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Epstein–Barr virus-positive mucocutaneous ulcer of the oral cavity in a patient who had had a renal transplant
YBJOM-5434; No. of Pages 3
ARTICLE IN PRESS Available online at www.sciencedirect.com
ScienceDirect British Journal of Oral and Maxillofacial Surgery xxx (2017) xxx–xxx
Case report
Epstein–Barr virus-positive mucocutaneous ulcer of the oral cavity in a patient who had had a renal transplant O. Onafowokan ∗ , W. Rodgers, E. Gruber Royal Free Hospital, Pond Street, London, NW3 2QG Greater London Accepted 4 June 2018
Abstract The Epstein–Barr virus-positive mucocutaneous ulcer is a new phenomenon that was first described in 2014, and we know of only 67 reported cases. We describe a case in a patient who had had a renal transplant. Crown Copyright © 2018 Published by Elsevier Ltd on behalf of The British Association of Oral and Maxillofacial Surgeons. All rights reserved.
Keywords: Epstein Barr Virus; Oral; Mucocutaneous ulcer; Lymphoproliferative Disorders (LPD); Post Transplant
Introduction The Epstein Barr Virus (EBV), which affects 90% of the population,1 has a predilection for B cells, in which it elicits transformation and proliferation.2 In immunocompetent people, cell-mediated immunity prevents infection, but the virus remains latent in the memory of B cells.1 EBV-positive mucocutaneous ulcers arise most commonly in the oral mucosa, as the oral cavity has the highest concentration of infected B cells in Waldeyer’s ring. This predilection for B cells can cause a range of EBV-associated disorders such as classic Hodgkin lymphoma, post-transplant lymphoproliferative disorder, and EBV-positive mucocutaneous ulcers.3 EBV-positive mucocutaneous ulcers were first reported in 2010 by Dojcinov et al,4 who described 26 patients with lesions of the oral cavity, skin, and colon. Immunosuppressive medication and immunosenescence were identified as ∗
Corresponding author. E-mail addresses: [email protected] (O. Onafowokan), [email protected] (W. Rodgers), [email protected] (E. Gruber).
causative factors. The World Health Organization included the disorder in their revision of haematological malignancies in 2016.5
Case report A 56-year-old man was referred to Barnet maxillofacial department by his dentist, with a five-week history of a nonhealing ulcer. He had reported mild discomfort over this period, although the ulcer had remained stable. He had had a renal transplant in 2002 and took anti-rejection medication, but was otherwise fit and well. He had a 10 × 4 mm ulcer beneath his lower central incisors that was oval in shape (Fig. 1). There was no associated mobility of the teeth or lymphadenopathy, and plain film radiographs showed no abnormalities. Histological analysis of a biopsy specimen showed ulcerated gingival tissue covered in a necroinflammatory slough that contained large atypical lymphoid cells scattered with a background of mixed inflammatory infiltrate. EBER (Epstein–Barr virus-encoded small RNA) in situ was found in the large lymphoid cells. There was no dysplasia. Further imaging and subsequent
https://doi.org/10.1016/j.bjoms.2018.06.003 0266-4356/Crown Copyright © 2018 Published by Elsevier Ltd on behalf of The British Association of Oral and Maxillofacial Surgeons. All rights reserved.
Please cite this article in press as: Onafowokan O, et al. Epstein–Barr virus-positive mucocutaneous ulcer of the oral cavity in a patient who had had a renal transplant. Br J Oral Maxillofac Surg (2017), https://doi.org/10.1016/j.bjoms.2018.06.003
ARTICLE IN PRESS
YBJOM-5434; No. of Pages 3
2
O. Onafowokan et al. / British Journal of Oral and Maxillofacial Surgery xxx (2017) xxx–xxx
Table 1 Treatments for Epstein–Barr virus-positive mucocutaneous ulcers in 67 patients and number (n = 49) who had complete remission. Treatment
Complete remission
Reduction in immunosuppressants No treatment Combination of treatment Chemotherapy* Radiotherapy Operation Not stated
24/27 8/13 5/5 7/11 4/4 1/1 6
∗
Lost to follow up (n = 2). Fig. 2. Healed ulcer.
Fig. 1. Persistent ulcer with exudate.
blood tests showed no proliferative disease, and a diagnosis of EBV-positive mucocutaneous ulcer was made. He was referred to the haematology and transplant team at the Royal London Hospital for a second opinion and continued to attend the maxillofacial department for reviews. Five months after its initial appearance, the lesion had regressed spontaneously (Fig. 2).
Discussion In our review we found reports of only 67 patients and no consensus about treatment. Information about six was not available and two were lost to follow up, so outcomes were reported in 59. Of these, 49 obtained complete remission regardless of the type of treatment (Table 1). Follow up was for a mean (range) of 12 (1–72) months.1,2 Reports have suggested that favourable outcomes can be achieved by reductions in the dose of immunosuppressants,1,3,4,6 however, four had a relapsingremitting course and four had progressive disease, one of whom died.
Table 2 shows the features that differentiate EBV-positive mucocutaneous ulcers from lymphoproliferative disease. Patients with EBV-positive mucocutaneous ulcers probably have a compromised immune response that allows systemic control of the virus, but also allows isolated local proliferation. An increase in immunosuppression may tip the balance from localised disease to systemic lymphoproliferative disease,4,6 and the cause of immunosuppression should be identified to rule this out. A conservative approach seems sensible, as reports show that 24/27 patients obtained complete remission when the doses of immunosuppressants were reduced. It is important to investigate patients with chronic non-healing ulcers, particularly as some immunosuppressants favour the proliferation of EBV.4,6 Cases of EBV-positive mucocutaneous ulcers may be under diagnosed, as some regress spontaneously and some may be attributed to HIV or treatment with methotrexate. Accurate diagnosis will potentially prevent further radical treatment that would be needed in cases of lymphoproliferative disease or post-transplant lymphoproliferative disorder.
Conflict of interest We have no conflicts of interest.
Ethics statement/confirmation of patient’s permission Ethics approval not applicable. The patient’s permission was obtained.
Table 2 Features that differentiate Epstein Barr virus (EBV)-positive mucocutaneous ulcers from lymphoproliferative disease. EBV-positive mucocutaneous ulcer
Lymphproliferative disease (Hodgkin’s)
Presenting feature
Localised oral ulceration, with no systemic involvement
EBV viraemia Immunochemistry
Not present EBV-encoded small RNA (EBER) found in multiple cells
Hodgkin’s typically presents with nodal involvement, and rarely, if ever, with an isolated mucocutaneous ulcer4,6 Present6 EBER found only in Reed–Sternberg-like cells
Please cite this article in press as: Onafowokan O, et al. Epstein–Barr virus-positive mucocutaneous ulcer of the oral cavity in a patient who had had a renal transplant. Br J Oral Maxillofac Surg (2017), https://doi.org/10.1016/j.bjoms.2018.06.003
YBJOM-5434; No. of Pages 3
ARTICLE IN PRESS O. Onafowokan et al. / British Journal of Oral and Maxillofacial Surgery xxx (2017) xxx–xxx
References 1. Au JK, Said JW, Sepahdari AR, et al. Head and neck Epstein–Barr virus mucocutaneous ulcer: case report and literature review. Laryngoscope 2016;126:2500–4. 2. Attard A, Praveen P, Dunn P, et al. Epstein–Barr virus-positive mucocutaneous ulcer of the oral cavity: the importance of having a detailed clinical history to reach a correct diagnosis. Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e37–9. 3. 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 2016;5:13.
3
4. Dojcinov SD, Venkataraman G, Raffeld M, et al. EBV positive mucocutaneous ulcer—a study of 26 cases associated with various sources of immunosuppression. Am J Surg Pathol 2010;34:405–17. 5. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016;127:2375–90. 6. Hart M, Thakral B, Yohe S, et al. EBV-positive mucocutaneous ulcer in organ transplant recipients: a localized indolent posttransplant lymphoproliferative disorder. Am J Surg Pathol 2014;38:1522–9.
Please cite this article in press as: Onafowokan O, et al. Epstein–Barr virus-positive mucocutaneous ulcer of the oral cavity in a patient who had had a renal transplant. Br J Oral Maxillofac Surg (2017), https://doi.org/10.1016/j.bjoms.2018.06.003
ARTICLE IN PRESS Available online at www.sciencedirect.com
ScienceDirect British Journal of Oral and Maxillofacial Surgery xxx (2017) xxx–xxx
Case report
Epstein–Barr virus-positive mucocutaneous ulcer of the oral cavity in a patient who had had a renal transplant O. Onafowokan ∗ , W. Rodgers, E. Gruber Royal Free Hospital, Pond Street, London, NW3 2QG Greater London Accepted 4 June 2018
Abstract The Epstein–Barr virus-positive mucocutaneous ulcer is a new phenomenon that was first described in 2014, and we know of only 67 reported cases. We describe a case in a patient who had had a renal transplant. Crown Copyright © 2018 Published by Elsevier Ltd on behalf of The British Association of Oral and Maxillofacial Surgeons. All rights reserved.
Keywords: Epstein Barr Virus; Oral; Mucocutaneous ulcer; Lymphoproliferative Disorders (LPD); Post Transplant
Introduction The Epstein Barr Virus (EBV), which affects 90% of the population,1 has a predilection for B cells, in which it elicits transformation and proliferation.2 In immunocompetent people, cell-mediated immunity prevents infection, but the virus remains latent in the memory of B cells.1 EBV-positive mucocutaneous ulcers arise most commonly in the oral mucosa, as the oral cavity has the highest concentration of infected B cells in Waldeyer’s ring. This predilection for B cells can cause a range of EBV-associated disorders such as classic Hodgkin lymphoma, post-transplant lymphoproliferative disorder, and EBV-positive mucocutaneous ulcers.3 EBV-positive mucocutaneous ulcers were first reported in 2010 by Dojcinov et al,4 who described 26 patients with lesions of the oral cavity, skin, and colon. Immunosuppressive medication and immunosenescence were identified as ∗
Corresponding author. E-mail addresses: [email protected] (O. Onafowokan), [email protected] (W. Rodgers), [email protected] (E. Gruber).
causative factors. The World Health Organization included the disorder in their revision of haematological malignancies in 2016.5
Case report A 56-year-old man was referred to Barnet maxillofacial department by his dentist, with a five-week history of a nonhealing ulcer. He had reported mild discomfort over this period, although the ulcer had remained stable. He had had a renal transplant in 2002 and took anti-rejection medication, but was otherwise fit and well. He had a 10 × 4 mm ulcer beneath his lower central incisors that was oval in shape (Fig. 1). There was no associated mobility of the teeth or lymphadenopathy, and plain film radiographs showed no abnormalities. Histological analysis of a biopsy specimen showed ulcerated gingival tissue covered in a necroinflammatory slough that contained large atypical lymphoid cells scattered with a background of mixed inflammatory infiltrate. EBER (Epstein–Barr virus-encoded small RNA) in situ was found in the large lymphoid cells. There was no dysplasia. Further imaging and subsequent
https://doi.org/10.1016/j.bjoms.2018.06.003 0266-4356/Crown Copyright © 2018 Published by Elsevier Ltd on behalf of The British Association of Oral and Maxillofacial Surgeons. All rights reserved.
Please cite this article in press as: Onafowokan O, et al. Epstein–Barr virus-positive mucocutaneous ulcer of the oral cavity in a patient who had had a renal transplant. Br J Oral Maxillofac Surg (2017), https://doi.org/10.1016/j.bjoms.2018.06.003
ARTICLE IN PRESS
YBJOM-5434; No. of Pages 3
2
O. Onafowokan et al. / British Journal of Oral and Maxillofacial Surgery xxx (2017) xxx–xxx
Table 1 Treatments for Epstein–Barr virus-positive mucocutaneous ulcers in 67 patients and number (n = 49) who had complete remission. Treatment
Complete remission
Reduction in immunosuppressants No treatment Combination of treatment Chemotherapy* Radiotherapy Operation Not stated
24/27 8/13 5/5 7/11 4/4 1/1 6
∗
Lost to follow up (n = 2). Fig. 2. Healed ulcer.
Fig. 1. Persistent ulcer with exudate.
blood tests showed no proliferative disease, and a diagnosis of EBV-positive mucocutaneous ulcer was made. He was referred to the haematology and transplant team at the Royal London Hospital for a second opinion and continued to attend the maxillofacial department for reviews. Five months after its initial appearance, the lesion had regressed spontaneously (Fig. 2).
Discussion In our review we found reports of only 67 patients and no consensus about treatment. Information about six was not available and two were lost to follow up, so outcomes were reported in 59. Of these, 49 obtained complete remission regardless of the type of treatment (Table 1). Follow up was for a mean (range) of 12 (1–72) months.1,2 Reports have suggested that favourable outcomes can be achieved by reductions in the dose of immunosuppressants,1,3,4,6 however, four had a relapsingremitting course and four had progressive disease, one of whom died.
Table 2 shows the features that differentiate EBV-positive mucocutaneous ulcers from lymphoproliferative disease. Patients with EBV-positive mucocutaneous ulcers probably have a compromised immune response that allows systemic control of the virus, but also allows isolated local proliferation. An increase in immunosuppression may tip the balance from localised disease to systemic lymphoproliferative disease,4,6 and the cause of immunosuppression should be identified to rule this out. A conservative approach seems sensible, as reports show that 24/27 patients obtained complete remission when the doses of immunosuppressants were reduced. It is important to investigate patients with chronic non-healing ulcers, particularly as some immunosuppressants favour the proliferation of EBV.4,6 Cases of EBV-positive mucocutaneous ulcers may be under diagnosed, as some regress spontaneously and some may be attributed to HIV or treatment with methotrexate. Accurate diagnosis will potentially prevent further radical treatment that would be needed in cases of lymphoproliferative disease or post-transplant lymphoproliferative disorder.
Conflict of interest We have no conflicts of interest.
Ethics statement/confirmation of patient’s permission Ethics approval not applicable. The patient’s permission was obtained.
Table 2 Features that differentiate Epstein Barr virus (EBV)-positive mucocutaneous ulcers from lymphoproliferative disease. EBV-positive mucocutaneous ulcer
Lymphproliferative disease (Hodgkin’s)
Presenting feature
Localised oral ulceration, with no systemic involvement
EBV viraemia Immunochemistry
Not present EBV-encoded small RNA (EBER) found in multiple cells
Hodgkin’s typically presents with nodal involvement, and rarely, if ever, with an isolated mucocutaneous ulcer4,6 Present6 EBER found only in Reed–Sternberg-like cells
Please cite this article in press as: Onafowokan O, et al. Epstein–Barr virus-positive mucocutaneous ulcer of the oral cavity in a patient who had had a renal transplant. Br J Oral Maxillofac Surg (2017), https://doi.org/10.1016/j.bjoms.2018.06.003
YBJOM-5434; No. of Pages 3
ARTICLE IN PRESS O. Onafowokan et al. / British Journal of Oral and Maxillofacial Surgery xxx (2017) xxx–xxx
References 1. Au JK, Said JW, Sepahdari AR, et al. Head and neck Epstein–Barr virus mucocutaneous ulcer: case report and literature review. Laryngoscope 2016;126:2500–4. 2. Attard A, Praveen P, Dunn P, et al. Epstein–Barr virus-positive mucocutaneous ulcer of the oral cavity: the importance of having a detailed clinical history to reach a correct diagnosis. Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e37–9. 3. 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 2016;5:13.
3
4. Dojcinov SD, Venkataraman G, Raffeld M, et al. EBV positive mucocutaneous ulcer—a study of 26 cases associated with various sources of immunosuppression. Am J Surg Pathol 2010;34:405–17. 5. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016;127:2375–90. 6. Hart M, Thakral B, Yohe S, et al. EBV-positive mucocutaneous ulcer in organ transplant recipients: a localized indolent posttransplant lymphoproliferative disorder. Am J Surg Pathol 2014;38:1522–9.
Please cite this article in press as: Onafowokan O, et al. Epstein–Barr virus-positive mucocutaneous ulcer of the oral cavity in a patient who had had a renal transplant. Br J Oral Maxillofac Surg (2017), https://doi.org/10.1016/j.bjoms.2018.06.003