Endocrine Pathology最新文献

Thada: IGF2BP3 fusion results in IGF2BP3 (IMP3) overexpression, driving a subset of RAS-like indolent thyroid tumors, typically noninvasive follicular thyroid neoplasm with papillary like nuclear features (NIFTP) or minimally invasive encapsulated follicular variant of papillary thyroid carcinoma (miEFVPTC). These also have distinct morphologic features that have yet to be characterized. We assessed 51 cases of surgically resected thyroid nodules with IMP3 positivity or IGF2BP3 overexpression (IMP3+) and compared them to 113 pathologically similar cases without IMP3 positivity (IMP3-) within the same time frame (2014-2025). IMP3+ cases were diagnosed as miEFVPTC (n=36), NIFTP (n=14), with only one follicular adenoma. On comparative morphologic analysis, key features selectively noted in IMP3+ tumors included: low power "pale blue" optical clarity, condensation of cellularity at the nodule periphery, microfollicles interspersed between macrofollicles, perifollicular sclerosis, clear cytoplasm, perinuclear indentation by cytoplasmic vacuoles, "squared-off" nuclei, prominent single nuclear grooves, grade 3 nuclei, and background chronic lymphocytic thyroiditis. Oncocytic cytoplasm and solid/trabecular/insular growth were exclusive to the IMP3- group. Only one of 34 (2.9%) tested cases was weakly HBME-1 positive in the IMP3+ group. A multiple logistic regression model predicting IMP3 status included microfollicles interspersed between macrofollicles, clear cytoplasm, perinuclear indentation by cytoplasmic vacuoles, "squared-off" nuclei, and background chronic lymphocytic thyroiditis (AUC: 0.957, AIC: 63.858, BIC: 81.109). Adding HBME-1 status resulted in a slightly more discriminatory model (AUC: 0.987, AIC: 58.087, BIC: 78.214). No significant difference in disease-free survival was observed between IMP3+ and IMP3- groups (log-rank p = 0.348), although analysis was limited by short follow-up and very few events. In the IMP3+ group (median follow up: 23.3 months), one case recurred 155 months after incomplete excision. IMP3-positive/IGF2BP3-overexpressing thyroid tumors have a RAS-like profile and likely indolent clinical behavior. We demonstrate that they have distinct cytomorphologic features that allow for recognition. The exaggerated overt nuclear features may lead to misclassification as more aggressive subtypes (i.e. conventional). HBME-1 negativity is characteristic and can aid in recognition of IMP3+ tumors.

It has been recently demonstrated that papillary thyroid carcinomas (PTCs) that develop distant metastases are characterized by three genetic alterations: Chr1q^amp, TERT_locus^amp, TERT_promoter^mut. This signature, named THYT1, holds the potential as an early prognostic predictor to identify patients at risk for disease progression. To implement the use of this signature in clinical practice we first developed a droplet digital PCR approach for a faster and cost-effective detection of the THYT1 in PTCs, then we validated its performance in a retrospective monocentric case-control training cohort (N = 90) of PTCs and in a separated multicentric validation cohort (N = 143) of PTCs. We also investigated THYT1 feasibility in cytological pre-surgical thyroid smears. In the training set, THYT1 evaluation by ddPCR showed 93% rate of concordance with the THYT1 status previously determined and correctly identified THYT1-positive and THYT1-negative PTCs with a 96% sensitivity and a 92% specificity. In the validation cohort, THYT1 identified up to 80% of distantly metastatic PTCs and significantly correlated with reduced overall survival. THYT1 signature was effective in anticipating at diagnosis both synchronous and metachronous metastases in advance of up to 19 years. These data confirm that THYT1 is an easy-to-use, rapidly available prognostic test to help refining the selection of patients with indolent lesions that could be eligible for conservative treatment strategies.

Thymic and pulmonary neuroendocrine neoplasms (NEN) are morphologically similar but arise from different embryonic tissues. Whether this similarity extends to shared molecular programs is unclear. We compared 45 thymic and 37 pulmonary NEN by immunohistochemistry, targeted and exome sequencing, NanoString RNA profiling and mass spectrometry-based proteomics. The RNA and proteomic profiles of pulmonary and thymic neuroendocrine tumors (LuNET and TNET) were clearly different, while the profiles of neuroendocrine carcinomas of both organs (LuNEC and TNEC) were largely overlapping. A subgroup of TNET corresponding to NET G3 clustered with lower-grade thymic NET rather than NEC. NET of both organs showed a low mutational burden and were proliferatively quiescent but diverged metabolically: LuNET showed broad metabolic and stress signaling and TNET a quiescent phenotype with PI3K/AKT/mTOR as the only enriched pathway. NEC of both organs converged on cell cycle activation and metabolic depletion with frequent TP53 and RB1 co-inactivation, but diverged immunologically: LuNEC were immune-hot, whereas TNEC showed epithelial-mesenchymal transition and a markedly lower mutational burden. CD44 stood out in both the transcriptomic and the proteomic analysis and was therefore immunohistochemically validated in an independent, larger cohort that included also gastrointestinal and pancreatic tumors. CD44 was high in pulmonary NET and low in every other subgroup (p = 2.1 × 10⁻¹³), identifying it as a new complementary marker of pulmonary origin. In summary, thoracic NEN segregate by anatomical origin as well as by differentiation grade. Wether these differences require treatments adapted to the organ of origin remains to be established.

Ampullary somatostatin-producing D-cell neuroendocrine tumors are rare neoplasms that may be associated with type 1 neurofibromatosis. The molecular features of sporadic ampullary somatostatin-producing D-cell neuroendocrine tumors (SAMSOM-NETs) remain poorly characterized. We performed an integrated morphological, immunohistochemical, and genomic analysis of a multicenter series of SAMSOM-NETs. Eleven cases were included (73% male; median age: 63 years). All six patients who underwent lymphadenectomy were staged as pN1, and liver metastases were found in three cases; however, no tumor-related deaths occurred (median follow-up: 104 months). Common histologic features that can pose diagnostic challenges in the differential diagnosis with adenocarcinoma included a tubulo-glandular architecture (100%), periodic Acid-Schiff (PAS)-positive intraluminal mucin (73%), MUC1 expression (100%), and carcinoembryonic antigen (45%) expression. All tumors exhibited dot-like cytoplasmic reactivity for cytokeratins (CK) CAM5.2 or CK AE1/AE3, and 82% were CK7-positive. ISL1 and PDX1 were diffusely expressed in all cases, while CDX2 was positive in 54% and ARX showed only focal expression in four tumors. Genomic profiling revealed microsatellite stability and low tumor mutational burden. Alterations in the RAS pathway, including HRAS mutations (4 cases, 36%), a KRAS mutation (1 case), and NF1 alterations (one case), were identified in 54% of cases and in all tumors with liver metastases. Additional molecular findings included a CDK12 splice-site alteration and an NTRK3::PRDM4 fusion. Potentially actionable alterations affecting kinase-related pathways were detected in 64% of tumors. Our findings support SAMSOM-NET as a peculiar neuroendocrine tumor subtype showing distinctive histologic and molecular characteristics with potential diagnostic and therapeutic implications.

Neuroendocrine neoplasms (NEN) comprise well-differentiated neuroendocrine tumours (NET) and neuroendocrine carcinomas (NEC), whose distinction is clinically critical. Although c-MYC alterations have been implicated in NEC pathogenesis, c-MYC expression across NEC subtypes and anatomical sites, as well as in NET, remains incompletely defined. We analysed c-MYC immunohistochemically in 1380 resected NEN using the Immunoreactive Score (IRS: negative 0-1, weak 2-3, moderate 4-8, strong 9-12). Overall, c-MYC positivity (IRS ≥ 2) was observed in 13.3% of NEN. Expression was detected in 43% of NEC (164/381), including strong staining in 19.4%, whereas it was rare in NET and pulmonary carcinoids (20/999; 2%; p ≤ 0.001). Within NEC, c-MYC expression was enriched in LCNEC and MiNEN compared with SCNEC and Merkel cell carcinoma (p ≤ 0.001) and occurred more often in gastroenteropancreatic than in pulmonary NEC (57.6% vs. 37.3%; p ≤ 0.001). Among NET, G3 tumours showed the highest positivity rate (6/35; 17.1%), although this was significantly lower than in NEC (p ≤ 0.001), with strong expression observed in only one NET G3 (2.9%). No association between c-MYC expression and survival was identified in either NEC or NET. Our study confirms c-MYC expression as a common event in NEC and highlights differences across histological subtypes and anatomical sites, while demonstrating its absence in most low-proliferative NET. A subset of NET G3 tumours exhibits weak to moderate c-MYC expression at levels far below those seen in NEC, suggesting that strong c-MYC positivity may support a NEC classification in borderline cases but does not represent a definitive discriminatory marker.

Non-functioning pancreatic neuroendocrine tumors (NF-pNETs) show a variable prognosis. Despite 40-60% of patients remaining recurrence-free after surgery, guidelines recommend ≥ 10 years of follow-up. Recent studies identify prognostic subgroups based on ATRX, DAXX, and MEN1 mutations and chromosomal aneuploidy, highlighting a subgroup with favorable prognosis. We aimed to classify resected NF-pNETs into molecular subgroups using ATRX, DAXX, and Menin immunohistochemistry as surrogate markers for genomic status. To do so, we retrospectively collected resected primary sporadic grade 1 and 2 NF-pNETs without synchronous metastases from five international local pathology archives. ATRX, DAXX, and Menin immunohistochemistry was performed, and tumors were categorized into three groups: ATRX-DAXX-loss-group (ATRX or DAXX loss), isolated-Menin-loss-group (Menin loss without ATRX and DAXX loss), and unspecified-group (retained Menin, ATRX and DAXX). Kaplan-Meier analysis evaluated prognostic differences, and multivariable Cox regression assessed the added value of molecular subgroups beyond established prognostic factors. In total, 139 patients with grade 1 (64%) and 2 (36%) NF-pNETs were included. The median follow-up was 28 months (range 0-195) and recurrences occurred in 20% (28/139). No recurrences occurred in the isolated-Menin-loss-group (0/33), versus 12.5% (8/64) in the unspecified-group and 48% (20/42) in the ATRX-DAXX-loss-group. Kaplan-Meier analysis showed better recurrence-free interval in the isolated-Menin-loss-group than other subgroups (P < 0.001). In univariate analysis, the isolated-Menin-loss-group had a lower recurrence hazard (HR 0.03; 95%CI: 0.00-0.55; P = 0.018), than other subgroups, with little change in the hazard ratio after adjustment, but loss of significance. In conclusion, molecular subclassification by immunohistochemistry identifies NF-pNET patients with a low risk of recurrence and lays the groundwork for future prospective studies assessing genetics-based risk stratification as a tool for guiding clinical management.

Neuroendocrine neoplasms (NENs) of the urinary bladder are rare but highly aggressive tumors that account for under 1% of bladder malignancies. The 2022 WHO classification recognizes small cell neuroendocrine carcinoma (SCNEC), large cell neuroendocrine carcinoma (LCNEC), mixed neuroendocrine neoplasms (MiNEN), well-differentiated neuroendocrine tumor (NET), and paraganglioma; however, this framework is largely extrapolated from other organ systems and does not fully capture the biological complexity of bladder NENs. Most cases represent poorly differentiated neuroendocrine carcinomas, frequently admixed with urothelial carcinoma and characterized by recurrent TP53 and RB1 inactivation, TERT promoter mutations, and epigenetic dysregulation. Emerging transcriptomic data further identify lineage-defined subgroups within SCNEC and LCNEC based on ASCL1, NEUROD1, and POU2F3 expression, with potential prognostic and therapeutic relevance. This review integrates histopathologic, immunophenotypic, and molecular data to highlight diagnostic challenges, biologic heterogeneity, and limitations of current classification schemes. We propose a refined, bladder-specific framework that incorporates proliferative indices, molecular alterations, and recognition of mixed neuroendocrine-non-neuroendocrine neoplasms, with the goal of improving diagnostic reproducibility and informing future biomarker-driven therapeutic strategies.

Adrenal and extra-adrenal paragangliomas (PPGLs) are highly heritable non-epithelial neuroendocrine neoplasms. Through a retrospective chart review of 110 individuals diagnosed with PPGLs at the University Health Network in Toronto, Canada (2011-2023), we characterized germline findings, tumor features, self-reported ethnicity, and variant reclassification across a multi-ethnic cohort using targeted germline panel sequencing, whole genome sequencing (WGS), and optical genome mapping (OGM). Panel sequencing identified pathogenic or likely pathogenic (P/LP) germline variants in 28.18% (31/110) of individuals, with five variants of uncertain significance (VUS) in PPGL predisposition genes reclassified to P/LP during the study period (32.7%, 36/110). VUS rates were comparable across ethnic groups (16.28%, 7/43 in the group of non-European ethnicities; 17.24%, 10/58 in the group of European ethnicities), but the non-European group had a lower rate of VUS-to-P/LP reclassification (28.57%, 2/7 vs. 40.0%, 4/10). Uninformative targeted panel testing was supplemented by WGS in seven individuals with succinate dehydrogenase (SDH)-deficient tumors, leading to detection of P/LP in 6/7 cases (85.7%). Broader sequencing also uncovered incidental P/LP variants in genes without an established PPGL association, including TSC1 and PALB2. OGM resolved a complex structural variant (SV) involving SDHA as an inverted tandem duplication that WGS alone could not fully characterize. Our findings support a tiered diagnostic approach: comprehensive germline panels and tumor SDHB immunohistochemistry to maximize solved cases, with WGS and OGM reserved for select unresolved cases, and highlight the importance of equitable variant interpretation across diverse PPGL populations.

Paragangliomas (PGLs) are rare neural crest-derived tumors with highly variable morphology and clinical behavior. These tumors can present with cystic and necrotic alterations that may influence the clinical presentation of affected patients. However, prevalence and clinical significance of these pathological alterations remain poorly understood. In this retrospective study (2011-2021), 103 patients with confirmed PGLs were examined for cystic and necrotic alterations based on imaging and pathology reports as well as pathological re-evaluation. Cystic alterations, including microscopic, macroscopic, and pseudocystic alterations, were observed in 61.8% of PGLs. Regardless of their pathomorphological presentation, cystic alterations did not affect the clinical presentation of these patients. In contrast, necrotic alterations were identified in 3.9% of PGLs and were associated with a higher rate of metastasis (75% vs. 10%, p = 0.0124), larger tumor volume (53.6 cm³ vs. 6.6 cm³p = 0.0339), and more pronounced signs and symptoms, including hypertension, palpitations, and weakness compared to patients without cystic/necrotic lesions. The prevalence of cystic and necrotic lesions was higher in adrenal than extra-adrenal PGLs. An additional meta-analysis of 235 patients with PGLs confirmed the increased rate of metastasis in necrotic PGLs (16% vs. 4.5%, p = 0.0369), which were also significantly more frequently associated with cardiovascular complications (p < 0.0001) than cystic PGLs. Considering pathological alterations, particularly necrotic lesions, may substantially affect the clinical management of patients with PGLs. Incorporating these features into preoperative management and follow-up strategies might be crucial, given the higher metastatic potential and increased cardiovascular risk associated with necrotic PGLs.