Lateral neck sentinel lymph node biopsy in papillary thyroid carcinoma, is it really necessary? A randomized, controlled study Se Kyung Lee, MD,a Jun Ho Lee, MD,a Soo Youn Bae, MD,a Jiyoung Kim, MD,a Minkuk Kim, MD,a Hyun-Chul Lee, MD,a Yoon Yang Jung, MD,b Won Ho Kil, MD, PhD,a Seok Won Kim, MD, PhD,a Jeong Eon Lee, MD, PhD,a Seok Jin Nam, MD, PhD,a Jun-Ho Choe, MD, PhD,a Jung-Han Kim, MD, PhD,a and Jee Soo Kim, MD, PhD,a Seoul, South Korea

Background. Although occult metastasis to lymph node in the lateral neck compartment is common in papillary thyroid carcinoma (PTC), the clinical impact of these metastasis is unknown. We hypothesized that sentinel lymph node biopsy (SLNB) of the lateral neck compartment with radioisotopes may detect occult metastasis, which could prevent recurrence. Methods. This randomized, controlled study was conducted from June 2009 to January 2011 and included 283 patients with PTC who were receiving treatment at the Samsung Medical Center. Results. Of the 283 patients enrolled in the study, 141 were randomized to a lateral SLNB (LSLNB) group and 142 patients were to the control group. Lateral sentinel lymph nodes (LSLNs) were identified in 80 of the 127 patients (63.0%) for whom stimulated thyroglobulin (sTg) levels were available. Among the 80 patients with LSLNs, 24 (30.0%) had metastases and underwent an ipsilateral modified radical neck dissection. Among the 191 patients for whom repeated sTg test results were available, the first median level of sTg in the LSLNB study group was less compared with the control group (P = .012, adjusted for duration). However, the second sTg level (after the first radioactive iodine ablation) was not different between the 2 groups. Moreover, the sTg levels were not significantly different between the LSLNpositive (n = 23) and other patients (n = 168) after the first and second ablations. During patient follow-up (median, 39 months; range, 7–55), 3 cases of recurrence were observed in the control group and 1 case in the study group (a LSLN had not been detected in this case). Conclusion. Although LSLNB was able to remove occult metastasis in PTC, this procedure had no effect on either sTg levels or on recurrence rates at a mean follow-up of 39 months. Additional long-term studies are needed to explore fully the clinical usefulness of LSLNB in the prevention of PTC recurrence. (Surgery 2015;157:518-25.) From the Division of Breast and Endocrine Surgery, Department of Surgery,a and the Department of Pathology,b Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

ALTHOUGH LATERAL NECK NODE METASTASES in papillary thyroid cancer (PTC) are common,1-3 the prognostic importance of lateral neck occult lymph node metastasis in thyroid carcinoma remains controversial. As suggested by the revised 2009 guidelines of the American Thyroid Association,3,4 Conflict of interest: The authors declare no conflicts of interest. Accepted for publication October 23, 2014. Reprint requests: Jee Soo Kim, MD, PhD, Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2014.10.013

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functional compartmental resection approaches such as modified radical neck dissection (MRND) can be useful for decreasing recurrence and possibly death in patients with clinically evident nodal disease; in contrast, prophylactic MRND may cause unexpected complications and is of no proven benefit. Sentinel lymph node biopsy (SLNB) in thyroid cancer was first introduced in 1998.5 Most studies of SLNB have focused on the central neck nodes; reports describing SLNB of the lateral neck node are rare.6,7 We first reported a prospective study demonstrating that lateral SLNB (LSLNB) using a radioisotope was useful for detecting occult metastases.7 In our previous report, we focused on the incidence of occult metastases, the feasibility of LSLNB, and the potential indications of LSLNB.

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Because PTC is indolent and responds well to radioactive iodine (RAI) ablation, the more important perspective for the clinical application of LSLNB is its impact on patient outcomes, such as recurrence and survival. This report presents a short-term follow-up study (mean, 30 months) focusing on the usefulness of LSLNB. The level of preablative stimulated thyroglobulin (sTg), which is considered to be a predictor of residual and recurrent disease, was used as a surrogate measure to predict the benefit of LSLNB.4,8,9 In this study, we tested the hypothesis that LSLNB could detect and remove occult metastases, and eventually decrease recurrence in the lateral compartment. PATIENTS AND METHODS Study design and patient selection. This prospective study was conducted on patients with PTC, with the aim of evaluating the efficacy of SLNB in LSLNB. Approval was granted by the Institutional Review Board of Samsung Medical Center (ClinicalTrials.gov ID, NCT01137097). Patients with tumors >1 cm in size or with clinically suspicious preoperative central neck node metastasis were enrolled in this study. Patients with lateral neck lymph node metastases that had been confirmed by a fine-needle aspiration biopsy were excluded. All patients included in this study underwent a CT preoperative of the neck. We used CT rather than cervical ultrasonography, as used by other groups, to investigate the presence of cervical node disease. The primary objective in this prospective study was to assess the protective role of LSLNB against PTC recurrence. The secondary purpose was to investigate the feasibility of LSLNB. Patient sample size was calculated assuming an enrollment duration of 3 years and an average follow-up of 13 years, an estimated 3-year recurrence rate of 5% in the control group and 2% in the study group, and a type I error of a = 0.05 with 80% power. Using these parameters, we calculated that 133 patients in each group were required to support our primary purpose. From June 2009 to January 2011, 283 patients with PTC were enrolled for this study in the Department of Surgery at the Samsung Medical Center. Patients were assigned randomly to 1 of the 2 groups using a computer-generated randomization code. In total, 141 patients were injected with radioisotope in the LSLNB study group and 142 patients underwent total thyroidectomy or lobectomy and central neck node dissection as a control group. The CONSORT (Consolidated Standards

Fig 1. CONSORT diagram showing participant flow through the study. *Patients who had frozen negative and permanent positive metastases in the sentinel; only radioactive iodine (RAI) ablation was performed, without additional modified radical neck dissection (MRND). F/U, Follow-up; LSLN, lateral sentinel lymph node; sTg, stimulated thyroglobulin.

of Reporting Trials) diagram, which describes the patients flow through each step of this preliminary study, is shown in Fig 1. To determine the effect of LSLNB on postoperative sTg levels, we selected patients who had undergone $2 RAI ablation therapies and had undergone a total thyroidectomy; lobectomy patients were excluded. Among the 283 patients who were enrolled for this randomized, controlled trial, the effects of RAI ablation were only analyzed in 191 patients. Procedure. On the day of the operation, patients underwent preoperative lymphoscintigraphy after the intratumoral injection of a Tc-99m phytate 1 mCi in 0.1–0.2 mL 0.9% NaCl under ultrasonographic guidance. Total thyroidectomy or lobectomy with central neck dissection preceded SLN detection to avoid interference by primary tumor radioactivity. After total thyroidectomy or lobectomy, the dissections were performed toward the internal jugular chain beneath the sternocleidomastoid muscle. A handheld, collimated gamma probe and lymphoscintigraphy were used to scan the lateral compartments (through skin and under the SCM) for ‘‘radioactive’’ lymph nodes (Fig 2). Removed SLNs were submitted immediately for

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Fig 2. Lymphoscintigraphy with lateral sentinel lymph nodes. ANT, Anterior; LT LAT, left lateral; POST, posterior; RT LAT, right lateral.

frozen biopsy. If any of the SLNs were positive for metastasis on the frozen sections, MRND was performed immediately. In cases for which the frozen section was negative but the final pathology report detailed microscopic positivity in the lateral sentinel nodes, RAI ablations were performed without additional MRND. After surgery, a followup visit was conducted every 6 months in the first year. Although patients with tumors >1 cm in size or with clinically suspicious central neck node metastasis were enrolled originally, some patients were later found to have only smaller PTC tumors or no central neck node metastasis on the permanent section. In these cases, RAI ablations were omitted.4,10 Postoperative RAI ablations were performed based on the revised American Thyroid Association thyroid cancer guidelines and the decision of the medical thyroid specialist.4 In this study, we assessed the effect of LSLNB on PTC by monitoring sTg levels postoperatively. We excluded 14 patients from the study group and 9 from the control group because their sTg levels were not available owing to loss to follow-up, lobectomy, or lack of ablation (Fig 1). Statistical analysis. Continuous variables were compared between the 2 groups using the Student t test or the Wilcoxon 2-sample test; categorical variables were analyzed using the Chi-square test or Fisher exact test. Kaplan–Meier survival analysis was used to analyze disease-free survival and overall survival times. Levels of sTg at various time points were compared. P values were adjusted based on Bonferroni’s correction for multiple comparisons.

Owing to the skewed distribution of the sTg levels, these data were natural log-transformed. Data were analyzed using a linear regression model after adjusting for duration. All statistical analysis was executed using SAS version 9.3 (SAS Institute, Cary, NC). RESULTS Comparison of characteristics by study group. A total of 260 patients with PTC for whom follow-up sTg levels were available were analyzed in this study (Table I). The mean patient age at diagnosis was 47 years (range, 21–74), and the median tumor diameter was 1.4 cm. Clinicopathologic characteristics including age, sex, tumor location, tumor size, multiplicity, tumor extent, presence of thyroiditis, number of involved LNs, resection margin status, ablation frequency, and ablation dose were not significantly different between the study and control groups. Metastases of sentinel lymph nodes in the lateral neck compartment. Lateral sentinel lymph nodes (LSLNs) were identified in 80 of the 127 patients (63.0%) for whom sTg levels were available (Table II). No clinicopathologic factors were related to the detection of LSLNs. Among the 80 patients with identified LSLNs, 24 (30.0%) had metastases, and 19 underwent immediate MRND. Another 5 patients had frozen negative but permanent section–positive LSLN results and underwent only RAI ablation without additional MRND. The RAI scans for these 5 patients did not reveal the abnormal uptake. The number of central neck lymph node metastases was the only predictor of

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Table I. Comparison of characteristics by study groups (n = 260) Characteristic

Study (+; n = 127)

Study (; n = 133)

Age (mean ± SD), y Sex (male:female), % Laterality (right:left:both), % Tumor size (cm), median (range) Multiple tumors, n (%) No. of tumors, median (range) Extent (%) Confined to thyroid Perithyroid Extrathyroid Dissected CLN, median (range) Involved CLN, median (range) Total involved LNs, median (range) Thyroiditis (%) +  Resection margin (%) +  Ablation (frequency), median (range) Ablation (mCi), median (range)

47.1 ± 10.9 27 (21):100 (79) 52 (41):47 (37):28 (22) 1.2 (0.4–4.4) 48 (38) 1 (1–5)

47.4 ± 10.4 33 (25):100 (75) 58 (44):42 (32):22 (25) 1.2 (0.1–4.5) 51 (38) 1 (1–13)

41 59 27 10 1 1

(32) (46) (21) (1–31) (0–11) (0–14)

33 (26) 94 (74) 5 122 2 75

29 74 30 10 1 1

(22) (56) (23) (1–26) (0–10) (0–10)

29 (22) 104 (78)

(3.94) (96) (1–5) (5–315)

5 128 2 105

(3.76) (96) (1–3) (5–255)

P value .827* .497y .644y .445z .927y .806z .152y

.746z .229z .069z .429y >0.999x .766z .054z

*Student t test. yChi-square test. zWilcoxon 2-sample test. xFisher exact test. CLN, Central neck lymph node; LN, lymph node.

metastasis of the lateral lymph node (P = .001). Age, sex, laterality, tumor size, multiplicity, tumor extent, presence of thyroiditis, and involvement of the resection margin were not significant predictors of metastasis. In cases of SLN metastasis, a greater number of treatments and greater total doses of RAI ablations were performed. Characteristics of the 24 patients with metastatic LSLNs. The mean age of the 24 patients with metastatic LSLNs was 43 years (Table III). The mean size of the main tumor was 1.5 cm. Among these 24 patients, 17 had a single lesion. Additionally, 7 cases were confined to the intrathyroidal region, 11 to the perithyroidal region, and 6 were extrathyroidal. The median numbers of detected and retrieved LSLNs were 7 and 2.5, respectively; moreover, no LSLN showed extranodal extension. The largest metastatic LSLN was 1.5 cm. Among the 19 patients who underwent immediate MRND, only 4 patients had only a single LSLN metastasis. Short-term follow-up results between the LSLNB group and control group. Among the 260 patients, 191 patients underwent $2 RAI ablations (Table IV). To determine the effects of this therapy, the sTg levels at each time point were compared between the 2 groups. The first RAI

ablation was performed at a median of 2.8 months and the second RAI ablation at a median of 11 months after thyroidectomy. Initially, the sTg levels of the LSLNB study and control groups were compared by the intention-to-treat principle. Second, the sTg level of the MRND and nonMRND groups were compared, because different surgical methods could have affected the sTg levels. Finally, because the removal of the LSLNs metastases itself could have impacted on the levels of sTg, the sTg levels of the LSLN-positive group were compared with others. Among 191 patients for whom multiple sTg measurements were available, the initial median level of sTg in the LSLNB group was less (P = .012, adjusted for duration) than that in the control group. The second sTg level (after first ablation), however, was not different between the 2 groups. Other comparison did not reveal any significant differences of the first or second sTg levels between the various groups (MRND vs non-MRND and LSLN+ vs others). During follow-up (median duration, 39 months; range, 7–55), 3 cases of recurrence were detected among the controls. One case of recurrence developed in the study group. In the latter case, LSLNB had not been performed, because a SLN

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Table II. Predictive factors for metastasis to the lateral sentinel lymph node (n = 80) Factor

Metastasis (n = 24)

No metastasis (n = 56)

P value

Age (mean ± SD) Sex (male:female), % Laterality, % (right:left:both) Tumor size (cm), median (range) Multiple tumors (%) No. of tumors, median (range) Extent (%) Confined to thyroid Perithyroid Extrathyroid Dissected CLN, median (range) Involved CLN, median (range) Total involved LNs, median (range) Thyroiditis +  Resection margin (%) +  Ablation (frequency), median (range) Ablation (mCi), median (range)

43 ± 11 4 (17):20 (83) 9 (38):10 (42):5 (21) 1.3 (0.7–3.1) 7 (29) 1 (1–3)

47 ± 11 12 (21):44 (79) 22 (39):23 (41):11 (20) 1.3 (0.4–2.8) 20 (36) 1 (1–5)

.161* .765x .987y .141z .570y .454z .592y

7 11 6 10 4 7

(29) (46) (25) (4–30) (0–11) (1–14)

5 (21) 19 (79)

21 26 9 10.5 1 0

(38) (46) (16) (1–31) (0–10) (0–10)

.936z

Lateral neck sentinel lymph node biopsy in papillary thyroid carcinoma, is it really necessary? A randomized, controlled study.

Although occult metastasis to lymph node in the lateral neck compartment is common in papillary thyroid carcinoma (PTC), the clinical impact of these ...
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