Optimal value of lymph node ratio and metastatic lymph node size to predict risk of recurrence in pediatric thyroid cancer with lateral neck metastasis.

BACKGROUND: No specific guideline exists for risk stratification based on lymph node (LN) status in pediatric thyroid cancer. The purpose of our study is to identify optimal values of lymph node ratio (LNR) and largest metastatic LN size for predicting recurrent/persistent disease, especially in children with lateral neck metastasis (N1b). METHODS: We conducted a retrospective study from January 1997 to June 2018 at Samsung Medical Center. A total of 50 papillary thyroid carcinoma (PTC) patients who underwent total thyroidectomy + both central neck dissection (CND) + modified radical neck dissection (MRND) (unilateral or bilateral) was enrolled. RESULTS: The median follow-up duration was 60.8 months (range, 6.2-247 months). The mean age was 14.6 years, and the mean tumor size was 2.9 cm. Mean size of the largest metastatic LN was 1.5 cm. Mean value of central LNR was 0.6, and mean value of lateral LNR was 0.3. Largest metastatic LN size [HR = 2.0 (95% CI 1.0-4.0), p = 0.040] and lateral LNR [HR = 43.6 (95% CI 2.2-871.0), p = 0.014] were significant prognostic factors for recurrence. The optimal combination of lateral LNR and largest metastatic LN size to predict recurrence were 0.3 and 2.5 cm, respectively, with the largest AUC (AUC at 60 months = 77.4) and significant p-value (p = 0.009 and p = 0.021) (Table 3). Kaplan-Meier curves showed significant differences in recurrence-free survival (RFS) rates among four groups (Fig. 2A,2B). CONCLUSIONS: In pediatric PTC patients with N1b, lateral LNR and largest metastatic LN size are significant predictors for recurrence. Children with lateral LNR > 0.3 or any metastatic lymph node > 2.5 cm in the largest dimension have higher risk for recurrence. Children are classified as extensive N1b if lateral LNR > 0.3 or pathologic N1 with largest LN size > 2.5 cm, and vice versa.

Is total thyroidectomy with bilateral central neck dissection the only surgery for papillary thyroid carcinoma patients with clinically involved central nodes?

BACKGROUND: In clinical practice, we often observed that patients who underwent total thyroidectomy due to clinically involved nodal disease (cN1a) actually had less extensive CLNM on final pathology. This study investigates whether total thyroidectomy and therapeutic bilateral CND are necessary for all PTC patients with cN1a. METHODS: This study retrospectively reviewed 899 PTC patients who underwent total thyroidectomy with bilateral CND from January 2012 to June 2017. The patients were divided into two groups according to pre-operative central lymph node (CLN) status: cN0, no suspicious CLNM; cN1a, suspicious CLNM. We compared the clinicopathological features of these two groups. RESULTS: There was no significant difference in recurrence between cN0 and cN1a groups after a mean follow-up time of 59.1 months. Unilateral cN1a was related to the largest central LN size ≥ 2 mm (OR = 3.67, p < 0.001) and number of CLNM > 5(OR = 2.24, p = 0.006). On the other hand, unilateral cN1a was not associated with an increased risk of contralateral lobe involvement (OR = 1.35, p = 0.364) and contralateral CLNM (OR = 1.31, p = 0.359). Among 106 unilateral cN1a patients, 33 (31.1%) were found to be pN0 or had ≤ 5 metastatic CLNs with the largest node smaller than 2 mm. CONCLUSIONS: Most cN1a patients were in an intermediate risk group for recurrence and required total thyroidectomy. However, lobectomy with CND should have performed in approximately 30% of the cN1a patients. Pre-operative clinical examination, meticulous radiologic evaluation, and intra-operative frozen sections to check the nodal status are prerequisites for this approach.

Total thyroidectomy can be overtreatment in cN1a papillary thyroid carcinoma patients whose tumor is smaller than 1 cm.

BACKGROUND: The 2015 American Thyroid Association (ATA) guidelines recommend pursuing total thyroidectomy with therapeutic central lymph-node dissection (CND) in patients with clinically apparent nodal disease (cN1a), regardless of tumor size. The aim of this study was to investigate whether total thyroidectomy is necessary for thyroid papillary microcarcinoma (PTMC) patients with preoperative unilateral cN1a. METHODS: This study included 295 papillary thyroid microcarcinoma patients who underwent total thyroidectomy with bilateral CND from January 2012 to June 2015. RESULTS: The median follow-up time was 42.5 months. Locoregional recurrence (LRR) was observed in only two (0.9%) patients. Among 70 cN1a patients, only 19 (27.1%) were at intermediate risk for disease recurrence and required total thyroidectomy per the ATA guidelines. Lobectomy can be considered as a treatment option for the remaining patients (72.9%). CONCLUSIONS: Our study showed that more than two-thirds of PTMC patients with clinical nodal disease who underwent total thyroidectomy and CND were actually lobectomy candidates. Total thyroidectomy as the first surgical option for cN1a, especially in PTMC patients, should be reconsidered.

The clinical impact of extrathyroidal extensions on prognoses in pediatric differentiated thyroid cancers.

BACKGROUND: The prognostic impact of extrathyroidal extensions (ETE) on clinical outcomes has not been well studied in pediatric thyroid cancers. The aim of this study was to analyze the clinicopathological characteristics and clinical outcomes according to the extent of ETE in pediatric and adolescent thyroid cancers. METHODS: This study retrospectively reviewed 89 papillary thyroid carcinoma (PTC) patients less than 19 years of age who underwent total thyroidectomy with central neck dissections (CND) between 1997 and 2018. We compared the clinicopathological features among three groups: no ETE, microscopic ETE, and gross ETE. RESULTS: The median follow-up time was 111 months. The mean age was 15.3 years and the mean tumor size was 2.4 cm. Tumor sizes larger than 2 cm (OR = 9.2, p = 0.001), exhibited bilaterality (OR = 4.3, p = 0.006), were an aggressive variant (OR = 5.8, p = 0.006), and exhibited central lymph node metastasis (OR = 1.3, p = 0.018), lateral lymph node metastasis (OR = 9.2, p = 0.001), recurrence (OR = 3.9, p = 0.038), and distant metastasis (OR = 4.4, p = 0.016) were associated with gross ETE. There was no remarkable difference in clinicopathological characteristics between the no ETE group and microscopic ETE group, except for aggressive variants (OR = 5.5, p = 0.008). There was a significant difference in recurrence-free survival (RFS) rates according to the extent of ETE (p = 0.025). Furthermore, the distant metastasis-free survival curve presented a significant difference among the three groups (p = 0.018). Both microscopic ETE and gross ETE were significantly associated with worse prognoses in pediatric thyroid cancers. CONCLUSIONS: We recommend that microscopic ETE should be included in the intermediate risk category and that gross ETE should be stratified in the high risk group in future revisions of ATA pediatric guidelines.

Feasibility of lateral sentinel lymph node biopsy in medullary thyroid cancer: Surrogate tool for determining prophylactic lateral neck dissection-A pilot study.

BACKGROUNDS: This study aimed to evaluate usefulness of lateral sentinel lymph node biopsy (SLNB) in determining lateral neck dissection (LND) of patients with medullary thyroid cancer (MTC). METHODS: Sixteen patients with MTC were enrolled in the study from January 2013 to June 2019. Intratumoral injection of technetium (Tc)-99m phytate followed by lymphoscintigraphy was performed preoperatively. Lateral sentinel lymph nodes were detected by a collimated gamma probe and underwent frozen analysis. Ipsilateral LND was performed in all patients to assess lateral LN status. RESULTS: The identification rate of sentinel lymph nodes (SLNs) detected by radioisotope was 87.5% (14 of 16 patients). The sensitivity, specificity, positive predictive value, and negative predictive value of frozen analyses were 66.7%, 100%, 100%, and 91.6%, respectively. Based on final histopathology, however, the diagnostic values of lateral SLNB were all 100%. CONCLUSIONS: This study showed that lateral SLNB can be a promising surgical tool for decisions on LND in patients with MTC.

Occult contralateral central neck metastasis in papillary thyroid carcinoma with preoperatively documented ipsilateral lateral neck metastasis.

BACKGROUND: This study was conducted to evaluate risk factors and long-term prognosis of contralateral central neck metastasis (CCNM) in papillary thyroid cancer (PTC) patients with ipsilateral lateral neck metastasis. We present clinical evidence to aid in surgical decision-making regarding the extent of central neck dissection (CND), focusing on separation between ipsilateral and contralateral sides. METHODS: A total of 379 PTC patients who underwent total thyroidectomy and concomitant bilateral central neck dissection with ipsilateral lateral neck dissection (LND) at a single institution was retrospectively included between January 1997 and December 2015. RESULTS: The median follow-up time was 83.2 months, the mean age was 44.3 years, and the mean tumor size was 1.5 cm. Among the study sample, 266 patients were female (70.2%) and 113 (29.8%) were male. Of 379 patients, CCNM was present in 34.6%. In multivariate analysis, male sex (adjusted OR = 2.46, p = 0.002), bilaterality (adjusted OR = 2.58, p = 0.004), number of metastatic ipsilateral central lymph nodes (adjusted OR = 1.15, p = 0.002), number of metastatic lateral lymph nodes (adjusted OR = 1.48, p < 0.001), and three-level metastasis (adjusted OR = 2.46, p = 0.012) were identified as risk factors of CCNM. Overall recurrence occurred in 6.0% and 11.5% of patients in the CCNM (-) group and CCNM (+) group, respectively. In addition, contralateral recurrence was observed in 1.2% patients and 0.8% patients in the CCNM (-) group and CCNM (+) group, respectively. However, CCNM did not significantly increase risk of recurrence (adjusted HR = 1.01, p = 0.981). CONCLUSIONS: Although the probability of pathological CCNM is not negligible, CCNM was not associated with higher risk of recurrence. This study suggest that central neck dissection may be limited to the ipsilateral side, and the result regarding prognosis of CCNM may help to avoid bilateral CND so that it could have potential to minimize unnecessary surgery-related complications such as recurrent laryngeal nerve(RLN) injury or hypoparathyroidism.

Does microscopic positive tumor margin in papillary thyroid cancer really matter?

BACKGROUND: The clinical impact of microscopically positive tumor margin in papillary thyroid cancer is not well studied. The aim of this study is to evaluate the clinical importance of a microscopically positive margin for recurrence in papillary thyroid cancer patients and to examine whether recurrence and recurrence-free survival were affected by the location of the positive margin-anterior or posterior. METHODS: We conducted a retrospective cohort study at a single institution. From January 1997 to June 2015,6,293 papillary thyroid cancer patients who underwent total thyroidectomy with or without neck dissection (central and/or lateral) at the Thyroid Cancer Center of Samsung Medical Center (Seoul, South Korea) were included in the analyses. RESULTS: Of the 6,293 papillary thyroid cancer patients, an operative margin was microscopically involved in 313 (5.0%) on final pathologic report. The mean follow-up time was 77.5 months, and locoregional recurrence was observed in 244 (3.9%) patients. The presence of a microscopically positive margin did not increase the risk of locoregional recurrence (adjusted hazard ratio = 1.079, P = .140) after adjustment for other statistically significant factors in the Cox proportional hazard model. In addition, posterior positive margin was not a risk factor for locoregional recurrence as well (adjusted hazard ratio = 1.24, P = .672). In a propensity score-matching analysis, a microscopically positive margin did not increase the risk of locoregional recurrence. CONCLUSION: Microscopic involvement of the operative margin in papillary thyroid cancer patients, whether anteriorly or posteriorly, does not appear be an independent prognostic factor in recurrence-free survival rates.

Superior Located Papillary Thyroid Microcarcinoma is a Risk Factor for Lateral Lymph Node Metastasis.

BACKGROUND: It is important to identify prognostic factors for lateral lymph node metastasis (LLNM) in papillary thyroid microcarcinoma (PTMC) because they determine the extent of surgery. Several similarly designed studies have investigated predictors of LLNM, but with no more than 1000 cases. In addition, there are no recommendations or guidelines covering the differences in risk by tumor location. This study is the largest, using a papillary thyroid microcarcinoma population with 2967 patients. The purpose of this study is to address predictive factors of LLNM, focusing on lesion location. PATIENTS AND METHODS: We retrospectively reviewed the data of 2967 PTMC patients who underwent total thyroidectomy and central neck dissection and/or lateral neck dissection (unilateral or bilateral) between January 1997 and June 2015. RESULTS: On multivariate analysis, superior lesion [adjusted odds ratio (OR) 3.32, p < 0.000], male gender (adjusted OR 1.39, p = 0.0047), age under 45 years (adjusted OR 1.42, p = 0.015), and central lymph node metastasis (adjusted OR 3.40, p < 0.000) were significant predictors of high-risk LLNM. Superior lesion [hazard ratio (HR) 2.32, p = 0.005] and central lymph node metastasis (CLNM, HR 7.12, p < 0.000) were significant risk factors for locoregional recurrence (LRR). To reduce the effect of selection bias, we performed propensity score matching analysis with regard to tumor location. With a total of 1138 patients with matched data and 569 patients for each location, superior lesion (adjusted OR 3.17, p < 0.000), age under 45 years (adjusted OR 1.73, p = 0.005), and CLNM (adjusted OR 2.77, p < 0.000) were independent predictive factors of LLNM. Superior lesion (HR 2.28, p = 0.04) and CLNM (HR 5.32, p = 0.001) were significant risk factors for LRR. CONCLUSIONS: In addition to young age, male gender, and CLNM identified in previous studies, meticulous assessment for LLNM is required in PTMC patients when lesions are located in the superior pole of the thyroid during preoperative evaluation or postoperative follow-up, because superior located papillary microcarcinoma is a risk factor for LLNM and LRR.

Predictive Factors of Lymph Node Metastasis in Follicular Variant of Papillary Thyroid Carcinoma.

BACKGROUND: Compared with conventional papillary thyroid carcinoma (PTC), follicular variant of PTC (FV-PTC) shows less aggressive behavior and better prognosis. Nonetheless, regional lymph node (LN) metastasis was found in 22.8% of FV-PTC patients. Because LN metastasis is a proven predictor of recurrence in PTC, it is important to assess LN metastasis in FV-PTC patients. METHODS: We retrospectively reviewed 134 FV-PTC patients who underwent thyroidectomy with neck dissection. RESULTS: Central LN metastasis (CLNM) and lateral LN metastasis (LLNM) were found in 50 (37.3%) and 16 (11.9%) patients, respectively. In the multivariate analysis for CLNM, male sex (adjusted OR 4.735, p = 0.001), nonencapsulated form (adjusted OR 2.863, p = 0.022), and tumor size >1.0 cm (adjusted OR 3.157, p = 0.008) were independent predictors of high prevalence of CLNM in FV-PTC patients. In the multivariate analysis for LLNM, microscopic extrathyroidal extension (ETE) (adjusted OR 3.939, p = 0.041) and CLNM (adjusted OR 13.340, p = 0.001) were independent predictors of high prevalence of LLNM in FV-PTC patients. CONCLUSIONS: Meticulous perioperative evaluation and prophylactic central neck dissection may be beneficial for FV-PTC patients with male sex, nonencapsulated form, and tumor size >1.0 cm. Moreover, cautious perioperative evaluation of lateral neck LN may be mandatory for FV-PTC patients with microscopic ETE and CLNM.