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.

A case of central nervous system lesion pathologically characterized by angiocentric, T-cell-rich lymphoid cell infiltrates: a case report and literature review.

Lymphomatoid granulomatosis (LYG) is a rare lymphoproliferative disease with angiocentric and angiodestructive infiltrates, and by definition, Epstein-Barr virus (EBV)-associated B-cell malignancy. It most frequently involves the lung, and in some cases, the lesions are confined to the central nervous system (isolated CNS-LYG). However, it remains a controversial disease in terms of pathophysiology, especially in those confined to the CNS. We report the case of a 37-year-old man with CNS lesion pathologically characterized by angiocentric, T-cell-rich lymphoid cell infiltrates that resembled CNS-LYG. The lesion was clinically aggressive with subacute onset and irregular ring-like enhancement on MRI. The resected specimen showed no cytological atypia, EBV-infected cells, or monoclonality for IgH and TCR gene rearrangements. Considering the possibility of latent malignancy, the patient was successfully treated with corticosteroid and chemoradiotherapy with high-dose methotrexate. The present case and the literature suggest that EBV-negative CNS lesions with angiocentric lymphoid infiltrates are probably heterogeneous in their pathogenesis, including those that could fit into the so-called CNS-LYG and those with T-cell predominance. The accumulation of similar cases is warranted for the classification and appropriate treatment of these lesions.

Magnesium Restores Activity to Peripheral Blood Cells in a Patient With Functionally Impaired Interleukin-2-Inducible T Cell Kinase.

Interleukin-2-inducible T cell kinase (ITK) is critical for T cell signaling and cytotoxicity, and control of Epstein-Barr virus (EBV). We identified a patient with a novel homozygous missense mutation (D540N) in a highly conserved residue in the kinase domain of ITK who presented with EBV-positive lymphomatoid granulomatosis. She was treated with interferon and chemotherapy and her disease went into remission; however, she has persistent elevation of EBV DNA in the blood, low CD4 T cells, low NK cells, and nearly absent iNKT cells. Molecular modeling predicts that the mutation increases the flexibility of the ITK kinase domain impairing phosphorylation of the protein. Stimulation of her T cells resulted in reduced phosphorylation of ITK, PLCγ, and PKC. The CD8 T cells were moderately impaired for cytotoxicity and degranulation. Importantly, addition of magnesium to her CD8 T cells in vitro restored cytotoxicity and degranulation to levels similar to controls. Supplemental magnesium in patients with mutations in another protein important for T cell signaling, MAGT1, was reported to restore EBV-specific cytotoxicity. Our findings highlight the critical role of ITK for T cell activation and suggest the potential for supplemental magnesium to treat patients with ITK deficiency.

Simultaneous Presentation of Lymphomatoid Granulomatosis and Multiple myeloma in an Immunodeficient Patient with Rheumatoid Arthritis.

A 75-year-old Japanese woman with a 20-year history of rheumatoid arthritis presented with symptomatic bilateral pleural effusion and lung and brain tumors. She had received methotrexate for five years and tacrolimus for one year. A brain biopsy specimen showed the pathological features of lymphoproliferative disease, but a bone marrow biopsy showed proliferation of plasma cells. She was finally diagnosed with coexistent lymphomatoid granulomatosis (LYG) of the brain and lung and multiple myeloma (MM) of the bone marrow and received chemotherapy for both. This report shows that immunodeficient patients are at risk of developing the unusual coexistence of LYG and MM.

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.

B-cell Lymphoproliferative Disorders Associated with Primary and Acquired Immunodeficiency.

The diagnosis of lymphoproliferative disorders associated with immunodeficiency can be challenging because many of these conditions have overlapping clinical and pathologic features and share similarities with their counterparts in the immunocompetent setting. There are subtle but important differences between these conditions that are important to recognize for prognostic and therapeutic purposes. This article provides a clinicopathologic update on how understanding of these B-cell lymphoproliferations in immunodeficiency has evolved over the past decade.

Pulmonary sarcoid-like granulomatosis after multiple vaccinations of a long-term surviving patient with metastatic melanoma.

Autoimmune side effects are frequent in patients with cancer treated with immune checkpoint-targeting antibodies, but are rare with cancer vaccines. Here, we present a case report on a patient with metastatic melanoma who developed pulmonary sarcoid-like granulomatosis following repetitive vaccinations with peptides and CpG. Despite multiple metastases, including one lesion in the brain, the patient is alive and well more than 13 years after the diagnosis of metastatic disease. The strongly activated tumor-specific CD8(+) T cells showed robust long-term memory and effector functions. It is possible that long-term survival and adverse autoimmune events may become more common for vaccines inducing robust anticancer immune responses as were present in this patient.

[Methotrexate-related lymphomatoid granulomatosis successfully treated with discontinuation of methotrexate and radiotherapy to brain].

A 70-year-old woman with rheumatoid arthritis treated with methotrexate (MTX) complained of right arm weakness. On CT and MRI, tumors were found in the right frontal lobe, bilateral lungs, and left renal parenchyma. She was diagnosed as having lymphomatoid granulomatosis (LYG) grade 2 on thoracoscopic biopsy of the left lung. We discontinued MTX and treated a mass lesion in the right frontal lobe with stereotactic radiotherapy. As a result, the tumors showed a gradual reduction in size, and the patient achieved complete remission. LYG is a rare lymphoproliferative disorder, and has various clinical characteristics. We describe herein a patient with LYG grade 2 with cerebral, pulmonary, and renal lesions, who has maintained a complete remission for six months, to date, after treatment.

Mono-belly and beyond: spectrum of imaging manifestations of EBV infection in the abdomen.

Epstein-Barr virus (EBV) is a DNA virus from the herpes virus group affecting only humans. More than 90% adults are infected by the virus, but very few ever have symptoms. Within the abdomen, both solid and hollow viscera can be involved in symptomatic disease. Awareness of the spectrum of imaging findings, high index of suspicion, and appropriate clinical and laboratory information can help in the early and accurate diagnosis in these cases.

Lymphomatoid granulomatosis: a practical review for pathologists dealing with this rare pulmonary lymphoproliferative process.

Lymphomatoid granulomatosis (LYG) is a rare B-cell lymphoproliferative disorder predominantly involving the lungs, but poorly-recognized among clinicians and pathologists. It is an Epstein-Barr virus (EBV)-driven disease mimicking several other diseases on clinical and radiological grounds, generally showing multiple, bilateral nodular, ill-defined infiltrates of the lungs tending to coalescence and/or cavitation. LYG often affects middle-aged males with an underlying immunodeficiency and commonly involves skin and central nervous system during disease progression. Diagnosis requires a generous biopsy and careful histologic examination with immunohistochemical staining and molecular demonstration of EBV genome in large atypical B-cells. LYG is graded as I to III based on the number of large EBV-positive B-cells; grades II/III are now considered as a peculiar variant of T-cell rich diffuse large B-cell lymphoma. In this brief review, clinical, radiologic and pathologic features of LYG will be analyzed with focus on differential diagnosis, the most appropriate treatment and prognosis.

Possible donor-recipient bartonellosis transmission in a pediatric liver transplant.

Bartonella henselae is the causative agent of cat-scratch disease and other disorders, including hepatosplenic granulomatosis. This infection has only rarely been reported after solid organ transplantation, where it can mimic the more common post-transplant lymphoproliferative disease. Here we present a case of asymptomatic B. henselae hepatic and lymph nodal granulomatosis in a pediatric patient who had received orthotopic liver transplant 2 months before; we hypothesize that the causative agent was transmitted from the donor. This infection developed early in the post-transplant period; the disease involved only the graft liver and the regional lymph nodes, and the patient did not have a cat or any history of contact, scratches, or bites by a cat. In our patient this infection resolved successfully with a combination of 2 associated antibiotics and reduction of immunosuppressive therapy.

Lymphomatoid granulomatosis and diffuse alveolar damage associated with methotrexate therapy in a patient with rheumatoid arthritis.

We report on a patient of rheumatoid arthritis (RA) who sequentially developed an axillary mass and a fatal interstitial pneumonia during a 2-year course of methotrexate (MTX) therapy. Autopsy revealed a systemic lymph node involvement and the diagnosis of Epstein-Barr virus (EBV)-related lymphoproliferative disease (LPD) with the features of lymphomatoid granulomatosis was made. The lung tissue specimens revealed a typical diffuse alveolar damage (DAD), and small nodules consisting of atypical B lymphocytes showing positive staining for EBV were sparsely recognized only in basal lungs. This is the first report of a RA patient receiving MTX therapy sequentially developing MTX-associated lymphomatoid granulomatosis and DAD.

[Reactivation of Epstein-Barr virus is involved in the pathogenesis of lymphomatoid granulomatosis].

Recent studies point to a role of Epstein-Barr virus in the pathogenesis of lymphomatoid granulomatosis. Little is however known about the association of the pathogenesis of the disease with Epstein-Barr virus reactivation. A 46-year-old man presented with fever and general malaise. He had been admitted with fever of unknown origin 10 years previously. Chest radiographs and CT scans showed multiple nodular shadows in both lung fields. PET/CT showed strong accumulation in lung nodules, femoral muscle, lumbar subcutaneous nodule. He died of rapidly progressive neurological lesions. The definitive diagnosis of lymphomatoid granulomatosis was made from histological findings of the surgical biopsy specimen and at autopsy. Elevation of early antigen-IgG titer in serum was shown in this case. This result suggests that reactivation of Epstein-Barr virus is involved in the development of the disease.

Posttransplantation lymphoproliferative disease with features of lymphomatoid granulomatosis in a lung transplant patient.

A 58-year-old lung transplant patient developed worsening shortness of breath and indurated erythematous plaques on the lower left leg. A skin biopsy specimen revealed a dense angiocentric and angioinvasive infiltrate in the mid to reticular dermis and panniculus containing large, atypical lymphocytes with convoluted nuclei and prominent nucleoli. Immunohistochemical stains showed that the atypical cells were of B-cell origin, and that Epstein-Barr virus was present. Molecular studies demonstrated B-cell clonality. The patient was successfully treated with rituximab. The clinical and pathologic features in this case represent posttransplantation lymphoproliferative disease with features of lymphomatoid granulomatosis. The case also highlights the importance of clinical and pathologic examination of cutaneous lesions in the evaluation of lymphoproliferative disorders for patients undergoing transplantation.