Diagnosis of gamma/delta mycosis fungoides requires longitudinal clinical observation

Abstract

To the Editor: It is unclear whether epidermotropic cutaneous T cell lymphomas (CTCLs) exhibiting a T-cell receptor gamma delta (TCRγδ) phenotype initially presenting with patches and plaques should be considered a variant of mycosis fungoides (γδ-MF) or as primary cutaneous γδ T cell lymphomas (PCγδTCL).1Guitart J. Weisenburger D.D. Subtil A. et al.Cutaneous γδ T-cell lymphomas: a spectrum of presentations with overlap with other cytotoxic lymphomas.Am J Surg Pathol. 2012; 36: 1656-1665Crossref PubMed Google Scholar, 2Merrill E.D. Agbay R. Miranda R.N. et al.Primary cutaneous T-cell lymphomas showing gamma-delta (γδ) phenotype and predominantly epidermotropic pattern are clinicopathologically distinct from classic primary cutaneous γδ T-cell lymphomas.Am J Surg Pathol. 2017; 41: 204-215Crossref PubMed Scopus (40) Google Scholar, 3Kempf W. Kazakov D.V. Scheidegger P.E. Schlaak M. Tantcheva-Poor I. Two cases of primary cutaneous lymphoma with a γ/δ+ phenotype and an indolent course: further evidence of heterogeneity of cutaneous γ/δ+ T-cell lymphomas.Am J Dermatopathol. 2014; 36: 570-577Crossref PubMed Scopus (22) Google Scholar Because PCγδTCL is considered an aggressive lymphoma,4Toro J.R. Liewehr D.J. Pabby N. et al.Gamma-delta T-cell phenotype is associated with significantly decreased survival in cutaneous T-cell lymphoma.Blood. 2003; 101: 3407-3412Crossref PubMed Scopus (229) Google Scholar the misclassification of epidermotropic PCγδTCL as MF may delay the decision to use systemic treatments. Our objective was to identify unique features that differentiate γδ-MF from epidermotropic PCγδTCL. We reviewed 4 patients (2 women and 2 men 39-71 years of age) from our cutaneous lymphoma clinic who presented with features resembling early-stage MF (stages IA-IB) and who had the TCRγδ phenotype. The clinical courses and histopathologic and immunophenotypic profiles of each patient are described in detail (Supplemental Tables I and II available via Mendeley at https://doi.org/10.17632/fhww2x8yy6.2). Cutaneous signs preceded the first diagnostic biopsy specimen by a median of 20 months (range 6-48 months), with a median follow-up of 64 months. Stage progression was noted in 3 patients, and 1 patient died. Besides case 1, all patients presented with patches and plaques on the distal extremities or the face rather than on sun-protected areas typical for MF. When disease progressed to tumors, the localization was atypical for classic MF (ie, the face and plantar aspects of the feet; Fig 1 and Supplemental Fig S1). Histologically, the infiltrate was indistinguishable from classic early-stage MF (Supplemental Figs S2 and S3). Immunophenotypically, cases demonstrated cytotoxic markers (granzyme B or T-cell intracellular antigen 1), a double-negative phenotype (CD4−/CD8−), an absence of TCR-βF1, positivity for TCRγδ, and monoclonal rearrangements of TCRγ genes. In all cases, Epstein–Barr virus–encoded small RNA in situ hybridization, peripheral blood flow cytometric analysis, and positron emission tomography–computed tomography scan for systemic involvement were negative. In cases 1 and 2, lymphoma was controlled by skin-directed therapies, while a combination of skin-directed and systemic therapies failed to control the aggressive disease in cases 3 and 4. An additional 29 similar cases were identified in the published literature (Supplemental Table III). Initial cutaneous lesions developed in non–sun exposed regions in approximately half of cases with a majority demonstrating a CD4−/CD8− double negative phenotype. There was an average survival of 107 months (8.9 years) from the onset of symptoms and an approximate average survival from the date of diagnosis of ≥26 months. Stage progression was noted in approximately 50% of patients, with 2 patients dying of disease. In conclusion, CTCLs clinically and histologically presenting as early-stage MF with a cytotoxic and γδ phenotype seem to have a more aggressive disease course compared with classic MF. We suggest reserving the diagnosis of γδ-MF only after an indolent clinical course is established. Patches and plaques beyond the bathing suit area, the atypical location of early tumors, γδ-phenotype, an aberrant immunophenotype (CD4−/CD8−, activated cytotoxic molecules), and early disease progression should prompt more aggressive clinical follow-up and the consideration of early systemic therapy because these patients are better diagnosed with primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma5Guitart J. Estela Martinez-Escala M. Subtil A. et al.Primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphomas: reappraisal of a provisional entity in the 2016 WHO classification of cutaneous lymphomas.Mod Pathol. 2017; 30: 761-772Crossref PubMed Scopus (61) Google Scholar or epidermotropic PCγδTCL.