Address for correspondence : Myung-Chul Lee, MD, PhD, Department of Otorhinolaryngology- Head & Neck Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences (KIRAMS), 75 Nowon-ro, Nowon-gu, Seoul 01812, Korea
Tel : +82-2-970-2173, Fax : +82-2-970-2450, E-mail : lmc@daum.net

Introduction

Papillary thyroid carcinoma (PTC) is known as the most common type of thyroid cancer and shows an excellent prognosis with the overall 10-year survival rate >90%.1) With the development of radiological imaging, especially ultrasonography, the incidence of thyroid cancer has been increasing, and the diagnosis of papillary thyroid microcarcinoma (primary tumor ≤1.0 cm) has shown the highest rate of increase.2) Due to the increased incidence of small thyroid cancer, the extent of thyroid surgery has been a matter of controversy.3)
Total thyroidectomy or lobectomy can be an option for the surgery of thyroid cancer. According to American Thyroid Association (ATA) guidelines, thyroid lobectomy alone may be enough treatment for small (<1 cm), low-risk, unifocal, intrathyroidal papillary carcinomas without prior head and neck irradiation and clinical cervical lymph node (LN) metastasis.4) In European Thyroid Association guidelines, lobectomy is recommended when PTC is unifocal tumor <1 cm with no nodal or distant metastases and no radiation history.5)
However, traditionally, total thyroidectomy has been recommended against lobectomy for PTC in the aspect of lower recurrence and mortality rates irrespective of tumor size.4) Recently, some researchers have insisted that there is no difference in survival and locoregional recurrence in low-risk PTC between total thyroidectomy and lobectomy.6) Moreover, there has been a report describing a good long-term result from lobectomy even in the PTC with large (>1 cm) size.7) In addition, lobectomy may also reduce the chance of thyroid hormone replacement therapy and surgical complications such as hypoparathyroidism and recurrent laryngeal nerve injury, compared to total thyroidectomy.3)
Performing prophylactic central lymph node dissection (cND) during lobectomy is another controversial matter. According to ATA guidelines, prophylactic cND is recommended for PTC patients with advanced primary tumor (T3, 4) and clinically uninvolved central LN.3) To date, most of reports have dealt with prophylactic cND with total thyroidectomy. However, there have been few reports describing role of prophylactic cND combined with lobectomy.8,9)
In the present study, we attempted to analyze long term follow-up results of a large number of PTC patients who underwent thyroid lobectomy with or without cND as initial operation at Korea Cancer Center Hospital (KCCH) to evaluate the usefulness of lobectomy and prophylactic ipsilateral cND.

Subjects and Method

Patients
The medical records of 953 PTC patients who underwent thyroid lobectomy with/without prophylactic ipsilateral cND as an initial surgery at KCCH between January 2001 and December 2010 were retrospectively reviewed. The surgeries were performed by three surgeons with extensive experiences and expertise in thyroid surgery. All of the patients in the present study underwent ultrasonography (USG) and fine needle aspiration biopsy (FNAB) for diagnosis. A radiologist performed USG and FNAB for all the nodules suspicious for malignancy in both side of thyroid. Included patients were preoperatively diagnosed as small size (<2 cm, T1) PTC without clinically apparent LN and distant metastasis, extrathyroidal extension, familial history of thyroid cancer, and history of radiation exposure to neck. Although nodule(s) in contralateral lobe are present, if they were identified as benign nodule(s) by ultrasonography and FNA findings, we included these patients for lobectomy. In addition, patients who were diagnosed as follicular neoplasm regardless of size preoperatively but as PTC postoperatively were also included in this study. Patients who were diagnosed as a follicular variant, an oxyphilic cell variant, a diffuse sclerosing variant or a tall cell variant PTC pre- or post-operatively were excluded from this study for homogeneity of study objects. A laryngoscopic examination was performed to evaluate vocal cord mobility preoperatively and 1 day postoperatively in all patients. Out of 953 patients, 47 patients underwent immediate completion thyroidectomy within 7 months from the initial surgery because of more than 3 LN positivity or the patients' requests. These 47 patients were excluded from this study. Without immediate completion thyroidectomy, 906 patients were followed up to May 2014. All 906 patients were followed up for more than 3 years. During follow-up periods, 52 patients out of 906 had recurred and undergone completion thyroidectomy. This study analyzed 52 patients who had recurred and compared these patients with 854 patients who had not recurred. All of data analyzed in this study included the patients' clinicopathologic characteristics (gender, age, tumor sizes, extrathyroidal extension, multiplicity of tumor, and LN metastasis, and USG finding), operation information, postoperative vocal cord palsy, postoperative treatment, and follow up periods. The Institutional Review Board of KCCH approved this study (K-1410-002-059).

Surgical strategy
For all the patients in the present study, we performed conventional open thyroid lobectomy as an initial surgery. Thyroid lobectomy involved the removal of one lobe and isthmus. Prophylactic ipsilateral cND was performed for some patients at surgeons' discretion according to tumor size, location, operative findings and etc., in the area bordered by the medial border of the carotid sheath laterally, trachea medially, hyoid bone superiorly, and the suprasternal notch inferiorly. During surgery, recurrent laryngeal nerves and parathyroid glands were identified and preserved meticulously.

Postoperative follow-up
After surgery, all the patients underwent a routine USG and thyroid function test including free T4, T3, thyroid stimulating hormone, and unstimulated thyroglobulin for surveillance for recurrence every 6 month or a year. When recurrence is suspected, FNAB was performed additionally for confirmation. For patients with cytologically-proven recurrences, completion thyroidectomy with/without cND according to the recurrence patterns and postoperative radioactive iodine (RAI) treatment were performed to ablate remnant thyroid tissue.

Statistical analysis
The data were statistically analyzed by using the SPSS version 18.0 software package (SPSS Inc., Chicago, IL, USA). By using independent t-test and chi-square test, 52 PTC patients with recurrence and 856 PTC patients without recurrence were compared in terms of various variables. The overall recurrence-free survival (RFS) rate, remnant thyroid RFS (RT-RFS) rate, LN-RFS rate, overall survival (OS) rate, and disease specific survival rate were calculated with survival analysis (Kaplan-Meier method). To find out risk factors, eight potential risk factors such as gender, age, primary tumor size, extrathyroidal extension, multiplicity, performance of cND, LN metastasis, and presence of nodules at contralateral lobe were subjected to univariate analyses by the Kaplan-Meier method and log-rank test. From univariate analyses, factors with a p<0.20 were subjected to multivariate analyses by the Cox proportional hazard model. The threshold of age for the statistical analyses were ≥45 years old. The chi-square test was performed to analyze categorical data. The significance level in the statistical tests in this study was set at p<0.05.

Results

Patients' characteristics
Patients' characteristics are shown in Table 1. Patients were divided into two groups according to recurrence. Out of 906 PTC patients, only 52 (5.7%) patients had shown the recurrence on the remnant thyroid and/or LN. In a matter of gender, two groups did not show any significant difference (p=0.495). Mean age of patients were 47.8±10.3 years old for a group without recurrence and 45.0±8.6 years old for a group with recurrence, respectively (p=0.111). Primary tumor size was categorized into four groups, ≤10 mm, >10 to ≤20 mm, >20 to ≤40 mm, and >40 mm. Statistically, size in recurrence group was statistically bigger than that in non-recurrence group (p<0.001). Extrathyroidal extension, multiplicity of tumor, and pathological LN metastasis did not show any significant differences between two groups (p=0.331, 0.171, and 0.738, respectively). Performance of prophylactic ipsilateral cND was less frequent in recurrence group (p=0.027). Nodule(s) at contralateral lobe were significantly frequent in patients with recurrence (44.2% vs. 20.7%, p<0.001). Follow-up durations were 61.8±28.4 months for a group of no recurrence and 87.6±32.4 months for a group of recurrence. The average time interval from initial lobectomy to recurrence was 47.1±31.9 months.

Ipsilateral central LN recurrences after ipsilateral prophylactic cND
Ipsilateral cND was performed in 606 cases (606/906, 66.9%) (Table 2). Ipsilateral central LN recurrences were found in 1 out of 606 cND (+) cases, and 6 out of 300 cND (-) cases (p=0.0103).

Immediate completion thyroidectomy
Like mentioned in 'Subjects and Method', 47 patients out of 953 patients underwent immediate completion thyroidectomy after the initial thyroid lobectomy with prophylactic ipsilateral cND. All these 47 patients underwent prophylactic ipsilateral cND. More than 3 LN positivity was an indication for immediate completion thyroidectomy, but some patients wanted immediate completion thyroidectomy due to the concern for recurrence and underwent immediate completion thyroidectomy even though they had less than 2 LN positivity. Number of LN positivity at initial prophylactic ipsilateral cND was averaged 2.4 per patient in these 47 patients. All these patients were postoperatively treated with RAI.

Prophylactic ipsilateral cND and completion thyroidectomy after recurrence
Prophylactic ipsilateral cND was performed on 606 patients out of 906 patients (606/906, 66.9%). Among them, 117 patients (117/606, 19.3%) had central LN metastases and did not undergo immediate completion thyroidectomy. All these 117 patients were followed up, and 8 patients out of 117 patients (8/117, 6.8%) had recurred during follow up and underwent completion thyroidectomy. Number of LN positivity was averaged 1.5 per patient. All eight patients with completion thyroidectomy were postoperatively treated with RAI to ablate remnant thyroid tissue.

Recurrence patterns
Recurrence patterns are shown in Table 3. Out of 52 patients, 32 patients (61.5%) have recurred at the remnant thyroid and 11 patients (21.2%) at the LN. Concurrent recurrences on both remnant thyroid and LN were found in 9 patients (17.3%).

OS and disease specific survival rates
OS and disease specific survival rates at 10 years were 99.6% and 100%.

Overall recurrence
Overall recurrence was detected in 52 (5.7%) of 906 patients during follow-up. Kaplan-Meier curves demonstrated that the overall RFS rates at 5 and 10 years after initial surgery were 97.1% and 81.0%, respectively. Among 8 potential risk factors, age ≥45 years old, no prophylactic cND, and contralateral nodules were significantly associated with overall RFS rates according to univariate analysis (p<0.001, 0.048, and <0.001, respectively) (Table 4). Age ≥45 years old and contralateral nodule(s) at initial surgery were found significant in multivariate analysis (p=0.009 and 0.003, respectively) (Table 4). The hazard ratios for overall recurrence with age ≥45 years old and contralateral nodules at initial surgery were 2.18 and 2.40, respectively (Table 4).

Recurrence in the remnant thyroid
The RT recurrence was diagnosed in 41 (4.5%) of 906 patients during follow up duration (Table 3). The RT-RFS rates at 5 and 10 years after initial surgery were 95.8% and 89.7%, respectively. In univariate analysis, old age, multiplicity, and contralateral nodule(s) were significant risk factors of RT-RFS (p=0.003, 0.011, and <0.001, respectively) (Table 5). However, in multivariate analysis, only contralateral nodule(s) at initial surgery were assessed significant (p<0.001) (Table 5). The hazard ratio for RT recurrence with contralateral nodule(s) at initial surgery was 3.39 (Table 5).

Recurrence in the LN
The LN recurrence was diagnosed in 20 (2.2%) of 906 patients during follow-up (Table 3). The LN-RFS rates at 5 and 10 years after initial surgery were 98.9% and 95.5%, respectively. In univariate analysis, old age, tumor size, and extrathyroidal extension were significant risk factor of LN recurrence (p=0.041, <0.001, and 0.027, respectively) (Table 6). Old age, tumor size, no prophylactic cND, and pathological LN metastasis were ascertained significant in multivariate analysis (p=0.026, 0.016, 0.010, and 0.008, respectively) (Table 6). The hazard ratios for LN recurrence with age ≥45 years old, primary tumor size >10 mm, no prophylactic cND, and pathological LN metastasis at initial surgery were 3.49, 4.52, 10.95, and 12.34, respectively (Table 6).

Complications
Four (0.4%) patients experienced transient vocal cord palsy, among them, only 1 (0.1%) patient showed permanent vocal cord palsy. Otherwise no specific complications were noted.

Discussion

Even though there are controversies for the optimal treatment for PTC, lobectomy is generally recommended for low risk patients with unifocal PTC <10 mm, and the absence of neck LN and distant metastasis.4) Because of very indolent characteristics of PTC and conventional preferences toward total thyroidectomy, little is known about long-term results after lobectomy. Aim of this study was to analyze the treatment results of lobectomy and prophylactic ipsilateral cND for low risk PTC.
In the present study, we tried to focus on some well-known risk factors which have influence on recurrences not survival, and recurrence rate and patterns after lobectomy due to excellent overall and disease specific survival rate.
In simple comparison between recurrence and non-recurrence groups (Table 1), this study identified that size, prophylactic ipsilateral cND and nodule(s) at contralateral lobe were found more in recurrence group. Conventional risk factor systems such as tumor, LNs, metastasis, age, metastasis, extent of disease, size, age, grade, extent of disease, size, and metastasis, age at presentation, completeness of surgical resection, extrathyroidal invasion, size did not include prophylactic cND and nodule(s) at contralateral lobe.10) Hence, we suggest that prophylactic cND and nodule(s) at contralateral lobe may be considered as additional risk factors to conventional risk systems when lobectomy was planned for early stage PTC.
We investigated ipsilateral central LN recurrences after ipsilateral prophylactic cND (Table 2). Ipsilateral central LN recurrences occurred less when ipsilateral cND were performed (p=0.0103). In accordance with our data, prophylactic cND along with lobectomy had been reported to decrease the locoregional recurrence in previous report.11) Addition of cND can increase the incidence of hypoparathyroidism in total thyroidectomy, but in lobectomy, does not.12) If cND is performed by experienced surgeons, additional operative time is not so long (-10 min) and additional recurrent laryngeal damage is minimal.3,9) Hence we suggest concomitant prophylactic ipsilateral cND if lobectomy is performed for low risk PTC patients.
In the present study, 52 (5.7%) out of 906 patients had recurred at the remnant thyroid and/or LN. Recurrence rates (10.3%) at 10 years in the remnant thyroid were higher, but recurrence rates (4.5%) at 10 years in the regional LN were lower than previous report.7) Differences in recurrence rates from our study may be due to operative indication and surgical strategies.
To analyze recurrence patterns (Table 3), most of recurrences occurred in the remnant thyroid (41/52, 78.8%). Among patients who recurred in the remnant thyroid (n=41), 22 patients had nodule(s) in contralateral lobe initially, which were considered as benign nodule(s) in USG and/or FNAB. According to the ATA guidelines for patients with thyroid nodules and differentiated thyroid cancer and national comprehensive cancer network guidelines, PTC patients with multiple or bilateral nodule(s) are indicated for total thyroidectomy.4) If we had followed these guidelines, all 200 patients who had contralateral nodule(s) initially should have undergone total thyroidectomy (Table 1). However, in our institute, if nodule(s) in contralateral lobe were identified to be benign thyroid nodules by USG findings and/or FNAB, we performed lobectomy when lesion was small (<20 mm), unifocal, and showed no clinical central LN involvement, no prior radiation history, no distant metastasis, no extrathyroidal extension, and no aggressive variant. As a result, 200 patients who had contralateral nodule(s) avoided total thyroidectomy and underwent lobectomy, and among them, 22 (11%) patients recurred in remnant thyroid. The longer follow-up of the other patients without recurrence may reveal more remnant thyroid recurrence, but considering the indolent, less fatal nature of PTC, possibility of no thyroxine replacement, and possible complications from total thyroidectomy such as hypoparathyroidism and laryngeal nerve injury,12) lobectomy can be a good option for patients. We insist that meticulous investigation of contralateral lobe is most critical with this findings if lobectomy is planned.
The present study demonstrated that old age (≥45) and presence of contralateral nodule(s) at initial surgery were significant risk factors for overall recurrence, and the presence of contralateral nodule(s) at initial surgery alone was a significant risk factor for the remnant thyroid recurrence in the multivariate analysis (Table 4 and 5). Though absolute whole recurrent cases were small (52/906, 5.7%), more meticulous examinations on contralateral lobe at initial work up might lead to decrease of recurrence in contralateral lobe and consequently of overall recurrence by change of initial plan from lobectomy to total thyroidectomy. In addition, it is evident that more careful postoperative surveillance for recurrences in contralateral lobe is needed after lobectomy from these findings.
Old age, larger tumor size, no performance of prophylactic ipsilateral cND, and pathological LN metastasis were significant risk factors for lymph nodal recurrence (Table 6). Age, size, and LN metastasis are well known risk factors for recurrence and death, but little is known about necessity and usefulness of prophylactic ipsilateral cND in low risk PTC. With findings mentioned above (Table 2), these findings suggest that addition of prophylactic ipsilateral cND is beneficial in terms of LN recurrences.
After thyroid surgery, most annoying postoperative complications are vocal cord paralysis and hypoparathyroidism. These two complications are less conspicuous or not present in lobectomy compared to total thyroidectomy.
Present study has several advantages. Our study was performed in a large number of cases (906 cases) with a long follow-up duration (61.85 months in non-recurrence group and 87.62 months in recurrence group) in a single institute. Most previous large scale multicenter studies can have bias from different disciplines, protocol and techniques of many surgeons. Our studies involved only 3 experienced head and neck senior surgeons with extensive experiences and single institute experience can provide more detailed and reliable informations and more similar level of preoperative evaluation, perioperative and postoperative management than those from multiple institutes.
This study also has some limitations. Firstly, this study was not a prospective but a retrospective study. Due to life-long indolent biological characteristics and the excellent prognosis of PTC, randomized prospective study for determining the optimal thyroid surgery has not been reported before and is extremely hard to perform.4) Further studies involving more patients with prospective setting if possible will be necessary to gain more high level of statistical power and evidence. Secondly, for a similar reason, longer follow up periods for the patients will be needed to get more accurate RFS rate at 5-, 10-, 20-, and 30-year. It is previously reported that at least 3, 100 to 10, 400 PTC patients with more than 6 years of follow up duration would be required to perform a survival analysis.13) Longer follow up duration will lead to get long-term RFS rate and identify more accurate risk factors for recurrence and death. Thirdly, the present study did not present the comparison between lobectomy and total thyroidectomy. Several researches have dealt with the comparison between lobectomy and total thyroidectomy.14,15) However, we think this present research has important meanings in the perspective that we presented results from many lobectomy cases performed in the homogenous indication similar with recent guidelines in a single institute.
In conclusion, lobectomy with prophylactic ipsilateral cND may be a good option for well selected low risk patients due to excellent overall survival, recurrence rates, and minimal complication rates. If risk factors such as old age, size >10 mm, no performance of prophylactic cND, pathological LN metastasis, and contralateral nodule(s) are present, more meticulous work-up and surveillances are needed when lobectomy is planned.

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