Dr.

Shriniwas b Rushi MD
A variety of T and B-cell neoplasms can involve
skin, either primarily or secondarily.

 Primary cutaneous lymphoma : cutaneous T-

cell lymphomas (CTCLs) and cutaneous B-
cell lymphomas (CBCLs) that present in the skin
with no evidence of extracutaneous disease at
the time of diagnosis.

 Secondary
cutaneous lymphomas : systemic
lymphomas that secondarily involve the skin.
 After the gastrointestinal tract, the skin is the second most common site of
extranodal non-Hodgkin lymphoma.

 Estimated annual incidence 1:100,000.

 Have a completely different clinical behavior and prognosis from histologically

similar systemic lymphomas, which may involve the skin secondarily.

 Hence, require different types of treatment as opposed to systemic

lymphomas.

 For that reason, the European Organization for Research and Treatment of
Cancer (EORTC) classification for primary cutaneous lymphomas and the World
Health Organization (WHO) classification for tumors of hematopoietic and
lymphoid tissues included primary cutaneous lymphomas as separate entities. A
consensus classification was developed in 2005 referred to as ―WHO-EORTC
Classification of Cutaneous Lymphomas‖.

 65% of all Primary Cutaneous Lymphomas are of T-cell type.

•CLASSIFICATION
•CLINICAL
FEATURES
•TREATMENT
WHO-EORTC Classification Frequency, % 5-Year Survival Rate, %
Indolent Clinical Behavior
Mycosis fungoides (MF) 44 88
MF variants and subtypes
—Folliculotropic MF 4 80

—Pagetoid reticulosis <1 100

—Granulomatous slack skin <1 100

Primary cutaneous CD30+ lymphoproliferative disorder

—Primary cutaneous anaplastic large cell lymphoma 8 95

—Lymphomatoid papulosis 12 100

Subcutaneous panniculiticlike T-cell lymphoma (provisional) 1 82

Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional) 2 75

Aggressive Clinical Behavior

Sézary syndrome 3% 24%

Adult T-cell leukemia/lymphoma NR* NR

Extranodal NK/T-cell lymphoma, nasal type NR NR

Primary cutaneous peripheral T-cell lymphoma, unspecified 2 16

Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (provisional) <1 18

Cutaneous gamma/delta T-cell lymphoma (provisional) <1 NR

Precursor Hematologic Neoplasm (not a T-cell lymphoma)

CD4+/CD56+ hematodermic neoplasm (blastic NK-cell lymphoma)
NR
NR
 Extranodal Non-Hodgkins lymphoma of T-cell
origin, with primary involvement of the skin.
 First case described in 1806 by Alibert:
―mushroom like tumors‖
 Most common type of CTCL
 Accounts for almost 50% of all primary cutaneous
lymphomas and 2.2% of all lymphomas.
 3 cases/ 1,000,000/ year<1000/year US
 Peak age 55-60
 Male: female 2:1

 More common in African-Americans

 Heterogeneity in presentation.
 Indolent cutaneous eruption with erythematous
scaly patches or plaques, typically bathing trunk
distribution.
 Poikiloderma may be seen - presence of mottled
pigmentation, epidermal atrophy, and
telangiectasia associated with slight infiltration.
 3 Phases of progression:
 Macular erythematous eruption
 Plaque/Patch phase, resembles eczema/psoriasis
 Tumor nodules/ generalized erythroderma and associated
adenopathy or visceral involvement ( Often seen in Sezary
Syndrome)
 Circulating Sezary Cells
Patch &
Tumor Erythroderma
Plaque
 This Sezary cell is the malignant
Circulating Sezary Cell pleomorphic T cellseen in mycosis
fungoides and has a convoluted nucleus
 Sezary cells are mononuclear cells with a
cerebriform nucleus
 Small numbers of these cells can be seen
among healthy individuals
 In MF, an increased number of Sezary cells
seen in the peripheral blood.
 An absolute count ≥1000 Sezary cells/cubic
mm is a diagnostic criterion for Sezary
syndrome.
 Extracutaneous manifestations :
 involvement of regional lymph nodes (approximately 30
percent in MF )
 Lungs
 Spleen
 Liver
 Gastrointestinal tract.
 Bone marrow involvement is rare
 Progression to Extracutaneous disease correlates with
extent of skin disease
 Limited patch or plaque very rare
 Generalized plaque 8 %
 Tumorous or generalized erythroderma30-40% 
Hence, extracutaneous is more commonly seen in Sezary
syndrome.

Hoppe RT, Kim YH,Clinical features, staging, and prognosis of mycosis fungoides and Sezary syndrome, Uptodate.com, 11/06
 INVESTIGATION
SKIN BIOPSY
LYMPH NODE BIOPSY
IMMUNOPHENOTYPING
MOLECULAR ANALYSIS
(Southern Blot analysis or PCR
amplification method)
PATHOLOGY
-Atypical SMALL to MEDIUM sized mononuclear cells with cerebriform
nuclei infiltrating the upper dermis among epidermal keratinocytes
(epidermotropism) or forming intraepidermal aggregates (Pautrier
microabscesses).
- Pautrier's abscesses – pathognomonic but present only in 38 % cases of
MF
- Hyperconvoluted intraepidermal lymphocytes
- Lymphocytes aligned within the basal layer
Histology of a enlarged LN may reveal dermatopathic lymphadenitis,
with sinus histiocytosis and a small number of atypical lymphocytes.
The degree to which the LN is replaced by these atypical cells can be
described as a grade. This grade has prognostic significance ( See graph
: Extracutaneous involvment – Prognosis)
Help distinguish MF and Sezary syndrome from reactive or inflammatory
lymphoid infiltrates in the skin which display markers of mature
lymphocytes. Mature T-cell markers include CD2, CD3, CD5 & CD7 Lack
of one or more of these markers indicates a more immature cell and is
strongly suggestive of lymphoma
TCR gene rearrangements ( to demonstrate clonality  neoplastic T
cells exhibit clonal TCR gene rearrangements)
Skin biopsy from a patient with
mycosis fungoides, showing a large
cluster of atypical lymphocytes in
the epidermis (Pautrier
microabscess, arrow).
 ISCL/EORTC Diagnostic algorithm :

 Point based system

 A total of 4 points is required for the diagnosis of MF

based on any combination of points from the

clinical, histopathologic, molecular biological, and
immunopathologic criteria.
 Clinical Findings
 Skin Biopsy ( Histopathology)
 Molecular criteria
 Immunophenotyping : CD3+, CD4+, CD8-, CD30-
, CD45RO+, TCR gene rearrangements
 CRITERIA SCORING SYSTEM
Clinical 2 points for basic criteria and two additional criteria
1 point for basic criteria and one additional criterion

Basic
1. Persistent and/or progressive patches/thin plaques
Additional:
1. Non-sun exposed location
2. Size/shape variation
3. Poikiloderma
Histopathologic 2 points for basic criteria and two additional criteria

1point for basic criteria and one additional criterion

BASIC
1. Superficial lymphoid infiltrate
Additional:
1. Epidermotropism without spongiosis

2. Lymphoid atypia  cells with enlarged hyperchromatic nuclei and irregular

or cerebriform nuclear contours.
Molecular biological
1. Clonal TCR gene rearrangement 1 point for clonality
Immunopathologic
1. <50 percent CD2+, CD3+, and/or CD5+ T-cells 1 point for one or more criteria

2. <10 percent CD7+ T cells

3. Epidermal/dermal discordance of CD2, CD3, CD5, or
CD7
 Skin evaluation : percentage of involved body
surface area must be estimated.
 Imaging Studies : CXR, CT Chest/ Abd/ pelvis with
or without PET to evaluate the visceral
involvement and adenopathy.
 Lymph node biopsy : The involved lymphnodes
seen clinically or on PET/CT need to be biopsied.
 Bone marrow aspirate & Biopsy : Not routinely
employed as part of the initial staging procedure
for MF. However, indicated in select cases to
document visceral disease if marrow involvement
is suspected, for eg: as in the setting of B2 blood
involvement or in patients with an unexplained
hematologic abnormality.
 T (skin)
T1 Limited patch/plaque/papules (< 10 percent of total skin
surface)
T2 Generalized patch/plaque/papules (>10 percent of total skin
surface)
T3 Tumors ( 1 cm diameter)
T4 Generalized erythroderma (confluence of erythema
covering 80 percent body surface area)
N (nodes) #
N0 Lymph nodes clinically 1.5 cm (biopsy not required)

N1 Lymph nodes enlarged clinically, but histologically uninvolved

(includes "reactive" and "dermatopathic" nodes)

N2 Lymph nodes enlarged clinically and abnormal cells are

present on histology but they do not efface the nodal
architecture.
N3 Lymph nodes enlarged clinically. On histology, there is partial
or complete effacement of the nodal architecture by
abnormal cells.
M (viscera)
M0 No visceral involvement
M1 Visceral involvement (histologically confirmed)
B (blood) #
B0 No circulating atypical (Sezary) cells (<5 percent of
lymphocytes)
B1 Circulating atypical (Sezary) cells (5 percent of lymphocytes)

B2 High blood tumor burden: 1000/microL Sezary cells with

positive clone
IA T1 - Patch/Plaque
IB T2 - Patch/Plaque
IIA N1 - Clinical Nodes
IIB T3 - Tumors
III T4 - Erythroderma
IVA N2-N3 - Path Nodes
IVB M1 - Visceral Mets
1-4 represent T1 to T4.

Mycosis fungoides and Sézary Syndrome. Semin Oncol 1999; 26:276. figure 1, page 279.
1: 543 patients with disease apparently limited to the skin (clinical stages
I/II/III); 2: 57 patients with extracutaneous disease (clinical stage IV) at the
time of presentation.
Kim, YH, Hoppe, RT. Mycosis fungoides and Sézary Syndrome. Semin Oncol
.
1999; 26:276. figure 2, page 280.
 Good-Risk:
 Patch/Plaque only
 Survival >12 years
 Intermediate-risk:
 Tumors/erythroderma
 Plaque + node/blood
 Survival 5 years
 Poor-risk:
 Visceral involvement
 Survival 2.5 years
MYCOSIS FUNGOIDES
 Cures generally unattainable
 Goals of treatment are symptom relief and cosmetic improvement (palliation)
 Early aggressive therapy results in high complete remission rates but no
significant difference in DFS or OS.
 Patients are susceptible to infections with skin flora; immune suppression is
undesirable

 Skin Directed
 Phototherapy : UVB (Ultraviolet B) or PUVA ( Psoralen + UVA photochemotherapy)
 Topical chemotherapy :- Nitrogen Mustard (HN2) or Carmustine (BCNU)
 Radiation therapy ( Electron Beam Therapy, TSEBT – Total Skin Electron Beam Therapy)
 Topical Retinoids ( Baexarotene)
 Topical Corticosteroids

 Systemic
 Photopheresis
 Biologic Therapies : ( IFN alfa, Denileukin diftitox)
 Retinoids/Rexinoids ( Oral Bexarotene or Isotretinoin)
 HDAC ( Histone Deacetylase inhibitors) - Vorinostat
 Chemotherapy ( Single agent chemotherapy – Methotrexate, Doxil, Gemcitabine,
Chlorambucil, Cyclophosphamide)
 TYPE TREATMENT MODALITY

PATCH/ PLAQUE Skin Directed: Local/Total

REFRACTORY PLAQUE Systemic +/- Skin Directed

ERYTHRODERMA Systemic +/- Skin Directed

TUMOR Rad Rx +/- Systemic

LYMPH NODE Rad Rx +/- Systemic

 Ingestion of 8-methoxypsoralen (0.6mg/kg, 2
hours before UVA exposure)
 Becomes activated when exposed to UV light
and increases the skin's sensitivity to UV light
and hence, improves the effectiveness of UV
light therapy
 Treatments 3x/wk with subsequent tapering
 65% Complete Response, 95% OR, duration of
response 43 months, Mean survival 8.5 years
in Stage I
 Adverse effects : nausea, erythema, pruritis,
dry skin, secondary skin malignancies
 Nitrogen Mustard (HN2) or Carmustine
(BCNU)
 Overall Response Rates 70-90% in Stage I
disease
 Adverse effects: contact
dermatitis, erythema, telangiectasias
 CTCL is very radiosensitive
 Use of Electron Beam Therapy limits
toxicity, <5% of dose travels beyond 2cm
 Standard total dose is 36 Gy
 CR 56-96% in Stage IA-IIA
 Given in combination with other agents to
avoid relapse
 Toxicity: erythema, pain, swelling, hair
and nail loss, secondary skin cancer
 Reserved for Sezary Syndrome (Stage
IVA1) and Stage IIIB disease
 Technique:
 Patient ingests 8-MOP. Leukapheresis,
mononuclear fraction of patient‘s WBCs
are collected and exposed to UVA, then
returned to patient. UVA is toxic to cells
and reinfused cells stimulate a selective
immune response against malignant cells.
 RR (response rate) 73%, median survival 5
years in one study of pt‘s with mainly SS
 ORR 79% in pts with all stage disease
 Maximum dose limited by side effects
 Started at 3million U and titrated up to
maximum of 15million U 3x/wk
 In one study combining PUVA with IFN 12
million Units 3x/wk – ORR 88%, CR
62%, response duration 28 months
 Novel Retinoid – Rexinoid
 FDA approved for use in advanced MF i.e;
Stage IIB to IVB in patients who have not
responded to at least one prior systemic
therapy
 Selectively activates retinoid X receptors
(nuclear hormone receptors)
 Acts on retinoid response elements to
alter gene expression
 A phase II/III trial
of bexarotene in 94
patients with
advanced stage MF
(stages IIB to IVB) who
were refractory to
conventional therapy
reported overall
response rates of 45
and 55 percent of
patients started on
oral doses of 300 and
greater than 300
mg/m(2) per day,
respectively
 Adverse effects :

 Hypertriglyceridemia 63%
 Most patients require drugs to reduce hypertriglyceridemia
such as statin or fibrates. Diet should include Vitamin E and
dietary consultation, especially for monotherapy patients.


 Hypothyroidism 43%
 These patients need synthroid supplements.

 Leukopenia 7%
 Dose adjustments control leukopenia
 Teratogenic
 Oral HDAC (Histone Deacetylase) inhibitor
 Partial response rates in MF of 30 percent
 Approved by the FDA for the treatment of
cutaneous T-cell lymphoma (CTCL) in patients
with progressive, persistent, or recurrent disease
on or following two systemic therapies.
 Common Side effects :
 Gastrointestinal symptoms
(diarrhea, nausea, anorexia, weight
decrease, vomiting, constipation)
 Constitutional symptoms (fatigue, chills)
 Hematologic abnormalities (thrombocytopenia, anemia)
 Taste disorders (dysgeusia, dry mouth)
 Abnormal laboratory values include high
glucose, abnormal EKGs
Hoppe RT, Kim YH,Clinical features, staging, and prognosis of mycosis fungoides and Sezary syndrome, Uptodate.com,
11/06
 Likelyrepresents leukemic phase of mycosis
fungoides.
 Sezary Syndrome:
 Generalized erythroderma + intense Pruritis
 Lymphadenopathy
 Atypical T- cells (Sezary cells) in the peripheral blood ( An
absolute count ≥1000 Sezary cells/cubic mm is a
diagnostic criterion for Sezary syndrome  equivalent to
the B2 designation in the TNMB classification syndrome).
 Low levels of Sezary-like cells can be detected
in the peripheral blood of patients with benign
skin conditions. Hence, diagnostic criteria of
Sezary syndrome uses an absolute Sezary cell
count of >1000/microL with positive clones
 Diagnosis is made when there is a clonal
rearrangement of the T-cell receptor (TCR) in
the blood (identified by PCR or southern blot
analysis) plus
either
 an absolute Sezary cell count of at least 1000
cells/microL
or one of the following two criteria
 Increased CD4+ or CD3+ cells with a CD4 to CD8
ratio of 10 or more.
 Increased CD4+ cells with an abnormal
phenotype (such as a CD4+ to CD7- ratio ≥40
percent or a CD4+ to CD26- ratio ≥30 percen
 Treatment includes Extracorporeal Photopheresis
( ECP) alone or in combination with other
therapies ( IFNα) OR 30-80% and CR 15-25%.

 Recent studies report benefitis with Bexarotene

and Alemtuzumab (anti-CD52) therapies – more
data needed.

 Prognosis - generally poor with a median survival

between 2 and 4 years.

 Most patients die of opportunistic infections that

are due to immunosuppression
Variant/subtype Clinical/pathological features
Folliculotropic MF (follicular cell lymphoma) •Localised form of cutaneous T-cell lymphoma in
which there is a slowly enlarging solitary patch,
plaque or tumor.
•Lacks Evidence of Epidermotropism.
•Biopsy shows characteristic lymphomatous change
around hair follicles ( folliculotropism)
•Most commonly found in the head and neck area.
•Skin lesions are often associated with alopecia, and
sometimes with mucinorrhea (see alopecia
mucinosa).
•Worse prognosis compared to other MF variants –
requires aggressive therapy
Pagetoid reticulosis •Localised patches or plaques with an intraepidermal
growth of neoplastic T cells.
•Presents as a solitary psoriasis-like or hyperkeratotic
patch or plaque, usually on the extremities.

Granulomatous slack skin •Extremely rare subtype characterised by slow

development of folds of lax skin in the major skin
folds.
•Skin folds show a granulomatous infiltrate with
clonal T cells.
•Occurs most commonly in the groin and underarm
regions.
 •Primary cutaneous anaplastic large cell lymphoma (C-ALCL)
•Lymphomatoid papulosis (LyP)
•Borderline cases

 Second most common group of cutaneous T-cell lymphomas (CTCLs)

 Accounts for approximately 30% of CTCLs.

 C-ALCL and LyP form a spectrum of disease  histologic criteria alone

are often insufficient to differentiate between these 2 ends of this
spectrum.

 The clinical appearance and course are used as decisive criteria for
the definite diagnosis and choice of treatment.

 ―Borderline case" refers : refers to cases in which, despite careful

clinicopathologic correlation, a definite distinction between C-ALCL
and LyP cannot be made. Clinical examination during further follow-
up will generally disclose whether the patient has C-ALCL or LyP.
A 40-year-old woman
complains of a
recurrent skin
rash, which she
describes as "bug
bites." that
spontaneously regress
with in 2 to 3 weeks.
Skin biopsy results
demonstrate an
atypical lymphoid
infiltrate, which is
CD30 positive.
 A chronic, recurrent, self-healing papulonecrotic or
papulonodular skin disease with histologic features suggestive
of a (CD30+) malignant lymphoma.
 First described by Macau-ley in 1968 – in his
words, he discussed a case in which "repeated
biopsies of ... skin lesions consistently reveal an
alarming infiltrate of large pleomorphic hyper-
chromatic cells which expert histopathologists
and hematologists ... variously classified as
highest grade malignant lymphoma, malignant
reticulosis, metastatic carcinoma, malignant
melanoma, undifferentiated malignant tumor."

 ―A self-healing rhythmical paradoxical eruption,

histologically malignant but clinically benign.‖

 Frequently misdiagnosed.
 Despite modern techniques, cannot be definitively
diagnosed by pathologists without pertinent clinical
information.

 Histologically, the proliferation is malignant and may

possess any or all of the features of T-cell malignancy,
including aberrant T-cell antigen expression and
clonal rearrangement of T-cell receptor genes. Clonal
T-cell gene rearrangement can be seen in 60 to 70%
cases.

 The component cells are highly anaplastic and express

the CD30 antigen. Histopathologic features
considerably overlap those of anaplastic large-cell
lymphoma or in some cases, the histologic features
more closely resemble those of mycosis fungoides.
 Thesedifficulties can lead to a mistaken
pathologic diagnosis of malignant lymphoma
or other types of cancer.

 Clinical criteria for the diagnosis :

 The defining clinical feature of this disease is
spontaneous regression . The patient must be
observed without treatment to determine
whether spontaneous regression will occur.
 Histopathology

 Histologic picture is extremely variable.

 Three histologic subtypes :

 Represent a spectrum with overlapping features.

 LyP type A : most common ( 75%) - scattered small clusters of

large, sometimes multinucleated or Reed-Sternberg-like, CD30+ cells
are intermingled with numerous inflammatory cells
(histiocytes, small lymphocytes, neutrophils, and/or eosinophils).

 LyP type B : uncommon (less than 10%) - characterized by an

epidermotropic infiltrate of small atypical cells with cerebriform
nuclei similar to that observed in MF. . CD30+ large cells are rare or
absent, but epidermotropism is more common in this variant.

 LyP type C : demonstrate a monotonous population or large clusters

of large CD30+ T cells with relatively few admixed inflammatory
cells. Histologically, indistinguishable from Anaplastic Large Cell
Lymphoma, with the exception of the minimal subcutaneous invasion.
 Clinical Features

 Generally occurs in adults

(median age, 45 yrs)

 Clinically benign.

 Recurrent crops of self-healing, red-brown, centrally

hemorrhagic or necrotic papules and nodules on the trunk
or extremities, which can evolve in to papulovesicular or
pustular lesions.

 Lesions are much smaller than anaplastic large cell

lymphoma (<2 cm)

 Spontaneously resolve in 4-6 weeks, leaving

hyperpigmentation or atrophic scars.

 Unless accompanied by systemic lymphoma, most patients

have no constitutional symptoms
 Clinical Features

 Nosingle clinical characteristic at

presentation can distinguish Lyp
from Lymphoma with absolute
certainty. The following features at
presentation may indicate the
condition is probably malignant :
 Presence of a solitary skin lesion > 3cm in
diameter.
 Persistence without a spontaneous
regression.
 Presence of significant lymphadenopathy. The
involved lymphnode must be biopsied to rule
out lymphoma.
 Treatment

 Curative therapy is not available.

 None of the available treatment modalities affects the

natural course of the disease  Hence, short-term
benefits of active treatment should be balanced carefully
against the potential side effects.

 Beneficial effects have been reported of PUVA (Oral

psoralen plus UVA phototherapy) and topical
chemotherapy.

 Low-dose oral methotrexate (5-20 mg/wk) - most

effective therapy to suppress the development of new skin
lesions. However, the disease recurs within 1-2 weeks after
discontinuing the therapy.

 Therefore, in patients with relatively few and nonscarring

lesions, long-term follow-up without active treatment
should be considered.
 Prognosis & Predictive factors

 Excellent prognosis.

 Waxingand waning course. The disease

duration may vary from several months
to more than 40 years.

 10to 20% cases may progress to or may

have an associated malignancies such as
Hodgkin disease, mycosis fungoides, or
primary cutaneous anaplastic large cell
lymphoma.
 Prognosis & Predictive factors
No single criterion is available to predict
evolution to malignant lymphoma.

 Careful long-term follow-up is needed.

 Histologically, not possible to definitively diagnose malignant

transformation when the disease is confined to skin.
 Suggested features indicative of lymphoma are : a high ratio of
atypical cells to inflammatory cells, infiltration of atypical cells in
to subcutis and a change in the tumor cell immunophenotype with
further loss of T-Cell antigens. On the other hand, when the extra-
cutaneous dissemination occurs, the diagnosis of lymphoma is
straightforward.

 In the disease course, the following clinical features may

indicate transformation to lymphoma.
 A rapidly growing skin lesion that fails to regress spontaneously
 A lesion that becomes resistant to topical treatment such as PUVA
 A lesion that exceeds 3 cm in diameter.
 A CD30+ anaplastic large cell lymphoma with skin-only
involvement without systemic dissemination at presentation.
 Accounts for 9% of all cutaneous Lymphomas.
 No history of prior or concurrent MF or LyP
 Must be differentiated from Secondary
cutaneous involvement of Systemic Anaplastic
Large Cell Lymphoma which requires aggressive
chemotherapy.
 Primary C-ALCL does not have extracutaneous
manifestations at presentation. Patients with widespread
systemic and cutaneous disease at first presentation
should be considered to have the systemic form with skin
involvement.
 No t(2;5) translocation in pC-ALCL ( unlike CD30+ systemic
ALCL)
 No expression of the ALK protein and EMA ( Epithelial
Membrane Antigen) in primary cutaneous ALCL.
 Differential Diagnosis:
 Systemic ALCL involving skin
 Lymphomatoid papulosis
 Transformed MF
• Biopsy proven history of MF
• Infiltrate >25% large T-cells (>x4 small lymphocyte)
• In 1/3 cases majority of cells CD30+
• Usually correlates with tumour-stage lesions
• Very poor outcome: 5-year survival ~20%
 Benign lesions with CD30-positive cells
• Drug reaction (carbamazepine)
• Viral infection (molluscum, herpes simplex)
• Arthropod bite reactions (scabies)
 Diffuse non-
epidermotropic infiltrate
of large T-cells

 80% anaplastic morphology

• Round, oval, irregular
nuclei
• Prominent nucleoli
• Abundant cytoplasm
• R-S-like cells

 20% large T-cells

• Pleomorphic
• Immunoblastic

Note: ANAPLASTIC or LARGE CELL HAS NO

EFFECT ON OUTCOME
 Clinical Features
 Usually, arises as a solitary
reddish nodule, which may
became ulcerated.
 Multifocal lesions seen in about
20% of patients.
 Lesions may show partial or
complete spontaneous
regression
 Regional lymph nodes may
become involved in 10% of
patients
 PET/CT or CT w/contrast
should be performed to
exclude the possibility of
primary visceral/nodal disease
and to evaluate for nodal
extension.
 Prognosis is generally
favorable.
 TREATMENT
 Patients presenting with a solitary or
few localized nodules or tumors 
Radiotherapy or surgical excision is the
first choice of treatment.
 Patients presenting with multifocal
skin lesions  low-dose
methotrexate, (as in LyP).
 Patients presenting with or developing
extracutaneous disease or rare patients
with rapidly progressive skin disease 
doxorubicin-based multiagent
chemotherapy.
A) Diffuse dermal infiltrate of
large atypical cells admixed
with small lymphocytes.
B) The large atypical cells are
strongly positive for CD30.
(C-D) The histologic picture
in panels A and B can be
found both in C-ALCL and
in LyP.
The final diagnosis depends on
the clinical presentation.
C) In combination with the
solitary tumor of the patient
shown in panel C the
definite diagnosis will be C-
ALCL.
D) In combination with
recurrent, self-healing
papulonecrotic skin lesions
in D, the final diagnosis is
LyP.
Alpha-beta
 Very rare Primary Cutaneous T cell Lymphoma ( < 1% of
CTCL)
 Described in 1991 by Gonzalez et al and is currently
recognized as a distinct lymphoma in WHO classification
 Malignant alpha/beta+/CD8+, CD4- T cells preferentially
infiltrate the subcutaneous tissue.
 Two groups of SPTL distinguished with a different
histology, phenotype, and prognosis :
 SPTCL with α/ β T-cell phenotype
 usually CD8+, CD4-
 restricted to the subcutaneous tissue (no dermal and/or epidermal
involvement)
 indolent clinical Course.
 SPTCL with γ/δ T-cell phenotype
 CD8-, CD4- and CD56 +
 neoplastic infiltrates subcutaneous tissue, Epidermis and dermis.
 very poor prognosis.
 WHO-EORTC classification uses the term ―SPTL‖ only for
cases with an α/ β T-cell phenotype. Cases with a γ/δ T-
cell phenotype are seperately classified as cutaneous γ/δ
T-cell lymphomas.
 Clinical Features :
 Multiple subcutaneous nodules involving trunk and
extremities, rarely, the face.
 Constitutional symptoms : fever, fatigue, and weight loss
may be present.
 Pancytopenia : usually, due to cytokine mediated BM
suppression ( direct BM involvement is seen only in 8%
cases)
 Hemophagocytic syndrome : less common with SPTCL,
more commonly seen with ( in 1/3 cases) cutaneous γ/δ
T-cell lymphomas
 Extracutaneous dissemination is rare.

 Treatment : The clinical course is indolent and 5

year survival 80% for this α/ β, CD8+ T-cell
phenotype . Treatment modailities may include
Radiotherapy in localized disease and Systemic
corticosteroids. Doxorubicin based chemotherapy
can be used in extensive or recurrent disease.
 A variant of SPTL with clonal T-Cell receptor gamma-
delta chain gene rearrangements.
 Constitutes 25% of SPTL cases.
 As per WHO-EORTC classification, this is classified as an
entity distinct from SPTL.
 Prognosis extremely poor
 Clinical Features
 Multiple subcutaneous nodules with ulceration/necrosis, mostly on
the extremities..
 Pancytopenia
 1/3 cases may present with or complicated by Hemophagocytic
syndrome leading to rapid downhill course { histiocytes engulf
RBCs, white cells, platelets  infiltrate spleen (splenomegaly),
liver(hepatomegaly) and lead to jaundice, liver failure and
sometimes, death due to complications from cytopenias}
 Rx: Systemic chemotherapy , results disappointing –
resistant to multi-agents. Median survival 15 mos.
 T-cell neoplasm caused by a retrovirus infection
with human T-lymphotropic virus (HTLV I).
 Endemic in areas with a high prevalence of HTLV-1
eg: southwest Japan,the Caribbean islands, South
America, and parts of Central Africa.
 ATLL develops in 1% to 5% of seropositive
individuals after more than 2 decades of viral
persistence.
 Characterized large numbers of circulating
atypical cells.
 Skin lesions resemble MF and
histologically, indistinguishable from MF. The
neoplastic T cells express a CD3+, CD4+, CD8-
phenotype. CD25 is highly expressed
 Genetic features : Clonal TCR-Gene
rearrangements seen. Clonally integrated HTLV-1
genes found in all cases  helpful to differentiate
chronic ATLL from classic MF or SS.
 Can be divided into acute and chronic types.
 Acute ATLL :
 Skin lesions ( nodules, tumors, plaques or papules) similar to those
found in mycosis fungoides or Sézary syndrome
 Enlarged lymph glands
 Hypercalcemia
 Bone lesions.
 Numerous circulating atypical cells
 Prognosis is poor for this type with survival ranging from 2 weeks to
more than 1 year.

 Chronic ATLL
 skin lesions only ( closely resemble MF)
 Circulating atypical cells are few or absent
 Indolent clinical course and better survival, however this may
transform into an acute phase with an aggressive course.
 Rx: Skin targeted therapies similar to MF in chronic cases.
Acute ATLL requires systemic chemotherapy.
 More common in males. Seen in Asia, South
America and Central America.
 EBV associated Lymphoma.
 Multiple plaques and tumors on the trunk/
extremities and in the Nose/ Nasopharynx.
 Systemic symptoms such as fever and weight
loss. An associated hemophagocytic syndrome
may be seen
 The malignant cells are usually CD2 and CD56
positive (NK cell phenotype) - Epstein-Barr
virus (EBV) are commonly positive. Rarely, cells
may have a true cytotoxic T-cell phenotype.
 Very aggressive disease, Rx with Systemic
Chemotherapy, Median survival < 1yr .
 characterized by a proliferation of
epidermotropic CD8 cytotoxic T-cells and an
aggressive clinical behavior.
 presents with eruptive papules, nodules, and
tumors with central ulceration. Visceral
involvement (CNS, Lung, Testes ) can be seen
but LN are usually spared.
 Rx: anthracycline-based systemic
chemotherapy
 Median survival : 32 months
 Heterogeneous group which includes all T-cell
neoplasms that do not fit into any of the better
defined subtypes of T-cell lymphoma/leukemia.
 Out of this group, primary cutaneous aggressive
epidermotropic CD8 cytotoxic T-cell
lymphoma, cutaneous gamma-delta T-cell
lymphoma, and primary cutaneous smallmedium
CD4 T-cell lymphoma can be separated out as
provisional entities.
 Remaining diseases that do not fit into either of
these provisional entities must be the designated
as PTL, unspecified.
 In all these cases a diagnosis of MF must be ruled
out by complete clinical examination and an
accurate clinical history.
•CLASSIFICATION
•CLINICAL
FEATURES
•TREATMENT
 Primary
cutaneous marginal zone B-cell
lymphoma

 Primary
cutaneous follicle center
lymphoma

 Primary
cutaneous diffuse large B-cell
lymphoma, leg type

 Primary
cutaneous diffuse large B-cell
lymphoma, other

 Intravascular large B-cell lymphoma

PCMZL
 An indolent lymphoma composed of small B
cells, including marginal zone (centrocyte-like)
cells, lymphoplasmacytoid cells, and plasma
cells.
 Considered as a part of group of extranodal
marginal zone B-cell lymphomas commonly
involving mucosal sites, called MALT (mucosa-
associated lymphoid tissue) lymphomas.
 Variants include primary cutaneous
immunocytoma and primary cutaneous
plasmacytoma.
 Accounts for 10% of all cutaneous lymphomas.
 In some cases of PCMZL in Europe , an
association with Borrelia burgdorferi infection
has been reported in but not in Asian cases or
cases from the United States.
 Clinical Features:
 Red to violaceous papules, plaques or nodules on trunk or
extremities.
 Usually, multifocal lesions.
 In some cases, spontaneous resolution of lesions may occur.
 Anetoderma ( flaccid or herniated-sac like skin due to loss of
dermal elastic tissue) may develop at the site of
spontaneous resolution.
 Histopathology :
 Nodular or diffuse skin infiltrates of small lymphocytes,
marginal zone B cells (centrocyte-like cells), and plasma
cells with sparing of epidermis.
 Immunophenotyping reveals marginal zone B cells expressing
CD20, CD79a, and bcl-2, but are negative for CD5, CD10, and
bcl-6 (distinction from PCFCL)
 Characteristic
clinical
presentation with
multiple nodules
and small tumors
on the back and
arms
 Solitary or a few lesions
 Treat with radiotherapy or surgical excision.
 Patients with associated B.burgdorferi infection
 Systemic antibiotics - Doxycycline at 100 mg twice daily for 3
weeks or pulse therapy with cefotaxime
 Multifocal skin lesions
 Chlorambucil or
 Intralesional or subcutaneous administration of interferon
alpha  CR 50%
 Intralesional or systemic anti-CD20 antibody (Rituximab)
 Frequent skin relapses – options
 topical or intralesional steroids or
 Observation alone ( as in other indolent B-cell lymphomas)
 Prognosis : Excellent, 5 yr survival 100%
PCFCL
 A tumor of neoplastic follicle center cells, usually
a mixture of centrocytes (small and large cleaved
follicle center cells) and variable numbers of
centroblasts (large noncleaved follicle center cells
with prominent nucleoli)
 Variants ( according to growth pattern) :
follicular, follicular and diffuse, diffuse variants.
 Immunophenotype: Neoplastic B cells express
CD20, CD79a and bcl-6. bcl-2 protein not
expressed by PCFCL( unlike nodal or secondary
cutaneous follicular lymphomas). Does not have
t(14.18) unlike systemic follicular lymphoma.
 C/F : Solitary nodules or grouped plaques/ tumors
- found most frequently in the head and neck
area. Multifocal lesions are rare
 Prognosis : Excellent, 5yr Survival > 90%
(A) Typical presentation with tumors
on the chest surrounded by less
infiltrated erythematous skin
lesions.

(B) Presentation with multiple

tumors confined to the scalp.

(C) Diffuse dermal infiltrate mainly

consisting of large centrocytes
and multilobated cells

(D) Serial sections stained for CD20

(D) and bcl-2 (E). Bcl-2 is
expressed by perivascular T
cells, but not by the neoplastic
B cells.).
 Localized or few scattered skin lesions 
radiotherapy is the preferred mode of treatment
( even in cases with a predominance of large
―cleaved‖ cells).

 Cutaneous relapses can be seen in 20% cases and

does not indicate progressive disease. Rx with
Radiotherapy.

 Extensive cutaneous disease and extracutaneous

disease  Anthracycline-based chemotherapy .

 Systemic or intralesional Rituximab  benefits in

some studies. Need more data.
PLBCL-Leg
A tumor with predominance or confluent
sheets of centroblasts and immunoblasts
( mostly large B-cells. Small cells are lacking).
 Characteristically, appears on the lower legs.
Can occur on other parts of the body.
 Most commonly affects Elderly Women.
 Neoplastic B-cells express CD-20 and CD79a.
Also, show strong bcl-2 expression and
express MUM-1/IRF4 protein ( unlike PCFCL).
t(14,18) is absent.
 Red or bluish-red appear on the lower legs and
frequently grow into large tumors that extend deep
into the fat.
 Unlike cutaneous follicle center lymphoma, LBCL-L
tumors develop quickly over weeks and months, usually
becoming open sores and spreading outside the skin (
extracutaneous dissemination).
 Prognosis is worse than PCFCL. 5-year survival 55%.
 PCLBCLs on the leg have an inferior prognosis
compared to PCLBCLs presenting at other sites.
 The presence of multiple skin lesions at diagnosis is a
significant adverse risk factor. In a recent study, patients
presenting with a single skin tumor on one leg had 5-year
survival of 100%, whereas patients presenting with
multiple skin lesions on one or both legs had a disease-
related 5-year survival of 45% and 36%, respectively
A. Clinical presentation
with multiple tumors
on right lower leg.
B. Monotonous
proliferation of
centroblasts and
immunoblasts
C. Characteristically,
the neoplastic B
cells strongly
express bcl-2 (C)
and Mum-1/IRF-4
(D).
 Treated as systemic diffuse large B-cell
lymphomas with anthracycline-based
chemotherapy.
 In patients presenting with a single small skin
tumor  radiotherapy may sometimes be
considered.
 Systemic administration of anti-CD20 antibody
(rituximab) has proved effective in some
patients, but long-term follow-up data are not
available and the place of rituximab in the
treatment of PCLBCL, either as single agent
therapy or in combination with systemic
chemotherapy remains to be established
PLBCL-Other
 ―PCLBCL-Other‖ refers to cases of large B-cell lymphoma
arising in the skin which do not belong to the groups of
PCFCL and PCLBCL, leg type.

 They include morphologic variants of diffuse large B-cell

lymphomas
 anaplastic BCL
 plasmablastic lymphoma
 T-cell/histiocyte rich large B-cell lymphomas.

 The lymphomas usually appear on the head, trunk or

extremities. Most often these are cutaneous
manifestations of systemic lymphomas and have to be
treated the same way.

 The prognosis is excellent unlike their nodal counterparts.

 Plasmablastic lymphomas are seen almost exclusively in

the setting of HIV infection or other immune deficiencies.
 Well-defined subtype of large B-cell lymphoma.

 Defined by an accumulation of large neoplastic B cells within blood

vessels. Usually, affects the central nervous system, lungs, and skin .

 Histologically, dilated blood vessels in the dermis and subcutis are filled
and extended by a proliferation of large neoplastic B cells.

 Prognosis : poor. Patients often have widely disseminated disease, but

cases with only skin involvement may occur. 3 yr Survival 56% vs. 22%
for skin only vs. disseminated disease.

 CF: Presents as violaceous patches and plaques or teleangiectatic skin

lesions usually on the (lower) legs or the trunk.

 Rx : Multiagent chemotherapy, both for disseminated and skin-limited

disease.
•CLASSIFICATION
 Groupof conditions that simulate a
lymphoma , but behave in a harmless
manner.

 Usually,
a reactive process, though a number
of these can be difficult to distinguish from a
lymphoma

 T-cell and B-Cell Pseudolymphomas.

Clinicopathologic condition Simulated malignant lymphoma
•Actinic Reticuloid •Mycosis Fungoides/ Sezary Syndrome
•Lymphomatoid contact dermatitis
•Lymphomatoid drug reaction, T cell type
•Solitary T-cell pseudolymphoma (‘unilesional mycosis
fungoides’)
•Lichenoid (‘lymphomatoid’) keratosis
•Lichenoid pigmented purpuric dermatitis
•Lichen sclerosus
•Atypical lymphoid infiltrates (CD30+) associated •Lymphomatoid papulosis / Anaplastic large cell
with:Orf– Milkers nodule lymphoma – CD30+
•Herpes simplex &
•Molluscum contagiosum
•Arthropod (insect) reactions (including nodular scabies)

•Lupus panniculitis •Subcutaneous T-cell lymphoma

Lymphocytoma cutis •B cell lymphomas Follicle center lymphoma
•Marginal zone B-cell lymphoma
•Large B-cell lymphoma

•Lymphomatoid drug reaction, B cell type •Follicle center lymphoma

•Pseudolymphoma after vaccination •Marginal zone B-cell lymphoma
•Pseudolymphoma in tattoos
•Pseudolymphoma caused by Hirudo medicinalis therapy

•Morphoea, inflammatory stage

•Syphilis (secondary) • Marginal zone B-cell lymphoma
•Jessner's lymphocytic infiltrate •Chronic lymphocytic leukaemia, B cell type

•Inflammatory pseudotumour •Plasmacytoma

•Marginal zone B-cell lymphoma
Definition
1. Lymphoid infiltrate highly suggestive of
CTCL

2. Clinical features NOT consistent with

CTCL
• Identification of causative agent
• Uncommon presentation or course
1. Well defined clinicopathological entities :

• Drug induced
 Anticonvulsants; phenytoin, carbamazepine
 ACE inhibitors
 Miscellaneous; atenolol, allopurinol, mexilitine,
cyclosporine, antihistamines, griseofulvin

• Insect bite reactions

• Lymphomatoid contact dermatitis
• Actinic reticuloid;
 chronic photosensitive dermatitis
 Scaly erythema of exposed skin

 2. Idiopathic

Clinical course/ HISTOLOGY/ IMMUNOPHENOTYPING/ MOLECULAR

ANALYSIS to be used in differentiating them from true CTCL
TWO PATTERNS:
1. Band-like infiltrate (MF-like)
• Subepidermal infiltrate
• Atypical medium sized cerebriform cells +/- blasts, histiocytes
• Few/no eosinophils, plasma cells
Seen in all types of CTCPL except insect bite reactions.

2. Nodular pattern
• Many small round T-cells
• Scattered T-blasts & medium/large cerebriform cells
• Histiocytes usually numerous +/- plasma cells, eosinophils
Seen in
• Drug induced CTCPL
• Persistent arthropod bite reactions
• Idiopathic CTCPL
 Features which strongly suggest MF
1. Pautrier‘s microabscesses
2. Medium/large cerebriform cells in epidermis
3. Linear epidermotropism
4. Disproportionate epidermotropism
5. ‗Haloed‘ lymphocytes in epidermis
 ACTINIC RETICULOID vs MYCOSIS FUNGOIDES
• CD8+ T-cells, MF usually CD4+
• Multinucleate giant cells – fibroblasts,
histiocytes
• Vertically orientated collagen in papillary
dermis
ABERRANT PHENOTYPE
 1.Loss of pan-T-cell antigens
CD2, CD3, CD5, CD7
BUT also lost in some benign conditions (esp CD7)

 2. Ratio of CD4:CD8
 vast excess
 dual expression
 no expression

MONOCLONAL TCR RE-ARRANGEMENT

 BUT monoclonality found in typically benign
lesions also e.g. lichen planus, pityriasis lichenoides, LSA
 thus monoclonal but benign infiltrates may arise in
the skin
Additional Useful Notes
 Neoplastic cells show clonal TCR GENE
REARRANGEMENTS.
 Clonal TCR rearrangements ( dominant T-CELL
Clone) does not always indicate malignancy 
Several benign lymphocyte-mediated dermatoses
exist, including lymphomatoid papulosis, Mucha-
Habermann disease, lymphomatoid drug
eruptions, actinic reticuloid, and lichen planus,
all of which demonstrate a dominant T-cell
clone in some cases.
 Detection of Clonal alpha-beta vs. gamma-delta
TCR gene rearrangments is of prognostic
significance in SPTL. Gamma-delta carries very
poor prognosis.
CD Type Representative Also Known As
Cells
CD2 T, NK Sheep RBC
CD3 T

CD4 T subset Helper

CD5 T

CD7 T, NK Prothymocyte
CD 8 T subset, NK Suppressor
CD25 Active T, B, M IL-2R (Tac)
CD30 Active T, B Ki-1
CD45 T subset CLA
CD56 NK NCAM
CD20-B-cell
marker
Cd138 and
CD79a– plasma
cell markers 9
usually CD20 –
VE)
 Immunophenotyping in anaplastic large cell lymphoma (ALCL) exhibits consistently strong
CD30 expression in all clinical and pathologic subtypes – Most tumor cells are T Cell
Phenotype ( frequent CD3 expression, clonal T-cell receptor gene rearrangements and lack
of B-cell – associated markers) or null cell phenotype. In ALCL, B-cell antigenic expression is
rare and is commonly observed in the HIV-related clinical form. In fact, these B-cell cases
of ALCL are classified separately in the World Health Organization classification under
diffuse, large, B-cell lymphoma
 Primary systemic anaplastic large cell lymphoma (ALCL) is typically in an advanced stage at
patient presentation, and the disease is rapidly progressive. These patients demonstrate an
increased frequency of bone marrow involvement (30%) and extranodal involvement,
including skin (21%), bone (17%), soft tissues (17%), lung (11%), liver (8%), and, rarely, the
gastrointestinal tract and central nervous system. Systemic symptoms are observed in 75%
of patients, with fever the most common symptom. The primary systemic form, unlike the
primary cutaneous form, generally stains positive for EMA and usually displays the t(2;5)
translocation and the chimeric p80 protein ( NPM-ALK fusion protein – NPM on
chromosome 5 joined with ALK on chromosome 2) with PCR and antibody studies.
 Primary cutaneous anaplastic large cell lymphoma (ALCL) usually manifests as a single or
localized cluster of erythematous skin nodules, some of which may demonstrate superficial
ulcerations. As many as 25% of patients have some degree of spontaneous regression of
these lesions. Although most cases present with local involvement, patients may rarely
present with disseminated cutaneous disease and are at higher risk of developing spread to
other organs.
 Most cases of HIV-related anaplastic large cell lymphoma
(ALCL) are actually of B-cell origin and seem instead to be
related to the anaplastic variant of diffuse large B-cell
lymphoma. Many patients demonstrate infection with
the Epstein-Barr virus, which is absent in those with the T-cell or
null-cell types of anaplastic large cell lymphoma (ALCL).
 Secondary anaplastic large cell lymphoma (ALCL) evolves from
other lymphomas, most frequently from peripheral T-cell
lymphomas, mycosis fungoides, Hodgkin disease, or
lymphomatoid papulosis. This form of anaplastic large cell
lymphoma (ALCL) tends to arise in older adults, is commonly ALK
negative (chr 2, 5 translocation), and carries a poor prognosis.
 Patients with anaplastic large cell lymphoma (ALCL) present with
either a primary cutaneous form or a systemic form of the illness.
Patients may present with isolated lymphadenopathy or with
extranodal disease at any site, including the gastrointestinal
tract and bone. Patients with infiltration into musculoskeletal
tissues (eg, psoas muscle) can present with backache.