Impact of Extranodal Extension on Risk Stratification in Papillary Thyroid Carcinoma

Abstract

Background: The current American Thyroid Association risk-stratification system for papillary thyroid carcinoma (PTC) incorporates the number and size of positive lymph nodes (LNs) but places less weight on extranodal extension (ENE). This study investigated how to incorporate ENE into the current system to predict recurrence better in PTC N1 patients. Methods: A total of 369 N1 PTC patients without distant metastasis were enrolled. The combination of number of positive LNs and LNs with ENE that had the highest C-index were identified with multivariable Cox proportional hazards models. ENE number was incorporated into the current system considering the recurrence rate and unadjusted and adjusted hazard ratios (HRs) of the subgroups. Kaplan-Meier curves for recurrence based on current and alternative systems were compared by log-rank test. Results: The recurrence rate for the subgroup with five or fewer positive LNs and one to three ENEs (7/61; 11.5%) was higher than that of the subgroup with five or fewer positive LNs without ENE (5/129; 3.9%; adjusted HR = 3.42 [confidence interval (CI) 0.99-11.75]; p = 0.050). In contrast, adjusted HRs of the subgroup with more than five positive LNs and one to three ENEs (2.33 [CI 0.52-10.35]) or with four or more ENEs (3.86 [CI 1.05-14.17]) were not higher than those of the subgroup with more than five LNs without ). Incorporating ENE into the current system as an intermediate-risk group yielded a lower log-rank p-value (0.05 vs. 0.01) than the current system. Conclusions: The presence of ENE in low volume LN metastasis confers an intermediate risk of recurrence.Incorporating ENE into the current system allows more accurate decisions regarding further management of PTC N1 patients.

Detailed characterization of metastatic lymph nodes improves the prediction accuracy of currently used risk stratification systems in N1 stage papillary thyroid cancer

“…N1 PTC patients were divided into three groups according to the fraction of MLNs with ENE; ENE was a strong predictor, as shown in univariable and multivariable Cox proportional hazard models (highest HR). Since the presence of ENE might be closely related to the actual number of MLNs, the inclusion of ENE in the 2015 ATA RSS may be difficult (24,38). However, as demonstrated in this study, the use of appropriate statistical analyses to estimate the optimal number or proportion may enable the incorporation of ENE as a clinically useful predictor (24).…”

“…Since the presence of ENE might be closely related to the actual number of MLNs, the inclusion of ENE in the 2015 ATA RSS may be difficult (24,38). However, as demonstrated in this study, the use of appropriate statistical analyses to estimate the optimal number or proportion may enable the incorporation of ENE as a clinically useful predictor (24). Despite the presence of several MLNs with DR, we selected and analyzed the most severe MLNs, which proved to be a prognostic predictor.…”

“…The lymph node ratio (LNR), which is the ratio of the number of positive lymph nodes (LNs) to the total number of surgically removed LNs, reflects an adequate intraoperative evaluation (18,19,20,21). Extranodal extension (ENE) is a marker of clinically significant MLNs (22,23,24). Desmoplastic reaction (DR), which is the growth of dense connective tissue or stroma around malignant neoplasms, is a predictor of LN recurrence and can be present around the actual metastatic lesions in MLNs (25).…”

Prognostic value of lymph node ratio in children and adolescents with papillary thyroid cancer

“…The following study limitations, conversely, should be considered: (1) Although other nodal characteristics, such as extra‐nodal extension 35 and metastatic LN size, 19 may carry prognostic information, it was not possible to retrieve data on these histologic details consistently in this retrospective study over a period of 10 years; (2) Various pathological subtypes (eg tall‐cell and columnar‐cell variants) were not considered in our analyses due to their extremely rare incidence; (3) We did not have genomic information on patients that might impact their competing risks of cancer persistence and recurrence. Recently, genetic markers have also been proposed as prognostic factors for paediatric DTC 36,37 .…”

Extranodal Extension Is an Independent Prognostic Factor in Papillary Thyroid Cancer: A Propensity Score Matching Analysis

“…The presence of ENE is an important prognostic indicator in breast cancer and oral cancer. It has been previously suggested that a new risk stratification system incorporating ENE for predicting structural recurrent disease should be developed, but Shen et al questioned this (11,12). The prognostic role of ENE in PTC has long been controversial.…”