Cutaneous Lymphomas - Usmlestep3blog.com

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Target Audience Oncology Fellows, Oncology
physicians, Oncologists Archer Board Review
Courses www.Ccsworkshop.com
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• 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.

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• After the gastrointestinal tract, the skin is the
  second most common site of extranodal non-Hodgkin
  lymphoma.
• Estimated annual incidence 1100,000.
• 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.

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CLASSIFICATION CLINICAL FEATURES TREATMENT
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WHO-EORTC Classification Frequency, 5-Year Survival Rate,
Indolent Clinical Behavior Indolent Clinical Behavior Indolent Clinical Behavior
Myco
MF v MF v MF v
Fo
Pa
Gr
Prima Prima Prima
Pri
Lymp
Subcu
Prima
Aggressive Clinical Behavior Aggressive Clinical Behavior Aggressive Clinical Behavior
Séza
Adul
Extra
Prima
Prima
Cuta
Precursor Hematologic Neoplasm (not a T-cell lymphoma) Precursor Hematologic Neoplasm (not a T-cell lymphoma) Precursor Hematologic Neoplasm (not a T-cell lymphoma)
CD4
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• 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?lt1000/year US
• Peak age 55-60
• Male female 21
• More common in African-Americans

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• 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

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Patch Plaque
Erythroderma
Tumor
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This Sezary cell is the malignant pleomorphic T
cellseen in mycosis fungoides and has a
convoluted nucleus
Circulating Sezary Cell
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• 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.

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• 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
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INVESTIGATION PATHOLOGY
SKIN BIOPSY -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
LYMPH NODE BIOPSY 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)
IMMUNOPHENOTYPING 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
MOLECULAR ANALYSIS (Southern Blot analysis or PCR amplification method) TCR gene rearrangements ( to demonstrate clonality ? neoplastic T cells exhibit clonal TCR gene rearrangements)
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Skin biopsy from a patient with mycosis
fungoides, showing a large cluster of atypical
lymphocytes in the epidermis (Pautrier
microabscess, arrow).
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• 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

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Clinical
Basic 1. Persistent
Additional
1. Non-sun
2. Size/sh
3. Poikilo
Histopathol
BASIC 1. Superfi
Additional
1. Epidermo
2. Lympho
Molecular Molecular
1. Clonal
Immunop Immunop
1. lt50 pe
2. lt10 percent CD7 T cells
3. Epidermal/dermal discordance of CD2, CD3, CD5, or CD7
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• 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.

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T1 T2 T3 T4
N0 N1 N2 N3
M0 M1 B0 B1 B2
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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
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1-4 represent T1 to T4. Mycosis fungoides and
Sézary Syndrome. Semin Oncol 1999 26276. figure
1, page 279.
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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 26276. figure 2, page 280.
.
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• Good-Risk

• Patch/Plaque only
• Survival gt12 years
• Intermediate-risk
• Tumors/erythroderma
• Plaque node/blood
• Survival 5 years
• Poor-risk
• Visceral involvement
• Survival 2.5 years

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MYCOSIS FUNGOIDES
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• 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)

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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
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• 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

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• Nitrogen Mustard (HN2) or Carmustine

• (BCNU)
• Overall Response Rates 70-90 in Stage I disease
• Adverse effects contact
• dermatitis, erythema, telangiectasias

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• CTCL is very radiosensitive
• Use of Electron Beam Therapy limits toxicity, lt5
  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

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• Reserved for Sezary Syndrome (Stage
• IVA1) and Stage IIIB disease
• Technique
• Patient ingests 8-MOP.
• Leukapheresis, mononuclear fraction of patients
  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 pts with mainly SS

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• 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

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• 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

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• 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

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• 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

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• 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

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Hoppe RT, Kim YH,Clinical features, staging, and
prognosis of mycosis fungoides and Sezary
syndrome, Uptodate.com, 11/06
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• Likely represents 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 gt1000/microL with positive clones

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• 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

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• Treatment includes Extracorporeal Photopheresis (
  ECP) alone or in combination with other therapies
  ( IFNS) ?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

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Variant/s Folliculo
Pagetoid
Granuloma
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• 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.

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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.
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A chronic, recurrent, self-healing papulonecrotic
or papulonodular skin disease with histologic
features suggestive of a (CD30) malignant
lymphoma.
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• 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.

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• 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.

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• These difficulties 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.

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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.

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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 (lt2 cm)
• Spontaneously resolve in 4-6 weeks, leaving
• hyperpigmentation or atrophic scars.
• Unless accompanied by systemic lymphoma, most
  patients have no constitutional symptoms

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Clinical Features
?No single 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 gt 3cm in
• diameter.
• Persistence without a spontaneous regression.
• Presence of significant lymphadenopathy. The
  involved lymphnode must be biopsied to rule out
  lymphoma.

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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.

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Prognosis Predictive factors
?Excellent prognosis. ?Waxing and waning course.
The disease duration may vary from several months
to more than 40 years. ?10 to 20 cases may
progress to or may have an associated
malignancies such as Hodgkin disease, mycosis
fungoides, or primary cutaneous anaplastic large
cell lymphoma.
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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.

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A CD30 anaplastic large cell lymphoma with
skin-only involvement without systemic
dissemination at presentation.
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• 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(25) translocation in pC-ALCL ( unlike CD30
  systemic ALCL)
• No expression of the ALK protein and EMA (
  Epithelial Membrane Antigen) in primary cutaneous
  ALCL.

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• Differential Diagnosis

• Systemic ALCL involving skin
• Lymphomatoid papulosis
• Transformed MF
• Biopsy proven history of MF
• Infiltrate gt25 large T-cells (gtx4 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)

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• 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

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• 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.

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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.
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• Diffuse dermal infiltrate of large atypical cells
  admixed with small lymphocytes.
• 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.
• In combination with the solitary tumor of the
  patient shown in panel C the definite diagnosis
  will be C- ALCL.
• In combination with recurrent, self-healing
  papulonecrotic skin lesions in D, the final
  diagnosis is LyP.

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Alpha-beta
62

• Very rare Primary Cutaneous T cell Lymphoma ( lt
  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 S/ s T-cell phenotype
• usually CD8, CD4-
• restricted to the subcutaneous tissue (no dermal
  and/or epidermal
• involvement)
• indolent clinical Course.
• SPTCL with Š/š 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 S/ s T-cell phenotype.
  Cases with a Š/š T- cell phenotype are seperately
  classified as cutaneous Š/š T-cell lymphomas.

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• 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
  Š/š T-cell lymphomas
• Extracutaneous dissemination is rare.
• Treatment The clinical course is indolent and 5
  year survival 80 for this S/ s, 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.

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65

• 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.

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67

• 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.

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• 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.

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70

• 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 lt 1yr .

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• 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

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• 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.

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CLASSIFICATION CLINICAL FEATURES TREATMENT
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• 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

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PCMZL
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• 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.

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• 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)

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• Characteristic clinical presentation with
  multiple nodules and small tumors on the back and
  arms

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• 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

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PCFCL
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• 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 gt 90

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• Typical presentation with tumors on the chest
  surrounded by less infiltrated erythematous skin
  lesions.
• Presentation with multiple tumors confined to the
  scalp.
• Diffuse dermal infiltrate mainly consisting of
  large centrocytes and multilobated cells
• 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.).

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• 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.

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PLBCL-Leg
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• 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.

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• 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

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1. Clinical presentation with multiple tumors on
   right lower leg.
2. Monotonous proliferation of centroblasts and
   immunoblasts
3. Characteristically, th e neoplastic B cells
   strongly express bcl- 2 (C) and Mum- 1/IRF-4 (D).

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• 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

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PLBCL-Other
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• ?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.

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• 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.

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CLASSIFICATION
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• Group of 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.

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Clinicopathologic condition Simulated malignant lymphoma
Actinic Reticuloid 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 Mycosis Fungoides/ Sezary Syndrome
Atypical lymphoid infiltrates (CD30) associated withOrf Milkers nodule Herpes simplex Molluscum contagiosum Arthropod (insect) reactions (including nodular scabies) Lymphomatoid papulosis / Anaplastic large cell lymphoma CD30
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 Pseudolymphoma after vaccination Pseudolymphoma in tattoos Pseudolymphoma caused by Hirudo medicinalis therapy Follicle center lymphoma Marginal zone B-cell lymphoma
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
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• Definition
• Lymphoid infiltrate highly suggestive of CTCL
• Clinical features NOT consistent with CTCL
• Identification of causative agent
• Uncommon presentation or course

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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

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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.
• 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