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.

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.

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.

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.

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.

A 71-Year-Old Man With Diffuse Waxing and Waning Multifocal Lung Lesions, Empyema, and Episodic Fevers Reveals a Rare Diagnosis.

CASE PRESENTATION: A 71-year-old man with history of gastroesophageal reflux disease, chronic sinusitis, arthritis, hypothyroidism, and anemia of chronic disease initially sought treatment with a recurrent left pleural effusion along with other abnormal lung findings on chest CT scan. Before his referral, he was being managed for 3 years at his local hospital for waxing and waning fevers, fatigue, productive cough, chills, and night sweats. He did not report any hemoptysis or chest pain, but reported weight loss of 13 kgs in 15 months. During those 3 years, he was treated with multiple courses of antibiotics and steroids with temporary relief of symptoms. At that time, his chronic sinusitis was suspected to be the cause of his symptoms and he underwent balloon sinuplasty. He was receiving daily sublingual immunotherapy for inhaled respiratory allergens for the previous year after showing positive test results for 17 inhaled allergens. The patient had no other known immunologic workup before our evaluation.

A case of lymphomatoid granulomatosis with central nervous system involvement successfully treated with IFNα.

Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)-driven B-cell lymphoproliferative disease affecting mainly extranodal sites such as the lung, central nervous system (CNS), skin, kidney, and liver. We report a case of low-grade LYG involving the CNS that was successfully treated with interferon alpha (IFNα). A 69-year-old woman developed necrotic erythema of the skin and was initially diagnosed with pyoderma gangrenosum based on skin biopsy. She showed a limited response to prednisolone. Approximately 6 months after the initial onset, low-grade LYG was diagnosed after detection of CNS lesions on brain biopsy. The whole blood EBV-DNA load determined by real-time polymerase chain reaction was slightly elevated. Two months into IFNα therapy, skin and CNS lesions had responded favorably and the EBV-DNA load decreased. IFNα plays an important role in treatment of LYG through its antiproliferative, immunomodulatory, and anti-EBV effects. To our knowledge, this is the first case report of successful treatment with IFNα in Japan. Further investigation is necessary to determine optimal use of IFNα for LYG.

High-grade Primary Central Nervous System Lymphomatoid Granulomatosis: Successful Rituximab Monotherapy.

The primary central nervous system (CNS) presentation of lymphomatoid granulomatosis (LYG) is rare, and no standard therapy for LYG with primary CNS symptoms exists. CNS-LYG patients usually survive for only less than a year from diagnosis. This is the first report of high-grade primary CNS-LYG with monoclonality that was successfully treated with rituximab monotherapy, resulting in a durable remission for more than 1 year in a 66-year-old woman with pemphigus vulgaris who was also on immunosuppressive therapy.

Primary Central Nervous System Lymphomatoid Granulomatosis Presenting as Diffuse Corpus Callosum Lesions.

Lymphomatoid granulomatosis (LYG) is a rare lymphoproliferative disease characterized by angiocentric and angiodestructive infiltrate. It primarily affects the lung and sometimes may also affect the central nervous system (CNS), skin, kidney, liver, etc., but the involvement of lymph nodes and/or bone marrow is extremely rare, and if present, other diagnoses are usually considered. Isolated CNS involvement is very rare, and its pathogenesis and biological behavior have been controversially discussed. Here, we report a 46-year-old man with diffuse and symmetrical corpus callosum involvement. The histopathological findings were in keeping with LYG. Since there was no evidence of involvement of other organs, he was diagnosed with primary CNS-LYG. He responded well to steroids and his symptoms improved significantly. We also conduct an English literature review to provide clues for the diagnosis and treatment of this disease.

Use of rituximab in lymphomatoid granulomatosis with isolated central nervous system involvement.

A 33-year-old woman presented to the emergency room with severe headaches. A CT scan of the head revealed two brain lesions with associated vasogenic oedema. Diagnostic resection of one of the lesions followed by pathological analysis revealed grade III lymphomatoid granulomatosis (LYG). Staging investigations elsewhere in the body were negative, isolating this case of LYG to the central nervous system, an atypical presentation. After the resection, she was treated with single-agent rituximab 375 mg/m2 The follow-up MRI demonstrated the resolution of brain lesions and no progression of the disease.

[A Case of Primary Central Nervous System Lymphomatoid Granulomatosis that was Completely Ameliorated by Corticosteroid Treatment].

Lymphomatoid granulomatosis (LYG) is an angiocentric, angiodestructive lymphoreticular proliferative disease that usually affects the lungs but it has been speculated to also effect the central nervous system (CNS). However, unique primary LYG of the CNS has rarely been reported in the literature. Herein, we describe a clinical case of a 37-year-old female patient with grade 1 primary CNS-LYG having a good prognosis owing to corticosteroid treatment. The aforesaid patient, presented with a headache and left leg weakness with no evidence of a systemic disease. MRI revealed multiple small enhancing nodules in the right hemisphere with diffuse high-intensity lesions on T2/ FLAIR image. A brain biopsy showed lymphohistiocytic cells with blood vessels infiltrated with CD3+ and CD20+. The Epstein-Barr virus encoded small RNA-ISH test was negative. Based on the above findings, grade 1 primary CNS-LYG was diagnosed. Following the administration of oral corticosteroids, a systemic high-dose corticosteroid therapy was administrated. Complete remission was achieved and maintained for 24 months following treatment. Grade 1 primary CNS-LYG is a rare disease that is not apparently associated with the Epstein-Barr virus (EBV) and possibly yields much better prognosis than the frequently EBV-positive systemic LYG with CNS localization. (Received November 5, 2019; Accepted November 20, 2019; Published February 1, 2020).

Case 259: Primary Central Nervous System Lymphomatoid Granulomatosis Mimicking Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS).

History In November 2012, a previously healthy 31-year-old woman was admitted to our hospital with a 2-month history of right-sided numbness, diplopia, and intermittent nausea and dizziness. She did not have a history of fever, weight loss, headache, photophobia, seizure, or extremity weakness. Physical examination revealed left abduction limitation and right-sided hypoesthesia. Kernig and Brudzinski signs were absent, and pathergy test results were negative. Laboratory evaluation revealed normal complete and differential blood counts, normal serum chemistry, and normal immune function. Analysis of her serum was negative for antiaquaporin 4 antibody, rheumatism antibody profile, and paraneoplastic profile. Serum analysis was also negative for human immunodeficiency virus type 1 and 2 RNA, hepatitis B and C antigen or antibody profile, and fluorescent treponemal antibody absorption. Cerebrospinal fluid (CSF) analysis revealed clear fluid, a normal glucose level, an elevated protein level (45 mg/dL; normal range, 20-40 mg/dL), and an elevated white blood cell count (10/mm3 [0.01 ×109/L]; normal range, 0-8/mm3 [{0-0.008} ×109/L]; 81% lymphocytes, 19% monocytes). No CSF-specific oligoclonal bands were detected. Gram staining, acid-fast staining, and lactic acid and cryptococcal antigen test results were negative. CSF did not grow any bacteria, fungus, or acid-fast bacillus at culture. Spinal cord MRI, brain MR angiography, and CT of the chest, abdomen, and pelvis revealed normal findings (images not shown). Brain MRI and gadolinium-enhanced (20 mL gadopentetate dimeglumine, BeiLu Pharmaceutical, Beijing, China) MRI were performed. The patient's clinical symptoms and imaging findings responded to treatment with a high dose of steroids. However, the patient's symptoms exhibited clinical and radiologic progression as she attempted to taper the steroid dose. She arbitrarily stopped taking the steroids and started traditional Chinese treatment instead. However, her condition was not controlled. In November 2013, she was readmitted with worsening dizziness and diplopia accompanied by hearing loss, tinnitus, slurred speech, drinking-induced cough, walking instability, and involuntary outbursts of laughter and crying. Dysmetria, ataxia, brisk tendon reflexes, pathologic reflexes, and pseudobulbar signs were observed bilaterally. Repeated biochemical and immune tests did not yield positive findings. CSF analysis revealed mild lymphocytic pleocytosis (white blood cell count, 8/mm3 [0.008 ×109/L]; 83% lymphocytes, 17% monocytes) and a slightly elevated total protein level (46 mg/dL). Brain PET revealed diffuse high metabolism in the midbrain and pons (images not shown). Whole-body PET was negative for malignancy (images not shown). Brain MRI and gadolinium-enhanced MRI were performed. The patient's clinical symptoms and imaging findings improved after treatment with a high dose of steroids. Thereafter, intravenous cyclophosphamide therapy was added after her condition deteriorated again when the prednisone dose was tapered to 20 mg per day in March 2014. Her pontocerebral symptoms were relatively stable in the following year, with apparent diminishment of lesions in the brainstem and cerebellum observed at brain PET (images not shown). Follow-up MR images were obtained in July 2014. Subsequently, the patient exhibited clinical and radiologic aggravation. MR images were obtained again in July 2015 and February 2016. The patient underwent biopsy of the right frontal lobe, and a histopathologic examination was performed in August 2015. Afterward, her condition worsened, and she died in September 2016.

The Spontaneous Regression of Grade 3 Methotrexate-related Lymphomatoid Granulomatosis: A Case Report and Literature Review.

Lymphomatoid granulomatosis (LYG) is a rare lung disorder diagnosed by radiological imaging of multiple pulmonary nodules and occasionally induced by methotrexate (MTX) use. To date, the treatment of LYG has not been standardized. We herein report the case of a patient with grade 3 MTX-related LYG who presented a bulky lung mass. Importantly, the disease condition only improved after the discontinuation of MTX and remained stable for more than 1 year. Chest physicians should be aware that LYG can develop as a single lung mass and spontaneously regress, even without aggressive chemotherapy, following the cessation of MTX.

Angiocentric lymph proliferative disorder (lymphomatoid granulomatosis) in a person with newly-diagnosed HIV infection: a case report.

BACKGROUND: Angiocentric lymph proliferative disorder (ALPD) is a granulomatous lymphoproliferative condition associated with various primary and secondary immunodeficiency states. ALPD is so rare that its prevalence has not been established. Typically affecting middle-aged adults, this condition is often found in the context of Epstein Bar Virus infection and consists of angiocentric and angioinvasive pulmonary infiltrates. Herein, we present a biopsy-proven case of a patient manifesting with a viral meningoencephalomyelitis-like picture with brain, spinal cord, renal and splenic lesions. The diagnosis was confirmed to be ALPD in the context of newly diagnosed HIV infection. CASE PRESENTATION: A 35 year-old homosexual man presented with a 5-week history of headaches followed by a 3-week history of horizontal diplopia, limb weakness and right 6th cranial nerve palsy. Lumbar puncture revealed a lymphocytic pleocytosis, high protein and low glucose. Magnetic Resonance Imaging showed scattered lesions throughout the brain and spinal cord and Computed Tomography of the abdomen and pelvis revealed hypodensities involving the kidneys and spleen. HIV testing was positive, with a viral load of 11,096 copies/mL and CD4 count of 324 cells/µL. Serum Epstein Bar virus PCR was positive with 12,434 copies/ml. Right frontal brain biopsy revealed gray matter containing angiogentric cerebritis with organizing infarction but Epstein Bar Virus-in situ preparations were negative and no viral inclusions were identified. A diagnosis of ALPD (also known as lymphomatoid granulomatosis) was made. The patient was initiated on antiretroviral therapy and treated with intravenous rituximab every 3 weeks for 4 cycles and made progressive improvements. By the time of discharge his strength had improved and he was ambulating again although with a walker. Within 2 months, his HIV viral load was suppressed. Magnetic Resonance Imaging of the brain 6 months later revealed interval improvement. At his most recent follow-up, 34 months later, his neurological symptoms had almost completed resolved. CONCLUSION: Albeit rare, ALPD should be considered in the differential diagnosis of central nervous system lesions in persons with HIV once common etiologies have been eliminated. Furthermore, ALPD involving the central nervous system may occur in in the absence of documented EBV infection in the central nervous system.