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.

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.

Pathobiology and treatment of lymphomatoid granulomatosis, a rare EBV-driven disorder.

Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)-driven B-cell lymphoproliferative disease (LPD). This disease is hypothesized to result from defective immune surveillance of EBV, with most patients showing evidence of immune dysfunction, despite no known primary immunodeficiency. Pathologically, LYG is graded by the number and density of EBV+ atypical B cells, and other characteristic findings include an angioinvasive/angiodestructive reactive T-cell infiltrate and various degrees of necrosis. Clinically, LYG universally involves the lungs with other common extranodal sites, including skin, central nervous system, liver, and kidneys. Nodal and/or bone marrow involvement is extremely rare and, if present, suggests an alternative diagnosis. Treatment selection is based on histologic grade and underlying pathobiology with low-grade disease hypothesized to be immune-dependent and typically polyclonal and high-grade disease to be immune-independent and typically oligoclonal or monoclonal. Methods of augmenting the immune response to EBV in low-grade LYG include treatment with interferon-α2b, whereas high-grade disease requires immunochemotherapy. Given the underlying defective immune surveillance of EBV, patients with high-grade disease may have a recurrence in the form of low-grade disease after immunochemotherapy, and those with low-grade disease may progress to high-grade disease after immune modulation, which can be effectively managed with crossover treatment. In patients with primary refractory disease or in those with multiple relapses, hematopoietic stem cell transplantation may be considered, but its efficacy is not well established. This review discusses the pathogenesis of LYG and highlights distinct histopathologic and clinical features that distinguish this disorder from other EBV+ B-cell LPDs and lymphomas. Treatment options, including immune modulation and combination immunochemotherapy, are discussed.

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.

Mimickers of pulmonary lymphoma.

There are multiple entities that involve the lung that have radiographic, clinical, and morphologic overlaps with pulmonary lymphoma. In this review, we will discuss these entities in detail and provide relevant updates.

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.

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.

Lymphoproliferative Disorders of the Lung.

This review aims to describe some of the most frequent lymphoproliferative disorders arising from the lung: pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma, lymphomatoid granulomatosis (LG), multicentric Castleman disease (MCD), primary effusion lymphoma (PEL), and nodular lymphoid hyperplasia (NLH). Primary pulmonary lymphoma is defined as a clonal lymphoproliferative disorder affecting one or both lungs, without extrapulmonary involvement 3 months after diagnosis, and includes pulmonary MALT lymphoma and LG. MALT lymphoma is the most common pulmonary lymphoma. The disease is slow growing, most often asymptomatic, and revealed by chronic alveolar opacity on radiography. The diagnosis should involve minimally invasive techniques, and the prognosis is typically excellent. LG is a rare B-cell lymphoma driven by Epstein-Barr virus infection. The disease may mimic pulmonary vasculitis, often revealed by systemic signs. The diagnosis usually requires surgical lung biopsy. Its evolution is unpredictable, but median survival is poor and chemotherapy is usually proposed. MCD and PEL are both driven by Human herpesvirus 8 infection. Patients with MCD present with fever and lymphadenopathy associated with interstitial lung disease. PEL provokes a febrile, lymphocytic-exudative pleural effusion, without any pleural mass on CT. Specific chemotherapy is urgent for both MCD and PEL. NLH is a benign lymphoproliferative disorder of the lung that is usually asymptomatic and revealed by a single nodular opacity. The prognosis is good, without recurrence after surgical resection.

A Rare Case of Pulmonary Lymphomatoid Granulomatosis.

In this report, we discuss an unusual case of pulmonary lymphomatoid granulomatosis (LYG), a rare form of angiocentric and angiodestructive lymphoproliferative disorder. This disease is thought to be caused by Epstein-Barr virus-induced lymphoproliferation. A 39-year-old male with no signi ficant past medical history presented with flu-like symptoms. Upon further evaluation, laboratory studies noted pancytopenia, and a chest X-ray showed bilateral nodular densities. A computerized tomography (CT) scan demonstrated bilateral pulmonary nodules and splenomegaly. A biopsy of the pulmonary nodules revealed polymorphous, CD3-positive, lymphohistiocytic, inflammatory in filtrate within the walls of the arterioles and venules with associated necrosis. This histopathology is consistent with LYG. The patient was started on a regimen of rituximab, and he signi ficantly improved within a few weeks after the initiation of therapy, including resolution of the pancytopenia. A repeat CT scan showed the decreased size of the lung nodules. This case was histopathologically consistent with LYG but negative for Epstein-Barr virus ribonucleic acid. This demonstrates the potential for diagnostic difficulty in a case presentation of multiple pulmonary nodules. Extensive work-up for neoplastic, infectious, inflammatory, and autoimmune etiologies needs to be done in such cases. A prompt diagnosis of LYG is necessary for optimal management and improved patient outcomes.

Epstein-Barr virus-driven B Cell Proliferation with CD4+ T Cell Expansion: A Lymphomatoid Granulomatosis-like Disease Related to Hyperinterleukin-10 Secretion of Remarkably Favourable Outcome with Rituximab.

Granulomatous lymphomatosis is an Epstein-Barr virus (EBV)-driven B cell proliferation associated with an exuberant CD4(+) T cell reaction with usually histopathological pictures of angiocentrism. So far, the characteristics of CD4(+) T cells in granulomatous lymphomatosis and the mechanism leading to their expansion remain poorly explored. We report a 56-year-old female with a past history of cold agglutinin disease, which was successfully treated with 4 weekly infusions of rituximab. She presented one year later with features of granulomatous lymphomatosis that resulted in severe lung and bone marrow infiltration. We provide evidence that CD4(+) T cell expansion was oligoclonal, involved anergic cells and did not result from an EBV-driven stimulation. Rather, it resulted possibly from a high production of interleukin-10 by immunoblastic EBV-positive B cells. The outcome was remarkably favourable with rituximab and steroids. Our results suggest that an EBV-driven B cell proliferation should be investigated in patients presenting with a CD4(+) T cells alveolitis or other systemic manifestations resulting from a CD4(+) T cell expansion. These features should prompt to introduce an immunosuppressive therapy including steroids and rituximab. Our results deserve further investigations to confirm our pathophysiological hypotheses in CD4(+) T cell expansions associated with EBV-driven B cell proliferations and to assess whether granulomatous lymphomatosis could result from comparable mechanisms.

Lymphomatoid granulomatosis presenting with cutaneous involvement: a case report and review of the literature.

Lymphomatoid granulomatosis (LG) is a rare Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorder presenting in middle adulthood that nearly always affects the lungs and shows cutaneous involvement in up to 50% of cases. Skin lesions are present at the time of diagnosis in roughly one-third of patients and may precede the development of lung lesions in as many as 10-15%. Recognition by both the dermatologist and dermatopathologist is therefore crucial for early and accurate diagnosis. While skin involvement is grossly and microscopically diverse, the disease most commonly presents as erythematous subcutaneous and dermal nodules showing the classic histopathologic triad of transmural lymphocytic angiitis, atypical B-lymphocytes in a polymorphous T-cell background, and necrotic foci within lymphoid aggregates. We present a case of lymphomatoid granulomatosis initially presenting with cutaneous lesions, with an accompanying review of the literature.

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.

Angiocentric and intravascular lymphomas.

Under the generic diagnosis of angiocentric and intravascular lymphomas are included several subtypes of lymphomas histopathologically characterized either by the predominantly endovascular-endoluminal presence of neoplastic lymphocytes of B-T or NK/T cell origin, or by a pathologic process centered around a blood vessels secondarily infiltrated and invaded by the spreading infiltrate. This group of lymphoproliferative disorders is heterogeneous regarding phenotype, but they share common features that are multiorgan involvement, worse prognosis, and, frequently Ebstein-Barr virus (EBV) genomic integration. At onset, some of these rare lymphomas, e.g. intravascular large cell lymphoma or lymphomatoid granulomatosis (Liebow dieases), are misdiagnosed as inflammatory diseases. The actual treatments of these disorders are based upon chemotherapy and/or chemotherapy plus bone marrow transplantation with variable results. Therapeutic approaches for EBV related angiocentric and intravascular lymphomas, similarly to those employed for other viral induced lymphoproliferative disease would comprise the employment of chemotherapy together with drugs able to interfere with viral infection. Such an approach has been used in rare cases of EBV-positive diffuse large B-cell lymphoma of the elderly, a lymphoproliferative disorders which development is linked to immunosuppression due to senescence. The present review will focus on intravascular and angiocentric lymphomas providing histopathologic, immunophenotypical and molecular data useful to overcome to a specific diagnosis and to differentiate them from other lymphoproliferative disorders showing a secondary vascular engulfment and infiltration and some vasculitides showing overlapping histopathologic features.

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.

Current histological diagnosis of lymphomatoid granulomatosis.

The current histological criteria for the diagnosis of lymphomatoid granulomatosis (LYG) are reviewed and summarized. The majority of patients present with multiple bilateral nodules involving the lung. Key histologic features necessary for the diagnosis include a mixed mononuclear cell infiltrate that shows vascular infiltration, appreciable numbers of T-cells, and variable numbers of CD20-positive B cells that show positivity for EBER by in situ hybridization.

Prominent CD56 expression by damaged and regenerating muscle fibers in the skin.

BACKGROUND: Antibodies to CD56 label natural killer cells as well as tissues with neural and neuroendocrine differentiation. Despite its apparently limited distribution, other conditions may unexpectedly show strong CD56 expression. METHODS: We report three cases to document another setting with strong expression of CD56 in the skin: damaged and/or regenerating muscle fibers. One case of cutaneous lupus erythematosus, one case of lymphomatoid granulomatosis, and one case of a dermal scar adjacent to cutaneous muscle fibers were evaluated with a panel of antibodies, including CD56. RESULTS: All cases showed histopathologic evidence of muscle fiber damage in the setting of lymphocytic infiltration or trauma. All cases showed prominent expression of CD56 by damaged and/or regenerating muscle fibers. The degree of CD56 expression was directly proportional to the proximity to the injury site and inversely proportional to fiber diameter. CONCLUSIONS: Even though CD56 is a useful marker for certain cytotoxic lymphomas and neural/neuroendocrine neoplasms, its expression is not limited to these conditions. Our cases highlight another unexpected example of strong CD56 expression in the skin: damaged and/or regenerating muscle fibers. The growing list of CD56-positive conditions suggests that this marker may not be as specific as initially assumed.

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.