Chronic lymphocytic infiltration with pontine perivascular enhancement responsive to steroids (CLIPPERS) and its association with Epstein-Barr Virus (EBV)-related lymphomatoid granulomatosis: a case report.

BACKGROUND: Chronic lymphocytic infiltration with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a neuro-inflammatory syndrome first described in 2010. It has a relationship with lymphoproliferative disorders that has not been fully elucidated. This case represents an unusual progression of CLIPPERS to Epstein-Barr Virus (EBV)-related lymphomatoid granulomatosis (LYG). The exact connection between CLIPPERS and LYG remains poorly understood. CASE PRESENTATION: We present a case of a 75-year-old man who was diagnosed with CLIPPERS with initial response to immunosuppression but later progressed to EBV-related LYG. EBV polymerase chain reaction (PCR) was detected in his cerebrospinal fluid (CSF), and repeat imaging revealed findings that were uncharacteristic for CLIPPERS; thereby prompting a brain biopsy which led to a diagnosis of EBV-related LYG. This case highlights the following learning points: 1) CLIPPERS cases are often part of a spectrum of lymphomatous disease, 2) CLIPPERS can be associated with EBV-related lymphoproliferative disorders such as LYG, and 3) EBV detection in CSF should prompt earlier consideration for brain biopsy in patients. CONCLUSIONS: Our case highlights the difficulty in distinguishing CLIPPERS from other steroid-responsive conditions such as neoplastic and granulomatous diseases. Given the association of CLIPPERS with EBV-related LYG as demonstrated in this case, we recommend testing for EBV in CSF for all patients with suspected CLIPPERS. An early referral for brain biopsy and treatment with rituximab should be considered for patients with suspected CLIPPERS who test positive for EBV in their CSF.

Neuroimages and Neuropathology of a Stroke-Like Cerebral Lymphomatoid Granulomatosis.

A 70-year-old man presented to the Emergency Department reporting the acute onset of non-fluent aphasia, hyposthenia, and hemi-anesthesia of the right body. Brain computerized tomography revealed a subcortical hypodense lesion in the middle cerebral artery territory. Neck ultrasounds of internal and external carotid arteries and of the vertebral arteries showed a focal moderate stenosis of the left internal carotid artery due to a soft atheromasic plaque. These findings that were initially consistent with a diagnosis of an ischemic stroke were not confirmed by magnetic resonance (MR). The latter showed an hyperintense lesion on FLAIR and T2-weighted sequences located in the left centrum semiovale, corona radiata, and thalamus, with a well-defined regular rim and a mild compressive effect on the lateral ventricle, with diffusivity restriction but without ADC reduction and with a punctate and serpiginous gadolinium enhancement on T1 sequences (Figure 1). Within the first day of observation, the patient started complaining progressive mental deterioration, in absence of any other possible causes, and a total body CT scan excluded any other organ involvement. Patient was then referred to the neurosurgeon in order to perform a brain biopsy. The neuropathology was compatible with the diagnosis of cerebral lymphomatoid granulomatosis (LG) (Figure 1).

Cartilage hair hypoplasia with cutaneous lymphomatoid granulomatosis.

Cartilage-hair hypoplasia (CHH) is an autosomal recessive chondrodysplasia characterized by short-stature, sparse hair and impaired cellular immunity. We describe a young girl who was diagnosed with CHH based on the findings of recurrent infections, short stature with metaphyseal chondrodysplasia, and a confirmed bi-allelic RMRP gene mutation. At 13 years, the patient developed an Epstein-Barr virus (EBV)-driven lymphoproliferative disorder involving the lung, which responded partially to chemotherapy. Simultaneously, she developed multiple indurated plaques involving her face, which had histological findings of granulomatous inflammation and EBV-associated low-grade lymphomatoid granulomatosis. The patient received a matched unrelated peripheral blood stem cell transplant at 15 years of age, and her immunological parameters and skin lesions improved. Lymphomatoid forms of granulomatosis and cutaneous EBV-associated malignancies have not been described previously in CHH. This case highlights the possibility of EBV-associated cutaneous malignancy in CHH.

Lymphomatoid Granulomatosis in a 14-Year-Old Boy with Trisomy 21 and History of B-Lymphoblastic Leukemia/Lymphoma.

BACKGROUND: Lymphomatoid granulomatosis is a EBV-driven lymphoproliferative disorder that has been reported in association with immunodeficiency, but only exceptionally in patients with hematopoietic malignancy. CASE REPORT: A 14-year-old boy with trisomy-21 and a history of B-lymphoblastic leukemia/lymphoma (B-ALL) diagnosed 1.5 years prior, on maintenance chemotherapy, presented with fever and respiratory symptoms. Chest X-ray revealed right-lower-lobe consolidation. He was treated for pneumonia but continued to be febrile with worsening respiratory status, with development of additional pulmonary and liver nodules. No infectious etiology was identified. Following nondiagnostic lung and liver biopsies, the largest pulmonary mass was resected. The histopathologic findings were diagnostic of lymphomatoid granulomatosis. There was no residual B-ALL. The patient's status continued to deteriorate and he died shortly thereafter. CONCLUSION: Relative immunosuppression due to maintenance therapy for B-ALL can lead to lymphomatoid granulomatosis.

Orbital lymphomatoid granulomatosis - a rare cause of proptosis.

A 1-year-old girl with unilateral proptosis was found to have primary orbital lymphomatoid granulomatosis - a condition rarely occurring in children. This multisystem angiocentric, angiodestructive, lymphoproliferative disease typically involves the lungs, with ocular involvement being extremely uncommon. Our case serves to illustrate the imaging findings of this unusual condition and highlight a rare cause of proptosis.

Pulmonary lymphomatoid granulomatosis in a 4-year-old girl.

Lymphomatoid granulomatosis is a rare lymphoproliferative disease associated with the Epstein-Barr virus that commonly affects the lung. There is limited literature on cases of pediatric lymphomatoid granulomatosis. Half of all cases of lymphomatoid granulomatosis develop during the treatment of leukemia. Herein, we describe a case of lymphomatoid granulomatosis in a previously healthy child without leukemia.

An eschar and violaceous nodules as the presenting signs of lymphomatoid granulomatosis.

Lymphomatoid granulomatosis (LYG) is a rare B-cell lymphoproliferative disorder associated with infection by Epstein-Barr virus (EBV). The lung is the most common site of involvement, but LYG may initially manifest in the skin. LYG has been associated with immune dysregulation. Treatment regimens are not well-defined, but clinical trials targeting EBV have been successful. We report a 31-year-old male with LYG who presented with cutaneous symptoms. The skin biopsy was devoid of B-cells and non-reactive for EBV. We present this case to emphasize the role of dermatologists in the diagnosis of LYG and to caution clinicians that cutaneous lesions may lack diagnostic evidence of EBV infection.

[Lymphomatoid granulomatosis - the past and present]. / Lymfomatoidní granulomatóza - minulost a soucasnost.

BACKGROUND: Lymphomatoid granulomatosis (LyG) is a rare multisystemic angiocentric and angiodestructive B lymphoproliferative disease that was first described by Liebow in 1972. Disease was then in the "gray zone" between vasculitis and lymphoproliferative disease. LyG is currently categorized as a primary B lymphoproliferative disease associated with Epstein-Barr (EB) virus according to the World Health Organization (WHO) classification of tumours. EPIDEMIOLOGY, CLINICAL COURSE AND TREATMENT: Lymphomatoid granulomatosis is a rare disease with unknown prevalence. It occurs more often in males (male : female ratio 2 : 1) between the 5th to 6th decade of life and is more frequent in Europe than in Asia. Lungs are typically the predominantly affected organ; the disease spreads predominantly by extralymphatic manner. Spleen and lymph nodes are affected at an advanced stage. The clinical features are often nonspecific. Dyspnea, cough, hemoptysis, chest pain are the most common features with/without B symptoms (fever, night sweats, weight loss) in the pulmonary involvement. The radiographic finding of the lung is very diverse, but when there are multiple bilateral nodular lesions with basal predominance in perilymphatic distribution, we should think of this disease, although LyG rarely occurs. The histopathologic examination of affected tissue (most commonly the lung) is necessary to confirm the diagnosis. The thoracoscopy is used mainly. When the pulmonary findings are without any response to antibiotics, the autoimmune cause and other granulomatous inflammations (tuberculosis, sarcoidosis, etc.) are excluded, this diagnostic performance is indicated. Prognosis is variable - from spontaneous remission to progressive disease, often with aggressive behavior. Median survival is 14 months from diagnosis and mortality rate is 60% in the first year - despite the treatment. Treatment strategy is chosen depending on the histological grade. The therapy is not yet standardized. Interferon α, rituximab, glucocorticoids, cyclophosphamide and combined immunochemotherapy have been used for the treatment. The disease may lead to pulmonary failure, fatal CNS (central nervous system) involvement and sometimes develops into progressive EB virus positive lymphoproliferative disorder. CONCLUSION: Improvements in understanding of the biology of LyG, especially in determining the precise role of EB virus infection in its pathogenesis may lead to optimization of treatment strategies for this disease. Novel treatment modalities are urgently needed due to unfavourable prognosis. Adoptive immunotherapy appeals to be a promising approach.

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.

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.

Unique presentation of testicular involvement in lymphomatoid granulomatosis.

BACKGROUND: Lymphomatoid granulomatosis is a rare angiodestructive B-cell lymphoproliferative disorder associated with Epstein-Barr virus infection. It predominantly affects the lungs, skin, liver, kidneys, spleen, and central nervous system. Testicular involvement has never previously been described. The authors present the first documented case of testicular involvement in lymphomatoid granulomatosis. CASE REPORT: A 55-year-old gentleman with confirmed lymphomatoid granulomatosis on lung biopsy was noted to have a swelling in his scrotum. Ultrasound scanning demonstrated multiple ill-defined areas of reduced echogenicity throughout both testes with evidence of increased vascularity. Biopsy of the testis confirmed the presence of lymphomatoid granulomatosis. The patient was commenced on alpha-interferon therapy. However, marked clinical improvement occurred only following addition of high-dose oral corticosteroid approximately 1 week later. This resulted in resolution of the testicular swelling and his other symptoms. CONCLUSION: Prognosis with lymphomatoid granulomatosis depends mainly on grade. Our patient responded well to therapy but will continue to be closely followed up in the outpatient setting.

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.

[Lymphomatoid granulomatosis revealed by cutaneous lesions]. / Granulomatose lymphomatoïde de révélation cutanée.

BACKGROUND: Lymphomatoid granulomatosis is a rare Epstein Barr virus (EBV)-related lymphoproliferative disorder. It most frequently involves the lungs, skin and central nervous system and arises preferentially in patients with immune disorders. Here we report a case revealed by cutaneous lesions in an immunocompetent patient. CASE REPORT: A 56-year-old man consulted for erythematous nodules of the trunk associated with malaise and marked weight loss (14kg). In a few days the nodules became necrotic. Two weeks later a cough appeared and the chest computerized tomography showed multiple poorly defined nodular opacities with a peribronchovascular distribution. Cutaneous and pulmonary biopsies showed an infiltrate composed of medium-sized atypical lymphocytes T and B. EBV was present in the infiltrate (in situ hybridization) with a high EBV load in plasma. All of these data helped confirm the diagnosis of lymphoid granulomatosis. Despite aggressive treatment with polychemotherapy, the patient died after 2 months. DISCUSSION: Lymphomatoid granulomatosis represents a diagnostic challenge. In most cases, the presenting symptoms are not specific: malaise, weight loss, fever and cough. Moreover histology is difficult because of the T-cell-rich background. It is essential to consider this diagnosis in cases of cutaneous and pulmonary symptoms.

A 67-Year-Old Woman With Abdominal Pain, Paresthesia, and Rapidly Expanding Lung Nodule.

CASE PRESENTATION: A 67-year-old woman with a medical history significant for hypertension, hyperlipidemia, type 2 diabetes mellitus, OSA, and schizophrenia was admitted multiple times the previous 3 months for generalized abdominal pain. Her most recent admission was unique for new onset bilateral upper and lower extremity weakness with paresthesia. Pertinent review of systems included malaise, fever, cough, left lower quadrant pain without weight loss, and rash. Previous evaluation included multiple CT scans of her abdomen that revealed colonic thickening. Ensuing colonoscopy revealed chronic ulcers with cytopathic changes consistent with cytomegalovirus.

Isolated central nervous system involvement by lymphomatoid granulomatosis in an adolescent: a case report and review of literature.

Lymphomatoid granulomatosis is an Epstein-Barr virus-associated multisystem disease that combines granulomatous inflammatory process with lymphoproliferative potential. It predominantly affects lungs, skin, and brain and is characterized by multifocal, transmural, angiocentric, and angiodestructive pleomorphic lymphoid infiltrate in a perivascular distribution. Lymphomatoid granulomatosis is generally considered to be a neoplastic B-cell proliferation that has traditionally been associated with poor prognosis, evolving as a progressive multisystem disease transforming into B-cell lymphoma, with a median survival of 14 to 16 months only. Its lymphomatous nature explains prompt response to steroids and systemic chemotherapy, although appropriate optimal management still remains to be defined. The authors report on a young boy who presented with features of raised intracranial tension and sudden onset seizures. Neuroimaging showed 2 space-occupying lesions, larger in the left frontoparietal region with heterogeneous enhancement, moderate perifocal edema, compression, and mass effect. He underwent surgical decompression of the dominant lesion with prompt relief of symptoms. The diagnosis of lymphomatoid granulomatosis was confirmed on light microscopy and immunohistochemistry. An extensive systemic work-up ruled out other site(s) of involvement. He was successfully treated with aggressive systemic chemotherapy and moderate dose of whole-brain radiotherapy. Awareness of disease spectrum in the central nervous system may permit early diagnosis and thus allow institution of timely appropriate therapy.

Extranodal NK/T cell lymphoma and lymphomatoid granulomatosis in a patient with chronic lymphocytic leukaemia: Case report for a new perspective on Richter syndrome.

RATIONALE: Richter syndrome (RS) defines the transformation of chronic lymphocytic leukemia (CLL) into a more aggressive lymphoma. Although the term RS is most often reserved for transformation of CLL into diffuse large B-cell lymphoma (DLBCL), and less frequently Hodgkin lymphoma , the list of cases with more variable presentations in the literature is growing. PATIENT CONCERNS: A 71-year-old Caucasian man initially consulted an otolaryngologist for a 1-year history of nasal congestion. DIAGNOSES: The asynchronous occurrence of 2 rare angiocentric Epstein-Barr virus (EBV)-related lymphoproliferative disorders in a patient with CLL, specifically clonally related lymphomatoid granulomatosis (LYG), and an extranodal NK/T-cell lymphoma, nasal type, are described herein. INTERVENTIONS: Radiation therapy and a regimen of cis-platinum were administered for the NK/T cell lymphoma, and ibrutinib for LYG. OUTCOMES: The patient remains in complete clinical remission 8 years after the diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma and recurrent extranodal NK/T cell lymphoma, and 2 years after the diagnosis of clonally related LYG. LESSONS: Although the precise pathogenesis of RS remains incompletely understood, various molecular alterations, in particular long-term immunosuppression, may lead to RS, similar to the causal link existing between non-Hodgkin lymphomas and HIV infection, and post-transplantation lymphoproliferative disorders. EBV infection is linked to the pathogenesis of several types of lymphomas and found in a subset of patients with RS; immunosuppression, in the context of CLL or other pathological conditions or pharmacological agents, can disrupt the fine balance between virus and the host immune system, and result in EBV-driven lymphoproliferations of B-, T-, or NK-cell origin. The findings of our literature review thus suggest that such non-diffuse large B-cell lymphoma , non-Hodgkin lymphoma CLL transformations, may be considered as rare variants of RS.

A 53-Year-Old Man Presenting With Diplopia and Cavitary Lung Nodules.

CASE PRESENTATION: A 53-year-old Chinese man presented with 1 week of worsening diplopia and left-sided facial droop. His symptoms developed during a readmission for elective drainage and curettage of a perianal abscess that recurred despite drainage 2 weeks before. He denied having other neurologic symptoms, and did not report any cough, sputum production, night sweats, or fever. He was a lifelong nonsmoker with a history of polymyositis treated with mycophenolate mofetil for the last 4 years. He had undergone surgical resection for jejunal adenocarcinoma 12 years prior to this presentation. No evidence of recurrence was detected on surveillance gastrointestinal endoscopies and CT scans.