Epstein-Barr Virus Upper Gastrointestinal Tract Mucocutaneous Ulceration in a Renal Transplant Recipient with Leucopenia and Hypogammaglobulinaemia ()
1. Introduction
EBV mucocutaneous ulceration is a rare complication that has previously been described in human immunodeficiency virus (HIV) infection, immunosuppressive therapy for inflammatory arthritis, and age-related immunosenescence [1] [2]. It is most commonly associated with the use of methotrexate, azathioprine, and ciclosporin [2] [3] [4]. Approximately 20% of cases present with painful ulceration involving the gastrointestinal tract, however diagnosis can be challenging and requires clinicopathological correlation [2] [3] [4] [5].
EBV mucocutaneous ulceration affecting the oral mucosa has also been described in immunosuppressed patients, including patients who have undergone haematological and solid organ transplantation [6] [7]. EBV recipient-negative, donor-positive transplantations are at the highest risk, and an association with hypogammaglobulinaemia has been described [3] [8]. Human herpesvirus (HHV) 8 infection is an important differential diagnosis in renal transplant recipients with non-healing mucosal ulcers [6].
2. Case Presentation
A 64-year-old female with a deceased-donor renal transplant, performed for end-stage renal failure secondary to obstructive nephropathy, presented nine months post-transplantation with severe oral and epigastric pain. Her post-transplantation period was remarkable for subclinical vascular rejection on three month protocol biopsy (treated with three doses of intravenous methylprednisolone and change of calcineurin inhibitor from ciclosporin to tacrolimus), cytomegalovirus (CMV) viraemia at seven months post-transplantation (treated with therapeutic-dose valganciclovir), and recurrent gastrointestinal infections (two episodes of Camplyobacter jejuni enterocolitis and two episodes of Clostridium difficile colitis) necessitating reduction of her mycophenolate mofetil (MMF) dose. At the time of admission, the patient’s immunosuppressive regime comprised of prednisone (7.5 mg once daily), MMF (750 mg twice daily), and tacrolimus (trough levels 8 - 10 ug/L).
Examination revealed a large (32 mm by 20 mm), superficial, well-circumscribed ulcer on the left base of the tongue (Figure 1) without dental caries, lymphadenopathy or other organomegaly. Her renal function and electrolytes were normal, tacrolimus trough level within target range (9.0 μg/L), and full blood count revealed mild leucopenia (WBC 2.1 × 109/L, neutrophils 1.4 × 109/L). Viral swabs of the ulcer were negative for herpes simplex virus (HSV) 1 and 2, enterovirus, and varicella zoster virus (VZV) by polymerase chain reaction (PCR). She was HIV and hepatitis C virus antibody negative, hepatitis B virus immune, and serum PCR negative for CMV, EBV, parvovirus, HHV-6, and HHV-8. The serum protein electrophoresis and serum free light chains were normal; however, the serum IgG (5.3 g/L) and IgM (0.2 g/L) were suppressed. An orthopantomogram (OPG) was normal and computed tomography (CT) head and neck with contrast showed no evidence of a mass, abscess, or lymphadenopathy.
An oesophago-gastro-duodenoscopy (OGD) revealed four (5 - 7 mm) non-bleeding, cratered ulcers in the pre-pyloric region of the stomach (Figure 2), snare-biopsies of which revealed active inflammation without evidence of
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Figure 1. Superficial ulcer (32 mm by 20 mm) at the left base of the tongue in a patient nine months post deceased-donor renal transplantation.
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Figure 2. OGD image of gastric ulcers (5 - 7 mm) in the pre-pyloric region of the stomach in a patient nine months post deceased-donor renal transplantation.
Helicobacter pylori, CMV inclusions, or malignant infiltration. Core biopsies of the tongue ulcer revealed intermediate-sized lymphocytes with EBV positivity on immunohistochemical staining in keeping with EBV mucocutaneous ulceration, without evidence of Hodgkin or Reed-Sternberg cells, lymphoma, or carcinoma in situ. These biopsies were PCR negative for CMV, HSV, VZV, and enterovirus. PCR analysis revealed polyclonal pattern of immunoglobulin heavy chain (IgH) and T-cell receptor gamma (TCR γ) PCR primers.
The patient’s serum lymphocyte subsets and lymphocyte cell lines were normal. Additionally, B-cell subsets revealed normal immunophenotype with normal naïve and switched memory B-cells, but low memory B-cells of unclear significance. The hypogammaglobinaemia and low memory B-cells were deemed to be in keeping with secondary immunodeficiency. The patient’s MMF was reduced to 500 mg twice daily and target tacrolimus trough level lowered to 6 - 8 μg/L. The patient was subsequently followed up at eight weeks in the out-patient renal transplant clinic, at which time her tongue ulcer had completely resolved. Repeat OGD at twelve weeks confirmed complete resolution of the gastric ulcers.
3. Discussion
This is the first case of EBV mucocutaneous ulceration to be reported in a renal transplant recipient in New Zealand. The pathophysiology of EBV mucocutaneous ulceration is ill defined; however, it is postulated that T-cell mediated immunosurveillance is reduced by immunosuppression, which allows for the proliferation of EBV-infected B-cells [3]. Macroscopically, EBV mucocutaneous ulcers are large, superficial, and well-circumscribed (Figure 1 and Figure 2) [2] [3]. The microscopic appearances consist of a prominent rim of T-cells in the ulcer base with mixed haematolymphoid infiltrate and atypical B-cells positive for EBV by in situ hybridisation [2] [3] [6] [7].
Approximately 40% of cases are clonal for immunoglobulin receptor gene or T-cell gene rearrangement on PCR analysis [2]. EBV mucocutaneous ulceration is postulated to be on the disease spectrum with post-transplant lymphoproliferative disorder (PTLD) and classical Hodgkin lymphoma [1] [2] [9]. Clonality of immunoglobulin receptor gene or T-cell receptor gene rearrangements, serum EBV PCR positivity, and failure to respond to immunosuppression reduction, are associated with aggressive disease and PTLD transformation [2] [3].
At first glance, EBV mucocutaneous ulceration may appear indolent, however it is not currently possible to predict the risk of refractory disease or transformation to PTLD [2] [3]. The mainstay of treatment is reduction of immunosuppression, which leads to resolution of ulceration within four to six weeks in approximately 45% of cases [2] [3] [5] [7]. High clinical suspicion is required as failure to respond to treatment, or transformation to PTLD, results in significant mortality [3] [5] [6]. B-cell depleting chemotherapies have been utilised in cases of refractory EBV mucocutaneous ulceration with varying degrees of success [2] [3] [4] [9].