Indian Journal of Pathology and Microbiology

: 2018  |  Volume : 61  |  Issue : 2  |  Page : 255--257

Methotrexate-associated Epstein–Barr virus mucocutaneous ulcer: A case report and review of literature

Priyanka Yogendra Ravi, Elanthenral Sigamani, Yasir Jeelani, Marie Therese Manipadam 
 Department of General Pathology, Christian Medical College, Vellore, Tamil Nadu, India

Correspondence Address:
Marie Therese Manipadam
Department of General Pathology, Christian Medical College, 4th Floor, Asha Building, Vellore - 632 004, Tamil Nadu


Epstein–Barr virus-positive mucocutaneous ulcer (EBVMCU) comprises part of the spectrum of B-cell lymphoproliferative disorders, reported in settings of immunosenescence and iatrogenic immunosuppression, affecting the oropharyngeal mucosa, skin, and gastrointestinal tract. We report a case of a 59-year-old female, known case of rheumatoid arthritis on methotrexate (MTX) for 15 years, who presented with an ulcer in the inner aspect of her cheek region for 2 years. Clinical examination revealed an infiltrative lesion involving the lower gingivobuccal sulcus of size 2 cm × 3 cm extending to the alveolus with level I lymph nodes, suspicious for carcinoma buccal mucosa. Anti-EBV-capsid antigen-immunoglobulin M and qualitative EBV polymerase chain reaction of peripheral blood were negative. Histopathological examination revealed atypical lymphoid cells with enlarged vesicular nuclei, prominent nucleoli, and moderate eosinophilic cytoplasm, few with binucleation (CD20 focally positive, CD79a focally positive, CD30+, EBV LMP-1+, MIB-I 60%) consistent with EBVMCU, MTX-associated. This is the first case report from India.

How to cite this article:
Ravi PY, Sigamani E, Jeelani Y, Manipadam MT. Methotrexate-associated Epstein–Barr virus mucocutaneous ulcer: A case report and review of literature.Indian J Pathol Microbiol 2018;61:255-257

How to cite this URL:
Ravi PY, Sigamani E, Jeelani Y, Manipadam MT. Methotrexate-associated Epstein–Barr virus mucocutaneous ulcer: A case report and review of literature. Indian J Pathol Microbiol [serial online] 2018 [cited 2020 Jul 8 ];61:255-257
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The association of Epstein–Barr virus (EBV) and B-cell lymphoproliferative disorders (LPDs) is well established. After primary infection at an early stage, EBV persistently infects B-cells in majority of adults, thereby eliciting transformation and multiplication through a variety of complex mechanisms such as the nuclear factor kappa B pathway.[1],[2] Normally, the EBV-induced B-cell proliferation is counterbalanced by immunologic interactions, thus maintaining the EBV-infected cells at a low level.[3] Immunosuppression (IS) with a wide array of agents affects immune surveillance and homeostasis, thus permitting emergence of EBV-LPD. Immunosenescence has also been recently described to be associated with EBV-LPDs.[4]

We report a case of a 59-year-old female who developed a mucocutaneous ulcer (MCU) associated with IS, the first case report of EBV-associated MCU from India to the best of our knowledge.

 Case Report

A 59-year-old female presented with an ulcer in the inner aspect of her right cheek associated with pain and difficulty in speaking for 2 months. She was a known case of rheumatoid arthritis on methotrexate (MTX) for 15 years. There was no history of trauma, smoking, or tobacco consumption. Clinical examination revealed an infiltrative lesion on the right buccal mucosa involving the lower gingivobuccal sulcus of size 2 cm × 3 cm extending to the alveolus. Regions 46 and 47 appeared indurated with palpable lymph nodes involving the right side of region IB. Systemic examinations were within normal limits. The clinical impression was of carcinoma buccal mucosa. Investigations revealed a normal hemogram; viral markers were negative. Liver and renal functions were normal. Anti-EBV-CA-IgM and qualitative EBV polymerase chain reaction of peripheral blood were negative. The lesion was excised and sent for histopathology.

Gross examination showed mucosa-covered tissue measuring 0.3 cm × 0.2 cm × 0.1 cm.

Microscopy revealed buccal mucosa with ulceration and acute inflammatory exudate. The subepithelial stroma was infiltrated by numerous medium-to-large lymphoid cells with focal angiocentricity displaying enlarged vesicular nuclei, prominent nucleoli, and eosinophilic cytoplasm. Few binucleate cells were present, but classical RS cells were not seen. Admixed were few histiocytes, immunoblasts, and eosinophils. On immunohistochemistry, the neoplastic lymphoid cells were CD30 and EBV-LMP1 positive. CD20 and CD79a were strongly positive in 30% of cells, many being perivascular. The Ki-67-labeling index was 60%. Pan-cytokeratin, CD56, CD3, CD138, CD15, and anaplastic lymphoma kinase-1 were negative [Figure 1] and [Figure 2].{Figure 1}{Figure 2}

In view of the history of MTX-induced IS, histology, and supporting immunohistochemistry, a diagnosis consistent with EBV-positive MCU (EBVMCU) was made.

IS was discontinued, and the patient was started on metronidazole leading to healing of the ulcer.


Dojcinov et al. first reported the entity EBVMCU in 26 patients, 9 associated with IS caused by MTX, azathioprine, and cyclosporine-A given for autoimmune diseases and 17 with ulceration of the skin or mucosa with no systemic involvement as evident in this case.[4],[5] EBVMCU is an entity associated with IS from a variety of origins, suggesting a common pathogenetic mechanism. The lesion is characterized by an isolated and circumscribed cutaneous and mucosal presentation with an indolent behavior and a self-limited clinical course being thought to have resulted from a minimal and localized lapse in immunosurveillance over EBV. The morphologic and immunophenotypic features at times may be mistaken for classical Hodgkin lymphoma (CHL) due to the overlap with CD15 positivity and CD20.[4]

The diagnostic morphologic features include (i) well-circumscribed and superficial lesion surrounded by prominent rim of small T-lymphocytes at the base. (ii) Subepithelial infiltrates containing pleomorphic blasts that may be reminiscent of RS cells admixed with a polymorphous infiltrate, eosinophils being prominent sometimes. (iii) The blasts are of B-cell origin with concomitant positivity for CD30, CD45, and EBV in most cases. CD20 is negative in approximately 11.5% of cases, focal/weak staining in approximately 19%.[4] CD15 positivity may be noted, thus mimicking a diagnosis of CHL. In this case, the blasts were positive for CD30 and EBV-LMP1 and focally positive for CD20 and CD79a. (iv) The infiltrate is also known to contain abundant CD8-positive T-cells and large numbers of EBV-positive plasmacytoid apoptotic cells, not common to CHL. Thus, the presence of abundant apoptosis rules out the diagnosis of EBV-associated CHL, its presence being suggestive of preserved normal control mechanisms and lack of a transformed phenotype.[4],[6]

In EBV-LPDs associated with MTX, the lack of expression of CD15 in CD30-positive Hodgkin/Reed–Sternberg (HRS)-like cells rules out CHL.[7] An additional parameter not typical for CHL is the wide range in cell size of the EBV-positive cells as highlighted by CD20, CD30, and EBV-encoded RNA. Typically, these cells include some small lymphocytes, immunoblasts, and large HRS-like cells which unlike CHL are CD45 positive.[4] In addition, the CD15-positive cells in CHL do not harbor Oct-2 and Bob-1. A uniform positivity for EBV-LMP1 on immunohistochemistry in a spectrum of cells rules out CHL with an underlying history of MTX-induced IS. The presentation of EBVMCU as an isolated ulcerating lesion without a tumor mass and no systemic involvement rules out the diagnosis of an aggressive posttransplant LPD.[8]

As far as the mechanism of action for MTX is concerned for EBVMCU, MTX directly induces EBV replication by activation of early viral promoters.[9] Most cases diagnosed with EBVMCU on IS have regressed on withdrawal of the drug.[4]

Another close differential is lymphomatoid granulomatosis; however, the lack of pulmonary involvement, strong CD30 positivity, and downregulation of CD20 argues against the diagnosis. CD30+ LPD of the oral cavity is also a differential; however, these tumors are typically negative for EBV-LMP1 and CD20 and positive for T-cell markers.[10]


EBVMCU is a unique entity that must be considered as a differential diagnosis of in a case presenting with mucosal ulceration. Differentiation from aggressive lymphoma which is a histologic mimic is essential because EBVMCU due to IS can resolve on withdrawal of immunosuppressive agents.

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Conflicts of interest

There are no conflicts of interest.


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