Biopsies taken from two clinically similar lesions at different anatomical sites revealed an unexpected answer: one lesion still showed her known mycosis fungoides, while the other harbored a completely distinct malignancy, an Epstein-Barr virus-positive diffuse large B-cell lymphoma. The case, reported as a letter to the editor in the Journal of Cutaneous Immunology and Allergy by dermatologists at Niigata University Graduate School of Medical and Dental Sciences, illustrates how secondary lymphomas arising during the course of advanced cutaneous T-cell lymphoma can closely mimic disease progression and delay correct diagnosis.
Mycosis fungoides typically follows an indolent clinical course over years or decades, but a subset of patients progresses to advanced-stage disease and faces an increased risk of developing secondary malignancies, including B-cell lymphomas. The clinical manifestations of such secondary lymphomas may overlap with those of progressive mycosis fungoides, potentially leading to diagnostic delay. The authors note that this risk may relate to immune dysregulation associated with the disease itself as well as the cumulative effects of T-cell-directed therapies. EBV-positive diffuse large B-cell lymphoma can arise in immunosuppressed patients, although its occurrence during the course of mycosis fungoides remains poorly characterized, making this reported case a useful clinical teaching point.
The patient’s medical history illustrates the intensive treatment burden that can accumulate in advanced disease. Diagnosed originally with stage IB mycosis fungoides, she was referred to the Niigata department eight years before this admission because of developing cutaneous tumor lesions. Histopathological examination at that time was consistent with conventional mycosis fungoides without evidence of large-cell transformation. Over the ensuing years she received multiple therapies, including bexarotene, interferon-gamma and brentuximab vedotin. More recently she was treated with forodesine for one year, followed by mogamulizumab for five months, during which her disease progressed.
Because a prior skin biopsy had demonstrated CD30 expression in approximately 10 percent of her atypical lymphoid cells, her team re-administered brentuximab vedotin in combination with local radiation therapy for seven months. Despite temporary stability, generalized tumors with ulceration rapidly enlarged. Longitudinal changes in serum lactate dehydrogenase, immunoglobulin G and absolute lymphocyte counts were also tracked. The authors judged that this rapid clinical deterioration was atypical for the preceding course of her mycosis fungoides, and that judgment prompted them to reassess the histopathology of lesions at different anatomical sites rather than assume uniform progression.
Palliative resections were performed on lesions from the left waist and the right forearm, both to relieve pain and to clarify the nature of the rapidly progressive tumors. The histopathological contrast between the two specimens proved decisive. The waist lesion showed a dense lymphoid infiltration extending from the dermis into the subcutaneous tissue, composed of small-to-medium-sized atypical cells. These cells expressed the T-cell markers CD3 and CD4 but lacked CD20, a B-cell marker, and CD30. They were also negative for EBV-encoded RNA in situ hybridization, or EBER-ISH, a technique that detects viral RNA transcripts within tissue sections. This profile was consistent with her known mycosis fungoides.
The forearm lesion told a different story. It contained large atypical cells within the subcutaneous tissue that expressed CD20 and CD30, and EBER-ISH was positive. These cells were negative for T-cell markers. Ki-67 staining, which marks proliferating cells, showed a high proliferative index in both the superficial and deep components of the lesion.
Quantitative polymerase chain reaction testing for EBV DNA in whole blood showed a viral load of 5 times 10 to the second power copies per milliliter, a comparatively low figure. The authors emphasize that circulating EBV-DNA levels may remain low despite substantial local tumor activity, meaning that 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. The EBV latency pattern in the tumor could not be determined because immunohistochemical staining for the viral proteins LMP1 and EBNA2 was not performed.
The clinical outcome was grim. Following the diagnosis of EBV-positive diffuse large B-cell lymphoma, the patient’s disease progressed rapidly. Systemic chemotherapy, including the R-CHOP regimen commonly used for diffuse large B-cell lymphoma, was not administered because of her poor performance status. A lymph node biopsy was not performed because of her poor condition and her own preference. The patient passed away three months later from progressive lymphoma, and no autopsy was undertaken. The authors acknowledge these gaps as limitations: without lymph node biopsy or autopsy, the systemic distribution of the B-cell lymphoma could not be histologically established, and progression of mycosis fungoides alone could not be completely excluded given the disease’s heterogeneity. Nevertheless, the forearm lesion’s distinct immunophenotype, including CD20 and EBER positivity, supported the diagnosis of EBV-positive diffuse large B-cell lymphoma.
The broader context matters for clinicians managing cutaneous T-cell lymphoma. B-cell lymphomas arising in patients with mycosis fungoides or its leukemic variant, Sezary syndrome, are uncommon but may mimic progression of the underlying disease. EBV-associated B-cell lymphoproliferative disorders have been reported in patients with T-cell lymphomas in the setting of impaired immune surveillance, and patients with mycosis fungoides or Sezary syndrome are at increased risk of secondary hematologic malignancies, including in early-stage disease. This association may involve disease-related immune dysfunction as well as treatment-associated impairment of immune surveillance. In this patient, longstanding advanced mycosis fungoides and exposure to multiple systemic therapies may have contributed to impaired immune surveillance, although the authors caution that a direct causal relationship between any individual therapy and the development of EBV-positive diffuse large B-cell lymphoma cannot be established from a single case.
The practical lesson the authors draw is about sampling strategy. Rapidly progressive lesions could easily have been interpreted as progression to tumor-stage mycosis fungoides or large-cell transformation, yet the two lesions examined were clinically similar while representing histopathologically different lymphoid neoplasms. This underscores the value of sampling multiple lesions when the clinical course becomes atypical or unexpectedly aggressive, since a single biopsy may not adequately represent clinically heterogeneous lesions. Careful comparison of newly developing lesions with the patient’s previous clinical and histopathological findings may provide clues to an alternative diagnosis, and changes in lesion morphology or behavior should prompt renewed histopathological assessment rather than an assumption of uniform disease progression. Repeated multisite biopsies, including nodal biopsy when feasible, should be considered in patients with atypical or discordant progression. The case highlights the importance of considering EBV-associated B-cell lymphoma when patients with mycosis fungoides develop atypical or rapidly progressive lesions, and in particular of evaluating for EBV using EBER-ISH when diffuse large B-cell lymphoma is suspected during the course of the disease.
Subject of Research: A case report of EBV-positive diffuse large B-cell lymphoma arising during advanced mycosis fungoides and mimicking disease progression.
Article Title: A case of EBV-positive diffuse large B-cell lymphoma arising in advanced mycosis fungoides mimicking disease progression
Article References: Uchida, S., Katsumi, T., Sato, M., Saito, Y., Yuki, A., & Abe, R. (2026). A case of EBV-positive diffuse large B-cell lymphoma arising in advanced mycosis fungoides mimicking disease progression. Journal of Cutaneous Immunology and Allergy, 9, Article 17789. https://doi.org/10.3389/jcia.2026.17789
Image Credits: AI Generated
Keywords: mycosis fungoides, EBV-positive diffuse large B-cell lymphoma, Epstein-Barr virus, cutaneous T-cell lymphoma, secondary lymphoma, EBER-ISH, immune surveillance, biopsy, immunosuppression, case report, case, EBV-positive
News Source: Ophelia Keating. (October 29, 2026). Rare EBV-Positive Lymphoma Masqueraded as Advanced Mycosis Fungoides Progression. Scienmag.
