EBV-positive mucocutaneous ulcer

EBV-positive mucocutaneous ulcer is a new provisional category in the current WHO classification for lymphoid neoplasms. It has been differentiated from ^EBV+ DLBCL, NOS due to its self-limiting course and good response to conservative measures. This EBV-associated lymphoproliferative disease (see EBV infections below) occurs preferentially in older patients with various types of (e.g. therapeutically induced) or infectious (^HIV+) immunodeficiency (Bunn B et al. 2015).

Isolated cutaneous and mucosal ulcers can manifest in patients during immunosuppression with MTX, AZA, CyA. However, they can also occur in older patients without immunosuppressive therapy.

w>m; 1 case per year/3 million inhabitants.

80 years (64-101)

The average age of patients receiving immunosuppressive treatment (MTX, AZA and CyA) was 69 years (42-80)

In a larger review study, around 50% of patients received immunosuppressive drugs due to an autoimmune disease (rheumatoid arthritis, ulcerative colitis, sarcoidosis with myasthenia gravis, systemic lupus erythematosus) or after an allogeneic stem cell transplant.

Oropharyngeal mucosa (buccal mucosa, tongue, tonsils, palate); esophagus, colon and rectum.

Skin: lip skin, arms, breast region.

Associated regional, but not systemic, lymphadenopathy is not uncommon. No hepatosplenomegaly or bone marrow involvement.

Flat, sharply defined mucosal or skin ulcers. The underlying infiltrate is polymorphic and consists of a mixture of lymphocytes and immunoblasts. Isolated plasma cells, histiocytes and (sometimes abundant) eosinophils. There are also isolated large pleomorphic blasts reminiscent of Hodgkin and Reed-Sternberg cells (HRS).

It is not uncommon for medium-sized arteries to be thrombosed in large lesions. This was usually accompanied by surrounding necrosis, in addition to superficial ulceration, which was very marked in one case. The base of the lesions was sharply demarcated by a rim of small lymphocytes. The adjacent squamous epithelium showed reactive nuclear atypia, often with pseudoepitheliomatous hyperplasia.

In the colon and rectum, the lymphocytic infiltrate penetrates the intestinal crypts, which are otherwise unremarkable.

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Immunohistochemistry: The pleomorphic HRS cells showed a B-cell phenotype. The lesional blasts are > 50% CD45 positive. A small proportion of pleomorphic lesional blasts are positive for PAX5 and Oct-2 with variable expression of Bob.1. These cells may be positive for CD30. CD15 is co-expressed in about 50% of cases. In all cases tested, the lesional blasts are positive for LMP1. A large number of T lymphocytes express CD3. Scattered larger cells with immunoblastic characteristics and a large number of medium-sized cells are found among the T cells. CD4-positive T> CD8 -positive cells. The T cells with large and medium-sized morphology tend to be CD8-positive. There is evidence of positivity for EBER. The epithelium itself is negative. The lesional cells are also positive for LMP1. The EBER-positive nuclei vary in size. Both monoclonal Ig rearrangements and monoclonal TCR gene rearrangements are detectable. A monoclonal or restricted T-cell response is mainly observed in age-related and iatrogenic cases.

Favorable; apart from the need for treatment of the underlying disease, the ulcers should be treated conservatively with local therapy. There is a strong tendency towards spontaneous healing.

Epstein-Barr virus (EBV) has long been associated with B-cell lymphoproliferative disorders in patients with various forms of immunodeficiency. After a primary infection at an early age, EBV permanently infects the B cells of most adults. The virus triggers B-cell transformation and proliferation through complex mechanisms.

The products of viral genes upregulate a variety of cellular antigens and genes in B cells. Important molecular signaling pathways that control the cell cycle, such as NF-kB, are activated and virus-induced cytokines exert paracrine proliferative effects. Under physiologic circumstances, the inherent propensity of EBV to induce B cell proliferation is balanced by complex immunologic interactions that keep the total number of EBV-infected B cells in the body at a very low level.

Immunosuppression impairs various aspects of immune homeostasis and surveillance, allowing the occurrence of EBV-induced B-cell lymphoproliferative disorders (EBV-LPDs), including muco-cutaneous ulcer.

1. Bunn B et al (2015) EBV-positive mucocutaneous ulcers of the oral cavity associated with HIV/AIDS. Oral Surg Oral Med Oral Pathol Oral Radiol 120:725-732.
2. Daroontum T et al (2018) Comparison of Epstein-Barr virus-positive mucocutaneous ulcer associated with treated lymphoma ormethotrexate in Japan. Histopathology doi: 10.1111/his.13464.
3. Dojcinov SD et al (2010) EBV positive mucocutaneous ulcer--a study of 26 cases associated with various sources of immunosuppression. On J Surg Pathol 34:405-417.
4. Lamos C. et al (2017) Aggressive primary cutaneous B-cell lymphomas and new EBV-positive entities. The dermatologist 68: 727-739