Section 4 -

Diagnosis of the Early Lesions of Mycosis Fungoides Bruce R. Smoller Professor and Chair Hough Endowed Chair in Pathology Department of Pathology University of Arkansas for Medical Sciences

Click here to download handout in pdf format for the current section (1.70 MB) Context Early diagnosis is a clinical-pathologic correlation that often requires immunologic and molecular data to establish the diagnosis Reliance of purely histologic features raises a differential diagnosis (to be discussed in a later presentation) Usual clinical context is that of long-standing erythematous patches with slight scale Often on buttocks and flanks but can be any site Most common in middle-aged to elderly patients Most common type of CTCL; accounts for about 50% of all cutaneous lymphomas Clinical - Early MF Histologic features Architectural Cytologic Architectural features Cited in literature: Psoriasiform epidermal hyperplasia or atrophy Epidermotropism Single lymphocytes along the DEJ Collections of atypical lymphocytes within the epidermis (Pautrier's microabscesses) Papillary dermal fibrosis Superficial bandlike or patchy infiltrate of lymphocytes "Naked underbelly" sign Statistically good discriminators: Halos around nuclei Pautrier's microabscesses Large single lymphocytes within epidermis Single lymphocytes along dermal epidermal junction Excess numbers of lymphocytes in epidermis compared with amount of spongiosis (epidermotropism) Parameters that are not good discriminators: Papillary dermal fibrosis Acanthosis or atrophy Dying keratinocytes Dermal lymphocyte "atypia" Presence of eosinophils and/or plasma cells Mitotic activity - minimal in early stage lesions Cytologic features Description in literature: Small to medium-sized lymphocytes with indented, cerebriform nuclei (sometimes hyperchromatic) Transformation to larger cells with vesicular nuclei and visible nucleoli occurs later in course of disease and is outside realm of this presentation Study results: Intraepidermal lymphocytes - several studies confirm this as reproducible Size - about size of keratinocyte nuclei Shape - markedly convoluted as at low magnification Dermal lymphocytes - not as useful - difficult to tell reactive dermal T cell from scattered atypical cells Size Shape Histologic features and prognosis Most patients with early patch/plaque stage MF have essentially normal life expectancy Small subset have rapidly progressive disease Not possible to discriminate these patients based upon histologic features of early biopsies - likely molecular fingerprint will provide the answers Overall prognosis Stage 1a (patches and plaques < 10% of body surface area): 97%-98% 10 year survival Stage 1b (patches and plaques > 10% of body surface area): 83% 10 year survival Tumors: 42% 10 year survival Lymph node involvement: 20% 10 year survival Ancillary techniques Immunostains T-cell gene rearrangement studies Useful Immunostains in Mycosis Fungoides CD2 CD3 CD4 CD5 CD8 CD7 CD30 Immunostains in MF Some disagreement about diagnostic criteria Most authors include CD4+ and CD8+ epidermotropic T cell lymphomas into category of MF (WHO) Minority prefer to separate CD8+ epidermotropic T cell lymphomas from the vast majority of CD4+ cases traditionally considered to be MF Recent WHO Classification suggests same clinical course and prognosis and no reason to separate Immunostains in early lesions of MF Study results: CD4+, CD8-, CD7- is most commonly observed phenotype Loss of pan T-cell antigens CD2, CD3, CD5 also seen in minority of early cases 75% of cases, immunostains served only to confirm H and E diagnosis In series of 250 cases, immunostains based upon loss of pan T-cell surface antigens revealed an earlier diagnosis than H and E in 4% of cases - but remember the life expectancy data! T-cell gene rearrangements in Mycosis Fungoides Sensitivity Specificity T-cell gene rearrangements Sensitivity > 80% of patch-stage lesions of MF will demonstrate a clonal rearrangement using PCR technology Useful to confirm diagnosis if clinically suspicious and routine histology is less than fully diagnostic "Negative" result does NOT rule out MF diagnosis Close to 100% of later stage lesions demonstrate clonality, but not often needed in these cases Specificity Clonality has been demonstrated in lymphomatoid papulosis, "parapsoriasis"(small and large plaque), PLEVA, PLC - still controversial how these entities related to T cell lymphoproliferative disorders Also demonstrated in disease with no known potential for malignant transformation: Lichen planus Pigmented purpuric eruption Important to have high index of suspicion when ordering test and to interpret findings in context to avoid over diagnosis "Positive" result does not necessarily imply MF diagnosis Genetic aberrations in MF Chromosomal loss at 10q and abnormalities in p15, p16 and p53 tumor suppressor genes commonly seen in patients with MF - not specific No specific chromosomal translocations associated with MF Differential diagnosis Pityriasis lichenoides chronica Digitate dermatosis (small plaque parapsoriasis, guttate parapsoriasis) Pityriasis rubra pilaris Lymphomatoid papulosis Pityriasis lichenoides chronica Smaller, more discrete lesions Less intense infiltrate Scattered dying keratinocytes (unusual finding in MF) Slight hemorrhage Lack of Pautrier's microabscesses, single atypical lymphocytes within epidermis and along DEJ Digitate dermatosis Characteristic clinical appearance Small foci of epidermotropism, often with mild spongiosis Lymphocyte "atypia" not present No Pautrier's microabscesses Pityriasis rubra pilaris Clinical "skip areas" helpful if present Psoriasiform hyperplasia with scattered dying keratinocytes Pattern of alternating ortho- and parakeratosis Folliculo-centric process Minimal lymphoid infiltrate Lymphomatoid papulosis Often multiple small papules/nodules without plaques Deeper infiltrate than MF Often many eosinophils Cytologic atypia in most cases more dramatic than in early MF Arriving at a final diagnosis In most cases, patients must have an appropriate clinical presentation and course Histologic findings should demonstrate many, if not all, of the established criteria In cases with some uncertainty, confirming the T cell nature (often with loss of surface antigens) can increase certainty Given a high index of suspicion, a positive gene rearrangement results in a high likelihood of a correct diagnosis Diagnostic possibilities Atypical lymphoid infiltrate Suggestive of mycosis fungoides Strongly suggestive of mycosis fungoides Consistent with mycosis fungoides Mycosis fungoides References – Diagnosis of early mycosis fungoides Zackheim H, Amin S, Kashani-Sabet M et al. Prognosis in cutaneous T cell lymphoma by skin stage: long term survival in 489 patients. J Am Acad Dermatol 1999; 40: 418-425. Smoller BR, Santucci M, Wood GS et al. Histopathology and genetics of cutaneous T-cell lymphoma Hematol Oncol Clin North Am 2003; 17: 1277-1311. Nickoloff BJ. Light-microscopic assessment of 100 patients with patch-plaque-stage mycosis fungoides. Am J Dermatopathol 1988; 10: 469-477. Karenko L, Hyytinen E, Sarna A et al. Chromosomal abnormalities in cutaneous T-cell lymphoma and its premalignant conditions as detected by G-banding and interphase cytogenetic methods. J Invest Dermatol 1997; 108: 22-29. Smoller BR, Bishop K, Glusac EJ, Bhargava V, Kim Y, Warnke RA: Re-assessment of lymphocyte immunophenotyping in the diagnosis of patch and plaque stage lesions of mycosis fungoides. Applied Immunohistochemistry 1995; 3: 32-36. Smoller BR, Bishop K, Glusac EJ, Kim YH, Hendrickson MR: Re-evaluation of histologic parameters in diagnosing mycosis fungoides. Am J Surg Pathol 1995; 19:1423-1430. Willemze R, Jaffe ES, Cerroni L et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105: 3768-3785.