World Health Organization Classification Research Articles

Diagnostic Biomarkers in Renal Cell Tumors According to the Latest WHO Classification: A Focus on Selected New Entities

The fifth edition of the World Health Organization (WHO) classification for urogenital tumors, released in 2022, introduces some novelties in the chapter on renal epithelial tumors compared to the previous 2016 classification. Significant changes include the recognition of new disease entities and adjustments in the nomenclature for certain pathologies. Notably, each tumor entity now includes minimum essential and desirable criteria for reliable diagnosis. This classification highlights the importance of biological and molecular characterization alongside traditional cytological and architectural features. In this view, immunophenotyping through immunohistochemistry (IHC) plays a crucial role in bridging morphology and genetics. This article aims to present and discuss the role of key immunohistochemical markers that support the diagnosis of new entities recognized in the WHO classification, focusing on critical topics associated with single markers, in the context of specific tumors, such as the clear cell capillary renal cell tumor (CCPRCT), eosinophilic solid and cystic renal cell carcinoma (ESC-RCC), and so-called “other oncocytic tumors”, namely the eosinophilic vacuolated tumor (EVT) and low-grade oncocytic tumor (LOT). Their distinctive characteristics and immunophenotypic profiles, along with insights regarding diagnostic challenges and the differential diagnosis of these tumors, are provided. This state-of-the-art review offers valuable insights in biomarkers associated with novel renal tumors, as well as a tool to implement diagnostic strategies in routine practice.

Morphologic Features of Invasion in Lung Adenocarcinoma: Diagnostic Pitfalls.

Reproducibility of pulmonary invasive adenocarcinoma diagnosis is poor when applying the World Health Organization (WHO) classification. In this article, we aimed first to explain by 3-dimensional morphology why simple pattern recognition induces pitfalls for the assessment of invasion as applied in the current WHO classification of pulmonary adenocarcinomas. The underlying iatrogenic-induced morphologic alterations in collapsed adenocarcinoma in situ overlap with criteria for invasive adenocarcinoma. Pitfalls in seemingly acinar and papillary carcinoma are addressed with additional cytokeratin 7 and elastin stains. In addition, we provide more stringent criteria for a better reproducible and likely generalizable classification.

Against all odds: successful pregnancy in an adult patient with unrepaired coarctation of the aorta.

According to the modified World Health Organization classification, pregnant women with unrepaired aortic coarctation are at very high risk for both maternal and fetal complications and should, therefore, be counselled against pregnancy. The most frequent maternal complications include systemic hypertension, renal failure, preeclampsia, and aortic dissection. Herein, we describe a successful pregnancy in an adult patient with unrepaired aortic coarctation.

Head-to-head: Should Ki67 proliferation index be included in the formal classification of pulmonary neuroendocrine neoplasms?

The reporting of lung neuroendocrine neoplasms (NENs) according to the 2021 World Health Organisation (WHO) is based on mitotic count per 2 mm2, necrosis assessment and a constellation of cytological and immunohistochemical details. Accordingly, typical carcinoid and atypical carcinoid are low- to intermediate-grade neuroendocrine tumours (NETs), while large-cell neuroendocrine carcinoma (NEC) and small-cell lung carcinoma are high-grade NECs. In small-sized diagnostic material (cytology and biopsy), the noncommittal term of carcinoid tumour/NET not otherwise specified (NOS) and metastatic carcinoid NOS have been introduced with regard to primary and metastatic diagnostic settings, respectively. Ki-67 antigen, a well-known marker of cell proliferation, has been included in the WHO classification as a non-essential but desirable criterion, especially to distinguish NETs from high-grade NECs and to delineate the provisional category of carcinoid tumours/NETs with elevated mitotic counts (> 10 mitoses per mm2) and/or Ki-67 proliferation index (≥ 30%). However, a wider use of this marker in the spectrum of lung NENs continues to be highly reported and debated, thus witnessing a never-subsided attention. Therefore, the arguments for and against incorporating Ki-67 in the classification and clinical practice of these neoplasms are discussed herein in detail.

Meningioma recurrence: Time for an online prediction tool?

Background: Meningioma, the most common brain tumor, traditionally considered benign, has a relatively high risk of recurrence over a patient’s lifespan. In addition, with the emergence of several clinical, radiological, and molecular variables, it is becoming evident that existing grading criteria, including Simpson’s and World Health Organization classification, may not be sufficient or accurate. As web-based tools for widespread accessibility and usage become commonplace, such as those for gene identification or other cancers, it is timely for meningioma care to take advantage of evolving new markers to help advance patient care. Methods: A scoping review of the meningioma literature was undertaken using the MEDLINE and Embase databases. We reviewed original studies and review articles from September 2022 to December 2023 that provided the most updated information on the demographic, clinical, radiographic, histopathological, molecular genetics, and management of meningiomas in the adult population. Results: Our scoping review reveals a large body of meningioma literature that has evaluated the determinants for recurrence and aggressive tumor biology, including older age, female sex, genetic abnormalities such as telomerase reverse transcriptase promoter mutation, CDKN2A deletion, subtotal resection, and higher grade. Despite a large body of evidence on meningiomas, however, we noted a lack of tools to aid the clinician in decision-making. We identified the need for an online, self-updating, and machine-learning-based dynamic model that can incorporate demographic, clinical, radiographic, histopathological, and genetic variables to predict the recurrence risk of meningiomas. Conclusion: Although a challenging endeavor, a recurrence prediction tool for meningioma would provide critical information for the meningioma patient and the clinician making decisions on long-term surveillance and management of meningiomas.

Genomic medicine advances for brain tumors.

Cancer genome profiling has revealed important genetic alterations that serve as prognostic indicators and guides for treatment decisions, enabling precision medicine. The shift to molecular diagnosis of brain tumors, as reflected in the 2021 World Health Organization Classification of Tumors of the Central Nervous System, is a crucial role for treatment decision-making. This review discusses the significance and role of cancer genome profiling in precision medicine for malignant brain tumors, particularly gliomas. Furthermore, we explore the progress in cancer genome analysis, focusing on cancer gene panel testing, integration of genomic information in brain tumor classification, and hereditary tumors. Additionally, we discuss the transformative effect of genomic medicine on early detection, risk assessment, and precision medicine strategies. The tumor mutational burden in brain tumors is considered low, but the application of molecular targeted drugs, such as isocitrate dehydrogenase inhibitors, v-raf murine sarcoma viral oncogene homolog B1 inhibitors, fibroblast growth factor receptor inhibitors, neurotrophic tyrosine receptor kinase, mechanistic target of rapamycin inhibitors, and anti-programmed death receptor-1 antibody drugs are promising for glioma treatment. We also discuss the future prospects of molecular targeted drugs.

The Observation at Mean Oedema Index Variations with Location and Histological subtypes in Supratentorial WHO G-I Meningiomas

Background: The term meningioma is the noncommittal, all-encompassing name coined by Harvey Cushing for this tumor of meninges which is usually benign. The severity and variety of the peritumoral brain oedema may limit operative exposure and increase the difficulties of intraoperative procedures; however, its pathogenesis is not clearly documented. Several factors, such as tumor size, location and histology, mechanical compression of draining vein by the tumor have been proposed as mechanism of peritumoral brain oedema Aims: The objective of this study was to determination of mean oedema index in different locations and histological subtypes in patients with supratentorial WHO GI meningiomas Methods: The study was conducted in the Department of Neurosurgery, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh from September, 2016 to March, 2018. This study was a cross sectional study. Data collection sheets were used to collect necessary information. Total 75 cases were selected consistent with inclusion and exclusion criteria. Tumor volume and localization and the presence of peritumoral brain oedema (PTBOe) were determined by MRI (Magnetic Resonance Image). All patients underwent microsurgical removal of tumor. Surgically resected meningiomas were classified histopathologically based on criteria of the new World Health Organization (WHO) classification. Regarding location and histological subtypes of tumor the study population were divided into 6 groups and 8 groups respectively.Statistical analyses were done by Statistical Packages for Social Sciences (SPSS-v.25). Results: A total 75 cases were selected consistent with inclusion and exclusion criteria from September, 2016 to March, 2018. Regarding location; the mean oedema index for each of the six groups was calculated and recorded. The F value was 5.97 and the P-value was 0.0001 which was less than 0.05. This result signifies that there was association between perilesional oedema in supratentorial meningioma to its location. So, Mean Oedema Index in Intracranial Supratentorial Meningiomas vary with its location. On the other hand, regarding histopathological subtypes, meningiomaswere divided into eight groups-the mean oedema index of each of the eight groups was calculated and recorded. The F value was 1.62 and P-value was 0.145 which was more than 0.05. This result signifies that there was no association between perilesional oedema in supratentorial meningioma to its histological subtypes. So mean oedema index in intracranial supratentorial meningiomas does not vary with its histological subtypes. Conclusion: Mean Oedema Index in Intracranial Supratentorial Meningiomas vary with its location but does not vary with histological subtypes Bang. J Neurosurgery 2023; 13(1): 10-13

Predicting survival in patients with myelodysplastic/myeloproliferative neoplasms with SF3B1 mutation and thrombocytosis.

We investigated data from 180 consecutive patients with myelodysplastic/myeloproliferative neoplasms with SF3B1 mutation and thrombocytosis (MDS/MPN-SF3B1-T) who were diagnosed according to the 2022 World Health Organization (WHO) classification of myeloid neoplasms to identify covariates associated with survival. At a median follow-up of 48 months (95% confidence interval [CI] 35-61 months), the median survival was 69 months (95% CI 59-79 months). Patients with bone marrow ring sideroblasts (RS) < 15% had shorter median overall survival (OS) than did those with bone marrow RS ≥ 15% (41 months [95% CI 32-50 months] versus 76 months [95% CI 59-93 months]; P < 0.001). According to the univariable analyses of OS, age ≥ 65 years (P < 0.001), hemoglobin concentration (Hb) < 80 g/L (P = 0.090), platelet count (PLT) ≥ 800 × 10E + 9/L (P = 0.087), bone marrow RS < 15% (P < 0.001), the Revised International Prognostic Scoring System (IPSS-R) cytogenetic category intermediate/poor/very poor (P = 0.005), SETBP1 mutation (P = 0.061) and SRSF2 mutation (P < 0.001) were associated with poor survival. Based on variables selected from univariable analyses, two separate survival prediction models, a clinical survival model, and a clinical-molecular survival model, were developed using multivariable analyses with the minimum value of the Akaike information criterion (AIC) to specifically predict outcomes in patients with MDS/MPN-SF3B1-T according to the 2022 WHO classification.

Update on primary cutaneous T-cell lymphomas rare subtypes

Rare subtypes of cutaneous T-cell lymphomas (CTCL) include four entities, primary cutaneous γδ T-cell lymphoma, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, and primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorders, primary cutaneous acral CD8+ T-cell lymphoma, which were previously considered provisional and are now included in the new 5th World Health Organization classification of hematolymphoid tumors as distinct entities. An updated summary of the clinical, histological, and genomic characteristics of these uncommon CTCL subtypes is given in this review, with a focus on the growing body of knowledge regarding their classification and possible treatment strategies.

A case of hyalinizing trabecular tumor of the thyroid: diagnostic significance of PAX8-GLIS3 fusion

BackgroundHyalinizing trabecular tumor (HTT) is an uncommon follicular cell-derived thyroid tumor classified as a low-risk neoplasm by the World Health Organization Classification of Tumors of Endocrine Organs, 5th edition. The PAX8-GLIS3 gene fusion is reportedly a pathognomonic genetic alteration of HTT.Case presentationA 43-year-old Japanese female was incidentally discovered to have an 8-mm, well-defined, hypoechoic mass in the left lobe of the thyroid gland by ultrasound examination. Contrast-enhanced computed tomography scan revealed a solid mass exhibiting slight homogeneous enhancement in the lower pole of the thyroid gland. The mass was diagnosed as atypia of undetermined significance by fine-needle aspiration cytology. The patient underwent left hemithyroidectomy with routine central compartment dissection. Histologic findings revealed tumor cells with elongated nuclei and intranuclear pseudoinclusions arranged with trabeculae architecture or small nests in hyalinized stroma. Weak membranous and cytoplasmic staining was found by MIB1 (Ki-67) immunostaining. The final diagnosis was HTT of the thyroid gland. Next-generation sequencing genetic analysis of a surgical specimen revealed no pathologic mutations, including BRAF, H/K/NRAS, or RET-PTC fusions. The PAX8-GLIS3 fusion was detected by RT-PCR.ConclusionsA rare case of HTT was demonstrated through imaging, cytologic, histologic and molecular investigations. PAX8-GLIS3 fusion detected by RT-PCR and Sanger sequencing was confirmed to be a genetic hallmark of HTT.

Galectin-3 expression by thyroid neoplasms in a center in southwest Nigeria

Background: Galectin-3 (GAL-3), which is known to be expressed in certain normal tissues and is implicated in tumor progression and metastasis, serves as a valuable marker for distinguishing malignant thyroid lesions from benign thyroid lesions. This study aimed to assess the clinical and histopathological features of thyroid neoplasms at OAUTHC Ile Ife utilizing GAL-3 immunohistochemistry and to compare these findings with those of studies conducted in other regions of the world. Materials and Methods: Histology slides from 56 patients with thyroid neoplasms spanning a 20-year period were subjected to immunohistochemical staining with monoclonal antibodies against GAL-3. Evaluation was based on the 2022 World Health Organization Classification of Thyroid Neoplasms, categorizing marker expression as follows: 1+ (10–25% stained cells), 2+ (26–50% stained cells), 3+ (51–75% stained cells), and 4+ (&gt;75% stained cells). Negative staining indicated no staining, while localized staining (focal) represented &lt;50% of cells stained (1+ or 2+), and diffuse staining indicated &gt;50% of cells stained (3+ or 4+). Results: A total of 56 patients with neoplastic thyroid disease were studied, including 15 males and 41 females. Among the 16 benign neoplastic lesions, four (25.0%) exhibited focal GAL-3 expression, while 12 (75.0%) showed no expression. Among the forty malignant neoplastic lesions, five (12.5%) tested negative for the GAL-3 immunomarker, while 35 (87.5%) demonstrated positive expression to varying degrees. Among the positive malignant lesions, two (5.0%) displayed focal GAL-3 expression, while 33 (82.5%) exhibited diffuse staining of tumor cells. The diffuse and strong expression of GAL-3 was significantly greater in malignant thyroid neoplasms than in benign neoplasms (p&lt;0.05). The sensitivity and specificity of GAL-3 were 88% and 75%, respectively. Conclusion: Our findings align with the previous research indicating that diffuse and strong immunohistochemical expression of GAL-3 is indicative of thyroid gland malignancy. GAL-3 serves as a valuable tool in diagnosing thyroid neoplasms, particularly in cases where histomorphologic characteristics are inconclusive or unclear.

A clinicopathological study of non-functioning pituitary neuroendocrine tumours using the World Health Organization 2022 classification.

The 2022 World Health Organization (WHO) classification of pituitary neuroendocrine tumour (PitNET) supersedes the previous one in 2017 and further consolidates the role of transcription factors (TF) in the diagnosis of PitNET. Here, we investigated the clinical utility of the 2022 WHO classification, as compared to that of 2017, in a cohort of patients with non-functioning PitNET (NF-PitNET). A total of 113 NF-PitNET patients who underwent resection between 2010 and 2021, and had follow-up at Queen Mary Hospital, Hong Kong, were recruited. Surgical specimens were re-stained for the three TF: steroidogenic factor (SF-1), T-box family member TBX19 (TPIT) and POU class 1 homeobox 1 (Pit-1). The associations of different NF-PitNET subtypes with tumour-related outcomes were evaluated by logistic and Cox regression analyses. Based on the 2022 WHO classification, the majority of NF-PitNET was SF-1-lineage tumours (58.4%), followed by TPIT-lineage tumours (18.6%), tumours with no distinct lineage (16.8%) and Pit-1-lineage tumours (6.2%). Despite fewer entities than the 2017 classification, significant differences in disease-free survival were present amongst these four subtypes (Log-rank test p=0.003), specifically between SF-1-lineage PitNET and PitNET without distinct lineage (Log-rank test p<0.001). In multivariable Cox regression analysis, the subtype of PitNET without distinct lineage (HR 3.02, 95% CI 1.28-7.16, p=0.012), together with tumour volume (HR 1.04, 95% CI 1.01-1.07, p=0.017), were independent predictors of a composite of residual or recurrent disease. The 2022 WHO classification of PitNET is a clinically useful TF and lineage-based system for subtyping NF-PitNET with different tumour behaviour and prognosis.

Benign mesothelial tumors

Benign mesothelial tumors are rarer than malignant mesotheliomas and are often found in the peritoneum as incidental findings in women. They include the adenomatoid tumor (AT), the well-differentiated mesothelial tumor (WDPMT), the mesothelioma in situ (MIS), and the solid papillary mesothelial tumor (SPMT). ATs are always benign and predominantly manifest in the genital tract. WDPMTs can develop multifocally and are prone to recurrence, particularly in the case of incomplete resection. Only MISs are considered aconfirmed precursor lesion of malignant mesothelioma according to the currently valid World Health Organization (WHO) classifications. As with malignant mesothelioma, alterations of BAP1, MTAP, and p16 are detectable for MIS in contrast to the other three tumors. SPMTs cannot be clearly assigned to the other mesothelial tumors and have so far only been described in the peritoneum in women with abenign course.

An overview on liposarcoma subtypes: Genetic alterations and recent advances in therapeutic strategies.

Liposarcoma (LPS) is a rare malignancy of adipocytic differentiation. According to World Health Organization classification, LPS comprises of four principle subtypes Atypical lipomatous tumor/Well-differentiated liposarcoma (ATL/WDLPS), Dedifferentiated liposarcoma (WDLPS), Myxoid liposarcoma (MLPS), and Pleomorphic liposarcoma (PLPS). Each subtype can develop at any location and shows distinct clinical behavior and treatment sensitivity. ATL/ WDLPS subtype has a higher incidence rate, low recurrence, and is insensitive to radiation and chemotherapy. DDLPS is the focal progression of WDLPS, which is aggressive and highly metastasizing. MLPS is sensitive to radiation and chemotherapy, with a higher recurrence rate and metastasis. PLPS subtype is highly metastasizing, has a poor prognosis, and exhibiting higher recurrence rate. Initial histological analysis provides information for the characterization of LPS subtypes', further molecular and genetic analysis provides certain subtype specifications, such as gene amplifications and gene fusions. Such molecular genetic alterations will be useful as therapeutic targets in various cancers, including the LPS subtypes. A wide range of novel therapeutic agents based on genetic alterations that aim to target LPS subtypes specifically are under investigation. This review summarizes the LPS subtype classification, their molecular genetic characteristics, and the implications of genetic alterations in therapeutics.

Discriminating Interpatient Variabilities of RAS Gene Variants for Precision Detection of Thyroid Cancer.

Interpatient variabilities in genomic variants may reflect differences in tumor statuses among individuals. To delineate interpatient variabilities in RAS variants in thyroid tumors based on the fifth World Health Organization classification of thyroid neoplasms and assess their diagnostic significance in cancer detection among patients with thyroid nodules. This prospective diagnostic study analyzed surgically resected thyroid tumors obtained from February 2016 to April 2022 and residual thyroid fine-needle aspiration (FNA) biopsies obtained from January 2020 to March 2021, at Mount Sinai Hospital, Toronto, Ontario, Canada. Data were analyzed from June 20, 2022, to October 15, 2023. Quantitative detection of interpatient disparities of RAS variants (ie, NRAS, HRAS, and KRAS) was performed along with assessment of BRAF V600E and TERT promoter variants (C228T and C250T) by detecting their variant allele fractions (VAFs) using digital polymerase chain reaction assays. Interpatient differences in RAS, BRAF V600E, and TERT promoter variants were analyzed and compared with surgical histopathologic diagnoses. Malignancy rates, sensitivity, specificity, positive predictive values, and negative predictive values were calculated. A total of 438 surgically resected thyroid tumor tissues and 249 thyroid nodule FNA biopsies were obtained from 620 patients (470 [75.8%] female; mean [SD] age, 50.7 [15.9] years). Median (IQR) follow-up for patients who underwent FNA biopsy analysis and subsequent resection was 88 (50-156) days. Of 438 tumors, 89 (20.3%) were identified with the presence of RAS variants, including 51 (11.6%) with NRAS, 29 (6.6%) with HRAS, and 9 (2.1%) with KRAS. The interpatient differences in these variants were discriminated at VAF levels ranging from 0.15% to 51.53%. The mean (SD) VAF of RAS variants exhibited no significant differences among benign nodules (39.2% [11.2%]), noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTPs) (25.4% [14.3%]), and malignant neoplasms (33.4% [13.8%]) (P = .28), although their distribution was found in 41.7% of NIFTPs and 50.7% of invasive encapsulated follicular variant papillary thyroid carcinomas (P < .001). RAS variants alone, regardless of a low or high VAF, were significantly associated with neoplasms at low risk of tumor recurrence (60.7% of RAS variants vs 26.9% of samples negative for RAS variants; P < .001). Compared with the sensitivity of 54.2% (95% CI, 48.8%-59.4%) and specificity of 100% (95% CI, 94.8%-100%) for BRAF V600E and TERT promoter variant assays, the inclusion of RAS variants into BRAF and TERT promoter variant assays improved sensitivity to 70.5% (95% CI, 65.4%-75.2%), albeit with a reduction in specificity to 88.8% (95% CI, 79.8%-94.1%) in distinguishing malignant neoplasms from benign and NIFTP tumors. Furthermore, interpatient differences in 5 gene variants (NRAS, HRAS, KRAS, BRAF, and TERT) were discriminated in 54 of 126 indeterminate FNAs (42.9%) and 18 of 76 nondiagnostic FNAs (23.7%), and all tumors with follow-up surgical pathology confirmed malignancy. This diagnostic study delineated interpatient differences in RAS variants present in thyroid tumors with a variety of histopathological diagnoses. Discrimination of interpatient variabilities in RAS in combination with BRAF V600E and TERT promoter variants could facilitate cytology examinations in preoperative precision malignancy diagnosis among patients with thyroid nodules.

Cardiovascular Risk Assessment in Pregnancy: Findings From a Large Urban Academic Medical Center [ID 2683572

INTRODUCTION: The goal of this study is to describe patients who screened positive and had true cardiovascular disease (CVD) identified using a risk assessment tool in pregnancy or postpartum. METHODS: This is a prospective validation study of the CVD screening algorithm proposed by the California Maternal Quality Care Collaborative (CMQCC). The CVD risk assessment tool was embedded in the electronic medical record for use by all prenatal care providers with a goal of at least one CVD risk assessment during pregnancy and/or postpartum period. Patients identified with increased risk of CVD received an echocardiogram, electrocardiogram, and cardiology consultation. We describe the assessment tool responses, timing of assessment, cardiac findings, and subsequent interventions. This study was approved by the IRB at Albert Einstein College of Medicine. RESULTS: A total of 1,877 patients were screened as of September 1, 2023, with 148 screening positive for at risk of CVD. Thirty-two patients were found to be true positives including 2 (6.25%) with systolic and/or diastolic dysfunction, 10 (31.3%) with ventricular dilation or hypertrophy, and 23 (71.9%) with a valvular abnormality. CONCLUSION: All 32 true-positive cases were seen by a multidisciplinary cardio-obstetrics team at least once. Ten patients had multiple visits with the cardio-obstetrics team. Three patients were deemed to be of higher risk for decompensation during labor by modified World Health Organization classification and required detailed plans for intrapartum and postpartum management. Seven patients were started on cardiovascular medications. The cardiovascular risk assessment tool proved valuable for identifying and providing individualized care for cardio-obstetric patients.

EBV-RELATED LYMPHOPROLIFERATIVE DISEASES: A REVIEW IN LIGHT OF NEW CLASSIFICATIONS

Epstein-Barr virus (EBV) is a prevalent virus that can be detected in the vast majority of the population. Most people are asymptomatic and remain chronically infected throughout their lifetimes. However, in some populations, EBV has been linked to a variety of B-cell lymphoproliferative disorders (LPDs), such as Burkitt lymphoma, classic Hodgkin lymphoma, and other LPDs. T-cell LPDs have been linked to EBV in part of peripheral T-cell lymphomas, angioimmunoblastic T-cell lymphomas, extranodal nasal natural killer/T-cell lymphomas, and other uncommon histotypes. This article summarizes the current evidence for EBV-associated LPDs in the light of the upcoming World Health Organization classification and the 2022 ICC classification. Keywords: Epstein Barr Virus: EBV, Lymphoma; Lymphoproliferative Diseases.WHO Classification.

What is new in the 5th edition of the World Health Organization classification of mature B and T/NK cell tumors and stromal neoplasms?

The classification of tumors is essential in the diagnosis and clinical management of patients with malignant neoplasms. The World Health Organization (WHO) provides a globally applicable classification scheme of neoplasms and it was updated several times. In this review, we briefly outline the cornerstones of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours on lymphoid neoplasms. As is adopted throughout the 5th edition of the WHO classification of tumors of all organ systems, entities are listed by a hierarchical system. For the first time, tumor-like lesions have been included in the classification, and modifications of nomenclature for some entities, revisions of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities are presented along with mesenchymal lesions specific to the stroma of lymph nodes and the spleen. In addition to specific outlines on constitutional and somatic genetic changes associated with given entities, a separate chapter on germline predisposition syndromes related to hematologic neoplasms has been added.

Inhibitory Effects of Metformin for Pancreatic Neuroendocrine Neoplasms: Experimental Study on Mitochondrial Function

Although pancreatic neuroendocrine neoplasms (panNENs) are much less common and have a better prognosis than exocrine pancreatic cancers, their recurrence rate is not low, even in Grade 1 (World Health Organization classification) panNEN. Recently, there have been several reports that the progression-free survival in patients with unresectable panNEN could be improved by an antidiabetic drug, metformin, with the co-treatment of everolimus or a somatostatin analog. In this study, we aimed to evaluate the effects of metformin on cell metabolism and viability using the panNEN cell line, QGP-1, and RIN-m in culture. We observed an inhibitory effect of metformin on QGP-1 cell proliferation in a dose-dependent manner. Metformin was found to decrease the oxygen consumption rate in QGP-1 and RIN-m cells after metformin 48 h treatment and immediately after exposure. Cell proliferation was suppressed after metformin treatment. Phosphorylated adenosine monophosphate-activated protein kinase (AMPK) expression was increased, and cyclin D1 expression was decreased in RIN-m cells 24 h after metformin treatment by Western blotting in a dose-dependent manner. In conclusion, suppressive mitochondrial respiration and AMPK activation by metformin are, thus, suggested to inhibit panNEN cell viability and cell survival.

CEBPA mutations in acute myeloid leukemia: implications in risk stratification and treatment.

Mutations in CCAAT enhancer binding protein α (CEBPA) occur in approximately 10% of patients with de novo acute myeloid leukemia (AML). Emerging evidence supports that in-frame mutations in the basic leucine zipper domain of CEBPA (CEBPAbZIP-inf) confer a survival benefit, and CEBPAbZIP-inf replaced CEBPA double mutations (CEBPAdm) as a unique entity in the 2022 World Health Organization (WHO-2022) classification and International Consensus Classification (ICC). However, challenges remain in daily clinical practice since more than 30% patients with CEBPAbZIP-inf die of AML despite intensive treatment. This review aims to provide a comprehensive summary of the heterogeneities observed in AML with CEBPAdm and CEBPAbZIP-inf, and will discuss the prognostic implications of concurrent mutations and novel mechanistic targets that may inform future drug development. The ultimate goal is to optimize clinical management and to provide precision medicine for this category of patients.