Modern Pathology最新文献

{"title":"DNA Methylation and P53 Immunohistochemistry as Prognostic Biomarkers for Vulvar Lichen Sclerosus","authors":"","doi":"10.1016/j.modpat.2024.100553","DOIUrl":"10.1016/j.modpat.2024.100553","url":null,"abstract":"<div><p>Vulvar lichen sclerosus (LS) is an inflammatory dermatosis that can progress to human papillomavirus (HPV)-independent vulvar intraepithelial neoplasia (HPVi VIN) and vulvar squamous cell carcinoma (VSCC). Although LS has a much lower cancer risk compared with HPVi VIN (5% versus 50%, respectively), its incidence is significantly higher. Therefore, there is a clinical need to identify LS patients with an increased cancer risk. Our objective was to study the value of DNA methylation and p53 immunohistochemistry (IHC) as prognostic biomarkers for progression to cancer in patients with LS. Vulvar tissues from 236 patients were selected, including 75 LS and 68 HPVi VIN, both with and without cancer development, 32 VSCC, and 61 healthy vulvar controls. Samples were subjected to p53 IHC and DNA methylation analysis of a 3-gene marker panel containing <em>ZNF582</em>, <em>SST</em>, and <em>miR124-2</em>. Methylation levels and p53 IHC status (mutant or wild-type) were assessed and compared among all disease categories. Odds ratios were determined to identify whether the biomarkers were associated with progression to cancer in patients with LS. The highest methylation levels were found in HPVi VIN and VSCC, followed by LS and healthy vulvar controls. The largest heterogeneity in methylation levels was observed in LS cases. In fact, the 3-marker panel tested positive in 70% of LS, which progressed to VSCC versus only 17% of LS in patients without cancer development (<em>P</em> = .002). Also, mutant p53 IHC was observed more frequently in LS with progression to VSCC compared with nonprogressive LS cases (42% versus 3%, respectively, <em>P</em> = .001). Multivariable analysis identified a mutant p53 status as the only independent risk factor for cancer development in LS (odds ratio: 34.0, 95% CI: 1.4-807.4). In conclusion, DNA methylation testing and p53 IHC show strong potential as prognostic biomarkers for the identification of LS patients at high risk of progression to cancer.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0893395224001339/pdfft?md5=a7de351211dba8453f59fc093a28f4b0&pid=1-s2.0-S0893395224001339-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141458048","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":"Expression of L1 Cell Adhesion Molecule, a Nephronal Principal Cell Marker, in Nephrogenic Adenoma","authors":"Rahul Mannan ,&nbsp;Xiaoming Wang ,&nbsp;Somnath Mahapatra ,&nbsp;Susanna Wang ,&nbsp;Anya K. Chinnaiyan ,&nbsp;Stephanie L. Skala ,&nbsp;Yuping Zhang ,&nbsp;Lisa M. McMurry ,&nbsp;Sylvia Zelenka-Wang ,&nbsp;Xuhong Cao ,&nbsp;Ankur R. Sangoi ,&nbsp;Vipulkumar Dadhania ,&nbsp;Maria M. Picken ,&nbsp;Santosh Menon ,&nbsp;Hikmat Al-Ahmadie ,&nbsp;Arul M. Chinnaiyan ,&nbsp;Saravana M. Dhanasekaran ,&nbsp;Rohit Mehra","doi":"10.1016/j.modpat.2024.100540","DOIUrl":"10.1016/j.modpat.2024.100540","url":null,"abstract":"<div><p>Nephrogenic adenoma (NA) is a benign, reactive lesion seen predominantly in the urinary bladder and often associated with antecedent inflammation, instrumentation, or an operative history. Its histopathologic diversity can create diagnostic dilemmas and pathologists use morphologic evaluation along with available immunohistochemical (IHC) markers to navigate these challenges. IHC assays currently do not designate or specify NA’s potential putative cell of origin. Leveraging single-cell RNA-sequencing technology, we nominated a principal (P) cell–collecting duct marker, L1 cell adhesion molecule (L1CAM), as a potential biomarker for NA. IHC characterization revealed L1CAM to be positive in all 35 (100%) patient samples of NA; negative expression was seen in the benign urothelium, benign prostatic glands, urothelial carcinoma (UCA) in situ, prostatic adenocarcinoma, majority of high-grade UCA, and metastatic UCA. In the study, we also used single-cell RNA sequencing to nominate a novel compendium of biomarkers specific for the proximal tubule, loop of Henle, and distal tubule (DT) (including P and intercalated cells), which can be used to perform nephronal mapping using RNA in situ hybridization and IHC technology. Employing this technique on NA we found enrichment of both the P-cell marker L1CAM and, the proximal tubule type-A and -B cell markers, <em>PDZKI1P1</em> and <em>PIGR,</em> respectively. The cell-type markers for the intercalated cell of DTs (<em>LINC01187</em> and FOXI1), and the loop of Henle (<em>UMOD</em> and <em>IRX5)</em>, were found to be uniformly absent in NA. Overall, our findings show that based on cell type–specific implications of L1CAM expression, the shared expression pattern of L1CAM between DT P cells and NA. L1CAM expression will be of potential value in assisting surgical pathologists toward a diagnosis of NA in challenging patient samples.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0893395224001200/pdfft?md5=777e0db66c59ab82dca69286a363e438&pid=1-s2.0-S0893395224001200-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432292","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":"RB1 Genetic Alterations in Estrogen Receptor–Positive Breast Carcinomas: Correlation With Neuroendocrine Differentiation","authors":"Christopher J. Schwartz ,&nbsp;Antonio Marra ,&nbsp;Pier Selenica ,&nbsp;Andrea Gazzo ,&nbsp;Kiki Tan ,&nbsp;Dara Ross ,&nbsp;Pedram Razavi ,&nbsp;Sarat Chandarlapaty ,&nbsp;Britta Weigelt ,&nbsp;Jorge S. Reis-Filho ,&nbsp;Edi Brogi ,&nbsp;Fresia Pareja ,&nbsp;Hannah Y. Wen","doi":"10.1016/j.modpat.2024.100541","DOIUrl":"10.1016/j.modpat.2024.100541","url":null,"abstract":"<div><p>Genetic alterations in the retinoblastoma susceptibility gene (<em>RB1</em>) are present in up to 40% of triple-negative breast cancers (BCs) and frequent in tumors with neuroendocrine differentiation, including small cell neuroendocrine carcinoma. Data on <em>RB1</em> genetic alterations in estrogen receptor (ER)–positive BCs are scarce. In this study, we sought to define the morphologic, immunohistochemical, and genetic features of ER-positive BCs harboring somatic alterations in <em>RB1</em>, with emphasis on neuroendocrine differentiation. ER-positive BCs with pathogenic <em>RB1</em> genetic alterations were identified in &lt;1% of cases (N = 55) from a cohort of 6026 BCs previously subjected to targeted next-generation sequencing, including 23 primary BCs (pBCs) and 32 recurrent/metastatic BCs (mBCs). In cases where loss of heterozygosity of the wild-type <em>RB1</em> allele could be assessed (93%, 51/55), most pBCs (82%, 18/22) and mBCs (90%, 26/29) exhibited biallelic <em>RB1</em> inactivation, primarily through loss-of-function mutation and loss of heterozygosity (98%, 43/44). Upon histologic review, a subset of <em>RB1</em>-altered tumors exhibited neuroendocrine morphology (13%, 7/55), which correlated with expression of neuroendocrine markers (39%, 9/23) in both pBCs (27%, 3/11) and mBCs (50%, 6/12). Loss of Rb protein expression was observed in BCs with biallelic <em>RB1</em> loss only, with similar frequency in pBCs (82%, 9/11) and mBCs (75%, 9/12). All cases with neuroendocrine marker expression (n = 9) and/or neuroendocrine morphology (n = 7) harbored biallelic genetic inactivation of <em>RB1</em> and exhibited Rb loss of expression. <em>TP53</em> (53%, 29/55) and <em>PIK3CA</em> (45%, 25/55) were the most frequently comutated genes across the cohort. Overall, these findings suggest that ER-positive BCs with biallelic <em>RB1</em> genetic alterations frequently exhibit Rb protein loss, which correlates with neuroendocrine differentiation in select BCs. This study provides insights into the molecular and phenotypic heterogeneity of BCs with <em>RB1</em> genetic inactivation, underscoring the need for further research into the potential clinical implications associated with these tumors.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141427219","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":"Clinicopathologic Features of Gastrointestinal Tract Langerhans Cell Histiocytosis","authors":"Shaomin Hu ,&nbsp;Rondell P. Graham ,&nbsp;Won-Tak Choi ,&nbsp;Kwun Wah Wen ,&nbsp;Juan Putra ,&nbsp;Wei Chen ,&nbsp;Jingmei Lin ,&nbsp;Ivan A. Gonzalez ,&nbsp;Nicole Panarelli ,&nbsp;Qiang Liu ,&nbsp;Lei Zhao ,&nbsp;Shunyou Gong ,&nbsp;Melissa Mejia-Bautista ,&nbsp;David J. Escobar ,&nbsp;Changqing Ma ,&nbsp;Akram Shalaby ,&nbsp;Xiaotang Du ,&nbsp;Liang-I Kang ,&nbsp;Wei Zhang ,&nbsp;Xiuxu Chen ,&nbsp;Yue Xue","doi":"10.1016/j.modpat.2024.100543","DOIUrl":"10.1016/j.modpat.2024.100543","url":null,"abstract":"<div><p>Gastrointestinal (GI) tract involvement by Langerhans cell histiocytosis (LCH) is rare and its clinicopathologic characteristics have only been described in case reports and small series. We reviewed hematoxylin and eosin and CD1a, S100, and Langerin immunohistochemical–stained slides from 47 patients with well-documented demographic and clinical findings. Our cases included 8 children and 39 adults, with a mean follow-up of 63 months. All pediatric patients had concurrent multisystem LCH, presented with GI symptoms, and showed nonpolypoid lesions. Seven (88%) showed multifocal GI disease, including 5 with multiple GI organ involvement. All sampled lesions from children exhibited infiltrative growth. More than half had died of the disease or manifested persistent LCH at last follow-up. Twenty-five of 39 (64%) adults had LCH involving only the GI tract (single system), with the remaining 14 (36%) exhibiting multisystem disease. Adult single-system GI LCH was typically encountered incidentally on screening/surveillance endoscopy (72%). Most exhibited isolated colorectal involvement (88%) as a solitary polyp (92%), with a well-demarcated/noninfiltrative growth pattern (70%), and excellent prognosis (100%). In comparison, adult patients with multisystem LCH more frequently presented with GI symptoms (92%, <em>P</em> &lt; .001), noncolorectal GI site involvement (50%, <em>P</em> = .02), multifocal GI lesions (43%, <em>P</em> = .005), nonpolypoid lesions (71%, <em>P</em> &lt; .001), infiltrative histologic growth pattern (78%, <em>P</em> = .04), and persistent disease (57%, <em>P</em> &lt; .001). Adult patients with multisystem LCH appear to exhibit similar clinicopathologic features to those of pediatric patients. These results demonstrated that adults with single-system LCH involving the GI tract have an excellent prognosis, whereas multisystem LCH occurring at any age carries an unfavorable prognosis. High-risk features of GI LCH include pediatric age, GI symptomatology, noncolorectal GI involvement, multifocal GI disease, nonpolypoid lesions, and infiltrative growth pattern.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141427131","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":"Performance Evaluation of a Novel Artificial Intelligence–Assisted Digital Microscopy System for the Routine Analysis of Bone Marrow Aspirates","authors":"Adam Bagg ,&nbsp;Philipp W. Raess ,&nbsp;Deborah Rund ,&nbsp;Siddharth Bhattacharyya ,&nbsp;Joanna Wiszniewska ,&nbsp;Alon Horowitz ,&nbsp;Darrin Jengehino ,&nbsp;Guang Fan ,&nbsp;Michelle Huynh ,&nbsp;Abdoulaye Sanogo ,&nbsp;Irit Avivi ,&nbsp;Ben-Zion Katz","doi":"10.1016/j.modpat.2024.100542","DOIUrl":"10.1016/j.modpat.2024.100542","url":null,"abstract":"<div><p>Bone marrow aspiration (BMA) smear analysis is essential for diagnosis, treatment, and monitoring of a variety of benign and neoplastic hematological conditions. Currently, this analysis is performed by manual microscopy. We conducted a multicenter study to validate a computational microscopy approach with an artificial intelligence–driven decision support system. A total of 795 BMA specimens (615 Romanowsky-stained and 180 Prussian blue–stained) from patients with neoplastic and other clinical conditions were analyzed, comparing the performance of the Scopio Labs X100 Full Field BMA system (test method) with manual microscopy (reference method). The system provided an average of 1,385 ± 536 (range, 0-3,131) cells per specimen for analysis. An average of 39.98 ± 19.64 fields of view (range, 0-140) per specimen were selected by the system for analysis, of them 87% ± 21% (range, 0%-100%) were accepted by the qualified operators. These regions were included in an average of 17.62 ± 7.24 regions of interest (range, 1-50) per specimen. The efficiency, sensitivity, and specificity for primary and secondary marrow aspirate characteristics (maturation, morphology, and count assessment), as well as overall interuser agreement, were evaluated. The test method showed a high correlation with the reference method for comprehensive BMA evaluation, both on Romanowsky- (90.85% efficiency, 81.61% sensitivity, and 92.88% specificity) and Prussian blue–stained samples (90.0% efficiency, 81.94% sensitivity, and 93.38% specificity). The overall agreement between the test and reference methods for BMA assessment was 91.1%. For repeatability and reproducibility, all standard deviations and coefficients of variation values were below the predefined acceptance criteria both for discrete measurements (coefficient of variation below 20%) and differential measurements (SD below 5%). The high degree of correlation between the digital decision support system and manual microscopy demonstrates the potential of this system to provide a high-quality, accurate digital BMA analysis, expediting expert review and diagnosis of BMA specimens, with practical applications including remote BMA evaluation and possibly new opportunities for the research of normal and neoplastic hematopoiesis.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0893395224001224/pdfft?md5=088a31cd67a8dac2fce1558078c9ce0e&pid=1-s2.0-S0893395224001224-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141427132","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":"Comparative Performance Analysis of Idylla and Archer in the Detection of Gene Fusions in Spitzoid Melanocytic Tumors","authors":"","doi":"10.1016/j.modpat.2024.100538","DOIUrl":"10.1016/j.modpat.2024.100538","url":null,"abstract":"<div><p>Melanocytic neoplasms with spitzoid histomorphology are often difficult to classify without identifying genetic drivers such as kinase fusions. Traditional diagnostic methods, such as immunohistochemistry, can yield inconclusive results, and advanced techniques such as the Archer fusion assay are often inaccessible and costly. The Idylla GeneFusion Assay might offer a rapid and cost-effective alternative. This study compared Idylla and Archer in identifying <em>ALK</em>, pan-<em>NTRK</em>, <em>RET</em>, and <em>ROS1</em> gene fusions. Of the 147 samples where next-generation sequencing did not detect genetic drivers, 89 (60.5%) meeting the tissue requirements were further analyzed using Idylla (Cohort A). Idylla demonstrated a sensitivity of 75% and a specificity of 100% in detecting these fusions. Additionally, among 27 randomly selected cases (Cohort B) that failed to meet the inclusion criteria, Idylla maintained the same levels of sensitivity and specificity. Our findings also show that Idylla can be effectively conducted with isolated RNA, broadening its applicability beyond tissue samples. Although the Idylla assay may not replace more comprehensive molecular assays such as Archer, it could serve as a valuable initial screening tool in diagnosing spitzoid melanocytic tumors.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0893395224001182/pdfft?md5=a399d23ed67d47bd28b5f04eb0f79201&pid=1-s2.0-S0893395224001182-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141331428","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":"Spindle Cell Lesions with Oncogenic EGFR Kinase Domain Aberrations: Expanding the Spectrum of Protein Kinase–Related Mesenchymal Tumors","authors":"Silvia Vallese ,&nbsp;Sabina Barresi ,&nbsp;Laura Hiemcke-Jiwa ,&nbsp;Sara Patrizi ,&nbsp;Lennart Kester ,&nbsp;Isabella Giovannoni ,&nbsp;Antonello Cardoni ,&nbsp;Lucia Pedace ,&nbsp;Claudia Nardini ,&nbsp;Chantal Tancredi ,&nbsp;Martina Desideri ,&nbsp;Andreas von Deimling ,&nbsp;Rosa M. Mura ,&nbsp;Michela Piga ,&nbsp;Maria E. Errico ,&nbsp;Alessandra Stracuzzi ,&nbsp;Rita Alaggio ,&nbsp;Evelina Miele ,&nbsp;Uta Flucke","doi":"10.1016/j.modpat.2024.100539","DOIUrl":"10.1016/j.modpat.2024.100539","url":null,"abstract":"<div><p><em>EGFR</em> aberrations are reported in a subset of myofibroblastic lesions with kinase domain duplication (<em>EGFR</em>-KDD) and exon 20 mutations being assigned to infantile fibrosarcomas (IFS), mesoblastic nephroma, and fibrous hamartoma of infancy (FHI), respectively. In this retrospective study, we correlated molecular findings with the histomorphology of 14 myofibroblastic lesions harboring such genetic changes identified by NGS. We additionally performed DNA methylation profiling (DNAmp) and immunohistochemistry. Lesions were from 10 males and 4 females with a mean age of 3 years (range, 0.3-14) and occurred subcutaneously in the upper limbs (<em>n</em> = 5), lower limbs (<em>n</em> = 3), back/thorax (<em>n</em> = 5), and the nasal cavity (<em>n</em> = 1). Eleven were cured by surgery, including 1 relapsed case. Two patients were lost to follow-up. One case was very recent, and the patient was biopsied. Histologically, the lesions showed a wide spectrum varying from classic FHI (<em>n</em> = 9) to IFS (<em>n</em> = 1) or lipofibromatosis-like tumors (LFT-like) (<em>n</em> = 2) or dermatofibrosarcoma protuberans-like (DFSP-like) (<em>n</em> = 1) to a predominantly myxoid spindle cell lesion (<em>n</em> = 1). Immunohistochemically, all neoplasms stained with CD34, whereas S100 was positive in 2/14. EGFR expression was observed in 9/10 cases. Molecularly, the IFS and 1 LFT-like harbored <em>EGFR</em>-KDD, whereas an exon 20 mutation was identified in all FHI, 1 LFT-like, the DFSP-like, and in predominant myxoid spindle cell lesion. By DNAmp, all but 2 cases formed a well-defined cluster, demonstrating that these lesions are also epigenetically related. In conclusion, <em>EGFR</em> kinase domain aberrations found in FHI, IFS, LFT-like, DFSP-like, and a spindle cell lesion with a predominant myxoid stroma of children and adolescents showed that these neoplasms with a broad morphologic spectrum belong to the group of protein kinase–related lesions with a distinct epigenetic signature. Molecular analyses, including DNAmp, help to identify and characterize this emerging category and become mandatory when targeted treatment is considered.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141331429","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":"Superficial Neurocristic EWSR1::FLI1 Fusion Tumor: A Distinctive, Clinically Indolent, S100 Protein/SOX10-Positive Neoplasm","authors":"Andrew L. Folpe ,&nbsp;Michael T. Tetzlaff ,&nbsp;Steven D. Billings ,&nbsp;Jorge Torres-Mora ,&nbsp;Alexander David Borowsky ,&nbsp;Teresa C. Santiago ,&nbsp;Baptiste Ameline ,&nbsp;Daniel Baumhoer","doi":"10.1016/j.modpat.2024.100537","DOIUrl":"10.1016/j.modpat.2024.100537","url":null,"abstract":"<div><p>It is now understood that identical gene fusions may be shared by different entities. We report a distinctive neoplasm of the skin and subcutis, harboring the Ewing sarcoma-associated <em>EWSR1::FLI1</em> fusion but differing otherwise from Ewing sarcoma. Slides and blocks for 5 cutaneous neoplasms coded as other than Ewing sarcoma and harboring <em>EWSR1::FLI1</em> were retrieved. Immunohistochemical and molecular genetic results were abstracted from reports. Methylation profiling was performed. Clinical information was obtained. The tumors occurred in 4 men and 1 woman (median: 25 years of age; range: 19-69 years) and involved the skin/subcutis of the back (2), thigh, buttock, and chest wall (median: 2.4 cm; range: 1-11 cm). Two tumors were present “years” before coming to clinical attention. The lesions were multinodular and circumscribed and consisted of nests of bland, round cells admixed with hyalinized collagenous bands containing spindled cells. Hemorrhage and cystic change were often present; necrosis was absent. All were diffusely S100 protein/SOX10-positive; 4 of 5 were CD99-negative. One tested case was strongly positive for NKX2.2. A variety of other tested markers were either focally positive (glial fibrillary acidic protein, p63) or negative. Molecular genetic results were as follows: <em>EWSR1</em> exon 7::<em>FLI1</em> exon 8, <em>EWSR1</em> exon 11::<em>FLI1</em> exon 5, <em>EWSR1</em> exon 11::<em>FLI1</em> exon 6, <em>EWSR1</em> exon 7::<em>FLI1</em> exon 6, and <em>EWSR1</em> exon 10::<em>FLI1</em> exon 6. Methylation profiling (3 cases) showed these to form a unique cluster, distinct from Ewing sarcoma. All patients underwent excision with negative margins; one received 1 cycle of chemotherapy. Clinical follow-up showed all patients to be alive without disease (median: 17 months; range: 11-62 months). Despite similar gene fusions, the morphologic, immunohistochemical, epigenetic, and clinical features of these unique <em>EWSR1::FLI1</em>-fused neoplasms of the skin and subcutis differ substantially from Ewing sarcoma. Interestingly, <em>EWSR1</em> rearrangements involved exons 10 or 11, only rarely seen in Ewing sarcoma, in a majority of cases. Superficial neurocristic <em>EWSR1::FLI1</em> fusion tumors should be rigorously distinguished from true cutaneous Ewing sarcomas.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141311122","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":"ALK-Rearranged Renal Cell Carcinoma: A Multi-Institutional Study of 9 Cases With Expanding the Morphologic and Molecular Genetic Spectrum","authors":"Ming Zhao ,&nbsp;Xiaona Yin ,&nbsp;Xiaoqun Yang ,&nbsp;Hualei Gan ,&nbsp;Ni Chen ,&nbsp;Guangjie Duan ,&nbsp;Yanfeng Bai ,&nbsp;Xiaodong Teng ,&nbsp;Jiayun Xu ,&nbsp;Rong Fang ,&nbsp;Suying Wang ,&nbsp;Shan Zhong ,&nbsp;Xiaotong Wang ,&nbsp;Lisong Teng","doi":"10.1016/j.modpat.2024.100536","DOIUrl":"10.1016/j.modpat.2024.100536","url":null,"abstract":"<div><p><em>ALK</em>-rearranged renal cell carcinoma (ALK-RCC) is rare, molecularly defined RCC subtype in the recently published fifth edition of World Health Organization classification of tumors. In this study, we described 9 ALK-RCCs from a clinicopathologic, immunohistochemical, and molecular genetic aspect, supporting and extending upon the observations by previous studies regarding this rare subgroup of RCC. There were 6 male and 3 female patients with ages ranging from 14 to 59 years (mean, 34.4 years). None of the patients had sickle cell trait. The diagnosis was based on radical or partial nephrectomy specimen for 8 patients and on biopsy specimen for 1. Tumor size ranged from 2.5 to 7.2 cm (mean, 2.8 cm). Follow-up was available for 6 of 9 patients (6-36 months); 5 had no tumor recurrence or metastasis and 1 developed lung metastasis at 24 months. The patient was subsequently treated with resection of the metastatic tumor followed by crizotinib-targeted therapy, and he was alive without tumor 12 months later. Histologically, the tumors showed a mixed growth of multiple patterns, including papillary, solid, tubular, tubulocystic, cribriform, and corded, often set in a mucinous background. The neoplastic cells had predominantly eosinophilic cytoplasm. Focally, clear cytoplasm with polarized nuclei and subnuclear vacuoles (n = 1), and pale foamy cytoplasm (n = 1) were observed on the tumor cells. The biopsied tumor showed solid growth of elongated tubules merging with bland spindle cells. Other common and uncommon features included psammomatous microcalcifications (n = 5), rhabdoid cells (n = 4), prominent intracytoplasmic vacuoles (n = 4), prominent chronic inflammatory infiltrate (n = 3), signet ring cell morphology (n = 2), and pleomorphic cells (n = 2). By immunohistochemistry, all 9 tumors were diffusely positive for ALK(5A4) and 4 of 8 tested cases showed reactivity for TFE3 protein. By fluorescence in situ hybridization analysis, <em>ALK</em> rearrangement was identified in all the 9 tumors; none of the tested tumors harbored <em>TFE3</em> rearrangement (0/4) or gains of chromosomes 7 and 17 (0/3). <em>ALK</em> fusion partners were identified by RNA-sequencing in all 8 cases analyzed, including <em>EML4</em> (n = 2), <em>STRN</em> (n = 1), <em>TPM3</em> (n = 1), <em>KIF5B</em> (n = 1), <em>HOOK1</em> (n = 1), <em>SLIT1</em> (n = 1), and <em>TPM1</em>(3'UTR) (n = 1). Our study further expands the morphologic and molecular genetic spectrum of ALK-RCC.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141296396","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":"Development and Validation of a HER2-Low Focused Immunohistochemical Scoring System With High-Interobserver Concordance: The Australian HER2-Low Breast Cancer Concordance Study","authors":"Gelareh Farshid ,&nbsp;Jane Armes ,&nbsp;Benjamin Dessauvagie ,&nbsp;Amardeep Gilhotra ,&nbsp;Beena Kumar ,&nbsp;Hema Mahajan ,&nbsp;Ewan Millar ,&nbsp;Nirmala Pathmanathan ,&nbsp;Cameron Snell","doi":"10.1016/j.modpat.2024.100535","DOIUrl":"10.1016/j.modpat.2024.100535","url":null,"abstract":"<div><p>The DESTINY Breast-04 trial revealed survival advantages of trastuzumab deruxtecan for women with metastatic HER2-low breast cancer (1+ or 2+ immunohistochemistry [IHC], without amplification). Although this trial applied the 2018 Americal Society of Clinial Oncology (ASCO)/College of American Pathologists (CAP) HER2 IHC scoring criteria, the subjectivity and imprecision in IHC scoring have raised concerns that patients’ treatment may be misaligned. Our group of 9 experienced breast pathologists collated a deidentified set of 60 breast cancer core biopsies from 3 laboratories, evaluated with the Ventana 4B5 HER2 assay and mostly scored locally as HER2 0 or 1+. Based on ASCO/CAP 2018 criteria and our extensive experience of reporting HER2 IHC, we specified scoring conventions for cancers with low levels of HER2 protein expression, articulating specific scoring pitfalls. Each pathologist then reviewed digitized whole slide images of the IHC slides and scored the HER2 expression for each case. At a subsequent consensus workshop, we reviewed the cases jointly to establish consensus scores for each case and determine the percentage of HER2 expressing tumor cells. Consensus was reached on all cases, with 40 classified as 1+ and 3 as 2+ (not amplified), totaling 43 (71.7%) HER2-low cancers. The remaining cases were HER2 0. In 93.3% of cases (56/60), the consensus score matched with the majority opinion of pathologists’ independent scores. Seven (41.2%) of the 17 cases reported locally as HER2 0 were classified as HER2 low. Conversely, among 32 cases with local scores of 1+, 7 (21.8%) were reclassified as ultralow or null. Individual pathologists’ accuracy in matching the consensus scores ranged from 73.3% to 91.67% (mean, 80.74%). Among HER2-low cancers those in which &lt;20% of the tumor cells expressed HER2 had the lowest concordance levels. Observers Cohen’s κ coefficients for concordance were excellent for 4, good in 1, and moderate in the 4 observers. This reference set of cases with expert consensus HER2 scores will be invaluable for peer training and development of our national external quality assurance program for HER2-low cancers. For assessing breast cancers at the low end of HER2 protein expression, our targeted scoring criteria and explicit instruction on pitfalls improved pathologists’ accuracy and concordance.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141296407","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}