PATHOLOGICA最新文献

{"title":"Malignant metastatising solitary fibrous tumor of the ovary with additional dedifferentiation and osteoid deposition: an unusual presentation, with a brief description of a diagnostic alghoritm.","authors":"Livia Maccio, Emma Bragantini, Mattia Barbareschi, Alessia Piermattei, Angela Santoro, Gian Franco Zannoni","doi":"10.32074/1591-951X-N1180","DOIUrl":"10.32074/1591-951X-N1180","url":null,"abstract":"<p><p>Solitary fibrous tumor (SFT) is a rare spindle cell neoplasm showing fibroblastic differentiation, initially observed in the pleura, but now currently recognized to develop in any extrapleuric location ^1,2. In the female genital tract, SFTs are extremely rare and have a predilection for the vulva, vagina and cervix ^2,3. There are very few cases of ovarian SFTs having been reported in the literature. Malignant SFTs of the ovary are exceedingly rare neoplasms characterized by their mesenchymal origin and distinctive histopathological features. First identified as a separate entity in soft tissues, SFTs of the ovary represent a diagnostic and therapeutic challenge due to their rarity and overlapping characteristics with other ovarian neoplasms. These tumors are generally considered benign, but their malignant variants can exhibit aggressive behavior, including metastasis and recurrence. The pathogenesis of SFTs is associated with molecular abnormalities, particularly NAB2-STAT6 gene fusions ⁴, which play a crucial role in diagnosis and may have prognostic implications. Our case of ovarian malignant SFT showed an unusual pattern of dedifferentiation. The conventional SFT component displays a pattern less architecture, uniform fibroblastic morphology, prominent branching vessels, and is diffusely positive for CD34 and STAT6. However, there is an abrupt transition to a pleomorphic, high mitotic rate component with fascicular spindle cell morphology resembling a smooth muscle neoplasm. This dedifferentiated area is positive for SMA and desmin but negative for CD34 and STAT6 and includes focal ossification. Stains for MDM2, CDK4, and caldesmon are negative. The case is notable for its atypical progression, as most dedifferentiated SFTs transition directly from a benign-appearing SFT to a high-grade component without signs of malignancy in the conventional SFT region.</p>","PeriodicalId":45893,"journal":{"name":"PATHOLOGICA","volume":"117 5","pages":"508-512"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12743364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145846621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Standardizing the pathologic assessment of HER2-(ultra)low breast cancer: insights from a national Italian project.","authors":"Bruna Cerbelli, Stefano Marletta, Michelina Amato, Michela Campora, Leopoldo Costarelli, Antonio Cossu, Veronica Errigo, Gerardo Ferrara, Maria Pia Foschini, Renato Franco, Nicola Fusco, Antonio Marchetti, Mauro G Mastropasqua, Enrico Orvieto, Francesca Pietribiasi, Moira Ragazzi, Antonio Rizzo, Alfredo Santinelli, Fabrizio Zanconati, Giulia d'Amati, Cristian Scatena, Isabella Castellano","doi":"10.32074/1591-951X-1565","DOIUrl":"10.32074/1591-951X-1565","url":null,"abstract":"<p><strong>Objective: </strong>Novel therapies for HER2-(ultra)low breast cancer (BC) have changed the traditional binary classification of HER2 status into a multi-tiered system that captures the full spectrum of expression as determined by immunohistochemistry (IHC). Several pre-analytical and analytical variables can influence the accurate identification of HER2 expression within the lowest IHC range.</p><p><p>Herein, we present the findings of a national Italian project addressing the diagnostic challenges associated with HER2-(ultra)low BCs and their proper classification.</p><p><strong>Material and methods: </strong>A total of 121 pathologists from various regions and institutions were recruited and asked to: i) complete an online survey addressing key pre-analytical and analytical issues affecting HER2 status reporting in BC; ii) score 8 cases of IHC HER2-(ultra)low whole slide images (WSI) shared online; iii) participate in on-site meetings to discuss the results and evaluate 8 additional challenging WSIs. The assessments were subsequently compared to those of an expert panel.</p><p><strong>Results: </strong>Several pre-analytical and analytical concerns emerged from the questionnaire, such as reporting resection cold ischemia time and decalcification agent of choice and the employment of adequate HER2 controls. Regarding the WSIs, a substantial overall agreement (69%) with the expert panel was observed (74% in the online phase and 64% in the on-site phase), along with substantial to excellent consensus (≥ 61%) in over 60% of the samples. Most discordances emerged in the on- site cohort, which was enriched with challenging cases, particularly within the HER2 0+/ultralow spectrum, which demonstrated an overall agreement of 48%.</p><p><strong>Conclusions: </strong>This nationwide study highlights the complexities of accurately classifying HER2-(ultra)low breast cancers, particularly within the HER2-ultralow subset. While a substantial level of agreement with expert assessments was achieved, the variability observed in more challenging cases underscores the need for standardized interpretation criteria, enhanced training, and continuous quality assurance measures.</p>","PeriodicalId":45893,"journal":{"name":"PATHOLOGICA","volume":"117 6","pages":"559-570"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13094311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147640213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Marked hepatic fibrosis with progression towards cirrhosis in generalized arterial calcification of infancy: an unreported association observed in a case carryng a novel <i>ENPP1</i> variant.","authors":"Anna Maria Buccoliero, Giorgia Mancano, Maria Luce Cioni, Caterina Panzuto, Rosangela Artuso, Viviana Palazzo, Giovanni Battista Calabri, Guglielmo Capponi, Abramo Ponticelli, Chiara Caporalini, Federico Bertini, Ludovico D'Incerti, Elisa Severi, Angela Peron, Marco Moroni","doi":"10.32074/1591-951X-1624","DOIUrl":"10.32074/1591-951X-1624","url":null,"abstract":"<p><p>Generalized arterial calcification of infancy (GACI) is a rare autosomal recessive disorder characterized by dysregulated calcium-phosphate metabolism, leading to mineral deposition within the internal elastic lamina of medium- and large-sized arteries. This results in arterial wall thickening and luminal narrowing due to intimal hyperplasia, causing significant vascular disruption. Approximately 70% of cases (GACI type 1) are caused by biallelic loss-of-function mutations in the <i>ENPP1</i> gene, with nearly 40 pathogenic variants reported. We report a case of an infant diagnosed with GACI type 1 who died at 7 weeks of age. The patient was delivered via cesarean section at 36 weeks of gestation after a pregnancy complicated by polyhydramnios. The parents were second-degree cousins, with a history of two neonatal deaths of unknown etiology and one miscarriage. Autopsy revealed diffuse arterial calcification with prominent involvement of the coronary arteries. Notably, the liver showed fibrosis progressing to cirrhosis. Genetic analysis through trio exome sequencing identified a novel homozygous nonsense variant in <i>ENPP1</i> (c.553C > T; p.Gln185Ter), inherited from both parents. This stop-gain variant is predicted to produce a severely truncated, non-functional or absent protein. This case is notable for two key aspects: a previously unreported association between GACI and progressive hepatic fibrosis evolving into cirrhosis, and the identification of a novel pathogenic <i>ENPP1</i> variant not previously described in the literature.</p>","PeriodicalId":45893,"journal":{"name":"PATHOLOGICA","volume":"117 6","pages":"610-617"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13094313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147640266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Next-generation sequencing methodologies to identify patients for targeted therapy: focus on HR+/HER2- metastatic breast cancer.","authors":"Umberto Malapelle, Simonetta Buglioni, Isabella Castellano, Carmen Criscitiello, Giuseppe Curigliano, Giulia d'Amati, Carmine De Angelis, Dario de Biase, Francesco Pepe, Giuseppe Perrone, Cristian Scatena, Maria Scatolini, Dario Trapani, Konstantinos Venetis, Nicola Fusco","doi":"10.32074/1591-951X-1531","DOIUrl":"10.32074/1591-951X-1531","url":null,"abstract":"<p><p>Alterations in the phosphoinositide 3-kinase (PI3K)/AKT/PTEN signaling pathway are a well-recognized mechanism of resistance in hormone receptor-positive, HER2-negative metastatic breast cancer (HR+/HER2- mBC). These alterations are present in approximately half of patients with HR+/HER2- mBC. The major alterations in the pathway are somatic mutations in the <i>PIK3CA</i> (40-45%) and <i>AKT1</i> (5%) genes, and loss-of-function alterations in <i>PTEN</i> (5-10%). New targeted agents that act against these alterations have been developed. Therefore, it is important to determine the mutational status of genes in this pathway to potentially offer a therapeutic alternative for these patients. In this review, we discuss the clinical and biological significance of PI3K pathway alterations in HR+/HER2- mBC, focusing on tumors that progress following endocrine therapy and CDK4/6 inhibitor treatment. We then highlight how different diagnostic strategies, including sample type, testing methodology, and timing, can improve the identification of patients who are eligible for targeted therapies and promote the effective integration of molecular diagnostics into routine clinical care.</p>","PeriodicalId":45893,"journal":{"name":"PATHOLOGICA","volume":"117 6","pages":"546-558"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13094335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147640210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI-assisted sentinel lymph node examination and metastatic detection in breast cancer: the potential of ChatGPT for digital pathology research.","authors":"Giuseppe Angelico, Saveria Spadola, Angela Santoro, Antonino Mulè, Federica D'Aquila, Gabriele La Cava, Stefano Marletta, Michele Valente, Belen Padial Urtueta, Francesca Addante, Nadine Narducci, Lorenzo Memeo, Cristina Colarossi, Antonio Rizzo, Gian Franco Zannoni","doi":"10.32074/1591-951X-N1068","DOIUrl":"10.32074/1591-951X-N1068","url":null,"abstract":"<p><strong>Objective: </strong>Traditional pathological examination of lymph nodes is labor-intensive and has shown variability in diagnostic accuracy. Recent advancements in artificial intelligence (AI) provide promising opportunities to enhance and standardize pathological workflows. AI-based image analysis models, particularly those utilizing deep learning algorithms, have demonstrated potential in automating and improving diagnostic accuracy in histopathology. This study aimed to evaluate the performance of a novel AI model known as ChatGPT-4 in detecting metastatic involvement in sentinel lymph nodes (SLNs) from breast cancer cases.</p><p><strong>Methods: </strong>We utilized digital slides from frozen sections, which are commonly employed intraoperatively, to assess the model's diagnostic accuracy. A total of 90 SLNs were retrospectively collected and analyzed using ChatGPT-4. The generated diagnoses were evaluated by two senior pathologists.</p><p><strong>Results: </strong>The AI model achieved an overall accuracy of 92.2%, with a sensitivity of 100% and specificity of 80.6%. The study highlights the practical applicability of AI in diagnosing SLN metastasis, emphasizing the importance of frozen sections in real-world scenarios.</p><p><strong>Conclusions: </strong>These findings suggest that integrating AI models like ChatGPT-4 into pathological workflows could enhance diagnostic accuracy and efficiency in breast cancer treatment.</p>","PeriodicalId":45893,"journal":{"name":"PATHOLOGICA","volume":"117 5","pages":"468-474"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12743367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145846973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mucoepidermoid carcinoma of the thymus: a case report with emphasis on the differential diagnosis.","authors":"Angelina Pernazza, Gian Marco Andreoli, Luigi Vittori, Carolina Carillo, Daniele Diso, Paolo Graziano","doi":"10.32074/1591-951X-1271","DOIUrl":"10.32074/1591-951X-1271","url":null,"abstract":"<p><p>Primary thymic mucoepidermoid carcinoma (TMEC) is extremely rare and only a few cases have been reported in the literature. We describe the case of a TMEC in elderly man, with atypical morphological features that could lead potential diagnostic pitfall. Herein, we suggest a practical approach that may help guide pathologists in their differential diagnosis to distinguish TMEC from other thymic mimics.</p>","PeriodicalId":45893,"journal":{"name":"PATHOLOGICA","volume":"117 5","pages":"519-522"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12743365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145846589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relevance of next-generation sequencing in the differential diagnosis of meningeal mesenchymal tumors: primary meningeal dedifferentiated chondrosarcoma of the cavernous sinus.","authors":"Nicolò Caldonazzi, Gonzalo Hernandez Gamero, Andrea Mafficini, Valeria Barresi","doi":"10.32074/1591-951X-1368","DOIUrl":"10.32074/1591-951X-1368","url":null,"abstract":"<p><p>Primary mesenchymal tumors of the meninges include various types, with meningioma being the most prevalent. Non-meningothelial primary tumors of the meninges are uncommon and present diagnostic difficulties due to their potential morphological similarities with each other and with the anaplastic subtype of meningioma. Intracranial dedifferentiated chondrosarcoma is extremely rare and is defined by the presence of both a conventional chondrosarcoma component and a non-cartilaginous sarcoma component. Diagnosing this tumor can be particularly challenging in biopsy samples or when the chondrosarcoma component is not prominently represented. We report a rare case of dedifferentiated chondrosarcoma of the cavernous sinus in a specimen containing only the dedifferentiated component and exhibiting an <i>IDH1</i> mutation, underscoring the importance of genetic characterization for the differential diagnosis of tumors in this anatomical region. Given the recent evidence supporting the efficacy of IDH inhibitors in chondrosarcomas, identifying mutations in these genes may also have significant therapeutic implications.</p>","PeriodicalId":45893,"journal":{"name":"PATHOLOGICA","volume":"117 6","pages":"598-602"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13094312/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147640180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MTAP in small biopsy samples of pancreatic lesions: a potential diagnostic biomarker. Immunohistochemical, fluorescence in situ hybridization and molecular analysis.","authors":"Stefano Lucà, Cecilia Salzillo, Valeria Masola, Ferdinando De Vita, Danilo Porpora, Giovanni Conzo, Giovanni Savarese, Roberto Sirica, Immacolata Cozzolino, Eduardo Clery, Federica Zito Marino, Renato Franco, Marco Montella","doi":"10.32074/1591-951X-1243","DOIUrl":"10.32074/1591-951X-1243","url":null,"abstract":"<p><strong>Background: </strong>Most pancreatic ductal adenocarcinoma (PDAC) are diagnosed with fine needle aspiration biopsies (FNAB). Some benign mimickers exist, and the differential diagnosis can be challenging. Immunohistochemistry (IHC) is a useful diagnostic tool, and some biomarkers have been studied in this clinical setting. Homozygous deletion (HD) of CDKN2A is observed in about 40% of PDAC, and methylthioadenosine phosphorylase (MTAP) IHC has been identified as a reliable surrogate marker for this alteration. The aim of our study is to evaluate the value of MTAP IHC status in the diagnosis of PDAC.</p><p><strong>Materials and methods: </strong>We collected 27 EUS-FNAB of pancreatic masses. MTAP and S100P IHC were performed. The IHC status of MTAP has been correlated with CDKN2A molecular status studied by fluorescence in-situ hybridization (FISH) and next-generation sequencing (NGS).</p><p><strong>Results: </strong>Approximately 25% of FNAB diagnosed as PDAC showed complete loss of MTAP expression. Our results demonstrated a very high positive predictive value (100%), with a modest sensitivity (31.5%) but a high specificity (100%) for the diagnosis of PDAC. Regarding S100P, 71% of PDAC cases tested positive, whereas the only case diagnosed as benign was negative. The concordance between CDKN2A molecular status by FISH and MTAP expression by immunohistochemistry did not prove to be optimal. Interestingly, some FISH wild-type samples showed HD in NGS.</p><p><strong>Discussion: </strong>An immunohistochemical immunohistochemical panel including MTAP and S100P improves diagnostic accuracy in PDAC diagnosis, showing a better sensitivity (75%) and the same specificity compared to single markers. FISH showed an incomplete sensitivity in identifying all cases with HD of CDKN2A, with two cases MTAP negative by IHC and identified as deleted only by molecular study.</p>","PeriodicalId":45893,"journal":{"name":"PATHOLOGICA","volume":"117 5","pages":"486-495"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12743368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145846645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>PIK3CA</i> testing in HR+/HER2- metastatic breast cancer: assessing pathology laboratories capacity and needs.","authors":"Eltjona Mane, Giulia Cursano, Konstantinos Venetis, Chiara Frascarelli, Francesco Pepe, Mariantonia Nacchio, Lucia Palumbo, Pasquale Pisapia, Elisa De Camilli, Isabella Castellano, Bruna Cerbelli, Leopoldo Costarelli, Giulia d'Amati, Antonio Rizzo, Alfredo Santinelli, Cristian Scatena, Carmen Criscitiello, Carmine De Angelis, Maria Vittoria Dieci, Giancarlo Troncone, Giuseppe Curigliano, Giuseppe Viale, Elena Guerini-Rocco, Umberto Malapelle, Nicola Fusco","doi":"10.32074/1591-951X-1603","DOIUrl":"10.32074/1591-951X-1603","url":null,"abstract":"<p><p>The management of hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (MBC) relies on molecular testing to inform treatment decisions. <i>PIK3CA</i> mutations, present in ~40% of cases, represent a key predictive biomarker for PI3K-pathway-targeted therapies. Despite its clinical relevance, <i>PIK3CA</i> testing continues to face challenges related to laboratory organization, standardization, and access. We conducted a nationwide, cross-sectional survey to evaluate current practices and institutional readiness for PIK3CA testing in Italy, in the context of the anticipated expansion of PI3K-targeted therapies, including inavolisib. A total of 118 healthcare professionals from institutions across 15 regions participated, providing data on test availability, laboratory workflows, analytical methodologies, accreditation status, and implementation barriers. Descriptive statistics were used for analysis. Overall, 88.1% of institutions reported the ability to perform PIK3CA testing, with 57.6% offering on-site analysis. Testing was predominantly performed in pathology laboratories (76.5%), followed by molecular biology (16.2%) and genetics laboratories (7.4%). However, 46.6% of institutions lacked formal molecular accreditation, and ISO:15189 certification remained uncommon. Pre-analytical workflows relied mainly on formalin-fixed paraffin-embedded (FFPE) tissue samples (89.7%), with limited routine use of liquid biopsy. Next-generation sequencing (NGS) was the most frequently adopted analytical approach (45.6%), followed by combined NGS and PCR-based strategies (36.8%). Most institutions reported turnaround times of 7-15 days. In conclusion, this updated survey indicates progress in access to PIK3CA testing and consolidation of NGS-based methodologies in Italy. Nevertheless, persistent gaps in accreditation, heterogeneous workflows, and limited integration of liquid biopsy highlight ongoing challenges in standardization and diagnostic equity. Coordinated national strategies will be essential to ensure consistent, high-quality molecular diagnostics in HR+/HER2- MBC.</p>","PeriodicalId":45893,"journal":{"name":"PATHOLOGICA","volume":"117 6","pages":"571-579"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13094337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147640271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinicopathological and molecular perspectives on thoracic SMARCA4-deficient undifferentiated tumors and SMARCA4-deficient non-small cell lung carcinomas.","authors":"Sumanta Das, Pallavi Mishra, Sunita Ahlawat","doi":"10.32074/1591-951X-1272","DOIUrl":"10.32074/1591-951X-1272","url":null,"abstract":"<p><p>SMARCA4-deficient tumors of the thoracic cavity represent a newly emerging group of aggressive neoplasms driven by inactivation of the SMARCA4 gene, a key member of the SWI/SNF chromatin remodeling complex. These tumors are broadly classified into thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) and SMARCA4-deficient non-small cell lung carcinomas (SMARCA4-dNSCLC). Despite some overlap in genomic alterations, especially smoking-related mutations like TP53, KRAS, and KEAP1, these entities differ in histomorphology, immunoprofile, and biological behavior. SMARCA4-UTs are undifferentiated, often rhabdoid in appearance, with loss of epithelial markers and gain of stem cell markers such as SOX2 and SALL4, while SMARCA4-dNSCLCs retain some epithelial differentiation. Radiologically, these tumors often present as large central thoracic masses with high metabolic activity and early metastases. Both tumor types show poor prognosis, with limited response to conventional therapies. Immunotherapy, particularly immune checkpoint inhibitors, shows promise even in PD-L1-negative cases, and emerging epigenetic and molecular targeted therapies are under investigation. It is crucial to distinguish SMARCA4-UT and SMARCA4-dNSCLC by appropriate use of histopathology, immunohistochemistry, and molecular studies, considering the prognosis and treatment response. Our review focuses on the advancement of understanding the clinicopathological spectrum of both entities, their genetic landscape, and current treatment options.</p>","PeriodicalId":45893,"journal":{"name":"PATHOLOGICA","volume":"117 5","pages":"455-467"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12743361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145847013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}