Pulmonary lymphomatoid granulomatosis in a patient with long-term use of a tumour necrosis factor-α inhibitor.

A man in his 60s presented with intermittent constitutional symptoms along with waxing and waning chest radiographic abnormalities, eventually leading to a diagnosis of lymphomatoid granulomatosis (LYG). LYG is a rare, progressive Epstein-Barr virus (EBV)-driven lymphoproliferative disease associated with immune dysregulation most commonly involving the lungs. The diagnosis requires tissue biopsy; thus, the decision to pursue tissue sampling with histopathology examination in a timely manner is essential. Currently, there are no established guidelines regarding the treatment of LYG, which varies from cessation of immunosuppressants to immunochemotherapy and usually requires multidisciplinary team discussion.

Epstein-Barr virus-positive CD30+ B-cell lymphoproliferative disease with histologic features resembling grade III lymphomatoid granulomatosis induced by methotrexate.

Methotrexate (MTX) is a first-line systemic medication used to treat rheumatoid arthritis because of its immunomodulatory effects. However, MTX has also been linked to the development of lymphoproliferative disorders (LPD) in patients with rheumatoid arthritis. We describe a patient with long-standing rheumatoid arthritis treated with MTX who developed cutaneous Epstein-Barr virus (EBV)-positive B cell lymphoproliferative disease resembling grade III lymphomatoid granulomatosis localized to the right leg. The lymphomatoid process resolved with withdrawal of the MTX. The pathogenesis of iatrogenic lymphoproliferative disorder was most likely triggered by the rheumatoid inflammation and the immunosuppressing effects of MTX, which led to EBV reactivation. We recommend a trial of MTX discontinuation prior to considering chemotherapy in patients with rheumatoid arthritis treated with MTX who develop EBV-positive B cell lymphoproliferative disease resembling a high grade B-cell lymphoma.

Interferon alfa-2b in patients with low-grade lymphomatoid granulomatosis and chemotherapy with DA-EPOCH-R in patients with high-grade lymphomatoid granulomatosis: an open-label, single-centre, phase 2 trial.

BACKGROUND: Lymphomatoid granulomatosis is a rare Epstein-Barr virus-associated B-cell lymphoproliferative disorder with a median overall survival of less than 2 years. In this study, we hypothesised that low-grade lymphomatoid granulomatosis is immune-dependent and high-grade lymphomatoid granulomatosis is immune-independent. On the basis of this hypothesis, we investigated the activity and safety of new treatment with immunotherapy in patients with low-grade disease and standard chemotherapy in patients with high-grade disease. METHODS: In this open-label, single-centre, phase 2 trial, we enrolled patients aged 12 years or older with untreated, or relapsed or refractory lymphomatoid granulomatosis at the National Cancer Institute (National Institutes of Health, Bethesda, MD, USA). Patients with low-grade disease received dose-escalated interferon alfa-2b, starting at 7·5 million international units subcutaneously three times per week for up to 1 year past best response, and patients with high-grade disease received six cycles every 3 weeks of intravenous, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R). Starting doses were 50 mg/m2 per day as a continuous intravenous infusion from day 1 to day 4 (96 h) for etoposide; 60 mg/m2 twice daily by mouth from day 1 to day 5 for prednisone; 0·4 mg/m2 per day as a continuous intravenous infusion from day 1 to day 4 (96 h) for vincristine; 750 mg/m2 intravenous on day 5 for cyclophosphamide; 10 mg/m2 per day as a continuous intravenous infusion from day 1 to day 4 (96 h) for doxorubicin; and 375 mg/m2 intravenous on day 1 for rituximab. The doses of doxorubicin, etoposide, and cyclophosphamide were adjusted up or down on the basis of neutrophil and platelet nadirs. Patients with residual or progressive disease after initial therapy crossed over to alternative therapy. The primary endpoint was the proportion of patients who had an overall response and the 5-year progression-free survival after initial or cross-over treatment. Analysis of response included all participants who underwent restaging imaging; safety analysis included all patients who received any dose of study drugs. The trial is open for enrolment and is registered at ClinicalTrials.gov, NCT00001379. FINDINGS: 67 patients were enrolled between Jan 10, 1991, and Sept 5, 2019 (42 [63%] were male). 45 patients received initial treatment with interferon alfa-2b (16 of whom crossed over to DA-EPOCH-R) and 18 received initial treatment with DA-EPOCH-R (eight of whom crossed over to interferon alfa-2b); four underwent surveillance only. After initial treatment with interferon alfa-2b, the overall response was 64% (28 of 44 evaluable patients) with 61% (27 of 44) having a complete response, whereas, after cross-over treatment with interferon alfa-2b, the overall response was 63% (five of eight evaluable patients) with 50% (four of eight) having a complete response. After initial treatment with DA-EPOCH-R, the overall response was 76% (13 of 17 evaluable patients) with 47% (eight of 17) having a complete response, whereas, after cross-over treatment with DA-EPOCH-R, the overall response was 67% (ten of 15 evaluable patients) with 47% (seven of 15) having a complete response. 5-year progression-free survival was 48·5% (95% CI 33·2-62·1) after initial treatment with interferon alfa-2b, 50·0% (15·2-77·5) after cross-over treatment with interferon alfa-2b, 25·4% (8·2-47·2) after initial treatment with DA-EPOCH-R, and 62·5% (34·9-81·1) after cross-over treatment with DA-EPOCH-R. The most common grade 3 or worse adverse events in patients treated with interferon alfa-2b included neutropenia (27 [53%] of 51 patients), lymphopenia (24 [47%]), and leukopenia (24 [47%]). The four most common grade 3 or worse adverse events in patients treated with DA-EPOCH-R included neutropenia (29 [88%] of 33 patients), leukopenia (28 [85%]), infection (18 [55%]), and lymphopenia (17 [52%]). Serious adverse events occurred in 13 (25%) of 51 patients receiving treatment with interferon alfa-2b and 21 (64%) of 33 patients receiving DA-EPOCH-R, with five treatment-related deaths: one thromboembolic, one infection, and one haemophagocytic syndrome with interferon alfa-2b, and one infection and one haemophagocytic syndrome with DA-EPOCH-R. INTERPRETATION: Interferon alfa-2b is efficacious for treating low-grade lymphomatoid granulomatosis and hence reducing progression to high-grade disease, whereas patients with high-grade lymphomatoid granulomatosis showed expected responses to chemotherapy. Uncontrolled immune regulation of Epstein-Barr virus is hypothesised to result in the emergence of low-grade disease after chemotherapy, for which treatment with interferon alfa-2b is efficacious. FUNDING: Intramural Research Programs of the National Cancer Institute and National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Rituximab Monotherapy for Grade 2-3 Lymphomatoid Granulomatosis with Central Nervous System Involvement in a Patient Receiving Methotrexate for Rheumatoid Arthritis.

Lymphomatoid granulomatosis (LYG) is a rare lymphoproliferative disorder (LPD). The optimal management strategy of methotrexate (MTX) related-LPD with central nervous system (CNS) involvement and histological features of LYG remains unclear. We herein report a case of grade 2-3 LYG in a rheumatoid arthritis patient, in which an intracranial mass accompanied by hemorrhaging and pulmonary and skin lesions developed. The patient received successful rituximab monotherapy. The tumor cells in the skin and brain showed monoclonal and oligoclonal proliferation, respectively. Our case suggests that rituximab monotherapy may be effective against MTX-LPD with CNS involvement, especially in cases with LYG histology.

An atypical case of a pulmonary mass in an immunocompromised patient.

OBJECTIVES: Pulmonary lymphomatoid granulomatosis (PLG) is a rare angiocentric and angiodestructive EBV-associated lymphoproliferative disorder which almost always affects the lungs. PLG is more commonly diagnosed in patients with immunodeficiency and is associated with Epstein-Barr virus (EBV). 'Drug induced PLG' or 'iatrogenic immunodeficiency-associated lymphoproliferative disorder' is a special form of PLG described in patient with inflammatory bowel diseases treated with Azathioprine. METHODS: We report a case of drug-induced PLG in a 68-year-old patient with Crohn's disease presenting with pain at the right hemithorax, fatigue and shortness of breath with a pulmonary mass. RESULTS: Although initial diagnostic findings were misleading, an open lung biopsy eventually led to the diagnosis of drug-induced PLG. CONCLUSION: The diagnosis of PLG is challenging because the disease is rare and the histological features can be very subtle. Correct diagnosis relies on histopathology and immunohistochemical staining and EBV RNA in situ hybridization with sampling of large and different amounts of pathologic tissue in the hands of expert pathologists. In drug-induced PLG specifically, withdrawal of the immunosuppressive agent can lead to disease regression.

Un raro trastorno linfoproliferativo asociado a terapia inmunomoduladora en la enfermedad de Crohn / A rare lymphoproliferative disorder associated with immunomodulating therapy in Crohn's disease

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A Case of Methotrexate-Associated Lymphoproliferative Disorder (Lymphomatoid Granulomatosis) of the Skin.

Iatrogenic lymphoproliferative disorder (LPD) can develop in patients treated with immunosuppressive drugs for autoimmune or other inflammatory diseases. Here, we report a case of lymphomatoid granulomatosis of the skin that occurred as a methotrexate (MTX)-associated LPD. We also review the relevant literature. A 73-year-old woman presented to our department with an approximately 10-year history of MTX therapy for rheumatoid arthritis. Three months earlier, she noticed a small nodule in her right upper arm. It gradually enlarged, and the center began to decay. Grossly, the lesion was 40 × 40 mm in size with ulceration, and the surrounding skin presented dark red erythema. A biopsy specimen was taken for definitive diagnosis. Histologically, infiltrating growth of medium-to-large atypical lymphocytes was observed underneath the ulceration and was accompanied by small reactive lymphocytes. The atypical lymphocytes demonstrated a tendency to infiltrate the vessels, which showed an angiocentric pattern. Immunohistochemistry revealed that the atypical lymphoid cells were positive for CD79a, CD20, and CD30. In addition, in situ hybridization for Epstein-Barr virus (EBV) revealed expression of EBV-encoded small RNAs. The patient was diagnosed with MTX-associated LPD (lymphomatoid granulomatosis), owing to her history of MTX treatment, the expression of the atypical lymphocytes for B-cell markers and EBV-encoded small RNA, and the angiocentric infiltrating pattern. The lesion reportedly disappeared after withdrawal of MTX.

A rare lymphoproliferative disorder associated with immunomodulating therapy in Crohn's disease.

Lymphomatoid granulomatosis is a rare lymphoproliferative disorder associated with immunosuppressive therapy in inflammatory bowel disease. We present the case of a patient with Crohn's disease and treated azathioprine that develops lymphomatoid granulomatosis, as well as its diagnostic process and the chosen treatment. Lymphomatoid granulomatosis is a serious disease barely described and whose suspicion is essential for its prognosis.

A surgical case of methotrexate-associated lymphomatoid granuloma.

We reported a surgical case of methotrexate-associated lymphomatoid granuloma. A 69-year-old female had been treated with methotrexate for rheumatoid arthritis for 35 months. The patient underwent partial resection of the right upper pulmonary lobe for lung cancer when she was 67 years old. A nodule was detected in the left lung field on a chest radiograph performed during the postoperative follow-up period. Computed tomography revealed a 28-mm nodule in the lower left pulmonary lobe. A transbronchial biopsy examination did not lead to a diagnosis. The pulmonary nodule subsequently increased in size. We suspected a malignant tumor and performed lower left lobectomy. A pathological examination revealed lymphomatoid granuloma. Finally, the patient was diagnosed with methotrexate-associated lymphomatoid granuloma based on her history of oral methotrexate treatment.

Síndrome autoinmune/inflamatorio inducido por adyuvante que debuta con manifestaciones pulmonares y articulares / Adjuvant induced autoimmune/inflammatory syndrome presenting as joint and lung manifestations

Mujer de 59 años de edad, la cual cuenta con antecedente de aplicación de material oleoso en los glúteos hace 11 años; posteriormente hace 18 meses comienza con cuadro de poliartritis aditivas simétricas, así como afección en las vías aéreas superior e inferior, sin evidencia de alteración por granulomatosis con poliangitis (Wegener). Presenta en suero autoanticuerpos, y se toma biopsia de piel donde se observa granuloma por cuerpo extraño. Se concluye con síndrome autoinmune/inflamatorio inducido por adyuvante, en el que la afección pulmonar es una manifestación atípica en la presentación inicial de la enfermedad (AU)

A 59-year-old female with a history of injection of an oily material in the buttocks 11 years ago. She developed symmetric additive polyarthritis as well as superior and inferior airways involvement. There was no evidence of granulomatosis with polyangiitis (Wegener). She had several serum autoantibodies and a skin biopsy showed a foreign body granuloma. The diagnosis of adjuvant induced autoimmune/inflammatory syndrome was made. The pulmonary involvement was an atypical manifestation at the onset of disease (AU)

Grade 3 lymphomatoid granulomatosis in a patient receiving methotrexate therapy for rheumatoid arthritis.

Lymphomatoid granulomatosis (LyG) is a rare, B-cell derived, lymphoproliferative disorder that often presents as pulmonary nodular lesions with a histopathology of lymphatic invasion of the vascular wall. The development of LyG may be associated with reactivation of the Epstein-Barr virus under an immunosuppressive state. We herein report a case of Grade 3 LyG that developed during methotrexate therapy for rheumatoid arthritis and regressed following the withdrawal of the drug.

Lymphomatoid granulomatosis associated with azathioprine therapy in Crohn disease.

BACKGROUND: Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus-associated lymphoproliferative disorder. It most often occurs in patients with immunodeficiency and the clinical course ranges from indolent behavior to that of an aggressive malignancy. Pulmonary, central nervous system and dermatological manifestations are most common. To our knowledge this is the first reported case of LYG related to azathioprine therapy in Crohn disease. CASE PRESENTATION: A twenty-six year old Caucasian woman with colonic Crohn disease on maintenance azathioprine therapy presented with right upper quadrant pain and fever. Diagnostic imaging revealed extensive liver, pulmonary and cerebral lesions. A diagnosis of LYG was made based on the pattern of organ involvement and the immunohistochemical features on liver and lung biopsy. CONCLUSIONS: Thiopurine therapy for inflammatory bowel disease is associated with an increased incidence of lymphoproliferative disorders. This report highlights the diagnostic challenges associated with LYG. As long-term thiopurine therapy remains central to the management of inflammatory bowel diseases it is essential that both patients and clinicians are aware of this potential adverse outcome.

[Methotrexate-related lymphomatoid granulomatosis in a patient with rheumatoid arthritis].

A 76-year-old man who was taking prednisolone and methotrexate for rheumatoid arthritis presented with gastric ulcers. Chest X-ray images showed multiple pulmonary nodules. Transbronchial lung biopsy specimens showed lymphocytic infiltrates but no malignant cells. The radiographic findings gradually ameliorated over a month, but then deteriorated 5 months later. We performed video-assisted thoracoscopic biopsy of the left lung, and the biopsy specimens showed lymphocytic infiltration with necrosis, in which the atypical lymphocytes were positive for Epstein-Barr virus-encoded small RNAs in situ hybridization (EBER-ISH). A diagnosis of lymphomatoid granulomatosis was determined. One year before this diagnosis, the patient was found to have an inflammatory liver tumor that had disappeared spontaneously within a month. A new pathological review of the liver and stomach lesions demonstrated EBER-ISH-positive lymphocytes, and therefore we assumed that they were pathological features of lymphomatoid granulomatosis. The chest radiographic findings improved gradually after the discontinuation of methotrexate. We therefore suggest that methotrexate treatment may be associated with the development of lymphomatoid granulomatosis in patients with rheumatoid arthritis. Lymphoproliferative disorders, including lymphomatoid granulomatosis, should be considered in patients with rheumatoid arthritis who are receiving methotrexate.

A case of lymphomatoid granulomatosis-like lung lesions with abundant infiltrating IgG4-positive plasma cells whose serum IgG4 levels became high following the start of corticosteroid therapy.

A 59-year-old man with a history of prostate hyperplasia was admitted to our hospital for further examination of a lung mass and renal dysfunction. Lung biopsy specimens revealed that inflammatory cells had infiltrated into the blood vessel walls. We initially suspected lymphomatoid granulomatosis, but Epstein Barr virus-encoded small RNA was negative. However, 50% of the infiltrating plasma cells were positive for IgG4. Furthermore, the kidneys and prostate contained abundant IgG4-positive plasma cells. He was diagnosed with IgG4-related sclerosing disease even though serum IgG4 levels were not elevated (45.7 mg/dL). Prednisolone reduced the lung masses and ameliorated renal function, but the serum IgG4 level increased (377 mg/dL). Seronegative IgG4-related sclerosing disease should be considered when patients present with such symptoms and treatment responses, and the secretion of IgG4 might be blocked by its active synthesis.