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A Practical Approach to Accurate Classification and Staging of Mycosis Fungoides and Sézary Syndrome

Bjorn Rhys Thomas, MBBS1 and Sean Whittaker, MB, MD, FRCP2
1Department of Genetics & Molecular Medicine, School of Medicine King’s College, London, UK
2Skin Tumour Unit, St. John's Institute of Dermatology, Guys and St. Thomas Hospital, London, UK

ABSTRACT

Cutaneous T-cell lymphomas are rare, distinct forms of non-Hodgkin’s lymphomas. Of which, mycosis fungoides (MF) and Sézary 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.

Key Words: CTCL, cutaneous T-cell lymphoma, mycosis fungoides, neoplasm staging, Sézary syndrome, therapy

Primary cutaneous lymphomas (PCL) are rare forms (2%) of non-Hodgkin's lymphomas with an annual incidence of 0.3-1 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 (Table 1).1,2

Mycosis fungoides (MF) represents the most common variant of CTCL3 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 Sézary syndrome (SS) is a rare CTCL variant closely related to MF and has classically been described as a triad of erythroderma, generalized lymphadenopathy and Sézary 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.

Classification
Cutaneous T-cell and NK-cell lymphomas Mycosis fungoides
MF variants and subtypes
  • Folliculotropic MF
  • Pagetoid reticulosis
  • Granulomatous slack skin
Sézary syndrome
Adult T-cell leukemia/lymphoma
Primary cutaneous CD30+ lymphoproliferative disorders
  • Primary cutaneous anaplastic large cell lymphoma
  • Lymphomatoid papulosis
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 (provisional)
  • 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 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)
Table 1. WHO-EORTC classification of cutaneous lymphoma with primary cutaneous manifestations1

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 (Table 2).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: Sézary 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 clinico-pathological evaluation with a dermatologist and experienced pathologist in PCLs is recommended (Table 3).

Criteria Scoring*
Essential Additional Other 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 additional criteria Any 1 additional criteria
Histopathologic Superficial lymphoid infiltrate
  1. Epidermotropism
  2. Lymphoid atypia
Any 2 additional criteria Any 1 additional criteria
Molecular biological Clonal TCR gene rearrangement N/A Present
Immunopathologic
  1. CD2+, CD3+ and/or CD5+ >50% of T cells
  2. >10% CD7+ T cells
  3. Epidermal/dermal discordance of CD2+, CD3+, CD5+ or CD7- (T cell antigen loss confined to epidermis)
N/A Any 1 additional criteria
Table 2. An algorithm for diagnosing early MF* (ISCL)2,3; * A total of 4 points is required to make a diagnosis of MF
Evaluation/Staging
Physical exam Skin lesions
  • If patch/plaques or erythroderma: determine percentage of body surface area and note any ulceration
  • If tumors: note the total number, largest lesion, and regions affected
Lymph nodes
  • Note: if >1.5 cm or firm, irregular, clustered, or fixed
Organomegaly
  • Present/not present
Skin biopsy Site
  • Most indurated area and compare plaques to tumors
  • 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
Bloods tests
  • CBC, liver function tests, LDH and chemistries
  • TCR gene analysis - to compare with tissue biopsy
  • Analyze any abnormal lymphocytes - Sézary cell count and/or flow cytometry (CD4+/CD7- or CD4+/CD26-)
Radiology
  • Chest X-ray in T1-2N0B0 with limited skin involvement and no organ specific complaints
  • 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
Table 3. Evaluation/staging of patients with MF/SS2,3; 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 (Table 4). 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 (Table 5).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 µm - 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

TNM Classification Features
Skin T1 Patches*, papules and/or plaques <10% of body surface (T1a: Patch - T1b: Plaque +/- patch)
T2 Patches, papules and/ore plaques >10% of body surface (T2a: Patch - T2b: Plaque +/- patch)
T3 One or more tumors (>1 cm diameter)
T4 Confluent erythema >80% of body surface
Node N0 No abnormal peripheral lymph nodes (LN) - no biopsy required
N1 Abnormal LN - Dutch grade 1 - dermatopathic lymphadenopathy (DL)
- NCI-VA+ LN0-2 (N1a: Clone - N1b: Clone +) - occasional to many lymphocytes
N2 Abnormal LN - Dutch grade 2 - DL: early atypical lymphocyte involvement
- NCI-VA LN3 (N2a: Clone - N2b: Clone +) - aggregates of atypical lymphocytes
N3 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
Nx Abnormal lymph nodes - no confirmatory histology
Visceral M0 No visceral organs involved
M1 Viscera involved (with pathological confirmation - imaging for spleen/liver)
Blood B0 >5% of peripheral blood lymphocytes are Sézary cells (B0a: Clone - B0b: Clone +)
B1 >5% of peripheral blood lymphocytes are Sézary cells (B1a: Clone - B1b: Clone +)
B2 High tumour burden: ≥1000/µL Sézary cells with Clone +
Table 4. Classification of MF/SS (ISCL/EORTC revision)2,3,10,11
* Patches are without elevation or induration; + National Cancer Institute and Veteran’s Administration Hospital classification
Limited-stage Disease
IA T1, N0, M0, B0-1
IB T2, N0, M0, B0-1
IIA T1-2, N1-2, M0, B0-1
Advanced-stage Disease
IIB T3, N0-2, M0, B0-1
IIIA T4, N0-2, M0, B0
IIIB T4, N0-2, M0, B1
IVA1 T1-4, N0-2, M0, B2
IVA2 T1-4, N3, M0, B0-2
IVB T1-4, N0-3, M1, B0-2
Table 5. Staging of MF/SS (ISCL/EORTC revision)2,3
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 65-85% of patients being stage IA or IB at diagnosis.2,12-14

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.1,2,15-17 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% Sézary 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 (Table 6).14

Characteristics Better OS, DSS or decreased RDP Worse OS, DSS or increased RDP
Univariate analysis Advanced clinical stage; increased age; male sex; increased LDH; large-cell transformation OS, DSS and RDP
Hypopigmented MF; MF with lymphomatoid papulosis; poikilodermatous MF; OS and RDP
Folliculotropic MF RDP only
Multivariate analysis Advanced skin (T) stage; blood stage B0b (blood clone without Sézary cells); increased LDH; folliculotropic MF OS, DSS and RDP
Large-cell transformation RDP only
Advanced N, M and B stages; increased age; male sex OS and DSS
Table 6. Prognostic characteristics in MF/SS defined from a cohort of 1,502 patients2,14
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, 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. Table 7 summarizes many of the available therapies.

Therapy MF SS/Erythrodermic Comments*
Limited stage Advanced stage MF
Expectant therapy** +++ Stage IA with steroid if needed
Topical corticosteroids ++++ ++ +++ Symptom control/complete responses may occur
Psoralen + ultraviolet A (PUVA) ++++ + +++ Rate of durable remission is low
UVB (TLO1) phototherapy +++ + ++ More effective for patches
Topical chemotherapy ++ Limited availability currently
Imiquimod + Small/limited lesions
Photodynamic therapy + Limited evidence and causes severe pain
Retinoids + + + Usually second-line
Bexarotene ++ +++ +++ Can be used with PUVA or interferon-alpha FDA/EMA approved
Interferon-alpha ++ ++++ ++++ EMA approved
HDACi (vorinostat; romidepsin) + ++++ ++++ FDA approved
Oral methotrexate + ++ +++ Low dose weekly for stage III
Radiotherapy ++++ ++ Highly effective for localized large plaques/tumour/nodules
Total skin electron beam (TSEB) ++ +++ + For widespread disease
Systemic chemotherapy +++ ++ High response rates but short duration
Extracorporeal photopheresis (ECP) + + ++++ Evidence suggests that best for patients with peripheral blood involvement
Autologous transplantation + + Not associated with durable remissions
Allogenic transplantation ++ ++ Reduced intensity regimens offer promising option for selected patients with advanced disease
Denileukin diftitox +++ +++ Limited availability at present
Alemtuzumab + +++ OasdfRDP
Proteasome inhibitors Under investigation
Immunomodulatory agents (lenalidomide) Under investigation
Table 7. Summary of therapies available for MF/SS2,19; + = 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

  1. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005 May 15;105(10):3768-85.
  2. Prince HM, Whittaker S, Hoppe RT. How I treat mycosis fungoides and Sezary syndrome. Blood. 2009 Nov 12;114(20):4337-53.
  3. Olsen E, Vonderheid E, Pimpinelli N, et al. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 2007 Sep 15;110(6):1713-22.
  4. Burg G, Kempf W, Cozzio A, et al. WHO/EORTC classification of cutaneous lymphomas 2005: histological and molecular aspects. J Cutan Pathol. 2005 Nov;32(10):647-74.
  5. Wieselthier JS, Koh HK. Sezary syndrome: diagnosis, prognosis, and critical review of treatment options. J Am Acad Dermatol. 1990 Mar;22(3):381-401.
  6. Akilov OE, Geskin L. Therapeutic advances in cutaneous T-cell lymphoma. Skin Therapy Lett. 2011 Feb;16(2):1-5.
  7. Diwan AH, Prieto VG, Herling M, et al. Primary Sezary syndrome commonly shows low-grade cytologic atypia and an absence of epidermotropism. Am J Clin Pathol. 2005 Apr;123(4):510-5.
  8. Pimpinelli N, Olsen EA, Santucci M, et al. Defining early mycosis fungoides. J Am Acad Dermatol. 2005 Dec;53(6):1053-63.
  9. Guitart J, Kennedy J, Ronan S, et al. Histologic criteria for the diagnosis of mycosis fungoides: proposal for a grading system to standardize pathology reporting. J Cutan Pathol. 2001 Apr;28(4):174-83.
  10. Sausville EA, Worsham GF, Matthews MJ, et al. Histologic assessment of lymph nodes in mycosis fungoides/Sezary syndrome (cutaneous T-cell lymphoma): clinical correlations and prognostic import of a new classification system. Hum Pathol. 1985 Nov;16(11):1098-109.
  11. Scheffer E, Meijer CJ, Van Vloten WA. Dermatopathic lymphadenopathy and lymph node involvement in mycosis fungoides. Cancer. 1980 Jan 1;45(1): 137-48.
  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):3082-7.
  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):857-66.
  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):4730-9.
  15. Zackheim HS, Amin S, Kashani-Sabet M, et al. Prognosis in cutaneous T-cell lymphoma by skin stage: long-term survival in 489 patients. J Am Acad Dermatol. 1999 Mar;40(3):418-25.
  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):504-10.
  17. Diamandidou E, Cohen PR, Kurzrock R. Mycosis fungoides and Sezary syndrome. Blood. 1996 Oct 1;88(7):2385-409.
  18. Heald P, Latkowski J, Wilson L, et al. Successful therapy of cutaneous T-cell lymphoma. Expert Rev of Dermatol. 2008 Feb;3(1):99-110(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):1014-30.

In this issue:

  1. Rosacea: Update on Management and Emerging Therapies
  2. A Practical Approach to Accurate Classification and Staging of Mycosis Fungoides and Sézary Syndrome
  3. Update on Drugs and Drug News - November-December 2012