Primary cutaneous CD8‐positive aggressive epidermotropic cytotoxic T‐cell lymphoma initially demonstrating near‐complete metabolic response to BV‐CHEP

Dear Editors, A previously healthy 63-year-old male was referred to our tertiary dermatology clinic with a 6-month history of a disseminated pruritic, weeping rash. Prior biopsies of skin lesions and bacterial swabs demonstrated spongiotic dermatitis and chronic folliculitis with methicillin-susceptible Staphylococcus aureus, suggesting concomitant folliculitis and eczema. The patient was initially managed as infected eczema with multiple courses of oral antibiotics and topical corticosteroids. However, the patient's cutaneous eruption failed to improve and continued to evolve rapidly into ulcerated plaques and tumor-like nodules. Clinical examination showed erythematous plaques with crusting and folliculitis on his scalp. A polymorphic eruption was observed on the trunk and limbs, consisting of impetiginized, crusted follicular- and non-follicular-based papules and plaques, erosions, ecthyma-like plaques, and eczematous plaques. Intertriginous eroded ulcerated plaques with overlying slough were seen in his groin folds and axillae. Large nodules occupied his submental space and right axilla (Figure 1). Blood tests on admission were unremarkable, except for mild eosinophilia (0.69 × 109/l; reference: < 0.5 × 109/l) and elevated C-reactive protein (20 mg/l; reference: < 5 mg/l). Based on his previous histopathology and mild eosinophilia, a broad differential diagnosis of cutaneous T-cell lymphoma (such as tumor-stage mycosis fungoides), kerion, atypical infection, pemphigus foliaceus, and parapsoriasis were considered. Further skin swabs and biopsies were taken from his left axilla, abdomen, right axillary, and submental nodule. Tissue culture was positive for Proteus mirabilis and Klebsiella pneumonia with negative mycology on culture and periodic acid-Schiff stain. On histology, the tumor comprised an epidermotropic lymphoma formed by atypical lymphoid cells with enlarged nuclei, variably apparent nucleoli, and limited eosinophilic to clear cytoplasm. Extensive ulceration, with the limited viable epidermis present, showed prominent epidermotropism and adnexotropism (Figure 2). Immunohistochemistry revealed that the neoplastic cells were CD3- and CD8-positive, βF1-expressing T lymphocytes with aberrant loss of CD5. No expression of CD56 or Epstein-Barr virus-encoded RNA (EBER) was detected. Only scant labeling of the malignant population for CD30 was observed. CD4 expression was equivocal or probable in a minor subset of the neoplastic cells (Figure 2). Flow-cytometry immunophenotyping of peripheral blood did not show B-cell or aberrant T-cell populations. The histological findings supported an epidermotropic T-cell lymphoma with specific differentials of primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma (PCAECyTCL), CD8-positive mycosis fungoides with large cell transformation, and secondary involvement by nodal T-cell lymphoma. Given the acute and aggressive progression of the patient's lesions, PCAECyTCL was the favored diagnosis following a multidisciplinary discussion with hematology and dermatopathology departments. To balance treatment response and infection risk, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) were initiated as bridging chemotherapy, followed by brentuximab vedotin, cyclophosphamide, doxorubicin, etoposide, and prednisone (BV-CHEP) for five cycles. Brentuximab CHEP was selected as a more definitive therapy once a degree of CD30 expression was established based on regulatory requirements and the abysmal prognosis in PCAECyTCL treated with standard CHOP regimens. BV-CHEP outcomes in a presented phase II trial showed no significant difference in terms of CD30 expression.1, 2 There was an upfront intention to pursue an allogeneic bone marrow transplant if complete remission was achieved and a suitable donor was found.3 An interim fludeoxyglucose positron emission tomography (FDG-PET) post-cycle 4 demonstrated a significant metabolic response of most disease sites (Figure 3). However, persistent disease was seen on the submental cutaneous lesion and lung lesions. A biopsy of the lung lesion showed PCAECyTCL. Despite a cycle of gemcitabine, dexamethasone, and cisplatin (GDP) salvage chemotherapy, the patient's disease progressed clinically, with recurrence of cutaneous lesions on the torso and back. He opted to discontinue chemotherapy at that point and died approximately 7 months after the initial diagnosis. Primary cutaneous aggressive epidermotropic CD8⁺ cytotoxic T-cell lymphoma remains poorly understood and was only formally recognized in the 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours, published in 2023.4, 5 First described by Berti et al. in 1999, PCAECyTCL is characterized by epidermal infiltration of cytotoxic T cells that rapidly cause progressive epidermal necrosis and widespread skin ulcerations.6, 7 The histological presentation of PCAECyTCL may be variable, with the atypical lymphoid infiltrate generally showing prominent epidermotropism and folliculotropism. Primary diagnosis of cutaneous T-cell lymphomas often requires a comprehensive integration of clinical, routine microscopic, immunophenotypic, and, in some cases, molecular studies.8 PCAECyTCL follows an aggressive clinical course, with rapid cutaneous and systemic spread and an average 5-year survival of 18%.8 Treatment options are manifold and depend on disease extent and treatment intent: topical corticosteroids, phototherapy, chemotherapy (e.g., CHOP or more intensive regimens), targeted therapy (e.g., brentuximab), radiotherapy, and allogeneic stem cell transplantation have been studied. Janus kinase inhibitors have also recently shown potential as a novel agent for cutaneous T-cell lymphomas.9 The essential criteria listed in the 2023 WHO classification includes an “epidermotropic-adnexotropic cutaneous diffuse infiltrate, consisting of pleomorphic cytotoxic EBV negative α/β T-lymphocytes, and ulcerated or erosive plaques and tumors without spontaneous resolution.”4 Detailed immunophenotyping may be of diagnostic utility as the infiltrate typically comprises immature CD8-positive α/β T cells (CD2−, CD5−, CD7+, CD45RA+, CD45RO−).10, 11 Given the aggressive clinical course of PCAECyTCL, early diagnosis and multidisciplinary management by dermatologists, hematologists, pathologists, and medical/radiation oncologists are vital to maximize survival.5 We thank the Radiology Department of Royal Perth Hospital and the Nuclear Medicine Department of Sir Charles Gairdner Hospital for providing radiologic interpretations of diagnostic imaging included in this publication. None.