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Division of Oral and Maxillofacial Pathology, East Carolina University, Greenville, NC, USADepartment of Surgical Sciences, East Carolina University School of Dental Medicine, Greenville, NC, USA
Division of Oral and Maxillofacial Surgery, East Carolina University, Greenville, NC, USADepartment of Surgical Sciences, East Carolina University School of Dental Medicine, Greenville, NC, USA
A 63-year-old Caucasian male presented to East Carolina University School of Dental Medicine after being referred from an outside Ear, Nose, and Throat specialist due to long-standing irritation on the buccal aspect of the right lower gingiva. The patient reported that the lesion arose in September 2020 and that it started with inflammation and irritation after a zirconia crown was delivered in tooth #30 by a general dentist. Due to the unresolved inflammation that later developed into an ulcer, the patient was referred to an external periodontist who performed a biopsy diagnosed as “atypical lymphoid proliferation” by an external laboratory. Due to a strong suspicion of a malignant lymphoproliferative disorder, the patient was referred East Carolina University School of Dental Medicine for specialized dental care.
The patient's medical history was significant for prostate disease, hypertension, arthritis, polymyalgia rheumatica (PMR), and gastroesophageal reflux. He is also a former smoker and an occasional alcohol user. At the time of consultation, his medications and daily doses included Methotrexate 2.5 mg, Prednisone 5 mg, Tramadol HCL 50 mg, Amlodipine Besylate 10 mg, Losartan Potassium 25 mg, Silodosin 8 mg, Solifenacin 5 mg, Esomeprazole 40 mg, Azathioprine 50 mg, Folic Acid 1 mg, and Vitamin D3. An extraoral examination yielded no head and neck lymphadenopathy, normal salivary gland palpation, and facial symmetry. An intraoral examination revealed a white-gray necrotic ulcer on the buccal marginal and attached gingiva of teeth #29 and 30. Significant necrotic debris and gingival recession were also seen within the ulcer bed (Figure 1). No bleeding, purulence, foul odor, or tooth mobility were identified. The patient stated no pain but alluded to mild occasional soreness and complained of constant food entrapment in the area. Notably, the overall oral hygiene of the patient was excellent.
Fig. 1Initial clinical presentation before irrigation with 0.12% chlorhexidine gluconate. The debris was removed to reveal nonbleeding exposed bone. Significant gingival recession is evident.
A panoramic radiograph was taken, which revealed a normal trabecular pattern around tooth #30 but with a minor loss of radiodensity (Figure 2). Tooth #30 had an intact lamina dura, a widened periodontal ligament space, and mild horizontal bone loss on the mesial aspect (distal of #29).
Fig. 2Panoramic radiograph. Mild radiolucency present on the cervical bone surrounding tooth #30 and on distal of #29.
Upon anamnesis, the patient also revealed that he was on an oral antiresorptive medication (Alendronate Sodium 70 mg), and an intravenous bisphosphonate (Zoledronic Acid 5 mg) before that, but the medication was stopped by his treating physician 1 year ago. He also stated that a crown-lengthening procedure was done at this site before the crown was delivered. During the initial consult, atraumatic irrigation of the area with 0.12% chlorhexidine gluconate was performed revealing nonbleeding exposed bone. The irrigation removed small fragments of necrotic bone and food debris from the area. The patient was then referred to the ECU Division of Oral and Maxillofacial Surgery for further treatment.
DIFFERENTIAL DIAGNOSES
Due to the clinical presentation, past medical history, and medications, a preliminary diagnosis of medication-related osteonecrosis of the jaws (MRONJ) was initially considered. The American Association of Oral and Maxillofacial Surgery position paper estimates an MRONJ incidence between 0.8% and 12%. Also, although MRONJ can occur in both jaws, the mandible appears to be prone to developing these lesions after invasive surgical procedures.
A second differential diagnosis would be necrotizing periodontal disease (NPD), such as necrotizing ulcerative gingivitis and necrotizing ulcerative periodontitis.
Microbiome pathogens associated with NPD include spirochetes, Prevotella intermedia, Fusobacterium species, and Peptostreptococcus genus. Because there was evidence of mild alveolar bone loss at #30, the condition would be necrotizing ulcerative periodontitis; however, the bone loss may be attributed to the crown lengthening surgery. Interestingly, the condition was localized to #30 and distal of #29. Within the limitations of the panoramic radiograph for evaluation of interproximal bone levels, the remainder of the dentition appeared to exhibit an intact periodontium, and plaque levels were remarkably low. The patient, besides taking Methotrexate and Azathioprine which are both immunosuppressive drugs, did not report previous diagnosis of immune deficiency, acute psychological stress, or insufficient sleep, which are risk factors for NPD.
A third consideration for the differential diagnoses was some form of a lymphoproliferative disorder. This consideration was prompted by the initial biopsy report, from an external hematopathology service at the originating laboratory, which stated that the microscopic findings were “concerning for a hematopoietic neoplasm.” Although no constitutional symptoms were identified at the clinical exam, and our patient had no previous history of any form of transplants, several studies have reported the gingiva or palate as the areas with the highest incidence for oral lymphomas.
Other reported signs and symptoms at the time of diagnosis included inflammation, ulceration, thickening of the periodontal ligament, and the loss of lamina dura.
Due to the patient's PMR diagnosis and consequent immunomodulation therapy, a fungal infection was also considered as a differential diagnosis. Indeed, the incidence of superficial and invasive oral fungal infections has been increasing in populations, mainly in patients receiving immunosuppressive therapy.
Incidence of infections associated with oral glucocorticoid dose in people diagnosed with polymyalgia rheumatica or giant cell arteritis: a cohort study in England.
The most common organisms responsible for opportunistic invasive fungal infections are Histoplasma capsulatum and Aspergillus spp., which usually present in the buccal mucosa, gingiva, palate, and tongue. They can often resemble a malignant process.
The patient was instructed to remain vigilant with oral hygiene, and a prescription for chlorhexidine gluconate 0.12% mouthrinse was sent to his pharmacy. A month later, the clinical presentation seemed to improve with this regimen. There was no clinical suggestion of a more severe pathology. There was minimal tooth mobility, and no exposed bone identified at that time. Food debris was irrigated from the mucosal defect, and a new follow-up appointment was scheduled.
Despite the use of oral rinses and the patient's excellent oral hygiene, at 1-month follow-up, the loss of facial gingiva recurred and appeared worse with involvement of the facial of tooth #29 and lingual of tooth #30. No tooth mobility was identified at that time, but the symptoms remained the same. The previous microscopic slides and reports from the biopsy were requested for examination before further surgical sampling.
Microscopic examination revealed 2 fragments of oral mucosa partially surfaced by stratified squamous epithelium. The underlying connective tissue contained a dense inflammatory cell infiltrate, which extended deep into all surgical margins (Figures 3A and B). Large, atypical cells were identified as of concern, displaying brisk mitotic activity within the mentioned infiltrate (Figures 3C and D). The immunohistochemical panel provided with the biopsy showed that said atypical cells were positive for CD45, CD20, BCL-2, BCL-6, and CD30 (Figure 4). Periodic acid-Schiff and Grocott's methenamine silver stains failed to identify invasive fungal organisms. The cell population of interest was negative for pancytokeratin, CD34, ALK-1, CD117, and CD1a.
Fig. 3Representative section of the incisional biopsy; hematoxylin & eosin stain. (A) Lower-power view of fragment of oral mucosa, surfaced by oral mucosa (20 × magnification). (B) Second fragment of oral mucosa, note the density and spread of the inflammatory infiltrate to the deep margin of the specimen (20 × magnification). (C) High-power view of cell population of interest. Note degree of pleomorphism and somewhat perivascular arrangement (200 × magnification). (D) Large atypical mononuclear cells identified. Also note the mild presence of cell undergoing mitosis (400 × magnification). A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM06659.
Due to the morphologic appearance and immunohistochemical expression of the large, atypical cell population of interest, Epstein-Barr virus (EBV)-encoded RNA (EBER) in situ hybridization was performed, which showed solid nuclear reactivity in the cell population of interest (Figure 5). A diagnosis of EBV-driven lymphoproliferative disorder consistent with an EBV-positive mucocutaneous ulcer (EBV+MCU) was made. The patient was unfortunately lost to follow-up by the time of submission of this manuscript.
Fig. 5Epstein-Barr virus-encoded RNA in situ hybridization. (A) Lower-power field shows numerous positive cells (20 × magnification). (B) High power magnification of positive atypical mononuclear cells (green arrow) (400 × magnification).
The oral cavity is a primary site for transmission and persistence of EBV, which then can disseminate to other anatomic sites through circulating B-lymphocytes. The EBV is periodically shed in the saliva through the lifetime of the infected individual and can be transmitted through this media. Viruses released from B cells can then infect the epithelial cells where the virus is amplified.
Although EBV infections typically have no pathogenic consequences, in some cases, EBV has been associated with several lymphoid and epithelial malignancies arising in the oral cavity and other anatomic locations.
In cases of immunosuppression, there is an increased risk for developing EBV-associated entities such as plasmablastic lymphoma, EBV-positive smooth muscle neoplasms, oral hairy leukoplakia, and post-transplant lymphoproliferative disorder.
Although the condition responds well to glucocorticosteroids, the administration of chemotherapeutic and immunosuppressant drugs, such as Methotrexate, is recommended in patients with a refractory disease.
2015 Recommendations for the management of polymyalgia rheumatica: a European League against Rheumatism/American College of Rheumatology collaborative initiative.
In 2010, the EBV-positive mucocutaneous ulcer was initially described by Dojcinov et al. in a series of ulcerative lesions with predilection of the oral and oropharyngeal mucosa in mostly older patients that were immunocompromised.
Our patient presented as an older gentleman with long-term use of immunosuppressive medication to treat PMR and arthritis.
Since its initial description, several groups have described this rare entity as a sharply circumscribed ulcer localized to the oral mucosa, gastrointestinal tract, or skin.
The microscopic presentation is characterized by a polymorphous inflammatory cell infiltrate in the ulcer bed, composed of lymphocytes, immunoblasts, plasma cells, and histiocytes. These immunoblasts will often show a Reed-Sternberg-like (RS) appearance with strong nuclear positivity for EBV, demonstrated with EBER in situ hybridization.
Our case showed similar cytologic features on light microscopy and showed a similar reactivity panel to the one reported: CD30, CD45, and BCL-6. Also, the RS-like atypical cells exhibit a strong EBER nuclear signal.
Other entities have been previously described as histopathologic differential diagnoses of EBV+MCU, such as classical Hodgkin lymphoma. However, in classical Hodgkin lymphoma, the RS cells are usually negative for CD45 and CD20 immunohistochemical stains, and these types of malignancies seldom occur in extranodal sites in the head and neck.
Another important differential diagnosis is diffuse large B cell lymphoma (DLBCL), which can also share significant microscopic and immunohistochemical similarities with EBV+MCU. Nonetheless, in most cases of DLBCL, the RS-like cells express BCL-2 and BCL-6, and in only a small percentage cases, said large RS-like cells are positive for CD30, mostly in cases associated with anaplastic morphology, which was not present in our biopsy.
However, like in our patient, the clinical course of EBV+MCU is indolent in most cases, usually encountered in immunosuppressed patients, and often appears in areas of chronic tissue damage, like the gingiva.
Lastly, anaplastic large cell lymphoma may resemble EBV+MCU histologically; however, this is considered an aggressive CD30 positive T-cell lymphoma and is characteristically negative for EBER.
To the best of our knowledge, there are only a few previously reported cases of EBV+MCU with chronic exposed bone clinically mimicking MRONJ in patients with a previous history of antiresorptive medication use.
In all of the cases, including ours, the histologic features on an initial incisional biopsy prompted a further investigation to rule out a malignant lymphoreticular neoplasm. Also, all of the patients had some form of immunosuppression and presented with a large necrotic ulcer with underlying bony involvement. Similarly, other groups have reported similar diseases associated with the long-term use of Methotrexate as Methotrexate-related lymphoproliferative disorder.
This entity has also been reported in association with EBV, which exhibited a similar clinical presentation to MRONJ, and might be the diagnosis of our patient. Although the underlying mechanism remains unclear, the immunomodulation therapies administered to patients with persistent immunologic disorders can potentiate the proliferation of latent EBV infection and the clonal selection of B cells. An example of this has been the increased incidence of lymphoproliferative disorders in the patients with rheumatoid arthritis and long-term treatment with Methotrexate.
If the patient returns for treatment and follow-up, we planned to explore this route in conjunction with his medical team.
CONCLUSION
This case highlighted the importance of a microscopic examination of any long-standing ulcerative condition in the oral cavity and considering EBV+MCU mimicking MRONJ, especially in patients with some form of immunosuppression or previous history of antiresorptive medication use. It is crucial that the clinician periodically screen the patients under systemic corticosteroid therapy or chemotherapeutic agents such as Methotrexate. An interdisciplinary approach with the patient-physician is recommended for the management of these patients and is imperative when developing a treatment plan.
The EBV can persist in the oral cavity through saliva and oral epithelium. The latent presence of this virus in patients that are immunocompromised may induce malignant lymphoproliferative disorders and chronic diseases that can be hard to manage and may incur long-term consequences. Close clinical follow-up should be conducted for prevention and early diagnosis.
Disclosures
none.
References
Ruggiero SL
Dodson TB
Fantasia J
et al.
American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw—2014 update.
Incidence of infections associated with oral glucocorticoid dose in people diagnosed with polymyalgia rheumatica or giant cell arteritis: a cohort study in England.
2015 Recommendations for the management of polymyalgia rheumatica: a European League against Rheumatism/American College of Rheumatology collaborative initiative.
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