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
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.
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.
|Cutaneous T-cell and NK-cell lymphomas||Mycosis fungoides|
|MF variants and subtypes|
|Adult T-cell leukemia/lymphoma|
|Primary cutaneous CD30+ lymphoproliferative disorders|
|Subcutaneous panniculitis-like T-cell lymphoma|
|Extranodal NK/T-cell lymphoma, nasal type|
|Primary cutaneous peripheral T-cell lymphoma, unspecified|
|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|
|Precursor hematologic neoplasm||CD4+/CD56+ hematodermic neoplasm (blastic NK-cell lymphoma)|
|Table 1. WHO-EORTC classification of cutaneous lymphoma with primary cutaneous manifestations1|
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).
|Essential||Additional||Other||Major (2 points)||Minor (1 Point)|
|Clinical||Persistent and/or progressive patches/thin plaques||Any 2 additional criteria||Any 1 additional criteria|
|Histopathologic||Superficial lymphoid infiltrate||Any 2 additional criteria||Any 1 additional criteria|
|Molecular biological||Clonal TCR gene rearrangement||N/A||Present|
|Immunopathologic||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|
|Physical exam||Skin lesions|
|Lymph node biopsy||Which node? Excision biopsy or core biopsy preferred to FNA|
|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
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
|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
|IA||T1, N0, M0, B0-1|
|IB||T2, N0, M0, B0-1|
|IIA||T1-2, N1-2, M0, B0-1|
|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
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
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.
|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|
|Photodynamic therapy||+||Limited evidence and causes severe pain|
|Bexarotene||++||+++||+++||Can be used with PUVA or interferon-alpha FDA/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|
|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
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.
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