Pub Date : 2026-06-01Epub Date: 2026-03-02DOI: 10.1016/j.humpath.2026.106097
Jenni Kotola , Anselm Tamminen
Background
In current practice, the traditional strategy of excising all IDPs has been replaced by more selective management. However, criteria for selecting patients for surveillance remain unclear, and no widely accepted predictive model exists.
Methods
We retrospectively analyzed real-world data from 325 cases of IDPs diagnosed via core needle biopsy (CNB) at a tertiary teaching hospital between 2010 and 2023. We assessed upgrade rates to malignancy and evaluated potential predictive factors. Two previously published models were applied to our cohort, and a new model was developed based on our data.
Results
Overall, 17% (55/325) of IDPs were upgraded to malignancy. Among lesions without atypia on CNB (n = 215), the upgrade rate was 8.8% (19/215), compared to 40% (23/58) in those with atypia (p < 0.001). Previously suggested models yielded modest results when applied to our study population. First model would have spared 11% (24/215) of patients from surgery, while the second model would have spared 17% (36/215), with one missed upgrade. Our model identified all upgraded cases and would have spared 33% (72/215) of non-atypical IDPs from surgery.
Conclusions
Atypia on CNB is a strong predictor of upgrade to malignancy. Existing models showed limited utility in reducing unnecessary surgeries. Our proposed model demonstrated improved performance and may support more individualized management of IDPs.
{"title":"Upgrade risk in intraductal papillomas: A retrospective analysis of real-world data and predictive model development","authors":"Jenni Kotola , Anselm Tamminen","doi":"10.1016/j.humpath.2026.106097","DOIUrl":"10.1016/j.humpath.2026.106097","url":null,"abstract":"<div><h3>Background</h3><div>In current practice, the traditional strategy of excising all IDPs has been replaced by more selective management. However, criteria for selecting patients for surveillance remain unclear, and no widely accepted predictive model exists.</div></div><div><h3>Methods</h3><div>We retrospectively analyzed real-world data from 325 cases of IDPs diagnosed via core needle biopsy (CNB) at a tertiary teaching hospital between 2010 and 2023. We assessed upgrade rates to malignancy and evaluated potential predictive factors. Two previously published models were applied to our cohort, and a new model was developed based on our data.</div></div><div><h3>Results</h3><div>Overall, 17% (55/325) of IDPs were upgraded to malignancy. Among lesions without atypia on CNB (n = 215), the upgrade rate was 8.8% (19/215), compared to 40% (23/58) in those with atypia (p < 0.001). Previously suggested models yielded modest results when applied to our study population. First model would have spared 11% (24/215) of patients from surgery, while the second model would have spared 17% (36/215), with one missed upgrade. Our model identified all upgraded cases and would have spared 33% (72/215) of non-atypical IDPs from surgery.</div></div><div><h3>Conclusions</h3><div>Atypia on CNB is a strong predictor of upgrade to malignancy. Existing models showed limited utility in reducing unnecessary surgeries. Our proposed model demonstrated improved performance and may support more individualized management of IDPs.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"172 ","pages":"Article 106097"},"PeriodicalIF":2.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147354708","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 : 2026-06-01Epub Date: 2026-03-03DOI: 10.1016/j.humpath.2026.106099
Yue Yu , Yingjing Wang , Xiao Cheng, Xuan Chen, Wei Zhao, Suying Wang, Huizhi Zhang
Clear cell renal cell carcinoma (ccRCC) with sarcomatoid and/or rhabdoid differentiation—distinct dedifferentiation phenotypes—exhibits high aggressiveness and poor prognosis. Despite recent advances, their clinicopathologic and molecular characteristics remain incompletely defined. This study analyzed 21 such cases, predominantly in males (19 patients), with a median age of 64 years (range: 29 – 83 years) and average tumor size of 6.1 cm (range: 3.5 – 14 cm). Among these, 14 cases showed sarcomatoid differentiation, 11 cases exhibited rhabdoid differentiation, and four cases demonstrated both types simultaneously. Most tumors (16/21, 76.19%) exhibited necrosis. Two patients presented with synchronous pulmonary metastases at diagnosis, and six developed distant metastases (bone/lung/liver/brain) 4 - 30 months postoperatively. Next-generation sequencing revealed that 90.5% (19/21) of samples harbored VHL gene alterations, which represent the initial driver mutation in ccRCC development. Additionally, chromatin remodeling genes showed enriched abnormalities, including PBRM1 (52.4%, 11/21), BAP1 (33.3%, 7/21) and SETD2 (19.0%, 4/21), suggesting a potential role for these genes in the transformation to sarcomatoid and/or rhabdoid morphology. Notably, 28.6% of tumors had TSC/MTOR pathway alterations, and TP53 mutations (33.3%) were significantly associated with poor prognosis (p = 0.049). No statistically significant differences in driver mutation prevalence or prognosis were observed between sarcomatoid and rhabdoid differentiation. These findings highlight the value of molecular stratification in elucidating pathogenesis and guiding targeted therapy for this aggressive ccRCC subtype, particularly emphasizing TP53 as a prognostic biomarker and TSC/MTOR alterations as potential therapeutic targets.
{"title":"Clinical, pathologic, and molecular profiles of sarcomatoid and rhabdoid differentiated clear cell renal cell carcinoma: A series of 21 tumors","authors":"Yue Yu , Yingjing Wang , Xiao Cheng, Xuan Chen, Wei Zhao, Suying Wang, Huizhi Zhang","doi":"10.1016/j.humpath.2026.106099","DOIUrl":"10.1016/j.humpath.2026.106099","url":null,"abstract":"<div><div>Clear cell renal cell carcinoma (ccRCC) with sarcomatoid and/or rhabdoid differentiation—distinct dedifferentiation phenotypes—exhibits high aggressiveness and poor prognosis. Despite recent advances, their clinicopathologic and molecular characteristics remain incompletely defined. This study analyzed 21 such cases, predominantly in males (19 patients), with a median age of 64 years (range: 29 – 83 years) and average tumor size of 6.1 cm (range: 3.5 – 14 cm). Among these, 14 cases showed sarcomatoid differentiation, 11 cases exhibited rhabdoid differentiation, and four cases demonstrated both types simultaneously. Most tumors (16/21, 76.19%) exhibited necrosis. Two patients presented with synchronous pulmonary metastases at diagnosis, and six developed distant metastases (bone/lung/liver/brain) 4 - 30 months postoperatively. Next-generation sequencing revealed that 90.5% (19/21) of samples harbored <em>VHL</em> gene alterations, which represent the initial driver mutation in ccRCC development. Additionally, chromatin remodeling genes showed enriched abnormalities, including <em>PBRM1</em> (52.4%, 11/21), <em>BAP1</em> (33.3%, 7/21) and <em>SETD2</em> (19.0%, 4/21), suggesting a potential role for these genes in the transformation to sarcomatoid and/or rhabdoid morphology. Notably, 28.6% of tumors had TSC/MTOR pathway alterations, and <em>TP53</em> mutations (33.3%) were significantly associated with poor prognosis (p = 0.049). No statistically significant differences in driver mutation prevalence or prognosis were observed between sarcomatoid and rhabdoid differentiation. These findings highlight the value of molecular stratification in elucidating pathogenesis and guiding targeted therapy for this aggressive ccRCC subtype, particularly emphasizing TP53 as a prognostic biomarker and TSC/MTOR alterations as potential therapeutic targets.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"172 ","pages":"Article 106099"},"PeriodicalIF":2.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147365039","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 : 2026-06-01Epub Date: 2026-02-18DOI: 10.1016/j.humpath.2026.106076
Yuri Merlotti Gomes , João Víctor Alves de Castro , Nicolai Merlotti Gomes , Rodrigo Fonseca Abreu , Leslie Domenici Kulikowski , Beatriz Martins Wolff , Clóvis Antonio Pinto , Antonio G. Nascimento , Ronaldo Nunes Toledo , Anders Meyer , Igor Lima Fernandes , Cristovam Scapulatempo Neto , Philipp Jurmeister , David Capper , Josephine K. Dermawan , Karen J. Fritchie , Stephania Martins Bezerra , Felipe D'Almeida Costa
Biphenotypic sinonasal sarcoma (BSS) is a rare mesenchymal neoplasm characterized by dual neural and myogenic differentiation, recurrent PAX3 gene rearrangements, and low-grade morphology. High-grade transformation has been described, posing significant diagnostic challenges due to overlap among sinonasal tumors. DNA methylation profiling has emerged as a powerful diagnostic tool for sinonasal neoplasms, although BSS was not included in previous cohorts. In this study, we investigated the DNA methylation profile of BSS and its relationship with fusion type and high-grade transformation. Fourteen BSS samples were retrospectively collected from four academic institutions. All cases underwent genome-wide methylation profiling using the Illumina Infinium MethylationEPIC array, and available clinical, radiological, histopathologic, and immunohistochemical data were reviewed. RNA sequencing was performed when sufficient material was available. Methylation profiles were analyzed using t-distributed stochastic neighbor embedding (t-SNE) and compared with a reference cohort of sinonasal tumors. The median patient age was 52.7 years, with a female predominance (M:F ratio 1:2.25). The most common fusion was PAX3::MAML3 (6/12, 50.0%), followed by PAX3::FOXO1 and other rare rearrangements, including PAX3::NCOA2, PAX3::YAP1, and FUS::POU2AF3, detected in one case each (1/12, 8.3%). Most importantly, all BSS samples formed a cohesive epigenetic group upon dimensionality reduction, clearly separated from other sinonasal tumors. No specific clustering was seen among different fusion types or tumor grade. Our findings support that BSS represents a unique and molecularly distinct sinonasal sarcoma with a characteristic DNA methylation signature, independent of gene fusion partners or histologic progression, providing a valuable tool for the classification of challenging cases.
{"title":"Epigenetic profiling of biphenotypic sinonasal sarcoma across fusion variants and high-grade transformation","authors":"Yuri Merlotti Gomes , João Víctor Alves de Castro , Nicolai Merlotti Gomes , Rodrigo Fonseca Abreu , Leslie Domenici Kulikowski , Beatriz Martins Wolff , Clóvis Antonio Pinto , Antonio G. Nascimento , Ronaldo Nunes Toledo , Anders Meyer , Igor Lima Fernandes , Cristovam Scapulatempo Neto , Philipp Jurmeister , David Capper , Josephine K. Dermawan , Karen J. Fritchie , Stephania Martins Bezerra , Felipe D'Almeida Costa","doi":"10.1016/j.humpath.2026.106076","DOIUrl":"10.1016/j.humpath.2026.106076","url":null,"abstract":"<div><div>Biphenotypic sinonasal sarcoma (BSS) is a rare mesenchymal neoplasm characterized by dual neural and myogenic differentiation, recurrent <em>PAX3</em> gene rearrangements, and low-grade morphology. High-grade transformation has been described, posing significant diagnostic challenges due to overlap among sinonasal tumors. DNA methylation profiling has emerged as a powerful diagnostic tool for sinonasal neoplasms, although BSS was not included in previous cohorts. In this study, we investigated the DNA methylation profile of BSS and its relationship with fusion type and high-grade transformation. Fourteen BSS samples were retrospectively collected from four academic institutions. All cases underwent genome-wide methylation profiling using the Illumina Infinium MethylationEPIC array, and available clinical, radiological, histopathologic, and immunohistochemical data were reviewed. RNA sequencing was performed when sufficient material was available. Methylation profiles were analyzed using t-distributed stochastic neighbor embedding (t-SNE) and compared with a reference cohort of sinonasal tumors. The median patient age was 52.7 years, with a female predominance (M:F ratio 1:2.25). The most common fusion was <em>PAX3</em>::<em>MAML3</em> (6/12, 50.0%), followed by <em>PAX3</em>::<em>FOXO1</em> and other rare rearrangements, including <em>PAX3</em>::<em>NCOA2</em>, <em>PAX3</em>::<em>YAP1</em>, and <em>FUS</em>::<em>POU2AF3</em>, detected in one case each (1/12, 8.3%). Most importantly, all BSS samples formed a cohesive epigenetic group upon dimensionality reduction, clearly separated from other sinonasal tumors. No specific clustering was seen among different fusion types or tumor grade. Our findings support that BSS represents a unique and molecularly distinct sinonasal sarcoma with a characteristic DNA methylation signature, independent of gene fusion partners or histologic progression, providing a valuable tool for the classification of challenging cases.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"172 ","pages":"Article 106076"},"PeriodicalIF":2.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146258258","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 : 2026-05-01Epub Date: 2026-02-10DOI: 10.1016/j.humpath.2026.106073
Sharon Koorse Germans , Olga K. Weinberg , Weina Chen , Miguel Cantu , Mingyi Chen , Dwight Oliver , Prasad Koduru , Lindsay Bigham
Background
Nucleophosmin 1 (NPM1) mutations define a major molecular subtype of acute myeloid leukemia (AML). Although RT-PCR and next-generation sequencing (NGS) remain the gold standard for diagnosis and minimal/measurable residual disease (MRD) assessment, NPM1 mutant-specific immunohistochemistry (NPM1m IHC) using monoclonal antibodies presents a rapid and cost-effective alternative. Correlation between NPM1m IHC patterns and specific NPM1 mutation subtypes remain underexplored.
Objectives
Evaluate the diagnostic utility of NPM1m IHC in AML with NPM1 mutation and to assess its correlation with mutation subtypes, morphologic features, cytogenetic profiles, co-mutations, and clinical outcomes.
Methods
A retrospective cohort of 36 AML cases with confirmed NPM1 mutations (2018-2024) were analyzed for clinicopathologic variables, cytogenetics, PCR/NGS data, and NPM1m IHC results with subgroup analysis between Type A (n = 28) and non-Type A (n = 8) mutations.
Results
NPM1m IHC positivity was observed in all insertional NPM1 mutation subtypes with two distinct staining patterns: homogeneous and two-toned, with two-toned pattern more frequent in Type A mutations. Non-Type A mutations were more often associated with complex karyotypes and showed a trend toward less frequent FLT3 co-mutations. Monocytic differentiation and cup-like nuclear morphology were assessed in both subgroups. No significant difference in survival or remission rates was observed between groups, although Type A mutations exhibited higher rates of dysplasia (p = 0.03).
Conclusion
NPM1m IHC is a sensitive and timely surrogate marker for insertional NPM1 mutations, correlating well with molecular results and useful in both immediate diagnosis and MRD evaluation. This study reveals subtype-specific morphologic and cytogenetic associations and highlights the need for further investigation into non-insertional NPM1 mutations and their detection challenges.
{"title":"Correlation of NPM1 immunohistochemistry with mutation subtypes, clinicopathologic variables and molecular testing in AML with NPM1 mutation","authors":"Sharon Koorse Germans , Olga K. Weinberg , Weina Chen , Miguel Cantu , Mingyi Chen , Dwight Oliver , Prasad Koduru , Lindsay Bigham","doi":"10.1016/j.humpath.2026.106073","DOIUrl":"10.1016/j.humpath.2026.106073","url":null,"abstract":"<div><h3>Background</h3><div>Nucleophosmin 1 <em>(NPM1</em>) mutations define a major molecular subtype of acute myeloid leukemia (AML). Although RT-PCR and next-generation sequencing (NGS) remain the gold standard for diagnosis and minimal/measurable residual disease (MRD) assessment, NPM1 mutant-specific immunohistochemistry (NPM1m IHC) using monoclonal antibodies presents a rapid and cost-effective alternative. Correlation between NPM1m IHC patterns and specific NPM1 mutation subtypes remain underexplored.</div></div><div><h3>Objectives</h3><div>Evaluate the diagnostic utility of NPM1m IHC in AML with <em>NPM1</em> mutation and to assess its correlation with mutation subtypes, morphologic features, cytogenetic profiles, co-mutations, and clinical outcomes.</div></div><div><h3>Methods</h3><div>A retrospective cohort of 36 AML cases with confirmed <em>NPM1</em> mutations (2018-2024) were analyzed for clinicopathologic variables, cytogenetics, PCR/NGS data, and NPM1m IHC results with subgroup analysis between Type A (n = 28) and non-Type A (n = 8) mutations.</div></div><div><h3>Results</h3><div>NPM1m IHC positivity was observed in all insertional <em>NPM1</em> mutation subtypes with two distinct staining patterns: homogeneous and two-toned, with two-toned pattern more frequent in Type A mutations. Non-Type A mutations were more often associated with complex karyotypes and showed a trend toward less frequent <em>FLT3</em> co-mutations. Monocytic differentiation and cup-like nuclear morphology were assessed in both subgroups. No significant difference in survival or remission rates was observed between groups, although Type A mutations exhibited higher rates of dysplasia (p = 0.03).</div></div><div><h3>Conclusion</h3><div>NPM1m IHC is a sensitive and timely surrogate marker for insertional <em>NPM1</em> mutations, correlating well with molecular results and useful in both immediate diagnosis and MRD evaluation. This study reveals subtype-specific morphologic and cytogenetic associations and highlights the need for further investigation into non-insertional <em>NPM1</em> mutations and their detection challenges.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"171 ","pages":"Article 106073"},"PeriodicalIF":2.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146179263","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 : 2026-05-01Epub Date: 2026-01-22DOI: 10.1016/j.humpath.2026.106059
Douglas Jian-Xian Wu, Richard Pacheco, Emily Chan, Alarice Cheng-Yi Lowe, Ankur R. Sangoi
Over the past 2 decades, we have increasingly encountered prostatic adenocarcinoma (PCA) presenting as urinary bladder tumors in routine practice as well as among consultation/medicolegal cases. Given the ramifications of a potential misdiagnosis of PCA as urothelial carcinoma (UC), herein we explore clinicopathologic features among a large cohort of PCA identified on transurethral bladder tumor resection (TURBT). A retrospective re-review identified 54 TURBTs containing PCA from a single tertiary care academic hospital (2003–2025). Of the 27 patients with prior PCA history, urologists were concerned for PCA in 86 %, but history/suspicion was only conveyed in 32 % of accompanying specimen requisition sheets. For patients without PCA history, urologists were occasionally (29 %) suspicious for PCA, mentioning this possibility on requisition sheets in all (100 %) of cases. Most tumors were from the bladder neck or base (72 %). Pseudopapillary/papillary-like growth pattern was often seen (46 %). The predominant architecture was solid or nested/corded (70 %) followed by glandular (26 %) and acinar (4 %). Nuclei in most cases were uniform/round (89 %) with prominent nucleoli predominant in most cases (56 %) while the cytoplasm was more often “pale/bubbly” (72 %) versus “dense/glassy” (28 %). Pseudopapillary/papillary-like growth compounded with solid to nested architecture within PCA can mimic UC on TURBT specimens, although nuclear features/prominent nucleoli can be a helpful clue. While clinical/cystoscopic findings (e.g. tumor site) may suggest PCA on TURBT, this information does not always accompany the specimen, requiring confirmatory chart review for putative cases as well as judicious use of immunohistochemistry.
{"title":"Prostatic adenocarcinoma identified on transurethral resection of bladder tumor: A clinicopathologic series of a diagnostically relevant potential pitfall","authors":"Douglas Jian-Xian Wu, Richard Pacheco, Emily Chan, Alarice Cheng-Yi Lowe, Ankur R. Sangoi","doi":"10.1016/j.humpath.2026.106059","DOIUrl":"10.1016/j.humpath.2026.106059","url":null,"abstract":"<div><div>Over the past 2 decades, we have increasingly encountered prostatic adenocarcinoma (PCA) presenting as urinary bladder tumors in routine practice as well as among consultation/medicolegal cases. Given the ramifications of a potential misdiagnosis of PCA as urothelial carcinoma (UC), herein we explore clinicopathologic features among a large cohort of PCA identified on transurethral bladder tumor resection (TURBT). A retrospective re-review identified 54 TURBTs containing PCA from a single tertiary care academic hospital (2003–2025). Of the 27 patients with prior PCA history, urologists were concerned for PCA in 86 %, but history/suspicion was only conveyed in 32 % of accompanying specimen requisition sheets. For patients without PCA history, urologists were occasionally (29 %) suspicious for PCA, mentioning this possibility on requisition sheets in all (100 %) of cases. Most tumors were from the bladder neck or base (72 %). Pseudopapillary/papillary-like growth pattern was often seen (46 %). The predominant architecture was solid or nested/corded (70 %) followed by glandular (26 %) and acinar (4 %). Nuclei in most cases were uniform/round (89 %) with prominent nucleoli predominant in most cases (56 %) while the cytoplasm was more often “pale/bubbly” (72 %) versus “dense/glassy” (28 %). Pseudopapillary/papillary-like growth compounded with solid to nested architecture within PCA can mimic UC on TURBT specimens, although nuclear features/prominent nucleoli can be a helpful clue. While clinical/cystoscopic findings (e.g. tumor site) may suggest PCA on TURBT, this information does not always accompany the specimen, requiring confirmatory chart review for putative cases as well as judicious use of immunohistochemistry.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"171 ","pages":"Article 106059"},"PeriodicalIF":2.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043988","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}
Differentiating among hepato-pancreato-biliary (HPB) cancers like cholangiocarcinoma (CCA), hepatocellular carcinoma (HCC), pancreatic cancer (PC), and gallbladder cancer (GBC) can be challenging. To address this, our study used fluorescence in situ hybridization (FISH) to identify 1p36 chromosomal abnormality patterns in 100 HPB cancer patients. We found consistent 1p36 loss in CCA, IPNB, GBC, and PC, while HCC uniquely exhibited normal, loss, and gain patterns. Notably, this 1p36 gain showed a sensitivity was 45.71 % and specificity was 100 % for differentiating HCC from CCA and other HPB cancers, while 1p36 loss proved highly sensitive (100 %) and specific (85.71 %) for distinguishing CCA from HCC, though its ability to differentiate CCA from others was limited. Beyond diagnosis, a high burden of 1p36 loss was a significant prognostic factor for shorter overall survival in CCA (p = 0.024) and in the combined CCA/IPNB cohort (p = 0.015). More importantly, 1p36 loss also significantly correlated with tumor differentiation in CCA (p < 0.05). These results suggest that assessment of 1p36 status by FISH may serve as a complementary molecular approach to conventional histopathology and immunohistochemistry, providing additional differential diagnostic HCC from CCA and other diagnostically challenging HPB cancers and serve as promising prognostic biomarkers for CCA and IPNB.
{"title":"Discovery and clinical significance of 1p36 chromosomal aberrations in differentiating hepatocellular carcinoma from other hepatobiliary cancers","authors":"Wantakan Ngamsangiam , Sutheemon Techa-ay , Prakasit Sa-ngiamwibool , Sasithorn Watcharadetwittaya , Raksawan Deenonpoe , Anchalee Techasen , Adjima Luechine , Watcharin Loilome , Malinee Thanee","doi":"10.1016/j.humpath.2026.106053","DOIUrl":"10.1016/j.humpath.2026.106053","url":null,"abstract":"<div><div>Differentiating among hepato-pancreato-biliary (HPB) cancers like cholangiocarcinoma (CCA), hepatocellular carcinoma (HCC), pancreatic cancer (PC), and gallbladder cancer (GBC) can be challenging. To address this, our study used fluorescence in situ hybridization (FISH) to identify 1p36 chromosomal abnormality patterns in 100 HPB cancer patients. We found consistent 1p36 loss in CCA, IPNB, GBC, and PC, while HCC uniquely exhibited normal, loss, and gain patterns. Notably, this 1p36 gain showed a sensitivity was 45.71 % and specificity was 100 % for differentiating HCC from CCA and other HPB cancers, while 1p36 loss proved highly sensitive (100 %) and specific (85.71 %) for distinguishing CCA from HCC, though its ability to differentiate CCA from others was limited. Beyond diagnosis, a high burden of 1p36 loss was a significant prognostic factor for shorter overall survival in CCA (p = 0.024) and in the combined CCA/IPNB cohort (p = 0.015). More importantly, 1p36 loss also significantly correlated with tumor differentiation in CCA (p < 0.05). These results suggest that assessment of 1p36 status by FISH may serve as a complementary molecular approach to conventional histopathology and immunohistochemistry, providing additional differential diagnostic HCC from CCA and other diagnostically challenging HPB cancers and serve as promising prognostic biomarkers for CCA and IPNB.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"171 ","pages":"Article 106053"},"PeriodicalIF":2.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046501","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 : 2026-05-01Epub Date: 2026-02-06DOI: 10.1016/j.humpath.2026.106072
Huili Li , Andres Matoso
Bladder paraganglioma is an exceptionally rare neuroendocrine tumor with important diagnostic and prognostic implications. We retrospectively analyzed 110 bladder paragangliomas diagnosed between 2000 and 2025 to better characterize clinicopathologic features, immunophenotypic patterns, and clinical outcomes, with particular emphasis on S100, SOX10, and SDHB immunohistochemistry. The cohort showed a slight female predominance (F:M = 1.34) and a mean age at diagnosis of 62.7 years. Most tumors involved the muscularis propria, supporting a bladder wall origin. Among cases with available S100 staining, nearly half (48.5%) demonstrated diffuse, strong S100 expression in both chromaffin and sustentacular cells, an unusual pattern that frequently caused diagnostic confusion and was the reason for consultation. In contrast, SOX10 expression remained restricted to sustentacular cells in all tested tumors, underscoring its reliability as a Schwannian marker. Loss of SDHB expression was identified in 14.5% of tumors and was significantly associated with younger age, male sex, absence of diffuse S100 expression, and metastatic disease. All S100-positive tumors retained SDHB expression. Among patients with available follow-up, 20% developed metastatic disease, with a 5-year metastatic rate of 38.5%; most metastatic tumors showed SDHB loss and were S100-negative. No paraganglioma-related deaths were documented. These findings demonstrate that diffuse S100 positivity in bladder paraganglioma is relatively common and represents a significant diagnostic pitfall. Importantly, S100-positive tumors appear to be associated with intact SDHB expression and a potentially less aggressive phenotype, whereas SDHB loss identifies a higher-risk subset with increased metastatic potential.
{"title":"S100 expression and SDHB status define distinct biological subsets of bladder paraganglioma","authors":"Huili Li , Andres Matoso","doi":"10.1016/j.humpath.2026.106072","DOIUrl":"10.1016/j.humpath.2026.106072","url":null,"abstract":"<div><div>Bladder paraganglioma is an exceptionally rare neuroendocrine tumor with important diagnostic and prognostic implications. We retrospectively analyzed 110 bladder paragangliomas diagnosed between 2000 and 2025 to better characterize clinicopathologic features, immunophenotypic patterns, and clinical outcomes, with particular emphasis on S100, SOX10, and SDHB immunohistochemistry. The cohort showed a slight female predominance (F:M = 1.34) and a mean age at diagnosis of 62.7 years. Most tumors involved the muscularis propria, supporting a bladder wall origin. Among cases with available S100 staining, nearly half (48.5%) demonstrated diffuse, strong S100 expression in both chromaffin and sustentacular cells, an unusual pattern that frequently caused diagnostic confusion and was the reason for consultation. In contrast, SOX10 expression remained restricted to sustentacular cells in all tested tumors, underscoring its reliability as a Schwannian marker. Loss of SDHB expression was identified in 14.5% of tumors and was significantly associated with younger age, male sex, absence of diffuse S100 expression, and metastatic disease. All S100-positive tumors retained SDHB expression. Among patients with available follow-up, 20% developed metastatic disease, with a 5-year metastatic rate of 38.5%; most metastatic tumors showed SDHB loss and were S100-negative. No paraganglioma-related deaths were documented. These findings demonstrate that diffuse S100 positivity in bladder paraganglioma is relatively common and represents a significant diagnostic pitfall. Importantly, S100-positive tumors appear to be associated with intact SDHB expression and a potentially less aggressive phenotype, whereas SDHB loss identifies a higher-risk subset with increased metastatic potential.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"171 ","pages":"Article 106072"},"PeriodicalIF":2.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146142215","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 : 2026-05-01Epub Date: 2026-02-06DOI: 10.1016/j.humpath.2026.106071
Xenia Parisi , L. Jeffrey Medeiros
We report 31 cases of follicular lymphoma (FL) with signet ring (SR) cells, representing <0.05% of FLs diagnosed at our institution. The cohort includes 16 women and 15 men with a median age of 65 years (range, 26–87). All patients presented with lymphadenopathy. Twenty-three (74%) patients had advanced stage disease and 8 (26%) had localized (stage I or II) disease. Twenty-one (68%) patients underwent excisional biopsy, 8 core needle biopsy and 2 fine needle aspiration. All 29 neoplasms with biopsy specimens had a follicular pattern, at least in part, but 9 had diffuse areas. These neoplasms were grade 1-2 in 19 cases and grade 3A in 10 cases. In addition, 1 patient had FL grade 1-2 in the nasopharynx and FL grade 3A FL in a regional lymph node and 1 patient had FL grade 3A (25% of the specimen) associated with diffuse large B-cell lymphoma. We semi-quantified the percentage of SR cells as follows: 5-10% in 3 cases, 11-25% in 8, 26-50% in 9, 51-75% in 10 and > 75% in 1 neoplasm. Immunophenotypic analysis using immunohistochemistry was performed in all cases and flow cytometry immunophenotypic analysis was performed in 24 cases. All neoplasms were positive for pan-B-cell markers and lacked T-cell antigens. CD10 was positive in 28 of 30 (93%) cases, and BCL2 and BCL6 were positive in all 20 and 18 cases assessed, respectively. IGH::BCL2 was detected in all 10 cases tested by fluorescence in situ hybridization. Targeted next-generation sequencing analysis performed successfully on 4 cases identified recurrent mutations in genes often involved in FL, such as KMT2D and TNFRSF14. In conclusion, in this retrospective study we provide the largest case series of FL-SR. We show that SR cells can be numerous in FL, but otherwise these cases resemble classic FL. We also provide results of next generation sequencing data on 4 cases which heretofore has not been reported.
{"title":"Follicular lymphoma with signet ring cell morphology: Clinicopathologic analysis of 31 cases","authors":"Xenia Parisi , L. Jeffrey Medeiros","doi":"10.1016/j.humpath.2026.106071","DOIUrl":"10.1016/j.humpath.2026.106071","url":null,"abstract":"<div><div>We report 31 cases of follicular lymphoma (FL) with signet ring (SR) cells, representing <0.05% of FLs diagnosed at our institution. The cohort includes 16 women and 15 men with a median age of 65 years (range, 26–87). All patients presented with lymphadenopathy. Twenty-three (74%) patients had advanced stage disease and 8 (26%) had localized (stage I or II) disease. Twenty-one (68%) patients underwent excisional biopsy, 8 core needle biopsy and 2 fine needle aspiration. All 29 neoplasms with biopsy specimens had a follicular pattern, at least in part, but 9 had diffuse areas. These neoplasms were grade 1-2 in 19 cases and grade 3A in 10 cases. In addition, 1 patient had FL grade 1-2 in the nasopharynx and FL grade 3A FL in a regional lymph node and 1 patient had FL grade 3A (25% of the specimen) associated with diffuse large B-cell lymphoma. We semi-quantified the percentage of SR cells as follows: 5-10% in 3 cases, 11-25% in 8, 26-50% in 9, 51-75% in 10 and > 75% in 1 neoplasm. Immunophenotypic analysis using immunohistochemistry was performed in all cases and flow cytometry immunophenotypic analysis was performed in 24 cases. All neoplasms were positive for pan-B-cell markers and lacked T-cell antigens. CD10 was positive in 28 of 30 (93%) cases, and BCL2 and BCL6 were positive in all 20 and 18 cases assessed, respectively. <em>IGH::BCL2</em> was detected in all 10 cases tested by fluorescence in situ hybridization. Targeted next-generation sequencing analysis performed successfully on 4 cases identified recurrent mutations in genes often involved in FL, such as <em>KMT2D</em> and <em>TNFRSF14.</em> In conclusion, in this retrospective study we provide the largest case series of FL-SR. We show that SR cells can be numerous in FL, but otherwise these cases resemble classic FL. We also provide results of next generation sequencing data on 4 cases which heretofore has not been reported.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"171 ","pages":"Article 106071"},"PeriodicalIF":2.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146142211","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 : 2026-05-01Epub Date: 2026-01-23DOI: 10.1016/j.humpath.2026.106057
Guilin Tang , Sa A. Wang , Wei Ying Jen , L. Jeffrey Medeiros , Wei Wang , Hong Fang , Shimin Hu , Nitin Jain , Elias Joseph Jabbour , Ying S. Zou , Jie Xu
Rearrangements involving BCL11B have emerged as important structural variants in acute leukemias with T lineage differentiation, yet their prevalence and biological significance remain incompletely defined. Using optical genome mapping (OGM), we identified BCL11B rearrangements in 25 of 2325 hematologic malignancies, restricted to T-lymphoblastic leukemia particularly early T precursor (ETP) subtype, mixed phenotype acute leukemia T/myeloid, and rare acute myeloid leukemia. Breakpoints at 14q32.2 were highly variable and largely cryptic by karyotyping. Twelve putative partner genes were detected, including four previously reported (TLX3, ARID1B, CDK6, and CCDC26) and 8 novel partners (FOXF1, TLX1, NUP98, LMO2, GAPDHP71, GRM4, TNFAIP3, and TRRAP). Evaluation of BCL11B expression showed that rearrangements involving partners currently considered “BCL11B-activated”, such as ARID1B, CCDC26, and CDK6, did not uniformly associate with BCL11B overexpression. Conversely, cases with TLX3::BCL11B, previously thought to upregulate TLX3, demonstrated strong BCL11B expression (3 of 4 cases). Clinically, newly diagnosed patients, most treated with venetoclax based regimens, achieved high remission rates. Our data delineate the structural diversity of BCL11B rearrangements identified by OGM and show that BCL11B activation cannot be reliably inferred from partner gene identity alone. BCL11B immunohistochemistry as a practical surrogate for assessing BCL11B activation is recommended in routine practice.
{"title":"Acute leukemia with BCL11B rearrangements: Genetic landscape, BCL11B expression, and therapeutic response","authors":"Guilin Tang , Sa A. Wang , Wei Ying Jen , L. Jeffrey Medeiros , Wei Wang , Hong Fang , Shimin Hu , Nitin Jain , Elias Joseph Jabbour , Ying S. Zou , Jie Xu","doi":"10.1016/j.humpath.2026.106057","DOIUrl":"10.1016/j.humpath.2026.106057","url":null,"abstract":"<div><div>Rearrangements involving <em>BCL11B</em> have emerged as important structural variants in acute leukemias with T lineage differentiation, yet their prevalence and biological significance remain incompletely defined. Using optical genome mapping (OGM), we identified <em>BCL11B</em> rearrangements in 25 of 2325 hematologic malignancies, restricted to T-lymphoblastic leukemia particularly early T precursor (ETP) subtype, mixed phenotype acute leukemia T/myeloid, and rare acute myeloid leukemia. Breakpoints at 14q32.2 were highly variable and largely cryptic by karyotyping. Twelve putative partner genes were detected, including four previously reported (<em>TLX3, ARID1B, CDK6, and CCDC26</em>) and 8 novel partners (<em>FOXF1, TLX1, NUP98, LMO2, GAPDHP71, GRM4, TNFAIP3</em>, and <em>TRRAP)</em>. Evaluation of BCL11B expression showed that rearrangements involving partners currently considered “<em>BCL11B</em>-activated”, such as <em>ARID1B</em>, <em>CCDC26</em>, and <em>CDK6</em>, did not uniformly associate with <em>BCL11B</em> overexpression. Conversely, cases with <em>TLX3::BCL11B</em>, previously thought to upregulate <em>TLX3</em>, demonstrated strong <em>BCL11B</em> expression (3 of 4 cases). Clinically, newly diagnosed patients, most treated with venetoclax based regimens, achieved high remission rates. Our data delineate the structural diversity of <em>BCL11B</em> rearrangements identified by OGM and show that <em>BCL11B</em> activation cannot be reliably inferred from partner gene identity alone. BCL11B immunohistochemistry as a practical surrogate for assessing <em>BCL11B</em> activation is recommended in routine practice.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"171 ","pages":"Article 106057"},"PeriodicalIF":2.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046439","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 : 2026-05-01Epub Date: 2026-01-22DOI: 10.1016/j.humpath.2026.106054
Julia Gallardo, Emrah Gumusgoz , James M. Mitchell, Suntrea Hammer, Zhikai Chi, Purva Gopal, Dipti M. Karamchandani
Existing data characterize “classic" Epstein-Barr virus (EBV) positive gastric carcinoma (GC) histologically as GC with lymphoid stroma (or lymphoepithelioma-like or medullary) exhibiting sheets or syncytia of malignant cells with prominent intratumoral lymphocytes. This diagnosis has clinical implications, given the associated frequent programmed death-ligand 1 gene amplification, and clear benefit from immunotherapy. However, there appears to be a paucity of published data regarding characteristic histologic features of EBV-GC. We evaluated 19 EBV-GC specimens (11 biopsies; 8 resections) retrieved from 13 patients and found that a unique reticular pattern was identified in 17 of 19 (89 %) specimens, either as an exclusive pattern in 26 %, or as a mixed pattern in 63 % specimens. Most patients were male (85 %), with an average age of 61.5 years, mostly of Hispanic or Black (77 %) ethnicity, and showed a predilection for proximal stomach (69 %). Associated prominent intratumoral inflammation was seen in cases retrieved from all patients (lymphocytic: 7, mixed: 6). Although a similar lace-like pattern has been implicitly cited in association with early stage EBV-GC, we report a unique reticular pattern with intratumoral inflammation that was seen more commonly than widely known “classic” histology and was even seen in association with advanced pathologic stage. We propose that ancillary EBV testing be performed on all gastric tumors with this distinctive pattern, and with other patterns with prominent (including mixed) intratumoral inflammation, to screen for EBV-GC cases, thus detecting patients who may be eligible for immunotherapy with important therapeutic implications.
{"title":"Epstein-Barr virus associated gastric carcinoma: A clinicopathologic study with recognition of a distinctive reticular histologic pattern","authors":"Julia Gallardo, Emrah Gumusgoz , James M. Mitchell, Suntrea Hammer, Zhikai Chi, Purva Gopal, Dipti M. Karamchandani","doi":"10.1016/j.humpath.2026.106054","DOIUrl":"10.1016/j.humpath.2026.106054","url":null,"abstract":"<div><div>Existing data characterize “classic\" Epstein-Barr virus (EBV) positive gastric carcinoma (GC) histologically as GC with lymphoid stroma (or lymphoepithelioma-like or medullary) exhibiting sheets or syncytia of malignant cells with prominent intratumoral lymphocytes. This diagnosis has clinical implications, given the associated frequent programmed death-ligand 1 gene amplification, and clear benefit from immunotherapy. However, there appears to be a paucity of published data regarding characteristic histologic features of EBV-GC. We evaluated 19 EBV-GC specimens (11 biopsies; 8 resections) retrieved from 13 patients and found that a unique reticular pattern was identified in 17 of 19 (89 %) specimens, either as an exclusive pattern in 26 %, or as a mixed pattern in 63 % specimens. Most patients were male (85 %), with an average age of 61.5 years, mostly of Hispanic or Black (77 %) ethnicity, and showed a predilection for proximal stomach (69 %). Associated prominent intratumoral inflammation was seen in cases retrieved from all patients (lymphocytic: 7, mixed: 6). Although a similar lace-like pattern has been implicitly cited in association with early stage EBV-GC, we report a unique reticular pattern with intratumoral inflammation that was seen more commonly than widely known “classic” histology and was even seen in association with advanced pathologic stage. We propose that ancillary EBV testing be performed on all gastric tumors with this distinctive pattern, and with other patterns with prominent (including mixed) intratumoral inflammation, to screen for EBV-GC cases, thus detecting patients who may be eligible for immunotherapy with important therapeutic implications.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"171 ","pages":"Article 106054"},"PeriodicalIF":2.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044004","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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