Comparative Study on Epstein-Barr Virus-Positive Mucocutaneous Ulcer and Methotrexate-Associated Lymphoproliferative Disorders Developed in the Oral Mucosa: A Case Series of 10 Patients and Literature Review.

Kyoichi Obata,Shoji Ryumon,Koki Umemori,Mayumi Yao,Tatsuo Okui,Kisho Ono,Akira Sasaki,Sawako Ono,Norie Yoshioka,Soichiro Ibaragi

doi:10.3390/diagnostics11081375

Abstract

Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is an iatrogenic immunodeficiency-associated lymphoproliferative disorder that occurs mainly with MTX use. This disorder has been associated with Epstein-Barr virus (EBV) infection. In 2017, the WHO newly defined the disease concept of EBV-positive mucocutaneous ulcer (EBV-MCU) as a good-prognosis EBV-related disease. Here, we report 10 cases of MTX-LPD or EBV-MCU in the oral mucosa. This retrospective, observational study was conducted with MTX-LPD or EBV-MCU in the oral mucosa patients who visited us during the nine year period from 2012 to 2021. We gathered the basic information, underlying disease, histopathological evaluation, treatment and prognosis for the subjects. All were being treated with MTX for rheumatoid arthritis. EBV infection was positive in all cases by immunohistochemistry. A complete or partial response was obtained in all cases with the withdrawal of MTX. Our results suggests that the most common risk factor for developing EBV-MCU is the use of immunosuppressive drugs. The most common site of onset is the oral mucosa, which may be attributed to the mode of EBV infection and the high incidence of chronic irritation of the oral mucosa. A small number of patients had been diagnosed with MTX-LPD, but we consider that these cases were EBV-MCU based on our study.

Highlights

Methotrexate (MTX) is an immunosuppressive antifolate that was approved as a therapeutic agent for rheumatoid arthritis (RA) by the FDA in 1988
In 1991, Ellman et al reported MTX-associated lymphoproliferative disorder (MTX-lymphoproliferative disorders (LPD)) as a lymphoma that occurred in RA patients using MTX, with more than 100 cases reported at that time [6]
This case series was composed of 10 patients with MTX-LPD or Epstein-Barr virus (EBV)-MCU occurring in the oral mucosa who visited the Department of Oral and Maxillofacial Surgery, Okayama University Hospital (Okayama, Japan) and the Department of Dentistry and Oral Surgery, Tsuyama Chuo Hospital (Okayama, Japan) during the nine year period from 2012 to 2021

Summary

Introduction

Methotrexate (MTX) is an immunosuppressive antifolate that was approved as a therapeutic agent for rheumatoid arthritis (RA) by the FDA in 1988. MTX is the anchor drug in RA treatment because of its high efficacy rate, continuation rate, and inhibitory effect on bone destruction and improvement of quality of life [1,2]. MTX has various side effects, such as bone marrow suppression, increased risk of interstitial pneumonia, and gastrointestinal tract disorders [1,3,4,5]. In 1991, Ellman et al reported MTX-associated lymphoproliferative disorder (MTX-LPD) as a lymphoma that occurred in RA patients using MTX, with more than 100 cases reported at that time [6]. In 2008, MTX-LPD was classified as one of the “other iatrogenic immunodeficiency-associated lymphoproliferative disorders” in the WHO Classification of Tumors of Haematopoietic and Lymphoid Tissue [7]. The progression of RA is considered to be a risk factor for the onset of MTX-LPD, the pathogenesis of MTX-LPD remains poorly understood [8]

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