Pub Date : 2024-10-16DOI: 10.1016/j.modpat.2024.100633
Laura M.G. van Huizen , Max Blokker , Johannes M.A. Daniels , Teodora Radonic , Jan H. von der Thüsen , Mitko Veta , Jouke T. Annema , Marie Louise Groot
Lung cancer is one of the most prevalent and lethal cancers. To improve health outcomes while reducing health care burden, it becomes crucial to move toward early detection and cost-effective workflows. Currently, there is no method for the on-site rapid histologic feedback on biopsies taken in diagnostic, endoscopic, or surgical procedures. Higher harmonic generation (HHG) microscopy is a laser-based technique that provides images of unprocessed tissue. In this study, we report the feasibility of an HHG portable microscope in the clinical workflow in terms of acquisition time, image quality, and diagnostic accuracy in suspected pulmonary and pleural malignancy. One hundred nine biopsies of 47 patients were imaged and a biopsy overview image was provided within a median acquisition time of 6 minutes after excision. The assessment by pathologists and an artificial intelligence algorithm showed that image quality was sufficient for a malignancy or nonmalignancy diagnosis in 97% of the biopsies, and 87% of the HHG images were correctly scored by the pathologists. HHG is therefore an excellent candidate to provide a rapid pathology outcome on biopsy samples, enabling immediate diagnosis and (local) treatment.
{"title":"Rapid On-Site Histology of Lung and Pleural Biopsies Using Higher Harmonic Generation Microscopy and Artificial Intelligence Analysis","authors":"Laura M.G. van Huizen , Max Blokker , Johannes M.A. Daniels , Teodora Radonic , Jan H. von der Thüsen , Mitko Veta , Jouke T. Annema , Marie Louise Groot","doi":"10.1016/j.modpat.2024.100633","DOIUrl":"10.1016/j.modpat.2024.100633","url":null,"abstract":"<div><div>Lung cancer is one of the most prevalent and lethal cancers. To improve health outcomes while reducing health care burden, it becomes crucial to move toward early detection and cost-effective workflows. Currently, there is no method for the on-site rapid histologic feedback on biopsies taken in diagnostic, endoscopic, or surgical procedures. Higher harmonic generation (HHG) microscopy is a laser-based technique that provides images of unprocessed tissue. In this study, we report the feasibility of an HHG portable microscope in the clinical workflow in terms of acquisition time, image quality, and diagnostic accuracy in suspected pulmonary and pleural malignancy. One hundred nine biopsies of 47 patients were imaged and a biopsy overview image was provided within a median acquisition time of 6 minutes after excision. The assessment by pathologists and an artificial intelligence algorithm showed that image quality was sufficient for a malignancy or nonmalignancy diagnosis in 97% of the biopsies, and 87% of the HHG images were correctly scored by the pathologists. HHG is therefore an excellent candidate to provide a rapid pathology outcome on biopsy samples, enabling immediate diagnosis and (local) treatment.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 1","pages":"Article 100633"},"PeriodicalIF":7.1,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470036","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 : 2024-10-12DOI: 10.1016/j.modpat.2024.100631
João Lobo , Bassel Zein-Sabatto , Priti Lal , George J. Netto
Bladder cancer (BC) remains a major disease burden in terms of incidence, morbidity, mortality, and economic cost. Deciphering the intrinsic molecular subtypes and identification of key drivers of BC has yielded successful novel therapeutic strategies. Advances in computational and digital pathology are reshaping the field of anatomical pathology. This review offers an update on the most relevant computational algorithms in digital pathology that have been proposed to enhance BC management. These tools promise to enhance diagnostics, staging, and grading accuracy and streamline efficiency while advancing practice consistency. Computational applications that enable intrinsic molecular classification, predict response to neoadjuvant therapy, and identify targets of therapy are also reviewed.
{"title":"Digital and Computational Pathology Applications in Bladder Cancer: Novel Tools Addressing Clinically Pressing Needs","authors":"João Lobo , Bassel Zein-Sabatto , Priti Lal , George J. Netto","doi":"10.1016/j.modpat.2024.100631","DOIUrl":"10.1016/j.modpat.2024.100631","url":null,"abstract":"<div><div>Bladder cancer (BC) remains a major disease burden in terms of incidence, morbidity, mortality, and economic cost. Deciphering the intrinsic molecular subtypes and identification of key drivers of BC has yielded successful novel therapeutic strategies. Advances in computational and digital pathology are reshaping the field of anatomical pathology. This review offers an update on the most relevant computational algorithms in digital pathology that have been proposed to enhance BC management. These tools promise to enhance diagnostics, staging, and grading accuracy and streamline efficiency while advancing practice consistency. Computational applications that enable intrinsic molecular classification, predict response to neoadjuvant therapy, and identify targets of therapy are also reviewed.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 1","pages":"Article 100631"},"PeriodicalIF":7.1,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470035","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 : 2024-10-10DOI: 10.1016/j.modpat.2024.100630
Ya-Ting Tai , Wei-Chou Lin , Jieru Ye , Denis T.-H. Chen , Ko-Chen Chen , Duncan Y.-T. Wang , Tuan Z. Tan , Lin-Hung Wei , Ruby Y.-J. Huang
Ovarian clear cell carcinoma (OCCC) has a high incidence in Asia, with a frequent occurrence at an early stage, but without sufficient data on molecular stratification for high-risk patients. Recently, immune-hot features have been proposed as indicators of poor prognosis in early stage OCCC. Specific patterns of intratumoral heterogeneity associated with immune-hot features must be defined. NanoString Digital Spatial Profiling technology (Cold spring biotech corp.) was used to decipher the spatial distribution of the 18-plex protein panel. Regions of interest (ROIs) were collected based on the reference hematoxylin and eosin–stained morphology. Areas of illumination (AOIs) were defined according to the ROI segmentation using the fluorescence signals of the visualization markers pan-cytokeratin (PanCK), CD45, or DNA. Unsupervised hierarchical clustering of 595 AOIs from 407 ROIs showed that the PanCK segments expressed different combinations of immune markers, suggestive of immune mimicry. The following 3 immune-hot clusters were identified: granzyme B–high, immune signal-high , and immune-like cells; the following 2 immune-cold clusters were identified: fibronectin-high and immune checkpoint–high cells. In tumor samples at the International Federation of Gynecology and Obstetrics stage IC1/2 experiencing recurrence, there was an increased occurrence of PanCK+ AOIs with immune signal-high and immune-like cell groups in the papillary morphology surrounded by macrophage lineage tumor-infiltrating immune cells (TIIs). In contrast, for tumor samples at the International Federation of Gynecology and Obstetrics stage IC3/II with recurrence, PanCK+ AOIs were prevalent in the fibronectin-high group, particularly in those with a tubulocystic morphology surrounded by lymphoid lineage non-TIIs. Our study on the spatial profiling of early stage OCCC tumors revealed that the immune mimicry of tumor cells, presence of TIIs, and morphologic patterns were associated with recurrence, which switched during tumor progression.
卵巢透明细胞癌（OCCC）在亚洲的发病率很高，常发生在早期阶段，但没有足够的数据对高危患者进行分子分层。最近，免疫热特征被认为是早期卵巢透明细胞癌预后不良的指标。必须明确与免疫热特征相关的瘤内异质性的具体模式。NanoString Digital Spatial Profiling技术用于解读18复合物蛋白质面板的空间分布。根据参考苏木精和伊红（H&E）染色形态收集 ROI。利用可视化标记泛角蛋白（PanCK）、CD45或DNA的荧光信号，根据ROI分割定义照明区域（AOI）。对来自 407 个 ROI 的 595 个 AOI 进行无监督分层聚类显示，PanCK 区段表达了不同的免疫标记物组合，表明存在免疫拟态。确定了三个免疫热簇：颗粒酶 B 高（GZMB）、免疫信号高（IH）和免疫样细胞（IL）；确定了两个免疫冷簇：纤连蛋白高（FN）和免疫检查点高细胞（IC）。在复发的 FIGO IC1/2 期肿瘤样本中，PanCK+ AOIs 的发生率增加，IH 和 IL 组呈乳头状形态，周围有巨噬细胞系肿瘤浸润免疫细胞（TIIs）。相反，对于 FIGO IC3/II 期复发的肿瘤样本，PanCK + AOIs 在 FN 组中很普遍，尤其是那些形态为管状囊肿、周围有淋巴系非 TIIs 的样本。我们对早期 OCCC 肿瘤进行的空间图谱分析表明，肿瘤细胞的免疫拟态、TIIs 的存在和形态模式与复发有关，这些因素在肿瘤进展过程中会发生转换。
{"title":"Spatial Profiling of Ovarian Clear Cell Carcinoma Reveals Immune-Hot Features","authors":"Ya-Ting Tai , Wei-Chou Lin , Jieru Ye , Denis T.-H. Chen , Ko-Chen Chen , Duncan Y.-T. Wang , Tuan Z. Tan , Lin-Hung Wei , Ruby Y.-J. Huang","doi":"10.1016/j.modpat.2024.100630","DOIUrl":"10.1016/j.modpat.2024.100630","url":null,"abstract":"<div><div>Ovarian clear cell carcinoma (OCCC) has a high incidence in Asia, with a frequent occurrence at an early stage, but without sufficient data on molecular stratification for high-risk patients. Recently, immune-hot features have been proposed as indicators of poor prognosis in early stage OCCC. Specific patterns of intratumoral heterogeneity associated with immune-hot features must be defined. NanoString Digital Spatial Profiling technology (Cold spring biotech corp.) was used to decipher the spatial distribution of the 18-plex protein panel. Regions of interest (ROIs) were collected based on the reference hematoxylin and eosin–stained morphology. Areas of illumination (AOIs) were defined according to the ROI segmentation using the fluorescence signals of the visualization markers pan-cytokeratin (PanCK), CD45, or DNA. Unsupervised hierarchical clustering of 595 AOIs from 407 ROIs showed that the PanCK segments expressed different combinations of immune markers, suggestive of immune mimicry. The following 3 immune-hot clusters were identified: granzyme B–high, immune signal-high , and immune-like cells; the following 2 immune-cold clusters were identified: fibronectin-high and immune checkpoint–high cells. In tumor samples at the International Federation of Gynecology and Obstetrics stage IC1/2 experiencing recurrence, there was an increased occurrence of PanCK+ AOIs with immune signal-high and immune-like cell groups in the papillary morphology surrounded by macrophage lineage tumor-infiltrating immune cells (TIIs). In contrast, for tumor samples at the International Federation of Gynecology and Obstetrics stage IC3/II with recurrence, PanCK+ AOIs were prevalent in the fibronectin-high group, particularly in those with a tubulocystic morphology surrounded by lymphoid lineage non-TIIs. Our study on the spatial profiling of early stage OCCC tumors revealed that the immune mimicry of tumor cells, presence of TIIs, and morphologic patterns were associated with recurrence, which switched during tumor progression.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 1","pages":"Article 100630"},"PeriodicalIF":7.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470037","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 : 2024-10-09DOI: 10.1016/j.modpat.2024.100628
Nadarra L. Stokes , Ameya Patil , Oyedele Adeyi , Amarpreet Bhalla , Ian Brown , Kathleen Byrnes , Julien Calderaro , Diane Chen , Wei Chen , Caroline Cooper , Deepti Dhall , Wendy Frankel , Gretchen Galliano Gooch , Raul S. Gonzalez , Suntrea Hammer , Gillian Hale , Stephen Lagana , Catriona McKenzie , Daniela S. Allende , Roger K. Moreira , Rondell P. Graham
Wilson disease (WD) is a rare autosomal recessive condition with protean clinical manifestations that result from biallelic ATP7B mutations. However, nondestructive tissue tests to be applied clinically to tissue specimens are not widely available to effectively assess patients for possible WD. Previously, we showed that metallothionein (MTH) immunohistochemistry (IHC) has a high sensitivity and specificity for WD diagnosis and, thus, represents a potentially powerful diagnostic tool that can be used in routine histologic sections. This study aimed to validate this finding in a large cohort of bona fide patients with WD and to correlate metallothionein expression with other histologic features. We identified 91 cases of WD, which included 28 needle biopsies and 64 explants from 14 centers worldwide. Histologic features were evaluated, and a histopathological pattern was assigned to each case. All cases were evaluated with Masson trichrome and MTH IHC (clone UC1MT, Abcam) using a previously published technique. Liver tissues from chronic cholestatic diseases (n = 42) were used as controls. The median age of the cohort was 28.5 years. Of the 91 total cases, 83 were positive for MTH immunostain. In the controls, all 42 cases were negative for MTH immunostain. The sensitivity and specificity of MTH immunostain for WD were 91.20% and 100%, respectively. MTH IHC is a highly sensitive and specific cost-effective screening tool for WD. It can be used for patients across age groups, varied histologic patterns, and fibrosis stages. This marker could prove to be a valuable tool in the evaluation of patients with possible WD.
{"title":"Validation of Metallothionein Immunohistochemistry as a Highly Sensitive Screening Test for Wilson Disease","authors":"Nadarra L. Stokes , Ameya Patil , Oyedele Adeyi , Amarpreet Bhalla , Ian Brown , Kathleen Byrnes , Julien Calderaro , Diane Chen , Wei Chen , Caroline Cooper , Deepti Dhall , Wendy Frankel , Gretchen Galliano Gooch , Raul S. Gonzalez , Suntrea Hammer , Gillian Hale , Stephen Lagana , Catriona McKenzie , Daniela S. Allende , Roger K. Moreira , Rondell P. Graham","doi":"10.1016/j.modpat.2024.100628","DOIUrl":"10.1016/j.modpat.2024.100628","url":null,"abstract":"<div><div>Wilson disease (WD) is a rare autosomal recessive condition with protean clinical manifestations that result from biallelic <em>ATP7B</em> mutations. However, nondestructive tissue tests to be applied clinically to tissue specimens are not widely available to effectively assess patients for possible WD. Previously, we showed that metallothionein (MTH) immunohistochemistry (IHC) has a high sensitivity and specificity for WD diagnosis and, thus, represents a potentially powerful diagnostic tool that can be used in routine histologic sections. This study aimed to validate this finding in a large cohort of bona fide patients with WD and to correlate metallothionein expression with other histologic features. We identified 91 cases of WD, which included 28 needle biopsies and 64 explants from 14 centers worldwide. Histologic features were evaluated, and a histopathological pattern was assigned to each case. All cases were evaluated with Masson trichrome and MTH IHC (clone UC1MT, Abcam) using a previously published technique. Liver tissues from chronic cholestatic diseases (n = 42) were used as controls. The median age of the cohort was 28.5 years. Of the 91 total cases, 83 were positive for MTH immunostain. In the controls, all 42 cases were negative for MTH immunostain. The sensitivity and specificity of MTH immunostain for WD were 91.20% and 100%, respectively. MTH IHC is a highly sensitive and specific cost-effective screening tool for WD. It can be used for patients across age groups, varied histologic patterns, and fibrosis stages. This marker could prove to be a valuable tool in the evaluation of patients with possible WD.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 1","pages":"Article 100628"},"PeriodicalIF":7.1,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391763","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 : 2024-10-09DOI: 10.1016/j.modpat.2024.100629
M. Herman Chui , Qianqian Song , Jiarun Zhu , Yuchen Jiao , Brant Wang , Yeh Wang , Tian-Li Wang , Russell Vang , Ie-Ming Shih
The current paradigm implicates a fallopian tube precursor as the origin of most ovarian high-grade serous carcinomas (HGSCs). However, a rare subset of HGSCs develop via a distinct pathway from low-grade serous ovarian neoplasms (namely, serous borderline tumors and low-grade serous carcinoma). This alternate pathway for the development of HGSC and other poorly differentiated carcinomas of the ovary is not well understood. To elucidate the molecular pathogenesis and evolutionary trajectory of histologic transformation of low-grade serous neoplasms, we performed whole exome sequencing on microdissected low-grade and higher-grade components from 7 cases of serous borderline tumor or low-grade serous carcinoma associated with a synchronous or metachronous indeterminate/high-grade carcinoma. In most cases, there were relatively few somatic mutations shared between matched low-grade and higher-grade tumors compared with private mutations specific to each component (ie, phylogenetic trees with short trunks and long branches). Truncal mutations, present across all tumor samples from a given patient, included known drivers of low-grade serous neoplasms: KRAS (G12D, n = 4), BRAF (G469A, n = 1), NF2 (n = 1), and USP9X (n = 1). Transformation to HGSC was associated with a TP53 mutation with bi-allelic inactivation in 3 cases, all with severe nuclear atypia, and associated with genome-wide copy number alterations and allelic imbalances. TP53-wildtype tumors comprised a morphologic spectrum, which included indeterminate-grade serous carcinomas with moderate nuclear atypia and high mitotic activity, although lacking extensive chromosomal instability (n = 2) and poorly differentiated carcinomas (n = 2, including a high-grade Mullerian carcinoma and an undifferentiated carcinoma with sarcomatoid features). In summary, synchronous and metachronous low-grade serous neoplasms and higher-grade carcinomas are clonally related. Early genetic divergence, most evident in cases with TP53 mutations, suggests that high-grade transformation may be a relatively early molecular event.
{"title":"Early Genetic Divergence of High-Grade Carcinomas Originating from Low-Grade Serous Ovarian Neoplasms","authors":"M. Herman Chui , Qianqian Song , Jiarun Zhu , Yuchen Jiao , Brant Wang , Yeh Wang , Tian-Li Wang , Russell Vang , Ie-Ming Shih","doi":"10.1016/j.modpat.2024.100629","DOIUrl":"10.1016/j.modpat.2024.100629","url":null,"abstract":"<div><div>The current paradigm implicates a fallopian tube precursor as the origin of most ovarian high-grade serous carcinomas (HGSCs). However, a rare subset of HGSCs develop via a distinct pathway from low-grade serous ovarian neoplasms (namely, serous borderline tumors and low-grade serous carcinoma). This alternate pathway for the development of HGSC and other poorly differentiated carcinomas of the ovary is not well understood. To elucidate the molecular pathogenesis and evolutionary trajectory of histologic transformation of low-grade serous neoplasms, we performed whole exome sequencing on microdissected low-grade and higher-grade components from 7 cases of serous borderline tumor or low-grade serous carcinoma associated with a synchronous or metachronous indeterminate/high-grade carcinoma. In most cases, there were relatively few somatic mutations shared between matched low-grade and higher-grade tumors compared with private mutations specific to each component (ie, phylogenetic trees with short trunks and long branches). Truncal mutations, present across all tumor samples from a given patient, included known drivers of low-grade serous neoplasms: <em>KRAS</em> (G12D, n = 4), <em>BRAF</em> (G469A, n = 1), <em>NF2</em> (n = 1), and <em>USP9X</em> (n = 1). Transformation to HGSC was associated with a <em>TP53</em> mutation with bi-allelic inactivation in 3 cases, all with severe nuclear atypia, and associated with genome-wide copy number alterations and allelic imbalances. <em>TP53</em>-wildtype tumors comprised a morphologic spectrum, which included indeterminate-grade serous carcinomas with moderate nuclear atypia and high mitotic activity, although lacking extensive chromosomal instability (n = 2) and poorly differentiated carcinomas (n = 2, including a high-grade Mullerian carcinoma and an undifferentiated carcinoma with sarcomatoid features). In summary, synchronous and metachronous low-grade serous neoplasms and higher-grade carcinomas are clonally related. Early genetic divergence, most evident in cases with <em>TP53</em> mutations, suggests that high-grade transformation may be a relatively early molecular event.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 1","pages":"Article 100629"},"PeriodicalIF":7.1,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400755","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 : 2024-09-26DOI: 10.1016/j.modpat.2024.100627
Paweł Karpinski , Javier E. Mendez-Pena , Cheng-Lin Wu , Ali Akalin , Kristine M. Cornejo , Yin P. Hung , Mai P. Hoang
Although of therapeutic importance, a single sensitive and specific immunostain to distinguish Merkel cell carcinoma (MCC) from mimics is not currently available. In addition, single tumor cells are difficult to detect in sentinel lymph node biopsy. Leveraging publicly available data sets of 9264 solid tumors and >600,000 single-cell transcriptomes, we identified POU4F3 to be a specific marker of MCC. Analyses of Pan-Cancer RNA bulk sequencing data of 24 tumor types from Tumor Cancer Genomic Atlas data sets as well as non-Tumor Cancer Genomic Atlas small cell lung carcinoma and MCC data sets confirmed POU4F3 specificity for MCC. Single-cell RNA-sequencing analyses also confirmed the lack of POU4F3 expression in lung small cell carcinoma as well as a variety of normal tissues. Nuclear POU4F3 immunohistochemical expression was noted in 98.7% of 153 MCCs and in only 1.7% of mimics (3 of 180 cases, including 95 small cell carcinomas, of which 55 were from lungs and the remainder from other sites). Three POU4F3-positive non-MCC cases were from lungs (2 cases) and vagina (1 case). All 153 tested MCC cases were negative for ASCL1, a key transcriptional regulator highly expressed in small cell lung carcinoma. NeuroD1 was seen in a subset of MCC cases (20.9%, 32/153). POU4F3 immunostain was performed on 29 sentinel lymph nodes, and strong POU4F3 nuclear expression facilitated the ease of metastasis detection, even single tumor cells. Our study built on prior works shows that POU4F3 is a sensitive and specific clinical marker of MCC.
{"title":"POU4F3 Is a Sensitive and Specific Marker of Merkel Cell Carcinoma","authors":"Paweł Karpinski , Javier E. Mendez-Pena , Cheng-Lin Wu , Ali Akalin , Kristine M. Cornejo , Yin P. Hung , Mai P. Hoang","doi":"10.1016/j.modpat.2024.100627","DOIUrl":"10.1016/j.modpat.2024.100627","url":null,"abstract":"<div><div>Although of therapeutic importance, a single sensitive and specific immunostain to distinguish Merkel cell carcinoma (MCC) from mimics is not currently available. In addition, single tumor cells are difficult to detect in sentinel lymph node biopsy. Leveraging publicly available data sets of 9264 solid tumors and >600,000 single-cell transcriptomes, we identified <em>POU4F3</em> to be a specific marker of MCC. Analyses of Pan-Cancer RNA bulk sequencing data of 24 tumor types from Tumor Cancer Genomic Atlas data sets as well as non-Tumor Cancer Genomic Atlas small cell lung carcinoma and MCC data sets confirmed <em>POU4F3</em> specificity for MCC. Single-cell RNA-sequencing analyses also confirmed the lack of <em>POU4F3</em> expression in lung small cell carcinoma as well as a variety of normal tissues. Nuclear POU4F3 immunohistochemical expression was noted in 98.7% of 153 MCCs and in only 1.7% of mimics (3 of 180 cases, including 95 small cell carcinomas, of which 55 were from lungs and the remainder from other sites). Three POU4F3-positive non-MCC cases were from lungs (2 cases) and vagina (1 case). All 153 tested MCC cases were negative for ASCL1, a key transcriptional regulator highly expressed in small cell lung carcinoma. NeuroD1 was seen in a subset of MCC cases (20.9%, 32/153). POU4F3 immunostain was performed on 29 sentinel lymph nodes, and strong POU4F3 nuclear expression facilitated the ease of metastasis detection, even single tumor cells. Our study built on prior works shows that POU4F3 is a sensitive and specific clinical marker of MCC.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 1","pages":"Article 100627"},"PeriodicalIF":7.1,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350234","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 : 2024-09-25DOI: 10.1016/j.modpat.2024.100626
Grant M. Fischer, Navin R. Mahadevan, Jason L. Hornick, Christopher D.M. Fletcher, Eleanor Russell-Goldman
Undifferentiated melanoma, defined as melanoma that has lost all usual phenotypic and immunohistochemical characteristics of conventional melanoma, can pose significant diagnostic challenges. Molecular studies have advanced our understanding of undifferentiated melanoma by demonstrating that a subset of these tumors harbors known melanoma driver alterations in genes such as BRAF, NRAS, and NF1. However, there is a paucity of data describing genetic alterations that may distinguish undifferentiated melanoma from conventional melanoma. In this study, we directly compared the genomic profiles of undifferentiated melanoma to a cohort of conventional melanomas, including 14 undifferentiated melanoma cases (comprised of 2 primary cases, 2 cutaneous recurrences, and 10 metastases) and a cohort of 127 conventional melanomas including primary, recurrent, and metastatic cases. Targeted sequencing of 447 cancer-associated genes was performed, including identification of mutations and copy number alterations. NRAS was the most frequent melanoma driver in undifferentiated melanoma (8/14 cases, 57%), although notably, only 1 undifferentiated melanoma harbored an NRAS Q61R mutation. Compared with the conventional melanoma cohort, undifferentiated melanoma demonstrated statistically significant enrichment of pathogenic activating RAC1 mutations (6/14 total cases, 43%), including P29S (4/6 cases), P29L (1/6 cases), and D11E (1/6 cases). In addition to providing insight into the molecular pathogenesis of undifferentiated melanoma, these findings also suggest that RAS Q61R immunohistochemistry may have limited utility for its diagnosis. The presence of recurrent RAC1 mutations in undifferentiated melanoma is also notable as these alterations may contribute to mitogen-activated protein kinase pathway–targeted therapy resistance. Furthermore, the RAC1 alterations identified in this cohort have been shown to drive a melanocytic to mesenchymal switch in melanocytes, offering a possible explanation for the undifferentiated phenotype of these melanomas.
{"title":"A Comparative Genomic Study of Conventional and Undifferentiated Melanoma","authors":"Grant M. Fischer, Navin R. Mahadevan, Jason L. Hornick, Christopher D.M. Fletcher, Eleanor Russell-Goldman","doi":"10.1016/j.modpat.2024.100626","DOIUrl":"10.1016/j.modpat.2024.100626","url":null,"abstract":"<div><div>Undifferentiated melanoma, defined as melanoma that has lost all usual phenotypic and immunohistochemical characteristics of conventional melanoma, can pose significant diagnostic challenges. Molecular studies have advanced our understanding of undifferentiated melanoma by demonstrating that a subset of these tumors harbors known melanoma driver alterations in genes such as <em>BRAF</em>, <em>NRAS</em>, and <em>NF1</em>. However, there is a paucity of data describing genetic alterations that may distinguish undifferentiated melanoma from conventional melanoma. In this study, we directly compared the genomic profiles of undifferentiated melanoma to a cohort of conventional melanomas, including 14 undifferentiated melanoma cases (comprised of 2 primary cases, 2 cutaneous recurrences, and 10 metastases) and a cohort of 127 conventional melanomas including primary, recurrent, and metastatic cases. Targeted sequencing of 447 cancer-associated genes was performed, including identification of mutations and copy number alterations. <em>NRAS</em> was the most frequent melanoma driver in undifferentiated melanoma (8/14 cases, 57%), although notably, only 1 undifferentiated melanoma harbored an <em>NRAS</em> Q61R mutation. Compared with the conventional melanoma cohort, undifferentiated melanoma demonstrated statistically significant enrichment of pathogenic activating <em>RAC1</em> mutations (6/14 total cases, 43%), including P29S (4/6 cases), P29L (1/6 cases), and D11E (1/6 cases). In addition to providing insight into the molecular pathogenesis of undifferentiated melanoma, these findings also suggest that RAS Q61R immunohistochemistry may have limited utility for its diagnosis. The presence of recurrent <em>RAC1</em> mutations in undifferentiated melanoma is also notable as these alterations may contribute to mitogen-activated protein kinase pathway–targeted therapy resistance. Furthermore, the <em>RAC1</em> alterations identified in this cohort have been shown to drive a melanocytic to mesenchymal switch in melanocytes, offering a possible explanation for the undifferentiated phenotype of these melanomas.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"37 12","pages":"Article 100626"},"PeriodicalIF":7.1,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350230","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 : 2024-09-25DOI: 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}
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