Modern Pathology最新文献

{"title":"Congenital Peribronchial Myofibroblastic Tumors Harbor a Recurrent EGFR Kinase Domain Duplication","authors":"Sheren Younes ,&nbsp;Carlos J. Suarez ,&nbsp;Jennifer Pogoriler ,&nbsp;Tricia Bhatti ,&nbsp;Archana Shenoy ,&nbsp;Raya Saab ,&nbsp;Lea F. Surrey ,&nbsp;Serena Y. Tan","doi":"10.1016/j.modpat.2024.100661","DOIUrl":"10.1016/j.modpat.2024.100661","url":null,"abstract":"<div><div>Congenital peribronchial myofibroblastic tumor (CPMT) is a rare benign infantile pulmonary neoplasm that presents prenatally, or early in infancy, and exhibits distinctive histologic features characterized by the presence of cartilaginous islands intermixed with bland spindle cells, not uncommonly displaying prominent mitoses. Despite its benign nature, CPMT can lead to fetal demise, postnatal respiratory distress, or complications from perinatal surgical resection. Although the morphologic and clinical features of CPMT are well described, its molecular features and oncogenesis remain elusive. Following the detection of <em>EGFR</em> kinase domain duplication (KDD) of exons 18 to 25 in an index case, we identified 3 additional cases of morphologically classic and clinically well-characterized CPMTs from the archives and performed targeted RNA- and DNA-based profiling via next-generation sequencing for detection of rearrangements, sequence variants, and copy number variants on all cases. Two cases were detected prenatally, 1 patient presented at birth, and 1 at 8 weeks of life. All tumors were resected, with a follow-up period ranging from 0 days to 10 years. One patient died shortly after surgical resection, and the other 3 had no recurrences. In all cases, <em>EGFR</em> KDD was detected. In 2 out of 4 cases, gains of select whole chromosomes were noted. Our findings establish <em>EGFR</em> KDD as a recurrent oncogenic driver of CPMT. Notably, this alteration is also found in classical congenital mesoblastic nephromas, infantile kidney tumors with which CPMTs share striking morphologic and clinical similarities. This strongly suggests that CPMTs and classical congenital mesoblastic nephromas share common oncogenesis, and represent the same tumor in different locations. <em>EGFR</em> KDDs have also been reported in neonatal soft tissue tumors with infantile fibrosarcoma-like histology and cartilaginous differentiation, raising questions about their relationship. <em>EGFR</em> KDD emerges as a diagnostic marker, a potential therapeutic target, and a window into the oncogenesis of a distinct subset of infantile mesenchymal tumors.</div></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":"38 2","pages":"Article 100661"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693123","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":"Spatial transcriptomics reveals cancer and stromal cell heterogeneity between center and invasive front of pancreatic cancer.","authors":"Tine Norman Alver, Helga Bergholtz, Maia Blomhoff Holm, Linda Trobe Dorg, Martina Landschoof Skrede, Elin Hegland Kure, Caroline Sophie Verbeke","doi":"10.1016/j.modpat.2025.100726","DOIUrl":"https://doi.org/10.1016/j.modpat.2025.100726","url":null,"abstract":"<p><p>Intratumor heterogeneity is considered a major cause of treatment failure in pancreatic ductal adenocarcinoma (PDAC). In recent years, marked heterogeneity at the genomic and transcriptional level has been revealed, but the spatial distribution of the heterogeneous cell populations has not been considered. Yet, it is assumed that cancer cells at the invasive front are endowed with enhanced migratory and invasive properties, although evidence is scanty, and cancer-associated fibroblasts (CAFs) in this location have not been characterized. In this study, digital spatial profiling was used to compare the transcriptional profiles of cancer cells and CAFs in the tumor center versus the invasive front of human PDAC. Four well differentiated PDACs with conventional morphology were investigated with the GeoMx system (Nanostring). Regions of interest were analyzed in the tumor center and at the invasive front using a whole transcriptome assay in cancer cell and CAF segments separately. Three of the PDACs harbored mutated KRAS, while the fourth case was confirmed wild-type KRAS. Substantial inter-regional heterogeneity was identified, with increased activity of pathways associated with cellular stress (including TNFα-signaling via NFκB, hypoxia, P53 pathway), proliferation (MYC targets, mitotic spindle), glycolysis, and epithelial-mesenchymal transition at the invasive front in both the cancer cell and CAF segments compared to the center of the tumor. Immunohistochemical validation on 17 PDACs of well, moderate and poor differentiation confirmed significant inter-regional heterogeneity in the expression level of markers of EMT and glycolysis. The results of this study show that in PDAC, transcriptional profiles of both cancer cells and CAFs differ between the center of the tumor and the invasive front.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"100726"},"PeriodicalIF":7.1,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075261","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":"The Diagnostic Utility of TRBC1 Immunohistochemistry in Mature T-Cell Lymphomas.","authors":"Ting Zhou, Rohan Sardana, Ozgur Can Eren, Melissa Pulitzer, Achim Jungbluth, Ahmet Dogan, Megan S Lim","doi":"10.1016/j.modpat.2025.100725","DOIUrl":"https://doi.org/10.1016/j.modpat.2025.100725","url":null,"abstract":"<p><p>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 (FFPE) tissue. Utilizing DeepLIIF image analysis, we quantified TRBC1 positivity among CD3-positive cells in a training cohort comprising 34 cases of alpha/beta 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 (ROC) analysis of the training cohort established the optimal cut-off 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 (r = 0.78, p < 0.001) and a high categorical agreement (85.9%) in classifying monotypic versus polytypic staining. Discrepancies in categorization were associated with low tumor percentages. Furthermore, multiplex immunofluorescence (MIF) 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.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"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, Baptiste Ameline, Willem H Schreuder, Károly Szuhai, Wierd Kooistra, Léon van Kempen, Ghazaleh S H Japalagh, Inge H Briaire-de Bruijn, Stijn W van der Meeren, Maarten C Kleijwegt, Max Witjes, Sarina E C Pichardo, Wouter R van Furth, Tereza Lausová, Gerben E Breimer, W Weibel Braunius, Jan de Lange, Kirsten van Langevelde, Herman M Kroon, Mari F C M van den Hout, Sjors A Koppes, Simon Haefliger, Marc L Ooft, Ilse C H van Engen-van Grunsven, Uta E Flucke, Laura Hiemcke-Jiwa, Dilara C Savci-Heijink, Gilles F H Diercks, Jan J Doff, Albert J H Suurmeijer, Judith V M G Bovée, Andreas von Deimling, Daniel Baumhoer, Arjen H G Cleven","doi":"10.1016/j.modpat.2025.100717","DOIUrl":"https://doi.org/10.1016/j.modpat.2025.100717","url":null,"abstract":"<p><p>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 GNAS mutations in FD, SATB2 fusions in PsOF, mutations involving the RAS-MAPK signaling pathway in COD, and MDM2 amplification in LGOS. Since DNA methylation and copy number profiling are well established for the classification of central nervous system tumors, our aim was 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 (n = 20), COF (n = 13), JTOF (n = 10), PsOF (n = 25), FD (n = 23), LGOS (n = 4), and high-grade osteosarcoma (HGOS; n = 11). Genome-wide DNA methylation and copy number variation data were generated using the Illumina Infinium Methylation EPIC array interrogating >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 to 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 high-grade osteosarcomas in the craniofacial bones, which is of diagnostic value in challenging cases with overlapping clinicopathological features.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"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":"","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, Max Kamm, Barbara Titze, Anna Höink, Hagen Vorwerk, Karl-Dietrich Sievert, Jan Groetzner, Ulf Titze","doi":"10.1016/j.modpat.2025.100720","DOIUrl":"https://doi.org/10.1016/j.modpat.2025.100720","url":null,"abstract":"<p><p>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 the 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 to 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. 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.</p>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":" ","pages":"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":"","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}