Restratification of Patients with Intermediate-Risk Papillary Thyroid Carcinoma.

BACKGROUND: Long-term management and follow-up strategies in patients with intermediate-risk papillary thyroid carcinoma (PTC) according to the American Thyroid Association (ATA) are still controversial due to the paucity of data on unique risk factors or a risk stratification system predictive of long-term outcomes. PATIENTS AND METHODS: This study included 649 patients with PTC who underwent an initial surgical treatment. Retrospectively enrolled patients were categorized according to the ATA risk stratification system. Intermediate-risk patients were further categorized into subgroups by the number of ATA intermediate risk factors. The recurrence-free survival (RFS) rates of these subgroups were compared with those of low- and high-risk patient groups. Additionally, the patients were classified according to their response to the initial therapy using the dynamic risk stratification (DRS) system, and the percentages of patients in each category were compared among the subgroups. RESULTS: The median follow-up period was 102 months. Structural recurrence occurred in 9.2% of all enrolled patients (60/649) and in 13.0% of intermediate-risk patients (40/308). Patients with two or more current intermediate risk factors had a poorer RFS than patients with only one risk factor (p < 0.001) and showed a comparable RFS to high-risk patients (p > 0.050). The percentages of patients with an excellent response category for DRS significantly decreased with an increase in the number of intermediate risk factors. CONCLUSION: Subclassification according to the number of intermediate risk factors may be useful to better predict the RFS and the response to initial therapy in patients with intermediate-risk PTC.

Optimal cutoff values of primary tumour size to better predict long-term outcomes in patients with papillary thyroid carcinoma undergoing total thyroidectomy: A preliminary study using restricted cubic spline analysis.

OBJECTIVE: Primary tumour size (PTS) is known to be a significant prognostic factor in patients with papillary thyroid carcinoma (PTC) undergoing thyroidectomy. Although cutoff values of 2 and 4 cm are widely used in surgical extent decision and long-term outcomes predictions, the effectiveness of arbitrary cutoff values in stratifying patients for target outcomes is questionable. This study aimed to determine new optimal cutoffs of PTS. DESIGN, PATIENT AND MEASUREMENTS: Patients (n = 529) with PTC who underwent total thyroidectomy were retrospectively reviewed. After risk factor analysis for structural recurrence, the optimal cutoffs of PTS were automatically calculated using restricted cubic spline analysis and X-tile software. Subgroups were classified based on the newly determined cutoff values. Both the recurrence-free survival (RFS) and the proportion of patients in each response-to-therapy category, using the dynamic risk stratification system (DRS), were compared between the subgroups. RESULTS: PTS was confirmed as an independent risk factor for structural recurrence. The optimal cutoff values were calculated as 1.4 and 3.0 cm. The subgroups stratified using these newly determined cutoffs showed significantly different RFS and DRS based on the response to initial therapy, but the subgroups classified using the cutoffs of 2 and 4 cm did not. CONCLUSIONS: The newly determined cutoff values of PTS may be useful in better stratifying patients with PTC undergoing thyroidectomy for target outcomes and can be considered as a new definition in staging and risk stratification systems.

Inhibition of the ERK1/2-mTORC1 axis ameliorates proteinuria and the fibrogenic action of transforming growth factor-ß in Adriamycin-induced glomerulosclerosis.

Transforming growth factor-ß (TGF-ß) plays crucial roles in the development of focal segmental glomerulosclerosis, but key molecular pathways remain unknown. Here, we identified the regulation of mammalian target of rapamycin complex1 (mTORC1) by TGF-ß via ERK1/2 in the Adriamycin-induced murine model of focal segmental glomerulosclerosis. Adriamycin administration elicited early activation of TGF-ß-ERK1/2-mTORC1 in podocytes, which persisted at later stages of albuminuria and glomerulosclerosis. Phosphorylation of the TGF-ß receptor-I (TGF-ßRI), Smad3, ERK1/2 and ribosomal protein S6 were evident in the glomeruli of adriamycin-treated mice. Targeting TGFß-RI and mTORC1 with pharmacological inhibitors suppressed TGF-ß signaling in glomeruli and significantly reduced albuminuria, glomerulosclerosis, protein levels of collagen 4α3, plasminogen activator inhibitor-1, and vimentin and restored mRNA levels of podocyte markers. Low dose US Food and Drug Administration (FDA)-approved MEK/ERK inhibitor trametinib/GSK1120212 blunted TGF-ß1-induced mTORC1 activation in podocytes, ameliorated up-regulation of TGF-ß, plasminogen activator inhibitor-1, monocyte chemoattractant protein-1, fibronectin and α-smooth muscle actin and prevented albuminuria and glomerulosclerosis with improved serum albumin. In cultured podocytes, this pathway was found to be associated with translation of fibrogenic collagen 4α3 and plasminogen activator inhibitor-1, without influencing their transcription. Notably, rapamycin suppressed upstream p-TGF-ßRI, p-Smad3 and p-ERK1/2, and trametinib down-regulated upstream p-Smad3 in ex vivo and in vivo studies, indicating that harmful paracrine signaling among glomerular cells amplified the TGF-ß-ERK1/2-mTORC1 axis by forming a positive feedback loop. Thus, an accentuated TGF-ß-ERK1/2-mTORC1 pathway is suggested as a central upstream mediator to develop proteinuria and glomerulosclerosis. Hence, preventing activation of this vicious loop by trametinib may offer a new therapeutic strategy for glomerular disease treatment.

c-Met-mediated reactivation of PI3K/AKT signaling contributes to insensitivity of BRAF(V600E) mutant thyroid cancer to BRAF inhibition.

BRAF (V600E) mutation is the most commonly detected genetic alteration in thyroid cancer. Unlike its high treatment response to selective BRAF inhibitor (PLX4032) in metastatic melanoma, the treatment response in thyroid cancer is reported to be low. The purpose of this study is to investigate the resistance mechanism responsible for this low treatment response to BRAF inhibitor in order to maximize the effect of targeted therapy. We examined the expression of feedback regulation mechanisms and alterations in the upper signal transduction pathway in thyroid cancer cell lines harboring BRAF mutation. Also, we investigated the effect of dual inhibition from combinatorial therapy. Two thyroid cancer cell lines, 8505C (anaplastic thyroid cancer) and BCPAP (papillary thyroid cancer) were selected and treated with PLX4032 and its drug sensitivity were examined and compared. Further investigation on the changes in signals responsible for the different treatment response to PLX4032 was carried out and the same experiment was performed on orthotopic xenograft mouse models. Unlike BCPAP cells, 8505C cells presented drug resistance to PLX4032 treatment and this was mainly due to increased expression of c-Met. Effective inhibitions of c-Met, p-AKT, and p-ERK were achieved after dual treatment with BRAF inhibitor (PLX4032) and c-Met inhibitor (PHA665752). Similar results were confirmed by in vivo study with orthotopic xenograft mouse model. c-Met-mediated reactivation of the PI3K/AKT pathway and MAPK pathway contributes to the relative insensitivity of BRAF (V600E) mutant anaplastic thyroid cancer cells to PLX4032. Dual inhibition of BRAF and c-Met leads to sustained treatment response. © 2015 Wiley Periodicals, Inc.

Subcategorization of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS): a study applying Thyroid Imaging Reporting and Data System (TIRADS).

OBJECTIVE: To evaluate the clinical significance and compare the imaging features according to the Thyroid Image Reporting and Data System (TIRADS) between atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) subcategories. DESIGN & PATIENTS: A total of 192 thyroid nodules in 188 patients (mean age: 50·2 ± 11·8 years) that had been initially diagnosed as AUS/FLUS on US-guided fine needle aspiration (US-FNA) were included. One cytopathologist retrospectively reviewed the cytology slides, subcategorizing cytology results into AUS and FLUS. A TIRADS category was assigned to each thyroid nodule according to the number of suspicious US features. Clinical, US features and malignancy rates were compared between the two subcategories. RESULTS: Of the 192 AUS/FLUS lesions, 149 (77·6%) were subcategorized as AUS and 43 (22·4%) as FLUS. Of the 192 AUS/FLUS nodules, 82 (42·7%) were malignant. The malignancy rates between AUS and FLUS subcategories were not significantly different, 45·6% to 32·6%, respectively (P = 0·127). When applying TIRADS, significant differences were seen in TIRADS category between benign and malignant nodules in the AUS subcategory (P < 0·001), but not in the FLUS subcategory (P = 0·414). The malignancy rates in TIRADS categories 3, 4a, 4b, 4c and 5 were 15·4%, 22·2%, 33·3%, 57·1% and 80·0% (P < 0·001) in AUS nodules and 40·0%, 50·0%, 23·5%, 22·2% and 0·0% (P = 0·414) in FLUS nodules, respectively. CONCLUSION: Suspicious US features are useful in predicting malignancy among AUS subcategories but not in FLUS subcategories. Subcategorization into AUS and FLUS cytology may be helpful in deciding upon treatment or management of thyroid nodules.

Human Papillomavirus and Epidermal Growth Factor Receptor in Oral Cavity and Oropharyngeal Squamous Cell Carcinoma: Correlation With Dynamic Contrast-Enhanced MRI Parameters.

OBJECTIVE: The objective of this study was to investigate differences in dynamic contrast-enhanced MRI (DCE-MRI) parameters on the basis of the status of human papillomavirus (HPV) and epidermal growth factor receptor (EGFR) biomarkers in patients with squamous cell carcinoma (SCC) of the oral cavity and oropharynx by use of histogram analysis. MATERIALS AND METHODS: A total of 22 consecutive patients with oral cavity and oropharyngeal SCC underwent DCE-MRI before receiving treatment. DCE parameter maps of the volume transfer constant (K(trans)), the flux rate constant (kep), and the extravascular extracellular volume fraction (ve) were obtained. The histogram parameters were calculated using the entire enhancing tumor volume and were compared between the patient subgroups on the basis of HPV and EGFR biomarker statuses. RESULTS: The cumulative histogram parameters of K(trans) and kep showed lower values in the HPV-negative and EFGR-overexpression group than in the HPV-positive EGFR-negative group. These differences were statistically significant for the mean (p = 0.009), 25th, 50th, and 75th percentile values of K(trans) and for the 25th percentile value of kep when correlated with HPV status in addition to the mean K(trans) value (p = 0.047) and kep value (p = 0.004) when correlated with EGFR status. No statistically significant difference in ve was found on the basis of HPV and EGFR status. CONCLUSION: DCE-MRI is useful for the assessment of the tumor microenvironment associated with HPV and EGFR biomarkers before treatment of patients with oral cavity and oropharyngeal SCC.

Applying Ultrasound-Guided Core Needle Biopsy for Diagnosis of Thyroid Masses: Preliminary Results From a Single Institution.

OBJECTIVES: The purpose of this study was to investigate the level of conclusive results obtained with ultrasound (US)-guided core needle biopsy (CNB) and how this method should be applied for diagnosis of thyroid nodules. METHODS: From January 2013 to November 2014, US-guided CNB was performed in 84 thyroid lesions of 83 patients. Based on CNB pathologic reports, thyroid nodules were divided into 2 categories: conclusive (nodules reaching a definite pathologic diagnosis suggesting benignity or malignancy) and inconclusive (nodules that were not able to reach a definite diagnosis because of ambiguous results). Medical records and US examinations were reviewed and compared. RESULTS: The mean age of the 83 patients ± SD was 49.7 ± 14.1 years. Of the 84 thyroid nodules, 73 (86.9%) were diagnosed as benign or malignant and 11 (13.1%) as inconclusive by CNB pathologic analysis. Among the 11 nodules with inconclusive results, the possibility of a follicular neoplasm was suggested in 8 nodules (72.7%). No significant difference was seen in tumor size and US features when comparing the nodules with conclusive and inconclusive results (all P >.05). CONCLUSIONS: Ultrasound-guided CNB may have supplemental roles in addition to US-guided fine-needle aspiration for diagnosis of selected cases. A considerable proportion of inconclusive results are seen on US-guided CNB, especially for diagnosis of follicular lesions, which must be considered when using this method for diagnosis of thyroid nodules.

Recurrence Risk Evaluation in Patients with Papillary Thyroid Carcinoma: Multicenter Machine Learning Evaluation of Lymph Node Variables.

Background: Lymph node (LN)-related risk factors have been updated to predict long-term outcomes in patients with papillary thyroid carcinoma (PTC). However, those factors' analytic appropriateness and general applicability must be validated. This study aimed to assess LN-related risk factors, and suggest new LN-related risk categories. Methods: This multicenter observational cohort study included 1232 patients with PTC with N1 disease treated with a total thyroidectomy and neck dissection followed by radioactive iodine remnant ablation. Results: The median follow-up duration was 117 months. In the follow-up period, structural recurrence occurred in 225 patients (18.3%). Among LN-related variables, the presence of extranodal extension (p < 0.001), the maximal diameter of metastatic LN foci (p = 0.029), the number of retrieved LNs (p = 0.003), the number of metastatic LNs (p = 0.003), and the metastatic LN ratio (p < 0.001) were independent risk factors for structural recurrence. Since these factors showed a nonlinear association with the hazard ratio of recurrence-free survival (RFS) rates, we calculated their optimal cutoff values using the K-means clustering algorithm, selecting 0.2 cm and 1.1 cm for the maximal diameter of metastatic LN foci, 4 and 13 for the number of metastatic LN, and 0.28 and 0.58 for the metastatic LN ratio. The RFS curves of each subgroup classified by these newly determined cutoff values showed significant differences (p < 0.001). Each LN risk group also showed significantly different RFS rates from the others (p < 0.001). Conclusions: In PTC patients with an N1 classification, our novel LN-related risk estimates may help predict long-term outcomes and design postoperative management and follow-up strategies. After further validation studies based on independent datasets, these risk categories might be considered when redefining risk stratification or staging systems.

ALU and LINE-1 hypomethylations in multistep gastric carcinogenesis and their prognostic implications.

Focal CpG island hypermethylation and diffuse genomic hypomethylation signify the changes in the DNA methylation status in cancer cells. ALU and LINE-1 repetitive DNA elements comprise ~28% of the human genome. PCR-based measurements of these repetitive DNA elements can be used as a surrogate marker of the genomewide methylation content. Our study aimed to identify the timing of ALU and LINE-1 hypomethylations during multistep gastric carcinogenesis and their prognostic implications in gastric cancer (GC). In our study, we analyzed the methylation statuses of ALU and LINE-1 in 249 cases of gastric biopsy samples and another independent set of 198 cases of advanced GC by pyrosequencing. Regardless of the Helicobacter pylori infection status, a significant decrease in the ALU methylation levels was noted during the transitions from chronic gastritis to intestinal metaplasia and from gastric adenoma to GC. LINE-1 methylation decreased during the transition from intestinal metaplasia to gastric adenoma and no further decrease occurred during the transition from gastric adenoma to GC. A low LINE-1 methylation status was strongly associated with poor prognosis in GC. A multivariate analysis revealed that LINE-1 methylation status was an independent prognostic factor. Our findings suggest that ALU and LINE-1 hypomethylations are early events during multistep gastric carcinogenesis. Furthermore, the LINE-1 methylation status can be used as a molecular biomarker to define a subset of GC patients with poor prognosis.

Distinct patterns of promoter CpG island methylation of breast cancer subtypes are associated with stem cell phenotypes.

Although DNA methylation profiles in breast cancer have been connected to breast cancer molecular subtype, there have been no studies of the association of DNA methylation with stem cell phenotype. This study was designed to evaluate the promoter CpG island methylation of 15 genes in relation to breast cancer subtype, and to investigate whether the patterns of CpG island methylation in each subtype are associated with their cancer stem cell phenotype represented by CD44+/CD24- and ALDH1 expression. We performed MethyLight analysis of the methylation status of 15 promoter CpG island loci involved in breast cancer progression (APC, DLEC1, GRIN2B, GSTP1, HOXA1, HOXA10, IGF2, MT1G, RARB, RASSF1A, RUNX3, SCGB3A1, SFRP1, SFRP4, and TMEFF2) and determined cancer stem cell phenotype by CD44/CD24 and ALDH1 immunohistochemistry in 36 luminal A, 33 luminal B, 30 luminal-HER2, 40 HER2 enriched, and 40 basal-like subtypes of breast cancer. The number of CpG island loci methylated differed significantly between subtypes, and was highest in the luminal-HER2 subtype and lowest in the basal-like subtype. Methylation frequencies and levels in 12 of the 15 genes differed significantly between subtypes, and the basal-like subtype had significantly lower methylation frequencies and levels in nine of the genes than the other subtypes. CD44+/CD24- and ALDH1+ putative stem cell populations were most enriched in the basal-like subtype. Methylation of promoter CpG islands was significantly lower in CD44+/CD24-cell (+) tumors than in CD44+/CD24-cell (-) tumors, even within the basal-like subtype. ALDH1 (+) tumors were also less methylated than ALDH1 (-) tumors. Our findings showed that promoter CpG island methylation was different in relation to breast cancer subtype and stem cell phenotype of tumor, suggesting that breast cancers have distinct patterns of CpG island methylation according to molecular subtypes and these are associated with different stem cell phenotypes of the tumor.

Fine Needle Aspiration Cytology vs. Core Needle Biopsy for Thyroid Nodules: A Prospective, Experimental Study Using Surgical Specimen.

Purpose: To evaluate and compare the diagnostic outcomes of ultrasonography (US)-guided fine needle aspiration (FNA) and core needle biopsy (CNB) performed on the same thyroid nodule using a surgical specimen for direct comparison. Materials and Methods: We included 89 thyroid nodules from 88 patients from February 2015 to January 2016. The inclusion criterion was thyroid nodules measuring ≥ 20 mm (mean size: 40.0 ± 15.3 mm). Immediately after surgical resection, FNA and subsequent CNB were performed on the surgical specimen under US guidance. FNA and CNB cytopathologic results on the specimen were compared with the surgical diagnosis. Results: Among the 89 nodules, 30 were malignant and 59 were benign. Significantly higher inconclusive rates were seen in FNA for malignant than benign nodules (80.0% vs. 39.0%, p < 0.001). For CNB, conclusive and inconclusive rates did not differ between benign and malignant nodules (p = 0.796). Higher inconclusive rates were seen for FNA among cancers regardless of US features, and in the subgroup of size ≥ 40 mm (62.5% vs. 22.9%, p = 0.028). Eleven cancers were diagnosed with CNB (36.7%, 11/30), while none was diagnosed using FNA. Conclusion: In this experimental study using surgical specimens, CNB showed a potential to provide improved diagnostic sensitivity for thyroid cancer, especially when a conclusive diagnosis is limited with FNA.

Detailed characterization of metastatic lymph nodes improves the prediction accuracy of currently used risk stratification systems in N1 stage papillary thyroid cancer.

OBJECTIVE: The characteristics of metastatic lymph nodes (MLNs) have been investigated as important predictors of recurrence and progression in papillary thyroid cancer (PTC). However, clinically applicable risk stratification systems are limited to the assessment of size and number of MLNs. This study investigated the predictive value of detailed characteristics of MLNs in combination with currently used risk stratification systems. DESIGN AND METHODS: We retrospectively characterized 2811 MLNs from 9014 harvested LNs of 286 patients with N1 PTC according to the maximum diameter of MLN (MDLN), maximum diameter of metastatic focus (MDMF), ratio of both diameters (MDMFR), lymph node ratio (LNR, number of MLNs/number of total harvested LNs), presence of extranodal extension (ENE), desmoplastic reaction (DR), cystic component, and psammoma body. RESULTS: Factors related to the size and number of MLNs were associated with increased risk of recurrence and progression. Extensive presence of ENE (>40%) and DR (≥50%) increased the risk of recurrence/progression. The combination of MDLN, LNR, ENE, and DR had the highest predictive value among MLN characteristics. Combination of these parameters with ATA risk stratification or 1-year response to therapy improved the predictive power for recurrence/progression from a Harrell's C-index of 0.781 to 0.936 and 0.867 to 0.960, respectively. CONCLUSIONS: The combination of currently used risk stratification systems with detailed characterization of MLNs may improve the predictive accuracy for recurrence/progression in N1 PTC patients.

Expression of CD9 and CD82 in papillary thyroid microcarcinoma and its prognostic significance.

INTRODUCTION: papillary thyroid microcarcinoma is a well-known malignant neoplasm with good prognosis. The known prognostic factors are patient's age, multifocality, and extrathyroidal extension. CD9 and CD82, members of the tetraspanin family, are expressed in numerous cancer cells and play many roles associated with the cellular process. MATERIAL AND METHODS: we investigated the immunohistochemical expression of CD9 and CD82 in papillary thyroid microcarcinoma and analysed the clinicopathological and prognostic significance. For the retrospective analysis, we collected the cases of 553 PTMC patients who had undergone thyroidectomy. RESULTS: The group with lymph node metastasis showed higher immunostaining intensity for CD9 than the group without metastasis (p = 0.002). In multivariate analysis, high CD9 intensity (OR = 1.58 in 3+, p = 0.0025) correlated with lymph node metastasis. CONCLUSION: We suggest CD9 as a predictive prognostic factor for lymph node metastasis in PTMC.

Peripheral location and infiltrative margin predict invasive features of papillary thyroid microcarcinoma.

OBJECTIVE: Tumor location in papillary thyroid microcarcinoma (PTMC) might determine tumor outgrowth from the thyroid gland. However, the clinical implications of tumor location and minimal extrathyroid extension (mETE) have not been well elucidated. We aimed to investigate the relationship between tumor location and mETE to predict the aggressiveness of PTMC. METHODS: A total of 858 patients with PTMC were grouped according to tumor location on ultrasonography: central (cPTMC) and peripheral PTMC (pPTMC). PTMC without mETE (PTMC-mETE(-)) was divided further according to margin shape: encapsulated (E-) or infiltrative (I-). To understand the molecular biologic characteristics of PTMC presenting with an I-margin and mETE, transcriptome data from TCGA-THCA were analyzed using Gene Set Enrichment Analysis (GSEA). RESULTS: pPTMC (n = 807, 94.1%) accounted for the majority of cases; mETE was identified only in pPTMC (403/807; 49.9%). pPTMC-mETE(+) showed aggressive clinical characteristics that increased the odds ratio (OR) for lymph node metastasis (LNM). Interestingly, subgroup analysis of PTMC-mETE(-) revealed that the I-margin also increased the OR for LNM, independent of other clinical factors. GSEA of TCGA-THCA data suggested coordinated upregulation of genes related to epithelial-mesenchymal transition (EMT) in PTC with mETE. Immunohistochemical staining for laminin subunit gamma 2 (LAMC2), CD59, E-cadherin and vimentin showed that these markers of EMT were associated with progressive changes in E-margin PTMC-mETE(-), I-margin PTMC-mETE(-) and pPTMC-mETE(+). CONCLUSION: mETE related to peripheral location of PTMC is an important predictor of tumor invasiveness, as is the I-margin, which presents with EMT features similar to mETE. I-margin PTMC-mETE(-) and pPTMC-mETE(+) might reflect the pattern of invasive PTMC.

Effects of Oxytocin on Cell Proliferation in a Corticotroph Adenoma Cell Line.

BACKGROUND: Oxytocin (OXT) has been reported to act as a growth regulator in various tumor cells. However, there is a paucity of data on the influence of OXT on cell proliferation of corticotroph adenomas. This study aimed to examine whether OXT affects cell growth in pituitary tumor cell lines (AtT20 and GH3 cells) with a focus on corticotroph adenoma cells. METHODS: Reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay were conducted with AtT20 cells to confirm the effects of OXT on hormonal activity; flow cytometry was used to assess changes in the cell cycle after OXT treatment. Moreover, the impact of OXT on proliferating cell nuclear antigen (PCNA), nuclear factor κB, and mitogen-activated protein kinase signaling pathway was analyzed by Western blot. RESULTS: OXT treatment of 50 nM changed the gene expression of OXT receptor and pro-opiomelanocortin within a short time. In addition, OXT significantly reduced adrenocorticotropic hormone secretion within 1 hour. S and G2/M populations of AtT20 cells treated with OXT for 24 hours were significantly decreased compared to the control. Furthermore, OXT treatment decreased the protein levels of PCNA and phosphorylated extracellular-signal-regulated kinase (P-ERK) in AtT20 cells. CONCLUSION: Although the cytotoxic effect of OXT in AtT20 cells was not definite, OXT may blunt cell proliferation of corticotroph adenomas by altering the cell cycle or reducing PCNA and P-ERK levels. Further research is required to investigate the role of OXT as a potential therapeutic target in corticotroph adenomas.

The prevalence and surgical outcomes of Hürthle cell lesions in FNAs of the thyroid: A multi-institutional study in 6 Asian countries.

BACKGROUND: Hürthle cell-rich nodules (HCNs) encompass non-neoplastic to malignant lesions. There is paucity of literature on the frequency distribution of HCNs among Bethesda categories, histologic follow-up, risk of malignancy (ROM), and risk of neoplasia (RON). The objective of this retrospective, multi-institutional study was to determine the prevalence of the cytologic diagnostic category and surgical outcomes of patients with HCN. METHODS: Nine tertiary health centers representing 6 Asian countries participated. Cases were retrieved from respective databases. The Bethesda System for Reporting Thyroid Cytopathology was used. Cytology results were correlated with surgical diagnoses. RESULTS: Of 42,190 thyroid aspirates retrieved, 760 (1.8%) had a Hürthle cell predominance. Most (61%) were categorized as atypia of undetermined significance/follicular lesion of undetermined significance, Hürthle cell type" (AUS-H); 35% were categorized as follicular neoplasm, Hürthle cell type (FN-H); and 4% were categorized as suspicious for malignancy (SFM). Histologic follow-up was available for 288 aspirates (38%). Most were benign on resection (66%), and the most common histologic diagnosis was Hürthle cell adenoma (28.5%). The ROM for AUS-H, FN-H, and SFM, as calculated on resected nodules, was 32%, 31%, and 71%, respectively; and the RON was 47%, 81%, and 77%, respectively. The 5 institutions that had an AUS-H:HCN ratio below 0.5 diagnosed HCN less frequently as AUS-H than as FN-H. CONCLUSIONS: This is the largest, contemporary, multi-institutional series of HCNs with surgical follow-up. Although there was wide interinstitutional variation in prevalence and surgical outcomes, there was no significant difference in the ROM among institutions. The categories AUS-H and FN-H had a similar ROM for resected nodules.

Primary Bone Marrow B-Cell Lymphoma Undetected by Multiple Imaging Modalities That Initially Presented with Hypercalcemia.

PURPOSE: We report a rare case of severe hypercalcemia that was ultimately diagnosed as primary bone marrow diffuse large B-cell lymphoma (BCL). CASE REPORT: A 74-year-old male patient visited our hospital complaining of tenderness and swelling of the left knee caused by supracondylar fracture of the left distal femur. His initial blood tests showed a serum calcium level of 13.9 mg/dL, inorganic phosphorus of 4.34 mg/dL, and a serum creatinine level of 1.54 mg/dL. A serum assay of intact parathyroid hormone showed 5.24 pg/mL, and the patient's serum 25(OH)D level was 22.33 ng/mL. To exclude malignancy, we performed imaging studies, including abdomen or chest computed tomography and positron emission tomography-computed tomography; however, no suspicious lesion was found, although the serum PTH-related peptide level was elevated at 4.0 pmol/L. A bone marrow biopsy was performed to identify any hidden hematologic malignancy. As a result, the pathology of bone marrow confirmed the presence of atypical lymphocytes that stained positive for the CD20 marker, which is consistent with BCL involving the bone marrow. CONCLUSION: This case highlights the importance of pursuing a thorough workup for rare underlying causes of hypercalcemia when parathyroid-related etiologies can be excluded.

Predicting lymph node metastasis in patients with papillary thyroid carcinoma by vascular index on power Doppler ultrasound.

BACKGROUND: For patients with papillary thyroid carcinoma (PTC), lymph node metastasis is associated with an increased recurrence rate. The purpose of this study was to investigate whether the vascular endothelial growth factor (VEGF), microvessel density (MVD), and vascular index (VI) can predict lymph node metastasis in patients with PTC. METHODS: From January 2011 to October 2011, 202 patients with PTCs underwent preoperative staging ultrasound evaluation. To evaluate vascularity, we measured the VI, VEGF expression, and MVD. RESULTS: The VI was significantly correlated with MVD (p = .009). On multivariate analysis, young age showed a significant correlation with lymph node metastasis (p < .001; p < .001; p < .001). However, the other clinicopathologic features, VEGF, MVD, and VI failed to show any significant correlations with lymph node metastasis. CONCLUSION: Although the VI showed significant correlation with MVD, it was not significantly correlated to lymph node metastasis. © 2016 Wiley Periodicals, Inc. Head Neck 39: 334-340, 2017.

Thyroid Fine-Needle Aspiration Cytology Practice in Korea.

We reviewed the current status of thyroid fine-needle aspiration cytology (FNAC) in Korea. Thyroid aspiration biopsy was first introduced in Korea in 1977. Currently, radiologists aspirate the thyroid nodule under the guidance of ultrasonography, and cytologic interpretation is only legally approved when a cytopathologist makes the diagnosis. In 2008, eight thyroid-related societies came together to form the Korean Thyroid Association. The Korean Society for Cytopathology and the endocrine pathology study group of the Korean Society for Pathologists have been updating the cytologic diagnostic guidelines. The Bethesda System for Reporting Thyroid Cytopathology was first introduced in 2009, and has been used by up to 94% of institutions by 2016. The average diagnosis rates are as follows for each category: I (12.4%), II (57.9%), III (10.4%), IV (2.9%), V (3.7%), and VI (12.7%). The malignancy rates in surgical cases are as follows for each category: I (28.7%), II (27.8%), III (50.6%), IV (52.3%), V (90.7%), and VI (100.0%). Liquid-based cytology has been used since 2010, and it was utilized by 68% of institutions in 2016. The categorization of thyroid lesions into "atypia of undetermined significance" or "follicular lesion of undetermined significance" is necessary to draw consensus in our society. Immunocytochemistry for galectin-3 and BRAF is used. Additionally, a molecular test for BRAF in thyroid FNACs is actively used. Core biopsies were performed in only 44% of institutions. Even the institutions that perform core biopsies only perform them for less than 3% of all FNACs. However, only 5% of institutions performed core biopsies up to three times more than FNAC.