A case of EBV-positive diffuse large B-cell lymphoma arising in advanced mycosis fungoides mimicking disease progression

Dear Editor, Although mycosis fungoides (MF) typically follows an indolent clinical course, a subset of patients progresses to advanced-stage disease and are at increased risk of developing secondary malignancies, including B-cell lymphomas [1]. The clinical manifestations of secondary lymphoma may overlap with those of progressive MF, potentially leading to diagnostic delay. This risk may be related to MF-associated immune dysregulation and cumulative effects of T-cell-directed therapies [1,2]. EBV-positive diffuse large B-cell lymphoma (DLBCL) can arise in immunosuppressed patients, although its occurrence during MF remains poorly characterized. Here, we report a case of EBV-positive DLBCL developing during the course of advanced MF, highlighting the diagnostic challenge of distinguishing secondary lymphoma from MF progression. This case also illustrates the importance of reassessing clinically discordant lesions rather than attributing all newly developing tumors to progression of the underlying MF.A 52-year-old female with a 24-year history of MF (initially stage IB) was referred to our department eight years ago because of the development of cutaneous tumor lesions.evidence of large-cell transformation. She received multiple therapies, including bexarotene, interferon-gamma and brentuximab vedotin. Recently, she was treated with forodesine for one year, followed by mogamulizumab for five months, resulting in progressive disease (Supplementary Figure 1A-D). Because a prior skin biopsy had demonstrated CD30 expression in approximately 10% of atypical lymphoid cells, brentuximab vedotin was readministered in combination with local radiation therapy for seven months. Despite temporary stability, generalized tumors with ulceration rapidly enlarged. Contrast-enhanced CT showed deep lymphadenopathy, and serum soluble interleukin-2 receptor (sIL-2R) increased from 3,153 to 4,111 U/L within one month (Supplementary Figure 1E).Longitudinal changes in serum LDH, IgG, and absolute lymphocyte counts were also evaluated (Supplementary Figure 1E). The rapid clinical deterioration was considered atypical for the preceding course of her MF and prompted histopathological reassessment of lesions at different anatomical sites. Palliative resections were performed on lesions from the left waist and right forearm to relieve pain and to clarify the nature of the rapidly progressive tumors (Figure 1A,G).Histopathology of the waist lesion showed a dense lymphoid infiltration extending from the dermis to the subcutaneous tissue, composed of small-to-medium-sized atypical cells (Figure 1B,C, Supplementary Figure 2A,B). These cells expressed CD3 and CD4 (Figure 1D) but lacked CD20 (Figure 1E) and CD30 (Supplementary Figure 2C). They were also negative for EBV-encoded RNA in situ hybridization (EBER-ISH) (Figure 1F), consistent with her known MF. In contrast, the forearm lesion showed large atypical cells in the subcutaneous tissue (Figure 1H,I) that expressed CD20 (Figure 1J, Supplementary Figure 2D) and CD30 (Supplementary Figure 2F). EBER-ISH was positive in the forearm lesion (Figure 1K). These cells were negative for T-cell markers (Figure 1L, Supplementary Figure 2E). Ki-67 showed a high proliferative index in both the superficial and deep components (Supplementary Figure 2G,H). The predominantly monomorphic proliferation of large atypical B cells, together with EBER positivity and a high proliferative index, supported the diagnosis of EBV-positive DLBCL rather than a polymorphic EBV-associated B-cell lymphoproliferative disorder. Thus, simultaneous examination of two clinically distinct lesions demonstrated persistent MF in the waist lesion and EBV-positive DLBCL in the forearm lesion. This clinicopathological discordance was critical for recognizing that the rapidly progressive lesions could not be explained solely by progression of the pre-existing MF. Quantitative polymerase chain reaction (PCR) for EBV-DNA using whole blood showed a viral load of 5×10 2 copies/mL. The EBV latency pattern could not be determined because immunohistochemical staining for LMP1 and EBNA2 was not performed. Following the diagnosis of EBV-positive DLBCL, the patient's disease progressed rapidly. Systemic chemotherapy, including R-CHOP, was not administered because of her poor performance status. Lymph node biopsy was not performed because of poor condition and patient preference. The patient passed away three months later because of progressive lymphoma. No autopsy was undertaken.B-cell lymphomas arising in patients with MF/SS are uncommon but may mimic progression of the underlying disease [1,3,4]. EBV-associated B-cell lymphoproliferative disorders have been reported in patients with T-cell lymphomas in the setting of impaired immune surveillance [2,5]. Patients with MF/SS are at increased risk of secondary hematologic malignancies, including in early-stage disease [1,4]. This association may involve diseaserelated immune dysfunction as well as treatment-associated impairment of immune surveillance. In our patient, longstanding advanced MF and exposure to multiple systemic Changes in lesion morphology or behavior should prompt renewed histopathological assessment rather than assumption of uniform disease progression. Although progression of MF alone could not be completely excluded given MF heterogeneity, the forearm lesion showed a distinct immunophenotype, including CD20 and EBER positivity, supporting the diagnosis of EBV-positive DLBCL. Moreover, our case indicates that circulating EBV-DNA levels may remain low despite substantial local tumor activity; thus, low PCR titers do not exclude EBV-associated malignancies. Tissue-based evaluation therefore remains important when clinical or histopathological findings raise suspicion for an EBV-associated lymphoproliferative disorder. Repeated multisite biopsies, including nodal biopsy when feasible, should be considered in patients with atypical or discordant progression. A limitation of our case is that lymph node biopsy and autopsy were not performed; therefore, the systemic distribution of B-cell lymphoma could not be histologically established. This case highlights the importance of considering EBV-associated B-cell lymphoma when patients with MF develop atypical or rapidly progressive lesions. In particular, evaluation for EBV using EBER-ISH should be considered when DLBCL is suspected during the course of MF.Figure1. Clinical and histopathological findings.Clinical presentation of MF, erythematous nodule on the left waist (A). The pathological findings showed dermal to subcutaneous lymphoid infiltration (B) and small to medium atypical cells (C). Immunohistochemical staining: the majority of the cells are positive for CD4 (D), and negative for CD20 (E), EBER-ISH (F).Clinical findings of DLBCL. Three nodules on the right arm (G). The pathological findings showed subcutaneous lymphoid infiltration (H) and large, atypical cells (I).Immunohistochemical staining: the large cells are positive for CD20 (J), EBER-ISH (K). CD4 is expressed only in a few small-sized cells (L).