Modern Pathology最新文献

{"title":"Comparison of Primary and Metastatic Fumarate Hydratase-Deficient Renal Cell Carcinomas Documents Morphologic Divergence and Potential Diagnostic Pitfall With Peritoneal Mesothelioma","authors":"","doi":"10.1016/j.modpat.2024.100561","DOIUrl":"10.1016/j.modpat.2024.100561","url":null,"abstract":"<div><p>Fumarate hydratase (FH)-deficient renal cell carcinomas are rare neoplasms characterized by wide morphologic heterogeneity and pathogenetic mutations in the <em>FH</em> gene. They often show aggressive behavior with rapid diffusion to distant organs, so novel therapeutic scenarios have been explored, including EGFR inhibitors and PD-L1 expression for targeted immunotherapy. Herein, we investigated a series of 11 primary FH-deficient renal cell carcinomas and 7 distant metastases to evaluate tumor heterogeneity even in metastatic sites and estimate the specific spread rates to various organs. Furthermore, the tumors were tested for immunohistochemical PD-L1 expression and <em>EGFR</em> mutations. Most metastatic cases involved the abdominal lymph nodes (4/7; 57%), followed by the peritoneum (3/7; 42%), the liver (2/7; 29%), and the lungs (1/7; 14%). Six metastatic localizations were histologically documented, revealing a morphologic heterogeneous architecture often differing from that of the corresponding primary renal tumor. Peritoneal involvement morphologically resembled a benign reactive mesothelial process or primary peritoneal mesothelioma, thus advocating to perform an accurate immunohistochemical panel, including PAX8 and FH, to reach a proper diagnosis. A pure low-grade succinate dehydrogenase–looking primary FH-deficient renal cell carcinoma was also recorded. As for therapy, significant PD-L1 labeling was found in 60% of primary renal tumors, whereas none of them carried pathogenetic <em>EGFR</em> mutations. Our data show that FH-deficient renal cell carcinoma may be morphologically heterogeneous in metastases as well, which involve the lymph nodes, the liver, and the peritoneum more frequently than other renal tumors. Due to the high frequency of this latter (42%), pathologists should always be concerned about ruling out mesothelial-derived mimickers, and the occurrence of rarer, primary, low-grade–looking types. Finally, contrary to <em>EGFR</em> mutations, PD-L1 expression could be a possible predictive biomarker for the therapy of these tumors.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0893395224001418/pdfft?md5=a38c1e0947d0942b39293eb53c0710eb&pid=1-s2.0-S0893395224001418-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141600580","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":"Undifferentiated Round Cell Sarcoma With CRTC1::SS18 Fusion: Expanding Clinicopathologic Features of a Rare Translocation Sarcoma With Prominent Desmoplastic Stroma","authors":"","doi":"10.1016/j.modpat.2024.100555","DOIUrl":"10.1016/j.modpat.2024.100555","url":null,"abstract":"<div><p>Undifferentiated round cell sarcomas (URCS) represent a diverse group of tumors, including conventional Ewing sarcoma, round cell sarcoma with <em>EWSR1/FUS</em>–non-ETS fusions, <em>CIC</em>-rearranged sarcoma, and sarcoma with <em>BCOR</em> alterations. Since 2018, 3 cases of URCS with a novel <em>CRTC1</em>::<em>SS18</em> gene fusion have been reported in the literature. Herein, we report 3 additional cases of <em>CRTC1</em>::<em>SS18</em> sarcoma, thereby doubling the number of described cases and expanding the clinicopathologic features of this rare translocation sarcoma. Together with the previously reported cases, we show that the male-to-female ratio is 1:2 with a median age of 34 years (range, 12-42 years). Tumors occurred primarily in intramuscular locations involving the lower extremity. Histologically, all tumors contained uniform round-to-epithelioid cells with a moderate amount of eosinophilic cytoplasm growing in sheets and nests with prominent desmoplastic stroma reminiscent of desmoplastic small round cell tumor. Immunohistochemical results were nonspecific, demonstrating variable expression of CD99 (patchy), ALK, GATA3, and cyclin D1. RNA sequencing revealed <em>CRTC1</em>::<em>SS18</em> gene fusions in all cases, involving exons 1 to 2 of <em>CRTC1</em> (the 5′ partner gene) on chromosome 19 and either exon 2 or exon 4 of <em>SS18</em> (the 3′ partner gene) on chromosome 18. The clinical course was variable. Although 1 previously reported case demonstrated aggressive behavior with a fatal outcome, 2 others had a relatively indolent course with gradual growth for 6 to 7 years prior to resection. Two cases developed metastatic disease, including 1 case with bilateral lung metastasis and 1 with locoregional spread to a lymph node. By analyzing the clinicopathologic features, we aimed to improve recognition of this rare translocation sarcoma to better understand its biologic potential, optimize patient management, and expand the current classification of URCS.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141555223","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":"Single-Cell Transcriptome Analysis Reveals 2 Subtypes of Tumor Cells of Sclerosing Pneumocytoma With Distinct Molecular Features and Clinical Implications","authors":"","doi":"10.1016/j.modpat.2024.100560","DOIUrl":"10.1016/j.modpat.2024.100560","url":null,"abstract":"<div><p>Pulmonary sclerosing pneumocytoma (PSP) is a rare, distinctive benign lung adenoma of pneumocyte origin. Despite its rarity, the tumor’s unique cellular morphology has sparked ongoing debates regarding the origin of its constituent cells. This study aimed to elucidate the molecular features of PSP tumor cells and enhance our understanding of the cellular processes contributing to PSP formation and biological behavior. Tissue samples from PSP and corresponding normal lung tissues (n = 4) were collected. We employed single-cell RNA sequencing and microarray-based spatial transcriptomic analyses to identify cell types and investigate their transcriptomes, with a focus on transcription factors, enriched gene expression, and single-cell trajectory evaluations. Our analysis identified 2 types of tumor cells: mesenchymal-epithelial dual-phenotype (MEDP) cells and a distinct subpopulation of type II alveolar epithelial cells exhibiting characteristics slightly reminiscent of type I alveolar epithelial cells (AT2Cs) corresponding to histologic round stromal cells and surface cuboidal cells, respectively. MEDP cells displayed weak alveolar epithelial differentiation but strong collagen production capabilities, as indicated by the expression of both TTF-1 and vimentin. These cells played a pivotal role in forming the solid and sclerotic areas of PSP. Moreover, MEDP cells exhibited a pronounced propensity for epithelial-mesenchymal transition, suggesting a greater potential for metastasis compared with AT2Cs. The capillary endothelial cells of PSP displayed notable diversity. Overall, this study provides, for the first time, a comprehensive mapping of the single-cell transcriptome profile of PSP. Our findings delineate 2 distinct subtypes of tumor cells, MEDP cells and AT2Cs, each with its own biological characteristics and spatial distribution. A deeper understanding of these cell types promises insights into the histology and biological behaviors of this rare tumor.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141555222","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":"Immune Phenotype-Genotype Associations in Primary Clear Cell Renal Cell Carcinoma and Matched Metastatic Tissue","authors":"","doi":"10.1016/j.modpat.2024.100558","DOIUrl":"10.1016/j.modpat.2024.100558","url":null,"abstract":"<div><p>Adjuvant immunotherapy has been recently recommended for patients with metastatic clear cell renal cell carcinoma (ccRCC), but there are no tissue biomarkers to predict treatment response in ccRCC. Potential predictive biomarkers are mainly assessed in primary tumor tissue, whereas metastases (METs) remain understudied. To explore potential differences between genomic alterations and immune phenotypes in primary tumors and their matched METs, we analyzed primary tumors (PTs) of 47 ccRCC patients and their matched distant METs by comprehensive targeted parallel sequencing, whole-genome copy number variation analysis, determination of microsatellite instability, and tumor mutational burden. We quantified the spatial distribution of tumor-infiltrating CD8⁺ T cells and coexpression of the T-cell-exhaustion marker thymocyte selection-associated high mobility group box (TOX) by digital immunoprofiling and quantified tertiary lymphoid structures. Most METs were pathologically “cold.” Inflamed, pathologically “hot” PTs were associated with decreased disease-free survival, worst for patients with high levels of CD8⁺TOX⁺ T cells. Interestingly, inflamed METs showed a relative increase in exhausted CD8⁺TOX⁺ T cells and increased accumulative size of tertiary lymphoid structures compared with PTs. Integrative analysis of molecular and immune phenotypes revealed <em>BAP1</em> and <em>CDKN2A/B</em> deficiency to be associated with an inflamed immune phenotype. Our results highlight the distinct spatial distribution and differentiation of CD8+ T cells at metastatic sites, and the association of an inflamed microenvironment with specific genomic alterations.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0893395224001388/pdfft?md5=64710c524cf3d80798aa4ff621a2d88a&pid=1-s2.0-S0893395224001388-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141538159","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":"Fluorescence Confocal Microscopy Can Accelerate Diagnosis of Cervical Lymphadenopathy","authors":"","doi":"10.1016/j.modpat.2024.100559","DOIUrl":"10.1016/j.modpat.2024.100559","url":null,"abstract":"<div><p>Fluorescence confocal microscopy (FCM) is an optical technique that uses laser light sources of different wavelengths to generate real-time images of fresh, unfixed tissue specimens. Unlike conventional histologic evaluation methods, FCM is able to assess fresh tissue samples without the associated cryo artifacts typically observed after frozen sectioning. The purpose of this study was to evaluate the utility of FCM imaging in the differential diagnosis of cervical lymphadenopathy. Twenty-two cervical lymph node specimens from patients with lymphadenopathy of unknown origin were imaged by FCM. Two pathologists independently evaluated the scans for suspicion of malignancy and preliminary diagnosis. Malignancy was reliably excluded or confirmed by both pathologists with a sensitivity of 90.9% for pathologist 1 and 100% for pathologist 2. The specificity was 100% for both pathologists. For the preliminary diagnosis, almost perfect agreement with the final diagnosis was observed for both pathologists (κ = 0.94 for pathologist 1 and κ = 1.00 for pathologist 2). This is the first study to investigate lymph node specimens with different diagnoses, including lymphoma, using FCM. Our results indicate that differential diagnosis of lymph node specimens is feasible in FCM images, thus encouraging further exploration of FCM imaging in lymph node specimens to accelerate diagnosis and open the possibility of digitizing diagnosis on fresh, unfixed tissue.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S089339522400139X/pdfft?md5=bc67a3cf2c97ed1f630ec176f137d703&pid=1-s2.0-S089339522400139X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141538158","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":"Quantitative Measurement of HER2 Expression in Non–Small Cell Lung Cancer With a High-Sensitivity Assay","authors":"","doi":"10.1016/j.modpat.2024.100556","DOIUrl":"10.1016/j.modpat.2024.100556","url":null,"abstract":"<div><p>Recently, low human epidermal growth factor receptor 2 (HER2) protein expression has been proposed as a predictive biomarker for response to the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in metastatic breast cancer. HER2 expression in non–small cell lung cancer (NSCLC) patients has never been carefully measured, and little is known about the frequency of cases with unamplified but detectable levels of the protein. Although some HER2-targeted therapies have been studied in NSCLC patients, they have been restricted to those with genomic <em>ERBB2</em> gene alterations, which only represent relatively rare cases of NSCLC. Still, emerging investigations of T-DXd in NSCLC have shown promise in patients with unamplified HER2. Taken together, we hypothesize that there may be many cases of NSCLC with levels of HER2 protein expression comparable with levels seen in breast cancer that benefit from T-DXd.</p><p>Here, we used a previously validated, analytic, quantitative immunofluorescence (QIF) assay that is more sensitive than legacy clinical HER2 immunohistochemistry assays. We measured HER2 protein levels in NSCLC cases to determine the proportion of cases with detectable HER2 expression. Using cell line calibration microarrays alongside our QIF method enabled us to convert HER2 signal into units of attomoles per mm². We found that over 63% of the 741 analyzed NSCLC cases exhibited HER2 expression above the limit of detection, with more than 17% of them exceeding the lower limit of quantification. Although the threshold for response to T-DXd in breast cancer is still unknown, many cases of NSCLC have expression in a range comparable to breast cancer cases with immunohistochemistry scores of 1+ or 2+. Our assay could potentially select NSCLC cases with a detectable target (ie, HER2) that might benefit from HER2 antibody-drug conjugates, irrespective of <em>ERBB2</em> genomic alterations.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534830","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":"Differential NEUROD1, ASCL1, and POU2F3 Expression Defines Molecular Subsets of Bladder Small Cell/Neuroendocrine Carcinoma With Prognostic Implications","authors":"","doi":"10.1016/j.modpat.2024.100557","DOIUrl":"10.1016/j.modpat.2024.100557","url":null,"abstract":"<div><p>Small cell carcinomas (SMC) of the lung are now molecularly classified based on the expression of transcriptional regulators (NEUROD1, ASCL1, POU2F3, and YAP1) and DLL3, which has emerged as an investigational therapeutic target. PLCG2 has been shown to identify a distinct subpopulation of lung SMC with stem cell-like and prometastasis features and poor prognosis. We analyzed the expression of these novel neuroendocrine markers and their association with traditional neuroendocrine markers and patient outcomes in a cohort of bladder neuroendocrine carcinoma (NEC) consisting of 103 SMC and 19 large cell NEC (LCNEC) assembled in tissue microarrays. Coexpression patterns were assessed and integrated with detailed clinical annotation including overall (OS) and recurrence-free survival (RFS) and response to neoadjuvant/adjuvant chemotherapy. We identified 5 distinct molecular subtypes in bladder SMC based on the expression of ASCL1, NEUROD1, and POU2F3: ASCL1+/NEUROD1− (n = 33; 34%), ASCL1− /NEUROD1+ (n = 21; 21%), ASCL1+/NEUROD1+ (n = 17; 17%), POU2F3+ (n = 22, 22%), and ASCL1− /NEUROD1− /POU2F3− (n = 5, 5%). POU2F3+ tumors were mutually exclusive with those expressing ASCL1 and NEUROD1 and exhibited lower expression of traditional neuroendocrine markers. PLCG2 expression was noted in 33 tumors (32%) and was highly correlated with POU2F3 expression (<em>P</em> &lt; .001). DLL3 expression was high in both SMC (n = 72, 82%) and LCNEC (n = 11, 85%). YAP1 expression was enriched in nonneuroendocrine components and negatively correlated with all neuroendocrine markers. In patients without metastatic disease who underwent radical cystectomy, PLCG2+ or POU2F3+ tumors had shorter RFS and OS (<em>P</em> &lt; .05), but their expression was not associated with metastasis status or response to neoadjuvant/adjuvant chemotherapy. In conclusion, the NEC of the bladder can be divided into distinct molecular subtypes based on the expression of ASCL1, NEUROD1, and POU2F3. POU2F3-expressing tumors represent an ASCL1/NEUROD1-negative subset of bladder NEC characterized by lower expression of traditional neuroendocrine markers. Marker expression patterns were similar in SMC and LCNEC. Expression of PLCG2 and POU2F3 was associated with shorter RFS and OS. DLL3 was expressed at high levels in both SMC and LCNEC of the bladder, nominating it as a potential therapeutic target.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534829","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":"Comprehensive Characterization of Intraductal Oncocytic Papillary Neoplasm of the Pancreas: A Systematic and Critical Review","authors":"","doi":"10.1016/j.modpat.2024.100554","DOIUrl":"10.1016/j.modpat.2024.100554","url":null,"abstract":"<div><p>Intraductal oncocytic papillary neoplasm (IOPN) of the pancreas is a recently recognized pancreatic tumor. Here, we aimed to determine its most essential features with the systematic review tool. PubMed, Scopus, and Embase were searched for studies reporting data on pancreatic IOPN. The clinicopathologic, immunohistochemical, and molecular data were extracted and summarized. Then, a comparative analysis of the molecular alterations of IOPN with those of pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasm from reference cohorts (including The Cancer Genome Atlas) was conducted. The key findings from 414 IOPNs were as follows: 1) The male-to-female ratio was 1.5:1. Pancreatic head was the most common site (131/237; 55.3%), but a diffuse tumor extension involving more than one pancreatic segment was described in about 1 out of 5 cases (49/237; 20.6%). The mean size was 45.5 mm. An associated invasive carcinoma was present in 50% of cases (168/336). In those cases, most tumors were pT1 or pT2 and pN0 (&gt;80%), and vascular invasion was uncommon (20.6%). Regarding survival, more than 90% of patients were alive after surgical resection. 2) Immunohistochemical and molecular features were as follows. The most commonly expressed mucins were MUC5AC (110/112; 98.2%) and MUC6 (78/84; 92.8%). Compared with pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasm, the classic pancreatic drivers <em>KRAS</em>, <em>TP53</em>, <em>CDKN2A</em>, <em>SMAD4</em>, and <em>GNAS</em> were less altered in IOPN (<em>P</em> &lt; .01). Moreover, fusions involving <em>PRKACA</em> or <em>PRKACB</em> gene were detected in all of the 68 cases examined, with <em>PRKACB::ATP1B1</em> being the most common (27/68 cases; 39.7%). These genomic events emerged as an entity-defining molecular alteration of IOPN (<em>P</em> &lt; .01). Thus, such fusions represent a promising biomarker for diagnostic purposes. Recent evidence also suggests their role in influencing the acquisition of oncocytic morphology. IOPN is a distinct pancreatic neoplasm with specific clinicopathologic and molecular features. Considering the clinical or prognostic implications, its recognition is essential for pathologists and, ultimately, patients’ management</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0893395224001340/pdfft?md5=f907740a845cfca52fe72095de37159c&pid=1-s2.0-S0893395224001340-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476882","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":"PLAG1-Rearranged Uterine Sarcomas: A Study of 11 Cases Showing a Wide Phenotypical Spectrum Not Limited to Myxoid Leiomyosarcoma-like Morphology","authors":"Michael Michal ,&nbsp;Abbas Agaimy ,&nbsp;Sabrina Croce ,&nbsp;Gunhild Mechtersheimer ,&nbsp;John M. Gross ,&nbsp;Deyin Xing ,&nbsp;Debra A. Bell ,&nbsp;Sounak Gupta ,&nbsp;Elaheh Mosaieby ,&nbsp;Petr Martínek ,&nbsp;Natálie Klubíčková ,&nbsp;Květoslava Michalová ,&nbsp;Jiří Bouda ,&nbsp;Jindřich Fínek ,&nbsp;Tahyna Hernandez ,&nbsp;Michal Michal ,&nbsp;J. Kenneth Schoolmeester ,&nbsp;Ondrej Ondič","doi":"10.1016/j.modpat.2024.100552","DOIUrl":"10.1016/j.modpat.2024.100552","url":null,"abstract":"<div><p><em>PLAG1</em> gene fusions were recently identified in a subset of uterine myxoid leiomyosarcomas (M-LMS). However, we have encountered cases of <em>PLAG1</em>-rearranged uterine sarcomas lacking M-LMS-like morphology and/or any expression of smooth muscle markers. To better characterize their clinicopathologic features, we performed a multiinstitutional search that yielded 11 cases. The patients ranged in age from 34 to 72 years (mean, 57 years). All tumors arose in the uterine corpus, ranging in size from 6.5 to 32 cm (mean, 15 cm). The most common stage at presentation was pT1b (n = 6), and 3 cases had stage pT1 (unspecified), and 1 case each presented in stages pT2a and pT3b. Most were treated only with hysterectomy and adnexectomy. The follow-up (range, 7-71 months; median, 39 months) was available for 7 patients. Three cases (7-21 months of follow-up) had no evidence of disease. Three of the 4 remaining patients died of disease within 55 to 71 months, while peritoneal spread developed in the last patient, and the patient was transferred for palliative care at 39 months. Morphologically, the tumors showed a high intertumoral and intratumoral heterogeneity. M-LMS-like and epithelioid leiomyosarcoma–like morphology were present in 3 and 5 primary tumors, respectively, the remaining mostly presented as nondescript ovoid or spindle cell sarcomas. Unusual morphologic findings included prominently hyalinized stroma (n = 3), adipocytic differentiation with areas mimicking myxoid liposarcoma (n = 2), osteosarcomatous differentiation (n = 1), and undifferentiated pleomorphic sarcoma–like areas (n = 1). The mitotic activity ranged from 3 to 24 mitoses per 10 high-power fields (mean, 9); 3 of 10 cases showed necrosis. In 3 of 11 cases, no expression of smooth muscle actin, h-caldesmon, or desmin was noted, whereas 5 of 5 cases expressed PLAG1. By RNA sequencing, the following fusion partners were identified: <em>PUM1</em>, <em>CHCHD7</em> (each n = 2), <em>C15orf29</em>, <em>CD44</em>, <em>MYOCD</em>, <em>FRMD6</em>, <em>PTK2</em>, and <em>TRPS1</em> (each n = 1). One case only showed <em>PLAG1</em> gene break by fluorescence in situ hybridization. Our study documents a much broader morphologic spectrum of <em>PLAG1</em>-rearranged uterine sarcomas than previously reported, encompassing but not limited to M-LMS-like morphology with occasional heterologous (particularly adipocytic) differentiation. As it is currently difficult to precisely define their line of differentiation, for the time being, we suggest using a descriptive name “<em>PLAG1</em>-rearranged uterine sarcoma.”</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469439","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":"Mapping the Spatial Dynamics of the CD4+ T Cell Spectrum in Classical Hodgkin Lymphoma","authors":"Victoria Menéndez ,&nbsp;José L. Solórzano ,&nbsp;Mónica García-Cosío ,&nbsp;Laura Cereceda ,&nbsp;Eva Díaz ,&nbsp;Mónica Estévez ,&nbsp;Giovanna Roncador ,&nbsp;Zaira Vega ,&nbsp;Carlos Montalbán ,&nbsp;Arutha Kulasinghe ,&nbsp;Juan F. García","doi":"10.1016/j.modpat.2024.100551","DOIUrl":"10.1016/j.modpat.2024.100551","url":null,"abstract":"<div><p>As around 25% to 30% of classical Hodgkin lymphoma (cHL) patients with advanced stages do not respond to standard therapies, the tumor microenvironment of cHL is one avenue that may be explored with the aim of improving risk stratification. CD4+ T cells are thought to be one of the main cell types in the tumor microenvironment. However, few immune signatures have been studied, and many of these lack related spatial data. Thus, our aim is to spatially resolve the CD4+ T cell subtypes that influence cHL outcome, depicting new immune signatures or transcriptional patterns that are in crosstalk with the tumor cells. This study was conducted using the NanoString GeoMx digital spatial profiling technology, based on the selection of distinct functional areas of patients’ tissues followed by gene-expression profiling. The goals were to assess the differences in CD4+ T cell populations between tumor-rich and immune-predominant areas defined by different CD30 and PD-L1 expression levels and seek correlations with clinical metadata. Our results depict a complex map of CD4+ T cells with different functions and differentiation states that are enriched at distinct locations, the flux of cytokines and chemokines that could be related to these, and the specific relationships with the clinical outcome.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469438","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}