Resident Program - Case of the Month

December 2022 – Presented by Dr. Jasper X. Zheng (Mentored by Dr. Elham Vali Betts)

Discussion

Introduction:

Epstein-Barr virus (EBV) positive B-cell lymphoproliferative disorders (LPDs) are diseases with heterogenous prognosis that range from self-limiting, localized conditions to aggressive lymphomas. The pathogenesis of EBV associated B-cell LPDs are believed to be due to the disruption in the balance of complex immunological interactions (possibly related to alteration in cytotoxic T-cell functionality under immunosuppressed conditions [8]) that normally reduce and eliminate EBV induced B-cell transformation and proliferation [2]. Herein, we present a case of EBV-positive mucocutaneous ulcer (EBVMCU), an indolent condition on the spectrum of EBV positive LPDs.

Clinical Presentation:

EBV-positive MCU present as isolated often painful well circumscribed ulcerative lesions most commonly in the oral mucosa, tonsils, palate, skin, or in the gastrointestinal tract; and typically, in immunosuppressed patients of various causes (age-related, autoimmune, iatrogenic, HIV, and posttransplant settings) [8]. No systemic lymphadenopathy, hepatosplenomegaly, or bone marrow involvement has been reported [3-8].

Macro and Microscopic Features:

Macroscopically, the EBV-positive MCU ulceration is shallow and without discernable mass formation. Microscopically, the ulcerative lesion is sharply-circumscribed by a rim of small T-cells (CD8+) containing a polymorphous mixed inflammatory infiltrate of scattered small to large lymphoid cells (mixture of CD20+, and CD3+ lymphoid cells), plasma cells, eosinophils, histiocytes, immunoblasts, and large EBV-infected Hodgkin/Reed-Sternberg resembling B cells (CD30+, CD15+/–) [8]. Angioinvasion, thrombosis, necrosis, and apoptotic cells can also be present.

Immunophenotypic Profile:

Immunophenotypically, these large lymphoid cells are at the very least partially CD20 positive with expression of non-germinal center B cell programing (PAX5+, OCT2+, MUM1+, CD10-, and BCL6-) [8].  As forementioned, the large EBV-infected Hodgkin/Reed-Sternberg like cells can express CD30+, LMP1+, and, at times, CD15+ [8].

Molecular Profile:

No diagnostic molecular pathology has been identified. Approximately 40% of the reported cases has IGH-rearrangement [2,3,7], and approximately 35% of the reported cases has TCR rearrangement [3,7].

Differential Diagnosis:

Due to the increased large immunoblasts and Hodgkin/Reed-Sternberg like cells, the differential diagnosis of EBV-positive MCU includes polymorphic B-cell lymphoproliferative disorders (LPDs), EBV-positive diffuse large B-cell lymphoma (DLBCL) and classic Hodgkin lymphoma (CHL).

Clinically, EBV-positive diffuse large B-cell lymphoma (DLBCL) and classic Hodgkin lymphoma (CHL) will manifest as mass formations instead of shallow ulcers. Furthermore, the sharply circumscribed and localized cutaneous and mucosal presentation of EBV-positive MCU is unlike the macroscopic and histological findings of polymorphic LPDs, DLBCL or CHL [8]. The presence of intact B-cell program with CD45 expression in EBV-positive MCU may aid in the exclusion of the possible differential of CHL [5]. Nevertheless, the diagnosis of skin or mucosal classic Hodgkin lymphoma requires careful consideration.

The presence of angioinvasion and necrosis in a nasal or oropharyngeal location raises the possibility of extranodal NK/T-cell lymphoma; however, such entity can be excluded by the lack of CD56, cCD3, and other NK/T-cell immunohistochemical staining profiles [8].

Prognosis and Treatment:

EBV positive mucocutaneous ulcer has a favorable prognosis where majority of the cases will regress spontaneously or with the withdrawal of immunosuppressive therapy. Although relapsing disease course is possible, there has been zero reported incidence of progression. Relapsing and remitting disease courses have been documented to resolve with radiation, chemotherapy, or other localized treatments [5, 8].

References

1. Farrell PJ. Epstein-Barr Virus and Cancer. Annu Rev Pathol. 2019 Jan 24;14:29-53. doi: 10.1146/annurev-pathmechdis-012418-013023. Epub 2018 Aug 20. PMID: 30125149.
2. Hart, Melissa MD*; Thakral, Beenu MD*; Yohe, Sophia MD*,†; Balfour, Henry H. Jr MD‡; Singh, Charanjeet MD*; Spears, Michael MD†; McKenna, Robert W. MD*. EBV-positive Mucocutaneous Ulcer in Organ Transplant Recipients: A Localized Indolent Posttransplant Lymphoproliferative Disorder. The American Journal of Surgical Pathology 38(11):p 1522-1529, November 2014. | DOI: 10.1097/PAS.0000000000000282
3. 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 Mar;34(3):405-17. doi: 10.1097/PAS.0b013e3181cf8622. PMID: 20154586; PMCID: PMC6437677.
4. Attard AA, Praveen P, Dunn PJ, James GJ. Epstein-Barr virus-positive mucocutaneous ulcer of the oral cavity: the importance of having a detailed clinical history to reach a correct diagnosis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012 Aug;114(2):e37-9. doi: 10.1016/j.oooo.2012.04.003. PMID: 22769419.
5. Natkunam Y, Goodlad JR, Chadburn A, de Jong D, Gratzinger D, Chan JK, Said J, Jaffe ES. EBV-Positive B-Cell Proliferations of Varied Malignant Potential: 2015 SH/EAHP Workshop Report-Part 1. Am J Clin Pathol. 2017 Feb 1;147(2):129-152. doi: 10.1093/ajcp/aqw214. PMID: 28395107; PMCID: PMC6248636.
6. Prieto-Torres L, Eraña I, Gil-Redondo R, Gómez de la Riva I, Manso R, Pajares R, Córdoba R, Machan S, Ara M, Requena L, Piris MÁ, Rodríguez-Pinilla SM. The Spectrum of EBV-Positive Mucocutaneous Ulcer: A Study of 9 Cases. Am J Surg Pathol. 2019 Feb;43(2):201-210. doi: 10.1097/PAS.0000000000001186. PMID: 30418184.
7. Ikeda T, Gion Y, Sakamoto M, Tachibana T, Nishikori A, Nishimura MF, Yoshino T, Sato Y. Clinicopathological analysis of 34 Japanese patients with EBV-positive mucocutaneous ulcer. Mod Pathol. 2020 Dec;33(12):2437-2448. doi: 10.1038/s41379-020-0599-8. Epub 2020 Jun 19. PMID: 32561847.
8. Haematolymphoid Tumours, 5^th Edition, WHOCancer. 1985 Aug 15;56(4):883-93.