Polymorphic lymphoproliferative disorder arising in a rheumatoid arthritis patient, presenting as fibrin-associated large B-cell lymphoma-like lesions in aortic and mitral valves.

We herein report a case of methotrexate-associated lymphoproliferative disorder (MTX-LPD) showing fibrin-associated large B-cell lymphoma-like heart valve lesions, and Epstein-Barr virus (EBV)-positive mucocutaneous ulcer-like cutaneous and oral mucosal lesions. MTX-LPD is a critical complication that can occur in RA patients who are treated with MTX. EBV also plays a defining or important role in LPDs. Among the sites of MTX-LPD, 40-50% occur in extranodal sites, including the gastrointestinal tract, skin, liver, lung, and kidney. There are few reports of MTX-LPDs involving the heart valves, and to the best of our knowledge, this is the first case to be reported in the English literature. The possibility of EBV-positive LPD should be considered in RA patients, even in patients with an atypical site, as in this case.

Cessation of methotrexate and a small intestinal resection provide a good clinical course for a patient with a jejunum perforation induced by a methotrexate-associated lymphoproliferative disorder: a case report.

BACKGROUND: Methotrexate (MTX) is a frequently used drug in the treatment of rheumatoid arthritis (RA), but occurrences of lymphoproliferative disorders (LPD) have been reported in patients undergoing an MTX regimen. Almost half of the patients with methotrexate-associated lymphoproliferative disorders (MTX-LPD) have extranodal lesions; moreover, although extremely rare, digestive tract perforations resulting from the extranodal lesions of MTX-LPD have also been reported. CASE PRESENTATION: We describe the case of an 81-year-old woman with RA who had been prescribed MTX at 6 mg per week for the past 11 years. She was admitted to our hospital with occasional abdominal pain and was first diagnosed with enteritis. Her abdominal pain did not improve, and a computed tomography scan showed abdominal effusion and free air in the abdominal cavity. She was diagnosed with a digestive tract perforation and underwent emergency surgery. The perforation site was identified in the jejunum, and she underwent small intestinal resection around the perforated region. The pathological findings showed an ulcer in the jejunum and infiltration of large atypical lymphocytes around the perforated region. An immunohistochemical examination revealed the expression of a cluster of differentiation 20 and latent membrane protein 1. Considering the patient's history of RA treated with MTX, she was diagnosed as having Epstein-Barr virus (EBV)-related MTX-LPD with a histological diagnosis of EBVMCU. MTX was discontinued after the surgery, and her soluble interleukin-2 receptor (sIL-2R) levels had returned to normal 1 year later. She has had a good course for the 2 years since surgery and remains asymptomatic with no recurrence of MTX-LPD, as confirmed by the sIL-2R levels. CONCLUSION: We experienced a rare case of the jejunum perforation induced by MTX-LPD. Since only a few cases have been reported of a patient with small intestinal perforation induced by MTX-LPD, further research is necessary to evaluate the clinicopathological features of MTX-LPD. The patient had disease remission after surgery and by discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, could have a higher likelihood of remission, which could have been a factor in the present case.

A rare case of Epstein-Barr virus-positive mucocutaneous ulcer that developed into an intestinal obstruction: a case report.

BACKGROUND: Epstein-Barr virus-positive mucocutaneous ulcer (EBV-MCU) is a new category of mature B-cell neoplasms. Ulcers occur in the oropharyngeal mucosa, skin, and gastrointestinal tract. The onset of EBV-MCU is suggested to be related to the decreased immunity of the patient, the causes of which include the use of immunosuppressive agents and aging. EBV-MCU may regress spontaneously and it often has a benign course after the dose reduction or discontinuation of immunosuppressive agents or during follow-up. Here, we report the case of a patient who required surgical resection for the intestinal obstruction arising from EBV-MCU. CASE PRESENTATION: A Japanese elderly male visited our hospital with chief complaints of a palpable mass and dull pain in the left upper quadrant, loss of appetite, and weight loss. Although abdominal computed tomography and total colonoscopy (TCS) revealed a tumor with circumferential ulcer in the transverse colon, histopathological analysis of a biopsy specimen of this lesion showed only nonspecific inflammation. Because the tumor spontaneously regressed during the time he underwent tests to obtain a second opinion from another hospital, TCS was reperformed on the patient. TCS revealed that the tumor decreased in size and the inflammatory changes in the surrounding mucosa tended to improve; however, tightening of the surrounding mucosa due to scarring was observed. Another histopathological analysis of a biopsy specimen showed widespread erosion of the mucosa and the formation of granulation tissue with marked infiltration of various inflammatory cells into the mucosal tissue of the large intestine. Moreover, some of the B-lymphocyte antigen CD20-positive B cells were also positive for EBV-encoded small RNA-1, suggesting the possibility of EBV-MCU. Later, the tumor developed into an intestinal obstruction; thus, the transverse colon was resected. Histopathological analysis of the resected specimen demonstrated scattered Hodgkin and Reed-Sternberg-like multinucleated large B cells in addition to EBER-1-positive cells. The patient was finally diagnosed as having EBV-MCU. CONCLUSIONS: This is the first report of a case of EBV-MCU that developed into an intestinal obstruction requiring surgical resection. It is necessary to consider the possibility of EBV-MCU when examining an ulcerative or tumorous lesion in the gastrointestinal tract.

Diagnostic utility of cytology in a patient with Epstein-Barr virus-positive mucocutaneous ulcer in palatine tonsils: A case report.

Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is a newly established immunodeficiency-related disease. Herein, we report a case of EBVMCU and focus on its cytological usefulness for diagnosis. An 82-year-old man manifested pharyngalgia, dysphagia, and oral pain. His medical history included rheumatoid arthritis that had been treated with methotrexate. Clinically, peritonsillar abscess was suspected, but since neoplastic lesions, including malignant lymphoma (ML), could not be excluded, a series of cytohistological examination was attempted. Despite some alarming findings (e.g., frequent mitoses), fine-needle aspiration and touch imprint cytology consistently revealed a heterogeneous population of lymphoid and plasmacytoid cells with mild nuclear atypia. The final diagnosis of EBVMCU was established based on the permanent histologic specimen; however, retrospectively, cytology was more representative of the benign nature of the lesion than histology, helping a great deal to differentiate it from ML. Cytology can be a useful tool for the correct diagnosis of EBVMCU.

EBV-positive mucocutaneous ulcer arising in methotrexate-treated rheumatoid arthritis patients: a clinicopathological study of 12 cases with analysis of PD-L1 expression.

Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is a newly recognized disease entity characterized by EBV-positive atypical B-cell proliferation. EBVMCU is a localized self-limited disease that affects mucosa and skin, especially the oral cavity. EBVMCU develops in immunosuppressive patients, such as those with methotrexate (MTX)-administrated rheumatoid arthritis (RA). Here we clinicopathologically analyzed 12 EBVMCU patients in a single institution. All cases were administrated MTX for RA, and five cases occurred in the oral cavity. All cases except one had demonstrated spontaneous regression after withdrawal of the immunosuppressive agent. We found 4 of 5 cases in the oral cavity had preceding traumatic events in the same site within a week before the onset of EBVMCU. Although there is no detailed and large study that has analyzed the trigger of EBVMCU, a traumatic event would indeed be a significant trigger for EBVMCU in the oral cavity. The cases were histologically classified; six cases were diffuse large B-cell lymphoma-type, five were polymorphous-type, and one was Hodgkin-like lesion type due to morphological appearance and immunophenotype. The PD-L1 expression was also examined by two antibodies for PD-L1 (E1J2J and SP142). Both antibodies revealed identical results for PD-L1 expression, and three cases were positive for PD-L1. The application of SP142 for evaluating the immune status of lymphomagenesis has also been proposed. Nine of 12 cases were negative for PD-L1, which implies that most EBVMCU cases may be caused by an immunodeficiency, rather than an immune-evasion, mechanism. However, as three cases were positive for PD-L1, immune escape may underly the pathogenesis in a subset of EBVMCU cases.

Age Related Immunosenescence Epstein-Barr Virus-positive Mucocutaneous Ulcer of the Palate Mimicking Medication-related Osteonecrosis of the Jaw.

Epstein-Barr virus (EBV) -positive mucocutaneous ulcer (EBVMCU) was first described as a lymphoproliferative disorder in 2010. In recent years, EBVMCU has been reported in the field of oral surgery. On the other hand, medication-related osteonecrosis of the jaw (MRONJ) is an osteomyelitis that occurs in patients receiving antiresorptive agents including bisphosphonates (BP) and/or denosumab developing with bacterial infections such as dental diseases and mucositis. MRONJ caused by EBVMCU in the elderly has not been reported. Here, we report a rare case of MRONJ caused by EBVMCU in the elderly. The patient, an 82-year-old woman, had received BP for more than 2 years. An ulcerative lesion was found in the palatal mucosa; biopsy performed from the site confirmed the diagnosis of EBVMCU. At follow-up, the lesion disappeared spontaneously. At the 6-month follow-up, bone formation was observed at the site of the lesion, and the sequestrum was removed. At the 12-month follow-up healing of the EBVMCU region was seen indicating a good prognosis.

Immunomodulator-associated Epstein-Barr virus-positive mucocutaneous ulcer in a patient with refractory Crohn's disease.

Epstein-Barr virus (EBV)-positive mucocutaneous ulcer is a B-cell lymphoproliferative disorder occurring in elderly or iatrogenic immunocompromised patients. We report a 27-year-old male patient with Crohn's disease (CD) who developed immunomodulator-associated lymphoproliferative disorder. The patient was diagnosed with CD at the age of 17 and was treated with maintenance therapy including high-dose infliximab and azathioprine. When he was admitted to our hospital with a diagnosis of intestinal obstruction, his abdominal computed tomography findings showed not only colonic wall thickening and narrowing of the descending colon but also multiple liver tumor lesions. His ileus symptom improved with conservative therapy, and a pathological evaluation of the tissue biopsy specimens from the descending colon and liver lesions indicated a morphological diagnosis of EBV-positive diffuse large B-cell lymphoma. This was a case of iatrogenic immunodeficiency-associated lymphoproliferative disorder due to an immunomodulator. The treatment was initiated with chemotherapy, but he died of disease progression 10 months after the diagnosis of lymphoma. Although cases of lymphoproliferative disorder due to treatment modalities used for CD are rare in Japan, an increase in the risk of lymphoproliferative diseases should be considered in patients with CD treated with immunomodulatory agents.