A 69-year-old female living donor kidney transplant recipient presented with right facial painful edema. The patient’s body mass index was 14 (kilograms per meter squared), and her creatinine clearance was 15 mL/min. A computed tomography detected a subcutaneous mass under the nasolabial fold in contact with the maxillary bone. A biopsy from an ipsilateral oral mucosal ulcer returned the diagnosis of Epstein-Barr virus-positive mucocutaneous ulcer. Within 2 weeks, the lesion perforated the tissue. The mass and the affected bone were removed, and histopathology detected inflammation with many microorganisms. The opportunistic pathogen Streptococcus anginosus was isolated from wound cultures. Immunosuppressives were restricted, antibiotics were administered, and the patient started hemodialysis. Rituximab was applied for the lymphoproliferative disease. The lesion healed, allowing for surgical restoration. Two years later, the patient has remained free of local pathology and with improved nutritional and functional status. Epstein-Barr virus-positive mucocutaneous ulcers should be considered in the differential diagnosis of oral and facial lesions of immunocompromised patients and may be complicated with bacterial infections.
Key words : Posttransplant lymphoproliferative disorders; Renal transplant, Streptococcus anginosus
Although kidney transplantation is the treatment of choice for patients with end-stage renal disease, chronic immunosuppression can pose various risks for patients, including opportunistic infections and certain types of malignancies, such as posttransplant lymphoproliferative disorder (PTLD).1
In this report, we have described an impressive case of a kidney transplant recipient who presented Streptococcus anginosus with an oral Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU), a recently recognized and rare type of PTLD,2 which was complicated by infection with the opportunistic pathogen Streptococcus anginosus.3
All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional review board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent for submitting this case report was obtained from the patient.
A 69-year-old female patient presented with right facial painful edema and an ipsilateral oral mucosal ulcer. Because of end-stage renal disease of unknown origin, she received a living donor kidney transplant from her father 29 years ago. As a result of Kaposi sarcoma at year 2 posttransplant, she remained only under methylprednisolone (4 mg/day) and an antimetabolite, which was mycophenolate mofetil (750 mg twice per day) at the time of presentation. Except for mild hypertension, the patient did not have any other comorbidities. At presentation, she was cachectic with a body mass index equal to 14 (kilograms per meter squared). She was not febrile, but her white blood cell count was 14?700/?L (90% neutrophils) and her C-reactive protein level was 3 mg/dL. According to the patient’s records, serum creatinine was stable at 3.0 mg/dL and creatinine clearance was 15 mL/min. Because of the advanced kidney failure, an arteriovenous fistula had already been constructed. Peripheral blood Epstein-Barr virus (EBV) DNA polymerase chain reaction was negative.
A computed tomography scan revealed a subcutaneous mass under the nasolabial fold in contact with the maxillary bone (Figure 1A). No enlarged lymph nodes, splenomegaly, or other possibilities related to the event pathology were detected. An oral ulcer biopsy was taken, and the patient was discharged with empiric oral antibiotic therapy (ciprofloxacin) while she waited for the result of the biopsy and the surgical resection of the mass. However, within 2 weeks, she returned to the hospital because the lesion had perforated the tissue (Figure 1B). Biopsy from the oral ulcer returned a diagnosis of EBVMCU. The mass and the affected bone were removed, and histopathology of this lesion detected fibrotic or bone tissue, respectively, along with inflammation and many microorganisms. Wound cultures revealed infection with Streptococcus anginosus.
Administration of the antimetabolite was stopped, amoxicillin/clavulanate was administered according to the antibiogram, and the patient started hemodialysis. Rituximab (3 weekly doses of 375 mg/m2) was administered for the PTLD. The lesion healed, allowing surgical reconstruction. The patient remains on hemodialysis 2 years later but is free of local pathology (Figure 1C) and with improved nutritional (body mass index of 20) and functional status.
The incidence of PTLD in kidney transplant recipients ranges from 0.8% to 2.5%. Posttransplant lymphoproliferative disorders present 2 peaks: the first during year 1 posttransplant and the second 5 to 15 years later. However, late (ie, more than 20 years posttransplant) cases of PTLD are on the rise. Posttransplant lymphoproliferative disorders include a wide range of diseases, from benign lymphoid proliferation to aggressive malignancy. The cumulative immunosuppressive burden and the oncogenic impact of EBV are the 2 main risk factors. Treatment for PTLD involves reducing immunosuppression, rituximab, alone, or in combination with other chemotherapeutics, surgical resection, and local radiation therapy.4
Epstein-Barr virus-positive mucocutaneous ulcer is a recently recognized and rare type of PTLD.2,5 It is a B-cell lymphoproliferative disease related to immunosuppression or age-associated immunosenescence. In addition to organ transplant recipients, EBVMCU has been described in several other pathologic entities characterized by immunodeficiency and those treated with immunosuppressive medications (such as methotrexate, azathioprine, mycophenolate, cyclosporine, tacrolimus, and tumor necrosis factor inhibitors). Because our patient received a kidney transplant 29 years ago, the cumulative immunosuppressive burden was high. Although EBVMCU appears mostly as a well-circumscribed, shallow, often painful, usually unifocal mucocutaneous ulcer in the oropharyngeal region, it can be less frequently shown in the large bowel or rectum mucosa or the lips, arms, and chest skin. Systemic lymphadenopathy is always absent, but isolated regional, possibly reactive lymphadenopathy can occur. Histologically, EBVMCU is characterized by a polymorphous infiltrate consisting of a mixture of lymphocytes, plasma cells, histiocytes, eosinophils, and, most importantly, atypical large EBV-positive B-cell blasts frequently with Reed-Sternberg cell-like morphology. At the base of the lesion, small T cells predominate. Large cells are PAX-5+, OCT-2+, MUM-1+, BOB-1+/-, and CD45+/-. Reed-Sternberg-like cells are CD30+ with frequent CD15 coexpression. In one-third of cases, CD20 expression is reduced or absent. All cases are EBV positive, whereas B-cell or T-cell clonality is present in only about 40% of cases. Contrary to other EBV-related lymphoproliferative diseases, in EBVMCU, peripheral blood EBV DNA polymerase chain reaction results are usually negative.2,5-7 Often, EBVMCU has a benign and self-limited course.6 However, some patients experience a persistent debilitating course, which requires aggressive therapy.7
Because patients with EBVMCU are immunosuppressed, bacterial infection may complicate the course of the disease. In addition to the need for an immunosuppressive regimen for many years, our patient was 69 years old, and her graft function corresponded to chronic kidney disease stage 5. Adaptive immunity, which plays a significant role in restricting EBV infection, is disturbed in patients with advanced renal failure.8 In our case, the opportunistic pathogen Streptococcus anginosus was isolated. Along with Streptococcus intermedius and Streptococcus constellatus, Streptococcus anginosus belongs to the Streptococcus anginosus group, once known as Streptococcus milleri group. Although it is part of the normal flora of the oropharynx and the digestive, upper respiratory, and reproductive tracts, Streptococcus anginosus is increasingly recognized as an emerging pathogen that can induce pyogenic infections, frequently in the form of abscesses, especially in patients with comorbidities such as malignancies and diabetes.3 Often, in Streptococcus anginosus infections, the probable portal of entry is associated with mucosal-barrier trauma,9 which, in our case, was the EBVMCU. In addition, this pathogen has been incriminated in cases of jaw osteomyelitis.10
Thus, EBVMCU should be considered in the differential diagnosis of oral and facial lesions of immunocompromised patients and may be complicated with bacterial, often opportunistic, infections.
Volume : 19
Issue : 8
Pages : 868 - 870
DOI : 10.6002/ect.2021.0053
From the 1Department of Nephrology and the 2Department of Interventional Radiology, Faculty of Medicine, University of Thessaly, Larissa, Greece
Acknowledgements: The authors report no conflicts of interest. This study was funded only by the resources of our departments.
Corresponding author: Theodoros Eleftheriadis, Department of Nephrology, Faculty of Medicine, University of Thessaly, Biopolis, Mezourlo Hill, 41110 Larissa, Greece
Phone: +30 2413 501665
Figure 1.Course of Subcutaneous 3-cm-Diameter Mass Under the Right Nasolabial Fold in Contact With the Maxillary Bone