In search of new stratification strategies: tissue proteomic profiling of papillary thyroid microcarcinoma in patients with localized disease and lateral neck metastases.

INTRODUCTION: Papillary thyroid carcinomas (PTC) are the most common thyroid malignancies that are often diagnosed as microcarcinomas when the tumor is less than one centimetre in diameter. Currently, there are no valid stratification strategies that would reliably assess the risk of lateral neck metastases and optimize surgical treatment. MATERIALS AND METHODS: Aiming to find potential tissue biomarkers of metastatic potential, we conducted a cross-sectional proteomic pilot study on formalin-fixed paraffin-embedded tissues of metastatic (N = 10) and non-metastatic (N = 10) papillary thyroid microcarcinoma patients. Samples were analysed individually using liquid chromatography/mass spectrometry, and the differentially expressed proteins (DEP) were functionally annotated. RESULTS: We identified five overexpressed DEPs in the metastatic group (EPB41L2, CSE1L, GLIPR2, FGA and FGG) with a known association to tumour biology. Using bioinformatic-based tools, we found markedly different profiles of significantly enriched biological processes between the two groups. CONCLUSIONS: The identified DEPs might have a role as potential tissue biomarkers for PTC metastases. However, further prospective research is needed to confirm our findings.

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.

Can Unilateral Therapeutic Central Lymph Node Dissection Be Performed in Papillary Thyroid Cancer with Lateral Neck Metastasis?

Objectives: Unilateral or bilateral prophylactic central neck dissection (CND) in papillary thyroid cancer (PTC) is still controversial. We aimed to evaluate the risk factors for contralateral paratracheal lymph node metastasis and whether CND might be performed unilaterally. Methods: Prospectively collected data of patients who underwent bilateral CND and lateral neck dissection (LND) with thyroidectomy due to PTC with lateral metastases, between January 2012 and November 2019, were evaluated retrospectively. The patients were divided into two groups according to the presence (Group 1) and absence (Group 2) of metastasis in the contralateral paratracheal region.A total of 42 patients (46 ±15.7 years) were operated. In the contralateral paratracheal region, Group 1 (35.7%) had metastases, while Group 2 (64.3%) had no metastases. In groups 1 and 2, metastasis rates were 100% vs 77.8% (p=0.073), 46.7% vs 18.5% (p=0.078), and 80% vs 40.7% (p=0.023) for the ipsilateralparatracheal, prelaryngeal and pretracheal lymph nodes, respectively.The number of metastatic lymph nodes in the central region was significantly higher in Group 1 compared to Group 2 as; 10.7±8.4 vs. 2.6±2.4 (p=0.001) in bilateral central region material; 8.3±7.4 vs. 2.9±2.7 (p=0.001) in lateral metastasis with ipsilateral unilateral central region; 3.8±3.4 vs. 1.9±1.9 (p=0.023) in ipsilateralparatracheal area; and 3.7±4.6 vs. 0.6±0.9 (p=0.001) in pretracheal region, respectively. However, no significant difference was found regarding the prelaryngeal region material (0.9±1.8 vs. 0.2±0.4 (p=0.71)). Results: >2 metastatic central lymph nodes in unilateral CND material (AUC: 0.814, p<0.001, J=0.563) can estimate contralateral paratracheal metastasis with 93% sensitivity, 63% specificity, while >2 pretracheal metastatic lymph nodes (AUC: 0.795, p<0.001, J: 0.563) can estimate contralateral paratracheal metastasis with 60% sensitivity and 96.3% specificity. Conclusion: In patients with lateral metastases, the rate of ipsilateralparatracheal metastasis is 85%, while the rate of contralateral paratracheal metastasis is 35.7%. The number of ipsilateral central region or pretracheal lymph node metastases may be helpful in predicting contralateral paratracheal lymph node metastases. Notably, unilateral CND may be performed in the presence of ≤ 2 metastases in the ipsilateral central region.

Differentiated Thyroid Cancer: The Role of ATA Nodal Risk Factors in N1b Patients.

OBJECTIVES/HYPOTHESIS: Nodal involvement is frequent in patients with differentiated thyroid cancers (DTCs), but its prognostic relevance is not univocal. Some characteristics of nodal metastases can increase the risk of recurrence. We attempted to quantify the impact on survival of nodal factors included in the American Thyroid Association (ATA) risk stratification system in N1b patients with DTC. STUDY DESIGN: Retrospective study. METHODS: A retrospective analysis of patients affected by DTC who underwent therapeutic lateral neck dissection (ND) was performed. The impact on the prognosis of the number of positive lymph nodes (LNs), dimension of nodal metastasis, and microscopic and macroscopic extranodal extension (miENE and maENE, respectively) was investigated. RESULTS: The study included 347 N1b patients who underwent 401 therapeutic lateral NDs. Mean number of positive LNs was nine, mean nodal ratio was 0.27, and mean diameter of metastasis was 15.5 mm. ENE was detected in 25.9% of patients (22.5% miENE and 3.5% maENE). In univariate analysis, the presence of maENE had an impact on disease specific survival (DSS) (P = .023); increasing number of positive LNs affected DSS and locoregional control (LRC) (P = .009 and =.006, respectively); increasing metastatic node dimension was a risk factors for overall survival, DSS, and metastases free survival (MFS) (P = .05, =.013 and =.016). In multivariate analysis, number of positive LNs and LN dimension were independent risk factors for LRC and MFS, respectively (HR 1.1, P = .028; HR 1.1, P = .026). CONCLUSIONS: In our analysis on a cohort of N1b patients, the number of positive LNs and LN dimension were confirmed as independent risk factors for locoregional and distant recurrence, respectively. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1029-E1034, 2021.

Diagnostic Accuracy of Ultrasound for the Evaluation of Lateral Compartment Lymph Nodes in Papillary Thyroid Carcinoma.

AIMS: To evaluate the diagnostic accuracy of ultrasound (US) assessing the lateral compartment lymph node metastasis in patients with primary papillary thyroid carcinoma (PTC), and to demonstrate the incidence and patterns of the lateral lymph node metastasis. METHODS: We retrospectively reviewed 198 patients with primary PTC who underwent thyroidectomy in addition to modified lateral neck dissections (MLND) involving level II to level V due to clinically positive lateral neck disease. A skilled and experienced single operator performed all US examinations. Surgical pathology results were accepted as the reference method and sensitivity, specificity, and diagnostic accuracy of US in detecting metastatic lymph nodes established using level-by-level analysis. RESULTS: In the study cohort, 10.1% of the patients had lateral compartment lymph node metastases without any central compartment involvement. For the lateral compartment, 48.5% had level II, 74.7% had level III, 64.6% had level IV, and 29.3% of the patients had level V metastasis. None of the patients had isolated level V metastasis. The sensitivity, specificity, and diagnostic accuracy of US in identifying lateral lymph compartment metastasis ranged from 87% to 91.4%, 92% to 98.6% 92.4% to 96%, respectively. However, the sensitivity (74.7%) and diagnostic accuracy (76.2%) of US significantly decreased for the central compartment while specificity (90%) remained similar. CONCLUSION: US performed by a skilled operator has an excellent diagnostic accuracy for the evaluation of lateral cervical lymph nodes in primary PTC; thus, might enable precise tailoring of the management strategies. Moreover, the high incidence of level V involvement favors MLND over selective approaches.

Cystic Lateral Lymph Node Metastases From Papillary Thyroid Cancer Patients.

OBJECTIVES/HYPOTHESIS: Papillary thyroid carcinoma (PTC) tends to metastasize rather early to local lymph nodes (LNs). Incidences of cystic LN metastases is relatively rare compared with that of solid LN metastases. Few studies have attempted to assess the characteristics in these patients. This study aimed to compare the clinicopathologic characteristics and surgical outcomes between patients with cystic LN metastases and those with solid LN metastases. STUDY DESIGN: Retrospective cohort study. METHODS: We retrospectively reviewed the data of 1,028 patients with N1b PTC who underwent bilateral total thyroidectomy with central compartment neck dissection and modified radical neck dissection between January 2005 and September 2011. Of these, 136 (13.2%) had cystic LN metastases and 892 (86.8%) had solid LN metastases. Clinicopathologic characteristics and surgical outcomes were compared between these two patient groups. RESULTS: The proportion of patients with thyroid tumor multifocality was relatively higher in the cystic node cohort (19.9% vs. 12.7%, P = .048). The number of total metastatic LNs and positive lateral LNs was slightly higher in the cystic node cohort (11.3 ± 8.9 vs. 9.7 ± 7.5, P = .029 and 6.9 ± 6.3 vs. 5.5 ± 4.6, P = .018, respectively). The proportion of patients with recurrence was higher in the cystic node cohort (14.0% vs. 3.0%, P < .001). Multivariate analysis indicated that cystic nodes were a significant risk factor for recurrence (hazard ratio: 5.265, 95% confidence interval: 2.898-9.563). CONCLUSIONS: This study demonstrates that cystic lateral LN metastases are associated with aggressive tumor behavior in PTC patients. and that their presence is a significant independent prognostic factor for disease-free survival. LEVEL OF EVIDENCE: 2b Laryngoscope, 2020.

Lateral neck metastases in the ipsilateral and contralateral compartments of papillary thyroid carcinoma located in one lobe.

BACKGROUND: Papillary thyroid carcinoma (PTC) frequently involves lymph nodes in the lateral compartment, but PTC located in one lobe rarely metastasizes to bilateral lateral nodes. This study was designed to evaluate the clinicopathological features of patients with PTC limited to one lobe but with bilateral lateral neck metastasis (LNM). METHODS: Between January 2009 and December 2013, 698 patients with unilateral PTC with LNM were analysed. Of these patients, 651 had unilateral LNM (ULNM) and 47 had bilateral LNM (BLNM). The clinicopathological characteristics of the two groups were analysed. RESULTS: There were no significant between-group differences in age, extrathyroidal extension, multifocality in one lobe, thyroiditis or psammomatous calcification. Male sex (51.1% versus 29.8%; P = 0.002), central compartment metastasis (91.5% versus 78.6%, P = 0.035), aggressive subtype of PTC (23.4% versus 8.8%; P = 0.001) and Delphian node metastasis (36.2% versus 18.1% versus 36.2%, P = 0.002) were significantly more frequent, and mean primary tumour size (1.79 ± 1.12 cm versus 1.34 ± 0.83 cm, P = 0.010) significantly larger in the BLNM than in the ULNM group. CONCLUSIONS: Although few patients with PTC located in one lobe have BLNM, the contralateral lateral compartment should be carefully evaluated for BLNM in males and in patients with a primary tumour size >2 cm, aggressive subtype of PTC, central node metastasis and Delphian node metastasis.

Preoperative serum VEGF-C but not VEGF-A level is correlated with lateral neck metastasis in papillary thyroid carcinoma.

BACKGROUND: This study aimed to investigate the relationships between serum vascular endothelial growth factor (VEGF)-A or VEGF-C levels and lymph node metastasis (LNM) status in patients with papillary thyroid carcinoma (PTC). METHODS: The study enrolled 150 patients with pathologically proven PTC who underwent surgery: PTC without LNM, PTC with central neck metastasis, and PTC with lateral neck metastasis. RESULTS: Preoperative serum VEGF-A levels were 300.12 ± 80.80 pg/mL overall and were not correlated with the presence of LNM. Preoperative serum VEGF-C levels were 132.41 ± 48.48 pg/mL overall and were significantly correlated with the presence of LNM. Serum VEGF-C levels were further increased in patients with lateral neck metastasis and positively correlated with the number of metastatic LNs (rho = 0.252, P = 0.002). Serum VEGF-C, but not VEGF-A, was identified as a significant predictor of lateral neck metastasis. CONCLUSION: Serum VEGF-C might be a clinically relevant biomarker of lateral neck metastasis in patients with PTC.

Accuracy of preoperative MRI to assess lateral neck metastases in papillary thyroid carcinoma.

Primary treatment of papillary thyroid carcinoma (PTC) with lateral lymph node metastasis is surgery, but the extent of lateral neck dissection remains undefined. Preoperative imaging is used to guide the extent of surgery, although its sensitivity and specificity for defining the number and level of affected lymph nodes on the lateral neck is relatively modest. Our aim was to assess the role of preoperative magnetic resonance imaging (MRI) in predicting the requisite levels of neck dissection in patients with regionally metastatic PTC, with a focus on Levels II and V. All patients with PTC and lateral neck metastasis who had undergone neck dissection at the Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital, Helsinki, Finland from 2013 to 2016 and had a preoperative MRI available were retrospectively reviewed. A head and neck radiologist re-evaluated all MRIs, and the imaging findings were compared with histopathology after neck dissection. In the cohort of 39 patients, preoperative MRI showed concordance with histopathology for Levels II and V as follows: sensitivity of 94 and 67%, specificity of 20 and 91%, positive predictive value of 56 and 75%, and negative predictive value of 75 and 87%, respectively. In PTC, MRI demonstrated fairly high specificity and negative predictive value for Level V metastasis, and future studies are needed to verify our results to omit prophylactic dissection of this level. Routine dissection of Level II in patients with regionally metastatic PTC needs to be considered, as MRI showed low specificity.

Surgical Outcomes of Robotic MRND versus Conventional Open MRND for Papillary Thyroid Carcinoma with Lateral Neck Node Metastasis: Comparative Analysis using Propensity Score Matching / 대한내분비외과학회지

PURPOSE: During the past decade, various endoscopic thyroid surgeries have been conducted, each with its own benefits. The incorporation of robotic systems to endoscopic thyroid surgery has improved the visualization and precision of endoscopic techniques. We previously reported our initial experience with robotic modified radical neck dissection (MRND) of papillary thyroid carcinoma (PTC) with lateral neck node metastasis (LNM). The aim of this study was to compare surgical outcomes of robotic vs. conventional open MRND of PTC with LNM using propensity score matching. METHODS: From January 2008 to February 2011, 515 patients with PTC with LNM were enrolled. One hundred patients underwent robotic MRND, and 415 patients underwent conventional open MRND. These two groups were retrospectively compared with respect to their clinicopathological characteristics, surgical outcomes, and surgical completeness. Furthermore, to avoid selection bias, propensity score matching analysis was used to compare surgical outcomes of each group without any compounding factors. RESULTS: The operative time for the robotic MRND was longer than for the open MRND (297.9±60.2 min vs. 212.1±55.6 min, P=0.089). However, the mean numbers of retrieved lymph nodes and mean hospital stay after surgery were similar in the two groups (36.0±12.9 vs. 40.8±13.3, P=0.235), (6.1±1.6 days vs. 6.1±2.1 days, P=0.577). The complication rates were similar between the two groups, and there was no statistical difference in postoperative thyroglobulin levels between groups (0.51±0.83 ng/ml vs. 0.89±2.46 ng/ml, P=0.593). CONCLUSION: According to our study, robotic MRND shows similar surgical outcomes to conventional open MRND after case-matched analyses. We suggest that robotic MRND is an acceptable alternative as an operative method for PTC with LNM, resulting in excellent cosmesis and patient satisfaction.