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A Practical Approach to Accurate Classification and Staging of Mycosis Fungoides and Szary Syndrome
Bjorn Rhys Thomas, MBBS, Sean Whittaker, MB, MD, FRCP Skin Therapy Letter. 2012;17(10)

Abstract and Introduction

Abstract

Cutaneous T-cell lymphomas are rare, distinct forms of non-Hodgkin's lymphomas. Of which, mycosis fungoides (MF) and Szary syndrome (SS) are two of the most common forms. Careful, clear classification and staging of these lymphomas allow dermatologists to commence appropriate therapy and allow correct prognostic stratification for those patients affected. Of note, patients with more advanced disease will require multi-disciplinary input in determining specialist therapy. Literature has been summarized into an outline for classification/staging of MF and SS with the aim to provide clinical dermatologists with a concise review.
Introduction

Primary cutaneous lymphomas (PCL) are rare forms (2%) of non-Hodgkin's lymphomas with an annual incidence of 0.31 per 100,000.[1] These lymphomas include both primary cutaneous T-cell (75%) and B-cell lymphomas defined by presentation at the time of diagnosis without any extracutaneous sites of disease.1 In 2005, the two classification systems for cutaneous T-cell lymphoma (CTCL), namely the World Health Organization (WHO) and European Organization for Research and Treatment of Cancer (EORTC), were combined, providing distinct subtypes based on clinico-pathologic criteria ().[1,2]
Table 1. WHO-EORTC classification of cutaneous lymphoma with primary cutaneous manifestations1

Classification Cutaneous T-cell and NK-cell lymphomas Mycosis fungoides Folliculotropic MF MF variants and subtypes Pagetoid reticulosis Granulomatous slack skin Szary syndrome Adult T-cell leukemia/lymphoma Primary cutaneous anaplastic large cell lymphoma Lymphomatoid papulosis Subcutaneous panniculitis-like T-cell lymphoma Extranodal NK/T-cell lymphoma,
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Primary cutaneous CD30+ lymphoproliferative disorders

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nasal type Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (provisional) Primary cutaneous peripheral T-cell lymphoma, unspecified Cutaneous gamma/delta T-cell lymphoma (provisional) Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional) Cutaneous B-cell lymphomas Primary cutaneous marginal zone Bcell lymphoma Primary cutaneous follicle center lymphoma Primary cutaneous diffuse large Bcell lymphoma, leg type Primary cutaneous diffuse large Bcell lymphoma, other CD4+/CD56+ hematodermic Precursor hematologic neoplasm (blastic NK-cell neoplasm lymphoma) Mycosis fungoides (MF) represents the most common variant of CTCL[3] and is characterized by a monoclonal proliferation of epidermotropic CD4+/CD45RO+ T-cells often with aberrant expression of mature T-cell antigens.[1,4] MF (Alibert-Bazin type) is characterized by the presence of polymorphic patches, plaques, and tumors.[1] Szary syndrome (SS) is a rare CTCL variant closely related to MF and has classically been described as a triad of erythroderma, generalized lymphadenopathy and Szary cells (atypical neoplastic T lymphocytes with hyperconvoluted cerebriform nuclei) in the skin, blood, and lymph nodes.[1,5,6] The WHO-EORTC system currently distinguishes SS as a separate entity from MF, but rare cases of SS preceded by typical MF have been described.[3,7] In this article, we will focus primarily on the evaluation and classification of these conditions and summarize the available therapies. Intravascular large B-cell lymphoma

Evaluation
A confident diagnosis of MF can only be made from a combination of clinical and pathologic findings. Characteristic pathologic features include cytologically atypical lymphocytes with cerebriform nuclei (described above) either colonizing the basal layer of the epidermis (epidermotropism) or forming clusters of cells in the epidermis (Pautrier microabscesses) with or without a band of cytologically atypical cells in the upper dermis.[1,8,9] An algorithm for the diagnosis of early-stage MF has been suggested by the International Society of Cutaneous Lymphoma (ISCL), which includes clinico-pathological correlation and immunophenotypic and clonal T-cell receptor gene rearrangement studies, providing minimum criteria for diagnosis ().[2,8] For SS, ISCL recommends the presence of erythroderma and the demonstration of the same T-cell clone (using polymerase chain reaction [PCR] or Southern blot of the T-cell receptor [TCR] gene) in skin and blood plus one of the following: Szary cell count >1000 cells/mm3; expanded CD4+ population with CD4/CD8 ratio >10; or loss of T-cell antigens (CD2, CD3, CD4, CD5 and CD7).[1] It must be appreciated that the diagnosis of early MF can be difficult and repeated biopsies may be required.[2,8] Careful clinicopathological evaluation with a dermatologist and experienced pathologist in PCLs is recommended ().

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Table 2. An algorithm for diagnosing early MF* (ISCL)2,3

Criteria Essential Additional Other

Scoring* Major (2 points) Minor (1 Point)

Clinical

Persistent and/or progressive patches/thin plaques

1. Non-sun exposed location 2. Size/shape variation 3. Poikiloderma Any 2 Any 1 additional additional criteria criteria

Histopathologic

Superficial lymphoid infiltrate

1. Epidermotropism 2. Lymphoid atypia Clonal TCR gene rearrangement 1. CD2+, CD3+ and/or CD5+ >50% of T cells 2. >10% CD7+ T cells

Any 2 Any 1 additional additional criteria criteria

Molecular biological

N/A

Present

Immunopathologic

3. Epidermal/dermal discordance of CD2+, CD3+, CD5+ or CD7(T cell antigen loss confined to epidermis)

N/A

Any 1 additional criteria

*A total of 4 points is required to make a diagnosis of MF

Table 3. Evaluation/staging of patients with MF/SS2,3

Evaluation/Staging Physical exam Skin lesions If tumors: note the total number, largest lesion, and regions affected If patch/plaques or erythroderma: determine percentage of body surface area and note any ulceration

Lymph nodes

Note: if >1.5 cm or firm, irregular, clustered, or fixed

Organomegaly
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Present/not present
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Skin biopsy

Most indurated area and compare plaques to tumors Site The site should be free from topical steroid for at least 2 weeks

Tests

Immunophenotyping for CD2/3/4/5/7/8 and B-cell markers such as CD20, CD79a, as well as other markers such as CD56 and Ki67 may be indicated TCR gene analysis for clonal TCR gene rearrangements

CBC, liver function tests, LDH and chemistries Bloods tests TCR gene analysis - to compare with tissue biopsy Analyze any abnormal lymphocytes - Szary cell count and/or flow cytometry (CD4+/CD7- or CD4+/CD26-)

Chest X-ray in T1-2N0B0 with limited skin involvement and no organ specific complaints Radiology CT scan of chest, abdomen, and pelvis for all other groups. Role of FDG-PET scan has yet to be defined Lymph node biopsy

Which node? Excision biopsy or core biopsy preferred to FNA

If nodes >1.5 cm or firm, irregular, clustered, or fixed Choose largest node draining an involved area or the node with the highest standardized uptake value from FDG-PET scan

Tests

Light microscopy/immunophenotypic studies/TCR gene analysis

CBC = complete blood count FDG-PET = fluorodeoxyglucose-positron emission tomography; FNA = fine-needle aspiration; TCR = T-cell receptor

Classification/Staging
The management of MF/SS is a stage-based approach derived from the TNM (tumor-node-metastasis) Classification of Malignant Tumours (). Patients with Stage IA, IB or IIA have an early stage disease compared to IIB (tumor), III (erythroderma), and IV (pathologically involved nodes - IVA; visceral involvement - IVB) have advanced-stage disease ().[2] Of note, there are two main classifications for lymph node involvement. The Dutch system defines atypical cells as cerebriform cells with a diameter >7.5 m - increasing grade is associated with increased involvement of these cells.[10] The second system, the National Cancer Institute and Veteran's Administration Hospital (NCI-VA) classification focuses primarily on the number of cells within the paracortex of the lymph node and their subsequent effect on the structure of the node.[11]

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Table 4. Classification of MF/SS (ISCL/EORTC revision)2,3,10,11

TNM Classification Skin T1 T2 T3 T4 Node N0 N1

Features Patches*, papules and/or plaques <10% of body surface (T1a: Patch - T1b: Plaque +/- patch) Patches, papules and/ore plaques >10% of body surface (T2a: Patch - T2b: Plaque +/- patch) One or more tumors (>1 cm diameter) Confluent erythema >80% of body surface No abnormal peripheral lymph nodes (LN) - no biopsy required Abnormal LN - Dutch grade 1 - dermatopathic lymphadenopathy (DL) - NCI-VA+ LN0-2 (N1a: Clone N1b: Clone +) - occasional to many lymphocytes Abnormal LN - Dutch grade 2 - DL: early atypical lymphocyte involvement - NCI-VA LN3 (N2a: Clone - N2b: Clone +) - aggregates of atypical lymphocytes Abnormal LN - Dutch grade 3 - many atypical lymphocytes with partial effacement of LN - Dutch grade 4 - complete effacement of LN - NCI-VA LN4 (N3a: Clone - N3b: Clone +) - partial/complete effacement of LN Abnormal lymph nodes - no confirmatory histology No visceral organs involved Viscera involved (with pathological confirmation - imaging for spleen/liver) >5% of peripheral blood lymphocytes are Szary cells (B0a: Clone - B0b: Clone +) >5% of peripheral blood lymphocytes are Szary cells (B1a: Clone - B1b: Clone +) High tumour burden: !1000/L Szary cells with Clone +

N2

N3 Nx Visceral M0 M1 Blood B0 B1 B2

* Patches are without elevation or induration; + National Cancer Institute and Veteran's Administration Hospital classification
Table 5. Staging of MF/SS (ISCL/EORTC revision)2,3

Limited-stage Disease IA IB IIA T1, N0, M0, B0-1 T2, N0, M0, B0-1 T1-2, N1-2, M0, B0-1

Advanced-stage Disease IIB IIIA IIIB T3, N0-2, M0, B0-1 T4, N0-2, M0, B0 T4, N0-2, M0, B1

IVA1 T1-4, N0-2, M0, B2

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IVA2 T1-4, N3, M0, B0-2 IVB T1-4, N0-3, M1, B0-2

T1-4: tumor stage; N0-3: nodal stage; M0-1: visceral organs; B1-2: peripheral blood

Prognosis
The prognosis of MF/SS is primarily based on stage, particularly the extent/type of lesions and presence of extracutaneous disease,[1,2] emphasising the importance of thorough patient workup. Of note, MF/SS are thought as incurable diseases but the majority of patients with MF have an indolent disease course with 6585% of patients being stage IA or IB at diagnosis.[2,1214] Patients with stage IA disease have a median survival of more than 12 years and no decrease in survival when compared to an age-, sex- and race-match control population.[1,2,1517] It is now appreciated that for patients with stage IB, the presence of plaques (T2b) is associated with a worse prognosis and increased risk of disease progression when compared to those with only patches (T2a).[12] In contrast, patients with more advanced stage disease (stages IIB, III, IVA) have a median survival of 5 years and stage IVB patients have a median survival of 2.5 years.[2,12,13,15,17] More specifically, patients with dermatopathic nodes (N1) also have a poorer survival when compared to those with no palpable nodes (N0). The presence of abnormal nodes with no histological confirmation (Nx) is also associated with mortality/poor outcome.[14] A recent study also showed that patients with stage B0b (<5% Szary cells with a T-cell clone) have a significantly worse overall and disease-specific survival with an increased risk of progression when compared to B0a (without a T-cell clone). A comparison study between stages B1 and B2 showed no significant difference in survival outcomes ().[14]
Table 6. Prognostic characteristics in MF/SS defined from a cohort of 1,502 patients2,14

Characteristics Univariate analysis Advanced clinical stage; increased age; male sex; increased LDH; large-cell transformation Hypopigmented MF; MF with lymphomatoid papulosis; poikilodermatous MF; Folliculotropic MF Multivariate Advanced skin (T) stage; blood stage B0b (blood clone analysis without Szary cells); increased LDH; folliculotropic MF Large-cell transformation Advanced N, M and B stages; increased age; male sex

Better OS, DSS or Worse OS, DSS or decreased RDP increased RDP OS, DSS and RDP OS and RDP RDP only OS, DSS and RDP RDP only OS and DSS

OS = overall survival; DSS = disease-specific survival; RDP = risk of disease progression

Treatment
Successful treatment of MF/SS requires appropriate classification/staging, multi-disciplinary input and personalized patient therapy (including age, co-morbidities, and performance status).[2] Treatment should be focused on trying to induce sustained remission as measured by tumor burden.[16] At present, there are no curative therapies and sometimes palliative options are the only appropriate therapeutic intervention18 with maintenance of a patient's quality of life. The standard approach for early stage disease is skin-directed therapy including topical agents, phototherapy,
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and radiotherapy. Long-term durable remissions are rare. Total skin electron beam (TSEB) therapy and immunobiologics are key options for patients with disease that is resistant to skin-directed treatments. Patients in advanced disease stages often receive chemotherapy but responses are rarely sustained. Several novel agents such as fusion toxins (denileukin diftitox), bexarotene, and histone deacetylase (HDAC) inhibitors have received US FDA approval during the last few years and offer promising alternatives to chemotherapy. Similarly, data on antibodies such as alemtuzumab suggests significant and occasionally durable responses. summarizes many of the available therapies.
Table 7. Summary of therapies available for MF/SS2,19

MF Therapy Limited Advanced stage stage +++ ++++ ++++ +++ ++ + + + ++ ++ + + ++++ ++ + +++ ++++ ++++ ++ ++ +++ +++ + + + ++ + +

SS/Erythrodermic MF Comments*

Expectant therapy** Topical corticosteroids Psoralen + ultraviolet A (PUVA) UVB (TLO1) phototherapy Topical chemotherapy Imiquimod Photodynamic therapy Retinoids Bexarotene Interferon-alpha HDACi (vorinostat; romidepsin) Oral methotrexate Radiotherapy Total skin electron beam (TSEB) Systemic chemotherapy Extracorporeal photopheresis (ECP) Autologous transplantation Allogenic

Stage IA with steroid if needed +++ +++ ++ Symptom control/complete responses may occur Rate of durable remission is low More effective for patches Limited availability currently Small/limited lesions Limited evidence and causes severe pain + +++ ++++ ++++ +++ Usually second-line Can be used with PUVA or interferon-alpha FDA/EMA approved EMA approved FDA approved Low dose weekly for stage III Highly effective for localized large plaques/tumour/nodules + ++ ++++ + For widespread disease High response rates but short duration Evidence suggests that best for patients with peripheral blood involvement Not associated with durable remissions

Reduced intensity regimens offer promising

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transplantation

++

++

option for selected patients with advanced disease

Denileukin diftitox Alemtuzumab Proteasome inhibitors Immunomodulatory agents (lenalidomide)

+++ +

+++ +++

Limited availability at present OasdfRDP Under investigation Under investigation

+ = frequency of use; * Refer to National Cancer Center Network and EORTC consensus recommendations for further guidelines and information regarding therapy for MF/SS; ** Active surveillance - reviewing at regular intervals and reserving treatment for disease-related symptoms; EMA = European Medicines Agency

Conclusion
Appropriate therapy for advanced stages of MF/SS can only be initiated based on a multi-disciplinary approach (including dermatologists, pathologists, and oncologists) to classification and staging. Accurate staging and work-up will allow appropriate therapy and prognostic details to be delivered to each individual patient.
References

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fungoides/Sezary syndrome (cutaneous T-cell lymphoma): clinical correlations and prognostic import of a new classification system. Hum Pathol. 1985 Nov;16(11):1098109. 11. Scheffer E, Meijer CJ, Van Vloten WA. Dermatopathic lymphadenopathy and lymph node involvement in mycosis fungoides. Cancer. 1980 Jan 1;45(1): 13748. 12. Arulogun SO, Prince HM, Ng J, et al. Long-term outcomes of patients with advanced-stage cutaneous T-cell lymphoma and large cell transformation. Blood. 2008 Oct 15;112(8):30827. 13. Kim YH, Liu HL, Mraz-Gernhard S, et al. Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression. Arch Dermatol. 2003 Jul;139(7):85766. 14. Agar NS, Wedgeworth E, Crichton S, et al. Survival outcomes and prognostic factors in mycosis fungoides/Sezary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol. 2010 Nov 1; 28(31):47309. 15. Zackheim HS, Amin S, Kashani-Sabet M, et al. Prognosis in cutaneous T-cell lymphoma by skin stage: longterm survival in 489 patients. J Am Acad Dermatol. 1999 Mar;40(3):41825. 16. van Doorn R, Van Haselen CW, van Voorst Vader PC, et al. Mycosis fungoides: disease evolution and prognosis of 309 Dutch patients. Arch Dermatol. 2000 Apr;136(4):50410. 17. Diamandidou E, Cohen PR, Kurzrock R. Mycosis fungoides and Sezary syndrome. Blood. 1996 Oct 1;88(7):2385409. 18. Heald P, Latkowski J, Wilson L, et al. Successful therapy of cutaneous T-cell lymphoma. Expert Rev of Dermatol. 2008 Feb;3(1):99110(12). 19. Trautinger F, Knobler R, Willemze R, et al. EORTC consensus recommendations for the treatment of mycosis fungoides/Sezary syndrome. Eur J Cancer. 2006 May;42(8):101430. Skin Therapy Letter. 2012;17(10) 2012 SkinCareGuide.com

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