Ulcerating Esophageal Lesions

Question: A 76-year-old man with a history of rheumatoid arthritis (RA), ischemic heart disease, and cerebral infarction visited our hospital because of chest pain during swallowing. He was taking methotrexate (MTX) 6 mg/wk, prednisolone 2 mg/d, tacrolimus 2.5 mg/d, and clopidogrel 75 mg/d. Chest and abdominal enhanced computed tomography scans revealed thickening of the esophagus, swelling of the tracheal bifurcation, and enlargement of paraesophageal lymph nodes. Esophagogastroduodenoscopy showed 2 ulcerating lesions, one in the middle thoracic and the other in the lower thoracic esophagus. The former involved one-half the circumference and was deeply ulcerated (Figure A). An intraepithelial papillary capillary loop around the ulcer was type A according to the Japan Esophageal Society Classification (Figure B). The lesion located in the lower thoracic esophagus was 10 mm in diameter (Figure C), and its intraepithelial papillary capillary loop was also type A. What is the diagnosis and how should these lesions be treated? See the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI. Biopsies from the margins of the ulcers showed no atypical cells. Although infiltration of inflammatory cells was seen, periodic acid-Schiff staining and immunostaining for herpes simplex virus-I/cytomegalovirus were negative. Thus, the cause of ulcers was not identified. The patient underwent another endoscopic examination 1 month later because malignant tumors such as malignant lymphoma or esophageal cancer had not definitively been ruled out. Although granulation tissue was identified in both ulcers, they remained open. Repeat biopsies were taken from the centers and margins of the ulcers. These specimens showed proliferation of large atypical lymphocytes against a background of infiltration of various other inflammatory cells (Figure D and E). Immunostaining was positive for CD20 (Figure F) and Epstein-Barr virus (EBV)-encoded small RNA in situ hybridization (Figure G). EBV-positive lymphoproliferative disorder was therefore suspected. Given our patient’s history of taking MTX for RA, we considered EBV-positive mucocutaneous ulcers (EBV-MCUs). After review by the rheumatology department, his MTX was discontinued and he was followed without chemotherapy. One month after discontinuing MTX, his symptoms had resolved and the ulcers had healed (Figure H shows the scar in the middle thoracic esophagus). Taking these data together, we diagnosed these ulcers as MTX-related EBV-MCUs. EBV-MCUs were first reported as a subtype of lymphoproliferative disorder in 20101Dojcinov S.D. Venkataraman G. Raffeld M. et al.EBV positive mucocutaneous ulcer--a study of 26 cases associated with various sources of immunosuppression.Am J Surg Pathol. 2010; 34: 405-417Crossref PubMed Scopus (374) Google Scholar and listed as a new disease in the fourth revised edition of the World Health Organization classification.2Gaulard P, Swerdlow SH, Harris NL, et al. EBV-positive mucocutaneous ulcer. In: Swerdlow SH, Campo E, Harris NL, et al, eds. World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues. France: Lyon, 2017:307–308.Google Scholar EBV-MCUs often occur in patients who are taking MTX for RA and in older patients. It commonly occurs on the skin and oral mucosa and rarely in the remainder of the gastrointestinal tract.3Ikeda T. Gion Y. Yoshino T. et al.A review of EBV-positive mucocutaneous ulcers focusing on clinical and pathological aspects.J Clin Exp Hematop. 2019; 59: 64-71Crossref PubMed Google Scholar In particular, to our knowledge, no cases in the esophagus have previously been reported. Given that EBV-MCUs spontaneously heal on discontinuation of MTX, they must be distinguished from malignant lymphoma to avoid unnecessary chemotherapy. However, it is difficult to make this distinction solely on the basis of endoscopic and pathological features; the presence or absence of a history of RA and treatment with MTX or other immunosuppressive agents are important factors when considering a diagnosis of EBV-MCU. We here report a case of EBV-MCU in the esophagus. EBV-MCU should be included in the differential diagnosis when esophageal ulcers are found in patients with RA, especially those who are taking MTX.