The Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) is widely used for risk stratification in pheochromocytoma and paraganglioma (PPGL), but its clinical utility is limited by inter-observer variability of its parameters and inconsistent predictive performance. Methods: We conducted a multicenter retrospective study of 1,518 patients with PPGL from five tertiary referral centers in Korea. Prognostic utility of PASS system was assessed using logistic regression, Kaplan-Meier analysis, and receiver operating characteristic (ROC) curve analysis. Inter-observer variability was inferred by comparing area under the ROC curve (AUCs) across institutions. Simplified PASS systems were developed based on multivariable analysis of key histopathological parameters. Results: The PASS system was a significant predictor of adverse events and recurrence-free survival. Although the PASS system demonstrated only modest discriminative ability (AUC, 0.673), it showed a high negative predictive value (NPV, 0.885), supporting its usefulness as a screening tool for benign behavior. However, there was significant inter-institutional variability in PASS performance (AUC; range, 0.513 to 0.727; p < .05). The 3-factor Simple PASS, which incorporates necrosis, spindling, and mitotic figures, exhibited less inter-observer variation. The 4-factor Simple PASS, which adds vascular invasion to the 3-factor model, also showed reduced inter-observer variability and improved AUC and NPV compared to the original PASS system. Conclusions: In this multicenter cohort, the PASS system demonstrated high NPV and screening potential, but significant inter-observer variability remains a challenge. Simplification of the PASS system and enhanced pathologist training may improve reproducibility and clinical utility in PPGL risk stratification.

Background and Objectives: Studies investigating the correlation between papillary thyroid carcinoma (PTC) tumor size and the prevalence of the B-type Raf kinase (BRAF) mutation have yielded conflicting results. Therefore, we evaluated the prevalence of BRAF mutation according to tumor size in a large cohort of PTC patients to clarify this association. Materials and Methods: We retrospectively analyzed 6,438 patients with surgically diagnosed classic PTC between January 2009 and December 2017 at Samsung Medical Center, Seoul, Republic of Korea.During the study period, BRAF mutation testing was attempted on all fine-needle aspiration specimens, except for a small number of inadequate specimens. All other histologic subtypes were excluded. The prevalence of BRAF mutation was assessed based on tumor size, and further analyzed by age group and sex according to tumor size. Results: The overall prevalence of BRAF mutation was 79.2%. When PTCs ≤1 cm were excluded, the prevalence was 77.2%. The prevalence significantly decreased with increasing tumor size (p for trend ＜0.001). It was significantly higher in men than in women (p=0.013), but did not differ by age. The inverse correlation between tumor size and prevalence was prominent in patients aged 20-49 years but was less distinct in those aged 50 years and older. Conclusion In this large cohort of patients with PTC, the prevalence of BRAF mutation significantly decreased with increasing tumor size. These findings suggest that BRAF mutation is enriched in smaller surgically treated classic PTCs and may provide a hypothesis-generating clue regarding its role in early PTC development, although selection bias cannot be excluded.

Background and Objectives: Telomerase reverse transcriptase (TERT) promoter mutations are a poor prognostic factor in differentiated thyroid carcinoma (DTC). However, their prognostic value in anaplastic thyroid carcinoma (ATC) is unclear. Therefore, we investigated whether TERT promoter mutations also act as an independent poor prognostic factor in ATC. Materials and Methods: We reviewed the medical records of 41 patients with ATC who underwent the TERT promoter mutations test at Samsung Medical Center between November 1995 and December 2022. The aggressive treatment group was defined as patients who underwent surgery, external radiotherapy, and systemic therapy. Results: Among 41 patients, 15 (36.6%) showed TERT promoter mutations. There only differences in the clinicopathological characteristics between the TERT-mutant and wild-type groups were tumor size and coexistence of DTC. Median tumor size in the TERT-mutant group was 5.1 cm (3.0-11.0), which was significantly larger than that in the wild-type group (4.1 cm, 0.8-8.0, p=0.010). Nevertheless, the TERT-mutant group received relatively more aggressive treatment (53.3% vs. 19.2%, p=0.056), and the overall survival of the TERT-mutant group was longer than that of the wild-type group (9.4 months [0.4-51.5] vs. 7.1 months [0.4-49.5]), but its difference was not significant (p=0.458). In multiple regression analysis, distant metastasis was a significant prognostic factor, but TERT promoter mutation was not. Conclusion Unlike in DTC, TERT promoter mutations were not an independent poor prognostic factor in ATC.

Background and Objectives: Telomerase reverse transcriptase (TERT) promoter mutations are a poor prognostic factor in differentiated thyroid carcinoma (DTC). However, their prognostic value in anaplastic thyroid carcinoma (ATC) is unclear. Therefore, we investigated whether TERT promoter mutations also act as an independent poor prognostic factor in ATC. Materials and Methods: We reviewed the medical records of 41 patients with ATC who underwent the TERT promoter mutations test at Samsung Medical Center between November 1995 and December 2022. The aggressive treatment group was defined as patients who underwent surgery, external radiotherapy, and systemic therapy. Results: Among 41 patients, 15 (36.6%) showed TERT promoter mutations. There only differences in the clinicopathological characteristics between the TERT-mutant and wild-type groups were tumor size and coexistence of DTC. Median tumor size in the TERT-mutant group was 5.1 cm (3.0-11.0), which was significantly larger than that in the wild-type group (4.1 cm, 0.8-8.0, p=0.010). Nevertheless, the TERT-mutant group received relatively more aggressive treatment (53.3% vs. 19.2%, p=0.056), and the overall survival of the TERT-mutant group was longer than that of the wild-type group (9.4 months [0.4-51.5] vs. 7.1 months [0.4-49.5]), but its difference was not significant (p=0.458). In multiple regression analysis, distant metastasis was a significant prognostic factor, but TERT promoter mutation was not. Conclusion Unlike in DTC, TERT promoter mutations were not an independent poor prognostic factor in ATC.

Objective: To investigate the association of ultrasound (US) features of follicular thyroid carcinoma (FTC) with tumor invasiveness and prognosis based on the World Health Organization (WHO) classification and telomerase reverse transcriptase (TERT) promoter mutations. Materials and Methods: This retrospective study included 54 surgically confirmed FTC patients with US images and TERT promoter mutations (41 females and 13 males; median age [interquartile range], 40 years [30–51 years]). The WHO classification consisted of minimally invasive (MI), encapsulated angioinvasive (EA), and widely invasive (WI) FTCs. Alternative classifications included Group 1 (MI-FTC and EA-FTC with wild type TERT), Group 2 (WI-FTC with wild type TERT), and Group 3 (EA-FTC and WI-FTC with mutant TERT). Each nodule was categorized according to the US patterns of the Korean Thyroid Imaging Reporting and Data System (K-TIRADS) and American College of Radiology-TIRADS (ACR-TIRADS). The JonckheereTerpstra and Cochran-Armitage tests were used for statistical analysis. Results: Among 54 patients, 29 (53.7%) had MI-FTC, 16 (29.6%) had EA-FTC, and nine (16.7%) had WI-FTC. In both the classifications, lobulation, irregular margins, and final assessment categories showed significant differences (all Ps ≤ 0.04).Furthermore, the incidences of lobulation, irregular margin, and high suspicion category tended to increase with increasing tumor invasiveness and worse prognosis (all Ps for trend ≤ 0.006). In the WHO groups, hypoechogenicity differed significantly among the groups (P = 0.01) and tended to increase in proportion as tumor invasiveness increased (P for trend = 0.02). In the alternative group, punctate echogenic foci were associated with prognosis (P = 0.03, P for trend = 0.03). Conclusion Increasing tumor invasiveness and worsening prognosis in FTC based on the WHO classification and TERT promoter mutation results were positively correlated with US features that indicate malignant probability according to both K-TIRADS and ACR-TIRADS.

Background and Objectives: Telomerase reverse transcriptase (TERT) promoter mutations are a poor prognostic factor in differentiated thyroid carcinoma (DTC). However, their prognostic value in anaplastic thyroid carcinoma (ATC) is unclear. Therefore, we investigated whether TERT promoter mutations also act as an independent poor prognostic factor in ATC. Materials and Methods: We reviewed the medical records of 41 patients with ATC who underwent the TERT promoter mutations test at Samsung Medical Center between November 1995 and December 2022. The aggressive treatment group was defined as patients who underwent surgery, external radiotherapy, and systemic therapy. Results: Among 41 patients, 15 (36.6%) showed TERT promoter mutations. There only differences in the clinicopathological characteristics between the TERT-mutant and wild-type groups were tumor size and coexistence of DTC. Median tumor size in the TERT-mutant group was 5.1 cm (3.0-11.0), which was significantly larger than that in the wild-type group (4.1 cm, 0.8-8.0, p=0.010). Nevertheless, the TERT-mutant group received relatively more aggressive treatment (53.3% vs. 19.2%, p=0.056), and the overall survival of the TERT-mutant group was longer than that of the wild-type group (9.4 months [0.4-51.5] vs. 7.1 months [0.4-49.5]), but its difference was not significant (p=0.458). In multiple regression analysis, distant metastasis was a significant prognostic factor, but TERT promoter mutation was not. Conclusion Unlike in DTC, TERT promoter mutations were not an independent poor prognostic factor in ATC.

Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a hereditary disorder caused by germline inactivating mutations in the PTEN tumor suppressor gene. As a type of PHTS, Cowden syndrome is associated with abnormalities of the thyroid, breast, uterus, and gastrointestinal tract. A 52-year-old-woman visited the outpatient clinic of our endocrinology clinic with multiple thyroid nodules and Hashimoto's thyroiditis. Computed tomography imaging revealed a multinodular mass measuring up to 3.5 cm in the left thyroid lobe, causing laryngotracheal airway displacement. The total thyroidectomy specimen revealed multiple follicular adenomas and adenomatous nodules with lymphocytic thyroiditis and lipomatous metaplasia in the background. The patient was suspected of PTHS based on her thyroid pathology, family history, and numerous hamartomatous lesions of the breast, uterus, and skin. Her diagnosis was confirmed through molecular testing. This case demonstrates that pathologists must be well acquainted with thyroid pathology in PHTS.

Background: Telomerase reverse transcriptase (TERT) promoter mutations are associated with increased recurrence and mortality in patients with thyroid carcinoma. Previous studies on TERT promoter mutations were retrospectively conducted on a limited number of patients. Methods: We prospectively collected data on all consecutive patients who underwent thyroid carcinoma surgery between January 2019 and December 2020 at the Samsung Medical Center, Seoul, Korea. We included 2,092 patients with thyroid carcinoma. Results: Of 2,092 patients, 72 patients (3.4%) had TERT promoter mutations. However, the frequency of TERT promoter mutations was 0.5% in papillary thyroid microcarcinoma (PTMC) ≤1 cm and it was 5.8% in papillary thyroid carcinoma (PTC) >1 cm. The frequency of TERT promoter mutations was significantly associated with older age at diagnosis (odds ratio [OR], 1.12; P<0.001), larger primary tumor size (OR, 2.02; P<0.001), and aggressive histological type (OR, 7.78 in follicular thyroid carcinoma; OR, 10.33 in poorly differentiated thyroid carcinoma; OR, 45.92 in anaplastic thyroid carcinoma; P<0.001). Advanced T stage, advanced N stage, and distant metastasis at diagnosis were highly prevalent in mutated thyroid cancers. However, initial distant metastasis was not present in patients with TERT promoter mutations in PTMC. Although the C228T mutation was more highly detected than the C250T mutation (64 cases vs. 7 cases), there were no significant clinicopathological differences. Conclusion This study is the first attempt to investigate the frequency of TERT promoter mutations in a real-world setting. The frequency of TERT promoter mutations in PTC was lower than expected, and in PTMC, young patients, and female patients, the frequency was very low.

Because different types of thyroid malignancies have distinct embryological origins, coexisting tumors are rarely observed. We describe a coexisting papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC) first suspected by fine-needle aspiration cytology (FNAC). A 57-year-old female presented with an irregular mass in the right thyroid lobe. The cytopathologic findings of fine-needle aspiration showed two components: a papillary-like arrangement consisting of cells with pale enlarged nuclei indicative of PTC and loose clusters comprised of oval cells with granular chromatin indicative of MTC. The diagnosis of a coexisting PTC and MTC was initially confirmed by calcitonin immunocytochemistry and later after total thyroidectomy. Although some surgical case reports of PTC and MTC coexisting in either the same or different lobes have been documented, a case suspected by FNAC before the surgery has rarely been reported. Because appropriate treatment and prognosis of PTC and MTC are different, cytopathologists should be aware of this rare entity.

Purpose: This study investigated the ultrasound (US) features of malignancy in patients with Hürthle cell neoplasms (HCNs) of the thyroid gland. Methods: The present study included 139 HCNs that had undergone surgical excision at a single institution from 1996 to 2020 and had preoperative US images. The sonographic characteristics of HCNs were correlated with their pathological results. The US findings associated with malignancy were explored using logistic regression analysis, and the diagnostic performance and cutoff were assessed using receiver operating characteristic analysis. Results: The most common US findings of HCNs were a solid content (76.3%), oval to round shape (100%), hypoechogenicity (70.5%), a smooth margin (95.0%), the halo sign (90.6%), and no calcifications (93.5%). HCNs were commonly smaller in pathologic measurements than in US measurements (smaller, same, and greater than US measurements in 60.4%, 21.6%, and 18.0% of HCNs, respectively; P<0.001). On US, malignant nodules were significantly larger than benign nodules (3.4±1.6 cm vs. 2.2±1.2 cm, P<0.001). Multiple logistic regression showed that the US tumor size was an independent predictor of malignancy (P=0.001; odds ratio, 1.730 for a 1-cm increase [95% confidence interval, 1.258 to 2.375]). The best cutoff US tumor size for predicting malignancy was 3.35 cm (sensitivity, 53.1%; specificity, 87.9%). Conclusion The US tumor size was found to be an independent predictor of malignancy in HCNs, and a US tumor size >3.35 cm might be used as a criterion to suggest malignancy. The size of HCNs often showed discrepancies between US and pathologic measurements.