Endocrine Pathology最新文献

The prognosis of thyroid cancer in patients varies significantly based on different pathological types or distinct clinical situations. Investigating the expression of immune checkpoint molecules PD-L1 and B7-H3 in high-risk thyroid cancer and their correlation with clinicopathological features and prognosis will contribute to the development of novel therapeutic strategies. A retrospective sample of 202 patients with thyroid cancer who underwent surgery at the Cancer Hospital of the Chinese Academy of Medical Sciences was collected, including 33 cases of anaplastic thyroid cancer (ATC), 21 cases of differentiated thyroid cancer (DTC) with distant metastasis (DM), 7 cases of differentiated high-grade thyroid carcinoma (DHGTC), and 109 cases of aggressive subtypes of papillary thyroid carcinoma (PTC) (including 28 cases of tall cell PTC, 31 cases of diffuse sclerosing PTC, 20 cases of solid PTC, 15 cases of columnar cell PTC, and 15 cases of hobnail PTC). In the control group, there were 32 cases of classic PTC. The differences in protein expression between PD-L1 and B7-H3 in several high-risk thyroid cancers and normal tissues and controls were compared by immunohistochemical staining, and the clinicopathological features and prognostic relevance were statistically analyzed. The expression of PD-L1 in ATC (P < 0.001), tall cell PTC (P = 0.031), and DHGTC (P = 0.003) was significantly higher than that in classic PTC. The expression of B7-H3 in ATC (P < 0.001), DTC with DM (P = 0.001), diffuse sclerosing PTC (P = 0.013), columnar cell PTC (P = 0.007), solid PTC (P < 0.001), hobnail PTC (P < 0.001), and DHGTC (P < 0.001) was significantly higher than that in classic PTC. In ATC, PD-L1 expression correlated significantly with extrathyroidal extension (ETE) (P = 0.027) and B7-H3 expression correlated significantly with male patients (P = 0.031) and lymph node metastasis (LNM) (P = 0.026). The positive expression of B7-H3 (P = 0.041) was an independent risk factor for disease progression in ATC. B7-H3 positive expression (P = 0.049), PD-L1 positive expression (P = 0.015), and tumor diameter ≥ 2 cm (P = 0.038) were independent risk factors for disease progression in patients with DTC with DM. PD-L1 positive expression (P = 0.019) and tumor diameter ≥ 2 cm (P = 0.018) were independent risk factors for disease progression in patients with aggressive subtypes of PTC. B7-H3 and PD-L1 are expected to be effective prognostic indicators for patients with aggressive thyroid cancer, which can help in optimization of individualized treatment strategies. Immunotherapy targeting these two molecules may provide new and complementary ideas for the treatment of high-risk/refractory thyroid cancer.

RAS p.Q61R is the most prevalent hot-spot mutation in RAS and RAS-like mutated thyroid nodules. A few studies evaluated RAS p.Q61R by immunohistochemistry (RASQ61R-IHC). We performed a retrospective study of an institutional cohort of 150 patients with 217 thyroid lesions tested for RASQ61R-IHC, including clinical, cytologic and molecular data. RASQ61R-IHC was performed on 217 nodules (18% positive, 80% negative, and 2% equivocal). RAS p.Q61R was identified in 76% (n = 42), followed by RAS p.Q61K (15%; n = 8), and RAS p.G13R (5%; n = 3). NRAS p.Q61R isoform was the most common (44%; n = 15), followed by NRAS p.Q61K (17%; n = 6), KRAS p.Q61R (12%; n = 4), HRAS p.Q61R (12%; n = 4), HRAS p.Q61K (6%; n = 2), HRAS p.G13R (6%; n = 2), and NRAS p.G13R (3%; n = 1). RASQ61R-IHC was positive in 47% of noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP; 17/36), 22% of follicular thyroid carcinomas (FTC; 5/23), 10% of follicular thyroid adenomas (FTA; 4/40), and 8% of papillary thyroid carcinomas (PTC; 9/112). Of PTC studied (n = 112), invasive encapsulated follicular variant (IEFVPTC; n = 16) was the only subtype with positive RASQ61R-IHC (56%; 9/16). Overall, 31% of RAS-mutated nodules were carcinomas (17/54); and of the carcinomas, 94% (16/17) were low-risk per American Thyroid Associated (ATA) criteria, with only a single case (6%; 1/17) considered ATA high-risk. No RAS-mutated tumors recurred, and none showed local or distant metastasis (with a follow-up of 0–10 months). We found that most RAS-mutated tumors are low-grade neoplasms. RASQ61R-IHC is a quick, cost-effective, and reliable way to detect RAS p.Q61R in follicular-patterned thyroid neoplasia and, when malignant, guide surveillance.

Follicular thyroid carcinoma (FTC) is recognized by its ability to invade the tumor capsule and blood vessels, although the exact molecular signals orchestrating this phenotype remain elusive. In this study, the spatial transcriptional landscape of an FTC is detailed with comparisons between the invasive front and histologically indolent central core tumor areas. The Visium spatial gene expression platform allowed us to interrogate and visualize the whole transcriptome in 2D across formalin-fixated paraffin-embedded (FFPE) tissue sections. Four different 6 × 6 mm areas of an FTC were scrutinized, including regions with capsular and vascular invasion, capsule-near area without invasion, and a central core area of the tumor. Following successful capturing and sequencing, several expressional clusters were identified with regional variation. Most notably, invasive tumor cell clusters were significantly over-expressing genes associated with pathways interacting with the extracellular matrix (ECM) remodeling and epithelial-to-mesenchymal transition (EMT). Subsets of these genes (POSTN and DPYSL3) were additionally validated using immunohistochemistry in an independent cohort of follicular thyroid tumors showing a clear gradient pattern from the core to the periphery of the tumor. Moreover, the reconstruction of the evolutionary tree identified the invasive clones as late events in follicular thyroid tumorigenesis. To our knowledge, this is one of the first 2D global transcriptional mappings of FTC using this platform to date. Invasive FTC clones develop in a stepwise fashion and display significant dysregulation of genes associated with the ECM and EMT - thus highlighting important molecular crosstalk for further investigations.

In the last two decades, the increasing availability of technologies for molecular analyses has allowed an insight in the genomic alterations of neuroendocrine neoplasms (NEN) of the gastrointestinal tract and pancreas. This knowledge has confirmed, supported, and informed the pathological classification of NEN, clarifying the differences between neuroendocrine carcinomas (NEC) and neuroendocrine tumors (NET) and helping to define the G3 NET category. At the same time, the identification genomic alterations, in terms of gene mutation, structural abnormalities, and epigenetic changes differentially involved in the pathogenesis of NEC and NET has identified potential molecular targets for precision therapy. This review critically recapitulates the available molecular features of digestive NEC and NET, highlighting their correlates with pathological aspects and clinical characteristics of these neoplasms and revising their role as predictive biomarkers for targeted therapy. In this context, the feasibility and applicability of a molecular classification of gastrointestinal and pancreatic NEN will be explored.

Traditionally considered non-functional low proliferative benign neuroendocrine proliferations measuring less than 5 mm, pancreatic (neuro)endocrine microadenomas are now classified as pancreatic neuroendocrine microtumors in the 2022 WHO classification of endocrine and neuroendocrine tumors. This case report discussed the features of an incidentally identified 4.7-mm glucagon-expressing pancreatic neuroendocrine microtumor with MEN1 mutation only, chromosomally stable and an epigenetic alpha-like phenotype. The tumor was associated with an unexplained increased proliferation rate in Ki-67 of 15%. There was no associated DAXX/ATRX deficiency. The presented case challenges the conventional thought of a low proliferative disease of the so-called "pancreatic neuroendocrine microadenomas" and provides additional support to the 2022 WHO classification that also requires grading of these neoplasms. Despite exhibiting molecular features of less aggressive behavior, the case also underscores the biological complexity of pancreatic neuroendocrine microtumors. By recognizing the heterogenous spectrum of neuroendocrine neoplasms, the current case also contributes to ongoing discussions on how to optimize the clinical management of such tumors.

Appendiceal neuroendocrine tumors (NETs) are common and often are identified as incidental lesions at the time of appendectomy. The guidelines for management are based on tumor size, degree of invasion, and the Ki67 proliferation index. Most small bowel NETs are composed of serotonin-producing EC-cells, but there are multiple other neuroendocrine cell types. In the rectum, there are L-cell tumors that express peptide YY (PYY), glucagon-like peptides (GLPs), and pancreatic polypeptide (PP); they are thought to have a better prognosis than serotonin-producing tumors. We investigated whether the appendix has distinct neuroendocrine tumor types based on cell type and whether that distinction has clinical significance. We collected 135 appendiceal NETs from the pathology archives of UHN Toronto and UHCMC (Cleveland). We analyzed the expression of biomarkers including CDX2, SATB2, PSAP, serotonin, glucagon (that detects GLPs), PYY, and pancreatic polypeptide (PP) and correlated the results with clinicopathologic parameters. Immunohistochemistry identified three types of appendiceal NETs. There were 75 (56%) classified as EC-cell tumors and 37 (27%) classified as L-cell tumors; the remaining 23 (17%) expressed serotonin and one of the L-cell biomarkers and were classified as mixed. EC-cell tumors were significantly larger with more extensive invasion involving the muscularis propria, subserosa, and mesoappendix compared with L-cell tumors. Mixed tumors were intermediate in all of these parameters. Both EC-cell and mixed tumors had lymphatic and/or vascular invasion while L-cell tumors had none. Unlike EC-cell NETs, L-cell tumors were not associated with lymph node metastasis. Tumor type correlated with pT stage and the only patient with distant metastatic disease in this series had an EC-cell tumor. Our study confirms that appendiceal NETs are not a homogeneous tumor population. There are at least three types of appendiceal NET, including EC-cell, L-cell, and mixed tumors. This information is important for surveillance of patients, as monitoring urinary 5HIAA levels is only appropriate for patients with serotonin-producing tumors, whereas measurement of GLPs and/or PP is more appropriate for patients with L-cell tumors. Our data also show that tumor type is of significance with EC-cell tumors exhibiting the most aggressive behavior.