Modern Pathology最新文献

{"title":"The Diagnostic Utility of TRBC1 Immunohistochemistry in Mature T-Cell Lymphomas","authors":"Ting Zhou,&nbsp;Rohan Sardana,&nbsp;Ozgur Can Eren,&nbsp;Melissa Pulitzer,&nbsp;Achim Jungbluth,&nbsp;Ahmet Dogan,&nbsp;Megan S. Lim","doi":"10.1016/j.modpat.2025.100725","DOIUrl":"10.1016/j.modpat.2025.100725","url":null,"abstract":"<div><div>T-cell clonality assessment constitutes an essential part of the diagnostic evaluation of suspected T-cell neoplasms. Recent advances in flow cytometry–based analysis of TCR β-chain constant region 1 (TRBC1) have introduced an accurate method of assessment of T-cell clonality. Its broader applicability is constrained due to the requirement of viable cells. Furthermore, the utility of the TRBC1 antibody in tissue immunohistochemistry (IHC) has not been comprehensively addressed. Herein, we validated an IHC-based approach to assess T-cell clonality using formalin-fixed, paraffin-embedded tissue. Utilizing DeepLIIF image analysis, we quantified TRBC1 positivity among CD3-positive cells in a training cohort comprising 34 cases of α/β T-cell neoplasms and 29 cases of reactive lymphoid tissue as controls. In an independent validation cohort comprising 29 T-cell neoplasms and 20 controls, similar image quantification was conducted by a pathologist uninvolved in the analysis of the training cohort and blinded to the diagnoses. Receiver operating characteristic analysis of the training cohort established the optimal cutoff points for monotypic TRBC1 expression—79.0% or higher indicating monotypic positivity and 36.3% or lower denoting negativity. These thresholds demonstrated robust metrics in both the training (sensitivity 88.2%, specificity 93.1%, positive predictive value 93.8%, negative predictive value 87.1%) and the validation cohorts (sensitivity 93.1%, specificity 95.0%, positive predictive value 96.4%, negative predictive value 90.5%). TRBC1 IHC was correlated with flow cytometry in 52 cases, which demonstrated a strong quantitative correlation of TRBC1 positivity (<em>r</em> = 0.78; <em>P</em> &lt;.001) and a high categoric agreement (85.9%) in classifying monotypic versus polytypic staining. Discrepancies in categorization were associated with low tumor percentages. Furthermore, multiplex immunofluorescence was performed in 15 cases for targeted quantification of TRBC1 expression in CD3-positive, PAX5-negative cells, achieving a concordance of 86.7% with IHC. In summary, TRBC1 IHC offers a reliable and practical complementary method for assessing T-cell clonality.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 6","pages":"Article 100725"},"PeriodicalIF":7.1,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066744","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}

{"title":"Pediatric-type Myoid Neoplasms of Somatic Soft Tissue: A Clinicopathological and Molecular Genetic Study of 78 Tumors, Highlighting Indolent Clinical Behavior and Frequent SRF Gene Rearrangements","authors":"Erin L.J. Alston ,&nbsp;Judith Jebastin Thangaiah ,&nbsp;Ross Rowsey ,&nbsp;Christopher D. Hofich ,&nbsp;Troy Gliem ,&nbsp;Andrea C. Bakker ,&nbsp;Mark Sabbagh ,&nbsp;Alanna J. Church ,&nbsp;David J. Papke Jr. ,&nbsp;Andrew L. Folpe ,&nbsp;Alyaa Al-Ibraheemi","doi":"10.1016/j.modpat.2025.100722","DOIUrl":"10.1016/j.modpat.2025.100722","url":null,"abstract":"<div><div>Soft tissue tumors with smooth muscle differentiation are rare in pediatric patients. Despite often showing morphologic features sufficient for classification as “leiomyosarcoma” in adults (eg, high cellularity and mitotic activity), clinical follow-up has shown only indolent behavior. The pathological features of recently reported <em>SRF</em>-rearranged “cellular myofibromas/myopericytomas,” typically occurring in children, overlap with those of true smooth muscle tumors. We studied a large series of pediatric tumors with morphologic and immunohistochemical evidence of smooth muscle differentiation, with the goals of better understanding their natural history and molecular genetic features. Seventy-eight tumors were identified in 45 males and 33 females, with a median age of 10 years. Clinical follow-up (50 patients; median, 45.5 months) disclosed local recurrence in 7 patients (15%). No metastases or deaths because of disease occurred. Group 1 (73/78) tumors consisted of cellular fascicles of mildly to at most moderately atypical, bland, ovoid to spindled cells with distinctly eosinophilic cytoplasm, appreciable mitotic activity (median, 5/50 high-power fields), and no necrosis. Group 2 tumors (5/78) showed greater cellularity, significant nuclear pleomorphism, and brisk mitotic activity (median, 59/50 high-power fields). Subsets of group 1 tumors harbored <em>SRF</em> rearrangements (16/47), and all group 2 tumors showed <em>TP53</em> biallelic inactivation (5/5). <em>SRF</em> fusion partners included <em>CITED1</em>, <em>NCOA2</em>, <em>C3orf62</em>, <em>RELA</em>, <em>ARGFXP1</em>, <em>ARNTI2</em>, <em>ICA1L</em>, and unknown (n = 1). We conclude that the prognosis for pediatric tumors with smooth muscle differentiation that fall into group 1 is excellent. <em>SRF</em> rearrangements are present in a significant minority of tumors, typically showing features of smooth muscle rather than myopericytic differentiation. A smaller subset with more worrisome morphologic features harbor biallelic inactivation of <em>TP53</em>. To emphasize their unique features, we propose the term “pediatric-type myoid neoplasms of somatic soft tissue” rather than simply “leiomyoma” or “leiomyosarcoma” for group 1 tumors, and the designation of leiomyosarcoma in children should be limited to group 2 tumors.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 5","pages":"Article 100722"},"PeriodicalIF":7.1,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047063","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}

{"title":"Classification of Fibro-Osseous Tumors in the Craniofacial Bones Using DNA Methylation and Copy Number Alterations","authors":"Tony G. Kleijn ,&nbsp;Baptiste Ameline ,&nbsp;Willem H. Schreuder ,&nbsp;Károly Szuhai ,&nbsp;Wierd Kooistra ,&nbsp;Léon van Kempen ,&nbsp;Ghazaleh S.H. Japalagh ,&nbsp;Inge H. Briaire-de Bruijn ,&nbsp;Stijn W. van der Meeren ,&nbsp;Maarten C. Kleijwegt ,&nbsp;Max Witjes ,&nbsp;Sarina E.C. Pichardo ,&nbsp;Wouter R. van Furth ,&nbsp;Tereza Lausová ,&nbsp;Gerben E. Breimer ,&nbsp;Weibel Braunius ,&nbsp;Jan de Lange ,&nbsp;Kirsten van Langevelde ,&nbsp;Herman M. Kroon ,&nbsp;Mari F.C.M. van den Hout ,&nbsp;Arjen H.G. Cleven","doi":"10.1016/j.modpat.2025.100717","DOIUrl":"10.1016/j.modpat.2025.100717","url":null,"abstract":"<div><div>Fibro-osseous tumors of the craniofacial bones are a heterogeneous group of lesions comprising cemento-osseous dysplasia (COD), cemento-ossifying fibroma (COF), juvenile trabecular ossifying fibroma (JTOF), psammomatoid ossifying fibroma (PsOF), fibrous dysplasia (FD), and low-grade osteosarcoma (LGOS) with overlapping clinicopathological features. However, their clinical behavior and treatment differ significantly, underlining the need for accurate diagnosis. Molecular diagnostic markers exist for subsets of these tumors, including <em>GNAS</em> mutations in FD, <em>SATB2</em> fusions in PsOF, mutations involving the RAS-MAPK signaling pathway in COD, and <em>MDM2</em> amplification in LGOS. Because DNA methylation and copy number profiling are well established for the classification of central nervous system tumors, we aimed to investigate whether this tool might be used as well for classifying fibro-osseous tumors in the craniofacial bones. We collected a well-characterized, multicenter cohort with available molecular data, including COD (<em>n</em> = 20), COF (<em>n</em> = 13), JTOF (<em>n</em> = 10), PsOF (<em>n</em> = 25), FD (<em>n</em> = 23), LGOS (<em>n</em> = 4), and high-grade osteosarcoma (HGOS; <em>n</em> = 11). Genome-wide DNA methylation and copy number variation data were generated using the Illumina Infinium Methylation EPIC array interrogating &gt;850 000 CpG sites. DNA methylation profiling yielded evaluable results in 73/106 tumors, including 6 CODs, 12 COFs, 6 JTOFs, 19 PsOFs, 18 FDs, 2 LGOSs, and 10 HGOSs. Unsupervised clustering and dimensionality reduction (Uniform Manifold Approximation and Projection) revealed that FD, extragnatic PsOF, and HGOS formed distinct clusters. Surprisingly, COD, COF, JTOF, and mandibular PsOF clustered together, apart from other craniofacial bone tumors. LGOS did not form a distinct cluster, likely due to the low number of cases. Copy number analysis revealed that FD, COD, COF, JTOF, and PsOF were typically characterized by flat copy number profiles compared with LGOS with gains of chromosome 12 and HGOS with multiple heterogeneous copy number alterations. In conclusion, using DNA methylation and copy number profiles, benign fibro-osseous tumors can be separated from low-grade and HGOSs in the craniofacial bones, which is of diagnostic value in challenging cases with overlapping clinicopathological features.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 6","pages":"Article 100717"},"PeriodicalIF":7.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143039954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ex Vivo Fluorescence Confocal Microscopy for Intraoperative Evaluations of Staple Lines and Surgical Margins in Specimens of the Lung—A Proof-of-Concept Study","authors":"Felix Hildebrandt ,&nbsp;Max Kamm ,&nbsp;Barbara Titze ,&nbsp;Anna Höink ,&nbsp;Hagen Vorwerk ,&nbsp;Karl-Dietrich Sievert ,&nbsp;Jan Groetzner ,&nbsp;Ulf Titze","doi":"10.1016/j.modpat.2025.100720","DOIUrl":"10.1016/j.modpat.2025.100720","url":null,"abstract":"<div><div>Intraoperative consultation is frequently used during the surgical treatment of lung tumors for the diagnosis of malignancy and the assessment of surgical margins. The latter is often problematic given the nature of applied staple lines, which cannot be readily examined in frozen sections. Seventy-nine samples of surgical margins (71 staple lines and 8 open margins) from 52 lung specimens were examined using an ex vivo fluorescence confocal microscope (FCM). The diagnoses of the FCM scans were compared with the corresponding paraffin section images of the same material. The procedure provided intraoperative FCM imaging of the surgical margins and staple lines without having to remove the metal clips. Tumor-involved open margins (5/5) and tumor-involved staple lines (3/4) were correctly identified in the FCM images. The results also provided additional information to the conventional frozen sections (FS). To our knowledge, this is the first time staple lines of lung specimens have been visualized as preserved tissue using FCM. The method potentially provides an additional approach for intraoperative decisions when the margins in conventional frozen sections are unclear. Our promising results, however, need to be validated on a larger number of cases.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 6","pages":"Article 100720"},"PeriodicalIF":7.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Digital Profiling of Immune Biomarkers in Breast Cancer: Relation to Anthracycline Benefit","authors":"Elahe Shenasa ,&nbsp;Ye He ,&nbsp;Zehui Wang ,&nbsp;Dongsheng Tu ,&nbsp;Dongxia Gao ,&nbsp;Zuzana Kos ,&nbsp;Shelby Thornton ,&nbsp;Torsten O. Nielsen","doi":"10.1016/j.modpat.2025.100718","DOIUrl":"10.1016/j.modpat.2025.100718","url":null,"abstract":"<div><div>Assessment of the tumor-immune microenvironment can be used as a prognostic tool for improved survival and as a predictive biomarker for treatment benefit, particularly from immune-modulating treatments including cytotoxic chemotherapy. Using digital spatial profiling (DSP), we studied the tumor-immune microenvironment of 522 breast cancer cases by quantifying 35 immune biomarkers on tissue microarrays from the MA.5 phase III clinical trial. In this trial, node-positive breast cancer patients were randomized to receive either non-anthracycline chemotherapy (cyclophosphamide, methotrexate, 5’-fluorouracil [CMF]) or anthracycline-containing cytotoxic chemotherapy (CEF). Donor block hematoxylin and eosin (H&amp;E)-stained sections were scored for the level of stromal tumor-infiltrating lymphocytes (sTILs), according to the international guidelines. We hypothesized that patients with higher levels of tumor-immune infiltration, assessed by either DSP or H&amp;E staining, would benefit from CEF (relative to CMF) more than patients with lower immune infiltration. Unsupervised hierarchical clustering of digitally scored biomarkers revealed 2 patient clusters: immune infiltrated versus ignored. Following a prespecified statistical plan crafted to meet REMARK (REporting recommendations for tumor MARKer prognostic studies) guidelines, we found that the DSP-derived Immune Cluster assignment did not predict an improved 10-year relapse-free survival for patients receiving CEF compared with CMF. However, a secondary hypothesis revealed a significant predictive value for H&amp;E sTILs assessed on full-faced sections for CEF benefit over CMF in the entire cohort and the human epidermal growth factor receptor 2-enriched subset. As exploratory analyses, supervised clustering of DSP-scored biomarkers suggested that low levels of T-cell immunoglobulin and mucin domain 3 TIM-3 and high levels of human leukocyte antigen HLA-DR and programmed cell death protein ligand PD-L-1 are associated with sensitivity to CEF. Although novel high-plex techniques provide a detailed insight into the tumor microenvironment, conventional H&amp;E staining remains a powerful tool that can be applied to full-faced sections to assess the value of the immune microenvironment, particularly sTILs, in predicting benefits from immunogenic chemotherapies.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 5","pages":"Article 100718"},"PeriodicalIF":7.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diffuse Cyclin D1 and SPINK1 Expression in Gastric Oxyntic Gland Neoplasms: Promising Diagnostic Markers Identified Using Spatial Transcriptome Analysis","authors":"Aya Shinozaki-Ushiku ,&nbsp;Daizo Koinuma ,&nbsp;Atsuhito Nakayama ,&nbsp;Junichi Nawa ,&nbsp;Mitsuhiro Fujishiro ,&nbsp;Tetsuo Ushiku","doi":"10.1016/j.modpat.2025.100719","DOIUrl":"10.1016/j.modpat.2025.100719","url":null,"abstract":"<div><div>Oxyntic gland neoplasms typically arise in <em>Helicobacter pylori</em>–naive stomachs and are composed predominantly of chief cells, with a smaller component of parietal cells. Their pathologic diagnosis can be challenging owing to minimal cellular atypia. Especially in biopsy specimens with a limited tumor volume or when pathologists have limited experience in diagnosing this neoplasm, distinguishing them from normal oxyntic glands can be difficult, and no reliable diagnostic markers are currently available. In this study, single-cell spatial transcriptome analysis successfully identified significant upregulation of <em>CCND1</em> and <em>SPINK1</em> in all 6 analyzed cases of oxyntic gland neoplasms compared with normal oxyntic glands. Immunohistochemical analysis confirmed this finding in 21 endoscopically resected cases of oxyntic gland neoplasms, demonstrating that cyclin D1 and serine peptidase inhibitor Kazal type 1 (SPINK1) were diffusely expressed in oxyntic gland neoplasms, whereas their expression was scarcely observed in normal oxyntic glands, with a few of them showing weak to moderate staining. Even in biopsy specimens, these 2 markers highlighted the tumor areas and clearly distinguished neoplastic from normal oxyntic glands. Nonneoplastic foveolar epithelia and mucous neck cells also showed positive staining for both cyclin D1 and SPINK1. In addition, a mild increase in cyclin D1 expression and patchy or mosaic expression of SPINK1 were observed in fundic gland polyps, <em>H. pylori</em>–associated gastritis, and pyloric gland adenomas, whereas a diffuse staining pattern was specific to oxyntic gland neoplasms. These observations suggest that cyclin D1 and SPINK1 are reliable markers in differentiating oxyntic gland neoplasms from nonneoplastic oxyntic glands and pyloric gland adenomas. Cyclin D1 is commonly used for immunostaining in many pathology departments, and owing to its higher sensitivity and specificity compared with SPINK1, it is considered the best diagnostic marker.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 5","pages":"Article 100719"},"PeriodicalIF":7.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040020","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}

{"title":"TP53 Wild-Type, Human Papillomavirus-Independent Anal Growth/(Intra)Epithelial Lesion (ANGEL): A Potential Precursor of Anal Squamous Cell Carcinoma","authors":"Andre Pinto ,&nbsp;Aatur D. Singhi ,&nbsp;Lysandra Voltaggio ,&nbsp;Kevan Salimian ,&nbsp;Jacqueline Birkness-Gartman ,&nbsp;Elizabeth A. Montgomery","doi":"10.1016/j.modpat.2025.100721","DOIUrl":"10.1016/j.modpat.2025.100721","url":null,"abstract":"<div><div>Human papillomavirus (HPV) underpins ∼90% of squamous cell carcinomas (SCCs) of the anus and perianal region. These tumors usually arise in association with precursor lesions such as anal intraepithelial neoplasia/high-grade squamous intraepithelial lesion, whereas a small subset of HPV-negative cancers may harbor mutations in <em>TP53</em>. Recently, vulvar lesions termed differentiated exophytic vulvar intraepithelial lesion/vulvar acanthosis with altered differentiated have been recognized as HPV-independent, <em>TP53</em> wild-type precursors for vulvar carcinoma; however, analogous anal lesions have not been described. Cases of diagnostically challenging, <em>TP53</em> wild-type HPV-negative anal squamous lesions with unusual histologic features including acanthosis and/or verrucous architecture were retrospectively identified. Lesions with koilocytic changes, lack of surface maturation, or significant cytologic atypia were excluded. HPV status was determined by immunohistochemistry for p16 and/or in situ hybridization for low- and high-risk strains, whereas <em>TP53</em> status was assessed using immunohistochemistry and molecular studies in a subset of cases, with targeted molecular sequencing performed in 3 of these. All lesions (5/5) arose in men, ages ranging from 55 to 78 years (median: 65 years). Verrucous architecture was seen in 2 of 5 cases, 2 of 5 were predominantly acanthotic, and 1 of 5 had both verrucous and acanthotic growth. The lesions were characterized by hyperkeratosis (5/5), hypergranulosis (5/5), and cytoplasmic pallor of upper epithelial layers (2/5). All cases were negative for HPV and had wild-type p53 expression. Three cases with sufficient material for sequencing lacked alterations within the entire coding sequencing of <em>TP53</em>. Invasive SCC was concurrently present in 3 of 5 cases. In summary, verrucous and acanthotic HPV-independent TP53 wild-type squamous proliferation of the anal and perianal region, referred to herein as anal growth/(intra)epithelial lesion (ANGEL), are premalignant lesions that have the potential to become invasive, as most of our cases demonstrated synchronous SCC.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 5","pages":"Article 100721"},"PeriodicalIF":7.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040148","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}

{"title":"Frank Invasion in Tall Cell Carcinoma With Reversed Polarity of the Breast: Report of Two Cases","authors":"Rachel Han ,&nbsp;Fresia Pareja ,&nbsp;Dara S. Ross ,&nbsp;Anne Grabenstetter ,&nbsp;Hannah Y. Wen ,&nbsp;Edi Brogi","doi":"10.1016/j.modpat.2025.100714","DOIUrl":"10.1016/j.modpat.2025.100714","url":null,"abstract":"<div><div>Tall cell carcinoma with reversed polarity (TCCRP) is a rare neoplasm of the breast composed of columnar tumor cells arranged in solid and solid-papillary nests with evidence of apical nuclear polarity. No frank invasion is evident despite the lack of a myoepithelial cell layer throughout the tumor. TCCRP has a triple-negative or hormone receptor-low immunophenotype. Recurrent <em>IDH2</em> R172 hotspot mutation coexisting with genetic alterations in the PI3K pathway characterizes this tumor. Here, we report on 2 postmenopausal patients with TCCRP with frank stromal invasion. <em>IDH2</em> R172 mutations were detected in both tumors by immunohistochemistry. Targeted sequencing of case 2 demonstrated the presence of <em>IDH2</em> R172T and <em>RTEL1</em> E839K mutations. Both patients underwent breast conservation surgery, radiation therapy, and adjuvant endocrine therapy with anastrozole and demonstrated no evidence of disease at 65 and 25 months, respectively. This study suggests that TCCRP may give rise to frank invasive carcinoma, the prognostic significance of which is yet unknown.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 5","pages":"Article 100714"},"PeriodicalIF":7.1,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008508","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}

{"title":"Physical Color Calibration of Digital Pathology Scanners for Robust Artificial Intelligence–Assisted Cancer Diagnosis","authors":"Xiaoyi Ji ,&nbsp;Richard Salmon ,&nbsp;Nita Mulliqi ,&nbsp;Umair Khan ,&nbsp;Yinxi Wang ,&nbsp;Anders Blilie ,&nbsp;Henrik Olsson ,&nbsp;Bodil Ginnerup Pedersen ,&nbsp;Karina Dalsgaard Sørensen ,&nbsp;Benedicte Parm Ulhøi ,&nbsp;Svein R. Kjosavik ,&nbsp;Emilius A.M. Janssen ,&nbsp;Mattias Rantalainen ,&nbsp;Lars Egevad ,&nbsp;Pekka Ruusuvuori ,&nbsp;Martin Eklund ,&nbsp;Kimmo Kartasalo","doi":"10.1016/j.modpat.2025.100715","DOIUrl":"10.1016/j.modpat.2025.100715","url":null,"abstract":"<div><div>The potential of artificial intelligence (AI) in digital pathology is limited by technical inconsistencies in the production of whole slide images (WSIs). This causes degraded AI performance and poses a challenge for widespread clinical application, as fine-tuning algorithms for each site is impractical. Changes in the imaging workflow can also compromise diagnostic accuracy and patient safety. Physical color calibration of scanners, relying on a biomaterial-based calibrant slide and a spectrophotometric reference measurement, has been proposed for standardizing WSI appearance, but its impact on AI performance has not been investigated. We evaluated whether physical color calibration can enable robust AI performance. We trained fully supervised and foundation model–based AI systems for detecting and Gleason grading prostate cancer using WSIs of prostate biopsies from the STHLM3 clinical trial (n = 3651) and evaluated their performance in 3 external cohorts (n = 1161) with and without calibration. With physical color calibration, the fully supervised system’s concordance with pathologists’ grading (Cohen linearly weighted κ) improved from 0.439 to 0.619 in the Stavanger University Hospital cohort (n = 860), from 0.354 to 0.738 in the Karolinska University Hospital cohort (n = 229), and from 0.423 to 0.452 in the Aarhus University Hospital cohort (n = 72). The foundation model’s concordance improved as follows: from 0.739 to 0.760 (Karolinska), from 0.424 to 0.459 (Aarhus), and from 0.547 to 0.670 (Stavanger). This study demonstrated that physical color calibration provides a potential solution to the variation introduced by different scanners, making AI-based cancer diagnostics more reliable and applicable in diverse clinical settings.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 5","pages":"Article 100715"},"PeriodicalIF":7.1,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Claudin 18.2 Expression in 1404 Digestive Tract Adenocarcinomas Including 1175 Colorectal Carcinomas: Distinct Colorectal Carcinoma Subtypes Are Claudin 18.2 Positive","authors":"Kelsey E. McHugh ,&nbsp;Rish K. Pai ,&nbsp;Robert C. Grant ,&nbsp;Steven Gallinger ,&nbsp;Jon Davison ,&nbsp;Changqing Ma ,&nbsp;Reetesh K. Pai","doi":"10.1016/j.modpat.2025.100712","DOIUrl":"10.1016/j.modpat.2025.100712","url":null,"abstract":"<div><div>Claudin 18.2 (CLDN18.2) immunohistochemical (IHC) expression can be used to select patients with gastric/gastroesophageal junction adenocarcinomas for zolbetuximab (IMAB362) therapy, zolbetuximab (IMAB362) being a monoclonal antibody targeting CLDN18.2. The aim of this study was to correlate IHC expression of CLDN18.2 with clinicopathologic and molecular features in a large series of digestive tract cancers. IHC for CLDN18.2 was performed on tissue microarrays from 1404 adenocarcinomas including 155 gastric/gastroesophageal, 74 pancreatic ductal, and 1175 colorectal (576 in the initial test cohort; 599 in the subsequent validation cohort), and correlated with HER2 and mismatch repair (MMR) status. Cases were scored as CLDN18.2 positive or negative, with positivity defined as moderate-to-strong membranous staining in ≥75% of tumor cells. CLDN18.2 expression was correlated with clinicopathologic and molecular features for all colorectal adenocarcinomas. CLDN18.2 was positive in 39% (61/155) of gastric/gastroesophageal adenocarcinomas, 38% (28/74) of pancreatic ductal adenocarcinomas, and 3.4% (40/1175) of colorectal adenocarcinomas (<em>P</em> &lt; .001). For gastric/gastroesophageal and pancreatic ductal adenocarcinoma, there was no correlation between CLDN18.2 expression and either HER2 or MMR status. In contrast, CLDN18.2-positive colorectal adenocarcinomas had distinct clinicopathologic and molecular features. CLDN18.2-positive colorectal adenocarcinomas were more frequently proximally located and were more often MMR deficient and <em>BRAF</em> V600E positive (all with <em>P</em> &lt; .05). Quantitative pathologic analysis using the digital pathology biomarker QuantCRC (Aiforia) demonstrated marked differences in histologic features between CLDN18.2-positive and CLDN18.2-negative colorectal adenocarcinomas, with CLDN18.2-positive tumors having an increased tumor:stroma ratio and %mucin but decreased %immature stroma in both the test and validation cohorts (all with <em>P</em> &lt; .05). In conclusion, CLDN18.2-positive colorectal adenocarcinomas are frequently MMR deficient and <em>BRAF</em> V600E mutated, and demonstrate distinct histologic features. Future studies addressing the efficacy of zolbetuximab therapy in this subset of colorectal cancers are needed.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 5","pages":"Article 100712"},"PeriodicalIF":7.1,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008494","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}