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.

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).

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

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

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.

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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