Lymphomatoid granulomatosis mimicking PJP infection.

A male patient in his 40s who had been unwell for months with fever of unknown origin and clinicopathological features suspicious for haemophagocytic lymphohistiocytosis presented to hospital with worsening subacute shortness of breath. CT pulmonary angiogram demonstrated ground glass changes involving all lung lobes with an apicobasal gradient. These changes, combined with long-term steroid exposure for granulomatous hepatitis without pneumocystis prophylaxis, raised concern for pneumocystis jirovecii pneumonia (PJP). A subsequent bronchoscopic lavage specimen was positive on PCR for PJP and the patient was started on appropriate therapy. Clinical and radiological changes initially improved but after completion of therapy, symptoms and radiological abnormalities returned. Retreatment with second-line treatment resulted again in initial improvement followed by relapse with acute deterioration. Further investigations for an alternate diagnosis were made, with a surgical lung biopsy performed finally revealing immunosuppression-related Epstein-Barr virus positive large B cell lymphoma with lymphomatoid granulomatosis of grade 3 pattern.

18F-FDG PET/CT characterization and response evaluation in a case of lymphomatoid granulomatosis involving the main pulmonary artery.

Main pulmonary artery (MPA) involvement of lymphomatoid granulomatosis (LYG) is extremely rare. We described fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) findings in a case with LYG originated from the MPA. Fluorine-18-FDG PET/CT demonstrated nodular hypermetabolic foci in the MPA, corresponding well to the intraluminal filling defects on CT pulmonary angiography, and the secondary right heart dysfunction was observed. Final diagnosis was made after transcatheter MPA biopsies and multi-disciplinary consultation. The patient recovered completely following the steroid therapy and MPA stenting, which was illustrated on the second 18F-FDG PET/CT.

Acute respiratory failure developing in a patient with lymphomatoid granulomatosis.

Lymphomatoid granulomatosis (LYG) is a rare B cell lymphoproliferative disorder associated with Epstein-Barr virus infection. LYG diagnosis is often difficult because of non-specific and varied radiological and pathological findings. The lung is the most common organ of LYG occurrence, but extrapulmonary lesions involving the central nervous system, skin, kidneys and liver are observed. A surgical biopsy is often inevitable for LYG diagnosis.We encountered a man in his 50s who presented with progressive dyspnoea. Extrapulmonary lesions were not observed. Although he developed respiratory failure within a short period, a low dose of corticosteroid relieved his symptoms. Video-assisted thoracoscopic lung biopsy revealed grade 1 LYG. The patient was successfully treated with chemotherapy, including rituximab. Only a few cases of LYG with progressive respiratory failure are reported, and most have been diagnosed via autopsy. Our case highlights the importance of performing a surgical lung biopsy at the appropriate time to diagnose LYG.

Lymphomatoid Granulomatosis: A Case Report and Literature Review of a Rare Pediatric Disorder From Pakistan.

BACKGROUND: Lymphomatoid granulomatosis (LYG) is a rare pediatric disorder driven by the Epstein-Barr virus and is considered as a part of the lymphoma spectrum. It is mostly associated with immune deficiency and patients on immunosuppressive therapy, especially with acute leukemia. It can present as a multisystemic disease, diagnosed on biopsy as atypical lymphocytes with an angiocentric pattern against a background composed of histiocytes, neutrophils, and extensive T-cell infiltration. OBSERVATION: We report 3 cases of children with Lymphomatoid granulomatosis, one with Langerhans cell histiocytosis. CONCLUSION: Combination chemotherapy was used for the treatment of Lymphomatoid granulomatosis; however, the prognosis is guarded. One of 3 patients is alive and in remission on the last follow-up visit at 15 months.

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.

Lymphomatoid granulomatosis with the central nervous system involvement as the main manifestation: a case report.

BACKGROUND: Lymphomatoid granulomatosis (LyG) is a rare extralymphatic lymphoproliferative disease characterized by lymphocytic invasion into vascular walls and damage to blood vessels. The lungs are affected in 90% of LyG cases, followed by the skin, central nervous system (CNS), kidneys and liver. CASE PRESENTATION: Here we report a case of a young woman with LyG, with CNS involvement as the initial clinical manifestation. Computer tomography (CT) scans showed multiple nodular, patchy and flocculent high-density shadows in both lungs without mediastinal lymph node enlargement. Magnetic resonance imaging (MRI) scans showed multiple abnormal signal intensities in the right cerebellar hemisphere, frontal, parietal and temporal lobes, and dorsal brainstem, which became patchy and annular after enhancement. The post-operative pathological analysis of lesion samples confirmed the diagnosis of grade II LyG. CONCLUSIONS: LyG should be concerned in young adults showing multiple radiological brain and lung lesions. Resection and postoperative medication of steroid hormones and IFN-α may be effective in the treatment of LyG.

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.

EBV Positive Lymphomatoid Granulomatosis Following Dental Extractions.

Epstein-Barr virus (EBV) associated lymphoproliferative disorders includes a diverse group of diagnoses, encompassing both B-cell and T-cell lineages. With EBV mucocutaneous ulcers becoming a World health Organization diagnosis in 2018, introduction of the disease entity will be beneficial to the practicing otolaryngologist. We are reporting a case of a 69-year-old male with history of rheumatoid arthritis on methotrexate, recently undergoing dental extractions, who then developed multiple oral ulcerations and bony erosions of his palate and alveolar ridge. Associated symptoms included a large 3.0 cm neck mass, splenomegaly, and pulmonary nodules. Histopathology showed EBV+ lymphomatoid granulomatosis. Upon removal of immunosuppressive agent, patient's symptoms improved with resolution of oral lesions, as well as systemic symptoms.

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.

High-dose chemotherapy and autologous stem cell transplantation in primary lymphomatoid granulomatosis of the central nervous system.

Primary lymphomatoid granulomatosis of the CNS (CNS-LG) is a rare lymphoid neoplasia associated Epstein-Barr Virus (EBV) and often accompanied by immunodeficiencies. No treatment standards have been defined yet. However, due to often devastating neurologic sequelae and based on similarities to diffuse large B-cell lymphoma, curative treatment requires intensive therapy protocols resembling protocols applied in CNS lymphoma. Here, the clinical courses and treatments of four primary CNS-LG patients in analogy to aggressive CNS-lymphomas including methotrexate, thiotepa, cytarabine, carmustine, and rituximab are presented. This is the first report on high-dose chemotherapy with CNS-directed drugs and autologous blood stem cell transplantation in primary CNS-LG.

An update on viral-induced cutaneous lymphoproliferative disorders. CME Part I.

Viral-induced cutaneous T-cell lymphomas are an uncommon group of lymphoproliferative disorders characterized by a viral infection of T and natural killer (NK) cells. This group of cutaneous T-cell lymphomas is more commonly encountered in Asians and Native Americans from Central and South America compared with Western populations. Viral-associated lymphoproliferative disorders include a spectrum of entities that range from nonneoplastic lesions, such as chronic active Epstein-Barr virus infection and infective dermatitis to malignant diseases, such as extranodal NK/T-cell lymphoma, hydroa vacciniforme-like T-cell lymphoma, and adult T-cell leukemia/lymphoma. This review article will focus on hydroa vacciniforme-like lymphoproliferative disorder, extranodal NK/T-cell lymphoma, adult T-cell leukemia/lymphoma, lymphomatoid granulomatosis, and Epstein-Barr virus-positive mucocutaneous ulcers. We will review the pathogenesis of these conditions and the challenges of making a timely diagnosis in early-stage disease and discuss the common clinicopathologic manifestations, mutational landscape, and approaches to treat these highly aggressive and frequently lethal types of lymphoma.

Brain PET Imaging of 11C-Methionine, 18F-FDG, and 18F-THK5351 in a Case of Lymphomatoid Granulomatosis.

ABSTRACT: A 52-year-old woman complained of upper respiratory symptoms and subsequently developed Wallenberg syndrome. Chest CT and brain MRI revealed multiple nodular lesions in the lungs and brain. She was pathologically diagnosed with low-grade lymphomatoid granulomatosis by lung biopsy. Brain PET examinations using 11C-methionine, 18F-FDG, and 18F-THK5351 were performed. Uptake of 11C-methionine and 18F-FDG was slightly increased in some lesions, likely reflecting the degree of inflammatory cell infiltration. 18F-THK5351 uptake was significantly increased in all lesions, likely reflecting the degree of reactive astrogliosis. This case illustrates the utility of PET studies for diagnosing lymphomatoid granulomatosis and provides insight into its pathophysiology.

Impact of Epstein-Barr virus infection in patients with inflammatory bowel disease.

A high prevalence of Epstein-Barr virus (EBV) infection in patients with inflammatory bowel disease (IBD) has been reported in many case reports and studies; thus, the association between EBV and IBD has gained increasing attention. Patients with IBD are at an increased risk of opportunistic EBV infection owing to the common use of immunomodulators. EBV infection in IBD patients can cause various complications, including superimposed viral colitis, which is associated with chronicity, exacerbation, and poor prognosis of refractory IBD, and can induce progression to lymphoproliferative disorders, such as EBV-positive mucocutaneous ulcer (EBVMCU), lymphomatoid granulomatosis (LYG), hemophagocytic lymphohistiocytosis (HLH) and diffuse large B-cell lymphoma (DLBCL). It has been suggested to screen for EBV before initiating immunosuppressive therapy and monitor the status of EBV infection in patients with IBD, especially those who are EBV-seronegative and have a risk of primary EBV infection. Clinicians should also be careful of misdiagnosing IBD and EBV-associated lymphoproliferative diseases due to similarities in both clinical symptoms and endoscopic manifestations. Withdrawal of immunosuppressants has been shown to be an effective strategy to achieve remission of disease at the time of EBV diagnosis, but antiviral therapy remains controversial. The present review aims to describe the characteristics of the complications caused by EBV infection and generalize the recent research progress on and challenges caused by EBV infection in IBD patients. The literature for writing this review was collected from 'PubMed' research engine. The keywords 'inflammatory bowel disease and Epstein-Barr virus' or 'ulcerative colitis and Epstein-Barr virus' or 'Crohn's disease and Epstein-Barr virus' were used to collect the literature and relevant papers were collected to help writing this review.

A Case of Lymphomatoid Granulomatosis in a Lymph Node with Unique Clinical and Histopathologic Features.

BACKGROUND Lymphomatoid granulomatosis (LyG) is a rare lymphoproliferative disorder associated with Epstein-Barr virus (EBV) in which there is an infection of B cells and numerous reactive T cells. The lymphoproliferative disorder progresses to organ infiltration and resultant dysfunction of affected organs. Histologically, it is characterized by a triad of polymorphic lymphoid infiltrate, angiitis, and granulomatosis. The lungs are the most commonly involved sites for lymphomatoid granulomatosis, but other sites that can be involved include the liver, skin, and central nervous system. The signs and symptoms of LyG can vary, and can produce generalized symptoms such as cough, shortness of breath, and chest tightness, but can vary depending on the location of LyG. CASE REPORT We report a case of a 60-year-old man who presented with altered mental status. Cross-sectional imaging of the brain was negative for any acute intracranial process, but a fine-needle biopsy of a retroperitoneal lymph node revealed nodular polymorphous mononuclear infiltrates containing atypical large EBV-positive B cells with positive EBER and CD30, consistent with lymphomatoid granulomatosis. The patient was started on a regimen of brentuximab/bendamustine, and instructed to follow up with Oncology on an outpatient basis. CONCLUSIONS Treatment options for lymphomatoid granulomatosis are based on the disease grading. Lymphomatoid granulomatosis can be classified by using a grading system determined by the number of EBV-positive large B cell malignant cells, along with necrosis. The most effective treatment for lymphomatoid granulomatosis is unknown, but at this time treatment protocols are based on the grade of the disease. The clinical and histological features of lymphomatoid granulomatosis are discussed in this case report.