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1.  Hybrid-type endoscopic thyroidectomy (HET: Tori’s method) for differentiated thyroid carcinoma including invasion to the trachea 
Surgical Endoscopy  2013;28(3):902-909.
Background
Endoscopic thyroidectomy (ET) or robotic thyroidectomy is yet to be applied to thyroid carcinoma invasive to the trachea and to wide lymph node node metastasis. On the other hand, small-incision thyroidectomy lacks sufficient working space and clear vision. The author has newly developed hybrid-type endoscopic thyroidectomy (HET) to overcome these problems.
Methods
From March 2011 to February 2012, HET was performed for 85 patients. Clinicopathologic characteristics were analyzed. To evaluate the superiority of HET for malignancy representatively, conventional lobectomy with central compartment node dissection (CCND) performed 1 year previously was compared with HET. In lobectomy and node dissection, a single skin incision (1.5 cm) is made above the clavicle, with a port incision (5 mm) made 3 cm below the clavicle. Then CCND is performed directly through the incision by lifting up the isthmus. To obtain sufficient working space for the lobectomy, the strap muscles are taped and pulled toward the head, then hung by the cradle. The thyroid lobe is retracted to the midline with a retractor, followed by isolation of the inferior laryngeal nerve and transection of the inferior thyroid vessels with the monitor of the scope. Lateral lymph nodes dissection can be performed at the same time, if necessary. In total thyroidectomy, the same procedure is performed at the opposite side. The scalpel can be used to shave through each incision in case of tracheal invasion.
Results
Of the 85 cases, 62 were malignant, involving papillary thyroid carcinoma (PTC), and 23 were benign. Total thyroidectomy was performed for 22 of the PTC cases and CCND for 49 of the cases. Shaving for tracheal invasion was performed for eight patients. No mortality, complications, recurrence, or metastasis was found 1–2 years after the operation. Compared with conventional thyroidectomy, HET was superior in blood loss, visual analog scale, and postoperative hospital stay.
Conclusion
The author’s method (Tori’s method) might be less invasive, cosmetically excellent, and moreover, safe and feasible for differentiated thyroid carcinoma including invasion to the trachea.
doi:10.1007/s00464-013-3245-4
PMCID: PMC3931932  PMID: 24263457
Endoscopic thyroidectomy; Thyroid cancer; Tracheal invasion; Hybrid-type operation; HET (Tori’s method)
2.  Aggressive Variants of Papillary Thyroid Microcarcinoma Are Associated with Extrathyroidal Spread and Lymph-Node Metastases: A Population-Level Analysis 
Thyroid  2013;23(10):1305-1311.
Background
Tall cell variant (TCV) and diffuse sclerosing variant (DSV) of papillary thyroid cancer are aggressive subtypes, for which tumors ≤1 cm have not been exclusively studied.
Methods
The SEER database (1988–2009) was used to compare characteristics of TCV ≤1 cm (mTCV) and DSV ≤1 cm (mDSV) with classic papillary thyroid microcarcinoma (mPTC). Survival was analyzed with the Kaplan–Meier method and log-rank test, and risk factors for nodal metastases with chi-square analysis and binary logistic regression.
Results
There were 97 mTCV, 90 mDSV, and 18,260 mPTC patients. mTCV incidence increased by 79.9% (p=0.153) over the study period, while mDSV incidence decreased by 10.3% (p=0.315). Compared to classic mPTC, mTCV tended to be larger on average (7.1 mm vs. 5.3 mm, p<0.001), with higher rates of multifocality (47.2% vs. 34.0% respectively, p=0.018) and lymph-node examination (63.9% vs. 39.2% respectively, p<0.001), while in mDSV, nodal metastases were more frequent (57.1% vs. 33.1% respectively, p=0.007). Both aggressive variants had higher rates of extrathyroidal extension (27.8% mTCV vs. 13.3% mDSV vs. 6.1% mPTC, p<0.001). Aggressive variants also received radioactive iodine more frequently (39.2% mTCV vs. 40.0% mDSV vs. 29.1% mPTC, p<0.001). However, they were not statistically more likely to receive thyroidectomy over lobectomy compared to classic mPTC. There were no significant differences in overall and disease-specific survival between the histologies. In mTCV, after adjustment, extrathyroidal extension was independently associated with size >7 mm (odds ratio (OR) 4.4 [CI 1.5–13.6]) and nodal metastasis with multifocality (OR 5.4 [CI 1.3–23.4]) and extrathyroidal extension (OR 5.8 [CI 1.3–25.4]). No statistically significant predictors of extrathyroidal extension or nodal metastasis in mDSV were observed.
Conclusions
Aggressive variants of mPTC tend to exhibit more aggressive pathologic characteristics than classic mPTC, but survival appears to be similar. Treatment with total thyroidectomy and central lymphadenectomy may be warranted if the diagnosis can be made pre- or intraoperatively.
doi:10.1089/thy.2012.0563
PMCID: PMC3783926  PMID: 23600998
3.  Predictors of thyroid tumor aggressiveness. 
Western Journal of Medicine  1996;165(3):131-138.
Thyroid cancers are classified as papillary, follicular (including Hürthle cell), medullary, and anaplastic. Papillary cancers account for about 82% of all thyroid cancers, follicular about 8%, medullary about 6%, Hürthle cell 3%, and anaplastic 1%. The prognosis of patients with papillary thyroid cancer is usually favorable, whereas most patients with anaplastic cancer die within 6 months. The behavior of papillary thyroid cancer can be predicted by patient age, sex, tumor size, local invasion, angioinvasion, lymph node metastases, distant metastases, as well as tumor differentiation and ability to take up radioactive iodine. Thus, older male patients with larger or invasive tumors, with angioinvasion, lymph node or distant metastases, and with tumors that do not take up radioactive iodine or cannot be completely surgically resected have a worse prognosis. Anaploid tumors, tumors with a low adenylate cyclase response to thyroid-stimulating hormone tumors, tumors that are ras-and gsp-positive, and tumors that are p21-positive and p53-positive also appear to behave in a more aggressive manner. In contrast, lymphocytic thyroiditis associated with papillary thyroid cancer predicts fewer recurrences and an improved survival. The treatment of patients with papillary thyroid cancer is controversial primarily because most patients do well with relatively minimal therapy, and there are no prospective studies concerning the merits of various treatments. Much of the controversy relates to the safety of thyroidectomy versus other procedures and, to a lesser extent, when to do a central or modified radical neck dissection. The rate of recurrence is lower, and the death rate may also be lower when patients are treated initially by total thyroidectomy. The rationale for total thyroidectomy is that it enables one to use radioactive iodine to detect and treat local and distant metastases, and it makes serum thyroglobulin determination more sensitive for detecting persistent disease. Total thyroidectomy should be associated with a permanent complication rate of less than 2%. Thyroid-stimulating hormone suppression therapy is recommended by most experts for patients with differentiated thyroid cancer and supported by most clinical and laboratory studies. Central and lateral node selection is recommended for patients with palpable lymphadenopathy.
Images
PMCID: PMC1303719  PMID: 8909165
4.  Pattern, predictors, and recurrence of cervical lymph node metastases in papillary thyroid cancer 
Contemporary Oncology  2013;17(6):504-509.
Aim of the study
This study investigated the pattern, predictors, and recurrence of node metastasis in papillary thyroid cancer patients.
Material and methods
One hundred and 65 papillary thyroid cancer (PTC) patients who underwent total thyroidectomy and cervical lymph node (LN) dissection (LND), in which more than 12 lymph nodes were dissected, were examined. The nodes were classified from levels I to VI. Final pathologic diagnosis of positive lymph node metastases in the differential node levels was determined.
Results
Cervical metastases of PTC were most commonly encountered in level VI, followed by levels III and IV, and then levels II and V. Metastases in level I seldom occurred. Skip metastases occurred in nine patients. Univariate analysis suggested that multifocality and extracapsular invasion were associated with LN metastases. The metastatic ratio for micro PTC and local canceration derived from benign lesions and encapsulation was low. Multivariate analysis showed that LN metastases were closely related to invasion of the thyroid capsule and primary PTC. Standardized estimation showed that the encapsulating pattern had the greatest impact on developing cervical LN metastases. Lymph node recurrence was observed in 11 patients.
Conclusions
The metastatic pattern of PTC assists in delineating the extent of selective LND. Routine bilateral central node dissection at the time of thyroidectomy is recommended. Comprehensive selective LND is recommended in multifocal PTC and with capsular invasion.
doi:10.5114/wo.2013.38910
PMCID: PMC3934041  PMID: 24592137
papillary thyroid cancer (PTC); cervical lymph node metastases; lymph node dissection (LND)
5.  Lymph Node Ratio Predicts Recurrence in Papillary Thyroid Cancer 
The Oncologist  2013;18(2):157-162.
This study aims to determine how the lymph node ratio may be used to predict the likelihood of recurrence for patients with papillary thyroid cancer.
Learning Objectives
Explain how lymph node ratio can be used to predict disease recurrence for papillary thyroid cancer.Cite the threshold total and central lymph node ratios that best predict recurrence.Describe ways in which lymph node ratio can be useful in guiding postoperative follow-up.
Background.
Lymph node metastasis occurs in 20%–50% of patients presenting for initial treatment of papillary thyroid cancer (PTC). The significance of lymph node metastases remains controversial, and the aim of this study is to determine how the lymph node ratio (LNR) may predict the likelihood of disease recurrence.
Methods.
We conducted a retrospective review of patients undergoing total thyroidectomy for PTC at our institution from 2005 to 2010. A total LNR (positive nodes to total nodes) and central lymph node ratio (cLNR) was calculated. Regression was used to determine a threshold LNR that best predicted recurrence. Multivariate logistic regression then determined the influence of LNR on recurrence while accounting for other known predictors of recurrence. Kaplan-Meier analysis and the log-rank test were used to compare differences in disease-free survival.
Results.
Of the 217 patients undergoing total thyroidectomy for PTC, 69 patients had concomitant neck dissections. Sixteen (23.2%) patients developed disease recurrence. When disease-free survival functions were compared, we found that patients with a total LNR ≥0.7 (p < .01) or a cLNR ≥0.86 (p = .04) had significantly worse disease-free survival rates than patients with ratios below these threshold values. Considering other known predictors of recurrence, we found that LNR was significantly associated with recurrence (odds ratio: 19.5, 95% confidence interval: 4.1–22.9; p < .01).
Conclusions.
Elevated total LNR and cLNR are strongly associated with recurrence of PTC after initial operation. LNR in PTC is a tool that can be used to determine the likelihood of the patient developing recurrent disease and inform postoperative follow-up.
doi:10.1634/theoncologist.2012-0240
PMCID: PMC3579599  PMID: 23345543
Thyroid cancer; Recurrence; Lymph node metastases; Quality measure; Lymph node ratio
6.  Total thyroidectomy without prophylactic central neck dissection in clinically node-negative papillary thyroid cancer: is it an adequate treatment? 
Background
Cervical lymph node metastases in papillary thyroid cancer are common. Although central neck dissection is indicated in clinically nodal-positive disease, it remains controversial in patients with no clinical evidence of nodal metastasis. The aim of this retrospective study was to determine the outcomes of clinically lymph node-negative patients with papillary thyroid cancer who underwent total thyroidectomy without a central neck dissection, in order to determine the rates of recurrence and reoperation in these patients compared with a group of patients submitted to total thyroidectomy with central neck dissection.
Methods
Two-hundred and eighty-five patients undergoing total thyroidectomy with preoperative diagnosis of papillary thyroid cancer, in the absence of suspicious nodes, were divided in two groups: those who underwent a thyroidectomy only (group A; n = 220) and those who also received a central neck dissection (group B; n = 65).
Results
Six cases (2.1%) of nodal recurrence were observed: 4 in group A and 2 in group B. Tumor histology was associated with risk of recurrence: Hürthle cell-variant and tall cell-variant carcinomas were associated with a high risk of recurrence. Multifocality and extrathyroidal invasion also presented a higher risk, while smaller tumors were at lower risk.
Conclusions
The role of prophylactic central lymph node dissection in the management of papillary thyroid cancer remains controversial. Total thyroidectomy appears to be an adequate treatment for clinically node-negative papillary thyroid cancer. Prophylactic central neck dissection could be considered for the more appropriate selection of patients for radioiodine treatment and should be reserved for high-risk patients only. No clinical or pathological factors are able to predict with any certainty the presence of nodal metastasis. In our experience, tumor size, some histological types, multifocality, and locoregional infiltration are related to an increased risk of recurrence. The potential use of molecular markers will hopefully offer a further strategy to stratify the risk of recurrence in patients with papillary thyroid cancer and allow a more tailored approach to offer prophylactic central neck dissection to patients with the greatest benefit. Multi-institutional larger studies with longer follow-up periods are necessary to draw definitive conclusions.
doi:10.1186/1477-7819-12-152
PMCID: PMC4032348  PMID: 24885654
Papillary thyroid carcinoma; Central neck dissection; Total thyroidectomy
7.  Pattern of regional metastases and prognostic factors in differentiated thyroid carcinoma 
Summary
The meaning of nodal metastases in well-differentiated thyroid carcinoma is controversial. The Authors analyse the impact of lymphatic spread reviewing 1503 cases of well-differentiated thyroid carcinoma treated at the National Cancer Institute of Rome between 1988 and 2005, in order to detect significant prognostic factors through multivariate analysis. Overall, 462 cases of locally advanced well-differentiated thyroid carcinoma, were considered. A multivariate analysis of a subgroup, comprising 97 N+ consecutive cases of well-differentiated thyroid carcinoma, previously untreated, was performed to study prognostic factors for local (N+) and distant (M+) metastasis in well-differentiated thyroid carcinoma. Of the 97 cases, 88 were submitted to surgery for a large well-differentiated thyroid carcinoma, 9 for occult differentiated thyroid carcinoma. After surgery, 12 patients were lost to follow-up, 8 resulted pathologically negative, therefore only 77 cases of pN1 well-differentiated thyroid carcinoma were studied. Considering all cases of well-differentiated thyroid carcinoma, 10-year-overall survival was 58.7% for locally advanced well-differentiated thyroid carcinoma, compared to 94.8% in low stage cases. Neck dissection, margin infiltration and extra-capsular spread were significant prognostic factors. The Authors present a retrospective study of 77 patients with primary differentiated thyroid carcinoma, submitted to thyroidectomy and neck dissection aimed at analysing distribution of nodal metastases according to Robbins’ levels classification and defining their prognostic value. All N1b cases, retrospectively reviewed (n. 77), presented clinical and histological evidence of neck nodes metastases from differentiated thyroid carcinoma; histological reports indicated tumour localisation and topographical distribution of metastases; papillary carcinoma was the most common type (72 cases), followed by follicular carcinoma (5 cases). Surgical treatment always comprised total thyroidectomy and 6th level dissection. Overall 52 cases were submitted to monolateral neck dissection, 25 to bilateral neck dissection. Treatment of the lateral neck was postero-lateral neck dissection (n. 53), selective lateral neck dissection (n. 20), modified radical and radical (n. 29). Cervical level IV was the most frequently involved (52%), extra-capsular spread of metastases was identified in 22% of the cases. Statistically significant prognostic factors for distant metastases and recurrence on the neck were follicular carcinoma (p < 0.01) and extra-capsular spread (p < 0.001). Age, pT, sex, number of positive nodal metastases, T-extension and the number of nodal positive levels were not significant. In the Authors’ experience, histological grade of differentiation, wide tumour excision and neck dissection, in cases of N1b well-differentiated thyroid carcinoma, without residual disease (R1, R2), in the central and lateral neck, are determinant prognostic factors. Extracapsular spread in particular, was found to be a highly predictive factor either of distant metastasis or regional recurrence.
PMCID: PMC2868202  PMID: 20463835
Thyroid carcinoma; Nodal metastases; Extra-capsular spread
8.  Impact of Routine Unilateral Central Neck Dissection on Preablative and Postablative Stimulated Thyroglobulin Levels after Total Thyroidectomy in Papillary Thyroid Carcinoma 
Annals of Surgical Oncology  2011;19(1):60-67.
Background
Prophylactic central neck dissection (CND) remains controversial in papillary thyroid carcinoma (PTC). Because postsurgical stimulated thyroglobulin (sTg) level is a good surrogate for recurrence, the study aimed to evaluate the impact of prophylactic CND on preablative and postablative sTg levels after total thyroidectomy.
Methods
Of the 185 patients retrospectively analyzed, 82 (44.3%) underwent a total thyroidectomy and prophylactic CND (CND-positive group) while 103 (55.7%) underwent total thyroidectomy only (CND-negative group). All patients had no preoperative or intraoperative evidence of lymph node metastases. Clinicopathological characteristics, postoperative outcomes, and preablative and postablative sTg levels were compared between the two groups. Preablative sTg level was taken at the time of radioiodine ablation, while postablative sTg level was taken 6 months after ablation. A multivariable analysis was conducted to identify factors for preablative athyroglobulinemia (sTg < 0.5 μg/L).
Results
Relative to the CND-negative group, the CND-positive group had larger tumors (15 mm vs. 10 mm, P < 0.005), more extrathyroidal extension (26.8% vs. 14.6%, P < 0.003), more tumor, node, metastasis system stage III disease (32.9% vs. 9.7%, P < 0.001), and more temporary hypoparathyroidism (18.3% vs. 8.7%, P = 0.017). Fourteen patients (17.1%) in the CND-positive group were upstaged from stages I/II to III as a result of prophylactic CND. The CND-positive group experienced lower median preablative sTg (<0.5 μg/L vs. 6.7 μg/L, P < 0.001) and a higher rate of preablative athyroglobulinemia (51.2% vs. 22.3%, P = 0.024), but these differences were not observed 6 months after ablation. Prophylactic CND was the only independent factor for preablative athyroglobulinemia.
Conclusions
Although performing prophylactic CND in total thyroidectomy may offer a more complete initial tumor resection than total thyroidectomy alone by minimizing any residual microscopic disease, such a difference becomes less noticeable 6 months after ablation.
doi:10.1245/s10434-011-1833-x
PMCID: PMC3251780  PMID: 21681379
9.  Video-assisted thyroidectomy: lessons learned after more than one decade 
Summary
In selected patients, video-assisted thyroidectomy can be considered a safe and validated procedure offering significant advantages over conventional surgery, with no additional morbidity. Aim of this study was to evaluate the results obtained in a series of patients selected for video-assisted thyroidectomy over a 10-years period. All patients who underwent video-assisted thyroidectomy from June 1998 to June 2009 were considered. The eligibility criteria for video-assisted thyroidectomy are: thyroid nodules ≤ 35 mm; estimated thyroid volume < 30 ml; no previous conventional neck surgery and/or radiation therapy; small, low-risk papillary thyroid carcinoma. A total of 1363 video-assisted thyroidectomies were attempted in the time period considered. Conversion to the conventional procedure was necessary in 7 cases. Thyroid lobectomy was successfully performed in 157 cases, total thyroidectomy in 1175, and completion thyroidectomy in 24. In 126 patients, the central neck nodes were removed through the same access. Simultaneous video-assisted parathyroidectomy, for a parathyroid adenoma, was performed in 42 patients. Pathological studies showed benign disease in 986 cases, papillary thyroid carcinoma in 368 cases, C-cells hyperplasia in 1 case, and medullary microcarcinoma in 1 patients with RET germline mutation. Post-operative complications included 27 transient and 1 definitive recurrent laryngeal nerve palsy, 230 transient hypocalcemia, 10 definitive hypoparathyroidism, 4 postoperative hematoma and 5 wound infection.
PMCID: PMC2868209  PMID: 20463836
Thyroidectomy; Minimally invasive thyroidectomy; Endoscopic thyroidectomy
10.  Clinical characteristics and surgical resection of multifocal papillary thyroid carcinoma: 168 cases 
Purpose: To investigate clinical characteristics and surgical treatment of multifocal papillary thyroid carcinoma. Methods: A total of 648 patients diagnosed with papillary thyroid carcinoma were enrolled, 168 with multifocal papillary thyroid carcinoma. Clinicopathological factors including gender, age at diagnosis, family history of thyroid tumor, multiplicity and bilaterality of tumor, extra-thyroidal extension, lymph node involvement and other factors were statistically compared. Results: The incidence of multifocal papillary thyroid carcinoma was 25.9% and 117 presented with bilateral thyroid gland lesions. In multifocal group, patients had a higher ratio of male subjects, family history of thyroidal tumor, neck lymph node metastasis and extra-thyroidal extension by B-ultrasound. Solitary papillary thyroid carcinoma tended to be with a higher rate of benign goiters. In multifocal group, males with neck lymphadenectasis, ≥ 3 tumor masses or bilaterality of tumors tended to present with larger tumors, a higher incidence of neck lymph node metastasis and extra-thyroidal extension. 164 cases completed the follow-up, 5 died, 1 suspected with lung metastasis and still survived, 6 underwent repeated surgery due to lymph node recurrence at 3-41 months postoperatively and 2 surgically treated with recurrent gland tumor. Overall 1-, 2-, 5-, and 10-year survival rate was 98.2%, 97.4%, 96.5% and 96.5%, respectively. Conclusion: Multifocal papillary thyroid carcinoma is more malignant and highly differentiated than solitary lesions. Total thyroidectomy combined with neck dissection of central compartment could be utilized as standard treatment. Lateral nodular dissection should be considered for the patients with lymph node metastasis.
PMCID: PMC4307557  PMID: 25664110
Thyroid tumors; thyroidectomy; neck lymph node dissection; papillary carcinoma
11.  Clinical predictors of right upper paraesophageal lymph node metastasis from papillary thyroid carcinoma 
Background
Central and lateral lymph node metastases are quite common in patients with papillary thyroid carcinoma, and the predictors for those metastases have been well studied. Right upper paraesophageal lymph node metastasis has rarely been studied. The aim of this study was to identify the clinicopathological characteristics that may be risk factors for right upper paraesophageal lymph node metastasis in patients with papillary thyroid carcinoma.
Methods
This was a prospective observational study of 243 patients with papillary thyroid carcinoma (PTC) who underwent total thyroidectomy and comprehensive central lymph node dissection with or without lateral lymph node dissection between April 2008 and January 2010. The clinicopathologic findings from these patients were investigated and the patterns of lymph node metastasis were analyzed in the patients who had right upper paraesophageal lymph node disease.
Results
Of the 243 patients undergoing lymph node dissection, 14 had right upper paraesophageal lymph node metastases. Two of these patients had right upper paraesophageal lymph node metastasis only, without central compartment metastasis. Univariate analysis of clinicopathologic findings showed that right upper paraesophageal lymph node metastasis had significant association with larger primary tumors, multifocal tumors, extrathyroid extension, and lymphatic invasion (p <0.05 for each factor).
Conclusions
Although there were no independent predictors of right upper paraesophageal lymph node metastasis, it can be the only site of metastasis without other compartmental metastasis. Therefore, during surgery for patients with central or lateral lymph node metastases from PTC, it may be helpful to examine the right upper paraesophageal lymph nodes.
doi:10.1186/1477-7819-10-164
PMCID: PMC3490984  PMID: 22897890
Paraesophageal lymph node; Thyroid cancer; Papillary thyroid carcinoma
12.  Video-Assisted Thyroidectomy for Papillary Thyroid Carcinoma 
Journal of Oncology  2010;2010:148542.
Background. The results of video-assisted thyroidectomy (VAT) were evaluated in a large series of patients with papillary thyroid carcinoma (PTC), especially in terms of completeness of the surgical resection and short-to-medium term recurrence. Methods. The medical records of all patients who underwent video-assisted thyroidectomy for PTC between June 1998 and May 2009 were reviewed. Results. Three hundred fifty-nine patients were included. One hundred twenty-six patients underwent concomitant central neck node removal. Final histology showed 285 pT1, 26 pT2, and 48 pT3 PTC. Lymph node metastases were found in 27 cases. Follow-up was completed in 315 patients. Mean postoperative serum thyroglobulin level off levothyroxine was 5.4 ng/mL. Post operative ultrasonography showed no residual thyroid tissue in all the patients. Mean post-operative 131I uptake was 1.7%. One patient developed lateral neck recurrence. No other recurrence was observed.
doi:10.1155/2010/148542
PMCID: PMC2952809  PMID: 20953412
13.  Experience and analysis of Delphian lymph node metastasis in patients with papillary thyroid carcinoma 
Background
Recently, lymph node metastasis (LNM) has been regarded as an important factor influencing loco-regional recurrence and survival rate in papillary thyroid cancer (PTC) patients. The aims of this study were to investigate the detection rate and metastasis rate of the Delphian lymph node (DLN) and clinical patterns related to regional LNM, and to examine how DLN metastasis affects PTC treatment.
Methods
We reviewed the medical records of 413 patients with pathologically confirmed PTC from among 452 patients who underwent thyroid surgery between January 2010 and October 2010 in the Department of Endocrine Surgery at Kosin University Gospel Hospital in Busan, South Korea.
Results
Multivariate analyses revealed a significantly higher proportion of cases with lymphovascular invasion (56.6% vs. 12.5%, P <0.001), central neck node metastasis (88.6% vs. 34.5%, P <0.001) and lateral neck node metastasis (47.2% vs. 10.2%, P <0.005) among cases with DLN metastasis compared to those without. The negative predictive value (NPV) of DLN metastasis with regard to the presence of contralateral central LNM for cases with a tumor size 1 cm or smaller than 1 cm was found to be 93.3% (127/136).
Conclusion
When DLN metastasis is not detected in papillary thyroid microcarcinomas (PTMC), thyroid lobectomy on the affected side and ipsilateral central neck lymph node dissection should be sufficient. In addition, even in cases where lateral neck LNM is not detected on preoperative examination, if DLN metastasis is detected postoperatively, more careful attention should be paid to the lateral neck nodes during follow-up.
doi:10.1186/1477-7819-10-226
PMCID: PMC3542107  PMID: 23110552
Delphian lymph node; Papillary thyroid cancer; Central neck lymph node
14.  The pros and cons of prophylactic central neck dissection in papillary thyroid carcinoma 
Gland Surgery  2013;2(4):196-205.
Prophylactic central neck dissection (pCND) for management of papillary thyroid carcinoma (PTC) is controversial. Compared to many malignancies, PTC has a high overall survival but local recurrence due to lymph node metastases continue to present management challenges. Unlike lateral cervical nodal metastasis metastasis, central neck nodal metastasis are unable to be reliably detected clinically or radiologically at pre-operative assessment. Residual disease (recurrent or persistent) typically requires re-operative surgery in the central compartment, which carries a heightened risk of significant morbidity. These nodal groups can be accessed during the index thyroidectomy for PTC. Thus, pCND offers potential to reduce the rates of recurrence and the need for re-operative surgery in the central neck. This benefit needs to be balanced with the potential morbidity risk from pCND itself at the index resection. This review will discuss the advantages and disadvantages of pCND with regard to long-term outcomes and potential morbidity. The rationale of pCND will be discussed, along with the indications for ipsilateral and contralateral pCND, the role of re-operative surgery for recurrence and the use of selective versus routine pCND. Strategies to select higher risk patients for pCND with the use of molecular markers will be addressed, along with a discussion of quality of life (QoL) research in PTC.
doi:10.3978/j.issn.2227-684X.2013.10.05
PMCID: PMC4115751  PMID: 25083483
Lymph node; metastasis; prophylactic; elective; morbidity
15.  Risk factor analysis for central nodal metastasis in papillary thyroid carcinoma 
Oncology Letters  2014;9(1):103-107.
Lymph node involvement is associated with recurrence in papillary thyroid carcinoma (PTC). The central neck compartment (level VI) lymph nodes are at the greatest risk of metastases from PTC, but the role of central neck dissection (CND) remains controversial, particularly in PTC without clinical cervical lymph node metastasis (cN0). The present study aimed to identify risk factors of central cervical nodal metastasis and the safety of CND in patients with cN0 PTC. The current study retrospectively investigated 389 patients who had been followed up for 12.0–25.5 months after surgery, and were divided into positive or negative lymph node involvement groups according to the pathological results subsequent to this surgery. Univariate and multivariate analyses were used to study the risk factor of central node involvement. The mean tumor size was 0.71±0.35 cm (range, 0.1–2.0 cm). There was no significant difference in the rate of central lymph node involvement based on age (<45 or ≥45 years) or tumor focality (unifocal or multifocal). However, there were significant differences based on gender, extra-thyroid invasion and tumor size (P<0.05). The incidence of transient hypoparathyroidism and transient vocal cord paralysis following CND was 12.34 and 4.11%, respectively. No patient experienced permanent hypoparathyroidism or vocal cord paralysis. One patient (1/389; 0.23%) experienced disease recurrence during the follow-up. A larger tumor size and the male gender were significantly associated with the central nodal metastasis rate for cN0 PTC with a tumor size of <2.0 cm. CND for cN0 PTC patients was safe and the tumor-associated recurrence rate following CND plus total thyroidectomy was low. The present study suggests that CND should be conducted for male cN0 PTC patients with a larger tumor size (≥0.5 cm).
doi:10.3892/ol.2014.2667
PMCID: PMC4246692  PMID: 25435941
papillary thyroid carcinoma; central neck dissection; total thyroidectomy; hypoparathyroidism; vocal cord paralysis
16.  Prognosis of Patients with Papillary Thyroid Carcinoma Located in One Lobe Showing Lateral Node Metastasis in the Contralateral but Not Ipsilateral Compartment 
Journal of Thyroid Research  2011;2012:953603.
Papillary thyroid carcinoma (PTC) frequently metastasizes to the lymph node in lateral compartment, which can often be detected on preoperative ultrasonography (N1b). However, PTC located in one lobe showing contralateral but not ipsilateral N1b is not common. We analyzed the clinicopathological features and prognosis of 13 patients with PTC limited in one lobe showing contralateral but not ipsilateral N1b. Sizes of the primary lesions ranged from 0.8 cm to 3.0 cm and only 2 tumors showed extrathyroid extension. Metastatic lateral node measured from 0.6 to 3.1 cm. Ten patients showed pathological central node metastasis and 5 had minute PTC lesions in the contralateral lobe. However, 3 patients did not show either of these. None of the patients have developed carcinoma recurrence or died of carcinoma to date. Taken together, PTC located in one lobe with contralateral but not ipsilateral N1b is rare and generally shows an indolent behavior. Although most patients had central node metastasis and/or minute PTC lesions in the contralateral lobe, it is also possible for carcinoma cells to metastasize directly from primary lesions to the contralateral lateral node. Total thyroidectomy with central node dissection and therapeutic MND of the contralateral compartment may be an acceptable surgical design and bilateral MND might not be mandatory.
doi:10.1155/2012/953603
PMCID: PMC3154792  PMID: 21860807
17.  BRAF Mutation Testing of Thyroid Fine-Needle Aspiration Biopsy Specimens for Preoperative Risk Stratification in Papillary Thyroid Cancer 
Journal of Clinical Oncology  2009;27(18):2977-2982.
Purpose
This study investigated the utility of BRAF mutation testing of thyroid fine-needle aspiration biopsy (FNAB) specimens for preoperative risk stratification in papillary thyroid cancer (PTC).
Patients and Methods
We assessed the T1799A BRAF mutation status in thyroid FNAB specimens obtained from 190 patients before thyroidectomy for PTC and its association with clinicopathologic characteristics of the tumor revealed postoperatively.
Results
We observed a significant association of BRAF mutation in preoperative FNAB specimens with poorer clinicopathologic outcomes of PTC. In comparison with the wild-type allele, BRAF mutation strongly predicted extrathyroidal extension (23% v 11%; P = .039), thyroid capsular invasion (29% v 16%; P = .045), and lymph node metastasis (38% v 18%; P = .002). During a median follow-up of 3 years (range, 0.6 to 10 years), PTC persistence/recurrence was seen in 36% of BRAF mutation–positive patients versus 12% of BRAF mutation–negative patients, with an odds ratio of 4.16 (95% CI, 1.70 to 10.17; P = .002). The positive and negative predictive values for preoperative FNAB-detected BRAF mutation to predict PTC persistence/recurrence were 36% and 88% for overall PTC and 34% and 92% for conventional PTC, respectively.
Conclusion
Preoperative BRAF mutation testing of FNAB specimens provides a novel tool to preoperatively identify PTC patients at higher risk for extensive disease (extrathyroidal extension and lymph node metastases) and those who are more likely to manifest disease persistence/recurrence. BRAF mutation, as a powerful risk prognostic marker, may therefore be useful in appropriately tailoring the initial surgical extent for patients with PTC.
doi:10.1200/JCO.2008.20.1426
PMCID: PMC2702231  PMID: 19414674
18.  Papillary thyroid carcinoma with thyroiditis: lymph node metastasis, complications 
Purpose
The aim of this study was to evaluate the clinicopathologic characteristics of papillary thyroid cancer with thyroiditis, and to determine the rate of its complications for it.
Methods
A retrospective review of 1,247 patients with papillary thyroid cancer who underwent primary thyroidectomy was performed. Among them, 316 patients had thyroiditis (group I) while 931 patients had no thyroiditis (group II), as reflected in the final pathologic reports. The two groups' clinicopathologic results and rate of complications were compared.
Results
Female gender, preoperative hypothyroidism, total thyroidectomy, no extrathyroid extension, no lymphovascular invasion, and no perineural invasion were associated with group I. More central lymph nodes were removed in group I than in group II, but there were fewer central lymph nodes with metastasis in group I than in group II. For the lateral lymph nodes, the two groups had the same numbers of removed nodes and nodes with metastatic tumor. Multivariate analysis revealed female predominance, more cases of preoperative hypothyroidism, more dissected lymph nodes, and fewer lymph nodes with metastasis in group I. Among the patients who underwent lobectomy, postoperative hypothyroidism occurred more in group I than in group II (P < 0.001). There was no difference in postoperative complications between the two groups.
Conclusion
Papillary thyroid cancer with thyroiditis showed less aggressive features. Postoperative hypothyroidism occurred more in the patients with thyroiditis.
doi:10.4174/jkss.2013.85.1.20
PMCID: PMC3699683  PMID: 23833756
Thyroiditis; Papillary thyroid cancer; Hypothyroidism
19.  Indications for the Gasless Transaxillary Robotic Approach to Thyroid Surgery: Experience of Forty-Seven Procedures at the American Hospital of Paris 
European Thyroid Journal  2013;2(2):102-109.
Background
Thyroid surgery is in a state of evolution from traditional open approaches to novel robotic techniques. The gasless transaxillary approach to thyroid surgery is effective in the management of thyroid cancer, and complications after robotic thyroidectomy are no higher than experienced after open or endoscopic techniques. The transaxillary robotic approach also avoids an anterior neck scar. This paper presents what the authors believe to be the largest cohort of patients reported in Europe undergoing gasless transaxillary robotic thyroid surgery, with the aim of defining the indications for this procedure.
Methods
Forty-six patients underwent robotic thyroid surgery via the transaxillary approach and were enrolled in this study between March 2010 and September 2012. All patients were operated on by one surgeon at one clinical center. Reviewed data included patient characteristics, pathological characteristics, extent of surgery and postoperative complications. The mean follow-up time was 7.29 months.
Results
Forty-six patients underwent 47 procedures, the average age of the patients was 43 years and the male to female ratio was 1:22. Undertaken were 30 lobectomies, 3 subtotal thyroidectomies, 13 total thyroidectomies and 1 totalization. One case was converted to an open procedure. The ratio of malignant to benign disease was 1:6.67 (6:40 cases) and analysis of the surgical specimens showed 6 follicular lesions, 24 follicular adenomas, 3 colloid lesions, 1 case of thyroiditis/lymphatic lesion, 3 adenomatoid lesions, 3 oncocytic adenomas, 3 papillary cancers and 3 microcapillary cancers. The overall average size of an individual specimen removed was 45.40 ± 28.95 cm3 (range 5-160, n = 47) and the average largest diameter of the lesion removed was 3.72 ± 0.95 cm (range 1.4-6.0, n = 47). Postoperatively, there were 5 recurrent laryngeal nerve injuries (4 transient), 2 transient brachial plexopathies, 1 case of postoperative dysphagia and 1 of collection of blood at the site of surgery. There were no cases of disease recurrence at follow-up.
Conclusions
The gasless robotic transaxillary approach to thyroid surgery has been predicted to become a standard technique. It has been shown to be efficacious in the management of thyroid cancer with lateral neck metastases; however, more data relating to oncological safety in long-term follow-up is required. This intervention is also appropriate for benign thyroid disease including Graves' disease. To achieve consistently successful results, careful patient selection is fundamental in terms of patient characteristics and the anatomical aspects of the lesion. This is especially important with a geographical expansion to include North America and Europe. The excellent cosmetic results of this procedure make it ideal for patients who have esthetic concerns regarding particular difficulties with healing; however, in common with all new surgical procedures, further evidence must be sought to confirm its indications over time.
doi:10.1159/000350854
PMCID: PMC3821510  PMID: 24783047
Thyroid disease; Transaxillary robotic thyroid surgery; Cosmesis

20.  Role of prophylactic central neck dissection in cN0 papillary thyroid cancer 
Summary
Prophylactic central neck dissection in papillary thyroid cancer is controversial. In this retrospective cohort study, the aim was to assess possible advantages of prophylactic central neck dissection with total thyroidectomy in cN0 papillary thyroid cancer. A total of 244 consecutive patients with papillary thyroid cancer, without clinical and ultrasound nodal metastases (cN0), were evaluated out of 1373 patients operated for a thyroid disease at the Istituto Europeo di Oncologia, Milan, Italy from 1994 to 2006. Of these 244 patients, 126 (Group A) underwent thyroidectomy with central neck dissection, while 118 (Group B) underwent thyroidectomy alone. Demographic, clinical and pathological features were analysed. Overall recurrence rate was 6.3% (8/126) in Group A and 7.7% (9/118) in Group B, with a mean follow-up of 47 (Group A) and 64 (Group B) months. In Group A patients, 47% were pN1a and all patients with recurrence had nodal involvement (p = 0.002). Survival rate did not differ in the two groups. Nine patients were lost to follow-up. Group A patients were older and their tumours were larger in size; according to the pT distribution, a higher extra-capsular invasion rate was observed. The two groups were equivalent as far as concerns histological high risk variants and multifocality. Nodal metastases correlated with stage: pT1-2 vs. pT3-T4a, p = 0.0036. A lower risk of nodal metastases was related to thyroiditis (p = 0.0034). In conclusion, central neck metastases were predictive of recurrence without influencing prognosis. From data obtained, possible greatest efficacy of central neck dissection in pT3-4 papillary thyroid cancer without thyroiditis is suggested.
PMCID: PMC2808683  PMID: 20111614
Thyroid; Papillary thyroid cancer; Nodal metastases; Central neck dissection
21.  Long-Term Outcome of Comprehensive Central Compartment Dissection in Patients with Recurrent/Persistent Papillary Thyroid Carcinoma 
Thyroid  2011;21(12):1309-1316.
Background
Persistent or recurrent papillary thyroid carcinoma (PTC) occurs in some patients after initial thyroid surgery and often, radioactive iodine treatment. Here, we identify the efficacy, safety, and long-term outcome of our current surgical management paradigm for persistent/recurrent PTC in the central compartment in an interdisciplinary thyroid cancer clinical and research program at a tertiary thyroid cancer referral center.
Methods
We retrospectively analyzed our standardized approach of comprehensive bilateral level VI/VII lymph node dissection (SND [VI, VII]) for cytologically confirmed PTC in the central compartment.
Results
From 1994 to 2004, 210 patients, median age 42 (range 12–82) underwent SND (VI, VII). Most patients (106, 51%) had already undergone ≥2 surgical procedures for persistent or recurrent disease, and 31 (15%) had distant metastases at presentation. Postoperatively, 104 (71%) of the 146 patients who were thyroglobulin (Tg) positive had no evidence of disease. Anti-Tg antibodies were present in 38 patients (18%), 17 of whom (53%) did not have anti-Tg antibodies postoperatively. Fourteen patients (7%) were hypoparathyroid at presentation, and 2 more (1%) became permanently hypoparathyroid after surgery. Four patients (2%) experienced recurrent laryngeal nerve paralysis (RLNP) of a previously functioning nerve. Unanticipated RLNP was observed in only one nerve at risk. External beam radiation was given to 33 patients (17%). An additional 17 patients (8%) developed distant metastases during follow-up. At the last follow-up, 130 (66%) of the 196 patients had no detectable Tg; of these, 99 (76%) had no further evidence of disease. A median of 7.25 years after surgery, 167 (90%) of the 185 patients were without evidence of central disease, and 18 (10%) had developed central compartment recurrences within a median interval of 24.3 months. Of those with recurrence, 16 out of 18 patients (89%) underwent a subsequent surgical procedure, thus resulting in an overall 98% central compartment control rate. Kaplan–Meier disease-specific survival at 10 years was 98.9% for patients <45 years old and 77.9% for those ≥45 years old (log-rank p<0.00001). The only predictor of central compartment recurrence was malignancy in a thyroid remnant noted within the central compartment surgical specimen.
Conclusions
Bilateral comprehensive level VI/VII dissections are safe and effective for long-term control of recurrent/persistent PTC in the central lymphatic compartment.
doi:10.1089/thy.2011.0170
PMCID: PMC3968954  PMID: 22136266
22.  Nodal recurrence in the lateral neck after total thyroidectomy with prophylactic central neck dissection for papillary thyroid cancer 
Langenbeck's Archives of Surgery  2013;399(2):237-244.
Purpose
The aim of this study was to examine risk factors for nodal recurrence in the lateral neck (NRLN) in patients with papillary thyroid cancer (PTC) who underwent total thyroidectomy with prophylactic central neck dissection (TT + pCND).
Methods
This was a retrospective cohort study of patients with PTC who underwent TT + pCND. Data of all patients treated over a 10-year period (between 1998 and 2007) were analysed. The primary outcome was prevalence of NRLN within the 5-year follow-up after initial surgery. Predictors of NRLN were determined in the univariable and multivariable analysis.
Results
Of 760 patients with PTC included in this study, 44 (6.0 %) developed NRLN. In the univariable analysis, the following factors were identified to be associated with an increased risk of NRLN: positive/negative lymph node ratio ≥0.3 (odds ratio (OR) 14.50, 95 % confidence interval (CI) 7.21 to 29.13; p < 0.001), central lymph node metastases (OR 7.47, 95 % CI 3.63 to 15.38; p < 0.001), number of level VI lymph nodes <6 in the specimen (OR 2.88, 95 % CI 1.21 to 6.83; p = 0.016), extension through the thyroid capsule (OR 2.55, 95 % CI 1.21 to 5.37; p = 0.013), localization of the tumour within the upper third of the thyroid lobe (OR 2.35, 95 % CI 1.27 to 4.34; p = 0.006) and multifocal lesions (OR 1.85, 95 % CI 1.01 to 3.41; p = 0.048).
Conclusions
Central lymph node metastases together with positive to negative lymph node ratio ≥0.3 represent the strongest independent prognostic factors for the PTC recurrence in the lateral neck.
doi:10.1007/s00423-013-1135-9
PMCID: PMC3916707  PMID: 24213969
Prophylactic central neck dissection; Papillary thyroid cancer; Nodal recurrence in the lateral neck; Hypoparathyroidism; Recurrent laryngeal nerve injury
23.  Prognostic parameters for recurrence of papillary thyroid microcarcinoma 
BMC Cancer  2008;8:296.
Background
Papillary thyroid microcarcinoma (PTMC) is defined as a papillary thyroid carcinoma less than or equal to 1.0 cm in size. Independent prognostic factors for clinical recurrence of PTMC have not been clearly delineated.
Methods
Clinicopathological parameters predicting PTMC recurrence were determined by retrospective analysis of 307 patients.
Results
Of the 293 patients eligible for analysis, 14 (5%) had recurrence during a median follow-up time of 65 months. Recurrence was observed in 8 of 166 patients (0.5%) treated with total or near-total thyroidectomy; gender (P = 0.02) and presence of lateral cervical node metastases at initial surgery (P = 0.01) were associated with recurrence. Six of the 127 patients (0.5%) treated with hemi- or subtotal thyroidectomy experience recurrences, but no significant prognostic factor for recurrence was identified. Multivariate Cox-regression analysis showed that gender and cervical lymph node metastasis were significant variables
Conclusion
PTMC showed very diverse disease extent and could not be regarded as indolent, relatively benign disease based on the primary tumor size. The extent of surgery should be based on prognostic parameters, such as gender and lateral neck node metastasis, in patients with PTMC.
doi:10.1186/1471-2407-8-296
PMCID: PMC2576338  PMID: 18851763
24.  Is Routine Central Neck Dissection Necessary for the Treatment of Papillary Thyroid Microcarcinoma? 
Objectives
It remains unclear as to whether routine central neck dissection (CND) is necessary when performing surgery to treat patients with papillary thyroid microcarcinoma (PTMC). To determine the necessity for routine CND in PTMC patients, we reviewed the clinicopathologic and laboratory data of the patients of PTMC.
Methods
Between September 2001 and July 2005, 101 patients with PTMC and clinical N0 disease were retrospectively reviewed. The study cohort was devided into groups: the total thyroidectomy plus CND group (the CND group, N=48) and the total thyroidectomy without CND group (the no CND group, N=53). The serum stimulated thyroglobulin (Tg) levels were measured after surgery and prior to radioactive iodine ablation therapy (RAI) and at 6-12 months after RAI. Pathology, the Tg levels and recurrence data were compared between the 2 groups.
Results
Central nodal metastases were found in 18 of the 48 CND patients (37.5%). The incidence of Tg levels >5 ng/mL at RAI was higher in the no CND patients and in the 18 node-positive CND patients compared with the 30 node-negative CND patients (22-24% vs. 3%, respectively, P=0.020-0.058). The difference when performing a similar comparison using a >2 ng/mL Tg threshold level showed no significance (10-11% vs. 4%, respectively, P>0.1). Two of the no CND patients and one node-positive CND patient had recurrences in the thyroid bed or lateral neck during a mean follow-up of 24 months.
Conclusion
The data showed that occult metastasis to the central neck is common in PTMC patients. A CND provides pathologic information about the nodal metastases, and it potentially provides guidance for planning the postoperative RAI. However, the long-term benefit of CND on recurrence and survival remains somewhat questionable.
doi:10.3342/ceo.2008.1.1.41
PMCID: PMC2671760  PMID: 19434261
Papillary microcarcinoma; Central compartment; Neck dissection; Neoplasm metastasis; Thyroglobulin
25.  Late Recurrences of Thyroid Carcinoma 24 Years after a Complete Remission: When Monitoring Should be Stopped? 
Renal metastases from thyroid carcinoma are very rare, late recurrences of papillary thyroid carcinomas (PTC) are not reported in literature and there is no universal recommendation for optimum duration of follow-up of thyroid carcinoma. We present herein a case of late renal recurrence of follicular variant PTC (FV-PTC). This study is a case report of renal metastasis revealing a late recurrence of FV-PTC. An 81-year-old woman with previously treated FV-PTC 24 years ago by total thyroidectomy, lymph nodes dissection and radioiodine therapy presented with sudden gross-hematuria. Computerized tomography scan (CT-scan) revealed a 70-mm right renal mass and histological diagnosis after nephrectomy demonstrated recurrence of FV-PTC with a positive thyroglobulin immunostaining. Despite of 131I-radioiodine therapy postoperatively, the serum thyroglobulin (Tg) increased and positron emission tomography combined to CT-scan showed 4 years later, an abdominal lymph node and distant metastases. Now the patient is alive but her general condition is too poor for systemic adjuvant therapy. This case illustrates the need of prolonged follow-up after surgery of high-risk FV-PTC.
doi:10.4103/1450-1147.98749
PMCID: PMC3425233  PMID: 22942786
Late recurrence; renal metastasis; thyroid carcinoma

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