American Journal of Surgical Pathology最新文献

{"title":"Renal Synovial Sarcoma Revisited: Clinicopathologic and Molecular Insights From 70 Cases With Report of a Rare SS18::NEDD4 Fusion.","authors":"Hui Min Tan, Busra Yaprak Bayrak, Katrina Collins, Ziying Ye, Rumeal D Whaley, Ming Liang Oon, Geethanjali Gude, Wai-Tung Lee, Fei Chen, Wendong Yu, Mahmut Akgul, Pedram Argani, Fang-Ming Deng, Michelle R Downes, Nancy Greenland, Sounak Gupta, Huiying He, Jiaoti Huang, Timothy D Jones, Selva Kabul, Seema Kaushal, Kemal Kosemehmetoglu, Antonio Lopez-Beltran, Fiona Maclean, Rohit Mehra, Ankur R Sangoi, Rajal B Shah, Stephanie E Siegmund, Puay Hoon Tan, Toyonori Tsuzuki, Bangchen Wang, Sean R Williamson, Chin-Lee Wu, Douglas Jian-Xian Wu, Ting Zhao, Qiu Rao, Liang Cheng","doi":"10.1097/PAS.0000000000002610","DOIUrl":"https://doi.org/10.1097/PAS.0000000000002610","url":null,"abstract":"<p><p>Synovial sarcoma is a rare malignant mesenchymal neoplasm that typically occurs in soft tissue sites, and the kidney is an uncommon primary location. Previous studies of primary renal synovial sarcoma are limited by small sample sizes, and our understanding remains incomplete. Here, we present the largest multi-institutional case series to date of primary renal synovial sarcoma, with a focus on novel and molecular findings. A total of 70 cases were contributed by multiple institutions. Comprehensive clinical and histopathologic data were collected and analyzed. The mean patient age was 40 years, with a male-to-female ratio of 1.9:1. The most common presenting signs and symptoms were pain and hematuria. The mean tumor size was 11.6 cm (range: 2.3 to 26 cm), with frequent cystic change and necrosis. The mean follow-up was 29 months (range: 2 to 129 mo), and the rates of metastasis, recurrence, and death due to disease were 62.7%, 33.3%, and 50.0%, respectively. Histologically, 56.1% were monophasic synovial sarcoma, 15.1% were biphasic, and 28.8% were poorly differentiated or showed round cell features. Molecularly, SS18::SSX2 fusion was detected in the majority of cases assessed (n=19), followed by SS18::SSX1 fusion (n=6) and a rare SS18::NEDD4 fusion (n=1). Given the morphologic and immunohistochemical overlaps with many other neoplasms, accurate diagnosis with preferably molecular techniques is crucial for appropriate prognostication and treatment of this aggressive tumor.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878884","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":"Expanding the Morphologic, Clinical, and Molecular Spectrum of Succinate Dehydrogenase A (SDHA)-Deficient Renal Cell Carcinoma: A Case Series With Review of Literature.","authors":"Shivani Kandukuri, Anandi Lobo, Harrison Tsai, Manju Aron, Shilpy Jha, Michelle S Hirsch, Sambit Mohanty","doi":"10.1097/PAS.0000000000002611","DOIUrl":"https://doi.org/10.1097/PAS.0000000000002611","url":null,"abstract":"<p><p>Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is defined by mutations in SDH subunits (A, B, C, or D) and is associated with hereditary paraganglioma-pheochromocytoma syndrome and gastrointestinal stromal tumors (GISTs) in some patients. This multi-institutional study analyzed 5 SDHA-deficient RCCs using morphology, immunohistochemistry (IHC), and next-generation sequencing (NGS). Patients had a median age of 40 years with male predominance (4:1). Initially, tumors were diagnosed as SDHA-deficient RCC (1), collecting duct carcinoma (1), or high-grade RCC, NOS (3). NGS subsequently identified 4 tumors as SDHA-deficient RCC. Common histologic features included papillary (100%) and nested (100%) architecture, solid growth (80%), eosinophilic/flocculent cytoplasm (100%), cytoplasmic vacuoles with inclusions (80%), and nuclear grooves (20%). Four of 5 tumors were high-grade (ISUP/WHO grade 3) with desmoplastic stroma and occasional inflammation. All tumors showed loss of SDHB expression (5/5), while SDHA expression was lost in 4/5, demonstrating that SDHA IHC may be preserved despite SDHA mutation. NGS identified SDHA mutations in four tumors. During follow-up, 2 of 4 patients developed metastases within 14 to 34 months, whereas the remaining 2 had no spread after 11 to 19 months. SDHA-deficient RCC displays a spectrum from classic SDHB-deficient RCC morphology to heterogeneous high-grade tumors. It should be considered in high-grade RCCs, particularly RCC NOS with papillary or collecting duct carcinoma-like morphology and vacuolated tumor cells. NGS is recommended, especially when SDHB loss is detected, as SDHA IHC may be retained. Unlike most SDHB-deficient RCCs, SDHA-deficient RCC appears more aggressive, with increased metastatic risk and poorer prognosis.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878931","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 Expression of RORγt and T-bet in ALK-Negative Anaplastic Large Cell Lymphoma: Implications for Biological Heterogeneity and Differential Diagnosis.","authors":"Aya Muramatsu, Daisuke Yamashita, Yuta Tsuyuki, Akira Satou, Naoko Asano, Waki Hosoda, Kennosuke Karube, Shigeo Nakamura, Seiichi Kato","doi":"10.1097/PAS.0000000000002602","DOIUrl":"https://doi.org/10.1097/PAS.0000000000002602","url":null,"abstract":"<p><p>ALK-negative anaplastic large cell lymphoma (ALK-negative ALCL) frequently expresses cytotoxic molecules, which may complicate its distinction from peripheral T-cell lymphoma NOS (PTCL-NOS), particularly in cytotoxic molecule-positive cases. Among these, nodal EBV-negative cytotoxic T-cell lymphoma (CTL) represents an important diagnostic consideration. We evaluated the clinicopathological features of ALK-negative ALCL in comparison with nodal EBV-negative CTL and ALK-positive ALCL, with a focus on the immunohistochemical expression of master transcription factors (RORγt, T-bet, and GATA3). RORγt expression was significantly more frequent in ALK-negative ALCL than in nodal EBV-negative CTL (11/21 [52%] vs. 2/25 [8%]; P=0.001), and was uniformly present in ALK-positive ALCL (10/10 [100%]; P=0.012 vs. ALK-negative ALCL). In contrast, T-bet expression was less frequent in ALK-negative ALCL (2/21 [10%]) than in nodal EBV-negative CTL (9/25 [36%]; P=0.045), and was absent in all ALK-positive ALCL cases. RORγt and T-bet expression were largely mutually exclusive across the cohort, with only one overlapping case. GATA3 expression was absent in all evaluable cases of nodal EBV-negative CTL and ALK-positive ALCL, and was detected in only 2 of 19 ALK-negative ALCL cases (11%). These findings suggest that ALK-negative ALCL shows a distinct transcription factor profile characterized by frequent RORγt expression and infrequent T-bet expression, in contrast to nodal EBV-negative CTL. Assessment of these markers may provide a useful adjunct in the differential diagnosis of cytotoxic T-cell lymphomas, particularly in diagnostically challenging cases.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878941","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":"International Society of Urological Pathology Multidisciplinary Expert Consultation Conference on Evaluation of Treatment Effects in Prostate and Bladder Cancer: Working Group 2: The Urinary Bladder.","authors":"Michelle R Downes, Sara E Wobker, Steven C Smith, Markus Eckstein, Mahmut Akgul, Dilek E Baydar, Fadi Brimo, Eva Compérat, Arndt Hartmann, Ashish M Kamat, Anandi Lobo, Maria R Raspollini, Ankur R Sangoi, Shahrokh F Shariat, Toyonori Tsuzuki, Bas W G van Rhijn, Sean R Williamson, Geert J L H van Leenders, Liang Cheng, Antonio Lopez-Beltran","doi":"10.1097/PAS.0000000000002613","DOIUrl":"https://doi.org/10.1097/PAS.0000000000002613","url":null,"abstract":"<p><p>Treatment effects in the urinary bladder are variable and range from localized post-transurethral resection changes to widespread systemic therapy effects. The International Society of Urological Pathology (ISUP) organized a consensus meeting in Vienna, Austria, in September 2025, focused on the evaluation of treatment effects in both the prostate and bladder. Working Group 2 was assigned the topic of the urinary bladder, and a group of pathologists and clinicians was convened. They worked cooperatively to develop a 30-question, premeeting survey for the ISUP membership, which covered the following topics: systemic therapy-related changes, intravesical therapy and radiotherapy-related changes, macroscopic examination and reporting of treated bladder specimens, and relevant ancillary testing methods for grossly residual and/or minimal residual disease. The premeeting survey results highlighted uncertainty about tumor regression grading (TRG), variability in reporting practices for post-resection and intravesical therapy cases, and divergent opinions on the potential utility of molecular testing. Based on findings from this crowd-sourced experience, the Working Group researched the primary medical literature to study the problematic premeeting survey topics, curated focused presentations of published experience for the consensus meeting participants and developed refined consensus questions for consensus voting. Consensus was achieved in 18/19 polling statements. Use of molecular tests to distinguish benign mimickers from carcinoma did not reach consensus. Overall, the surveys and in-person consensus voting supported standardized reporting practices and terminology for post-therapy cases, interdisciplinary development of a bladder TRG scheme, and the utility of select molecular and immunohistochemical testing in the post-treatment setting.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872703","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":"Unique Thyroid Carcinoma With Somatic Inactivating TSC2 Mutations, Follicular and Melanocytic Differentiation and Distinct Morphologic Features.","authors":"Chatchanan Ausavarungnirun, Muhammad Usama, Daniel Ngov, Ami U Badami, Amanda S Karcioglu, Todd G Kroll","doi":"10.1097/PAS.0000000000002608","DOIUrl":"https://doi.org/10.1097/PAS.0000000000002608","url":null,"abstract":"<p><p>Thyroid carcinomas with mutations in the TSC2 gene have been described rarely. Here, we report a unique thyroid carcinoma that has somatic mutations in TSC2, follicular and melanocytic differentiation and distinct morphologic features, supported by a comprehensive molecular-genetic analyses. No other known pathogenic driver mutations were identified. The TSC2 mutations are predicted to be truncating and result in constitutive activation of mammalian target of rapamycin (mTOR) signaling that was confirmed by transcriptome expression profiling. This is the first demonstration of a thyroid follicular tumor with melanocytic differentiation and corresponding Melan-A expression may be a biomarker for this thyroid cancer. Its diffuse papillary architecture, macronuclei, multinuclear aggregates and intratumoral T lymphocytes are morphologic features not yet described in other TSC2-mutated thyroid carcinomas. Morphologic overlap with classic thyroid papillary carcinoma and known technical difficulties in sequencing the large TSC2 gene make it likely that TSC2-mutated thyroid carcinomas have been underdiagnosed so far. We suggest that TSC2-mutated thyroid carcinoma should be considered in the differential diagnosis of any thyroid tumor that has unusual morphologic and immunohistochemical features or lacks known driver mutations in thyroid cancer.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872669","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":"Immunohistochemical and Molecular Features Distinguishing Metaplastic Breast Carcinoma With Squamous Differentiation From Cutaneous Squamous Cell Carcinoma.","authors":"Cooper D Rutland, Leandra G Kingsley, Sabrina Zdravkovic, Poonam Vohra, Yunn-Yi Chen, Gregor Krings, Gregory R Bean","doi":"10.1097/PAS.0000000000002601","DOIUrl":"https://doi.org/10.1097/PAS.0000000000002601","url":null,"abstract":"<p><p>Metaplastic breast carcinoma (MBC) with squamous differentiation can often be diagnosed by routine histopathologic evaluation, but cutaneous squamous cell carcinoma (cSCC) may enter the differential diagnosis in selected pure squamous carcinomas involving the breast/chest, particularly in limited samples or cases lacking definitive epidermal connection, ductal carcinoma in situ, or complete clinical information. Determining the site of origin is clinically important because management strategies for breast and cutaneous carcinomas differ substantially. We sought to identify immunohistochemical and genetic features that could distinguish MBC with squamous differentiation from cSCC arising in breast/chest skin in cases of uncertain origin. To this end, we comprehensively characterized 15 MBC with pure to mixed squamous differentiation and 18 invasive/in situ cSCC arising in breast/chest skin. Comparisons between these cohorts and 48 SCC of other anatomic sites identified significant immunohistochemical differences, with CK7, SOX10, and TRPS1 expression more frequent in MBC than cSCC (P=0.0005, 0.0227, and 0.0290, respectively). HER2 overexpression was identified only in breast and esophageal carcinomas. Next-generation sequencing of the breast/chest tumors demonstrated more frequent PIK3CA/PIK3R1 alterations in MBC than cSCC (P=0.0040), whereas NOTCH1 mutations were exclusive to cSCC (P=0.0407). cSCC showed higher tumor mutational burden and percentage of ultraviolet-associated mutations than MBC (P=0.0002 and <0.0001, respectively). These distinguishing features were then applied to 9 additional breast cases of uncertain origin, demonstrating the added value of molecular data in diagnostically challenging cases. Overall, these findings support a stepwise diagnostic approach integrating immunohistochemistry, selected molecular features, and clinicopathologic context to aid in this distinction.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872696","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":"Papillary Renal Neoplasm With Reverse Polarity Is a Distinct Distal Nephron-Derived Tumor With Unique Methylation Profile.","authors":"Kyung Park, Yuxiu Wang, Kisong Kim, Jonathan Serrano, Fei Chen, Varshini Vasudevaraja, Xiaojun Feng, Leili Mirsadraei, Matija Snuderl, Fang-Ming Deng","doi":"10.1097/PAS.0000000000002568","DOIUrl":"10.1097/PAS.0000000000002568","url":null,"abstract":"<p><p>Papillary renal neoplasm with reverse polarity (PRNRP) has been proposed as a distinct subtype of renal cell neoplasm with recurrent KRAS mutations and indolent behavior. However, its epigenetic landscape is poorly understood. In this study, 12 PRNRPs and a PRNRP initially diagnosed as \"papillary adenoma\" were analyzed. All 13 cases underwent targeted next-generation sequencing for driver mutations. Eleven PRNRPs were profiled using the Illumina MethylationEPIC array and compared with a reference cohort of 71 common renal cell tumors. KRAS mutations were identified in 12 of 13 (92%) cases of PRNRP. Copy-number analysis from methylation profiling showed that 9 of 11 (82%) PRNRPs lacked copy-number changes. Two cases showed a focal loss of chromosome 8 and a gain of chromosome 16, respectively. Unsupervised clustering based on methylation data showed that PRNRPs form a distinct epigenetic group, separate from papillary renal cell carcinomas (pRCCs) and other major renal tumors, but with the closest affinity to clear cell papillary renal cell tumors. In addition, DNA methylation analysis suggested PRNRP may arise from the distal nephron, in contrast to pRCC, which appears to recapitulate proximal tubules. These findings support PRNRP as a subtype of renal cell neoplasm with a distinct epigenetic signature.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"1046-1054"},"PeriodicalIF":4.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148262908","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 Study of 39 Mismatch Repair-deficient Sarcomas Demonstrates Recurrent Histologic Patterns and Supports Universal Screening of Pleomorphic Rhabdomyosarcoma, Uterine Leiomyosarcoma, and Undifferentiated and Unclassified Sarcomas.","authors":"Igor Odintsov, Jonathan A Nowak, Esther Baranov, Thierry Alcindor, Candace L Haddox, Vinayak Venkataraman, Lynette M Sholl, Suzanne George, Leona A Doyle, Mark Redston, David J Papke","doi":"10.1097/PAS.0000000000002579","DOIUrl":"10.1097/PAS.0000000000002579","url":null,"abstract":"<p><p>Mismatch repair-deficient (dMMR) sarcomas are rare and incompletely characterized. Here, we studied 39 sarcomas with high microsatellite instability (MSI-H) and/or biallelic MMR gene inactivation (21 MSH2 , 9 MLH1 , 4 PMS2 , 4 MSH6 , 1 EPCAM ). All tumors evaluated with immunohistochemistry (IHC; n = 36) showed loss of MMR protein expression. Eight sarcomas were index neoplasms among the 15 patients with documented Lynch syndrome. Eighteen of 1531 sarcomas (1.2%) in our sequencing database were dMMR, with enrichment in pleomorphic rhabdomyosarcoma (PRMS; 1/5), uterine leiomyosarcoma (LMS; 7/124; 5.6%), and unclassified/undifferentiated pleomorphic sarcoma (UPS; 6/259; 2.3%). MMR IHC screening of independent cases confirmed MMR deficiency in PRMS (2/20), uterine LMS (2/20), and unclassified/UPS (1/20). Two histologic patterns were identified among unclassified/UPS. Ten tumors, designated \"distinctive lobulated inflammatory sarcoma\" (DLIS), showed lobular architecture, florid inflammation, and histiocytoid, variably pleomorphic neoplastic cells. All 6 patients with DLIS and follow-up (median: 6.0 y; range: 3 mo to 8.6 y) were alive with no evidence of disease (ANED), and 2 DLIS responded completely to immune checkpoint inhibition. A morphologically different group of 6 unclassified high-grade sarcomas showed sheets of epithelioid-to-rhabdoid cells with eosinophilic cytoplasm; among 5 patients with follow-up (median: 1.1 y; range: 4 mo to 6.9 y), only 1 was ANED. Surprisingly, all 3 PRMS patients with follow-up (median: 5.7 y; range: 4.2 to 8.3 y) were ANED, including 2 with complete responses of metastases to systemic therapy. We conclude that PRMS, uterine LMS, and unclassified/UPS showed sufficiently prevalent MMR deficiency to justify prospective MMR IHC screening for Lynch syndrome and to identify patients who might benefit from immune checkpoint inhibition. Histologic subtyping of unclassified sarcomas predicted prognosis and therapeutic response. We propose universal MMR IHC screening of (1) PRMS, (2) uterine LMS, (3) unclassified/UPS, and (4) any sarcoma in a patient with a personal or family history of Lynch syndrome.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"1029-1045"},"PeriodicalIF":4.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148222623","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":"DLL3 Expression in a Genotyped Cohort of Sporadic Medullary Thyroid Carcinomas.","authors":"Maria Cristina Riascos, Fedaa Najdawi, Sara Ahmadi, Thomas J Roberts, Kartik Sehgal, Justine A Barletta","doi":"10.1097/PAS.0000000000002571","DOIUrl":"10.1097/PAS.0000000000002571","url":null,"abstract":"<p><p>Delta-like ligand 3 (DLL3) has been identified as a therapeutic target in high-grade neuroendocrine carcinomas, particularly small cell lung carcinoma. Data on DLL3 expression in medullary thyroid carcinoma (MTC) are limited; moreover, the relationship between DLL3 expression and MTC genotype has not been explored. We evaluated DLL3 expression (based on staining intensity and percentage of positive cells) in a genotyped cohort of sporadic MTC. In our cohort of 39 cases, 27 (69%) tumors were positive for DLL3, including 1 (4%) with low DLL3 expression, 10 (26%) with moderate expression, and 16 (41%) with high expression. DLL3 expression was significantly associated with grade ( P =0.036), presence of a RET mutation ( P =0.014), presence of lymph node metastases at diagnosis ( P <0.005), and disease progression ( P <0.005). All 9 (100%) high-grade tumors were positive for DLL3. In contrast, 18 (60%) of 30 low-grade tumors were DLL3 positive. DLL3 was positive in 17 (89%) of 19 RET -mutated tumors, 4 (50%) of 8 RAS -mutated tumors, and 6 (50%) of 12 RET/RAS wild-type tumors. All 24 primary tumors with associated lymph node metastases at diagnosis were positive for DLL3. Among cases with follow-up data (n=35), all 17 tumors with disease progression were DLL3 positive (13 RET -mutated tumors, 1 RAS -mutated tumor, and 3 RET/RAS wild-type tumors), including 5 with moderate expression and 12 with high expression. Most MTCs express DLL3; moreover, DLL3 expression is associated with lymph node metastases at diagnosis and disease progression, indicating that DLL3 may be an effective therapeutic target in MTC.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"1076-1085"},"PeriodicalIF":4.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148196970","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":"Ovarian Mucinous Neoplasms Associated With Mesonephric-like Lesions: An Updated Study With Novel Pathologic Features.","authors":"Colton Smith, Jonathan Dudley, Johanna Savage, Koen Van de Vijver, Liu Hong, Weihua Song, Gözde Kir, Katerina Kearns, Delaram Shakiba, Kathi H Adamson, Saron A Smith, Yun Wang, Mei Liu, Aijun Liu, Russell Vang, W Glenn McCluggage, Deyin Xing","doi":"10.1097/PAS.0000000000002573","DOIUrl":"10.1097/PAS.0000000000002573","url":null,"abstract":"<p><p>The coexistence of benign mesonephric-like proliferation (MLP), mesonephric-like hyperplasia (MLH), and mesonephric-like adenocarcinoma (MLA) with ovarian mucinous cystadenoma or mucinous borderline tumor (MBT) has been previously reported; however, this phenomenon is exceedingly rare, and understanding of the pathology and biology remains limited. Here we report additional cases, with an emphasis on expanded observations and novel pathologic features. This series included 9 cases: (1) 2 cases of mixed MLA and endometrioid adenocarcinoma associated with cystic mucinous neoplasm of lower gastrointestinal (GI) type (case 1) or mucinous cystadenoma (case 2); (2) 1 case of MLA associated with MBT and mucinous adenocarcinoma (case 3); (3) 4 cases of MLA associated with MBT (cases 4 and 5) or mucinous cystadenoma (cases 6 and 7); and (4) 2 cases of MLP/MLH associated with MBT (cases 8 and 9). All mesonephric-like lesions were diffusely positive for PAX8 and either diffusely (7 cases) or focally (2 cases) positive for GATA3. Focal TTF-1 expression was observed in 4 cases (4/9, 44.4%). All mucinous tumors, except for case 1, showed either focal (4 cases) or diffuse (4 cases) PAX8 positivity. Molecular analysis in case 1 revealed a common KRAS p.G12A driver mutation in all 3 tumor components (MLA, endometrioid adenocarcinoma, and mucinous tumor), indicating clonal relatedness. In contrast, pathogenic somatic mutations in ARID1A , DNMT3A , PIK3CA , and TET2 were detected only in the MLA and endometrioid adenocarcinoma, but not in the mucinous tumor component, suggesting lineage-specific differentiation. Notably, case 1 represents the first reported example of a mesonephric-like lesion associated with a mucinous tumor exhibiting lower GI morphology and immunophenotype. Case 3 represents the first case with mucinous adenocarcinoma in this scenario. Case 9 represents the first reported instance in which both ovaries were independently involved by MLP/MLH and MBT. The presence of benign MLP/MLH alongside MLA suggests that the former may represent noncancerous precursor lesions with the potential to develop into MLA; they may represent benign (MLP) or borderline (MLH) mesonephric-like lesions. Whether mesonephric-like lesions serve as precursors of ovarian mucinous tumors remains debated, but their coexistence in the ovary, as documented in 20 cases to date (including previously published cases and the current series), may represent a unique biological process and provide an ideal model for investigating mechanisms of transdifferentiation and tumorigenesis.</p>","PeriodicalId":7772,"journal":{"name":"American Journal of Surgical Pathology","volume":" ","pages":"1086-1096"},"PeriodicalIF":4.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148025674","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}