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 Table of Contents  
Year : 2022  |  Volume : 2  |  Issue : 4  |  Page : 173-177

Epstein–Barr virus mucocutaneous ulcer: A rare cause of drug-induced lower gastrointestinal bleed

1 Department of Gastroenterology, MGM Hospital, Chennai, Tamil Nadu, India
2 Department of Hepatology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
3 Department of Surgical Gastroenterology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India

Date of Submission19-Jul-2022
Date of Decision24-Aug-2022
Date of Acceptance30-Aug-2022
Date of Web Publication13-Oct-2022

Correspondence Address:
Jayanthi Venkataraman
Department of Hepatology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ghep.ghep_20_22

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We report a case of a young female with cirrhosis due to autoimmune hepatitis who presented with significant hematochezia. She was on azathioprine for 3 years. At colonoscopy, she had two synchronous bleeding polypoidal colonic lesions that required an emergency left hemicolectomy. Immunohistochemistry confirmed the diagnosis of Epstein–Barr virus-positive mucocutaneous ulcers (EBV-MCU).

Keywords: Autoimmune hepatitis, Epstein–Barr virus, lymphoproliferative disorder, mucocutaneous ulcer, Reed–Sternberg-like cell

How to cite this article:
Sathiyasekaran M, Prakash S A, George TJ, D'Cruze L, Bhargav V Y, Shankar S, Venkataraman J. Epstein–Barr virus mucocutaneous ulcer: A rare cause of drug-induced lower gastrointestinal bleed. Gastroenterol Hepatol Endosc Pract 2022;2:173-7

How to cite this URL:
Sathiyasekaran M, Prakash S A, George TJ, D'Cruze L, Bhargav V Y, Shankar S, Venkataraman J. Epstein–Barr virus mucocutaneous ulcer: A rare cause of drug-induced lower gastrointestinal bleed. Gastroenterol Hepatol Endosc Pract [serial online] 2022 [cited 2022 Nov 27];2:173-7. Available from: http://www.ghepjournal.com/text.asp?2022/2/4/173/358472

  Introduction Top

Epstein–Barr virus-positive mucocutaneous ulcers (EBV-MCU) is a rare EBV-associated lymphoproliferative disorder with a very close morphologic and immunophenotypic similarities to Hodgkin's lymphoma and diffuse large B-cell lymphoma (DLBCL). The ulcerated lesions are usually single or are multifocal, seen commonly in the oropharynx, gastrointestinal tract, and the skin. Lesions are due to the activation of latent EBV in the setting of immunosuppression (drugs, old age, and primary immunodeficiency). There is proliferation of B- and T-lymphocytes. The management is tailored to identifying the triggering factor. Spontaneous remission is rare. The first line involves reducing the dose of immunosuppressant agent. Other specific therapy includes the use of CD20 or CD30 directed antibody therapy, radiation therapy, local surgical excision, systemic chemotherapy, or a combination of these therapies.

  Case Report Top

A 38-year-old female, with cirrhosis due to autoimmune hepatitis, on azathioprine for 3 years presented with a history of intermittent, colicky, postprandial left hypochondrium pain for 3 months. The pain would last for 30–45 min and would get relieved with the passage of normal colored liquid stools. There were at least 2–3 similar episodes of pain in a week. She also had anorexia and weight loss of 6 kg during this period. She was on treatment for a hypothyroid state.

On evaluation in the primary hospital, computed tomography of the abdomen revealed a shrunken liver, minimal ascites, and irregular, asymmetric, circumferential wall thickening of the distal transverse colon with marked pericolonic fat stranding and multiple pericolonic lymph nodes. The patient underwent colonoscopy that identified 2 synchronous, circumferential, ulceroproliferative lesions, one in the rectosigmoid region, extending 5 cm proximally [Figure 1] and the other approximately 3 cm in the distal transverse colon [Figure 1]; rest of the colon was normal. The histopathology was suggestive of polymorphic lymphoproliferative disorder (B cell lymphoma) with a differential of a possible iatrogenic immunodeficiency state associated lymphoproliferative disorder (due to immunosuppressant).
Figure 1: Colonoscopy showing polypoidal nodular lesion in rectosigmoid and distal transverse colon

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A week following the initial evaluation, the patient presented to the emergency room at another hospital with hematochezia and postural hypotension. She had 4 episodes of recurrent major bleed approximately 250–300 mL within a span of 24 h. During this episode, there was no history of abdominal pain nor was there a noticeable lump, abdominal distension, or alteration in the sleep pattern.

On examination, she was thin built with a body index mass of 21 kg/m2. Her pulse rate was 118/min with a blood pressure of 110/70 mmHg. She had pinched facies, suggestive of scleroderma. Liver span was normal, spleen was palpable 3 cm below costal margin; there was minimal free fluid. Cardiovascular, respiratory, and central nervous systems were normal.


Hemogram: Hb 9.8 g/dL, white blood cell: 7800 cells/cumm3; platelet count 101 × 103/μL, blood sugar, renal function tests, liver biochemistry, and serum electrolytes were normal. Serum albumin was 2.8 g/dL and international normalized ratio was 1.45.

An unprepared colonoscopy was done and the source of bleed [Figure 1] was confirmed to be the earlier documented colonoscopic lesions with active bleeding from the transverse colon lesion. The patient was taken up for an emergency laparotomy. A rectosigmoid lesion was palpable that was densely adherent anteriorly to the uterus; the proximal lesion had creeping fat around it with perisplenic collaterals. The distal colorectum was dissected and transection was done at the upper third of the rectum. Mid-transverse colon was dissected and the end was brought out as end colostomy and involved colon was removed. There was no regional lymphadenopathy. The liver was cirrhotic, with perisplenic collaterals.

Grossly [Figure 2]a, the serosa of the resected specimen was normal, the sigmoid lesion was approximately 3 cm × 1.5 cm × 1 cm felt hard, and was embedded within the pericolorectal fat along with a few sub-centimeter lymph nodes. On dissecting the specimen, the colonic mucosa from the two sites of lesion showed surface ulceration [Figure 2]b. No other nodular ulcerated mass lesion was seen.
Figure 2: (a) Resected specimen: Creeping pad of fat on external surface, (b). Mucosa shows surface ulceration. No polypoidal lesion seen

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Microscopically [Figure 3]a, [Figure 3]b, [Figure 3]c, there were areas of ulceration with dense band of polymorphous infiltrate composed of plasma cells, lymphocytes, and histiocytes. There were few lymphoid cells with angulated nuclei and pale cytoplasm. The Reed–Sternberg-like cells were positive for CD15, CD20, CD30, CD45, Paired box 5 (PAX-5), and Epstein–Barr Virus (EBV) latent membrane protein (LMP). Background lymphocytes were positive for CD3 [Figure 4]. The positive immunohistochemistry (IHC) markers were similar to the mucosal biopsy specimens [Table 1]. A final diagnosis of EBV-MCU in a patient on immunosuppressant (azathioprine) masquerading as gastrointestinal bleed was made.
Figure 3: Histopathology (H and E stain): (a) Histology of ulcerated lesion (b) Note dense lymphocyte infiltration (c) Abnormal macrophage resembling Reid–Sternberg Cell

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Figure 4: Immunohistochemistry positive for CD15, CD20 and CD30

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Table 1: Comparative immunohistochemistry in endoscopy biopsy and resected specimen

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  Discussion Top

Our patient is the first reported case of EBV-MCU documented in a female patient on azathioprine for autoimmune hepatitis that closely mimicked a neoplastic lymphoproliferative colonic lesion. The persistent significant bleed necessitated a surgical intervention.

Moran et al.,[1] reported a case of EBV-MCU diagnosed in a patient on immunosuppressant for Crohn's disease which progressed to Hodgkin's lymphoma 18 months after cessation of biological (infliximab) and presented as life-threatening gastrointestinal bleed requiring colectomy.

EBV-MCU is a B-cell lymphoproliferative disorder and was first described in 2010,[2] by the World Health Organisation.

The disorder is driven by a latent EBV infection which gets activated due to either tempering of the immunosurveillance related to iatrogenic immunosuppression (56%), primary immunodeficiency (4%; age 45–61 years), or age-related immunosenescence, i.e., advanced age (40%; median age 63 years). Common immunosuppressant's that can predispose to EBV-MCU include azathioprine, methotrexate, cyclosporine and tumour necrosis factors. Under these immunosuppressed circumstances, there is an EBV-driven lymphoproliferation, expansion of clonal lymphocyte and lymphocyte transformation.

A total of 121 cases, with a median age of 66.4 years was reported between 2010 and 2018; 66% were due to iatrogenic immunodeficiency.[2],[3],[4] EBV-MCU seems to have a predilection for women, reasons for which are not known. In general, EBV-related lymphoproliferative disorders have no gender bias except Burkitt's lymphoma and mixed cellularity subtype of classic Hodgkin's lymphoma both of which are common in men. When there is a lapse in the immune surveillance over EBV, the homeostasis of the persistent infected state is disturbed, resulting in EBV-related lymphoproliferative disorders.

The lesions are usually well-circumscribed ulcers involving the oropharynx, skin, and gastrointestinal tract and may have Hodgkin's Lymphoma like features. The majority of ulcers (70%) are in the oral cavity. EBV is secreted in the saliva and trauma and inflammation of the mucosa cause ulcerations. Gastrointestinal involvement is less common and may occur in the esophagus, colon, rectum, or perianal region. These ulcers are indolent and have a chronic course with spontaneous regression. Majority undergo remission with withdrawal or reduction of immune suppression and rarely progress to lymphoma.

The link between Epstein–Barr Virus and mucocutaneous ulcer

Though described as mucocutaneous, EBV-MCU lesions have been described in the skin (29%), the gastrointestinal tract (19%; gut-associated lymphoid tissue), and oropharynx (52%).

EBV is a human herpes virus 4 and is transmissible between humans through saliva and is acquired in the first few years of life. The high prevalence of EBV in oropharynx is because of the initial inoculation of the EBV in this region. The virus preferably infects B cells and remains latent for several years within its nucleus as memory B cell, with the persistence of the latent infection in the Waldeyer's ring.[5] Individuals at this stage may be asymptomatic or present as a self-limited lymphoproliferative infective mononucleosis.

When the activation occurs due to an immunosuppressed state, B-cell transformation and proliferation take place. EBV-positive large atypical immunoblasts or Hodgkin Reed–Sternberg (HRS) like cells are characteristic of the cutaneous or mucosal lesions. The expression of CD20 and CD30 positivity indicates activated B lymphocytes. The atypical cells vary in size from small to large and distributed in a dense polymorphic infiltrate as was seen in our patient. T cell and natural killer cells can also be affected either by surrounding EBV-infected B cells or are directly infected by EBV. The histological features, therefore, overlap with other B-cell proliferative neoplasms. [Table 2] shows the various spectrum of EBV-associated lymphoproliferative disorders.[5]
Table 2: Spectrum of lymphoproliferative disorders due to EpsteinBarr virus

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Major histological differentials for EBV-MCU are Classical Hodgkin's Lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL). EBV-MCU unlike cHL is not associated with regional/systemic lymphadenopathy, hepatosplenomegaly, or bone marrow involvement. The IHC staining strongly supports the origination of the atypical cells from B cells that are PAX-5, OCT-2, and BOB-1 positive. The presence of CD20 like cell supports EBV-MCU rather than cHL. CD15 positivity may indicate cHL. EBV-positive DLBCL has many overlapping features with EBV-MCU such as CD20 positive, CD30 positive, and CD15 positive HRS-like cells. EBV-DLBCL is seen in older individuals, those with high-grade lymphoma and with a poor prognosis. Polymerase chain reaction (PCR) may show clonal immunoglobulin heavy chain gene arrangements in EBV-positive DLBCL rather than EBV-MCUs. We did not suspect DLBCL in our patient and therefore PCR immunoglobulin profile was not done.

The EBV-CMU lesions are usually solitary but can be multifocal in 17%. A typical EBV-MCU appears as a sharply circumscribed mucosal or cutaneous ulcer (single or several) with underlying infiltration of small lymphocytes, atypical large lymphocytes, immunoblasts and mixture of scattered plasma cells, eosinophils, and histiocytes. The atypical lymphocytes are large and pleomorphic immunoblasts with frequent HRS morphology. These were also the characteristics seen in our patient.


EBV-MCU is generally self-limited with an indolent benign clinical course and often resolves if the cause is identified. Most respond with a reduction in dose of immunosuppressant. At times, there is a need for an add-on of rituximab or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone combination regimen with or without radiation. Rituximab is a highly selective antibody against CD20. The drug causes selective depletion of B cells and in addition selectively reduces local clonal B-cell proliferative response. The disease course can at times be heterogeneous as in our patient who required an aggressive intervention of surgical resection.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Moran NR, Webster B, Lee KM, Trotman J, Kwan YL, Napoli J, et al. Epstein Barr virus-positive mucocutaneous ulcer of the colon associated Hodgkin lymphoma in Crohn's disease. World J Gastroenterol 2015;21:6072-6.  Back to cited text no. 1
Dojcinov SD, Venkataraman G, Raffeld M, Pittaluga S, Jaffe ES. EBV positive mucocutaneous ulcer – A study of 26 cases associated with various sources of immunosuppression. Am J Surg Pathol 2010;34:405-17.  Back to cited text no. 2
Juan A, Lobatón T, Tapia G, Mañosa M, Cabré E, Domènech E. Epstein-Barr virus-positive mucocutaneous ulcer in Crohn's disease. A condition to consider in immunosuppressed IBD patients. Dig Liver Dis 2017;49:934-7.  Back to cited text no. 3
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;61:255-7.  Back to cited text no. 4
[PUBMED]  [Full text]  
Roberts TK, Chen X, Liao JJ. Diagnostic and therapeutic challenges of EBV-positive mucocutaneous ulcer: A case report and systematic review of the literature. Exp Hematol Oncol 2015;5:13.  Back to cited text no. 5


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2]


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