Extrathyroidal Extension Is Associated with Compromised Survival in Patients with Thyroid Cancer

Abstract

Background:

Patients with thyroid cancer who have extrathyroidal extension (ETE) are considered to have more advanced tumors. However, data on the impact of ETE on patient outcomes remain limited. The purpose of this study was to evaluate the association between ETE and survival in patients with thyroid cancer.

Methods:

The National Cancer Database (1998–2012) was queried for all adult patients with differentiated thyroid cancer and medullary thyroid cancer. Patients were divided into three groups: no ETE (T1 and T2 tumors), minimal ETE (T3 tumors <4 cm), and extensive ETE (T4 tumors <4 cm). Patient demographic, clinical, and pathologic factors were evaluated for all patients. A Cox proportional hazards model was developed for each histology to identify factors associated with survival.

Results:

In total, 241,118 patients with differentiated thyroid cancer met the inclusion criteria; 86.9% had no ETE, 9.1% minimal ETE, and 4.0% extensive ETE. Compared with patients with no ETE, patients with minimal and extensive ETE were more likely to have larger tumors (1.4 cm vs. 1.8 cm and 2.0 cm, respectively), lymphovascular invasion (8.6% vs. 28.0% and 35.1%, respectively), positive margins after thyroidectomy (6.1% vs. 35.2% and 45.9%, respectively), and regional lymph node metastases (32.5% vs. 67.0% and 74.6%, respectively; all p < 0.01). After adjustment, minimal ETE (hazard ratio [HR] = 1.13; p < 0.01) and extensive ETE (HR = 1.74; p < 0.01) were associated with compromised survival for patients with differentiated thyroid cancer. In total, 3415 patients with medullary thyroid cancer met the inclusion criteria; 87.9% had no ETE, 7.1% minimal ETE, and 5.0% extensive ETE. Compared with patients with no ETE, patients with minimal and extensive ETE were more likely to have larger tumors (1.7 cm vs. 2.2 cm and 2.2 cm, respectively), lymphovascular invasion (19.2% vs. 68.9% and 79.3%, respectively), positive margins after thyroidectomy (5.8% vs. 44.1% and 51.9%, respectively), and regional lymph node metastases (39.0% vs. 90.5% and 94.4%, respectively; all p < 0.01). After adjustment, extensive ETE (HR = 1.63; p = 0.01) was associated with compromised survival for patients with medullary thyroid cancer.

Conclusion:

In patients with differentiated and medullary thyroid cancers, ETE is associated with compromised survival. Given these findings, ETE should be included in the thyroid cancer treatment guidelines.

Introduction

Thyroid cancer is the most common endocrine malignancy (1). The incidence of thyroid cancer is increasing faster than any other malignancy in the United States (2). The mainstay of treatment includes surgical resection of the thyroid gland with adjuvant treatment, including radioactive iodine ablation in select cases (3,4). There are many risk factors and indicators of more advanced disease, including male sex, older age, increased tumor size, and extrathyroidal extension (ETE) (5,6).

ETE is defined as tumor growth outside of the thyroid gland and into the nearby or surrounding tissues. For differentiated and medullay thyroid cancers, the American Joint Committee on Cancer (AJCC) includes ETE as part of the staging system. It defines T3 as a “tumor more than 4 cm in greatest dimension limited to the thyroid or any tumor with minimal ETE,” T4a as a “a tumor of any size that has grown beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve,” and T4b as a “tumor of any size that invades the prevertebral fascia or encases the carotid artery or mediastinal vessels” (7).

While patients with thyroid cancer with ETE are considered to have more advanced tumors, little is known about the impact of ETE on patient outcomes. To date, there have been no studies in a nationwide database examining the association of ETE on survival in patients with thyroid cancer. It was hypothesized that ETE is associated with compromised survival in patients with thyroid cancer.

Methods

The National Cancer Data Base (NCDB) is a joint collaboration of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. It is a nationwide, facility-based, comprehensive clinical surveillance data set. It currently contains >29 million cancer cases from >1500 Commission on Cancer–accredited cancer programs from all 50 states, Puerto Rico, and the District of Columbia. More than 85% of all new thyroid cancer cases in the United States are captured in the database (8).

Data were coded according to the Commission on Cancer Registry Operations and Data Standards Manual, the AJCC Manual for Staging of Cancer, and the International Classification of Disease for Oncology. Data were de-identified and submitted to the NCDB in compliance with the Health Insurance Portability and Accountability Act (9). The Institutional Review Board granted this study an exempt status.

The NCDB (1998–2012) was queried for all adult patients (aged ≥18 years) with a diagnosis of differentiated and medullary thyroid cancer. Patients were divided into three cohorts: no ETE, minimal ETE, and extensive ETE. Tumors >4.0 cm were excluded due to incomplete coding data for ETE with large tumors and also to eliminate any potential bias due to tumor size. No ETE was defined as T1 and T2 tumors. Minimal ETE was defined as T3 tumors <4.0 cm. Extensive ETE was defined as T4 tumors <4.0 cm. Differentiated and medullary thyroid cancer were analyzed separately. Medullary cancer patients with distant metastases were excluded from the analysis.

Patient variables including age at diagnosis, sex, race/ethnicity, annual income, insurance, year of diagnosis, distance travelled to treating institution, and comorbidities were extracted from the database. Comorbidity was represented by the modified Charlson/Deyo scoring system. Annual income levels were assigned by the NCDB by linking a patient's zip code to the year 2000 U.S. census data. Clinical and pathologic variables of interest included tumor size, lymph node involvement, and distant metastases. All variables were categorized by ETE status.

Statistical analysis

Baseline characteristics were reported using frequencies and proportions for categorical variables and mean and standard deviation for continuous variables. Data were compared utilizing the chi-square test, Student's t-test, and analysis of variance. Overall survival was defined from the time of diagnosis to the time of death or last follow-up. Survival time was censored for patients alive at the end of the study period. Patients with zero months of follow-up were excluded. Estimates and confidence intervals (CIs) of overall survival proportions were computed using the Kaplan–Meier method, and survival distributions were compared across groups using the log-rank test.

A multivariable Cox proportional hazards model was used to examine the adjusted association of ETE with overall survival. The model adjusted for the effects of patient demographic, clinical, and pathologic characteristics, including sex, age, race/ethnicity, income status, insurance status, comorbidity score, facility type, size of tumor, histology (differentiated thyroid cancer only—papillary, follicular, and Hürthle), surgery performed, margin status, lymph node status, radioactive iodine therapy (differentiated thyroid cancer only), and radiation therapy (medullary thyroid cancer only).

Two-sided statistical tests were specified in all analyses, and p-values <0.05 were considered statistically significant.

Results

In total, 241,118 patients with differentiated thyroid cancer met the inclusion criteria; 209,471 (86.9%) had no ETE, 21,907 (9.1%) minimal ETE, and 9740 (4.0%) extensive ETE. Compared with patients with no ETE, patients with minimal and extensive ETE were more likely to be male (20.3% vs. 25.6% and 29.1%, respectively), older (49 years vs. 50 years and 52 years, respectively), and more likely to have a higher comorbidity score (2.3% vs. 2.4% and 2.9%, respectively; all p < 0.01). Compared with patients with no ETE, patients with minimal and extensive ETE were more likely to have larger tumors (1.4 cm vs. 1.8 cm and 2.0 cm, respectively), lymphovascular invasion (8.6% vs 28.0% and 35.1%, respectively), positive margins after thyroidectomy (6.1% vs. 35.2% and 45.9%, respectively), and regional lymph node metastases (32.5% vs. 67.0% and 74.6%, respectively; all p < 0.01; Table 1).

Table 1.

Clinical, Demographic, and Pathologic Factors for Patients with Differentiated Thyroid Cancer by ETE Status

	No ETE, N = 209,471 (%)	Minimal ETE, N = 21,907 (%)	Extensive ETE, N = 9740 (%)	p-Value
Sex				<0.01
Female	166,959 (79.7)	16,301 (74.4)	6904 (70.9)
Age in years, mean ± SD	48.8 ± 14.5	50.0 ± 15.0	51.9 ± 16.5	<0.01
Race/ethnicity				<0.01
White	180,724 (87.9)	18,592 (86.8)	8398 (87.9)
Black	13,942 (6.8)	975 (4.6)	407 (4.3)
Asian	8710 (4.2)	1515 (7.1)	637 (6.7)
Other	2237 (1.1)	326 (1.5)	112 (1.1)
Annual income				<0.01
<$35,000	49,137 (24.4)	6455 (29.9)	2491 (26.7)
≥$35,000	151,871 (75.6)	15,132 (70.1)	6835 (73.3)
Insurance status				<0.01
None	4859 (2.4)	592 (2.8)	305 (3.2)
Government	45,760 (22.3)	5377 (25.1)	2717 (28.9)
Private	154,369 (75.3)	15,448 (72.1)	6381 (65.4)
Charlson Deyo score				<0.01
0	144,872 (85.1)	18,178 (84.0)	4187 (83.1)
1	21,476 (12.6)	2952 (13.6)	703 (14.0)
≥2	3962 (2.3)	520 (2.4)	149 (2.9)
Facility type				<0.01
Academic	84,486 (40.4)	10,498 (48.0)	4059 (41.7)
Comprehensive	109,663 (52.4)	10,288 (47.0)	4998 (51.3)
Community	15,226 (7.2)	1104 (5.0)	680 (7.0)
Facility location				<0.01
Northeast	52,403 (25.0)	6880 (31.4)	2358 (24.2)
Midwest	50,901 (24.3)	4545 (20.7)	2163 (22.2)
South	70,134 (33.5)	6413 (29.3)	3089 (31.7)
West	36,033 (17.2)	4069 (18.6)	2132 (21.9)
Histology				<0.01
Papillary	195,096 (93.1)	21,438 (97.8)	9338 (95.9)
Follicular	10,186 (4.9)	276 (1.3)	267 (2.7)
Hürthle	4195 (2.0)	193 (0.9)	137 (1.4)
Size in cm, mean ± SD	1.4 ± 9.6	1.8 ± 8.6	2.0 ± 9.6	<0.01
Lymphovascular invasion	4853 (8.6)	2328 (28.0)	332 (35.1)	<0.01
Extent of surgery				<0.01
Total thyroidectomy	168,751 (80.6)	20,592 (94.0)	8913 (91.5)
Lobectomy	35,507 (17.0)	887 (4.0)	546 (5.6)
Positive margin status	12,103 (6.1)	7366 (35.2)	3993 (45.9)	<0.01
Positive regional lymph nodes	31,486 (32.5)	10,754 (67.0)	5040 (74.6)	<0.01
Positive distant metastases	629 (0.3)	222 (1.1)	256 (2.7)	<0.01
RAI therapy	92,220 (44.0)	15,409 (72.1)	6265 (64.3)	<0.01

ETE, extrathyroidal extension; SD, standard deviation; RAI, radioactive iodine.

Differentiated thyroid cancer patients with no ETE had improved overall survival compared with those with minimal and extensive ETE (p < 0.01). Five-year survival for patients with no ETE was 96%, those with minimal ETE 94%, and those with extensive ETE 88%.

After adjustment for patient demographic, clinical, and pathologic factors, minimal ETE (hazard ratio [HR] = 1.13, p < 0.01) and extensive ETE (HR = 1.74, p < 0.01) were associated with compromised survival when compared with no ETE for differentiated thyroid cancer (Table 2).

Table 2.

Cox Proportional Hazards Model Demonstrating Factors Associated with Overall Survival in Patients with Differentiated Thyroid Cancer

	Hazard ratio	Confidence interval	p-Value
ETE (reference: none)
Minimal ETE	1.13	1.05–1.22	<0.01
Extensive ETE	1.74	1.64–1.86	<0.01
Male sex	1.60	1.54–1.66	<0.01
Age (decade)	1.90	1.87–1.93	<0.01
Race/ethnicity (reference: white)
Black	1.30	1.21–1.39	<0.01
Asian	0.77	0.68–0.86	<0.01
Low income	1.27	1.22–1.32	<0.01
Insurance (reference: private)
None	1.44	1.24–1.67	<0.01
Government	1.65	1.57–1.73	<0.01
Charlson Deyo score (reference: 0)
1	1.55	1.47–1.64	<0.01
≥2	2.89	2.66–3.13	<0.01
Facility type (reference: academic)
Comprehensive	0.99	0.96–1.04	0.86
Community	1.03	0.96–1.11	0.35
Histology (reference: papillary)
Follicular	1.19	1.10–1.29	<0.01
Hürthle	1.21	1.10–1.34	<0.01
Size (cm)	1.07	1.05–1.09	<0.01
Lobectomy	1.06	1.01–1.11	0.03
Positive margins	1.21	1.14–1.28	<0.01
Positive lymph nodes	1.50	1.43–1.57	<0.01
RAI	0.71	0.68–0.74	<0.01

Lymphovascular invasion was not included in the above analysis, as it is a variable that was added to the NCDB in 2010. If it was included in the analysis, all patients diagnosed prior to 2010 would be excluded.

For medullary thyroid cancer, 3415 patients met the inclusion criteria; 3001 (87.9%) had no ETE, 242 (7.1%) minimal ETE, and 172 (5.0%) extensive ETE. Compared with patients with no ETE, patients with minimal and extensive ETE were more likely to be male (34.0% vs. 45.0% and 54.7%, respectively; p < 0.01). There was no difference between the three groups with regards to patient age or comorbidity score. Compared with patients with no ETE, patients with minimal and extensive ETE were more likely to have larger tumors (1.7 cm vs. 2.2 cm and 2.2 cm, respectively), lymphovascular invasion (19.2% vs. 68.9% and 79.3%, respectively), positive margins after thyroidectomy (5.8% vs. 44.1% and 51.9%, respectively), and regional lymph node metastases (39.0% vs. 90.5% and 94.4%, respectively; all p < 0.01; Table 3).

Table 3.

Clinical, Demographic, and Pathologic Factors for Patients with Medullary Thyroid Cancer by ETE Status

	No ETE, N = 3001 (%)	Minimal ETE, N = 242 (%)	Extensive ETE, N = 172 (%)	p-Value
Sex				<0.01
Female	1981 (66.0)	133 (55.0)	78 (45.3)
Age in years, mean ± SD	54.2 ± 15.3	56.1 ± 14.2	54.6 ± 15.0	0.19
Race/ethnicity				0.39
White	2559 (87.2)	208 (88.1)	152 (88.4)
Black	268 (9.1)	18 (7.6)	12 (7.0)
Asian	80 (2.7)	6 (2.6)	7 (4.1)
Other	29 (1.0)	4 (1.7)	1 (0.5)
Annual income				0.04
<$35,000	780 (27.1)	54 (23.4)	54 (31.8)
≥$35,000	2102 (72.9)	177 (76.6)	116 (68.2)
Insurance status				0.93
None	72 (2.5)	5 (2.1)	6 (3.6)
Government	946 (32.4)	79 (33.8)	50 (30.1)
Private	1899 (65.1)	150 (64.1)	110 (66.3)
Charlson Deyo score				0.55
0	2211 (83.1)	210 (86.8)	119 (84.4)
1	378 (14.2)	26 (10.7)	17 (12.1)
≥2	72 (2.7)	6 (2.5)	5 (3.5)
Facility type				0.09
Academic	1570 (52.4)	144 (59.8)	87 (50.6)
Comprehensive	1241 (41.4)	89 (36.9)	77 (44.8)
Community	188 (6.2)	8 (3.3)	8 (4.6)
Facility location				0.17
Northeast	696 (23.2)	70 (29.0)	44 (25.6)
Midwest	765 (25.5)	49 (20.2)	35 (20.3)
South	1088 (36.3)	83 (34.3)	62 (36.0)
West	452 (15.0)	40 (16.5)	31 (18.1)
Size in cm, mean ± SD	1.7 ± 1.0	2.2 ± 0.9	2.2 ± 0.9	<0.01
Lymphovascular invasion	155 (19.2)	51 (68.9)	23 (79.3)	<0.01
Extent of surgery				<0.01
Total thyroidectomy	2674 (89.1)	234 (96.7)	156 (90.7)
Lobectomy	278 (9.3)	3 (1.2)	9 (5.2)
Positive margin status	166 (5.8)	101 (44.1)	81 (51.9)	<0.01
Positive regional lymph nodes	830 (39.0)	199 (90.5)	153 (94.4)	<0.01
External beam radiation	95 (3.2)	48 (20.8)	64 (37.2)	<0.01

Medullary thyroid cancer patients with no ETE had improved overall survival compared with those with minimal and extensive ETE (p < 0.01). Patients with no ETE had a five-year survival of 93%. Five-year survival for patients with no ETE was 93%, those with minimal ETE 83%, and those with extensive ETE 75%.

After adjustment for patient demographic, clinical, and pathologic factors, extensive ETE (HR = 1.63, p = 0.01) was associated with compromised survival when compared with no ETE for medullary thyroid cancer patients (Table 4). Minimal ETE (HR = 1.44, p = 0.07) was not significantly associated with compromised survival for patients with medullary thyroid cancer.

Table 4.

Cox Proportional Hazards Model Demonstrating Factors Associated with Overall Survival in Patients with Medullary Thyroid Cancer

	Hazard ratio	Confidence interval	p-Value
ETE (reference: none)
Minimal	1.44	0.96–2.16	0.07
Extensive	1.63	1.12–2.36	0.01
Male sex	1.55	1.23–1.95	<0.01
Age (decade)	1.66	1.48–1.86	<0.01
Race/ethnicity (reference: white)
Black	1.06	0.66–1.69	0.81
Asian	1.19	0.59–2.43	0.63
Low income	1.21	0.94–1.55	0.14
Insurance (reference: private)
None	1.89	0.92–3.90	0.08
Government	1.18	0.88–1.58	0.27
Charlson Deyo score (reference: 0)
1	1.20	0.86–1.66	0.29
≥2	2.06	1.17–3.64	0.01
Facility type (reference: academic)
Comprehensive	1.26	0.99–1.60	0.07
Community	1.90	1.28–2.81	<0.01
Size (cm)	1.22	1.08–1.37	<0.01
Lobectomy	1.36	0.95–1.94	0.10
Positive margins	1.34	0.98–1.84	0.07
Positive lymph nodes	2.03	1.55–2.64	<0.01
External beam radiation	1.25	0.89–1.76	0.20

Discussion

Patients with thyroid cancer with ETE are considered to have more advanced tumors, but little is known about the impact of ETE on patient outcomes. This is the first study to examine the association of ETE and survival in patients with thyroid cancer at a national level. The study demonstrated compromised survival for patients with ETE with both differentiated thyroid cancer and medullary thyroid cancers.

There have been few other studies evaluating ETE in patients with thyroid cancer. One study examined the association between aggressive variants of papillary thyroid cancer and ETE. Kuo et al. utilized the Surveillance, Epidemiology, and End Results database to identify >18,000 patients with papillary thyroid microcarcinomas (10). Patients with tall-cell variant and diffuse sclerosing microcarcinomas, more aggressive variants of papillary microcarcinomas, were more likely to have ETE compared to classic papillary thyroid cancers. There was no difference in disease-specific survival between these groups of patients with papillary microcarcinomas.

Other studies have examined ETE in poorly differentiated thyroid cancer. Ibrahimpasic et al. retrospectively reviewed all thyroid cancer patients at Memorial Sloan-Kettering Cancer Center undergoing primary surgical resection (11). The authors identified 91 patients with poorly differentiated thyroid cancer, 27 of whom had ETE. The majority of patients with ETE were older and had tumors >4.0 cm. These patients were more likely to have positive margins after thyroidectomy, metastatic lymph nodes, and distant metastases. Their results, albeit in a restricted cohort, are similar to the present study.

Another study examined the association between ETE and extranodal extension in well-differentiated thyroid cancer. Clain et al. identified 193 patients who underwent total or completion thyroidectomy. The authors concluded that patients with ETE were 12 times more likely to have lymph nodes in the primary setting with ETE than patients with intrathyroidal primary tumors (12).

It was not possible to examine cancer recurrence in the current data set. However, one study examined this issue in patients with papillary thyroid cancer. Radowsky et al. compared papillary thyroid cancer patients with and without ETE (13). Patients with ETE were more likely to have clinical recurrence of disease. Another study examined disease-specific survival in patients with papillary thyroid cancer. Ito et al. examined >1000 patients with papillary thyroid cancer at their institution over a five-year period and followed them for at least five years postoperatively [10]. After adjustment, they found that extensive ETE was associated with compromised survival. However, minimal ETE was not found to be independently associated with survival.

The NCDB does not encompass disease recurrence or disease-specific survival. Still, it was found that overall survival was clearly comprised for patients with ETE. The degree of ETE was found to have a step-wise reduction in patient survival for both differentiated and medullary thyroid cancer patients. Given the large cohort of patients, this study is one of the first to be able to demonstrate compromised survival for patients whose tumors have minimal and extensive ETE. While minimal ETE for patients with medullary thyroid cancer was not statistically associated with compromised survival, it was approaching significance, likely demonstrating a true trend. The lack of significance is likely due to inadequate statistical power in this patient group.

Given the paucity of data in the literature, there is little mention regarding the effect of ETE in the 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer and no mention of ETE in the 2015 Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma. According to the American Thyroid Association, minimal ETE is associated with intermediate risk, and extensive ETE with high risk for differentiated thyroid cancer. The American Thyroid Association practice guidelines recommend total thyroidectomy for patients with ETE and postoperative radioactive iodine ablation for high-risk differentiated thyroid cancer. However, the guidelines state these are weak recommendations with poor-quality evidence (3,4). The present study demonstrates that ETE is an important factor, and suggests that it should be incorporated into treatment guidelines for both differentiated and medullary thyroid cancer.

The limitations of this study include those inherent to studies from large databases, such as the potential for coding errors. However, data reporting to the NCDB is highly standardized and heavily audited. Another limitation of this study is the lack of recurrence data and disease-specific survival, as the NCDB only reports overall survival. The strengths of this study lie in the large number of patients evaluated and the fact that it encompasses contemporary population-level data.

Conclusion

This is the first study utilizing a nationwide database examining the association of ETE on survival in patients with thyroid cancer. In patients with differentiated thyroid cancer, ETE appears to be associated with compromised survival in a dose-dependent fashion. In patients with medullary thyroid cancer, extensive ETE is associated with compromised survival, while minimal ETE trends toward compromised survival. Further studies are needed to clarify this point. However, given these findings, ETE should be included in the thyroid cancer treatment guidelines.

Footnotes

Acknowledgments

The data used in the study are derived from a de-identified National Cancer Data Base file. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed, or the conclusions drawn from these data by the investigators.

Author Disclosure Statement

JAS is a member of the Data Monitoring Committee of the Medullary Thyroid Cancer Consortium Registry, supported by GlaxoSmithKline, NovoNordisk, Astra Zeneca, and Eli Lilly. For the remaining authors, no competing financial interests exist.

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National Cancer Institute. SEER Cancer Statistics Review, 1975–2002 Available at: www.seer.cancer.gov/csr/1975_2002/ (accessed December 15, 2015 ).

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