Strap muscle invasion in differentiated thyroid cancer does not impact disease-specific survival: a population-based study

The American Joint Committee on Cancer (AJCC) 8th TNM staging system of differentiated thyroid cancer defines gross strap muscle invasion as T3b stage. However, the impact of strap muscle invasion on disease-specific survival (DSS) remains controversial. To elucidate the survival impact of strap muscle invasion of any degree in thyroid cancers, the Surveillance, Epidemiology, and End Results (SEER) database (1973–2018) was queried for thyroid cancer only patients on July 2019 (n = 19,914). The Cox proportional hazard analysis with multivariable adjustment revealed that strap muscle invasion was not a significant factor for DSS in tumors equal to or smaller than 40 mm (hazard ratio (HR) = 1.620 [confidence interval (CI) 0.917 – 2.860]; p = 0.097). The competing risk analysis with multivariable adjustment showed that strap muscle invasion did not significantly impact DSS regardless of tumor size or cause of death (cancer-caused death (Subdistribution HR (SDHR) = 1.567 [CI 0.984 – 2.495]; p = 0.059); deaths to other causes (SDHR = 1.155 [CI 0.842 – 1.585]; p = 0.370). A “modified” staging schema discarding strap muscle invasion as a T stage criterion showed better 10-year DSS distinction between T stages. The modified staging schema may better reflect cancer-caused death risk and may prevent potential overstaging.


Scientific Reports
| (2020) 10:18248 | https://doi.org/10.1038/s41598-020-75161-y www.nature.com/scientificreports/ cancer survival surveillance in the United States. This openly available database has compiled cancer incidence and survival data since 1973. Accordingly, it is an ideal database for analyzing the effect of gross ETE on overall survival in thyroid cancer. Therefore, the purpose of this study was to explore the impact of strap muscle invasion alone, both minimal and gross, on the disease-specific survival (DSS) of differentiated thyroid cancer (DTC) patients using the SEER database, and to potentially improve the survival prediction power of the TNM staging schema.
Prognostic impact of strap muscle invasion alone on 10-year DSS. Cox proportional hazard analysis was performed to estimate the prognostic impact of strap muscle invasion on DSS in all patients (n = 19,914) and in the subgroup of patients with tumor size equal to or smaller than 40 mm (n = 17,837) ( Table 3). Univariable and multivariable analyses revealed that strap muscle invasion alone as well as age, tumor size, major organ invasion, major vessel invasion, LN metastasis, distant metastasis, and chemotherapy were significant prognostic factors for DSS. Subgroup analysis of tumors equal to or smaller than 40 mm in size showed that although strap muscle invasion alone was a significant prognostic factor for DSS on univariable Cox regression analysis, it was not a significant prognostic factor for DSS on multivariable analysis.  Table S1). In addition, in the subgroup of patients 55 years old of age or older, multivariable competing risk analysis showed that strap muscle invasion only did not significantly impact death due to any cause, despite its significance on univariable competing risk analysis (Supplementary Table S2).
10-year DSS according to the T stages of the AJCC 8th TNM staging and the modified TNM staging schemas. Table 2 showed the 10-year DSS and the number of patients in each T stage according to either the AJCC 8th TNM staging schema or the "modified" TNM staging schema (discarding strap muscle invasion from the T stage criteria). While there was an overall negative correlation between T stage and 10-year DSS per the AJCC 8th staging schema, the T3b stage showed better 10-year DSS than the T3a stage (Fig. 1a).
Evaluation of the power of survival prediction for the AJCC 8th and the modified TNM staging schemas. The Harrell's C concordance indices (C-indices) of the AJCC 8th and the modified TNM staging schemas was estimated as 0.9418 and 0.9405, respectively, but without statistically significant difference (p = 0.220). The proportion of variance explained (PVE) for DSS prediction with the AJCC 8th and the modified TNM staging schemas was estimated as 4.45% and 4.43%, respectively.

Discussion
This study suggested that strap muscle invasion alone of any degree was not a statistically significant prognostic factor of DSS in all tumor sizes of DTC. In particular, this finding may significantly impact tumors equal to or smaller than 40 mm, which may be overstaged by the current AJCC 8th TNM staging schema. In addition, survival analysis of the T3b group according to the AJCC 8th TNM staging schema showed that it consists of a heterogeneous group of patients with significantly different DSS according to tumor size. T3b patients reallocated to either the T1 or T2 stage according to the suggested modified staging schema showed significantly better DSS compared to those in the T3 stage. Historically, ETE was assumed to have a positive correlation with compromised survival in DTC 16,17 , but with some controversy 18,19 . While minimal ETE was totally discarded from the AJCC 8th TNM staging schema, gross strap muscle invasion was introduced as the new T3b stage regardless of tumor size. However, there have been suggestions that even gross strap muscle invasion does not impact survival in patients with DTC [8][9][10][11]13,20 . Indeed, the AJCC 8th staging schema contains in-stage heterogeneity in regards to DSS prediction 21 . One potential source of this heterogeneity may be due to the prognostic impact of strap muscle invasion. A recent study of a total  13 . Another study on 3104 patients with either papillary or follicular thyroid carcinoma revealed that gross strap muscle invasion does not significantly impact DSS in tumors equal to or smaller than 40 mm, and that DSS of the T3b stage did not significantly differ from that of the T2 stage (median follow-up 10 years; interquartile range, 8.1-12 years) 11 . This population-based study utilized the SEER database 15 without discrimination of tumor size to reveal that strap muscle invasion alone does not significantly impact DSS, regardless of tumor size or cause of death. This may have particular clinical impact on tumors equal to or smaller than 40 mm which may be appropriately downstaged. Although the estimated C-indices and PVE did not reveal statistically significant differences in the predictive power of the current AJCC 8th and the suggested modified TNM staging schemas, better survival curve separation was observed per the modified staging schema with statistical significance.
Invasion of strap muscle in any degree may not have significant survival impact due to the relative complexity of posterior anatomical structures such as trachea, recurrent laryngeal nerve, and prevertebral fascia. Critical laryngotracheal structure invasion leads to a higher possibility of incomplete resection and therefore to higher clinical recurrence and poorer prognosis 9 . On the other hand, strap muscles can be relatively easily resected in the presence of tumor invasion 13,22 , accounting for their lack of significant impact on DSS. Consequently, anterior or posterior ETE have been suggested as more appropriate staging factors than gross strap muscle invasion 13,23 . Therefore, the dismissal of both minimal and gross strap muscle invasion may lead to better allocation by the www.nature.com/scientificreports/ TNM staging schema and better reflection of DSS, as suggested by the modified staging schema, particularly for tumors equal to or smaller than 40 mm. There are several limitations to our study. First, the retrospective nature of this study may have caused an inherent bias. Second, the SEER database did not distinguish between minimal and gross strap muscle invasion. However, any ETE beyond strap muscle invasion was explicitly recorded and an inference was made that the code for strap muscle invasion included both minimal and gross strap muscle invasion collectively. Thus, the purpose of this study was limited to exploring the potential changes in TNM staging with the collective dismissal of both minimal and gross strap muscle invasions. Third, the SEER database did not include recurrence data, which limited the analysis of the impact of strap muscle invasion alone on disease-free survival. Strengths of the present study include the use of a national, comprehensive database with analyses of prognostic variables in all tumor size groups as well as tumor size and age subgroups. Moreover, competing risk analysis offered a more accurate evaluation of potential prognostic variables relative to other causes of death.
In conclusion, strap muscle invasion alone of any degree does not significantly impact DSS in DTC patients, regardless of tumor size. The modified TNM staging schema suggests potential modification of the TNM staging schema to better reflect the risk of cancer-caused death and to prevent potential overstaging of tumors, particularly those equal to or smaller than 40 mm in size.  Table S3), and (3) patients who underwent surgery with or without adjuvant radiation therapy or chemotherapy. Patients with medullary carcinoma, mixed medullary carcinoma component, insular carcinoma, and anaplastic thyroid cancer were excluded. In addition, patients with unknown race, unknown tumor grade, unknown ETE, unavailable or incomplete TNM staging data, death certificate or autopsy alone, or unknown cause of death were excluded (Fig. 3). The extension item of the SEER Cancer Schema (CS) version 02.05.50, which encodes tumor ETE based on pathologic and/or clinical information, does not explicitly distinguish between minimal or gross strap muscle invasion. However, since more advanced   Based on our hypothesis that minimal and gross strap muscle invasion collectively in the absence of other risk factors does not significantly impact DSS, we suggested a "modified" staging schema thereby discarding strap muscle invasion of any degree from the T staging criteria. Therefore, T3b stage according to the AJCC 8th TNM staging schema were reallocated depending on tumor size only, into either the T1a, T1b, T2, or T3 stage per the modified staging schema. The staging of major adjacent structures extension (i.e., T4a or T4b stages) remained unchanged.   [24][25][26][27][28][29] . The Cox proportional hazard analysis was used to examine the effects of clinical factors and histopathologic characteristics of DTC on DSS. Competing risk analysis by proportional subdistribution hazards regression modeling was performed 26,30 . In this study, competing risk was considered death due to other causes since deaths unrelated to DTC may obscure the ability to observe cancer-caused deaths 31 . Kaplan-Meier estimation and the log rank test were used to assess 10-year DSS probability and DSS curves according to T stages based on either the AJCC 8th TNM staging schema or the modified TNM staging schema. The measure of discrimination for survival prediction was estimated using C-index, and goodness-of-fit for survival prediction was estimated using the PVE for both staging schemas 32 . All tests were two-sided, and a p-value of less than 0.05 was considered statistically significant.