Research Article: Minimal extrathyroidal extension affects the prognosis of differentiated thyroid cancer: Is there a need for change in the AJCC classification system?

Date Published: June 14, 2019

Publisher: Public Library of Science

Author(s): Zeming Liu, Yihui Huang, Sichao Chen, Di Hu, Min Wang, Ling Zhou, Wei Zhou, Danyang Chen, Haifeng Feng, Wei Wei, Chao Zhang, Wen Zeng, Liang Guo, Scott M. Langevin.


Minimal extrathyroidal extension (ETE) is defined as tumor cells extending to the sternothyroid muscle or perithyroidal soft tissue. However, there is controversy regarding whether the magnitude of ETE (minimal or gross) should be considered in assigning a precise TNM stage to patients with thyroid cancer in the seventh/eighth editions of the AJCC system. The present study evaluated Surveillance, Epidemiology, and End Results data from 107,114 patients with differentiated thyroid cancer (2004–2013) to determine whether the magnitude of ETE (thyroid confinement, minimal, or gross) influenced the ability to predict cancer-specific survival (CSS) and overall survival (OS). Patient mortality was evaluated using Cox proportional hazards regression analyses and Kaplan-Meier analyses with log-rank tests. The cancer-specific mortality rates per 1,000 person-years were 1.407 for the thyroid confinement group (95% CI: 1.288–1.536), 5.133 for the minimal ETE group (95% CI: 4.301–6.124), and 29.735 for the gross ETE group (95% CI: 28.147–31.412). Relative to the thyroid confinement group, patients with minimal ETE and gross ETE had significantly poorer CSS and OS in the univariate and multivariate analyses (both P<0.001). After propensity-score matching according to age, sex, and race, we found that thyroid confinement was associated with better CSS and OS rates than minimal ETE (P<0.001) and gross ETE (P<0.001). These results from a population-based cohort provide a reference for precise personalized treatment and management of patients with minimal ETE. Furthermore, it may be prudent to revisit the magnitude of ETE as advocated by the AJCC and currently used for treatment recommendation by the American Thyroid Association.

Partial Text

The incidence of thyroid cancer has generally been increasing during recent decades, although the mortality rate has steadily declined [1]. For example, during 2008–2012, most countries had age-standardized mortality rates of 0.20–0.40/100,000 men and 0.20–0.60/100,000 women, with steady increases among both sexes in the incidence of thyroid cancer (mainly papillary carcinoma) [1]. Differentiated thyroid carcinomas include papillary and follicular thyroid carcinomas [2], which are among the most curable of all cancers. However, some patients have a high risk of recurrence or even death from papillary and follicular thyroid carcinomas [3], with specific clinicopathological features being associated with progression and a dire prognosis even after extensive surgery, radioactive iodine (RAI) ablation therapy, and thyroid-stimulating hormone suppression [4]. Thus, well-established clinicopathological indicators must be used to predict patient prognosis and select treatment for differentiated thyroid carcinoma.

This study’s retrospective protocol was approved by Zhongnan Hospital and Union hospital’s ethical review board and complied with the ethical standards of the Declaration of Helsinki, as well as the relevant national and international guidelines. The study cohort was comprised of 107,114 patients with differentiated thyroid cancer from the SEER database (2004–2013). Among these patients, the extent of tumor extension was classified as confinement to the thyroid parenchyma (80.5%), minimal ETE (6.0%), or gross ETE (10.2%). A total of 3,529 patients were excluded based on missing or unknown data regarding tumor extension.

Cases with ETE can be classified as minimal ETE (i.e., extension to the thyroid capsule, sternothyroid muscle, or perithyroidal soft tissue) or gross ETE (i.e., extension to the subcutaneous soft tissue, larynx, esophagus, trachea, recurrent laryngeal nerve, prevertebral fascia, mediastinal vessels, or carotid arteries) [14]. The magnitude of ETE has historically been thought to influence the assignment of T status, which in turn influences the TNM stage and selection of treatment options. However, it is difficult to define the precise boundary of extrathyroid and intrathyroidal tissues when determining the extent of cancer invasion, as both living patients and autopsy cases have failed to exhibit a complete or continuous fibrous capsule around the thyroid gland. This is a source of concern at our institution, as patients with AJCC stage III and stage IV tumors are routinely treated using RAI remnant ablation, or using external beam radiation therapy if they are older and have RAI-resistant tumors [15, 16]. Thus, there is debate regarding the importance of ETE in predicting the progression of differentiated thyroid carcinoma.

In conclusion, we suggest that minimal ETE may be associated with an increased risk of poor CSS and OS outcomes. In addition, patients with gross ETE have a greater risk of poor outcomes than patients with minimal ETE or thyroid confinement. Therefore, we believe that further discussion and research are needed to examine the omission of minimal ETE from the current AJCC staging system.