Endocrine Pathology最新文献

{"title":"A Cauda Equina Neuroendocrine Tumor with Tyrosine Hydroxylase Expression.","authors":"Knarik Arkun, Zahra Jalali, Mina G Safain, Arthur S Tischler","doi":"10.1007/s12022-026-09929-9","DOIUrl":"10.1007/s12022-026-09929-9","url":null,"abstract":"","PeriodicalId":55167,"journal":{"name":"Endocrine Pathology","volume":"37 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148610145","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":"Expansion of Germline Variants in Primary Hyperparathyroidism: Fumarate Hydratase Deficiency as a Cause of Parathyroid Adenomas.","authors":"Hussam Alkaissi, Elias Chuki, Yi Liu, James Welch, Lynn Bliss, Niharika Shah, Sunita K Agarwal, William F Simonds, Martha Quezado, Sanaz Sakiani, Thorkell Andresson, Karel Pacak, Naris Nilubol, Lee S Weinstein, Christopher A Febres-Aldana, Smita Jha","doi":"10.1007/s12022-026-09928-w","DOIUrl":"10.1007/s12022-026-09928-w","url":null,"abstract":"<p><p>A substantial fraction (60-85%) of hereditary primary hyperparathyroidism (hPHPT) lacks an identifiable genetic etiology. We describe fumarate hydratase (FH) mutations as a potential cause of hPHPT, expanding the phenotypic spectrum of FH deficiency tumor predisposition syndromes. In an index patient who presented with asymptomatic hypercalcemia and a chief-to-transitional cell-dominant parathyroid adenoma, whole-exome sequencing revealed two unique heterozygous FH variants (germline p.Gln376fs*2; somatic p.Pro503_Lys504dup). Functional inactivation of FH was supported by diffuse nuclear and cytoplasmic 2-succinocysteine immunoreactivity and elevated fumarate/malate ratio in tumor tissue. This individual did not show classic HLRCC manifestations. Preserved FH protein expression suggested residual enzymatic activity, which may account for an attenuated phenotype. To assess broader relevance, no additional patients with bona fide FH-deficient parathyroid adenoma were identified among 130 individuals with suspected hPHPT of unknown etiology evaluated at our institute. In a complementary cohort of 11 patients with pheochromocytoma/paraganglioma syndrome harboring pathogenic germline heterozygous FH variants, one female (FH p.Thr234Ala) presented with multi-gland disease requiring parathyroidectomy at age 40 years, features suspicious for hPHPT. These findings support fumarate hydratase deficiency as a plausible etiology for a subset of parathyroid adenomatous disease. Thus, consideration of parathyroid function surveillance in patients with fumarate hydratase deficiency tumor predisposition syndromes may be warranted. CLINICAL TRIAL NUMBER: NCT04969926.</p>","PeriodicalId":55167,"journal":{"name":"Endocrine Pathology","volume":"37 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13391723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148551508","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":"Circulating Tumor DNA Analysis in Adrenocortical Carcinoma: A Retrospective Cohort Study.","authors":"Vania Balderrama-Brondani, Leonardo Marcal, Mohammad Jad Moussa, James P Long, Jeena Varghese, Steven G Waguespack, Camilo Jimenez, Paul H Graham, Sarah B Fisher, Nancy Perrier, Amishi Y Shah, Rahul Sheth, Miao Zhang, Matthew T Campbell, Mouhammed Amir Habra","doi":"10.1007/s12022-026-09927-x","DOIUrl":"10.1007/s12022-026-09927-x","url":null,"abstract":"<p><p>Adrenocortical carcinoma (ACC) is a rare malignancy with high recurrence rates. Circulating tumor DNA (ctDNA) is a minimally invasive, blood-based biomarker with multiple oncologic applications. The role of ctDNA in ACC care remains understudied. This retrospective, single-institution, study evaluated real-world use of ctDNA testing in patients with ACC and its correlation with imaging-based tumor burden. Patients with ACC (≥ 18 years) who underwent ctDNA testing via a clinically validated, personalized, tumor-informed assay (Signatera™, Natera) during their disease course were reviewed, and clinical data were obtained from the medical records. ctDNA results were tested for association with disease status and tumor burden determined by concurrent imaging and clinical evaluation. Twenty patients (55% male) were included; the median age at first ctDNA assessment was 58.3 years (range, 23.3-81.1). A total of 87 ctDNA tests were analyzed (median, 4 tests/patient; interquartile range [IQR], 1-6). The median ctDNA level was 1.27 mean tumor molecules/mL (IQR, 0.05-22.86). Detected ctDNA was strongly associated with evidence of disease (odds ratio, 74; 95% confidence interval, 9-3438). The ctDNA assay demonstrated high sensitivity (88%), specificity (91.7%), and overall accuracy (88.5%), with a positive post-test probability of 98% and a negative post-test probability of 45%. In addition, ctDNA levels were positively correlated with tumor burden (Spearman R = 0.844; p < 0.001). These findings support the potential value of ctDNA testing for disease monitoring in ACC and it may support a more personalized approach to this rare disease.</p>","PeriodicalId":55167,"journal":{"name":"Endocrine Pathology","volume":"37 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13379401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148474370","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":"Integrated Pathologic, Genomic, and Transcriptomic Analysis of Renal Neuroendocrine Tumors Reveals Neuroendocrine Transcriptional Programs and Associated Gastrointestinal-Type Epithelium in a Subset of Cases.","authors":"Eric D Young, Riya Dua, Stephen Kwak, Pedram Argani, Yasser Ged, Roy Elias, Ezra Baraban","doi":"10.1007/s12022-026-09925-z","DOIUrl":"10.1007/s12022-026-09925-z","url":null,"abstract":"<p><p>Renal well-differentiated neuroendocrine tumors (RenNETs) are rare primary renal neoplasms with enigmatic histogenesis. To define the molecular features of RenNETs and clarify their relationship to neuroendocrine tumors (NETs) from other sites, we performed whole-exome DNA sequencing and transcriptomic profiling on six RenNETs. In one case, adjacent non-neuroendocrine cystic epithelium and a regional lymph node metastasis were independently analyzed. RenNETs demonstrated a low-to-intermediate tumor mutational burden and recurrent copy number alterations, including losses involving chromosomes 3, 11, and 18 and gains involving chromosomes 1, 2, 8, and 14, partially overlapping those reported in gastroenteropancreatic NETs, in the absence of alterations in canonical NET-associated driver genes. RNA sequencing revealed marked upregulation of genes involved in neuroendocrine differentiation, peptide processing, and pancreatic beta cell function, accompanied by loss of renal lineage markers, indicating a neuroendocrine transcriptional program distinct from other primary renal neoplasms. RenNETs showed heterogeneous activation of hormone related transcriptional programs, rather than conforming to a discrete EC-cell or L-cell signature. Immunohistochemistry confirmed strong membranous expression of somatostatin receptor 2A (SSTR2A) in all cases, supporting established imaging and therapeutic paradigms used for NETs. Notably, two RenNETs were associated with adjacent CDX2-positive epithelial-lined cysts with intestinal differentiation. In one case, a shared somatic mutation was identified across the epithelial cyst, the adjacent RenNET, and a nodal metastasis, providing genetic evidence of a common clonal origin and implicating gastrointestinal-type epithelium as a potential precursor lesion in a subset of cases. Features supporting teratomatous origin, such as chromosome 12p gains or other germ cell tumor elements, were not identified. Together, these findings demonstrate that RenNETs exhibit convergent transcriptomic and phenotypic neuroendocrine programs, along with partial copy number overlap, with well-differentiated gastroenteropancreatic NETs, and support a model in which RenNETs may arise from developmentally displaced or aberrantly differentiated epithelial precursors with gastrointestinal-type differentiation, although this hypothesis requires validation in larger cohorts.</p>","PeriodicalId":55167,"journal":{"name":"Endocrine Pathology","volume":"37 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148474434","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":"Prevalence and Histologic Features of Multifocal Fibrosing Thyroiditis in the Routine Pathology Practice.","authors":"Floriana Jessica Di Paola, Maria Vittoria Altavilla, Giulia Calafato, Thais Maloberti, Federico Chiarucci, João Vale, Antonio De Leo, Dario de Biase, Catarina Eloy, Giovanni Tallini","doi":"10.1007/s12022-026-09926-y","DOIUrl":"10.1007/s12022-026-09926-y","url":null,"abstract":"<p><p>Multifocal fibrosing thyroiditis (MFT) is a poorly understood condition characterized by multiple fibrotic scar-like lesions with paucicellular core and peripheral follicular cell atypia. Described by Dr. Rosai in 1990 in consultation cases, MFT has received limited attention due to its perceived rarity. To define its prevalence and clinicopathologic features in the routine practice, consecutive thyroid resections were analyzed from the archives of two medical institutions in Italy and Portugal. Among 1,736 resections 27 MFT were identified (1.56%), corresponding to a detection rate of 1.34% MTF cases per year in the study cohort. No significant difference between Italian and Portuguese cases were observed. Twenty-three of 27 (85.2%) patients were female. Age range was 34-69 years (median: 52). Autoimmune thyroiditis affected 7/27 patients (25.9%), with clinical hypothyroidism in four (14.8%). Clinical hyperthyroidism was present in 4/27 patients (14.8%), including 2 cases of hyperfunctioning adenoma, 1 case of toxic multinodular goiter, and 1 case of Graves' disease. In 2/27 cases (7.4%) thyroid resection was performed due to fibrotic MFT foci mimicking PTC. Malignant thyroid nodules - papillary thyroid carcinoma (PTC) in all cases - or other benign nodules caused thyroid resection in 10/27 (37.0%) and in 12/27 (44.4%) cases, respectively; Hashimoto thyroiditis (2 cases) and Graves disease (1 case) caused thyroid resection in the remaining cases. Meticulous histologic examination disclosed additional alterations in 25/27 cases (92.6%), often overlapping with each other and with PTC: incidental millimetric PTC in 7/27 cases (25.9%), follicular nodular disease in 17/27 cases (62.9%), chronic lymphocytic thyroiditis/Hashimoto thyroiditis in 14/27 (51.8%). No genetic alteration was identified in any of the 15/27 cases tested. In the routine practice MFT is an uncommon disorder affecting diseased thyroids that simulates PTC. Its cause remains elusive.</p>","PeriodicalId":55167,"journal":{"name":"Endocrine Pathology","volume":"37 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13372847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148450616","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":"An Integrative RNA Spliceosomic Landscape of Pancreatic Neuroendocrine Tumors Identifies Clinically Relevant Molecular Subgroups.","authors":"Ricardo Blázquez-Encinas, Víctor García-Vioque, Andrea Mafficini, Luca Landoni, Daniel Ruiz-Palacios, Laura Gutiérrez-Camacho, María Trinidad Moreno-Montilla, Nicolas Alcala, Sebastián Ventura, Eduardo Eyras, Salvatore Paiella, Roberto Salvia, Vita Rovite, Matthieu Foll, Claudio Luchini, Lynnette Fernandez-Cuesta, Rita T Lawlor, Aldo Scarpa, Alejandro Ibáñez-Costa, Sergio Pedraza-Arevalo, Justo P Castaño","doi":"10.1007/s12022-026-09923-1","DOIUrl":"10.1007/s12022-026-09923-1","url":null,"abstract":"<p><p>Alterations in alternative splicing are emerging as a novel cancer hallmark, offering new insights into tumor biology. However, integrative analyses of splicing are still scarce, particularly in rare cancers like pancreatic neuroendocrine tumors (PanNETs), whose striking heterogeneity complicates patient diagnosis and treatment. Here, we provide the first comprehensive characterization of the RNA splicing landscape in PanNETs through integrative analysis of RNA-seq data from 174 tumor samples. We identified three robust spliceosomic groups (SPN1, SPN2, SPN3) each associated with unique clinical and molecular characteristics. SPN1 displayed intermediate clinical behavior alongside enhanced mTOR signaling; SPN2 was characterized by a less secretory phenotype, enrichment in alpha-cell markers and somatostatin receptors, increased metastasis, and frequent mutations in MEN1 and DAXX/ATRX genes; in contrast, SPN3 was composed mainly by low grade tumors with beta-cell marker expression and the lowest mutational rate, yet it also contained all the highly proliferative neoplasms. Moreover, each group had a specific alternative splicing events signature, revealing an unprecedented discovery: the association between the expression profile of the splicing machinery and its product, the splicing variants. We provide a detailed characterization of the molecular and functional consequences of the splice variants defining each of the spliceosomic groups. These findings underscore the previously unrecognized yet significant impact of RNA splicing on PanNET heterogeneity and suggest that detailed splicing profiles could serve as valuable tools for identifying novel biomarkers and therapeutic targets. Thus, beyond providing crucial insights into PanNET molecular biology, our study offers a foundation for future studies exploring personalized therapeutic strategies based on splicing features.</p>","PeriodicalId":55167,"journal":{"name":"Endocrine Pathology","volume":"37 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13350132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148414062","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":"Distinct ALK Expression Patterns Are Associated with Canonical and Noncanonical STRN::ALK Transcript Architectures in Oncocytic Thyroid Neoplasms.","authors":"Debora Mota Dias Thomaz, Thais Biude Mendes, Thaise Nayane Ribeiro Carneiro, Luiza Sisdelli, Ana Carolina de Jesus Paniza, André Uchimura Bastos, Janete Maria Cerutti","doi":"10.1007/s12022-026-09924-0","DOIUrl":"10.1007/s12022-026-09924-0","url":null,"abstract":"<p><p>Oncocytic thyroid carcinomas are characterized by a unique chromosomal landscape and frequent resistance to radioactive iodine therapy, underscoring the need for improved molecular characterization. Although ALK rearrangements, particularly STRN::ALK fusions, have been described in thyroid carcinomas, their biological and clinical significance in oncocytic thyroid neoplasms remains unclear. This study investigated STRN exon 3-ALK exon 20-derived transcripts in 56 oncocytic thyroid neoplasms using RT-PCR, followed by cloning and Sanger sequencing of positive cases. Transcript-positive cases were further evaluated by fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and in silico structural modeling. STRN::ALK-derived transcripts were detected in 9 of 56 tumors; however, their frequency reflected the combined detection of distinct transcript architectures. Only 2 of 56 tumors (3.6%) harbored canonical in-frame STRN::ALK fusions, whereas 7 of 56 tumors (12.5%) contained noncanonical out-of-frame variants. Although ALK rearrangement by FISH was confirmed in all transcript-positive tumors irrespective of transcript architecture, detectable ALK protein expression by IHC was observed only in tumors harboring canonical in-frame fusions, whereas all noncanonical variants lacked detectable ALK protein expression. Structural modeling was concordant with these observations, suggesting preservation of kinase-domain features in canonical fusions and predicted disruption in noncanonical variants. Overall, STRN::ALK transcripts in oncocytic thyroid neoplasms exhibit marked architectural heterogeneity with distinct ALK protein expression patterns. ALK FISH-positive/IHC-negative cases should be interpreted cautiously, as they may not represent biologically equivalent ALK-driven neoplasia, with uncertain therapeutic relevance. Integrated molecular and protein-level assessment may support interpretation of ALK alterations in oncocytic thyroid neoplasms.</p>","PeriodicalId":55167,"journal":{"name":"Endocrine Pathology","volume":"37 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13328310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148371049","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":"Neuroendocrine Tumors of the Gallbladder: A Multicenter Case Series and Systematic Literature Review Indicating Predominantly Non-Aggressive Tumor Behavior and a Common Association with Cholesterol Polyps and Cholesterolosis.","authors":"Alessandro Vanoli, Yue Xue, Atsuko Kasajima, Rebecca Ruffoni, Zeynep Çağla Tarcan, Nuray Tezcan, Xiuli Liu, Pooja Navale, Ahmed Mohamed, Irene Gullo, Roberto Silva, Giulia Vocino Trucco, Marco Volante, Maria Giulia Disanto, Cecilia Taverna, Elif Kuzucular, Claudio Luchini, Juan Carlos Roa, Irene Esposito, Stefano La Rosa, Burcin Pehlivanoglu, Michelle Reid, Günter Klöppel, Olca Basturk, Volkan Adsay","doi":"10.1007/s12022-026-09921-3","DOIUrl":"10.1007/s12022-026-09921-3","url":null,"abstract":"<p><p>Current data on neuroendocrine tumors (NETs) of the gallbladder and cystic duct (GB-NETs) are highly limited, and the available evidence, largely derived from cancer registry data, suggests that these tumors exhibit a substantially more aggressive clinical behavior than NETs arising at other anatomical sites. We analyzed 26 GB-NETs. Female-to-male ratio: 1.9:1; median age: 50 years. They were typically incidental small (median: 0.8 cm, range: 0.08-2.3 cm) tumors, with 81% classified as grade 1 (G1), either pT1 or pT2, and 38% showing a paraganglioma-like pattern at least focally. Body/fundus tumors were mostly polypoid while neck/cystic duct examples showed mural growth. Symplastic pleomorphism was found in 11%, pseudoglandular structures in 50% and psammomatous intraluminal calcifications in 15%. Pancreatic polypeptide, somatostatin, and gastrin were detected in 5/7 (71%), 5/8 (62.5%), and 4/7 (57%) tested cases, respectively. ISLET1 and ARX were diffusely expressed in all 5 tested cases. Cholesterolosis was common, and six appeared to arise within cholesterol polyps. None had any evidence of metastasis and all 12 patients with available follow-up were alive without disease after a median follow-up of 30 months. Critical review of the literature (79 bona-fide GB-NETs) showed that tumors > 2 cm and grade 3 (G3) were enriched among metastatic GB-NETs. In conclusion, GB-NETs are generally indolent neoplasms, in contrast to gallbladder neuroendocrine carcinomas. Tumor size and grade may help predict metastatic potential, while the relatively frequent paraganglioma-like morphology, often associated with diffuse somatostatin expression, can represent a diagnostic pitfall. Their frequent association with cholesterol polyps also suggests a possible etiopathogenetic link.</p>","PeriodicalId":55167,"journal":{"name":"Endocrine Pathology","volume":"37 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13260158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148220700","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":"Genomic Catastrophe Defines the Evolutionary Trajectory of Adrenocortical Carcinoma.","authors":"Samuel Backman, Fredrik Axling, Liang Zhang, Johan Botling, C Christofer Juhlin, Elham Barazeghi, Britt Skogseid, Branislav Klimácek, Matilda Annebäck, Jan Zedenius, Olov Norlén, Peter Stålberg, Joakim Crona, Tobias Åkerström","doi":"10.1007/s12022-026-09922-2","DOIUrl":"10.1007/s12022-026-09922-2","url":null,"abstract":"<p><p>The mechanisms underlying how adrenocortical carcinoma (ACC) progresses into a metastatic and lethal disease remain poorly understood. To address this, we performed comprehensive genomic analyses to delineate the evolutionary trajectory of advanced ACC. Fresh frozen tumour samples (n = 29) were obtained from nine patients, all of whom had matched primary and relapse specimens, including recurrent (n = 4) and metastatic (n = 11) lesions. In four patients, multiple primary and metastatic samples were available, enabling detailed evolutionary comparisons. All tumours underwent whole-genome sequencing, RNA sequencing, and DNA methylation profiling. Our analyses revealed that seven of nine patients exhibited global loss of heterozygosity (LOH) often followed by whole-genome doubling, resulting in copy-neutral LOH. SNP-based analyses indicated that these alterations occurred as a single catastrophic event that was conserved across all matched samples within each patient, suggesting that this event constitutes a truncal feature of the evolutionary tree. These results support a model in which chromosomal aneuploidy is important in ACC tumourigenesis, potentially distinguishing carcinomas from benign adrenal adenomas. This may explain the rarity of adenoma-to-carcinoma transformation and suggest a diagnostic and therapeutic relevance of chromosomal instability in ACC.</p>","PeriodicalId":55167,"journal":{"name":"Endocrine Pathology","volume":"37 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13249746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148213523","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":"Three-Tier Prognostic Stratification of Lung Carcinoids (NET G1-G2-G3) by Multivariable, Data-Driven Integration of Ki-67 and Mitotic Count.","authors":"Giulia Orlando, Valentina Veronesi, Eleonora Duregon, Vanessa Zambelli, Francesco Leo, Elisa Carla Fontana, Enrico Ruffini, Luisella Righi, Giuseppe Pelosi, Marco Volante, Mauro Papotti","doi":"10.1007/s12022-026-09920-4","DOIUrl":"10.1007/s12022-026-09920-4","url":null,"abstract":"<p><p>Pulmonary neuroendocrine tumors (NETs) include typical and atypical carcinoids, corresponding to low- and intermediate-grade malignancies. Integration of necrosis, mitotic count per 2 mm² (MC), and Ki-67 index, a desirable criterion in the current WHO scheme, may enable a classification framework beyond conventional histology. We used a clustering method for mixed-type data, including necrosis, MC and Ki-67 index, on a single-institution cohort of 358 typical and 125 atypical carcinoids with long-term follow-up. An external validation series of 259 additional carcinoids was used. A three-cluster solution was selected, yielding a tiered prognostic stratification model, that included NETG1 (383 cases; mean MC: 0.7; necrosis: 8.1% of cases; mean Ki-67 index: 2.5%), NETG2 (77 cases; mean MC 2.3; necrosis 27.3%; mean Ki-67: 11.4%), and NETG3 (23 cases; mean MC: 5.5; necrosis 60.9%; mean Ki-67: 25.1%). The model was independent of histological classification. Ki-67 index was the strongest discriminator, distinguishing NET G1 tumors with a Ki-67 index < 6% from NET G3 tumors (Ki-67 > 16%), while MC contributed to identifying a subset of NET G2 tumors. The selected cut-offs were derived through a statistical approach evaluating hundreds of decision-tree configurations, following a sequential algorithm from Ki-67 to MC, with 6-16% identified as the most informative Ki-67 range for intermediate stratification. Necrosis added no discriminative value, as it was closely correlated with the Ki-67 index and MC. This classification corresponded to a progressive worsening of overall survival and, more significantly, relapse-free survival, and it was transferable to the external cohort. In conclusion, based on routinely available pathological parameters, this model provides a practical and reproducible classification of resected pulmonary NETs, overcoming the traditional typical-atypical carcinoid dichotomy and is potentially applicable to biopsy material.</p>","PeriodicalId":55167,"journal":{"name":"Endocrine Pathology","volume":"37 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13194188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147984596","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}