Modern Pathology (2017) 30, 761–772 © 2017 USCAP, Inc All rights reserved 0893-3952/17 $32.00 761 Primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphomas: reappraisal of a provisional entity in the 2016 WHO classification of cutaneous lymphomas Joan Guitart1, M Estela Martinez-Escala1, Antonio Subtil2, Madeleine Duvic3, Melissa P Pulitzer4, Elise A Olsen5, Ellen Kim6, Alain H Rook6, Sara S Samimi6, Gary S Wood7, Michael Girardi2, Jacqueline Junkins-Hopkins8, Doina S Ivan3, M Angelica Selim5, Kimberly A Sable1, Pooja Virmani5, Laura B Pincus9, Michael T Tetzlaff3, Jinah Kim10 and Youn H Kim10 1Department of Dermatology and Pathology, Northwestern University Feinberg Medical School, Chicago, IL, USA; 2Department of Dermatology and Pathology, Yale University, New Haven, CT, USA; 3Departments of Dermatology and Pathology, MD Anderson, Houston, TX, USA; 4Department of Dermatology and Pathology, Sloan Kettering Cancer Center, New York, NY, USA; 5Department of Dermatology and Pathology, Duke University, Durham, NC, USA; 6Department of Dermatology and Pathology, University of Pennsylvania, Philadelphia, PA, USA; 7Department of Dermatology and Pathology, University of Wisconsin VAMC, Madison, WI, USA; 8Department of Dermatology and Pathology, Ackerman Academy, New York, NY, USA; 9Department of Dermatology and Pathology, University of California in San Francisco, San Francisco, CA, USA and 10Department of Dermatology and Pathology, Stanford University, Stanford, CA, USA Primary cutaneous CD8-positive aggressive epidermotropic T-cell lymphoma is a rare and poorly characterized variant of cutaneous lymphoma still considered a provisional entity in the latest 2016 World Health Organization Classification of Cutaneous lymphomas. We sought to better characterize and provide diagnostic and therapeutic guidance of this rare cutaneous lymphoma. Thirty-four patients with a median age of 77 years (range 19–89 years) presented primarily with extensive annular necrotic plaques or tumor lesions with frequent mucous membrane involvement. The 5-year survival was 32% with a median survival of 12 months. A subset of 17 patients had a prodrome of chronic patches prior to the development of aggressive ulcerative lesions. We identified cases with lack of CD8 or αβ T-cell receptor expression yet with similar clinical and pathological presentation. Allogeneic stem cell transplantation provided partial or complete remissions in 5/6 patients. We recommend the term primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma as this more broad designation better describes this clinical-pathologic presentation, which allows the inclusion of cases with CD8 negative and/or αβ/γδ T-cell receptor chain double-positive or double-negative expression. We have identified early skin signs of chronic patch/plaque lesions that are often misdiagnosed as eczema, psoriasis, or mycosis fungoides. Our experience confirms the poor prognosis of this entity and highlights the inefficacy of our standard therapies with the exception of allogeneic stem cell transplantation in selected cases. Modern Pathology (2017) 30, 761–772; doi:10.1038/modpathol.2016.240; published online 27 January 2017 Primary cutaneous CD8-positive aggressive epider- 2016 classification of cutaneous lymphomas.1 In motropic T-cell lymphoma remains a provisional part, the problem with CD8-positive aggressive entity in the latest World Health Organization epidermotropic T-cell lymphoma is that they have been poorly characterized to date owing to the rarity of the condition. Historically, this condition was Correspondence: Dr J Guitart, MD, Department of Dermatology and known in the dermatology literature as generalized Pathology, Northwestern University Feinberg School of Medicine pagetoid reticulosis or Ketron–Goodman disease and 676N, St Clair street, Suite 1600, Chicago, IL 60611, USA. was characterized by rapidly evolving and exten- E-mail: [email protected] Received 19 September 2016; revised 15 December 2016; accepted sively ulcerated annular plaques associated with a 19 December 2016; published online 27 January 2017 poor prognosis. The histopathology has been www.modernpathology.org Primary cutaneous cytotoxic T-cell lymphoma 762 J Guitart et al reported to be characteristic, with an infiltrate of presented to the group. Clinical data including monomorphous medium-sized atypical lymphocytes gender, age, race, nature, extent and duration of the involving the epidermal thickness in a so-called lesions, constitutional symptoms, past medical his- pagetoid pattern. Although clinically this condition tory, results of staging bone marrow biopsy and was known to result in widespread ulcerations from imaging tests, response to therapies, outcome, and epidermal necrosis, the cytotoxic phenotype with duration of follow-up were obtained. The original CD8 expression was first reported by Agnarsson histopathological slides including immunohisto- et al. in 1990, and the term CD8-positive aggressive chemical markers were reviewed by the group and epidermotropic T-cell lymphoma was first coined by a consensus diagnosis was rendered. Skin biopsies Berti et al. in 1999.2,3 We have observed cases with from the 30 selected patients were reviewed. Several similar clinical-pathologic features, cytotoxicity, and parameters including the distribution of the infiltrate aggressive course without CD8 expression. Our goal within the epidermal, dermal and subcutaneous is to redefine this entity using the more broad and compartments, distribution of the intraepidermal inclusive term primary cutaneous aggressive epider- lymphocytes, cell size, adnexotropic features (folli- motropic cytotoxic T-cell lymphoma (PCAECyTCL). culotropism and syringotropism), presence or Herein we present the largest series of primary absence of epidermal necrosis, interface reaction, cutaneous aggressive epidermotropic cytotoxic ulceration, hemorrhage, angiocentricity, or vasculitis T-cell lymphoma reported to date, collected from were assessed by the group on a multiheaded several cutaneous lymphoma centers in the United microscope. Other notable histological findings such States. as presence of other inflammatory cells (eosinophils, neutrophils, plasma cells, histiocytes), granuloma formation, mucin deposits, karyorrhexis, or hemo- Materials and methods phagocytosis were documented. Descriptive statistics including median (with A group of pathologists and dermatologists from range) and counts (with percentages) were deter- some of the largest cutaneous lymphoma centers in mined and compared using U Mann − Whitney and the United States met on two occasions in Chicago to Fisher’s Exact tests, respectively. Five-year survival review each institutional experience including the rate was performed using Kaplan–Meier method. clinical and pathological material of primary cuta- Categorical clinical and pathological characteristics neous aggressive epidermotropic cytotoxic T-cell were compared using log-rank tests to overall out- lymphoma. Approval from the Institutional Review come and survival rates. Survival analysis was Board at Northwestern University encompassing all performed from date of diagnosis. As this was a centers was obtained. Entering criteria included a retrospective analysis, data were missing for some clinical presentation with patches, plaques, or cases. All analyses were done on the available data. nodules with erosive or necrotic features covering All tests were performed using SPSS statistics soft- 41% of the body surface area. Cases with localized ware (Chicago, IL, USA) with a type I error rate of pagetoid reticulosis (Woringer–Kolopp disease) were 5%. P-valueso0.05 were considered indicative of excluded. The cases included were characterized by a trend. (1) a pagetoid pattern of T-cells with expression of at least one pan-T-cell marker (2) positivity for CD8 and βF1 (αβ T-cell receptor heterodimer) and (3) negativ- ity for the γδ T-cell receptor heterodimer marker Results γ (clone 3.20, Thermo/Fisher Scientific, Waltham, Clinical Data MA, USA). However, these criteria were revised when we encountered cases that fulfilled clinico- Upon a consensus review of a total of 52 cases, 30 pathologic criteria but with variable CD8 and/or were deemed to fulfill the diagnostic criteria and T-cell receptor immunophenotype. An extensive confirmed by the group as primary cutaneous immunohistochemistry panel of monoclonal antibo- aggressive epidermotropic cytotoxic T-cell lym- dies against CD2, CD3, CD4, CD5, CD7, CD8, CD20, phoma and 4 additional cases were added to the CD30, CD45RA, CD56, T-cell intracellular antigen-1, series over the ensuing months (Table 1). One case and granzyme B was performed in most cases. In had been previously published as a case report.4 All addition Epstein–Barr virus ribonucleic acid expres- cases were collected between 1995 and 2015. Most of sion was evaluated using Epstein–Barr encoding the cases excluded were redefined after reviewing region in situ hybridization and T-cell receptor clinical and histological parameters by the group as clonality analysis with polymerase chain reaction CD8-positive mycosis fungoides, pagetoid reticulosis based methods using BIOMED-2 protocol was or dermal CD8-positive T-cell lymphomas without reported when available from skin, blood, nodal, marked epidermotropism or pagetoid features. and bone marrow biopsy samples. The cohort consisted of 34 patients (25 male, 9 Electronic medical records were reviewed and female) with a median age of 77 years (range