Endocrine Pathology最新文献

Endocrine and neuroendocrine malignancies, including epithelial neuroendocrine neoplasms (NENs), phaeochromocytoma/paraganglioma (PPGL), adrenocortical carcinoma (ACC) and thyroid cancers, represent a heterogeneous group of tumours often characterised by dysregulated receptor tyrosine kinase signalling and with limited systemic treatment options. Cabozantinib is a multikinase inhibitor implicated in tumour angiogenesis, growth, and therapeutic resistance, and its use has been reported in many of these tumours. We performed a narrative review assessing cabozantinib monotherapy or combination regimens in patients with progressive neuroendocrine neoplasms. In NENs, monotherapy achieved a disease control rate (DCR) of up to 83% and a progression-free survival (PFS) of 8.4 months in extra-pancreatic subtypes, and 13.8 months in pancreatic subtypes. Combination therapies yielded modest efficacy with a PFS up to 13.0 months. In metastatic PPGLs, monotherapy achieved an objective response rate (ORR) of 25%, a median PFS of 16.6 months and overall survival (OS) of 24.9 months; combination with atezolizumab showed an ORR of 15.4% and a PFS of 8.4 months. In adrenocortical cancer, the DCR reached 78%, PFS up to 7.2 months, and OS up to 23.9 months. In differentiated thyroid cancer, PFS 11.4 months and OS 26.3 months; in RET M918T-mutant medullary thyroid cancer, OS improved to 44.3 months. Cabozantinib represents a promising therapeutic option across endocrine and neuroendocrine malignancies, particularly in settings with limited treatment alternatives, although the reported rates of control have not been dramatic and adverse effects not insignificant. However, it offers the possibility of exploring more effective molecular approaches, especially with biomarker-based stratification and combinatorial approaches.

The diagnosis and prognosis of follicular thyroid neoplasms are based on the identification of capsular and vascular invasion. Although conventional histology allows accurate classification in most cases, its inherent limitations in tissue sampling can result in misjudgment of both the presence and extent of invasion, and occasionally result in diagnostic inaccuracies. Consequently, unexpected tumor recurrence or overtreatment still represent significant clinical challenges. To mitigate these limitations, emerging diagnostic approaches are exploring advanced imaging modalities. X-ray 3D virtual histology has been reported to enable non-destructive and comprehensive sampling of the entire tumor volume embedded in formalin-fixed paraffin-embedded blocks. In thisstudy, the X-ray 3D virtual histology technique is first evaluated by classifying 99 follicular thyroid carcinomas and 31 follicular adenomas, achieving an accuracy of 89.2%. It is then applied to tissue blocks from five relapse cases that were postoperatively diagnosed as adenomas using conventional histology. Three of five tumors exhibited at least one unequivocal focus of vascular invasion, reinforcing that even a single well-defined focus portends significant risk of recurrence and distant metastasis. Although histological confirmation at this stage remained necessary, X-ray 3D virtual histology proved to be a valuable screening method.

About 40% of non-functioning (NF) Pancreatic Neuroendocrine Tumors (PanNETs) harbour mutations in MEN1, often co-occurring with DAXX/ATRX. While the ADM group (MEN1 and DAXX/ATRX co-mutated) exhibits homogeneous genetic and epigenetic features and a consistent risk of relapse, it shows considerable variability in treatment response, suggesting an underlying molecular diversity. In this study we aimed to elucidate the molecular mechanisms underlying this heterogeneity of ADM PanNETs by integrating transcriptomic (n = 36) and DNA methylation (n = 93) data. First, DNA methylation discriminates ADM-PanNET from PanNET mutated only in MEN1 (α-like), revealing enhancer, peri-centromeric, and telomeric methylation changes associated with alternative lengthening of telomeres and increased chromosomal instability. Transcriptomic analysis further revealed three distinct ADM subtypes: ADM hypoxic, ADM NST (No Special Type), and ADM immunosuppressive. The ADM hypoxic subtype is characterized by strong hypoxia signature, likely regulated epigenetically. The ADM NST subtype appears to be primarily driven by epigenetic changes that promote proliferation. Notably, the ADM immunosuppressive subtype, although significantly smaller (< 2.5 cm, p = 0.023), exhibits strong immune and metastasis-like signatures, suggesting a uniquely aggressive biology despite its reduced size. By defining these three novel ADM subtypes, our study provides a refined framework for understanding PanNET heterogeneity. This classification underscores potential diagnostic markers and highlights distinct biological vulnerabilities that may inform the development of subtype-tailored therapeutic strategies.

Recent studies have shown that pulmonary neuroendocrine tumor (NET) subgroups, defined by the transcription factors OTP and ASCL1, correlate with age, sex, and tumor location. Their relationships with histology and hormone production, however, remain unclear. We analyzed 170 pulmonary NETs classified by OTP (O) and ASCL1 (A) expression into four groups: O + /A + , O + /A-, O-/A + , and O-/A-. Subgroups were assessed for histology, hormone expression, therapy-related markers, outcomes, and matched metastases. Among 152 resected primaries, O + /A + tumors (38%) were most frequent, occurring mainly in females (median age 72 years), and typically showed central or peripheral location, solid/spindle morphology with diffuse gastrin-releasing peptide (GRP), and focal ACTH/calcitonin. They also showed strong DLL3 expression and pronounced neuroendocrine cell hyperplasia. O + /A- tumors (23%) occurred predominantly in females (median age 56 years) with solid/trabecular patterns, occasional/ACTH, and strong SSTR2A/5 expression. O-/A- tumors (25%) were more common in males (median age 70 years), often central with solid/trabecular or oncocytic histology, serotonin expression (24%), and frequently SSTR2A-positivity. O-/A + tumors (14%) occurred across both sexes (median age 58 years), were centrally located, and solid, sometimes oncocytic features with moderate DLL3/SSTR2A expression. Metastases mirrored their primaries in transcription factor and hormone profiles. In the univariate analysis, OTP-negative tumors were associated with poorer disease-free survival (DFS). However, the multivariate analysis identified Ki67-based WHO grades (G1-G3) as the only independent prognostic factors. In conclusion, integrating OTP and ASCL1 refines pulmonary NET classification into four histologically and biologically distinct subgroups, providing additional insight into tumor heterogeneity. O + /A + tumors showed solid-spindle features and diffuse GRP and frequent ACTH expression, trabecular patterns characterized ASCL1-negative tumors, while oncocytic histology predominated in OTP-negative tumors, highlighting their role in defining tumor heterogeneity.

Alkylating agent-based chemotherapy is one of the main treatment options for patients with metastatic pancreatic neuroendocrine tumors (PanNETs).However, it favors the acquisition of a hypermutator phenotype, suggesting a potential benefit of immunotherapy.We aimed to describe the efficacy of immunotherapy in an international retrospective cohort of patients with metastatic well-differentiated PanNETs pretreated with alkylating therapy. The primary endpoint was progression-free survival (PFS) and the main secondary endpoint was the radiological objective response rate (ORR). We explored the impact of tumor mutation burden (TMB) and mismatch repair deficiency (MMRd), and evaluated variables associated with PFS.We included 64 patients with heavily pretreated PanNETs (median Ki-67 28%). Among 51 PanNETs with mutational profiling, 37 (73%) were TMB^high (median 35 mut/Mb). Among 46 PanNETs with available MMR status, 18 (39%) were MMRd, representing 49% of all TMB^high PanNETs. Immunotherapy consisted of a single (31%) or a dual (69%) immune checkpoint inhibitor. Median PFS was 3.2 months (95% CI, 1.3-5.0.3.0) and the ORR was 17%. Patients with TMB^high PanNETs had longer PFS (median 3.8 vs. 2.3 months, p = 0.015) and higher ORR (30% vs. 0%, p = 0.002) compared with TMB^low/unk cases. Patients with MMRd PanNETs had longer PFS (median 8.9 vs. 2.7 months, p = 0.003) and higher ORR (44% vs. 7%, p < 0.001) compared with MMRp/unk. On multivariable analyses, MMRd predicted longer PFS (HR 0.42, 95% CI [0.20-0.82], p = 0.015).Overall, immunotherapy may be effective against alkylating-pretreated metastatic PanNETs exhibiting TMB^high and MMRd. MMR immunohistochemistry and TMB assessment could be implemented in the routine assessment of alkylating-pretreated metastatic PanNETs.

Rb and p53 status helps distinguishing well from poorly differentiated high-grade neuroendocrine neoplasms (HG-NENs) and may predict response to platinum-based chemotherapy. Historically, gene and protein profile correlations for Rb and p53 were performed on frozen samples using high-throughput techniques efficient for copy number determination. This situation differs from routine practice in which NGS is not available everywhere and small deletions may be hard to detect on formalin-fixed paraffin-embedded (FFPE) samples with a gene panel approach. This study aimed at describing the immunohistochemical (IHC) staining patterns of Rb, p16, and p53 in a large cohort of well and poorly differentiated lung and pancreatic HG-NENs, and comparing the performance of Rb/p53 NGS profiling with IHC to detect molecular alterations. Rb, p16, and p53 protein status were determined by IHC in 132 HG-NENs (79 pulmonary and 53 pancreatic). NGS was performed on a subset of 63 tumors. Three IHC patterns were observed in HG-NENs: (i) loss of expression (Rb^loss = 45.4% with p16^strong expression in most cases, p53^loss = 32.6%), (ii) variable expression (Rb^var = 40.8% including 12 cases with p16^strong, p53^var = 37.1%), (iii) strong expression (Rb^strong = 13.6%, p53^strong = 30.3%). NGS testing and IHC agreed in 76.2% and 82.5% of cases for Rb and p53, respectively. Abnormal Rb & p53 IHC profiles, highly suggestive of a molecular alteration, were missed by NGS in 42% and 20.5% of cases, respectively. In conclusion, IHC is a reliable, rapid, and cost-effective screening method in HG-NENs for Rb/p53 status.

Atypical carcinoids (ACs) and large cell neuroendocrine carcinomas (LCNECs) are defined by the WHO as intermediate- and high-grade lung neuroendocrine neoplasms, respectively, based on morphological criteria; however, treatment strategies remain debated. Given the emerging role of the tumor microenvironment (TME) and tumor-infiltrating lymphocytes (TILs) in cancer prognosis and therapy response, this study aimed to characterize the immune landscape of ACs and LCNECs comprehensively. Immunohistochemistry for T-cell markers (CD3, CD8), immune checkpoints (PD-1, PD-L1), HLA molecules (HLA-DR, HLA-I), and fibroblasts (α-SMA) was performed on a re-evaluated cohort of 56 ACs and 104 LCNECs. Digital image analysis quantified intra-tumor (iTILs) and stromal (sTILs) CD3 and CD8 TILs in the whole slide and in specific tumor regions (invasive margin [IM] and central tumor [CT]). LCNECs exhibited significantly higher stromal T-cell infiltration, immune checkpoint expression, and HLA compared to ACs (p < 0.001), while α-SMA was more prominent in ACs. No ACs showed PD-L1 tumor expression. Digital quantification confirmed greater iTILs and sTILs in LCNECs across all regions, with moderate concordance to manual counts. Interestingly, TIL parameters were higher at the IM than in the CT (p < 0.001). Using Boruta feature selection algorithm, Principal Component Analysis and Hierarchical Clustering, three patient clusters were identified: Cluster 1 (mainly ACs, low TILs, favorable prognosis), Cluster 2 (mixed histology, intermediate TILs, moderate prognosis), and Cluster 3 (mostly LCNECs, high TILs, poor prognosis), with distinct TME marker profiles. PD-L1 tumor expression was strongly linked to Cluster 3. These findings suggest that ACs and LCNECs may be stratified into three distinct immune clusters, highlighting the heterogeneity of their tumor microenvironment and providing a rationale for further translational studies.

Poorly differentiated thyroid carcinoma (PDTC) is a rare thyroid cancer with aggressive clinical course and peculiar clinical/pathological characteristics but lacking effective therapeutic options, when surgery is not curative. We aimed at the molecular characterization of PDTC with a specific focus on the identification of potential therapeutic targets. A series of PDTC cases was selected from a multi-institutional network. Fifty-nine samples underwent wide targeted DNA and RNA next-generation sequencing (NGS) testing and immunohistochemical analysis for mismatch repair (MMR) proteins. Gene fusion analysis was enriched by 25 additional samples. Prevalence of MMR protein loss was 11.9%. The most prevalent mutations were in NRAS (25%) and TP53 (25%), mutually exclusive. TERT promoter (TERTp) mutations were detected in 19.6% of cases (10/51). NRAS-mutated cases were enriched for mutations in genes belonging to the same pathway. TP53-mutated samples lacked TERTp co-mutations, but were associated with mutations in PTEN and in genes related to MMR system and/or loss of MMR proteins. TERTp mutations were the most prevalent alterations (28%, 7/25) in a third group that lacked NRAS or TP53 mutations. Four cases harbored gene fusions, including two cases harboring the TBL1XR1::PIK3CA fusion that has never been reported in thyroid cancer, so far. In conclusion, PDTC may be genomically segregated in subgroups with specific molecular characteristics. Overall, targetable gene fusions have a prevalence of 9% (4/42). Moreover, 47% of cases are potential candidates for individualized target therapies since they harbor mutations in genes coding for potentially targetable molecules and/or have defects in the MMR system.