Prediction model for pheochromocytoma/paraganglioma using nCounter assay.

BACKGROUND: World Health Organization defined pheochromocytomas/paragangliomas (PPGL) as malignant tumors in 2017 because the existing classification system could not reflect locally aggressive behavior sufficiently. However, predicting the likelihood of metastasis remains a crucial part of the treatment strategy. METHODS: From one tertiary care hospital and one secondary hospital, 97 PPGL cases were selected. Medical records of PPGL cases with the presence of formalin-fixed and paraffin-embedded (FFPE) tissue of primary lesion were reviewed. For FFPE tissues, a nCounter assay was conducted to determine differently expressed genes between metastatic and non-metastatic PPGL groups. Performances of prediction models for the likelihood of metastasis were calculated. RESULTS: Of a total of 97 PPGL cases, 39, 20, and 38 were classified as benign, malignant, and validation, respectively. In the nCounter assay, CDK1, TYMS, and TOP2A genes showed significant differences in expression. Tumor size was positively correlated with CDK1 expression level. The Lasso regression model showed supreme performance of sensitivity 91.7% and specificity 95.5% when those significant factors were considered. CONCLUSION: Machine learning of multi-modal classifiers can be used to create a prediction model for metastasis of PPGL with high sensitivity and specificity using nCounter assay. Moreover, CDK1 inhibitors could be considered for developing drug treatment.

NTRK Fusion in a Cohort of BRAF p. V600E Wild-Type Papillary Thyroid Carcinomas.

Owing to the availability of a potent tropomyosin receptor kinase (TRK) inhibitor, it is necessary to develop an effective strategy to identify an enriched population of NTRK fusions in papillary thyroid carcinoma (PTC) in routine diagnostic practice. The reported prevalence of NTRK fusion in a large cohort of PTC is ∼3%. We performed an analysis to refine the characteristic histologic features of PTCs harboring NTRK fusions and further validate the diagnostic utility of pan-TRK immunohistochemistry as a screening tool. In this study, 450 PTCs known to harbor no BRAF p. V600E mutations were screened by pan-TRK immunohistochemistry, and the cases with TRK expression were confirmed by RNA-based next-generation sequencing assay. Eleven NTRK fusion cases were detected (2.4%), and all PTCs were classical subtypes. NTRK1 and NTRK3 were involved in the fusion with 9 different partner genes. Most cases showed similar characteristic histologic findings. Nodular permeative border, multinodular growth with a predominantly follicular pattern, extensive lymphatic invasion, and prominent internodular and intratumoral fibrosis were the characteristic histologic features of NTRK-rearranged PTCs. The ill-defined margins in the ultrasonography findings, which could not be clearly distinguished from the adjacent nontumorous thyroid tissue, were nodular permeative margins in histologic findings. Therefore, preoperative ultrasonographic findings in nodule margins were consistent with the final histologic findings. NTRK1/3 fusion in PTCs showed an overall sensitivity of 100% (95% CI, 71.51%-100%) and specificity of 100% (95% CI, 71.51%-100%) in the 22 cases examined, as confirmed with next-generation sequencing. Our study provides an integrative report of the preoperative ultrasonographic, histologic, immunohistochemical, and molecular features of NTRK-rearranged PTCs. Based on these findings, we propose an algorithmic approach for the stepwise assessment of NTRK fusions in PTCs.

Selection Criteria for Completion Thyroidectomy in Follicular Thyroid Carcinoma Using Primary Tumor Size and TERT Promoter Mutational Status.

BACKGROUND: A stepwise surgical approach with hemithyroidectomy and completion thyroidectomy was used to achieve definite characterization of follicular thyroid carcinoma (FTC). Choosing appropriate candidates for completion thyroidectomy has been controversial. OBJECTIVE: The aim of this study was to clarify the selection criteria for completion thyroidectomy using telomerase reverse transcriptase (TERT) promoter mutation. METHODS: A total of 87 FTC patients who had information about TERT promoter mutation from August 1995 to November 2020 were investigated. The cumulative risk of initial distant metastasis, disease recurrence, and cancer-specific death according to primary tumor size in each of the World Health Organization (WHO) 2017 classifications were calculated. RESULTS: Of the 87 patients, 8 (9.2%) had initial distant metastasis and 15 (17.2%) had persistent disease or developed structural recurrence. The threshold diameter for initial distant metastasis, disease recurrence, and cancer-specific death was 2 cm in minimally invasive FTC (MI-FTC) with mutant TERT (M-TERT) and in encapsulated angioinvasive FTC (EA-FTC) with M-TERT, while that in MI-FTC with wild-type TERT (WT-TERT) and EA-FTC with WT-TERT was 4 cm. The cumulative risk of initial distant metastasis, disease recurrence, and cancer-specific death according to primary tumor size in each WHO 2017 classification was significantly different only in patients with WT-TERT (p = 0.001, p = 0.019, and p = 0.005, respectively). CONCLUSIONS: The data suggest 2 cm as a critical threshold diameter for performance of completion thyroidectomy in MI-FTC with M-TERT and EA-FTC with M-TERT. TERT promoter mutational status can help select candidates for completion thyroidectomy.

Molecular classification of follicular thyroid carcinoma based on TERT promoter mutations.

Follicular thyroid carcinoma (FTC) has different clinicopathological characteristics than papillary thyroid carcinoma. However, there are no independent systems to predict cancer-specific survival (CSS) in FTC. Telomerase reverse transcriptase (TERT) promoter mutations are associated with tumor aggressiveness. Thus, it could be a potential prognostic marker. The aim of this study was to refine the CSS risk prediction using TERT promoter mutations in combination with the fourth edition of World Health Organization (WHO 2017) morphological classification. We investigated 77 FTC patients between August 1995 and November 2020. Cox regression was used to calculate hazard ratios to derive alternative groups. Disease-free survival (DFS) and CSS predictability were compared using Proportion of variation explained (PVE) and C-index. CSS was significantly different in encapsulated angioinvasive (EA)-FTC patients stratified by TERT promoter mutations [wild-type (WT-TERT) vs. mutant (M-TERT); P < 0.001] but not in minimally invasive (MI)-FTC and widely invasive (WI)-FTC patients (P = 0.691 and 0.176, respectively). We defined alternative groups as follows: Group 1 (MI-FTC with WT-TERT and M-TERT; EA-FTC with WT-TERT), Group 2 (WI-FTC with WT-TERT), and Group 3 (EA-FTC with M-TERT; WI-FTC with M-TERT). Both PVE (22.44 vs. 9.63, respectively) and C-index (0.831 vs. 0.731, respectively) for CSS were higher in the alternative groups than in the WHO 2017 groups. Likewise, both PVE (27.1 vs. 14.9, respectively) and C-index (0.846 vs. 0.794, respectively) for DFS were also higher in the alternative groups than in the WHO 2017 groups. Alternative group harmonizing of the WHO 2017 classification and TERT promoter mutations is effective in predicting CSS in FTC patients, thereby improving DFS predictability.

Approach to Bethesda system category III thyroid nodules according to US-risk stratification.

This study evaluated how to manage Bethesda category III (Bethesda III) (atypia of undetermined significance/follicular lesion of undetermined significance [AUS/FLUS]) thyroid nodules according to the Korean Thyroid Imaging Reporting and Data System (K-TIRADS) to reduce unnecessary surgeries. A total of 161 thyroid nodules diagnosed as Bethesda III underwent surgery from 2016 to 2019. Ultrasonography-guided fine-needle aspiration (US-FNA) or core needle biopsy (CNB) was used for repeat examination. K-TIRADS category was assigned to the thyroid nodules. The proportion of malignancy in Bethesda III nodules confirmed by surgery were significantly increased in proportion relative to K-TIRADS with 60.0% low suspicion, 88.2% intermediate suspicion, and 100% high suspicion nodules (p < 0.001). The proportion of malignancy in AUS and FLUS were significantly different (94.2% vs. 40.0% p = 0.003). The proportion of malignancy in AUS increased with K-TIRADS categories, but there was no difference in FLUS. All K-TIRADS high suspicion nodules were AUS as papillary carcinomas (99%), while 80% of FLUS nodules and 50% of follicular carcinomas showed K-TIRADS low suspicion. In 116 nodules with repeat FNA or CNB after initial Bethesda III results, the conclusive result rate was significantly increased in proportion to K-TIRADS with 58.3% low suspicion, 83.3% intermediate suspicion, and 88.8% high suspicion nodules (p = 0.015). K-TIRADS low suspicion nodules of Bethesda III nodules should be managed after risk-benefit consideration rather than immediate surgery or repeat examination. K-TIRADS for Bethesda III nodules can predict papillary carcinoma well, but not follicular carcinoma.

Is total thyroidectomy with bilateral central neck dissection the only surgery for papillary thyroid carcinoma patients with clinically involved central nodes?

BACKGROUND: In clinical practice, we often observed that patients who underwent total thyroidectomy due to clinically involved nodal disease (cN1a) actually had less extensive CLNM on final pathology. This study investigates whether total thyroidectomy and therapeutic bilateral CND are necessary for all PTC patients with cN1a. METHODS: This study retrospectively reviewed 899 PTC patients who underwent total thyroidectomy with bilateral CND from January 2012 to June 2017. The patients were divided into two groups according to pre-operative central lymph node (CLN) status: cN0, no suspicious CLNM; cN1a, suspicious CLNM. We compared the clinicopathological features of these two groups. RESULTS: There was no significant difference in recurrence between cN0 and cN1a groups after a mean follow-up time of 59.1 months. Unilateral cN1a was related to the largest central LN size ≥ 2 mm (OR = 3.67, p < 0.001) and number of CLNM > 5(OR = 2.24, p = 0.006). On the other hand, unilateral cN1a was not associated with an increased risk of contralateral lobe involvement (OR = 1.35, p = 0.364) and contralateral CLNM (OR = 1.31, p = 0.359). Among 106 unilateral cN1a patients, 33 (31.1%) were found to be pN0 or had ≤ 5 metastatic CLNs with the largest node smaller than 2 mm. CONCLUSIONS: Most cN1a patients were in an intermediate risk group for recurrence and required total thyroidectomy. However, lobectomy with CND should have performed in approximately 30% of the cN1a patients. Pre-operative clinical examination, meticulous radiologic evaluation, and intra-operative frozen sections to check the nodal status are prerequisites for this approach.

Hyperattenuating adrenal lesions in lung cancer: biphasic CT with unenhanced and 1-min enhanced images reliably predicts benign lesions.

OBJECTIVES: To investigate usefulness of biphasic computed tomography (CT) in characterizing hyperattenuating adrenal lesions in lung cancer. METHODS: This retrospective study included 239 patients with lung cancer who underwent adrenal CT for hyperattenuating (> 10 Hounsfield unit) adrenal lesions. Adrenal CT comprised unenhanced and 1-min and 15-min enhanced images. We dichotomized adrenal lesions depending on benign or metastatic lesions. Reference standard for benignity was histologic confirmation or ≥ 6-month stability on follow-up CT. Two independent readers analyzed absolute (APW) or relative percentage wash-out (RPW) using triphasic CT, and enhancement ratio (ER) or percentage wash-in (PWI) using biphasic CT (i.e., unenhanced and 1-min enhanced CT). Criteria for benignity were as follows: criteria 1, (a) APW ≥ 60% or (b) RPW ≥ 40%, and criteria 2, (a) ER > 3 and (b) PWI > 200%. We analyzed area under the curve (AUC) and accuracy for benignity, and inter-reader agreement. RESULTS: Proportion of benign adrenal lesion was 71.1% (170/239). For criteria 1 and 2, AUCs were 0.872 (95% confidence interval [CI], 0.822-0.911) and 0.886 (95% CI, 0.838-0.923), respectively, for reader 1 (p = 0.566) and 0.816 (95% CI, 0.761-0.863) and 0.814 (95% CI, 0.759-0.862), respectively, for reader 2 (p = 0.955), and accuracies were 87.9% (210/239) and 86.2% (206/239), respectively, for reader 1 (p = 0.479) and 81.2% (194/239) and 80.3% (192/239), respectively, for reader 2 (p = 0.763). Weighted kappa was 0.725 (95% CI, 0.634-0.816) for criteria 1 and 0.736 (95% CI, 0.649-0.824) for criteria 2. CONCLUSION: Biphasic CT can reliably characterize hyperattenuating adrenal lesions in patients with lung cancer. KEY POINTS: • Criteria from biphasic computed tomography (CT) for diagnosing benign adrenal lesions were enhancement ratio of > 3 and percentage wash-in of > 200%. • In the analysis by two independent readers, area under the curve between criteria 1 and 2 was not significantly different (0.872 and 0.886 for reader 1; 0.816 and 0.814, for reader 2; p > 0.05 for each comparison). • Wash-in characteristics from biphasic CT are helpful to predict benign adrenal lesions in lung cancer.

Ultrasonographic characteristics of medullary thyroid carcinoma according to nodule size: application of the Korean Thyroid Imaging Reporting and Data System and American Thyroid Association guidelines.

BACKGROUND: Few studies have categorized ultrasound (US) findings of various sized medullary thyroid carcinomas (MTCs) according to updated guidelines. PURPOSE: To evaluate and compare the differences in US findings of MTC according to nodule size, using the Korean Thyroid Imaging Reporting and Data System (K-TIRADS) and American Thyroid Association (ATA) guidelines. MATERIAL AND METHODS: The study included 119 patients with 129 MTC nodules, which were surgically confirmed at our institution between March 1999 and September 2017. Nodules were divided into large (≥1.0 cm) and small (<1.0 cm) groups. US images were analyzed according to the K-TIRADS and ATA guidelines. The differences in US characteristics between small and large nodules were compared using Fisher's exact or Chi-square tests. RESULTS: Of 129 MTC nodules, 84 (65.1%) were large nodules and 45 (34.9%) were small nodules. According to the nodule size, small MTC nodules were classified more commonly as high suspicion by K-TIRADS and ATA (95.6% and 93.3%, respectively) (P < 0.001), but presented neither cystic change, isoechogenicity, nor low suspicion category by K-TIRADS and ATA. In contrast, large MTC nodules showed more frequently cystic change (15.5%), isoechogenicity (16.7%), smooth margins (50%), or low or intermediate suspicion US features by K-TIRADS and ATA (59.6% and 36.0%, respectively) (all P values < 0.001). CONCLUSION: Most small MTC nodules are classified as high suspicion on US, whereas large MTC nodules are diagnosed more frequently as low or intermediate suspicion by K-TIRADS and ATA.

Ultrasound-guided fine-needle aspiration or core needle biopsy for diagnosing follicular thyroid carcinoma?

OBJECTIVE: We evaluated the preoperative diagnostic values of ultrasound (US), fine-needle aspiration (FNA) and core needle biopsy (CNB) leading to surgery in patients with FTC. METHODS: From October 1994 to July 2016, 298 patients with FTC who had preoperative US images and underwent US-guided FNA or CNB and surgery were included in this study. We evaluated the results of preoperative FNA or CNB based on the Bethesda system and the US findings according to the Korean thyroid imaging reporting and data system (K-TIRADS). RESULTS: Predominant US features of FTC showed solid, hypo- or iso-echogenicity, oval smooth margin and halo with no calcification. Based on K-TIRADS, 140 (47.0%) patients with FTC were categorized as low suspicion, 133 (44.63%) as intermediate suspicion and 25 (8.4%) as high suspicion at US. Considering only FNA cytology (n = 230), 6.9% were revealed as Bethesda class I, 16.1% as class II, 37.0% as class III, 29.1% as class IV and 10.9% as class V. Considering the 68 cases with CNB results, 2.9% were revealed as class I, 4.4% as class II, 20.6% as class III and 72.1% as class IV. Despite multiple FNAs, 16.7% of the 84 patients with FTC still obtained Bethesda class I or class II. CNB results in patients with FTC had a significantly higher rate of Bethesda class IV compared to the FNA results (P < .001). FTCs with distant metastasis exhibited a significantly higher rate of Bethesda classes IV and V compared to those without distant metastasis (P = .004). CONCLUSION: Surgery for FTC is deferred only with preoperative US and FNA. CNB in patients with FTC can lead to surgery better than FNA. Therefore, if the US feature is characteristic and a serially growing large nodule is suspected, the first attempt of CNB may be helpful in selecting a surgical candidate.

Case of medullary thyroid carcinoma with desmoid-type fibromatosis.

A 36-year-old man was admitted to hospital for a right thyroid nodule incidentally discovered on a chest computed tomography scan for a rib fracture. He had no history of radiation to the head and neck, no known family history of endocrine disease, and no medical or surgical history. A 17 × 10 mm, well-demarcated, multinodular, whitish nodule with neither necrosis nor hemorrhage was found in the right thyroid. Microscopically, the tumor consisted of epithelial cell nests with oval, plasmacytoid or polygonal cells with speckled chromatin, inconspicuous nucleoli and granular cytoplasm. The surrounding stroma showed amyloid deposition and prominent spindle cell proliferation with myxoid substance. Epithelial cell nests showed an immunoreactive pattern for typical medullary thyroid carcinoma (MTC), and the spindle cell stroma showed nuclear expression of beta-catenin. This may be the first report on histopathologic findings of MTC with desmoid-type fibromatosis. Further studies are necessary to discover the clinicopathologic characteristics and pathogenesis of this rare type of tumor.

Highly Sensitive and Specific Molecular Test for Mutations in the Diagnosis of Thyroid Nodules: A Prospective Study of BRAF-Prevalent Population.

Molecular testing offers more objective information in the diagnosis and personalized decision making for thyroid nodules. In Korea, as the BRAF V600E mutation is detected in 70-80% of thyroid cancer specimens, its testing in fine-needle aspiration (FNA) cytology specimens alone has been used for the differential diagnosis of thyroid nodules until now. Thus, we aimed to develop a mutation panel to detect not only BRAF V600E, but also other common genetic alterations in thyroid cancer and to evaluate the diagnostic accuracy of the mutation panel for thyroid nodules in Korea. For this prospective study, FNA specimens of 430 nodules were obtained from patients who underwent thyroid surgery for thyroid nodules. A molecular test was devised using real-time PCR to detect common genetic alterations in thyroid cancer, including BRAF, N-, H-, and K-RAS mutations and rearrangements of RET/PTC and PAX8/PPARr. Positive results for the mutation panel were confirmed by sequencing. Among the 430 FNA specimens, genetic alterations were detected in 293 cases (68%). BRAF V600E (240 of 347 cases, 69%) was the most prevalent mutation in thyroid cancer. The RAS mutation was most prevalently detected for indeterminate cytology. Among the 293 mutation-positive cases, 287 (98%) were diagnosed as cancer. The combination of molecular testing and cytology improved sensitivity from 72% (cytology alone) to 89% (combination), with a specificity of 93%. We verified the excellent diagnostic performance of the mutation panel applicable for clinical practice in Korea. A plan has been devised to validate its performance using independent FNA specimens.

Molecular genotyping of the non-invasive encapsulated follicular variant of papillary thyroid carcinoma.

AIMS: The non-invasive encapsulated follicular variant of papillary thyroid carcinoma (FVPTC) has been managed as a low-risk malignancy. Recently, a proposal was made to reclassify this tumour type as a premalignant lesion and rename it non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). This study aims to provide the first comprehensive study on molecular genotype-phenotype correlations of encapsulated FVPTC. METHODS AND RESULTS: This study was performed on 177 consecutive FVPTCs from January 2014 to April 2016. These were classified as non-invasive encapsulated FVPTC (n = 74) invasive encapsulated FVPTC (n = 51), and infiltrative FVPTC (n = 52), according to standard criteria, by two independent pathologists. Genetic alterations and other clinicopathological information were compared. BRAFV600E was found in 12.2% (non-invasive) and 11.8% (invasive) of encapsulated FVPTCs, and in 34.6% of infiltrative FVPTCs (P = 0.001). Mutation in encapsulated FVPTCs was limited to cases with rare or abortive papillae. RET-PTC1 and RET-PTC3 rearrangements were present (11.5%) only in infiltrative FVPTCs. In contrast, NRAS, HRAS and KRAS mutations were observed more often in encapsulated FVPTCs (48.6% in non-invasive and 66.7% in invasive) than in infiltrative FVPTCs (15.4%) (P < 0.001). Preoperative cytological examination did not distinguish between non-invasive and invasive encapsulated FVPTCs, whereas infiltrative FVPTC was more likely to be Bethesda class V/VI than the encapsulated type (60.4% versus 38.1%; P = 0.01). CONCLUSIONS: There were no differences in clinicopathological or molecular profiles between non-invasive and invasive encapsulated FVPTCs, except in vascular and capsular invasion. Therefore, the diagnosis of NIFTP, like that of follicular adenoma, may require surgical resection and exclusion of those tumours with any papillae.

Diagnostic value of HBME-1, CK19, Galectin 3, and CD56 in the subtypes of follicular variant of papillary thyroid carcinoma.

Our aim is to explore differences in Hector Battifora mesothelial-1 (HBME-1), cytokeratin-19 (CK19), Galectin-3 (Gal-3), and CD56 expression in infiltrative follicular variants of papillary carcinoma (IFVPTC) and encapsulated follicular variants of papillary carcinoma (EFVPTC) and to provide clues for distinguishing the two subtypes preoperatively. Tissue microarrays from 100 EFVPTC (45 non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) and 55 invasive EFVPTCs), 43 IFVPTCs, and 64 follicular neoplasms (FN) were immunostained with HBME-1, CK19, Gal-3, and CD56. Each case was scored 1 point for every positive result. Immunohistochemical expression was not significantly different in invasive EFVPTC and NIFTP, except for that of HBME-1. HBME-1, CK19, Gal-3, and CD56 expression were significantly higher in IFVPTC than in EFVPTC. At the cutoff of 3 points, the score method had special diagnostic value for differentiating IFVPTC from EFVPTC and FN and for predicting lymph node metastasis. Scoring of immunohistochemistry results may be applied to core biopsy or cell blocks to assist ultrasonographic, cytologic and molecular tests in differentiating IFVPTC and EFVPTC preoperatively, possibly appropriately guiding EFVPTC preoperatively for limited operation or active surveillance.

Identification of Driving ALK Fusion Genes and Genomic Landscape of Medullary Thyroid Cancer.

The genetic landscape of medullary thyroid cancer (MTC) is not yet fully understood, although some oncogenic mutations have been identified. To explore genetic profiles of MTCs, formalin-fixed, paraffin-embedded tumor tissues from MTC patients were assayed on the Ion AmpliSeq Cancer Panel v2. Eighty-four sporadic MTC samples and 36 paired normal thyroid tissues were successfully sequenced. We discovered 101 hotspot mutations in 18 genes in the 84 MTC tissue samples. The most common mutation was in the ret proto-oncogene, which occurred in 47 cases followed by mutations in genes encoding Harvey rat sarcoma viral oncogene homolog (N = 14), serine/threonine kinase 11 (N = 11), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (N = 6), mutL homolog 1 (N = 4), Kiesten rat sarcoma viral oncogene homolog (N = 3) and MET proto-oncogene (N = 3). We also evaluated anaplastic lymphoma kinase (ALK) rearrangement by immunohistochemistry and break-apart fluorescence in situ hybridization (FISH). Two of 98 screened cases were positive for ALK FISH. To identify the genomic breakpoint and 5' fusion partner of ALK, customized targeted cancer panel sequencing was performed using DNA from tumor samples of the two patients. Glutamine:fructose-6-phosphate transaminase 1 (GFPT1)-ALK and echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusions were identified. Additional PCR analysis, followed by Sanger sequencing, confirmed the GFPT1-ALK fusion, indicating that the fusion is a result of intra-chromosomal translocation or deletion. Notably, a metastatic MTC case harboring the EML4-ALK fusion showed a dramatic response to an ALK inhibitor, crizotinib. In conclusion, we found several genetic mutations in MTC and are the first to identify ALK fusions in MTC. Our results suggest that the EML4-ALK fusion in MTC may be a potential driver mutation and a valid target of ALK inhibitors. Furthermore, the GFPT1-ALK fusion may be a potential candidate for molecular target therapy.

Predictive Factors of Lymph Node Metastasis in Follicular Variant of Papillary Thyroid Carcinoma.

BACKGROUND: Compared with conventional papillary thyroid carcinoma (PTC), follicular variant of PTC (FV-PTC) shows less aggressive behavior and better prognosis. Nonetheless, regional lymph node (LN) metastasis was found in 22.8% of FV-PTC patients. Because LN metastasis is a proven predictor of recurrence in PTC, it is important to assess LN metastasis in FV-PTC patients. METHODS: We retrospectively reviewed 134 FV-PTC patients who underwent thyroidectomy with neck dissection. RESULTS: Central LN metastasis (CLNM) and lateral LN metastasis (LLNM) were found in 50 (37.3%) and 16 (11.9%) patients, respectively. In the multivariate analysis for CLNM, male sex (adjusted OR 4.735, p = 0.001), nonencapsulated form (adjusted OR 2.863, p = 0.022), and tumor size >1.0 cm (adjusted OR 3.157, p = 0.008) were independent predictors of high prevalence of CLNM in FV-PTC patients. In the multivariate analysis for LLNM, microscopic extrathyroidal extension (ETE) (adjusted OR 3.939, p = 0.041) and CLNM (adjusted OR 13.340, p = 0.001) were independent predictors of high prevalence of LLNM in FV-PTC patients. CONCLUSIONS: Meticulous perioperative evaluation and prophylactic central neck dissection may be beneficial for FV-PTC patients with male sex, nonencapsulated form, and tumor size >1.0 cm. Moreover, cautious perioperative evaluation of lateral neck LN may be mandatory for FV-PTC patients with microscopic ETE and CLNM.

Preoperative differentiation between noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and non-NIFTP.

BACKGROUND: A recent concept was proposed that the noninvasive encapsulated follicular variant of papillary thyroid carcinoma reclassified as "noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)" is benign. Our aim was to identify the differences between NIFTP and non-NIFTP preoperatively. METHODS: This retrospective study included a total of 208 patients with 208 follicular variant of papillary thyroid carcinomas (FVPTC) that were surgically confirmed at three university hospitals from 2008 to 2014. Clinical factors, the biopsy techniques and ultrasonography (US) imaging characteristics were compared between the NIFTP and non-NIFTP groups. RESULTS: A total of 34 NIFTP (16·3%) and 174 non-NIFTP (83·7%) were observed. For NIFTPs, the need for surgery was indicated by ultrasonography-guided fine needle aspiration (US-FNA) in 54·3% and by ultrasonography-guided core needle biopsy (US-CNB) in 100% (P = 0·008). For non-NIFTP, no significant difference was noted in the rates of surgical indication between US-FNA and US-CNB (62·6% vs 78·9%, P = 0·054). The most common biopsy diagnosis of NIFTP was Bethesda category V (28·6%) in the US-FNA group and category IV (45·5%) in the US-CNB group. US diagnosis of NIFTP had a significantly lower rate of the high suspicion of malignancy than that of non-NIFTP (14·7% vs 37·9%, P = 0·024). Central nodal metastasis was found in only one case (2·9%) of NIFTP patients, but none had distance metastasis or recurrence. CONCLUSION: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features lacks malignant US features and is better triaged using US-CNB than using US-FNA to facilitate the surgical management. US evaluation is pivotal in determining the next step of FVPTC management.

Ultrasonographic features and clinical characteristics of Warthin-like variant of papillary thyroid carcinoma.

Warthin-like variant of papillary thyroid carcinoma (WVPTC) is a rare entity recently characterized. We evaluated ultrasonographic (US) features and clinical characteristics of WVPTC. Nine patients were diagnosed with WVPTC through surgery in our institution from May 2005 to January 2015. Eight of nine patients had available preoperative US images. A retrospective review of the US and clinical characteristics was performed. WVPTC compromised of 0.06% of 14,071 PTCs surgically confirmed. A mean age of nine patients was 53.2 years (range, 32-75 years). The mean nodule size of nine WVPTCs was 0.9 cm (range, 0.5-1.5 cm). Two patients showed central nodal metastasis and one patient with conventional PTC as an index tumor underwent central and lateral neck dissection. No one showed recurrence or distant metastasis during the follow-up period (mean, 4.6 years; range, 0.6-10 years). The most common US features of WVPTCs were solid composition (62.5%), hypoechogenicity (75%), and wider-than-tall shape (100%), respectively. Four (50%) of eight nodules showed well-defined margin and three (37.5%) of them had cystic component. One of eight resembled focal thyroiditis. Three nodules were considered as probably benign with US. All nine cases demonstrated underlying heterogeneous parenchymal echogenicity and accompanied chronic lymphocytic thyroiditis in permanent sections. Thyroid function tests in all patients were normal except for one with subclinical hypothyroidism. WVPTC is an uncommon subtype of PTC and has favorable prognosis, which can be misdiagnosed as a probably benign nodule or focal thyroiditis with US. All cases are associated with heterogeneous parenchyma in the background.

Sonographic and cytopathologic correlation of papillary thyroid carcinoma variants.

Papillary thyroid carcinoma (PTC) is the most common thyroid cancer and constitutes more than 70% of thyroid malignancies. Although TNM staging is the most widely used parameter for determination of therapeutic plans, recent studies have suggested that different histopathologic variants of PTC can also have different clinical courses and patient prognoses. Sonographic criteria for PTC are well established and include a taller-than-wide shape, an irregular margin, microcalcifications, and marked hypoechogenicity. The role of sonography has expanded to enable the characterization of PTC variants based on their sonographic features. Tall cell and diffuse sclerosing variants appear to have more aggressive clinical courses with unfavorable prognoses, whereas the more recently described cribriform-morular and Warthin-like variants have relatively indolent clinical courses. The prognoses of patients with follicular, solid, columnar cell, and oncocytic variants are still controversial and may be similar to the prognosis of conventional PTC. Understanding the sonographic characteristics of PTC variants with clinicopathologic correlation may be helpful for suggesting an appropriate treatment plan.

Atypia of undetermined significance in thyroid fine-needle aspiration cytology: prediction of malignancy by US and comparison of methods for further management.

BACKGROUND: Further management for thyroid nodules with cytological atypia of undetermined significance (AUS) has made controversial conclusions. The aim of this study was to evaluate the most reliable ultrasonography (US) findings to predict malignancy in thyroid nodules with AUS, and to compare inconclusive rates of repeat fine-needle aspiration (rFNA) and core needle biopsy (CNB) in nodules with AUS. METHODS: We retrospectively reviewed cases of thyroid nodules with AUS from 8,421 US-guided fine-needle aspirations in our institution between 2010 and 2012. Nodules were confirmed either surgically or followed-up for at least 1 year and were compared based on nodule size, US findings, and US diagnosis to predict malignancy. Inconclusive rates of rFNA and CNB after initial AUS were compared. RESULTS: The incidence of AUS in all thyroid nodules was 3.2 % (273 of 8,421). Malignancies were identified in 42.1 % (64 of 152) nodules with surgery or sufficient follow-up. In univariate analysis, not-oval to round shape, irregular margin, taller-than-wide orientation, hypoechogenicity, marked hypoechogenicity, microcalcifications, and malignant US diagnosis were more frequent in actual malignancies (p < 0.05). In multivariate analysis, hypoechogenicity, marked hypoechogenicity, and malignant US diagnosis were significantly more frequent in malignancies (p < 0.05). With respect to further management of AUS, the inconclusive rate of CNB (17.6 %, 6/34) was significantly lower than that of rFNA (37.3 %; 44 of 118) (p = 0.032). CONCLUSIONS: Nodule echogenicity and US diagnosis can be predictive factors of malignancies for the thyroid nodules with cytological AUS. The CNB is more useful than rFNA for reducing the frequency of inconclusive results after initial AUS.