Pub Date : 2024-09-25DOI: 10.1016/j.modpat.2024.100625
Philipp Jurmeister , Maximilian Leitheiser , Alexander Arnold , Emma Payá Capilla , Liliana H. Mochmann , Yauheniya Zhdanovic , Konstanze Schleich , Nina Jung , Edgar Calderon Chimal , Andreas Jung , Jörg Kumbrink , Patrick Harter , Niklas Prenißl , Sefer Elezkurtaj , Luka Brcic , Nikolaus Deigendesch , Stephan Frank , Jürgen Hench , Sebastian Försch , Gerben Breimer , Stephan Ihrler
Tumors of the major and minor salivary glands histologically encompass a diverse and partly overlapping spectrum of frequent diagnostically challenging neoplasms. Despite recent advances in molecular testing and the identification of tumor-specific mutations or gene fusions, there is an unmet need to identify additional diagnostic biomarkers for entities lacking specific alterations. In this study, we collected a comprehensive cohort of 363 cases encompassing 20 different salivary gland tumor entities and explored the potential of DNA methylation to classify these tumors. We were able to show that most entities show specific epigenetic signatures and present a machine learning algorithm that achieved a mean balanced accuracy of 0.991. Of note, we showed that cribriform adenocarcinoma is epigenetically distinct from classical polymorphous adenocarcinoma, which could support risk stratification of these tumors. Myoepithelioma and pleomorphic adenoma form a uniform epigenetic class, supporting the theory of a single entity with a broad but continuous morphologic spectrum. Furthermore, we identified a histomorphologically heterogeneous but epigenetically distinct class that could represent a novel tumor entity. In conclusion, our study provides a comprehensive resource of the DNA methylation landscape of salivary gland tumors. Our data provide novel insight into disputed entities and show the potential of DNA methylation to identify new tumor classes. Furthermore, in future, our machine learning classifier could support the histopathologic diagnosis of salivary gland tumors.
大唾液腺和小唾液腺肿瘤在组织学上包括多种多样且部分重叠的肿瘤，在诊断上经常具有挑战性。尽管最近在分子检测和肿瘤特异性突变或基因融合的鉴定方面取得了进展，但对于缺乏特异性改变的实体来说，鉴定其他诊断生物标志物的需求仍未得到满足。在这项研究中，我们收集了一个包含 20 种不同唾液腺肿瘤实体的 363 个病例的综合队列，并探索了 DNA 甲基化对这些肿瘤进行分类的潜力。我们能够证明大多数实体都显示出特定的表观遗传特征，并提出了一种机器学习算法，其平均平衡准确率达到了 0.991。值得注意的是，我们发现楔形腺癌在表观遗传学上有别于经典的多形性腺癌，这有助于对这些肿瘤进行风险分层。肌上皮瘤和多形性腺瘤形成了一个统一的表观遗传学类别，支持了具有广泛但连续形态谱的单一实体的理论。此外，我们还发现了一个组织形态异质但表观遗传学上不同的类别，它可能代表了一个新的肿瘤实体。总之，我们的研究提供了唾液腺肿瘤 DNA 甲基化图谱的全面资源。我们的数据提供了对有争议实体的新见解，并显示了 DNA 甲基化在识别新肿瘤类别方面的潜力。此外，我们的机器学习分类器将来还能支持涎腺肿瘤的组织病理学诊断。
{"title":"DNA Methylation Profiling of Salivary Gland Tumors Supports and Expands Conventional Classification","authors":"Philipp Jurmeister , Maximilian Leitheiser , Alexander Arnold , Emma Payá Capilla , Liliana H. Mochmann , Yauheniya Zhdanovic , Konstanze Schleich , Nina Jung , Edgar Calderon Chimal , Andreas Jung , Jörg Kumbrink , Patrick Harter , Niklas Prenißl , Sefer Elezkurtaj , Luka Brcic , Nikolaus Deigendesch , Stephan Frank , Jürgen Hench , Sebastian Försch , Gerben Breimer , Stephan Ihrler","doi":"10.1016/j.modpat.2024.100625","DOIUrl":"10.1016/j.modpat.2024.100625","url":null,"abstract":"<div><div>Tumors of the major and minor salivary glands histologically encompass a diverse and partly overlapping spectrum of frequent diagnostically challenging neoplasms. Despite recent advances in molecular testing and the identification of tumor-specific mutations or gene fusions, there is an unmet need to identify additional diagnostic biomarkers for entities lacking specific alterations. In this study, we collected a comprehensive cohort of 363 cases encompassing 20 different salivary gland tumor entities and explored the potential of DNA methylation to classify these tumors. We were able to show that most entities show specific epigenetic signatures and present a machine learning algorithm that achieved a mean balanced accuracy of 0.991. Of note, we showed that cribriform adenocarcinoma is epigenetically distinct from classical polymorphous adenocarcinoma, which could support risk stratification of these tumors. Myoepithelioma and pleomorphic adenoma form a uniform epigenetic class, supporting the theory of a single entity with a broad but continuous morphologic spectrum. Furthermore, we identified a histomorphologically heterogeneous but epigenetically distinct class that could represent a novel tumor entity. In conclusion, our study provides a comprehensive resource of the DNA methylation landscape of salivary gland tumors. Our data provide novel insight into disputed entities and show the potential of DNA methylation to identify new tumor classes. Furthermore, in future, our machine learning classifier could support the histopathologic diagnosis of salivary gland tumors.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 12","pages":"Article 100625"},"PeriodicalIF":7.1,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350232","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}
Pub Date : 2024-09-24DOI: 10.1016/j.modpat.2024.100624
Dario de Biase , Jacopo Lenzi , Claudio Ceccarelli , Thais Maloberti , Marco Grillini , Camelia Alexandra Coadǎ , Claudio Zamagni , Pierandrea De Iaco , Anna Myriam Perrone , Donatella Santini , Martin Köbel , Cheng-Han Lee , Giovanni Tallini , Antonio De Leo
Compartmentation of the immune response into 3 main spatial cancer-immune phenotypes (SCIs) – inflamed, excluded, and desert – has been proposed as the main predictor of response to immune checkpoint inhibitors in solid tumors. The objective of the study was to define and characterize the SCI in a consecutive series of 213 endometrial carcinomas (ECs) by correlating it with molecular subtypes, clinicopathologic features, and prognosis. Immunohistochemistry (IHC) and next-generation sequencing were used to assign surrogate molecular EC subtypes: POLE mutant (POLE), mismatch repair deficient (MMRd), TP53 mutant (p53abn), and no specific molecular profile (NSMP). Immune cell markers (CD20, CD3, CD8, CD68, PD-L1) were assessed by IHC on whole sections and quantified by digital image analysis to define the 3 SCIs. ECs were stratified into 4 molecular subtypes: 17 (8.0%) POLE, 68 (31.9%) MMRd, 42 (19.7%) p53abn, and 86 (40.4%) NSMP. SCI determination showed 105 (49.3%) inflamed, 62 (29.1%) desert, and 46 (25.6%) excluded tumors. The inflamed phenotype was more prevalent in MMRd (64.7%) and POLE (76.5%) subtypes compared with NSMP (45.3%) and p53abn (21.4%). SCI revealed a strong correlation with disease-free survival in NSMP tumors: inflamed 96.2%, desert 83.2%, and excluded 40.5%. The SCI prognostic impact was also maintained in NSMP cases treated with adjuvant therapy resulting in a significant difference in recurrence between the inflamed and excluded phenotypes. To simplify SCI determination, a subset of immune cell markers was selected as appropriate to define the 3 SCI patterns: high intraepithelial CD8 for the inflamed phenotype; CD68, CD20, and PD-L1 to discriminate between desert and excluded tumors. The integration of SCI into molecular classification could be a promising opportunity to improve the prognostic risk stratification of patients and may guide the therapeutic approach, particularly in the NSMP subtype. Thus, the different patterns of immune response are a new prognostic parameter in the NSMP subtype.
{"title":"Spatial Cancer-Immune Phenotypes Predict Shorter Recurrence-Free Survival in the No Specific Molecular Profile Molecular Subtype of Endometrial Carcinoma","authors":"Dario de Biase , Jacopo Lenzi , Claudio Ceccarelli , Thais Maloberti , Marco Grillini , Camelia Alexandra Coadǎ , Claudio Zamagni , Pierandrea De Iaco , Anna Myriam Perrone , Donatella Santini , Martin Köbel , Cheng-Han Lee , Giovanni Tallini , Antonio De Leo","doi":"10.1016/j.modpat.2024.100624","DOIUrl":"10.1016/j.modpat.2024.100624","url":null,"abstract":"<div><div>Compartmentation of the immune response into 3 main spatial cancer-immune phenotypes (SCIs) – inflamed, excluded, and desert – has been proposed as the main predictor of response to immune checkpoint inhibitors in solid tumors. The objective of the study was to define and characterize the SCI in a consecutive series of 213 endometrial carcinomas (ECs) by correlating it with molecular subtypes, clinicopathologic features, and prognosis. Immunohistochemistry (IHC) and next-generation sequencing were used to assign surrogate molecular EC subtypes: <em>POLE</em> mutant (<em>POLE</em>), mismatch repair deficient (MMRd), <em>TP53</em> mutant (p53abn), and no specific molecular profile (NSMP). Immune cell markers (CD20, CD3, CD8, CD68, PD-L1) were assessed by IHC on whole sections and quantified by digital image analysis to define the 3 SCIs. ECs were stratified into 4 molecular subtypes: 17 (8.0%) <em>POLE</em>, 68 (31.9%) MMRd, 42 (19.7%) p53abn, and 86 (40.4%) NSMP. SCI determination showed 105 (49.3%) inflamed, 62 (29.1%) desert, and 46 (25.6%) excluded tumors. The inflamed phenotype was more prevalent in MMRd (64.7%) and <em>POLE</em> (76.5%) subtypes compared with NSMP (45.3%) and p53abn (21.4%). SCI revealed a strong correlation with disease-free survival in NSMP tumors: inflamed 96.2%, desert 83.2%, and excluded 40.5%. The SCI prognostic impact was also maintained in NSMP cases treated with adjuvant therapy resulting in a significant difference in recurrence between the inflamed and excluded phenotypes. To simplify SCI determination, a subset of immune cell markers was selected as appropriate to define the 3 SCI patterns: high intraepithelial CD8 for the inflamed phenotype; CD68, CD20, and PD-L1 to discriminate between desert and excluded tumors. The integration of SCI into molecular classification could be a promising opportunity to improve the prognostic risk stratification of patients and may guide the therapeutic approach, particularly in the NSMP subtype. Thus, the different patterns of immune response are a new prognostic parameter in the NSMP subtype.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 1","pages":"Article 100624"},"PeriodicalIF":7.1,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350235","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}
Pub Date : 2024-09-24DOI: 10.1016/j.modpat.2024.100616
Benzion Samueli, Hikmat Al-Ahmadie, Ying-Bei Chen, Anuradha Gopalan, Judy Sarungbam, Satish K. Tickoo, Victor E. Reuter, Samson W. Fine, Jie-Fu Chen
Gain-of-function isocitrate dehydrogenase (IDH) mutations are pathogenically significant in many tumor types and are actionable in cholangiocarcinoma, low-grade glioma, and acute myeloid leukemia. Rare IDH mutations have been described in prostatic adenocarcinoma (PCa). Recent publications have suggested that psammomatous calcifications in PCa are associated with IDH1 mutations. In this retrospective study, we queried our institutional clinical sequencing database (cohort 1), and previously published PCa data sets in cBioPortal (cohort 2). Samples were stratified based on oncogenic hotspot IDH mutations at IDH1 R132 and IDH2 R140/R172, and other nonhotspot IDH mutations. Seventeen (0.4%) cases were identified from 4033 PCa cases in cohort 1 harboring mutually exclusive oncogenic hotspot IDH1 (N = 15, 1 of which was subclonal) or IDH2 (N = 2) mutations, and 20 (0.5%) cases had nonhotspot IDH1/2 mutations. A histologic review of 13 cases with IDH1 hotspot mutations and available material showed grade group 3 or higher disease. Immunohistochemistry was performed on cases with IDH1 hotspot mutations when possible and showed AR, PSA, PSMA, and NKX3.1 positive in all the 4 cases stained. In cohort 2, 9 cases (0.3%) harboring IDH1 hotspot mutations were identified from 2749 patients, and 9 cases carried nonhotspot IDH1/2 mutations. The combined cohorts of 23 PCa cases with clonal IDH1 hotspot mutations had no ETS fusions, SPOP hotspot mutations, and somatic or germline alterations in BRCA1/2, ATM, RB1, or AR; 19 cases with successful microsatellite instability testing were all microsatellite stable. Conversely, among 29 cases with nonhotspot IDH mutations, there were 4 with TMPRSS2::ERG fusions, 6 with SPOP hotspot mutations, and 10 with AR amplifications/hotspot mutations; 8 were microsatellite instability high. Notably, two cases with IDH1 hotspot mutations had psammomatous calcifications. Our findings provide evidence that IDH1 hotspot mutations serve as driver alterations in this rare yet distinct molecular subset of PCa. Further studies are warranted to correlate response to androgen deprivation and IDH inhibitors.
{"title":"Histopathologic and Molecular Characterization of IDH-Mutant Prostatic Adenocarcinoma","authors":"Benzion Samueli, Hikmat Al-Ahmadie, Ying-Bei Chen, Anuradha Gopalan, Judy Sarungbam, Satish K. Tickoo, Victor E. Reuter, Samson W. Fine, Jie-Fu Chen","doi":"10.1016/j.modpat.2024.100616","DOIUrl":"10.1016/j.modpat.2024.100616","url":null,"abstract":"<div><div>Gain-of-function isocitrate dehydrogenase (<em>IDH</em>) mutations are pathogenically significant in many tumor types and are actionable in cholangiocarcinoma, low-grade glioma, and acute myeloid leukemia. Rare <em>IDH</em> mutations have been described in prostatic adenocarcinoma (PCa). Recent publications have suggested that psammomatous calcifications in PCa are associated with <em>IDH1</em> mutations. In this retrospective study, we queried our institutional clinical sequencing database (cohort 1), and previously published PCa data sets in cBioPortal (cohort 2). Samples were stratified based on oncogenic hotspot <em>IDH</em> mutations at <em>IDH1</em> R132 and <em>IDH2</em> R140/R172, and other nonhotspot <em>IDH</em> mutations. Seventeen (0.4%) cases were identified from 4033 PCa cases in cohort 1 harboring mutually exclusive oncogenic hotspot <em>IDH1</em> (N = 15, 1 of which was subclonal) or <em>IDH2</em> (N = 2) mutations, and 20 (0.5%) cases had nonhotspot <em>IDH1</em>/<em>2</em> mutations. A histologic review of 13 cases with <em>IDH1</em> hotspot mutations and available material showed grade group 3 or higher disease. Immunohistochemistry was performed on cases with <em>IDH1</em> hotspot mutations when possible and showed AR, PSA, PSMA, and NKX3.1 positive in all the 4 cases stained. In cohort 2, 9 cases (0.3%) harboring <em>IDH1</em> hotspot mutations were identified from 2749 patients, and 9 cases carried nonhotspot <em>IDH1/2</em> mutations. The combined cohorts of 23 PCa cases with clonal <em>IDH1</em> hotspot mutations had no ETS fusions, <em>SPOP</em> hotspot mutations, and somatic or germline alterations in <em>BRCA1/2, ATM, RB1,</em> or <em>AR</em>; 19 cases with successful microsatellite instability testing were all microsatellite stable. Conversely, among 29 cases with nonhotspot <em>IDH</em> mutations, there were 4 with <em>TMPRSS2::ERG</em> fusions, 6 with <em>SPOP</em> hotspot mutations, and 10 with <em>AR</em> amplifications/hotspot mutations; 8 were microsatellite instability high. Notably, two cases with <em>IDH1</em> hotspot mutations had psammomatous calcifications. Our findings provide evidence that <em>IDH1</em> hotspot mutations serve as driver alterations in this rare yet distinct molecular subset of PCa. Further studies are warranted to correlate response to androgen deprivation and IDH inhibitors.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 1","pages":"Article 100616"},"PeriodicalIF":7.1,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350233","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}
Pub Date : 2024-09-23DOI: 10.1016/j.modpat.2024.100615
Fnu Aakash , Savanah D. Gisriel , Amer M. Zeidan , John M. Bennett , Rafael Bejar , Jan Philipp Bewersdorf , Uma M. Borate , Jacqueline Boultwood , Andrew M. Brunner , Rena Buckstein , Hetty E. Carraway , Jane E. Churpek , Naval G. Daver , Amy E. DeZern , Fabio Efficace , Pierre Fenaux , Maria E. Figueroa , Guillermo Garcia-Manero , Steven D. Gore , Peter L. Greenberg , Sanam Loghavi
Myelodysplastic neoplasms/syndromes (MDS) are a heterogeneous group of biologically distinct entities characterized by variable degrees of ineffective hematopoiesis. Recently, 2 classification systems (the 5th edition of the World Health Organization Classification of Haematolymphoid tTumours and the International Consensus Classification) further subcharacterized MDS into morphologically and genetically defined groups. Accurate diagnosis and subclassification of MDS require a multistep systemic approach. The International Consortium for MDS (icMDS) summarizes a contemporary, practical, and multimodal approach to MDS diagnosis and classification.
{"title":"Contemporary Approach to the Diagnosis and Classification of Myelodysplastic Neoplasms/Syndromes—Recommendations From the International Consortium for Myelodysplastic Neoplasms/Syndromes (MDS [icMDS])","authors":"Fnu Aakash , Savanah D. Gisriel , Amer M. Zeidan , John M. Bennett , Rafael Bejar , Jan Philipp Bewersdorf , Uma M. Borate , Jacqueline Boultwood , Andrew M. Brunner , Rena Buckstein , Hetty E. Carraway , Jane E. Churpek , Naval G. Daver , Amy E. DeZern , Fabio Efficace , Pierre Fenaux , Maria E. Figueroa , Guillermo Garcia-Manero , Steven D. Gore , Peter L. Greenberg , Sanam Loghavi","doi":"10.1016/j.modpat.2024.100615","DOIUrl":"10.1016/j.modpat.2024.100615","url":null,"abstract":"<div><div>Myelodysplastic neoplasms/syndromes (MDS) are a heterogeneous group of biologically distinct entities characterized by variable degrees of ineffective hematopoiesis. Recently, 2 classification systems (the 5th edition of the World Health Organization Classification of Haematolymphoid tTumours and the International Consensus Classification) further subcharacterized MDS into morphologically and genetically defined groups. Accurate diagnosis and subclassification of MDS require a multistep systemic approach. The International Consortium for MDS (icMDS) summarizes a contemporary, practical, and multimodal approach to MDS diagnosis and classification.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 12","pages":"Article 100615"},"PeriodicalIF":7.1,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350231","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}
Pub Date : 2024-09-13DOI: 10.1016/j.modpat.2024.100597
Cheng Lei , Peng Zhou , Yi Sun , Qingchun Liang
{"title":"RNA Sequencing May Call CEP170::RAD51B Fusion Because of Alignment Artifacts","authors":"Cheng Lei , Peng Zhou , Yi Sun , Qingchun Liang","doi":"10.1016/j.modpat.2024.100597","DOIUrl":"10.1016/j.modpat.2024.100597","url":null,"abstract":"","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 10","pages":"Article 100597"},"PeriodicalIF":7.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142229452","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}
Pub Date : 2024-09-12DOI: 10.1016/j.modpat.2024.100609
Liron Pantanowitz , Matthew Hanna , Joshua Pantanowitz , Joe Lennerz , Walter H. Henricks , Peter Shen , Bruce Quinn , Shannon Bennet , Hooman H. Rashidi
In the realm of health care, numerous generative and nongenerative artificial intelligence and machine learning (AI-ML) tools have been developed and deployed. Simultaneously, manufacturers of medical devices are leveraging AI-ML. However, the adoption of AI in health care raises several concerns, including safety, security, ethical biases, accountability, trust, economic impact, and environmental effects. Effective regulation can mitigate some of these risks, promote fairness, establish standards, and advocate for more sustainable AI practices. Regulating AI tools not only ensures their safe and effective adoption but also fosters public trust. It is important that regulations remain flexible to accommodate rapid advances in this field to support innovation and also not to add additional burden to some of our preexisting and well-established frameworks. This study covers regional and global regulatory aspects of AI-ML including data privacy, software as a medical device, agency approval and clearance pathways, reimbursement, and laboratory-developed tests.
{"title":"Regulatory Aspects of Artificial Intelligence and Machine Learning","authors":"Liron Pantanowitz , Matthew Hanna , Joshua Pantanowitz , Joe Lennerz , Walter H. Henricks , Peter Shen , Bruce Quinn , Shannon Bennet , Hooman H. Rashidi","doi":"10.1016/j.modpat.2024.100609","DOIUrl":"10.1016/j.modpat.2024.100609","url":null,"abstract":"<div><div>In the realm of health care, numerous generative and nongenerative artificial intelligence and machine learning (AI-ML) tools have been developed and deployed. Simultaneously, manufacturers of medical devices are leveraging AI-ML. However, the adoption of AI in health care raises several concerns, including safety, security, ethical biases, accountability, trust, economic impact, and environmental effects. Effective regulation can mitigate some of these risks, promote fairness, establish standards, and advocate for more sustainable AI practices. Regulating AI tools not only ensures their safe and effective adoption but also fosters public trust. It is important that regulations remain flexible to accommodate rapid advances in this field to support innovation and also not to add additional burden to some of our preexisting and well-established frameworks. This study covers regional and global regulatory aspects of AI-ML including data privacy, software as a medical device, agency approval and clearance pathways, reimbursement, and laboratory-developed tests.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 12","pages":"Article 100609"},"PeriodicalIF":7.1,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291430","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}
Pub Date : 2024-09-10DOI: 10.1016/j.modpat.2024.100613
Yen Chen Kevin Ko , Kelly Yi Ping Liu , Esther Chen , Sarah Yuqi Zhu , Catherine F. Poh
Grading of oral epithelial dysplasia (OED) can be challenging with considerable intraobserver and interobserver variability. Abnormal immunohistochemical staining patterns of the tumor suppressor protein, p53, have been recently shown to be potentially associated with progression in OED. We retrospectively identified 214 oral biopsies from 203 patients recruited in a longitudinal study between 2001 and 2008 with a diagnosis of reactive, nondysplastic lesions, low-grade lesions (mild OED and moderate OED) and high-grade lesions (HGLs; severe OED/carcinoma in situ). Tissue microarrays were constructed from the most representative area of the pathology. Three consecutive sections were sectioned and stained for hematoxylin and eosin, p53 immunohistochemistry, and p16 immunohistochemistry. The staining results were reviewed by 2 pathologists (Y.C.K.K., C.F.P.) blinded to clinical outcome. Samples were categorized into p53 abnormal OED (n = 46), p53 conventional OED (n = 118), and p53 human papillomavirus (HPV) OED (HPV associated) (n = 12) using a previously published pattern-based approach. All cases of p53 HPV OED (HPV associated) were identified in HGLs. In contrast, cases of p53 abnormal OED were observed in mild OED (9.5%), moderate OED (23%), and severe OED/carcinoma in situ (51%). None of the 27 reactive or nondysplastic lesions showed abnormal p53 staining patterns. Among the 135 low-grade lesions, 23 cases (17.0%; 2 mild OEDs and 21 moderate OEDs) progressed to HGL or squamous cell carcinoma, with 11 cases showing progression within the first 3 years. Remarkably, 82% (9/11) of these faster progressors showed abnormal p53 patterns. Survival analysis revealed that p53 abnormal OED had significantly poorer progression-free probability (P < .0001) with hazard ratio of 11.24 (95% CI, 4.26-29.66) compared with p53 conventional OED. Furthermore, p53 abnormal OED had poorer local recurrence–free survival compared with p53 wild-type OED (P = .03). The study supports that OED with p53 abnormal pattern is at high risk for progression and recurrence independent of the dysplasia grade.
{"title":"p53 Abnormal Oral Epithelial Dysplasias are Associated With High Risks of Progression and Local Recurrence—A Retrospective Study in a Longitudinal Cohort","authors":"Yen Chen Kevin Ko , Kelly Yi Ping Liu , Esther Chen , Sarah Yuqi Zhu , Catherine F. Poh","doi":"10.1016/j.modpat.2024.100613","DOIUrl":"10.1016/j.modpat.2024.100613","url":null,"abstract":"<div><div>Grading of oral epithelial dysplasia (OED) can be challenging with considerable intraobserver and interobserver variability. Abnormal immunohistochemical staining patterns of the tumor suppressor protein, p53, have been recently shown to be potentially associated with progression in OED. We retrospectively identified 214 oral biopsies from 203 patients recruited in a longitudinal study between 2001 and 2008 with a diagnosis of reactive, nondysplastic lesions, low-grade lesions (mild OED and moderate OED) and high-grade lesions (HGLs; severe OED/carcinoma in situ). Tissue microarrays were constructed from the most representative area of the pathology. Three consecutive sections were sectioned and stained for hematoxylin and eosin, p53 immunohistochemistry, and p16 immunohistochemistry. The staining results were reviewed by 2 pathologists (Y.C.K.K., C.F.P.) blinded to clinical outcome. Samples were categorized into p53 abnormal OED (n = 46), p53 conventional OED (n = 118), and p53 human papillomavirus (HPV) OED (HPV associated) (n = 12) using a previously published pattern-based approach. All cases of p53 HPV OED (HPV associated) were identified in HGLs. In contrast, cases of p53 abnormal OED were observed in mild OED (9.5%), moderate OED (23%), and severe OED/carcinoma in situ (51%). None of the 27 reactive or nondysplastic lesions showed abnormal p53 staining patterns. Among the 135 low-grade lesions, 23 cases (17.0%; 2 mild OEDs and 21 moderate OEDs) progressed to HGL or squamous cell carcinoma, with 11 cases showing progression within the first 3 years. Remarkably, 82% (9/11) of these faster progressors showed abnormal p53 patterns. Survival analysis revealed that p53 abnormal OED had significantly poorer progression-free probability (<em>P</em> < .0001) with hazard ratio of 11.24 (95% CI, 4.26-29.66) compared with p53 conventional OED. Furthermore, p53 abnormal OED had poorer local recurrence–free survival compared with p53 wild-type OED (<em>P</em> = .03). The study supports that OED with p53 abnormal pattern is at high risk for progression and recurrence independent of the dysplasia grade.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 12","pages":"Article 100613"},"PeriodicalIF":7.1,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291428","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}
Pub Date : 2024-09-10DOI: 10.1016/j.modpat.2024.100614
Tami Yu-Yu Lin , Kelly Yi Ping Liu , Rachel Novack , Pushwant S. Mattu , Tony L. Ng , Lynn N. Hoang , Eitan Prisman , Catherine F. Poh , Yen Chen Kevin Ko
Most (60%-80%) of the oral cavity invasive squamous cell carcinoma (OSCC) demonstrate molecular alterations in TP53. The presence of TP53 mutations in multiple organ systems has been associated with a more aggressive clinical course. This study aimed to classify OSCC into p53 wild-type OSCC and p53-abnormal OSCC using p53 immunohistochemistry and to determine if abnormal p53 status correlates with a higher risk of lymph node metastasis at the time of surgery. A total of 101 patients with OSCC resection and cervical lymph node dissection were identified. p53 immunohistochemistry was performed for all cases and scored into p53 wild-type (p53-HPV: midepithelial/basal sparing, markedly reduced [null-like]/basal sparing; p53-conventional: scattered basal, patchy basal/parabasal) and p53-abnormal (overexpression basal/parabasal only, overexpression basal/parabasal to diffuse, null, and cytoplasmic) patterns. p16 immunohistochemistry and high-risk HPV RNA in situ hybridization were used to confirm the HPV status in cases showing midepithelial/basal sparing or markedly reduced (null-like)/basal sparing pattern. Logistic regression analysis was performed to investigate the association of p53 status, tumor size, depth of invasion, and pT stage against lymph node status. We identified 22 cases with p53 wild-type patterns (16 p53-conventional, 6 p53-HPV) and 79 cases with p53-abnormal patterns. Two of 22 p53 wild-type cases had positive lymph nodes (1 p53-conventional, 1 p53-HPV), whereas 40 of 79 p53-abnormal cases had positive lymph nodes (P < .001). Multivariate analysis showed that p53-abnormal pattern was an independent risk factor associated with positive node(s) with an odds ratio of 8.12 (95% CI, 2.10-53.78; P = .008).
p53-Abnormal OSCCs were significantly more likely to be associated with positive lymph node status than p53 wild-type OSCCs at the time of surgery. Further investigation with long-term follow-up is required to determine its clinical application before surgery planning.
{"title":"Abnormal p53 Immunohistochemical Patterns Are Associated with Regional Lymph Node Metastasis in Oral Cavity Squamous Cell Carcinoma at Time of Surgery","authors":"Tami Yu-Yu Lin , Kelly Yi Ping Liu , Rachel Novack , Pushwant S. Mattu , Tony L. Ng , Lynn N. Hoang , Eitan Prisman , Catherine F. Poh , Yen Chen Kevin Ko","doi":"10.1016/j.modpat.2024.100614","DOIUrl":"10.1016/j.modpat.2024.100614","url":null,"abstract":"<div><div>Most (60%-80%) of the oral cavity invasive squamous cell carcinoma (OSCC) demonstrate molecular alterations in <em>TP53</em>. The presence of <em>TP53</em> mutations in multiple organ systems has been associated with a more aggressive clinical course. This study aimed to classify OSCC into p53 wild-type OSCC and p53-abnormal OSCC using p53 immunohistochemistry and to determine if abnormal p53 status correlates with a higher risk of lymph node metastasis at the time of surgery. A total of 101 patients with OSCC resection and cervical lymph node dissection were identified. p53 immunohistochemistry was performed for all cases and scored into p53 wild-type (p53-HPV: midepithelial/basal sparing, markedly reduced [null-like]/basal sparing; p53-conventional: scattered basal, patchy basal/parabasal) and p53-abnormal (overexpression basal/parabasal only, overexpression basal/parabasal to diffuse, null, and cytoplasmic) patterns. p16 immunohistochemistry and high-risk HPV RNA in situ hybridization were used to confirm the HPV status in cases showing midepithelial/basal sparing or markedly reduced (null-like)/basal sparing pattern. Logistic regression analysis was performed to investigate the association of p53 status, tumor size, depth of invasion, and pT stage against lymph node status. We identified 22 cases with p53 wild-type patterns (16 p53-conventional, 6 p53-HPV) and 79 cases with p53-abnormal patterns. Two of 22 p53 wild-type cases had positive lymph nodes (1 p53-conventional, 1 p53-HPV), whereas 40 of 79 p53-abnormal cases had positive lymph nodes (<em>P</em> < .001). Multivariate analysis showed that p53-abnormal pattern was an independent risk factor associated with positive node(s) with an odds ratio of 8.12 (95% CI, 2.10-53.78; <em>P</em> = .008).</div><div>p53-Abnormal OSCCs were significantly more likely to be associated with positive lymph node status than p53 wild-type OSCCs at the time of surgery. Further investigation with long-term follow-up is required to determine its clinical application before surgery planning.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 12","pages":"Article 100614"},"PeriodicalIF":7.1,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291426","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}
Pub Date : 2024-09-10DOI: 10.1016/j.modpat.2024.100611
Miroslava Flídrová , Nikola Hájková , Jan Hojný , Jiří Dvořák , Romana Michálková , Eva Krkavcová , Jan Laco , W. Glenn McCluggage , Giovanna Giordano , Enrico Maria Silini , Květoslava Michalová , Magdalena Bizoń , Kristýna Němejcová , Pavel Dundr , Michaela Kendall Bártů
Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare tumor of uncertain lineage and low malignant potential. Most tumors behave in a benign manner, but a subset of UTROSCT exhibit an aggressive clinical course with recurrences and metastases. The recurrent molecular alterations in UTROSCT mostly represent gene fusions involving NCOA1-3. We performed a comprehensive clinicopathological, morphologic, immunohistochemical, and molecular analysis on a cohort of 35 UTROSCT. The tumors exhibited various architectural patterns (diffuse, corded/trabecular, tubular, sertoliform, fascicular, whorled, nested, microfollicular, and pseudoglandular), often in combination. The immunohistochemical analysis confirmed the polyphenotypic immunoprofile, often with coexpression of sex cord–stromal, smooth muscle, and epithelial markers, as well as hormone receptors. Next-generation sequencing RNA analysis revealed recurrent NCOA1-3 gene fusions in 22/32 analyzed cases (69%), including ESR1::NCOA3 (11/22), GREB1::NCOA2 (7/22), ESR1::NCOA2 (3/22), and GREB1::NCOA1 (1/22). Tumor mutation burden was low in all cases. The fusion-positive cases exhibited statistically significant association with whorled architecture, conversely necrosis was associated with fusion-negative status. We did not find a significant relationship between any architectural pattern and GREB1 alterations, but the NCOA2-altered tumors were associated with pseudoglandular architecture. The GREB1-altered cases occurred in older patients and tended to be more often intramural masses compared with ESR1-altered cases. On the contrary, the ESR1-altered cases presented more often like submucosal or polypoid tumors. Two tumors exhibited aggressive behavior with recurrent disease. Both of these cases harbored a GREB1::NCOA2 fusion. Unsupervised hierarchical cluster analysis of our cohort revealed 2 main clusters. The tumors with GREB1 or NCOA2 fusion cluster together, suggesting that there are underlying molecular differences between these cases and cases with ESR1::NCOA3 fusion or without fusion. Our findings contribute to the growing knowledge about a rare neoplasm with currently uncertain biological behavior.
{"title":"Unraveling the Molecular Landscape of Uterine Tumor Resembling Ovarian Sex Cord Tumor: Insights From A Clinicopathological, Morphologic, Immunohistochemical, and Molecular Analysis of 35 Cases","authors":"Miroslava Flídrová , Nikola Hájková , Jan Hojný , Jiří Dvořák , Romana Michálková , Eva Krkavcová , Jan Laco , W. Glenn McCluggage , Giovanna Giordano , Enrico Maria Silini , Květoslava Michalová , Magdalena Bizoń , Kristýna Němejcová , Pavel Dundr , Michaela Kendall Bártů","doi":"10.1016/j.modpat.2024.100611","DOIUrl":"10.1016/j.modpat.2024.100611","url":null,"abstract":"<div><div>Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare tumor of uncertain lineage and low malignant potential. Most tumors behave in a benign manner, but a subset of UTROSCT exhibit an aggressive clinical course with recurrences and metastases. The recurrent molecular alterations in UTROSCT mostly represent gene fusions involving <em>NCOA1</em>-<em>3</em>. We performed a comprehensive clinicopathological, morphologic, immunohistochemical, and molecular analysis on a cohort of 35 UTROSCT. The tumors exhibited various architectural patterns (diffuse, corded/trabecular, tubular, sertoliform, fascicular, whorled, nested, microfollicular, and pseudoglandular), often in combination. The immunohistochemical analysis confirmed the polyphenotypic immunoprofile, often with coexpression of sex cord–stromal, smooth muscle, and epithelial markers, as well as hormone receptors. Next-generation sequencing RNA analysis revealed recurrent <em>NCOA1</em>-<em>3</em> gene fusions in 22/32 analyzed cases (69%), including <em>ESR1</em>::<em>NCOA3</em> (11/22), <em>GREB1</em>::<em>NCOA2</em> (7/22), <em>ESR1</em>::<em>NCOA2</em> (3/22), and <em>GREB1</em>::<em>NCOA1</em> (1/22). Tumor mutation burden was low in all cases. The fusion-positive cases exhibited statistically significant association with whorled architecture, conversely necrosis was associated with fusion-negative status. We did not find a significant relationship between any architectural pattern and <em>GREB1</em> alterations, but the <em>NCOA2</em>-altered tumors were associated with pseudoglandular architecture. The <em>GREB1</em>-altered cases occurred in older patients and tended to be more often intramural masses compared with <em>ESR1</em>-altered cases. On the contrary, the <em>ESR1</em>-altered cases presented more often like submucosal or polypoid tumors. Two tumors exhibited aggressive behavior with recurrent disease. Both of these cases harbored a <em>GREB1</em>::<em>NCOA2</em> fusion. Unsupervised hierarchical cluster analysis of our cohort revealed 2 main clusters. The tumors with <em>GREB1</em> or <em>NCOA2</em> fusion cluster together, suggesting that there are underlying molecular differences between these cases and cases with <em>ESR1</em>::<em>NCOA3</em> fusion or without fusion. Our findings contribute to the growing knowledge about a rare neoplasm with currently uncertain biological behavior.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 12","pages":"Article 100611"},"PeriodicalIF":7.1,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291435","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}
Pub Date : 2024-09-10DOI: 10.1016/j.modpat.2024.100610
Charlotte Syrykh , Valentina Di Proietto , Eliott Brion , Christiane Copie-Bergman , Fabrice Jardin , Peggy Dartigues , Philippe Gaulard , Thierry Jo Molina , Josette Briere , Lucie Oberic , Corine Haioun , Hervé Tilly , Charles Maussion , Mehdi Morel , Jean-Baptiste Schiratti , Camille Laurent
Large B-cell lymphoma (LBCL) is a heterogeneous lymphoid malignancy in which MYC gene rearrangement (MYC-R) is associated with a poor prognosis, prompting the recommendation for more intensive treatment. MYC-R detection relies on fluorescence in situ hybridization method which is time consuming, expensive, and not available in all laboratories. Automating MYC-R detection on hematoxylin-and-eosin–stained whole slide images of LBCL would decrease the need for costly molecular testing and improve pathologists’ productivity. We developed an interpretable deep learning algorithm to detect MYC-R considering recent advances in self-supervised learning and providing an extensive comparison of 7 feature extractors and 6 multiple instance learning models, themselves. Four different multicentric cohorts, including 1247 patients with LBCL, were used for training and validation. The best deep learning model reached an average area under the receiver operating characteristic curve score of 81.9% during crossvalidation on the largest LBCL cohort, and area under the receiver operating characteristic curve scores ranging from 62.2% to 74.5% when evaluated on other unseen cohorts. In addition, we demonstrated that using this model as a prescreening tool (with a false-negative rate of 0%), fluorescence in situ hybridization testing would be avoided in 35% of cases. This work demonstrates the feasibility of developing a medical device to efficiently detect MYC gene rearrangement on hematoxylin-and-eosin–stained whole slide images in daily practice.
大 B 细胞淋巴瘤（LBCL）是一种异质性淋巴恶性肿瘤，其中 MYC 基因重排（MYC-R）与预后不良有关，因此建议进行更深入的治疗。MYC-R 的检测依赖荧光原位杂交（FISH）方法，这种方法耗时长、成本高，而且并非所有实验室都能采用。在苏木精和伊红（HE）染色的LBCL全切片图像（WSI）上自动检测MYC-R将减少对昂贵的分子检测的需求，并提高病理学家的工作效率。考虑到自监督学习的最新进展，我们开发了一种可解释的深度学习（DL）算法来检测 MYC-R，并对七种特征提取器和六种多实例学习模型进行了广泛比较。四个不同的多中心队列（包括 1 247 名 LBCL 患者）被用于训练和验证。在对最大的 LBCL 队列进行交叉验证时，最佳 DL 模型的平均 ROC AUC 得分为 81.9%，在对其他未见队列进行评估时，ROC AUC 得分为 62.2% 到 74.5%。此外，我们还证明，使用该模型作为预筛工具（假阴性率为 0%），可避免 35% 的病例进行 FISH 检测。这项工作证明了在日常实践中开发一种医疗设备来有效检测 HE WSI 上 MYC 基因重排的可行性。
{"title":"MYC Rearrangement Prediction From LYSA Whole Slide Images in Large B-Cell Lymphoma: A Multicentric Validation of Self-supervised Deep Learning Models","authors":"Charlotte Syrykh , Valentina Di Proietto , Eliott Brion , Christiane Copie-Bergman , Fabrice Jardin , Peggy Dartigues , Philippe Gaulard , Thierry Jo Molina , Josette Briere , Lucie Oberic , Corine Haioun , Hervé Tilly , Charles Maussion , Mehdi Morel , Jean-Baptiste Schiratti , Camille Laurent","doi":"10.1016/j.modpat.2024.100610","DOIUrl":"10.1016/j.modpat.2024.100610","url":null,"abstract":"<div><div>Large B-cell lymphoma (LBCL) is a heterogeneous lymphoid malignancy in which <em>MYC</em> gene rearrangement (<em>MYC</em>-R) is associated with a poor prognosis, prompting the recommendation for more intensive treatment. <em>MYC</em>-R detection relies on fluorescence in situ hybridization method which is time consuming, expensive, and not available in all laboratories. Automating <em>MYC</em>-R detection on hematoxylin-and-eosin–stained whole slide images of LBCL would decrease the need for costly molecular testing and improve pathologists’ productivity. We developed an interpretable deep learning algorithm to detect <em>MYC</em>-R considering recent advances in self-supervised learning and providing an extensive comparison of 7 feature extractors and 6 multiple instance learning models, themselves. Four different multicentric cohorts, including 1247 patients with LBCL, were used for training and validation. The best deep learning model reached an average area under the receiver operating characteristic curve score of 81.9% during crossvalidation on the largest LBCL cohort, and area under the receiver operating characteristic curve scores ranging from 62.2% to 74.5% when evaluated on other unseen cohorts. In addition, we demonstrated that using this model as a prescreening tool (with a false-negative rate of 0%), fluorescence in situ hybridization testing would be avoided in 35% of cases. This work demonstrates the feasibility of developing a medical device to efficiently detect <em>MYC</em> gene rearrangement on hematoxylin-and-eosin–stained whole slide images in daily practice.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 12","pages":"Article 100610"},"PeriodicalIF":7.1,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291427","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}
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