What is Mycosis Fungoides?
Mycosis fungoides is the most common form of cutaneous T-cell lymphoma (CTCL), characterized by malignant skin-homing CD4+ T cells that infiltrate the skin, presenting as patches, plaques, and tumors in progressive stages. 1
Disease Characteristics
Mycosis fungoides accounts for approximately 60% of all cutaneous T-cell lymphoma diagnoses and represents an indolent lymphoproliferative disorder distinct from other non-Hodgkin's lymphomas. 1, 2
The disease progresses through three distinct clinical stages: patch stage (flat, scaly lesions), plaque stage (raised, infiltrated lesions), and tumor stage (nodular masses), most commonly affecting the buttocks, trunk, and breast. 2
The clinical presentation frequently mimics common inflammatory dermatoses such as eczema and psoriasis, making early diagnosis particularly challenging and often requiring multiple skin biopsies to identify characteristic epidermotropic infiltrates of small to medium-sized lymphocytes. 2
Prognosis and Staging
Prognosis depends critically on the type and extent of skin lesions and presence of extracutaneous disease, with staging following the modified ISCL/EORTC TNM classification system that incorporates skin (T), lymph node (N), visceral (M), and blood (B) involvement. 1
Early-stage disease (IA-IB) carries a relatively favorable prognosis with 5-year survival rates of 68-73%, while advanced stages with nodal or visceral involvement have significantly worse outcomes. 3
A critical prognostic factor emerging from recent research is the tumor clone frequency (TCF) measured by high-throughput sequencing of the T-cell receptor β gene in lesional skin—a TCF >25% in early-stage patients predicts aggressive disease progression more accurately than traditional staging criteria. 4
Treatment Approach
Early Stage Disease (IA-IB)
Skin-directed therapy is the cornerstone of treatment for early-stage mycosis fungoides, with topical corticosteroids, phototherapy (PUVA or narrowband UVB), and topical chemotherapy agents representing first-line options. 5, 6
PUVA phototherapy achieves response rates of 79-88% in stage IA and 52-59% in stage IB disease, making it a highly effective first-line option for extensive patch/plaque disease. 5
Narrowband UVB (311 nm) is specifically recommended for patients with patches or very thin plaques, achieving 81-86% complete response rates. 6
Topical corticosteroids, topical bexarotene gel, and topical carmustine (BCNU) represent alternative first-line options for limited disease. 5, 7
Local radiotherapy (20-24 Gy) can be curative in patients with early localized disease and pagetoid reticulosis, using superficial orthovoltage radiotherapy (2-3 fractions of 400 cGy at 80-120 kV). 5, 3
Intermediate Stage Disease (IIA-IIB)
For stage IIA disease with extensive plaques, PUVA phototherapy or topical mechlorethamine remains first-line, with radiotherapy reserved for localized resistant lesions—systemic chemotherapy should be avoided as it provides no survival benefit despite higher toxicity. 3
Patients developing one or a few tumors (stage IIB) require systemic therapy in addition to skin-directed approaches, with PUVA combined with interferon-alpha or systemic retinoids (bexarotene) representing the standard combination approach. 5, 6
Total skin electron beam (TSEB) therapy is effective but insufficient as monotherapy for stage IIB disease and should be combined with systemic agents. 5
A landmark randomized trial demonstrated that combined TSEB plus multiagent chemotherapy (CAVE regimen) showed no difference in disease-free or overall survival compared to palliative skin-directed therapy alone (38% vs 18% complete response), despite significantly greater morbidity with chemotherapy. 3
Advanced Disease (III-IV)
Erythrodermic CTCL patients (stage III/IVA) should receive extracorporeal photopheresis (ECP) combined with interferon-alpha as first-line therapy, as responses to chemotherapy are generally poor and infectious complications represent the primary cause of death. 5, 6
ECP achieves overall response rates of 35-71% in erythrodermic disease and is particularly effective for patients with peripheral blood involvement. 5, 6
Systemic retinoids (bexarotene), histone deacetylase inhibitors (vorinostat), and fusion toxin denileukin diftitox represent additional systemic options for advanced disease. 5, 7
Chemotherapy is only indicated in patients with effaced lymph nodes or visceral involvement (stage IV) or widespread tumor-stage MF that cannot be controlled with skin-targeted and immunomodulating therapies. 5
Single-agent chemotherapy options include gemcitabine and liposomal doxorubicin, while multi-agent regimens achieve complete responses of approximately 30% but these are short-lived (median duration 3-41 months). 5
Allogeneic stem cell transplantation may be considered in young patients with refractory, progressive MF or SS, particularly those identified early with high tumor clone frequency (>25%) before disease becomes treatment-refractory. 5, 4
Critical Treatment Principles
Aggressive polychemotherapy should be avoided as initial therapy since it does not improve overall survival and significantly increases infectious complications that are the primary cause of death in advanced MF. 6
The realistic goal for CTCL treatment is achieving long-lasting remissions with drugs that can be safely used without long-term toxicity, NOT cure in most cases, and quality of life must be prioritized when discussing therapeutic options. 6, 3
Maintenance therapy after achieving remission is rarely effective at preventing relapse and should be avoided to limit cumulative toxicity, particularly with PUVA where total dose restrictions are critical. 3
In treatment-resistant cases of late-stage disease, palliative radiotherapy and/or chemotherapy may produce significant short-term benefit, but the patient's quality of life should always be given priority. 5