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The World Health Organization (WHO) "Classification of Tumours of Haematopoietic and Lymphoid Tissues", published in 2001 and subsequently updated in 2008 and 2017, defined disease entities based on morphologic and phenotypic characteristics, clinical features, and genomic findings. Recently, the criteria for the diagnosis of many lymphoma entities have been refined in a proposal by the International Consensus Classification (ICC). Some provisional categories have now been recognized as "definite" entities, while other categories have undergone major revision. This article reports on the major revisions in the criteria and definition of B- and T-/NK-cell lymphomas by the ICC system. [ABSTRACT FROM AUTHOR]

Objectives: Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma derived from T-follicular helper cells. For pathologists, diagnosing AITL may be challenging due to its wide clinical and histopathologic spectrum, which can mimic a variety of reactive and neoplastic processes.Methods: We summarize and discuss the clinicopathologic features of AITL, emphasizing diagnostic tools available to the practicing pathologist. Common diagnostic dilemmas are discussed.Results: AITL exhibits various histologic patterns and is often associated with a prominent microenvironment that can obscure the neoplastic cells. Atypical B-cell proliferations, which can take a number of forms, are common in AITL, and clonal B-cell expansion can be seen. The atypical B cells can closely resemble Hodgkin/Reed-Sternberg cells, leading to misdiagnosis as classic Hodgkin lymphoma. Molecular studies have revealed recurrent genetic alterations, which can aid in differential diagnosis, particularly in problematic cases.Conclusions: Given the complex diagnostic challenges in AITL, an integrated approach, incorporating clinical, morphologic, immunophenotypic, and molecular findings, is helpful to reach an accurate diagnosis. [ABSTRACT FROM AUTHOR]

Intravascular large B cell lymphoma (IVLBCL) is a rare, aggressive, extranodal large B cell lymphoma characterised by growth of tumour cells within the lumen of vessels, particularly capillaries. Programmed cell death ligand 1 (PD‐L1) is a cell surface glycoprotein that interacts with programmed death 1 (PD‐1) on the T cell surface, leading to modulation of the immune response. PD‐L1 is a targetable immune check‐point molecule that is expressed on neoplastic cells in various cancers, including a subset of lymphomas. We correlated the expression of PD‐L1 with clinical and pathological findings in this rare disease. Eleven cases of IVLBCL were identified in the archives of Laboratory of Pathology at the National Cancer Institute, NIH. A panel of immunostains (CD20, CD3, CD5, PD‐L1) was performed. The cases were classified as the classic form or the variant associated with haemophagocytic syndrome (HPS) based on published 2017 WHO criteria. Three cases (27.3%) were HPS variant and eight cases (72.7%) were the classic form. Five (45.5%) of 11 cases were CD5‐positive; two of three (66%) were HPS variants and three of eight (37.5%) were classic form. Overall, four of nine evaluable cases (44.4%) were positive for PD‐L1, three of which were classic. Only one CD5‐positive case was PD‐L1‐positive, a classic variant. In summary, a subset of IVLBCL express PD‐L1. Although limited, these data suggest that PD‐L1 is expressed in both the so‐called classic form as well as the HPS variant. PD‐L1 is expressed irrespective of CD5 expression. Finally, detection of PD‐L1 expression in a subset of IVLBCL lymphoma cases may identify patients who might benefit from targeted immunotherapy. [ABSTRACT FROM AUTHOR]

Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8-negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti-interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as secondand third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future. [ABSTRACT FROM AUTHOR]

Objectives: The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology aimed to review primary immunodeficiency and related lymphoproliferations. Methods: Primary immunodeficiencies were divided into immune dysregulation, DNA repair defects, low immunoglobulins, and combined immunodeficiencies. Results: Autoimmune lymphoproliferative syndrome (ALPS) is a prototypical immune dysregulation-type immunodeficiency, with defects in T-cell signaling or apoptosis, expansion of T-cell subsets, and predisposition to hemophagocytic lymphohistiocytosis. DNA repair defects directly predispose to malignancy. Low immunoglobulin immunodeficiencies such as common variable immunodeficiency (CVID) have underlying T-cell repertoire abnormalities predisposing to autoimmunity and B-cell lymphoproliferations. The full spectrum of B-cell lymphoproliferative disorders occurs in primary immunodeficiency. Conclusions: Lymphoproliferations in primary immunodeficiency mirror those in other immunodeficiency settings, with monomorphic B- and sometimes T lymphoproliferative disorders enriched in DNA repair defects. Distinctive T-cell subset expansions in ALPS, CVID, and related entities can mimic lymphoma, and recognition of double-negative T-cell or cytotoxic T-cell expansions is key to avoid overdiagnosis. [ABSTRACT FROM AUTHOR]

Objectives: The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology aimed to review primary immunodeficiency and related lymphoproliferations.Methods: Primary immunodeficiencies were divided into immune dysregulation, DNA repair defects, low immunoglobulins, and combined immunodeficiencies.Results: Autoimmune lymphoproliferative syndrome (ALPS) is a prototypical immune dysregulation-type immunodeficiency, with defects in T-cell signaling or apoptosis, expansion of T-cell subsets, and predisposition to hemophagocytic lymphohistiocytosis. DNA repair defects directly predispose to malignancy. Low immunoglobulin immunodeficiencies such as common variable immunodeficiency (CVID) have underlying T-cell repertoire abnormalities predisposing to autoimmunity and B-cell lymphoproliferations. The full spectrum of B-cell lymphoproliferative disorders occurs in primary immunodeficiency.Conclusions: Lymphoproliferations in primary immunodeficiency mirror those in other immunodeficiency settings, with monomorphic B- and sometimes T lymphoproliferative disorders enriched in DNA repair defects. Distinctive T-cell subset expansions in ALPS, CVID, and related entities can mimic lymphoma, and recognition of double-negative T-cell or cytotoxic T-cell expansions is key to avoid overdiagnosis. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a CD30-positive T-cell non-Hodgkin lymphoma that morphologically resembles ALK-positive ALCL but lacks chromosomal rearrangements of the ALK gene. The genetic and clinical heterogeneity of ALK-negative ALCL has not been delineated. We performed immunohistochemistry and fluorescence in situ hybridization on 73 ALK-negative ALCLs and 32 ALK-positive ALCLs and evaluated the associations among pathology, genetics, and clinical outcome. Chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8% of ALK-negative ALCLs, respectively. These rearrangements were mutually exclusive and were absent in ALK-positive ALCLs. Five-year overall survival rates were 85% for ALK-positive ALCLs, 90% for DUSP22-rearranged ALCLs, 17% for TP63-rearranged ALCLs, and 42% for cases lacking all 3 genetic markers (P < .0001). Hazard ratios for death in these 4 groups after adjusting for International Prognostic Index and age were 1.0 (reference group), 0.58, 8.63, and 4.16, respectively (P = 7.10 x 10-5). These results were similar when restricted to patients receiving anthracycline-based chemotherapy, as well as to patients not receiving stem cell transplantation. Thus, ALK-negative ALCL is a genetically heterogeneous disease with widely disparate outcomes following standard therapy.DUSP22 and TP63 rearrangements may serve as predictive biomarkers to help guide patient management. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) is a disease with distinctive clinical findings, as well as a unique morphology and immunophenotype. These features typically allow for a reliable and reproducible diagnosis in nearly all situations. However, certain morphological features of HCL, such as villous cytoplasmic projections or characteristic tissue specific infiltrative patterns, including red pulp expansion with pseudosinuses, may be seen in other B-cell lymphoproliferative disorders. A methodical and thorough approach evaluating the clinical, cytological, histological, architectural, and immunophenotypic features is described and will aid in rendering the appropriate diagnosis. This is paramount as current data indicate that hairy cell leukemia -- variant and other splenic B-cell lymphomas must be distinguished from HCL, as the response to therapy differs in these disorders. [ABSTRACT FROM AUTHOR]

Natural killer cell malignancies, although increasingly recognized, remain rare tumors within the USA and Europe. They are somewhat more common in Asia, and have been best characterized within this population. We present a case of a young Caucasian woman who presented acutely with an aggressive natural killer cell leukemia/lymphoma. Use of Telesynergy™ technology enabled a transatlantic telemedicine conference with colleagues in a center of expertise. Unfortunately the patient was ultimately refractory to both conventional chemotherapy and Campath-1H and her disease course was fulminant, as has been described previously in this condition. We review the possible therapeutic options for this extremely aggressive malignancy and briefly discuss our center's experience of telemedicine technology. [ABSTRACT FROM AUTHOR]

the article focuses on follicular lymphoma (FL) disease. Topics discussed include talks about lymphoid cells which expressed homing receptor found on normal mucosal T and B lymphocytes as well as lymphomas of mucosal-associated lymphoid tissue (MALT); lymphoid cells use gene expression profiling of paraffin embedded sections to examine a panel of cytokines and chemokines; and mentions microenvironment relevant to the disease pathophysiology.

Examines the common threads of mucosa-associated lymphoid tissue lymphoma pathogenesis from infection to translocation. Occurrence of essential mixed cryoglobulinemia associated with chronic hepatitis virus C infection; Development of autonomous clonal proliferation; Process of recapitulation of the normal immune response and normal lymphocyte development.

Summary: Peripheral T‐cell lymphomas (PTCL) are morphologically and biologically heterogeneous and a subset expresses CD30, including anaplastic large cell lymphomas (ALCL) and a minority of PTCL, not otherwise specified (PTCL, NOS). ALCL with ALK translocations (ALCL, ALK+) are readily identified by routine diagnostic methods, but differentiating ALCL without ALK translocation (ALCL, ALK−) and PTCL, NOS expressing CD30 (PTCL CD30+) can be challenging. Furthermore, rare PTCL co‐express CD30 and CD15 (PTCL CD30+CD15+); some resemble ALCL, ALK− while others resemble classic Hodgkin lymphoma. To explore the relationship between PTCL CD30+CD15+ and ALCL, ALK−, we analysed 19 cases of PTCL with CD30 expression, previously diagnosed as ALCL, ALK− (nine cases) and PTCL CD30+CD15+ (10 cases) for DUSP22/IRF4 rearrangements, coding RNA expression and selected transcriptome analysis using the NanoString nCounter gene expression analysis platform. Unsupervised clustering showed no clear segregation between ALCL, ALK− and PTCL CD30+CD15+. Three cases previously classified as PTCL CD30+CD15+ showed DUSP22/IRF4 rearrangements, favouring a diagnosis of ALCL, ALK−. Our results suggest that cases previously designated PTCL CD30+CD15+, likely fall within the spectrum of ALCL, ALK−; additionally, a subset of ALCL, ALK− with DUSP22/IRF4 rearrangement expresses CD15, consistent with previous reports and expands the immunophenotypic spectrum of this lymphoma subgroup. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article about mucocutaneous ulcer in immunodeficiency setting.

The article presents a case study of a 52-year-old man who had an enlarged left axillary lymph node. It discusses cohesive growth of atypical large lymphoid cells with multilobated nuclei and abundant cytoplasm as shown in hematoxylin and eosin staining as well as provides information on anaplastic T-cell lymphoma and classical Hodgkin lymphoma

The article offers information on a 36-year-old woman with hyperpigmented discoid lesions on her thighs and hands including formation of Pautrier-like microabscesses due to epidermal infiltration by lymphoid cells, positive results for CD3 in neoplastic cells and presents images related to the same.

Editorial. Discusses the problems associated with the diagnosis of primary central nervous lymphoma (PCNSL) in acquire immune deficiency syndrome (AIDS) patients. Presence of central nervous system (CNS) lesions in AIDS patients; Information on other medical conditions which show CNS lesions; Separation of PCNSL from these medical conditions; Reference to the frequency of PCNSL in AIDS patients.

As we have previously discussed,[[2]] the term "plasmablasts" has been widely used in the literature to describe the KSHV-infected B-lineage cells in the lymph nodes of KSHV-MCD, although it may be debatable whether these cells truly represent plasmablasts. Abbreviations DLBCL diffuse large B-cell lymphoma FITC fluorescein isothiocyanate FMO Fluorescence Minus One FSC forward scatter H&E haematoxylin and eosin HHV8 human herpesvirus 8 Ig immunoglobulin KSHV Kaposi sarcoma-associated herpesvirus LANA-1 latency associated nuclear antigen-1 LRP lambda-restricted plasmablastic population MCD multicentric Castleman disease PEL primary effusion lymphoma SSC side scatter We appreciate the insightful comments by Vanjak et al. regarding our recent publication 'A novel approach for characterization of KSHV-associated multicentric Castleman disease from effusions'.[1] In our report, we used a broad definition of "plasmablasts" to describe the Kaposi sarcoma-associated herpesvirus (KSHV)-infected, lambda-restricted B-lineage cells in KSHV-associated multicentric Castleman disease (KSHV-MCD), referred to as the lambda-restricted plasmablastic population (LRP) in the publication. The normal B cells were negative for LANA-1 and served as an internal negative control. gl Vanjak et al. raised an important point regarding the specificity of the flow cytometry-based analysis in differentiating between KSHV-MCD and other KSHV-associated lymphoproliferations, including PEL and KSHV/human herpesvirus 8 (HHV8)-positive diffuse large B-cell lymphoma (KSHV/HHV8 SP + sp DLBCL). [Extracted from the article]

Objectives: The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology aimed to review immunodeficiency-related T- and natural killer (NK)-cell lymphoproliferations.Methods: The Workshop Panel reviewed 88 T- or NK-cell lymphoproliferations and rendered consensus diagnoses.Results: Hyperplasias of T-cell subsets may be clonal; retained architecture and the clinical setting support a benign diagnosis. Specific associations include hepatosplenic T-cell lymphoma with iatrogenic immunosuppression and breast implants with an indolent variant of anaplastic large cell lymphoma. Epstein-Barr virus (EBV)-positive T-cell lymphomas rarely occur in the acquired immunodeficiency setting. Systemic T- and NK-cell lymphoma of childhood overlaps with chronic active EBV and reversible hemophagocytic lymphohistiocytosis-related T-cell lymphoproliferations.Conclusions: Immunodeficiencies predispose to T-cell hyperplasias, which must not be overdiagnosed as lymphoma. Many T-cell lymphomas in the immunodeficiency setting are likely coincidental, with specific exceptions. Systemic T- or NK-cell lymphomas are part of a spectrum of EBV+ T or NK lymphoproliferations and can present in the acquired immunodeficiency setting. [ABSTRACT FROM AUTHOR]

Summary: A biopsy of lymphoid tissue is currently required to diagnose Kaposi sarcoma‐associated herpesvirus (KSHV)‐associated multicentric Castleman disease (KSHV–MCD). Patients showing clinical manifestations of KSHV–MCD but no pathological changes of KSHV–MCD are diagnosed as KSHV inflammatory cytokine syndrome. However, a lymph node biopsy is not always feasible to make the distinction. A pathognomonic feature of lymph nodes in KSHV–MCD is the expansion of KSHV‐infected, lambda‐restricted but polyclonal plasmablasts. To investigate whether these cells also reside in extra‐nodal sites, effusion from 11 patients with KSHV–MCD and 19 with KSHV inflammatory cytokine syndrome was analysed by multiparametric flow cytometry. A distinct, lambda‐restricted plasmablastic population (LRP) with highly consistent immunophenotype was detected in effusions in 8/11 patients with KSHV–MCD. The same population was also observed in 7/19 patients with KSHV inflammatory cytokine syndrome. The detection of LRP stratified KSHV inflammatory cytokine syndrome into two clinically distinct subgroups; those with detectable LRP closely resembled KSHV–MCD, showing similar KSHV viral load, comparable severity of thrombocytopenia and hypoalbuminaemia, and similar incidences of hepatosplenomegaly. Collectively, the detection of LRP by flow cytometry can serve as a valuable tool in diagnosing KSHV–MCD. KSHV inflammatory cytokine syndrome with LRP in effusions may represent a liquid‐form of KSHV–MCD. [ABSTRACT FROM AUTHOR]

Nodal peripheral T cell lymphoma (PTCL) with T follicular helper (TFH) cell phenotype is a provisional entity added to the 2016 revised WHO classification of haematological malignancies. These lymphomas have an aggressive clinical course and respond poorly to conventional treatments. Distinct histological features have not been well described. Additionally, the minimum criteria for diagnosis is not well established but detection of at least two TFH markers in addition to CD4 is suggested to assign a TFH cell phenotype. Some pathological features of angioimmunoblastic T cell lymphoma (AITL) such as recurrent molecular alterations are commonly found. As the name suggests, these lymphomas are nodal in origin with patients presenting with widespread lymphadenopathy. We describe the first documented case of nodal PTCL with a TFH phenotype presenting as an isolated mesenteric mass with no nodal involvement. [ABSTRACT FROM AUTHOR]

Acquired generalized lipodystrophy (AGL) is a rare disease thought to result from autoimmune destruction of adipose tissue. Peripheral T-cell lymphoma (PTCL) has been reported in two AGL patients. We report five additional cases of lymphoma in AGL, and analyze the role of underlying autoimmunity and recombinant human leptin (metreleptin) replacement in lymphoma development. Three patients developed lymphoma during metreleptin treatment (two PTCL and one ALK-positive anaplastic large cell lymphoma), and two developed lymphomas (mycosis fungoides and Burkitt lymphoma) without metreleptin. AGL is associated with high risk for lymphoma, especially PTCL. Autoimmunity likely contributes to this risk. Lymphoma developed with or without metreleptin, suggesting metreleptin does not directly cause lymphoma development; a theoretical role of metreleptin in lymphoma progression remains possible. For most patients with AGL and severe metabolic complications, the proven benefits of metreleptin on metabolic disease will likely outweigh theoretical risks of metreleptin in lymphoma development or progression. [ABSTRACT FROM AUTHOR]

Germinal centre B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is a common malignancy, yet the signalling pathways that are deregulated and the factors leading to its systemic dissemination are poorly defined. Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a Gα12 and Gα13 coupled receptor, promotes growth regulation and local confinement of germinal centre B cells. Recent deep sequencing studies of GCB-DLBCL have revealed mutations in many genes in this cancer, including in GNA13 (encoding Gα13) and S1PR2 (refs 5,6, 7). Here we show, using in vitro and in vivo assays, that GCB-DLBCL-associated mutations occurring in S1PR2 frequently disrupt the receptor's Akt and migration inhibitory functions. Gα13-deficient mouse germinal centre B cells and human GCB-DLBCL cells were unable to suppress pAkt and migration in response to S1P, and Gα13-deficient mice developed germinal centre B-cell-derived lymphoma. Germinal centre B cells, unlike most lymphocytes, are tightly confined in lymphoid organs and do not recirculate. Remarkably, deficiency in Gα13, but not S1PR2, led to germinal centre B-cell dissemination into lymph and blood. GCB-DLBCL cell lines frequently carried mutations in the Gα13 effector ARHGEF1, and Arhgef1 deficiency also led to germinal centre B-cell dissemination. The incomplete phenocopy of Gα13- and S1PR2 deficiency led us to discover that P2RY8, an orphan receptor that is mutated in GCB-DLBCL and another germinal centre B-cell-derived malignancy, Burkitt's lymphoma, also represses germinal centre B-cell growth and promotes confinement via Gα13. These findings identify a Gα13-dependent pathway that exerts dual actions in suppressing growth and blocking dissemination of germinal centre B cells that is frequently disrupted in germinal centre B-cell-derived lymphoma. [ABSTRACT FROM AUTHOR]

The article discusses the importance of pathology in cancer research. The advent of molecular biology broke the association between cancer research and pathology as healthcare practitioners became more interested in tumor's molecular alterations. The authors says that a multidisciplinary approach in translational research that combines pathology and molecular biology is needed to better understand cancerous tumors.

The article presents an overview of mycosis fungoides and Sézary syndrome, which are the most common cutaneous T-cell lymphomas which affect the skin as a primary site and are a heterogeneous group of neoplasms. A discussion of the causes of the fungoides, which remain unknown, and of the prognosis of patients who have them, is presented. Experimental treatments which may eventually be used to cure the fungoides are discussed. The epidemiology, genetic basis of and management of the fungoides is examined.

Background The introduction of new treatments for hairy cell leukemia has resulted in improved patient survival but also engendered increasing concern about the possibility of excess second cancers. The available evidence is conflicting, with most risk estimates based on sparse numbers. To our knowledge, no study has evaluated cause-specific mortality in patients with hairy cell leukemia. Methods We quantified second cancer incidence and cause-specific mortality among 3104 two-month survivors of hairy cell leukemia who were reported to 16 population-based registries in the Surveillance, Epidemiology and End Results (SEER) Program between 1973 and 2002. Standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) were used to quantify the risk of second cancers and causes of death, respectively. The cumulative probability of a second cancer among survivors of hairy cell leukemia was calculated using a competing risk model. All statistical tests were two-sided. Results Mean follow-up of hairy cell leukemia survivors was 6.5 years (range, 2 months-29.3 years). Second cancer risk was statistically significantly elevated (SIR = 1.24, 95% confidence interval [CI] = 1.11 to 1.37) compared with the general population. Survivors had statistically significantly higher risks of Hodgkin lymphoma (SIR = 6.61, 95% CI = 2.13 to 15.42), non-Hodgkin lymphoma (SIR = 5.03, 95% CI = 3.77 to 6.58), and thyroid cancer (SIR = 3.56, 95% CI = 1.30 to 7.74) and a lower risk of lung cancer (SIR = 0.63, 95% CI = 0.42 to 0.90). The cumulative probability of all second cancers was estimated to be 31.9% (95% CI = 26.2 to 37.6) 25 years after hairy cell leukemia diagnosis. Among 10000 hairy cell leukemia patients, a total excess of about 34 cancers, including 21 non-Hodgkin lymphomas, 2 Hodgkin lymphomas, and 7 solid tumors (including 2 thyroid cancers), might be observed per year. Deaths due to solid tumors were not elevated compared with the general population (SMR = 0.9), and there were statistically significant deficits in mortality due to both cardiovascular (SMR = 0.67, 95% CI = 0.56 to 0.80) and cerebrovascular (SMR = 0.61, 95% CI = 0.38 to 0.93) disease. Conclusions Patients with hairy cell leukemia are at increased risk of Hodgkin lymphoma, non-Hodgkin lymphoma, and thyroid cancer. The decrease in lung cancer incidence and smoking-associated vascular mortality may reflect an inverse association of tobacco use with hairy cell leukemia. Future studies should address the roles of immunologic impairment inherent to hairy cell leukemia, treatment modalities, and other factors as codeterminants of morbidity and mortality in hairy cell leukemia survivors. [ABSTRACT FROM AUTHOR]

Presents a study on the incidence, presentation, and prognosis of HIV-associated non-Hodgkin lymphoma (HIV-NHL). Highly active antiretroviral therapy (HAART) and the lifetime incidence of HIV-NHL; Factors used to establish the prognosis of patients with HIV-NHL; Major categories of HIV-associated lymphomas; Concerns raised by concomitant therapies.

Objective: To describe the incidence of non-Hodgkin lymphoma in a group of patients with symptomatic human immunodeficiency virus (HIV) infection receiving long-term dideoxynucleoside antiretroviral therapy.Design: We examined the records of all patients with the acquired immunodeficiency syndrome (AIDS) or severe AIDS-related complex who were entered into three long-term phase I trials of zidovudine (azidothymidine, AZT) or zidovudine-containing regimens at the National Cancer Institute between 1985 and 1987.Setting: The Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland.Participants: Fifty-five HIV-infected patients with AIDS or severe AIDS-related complex.Measurements and Main Results: Eight of fifty-five patients (14.5%; 95% CI, 6.5% to 26.7%) developed a high-grade non-Hodgkin lymphoma of B-cell type, a median of 23.8 months (range, 13 to 35 months) after starting antiretroviral treatment. Using the method of Kaplan and Meier, the estimated probability of developing lymphoma by 30 months of therapy was 28.6% (CI, 13.7% to 50.3%) and by 36 months, 46.4% (CI, 19.6% to 75.5%). The patients who developed lymphoma had less than 100 T4 cells/mm3 for a median of 17.8 months (range, 7 to 35 months) and less than 50 T4 cells/mm3 for a median of 15.3 months (range, 5.5 to 35 months) before the diagnosis. All patients presented with non-Hodgkin lymphoma in extranodal sites, and two developed primary brain involvement in the setting of Toxoplasma infection.Conclusion: Patients with symptomatic HIV infection who survive for up to 3 years on antiretroviral therapy may have a relatively high probability of developing non-Hodgkin lymphoma. Prolonged survival in the setting of profound immunosuppression with substantial T4-cell depletion is probably an important factor in the development of these lymphomas. However, a direct role of therapy itself cannot be totally discounted. As improved therapies for the treatment of HIV infection and its complications result in prolonged survival, non-Hodgkin lymphoma may become an increasingly significant problem. [ABSTRACT FROM AUTHOR]

Focuses on angioimmunoblastic lymphadenopathy with dysproteinemia affecting the lymph nodes. Description of the disorder; Requirements for diagnosis; Details of how the disease develops; Prognosis of the disorder; Findings from treatment with corticosteroid and immunosuppressive agents.

Epstein-Barr virus (EBV) normally infects B cells, but in some persons the virus infects T or NK cells. Infection of B cells can result in infectious mononucleosis, and the virus is associated with several B cell malignancies including Hodgkin lymphoma, Burkitt lymphoma, and diffuse large B cell lymphoma. Infection of T or NK cells with EBV is associated with extranodal NK/T cell lymphoma, aggressive NK-cell leukemia, systemic EBV-associated T-cell lymphoma, and chronic active EBV disease, which in some cases can include hydroa vacciniforme-like lymphoproliferative disease and severe mosquito bite allergy. While NK and T cell lymphoproliferative disease is more common in Asia and Latin America, increasing numbers of cases are being reported from the United States and Europe. This review focuses on classification, clinical findings, pathogenesis, and recent genetic advances in NK and T cell lymphoproliferative diseases associated with EBV. [ABSTRACT FROM AUTHOR]

We initially considered a diagnosis of anaplastic large cell lymphoma, ALK-negative, when evaluating the excisional biopsy performed 7.5 years following the initial biopsy. Sheets of large anaplastic cells, strong expression of CD30 and CD4 and lack of B cell marker expression supported this impression. EBV infection is known to up-regulate CD30 and can down-regulate B cell programme expression, and rare cases of EBV-positive CD30/CD4 SP + sp large cell lymphoma arising from chronic lymphocytic leukaemia have been described.[16]. [Extracted from the article]

To evaluate the feasibility and clinical efficacy of the combination of alemtuzumab with dose-adjusted etoposide/cyclophosphamide/doxorubicin/vincristine/prednisone (DA-EPOCH) as upfront therapy for untreated aggressive T and NK cell lymphomas, a phase 1/2 trial was conducted. Thirty patients were treated with the study regimen, consisting of alemtuzumab on day 1 of a 21 day cycle with standard dosing of DA-EPOCH for 6–8 cycles. Alemtuzumab 30 mg IV was used for the phase 2 component. Of 30 treated patients, 17 had a complete response (CR) and eight had a partial response (83.3% overall response rate). The median overall survival and progression-free survival were 20.2 and 6.6 months, respectively. There were five treatment-related deaths on study mainly due to infectious complications, including one case each of disseminated toxoplasmosis and pneumonia and two cases of sepsis. Alemtuzumab with DA-EPOCH is of limited clinical utility due to unacceptable toxicity, despite the high rate of CR. [ABSTRACT FROM AUTHOR]

Indolent T-cell lymphoproliferative disorder (T-LPD) of the gastrointestinal (GI) tract is a new provisional entity in the 2016 revision of the World Health Organization classification. The disease has an indolent course and progression to aggressive T-cell lymphoma has rarely been reported. We describe a case of a 37-year-old male with indolent T-LPD of the GI tract who 3 years later developed aggressive T-cell lymphoma and died of progressive disease. An infiltrate of indolent T-LPD in the GI tract and aggressive lymphoma diagnosed from the liver biopsy had similar immunophenotype, but cellular infiltrate in the liver showed more atypia compared with the GI biopsies of indolent T-LPD. Moreover, T-cell gene rearrangement studies showed an identical clonal rearrangement in indolent T-LPD and aggressive lymphoma. Patients with indolent T-LPD of the GI tract need a long-term follow-up, as some of them may develop more aggressive lymphoma. [ABSTRACT FROM AUTHOR]

Summary: The Hodgkin lymphomas are a family of unique lymphoma subtypes, in which the nature of the neoplastic cell was enigmatic for many years. Much of the mystery has been solved, with all forms now considered to be of B‐cell origin, in most cases of germinal centre derivation. Today we recognize Hodgkin lymphoma as an eponym that encompasses multiple entities. One of the unifying themes is the major contribution from the tumour microenvironment. Both the character of the neoplastic cells and the nature of the immune environment are critical to accurate diagnosis. Moreover, an understanding of the molecular alterations that characterize both the neoplastic cells and their microenvironment have led to therapeutic advances, targeting both neoplastic and reactive components. Other conditions may foster a similar inflammatory milieu and lead to lymphoproliferations that mimic the Hodgkin lymphomas. In this review we provide an update on the diagnostic features of the various subtypes and include additional information relevant for prognostic evaluation and investigation of potential therapeutic targets. Additionally, we also discuss those conditions that often cause confusion in diagnosis and need to be distinguished from the Hodgkin lymphomas. [ABSTRACT FROM AUTHOR]

Immunodeficiency-associated lymphoproliferative disorders (IA-LPDs) are pathologically and clinically heterogeneous. In many instances, similar features are shared by a spectrum of IA-LPDs in clinically diverse settings. However, the World Health Organization (WHO) classifies IA-LPDs by their immunodeficiency setting largely according to the paradigm of posttransplant lymphoproliferative disorders but with inconsistent terminology and disease definitions. The field currently lacks standardization and would greatly benefit from thinking across immunodeficiency categories by adopting a common working vocabulary to better understand these disorders and guide clinical management. We propose a 3-part unifying nomenclature that includes the name of the lesion, associated virus, and the specific immunodeficiency setting for all IA-LPDs. B-cell lymphoproliferative disorders (LPDs) are usually Epstein-Barr virus (EBV)1 and show a spectrum of lesions, including hyperplasias, polymorphic LPDs, aggressive lymphomas, and, rarely, indolent lymphomas. Human herpes virus 8-associated LPDs also include polyclonal and monoclonal proliferations. EBV2 B-cell LPDs and T- and NK-cell LPDs are rare and less well characterized. Recognition of any immunodeficiency is important because it impacts the choice of treatment options. There is an urgent need for reappraisal of IA-LPDs because a common framework will facilitate meaningful biological insights and pave the way for future work in the field. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy, but some patients have a very indolent evolution. This heterogeneous course is related, in part, to the different biological characteristics of conventional MCL (cMCL) and the distinct subgroup of leukemic nonnodal MCL (nnMCL). Robust criteria to distinguish these MCL subtypes and additional biological parameters that influence their evolution are not well defined. We describe a novel molecular assay that reliably distinguishes cMCL and nnMCL using blood samples. We trained a 16-gene assay (L-MCL16 assay) on the NanoString platform using 19 purified leukemic samples. The locked assay was applied to an independent cohort of 70 MCL patients with leukemic presentation. The assay assigned 37% of cases to nnMCL and 56% to cMCL. nnMCL and cMCL differed in nodal presentation, lactate dehydrogenase, immunoglobulin heavy chain gene mutational status, management options, genomic complexity, and CDKN2A/ATM deletions, but the proportion with 17p/TP53 aberrations was similar in both subgroups. Sequential samples showed that assay prediction was stable over time. nnMCL had a better overall survival (OS) than cMCL (3-year OS 92% vs 69%; P = .006) from the time of diagnosis and longer time to first treatment. Genomic complexity and TP53/CDKN2A aberrations predicted for shorter OS in the entire series and cMCL, whereas only genomic complexity was associated with shorter time to first treatment and OS in nnMCL. In conclusion, the newly developed assay robustly recognizes the 2 molecular subtypes of MCL in leukemic samples. Its combination with genetic alterations improves the prognostic evaluation and may provide useful biological information for management decisions. [ABSTRACT FROM AUTHOR]

Human gammaherpesviruses are associated with malignancies in HIV infected individuals; in macaques used in non-human primate models of HIV infection, gammaherpesvirus infections also occur. Limited data on prevalence and tumorigenicity of macaque gammaherpesviruses, mostly cross-sectional analyses of small series, are available. We comprehensively examine all three-rhesus macaque gammaherpesviruses -Rhesus rhadinovirus (RRV), Rhesus Lymphocryptovirus (RLCV) and Retroperitoneal Fibromatosis Herpesvirus (RFHV) in macaques experimentally infected with Simian Immunodeficiency Virus or Simian Human Immunodeficiency Virus (SIV/SHIV) in studies spanning 15 years at the AIDS and Cancer Virus Program of the Frederick National Laboratory for Cancer Research. We evaluated 18 animals with malignancies (16 lymphomas, one fibrosarcoma and one carcinoma) and 32 controls. We developed real time quantitative PCR assays for each gammaherpesvirus DNA viral load (VL) in malignant and non-tumor tissues; we also characterized the tumors using immunohistochemistry and in situ hybridization. Furthermore, we retrospectively quantified gammaherpesvirus DNA VL and SIV/SHIV RNA VL in longitudinally-collected PBMCs and plasma, respectively. One or more gammaherpesviruses were detected in 17 tumors; generally, one was predominant, and the relevant DNA VL in the tumor was very high compared to surrounding tissues. RLCV was predominant in tumors resembling diffuse large B cell lymphomas; in a Burkitt-like lymphoma, RRV was predominant; and in the fibrosarcoma, RFHV was predominant. Median RRV and RLCV PBMC DNA VL were significantly higher in cases than controls; SIV/SHIV VL and RLCV VL were independently associated with cancer. Local regressions showed that longitudinal VL patterns in cases and controls, from SIV infection to necropsy, differed for each gammaherpesvirus: while RFHV VL increased only slightly in all animals, RLCV and RRV VL increased significantly and continued to increase steeply in cases; in controls, VL flattened. In conclusion, the data suggest that gammaherpesviruses may play a significant role in tumorogenesis in macaques infected with immunodeficiency viruses. [ABSTRACT FROM AUTHOR]

The article discusses the phase 1 dose escalation research of siplizumab, an anti-CD2 monoclonal antibody, for the treatment of aggressive peripheral T-cell lymphomas (PTCL). Topics discussed include the inferior overall survival (OS) and progression-free survival (PFS) of T and natural-killer (NK)-cell neoplasms and the feasibility and safety of administering siplizumab with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab in PTCL patients.

The adult high-grade B-cell lymphomas sharing molecular features with Burκitt lymphoma (BL) arehighly aggressivelymphomaswithpoor clinicaloutcome. High-resolutionstructural and functional genomic analysis of adult Burκitt lymphoma (BL) and high-grade B-cell lymphoma with BL gene signature (adult-molecularly defined BL [mBL]) revealed the MYCARF- p53 axis as the primary deregulated pathway. Adult-mBL had either unique or more frequent genomic aberrations (del13q14, del17p, gain8q24 and gain18q21) compared with pediatric-mBL, but shared commonly mutated genes. Mutations in genes promoting the tonic B-cell receptor (BCR)→PI3K pathway (TCF3 and ID3) did not differ by age, whereas effectors of chronic BCR→NF-κB signaling were associated with adult-mBL. A subset of adult-mBL had BCL2 translocation and mutation and elevated BCL2 mRNA and protein expression, but had a mutation profile similar to mBL. These double-hit lymphomas may have arisen from a tumor precursor that acquired both BCL2 and MYCtranslocations and/or KMT2D(MLL2)mutation. Gain/amplificationofMIR17HGandits paralogue lociwasobserved in 50% of adult-mBL. In vitro studies suggested miR-17∼92's role in constitutive activation of BCR signaling and sensitivity to ibrutinib. Overall integrative analysis identified an interrelated gene networκ affected by copy number andmutation, leading to disruption of the p53 pathway andtheBCR→PI3Kor NF-κBactivation,which canbe further exploited in vivobysmall-molecule inhibitors for effective therapy in adult-mBL. [ABSTRACT FROM AUTHOR]

Pediatric-type follicular lymphoma (PTFL) is a B-cell lymphoma with distinctive clinicopathological features. Recently, recurrent genetic alterations of potential importance for its pathogenesis that disrupt pathways associated with the germinal center reaction (TNFRSF14, IRF8), immune escape (TNFRSF14), and anti-apoptosis (MAP2K1) have been described. In an attempt to shed more light onto the pathogenesis of PTFL, an integrative analysis of these mutations was undertaken in a large cohort of 43 cases previously characterized by targeted next-generation sequencing and copy number array. Mutations in MAP2K1 were found in 49% (20/41) of the cases, second in frequency to TNFRSF14 alterations (22/41; 54%), and all together were present in 81% of the cases. Immunohistochemical analysis of the MAP2K1 downstream target extracellular signal-regulated kinase demonstrated its phosphorylation in the evaluable cases and revealed a good correlation with the allelic frequency of the MAP2K1 mutation. The IRF8 p.K66R mutation was present in 15% (6/39) of the cases and was concomitant with TNFRSF14 mutations in 4 cases. This hot spot seems to be highly characteristic for PTFL. In conclusion, TNFRSF14 and MAP2K1 mutations are the most frequent genetic alterations found in PTFL and occur independently in most cases, suggesting that both mutations might play an important role in PTFL lymphomagenesis. [ABSTRACT FROM AUTHOR]

Activating Janus kinase (JAK) and signal transducer and activator of transcription (STAT) mutations have been discovered in many T-cell malignancies, including anaplastic lymphoma kinase (ALK)- anaplastic large cell lymphomas (ALCLs). However, such mutations occur in a minority of patients. To investigate the clinical application of targeting JAK for ALK- ALCL, we treated ALK- cell lines of various histological origins with JAK inhibitors. Interestingly, most exogenous cytokine-independent cell lines responded to JAK inhibition regardless of JAK mutation status. JAK inhibitor sensitivity correlated with the STAT3 phosphorylation status of tumor cells. Using retroviral shRNA knockdown, we have demonstrated that these JAK inhibitorsensitive cells are dependent on both JAK1 and STAT3 for survival. JAK1 and STAT3 gain-of-function mutations were found in some, but not all, JAK inhibitor-sensitive cells. Moreover, the mutations alone cannot explain the JAK1/STAT3 dependency, given that wildtype JAK1 or STAT3 was sufficient to promote cell survival in the cells that had either JAK1or STAT3 mutations. To investigate whether other mechanisms were involved, we knocked down upstream receptors GP130 or IL-2Rγ. Knockdown of GP130 or IL-2Rγ induced cell death in selected JAK inhibitor-sensitive cells. High expression levels of cytokines, including IL-6, were demonstrated in cell lines as well as in primary ALK- ALCL tumors. Finally, ruxolitinib, a JAK1/2 inhibitor, was effective in vivo in a xenograft ALK- ALCL model. Our data suggest that cytokine receptor signaling is required for tumor cell survival in diverse forms of ALK- ALCL, even in the presence of JAK1/STAT3 mutations. Therefore, JAK inhibitor therapy might benefit patients with ALK- ALCL who are phosphorylated STAT3+. [ABSTRACT FROM AUTHOR]

Objectives: The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology submitted small and large B-cell lymphomas (BCLs), including classical Hodgkin lymphoma (CHL), in the context of immunodeficiency.Methods: Clinicopathologic and molecular features were studied to explore unifying concepts in malignant B-cell proliferations across immunodeficiency settings.Results: Cases submitted to the workshop spanned small BCLs presenting as nodal or extranodal marginal zone lymphoma and lymphoplasmacytic lymphoma, Epstein-Barr virus (EBV) positive in 75% of cases. Submitted large BCLs formed a spectrum from diffuse large B-cell lymphoma (DLBCL) to CHL across immunodeficiency settings. Additional studies demonstrated overexpression of PD-L1 and molecular 9p24 alterations in the large BCL spectrum and across different immunodeficiency settings.Conclusions: Small BCLs occur in all immunodeficiency settings, and EBV positivity is essential for their recognition as immunodeficiency related. Large BCLs include a spectrum from DLBCL to CHL across all immunodeficiency settings; immunohistochemical and molecular features are suggestive of shared pathogenetic mechanisms involving PD-L1 immune checkpoints. [ABSTRACT FROM AUTHOR]

Objectives: The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology aimed to review immunodeficiency-related lymphoproliferative disorders with plasmablastic and plasma cell differentiation.Methods: The workshop panel reviewed human herpes virus 8 (HHV8)/Kaposi sarcoma herpesvirus (KSHV)-associated lesions and other lesions exhibiting plasma cell differentiation, including plasmablastic proliferations with features of myeloma/plasmacytoma, plasmablastic neoplasms presenting in extranodal sites and effusion-based lymphomas, and rendered a consensus diagnosis.Results: The spectrum of HHV8/KSHV-associated proliferations ranged from multicentric Castleman disease (MCD) to MCD with plasmablastic aggregates to HHV8+ diffuse large B-cell lymphoma and germinotrophic lymphoproliferative disorder. Comparisons across effusion-based lymphomas with and without HHV8/KSHV and plasmablastic lymphomas in immunodeficient and immunocompetent patients were discussed.Conclusions: The presence or absence of HHV8/KSHV is a defining feature in disorders associated with Castleman disease, although their differential diagnosis and recognition of progression may be challenging. Plasmablastic proliferations overlap with myeloma/plasmacytoma as well as extranodal and effusion-based lymphomas. The involvement of Epstein-Barr virus is typically variable. [ABSTRACT FROM AUTHOR]

The article discusses the 2015 Workshop on Immunodeficiency and Dysregulation organized by the Society for Hematopathology (SH) and the European Association for Haematopathology (EAHP), focusing on lymphoproliferative disorders (LPDs), oncogenic viruses, and nomenclature.

Objectives: The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology aimed to review B-cell proliferations of varied malignant potential associated with immunodeficiency.Methods: The Workshop Panel reviewed all cases of B-cell hyperplasias, polymorphic B-lymphoproliferative disorders, Epstein-Barr virus (EBV)-positive mucocutaneous ulcer, and large B-cell proliferations associated with chronic inflammation and rendered consensus diagnoses. Disease definitions, boundaries with more aggressive B-cell proliferations, and association with EBV were explored.Results: B-cell proliferations of varied malignant potential occurred in all immunodeficiency backgrounds. Presentation early in the course of immunodeficiency and in younger age groups and regression with reduction of immunosuppression were characteristic features. EBV positivity was essential for diagnosis in some hyperplasias where other specific defining features were absent.Conclusions: This spectrum of B-cell proliferations show similarities across immunodeficiency backgrounds. Localized forms of immunodeficiency disorders arise in immunocompetent patients most likely due to chronic immune stimulation and, despite aggressive histologic features, often show indolent clinical behavior. [ABSTRACT FROM AUTHOR]

Summary Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive and largely incurable hematologic malignancy originating from plasmacytoid dendritic cells (pDCs). Using RNAi screening, we identified the E-box transcription factor TCF4 as a master regulator of the BPDCN oncogenic program. TCF4 served as a faithful diagnostic marker of BPDCN, and its downregulation caused the loss of the BPDCN-specific gene expression program and apoptosis. High-throughput drug screening revealed that bromodomain and extra-terminal domain inhibitors (BETis) induced BPDCN apoptosis, which was attributable to disruption of a BPDCN-specific transcriptional network controlled by TCF4-dependent super-enhancers. BETis retarded the growth of BPDCN xenografts, supporting their clinical evaluation in this recalcitrant malignancy. [ABSTRACT FROM AUTHOR]

A revision of the nearly 8-year-old World Health Organization classification of the lymphoid neoplasms and the accompanying monograph is being published. It reflects a consensus among hematopathologists, geneticists, and clinicians regarding both updates to current entities as well as the addition of a limited number of new provisional entities. The revision clarifies the diagnosis and management of lesions at the very early stages of lymphomagenesis, refines the diagnostic criteria for some entities, details the expanding genetic/molecular landscape of numerous lymphoid neoplasms and their clinical correlates, and refers to investigations leading to more targeted therapeutic strategies. The major changes are reviewed with an emphasis on the most important advances in our understanding that impact our diagnostic approach, clinical expectations, and therapeutic strategies for the lymphoid neoplasms. [ABSTRACT FROM AUTHOR]