Download PDF
CC BY 4.0 · Eur J Dent 2022; 16(03): 703-709
DOI: 10.1055/s-0041-1739545
Case Report

Multifocal Oral Epstein–Barr Virus-Positive Mucocutaneous Ulcers Associated with Dual Methotrexate and Leflunomide Therapy: A Case Report

Sumana Kunmongkolwut
1   Department of Oral Pathology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
,
Chatchawan Amornkarnjanawat
2   Department of Dentistry, Surin Hospital, Surin, Thailand
,
Ekarat Phattarataratip
1   Department of Oral Pathology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
› Author Affiliations Funding None.
› Further Information
Also available at
   Permissions and Reprints

Abstract

Epstein–Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) is a unique clinicopathologic entity of lymphoproliferative disorder, occurring in immunosuppressed patients. Due to its rarity, EBVMCU may be under-recognized by clinicians as well as pathologists. In addition, its clinical and histopathologic features overlap with other benign and malignant conditions, making a diagnosis challenging. This report presents an unusual case of multifocal oral EBVMCUs in a 52-year-old female patient with rheumatoid arthritis, receiving the combination of methotrexate and leflunomide for 5 years. The patient presented with persistent multiple large painful ulcers involving her palate and gingiva for 6 months. The histopathologic examination revealed extensive ulceration with diffuse polymorphic inflammatory infiltrate admixed with scattered atypical lymphoid cells showing occasional Hodgkin and Reed/Sternberg-like cell features. These atypical cells showed immunoreactivity for CD20, CD30 and MUM1/IRF4. EBV-encoded small RNA in situ hybridization was positive, validating the presence of EBV-infected cells. Two months after discontinuation of both immunosuppressive medications, oral lesions gradually regressed. At 9-month follow-up, no evidence of relapsing oral EBVMCU has been observed. The multifocal presentation of EBVMCU is rare and could be resulted from the overwhelming immune suppression by long-term use of dual immunosuppressants. Its diagnosis requires comprehensive correlation of patient history, clinical findings, histopathologic, and immunophenotypic features. The ability of EBVMCU to regress following removal of immunosuppressive causes is in drastic contrast to a variety of its potential clinical and histopathologic mimics. Therefore, accurate diagnosis is crucial to avoid unnecessary patient management and achieve optimal patient outcomes.

Keywords

Epstein–Barr virus infections - leflunomide - lymphoproliferative disorders - methotrexate - oral ulcerations

Note

Written informed consent was obtained from the patient for the publication of this case report and any accompanying images. All data was anonymized.


Authors' Contributions

S.K. collected the patient data, drafted, and wrote the manuscript. C.A. collected and provided the clinical data of the patient and performed regular clinical follow-up. E.P. analyzed and interpreted the histological findings, reviewed, and revised the manuscript. All authors read and approved the final manuscript.




Publication History

Article published online:
11 January 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

 

  • References

  • 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 (03) 405-417
    CrossrefPubMedGoogle Scholar
  • 2 Gaulard P, Swerdlow SH, Harris NL, Sundstrom C, Jaffe ES. EBV-positive mucocutaneous ulcer. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th edition.. Lyon: IARC; 2017: 307-308
    Google Scholar
  • 3 Ikeda T, Gion Y, Nishimura Y, Nishimura MF, Yoshino T, Sato Y. Epstein-Barr Virus-positive mucocutaneous ulcer: a unique and curious disease entity. Int J Mol Sci 2021; 22 (03) 1053 DOI: 10.3390/ijms22031053.
    CrossrefPubMedGoogle Scholar
  • 4 Bunn B, van Heerden W. EBV-positive mucocutaneous ulcer of the oral cavity associated with HIV/AIDS. Oral Surg Oral Med Oral Pathol Oral Radiol 2015; 120 (06) 725-732
    CrossrefPubMedGoogle Scholar
  • 5 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 2016; 5: 13 DOI: 10.1186/s40164-016-0042-5.
    CrossrefPubMedGoogle Scholar
  • 6 Goronzy JJ, Weyand CM. Mechanisms underlying T cell ageing. Nat Rev Immunol 2019; 19 (09) 573-583
    CrossrefPubMedGoogle Scholar
  • 7 Ikeda T, Gion Y, Sakamoto M. et al. Clinicopathological analysis of 34 Japanese patients with EBV-positive mucocutaneous ulcer. Mod Pathol 2020; 33 (12) 2437-2448
    CrossrefPubMedGoogle Scholar
  • 8 Sinit RB, Horan KL, Dorer RK, Aboulafia DM. Epstein-Barr virus-positive mucocutaneous ulcer: case report and review of the first 100 published cases. Clin Lymphoma Myeloma Leuk 2019; 19 (02) e81-e92
    CrossrefPubMedGoogle Scholar
  • 9 Cronstein BN, Aune TM. Methotrexate and its mechanisms of action in inflammatory arthritis. Nat Rev Rheumatol 2020; 16 (03) 145-154
    CrossrefPubMedGoogle Scholar
  • 10 Chamorro-Petronacci C, García-García A, Lorenzo-Pouso AI. et al. Management options for low-dose methotrexate-induced oral ulcers: a systematic review. Med Oral Patol Oral Cir Bucal 2019; 24 (02) e181-e189
    PubMedGoogle Scholar
  • 11 Deeming GMJ, Collingwood J, Pemberton MN. Methotrexate and oral ulceration. Br Dent J 2005; 198 (02) 83-85
    CrossrefPubMedGoogle Scholar
  • 12 Troeltzsch M, von Blohn G, Kriegelstein S. et al. Oral mucositis in patients receiving low-dose methotrexate therapy for rheumatoid arthritis: report of 2 cases and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol 2013; 115 (05) e28-e33
    CrossrefPubMedGoogle Scholar
  • 13 Huang RY, Pan HD, Wu JQ. et al. Comparison of combination therapy with methotrexate and sinomenine or leflunomide for active rheumatoid arthritis: a randomized controlled clinical trial. Phytomedicine 2019; 57: 403-410
    Google Scholar
  • 14 Kalogirou EM, Katsoulas N, Tosios KI, Lazaris AC, Sklavounou A. Non-healing tongue ulcer in a rheumatoid arthritis patient medicated with leflunomide. An adverse drug event?. J Clin Exp Dent 2017; 9 (02) e325-e328
    PubMedGoogle Scholar
  • 15 Yoo HG, Yu HM, Jun JB, Jeon HS, Yoo WH. Risk factors of severe infections in patients with rheumatoid arthritis treated with leflunomide. Mod Rheumatol 2013; 23 (04) 709-715
    CrossrefPubMedGoogle Scholar
  • 16 Sharma B, Koshy G, Kapoor S. Traumatic ulcerative granuloma with stromal eosinophilia: a case report and review of pathogenesis. J Clin Diagn Res 2016; 10 (10) ZD07-ZD09
    PubMedGoogle Scholar
  • 17 Vélez A, Alamillos FJ, Dean A, Rodas J, Acosta A. Eosinophilic ulcer of the oral mucosa: report of a recurrent case on the tongue. Clin Exp Dermatol 1997; 22 (03) 154-156
    CrossrefPubMedGoogle Scholar
  • 18 Hirshberg A, Amariglio N, Akrish S. et al. Traumatic ulcerative granuloma with stromal eosinophilia: a reactive lesion of the oral mucosa. Am J Clin Pathol 2006; 126 (04) 522-529
    CrossrefPubMedGoogle Scholar
  • 19 Valenzuela-Narváez R, Valenzuela DA, Valenzuela DR. et al. An unusual granular ulcer secondary oral tuberculosis of vestibule mandibular mucosa. Eur J Dent 2020; 14 (02) 331-334
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Lopez R, Fernandez O, Jara G, Baelum V. Epidemiology of necrotizing ulcerative gingival lesions in adolescents. J Periodontal Res 2002; 37 (06) 439-444
    CrossrefPubMedGoogle Scholar
  • 21 Malek R, Gharibi A, Khlil N, Kissa J. Necrotizing ulcerative gingivitis. Contemp Clin Dent 2017; 8 (03) 496-500
    CrossrefPubMedGoogle Scholar
  • 22 Ikeda T, Gion Y, Yoshino T, Sato Y. A review of EBV-positive mucocutaneous ulcers focusing on clinical and pathological aspects. J Clin Exp Hematop 2019; 59 (02) 64-71
    CrossrefPubMedGoogle Scholar
  • 23 Ok CY, Papathomas TG, Medeiros LJ, Young KH. EBV-positive diffuse large B-cell lymphoma of the elderly. Blood 2013; 122 (03) 328-340
    CrossrefPubMedGoogle Scholar
  • 24 Akrish SJ, Rachmiel A, El-Naaj IA, Ben-Izhak O. Clinical pathologic conference case: an older woman with a painless, deep, and indurated ulcer on her mandibular alveolar mucosa. Oral Surg Oral Med Oral Pathol Oral Radiol 2020; 129 (01) 3-7
    CrossrefPubMedGoogle Scholar
  • 25 Sciallis AP, Law ME, Inwards DJ. et al. Mucosal CD30-positive T-cell lymphoproliferations of the head and neck show a clinicopathologic spectrum similar to cutaneous CD30-positive T-cell lymphoproliferative disorders. Mod Pathol 2012; 25 (07) 983-992
    CrossrefPubMedGoogle Scholar