Cutaneous Lymphoma: Epidemiology, Diagnosis and Staging Amit G. Pandya, MD Professor Department of Dermatology University of Texas Southwestern Medical Center Dallas, Texas
The UTSW Clinic for Cutaneous Lymphoproliferative Disorders •
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Clinic Physicians: – Amit G. Pandya, MD – Dermatopathology Fellow – Dermatology Resident Supporting Physicians: – Cockerell and Associates – Madeleine Duvic, MD – Hematology/Oncology – Radiation Oncology Support Group Leaders: – LeDawn Feris – Billy Williams Nursing Support – Jennifer Cichy, RN
Epidemiology of CTCL •
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Annual incidence is 6.4 cases/ million and increases every decade Incidence in Blacks 1.5 times higher than Whites and has poorer prognosis Incidence in Asians and Hispanics 0.6 that of Whites Male: Female ratio is 2:1 Peak age at presentation- 55-60 yrs
Criscione VD, Weinstock MA, Arch Dermatol 2007; 143:854-859
WHO-EORTC Classification of Cutaneous Lymphomas •
Cutaneous T-cell and NK cell lymphomas – Mycosis fungoides – MF variants and subtypes • Folliculotropic MF • Pagetoid reticulosis • Granulomatous slack skin – Sezary syndrome – Adult T-cell leukemia/lymphoma – Primary cutaneous CD30+ lymphoproliferative disorders • Primary cutaneous anaplastic large cell lymphoma • Lymphomatoid papulosis Willemze R, et al, Blood 2005; 105:3768-3785
– Subcutaneous panniculitis-like T-cell lymphoma – Extranodal NK/T-cell lymphoma, nasal type – Primary cutaneous peripheral T-cell lymphoma, unspecified • Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma • Cutaneous gamma/delta Tcell lymphoma • Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma
WHO-EORTC Classification of Cutaneous Lymphomas • Cutaneous B-cell lymphomas – 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 • Precursor hematologic neoplasm – CD4+/CD56+ hematodermic neoplasm (blastic NK-cell lymphoma
Willemze R, et al, Blood 2005; 105:3768-3785
Diagnosis of Cutaneous T-Cell Lymphoma • • • • •
MF is the most common form of CTCL Main difficulty in diagnosis is that early disease is nonspecific There is a close resemblance to eczematous dermatitis Several biopsies may be needed to establish diagnosis Average time from onset of lesions to definitive diagnosis is 4 to 10 years
Latkowski et al. Cutaneous T cell lymphomas. In: Freedberg et al, eds. Fitzpatrick’s Dermatology in General Medicine. 6th ed. Vol 2. New York: McGraw-Hill; 2003:1537–1558.
Diagnosing Early MF •
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New algorithm developed by the International Society for Cutaneous Lymphoma Relies on both clinical and histologic criteria Emphasis on basic findings
Pimpinelli et al, JAAD 2005; 53:1053-1063
Cutaneous T Cell Lymphoma- Staging Workup •
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Complete physical examination including – Determination of types of skin lesions – If only patch/plaque disease or erythroderma, estimate percentage of body surface area involved and note any ulceration of lesions – If tumors present, determine total number of lesions, aggregate volume, largest size lesion, and regions involved – Identification of any palpable lymph node, especially those > 1.5 cm in diameter or firm, irregular, clustered, or fixed – Identification of any organomegaly Skin biopsy – Most indurated area if only one biopsy – Immunophenotyping to include at least the following markers: CD2, CD3, CD4, CD5, CD7, CD8, and a B-cell marker such as CD20. CD30 may also be indicated in cases where lymphomatoid papulosis, anaplastic lymphoma, or large-cell transformation is considered – Evaluation for clonality of TCR gene rearrangement
Olsen E, et al, Blood 2007; 110:1713-1722
Cutaneous T Cell Lymphoma- Staging Workup •
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Blood tests – CBC with manual differential, liver function tests, LDH, comprehensive chemistries – TCR gene rearrangement and relatedness to any clone in skin – Analysis for abnormal lymphocytes by either Sézary cell count with determination absolute number of Sézary cells and/or flow cytometry (including CD4+/CD7- or CD4+/CD26-) Radiologic tests – In patients with T1N0B0 stage disease who are otherwise healthy and without complaints directed to a specific organ system, and in selected patients with T2N0B0 disease with limited skin involvement, radiologic studies may be limited to a chest X-ray or ultrasound of the peripheral nodal groups to corroborate absence of adenopathy – In all patients with other than presumed stage IA disease, or selected patients with limited T2 disease and the absence of adenopathy or blood involvement, CT scans of chest, abdomen, and pelvis alone +/- FDG-PET scan are recommended to further evaluate any potential lymphadenopathy, visceral involvement, or abnormal laboratory tests. In patients unable to safely undergo CT scans, MRI may be substituted. Olsen E, et al, Blood 2007; 110:1713-1722
Cutaneous T Cell Lymphoma- Staging Workup •
Lymph node biopsy – Excisional biopsy is indicated in those patients with a node that is either > 1.5 cm in diameter and/or is firm, irregular, clustered, or fixed – Site of biopsy: Preference is given to the largest lymph node draining an involved area of the skin or if FDG-PET scan data are available, the node with highest standardized uptake value (SUV). – If there is no additional imaging information and multiple nodes are enlarged and otherwise equal in size or consistency, the order of preference is cervical, axillary, and inguinal areas. – Analysis: pathologic assessment by light microscopy, flow cytometry, and TCR gene rearrangement.
Olsen E, et al, Blood 2007; 110:1713-1722
CTCL- Clinical Presentations • • • • • • • •
Erythematous patches Scaly plaques Often confined to boxer short distribution Nodules Tumors Ulcers Bullae Poikiloderma
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Alopecia Follicular prominence Hyperpigmentation Hypopigmentation Erythroderma Subcutaneous nodules Slack skin Palmoplantar keratoderma
CTCL- Histopathology •
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Early CTCL may resemble other dermatoses both clinically and histopathologically Often difficult to diagnose, particularly in early disease Histopathology: Pautrier’s microabscesses, epidermotropism, atypical mononuclear cells, dense upper dermal band-like or superficial perivascular infiltrate, minimal spongiosis A panel of 7 dermatopathologists did not agree in over 50% of specimens reviewed Up to 30% of readings were different when the same dermatopathologist was given the same specimen twice Olerud JE et al, Arch Dermatol 1992; 128:501
CTCL- Histopathology • •
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Oncologists- histologic diagnosis is the final diagnosis Primary cutaneous lymphomas may not be classified on the basis of histologic criteria alone. Different types of CTCL with a different clinical behavior and different therapeutic requirements may have an identical histologic appearance The histologic diagnosis is not the final diagnosis, and cannot be used as a therapeutic guideline
Willemze R, Ann Oncol (Suppl. 1): S11-S15, 2000
Cutaneous T Cell Lymphoma- T Stage at Initial Presentation T stage
T1: Limited plaques, papules, or patches involving less than 10% body surface area
42%
T2: Generalized plaques, papules, or patches involving 10% or greater body surface area
30%
T3: Cutaneous tumor (one or more)
16%
T4: Erythroderma (generalized)
12%
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72%
CTCL- Overall Survival • • • • • •
Limited Patch/ Plaque >12 yrs Cutaneous tumors 3.2 years Erythroderma 4.6 yrs Sezary syndrome 2.5 yrs Very few patients with limited plaque disease actually die of CTCL One fifth of patients with generalized plaque disease die of CTCL, often due to development of tumors and visceral disease
Kim Y et al, Arch Dermatol 1996; 132:1309
Cutaneous T Cell Lymphoma Staging • Lymph Node Class (biopsy) – LN1: Reactive node – LN2: Dermatopathic node, small clusters of convoluted cells – LN3: Dermatopathic node, large clusters of convoluted cells – LN4: Effacement of normal architecture by convoluted cells
Stage Ia CTCL- A Long-term Outcome Analysis • • • •
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32.5 year retrospective analysis of 122 patients Survival similar to that of a race, age, and sex-matched control population Median survival has not been reached after 32.5 years 9% progressed to more advanced disease (ave age 61 yrs vs 48 yrs for those who did not) Only 3 patients (2%) died of disease TSEB produced a higher freedom-fromrelapse outcome than nitrogen mustard, but the long-term survival was the same The authors recommend nitrogen mustard for stage Ia CTCL
Kim Y et al, Arch Dermatol 1996; 132:1309
Kim Y et al, Arch Dermatol 1996; 132:1309
Generalized Patch or Plaque CTCL (Stage T2) • • • • •
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35.5 year retrospective analysis of 176 patients 24% had disease progression to more advanced stages 20% died of disease Presence of lymphadenopathy (stage IIa) did not affect long-term survival TSEB gave a higher freedom-fromrelapse outcome compared to topical nitrogen mustard, but overall survival was the same Median survival was 11.7 years Long-term survival of patients with lymphadenopathy (stage IIa) was not different from those without adenopathy (stage Ib) Kim Y et al, Arch Dermatol 1999; 135:26
Kim Y et al, Arch Dermatol 1999; 135:26
Kim Y et al, Arch Dermatol 1999; 135:26
Cutaneous T Cell Lymphoma Staging • • • • •
Stage IIA T1, T2 (limited or generalized plaques) Ad+ (palpable adenopathy) LN1, LN2 (reactive or minimally dermatopathic node) V- (no visceral involvement)
Cutaneous T Cell Lymphoma Staging • • • • •
Stage IIB T3 (cutaneous tumors) Ad+/- (presence or absence of lymphadenopathy) LN1, LN2 (reactive or minimally dermatopathic node) V- (no visceral involvement)
Cutaneous T Cell Lymphoma Staging • • • • •
Stage III T4 (erythroderma) Ad+/- (presence or absence of lymphadenopathy) LN1, LN2 (reactive or minimally dermatopathic node) V- (no visceral involvement)
Cutaneous T Cell Lymphoma Staging •
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Stage IVA – T1-T4 (any cutaneous manifestation) – Ad+/- (presence or absence of lymphadenopathy) – LN3, LN4 (large clusters of tumor cells or effacement) – V- (no visceral involvement) Stage IVB – T1-T4 (any cutaneous manifestation) – Ad+/- (presence or absence of lymphadenopathy) – LN1-LN4 (any lymph node class) – V+ (visceral involvement)
Sezary Syndrome • Erythroderma, lymphadenopathy, pruritus • Review of 100 lymphocytes on a smear (Sezary prep) reveals 520% Sezary cells with cerebriform nuclei • > 1000 cells/m2 on flow cytometry, which detects an expansion of the CD4+, CD7-, CD26- population • Poor prognosis • Average survival after diagnosis is 30 months Risk group Sezary count (mm3) CD4/CD8 Ad Low 20 +
Sezary Syndrome
UT Southwestern CTCL Clinic: Summary of Patients (2007) Stage No. of Patients Ia 50 Ib 70 IIa 28 IIb 8 III 7 IV 6 Sezary 14 B cell lymphoma 10 Pseudolymphoma 10 Total 203
% 25 34 14 4 3 3 7 5 5
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73%
CTCL Clinic Observations •
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Careful review of the clinical and histologic presentation often “rules out” CTCL in referred patients Diagnoses in patients who were thought to have CTCL: – Drug eruption – Atopic dermatitis – Lichen planus – Lupus erythematosus – Cutaneous lymphoid hyperplasia (pseudolymphoma) – Pigmented purpuric dermatosis – Tinea versicolor
Summary • Cutaneous lymphomas are uncommon • Diagnosis is based on physical exam findings and microscopic observations seen on skin biopsies • Staging of cutaneous lymphomas is important to determine the prognosis and to select appropriate treatment
