Pub Date : 2025-09-02DOI: 10.1016/j.labinv.2025.104236
Victoria Mahar, Zachary Colburn, Joshua Sakai
Challenging pathology case consultations require the shipment of irreplaceable patient materials to the consultants’ location for evaluation. In the military, consultants and generalists span geographically diverse locations. Shipped cases risk diagnostic delays, loss, and irreparable damage in transit over extensive distances. Using digital pathology for consultation eliminates these risks. Digital pathology implementation efforts in the Military Health System have been unsuccessful; however, triservice pathologists’ attitudes toward this innovation have never been investigated. Our explanatory mixed-methods study used a web-based needs assessment and interviews to understand pathologists’ facilitators and barriers to using digital pathology for consultation. We believe that understanding their perceptions is critical if further implementation efforts are to be successful. Analyses showed that pathologists were receptive to enterprise-wide implementation, especially if it improved turnaround time and allowed immediate subspecialist feedback. Future implementation efforts may benefit from comprehensive technical support combined with a consolidated digital pathology program office for implementation and sustainment guidance.
{"title":"Telepathology for Consultation in the Military Health System: An Evaluation of Pathologists’ Impressions of Facilitators and Barriers Prior to Implementation","authors":"Victoria Mahar, Zachary Colburn, Joshua Sakai","doi":"10.1016/j.labinv.2025.104236","DOIUrl":"10.1016/j.labinv.2025.104236","url":null,"abstract":"<div><div>Challenging pathology case consultations require the shipment of irreplaceable patient materials to the consultants’ location for evaluation. In the military, consultants and generalists span geographically diverse locations. Shipped cases risk diagnostic delays, loss, and irreparable damage in transit over extensive distances. Using digital pathology for consultation eliminates these risks. Digital pathology implementation efforts in the Military Health System have been unsuccessful; however, triservice pathologists’ attitudes toward this innovation have never been investigated. Our explanatory mixed-methods study used a web-based needs assessment and interviews to understand pathologists’ facilitators and barriers to using digital pathology for consultation. We believe that understanding their perceptions is critical if further implementation efforts are to be successful. Analyses showed that pathologists were receptive to enterprise-wide implementation, especially if it improved turnaround time and allowed immediate subspecialist feedback. Future implementation efforts may benefit from comprehensive technical support combined with a consolidated digital pathology program office for implementation and sustainment guidance.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 11","pages":"Article 104236"},"PeriodicalIF":4.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-02DOI: 10.1016/j.labinv.2025.104235
Ya-ting Qiu , Long-feng Ke , Wen-wen Zhang , Shu-yi Lu , Chen-yu Wu , Yun-li Xie , Yu Chen , Gang Chen , Yan-ping Chen
The BRAFV600E mutation test for melanoma patients has become the key to precision therapy. In this study, we compared the concordance of immunohistochemistry (IHC), quantitative real-time PCR (qPCR), and next-generation sequencing (NGS) in detecting the BRAFV600E mutation in a Chinese melanoma patient population. In addition, this study evaluated the BRAFV600E mutation heterogeneity between primary and metastatic melanoma sites, as well as within the same lesion, and investigated the association between BRAFV600E mutation status and tumor cell morphology. A total of 880 samples from 555 patients diagnosed with malignant melanoma were collected, and IHC for BRAFV600E was conducted. Of these, 385 were subjected to qPCR and 115 to NGS concurrently. Inter and intratumor heterogeneities of BRAFV600E mutations were compared. Hematoxylin and eosin (H&E) stain was performed, and the cell morphologies were reviewed. The IHC and qPCR results were discordant in 14 cases, yielding a concordance rate of 96.36%. IHC and NGS results showed a concordance rate of 97.39%. The sensitivity and specificity of BRAFV600E detection by IHC were 96.95% and 99.46%, with an overall concordance rate of 98.80%. One of 130 patients (0.77%) showed intertumor heterogeneity, and 3 of 880 samples (0.34%) showed intratumor heterogeneity. VE1 staining patterns significantly differed across cell morphologies (P < .01). Compared with qPCR and NGS, VE1 IHC offers high sensitivity, specificity, and consistency in detecting the BRAFV600E mutation in melanomas. The BRAFV600E mutation in melanoma exhibits low intertumor and intratumor heterogeneities and is significantly associated with tumor cell morphology; tumors with epithelioid cell morphology are most likely to harbor the BRAFV600E mutation.
{"title":"Association of the BRAFV600E Mutation With Morphology and Heterogeneity in Melanoma","authors":"Ya-ting Qiu , Long-feng Ke , Wen-wen Zhang , Shu-yi Lu , Chen-yu Wu , Yun-li Xie , Yu Chen , Gang Chen , Yan-ping Chen","doi":"10.1016/j.labinv.2025.104235","DOIUrl":"10.1016/j.labinv.2025.104235","url":null,"abstract":"<div><div>The <em>BRAFV600E</em> mutation test for melanoma patients has become the key to precision therapy. In this study, we compared the concordance of immunohistochemistry (IHC), quantitative real-time PCR (qPCR), and next-generation sequencing (NGS) in detecting the <em>BRAFV600E</em> mutation in a Chinese melanoma patient population. In addition, this study evaluated the <em>BRAFV600E</em> mutation heterogeneity between primary and metastatic melanoma sites, as well as within the same lesion, and investigated the association between <em>BRAFV600E</em> mutation status and tumor cell morphology. A total of 880 samples from 555 patients diagnosed with malignant melanoma were collected, and IHC for <em>BRAFV600E</em> was conducted. Of these, 385 were subjected to qPCR and 115 to NGS concurrently. Inter and intratumor heterogeneities of <em>BRAFV600E</em> mutations were compared. Hematoxylin and eosin (H&E) stain was performed, and the cell morphologies were reviewed. The IHC and qPCR results were discordant in 14 cases, yielding a concordance rate of 96.36%. IHC and NGS results showed a concordance rate of 97.39%. The sensitivity and specificity of BRAFV600E detection by IHC were 96.95% and 99.46%, with an overall concordance rate of 98.80%. One of 130 patients (0.77%) showed intertumor heterogeneity, and 3 of 880 samples (0.34%) showed intratumor heterogeneity. VE1 staining patterns significantly differed across cell morphologies (<em>P</em> < .01). Compared with qPCR and NGS, VE1 IHC offers high sensitivity, specificity, and consistency in detecting the <em>BRAFV600E</em> mutation in melanomas. The <em>BRAFV600E</em> mutation in melanoma exhibits low intertumor and intratumor heterogeneities and is significantly associated with tumor cell morphology; tumors with epithelioid cell morphology are most likely to harbor the <em>BRAFV600E</em> mutation.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 11","pages":"Article 104235"},"PeriodicalIF":4.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01DOI: 10.1016/j.labinv.2025.104234
Frank W.J. Heijboer , Jules L. Derks , Dana A.M. Mustafa , Nicole Rijnsburger , Bregtje C.M. Hermans , Lisa M. Hillen , PALGA-Group , Ernst-Jan M. Speel , Anne-Marie C. Dingemans , Jan H. von der Thüsen
Large-cell neuroendocrine carcinoma (LCNEC) can be genomically subtyped into small-cell lung cancer (SCLC) and non-SCLC–like. Neurogenic differentiation 1 (NEUROD1), achaete-scute homolog 1 (ASCL1), POU class 2 homeobox 3 (POU2F3), and yes-associated protein 1 (YAP1) (NEUROD1, ASCL1, POU2F3, and YAP1 [NAPY]) subtypes have been reported for SCLC. We immunohistochemically evaluated NAPY in LCNEC alongside relevant protein expression data. Tissue microarrays from 133 stage I-III resected LCNEC were reviewed and immunostained for NAPY, protein retinoblastoma (pRb), delta-like ligand 3 (DLL3), cMYC, and thyroid transcription factor 1. An H-score of >10 was considered positive (+), and >50, dominant. Unsupervised clustering and spatial immune RNA profiling using GeoMx Digital Spatial Profiling (NanoString Technology) were performed. Clinical data were obtained from the Netherlands Cancer Registry. ASCL1 was dominant in 26% and NEUROD1 in 18% of LCNEC. pRb loss was observed in 75%, and DLL3+, cMYC+, and thyroid transcription factor 1+ in 66%, 26%, and 70%, respectively. Unsupervised clustering identified 5 expression-based subgroups: NEUROD1high-ASCL1high (10%), ASCL1high (22%), POU2F3high (5%), YAP1high (11%), and NAPYlow (51%). Both ASCL1high subgroups correlated with DLL3high and high neuroendocrine (NE) marker expression. YAP1high was enriched for pRb+. POU2F3high and YAP1high subgroups were NE marker low and DLL3low. GeoMX Digital Spatial Profiling identified 4 upregulated genes involved in immune system and/or tumor development in the NEUROD1high-ASCL1high-POU2F3high- group. In this comprehensive evaluation of NAPY markers in LCNEC, we observed 5 expression-based subgroups: NEUROD1high-ASCL1high, ASCL1high, POU2F3high, YAP1high, and NAPYlow. The NE subgroups (NEUROD1high-ASCL1high and ASCL1high) were recognized with DLL3high expression. Compared with the proportion known in SCLC, more NAPYlow and YAP1high and fewer POU2F3high cases were identified. Application of NAPY in LCNEC provides a more modest discrimination of subgroups compared with SCLC. Further research on potential drug targets is warranted, ie, differences in DLL3 and YAP1 expression could guide personalized treatment strategies.
{"title":"Comprehensive Analysis of Neurogenic Differentiation Factor 1 (NEUROD1), Achaete-Scute Homolog 1 (ASCL1), POU Class 2 Homeobox 3 (POU2F3), and Yes-Associated Protein 1 (YAP1) Expression Signatures Reveals Unique Large-Cell Neuroendocrine Carcinoma (LCNEC) Subgroups With Potential Therapeutic Implications","authors":"Frank W.J. Heijboer , Jules L. Derks , Dana A.M. Mustafa , Nicole Rijnsburger , Bregtje C.M. Hermans , Lisa M. Hillen , PALGA-Group , Ernst-Jan M. Speel , Anne-Marie C. Dingemans , Jan H. von der Thüsen","doi":"10.1016/j.labinv.2025.104234","DOIUrl":"10.1016/j.labinv.2025.104234","url":null,"abstract":"<div><div>Large-cell neuroendocrine carcinoma (LCNEC) can be genomically subtyped into small-cell lung cancer (SCLC) and non-SCLC–like. Neurogenic differentiation 1 (NEUROD1), achaete-scute homolog 1 (ASCL1), POU class 2 homeobox 3 (POU2F3), and yes-associated protein 1 (YAP1) (NEUROD1, ASCL1, POU2F3, and YAP1 [NAPY]) subtypes have been reported for SCLC. We immunohistochemically evaluated NAPY in LCNEC alongside relevant protein expression data. Tissue microarrays from 133 stage I-III resected LCNEC were reviewed and immunostained for NAPY, protein retinoblastoma (pRb), delta-like ligand 3 (DLL3), cMYC, and thyroid transcription factor 1. An H-score of >10 was considered positive (+), and >50, dominant. Unsupervised clustering and spatial immune RNA profiling using GeoMx Digital Spatial Profiling (NanoString Technology) were performed. Clinical data were obtained from the Netherlands Cancer Registry. ASCL1 was dominant in 26% and NEUROD1 in 18% of LCNEC. pRb loss was observed in 75%, and DLL3+, cMYC+, and thyroid transcription factor 1+ in 66%, 26%, and 70%, respectively. Unsupervised clustering identified 5 expression-based subgroups: NEUROD1<sup>high</sup>-ASCL1<sup>high</sup> (10%), ASCL1<sup>high</sup> (22%), POU2F3<sup>high</sup> (5%), YAP1<sup>high</sup> (11%), and NAPY<sup>low</sup> (51%). Both ASCL1<sup>high</sup> subgroups correlated with DLL3<sup>high</sup> and high neuroendocrine (NE) marker expression. YAP1<sup>high</sup> was enriched for pRb+. POU2F3<sup>high</sup> and YAP1<sup>high</sup> subgroups were NE marker low and DLL3<sup>low</sup>. GeoMX Digital Spatial Profiling identified 4 upregulated genes involved in immune system and/or tumor development in the NEUROD1<sup>high</sup>-ASCL1<sup>high</sup>-POU2F3<sup>high</sup>- group. In this comprehensive evaluation of NAPY markers in LCNEC, we observed 5 expression-based subgroups: NEUROD1<sup>high</sup>-ASCL1<sup>high</sup>, ASCL1<sup>high</sup>, POU2F3<sup>high</sup>, YAP1<sup>high</sup>, and NAPY<sup>low</sup>. The NE subgroups (NEUROD1<sup>high</sup>-ASCL1<sup>high</sup> and ASCL1<sup>high</sup>) were recognized with DLL3<sup>high</sup> expression. Compared with the proportion known in SCLC, more NAPY<sup>low</sup> and YAP1<sup>high</sup> and fewer POU2F3<sup>high</sup> cases were identified. Application of NAPY in LCNEC provides a more modest discrimination of subgroups compared with SCLC. Further research on potential drug targets is warranted, ie, differences in DLL3 and YAP1 expression could guide personalized treatment strategies.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 11","pages":"Article 104234"},"PeriodicalIF":4.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-27DOI: 10.1016/j.labinv.2025.104233
Nay N.N. Chan , Patricia Gaule , Julia Benanto , Liam Scott , Charles J. Robbins , Mengni He , Katherine Bates , Revekka Khaimova , Daniel C. Liebler , Regan Fulton , David L. Rimm
The recent approval of antibody-drug conjugates targeting human epidermal growth factor receptor 2 (HER2) (such as trastuzumab deruxtecan [T-DXd]) has led to challenges for the immunohistochemical (IHC) companion diagnostic test because the test was optimized for gene-amplified levels of HER2. Here, we develop and validate an objective test for low-level HER2 expression toward more accurate selection of patients for T-DXd. We validated the high-sensitivity HER2 assay using a mix of the requirements for an IHC assay and that of a ligand-binding assay. Then, we prospectively tested it on 316 core biopsy specimens received by the Yale Pathology Laboratories from August 2022 to August 2023. Using a 40-case breast cancer tissue validation set, we find very high accuracy and precision with a coefficient of variation <10% and define a reportable range for the assay in attomoles per square millimeter. These prospective cases not only show the dynamic range of HER2 expression but also the discordance of Yale Pathology Labs staff pathologist scores with quantitative measurements, especially in the low range of HER2. We find that 6% of the cohort was below the limit of detection of this more sensitive assay, whereas 71% of the IHC 0 cases were above the limit of quantification. Efforts are underway to determine a possible threshold expression level required for T-DXd response. In summary, this assay validation study provides a method for accurate, objective measurement of HER2 and has the potential to improve selection of patients for T-DXd or similarly targeted antibody-drug conjugate therapies in future.
{"title":"Validation and Prospective Testing of a High-Sensitivity, Quantitative Analytic Assay for HER2 on Histopathology Slides","authors":"Nay N.N. Chan , Patricia Gaule , Julia Benanto , Liam Scott , Charles J. Robbins , Mengni He , Katherine Bates , Revekka Khaimova , Daniel C. Liebler , Regan Fulton , David L. Rimm","doi":"10.1016/j.labinv.2025.104233","DOIUrl":"10.1016/j.labinv.2025.104233","url":null,"abstract":"<div><div>The recent approval of antibody-drug conjugates targeting human epidermal growth factor receptor 2 (HER2) (such as trastuzumab deruxtecan [T-DXd]) has led to challenges for the immunohistochemical (IHC) companion diagnostic test because the test was optimized for gene-amplified levels of HER2. Here, we develop and validate an objective test for low-level HER2 expression toward more accurate selection of patients for T-DXd. We validated the high-sensitivity HER2 assay using a mix of the requirements for an IHC assay and that of a ligand-binding assay. Then, we prospectively tested it on 316 core biopsy specimens received by the Yale Pathology Laboratories from August 2022 to August 2023. Using a 40-case breast cancer tissue validation set, we find very high accuracy and precision with a coefficient of variation <10% and define a reportable range for the assay in attomoles per square millimeter. These prospective cases not only show the dynamic range of HER2 expression but also the discordance of Yale Pathology Labs staff pathologist scores with quantitative measurements, especially in the low range of HER2. We find that 6% of the cohort was below the limit of detection of this more sensitive assay, whereas 71% of the IHC 0 cases were above the limit of quantification. Efforts are underway to determine a possible threshold expression level required for T-DXd response. In summary, this assay validation study provides a method for accurate, objective measurement of HER2 and has the potential to improve selection of patients for T-DXd or similarly targeted antibody-drug conjugate therapies in future.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 12","pages":"Article 104233"},"PeriodicalIF":4.2,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-25DOI: 10.1016/j.labinv.2025.104232
Lydia Kirsche , Lars Jansen , Annett Petzold , Petra Reinecke , Peter Behrens , Carol Geppert , Nikolaus Gaßler , Matthias Dürst
Human papillomavirus (HPV) DNA integration into the host genome is a frequent event in cervical carcinogenesis and may drive clonal expansion of the affected cells. Based on viral cellular junction (vcj) sequences, highly specific vcj-PCRs can be designed to detect viral integrants in DNA from cervical cell scrapes or tissue samples. In a recent study, such patient-specific vcj-PCR assays were employed for the detection of recurrent high-grade squamous intraepithelial lesions (HSIL) during postoperative surveillance. Although the specificity of vcj-PCR was 100%, only 50% of the recurrences were detected using this approach. The focus of the current study was to analyze the cause of this limited sensitivity. Using chemical microdissection and subsequent vcj-PCR analysis, we could demonstrate that the majority of lesions have a heterogeneous integrant pattern. Only 2 of 16 cones showed a homogeneous distribution of the respective integrants throughout the entire lesion. The other lesions displayed clonal outgrowths harboring the integrant in a background HPV16/18 DNA-positive HSIL tissue. In 4 cases, the respective integrant was undetectable in the lesion. These findings indicate that vcj-PCR has limited sensitivity for the detection of recurrent disease owing to intralesional heterogeneity. The observed heterogeneous integrant pattern may thus reflect the multifocal nature of most large HSIL. Alternatively, the possibility that HPV integration may be a late event in the carcinogenic process also needs to be considered.
{"title":"Heterogeneous Distribution of Human Papillomavirus (HPV) Integration Sites in Cervical Precancers Compromises the Diagnostic Accuracy of Integrant-Specific PCR","authors":"Lydia Kirsche , Lars Jansen , Annett Petzold , Petra Reinecke , Peter Behrens , Carol Geppert , Nikolaus Gaßler , Matthias Dürst","doi":"10.1016/j.labinv.2025.104232","DOIUrl":"10.1016/j.labinv.2025.104232","url":null,"abstract":"<div><div>Human papillomavirus (HPV) DNA integration into the host genome is a frequent event in cervical carcinogenesis and may drive clonal expansion of the affected cells. Based on viral cellular junction (vcj) sequences, highly specific vcj-PCRs can be designed to detect viral integrants in DNA from cervical cell scrapes or tissue samples. In a recent study, such patient-specific vcj-PCR assays were employed for the detection of recurrent high-grade squamous intraepithelial lesions (HSIL) during postoperative surveillance. Although the specificity of vcj-PCR was 100%, only 50% of the recurrences were detected using this approach. The focus of the current study was to analyze the cause of this limited sensitivity. Using chemical microdissection and subsequent vcj-PCR analysis, we could demonstrate that the majority of lesions have a heterogeneous integrant pattern. Only 2 of 16 cones showed a homogeneous distribution of the respective integrants throughout the entire lesion. The other lesions displayed clonal outgrowths harboring the integrant in a background HPV16/18 DNA-positive HSIL tissue. In 4 cases, the respective integrant was undetectable in the lesion. These findings indicate that vcj-PCR has limited sensitivity for the detection of recurrent disease owing to intralesional heterogeneity. The observed heterogeneous integrant pattern may thus reflect the multifocal nature of most large HSIL. Alternatively, the possibility that HPV integration may be a late event in the carcinogenic process also needs to be considered.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 11","pages":"Article 104232"},"PeriodicalIF":4.2,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-19DOI: 10.1016/j.labinv.2025.104214
Claudio Luchini , Carlotta Franzina , Federico Caldart , Nicolò De Pretis , Manola Crestani , Massimo Donadelli , Paola Mattiolo , Alessandra Fiore , Federica Danzi , Riccardo De Robertis , Michele Bevere , Roberto Baldan , Laura Tommasi , Nicolò Vianini , Paolo Bernardi , Mirco Galiè , Antonio Pea , Rachele Ciccocioppo , Mirko D’Onofrio , Roberto Salvia , Luca Frulloni
Obesity-related diseases and perturbations of fat metabolism represent some of the most common health challenges. In this complex scenario, recent evidence has suggested the emergence of a condition related to fat accumulation in the pancreas, which is generally referred to as fatty pancreas disease. This study aimed to clarify the different compartments of intrapancreatic fat deposition. The study cohort is represented by 100 patients who underwent pancreatic surgical resection. The pancreatic neck margin was analyzed with hematoxylin and eosin for evaluating tissue composition and with Oil Red O, a fat-specific histochemical staining, highlighting lipid droplets as red signals, for evaluating the presence of intracellular fat. Two cases were also analyzed with electron microscopy as cross-sectional validation. Regarding tissue composition, the most prevalent component was normal pancreatic parenchyma (mean value, 71.8%), followed by fibrosis (17.3%) and interlobular/intralobular fat (10.9%). Regarding intracellular fat deposition, Oil Red O–positive intracytoplasmic lipid droplets were present in most patients. The tissue areas with the highest levels of fat deposition were Langerhans’ islets, with neuroendocrine/insular cells showing more commonly a diffuse pattern of fat accumulation (>75% of cells). Electron microscopy confirmed the presence of intracytoplasmic lipid vacuoles in neuroendocrine/insular cells. Our findings showed the presence of different compartments of intrapancreatic fat deposition, both in terms of tissue composition and intracellular compartmentalization. Understanding the mechanisms of fat deposition in the pancreas is crucial toward improving the general knowledge on fatty pancreas disease, also opening new perspectives for the study of lipid metabolism and the treatment of fat-related diseases.
肥胖相关疾病和脂肪代谢紊乱是一些最常见的健康挑战。在这种复杂的情况下，最近的证据表明出现了一种与胰腺脂肪堆积有关的疾病，通常被称为脂肪性胰腺疾病。本研究旨在阐明胰腺内脂肪沉积的不同区室。该研究队列由100例接受胰腺手术切除的患者代表。胰颈缘用苏木精-伊红染色评估组织组成，用Oil Red O（一种脂肪特异性组织化学染色，突出脂滴作为红色信号）评估细胞内脂肪的存在。两个病例也用电子显微镜分析作为横断面验证。在组织组成方面，最常见的是正常胰腺实质（平均值：71.8%），其次是纤维化（17.3%）和小叶间/小叶内脂肪（10.9%）。关于细胞内脂肪沉积，大多数患者存在油红o阳性的胞浆内脂滴。脂肪沉积水平最高的组织区域是朗格汉斯胰岛，神经内分泌/岛细胞更常见地表现为弥漫性脂肪堆积（约占细胞的75%）。电镜检查证实在神经内分泌/岛细胞中存在胞浆内脂泡。我们的研究结果表明，在组织组成和细胞内区隔化方面，胰腺内脂肪沉积存在不同的区隔。了解胰腺脂肪沉积的机制对于提高对脂肪性胰腺疾病的认识至关重要，也为脂质代谢的研究和脂肪相关疾病的治疗开辟了新的视角。
{"title":"Fatty Pancreas Disease: An Integrated Study on Frozen Tissues Shows Distinct Compartments of Interlobular/Intralobular, Intra-Acinar, and Intra-Islet Fat Deposition","authors":"Claudio Luchini , Carlotta Franzina , Federico Caldart , Nicolò De Pretis , Manola Crestani , Massimo Donadelli , Paola Mattiolo , Alessandra Fiore , Federica Danzi , Riccardo De Robertis , Michele Bevere , Roberto Baldan , Laura Tommasi , Nicolò Vianini , Paolo Bernardi , Mirco Galiè , Antonio Pea , Rachele Ciccocioppo , Mirko D’Onofrio , Roberto Salvia , Luca Frulloni","doi":"10.1016/j.labinv.2025.104214","DOIUrl":"10.1016/j.labinv.2025.104214","url":null,"abstract":"<div><div>Obesity-related diseases and perturbations of fat metabolism represent some of the most common health challenges. In this complex scenario, recent evidence has suggested the emergence of a condition related to fat accumulation in the pancreas, which is generally referred to as fatty pancreas disease. This study aimed to clarify the different compartments of intrapancreatic fat deposition. The study cohort is represented by 100 patients who underwent pancreatic surgical resection. The pancreatic neck margin was analyzed with hematoxylin and eosin for evaluating tissue composition and with Oil Red O, a fat-specific histochemical staining, highlighting lipid droplets as red signals, for evaluating the presence of intracellular fat. Two cases were also analyzed with electron microscopy as cross-sectional validation. Regarding tissue composition, the most prevalent component was normal pancreatic parenchyma (mean value, 71.8%), followed by fibrosis (17.3%) and interlobular/intralobular fat (10.9%). Regarding intracellular fat deposition, Oil Red O–positive intracytoplasmic lipid droplets were present in most patients. The tissue areas with the highest levels of fat deposition were Langerhans’ islets, with neuroendocrine/insular cells showing more commonly a diffuse pattern of fat accumulation (>75% of cells). Electron microscopy confirmed the presence of intracytoplasmic lipid vacuoles in neuroendocrine/insular cells. Our findings showed the presence of different compartments of intrapancreatic fat deposition, both in terms of tissue composition and intracellular compartmentalization. Understanding the mechanisms of fat deposition in the pancreas is crucial toward improving the general knowledge on fatty pancreas disease, also opening new perspectives for the study of lipid metabolism and the treatment of fat-related diseases.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 11","pages":"Article 104214"},"PeriodicalIF":4.2,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-13DOI: 10.1016/j.labinv.2025.104225
Jaekwon Seok , Hee Jeong Kwak , Chan-Koo Kang , Ah Ram Kim , Woo Suk Choi , Hyoung Keun Park , Sung Hyun Paick , Hyeong Gon Kim , Yeonjoo Kwak , Tak-Il Jeon , Kyung Min Lim , Baeckseung Lee , Aram Kim , Ssang-Goo Cho
{"title":"Corrigendum to ‘Development of a Technique for Diagnosis and Screening of Superficial Bladder Cancer by Cell-Pellet DNA From Urine Sample’ [Laboratory Investigation 105 (2025) 104124]","authors":"Jaekwon Seok , Hee Jeong Kwak , Chan-Koo Kang , Ah Ram Kim , Woo Suk Choi , Hyoung Keun Park , Sung Hyun Paick , Hyeong Gon Kim , Yeonjoo Kwak , Tak-Il Jeon , Kyung Min Lim , Baeckseung Lee , Aram Kim , Ssang-Goo Cho","doi":"10.1016/j.labinv.2025.104225","DOIUrl":"10.1016/j.labinv.2025.104225","url":null,"abstract":"","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 9","pages":"Article 104225"},"PeriodicalIF":4.2,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144829716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-06DOI: 10.1016/j.labinv.2025.104227
Hao Lin , Jia-Jie Liang , Chen-Xi Zhang , Qi-Wen Man , Rui-Fang Li , Lin-Zhou Zhang , Bing Liu
Cellular senescence and its associated microenvironment play a pivotal role in tumor initiation and progression. Although ameloblastoma (AM) is classified as a benign tumor, it is characterized by local invasiveness and a high recurrence rate. In this study, we identified a distinct population of senescent epithelial cells using senescence-associated β-galactosidase staining and explored the role of this subpopulation in AM progression. The CellChat tool was utilized to map intercellular communication networks, revealing that this senescent cell cluster promotes stemness in neighboring cells and drives angiogenesis and osteoclastogenesis, which was subsequently confirmed by a series of in vitro experiments. Moreover, conditioned medium from these senescent cells significantly enhanced tumor growth in patient-derived organoids. Clinical data further demonstrated that elevated levels of cellular senescence were strongly associated with greater tumor invasiveness and poorer prognosis in AM patients. In conclusion, our findings suggest that targeting this specific subset of senescent epithelial cells may offer a novel therapeutic approach for AM management, potentially reducing tumor aggressiveness and recurrence.
{"title":"Senescent Epithelial Cells Serve as Invasive Growth Drivers in Ameloblastoma","authors":"Hao Lin , Jia-Jie Liang , Chen-Xi Zhang , Qi-Wen Man , Rui-Fang Li , Lin-Zhou Zhang , Bing Liu","doi":"10.1016/j.labinv.2025.104227","DOIUrl":"10.1016/j.labinv.2025.104227","url":null,"abstract":"<div><div>Cellular senescence and its associated microenvironment play a pivotal role in tumor initiation and progression. Although ameloblastoma (AM) is classified as a benign tumor, it is characterized by local invasiveness and a high recurrence rate. In this study, we identified a distinct population of senescent epithelial cells using senescence-associated β-galactosidase staining and explored the role of this subpopulation in AM progression. The CellChat tool was utilized to map intercellular communication networks, revealing that this senescent cell cluster promotes stemness in neighboring cells and drives angiogenesis and osteoclastogenesis, which was subsequently confirmed by a series of <em>in vitro</em> experiments. Moreover, conditioned medium from these senescent cells significantly enhanced tumor growth in patient-derived organoids. Clinical data further demonstrated that elevated levels of cellular senescence were strongly associated with greater tumor invasiveness and poorer prognosis in AM patients. In conclusion, our findings suggest that targeting this specific subset of senescent epithelial cells may offer a novel therapeutic approach for AM management, potentially reducing tumor aggressiveness and recurrence.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":"105 11","pages":"Article 104227"},"PeriodicalIF":4.2,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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