From Panniculitis to Epstein–Barr Virus-Associated Mucocutaneous Ulcer: A Diagnostic Challenge

To the Editor: Epstein–Barr virus (EBV)-associated mucocutaneous ulcer (EBV-MCU) is a recently described entity within the spectrum of EBV-associated lymphoproliferative disorders.1 It primarily affects elderly patients or those with some degree of primary or secondary immunosuppression.1,2 The clinical presentation is variable but often consists of a chronic, indolent ulcer located on the skin or mucosal surfaces (oral cavity and gastrointestinal tract).3 The proliferation of B lymphocytes is usually accompanied by a marked inflammatory component and/or necrosis, which may complicate the diagnosis.2,4,5 We report the case of a 79-year-old woman with type 1 diabetes mellitus, hypertension, dyslipidemia, primary autoimmune hypothyroidism, systemic lupus erythematosus, Sjögren syndrome, and antiphospholipid syndrome, who was receiving mycophenolate and corticosteroid therapy. She presented with a swollen, elevated plaque on the right leg that had progressively enlarged over the previous 2 years (Fig. 1). The initial biopsy was diagnosed as a lobular panniculitis with vasculitis (EBV in situ hybridization was not performed). The lesion evolved into a chronic ulcer with a tortuous course, and a repeat biopsy was obtained 6 months later. Histopathologic examination revealed a diffuse B-cell lymphoproliferative process composed of medium-sized CD20-positive lymphocytes involving the dermis and hypodermis, accompanied by abundant T lymphocytes (CD3+/CD7+) and numerous plasma cells (Fig. 2). In situ hybridization for immunoglobulin light chains demonstrated kappa light-chain restriction. Polymerase chain reaction based molecular studies confirmed a clonal rearrangement of the IgH immunoglobulin gene. Immunohistochemical studies showed CD30 expression in medium-sized atypical lymphoid cells, with concomitant MUM1 positivity, whereas CD15 was negative; no Sternberg-like cells were identified. A positive result for EBV by in situ hybridization (EBER) and a negative EBV viral load in peripheral blood led to the diagnosis of EBV-associated mucocutaneous ulcer.FIGURE 1.: Cutaneous ulcer on the lower limb with erythematous and indurated borders, necrotic center, and fibrinous base.FIGURE 2.: Initial histologic examination showing lobular panniculitis with a dense lymphoplasmacytic inflammatory infiltrate (A). Medium-sized vessel with mural necrosis and lymphocytic inflammatory infiltrate (B). Strong EBER-positive staining (inset). Detail of inflammatory cellularity composed of lymphocytes, plasma cells, and histiocytes (C). Subsequent histologic study demonstrating diffuse lymphoplasmacytic infiltration in the dermis and hypodermis (D). Immunohistochemical staining showed a predominance of CD20-positive B lymphocytes (E), EBER positivity (F), and accompanying CD3-positive T lymphoid cells (G).EBV-MCU is typically described in immunosuppressed patients—either because of advanced age, immunosuppressive therapy, as in our case, or other causes.2,4 It is characterized by the appearance of a solitary, usually indolent ulcer, with histopathology showing a proliferation of EBV-infected B lymphocytes.1,4 Unlike aggressive EBV-associated lymphomas, EBV-MCU may present with minimal systemic symptoms and, in some cases, may undergo spontaneous regression after reduction or withdrawal of the immunosuppressive factor.1,2,4 In our patient, the coexistence of multiple autoimmune diseases together with chronic corticosteroid and mycophenolate therapy contributed to a significant state of immunosuppression. As shown by several studies,1,2,4 these factors predispose to the development of EBV-associated lymphoproliferative processes, including mucocutaneous ulcers. In our opinion, the most striking feature of this case is the initial presentation as lobular panniculitis with a lymphoplasmacytic infiltrate and medium-vessel vasculitis, suggesting erythema induratum. The characteristic histopathologic pattern of EBV-MCU consists of a cutaneous ulcer with a diffuse dermal proliferation of CD20-positive B lymphocytes showing light-chain restriction and EBER positivity,1,4,5 along with reactive T cells and an accompanying inflammatory infiltrate composed of plasma cells, histiocytes, and eosinophils. Angiocentricity and angioinvasion of the lymphoid infiltrate with vascular necrosis mimicking vasculitis may also be observed. Therefore, it is important to include EBV-positive mucocutaneous ulcer in the differential diagnosis of lobular panniculitis with vasculitis, especially in immunocompromised patients. Finally, it is essential to differentiate EBV-MCU from EBV-positive diffuse large B-cell lymphoma (DLBCL-EBV+), given their distinct management and prognosis.1,3,5 Unlike EBV-MCU, DLBCL-EBV+ typically presents as tumor masses, often multifocal, with a monomorphic infiltrate of large B cells, frequent angioinvasion and necrosis, and a more aggressive clinical course, usually in immunocompetent elderly patients. In EBV-MCU, large cells commonly coexpress CD30 and CD15, and the proliferation is usually localized and self-limited, whereas in DLBCL-EBV+, the proliferation is diffuse, with a high proliferative index and uniform expression of B-cell markers. Furthermore, EBV viral load in peripheral blood is typically low or undetectable in EBV-MCU, whereas it tends to be elevated in DLBCL-EBV+. Integration of clinical, histopathologic, immunophenotypic, and virologic findings, as well as the patient's immune status, is therefore essential for accurate diagnosis. In conclusion, in the presence of an atypical chronic cutaneous ulcer with histopathologic findings of EBV-associated B-cell proliferation—particularly in an immunosuppressed patient—EBV-associated mucocutaneous ulcer should be considered among the main diagnostic possibilities and distinguished from aggressive lymphomas. Prognosis and management differ substantially; hence, close clinicopathologic correlation is recommended for accurate characterization, to avoid overtreatment or diagnostic delay.