Mycosis Fungoides Treatment Guidelines: Helping Clinicians with Early Diagnosis

Early diagnosis of mycosis fungoides (MF), a primary cutaneous T-cell lymphoma (CTCL), is important to allow for timely management and optimal prognosis. A panel of experts including 6 dermatologists, 1 hematologist, 1 oncologist, and 2 dermatopathologists met to identify real-life barriers to early MF diagnosis and provide guidance for clinicians evaluating patients with chronic rash.

Real-Life Barriers to Early MF Diagnosis

• Delays during initial diagnosis typically occur.
  • MF lesions may be easily overlooked since they occur on areas of the skin usually protected from the sun (sanctuary sites).
  • MF variants are frequently misdiagnosed as physicians may be unaware of intra-individual variability of MF lesions.

• Delays occur during pathologic assessment as well.
  • Shave biopsies are useful in classical MF but not sufficient in evaluating important diagnostic features for MF variants.
  • General dermatopathologists and pathologists may not be sufficiently specialized to recognize MF variant characteristics.
  • Sampling errors may occur, especially with folliculotropic MF which requires deep sectioning of specimens which may not be performed if adnexal structures, such as hair follicles, are absent.
  • Time from biopsy to pathology report can be prolonged, especially when performed by nonspecialists. This has been compounded by COVID-19 pandemic-induced delays.

• Decreased access to specialized care is an issue for patients with limited or no medical insurance due to the high cost of MF therapy.

How to Correctly Diagnose MF

• Perform a thorough physical examination and identify suspected lesions, taking multiple biopsies from representative lesions and evaluate them for pathology. MF can resemble vitiligo, psoriasis, atopic dermatitis, fungal infection, and can sometimes occur on sun-exposed areas of the skin.
• Use a validated scoring system to correlate between clinical and histopathologic findings. The following scoring systems are effective for classic MF, but not for MF variants:
  • The International Society for Cutaneous Lymphoma (ISCL) score for early MF diagnosis is based on clinical, histopathologic, and immunohistochemical findings, as well as T-cell receptor (TCR) gene rearrangement. This is useful for physicians who see few MF patients.
  • The Guitart et al. criteria scores pathology based on assessments such as infiltrate density, nature, and extent of epidermotropism, and lymphocytic atypia grade.
  • Classic early histopathologic MF features reveal superficial lymphoid infiltrates with epidermotropism. Early-stage lesions often do not show a typical pattern, however; lymphocytes may show minimal or no atypical features and little or no evidence of epidermotropism.

• Immunophenotyping of the skin, specifically intraepidermal lymphocytes, is important for proper diagnosis.
  • A panel of markers including CD3, CD4, CD5, CD7, CD8, and CD20 can aid diagnosis. Intra-epidermal T cells in early-stage MF usually have a CD3⁺CD4⁺CD8^– phenotype; other phenotypes that have been observed include CD3⁺CD4^–CD8⁺ and CD3⁺CD4^–CD8^–.
  • Polymerase chain reaction (PCR) to identify TCR gene rearrangement is helpful, especially in histopathologically suspicious but not diagnostic cases.

  • High-throughput, next-generation TCR skin biopsy gene sequencing or peripheral blood samples is an emerging technique that is potentially more specific than PCR-based techniques for differentiating MF from benign inflammatory dermatoses.

  • Ultimately, clinical findings should guide the diagnostic process.

• To increase biopsy yield, discontinue topical corticosteroids and other skin-directed therapies 2 or more weeks before biopsy, have patients avoid sunbathing, and perform 2 or more punch biopsies of the most representative lesion.
  • If lesions are variable, take multiple biopsies from several lesions. A punch size of 6 mm in diameter is preferred.
  • Perform deeper punch biopsies in cases where adnexotropic/folliculotropic involvement is suspected. If hair follicles are not observed, order additional deeper sections.
  • If a biopsy is inconclusive, monitor lesions for change or progression.

Tools for Clinicians

• Increase awareness among physicians, especially dermatologists and oncologists, of the characteristics and proper treatment for MF.
  • Utilize diagnostic checklists (Boxes 1 and 2 below) proposed by the panelists to help clinicians recognize MF and refer patients for further evaluation.

• Patients with clinically suspected MF should be referred directly to centers of excellence for a complete diagnostic workup. Biopsies should be sent to a dermatopathologist or pathologist who specializes in CTCL.

Box 1 Features Suggestive of MF or Variants

Main clinical clues for early MF or MF variant that should raise the red flag

Persistent and/or progressive erythematous patches/plaques, sometimes with skin atrophy, especially in sanctuary areas Persistent and/or progressive hypopigmented or hyperpigmented patches/plaques, sometimes with skin atrophy, especially in sanctuary areas Elongated patches/plaques, especially that follow the cleavage lines, or kidney-shaped lesions located along the sides of the trunk and/or inner aspects of the extremities Nonspecific dermatitis’ on nonsanctuary areas that may be associated with pruritus, especially if progressive Any unusual atopic dermatitis: • Presumed ‘late-onset atopic dermatitis’, especially in the absence of a family/personal history of atopic dermatitis or atopic diathesis during childhood • Absence of pruritus • Prominent infiltration/induration of lesions on palpation • Worsening of an eruption diagnosed as atopic dermatitis during treatment with appropriate therapies: topical agents and systemic treatment Any unusual psoriasis vulgaris: • Psoriasiform lesions with erosions/ulceration and/or impetiginization • Worsening of an eruption diagnosed as psoriasis during treatment with appropriate therapies: topical agents and systemic treatment • ‘Psoriatic lesions’ with crosions/ulceration and/or impetiginization Any unusual keratoderma palmaris and/or plantaris after excluding the most common causes: • Psoriasis, contact dermatitis/atopic dermatitis, and/or tinea Any unusual follicular-based rash: • Erythematous, hypopigmented and/or hyperpigmented patches/ plaques with follicular accentuation • Lesions resembling keratosis pilaris but in an unusual distribution and/or in clusters sometimes on faint base • Acneiform eruptions in the absence of any relevant drug or known relevant associated condition; comedones in locations not characteristic of acne or hidradenitis suppurativa; acneiform and concomitant eczematous or psoriasiform lesions in the same areas • Localized hair loss on what seems to be ‘dermatitis’ or in areas without lesions but only with scales (also look for focal eyebrow loss) Any unusual chronic pigmented purpuric dermatosis: • Patches/plaques in an extensive distribution (beyond the lower legs, occasionally with the buttocks — the usual locations in most cases) • Coexisting with ‘nonspecific dermatitis’

Box 2 Histopathologic and Immunopathologic Checklist

Histopathologic features suggestive of early MF	Pitfalls
Epidermis •Pautrier micro-abscesses •Lymphocytic epidermotropism generally without spongiosis •Epidermal lymphocytes larger than dermal lymphocytes •Tagging (lining up) of lymphocytes at the dermoepidermal junction •High nuclear variability, hyperchromatic and/or folded nuclei, pericellular halo	•Spongiotic Langerhans’ cell vesicles •Spongiosis •Interface or lichenoid dermatitis •Nuclear irregularities seen with interface/lichenoid dermatitis
Dermis •Superficial dermal band-like lymphoid infiltrate •Fibrosis of papillary dermis(sign of chronicity) •Variant folliculotropic MF: perifollicular lymphocytic infiltrate with folliculotropism with/without follicular mucinosis	•Lichenoid dermatitis, PPD •Chronic/lichenified dermatitis •Perifollicular infiltrates may be sparse
Immunopathologic features suggestive of early MF •Increased CD4:CD8 ratio (CD4-, CD8+ or CD4-CD8-) • Loss of T-cell-marker expression on CD4+ lymphocytes	•CD4-CD8 can also be observed after skin-directed (eg topical steroid) therapy •BID (drug- and contacted-related) associated with loss of pan T-cell marker, particularly CD7

Disclosure: Several study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.