Multiple cutaneous ulcers revealing a primary cutaneous Epstein‐Barr virus‐positive diffuse large B‐cell lymphoma

Abstract Primary cutaneous EBV‐positive diffuse large B‐cell lymphoma is an exceptional and aggressive neoplasia with a poorer prognosis than other cutaneous lymphoma. Our observation points out the rarity of the presentation and the dismal clinical course.


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TEDBIRT ET al. characterized by an isolated, circumscribed mucosal or cutaneous ulcers. By contrast, EBV-MCU has an indolent course. 3 We report a case of an elderly patient who presented multiple cutaneous ulcerations diagnosed as primary cutaneous EBV-positive DLBCL.

| CASE REPORT
A 77-year-old man presented with 4-month history of unexplored diffuse nodules, which progressively evolved into painful large ulcers involving the tendons and which did not improve despite multiple oral antibiotics. He had a medical history of ischemic stroke, Parkinson's disease, and arterial hypertension. No previous biopsies or imaging studies was done in the four months before diagnosis. Clinical examination revealed impaired general condition and three large ulcerations measuring 15 × 10 cm on the lower limb, 8 × 6 cm on the back and 2 × 4 cm on the forearm ( Figure 1A-C). The patient had no mucosal lesions and no peripheral lymphadenopathies.
Skin biopsies showed a dense and deep infiltrate of neoplastic lymphoid cells with large basophilic cytoplasm, irregular and vesicular chromatin with oval to round small nucleoli ( Figure 2). Most cells were huge, noncleaved, centroblasts-like, and immunoblast-like. Immunohistochemical staining showed a B-cell population positive for CD20, CD30, PAX-5, MUM-1, and EBER ( Figure 3A-C), and negative for CD10 and BCL6 associated with a minority of CD2+, CD3+, CD5 + reactive T-cell population. Mitotic figures were frequent with around 80% of tumor cells that were labelled with the Ki67 marker ( Figure 3D). EBV viral load in blood was 8418 UI/mL. 18F-fluorodeoxyglucose positron-emission tomography showed spleen and mediastinum involvement and several cutaneous and subcutaneous localizations ( Figure 4). Clonality testing on skin biopsies revealed monoallelic  The diagnosis of primary cutaneous EBV-positive DLBCL with rapid skin dissemination and systemic involvement was retained. Due to the patient's comorbidities, palliative therapy with corticosteroids and intravenous rituximab 375 mg/ m 2 for four weekly cycles was initiated. Unfortunately, skin lesions did not improve and the patient died four months after the diagnosis.

| DISCUSSION
Viruses can lead to systemic lymphoma such as human T-lymphotropic virus 1 (HTLV-1) which causes T-cell lymphoma 5 or even more rarely human herpesvirus 8 (HHV8) associated with DLBCL. 6 EBV is a ubiquitous lymphotropic herpesvirus that infects 80%-90% of adults in the world. 7 EBV is also highly associated with lymphoproliferative disorders such as Burkitt lymphoma, 8 Hodgkin disease 9 and extranodal natural killer (NK)/T-cell lymphoma of nasal type. 10 Based on the revised 4th Edition of the WHO classification of tumors of the hematopoietic system, 1 EBV-MCU; primary EBV-positive DLBCL; plasmablastic lymphoma; lymphomatoid granulomatosis; cutaneous post-transplant lymphoproliferatice disorders are EBV-associated B-cell neoplasia that can affect the skin. Among these entities, primary EBV-DLBCL must be distinguished from EBV-MCU that may commonly affect the elderly. Indeed, EBV-MCU typically affects immunosuppressed patients and presents as a solitary ulceration in the skin, oral cavity, or gastrointestinal tract without systemic involvement. 3 This pseudomalignant entity has a good prognosis with spontaneous regression of ulcerations in 25% of patients. 11 Primary cutaneous EBV-positive DLBCL is an exceptional entity which seems to be more frequent in Asian populations than in Western countries with a slight male predominance. 2 Frequency of primary cutaneous EBV-positive DLBCL range from 8.7% to 11.4% in Asian countries, as compared to less than 5% in Western countries.
This rare entity predominantly affects the immunosenescent elderly and is characterized by an unfavorable prognosis and poor response to treatment. 2 The age-related immunodepression, so called immunosenescence, modifies T-cell homeostasis through a decrease of thymic output of naïve T cells due to thymic involution and an accumulation of viral specific CD8 + T cells 12 associated with profound functional changes in CD4 + T cells, 13 facilitating the growth of a state of chronic inflammatory process called "inflammaging" probably involved in EBV-reactivation and neoplasms onset. However, the molecular details of EBV reactivation process remains largely unclear. The exanthem of mononucleosis (more frequently observed after administration of ampicillin), oral hairy leukoplasia in immunosuppressed HIV-positive and HIV-negative patients, papular acrodermatitis of childhood (Gianotti-Crosti syndrome) and acute genital ulcers (ulcer of Lipschutz) are the most common mucocutaneous manifestations related to EBV infection. 14,15 Other cutaneous manifestations have been linked to EBV such as hypersensitivity of mosquito bites, hydroa vacciniforme, and drug reaction with eosinophilia and systemic symptoms. 15 The clinical presentations of primary cutaneous EBVpositive DLBCL are variable, ranging from a single nodule to multiple plaques. 16 An involvement of other organs should be investigated such as bone marrow, lungs, gastrointestinal tract, and ear, nose and throat (ENT) region. 17 Primary cutaneous EBV-positive DLBCL is diagnosed with a skin biopsy with or without an excisional biopsy of a suspicious lymph node, which always shows positivity for EBER through in situ hybridization analysis. 18 Typically, EBV-DLBCL has a nongerminal center (non-GC) phenotype (CD10-, BCL-6 ±, MUM1+) with an expression of pan B-cell markers by immunohistochemical staining (CD19, CD20, CD22, CD79a, PAX-5).
When possible, the first-line treatment may include rituximab monotherapy as single agent 19 or associated with anthracycline-based chemotherapy such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) by analogy with post-transplant lymphoproliferative disorders and non-EBV-DLBCL treatments 20,21 because no standard of care exist in this very rare disease. In addition, the treatment is often challenging because of the severity of the pathology and patients' age and comorbidities. EBV viral load, as measured by quantitative molecular analysis of the viral genome in blood, may serve as a biomarker for predicting and monitoring the course of EBV-associated diseases. 22

| CONCLUSION
To conclude, we report here an exceptional cause of multiple cutaneous ulcers in an elderly patient corresponding to a primary cutaneous EBV-positive DLBCL with a very uncommon presentation and a dismal clinical course. This case highlights this very rare immunosenescence-associated lymphoid malignancy as an edifying cause of multiple skin ulcerations, to be distinct from other leg ulcers unrelated to arterial and venous disease. Although rare, this etiology must be mentioned in case of cutaneous ulcers in elderly patients with impaired general condition and justifies performing early skin biopsies. The treatment remains to be challenging and there is a need for alternative therapeutic approach because of the dismal clinical course and patients' age and comorbidities.