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Mycosis fungoides and the Sézary syndrome (MF/SS) are neoplasias of malignant T lymphocytes that usually possess the helper/inducer cell surface phenotype. These kinds of neoplasms initially present as skin involvement and as such have been classified as cutaneous T-cell lymphomas. These types of lymphomas are included in the Revised European-American Lymphoma classification as low-grade T-cell lymphomas, which should be distinguished from other T-cell lymphomas that involve the skin, such as anaplastic large cell lymphoma (CD30 positive), peripheral T-cell lymphoma (CD30 negative, with no epidermal involvement), adult T-cell leukemia/lymphoma (usually with systemic involvement), or subcutaneous panniculitic T-cell lymphoma.[2,3] These histologic types of T-cell lymphomas are discussed in another PDQ summary. (Refer to the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.) In addition, a number of benign or very indolent conditions can be confused with mycosis fungoides. Consultation with a pathologist who has expertise in distinguishing these conditions is important.
The prognosis of patients with MF/SS is based on the extent of disease at presentation (stage). The presence of lymphadenopathy and involvement of peripheral blood and viscera increase in likelihood with worsening cutaneous involvement and define poor prognostic groups. The median survival following diagnosis varies according to stage. Patients with stage IA disease have a median survival of 20 or more years. The majority of deaths for this group are not caused by, nor are they related to, MF. In contrast, more than 50% of patients with stage III through stage IV disease die of MF, with a median survival of less than 5 years.[5,6,7] A report on 1,798 patients from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program (SEER) database found an increase in second malignancies (standardized incidence ratio of 1.32; 95% confidence interval, 1.15–1.52), especially for Hodgkin and non-Hodgkin lymphoma and for myeloma.
Typically, the natural history of MF is indolent. Symptoms of the disease may present for long periods, an average of 2 to 10 years, as waxing and waning cutaneous eruptions prior to biopsy confirmation. MF/SS is treatable with available topical and/or systemic therapies. Curative modalities, however, have thus far proven elusive, with the possible exception of patients with minimal disease confined to the skin.
Cutaneous disease typically progresses from an eczematous patch/plaque stage covering less than 10% of the body surface (T1) to plaque stage covering 10% or more of the body surface (T2), and finally to tumors (T3) that frequently undergo necrotic ulceration.[4,10] SS presents with generalized erythroderma (T4) and peripheral blood involvement. However, there is some disagreement about whether the MF and SS are actually variants of the same disease. There is consensus that patients with SS have a poor prognosis (median survival of 4 years). Cytologic transformation from a low-grade lymphoma to a high-grade lymphoma sometimes occurs during the course of these diseases and is associated with a poor prognosis.[13,14] A retrospective analysis of 100 cases with large-cell transformation found reduced disease-specific survival with extracutaneous transformation, increased extent of skin lesions, and CD30 negativity. A common cause of death during the tumor phase is sepsis from Pseudomonas aeruginosa or Staphylococcus aureus caused by chronic skin infection with staph species and subsequent systemic infections.
The histologic diagnosis of mycosis fungoides and the Sézary syndrome (MF/SS) is usually difficult to determine in the initial stages of the disease and may require the review of multiple biopsies by an experienced pathologist.
A definitive diagnosis from a skin biopsy requires the presence of MF/SS cells (convoluted lymphocytes), a band-like upper dermal infiltrate, and epidermal infiltrations with Pautrier abscesses (collections of neoplastic lymphocytes). A definitive diagnosis of SS may be made from a peripheral blood evaluation when skin biopsies are consistent with the diagnosis. Supportive evidence for circulating Sézary cells is provided by T-cell receptor gene analysis, identification of the atypical lymphocytes with hyper-convoluted or cerebriform nuclei, and flow cytometry with the characteristic deletion of cell surface markers such as CD7 and CD26. However, none of these is individually pathognomonic for lymphoma. [1,2]
The stages that follow are defined by TNM classification. Peripheral blood involvement with mycosis fungoides or Sézary syndrome (MF/SS) cells is correlated with more advanced skin stage, lymph node and visceral involvement, and shortened survival but probably provides no independent prognostic information beyond that associated with TNM staging. In a multivariate analysis, the two most important prognostic factors are the presence of visceral disease and type of skin involvement.
MF/SS have a formal staging system proposed by the International Society for Cutaneous Lymphomas (ISCL) and the European Organization of Research and Treatment of Cancer (EORTC).
Definitions of TNM
The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification to define MF.
Treatment options for patients with mycosis fungoides and the Sézary syndrome (MF/SS) include:[1,2,3]
These types of treatments produce remissions, but long-term remissions are uncommon. Treatment, therefore, is considered palliative for most patients, though major symptomatic improvement is regularly achieved. Survival in excess of 8 years, however, is common for patients with early stages of disease. All patients with MF/SS are candidates for clinical trials evaluating new approaches to treatment.
Current areas of interest in clinical trials for MF confined to the skin include combined modality therapies containing both topical and systemic agents such as TSEB combined with chemotherapy, topical mechlorethamine or PUVA combined with interferon, or wide-field radiation techniques with PUVA. Reports are available of activity for extracorporeal photochemotherapy using psoralen; interferon-gamma or interferon-alpha; pentostatin; retinoids; fludarabine; acyclovir; 2-chlorodeoxyadenosine; serotherapy with unlabeled, toxin-labeled, or radiolabeled monoclonal antibodies; cell surface receptor ligand-toxin fusion protein; and, methotrexate.[3,5,6,7,8,9,10,11,12,13,14] Antigen-specific vaccination using dendritic cells  and UVB are also under clinical evaluation.
Since several forms of treatment can produce complete resolution of skin lesions in this stage, the choice of therapy is dependent on local expertise and the facilities available. With therapy, the survival of patients with stage IA disease can be expected to be the same as age and gender-matched controls.[1,2]
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I mycosis fungoides/Sezary syndrome. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
No curative therapy exists for patients with stage II disease. The choice of initial palliative therapy is, therefore, dependent on the patient's symptoms and the local expertise with each modality.
A randomized study of 103 patients compared combined total-skin electron-beam radiation (TSEB) plus combination chemotherapy with conservation therapy consisting of sequential topical therapies. In the latter group, combination chemotherapy was reserved for symptomatic extracutaneous disease or for disease refractory to topical therapies. Patients with any stage were eligible. Although the complete response rate was higher with combined therapy, toxic effects were considerably greater, and no difference was seen in disease-free or overall survival between the two groups.[Level of evidence: 1iiA]
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II mycosis fungoides/Sezary syndrome. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
No curative treatment exists for patients with stage III disease. The initial choice of palliative therapy is, therefore, dependent on the local expertise with each modality.
Treatment options (note that in this clinical setting, the skin is easily injured; any of the topical therapies must be administered with extreme caution):[2,3]
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III mycosis fungoides/Sezary syndrome. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
The use of single alkylating agents has produced objective responses in 60% of patients with a duration of less than 6 months. One of the alkylating agents (e.g., mechlorethamine, cyclophosphamide, or chlorambucil), or the antimetabolite methotrexate is the most frequently used. Single agents have not been shown to cure any patients, and insufficient data exist to determine if these agents prolong survival. Combination chemotherapy is not definitely superior to single agents. Even in stage IV disease, treatments directed at the skin may provide significant palliation.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV mycosis fungoides/Sezary syndrome. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
The treatment of relapsed patients with cutaneous T-cell lymphomas involves the joint decisions of the dermatologist, medical oncologist, and radiation oncologist. It may be possible to re-treat localized areas of relapse in the skin with additional electron-beam radiation or possibly to repeat total-skin electron-beam radiation therapy (TSEB). Photon radiation to bulky skin or nodal masses may prove beneficial. If these options are not possible, then continued topical treatment with other modalities such as mechlorethamine or psoralen and ultraviolet A radiation (PUVA) may be warranted to relieve cutaneous symptoms.
Clinical trials, if possible, should be considered as the next therapeutic option. Options under clinical evaluation include:[2,3]
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent mycosis fungoides/Sezary syndrome. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Mycosis Fungoides and the Sézary Syndrome
Revised text to state that the Sézary syndrome (SS) presents with generalized erythroderma (T4) and peripheral blood involvement. Also added text to state that there is consensus that patients with SS have a poor prognosis (cited Kubica et al. as reference 12). Added text to state that a retrospective analysis of 100 cases with large-cell transformation found reduced disease-specific survival with extracutaneous transformation, increased extent of skin lesions, and CD30 negativity (cited Benner et al. as reference 15).
Treatment Option Overview
Added text to include pralatrexate as a treatment option for patients with mycosis fungoides and the Sézary syndrome (MF/SS) (cited Horwitz et al. as reference 4).
Stage I Mycosis Fungoides
Added Navi et al. as reference 11.
Added text to include pralatrexate as a treatment option for patients with stage I mycosis fungoides (cited Horwitz et al. as reference 22).
Stage II Mycosis Fungoides
Added Navi et al. as reference 9.
Added text to include pralatrexate as a treatment option for patients with stage II mycosis fungoides (cited Horwitz et al. as reference 21).
Stage III Mycosis Fungoides
Added text to include oral methotrexate as a treatment option for patients with stage III mycosis fungoides (cited Zackheim et al. as reference 24).
Added text to include pralatrexate as a treatment option for patients with stage III mycosis fungoides (cited Horwitz et al. as reference 28).
Stage IV Mycosis Fungoides and the Sézary Syndrome
Added Navi et al. as reference 7.
Added text to include oral methotrexate as a treatment option for patients with stage IV MF/SS (cited Zackheim et al. as reference 26).
Added text to include pralatrexate as a treatment option for patients with stage IV MF/SS (cited Horwitz et al. as reference 30).
Recurrent Mycosis Fungoides and the Sézary Syndrome
Added Schlaak et al. as reference 13.
Added text to include pralatrexate as a treatment option for patients with recurrent MF/SS (cited Horwitz et al. as reference 16).
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of mycosis fungoides and the Sézary Syndrome. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewer for Mycosis Fungoides and the Sézary Syndrome Treatment is:
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Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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National Cancer Institute: PDQ® Mycosis Fungoides and the Sézary Syndrome Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/mycosisfungoides/HealthProfessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2013-08-12
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