Residency · Residency · Dermatology

Cutaneous T-Cell Lymphoma: Mycosis Fungoides and Sezary Syndrome

Overview

Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of non-Hodgkin lymphomas arising from skin-homing mature T cells. Mycosis fungoides (MF) is the most common CTCL, accounting for approximately 50 percent of all primary cutaneous lymphomas. Sezary syndrome (SS) is the leukemic variant with an aggressive course and poor prognosis. The WHO-EORTC classification distinguishes indolent from aggressive subtypes.

Mycosis Fungoides

Pathogenesis

MF arises from neoplastic proliferation of mature, skin-tropic CD4-positive T cells, typically of an effector memory phenotype. Clonal T-cell receptor gene rearrangement can be detected. These malignant T cells commonly lose surface markers, with CD7 being most frequently lost, followed by CD26. The tumor microenvironment is characterized by a Th2-skewed cytokine milieu that promotes immune evasion and disease progression. Molecular alterations include JAK/STAT pathway dysregulation and epigenetic changes involving DNMT3A, TET2, and IDH2 mutations.

Clinical Stages

Patch Stage

The earliest stage presents with erythematous, flat, well-demarcated patches with fine scale. There is a characteristic predilection for the "bathing suit" distribution, involving the buttocks, proximal thighs, and trunk -- areas typically not exposed to sun. The patches have a wrinkled "cigarette paper" texture. This stage is frequently misdiagnosed as eczema, psoriasis, or tinea corporis, often for years, with a mean diagnostic delay of 3 to 6 years. Poikiloderma (a combination of atrophy, telangiectasia, and dyspigmentation) suggests poikilodermatous MF.

Plaque Stage

Plaques are thickened, indurated, well-defined lesions that are often annular or serpiginous. They are more infiltrated than patch-stage lesions and may develop within pre-existing patches. Histologically, there is greater epidermal and dermal involvement.

Tumor Stage

Tumors are dome-shaped, often ulcerated nodules of 1 cm or greater. They can arise within patches or plaques or appear de novo (the d'emblee variant). The tumor stage carries a higher risk of systemic spread and large-cell transformation and portends a significantly worse prognosis.

Clinical Variants

Folliculotropic MF involves the hair follicle and presents with follicular papules, comedonal lesions, alopecia, and mucinous degeneration (follicular mucinosis). It has a predilection for the head and neck, is more aggressive than classic MF, and is resistant to skin-directed therapy. Histology shows a dense folliculotropic infiltrate that may spare the epidermis. Pagetoid reticulosis (Woringer-Kolopp) presents as a solitary hyperkeratotic plaque, usually on an extremity, with indolent behavior and excellent prognosis with local therapy. Granulomatous slack skin is rare, producing lax pendulous skin folds in intertriginous areas from a dense granulomatous infiltrate with elastophagocytosis. Hypopigmented MF is common in children and young adults with darker skin types. It is often CD8-positive (rather than the typical CD4-positive), carries an excellent prognosis, and may be misdiagnosed as vitiligo, pityriasis alba, or pityriasis versicolor.

<image>Clinical photographs showing the three classic stages of mycosis fungoides: patches (erythematous flat lesions), plaques (thickened indurated lesions), and tumors (dome-shaped ulcerated nodules)</image>

Histopathology

Patch stage shows a sparse band-like lymphocytic infiltrate in the upper dermis with epidermotropism, in which lymphocytes align along the basal layer, sometimes with a surrounding halo ("haloed lymphocytes"). Notably, there is minimal spongiosis, which distinguishes MF from eczema. Plaque stage shows a denser dermal infiltrate with more prominent epidermotropism and Pautrier microabscesses (collections of atypical lymphocytes within the epidermis). Tumor stage demonstrates a dense dermal infiltrate with loss of epidermotropism and medium-to-large atypical lymphocytes with cerebriform nuclei. The immunophenotype is CD3-positive, CD4-positive, CD8-negative, and CD45RO-positive, with loss of CD7 and/or CD26 (hypopigmented MF is often CD3-positive, CD4-negative, CD8-positive). TCR gene rearrangement by PCR can detect a clonal T-cell population, which supports the diagnosis but is not independently diagnostic.

Staging (TNMB System - ISCL/EORTC)

The staging system uses tumor (T), node (N), metastasis (M), and blood (B) classifications. T1 denotes patches or plaques involving less than 10 percent of body surface area (T1a for patches only, T1b for plaques). T2 involves 10 percent or more of BSA. T3 indicates tumors of 1 cm or greater. T4 indicates erythroderma covering 80 percent or more of BSA. Nodal involvement ranges from N0 (no abnormal nodes) through N3 (histologically involved nodes). M0 and M1 reflect the absence or presence of visceral involvement. Blood involvement ranges from B0 (less than 5 percent atypical lymphocytes) through B1 (more than 5 percent atypical lymphocytes not meeting B2 criteria) to B2 (1,000 or more Sezary cells per microliter with a positive clone).

Overall staging correlates with prognosis: Stage IA (T1 N0 M0 B0-1) has a 10-year overall survival of approximately 97 percent. Stage IB (T2) drops to approximately 83 percent. Stage IIB (T3) falls to approximately 42 percent. Stage III reflects erythrodermic MF. Stage IVA1 corresponds to Sezary syndrome (B2 involvement), Stage IVA2 to histologically involved nodes (N3), and Stage IVB to visceral involvement (M1).

Sezary Syndrome

Diagnostic Criteria (ISCL)

The diagnosis of Sezary syndrome requires erythroderma covering 80 percent or more of BSA plus at least one of the following: an absolute Sezary cell count of 1,000 or more per microliter, a CD4/CD8 ratio of 10 or greater, aberrant loss of CD7 on 40 percent or more of CD4-positive cells or loss of CD26 on 30 percent or more of CD4-positive cells, or a T-cell clone in blood matching the skin clone by PCR or Southern blot. Clinical features include generalized exfoliative erythroderma, severe pruritus, lymphadenopathy, leonine facies, palmoplantar keratoderma, ectropion, and alopecia. The prognosis is poor with a median survival of 2 to 4 years.

Differentiation from Erythrodermic MF

Sezary syndrome presents as de novo erythroderma with leukemic involvement, while erythrodermic MF develops progressively from pre-existing patches and plaques. In practice, overlap exists, and the distinction is made by blood criteria.

<image>Clinical photograph of Sezary syndrome showing generalized exfoliative erythroderma with leonine facies, alongside peripheral blood smear showing characteristic Sezary cells with cerebriform nuclei</image>

Treatment

Skin-Directed Therapy (Early Stage: IA-IIA)

Topical corticosteroids are first-line for patch-stage MF, using moderate to high potency formulations with complete response in 63 percent of limited patch disease. Topical nitrogen mustard (mechlorethamine) is available as a 0.016 percent gel (Valchlor) applied daily to affected areas, achieving response rates of 50 to 75 percent for T1 and 25 to 35 percent for T2 disease, with contact dermatitis occurring in approximately 30 percent. Topical retinoids include bexarotene 1 percent gel (an RXR agonist) and tazarotene (an RAR agonist, used off-label).

Phototherapy is a cornerstone of early-stage treatment. NB-UVB at 311 nm is effective for patch-stage MF and is used as first-line therapy alongside topicals, administered 2 to 3 times weekly with response rates of 54 to 90 percent. It is less effective for plaque-stage disease due to insufficient penetration. PUVA (psoralen plus UVA) penetrates deeper and is effective for both patches and thin plaques with response rates of 62 to 90 percent, but long-term SCC risk limits cumulative exposure.

Total skin electron beam therapy (TSEBT) delivers 12 to 36 Gy to the entire skin surface, achieving complete response in 60 to 95 percent of T2 to T3 disease. Low-dose TSEBT at 12 Gy maintains efficacy for palliation with less toxicity. Side effects include temporary alopecia, anhidrosis, radiation dermatitis, and nail loss. Localized radiation at low doses (8 to 12 Gy) is often effective for isolated tumors or localized plaques refractory to other skin-directed therapy, reflecting the high radiosensitivity of MF.

Systemic Therapy (Advanced Stage: IIB-IV)

Interferon-alfa combined with phototherapy or retinoids achieves overall response rates of 40 to 70 percent. Oral bexarotene, an RXR-selective retinoid given at 300 mg/m2/day, achieves response rates of 45 to 55 percent and can be combined with other modalities. Its side effects are notable: hypertriglyceridemia is essentially universal, and central hypothyroidism and leukopenia also occur.

HDAC inhibitors offer another systemic option. Vorinostat is FDA-approved for refractory CTCL with an overall response rate of approximately 30 percent. Romidepsin, administered intravenously, is also FDA-approved with an overall response rate of approximately 34 percent. Both work through epigenetic modulation via histone deacetylase inhibition, promoting cell cycle arrest and apoptosis.

Antibody-based therapies include brentuximab vedotin, an anti-CD30 antibody-drug conjugate FDA-approved for CD30-positive CTCL after prior systemic therapy. The ALCANZA trial showed an ORR4 of approximately 56 percent versus 12 percent for physician's choice. CD30 expression of 10 percent or greater on tumor cells is the threshold used. Peripheral neuropathy is the dose-limiting side effect. Mogamulizumab, an anti-CCR4 antibody, is FDA-approved for relapsed or refractory MF and SS. The MAVORIC trial demonstrated superior progression-free survival versus vorinostat with overall response rates of approximately 28 percent for MF and 37 percent for SS. It carries a black box warning for severe dermatitis (GVHD-like reaction in stem cell transplant recipients).

Extracorporeal photopheresis (ECP) is preferred for erythrodermic MF and Sezary syndrome. The process involves leukapheresis, UVA exposure of the buffy coat with 8-MOP, and reinfusion. It induces apoptosis of malignant T cells and immune modulation, with response rates of 30 to 80 percent in erythrodermic MF and SS. It is often combined with interferon, bexarotene, or mogamulizumab.

Chemotherapy with single agents such as gemcitabine (overall response rate approximately 70 percent) or liposomal doxorubicin (overall response rate approximately 40 to 88 percent) is used for aggressive or transformed disease. Multiagent chemotherapy produces limited duration of response and is not curative. Allogeneic stem cell transplant is the only potentially curative option, reserved for young, fit patients with aggressive or refractory disease. Reduced-intensity conditioning is preferred, with long-term disease control in 30 to 50 percent of select patients, though morbidity and mortality are significant.

Large-Cell Transformation

Large-cell transformation is defined as more than 25 percent large cells in biopsy or formation of microscopic nodules of large cells. It occurs in 20 to 55 percent of tumor-stage MF and is associated with rapid progression. Loss of CD30 positivity is adverse, while CD30-positive transformation may respond to brentuximab vedotin. Prognosis is poor with median survival of approximately 2 years post-transformation.

<image>Treatment algorithm for mycosis fungoides showing stage-based approach: skin-directed therapies for early stage (IA-IIA) and systemic therapies for advanced stage (IIB-IVB) with specific agents listed at each decision point</image>

Clinical Pearls

Any persistent "eczema" in a bathing suit distribution that is unresponsive to topical steroids in a middle-aged or older patient should prompt biopsy to exclude MF -- the mean diagnostic delay is 3 to 6 years. Histopathology of early patch-stage MF can be subtle, and clinicopathologic correlation is essential; a single non-diagnostic biopsy does not exclude MF, and serial biopsies from different lesions over time may be required. Hypopigmented MF in young patients with dark skin is frequently misdiagnosed as vitiligo or pityriasis alba, and NB-UVB is the treatment of choice with usually excellent responses. CD30 expression should be assessed on all MF biopsies because CD30-positive disease may respond to brentuximab vedotin regardless of stage. Sezary syndrome has the worst prognosis among CTCL subtypes, and extracorporeal photopheresis combined with systemic agents (interferon, bexarotene, mogamulizumab) is the typical multimodality approach.

References

• Willemze R, et al. The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas. Blood. 2019;133(16):1703-1714
• Olsen EA, et al. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome (ISCL/EORTC). Blood. 2007;110(6):1713-1722
• Prince HM, et al. Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA). Lancet. 2017;390(10095):555-566
• Kim YH, et al. Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC). Lancet Oncol. 2018;19(9):1192-1204
• Hristov AC, et al. Mycosis fungoides and Sezary syndrome: 2019 update on diagnosis, risk-stratification, and management. Am J Hematol. 2019;94(9):1027-1041

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