EBV positive mucocutaneous ulcer--a study of 26 cases associated with various sources of immunosuppression

Abstract

We describe a series of Epstein Barr virus (EBV)-positive circumscribed, ulcerative lesions associated with various types of immunosuppression (IS). The study group (26 patients) comprised 10 males and 16 females, median age 77 years (range 42 to 101). IS in 9 cases included azathioprine (AZA), methotrexate (MTX) or cyclosporin-A (CyA). Seventeen patients had age-related immunosenescence. Patients presented with isolated sharply circumscribed ulcers involving oropharyngeal mucosa (16), skin (6), and gastrointestinal tract (4). Lesions were histologically characterized by a polymorphous infiltrate and atypical large B-cell blasts often with Hodgkin/Reed-Sternberg (HRS) cell-like morphology. The B cells showed strong CD30 and EBER positivity, some with reduced CD20 expression, in a background of abundant T cells. CD15 was positive in 43% of cases (10/23). The pathologic features were identical regardless of the anatomic site or cause of IS. Polymerase chain reaction revealed 39% (7/18) clonal Ig gene rearrangements with 38% (6/16) and 31% (5/16) clonal and restricted T-cell patterns, respectively. Twenty-five percent of patients (5/20) received standard chemotherapy and/or radiotherapy. Forty-five percent (9/20) regressed spontaneously with no treatment and 15% (3/20) were characterized by a relapsing and remitting course. All of the iatrogenic lesions (6/6) with available follow-up responded to reduction of IS. All patients achieved complete remission with no disease-associated deaths over a median follow-up period of 22 months (range 3 to 72). We propose EBV-positive mucocutaneous ulcer as a newly recognized clinicopathologic entity with Hodgkin-like features and a self-limited, indolent course, generally responding well to conservative management. Association with various forms of IS implies a common pathogenetic mechanism. The localized nature of the disease may be owing to a minimal and localized lapse in immunosurveillance over EBV.

Figure 1.

EBVMCU in a patient treated with methotrexate (MTX) for rheumatoid arthritis (case 23). Spontaneous resolution after withdrawal of MTX. (a) At presentation the ulcer had perforated from the buccal sulcus onto the skin surface of the lower lip. Ulcer healing (b) 2 weeks, (c) 4 weeks and (d) 8 weeks after withdrawal of MTX.

Figure 2.

Histological features of EBVMCU. (a) Well circumscribed ulcerated mucosal lesion with a band-like infiltrate underlying squamous mucosa. (b) The infiltrate is polymorphous, containing lymphocytes, histiocytes, immunoblasts, Hodgkin-like cells and apoptotic bodies. Intermediate size lymphoid cells with angulated nuclei and pale cytoplasm are present. (c) The lymphoid blasts show marked pleomorphism with Hodgkin and Reed-Sternberg cell features. (d) Eosinophils appear focally prominent. (e) Scattered apoptotic cells with plasmacytoid features are noted. (f) A thrombosed vessel with an aggregate of large cells adherent to and infiltrating the vessel wall. (g) The base of the lesion is rimmed off by a band of small lymphocytes. (h) Rectal lesion containing a polymorphous infiltrate between the crypts. (HE, original magnification: a X 20; g X 40; h X 100; b, f X 200; c, d X 400; e X 600).

Figure 3.

Immunohistochemical features of EBVMCU. (a) CD20 highlights a range of cell sizes including the large pleomorphic blasts. (b) In some cases, the lesional cells showed a reduced level of expression of CD20. (c) PAX5 and (d) Oct-2 are positive in the pleomorphic blasts. (e) Bob.1 is largely negative. (f) There is strong nuclear expression of MUM1. (g) There is abundant expression of CD30 highlighting a range of cell sizes. (h) Few atypical cells show expression of CD15 but in some cases (i) most cells were positive. (j) The background lymphocytic infiltrate is CD3 positive. There is a variation of cell size with occasional intermediate size cells. (k) The infiltrating T-cells are highlighted by CD8. (Original magnification: a-g X 400; h-k X 600).

Figure 4.

Expression of EBV markers in EBVMCU and T-cell PCR. (a) Linear positivity for EBER underlying the ulcerated mucosal squamous epithelium. The epithelium itself is negative. (b) The lesional cells are also positive for LMP1. (c) The EBER positive nuclei are of variable size. (d) Polyacrilamide PCR gel with TCR gamma primers showing multiple, reproducible prominent bands (boxed), highlighting the “restricted” T-cell response. (e) Inset of a genescan plot with the Biomed-2 TCR gamma primers show multiple irregular peaks (arrows) in keeping with the “restricted” T-cell response. (Original magnification: a X 20; b, c X 400).