Abdalla Asi Ryia Kuklani
| Abdalla Asi Ryia Kuklani |
Abdalla Asi Ryia Kuklani1, Rabie Shanti2, Faizan Alawi3
Rabie Shanti2
1Pathology and Laboratory Medicine Temple University Lewis Katz School of Medicine; 2Oral and Maxillofacial Surgery, University of Pennsylvania School of Dental Medicine; 3Department of Pathology, University of Pennsylvania School of Dental Medicine
Introduction
Epstein-Barr virus (EBV) is a member of the herpes virus family, and is one of the most common human viruses. EBV causes latent infection in humans and it may lead to various diseases and lymphoproliferative disorders (LPD) even during latency period. EBV-positive mucocutaneous ulcer (EBVMCU) is characterized clinically by cutaneous and/or mucosal ulcers in patients receiving immunosuppressive drugs, most commonly methotrexate and azathioprine (iatrogenic immunosuppression) or in elderly patients with age related immunosenescence. It was first described in 2010 by Dojcinov et al1 and listed as a distinctive clinicopathologic entity in 26 patients. Clinically it presents as a well-defined ulceration involving the oral cavity, skin, or the gastrointestinal tract.2 Microscopically, these lesions are characterized by mucosal and/or cutaneous ulcers with a polymorphic, mixed inflammatory infiltrate in the connective tissue, composed of lymphocytes, plasma cells, eosinophils, histiocytes, and large atypical lymphoid cells, sometimes resembling Hodgkin Reed-Sternberg (HRS)-like cells. Some cases may resemble DLBCL or a post-transplant lymphoproliferative disorder. Despite the atypical histopathologic features, suggesting an overt lymphoma, most EBVMCU cases follow an indolent self-limiting clinical course without progression to a disseminated disease. 3-4
Methods
Case Report A 68-year-old man was referred to an oral surgeon by his dentist, for evaluation of an ulcerated lesion of the right maxillary anterior gingiva of unknown duration. The patient’s medical history was significant for kidney mass and colon polyps with a diagnosis of oncocytoma and tubular adenomas, respectively. Clinical examination revealed an approximately 2x1 cm, nonpainful, reddish, ulcerated lesion on the right anterior maxillary gingiva involving tooth #7 and 8 (Fig 1). A radiograph revealed a radiolucent lesion of right anterior maxillary apex (Fig 2). The patient underwent an incisional biopsy of the lesion, which showed ulcerated mucosa with acute inflammatory infiltrate with foci of necrosis and accompanying atypical heterogeneous lymphohistiocytic infiltrate comprising many intermediate to large sized lymphocytes with irregular nuclear contours, abundant clear cytoplasm and scattered mitotic figures (Fig 3a-b). A few transformed larger cells with HRS-cell-like morphology were also present (Fig 3c). Immunohistochemically, the atypical cells show heterogeneous positivity for CD20, and were positive for Pax-5, MUM1, and CD30 (Fig 4a-e). A subset was weakly positive for CD79a and the atypical cells were negative for CD45, CD15, CD10, and BCL6. CD138 and ALK1 were negative. Many infiltrating T-cells showed no loss of pan T-cell antigens (CD2, CD3, CD5 and CD7). The proliferative index was 30-40% by Ki-67 and EBV-encoded RNA by in-situ hybridization (EBER-ISH) was positive in scattered larger and few other infiltrating cells (Fig 5). The pathologic diagnosis was EBV-positive lymphoproliferative disorder with the differential diagnosis including EBV-positive mucocutaneous ulcer (EBVMCU) or other EBV-positive lymphoproliferative disorder. Correlation with patient’s immune status, medication history (to exclude iatrogenic immunodeficiency), and peripheral blood EBV titers was recommended. Additionally, correlation with clinical and radiographic findings was recommended to exclude secondary involvement of the oral mucosa from a systemic lymphoma prior to considering EBVMCU. A clinicopathologic diagnosis of EBVMCU was established since clinically this was an isolated lesion in the absence of clinical evidence for lymphadenopathy or systemic lymphoproliferative disorder. The patient was appropriately followed without treatment and had a complete resolution of the intraoral lesion without evidence of recurrence. However, the patient subsequently, two and a half years later from the initial biopsy, was diagnosed with sarcoidosis and diffuse large B-cell lymphoma, non-germinal center-type involving the colon.
Results
Discussion EBV gene products interact with the molecular pathways of the cell cycle and induce B-cell transformation and proliferation; latent EBV infection is associated with various lymphoproliferative malignancies (Hodgkin and non-Hodgkin lymphomas).5,6 EBV persistently infects B cells, but an immunocompetent host maintains a low number of infected B cells. EBV-associated lymphoproliferative disorders are seen in a wide variety of immunosuppressed states. EBVMCU is associated with immunosuppression and typified by a solitary, slow-developing, well-circumscribed, and indurated ulcer7 with an indolent clinical course; in most cases, there was either spontaneous regression of the lesions after reduction in iatrogenic immunosuppression or persistence of the disease in a confined manner. According to the authors on a published series7, all reported patients had medication-related immunosuppression (azathioprine, methotrexate, or cyclosporine) for various autoimmune disorders or age-related immunosenescence. The median age in the latter group was 80 years. Involved sites included the oropharyngeal mucosa (most frequently), skin, esophagus, and the gastrointestinal tract. Clinical presentation Since the first description of EBVMCU in 2010, 25 additional cases have been reported. In addition, several cases of isolated mucocutaneous ulcers in the setting of immunosuppression were published prior to 2010 and some may in fact represent cases of EBVMCU, although thorough pathologic findings were not reported. 8-9 The incidence of EBVMCU is not established and this entity is likely under-recognized as some lesions may spontaneously regress without biopsy or pathologic evaluation, while other lesions may be misclassified as nonspecific ulcers, Hodgkin lymphoma, or diffuse large B-cell lymphoma, given the presence of large, atypical lymphocytes with HRS cell-like morphology and immunophenotype.10 Histopathology EBVMCU has distinctive pathologic features that may be regarded as distinctive of the condition. Notable features are unifocal mucosal or cutaneous ulcers that are histologically characterized by proliferating EBV-positive atypical B cells. Because EBVMCUs are localized lesions, lymphadenopathy or involvement of any other organ is usually not evident 11-13, although rarely regional isolated lymphadenopathy may be present. Lesions have characteristic architecture in the form of a prominent rim of small T-lymphocytes at the base. The infiltrate contains abundant CD8 positive T-cells, and occasionally atypical lymphoid cells with plasmacytoid features, and apoptotic cells. It has been proposed that EBV may be able to rescue germinal center cells from undergoing apoptosis by providing the CD40-mediated survival stimulus resulting in the perpetual activation of the NFkB pathway that stimulates proliferation and abrogates apoptosis. Thus, the presence of prominent apoptotic cells in EBVMCU may be a hallmark of retained normal control mechanisms.1 Treatment & Prognosis EBVMCU may presently be misdiagnosed as other forms of post-transplant lymphoproliferative disorders or in a post-transplant population as post-transplant lymphoproliferative disorder (PTLD), thereby under-reporting its incidence. Distinguishing EBVMCU from other forms of lymphoproliferative disorders may prevent exposure of these patients from the unnecessary risks of chemotherapy.23 Both cell-mediated immunity and humoral immunity are required to control EBV-driven lymphoproliferation, and deficiency in cytotoxic CD8 T-cell function, effector CD4 T-cell function, or in immunostimulatory gammaglobulin production enables EBV persistence.24 When possible, treatment outcomes overwhelmingly favor conservative approach in EBVMCU of the head and neck, with an overall 96.6% complete remission rate. Additionally, 94.1% of those managed conservatively by reduction of immunosuppression or observation achieved complete remission.23
Conclusion
In this report we present a case of EBV associated mucocutaneous ulcer as a distinct pathological entity associated with immunosuppression from a variety of origins, suggesting a common pathogenetic mechanism. It may result from a minimal and localized lapse in immunosurveillance over EBV. Correct diagnosis is facilitated by consideration of the clinical history and the observed spectrum in the EBV positive cells. The management approach is highlighted for this usually indolent and localized disease.