Search Results (18)

Background: Oncocytic thyroid carcinoma (OTC) was previously considered a variant of follicular thyroid carcinoma (FTC) but has recently been reclassified as a separate form of thyroid cancer. This study aimed to demonstrate that FTC and OTC are fundamentally distinct entities that can potentially be differentiated preoperatively through cytology and/or molecular testing. Methods: A retrospective chart review of patients diagnosed with FTC and OTC operated upon at two university health centers from January 2016 to September 2023 (n = 3219) was conducted. Molecular testing results were correlated with histopathologic diagnosis. Results: Fifty patients met the inclusion criteria. FTC was identified in 27 (54.0%) patients, and OTC in 23 (46.0%) patients. Patients with OTC were older (61.8 years) than FTC patients (51.2 years) (p = 0.013). Moreover, aggressive tumors were found in 39.1% (9/23) of OTCs compared to 11.1% (3/27) of FTCs (p = 0.021). Amongst Bethesda category III and IV nodules, 17 out of 20 (85.0%) OTC cytology reports demonstrated an oncocytic subtype compared to only 5 out of 24 FTC cytology reports (20.8%) (p = 0.002). On molecular testing, the EIF1AX alteration was exclusively present in OTCs while the PAX8/PPARy and PTEN alterations were exclusively found in FTCs. Copy number alterations (CNAs) were found to be more prevalent in OTC (66.7%) compared to FTC (33.3%), and they were not indicative of tumor aggressiveness. Within the OTC group, all three patients who had a TP53 alteration were diagnosed with aggressive cancer. Lastly, the OTCs exhibited a higher frequency of multiple alterations on molecular testing (66.7%) compared to FTCs (33.3%). Conclusion: To our knowledge, this is the largest study to date comparing the clinical application of abnormalities found on molecular testing for FTC and OTC. It further demonstrates the distinct clinicopathological and molecular characteristics of OTC. Full article

Obesity’s role in thyroid cancer development is still debated, as well as its association with aggressive histopathological subtypes (AHSs). To clarify the link between Body Mass Index (BMI) and AHS of differentiated thyroid carcinoma (DTC), we evaluated patients who underwent thyroidectomy for DTC from 2020 to 2022 at four European referral centres for endocrine surgery. Based on BMI, patients were classified as normal-underweight, overweight, or obese. AHSs were defined according to 2022 WHO guidelines. Among 3868 patients included, 34.5% were overweight and 19.6% obese. Histological diagnoses were: 93.6% papillary (PTC), 4.8% follicular (FTC), and 1.6% Hürthle cell (HCC) thyroid carcinoma. Obese and overweight patients with PTC had a higher rate of AHSs (p = 0.03), bilateral, multifocal tumours (p = 0.014, 0.049), and larger nodal metastases (p = 0.017). In a multivariate analysis, BMI was an independent predictor of AHS of PTC, irrespective of gender (p = 0.028). In younger patients (<55 years old) with PTC > 1 cm, BMI predicted a higher ATA risk class (p = 0.036). Overweight and obese patients with FTC had larger tumours (p = 0.036). No difference was found in terms of AHS of FTC and HCC based on BMI category. Overweight and obese patients with PTC appear to be at an increased risk for AHS and aggressive clinico-pathological characteristics. Full article

In 2022, the new WHO Classification of Endocrine and Neuroendocrine Tumors, Fifth Edition (beta version) (WHO 5th), was published. Large-scale genomic analyses such as The Cancer Genome Atlas (TCGA) have revealed the importance of understanding the molecular genetics of thyroid tumors. Consequently, the WHO 5th was fundamentally revised, resulting in a systematic classification based on the cell of origin of tumors and their clinical risk. This paper outlines the following critical points of the WHO 5th. 1. Genetic mutations in follicular cell-derived neoplasms (FDNs) highlight the role of mutations in the MAP kinase pathway, including RET, RAS, and BRAF, as drivers of carcinogenesis. Differentiated thyroid cancers such as follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC) have specific genetic alterations that correlate with morphological classifications: RAS-like tumors (RLTs) and BRAF p.V600E-like tumors (BLTs), respectively. 2. The framework for benign lesions has been revised. The WHO 5th introduces a new category: “developmental abnormalities”. Benign FDNs comprise “thyroid follicular nodular disease”, follicular thyroid adenoma (FTA), FTA with papillary architecture, and oncocytic adenoma (OA). “Hürthle cell adenoma/carcinoma” is renamed oncocytic adenoma/carcinoma of the thyroid (OA/OCA), which can be distinguished from FTA/FTC by its unique genetic background. 3. Low-risk tumors include NIFTP, TT-UMP, and HTT, and they have an extremely low malignant potential or an uncertain malignant potential. 4. PTC histological variants are reclassified as “subtypes” in the WHO 5th. 5. The concept of high-grade carcinomas is introduced, encompassing poorly differentiated thyroid carcinoma (PDTC), differentiated high-grade thyroid carcinoma (DHGTC), and high-grade medullary thyroid carcinoma (MTC). 6. Squamous cell carcinoma is included in anaplastic thyroid carcinoma (ATC) in the WHO 5th due to their shared genetic and prognostic features. 7. Other miscellaneous tumors are categorized as salivary-gland-type carcinomas of the thyroid, thyroid tumors of uncertain histogenesis, thymic tumors within the thyroid, and embryonal thyroid neoplasms. The WHO 5th thus emphasizes the importance of classifying tumors based on both genetic abnormalities and histomorphology. This approach aids in achieving accurate pathological diagnosis and facilitates the early selection of appropriate treatment options, including molecular targeted therapies. Full article

Background: Thyroid carcinoma (TC) is the most common endocrine cancer, with papillary thyroid carcinoma (PTC) being the most common subtype. BRAF and RAS oncogene were characterized as the most frequently altered genes in PTC, with a strong association between genotype and histotype. The most common mutation in BRAF gene is V600E and is prevalent in classic and aggressive variants of PTC, while BRAF K601E mutation is the most common among the other rare BRAF mutations. BRAF K601E mutated thyroid carcinomas are usually characterized by low aggressiveness, except for anecdotal cases of poorly differentiated TC. Case presentation: We described a case of oncocytic carcinoma of the thyroid (OCA) with an aggressive clinical course, including widespread metastasis and resistance to radioiodine treatment. Molecular analysis revealed the exclusive presence of the BRAF K601E mutation in both primary tumor and metastatic lesions. Accordingly, a revision of the literature about aggressive TC cases carrying BRAF K601E mutation was performed. Conclusion: Although rare, this case emphasizes the relevance of considering BRAF K601E mutation in advanced non-PTC thyroid carcinomas, since it can be considered an actionable mutation for target therapies. Full article

Hurthle cell (HC), anaplastic (AC), and medullary (MC) carcinomas are low frequency thyroid tumors that pose several challenges for physicians and pathologists due to the scarcity of cases, information, and histopathological images, especially in the many areas around the world in which sophisticated molecular and genetic diagnostic facilities are unavailable. It is, therefore, cogent to provide tools for microscopists to achieve accurate diagnosis, such as histopathological images with reliable biomarkers, which can help them to reach a differential diagnosis. We are investigating whether components of the chaperone system (CS), such as the molecular chaperones, can be considered dependable biomarkers, whose levels and distribution inside and outside cells in the tumor tissue could present a distinctive histopathological pattern for each tumor type. Here, we report data on the chaperones Hsp27, Hsp60, and Hsp90. They presented quantitative levels and distribution patterns that were different for each tumor and differed from those of a benign thyroid pathology, goiter (BG). Therefore, the reported methodology can be beneficial when the microscopist must differentiate between HC, AC, MC, and BG. Full article

Differentiated thyroid cancer (DTC) from follicular epithelial cells is the most common form of thyroid cancer. Beyond the common papillary thyroid carcinoma (PTC), there are a number of rare but difficult-to-diagnose pathological classifications, such as follicular thyroid carcinoma (FTC). We employed deep convolutional neural networks (CNNs) to facilitate the clinical diagnosis of differentiated thyroid cancers. An image dataset with thyroid ultrasound images of 421 DTCs and 391 benign patients was collected. Three CNNs (InceptionV3, ResNet101, and VGG19) were retrained and tested after undergoing transfer learning to classify malignant and benign thyroid tumors. The enrolled cases were classified as PTC, FTC, follicular variant of PTC (FVPTC), Hürthle cell carcinoma (HCC), or benign. The accuracy of the CNNs was as follows: InceptionV3 (76.5%), ResNet101 (77.6%), and VGG19 (76.1%). The sensitivity was as follows: InceptionV3 (83.7%), ResNet101 (72.5%), and VGG19 (66.2%). The specificity was as follows: InceptionV3 (83.7%), ResNet101 (81.4%), and VGG19 (76.9%). The area under the curve was as follows: Incep-tionV3 (0.82), ResNet101 (0.83), and VGG19 (0.83). A comparison between performance of physicians and CNNs was assessed and showed significantly better outcomes in the latter. Our results demonstrate that retrained deep CNNs can enhance diagnostic accuracy in most DTCs, including follicular cancers. Full article

Thyroid cancer is the most common endocrine malignancy. However, the cytological diagnosis of follicular thyroid carcinoma (FTC), Hürthle cell carcinoma (HCC), and follicular variant of papillary thyroid carcinoma (FVPTC) and their benign counterparts is a challenge for preoperative diagnosis. Nearly 20–30% of biopsied thyroid nodules are classified as having indeterminate risk of malignancy and incur costs to the health care system. Based on that, 120 patients were screened for the main driver mutations previously described in thyroid cancer. Subsequently, 14 mutation-negative cases that are the main source of diagnostic errors (FTC, HCC, or FVPTC) underwent RNA-Sequencing analysis. Somatic variants in candidate driver genes (ECD, NUP98,LRP1B, NCOR1, ATM, SOS1, and SPOP) and fusions were described. NCOR1 and SPOP variants underwent validation. Moreover, expression profiling of driver-negative samples was compared to 16 BRAF V600E, RAS, or PAX8-PPARg positive samples. Negative samples were separated in two clusters, following the expression pattern of the RAS/PAX8-PPARg or BRAF V600E positive samples. Both negative groups showed distinct BRS, ERK, and TDS scores, tumor mutation burden, signaling pathways and immune cell profile. Altogether, here we report novel gene variants and describe cancer-related pathways that might impact preoperative diagnosis and provide insights into thyroid tumor biology. Full article

Background. The prevalence of thyroid nodules increases with age. Their management takes into account the presence of co-morbidities, which are frequent among the elderly. We sought to highlight the differences between the elderly and the general population in cytological and histological diagnoses. Methods. In this retrospective cohort study, we gathered 13,747 nodule data and compared cytological and histological diagnoses between patients aged over 65 years and a control group. Results. Elderly patients had a higher prevalence of cytologically benign nodules and, consequently, they were less frequently subject to surgery. However, there were no differences in terms of malignancy-risk after surgery. At histology, elderly patients often presented aggressive histology such as medullary thyroid carcinoma, poorly-differentiated and anaplastic cancer, tall cell variant of papillary thyroid carcinoma and Hürthle cell carcinoma. Even in presence of well-differentiated cancer, older patients had higher rates of local invasiveness, lateral lymph node involvement and vascular invasion. Conclusion. Thyroid nodules in elderly patients represent a challenging entity since they are very often benign, but, in case of malignancy, aggressive histotypes and high-risk features are more frequent. Therefore, presurgical characterization of nodules in older patients is crucial and might require strict monitoring. Full article

In previous studies, we described a method for detecting and typing malignant tumors of the thyroid gland in fine-needle aspiration biopsy samples via analysis of a molecular marker panel (normalized HMGA2 mRNA level; normalized microRNA-146b, -221, and -375 levels; mitochondrial-to-nuclear DNA ratio; and BRAF^V600E mutation) in cytological preparations by quantitative PCR. In the present study, we aimed to estimate the specificity of the typing of different thyroid tumors by the proposed method. Fine-needle aspiration cytological preparations from 278 patients were used. The histological diagnosis was known for each sample. The positive and negative predictive values of the method assessed in this study were, respectively, 100% and 98% for papillary thyroid carcinoma (n = 63), 100% and 100% for medullary thyroid carcinoma (n = 19), 43.5% and 98% for follicular carcinoma (n = 15), and 86% and 100% for Hürthle cell carcinoma (n = 6). Thus, we demonstrate that the diagnostic panel, including the analysis of microRNA expression, mRNA expression, the BRAF^V600E mutation, and the mitochondrial-to-nuclear DNA ratio, allows the highly accurate identification of papillary thyroid carcinoma, medullary thyroid carcinoma, and Hürthle cell carcinoma but not malignant follicular tumors (positive predictive value was below 50%). Full article

Hürthle cell carcinoma (HCC) represents 3–4% of thyroid carcinoma cases. It is considered to be more aggressive than non-oncocytic thyroid carcinomas. However, due to its rarity, the pathological characteristics and biological behavior of HCC remain to be elucidated. The Hürthle cell is characterized cytologically as a large cell with abundant eosinophilic, granular cytoplasm, and a large hyperchromatic nucleus with a prominent nucleolus. Cytoplasmic granularity is due to the presence of numerous mitochondria. These mitochondria display packed stacking cristae and are arranged in the center. HCC is more often observed in females in their 50–60s. Preoperative diagnosis is challenging, but indicators of malignancy are male, older age, tumor size > 4 cm, a solid nodule with an irregular border, or the presence of psammoma calcifications according to ultrasound. Thyroid lobectomy alone is sufficient treatment for small, unifocal, intrathyroidal carcinomas, or clinically detectable cervical nodal metastases, but total thyroidectomy is recommended for tumors larger than 4 cm. The effectiveness of radioactive iodine is still debated. Molecular changes involve cellular signaling pathways and mitochondria-related DNA. Current knowledge of Hürthle cell carcinoma, including clinical, pathological, and molecular features, with the aim of improving clinical management, is reviewed. Full article

This study assesses the role of [¹⁸F] FDG PET/CT, fine needle aspiration (FNA) cytology and ultrasound in the 1–2% of patients with focally positive thyroid nodules on FDG PET/CT. All FDG PET/CT scans with focally increased thyroid FDG PET/CT uptake performed over 37 months in one institution were matched to patients undergoing thyroid FNA. Diffuse FDG PET/CT uptake patients were excluded. A total of 47 patients showed focally increased thyroid uptake. Consistent with previous studies, 18 (38.2%) patients had malignancy—12 primary thyroid carcinoma, 1 parathyroid carcinoma, 3 metastatic carcinoma to the thyroid and 2 lymphoma. A total of 15 (31.9%) lesions categorized as non-malignant contained Hürthle cells/oncocytes. A total of 14 lesions (29.8%) had focally increased FDG PET/CT uptake with no specific cytological or histopathological cause identified. No focally PET avid Hürthle cell/oncocytic lesions were found to be malignant. Exclusion of oncocytic lesions increased the calculated risk of malignancy (ROM) of focally PET avid nodules from 38% to 68%. It may be useful to exclude focally FDG PET/CT avid Hürthle cell/oncocytic lesions, typically reported as follicular neoplasm or suspicious for a follicular neoplasm, Hürthle cell type (Oncocytic) type, RCPath Thy 3F: Bethesda IV or sometimes Thy 3a: Bethesda III FNAs) from ROM calculations. Oncocytic focally PET/CT FDG avid lesions appear of comparatively lower risk of malignancy and require investigation or operation but these lesions should be readily identified by FNA cytology on diagnostic work up of focally PET avid thyroid nodules. Full article

The aim of this study was to compare the diagnostic effectiveness of EU-TIRADS in two groups of nodules with equivocal cytology (categories III-V of Bethesda system), with and without Hürthle cells (HC and non-HC). The study included 162 HC and 378 non-HC nodules with determined histopathological diagnosis (17.9% and 15.6% cancers). In both groups calculated and expected risk of malignancy (RoM) for high, intermediate and benign risk categories of EU-TIRADS were concordant. RoM for low risk category was higher than expected in both groups, but especially in HC (HC: 13.9%, non-HC: 7.0%, expected: 2–4%). The majority of cancers in HC of that category were follicular thyroid carcinomas (FTC) and Hürthle cell thyroid carcinoma (HTC) (60.0% vs. non-HC: 16.7%). The diagnostic efficacy of EU-TIRADS was lower in HC (the area under the receiver operating characteristics curve (AUC): 0.621, sensitivity (SEN): 44.8%, specificity (SPC): 78.9% for high risk threshold) than in non-HC (AUC: 0.711, SEN: 61.0%, SPC: 77.7%). AUC was the highest for category V (AUC > 0.8, both groups) and the lowest for category IV (inefficient, both group). If intermediate risk category was interpreted as an indication for surgery, 25% of cancers from category III and 21.4% from category IV would not be treated in the HC group (0.0% and 7.4% from non-HC group, respectively). EU-TIRADS does not aid making clinical decisions in patients with cytologically equivocal HC nodules, particularly those classified into category IV of Bethesda System for Reporting Thyroid Cytopathology (BSRTC). Full article

The aim was to compare the usefulness of selected thyroid sonographic risk-stratification systems in the diagnostics of nodules with indeterminate/suspicious cytology or unequivocal cytology in a population with a history of iodine deficiency. The diagnostic efficacy of ACR-TIRADS (the American College of Radiology Thyroid Imaging Reporting and Data Systems), EU-TIRADS (European Thyroid Association TIRADS), Korean-TIRADS, Kwak-TIRADS, AACE/ACE-AME-guidelines (American Association of Clinical Endocrinologists/ American College of Endocrinology-Associazione Medici Endocrinologi guidelines) and ATA-guidelines (American Thyroid Association guidelines) was evaluated in 1000 nodules with determined histopathological diagnosis: 329 FLUS/AUS (10.6% cancers), 167 SFN/SHT (11.6% cancers), 44 SM (77.3% cancers), 298 BL (benign lesions), 162 MN (malignant neoplasms). The percentage of PTC (papillary thyroid carcinoma) among cancers was higher in Bethesda MN (86.4%) and SM (suspicion of malignancy) nodules (91.2%) than in FLUS/AUS (57.1%, p < 0.005) and SFN/SHT (suspicion of follicular neoplasm/ suspicion of Hürthle cell tumor) nodules (36.8%, p < 0.001). TIRADS efficacy was higher for MN (AUC: 0.827–0.874) and SM nodules (AUC: 0.775–0.851) than for FLUS/AUS (AUC: 0.655–0.701) or SFN/SHT nodules (AUC: 0.593–0.621). FLUS/AUS (follicular lesion of undetermined significance/ atypia of undetermined significance) nodules assigned to a high risk TIRADS category had malignancy risk of 25%. In the SFN/SHT subgroup none TIRADS category changed nodule’s malignancy risk. EU-TIRADS and AACE/ACE-AME-guidelines would allow diagnosing the highest number of PTC, FTC (follicular thyroid carcinoma), HTC (Hürthle cell carcinoma), MTC (medullary thyroid carcinoma). The highest OR value was for Kwak-TIRADS (12.6) and Korean-TIRADS (12.0). Conclusions: TIRADS efficacy depends on the incidence of PTC among cancers. All evaluated TIRADS facilitate the selection of FLUS/AUS nodules for the surgical treatment but these systems are not efficient in the management of SFN/SHT nodules. Full article

Hürthle cell carcinomas (HCC) are rare differentiated thyroid cancers that display low avidity for radioactive iodine and respond poorly to kinase inhibitors. Here, using next-generation sequencing, we analyzed the mutational status of primary tissue and poorly differentiated metastatic tissue from two HCC patients. In both cases, metastatic tissues harbored a mutation of SETD2, each resulting in loss of the SRI and WW domains of SETD2, a methyltransferase that trimethylates H3K36 (H3K36me3) and also interacts with p53 to promote its stability. Functional studies of the novel p.D1890fs6* mutation (case 1) revealed significantly reduced H3K36me3 levels in SETD2-mutated tissue and primary cell cultures and decreased levels of the active form of p53. Restoration of SETD2-wildtype expression in the SETD2-mutant cells significantly reduced the expression of four well-known stemness markers (OCT-4, SOX2, IPF1, Goosecoid). These findings suggest potential roles for SETD2 loss-of-function mutations in HCC progression, possibly involving p53 destabilization and promotion of stemness. Their prevalence and potential treatment implications in thyroid cancer, especially HCC, require further study. Full article