Fibroblastic foci (FF) are considered important findings of usual interstitial pneumonia (UIP); however, they are not only specific to UIP but also observed in various fibrotic interstitial lung diseases (ILDs). Previous studies have reported the significance of FF comparing UIP with nonspecific interstitial pneumonia (NSIP) or secondary interstitial pneumonia, such as collagen vascular disease–related ILD (CVD-ILD) or fibrotic hypersensitivity pneumonitis (FHP). However, only few studies have mentioned their location, and no reports have shown significant results regarding their location. This study aimed to compare the spatial distribution of FF across various forms of ILDs, based on anatomical location. Among patients who underwent lung transplantation at Kyoto University Hospital between April 1, 2008, and March 31, 2023, those diagnosed with idiopathic pulmonary fibrosis (IPF) (n = 24), idiopathic NSIP (n = 11), CVD-ILD (n = 36), and FHP (n = 12) were included, and 744 slides were obtained. FF were classified into 4 categories: peripheral, such as subpleural/paraseptal; intralobular, along the alveolar wall (aFF); centrilobular (cFF); and distorted or dense fibrotic lesions. The number of total and each location’s FF/cm2 were counted, and the percentage of each location’s FF was calculated. IPF showed more total FF and peripheral FF than NSIP. FHP had more cFF than CVD (P = .026) and NSIP (P = .018). The dFF was higher in IPF than that in CVD (P = .018) and NSIP (P = .039). The aFF/total FF ratio was higher in CVD than that in FHP (P = .021) and IPF (P < .001). A high cFF/total FF ratio was correlated with FHP versus IPF (P = .032). In conclusion, FF with existing peripheral and distorted/dense fibrosis were more closely related to IPF, whereas cFF were highly correlated with FHP. Moreover, a high aFF/total FF ratio was suggestive of CVD.
{"title":"Location of Fibroblastic Foci: Does the Lesion You Observe Really Suggest Usual Interstitial Pneumonia?","authors":"Hiroyuki Katsuragawa , Hiroaki Ito , Tomohiro Handa , Masatsugu Hamaji , Toshi Menju , Ryo Sakamoto , Hiroshi Date , Hironori Haga , Akihiko Yoshizawa","doi":"10.1016/j.modpat.2024.100675","DOIUrl":"10.1016/j.modpat.2024.100675","url":null,"abstract":"<div><div>Fibroblastic foci (FF) are considered important findings of usual interstitial pneumonia (UIP); however, they are not only specific to UIP but also observed in various fibrotic interstitial lung diseases (ILDs). Previous studies have reported the significance of FF comparing UIP with nonspecific interstitial pneumonia (NSIP) or secondary interstitial pneumonia, such as collagen vascular disease–related ILD (CVD-ILD) or fibrotic hypersensitivity pneumonitis (FHP). However, only few studies have mentioned their location, and no reports have shown significant results regarding their location. This study aimed to compare the spatial distribution of FF across various forms of ILDs, based on anatomical location. Among patients who underwent lung transplantation at Kyoto University Hospital between April 1, 2008, and March 31, 2023, those diagnosed with idiopathic pulmonary fibrosis (IPF) (n = 24), idiopathic NSIP (n = 11), CVD-ILD (n = 36), and FHP (n = 12) were included, and 744 slides were obtained. FF were classified into 4 categories: peripheral, such as subpleural/paraseptal; intralobular, along the alveolar wall (aFF); centrilobular (cFF); and distorted or dense fibrotic lesions. The number of total and each location’s FF/cm<sup>2</sup> were counted, and the percentage of each location’s FF was calculated. IPF showed more total FF and peripheral FF than NSIP. FHP had more cFF than CVD (<em>P</em> = .026) and NSIP (<em>P</em> = .018). The dFF was higher in IPF than that in CVD (<em>P</em> = .018) and NSIP (<em>P</em> = .039). The aFF/total FF ratio was higher in CVD than that in FHP (<em>P</em> = .021) and IPF (<em>P</em> < .001). A high cFF/total FF ratio was correlated with FHP versus IPF (<em>P</em> = .032). In conclusion, FF with existing peripheral and distorted/dense fibrosis were more closely related to IPF, whereas cFF were highly correlated with FHP. Moreover, a high aFF/total FF ratio was suggestive of CVD.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 3","pages":"Article 100675"},"PeriodicalIF":7.1,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770358","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 : 2024-11-29DOI: 10.1016/j.modpat.2024.100676
Phoebe M. Hammer , Amir Momeni-Boroujeni , David L. Kolin , Leandra Kingsley , Ann Folkins , Rachel L.P. Geisick , Chandler Ho , Carlos J. Suarez , Brooke E. Howitt
Uterine carcinosarcomas (UCS) are high-grade biphasic neoplasms with generally poor outcomes. Based on The Cancer Genome Atlas molecular classification of endometrial carcinomas, the majority of UCS are classified as copy-number high/serous-like (p53-abnormal); however, a small subset represent other molecular subtypes, including those that harbor POLE mutations. We identified 11 POLE-mutated (POLEmut) UCS across 3 institutions and assessed the clinical, histopathologic, immunohistochemical, and molecular features of these tumors. POLEmut UCS occurred in adult women (median age, 64 years; range, 48-79 years) and usually presented as The International Federation of Gynecology and Obstetrics 2009 clinical stage IA (n = 4) or IB (n = 3). Almost all tumors were predominantly carcinomatous (n = 10), with most showing endometrioid morphology (n = 7), followed by ambiguous (n = 4) and serous (n = 3) histotypes. By immunohistochemistry, 7 tumors showed aberrant or subclonally aberrant expression of p53, 6 of which harbored pathogenic mutations in TP53 by sequencing. Other frequent mutations included PIK3CA (10/11), PTEN (8/11), RB1 (7/11), ARID1A (7/11), ATM (6/11), PIK3RA (5/11), and FBXW7 (4/11). Two tumors demonstrated loss of mismatch repair protein expression, and 1 had subclonal loss. Heterologous differentiation was uncommon, and only chondrosarcomatous type (n = 2) was observed. Mean and median follow-ups were 24.3 and 14.1 months, respectively (range, 1.4-61.1 months). Ten patients (91%) had no recurrences or death from disease, although 3 of these had follow-up periods <1 year. One patient, with the subclonal POLE variant, presented with stage IV disease and died 1.4 months after surgery. In conclusion, POLEmut UCS demonstrate unique morphologic and immunohistochemical features compared with their p53-abnormal counterparts and may have significant prognostic differences. Our study supports full molecular classification of UCS. We also raise awareness for potentially assessing POLE mutation allele frequency and clonality in consideration of classifying a tumor as POLEmut.
{"title":"POLE-Mutated Uterine Carcinosarcomas: A Clinicopathologic and Molecular Study of 11 Cases","authors":"Phoebe M. Hammer , Amir Momeni-Boroujeni , David L. Kolin , Leandra Kingsley , Ann Folkins , Rachel L.P. Geisick , Chandler Ho , Carlos J. Suarez , Brooke E. Howitt","doi":"10.1016/j.modpat.2024.100676","DOIUrl":"10.1016/j.modpat.2024.100676","url":null,"abstract":"<div><div>Uterine carcinosarcomas (UCS) are high-grade biphasic neoplasms with generally poor outcomes. Based on The Cancer Genome Atlas molecular classification of endometrial carcinomas, the majority of UCS are classified as copy-number high/serous-like (p53-abnormal); however, a small subset represent other molecular subtypes, including those that harbor <em>POLE</em> mutations. We identified 11 <em>POLE</em>-mutated (<em>POLE</em>mut) UCS across 3 institutions and assessed the clinical, histopathologic, immunohistochemical, and molecular features of these tumors. <em>POLE</em>mut UCS occurred in adult women (median age, 64 years; range, 48-79 years) and usually presented as The International Federation of Gynecology and Obstetrics 2009 clinical stage IA (n = 4) or IB (n = 3). Almost all tumors were predominantly carcinomatous (n = 10), with most showing endometrioid morphology (n = 7), followed by ambiguous (n = 4) and serous (n = 3) histotypes. By immunohistochemistry, 7 tumors showed aberrant or subclonally aberrant expression of p53, 6 of which harbored pathogenic mutations in <em>TP53</em> by sequencing. Other frequent mutations included <em>PIK3CA</em> (10/11), <em>PTEN</em> (8/11), <em>RB1</em> (7/11), <em>ARID1A</em> (7/11), <em>ATM</em> (6/11), <em>PIK3RA</em> (5/11), and <em>FBXW7</em> (4/11). Two tumors demonstrated loss of mismatch repair protein expression, and 1 had subclonal loss. Heterologous differentiation was uncommon, and only chondrosarcomatous type (n = 2) was observed. Mean and median follow-ups were 24.3 and 14.1 months, respectively (range, 1.4-61.1 months). Ten patients (91%) had no recurrences or death from disease, although 3 of these had follow-up periods <1 year. One patient, with the subclonal <em>POL</em>E variant, presented with stage IV disease and died 1.4 months after surgery. In conclusion, <em>POLE</em>mut UCS demonstrate unique morphologic and immunohistochemical features compared with their p53-abnormal counterparts and may have significant prognostic differences. Our study supports full molecular classification of UCS. We also raise awareness for potentially assessing <em>POLE</em> mutation allele frequency and clonality in consideration of classifying a tumor as <em>POLE</em>mut.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 3","pages":"Article 100676"},"PeriodicalIF":7.1,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770365","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 : 2024-11-28DOI: 10.1016/j.modpat.2024.100674
Christopher A. Febres-Aldana , Mahmoud M. Elsayad , Maelle Saliba , Umesh Bhanot , Peter Ntiamoah , Anjanie Takeyama , Bibianna M. Purgina , Paula A. Rodriguez-Urrego , Zlatko Marusic , Antonia Jakovcevic , Deborah J. Chute , Lara A. Dunn , Ian Ganly , Marc A. Cohen , David G. Pfister , Ronald A. Ghossein , Marina K. Baine , Natasha Rekhtman , Snjezana Dogan
The diagnosis and treatment of sinonasal small round epithelial/neuroepithelial malignancies depend on the expression of conventional neuroendocrine markers (NEMs), such as synaptophysin, chromogranin A, INSM1, and CD56/NCAM1. However, these tumors remain diagnostically challenging because of overlapping histologic and immunohistochemical features. The transcriptional regulators ASCL1, NEUROD1, POU2F3, and YAP1 are novel NEM (nNEM) used for the subtyping of small-cell lung cancer (SCLC). Here, we assessed the immunoexpression of nNEM in 76 sinonasal malignancies, including 27 olfactory neuroblastomas (ONB), 14 small-cell neuroendocrine carcinomas (SCNEC), 2 large-cell neuroendocrine carcinomas, 12 sinonasal undifferentiated carcinomas (SNUC), 7 olfactory carcinomas (OC), 11 SWI/SNF-deficient carcinomas, and 3 neuroendocrine tumors. We correlated nNEM expression with the extent of neuroendocrine (NE) differentiation, as defined by averaged conventional NEM expression (NE-high: H-score, ≥150; NE-low: H-score, <150). Dominant NE subtypes were defined by the nNEM with the highest H-score. Coexpression of 2 nNEM with <100 H-score difference defined a codominant NE subtype. NE differentiation positively correlated with NEUROD1 and negatively with YAP1 expression (P < .0001). ONB were NE-high (96%), and all were NEUROD1-dominant/POU2F3-negative/ASCL1-negative (low)/YAP1-negative (low). In contrast to ONB, all OC were NE-low, mostly (71%) codominant subtypes, NEUROD1-low (negative) (100%, P = .0001), and YAP1 high (71%; P = .0001). Most notably, all SNUC were POU2F3-(co)dominant/NEUROD1-negative irrespective of the IDH2 mutations. Sinonasal tumors with high POU2F3 expression showed enrichment for “tuft cell carcinoma” and tuft cell signatures (P = .009). Similar to SCLC, SCNEC was heterogeneous in terms of nNEM expression comprising several molecular subtypes, including ASCL1-(co)dominant (43%) cases. All SWI/SNF-deficient carcinomas were consistently ASCL1/NEUROD1/POU2F3-negative and YAP1-positive. ASCL1/NEUROD1/POU2F3/YAP1 are useful markers in the differential diagnosis of ONB, SNUC, OC, and SWI/SNF-deficient carcinomas. Subsets of SNUC and large-cell neuroendocrine carcinomas may represent tuft cell–like carcinomas, suggesting that the tuft cell could be explored as the cell of origin for these tumors. The therapeutic vulnerabilities associated with POU2F3 expression in SCLC suggest that a similar approach might be considered for POU2F3-positive carcinomas of the sinonasal tract. Given their diagnostic and possible therapeutic relevance, nNEM have the potential to transform the way we approach the diagnosis and management of sinonasal small round epithelial/neuroepithelial malignancies.
{"title":"Analysis of ASCL1/NEUROD1/POU2F3/YAP1 Yields Novel Insights for the Diagnosis of Olfactory Neuroblastoma and Identifies Sinonasal Tuft Cell–Like Carcinoma","authors":"Christopher A. Febres-Aldana , Mahmoud M. Elsayad , Maelle Saliba , Umesh Bhanot , Peter Ntiamoah , Anjanie Takeyama , Bibianna M. Purgina , Paula A. Rodriguez-Urrego , Zlatko Marusic , Antonia Jakovcevic , Deborah J. Chute , Lara A. Dunn , Ian Ganly , Marc A. Cohen , David G. Pfister , Ronald A. Ghossein , Marina K. Baine , Natasha Rekhtman , Snjezana Dogan","doi":"10.1016/j.modpat.2024.100674","DOIUrl":"10.1016/j.modpat.2024.100674","url":null,"abstract":"<div><div>The diagnosis and treatment of sinonasal small round epithelial/neuroepithelial malignancies depend on the expression of conventional neuroendocrine markers (NEMs), such as synaptophysin, chromogranin A, INSM1, and CD56/NCAM1. However, these tumors remain diagnostically challenging because of overlapping histologic and immunohistochemical features. The transcriptional regulators ASCL1, NEUROD1, POU2F3, and YAP1 are novel NEM (nNEM) used for the subtyping of small-cell lung cancer (SCLC). Here, we assessed the immunoexpression of nNEM in 76 sinonasal malignancies, including 27 olfactory neuroblastomas (ONB), 14 small-cell neuroendocrine carcinomas (SCNEC), 2 large-cell neuroendocrine carcinomas, 12 sinonasal undifferentiated carcinomas (SNUC), 7 olfactory carcinomas (OC), 11 SWI/SNF-deficient carcinomas, and 3 neuroendocrine tumors. We correlated nNEM expression with the extent of neuroendocrine (NE) differentiation, as defined by averaged conventional NEM expression (NE-high: H-score, ≥150; NE-low: H-score, <150). Dominant NE subtypes were defined by the nNEM with the highest H-score. Coexpression of 2 nNEM with <100 H-score difference defined a codominant NE subtype. NE differentiation positively correlated with NEUROD1 and negatively with YAP1 expression (<em>P</em> < .0001). ONB were NE-high (96%), and all were NEUROD1-dominant/POU2F3-negative/ASCL1-negative (low)/YAP1-negative (low). In contrast to ONB, all OC were NE-low, mostly (71%) codominant subtypes, NEUROD1-low (negative) (100%, <em>P</em> = .0001), and YAP1 high (71%; <em>P</em> = .0001). Most notably, all SNUC were POU2F3-(co)dominant/NEUROD1-negative irrespective of the <em>IDH2</em> mutations. Sinonasal tumors with high <em>POU2F3</em> expression showed enrichment for “tuft cell carcinoma” and tuft cell signatures (<em>P</em> = .009). Similar to SCLC, SCNEC was heterogeneous in terms of nNEM expression comprising several molecular subtypes, including ASCL1-(co)dominant (43%) cases. All SWI/SNF-deficient carcinomas were consistently ASCL1/NEUROD1/POU2F3-negative and YAP1-positive. ASCL1/NEUROD1/POU2F3/YAP1 are useful markers in the differential diagnosis of ONB, SNUC, OC, and SWI/SNF-deficient carcinomas. Subsets of SNUC and large-cell neuroendocrine carcinomas may represent tuft cell–like carcinomas, suggesting that the tuft cell could be explored as the cell of origin for these tumors. The therapeutic vulnerabilities associated with POU2F3 expression in SCLC suggest that a similar approach might be considered for POU2F3-positive carcinomas of the sinonasal tract. Given their diagnostic and possible therapeutic relevance, nNEM have the potential to transform the way we approach the diagnosis and management of sinonasal small round epithelial/neuroepithelial malignancies.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 3","pages":"Article 100674"},"PeriodicalIF":7.1,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755395","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 : 2024-11-26DOI: 10.1016/j.modpat.2024.100673
Hooman H. Rashidi , Matthew G. Hanna , Liron Pantanowitz
{"title":"Introducing an Essential 7-Part Artificial Intelligence Review Series: A Guided Journey Into the Future of Pathology and Medicine","authors":"Hooman H. Rashidi , Matthew G. Hanna , Liron Pantanowitz","doi":"10.1016/j.modpat.2024.100673","DOIUrl":"10.1016/j.modpat.2024.100673","url":null,"abstract":"","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 3","pages":"Article 100673"},"PeriodicalIF":7.1,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739833","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 : 2024-11-22DOI: 10.1016/j.modpat.2024.100663
Hooman H. Rashidi , Bo Hu , Joshua Pantanowitz , Nam Tran , Silvia Liu , Alireza Chamanzar , Mert Gur , Chung-Chou H. Chang , Yanshan Wang , Ahmad Tafti , Liron Pantanowitz , Matthew G. Hanna
The rapidly evolving landscape of artificial intelligence (AI) and machine learning (ML) in medicine has prompted medical professionals to increasingly familiarize themselves with related topics. This also demands grasping the underlying statistical principles that govern their design, validation, and reproducibility. Uniquely, the practice of pathology and medicine produces vast amount of data that can be exploited by AI/ML. The emergence of generative AI, especially in the area of large language models and multimodal frameworks, represents approaches that are starting to transform medicine. Fundamentally, generative and traditional (eg, nongenerative predictive analytics) ML techniques rely on certain common statistical measures to function. However, unique to generative AI are metrics such as, but not limited to, perplexity and BiLingual Evaluation Understudy score that provide a means to determine the quality of generated samples that are typically unfamiliar to most medical practitioners. In contrast, nongenerative predictive analytics ML often uses more familiar metrics tailored to specific tasks as seen in the typical classification (ie, confusion metrics measures, such as accuracy, sensitivity, F1 score, and receiver operating characteristic area under the curve) or regression studies (ie, root mean square error and R2). To this end, the goal of this review article (as part 4 of our AI review series) is to provide an overview and a comparative measure of statistical measures and methodologies used in both generative AI and traditional (ie, nongenerative predictive analytics) ML fields along with their strengths and known limitations. By understanding their similarities and differences along with their respective applications, we will become better stewards of this transformative space, which ultimately enables us to better address our current and future needs and challenges in a more responsible and scientifically sound manner.
{"title":"Statistics of Generative Artificial Intelligence and Nongenerative Predictive Analytics Machine Learning in Medicine","authors":"Hooman H. Rashidi , Bo Hu , Joshua Pantanowitz , Nam Tran , Silvia Liu , Alireza Chamanzar , Mert Gur , Chung-Chou H. Chang , Yanshan Wang , Ahmad Tafti , Liron Pantanowitz , Matthew G. Hanna","doi":"10.1016/j.modpat.2024.100663","DOIUrl":"10.1016/j.modpat.2024.100663","url":null,"abstract":"<div><div>The rapidly evolving landscape of artificial intelligence (AI) and machine learning (ML) in medicine has prompted medical professionals to increasingly familiarize themselves with related topics. This also demands grasping the underlying statistical principles that govern their design, validation, and reproducibility. Uniquely, the practice of pathology and medicine produces vast amount of data that can be exploited by AI/ML. The emergence of generative AI, especially in the area of large language models and multimodal frameworks, represents approaches that are starting to transform medicine. Fundamentally, generative and traditional (eg, nongenerative predictive analytics) ML techniques rely on certain common statistical measures to function. However, unique to generative AI are metrics such as, but not limited to, perplexity and BiLingual Evaluation Understudy score that provide a means to determine the quality of generated samples that are typically unfamiliar to most medical practitioners. In contrast, nongenerative predictive analytics ML often uses more familiar metrics tailored to specific tasks as seen in the typical classification (ie, confusion metrics measures, such as accuracy, sensitivity, F1 score, and receiver operating characteristic area under the curve) or regression studies (ie, root mean square error and R<sup>2</sup>). To this end, the goal of this review article (as part 4 of our AI review series) is to provide an overview and a comparative measure of statistical measures and methodologies used in both generative AI and traditional (ie, nongenerative predictive analytics) ML fields along with their strengths and known limitations. By understanding their similarities and differences along with their respective applications, we will become better stewards of this transformative space, which ultimately enables us to better address our current and future needs and challenges in a more responsible and scientifically sound manner.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 3","pages":"Article 100663"},"PeriodicalIF":7.1,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695549","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 : 2024-11-20DOI: 10.1016/j.modpat.2024.100660
Ezgi Dicle Serbes , Nanda Horeweg , Carlos Parra-Herran , Renske van Rijnsoever , Jan J. Jobsen , Ina Jurgenliemk-Schulz , Nienke Kuijsters , Remi A. Nout , Marie A.D. Haverkort , Melanie E. Powell , Pearly Khaw , Marie Plante , Catherine Genestie , Hans W. Nijman , Carien L. Creutzberg , Tjalling Bosse , Claire J.H. Kramer
Of the 4 molecular subtypes of endometrial cancer (EC), p53-abnormal (p53abn) EC is associated with abundant copy number alterations and the worst clinical outcome. Patients with p53abn EC have the highest risk of disease recurrence and death, independent of tumor grade and histologic subtype. Currently, all invasive p53abn ECs are considered high risk, and no prognostic biomarkers have yet been found that can aid in clinical management. Here, we aimed to test whether loss of retinoblastoma (RB) protein expression using immunohistochemistry has the potential for prognostic refinement of p53abn EC. A large cohort of 227 p53abn ECs collected from the PORTEC-1/2/3 clinical trials and the Medisch Spectrum Twente cohort study was investigated, and RB loss was identified in 7.0% (n = 16/227). RB-lost p53abn ECs were predominantly high-grade endometrioid ECs (n = 6, 37.5%) and carcinosarcomas with endometrioid-type epithelial component (n = 5, 31.3%). Histologically, RB-lost p53abn ECs were typified by high-grade nuclear atypia (n = 16, 100%), predominantly solid growth pattern (n = 15/16, 93.8%), and polypoid growth (n = 9/16, 56.3%). Copy number loss involving the RB1 locus was identified in the majority of RB-lost p53abn EC (n = 13/14, 92.9%), explaining the loss of RB expression. Comparative analysis also showed that RB-lost p53abn ECs were diagnosed at earlier stages than RB-retained p53abn EC (P = .014). Interestingly, RB-lost p53abn EC showed prolonged time to overall recurrence (P = .038), even within stage I alone (P = .040). These findings highlight distinct morphomolecular features in RB-lost p53abn ECs and confirm the utility of RB immunohistochemistry as a surrogate for underlying molecular RB1 alterations. To our knowledge, this is the first study to show the potential use of RB in prognostic refinement of p53abn EC, although validation is warranted.
{"title":"Retinoblastoma Protein Loss in p53 Abnormal Endometrial Carcinoma: Histologic and Clinicopathological Correlates","authors":"Ezgi Dicle Serbes , Nanda Horeweg , Carlos Parra-Herran , Renske van Rijnsoever , Jan J. Jobsen , Ina Jurgenliemk-Schulz , Nienke Kuijsters , Remi A. Nout , Marie A.D. Haverkort , Melanie E. Powell , Pearly Khaw , Marie Plante , Catherine Genestie , Hans W. Nijman , Carien L. Creutzberg , Tjalling Bosse , Claire J.H. Kramer","doi":"10.1016/j.modpat.2024.100660","DOIUrl":"10.1016/j.modpat.2024.100660","url":null,"abstract":"<div><div>Of the 4 molecular subtypes of endometrial cancer (EC), p53-abnormal (p53abn) EC is associated with abundant copy number alterations and the worst clinical outcome. Patients with p53abn EC have the highest risk of disease recurrence and death, independent of tumor grade and histologic subtype. Currently, all invasive p53abn ECs are considered high risk, and no prognostic biomarkers have yet been found that can aid in clinical management. Here, we aimed to test whether loss of retinoblastoma (RB) protein expression using immunohistochemistry has the potential for prognostic refinement of p53abn EC. A large cohort of 227 p53abn ECs collected from the PORTEC-1/2/3 clinical trials and the Medisch Spectrum Twente cohort study was investigated, and RB loss was identified in 7.0% (<em>n</em> = 16/227). RB-lost p53abn ECs were predominantly high-grade endometrioid ECs (<em>n</em> = 6, 37.5%) and carcinosarcomas with endometrioid-type epithelial component (<em>n</em> = 5, 31.3%). Histologically, RB-lost p53abn ECs were typified by high-grade nuclear atypia (<em>n</em> = 16, 100%), predominantly solid growth pattern (<em>n</em> = 15/16, 93.8%), and polypoid growth (<em>n</em> = 9/16, 56.3%). Copy number loss involving the <em>RB1</em> locus was identified in the majority of RB-lost p53abn EC (<em>n</em> = 13/14, 92.9%), explaining the loss of RB expression. Comparative analysis also showed that RB-lost p53abn ECs were diagnosed at earlier stages than RB-retained p53abn EC (<em>P</em> = .014). Interestingly, RB-lost p53abn EC showed prolonged time to overall recurrence (<em>P</em> = .038), even within stage I alone (<em>P</em> = .040). These findings highlight distinct morphomolecular features in RB-lost p53abn ECs and confirm the utility of RB immunohistochemistry as a surrogate for underlying molecular <em>RB1</em> alterations. To our knowledge, this is the first study to show the potential use of RB in prognostic refinement of p53abn EC, although validation is warranted.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 3","pages":"Article 100660"},"PeriodicalIF":7.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693201","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 : 2024-11-20DOI: 10.1016/j.modpat.2024.100664
William J. Sande , Andrew L. Folpe , Paige O’Connor , Daniel Graham , Jeremy F. Molligan , Ying-Chun Lo , Yvonne Y. Cheung , Baptiste Ameline , Daniel Baumhoer , Dorothee Harder , Kevin A. Raskin , Christopher W. Mount , Yin P. Hung , Gunnlaugur Petur Nielsen , Darcy A. Kerr , Darya Buehler , Doris E. Wenger , Judith Jebastin Thangaiah
Poorly differentiated chordoma (PDC) is an aggressive subtype of chordoma characterized by SMARCB1 (INI1) loss and a dismal prognosis. It typically involves the axial skeleton, most commonly the skull base and the cervical spine. To our knowledge, only 5 cases of extraaxial PDC (EAPDC) have been reported, and the natural history of these tumors is not fully understood. We studied 6 cases of EAPDC, with the goal of better understanding these exceptionally rare tumors. The tumors occurred in 4 women and 2 men, ranging from 37 to 68 years of age (median, 57.5 years) and involved or originated in the left knee joint (3 cases), right knee joint (2 cases), and right wrist (1 case). Grossly, all were solid and lobulated, with areas of necrosis. Histologically, the tumors were identical to axial PDC, with sheets and lobules of overtly malignant-appearing epithelioid-to-rhabdoid cells with prominent nucleoli. Mitotic activity and necrosis were present. By immunohistochemistry, all cases expressed keratins and brachyury and were SMARCB1 deficient. Molecular genetic analysis identified SMARCB1 loss-of-function alterations in 4 of the tested cases, including mutations (2 cases) and copy number loss (2 cases). DNA methylation profiling of 4 cases of EAPDC showed clustering with axial PDC. Clinical follow-up (6 patients; median, 11.5 months; range, 1-26 months) showed 4 patients to have received transfemoral amputation and 1 extraarticular resection. None received neoadjuvant radiotherapy; 1 received neoadjuvant chemotherapy and 1 adjuvant chemotherapy/immunotherapy. Local recurrences were seen in 2 patients at 7 and 8 months; 3 patients developed metastases 7-11 months after surgery. Two patients were alive with metastatic disease (at 7 and 13 months), 1 died of disease (20 months), and 3 were disease free (1-26 months). We conclude that EAPDC are aggressive malignancies with an unusual predilection for the knee joint and unknown pathogenesis.
{"title":"Extraaxial Poorly Differentiated Chordoma: Clinicopathologic and Molecular Genetic Characterization","authors":"William J. Sande , Andrew L. Folpe , Paige O’Connor , Daniel Graham , Jeremy F. Molligan , Ying-Chun Lo , Yvonne Y. Cheung , Baptiste Ameline , Daniel Baumhoer , Dorothee Harder , Kevin A. Raskin , Christopher W. Mount , Yin P. Hung , Gunnlaugur Petur Nielsen , Darcy A. Kerr , Darya Buehler , Doris E. Wenger , Judith Jebastin Thangaiah","doi":"10.1016/j.modpat.2024.100664","DOIUrl":"10.1016/j.modpat.2024.100664","url":null,"abstract":"<div><div>Poorly differentiated chordoma (PDC) is an aggressive subtype of chordoma characterized by SMARCB1 (INI1) loss and a dismal prognosis. It typically involves the axial skeleton, most commonly the skull base and the cervical spine. To our knowledge, only 5 cases of extraaxial PDC (EAPDC) have been reported, and the natural history of these tumors is not fully understood. We studied 6 cases of EAPDC, with the goal of better understanding these exceptionally rare tumors. The tumors occurred in 4 women and 2 men, ranging from 37 to 68 years of age (median, 57.5 years) and involved or originated in the left knee joint (3 cases), right knee joint (2 cases), and right wrist (1 case). Grossly, all were solid and lobulated, with areas of necrosis. Histologically, the tumors were identical to axial PDC, with sheets and lobules of overtly malignant-appearing epithelioid-to-rhabdoid cells with prominent nucleoli. Mitotic activity and necrosis were present. By immunohistochemistry, all cases expressed keratins and brachyury and were SMARCB1 deficient. Molecular genetic analysis identified <em>SMARCB1</em> loss-of-function alterations in 4 of the tested cases, including mutations (2 cases) and copy number loss (2 cases). DNA methylation profiling of 4 cases of EAPDC showed clustering with axial PDC. Clinical follow-up (6 patients; median, 11.5 months; range, 1-26 months) showed 4 patients to have received transfemoral amputation and 1 extraarticular resection. None received neoadjuvant radiotherapy; 1 received neoadjuvant chemotherapy and 1 adjuvant chemotherapy/immunotherapy. Local recurrences were seen in 2 patients at 7 and 8 months; 3 patients developed metastases 7-11 months after surgery. Two patients were alive with metastatic disease (at 7 and 13 months), 1 died of disease (20 months), and 3 were disease free (1-26 months). We conclude that EAPDC are aggressive malignancies with an unusual predilection for the knee joint and unknown pathogenesis.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 3","pages":"Article 100664"},"PeriodicalIF":7.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693198","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 : 2024-11-09DOI: 10.1016/j.modpat.2024.100649
Alexis Trecourt , Isabelle Treilleux , Daniel Pissaloux , Marie Donzel , Brice Thamphya , Franck Thirode , Aurélie Houlier , Sandrine Paindavoine , Tatiana Franceschi , Aline Baltrès , Witold Gertych , Pierre-Adrien Bolze , Pierre Antoine Chaix , Charlotte Roux-Terrier , Françoise Descotes , Isabelle Ray-Coquard , Jonathan Lopez , Mojgan Devouassoux-Shisheboran
Primary vulvar and vaginal adenocarcinomas of intestinal type (VVAIts) are very rare tumors, displaying morphologic and immunohistochemical overlap with colorectal adenocarcinomas. However, their immunoprofile and genomics are poorly studied, and their origin is still debated. Here, we studied a series of 8 VVAIts (4 vulvar and 4 vaginal) using a large panel of immunohistochemistry and DNA and RNA sequencing with clustering analyses. All tumors shared a similar morphology with colorectal adenocarcinomas and diffuse CK20 and CDX2 expression. SATB2 diffuse positivity was observed in 62.5% of tumors and CK7 in 82.5%, whereas PAX8, SOX17, p16, and estrogen and progesterone receptors were always negative. A p53 mutated-type expression was observed in 75% of tumors. All tumors were mismatch repair proficient. Neither human papillomavirus DNA nor pathogenic transcript fusions were detected. The most frequent molecular alterations were TP53 and KRAS variants in 71.4% and 42.9%, respectively. The transcriptomic analysis highlighted a robust VVAIts cluster distinct from endocervical, ovarian, lung, thyroid, salivary glands, breast, and renal carcinomas but failed to differentiate vulvar from vaginal intestinal-type tumors. On 2 different clustering analyses, VVAIts clustered altogether, very close to colorectal adenocarcinomas. Compared with endocervical adenocarcinomas of intestinal type, VVAIts had a significantly lower expression of SOX17 and epithelial-mesenchymal transition genes and a higher mitogen-activated protein kinase pathway gene expression. These results suggest that Müllerian structures leading to cervical adenocarcinomas may undergo intestinal-type transdifferentiation via an epithelial-mesenchymal transition phenomenon. Conversely, mitogen-activated protein kinase pathway activation in VVAIts, which plays a major role in colorectal adenocarcinomas, may indicate a close relationship in the carcinogenesis of these tumors. Our results indicate that adenocarcinomas of intestinal type, in the distal vagina or vestibular vulva, might be a unique and single entity, probably originating from cloacogenic embryonic remnants and/or ectopic colorectal mucosae inclusions. An open question would be to explore the efficacy of systemic drugs prescribed in colorectal cancers, in VVAIts.
{"title":"Primary Vulvar and Vaginal Adenocarcinomas of Intestinal Type Are Closer To Colorectal Adenocarcinomas Than To Carcinomas of Müllerian Origin","authors":"Alexis Trecourt , Isabelle Treilleux , Daniel Pissaloux , Marie Donzel , Brice Thamphya , Franck Thirode , Aurélie Houlier , Sandrine Paindavoine , Tatiana Franceschi , Aline Baltrès , Witold Gertych , Pierre-Adrien Bolze , Pierre Antoine Chaix , Charlotte Roux-Terrier , Françoise Descotes , Isabelle Ray-Coquard , Jonathan Lopez , Mojgan Devouassoux-Shisheboran","doi":"10.1016/j.modpat.2024.100649","DOIUrl":"10.1016/j.modpat.2024.100649","url":null,"abstract":"<div><div>Primary vulvar and vaginal adenocarcinomas of intestinal type (VVAIts) are very rare tumors, displaying morphologic and immunohistochemical overlap with colorectal adenocarcinomas. However, their immunoprofile and genomics are poorly studied, and their origin is still debated. Here, we studied a series of 8 VVAIts (4 vulvar and 4 vaginal) using a large panel of immunohistochemistry and DNA and RNA sequencing with clustering analyses. All tumors shared a similar morphology with colorectal adenocarcinomas and diffuse CK20 and CDX2 expression. SATB2 diffuse positivity was observed in 62.5% of tumors and CK7 in 82.5%, whereas PAX8, SOX17, p16, and estrogen and progesterone receptors were always negative. A p53 mutated-type expression was observed in 75% of tumors. All tumors were mismatch repair proficient. Neither human papillomavirus DNA nor pathogenic transcript fusions were detected. The most frequent molecular alterations were <em>TP53</em> and <em>KRAS</em> variants in 71.4% and 42.9%, respectively. The transcriptomic analysis highlighted a robust VVAIts cluster distinct from endocervical, ovarian, lung, thyroid, salivary glands, breast, and renal carcinomas but failed to differentiate vulvar from vaginal intestinal-type tumors. On 2 different clustering analyses, VVAIts clustered altogether, very close to colorectal adenocarcinomas. Compared with endocervical adenocarcinomas of intestinal type, VVAIts had a significantly lower expression of <em>SOX17</em> and epithelial-mesenchymal transition genes and a higher mitogen-activated protein kinase pathway gene expression. These results suggest that Müllerian structures leading to cervical adenocarcinomas may undergo intestinal-type transdifferentiation via an epithelial-mesenchymal transition phenomenon. Conversely, mitogen-activated protein kinase pathway activation in VVAIts, which plays a major role in colorectal adenocarcinomas, may indicate a close relationship in the carcinogenesis of these tumors. Our results indicate that adenocarcinomas of intestinal type, in the distal vagina or vestibular vulva, might be a unique and single entity, probably originating from cloacogenic embryonic remnants and/or ectopic colorectal mucosae inclusions. An open question would be to explore the efficacy of systemic drugs prescribed in colorectal cancers, in VVAIts.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 2","pages":"Article 100649"},"PeriodicalIF":7.1,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623664","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 : 2024-11-09DOI: 10.1016/j.modpat.2024.100653
Daan J. Geijs , Lisa M. Hillen , Stephan Dooper , Veronique Winnepenninckx , Vamsi Varra , David R. Carr , Kathryn T. Shahwan , Geert Litjens , Avital Amir
Basal cell carcinoma (BCC) is the most frequently diagnosed form of skin cancer, and its incidence continues to rise, particularly among older individuals. This trend puts a significant strain on health care systems, especially in terms of histopathologic diagnostics required for Mohs micrographic surgery (MMS), which is used to treat BCC in sensitive locations to minimize tissue loss. This study aims to address the challenges in BCC detection within MMS whole-slide images by developing and evaluating a deep learning model that bridges weakly supervised learning with interpretable segmentation-based methods through attention maps. Utilizing data sets from 2 medical centers, the model demonstrated an average area under the receiver operating characteristic curve (AUC) of 0.958 on internal testing and an AUC of 0.934 on an independent third external data set despite no fine-tuning or preprocessing for the latter. Attention maps provided insights into the model’s decision making, highlighting critical regions for slide-level classification. The sensitivity of the attention maps in localizing tumor regions was 0.853 when no filtering was applied and gave 8 revision false positives per slide on average and was reduced to an average of 2 false positives per slide with a sensitivity of 0.873 when detections smaller than 200 μm were removed from the attention maps. These findings indicate that the deep learning model is highly effective in detecting BCC in MMS whole-slide images, with robust performance across different data sets and conditions. The use of attention maps enhances the model’s interpretability, making it a promising tool for aiding dermatopathologists and MMS surgeons.
{"title":"Weakly Supervised Classification of Mohs Surgical Sections Using Artificial Intelligence","authors":"Daan J. Geijs , Lisa M. Hillen , Stephan Dooper , Veronique Winnepenninckx , Vamsi Varra , David R. Carr , Kathryn T. Shahwan , Geert Litjens , Avital Amir","doi":"10.1016/j.modpat.2024.100653","DOIUrl":"10.1016/j.modpat.2024.100653","url":null,"abstract":"<div><div>Basal cell carcinoma (BCC) is the most frequently diagnosed form of skin cancer, and its incidence continues to rise, particularly among older individuals. This trend puts a significant strain on health care systems, especially in terms of histopathologic diagnostics required for Mohs micrographic surgery (MMS), which is used to treat BCC in sensitive locations to minimize tissue loss. This study aims to address the challenges in BCC detection within MMS whole-slide images by developing and evaluating a deep learning model that bridges weakly supervised learning with interpretable segmentation-based methods through attention maps. Utilizing data sets from 2 medical centers, the model demonstrated an average area under the receiver operating characteristic curve (AUC) of 0.958 on internal testing and an AUC of 0.934 on an independent third external data set despite no fine-tuning or preprocessing for the latter. Attention maps provided insights into the model’s decision making, highlighting critical regions for slide-level classification. The sensitivity of the attention maps in localizing tumor regions was 0.853 when no filtering was applied and gave 8 revision false positives per slide on average and was reduced to an average of 2 false positives per slide with a sensitivity of 0.873 when detections smaller than 200 μm were removed from the attention maps. These findings indicate that the deep learning model is highly effective in detecting BCC in MMS whole-slide images, with robust performance across different data sets and conditions. The use of attention maps enhances the model’s interpretability, making it a promising tool for aiding dermatopathologists and MMS surgeons.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 2","pages":"Article 100653"},"PeriodicalIF":7.1,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623914","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}
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