Definition/General
Introduction:
Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma, representing 50-60% of all primary cutaneous lymphomas
It is characterized by epidermotropic infiltration of malignant T-lymphocytes with distinctive cerebriform nuclei
The disease typically follows an indolent course with three classical stages: patch, plaque, and tumor
Early diagnosis is challenging due to resemblance to benign inflammatory dermatoses.
Origin:
Originates from mature CD4+ T-helper lymphocytes that have acquired skin-homing properties
Shows clonal T-cell receptor gene rearrangements
Memory T-cell phenotype (CD45RO+) is characteristic
Expresses cutaneous lymphocyte antigen (CLA) which mediates skin tropism
Chronic antigenic stimulation may precede malignant transformation
Tumor microenvironment interactions are crucial for disease progression.
Classification:
WHO-EORTC classification recognizes classical mycosis fungoides and several variants
Folliculotropic mycosis fungoides (involves hair follicles)
Pagetoid reticulosis (localized epidermotropic variant)
Granulomatous slack skin (rare granulomatous variant)
Staging follows TNM system: T (skin involvement), N (lymph nodes), M (visceral involvement), B (blood involvement).
Epidemiology:
Incidence 4-6 cases per million per year
Male predominance (M:F = 1.6-2.4:1)
Peak incidence in 5th-6th decades
Most common primary cutaneous lymphoma worldwide
Geographic clustering reported in some areas
Environmental factors may contribute to pathogenesis
Indian population shows similar demographic patterns with possible regional variations.
Clinical Features
Presentation:
Progressive clinical course through three stages
Patch stage: flat, scaly, erythematous lesions resembling eczema
Plaque stage: raised, indurated lesions with well-defined borders
Tumor stage: large nodular lesions that may ulcerate
Pruritus is prominent throughout all stages
Erythroderma may develop in advanced cases.
Symptoms:
Intense pruritus (>90% of patients)
Burning or stinging sensation
Skin pain in tumor stage
Hair loss (alopecia) particularly in folliculotropic variant
Nail changes (dystrophy, onycholysis)
Constitutional symptoms in advanced disease (fever, weight loss, night sweats)
Secondary bacterial infections due to scratching and skin barrier disruption.
Risk Factors:
Advanced age (peak 5th-6th decades)
Male gender
Chronic inflammatory skin conditions
Occupational chemical exposure (agricultural, industrial)
Environmental toxins (pesticides, solvents)
Immunosuppression (organ transplant, HIV)
Genetic predisposition (familial cases rare)
HLA associations (HLA-DR5, HLA-DQ1).
Screening:
Clinical examination of skin lesions with photography
Dermoscopy may reveal specific features
Skin biopsy from representative lesions
Multiple biopsies often required for diagnosis
Flow cytometry of peripheral blood if Sézary syndrome suspected
Staging workup includes imaging studies and laboratory tests.
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Gross Description
Appearance:
Patch stage: flat, scaly, erythematous patches with fine scale
Plaque stage: raised, indurated plaques with thick scale and well-demarcated borders
Tumor stage: large nodules (>1 cm) that may ulcerate and become fungating
Poikiloderma: combination of atrophy, telangiectasia, and hyperpigmentation
Erythroderma: generalized redness affecting >80% body surface area.
Characteristics:
Asymmetric distribution of lesions
Preference for sun-protected areas (buttocks, trunk, proximal extremities)
Bathing suit distribution pattern characteristic
Well-demarcated borders in plaque stage
Central clearing may create annular patterns
Scale varies from fine to thick and adherent
Color ranges from pink to deep red to violaceous.
Size Location:
Patch lesions: few centimeters to extensive areas
Plaque lesions: typically 2-20 cm in diameter
Tumor lesions: >1 cm, may reach 10+ cm
Predilection sites: buttocks (most common), trunk, thighs, arms
Face involvement usually in advanced stages
Palmoplantar involvement rare but described
Genital involvement occasionally seen.
Multifocality:
Multifocal presentation typical
Bilateral and symmetric distribution common
Progressive spread to new anatomical sites
Lymph node enlargement in advanced stages
Visceral involvement indicates tumor stage
Transformation to large cell lymphoma may occur focally
Secondary cutaneous spread from nodal involvement possible.
Microscopic Description
Histological Features:
Epidermotropism is the hallmark feature (lymphocytes infiltrating epidermis without significant spongiosis)
Cerebriform nuclei with convoluted, coffee-bean-like nuclear contours
Pautrier microabscesses (small collections of malignant lymphocytes within epidermis)
Band-like lymphoid infiltrate in papillary dermis
Basilar epidermotropism along basement membrane.
Cellular Characteristics:
Small to medium-sized lymphocytes with characteristic cerebriform nuclei
Hyperchromatic, convoluted nuclei with grooves and folds
Scant cytoplasm with irregular cell borders
Nuclear size similar to or slightly larger than dermal lymphocytes
Mitotic activity generally low in early stages
Large cell transformation may occur with increased nuclear size and prominent nucleoli.
Architectural Patterns:
Epidermotropism without spongiosis (pathognomonic early feature)
Linear arrangement of lymphocytes along basilar epidermis
Pautrier microabscesses within epidermis (highly characteristic)
Band-like dermal infiltrate in upper dermis
Perivascular and periadnexal distribution in dermis
Follicular involvement in folliculotropic variant.
Grading Criteria:
Clinical staging more important than histological grading
Degree of epidermotropism varies with stage
Dermal infiltrate density increases with progression
Large cell transformation (>25% large cells) indicates aggressive behavior
Loss of epidermotropism in advanced stages
Ki-67 proliferation index increases with stage progression.
Immunohistochemistry
Positive Markers:
CD3 (pan-T-cell marker, positive)
CD4 (positive in >90% of cases)
CD2 (usually positive)
CD5 (may be lost in tumor cells)
CD45RO (memory T-cell marker, positive)
Cutaneous lymphocyte antigen (CLA) (skin-homing marker)
CCR4 (chemokine receptor, often positive)
PD-1 (variable expression).
Negative Markers:
CD7 (characteristically lost in >80% cases)
CD8 (negative in typical MF)
CD20 (B-cell marker, negative)
CD30 (negative except in large cell transformation)
CD56 (NK marker, negative)
TIA-1 (cytotoxic marker, negative in typical MF)
Granzyme B (negative in typical MF)
EBER (EBV marker, negative).
Diagnostic Utility:
Loss of CD7 is most important diagnostic marker (aberrant T-cell phenotype)
CD4+ helper phenotype predominant
Preservation of CD2, CD3, CD5 supports T-cell lineage
CLA positivity confirms skin-homing phenotype
Ki-67 shows low proliferation in early stages (<10%)
Double immunostaining (CD3/CD7) helpful to identify aberrant cells.
Molecular Subtypes:
Classical MF (CD4+, CD7-)
CD8+ variant (rare, more aggressive)
CD4-/CD8- variant (double-negative, aggressive)
Folliculotropic MF (similar immunoprofile)
Large cell transformation (CD30+ in transformed cells)
Granulomatous slack skin (CD68+ macrophages prominent)
Pagetoid reticulosis (often CD8+ phenotype).
Molecular/Genetic
Genetic Mutations:
Clonal T-cell receptor gene rearrangements (diagnostic requirement)
TP53 mutations in advanced stages and transformation
CDKN2A/B deletions (p16/p15 tumor suppressors)
FAS mutations (apoptosis resistance)
PIK3CA mutations
PLCG1 mutations
TNFRSF1B mutations
Complex chromosomal abnormalities in tumor stage.
Molecular Markers:
T-cell receptor clonality by PCR or Southern blot
Loss of heterozygosity at multiple chromosomal loci
Th2 cytokine profile (IL-4, IL-5, IL-10)
Increased IL-10 production
Decreased interferon-γ
Abnormal apoptosis resistance
Telomerase activity increased
MicroRNA dysregulation (miR-21 upregulation).
Prognostic Significance:
Stage is most important prognostic factor
Early stage (IA-IIA): 10-year survival >80%
Advanced stage (IIB-IV): 10-year survival <50%
Large cell transformation indicates poor prognosis (median survival 1-2 years)
Folliculotropic variant has worse prognosis than classical MF
Age >60 years and thick plaques are poor prognostic factors.
Therapeutic Targets:
Topical therapies: nitrogen mustard, carmustine, corticosteroids
Phototherapy: PUVA, narrowband UVB
Radiation therapy: total skin electron beam, localized RT
Systemic retinoids: bexarotene (RXR agonist)
HDAC inhibitors: vorinostat, romidepsin
Monoclonal antibodies: alemtuzumab (anti-CD52)
Immunomodulators: interferon-α, imiquimod.
Differential Diagnosis
Similar Entities:
Chronic eczematous dermatitis (atopic, contact, nummular)
Psoriasis (chronic plaque type)
Pityriasis lichenoides chronica
Large plaque parapsoriasis
Drug eruptions
Erythroderma of other causes
Other cutaneous lymphomas (B-cell, NK/T-cell)
Pseudolymphoma (lymphomatoid contact dermatitis).
Distinguishing Features:
Mycosis fungoides: epidermotropism without spongiosis, cerebriform nuclei, CD7 loss, clonal TCR
Chronic dermatitis: spongiosis, eosinophils, polyclonal infiltrate
Psoriasis: acanthosis, neutrophils, Munro microabscesses
Parapsoriasis: interface changes, may be preneoplastic
Drug eruptions: eosinophils, temporal relationship
B-cell lymphomas: CD20+, nodular pattern.
Diagnostic Challenges:
Early patch stage closely mimics benign dermatoses
Minimal epidermotropism in some cases
Spongiosis may be present in early lesions
Polyclonal infiltrates in some early cases
Large cell transformation may obscure original diagnosis
Folliculotropic variant lacks epidermotropism
Multiple biopsies often required for definitive diagnosis.
Rare Variants:
Folliculotropic mycosis fungoides (involves follicles, worse prognosis)
Pagetoid reticulosis (localized, excellent prognosis)
Granulomatous slack skin (granulomatous inflammation)
Hypopigmented MF (common in children and dark-skinned patients)
Poikilodermatous MF
Bullous MF (rare)
Palmoplanter MF
Invisible MF (minimal clinical findings).
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Skin biopsy from [anatomical site], [patch/plaque/tumor] lesion
Primary Diagnosis
Mycosis fungoides, [classical/variant type]
WHO-EORTC Classification
Mycosis fungoides (WHO-EORTC classification)
Histological Features
Shows epidermotropism with cerebriform lymphocytes infiltrating epidermis without significant spongiosis
Epidermotropism Assessment
Epidermotropism: [prominent/moderate/minimal]; Pattern: [basal/full thickness]; Pautrier microabscesses: [present/absent]
Cellular Morphology
Lymphocytes show cerebriform nuclei with convoluted contours; Size: [small/medium/large cell component if present]
Dermal Infiltrate
Dermal infiltrate: [band-like/perivascular]; Density: [sparse/moderate/dense]; Distribution: [superficial/deep]
Immunohistochemistry
CD3+, CD4+, CD2+, CD7- (loss in tumor cells), CD8-, CD20-, Ki-67: [percentage]%
Molecular Studies
T-cell receptor gene rearrangement: clonal [TCR-gamma/TCR-beta]
Clinical Stage Assessment
Clinical stage: [IA/IB/IIA/IIB/III/IV]; T-classification: [T1/T2/T3/T4]
Final Diagnosis
Mycosis fungoides, [specify variant if applicable], WHO-EORTC classification