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.

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.

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.

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.

Isolated lymphomatoid granulomatosis of the central nervous system: A case report and literature review.

Lymphomatoid granulomatosis (LYG) is an angiocentric and angiodestructive lymphoproliferative disease which can involve multiple organs of the body and is most common in the lungs. Its pathological features are proliferation of large atypical B-cells related to Epstein-Barr virus, T-cell infiltration and tissue necrosis. This disease is rare, and LYG which uniquely involves the central nervous system (CNS) is extremely rare. In this paper, we report a case of isolated lymphomatoid granulomatosis of the CNS (iCNS-LYG) diagnosed by histological biopsy and we review the clinical features of all similar cases reported in the past 46 years. A total of 49 cases of iCNS-LYG have been reported to date. The clinical, imaging and pathological features of iCNS-LYG are discussed in combination with a literature review.

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.

Lymphomatoid Granulomatosis: A Single Institution Experience and Review of the Literature.

BACKGROUND: Lymphomatoid granulomatosis (LYG) is a rare B-cell lymphoproliferative disorder with frequent extranodal presentation and involvement of the respiratory system. The purpose of this study is to describe the clinical characteristics, pathologic findings, and treatment outcomes of LYG in a single tertiary institution. METHODS: This is a retrospective review of series of cases of LYG diagnosed at Moffitt Cancer Center (MCC) between 2000 and 2011. We describe clinical presentation, histopathologic findings, and treatment outcomes. RESULTS: We identified 11 cases of biopsy-proven LYG at our institution. All patients presented with lung involvement by LYG. Nine patients were treated with rituximab-based chemotherapy. The overall response rate was 63.6% (complete response rate, 36.44%). Extra-pulmonary involvement was common (central nervous system, kidney, adrenal glands, testicles, and liver). The median overall survival and progression-free survival were 23 and 12.2 months, respectively. CONCLUSIONS: LYG is a rare B-cell lymphoproliferative disorder with involvement if the respiratory system. The presentation is heterogeneous, and response to therapy is variable. Although it is considered a poor prognosis disease, long-term survivors in remission have been described.

Granulomatous Lymphoproliferative Disorders: Granulomatous Slack Skin and Lymphomatoid Granulomatosis.

Granulomatous cutaneous T-cell lymphomas (CTCL) and lymphomatoid granulomatosis are considered granulomatous lymphoproliferative disorders. The most common types of granulomatous CTCL are granulomatous mycosis fungoides and granulomatous slack skin. Lymphomatoid granulomatosis is a rare Epstein-Barr virus driven lymphoproliferative disorder. This article reviews the etiopathogenesis, clinical presentation, systemic associations, and management of both granulomatous slack skin syndrome and lymphomatoid granulomatosis.

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.

Fatal lymphomatoid granulomatosis with primary CNS-involvement in an immunocompetent 80-year-old woman.

An 80-year-old woman presented with weight loss, fatigue, dizziness and a brain stem lesion. Extensive work-up revealed lymphomatoid granulomatosis (LYG) with primary clinical manifestation in the central nervous system (CNS), a rare Epstein-Barr virus-driven multisystem lymphoproliferative disorder, to be causative for the symptoms. Immunochemotherapy consisting of rituximab and temozolomide was started, but the disease progressed and the patient subsequently died. Histology, diagnostic criteria, differential diagnosis and treatment options for LYG with CNS involvement are discussed. This case demonstrates that LYG with CNS involvement may necessitate more aggressive treatment approaches than combination therapy with rituximab and temozolomide.

[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.

[Lymphomatoid granulomatosis]. / Granulomatose lymphomatoïde.

Lymphomatoid granulomatosis, described in 1972 by Liebow, is a rare, Epstein-Barr virus (EBV)-associated lymphoproliferative disorder, involving the lung, and often the skin or the central nervous system. It could have a systemic course making its diagnosis difficult. Controversy still remains about precise taxonomy and lymphomatoid granulomatosis is classified as a lymphoma, whose severity extends from indolent forms to aggressive large B cell lymphomas. Histology is essential and shows characteristically an inflammatory angiocentric infiltrate, composed with polymorphous mononucleated cells containing a varying number of large atypical CD20-positive B-lymphocytes within a background of numerous small reactive CD3-positive T-lymphocytes, often associated with necrosis. In situ hybridization often shows EBV RNA within atypical B-cells. Atypical large B-lymphocytes proportion and to a lesser degree EBV-positive B-lymphocytes proportion allow to classify the disease (grade I to III) and have a prognostic value. An aggressive form of B lymphoma occurs in 7 to 47% of cases during lymphomatoid granulomatosis course. Moreover, grade III diseases share numerous characteristics of lymphoma and often require chemotherapy. Several conditions mimic lymphomatoid granulomatosis, and include various hematologic malignancies (large B-cells lymphomas, T/NK lymphomas, post-immunodepression lymphoproliferative disorders) or granulomatosis with polyangiitis. The objective of this article is to review the clinical, radiological, histological and therapeutic characteristics of this rare disorder.

[Relapsed pulmonary lymphomatoid granulomatosis grade III: curative treatment with radioimmune therapy and autologous stem cell transplantation]. / Pulmonale lymphomatoide Granulomatose Grad III: kurativer Therapieansatz mit Radioimmuntherapie und autologer Stammzelltransplantation.

HISTORY AND ADMISSION FINDINGS: A 36-year-old woman presented with dyspnea, dry cough and severe chest pain. She had been treated for persistent shoulder pain for several months. Clinical findings were non-conclusive. Lactate dehydrogenase was slightly elevated, C-reactive protein was increased. INVESTIGATIONS: A chest X-ray and subsequent computed tomography (CT) scans showed a lesion measuring 10×8 cm in the right upper pulmonary lobe. A CT-guided biopsy was obtained and the histological examination revealed a dense lymphocytic infiltrate with abundant blasts in addition to areas of necrosis and fibrosis. These findings were consistent with lymphomatoid granulomatosis grade III. TREATMENT AND COURSE: After 6 cycles of rituximab, cyclophosphamide, doxorubicin, vincristin and prednisolone (R-CHOP), an early relapse developed which was treated with rituximab, ifosphamid, methotrexate and etoposide. Good partial remission was achieved after consolidating high-dose chemotherapy followed by autologous stem cell transplantation (ASCT). After two years of rituximab maintenance treatment positron emission tomography (PET-CT) revealed an increase of metabolic activity. A second high-dose therapy was then combined with Y-90 ibritumomab tiuxetan, which was well tolerated. During remission the previously present lymphoma lesion of the lung was resected. Histology did not reveal any residual active lymphomatoid granulomatosis. Complete remission has so far been maintained for one year after ASCT. CONCLUSIONS: Combination of Y-90 ibritumomab tiuxetan and high-dose chemotherapy followed by ASCT may offer an efficacious and well-tolerated targeted treatment approach for patients with relapsed lymphomatoid granulomatosis.

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.

[Lymphomatoid granulomatosis--a short description of an unusual case of the disease]. / Lymphomatoide Granulomatose--eine kurze Darstellung der Erkrankung anhand eines aussergewöhnlichen Falles.

Lymphomatoid granulomatosis (LYG) is a rare disease with an unknown pathogenesis. It is considered as a B-cell disorder with an uncertain malignant potential. The disease is classified as an angiocentric and angiodestructive lymphoproliferative disorder. EBV-association (LMP1) and the detection of the surface antigens CD20 and CD30 are the characteristic pathological findings. The lung, the nervous system, the kidneys and the liver are affected most frequently. In the present report the case of a 79-year-old man is described, who showed a cavity in the upper right lobe which was opened out into the trachea. The initial CXR and CT scan demonstrated a large nodular air space opacity (reversed halo sign) on the upper right area and a smaller one on the left side. In addition to CT and bronchoscopy, a surgical biopsy was performed to confirm the diagnosis of lymphomatoid granulomatosis. Treatment consisted in chemotherapy with rituximab, cyclophosphamide, vincristine and prednisolone (R-CVP). Three months after confirmation of diagnosis the patient died of an abscess-forming pneumonia.

A case of lymphomatoid granulomatosis followed for 14 months on the basis of clinical and histological findings.

Lymphomatoid granulomatosis (LYG) is a systemic granulomatous disease characterized by B-cell proliferation of uncertain malignant potential. It most frequently affects the lungs but also occasionally affects the central nervous system. Its pathophysiology is unclear in numerous respects, thus making it difficult to diagnose and treat. We recently encountered a case of LYG that was followed clinically and histologically for 14 months. A 55-year-old man was hospitalized with multiple brain tumors for which the final diagnosis was not made until the second surgery, 14 months after the first intervention. Following the diagnosis, he was treated with steroid pulse therapy. At present, 3.5 years after the onset of LYG, the patient is in good condition with no signs of tumor recurrence. Although LYG is usually graded on the basis of histological findings, this patient showed no histological changes or any increase in disease grade during the 14-month follow-up period.