Pub Date : 2026-03-01Epub Date: 2026-01-09DOI: 10.1016/j.modpat.2026.100959
Jennifer X. Ji , Amr El Maghrabi , Hezhen Carl Ren , Lawrence H. Lee , Sean Young , Stephen T. Yip , Jinesa Moodley , Chi Lai , Hemlata Shirsat , Elan Hahn , Lien N. Hoang , Johanna Mabray , Paras Patel , Gang Wang , Catherine F. Poh , Tony L. Ng , Yen Chen Kevin Ko
The diagnosis of oral epithelial dysplasia has a high degree of inter- and intraobserver variability. It is especially challenging to distinguish dysplasia from reactive squamous mucosa in the context of concurrent candidiasis. The accurate and timely diagnosis of dysplasia is imperative for patient outcomes, as progression to invasive squamous cell carcinoma will result in significant morbidity and mortality. The current management for patients with candidiasis is to treat with antifungals and rebiopsy if refractory. The treatment may be trialed for a few months, thus delaying appropriate treatment if underlying dysplasia is not identified. In this study, we collected cases of oral candidiasis with atypia and characterized them into molecularly defined groups using targeted next-generation sequencing, fluorescence in situ hybridization, and p53, p16, and MTAP immunohistochemistry. We identify a distinct molecular signature using immunohistochemical markers to capture oral dysplasia with concurrent candidiasis. We also postulate that p53 wild-type, p16 abnormal oral epithelial dysplasia cases are precursor lesions to p53 wild-type, p16 abnormal squamous cell carcinoma. In addition, we identify p53 wild-type, p16 wild-type oral epithelial dysplasia with verruciform and acanthotic features with HRAS or PIK3CA alterations as precursors to verrucous carcinoma. The proposed pattern-based p16 and p53 algorithm in our study will not only more accurately diagnose dysplasia in the context of oral candidiasis but may also provide prognostically significant information to guide clinical management of oral dysplastic lesions.
{"title":"Utility of p53, p16, and MTAP Immunohistochemistry in Oral Epithelial Dysplasia With Concurrent Candidiasis: A Novel Pattern-based Approach","authors":"Jennifer X. Ji , Amr El Maghrabi , Hezhen Carl Ren , Lawrence H. Lee , Sean Young , Stephen T. Yip , Jinesa Moodley , Chi Lai , Hemlata Shirsat , Elan Hahn , Lien N. Hoang , Johanna Mabray , Paras Patel , Gang Wang , Catherine F. Poh , Tony L. Ng , Yen Chen Kevin Ko","doi":"10.1016/j.modpat.2026.100959","DOIUrl":"10.1016/j.modpat.2026.100959","url":null,"abstract":"<div><div>The diagnosis of oral epithelial dysplasia has a high degree of inter- and intraobserver variability. It is especially challenging to distinguish dysplasia from reactive squamous mucosa in the context of concurrent candidiasis. The accurate and timely diagnosis of dysplasia is imperative for patient outcomes, as progression to invasive squamous cell carcinoma will result in significant morbidity and mortality. The current management for patients with candidiasis is to treat with antifungals and rebiopsy if refractory. The treatment may be trialed for a few months, thus delaying appropriate treatment if underlying dysplasia is not identified. In this study, we collected cases of oral candidiasis with atypia and characterized them into molecularly defined groups using targeted next-generation sequencing, fluorescence in situ hybridization, and p53, p16, and MTAP immunohistochemistry. We identify a distinct molecular signature using immunohistochemical markers to capture oral dysplasia with concurrent candidiasis. We also postulate that p53 wild-type, p16 abnormal oral epithelial dysplasia cases are precursor lesions to p53 wild-type, p16 abnormal squamous cell carcinoma. In addition, we identify p53 wild-type, p16 wild-type oral epithelial dysplasia with verruciform and acanthotic features with <em>HRAS</em> or <em>PIK3CA</em> alterations as precursors to verrucous carcinoma. The proposed pattern-based p16 and p53 algorithm in our study will not only more accurately diagnose dysplasia in the context of oral candidiasis but may also provide prognostically significant information to guide clinical management of oral dysplastic lesions.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 3","pages":"Article 100959"},"PeriodicalIF":5.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952776","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 : 2026-02-26DOI: 10.1016/j.modpat.2026.100981
Jessica L Davis, Azadeh Samiei
With the rapid advancement of molecular pathology and the explosion of genomic data, our understanding of neoplasms continues to evolve. In this review, we introduce 3 recently classified mesenchymal neoplasms, the categorization of which was refined based on their underlying molecular genetic profiles. These entities were recently highlighted by the senior author at the United States and Canadian Academy of Pathology Long Course. To underscore the importance of their proper recognition, this review was prepared to reach a broader audience. Recognition of these tumors is particularly important because their mimickers often have markedly disparate prognoses and management strategies, making accurate diagnosis critical. The 3 entities discussed in this study are the following: (1) SRF-rearranged myoid neoplasms (formerly cellular myofibroma), (2) superficial CD34-positive fibroblastic tumors, and (3) kinase-altered spindle cell neoplasms. This review aimed to highlight the key clinicopathologic features of these tumors to facilitate accurate diagnosis, discuss ancillary studies that assist in navigating the differential diagnoses, and outline strategies to avoid common diagnostic pitfalls. Finally, we emphasize when molecular characterization may be necessary to guide diagnosis and support appropriate clinical management.
{"title":"Emerging Molecularly Defined Bone and Soft Tissue Diagnoses: When Do They Matter?","authors":"Jessica L Davis, Azadeh Samiei","doi":"10.1016/j.modpat.2026.100981","DOIUrl":"10.1016/j.modpat.2026.100981","url":null,"abstract":"<p><p>With the rapid advancement of molecular pathology and the explosion of genomic data, our understanding of neoplasms continues to evolve. In this review, we introduce 3 recently classified mesenchymal neoplasms, the categorization of which was refined based on their underlying molecular genetic profiles. These entities were recently highlighted by the senior author at the United States and Canadian Academy of Pathology Long Course. To underscore the importance of their proper recognition, this review was prepared to reach a broader audience. Recognition of these tumors is particularly important because their mimickers often have markedly disparate prognoses and management strategies, making accurate diagnosis critical. The 3 entities discussed in this study are the following: (1) SRF-rearranged myoid neoplasms (formerly cellular myofibroma), (2) superficial CD34-positive fibroblastic tumors, and (3) kinase-altered spindle cell neoplasms. This review aimed to highlight the key clinicopathologic features of these tumors to facilitate accurate diagnosis, discuss ancillary studies that assist in navigating the differential diagnoses, and outline strategies to avoid common diagnostic pitfalls. Finally, we emphasize when molecular characterization may be necessary to guide diagnosis and support appropriate clinical management.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100981"},"PeriodicalIF":5.5,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147317554","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 : 2026-02-24DOI: 10.1016/j.modpat.2026.100979
Shuji Momose, Keisuke Sawada, Theodora Nedeva, Wataru Yamamoto, Takahisa Yamashita, Hiroki Imada, Natsuko Takayanagi, Ken Naganuma, Yasuyuki Takahashi, Takayuki Tabayashi, Akiko Adachi, Morihiro Higashi, David W Scott, Andreas Rosenwald, Hilka Rauert-Wunderlich
Diffuse large B-cell lymphoma/High-grade B-cell lymphoma with MYC and BCL2 rearrangement (DLBCL/HGBCL-MYC/BCL2) is a distinct disease entity with worse prognosis and is usually diagnosed with identification of MYC and BCL2 rearrangement by fluorescence in situ hybridization (FISH) analysis. Recent progress in gene expression analysis has identified a dark zone signature (DZsig), which characterizes a gene expression profile (GEP) for DLBCL/HGBCL-MYC/BCL2. Notably, DZsig includes both MYC/BCL2-double-hit and non-double-hit cases with DLBCL, and high-grade and Burkitt morphologies; importantly, the latter group is present in numbers that are comparable to or greater than the former group. Although GEP analysis can identify cases exhibiting HGBCL-like biology regardless of double-hit status, GEP analysis will not be globally applied to DLBCL cases due to cost and equipment constraints. Therefore, simpler surrogate approaches for detecting DZsig, such as immunohistochemistry (IHC), are desired. Here, we attempted to develop an immunohistochemical approach that can serve as an alternative to GEP or FISH assays utilizing 287 tumors with DLBCL morphology, regardless of double-hit status. Our strategy for detecting DZsig by IHC is based on a two-step algorithm, which involves applying the Hans classifier and antibodies to MYC, ALOX5, and LMO2. The DZ-IHC algorithm had a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 76.2%, 95.5%, 59.3%, and 98.1%, respectively. The 5-year overall survival (OS) rates for immunohistochemical DZ (iDZ)-positive, iDZ-negative subtypes in GCB-type and non-GCB-type tumors were 55%, 82%, and 69%, respectively (p < 0.01), which is similar to that reported using the GEP assay. To date, this represents the largest cohort evaluated for DZsig selection by IHC; nevertheless, the algorithm is not yet adequate for routine application owing to its suboptimal PPV and further improvements are needed for clinical implementation.
{"title":"The Complexity and Challenges of Translating the Dark Zone Signature into Immunohistochemistry in Diffuse Large B-Cell Lymphoma.","authors":"Shuji Momose, Keisuke Sawada, Theodora Nedeva, Wataru Yamamoto, Takahisa Yamashita, Hiroki Imada, Natsuko Takayanagi, Ken Naganuma, Yasuyuki Takahashi, Takayuki Tabayashi, Akiko Adachi, Morihiro Higashi, David W Scott, Andreas Rosenwald, Hilka Rauert-Wunderlich","doi":"10.1016/j.modpat.2026.100979","DOIUrl":"https://doi.org/10.1016/j.modpat.2026.100979","url":null,"abstract":"<p><p>Diffuse large B-cell lymphoma/High-grade B-cell lymphoma with MYC and BCL2 rearrangement (DLBCL/HGBCL-MYC/BCL2) is a distinct disease entity with worse prognosis and is usually diagnosed with identification of MYC and BCL2 rearrangement by fluorescence in situ hybridization (FISH) analysis. Recent progress in gene expression analysis has identified a dark zone signature (DZsig), which characterizes a gene expression profile (GEP) for DLBCL/HGBCL-MYC/BCL2. Notably, DZsig includes both MYC/BCL2-double-hit and non-double-hit cases with DLBCL, and high-grade and Burkitt morphologies; importantly, the latter group is present in numbers that are comparable to or greater than the former group. Although GEP analysis can identify cases exhibiting HGBCL-like biology regardless of double-hit status, GEP analysis will not be globally applied to DLBCL cases due to cost and equipment constraints. Therefore, simpler surrogate approaches for detecting DZsig, such as immunohistochemistry (IHC), are desired. Here, we attempted to develop an immunohistochemical approach that can serve as an alternative to GEP or FISH assays utilizing 287 tumors with DLBCL morphology, regardless of double-hit status. Our strategy for detecting DZsig by IHC is based on a two-step algorithm, which involves applying the Hans classifier and antibodies to MYC, ALOX5, and LMO2. The DZ-IHC algorithm had a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 76.2%, 95.5%, 59.3%, and 98.1%, respectively. The 5-year overall survival (OS) rates for immunohistochemical DZ (iDZ)-positive, iDZ-negative subtypes in GCB-type and non-GCB-type tumors were 55%, 82%, and 69%, respectively (p < 0.01), which is similar to that reported using the GEP assay. To date, this represents the largest cohort evaluated for DZsig selection by IHC; nevertheless, the algorithm is not yet adequate for routine application owing to its suboptimal PPV and further improvements are needed for clinical implementation.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100979"},"PeriodicalIF":5.5,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147308002","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 : 2026-02-17DOI: 10.1016/j.modpat.2026.100978
Emma Siili, Mikko Loukovaara, Ralf Bützow, Annukka Pasanen
Endometrial carcinoma with no specific molecular profile (NSMP) is a clinicopathologically heterogeneous group of diseases with an overall intermediate prognosis. Prognostic refinement is needed for better personalized treatment. The updated European Society of Gynecological Oncology-European Society for Radiotherapy and Oncology-European Society of Pathology guidelines for endometrial carcinoma stratify NSMP according to histotype and estrogen receptor (ER) status. ER (with other ancillary markers) also helps differentiate histotypes of endometrial carcinoma. This study describes clinicopathological characteristics of ER-positive and -negative-NSMP endometrial carcinoma. Furthermore, we investigate the prognostic and diagnostic significance of ER, GATA3, TTF1, and KRAS in a large and relatively unselected NSMP carcinoma cohort. POLE sequencing results and immunohistochemistry for p53, mismatch repair proteins, and ER were available for 930 samples of endometrial carcinoma. Within NSMP cases (n = 377), 22 samples presented ER staining in <1% of the carcinoma cells, 5 cases in 1% to 9%, and 350 cases in ≥10%. ER expression ≥10% predicted an excellent outcome (comparable with POLE-mutated cases) in univariable analysis, where ER negativity (<10%) was associated with a poor outcome (comparable with p53 abnormal cases). Most ER-positive NSMP cases were low-grade endometrioid carcinomas, whereas most ER-negative NSMP cases were nonendometrioid or high-grade endometrioid carcinomas. In addition to high-risk histotype, ER negativity was associated with various other clinicopathological risk factors. In multivariable analysis adjusting for histotype and other risk factors, ER did not independently predict disease progression (P = .814). No disease-related deaths were observed in the rare (n = 3) patients with ER-negative-low-grade endometrioid carcinoma. GATA3/TTF1 positivity and KRAS mutation were discovered not only in mesonephric-like carcinoma but also in endometrioid carcinoma. No prognostic relevance was found for these markers. In conclusion, the different prognosis of ER-positive vs ER-negative-NSMP endometrial carcinoma is not attributable to ER status itself but rather to its strong correlation with histotype and other clinicopathological risk factors. Limited specificity of GATA3, TTF1, and KRAS warrants caution in their use as diagnostic markers of mesonephric-like carcinoma.
{"title":"Estrogen Receptor, GATA-3, TTF-1, and KRAS in Endometrial Carcinoma of No Specific Molecular Profile: Prognostic or Diagnostic Markers?","authors":"Emma Siili, Mikko Loukovaara, Ralf Bützow, Annukka Pasanen","doi":"10.1016/j.modpat.2026.100978","DOIUrl":"10.1016/j.modpat.2026.100978","url":null,"abstract":"<p><p>Endometrial carcinoma with no specific molecular profile (NSMP) is a clinicopathologically heterogeneous group of diseases with an overall intermediate prognosis. Prognostic refinement is needed for better personalized treatment. The updated European Society of Gynecological Oncology-European Society for Radiotherapy and Oncology-European Society of Pathology guidelines for endometrial carcinoma stratify NSMP according to histotype and estrogen receptor (ER) status. ER (with other ancillary markers) also helps differentiate histotypes of endometrial carcinoma. This study describes clinicopathological characteristics of ER-positive and -negative-NSMP endometrial carcinoma. Furthermore, we investigate the prognostic and diagnostic significance of ER, GATA3, TTF1, and KRAS in a large and relatively unselected NSMP carcinoma cohort. POLE sequencing results and immunohistochemistry for p53, mismatch repair proteins, and ER were available for 930 samples of endometrial carcinoma. Within NSMP cases (n = 377), 22 samples presented ER staining in <1% of the carcinoma cells, 5 cases in 1% to 9%, and 350 cases in ≥10%. ER expression ≥10% predicted an excellent outcome (comparable with POLE-mutated cases) in univariable analysis, where ER negativity (<10%) was associated with a poor outcome (comparable with p53 abnormal cases). Most ER-positive NSMP cases were low-grade endometrioid carcinomas, whereas most ER-negative NSMP cases were nonendometrioid or high-grade endometrioid carcinomas. In addition to high-risk histotype, ER negativity was associated with various other clinicopathological risk factors. In multivariable analysis adjusting for histotype and other risk factors, ER did not independently predict disease progression (P = .814). No disease-related deaths were observed in the rare (n = 3) patients with ER-negative-low-grade endometrioid carcinoma. GATA3/TTF1 positivity and KRAS mutation were discovered not only in mesonephric-like carcinoma but also in endometrioid carcinoma. No prognostic relevance was found for these markers. In conclusion, the different prognosis of ER-positive vs ER-negative-NSMP endometrial carcinoma is not attributable to ER status itself but rather to its strong correlation with histotype and other clinicopathological risk factors. Limited specificity of GATA3, TTF1, and KRAS warrants caution in their use as diagnostic markers of mesonephric-like carcinoma.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100978"},"PeriodicalIF":5.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146227532","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 : 2026-02-01Epub Date: 2025-12-30DOI: 10.1016/j.modpat.2025.100956
Zofia Hélias-Rodzewicz , Irena Antonia Ungureanu , Paul Geraeds Kemps , Jean Donadieu , Sébastien Héritier , Mohamed-Aziz Barkaoui , Nathalie Terrones , Rim Ben Jannet , Mariama Bakari , Thamila Satour , Maxime Battistella , Philippe Drabent , Pierre Sohier , Pierre Reimbold , Marie-Laure Jullié , Ahmed Idbaih , Fleur Cohen-Aubart , Abdellatif Tazi , Frédéric Charlotte , Sylvie Fraitag , Jean-François Emile
Anaplastic lymphoma kinase (ALK)–positive histiocytosis is a rare histiocytic neoplasm defined by oncogenic ALK fusions. The disease frequently involves the nervous system and is responsive to ALK inhibition. A distinct subset of histiocytoses expresses ALK in the absence of detectable ALK fusions. We aimed to determine the frequency and molecular characteristics of these ALK protein–positive, fusion–negative neoplasms. RNA was extracted from histiocytosis-affected tissue samples of 398 patients with diverse histiocytoses, converted to cDNA, and subjected to targeted sequencing using a custom gene panel. ALK fusions and gene expression levels were assessed; the presence of ALK isoforms was investigated using targeted digital PCR. In a subset of cases, ALK protein expression was evaluated using immunohistochemistry (clone 1A4). Of 398 cases, 303 (76%) passed quality control and were included in the analysis. Among these, 64 (21.5%) had substantial ALK gene expression, while not harboring ALK fusions. Immunohistochemistry revealed consistent nuclear and cytoplasmic ALK expression in these cases, whereas ALK expression in fusion-positive cases was restricted to the cytoplasm. Analysis of ALK intron 19 expression by targeted PCR revealed the presence of a novel ALK isoform (ALKATI), which was linked to nuclear ALK expression. No specific clinical or molecular features distinguished histiocytic neoplasms with ALKATI from those without. In conclusion, many histiocytic neoplasms express ALK but are not ALK-positive histiocytosis. Most cases can be identified by nuclear ALK expression, which is linked to alternative transcription initiation—a known mechanism of ALK activation independent of genetic aberrations. Future studies should elucidate whether these neoplasms respond to ALK inhibition.
{"title":"ALKATI Drives Nuclear Anaplastic Lymphoma Kinase (ALK) Expression in Histiocytic Neoplasms Without ALK Fusions","authors":"Zofia Hélias-Rodzewicz , Irena Antonia Ungureanu , Paul Geraeds Kemps , Jean Donadieu , Sébastien Héritier , Mohamed-Aziz Barkaoui , Nathalie Terrones , Rim Ben Jannet , Mariama Bakari , Thamila Satour , Maxime Battistella , Philippe Drabent , Pierre Sohier , Pierre Reimbold , Marie-Laure Jullié , Ahmed Idbaih , Fleur Cohen-Aubart , Abdellatif Tazi , Frédéric Charlotte , Sylvie Fraitag , Jean-François Emile","doi":"10.1016/j.modpat.2025.100956","DOIUrl":"10.1016/j.modpat.2025.100956","url":null,"abstract":"<div><div>Anaplastic lymphoma kinase (ALK)–positive histiocytosis is a rare histiocytic neoplasm defined by oncogenic <em>ALK</em> fusions. The disease frequently involves the nervous system and is responsive to ALK inhibition. A distinct subset of histiocytoses expresses ALK in the absence of detectable <em>ALK</em> fusions. We aimed to determine the frequency and molecular characteristics of these ALK protein–positive, fusion–negative neoplasms. RNA was extracted from histiocytosis-affected tissue samples of 398 patients with diverse histiocytoses, converted to cDNA, and subjected to targeted sequencing using a custom gene panel. <em>ALK</em> fusions and gene expression levels were assessed; the presence of <em>ALK</em> isoforms was investigated using targeted digital PCR. In a subset of cases, ALK protein expression was evaluated using immunohistochemistry (clone 1A4). Of 398 cases, 303 (76%) passed quality control and were included in the analysis. Among these, 64 (21.5%) had substantial <em>ALK</em> gene expression, while not harboring <em>ALK</em> fusions. Immunohistochemistry revealed consistent nuclear and cytoplasmic ALK expression in these cases, whereas ALK expression in fusion-positive cases was restricted to the cytoplasm. Analysis of <em>ALK</em> intron 19 expression by targeted PCR revealed the presence of a novel <em>ALK</em> isoform (<em>ALK</em><sup><em>ATI</em></sup>), which was linked to nuclear ALK expression. No specific clinical or molecular features distinguished histiocytic neoplasms with <em>ALK</em><sup><em>ATI</em></sup> from those without. In conclusion, many histiocytic neoplasms express ALK but are not ALK-positive histiocytosis. Most cases can be identified by nuclear ALK expression, which is linked to alternative transcription initiation—a known mechanism of ALK activation independent of genetic aberrations. Future studies should elucidate whether these neoplasms respond to ALK inhibition.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 2","pages":"Article 100956"},"PeriodicalIF":5.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889006","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 : 2026-02-01Epub Date: 2025-12-06DOI: 10.1016/j.modpat.2025.100946
Shruti Srikumar , Nick Evans , Melissa Yuwono Tjota , Mir Alikhan , Amandeep Kaur , Linda M. Sabatini , Nick Miller , Mike Bouma , Kruti P. Maniar , Megan Parilla
Endometrial carcinomas can be classified into 1 of 4 molecular subtypes, with the POLE-mutant subtype carrying the best prognosis. Pathogenic mutations in POLE are known to disrupt the proofreading function of DNA polymerase epsilon, resulting in an ultramutated genome, typically defined as ≥100 mutations per megabase. Routine next-generation sequencing was implemented on all endometrial carcinoma cases at our institution beginning in December 2023 to aid in molecular subclassification. During this routine sequencing, 6 POLE-mutated cases, with confirmed pathogenic POLE mutations, were observed to have a tumor mutational burden <100; prior to universal testing, only 1 such case had been identified. Endometrial carcinoma cases with pathogenic POLE mutations and tumor mutational burden <100 may be globally under-recognized, as universal testing is not yet a widely standard practice. These cases with pathogenic POLE mutations and a nonultramutated genome were found to have a lower frequency of classic morphologic “POLE features,” including high-grade histology, compared with classic ultramutated cases. The immunohistochemical profiles are also different from ultramutated counterparts, with a lower frequency of mismatch repair immunohistochemical abnormalities and p53 null or diffuse staining, and a higher likelihood of strong and diffuse estrogen receptor/progesterone receptor expression, aligning with fewer mutations in encoding genes. However, endometrial carcinoma with pathogenic POLE mutations, without ultramutation, appears to retain the “POLE-mutational signature” described in the literature. Additionally, clinical outcomes do not appear different; however, this phenomenon needs additional investigation.
{"title":"Pathogenic POLE-Mutated Endometrial Carcinomas With a Nonultramutated Genome","authors":"Shruti Srikumar , Nick Evans , Melissa Yuwono Tjota , Mir Alikhan , Amandeep Kaur , Linda M. Sabatini , Nick Miller , Mike Bouma , Kruti P. Maniar , Megan Parilla","doi":"10.1016/j.modpat.2025.100946","DOIUrl":"10.1016/j.modpat.2025.100946","url":null,"abstract":"<div><div>Endometrial carcinomas can be classified into 1 of 4 molecular subtypes, with the <em>POLE</em>-mutant subtype carrying the best prognosis. Pathogenic mutations in <em>POLE</em> are known to disrupt the proofreading function of DNA polymerase epsilon, resulting in an ultramutated genome, typically defined as ≥100 mutations per megabase. Routine next-generation sequencing was implemented on all endometrial carcinoma cases at our institution beginning in December 2023 to aid in molecular subclassification. During this routine sequencing, 6 <em>POLE-</em>mutated cases, with confirmed pathogenic <em>POLE</em> mutations, were observed to have a tumor mutational burden <100; prior to universal testing, only 1 such case had been identified. Endometrial carcinoma cases with pathogenic <em>POLE</em> mutations and tumor mutational burden <100 may be globally under-recognized, as universal testing is not yet a widely standard practice. These cases with pathogenic <em>POLE</em> mutations and a nonultramutated genome were found to have a lower frequency of classic morphologic “<em>POLE</em> features,” including high-grade histology, compared with classic ultramutated cases. The immunohistochemical profiles are also different from ultramutated counterparts, with a lower frequency of mismatch repair immunohistochemical abnormalities and p53 null or diffuse staining, and a higher likelihood of strong and diffuse estrogen receptor/progesterone receptor expression, aligning with fewer mutations in encoding genes. However, endometrial carcinoma with pathogenic <em>POLE</em> mutations, without ultramutation, appears to retain the “<em>POLE</em>-mutational signature” described in the literature. Additionally, clinical outcomes do not appear different; however, this phenomenon needs additional investigation.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 2","pages":"Article 100946"},"PeriodicalIF":5.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145701268","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 : 2026-02-01Epub Date: 2025-12-30DOI: 10.1016/j.modpat.2025.100955
Johann W. Schneider , Anthony B. Eason , Meredith Chambers , Huanjuan Su , Kyle Shifflett , Shuyan Guo , Micheline Sanderson , Cassandra Bruce-Brand , Henriette Burger , Dirk P. Dittmer
The lineage of the Kaposi sarcoma (KS) tumor cell remains elusive, limiting opportunities for targeted therapy. We performed concurrent spatial imaging of 5 bona fide lymphatic endothelial cell markers together with the KS herpesvirus viral protein latency-associated nuclear antigen (LANA) in 30 well-characterized HIV-positive KS biopsies (n = 1,740,744 cells). Nodular KS lesions showed significantly more circular nuclei than plaque KS, indicating distinct cellular morphologies. Both forms contained dense areas of LANA-positive cells—termed “LANA nests.” Among the endothelial cell markers, vascular endothelial growth factor receptor 3 was most abundantly expressed, although many vascular endothelial growth factor receptor 3–positive cells were LANA negative. Podoplanin and LYVE-1 consistently colocalized with each other, whereas CD31 and VE-Cadherin were variably expressed within and across lesions. Together, these observations reveal that KS lesions are composed of multiple microenvironments: LANA-dense nests, LANA-sparse fascicles, and mature lymphatic or blood vessels, some of which also harbored LANA-positive lining cells. At present, targeted therapies do not account for this variability; generally, responses are not based on pathology. Spatial changes in the tumor microenvironment that may provide insights into drug action and resistance mechanisms are missed.
{"title":"Spatial Profiling Shows That Lymphatic Endothelial Cells Form the Core of Kaposi Sarcoma (KS)","authors":"Johann W. Schneider , Anthony B. Eason , Meredith Chambers , Huanjuan Su , Kyle Shifflett , Shuyan Guo , Micheline Sanderson , Cassandra Bruce-Brand , Henriette Burger , Dirk P. Dittmer","doi":"10.1016/j.modpat.2025.100955","DOIUrl":"10.1016/j.modpat.2025.100955","url":null,"abstract":"<div><div>The lineage of the Kaposi sarcoma (KS) tumor cell remains elusive, limiting opportunities for targeted therapy. We performed concurrent spatial imaging of 5 bona fide lymphatic endothelial cell markers together with the KS herpesvirus viral protein latency-associated nuclear antigen (LANA) in 30 well-characterized HIV-positive KS biopsies (n = 1,740,744 cells). Nodular KS lesions showed significantly more circular nuclei than plaque KS, indicating distinct cellular morphologies. Both forms contained dense areas of LANA-positive cells—termed “LANA nests.” Among the endothelial cell markers, vascular endothelial growth factor receptor 3 was most abundantly expressed, although many vascular endothelial growth factor receptor 3–positive cells were LANA negative. Podoplanin and LYVE-1 consistently colocalized with each other, whereas CD31 and VE-Cadherin were variably expressed within and across lesions. Together, these observations reveal that KS lesions are composed of multiple microenvironments: LANA-dense nests, LANA-sparse fascicles, and mature lymphatic or blood vessels, some of which also harbored LANA-positive lining cells. At present, targeted therapies do not account for this variability; generally, responses are not based on pathology. Spatial changes in the tumor microenvironment that may provide insights into drug action and resistance mechanisms are missed.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 2","pages":"Article 100955"},"PeriodicalIF":5.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889389","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 : 2026-02-01Epub Date: 2026-01-09DOI: 10.1016/j.modpat.2025.100952
Daniel Rivera , Wei Cui , Juehua Gao , Deniz Peker , Qian-Yun Zhang , Rajan Dewar , Lianqun Qiu , Sergej Konoplev , Zhihong Hu , Koji Sasaki , Aileen Y. Hu , E. Shuyu , Meng Liu , Hong Fang , Wei Wang , Guilin Tang , Jane F. Apperley , Andreas Hochhaus , Jorge E. Cortes , Joseph D. Khoury , Shimin Hu
{"title":"Corrigendum to “Aleukemic Chronic Myeloid Leukemia Without Neutrophilia and Thrombocytosis: A Report From the BCR::ABL1 Pathology Group” [Modern Pathology. 2024;37(2):100406]","authors":"Daniel Rivera , Wei Cui , Juehua Gao , Deniz Peker , Qian-Yun Zhang , Rajan Dewar , Lianqun Qiu , Sergej Konoplev , Zhihong Hu , Koji Sasaki , Aileen Y. Hu , E. Shuyu , Meng Liu , Hong Fang , Wei Wang , Guilin Tang , Jane F. Apperley , Andreas Hochhaus , Jorge E. Cortes , Joseph D. Khoury , Shimin Hu","doi":"10.1016/j.modpat.2025.100952","DOIUrl":"10.1016/j.modpat.2025.100952","url":null,"abstract":"","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 2","pages":"Article 100952"},"PeriodicalIF":5.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941157","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}
Long-standing diabetes mellitus (long-DM) (≧3 years) is associated with worse clinical outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). Emerging evidence suggests that epigenetic alterations may contribute to this association; however, the underlying mechanisms remain largely unclear. This study aimed to elucidate the role of the tumor-suppressive long noncoding RNA maternally expressed gene 3 (MEG3) and related molecules in the development of PDAC with long-DM. A total of 117 patients who underwent surgical resection for PDAC at Hirosaki University Hospital were retrospectively analyzed. Histopathological assessment followed World Health Organization criteria and the Union for International Cancer Control tumor-node-metastasis classification. Promoter methylation of MEG3 was assessed via methylation-specific PCR using formalin-fixed paraffin-embedded tissue. MEG3 expression levels were assessed by real-time quantitative PCR. Additionally, proteomic profiling was performed using liquid chromatography-tandem mass spectrometry on formalin-fixed paraffin-embedded tissue samples. Among the 117 cases with PDAC, patients with long-DM exhibited significantly poorer tumor differentiation and reduced cancer-specific survival. MEG3 promoter methylation was more prevalent in patients with long-DM. MEG3 methylation was correlated with reduced MEG3 expression, increased venous invasion, higher recurrence rates, and worse prognosis. Proteomic analysis and protein structure prediction tool revealed F11 receptor (F11R) as a potential downstream effector of MEG3. F11R protein expression levels were evaluated using semiquantitative immunohistochemistry. Higher F11R expression was observed in patients with long-DM, correlating with poor histologic differentiation and unfavorable outcomes. Patients with PDAC showing simultaneous MEG3 methylation and F11R high expression were more likely to have long-DM, with additive effects of these changes and tumor recurrence. Our results demonstrated that MEG3 and its potential downstream regulator, F11R, could be involved in PDAC progression, particularly in patients with long-DM. The findings underscore the clinical significance of epigenetic regulation in DM-related PDAC, suggesting novel targets, such as MEG3 and F11R, for potential therapeutic intervention.
{"title":"MEG3 Promoter Methylation and F11 Receptor (F11R) Overexpression Define a High-Risk Subtype of Diabetic Pancreatic Cancer","authors":"Keisuke Yamazaki , Hiroki Mizukami , Takahiro Yamada , Yutaro Hara , Hiroaki Tamba , Yota Tatara , Zhenchao Wang , Akiko Itaya , Hanae Kushibiki , Masaki Ryuzaki , Takanori Sasaki , Hidefumi Ruike , Saori Ogasawara , Yi Tu , Keinosuke Ishido , Ken Itoh , Kenichi Hakamada","doi":"10.1016/j.modpat.2025.100953","DOIUrl":"10.1016/j.modpat.2025.100953","url":null,"abstract":"<div><div>Long-standing diabetes mellitus (long-DM) (≧3 years) is associated with worse clinical outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). Emerging evidence suggests that epigenetic alterations may contribute to this association; however, the underlying mechanisms remain largely unclear. This study aimed to elucidate the role of the tumor-suppressive long noncoding RNA maternally expressed gene 3 (<em>MEG3</em>) and related molecules in the development of PDAC with long-DM. A total of 117 patients who underwent surgical resection for PDAC at Hirosaki University Hospital were retrospectively analyzed. Histopathological assessment followed World Health Organization criteria and the Union for International Cancer Control tumor-node-metastasis classification. Promoter methylation of <em>MEG3</em> was assessed via methylation-specific PCR using formalin-fixed paraffin-embedded tissue. <em>MEG3</em> expression levels were assessed by real-time quantitative PCR. Additionally, proteomic profiling was performed using liquid chromatography-tandem mass spectrometry on formalin-fixed paraffin-embedded tissue samples. Among the 117 cases with PDAC, patients with long-DM exhibited significantly poorer tumor differentiation and reduced cancer-specific survival. <em>MEG3</em> promoter methylation was more prevalent in patients with long-DM. <em>MEG3</em> methylation was correlated with reduced <em>MEG3</em> expression, increased venous invasion, higher recurrence rates, and worse prognosis. Proteomic analysis and protein structure prediction tool revealed F11 receptor (F11R) as a potential downstream effector of <em>MEG3</em>. F11R protein expression levels were evaluated using semiquantitative immunohistochemistry. Higher F11R expression was observed in patients with long-DM, correlating with poor histologic differentiation and unfavorable outcomes. Patients with PDAC showing simultaneous <em>MEG3</em> methylation and F11R high expression were more likely to have long-DM, with additive effects of these changes and tumor recurrence. Our results demonstrated that <em>MEG3</em> and its potential downstream regulator, F11R, could be involved in PDAC progression, particularly in patients with long-DM. The findings underscore the clinical significance of epigenetic regulation in DM-related PDAC, suggesting novel targets, such as <em>MEG3</em> and F11R, for potential therapeutic intervention.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 2","pages":"Article 100953"},"PeriodicalIF":5.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781564","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 : 2026-02-01Epub Date: 2025-12-26DOI: 10.1016/j.modpat.2025.100954
Wen Shuai , Zhihong Hu , C. Cameron Yin , Lei Chen , Wei Wang , Guilin Tang , Dawen Sui , Shaoying Li , Jie Xu , Nourhan Ibrahim , Zenggang Pan , M. James You , Keyur P. Patel , Francisco Vega , L. Jeffrey Medeiros , Pei Lin
In 2021, the International Myeloma Working Group lowered the threshold to establish the diagnosis of primary plasma cell leukemia (pPCL) from ≥20% to ≥5% circulating plasma cells (CPCs) as assessed by morphologic evaluation (ME). However, the threshold for defining secondary PCL (sPCL) remains unclear. We retrospectively studied the clinicopathological features of 52 PCL patients, 30 pPCL and 22 sPCL, with ≥5% CPCs determined by either ME or flow cytometry immunophenotyping (FCI). FCI often revealed a higher percentage of CPCs than ME, likely due to difficulties in identifying morphologically abnormal plasma cells with certainty, and this discordance was statistically significant in sPCL patients. pPCL and sPCL both exhibited leukocytosis, thrombocytopenia, infrequent CD56 expression, high bone marrow tumor burden, and complex karyotypes. MYC rearrangement was observed only in sPCL cases. Paired cytogenetic data before and after leukemic transformation were available in a small subset of sPCL patients (8/22). Compared with the prior myeloma, sPCL more frequently harbored a complex karyotype, hypodiploidy, and additional cytogenetic abnormalities, most commonly gain of chromosome 1q. Using 5% CPCs as the diagnostic threshold, patients with sPCL had significantly poorer outcomes than patients with pPCL (P < .0001). Furthermore, the outcomes of sPCL patients with 5% to 19% CPCs were similarly poor as those patients with ≥20% CPCs (P = .4781), highlighting the need to recognize patients with ≥5% CPCs promptly. FCI appears to be a more sensitive method for this purpose in most cases. Using FCI, further studies are needed to determine whether a diagnostic threshold of 5% or lower may be used to establish the diagnosis of sPCL.
{"title":"Lowering the Diagnostic Threshold in Secondary Plasma Cell Leukemia? Comparison With Primary Cases and Implications for Flow Cytometry Immunophenotyping","authors":"Wen Shuai , Zhihong Hu , C. Cameron Yin , Lei Chen , Wei Wang , Guilin Tang , Dawen Sui , Shaoying Li , Jie Xu , Nourhan Ibrahim , Zenggang Pan , M. James You , Keyur P. Patel , Francisco Vega , L. Jeffrey Medeiros , Pei Lin","doi":"10.1016/j.modpat.2025.100954","DOIUrl":"10.1016/j.modpat.2025.100954","url":null,"abstract":"<div><div>In 2021, the International Myeloma Working Group lowered the threshold to establish the diagnosis of primary plasma cell leukemia (pPCL) from ≥20% to ≥5% circulating plasma cells (CPCs) as assessed by morphologic evaluation (ME). However, the threshold for defining secondary PCL (sPCL) remains unclear. We retrospectively studied the clinicopathological features of 52 PCL patients, 30 pPCL and 22 sPCL, with ≥5% CPCs determined by either ME or flow cytometry immunophenotyping (FCI). FCI often revealed a higher percentage of CPCs than ME, likely due to difficulties in identifying morphologically abnormal plasma cells with certainty, and this discordance was statistically significant in sPCL patients. pPCL and sPCL both exhibited leukocytosis, thrombocytopenia, infrequent CD56 expression, high bone marrow tumor burden, and complex karyotypes. <em>MYC</em> rearrangement was observed only in sPCL cases. Paired cytogenetic data before and after leukemic transformation were available in a small subset of sPCL patients (8/22). Compared with the prior myeloma, sPCL more frequently harbored a complex karyotype, hypodiploidy, and additional cytogenetic abnormalities, most commonly gain of chromosome 1q. Using 5% CPCs as the diagnostic threshold, patients with sPCL had significantly poorer outcomes than patients with pPCL (<em>P</em> < .0001). Furthermore, the outcomes of sPCL patients with 5% to 19% CPCs were similarly poor as those patients with ≥20% CPCs (<em>P</em> = .4781), highlighting the need to recognize patients with ≥5% CPCs promptly. FCI appears to be a more sensitive method for this purpose in most cases. Using FCI, further studies are needed to determine whether a diagnostic threshold of 5% or lower may be used to establish the diagnosis of sPCL.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"39 2","pages":"Article 100954"},"PeriodicalIF":5.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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