Revised World Health Organization Classification Research Articles

In-house molecular diagnosis of diffuse glioma updating the revised WHO classification by a platform of the advanced medical care system, Senshin-Iryo.

Since the World Health Organization (WHO) 2016 revision, the number of molecular markers required for diffuse gliomas has increased, placing a burden on clinical practice. We have established an in-house, molecular diagnostic platform using Senshin-Iryo, a feature of Japan's unique healthcare system, and partially modified the analysis method in accordance with the WHO 2021 revision. Herein, we review over a total 5 years of achievements using this platform. Analyses of IDH, BRAF, and H3 point mutations, loss of heterozygosity (LOH) on 1p/19q and chromosomes 10 and 17, and MGMT methylation were combined into a set that was submitted to Senshin-Iryo as "Drug resistance gene testing for anticancer chemotherapy" and was approved in August 2018. Subsequently, in October 2021, Sanger sequencing for the TERT promoter mutation was added to the set, and LOH analysis was replaced with multiplex ligation-dependent probe amplification (MLPA) to analyze 1p/19q codeletion and newly required genetic markers, such as EGFR, PTEN, and CDKN2A from WHO 2021. Among the over 200 cases included, 54 were analyzed after the WHO 2021 revision. The laboratory has maintained a diagnostic platform where molecular diagnoses are confirmed within 2 weeks. Initial expenditures exceeded the income from patient copayments; however, it has gradually been reduced to running costs alone and is approaching profitability. After the WHO 2021 revision, diagnoses were confirmed using molecular markers obtained from Senshin-Iryo in 38 of 54 cases (70.1%). Among the remaining 16 patients, only four (7.4%) were diagnosed with diffuse glioma, not elsewhere classified, which was excluded in 12 cases where glioblastoma was confirmed by histopathological diagnosis. Our Senshin-Iryo trial functioned as a salvage system to overcome the transition period between continued revisions of WHO classification that has caused a clinical dilemma in the Japanese healthcare system.

Changing the strategic paradigm for the treatment of adult acute myeloid leukemia

Background: Acute myeloid leukemia (AML) is a representative blood cancer, accounting for most adult leukemia cases in Korea. Until recently, intensive chemotherapy and hematopoietic stem cell transplantation were the only curative treatment options for AML. However, the recent introduction of new drugs is bringing about changes in the strategic paradigm for the treatment of AML.Current Concepts: Along with the clinical eligibility for receiving intensive treatment and hematopoietic stem cell transplantation, the most critical determinants in treating AML are precise classification and risk stratification based on cytogenetic and molecular information. The recently revised World Health Organization classification, newly proposed International Consensus Classification, and the latest version of the European LeukemiaNet risk stratification reflect the importance of cytogenetic and molecular information. Although there have been no significant changes for a long time in the landscape of AML, especially in the field of treatment, the treatment paradigm has started to evolve with the introduction of new drugs. This evolution is led by FLT3 inhibitors, Bcl-2 inhibitors, isocitrate dehydrogenase inhibitors, target agents against CD33 antigens, and liposomal formulations of chemotherapeutics.Discussion and Conclusion: Successful initial treatment to induce complete remission followed by post-remission treatment to remove residual disease can lead to the achievement of long-term survival and cure goals in AML. We hope that new drugs will markedly improve the treatment outcomes for patients with AML.

Characteristics of Hearing Loss Among Older Adults in the Korean Genome and Epidemiology Study: A Community-Based Longitudinal Cohort Study With an 8-Year Follow-up

This study investigated the 8-year incidence and progression of hearing loss (HL) and its types and examined the risk factors for changes in HL. This longitudinal cohort study analyzed data from the Korean Genome and Epidemiology Study (KoGES), an ongoing, prospective, community-based cohort study that has been conducted since 2001. Altogether, 1,890 residents of urban areas in Korea aged 45-75 years at time 1 (baseline) were included in the study. Pure-tone audiometry (PTA) testing was performed twice, at time 1 (2008-2009) and time 2 (2015-2018, follow-up), 8 years apart. HL grades were defined as seven mutually exclusive categories following the revised World Health Organization classification. Incidence was defined as PTA >20 dB HL in the better ear at time 2 among those without HL at time 1. Progression was defined as the progressive deterioration of HL among those with HL at time 1. The three types of HL constituted sensorineural (SNHL), conductive, and mixed HL. At time 1, 36.40% of patients were diagnosed with HL, which increased to 51.64% at time 2. The 8-year incidence of HL was 27.20%, and progressive deterioration of HL occurred in 23.11% of those with HL. SNHL was the most common type of HL, and its prevalence markedly increased at time 2. Multivariate analysis demonstrated that the incidence of HL was significantly associated with increasing age, male sex (odds ratio [OR], 1.73; 95% confidence interval [CI], 1.07-2.81), and diabetes mellitus (OR, 1.43; 95% CI, 1.04-1.96). Alcohol consumption was a risk factor for HL deterioration among those with HL at time 1. The prevalence and deterioration of HL were extremely high among older adults, and age was the strongest risk factor for these changes. Therefore, timely screening and intervention are necessary to prevent HL and delay its deterioration among older adults.

Poor Treatment Outcomes of Locally Advanced Cervical Adenocarcinoma of Human Papilloma Virus Independent Type, Represented by Gastric Type Adenocarcinoma: A Multi-Center Retrospective Study (Sankai Gynecology Study Group)

The revised World Health Organization classification of cervical cancer divides adenocarcinomas into human papillomavirus-associated (HPVa) and -independent (HPVi) types; the HPVi type is represented by the gastric type. The treatment outcomes of locally advanced adenocarcinoma (LaAC), based on this classification, are understudied. We investigated the outcomes of patients with HPVa and HPVi LaACs. Data for all consecutive patients with stage IB3 to IIIC1 adenocarcinoma who received treatment at 12 institutions throughout Japan between 2004 and 2009 were retrieved to analyze progression-free and overall survival. Central pathological review classified 103 and 48 patients as having HPVa and HPVi tumors, respectively. Usual- (84%) and gastric- (90%) type adenocarcinomas were the most frequent subtypes. Surgery was the primary treatment strategy for most patients. Progression-free and overall survival of patients with HPVi were worse than those of patients with HPVa (p = 0.009 and 0.032, respectively). Subgroup analysis by stage showed that progression-free survival was significantly different for stage IIB. The current surgical treatment strategy for LaACs is less effective for HPVi tumors than for HPVa tumors, especially those in stage IIB.

Genetic Landscape of Peripheral T-Cell Lymphoma

Peripheral T-Cell lymphoma (PTCL) comprises a heterogenous group of uncommon lymphomas derived from mature, post-thymic or “peripheral” T- and natural killer cells. The World Health Organization (WHO) emphasizes a multiparameter approach in the diagnosis and subclassification of these neoplasms, integrating clinical, morphologic, immunophenotypic, and genetic features into the final diagnosis. Clinical presentation is particularly important due to histologic, immunophenotypic and genetic variations within established subtypes, and no convenient immunophenotypic marker of monoclonality exists. In recent years, widespread use of gene expression profiling and next-generation sequencing (NGS) techniques have contributed to an improved understanding of the pathobiology in PTCLs, and these have been incorporated into the 2016 revised WHO classification of mature T- and NK-cell neoplasms which now encompasses nearly 30 distinct entities. This review discusses the genetic landscape of PTCL and its role in subclassification, prognosis, and potential targeted therapy. In addition to discussing T-Cell lymphoma subtypes with relatively well-defined or relevant genetic aberrancies, special attention is given to genetic advances in T-Cell lymphomas of T follicular helper cell (TFH) origin, highlighting genetic overlaps between angioimmunoblastic T-Cell lymphoma (AITL), follicular T-Cell lymphoma, and nodal peripheral T-Cell lymphoma with a TFH phenotype. Furthermore, genetic drivers will be discussed for ALK-negative anaplastic large cell lymphomas and their role in differentiating these from CD30+ peripheral T-Cell lymphoma, not otherwise specified (NOS) and primary cutaneous anaplastic large cell lymphoma. Lastly, a closer look is given to genetic pathways in peripheral T-Cell lymphoma, NOS, which may guide in teasing out more specific entities in a group of T-Cell lymphomas that represents the most common subcategory and is sometimes referred to as a “wastebasket” category.

DISTINCTION BETWEEN ACUTE MYELOID LEUKAEMIA WITH MYELODYSPLASIA-RELATED CHANGES AND MIXED-PHENOTYPE ACUTE LEUKAEMIA: A DIAGNOSTIC CHALLENGE

The revised 4 th edition of the World Health Organization (WHO) classification of tumours of haematopoietic and lymphoid tissues is based on clinical, morphological, immunophenotypic and genetic features. A case of acute myeloid leukaemia with myelodysplasia-related changes (AML-MRC) in which there was a mixed phenotype of blasts (B-cell/myeloid) has been previously described. We hereby also report an acute leukaemia case that had conflicting morphological and immunophenotypic findings, regarding the revised WHO classification. Patient was a 77 year-old female investigating anaemia for the past few months. Complete blood count (CBC) showed macrocytic anaemia (haemoglobin: 8.3 g/l; MCV: 102 fl) and thrombocytopenia (116 x 10 9 /l), with a normal leukocyte count. Bone marrow assessment was performed when the patient CBC showed circulating blasts. Bone marrow flow cytometry immunophenotyping (FCI) revealed two blast cell populations: one population (about 26% of events) had an immature B-cell phenotype with expression of cytCD22, cytCD79a, CD19, CD22, CD34, CD45(dim), CD58, CD81(dim), CD200, HLA-DR, nuTdT, and an aberrant CD13 and CD123 coexpression; while the other population (about 23% of events) had an immature myeloid phenotype with expression of CD4(dim), CD13, CD25, CD33, CD34, CD58, CD81, CD117, CD123, CD200 and HLA-DR. Neither population expressed cytCD3, cytMPO, CD2, CD3, CD7, CD10, CD11b, CD11c, CD18, CD20, CD36, CD56, CD64 or CD138. If classified isolated, the myeloid population would correspond to an acute myeloid leukaemia (AML) with minimal differentiation and the B-cell population, to a B-lymphoblastic leukaemia/lymphoma (B-ALL). In addition to the FCI data, bone marrow morphological evaluation revealed hypercellularity with severe multilineage dysplasia and two types of blasts with different sizes and morphology, blast cells accounted for 58% of cellularity. Cytogenetic studies showed a karyotype with 45,Xc, t(3;21)(q26;q22). FCI diagnosis considering the EGIL scoring system would be of a biphenotypic acute leukaemia, however to fit into the WHO classification of a mixed-phenotype acute leukaemia (MPAL), the myeloid population would need to express MPO or two monocytic markers, which was not what we observed. Nevertheless, bone marrow morphological findings were suggestive of AML-MRC. There are overlapping features between MPAL and genetically defined AML-MRC. A case series of MPAL identified complex karyotype as the most common genetic abnormality and the WHO classification specifies that AML with complex karyotypes should be classified as AML-MRC. It is recommended that karyotype findings should not be the sole deciding factor to distinguish MPAL from AML-MRC and other factors such as clinical history, morphological findings, immunophenotype and presence of somatic mutations associated with other neoplasms should be considered when leukemic blasts meet criteria for MPAL and the karyotype analysis has myelodysplasia-related abnormalities. Since we did not have access to karyotype results at diagnosis, a descriptive report of FCI and morphological findings was provided. In conclusion, FCI diagnosis of MPAL in the presence of myelodysplasia-related morphological alterations remains a challenge and should take into consideration other laboratory and clinical data.

Update on the Classification of and Diagnostic Approaches to Mature T-Cell Lymphomas.

In the 2017 revised World Health Organization classification of tumors of hematopoietic and lymphoid tissues, some mature T-cell lymphomas were reclassified and a few new provisional entities were established based on new data from clinical and laboratory studies. T follicular helper cell lymphoma is identified by T follicular helper cell markers. Anaplastic large cell lymphoma, ALK negative, is a better-defined entity based on genetic abnormalities, and breast implant-associated anaplastic large cell lymphoma is recognized as a provisional entity. The gastrointestinal T-cell lymphomas are reclassified, with addition of a new provisional entity, indolent T-cell lymphoproliferative disorder of the gastrointestinal tract, characterized by an indolent clinical course. To review the diagnostic approaches to reclassified and newly established entities of mature T-cell lymphomas, focusing on significant immunophenotypic features and molecular genetic abnormalities. Relevant new discoveries after the publication of the 2017 World Health Organization classification are included. Information from the literature most relevant to the 2017 World Health Organization revised classification and publications after 2016. Incorporating clinical, morphologic, and immunophenotypic features usually provides sufficient evidence to reach a preliminary diagnosis of mature T-cell lymphoma. Molecular genetic studies can be very helpful for the final diagnosis and classification, especially in challenging cases. Some molecular genetic features have been found in breast implant-associated anaplastic large cell lymphoma, distinct from anaplastic large cell lymphoma, ALK negative. Immunohistochemical staining of 4 markers may enable further subtyping of peripheral T-cell lymphomas.

Biological and therapeutic implications of a unique subtype of NPM1 mutated AML

In acute myeloid leukemia (AML), molecular heterogeneity across patients constitutes a major challenge for prognosis and therapy. AML with NPM1 mutation is a distinct genetic entity in the revised World Health Organization classification. However, differing patterns of co-mutation and response to therapy within this group necessitate further stratification. Here we report two distinct subtypes within NPM1 mutated AML patients, which we label as primitive and committed based on the respective presence or absence of a stem cell signature. Using gene expression (RNA-seq), epigenomic (ATAC-seq) and immunophenotyping (CyToF) analysis, we associate each subtype with specific molecular characteristics, disease differentiation state and patient survival. Using ex vivo drug sensitivity profiling, we show a differential drug response of the subtypes to specific kinase inhibitors, irrespective of the FLT3-ITD status. Differential drug responses of the primitive and committed subtype are validated in an independent AML cohort. Our results highlight heterogeneity among NPM1 mutated AML patient samples based on stemness and suggest that the addition of kinase inhibitors to the treatment of cases with the primitive signature, lacking FLT3-ITD, could have therapeutic benefit.

Predictors of severe dengue amongst children as per the revised WHO classification.

World Health Organization (WHO) revised its guidelines for classification and management of dengue in 2009. This revised system was found out to have good sensitivity and negative predictive value but poor specificity as well as positive predictive value. This retrospective study was carried out in a tertiary care hospital of Delhi, India to assess factors predicting the occurrence of severe dengue in children as per the revised classification. A total of 647 suspected dengue cases were admitted in the hospital in the year 2015. Detailed clinical and epidemiological data of 170 patients who were confirmed as dengue either by NS1 antigen test or by serology (Ig M positive) were recorded and statistically analyzed. The number of laboratory-confirmed cases was 170 and included thirty (17.65%) dengue fever (DF), 106 (62.35%) dengue with warning signs (DWS) and 34 (20.0%) severe dengue (SD) patients. Regression analysis revealed that presence of vomiting, altered sensorium, shock, peri-orbital edema, hepatomegaly, splenomegaly, severe anemia, thrombocytopenia, elevated urea and creatinine, decreased total protein and globulin were significantly associated with occurrence of severe disease. The addition of clinical features (peri-orbital edema and splenomegaly); and laboratory findings (elevated urea and creatinine, decreased serum protein and globulin) might help improve the sensitivity and specificity of the revised WHO dengue classification in predicting severe dengue.

MYC rearrangement but not extra MYC copies is an independent prognostic factor in patients with mantle cell lymphoma.

Mantle cell lymphoma (MCL) with MYC rearrangement (MYC-R) is rare and little is known about the importance of MYC extra copies (EC) in the absence of MYC-R in MCL patients. This study includes 88 MCL patients with MYC tested by fluorescence in situ hybridization and/or conventional cytogenetics, including 27 with MYC-R, 21 with MYC-EC, and 40 with normal MYC-NL. MCL patients with MYC-R more often had blastoid/pleomorphic morphology; a higher frequency of CD10, MYC, and simultaneous MYC and BCL2 expression; a higher level of MYC; and a higher Ki67 proliferation rate (P<0.05) than those without MYC-R. Although patients with MYC-R more frequently received intensive chemotherapy (P=0.001), their overall survival (OS) was significantly shorter than those without MYC-R. Compared with patients with MYC/BCL2 double-hit lymphoma (DHL), patients with MYC-R MCL had a similar OS but more commonly had bone marrow involvement, Ann Arbor stage IV disease, and a different immunophenotype. MCL patients with MYC-EC showed an OS intermediate between those with MYC-R and MYC-NL, either all or only blastoid/pleomorphic MCL patients included. Multivariate analysis showed that MYC-R, but not MYC-EC, had an independent and negative impact on OS. In conclusion, MYC-R but not MYC-EC showed a higher MYC expression and is an adverse prognostic factor for MCL patients. Although the OS of MCL patients with MYC-R is similar to that of MYC/BCL2DHL patients, these groups have different clinicopathologic features supporting the retention of MCL with MYC-R in the category of MCL, as recommended in the revised World Health Organization classification.

Update on the classification of myeloid neoplasms: The 2016 revised World Health Organization classification of hematopoietic and lymphoid neoplasms

Update on the classification of myeloid neoplasms: The 2016 revised World Health Organization classification of hematopoietic and lymphoid neoplasms

Identification of archaea community of the Papallacta geothermal source, located in Napo province –Ecuador, through new generation sequencing

Breast implant-associated anaplastic large cell lymphoma is a new provisional entity in the revised World Health Organization classification of lymphoid malignancies, the pathogenesis and cell of origin of which are still unknown. We performed gene expression profiling of microdissected breast implant-associated anaplastic large cell lymphoma samples and compared their transcriptional profiles with those previously obtained from normal T-cells and other peripheral T-cell lymphomas and validated expression of selected markers by immunohistochemistry. Our results indicate that most breast implant-associated anaplastic large cell lymphomas exhibit an activated CD4+ memory T-cell phenotype, which is associated with CD25 and FoxP3 expression. Gene ontology analyses revealed upregulation of genes involved in cell motility programs (e.g., CCR6, MET, HGF, CXCL14) in breast implant-associated anaplastic large cell lymphomas compared to normal CD4+ T-cells and upregulation of genes involved in myeloid cell differentiation (e.g., PPARg, JAK2, SPI-1, GAB2) and viral gene transcription (e.g., RPS10, RPL17, RPS29, RPL18A) compared to other types of peripheral T-cell lymphomas. Gene set enrichment analyses also revealed shared features between the molecular profiles of breast implant-associated anaplastic large cell lymphomas and other types of anaplastic large cell lymphomas, including downregulation of T-cell receptor signaling and STAT3 activation. Our findings provide novel insights into the biology of this rare disease and further evidence that breast implant-associated anaplastic large cell lymphoma represents a distinct peripheral T-cell lymphoma entity.

Transformed Mycosis Fungoides and Mimics: Exploring the Landscape of CD30+ Cutaneous T-Cell Lymphomas

Abstract Mycosis fungoides (MF) is an epidermotropic, primary cutaneous T-cell lymphoma (CTCL) with a generally indolent clinical course, although higher stage and transformed tumors can behave more aggressively. Large cell transformation may demonstrate CD30 expression and histologically resemble other CD30+ CTCLs, including lymphomatoid papulomatosis and cutaneous anaplastic large cell lymphoma. These entities are thought to exist on a spectrum with overlapping histologic features; however, it is of clinical importance that we do our best to accurately classify these entities due to the variability in treatment and prognosis. In this report, we present a case of CD30+ transformed MF and discuss the clues that allow us to make the challenging distinction between transformed MF and other CD30+ CTCLs. We review histologic and clinical features of these different disorders, with a focus on the revised World Health Organization classification of primary cutaneous lymphomas.

The effect of the revised WHO classification on the incidence of grade II meningioma

Introduction: A retrospective study over a three-year period at University Hospital of Wales (UHW) of the incidence of atypical cranial grade II meningioma both pre and post 2016 revision of The World Health Organisation (WHO) classification of tumours of the central nervous system.Subjects: All available histology from January 2015 to December 2017 of patients with cranial meningiomas.Method: Institutional online reporting system Welsh Clinical Portal to identify patients and view histology reports.Results: Overall 164 patient histology results were analysed (median age 59, age range 23-82, 74% females). There were 55 patients in 2015: 69.1% grade I, 29.1% grade II and 1.8% grade III. There were 109 patients in 2016/17; 68.8% grade I, 29.4% grade II, 1.8% grade III.Discussion: There is significant variability in the reported incidence of grade II meningioma, likely due to variation in local interpretation of diagnostic criteria. Neuropathologists at our institution have reported brain invasion as grade II prior to 2016. This was due to compelling published evidence that brain invasive meningiomas have recurrence and mortality rates similar to that of grade II meningioma as defined using other criteria. The new 2016 WHO criteria now recognise this specifically. As other institutions adapt to the amended 2016 guidelines we anticipate that there will be a greater consensus in line with our incidence rates of grade II meningioma.

Myeloproliferative Neoplasm in Newly Diagnosed Acute Ischemic Stroke Patients

Objective Myeloproliferative neoplasm (MPN) is considered as one of the risk factors of ischemic stroke. Some MPN patients manifest stroke as their first symptom. Our purpose was to assess diagnostic rate of MPN in newly diagnosed acute ischemic stroke patients. Methods This study was performed using National Health Insurance Service Ilsan Hospital dataset. Data retrieving was performed by defining by defining the patient with coding of acute ischemic stroke from January 2013 to June 2017. We selected only the patients who had checked brain magnetic resonance imaging and complete blood cell count (CBC) in emergency room or on admission. Among the results of CBC finding, hemoglobin and platelet count were analyzed. Erythrocytosis was defined >16.5 g/dL (male), >16 g/dL (female) according to revised World Health Organization (WHO) classification of polycythemia vera (PV) criteria. Thrombocytosis was >450,000/μL according to revised WHO classification of essential thrombocythemia (ET). Results Total number of newly diagnosed acute ischemic stroke was 1,613 patients. Seven patients (0.43%) were diagnosed MPN (ET=2, PV=5) after ischemic stroke. Patients who had thrombocytosis and erythrocytosis were 18 and 105, respectively. Three patients who had thrombocytosis were diagnosed MPN (ET=2, PV=1). Two patients with erythrocytosis were diagnosed MPN (PV=2). Two patients had both thrombocytosis and erythrocytosis, and two of them were diagnosed PV. Seventy-one patients who had erythrocytosis were normalized in follow-up period. Six patients who had thrombocytosis and 30 patients who had erythrocytosis did not further evaluate. Conclusion CBC has to be carefully read and MPN can be suspected. Diagnosis must be confirmed by hematologist to initiate appropriate treatment. It is important to recognized suspected MPN patients to prevent stroke. Key words: Stroke; Myeloproliferative neoplasm; Erythrocytosis; Thrombocytosis

Recurrent PDL1 expression and PDL1 (CD274) copy number alterations in breast implant–associated anaplastic large cell lymphomas

Breast implant-associated anaplastic large cell lymphoma (BI-ALCL) is a variant of anaplastic large cell lymphoma arising within seroma effusion associated with breast implants. BI-ALCL is a rare disease, recently recognized as a new provisional entity by the 2017 revised World Health Organization classification. All BI-ALCLs tested so far showed a "triple-negative" genetic profile-negative for ALK, DUSP22, and TP63 rearrangements-and were characterized by mutational and gene expression profiles consistent with aberrant activation of the JAK/STAT pathway. The active form of STAT3 (pSTAT3) is constantly expressed in BI-ALCLs and may favor tumor immune escape by triggering the transcription of PDL1 (CD274), a gene encoding the immune-checkpoint molecule programmed cell death ligand 1 (PDL1); immunohistochemical positivity for PDL1 has been recently described in 3 BI-ALCL cases, and one of them also harbored PDL1 gene amplification. We evaluated PDL1 and pSTAT expression by immunohistochemistry and PDL1 copy number alterations (CNAs) at chromosome 9p24.1 by fluorescent in situ hybridization in a cohort of 9 BI-ALCL cases; we also investigated the presence of tumor-infiltrating programmed cell death 1 (PD1)+ T cells (tumor-infiltrating lymphocytes, or TILs) and PDL1+ tumor-associated macrophages (TAMs) in BI-ALCL microenvironment. Tumor cells expressed PDL1 in 5 (56%) of 9 cases and harbored PDL1 CNAs in 3 (33%) of 9 cases; immunohistochemistry for pSTAT3 was positive in all 6 cases tested (100%), indicative of active JAK/STAT signaling. We observed PDL1 CNAs only among PDL1-positive cases, whereas PD1+ TILs and PDL1+ TAMs were present at variable levels in both PDL1-positive and PDL1-negative BI-ALCLs. We report frequent PDL1 expression and recurrent PDL1 CNAs in BI-ALCLs: our data suggest that 9p24.1 alterations represent a common mechanism of PDL1 overexpression in this disease, likely acting in synergy with constitutive pSTAT3 signaling. In PDL1-positive cases without chromosomal aberration, PDL1 expression may be induced by JAK/STAT signaling alone and/or others alternative pathways. BI-ALCL microenvironment hosts variable amounts of PD1+ TILs and PDL1+ TAMs, suggesting the presence of an active PD1/PDL1 axis. These findings may be of therapeutic value in advanced-stage patients who may benefit from a PD1/PDL1 blocking treatment.

Update on Lymphoma classification: The 2016 revised World Health Organization Classification of Hematopoietic and Lymphoid Neoplasms

Update on Lymphoma classification: The 2016 revised World Health Organization Classification of Hematopoietic and Lymphoid Neoplasms

Indolent T cell lymphoproliferative disorder with villous atrophy in small intestine diagnosed by single-balloon enteroscopy

Chronic diarrhea is one of the major symptoms in gastroenterology. However, this may be caused by pathologic conditions for which the diagnosis is critical. Villous atrophy, as an endoscopic lesion, accompanied by chronic diarrhea can occasionally be observed in the patients with inflammatory diseases of the gastrointestinal (GI) tract. Herein, we present a case with persistent diarrhea accompanied by intestinal wall thickening without any other significant endoscopic features other than villous atrophy in the jejunum and the ileum, where we diagnosed as an indolent T cell lymphoproliferative disorder (T-LPD) of the GI tract, defined in the 2016–2017 revised World Health Organization classification, via single-balloon enteroscopy (SBE). Interestingly, we found the same lymphocyte infiltration from the distal third portion of the duodenum, where gastroscopy could not reach, via SBE, even though no endoscopic findings were observed such as villous atrophy. Since infiltrating cells in the intestinal tissues were CCR4+, mogamulizumab was administered with resulting durable symptomatic remission for more than 2 years. Patients with persistent diarrhea may have serious small intestinal disorder including not only chronic inflammatory diseases but also lymphoid neoplasmic conditions including T-LPD of GI tract.

Epstein-Barr Virus-Associated T and NK-Cell Lymphoproliferative Diseases.

EBV-associated T and NK-cell lymphoproliferative diseases (EBV-T/NK LPDs) are characterized by the transformation and proliferation of EBV-infected T or NK cells. The 2016 revised World Health Organization classification recognizes the following EBV-positive lymphoproliferative disorders (LPD): chronic active EBV infection (CAEBV) of T- and NK-cell type (cutaneous and systemic forms), systemic EBV-positive T-cell lymphoma of childhood, aggressive NK-cell leukemia, extranodal NK/T-cell lymphoma, nasal type, and the new provisional entity primary EBV-positive nodal T/NK-cell lymphoma. EBV-associated hemophagocytic lymphohistiocytosis (HLH), although not included in the WHO classification because it is a reactive, inflammatory disease, is included in this review because it can be life-threatening and may have overlapping features with other EBV+ T/NK LPDs. EBV+ T/NK LPDs are rare diseases difficult to diagnose and manage properly, because some LPDs have unusual presentations, and discrepancies between clinical and histological findings might be encountered. Furthermore, EBV+ T/NK disorders share some clinico-pathological features, and may evolve into other categories during the clinical course, including malignant transformation of CAEBV. Here, we review the EBV+ T/NK LPDs in terms of their definitions, clinical features, histology, immunophenotype, molecular findings, and pathogenesis. This review aims to increase our understanding and awareness of the differential diagnosis among the different EBV+ T/NK LPDs. New insights into the genetic characteristics of these disorders will also be discussed.

Transcriptional analysis distinguishes breast implant-associated anaplastic large cell lymphoma from other peripheral T-cell lymphomas

Breast implant-associated anaplastic large cell lymphoma is a new provisional entity in the revised World Health Organization classification of lymphoid malignancies, the pathogenesis and cell of origin of which are still unknown. We performed gene expression profiling of microdissected breast implant-associated anaplastic large cell lymphoma samples and compared their transcriptional profiles with those previously obtained from normal T-cells and other peripheral T-cell lymphomas and validated expression of selected markers by immunohistochemistry. Our results indicate that most breast implant-associated anaplastic large cell lymphomas exhibit an activated CD4+ memory T-cell phenotype, which is associated with CD25 and FoxP3 expression. Gene ontology analyses revealed upregulation of genes involved in cell motility programs (e.g., CCR6, MET, HGF, CXCL14) in breast implant-associated anaplastic large cell lymphomas compared to normal CD4+ T-cells and upregulation of genes involved in myeloid cell differentiation (e.g., PPARg, JAK2, SPI-1, GAB2) and viral gene transcription (e.g., RPS10, RPL17, RPS29, RPL18A) compared to other types of peripheral T-cell lymphomas. Gene set enrichment analyses also revealed shared features between the molecular profiles of breast implant-associated anaplastic large cell lymphomas and other types of anaplastic large cell lymphomas, including downregulation of T-cell receptor signaling and STAT3 activation. Our findings provide novel insights into the biology of this rare disease and further evidence that breast implant-associated anaplastic large cell lymphoma represents a distinct peripheral T-cell lymphoma entity.