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Chyle leakage (CL) due to lymphatic injuries is one of the rare complications that can develop after thyroidectomy. There are few studies on lymphatic embolization performed in case of CL after thyroid surgery. We report two cases of CL after thyroid surgery that were effectively treated by thoracic duct embolization. The patients had previously undergone total thyroidectomy with central compartment neck dissection with or without modified radical neck dissection. The amount of drainage from the operative site was ＞1000 mL per day in one patient and ＞500 mL per day in the other. In both cases, CL stopped after the thoracic duct embolization. Thoracic duct embolization seems to be an effective and important treatment option for CL after thyroid surgery.

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Whether chronic lymphocytic thyroiditis (CLT) influences the risk of development and the progression of papillary thyroid cancer (PTC) remains uncertain. We investigated the effects of CLT on the clinicopathologic features and prognosis of PTC. Two thousand nine hundred twenty-eight consecutive patients with PTC treated between 2009 and 2017 were divided into two groups: one with chronic lymphocytic thyroiditis and one without; 1174 (40%) of the patients had coincident CLT. In univariate analysis, CLT correlated positively with small tumor size, frequent extrathyroidal extension, multifocal diseases, and p53 but negatively with central lymph node (LN) metastasis and BRAF mutation. In multivariate analysis, CLT was associated with extrathyroidal extension and multifocal disease; however, it was not a prognostic factor for recurrence even though it was associated with two aggressive factors. Compared with patients with PTC alone, there were more retrieved central LNs in the PTC + CLT group, and these patients also underwent more invasive diagnostic tests such as fine needle aspiration cytology and frozen biopsy of LN. The CLT patients with PTC had better behavior features and prognoses than did those with PTC alone despite frequent multifocality and extrathyroidal extension. However, precaution may be necessary to avoid performing invasive diagnostic procedures for lateral LN metastasis and to manage the patients appropriately.

Purpose We investigated the risk factors of indeterminate response (IDR) in patients who underwent recombinant human thyroid-stimulating hormone (rhTSH)-aided radioactive iodine therapy (RAIT). Methods A total of 128 patients with papillary thyroid cancer were included in this retrospective study. The patients were classified into excellent response and IDR groups based on follow-up diagnostic whole-body scintigraphy (WBS) and TSH-stimulated thyroglobulin (Tg). Indeterminate response was defined as the presence of a faint uptake in the thyroid bed on the diagnostic WBS or a TSH-stimulated Tg detectable, but less than 10 ng/mL. Parameters that act as significant risk factors for IDR, including age, sex, stage, surgeon, time interval between surgery and RAIT, post-treatment WBS finding, urine iodine-to-creatinine ratio, TSH-unstimulated Tg, and rhTSH-stimulated Tg, were analyzed using a Cox proportional hazards regression method. Results After treatment, 64 patients showed IDR. Recombinant human TSH-stimulated Tg was the only independent risk factor for predicting IDR. Patients with an rhTSH-stimulated Tg greater than 2 ng/mL prior to RAIT were 3.75 times more likely (95% confidence interval, 1.61-8.72) to have an IDR than those with a lower rhTSH-stimulated Tg (≤2 ng/mL). Conclusions Pre-RAIT TSH-stimulated Tg levels are a risk factor for IDR after RAIT.

Background/objective The diagnostic accuracy of fine needle aspiration biopsy (FNAB) seems limited in large thyroid nodules with Bethesda Cat. 2 result. We aimed to determine the incidence of carcinoma with benign cytology and the reason for the high false-positive rate in thyroid nodules ≥4 cm. Methods The records of 103 patients with thyroid nodules ≥4 cm with preoperative cytological diagnosis of Bethesda Cat. 2 who underwent thyroidectomy were consecutively reviewed. Characteristics between patients with malignant vs. benign pathology were compared. Results Forty patients (38.8%) had malignancy. Malignancy was subclassified into follicular variant of papillary thyroid carcinoma (43%), minimally invasive follicular thyroid carcinoma (20.0%), and minimally invasive Hurthle cell thyroid carcinoma (10.9%). Patients with malignant cytology had significantly more suspicious ultrasound findings than those with benign cytology (p = 0.001). Conclusions Preoperative FNAB showed high false-negative rates in patients with thyroid nodules ≥4 cm with benign cytology. These nodules have a high malignancy rate with suspicious ultrasound findings.

The incidence rates of structural persistent disease (PD) and recurrent disease (RD) after thyroidectomy, and their clinicoradiological (CT) characteristics, remain poorly understood. Therefore, we characterized differentiated thyroid cancer (DTC) patients who underwent re-operations, with a focus on preoperative CT scans. We examined neck CT scans obtained prior to initial surgery and reoperation, and classified the disease into four categories according to the persistence/recurrence and neck dissection/non-dissection status. In total, 121 of 9,173 DTC patients underwent reoperations to treat PD or RD; the mean time to reoperation was 25.5 and 54.1 months, respectively. Of all reoperations, 19% (23/121) were performed to treat RD; 81% (98/121) were performed to treat PD. Compared to RD, PD was commonly detected in the non-dissected neck. Tumor multiplicity and the number of pathologically positive lymph nodes were greater in the non-dissected than dissected neck. A review of the CT data revealed more false-negative findings on the 60-s- versus 30–40-s-delay scans of PD patients with non-dissected necks. In conclusion, most of the reoperations performed on DTC patients were for management of PD. Improved preoperative CT assessments and initial surgery, based on the information of clinico-radiological characteristics, are required in the care of DTC patients.

An intermediate cervical plexus block (CPB) targets the posterior cervical space between the sternocleidomastoid muscle and the prevertebral fascia. The phrenic nerve descends obliquely on the surface of the anterior scalene muscle beneath the prevertebral fascia after originating from the C3–C5 ventral rami. Therefore, the phrenic nerve can be affected by a local anesthetic during an intermediate CPB, depending on the permeability characteristics of the prevertebral fascia. This study investigated whether an intermediate CPB affects the phrenic nerve, inducing hemidiaphragmatic paresis. In this prospective observational study, 20 patients undergoing single-incision transaxillary robot-assisted right thyroidectomy were enrolled. The intermediate CPB (0.25% ropivacaine 0.2 ml/kg) was performed at the C4–5 intervertebral level carefully, without penetrating the prevertebral fascia, before the patient emerged from general anesthesia. Diaphragmatic motions of the block side were measured by M-mode ultrasonography at three time points: before anesthesia (baseline) and at 30 and 60 min after the intermediate CPB. Hemidiaphragmatic paresis was divided into three grades, depending on the percentage of diaphragm movement compared to the baseline: none (> 75%), partial paresis (25–75%), and complete paresis (

This study investigated the correlation between basal thyroglobulin (Tg) and recombinant human thyroid-stimulating hormone (rhTSH)-stimulated Tg in differentiated patients with thyroid cancer, and sought to determine whether the basal Tg level predicts the rhTSH-stimulated Tg level. We retrospectively enrolled 177 patients with papillary thyroid cancer (mean age = 44 years; 50 males, 127 females) who received rhTSH before radioiodine therapy (RIT). Serum Tg levels were measured 7 days before the 1st rhTSH injection (basal Tg) and on the days of RIT (rhTSH-stimulated Tg). Patients were divided into 3 groups according to rhTSH-stimulated Tg cut-off levels of 2, 5, and 10 ng/mL. The correlation between basal Tg and rhTSH-stimulated Tg levels was assessed, and whether basal Tg was useful in predicting the rhTSH-stimulated Tg level was determined. A significant positive correlation was observed between basal and rhTSH-stimulated Tg levels (|rho| = 0.48, P 0.3 or 0.5 ng/mL, then the rhTSH-stimulated Tg level can be expected to be sufficiently high to necessitate clinical examination.

Calcification is important for the diagnosis of papillary thyroid carcinoma (PTC). Runt-related transcription factor 2 (RUNX2), a master transcription factor associated with osteogenic differentiation, is reportedly related to PTC calcification and invasiveness. However, its regulatory role in this process is somewhat uncharacterized. Here, we attempted to identify genes that regulate RUNX2 and clarify its function in PTC carcinogenesis and calcification. The expression of RUNX2-upstream genes was evaluated by real-time PCR in Nthy-Ori 3-1 normal thyroid cells and TPC1 and BHP10-3 PTC cell lines. Luciferase and chromatin immunoprecipitation assays were performed with candidate genes after cloning the RUNX2 promoter. We found that RUNX2 promoter activity was enhanced by homeobox family A9 (HOXA9). Over-expression of HOXA9 was found to enhance alkaline phosphatase activity, mineralization, and in vitro tumour cell migration and invasion, whereas downregulation had the opposite effects. These results indicate that HOXA9, a positive regulator of RUNX2, can enhance calcification, migration, and invasion in PTC. Our data improve the understanding of the molecular mechanisms of microcalcification in PTC as well as tumorigenesis.

Background: Abnormal wound healing after thyroidectomy and a consequent scar is a common dermatologic consultation.Prevention of the possible hypertrophic scars and keloids is known to be challenging. Objectives: The objective of our study was to validate and confirm the efficacy and safety of low-level light therapy (LLLT) for the prevention of thyroidectomy scars on the neck. Methods: Fourty-one South Korean patients with linear surgical suture after thyroidectomy operation were treated with an 830/590nm light-emitting diode (Healite®). Each patient was treated daily of 60J/cm2(11 minutes) for a week starting on post-operation day one and treated 3 times per week for 3 more weeks. The control group consisted of 15 patients without any therapy except application of absorbent foam dressing. The scar prevention effects were evaluated at 1 month and 3 months after surgery.Colorimetric evaluation using a tristimulus color analyzer was done. The Vancouver Scar Scale (VSS), Global Assessment Score (GAS) and a subjective score ranging 1 to 4 was also measured. Results: The L* value and a* value decreased significantly on the 3 month follow up visit in the the treated groupcompared to the control group. Also, the average VSS and GAS was lower in the treated group. However, subjective measure did not show significant difference. Conclusion: LLLT using a 830/590nm light emitting diode may efficiently suppress the formation of thyroidectomy scars, and can be safely without noticeable side effects.

BRAF, a serine/threonine kinase and the v-RAF murine sarcoma viral oncogene homolog B1, is an activator of the mitogen-activated protein kinase (MAPK) pathway [1]. Mutations in BRAF constitutively activate the MAPK pathway, allowing human cancers to develop and progress [1,2]. Of the various BRAF mutations, BRAFV600E, a valine to glutamic acid substitution at codon 600, is the most common [1,3]. In clinical practice, the BRAFV600E mutation is of major interest because it is considered a critical diagnostic, prognostic, and predictive biomarker of many types of cancer [3-6]. Among the many endocrine malignancies, the BRAFV600E mutation is a reliable diagnostic marker of papillary thyroid carcinoma (PTC), as it is detected in 40%–80% of PTCs but virtually never in benign tumors [3,7]. Currently, the BRAFV600E mutation in PTC is typically identified using DNA-based methods such as direct sequencing, allele-specific polymerase chain reaction (PCR), or real-time PCR [7,8]. Although these methods all afford high sensitivity and specificity, expensive equipment and rigorous quality control are required [8-10]. Recently, the VE1 antibody, a monoclonal antibody against the BRAFV600E mutant protein, was investigated in terms of its detection of the BRAFV600E mutation [9]. Although VE1 immunostaining revealed a high concordance rate with molecular methods in surgical specimens of PTC [10-12], evaluation of VE1 in thyroid cytology samples is rarely performed, and its diagnostic value in cytology has not been well established [13-16]. In the present study, we evaluated the use of the VE1 antibody in cytology samples from ex vivo thyroid PTC specimens in order to overcome the drawbacks of fine-needle aspiration (FNA) including low cellularity and sampling/targeting errors [13,15,16], and the results were compared to the data from corresponding PTC tissues.

Background and Objectives Single-incision transaxillary robotic thyroidectomy (START) requires substantial tissue disruption, which produces moderate-to-severe pain in the axilla and neck areas during the early postoperative period. This study aimed to investigate the analgesic effects of ultrasound-guided serratus-intercostal plane blocks and intermediate cervical plexus blocks (CPBs) on the early postoperative pain after START. Methods We randomized 22 patients to undergo either ultrasound-guided serratus-intercostal plane and intermediate CPBs (the block group, n = 11) or to not undergo any block (the control group, n = 11). We compared postoperative axillary pain, postoperative neck pain, and analgesic use between the groups during the first 24 hours. The rescue analgesics were intravenous fentanyl (0.5 μg/kg) in the postanesthesia care unit, and intravenous ketorolac tromethamine (30 mg) in the general ward. Results The block group showed consistently lower pain scores than the control group in the axillary area in the first 24 hours and in the neck area only in the first 3 hours after surgery. The numbers (proportions) of patients who required analgesics were 11 (100%) in the control group and 6 (54.5%) in the block group during the first 24 hours (P = 0.035). No adverse effect was observed related to the peripheral nerve blocks. Conclusions After START, a serratus-intercostal plane block performed at the level of the third rib was an effective analgesic technique for axillary pain; however, the clinical effectiveness of intermediate CPB for neck pain may be limited.

BACKGROUND AND AIMS Papillary thyroid cancer (PTC) is the most frequent subtype among thyroid cancers. Lymph node (LN) metastases are frequent in PTC and the incidence is 60% on average. Recent studies have shown that there has been an increase in the mortality or recurrence with LN metastases and that more than 5 metastatic LNs are clinically important. Therefore, we investigated clinicopathologic factors associated with clinically important LN metastases. METHODS From January 2010 to October 2013, we retrospectively enrolled 2,628 PTC patients who underwent thyroidectomy at Ajou University Hospital. Among 1,425 patients with LN metastasis, 325 had ≥ 5 LN metastases. RESULTS In univariate analysis, young age (< 45 year), male gender, capsular invasion, multiplicity, tumor size, and lymphovascular invasion (p < 0.001) were statistically associated with both LN metastasis and ≥ 5 LN metastases. However, Braking Action Fair (BRAF) mutation was not important to predict LN metastasis (p > 0.05). In multivariate analysis, lymphovascular invasion was the most important factor (odds ratio: 4.7, 4.0) among other clinicopathologic factors (odds ratio:< 2.1). CONCLUSION Braking Action Fair (BRAF) mutation was not useful to predict the LN metastasis. However, lymphovascular invasion was the most important factor to predict more than five cervical LN metastasis which is very important clinically.

BACKGROUND Using a large set of genomic data from The Cancer Genome Atlas (TCGA), we classified BRAFwild papillary thyroid carcinomas (PTCs) into 2 subtypes with distinct molecular patterns and different clinical behaviors. We also suggested gene signatures (RAS-score) to predict molecular subtypes and clinical behaviors of BRAFwild PTC. METHOD Integrated genomic analysis was done using all genomic data of PTC in TCGA data portal (https://tcga-data.nci.nih.gov) and cancer browser (https://genome-cancer.ucsc.edu). Using Gene Ontology and a logistic regression test, we selected gene signatures (RAS-score) and applied this prediction model to the validation cohort (GSE60542). RESULT When we performed multiplatform genomic analysis, BRAFwild PTCs were divided into 2 molecular subtypes. Each subtype showed distinct molecular patterns and clinical behaviors. Gene signatures successfully predicted molecular subtype in another validation cohort. CONCLUSION We found that BRAFwild PTCs were divided into 2 molecular subtypes and each subtype showed distinct molecular patterns, different activated pathways, and different clinical behaviors.

B-RafV600E oncogene mutation occurs most commonly in papillary thyroid carcinoma (PTC) and is associated with tumor initiation. However, a genetic modification by B-RafV600E in thyrocytes results in oncogene-induced senescence (OIS). In the present study, we explored the factors involved in the senescence overcome program in PTC. First of all, we observed down-regulation of p-extracellular signal-regulated kinases 1/2 and up-regulation of dual specific phosphatase 6 (DUSP6) in the PTC with B-RafV600E mutation. DUSP6 overexpression in vitro induced extracellular signal-regulated kinases 1/2 dephosphorylation and inhibited B-RafV600E–induced senescence in thyrocytes. Although DUSP6 protein was degraded by B-RafV600E–induced reactive oxygen species (ROS), thyroid-stimulating hormone (TSH) stabilized DUSP6 protein by increasing Mn superoxide dismutase expression and inhibited B-RafV600E–induced senescence. Although serum TSH was not increased, its receptor was markedly upregulated in PTC with B-RafV600E. Furthermore, TSH together with DUSP6 reactivated Ras signaling, resulted in activation of Ras/AKT/glycogen synthase kinase 3β, and stabilized c-Myc protein by inhibiting its degradation. These observations led us to conclude that increased TSH signaling overcomes OIS and is essential for B-RafV600E–induced papillary thyroid carcinogenesis.

Using a large set of genomic data from The Cancer Genome Atlas (TCGA), we classified BRAFIntegrated genomic analysis was done using all genomic data of PTC in TCGA data portal (https://tcga-data.nci.nih.gov) and cancer browser (https://genome-cancer.ucsc.edu). Using Gene Ontology and a logistic regression test, we selected gene signatures (RAS-score) and applied this prediction model to the validation cohort (GSE60542).When we performed multiplatform genomic analysis, BRAFWe found that BRAF

Prophylactic dissection facilitates identification of central lymph node (LN) metastasis in patients with papillary thyroid cancer (PTC). Because most staging systems do not stratify risks by the number of LN metastases, postoperative treatments vary among different institutions. Therefore we investigated the significance of number of LN metastases in risk stratification for recurrence in PTC.A retrospective review was performed for 3,305 patients who had undergone thyroidectomy at Ajou University Hospital. A total of 2,462 patients (73.5 %) underwent total thyroidectomy, and another 3,152 (94.1 %) underwent central LN dissection. Lateral cervical LN dissection had been performed in 420 patients (12.5 %).There were 115 patients with recurrence (3.4 %). Recurrence-free rates were 94.6 % at 5 years and 89.4 % at 10 years. On univariate analysis, prognostic factors for recurrence were extent of thyroidectomy, tumor size, capsular invasion, T stage, N stage, number of LN metastasis, TNM stage, and radioactive iodine (RAI) therapy. On multivariate analysis, number of LN metastasis and N stage were significant prognostic factors for recurrence. Recurrence-free rate was significantly different between patients with 0-1 LN and those with 2 or more LN.Number of metastatic LN was a significant prognostic factor, in addition to the N stage. Therefore, number of metastatic LN must be considered for postoperative staging system to tailor treatment and follow-up recommendations. In addition, patients with ≥2 metastatic LN may benefit from total thyroidectomy and RAI therapy with postoperative follow-up with serum thyroglobulin.

Cellular senescence has been perceived as a barrier against carcinogenesis. However, the senescence-associated secretory phenotype (SASP) of senescent cells can promote tumorigenesis. Here, we show senescent tumour cells are frequently present in the front region of collective invasion of papillary thyroid carcinoma (PTC), as well as lymphatic channels and metastatic foci of lymph nodes. In in vitro invasion analysis, senescent tumour cells exhibit high invasion ability as compared with non-senescent tumour cells through SASP expression. Collective invasion in PTC is led by senescent tumour cells characterized by generation of a C-X-C-motif ligand (CXCL)12 chemokine gradient in the front region. Furthermore, senescent cells increase the survival of cancer cells via CXCL12/CXCR4 signalling. An orthotopic xenograft in vivo model also shows higher lymphatic vessels involvement in the group co-transplanted with senescent cells and cancer cells. These findings suggest that senescent cells are actively involved in the collective invasion and metastasis of PTC., The senescence-associated secretory phenotype of stromal cells can promote tumorigenesis. Here, the authors show that senescent cancer cells are localized at the invasive front in human papillary thyroid carcinoma, and that senescent cancer cells drive collective invasion via CXCL12 in mouse models.

Papillary thyroid carcinoma is the most common type of thyroid malignancy, and CD56, a neural cell adhesion molecule, is typically down-regulated in almost all cases of papillary thyroid carcinoma. Homeobox B9 is a transcription factor, belongs to the products of the homeobox transcription factor gene family, and has been known to regulate transcription of CD56 and to promote tumorigenicity and metastasis in some malignancies. In this study, we investigated the expression and relation of homeobox B9 to reduced expression of CD56 in papillary thyroid carcinomas and also a relationship between their expression and clinicopathologic parameters. Therefore, we performed CD56 and homeobox B9 immunohistochemical staining on 72 papillary thyroid carcinomas and Western blotting on 31 papillary thyroid carcinomas. CD56 protein staining revealed that it was reduced or absent in 65 papillary thyroid carcinomas (90.3%) and was related to silencing of homeobox B9 (77.8%) (P = .003). The loss of homeobox B9 expression was associated with extrathyroidal extension (P = .002), pathologic stage of tumor (P = .01), and age older than 45 years (P = .032). However, the CD56 staining did not reveal any significant relationship with clinicopathologic features (P > .05). In conclusion, reduced expression of CD56 is associated with homeobox B9 in papillary thyroid carcinomas. Furthermore, silencing of homeobox B9 is more common in older age and is linked to extrathyroidal extension and advanced pathologic stage of papillary thyroid carcinoma.

To use objective and subjective voice function analysis to compare outcomes in patients who had undergone conventional open thyroidectomy or robotic thyroidectomy. The study involved 88 consecutive patients who underwent thyroid surgery between May 2009 and December 2009; 46 patients underwent a conventional open thyroidectomy, and 42 underwent a robotic thyroidectomy. Auditory perceptual evaluation was used to make subjective assessments of voice function, and videolaryngostroboscopy, acoustic voice analysis with aerodynamic study, electroglottography, and voice range profile were used to make objective assessments. Each assessment was made before surgery, and at 1 week and 3 months after surgery. The conventional open and robotic thyroidectomy groups were similar in terms of age, gender ratio, and disease profile. We found that 18 (20.5%) of the 88 patients showed some level of voice dysfunction at 1 week after surgery; that the dysfunction resolved by 3 months after surgery in all cases; and that it was not permanent according to postoperative videolaryngostroboscopy. The conventional open and robotic thyroidectomy groups were found to have similar levels of dysfunction at 1 week after surgery, except for jitter, which was greater in the robotic group. For both groups, any such dysfunction spontaneously resolved by 3 months after surgery, and there were no significant differences between the groups in terms of any voice function parameter. Voice dysfunction was present after both open and robotic thyroidectomy (without any evident laryngeal nerve injury). However, function subsequently normalized to preoperative levels at 3 months after surgery in both groups. Voice function outcomes after robotic thyroidectomy are similar to those after conventional open thyroidectomy.

Objectives Approximately 5% of non-medullary thyroid cancer (NMTC) diagnoses are made against a background of familial predisposition and, in such instances, the disease is termed familial non-medullary thyroid cancer (FNMTC). To date, neither genetic alterations causing FNMTC nor genes predisposing to the condition have been described. The objective of the present study was to evaluate loss of heterozygosity (LOH) at the four known susceptibility loci (fPTC/PRN, NMTC1, MNG1, and TCO1) and to compare the mutation rates of RAS/RAF genes in patients with FNMTC and sporadic NMTC. Methods Fourteen FNMTCs in patients from seven families were analyzed in terms of involvement of the four susceptibility loci, and 63 thyroid cancer tumors [FNMTC (29) and NMTC (34)] were evaluated for the occurrence of mutations in BRAF, and H-, N-, and K-RAS, using polymerase chain reaction, single-strand conformation polymorphism (PCR-SSCP) analysis, and direct sequencing. Results Only five (35.7%) tumors showed loss of LOH at the three susceptibility loci (NMTC1, MNG1, or TCO1). These allelic losses did not show a specific pattern. Four (13.8%) FNMTCs and one (2.9%) NMTC had H-RAS (codon 12) mutations. Further, mutation of BRAF V600E was observed in 12 (41.4%) FNMTCs and 29 (85.3%) NMTCs. Conclusion Four known susceptibility loci are infrequently involved in FNMTC. Although further studies are needed, the present findings additionally suggest that somatic activation of oncogenes via BRAF and RAS mutation plays a role in FNMTC tumorigenesis. J. Surg. Oncol. 2012; 105:10–14. © 2011 Wiley Periodicals, Inc.

We investigated the clinical significance of diffuse uptake in remaining thyroid after unilateral lobectomy for thyroid cancer.A total of 144 thyroid cancer patients who underwent (18)F-FDG PET/CT after lobectomy were enrolled in the present study. The PET/CT images were evaluated for the presence of diffuse (18)F-FDG uptake with maximum SUV (SUVmax)2.0 in the residual thyroid and placed into one of two groups: with diffuse uptake and without diffuse uptake group. Clinical, laboratory, and PET/CT parameters in both groups were compared. Correlations between SUVmax of thyroid and available parameters were analyzed.Forty-two of 144 patients (29.2%) had diffuse thyroid uptake (mean SUVmax: 3.2 ± 1.1). All patients with diffuse uptake and 96 (94.1%) without diffuse uptake were receiving thyroxine therapy (P = 0.09). Thyroid function tests showed that most patients were euthyroid status (78.6 vs. 85.3%, P = 0.36). TgAb levels were significantly higher in patients with diffuse uptake (338.0 ± 664.6 vs. 57.3 ± 46.4, P 0.0001). Mean attenuation values in the diffuse uptake group were significantly lower (72.2 ± 15. vs. 97.0 ± 16.0, P 0.0001). An inverse correlation was found between SUVmax and mean attenuation values of residual thyroid in all patients (r = -0.57, P 0.0001) and subgroup with diffuse uptake (r = -0.31, P 0.05).In this study, diffuse (18)F-FDG uptake in the residual thyroid after unilateral lobectomy was a relatively frequent finding and may be associated with chronic thyroiditis. This uptake is not influenced by thyroid status or thyroxine therapy. The (18)F-FDG uptake is inversely correlated with mean attenuation value of thyroid.

Robotic thyroidectomy (RT) has recently emerged as a viable approach to thyroid surgery, resulting in better functional and cosmetic outcomes than afforded by open thyroidectomy (OT). The present multicenter study assessed the perioperative outcomes of RT and compared physician perspectives on the musculoskeletal ergonomic parameters associated with OT, endoscopic thyroidectomy (ET), and RT. We reviewed the medical records of 2014 consecutive patients who underwent RT, conducted by 7 surgeons, at 4 centers between October 2007 and June 2010. Patient characteristics, perioperative clinical results, complications, and pathologic outcomes were analyzed. Moreover, surgeons were surveyed to gather data on musculoskeletal discomfort experienced during OT, ET, and RT. Of the 2014 patients, 740 underwent total and 1274 subtotal thyroidectomy. Mean tumor diameter was 0.8 cm, and the mean number of retrieved central lymph nodes was 4.5 ± 3.9 (range 0–28). The rates of permanent recurrent laryngeal nerve injury and permanent hypocalcemia were 0.4 and 0.05%, respectively. Neck and/or back pain after OT, ET, and RT was experienced by 100, 85.7, and 28.6% of surgeons, respectively. When surgeons ranked the operative approaches in decreasing order of associated pain, 57.1% indicated ET > OT > RT, 28.6% selected OT > ET > RT, and 14.3% responded ET > RT > OT. RT is a feasible and safe procedure that may facilitate radical cervical lymph node dissection. Moreover, for surgeons, the RT resulted in less musculoskeletal discomfort than did OT or ET. A larger prospective study, with a longer follow-up, is needed to determine whether RT offers real benefits for both patients and surgeons.

Endoscopic thyroidectomy is a technically challenging procedure. Robot-assisted thyroidectomy has been recently introduced and offers improved visualization and dexterity. The present study compared conventional endoscopic and robotic thyroidectomy for thyroid cancer patients in terms of perioperative outcomes and learning curve. All operations were performed by the same surgeon.Between April 2007 and March 2010, 96 patients underwent endoscopic thyroidectomy (endoscopy group) and 163 patients underwent robotic thyroidectomy (robot group). A gasless transaxillary approach was used in both groups. The 2 groups were compared in terms of patient characteristics, perioperative clinical results, complications, and pathologic details. Learning curves for the 2 procedures were compared based on the number of cases required to reach a consistent operation time.Patient characteristics were similar for both groups. The mean total operation time for thyroidectomy with central compartment neck dissection was 142.7 ± 52.1 min in the endoscopy group and 110.1 ± 50.7 min in the robot group (P = .041). Both patient groups were similar in terms of pathological features including TNM stage, intraoperative blood loss, length of hospital stay, and complication rate. However, the mean number of retrieved central lymph nodes was 2.4 ± 1.9 for the endoscopy group and 4.5 ± 1.5 for the robot group (P = .004). The learning curve was 55-60 cases for endoscopic thyroidectomy and 35-40 cases for robotic thyroidectomy.Robotic thyroidectomy was found to be superior to endoscopic thyroidectomy in terms of operation time, lymph node retrieval, and learning curve. Complication rates and postoperative hospital stay were similar for the 2 procedures.

Robotic thyroidectomy and lymph node dissection is rapidly emerging as an alternative to conventional endoscopic thyroidectomy for thyroid carcinoma. Robot techniques incorporate the advantages of endoscopic procedures while overcoming some of the problems. We present the largest multi-institution clinical study of robotic thyroidectomy for thyroid carcinomas. The robotic thyroidectomy involved gasless transaxillary approach using the da Vinci surgical robot system. We reviewed a database of 1,043 consecutive patients with low-risk differentiated thyroid carcinoma who underwent robotic thyroidectomy between October 2007 and August 2009. Operations were performed by five surgeons at four academic centers. We analyzed perioperative, clinical, and pathological data. The study involved 71 men and 972 women, with a mean age of 39 (range, 15–70) years. All operations were performed successfully without any need for conventional open or endoscopic conversion. There were 366 total thyroidectomies and 677 subtotal thyroidectomies with cervical lymph node dissection. The mean overall operation time and console time were 132.4 and 63.9 min, respectively. There were ten (1%) major postoperative morbidities. The mean tumor size was 0.8 (range, 0.1–6.0) cm, and the mean number of retrieved central lymph nodes was 5.1 ± 3.8 (range, 0–26). The mean postoperative hospital stay was 2.9 (range, 1–8) days. Robotic thyroidectomy using gasless transaxillary method was feasible, safe, and provided good outcomes for patients with differentiated thyroid carcinoma. Robotic technology overcame some technical limitations associated with conventional endoscopy.

Robotic thyroidectomy using a gasless transaxillary approach, first described in 2008, has become popular. This study compared outcomes, including postoperative distress and patient satisfaction, for patients undergoing robotic thyroidectomy with those for patients treated by conventional open thyroidectomy. Of 84 prospectively enrolled patients, 41 underwent robotic thyroidectomy (the robot group), and 43 received conventional open thyroidectomy (the open group). All the patients were followed up for at least 3 months after surgery. Videolaryngostroboscopic examinations were performed preoperatively and after 1 week and after 3 months postoperatively. Postoperative pain and discomfort were evaluated using a symptom scale. Subjective voice and swallowing changes were assessed by questionnaires; and satisfaction with cosmetic outcome was measured by verbal response at 3 months. The two groups were similar in age, gender, type of operation, and final pathologic diagnosis. Although the mean operating time was significantly longer with the robotic technique than with open surgery, there were no between-group differences in postoperative pain or duration of hospital stay. No patient in either group experienced any major postoperative complication. Postoperative discomfort in the neck and swallowing disturbances were significantly more frequent in the open group than in the robot group, both at 1 week and at 3 months after surgery. However, there was no significant between-group difference in subjective voice parameters. At 3 months, the mean cosmetic satisfaction score was significantly higher in the robotic than in the open group. Although postoperative pain levels and complications were comparable in the two groups, conventional open thyroidectomy requires a shorter operative time. The robotic technique, however, offers several distinct advantages including very good to excellent cosmetic results, reduced postoperative neck discomfort, and fewer adverse swallowing symptoms.

The clinical behaviors and treatment outcomes of thyroid carcinomas in patients with Graves' disease is a matter of controversy. This study aimed to identify the clinicopathologic features, treatment outcome, and the indicators for predicting recurrence, and to suggest the optimal extent of surgery in these patients. We retrospectively analyzed data of 58 patients who underwent surgical treatment for differentiated thyroid cancer and concurrent Graves' disease. The follow-up period ranged from 23 to 260 months (mean+/-standard deviation, 116.8+/-54.0). In our series, the mean age was 40.8+/-12.7 yr (range, 15-70), with a male-to-female ratio of 1: 6.25. The mean tumor size was 13+/-9 mm (range, 3-62). The surgical methods included 19 cases of total thyroidectomy, 38 cases of subtotal thyroidectomy, and 1 case of completion total thyroidectomy. Locoregional recurrence occurred in four patients (6.9%). The 10-yr overall survival and disease-free survival of patients were 95.8% and 91.1%, respectively. Age over 45 yr (p=0.031), tumor size over 10 mm (p=0.049), multiplicity (p=0.007), extracapsular invasion (p=0.021), and clinical cancer (p=0.035) were significantly more prevalent in patients with locoregional recurrence than in those without recurrence. We recommend that Graves' disease patients should undergo regular ultrasonography screening for early detection of thyroid carcinoma. We also suggest that the choice of extent of surgery should depend on the diagnostic timing (clinical or incidental) and factors for predicting recurrence.

Objectives: Cyclooxygenase (COX)-2, which is the inducible form of the COX enzyme for prostaglandin synthesis and a key mediator of epithelial cell growth, has been shown to be up-regulated in gastrointestinal cancers. Additionally, regular intake of other non-steroidal anti-inflammatory drugs (NSAID) is known to decrease the incidence of these cancers. Therefore, the goals of the present study were to determine the possible involvement of COX-2 in human thyroid diseases. Methods: We used immunohistochemical staining and Western blot analysis to characterize the expression of COX-2 proteins in thyroid tissues from 64 patients with thyroiditis, benign tumors, and malignant tumors with or without metastasis. Immunoreactivity scores were calculated by multiplication of the determined grades. Results: COX-2 proteins were not expressed in normal thyroid tissues. However, each type of tumor tissue showed intense bands of COX-2 protein expression in Western blot analyses, and the immunoreactivity scores were 7.67±1.17 (SD) for thyroiditis, 7.87±0.9 for benign tumors, 7.53±1.53 for follicular cancer, 7.63±1.11 for papillary cancer without metastasis, and 7.17±1.55 for papillary cancer with metastasis. No significant differences were found in the levels of COX-2 expression between different tumor tissue types. Conclusion: No significant correlations were observed between clinical and/or pathological characteristics of thyroid tumors and the intensity of COX-2 protein expression. In addition, we found no difference in COX-2 protein expression between thyroiditis and thyroid tumors. Thus, up-regulation of COX-2 protein synthesis in human thyroid diseases does not appear to be of clinical significance.

Midkine is a multifunctional, heparin-binding growth factor that is frequently expressed in patients with malignancies but is undetectable in healthy adults. In various cancers, high expression of midkine is associated with aggressive clinical behavior and a poor prognosis. In the present study, we investigated the expression of midkine in papillary thyroid carcinoma (PTC) and assessed its association with a BRAFV600E mutation and the clinicopathological parameters. We determined the presence of a BRAFV600E mutation in 79 cases of PTC and examined the effects of the BRAFV600E mutation on midkine expression in primary thyrocytes. In addition, we evaluated the association between midkine expression and various clinicopathological parameters. We found that midkine is more frequently expressed in BRAFV600E PTC (68.3%) than in BRAF wild-type PTC (18.8%). BRAFV600E transduction could up-regulate midkine expression in primary thyrocytes. Moreover, midkine expression was associated with multiple lymph node (≥5) metastases in BRAFV600E PTC. In conclusion, our results suggest that midkine expression could be a clinically useful marker in predicting the presence of multiple lymph node metastases in BRAFV600E PTC.

Objectives: We evaluated the utility of the VE1 antibody that can detect a mutant protein resulting from the BRAF V600E mutation as a diagnostic tool for thyroid fine-needle aspiration cytology (FNAC). Methods: We performed VE1 immunocytochemistry on 202 FNAC specimens from surgically confirmed thyroid nodules. The results were compared with the molecular analyses of the BRAF mutation in these specimens matched with their corresponding histology. Results: Diagnoses of FNAC specimens included benign (9.4%), atypia of undetermined significance/follicular lesion of undetermined significance (11.4%), follicular neoplasm/suspicious for follicular neoplasm (2.0%), suspicious for malignancy (9.4%), and malignancy (65.8%). VE1 immunostaining was positive in 71.3% of FNAC specimens. The overall sensitivity of the VE1 antibody was 88.8%, specificity was 71.2%, positive predictive value was 88.2%, negative predictive value was 72.4%, and diagnostic accuracy was 83.7%. Conclusions: VE1 immunocytochemistry in thyroid FNAC as a screening test for BRAF mutations is highly specific for malignant category cases but can be suboptimal due to its high false-positive rate for the nonmalignant cases.

Purpose: Breast cancers in the early phase frequently undergo distant metastasis and survival of patients is greatly dependent on distant metastasis. The occurrence of micrometastasis has been suggested to relate with prognostic features of breast cancer, such as lymph node metastasis and the presence of vascular invasion. The aim of this study was to examine the presence of keratin-19 mRNA of epithelial tumors in bone marrow aspirates obtained from breast cancer patients and its possible correlation with tumor staging and disease-free survival. Methods: Bone marrow samples were obtained from 59 breast cancer patients at the time of surgery. We separated the mononuclear fraction from the samples and carried out nested reverse transcriptase polymerase chain reaction (RT-PCR) for the detection of keratin-19 mRNA with two different pairs of primers. After operation, the patients were followed up at 3month intervals. We studied the possible correlation of the detection of keratin-19 mRNA with tumor size, nodal involvement, stage and recurrence rate. Results: Bone marrow micrometastasis was detected by nested RT-PCR for keratin-19 mRNA in one of four patients with ductal carcinoma in situ (DCIS), 13 of 30 patients with T1, 11 of 20 patients with T2 and all four patients with T3 lesion. Recurrence was observed in seven cases and all of them were positive for micrometastasis in bone marrow. Conclusion: The method of nested RT-PCR to detect the presence of keratin-19 mRNA in bone marrow from patients with breast cancer is sensitive and reliable. Moreover, early recurrence was observed in the patients with the tumor mRNA detected in bone marrow. Additional studies with larger numbers of patients and longer follow-up are desirable.

Purpose: Papillary thyroid cancer (PTC) is the most frequent subtype among thyroid cancers. B-type Raf kinase (BRAF) mutation can be found in...

We investigated whether (131)I whole-body scintigraphy could predict functional changes in salivary glands after radioiodine therapy.We evaluated 90 patients who received initial high-dose (≥3.7 GBq) radioiodine therapy after total thyroidectomy. All patients underwent diagnostic (DWS) and post-ablation (TWS) (131)I whole-body scintigraphy. Visual assessment of salivary radioiodine retention on DWS and TWS was used to divide the patients into two types of groups: a DWS+ or DWS- group and a TWS+ or TWS- group. Salivary gland scintigraphy was also performed before DWS and at the first follow-up visit. Peak uptake and %washout were calculated in ROIs of each gland. Functional changes (Δuptake or Δwashout) of salivary glands after radioiodine therapy were compared between the two groups.Both peak uptake and the %washout of the parotid glands were significantly lower after radioiodine therapy (all p values0.001), whereas only the %washout were significantly reduced in the submandibular glands (all p values0.05). For the parotid glands, the TWS+ group showed larger Δuptake and Δwashout after radioiodine therapy than did the TWS- group (all p values0.01). In contrast, the Δuptake and Δwashout of the submandibular glands did not significantly differ between the TWS+ and TWS- groups (all p values0.05). Likewise, no differences in Δuptake or Δwashout were apparent between the DWS+ and DWS- groups in either the parotid or submandibular glands (all p values0.05).Salivary gland radioiodine retention on post-ablation (131)I scintigraphy is a good predictor of functional impairment of the parotid glands after high-dose radioiodine therapy.

Vascular endothelial growth factor (VEGF) is an angiogenic factor, and its expression has been rarely demonstrated in thyroid tumors. We, therefore, investigated the expression of VEGF messenger RNA (mRNA) and production of VEGF protein in cell lines from human primary and metastatic follicular (FTC-133, FTC-236, and FTC-238), papillary (TPC-1), Hurthle cell (XTC-1), and medullary thyroid cancers (MTC-1.1 and MTC-2.2), and in human thyroid tissues (papillary, follicular, medullary, and Hurthle cell cancers, follicular adenomas, and Graves' thyroid tissue) by Northern blot, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA) studies. All thyroid cell lines expressed a 4.2-kilobase VEGF mRNA. The VEGF mRNA levels were higher in the thyroid cancer cell lines than in primary cultures of normal thyroid cells, and higher in thyroid cancers of follicular than those of parafollicular cell origin. The VEGF mRNA levels were similar in primary and metastatic thyroid tumors. Immunohistochemical staining and Northern blot analysis of the cell lines correlated positively, thus thyroid cancer cell lines stained more intensely than normal thyroid cells and follicular tumor cells more intensely than parafollicular tumor cells. Again, no difference was noted in VEGF staining between primary and metastatic thyroid tumors. Deparafinized sections of papillary, follicular, and Hurthle cell cancers also stained much stronger than those of medullary thyroid cancers, benign, or hyperplastic (Graves' disease) thyroid tissue. Thyroid cancer cell lines (XTC-1 > TPC-1 > FTC-133 > MTC-1.1) also secreted more VEGF protein as measured by ELISA than did normal thyroid cells. VEGF secretion of cell lines derived from primary and metastatic thyroid tumors were similar. VEGF mRNA is therefore expressed, and VEGF protein is secreted by normal, hyperplastic, and neoplastic thyroid tissues. The higher levels of VEGF expression in differentiated thyroid cancers of follicular cell origin suggests a role in oncogenesis.

Approximately 5% of non-medullary thyroid cancer (NMTC) diagnoses are made against a background of familial predisposition and, in such instances, the disease is termed familial non-medullary thyroid cancer (FNMTC). To date, neither genetic alterations causing FNMTC nor genes predisposing to the condition have been described. The objective of the present study was to evaluate loss of heterozygosity (LOH) at the four known susceptibility loci (fPTC/PRN, NMTC1, MNG1, and TCO1) and to compare the mutation rates of RAS/RAF genes in patients with FNMTC and sporadic NMTC.Fourteen FNMTCs in patients from seven families were analyzed in terms of involvement of the four susceptibility loci, and 63 thyroid cancer tumors [FNMTC (29) and NMTC (34)] were evaluated for the occurrence of mutations in BRAF, and H-, N-, and K-RAS, using polymerase chain reaction, single-strand conformation polymorphism (PCR-SSCP) analysis, and direct sequencing.Only five (35.7%) tumors showed loss of LOH at the three susceptibility loci (NMTC1, MNG1, or TCO1). These allelic losses did not show a specific pattern. Four (13.8%) FNMTCs and one (2.9%) NMTC had H-RAS (codon 12) mutations. Further, mutation of BRAF V600E was observed in 12 (41.4%) FNMTCs and 29 (85.3%) NMTCs.Four known susceptibility loci are infrequently involved in FNMTC. Although further studies are needed, the present findings additionally suggest that somatic activation of oncogenes via BRAF and RAS mutation plays a role in FNMTC tumorigenesis.

Few reports have examined the use of recombinant human thyroid-stimulating hormone (rhTSH) for ablation of postsurgical thyroid remnants after low-dose radioactive iodine (RI) therapy, compared with conventional thyroid hormone withdrawal. We investigated whether patient preparation using rhTSH was comparable to conventional thyroid hormone withdrawal with respect to efficacy of postsurgical remnant ablation in low-risk patients receiving a 30 mCi RI. In addition, we also evaluated the impact of rhTSH (rhTSH vs. conventional thyroid hormone withdrawal) on quality of life (QoL) of thyroid cancer patients undergoing RI ablation.This study included three groups of patients, enrolled consecutively. From February 2006 to March 2007, 291 patients were enrolled and randomized, after total thyroidectomy: (1) withdrawal of levothyroxine (LT4) for 4 weeks (T4-WD Group, n = 89), (2) withdrawal of LT4 for 4 weeks plus 2 weeks on and then 2 weeks off liothyronine (LT3) (T3-WD Group, n = 133), and (3) rhTSH administration (rhTSH Group, n = 69). QoL was determined at the time of ablation.Patients in the three groups did not differ significantly in baseline characteristics or tumor, node and metastasis (TNM) staging. In all study groups, serum TSH levels showed very good stimulation (mean, 82.24 +/- 18.21 mU/L), without significant between-group differences (p = 0.5213). Follow-up examinations were performed 12 months after ablation to assess ablation outcome in each group by 131 whole body scans (WBSs), serum thyroglobulin measurement after TSH stimulation, and neck ultrasonography. The successful ablation rate was 91.0% in T4-WD Group, 91.7% in T3-WD Group, and 91.3% in rhTSH Group, without significant between-preparation differences (p = 0.2061). QoL was better preserved in rhTSH Group than in T4-WD and T3-WD Groups (p0.0001). However, there was no QoL difference at the time of ablation between T4-WD and T3-WD Groups.Our study indicates that use of rhTSH preserves QoL in patients undergoing RI ablation and affords an ablation success rate comparable to that seen after thyroid hormone withdrawal. Notably, ablation preparation using withdrawal of LT3 for 2 weeks did not prevent development of profound hypothyroidism, as also occurred when LT4 alone was withdrawn for 4 weeks.

Primary aldosteronism (PA) is a frequent cause of secondary hypertension and is amenable to surgical intervention when it is caused by aldosterone-producing adenoma (APA). Many patients, however, continue to require antihypertensive medications to control their blood pressure after adrenalectomy. The aim of this study was to determine the preoperative factors that predict clinical outcomes after adrenalectomy in patients with APA. We studied 27 patients (mean age 45+/-4 yr) who had APA and underwent unilateral adrenalectomy between December 1995 and September 2008 at our institution. Clinical and biochemical data were evaluated at baseline and after a mean follow-up of 51.8+/-47.0 months (range, 6-159). At the end of the follow-up, 16 patients (59.3%) were considered to experience "complete resolution" without postoperative medications, whereas 7 patients (25.9%) "improved" with medications and 4 patients (14.8%) were "uncontrolled." Three factors (< or =2 antihypertensive medications [P=0.007], duration of hypertension

We investigate the current status of endoscopic thyroidectomy in Korea. A representative questionnaire was sent to 21 members of the Korean Association of Endocrine Surgeons who were thought to be performing endoscopic thyroidectomy. All the reply letters were collected and analyzed. The response rate was 95%. A total of 1616 cases of endoscopic thyroidectomy were performed from the year 1998 to the year 2005. The patients included 71 men and 1545 women, with a mean age of 36.17 years. The mean operation time was 124.18 minutes and overall length of hospital stay was 4.31 days. Thyroid lobectomy and nodular hyperplasia were the most common procedures and prominent pathologic findings. Axillary approach was the most popular operative approach method. Gas insufflation and skin-lifting gasless method were used in 800 cases and 816 cases, respectively. Postoperative complication rate was 14.2%. Skin paresthesia was the most common complication. Conversion rate to conventional thyroidectomy was 2.2%. Korean experiences show that endoscopic thyroidectomy is a technically safe and feasible procedure. It is considered to be an important surgical tool that can be further progressed and that also has an excellent potential in a management of thyroid neoplasm.

The chronic use of immunosuppressive therapy in transplant recipients increases the long-term risk for carcinoma. However, there is insufficient knowledge regarding the incidence and biological behavior of papillary thyroid carcinomas (PTC) in renal allograft recipients. In the present study we examined the incidence and biological behavior of PTCs among 1739 patients transplanted between January 1986 and December 1999 who had been followed for a mean period of 137 months (range, 84-238 months). During the follow-up, 129 (7.4%) recipients were identified to display posttransplantation malignancies, including 12 (0.7%) with PTCs. The 6 male and 6 female patients had a mean age of 41 years (range, 23-57 years). Nine cases (incidentalomas) were diagnosed based on ultrasonographic (US) screening. Eight of those 9 were TNM stage I, 2 of the 3 clinical carcinomas were TNM stage IVa. During a mean follow-up of 94 months (range, 18-159 months), 2 (16.7%) PTC patients developed locoregional recurrence, but no patients showed distant metastases. These data showed that recipients had a higher incidence of PTC compared with the general Korean population (0.7% vs 0.02%). Posttransplantation PTC tended to show no difference in gender distribution, and was often associated with aggressive lymphatic metastasis. However, most incidentalomas showed favorable treatment outcomes. In conclusion, routine surveillance of the thyroid gland using US screening is recommended to ensure early detection, treatment, and favorable prognosis of PTC.

Papillary thyroid carcinoma (PTC) patients show a high rate of cervical lymphatic metastasis. However, there are no universal binding guidelines for the extent of lateral cervical lymph node dissection (LND) in such cases. In particular, the need for LND above the spinal accessory nerve (SAN) remains controversial. The present study examined whether level IIb lymph node (LN) dissection is always necessary in PTC patients with lateral cervical LN metastasis. The study prospectively examined 167 PTC patients with lateral cervical LN metastasis who underwent modified radical neck dissection (MRND) in our institution from November 2005 to March 2007. The MRND was bilateral in 24 cases. All patients underwent level II, III, IV, and V LND. Levels IIa and IIb LNs were individually dissected in all cases. All LND was performed using strict leveling criteria by a single operating team. The patterns of lymphatic metastasis and potential risk factors for level IIb LN involvement were evaluated. The most common site of metastasis was level III (80.6% of cases), followed by level IV (74.9%) and II (55.5%). The metastasis rates in level IIa and IIb were 55.5% and 6.8%, respectively; all level IIb LN metastasis was accompanied by level IIa metastasis (p = 0.001). In addition, level IIb LN metastasis was found to be associated with the aggressiveness of lymphatic metastasis (i.e., the total number of metastatic LNs) (p