Modern Pathology最新文献

{"title":"Independent Validation of a HER2-Low Focused Immunohistochemistry Scoring System for Enhanced Pathologist Precision and Consistency","authors":"Gelareh Farshid ,&nbsp;Jane Armes ,&nbsp;Benjamin Dessauvagie ,&nbsp;Amardeep Gilhotra ,&nbsp;Beena Kumar ,&nbsp;Hema Mahajan ,&nbsp;Ewan Millar ,&nbsp;Nirmala Pathmanathan ,&nbsp;Cameron Snell","doi":"10.1016/j.modpat.2024.100693","DOIUrl":"10.1016/j.modpat.2024.100693","url":null,"abstract":"<div><div>For 2 decades, the American Society of Clinial Oncology-College of American Pathologists human epidermal growth factor receptor 2 (HER2) testing criteria have included 0 and 1+ scores, but this distinction was inconsequential. Now, based on the DESTINY Breast-04 Trial (DB-04) results, for patients with metastatic breast cancer it underpins eligibility for trastuzumab-deruxtecan treatment. Discerning 0 from 1+ immunohistochemistry (IHC) staining is challenging, as HER2 low is not a biologically distinct cancer subset, there are no reference standards or controls, and second-tier tests (eg, in situ hybridization) do not apply. Prior reports cast doubt on the reliability of pathologists’ IHC scoring, with resulting treatment misalignments. With institutional review board approval, our group of 9 breast pathologists from 8 Australian laboratories had previously established HER2-low-focused scoring conventions, based on the American Society of Clinial Oncology-College of American Pathologists 2018 HER2 guidelines, and specifying common staining pitfalls. We reported the results of the first set of 60 breast cancers evaluated with these methods. After a 5-month washout, for the present validation study, we have compiled a second set of 64 HER2-negative invasive breast cancer core biopsies, all assessed with the Ventana 4B5 HER2 assay. We have each scored digitized images of HER2 IHC slides of the cases. Using the majority opinion as the target score, we have calculated our performance metrics. We have compared the results of our performance in set 1 and set 2 to assess the effectiveness of our approach and learning retention. The cases in this validation set included 40 (62.5%) HER2 low, 10 (17.2%) ultralow (UL), and 13 (18.8%) null cancers. Concordance was not achieved in 1 case. For distinguishing HER2 low from other cancers (UL and null combined) the mean values of our performance metrics were accuracy 89.58%, sensitivity 90.83%, specificity 87.50%, positive predictive value 95.63%, negative predictive value 83.59%, and Cohen kappa score 0.81. Comparing these results with our initial study, we have maintained our high level of performance across these parameters. Our mean kappa score is now in the excellent range for concordance. Maintaining high performance across a range of measures in 2 separate data sets validates the effectiveness of our HER2-low-focused scoring conventions. Having validated our approach, we will use these reference case sets with expert-level consensus scores for peer training and updating our national HER2 IHC external quality assurance program. In our ongoing studies, we are also assessing the performance of software algorithms to determine their suitability for the prescreening of HER2 IHC slides.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 4","pages":"Article 100693"},"PeriodicalIF":7.1,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational Pathology-Enabled Residual Tumor Estimation Is a Prognostic Factor for Overall Survival in Anal Squamous Cell Carcinoma","authors":"Paula Toro ,&nbsp;Ahmed Bakhshwin ,&nbsp;Bassel Zein-Sabatto ,&nbsp;Neha Khaitan ,&nbsp;Lauren Duckworth ,&nbsp;Ana Bennett ,&nbsp;Sarah S. Elsoukkary ,&nbsp;Xuefeng Zhang ,&nbsp;Sneha Govande ,&nbsp;Emily C. Zabor ,&nbsp;David Liska ,&nbsp;Ehsan Balagamwala ,&nbsp;Daniela S. Allende","doi":"10.1016/j.modpat.2024.100692","DOIUrl":"10.1016/j.modpat.2024.100692","url":null,"abstract":"<div><div>The incidence of anal squamous cell carcinoma (SCC) has increased, and treatment has shifted from surgery to chemoradiotherapy (CRT), with salvage abdominoperineal resection being reserved for persistent/recurrent cases. This study evaluates the utility of different tumor regression scoring systems in predicting survival in anal SCC patients, using pathologists’ observations and digital pathology. Data of cases managed surgically from 2005 to 2019 were collected. Residual tumor was assessed by multiple methods (gross tumor size, largest focus of tumor on hematoxylin and eosin (H&amp;E) slide, average of residual tumor in all submitted H&amp;E slides, Japanese Esophageal Society, Chirieac, Schneider, Hermann, and College of American Pathologists scoring system). Three expert pathologists individually estimated (“eyeballed”) the residual tumor percentage based on residual tumor/tumor bed (single representative H&amp;E slide). The QuPath software was used to measure tumor volume on the same slide. The American Joint Committee on Cancer eighth staging and outcome data were retrieved from electronic medical records. The study involved 48 participants, predominantly female (56%), with a median age of 57 years. Most were Caucasian. Human papillomavirus-positive was present in 77% of those assessed (17/22). Initial treatment included CRT, followed by abdominoperineal resection (79%) or pelvic exenteration (21%). Complications (13%), persistent disease (33%), and recurrence (54%) led to surgical interventions. Fifty-one percent had moderately differentiated SCC, whereas 42% were poorly differentiated. Lymphovascular invasion (44%), perineural invasion (38%), and lymph node metastasis (13%) were present. Distant metastasis was rare (2%). Median overall survival was 3.2 years. Positive margins (hazard ratio, 4.12; 95% CI, 1.83-9.28) and larger tumor size (hazard ratio, 1.02; 95% CI, 1.01-1.03) were associated with an increased hazard of death. Most residual tumor measurement methods were not significantly associated with overall survival. Interobserver agreement (based on “eyeballing”) was moderate (kappa, 0.4). Computational pathology-based residual tumor percentage was the only method significantly associated with outcome, with each 10% increase in the residual tumor percentage corresponding to a 1.23-fold higher hazard death (95% CI, 1.03; 1.46; <em>P</em> = .024). This study highlights computational pathology’s important role in predicting outcomes in anal SCC treated with CRT and surgery. Specifically, the computational assessment of the residual tumor percentage proves to be a strong predictor of overall survival, outperforming other established tumor regression scoring systems methods.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 4","pages":"Article 100692"},"PeriodicalIF":7.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficient and Generalizable Prediction of Molecular Alterations in Multiple-Cancer Cohorts Using Hematoxylin and Eosin Whole Slide Images","authors":"Kshitij Ingale ,&nbsp;Sun Hae Hong ,&nbsp;Qiyuan Hu ,&nbsp;Renyu Zhang ,&nbsp;Bolesław L. Osinski ,&nbsp;Mina Khoshdeli ,&nbsp;Josh Och ,&nbsp;Kunal Nagpal ,&nbsp;Martin C. Stumpe ,&nbsp;Rohan P. Joshi","doi":"10.1016/j.modpat.2024.100691","DOIUrl":"10.1016/j.modpat.2024.100691","url":null,"abstract":"<div><div>Molecular testing of tumor samples for targetable biomarkers is restricted by a lack of standardization, turnaround time, cost, and tissue availability across cancer types. Additionally, targetable alterations of low prevalence may not be tested in routine workflows. Algorithms that predict DNA alterations from routinely generated hematoxylin and eosin–stained images could prioritize samples for confirmatory molecular testing. Costs and the necessity of a large number of samples containing mutations limit approaches that train individual algorithms for each alteration. In this work, models were trained for simultaneous prediction of multiple DNA alterations from hematoxylin and eosin images using a multitask approach. Compared with biomarker-specific models, this approach performed better on average, with pronounced gains for rare mutations. The models reasonably generalized to independent temporal holdout, externally stained, and multisite The Cancer Genome Atlas test sets. Additionally, whole slide image embeddings derived using multitask models demonstrated strong performance in downstream tasks that were not a part of training. Overall, this is a promising approach to develop clinically useful algorithms that provide multiple actionable predictions from a single slide.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 4","pages":"Article 100691"},"PeriodicalIF":7.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ethical and Bias Considerations in Artificial Intelligence/Machine Learning","authors":"Matthew G. Hanna ,&nbsp;Liron Pantanowitz ,&nbsp;Brian Jackson ,&nbsp;Octavia Palmer ,&nbsp;Shyam Visweswaran ,&nbsp;Joshua Pantanowitz ,&nbsp;Mustafa Deebajah ,&nbsp;Hooman H. Rashidi","doi":"10.1016/j.modpat.2024.100686","DOIUrl":"10.1016/j.modpat.2024.100686","url":null,"abstract":"<div><div>As artificial intelligence (AI) gains prominence in pathology and medicine, the ethical implications and potential biases within such integrated AI models will require careful scrutiny. Ethics and bias are important considerations in our practice settings, especially as an increased number of machine learning (ML) systems are being integrated within our various medical domains. Such ML-based systems have demonstrated remarkable capabilities in specified tasks such as, but not limited to, image recognition, natural language processing, and predictive analytics. However, the potential bias that may exist within such AI-ML models can also inadvertently lead to unfair and potentially detrimental outcomes. The source of bias within such ML models can be due to numerous factors but is typically categorized into 3 main buckets (data bias, development bias, and interaction bias). These could be due to the training data, algorithmic bias, feature engineering and selection issues, clinic and institutional bias (ie, practice variability), reporting bias, and temporal bias (ie, changes in technology, clinical practice, or disease patterns). Therefore, despite the potential of these AI-ML applications, their deployment in our day-to-day practice also raises noteworthy ethical concerns. To address ethics and bias in medicine, a comprehensive evaluation process is required, which will encompass all aspects of such systems, from model development through clinical deployment. Addressing these biases is crucial to ensure that AI-ML systems remain fair, transparent, and beneficial to all. This review will discuss the relevant ethical and bias considerations in AI-ML specifically within the pathology and medical domain.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 3","pages":"Article 100686"},"PeriodicalIF":7.1,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered TP53, CDKN2A, ATM, EPHA7, POT1, CHEK1, GRIN2A, and EGFR Predict Shorter Survival in Penile Squamous Cell Carcinoma","authors":"Jan Hojný ,&nbsp;Jan Hrudka ,&nbsp;Zuzana Prouzová ,&nbsp;Michaela Kendall Bártů ,&nbsp;Eva Krkavcová ,&nbsp;Jiří Dvořák ,&nbsp;Romana Michálková ,&nbsp;David Čapka ,&nbsp;Nicolette Zavillová ,&nbsp;Radoslav Matěj ,&nbsp;Petr Waldauf","doi":"10.1016/j.modpat.2024.100689","DOIUrl":"10.1016/j.modpat.2024.100689","url":null,"abstract":"<div><div>Penile squamous cell carcinoma (pSCC) represents an uncommon malignancy characterized by stagnant mortality, psychosexual distress, and a highly variable prognosis. Currently, the World Health Organization distinguishes between human papillomavirus (HPV)–related and HPV-independent pSCC. Recently, there has been an evolving line of research documenting the enrichment of HPV-independent pSCC with a high tumor mutational burden (TMB) and programmed death ligand-1 expression, as well as clusters of genes associated with HPV status. In this study, we conducted comprehensive next-generation sequencing DNA profiling of 146 pSCC samples using a panel consisting of 355 genes associated with tumors. This profiling was correlated with immunohistochemical markers and prognostic clinical data. A survival analysis of recurrent genomic events (found in ≥10 cases) was performed. <em>TP53</em>, <em>CDKN2A</em>, <em>ATM</em>, <em>EPHA7</em>, <em>POT1</em>, <em>CHEK1</em>, <em>GRIN2A</em>, and <em>EGFR</em> alterations were associated with significantly shortened overall survival in univariate and multivariate analysis. HPV positivity, diagnosed through both p16 immunohistochemistry and HPV DNA analysis, displayed no impact on survival but was associated with high-grade, lymphatic invasion, programmed death ligand-1 negativity/weak expression, and low TMB. <em>FAT1</em>, <em>TP53</em>, <em>CDKN2A</em>, <em>CASP8</em>, and <em>HRAS</em> were more often mutated in HPV-independent pSCC. In contrast, HPV-associated pSCCs were enriched by <em>EPHA7</em>, <em>ATM</em>, <em>GRIN2A</em>, and <em>CHEK1</em> mutations. <em>PIK3CA</em>, <em>FAT1</em>, <em>FBXW7</em>, and <em>KMT2D</em> mutations were associated with high TMB. <em>NOTCH1</em>, <em>TP53</em>, <em>CDKN2A</em>, <em>POT1</em>, <em>KMT2D</em>, <em>ATM</em>, <em>CHEK1</em>, <em>EPHA3</em>, and <em>EGFR</em> alterations were related to adverse clinicopathologic signs, such as advanced stage, high tumor budding, and lymphovascular invasion. We detected 160 alterations with potential treatment implications, with 21.2% of samples showing alterations in the homologous recombination repair pathway. To the best of our knowledge, this study describes the largest cohort of pSCC with complex molecular pathologic, clinical, and prognostic analysis correlating with prognosis.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 4","pages":"Article 100689"},"PeriodicalIF":7.1,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Etiology and Outcomes of Kidney-Limited and Systemic Thrombotic Microangiopathy","authors":"Daan P.C. van Doorn ,&nbsp;Rachid Tobal ,&nbsp;Myrurgia A. Abdul-Hamid ,&nbsp;Pieter van Paassen ,&nbsp;Sjoerd A.M.E.G. Timmermans","doi":"10.1016/j.modpat.2024.100690","DOIUrl":"10.1016/j.modpat.2024.100690","url":null,"abstract":"<div><div>The syndromes of thrombotic microangiopathy (TMA) are associated with acute kidney injury and end-stage kidney disease. TMAs typically present with thrombocytopenia and microangiopathic hemolytic anemia (ie, systemic TMA). Kidney-limited TMA can occur, although often overlooked and undertreated. In this study, we studied the etiology and outcome of kidney-limited TMA. Patients with TMA on kidney biopsy, either systemic or kidney-limited, were recruited and classified as definite complement-mediated (C-)TMA (ie, ≥1 pathogenic complement gene variant), probable C-TMA (ie, massive ex vivo C5b9 formation without a pathogenic complement gene variant), and non (n)C-TMA (ie, normal ex vivo C5b9 formation). Morphologic features of TMA on kidney biopsy and their clinical correlates were studied. Patients were classified as definite C-TMA (<em>N</em> = 14; 18%), probable C-TMA (<em>N</em> = 21; 27%), or nC-TMA (<em>N</em> = 42; 55%), including 51 (66%) out of 77 patients with kidney-limited TMA. Patients with definite and probable C-TMA often presented with hemolysis (79% and 62% vs 34%; <em>P</em> = .007), glomerular thrombosis (79% and 76% vs 43%), a higher creatinine level (974 and 502 vs 280 μmol/L; <em>P</em> = .001), and a younger age (33 and 33 vs 40 years; <em>P</em> = .029) as compared with nC-TMA. Morphologic features neither defined etiology nor differed between systemic and kidney-limited TMA. Eculizumab improved kidney outcomes in patients with kidney-limited C-TMA but not in those with nC-TMA akin to patients with systemic C-TMA. Kidney outcomes were not affected by chronicity grading on kidney biopsy. Kidney-limited TMA is common in diverse TMAs, including C-TMA. A kidney biopsy is needed to detect TMA at the earliest possible stage of the disease. Morphology does not allow for the identification of etiology, and patients with kidney-limited TMA should therefore be screened for complement dysregulation, having a major impact on treatment and prognosis.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 4","pages":"Article 100690"},"PeriodicalIF":7.1,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Generative Artificial Intelligence in Pathology and Medicine: A Deeper Dive","authors":"Hooman H. Rashidi ,&nbsp;Joshua Pantanowitz ,&nbsp;Alireza Chamanzar ,&nbsp;Brandon Fennell ,&nbsp;Yanshan Wang ,&nbsp;Rama R. Gullapalli ,&nbsp;Ahmad Tafti ,&nbsp;Mustafa Deebajah ,&nbsp;Samer Albahra ,&nbsp;Eric Glassy ,&nbsp;Matthew G. Hanna ,&nbsp;Liron Pantanowitz","doi":"10.1016/j.modpat.2024.100687","DOIUrl":"10.1016/j.modpat.2024.100687","url":null,"abstract":"<div><div>This review article builds upon the introductory piece in our 7-part series, delving deeper into the transformative potential of generative artificial intelligence (Gen AI) in pathology and medicine. The article explores the applications of Gen AI models in pathology and medicine, including the use of custom chatbots for diagnostic report generation, synthetic image synthesis for training new models, data set augmentation, hypothetical scenario generation for educational purposes, and the use of multimodal along with multiagent models. This article also provides an overview of the common categories within Gen AI models, discussing open-source and closed-source models, as well as specific examples of popular models such as GPT-4, Llama, Mistral, DALL-E, Stable Diffusion, and their associated frameworks (eg, transformers, generative adversarial networks, diffusion-based neural networks), along with their limitations and challenges, especially within the medical domain. We also review common libraries and tools that are currently deemed necessary to build and integrate such models. Finally, we look to the future, discussing the potential impact of Gen AI on health care, including benefits, challenges, and concerns related to privacy, bias, ethics, application programming interface costs, and security measures.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 4","pages":"Article 100687"},"PeriodicalIF":7.1,"publicationDate":"2024-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatially Resolved Single-Cell Transcriptome Analysis of Mycosis Fungoides Reveals Distinct Biomarkers GNLY and FYB1 Compared With Psoriasis and Chronic Spongiotic Dermatitis","authors":"Joon Min Jung,&nbsp;Chong Hyun Won,&nbsp;Sung Eun Chang,&nbsp;Mi Woo Lee,&nbsp;Woo Jin Lee","doi":"10.1016/j.modpat.2024.100681","DOIUrl":"10.1016/j.modpat.2024.100681","url":null,"abstract":"<div><div>Early mycosis fungoides (MF) and inflammatory dermatoses including psoriasis and chronic spongiotic dermatitis are often difficult to differentiate. We explored diagnostic markers differentiating MF from psoriasis and chronic spongiotic dermatitis via spatially resolved single-cell transcriptome analysis. Single-cell transcriptomics of intraepidermal T cells of MF patches, psoriasis, and chronic spongiotic dermatitis were analyzed using CosMx spatial molecular imager utilizing surface markers, including CD3 and CD4. An immunohistochemical study with potential markers was performed to verify clinical utility. Compared with psoriasis and chronic spongiotic dermatitis, 41 upregulated differentially expressed genes (DEGs) in MF were associated with the T-cell receptor (TCR) signaling pathway and apoptosis regulation. Protein–protein interaction network analysis of these DEGs revealed a main cluster associated with TCR signaling. Pathway enrichment analysis showed that apoptosis, Th17 cell differentiation, and TCR signaling pathways were enriched in MF. <em>GNLY</em> and <em>FYB1</em>, DEGs with the highest fold-change values, were selected as potential diagnostic biomarkers for MF. For immunohistochemistry, biopsy specimens from 150 patients diagnosed with patch MF with CD4⁺ immunophenotype (<em>n</em> = 56), psoriasis (<em>n</em> = 48), and chronic eczema (<em>n</em> = 46) were included. The sensitivity and specificity of granulysin (GNLY) for distinguishing MF and psoriasis/chronic spongiotic dermatitis were 67.9% and 93.6%, respectively. For FYN-binding protein 1 (FYB1), those values were 73.2% and 69.2%, respectively. The area under the receiver operating characteristic curve values of GNLY and FYB1 were 0.86 and 0.79, respectively. In conclusion, granulysin and FYB1 can be promising diagnostic biomarkers for differentiating early-stage MF from psoriasis and chronic spongiotic dermatitis.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 3","pages":"Article 100681"},"PeriodicalIF":7.1,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic and Transcriptomic Analysis of Ameloblastoma Reveals Distinct Molecularly Aggressive Phenotypes","authors":"Constanza Marín-Márquez ,&nbsp;Akinyele O. Adisa ,&nbsp;Sven E. Niklander ,&nbsp;Janine Kirby ,&nbsp;Keith D. Hunter","doi":"10.1016/j.modpat.2024.100682","DOIUrl":"10.1016/j.modpat.2024.100682","url":null,"abstract":"<div><div>Ameloblastoma (AM) is a benign but locally infiltrative epithelial odontogenic neoplasm of the jawbones that may reach grotesque proportions and be highly recurrent if inadequately removed. The BRAF^V600E mutation has been demonstrated as a key molecular event in its development; nevertheless, there are many queries about its etiopathogenesis, which are yet to be answered. In this study, we aimed to integrate the results from whole-exome sequencing (WES) and RNA sequencing in AM samples to identify novel candidate genes that may be relevant to its pathogenesis. Thirteen-matched tumors were subjected to WES and RNA-seq, respectively, to detect gene mutations and gene expression profiles, along with the presence of gene fusions. Mutations were validated using Sanger sequencing, whereas transcriptome results were validated using qPCR. The results from both molecular techniques were merged in order to identify novel candidate genes that were biologically validated with immunohistochemistry. BRAF^V600E mutation was present in 62% of the analyzed cases, and each AM presented at least 2 or 3 mutations affecting cancer-driver genes. RNA-seq showed different molecular subgroups associated with an aggressive and cancer-related phenotype (epithelial-mesenchymal transition and KRAS gene sets). No gene fusions were detected among the cases. <em>CDH11</em> and <em>TGM2</em>, novel genes associated with epithelial-mesenchymal transition in AM, were selected and validated in tissues. Both WES and RNA-seq results showed gene alterations related to proliferation, cell differentiation, and metabolic processes. These results show that AM shares many of the hallmarks of cancer secondary to the presence of oncogenic mutations or activation of oncogenic signaling pathways.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 3","pages":"Article 100682"},"PeriodicalIF":7.1,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing Nodal Gamma-Delta T-Cell Lymphoma: Clinicopathological and Molecular Insights","authors":"Ming Liang Oon ,&nbsp;Jing Quan Lim ,&nbsp;Jan Bosch-Schips ,&nbsp;Fina Climent ,&nbsp;Rex K.H. Au-Yeung ,&nbsp;Bailey Hutchison ,&nbsp;Aliyah R. Sohani ,&nbsp;Ozgur Can Eren ,&nbsp;Jyoti Kumar ,&nbsp;Ahmet Dogan ,&nbsp;Choon-Kiat Ong ,&nbsp;Leticia Quintanilla-Martinez ,&nbsp;Siok-Bian Ng","doi":"10.1016/j.modpat.2024.100685","DOIUrl":"10.1016/j.modpat.2024.100685","url":null,"abstract":"<div><div>Peripheral T-cell lymphomas with gamma-delta phenotype (GDTCL) are rare lymphoid malignancies. Beyond the well-recognized entities of extranodal lymphomas with gamma-delta phenotype as defined by the fifth edition of the World Health Organization Classification of Hematolymphoid Tumors and 2022 International Consensus Classification, there is a group of poorly defined gamma-delta T-cell lymphomas with predominantly nodal presentation, termed as nodal GDTCL (nGDTCL). In this study, we present a series of 12 cases of Epstein-Barr virus-negative nGDTCL, highlighting the clinical, histopathological, and molecular features of this rare entity. Seven cases reported in the literature were included in the analysis. Of the 12 cases, nGDTCL shows an increased incidence in elderly men, with a median age of 65.5 years. All cases presented primarily with enlarged lymph nodes, and 4 cases (4/12, 33.3%) showed involvement of extranodal sites, including skin, liver, spleen, and bone marrow. Histologically, 9 cases showed a diffuse and monomorphic proliferation of mostly medium-to-large lymphoid cells, whereas 3 cases demonstrated lymphoepithelioid morphology. All cases (12/12, 100%) were positive for CD3 and TCRγδ. CD4, CD8, and CD56 were positive in 66.7% (8/12), 25% (3/12), and 8.3% (1/11) of cases, respectively. Most cases (8/12, 66.7%) showed a noncytotoxic phenotype. Using immunohistochemistry, the majority of cases (6/8, 75.0%) belonged to the peripheral T-cell lymphoma-GATA3 subtype with GATA3 and/or CCR4 expression and a noncytotoxic CD4-positive phenotype. Two cases (2/8, 25%) belonged to the peripheral T-cell lymphoma-TBX21 subtype, of which 1 displayed a cytotoxic CD8-positive phenotype. Next-generation sequencing was performed in 9 cases, and <em>TP53</em> mutation was detected in 66.7% (6/9) of the cases. Mutations of <em>ATM</em> and <em>KSR2</em> were identified in 2 cases each. It remains uncertain whether nGDTCL represents a distinct entity, and further studies are needed for better characterization. Nonetheless, nodal-based GDTCL should be distinguished from secondary nodal involvement by other extranodal GDTCL and Epstein-Barr virus-positive T/NK-cell lymphoproliferative diseases.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 3","pages":"Article 100685"},"PeriodicalIF":7.1,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}