World Health Organization Classification Research Articles

Comparison of MRI Sequences to Predict IDH Mutation Status in Gliomas Using Radiomics-Based Machine Learning.

Regarding the 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors, the isocitrate dehydrogenase (IDH) mutation status is one of the most important factors for CNS tumor classification. The aim of our study is to analyze which of the commonly used magnetic resonance imaging (MRI) sequences is best suited to obtain this information non-invasively using radiomics-based machine learning models. We developed machine learning models based on different MRI sequences and determined which of the MRI sequences analyzed yields the highest discriminatory power in predicting the IDH mutation status. In our retrospective IRB-approved study, we used the MRI images of 106 patients with histologically confirmed gliomas. The MRI images were acquired using the T1 sequence with and without administration of a contrast agent, the T2 sequence, and the Fluid-Attenuated Inversion Recovery (FLAIR) sequence. To objectively compare performance in predicting the IDH mutation status as a function of the MRI sequence used, we included only patients in our study cohort for whom MRI images of all four sequences were available. Seventy-one of the patients had an IDH mutation, and the remaining 35 patients did not have an IDH mutation (IDH wild-type). For each of the four MRI sequences used, 107 radiomic features were extracted from the corresponding MRI images by hand-delineated regions of interest. Data partitioning into training data and independent test data was repeated 100 times to avoid random effects associated with the data partitioning. Feature preselection and subsequent model development were performed using Random Forest, Lasso regression, LDA, and Naïve Bayes. The performance of all models was determined with independent test data. Among the different approaches we examined, the T1-weighted contrast-enhanced sequence was found to be the most suitable for predicting IDH mutations status using radiomics-based machine learning models. Using contrast-enhanced T1-weighted MRI images, our seven-feature model developed with Lasso regression achieved a mean area under the curve (AUC) of 0.846, a mean accuracy of 0.792, a mean sensitivity of 0.847, and a mean specificity of 0.681. The administration of contrast agents resulted in a significant increase in the achieved discriminatory power. Our analyses show that for the prediction of the IDH mutation status using radiomics-based machine learning models, among the MRI images acquired with the commonly used MRI sequences, the contrast-enhanced T1-weighted images are the most suitable.

Смешанная эпителиальная и стромальная опухоль в сочетании с онкоцитомой почки: редкий клинический случай и обзор литературы.

Introduction. Mixed epithelial and stromal tumors (MEST) of the kidney are rare neoplasms and, along with adult cystic nephroma, are grouped together called mixed epithelial and stromal tumors (World Health Organization Classification of Tumors of the Kidney, 2022). Clinically and radiologically, they mimic other cystic renal neoplasms, thus definitive diagnosis requires histological and immunohistochemical examination. Despite the benign course, MEST can undergo malignancy; isolated cases of recurrence have also been documented. Clinical case. Patient X, 65 years old, underwent robot-assisted left-side partial nephrectomy for cystic formations of the left kidney with a hypervascular soft tissue component along the medial semicircle of one of the cysts. According to histological examination, MEST of the left kidney in combination with oncocytoma was diagnosed. Conclusions. This article presents probably the first published case of MEST in combination with oncocytoma of the kidney.

Ultra-high b-value DWI accurately identifies isocitrate dehydrogenase genotypes and tumor subtypes of adult-type diffuse gliomas.

To distinguish isocitrate dehydrogenase (IDH) genotypes and tumor subtypes of adult-type diffuse gliomas based on the fifth edition of the World Health Organization classification of central nervous system tumors (WHO CNS5) in 2021 using standard, high, and ultra-high b-value diffusion-weighted imaging (DWI). This prospective study enrolled 70 patients with adult-type diffuse gliomas who underwent multiple b-value DWI. Apparent diffusion coefficient (ADC) values including ADCb500/b1000, ADCb500/b2000, ADCb500/b3000, ADCb500/b4000, ADCb500/b6000, ADCb500/b8000, and ADCb500/b10000 in tumor parenchyma (TP) and contralateral normal-appearing white matter (NAWM) were calculated. The ADC ratios of TP/NAWM were assessed for correlations with IDH genotypes, tumor subtypes, and Ki-67 status; diagnostic performances were compared. All ADCs were significantly higher in IDHmutant gliomas than in IDH wild-type gliomas (p < 0.01 for all); ADCb500/b8000 had the highest area under the curve (AUC) of 0.866. All ADCs were significantly lower in glioblastoma than in astrocytoma (p < 0.01 for all). ADCs other than ADCb500/b1000 were significantly lower in glioblastoma than in oligodendroglioma (p < 0.05 for all). ADCb500/b8000 and ADCb500/b10000 were significantly higher in oligodendroglioma than in astrocytoma (p = 0.034 and 0.023). The highest AUCs were 0.818 for ADCb500/b6000 when distinguishing glioblastoma from astrocytoma, 0.979 for ADCb500/b8000 and ADCb500/b10000 when distinguishing glioblastoma from oligodendroglioma, and 0.773 for ADCb500/b10000 when distinguishing astrocytoma from oligodendroglioma. Additionally, all ADCs were negatively correlated with Ki-67 status (p < 0.05 for all). Ultra-high b-value DWI can reliably separate IDH genotypes and tumor subtypes of adult-type diffuse gliomas using WHO CNS5 criteria. Ultra-high b-value diffusion-weighted imaging can accurately distinguish isocitrate dehydrogenase genotypes and tumor subtypes of adult-type diffuse gliomas, which may facilitate personalized treatment and prognostic assessment for patients with glioma. • Ultra-high b-value diffusion-weighted imaging can accurately distinguish subtle differences in water diffusion among biological tissues. • Ultra-high b-value diffusion-weighted imaging can reliably separate isocitrate dehydrogenase genotypes and tumor subtypes of adult-type diffuse gliomas. • Compared with standard b-value diffusion-weighted imaging, high and ultra-high b-value diffusion-weighted imaging demonstrate better diagnostic performances.

Abstract 3910: The Atlas of Blood Cancer Genomes: A resource for therapeutic and biomarker development

Abstract Developing a novel cancer therapy is an expensive, time-consuming, high-risk endeavor that involves identifying a molecular target as well as target indications. This process could be accelerated by a comprehensive interrogation of driver variants and gene expression profiles across cancer types. The Atlas of Blood Cancer Genomes (ABCG) project was initiated to elucidate the molecular basis of all leukemias and lymphomas, building on advances in genomic technologies, our capabilities for data analysis, and economies of scale. The ABCG project includes collaborators from 25 institutions worldwide who contributed samples from 10,512 patients comprising every type of blood cancer in the World Health Organization classifications. All cases were de-identified and their associated pathology and clinical information entered into a purpose-built web-based system. All cases underwent pathology and clinical data review by experienced hematopathologists and oncologists. Samples were subjected to whole exome DNA and RNA sequencing. We examined three classes of therapeutic targets with selected examples of application: 1. Surface markers: Surface markers are targets of many approved and experimental therapies in blood cancers (CAR-T cells, monoclonal and bispecific antibodies). We found that CD22, which has been evaluated as a target in diffuse large B-cell lymphoma (DLBCL), is also highly expressed in follicular lymphoma, adult ALL, mantle cell lymphoma, and high-grade B cell lymphoma, all areas of clinical need. We can evaluate the expression of virtually any marker or combination of markers across all blood cancers while noting areas of greatest clinical need within and across diseases, providing the basis to reclassify diseases by therapeutic target. 2. Genetic targets: Our work assesses the entire spectrum of genetic alterations including mutations and fusions. We found targetable alterations including BCR-ABL1 fusions, EZH2 Y641, IDH2 R140Q and BRAF V600E mutations in multiple cancers, albeit at low frequency, pointing to potential new indications for existing drugs in subsets of rare diseases. 3. Complex targets (immune or expression signatures or combinations of gene variants): Past work defined DLBCL immune and other signatures associated with response to avadomide, a novel cereblon inhibitor. We found that these signatures are also highly expressed in large subsets of peripheral T-cell lymphomas and acute myeloid leukemia, both areas of major unmet clinical need. Thus, we can interrogate immune and other signatures across the spectrum of cancers to uncover potential biomarkers of response. The ABCG project will enable the comprehensive study of genomic and clinicopathological features of all blood cancers. We anticipate that our data, approaches and results will provide a lasting resource for molecular classification and therapeutic development in all leukemias and lymphomas. Citation Format: Jennifer Shingleton, Raju Pillai, Sarah Ondrejka, Govind Bhagat, Amy Chadburn, Matthew McKinney, Jean Koff, Dina Soliman, Magdalena Czader, Abner Louissaint, Shaoying Li, Choon Kiat Ong, Amir Behdad, Andrew Evens, Yaso Natkunam, Mette Pedersen, Sirpa Leppa, Eric Tse, Jennifer Chapman, Catalina Amador-Ortiz, Yuri Fedoriw, Andrew Evans, Jiong Yan, Mina Xu, Kikkeri Naresh, Clay Parker, David Hsu, Sandeep Dave. The Atlas of Blood Cancer Genomes: A resource for therapeutic and biomarker development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3910.

Age-related dynamics in acute myeloid leukemia: Implications for prognosis, risk stratification, and treatment response

Abstract BACKGROUND: Acute myeloid leukemia (AML) is a complex, heterogeneous disease driven by acquired somatic mutations. The presence of specific mutations advances stratification, treatment, and prognosis. Linear accumulation of mutations over time is a crucial factor in cancer development, particularly among elderly patients. Our recent study on gene rearrangement in AML revealed a significant association between age and adverse risk cases. AIM: The aim of this study was to examine the distribution of age, molecular characteristics, risk stratification, and treatment response based on age among patients with de novo AML in Iraq. PATIENTS AND METHODS: A prospective cohort study enrolled 115 Iraqi adult patients diagnosed with de novo AML using morphology and flow cytometry from December 2020 to May 2022. The Leukemia Q-Fusion Screening Kit, employing multiplex reverse transcription–real-time quantitative polymerase chain reaction with 30 gene rearrangements, was employed for the identification of gene rearrangement. The patients received care and follow-up at the Hematology Unit of Baghdad Teaching Hospital in Medical City. Ethical approval from the College of Medicine’s Ethical Committee at the University of Baghdad was secured before commencing the research, ensuring adherence to ethical standards throughdout the study. RESULTS: The age distribution exhibited a bimodal pattern, with a mean of 45.1 ± 17.5 years, ranging from 18 to 84 years, and a median of 46 years. A total of 39.1% of patients were diagnosed with AML before the age of 35 years, while 43% were diagnosed after the age of 51 years. AML patients with RARA mutations, RUNX1:: RUNX1T1 alterations, and NPM1 mutations were predominantly observed in younger individuals, as well as those diagnosed with AML defined by differentiation. Conversely, KMT2A rearrangements were more prevalent among older age groups, with a statistically significant difference in the distribution of AML classifications according to the World Health Organization (WHO) by age categories (P = 0.001). The risk stratification based on age and response assessment showed a notable higher risk profile observed among elderly patients that was associated with adverse risk and poorer response and mortality (P &lt; 0.05). The prediction of treatment response accuracy rate was improved by adding age to the WHO classification and ELN 2022 risk stratification (73.5%–87.9%). CONCLUSION: Age significantly influences AML prognosis and treatment response. Incorporating age into risk stratification improves accuracy. Tailored approaches considering age are vital for optimizing AML management and outcomes.

Preoperative 11 C-Methionine PET-MRI in Pediatric Infratentorial Tumors.

MRI is the main imaging modality for pediatric brain tumors, but amino acid PET can provide additional information. Simultaneous PET-MRI acquisition allows to fully assess the tumor and lower the radiation exposure. Although symptomatic posterior fossa tumors are typically resected, the patient management is evolving and will benefit from an improved preoperative tumor characterization. We aimed to explore, in children with newly diagnosed posterior fossa tumor, the complementarity of the information provided by amino acid PET and MRI parameters and the correlation to histopathological results. Children with a newly diagnosed posterior fossa tumor prospectively underwent a preoperative 11 C-methionine (MET) PET-MRI. Images were assessed visually and semiquantitatively. Using correlation, minimum apparent diffusion coefficient (ADC min ) and contrast enhancement were compared with MET SUV max . The diameter of the enhancing lesions was compared with metabolic tumoral volume. Lesions were classified according to the 2021 World Health Organization (WHO) classification. Ten children were included 4 pilocytic astrocytomas, 2 medulloblastomas, 1 ganglioglioma, 1 central nervous system embryonal tumor, and 1 schwannoma. All lesions showed visually increased MET uptake. A negative moderate correlation was found between ADC min and SUV max values ( r = -0.39). Mean SUV max was 3.8 (range, 3.3-4.2) in WHO grade 4 versus 2.5 (range, 1.7-3.0) in WHO grade 1 lesions. A positive moderate correlation was found between metabolic tumoral volume and diameter values ( r = 0.34). There was no correlation between SUV max and contrast enhancement intensity ( r = -0.15). Preoperative 11 C-MET PET and MRI could provide complementary information to characterize pediatric infratentorial tumors.

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.

Comparison of 2009 and 2011 WHO Guidelines, and Scoring Models for Adult Hospitalized Dengue Infection: A Single Observation in Tangerang, Indonesia

&lt;p&gt;&lt;strong&gt;Background:&lt;/strong&gt; World Health Organization (WHO) published a dengue guideline in 2009 and in 2011 by WHO-SEARO. However, many of dengue cases in early phase do not meet all the criteria by WHO classification. Because of this condition there is a scoring model that was published in 2015, that might help in primary health care. Therefore, a study to compare those diagnostic tools especially in adult dengue patients in Banten is needed.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Aims:&lt;/strong&gt; This study is to know the comparison between 2009 version and 2011 version of dengue diagnostic guidelines by WHO and scoring model version.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods and Material:&lt;/strong&gt; This study used a descriptive method with a cross-sectional design at 60 adult dengue patients. Each patient is grouped according to diagnostic tools’ classification and will be analyzed using Chi-square.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results:&lt;/strong&gt; Results are grouped according to the WHO diagnosis from 2009 and 2011, presumptive model and probable models where there are 46 (77%), 48 (78%), 31(52%), and 15 (25%) of patients diagnosed with dengue infection. Overall, the diagnosis made by the 2009 WHO and the probable models has the most superior sensitivity and specificity values of 84,6% and 25%, and 82,4% and 97,7% respectively compared to other diagnostic tools. However, from the results of positive predictive values, probable models have a higher percentage than the 2009 WHO diagnosis.&lt;/p&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; The probable model is more sensitive and specific than other diagnostic results. These conclude that probable model is best tool for dengue infection screening in early phase of infection.

A Novel EPC1::KDM2B Fusion in High-grade Endometrial Stromal Sarcoma.

The spectrum of endometrial stromal sarcoma (ESS) has expanded substantially since the publication of the most recent World Health Organisation (WHO) Classification of Female Genital Tumours and the advent of widely available genomic testing. We describe a uterine mesenchymal tumor harboring a novel EPC1::KDM2B fusion, best classified within the umbrella of high-grade endometrial stromal sarcoma (HGESS). This tumor was composed of a uniform population of spindled cells with some myxoid stroma, a mitotic rate of up to 21/10 high-power fields, and a largely pushing margin with focal vascular invasion. Immunohistochemistry showed strong and diffuse cyclin D1 positivity while CD10, WT1, DOG1, CD117, CD34, CD99, S100, MelanA, SMA, desmin, and h-caldesmon were negative. The tumor was confined to the uterus and no recurrence has been detected thus far, albeit with a short follow-up interval of 9mo.

Electrocardiographic proarrhythmic changes in pregnancy of women with CHD.

Pregnancy-related physiological adaptations result in increased heart rate as well as electrocardiographic changes such as a mean QTc prolongation of 27 ms. Pregnant women with CHD are at increased risk for cardiovascular complications. The aim of this study was to identify risk factors for abnormally prolonged QTc interval-a risk factor for ventricular arrhythmias-in pregnant women with CHD. Retrospective longitudinal single-centre study. Pre-pregnancy demographic and electrocardiographic risk factors for abnormal QTc duration during pregnancy of (a) > 460 ms and (b) >27 ms increase were analyzed. Eighty-three pregnancies in 63 women were included, of which three had documented arrhythmias. All five Modified World Health Organization Classification of Maternal Cardiovascular Risk (mWHO) classeswere represented, with 15 pregnancies (18.1%) in mWHO class I, 26 (31.3%) in mWHO II, 28 (33.7%) in mWHO II-III, 11 (13.3%) in mWHO III, and three pregnancies (3.6%) in mWHO class IV. Heart rate and QTc interval increased, while QRS duration and PR interval shortened during pregnancy. QTc duration of > 460 ms was associated with increased pre-pregnancy QTc interval, QRS duration, and weight, as well as body mass index. QTc increase of > 27 ms was associated with increased heart rate prior to pregnancy. No significant associations of electrocardiographic changes with mWHO class or CHD type were identified. Increased QTc in pregnant women with CHD was associated with being overweight or having higher heart rate, QRS, or QTc duration prior to pregnancy. These patients should be monitored closely for arrhythmias during pregnancy.

Childhood and Adolescent Relapsed/Refractory Aggressive B-Cell Lymphomas With t(8;14) and BCL2 Expression, Burkitt Lymphoma Versus Diffuse Large B-Cell Lymphoma: A Diagnostic Challenge.

We present 2 diagnostically challenging cases of pediatric/adolescent relapsed/refractory aggressive mature B-cell non-Hodgkin lymphoma (B-NHL) within the spectrum of Burkitt lymphoma and diffuse large B-cell lymphoma and illustrate the different therapeutic regimens that are employed for pediatric and adult cancer centers. Both cases displayed varying-sized lymphoma cells with occasional single prominent nucleoli and heterogeneous BCL2 expression. Cytogenetics revealed complex karyotypes with t(8:14)(q24.2;q32) and IGH::MYC rearrangement by FISH. Next generation sequencing revealed deleterious TP53 and MYC mutations. We concluded that both could be diagnosed as "DLBCL-NOS with MYC rearrangement" using the current pathologic classifications, 2022 International Consensus Classification (ICC) and World Health Organization Classifications of Haematolymphoid Tumors (WHO-HAEM5). This report illustrates diagnostic challenges and treatment dilemmas that may be encountered, particularly for adolescent and young adults (AYA).

Evaluation of Usability and Efficacy of Strain Elastography Method Concurrently with Preoperative Ultrasonography in Cases of Hydatid Cyst

Abstract Background: Hydatid cysts (HCs), which are among the cystic lesions of the liver, are frequently encountered in endemic areas. Routine imaging modalities are sometimes insufficient to differentiate HC types, and ultrasound (US) elastography has just begun to be used for this purpose. In this study, the effectiveness of the strain elastography (SE) method in preoperative HC cases was investigated, and the relationship between HC types and elastography values was evaluated. Methods: HC cases that underwent SE simultaneously with preoperative US between January 2019 and February 2021 were evaluated retrospectively, and 75 cases were included in the study. In addition to elastography data, cyst typing according to the World Health Organization (WHO) classification was also available. Results: Thirty cases were male and 45 cases were female, the median age was 48 years, and the interquartile range was 41 years. According to the WHO classification, 15 cases were Type I, 27 cases were Type II, and 33 cases were Type III HC. Median strain ratio (SR) values were 5.69 (4.07–14.47) for Type I, median 1.49 (1.26–1.74) for Type II, and median 0.21 (0.13–0.30) for Type III, and there was a highly significant relationship between HC types and SR values (P &lt; 0.001). There was also a very strong (-) directional correlation between HC type and strain rate (P &lt; 0.001, Spemann rho (ρ): −0.928). Conclusion: US elastography is a new modality in the diagnosis of HC types, and there are few studies available. In this study, unlike the literature, it is the first time that HC typing and discrimination have been used using the SE technique, which is remarkable.

Prognostic impact of SF3B1 mutation and multilineage dysplasia in myelodysplastic syndromes with ring sideroblasts: a Mayo Clinic study of 170 informative cases.

The revised 4th edition of the World Health Organization (WHO4R) classification lists myelodysplastic syndromes with ring sideroblasts (MDS-RS) as a separate entity with single lineage (MDS-RS-SLD) or multilineage (MDS-RS-MLD) dysplasia. The more recent International Consensus Classification (ICC) distinguishes between MDS with SF3B1 mutation (MDS-SF3B1) and MDS-RS without SF3B1 mutation; the latter is instead included under the category of MDS not otherwise specified. The current study includes 170 Mayo Clinic patients with WHO4R-defined MDS-RS, including MDS-RS-SLD (N=83) and MDS-RS-MLD (N=87); a subset of 145 patients were also evaluable for the presence of SF3B1 and other mutations, including 126 with (87%) and 19 (13%) without SF3B1 mutation. Median overall survival for all 170 patients was 6.6 years with 5- and 10-year survival rates of 59% and 25%, respectively. A significant difference in overall survival was apparent between MDS-RS-MLD and MDS-RS-SLD (p<0.01) but not between MDS-RS with and without SF3B1 mutation (p=0.36). Multivariable analysis confirmed the independent prognostic contribution of MLD (HR 1.8, 95% CI 1.1-2.8; p=0.01) and also identified age (p<0.01), transfusion need at diagnosis (p<0.01), and abnormal karyotype (p<0.01), as additional risk factors; the impact from SF3B1 or other mutations was not significant. Leukemia-free survival was independently affected by abnormal karyotype (p<0.01), RUNX1 (0.02) and IDH1 (p=0.01) mutations, but not by MLD or SF3B1 mutation. Exclusion of patients not meeting ICC-criteria for MDSSF3B1 did not change the observations on overall survival. MLD-based, as opposed to SF3B1 mutationbased, disease classification for MDS-RS might be prognostically more relevant.

L1 Cell Adhesion Molecule (L1CAM) Expression and Molecular Alterations Distinguish Low-Grade Oncocytic Tumor From Eosinophilic Chromophobe Renal Cell Carcinoma

Renal low-grade oncocytic tumor (LOT) is a recently recognized renal cell neoplasm designated within the “other oncocytic tumors” category in the 2022 World Health Organization classification system. Although the clinicopathologic, immunohistochemical, and molecular features reported for LOT have been largely consistent, the data are relatively limited. The morphologic overlap between LOT and other low-grade oncocytic neoplasms, particularly eosinophilic chromophobe renal cell carcinoma (E-chRCC), remains a controversial area in renal tumor classification. To address this uncertainty, we characterized and compared large cohorts of LOT (n = 67) and E-chRCC (n = 69) and revealed notable differences between the 2 entities. Clinically, LOT predominantly affected women, whereas E-chRCC showed a male predilection. Histologically, although almost all LOTs were dominated by a small-nested pattern, E-chRCC mainly showed solid and tubular architectures. Molecular analysis revealed that 87% of LOT cases harbored mutations in the tuberous sclerosis complex (TSC)-mTOR complex 1 (mTORC1) pathway, most frequently in MTOR and RHEB genes; a subset of LOT cases had chromosomal 7 and 19q gains. In contrast, E-chRCC lacked mTORC1 mutations, and 60% of cases displayed chromosomal losses characteristic of chRCC. We also explored the cell of origin for LOT and identified L1 cell adhesion molecule (L1CAM), a collecting duct and connecting tubule principal cell marker, as a highly sensitive and specific ancillary test for differentiating LOT from E-chRCC. This distinctive L1CAM immunohistochemical labeling suggests the principal cells as the cell of origin for LOT, unlike the intercalated cell origin of E-chRCC and oncocytoma. The ultrastructural analysis of LOT showed normal-appearing mitochondria and intracytoplasmic lumina with microvilli, different from what has been described for chRCC. Our study further supports LOT as a unique entity with a benign clinical course. Based on the likely cell of origin and its clinicopathologic characteristics, we propose that changing the nomenclature of LOT to “Oncocytic Principal Cell Adenoma of the Kidney” may be a better way to define and describe this entity.

Potential Immunohistochemical Biomarkers for Grading Oral Dysplasia: A Literature Review.

Oral cancer is a prevalent global health issue, with significant morbidity and mortality rates. Despite available preventive measures, it remains one of the most common cancers, emphasising the need for improved diagnostic and prognostic tools. This review focuses on oral potentially malignant disorders (OPMDs), precursors to oral cancer, specifically emphasising oral epithelial dysplasia (OED). The World Health Organisation (WHO) provides a three-tier grading system for OED, and recent updates have expanded the criteria to enhance diagnostic precision. In the prognostic evaluation of OED, histological grading is presently regarded as the gold standard; however, its subjectivity and unreliability in anticipating malignant transformation or recurrence pose notable limitations. The primary objective is to investigate whether specific immunohistochemical biomarkers can enhance OED grading assessment according to the WHO classification. Biomarkers exhibit significant potential for comprehensive cancer risk evaluation, early detection, diagnosis, prognosis, and treatment optimisation. Technological advancements, including sequencing and nanotechnology, have expanded detection capabilities. Some analysed biomarkers are most frequently chosen, such as p53, Ki-67, cadherins/catenins, and other proteins used to differentiate OED grades. However, further research is needed to confirm these findings and discover new potential biomarkers for precise dysplasia grading and minimally invasive assessment of the risk of malignant transformation.

DNA methylation heterogeneity attributable to a complex tumor immune microenvironment prompts prognostic risk in glioma

ABSTRACT Gliomas are malignant tumours of the human nervous system with different World Health Organization (WHO) classifications, glioblastoma (GBM) with higher grade and are more malignant than lower-grade glioma (LGG). To dissect how the DNA methylation heterogeneity in gliomas is influenced by the complex cellular composition of the tumour immune microenvironment, we first compared the DNA methylation profiles of purified human immune cells and bulk glioma tissue, stratifying three tumour immune microenvironmental subtypes for GBM and LGG samples from The Cancer Genome Atlas (TCGA). We found that more intermediate methylation sites were enriched in glioma tumour tissues, and used the Proportion of sites with Intermediate Methylation (PIM) to compare intertumoral DNA methylation heterogeneity. A larger PIM score reflected stronger DNA methylation heterogeneity. Enhanced DNA methylation heterogeneity was associated with stronger immune cell infiltration, better survival rates, and slower tumour progression in glioma patients. We then created a Cell-type-associated DNA Methylation Heterogeneity Contribution (CMHC) score to explore the impact of different immune cell types on heterogeneous CpG site (CpG ct ) in glioma tissues. We identified eight prognosis-related CpG ct to construct a risk score: the Cell-type-associated DNA Methylation Heterogeneity Risk (CMHR) score. CMHR was positively correlated with cytotoxic T-lymphocyte infiltration (CTL), and showed better predictive performance for IDH status (AUC = 0.96) and glioma histological phenotype (AUC = 0.81). Furthermore, DNA methylation alterations of eight CpG ct might be related to drug treatments of gliomas. In conclusion, we indicated that DNA methylation heterogeneity is associated with a complex tumour immune microenvironment, glioma phenotype, and patient’s prognosis.

The 2022 classifications of B-cell lymphomas and plasma cell disorders

Tumors derived from B-lymphocytes at their various stage of maturation and differentiation (human B-cell lymphomas and leukemias) are the commonest hematological malignancies. Previous editions of the World Health Organization (WHO) classification of Hematopoietic and lymphoid neoplasms, edited in 2001, 2008, and 2017, intended to standardize the diagnosis of hemopoietic neoplasms overall. Recent advances in lymphoma research, mostly based on genomic as well as molecular analyses, have dramatically expanded our knowledge of lymphoma biology, this leading to improved diagnostic criteria, upgrading of provisional entities, and identification of new tumor types. In 2022, two frameworks for classifying hematolymphoid neoplasms were proposed: the WHO-HAEM5 and the International Consensus Classification (ICC). Since a common nosography is essential for advancing health science and providing a foundation for precision medicine, it is critical to recognize possible differences and harmonize the diverse approaches. In this article, the Authors summarizes the key differences between the two most recent classifications by focusing on tumors derived from B-lymphocytes and plasma cells.

Overview on WHO-HAEM5 and the diagnostic relevance of genetic alterations for the classification

Abstract The landscape of haematological malignancies is constantly evolving, driven by advances in our understanding of their genetic basis. This has cumulated within the 5th Edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours published in short form in 2022 [1, 2] and being available in full length both as “Blue Book” (in print expected early 2024) as well as web-based classification (see: https://tumourclassification.iarc.who.int/welcome/). Similarly, the importance of genetic alterations for the classification is highlighted in other classification systems related to haematologic neoplasms [3–5]. In this special issue of the Medizinische Genetik, we present a comprehensive overview of the genetic alterations contributing to the classification of haematolymphoid neoplasms in the 5th Edition of the WHO classification (WHO-HAEM5) and its diagnostic relevance in the context of various haematological malignancies.

Rare variant of large pediatric glioneuronal tumor with novel MYO5A::NTRK3 fusion: illustrative case.

Glioneuronal tumors (GNTs) comprise a rare class of central nervous system (CNS) neoplasms with varying degrees of neuronal and glial differentiation that predominately affect children and young adults. Within the current 2021 World Health Organization (WHO) classification of CNS tumors, GNTs encompass 14 distinct tumor types. Recently, the use of whole-genome DNA methylation profiling has allowed more precise classification of this tumor group. A 3-year-old male presented with a 3-month history of increasing head circumference, regression of developmental milestones, and speech delay. Magnetic resonance imaging of the brain was notable for a large left hemispheric multiseptated mass with significant mass effect and midline shift that was treated with near-total resection. Histological and molecular assessment demonstrated a glioneuronal tumor harboring an MYO5A::NTRK3 fusion. By DNA methylation profiling, this tumor matched to a provisional methylation class known as "glioneuronal tumor kinase-fused" (GNT kinase-fused). The patient was later started on targeted therapy with larotrectinib. This is the first report of an MYO5A::NTRK3 fusion in a pediatric GNT. GNT kinase-fused is a provisional methylation class not currently included in the WHO classification of CNS tumors. This case highlights the impact of thorough molecular characterization of CNS tumors, especially with the increasing availability of novel gene targeting therapies.

Clinical outcomes and implication of radioactive iodine therapy on cancer-specific survival in WHO classification of FTC.

The clinical outcomes and implications of radioactive iodine therapy (RAIT) on cancer-specific survival (CSS) in World Health Organization (WHO) classification of follicular thyroid carcinoma (FTC) are not well established. The data of eligible patients with minimally invasive FTC (mi-FTC), encapsulated angioinvasive FTC (ea-FTC), or widely invasive FTC (wi-FTC) between 2000 and 2020 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Cancer-specific survival (CSS), the primary outcome, was compared among the three subtypes of FTC patients before and after adjusting for differences using propensity score matching (PSM). The FTC patients in different subtypes were then divided into two groups: the RAIT group and the no-RAIT group. Cox proportional hazards regression analyses were applied to discover the relationships of factors associated with CSS in the each PSM cohort. A total of 2433 mi-FTC patients, 216 ea-FTC patients, and 554 wi-FTC patients were enrolled in the original cohorts, respectively. Patients with mi-FTC or ea-FTC had similar CSS (p =0.805), which was better than that of patients with wi-FTC (p <.001; p =0.021). Cox proportional hazards regression analysis revealed that RAIT was not associated with improved CSS in either the mi-FTC PSM cohort (HR =1.21, 95% CI=0.46-3.18, p =0.705) or the wi-FTC PSM cohort (HR =0.56, 95% CI=0.35-1.08, p =0.086). However, subgroup analysis demonstrated that wi-FTC patients with N1 stage (HR =0.44, 95% CI=0.20-0.99, p =0.018) or M1 stage (HR =0.25, 95% CI=00.11-0.53, p <.001) could gain CSS advantage from RAIT. The RAIT can provide a CSS advantage for wi-FTC patients who with N1-stage or M1-stage disease.