Mycosis Fungoides (MF)

What Is It?

Clinical Stages

1. Patch Stage

• Flat, macular, or slightly elevated patches, usually ≥5 cm
• Favor the "bathing suit area" - lower abdomen, buttocks, upper thighs, breasts in women
• Resemble eczema; pruritus (sometimes severe) is common
• Variants at this stage include poikiloderma vasculare atrophicans, large-plaque parapsoriasis, and "invisible MF" (histologically proven but visually subtle)
• Biopsy may not be diagnostic early on

Patch-stage MF: erythematous scaly patches on the trunk (Andrews' Diseases of the Skin)

2. Plaque Stage

• Lesions become more infiltrated, may resemble psoriasis or granulomatous dermatitis
• Plaques can reach up to 30 cm
• Palms and soles may be involved with hyperkeratotic, fissuring plaques
• Diagnosis is usually confirmed at this stage with biopsy

3. Tumor Stage

• Large nodules arise on infiltrated plaques
• Ulceration may occur
• Lymph node enlargement typically develops (nontender, firm, freely movable)
• A rare d'emblée form presents with tumors from the outset with no prior patches/plaques

Variants

• Folliculotropic MF - tumor cells invade hair follicles; can resemble lichen nitidus or lichen spinulosus
• Syringotropic MF - involves sweat glands
• Hypopigmented MF - predominates in dark-skinned children
• Granulomatous MF - poorer prognosis and poorer response to skin-directed therapy
• CD8+ MF - rare suppressor cell variant; can behave indolently or aggressively
• Pagetoid reticulosis (Woringer-Kolopp) - solitary lesion, excellent prognosis
• Vesicular/bullous, verrucous/hyperkeratotic, and pigmented purpura-like forms also exist

Histopathology

• Neoplastic T cells infiltrate the epidermis and upper dermis
• Epidermotropism - lymphocytes migrating into the epidermis is the hallmark
• Pautrier microabscesses - collections of atypical lymphocytes within the epidermis (highly characteristic but not always present)
• Tumor cells have cerebriform nuclei - hyperconvoluted, deeply indented nuclear membranes
• Dermal infiltrate is band-like in the upper dermis in patch stage
• CD4+, CD45RO+ (memory T-cell) immunophenotype in most cases

Pathogenesis

• MF cells express cutaneous lymphocyte antigen (CLA), which binds E-selectin on inflamed skin endothelium, enabling skin homing
• CCR4 (a chemokine receptor) is also expressed, with its ligand on basal keratinocytes
• Early MF: Th1-dominant environment with CD8+ tumor-infiltrating lymphocytes (TILs) that may suppress the malignant clone. Patients with >20% CD8+ cells survive longer
• Advanced MF/Sézary syndrome: shift to Th2 environment (via IL-4, IL-10), which downregulates suppressor cell function and allows clonal expansion
• Common chromosomal changes: gain of 7q36 and 7q21-22, loss of 5q13 and 9p21 (distinct from Sézary syndrome)
• Circulating malignant cells can be identified by flow cytometry as CD4+/CD7- or CD4+/CD26-

Staging (TNMB System)

Prognosis

• Stage IA: Life expectancy identical to general population; only 8-9% progress; only 2% die of disease
• Stage IB (T2): Median survival 11.7-15.6 years; 24% progress
• T3 (tumor stage): Median survival 3.2-8.4 years
• T4 (erythroderma): Median survival 1.8-3.7 years
• Palpable adenopathy: median survival 7.7 years vs. 21.8 years without
• Key negative prognostic factors: lymphadenopathy, tumors, cutaneous ulceration (any one reduces survival; all three together = median 1-year survival)
• Worse prognosis in non-Caucasian patients with early-onset MF, especially African American women
• Robbins Pathology notes median survival of ~10 years; transformation to aggressive T-cell lymphoma occasionally occurs as a terminal event

Relationship to Sézary Syndrome

• MF: progressive patch → plaque → tumor stages; extracutaneous disease only late
• Sézary syndrome: presents with generalized erythroderma + leukemia of cerebriform "Sézary cells" + generalized lymphadenopathy; skin rarely forms tumors; worse prognosis (minority survive 5 years)

Treatment (Skin-Directed)

• Topical corticosteroids (especially stage IA)
• Topical nitrogen mustard (mechlorethamine)
• Topical carmustine (BCNU)
• Phototherapy: Narrowband UVB (patch stage), PUVA (psoralen + UVA) for deeper plaques
• Total skin electron beam therapy (TSEBT)
• Topical retinoids (bexarotene gel)

• Systemic retinoids (bexarotene), interferon-alpha, extracorporeal photopheresis
• Targeted therapies: romidepsin, vorinostat (HDAC inhibitors), mogamulizumab (anti-CCR4)
• Systemic chemotherapy is reserved for refractory/advanced disease; early aggressive chemotherapy is not indicated given excessive morbidity and lack of curative benefit