c ryoglobulinemia and with LPL in
some but not all series, perhaps related
to geog rap hic d ifferenc es 1534 . 1271,
1450A, 1597 , 1680 , 1791 . 1932,21661 .
Some of the HCV-associated Iymphoplasmacytic proliferations even if monotypic, are non-progressive and others may
be more like chronic lymphocytic leukaemia (Cll) 11506. 23261. Treatment 01
these patients with anti -viral agents may
lead to regression 01 the Iymphoplasmacync proliferations {1434 . 2 1661. Apart
from the role 01 HCY, mast cells may help
drive the proliferation in LPL 122591.
Sites of invol vemen t
Most c ases involv e the BM and so me,
lymph nod es and other extranodal sites.
About 15- 30% of patien ts with WM also
have splenomegaly, hepa tomegaly and/or
adenopathy {5811 Per ipheral blood (PB)
may also be involved.
globulinemiaor IgM-monoclona1gamrT"l()o
pathy of undetermined significance and
only later develop an overt lPl 1370.
1230. 15241.
",.",unophenoIype
Most cells express surface Ig and the
ptasmacvnc cells express cytoplasmic Ig .
usually IgM. sometimes IgG and rarely IgA .
They are typ ically IgD- , express a-conassociated an tigens (CD 19. CD2O, C022 ,
CD79a) and are COS-. CD1o-. CD 1Q3-and
CD23- with frequent but not invariable
CD25 and CD38 expression. Some studies
report more varia tion especially in CD22
and CD23 expression . The p lasm a cells
are CD 138 positive . lack of CD5 in most
bu t not all cases an d the presenc e of
strong cytop lasm ic Ig are useful in the d istinct ion from ClU SLl.
Genetics
Antigen receptor genes
IG genes are rear ranged usually with V
regions that show somatic hyp ermutation
but lac k ongoing mutations (2349). The re
ma y be biased VHusag e 11026 , 1193 ).
l ymphOplasmacytic lymphoma
195
Definition
The hea vy chain d isea ses (HCD) comprise
Nt.. Harris
P G . Isaacson
1 M. Grogan
E.S. Jaffe
Epidemiology
Thi s is a rare d isea se of adults wi th a med ian age of 60 ; approximately 130 cases
hav e been described 1687 , 23521. There
ICD-O code
976213
,
Gamma heavy chain disease
Definition
Sites of involvement
The tumour may involve the lymph nodes,
Waldeyer ring . gastrointestinal tract and
other extranodal sites, bone marrow (8M),
liver, spleen and peripheral blood (PB).
Clinical features
Most patients have systemic symptoms
such as anorexia. wea kness. lever. weight
loss or recurrent bacterial infec tio ns.
Au toimm une manifes tations are found in
about 25% 01 the cases. mostlreq uently
rheumatoid arthritis, but also autoimmune
haemolytic anae mia or thrombocytopenia
or both, va sc ul itis, SjOgren synd rome,
systemic or cu taneous lupu s erythem atosus, myasthenia g ravis or thyroidit is 168 7,
997 . 235 2 ) Autoimmu ne d isease ma y
pre ce d e t he di agn osis of lymphoma
by seve ral yea rs Most pat ients have
~ .
..J!.
...,
Fig. 10.24 Gamma heavy lilain disease. A. This polymorptIous tymphoplasmacytic proIifefabon is coovised 01
admixed plasma cells, plasmacytoid ~es and IympIloid cells. B Immunollistochemistry shows monotypic
staining lor gammaheavy chain,
196
eosoc-
," ""'-
Fig. 10.25 Gamma heavychain oseese. Bone marruw biopsy. ASmall ~les cx:mposed of plasma cells Md tympnoid eels arepreserK. C(ll'I'Ipl'iSing awroxma!ety 5%oflhe
overaI marrow cellularity Some plasma cells appear malin. wtIile others are atypical WJ\h open etwomatin (B). C Immunohislochemital stain shows cytoplasmic IgG
Images COU'leSy of Dr. AJiyah Rallemtula h {1~l
Clinical features
Most patients present with a slowly progressive disease resemb ling chronic 1ymonccvtlc leukaemia Mu HCD differs from
most c ases of Cl l in the high frequency
of hepatosplenomegaly and the absence
of peripheral lymp had enop athy. Routine
serum protein electrophoresis is frequently
Immunophenotype
The cells contain monoclonal cytoplasmic
mu heavy chain , with or without monotypic light chain , express a-cen antigens ,
and are CD5 and COlO negative.
Geneti cs
Immun oglobul in genes are clonally rearrang ed and contain high levels of
somatic hype rmutation (6861. Deletions in
the mu heavy chain gene are presen t that
result in expression of a defective heavy
chain protein that cannot b ind light Chain
to form a complete immunoglobulin molecule 1686, 7291 . These oeienons involve
the VH region and variable amounts of the
CH 1 region , and there may be insertions
of large amounts of DNA of unknown
origin {686)
Postulated normaJ coun terpart
Post-germinal centre B cell which is able
to differentiate to a plasma cell , With an
abnormal mu heavy chain gene .
Prognosis
The clinical course is slowly progressive
in most cases (136. 686, 729. 23501.
Heavy chain diseases
197
-.
A ....
...
...
Fig. 10.27 Serum protem aleclrophoreSlI (SPE) and unne protein eleclrophoreSlS (UPE) in gamma heavy chain
eeeese. It dis1Inc:! bInd .... 1dent1fJed by SPE in Ih8irTIrluIogIotUn region1IIlOdal1o!he panof ongIl (A. IIITOW) The
1ok:oi.4IOi iIMllyped as IgG(t\llnoIed by the bind seen in lhelgG lane). but WIlhout a IXlrT9$pOI'ldin igIt d'\8Wl (0t'Iy
lain: pctyck:Jnal pa1lemS . . . seen in !he kappa and Iam/xIa tales) (A). UPE periormed rewaIedsirrU results , WIth a
broad ITIOIlOdonaI band correspondlllg 10 IgG withoul a rorrespooding lighl chain (B). Repmted from 11540A).
(1ma!;Ies allRlsy of Or. M. .......)
Variab le size
deletio n in HCO
Ant igenbinding
site
light-ehainbinding site:
deleted
in HCD
Complement-
(H ,
(Hl
binding site
eOOH
eOOH
Fig. 10.28Structure ol1heimmunoglobtJIIn rnoilIaMin heavychain disease. Animmunoglobl*1 mollIaM is ~
of two heavy chains (H) and two I9rt chains ll}. which are JOined by d,sulflcle bonds (5-S). The nmnallleavy ellalll
constant region has 3 ronstanl domaill5: CHI is responsible for binding 10 !he li!;.f11chain. CH2 10r binding to
~ and CH3 b' bindI'Ig 10 Fe recepttn. kllhe absence of an associaled (gill d1ain. lhe CH1 domain biIds
to heat-shock J:fCI\8in 78 and U"ldergo&$ ~ degadation; 1l1us. normaI lreeheavychains ae not secreted. In
I1eavy chain dtseases (HCD). ~ deIebons in lhe CHl domail preventboIh bi1dJng a11he heavychain 10
the light diann de\1'adation IIIh proteasane, and free heavy chalns are secreIed VanablHized delebons also
OCXU' inIhe heavy dIain lliversiIy I8giOn (OH). !he heavychain joining region(JH) and the I1eavy chainv.wiabIe rtlgiOn
(VH), COR denoIes COi ' .'ilh'llarily-.deteillil_tg region. a. light dIain const.Tlregion. COOH cartloxyt \emWIal.l
igIt chainjoiWIg region. NIi2 llITW'O lerrrN M:I VLIg1l chainv<wiclbIe region. ReprI1Md WIltI pemis:sicrllrom {154MJ.
(FJP8 QlU1esy cI OrN, M!nhi)
198
Definition
The ter m a lpha heavy chain d isease
(alp ha HCD) has been extensively used
in the liter ature , sinc e many case s are
initially recognized by the p resence of an
abn ormal alpha chain in the serum. However, the term nnmunoorouteranve small
intestinal d isease (IPSID) was adopted by
the WHO in 1978 and will be used here.
IPSID is a variant of extranodal marginal
zone lym phoma of mucosa assoc iated
lym phoi d tissue (MALT), in whic h defective alpha heavy c hains are secr eted ; It is
also d iscussed in the ch a pter on MALT
lymphoma. It occurs in young adu lts and
involves the g astrointestinal tract , resulting in malabsorption and d iarrhoea. tPSID
beg ins as a process somet imes reversible
by antibio tics but may progress to diffuse
large B-ce tl lymp homa (DLBCL ).
EpKlemKllogy
This is the mos t common of the heavy
chain d isea ses. Unlike the ot her HCD,
IPSID involves a young age group with a
peak inc id ence in the second and third
decades: it is rare in young ch ildre n and
older adults, and there is an equa l incidence in ma les and females. It is most
common in areas bordering the Mediterranean inc lud ing Israel, Egypt. Saudi
Arabia and North Africa . It is assoc iated
with low socioeconomic status including
poor hygiene, malnutrition and frequent intestinal infec tions {178 1, 18 12, 1988).
Etiology
Chronic intestinal infec tio n, with Campylobacter jejuni in some ca ses, is believed
to result in c hronic inflammation, a setting
in which neoplastic transformation of a
clone of abnormal 8 cells develops (12641.
Sites of involvement
This disorder involves the gastrointestinal
tract, mainly the small intestine and
mesenteric lymph nodes; gastric and
co lonic mucosa may be involved 1686J.
The 8 M and othe r organs are usually not
invo lved . although rare respiratory tract
involvement is described I1988 J.
Clinical featu res at presentation
Patients typica lly present with ma labsorption, d iarrhoea , hypocalcem ia, abdominal
pain . wasting . fever and steatorrhoea . Because of defective heavy cha in assembly
and con seq uent d iversaty oIlgA molecular
Mo<phology
The lamina propria of the bowel is heavily
infiltrated with plasma cells and admixed
small lymphocytes; marginal zone Bvcells
may be present with formation of lymphcepithelial lesions. The Iymphoplasmac ytic
infiltrate separates the crypts, and villous
atrophy may be present 110 12, 178 1,
18121. Sheets of large plasmacytoid cells
and immunoblasts that form solid , destructive aggregates WIth ulceration characterize progression to DLBCL 16861.
Immunop henotype
The plasma cells and marg inal zone cells
exp ress monoc lonal cytopl asmic alpha
c hain without light chain. Marg inal zone
cells express CD20 and are CDS and
COlO negative; plasma cells are typica lly
CD20 negative and CD138 positive 110 121.
Genetics
Immunog lobulin heavy and light cha in
genes are cioreuv rearranged and contain
high levels of somatic hyp ermutation
16861. Deletions in the alph a heavy chain
gene are present that result in expression
of a defective heavy c hain prote in that
cannot bind lig ht chain to form a complete lmmurcqiobuun mole cu le. These
deletions involve the VH region and CH I
reg ion, and there may be insertions of
199
A.w McKenna
RAKyle
WM Kuehl
T.M. Grogan
N.L. Harris
RW. Coupland
Monoclonal gammopathy of
undetermined significance
(MGUS)
the syndromes ueuneo by the consequence of tissue immunoglobulin deposilion, p rimary amyloidosis (Al) and light
and heavy chain deposition diseases.
The presence in the pe ripheral b lood (PB)
ot a tow leve l of pa raprotein that is be low
the us ual thr eshold for th e diagnosis of
plasma ce ll myeloma may prece de the
development of overt myeloma for a varying time: this phenomenon , kno wn as
monoclonal gammopathy of undetermined significance (MGUS), is also included in this chapter as a precursor
lesion. Other immunoglobulin-secreting
neoplasms that comprise both lymphocytes and plasma cells, including lymphOpiasmacytic lym phoma. Walden strom
macroglobulinemia and the heavy chain
diseases. are d isc ussed in other chapters,
---
Defin ition
MGUS is defined as the p resenc e in the
serum of an M-protein <30 gJ1..., bone marrow (BM) clonal plasma celts <10%, no
end organ damage (CRAB: hypercalcemia, renal insuffic ienc y. anaemia. bone
lesions) and no evidence of B-eell lym phoma or other disease known to produce an M-protein. Although it reflects the
presence or an ex panded clone of immunoglobulin-secreting cells. this process
is not co nside red neop lastic since it does
not alw ays progress to overt malig nancy.
The presence 01 a sma ll IgM paraprotein
(lg M MG US) is associated with a clone of
Iymphoplasmacytic cells that may progress
to a Iymphop lasmacytic lymphoma. and/
or Walden strom macroglobulinemia (WM).
Non- lg M MGUS (lgG, IgA l is associated
with tbe presence of clonal plasma cells,
and may progress to a malignant plasma
cell neoplasm . Although the two forms of
MG US may be id entica l in their clinical
presentation. they have a different genetic
b asis and different outcomes in terms of
malig nant prog ression ,
ICo-O code
9765/1
-""-
~g~y~uooe~
SI\1IIficanc.e (MGUS)
"""'""'"
" '"
Immunoglobulin depositiondiseases
Primaryamyloidosis
Systemic light andheavy cha in
deposrtoo diseases
200
Synonyms
Mo noc lonal g ammopathy, unattnbuted/
unassoctateo : Benign monoclonal gammopathy; Idiopathic paraproteinemia;
Noo-myelomatous gammopathy.
Ep;c'emioiogy
When sensitive techniques of deteclion
are use d, MG US is found in approximately 3% of persons ove r age 50 and in
mo re than 5% of individuals past 70
11232 1. MGUS is mo re common in men
than women (- 1.5:1) and more than twic e
as frequent in Afric an American s as in
Ca ucas ians 11 229 , 12491.
Etiology
No specific cause of MGUS has been
identified, It may be associated with connective tissue disorders, peripheral neurop athies. dermatological, endocrine and
liver d isea ses [ 12291. Transie nt oligoc lonal and mo noc lonal ga mmopa thies
have been described in patient s following
solid organ and 8 M/stem ce ll transplantation /1229. 149 1}.
Sites of involvement
The clonal plasma cells producing nonIgM MGUS are in the 8M ; Iymphoplasmacytic cells that produce IgM MGUS may
be in BM and other sites . such as spleen
and lymph nodes.
Clinical features
Patient s exhibit no symptoms or physical
findings related to MGUS. The typical taborator y and rad iog raph ic abno rmalities
associated with plasma ce ll myeloma are
lacking, The M-p rotein is usually discovered unexpectedly 00 serum protein electrophoresis . Approximately 70% are IgG.
Table 1D.G.(
Oi ll9';lOS ~C
criteria forMGUS
Lblirled m 156}.
both nume rica l and struc tural abnormalitie s in most patients { 113, 430 , 717, 7 18J.
The abnormalitie s in non-lg M MGU S are
the same as those fou nd in myeloma although the p reva lence may d iffer. Iransocations involving the IGH@gene ( 14q 32)
are fou nd in nearly hall of the c ases with
differen t studies showi ng tha t t( 11; 14)
(q23:q 32) is present in 15-25%, t(4 ; 14)
(p 16.3:q32) in 2-9% and t( 14.16XQ32:q23)
in 1- 5% 1113, 7 171. De letion s of 13q are
pres ent in 40 - 50 % of cases of MGU S
compared to 50% of those with myeloma
{717 , 7 18. 11801. It is not clear if 13q deletions sometimes are associated with
progression of MG US (1125, 12291 Hyperdiploidy is o bserved in about 40% 01
MGUS with chromosomal trisomies similar to those in myeloma 14301. No obvious
cl inical correlations are associated wi th
chromosome abnormalities in MGUS bu t
this may refl ec t lack 01 sufficient data
17171. Ac tivating K- and NRA$mutations
are much less frequent in MGU S (-5%)
compared to myeloma (30-40%) 11 821 1.
Although genetic alterations and gene expression patterns prob ably can distingu ish
adv anced myeloma Irom MGU S there are
no uneq uivocal intri nsic differences that
d istingui sh MGUS from myeloma .
noocrease
lUre appearing but mil d changes. inc luding cytop lasmic inclusions an d nucleoli,
areoccasionally observe d.
Irrmunophenotype
Staining tor CD 138 fa cil itat es enumeratio n
of plasma ce lls on 8M trephine b iopsies.
Geretics
Abnormal karyotypes are rarely seen in
UGUS FISH studies have damonstrated
1_.'
. , :-:
< .~
J ;
.~.
' ....
~
Fig.10.30 Plasma cell myeloma. A Gross photograph af thevertebral column. showingmultiple IyticIeSiOOs. filledwith
grey, fleshy tumour. B V&rtebral c:oh;mn after maceration, showingr'r'll; ltiple lytic lesions.
Fig. 10.31 Plasma eel myeloma. low (A) and high lB) rnagMJealions of a bone marrow biopsy. There is
exler\SMl marrow repIacernenI WItllneoplastic plasma eels. The palIem of in'O("Ii l8l ~ is mixed. fIIerstitJal nl loc3.
The plasma eels embil mature Iea!lns WlIh abI.ntaA: ~. eeeenn: Ikldei MltI marse dJromBtrl; II'OSlladc
visible ru:leoI.
201
9732/3
Synonyms
Multiple myeloma: Myelomatosis:medullary
plasmacytoma; Kahler's disease.
Epidemiology
Plasma cell myeloma comprises about
1% of malignant tumours. 10- 15% of
haema topoietic neoplasms and causes
20% 01 deaths from haematologic mauqnancies {1052, 16441. An estimated 2O,(XX)
cases were diag nosed and more than
10,000 patients died of myeloma in the
United States in 2007 110521. Plasma cell
myeloma is more common in men than
women (1.4: 1) and occurs twice as frequently in African America ns as in Caucasians 11844) Myeloma is not found in
children and only rarely in adults less than
30 years of age; the incidence increases
progressively with age thereafter, with approximately 90% of cases occurring over
age 50 and a median age at diagnosis of
about 70 years . The risk of plasma ceu
myeloma is 3.7 fold higher for individuals
with a first degree relative with the disease {2821.
\
Etiology
Chronic antigenic stimulation from infection or other chronic disease and exposure to specific toxic substances or
radiation has been associated with an increased incidence of plasma cell
myeloma {1289, 131 51 . An antigenic stimulus giving rise to mulliple ben ign clones
202
Related organ orlissue impalrment . (CRAB Irypertalcerma. renal nsutfioerq, AfIa6Wia,bone lesions)
Asymptomatic tsmoldeliogj myeloma
M-protein in S6f\J mat myeloma ~vels (>3OgIL)
AND/OR
UonodcI'IaI plasma eels usuaIy exceed 10'% 01 nucleated eels i'llhe marT\1IfI' I:d no!1Onal1eWtl is
designaled because abl:M: 5% 01 pabenls WIth s~tic; myeloma Ilave < 1O"fe manow plasma ceh.
The mo5l impcItantcrilerlalor symptomaoc myeloma aremaru1estalions 0( eod organ damage I1cIudIng
8naen'ia, hypercak::erma.1ytJC bone lesions, renal insu!lioeoty. hypefVlSCOSlfy. amy\Oidosts orl ecurrent
i'llections.
Modified from ,56).
20371
Macroscopy
In plasma cell myeloma. the bone defects
on gross examination are filled With a soft
gelatinous. fish-flesh. haernorrhagic nssce.
Urilr~
SeN M
~- I
I
.
1
~
.\-...!'"<'C.
"
.1>
!::
'--
-.EL
.. ... ....
~
~ . 10.33 Serum and urW1e prolein el8dropholesis and mrudtxalion from a 65-year-old llfl)III(Ifl wrth plasma ~
who presented wrth bact. reo,arv:l peMc PlWl arv:l ge. .... iilized weakness.There was .., t1ypeicaloei'la,
laUe oranaemia; howeYer. a skeletal Sl6'o'9y' I'8'o'eIIed Il'UIipIeIytJc tesions i'I tle sJuA. nbs . peIYis. etaYides, sc:apda
em spI'le_ A bMe marrow biopsy slowed 13%plasma
Pro!er'I eledJophole$iS {ElP) f'YeIled a 31 !J'1- ~
IgGk M-proIein and a 341.4il'9'24 h.1oI'ine M-proIeln. The M-proIeil was il:lenbMd byirmulofiuIial ...... UlNes4
(IFE) as IgG kappa (C<u\esy ofO!1 Frank H. Wtln. ok. arv:l Demis C. Wooten).
..-..
"'"
'*_
203
Morphology
Bone marrow biopsy
In co ntrast to normal plasma cells, which
are typi ca lly found in small clusters
around 8M arterioles, myeloma plas ma
cells usually occur in interstitial clusters,
focal nodules or diffuse sheets 1152, 2881.
There is often conside rable 8 M spa ring
and preservation of normal naernaropoesis. with interstitial and focal patterns
of involvement With diffuse involvement,
expansive areas of the BM are replaced
and haematopoiesis may be markedly
suppressed. There is typically progres o
sion from interstitial and focal disease in
early myeloma to d iffuse involvement in
proliferation and in disting uishing myeloma from other neop lasms. A CD138 stain
is useful for quantifying plasma cells. and
ctonentv can usually be established with
stains for kap pa and lambda light chains
156. 17311
Bone marrow aspiration
The number of plasma cells seen on aspirate smears varies from barely increased to upwa rds of 90% 112261.
Myeloma plasma cells vary from mature
forms indistinguishable from normal 10ifn.
mature , ptasmabiasuc. and pleomofphic
1152.288, 8401 . Mature plasma cells are
usually oval. with a round eccentrc
---
Fig. 10.36 Plasma cel myeloma. cykIlogic features If1 marrow aspirations showing 'o'ariatJon from mature l A-B) kl immature (e ,0) plasma cells. The more mallJ'e ceRs haveckJnped I1UCIe<Ir dlrumatin. abllld1tcytIpIasm. lownuclearcytoplasmic ratiO and only rare nucteoli (Xll'l"'4I3red kl the less mature eels . whiCh havemore prominent nudeoIi, loose
reticular chromatin and a higtlernuclear<ytoplasmtC rabo. 0 P1asmablasts from a p1asmablastic myeloma with
promineot nucleoli. retictJlar chromalln and high nuaear<ytoplasmic rato.
204
,
Fig. 10.37 Plasma cell myeloma. rncwphoIogic vnrG
on ~~_ A So-called Mott c:el MIl
abundant "grape-like" c-,1OPIasmic indo.JSi)ns d
irnml.Jnoglobulin, B Numerous Russel tooes
based
nucleus and "spoke wheel " Or "cloc kface" chromatin without nucleoli . There is
generally abundant basop hilic cytoplasm
and a perinuclear ror. In con trast, immature forms have more dispersed nuclear
chromatin, a higher nuclear/cytoplasmic
ratio. and often, prominent nucleoli. In almost 10% of case s there is plasmablastic
morphology 18401, Muhinueleated, poIylobated. pleomorphic plasma cells are
prCml nent in some case s 11 52 , 2881. BeC8lJSe nuclear immalu rity and pleomorphism rarely occ ur in react ive plasma
cells. they are reliable indicators of neoplastc plasma cells. The cytoplasm of
myeloma cells has abundant endoplasmic reticulum (ER), which may c on tain ,
condensed or crystallized c ytop lasmic Ig
producing a variety of morphologically
osnrcnve hOdi ngs, includIng : multiple
pale bluish-white, grape-like accumulallOl'l (Molt cells, Morula cells), cherry-red
refracnve round bootes (Russell bodies),
~ stalr'Ii"Ig gtycogen-rich rgA (flame
cells). overstuffed fIbrils (Gaucher-like
ceas. thesaurocyt es) and crystalline rods
12881. Other than the presence of crystalline rods, these changes are not
palhognomonic of mye loma since they
may be found in reactive p lasma cells .
In about 5% of cases of symptomatic
myeloma there are < 10% p lasma cells in
ee 8M aspirate smears 1561, This may be
due 10 a sub-optimal BM aspirate or the
frequent focal d istribution of myeloma in
the 8M In such instances, larg er numbers of plasma cells and foca l clusters
are sometimes obse rved in the trephine
biopsy sections, Biop sies d irect ed at
radiographic lesions may be nec essary to
establish the d iagno sis in some pa tients.
Peripheral blood
Rouleaux formation is usually the most
striking feature on PB smea rs and is related to the quantity and type of M-protein.
Aeckoevmrobtasnc reac tion is obse rved
in some cases. Plasma cells are found on
PB smearsin approximately 15% of cases,
usually in small numbers . Marked plasma cytosis eccoroenee plasma cellleul<.aerm.
KK1ney
.. .
COlO
CD20
FIg.1D.38 FlowcyDneIry tMstogams cia bcrle marlOWfrom, pabent WI01 plasma eel ~_ The l'lElq)Iaslic plasma
eels !We painB:! red: normal B~ _ bloe. The myeloma OllIs IlIPf8SS brlljlt C038and arenegatiY8 krano,
C019and COlO. They express CD56 and P<Wtial C045. arenegalI\'e lor surface igt4chains and eqJreSS cytIplasmic
IrmlUnophenotype
Plasma cell myelomas typically have
monotypic cytoplasmic Ig and lack surface Ig. They usua lly express CD79a,
VS38c, CDl38 and strong CD38, simila rly
to normal p lasma cells but in con trast 10
nor ma l p las ma c ells, they are nearl y
always CD19 negative ; CD56 is aberranll y expressed in 67- 79% of c ases
113 12. 1719, 19081. In add ition to CD56,
my eloma plasma ce lls may aberranuy
express CDl17. CD20 , CD52 and CO lO,
in decreas ing o rder of frequency , and
occasiona lly, myeloid and monocytic
ant igens are found (26, 850 ,131 21 Unlike
most myelomas. about 80 % of pl asma
ce illeukaemias are CDS6 neg ative 1757.
1719 , 19081. Some c ases are cy clin 0 1
po sitive , This fin d ing correla tes with the
p resenc e of 1( 11;14)( q13;q32) involvi ng
Ihe CCNDI g ene and has bee n associated with a Iymphopl asmacytic rrorpnologic appearance.
Genetics
Antigen recep tor genes
Immunog lobulin heavy and ligh t c hain
genes are
rearranged. There is a
high load of IGHV gene somatic hypermutation consistent with de rivation from a
post-cerrnmar centre, ant igen-driven
B~II 11341. Immu nog lobu lin gene deletion is sometimes found ; in patients WIth
cloreuv
48
205
Table10.06
Group
Tra n~tion
Primal)'
"""
O-Cytlin
Ploidy
F~qu&IlCy
Progno.i.
transJoc.tion
"'1
6021
CCNDJ
03
HH
3%
eeee
l1q1J
11Q1J
CCNOI
01
O.NH
16%
Go
01
"'"
3"
Go
"'"
"'"
"'"
"'"
"'"
....
01
0 1+02
....
H,NH
11%
? ""
?
HH
'"
01+02
D2
D2
"'"
"'"
"p16
FGFR3IIIMSET
02
NH>H
"'"
16q23
""'"
02
NH
D2
NH
4016
21lq11
",,/8
..
,.
15\
'"
? Go
""
""
""
ce.
206
s....
Criteria
"
"'
Median 5urvival
"moo"
Notstage I orIll"
"There are two calegorie$ Jar stage II: serun ~ <3.5 mgIl.. but seIVIl aItlumi'l <3.5 gll1.: or sen.m
~ 3.510 <5.5 mgIl.. rmpecbwe 01 the sen.rn all\rlWlleYeI.
ModIfIed from (842).
207
Table10.09
Cytogeneticprogoostic groups in plasma cell myeloma.
Unfivotll'lble risk:
9731/3
Epidemiology
Solitary plasmacytoma of bone comprises
3-5% of plasma cell neo p lasms 1561. It is
more c ommo n in men (65% ); media n age
at d iag nosis is 55 yea rs 156, 5821.
Sites of involvement
The most common sites are bones with
active 8 M naema topole sle: in orde r of freq uency , the vert ebrae . rib s. skull, pelvis,
femu r, clavicle and sca pul a 15821. Thoracic vertebrae are mo re commonly involved than cervical or lumbar, and long
bone invo lvement below the elbow or
knee is rare 156. 5451.
Extraosseous plasmacytoma
Definition
Clinical leatures
Patients most frequently present with
bone pain at the site of the lesion or with
a pathological fract ure . Verte bral lesions
may be associated wi th symptoma tic
cord com p ression 15451 . Sofl tiss ue extension may p roduce a pa lpa ble mass
1561. An M-protein is toone in se rum or
urine in 24-72% of patients 156, 582 ,
206 1,24031, In most cases ooivcionar immunoglobulins are at normal levels 1582,
206 11. There is no anaemia, hyperca lcemia or rena l failu re relate d to the plasmacytoma 156 1. MAl is useful to exclude
208
Exuaosseou s (ext ramedul lary ) pl asmacytomas are loc a lized plasma cell neoplasms that arise in tissues o ther than
bone. Lymphomas with prominent plasmac ytic d ifferentiatio n, partic ular ly extranod al ma rg inal zone (MALT) lymp ho ma,
must be excluded,
ICD-O code
973413
Synonym
Plasmacy toma. extramedullary.
Epidemiology
Extraosseous (ex trame d ullary) plasmacytomas constitute 3-5% of aU plasma
cell neoplasms 1221. Two thirds of patients
are ma le; the median age at diagnosis is
about 55 years.
Sites of invo lvement
Approximately 80 % of extraosseoos
plasmacytomas occur in the upper respirato ry tract , incfuding the oropharynx,
naso pha rynx, sinuses and larynx, but
they may occur in numerous other sites,
including the gastrointestinal tract (Gil,
lymph nodes. bladder, CNS. breast. thyroid . testis . parotid and skin 1221. Plasmacytomas of the up pe r respiratory track
sp read to cer vic al lymph nodes in - 15%
of cases 114601.
Clinical features
Symptoms are generally related to the
tumour mass and include rhino rrhoea,
ep istaxis and nasal obs truc tion , Radiographic and morphologic assessments
show no evidence of BM involvement. Approximately 20 % 01 pat ients have a small
M-p rotein, most commonly IgA 156. 20611
There are no c linical features of plasma
cell myelo ma.
Monoclonal immunoglobulin
deposition diseases
Fig. ' 0. t Plasmacytoma showlng absence dCOlO (A) iIfkl expressiorl dCD38IBI_
Primary amyloidosis
Definition
Primary amyloidosis is c aused by a
plasma c ell. or rarely. a Ivmoboorasmacvnc neoplasm that sec retes intact or
frag ment s of abnormal immunog lobulin
light chains, or rarely, heavy ch ains, wtuch
depo sit in various tissues and form a Bp leated sheet structu re (AL amyloid) that
b ind s Congo red dye with cha racteristic
bi refringence 1785, 786, 813, 1157,1225.
19941.
lCQ.O oode
9769/1
Epidemiology
The median age at dia gnosis of p rimary
<myloidosis is 64 years and >95% c:I pa1lE!fltS
are over 40; 65- 70%are male 11 225, 12281.
,...1&...~;:.La ili.&
fig. 10,. 2 Plasmacy1oma. Composrte figufe illuslrates immllooglobulin expression, A Typical plasma cell morphology B CyIoj)Iasmic kappa light chain posdlYity
CAbsenc8 01 lambda \ighl chaindiseaseexpl"llSSion. 0 Expression of cy10plasmicgammahea'IY chain, E.FAbsence 01 mil aridalpha hea'IY chains,
209
",
Fig. 10.43 PlasmaC811 grarUoma. A The "masselJed'oIp1asma cels SOlllates a neoplasm. ~ stamsl'lCM' poIytypiccy1qllasnic~Wilh someplasma
eels 8xpre$$1l'1Q (81 ~ 19l1 cham and somee~ (e) Ianbda i(;Tl d1aons
Clinical features
Clinical findi ngs are usually related to
deposition 01 amyloid in organs, resulting
in >90% of patients with primary amyloidosis and with a combination of immunofixation and serum free light cha in ratio
analysis in 99% 157. 1123 . 12251. Thelighl
chain is lambda in 70% of patients 112251.
Palhophyskllogy
AL amyloid is composed of intact
immunoglobulin light cha ins or rarely,
heavy cha ins that are secreted by m0nocl onal plasma celts and then ingested.
processed and discharged by macrophages into the extracellular matrix . The
accumulated amyloid includes both intact
light chain and fragments of the variable
(V) NH2-terminus region . All tight chain V
region fragmen ts are potentially amylodoqenic. and all plasma cell neoplasms
that produce VAVI have AL 11225 . 1994),
Macrosc opy
On gross inspec tion amyloi d has a dense
"porce lain-like" or waxy appearance,
f ig. 10."
210
Morph ology
Biopsy section s of 8M vary from no
pathologi c findings to extens ive replacement with amyloid, overt myel oma, or
rarely. lymp hopl asmac ytic lymph oma.
The most com mon findi ng is a mild
inc rease in pla sma c ells that may appear
norm al or exhibi l any of the changes
foun d in pl asma cell myeloma 11 2251,
Amyloid is p resent in many other tissues
and organs. In H&E stained sectio ns, it is
a p ink. amorphous. waxy-appearing substance , With a ch aracteristic cracking artifac t. Typically, it is found foc ally In
thic kened blood vess el wans. on basement membranes , and in the mtersmnm
01 tissues such as tat or BM 124331.
Macrop hages and foreign-body giant
celts may be found around deposits
Organ parenchyma may be massively replaced by amyloid (amyloidoma). Plasma
'j'
f,,,
'(;,,<,.
,J ,t-'
I '"
"L
"Ii
I~
~
."
..
;it,,~~..'..a>:L:l...,i'
FIg. 10.45 APrrnaty amyIaIdosIs in a pabetIl withplasma eel myeloma. Grossp/K*)graph of a section of heal1shows !he Iiffuse rilrgement charactefiStlC 01 amyloid deposition,
es;e::.ally III !he left 'tllfllncle. Bone marrow biopsy of pnmary amyloidosis sha.Wng etIaraclerisbc pale. waxy arnotpl'lous deposits (BI and associated hlSbocyte$, otIen
1TUlrIucIea1ed. andneoplasbc plasma eels (C).
Al amyloid from t c o n .
Irrvnunophenotype
The immunophenotypic features of the
plasma cells are simila r 10 lhose of
myeloma , Immunoh istochemical sta ining
of 8M seclions for kappa and lambd a
IigN chains shows a monoclonal plasma
cell staining pattern unless the clone is
IAlsually small and masked by rormat
poIyclonal plasma cells 1675, 2433,
24521 . Staining lor amyloid P componen t
is posmve. Immunohistochemical techniques using anti-amyloid fib ril antibodies
to At kappa and lambda are use lul in distinguishing prima ry and secondary amyloidosis (AA) in some c ases but are
definitive less than half the time {6751. AA
amyloid , however, can be rec og nized by
immunohistochemistry in essentially all
cases (571.
Genetics
The genetic abno rmalities reported ih pr imary amyloidosis are simil ar to those in
rm-lgM MGUS and plasma cell myeloma.
One exception is the unexplained observabon that lhet( 11;14) is p resent in >40%
01 individuals with amyloidosis but on ly
15-20% of those with a d iag nosis of nonIgM MGUS or myeloma 1718. 9121.
1304.5801
Synonym
Randall d isease {18141.
Epid emiolog y
These are rare d iseases of adults (med ian
age 56 years. range 33 -79) which occur
in association with either myeloma (65%
01 cases) or MG US 1304, 1085 , 1776,
1779 1. There is no evidence of an ethnicity effect and the rnale.ternale incidence
is nearly equal{304. 1085. 1779/.
Sites of lnvotvement
lCDD and HCDD may involve many organs . IT'OSl <Xm'T'IOl'lIy the kiOOeys 117761.
The liver. heart. nerves. blood vessels and
occasionally JOints may be involved 1106,
:4,934, 1005,1779,181 4,2433I .Thereis
prom inent deposition of the aberrant 19 on
basement membranes, elastic and cotIagen
fibres . Pulmooary involvement, eitherdiffuse
or nodular. has been reported {214. 18751
Clinical feat ures
Patient s present w ith symptoms 01 organ
dysfun c tion as a result of di ffuse, systemi c imm unoglobul in deposits, usually
manifested by nephrotic syndrome and/or
ren al failure 1564 . 1776 1, Symptomatic extrarenal d eposition in lCDD is unco mmon
and involves the heart (21%). liver (19%)
Progoosi.
The median survival for patients with primary amyloidosis is approximately 2
years trom diagnosis 112281. Patients with
amyloidosis and plasma cell mye lom a
have a shorter survi va l than tho se wit h
amyloidosis or myeloma alone 11225 1.
Plasma ce ll neoplasms
211
. ...
o ."
Pathophysiology
.-
''(5'
,
c:
V1IV1 variable reg ion , LCDD has a prevalence 01 kappa light chains (80%) with
overepreseotatco of the VICIV variable region 13041 Irrmunohistochemistry on 8M
sections may reveal an abe rrant kappa!
lambda ratio 124331.
Prognosis
The med ian ove rall survival lor patients
with LCDD is approximately 4 years.
Prognosis is correla ted with age. the presence of plasma cell myeloma and emarenat lig ht chain depos ition 11462 , 17761.
Synonym
Crow- Fukase synd rome.
Epidemiology
This is a rare disease. occurring predominantly in adu lts, and estimated to c0mprise 1- 2% of plasm a celt dvscrasas
114831. Many cases have been reported
from Ja pan. Men are affec ted slightly
more often than women (M.F ratio 1.41)
and the median age is about 50 years
F~ 10,48 lighI chain depoSlbon disease in kOIeyshowring (A) pale anorphous palttIes IIo'Iltlin gIorroenAi (nodulaf
gIomenJosdetosi) and (81 ~ stain stlowing renalllMar andel1rabbJlar c\epOSlbOn ~ Il.ippa IicJ1l
chain in a smooIh inearpallem.
2 12
15901.
Etiology
An imbalance of p ro-inflammator y c ytokines is common in POEMS syndrome.
Vascular endothelial growth factor (VEGF)
produced by the tumour cells may be responsible for some of the symp toms of
the disease 1634. 23631 . Some cases of
POEMS syndrome . especially those associated with Cas tleman disease, have
been reported to be associated with
hll'laflherpesvirus 8 (HHV8) 1175. 14831
Q inica! teensee
Most patents do not present With all of the
manifestations of POEMS syndrome and
not all are requi red for diagnosis. The
map clinical feature is a chronic pr ogressive polyneuropathy 15901. O rganamegaly is present in at least 50% of
patients and enoocnocoamv and skin
changes each in two-thirds 15901. In
75-85% of patients ther e is a serum
M-protein that is either IgG lambda or IgA
lambda; the quantity is typic ally low (median 1.1 g/d l ) 15901. An M-p rotein is
found in urine in <50% of patients. Relatively c ommon clinic al findi ng s include
edema an d serou s c avi ty effusions, pap illedema, thrombocytosis. weight loss,
fatigue, clu bbinq. bon e pain and arthralgias. Hypercalc emia, renal insufficiency.
and pathological fractures are rare. nacographic bone abnor malities are found in
nearly all cases. These vary from single
sclerotic lesions in about ha" to more than
three lesions in one-th ird of cases 15901_
Morphology
tissue. The 8 M away from the osteosclerotic lesion usually con tains <5% plasma
cells, which are typically normal appearing. In a minorit y of p atients with more
generalized osteosclerotic myelona. > 10%
p lasma cells may be found in random 8M
b iopsies 120581. Two-third s of patients
with lymphadenop athy have ch anges
conserera with the plasma cell variant of
Cesneman's disease 15901.
Immunophenotype
The plasma cells con tain monoclonal
cytoplasmic Ig which may be IgG QII IgA.
The ligh t chain is lambda in almost all
p atients.
Prognosis
The median overall survival is 14.7 years
1590, 14831. The most corrmon causes of
death are cardiorespiratory failu re and
infection.
213
Definition
Extranodal ma rginal zone lymphoma of
9699/3
Synonym
Extranodal ma rg inal zone B-ceillymphorna
Epidemiology
MALT lymp homa compr ises 7- 8% of all
B-eeillym phomas 151). and up 1050% of
pr imary ga stric lym p homa [600. 1801 1,
Fig. 10.0 ExtranociaI m<II'ginaI zcne lymphoma of IIUXJS&o<IS5OCi ~ bsue. A Resedlon specimenal a
gastric MAlT Iynll/1oma BMALT Iynll/1oma of fie ~ .
Fig. 10.5(1 Gaslnc MALT Iynll/1oma AThe\lmol.r oek SIIl'OUI'Id readNe IoIides al'lCl infjtraJe fie 1TIJCOSa. Thebkles have a twicaI staTy-sky appearanal. B The rna-gm zcne eels Itfillfaleltle IanwIa propria n a cIiIIMpaIIIm
a'ld haYe ooIaizedfie gemIIIiII oanIres d f8Idw B-alI",TheaJIonizecI kllIic:Jes donoI show a slaITy-sky ....
)
and thyroid . MALT lymp homa, Patie nts
with SjOgren synd rome (85) o r Iymphoepithelial saieoeruus (LESA) have a 44-fold
increased risk 01 d evelop ing overt lymphoma. com prisi ng a bout 4-7% of pa tients 111 14, 21501. Approximalely 85% 01
lymphomas in pa tients with SS/LESA are
MAlTlymphomas. Patients with Hashimoto
thyroiditis have a 3-lold excess risk of developing lymphoma and a lO- fold increased risk of thyroi d lymphoma, for an
overall lymphoma risk of 0.5-1 .5% 160.
958.11161_94%01 thyroid Iymphcmas have
evidence 01 lymphocytic thyroiditis 15581.
a-cens
ch romatin and incons picuous nucleoli, resem bling those 01 cerurocvtes: they have
relatively abundant, pale c ytoplasm. The
accu mulation of more pale-staining cytop lasm may lead to a monocytoi d appearance. Alterna tively. the ma rginal zone
Sites 01 irrvolvement
OinicaJ features
The majorityof patients present with stage
I or II disease . A min or ity of patien ts
(2- 20%) have bone marr ow (8 M) involvement 179. 1802. 2 1941. The trecuencv 01 8 M invo lvem ent is low er in
gastric cases and high er in MALT lymphomas arising in the lung and ocular adnexa 12193. 2 194). Multip le extranooa!
sitesmay be involved in up to 25% of gastric cases and 46% of extragastric c ases
at the time of presenta tion 118021. Multifocal nodal invo lveme nt is rare (7.5% of
thecases) 121931 . App lication of stag ing
systems for nodal lymphomas can be
misleading in MALT lymphomas. since involvement of mult ip le extranod al sites ,
particularly of pai red org ans (e .g . salivar y
glands) or org an systems (e.q . ga strointestinal tract. skin) may not reflec t trul y
disseminated d isea se. Prasmecvnc differenneuoe is a feature of many of the cases
and a serum paraprotein (M-compo nenl)
can be detec ted in a third of patient s with
MALT lymphoma 124291. The majo r ex ception is IPSID. in wh ic h an a berran t
a.lpha heavy chai n ca n usua lly be found
inlhe peripheral b lood 1178 11.
The lymphOma cells infilt rate around reactive B-cell follicles. exte rn al to a preserved follicle ma ntle . in a ma rginal zone
Extranodal marginal zone lymphoma of mucosa-associated lymphoid nssoe
215
a-ceus
tymoroeonreuauesons.
Differential diagnosis
The d iffer ential diagnosis of MALT lymphoma incl udes the react ive inflammatory
processes that typically precede the 1ymphoma including Hencobacter pylori
gastritis, Iymphoeplthelial
Hashimoto th yroiditis and other small
B-c elf lymphomas (follicular lymphoma,
mantle cel l lymphoma, small lymphocytic
lymphoma). Distinction from reactive
proc esses is based mainly on the presence of destructive infiltrates of extrafollicular Bceus. typically with the
morphology of marginal zone cells
12444 1. In borderline cases, rrmcropbenotypi ng 0..- molecular genetic analysis to
ass ess s-een cronantv is nec essa ry to
he lp establis h or exclude a d iag nosis of
MALT lym ph oma, although molecular
studies may also de monstra te clonal Bcells in some non-neoplastic MALT proliferat ions or per sistent cl onal population s
in gastric MA LT lymphomas even afte r
histo log ic co m plete remi ssio ns 11502,
1792,2457 1. Distinction from other sman
Bccell lymphomas is based on a co mbination of th e c harac terist ic morpholog ic
and immuno phenotypic features .
sraraoenes.
Table 10.10
AnatomiC Site distribution and freq~ (%) ofd1romosoma1lrans.localioos and trisomies 3 and 18 in MALT ~s'
t(11 ;1B)
(q21;q21)
t{14;18)
(q32;q21)
t{3;14)
(pl t ;q31)
t{l;14l
(p22;q32J
'3
."
' -16
t-s
11
-.,"'"
12-56
0-13
75
25
0-10
0-25
0-20
38
13
0-5
0-16
0-,
55
19
31-53
6-10
2-7
20
o-a
0-"
0-10
20
""""
0-17
0-50
17
Silo
-.........
St.,...
....
"""'
"'"
216
Genetics
Antigen receptor genes
Immunoglobulin heavy and light chain
genesare rearranged and srow somatic
hypermutalion of variable regions, consistent with derivation from a post-germinal
centre. memory B-ceIl1618. 1789 1.
217
E. Campo
SA Pileri
E.S. J affe
HK MOllerHermelink
B.N, Nalhwani
Definition
Nodal marginal zone lymphoma (NMZl)
is a primary nodal B-ceH neoplasm that
morphologically resembles lymph nodes
involved by MZL of exnarooet or splenic
types, but without evidence of extranodal
or splenic disease.
ICD-{) code
9699/3
Synonyms
Monocytoid Been lymphoma; peratonicutar s-een lymphoma: Nodal marginal
zone B-cefllymphoma.
Epidemology
Nodal MlL comprises only 1.5-1 .8% of
aillyrnphoid neoplasms 1195. 15781. Most
cases occur in adults with a median age
around 60 years and a similar proportion
in males and females 1731 _ This lymphoma may occur in children {21401.
Hepa titis C virus has been de tected in
Clinical features
Most patients present with asymptomatIC.
localized or generalized peripherallymphadenopathy 173. 1951. Presence at a
primary extrarocar marginal zone 1ymphoma should be ruled out since approximately one third of the cases pesentrqes
nodal MZL represent nodal disseminalial
F'IQ. 10.59 SpIIlIlIc type nodal marg.naI zone IympI'loma AAlIow magnrfJcation. note the loIIic:aar!1OWlh pallemwdh pa/IlI C8II1haI1ocaIy SInOIRl porbonsofIeacllYe genrnI
ceees B The ll.m:u lli ~ d a proIiIerabon aIsmall eels exp;vvjng between a reactiYe g&mWIiJI oentrean:!an IItIenua1ed mantle cell wf, C IgD ~ sI'OlIIS .. _
positivity aI tile b'nol.r t8Is IhaIIlmUld !he negaIrW lIllfII'*laI oenIre..tlefeas the residIJaI manIIe CJ!JIs are ~ posiIi'ooe. DCOlO staI'ing. The ILfro.J" eelsare oegaIMt _ _
toe resOaI gemWIaI centre iI jIOSltrYe EBCl2 stainrlg, The hm:ltI' eels are posANe wtlefeastie reacM gerrrWlaI centre is I"lllgaM
218
Mg. 10.60 NOOaI margnallOI18 ~. paediatnc typeCXIIllITIOIiy ex1Iibtts progressive ~sJormabon d gemW'IaI
0ilI'hS (A). The atypical eels are b..nd pnmarjyin !he irrtelloIiaAr areas andmay disrupt !he IoIices. B ~ SlaMWlg
hlfi\tIIIlhe lhr\4lI8d and elP'lnded manlle cvff: the lunJ::U eels are \gO negabve.
01 a MALT lymphoma. particularly in patents with Hashimoto thyroiditis or S;Ogren syndrome 1328.16011.
The tumour cells surround reac tive follicles and expand into the mtertomcutar
areas. Follicular colonization may be
present. In cases with a diffuse pattern.
follicl e remnants may be detected with
stains forfollicular denonnc cells and germinal centre markers . The tumour cells
are composed of variable numbers of
marginal zone (centrocvte-uke and monocytoid) Beene . plasma cells and scattered transformed B-c ells 1321, 1578.
1601 , 2264J . Cases with a predominant
rrcoocvtoio Been populatio n are uocommonoPlasma cell differentiation may be
prominent and the different ial diagnosis
with Iymphoplasmac ytic lymphoma or
even nodal plasmacytoma may be diff icult. Some of these cases may have
prominent eosinophilia. The presenc e of
remnants of follicul ar dendritic mesh works suggestive of co lonized follicles
would favour the diagnosis of noda l MZL.
Somecases have more numerous large
transformed cel ls (som etimes >20%).
However. these ce lls are usual ly mixed
with small cells and may be more common in the colonize d germinal centres
219
Follicular lymphoma
NL Harris
S.H Swerdlow
E.S. Jaffe
G.Olt
Definition
Follicular lymphoma (Fl ) is a neoplasm
ICD-O codes
Foll icul ar lymp hom a
Grade 1
Grade 2
Grade 3A
Grade 38
BN Nathwani
D. de Jong
T. Yoshino
D. Spagnolo
969013
969513
9691/3
9698/3
9698/3
Epi demiology
FL accounts for about 20% of all lymphomas with the highest incidence in the
USA and Western Europe. In Eastern Europe , Asia and in developing countries the
incidence is much lower 1371. It affects predominantly adults, with a median age in the
6th decade and a maJe:female ratio of 1.1.7
{511. FL rarety occurs in individuals under
the age of 20 years ; paeeenc patients are
predominantly ma les 1707, 133 7, 1754,
2 132 1.
>15teIlIrobIIsls per ~
""'" 3
]A
JB
Reportingof pft1em
Follicular
Follicular and diffuse
Focally f~ l ieu lar
."'"
.......
~
Sold _ _ da~~"'''_b_
Proportion folliCul.
>75%
25-75%
<25%
"'..
rmr
220
r.. IU3 FoIaAr IymJ:k.ma gradIlg. A Grade12 of], There is a monotonous pop,Aalion of smalleels 1IIidI irrelJJIar ru:Iei (oenb'OCyle$) WIth ody rare largeeels (cenlroblasts)
"'1lJ" II'O'W ~ oudeoI allda moderilIe amoum d tylopIasrn (amrov). Most of the largeru:Iei presentin this field are !hosed kAcular de!mlic cells (FOC) (amM16ad):
. . . DIlls IllrIe more dek:ate ru::lear merrtJranes and YIOIet-lXlloured 1'lJdri. alldare oIIen binucleate. B Grade 1-2d 3. The majority d the eels are centrocyles. but ~
fU1lfJIQII ter*obIasts all! present (arrows): several FOC WIth double nudeiall! present(arrowt1eatj). C Grade 31.. There all! more than 15 C8fIlrobIasls per high power field. bul
cnot)1eS in SIiI present. 0 GracIe 36. The majority01 tile cellsall! cerrtroblasls.
ce ntrocytes are not thought to be clinica lly sign ificant. Howeve r. the presence
of diffuse areas com prised entirely or predomi nantly of large blastic/transformed
cells (that would fulfill criteria for Grade 3
follicu lar lymphoma) in a FL of any grade
.....
'.~.~~'I:':'
Fig.IUI FoIcuIar lymphoma. Grade 1-2. with marginal zone dlfferentialion. A AI theperiphery d !he 1oI1ic:llls. ItIere is a pale rim lXlrT8SjXlIlding kl marginal zone tifferenlialion.
8 The centres oIlhe IoRides cootain tile typical mixture 01 cenlrocytes and cerllroblasl$, C The cells a1!he periphery 01 the IoIlides alll medill'l'l-SiZed cells wi1h slightly iflllQlAar
Q nI abI.nlao1ligh~y eosinophilic topale stainillQ C)1OllIasm, consistentwith marginal zone or monocytoKl fkells ,
Follicular lymphoma
221
is equivalent to diffuse larg e B-c ell lymphoma, and a separate dtagnosis of diffuse
large Be en lymphoma should be made
18971 (See grading of follicular lymphoma
qelowl Despite the unclear clinical significa nce of diffuse areas comprised predomina ntly of centrocvtes with ooly rare
centroblasts (Grade 1-2), It is recommended
that the relative pro por tions of follicu lar
and diffuse areas be noted in the pathology repo rt as follicu lar (> 75% follic ular),
follicular and diffuse (25 - 75% follicular ),
or foc ally follicular/pred ominantly d iffuse
25% follicular) 18971.
Diffuse follicular lymphoma
Rare lymphomas with the morphology al'ld
immunophenotype of FL have an entirely
dIffuse growth pattern. This p henomenon
is usually seen on small biopsy specimens.
and likely represents a di ffuse area in a Fl
that is not adequately sampled. In these
cases, the p athologist sho uld sug gest
that more tissue be obtained if possible.
A diagnos is of di ffuse FL may be mad e
when the lymphoma is c omposed of cells
resembling cen trocytes. with a m inor compo nent of centrobl asts and an entirely diffuse pattern ; both the small and large cells
must hav e the immunophenotype of germinal centre cells or presence of a classical
t(14:18) translocation should be demonstrated. Thus. a diagnosis of diffuse FL cannot be made without these ancillary studies.
Partial nodal involve men t and "in situ
follicular lymphoma
Non-neoplastic follicles may be pre sent in
lymph nodes involved by otherwise typic al
Fl, and their presenc e has been repor ted
to predict for lower stage at diag nosis 181.
Non-neop lastic follicles may also be partially colo nized by FL ce lls, both in lymph
nodes with area s of obv ious Fl, in lymph
nodes adjacent 10 those involved by Fl or
occasionanv in isolate d lymp h nodes in
patients with or without H, elsewhere. The
latter pattern has been called in situ"
follicular lymphoma (see be low) 14621.
Cytology
Fl is typically composed of the two types
of Bceus roemanv found in g erminal
centres . Small to medium-sized cells with
angulated. elongated , twisted Of cleaved
nuclei, inconspicuous nucleoli and scant
pa le c ytopl asm are c alled centrocvtes.
Large ce lls with usually round or oval, but
occasionally ind ented or mu ltilob ated
nuclei , vesicular chromatin , 1 to 3 peripheral nucleol i and a narrow rim of cytoplasm are c alled ce ntrobtasts. Typi cally,
they are at least 3 times the size 01 lymp hoc ytes, b ut they may be sm aller in
some c ases . Oentrocvtes p red ominate in
most cases; centroorasts are always pres ent. but are usually in the minority, so that
most cases have a monomorphic eppeeraoce . in contrast to reactive follicles .
The number of centroblasts varies from
c ase to case and is the basis 01grading .
In some c ases, neopl astic centrobleste
may have irregular or lobulated nuc lei resembling large centrocytes, and infrequent
c ases sho w nucl ei with very di sp ersed
c hromatin and a lymphob last -like appearance,
In about 10% of FL there may be disc rete
foci of marginal zone or monocytoid-appearing Be ene. typically at the pe riphery
Fig. 10.65 Follicular lymphoma assooated WJltJ DLBCL A ~ JoIdes arepresent on the rY1Itc. ...... . dlse
on the Iefl The ddluse Nea is a:JIIllI1sed precbninamlyof large eels linse'll. so separale diagrUrs ~ Cx.BCt.
is 1T1<Ide. B Slaining b' C021 sIlows FOemesI1worts in the loIdes. bill not in !he arNS of0lBCl.
Nea
Mat ure
a-cen neoplasms
Fig. 10.66 Bone rnarroIlt il'oUvement by loliaJlar~ . AAl kIwITIiIJ'Ilbbon .lhere lRpa'atr'abeo.*JlynllhcIl
BThe ~ are small cenln::JtyIe$
~.
rig. IU7 IrmulophenoIype of loIlicIAr~. AThe loIicIes and i1terlo1ioAar rtlgIORS contain CD20+ B-celIs.
BThe /oIIides are ISIilormIy BCl2+. C BCL6 is expressed by lhe follicles, but to a lesser degree by i1lerlollicular
neopIasbcceHs 0 COlOexpresslOfl is SII'l'Iilar 10 Ihat 01 BCL6.
Immunopheootype
The tumour cells are usually Slg+ (lgM+/IgD, IgG Of rarely IgA). express B-cell
associated antigens (C019, C020, C022,
C079a) and are BCL2+ . BCL6+, CDlO+ ,
CDS- and CD43-. Some cases, especially
grade 3B , may lack CO lO, but retain
BCL6 expression 1248, 346, 1111. 1239,
1668, 17601. COlO ex pression is often
stronger in the follicles than in interfollicutar neoplastic cells . and may be absent in
the mtertoucotar component, as well as in
areas of marginal zone d ifferentiation,
PB and BM 1599. 8991. BCl6 is frequently
downregulated in the jntertonlcutar areas .
IRF4/M UM 1 is typically abse nt in FL. Rare
c ases of predominantly Grade 3B, C01~
FL have been described that express
IRF4/M UM 1 and lac ked BCL2 rearrange
men t; 59% were associated with OLBCL
111111, Meshwork s of FOC are present in
fo llic ular areas 12508 ); thes e may be
spa rser than in normal foll icl es, and may
variab ly express C 0 21 and C023. so that
ant ibo dies to both ant igens may be
needed to de tect FOC meshwork s.
BCL2 p rotein is expressed by a variable
pro por tion of the neo plastic ce lls in
85-90% of cas es of g rade 1 and g rade 2
FL , but only 50% of gra de 3 FL using
standard antibodies 112381. In a proportion
of the cases, abse nce of BCL2 p rotein is
d ue to mutations in the BCL2 ge ne that
eliminate the epi tope s rec og nized by the
most commonly used antibody, and BCL2
ca n be de tect ed using antibodies to other
BCL2 epitopes 119731. BCL2 protein can
be useful in diSlinguishi ng neoplastic from
reac tive follicles, although ab sence of
BCL2 protein does not exclu de the diagnosis. It is essential for the d iagnosis of
"in sltil' Fl; in these cases and in partially
involv ed follicles, the expression of BCl2
is etten much stronger than in more typical neoplastic follic les. BCL2 protein is
FollICular lymphOma
223
. ..
w
w
w
w
>1'10
~llD'
01
O.
A ll
,)
>0)'"
O.
:10.......
1IO
...
..
..
B o.
--...
--
...
Fig.10.61 Survival Q.fVM lor pabents .... loIic:ljar ~. gr.Ided according to !he WHO cnteria {237.cj. A 0veraISIIViYaI d pabents lreatedWJlh regimens nollX:l'llaiWlg am.
(pdiative Ihefapy):!here is no cllfterenc:e in ~ lor patients with!J'ilOe 1 'IS grade 2 toIicuIar lymphoma (o- SO and 51150 centl'ObIastsl10 hpf).
those Mlh!Jade
3 (>150cenIrtJblas3I1 0 ~ hada sigMicamIy worse oYefaI survival. B 0ieraI $UI"o'FvaI of patientstrealed WIlh adriamycin-alnI regmeos (ar.tIMl intoot): Ihe 3 StniYaI a.nes
areidentical. irdcaIlrlg lhallhent is 110 Slnival benelk lor pabents WI1Il grade 1 and !1acIe 2 FLIrealed .... ~ 1M Ihat!he adYefse PfO!1lOSis of pde 3 Fl is elirTwWd
by 8WessiYe therapy. C Faln-lree Sln'ivaI of pabenls trealed with adriaJTl)Ul: lhere isa suggestion d. plaleau in Ihe cuvelor pde 3 Fl (>150 ~10~. SUlpSlng Ih8 ~ 01 an lor some d It'lese pabeflls; in lXlIlIrasl, palierlls WIth !7ade 1 rod grade 2 Fl conlInue toexperience re6apse$.
""'*
8ITl)'QIl
.,
20%
. 16
20%
15%
15%
15%
3Q27-26
6Q23-26'
I7p'
~ abnonnalitln
BCL2 reafT8rged
IlO%
BCl6~
15%
40%
224
20481
Histologicalgrade correlates with prognosis in follicular lymphoma, with grade 1-2
cases being indolen t and not usually CU"able, except for the infrequent localized
cases /40, 806. 1070 , 1335 1. The majority
of published studies show a signi fic antly
more aggressive clinical course for
ular lymphomas cl assified as large ce ll or
Grade3/40. 153. 1400. 14431; but the use
of regimens containing ad riamyc in and/or
rrtuximab may obviate these d ifferenc es
and requires further stud y 138, 153 ,752 ,
807,863 , 1102, 1860 , 2374, 23841.
Many stud ies have ind ic ated /47 , 1273 ,
1820, 23601 that the p resence of even
very large diffuse areas in fo llicul ar lymphoma classi fied as grade 1-2 ("small
cleaved" or "mixed sma ll and larg e ce ll")
doesnot significantly alter the p rognosis .
In most repoted studi es. cases 01g rade
3 Fl with diffuse areas >25% (no w rec ognized as areas of DLBCL) have a worse
prognosis than purely follicular cases 138,
153,752.807,883. 1860.2346.23841.
The presence 01 more !han 6 ctromosomal
breaks and a compl ex ka ryoty pe ha s
been shown to be assoc iated with a poor
outcome: in addition, de l 6q~26 , de l 17p
and mutations in TP53 as we ll as - 1p.
+ 12. +18p. - xp cooter a wor se prognosis
and a shorter lime to tran sformation
/1284. 22391. Rare c ases w ith both
14;18) and t(8;14) have a poor prognosis
[102.23431. Recent gene expression data
have suggested a role of the microenvironment, includi ng T-cells and accesso ry
cells including FOG and macrophages in
determining the clin ical behaviour of FL
1510. 804, 893J Currently, no spec ific
markers are available other than histo logicgrade and proliferation traction that
can be used in cli nica l prac tic e to predi ct
tome-
Variants
Paediatric follicular lymphoma
This va riant often involves cervic al lymph
nodes. other periphera l lymph nodes or
Waldeyer ring ; however. other extrarooat
involveme nt also oc cur s, with FL of the
testis well des cribed 1707 . 1337. 1754,
2132 1. Ch ild ren with FL typ ically have
early-staqe d isease 1707, 1337, 1754 ,
21321 Paed iatric follicular lymp homas
have many features ind istinguis hab le from
those seen in adults, but demonstrate an
inc reased proportion that are loc a lized.
lac k BCl2 protein expressio n and 1(14:18)
and are grade 3 11337.21321. They also
F"'II. lD.69 PalKMtric follicular lymphoma. A Follicles of varying size and shape. many WJlh preserved mantle zones. extending beyond 1tle ~ rooe capsuie.
~ of centroblasts (Grade 3). C The folliCleS are negative Jar Bell.
Follicular lymphoma
225
..
'."'"~'
A large nodules 01 lymphoid eels are present in lhe rru::tl5a The lolIides are I.IiformIy posItIveb BCL.2 (8) a'ldposiIiye lor C010 (e).
Intrafollicular neoplasiann
situ- follicular
lymphoma
Cases occur in whiCh architecturally
normal-appearing lymph nodes and other
~ tissues haveone or more follicles
that demonstrate BCL2-overexpressing
centrocytes and cennootasts. with or
without a monomorphic cytologic ap-
'.
226
Mafure
Been neoplasms
DefiMion
Prinary cutaneous follicle centre lymphoma
(PCFCL) is a tl.rnour of neoplastic follicle
centre cells, including centrocvtes and
variable numbers of cemrootasts. w ith a
follicular, follicular and d iffuse or d iffuse
gro.vth pattern, thai generally pr esen ts on
the headOf trunk 124071. Lymphoma s with
a diffuse growth pattern and a monotonous
proliferation of centrobasts and immunoblasts are. irrespective of site , cl assified
ro.ocode
The provisional COde proposed lor the
fourth edhon oi ICD-Q is 959713.
Synonym
Peucuotnsnocvtoma or me dorsum
Ic rostrs disease) 12061.
_ohlgy
Prinary cutaneous follicle centre lymphoma
is the most common type of pri mary c uta-
Siles of involvement
Primary cutaneous follicle cent re lymphoma
characteristically presen t with solitary or
localized skin lesion s o n th e sc alp , the
forehead or on the trunk. Approximately
5% present with skin lesions on the teg s.
and 15% with muttltocat skin lesions
(1170. 1993. 25021
Clinical features
The clinical presentation consists of firm
erythematous to violaceous plaq ues, nodlAesa nmocrsof variable size. Particu larly
on thetrunk. tumours may be surrounded
by erythematous papules and slightly
infiltrated . sometimes figu rate plaq ues.
which may precede the de velo pment of
1I.m:lurous lesions by mon ths o r yea rs
1200, 1933. 2409/. In the past PCFCL with
such a typical p resenta tion 00 the ba ck
'Nel"e referred to as "reticulohistiOCytoma
R, Willemze
SH . Swerdlo w
N.L. Harris
B. Vergier
Mo<phoklgy
Prmary cutaneous follicle centre Iyrnphcrna
show perivascu lar and oenacrexar to d iffuse infiltrate s with almos t cons tant sparing of the epi d ermis. The infiltrates show
a spectrum of growth patt ern s with a morphologic continuum from follic ular to follicul ar and d iffuse to diff use 11 933 , 2407,
24091. The lesions are composed predominan tly of med ium-si ze d and la rge
centrocy tes and variable proportions of
centrobtasts. In sma ll andlor early lesions
a cl ear-cu t fo llic ular gr owt h pattern or
more often remnants of a folli cular growth
pattern may be observed, In contrast to
c utaneous follic ula r hype rplas ias, the follic les in these PCFCL are ill-defi ned , show
a mo notonous p roliferation of BCL6+ follicle ce ntre ce lls enmeshed in a network
of CD21 + o r CD35 + follicula r dendritic
ce lls, lack ting ible body mac rophage s
and gen erally have an attencat ec or absent mantle zone (360, 818) Reactiv e Tc ells may be numerous and a prominent
strom al component is usually present.
Advanced tumours usually show a monoton ous population of large centrocvtes
and multilob ated cells and in rare cases
sp ind le-shaped c ells, with a variable ad m ixtu re of centro btasts 1206 . 36 2, 824,
1933,2409). React ive t-eens are less pronounced and follicular struct ures. if present before, are no longer visible exce pt for
occasional scattered CD2 1+ or CD35+
follicular de ndr itic cells.
Imm unophenoty pe
The neoplastic cel ls express C02Q and
C0 79a, but a re usua lly Ig negative ,
lesions 00 th echest
227
Fig. 10.74 Pmlatyeutaneous bide c:enn Iyn..,tonaWIth a cjtfuse growth pattern. A DrIfuse ~ inNIrate. BThe lI.rncU' ceIIlexpress CD2O. CAl tigher magIlIftcabon, aAllar iflfiltrllle containS many fTIIAt*:lbated
eees.
Genetics
Matu re
Mature ge rmin al
lymphocyte.
centre
d er ived
Definition
Mantle cell lymphoma (Mel) is a B-eell
C linical features
Most pat ients present with stage III or IV
d isea se w ith lym ph adenopat hy. hepatosplenomegaly and 8M involvement 1247.
329, 1605 , 2136 1. Per ip hera l b lood involv eme nt is common and present in almost all pat ients by flow cytometry 16911.
Some pati ents have a marked lymphocytosis mimicking p ro/ymphocytiC leukaemia (74, 247 . 1605 1
9673/3
SH Swerdlow
E. Campo
M. Seto
H .K. Mu ller-Herme link
t.1o<phology
Ep;demiology
eoneo 122551.
Sites of involvement
Lymph nodes are the most commonly involved site; the splee n and bone marrow
(BM), with or without per iph era l blood
(PBj involvement. are oth e r impor tant
sfes 01 disease 174. 24 7, 160 5 , 2 134 1.
Other extranodal sites are frequently involved, including the gastrointestina l tract
and Waldeyer ring 1772 , 1916) , Mo st
cases of multiple lymphomatous po lyposis represent mant le ce ll lymphoma
11203,161 1,19OO}.
vMlllnts
fllasIoij:
PIeo:Jraphic: calls art pleomorphic: butmany are IafgeWllh CMlI to irregularnudear coolours, geoeraIty pale
~ and often prominent nudeoli 11 at leastsome of the ceHs.
--
- SrnII eel: SrTllll IOJnd ~ WIth IIIOlll dumped chromalin, either admiJled or predlmnant, ITWIDJng
SlfIII tymphocytic tymplloma.
I,l;rgnI zone.Ike: prominenI loci r:A eels withabu'ltIanl pale ~ reserrtIIrlg marginal zone or
~ 8-alIsIlWIIIdling a ma'gIIl8I zone ~; sometines these paIef locimay aisO reserrtJle
~ C8'lIres r:A dnlnic ~ IIlukaerriaIsma ~~ .
B
Fig. 10.17 Mand. cell ~ invotving the alIon
(~ ~ pcIyJxlsis). !Jt'S5 ~. A
229
fig. 10.7' Mantle c:eI~ . ~ nodes. A There is dllfuse afChitedInI e!lacement and typical pale IIyaftzed vesseb . B in addl1JCl'l ~ ItfIuse areas. nofe!he prorrn!IC
vague neoplasbenodules. C A mantle zone QJOWlI1 pattem is seen II1ltis ~ node WIth an intacl artMBclure
230
BMI1
.1. -
INK4
G1
COK 4/6
Cyciin 01
------
pR B I!) + E2F
r ~
Cyclin E
COK 2
pRB/E2F
/
CiplKlp
Genetics
Antigen receptor genes
IrtYnunogtObu lin gene s are rea rranged.
Variable region g enes are unmutated in
the ma;ority 01 the cases. but in 15-40%
d the cases. /G g enes show somatic hypermutation although the load of mutations is usually lower than in mutated C l l
{322. 1143. 1652. 21921. A biased use of
!he VH genes is reported in MCl. suqgesting that these tumour s may originate
trom speci fic sub set s of a-ceus 1322 .
11 43. 1652. 2 1921. In cont rast to cu.,
VH3-21 gene usage in MCl occurs mainly
in cases that are uomuteted. have fewer
genomic imbalances and a better prognosis 121921 Also in contrast to Ct.t . the
VH gene muta tional status in MCl does
not correlate with survival or ZAP-70
expression 1322. 340. 11431.
Cytogenetic abnormalities and oncogenes
J
INK4
Cell
death
H MOM2 11-
p 14 ARF
ATM
Fig. 10.10 CeI cyde and DNA damage repw palhways altetedin matllle cel lymphoma. The cydin Ol lcydin
dependent kinase (CDK) 4/6 CQrr4lIeJ promoteS phospIuyIation d!he relinoblastoma prolein (pRB). This leads10
release of ee ElF lransmption racIors Yoftctlltlen lead 10 prt9'eSSiOn of ee eel cyde inlo!he S phase . Thecydin
D11COt< 416 compleJ isinhibiled by p16-. 8MIl is a ~ repressor of !heINK4afARFIocus.AbnonnaIiIies
in MeLltJat lead kl progresslOO of cells from GI to S phase incUIe increased cydin 01 in amost aI cases and b&s of
pl6"""". RB deletions. increased CDK4 alld increased 8MII in a minority of casesespecially lhose lhal are more
aggressive_ Dere\r.Jlated E2F also induces p14'" 1rw11Crip1lon. p14'" leads lDsIabiliz.ation of p5J by iMibIbng 1Ile
activiIy of MOM2 whietlleadsIII 1hedegradationof p5J. The Iurnl:u'suppressor p53leads 10 ifIcrea:sed expteSSlOll of
p21 in addition 10 leading 10 eel cycle arrest or apoptosis. The AT'" gene is required lor activation 0/ p5J after DNA.
damage. Many Mel ha~ ATMabnormalilies and some pabents have gernine mutabons ollhis gene. SCme Mel have
loss or tran~1 repression oIlt1e INK4afARFlocus lacking p16-,p14.... 1oss or mutation 01 TPSJor high Ieves otMDM2. Finally. cycIin ElCDK2 coepexesalso lead 10 cellcycle progression andare inhiMed by p21Ip27kipl . ln
Mel. increased levels of cydil'l 01 lead 10 seqtleSlraliOn eteese ce~ cycleinhibitors and. in addition, they may increase
p27degradalion.
231
Naive B
lymphocyte
GermHne
ATM
Classical
MCl
Early
MCl
Blastoid
MCl
. --
CHK2
t(11;14)
Cyclin 01
~
~
p16/CDK4/Rb
ARF/MdM2IQ53
Rb
Increased Genomic
Inst.bUIt)'
High
Proliferation
Fig.1U1 Proposed model of IIlCIlecWr patl10genEtSlS in Ihe deYeqmenl and progression of MCL The presence of ,A,1M or CHK2 ifIadivaIing nI.IlatiORS ifllhe gemWne 01 some
paller'll$ suggests Ihat they ITI3)' IacilrIale lhe ~ ofltle MrloIJ". The 1(11;14) transb:atiOn occurs in an immatJ.n 8-<:eII aI'lCIleads to Itl8 oonstitulive dereglJabon 01 cydln
01 _..,.,. ~ r:A IlnGur ~ on.............
of lymphoid ~ Acquqd inectrvaIion 01 DN " ~ ~ paIIlways may tac:iIRale!he dirteIoprt'Il
aI addJbmaI geneticalIeralions and expansion of MCt eels witha dassicallT'IOIphokIgy. Increased genomiC instal*y maytiWgel genesin the cJ3I C)'de and senesoence ~
pahways 1tIat \IlIOUd lead ~ JTOlI aggressi\'e Ya"IafIls of MCl. ModrIied WIth perrrissicrllrom Jes P. 8f aI. (1048A)
MeL.
Postulated normal count erpart
Peripheral Bccell of inner mantle zone,
mostly of naive pre-germinal centre type.
Prognosis and predictive factors
Mantle cell lymphoma has a median survival at 3-5 years, but the vast majority of
patients cannot be cured 1329 , 21361. The
impact of some of the newer therapeutic
approaches remains to be established
11917. 2487AI. The most consistently reported adverse nrstopatnoioqicat prognostic parameter is a high mitotic rate
232
Definition
[Muse large EkelllymphOma (DLBCL) is
ICD-OCOde
9680/3
Epidemiology
DLBCl . NOSco nstit utes 25-30% of ad ult
Etiology
The etiolog y of DLB CL , NOS rem ains
uOO1own.1t usually arises de novo {relerred
H. Stein
RA Warnke
W.C . Chan
E.S. Jaffe
to as prim ary) bu t c an represent progression or transformat ion (relerred to as second ary) of a less ag gressive lymphoma,
e.g. chronic lymphocytic IeukaemiaI small
lymphocytic lym phoma (CLLlSLL) . follicula r lymphoma, ma rginal zone lymphoma
Of
nodular lymphocyte predominant
Hodgkin lymphoma (NLPH L). Undertying
iTn'I..nxiefici is a sig1fficant risk tectoDLBCL, NOS occurring in the setting of
irTYrunodeficiency are more often EpsteinBarr virus (EBV)-positive than scoreorc
DLBCL, NOS. In DLBCL cases without an
overt irTVTlUnodefic iency. the EBV infect ion
rate is app roxima tely 10% 1993. 1690 1.
Sites of involvement
Patientsmay present Vv'iIh rKldaIlJ extranodal
disease wiItJ up to 40% being at least initially
confi ned to extranod al sites 18981 The most
common extran odar site is the gastrointestinal trac t (stomach and ileocoecal
region ) but virtua lly any extranodal loca hon
may be a prima ry she. Other common sites
of extranodal presentation incl ude bone,
tes t is. spl een, Wald eyer ring . sal iva ry
g land , thyroi d, liver, kid ney and adren al
g land . Cutaneous lympho mas co mposed
01larg e B lym phocytes are dea lt w ith separately in this volu me , Bone m arrow (BM)
invo lve m ent is reported in 11- 27% of
c ases 1327, 442 ) The de tec t ion ra te of
minimal invo lvement ma y be inc reased if
an ci llar y studies like immunohistochemistryor p e R are added to the mo rpnoioqical evaluation of the BM specimen (2 15 11.
Bone m arrow in volve ment may be with
J K C . Chan
K.C, Gatter
E. Campo
Clinical features
Pat ients usuatty present with a rapid ly
entargu'IQIl.mOUr mass at single Of multiple
nodal or extranodal SIIes_Almost ha lf 01
the patients have stage I or II d isease.
Most patients are asym ptoma tic but when
symptoms are p rese nt they are highly dependent on the site of involvement 151, 791 .
Morpho logy
Lym ph nodes demo nstrat e a d iffuse p rolife ration of large lym phoid ce lls that have
tota lly (more common pattern) or par tially
effaced th e arc hitecture . Partial nod al
invo lvement ma y be mtert oulcuter and/or
less commonly sinusoid al. The perinodal
tissue is often infiltrated , Broad or fine bands
at sclerosis may be observed. Cytomorphologi cally, DLBCL, NOS is d iverse and c an
be d ivided into co mm on an d rare mo rph olog ic va ria nts. Cases pr ed om inated
by medium-sized c ells may require spe c ial stud ies to ex clude ex tramed ulla ry
teckaemta s. Bu rkitt lymphoma variants
and bl astoid m antle cell lym phomas,
Fig. 10.83 DdIuse large B--c:eI~. cenlrotllastic vlll"ia'1l A T)'PIClII appearance. B In llise~, h II.m:u
eels have a potymorpnic and ~ed appearance.
Diffuse large B-celf lymphoma . not otherwise specilied
233
..
Anaplastic variant: This variant is characterized by large to very large round . oval
or polygonal cells With bizarre pleomorp hic nuclei tha t may resemble, at least in
pa rt, Hod gkin and/o r Reed-Sternberg
c ells, and may res em ble tumour cells of
""""""'"
~astiC
ArlapiasliC
Rare rTlOI'phologicvereots
MoIeaJlar subgroops
GemWIaI~~e {GC8 1
ImmurdlisllXtiemicalsubgroops
CD5-posiliveDLBCL
Germinal oontre EkelI-like (GCB)
Noo-ge!minaI OlIfltrelk:eHke (non-GCa)
DifluHlargeEken Iymphom. subtypes
PrYnary el'lusioo ~
Borcl.rllneeases
.....
B-<:eI~,
234
"""""""henotype
Bceus.
925.9941.
The prollferatloo fraction as detected by
~7 stall'ling is high (usually much more
than 40%) and may be greater than 90%
n SOOle cases 114781. p53 is expressed
n2O- 60% of cases 1420.1171 . 1281 .
24761.
i1 the ~ blJ:werealsool::lservecl
Chromosomal translocations
Up to 30 % of cases show abnor malities
of the 3q27 region involving the BC L6
gene, which is the commonest fransocaton
in OlBClI 158. 1620, 16261. Transloc ation
of the BCL2gene. Le. 1(14:18), a hallmark
of follicular lymphoma, occurs in 20-30%
of cases 1994. 13 16 . 2379}. A MYC rearrangement was observed in up to 10%
of an unselected series 01 cases 124811
and is usually associated With a complex
pattern of genetic alterations 19941. The
MYC break certoer is an IG gene in 60%
and a ~IG gene in 40% of cases 19941.
Approximately 20% of cases with a MYC
break have a concurrent fGH-BCL2
translocation and/or BCL6 break or both
1994. 22781. These cases usually have a
high proliferation (>90% Ki67+) and may
be better categorized as "B-ceillymplunas.
uncl assified with features inter mediate
Unfavourable variables
Age >60 yaars
Poor petfonnance status (ECOO:a)
Advanced Ann Arbor stage (1II-N)
Unfavourablt v"riables
AI patJeIlt$ Pati9nU SfU
0 1
2
3
0
1
2
45
' In patlel'Its s60year-okl fie age-.adjusted nternatiOnal prognosbc index (aaiPiI is caIcUated VIOIh
tnree unlavourable variables ltJal lOdude poor per.
formance slalus.aovancedAnnAibor stage and
higl serum l DH
235
Immunophenotype
A larg e num be r 01immuno histoc hemical
markers have been report ed to be assoc iated with prog nostic effects: the expression
01 BC l 2, X-li nked inh ib itor of apo ptosts
(XIAP), IRF4/MU M1, c vcnn 0 2, cyclin 03,
p53, C05, FOXP1, PKC-/I, ICAM1, HLA-OR,
c- FU P have been associated with an adverse p rogn osis and the exp ression of
acts, COlO , l M02 with a favo urable
outcome {10, 146, 196, 460, 526. 759 ,
88 1, 925, 1009, 1479 , 1546 , 23 18. 2463 )
However, the results o btained in thes e
different stud ies are often co nllic ting and
the ir interp retation is thus con troversi al.
Finally. the addit ion 01the anti-G020 antibody rituximab has improved the surviv al
of patients with OLBCl considerably {4551
and was repo rted to have elimina led the
nega tive impact of the expression of BCl2
and the positive impact of BCl6 on cli nical
outcome {455, 1528, 1529, 2423/. Patients
with EBV-infected OlBCl , as revea led by
EBER in Situ hybridization, have be en
found in one study to have a worse c linical
outcome tha n patients with an EBVnegative OLBCL 11690/.
236
r.
,-
-.--
----
r.. ~
:-t"- I "
..
~-,
Low-risk
--
~-
overall survival
r..
1."
-.--
. 1\
High-risk
.
r..
--
1.."
~-
low-fisk
"' ~l)
H igh -ri sk
Fig.10.85 OvefaB al'ld progreSSiOn-free surrival in diffuse large B-cellymphoma according 10 the age.adJusted
Intemabonal Prognostic Index in patients trealed W11h CHOP WIU1 and IIII'I1houI ntuximab ao::udI'lg to the study em
dl.ded byIheGElA (courtesy of Dr8. Corffier).
Immunohistochemical panels
Hans et al. I882} reported that a combination
of CO lO, Be l 6 an d IAF4!M UM 1 expression, the so-ca lled "Hans cla ssifier". cou ld
subdiv ide OlBC l patients into long- and
short-term surv ivors; this result has been
co nfirmed by some studies b ut not by
others 131, 460 ,1 339 , 1526, 16 10, 230 1).
Whether the ad di tion of rituximab to
Proliferation
A high proliferation fraction , as assessed
by the Ki67 index, has been associated
withworse survival in scme series 11478 1_
This is supported by one gene exp ression
study in which the proliferation signature
proved to be a strong predictor of an
adverse ootcome I1869J . However other
studies have failed to confirm a prognostic
value for the Ki67 index 1460, 1904.2423.
24961
Genebcs
In some studies, BCL6 translocation has
been reported 10 be associated with a
better prognos is, but not in others 1158.
1056.1188. t543 . 1596, 1620, t728.2339I.
In contrast. the presence of a MYC break
is ~nk ed with a very untavouratne outcome 19941. TP53 mutations have been
associated with poo r su rvival in some series of OLBCL incl udin g one study in
wh ich mutations in the DN A binding domain proved to be the most important predictcrj420, l OCXJ. 1171, 128 1. 2421, 24761_
p53 p rotein expression does not seem to
be of prog nostic value in DLBCL patients
11 187.1353,20431. Patients with a molecularly defined GCB-subtype of DLBCL
have been shown to have a significantly
better c linical outcome than those with the
ABC subtype 124. 994. 18691 Whether this
difference persists in patients treated with
rituximab remains to be seen . Other subgroups, i.e. oxidative phosphorylation".
- BC A/proliferation" and ' best response"
identified by gene arrays, did not predict
survival , but may suggest targets lor therapy 115071.
Microenvironment
t-eens
The"'PY
DLBCL are aggressive but potentially
cu rable with multi-agent chemotherapy.
The CHOP regimen has been the mainstay
of therapy for several decades. Whereas
attempts 10 improve ou tcome with more
intensive chemotherapy failed to show
additional benefit. The addition of the antiC020 monoclonal antibody rituximab to
CHOP (R-CHOP) has led 10 a marked
improvement in survival 14551.
237
T ceillhistiocyte-rich large
B-cell lymphoma
C . De Wolf-Peel ers
J. Delabie
E Campo
ES. Jaffe
G, Delsol
Definition
t-cemusnocvte-nchlarge B-eelltymphoma
ICD-Q code
968813
Synonyms
t -een-non B-celt lymphoma 118131. large
8 -eefl lymphoma ric h in t-eens and simulat ing Hodgkin d isease {4261. histiocyte
rictVT-eell-nch large B-eeillymphoma 15441.
Epidemiology
THRLBCL attects main ly m idd le-aged
man . It accounts for < 10% of all diffu se
large B-eeillymphomas (DlBCL)
Sites of involvement
THRLBCL mainly affects the lymph nodes
b ut bone ma rrow (8M), liver and spleen
involvement a re frequently found at d iag-
nose .
Clinical featu res
.....
.,.
....
b blt 10.17
T~
StageIII-/V
largeIk:eIIympIw)ma
12-61 )'Un
75%
64%
l iv&r inYOIvemeni
13-70%
Spleen in'lOlv&ment
33--67%
Bone marrowinvolvement
17-60%
238
Morphology
THRLBCL has a diffuse or less comm only
vaguely nodular gro wth pattern replacing
most of the no rma l lymp h node parenchyma . It is comprise d of scattered. sing le,
large B cells embed ded in a ba ckground
of small lymphocytes thai represent T cells ,
and var iable numbers of tustocvtes. The
tumour ce lls are always d ispersed and do
not form aggregates or sheets. These
cells may mimic the neoplastic lymphocyte pred omina nt (LP) c ells of nodular
lymphocyte-predominant Hodg kin lymphoma (NLPHL), but usually show a more
pronounced variation in size and in some
c ases may resembl e centroblast s or more
pleomorphic ce lls mimick ing Reed -Sternberg or Hodgkin cells 1598, 12991 They
are typ ica lly found with in clusters of
bland-looking non -ep ithelioid taetiocvtes
thai may not be obvious on conventional
examinatio n. These histiocytes represent
a main and d istinct ive component of
THRLBCL and are useful for the diag nosis
161. The background lymphocytes a re
nearly all of r-cennoeaee. Eosmopnns or
p lasma cells are not founo. The histolog y
resem bles cases of NLPHL with a d iffuse
co mponent, in which the LP cells have infiltrate the exnatoulcutar compartment but
these THALB CL-l ike areas in NLPHL do
not represent a transition towards THRLBCL
and do not c arry a bad prognostic signific anc e {252 1. Nevertheless. the re are
some ca ses of histologi cal progression in
NLPHL , in wh ic h the process is en tirely
diff use and lhe histolog ical ap pea rance is
virt ually ind isting uisha ble from de novo
THRLBCL. The relationship between secondary THAL BCL and pr imary cases rema ins controversial . They may represent
distinct, but morphologically and immu~
ph enotypically similar entities.
In the spleen. a multifoc al or mcroncouiar
involvement of the w hite pulp is found and
in the liver th e lymphomatous foci are
local ized in the portal tracts 1598) In
these extranooet loc ations as wel l as in
the BM . the lym p hom a is characteri zed
by the same co mposition as in the lymp h
nod e .
On rec urrence. the num ber of atyp ic al
Immunophenotype
The large atypical cells ex press pan
B-cell ma rkers and BCL6 ; a variable numbe r stain for BCL2 and EMA and no expressio n of C0 15. C030 and C0 138 is
found The bac kg round is co mpos ed of
var iab le number of C068-po sitive histocvtes and C0 3, COS, positive T cells. T-cell
rosett es around the tumour cell s and ramnants of B foll ic les or clusters of small B
lym phoCytes are ab sent. Lack of residual
IgO positive mantle cells and follicular
d ntic cell meshwork are of turtner diagnostic hel p differentiating THRLBCL from
NLPHL 16. 7251. There are aggressive
B-ceillymphomas, ric h in reactive
in wh ic h the neoplastic cells are sparse,
and are EBV-po sitive . In such c ases. the
neoplastic cells may exhibit a Hodgk in-hke
morp hology , Suc h cases should not be
class ified as THRLBC L, and should be
co nsidered w ithin the spectrum of EBV
pos itive OLBCL 11 2991.
oeo-
r-cees
Genetics
The tumou r B cells have the same clonal
rearranged IG genes carrying high rurber
of somatic mutations and intraclonal diversity 12631as germ inal centres ce lls.
l imited karyotypic studies have not
shown recurrent abnormalities. Comparative genomic hybri dization on rrucrodesectec tumour cells demonstrated more
imbalances in NLPHL than in THRlBC L
wiltl common anomalies involving 4q and
19p (7311. Gene expression profiling has
239
P.M. Kluin
M , Dec kert
J.A. Ferr y
Definition
Diffuse large B-cell lymphoma 01 the
central nervous system (eNS DLBCL)
represents all primary intracereb ral or intraocular lym phomas. Excluded are Iym.
phones of the dura . intravascula r large
B-eell lymphoma. lymphomas with evidence of systemic disease or secondary
lymphomas. as well as all inYTlUnodeficercv-eesoclatec lymphomas.
ICD-Ocode
Synonyms
These cases arealso diagnosed as prinary
e NS lymphoma (PCNSL) or prima ry intraocular lymphoma (PIOL) .
Ep;dem;,1ogy
e NS DLBCL represents < 1% 01 all nonHodgkin lymphomas (NHLl and ap prox imately 2-3% 01 all brain tumours. The
med ian age is approx imately 60 yea rs.
and there is a slight preponderance of
male patients, Some studies suggest an
increase in the incidence of e NS DlBCl
1485 1. bu t it is unk nown whether this is
due to improve d diagnostic tools or reflect s a real increase.
Etiolog y
Epstein-Barr virus is generally ab sent from
CNS DLBCL in immunocompetent patients,
Exp ress ion or abse nce of c hemo kines
and c bemo une rec ept o rs or c yto kines
may co ntribute to the spec ific localization
(2038 1. Tumour ce lls and endothelial cells
may interac t via ac tivation of Il 4 to crea te
Fig. 10.81 Nuclear ~bc resorIafIC8 imaging (MRI) of CNSOlBCL 11 aller gadoIinit,I'n infection IA);n:I tid
attenuated iflvefSion re<XIYf!f)' (FLAIR) sequenceslBI, There are I'l1O eManclflg mass lesions ifl lhe basal gar9a
(Courtesy of Or. F Glaus).
Fig. 10.88 Prmary cWIuse Iarge~ ~ oflhe CNS. A Aa:urIUalionof1u'nou" cells wtil ee perlVaso.b' space B More sold patIem. WIll stI scme ~ .
Ihe petivascUar space, C Strong IRF4IMUM1 stalnrog ifl JTDre than 7O'lIo of ee tumlu eels 1'1 CNS OLBCL
240
Deletion
'I
6p21.3
Gain
I
i
_..
Testis hemizygous
...,11
CNS~
.-.
II
II
',II
III
_.
r~
I~ I
Fig. l0J9 Alrwy CGtl analysis 0# 9 ~CNS Dl8Cl. 17primaryleslicular OLBO. and 18 primary nodal(stage U11)
tlBa.. s/'IoIWIg (somelimes vwy small <Ieletions at 6p2U
nrst.o-
Immu nophenotype
All tumou rs are positive for B-eell markers
C020, C022 or C079a, CO lO expression
is pre sent in approximately 10-20%,
BC L6 in 60 - 80% and strong IRF4/MUM 1
in appr ox imately 90 % 126 1, 324, 1305 1:
BCL2 express ion, not related to the
t( 14: t 8)(q3 2 :q21) , is freq uent 14531.
Genetics
Antigen receptor genes
CNS DLBCL contalna very high load of
(ongoing) soma tic hypermuta tions (up to
27%) and a striki ng ma intenance 01 the
open readi ng frame 115031. A biased use
of VH ge nes , in pa rticu lar VH4/34 , suggests an antigen dependent prolifera tion.
Mutations also affect BCL6, PIM1 , MYC,
RhoH/TTFn and PAXS 115051 .
241
Definition
A pr imary cutaneous diffuse large B-cel1
lymphoma composed exclusively 01large
transformed Beene. most corrmonly arising in the leg.
ICD-Ocode
968013
Epidemk>logy
Primary cutaneous diffuse large Bccell
lymphoma (PClBCL. leg type) constitute
4% of all primary cutaneous lymphomaS
and 20% of all primary cutaneous B-cell
lymphomas 124071 and typically occur in
elderly panents. in pa rticular in women,
with a M:F ratio of 1:3 - 4. The median age
is in the 7th decade 123341.
Sites of involvement
These lym phomas preferentially affect the
lower legs . bu t 10 - 15% arise at other
t-eens
drical
1".,..mOllheootype
Genetics
242
S. Nakamu ra
E.S. Jaffe
SH Swerdlow
Definition
Sites of involvement
70% of patients present with extr anodal
disease (most commonly skin. lung. tons il
and stomach) with or without sirrultaneous
lymph node involvement; 30% of pat ients
have lymph node disease alone /12 13.
16751,
phoma
ICl>{) code
9680/3
Syronyms
Senile EBV-associated B-c elf Iympho-
Epidemiology
Clinical features
The clinical features at presentation are
variable . More than half of the patients have
high or high-intermediate International
Prognostic Index (IPI) scores 11213, 1675,
1690.24731.
Morphology
The arch itecture of the involved tissues is
effa ced in contrast to infec tious rrooonucleosis. Although no longer considered to
be of clinical importance 116751. cases
were initially divided morphologically into
polymorphous and large-eell lymphoma
subtypes. both of which inclu de many
large transformed cellslimmunobl asts and
Hodgkin and Reed-Sternberg (HRSl-like
243
lrrmunophenotype
The neoplastic cell s are usually positive
f()( C020 and /or C079a. and light chain
restriction may be difficult to demonstrate.
COlO and BCl6 are usually negative.
244
116751.
J.K.C . Chan
K. Aozasa
P. Gaulard
.,
wus
960013
Ep;demiology
The interval between the onset of c hronic
trfIarrwnatiOf1 and malign ant lymphoma is
usually over 10 years 1408, 1024, 10251.
PAL develops in pat ient s with a 20-64
(median 37) year history of p yothorax
resuning from arti ficial pneumothorax lor
treatment of pu lmonary or p leural tuber-
Fig. 10.94 Pyoltuax-associaled~, MasM U!Iw' p ...... aw, SUffOlA'ldng !he'IIItoaie kJng
EOOIogy
ArMicial pneumothorax, used in the past
_l~
Tuberculous pleuritis
..
Ctvonic
pyOthOrax
(latent)
DevelOpment
otlymphoma
> 20 years
245
...
.' .. ".
..
,. :. .
.,.
..
.
. . ,".. ,
, . ~.
.,
..
.'*
~~~r.i; I
..' . . '.V
. ;'.
~
-:.'"
~~~~~~~i , . .,. ..'~'
.
.
.
~
I
...~
t ..
, . ~
' ~"
io , .
..
....
-,
f . ...
.. I
. :
i S., . - I
. .
"'
. ": .
I
oo ,'
' \ lit' \
, '..
~.
..
\ .
~.
"
f)
Flg.l0.96 Pyoltloralc-assoaated!yrT1lhoma. AMuse proliferatIOn al larye Iyrr1Ihoid cells WIth invrNJnoblastJc ~~. BTlIITll:U eels express COlO. C POSItive !q'lI15 It EBV
11 the nudeus of IurTna' eels by i'I situ hybrdzation WIth EBER probe.
m!!I!lIHlmlll
.----
---.-- ,
--'-.
---e---
246
lmmunophenotype
a-cen
Lymphomatoid granulomatosis
976611
conclr{lOI'l .
EbOogy
L~toid granulomatosis is an EBVdnYen Iymphoproliferalive disorder. Patients
A LlII19
Sites of invotvement
Pulmonary involvement occurs in over
90% 0 1 patients and is usually present at
initial diagnosis . Other common sites of
invo lvement include brain (26%), kidney
(32%), liver (29%) and skin (25-50%).
Upper respiratory tract and the gastrointesunartract may be affected, but are relatively uncanmon 14931. Lymph nodes and
spleen are very rarely involved 11 04 2.
1121,1182, 14461.
Clinical featu res
Patients frequ ently present with signs and
symptoms related to the respiratory tra ct.
suc h as co ugh (58%) , dy spnoe a (29%)
and c hest pai n (13%). Other co nstitutional
symptoms are common , including fever,
malaise , weig ht loss, neu rologi cal sympto ms , arthralgi as , mya lg ias and ga strointest inal sy mptoms . Patients w ith cent ral
nervous system disease may be asymptomatic or have var ied pr esent ation s depe nd ing o n the site of invo lvement suc h
as hearing loss, d ip lopi a, dy sarthria ,
ataxia and/or altered mental status 1170 71
Few pa tients present with asym ptomatic
disease 5%) 110421
Macroscopy
Lymphomatoid granulomatosis most commonly presents as pulmonary nodules
that vary in size. The lesions are most
often b ilateral in distribution, involving the
mid and lower lung fields . Larger nodules
freq uent ly exhibit central necrosis, and
may cavitate. Nodular lesion s are found
in the kidney and brain. usually associated with central necrosis . Skin les ions
are extremely d iverse in appearance.
S. Pittaluga
W.H. Wilson
E.S. Jaffe
Nodular lesions are found in the subcutaneous tissue. De rmal involvement may
also be seen . sometimes with necrosis
and ulceration . Cutaneous plaques or a
rrecuooaouiar rash are less COlTVTlOI1 cutaneousmanifestationsl170. 1042. 1121.
14461.
Lymphomatoid granulomatosis
247
cells are gen erally not pr esent. and if
seen. should raise the possibi lity of
Hodgkin lymphoma. Well-formed granulomas are typ ic ally absen t in lung and
most other extrarocat sites 11 3171. However, skin lesions often exhibit a prominent
gran ulomatous reac tion in subcutaneous
tissue 11701.
Vascular changes are prominent in lymphomatoid granulomatosis. Lymphocytic
vasculitis, with infiltration of the vascu lar
wall is seen in most cases. The vascular
infiltrahon may compromise the vascular
integrity, leading to infarct-like tissue
necrosis. More direc t vascular damage in
the form of fibrinoid necrosis is also cornmon, and is mediated by chemokines induced by EBV 121651. Lymphomatoid
granulomatosis must be dist inguished
from extranodal NK/T-cell lymphoma.
nasal type, which often has an aoqiodestrucnve growth pattern, and is also
associated with EBV 11037).
Grading
The grading of lymphomatoid qranuiomatosts relates to the proportion of EBVpositive B cells relative to the reactive
lymphocyte background 1862, 13 171. It is
most impo rtant to dis tinguish gr ade 3
from grade 1 or 2. A uniform population of
large atyp ical EBV-posilive B cells without
a polymorphous background should be
classified as diff use targe B-cell lymphoma. and is beyond the spec trum of
lymphomatoid granulomat osis as currently defined ,
248
Fig. 10,101 lymphomatoid granulomatosis. ... Grade I lesion of ltle king shows a potymorpnous infiltrate n lhe
vasculard . 8 A Qade mlesion oIlhe brlIlIl(X)rQlns runerous largelraIlSbll iid Iymp/loid eels, C These eels IN
positive lor Epstoo-Barr virusby in $Au Il)tInlZalJOO .... 1tle EBER prnbe. 0 ~ pleoo1aphic eels may be seen.
mostcommonly n Grade 111 lesions. rarety in Grade II.
extensive. By in situ hybri dization, EBVposit ive cells are extremely numerous
(>50lhigh power field) , and focally may
form small con fluent sheets. It is important to take into co nsideration that in situ
hybridization for EBV c an be unreliable
when large areas of necrosis are present
due to poor RNA preservation; additional
molecular studies for EBV may be help ful
Immunophenotype
The EBV-positive B ce lls usually express
C0 20 1862, 2159 , 24201. The c ells are
variably positive lor C030, but negative
for C0 15. LMP1 may be positive in the
larger atypi ca l and more pleomorphic
ce lls. Stains for cy toplasmi c immunoglobulin are frequ ently non-informative,
although in rare cases monoc lonal cytoplasmic immunog lobulin expression may
be seen, part icu larly in cells showing
plasmacytoid differentiation 1242O}, The
backgroond lymphocytes are C03-positive
T cells. with C04+ cells more frequent
than COB+ cells.
Genetics
In most cases of Grade 2 or Grade 3 disease . clonality of the immunoglobulln
genes can be demonstra ted by molecular
genetic techniques {861. 14461. In some
cases different clonal popul ations may be
identified in different anatom ic sites
Althoogh some patients with grade 3 lympho mato id granulomatosis may show
spontaneous reg re ssio n with immunotherapy or modification of the immune
state. for clinical purposes these patients
should be approached as diffuse large
B-ceil lymphoma 124201.
lymphomalOld granulomatOSIS
249
Definition
A diffuse large Bcemvmprorre aris ing in
the mediastint.rn from putative thymic Been
origin with distinctive clinical, immunophenotypic and genotypic features.
ICD-{) code
9679/3
Synonym
Mediaslinallarge Bc eli lymphoma .
Ep;demlology
Primarymediastinal large B<el11ymphoma
(PMBl) accounts tor 2-4% of non-Hodgkin
lym phomas (NHllI 150. 3501 and occurs
pre dominantly in young adults (median
age. -35 years) with a female predominanc e (M:F ratio, about 1:2) 1350. 1257,
1943, 25001.
Sites of invo lvement
PMBL most likely arises within the thymus.
Patient s p resent with a loca lized antero-
P. Gaulard
N.l. Harris
SA Piled
J.L. Kutok
F"'ll.10.103 PnmatymeliastJnat1arge8<:el ~
cens
Irrmunophenotype
PMBL expresses B-cell antigens such as
CD 19, CD 20. CD22 and CD79a, but, as a
rule, lacks immunoglobulin (Ig) 1150, 1092,
1328, 17441. CD30 is p resent in mo re
than 80% of the cas es, however, usually
weak and heterog eneous, co mpared to
Hodgkin lymph oma 1938, 1744 1, CD 15 is
occasionally present 115001. Tumour cells
are freq uently posi tive for IRF4/MUM1
(75%) and CD23 (70%), have variab le expression of BCl2 (55 - 80%) and BClS
(45- 100%) and CO lO is less common
Fig, 10,11)2 Pnmaty meciII5tlrl8I large 8<:eI ~, A Nuclei are lW'ld (centroI:llasl-Q) or someIines rTJ.IIlIlobated.
by ooIlIgenous Iilrosil. C Medium-silecI eels with large pale cyklplasm.
$epllIil1ed
250
H. Stein
A.M Kovrigina
E S, Jaffe
P. MOiler
23881.
Rearrangements 01 BCl2. BCL6 and M YC
genes are absent or rare 11944 . 1953 .
22711 whereasoecnvatco 01 P
and
TPS3genes have been reoortec {19531.
The discordant expression of components
of the B-cell receptor (BC A) (CD79a +.
slg-) is characteristic 01 PMBL 11092 .
'fI'-
nor to a defect
Fig. 10.107 Primary mediaslinal Iafge Ek::eIIlympl'loma A Most tumour cells express
express MAl. with a L)'loplasmlc re.nloroemenl in lhe Golgi area
con
251
S, Nakamura
M. Ponzon i
E. Campo
Definition
Sites of involvement
ICG<l code
97 1213
usually spared ,
Clinical features
Epkl~
eels .
252
Mature
a-ces neoplasms
'...->.
~
The neoplastic lymphoi d cells are mainly
lodged in the lumina of small or intermediate vessels in many organs. Fibrin
ttrombi , haemorrage and necrosis may be
observed in some cases. The tumour
cells are large with prominent nucleoli and
trequenl mitotic figures. Rare cases have
cells WIth anapl astic featu res or smaller
size 117691. Minimal extravascular joceIial 01 neoplastic cess may be seen. SirosoidaI involvemen t occurs in the liver,
8M 117691. Malignant cells are
occasionally detected in peripheral blood
sceenard
""'-'>op/lero
Tumour cells express B-cell-associated
antigens. Co5 and CotO coespresson is
seen in 38% and 13% 01 the cases,
respectively. Almos t all 01 Co1~neg ative
large B-cell
Genetics
Immunoglobulin ge nes are clonally rearranged. Karyotypi c abnorma lities have
been described but too few cases have
been stud ied 114951 .
253
G_ Delsol
E. Campo
AD. Gascoyne
Definition
ALK positive large B-ce ll lymphoma
(ALK-positive LBCL) is a neopl asm of
AlK-posi tive mooomorphic larg e immunoblast-like B cells, sometimes with erasma blaslic di fferentiation.
ICD-O code
9737/3
Synonyms
Large B-eell lymphoma expressing the
ALK kinase and lacking the 1(2;5) transl ocation; AL K-positive piasmatnesnc B-eell
lymphoma.
Epidemiology
This lymphoma is very rare 1% of
DLBC L) . w ith less than 40 c ases so fa r
been repo rted 1183 11. It seem s to occur
more frequ ently in ma le adu lts (M :F ratio,
3:1) and sp ans all age group s (9-70
years ) (med ian, 36 years) 118311.
Sites of involvement
The tumour mainly invotves lymph nodes
{9, 553, 761 , 1023, 1831,20751 or present s
as a medi astina l mass {527. 7881. Involvement of extranodal sites have been
also reported includin g na sop har ynx
11 644 1. to ngue 1527f, stomac h {1444j.
bone 1164-t) and soft tiss ues 14 171,
Cl inical featu res
Most pat ie nts prese nt with advanc ed
stage Ill/IV.
na.
10.112 ALK-posibve large B-eeil lympnoma, morpnologic features A T~re is massive invasion of lymphatic
sinuses B Neoplastic cells show immunoolastic and pla smablastic features
MO'Phoklgy
This lymphoma shows a sinusoid al growth
pattern and is composed of rrooororptuc
larg e imm unobtast- like cells with round
pa le nuclei co ntaining la rge central nu c leoli and abundant cytop lasm. Some
cases show plasmablastic differentiation
{553 . 761 1_Atypical multinucleated neop lastic g iant cells may be seen .
Immunophenotype
Lymphoma ce lls are strong ly positive for
ALK prot ein wi th a restricted g ranul ar
c yto pl asmic stainin g pa ttern highly ind icative of the exp ression of CLTCAL K
p rote in. Few c ases may show cytoplasmic, nucl ear and nucleolar ALK staining
associated with the NPM-Al K protein. In
adcIition,lhey also characteristically sl1rXr:jy
express EMA and plasma cell markers
such as CQ138 and VS38, being negative
for lineage-associated leukocyte antigens
(COO, C020, C079a) 1283, 553, 1962, 1963.
2075} . C0 45 is wea k or negative 1553.
761}. C030 is negative 1553}, although focal
and weak staining has been reported in
few cas es (2075] Most tumours express
cy top lasmic Ig (usually IgA, mo re rarely
IgG) with ligh t ch ain restrict ion 1553). As
de scri be d in some p lasma c ell tumours,
FIi- 10.111 IrrmJnoptlenoIype ofALK-posilive Iaf9lI ~ 1)mI:tloma. The turroor eels arepositive forEMA (A)WIth a CjIOpIasmiCmembranous pattem.IgA(BI. and ALI( (C} .....
a ntStricled CjIOpIasmiC~ pattem tir;;IIy iJclic3Iived \he e~ of \he CLTC-ALK fusion protein.
254
occasion al c ases are positive for c ytokeratin which, in addilioo to EMA posi tivity
and weak/negative staining for CD45,
may lead to the mista ken diagnosis of
carcinoma 120751 The tumours may be
also positive for CD4, CD57, IRF4/MUM1
120751. focally for CD43 120751and perIorin120751.
These tumours shoul d be distinguished
from CD30-po sitive AlK-positive T/null
eneoiastc large cell lym p homa and other
large B-ceil lymphomas with a sinusoidal
growth panern . and AlK-negative imrronoblasticlplasma blastic lym p homa s,
such as those involving the oral ca vity in
Hrv+ patients 14591.
Genetics
The immunog lobulin genes are clonally
rea rrang ed 1417, 761}. This tumo ur may
ex press full-leng th ALK 1553} b ut the key
oncogenic facto r is the AlK fusion p rotein
due to genetic alteration of the ALK locus
on chromosome 2. The most freq uent abnormali ty is the t(2;17Xp23;q23) respo nsible for Clathrin-ALK (CLTC-ALK) fusion
protein 1417 , 527 , 761 , 788 , 1023, 1444,
1831}. Few cases are assoc iated with the
t(2;5 Xp23 ;35) as de scr ibed in AlK-posjrive TlNull anaplastic large cell lymphoma
(AlCl ) 19, 16441. A c ryptic insertio n of
3'ALK gene sequences into chromosome
4q22-24 has a lso been repor ted 120751,
255
Plasmablastic lymphoma
H. Siein
N.l. Harris
E. Campo
Definition
P1asrnablastic lymphoma (PBL) is a diffuse
proliferation of large neoplastic cells most
of 'Nhich resemble B immunoblasts, but in
which all tumour cells have the immunephenotype of plasma cells. It was origina lly
described in the oral cavity but may occur
in other, predOminantly extrarooat sites .
ICD-O code
973513
Epidemiology
PSL is uncommon. It has its highest incidence in j-uv-ocenve individuals. predominantly males It may also be associated
with other immunodeficiency sla tes, including advanced age. The median age
at presen tation is around 50 years , with a
broad distribution, but mainly anecnnq
adults. Rare cases are seen in chi ldren
with immunodeficiency 1459. 5471.
Etiology
Immu nodefic iency. caused in the majority
Sites of involvement
prolife ration of cells resembling immunoblasts to cells with more obvious plasmacync differentiation, which may resemble
cases of prasmabtasnc p lasma ceM
myeloma. Mitotic ligures are frequent
Apoptouc cells and tingible body macrophages may be present. but are generaly
less prominent than in diffuse large B-eel
lymphoma. Cases with monomorphic
p1asmablastic cytology are most cx::mnc:ny
seen in the setting of H IV-infec lion and i'l
the oral. nasal and paranasar area (oral
mucosal type). Conversely, cases 'Mth
plasmacytic differentiation tend to OCClJ"
more corrmonly in othe r extranodaJ sues
as well as lymph nodes 1459 . 5471. The
differential diagnosis in the cases with
crasmacvnc differentiation may incluce
anaplastic or plasmablastic p lasma eel
myeloma, The presence of a high prolif
eranon fractioo, extranodallocalization, a
history of immune de fic iency. and the
presence of EBV by in situ hybridizahO"l
for EBER are useful in esta blishing the
d iag nosis of orasmabtasnc lymphoma
Immu nophenotype
The neoplast ic cell s ex press a plasmace ll ph enotyp e includ ing positivity for
CD t38 , CD 38, Vs38c and IRF4/MUM1
and are negative or only weakly positive
for CD45, C0 20 and PAX5. CD79a is pas.
itive in appoximately 50- 85% of the cases
F"tg. 10.tt3 It Plasmablaslic Iyr'I1Ihorna of the orallTUCOSilllrilh a ITlOlllJlmlll/liC prokIefalion of large.1mulobIastIc eels MIl promrlflflI oocleoIi. B PIasmabIasbc lymphoma"
plasmacytic dlllerenlialiOn. The Iur'ncU cells are large with rtu'Id nudei and showing coarse d'lnlfIIIbn and smaller or unapparenl nudeoIi. Smaller eels wrlh ~
<i!Ieranliabon arepresent.
256
ccseve
is rarely expressed. The rate 01 EBV-positivity is nearty 1(}()% in the oral mucosa!
type 01 PBL, in association with HIV-infeclion. H HV8 is consistently absent 1459 .
547,604,23191_
Genetics
Clonal IgH chain gene rearranqement is
demonstrable , even when irrmunoglobulin
expression is not detectab le , and the IgH
genes may show evidence of somatic
hypermutation or be in an unmutated
con figu ration 1744 1.
Ptasmablastic lymphoma
257
..
ICD-Ocode
The p rovisional code proposed for the
fou rth edition of ICD-O is 9738/3.
PG , Isaac son
E. Campo
N .L. Harris
Synonyms
HHV8-p ositive p lasmab lastic lym phoma
(HHV8 PL), Kap osi sarcoma herpes virus
(KSHV)-po silive p lasmabl astic lymphoma ,
Epidemio log y
HHV8 PL occurs worldwi de in HIV-po sil ive
patients who have develop ed HHV8 Mc a ,
It less commonly occurs in HIV-neg ative
pat ients who have d evelop ed HHV8 MCD
usually in reg ions whe re HHV8 is end em ic
(Af ric a and Med iterranea n coun tries)
12501.
Etiolog y
The neoplastic cells are positive for HHV8
in all cases. HHV8 encodes more than ten
homologues to cellular genes that provide
proliferative and anu-aooptouc signals
159,84 ,9 1, 10491.
Sites of involvement
The lymphoma characteristically involves
lymph nodes and sp leen but can crsseminate to other viscera via the blood stream
258
Fig. 10.116 HHV6-positive n1J1bc:errtrJc cas1l9man lisease. A The Ik:8I tilde WIth a IIOITlIiII genIWIII cenR ISU
I"OI.I'lded by a broad mantlezone. B ManIIe zone corUInsscattered plasmablasts. C This B<:eI lolIide shows pai1II
hyalftzalion 01 the germnaI centre WIth Bn atleoual8d manlle zone, D Gem.1aI centre contaiIWlg l'UTleI'OUl
...
~""",-
""""'phenotype
..1' . "
I
.-. .
",.
cosmve.
anIlQ8O.
.r..f....."-.
,
~c~:.
, .'
..
.noW....
.,...,
~ "
!u
.:~
...
'
. I .
.:.. ....;:!o..
Fig. 10.117 HHVS posltMll'flllllcenlric CaslIeman disease Wmulostained u HHV8 (A1. 1gM (8). (~d'Iafl (C)and
A light chain (D). The plasmablasts e.press ntranudear HHVS lANA. c1gM and show AIiI;;lt chain teSlrictIon.
InIeffoIK:uIar plasma cells e~ poIytypic IgIgtrl d'Ians.
Genetics
AntJgen receptor genes
Despse constant expression of monotypic
IgM by the plasmablasts in HHV8 MCO.
careful molecular studies have shown that
trey constitute a poivcionar population
161 91. The mic rolymphomas thai develop
asthedisease progresses may be monoor polyclonal and the frank HHV8 PL are
moooc ionai. In both disorders. the IG
genesare unrnutated.
Fig. 10.118 HHVBilositive p1asmablasticlymphoma. A Sheetsof p1a$ffi3bjasls efface normal lymph node archilectlJl1l
B High magnificaton of p1asmahlasts in (A),TUITlOIJ" cells immunostained !of ( 1g lightchain (C) and Achain(0) stow
Alightchain restriction ,
259
Primary effusion lymphoma
J. Said
E. Cesarman
Definition
Primary effusion lymphoma (PEL) is a
large B-cell neoplasm usually presenting
as serous effusions without detectable
tumour masses. It is universally associated with human herpesvirus B (HHVB).
also named Kaposi sarcoma herpesvirus
(KSHV). It most often occurs in the setting
of immunodeficiency. Some patients with
PEL secondarily develop solid tumours in
adjacent structures such as the pleura.
Rare HHV8-positive lymphomas indistinguishable from PEL present as solid lumour masses, and have been termed
extracavitarv PEL.
ICD-O code
Synonym
Epidem iology
The majority of cases arise in young or
middle-aged homosexualor bisexual males
with hum an immunodeficiency virus (HIV)
infection and severe immunodeficiency
11 555. 19 12). There is co-infection with
monoclonal Epstei n-Ba rr virus (EBV) 1372,
1555, 19121 . PEL has been repor ted in recip ients of solid org an transp lant s 1606,
1066, 13491. The disease also occurs in
the absen ce of immunod eficienc y, usually
_ ....
W'9'JIstarl.
patients have pre-existent or develop Ka-
967813
.A
Sites of involvement
The mo st common sites are the pleural.
pe ric ardtal and peri toneal cav ities. Typ ically only one body cav ity is involved
{169.556, 16651. Extracavitarv tumours
with morphologic and phenotypic cha rac teristics simila r to PEL occur in extranod al sites inclu ding the gastrointestinal
tract. skin. lung and CNS. or may involve
lymph nodes 1377, 487. 556},
Clinic al features
Patients typi cally present with effusions in
the abse nc e of lymphad enopathy or
organomega ly. App roximately half of the
Fig. '0.'" PmIafy eIlusion ~ (PEl.). A SokIlissue mass tomI'Ie ITIllliasIn.rn of an HIV+ patIenl WI\h PEl presenIing WI\h pINal elIusicln$. The 03Is<We Iar9t n
WI\h eosiIlOphIcIIIICfOflUdeoI and abundanl. cytoplasm. Mq ha\oe an anapIaslie or pIasmacybd appeatlI"It8. B ~ PEL
asa INl$$ in
lht Ilwgtbowel of 8fI HIV+ palJlri. The ru:Iei _ sml'jy positiYe lor IaIenlI*f\l8 Iltl1d1cn 'IIIilh nbocty m0RF13l..NA-1 f1.ANA).
'*"*.0.. ...
260
presenIilg""""
Morphology .
In cytocentrifuge preparations, the ce lls
exhibit a range of ap pea rances, from
large immunoblastic or plasmab lastic
cells to cells with more anaplastic morphology. Nuclei are large, rou nd to more irrequtar in shape, with promi nen t nu c leol i.
The cytoplasm can be abundant and is
deeply basophilic with vacuoles in occasional cells. A pe rinuclear hoI consistent
with plasmacytoid differentiation may be
inmJnopheootype
lymphoma cells usually express CD 45 .
but lack pan-Been markers such as
CD 19, CD2Q and C079a 11167. 15551.
f- c eu rec eptor genes (so-called genotypic infidel ity) 1956. 19101. Rare cases di ag nosed as TPEl have been reported
{487. 1263 1. No rec urrent chromosomal
abnormali ties have been identified. Compa rative genomic ana lysis has revealed
gains in c hromosomes 12 and X 115371HHV8 viral genomes are present in all
cases. Gene expression profiling of AIDSrelated PEL shows a d istinct prof ile with
features of both plasma c ells and EBVtransformed Iymphoblastoid cell lines
11 1591.
Postulated normal counterpart
Post-qermoat centre Been.
Prognosis and predictive factors
The clinical outlook is extremely unfavourable. and median survival is less
than six months. Rare cases have
responoec to chemotherapy and/or
immune modulation 17931.
261
Burkitt lymphoma
Definition
Burkrtt lymphoma (BLl is a Ekeillymphoma
with an extremely short doubling time that
often presents in extrenodet sites or as
an acute leukaemia. It is composed 01
monomorphic medium-sized transformed
cells. Translocation involving MYC is
highly characteristic bu t 001 specrtc. N o
single parameter (such as morphology,
genetic analysis or immunophenotyping)
can be used as the gold standard for the
ICD-Ocode
Burkitt lymphoma. NOS
9687/3
Epidemiology
Three cli nical variants of Burkin lymphoma
are rec ogn ized , each mani festing d ifferences in cli nic al presentation, morphology and biology.
Endemic BL: This varian t occurs in equatorial Afr ica , rep resenting the most common c hild hood mal ign anc y in this area
with an inci dence peak at a 10 7 year s and
a male.female rat io of 2: 11301, 24471. BL
is also endemic in Papua. New Guinea. In
endemi c region s there is a co rrelation between the geographical occ urrence and
some climati c fact or s (rainf all, altitude.
etc.) which correspond to the geog raph ical dis tribu tion of end emi c ma laria 1301 ,
656 ,2447 1.
Sporadic BL: This variant is seen throughout the world , mainly in ch ild ren and
young adu lts 1301,1 364,24471, The inc ide nce is low, representing only 1- 2% of
all lymp homas in Western Europe and in
the USA. BL acc ounts for 30 -50% of all
ch ildhood lymphom as. The med ian age
of the adul t pa tients is 30 years 1898 1. The
mare.temaie ratio is 2 or 3: 1, and in ch ild ren it is even mo re common among
males 12301. In some parts of the world,
for example, in South America and Nort h
Africa, both true sporad ic and endemic
variants are seen.
262
L Leoncini
M. Rap h a~1
H , Stein
NL Harris
E.S. Jaffe
P. M. Kluin
122911.
EBV may be detected in approx imately
30% of sporadic BL cases, howev er, a
low sccio-economio status and early EBV
infec tion are asso ciated with a high er
p revalence of EBV-positive sporadi c BL
In imm unod efic ie nc y-assoc iated c ases,
EBV is identified in onl y 25-40% o f the
c ases 18 77, 18181_BL is mo re co mmon in
HIV than in other forms 01 imm unosup pression and BL appears early in the prog ressio n of H IV infection when CD4 .
t-een counts are still high 11 301 1. This
sug gests that immunos uppression per 58
d oes not exp lain the incre ased risk of BL
A potential mechanistic link between ende mic and HIV-assoc iated BL lies in the
polyclonat Been activation that occurs
afte r mal aria and HIV infection. However,
the oncogenic role of HIV itself cannot be
rtg-10.124 &ni1l1ymp/lOma. loucl1 impmt. A The deeply basophilic cytoplasm can be appreciated as well as
abI.n1riipd vacuoles II the C)1OPIaSm. B The cells II It'is case are relatively S1rri1ar kI{Al.e:::ept !hey' havemore
~nudei.
Sites of involvement
ExtrallOdal sites are most often involved
'Mth some variation according to the clinical variants. However. in all three clinical
variants. patients are at risk tor cent ral
nervous system involvemen t. In endemic
BL.the jaws and other facial bones (orbi t)
are the site ot presentation in about 50%
01 the cases (301, 24471 The distal ileum,
caecum and/or omen tum, gonads, kidneys. lonq bones, thyroid, salivary glands
and breasts may also be affected either
w,th or without jaw involvement (302,
24471. Although loc alization may sometmes be found in the bone marrow (BM),
manifestation of leukaemia in the peri.
pheral blood (PB) is not present 1302,
24471. ln sporadic BL. jaw tumours are
very rare 11612). The majority of the cases
presents with abdominal masses 11 3641.
The ileo-caecal region rep resents the
most frequent site of involvement. SimiIar~ 10endemic BL, ovaries . kidneys and
breasts are also frequently involved.
Breast involvement totten bilateral and
massive) has been associated with onset
during puberty, pregnancy or lactation.
Retroperitoneal masses may result in
spinal CCH'd compression Wi th paraplegia,
l'yfTlph node presentation is seen more
ccmrnonly in adu lts than in chi ldren .
WaIdeyet mg and mediastinal involvement
ire rare. In invnunodelicieocyassociated
Burl<ittleukaemia variant
A leukaemic phase can be observe d
in p atients with bulky disease. but only
rare cases (mainly males) present purely
as acute leukaemia with PB and BM
involve ment 11 363, 1364. 20601. This
Burkitt leukaemia. or acu te lymphocytic
leukaemia-l3. according to the lormer FAB
classification. tends to involve the CNS at
diagnosis or early during the disease
course. Its rapid chemosensitivity easily
leads to an acute tumour lysis syndrome.
--
Fig.10.125 Burkitt IympIloma statned lor Goernsa ' AI and H&E (B) has lI'liform IumolJ" eels wdtl multiple smaI
ru:leoli and Ii'oeIy ~ chrornabn II theirradii ,In hs &.nIa ~ slaIned b Giemsa (C)in! H&E (D). 1lere
is !1Nternodear~
Burkitt lymphoma
263
...~
Fig. 10.126 BtnJn lymphoma. Imrnunohis1odlemistry shows a strong and homogeoeous stam.ng lor KJ67/MIBl (A) and C010 (Bl. C FISHfor MYC IIarmg probes {891"1.
~ one8Iellt..., ookx:aization aI bott1 probes (ted and greerl) a"Id oneallele WIth segregatJon aI boIh probes.
con
264
Genetics
Antigen receptor genes
The tumour cells show clonal IG rearrangements with somatic hypermutation.
B-celllymphoma, unclassifiable,
with features intermediate between
diffuse large B-cell lymphoma and
Burkitt lymphoma
Definition
Bcetl lymphomas with features intermeoete between dutuse large B-cell lymphoma (DlBCl) and Burkitt lymphoma
(BLl are aggressive lymp homa s that have
lymphoma (BlL).
The majority01 the cases in this category
have morpholog ical features that are
orermeotete between DLBCL and BL,
with some cells that are smaller than typ-
PM. Klu in
NL Harris
H . Stein
L. Leoncmi
EpidemkJk>gy
These lymphomas are relatively infrequent
ico-o code
-..,.""...
6L
N,,,
""""""
V..
No
Sometimes
""~
cormcn
V..
No
Sometimes
Sometimes
Sometimes
Sometimes
.,,,,,
No
8CL2expr..elon
~eg8tiVfl / weak
S"..
Gtnetic Into,.,
WYC rearrallg8ll1el1l
YIS'
""Ye"o
V..
"'"1G..uvc-
No
No
--
~ _ ooo
"""""""
No
No
V..
Prdiltrltion (KI61/MIB1)
>00% and tIor'roopene<H/s
~ orheterogerlElOOs
Iflte'
""""""
seeeeres
No
No
....
Yo.
No
N,,,
--........ --...... ,
-.... ........
""""""
Sites of involvement
More than half 01 the patients present with
widespread. etten extranodal disease.
Unlike BL , the re is no prefe rential localization in the ileocecal reg ion or jaws. The
bone marrow (BM) and perip heral b lood
(PB) may be involved as well.
Clinical leatures
Patients present with lymphadenopathy or
mass lesions in extranodal sites. Some
patients have a leukaemic presentation.
-ogy
968013
r.10.11 Iobpl'OClklgiCo. ~ and genetic Ieabns tlat may beusefIA ., <btl~ BL !romDLBCl.
ti51ic
M. Rapha~1
E. Campo
E.$. Jalfe
....
....
""""""
"
B-cell lymphoma , unclass ifiable . with features intermediate between DLBCL and Burkitt lymphoma
265
a.:
Fi~ 10.121 TI'nle ~ 8.14~ .. T~ BL tJ)ll'I(X)SllCI 01 fI'IlidI.m-sizl. IloulolllOUS eels wGI ftUId rlld8i.1TUIIPt ru:leoIi. ;n:l a rTD:letaIe an'lOI.Ill 01 ~ wIid1
1m a ~ awe<r.n. Prtrrnlnl apopUis is MIln:8d bythe presence 01 ~ 8l'9JfI'lg ~ daMs. oealJlg hi "stairy-skf patIlvn. NIne 0/11 expem v.tID IWirwed
hs case i1depeIldelltt Il'IlIde diqosis 01 BL..: 1 made a ~ cI ~ BL BIw:JJtB case will similar a.waI ~. tu WIO'l */'fI1 noe wriaIol., sizein! shape 01 reels. SiJ: ~ caIedIhrs BL and 5 caIed ~ atypical BL. CDLBCL WIIh a 1(8:'-4) has a pnmnenI starry-sky panem. The eels are Iargel' 1d more pIeomol~ 1hafl1he BurUI
and alypicaI BtnAI aISJllS. " " e4*1ScaIed lis CUlClMd2 caIed l at)'Ilc:aI BL ~ from tan tarns to.;n:I Homng SJ ~
(COlO. , BCLS+ . BCl2 and IRF4iMUM1or very weakly positive). Cases that morphologically resemble BL may be p laced
in this category when BCL2 is moderately
to strong ly positive. BCl2 positivity in a
case that otherwise might be classified as
Bl should suggest the possib ility 01 a
double hit lymphoma with both MYC and
BCL2lranslocations. The Ki67 lab eling
index is usually high. again raising the d ifferential diagnosis 01 Bl, bu t in reported
cases it varies between 50 and 100 %
\26 4, 890, 1438 1. Rare tumours with a
MYCwith or without BCL2rearrangement
are TdT positive; classification of these
cas es is con trove rsial , and the diagnosis
of lymphob lastic lymphoma may be preferre d 11 561 , 2 19 11 .The use fulness of
other markers rema ins to be estab lished
1922, 1858 ,2 179],
Geneti cs
IG genes are ctonauy rearranged.
Ap proximately 35-50% of the cases have
8q2 4/MYC transiocatioos 1890. 994, 14381.
However. whereas M YC in 8 L is juxtaposed to the one of the immunoglobulin
genes (IG- MYC). many of these cases
have other transiccauons (non IG-MYC).
Approximately 15% of the cases have a
BCL2 translocation, sometimes together
with a MYCtranslocation ("double hitlymphoma"). Cases previously classified as
Burkitt-like lymphoma may have a higher
frequency 01 MYC and BCL2 trensrocatons as well as double hits 11104, 1359 1.
Less frequently. BCL6 transiocanons are
seen , sometimes together with MYC andJor
BCL2. The relative incidence of double and
triple hit lymphomas increases w ith age.
266
E.S. Jaffe
H. Stein
S.H . Swerdlow
E. Campo
SA Pileri
N L. Harris
DeIini1icn
A B lineage lymphoma that demonstrate s
Imm unophenotype
The lymphoma cells exhibit an immunop heno type With transitional features
between CHL and PMBL (758 . 2265} .
Neopla stic cells typically express CD45.
In contrast to CHl . the B-eell program is
often preserved. but is aberrantly expressed
in concert with Hodgkin ma rkers. such as
CD30 and CD 15. CD 20 and CD79a are
frequently positive, and may be strongly
expresse d on the majorily of the tumour
c ells. C030 is pos itive and C015 is oosrtive in the majority of cas es. Surface or
c ytop lasmic immunoglob ulin (Ig) is absent. The transcription factors PAX5. QCT-2
and BOB.1 are usually expressed, BCl6
is variably positive but C010 is generaHy
negative. ALK is consistently negative.
The background lymphocytes are predominantly C03+ . CD4+ . as seen in CHL
In cases Ihat morphologically resemble
oodular sclerosis classical Hodgkin rym.
phooIa: (NSCHL). lSiform streng expression
01 C020 and other Be en markers and absence of CO 15 would favour the diagnosis of grey zone lymphoma. In cases Ihat
resemble PMBL. absence of C020. expression 01 CD 15 or p resence of EBV
would favour this diagnos is as welt.
MAL. a marker associ ated with PMBL, is
exp ressed in at least a subset of the cases
presenting with med iastinal disea se 1472.
2265). Suppo rting a relationship to PMBl .
nuclear c-REU p65 p rotein has been id entified in those cases tested [758. 1857}. In
one series. p53 was expressed in Ihe
Of
as a primary site.
IC().()
code
959613
Synonyms
Grey zone lymphoma 11895, 22651 , large
Been lymphom a with Hodg kin features
EpidemoIogy
These lymphomas are most common in
young men, usually presenting between
the ages 01 20-40 yea rs of age 1758.
22651. However, they have been reported
tI Individuals as youn g as 13 yea rs of
age. and in older adults beyond the age
of 70 Most cases have b een reporte d
Morpho log y
The lymp homa is typic ally composed of a
confluent, sheet-like growth of pleomorphic
tumour cells in a diffusely fibrotic stroma
1758.22651. Focal fibrous bands may be
seen in some cases . The cells are larger
and more p leomorphic than in the typical
case of PMBL. although some ceoucotastlike cells may be present. Pleomorphic
cells resembling lacunar cells and
Hoclgkin cells comprise the majOl'ityof the
infiltrate . A characterisnc feature is the
broad spectrum of cytological appearances with different areas of the lumour
Showing variations in cytological appe arance. i.e. some areas may mo re closely
resem ble CHL an d others ap pear mo re
like diffuse larg e B-eeil lymp homa. There
is usually a sparse inflamma tory infiltrate.
although scattered eosinop hils. lymphoc ytes an d histocyt es may be p resent.
Necrosis is frequ ent. but unlike CHL, the
necrotic areas do not c ontain neutrop hilic
infiltrates.
Sites 01 Involvement
The most common p resentation is with a
large anterior me diastinal mass. with or
W1lhout involvement 01 supraclavicular
trTllh nodes 1758. 22651. Other peripheral
~ node groups are less commonly
1'lYoIved. Theremay be spread to lung by
Orect extension. as well as spread to liver.
spleen and bone marrow. Non-lymphoid
l)'Qans are rarely involved. in cont rast to
PMBl.
CIncaI features
A. large mediastinal mass may be associ-
Fig. 10.129 B-ceII ~ WlIh features I1lermediate be'- dI1Iuse large B-ce. ~ and dassicaI HodglIIrl
lymphoma. Mediasbnalmass. A Lyrl'4Ihoma is composed of sheets 01 cells WJIh dearcytoplasm aoofine sderosrs. The
appearance resembles that of primary rnediastinallarge B-ceRIyrT'4)homa (PMBL). BTurrour cellswere stroogIy COl 5
positiveandalso CD30positive {nol shown).
B-ce illymphoma. uncla ssifiable, with features intermedi ate between DLBCL and Hodgki n lymphoma
267
fig . 10.130 Ik::eIIynlJ/lOma WIltIleallns inIemIe<iale betvIoeeo dtIfuse largeIk:elIIynlJ/lOma In! cIassi:aI Hodgkin
~. MediastJnaI mass. The ~ is COfT9)5ed rJ a sheel4e growth rJ eels wi\tI"i~ C)'t:lpIasm.
The inlrrnatay backgrol.nd is minimal. The phenotype resen'tIIed!hat rJ CHI.. WIth expression rJC030andC015.
bU: ~ lactn OCT21n! BOB 1 'fl'llnl po5Ilive
268
Mature
a-cen neoplasms
been shown between the two components 122651. Specific genetic changes
have not been associated with trenstormation of the lymphoma Of its components
to either CHL or PMBL Because the
mo rphological and phenotypic changes
are reversible, it is likely that epigenetic
rathe r than genetic alterations are
responsible for the change in morphology
an d immunophenotype 19331. A close
CHAPTER 11
Mature T and NK-cell Neoplasms
Adult T-eeilleukaemialtymphoma
Hepatosplenic T-eelllymphoma
Subcutaneous panniculitis-like T-eell lymphoma
Mycosis fungoides
Sezary syndrome
Primary cutaneous CD30 positive T-eeillymphoproliferative disorders
Primary cutaneous gamma-delta T-eell lymphomas
Peripheral T-<:ell lymphoma , NOS
Angioimmunoblastic T-eelllymphoma
Anaplastic large cell lymphoma (ALCL). ALK positive
Anaplastic large cell lymphoma (ALCL). ALK negative
D. Catovsky
H.K . Muller-Hermelink
E. Aalfkiaer
Definition
t -een prolymphocytic leukaemia (T-PLL) is
an aggressive t-een leukaemia characterized by the proliferation 01 small to
medium-sized prolymphocytes with a
mature post-thymic T-cell phenotype involving the peripheral blood (PB), bone
marrow (8M), lymph nodes. liver, spleen
and skin .
ICD-Ocode
9834/3
Synonym
t-een chronic lymphocytic leukaemia was
used historically as a synonym to- some
small cell variants
Epidemiology
T-PLL is rare. representing approximately
2% 01 cases of mature lymphocytic
leukaermas in adul ts over (he age of 30
I 1424 J; medi an age is 6S yea rs (range,
30-94 years).
Sites of involvement
Leukaemic t -eens are found in the PB.
8M, lym ph nod es. spleen. liver and sometimes skin.
Clinical features
Most patients pr esent with hep atospl enomegaly and genera lized lymphadenopathy.
Skin infiltration is seen in 20% 01pa tients,
and serou s effusion s, c hiefly pleural , in a
m inority ( 14241. Ana emi a an d thromboc ytopenia are co mmon and the lymphoc yte count is usually >100x 109/L and
> 200x 109/L in half of the patients. Serum
immunoglobulins are normal. Serology for
HTLV-1 is negative.
coa. a
Other tissues
Cutaneous involvement consists of pe rivascular or more dilfuse dermal infiltrates
without epi de rmotropism 11373, 1424 1.
The spleen histology shows d ense red
pu lp infiltration. whic h invades the spleen
c apsu le, b lood vess els a nd atrophied
white pulp 11663 1. In lymph nodes, the
involvement is d iffuse and tend s to predominate in the oaracortrcat areas , sometimes with sparing of tourcres Prom inent
high-endothelial venues may be numerous
and are often infiltrated by neop lastic c ells.
Ge netics
Antigen receptor genes
t-een receptor (TCR) genes , TRB@ and
TRG@, are clenatly rearra nged.
Cytoc hemistry
T orotvmohocyt es stain stron gly with
(I -na phthyl ac etate este rase and
acid
p hos phatase with do t-like stainin g in the
Golgi region 114251. f--iov.Iever, cytochemistry
is rarely used for routine diagnosis currently.
"'",p"o<ogy
Peripheral blood and bone marrow
The d iag nosis is made on P8 films which
show a predominance of small to
medium-sized lymphoid cells with nong ranular basophilic cytoplasm, round .
oval or markedly irregular nuclei and a
visible nucleolus. tn 25% of cases the cell
size is small and the nucleolus may not be
visible by light microscopy (small cell variant) 114261. In 5% of patients the nuclear
270
Immunophenoty pe
r-proiymonocvtes
----l...
f"i- 11.C3 T-<eI ~ IeuIo:.aemia " l~ node is ddfuseIy inIiIlrated, t:U: a IoIic:le is l.I\aIIeded. GIemsa
B F'forrWlenl I'io;tI encIolheliaI verUe shorImg Iu!lloos cees in tile Unen , in I!le waI aIld the aqacent
pnro1el Giemsa stall.
1QIl.
271
W C, Chan
K. Fou car
W G. Morice
Definition
r-cea large granular lymPhocytIC leukaemia
(T-lGll is a heterogeneous disorde r char-
acterized by a persisten t (>6 months) increase in the number 01 per ipheral b lood
(PB) large granular lymphocytes (LGl),
usually between 2-20x 1()8i\... without a
clearly iden tified cause.
ICD-O cod e
9831/3
Sites of invotvement
Ep;demiology
Tl GL leukaemia rep resents 2-3% of
cases of mature lymphocytic leukaemias.
There is an approxima tely equal ma le:lemale ratio with no clearly de fined age
peak . The disease is rare 3%) before 25
years and the majority of cases (73%)
occur in the 45-75 years ag e group _
Etiology
The und erlying palho p hysiologic mechanisms for T-LGL leukaemi a are not well
und erstood. This disorder is fairly unique
in that the cl onal T-LGL cells retain many
phenotypi c and functi ona l pr op ertie s of
normal cytotoxic effector r-ceus 12201,
One theory po stulates that T-LGL leukaemia arises in a selt ing of sustained
immune stimulation. The frequent assoc iation of T-LGL leukaem ia with autoimmune disord ers sup ports this hypothesis
1220, 2428 1. Absenc e of homeostat ic
apo plos is is also a feature of the T-LGL ,
as these cel ls exp ress high levels of FAS
and FASL , lead ing investiga tors to pr opose ac tivation of pr o-survival pa thway s
in T-LGL whic h p revent s FAS signaling
[648, 1954 1. FASL levels are ele vated
in sera of many patien ts, which may be
impo rtant in the pathogenesis of neutropen ia 113231.
Clonal expa nsions of T-LGl can be observed following allogeneic bo ne ma rrow
(BM ) transplantation, usually reflec ting a
restricted t-een reper toire. However, rare
cases of T-l Gl leukaemia have also been
observed as a torm 01 post-transplant
Iymphoproliferative disorder 1103, 15731.
A pitfall in diagnosis is the frequent d evelopmen t of oligoclonal T-cell populations
following anooeneic BM transplantation
272
D. Catovskv
" "_
F"IQ.tt.G4 The various na phologic 'IlWla"IIs of LGl. in !he perVoeraI bk:lod (Wriltlfs slain).
- .
f.. l1,D5 Bone marrow lindn;Js in H.Gl.Ieukaerria. A ~ceIs ridlr.rte mrslibaly. as dernalstTaIed by 5lai1b TlA1. B,C ReadiYe ~ iJW'e9iItes.l~
lDUesin... bone marrow irnrIuIostainec wrth iII'l..cD2O (S) Md ri-C03 ie). !k:eIs in ltle nodule /If1I8O'Ined wrth C03 poS/lro'e T<eIs lNl predominate iIllhe~.
but which mee t all other appropriate crtene. are consistent with this dia gnosis.
Despite the cvtopenlas. the 8M is norrrocellular or twoocenurar in about 50% of
cases; in the remainder, the 8 M is typically slightly hypercellular 1152 1, 1662} .
The granulocytic ser ies often show left
s meo matu ration and mild to moderate
-etccnn fibrosis is present 13901. The extent 01 8 M invo lvem ent is va riable and
LGL usually comprise less than 50% of
j-e cellula r e leme nts w ith inte rstitial/intrasinusoi da l infiltra tes which are d ifficu lt
toidentify by mo rpho logic review 11 52 1).
Non-neoplasl ic nod ular lymphoid agg regates containing many
surrounded
bya rim of CD4 + T-cells are also freq uently
present 11662 1. Sp lenic invo lvement is
characterize d b y inf iltration and exp ansco of the red pulp cords and sinuso ids
by T-LGL with spari ng of the often hyperplastic white p ulp 116631.
Cytochemistry
The granules are aci d phosphatase and
~ ~idase positive. However, enzyme
cytochemic al stains are rarely used for
rc:utine diagnosis.
Genetic s
Antigen receptor genes
Cases classified as T-lGlleukaemia are,
as a rule, clonal. as documented by TCR
gene rearrangement studies 11247f. The
TRG@gene is rearrang ed in all cases regardless of the type of receptors expressed. The TRG@gene is rearranged
in cas es expressing the TCfbP receptor,
but the TRB@ gene may be in ge rmhne
connquranon in cases expressing the
TCR')'l5 receptor 123361.
a-ceus
~
RGL leukaemia is typically a disorder of
mature CD3, COB and t-een receptor
(TeA) o il-positive cytotoxic t-eens 1390.
16831. Uncommon va riants include C04
TCfbIl-positive cases and TCfTr,S-positive
cases; approximately 60% 01 the ratter
Cytogenetic abnormalities
Thefe is no unique karyotypic abnormality,
but nume ric and structural chromosomal
abnormalities have been described in a
small number of cases 112471 _
Postu late d normal counterpart
COB-positive t-een subset for the common type and a subset and T lymphocytes lor the rare typ e expressing the
'" TCA
Prog nosis and predi ctive factor s
The tvmobopronterauon is typ ically indolent and non- prog ressive and some
investig ators feel that it is bett er regarded
as a c lonal d isord er of uncerta in sig nificance rather than a leukaemia. Morbid ity
is associated with the c ytopenias especially neutropenia, but mortality due to this
cause is uncommon. In a series of 68
pat ients, median survival was about 13
years 15631 . Rare cas es with an agg ressive course have been described 1773,
22491. Patients who require treatment
may benefit from cvcrosponne A, cyclophosphamide and corticosteroids, low
dose methotrexate or pen lostalin 11247,
16641.
273
N Villamor
W G . Moric e
W C . Chan
K. Fouc ar
Defin ition
Chronic Iymphoprolileralive disorders of
NK cells are rare and heterogeneous.
They are characterize d by a per sistent
(> 6 months) inc rease in peri pheral blood
(PS) NK cells (usually ~2x 109/l ) w ithout a
clearly identi fied ca use. It is d ifficult 10 d istinguish between reacti ve and neoplastic
conditions. without hig hly specialized
tecnoques. Chronic NK-ceU Iymphoproliterative disorder (ClP().NK) represents
a proliferat ion of NK cells associated with
a chronic c linic al course , and is co nsidered a provisiona l entity.
ICD-O code
9831 13
Synonyms
Ch ronic NK-cell lymphocytosis , chronic
NK-Iarge g ranular lymphocyte (LGL) tyroobopronterauve disorder. Nk -ceuuneaoe
granular lymphocyte prolifera tive disord er, Nk-ceu LGL lymp hoc ytos is. indolen t
larg e g ran ular NK-eeil lympho prol iferative
dis orde r.
Ep;dem;ology
CLPO-NK occurs predominantly in adu lts
with a median ag e of 60 yea rs without sex
p redominance 11248, 1304. 1799 1. Unlike
Epstein-Barr vi rus (EBV)-associated agg ressiv e Nc-ceu leukaem ia . there is no
rac ial or ge netic pred isposition .
Etiology
A transient increase in circul ating NK cells
may be encountered in many conditions
such as autoimmune d isorders Of viral infections 11248, 17991. NK-eell activation
d ue to an unknow n stimulus, presumably
v iral, is postulated to pla ya role in the
early pathogenesis of chronic IymphoproIilerative d isorders of NK cells by selecting NK-eell clones, althoug h no evidence
of direct NK-eell infection has bee n observed 113)4 .1340.1799.24831 , Agenetic
susceptibility may be linked to haplotypes
containing higher numbers of activating
kille r immunoglobulin-like rec ep tor (KfR)
genes (649, 1982, 2482),
274
Fig. 11.06 ChroniC tymphoproIifetative disorders of NKcells. Penpheral blood ftlms show the lymphocy1e 'Mth coarse
azlJfOPhilic granulation(A), ~mphocyle withnumerous ftne granuiations (8), lymphocyte withscarce granlriaoon ;,,\IlI
limit of~isi bility (e). 0 Intrasinusoidal marrow infiltrationby granzyme B positive cells, Note the bland nuclearcytology
of the antigen ~ti l'El cees.
Sites of involvement
Predominantly PB and bone marrow- (BM) .
Cl inic al features
The majority of patients are asymptomatic ,
but som e may present with systemi c
sym p toms and/or cytopenia(s) (mai nly
neutropenia and anaemia ). Lymphadenopathy, hepa tomegaly, splenomegaly and
cutaneous lesions are infrequent 11304.
1661, 1799 /. Chronic Iymphoproli le rative
disorders of NK cells may occur in associanoo with other med ical conditions such
as solid and haemato log ic tumours, vasc ulitis, splen ec tomy, neuropat hy and autoimmune d isorde rs 11304, 166 1, 1695,
1799 1.
The ci rculating NK cells are typically intermeot ate in size with round nuclei with
con d ensed ch romatin and moderate
amounts of slig htly basop hilic cytoplasm
co ntaining fine or coarse azurop hilic
gr anules. The BM biop sy is ch arac terized
receptor tsotcrms 1649. 24821. Other abnormalities of NKR incl ude uniform. bright
CD94/NKG2A heterodimer expression
and diminished CD 16 1 expression 11304.
1520. 1982. 236 11.
Genetics
Karyotype is norma l in most cases 11661.
1799. 21731. There are no rear rang ements of the immunoglobulin and
receptor genes. as expected fOf NK c ells.
In female patients. It is possible to exploit
x-cnrorosome inactiva tion as an indi rect
marker of c lonali ty. A skewe d ratio of
t-een
cess
Disease progre ssion with inc reasing lymphocytosis and worsening of cvtocemas
is ob served in some cases. The presence
of cv tcoeruas. rec urrent infec tions and
comorbi di ty may be harbingers of a
wor se prognosis. Rare c ases with either
spo ntaneous co mplete remission {1304.
1661, 1799. 2484 1or transtomaton toan
ag g ress ive NK -c ell d isorder have been
desc ribed 1990. 1628. 18781 The p resence of cytogenetic abnormalities may
imply a worse p rognosis and cou ld be related to ra re transformations reported in
the literatu re 11628 1.
275
J .K,C , Chan
E.S. Jane
E. Ra lfkiaer
Y-H . Ko
Definition
A systemic neoplastic proliferat ion of
Nx-cens almost always assoc iated w ith
Eps tein-Barr vir us (EBVj and an aggressive cl inical cour se .
ico-o eeee
9948/3
Syrooym
Aggressive NK-ce ll leuka emiaJlymphoma .
El' derr1iology
.1. ..
...
.....
Fig.11.07 Aggressive NK<e/l leukaemia A In !his blood smear. the neopIas1ic cells are IIefY similartl normal large
granular lymphocy1es, B In !his case, the neoplastic cells have basophiliC cyloJlIasm. and nuclei wiIh more open
chromatin and disbnd nudeoli. AzurophiliC I13nules can be observed in the cylopIasm, C The neoplaslic cells are
negative for s~ CD3 (leLl4), wtIiIe ee normal T lymphocytes are staifled. D The lleOPlastic cells show ~
illmunoreactivity lor C056.
dis ease with uniformly fatal outcome irrespective of treatme nt; and freq uent ex
pression of CD 16 11582, 2128 1.
Morpholog y
Ci rcula t ing leukaemic cel ls can show a
range of appearances from cells indistinguishable tram normal large granu lar lymphocytes to cel ls with atypical nuclei
featuring enlargement, irregular fold ings.
open c hromatin or distinct nucleoli. There
is an ample amount of pale or lighlly besophilic c yto plasm con taining fine (X
co arse azu rophilic granules , The 8M
show s mass ive, focal or subtle infiltratioo
by the neoplastic cells and there can be
intermi ng led react ive tuenocvtes wilh
nae rroonac ocvtoeis. In tissue sections
the leukaemic c ells show d iffuse or
pat chy destruct ive infiltrates. They often
appear monotonou s, with round or irregular nuclei, c ondensed c hromatin and
small nucleoli , but the y can sometimes
show sig nificant nucl ear pieororphem
There are freq uentty ad mixed apoptobc
1386.903. 11261.
A
Ft.l1.oaAgpssMI NK<el IetAaema. A Giemsa-stained I'I\TOW asprate. The neoplasllccels show pleolnoqnc
~ b*l ru:IIi. prorrinenI ru:illoli lWId cytopla:stric 3lIftlPhIc granJes in ltle basoIt*~ , Bl~
IIlde. The neopIastJc eels appear mOlloD lOUS. and poss.e$$ l'OI.I'ld nudei. There are many inl~
--
IrrmLllOphenotype
The neoplastic ce lls are CD2 +, surf ace
C03-. COOt: +, CD56+ and positive for
~ molecules. Thus . the irrmunopheoo-type is identical to that of exnenodet
cvto-
Genetics
cytogenetic stu dies and patt ern 01X c hromosome inaclivation in female pa tients.
,
,
,
j
,.
Agg ressive NK-ceil leukaemia
277
L. Ouintanilla-Martmez
H. Kimura
E.S. Jaffe
IC().() code
The provisional code proposed for the
fou rth edi tion of ICO-Q is 972413.
Historica lly this p roc ess has been d escri bed und er a variety of terms inclu di ng:
fulminant EBY+ t-een LPO of chil d hoo d ,
sporad ic fatal infec tious mononuc leosi s
(FIM); fulm inant haemophag ocytic syn d rom e in c hild ren in Taiwan 121151: fatal
EBV-associ ated baemopn aqocvttc syn drome in Japan 11 144 1: an d severe
CAE BV {1149, 1636,21271.
The term fulminant or fatal haemoph agocytic syndrome has been used to
describ e a systemic d isease secondary
to acute primary EBV infection affecting
previously healthy children . It has been
shown to be a monoclonal COB+ EBVassociated Iymphoproliferative disorder.
and therefore is now considered equivalent
to systemic E8V+ T-celllPD of childhood
Be ene.t-eens
Epidemiology
Systemic EBV +
LPO of childhood is
most prevalent in Asia . primarily in Japan
and Taiwan 111 44 , 1149 .2115.21271 , It
has been reported in Mexico and rarely in
Western countries 117971. It occurs mosl
often in children and yCM.mg adults. There
is no sex predilection .
t-een
l179n
Definition
t-een
Systemic EBV+
LPD of childhood is
a hfe-threatening illness of children and
you ng adults c haract erized by a c lonal
proliferation of EBV-infec ted
with an
activated cy toto xic ph enoty pe , It c an
occur shor tly after primary ac ute EBY infec tion or in the sell ing of chronic ac tive
EBV infe ction (CA EBV), It has a rap id progre ssion with mul tiple organ fa ilure , sepsis and death, usua lly from days to weeks.
This entity shows some overlapping clinico pathologic features w ith ag gr essive
NK-cellieukae mia.
t-eens
278
Etiology
Alt hough the etiology is unknown, its
association with primary EBV infection,
and the racial predisposition, strongly
suggests a genetic defect in the host
immune response 10 EBV 11 144, 1149,
1797, 21 15, 2127) ,
Sites of Invo lvement
It is a systemic di seas e. The mos t commonly involved sites are liver and spleen
followed by lym ph nodes, bone marrow
(BM) , skin and lung {1 144, 1149 , 1797
2115,21271
"_.1Ii
_ G .. .
Fig. 11.12 Systen"ic EBV. T<el lPO of childhood A The liver shows a subde sinUSOIdal lymphoid infiltrate Iac:U'lg cytOlogIc atypia EIyIhrqlhaglxyts is pronWIenl.
BThe rlliIlrabng Iyl'npI'locyfes are C08-positive. C Nearlyall ~ in the S1llUsoids are EBER-posb'te.
CDcaI features
Mmphoklgy
72 bp
TeRr
~ 11.13
lPO fA etill:tlOOd A The spleen sIJ:Ms depIebon fA tIM! ~e!up and prorninenl
inMrales. The nodules are composed predomil'Iaolly DI CQ4.poWte eels
I EBER inSCU ~ shcM t'lal 1tle C04-positiye eels are also positivelor EBV RNA.
SysIerNc EBV.
-ada! <n:l
T~
~ ~
EBV-~il jve
279
t-eens.
Hydroa vaccinfforme-Iike
lymphoma
Definition
Hyd roa vaccinnorrre-uke lymphoma is an
EBV-positive cutaneous t-een lymphoma
occurring in ch ildren, and associated with
sensitivity 10 insect bites and sun sensitivity.
Etiology
The neopl astic cells, usually T-eens. bu t
sometimes NK-cells, are nanetoerrec by
ESV. Patients exhibit hy pe rsensitivity to
sunlight, and insect bites , often mosquito
b ites, which precipitate cl inical symptoms
11582/.
Sites of involvement
This is a c utaneo us co nd itio n that p rimarily affec ts sun-expo sed skin, in particu lar
the fac e 1596 , 10271.
Clinical features
It is characterized by a p apulovesicular
er uption that generally proceeds to ulce ration and scarring. In some cases. systemic symptoms including feve r. wasting.
lym phadenopathy and hepatosplenomegaly may be present. partic ularly late
in the course of the disease {147 . 3991.
Mmpoology
The neoplastic
are generally small to
med ium in size w ithout sig nifica nt atyp ia.
The infiltrates show extension from the
ep id erm is to the subcutis , showing necrosis, angioc entric ity an d anqioin vasion.
The ov erlying epidermis is freq uen tly
ulcerated 11471.
cene
ICD-O code
The provisional code proposed lor the
fourth ed ition oflCD-O is 972513.
Irrrnuno phenotype
The cells have a cytotoxic
Of, less
often, NK-ce Uphenotype. with expression
of CD56.
Epidemiology
This co ndi tion is see n mainly in c hild ren
and ad ole scents from Asi a , or in Nat ive
Ame rica ns from Central and South Am erica , and Mex ic o. Like other Eb v- pos itive
and NK-c eillympho mas, pred isposition for this cond ition ma y be related to
a defec tive cytotoxic immune res ponse to
EBV. It is rare in adults 11 47, 432 1.
Genetic s
Most ca ses have clonal rearra ngements
01 the TCR ge nes Some c ases of NK
de rivation w ill not show TCR ge ne rearrangement 1399, 2455 1.
EBER in situ hybri di zation is expressed in
all 01the atyp ic al cells, but LMP 1 is generally neg ative . EBV is monocl ona l by
term inal repeat analysis.
t-een
280
Fig. 11.15 Hydroa vaccini!orme-like lymphoma. Sunexposed areas of the skin exhibit a papulO'lesiaJtar
eruption. Many of the lesions are ulcerated WltIl a
haemoo!lagic crust.
t-een
Definition
A peripheral T-cell neoplasm most ott en
composed of high ly pleomorphic lymphoid cells. The disease is usually w idely
roo code
9827/3
tffi.\Ll-4e1ated diseases.
~lit
difotd.rs
-..""
""'" ""
-""
l~
reoe(lymphoma)
~ ikll type
&,
P."".
-,'''''''"
K. Ohshima
E.S, Ja ffe
M . Kikuchi
Etiology
HTLV-1 is causally linked 10 ATLL, but
HTLV-1 infection alone is not sufficient to
resull in neoplastic transformation of infected cells. The p40 tall: vital protein
leads to tra nscri ptional ac tivation of many
genes in HTLV-1 infected lymphoc ytes
1726}. In add ition. the HTLV-1 basic leuc ine
zi pper fac to r (H8Z) is thought to be impo rtan t for T-cell proliferation and oncogenesis 119401. f-iowever, add itional genetic
alternations acquired ove r time may result
in th e dev elopment of a ma lig nanc y,
HTLV-1 also ca n indi rectly cause other
d iseases, suc h as HTLV-1 associate d
myelopathy /tropical spas tic parap a resis
{21481.
Gastroilleslinal lraC!
'-
Ulcersfu!1
T"m. ..
""
.... """""
~ dilO rden
""""""
.......
HTllJ.l..as:sociB\ed ~(HAB)
HltV-l~ 8l'thnlpIthy (liMP)
IfTtVl-a&SOCia1ed ,.eptwopaltly
Sites of involvement
Most ATLL patients present wit h wid espread lym ph node involvement as well
as involvement of PB , The number of cirdoes not correculating neopl astic
late with the degree of bone marrow (8M)
involvement, sug ges ting that ci rculating
cells are recru ited from other org ans suc h
as the ski n. In fact , the skin is the mos t
common ext ralymphatic site of involvemen t (>50%).
The distribution of the d isease is usually
syste mic, involving the spleen and extranodal sites including skin. lung , liver. gastrointestoatnact and central nervous system
1298 1. Epidemiologica l differences occur
in patterns of presentation. For example.
cens
Mao.........,...
fC.p.11.11 MAT-<8I ~.
fir'odIngs of cutaneous lesions have been dassrlied as
~ (A). paplAes {Sl n:I nrxUes (e).
Adult T-eellieukaemia/lymphoma
28 1
,- _
Table 11.G2
lXaglW)Slic mlefia fordiniCal subt)1les 0( Ad~ T<8llIeu~, Moddied from Shimoya-na at ai. {2010}.
Smoldering
N,
Bklod abnormal ~
LIlH
"""'"
"""'"
l~nopalhy
"'~
>"
""""
"""".......
No
No
No
Clu"onlc
Acut.
I.1o<phology
ATLL is charac terize d by a b road spectnm of cytological features 116301. Several
rang ing from sparse to mod erate. Os teoc lastic activity may be prom inent, eve n in
the absence of BM infiltrat ion by neop lastic cells .
Skin lesions are seen in mo re than 50% of
patients with ATlL. Epid ermal infiltration
wit h Pautrier-like rnicroabscesses are
commo n 116301. Dermal infiltr ation is
mainly pe rivas c ular. bu t la rge r tumour
nodu les with exten sion to subcutaneous
fat may be observed .
Diffus e infiltration of many organs is indicative of the systemic nature of the disease, a nd presence 01 circulating
malign ant cells.
Irrmunophenotype
Tumour cells express r-cea-assocretec
ant igens (C 02. CD3. CDS) . but usually
lack CD7. While most cases are CD4 +,
COB-, a few are CD4-, CD8+ or double
posi tive for CD4 and CDa. CD25 is
stron gly expressed in nearly all cases.
The large trans formed cells may be positive for CD3Q, but a re neg ative for AlK
121 49} and Cytotoxic molecules. In ad dition, tumou r celts frequently express the
chemoune receptor CCR4 and FOXP3, a
fea ture of reg ulatory t-eens 11 112},
Fig. 11.22 Neoplastic eels Jlihrale Ihe epidemIis, pr0ducing Pautrier e microabscesses.
Genetics
An tigen receptor genes
T-cell rec e ptor genes are clonatly rearranged 116311.
Oncogenes and other molecular changes
Neoplastic cells show monoclonal integration of HTLV-1. No clonal integration is
present in healthy carriers 122741. Tax, encoded by the HTLV-1 pX reg ion, is a critical nonst ructu rat pro tein that plays a
central role in reukaerrcqenese. and activa tes a variety of c ellular ge nes {17221.
Furthermore, enhanc ement of cyclic AMP
response ele ment b ind ing transc ription
fact or (CREB) phos phorylation by the
Fig. 11.23 Adu~ T-cee ietJkaemiaI1Y!ll1lhoma, A InItlis case, Itle infttlra le coessts of largeeens with anaplasticfealures,
B The cells arestrongJ y C030+, ra i~ng the differential diagnosis ofarlaplasliG large eel ~
Adult T-cellleukaemiaJtymphoma
283
~ (~ )
._....
CI'ftnIc ('52}
L.ymphomll ( 1&11)
. _
Col&5l
--...,
..
O'
"
-.....
No<
....ec
"
00
v....
Fig. 11.25 A &r.1vaI cJ paliln5 wiltIlOA T-<:elI~.Acute;nj ~1lluS Iorms I1a'o'8 l1l'i ~ ctilical 00U'Se. whe!'82S longer ~ i'I seen.,
paIIentS..etI ctwnic Of ~ disease. B MA T - a ' ~. HR\Ll proWaI ONA~ a"d cinicaI Sl.tJIype$
284
Definition
A predominantly ex tranodal lymphoma
characterized by vascular damage and
destruction, prominent necrosis , cytotoxic
phenotype and association with Ep steinBarr virus (EBV). It is d esig nated N KIT~
(1'lSlead of "NK") , bec ause whi le most
97 19/3
J .K.C. Chan
L Ouintanilfa-Martinez
JA Fer ry
S.-C. Peh
Sttes of involvement
Extranodal NK/T-ce Ulym phoma almost atways shows an extranodal presentation .
The upper aerodiq estive tract (nasal c avity, nasopharynx , parana sat sinuses ,
palate) is most co mmonly involved. with
the nasal c avity being th e p rototyp ic site
of invo lvement. Preferential sites o f exnanasat involvement incl ude the skin, soft
Syrooyms
AngiOCentric T-cell lymp homa; malign ant
il'idIlI1e reticulosis; polymorphic renculoSIS: lethal midline g ranuloma: anqlocen rIC immunopro hlerative lesion .
Epidemiology
Extranodal NKfT-c ell lymp homa is mo re
prevalent in Asi an s. and th e n ative Amer-
Fig. 11.26 E.x1rcn::ldaI NKIT-<:eI ~. nasattype. A fJparIsionol\tle nasal bIidge, B Cor!lMedlom:lp'n, The
Uncu II \tie nasal caVIty edenCls upwMl no toe ortlil reSIAlrlg II proplosis
EIioIogy
Li~ le is know n ab out the etiology of extram al NK/T-cell lymp homa , However, the
ofJfY strong association wit h EBV, irreeecnve of the et hnic or ig in of the pa llents, suggests a prob able pathogenic
Qeol the virus 170, 386, 389, 639, 1093 ,
'795, 22991 , The EBV is present in a
IXrIaI episomal form 170, 389 , 639 , 944 ,
KOO. 1448, 1795. 2 130,2299J with type II
lalency pattern (EBNA-1 + , EBNA-2-,
IMP1+), and commonly shows a 3O-base
pair deletion in the late nt membrane protein1 gene 1415 , 589 , 639 ,1 205 , 2 143J
Most stud ies sho w that the EBV is almost
l tlays of subtype A 11 48, 639, 1717,
21)), 22481 . The d isease activity c an also
te monitored by measuring Circ ulati ng
EBV DNA; a high titer is furthermore corI!Iated with extensive disease, un'r.Q.jrable response to therapy an d poor
s.tVival l1 OSI.
FIg. 11.21 ExtrarcdaI NKIT<.elI ~ ,nasaI-type . A F'!'ot!wlenI \k.efa1lon and necrosis 1\ ht nasal nu::osa
B Thenasal rru:osa ill dlIMely rihlBd 1nI e~ by.. abnarmaI WlOId irIIinIIt . The rru:usaI gIIilnds ~
showa pecuIar dear eel cNnge . C,D ~ NKIT<eI ~ in Itle IestJS C There is a tifIlJse dense1ymphoid infiltrate. wilhprorrW1enl ooagt*l1rve oeaosis. D TheneopIiIstic eels a~ monoICInOuS and are mediuTl-lIized.
Extranodal NKfT-ce lllymphoma , nasal type
285
Morphology
The histological features 01 extranooar
NKIT-ce ll lymphoma are similar irrespecuve of the site of involvem ent. Mucosal
sites often show extensive ulceration. The
lymphomatous infiltrate is diffuse and permeative . Mucosa l gland s often become
widely spaced or are lost. An anqcceotnc
and ang iode strucli ve growth pattern is
frequently present. and fibrinoid changes
can be seen in the blood vessels even in
the absence of arqtonvasion. Coagulative
286
w-ana,
~,
J'
'. I
.'.
" '.
are present
ExtrGrlOdal NK/T-celllymphomas, particularly those predominated by small or
mixed cell populations . or those accompanied by a heavy admixture of muammalory cells (small lymphocytes. plasma
cells, bstocvtes and eosinophi ls) may
ll'IlITIiC an innarrmatory p roc ess 1381.
911 1. The lymphoma can some times be
accompanied by florid p seudoep ithe jcn atous hyperplasia of the overlyi ng
epithelium
Irrmunophenotype
The most typical immunophenotype of
emanooat NK/T-ceillymphoma is: CD2+ ,
CD56+. surface CD3- (as demonstrated
on fresh or frozen tissue) and cytoplasmic
CO&+ (as demonstrated on fresh, frozen
or lixed tissues) {381 , 388, 1032, 1037,
22131. CD56, although a highly useful
marker for NKcells, is not specific for exlranodal NK/T-ceil lymphoma and c an be
expressed in peri pheral f -ceu lymphomas. particu larly tho se tha t ex press
the't6 l-cell receptor.
Cytotoxic molecules (such as granzyme
B. TIAl and perforin) are positive {639 1
Dlher T and NK-cell associated antigens
287
.,.'.
Fig. 11.34 Emnodal NKJT<elI ~phoma, nasa/type A,S The neoplasticcells show strong staining !ofcyloplasmic CD:k (A) and CD56 (B). C The neoplasticcells show s~
granular staining b granzyme B. 0 In situ hybridizabon!of EBV-eocoded RNA(EBER). InthiS rlasallumour, practically alilhe oeopIastic cells show nuclear labeling.
288
Enteropathy-associated T-cell
lymphoma
Defin~ion
G, all
H. Stein
t-een
Enteropathy-associa ted
lymphoma
(EATl) is an intestinal tumou r of intr aepithelial T lymphocytes , shcwv'ing varying
degrees of transformation but usually presenllng as a tumour composed of la rge
I)rnphOid cells. otten with an inflammatory
background. The adjacent small intestina l
mucosa shows villous atrop hy w ith c rypt
hyperplasia, In 10-20% of cases, the lymphoma is compose d of monom orphic
medium-sized ce lls . This monomorp hic
variant (type II EATl) may occur sooraorcally. without risk factors for coeliac
disease.
ICI}{) cod e
PG Isaa cson
A. Chon
97 1713
Syoonyms
Intestinal I-ceaIvmonoma (with and with-
E,>demkllogy
The disease is uncommon in most p arts
al tha world, but is seen with g reater frequency in those areas w ith a high prevalence of coeli ac d isease , in part ic ula r
Northern Europe . However, the monomorphic variant appears to have a b roader
geographic distribution, and is encounin Asia and oth er regions whe re
coeliac disease is rare .
eeo
Etiology
In EATL, the association w ith coeli ac disease is borne out by positive serolog ic al
iests. HLA 002 or Da B ex pression an d
associated clinical findings suc h as d ermalltis herpeutormle an d hyposp len ism
1569. 1921, 23051. In the monomorphic
form cI EATL, an association with coeli ac
c! seese and othe r risk tacto-s is not
prtM!O 15481. suggesting that the I1"lOflOrrorphic variant may represent a oistmct
osease entity,
Sites 01 involvement
The lymphoma occurs most commonly in
the jejunum ()( ileum. Presentation in me
duodenum , stomach, colon or outside the
gastrointesti nal trac t may occur but is
rare ,
Clinical features
In EAll. a small proportion of the patients
have a history of childhood onset coeliac
disease. Most show ad ult onset disease
()( are d iagnosed as having coeliac disease in the same clinical episode in which
the lymphoma is diagnosed . Patients
present with abdominal pain , often assoc iated w ith intestinal perforation In a p roportion of p atients, the re is a prod romal
per iod of refractory coe liac d isease that
is sometimes accompanied by intestinal
ulce ration (ulcerative jej unitis), The clini c al
Table 11.03 f eatJns d entelQpalhy-asslXialed __ Ieslillal T<.elI Iymphoma (EAll) and lTl(ll1Ol11Olpl"ic WestrIaI T<eI
lymphoma (Type" EAll~
EATl
Type liEAn
F""""""
Immuoophenolype (437}
CO,
C056
HLA-OQ2I-D08
GenetICS (543}
+ 9q31.3 or-1 6q12.1
._,
+ l Q322 -q41
+ 8q24
tUYCl
""
""
""'
""
2B9
,
f IJ 11.39 Type II enteropalhy-aSSOCl3led T-<:eI Iym-
Fig. 11.'1 PCR of D~ extraded from enteropathyassocialed TGlI ~ . M.1I'OlecUa' weio;tIt rn<rter;
p. positive contn:ll; N. negative contn:ll; IMes 1 iWlCI 2.
!ynlIhoma: lanes 3lmd -4, ~ non-Iymphomatlu
"""".
29 1
P. Gaulard
E.S. JaHe
L Krenacs
WR. Macon
Definition
Etiology
971613
Eoi_
HSTl is a rare form ct~. representing < 1% 01 all noo-Hodgkin lymphomas.
Peak incidence occurs in adolescents and
young adults. with a male predominance
Sites of involvement
Patients p resent with marked sprenomeg aly. usually with hepatomegaly. but
Fig. " ,43 Hepaklspleric T-eel lymphoma A Cords and sinIsoids ofh! spleenareirlfillra1ed by a ~ plJpl.UtIon of neoplastic ~ eels wrth ITl9liI.rn-size ru:iI
in! a mocIeraIe m.of palecytIplasm. B The neopIas1ic eels ddIuseIy in6IlraIe !he Ile9abc SirluSl::G C The bone marrow is usoaty tlypeft:eWar wilh neopIasbc OllIs inIInIrIJ
5nISOicIs. D NeopIas1ic caIs ~ wilh imrYulOhistx:totl,isty b CD3.
292
""'phoIogyThe spleen is enlarged with diffuse involvement of the red pulp, without any
gross lesions. Diffuse hepatic enlargement is present as well.
Histopathologi cally, the cells of HSTL are
monotooous, with medium-sized nuclei
and a rim of pale cytoplasm 14651. The
nuclear chromatin is loosely condensed
with small inconspic uous nucleoli . They
large cell
Of
""""""'-
t-eens
Genetics
The cells have rearranged TRGO genes
Cases of .,& origin show a brauetic rearrangement 01 TRGOgenes. TRBOgenes
are rearranged in up cases: however,
non-productive rearrangement of TRBO
genes have been reported in some .,&
cases 17641. Isoc hromosome 7Q is pre sent in most cases, and w ith disease prog ression a va riety of FISH patterns
Hepatosplemc T-eclllymphoma
I
293
Subcutaneous panniculitis-like
T-cell lymphoma
E,S, Ja ffe
P. Gaulard
E. Ralfkiaer
L. Cerroni
C.J .L.M. Meijer
Definition
Subcutaneou s pannic ulitis-like T-eeillymphoma (SPTeL) is a c ytotoxic t -een lymphoma, wh ich preferentially infiltrates
subcutaneous tissue . It is composed of
t-een
ICD-O code
970813
Epidemk>logy
SPTel is a rare lorm of lymphoma, repre senting <1% of alt non-Hodgkin lym-
Fig. 11.'4 SlIX:ulaneous panniCulibiHike T-ceII Iymphoma, Infiltrate is conMed 10 ltl& subculaneous bssue
wiltIoul invoIvemenl oI ltl& overlying demli:s orepidermis,
Tlible 11 .04 Oilfaf&l1tia1 diagoosis of neoplasms expre~ng T<eUandNK<eUmarkers with frequent cutaneous involvement.
CD3,
CD4, COl
CliniCalleatures
Disease
-.-,
T-cell
Uneagt
reee...
R
,....
r....
NK-oelI, somt-
Cytotoxic
' PTCt
T~ . extremities and
...-
Extranodal NKIT<:eM
Nodules, tumours
+,',
+, +,-
Mycosis IqoiOes
-~
......."""'"
. ~ pUHssoc:iaIed prolewl,
+,',
-1+
" +. -
CD56
_.
"""""'"
,....
Iines T.-
I;....
- '"
T1A1 itr'ldIorGranzyme Bat'Id1or perbin: SPTa.., subcWnecus~ T<eI~, TCL T<eI~ ; Al.Cl
~Jargeoel~.
294
trunk
EBV
moltculuo
Fig.11.46 A SlIbclItaneous panniculitis~ i ke T-cell lymphoma. Turrour cells are associated withabundant histiocytes containing apoplolic debris, B NeopIasticcellssurround fat cells,
~ witl1 some admixed histiocytes, C Neoplasticcells have round to oval hyperchromatic nudei with inconspicuous nucleoli and abundant pale cytOl)lasm.
CfnicaJ teanees
Clinical symptoms are primarily related 10
The i1I~ trate involves the fat lobules. usu ally WIth sparing 01 septa. The overlying
dermis and epidermis are typically uruo...::ived. The neoplastic cells range in size,
bullfl anygiven case, cell size is relatively
constant. The neop lastic cells have irregular and hyperchroma tic nucle i. The lymphoid cells have a rim of pale -stai ning
cytoplasm , A helpful di agnostic feature is
the rimming 01 the neoplastic ce lls surrounding individual fat ce lls. Adm ixed
Irrmmophenotype
Genetics
The neoplastic cells show rearrangement
of t-een recep tor genes. and are negative
for Ep stein-Barr viral sequences. No specific cytogenetic features have been reported.
Prognosi s and predic tive factors
Dissemination to lymph node s and other
org ans is fare 181 4, 1175. 19191, The
5-y ear median survival ove rall is 80%;
however. il a haemophagocytic syndrome
is present, the p rog nosis is poor 11413.
24081 Combination chemotherapy has
traditionally been used, but one study
suggests thaI more conservative irmulosup pressive regimens (cyclosporine,
prednisone, chlorambucil) may be effective {2273BI . A distinction Irom cutaneous
-yO t-een lym phomas is impor tant. since
SPTCL has a much better p rognosis
12254,2408 1.
295
Mycosis fungoides
Definition
Myco sis lungoides (MF) is an eoioermotrooic. primary cutaneous t-een lymphoma (CreL) cha racterized by infiltrates
E. Ratfkiaer
L. Cerroni
CA sander
8 .R. Smeller
R. Willemze
Table 11.05
CinIcaI stagIIg system lor mycosis UlpIes and S6zary syndrome. asrecenIIy propos.ed by\lle ISCL-EORTC {1642\.
Stage I
Disease conlilecl kl tile skin with pa1dleslpapuleslplaQues <10% (5Iage IA) ex:>10% (stage IBI of
the ski! Sl.dace; no ch:aIy abnom\aIlyn1tJ 1'IlXIe$.
Stage .
Skll'l~ WlltJ pa~BSSOOaIed 'II'lIh early(N1-N2)~ node rwotvemen! (Slage. AI ex skin irrIoOlvemel'll withone ormere un::us (:>l an) (stage 11B~
St.iJge III
Stage rI
!'to;;! t:bld UTn.r tud8tt (:>1000lt1 ~ SUary oeis l ard'or eXlerlsi'o'e ~ node ifflCIwment (NJ)orvisalrallll'Mllver'nel1 (Ml ).
lCD-Ocode
970013
Epidemiology
TOIbIe 11.06
staging lor dinicaIyabnormaIlyn1tJ nodes (:>1 .5 an)., mycosis!lJ1goides and 5ezary s.,..,.nme
ISCLreORTC (1642)
.,
DutchIystem (195aA)
NO clusifitation {lJ4(lA}
l NO. no atypicaIlymphocy1es
LN l : oa:asionaI, isolated atypK:aIlyn1JIlocyIes
lN2: ~ (3-6 oe1s ) d at)'piCal ~
.3
Calegory 4 wnpleteeflacemen1
of architecture
""''''''''-
Ol, dermatopathic lymphadenopathy; CMC, cerebriform mononlJdear cells with nllClei :>7.s...m
' N2 is divided into2 categories, N2a withoot donal!)'rearranged T-eellsand N2b with donaUy rearranged T-rels.
Morpholog y
The histolog y of the skin lesions varies
with the stage of the disease. Early patch
lesions show superficial band-like or
lichenoid infiltrates. ma inly consisting of
lymp hoc yte s and rnstocvtes. Atypical
296
lmmunophenotype
The typ ical phenotype is CD2+ . CD3+ .
TCRfl+. CDS+, C04 +. Coa- I1809I. Rare
c ases ma y be positive for CDa 118091.
Suc h c ases have the same clinical be-haviour and p rog nosis as CD4+ cases,
and should not be consi dered a separate
entity {24071. ACD8+ phenotype has been
re port ed more commonly in paediatric
MF. A lac k of C07 is freq uent in all stages
of the d isea se 118091. Other alterations in
antigens may be
the expression of
seen , but mainly occur in the advanced
(tumour) stages 118091. Cutaneous lymphocyte anti gen (CLA) associated With
lymphocyte homing to the skin is expressed in most cases. Cytotoxic granuteassociated proteins are only rarely
expressed in the early patch/plaque
lesions, but may be positive in a fraction
of the neoplastic cells in the more advanced lesions 123331_
t-een
f-ceu
pr oma.
or
Genetics
T<ell rec eptor genes are clonally rearranged in a variable proportion 01 cases ,
possibly depending upon the number 01
tumour cells and the detection technique
employed 11765. 23981.
Complex karyotypes are p resent in many
patients , in par tic ular in the advanced
stages 11 381 . 2 1901. A vast number of
Fig. 11.50 MF!um()IJf stage (AJ wiltl histological translotmation toa large cellymphoma (8).
Mycosis fungoides
?37
Fig. 11.$3 Mycosis l.npdes. A FoIo.*Jtropic myoosis foogoides Wlt!l atypic:al ~ irlfiltrabng a _bide
B Hole O8lebllforrn nudIi , C The alypicaleels areCOJ.potsi\i'we. 0 The irM:llYed loIde shows IIlI.ICinOuS ~lion
WIlh ~ of AIc:ian bkJe-positive matel'ial.
different structural and numerical alterations have been desc ribed . Constitutive
activation of STAT3 and macuvauon of
CDKN2A1p ltr" ... and PTEN have been
identified and may be associated with
d isease progression 11583. 1951,1952,
205 1, 24241. Ge ne ex p ress ion p rofi ling
studies have srown tumour necrosis tactoe
(TNF) antr-acootonc pathway activ ation in
the tumouri ge nesis of MF 1226 11.
Ponloulctroplc MF
Fo lliculotro pic MF is c haracte rized by the
presence of follicular infi ltrates of atypical
(cerebri form) CD4+ T lymphocyt es etten
with spari ng of the ep ide rmis 1797f. Most
c ases sho w muc inous de ge neratio n of
the hair fo llic les (fol licu lar mucinosis) bu t
similar c ases with out fo llicular mucinosis
have bee n reported {2297}. The lesions
p referentially involve the head an d neck
area and often present w ith g rouped follic ular papules associated with alopecia
298
Variants
Pagetoid reticulosis
Pag etoid reticulosis is characterized by
the presence of patches or plaques with
an intraepidermal proliferation of neoplastic t-eens 1870}. The term should only
be used for the localized type (WoringerKoIopp type) and not for the disseminated
type (Ketron-Goodman type) as cases
corresponding to the latter category woUd
currently most likely be classified as
aggressive epidermotropic C08-positive
CTCl or cutaneous y&-positive T-cell tyrophoma 124071. The atypical cells have
medium-sized or large. sometimes hyperchromatic and cerebriform nuclei, and either have a CD4+, C08- or a CD4- . CD8+
phenotype. CD30 is often expressed. In
contrast to classical MF. extracutaneous
dissemination or disease-related deaths
have never been reported 124071Granuloma tous slack skin
Granulomatous slack skin (GSS) is an extremely rare subtype of CTCl characterized by the slow developme nt of folds 01
lax skin in the major skin fol ds (axillae.
groin) and histologically by a g ranuloma
tous infilt rate with clonal CD4+ T cells.
abundant macrop hages and multinucleated g iant cells 123001, In approximately
one third of the repo rted patients. an assoc iation w ith C HL has be en observed,
An association with c lassical MF has also
been reported (2300 ). Mos t patients have
an indolent clinical c ourse [12611.
Sezary syndrome
Definition
5ezary syndrome (SS) is defined by the
reo ct erythroderma. generalized tym~lhy and the presence of CIOnaJIy
related neoplastic
with cerebriform
ru::lei (5eZ8ry cells) in skin , lymph nodes
and peripheral blood (PB). In addition.
nc. moreof the foiloNing criteria are reIpfed: an absolute 5ezary cell count of
aeasr 10CXJcelis per mm3,an expanded
CD4+ t-een population resulting in a
C04ICD8 ratio 01 more than 10 and/or
t-eens
9701/3
KDOcode
E. Ralfkiaer
R. Willemze
SJ . Whill aker
Clinical features
Immunophenotype
Tumo ur cells are CD2+, CD3+ , TC RB+
and CD5+ . Most cases are CD4+ . Exp ression of CDa is rare . Sezery cells express cutaneous lymphocyte antige n (CLA)
and the skin-homin g receptor CCR417031
and characteristically lack CD7 and CD26
1204 , 1571 , 2046}. T p lastin mRNA and
protein have been shown to be enha nced
in Sezary ce lls relativ ely 10 normal he lpe r
t-eens 11110 , 2 1161.
Ge netics
T-ce ll recept or genes are c lonally rearranged {1765 , 239 7, 2398) Recurrent
c hromosomal ab norma lities have not been
detected in SS, b ut com ple x karvotvpes
with numerical and structural alterations are
COTfT'Olandsimilafto MFl 161, 1381, 13821.
Sites 01 involvement
SS isa leukaemia an d thu s b y definition a
generalized disease. All viscera l organs
may be involved in the te rmi nal stages.
I"owever, there is often a remarkab le
homing
Ft ll j5
.-1""--
~d
Sezarv syndrome
299
Sites of involvement
The most freq uently affected sites include
trunk . face, extremities and buttoc ks .
appearance and coo-se are therefore critical lor the definite diagnosis. The term
"borderline" refers to cases in which , de.
spite careful clinicopathologic correlation.
a definite distinc tion be tween C-A lCl
and LyP cannot be made. However, clinical examination du ring follow-u p will generally disclose whether such p atien ts
have CALCL or LyP {172 1_From a clinical perspective LyP is not considered a
malignant d isorder , despite oemonstraton of monocionanty in many cases.
97 1813
Epidemiology
C-ALCl is the second most common type
01 CTCl 11721. The median age is 60
300
E. Ralfk iaer
R. Willemze
M. Paulli
M.E. Kadin
t-oea
Lymphomatoid papulosis
Defr'lilion
(;[}{) cod.
97 18/1
Epidomdogy
lyP most often occurs in adults (med ian
Fig. 11.59 lYfl'lhomaDd papIbas, l p A..lDlSISling d atypicaIlyrnphoid eels adrriJced \MGl many nftarrmaDyeels
(A). The alypical eels havea cerebriIorm or Hodglc.n-like ~y (B) and are strongty posrtiye forC030(el
-ogy
Genetics
Clonally rearranged T-een receptor genes
have been detected in approximately 60%
of lyP lesions 110791. Identical rearrangements have been demonstrated in LyP lesions and associated lymphomas 110791.
No consistent abnormalities have been
described The (2;5)(p 23;q35) translocation is not detected in l yP 1613. 614).
lmmunophenotype
The large atyp ic al cells in the l yP type A
and type C lesions have the same phenotype as the tumou r cells in C-AlCL
The atypical cells with ce rebriform nuclei
in the l yP. type B lesions have a CD3+.
CD4+ . COB phenotype and do not express CD30 124071. Rare cases of LyP
with COB and NK-cell phenotype have
been reported 1709. 13661.
Primary cutaneous CDJO.-posillVe T-eelllymphoproliferative disorders
301
P. Gaulard
E. Berti
A Willemze
E.S. Jaffe
Fig. 11.60 Primary ~s -yI) T-c:el IympIloma. l esions are dinicaIy diYefse. alld consist 01 plaques. with or....
out lkeration (A,B), ortulTOUrs (C). The lesion may consisl 01 an indlrclled plaque. with subl::ul<wleous i'IMtrcIIicn(DI.
Definition
Primary cutaneous rt'i t-een lymphoma
(PCGD-Tel) is a lymphoma composed of
a clonal proliferation of mature, activated
yS T-eells with a cytoto xic phenot ype . This
group includes c ases p reviousl y know n
as subc utaneous panniculitis-like t-een
lymphoma (SPTCl) with a y() ph enotyp e.
A possibly related co ndition may pres ent
primarily in mucosal sites. Whether cutaneou s and mucosal y(i TCl are all part of
a single disease, i.e. m uco-cutaneous yO
TCl , is not yet clear 11 040 , 24321.
ICD-O code
The provisional code p roposed for the
fourth edition of ICD-O is 9726/3
Epidemiology
PCGD-TCL are rare, representing approximately 1% of all cutaneous T-cell lymp homas 12254. 2407 , 24081. Most cases
occur in adults. Thereis no sex predilection.
T~ llymphoma .
The
[81,24321 .
Etiology
C linical features
The clinical presentation 01 patients with
PCGD-TCl is variable. The disease may
302
Fig. 11.63 Pnmary cutaneous yO T<811 tymphoma. H,slological penems arecverse. and maybe PiWlnicUitJs-like in the
OemIaI lnMration is usualfy present and !tie overlying epiOenTis may be ulcerated.
IticlUIeous fat
~
rnee ma)or histologic pa tterns of in'ldYement can be present in lhe skin: epillerrrolropic, dermal and subcutaneous.
O'ten more than one histologic pattern is
present in the same patient in different
tiopsy specimens 01' within a single
boosvsoeorren 1207,1 4 10,2254.24081.
Epidermal infiltration may occu r as mild
eccermotrocism to marked pagetoid
reticulosis-like infiltrates 1207. 1540, 18111.
The subcutaneous c ases may show rimmng of tat cells, similar to SPTCL 01 a ll
cngn, but in addition usually show dermal
Genetics
The c ells show clo nal rearrangement of
the TRG@ and TRO@genes. TRB@ may
be rearranged or deleted, but is not expressed. Cases with predominant subc utaneous involvement express Wi2, but this
has not been studied in other PCGD-TCL
117831. Epstein-Barr virus (EBV) is negative
lB1. 1091, 2254,24321.
Definition
This provisional entity is a cutaneous
T-eelllymphoma (CTCll characterized by
ponteraton 01 epioerrroncoc C[)B..positive
cytotoxic t -eens and aggressive cl inical
behaviour. Differentiation from omer types
of CTCL expressing a COBpositive cytotoxic t -een phenotype is based on the
cli nical presentation. clinic al behaviour
and certai n histological features, such as
marked eoioe rrrotroprsm with ep idermal
nec rosis.
IClJ.Ocode
970913
Epidemiology
This d isease is rare accounting for less
than 1% of all CTCL 11 2. 209, 24071 . It
occurs mainly in ad ults. There are no
known predisposing factors.
Sites of involvement
Most patients present with generalized
skin lesions.
Clinical features
Clinically, these lymphomas are cha racterized by local ized or disseminated
eruptive papules, nodules and tumours
show ing central ulceration and necrosis
or by superfic ial, hyper keratotic patches
and plaques 1209. 19341 _These lymphomas may disseminate to omer visce ral
sites (lung, testis. central nervous system,
oral mucosa), but lymph nodes are often
spared (209, 1404, 17901.
Morp hology
The histolog ical app earance is very
variable ranging from a lichenoid pattern
with marked . pag etoid eproermoeocls m
303
Genetics
The neop lastic T-eens show clonal TeR
gene rea rran ge ments. Specific genetic
ab nor mali ties have not b een described.
EBV is nega tive {174, 1410 1.
Postulated norma l counterpart
Skin-h omi ng. COB-positive. Cytotoxic
t-eens of ~ type.
Prognosis and predictive factors
These lymphomas often have an aggressive clinical course with a median survival
of 32 mon ths 12091. There is no difference
in survival between cases with a small or
large cell rTIOfphology 11741.
Definition
This p rovis ional entity is a cutaneous
T-cell lym phoma characterized by a pre.
dom inanc e of small to mediu m-sized
CD4-positive pleomorphic t-eens without
evi dence of patc hes and plaques typical
of mycosis fungoi des. A majority of cases
p resent with a solitary skin lesion .
teo-oro
970913
Epidemiology
This is a rare disease, accounting for 2%
of all c utaneous T-cell lymp homas 124071.
Fig. 11 .66 Primary wlarleOUs aggressive epidermotropic
C08-positive cylotox ~ 'l-cell lymphoma, Skin section
stained lor coe, highlighting the marked epdermojrcpism, with the majority of the neoplasticcells kxalized to
the epidermis.
ceus
a-cens
Gen etics
The TeR genes are cionanv rearranged
1209B. 234 11. Demonstration of an aterant t-een phenotype and clonality are
useful cri teria to differentiate these smaW
medium-sized p leomorp hic CTCL from
pseudo T-cell lymphomas. which also may
present wi th a solita ry p laq ue or nodule
11321 . Specific genetic abnormalities
have not been described. EBV is negative,
Sites of involvement
These lesions usua lly present w ith a sol itar y plaqu e or nodule, mo st co mmonly on
the fac e, neck or upper trunk 1174, 754A l .
Involveme nt of lower extre mities is rare .
By definition , there shou ld be an abse nce
of pat c he s ty pic al of mycos is fungo ides
{174 , 734 , 2098 , 23411.
Clinical features
Patients are generally asymptomatic , with
the detection of a single skin lesion being
the sole manifestation of d isease {17 4.
754Af. A minority or patients may p resent
wit h lar ge tumours, or multiple skin lesio ns {754AI.
MoqJhology
These lym phomas show dense. diffuse or
nodular infiltrates within the dermis with
tendency to infiltrate the subcutis. Epide rmotropism may be p resent focaUy. but
if conspicuous. consideration should be
given 10 the diagnosis 01 mycosis h.ngoides,
I
I
I
Postula ted normal counterpart
305
SA Pileri
E. Raltkiaer
D' D. Weisenb urger
S, Nakamura
I. Sng
HK MOlier-Hermelink
E.S. Jaffe
Definition
A heterogeneous category of nodal and
extranodal mature T-cell lymphomas. which
do not correspond to any of the apectticeny defined entit les 01 mature T-celilymphoma in the current classification.
ICD-O code
9702/3
Epidemiology
Fig. 11.69 Periphelill T.e:en lymphoma. NOS. A Diffuse infillrates of large !yrrlIhoid cells WIth pIeomOi phic, ~
nudei and prcminent 1'IJCleoIi. B In between the neopIastlc eels, !here arescaneeed eosinophiIs andI'kJmetOUS vessA
C Nutlei are marke<ly pleomorphic WIth po/)iobaled nuclear features. 0 In some cases. nudei areround and rrall)o
morphic in appaalill'lC8,
Table 11.07 Differential diagnosis of nodal penpteral T-Wli lymphoma, not otherwise specified ,
Disease
Immunophanotyplc fsaturlll
acre..
roc.
CO... _
+ . nearly a~ posiWe: oJ_.majOnly posrnve, .) +, rrirlOnCy pos.trve, FCC. kJIcuIitI' denlrtlic eees EBY.
Epsleirl-8arT virus.
eosmoonus.
123901.
Genetics
Antigen receptor genes
TCR genes are clonally rearranged in
most cases 118491.
cesson
Rg. 11.11 Periplleral T~ lymphoma, NOS. A NoIe the marked pleomorphism ollhe neoplasticpopulation. B"
Ki67Iabeling. C ~F l slall'lng.
Peripheral
307
Variants
Postu lated normal counter part
Activated mature T lymphocytes. mostly
CD4+ ce ntral memory type of the ad ap tive immune svtem 1523. 769. 1739AI.
Prognosis and pred ictive factor s
These are hig hly agg ressive lymp homa s,
with a poor resp onse to the rap y, freq uent
relap ses and low 5-yea r ove rall survival
and failure-free survival (20 -30%) 118491 .
The only fac tors c onsistently associate d
with prog nosis are stage and IPI sco re
11 849). New scoring systems have rece ntly
306
Follic ula r
This variant usually c onsists of atypical
dear celts forming intrafollicular aggregates
(mimicking follic ular lymp homa ). small
nod ular aggregates in a ba ckground of
progressive ly-tra nsformed ger minal centres (mi mic kin g nodular Iymphocytepredom inant Hodgkin lymphoma) or
enl arged perifollic ular zoneS/nodular aggreg ates surrounding hyperplastic follicles
(m imic king nod al margina l zone 1ymphoma) 1524. 18941. Despite a FTH phenl>
type, early stage d isea se, parti al lymph
node involvement, lac k of enlarged follic
ctar dendritic celt meshworks and lack cJ
prominent high endothelial veocies distngu ish it from typical angioimrnunoblasllC
T-eelllymphoma. Recently. a 1(5;9) Iranslocation has been reported in a subset cJ
cases with these featu res 121121. Other
terms have been used for this variant, n.
cluding per ifollicu lar. intrafollicular, paracortical nodular and expanded mantle
zone 11002, 13581.
T-zone
The T-zone vari ant is characterized by a
pe rifollic ular growth patte rn throughout
the lymph node 11894 , 23591. The ne0p lastic cells are p redominantly small wlll1
minimal cytological aty pi a, and the
process ma y be mista ken for benign
pa rac orttca t hyperp lasia. The cells express CD3 , CD4, and may show loss 01
CD5 or CD7, Some studi es have sug
ges te d that this variant may be associated with a more indo lent cou rse than
other PTCL, NOS 11894, 2359 1. but data
are limite d. Many PTCL can show focal
residu al tomcures: this histologic al feature
alone does not constitute evidence for the
'l-eone va riant.
A. Dog an
P. Gaulard
E.S. Jaffe
E. Halfkiae r
H .K, MuJler,Hermel ink
Definition
Angloimmunoblastic t-een lymphoma
(AITL) is a penpheral t -een lymphoma
970513
~ and historical annotation
""""""'" 15971.
-kllogy
"Ill occurs in the middle-aged and elderly, with an eq ual incidenc e in ma les and
females 15971. It is one of the mo re com--
E!K>kJgy
The nearly constant association with
EpsteinBarrvirus (EBV) has suggested a
possible role for the virus in the etiology,
possibly through antigen-d rive (6231.
fbwever, the neoplast ic T cell s are EBV
regative.
Ft 11.74
Sites of involvement
The pr imary site of d isease is Ihe lymp h
node and virtua lly all patie nts present with
general ize d lymp hadenopathy. In ad d ition, sp leen , liver. skin and bone marrow
(BM) are frequenlly involved 15971Cl inical featu res
AlTl ty pic ally pre sent s with advanced
stage disease, generalized lymp hadenopa thy, hepatosp lenom egaly. sys temic
sym ptoms, and poivcionar hypergamm aglobulinemia 1597, 1234A. 1529A, 202 11Skin rash , often with prur itus, is frequ ently
present. Other common find ings are pleural effusion, arthritis and ascites. l aboratory
find ings inc lude c ircu lating immun e co mplexes , cold agg lutinins with haemolytic
anaemia, positive rheumatoid fac tor and
anti -smooth muscle antibod ies,
Patients exhibit immunodefici ency sec ondary to the neoplastic proc e ss. In the
patterns of angioimrru'lobIstic T-cel lymphoma. AAn early case 'lWilh hypefpIastlc IoIidn and paracoI1icaI e~ (Pallem 1). BAcase MIll
JoIdes renWIscenl of cas1Ieman's disease MlI marked pcncorlicaI expMSion (Panem 2). C 0asSICiII1fuphoIogy WIll ~~ of normal ~ aM
IWd ma& "II"""'atIol, assooaIed WI\h aggegateS d 8typicaI ~ eels (Pattern 3)
~
309
pll'u .
...
'**
Fig. 11.75 AngioinYnlSIObIaslic T-ceII!yrr4tlcIna. A M~uclealed cells resermling Reed-Stemberg eels . B low poMf view of C02t imllllOOSlain h91191bng marbd
dendntIc eel pI ~ aIJoI l eUb ilWlllQ tIigtl 8l'lCIOh!iaI wenJIes. C The c::hactenstic pheno(ypeof tumou' eels expressrog CO] {Cl. COtO(D) and CXCl..1] (E). F E8Y~
B-ceI proWerallon in angw:irmw.Jnotlslic T-<:elI !yrr4tlcIna <loutiIe Sl<WIed lor C07'9a
~J and ESV-E8ER
lllue-oocIe).
r...
associated with incr eased follicular d end ritic cell meshworks. Early cases may
contain hyperplastic follic les with illdef ined bord er s an d the ch arac teristic
histology may be lim ited to the perifollicular areas w ith predominance of clear cells
118281. The relationship between AITl
showing limited caraccencar involvement
and the follic ular variant of perip heral
T-cell lymphoma . NOS rema ins to be cla rified . An ex pansion of B fmmunobrests is
usually present in lhe paracort ex. The expa nsion of normal Bccetls and follic ular
dendritic celts in the les ions ha s bee n
linked to the functi ona l properties of the
neoplastic cells as follic ular helper
(TFH) of the normal follicle The expression of CXC l 13 mediates expansion of
and , adh esion of
follicul ar d endritic
B-cell s to HEV with subseq uent entry to
the lymph nodes. EBV-positive Be ene are
nearly always present. They range in cell
size and e xpa nsio n of B lmmunobrasrs
may be prom inent 12377 . 2490J. The EBVpositive B lmrnunobrasuc pro liferati on
may progress. either composite with AITL.
or at relapse to EBV-positive diffuse large
a-cen lymphoma 15, 99 , 24901. EBVpos itive Reed -Sternb erg -like cells of
lineage may be present and may simulate
classical Hodgkin tyrnphoo1a 117941. In advanced cases. the inllarrmatory component is diminished. and the proportion of
c lear cells and large c ells is incr eased .
r...
Immunophenotype
The neoplastic
express most pan
t-een antig ens such as C03. C02 and
CDS and , in vast majo rity of the cases,
C 0 4 a lthough nume rous reactive C08+
t-eens
t-eens
are often p resent. Cha racteristically. the tumour cells show the phenotype
of normal TFH expressing COW, CXCl1J
and PD-1 in 60-11)0% of the cases 196
523. 605 , 85 11. This phenotype is helpfLl
Paracorte x
t-eens
ceus.
a-ces
310
't
Gcnninal Center
Flg.1'.16 TheoretiCal model of angioimmunoblastic T ce~ lymphoma patllogenesis. EBYpositive 8-c:eIIs pr&Sel'll EFl
proteins (e.g. EBNA-t) in assodalioo with MHC class II molecules. upregulaleCD28 ligand (BT). and ~ I:Co
stimulatory SlgrWs lor TFH eel adMlllon. TFH cells uPf89Jlate CXCR5 and CXCl.. t 3. CXCl13 promotes 8<111 II'
0'\lItmenl 1O h! I'fr!1ltl flOde 1tlrouo;1l 8lIlefenO!I of !k:::IllIs OIl "'lfl endoltleliaI vetUes (HEV) and ~
gemWIaI centres. h:Jeased 8-ceIsexpand in 1hepar3COI'Iel and ~ adMlled.sere paraa::wticaI Ek:eII bea:ir'ne EBr
translormed. CD21-positive dendri!(; cells expand from ee HEY Figure r&l'fOdtlCed with permission from 1623).
viraj
in distinguishing AITL from atypic al paracortical hyperplasia and other peri pheral
teen lymphomas 1631. 8521 as well as di-
Genetics
t-een rece pto r genes show clonal rearrangements in 75-90% of cases 197,
2155,23781_ Clonal immunoglobulin gene
rearrangements may be found in around
25-30% of cases 197. 21551. and correlate with expanded EBV+ Beene . The
most frequent cytogenelic abnormalities
are trisomy 3 , trisomy 5 and an additiona l
X chromosome 1597,19611 and comparative genetic hybrid ization has srcwn
gains of 22q , 19 and 11q 13 and losses of
a-ces
";
Angioirnmunoblastlc
r-cea lymphoma
311
Definit ion
Anaplast ic larg e ce ll lymphoma (ALC L),
anaplastic lymphom a kina se (ALK)-positive
is a T-cell lymp homa consisting of lymp hoid cells that are usually larg e with
abundant cytoplasm and pleomorphic ,
often horseshoe-shaped nuclei, wit h a
translocation involving the ALK gene and
expression 01 AlK protein, and exp ression
of CD30 AlCl withcomparable rrcepbologic and phenotypic features, bul lacking ALK rearrang ement an d the ALK
protein, are considered as a separate
category (ALCL. ALK-). A LCL, ALK + must
also be d istinguished from p rima ry c utaneous AlC L and from other subtypes of
T- Of B-ce ll lymphoma with anapl astic
features ancsor CD30 expression .
ico-o code
Sites of involvement
A LCL . ALK+ frequ ently involves bo th
lymph nodes and extra noda l site s. The
most commonly involved extranoda l sites
incl ud e skin , bone , soft tissues . lung and
liver 1285 . 668, 20871. Invo lvement of the
g ut and central nervo us syste m (CNS) is
rare . Mediastinal disease is less frequent
than in classical Hodgkin lym phoma. The
inc idence of bone marrow (B M) involvement is approximately 10% lNhenanaJyzed
with H&E . but is inc reased significantly
(30 %) when immunohistochemical stains
are used 17241 . since BM involve ment is
often su btl e. The small cell va riant of
ALCL. AL K+ may have a leukaemic pre sentation with peripheral blood (PB) involvement 1164 , 11521,
C linical features
The majority of patients (70%) present with
advanced stage III-IV disease with peripheral and/or abdom inal lymphadenopathy.
Mature T- and NK-ceU neoplasms
- - --
RD. Gascoyne
H Stein
M C . Kinney
50 .1-- 40
5
'0
j
Male (n : 22 8)
Female (n:158)
30
z 20
10
0."'"
. ..
...
''''''''!-E'''
- IJ~''?"'''P'',
. . II .. ... . ....
,0-"
_
1lI _~.
971 4/3
Epidemiology
ALCL, ALK+ accounts for ap prox imately
3% 01adult non-Hodgkin lymphomas and
10- 20% of childhood lymphomas 12OB71.
ALC L, ALK+ is most frequent in the first
three decades of lile 1188. 6681 and shcJWs
a male pre dom inanc e (M:F ratio 1.5: 1).
312
60 .,--
E.S. Jaffe
G _Delsol
B. Falini
H K MOtier-Hermelink
E. Campo
Fig. 11.77 Dlstnbution 0( anaplastic 1af9El oeIlymphoma (AlCL). ALK. by age (n=386).
20911.
Morp hology
A LCL, ALK+ show a broad morp holog ic
spectrum 1188, 383 , 55 1, 660, 898, 1033,
1 152, 1746 1. How eve r, all cases c onta in
a variable propo rtion of cells with ecce ntric . horse shoe- or kidney-sha ped nuc lei
often w ith an eos ino philic reg ion near the
nucleus . These ce lls have bee n referred
to as hallmark cells because they are
prese nt in alt lTI()(phologic variants (1881.
Although the hallmark cells are typically
larg e. smaller cells with simi lar cytologica l leatures may be seen and c an g reatly
aid in accurate diagnosis 11881. Depending upon the p lane of sec tion, some cells
may appear 10 co ntain nuclea r inc lusions,
but thes e are not true inclusion s but invagination s of the nuclea r membrane .
Ce lls wit h these fea tu res have been referred to as doughnut cells 11 0331.
Morphologic features of AlCL , ALK +
range Irom small ce ll neoplasms to an oppo site extr eme in whi c h very large cells
rarely 11881. Hallmark cells are always present and are often conce ntrated around
blood vessels 1188, 11521. This morphologic
varia nt of ALC L is ofte n misdiagnosed as
per ip hera l T-cell lymphoma. NOS by
313
I
Fig. 11 .13 Other tistological patterns of ALCl. (althese cases were positive lor ALK prolein). A AlCl shlWItng ~ large eels with round nucIel. B ALa. oonsrsMgd
pIeoi,o.,nc: Prt cells CAla.1I:h n signet rilg eels.
lmmuno phenoty pe
strongest CD30 expression is also present in the larger tumour cells. wtlich etten
cluster around blood vessels 11881. ALK
expression is absent from all postnatal
normal human tissues except rare cells in
the brain 117861. For this reason, immunohistochemistry has largely supplanted
molecular tests for the diagnosis of ALCl,
ALK +. Note that tor AlK staining it is ad visable 10 use monoc lonal antibodies
3 14
16691.
r-ceu
t-een
t-een
co-so-
t-een
~~~~~~~:~~~~~
: .~ ..
'.'
...
.. ,;,r.';.., '.... .,-
~ . .. . ~. ""'
' . .
~ ..1 '
1,\ \t
,;
. ~'
'
. : , .. . .;",.
. - ,..:.
y.
. ,.. . . -r-
' ..
~ ' . ... ..
"
~ ~"l '-:-"
J 7 ",/ 1 ~ "
' . ",
..
'
,.
"
.'
' .1':'
.r;
. ."
II
~
.......
~: ." . ' ," "
.' , ~ 't .. -J' \'" .. " .,l".'
; "'~" . . I t";
I " (,. ' ,~ ; n,
/t ....,>,'
'''-'15
/i'1. t"...<..
~ ..: ~: '.., : .. '.,
" 1 , ," ~ , .
.f ",,;- ,;:. ,
<,
, . 1 .,. , . ", ..
.. ,10'0 '
... -
"
__ ,
" ~
<:
- > 'f~ _
, .
'"
" f,
I.
_" ~ :I
..
(.y ,
L~
exhibit positivity for the cytotoxic associated antigens TIA 1, granzyme B, and/or
perforin 1722. 1192). COB is usually negative. but rare COB-posit ive cases exist.
C043 is expressed in two thir d s of the
cases. but this ant igen lac ks lineage
specificity. Tumour ce lls are variably po sitive for CD45 and CD45RO and strongly
cosisvefor CD25 15511. CD15 expression
IS rarely observed and when present only
,
,
"
>,
II
I
d
~ II
f-
te
is
8,
ul
'"es
Differential diagnosis
Arare distinc t d iffus e large B-cell Iym ptonawith immuno b lastic/plasmablas tic
ezeres expressing the ALK p rote in m ay
ll.perlicially resem ble ALCL, ALK+ d ue to
freq uent sinusoidal g rowth pa ttern. These
ftrl ptlomas exp ress EMA (as do ALCL)
bLot lack C0 30 and sho w a characteristic
Cjtcplasmic-restricted g ranular staining
l:ntJe ALK protein 1553J,
&me non-haematopo ietic neoplasms such
eest oorr wosercom a 1660 , 8981 and in~arrnatory myofibrob lastic tumours 1843}
may be positive fo r ALK but are mo rpho\:Jgically distingu ishable from ALCL and
re recanve for both CD30 and EMA.
lJenetics
Nltigen receptor genes
"wroximalely 90% of ALCl, AL K+ show
ctml rearrangement of the T-cell rec ep tor
ITCR) genes irrespective of wh ether they
exp ress t- een ant igens or not. The remainder sho w no rear rangement of TCR
or IG gen es 1722}.
Table 11 .08 Trans iocation s and fusion proteins inl'Ol'ling ALK at 2p23
ALK partner
MWtofALK
hybrid protein
ALKstainIng pattern
% 01
eases
t(2;5)(p23:q35)
NPM
80
84%
t(l ;2){q25:p23)
TPMJ
104
Diffuse cytoplasmicwith
peripheral intensification
13%
Chromosomal
anomaly
Inv(2){p23q35)
ATIC
96
Diffuse cytoplasmic
1%
t(2;3j{p23:q21)
TFG Xiong
TFG long
TFG sholt
113
97
85
Dnfuse cytoplasmic
Diffuse cytoplas mic
Diffuse cytoplasmic
<1%
t(2;17kp23:q23)
cac
250
<1%
t(2;X)(p23:q11-12)
MSN
125
Membrane staining
<1%
t(2;19)(p23:p13,1)
TPM4
95
Diffuse cytoplasmic
<1%
t(2;22)(p23;q11.2)
MYH9
220
Diffuse cytoplasmic
<1%
t(2;17kp23:q25)
AL017
NO
Diffuse cytoplasmic
<1%
<1 %
Others'
NPM, nucleophosmin gene; TPMJ and TPM4, non-musculartropomyos ingene: TFG. TRK-fused gene, three
different fusion proteins of 85, 97and 113kO(TFG-ALKs , TFGALKl , TFGALKxL) areassociated with the
1{2;3)(p23:q35) which involves theTFG: ATIC, arnoc-terrrwoe of 5-aminolmidazole-4-carboxamide ritlooucleolide
formyltransferasel lMPcyclohydrolase gene:
c1alhrin heavy polypeptide gene; MSN, moesingene: MYH9.
myosinheavy chain 9 gene; AL017, ALK lymphoma oligomerization partner on cororoscre 17,
" unpublished series of 270 cases ofALCL, ALK+
cnc.
3 15
1,00
ALK1+
n=215
0,75
0,50
ALK1
n-28
0,25
p= 0,001
125
250
Months
Fig. 11.87 0veraI so.nivaI d AlK-po6ItiYe and negalive petlents.
316
significantly than in other variants of 1ymp homa 1668, 7601. No differences have
bee n found betw ee n NPM -AlK-po sitive
tumours and tumours showi ng variant
transiocanons 1658. 66 9 , 760. 20131. II
might be that cases with small ce ll variant
histolog y d o not have the same
fav ourable prognosis as the other Al K
positive tu mour s since these patients
often present with di ssemi nated disease
at d iag nosis. ALCl , AlK+ patients have
a favo urable pr ogn osis compared with
AlCl , AlK-I668, 760 , 20 131. The ove rall
5-year surv ival rate in At.Ct. . AlK+ ap proaches 80% , in c ontrast to o nly 48% in
AlCl, AlK-. In the recent study by Savage
and co- workers {1943AI, the overallS-year
surv ival of AlCl , ALK+ pa tients is slig htly
lower (70%) due to the excicsoo of paed iatric pa tien ts. In the latter study, the
5-year la ilure free survival (FFS) of paIients with ALCL. ALK+ was 60% versus
36% lo r AlCL. Al K-. Relapses are not
uncommon (30% of cases), but often remain sensitive to c hemotherapy ; alkr
geneic BM trans pla nt may be ettecnve in
refract ory cases {13191. Since it is now
cle arly demon strated that AlK is essential for the p roliferati on and survival 01 the
cells of AlCL . ALK+ . it can be expected
that specific ALK inhib itors, c urrently
tested in prec linical models , may be available in the near future for c linical trials
117631
DY Mason
N.l. Harris
Definition
mimi c carcinoma Features such as sclerosis or eosinophils may occur, but when
present shou ld raise the susp icion of
CHL. The neoplastic ce lls show a similar
morphologica l spectrum to AlCL, ALK+ .
althOugh a osman ce ll variant" is not recognized. Biopsies typically show large
pleomorphic cells. sometimes conta ining
prom inent nucleoli. Multinucleated, including wreath-like. cel ls may also be
present and mitotic ligures are not infrequent In addition , to a variable degree,
"hall mark" celt s with eccentric . horseshoe- or kidney-shaped nuclei are seen .
The neoplastic cells in ALCL, AlK- tend
to be large r and more p leomorphic than
tho se seen in cl assic al AlCl, ALK+
and /or have a higher nociea rcytootasmc
ratio 1668, 1565 . 1762.20131 . The latter
feature may suggest a diagnosis ot PTCL,
NOS. but in the latter d isorder abnorma l
small to medium-s ized lymphocytes are
often admixed with a morphologically
homogeneous neoplastic cell popu lation.
and the sheet-like or sinus pattern of
infilt ration typical of ALCL is absent.
AlK-negative anaplastic large cell tymjtana (AlCL. ALK-l is included as a proM1aI entity. and is defined as a CD30+
k:eI neoplasm that is not reproducibly disWlgUiShable 00 morphologica l grounds
m AlK-positive AlCL (AlCL, AlK+). but
tacks anaplastic large c ell lymphoma ki-ase (AlKI protein. Most cases express
tcee -assoeateo markers and cytotoxic
J<WlJIe-associated proteins. AlCL. AlK!T\lSI be distingu ished from primary cuta-
ICHl).
roo code
G . Delsol
H . Stein
Sites of involvement
AlCL. ALK- involves both lymph nodes
and extrarooar nssue . although the latter
sites are less commonly involved than in
AlCL. AlK+ . Extranodal sites include
bone, soft tissues and skin . Cutaneous
cases must be d istinguished from primary
cutaneous AlCl and cases that invol ve
the gastrointestinal tract must be distingu ished from CD30-positive enteropathyassociated T-cell lymphomas.
Clinical featu res
Most patients present with ad vanced
stage til to IV disease. with peripheral
and/or abdom inal lym phadenopa thy, and
B symptoms 121801.
9702/3
",,,,,,hology
,
v
e
d
Y
,-
Is
E. Campo
M.C. Kinney
E.S. Jaffe
S. Falini
-"Ie peak
;r(!
Fig. 11.88 IrnmunostawlI1g lor COJO in cases of AlCl, AlK shows ee coheSive and inIra$inuSOidaI !Towlh
pattern of!le 1l.JOOU" and Ihe homogellllOUS eqJf9SSioo ofIt'iIIIllWter on 1l.JOOU" eels . Hole !le GoIgi- and ~
assodaled pattern of stanog Asteris.ls mcate ~ ~ lcIicies.
317
t-een
..
Fig. 11.89 ~ laalures of loll' cases d AlCl, ALK-. A Note \tie high nuclear 10 cytIplasmic rallo.
B ~ (lll'I'llWSj ewe present (otten In ~l btA otherlealuresof IiCJ(lgU1 tymptIoma we absenC. C Typical
mrph1ogicai and phenotypic fe.1IlIns of ALCl (a hallmark eel is arrowed) but arose in ee gaslrtllnleslNllrad
(glanlUar 8pI\tleil.ITl is seen WI the upper Ieft.l. 0 Case Wlth more celkJIar ~
r-ceu
t-een
Fig. 11.90 ALCl, ALK s/lowing a IIigh nudear 10cytIplasmic ratio. A Some featlJ'es suggest periphefaI T<.eI
1')'rr4lIlomI. NOS Horweotef. eOlnsiw CDJOellPes5lOl'l in eYefy c:eI is ctIariK::teI.sticol ALQ..ALK. (8). C l)'lT'9lOma
eels exp!e$S COO (e l and (;Of {D). tJle a \IeSSel SI.I'IOI.I'Ided by normal. smaI C03+ T<8k
318
r,~
a_
FiJ. 1U1 EJ+ression oflhe t)'t*lxiC TGI m.1I ef1 TlAt (A) and perfom (8) II
OOterantial dlagnosis
The principle dlfferenllal diagnosis of
Al Q.,ALK.
Genetics
The malOrity of cases shOw clonal rearrangement of the T-cell receptor (TCR)
genes, whe ther or not they express t-een
antigens.
No recurrent primary cytoqenenc abnormalities occur with any fre quency. Two
studies indicate a tendenc y of ALCl, AlKto differ (e.q. in terms of chromosome
losses or gai ns) both from PTCl, NOS
and from AlCl, ALK+, althoug h overlappin g fea tures can also be foun d 11923,
24921. Similarly, pu blished gene expression studies suggest that ALCL, ALK- has
a distinct p rofile but these results do not
p rov ide definitive evidence as to whether
the d iseas e is more closely related to
A LCL , A LK- o r to PTCl, NOS 11 37,1 24 2,
223 11
ALK. ALCl, AlK- must also be di stin guished from primary c utaneous AL C L,
;{1~h can have a similar phenotype and
rrPholog y, Clinical co rrelation with stagr,g ISot paramount importance in this d iflerenlial Primary cutaneous Al Cl has a
rruch better prognosis than AlCl, AlK-,
t-een
319
Introduction
Definition
Hod gkin lymphomas (HL) share the torlowing cha racteristics: (1) they usually
arise in lymph nodes, preferentially in the
c ervica l reg ion; (2) the majority 01 them
manifest clinically in young adults ; (3)
neopl astic tissues usu ally con tain a small
number 01 scattered large rroroouciesl ed and multinucleated tumour cells
(designated Hcx:Igkin and Reed-Sternberg
celts or HA S celts) residing in an abun dant heterogeneous admi xture of non neoplastic inflamma tory an d accessory
cell s ; (4) lhe tumour cells are often ringed
by T lymphocytes in a rosette-like manner,
Hodgkin lymp homa s account lor -30% of
all lymp homas. Their absolute inci dence
has not apparen tly chan g ed . in contrast
with non -Hodqkln lymp hom as where
there has been a steady increase in incidence.
H . Stein
Subclassificati on
Biological and clinic al studies in the last
30 years have shown that Hod gKin lymphomas are c omprised of two disease
entities 133 , 573 , 1406A. 16031: nodular
lym phocyte predominant HodgKin lymp homa (NL PHL) and classical Hod gkin
lym phoma (CHL ), These two entities drtfer in their clinical features and behaviour
as well as in the composition of the ir ce rlular backqrouoo and -diagnostically
most important- in the morphology. immunophenotype and the preservation or
extinction of B-eell gene expression program. Within classical HL, four subtypes
have been distinguished: nodular sclerosis, mixed cellularity, lymp hocyte-rich and
lym phocyte-d eple ted , These subtypes
differ in their sites of involvement. clinical
r. ble 12.01 Cotswold revision (l 320B) oI1he Ann Afbor stagingdasslblion (337AI.
322
HodgKin lymphOma
Stage Deflnllion
In'o'Olvemenl of a single ~ rooe regoo or IynllIloid structure (e,g. spleen, thymus, Wakleyerling).
It
Involvement of two orrrorelymph rooe regiol'ls 0fI1he same Side of the diaphragm (the med~slinum is
a sing~ site;hilar lymph nodes areIateraHzed): the number of anatomic sites shouldbe indiCatedby
suffix (e. g. I!:y,
III
Involliernent of ~h IXIde r&gion s or strllCtlJres0fI both sides of the diaphragm,
111 1 With or withoUt splenic, hilar, celiacor portal nodes
111 2 With paraaortic , iliac or mesentericnodes.
IV
E, involvement01a single extranodal site,or contigOO!Js or proximal 10 known nodal site of disease.
S, Poppema
G,oelsol
SA Pileri
H. Stein
S,H. Swerdlow
R,A, Warnke
E,S. Jaffe
DefirWon
'b:luIar lymphOCyte predominant Hodgkin
~phoma (Nl PHL) is a monoclonal
B-ceI neoplasm c harac terized by a nodu1M, Of a nodular and diffuse proliferation
rj scat tered large neoplastic ceus known
!S poocom or lymphocyte predominant
of
<
ecaoeo.
roo code
9659/3
Fig. 12.01 Nodoor lymphocyte predorrln8rI4 Hodgkin IymJtlorna (NlPHL). A Thenodules are usually 1arger1hin 1tYJse
present in follicular lymphoma andfollicular hyperplaSIa. and are closely packed and lack mantle zones. B Three
popcorn cells(ai'TOWS) with !tie typically lobated nudei areviSlbIe in a background 01 smail lymph(id eels anda lew
histiotytes. C TheCDlO staining revea ~ Itlalltle nodules oIltllsIymp/Ioma predomioarllty consisl of B-celIs, DAI hIifoer
magnilicabon. the strong membrane slllilling oIlhe popcorn cellslor COlO is visib~ ,
-~k>gy
~lPHL represen ts appro ximately 5% of
iiiKodgkin lymph oma s. Patients are prem inantly male and most freq uentl y in
te30-50 year age g roup.
Sites of involvement
~L
Cl
CfricaI features
\\:lsI patientspresent with loc alized peri.
~"lefal lymphad enop athy (staqe I or II).
5-25\ of patients p resen t with advanced
iQe disease 133. 20091.
~
-~ lymph
from classical HAS cells on purely rroprological gr ounds . The d ill use areas are
main ly composed of small lymphocytes
with ad mixed henccvtes which are either
single or in clusters. The proc ess is (arely
totally diffuse . According to current criteria
the oetecnon of one nodule showing
the typicalleatures of NLPHL in an otherwise diffuse growth pattern is sufficient 10
exclude the diagnosis of a primary
323
with progressive trans formation of ge rmina l centres (PTGC) adiacent to the lesion
or it may proceed or follo'N a diagnosis of
NlPHll33, 8981. It is uncertain whether
these lesions are preneoplastic . The vast
majority of patients with reac tive hyperp lasia and PTGC do not develop Hod g kin
Fig. 12.04 Nodular ~ predominant Hodgki1Iy1f4lhoma (Nl PHl). A C~smc positMIy of the popcom
eels lor J.<:haIn is seen, B Membrane and dot./ike stairWlg in the Go9region lor epdheIiaImembrane antigen (EMA)
is .mtlle li the popcorn eels
coa.
...
324
Hodgkin lymphoma
t-een-ncb
Genetics
LPeells have cio nauy rearranged immunoglobulin (IG) genes 1262 , 1387 , 1627l.
The clonal rearrangemen ts a re usually
ret delectable in who le tissue DNA
but only in the DNA of isolated single LP
cells, The variab le reg ion of the IG heavy
chain genes (VH) c arry a high load of
SO'llatic mutations , and also show signs
~O.6
J'le 0 ,4
Q.
0.2
~o..........-
325
Definition
Classical Hodg kin lymphoma (CHL) is a
monoclonal lymphoid neoplasm (in most
instances derived from B cells) composed
of mononuclear Hodgkin cells and multi-
"arIl~
COJO
CO"
004'
COlO
CO,"
'AX'
J chair!
I,
OCT-2
608 ,1
CO,
NlJ>Hl
-'
..,-,S
TeRBCl
-'
.,.,-
Perforin/Granzyme B
CO"
EMA
ALK
l MP1
.,-
.,-
SA Pile ri
LM . Weiss
S, Poppema
E.S. JaHe
96SOI3
ICD-O code
E,>demJology
Classical HL accounts for 95% of all
Hodgkin lymphomas. with a bimodal age
curve in resource-rich countries , showing
a peak at 15-35 years of age and a second
CHl
.,,.,,.'
.
-'
,.'
"
-'
-'
CD'
H. Stein
G. Delsol
-'
.,-
DlSC l
ALCl,
AlCl,
AlKt
AlK-
.,
>
>
.,-
-,
.,
n.a.
n.a.
1'1&.
.,.,-
.'
.,.,-
,.-,.
,..,-
n.a.
NlPHl. nodular IympilocyIe predominant Hodgkin lymphoma: TCRBCl, T~kid11arge 6-ee11 lymphoma:CHl,
classical Hodgkin lymphoma: DlBCl, (li1l1JSe large B<eIlIymp!loma;ALCl, aflaplaslic large T-oeII lymphoma,
+an cases are posihve. +1 majOrity of cases positive, -1+ minoOty creases positive. - allcases arenegative, S
strong elpression.
' Positive in rare cases,
PnJrninenI e~ III anaplaslic variant and variable expression in mediastmallargefk:8II subtype.
s0lxaSl0I'IaI cases may show local positMIy.
Present in up1040% 01 ee cases but usuaIy expressed 01\ a rninonIyofturnourceis WIlh variable 111eoso1y,
~ Up 10 10'li.lT1lI1lt be negab...e
' The COfTVTJJIl posiIMlyb IgG and boIhIg IighI chalf1s reIIects upta ke oflhese proIeins by !he hJrnoIJ"ceIs
rather ItIan S)flthe$i$
' Slmng e.q)rMSion bJnd in - 10'J1, of tIWI cases.
' Rarecases (- 10'Ji,) may shaw scatIered 'lW8iI/I posIbvily.
, any II minOrIty is negative
II; W8ak e.qnssion may be seen in VnOur eels in 51. 01 !he cases.
" Most ~ seen in DL.BCl wiII'I anapIask IfIOIllI'Dogy
_~r.
12.09 Classical Hodgkfl ~ A Mononuclear Hodgkrl eels (awws) and a rnbu:I8ated Reed-S1etlWg eel (lW1CI'tI!lead) areseee in a c:etiiIr
~ and tor\IaIIWIg hiStiocyIe$ and some eosirophis. B Onerrumified Hodgkil OlIIlamJw) rod w VItal Hodgkn eels can be seen.
120091.
ClircaI features
Patients usually present with pe ripheral
~thy, localized to 1 or 2 lymph
~e-bearing
Macroscopy
Lymph nod es are enla rged , encapsulated
-logy
The lymph node architecture is eHaced by
variable numbers of HRS cells admixed
with a rich in"arrvnalory background. Classical diagnostic Reed-Sternberg (AS) cells
are large. have abundant slightly basophilic cytoplasm and have at least two nuclear lobes or nuclei . The nuclei are large
and often rounded in contour with a prom inent, often irregular nuclear membrane,
pale c hromatin and usua lly one prom inent
eosinophilic nucleolus , w ith perinucle ar
clearing (halo), resemb ling a viral inclusion.
Diagnostic AS ce lls must have at least two
nuc leoli in two sep arate nuc lear lobes.
Mononucl ear variants are termed Hodgkin
ce lls. Some HA S cells may have conde nsed cyto plasm and pyknotic red dish
nuclei. These variants are known as mummifie d cells. Many of the neop lastic cel ls
are no t proto typic HRS cells. The lacunar
rid! n
327
328
HodgkIn lymphoma
infection 15521. EBV-encoded LMPl pos sesses strong transforming and annapootonc potential.
Expression (usually weak membranous or
sometimes globular cytoplasmic) 01 one
or more t-een antigens by a minority of
HRS cells may be encountered in some
cases 1504 /. This is, however. often difficult to assess because of the T cells that
usually surround the HRS cells . Most of
the T-cell antigen-po sitive classical HL
cases have IG gene rearrangement in the
HAS cells instead of t-een receptor gene
rearrangement. so that the expression of
t-een antigens is either aberra nt or artfactual \19871. Expression of epithelial
memb rane antigen (EMA) is rare and usually weak if present. A further characteristic finding is the absen ce of the
transcription factor OCT-2 in - 90% of
cases and absen ce of its coactivator
BOB,1 in the same frequency. Cases in
which both OCT-2 and BOB.l are ccexpressed are rare 113281, The transcr iption factor PU,1 is consis tently absent
from HRS ce lls 11328, 2250A). Most HRS
cells express the proliferation-associated
nuclear antigen Ki67 1775Cl.
CHl cases rich in neoplastic cells may
fig. 12.13 0assicaI HodgkIn ~ A EBV infected HRSceIs suongIy eapress!tle EBv~ 1alenI~
proIein 1fLMP1). B EBV4lf8ded HRS cells consistently ihow a 5trr6lg e~ of EBER il \llei' ~ as revealed
by l'lOIHadio<lcti il situ hybimalion.
cesesttaatzq.
Postulated normal counterpart
In more than 98% of CH L. the neoplastic
c ells are derived from mature B cells at
the germinal c entre stage of differentiation { 1105. 13881. In rare cases. they are
derived from peripheral (post-thymic ) T
cells 1514.1553. 1987 1.
Prognosis and predicti ve factors
Modern rad iation and chemotherapy
have made CH L curable in more than
85% of cases 1462A. 571AI Staging determ ines the mode of therapy. and both
clinical and laboratory pa rameters are relevant to prognosis 19041. The response
after two courses of ABVD as seen on
FOG -PET imaging is an important prognostic ind ica tor 1748A] Histo log ic subtype is less important as a p redictive
fact or 125. 10761.
23881
Epstein-Barr virus infection
-he prevalence of EBV in HRS ce lls var ies
according to the his tological subtype and
epidemiologic factors . The highest fre~iJency {.75 %) is found in MCCH L. and
ee cwest incidenc e ( 10-40%) in NSCH L
1992AI. In resou rce-poor reg ions and in
pa:ients infec ted with the human immune
delIClency virus. EBV infection is more
p-evaIenl approaching 100% 164A, 1277A,
2369.23701. The type of EBV strain also
enes among geographical areas. In resarce-rich cou ntries strain 1 p revails ,
i'ld in resourc e-poor countries strain 2.
~ 0081 infection by both strains is more
c:onmn in resource-poor countries 1280.
00.23701.
100
BEACOPP
80
COPP.ABVD
- - - -f I QQQ Q3)
onlyalkylating
(IQiS)
40
20
no treatment
(1940)
5 years
Fig. 12.1 4 HoclgIoo tymp/loma. Progress oflhe natrnent of advarad Slages since 1940.
329
H . Stein
A. von Wasiele wski
S. Pop pema
KA Mac l ennan
M. Guenova
Definition
Nodular sclerosis classical Hod gkin lymphoma (NSCHL) is a subtype of CHL
Characterized by collagen bands that surround at least one nodu le, and HOdgkin
and Reed-Sternberg (HRS) cells with
lacunar type morphology
ICD-Ocode
966313
Epidemkllogy
NSCHL accounts for apprOl(imately 70%
of CHL in EuroPe and USA ; rcwever. the
rate varies greatty among other geographiCal reg ions: II is more common in
resource-rich than in resccrce-occe areas .
and the risk is highest amon g those with
high socioeconomic status 14451. The incidence of NSCH L is similar in males an d
females and peaks at ages 15-34 years
11 01 . 1525A I.
r'lJ. 12.15 Nol1JIa' sdetosis dassicaI Hodgkll ~ ACTscan shcM$ a Ia'ge<Illeri:Jr mEdastlnaI mass. B0lIll
X-ray d ltle samepatient shows mecIia$bnal massel ceedKlg CJIl&oltwd of!he chest diameter.
Sites of involvement
Med iastinal involvement occurs in 80% of
cases, bulky disease in 54%, splenic
and/or lung involvement in 8-10%. bone
involvement in 5%, bone marrow (BM)
involvement in 3% and liver invol vement
in 2% 1456. 20091.
Clinica l fea tures
Most pat ient s p resent with Ann Arbo r
stage II d isease. B symptoms are encounte red in approxima te ly 40 % ot c ases
120091
Morp ho logy
lymph nodes have a nodular g rowth pat tern , with nod ules surrounde d by collagen bands (nodul ar sclerosis). The broad
fibroblas t-poor coll agen ban d s surroun d
at least one nodule . This fibrosing process
is usually associated wi th a thick en ed
lymph node capsule. The lymphoma contains a highly variable number of HRS
cells . sma ll lym phoc ytes and othe r nonneoplastic inflammatory cells. The HRS
cells tend 10 have more lob ated nuclei
with smaller lobes. less prominent nucleoli. and a larger amount of c ytop lasm than
in other types of CHL In formalin-tilled
tissues the cytoplasm of the HAS cells Ire330
HodgkIn lymphoma
quently shows retraction ot the cyto plasmic me mbra ne so that the cells see m to
be silting in lacunae. These ce lls hav e
the refore been de signa ted lacunar ce lls.
lacunar c ells may for m ce llular ag gregates . whi ch ma y be associ ated with
necrosi s and a histioc yt ic reaction. resembl ing nec rot izing g ranuloma s. When
agg reg ates are very prominent. the term
"syncyti al variant" has bee n used . Eosinephils, htsnoc vres. and to a lesse r exten t
neutroph ils, are often numerous 117431
Gra d ing ac c ord ing to the proportion of
HRS c ells or the characteristics 01 the
back groun d infiltrate (such as the number
of eosmo pbns) may predict prognosis in
some settings. b ut is not req uired for routine c linical p urpo ses 1936. 1356,2307.
2341AI: it may serve a research purpose
in protocol studies.
Immun op henotype
The mal ignant cells exhib it the CHL
ph enotype (see Introduction ): however.
associ ation with Epstein-Barr virus (EBV)
as demonstrated by EBEA or the EBV encoded lMP1 is less frequ ent (10-40%)
than in m ixed c ellul arity CHl 1918A.
919A, 237 4A. 23 77AI.
Prognosis and predicti ve factors
NSCHl has a better prog nosis overej
than that 01othe r types of CHl1251. Massive med iast inal disease is an adverse
p rog noshc fact or 120621.
L.M . Weiss
R. von Wasielewski
G Detsol
S. Poppema
H. Stein
Definition
.,heel cellularity classical Hodgkin Iymecre (Me e HL) is a sub type of c lassic al
Hodgkin lymphoma (C HL) w ith scattered
classical Hodgkin-Read-Sternberg (HRS)
cells in a diffuse Of vaguely nodular mixed
~tOfY bac kground without nod ular
sclerosing fibrosis. C ases wh ic h d o not III
Ino !he other subty pes are pu t in this cal"PY.
965213
iology
Siles 01 involvement
Peripheral lymph nodes are frequently
evolved and mediastinal involvement is
uncommon. The spleen is involved in
m . 8M in 10%. liver in 3% and other
opens in 1- 3% 14561.
".
Fig. 12.17 Milled celkllanly subtype of dassical Hodgklll~ . COJO.negatiYe ~, wrlh a prtIIIJUIICed
epithelioid dilrerenbatlon forming cilsters. predominate. The CD30 imrTlJl'lOSlaifIing ~ ee presence d a large
Reed-Slemberg cell and a sma. Hodgkin eel.
Immunophenotype
The ma lignant cell s exh ibit the CHL immunoobenotyoe : however, the EBVencoded lMP1 and EBEA are expres sed
muc h more frequently (approx imately
75% of cases) than in nodular scleros is
and lymphocyte-rich CHL 133).
Prog nosis and pred ictive factors
Before the introduct ion of mod ern therapy,
MCC HL had a worse p rog nosis than
nod ular sc lerosis and a better prognosis
than lymphoc yte-de pleted CHL. With current reg imens, these d ifferenc es have
targely vanished although rot entirely [251.
F'i- 12.1. lobed ~ MtItype of dassicalliIldgUl ~_ AThe nixed teUJr I'llitrate does nolconlaIn fIbrotIC bends.
IIIIIlld ceII.Mr rilltrate wiCI'I ~. IJIilO'OI)hageS and ~ is 'tiSibie
331
Definition
Epidemiology
l RC Hl comprises approximately 5% of
all CHL. in similar frequency to nodular
lymphocyte predominant Hodgkin lymphoma (NLPHl). The median age is similar to NlPHL and signJlicantty higher than
in other subtypes of CHL 15731. There is a
male predominance (70%) 120091.
Sites of invotvement
ICD-Ocode
332
9651/3
Hodgkin lymphoma
I. Anagnostopoulos
PG, Isaacson
H . Stein
Clinical'eatures
Most patients present with stage I Of II
disease. B symptoms are rare. The clinical features are similar to those of NlPHL
with the exception that multiple relapses
seem to occur less frequently 15731.
Morphology
There are two growth patterns: a corrmon
nodular one 133. 901 and a rare diffuse
one 1331. The nodules of the nodular vanant encompass most of the involved
tissue so that the T-zone is attenuated
The nodules are composed of smail lymctocyl:es and may harbour germinal ceores that are usually ecc entrically located
m relatively small or regressed . The HAS
cells are predomina ntty found within the
nodules but consrstennv outside of the
germinal centres. A proporti on of the HAS
cells may resemble l P ce lls or mononudear lacunar cells. This subtype can easily
be ccofuseo with the NlPHL. In the past.
approximately 30% of cases initially diagnosed as Nl PHl were lound to be
LRCHL j33l. The demonstration of an immunophenotype typical lor classical HAS
cellsisessential in making this distinction ,
Icsnopbus and/or neutrophils are absent
from the nodules and if present they are
located in the Inteetoutcurer zones and
are low in number, In rare instances , the
t-een-nett
,.
1~100)
U'H.
00
..
~r 1W2 ."'~ )
00
..
..
00
r,
-----
NSMCA.O (12$12....7)
J ..
00-
00-
1IlCK.1~100)
1.51
1~
1121 A 0eraI suMYaI byMldogIc SIbyplt. B 0YeraI evenl-Iree SU'\'MI by Ii:skllogic ~ {2OO9}.1..RCHL.
333
Lymphocyte-depleted classical
Hodgkin lymphoma
D. Benharroch
H . Stein
S.-C. Peh
Definition
ICD-O code
965313
Epidemiology
This is the rarest CHL subtype 1% of
cases in Western countries). 60-75% of
patients are male and the me dian age
ranges from 30-37 years 125, 20091 . This
subtype is often assoc iated wi th HIV infectio n and is seen mo re often in developin g countries {80S, 23 171.
Siles of involvement
LDCHL has a pred ilec tion for retroperitone al lymph nodes, abdominal organs,
and bone marrow.
Clinical features
l DCH L pr esents at a mo re advanced
stage (Ill-IV) and with B symptoms than
the other subtypes (1585, 2OO9}.
Mo<phology
Although the appearance of lDCHl is
highly variable. a unifying feature is the
relative predominance of HAS cells in
relation to the background lymphocytes.
One pattern may resemb le mixed cellularity but com pa red with increased numbe rs of prototypic HAS cell s. In some
cases, pleomorphic HAS cells may pred ominate, producing a sarcomatous appearance. These c ases may be ditticult to
differentiate from anaplastic forms of
large cell non-Hodgkin lymp homa
Anot her patter n is ch aracterized by diffuse fibrosis with or without a p roliferation
of fibroblasts an d only a few HA S cells.
Immunophenotype
The HAS cells show the same immunephenotype as in the other subtypes 01
c lassica l HL Most HIV + cases are EBV
infected and stain positively lor lMPl
1932.2020.22761. Coexpression 01 CD30
and PAX5 is very helpful in differentia ting
lDCHl from AlCl, ALK- .
Prognosis and predictive factors
Prior to modern therapy, the course 01
lDCHl was aggressive and it has remained so in some parts of Europe 125,
17821 and in developing countries . In the
US and UK, the course is comparable 10
other CHl subtypes of similar stage , Poeprognosis is seen in Hrv-rerateo lDCHL
patients.
De finition
Lymphoprouterauve diseases (LPD) associ ated with prima ry immune d isord ers
(PID) are lymphoid proliferatiOns that arise
as a result of illYTlune deficiency due to a
pr imary immunodeficiency or immunoregulatory c nsoroer. Because the pathology and pathogenesis of the more than
60 PIOare hete rogeneous. the manifestations of the Iymphoproliferalive diseases
are Ijghly variable. The PlD most frequently
assoc iated with LPD are ataxia telangiectasia (AT), WISkOll:-AIdrdl syndrome (W~),
oomr<Jnvariable_(CV1D),
Epidemiology
Age -sp ecific mo rtality rates for all neoplasms in patients WIth P1D are 10-200 limes
the expec ted rates lor the general po p utenon. Howev er, g ive n that PIO are rare
disorders . the overall occurrence of PID
associated LPD is low With the exception
of CVID . these di seases present primaril y
in the paediatric ag e group . They are
more common in male s than fema les, primarily because severa l of the primary
genetic ab normalities are X-linked, e .g
XLP, SCIO and hyper-lgM synd rome 110631,
Etiology
The c ause of the LPO is related to the underlying primary immune oetectl tsoa].
Epstein-Bar r viru s (EBV) is involved in the
majority of PIO-associated lymp hoi d proliferations [23021, In these cases, defective
T-ce ll immune surveill ance to EBV is believed to be the pr imary mechan ism 1935,
17881. The absence 01 T-cell control may be
complete. resulting in fatal infectious m0nonocieosrs. or partial. resulting in other LPD
t-eens
11042/
WAS is a complex immune d isord er. w ilh
defects in function of tceas. Beene. neutrophils and macrophages. T-cell dysfunclion
is significant . and tends to increas e in
severity d uring the course of the di sease.
Hypef-lgM syndrome results fran rTUtations
336
Fig. 13.B2 DiltLJse largeB-alIIymphoma II a pabenI WIth Ionp-slaodIng carmon ariabIe InrTulOdefiOelq ~
A l~ eels ant seetl ll asates IUd nt show marked pleoITuptlisnl. B L~ eels are EB'V---poslIM t,
EBER'" situ hybrWaticwl.
~
.I.s In other immune deficiency slates.
n
,.
,.
ia
polymorphous lymphoid
(M/alessimilar to those seen in Ihe post1arsplant setting, and frank lym phom as
tat do not differ from those in immunoerroeient hosts, The type and frequency
eech lesion differ among the PIO (Table
s-
1301),
,.
,h
a-
,e
b
/lori-neoplastic lesions
Crmary EBV infection in PIO may result in
fatal infectious mon onuc leosis (FIM) ,
curacterized by a high ty polymorphous
~,iferation of lymphoid ce lls showin g
ecerce of plasmac ytoid and immunetesc ditlerentiation . Reed-Sternberg-like
::etslllay be seen. This cond ition is prirrarly seen in patients with XlP (Duncan
~rome) [BOOI and SCID 11 7881. The
noma! a.cell pr onteranon is systemic,
'ldYi"g both lymphoid and non-iymphoid
~. most corrmor"lly the terminal ileum,
rlaer"cphagocytic syndrome is frequent,
Rl 'SlT'OSt readily identified in bone ma r(BM) aspirates. In CV IO, waxing an d
IymphoprOliferations ma y occur in
rcoes and extranocar sites, with
morphology including follicula r
IflerpIasia, and paraco-ncat expansion
Lymphomas
Lymphomas occurring in patients with
PIO do not genera lly d iffer in their morpholo gy from those occurrin g in immunocompetent hosts.
Lym phom atoid g ranulomatosis (LYG). an
EBV-driven proliferation of B-cells assoc iateo with a ma rke d t-een mtntratlon. is
inc rea sed in fre q ue nc y in patients with
WAS { 1003) (See Chap ter 10), The most
com mo n si tes of involvem ent ar e lung,
skin, brain and kid ney,
Diffuse la rge B-ceillymphoma (DLBCL) is
the mo st com m on type of lym phom a seen
in PIO in general; Hodgkin and Bur kitt
lymp ho mas 1224 11 an d peripheral r-celt
lym p homas also occur [ 17291, In AT, and
10 a lesser ex tent in NB S,
lymphomas an d leukaemias are mo re common than B-cell neoplasms 121641. Rare
cases of lru e pe rip he ral T-een lymphoma
have been se en in patients with ALPS
11729 . 21 08 1. Both T lymphoblastic Iymp homaaeukaerma (T AllJlBl) and T-cell
p rolym phocyt ic leukaemi a (T-PLl) have
been reported in PID.
t-een
Hodgkin lymphoma
Hodgkin lymphoma-like Iymphoproliferalions resembling those seen in the setting
01 methotrexate therap y as well as LPO
wilh all morphological and phenotypic
337
fig. 13.05 Reactive ~ node from a pabenl with ALPS. A There is prominent parac:ortlcal expansion. B ALPS tynllh node. Reaclive geminaI centres eve present and tle
C The ceb are slqllIy Ia'gerthanIIOITIIaI smallyrnphocyte$. wilh dispersed dYoma\Jl.
parac:or1eX is expMded.
Precursor lesions
The underlying primary immune disorder
is the principal precursor lesion leading to
the development of LPO. This morphological spectrum is accompanied by an increasing dominanl ccoar poputanoo: from
clearly poivcionel. to oligoclonal to mono-
Genetics
Antigen receptor genes
Since lPD in PID is a spectrum from reactive to aggressive Iymphoproliferalloos lhey
can be polyclonal, oIigoclonal or m0noclonal. FIM is generally poivcionai: overt
lymphomas such as OlBCl or Bunott 1ymphoma have clonal immunoglobulin heavy
and light-chain gene rearrangement 1638,
1256 . 19291. Presently there is only limited
expe rience with
clonality tests in the
selling of PID.
t-een
tmmunophenotype
Non-neoplastic proliferations
In ALPS. there is expans ion of a d istinc tive
CD 3 + CD4- CDB- CD45R A+ C045 ROnatve t-een pop ulation in the PB and BM,
The T cells ma y exp ress C05? but not
C025 Inc reased nu mbe rs of CD5+ polyc lonal B cells may also be seen ( 1300)
Hyper-lgM syndrome is cha racterized by
PB B cells tha t bear only Ig M and IgO.
Neoplasms
Most of the lymphomas in patients with
PIO are of B-ceillineage, and thus express
B-cell antigens co rresponding to their differentiation stage. EBY infection of B cells
often leads to down-regulation of s-een
antigens. Thus, C020. C0 19 an d C079a
may be negative or expressed on only
some of the neoplastic cells in EBY-positive
LPD . Sim ilarly, EBY leads 10 the expression of C030 in most cases . In patients
with EBY-positlve lPD resulting from defective immune surveillance, the latency
genes including LMPl may be expressed.
338
ro1e ~
,a
PIO is need ed , Allog eneic BM transp lantation has bee n used in patients with WAS,
SC IO and hyper-Ig M sy nd rome 1629,
8681, Since the EBV-d riven B-cell expansion in LYG is often not aut onomou s, it
may resp o nd to immu no regulatory the rapy using inte rferon u -2b 124201
I"""'"
GIn.{.) or protein!.)
Mosl commonISsOCiated
impkaled
dPlO"j
CorOled T.
9-1 6'Ji,
. . 1koI
-..nodefic:ienc:itt
....
1-5%
~1C)'
,sao,
VdlamofL2R.Il.J.R. tl-1R,
1l-9ft1L15R, tl-21R, JAK3
lunase: Il l R, C045,C036 or
1-'"
--
EBV--astOOated lesions.
(DlBCl. HodgloJn 'nphoma)
granular ~e 1etJkaer!ia
larve
i11ecbOns
Pndonlinantty
IfIIJbody PIOJ
CcrrIIOlwnabit
21-3 1%
..,..,lldeblrq
iClDl
0lI' welklefil'lfld
5--22%
iIIlmlmodtliciency
11l1 dro mes
WiskottAAjricl1
13%
ATM
NBSflNibrin)
WASP
Ij"'O'oole (WASI
Ataxialslangieeta sia
2-{l%
:AT)
NffJe9E!" tlreakage
l~ome (NBS)
OlMaMloflmmun.
1- 3%
<1%
SH2D1A
<1%
,-
~ulatjon
WlO\Ji...liYe
tfOtrne (XlP)
-~
.,........abve
"'-iAU'S.
CnI!--SrMh Syrd'ome)
8) (type 2b)
(3-9%)
"'-.
repol1s 01 severalnalional and i1teInational registnes TCR. T-(eII anligen receplor; NI. normal; ADA. aOenosIfIe deamioase: B. B~,
I T ~. !g, serum irmu'logIObI*l: AFP, e. fetoproleln. " "it where provicled n:licates appfOlUtTl8Ie %rJ pabenls II wtlom LPOdevelops.
' :W ~ !rom
primary IfTlmunedisorders
339
M. Raphael
J . Said
B. Bensch
E. Cesa rma n
NL Harr is
Definition
are heterogeneous and include lymphomas usually diagnosed in immunocompetent pa tients. as wett as those seen
much more often in the selting of HIV
infection. The most common HIV-associatec lymphomas include Burkitt lymphoma
Epidemiology
The incidence of all subtypes of nonHodgkin lymp homa (NHL) is increased
60-200 times in HIV-positive patients. In
partic ular, be fore highly act ive antiretroviral
therapy (HAART) was availab le , pr imar y
central nervous system (CN S) lym phoma
and BL w ere increa sed approximately
1000 times in co m parison with the general population 1193, 1283). Since the introduction of HAART. the risk of NH L
declined dramatically (from 53 to 23 standardized incidence ratio): the risk dec reased cons id erab ly in 1996 and has
remained sta ble ther eafter (646! Moreover. the d ecr eased incid en ce of most
Fig. 13.07 RadiaogicaI firdngs in HIV-assOOaled~ . A Nuc:le magnetICresonance (NMRj lnagilg $I2lfll
tile brain shows a Iiwge tl.molJ" mass in !he basal gangb. BMlIbple*'9 defects n seen in iYer
340
genetic abnormalities. cytokine deregulation , and the role of Epstein-Barr virus (EBV)
and Human Herpes Virus 8 (HHV8) 1336
3371. However, EBV-positive lymphomas
decreased in the HAA RT era 19411. HIVrelated lymphomas are consistently rroocclonal and are ch aract erized by a numbel
of common ge net ic abnormalities of MYC
and BCL6 genes, as well as tumour suppressor genes 1743, 22821. The recognition of a porv cionat or ono ocionar newe
of some f-nv-retatec lymphoid proliferations
suq qests a multistep lymphomaqeness
B--cell stimulation, hypergarnmaglobulinema
and persistent generalized lvmoreoercpa thy preced ing the development oi
these lymphomas probably reflect the roe
of chronic antigenic stimulation. Denotco
of the c ytokine network leading to hign
serum levels 01lL6 and IL 10 is a featured
Hrv-rerateo lym p homas assoc iated wltn
EBV or HHV8 . EBV is id entified in the reoplastic cells ot approx imately 40% of HIlirelated lymphomas , but the detectce d
EBV varies consi d erably with the site ct
presentation and histo log ical subtype
EBV infec tion occurs in 80--100% 01 pi"
mary CNS lymphomas 13251 and PEL
80% of DlBCl w ith fmm uoobtastc teatures and 30-50% of BL 1877!. Nearly <II
Hl cases in the settinq of HIV inlectlOll
are associated with EBV 1107, 2068
HHV8 is specifically associated with PEl,
which usu ally occurs in the late stagesIi
the disease, in the settmq of prof
immunosuppression 13721.
~.
:.8 0;
t.g. 13.10 Ii &r1utt lymphoma. eel ~ is urVIoon. B In arw;Jlher case of Burkill tymp/'lOma, eels show mud! great vanaIion in size and shape. C BI.rtillIynllhoma'"
pliI5trIaq'loid dItI8rentlation. eels have an ec:c:enbic rim rJ deepty stained cylopIasm
na.
11 11 Ii Prmary CNS lymphoma. dassIIied as liIfuse largeEk:eIIymphoma i'I an HIV-posiIiYe pabent. B Diffuse largeEk:eIIymphoma. irnrTulobIaslic variant. presenlIng in
.. a:nnI nervous system. Thecellshaveprominentcentral nucleoli. C Cells extllbit marked pIasrnar;ybd ddIenlnIiabOn.
Sites of involvement
These lymphomas display a marked
,e
,
,f
,-
,-
,f
,f
,-
,-
,"
.n
1 .
L.
of
.d
Clinical features
\tIs1 patients present with advanced clincal sta qe: bu lky d isea se with a hig h
HIV seropositivity and lymphoma and signilicanlty higher CD4 + f-cen counts (more
than 200x 1CJ61l) 121 1, 3351.
Morp hology
In HIV-positive pat ients, d ifferent ty pe s of
lymp homa can occur. Some are the same
ag g ressi ve B-c ell lym pho mas that develo p sporadically in the abse nce of HIV
infection, wh ile others co rrespond ing to
poly morph ic lymp hoid proliferations and
unu sual lymphoma bistotvpes occur more
spec ifically in AIDS patients,
Lymph omas also occurring
in immunocompetent patients
Burkitt lymphoma : Burkilllymphoma accounts for 30% of all HIV-assoc iated lymph omas, One third of cases displ ay the
spectrum of mo rp hologic fea tures descri be d in the Bl chapte r, with EBV be ing
positiv e in 30 % of cases 11 8 191. Two
thirds of cases show p lasmacytoid d ifferentiation, which is relatively unique to
AIDS pa tients. They are ch aracterized by
medium-sized ce lls with ab und ant basoph ilic cytoplasm, a nd an eccentric nucl eus , often with one c entrally loc ated
p rom inent nuc feolus. The ce lls often cootain cytoplasmic immu nog lobulin. EBV is
posi tive in 50-70% 01 cases 15 111
Diffuse large 8-cell lymphoma: The maJOl"Ity of these lymphomas contai n numerous
centroblasts , vari ably ad mixed with immuno btasts. This type acc ounts for
25-30% of HIV-assoc iated lymphomas ;
EBV is present in 30% of cas es, DlBCl
containing more than 90% immunoblasts
and usual ly exhi b iting p lasmacytoid tealures are cl assified as the immunoblastic
va riant. They account for about 10% of
HIV-assoc iated lymphomas, contain EBV
in 90% 01 cases, and allen occur fate in
the co urse of H IV disease. Primary ce ntral
nervous system lymphomas are usually of
the imm unob lastic type {325 f,
Hodg kin lymphoma. Most cases co rrespond to either the mixed ce llularity or
lymp hocyte dep leted forms 01 c lassical
HL Some c ases of nod ular scle rosis Hl
are also seen . HIV-re lated HL is associateo with EBV in nearly all cases: the cells
express Ihe latent mem brane protein 1
(LMP 1) and are EBER-po sitive. Atypical
forms with Hodgkin-like features may be
observed in such con text 11 9091.
Other lymphomas: Rare c ases of MALT
lymphoma have been described in both
paed iatric and ad ult pa tients with HIV
infection 11436 , 2 1871. Rare cases of
pe ripheral t-een and natu ral killer ce ll
341
M. RaphaAI
J. said
B. Bofisch
E. Cesarman
N L Harris
Definition
Lymphomas that d evelop in HIV-p ositive
pa tients are p redominan tly agg ressive
Bccef lym phomas. In a proportion of
are heterogeneous and include lymphomas usually diagnosed in immunocompeten t patients. as welt as those seen
much more often in the setting 01 HIV
inlec lion. The most common j-nv-assooateo lymphomas include: Burkitt lymphoma
(BL), diffu se large a-ces lymphoma
(DlBCL) (often involving the ce ntral nervous sys tem), primary effusion lymph oma
(PEL), and p lasmablastic lymphoma.
Hodgki n lymphoma (HL) is also incr eased
in the setting of HIV.
Epidemiology
The incidence of all subtypes of nonHodg kin lymphoma (NH L) is inc reased
60-2fXl times in HIV-positive patients, In
particular. before highly active antiretrovirar
the rapy (HAA RT) was available , primary
central nervou s system (CNS) lymphoma
and BL we re inc reased approximately
1(XX) times in compa rison with the q enere! po pulatio n 11 93 , 1283 ). Sinc e the introd uct ion of HAART, the risk of NHL
declined d ramati cally (from 53 to 23 sta ndardized incidence rati o ): the risk d ec reas ed c on sider ably in 1996 an d has
rema ined sta ble therea fter (6461. Mo reove r, the decreased inci denc e of most
Fig. 13.07 RadIOlogical findings in HIV-associaled lymphoma, It Nuclear ~ rescoeece (NMR) imag'ng scan d
ee bra,n shows a large tumour mass in 1Ile basal ganglia B Mufliple filling defects areseen in Mr,
AIDS-as soc iated NHL alte r HAART introd uction is consistent with improved CD4
co unts 1211, 2171 HAART is also associated with enhanced survival with a 75%
d ec rease in mo rta lity. although lymphomas now contri b ute to a greater percentage of first AID5-defining illness 1570.
6461. There has been an unexpected
increase in the incidence of HL since the
advent of HAART therapy /4511. Since HL
incidence is lowe r among patients with
severe immunosuppression than among
those with moderate immune defect, the
recent inc rease of HL incidence co uld be
po ssib ly related to imp rovements in CD4
counts 12181.
Etiology and pa thoge nesis
Lym phomas in HIV-pa tients a re hete rogeneou s, reflecting sev eral pathogenetic
mech anisms: ch ronic antigen stimulation,
gene tic abnormalities, cytokine deregulation , and the role of Epstein-Barr virus (EBV)
and Human Herpes Virus 8 (HHV8) (336,
33 7}, Howe ver, EBV-positive lymphomas
decreased in the HAA RT era /9411. HIV
related lymphomas are consistently rro-oclonal and are characterized by a number
of common genetic abnormalities of MYC
and BCL6 genes. as well as tumour ~
p ressor genes 1743, 22821. The recogrtton 01 a polyclonar or otigoclonal nature
of some HIV-reIated lymphoid proIiferam
suggests a multistep Iymphomagenesis
B-cell stirn,J1ation. hypergammagloblJlinemia
and persistent ge neralized lymphadenopa thy pre c ed ing the develop ment 01
these lymphomas probably reflect the role
of chronic antigenic stimulation , DisrupliOO
of me c ytokine netw ork leading 10 high
serum levels of IL6 and lL 10 is a reatoree
Hrv- rerated lymphomas associated with
EBV or HHVB. EBV is identified in the reoplastic cells of approximately 40% ot HIV
related lymphomas. but the detection ci
EBV varies considerably with the site ci
presenta tion an d histological subtype
EBV infection occurs in 80-100% of prmary CNS lymphom as /3251 and PEL
80% of DLBCL with imm unob lastic teatu res and 30--50% of BL /87 7). Nearly a~
HL c ases in the setting ot HIV infection
are associated with EBV P 07 , 20681,
HHV8 is specifically assoc iated with PEL
whic h usually OCCUfS in the late stagesof
the disease. in the selling of profound
immunosuppression 13721.
:. ~
l.
ens
Sites of involvement
These lymphomas display a marked
eropensrty to involve extranod at sites, in
carncurar the ga stroin testinal tract, e NS
(less frequent since HAART).liver and bone
matrow. The periph eral blood is rarely in-
Yost patients present with ad vanced clincal stag e; bulky di sease with a high
unour burden is frequent. lDH is usua lly
markedly elevated . There is a significant
relationship between the sub type of lymphoma and the HIV di sease status.
DLBCL more etten occurs in the setting 0 1
l:lng-standing AIDS and is associated
NI!h a trend toward s a higher rate of OJ)cctomsuc infec tions and lower CD4 +
T-re11 c ounts with a mean be low
lCKb: l lJ1lL. In con trast. BL occurs in less
.rrmunod efic ient patients. with a short er
mean interval between the d iag nosi s of
HIV seropos itivity and lymphoma and significantly higher CD4+ T-cell counts (more
than 200x 1()6!L) 12 11, 335 1.
Morphology
In Hrv-oosmve patients. different type s of
lymp hom a can occur. Some are the same
ag gressive B-een lymphomas that d evelop sporad ically in the ab sence of HIV
infec tion, wh ile others correspo nding to
polymorph ic lymphoid prol iferation s and
unusual lymphoma histotypes occur more
specifically in AIDS patients,
~.
Diffuse targe B-eelt lymphoma: The ma jority of Ihese lymphomas contain numerous
centrobl asts, variably admixed with immu nobtasts . This type accounts for
25-30% of j- nv-assoctateo lymphomas;
EBV is p resent in 30% of cases. DLBCL
containing more than 90% immunoblasts
and usually exhibiting plasmacytoid features are classified as the immunoblastic
variant. They ac count for about 10% of
HIV-associated lymphomas , conta in EBV
in 90% of case s, and often occur late in
the course of HIV disease. Primary cen tral
nervous system lymphomas are usually of
the immunoblastic type 13251.
Hodgkin lym phoma: Most cases correspond to either the mixe d c ellularity or
lym p hocyte d epleted forms of cl assical
HL. Some cases of nodular sclerosis HL
are also seen , HIV-relaled HL is associ ated with EBV in nearly all ca ses: the cells
express the latent memb rane p rotein 1
(LM P1) and are EBER-pos itive . Atypical
forms with Hodgkin-like features may be
observed in suc h con text 119091.
341
342
Post-transplant Iymphoproliferative
disorders
Definition
Post-transplant IyrrVloproIrferative osooes
SH Swerdlow
SA Webber
A . Chad burn
J A Ferry
lymphomas in allograft recipients are designated as they are in the normal host and
not considered a type of PTLO. Detection
of rare EBV-positive cells in the absence
01 an appropriate Iym phoi dlplasm ac ytic
proliferation is also not considered diagnost ic 01a PTLD
Ep idem iology
POSl-tran~ Iymphopolifer-
1M esease (PTlD).
e.ty Itsi0fll1
9971/1
PolymorphicPYlO
9971/3
llQrIOIllorphic PTL01
(classifyaccording to I)'mplloma lIMy membIt)
&t6# neoplasms
Diffuselarge B-celilymphoma
Burkilllymphorna
Plasma cell myeloma
Plasmacytomalikelesioo
"'"'"
T<eI fI60PIasms
Peo:'iptoeral T-cet lymphoma, NOS
HepatOSlllenic T-<;ell ~phoma
"*'
-..
regimen s and are best cons idered iatrogenic, rather than post-transplant, irTYn.Jno..
oencercy-associated LPO 115761.
Etiology
The ma;ority of PTLO are associated with
EBV infec tion (usually type A), and appear
to represent EBV-ioduced monoclonal or.
les s often, poIyclonaJ B-cell or monoclonal
proliferations that occur in a setting
of decreased
immune surveillance
1376,450,699. 730. 1166. 1569. 21331. Up
to 30% ot PTLO are EBV-nega tive with
some series reporting an even higher proportion of ca ses and with about 213 of
T-PTLO EBV-negative 1224 . 699. 1260.
1586.2 133 1. Furthermore. the proportion
of EBV-negative PTLO appears to be
inc reasi ng /15861 . EBV-negative PTLO
are more common in adults. tend to occur
later than EBV,poSit ive cases and are
more likely to be of monomorphic type
1791. 1586 J. Human herpes virus 8
(HHV8)-associated PTLO are reported including post-transplant primary effusion
lymphoma [606, 1106, 142 11; however,
the etiology of the vas t majority of EBVnegative PTLO is unkno wn . Some may be
due to ESV that is no lon ger detectable
[2073J, some d ue to other unknown
viruses and some due to chronic antigenic stimulation, includ ing by the transpl ant itself 1224) The EBV-negative cases
are still co nsidered to repre sent PTLO and
some may respond to decreased immunosuppression {15861.
The majority (>90%) of PTLO in solid organ
rec ip ients are of host origin and only a
minori ty of donor origin . Donor origin PTLO
appear to be most common in liver and
lung allograft rec ipients. and frequently
involve the allograft 178, 378 , 1255,2069,
23801. In contrast, the majority of PTLO in
BM allograft reci pients are of donor origin,
as would be expected. since successful
engraftment results in an imm une system
that is nearly exclusively of donor origin
t-een
t-een
125101.
Sites of involvement
Involvement of lymph node, gastrointestinal
tract. lungs and liver are common in all
Post-transplantlymphoproliterallve d soroers
343
Fig. 13.12 Intecbws rrDU'lUdeosis-ie(lM)Iesionfla D"ISiI ofan 11--year-<*l renal aIograftredpiert. lhefe ispesel
vatlon of cwertying epIlt1eiI.m and crypts. 1M normal tildes iJfI!I absenl and hire is a li1tuse ~ p1 oifelalo'L
Cflnical features
The clinical features 01 PTLO are high ly
variab le and correlate With the type of
allog raft, and to some extent, with the
morphologically de fined ca tegories. Almost all solid organ transplant recipients
are currently managed with a carcmeunn
inhibitor (cyc losporine or tacrolimus). With
Ihese agents. PTLO frequently presents in
the first year after transpl antation. earlier
than tended to be obser ved in the
pre-cyclosporine era 11 569. 1723}. EBVnegative PTLO and TINK-cell PTLO tend to
present later (med ian time to occ urrence
4- 5 years and 6.5 years, respe ctively)
11260. 1586. 21331. The majority of PTLD
in 8M allograft rec ipients dev elop within
the first six months 14991. PTLO presentation may be non-specific with features
such as malaise. lethargy, weight loss and
Table 13.03 PathologicevaluallOn ofspecimens for !hediagnosis of PM.
Method of tvalualion
Necessity
-...._- .........
Histopathology
EBV <blaIily
PUrpoIie
Assess possible
"Pnllin section i1vru~ ddlen fall k1demr.f1Slrale ~ 8-<;eIpopuIaIions, eY8I'1lf jn'SeI'C, Lriess 1henl1S pIasmacytit~.
~1f!he less senWo'e EBV-lMP1 ~ is posiIie. EBER in SlftsIlybrOZaIiOn is not rllQI,lO:l.
344
.s
scecmc
1435.21331
A number of additional prognostic factors
associated with an adverse outcome
include multiple sites of disease and
advanced stage, older ag e at diagnosis.
late onset d isease. high Internat ion al
Prognostic Ind ex and elevated lactate
dehydrogenase 1309, 435, 643, 792.22691.
However. risk factors for adverse outcome
vary g reatly between stud ies . Multi-site
d ise ase may not be a risk fact or lor
adverse outcome in paediatric patients
12367}. Overall , the mortality of PTLD is
g reate r in BM allog raft reci p ients than
solid organ allograft reci pients and may
be lowe r in c hildren than adults.
Post-transplantlymphOproliferatlYe disorders
345
Genet ics
Clonally rearranged immunoglobulin genes
are not expected in PH. although small
clonal pop ulations may be demonstrated
with Southern b lot analysis using probes
to the term inal rep eat regi on of the EBV.
Some 1M-like PTlD may have small monocl onal or oligoclonal pop ulations, The siq nificance of oligoclonality or a small c lonal
b and in these cases is unkno wn [ 1166,
24531. Flor id follicu lar hype rplasia (FFH)
does not usually demonstrate clonal B
cells b ut. as also repo rted in 1M-like
cases. rarely demonstrates simple clonal
cytogenetic abnormalities 122841.
PbIymorphic PTLD
Immunophenotype
Immunophenotypic studies shOw an admixture 01 pOIyclona/ B cells, p lasma cells
and T cells WithOut phenotypic aberrancy
EBV is present in many bu t not all of the
cases of nodal PH and cases describe d
as florid follicular hyperplasia 11 166, 22841.
1M-li ke cases are typic ally EBV-po sil ive
with EBV-l MP1+ immunoblasts 113301.
346
Definition
Polymorphic (P) PTlD are morphologically
po/yrTk)rphiclesions composed of immuneblasts. p lasma ce lls and small and intermediate-sized lymphoid cells that efface
the architecture of lymph nodes or form
destru ct ive extrano dal masses and that
do not lulfill the c riteria for any of the recognized types of lymphoma described fl
immunocompetent hosts. Distinction ci
some P-PTlD from more -monorrorohc'
(i.e. lymphom a-like) lesions that show pasmac ytic di fferentiation is not well-defined,
Clinical features
The frequ ency of P-PTlD var ies from en!
institution to another, rang ing from 20%10
over 80% of the cas es 1450, 699, 735
110 7,1 166 ,1 569 ,1 586 1. ln c hildren ltlis
is the most common type 01 PTl O 123671
and frequently follows p rimary EBV intec
lion. The cl inic al p resentation of lhese
cases is not distinguishable from PTLO
general. Reduction in renuooeuooessian leads to regression in a variable po
portion 01 cases ; others may progress.rd
require neenreot for lymphoma 11t 6f.
1569,2080,23671 .
Morphol ogy
In con trast to early PTlO lesions. P-PTlO
show effacement of the underlying tssce
architecture 1735. 8871, Unlike most tyrn.
phomas. however, they show the lull fange
cens
mnunophenotype
mmunop henoty pic studi es demonstrate
cells with or without lig ht c ha in c lass
restriction and a variable proportion at
'eieroceneous T cell s that sometimes
ceoonoete 1625. 1569J. light c ha in
class restrict ion , when present , may be
ttal. and some cases may demonstrate
OOIerent clona l populations in the same or
dferent sites 115691. Cases with cleercut
911 chain class restriction are recog ~IOO but this observation mus t be noted
fl the diagnos tic rep ort, as some of these
cases could also be cl ass ified as a
rrooornorp hic OLBCL-like PTLO w ith
resmecvttc d ifferentiation, a DLBC L-like
P'lDwith significa nt polym orph ism or as
I plasma ce ll neop lasm w ith inc reased
rsstormeo cells . Aeed-Stern be rg-Ii ke
:~I s when p resent a re often C030+,
[120. but C 0 15-{4061. Most cases of
~.pTLD contain numerous EBERpositive
:ellS. Detec tion of EBV by EBER in situ
~dization is a uselul tool in the differr.a l diagnosis of PTlO versus reject ion
allografts.
n
,I
,j
,e
10
5.
lis
i7 1
ecse
in
3S.,0-
,od
66.
""""
,LD
sue
ymnge
Monomorphic PTLD
The group of monomorphic (M) PTLO
fulfill the criteria tor o ne of the B-cell or
TIN K-<:e ll neoplasms that are recognized
in the immunoc om petent host and
scr ibed elsewhere in this monograph. The
only exception to this is that the small
B-<:elllymphoid neoplasms such as follicular lymphomas or MALT lymphomas are
not designated as PTLD even though
oe-
Definition
The monomorphic Been PTLD are fT'IOr'Il)clonal transformect B lymphocytic or ptasmacyt ic prol iferations that fulfill the criteria
for a diffuse large Been lymphoma. less
347
ext ramedullary plasmacytoma with involvement of the g astro intes tina l tract . lym ph
Morph ology
Monomorphic B-PTLD fu lfill the co nve ntional criteria for DLBCL Bu rkitt lymphoma,
Table 13.04
Cr ~eria
Immunopheno type
'"""'"
Hisl~thoIogy
.........
""""""'"
......
,oty . . . .
Pdymorphic PTLD
MollQl,lOIptic PTlO
Present
"""" .....
Hodgkn IymptIoma
"''''''
type PTLO
Genetics
"""_
.....
._Major findings
eels, :l irJm.IlDblasts,
Immu~
In sifu hybriciution
Pd B ails & a:lmiled
T eels: often EBVt
...
fu~ spectrumof
lymphoid maturation
Similar tootherCHL;
EBV+
der'nonslraled.
=
=
Pd, polycIooal; Md, mnc1onai: NK. nalufalkiller OIly: TeR,T-wl anbgen recepIor.
~
348
Genetics
Clona l IG gene rearrangement is present
in virtually all ca ses, and the major ity conta in EBV genome s, which, if pre sent. are
in clonal episomal form 1449, 450 , 11071.
Most cases hav e somatically mutated
IGV with a minority showing ongoing
mutations 13341. However, some cases
have IGV loci inactivation related 10cripp ling mutations as seen in Hl l333 l . Asio
non-PTlO DlBCL, on cogene abnormal~
ties (RAS or TP53 mut ati ons and MYC
rearran gements) may be found , and
BCL6 gene somatic hypermulation IS
c ommon; however, BCL6 trensiocatcos
are uncorrmon 1371, 11661. Cytogenetic
abnormalities are cornrnon, and are mere
freq uent than in the early or polymorphic
lesions 122841_ While some recurrent
abno rm alities are reported in PTlD such
as breaks involving lq ll -q21 region,
8q24.1, 3q27, 16p1 3, 14q32, l 1q23-24
and trisomies 9, 11, 7, X, 2 and 12, differert
studies find different conrnon abnorTnalles
1593.22841 . Comparative genomic hytnd ization studies demonstrate additional
gains and losses, althou gh no ind iviCUI
Md Bcells, norK:IonalT
celts
!\ ~.
-:r ~~c:.::c'~_~~:iZ~
Fig. 13.19 HodgkJHype PTLD 1l52-yearl male(post renal transpIanl). The Read-5tentlerg eels _
lJClSIq:Ns, ~ 0Ih WIlh C03O+ ellpfflSSion (B) n Golgi-Iype C01S expression Ie).
M-PTLD 13341.
Mo"","_
Moncmorphic
TIN K~ I
PTL.D
Definition
Monomorphic PilO of l IN K-ceil type
IT/NK-PTLD) include PTLO that fulfill the
criteria lor any of the T- or natural killer
(NK) cell lymphomas. They include almost
!he entire spectrum of T- or NK -eell neoplasms, with the larges t group being
oeripheral T-eeillymphoma, not otherwise
specified type. followed by bep atoeolenlc
Icelllymphoma. Other typ es of liNK-ceil
PTLD include T-cell large granular
~phoc yl8
leukaemia.
adult
T-cell
t-een
fmmunophenotype
T/NKPT LD show express ion of panand sometimes NK -associated antigens.
Depending on the specific type, they may
express CD 4 or COB, CD30, AL K an d
either ali orto T-cell rec eptors. A bout 1/3
of cases are EBV-positive .
t-een
Genetics
Cases of
or igi n hav e c lonal T-ce ll
recep tor ge ne rearrang ement. Chromosomal ab normalities are commo n and
similarto those seen in TIf\JK-cell neoplasms
in the immunocomp etent host suc h as
i(7)(q1 0 ) and +8 in mo st of the neoatosplenic
lymphomas 1593, 21331.
TP53 and othe r oncogene mu tations are
also reported in a high p rop ort ion of
T/NK - PTLD 19801.
r-ceu
r-ceu
ClassicalHodgldn lymphoma
IypePTLD
Classical Hodgkin lymphoma (CHL), the
least COlTlTlOl1 ma,or form of PTLO, occurs
in the post-transplant setting . roost often
in renal transplant patients, is almost
always EBV-positive and should fulfill the
criteria for CHL as described (See Chapter
12) . Because ReedSternberg-like celts
may be seen in early, polymorphic and
some monomorphic PTLD, the diagnosis
of HL must be based on both classical
morphologic and immunophenotypic features, preferably inclu ding both CD15 and
CD30 expression 11 570 , 18871. Although
CD15-negative cases occur. caution is
advised in maki ng the d iagnosis of CHLtype PTLD as these cases must be disting uished from Hodqkin-Hke lesions, in
which the EBV+ Aeed -Sternberg-like ceas
areCD45 +. CD 15-, CD20 + and where one
may find small and intermedi ate-sized
EBV+ lym phoi d ce lls as well 1406, 609,
823, 1570 , 1759 , 18171, Rare c ases may
fo llow other typ es of PTLO. Although the
d istincti on of Hodgkin-l ike PPTLD from
true HOdgkin type PTLD may be d iffic ult
in some cas es, the former are bett er characterized as eithe r a polymorph ic or
monomorphic PTLD. depending on their
overall morphologic features 11759,18171,
349
P. Gaulard
SH Swerdlow
N.l. Harris
E.S. Jaffe
G. SundstrOm
Definition
The other iatrogenic Iympho prolile rative
d isorders (L PD) are lympho id prolifera tion s
Epidemiology
The freque ncy of these disorders is not
well known, and it is dlfhcult to determine
how many are directly related to the iatrogenic immunosuppression rather than the
underlying disorder, Of to chance alone . It
is likely that the risk and type of LPO that
develop in this setting varies depending on
the type of irrmunosuppressive agent and
on the nature of the unde rlying disorder
being treated (e,g rheumatoid arth ritis
(RAJ. inflammatory bowel disease (IBO].
psoriasis and psortasc arthritis or other
autoimmune disorders) 13171, Methotrexate was the first reported immunosuppressive agent associated with LPD in this
rug
~ule
U~ng di$Ofdel
ThefaJ1Y duratiOn
Type of LPD
~ diseases,
3 year.i (0.5-5 ~l
OLBCL. If.
PoIymorptIIC LPO. PTCL
OLBCl. ottlerlype$
HSn.olIlertwes
psor1aSlS
Antagonists 01 TNFo:
InfIIIlITI3b (MAll)
~d lseases
patients)
Adalimuf1lilb (MAll)
Autoimmune diseases
NA
Altftype
Etarercept (fusion
protem with p75)
Autoimmune diseases
AJly type
NA, rv>l available: MAll. monoclonal antibody: TNF. tlll'llOtlr necrosis faclol': DLBCL. dlfllt$lliarge B-ce~ 'Ym~.
HL.1"lodgUl tymphorna; LPO, /yf1'lpI'qlroIOOrabYe disoI'def', PTCL, peripheral T<ellyn1lnoma: HSTl, hepatospl&ric
T<ellymphoma (reported only in pabenls eeeteo WIIh InlWnab. not with other drugs)
350
Sites rJ involvement
M10ng the cases reported in patients receiVIlg methotrexate, 40 - 50% have been
enrercoat. inclUding the gastrointestinal
sect, skin, liver and spleen, lung, kidney,
Ilyroid gland , bone marrow (BM) and soft
tssoe 1982, 19201, As with HSTL in other
sermqs. spleen. liver and BM are the
COOII'TIOIl sites of involvement of HSTL in
Crohn's disease pa tients receiving inflixrreb 11355. 18721
Histopathology
The d istr ibution of histologic types of
iatrog enic Iymphoprohferation s in nontransplantation sett ings appears to d iffer
from that seen in other immunod eficienc y
settings, with a probable increase in the
frequency of Hodgkin lymphoma and lymphoid proliferations with Hodgkin-like
features. Among patients treated with
methotrex ate . the reported cases are
most commonly OLBCL (35- 60%) and
CH L ( 12-25%). commonly of mixed
jpt
EBVt
EilfanOdal
Rtgr . n "
rsse
15/27
.,
7141
'"
.,
~BCL
64
11
FoIIbJlar lymphoma
'18
' /5
&r'o.itt lymphoma
1/3
0/1
!,IlL/MALT lymphoma
0!3
"
Lrmp'loplasmacytic lymphoma
casu
.,
012
.,
.,
3/5
0/3
1/1
a.
01
1/1
1/1
1/1
etrw R PO
1/1
1/1
1/1
10/12
2119
5118
PTCL
lbtgUI lymphornato
1Iod{I k~i
tI:GI
lnlons M
28
3IS
515
214
515
135
4011 06
32169
2&'90
r IlW. hal oIlhestCil9M. fle t1.rabCrl oIl1!lT1SS1CJ'1 was short 11- 10 mcnlhs) and c:hendherapy washfl reqlIIlld.
-n:ludes PTa.. notOlherwise s.pealiedand ~ T<eI ~.
1I.n. dIIIuse Iargt Ek:eIIymphoma; MZl.IUALlll'lill'glnal zone ~rnlCOS3-associated nphoid!issue
~ CLlISU.. d1roIic/yll'lphlXyliCleukaemaIsmaII ~~: PTa.. ~T-<dlyrrVona.
JD, ~oIlftlalrYe clIsorOer.
Immunopl1eoolype
The irrmunophenotype of the LPO does
not appear to d iffer from those of similar
histologica l types of lymphoma in ronirmlunosup pressed hosts, I~
type is a usefu l tool in the d istinct ion
between LPO with HL-like features - that
should 001 be considered to representHLand CHL . the large cells being C02O+!
CD30+iC 0 15- and C020-iCD30+! CD15+
respectively, EBV is variably positive.
Genetics
The genotype of these immunodeficiencyassociated LPD does not appear to differ
from lymp homas of similar histological
types n01 associated with immunosuppression.
Prog nosis and pred ictive fact ors
A significant p roportion of pat ients with
methotrexate-assoc iated LPO have shown
at least pa rtial regr ession in respo nse to
d rug withd rawal (Table 13.06): the majority of responses have occurred in EBVpositive cases 1982, 19201 A variab le
proportion of OlBCl (up to 40%) and
CHl (up to 30%) have reg ressed. while
most require cytotoxic the rapy: overall
survival of OLBCL is approximately 50%
[982 . 1088 . 1089, 10901. Some pa tients
whose LPO may initially regress after discon tinuation of MTX. regrow at a later
date and require chemotherapy {9821.
Regression after discontinuation of drug
seldom occurs in patients who develop
LPO following the administration of TNFn
blockers. Like in other ind ividuals without
overt immunodeficiency. cases of HSTLin
pat ients treated with infliximab appear to
be fatal 11355. 18721.
35 1
R. Jaffe
SA Pileri
F, Faccberu
O.M , Jone s
E.S Jaffe
r-cenrspe
~LT3L
OIll~5f
._~- -
<p
n_
..
-- . -- -----
","
'.
OM-esl'
c::::;co,..
. ,
.' !.~
,
...~...... ,,
.J.L(~
""'"
Fig.14.01 Sdlemabc diagram d!he 0f9II- Bolh maaopllages and dendritic eens (Mligen presenIilg eels) are ~
from a canmon bone marrow preanor. In contrast tokuIar deOO1IJc cells are Ihougt'4 m be d ~
origtn. - . rrost 4 I'lOl: III oeII poSItMt: ., aI eels negabve: ~+, a rrinorily of cells pos4Mt, 'I. vanabIe 1Jl18nsity,
354
Original diagnosis
Currently considered
--
AtCL
Pmwyeutaneous COJO.posilrye
...... ~ hisIJoc)1osfs
Enleropathy-type T-cel ~
~ ~!tlIc ~s
Subcutaneous ~ T-<:eII~wilh
....
TZIIt t4.02
HCIefTlCI/IQOCYIic s~s
Haemophagocytic syndromes
~ I!Wkers01 ~Iic
~ .
F"""""
CO"
""
lC
'DC
-c
..
. 1-
' 1-
CO2'
COJ5
ClJ68
CDl63
F_
'-""
''''''''''
5100
TCll
..
..
. /.
..
..
..
FDC
....
com
Facb' nna
T_
Pot
DiDC
.,-
-t,
..
..
+/++
,.
. /-
./ -
' 1_
. 1_
FCR, Fe IgG receptors (include C016, C032, C064 onsome cells); LC, la ngerh ans cell; IOC, interdigitating
dendriticcell; FOC, follicu lar dendritic cell: POC, plasmacytoid dendritic cell: Mia, macrophage: DIOC, dermal/interstitial dendriticcall: c. cytoplasmic: e. surface.
Expression is semiquanlitatlvelygraded 0 thrOlJQh H , + present, ++ high, +/-Iow or varies wilh cell activity.
Introduction
1
355
Histiocytic sarcoma
1M. Grogan
SA Pileri
J ,K ,C . Chan
L.M , Weiss
C.D .M. Retche r
Definition
HistiOCytic sarcoma is a malignant pronteration of cells showing morphologic and
ICD-O code
9755/3
Epidemiology
Histioc ytic sarcoma is a rare neoplasm
with cxty limited runbefs of reported series
of bona fide cases 1473. 886. 964.1087,
..
Etiology
Fig. 14.02 Histiocytic sarcoma. Ditluse etlacem&nl 01 arctlitectln is seen by a large eel prokIeraboo N iI
irdsmgiWlable from a diffuse latge Ek:eII lymphoma by c:onvenlionalllistopalhology
Morphology
The tum ou r co mp rises a diffu se roocohesi ve pro lifera tion of large cells (>20
IJm), but a sinuso idal distribution may be
seen in tymph node, liver and spleen. The
prolife ratin g cells may be monomorphic
Sites of involvement
The majority of cases present in extrarodal
sites {964, 1745 , 23451, most co mmonly
356
HistiOCytIC and
or. more commonly, pleomorphic. The individual neoplastic cells are usually large
lir
Fig. 14.1)4 HIstiocytic sattOI\"Ia, AHIstiocytic satO:llNI iNCM'lg tie bowlt B Nole tle al::u'ldarC cyt;)pIasm. wI'ich stans
stn:lf9Y b' C068 (e) and tysozyme (Dl
t-een
Genetic s
Histiocytic sarcomas usually lack clonal
Ig H or TCR rear rang ement s 1473), bu t
rare cases have been reported to show
ant ig en receptor ge ne rearrangements.
most likely repr es enti ng exa mp les of
transd ifferentiation 1886. 1810,23451.The
rare c ases a rising in med iast inal ger m
ce ll tumou r show isoc hromosome 12p .
id entic al to the gene tic c hange in the
germ cell tumour 115941.
HISllocytlC sarcoma
357
A. Ja ffe
L.M , Weiss
F. Faccnetn
ICD-O code
975 113
Synonyms
Histioc ytosis X, eosinophilic granulo ma (if
solitary lesion). Hano-Scnuner-Chnsnan
d isease (if multiple lesions), Lette rer-Siwe
d isease (if d isseminated o r viscera l involveme nt).
Epidemiolog y
The inc idence is about 5 per m illion po pulation pe r yea r, with most cases occurring
in child hood. There is a pred ilection for
males (M:F ratio 3.7:1) 117451 . The d isease
is more common in whites of northern
B
f ig. 14.05 I..angemat1s celllIstJotyklsls, A Radioo;1aph from a paten! WIth eosrIOptilic ~ cl bone .....
a discrete ~ lesion. B Agalun SC8l1 sI'lOWS high uptakei'llytic bone lesion.
Cl inical features
Patients with unifocal disease are LlSI.latf
older childrenor adults wOO rmsl: lXlrTJTUtf
present with a lytic bone lesion , eroong III
cortex. Solitary lesions at other sites peset
as mass lesions or enlarged lymph nodes.
Patients With unevstem momtocar disease
are usually young chil dren who presem
with mulliple or sequential destructive 00'Ie
lesions often associated with acaceot sdt
tissue masses. Skull and mandibular involvement is common. Diabetes insipidus
follows cranial involvement. Patients witt';
multisystem involvement are infants whJ
present with fever, c vtooenras. skin and
bone les ions and bepatcsplenomeqav
175, 14821 Pulmonary disease in childl'cj
is c linica lly variab le {16 19l.
There is an associatio n between lCH
and T lymphob last ic leukaemia, with the
leukaem ia-associ ated T-cell receptor gef1l!
rearrangement p resen t in the LCH cells:
this has been considered a transd ifferentiation phenomenon (6761.
Fig. 14.06 Langemans celMIiOC)1O$IS. A Numerous lange!t\arJS eeas are seen. wiItI scattered eosinophiIs and smallymphocy1es. S Ni*ll'oe typical cytlIocjit leau.d
I.Mgernans eel$. WIfl many nudei contaIIWIg IneargtOOYe$ CEosI'lophic microabscess.
358
1
Fl;. lUI langertIans eel ~...-aslruclln
A typical BII'bect granule is seen.
~
Tne key feature is the identification of the
l CH cells. These are oval, about 10 - 15
.m, recognized by me grooved. folded.
tdenled or lobulated nuclei with line
ctvomatin, inconspicuous nucleoli and thin
Immunophenotype
t-een
,
j
I
j
e
e
."
lIJastructure
-"IE! ultrastructural hallmark is the cyt o:mmic Birbeck granules whose presence
A
~
Fig.1U9 langerhans C&l1 hist~os~ . A,B This lymph node biopsy ~ extensive inwlvementof !he sinuses and
paracoucal regions.
...
Fig. 14.10 la'lge!tIar<s rei histloI:pJsis. A Connst!he bland I'IUl::lN' mor~wifl lhatol1he sarcoma (Seef ig
14.11 and 14.12). B ~ is !loCh I'IJderar and cytopIasnic W'IIh 5100. C COtastai'WIg is lA'lIofrnly SU'1ac:e WIlll a
~ dOC 0 L.angenn slaInilg is rrwn grarWr and cytlJlla$rTiC.
359
Clinica l features
Most instances are extra noda l involving
skin and bone an d muttltoc al. hig h-sla g e
d isease (III-IV) is seen in 44 %. Only 22%
are primarily nodal. Hep atosp lenomeg aly
is noted in 22% and pancytopenia in 11%.
Morphology
The most pro minent feature is the overtly
malignant cytology of a pIeom::lrphic turour.
and ooIy the phenotype and/or ultrastructure
w ill revea l the Langerhans cell de rivation .
Ch romatin is clumped and nucleoli are
conspicuous. Some cells may have the
COfT'4)Iex grt:lCNeS of the LGH cell. a key due
to the d iagnosi s. The mitot ic rate is high.
usually more than 50 per 10 high power
fields. Rare eosinophils may be admixed
9756/3
Synonyms
Dendritic/histiocyti c sarcom a , Lanqernans
cell type . malignant histiocytosis X.
Epidemiology
La ngerhans cell sarcoma is rare 1183,
232 . 1745 1. and almost all repo rted cases
are in adul ts. The median age is 39 years
(range. 10 - 72 years). A female p redominance is described (M:F ratio 2:1) 117451.
Sites of involvement
Skin and underlying soft tiss ue are the
most conrnon. with rrultiorgan involvement
that includes lymph nodes. lung . liver.
spleen and bone 1232. 696 . 1745 1.
360
Ultrastructure
Birbeck granules are present, ~ile
d esmosom es/j unc tion al specializations
are absent 117451.
Immunophenotype
The immunophenotype is identical to thai
of Langerhans ce ll histioc ytosis. amJough
the staining for the indivi dual markers can
be focal and pa tchy.
Postu lated normal counterpart
Mature langerhans cell.
Prognosis and predictive factors
Langer'hans cell sarcoma is an~,
tigh-grade malignancy with > 50% rrortaIti'
from progressive disease
L.M. Weiss
T. M. Grogan
J .K.C. Chan
Definitioo
power fields) . Necrosis is usually not present. There are often numerous admixed
lymphocytes, and less commonly, plasma
cells. The histological appearance is soretimes indistinguishable from a follicular
dendntic cell sarcoma and phenotyping is
necessary for precise d iagnosis.
roo coda
Inlerdigitaling dendritic
cell sarcoma
975713
E,;demOOgy
nterdig itating dendnlic cell sarcoma is an
extremelyrare neoplasm. With most Studies
CI'Ie
Fig. 14.13 Interdigitating dendriticcell serccna Tumour is YilQuetylobulatedin fymph node, and firm in con SiSterq
Pa'ients usua lly present with an asvrr otosere mass. although sys temic symptoms.
SlJ:h as fatigue, lever and night sweats,
have been reported. Rarely. there may be
generalized lymphadenopathy, splenomegaly or hepa tomegaly,
-y
361
Ultrastructure
The neoplastic cells show comple x interdigi tating cell processes, but well-formed
desmosomes are not present. Scattered
lysosomes may be present , but Birbeck
granules are not seen.
Immunophenotype
The neoplastic cells consistently express
S100 protein and vimentin with CO1a and
langenn being negative . They are usually
positive l or fascin and variab ly. weakly
positive for CD68 . lysozyme and C045.
Strong nuc lear staining for p53 may be
present. They are negative 104' markers 01
follicular dendritic ce lls (C021 . C023 and
COOS). nwecoeroxoase. COO4. specific
B-cell and T-cell associated antigens.
C030. epi thelial memb rane antigen and
cvtosereuns. The Ki67 index usually
ranges between 10 and 20% (med ian
11%) 1681). The admixed small lymphOcytes are almost always of T-cell lineage,
with near absence of B cells
Genetics
The irrvnunoglobulin heavy chain gene and
the beta. delta and gamma chain genes of
the T-cell recep tor are in a germline con-figuration 123751.
Postulated normal counterpart
Interdigitahng dendritic cell .
Prog nosis and pred ict ive factor s
Theclinical course is generally agg ressive.
with ab out one half of pat ients dy ing of
their disea se, Viscer al organs that are
commonly attected includ e the liver,
spleen , kid ney and lung . Stage may be
an impo rtant prognostic factor, however
histologic features have not been correlated with clinical outcome.
362
:D:' ~ .
~
. ~
Fig. 1.4.16 Inlerd~ ilaling dendritic cell sarcoma. A Nole ttle paraooctical pattern of tulTlOUf growth in the ~m ~ root
B There are scattered sma~ Iympllocytes througlloullhe lesion, CThe CD21stain is negalive on !he lurT'lOlX cek tu:
labels follicular dendritic cells in residual follicles. 0 In contrast. the slain for 5100 protein is strongly posili'le J\!tII
tulTlOO r cells.
J .K ,C . Chan
SA Pileri
G. Delsol
C.D .M, Fletcher
LM , Weiss
K L Grogg
Definition
Follicular dendritic cell (FDC) sarcoma is
a neoplastic proliferation of spindled to
ovoid cells showing morphologic and
immunop henoty p ic features of foll icular
dendritic cells.
975813
EpOdemdogy
Follicular dendrrtic cell sarcoma is a rare
144.385. 1501. 1591, 1724 , 1745,
23751. There is a wide age range, with an
ao:1Jt predominance (meanage, 44 years)
reooasn
sartlCII'l'I3.
'"""'"
363
. '1'
'6a,'tof'
,..(.:,,.'
\ . , ...:;, . . ..
. ...
.
~ .
~ . "'~
' ...
.. A I
" A
364
Ultrastructure
The neoplastic cells have elongated nuclei .
often with cytoplasmic invaginations. If-ere
are characteristically numerous long,
slender cytoplasmic proc esses , often
con nected by scattered , mature desmosomes. Birbeck g ranules an d numerous
Iysosome s are no t seen.
Immuno phenoty pe
Follic ular dendritic cell sarcoma is positive
lor o ne o r mor e of the follic ular dendritic
marke rs, suc h as C02 1, C D35, C023,
KiM4p and CNA .42 1159 11. Clus terin is almost always strongly positive, while this
marker is usually neg ativ e or only weakly
positive in other dendritic cell tumours
lB53. 8541. In addition, thel1.mour is usually
positive for desmoplakin, vimenbn, tascn,
epidermal growth factor rec e ptor and
HLA -OR 1384, 21221. It is variably positive
for epithelial membrane antige n, S l00
protein and C068. Exce ptionally. cytokeratin, CD 45 or C020 c an be expressed .
Staining for C0 1a. lysozyme, myeloperoxid ase, C034, C03 , CD79a. C030 and
HMB 45 are neg ative. Ki67 labeling range s
from t to 25% (mean, 13%).
The ad mixed small lymphocytes are
pr edominantly B cells in some cases.
Genetics
The immunoglobulin and
t-een receptor
crerc-
L.M . Weiss
J.K.C , Chan
C.D.M. Fletche r
code
The tumour is histologically similar to follicular dendritic cell sarcoma or interdigitating dendritic cell sarcoma, but lacks
the irrmunophenotypic profile of these
tlXT1ClU'" types. There are often interspersed
delicate collagen hbres . Ultrastructu rally,
the spindle cells shaw delicate cytoplasmic
extensions and featu res reminiscent of
myofib roblasts (filaments with occasional
fusiform densities, well-developed oesmosomal attachments, rough endoplasmic
reticulu m and basal lamina-like material),
The tumour cells show variable immunoreactivity lor smooth muscle actin, desmin,
cvtoeeratm ( in a dendritic pattern) and
CD68
975913
ICD-Ocode
9757/3
365
Disseminated juvenile
xanthogranuloma
Def inition
Disseminated juvenile xanthogranuloma
(JXG) is characterized by a proliferation
of histiocytes similar to those of the dermal
JXG . commonly having a loamy (xemromatous) component with Touton-type
giant cells. There is evidence 1Q( clonality
in some instances.
Synonyms
Deep JXG (if soft tissue involvement).
Benign cephalic histiocytosis. progressive
nodular histiocytosis or generalized (nonlipidemic) eruptive histiocytosis (cutaneous
disorders wi th multiple JXG but withou t
systemic mvotverrenn .
Xanthoma disseminaturn (if skin and
mucosal lesions).
Erdhesn-Chester disease (possible adult
form with bone and lung involvement)
12488A.238 1AI.
Epidemiolog y
Solitary dermal JXG is vastly more common than other forms and does not
progr ess to more d isseminated forms
1538Al. The majority 01deep, viscera l an d
d isseminated forms occ ur by age 10 years,
ha lf within the first yea r of life, except for
the adult Erobem-Cbester form 110458 1,
Etiology
There is a know n association with neurofibr oma tosis typ e 1 (NF l); pa tient s with
both are at slig htly high er risk of juvenile
myelomo nocytic
leu kaemia
(J MML)
125 1OAI. Patient s with bot h Langerhans
cell d isease (LCH ) and JXG are encountered.
Sites of Involvemen t
Skin an d soft tissues are most common,
and, in disseminated terms. mucosal surfaces es pecially upper aerocnoesuve
tract . The central nervous system, dura
and p ituitary stalk can be affec ted as well
as eye , liver, lung , lym ph node and bo ne
marrow (8 M). Retroperitoneal and pe riaortic involveme nt is noted in ErdheimChester d isease 1538A, 733A . 104581.
366
A, Jaffe
C.o.M . Fletcher
W. Burgdorf
Cl inical features
Skin lesions other than the common papular solitary fo rm are small (1-2 mm) and
multiple. Soft tissue lesions can be large.
and the lesions present as mass effect.
Optic lesion s can cause g laucoma , CNS
and pituitary lesions, like LCH. can c ause
diabetes I1sipidus, seizures, hydrocephalus
and mental status changes 1538A, 733A .
104S8 1. In contrast to LCH . liver involvemen t does not target the b iliary system Of
lead to sclerosing cI1oIar'Qrtls 11042A1. There
is some ca pacity lor lesions to slowly
regress. While JXG appears to be benign,
a concomitant macrophage activation
syndrome can lead to cytocentas. liver
damage and death in the system ic forms .
Morphology
The JXG cell is small and oval , sometimes
slightly spin dled with a bland round -toov al nucleus without g rooves and pink
cytopl asm. Touton cells are less common
at no n-derm al sites. The cells become
progressively lipid ized (xanthomatous) . A
mixed inflam matory component is invariable, Varia nts include epithelioid cells
with g lassy cy topla sm , The ultrastruct ural
feat ures a re histiocytic without otstlngu ish ing features 124BBAI.
lmmunophenotype
ln co mmon with macrophages, ce lls express vimentin, surface C0 14, C0 6B
(PG M 1) in a co ars e gr anu lar patt ern ,
C01 63 in surfac e and cytoplasmic pa ttern and Staoiun- t (MS- l antige n). Fac tor
Xnta stain ing is common but not unive rsal. Fascin stai ns the cell cytoplasm and
8 100 is variab ly pos itive in less than 20%
of the ca ses; however, none of these
ma rkers is specific lor JXG. C0 1a and
Langerin are negative 1392A, 118BA,
193 1A,24B8AI .
Genetics
No consistent cytogenetic or molecular
genetic change has been identified.
B and 't-een receptor gene rearrangement
are qe rtruire. An association with NFl is
known in some. There is evidence for
clonality in some instances 11045AI.
n-
mo..
Fig. tUS Systeri: JXG inYoMng Mr. A The nfiltrate is portal in natJSe but spares ee bi& duct. FewToulon cells
n p-esenl. 8 Faco Xilla There is d1ltuse stailing of the portal hJStJocy1eS.
367
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1.
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1103
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c-.$idI! 01 mtjgI ~
...a _
poonu.
regKlllI
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11.
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fok:uiIf tymclIlomas
""'JP~l60
823-832.
~1'I~~zr:N~
~ I. ~
K HIms........ It..JIlIaES
"""",,.I<A ~ S
F,,",lIn J
Ill. OlIN V. SlIn ti
1lIoOO99.1m1304
2,4,
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wlmll8<l".....~ 21J'l*of~
_
IIII'iII i nocluIar ~ palIIJn~
Pl)lWJIl
t.loote T. Hut:bon J. Jr L~ L L_ DB
R ShlwkK:i G CI'IIn we, G _
TC we.~ 00 Ar1'rIIi\I8 JO
R Slau:lI L.I.l f2OOOl. 0Iswld tycIlts 01 _
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AIiema.. C Sartl Ill, DlI AngeiIs R
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2&.
AImeK:la J. 0<Ia0 A. ~ M
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rlblhr3n
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a.ve
sece
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dYorIK:
p" .
Iltu__ preslX
ttgt>-~ ~ .-ld
Crwtr11C~"""""n"
lobI1l,1J.~J.SI~JF(19'1!l)
DNA
01 ....-..lII
moIul' . . . . ., muo\ple mytlom.l Bt J
HoJema!OI107 121131
27,
Aiona=m EL, Stamberg J, Kumar D
Jaffa ES, ~ W, Frtlnll C. SChiffer CA
o'Connell eA K~ S. SIaq SA.. "'bruuo
LV (19971 ~ 1q the pnmr,
~ IbnornoaIIy 1'1~ gaon...... T ... ~ L........ 1113157-
""
21,
AIWleIl R 8ryne& Rl<. Si'w'ak loll
Mler 01< (1997}. Ac.uIe myR:T..-emoa .....
1(69) (p23:q341 1tSSOOiIbOn ..... ~
Sti . basophil,i . nd initial C034 nag al'\1I
imm ~ til>e Am J Ciln Patl'ltj 107: 430-
:lIA
W-SlJ,lT~oI~""'"
1991 21'528-536
2t
I< lle<mejo JL. ~ K
(20051, Famlal ~aDon 01 ~
cyl>C 1ymph0m8 \Il'lltl ron-i'1oOgl.n 1ymp'Iom&
""'*'
IC~~ _ _ '"
"'tOI" *'..
. . . . , ~ 1yI'CIIllrIW"
W-"'IXJI1frlJm .. ~
Genes
33: ~
Owon_e-
31.
~
JR
",,"1Iige
W_tug&< 00 (1998). E~
flOfl-Hodg'Il" lymphomas d~ rI
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733743
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lIIJ8 01 Bd-6. COlO Bd-2. .-.cl am "dIlIef
. . . ~ . . . , ~ ...... JSurg
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25 132-7"1
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T, HllIllblirl T, Oscier D, Ohy~ikl K. TOYilmll
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1113. KoeIer A. 1A:lflt1!'lA, RasniI:tlIn M
BorIn Gf. Hebeda K. ~ w.., .....
KrlMnJHl<OO7I ~1l"J!.IOOSk~d
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~ Am J Sur;
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14 213121311
1188, K . - MH, Henn;ons; J. W'lli<"9 E.
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o. Maar1I:tnrie E. ScIv.Jmg E, 10ooPl.4 (1 9lJII
CIrlIcIj _ vance of BCU, IlCL6 anc Ill'C
l_lgllfIl8ll1s In
(io/IuSII
Illood 92 31523162.
118lA. KrousW , Haley JC RrMR ~L
Mor!In Co\. FItIl:M'CO 12001~ ".llMnla" ...
pIloma
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S _ K, SChmidt e, Hohr H. OI.-ltan&t/dlWli'ltl' t. F.,.;l r (2Q)31 0iI00rdanI _
lIWTO'* tnWIvelTllWll III ~ lIfge II-oIIIym;YIomI' 03I'IllIQM
l~lJtlI.4IrJ~ l...Wl""'-t
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1" ' . l<.rtI\ICS l. S<nl'lh UJ.
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HIImelr* HI( JIfle ES. RiflIId '" (2003) Tile
_
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~ ~ NK<:eI, gMlIfllI'- ToQII.1IllI
II'lllI*IIII ToQII ~ .....,.,.rJ otI\JIl'l
m ~ 1IMlMd . . . . . --.....,
Blood 101 358ll-35ll3
11" "- ~ t. TIIlJhoo::l L ~ T
pl""'''.
32: 362311
121'. Kv.SI'1<"'" HI>I. Tnie~ J (2001)
Cias$thC/IlIan 01ph.negalr.ie ~ m~
dIIIl;liaIrJ(Xl1AIllIQIII'l in~-.d..cl
CloUtlIIOuI CD~ ~
clIlUders _ I ~ ~ ToQII
pr.not~ J InelIl DerrnalI 109 636-040.
1205 " - rr. $IlIl tv. TSlI'Ig NY (2llOoI)
lQNI ~ llII~ in Ta'0N3n.'dnic:o(:IIIlDIDgIc: !Ilucty rJ 22 ta!I8S ,.." ~ rJ
llIIiIfIl ~ ....
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J Surg PIhII12 37So387
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21 312142,
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" , .. KnIIqn 8
E o.dIn C
(2006) PJorylllpllOeyle
_
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Onool n 2~12ll3
ms- ~ J WIII:W; I( FI'lRIn G
(1984). T-ceM:h ~ lklIlI 1ympI'ana, 10
lIlIOy rJ30 _ , IUppI.lI1ing ItII1i1loklgil; l'IetIft'lgIIIl8IIV IIllI IIcl rJ <*WeIll _ _ _
S/weIc)s
OJ
On PIhlIl06 ~ .
I2CMI. Kurzroa R. 8uescHlamos CEo
~ H FrtInIICh E T...cter st. Socikino
M PilIIl S Till&z 1>1(2001) BCR 1'e8fr".lfIge'menl-llllQ;llMl chronic myetogern.lIleIAenII
chronic
I~ n l p h ocy t i c I lI u kll m l ~ ,
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1410-1416
464~ 12
lil'llfl~ve
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II lhlI ywV--
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Pc.1~ ~i,*"""olifiII"aIIve
_rJ ............
c.a k-.gt. a
0.-
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""\1:1
oIfIIlQ~
Qn Pro<: 50 ~
122$. o(ylltRA Ger1zl.4A11995) PmwyrpIemic ifIl\'kIidow CiIlitII and lIIXr3lor'/ IN!Ins;" 414 ~ S4mwI ~ 32 4$-59
1226. Kylt RA. Gertz 1M, Wllzlg TE,!.usl JA
lllCY MO, ~ A. FonMCI R, ~_
Sv, Offord JR, llflOO OR, P~vak ME,
Themeal TM Greipp PR {200J). " - of
\021 P<o!Jel'llI ""th nt'WIy ~ mo.AbPlI
rrryeIorna 1>I.1yO COn Proc lB.213)
1227. Kyle RA. Grew PR(1900). Srooldenng
m\ihplo.! m~ N Er'9 J fMd 302: 1347_
,~,
P.!tIoI121
257260
1231. Kyle RA.
EilIlIi'\.&on
~ A.I(\lfUlPJ
Il'IdE8Vi-)~II~p;llltJlaIl(lI'Jpn
Jc.n::-Rea1ll: 12.13-t24O
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120CL
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_
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ll"l'k ....... n
e-- 2
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1235. l.ae /tolE. Armed L Niron WR (2002)
e.-..IS....,..,.,..~
1"IitloI118 n3-m
1231. llllOrtilla I VUque.! I Agifre X
liIT.t'/'Ol WJ. Vqmanos JL. GouIII!I A
CaIIIIN: WJ Odefo.., (2004, ~ ....
3G21~
<to: 119-189
we. Lll
**"-
~ AInl!lev1rrlro.lr()l241Q5.738
1241. t..vnarII l , Oasn.gue N PIAlord K,
DenoI:G, IAanameB (1999), A .--t.oIk:Of't~
TI'loU-ALK '" ~ ~ CIIlI ~
Cf$;jt!ld b~ a 1l.2)IQ25.p231 t'ansloclbofl,
!lkxId93, 3Oll8.3095,
1242, Lamant L d8 ReyT"liei A, Ovplenlllf
MM , Rickman DS. Saboord)' F. Gil.nalo S,
BrllglllfeS L, GauIard P, Espino$ E. 06lI0! G
12OO7j. Gene ~. pn! !lSIJdl profiling 0/ systemoc:
itrI8plaslic: lar\lHllll iympl'loma rIlVllai5 dI!et'.
erns bllsed on AlK status and ~ (llslJrld
r'I\OI'?hOlO9lC AtK+!oUbll'Jl'\Ii Blood 109 2156,,~
Bruo- t.
de P"elS 68. ~ N
Bam"""'" A Rvboa I. TerriM-\.aIXon'bII IIIJ
Robert A. RwIl F SctialtIlf O. ShoJt.iII.I Uon
S DeboI G (1996!.....h inc1dfIlDt rJ lie
~2 5~,p23 Q3S1 . . lIIocIIionil anapiISIc '-91
tell ~ end '" lIO< 01 0IIlId00l'I I'l
1tldgo;"1~.~ol~
~.
hMCf(lIa~
p..eo ommunostalfWJll
Blood 17 234-291
1245. ~ G ,\rwIibll C
G\'wI A. Soigo011991;. ~.,...
~~_Il-._""
~
1246.
~I S5
~
l'f"hPlDrna 8
G, OtoW A
References 403
lu~td'l
R Mnlloro C
0 (1991)
~eyndranlt"'" ~IIW'
fUoM a dIIlincl
tWmIIOI 78 161166
1247. Larny T. LOUIl"ran TP Jr pf199
fOIl
~_
Iv BrJ
CI.oowlI
tuIClI(8 IIrge
pa.V
- . . - Illood Rt 13 2JG-2"O
12.... l - r r l~ TP .Jr 12003
CtrGII . . . . 01 ~ pUir ~
....... s.r-~'-O-l8>'!lI5
12
!..In 0 Zlwr1g T ~ 5 2lwll; 'f
S/wl
Wq SS e.Jd $I bhn SH
Hi;lIlotI:l ~ lMcMo9 B y~ M. WIIk:h R
~ 0
~ P I'IoIlIIWI N (200S)
Ger-.c _ _ 1'1 tnl*egeresillfld~
litMIitI
__ HOdQ_,n
10
Iymp/IOrfta
319-418
Il'.
'll" 1l)S.13oCl
lao.
lJIC*)rId
R. a..r
.II.~"'(\9EllI)~~
~ cliIonleIs not IISSOOMCl . .
E-...a.r
W\IS
CInoxIl16 20522059
1261.
LeBootPE(19901).~siId<
~,,=
m 9, ~ O. Grdey G llAS50ll I,
CIporakl NE ~ til..
0 F~ TR
Hl:XMIf' Rtol, toni! t.lS 12(06) RisI.. of IIlOflI)doneI ~mmoptltl)' of urodeMmined SlgMI.
~ (t.lGUS)
a.rs
ma amoog
and ~ muttiple m~
...mote _ .
DiAno:lMl~, blcllogy
ar>d
mM~"""""~"'"
~-~~......
,...IA...."..., ldIIf*cIlor
(2006)
W()IId
Clll~,.rlCll!lOrl
~,lfln
OIyaMl2aOO!l
1?"6-1:l48
126' llwHI ~E.Mn'lA.~.Jl1C
P!Xt\II'I P &..w F !lolngoja D, ~ J
L-vne A GarlIo:ro.J Berdle P GoIIeYWI L
l.ortJJIIfy 0 f2OOl) lrmlu
.....
"*"**",..~
J""
,.... N Er'III
3SO 239-2'8
1265. lMU KillS(; Kfl,KS,~D Yq
WI .lu'lg \1M Cl'li HS (1999l ~
IJI'I'Ilh9US
c.I_~ trorn~l_
~R ~F.~G(2OOJ)
AI'l'l~~.&Oc29ol297
..... ~. . T<l!I~ ~ .
~1IQ2llIfroma~rrUbcen
~lII"lt-lge<TIell""'"
~ ~ of h
giW... _ .
I'Id ~ "C1CIIMUl~
rIIIc:.in:;:Iofhe~ollhe~
rftISlanCI proltIns t.lt}R1 'P~
~ilIfId ~ spedrIIm
~ cooIIIIIionI Nri J Surq PattQ \4
ilIfId
752763
1254. l . f1.OI'I RA, La lle<tu MM (1006]
ll'lefiljly-mlaled m~toid leu'ami;) a model
lor 1e<J ktmog&nelllS 11'I humans Ch!m
B~
1nler8d 153154:167195
~ AmJ~PIIIloIr-c
__
336-3oCJ
Iy ..e ~*"
phoIne 8Iood 98
27621770,
f2001l
~CQ~.IlOl-'
..,.., WIId&,.oms
J,_.
a.-r
Iw J HImIlal 82 S3--&t
1m.
l~E~A~
U. Hox/'lI D ~ w. ~ '"
,T'la'llI R, RMer A. " ' - H ~ A
(1.1 5I'lcUd I piIlIIeI ..... of fiOO. 10l9~ llt
UItd
lUgrlO!IIIC
CftI!I'O'l "" _ _ _
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''''"''''
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Spo'l;j
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'" I-IodgQ(s_
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"J
Ka"d rcllllly
e-.lJ5 781.7&t
m . tIO"illG."'*t PlhGIiA.E~F
PIQIlIlO l119991 The rodenoI rJ S8lXIIdIIy
....e _ ~/l.t 937-9015
lln. L....... D.
F CaIlIneM Iol
RIdbo-W- I ~ N, FeuolIoIol J Le
Mee F PlIIss G TaInW!l P GaclWd N
lJelrMlllr F, Pages MP, ~ UJ,
EcIId'e V SOle C, AoeI-I.OIseaJ H. l.aIaQIPochiIaIolI M 1200Z;, C04i') CD56( ') DC2
aeutl ~ ill charlldlll'lZlld tr,o 0'llCUfTIlrIl
dQnaI d>romoIomil d>argea a~ 8 n'\iIIO'
!Jltgel, a ~l\rly of 21 cases tr,o !he Groupe
F'anc"is de Cytogene'ique Ht>matMlogique
Abnd !*l. 41544159,
1280
V Fenau. P
~me
C (20051, CEBPA
lwOem18 19.129-33oC
1261, Leroy K, H8IOIJn C. Lepage E. le
MIIayeI N ~ F l.a/lcIvy<Ill E, MIognlfl V
fW B IlrJ\Jrlj C. ~ G ~ C
R~ F GNIrd P (<'002), p53 gII'lf IIIJCt""- . . ~ WIlh ilOOI !I,II'VMII in ll;M
and low1lill< I . . . . ri!\:lI dlIIuIe IIrgIa B-alI
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.... If>ym(llklll'f~ I
flIdy allOS
"'"
oes
12st. lfBlluMMI2001)
Rder1l~
404 References
ndctug
--.c. (UCR1).-oj ~
bIologoc ~ ...........
~ diRP:l NSPO"'Ift to starcIiIrdclIeflloI1Ir.
~ A so...-.t Clno::cIIoqy G<Ilup study BklOd
lit- 3323-3329
1270, l"-"- F, Ba.oerIe M, Hv,nI> "10
".,.. P 12001) lIofype-~ imrro;rqjiOO9I"ts WIIh a higl ~ of SOIIIabc ~.
"*'
~COp!l!l91
r-.loc:*wlS ., ~
Blood 14 11'96-1800
1265A. l _
P!1, lliMn8r WA CIri
t __ R. ~ EI,l ...."". EJ,l GIIllIlC
RobIr\-GuIQf! Ll 5.1."'9"" we I .
~~ofMTLVlllfld_
C8IO'l rJ . - higl'I-AIlr. po:1IlYIlOl Irf
1199<1\ TheefleclrJlII'lroc~
"'A
lnIJCancer5fl m .18!.
1287. levirle RL, lClllllUl l,l , I-lurlfy BJ,
Ml. Beran M. S1oI'!regerI E, Ber9"f R,Clark JJ
Wills SQ, Ngvy(lII llit , FloI'M NJ [sley E
0 ~ It. ArlitIylI
o ~C~AOIuaF daVlwA
SIIlRnt E Poggi S. PiIen S TOIl P
lAononI L
l HIIIIIC ~ P . ~ F
Aa1te
EG.......... DC
10llll-10ll9
~ FR. ~ Cl (1997)
LensD.De~PJ.IWI'ioudiRA.
lln.
~ M. ~""N.~ECrtDT
~T,MiqRU~C
~ C Moll< P (1991) T....-..: 0lIQOI'I'e nl progtlOIIc IIcI:n b" l""I')' meet-
1265.
1275,
ft. ~
...... ~
PUlr217: 126-1~
1m t ~ S HJrnl)Io1 T 0$CJtI' 0
DllInrrUIIqIIlrIg .,. ..-e IgM ..,....
* I ..... IIHgene ......... $IlIlI!I...:I C038
~llfldWlbl5 ~,1lO
T-..ntP,~C,o.mC,e..ng.r
CMltlll C 1'lqlll1olP.
F~
D. ....,."...
cane. 7 61).611]
A FftI/'Ilni S OO/W* It
0''''"'''-
.....,....
l'
aoos
TIl; lei SJ ~ DG
!I'UIIotl II !hi OIIinf k _ ..1M2 .. III
~ __ nMNI1YllrlCIoq1hli1"
myelOid ~ ...... ...,...,..
e-
CelI7 387-397
12" L~ EB P963\ lttA<_
~ aro;l ~
IIlJtJpiI
anIIIIia .. Anw'aII
e.-
Blood 1011'
137....,376
1291. l;",.ttoot J Hotller JK lip<nl<y A..
.....
U ~
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IJIIIf
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d _
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.. Cbon'~ L.-.-
Ie 16171623
1291. Ufl loIS.
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Nro J ~
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p/I()pIIsma(:yf
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JvnJ CIon PatIoIl20: 2.6.25)
1312. Lon P 0 - . R lnaJI G. \Wion CS
f2tllOC) FIlM ~ ~
...,. 01306 c.- Ql...... m,eIarnI Am
J ClIIPlIO 121 4B2-48i!
1311 l.otd:n KK ~..IE, DIdO CG.
HIlMI LA ...... ~ {19661 1'hJmc cy:sls ..
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Ql 91""* ..., ~ ~ ., a..-..41
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l.nIIlolS t1fiI.-
so 1.tcl.IlqlIon.J{
. . . . . . . /IgIlPr.... ~ , . . ,
e-,.
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1315. ~E.wnpJJ.lJrtloIW ~
ptng J Knell lFl RlltIIkl t,l c:ossm.. J
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'elXe~a
J. Monl...-o AG
SanIM AH
A, E~ A AIgutro Me,
!lItt:eniI P, f onHa S, Amonm ML , Cabedf,
;M, P,,'toO L, GonzaItt M, Sen '-'"ll"'ftl J. Jusbca
B, Orlao A (2~ 1 Cllnll::obioklgi",1
Ilmnun<,phenolypic, al'ld molecW, ch8recImJlicI a/ rnonocIoI\8l CD56-I+d,m chrome f\IIturlll
r.ell iIlrge granule' lyn,phocI'lOloil, Am J
PathQI165 1117' 127,
1305, Un CH. KuoKT Chuang SS, KOO SH
Chang JIi . Chang KC. Ii ", rIC. TWltl HF.
Che<lg III (2006), ~ a/ thlI expres
SQ:1 II'ld prognoslle ~ oIlW/!!lf1lIIlI&~I
,;w
'\'c..e.
Ii"""
m.acteflll
!I'm-
1308. lonUo..CV
sr....
L.onOll~W T-'II
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1-1. Su FH 'flO 1.1 ~
SY T..., HF (20051 ~ gf
cnp"........
etloOO'_'"
BIooa70181{,.1823
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EH .... Ma-goIicIc
;6, lOf'9l
~_Iesoonl:a~
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pe,iphef3l-b1ood
llunAt's~MoIe-.635.
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Ha'ro.O AA Om le. Dc>pn A. ~ F
RirrUUCl JC Ou UO. ls8::son PG (2001~
~ r:w: "'1.'61 llOIIM! gBIic: II'llCOSa-
- . . d IympIod _
IIIkUIIclIl
PI'b'!"-"'" hrJPV
III
LantllI
'57~
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321~3222
I'l
~ .. !WIll
~ C2JII ~ AmI
za
R..- ........-u
21~306
1J25A. l .. YJ ZI*'Q J ~ PJ
~ IC (,ge,) S. aI
en.. ET
"**- B otlI
~"lJIYIl"')'nl~~
. . , . . ~ .. J~2' 295129&2
132'&. l.claeIF.,....P lIcq", Kafi:llE
~ E PIIIIrs C "'-'.... ..-..:tI Ii
UdermC.Ib*"CS.lldrP CIIIooO. s., J
9n-&87.
1 32 ' l~ C , ~ 1
I-tJrMlIII Y, JoIl-""8OII K, fOIl HO. JoodI
PtrVlIIaI
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ol17. . . .
a ,
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.'L ArrI ~ 9 &I1J.855
1]37, UnlladlRB ~ ~ O Moln
J. Brit PM ~ RP ~ iT
!IiIrwtI FG 120021 CIt............. . . , . 01
to1IoJw ~~ .. cl*hn Elb:Id
9!t 1960-1!l601.
l1J1. l.osao5 IS. ~ M. 0IeIII '"
......-e R TIu1ilnon Y Oet.- PJ e.u.n
I'() IloIIlIon 0 ~ R (2002) 1....." . '
cI ..... Wo- 1IldA.e ~ ....
th:inIa
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DIfIetenbIl E,"" ertlIncIIt' ~ Ifld alJlfll&lion 01 B06 IIOBF.I, Oc;12, put and
I/fVI'IllIIOQlOlin in ructW IklII ~
!ktiII r'(ln-I;orlg:'l'l ~, .-.cl Hudgk"
!yn'ohomIs. J ,"s1hol20. tllHlQ,
1329. Loll ML, Veltl"ut, S Sr.hul)bfrj S,
R~ MG, Camon E, l.Jau, KH Cheng
..
,mo.
G(~
SMy
CCG~ '
c.ne.
Il6 2371).-
ImmunQOtlenotyping 01
sl~nd~ rd i zid
~rsot
tnplesleinings
Bm wilh
810ME D-I
""",mel
ll$'"
1\II1l~.e-:er34 148S-1500
~I'l~~"''''
Iive.-.,.... ........... cI aon.IIy fl
i1.RlbenPllQ66I.Reportdllll~
Ger'IIl 12
3'131~
l loUB. l _
1lII~.y$lem.~.W-1P
....,,-
Ac8dSOlJSA!l6 1"161~
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LcnglIy8J Jo ~GS
f"'"
~..amyetlp._
dlutdlnol <.1IiltlooIl
r:w: 161~
1)61 .
.. ~-.dIll'IIe~
References 405
lorI.lHC IllOiKlJIa Am J
'24.937~
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~ ... l'le\M~ ~ ~ T<:ell
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co..r Jll (1985) PncortciI ~ T<lIlI
~ k..."I1-...... 01 ~ ..."".. VII..-.t
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. . . K, Pm;u P. WrIght EO (21X161 C06~ ~ 8Il:l iIs
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bIok>c)iC /eall.OW "ilt1 three nO$IOOgic wrIarPI&,
J CinOrlcol15. 1664-1671
1369. Makl,nima H 110 T, Mom~ K,
NR'aurwa H, 5nlrr\Ol.laira S, KamiiO Y,
Nal<azaw:l y. Ictl1l;awa N. lXlOCl 1.1, KOOJly~sh i
H Kitano K Sarlo H, KIYCISilwa I( 11tV. F
120(7). CI\6rlI<II<ir'le s)"5~ <lI'Id tili$lJft onfiltm
IloI1 illllQ9rll!lSNll NK-<:elI leu~em . l au\; Ras
31 1237-1 245
1370. MRlco'vali L, Gllrming U. KuandgM A
De~R
M. Tra.-agino E Pa!lS8lT"Cltlb
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LA ~O(lJlllll)~davo
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~K""""""PS Hc*lanCA(19951
CIlIeroecM ....... III T-QII ~
. . . . . BrJ~IJ2"2U2Il6
1374. MaI\IM J, Betgsaoge! 0, K~ R
.10(\ I.lallll\lllment.
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in tvMn T-cell1Ml ~
Ieu~ ""til !unaIottII ~ b
~ 1i!1'*'Il Canter Rts 67' !56'1.!5616
v.--. T. EblIn
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lin
Moo\a
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PIitIUI 113 I14-z2
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b . . q'Il*lgII: at>
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Cltn(eI' 37 116165
1384. Mao X. O'cnard G, l jll<ngtOl1 OM,
R u~&.llil-Jones R. Yoong BD. WtltIlal;er SJ
(2003) A~lion n O.erI 'pf!l5s<on 0/
JUNE! IS i>l1OCl8IId w<th Cl'IfT\lIr; Q.J/MlfIOUI T
C8II~ Blood 101 1513-15111
1385. U!lo Z, ~ l. Raffwld
1.4. lU:t1ter 1.4, KII.9"'i J 8unlIc C, Hao1mIrIn
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~ HI(
0lI G FIn:l F RoetrtNald A (20071 19l1H
mulabllnlil sutul and donIilIty _ly1iI 01
R!d1ter'1 r..>siormIbcIll Am J Surg ~
32J6(lb.I614
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SproBIi 101. Rir\aIdI A.. Oenyel G Menaa/l A..
ea...... S. Billdo C, Dilgna-&c.-llIi ~. IWnnI,
lJ.l1}'" DorM!s ~
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rrwl<ar, BrJ HaolmiIIlOI12S' 129-142
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L Wh"'-" SJ (1999) ~ ~ p53 9""
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References 407
WI1t1~<*1it1j,rIOOl~ ~.
DB
PorJo:er
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I(fOIl
SM (2001)
01 ~ ...
( ~ lllecu'lll:Ql III 862 lXII\MCl,llM
I;lOre IIWlIM ~ by okdor b
c.,t:wn~ llloocl96 2496-2501
11 ~ P. f_ LM y~
itnnlIlIr>phto~ ~
WS!kJlleo'.JJlol. . . . . FBs..~
JA. DuCWI 00 "987~ SlIge IH loIcuW Iylnpi-.. dInlllt , _ .....
~
~,1lIood1l94514~
ean::.
, 456.
'"
*-'
!J1I"'lOtj18s ~ ~ ~ il t:If
_ _ _ """ IIrge ~ J tin PaI'IoI40
&4'~1
M (1980\1
..
......,.....n ......,...(
~
foI
lI~rhut,-- BrJ~
130 174-195
1416. McHiIJU
Coca- 0
HoM G
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CII't
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...,...
*""'"
~,,~"""""myebd
~.
144S. ........ U
'l'1IlKl T
SC Elwood L
1,1, .)MIll
ES (1981)
MgoacenlnC ~ IeSoOl'lS.
~ .....,... 01 w,,1Il oatS, tUn Pilhi
U Parrtw1l ....
lAc ~y D (1)61
S.
C a.tI1F
F.
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I.... t.IIrt;,e DU ItoIn't HP. Gr>e"'>MII' H
1........ 1<1. Kaumarm JJo ~II,ng E
~ R. K~ RA (2001 ~ P!'In8ty ~
noda pllIwnacytom.Js (pla6"\ilC)ilc I~m
1II'cln*) Am J Gin FalhOI115 119-126
t 4 1. Merdler T Coma' M8 Moon; R
UI~tte
:n-1I~'157
Blood 76 285-289.
145OA, MeleA. ?\lIIo<lI A, B,anco E. M u~to P
St~ A. S3npaolQ MG, larmllltl E, ~ RenzoA
Martro II,Lise V.
.~..,.~~~
lXllI"4*~ ~ ~
GetIft
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IMI~"""'"
llIoodiJ 3111.
S A96 5176-5779
1462. Merlin; G. SlorlIl MJ 120061 Osngerous
tmatI EkeI~ . Blood lOll: 2520-2530
1463. Mesa RA 1ian5Ol' CA R~i ,u m;lf SV
SdlrlJtde< G, T~tten A 120001 E,alUIlliOfl and
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f'oIId'llI' U ~ T. GaGnIt H (2002
ReepotlII 10 ... ba1 ~ 01 l!UbsySIIm
~ eel IvsIlocyIIslS an ~
~ nicalOf Ued Pedollr Or>::d 39'
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14n Uinkov
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...... 1M _ 0rlngIrI JJ 0. Boar IlL
. . . . . . . ~PllIIoI25 721-130
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Eryohomelage
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lhrorr'll:dic and ~
rna~.Il50CI8ISof~
ltl(llllymphoma22Sl1pll1141-56
'41 4. ~ Ichor F (20011, C~mr1k; myeloi-ll
WBmII blasl C1\III ...-- from pI1)9IfliIclr;
SlamCeh251 1141118
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(lWJ ), Trve hl">oeytl~ Iymplloma 01 !mal
1..15. Mlllttiren M.
F~tc!lI<
0011ur(;l)ll1~, Am J Cion
(2007) PmTlal'y~(f'MF).POSlpcly
eythetnIf _I ~ 1posl-PV I<IFI, llOII
-"'al hOmbocy\hemiB ITl)'BloftJms<s lposlET I<If) blasl phase Ptolf (pIdFBP)'
~ 00 ~ bI' II1e ..,tetll3llorlal
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R RJIz O..... I' L....- F (2OOIj AID
~ I(lenIiIIl$ orI!IltlIIl:UIr lqIll
11 ~ ptI(:UIICf5 ~ I'IIUI IkeI
..... ~ 107: 24ro-2H3
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J Suri P.-o
~ condolIOnI
27:1l'J5.i02
1496. M~IeJO M. Algar. 1". Mateo MS,
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__ rJ ~ "*\,WW zont
~7
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1501.
S.
ue-l~
toa-D,E-..J .... F
fit..
~_A.
.268--21.
1522. Monca 'fIG IlIealn ~ 00gIn ....
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"'~tt..-.prfttll)'lI'l~T.(lII
~,
"'igh\ ~
inlO
pamogeneti$
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1525. t.lorriI SW
UN V_ _ ldEI
232723lO.
""*'
~1lI~~.InlJe-:er
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*' A
,..,
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118-al1~ lIIilL~20:
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1511.
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LaboraIofy IindIngs IlI1d elinieaj CO\MWI of 33
Il8bWll ",In g.iIlUIIt ~
dIsorIlon.l-.~ l' 782788
1662, 0Ir4' N,
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1663.
N MalutM E, CalovtIly 0
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tI
011 G I. 'NohlJJlOCll' A.
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29~and.,....()l",.~
412 References
................,..... n l ~ ~
d 1l*UiIt~. 2lypesof ~ ~
I"UM 9'3de 3. &:Iod 99' 3lD6--J812
OI:tAL~A..~T,
16M.
~ W I<n/rIOillAI(, ~
J. Gmt..- A.01:
c.nc.
as.
~,1lIood
91:.292..(299.
1611.
~.
and ~ dlaradens1lCS 01
un
Kojwna".
'*'
can
ec
R Yeaeoros U
of tl3
a--
(2Ol'I~
WIll t.6.9)(P2J,Q34l.
a Iw,tt hq,ot<q-
MI J
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PIIbII 122
Adlva~ng
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CDll1i1C.IT(~) T-II ....c. Iymfl/>Oble6loe
IeuI<er!lA Illooll lOol S58-SOO
1&7' . PailIIlli E. Gciol.tJto4 O. Nel.tlerv D.
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ee
an
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1617, PiIIetIa E. FItfTllrdll M. ~ 0,
Be.....l1JM. Raoe'$JI J l.4zaruI H. 0ew8Id
G. R~JLI. Wr;k PH,T..-.- US.lool<AT
pnIdds
b""'~
d llCRAIll.
~~ . . . . d.~1stIo
...,.~ofECOG"ARC~SloI:ly
Em]
COoparaM ClrlI:Uo;y
~ R-m Co.A:i ~
e........
11 181111/190
1321.1331
r __ de tIitJtIII'I j,I,
w.eus RE. 8apAI VB Sp-y CJ
1692. P....... l
~JW e.-,D(\986~awo.r
~" WoI'eSPOQftA. ~
GJ. CalcI$, 0 (2007) ~ ........
tIM Illc*lnilI tl "11.1., oon-..
diu
!IlIlIl.o'.s"~~d"'"
QIllan
Pen.n.c.~ORl2006)
of hipIIlII C .... Il'l . . . . " . .
.... 1I'I_~dHCV~
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1611. PIkI!l<e" T"*:.D<I P ~ I
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~ResP!1r:::l179'.4~1
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'-'~ar>cl-r~~'
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Gec:wge F. PU P (2OGol) ~ . . . .
01 Nl( c:eII subsel <tsrIbuIiorl in lIOIlIlII..., I\iIl-
pt"",""8IWlcl_ilfgr...-~
...... a'ld
- * " I'WtrTtlo-
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TP
Jr.
a.buiT,cr....WC,
~JC.DlRoMoC ~RW,SeiIMo
F (199(1), ClnQIl toIQe a'Ml prt9'lOIIS d !hi
~"""~d'1anularlyrlVooo
Pfil\1'OSbC
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e.-.
~ d KIT moIaIIoos
-e)A Ik:\llIt myeloicI .......,..... ""'" i'Iv(\6;1lId
,n III)J lts
'*
R (1998) 8Cl-6
"**"IdIr9
B
101\
~ I'lIlOl'l\il
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lJSA95.11816-11821
1699. "-qualucci
r-.
1. ~ G.
ChI9ri RS
Ek>III 00It.M ~ ~
.'2 J,.Il)16
1100. "-n:lnli F. l.WINrtla l. 0!tInII E
e..C, e...v.t A.. ~ E ElarA::hi
101 An:wi L CaberkJn S PaKllltI C.1..a1:zalWlo
10112003 ~,.. . . _1'1 rtU'll ~
f IlIlly 011 . . ~ ,.. 01 ~
..,..... . n ......
~M
1).1'
1m. P - . I I F, ~ ....... E "'tani L
~ C L~ '" Bem8sconi P
~ 0Ik Pt,I CoUIilo 101 , PaIcuIo e
CC'Ille III ~ 'II 12005,1. ~
,...., fA llCJl'Iqt"."Ml a 1IirIljlt
SM)y fA 23 pIlift'IlI Cancer 104 1ll32
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. . a ..... dee~ww:ta_ll't'9"
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1711. PaIII Il8 '*"*-l AN 5ct*' CA
Aculil ~ ........ "-'
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NtI le 8eIu
..,. ~ Xl, ~ S. Kernwl St..
COIWI ...., ~ EW. ~ El
y~
AM.L Ml J i"lWnM:lI18, ~
1715. PelnonTC wet>erIey-Mell'l G \1919)
TheCllUIIII . . , ~ 01 'o:l1OlllllhJC eryItwocyaI& c-.1.lIb H.....,. 1 189--196
1716. P8<1f1rser1-6I"rgaatd J. em.lill_
DH, Desl<t F, AndfIrseI' MI< 120(6).AI\emRvll
gtrlt1ie pflhwaj'S ar'l<1 l:(l(lp(lralil'lg gene6e
lltIroomlll'Iti 1'1 lhll patt>ogeoosis of therapv'lIlated m~.Iody5plaSia ar'l<1 acute mtolOod
~~1lI'ni!I L.uk~mia 20, 1943-1949
1711. Peh SC, Kom lH Poppema S 120021
FrKlUflllt pre1flnce of !IUblype A VI' UI in
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171' ~ C B"rIIe $ ./ego
G........ D RobAarl:IN.?r-D
RawMJ
RPM]
A.'ftd III
rJ al56 /NCAl.I) on ~
cell II a !IIa'nwt of ~ cell
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.., of ...... JUbseI of "'lAIPe
mNIar!'4. l.eU<fmI 12 19711962
The
'*""'*
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~H.V_JP.t~e.
CoAIult G.
1labo~EloiIeklt
A Thuret I.
~ ~.~G Del"G.~
P8n;. J
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".
I nt,
P-.l C, Lfl
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".
..........
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-....dtoiCllJPllW*YC
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M, QrIi1f'l(\i E Klfisy C
T. Morra E ManegoIo:l C.
~ 4' 653-M 1
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23 11011103
(1_"
_01111_
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B .........
~ '" ~ J
('i9it ~ ~ due t:I a poIIl
1I'IUlItIIiDrl1l'l ....... ~ofC095-.o
...................... Iyo~. . . . . . qn.
_
T-ClII~. and HolIr;;orII di&~ F, Wcw;nann
e.
LC 6loorntIeld CD flr\JrI*Ig
AD (1918) 8IllIl CNlI as an inlIiltI ~ \IIfItIqI
.....oileIloon rJ cIwtlfIIC ~
A
ft!l2Y0124poolIenIs. NtI J Uedlll)- m220
1731, PfIllnon lC Brown SA, CrouoII
r,lladtnCWlc J 1191l6) Appicatoon of tilt
~ led\nic 10 bone I'I'IlII'1OW
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17$3. Pelerl<;ll'l If. Zhang Of (20041 ThB
811
in levkemog_ _
_EIIP~21,~1
mo,
laJ._
rr.
~_locabon
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17M ~ 8, JIrllil f. JoIy B MnI-
PyoI'o:n<...-:ilMd
_~ot""''''''rand'''oa;:aaillf'lII
. . . . . . . . B- nI T<:eIlNtU~ "'" J
~ P..-a 26 rn-732.
(If
hemaIo-
P-et,~I~
~l ~ ,
T.
""*"
~. , <hIr>d ~ ri!Y'
Gt!qlfI FfW'ICIS ll fhJde lIM l~
e - (GfElC" Am J Suo;/ PaihlI2J 137-
..
'
~...
0 I'orIifIrIi G.Wwnf
P, Fan:eI ... Arno:Ud L 11996) " -
"'*'"
e--.a.-.
~ ~ ~....-.c.b'1
cell
w,-.-
COoIiCD56 rw'i0lvOeil'l'OC
~-ClIII
Med~
au"
~ lymphoma IM!h
........ ~5O;802.a
1712. Piltri SA. Aseani 5 eo-. IIC
CampjdeIi C.Bacei f Pia:ir::' M. PlaaJge pp
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adJ ~
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1143. P<lfIIl SA, llseani S, LeorlCim t.
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G.ullwd p. ZUox:a E PllII'I F I*ta E.
SabIIn ~ $, Pll::ci:llIM JoI'tlton PW,
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F'IrX:a.'IJll!'P t.t..-"T,AklnkI"'CMIl~
(2003) """-'Y mecinW4I 8<.IlI ~
,.., ~ of BCl.~ _ancIlD'MlII'ite~rJ"~oon"""
ot
ss.
ommuod
ncaI ~ t) <:InIMr.:aiKln !rom
~ l~ SIlJCt,t
Group biIsIKI on 61 C3SIS ~ .1
'"
phome"l flIIOIlIe*cellfI'pn!S5I11~
T-oel ""UIItdIot:
PaIlof 27 121-
"'"""
mo
_,.+
JParo 1M
References 413
m~
.,..,
1715. Ptw1ll R.
~oo
P, ~ M. Ferro
fllCeQIOI' glWIYl\1I
s....g PIlhoI30
~Z
BOIII"..,.liIlIOn L8
0Irm8JI1S3 56!>-513.
1766. PonD:n M, ~ G, GWd VE. Del
Clft) B. ~M. ~A., Pdoo S
cekpea6c;~
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H ...... oI~ctII~
~II~""
llIl.)13
Mod PIh:Il 3:
e.. S
l7S5. Pw.,a'"
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~
~by~,.RHA~
..., ~ "
/IICfOII'f~ . . . , .
IIood 109:s.tZHoI2e
175'. PwlpOI Ill. CollO F. 811I 5 __ P
frWyIdI I F~ I'l ~ . E.
A.,CIfIPll E {19!lI~ pl6(1NI(.oII11l"'t
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~bydllllDnl,"""""Il'ICl~
l. c:aLOIII Ill.
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~ ...... of~WI'tym.
~
1757.
1lIood11 Zlln.15l&l
PtJ "-
m.zeo
t_
IIIId WI
ltrQt 011I
~
_'.~1II, Am
J
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1163. PMI R PtIIgnno E. r.laadiM. ApI
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~ JCliIItI_ 116 3111-3182
17601. Ptnl HA '*""-" "- SdNidIr A
Medl:ItC M Choq.iII 5 ~ v C1ItrIr.IM F.
ON F e - D . ~ E "'-"-BrI.nIII IoIF HntfI I. ~ 0 .... It.
414 References
H2.
F~
....,raboi.
mo.
a:nsenIUI
25 3168-3113
~
e. ZhIng B, Grf!9Olre
MJ.
1m.
Sttrnberg-Reed
28 l aa-19t.
~, J
Hl5lcchem Cyloctlem
13S. :151351.
1773. Porw P. Noonan RS, OraLi
/10 {1m) ,
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1774. I'QrIlcd< CS, DcrneiIy Ga, 0r1 J. 5traus
D. ytflal<)-n J.l.eiBnoll A. No)' A. O'Came:> 0,
"""""'ll. 5,
c, F'wa
_01~
"
TOWWd G
P.
SWbrl.~ M.RoecIA.
type) p .1l~"~"'~"'IlJl"I.11
on
1710.
e. C. 60IMiIl N,
x.
",..,. 01 ~
&.rtIt'11l'IlI~'"
H.-:JIIJO 2132
1181. Pra SK jlW)f Irmu..........
srnII
I ""'1 01 13 c.Bt
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11 1_11
1782. ~M E1C*\IP ..... 1.ytbnl
M. SII'Ichu N::.. lit '- rA.,1kolIII F. ~
CA. de l~'" (2004) F'fognotIc lIdorI"
Hor)g"" ~ LM ly:tlllllomll45 1133-
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end
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VdeItI!lll~ 01 glmmMl8lll T ~
DA (20041,
,,",-~~dC DZO~
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inS.
PtJrwo~3k:l /10.
J.OO$!;Y G,Ivay
K, S'tmky 0, ~ R ~ K. Walkei' H
TurtM A GoIdIlOe N-l e...>ett /10 (1996)
~~ ~ idenlified by
~ b~. IV CO:W iM!rU'
IftIS'OO II awlI ~ leuI<efl'lilo U2
~U82') 8kIod81 1162-1169
m!lA. PouaIo G, MImiro C. CtooallCl M,
t.IodaIo MI.. Ceselli S. IMzzI G SullMI S
F _ F. T.... P. Morell "'11!l9() la.
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....... ana ""ell ~ 8kIod
Il4 300173053.
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F (2003\
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~ d II tllIpllIIli5 C WIlt (1'IC1/)-llstociiIild nan-HcdgkiIl ~ bQIs Iht ...
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Illoocl
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17M. Rabbani GR, PlIj'likv Rl. Talfwj "'(1999) A Ioog-Ierm stud)' of palientl .....
dIronoc NlIInl kiler eel ~ Bt J
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IjICflln ctJooic Iyfrcnxy\ic leukenlla , N 1'lgI J
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1823 ~ AC, GIeeI1 MJ. Kw:md.' ..,
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SJ, RlChenls SJ . Morgan GJ. ,Jack AS, Hillmen
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EAYI C. sna ." Car'IIlI C. A _ A
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KIIrtJn PJ (2OCIEi) The I/lCldllflCf IIld an.tornic
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013 (C099) ~ '" IwImalOlogiC proIIer.lions COfT1IIlItes ""lh TdTposltr<lly Mod P.-..or
10,217.82.
1853. RobetClfyll RS. Boh ltng SO Medelros
LJ. Eleflitobil-Johnson KS !2000) ~olIiWaf
1152, Roberborl
Clunba- C, Qon
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on
c..r.r.:n
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lISe. Rodog SJ. Abr'an'In JS. PI!lO... GS
Treon SP. ~ OM. ~ HY, Sr<pp 1M,
KukIk JL(2006). He~ CD52.~
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rlI:KJlll3Iims
bona lor the 1158 0( alemtulUfTlIb (CAMPA TI11H). C~n c.r.c:et ReI; 12:71747179
1m. ROOo;j SJ. Sawge KJ, LfCasce AS,
Wq /\P, ~ lolL SloW MA, Hs ED,
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H.rbQmg MYC
1~ Am J
PahlI 32 113-122
1859 ll.~z.JtQ60 II. Vidlutli-dt II
CtuzH.~C, RllIl~R
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s.l J, CabaroII& F l2OO11 Pmwy _ _
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416 References
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~ S Gwf\ICfle F ~ N Jo\IIII:
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C F_. P,~C(2003J WArM...
l;InO:eI IfI(l bcIogK: . . , . 01 . . ~
m.dI'Ig ALl.l gene "'IAIIitI'I5; I fIlXIl'I 0159
c:a-. by" ~ FftflC8iI lfl~
CealIIn jGFHC) IrlCl. . Groope F..-.ca de
~ 11Ii'liIlOk:y(lI>IlGFCIi) 8lDod
101 Un-l283
1161. IbIIIIIIl lot; F~ S Ctout "~ Ll $Iinl.Arn. 1'. IlrIh N (1~) A
"""'" ~ ...~ IW:Uo.fIl eel WfCO-". "'dlPaIloIUIlt.8ld118 183-1.
1112. RoMo 0 eo-ti SJ ~ FIll ~
OJ."'" $1, &)on J.~ OJ. GrilIltlI
LlJ. ~ JT Vwidliil<i_ EA ~ G
w...... AE..1Ioooo1 NPf2000l CrtJ9w~
cryplic .ul..l.TO_ C8F ~\1 ~
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6eioa;hn"
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~ 2.(3' 290-293
1&86. Rowley
JO.
OIl'4y MJ
(2002)
0
."1 "'qed. ~ Oncd
13 1<10-1 49
1897. Ruggen M. TMelIO " Fr-enetl 101,
~ F (2OOl1 The . . o I ~
10 ~ 'oOfi or 8SSlf1IIaI ItroorWc,fltma i1 ~ ... ~ III
~ Nfl
Meo:l 139" 41O-f ~
IIge . RW: A RMdII U. SwenlIow SH
~ M. S1reIbel 8 Proc:clp G TuID RIl.
Cook JR (2007J E>hro?dal ~ zone 8cellymphornlls oIl1lll ot:JJIar
il\IIICIto
l~
"*'"
adnt.,
~~onl'te~cA
."
ow
Onrol17: 31223127
188l1, Rozm!n C,
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ll'f'llWY Cf-jS
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G.Yt>I-ConOe J. 0...- MJ. T8f(II W F'I1ka1 O.
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J"
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330-3~
1171
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RA 12ClO4) o.liind ... cell m~
l.oclez--&.*mo
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191)3. S!cdI S. Yintl G G<igklIIl. Rupoli S
~ru l. Mi rbnell V. BII'3.... S
L8llar'i'lo 1.1 FI'Ialli G (2OOCI) 0iIgl0IiI d
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~ ~ WId lllJlJxl(l(91-\. Gt\uIo
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1m. R ~ R Pwoy-.Jones ". ~
8IbIpl* V Aa*lD I WolherIpocn AC
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1t17. SMwmI I, Pe<u-Galan P ecur.
O. '-"1lO E 12006~ loIrie cell 1ymptunI.
(.eul;emll20 505-513
1927, S;;UIde' a, Middel P, Guna"'311 8.
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G!allt.- E. ~ R fuzw; L (2001)
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~k!lJ&.gPltlol16 ~
c.a.. MIdeJ'oI U
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Me. JIfI.
ES (1992)
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91- \116
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~ 00
<>-:o,ne RD,GrllI)Wl TW. DeutIIlI J, .ale ES
~ E, ......
HK, Sta<.oIlld
~ A, ~ E (2007;. SOedIc __
M a.b-.l.f1119ll5l ~ ~
. . . .:.1 drlocII ~~and _ _
/lISIodwIIaI1lody J
P-.oi 22 )21.
~ ~ - * ' I s in ~ oeI . .
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1932.
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"*" we.
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U5 A 103 120-125
GP. Gal.- Al-, e..m
_
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a ~ da5sIcaIior' $yIltItII'l "UIl
PalhoI16: 1091-1109,
OG &ycIo RU 0 - A.
M (11197) Bor'I ,,*1000' '~1Iblln lor cIIflQc .....,.od
_ _. , . IIIlecb of dIIImIIlMIlI b
clIirw"ll dYInc ~ 011 ~ 01 ....
_ nllWiapM Br J ItIeal*lIllll 35
1!M2. S3wgt OG Sl)do Rt.I. ~ AI
11!/91). ClN:3l
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d'ro'Il: m,elOId
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...." Blood 88 iJ8.4645
It. SIIllJca t.I. ~ Po NgtIIlinI l
<*ItymcII'IQIlIII~~
~ f t genotypIC analysis of aI~
(1991)
~~IklIII~.I
UOlQUlI
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IeYkamia
~llOa~~. dFoieloIlfld phero-
twc ~sbcs
01 11 palienb 8lood 76
15M62
1914, $Ionly 0, L-o II, ~~ A,
A. FlInctInG (2(001 A _
InG';I/loIogIc _
FlWlCIISdeC~~.UK
~ GrOI4l nl BlCIolED 1
.....
ear..
EI.I'OCl8II'I
..........
~~
~~
1DQoaII~
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o..aI
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Y. Va",.,. H, !<obIVY Y
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proleio
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~ 2 on P)'OlIlO!a.-3IIOCIllled lyTnp/IomB
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~. KopmI S.
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It)
I( t<irnIn Y
Sa....-na
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1136.
~ IS depenClIII OlIN ~
lS9c 205-213
1m . Sandbetg Y.
I9l*'ll
1lIood96 1287-1296
111U. S8IlO Y. Gao J e.- k.1lJlIgIq Y
SrnIl PM. Bnaga G. Ptrrit A. ~ L.
...-.,g ~ 0I9Cl6.1JInl"I
c::n:o.
- ~ .-.:I~
". .. eI*Y " . I ........., lIMnbIe P't9'lll_lela l~"'. 65318
1831. $aIg Y ~ Il T.-a T T. .
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.me.-
*!
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17
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......
orrOJ!\ 01
GrmlooadeO.~ Id.~
1'.iIPl*'.'
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P~
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202200
1916. Sai8f A. JwI1peQ N. BeIosIllo B,
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E.
~ 'eapiell~
Mltl ~ EJ)5lerl
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ttiitlpBl....".. cMgnclM of _ _
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References 417
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"'*'"
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1llood95 2937-
""
notmal acute
, NEJM358'190919 18
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ktiI lyon~ IlMlhtonIInl 01 pl6INk4A.163 and 0ft. ~J~107 101>113
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IC~ i1M 120(2) EIWI'IbIl 1llrombo-
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d",
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~1CIIl1ZIId
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I _
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ootc;om. on
myelood_ _
B, ZhiIng Y, W&Oer'
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"'*
0ralI22. 37.1-3T50
..,...
c-. .....
~ -.oj
..ncDy
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~
P, _
.~ in
""=
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eo.
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1m
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l..-l"
....... ' d ~ ~
XlM ~ ....._
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~ 01
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PlIdialr>c
~ . I ~'I*JpI.1llood7.'
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.-.d
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<0 821-83<
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C056>,
C018
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"lOUiI'I ~ torm of aeuII """&mia
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JAK2IXOfl 12 ~ ... ~ "llI1i
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'*
"'-
Gerol)pIc
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( 1 995~
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, . , . A.
II
AbliOT lSI' 01 3Q21 and 3Q26 ...
490-501
lllN. SecMfWall<1lf LM, t.\ol:WTl\ilnA". Baon
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11'123 abnonMIIIIIs. EU Coocer1tId Ac!loII
11(123 Wcn1lqll8<Jl:;_ 11" 84{l.844
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'""'l(Jfloprolilllo.....
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, In . . 00f>lui d globIII lI"'t ~ Blood '01
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~
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1tIemaMll19 42&.431
2tl1. ShiInoy.- Y ()ylwna T. AYlO N
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~...,. BlOOd 116 195.f-1960
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5 abllQl'II aliM&
~_Lymptwlma48
2101121 ....
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sr- Sf.
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N
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Chronr: m,li'oorY1iC 1toJ ~8OTiI.-x:on:II'Ig 10
c . . U 3J9..394
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CO. o..l G, ,fqJelbIum FR. Lnall AA
T.......... loIS, Ilerwlfll JM. $lIreoqIt Ol.
IoleIlwIltl S. ~ CL. Raww:nnIlh y
o\Ior'UIJ TA CIrnlI AJ. R-.:nli SC. Ii8lIr8mro
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a.oIlr
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."
11995),~~
MLL
'*'
~'-- Reo:9*IIgI~paI.
ea
1191.1195
2021. Soegerl 'N. Neo1 C AgIhe ..... Engelh<rd
_'9M*'I. l . . . . . 20 21&-223
2009. SJ'limIrlvI;uro-VOITIMgen
awe
a SOOAI-.tonoolOgy ~~ caopera.
(1.) ~ genotIlIC ~
.-..IyJiI of "1Iutal ...,
~
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l .._20.1m.1291
2IIl1. SIooIk lol., I<nI**'I KJ c....... PA..
~ 011 ThIIIII KS. ~ ..... PsoeI;t
E ~
[)Fl, ~.J.t, F-omlir>
a.. ...,
:HIlT.
~ p,~e,~. A,
I'Aa ~
63 634-638
aro.-
~ p. flay P ~ P
WhIltJ. ""'wlage JO,"-u:-S-: R Au W'(
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~ E ~ C. Fean:o 'I, FtIte'
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RI.~Jf Gugiiei!!lC.~
References 419
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.....,
sr.
MH
K (2002) . - . . . . . . , . ....
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t.Id* Y
P l19l12) l,..\I01IiIIkJIIIl
~ ... ~dcn:al'"
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2616.
20501. SarIn:) N:J ~...-.. .ro.-'ll
.If F_LE.~N.j ~ E .
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2056.
It. F"lh':ft C Mil A. JIuMI R
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DetadIon of o-M poi'II
Asp-816 -"
V... ~ pooIiMI
rnIal 0IIa
Fid lau<erTIIC <ell in II ~
s\'*IIC
muIocyloais end COIIQ)II'O\aIII t!lrorl"=
...
_rk.,
'i43-M3
2059, ~ V, Liu VJ 12006) From plas.
macyDd to dendn lic call' rnorphologiclll BOO
!UnctIOIlal $WJlrtIeI OOftllg plnmac/'bd predef\df$C call (I ,~t<tIdlBlt(lll Eur J lrr1munoj 36.
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ncn:itIYed c:eI lymjlfloma
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65 lll1IllI lfMlad WIll ... 1MBl*ioltnc prOOcoIs 8lool:l85 e&t061.,
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ullOlilrt
dIIry
.~~BrJ"""'
12. 717]26
2062. SI*hI: t, H~ 0 (1!l99)
~ !kiln of Hodgk,,'S ~ III
~$
Mao:n p ......... .10,
0Ia/lI V, _
I.ippn:d: ' ~ & YMIin$
c-..
~~m
lOU SjllIli ""- GIIIiIIircl OG 12002
bnlIng **n " ~
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P.thoIl32c 1-5
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AW
..., FonaIxhe.~1
__
"~done.-.:l'-"'bV.
gtII8C . , .
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(;IJI
01'1
e-.
6787~
$cllwM"llf'lI"" I T~ E SoIabar e,
Ha9II1 'II GeiI8Ir I( 0'10I A. l.ecInlr K.
V'-'Pl19Elll) Srsseme~_ _
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~ Cll'SlS $o2llI J HM1IalDI18 ?>-38
20M. SpwIaM V~E NaAG. TnlIU
l2lXXll. t1.mlln ~W\.IH54OC>
alad 1blgUI', lMMIe Samin cn:oI21 ~
'"
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"f1J5
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..ng ,..
~.
8l'IB/y1IS
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Bn.ming RO (19651 CIauilaboo 01 3!>8
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na
~ofdnl;alllfl(l~.,
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Pubnhars 9oIb:l,
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a<x.- If~ . . . . . .
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_t816)ipl1.p13) 11 . . . " . _ , . .....
~ 19)(plll113~~an:l_of,.
_ _ I.U All 19 367-379
201V.. SlrfJ, Ba-.l o...cz;g U "'MIoI
J, IoId\liIoA K ~ C ~ Gl*'ll"
~ Ih9tfl ~ l.IOS ~
of S<titypM. . . t , , * - , fll3CWl ~
"-* 8Iood e-:.r 50 0&$436
20M. SWll Tf; ........ WA FVw tV., Ho
w.-.l
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. . darI'Md
ee
2OIll.
l"lll* A. W-..el
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~ OIIa~~SOfClIIt
e.-- 2t
",.'"
20tl
s.n.z FIG
Ga)ron PS. . . . . .
s---
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se
~ F, Solar K. BaIaMn L
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w.-
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Maruy_ K. E__ PO It
a-.
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aro:lMTlnI h1slory el1 5 pabefllS, Bf J l:IerrYIm
121).56-46:1,
107 113\22,
206\1, Sttin H, 0i!l!lI V, MaraftOti l Jo. A
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Haem~ tol
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Arm<fageJO, 0Ithl V,
Oi:Maw Mauch P
edt..l~ 'M~
&W~ ~. ppI 21
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'"
c* ..., lIIItIOq'ft
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182-1.
Blood 91'.96-501,
Cross NC It oo:l),
Myaloproliferat'.... diliOl'Olln wdh lfanslocali:onl
of chromosome 5q3135 roitI 0Ilt>e p1aT9M.
oo,ivlld growth (actor rltC8Plo, 6ll1~ Acta
2085, Steer
(2007) AnaplaW:; ~ ~
<M...e IlIr\Je 8-<eII ~ ..... B compiex
~ and aypIi:; 3' AU< 9'JfIlI rnr.et'OfI 8)
~~
H. Hoovnel M. ~ r. W..... T.
Demel G, F"1Ii B (2001). ~T1on or
908 IIOBF.l a->d 0ct2 1Il d'** Hadg!<"
dIMasa but not in lympllocyle pradonlfln
H(xlglun d~ eateIallIs ..... ~
aa.
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ca, Roy V
(19904)
s.... CA.
1eu~i1~
e--
Br J
70 969-9n
21ll2. Sbroolo NA. "loIona,- we, ~
OS. e.;,.
BennetI JhI (1990) C/lrQno:
m,elon'o:lllCiCyK *"'- L . . - . 1660UKCCSG!UIy
c.
no
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'*ocIuclIon fA i
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21116. ShucMIl JA (2001) IndcIeo'Il T-npIlt.OIIIIc~ ..,011 ~
11.,..- '-kIIy A'ld ~ .... ~
.. _
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~ l ~ A. fMw' D. Sl8bflI1 ~,
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Vil/IIltlle fr8Quenciefi of IMl T 11~!IC'o
CMftj
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2111,
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2117.
Suat6z F ,WkxlonI<lI,~U9JeIF
~ t.l,
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""
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2132. ~SHOOl)4l
s..rm..
l200n
"*"
,. .,...,
"'ema ,. ."
Ga\'OOft PS Carroll AJ
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ItgtI ronconJente from I/IIieperIder'lllllJdles b)'
ll\e CNldre~'. C3nee< Gtoop ICCG) 8tlCl
m~109efIov9
invIJI(Q21Q261
I~~emias
";I~
8lood84 2S812ti8$
l U6. Suzuko H
"'sano
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au.
e-
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PIft;I
a..
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1131 ~SHI2OO1l T-<III8ldNK-<lIII
~ !r'""""",*'" eliot
dln HI J CIirlP.-u 127 .1'1134. s-do. SH. . . . . . - JA. ......,.,
tJ. 0hIh<II t-lS l.iIIIr TA SIIIl5feId AG
PIl83~ Cenroeyto: ~ a ~ ~
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8ld
..... ""'Jf'IIIOll13 18'-191
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('993) 9d-2l1fOW1l11 CIn'OCylC ~
f*3lIn .... -..:ty l.....- 1 1456-
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. . Vwch:lws1>ldl441 1000-1006
2146. T__.....a T, Ham 1M' luo WJ
~ S l::lIImIa I,l, AlllMI I( I100S
lois 01 pr9$SIOrI fA ~ __
....... 1NgIf>-2 ~ ~ 1 ilOOf P'O'1"
rtOIIisllle:-d~~t,&
p/>olnI h Je.ut 118 218221119
2141. T _ T. Luo WJ "-" IE ~
101, IudlI I( ~ I( QOO3I E4iU ....
1Ild~0I""'0II~"""
0IIl0ps on ~ ~ ~
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2141. T_ _ ~; I( Y~ It w--.
r ~ ... (1m. AckI: T-<lIII ......
&'ld HTtVl.-.ed~. G.m_CiIl
Rw32" '15
21'9 . T....., 101. AlcamRu t.l o.t- K
KdIIIi S KJkWli 101. Suzu. . . J lJi<I N
~ T jl995). C030 (1(,.1) ~ III
""'T-OIllI~.~
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S-S46
~I>cs ~26
2150. T
N. SokoIoIl L BarIh I'If p9STj
E.n
ary tvmphoid a~normalrlie5 III
s,;.gr.,'~
s-dIootStl,V~Wllu~LR,
21C2. T
Maul K
~~I"'"'J
"'...,
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~ ~ ",*"lIIOnI
""".
.-.d WIIIO\ll
J I.Ial 019 8
Reference s 421
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21M. TnbJ hi 8o:nanJ G........ G
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.-
v..... G ~ A. T....
2m .
l.I
Tha~
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~
TW,
~ ~ rJ
lyrIIIOid ~ cn..:w.
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phoIogc. Ill
pe**
r_I.""'I""~'
e'dlbll ~ IlIII"l-=
s...
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e.wo
tr....
lUI"*,,etI~.~cIIrIt
fI'I'lIIoerllJf
bllfl
422 References
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ficlopllhl:)
261-2t16
221M! n..J.K-.-..nt1M(2003lo.mc
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'*'"
eylhaemalrom~~
s.rr..
e--
scr.lIrlJW{2OO:lf ~..,~
of~lIgIIfOIlg~fIlDI
lIWI'CNI _ _
......... c:hrtne~~
e>.periIrIoI 011 160 peMrG, IlonI
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46 709-715
2211. ,"-"J.K~ ~.DiIhIV(2Q05l
1IJNI (lIlInIl poIycy1helIIIa \'If3 Mlh Ilto'r\tIl).
CflOeIs I1IImdn;J - * I I I 8YOmOOq1I\IllII
-",*!"IIImIld \13 213-219
~II"fIrD.I!"",*"",""""
2137.
dIoRlntrr~,"""'I_ylllll
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"""
10
1IIOC8Md
pI'oOplOlllli
bonuJl:;~
gre
AlJ(~
1ilf9ll0ll~
~ ~...,
BIooclIl3. 2463-2470
2117. T~1IC:Is1lJrl J. TtIIIIId< BK.
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2111. ...
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2168.
klw-m..
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~113 76).m
217S. T
POGF~ ~ ll'I"II II I
Will ;I
~ d .........". Inl J
Nslor)' d
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~ fI-orn bone....".. ~
LMJ~ L ~ 33' 201218
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f.atlGO V
v"" _
WJ,
Oruo A (2005/
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OI~ulan ly
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(lm~!loot.-.oor ~~ on oYonc:
lII'fIloIIIonou ...._ lCMl.~ 01
.....,... ,........, lfrQI ~ ....
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22't6. Thiele J. Kv~ 11M 0rJlJ A
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lIrve 8<AIlI ~
on Rdlwl"oorom..
lIo.ol._ 18 J.26.3JO
V~ R.
r.u.- E.
~~CC, ~J l.MMo
80nIctl 8 (1*1 1iOdgUI'1 ~
c-.FJ.V~S.WiwI1aWG.~SA.
c.ar
,, ~
s.won,...
...
5135:(1
2226. 1.... J. Qullmann H Wagntr S,
f ' " R (1991) ~ il
B. AngsIer
C, floc1> A, s.up. A, I( opper l. UlIOIt'lly A
(2C04) R~ ' * - the fhJlIlonIl
stalwol VH~&rIll ~ o/dIllYM
""*'
$lud)'. Aro'1
~C~J~.....-.oG.
....' dinIcal,
22U TrlQUIly M.
~ 1 9 .~1 3-43 7
8, iltgDIgnt C.
I(ur*l
11..
PllclIll"Onc:d37 1[18.114
2243. Tollil G (2007) lhe
",.
""
T~
I(
Y."", Y. s...;.K. ~
IoU'III( (1001~ 0 - . ; IlIqJiIIic"'t"l'Jlltl.....'~'~l)Illlolm
POGFR8 cll",,_. reIPOfICle<I 10 ,",,"",b
101. ~ U
""""'~LU_21
190-192
Br J
c..c.-
wu.......,
P'f')IhorI.IIIIOallI
''''II9*''*'' il the JH
\)lJ'IIl,Leu.lyrnp/lomll .t04 121730
ell ~ WI!Il
s..v
1lnmO.
22U. TorIikcNII: EE ~ HV. Hwn S
(2006~ A rr.-gnlllInt phInoIype on fokUllr
IympI'IorIIiI _111418)" -..lId
__
orGfy C)'IlgenIIc
typQIl 01 _ .
g.llllOI'II ~ J P-.oID 25&-26.t,
1251. 1~ .Jt e.t)' ". So:wtn l, T _
~
MId
136. 1024-1032
,,;m
~ demlased ~ ..
1lIOI41"""'~
eo-.
8loocll0l, 3oW73<l12
L-lIbbft61 "19-.126
2257. Toully EA 1I920)
1IliIl1Oln8\lll, ....
A c.- 01
,,~"-"JMedSDllil)
16-25.
delio.,"''''''
lMrVy Ii ~ (I\lI'qIII ~
2p2J 11\ "l.K~~. 2 _
Il~ A!.I(
fuHd kl Clla.
(cWnl dlW' ~ I l . Blood Il5
3204-l2Q7.
a...
2251.
mICftIeOJlIic.
T~
O. Sarb 00 Xu L I(ati
C015ol1CD40
IllrouQII
17 127!l-
""
mo.
Ii
....,~~a~
lIludy il . . . LeuiIamiI1: 4~
2281 . TrJl;ll)' L. W1-.dll1 R. DoV AN,
~ano.A..lBIer
,..,
111: 2253-2260
22&3 , T~A , ~.,F. Ben Smon
E. CalIeI.&oc:I1<J E, Felmen p. ~ L,
G3Uo S, rn..oa.:.mont C, CI\IfIoI C, Col!fiB,
8ergef F. Salles G (2005). AnIIy!iI<:I VH
margNl rooe IyIr(lOOma re'oWIIi
m8r>:ed ~~ betwMn ~ ...,
nodal tumors and ~ lhe exiIlenoe 01
<*nil &eledQI tiaElmaIJIogio: 90,..7Q.4 78
2264. T~ 1\. Felmen P, ~
8alChu E. Gal20 S. 8ll!eggoo L Bryon PA.
1hIItIklmonl C. Codfier 8, Sallas G, !IerlI'l" f
(:10061. A cil~ study 01 nodal
~ rore 8-0lIl ~ 1\ rtPort on21
genii in
C8S1&.~.t8.162173
References 423
"
A..
(2lIOOI ... , . .
__
c.rc
l
E
DV P*o fIG. F... 8
IALK~ ~
<-'.,..
jATJC.AlK) II ,
c-. ~ ALK~""-':_
c..e.
R-.lIO" 7'il3-798
2:26t.
J !IuIII.# 8Mllt N, ~
MJ. F", LA ~ RH, Gl!u fG Sl.ccap
P WQo:dIt ES (200 .....,.. 01 ..", ...
"*-a
~
~dIDdIr
.....
. . . lit iIraIl FwI'I ~"j,*,. T..........
lilliill' ~~, AlII J TIIf1ICIlIrC 5
pIl(I'II;L
r_
n.",
Hematll79:52--5ot
2279. 1JroIe<Ijc ... . Coorad C KMniIrasI"ev J.
A5IgOt K, COlZio It. 8I.-g G Oumn'ler R
(2OO5j COI<-C058' '-Iodemic1\o!lOlUSnli
Ill*' 11 ..... 'liiCJ'bd Iler"O*c eel phanoiypII.
I1IM!l PaIIol36 1Q20.1l)2~.
mel. vannge. JoN SctuJmg E. ~ T.
PtiIippo II. ~n:la K Kluin P (2000)
~ FISIi ~ 01 BCl2 ~
JM(2001l
CliIgnoIIIc~
of ~.
lhll\Ul8$lhcallOl'l
Res 25:603-625
2291. . ilII den!lol(h 0. j2O(l.t1 ,,~
MilIl ~ . , alIenoI ~ ......
II'IIectionlI .nd U'noof tIftIInCW? L.-at
0n00I 5.738-746
22U Q'l den .........ElwW< MM l2OO1l
PavoytnlIII nodtInaI ~ II tH,.
MIn ~0n.99
11.16
1293. van dill e.g A .."... L ~ 5
11Ml Iigh e~ d tht CC dIIrnokN
TARe II ~ celli A ~
lllIPIInIkII for tie d . . . . . . . T-eel .,..
..... HodgkIl'Jyrl'iph(I'IllI M1J FWrlI1S'"
1685-1691
8Iood 8ll
~A.P:-m5.~
'*-
MaDr1OnQl'lI:lsioo IU'nPal'd3$31!>-325
%285. Vailluetlil JR MedeI'tIS W, Ra!Sldakis
...
~ ~*
" '"
aooe). Gero3ri: ~
-.wus status
20
2205-m'
'"
e....
'"
In~
37' 1~
~: ~
1)811_
127l. l.lct.R 5, r.bwdo F ~ '"
Gr.......... ~ Ml FlIggICW "'. MIlIIIlI
~ rj ~ --Il"'O"'l ~
bOll II ~ ;.u ~ 01 HIV~
InI J
c.ro:-.e. 581-585
MuOC TnwlllE
J
T~OG,~
424 References
'"
5'11,
Oelabill J.
CoolevtlS L.DeW<JHPMIefI
GOO
V~ p.
e...wens Jl (19971.
(CDIl6)
E.~ of 87-2
moIaculeI by Ree<l-~ OllIs ol
YH l.JFY.OeWegt(RA.LJG(l99041 EpslIln-
8arT"""inlmal T<:e4I~I~
pI-.e ~ ~t rtlia*lM) on
or
In. 895-717
rille art 8t J
IiaelMlD
127 13713lil,
22M. .... . . P Horny HP, EscnbaI'o l.
LoM BJ, l.J C'f SdwIrW LB. r.wone G.
'-aJ: R ...... C ScJIar K. SIll!!T WR. Wdtlf K.
8Iwlrong 1m P . - - t l ~, ........ K.F
L......... II
DO, ~NI, 80ImIIII
""'**
IlIKIy
.....e e.n
Aclli
wa--
Cronwnelo'! lUI.
~.IN
IlfWCl YIP
119'17) ~ ol ~
M-
a.saIHOOgkll~ .~
'*
".,
L. . . . . 18 1911
QI stu:fy rj 119 ~ ~
c.w.
_ _ am ....
2295.
(~) ~iI"''IlIeolClllillc~1l
_9"'*_
2(),20221 0
22T3A.Tsiri\I01J6
__
PQqI H,I,
_~Senin...........a14751~
1131.1733
2296. vanDoorn R. [);Io...... R, V _ Wi
OIlt-l.""'nu JJ, van dtf Rllit-Helmer EM
a.--
S.
1J '257-~ ,
T. ...,
w.ng
lln-l182
e. .. ..., PO RaIl T
PO lSi
tt'jQi(lna)Jt
nPh
~D~J,~
~.lOI-.
Raap
_rJl"'WY~80l11~
5!lle'lt
PWIr H,
GJ.
_II~~~""
T.
I'M . l - . t K {1989!,
~ lAd
()rmIen
RIPlMII t,I
P, EconomopouIos
MI J Clin Palhol
In SopJIl, 51225127
2302.\. .... , KfIIf.en JH, .... Sd*l\lC.lGJIn
Q'l
25291
2271. T-.g P e-E.a..unA 1M
'l'f. Kr.- OU (1el161 lIbIo:UIr tfWIttIfto
~ defiaerlcyIn ctlldllfl
HC
~~T"-dolfJ~PIN
~rrc-td......,,_on~
120(4)
~ . . . . . . 15
F.~5,s.tIE.OawI F.~J.
Nt.
JH
~.,...,:lIIlIIlI.*'1d41_"'1
Kneken
ll"'lt..........."l...e
~~~?A_
0."',........
" ....
Z212. VIljltAP
4135--4142
2302. Van
v"
Reportoltlfee~
... . , ~ _
~196.382-3111
2lD1 .
IInIdl (J#I 80ennI EJ .... <Mf
H8. 5ctluuring E VIIfdonct LF, KJuin.
0na:lI 2.
I9l6-
ewaor~~ol~
sdIrosinlf H",.-,-s
~ b" ...-edId
197M2 8t J ~ 96 322-321
2J01. VMlde"'barglla E ~ C._
den 00n:I J WloclIrsU I 0eIIIl0I J SU Id
Thor.- J.~. JL, Mecuca C,
~
e.-
(2((16) Al.KilO$/IiYt
flIlon1a mM'I1d.ifl9
~
nOlluIIl
P~ltlol
XI 22~229
2311. Vassallo J
U'2~
s.J PUa. SU
'"
18931;39
.....
..",
~'-.-.,~
2321
n-zv VA.
* ......
r. . . .
01~~~'*
llnc:als P~ n- Tl .e , .
ZIl1 , VIOl F IMdaaaIi U, ~C
.u. 0 ~ R t.utn A AMIau tv f2OOl~
l~liC~T-OII~1I
!lOlII ~ A IRlIOIIaI ~ ..,;tI blaI-
Ie ~ . . . . . NIt J (l
Patd l1e
'1~19
nn
'"e.n
M.I
Hem8IoI J 5: 5~5J7
2341 . 'o'OIl defl DrllIIdl P. COcn EA (20021
l.ocaI1ad OJIIneoo!I smIlI 10 !IlIdI.o~
pIe(lrI\olJlIli T-QIllI ~ a NpOrt d 3
CUM $tlIbiI for -,.n. J "'" AcId l:IermIklI-46
.5
"*"
e--0lJ_'*'91 ' 2S
_3f'IClI
''''
2325,
__ 21 668.f1n
2328, VettIuIgh E Adllen R MaM 8,
M<l~,
v...,
232t
B 8Mod-R~ 1.1"
8lMIsy MH, Bt~ ... DubuI P.
o..-, U ~..I:. Tlilltl
f2lIl 'oIeCPII* 011I 00 PlOt QIty beQ..tl
Mallo'
531 5J ~
,6l-169
WaiIIlewtkI R (2003) ~ ~
"'II Iil'XIQI<I'l <11_ .-- ~ r..-u
progr'CIIlI 1ft Inlerrrediale ..., 1d"llnCed
8Iood101 ~
23U. VOI'Idlortled EC PeN J J<loMII P
A._
*"""
Searr 011
(2OO6f.
aDIeO.IS
progr(l(OI
auIlI II . ~
..a
1SC1.l~
nu
~ ~ ~I
..-....x.
FoIicUar ~ ... I ~
~
~<:IrIcalCOUltl .
I eat fIP(lIl nl _
d ... ...-- AItIl
"'Ill
v_ . . .
(199nCl.ll*-rogd_~II""
~~.G.Mr;k8,ThledeC ~
.Ii
..... m~
W_ IAMLI"" I'I(l ~
kltI "'"
and
I'I(l
.ldepIllldeo~ ~
111 1l!S6-1861
:zm.
...
~~
.....
bor1 JNQ _
and sIIOWS ~
myeklj:o........ iW"CI ~ _
~
1&tl1~
'""
..... CJ. ~
........ NatGen8l17'96-99
2345. Vol JA. ~ Sl. ~
Cl. Andl'il<o JW ........, M. AguIIfa NS
(2005) ~ - . . . . . a IUly 01 he
A (1m!. ~ d
""
1))&.1 308
'"
easel
TC, Arnilage
IicUIeriIy
00
J()
n.
iMOIOgOu' ~ /or
~ 1lOI'I-HoG9~
Iy!T'oma J ~
ClncoI16 ~9
2J,f7. Vyas1', CnapIlO JO (2OOTl- t.IoIIcuIIor
lI.oglrtJ ...,., Oowrl tyndlQrllll"lSodaled
IIokerrill, CJ.o'r Opin Peo:Ntr 19 ~ ,.
2348. WaggolI W, OreIIoIG, ~ FIF. MIl_
DY,
P3IhoI 28 5l!5-595
15571566,
233e, VOl H, Chevalilor S. Garand R, Motsan
JP. Pralooln V. ~vilOOr ~C, I.Ioreeu Jr .
Soohoo JP (1989). Clonal e.~ oliymp-hocytllS bearlllg The gamma delta T-oell
reoepIor .., I palimt wiII1 large ...,..,.,laI lyrnpIlo<;yle d*""". Blood 14 285-290.
2337. 'lifoll A, Gertz MA (20071. Walden!;lrom
~. Blood 109 5096--5103
21. VI"}IkIl. laueri C, 8dli R. NbJ K.
NII'duccI MG, Russo G, Roli>steon JL. Croce
CM (1998) ~laled erpression of TCll
canon Tcellau kernia in mr;:e. Pmc NalIAcId
USA 95. J88S.3869
lm. V*"o U. Gaidan:I G. BolIO 8. ~ G
Al.dIio E, Bettn M. CaM R. FIllib'le FI
Nowero D. Or!uc:ci L ~ G. Caplt> 0
p.w; G. Satco C, ZagoneI V Cwbone A.
UWa U. P""*tl G, Sagloo G. R~ L
(1998) ~ogemeo0t5 or bd-6. bQ.2. c-myt
IIllI liq tlelelIon n Il--<IdIuse Wge--ceI n~ etnr:II rflII!vance .. 71 palIenIs. Ann
sa
~.
2351.
40. 56-60
W"~roe1"RDed4er 01. ,
lBal1i1'1we) 82 2J&.2S0
2353,
WallSA.E,~ulP
SaodJW{l990l
ue
ClncoI9 5&--61
1lS(9 4',
2~.
~In"
..., I CDKSRAF'2
luIlon 11'I'" Gerw Cl.on_1'III$
~ 5 95l5lS
2355, Wltl C ~ G, ~ C.
e-.
q33,q'2q2~1
20.
fac::b 15 ~ II ero.F,*-
"".
23501, Watanuk,.YIyauchl
R. Kop"" Y,
References 425
0iI00lerI, a ~
oomplocaIm of tQkj 1lIg.l ll~?
Peooll T~ 3, lI5-99
on:lIt$"
~..,., lancIlJ67.23J.239
2361. W.... T Weber RG. ~ It Act:lf
B. MljW-PulIU B. ~ S. 8uIodlget R
~ R 0t0erl~ M SdwoIdIk P
Redent>et9w G. LithW P (2000)
CIlirilansloc ~ ~ II pn.
"*'1 cennI.-.rwouIo IiI'*Il ~ ~ ,.
~IW9f!k:lll1ype s..nP..u 10:73-84
230. 'Nfittwtb M. oa,. PJ. Nwi F, ~
Ell.. NJOIlf o ltD. ~ HA. ~
MS ~F ~JRl1996) Tht~
--.on '*"'-' E ~ ..... .-.cl
t1DdgI<.., " ' - I I ~ III~' I!IIuod
81 382$-38Jli
2371. W....c
.E
u o.y PJ
Noggll F PooooII
~F~P9~1N
I-WltyPS T ~ F ~
ER. ~ A. El SIfo, UR Widaw F. N
1.1. ~ C ~ T, R-'Ii R.
T * , - K, W..... I{[) e.n-..... JC,
N'/O"lP "- RI)'IIlI.lS
JR ll9961 ThefIIIt
sr.nm
w.w.
ditIInnI:
AId! 0. a.:t 14
2731
2371. Wtir EG AI ""-H.an U 8Ilr:sli DA.
GnIIn Col.. F.... S SnofI eo IlllIoooI!l MJ
e-
**
or-dItIdoon
L ~ 13. 566--567
w~E,uanleyPW.eo..MhlKcb
2373,
SW, I'tldIhiuI A, GrrfwI Xl (2007) SIanl
ill"l"1lion I'lhbIorI rJ ElCR..ABl. "" Iht 1r8II.
merit of Imaliflob. re"~\lInl tlYonoc m~eIOId
Cln:eI' 1: J.4S.:l66
2374. W_ nbur\l&' DD. Ande,son
*,"-nia, NatR..
J,
diagnootoc KCUtIlC; , ~
ty a.nd dirlr..) l ltIevllfl(;e. Mod Pathol11. 14211"
2314A, Wai$i LM (2000), EPioIflirl.8IIl" >'iruI
a.nd Ho'!9I" n'l dilMl.lMI.CurT 0nc0I R'P 2, 1!l\>.
""
Blood 61 47....18,
ES Uu XF Cheo '(y,
Shballl D. l.4edwoII U (19911 OtIlec!IllI1lftl
~ ~
mil ~ II
ilI'9'J"l\IIlunob'-lic lymplladenop;iltly and
aryoommunobleslJC 1y!nplII(llonop, t
IQo';Mlalm
01
E~'"
Blood 19 11l$.IM
~""~1ynI
~"'~AmJPtIQ
122 392)9'
426 References
PiIIIlaIl03 7~755.
2381. 'o\IerIzmIn S. Gteenberg ...
n.or- P
'*'D"lbc:
~ NN YIlIi 1.75-3-168
23S1A.WtIUmiIn S. JiIIfte R l20(6).
eano."5 25Wt>4
l3I2.
peh:
2759-2179.
23U. ~A.~C.~
S SiN A. Jell! ES. Soaber! P. Ra\IeIIo 1,1
l2lXXIl ~ 01 ilIIafrialy e ~
lII"- II ~ USI'l\l eDNA . . . . eeeIIlk:akln 01tMIm as ill . - ~ ..-t.
. b ' ~ ~ W -Blood
........
DielKIld J de uascaret A
GInebedlC C (t99n FIlkIAa' BrgoKelI,....
F....-.t A
""
2096-2109
2387. Wanlger MA,Gesk S. EhflIch S, MartrrJ.
SlJ btIro JI, Dyer MJ, S>eberl R. MoI~ P, 6a ~ h
TF(2007). Gai nsofREL In ",nmary mediastinal
B-<:&Il ~ r;oincida with l'II.ICiear <>tOUm<Jlillion of REI. protein, Genes Cho"on"osomts
Caoc&r 46. .4(l6.415
2388. Weniger MA, Melzne< I, Menz CK.
w....-
a.ca
,"~alT-<:eI:~,i~C
~ ~
~~II~~B--oII
~ ~ ~ 0 / 3 7 _.......
uSIIQ ~ ~
P'I*ni lllTi'f"
c.ro.-'J
M Ger.vge SL l\oICl: .E
~RA.~CO Caflgul lolA (2001)
ADIIIu rJ til """f>tpe . . . j)'IdcI!I P'JO'"
Pf1'OSIS on idI.4I <II nooo aculit mj'lkllll
Ieol<eme '"'" IllIII'III C)'tlgenIliQ .-.d lit
........ IIIr4Iim ~ 0/ fL T) C3'UI
.-.l ....._
grtII4l S -.:!y.
ReI 61
~ II..V~
e.-v..
24.2"12-2"19
e..e.
=mo
lO!l,5164-5161
2396. "-"'ltmil1 SP, RUOI*'! AS, Radlllld'llr
MD P-oIrOltlc K, Pilsd'1l<a P. l.aroIJer C, !laId..s
CD, Wen J, R..,.,. F, POWIi' BL, Kolitz JE,
Llrlllll FlA. Caligouri MA, Mar= G,
~ CD (20081 , FLU D8:l5i18Jli mullJ.
tKlnSare Il5wjat9d willi poor dilMM-frM 11K
viva! a.nd ~ di&tlnd ..... -e.prill&ion Ji9Nlture
aomng )'UIJf'9'" adUlts w it ~ de f\O\f(J cyklge<ltl.
ic: al l~ norm.Il a<:ulll m)'tlloid leul.(lIflia IlICklll\l
FUa Inlemlll t1f nrlem duplocntlQlll BQod 111:
1552.1558.
2397. Whitta kllf SJ, Smith NP (19921,
Diagnostic viJue 0/ T-<:ell reoevtClf bela gene
rtil rTatlQfmenl i/IiIlyM llI1 pilnphenl blood
~ 0/ DlItitlnt1 wtlh \lfYlhrodttmI J
1tWe$l Oerrn.tb< 99' )61Jli2.
we
ew..
(2000).
I;et-*'Y
~ ~ drIooole<, e~dullon
of TPO andMPL In I'M) Iamiies WI\II ~
,.,
Bf J Haemrtlol110 1ll4-
I'MIlIlll\JlOOU
~.
i1fIrIor cIrloaII
(d.
IXp'llMIOIl
eo..o w.o.- n
PIQIe
b .......... llIlI,.. . .
,. . . . .""" .. Sl
IOIiIIf)' ~
1!lJ21S31
e- 0/ .......
lWPIaI'\s,
..
we
ilklod 99 .3S6-.q,,)
rtlO.lS
e-
CJ (2007). SubOJtaMOuS
~t""'e
cell
ryrnpllorn.a defwlrtillII,
T
MId
72.'245
2411. wasms
UE.
. . .mem-n
CO
~S Hllm~~~
_~ ~
__
~oJfIlcbmc~
Subject Index
8pl 1 stemcel~
S)T'ldr'()'T'l8. 72
Bp t l stem cell syn d rome. 72
A
ABL1, 15,24-27,32,35.36.39, 44, 48.
65,69.80,65.86. 15 1, 171
Abnor mallocalizatioo of immature
precur sor s, 91 , tOO
ABA, 325
Accelerated phase . 25, 32. 43. 46
Aci d pho sphata se. 135, 136. 138. 177,
270,273.354
Activ ation-induced draminase. 32 4
Acu te (malignant) m yelofibrosis, 138
Ac ute (malignant) myelosc lerosis. 138
Ac ute ba sophilic leukaemia. 29. 13 7-138
Acu te eryt hroi d leukaemia. 2 1. 22. 27-30,
121 ,125, 130, 134 -135
Acute leukaemia, NOS. 151
Acu te leukaemlas. mixed p henotype , 22.
NOS. 154
Acute leukaemla s. mixed phe notype,
T/m yeloid , NOS, 153- 154
nwero-
350
t-een
AggessM>NK_
c -catemn. 102
Sub;ect index
4 29
~ltu'(JTt)l'xYloperia.
AML,
100. 107
leukaemia
Artemi s, 339
As ympto matic (smol de ring ) plasma cell
myeloma , 202
Ataxia-telang iectasia. 27 1. 336. 339
A ML with inv(3)(q21q26.2), 29 . 30 ,
116-117,125
A ML with 1( 15 : 17)(q22;q 12), 112
A ML1 ,36. 104. 111, 131, 170. 172
AM M,44
Amyloidoma .2 10
Amyloidosis. primary, 200 . 2Q9.21 1
Autoirrvnune Iymphoproliferative
synd rome . 165.336.339
see A LK
Bilinealleukaemia. 150
B lymphoblastic leukaemia/lymphoblastic
lymphoma, not otherwise specified,
168-170
B Lymphoblastic leukaemiaJIymphoma
w ith hyperdi ploi dy, 173-174
4 30
API2/MALT1 .163
BDCA-2ICD303, 146
Bence Jones pro tein , 197,205
BCR-ABl l , 15,24-27,32.35,36,38,39.
43 , 44 ,47.48, 5(}.53 . 64> 65. 69-7t . 76.
79-86,138, 151. 152. 171
BCl l 0 , 195,217
BMI1 , 231
Bod y ca vity ba sed lymphoma , 260
Bud d-Chia ri synd rome , 41 , 48
Bullous mastoc ytosis, 55
Burk itlleukaemia variant, 263
Burkitt leukaemiaJlympho ma , 168
Burkitt lymphoma, 141. 160 , 163 , 165.
166 , 176, 233, 235, 262 -264, 266, 337340 ,343,348,351
Burkitt-like lympho ma, 265, 266
C
CIEBptJ. 315 . 316
CA E, 2 1. 57 , 79. 130 , 132 , 134-136, 138,
140
CAlM-AF10, 178
Campyfobacter ieiuni. 166. 198 , 214
Canale-Smith synd rome , 339
SubieCl index
364-366
C02. 56, 57. 62. 70. 72, 79, 112. 113,
131.132.1 46.154.161 .163.177,246.
270.274,277.279.283.287.297,299.
300.303,304,3 10.315.318.326
3 10,31 4.318.324.326.338,343,364
CD4.79, 112, 114. 131-134. 140. 142.
144,1 46.161-163,177,224.246,248.
255,262.267,270-273.279.280,283.
287.290.293.294,297,298.300.301 .
~08 .3 10.31 1 ,3 15 .318.324 .325 .
~338 .340. 349.355 ,357 .360.365
333.338,344,347-349.351.364
C02 1. 162.216.220.221 ,224.227,311 .
324.333.355.357.362.364.365
C022. 138, 150. 152. 100. 181, 183. 189.
100. 1ro, 195, 223. Z35. 241. 250, 264 .266
C023. 70, 160. 180-182. 186. 192. 195,
216,219,221 ,224,231 ,250,311,362,
364.36S
C025, 56 , 57, 60-62, 70. 72, 138, 163.
171,1 89,1 90, 192, 195, 283, 287, 306,
315,338
307
C057, 161-163 . 224, 255, 273. 274. 277,
287,324.325.338
COOl . 23, 101. 105. 106, 116, 117, 136,
139, 140. 142. 144
CD64 . 79. 112-114. 116, 122, 131-134.
150.355
C068. 61, 79. 121, 133. 134. 140. 146.238 .
315,327.355,357,359 .362.364~
CD27,259
C0105.92
CD 117, 57, 59, 61, 62, 92, 101, 107. 112114.11 6.1 31-135,1 38, 140-142,144 .
146, 150. 153. 171, 177,205
C0 30-positive Iymphoproliferativ e
disorders, primary cutaneous, 3O()..30 1
CD34, 20, 23, 34, 44, 45, 47, 65, 79, 92,
96,100.101 ,105-107.11 0.11 2-114,
116,117.121 ,122,1 25,128.1 30-135,
137,138,140,142,144,146, 151,169,
173, 175,362,364
COK6, 186
CD26,299
Ceutvoes.
- dou ghnut. 3 12
- clear, 306
- flame, 205
- Gaucher-like. 205
- hallmark, 312, 3 13. 3 17
- hand-mirror, 169
- Hodgkin, 238 , 247, 326 , 327, 329
- l&H . 323
Subject index
431
Reed-Stemberg. 182,234.247,250,261 ,
300.3 10.313.322,327,337,347,364
CIMF, 44
CLA, 146,297,299,3OO
347,348,349
334.338,339,343,349
- Sezary. 299
- Touton, 366
CereOOIorm nJCIeus, 270, 296, 297, 298 , 3)1
Clattvin-AlK, 255
ClL
uacromans. 166
Chlorom a, 140
Chronic ac tive EBV infec tion, 278
Chronic eosinop hilic leukaemia (CEl). 23,
25,26.51-53.59. 6&71 ,73
CMMl- 1, 76, 78
CREB,283
CoREl . 228 , 267
Crohns disease, 292, 350, 35 1
Crosti's disease, 227
CTNNA1.102
Crow-Fuka se syndrome. 2 12
Cryptococcus meningitis, 284
432
Subject index
355
Diffuse large B-c eillymphoma. activated
B-cell-Iike, 235, 236
Essennarttuomoocytnaemta. 18,23,25,
39,4 1, 44,48-50, 64,85,104,139
Dohre body, 95
ETV6-AUNX1,172
EVI-l ,36
EVI1-AUNX1, 117
Dwarf megakaryocyte, 32
E
E2A-PBX1, 175
E47,il-iEB.178
EBEA,1 46.236,246,248.256.257.259.
279 ,280,287,315,319,328,330.331 .
341 ,346,347 ,363
Follicular Iymptloma,
FOXP1,227
FOXPJ, 163,283
Franklin disease, 196
Fulminant EBV+ t-een tymphoproliferative
disease 01 childhood, 278
Fuloronln_syncl<are,278
F
Faggot cells , 112, 113
Fanconi anaemia, 88, 106, 107
F~.
107, 165,272,277,287,336,338,339
t-een
lymphoma,
Gamma-delta ("to )
primary cutaneous, 163,302-303
GATA1. 142. 144
Ectropion. 299
EGR1. 102
EMA,
Embryonal carcinoma, 3 18
Ernpenpolests . 49
H
Haemog lobin, 23, 40, 41, 44, 48, SO, 65,
82,84 ,94 ,98, lOS, 122, 135, 136, 139
Haemophagocytic syndrome. 163, 252,
276-278,286. 295,313,.D3, 339, 354 ,
eeo
Subject index
433
166,292293, 343
Hereditary x-nreeo sid erobiasnc
anaemia, 96
HES6.147
HHVB.
t-een leukaemia
haematopoesis. 15.26,40,
HTLV-lasso::::iated ~, 281
234.257-260. 340.343
Interferon-a ,37
tynVona. 258
HRX, 114
HTlV-1 , see Huma n
virus type 1
252-253
~homa ,
166
Hypereosinophilic syndrome. 51
Histiocytosis X, 358
Hypodiploid AL L, 174
JAK2 V6 17F, 24 , 25, 27, 40 , 41 , 4345, 4750 ,62, 64 ,76,81 ,85,86. 102
JUNB, 299
Hodgkin lymphoma , cl assic al, Iymp hoc vte-c epreteo. 322. 334
IKARQS, 325
Hodgkin lymphoma. classical. mixed cellularity. 322, 326. 330, 331, 334, 341, 35 1
434
Subject inoex
366367
K
Kapo si sarcoma. 258 , 259
Kapos i sarcoma herpe s virus (KSHV)
pos itive ptasrrebrastc lymphoma .
258-259
Keratin , 357
LM 0 2, 177,236
MOS,
KiM4p ,364
L
L&H cells, 323
MICrocephaly. 339
LANA- 1, 259
lymphoepithehoid ,308
Mixed cellularity c lassica l Hodgkin Iymptona. 322. 326. 33), 331, 334 , 341, 351
lymphogranulomatosis. 322
254-255
l arge 8 -.c ell lymp homa arising in HHV8associated rnncennc Castleman
disease. 2S4-2S9
l arge 8 -c ell lymp homa exp ressing the
AlK kinase and lack ing the t(2 :5). 254
Ml LT1, 115
Ml LT2, 115
MLl T4 , 115
MLLT10 . 115
LATS2, 147
lCK, l77
Mastocytoma.ecrecuereccs. 6 1-63
teokoerymrobreetose. 44 , 45 . 46
LM01, l 77
Mastoc ytosis, 23 . 25 .
scet. 62
Subject index
43 5
~phic
MSN. 315
Mu heavy chain disease. 197-198
Myelomastocytic leukaemia , 56
NOTCH1.178
Myelomatosis. 202
231 ,235,237,241,242,251,262-266,
289.290,325,340,348
Mycosis fungoides. 294 . 296-298
Noonan syndrome, 82
MyeIoproIiferalNe neopIasm,lIldassdiable,
NUMA1 .114
64-65.85
Myeloproliferalive neoplasms (MPNj. 23,
31-66
OCT-2, 25 1, 267
Onychodystrophy, 299
..
M.itipIe
Osteosclerosis, 42
Naphthol-ASD-chloroacetate esterase ,
21,33, 34, 41, 45, 49 ,57 ,76,78,83,
105,11 2.1 30,140
on,
117
NBS1,339
p 18'N~olc ,
206, 231
Neurofibromin, 84
Myelodysplastic/myeloproliferative neoplasms (MDS/MPN), 18, 19, 22, 23, 2530,75-86,79,85,86 ,91 ,102,124,
127 129,1 40
p230, 35,39
MyelodysplastiC/myeloproliferative
neoplasm, unclassifiable, 85-86
Nibrin, 339
MyelodysplasticJmyeloprollferative
neoplasms, therapy-related , 127
Paornyelosis. 42
Pappenheimer body, 98
436
Sub;ecl index
NodaImarginalzroe~
219,3l3
166,218-
Paratomcutar B-ceillymphoma. 2 18
Paraneoplastic pemphigus. 363
Paroxysmal nocturna l haemog lobinuria,
91.106.107
oenropnne. 114
variant, 308
t-een
Peripheral
lymphoma , Iymphoepi thelioid variant . 308
Peripheral T-cell lymphoma, not otherwise
specified. 163 , 165 , 166, 177,287,
297, 306-308
Peripheral t-een lymphoma, primary
cutaneous. 302-305
PML-RARA, 29 , 30,112-114
Primary thrombocytosis, 48
40-42
PoIycythaemia vera , postpolycythaemic
myelofibrosis. 42-43
Polycythaemia vera , prepolycythaemic
phase, 40-4 1
Potycythaemia vera, spent phase, 40-41
Psoriasis, 350
PTEN.298
PTGC , 219 , 322 , 324
PTLO, see Post-transplant Iymphoproliferative disorders
PTlD. cIassicaJ _
type . 349
PrecurscrT~~,68,337
Pesticide, 166
PU. 1, 25 1, 328
r-ceu
t-ceuwm-
j-ceu
Subject index
43 7
Randalldisease. 211
RPN1-EVI 1, 30,1 16
RARS.
sroerobrasts
RUNX2 , 147
S1OO.355,358,362,364-366
Sclerosing cholangitis, 359 , 366
Sea-blue t ustccvtes. 33
347-349, 364
Splenic red pulp lymphoma with numerous basophilic villous lymphocytes, 191
278
Stabibn-f, 366
Starrysky pattern, 78. 169, 176.214.229,
264-266
STAT, 24, 251, 329
Stem cell acute leukaemia . 151
Strongyloidiasis, 282
SubCutaneous pan nicu litis-like T-cell
lymphoma, 163,294-295,302.355
SerpinA 1,315,316
SHP1 ,3 15
SHP2,82
101,104 ,136.139
Refractory anaemia With ring sideroblasts
88
sCD23,182
310.313.322.326 .327.330.331.337.
Refractory anaemia, 27 , 49 . 65 , 85. 88-91 ,
ABTN2,177
ABTN1,177
1M 107, 143
sivi.
Restrictive cardiomegaly, 51
185, 186
SOC- 1. 329
Sorafenib . 70
Splenic B-celi lymphoma with villous
lym p hoc ytes. 191
Splenic diffuse red pu lp small B-ee ll
lymphoma. 191-192
Sp lenic lymphoma w ith ci rculating villous
lym phocytes, 185
T
T lymphob lastic leukaemia/lymphoma,
161 ,1 65 , 176-178
T-be l, 189 , 190
T-cell ch ronic lymphoc ytic leukemia, 270
T-cell large g ranul ar lymp hoc ytic
leukaemi a, 163 , 2 72-273
T-cell proIymphocytic leukaemia, 163,270271, 337
T-c ell ric h large B-ceillymphoma. 238 ,
323 ,326
T-cell/histiocyte-rich large B-celllymphoma , 234, 238-239, 325
T-cell rec eptor (TCR), 112, 13 1, 146, 151,
158.161-164, 169,176-178,249.261 ,
270 ,273,275,277,279,280,283,287,
290 ,293-295,297,299-301 ,303,304.
307,311 .315.318,319,328,329,336,
338 ,339,348,349,357,358.362,364 ,
366
T-cell-rich B-eeillymphoma, 238
TCF3-PBX1, 175
1(3;5)(p2 1-25;q31-35), 71
1(4;22)(q 12;ql1),70
WDR48-PDGFRB.71
t(5;10)(q33 ;q21), 71
1(5;12)(q31;p13),72
t(5;12}(q3 1-33;q24),7 1
1(5;14)(q33 ;q24), 71
1(5;14)(q33;q32 ), 71
Tresaurocvtes. 205
t(5;16)(q33;p13).71
t(5;17)(q33 ;p13), 71
Thymoma, 364
TlA1. 79, 146. 163,273,274,287, 293,
295.300. 304,315, 3 18
Tingible body macro phage s, 220 , 227
TLX1 ,l77
ZAP-70, 182. 23 1
TLX3, 177
1( 10:11)(p13;q1 4).178
t(11;19)(q23;p1 3.3).11 5
1(1 4:16)(q32;q23),201
1(14:18),1 60, 163,164,186,217,222.
224, 225, 228,235,241,242,329
TPM3-PDGFRB,7 1
transiccauoos
1( 1;3Xp36,3;q21.2), 93
t(l ;5)(q21;q33), 71
t(1;5}(q23;q33),71
t( l ,14 ), 163, 178,217
329
Subject index
439