Pub Date : 2024-11-09DOI: 10.1016/j.modpat.2024.100655
Sonay Kuş Öztürk , John-Melle Bokhorst , Elias Baumann , Kieran Sheahan , Cornelis J.H. van de Velde , Corrie A.M. Marijnen , Geke A.P. Hospers , Michail Doukas , Michael Vieth , Alessandro Lugli , Iris D. Nagtegaal
Owing to insufficient evidence, tumor budding (TB) is not currently evaluated in colorectal cancer (CRC) biopsies. This study investigates TB in CRC by establishing the value of intratumoral budding (ITB) in resection specimens and assessing the feasibility and clinical value of TB in biopsies. TB was assessed using an algorithm in all cases. In a test cohort of 555 primarily surgically treated CRC patients, we assessed the prognostic impact of ITB compared with peritumoral budding (PTB). The distribution of ITB in the uppermost 5 mm of resection specimens was analyzed to validate TB counting in biopsies. We further validated the prognostic and predictive impact of TB in biopsies of 285 rectal cancer patients, focusing on overall survival and response to neoadjuvant therapy. High-grade TB, whether intratumoral or peritumoral and in biopsies or resections, was associated with advanced pathological stage, lymphatic invasion, infiltrative tumor border, and poor overall survival in the test cohort. Superficial ITBs (0-3 mm from the lumen) accurately predicted the final TB grade based on PTB in 87% of tumors, with 87% of tumors having at least 1 superficial ITB hotspot. ITB (hazard ratio, 3.5; 95% CI, 1.1-10.8) was an independent predictor of overall survival, unlike PTB. In the validation cohort, TB presence in biopsies significantly reduced the likelihood of achieving a pathological complete response (odds ratio, 0.3; 95% CI, 0.1-0.7; P = .007). ITB is as prognostic as PTB, and evaluating both can improve risk stratification in CRC. TB assessment in biopsies can identify poor prognosis and predict response to neoadjuvant therapy.
{"title":"Exploring Intratumoral Budding in Colorectal Cancer Using Computational Pathology: A Biopsy-Based Evaluation","authors":"Sonay Kuş Öztürk , John-Melle Bokhorst , Elias Baumann , Kieran Sheahan , Cornelis J.H. van de Velde , Corrie A.M. Marijnen , Geke A.P. Hospers , Michail Doukas , Michael Vieth , Alessandro Lugli , Iris D. Nagtegaal","doi":"10.1016/j.modpat.2024.100655","DOIUrl":"10.1016/j.modpat.2024.100655","url":null,"abstract":"<div><div>Owing to insufficient evidence, tumor budding (TB) is not currently evaluated in colorectal cancer (CRC) biopsies. This study investigates TB in CRC by establishing the value of intratumoral budding (ITB) in resection specimens and assessing the feasibility and clinical value of TB in biopsies. TB was assessed using an algorithm in all cases. In a test cohort of 555 primarily surgically treated CRC patients, we assessed the prognostic impact of ITB compared with peritumoral budding (PTB). The distribution of ITB in the uppermost 5 mm of resection specimens was analyzed to validate TB counting in biopsies. We further validated the prognostic and predictive impact of TB in biopsies of 285 rectal cancer patients, focusing on overall survival and response to neoadjuvant therapy. High-grade TB, whether intratumoral or peritumoral and in biopsies or resections, was associated with advanced pathological stage, lymphatic invasion, infiltrative tumor border, and poor overall survival in the test cohort. Superficial ITBs (0-3 mm from the lumen) accurately predicted the final TB grade based on PTB in 87% of tumors, with 87% of tumors having at least 1 superficial ITB hotspot. ITB (hazard ratio, 3.5; 95% CI, 1.1-10.8) was an independent predictor of overall survival, unlike PTB. In the validation cohort, TB presence in biopsies significantly reduced the likelihood of achieving a pathological complete response (odds ratio, 0.3; 95% CI, 0.1-0.7; <em>P</em> = .007). ITB is as prognostic as PTB, and evaluating both can improve risk stratification in CRC. TB assessment in biopsies can identify poor prognosis and predict response to neoadjuvant therapy.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 2","pages":"Article 100655"},"PeriodicalIF":7.1,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623641","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.2024.100651
Christopher M. Heaphy , Simmi Patel , Katelyn Smith , Anne R. Wondisford , Michelle L. Lynskey , Roderick J. O’Sullivan , Kimberly Fuhrer , Xiaoli Han , Raja R. Seethala , Ta-Chiang Liu , Dengfeng Cao , Onur Ertunc , Qizhi Zheng , Marija Stojanova , Amer H. Zureikat , Alessandro Paniccia , Kenneth Lee , Melanie C. Ongchin , James F. Pingpank , Herbert J. Zeh , Aatur D. Singhi
Molecular studies have shown alternative lengthening to telomeres (ALT) to be an important prognostic biomarker of shorter relapse-free survival (RFS) for patients with pancreatic neuroendocrine tumors (PanNETs) and other neoplasms. However, the preferred method of detecting ALT in tissue is by fluorescence in situ hybridization (FISH), which has several clinical limitations. These issues necessitate the creation of a chromogenic ALT assay that can be easily implemented into routine practice. A chromogenic in situ hybridization (CISH) assay was developed using genetically modified osteosarcoma cell lines, 20 normal pancreata, 20 ALT-positive PanNETs, and 20 ALT-negative PanNETs. Thereafter, it was validated on a multiinstitutional cohort of 360 surgically resected PanNETs and correlated with multiple clinicopathologic features, RFS, and FISH results. Separately, 109 leiomyosarcomas (LMS) were evaluated by both CISH and FISH, and, similarly, the prognostic significance of ALT status was assessed. Upon optimization, ALT–CISH was identified in 112 of 360 (31%) primary PanNETs and was 100% concordant with FISH testing. ALT correlated with several adverse prognostic findings and distant metastasis (all P < .004). The 5-year RFS for patients with ALT-positive PanNETs was 35% as compared with 94% for ALT-negative PanNETs. By multivariate analysis, ALT was an independent prognostic factor for shorter RFS. Similarly, ALT was associated with shorter RFS in patients with LMS and, analogous to PanNETs, a negative, independent prognostic factor. ALT–CISH was developed and validated in not only PanNETs but also sarcomas, specifically LMS. CISH testing has multiple advantages over FISH that facilitate its widespread clinical use in the detection of ALT and prognostication of patients with diverse neoplasms.
分子研究表明，ALT 是胰腺神经内分泌肿瘤（PanNET）和其他肿瘤患者缩短无复发生存期（RFS）的重要预后生物标志物。然而，检测组织中 ALT 的首选方法是荧光原位杂交 (FISH)，这种方法有一些临床局限性。鉴于这些问题，有必要开发一种易于在常规临床实践中使用的色原 ALT 检测方法。我们利用转基因骨肉瘤细胞系、20 个正常胰腺、20 个 ALT 阳性的 PanNET 和 20 个 ALT 阴性的 PanNET 开发了一种 CISH 检测方法。此后，在一个由 360 例手术切除的 PanNET 组成的多机构队列中对其进行了验证，并将其与多种临床病理特征、RFS 和 FISH 结果相关联。另外，还通过 CISH 和 FISH 评估了 109 例子宫肌瘤（LMS），并同样评估了 ALT 状态的预后意义。经优化后，360 个原发性 PanNET 中有 112 个（31%）确定了 ALT-CISH，且与 FISH 检测结果 100%一致。ALT 与几种不良预后结果和远处转移相关（所有 p
{"title":"Detection of Alternative Lengthening of Telomeres via Chromogenic In Situ Hybridization for the Prognostication of PanNETs and Other Neoplasms","authors":"Christopher M. Heaphy , Simmi Patel , Katelyn Smith , Anne R. Wondisford , Michelle L. Lynskey , Roderick J. O’Sullivan , Kimberly Fuhrer , Xiaoli Han , Raja R. Seethala , Ta-Chiang Liu , Dengfeng Cao , Onur Ertunc , Qizhi Zheng , Marija Stojanova , Amer H. Zureikat , Alessandro Paniccia , Kenneth Lee , Melanie C. Ongchin , James F. Pingpank , Herbert J. Zeh , Aatur D. Singhi","doi":"10.1016/j.modpat.2024.100651","DOIUrl":"10.1016/j.modpat.2024.100651","url":null,"abstract":"<div><div>Molecular studies have shown alternative lengthening to telomeres (ALT) to be an important prognostic biomarker of shorter relapse-free survival (RFS) for patients with pancreatic neuroendocrine tumors (PanNETs) and other neoplasms. However, the preferred method of detecting ALT in tissue is by fluorescence in situ hybridization (FISH), which has several clinical limitations. These issues necessitate the creation of a chromogenic ALT assay that can be easily implemented into routine practice. A chromogenic in situ hybridization (CISH) assay was developed using genetically modified osteosarcoma cell lines, 20 normal pancreata, 20 ALT-positive PanNETs, and 20 ALT-negative PanNETs. Thereafter, it was validated on a multiinstitutional cohort of 360 surgically resected PanNETs and correlated with multiple clinicopathologic features, RFS, and FISH results. Separately, 109 leiomyosarcomas (LMS) were evaluated by both CISH and FISH, and, similarly, the prognostic significance of ALT status was assessed. Upon optimization, ALT–CISH was identified in 112 of 360 (31%) primary PanNETs and was 100% concordant with FISH testing. ALT correlated with several adverse prognostic findings and distant metastasis (all <em>P</em> < .004). The 5-year RFS for patients with ALT-positive PanNETs was 35% as compared with 94% for ALT-negative PanNETs. By multivariate analysis, ALT was an independent prognostic factor for shorter RFS. Similarly, ALT was associated with shorter RFS in patients with LMS and, analogous to PanNETs, a negative, independent prognostic factor. ALT–CISH was developed and validated in not only PanNETs but also sarcomas, specifically LMS. CISH testing has multiple advantages over FISH that facilitate its widespread clinical use in the detection of ALT and prognostication of patients with diverse neoplasms.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 3","pages":"Article 100651"},"PeriodicalIF":7.1,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623722","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 : 2024-11-08DOI: 10.1016/j.modpat.2024.100652
Haoyang Mi , Ravi Varadhan , Ashley M. Cimino-Mathews , Leisha A. Emens , Cesar A. Santa-Maria , Aleksander S. Popel
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options, which warrants the identification of novel therapeutic targets. Deciphering nuances in the tumor microenvironment (TME) may unveil insightful links between antitumor immunity and clinical outcomes; however, such connections remain underexplored. Here, we employed a data set derived from imaging mass cytometry of 71 TNBC patient specimens at single-cell resolution and performed in-depth quantifications with a suite of multiscale computational algorithms. The TNBC TME reflected a heterogeneous ecosystem with high spatial and compositional heterogeneity. Spatial analysis identified 10 recurrent cellular neighborhoods—a collection of local TME characteristics with unique cell components. The prevalence of cellular neighborhoods enriched with B cells, fibroblasts, and tumor cells, in conjunction with vascular density and perivasculature immune profiles, could significantly enrich long-term survivors. Furthermore, relative spatial colocalization of SMAhi fibroblasts and tumor cells compared with B cells correlated significantly with favorable clinical outcomes. Using a deep learning model trained on engineered spatial data, we can predict with high accuracy (mean area under the receiver operating characteristic curve of 5-fold cross-validation = 0.71) how a separate cohort of patients in the NeoTRIP clinical trial will respond to treatment based on baseline TME features. These data reinforce that the TME architecture is structured in cellular compositions, spatial organizations, vasculature biology, and molecular profiles and suggest novel imaging-based biomarkers for the treatment development in the context of TNBC.
{"title":"Spatial Architecture of Single-Cell and Vasculature in Tumor Microenvironment Predicts Clinical Outcomes in Triple-Negative Breast Cancer","authors":"Haoyang Mi , Ravi Varadhan , Ashley M. Cimino-Mathews , Leisha A. Emens , Cesar A. Santa-Maria , Aleksander S. Popel","doi":"10.1016/j.modpat.2024.100652","DOIUrl":"10.1016/j.modpat.2024.100652","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options, which warrants the identification of novel therapeutic targets. Deciphering nuances in the tumor microenvironment (TME) may unveil insightful links between antitumor immunity and clinical outcomes; however, such connections remain underexplored. Here, we employed a data set derived from imaging mass cytometry of 71 TNBC patient specimens at single-cell resolution and performed in-depth quantifications with a suite of multiscale computational algorithms. The TNBC TME reflected a heterogeneous ecosystem with high spatial and compositional heterogeneity. Spatial analysis identified 10 recurrent cellular neighborhoods—a collection of local TME characteristics with unique cell components. The prevalence of cellular neighborhoods enriched with B cells, fibroblasts, and tumor cells, in conjunction with vascular density and perivasculature immune profiles, could significantly enrich long-term survivors. Furthermore, relative spatial colocalization of SMA<sup>hi</sup> fibroblasts and tumor cells compared with B cells correlated significantly with favorable clinical outcomes. Using a deep learning model trained on engineered spatial data, we can predict with high accuracy (mean area under the receiver operating characteristic curve of 5-fold cross-validation = 0.71) how a separate cohort of patients in the NeoTRIP clinical trial will respond to treatment based on baseline TME features. These data reinforce that the TME architecture is structured in cellular compositions, spatial organizations, vasculature biology, and molecular profiles and suggest novel imaging-based biomarkers for the treatment development in the context of TNBC.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 2","pages":"Article 100652"},"PeriodicalIF":7.1,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623883","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 : 2024-11-08DOI: 10.1016/j.modpat.2024.100656
Carina A. Dehner , Laura M. Warmke , Brandon Umphress , Faizan Malik , Jeffrey M. Cloutier , Josephine K. Dermawan , Mike Fritz , Syril Keena T. Que , Baptiste Ameline , Karen J. Fritchie , Darcy A. Kerr , Konstantinos Linos , Daniel Baumhoer , Steven D. Billings , Andrew L. Folpe
Superficial neurocristic EWSR1::FLI1 fusion tumor is a very recently described, clinically indolent tumor of the skin and superficial soft tissues, which differs in essentially all ways from Ewing sarcoma, despite harboring an identical fusion event. The EWSR1 and FLI1 genes are members of the FET and ETS gene family, respectively, and very rare examples of Ewing sarcoma harbor alternative FET::ETS fusion events, such as EWSR1::ERG, FUS::FLI1, FUS::ERG, EWSR1::ETV4, and others. We report 5 new cases of this very rare entity, harboring in 3 cases alternative FET::ETS fusion events. The tumors occurred in 2 males and 3 females (median age, 14 years, range, 8-69 years) and presented as solitary dermal/subcutaneous masses of the thigh, foot, shoulder, arm, and back (median size, 1.8 cm; range, 1-2 cm). All patients underwent wide excisions; one received adjuvant chemotherapy. Clinical follow-up on 3 patients (median, 24 months; range, 18-31 months) showed all to be without disease. Morphologically, all tumors displayed typical features of this entity as described, with nests of cytologically bland, diffusely S100 protein/SOX10-positive round cells without mitotic activity, surrounded by fibrous bands containing spindled cells with similar nuclear features. The tumors also showed membranous CD99 (4/5) and nuclear NKX2.2 (3/3) expression. RNA sequencing (5 cases) demonstrated FUS::FLI1, FUS::ERG, EWSR1::FLI1, EWSR1::ERG, and a novel FUS::ETV5. Methylation profiling (4 cases) showed all to cluster with previously reported superficial neurocristic EWSR1::FLI1 fusion tumors and apart from conventional and “adamantinoma-like” Ewing sarcoma. Our findings confirm the distinctive clinicopathological features of this very rare, recently described entity and expand its molecular genetic spectrum. Reflecting on these findings, we propose modifying the name of this entity to “superficial neurocristic FET::ETS fusion tumor.”
{"title":"Superficial Neurocristic FET::ETS Fusion Tumor: Expanding the Clinicopathological and Molecular Genetic Spectrum of a Recently Described Entity","authors":"Carina A. Dehner , Laura M. Warmke , Brandon Umphress , Faizan Malik , Jeffrey M. Cloutier , Josephine K. Dermawan , Mike Fritz , Syril Keena T. Que , Baptiste Ameline , Karen J. Fritchie , Darcy A. Kerr , Konstantinos Linos , Daniel Baumhoer , Steven D. Billings , Andrew L. Folpe","doi":"10.1016/j.modpat.2024.100656","DOIUrl":"10.1016/j.modpat.2024.100656","url":null,"abstract":"<div><div>Superficial neurocristic <em>EWSR1</em>::<em>FLI1</em> fusion tumor is a very recently described, clinically indolent tumor of the skin and superficial soft tissues, which differs in essentially all ways from Ewing sarcoma, despite harboring an identical fusion event. The <em>EWSR1</em> and <em>FLI1</em> genes are members of the FET and ETS gene family, respectively, and very rare examples of Ewing sarcoma harbor alternative FET::ETS fusion events, such as <em>EWSR1::ERG</em>, <em>FUS::FLI1</em>, <em>FUS::ERG</em>, <em>EWSR1::ETV4,</em> and others. We report 5 new cases of this very rare entity, harboring in 3 cases alternative FET::ETS fusion events. The tumors occurred in 2 males and 3 females (median age, 14 years, range, 8-69 years) and presented as solitary dermal/subcutaneous masses of the thigh, foot, shoulder, arm, and back (median size, 1.8 cm; range, 1-2 cm). All patients underwent wide excisions; one received adjuvant chemotherapy. Clinical follow-up on 3 patients (median, 24 months; range, 18-31 months) showed all to be without disease. Morphologically, all tumors displayed typical features of this entity as described, with nests of cytologically bland, diffusely S100 protein/SOX10-positive round cells without mitotic activity, surrounded by fibrous bands containing spindled cells with similar nuclear features. The tumors also showed membranous CD99 (4/5) and nuclear NKX2.2 (3/3) expression. RNA sequencing (5 cases) demonstrated <em>FUS::FLI1</em>, <em>FUS::ERG</em>, <em>EWSR1::FLI1</em>, <em>EWSR1::ERG</em>, and a novel <em>FUS::ETV5.</em> Methylation profiling (4 cases) showed all to cluster with previously reported superficial neurocristic <em>EWSR1</em>::<em>FLI1</em> fusion tumors and apart from conventional and “adamantinoma-like” Ewing sarcoma. Our findings confirm the distinctive clinicopathological features of this very rare, recently described entity and expand its molecular genetic spectrum. Reflecting on these findings, we propose modifying the name of this entity to “superficial neurocristic FET::ETS fusion tumor.”</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 2","pages":"Article 100656"},"PeriodicalIF":7.1,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623904","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 : 2024-11-02DOI: 10.1016/j.modpat.2024.100647
Luca Sigalotti , Anna Maria Frezza , Marta Sbaraglia , Elisa Del Savio , Davide Baldazzi , Beatrice Valenti , Elena Bellan , Ilaria De Benedictis , Michele Doni , Marco Gambarotti , Bruno Vincenzi , Antonella Brunello , Giacomo Giulio Baldi , Emanuela Palmerini , Sandro Pasquali , Maria Elena Ciuffetti , Veronica Varano , Filippo Cappello , Viviana Appolloni , Chiara Pastrello , Roberta Maestro
Epithelioid sarcoma (ES) is a rare tumor hallmarked by the loss of INI1/SMARCB1 expression. Apart from this alteration, little is known about the biology of ES. Despite recent advances in treatment, the prognosis of ES remains unsatisfactory. To elucidate the molecular underpinnings of ES, and to identify diagnostic biomarkers and potential therapeutic vulnerabilities, we performed an integrated omics profiling (RNA sequencing and methylation array) of 24 primary, untreated ESs. Transcriptome and methylome analysis identified 2 distinct molecular clusters that essentially corresponded to the morphologic variants of ES, classic ES (C-ES) and the more aggressive proximal ES (P-ES). The P-ES group was characterized by hyperactivation of GATA3 and MYC pathways, with extensive epigenetic rewiring associated with EZH2 overexpression. Both DNA methylation and gene expression analysis indicated a striking similarity with the “MYC subgroup” of atypical teratoid/rhabdoid tumor, another SMARCB1-deficient tumor, implying a shared molecular background and potential therapeutic vulnerabilities. Conversely, the C-ES group exhibited an endothelial-like molecular profile, with expression of vascular genes and elevated proangiogenic SOX17 signaling. Immunohistochemistry validated the overexpression of the chromatin regulators GATA3 (9/12 vs 0/16) and EZH2 (7/7 vs 2/6) in P-ESs, and of the vascular factors SOX17 (8/8 vs 1/10) and N-cadherin (5/9 vs 0/10) in C-ESs. Therefore, these molecules emerge as potential diagnostic tools to fill the gap represented by the lack of ES subtype-specific biomarkers. In summary, our study shows that P-ES and C-ES represent distinct molecular entities defined by MYC/GATA3 and SOX17/endothelial molecular traits, respectively. Besides providing insights into the biology of ES, our study pinpoints subtype-specific biomarkers and potential therapeutic vulnerabilities.
上皮样肉瘤（ES）是一种以 INI1/SMARCB1 表达缺失为特征的罕见肿瘤。除这一改变外，人们对 ES 的生物学特性知之甚少。尽管最近在治疗方面取得了进展，但 ES 的预后仍不令人满意。为了阐明 ES 的分子基础，确定诊断生物标志物和潜在的治疗漏洞，我们对 24 例未经治疗的原发性 ES 进行了综合全息图谱分析（RNA 测序和甲基化阵列）。转录组和甲基化组分析确定了两个不同的分子群，它们基本上对应于 ES 的形态变异，即典型 ES（C-ES）和更具侵袭性的近端 ES（P-ES）。P-ES 组的特点是 GATA3 和 MYC 通路的过度激活，以及与 EZH2 过度表达相关的广泛表观遗传学改组。DNA甲基化和基因表达分析表明，P-ES组与另一种SMARCB1缺陷肿瘤ATRT的 "MYC亚组 "有惊人的相似性，这意味着两者有共同的分子背景和潜在的治疗弱点。相反，C-ES 组则表现出内皮样分子特征，血管基因表达和促血管生成 SOX17 信号的升高。免疫组化验证了染色质调控因子GATA3（9/12 vs. 0/16）和EZH2（7/7 vs. 2/6）在P-ESs中的过表达，以及血管因子SOX17（8/8 vs. 1/10）和N-cadherin（5/9 vs. 0/10）在C-ESs中的过表达。因此，这些分子可作为潜在的诊断工具，填补ES亚型特异性生物标志物缺乏的空白。总之，我们的研究表明，P-ES 和 C-ES 分别代表了由 MYC/GATA3 和 SOX17/内皮分子特征定义的不同分子实体。除了深入了解 ES 的生物学特性外，我们的研究还指出了亚型特异性生物标志物和潜在的治疗弱点。
{"title":"Proximal and Classic Epithelioid Sarcomas are Distinct Molecular Entities Defined by MYC/GATA3 and SOX17/Endothelial Markers, Respectively","authors":"Luca Sigalotti , Anna Maria Frezza , Marta Sbaraglia , Elisa Del Savio , Davide Baldazzi , Beatrice Valenti , Elena Bellan , Ilaria De Benedictis , Michele Doni , Marco Gambarotti , Bruno Vincenzi , Antonella Brunello , Giacomo Giulio Baldi , Emanuela Palmerini , Sandro Pasquali , Maria Elena Ciuffetti , Veronica Varano , Filippo Cappello , Viviana Appolloni , Chiara Pastrello , Roberta Maestro","doi":"10.1016/j.modpat.2024.100647","DOIUrl":"10.1016/j.modpat.2024.100647","url":null,"abstract":"<div><div>Epithelioid sarcoma (ES) is a rare tumor hallmarked by the loss of INI1/SMARCB1 expression. Apart from this alteration, little is known about the biology of ES. Despite recent advances in treatment, the prognosis of ES remains unsatisfactory. To elucidate the molecular underpinnings of ES, and to identify diagnostic biomarkers and potential therapeutic vulnerabilities, we performed an integrated omics profiling (RNA sequencing and methylation array) of 24 primary, untreated ESs. Transcriptome and methylome analysis identified 2 distinct molecular clusters that essentially corresponded to the morphologic variants of ES, classic ES (C-ES) and the more aggressive proximal ES (P-ES). The P-ES group was characterized by hyperactivation of GATA3 and MYC pathways, with extensive epigenetic rewiring associated with <em>EZH2</em> overexpression. Both DNA methylation and gene expression analysis indicated a striking similarity with the “MYC subgroup” of atypical teratoid/rhabdoid tumor, another SMARCB1-deficient tumor, implying a shared molecular background and potential therapeutic vulnerabilities. Conversely, the C-ES group exhibited an endothelial-like molecular profile, with expression of vascular genes and elevated proangiogenic SOX17 signaling. Immunohistochemistry validated the overexpression of the chromatin regulators GATA3 (9/12 vs 0/16) and EZH2 (7/7 vs 2/6) in P-ESs, and of the vascular factors SOX17 (8/8 vs 1/10) and N-cadherin (5/9 vs 0/10) in C-ESs. Therefore, these molecules emerge as potential diagnostic tools to fill the gap represented by the lack of ES subtype-specific biomarkers. In summary, our study shows that P-ES and C-ES represent distinct molecular entities defined by MYC/GATA3 and SOX17/endothelial molecular traits, respectively. Besides providing insights into the biology of ES, our study pinpoints subtype-specific biomarkers and potential therapeutic vulnerabilities.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 1","pages":"Article 100647"},"PeriodicalIF":7.1,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567680","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 : 2024-11-02DOI: 10.1016/j.modpat.2024.100646
Catalina Amador , Dennis D. Weisenburger , Ana Gomez , Alyssa Bouska , Ahmad Alshomrani , Sunandini Sharma , Ab Rauf Shah , Timothy C. Greiner , Francisco Vega , Andreas Rosenwald , German Ott , Andrew L. Feldman , Elaine S. Jaffe , Neval Ozkaya , Sarah L. Ondrejka , James R. Cook , Philipp W. Raess , Kerry J. Savage , Graham W. Slack , Joo Y. Song , Javeed Iqbal
Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of neoplasms, with many cases remaining unclassifiable and categorized as PTCL-not otherwise specified (PTCL-NOS). Gene expression profiling (GEP) has delineated 2 prognostic subtypes within PTCL-NOS, PTCL-TBX21 and PTCL-GATA3, characterized by distinctive transcriptomes and a different prognosis. To further evaluate the pathologic features of these subgroups, 101 PTCL cases that did not meet specific criteria for well-defined T-cell lymphoma entities underwent detailed pathologic, immunophenotypic (including T follicular helper [TFH] biomarkers), and GEP analyses, separating them into PTCL-NOS (n = 63) and PTCL-TFH (also known as nodal PTCL-TFH, NOS, and TFH lymphoma, NOS) (n = 38). PTCL-NOS cases were further categorized into PTCL-GATA3 (n = 22; 34%) and PTCL-TBX21 (n = 41; 66%), and a significant association (P < .02) with overall survival was reaffirmed. Histopathologic assessment showed PTCL-GATA3 cases were characterized by monotonous medium-sized or large transformed cells with a minimal tumor microenvironment (TME) compared with PTCL-TBX21 cases, which consisted of pleomorphic cells in a polymorphous TME (P < .05). GEP analysis validated these TME distinctions. Immunophenotypic analysis showed that PTCL-GATA3 cases were predominantly CD4+CD8- and associated with significantly higher LEF1, MYC, and CD30 expression (P < .05). PTCL-TBX21 displayed a more diverse biomarker profile with the following 2 subgroups: one expressing cytotoxic antigens and enriched in CD8+CD4− or CD8−CD4− phenotype, and another lacking cytotoxic markers but showing a CD4+CD8− phenotype with increased ICOS expression, but devoid of other TFH markers. The PTCL-TFH cases correlated with an angioimmunoblastic T-cell lymphoma gene signature, had more Epstein-Barr encoding region-positive cells than the PTCL-GATA3 and PTCL-TBX21 cases, and a subset had some morphologic features of angioimmunoblastic T-cell lymphoma (P < .01). This study highlights the unique morphologic and phenotypic variations within the newly identified PTCL subtypes and should enable a more precise diagnosis and tailored therapeutic strategies in the future.
{"title":"Refining Diagnostic Subtypes of Peripheral T-Cell Lymphoma Using a Multiparameter Approach","authors":"Catalina Amador , Dennis D. Weisenburger , Ana Gomez , Alyssa Bouska , Ahmad Alshomrani , Sunandini Sharma , Ab Rauf Shah , Timothy C. Greiner , Francisco Vega , Andreas Rosenwald , German Ott , Andrew L. Feldman , Elaine S. Jaffe , Neval Ozkaya , Sarah L. Ondrejka , James R. Cook , Philipp W. Raess , Kerry J. Savage , Graham W. Slack , Joo Y. Song , Javeed Iqbal","doi":"10.1016/j.modpat.2024.100646","DOIUrl":"10.1016/j.modpat.2024.100646","url":null,"abstract":"<div><div>Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of neoplasms, with many cases remaining unclassifiable and categorized as PTCL-not otherwise specified (PTCL-NOS). Gene expression profiling (GEP) has delineated 2 prognostic subtypes within PTCL-NOS, PTCL-TBX21 and PTCL-GATA3, characterized by distinctive transcriptomes and a different prognosis. To further evaluate the pathologic features of these subgroups, 101 PTCL cases that did not meet specific criteria for well-defined T-cell lymphoma entities underwent detailed pathologic, immunophenotypic (including T follicular helper [T<sub>FH</sub>] biomarkers), and GEP analyses, separating them into PTCL-NOS (n = 63) and PTCL-TFH (also known as nodal PTCL-TFH, NOS, and TFH lymphoma, NOS) (n = 38). PTCL-NOS cases were further categorized into PTCL-GATA3 (n = 22; 34%) and PTCL-TBX21 (n = 41; 66%), and a significant association (<em>P</em> < .02) with overall survival was reaffirmed. Histopathologic assessment showed PTCL-GATA3 cases were characterized by monotonous medium-sized or large transformed cells with a minimal tumor microenvironment (TME) compared with PTCL-TBX21 cases, which consisted of pleomorphic cells in a polymorphous TME (<em>P</em> < .05). GEP analysis validated these TME distinctions. Immunophenotypic analysis showed that PTCL-GATA3 cases were predominantly CD4<sup>+</sup>CD8<sup>-</sup> and associated with significantly higher LEF1, MYC, and CD30 expression (<em>P</em> < .05). PTCL-TBX21 displayed a more diverse biomarker profile with the following 2 subgroups: one expressing cytotoxic antigens and enriched in CD8<sup>+</sup>CD4<sup>−</sup> or CD8<sup>−</sup>CD4<sup>−</sup> phenotype, and another lacking cytotoxic markers but showing a CD4<sup>+</sup>CD8<sup>−</sup> phenotype with increased ICOS expression, but devoid of other T<sub>FH</sub> markers. The PTCL-TFH cases correlated with an angioimmunoblastic T-cell lymphoma gene signature, had more Epstein-Barr encoding region-positive cells than the PTCL-GATA3 and PTCL-TBX21 cases, and a subset had some morphologic features of angioimmunoblastic T-cell lymphoma (<em>P</em> < .01). This study highlights the unique morphologic and phenotypic variations within the newly identified PTCL subtypes and should enable a more precise diagnosis and tailored therapeutic strategies in the future.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 2","pages":"Article 100646"},"PeriodicalIF":7.1,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567702","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 : 2024-10-26DOI: 10.1016/j.modpat.2024.100637
Zaibo Li, Yan Hu, Dan Jones, Weiqiang Zhao, Gary Tozbikian, Anil V. Parwani
Human epidermal growth factor receptor 2 (HER2)-positive breast carcinoma (BC) encompasses a spectrum of molecular subtypes, characterized by varying HER2/CEP17 ratios and HER2 copy numbers, influencing responses to anti-HER2 therapy. This study stratified HER2 fluorescence in situ hybridization (FISH)-positive patients into 3 distinct groups—group 1 with high copy number (G1-HC: ratio ≥2, copy number ≥6), group 1 with low copy number (G1-LC: ratio ≥2, copy number ≥4 and <6), and group 3 (G3: ratio <2.0, copy number ≥6.0)—and evaluated their clinicopathologic features, response to anti-HER2 therapy, and outcomes. In a cohort of 2702 continuous primary BCs, G1-HC BCs accounted for 304 cases (11.3%), G1-LC for 37 cases (1.4%), and G3 for 75 cases (2.8%). G1-HC BCs were associated with younger age, higher tumor grade, and estrogen receptor negativity compared with G1-LC BCs. Furthermore, G1-HC BCs exhibited increased progesterone receptor negativity and HER2 immunohistochemistry 3+ compared with G1-LC and G3 BCs. Analysis of the subgroup of HER2 immunohistochemistry 2+-only cases (n = 166) showed similar results. Notably, G1-HC patients exhibited significantly enhanced responses to anti-HER2 neoadjuvant chemotherapy compared with G1-LC and G3 patients. Conversely, G1-LC patients displayed a lower likelihood of disease-free status compared with G1-HC and G3 patients, albeit with no significant differences in overall survival, distant metastasis, or local recurrence among the groups. These findings offer valuable clinicopathologic insights into different HER2 FISH positive subgroups, potentially informing future criteria for interpreting HER2 FISH results.
{"title":"Clinicopathologic Characteristics and Follow-Up Outcomes of Invasive Breast Carcinoma With Different Positive HER2 Fluorescence In Situ Hybridization Patterns: Experience From a Single Academic Institution","authors":"Zaibo Li, Yan Hu, Dan Jones, Weiqiang Zhao, Gary Tozbikian, Anil V. Parwani","doi":"10.1016/j.modpat.2024.100637","DOIUrl":"10.1016/j.modpat.2024.100637","url":null,"abstract":"<div><div>Human epidermal growth factor receptor 2 (HER2)-positive breast carcinoma (BC) encompasses a spectrum of molecular subtypes, characterized by varying <em>HER2/CEP17</em> ratios and <em>HER2</em> copy numbers, influencing responses to anti-HER2 therapy. This study stratified <em>HER2</em> fluorescence in situ hybridization (FISH)-positive patients into 3 distinct groups—group 1 with high copy number (G1-HC: ratio ≥2, copy number ≥6), group 1 with low copy number (G1-LC: ratio ≥2, copy number ≥4 and <6), and group 3 (G3: ratio <2.0, copy number ≥6.0)—and evaluated their clinicopathologic features, response to anti-HER2 therapy, and outcomes. In a cohort of 2702 continuous primary BCs, G1-HC BCs accounted for 304 cases (11.3%), G1-LC for 37 cases (1.4%), and G3 for 75 cases (2.8%). G1-HC BCs were associated with younger age, higher tumor grade, and estrogen receptor negativity compared with G1-LC BCs. Furthermore, G1-HC BCs exhibited increased progesterone receptor negativity and HER2 immunohistochemistry 3+ compared with G1-LC and G3 BCs. Analysis of the subgroup of HER2 immunohistochemistry 2+-only cases (n = 166) showed similar results. Notably, G1-HC patients exhibited significantly enhanced responses to anti-HER2 neoadjuvant chemotherapy compared with G1-LC and G3 patients. Conversely, G1-LC patients displayed a lower likelihood of disease-free status compared with G1-HC and G3 patients, albeit with no significant differences in overall survival, distant metastasis, or local recurrence among the groups. These findings offer valuable clinicopathologic insights into different <em>HER2</em> FISH positive subgroups, potentially informing future criteria for interpreting <em>HER2</em> FISH results.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 1","pages":"Article 100637"},"PeriodicalIF":7.1,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567507","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 : 2024-10-23DOI: 10.1016/j.modpat.2024.100636
Tawsifur Rahman , Alexander S. Baras , Rama Chellappa
An integral stage in typical digital pathology workflows involves deriving specific features from tiles extracted from a tessellated whole-slide image. Notably, various computer vision neural network architectures, particularly the ImageNet pretrained, have been extensively used in this domain. This study critically analyzes multiple strategies for encoding tiles to understand the extent of transfer learning and identify the most effective approach. The study categorizes neural network performance into 3 weight initialization methods: random, ImageNet-based, and self-supervised learning. Additionally, we propose a framework based on task-specific self-supervised learning, which introduces a shallow feature extraction method, employing a spatial-channel attention block to glean distinctive features optimized for histopathology intricacies. Across 2 different downstream classification tasks (patch classification and weakly supervised whole-slide image classification) with diverse classification data sets, including colorectal cancer histology, Patch Camelyon, prostate cancer detection, The Cancer Genome Atlas, and CIFAR-10, our task-specific self-supervised encoding approach consistently outperforms other convolutional neural network–based encoders. The better performances highlight the potential of task-specific attention-based self-supervised training in tailoring feature extraction for histopathology, indicating a shift from using pretrained models originating outside the histopathology domain. Our study supports the idea that task-specific self-supervised learning allows domain-specific feature extraction, encouraging a more focused analysis.
{"title":"Evaluation of a Task-Specific Self-Supervised Learning Framework in Digital Pathology Relative to Transfer Learning Approaches and Existing Foundation Models","authors":"Tawsifur Rahman , Alexander S. Baras , Rama Chellappa","doi":"10.1016/j.modpat.2024.100636","DOIUrl":"10.1016/j.modpat.2024.100636","url":null,"abstract":"<div><div>An integral stage in typical digital pathology workflows involves deriving specific features from tiles extracted from a tessellated whole-slide image. Notably, various computer vision neural network architectures, particularly the ImageNet pretrained, have been extensively used in this domain. This study critically analyzes multiple strategies for encoding tiles to understand the extent of transfer learning and identify the most effective approach. The study categorizes neural network performance into 3 weight initialization methods: random, ImageNet-based, and self-supervised learning. Additionally, we propose a framework based on task-specific self-supervised learning, which introduces a shallow feature extraction method, employing a spatial-channel attention block to glean distinctive features optimized for histopathology intricacies. Across 2 different downstream classification tasks (patch classification and weakly supervised whole-slide image classification) with diverse classification data sets, including colorectal cancer histology, Patch Camelyon, prostate cancer detection, The Cancer Genome Atlas, and CIFAR-10, our task-specific self-supervised encoding approach consistently outperforms other convolutional neural network–based encoders. The better performances highlight the potential of task-specific attention-based self-supervised training in tailoring feature extraction for histopathology, indicating a shift from using pretrained models originating outside the histopathology domain. Our study supports the idea that task-specific self-supervised learning allows domain-specific feature extraction, encouraging a more focused analysis.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 1","pages":"Article 100636"},"PeriodicalIF":7.1,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504223","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 : 2024-10-21DOI: 10.1016/j.modpat.2024.100635
Maximus C.F. Yeung , Anthony P.Y. Liu , Sio-In Wong , Herbert H. Loong , Tony W.H. Shek
GLI1-altered mesenchymal tumors have recently emerged as a distinctive group of neoplasms characterized by GLI1 fusions or amplifications. Although there is clearly metastatic potential, the clinicopathologic features predicting for metastasis are currently unknown. Herein, we present 6 cases of GLI1-altered mesenchymal tumors with multiomics analysis. The median patient age was 50 years (range, 3-68 years). They arose from the extremities and trunk (2/6), head and neck region (2/6), and gastrointestinal tract (2/6). Histologically, they featured uniform round to ovoid cells with nested architecture and a rich vascular network. One case displayed abundant multinucleated giant cells. All stained positive for GLI1 (5/5) and CD56 (6/6). Molecularly, they featured GLI1 fusion (5/6) and amplification (1/6). Fusion partners included ACTB (3/5), TXNIP (1/5), and novel TUBA1B (1/5). Multiomics analysis revealed they possessed distinct expression and epigenomic profiles. All the 6 cases had follow-up information, with 5 of them having no evidence of disease at a median follow-up of 30 months (range, 17.3-102 months), and 1 case being died of disease with regional neck lymph node and bilateral lung metastasis at 81.5 months of follow-up. By incorporating cases reported in the literature, we analyzed clinicopathologic features of a total of 167 cases predictive of malignant behavior. We found that size ≥6 cm and mitotic count ≥5 per 10 high-power fields are predictive of metastasis. Cases with both high-risk features had significantly poorer survival. This study expands the literature database of GLI1-altered mesenchymal tumors and identifies features that can be used for risk stratification.
{"title":"GLI1-Altered Mesenchymal Tumor—Multiomic Characterization of a Case Series and Patient-Level Meta-analysis of One Hundred Sixty-Seven Cases for Risk Stratification","authors":"Maximus C.F. Yeung , Anthony P.Y. Liu , Sio-In Wong , Herbert H. Loong , Tony W.H. Shek","doi":"10.1016/j.modpat.2024.100635","DOIUrl":"10.1016/j.modpat.2024.100635","url":null,"abstract":"<div><div><em>GLI1</em>-altered mesenchymal tumors have recently emerged as a distinctive group of neoplasms characterized by <em>GLI1</em> fusions or amplifications. Although there is clearly metastatic potential, the clinicopathologic features predicting for metastasis are currently unknown. Herein, we present 6 cases of <em>GLI1</em>-altered mesenchymal tumors with multiomics analysis. The median patient age was 50 years (range, 3-68 years). They arose from the extremities and trunk (2/6), head and neck region (2/6), and gastrointestinal tract (2/6). Histologically, they featured uniform round to ovoid cells with nested architecture and a rich vascular network. One case displayed abundant multinucleated giant cells. All stained positive for GLI1 (5/5) and CD56 (6/6). Molecularly, they featured <em>GLI1</em> fusion (5/6) and amplification (1/6). Fusion partners included <em>ACTB</em> (3/5), <em>TXNIP</em> (1/5), and novel <em>TUBA1B</em> (1/5). Multiomics analysis revealed they possessed distinct expression and epigenomic profiles. All the 6 cases had follow-up information, with 5 of them having no evidence of disease at a median follow-up of 30 months (range, 17.3-102 months), and 1 case being died of disease with regional neck lymph node and bilateral lung metastasis at 81.5 months of follow-up. By incorporating cases reported in the literature, we analyzed clinicopathologic features of a total of 167 cases predictive of malignant behavior. We found that size ≥6 cm and mitotic count ≥5 per 10 high-power fields are predictive of metastasis. Cases with both high-risk features had significantly poorer survival. This study expands the literature database of <em>GLI1</em>-altered mesenchymal tumors and identifies features that can be used for risk stratification.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 1","pages":"Article 100635"},"PeriodicalIF":7.1,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504278","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 : 2024-10-16DOI: 10.1016/j.modpat.2024.100632
Igor Odintsov , Alexandra Isaacson , Karen J. Fritchie , Yin P. Hung , Pooria Khoshnoodi , Lynette M. Sholl , Christopher D.M. Fletcher , William J. Anderson
Clear cell stromal tumor is a recently described mesenchymal neoplasm of the lung, characterized by spindle cells with variably clear-to-pale eosinophilic cytoplasm and prominent vascularity, as well as a recurrent YAP1::TFE3 gene fusion in most cases. Diagnosis can be challenging given its rarity and the lack of supportive immunohistochemical (IHC) markers aside from TFE3. To date, less than 20 cases have been reported, and data on clinical behavior are also limited. Although most appear to be benign, aggressive behavior has been reported rarely. In this study, we present the largest multiinstitutional series of clear cell stromal tumor to date, comprising a total of 8 cases and including 6 previously unpublished cases. We investigate its clinicopathologic and genomic features, while also assessing the diagnostic use of IHC for YAP1 C-terminus. Five patients were men and 3 were women. The median age was 59 years (range: 35-84 years). In all cases, a TFE3 rearrangement was demonstrated by either fluorescence in situ hybridization or DNA/RNA sequencing. In 7 tumors, the YAP1::TFE3 fusion was identified by sequencing. We demonstrate that the combination of YAP1 C-terminus loss and TFE3 overexpression using IHC reliably predicts an underlying YAP1::TFE3 fusion in these neoplasms and may be more sensitive than TFE3 fluorescence in situ hybridization. Although the median follow-up time for our study was short (18 months, available in 7 cases), all cases pursued a benign clinical course, with no recurrences or metastases. Our study provides further characterization of this novel entity, supporting its wider recognition.
{"title":"Clear Cell Stromal Tumor of the Lung: Clinicopathologic, Immunohistochemical, and Molecular Characterization of Eight Cases","authors":"Igor Odintsov , Alexandra Isaacson , Karen J. Fritchie , Yin P. Hung , Pooria Khoshnoodi , Lynette M. Sholl , Christopher D.M. Fletcher , William J. Anderson","doi":"10.1016/j.modpat.2024.100632","DOIUrl":"10.1016/j.modpat.2024.100632","url":null,"abstract":"<div><div>Clear cell stromal tumor is a recently described mesenchymal neoplasm of the lung, characterized by spindle cells with variably clear-to-pale eosinophilic cytoplasm and prominent vascularity, as well as a recurrent <em>YAP1::TFE3</em> gene fusion in most cases. Diagnosis can be challenging given its rarity and the lack of supportive immunohistochemical (IHC) markers aside from TFE3. To date, less than 20 cases have been reported, and data on clinical behavior are also limited. Although most appear to be benign, aggressive behavior has been reported rarely. In this study, we present the largest multiinstitutional series of clear cell stromal tumor to date, comprising a total of 8 cases and including 6 previously unpublished cases. We investigate its clinicopathologic and genomic features, while also assessing the diagnostic use of IHC for YAP1 C-terminus. Five patients were men and 3 were women. The median age was 59 years (range: 35-84 years). In all cases, a <em>TFE3</em> rearrangement was demonstrated by either fluorescence in situ hybridization or DNA/RNA sequencing. In 7 tumors, the <em>YAP1</em>::<em>TFE3</em> fusion was identified by sequencing. We demonstrate that the combination of YAP1 C-terminus loss and TFE3 overexpression using IHC reliably predicts an underlying <em>YAP1::TFE3</em> fusion in these neoplasms and may be more sensitive than <em>TFE3</em> fluorescence in situ hybridization. Although the median follow-up time for our study was short (18 months, available in 7 cases), all cases pursued a benign clinical course, with no recurrences or metastases. Our study provides further characterization of this novel entity, supporting its wider recognition.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 1","pages":"Article 100632"},"PeriodicalIF":7.1,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470034","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号