Endocrine Pathology最新文献

{"title":"Impact of Molecular Testing on Surgical Decision-Making in Indeterminate Thyroid Nodules: A Global Meta-Analysis Across Test Generations.","authors":"Truong Phan-Xuan Nguyen, Andrey Bychkov, Chan Kwon Jung, Kennichi Kakudo, Chanchal Rana","doi":"10.1007/s12022-026-09917-z","DOIUrl":"10.1007/s12022-026-09917-z","url":null,"abstract":"<p><p>Thyroid nodules with indeterminate cytology represent a clinical challenge owing to uncertain malignancy risk, often leading to diagnostic surgery. Molecular testing has emerged as a promising adjunct to improve risk stratification and guide surgical decision-making. However, the clinical utility and impact of different molecular platforms remain debated. The present study evaluates the impact of molecular testing on surgical decision-making in indeterminate thyroid nodules and compares outcomes between first- and second-generation molecular platforms. A PRISMA-guided systematic review and meta-analysis identified 132 studies including 66,448 thyroid nodules, of which 30,292 (45.6%) were indeterminate (Bethesda III/IV). Pooled analyses included studies directly comparing conventional management with molecular testing or different molecular platforms. Primary outcomes were surgical resection rates and risk of malignancy (ROM), stratified by diagnostic approach and test generation. Conventional management demonstrated significantly higher surgical rates than molecular testing group (OR = 2.258, 95% CI: 1.548-3.293, p < 0.001). ROM among resected nodules was lower in the conventional management compared with the molecular testing group (OR = 0.594, 95% CI: 0.388-0.911, p = 0.017). First-generation molecular tests showed higher surgical rates and lower ROM than second-generation assays (OR = 1.709, 95% CI: 1.122-2.601, p = 0.013; OR = 0.665, 95% CI: 0.515-0.858, p = 0.002, respectively). Exclusion of non-invasive follicular thyroid neoplasm with papillary-like nuclear features attenuated differences in malignancy rates. Molecular testing significantly reduces surgical interventions in indeterminate thyroid nodules without evidence of reduced detection of clinically significant malignancy, particularly with second-generation platforms supporting more individualized and evidence-based management strategies.</p>","PeriodicalId":55167,"journal":{"name":"Endocrine Pathology","volume":"37 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147876650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Profiling of Digestive Grade 3 Neuroendocrine Tumors Reveals a Shared Molecular Framework with Lower-Grade Tumors, Marked Heterogeneity, and Therapeutic Opportunities.","authors":"Amedeo Sciarra, Laura Libera, Annarita Destro, Roberta Maragliano, Daniela Furlan, Vincenzo Guastafierro, Deborah Marchiori, Alessandro Vanoli, Raul S Gonzalez, Igor Letovanec, Stefano Lazzi, Stefano La Rosa, Silvia Uccella","doi":"10.1007/s12022-026-09918-y","DOIUrl":"10.1007/s12022-026-09918-y","url":null,"abstract":"<p><p>Well-differentiated neuroendocrine tumors, grade 3 (NETs G3) of the digestive system are high-grade neuroendocrine neoplasms characterized by well-differentiated neuroendocrine morphology and high proliferative activity. Their molecular identity and therapeutic vulnerabilities remain incompletely defined. We performed a transcriptomic analysis and a comprehensive genomic profiling of 40 cases, including 26 NETs G3, 8 NETs G1/G2, and 6 neuroendocrine carcinomas (NECs). Targeted sequencing assessed alterations at both the DNA and RNA level, and gene expression profiling was conducted using a targeted immune-oncology panel. NETs G3 retained recurrent alterations in chromatin-regulatory genes characteristic of well-differentiated tumors and largely lacked the consistent TP53 and RB1 inactivation typical of NECs. Transcriptomic and genomic analysis demonstrated separation of NECs from NETs, with NETs G3 partially overlapping with NETs G1/G2 supporting a model of molecular relatedness. However, when compared with NETs G1/G2, NETs G3 showed upregulation of extracellular matrix remodeling, metabolic reprogramming, and cytokine signaling pathways. NETs G3 were heterogeneous in terms of number of genomic alterations per case and involved genes. A distinctive genomic feature was the predominance of large-segment copy-number losses, frequently involving chromatin-regulatory regions on chromosomes X and 10. Potentially targetable alterations were detected in up to 25% of NETs G3. Analysis of immune microenvironment supported a poorly inflamed tumor status, with individual cases harboring microsatellite instability or enrichment in tumor-infiltrating lymphocytes potentially amenable to immunotherapy.</p>","PeriodicalId":55167,"journal":{"name":"Endocrine Pathology","volume":"37 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13167899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147876685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lineage Classification of Pituitary Neuroendocrine Tumors From Whole-Slide Images Using Attention-Guided Graph Representation Learning.","authors":"Jie Hao, Chen Wang, Jiao Li, Jiang Du, Qing Qian, Xing Liu","doi":"10.1007/s12022-026-09919-x","DOIUrl":"10.1007/s12022-026-09919-x","url":null,"abstract":"<p><p>Pituitary neuroendocrine tumors (PitNETs) are common sellar neoplasms and represent a major component of routine pituitary pathology. In the 2022 World Health Organization (WHO) Classification, transcription factor-defined lineage assignment is central to diagnosis. However, lineage-related morphologic information on routine hematoxylin and eosin (H&E)-stained whole-slide images (WSIs) has not been systematically characterized. We developed an attention-guided graph neural network to predict PitNET lineage directly from H&E-stained WSIs and to identify regions prioritized for classification. Consecutive patients who underwent surgical resection for PitNETs at Beijing Tiantan Hospital between 2021 and 2025 were included. In the internal hold-out set, the five fold-specific models achieved a mean F1-score of 92.78% and a mean balanced accuracy of 94.84%. In a temporally independent validation cohort, the final model achieved an F1-score of 87.64% and a balanced accuracy of 89.48%. Performance varied across lineages and histomorphologic subtypes, and the most common error pattern was misassignment of PIT-1 and T-PIT tumors to SF-1. Attention maps predominantly highlighted tumor-rich regions. Quantitative cell-level morphometry supported lineage-associated patterns, including larger cell and nuclear sizes in PIT-1 tumors, more elongated nuclei in SF-1 tumors, and higher cellular density with reduced intercellular spacing in T-PIT tumors. In six cases with multiple synchronous PitNETs of distinct lineages, patch-level prediction maps corresponded closely to transcription factor immunohistochemistry. In a small exploratory subset with available DNA methylation data, methylation classifier results were concordant with model predictions in 11 of 15 cases and with routine histopathologic diagnoses in 8 of 15 cases. These findings indicate that routine H&E-stained WSIs contain learnable morphologic information related to PitNET lineage. Attention-guided spatial modeling provides an interpretable framework for characterizing lineage-associated patterns in PitNETs.</p>","PeriodicalId":55167,"journal":{"name":"Endocrine Pathology","volume":"37 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147846447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinicopathologic and Molecular Features of Poorly Differentiated Thyroid Carcinomas in Adults ≤ 45 Years of Age.","authors":"Maria Cristina Riascos, Ellen Marqusee, Sara Ahmadi, Theodora Pappa, Adam S Fisch, Justine A Barletta","doi":"10.1007/s12022-026-09911-5","DOIUrl":"10.1007/s12022-026-09911-5","url":null,"abstract":"<p><p>The clinical behavior and molecular underpinnings of rare cases of poorly differentiated thyroid carcinoma (PDTC) diagnosed in young adults are not established. We evaluated 13 cases of PDTC in adult patients ≤ 45 years of age. The median age at diagnosis was 40 years (range 27 - 45 years). The median tumor size was 3.7 cm. The median mitotic count was 6 per 2 mm². Necrosis was present in 7 (54%) cases. Eleven (85%) cases were either encapsulated with extensive (≥ 4 foci) angioinvasion or widely invasive. Molecular analysis was available for nine (69%) cases and revealed two (22%) with PAX8::PPARG fusions, two (22%) with NRAS alterations, one (11%) with a DICER1 variant, one (11%) with alterations in ATM, CDKN1A and TERT, one (11%) with a TSC2 deletion and TERT copy number gain, and two (22%) with variants of uncertain significance only. Of the 12 (92%) patients with follow-up data available (median 6.2 years, range 1.5-16.4 years), the only patient who died of disease had distant metastases at diagnosis. Of the remaining patients with initial M0 disease, only one had disease recurrence, developing local recurrence and distant metastasis with persistent disease at last follow up. Our findings suggest that PDTC in adults ≤ 45 years of age at diagnosis, may have a better prognosis than is typically associated with PDTC despite high-grade features and invasive growth. Additionally, we found a higher rate of PAX8::PPARG fusions and a lower rate of TERT alterations, suggesting that the molecular profile might explain the improved survival.</p>","PeriodicalId":55167,"journal":{"name":"Endocrine Pathology","volume":"37 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147846438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thyroblastoma Dominated by a Primitive Small Round Cell Component: A Diagnostic Pitfall.","authors":"Atsuko Kasajima, Marco M E Vogel, Günter Klöppel, Abbas Agaimy, Costanza Chiapponi","doi":"10.1007/s12022-026-09916-0","DOIUrl":"10.1007/s12022-026-09916-0","url":null,"abstract":"","PeriodicalId":55167,"journal":{"name":"Endocrine Pathology","volume":"37 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13083454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147693585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thyroid Tumors of Uncertain Malignant Potential (UMP)- Clinicopathologic and Molecular Characterization of 324 Cases.","authors":"Bayan A Alzumaili, William C Faquin, Adam S Fisch, Tejas S Athni, Gregory W Randolph, Marika D Russell, Peter M Sadow","doi":"10.1007/s12022-026-09915-1","DOIUrl":"10.1007/s12022-026-09915-1","url":null,"abstract":"<p><p>Thyroid tumors with questionable capsular invasion (CI) or angioinvasion (AI) pose diagnostic and management challenges. The World Health Organization (WHO) recognizes these borderline entities as follicular tumors of uncertain malignant potential (FT-UMP) or well-differentiated tumors of uncertain malignant potential (WDT-UMP). We have conducted a retrospective, single-center study of all thyroid tumors diagnosed as UMP (2005–2025). Of 534 tumors initially labeled “uncertain malignant potential,” application of exclusion criteria yielded 324 tumors from 318 patients with questionable CI and/or AI. Clinicopathological characteristics, molecular testing data, postoperative laboratory values, imaging, and outcomes were analyzed. UMP was diagnosed in 0.5% of thyroid surgeries; median age 53-years and 2:1 female predominance. Cohort classification included oncocytic FT-UMP (OFT-UMP) (40%), FT-UMP (34%) and WDT-UMP (26%). Median tumor size was 3.2 cm. Molecular testing yielded RAS variants most frequently (79%), followed by RAS-like variants (4%), gene fusions (4%), PTEN loss (4%), and TERT promoter alterations (3%). With follow-up extending up to 15 years, no recurrences or metastases were recorded, supporting the UMP designation as tumors of low biological potential and favoring conservative management. Longer-term, multi-institutional studies will refine risk stratification and clinical management.</p>","PeriodicalId":55167,"journal":{"name":"Endocrine Pathology","volume":"37 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13283333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147629171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Well-Differentiated Neuroendocrine Tumors of Lung: A Case Series Supporting the IARC/WHO Common Classification of Neuroendocrine Tumor Nomenclature and Grading.","authors":"Eren Altun, Omid Savari, Mart Andrew Maravillas, Sylvia L Asa","doi":"10.1007/s12022-026-09914-2","DOIUrl":"10.1007/s12022-026-09914-2","url":null,"abstract":"<p><p>The aim of this study was to assess whether there is sufficient evidence to recommend a change in the classification of pulmonary tumors currently classified as “carcinoid” tumors to instead apply a system similar to that used for well-differentiated gastrointestinal and pancreatic neuroendocrine tumors (NETs) using the Ki67 proliferation index (PI). We retrospectively reviewed 124 cases of pulmonary NETs (“typical carcinoids” (TC) and “atypical carcinoids” (AC)) diagnosed at the University Hospitals Cleveland Medical Center between 2019 and 2025. Demographic, clinical, and pathology data were collected, including mitotic counts, necrosis, and Ki67 PI assessed in biopsy, resection, and metastatic specimens. Tumors were graded as G1 (≤ 3%), G2 (3–20%), and G3 (> 20%) according to the 5th edition WHO criteria for gastroenteropancreatic NETs. Grading based on Ki67 PI was significantly associated with lymphatic invasion (p = 0.007), lymph node metastasis (p = 0.016), liver metastasis (p = 0.047), AJCC stage at diagnosis (p < 0.001), and patient mortality (p = 0.047). This approach provided better correlation than necrosis for liver metastasis and mortality, better than mitoses for all negative outcomes than other than liver metastasis, and better than TC/AC classification for mortality. Tumors classified as G3 had significantly worse patient outcomes than those classified as G1 or G2. Incorporating Ki67 PI into the classification provides clinically important information regarding tumor progression, staging, and survival. These findings support the adoption of a three-tiered Ki67-based grading system (G1–G3) for pulmonary NETs, ​​similar to gastroenteropancreatic NETs.</p>","PeriodicalId":55167,"journal":{"name":"Endocrine Pathology","volume":"37 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13043553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147596373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased Frequency and Distinct Genotypic Patterns of Somatic Aldosterone-Driver Mutations in Aldosterone-Producing Micronodules from Primary Aldosteronism Patients.","authors":"Jung Soo Lim, Chun-Yi Wu, Zhaoping Qin, Chia-Jen Liu, Desmaré van Rooyen, Dina R Sapiro, Thomas J Giordano, Adina F Turcu, William E Rainey, Aaron M Udager","doi":"10.1007/s12022-026-09912-4","DOIUrl":"10.1007/s12022-026-09912-4","url":null,"abstract":"<p><p>Primary aldosteronism (PA) is the leading cause of endocrine hypertension. With the development of highly specific human aldosterone synthase (CYP11B2) antibodies for immunohistochemistry (IHC), the presence of microscopic subcapsular foci of CYP11B2-postive cells – now termed aldosterone-producing micronodules (APM) – has been documented in normal and PA adrenal glands, however, there continues to be debate regarding the role of APM in the pathogenesis of PA. In this study, CYP11B2 IHC-guided targeted next-generation sequencing (NGS) was utilized to characterize the frequency and spectrum of somatic aldosterone-driver mutations in APM identified within adrenal glands from deceased renal donors and patients with primary aldosteronism (PA). 59 subjects were enrolled (31 deceased renal donors and 28 PA patients), 173 APM were collected using CYP11B2-guided IHC (65 APM from 31 deceased renal donors and 108 APM from 28 PA patients), and NGS data was successfully obtained for 131 APM (51 APM from 31 deceased renal donors and 80 APM from 28 PA patients). Importantly, NGS identified aldosterone-driver mutations in a significantly higher proportion of APM from PA patients relative to deceased renal donors (71.3% compared to 45.1%; P-value < 0.05) – with the vast majority in either group being missense mutations in the L-type calcium channel gene CACNA1D. Interestingly, in PA patients, the presence of APA/APN harboring CACNA1D or ATP1A1 mutations was significantly associated with an increased frequency of APM with CACNA1D mutations, while APM from adrenal glands with KCNJ5 mutation-bearing APA/APN were more likely to be mutation-negative (P-values < 0.001 and < 0.05, respectively). Finally, clinical outcomes for PA patients were significantly associated with APM genotype, with post-surgical cure showing higher frequencies of KCNJ5-mutant and mutation-negative APM and a lower frequency of CACNA1D-mutant APM. Overall, our data support a link between the acquisition of somatic aldosterone-driver mutations in APM and PA pathogenesis and suggest the possibility of diverse genetic mechanisms underlying APM development in normal and PA adrenal glands. Furthermore, these results suggest that molecular diagnostic testing of CYP11B2-positive adrenal cortical lesions may help risk stratify patients in clinical practice.</p>","PeriodicalId":55167,"journal":{"name":"Endocrine Pathology","volume":"37 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13002656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147488605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and Pathological Features of EC-cell Familial Small Intestine Neuroendocrine Tumors: A Nationwide Cohort From the French GTE-RENATEN Network.","authors":"Thomas Hunaut, Laura Gérard, Agathe Hercent, Olivia Hentic, Bruno Buecher, Come Lepage, Thierry Lecomte, Philippe Thuillier, Christine Do Cao, Alice Durand, Guillaume Roquin, Céline Lepere, Maelle Lebras, Sophie Dominguez, Philippe Baltzinger, Pierre Devulder, Nathalie Guedj, Hedia Brixi, Thomas Féron, Jérôme Cros, Eric Pasmant, Catherine Lombard-Bohas, Thomas Walter, Guillaume Cadiot, Louis de Mestier","doi":"10.1007/s12022-026-09913-3","DOIUrl":"10.1007/s12022-026-09913-3","url":null,"abstract":"<p><p>EC-cell familial small intestine neuroendocrine tumors (EC-cell F-SINET) are a recently described but poorly characterized entity. We aimed to describe their clinical and pathological features, and to compare them to patients with a sporadic form (EC-cell S-SINET). We constituted a nationwide cohort including (retrospectively patients diagnosed before 2012 and prospectively from 2012 to 2022) all patients with F-SINET (histologically proven SINET in ≥ 2 first or second-degree relatives) managed in the French GTE-RENATEN network. Clinical and pathological data were described and compared to the GTE-RENATEN population-based cohort including 2460 patients with EC-cell S-SINET using multivariable logistic regression. The survival impact of EC-cell F-SINET was explored using Cox proportional hazard analyses. We included 92 patients with EC-cell F-SINET from 47 families. Median age at diagnosis was 60.4 years. Among these patients, 22% had a history of another cancer, 76.1% had synchronous or metachronous metastases, 38% had a carcinoid tumor syndrome, and median Ki-67 labeling index was 2%. Median survival was 204.6 months. Multifocal EC-cell SINET were present in 66.7% of patients with EC-cell F-SINET and were associated with poorer prognosis (p = 0.005). In comparison with EC-cell S-SINET patients, those with EC-cell F-SINET had more frequent multifocal primary tumor in the small bowel (p < 0.0001) and carcinoid syndrome (p = 0.038), lower Ki-67 index and tended to be younger (p = 0.094). After adjustment on independent prognostic factors (age at diagnosis, metastatic stage, carcinoid tumor syndrome and Ki-67 index), EC-cell F-SINET did not have a different prognosis than that of EC-cell S-SINET. Patients with EC-cell F-SINET are characterized by more frequent multifocal EC-cell SINETs and more frequent carcinoid tumor syndrome, but their prognosis seems similar compared to patients with EC-cell S-SINET.</p>","PeriodicalId":55167,"journal":{"name":"Endocrine Pathology","volume":"37 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147488673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In-depth Genetic and Molecular Characterization of Unilateral Coexisting Adrenal Cortical Adenoma and Carcinoma in the Context of MEN1 Syndrome.","authors":"Francesca Cioppi, Tommaso Orioli, Giulia Cantini, Tonino Ercolino, Federica Cioppi, Guillaume Assié, Anne Jouinot, Anna Aurora Dedonno, Raffaella Santi, Ronald R de Krijger, Mario Maggi, Matteo Benelli, Letizia Canu, Gabriella Nesi, Michaela Luconi","doi":"10.1007/s12022-026-09908-0","DOIUrl":"10.1007/s12022-026-09908-0","url":null,"abstract":"<p><p>Adrenal lesions often occur in patients with multiple endocrine neoplasia type 1 (MEN1), mostly adrenal cortical adenomas (ACAs), although the frequency of adrenal cortical carcinomas (ACCs) is higher than in the general population. The coexistence of benign and malignant masses has seldom been documented, leaving open the question of ACC progression from benign forms. We report a comprehensive genetic characterization of three adrenal cortical tumor samples obtained from a familial MEN1 patient, operated for the rapid progression of an initially stable nonfunctional adrenal incidentaloma. Histologically, the tumor consisted of a small ACA contiguous to a large ACC, which subsequently relapsed. Exome sequencing of ACC, ACA and recurrence evidenced a MEN1 loss of heterozygosity (LOH) in ACC but not in ACA, where, however, a second hit driven by alternative mechanisms could not be excluded. The majority of the ACA variants were found to co-occurred in ACC (n = 36/42) and were benign, except for two of unknown significance in KANK1 and REN genes, described as associated with renal cancer. Among variants shared between ACC and its recurrence (n = 69), 11 were Tier III, while 2 affecting TP53 and NF1 genes were pathogenic. Bioinformatic clonal evolution analysis identified one clone - characterized by TP53 and NF1 mutations - absent in ACA but present in ACC and recurrence, as well as 2 clones shared between ACA and ACC but lost in the recurrence. In conclusion, comparative Whole Exome Sequencing (WES) analysis of three adrenal tumors in a MEN1 patient suggests a possible relationship between malignant and benign lesions occurring in MEN1 patients, without, however, demonstrating any causal adenoma-to-carcinoma progression driven by MEN1 LOH. Overall, these data further suggest an increased risk of MEN1 patients to develop adrenocortical malignancy.</p>","PeriodicalId":55167,"journal":{"name":"Endocrine Pathology","volume":"37 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12975836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147437562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}