EBV-positive Mucocutaneous Ulcer Research Articles

Comparison of Epstein–Barr virus‐positive mucocutaneous ulcer associated with treated lymphoma or methotrexate in Japan

The aim of the present study was to compare treated lymphoma-associated Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) and methotrexate (MTX)-associated EBVMCU. Of a series of 15 Japanese patients (11 women, four men; median age 74years, range 35-84years), seven received MTX for the treatment of autoimmune disease and eight developed EBVMCU after treatment of malignant lymphoma [diffuse large B-cell lymphoma (n=4) without EBV association, adult T-cell leukaemia/lymphoma (n=2), angioimmunoblastic T-cell lymphoma (n=1), and follicular lymphoma (n=1)]. Ulcers were observed in the oral cavity (n=11), gastrointestinal tract (n=2), and skin (n=2). All were histologically characterised by a mixture of EBV-positive large B-cell proliferation and Hodgkin/Reed-Sternberg-like cells on a polymorphous background. A total of 46% (6/13) had monoclonal immunoglobulin heavy chain gene rearrangement, but none had clonal T-cell receptor gene rearrangement. Spontaneous regression occurred in 13 of 15 cases (87%); the other two cases (13%) achieved complete remission after treatment. Of two patients in the treated lymphoma-associated subgroup, one developed multiple new ulcerative lesions on previously unaffected skin, and the other had a relapse of EBVMCU in the oral cavity. No significant clinicopathological differences were found between the subgroups. Notably, none of the patients died from EBVMCU. However, the treated lymphoma-associated subgroup had lower overall survival (P=0.004) and a shorter follow-up period (P=0.003) than the MTX-associated subgroup, owing to death from non-associated causes. Treated lymphoma-associated EBVMCU, which is an indolent and self-limited condition, must be recognised to avoid misdiagnosing it as a relapse of malignant lymphoma during treatment.

Reexamining post-transplant lymphoproliferative disorders: Newly recognized and enigmatic types.

Post-transplant lymphoproliferative disorders (PTLD) are a known risk for both solid organ transplant and stem cell transplant recipients. Overall transplant recipients have a six fold increase in risk for developing any kind of non-Hodgkin lymphoma and PTLDs occur in up to 10% of SOT recipients. Several new entities have been accepted or renamed in the 2018 update of the WHO classification of tumors of hematopoietic and lymphoid neoplasms, including florid follicular hyperplasia and extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT-lymphoma) (excluding common locations such as stomach and salivary gland). Other more rare types of PTLD have been reclassified including EBV-positive mucocutaneous ulcer, which is now a recognized diagnosis in its own right and should not be considered polymorphous PTLD. In this paper newly recognized PTLD entities and more unusual PTLDs will be examined.

Azathioprine induced Epstein-Barr virus positive mucocutaneous ulcer: A case report

Azathioprine induced Epstein-Barr virus positive mucocutaneous ulcer: A case report

Hodgkin lymphoma of the uterine cervix

An important cause of malignancy in women, cervical neoplasia commonly takes the form of either invasive squamous cell carcinoma or glandular neoplasms. Classical Hodgkin's lymphoma of the uterine cervix is rare with limited cases recorded in the 1960s and 70s.1–4 We present a case of classical Hodgkin lymphoma of the cervix in a 50-year-old immunosuppressed patient with known sarcoidosis, who presented with prominent B symptoms and radiographic features suggestive of cervical malignancy with associated nodal disease. The lesion was initially biopsied and treated with ABVD with radiographic nodal response but minimal response in the primary. Subsequent hysterectomy revealed a 35 mm cervical mass with cervical ulceration. Histologically, the mass comprised enlarged and atypical lymphocytes, many with Reed-Sternberg appearance, occurring amongst a mixed inflammatory background rich in eosinophils, with extensive fibrosis and focal necrosis. A classical Hodgkin lymphoma phenotype was seen on immunohistochemistry, with negativity for CD45 and CD20, strong positivity for CD30, MUM-1 and EBER-ISH, weak positivity for Pax-5, CD15 and Oct-2, but with complete negativity for BOB-1. EBV-positive mucocutaneous ulcers, which histopathologically and immunohistochemically mimic classic Hodgkin lymphoma, have been reported in the literature5 usually occurring in immunocompromised patients. Clinical and radiological correlation is important when distinguishing between these two entities.

Epstein-Barr Virus-Positive Mucocutaneous Ulcer in an Immunosuppressed Patient

Immunosuppressive medications, frequently used to treat inflammatory bowel disease, have been linked to the development of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPD). We describe a case of an EBV-positive mucocutaneous ulcer involving the palate in an elderly woman with inactive Crohn’s disease. This patient had been on high-dose azathioprine for a decade. Following diagnosis of her LPD and discontinuation of azathioprine, her oral ulcers resolved completely.

Epstein-Barr virus-positive mucocutaneous ulcer colliding with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (malt lymphoma) that developed in the palatine tonsils of an immunocompetent patient after gastric lymphoma relapse.

Epstein-Barr virus-positive mucocutaneous ulcer colliding with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (malt lymphoma) that developed in the palatine tonsils of an immunocompetent patient after gastric lymphoma relapse.

A distinctive subgroup of oral EBV+ B-cell neoplasm with polymorphous features is potentially identical to EBV+ mucocutaneous ulcer

Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is a newly recognized provisional entity included in mature B-cell neoplasm in the latest 2016 World Health Organization Classification. It has a self-limited growth potential with a high predilection for oral cavities and occurs in age-related or iatrogenic immunodeficiency with indolent clinical courses. However, it shares histological features with EBV-positive diffuse large B-cell lymphoma (DLBCL), and this often leads to diagnostic challenges and controversies in patients with an oral EBV-positive B-cell neoplasm. The aim of this study was to better characterize and comprehend the pathophysiology of DLBCL and EBVMCU in the oral cavity. We conducted clinicopathologic and recurrent gene mutation analysis of 49 cases (14 EBV positive, 35 EBV negative), including cases diagnosed as DLBCL or B-cell lymphoproliferative disorders with high-grade morphology in the oral cavity. All EBV-positive cases matched the criteria of EBVMCU, with significantly earlier clinical stages than the EBV-negative group (P=.0006). Besides, histological analysis showed that all EBV-positive cases presented polymorphous features, whereas 91.4% (32/35) of the EBV-negative cases showed diffuse and monotonous proliferation (P<.0001). Furthermore, EBV-positive cases presented favorable clinical outcomes without disease-related death or recurrence. Gene mutation analysis (MYD88, CD79A, CD79B, CARD11, and EZH2) revealed that 33.3% (9/27) of EBV-negative cases harbored at least 1 gene mutation, whereas no gene mutation was observed in the EBV-positive group (0/11). These results suggest that oral EBV-positive B-cell lymphoid proliferation with polymorphous features often fulfill the criteria for EBVMCU, with clinicopathologically and genetically distinctive properties.

TRAUMATIC ULCERATIVE GRANULOMA WITH STROMAL EOSINOPHILIA IN PATIENTS WITH SOLID ORGAN TRANSPLANTATION: A SERIES OF SIX CASES

We present a series of traumatic ulcerative granulomas with stromal eosinophilia (TUGSE) in patients with solid organ transplant. The Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is in the TUGSE differential diagnosis in this patient population, and we sought to investigate the presence of EBV-positive and CD30-positive cells in these TUGSEs.

Aggressive primary cutaneous B-cell lymphomas and novel EBV+ entities

Primary cutaneous large B‑cell lymphomas (PCBLT), EBV-positive large B‑cell lymphomas, not otherwise specified (EBV+ DLBCL, NOS), and primary cutaneous intravascular large B‑cell lymphomas (PCIVLBL) are recognized as cutaneous lymphomas with intermediate to poor prognosis. Differentiation from indolent B‑cell lymphomas or other pathologies of the skin can be complex, both clinically and histologically, but vital for the outcome of the patient. The combination of immunotherapy and polychemotherapy regimens, such as R‑CHOP, has led to significant improvements in prognosis, especially in diffuse large B‑cell lymphomas. Therapeutic decisions need to be individually made for each patient, ideally within an interdisciplinary tumor conference. Immunosenescence may be an important factor in the pathogenesis of EBV+ DLBCL, NOS in elderly individuals. Their prognosis is less favorable than that of patients with EBV-negative PCBLT, whereby this has been observed particularly in elderly patients. One third of patients with PCIVLBL progress to systemic disease. The occurrence of nodal manifestation is rarely observed. Symptoms may vary depending on the organ system involved. Currently there are no evidence-based therapy recommendations due to the rarity of the disease. EBV-positive mucocutaneous ulcer is anew provisional category in the current WHO classification for lymphoid neoplasms. It has been segregated from EBV+ DLBCL, NOS due to its self-limiting course and good response to conservative therapy.

A rare case of Epstein-Barr virus mucocutaneous ulcer of the colon

Epstein-Barr virus mucocutaneous ulcer (EBVMCU) is a rare form of EBV lymphoproliferative disorder. The disease was recently described in 2010 for the first time in a case series and it...

EBV-positive mucocutaneous ulcer induced by chronic immunosuppression secondary to azathioprine for Crohn’s disease

EBV-positive mucocutaneous ulcer induced by chronic immunosuppression secondary to azathioprine for Crohn’s disease

Clinicopathologic analysis of Epstein-Barr virus-positive mucocutaneous ulcer

Clinicopathologic analysis of Epstein-Barr virus-positive mucocutaneous ulcer

Epstein–Barr virus-positive mucocutaneous ulcer in Crohn’s disease. A condition to consider in immunosuppressed IBD patients

Epstein–Barr virus-positive mucocutaneous ulcer (EBVMCU) is a little known entity that can affect the oropharyngeal mucosa, the gastrointestinal tract and the skin. The main risk factor for the development of this lesion is immunosuppression. Because its features are similar to other Epstein–Barr virus-associated lymphoproliferative disorders, a differential diagnosis can sometimes prove challenging. Here, we report the case of a man diagnosed with Crohn’s disease and treated with azathioprine and infliximab who developed ulceration at the rectum that was refractory to conventional medical treatment. Although the histological characteristics were suggestive of an EBVMCU, lymphoproliferative disease could not be ruled out. The patient did not improve after discontinuation of the treatment, a proctectomy was performed and the diagnosis of this disease was confirmed. Although very few cases of EBVMCU affecting the colon have been reported, its diagnosis should be always considered in refractory cases of inflammatory bowel disease with patients undergoing immunosuppressive treatment.

‘EBV positive muco-cutaneous ulcer’; A recently recognised clinicopathological entity

‘EBV positive muco-cutaneous ulcer’; A recently recognised clinicopathological entity

Iatrogenic Immunodeficiency-Associated Lymphoproliferative Disorder in a Pediatric Patient

It is estimated that approximately 90% of the adult population is infected with the Epstein Barr Virus (EBV). In states of immunosuppression, the disruption in immune regulation can manifest as lymphoproliferative disease that classically presents as a lymphoma. Rarely, EBV-driven lymphoproliferative disease can present as a mucocutaneous ulcer. While this phenomenon is becoming well documented in the adult population, cases affecting pediatric patients are lacking. In this report, we describe a case of a pediatric immunosuppressed patient presenting with an EBV-positive mucocutaneous ulcer. EBV-positive mucocutaneous ulcer in an immunosuppressed patient is an entity within the spectrum of iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPD) which closely resembles the better-categorized post-transplant lymphoproliferative disorder (PTLD). Though the concept of lymphoproliferative disorders in immunosuppressed patients has been well established, this is a unique case in a pediatric patient.

Diagnostic and therapeutic challenges of EBV-positive mucocutaneous ulcer: a case report and systematic review of the literature

BackgroundEpstein–Barr virus-positive mucocutaneous ulcer (EBVMCU) is a recently recognized B cell lymphoproliferative disorder that is driven by latent EBV infection and causes discrete ulcerations in the oropharynx, gastrointestinal tract, and skin. Local attenuation of immunosurveillance associated with iatrogenic immunosuppressant use, primary immunodeficiency, or age-associated immunosenescence has been implicated as a predisposing factor. This disorder is likely under reported, as it was only first defined in 2010 and shares histological features with other B-cell proliferative neoplasms. The first case series that described EBVMCU suggested that EBVMCU is generally self-limited and is likely to resolve without treatment. Since that publication, additional cases have been reported that describe a more heterogeneous clinical course, often requiring aggressive therapy. We now systematically review all published cases of EBVMCU and detail a case of aggressive and progressive EBVMCU, including diagnostic and management challenges, as well as successful treatment with radiation therapy.Case presentationA forty-nine year old woman presented with painful and debilitating multifocal oral EBVMCU that initially responded to four weekly doses of rituximab. Her disease relapsed within 3 months and continued to progress and cause significant morbidity. She was successfully treated with local external beam radiation therapy of 30 Gy in 15 fractions, with duration of response of at least 6 months.ConclusionsWe suggest that although many patients with EBVMCU experience a self-limited course, for others EBVMCU can be a debilitating, persistent disorder that requires aggressive therapy to prevent disease progression. CD20- and CD30-directed antibody therapy, local radiation therapy, local surgical excision, systemic chemotherapy, and a combination of these therapies have all been successfully used to treat EBVMCU with high rates of durable clinical remission. As EBVMCU is not currently included in the 2008 WHO classification of lymphoproliferative disorders and no evidence-based guidelines or expert opinions have been proposed to guide therapy, this case report and systematic review provides a foundation on which to guide therapeutic decisions.

EBV-positive mucocutaneous ulcer in organ transplant recipients: a localized indolent posttransplant lymphoproliferative disorder.

Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBV MCU) is a B-cell lymphoproliferative disorder occurring in elderly or iatrogenic immunocompromised patients. It has not been reported in solid organ transplant recipients. We observed 7 patients with EBV MCU in a cohort of 70 transplant recipients with EBV posttransplant lymphoproliferative disorder (PTLD). Transplants included: 5 renal, 1 heart, and 1 lung. Median patient age was 61; 5 were male. EBV MCU was observed in oral mucosa in 4 and gastrointestinal tract in 3. Duration of immunosuppressive therapy before EBV MCU was 0.6 to 13 years. Ulcers were undermined by inflammatory cells and polymorphic or monomorphic large cell lymphoproliferation. Reed-Sternberg-like cells were present in 5/7. Large B cells were CD20, CD30, and EBV-encoded RNA positive in all cases. Diagnosis in 3 recent patients was EBV MCU; 4 patients diagnosed before familiarity with EBV MCU were classified as monomorphic large cell (n=3) and polymorphic (n=1) PTLD. None of the patients had EBV DNA in their blood (<1000 copies/mL) at diagnosis or follow-up versus 35/44 transplant patients with systemic PTLD (P<0.001). All lesions resolved with reduced immunosuppression (7/7), change in immunosuppression (2/7), and rituximab (3/7). Five patients are living: 4 healthy, 1 awaiting second renal transplant. Two patients died 3 and 5 years after resolution of EBV MCU. No patient recurred with EBV MCU or other PTLDs. EBV MCU mimics more aggressive categories of PTLD but lacks EBV DNA in blood, which may be a useful distinguishing feature. Lesions are likely to resolve with conservative management. Awareness of EBV MCU in the posttransplant setting is necessary for appropriate diagnosis and treatment.

A Clinical, Pathological and Genetic Characterization of Methotrexate-Associated Lymphoproliferative Disorders

Background Methotrexate (MTX)-associated lymphoproliferative disorder (LPD) is a lymphoid proliferation or lymphoma in a patient immunosuppressed with MTX. As MTX has recently gained acceptance as a first-line therapy for rheumatoid arthritis (RA), the incidence of MTX-LPD is expected to increase. Epstein-Barr virus (EBV) infection is considered to play an important role in the pathogenesis of MTX-LPD, although EBV can only be detected on histopathological examination in only about half cases of MTX-LPD. Recently, LPD with EBV-positive mucocutaneous ulcer (EBVMCU) has been reported as a distinct disease entity with a self-limiting and indolent clinical course (1). EBVMCU is found in various conditions of immunosuppression, including MTX-LPD or in age-related immunosenescence. Although MTX-LPD often shows spontaneous regression, it is not clear whether MTX-LPD with EBVMCU has a better prognosis. Objectives The aim of this study is to clarify the clinical, histological and genetic factors that predict outcomes in patients with MTX-LPD. Methods Patients with MTX-LPD diagnosed between 2000 and 2012 were analyzed retrospectively regarding their clinical course, site of biopsy, histological type, Epstein-Barr virus (EBV) immunostaining and human leukocyte antigen (HLA) typing. Results Twenty-one patients, including 20 with RA and one with polymyositis were analyzed. The mean dose of MTX was 6.1 mg/week and the mean duration of treatment was 71.1 months. Clinically, five patients were diagnosed with EBV-positive mucocutaneous ulcer (EBVMCU). All had polymorphic histological findings and were more successfully treated solely by withdrawal of MTX than the other cases (75% versus 7.7%, P = 0.015). Genetically, the HLA-B15:11 haplotype was more frequent in patients with MTX-LPD than in healthy Japanese controls (P = 0.0043). EBV latency classification and HLA typing were not associated with the prognosis of MTX-LPD. Conclusions Our data demonstrate that EBVMCU, a specific clinical subgroup of MTX-LPD, had a better clinical outcome when MTX was withdrawn than other patients with MTX-LPD. References Dojcinov SD, Venkataraman G, Raffeld M, Pittaluga S, Jaffe ES. EBV positive mucocutaneous ulcer--a study of 26 cases associated with various sources of immunosuppression. Am J Surg Pathol. 2010 Mar;34(3):405-17. Acknowledgements The authors thank Dr. Toda, of the Center for Anatomical Studies at the Kyoto University Graduate School of Medicine for performing immunostaining studies and Dr. Inoko, of the Tokai University Department of Molecular Science, Division of Molecular Medical Science and Molecular Medicine for kindly providing the HLA data of Japanese patients with rheumatoid arthritis. Disclosure of Interest None Declared

A Clinical, Pathological, and Genetic Characterization of Methotrexate-associated Lymphoproliferative Disorders

Methotrexate-associated lymphoproliferative disorders (MTX-LPD) often regress spontaneously during MTX withdrawal, but the prognostic factors remain unclear. The aim of our study was to clarify the clinical, histological, and genetic factors that predict outcomes in patients with MTX-LPD. Patients with MTX-LPD diagnosed between 2000 and 2012 were analyzed retrospectively regarding their clinical course, site of biopsy, histological typing, Epstein-Barr virus (EBV) in situ hybridization and immunostaining, and HLA type. Twenty-one patients, including 20 with rheumatoid arthritis (RA) and 1 with polymyositis, were analyzed. The mean dose of MTX was 6.1 mg/week and the mean duration of treatment was 71.1 months. Clinically, 5 patients were diagnosed with EBV-positive mucocutaneous ulcer (EBVMCU) and had polymorphic histological findings. The proportion of those patients successfully treated solely by withdrawal of MTX was significantly greater than that of those without EBVMCU (75% vs 7.7%, p = 0.015). The HLA-B15:11 haplotype was more frequent in patients with EBV+ RA with MTX-LPD than in healthy Japanese controls (p = 0.0079, Bonferroni's method). EBV latency classification and HLA typing were not associated with the prognosis of MTX-LPD in our cohort. Our data demonstrate that patients in the EBVMCU, a specific clinical subgroup of MTX-LPD, had a better clinical outcome when MTX was withdrawn than did other patients with MTX-LPD.

SAT0069 A Clinical, Pathological and Genetic Characterization of Methotrexate-Associated Lymphoproliferative Disorders

BackgroundMethotrexate (MTX)-associated lymphoproliferative disorder (LPD) is a lymphoid proliferation or lymphoma in a patient immunosuppressed with MTX. As MTX has recently gained acceptance as a first-line therapy for rheumatoid arthritis...