September 2018 Case of the Month - Further Information

Submitted by Dr Jon Griffin

Clinical History:  An eighty-year-old male presented to the Oral Medicine department with a 2cm well-demarcated circumscribed erosive ulcer on the left hard palate of three weeks’ duration. The patient had concurrent night sweats and weight loss over this period. The past medical history included recurrent oral ulceration and white patches manifesting after a liver transplant 20 years previously for autoimmune hepatitis. He had also previously undergone surgery and adjuvant 5-FU based chemotherapy for colorectal carcinoma. At the time of this presentation, he was on long-term immunosuppressive therapy with Mycophenolate mofetil and Ciclosporin following his liver transplant. An urgent biopsy was done with a clinical query of a carcinoma.

 Macroscopic and Microscopic Description:  The tissue sections showed an ulcer with thick fibrino-purulent slough and an underlying polymorphous infiltrate of small and large lymphocytes, histiocytes and occasional eosinophils admixed with atypical pleomorphic cells with irregular nuclear margins. There was angioinvasion without perivascular necrosis. The rare atypical cells expressed PAX5, CD30, MUM1, BCL6 and OCT2. Ki67 showed a proliferation index of >80%. The background cell population was dominated by CD3+ T-cells in a peripheral ‘cuff’. In situ hybridisation (ISH) confirmed EBER expression in the atypical cells and smaller B-cells. PCR for both IgH and TCR showed a polyclonal pattern. Following the pathological diagnosis of an EBV-positive mucocutaneous ulcer (EBVMCU), MRI and PET scans confirmed an isolated left hard palatal lesion without systemic involvement. Analysis of whole blood revealed a low level EBV viraemia of 3000 copies per ml. The patient was managed conservatively by weaning of his immunosuppresive drugs and remains well and in remission by clinical assessment after 12 months follow up.

Diagnosis:  EBV-positive mucocutaneous ulcer (EBVMCU)

 

Discussion: 

EBVMCU belongs to a spectrum of EBV related lymphoproliferative disorders with variable prognosis (1) (table1).  Up to 90% of adults are exposed to EBV during the first few decades. After entry via a mucosal (typically oral) route, EBV preferentially infects B-cells by interaction with the CD21 receptor on B-cells.  Most often this is followed by developing viral latency, with the EBV dsDNA being incorporated into the B-cell nucleus (and persisting as an episome).  Latency progresses through three stages, termed Latency III to I respectively.  During latency the multiple EBV-encoded RNAs and proteins expressed promote B-lymphocyte proliferation and survival (latency III).  After initial proliferation, some EBV-infected naïve B-cells undergo somatic hypermutations (as in the germinal centre) and increase the clonal expansion of EBV-infected B-cells (latency II).  A long-term reservoir of EBV infected B-cells with minimal transcription of viral genes (latency I) is established when the germinal centre B-cells differentiate into long lived resting memory B-cells.   Both immunosuppression (primary and acquired) and immunosenescence are thought to diminish the EBV-responsive T-cells and reduce the ability of T-cells to recognize the full range of EBV epitopes.  There is also an age-related reduced capacity to generate new naïve T-cells (2). 

 In the setting of decreased T-cell surveillance of latently infected B cells there is unchecked replication. Concomitant inhibition of apoptosis by viral RNA also leads to expansion of transformed B-cells and this clinically manifests as one of several lymphoproliferative disorders.

To date, all reported cases of EBVMCU have been associated with immunosuppression in three settings: iatrogenic immunosuppression for solid organ or bone marrow transplant, or for treatment of an autoimmune disease; primary immunodeficiency; or age related immunosenesence. In one report, EBVMCU was the presenting disease in a patient with previously undiagnosed hypogammaglobulinaemia (3). In the 51 cases reported so far, the oral mucosa is the commonest affected site (41%) and the lesions are commonly solitary. Skin and gastrointestinal lesions comprise most of the remaining cases (4).

The histopathological features typically include a solitary circumscribed mucosal ulcer with a subjacent polymorphous lymphoid infiltrate. Immunoblasts with some features of Reed-Sternberg (RS) cells are scattered in a background of small lymphocytes, plasma cells, histiocytes and eosinophils. Angioinvasion is common. Immunohistochemically the RS-like cells express B cell markers, CD30 and MUM-1. The background lymphocytes are T-cells.  The atypical and smaller B-cells express EBER.

In a recent systematic review (5), 70% of the cases of EBVMCU published to date had an indolent course and responded well to reduction of immunosuppressive agents or observation in patients without iatrogenic immunosuppression. However, a significant minority of patients are reported to need aggressive treatment including chemo- and radiotherapy, local excision and anti-CD20 therapies. Some patients experience a relapsing and remitting disease, which can be difficult to manage.

Practice points

  • EBVMCU is a provisional new entity in the WHO 2017 classification of tumours of haematopoietic and lymphoid tissues.
  • EBVMCU should be considered in the differential diagnosis of mucocutaneous ulcers, particularly in the setting of immunosuppression. The histopathological differential diagnosis includes carcinoma and lymphoma.
  • Many cases will follow an indolent course with resolution upon reduction of immunosuppression.

References

  1. 1. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. Lyon: International Agency for Research on Cancer; 2017.
  2. 2. Ok CY, Li L, Young KH. EBV-driven B-cell lymphoproliferative disorders: from biology, classification and differential diagnosis to clinical management. Exp Mol Med. 2015 Jan 23;47:e132.
  3. 3. Kleinman S, Jhaveri D, Caimi P, Cameron R, Lemonovich T, Meyerson H, et al. A rare presentation of EBV+ mucocutaneous ulcer that led to a diagnosis of hypogammaglobulinemia. J Allergy Clin Immunol Pract. 2014 Dec;2(6):810–2.
  4. 4. 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.
  5. 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. 2015;5:13.
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