Abstract
Background:
This study assessed for disparities in the presentation and management of medullary thyroid cancer (MTC).
Methods:
Patients with MTC (2010–2020) were identified from the National Cancer Database. Differences in disease presentation and likelihood of guideline-concordant surgical management (total thyroidectomy and resection of ≥1 lymph node) were assessed by sex and race/ethnicity.
Results:
Of 6,154 patients, 68.2% underwent guideline-concordant surgery. Tumors >4 cm were more likely in men (vs. women: OR 2.47, p<0.001) and Hispanic patients (vs. White patients: OR 1.52, p=0.001). Non-White patients were more likely to have distant metastases (Black: OR 1.63, p=0.002; Hispanic: OR 1.44, p=0.038) and experienced longer time to surgery (Black: HR 0.66, p<0.001; Hispanic: HR 0.71, p<0.001). Black patients were less likely to undergo guideline-concordant surgery (OR 0.70, p=0.022).
Conclusions:
Male and non-White patients with MTC more frequently present with advanced disease, and Black patients are less likely to undergo guideline-concordant surgery.
Keywords: thyroid neoplasms, endocrine surgical procedures, guideline adherence, healthcare disparities
Graphical Abstract
INTRODUCTION
Thyroid cancer is the most common endocrine malignancy in the United States, with medullary thyroid cancer (MTC) accounting for approximately 2% of cases.1, 2 MTC is an aggressive subtype of thyroid cancer, with a recurrence rate between 20–30% and a mortality rate significantly higher than that of the well-differentiated subtypes.3-5 As MTC does not respond to radioactive iodine or conventional chemotherapy, aggressive surgical resection is considered the only curative treatment.2
Guideline-concordant care is essential to optimizing oncologic outcomes across numerous cancers.6-8 In MTC, recent work demonstrates a strong association between guideline-concordant surgery and improved survival.9 Despite this, nearly 25% of patients still do not receive appropriate care for MTC.9, 10 Moreover, across a range of cancers, the receipt of guideline-nonadherent care disproportionately affects patients from minority racial and ethnic backgrounds.11-13 For example, in well-differentiated thyroid cancer, lower rates of guideline-concordant care contribute to worse survival in Black patients.14-16 However, little is known about whether such disparities exist in the care of MTC.
Given the aggressive nature of MTC, improving rates of guideline-concordant surgery is essential for optimizing patient outcomes. However, without a more nuanced understanding of which patients are receiving inappropriate care and why, meaningful improvement may be elusive. Therefore, this study sought to assess for the presence of disparities according to patient characteristics and treatment setting in the presentation and management of MTC.
METHODS
Study Cohort
Adults diagnosed with MTC between 2010–2020 were identified from the National Cancer Database (NCDB), which contains data from approximately 1,500 participating institutions.24 The International Classification of Diseases for Oncology, 3rd Edition codes 8345, 8510, and 8513 were used to identify MTC.25 The following demographic characteristics were abstracted for each patient: age at diagnosis, sex, race, ethnicity, median income in the zip code of the patient’s home address, insurance type, and distance from patient’s home zip code to the treating facility. Additionally, the following clinical and treatment characteristics were obtained: Charlson-Deyo comorbidity score, primary tumor size, presence of clinically positive lymph nodes, presence of positive lymph nodes on surgical pathology, presence of distant metastasis, clinical stage according to the American Joint Committee on Cancer (AJCC) staging manual at time of diagnosis, treating facility code, surgical management, and time from diagnosis to surgery.
For analysis, race and ethnicity were categorized as non-Hispanic White, non-Hispanic Black, or Hispanic; due to the small number of patients remaining, those with another race/ethnicity were excluded. Insurance type was categorized as private, Medicare, Medicaid, or other/no insurance. Large tumor size was defined as >4 cm. The treating facility setting was dichotomized as academic or non-academic, as described in the NCDB. The extent of thyroid surgery was defined as none, less than lobectomy (including partial lobectomy or isthmusectomy only), lobectomy, and total thyroidectomy (including subtotal thyroidectomy). Finally, given that the NCDB provides the number of lymph nodes resected, but does not include whether a formal central or lateral lymph node dissection was performed, patients with ≥1 lymph node removed at the time of surgery were classified as having undergone lymphadenectomy. While this definition is imperfect, it has been utilized in several recent studies of MTC.9, 17, 18
Outcomes
The primary outcome was receipt of guideline-concordant surgical management. Patients were considered to have undergone guideline-concordant surgery if they underwent total thyroidectomy and removal of ≥1 lymph node.9, 17, 18 Secondary outcomes included (a) time to surgery, defined as days elapsed between diagnosis and surgery, (b) surgical margin status, and (c) overall survival. Analyses of these outcomes were limited to patients who did not have distant metastases at the time of diagnosis.
Statistical Analysis
Descriptive statistics were calculated, with categorical variables reported as frequencies with percentages and continuous variables reported as means with standard deviations or medians with interquartile ranges. Group comparisons were performed using Chi-square tests, Student’s t-tests, Wilcoxon rank-sum tests, and Kruskal-Wallis tests, as appropriate. Multivariable logistic regression analyses were used to assess the associations between sex, race/ethnicity, and disease severity at presentation, with adjustment for age, median local income quartile, insurance type, distance from treating facility, and Charlson-Deyo comorbidity score. For patients without distant metastases, mixed-effects models were used to estimate the associations between sex, race/ethnicity, and appropriate surgical management, with clustering by treating facility. Covariates included age at diagnosis, year of diagnosis, median local income quartile, insurance type, distance from treating facility, Charlson-Deyo comorbidity score, tumor size, presence of clinically positive lymph nodes, and treating facility type. For time to surgery, a multivariable Cox proportional hazards regression model was generated, with adjustment for the same covariates. In this analysis, a hazard ratio <1 indicates longer time to surgery. Next, a multivariable logistic regression model was used to assess for associations between patient and tumor characteristics, extent of surgery, and surgical margin status. Finally, for overall survival, another multivariable Cox proportional hazards model was generated, with adjustment for the above covariates as well as an indicator for receipt of guideline-concordant surgery.
Statistical analyses were performed using Stata, version 17.0 (Stata Corp, College Station, TX). This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines and was deemed exempt by the University of Pennsylvania’s Institutional Review Board.27
RESULTS
Cohort Characteristics
We identified 6,154 patients with MTC. The mean age was 57.0 (SD: 15.3) years, 42.7% were male, and 80.9% identified as non-Hispanic White. Slightly more than half (54.3%) had private insurance, and 44.7% were treated at an academic center. The median tumor size was 2.0 (IQR: 1.1–3.4) cm, and 7.9% of patients had distant metastases at presentation. 23.7% of patients had clinically positive lymph nodes, 51.7% had clinically negative lymph nodes, and 24.7% had no clinical lymph node data. On surgical pathology, 42.0% of patients had positive lymph nodes, of whom 29.1% were categorized as N1a (central neck), 51.0% were categorized as N1b (lateral neck), and 28.1% did not have a location specified.
The median time between diagnosis and surgery was 40 (IQR: 26–61) days. The majority of patients underwent total thyroidectomy (82.8%) and had ≥1 lymph node removed (75.1%). Of the patients had ≥1 lymph node removed, 83.5% had ≥4 lymph nodes removed, suggesting a high rate of intentional lymphadenectomy. Overall, 68.2% of patients underwent guideline-concordant surgery. The median duration of follow-up was 55.5 (IQR: 29–86.0) months, and a minority of patients (16.5%) died during the study period.
Differences in Disease Presentation
There were several sex-based differences in the presentation of MTC. Compared to women, men presented at an older mean age (58.0 vs. 56.3 years, p<0.001), with larger tumors (2.4 vs. 1.8 cm, p<0.001), and more frequently with positive regional lymph nodes (54.4% vs. 32.8%, p<0.001) and distant metastases (10.6% vs. 5.9%, p<0.001). After adjustment for observed demographic differences using multivariable regression, men were still more likely to present with tumors >4 cm in size (OR 2.47, 95% CI 2.12–2.88, p<0.001), positive lymph nodes (OR 2.87, 95% CI 2.51–3.28, p<0.001), and distant metastases (OR 1.86, 95% CI 1.52–2.28, p<0.001). These sex-based differences are shown in Table 1.
TABLE 1.
Characteristics of patients with medullary thyroid cancer, stratified by sex (2010–2020).
| Characteristic | Male N=2,625 |
Female N=3,096 |
p-value |
|---|---|---|---|
| Age | |||
| Years (SD) | 58.0 (15.0) | 56.3 (15.5) | <0.001 |
| Race/Ethnicity | |||
| Non-Hispanic White | 2,197 (84) | 2,782 (79) | <0.001 |
| Non-Hispanic Black | 225 (8.6) | 426 (12) | |
| Hispanic | 203 (7.7) | 321 (9.1) | |
| Median household income quartile | |||
| 1st (lowest) | 343 (13) | 524 (15) | 0.114 |
| 2nd | 451 (17) | 623 (18) | |
| 3rd | 542 (21) | 737 (21) | |
| 4th (highest) | 899 (34) | 1,185 (34) | |
| Unknown | 390 (15) | 460 (13) | |
| Insurance type | |||
| Private | 1,413 (54) | 1,929 (55) | 0.038 |
| Medicare | 858 (33) | 1,105 (31) | |
| Medicaid | 161 (6.1) | 271 (7.7) | |
| Other or no insurance | 193 (7.4) | 224 (6.4) | |
| Charlson-Deyo comorbidity score | |||
| 0 | 2,084 (79) | 2,873 (81) | 0.041 |
| 1 | 398 (15) | 494 (14) | |
| ≥2 | 143 (5.5) | 162 (4.6) | |
| AJCC clinical stage | |||
| I | 447 (17) | 997 (28) | <0.001 |
| II | 394 (15) | 627 (18) | |
| III | 166 (6.3) | 159 (4.5) | |
| IV | 769 (29) | 482 (14) | |
| Unknown | 849 (32) | 1,264 (36) | |
| Tumor size | |||
| Median (IQR) | 2.4 (1.3–4.0) | 1.8 (1.0–2.9) | <0.001 |
| Clinical lymph node status | |||
| Present | 903 (34) | 555 (16) | <0.001 |
| Absent | 1,105 (42) | 2,074 (59) | |
| Unknown | 617 (24) | 900 (26) | |
| Pathologic lymph node status | |||
| Present | 1,428 (54) | 1,159 (33) | <0.001 |
| Absent | 617 (24) | 1,411 (40) | |
| Unknown | 580 (22) | 959 (27) | |
| Distant metastases | |||
| Present | 279 (11) | 207 (5.9) | <0.001 |
| Absent | 2,273 (87) | 3,264 (92) | |
| Unknown | 73 (2.8) | 58 (1.6) | |
| Treatment setting | |||
| Academic | 1,257 (48) | 1,496 (42) | <0.001 |
| Non-academic | 1,022 (39) | 1,477 (42) | |
| Unknown | 346 (13) | 556 (16) | |
| Extent of surgery | |||
| None | 294 (11) | 242 (6.9) | <0.001 |
| Less than lobectomy | 18 (0.7) | 15 (0.4) | |
| Lobectomy | 122 (4.7) | 184 (5.2) | |
| Total thyroidectomy | 2,112 (80) | 2,984 (85) | |
| Unknown | 79 (3.0) | 104 (3.0) | |
| Lymphadenectomy | |||
| Yes | 2,048 (78) | 2,572 (73) | <0.001 |
| No | 552 (21) | 923 (26) | |
| Unknown | 25 (1.0) | 34 (1.0) | |
| Guideline-concordant surgery | |||
| Yes | 1,837 (70) | 2,362 (67) | 0.039 |
| No | 725 (28) | 1,075 (30) | |
| Unknown | 63 (2.4) | 92 (2.6) | |
| Vital status | |||
| Alive | 1,806 (69) | 2,816 (80) | <0.001 |
| Dead | 590 (22) | 425 (12) | |
| Unknown | 229 (8.7) | 288 (8.2) | |
There were also several differences in presentation according to race/ethnicity. Hispanic patients presented with a larger median tumor size (2.5 cm) than White patients (2.0 cm) and Black patients (2.0 cm) (p<0.001). While Black patients less frequently presented with positive lymph nodes on clinical assessment (20.3% vs. 23.9% of White vs. 26.2% of Hispanic patients, p=0.030) and pathologic assessment (34.9% vs. 42.8% of White vs. 43.3% of Hispanic patients, p<0.001), Black patients most frequently had no lymph nodes resected during surgery (30.9% vs. 23.0% of White vs. 25.0% of Hispanic patients, p<0.001), thereby hindering accurate comparison of regional disease spread.
On multivariable regression analysis, Hispanic patients remained more likely to present with tumors >4 cm compared to White patients (OR 1.52, 95% CI 1.17–1.97, p=0.001). There was no significant difference according to race/ethnicity in the likelihood of positive lymph nodes on preoperative imaging (Black: OR 0.87, 95% CI 0.68–1.10, p=0.242; Hispanic: OR 1.14, 95% CI 0.89–1.47, p=0.289) or on surgical pathology (Black: OR 0.92, 95% CI 0.73–1.16, p=0.477; Hispanic: OR 1.09, 95% CI 0.86–1.38, p=0.477). However, White patients were less likely to present with distant metastases than Black patients (OR 1.63, 95% CI 1.20–2.21, p=0.002) and Hispanic patients (OR 1.44, 95% CI 1.02–2.02, p=0.038). Differences in presentation by race/ethnicity are summarized in Table 2.
TABLE 2.
Characteristics of patients with medullary thyroid cancer, stratified by race/ethnicity (2010–2020).
| Characteristic | Non-Hispanic White N=4,979 |
Non-Hispanic Black N=651 |
Hispanic N=524 |
p-value |
|---|---|---|---|---|
| Age | ||||
| Years (SD) | 57.8 (15.1) | 55.0 (15.0) | 52.6 (16.5) | 0.025 |
| Sex | ||||
| Male | 2,197 (44) | 225 (35) | 203 (39) | <0.001 |
| Female | 2,782 (56) | 426 (65) | 321 (61) | |
| Median household income quartile | ||||
| 1st (lowest) | 566 (11) | 194 (30) | 107 (20) | <0.001 |
| 2nd | 846 (17) | 119 (18) | 109 (21) | |
| 3rd | 1,037 (21) | 126 (19) | 116 (22) | |
| 4th (highest) | 1,832 (37) | 116 (18) | 136 (26) | |
| Unknown | 698 (14) | 96 (15) | 56 (11) | |
| Insurance type | ||||
| Private | 2,794 (56) | 328 (50) | 220 (42) | <0.001 |
| Medicare | 1,667 (33) | 176 (27) | 120 (23) | |
| Medicaid | 255 (5.1) | 85 (13) | 92 (18) | |
| Other or no insurance | 263 (5.3) | 62 (9.5) | 92 (18) | |
| Charlson-Deyo comorbidity score | ||||
| 0 | 4,032 (81) | 471 (72) | 454 (87) | <0.001 |
| 1 | 706 (14) | 131 (20) | 55 (11) | |
| ≥2 | 241 (4.8) | 49 (7.5) | 15 (2.9) | |
| AJCC clinical stage | ||||
| I | 1,197 (24) | 141 (22) | 106 (20) | 0.092 |
| II | 801 (16) | 131 (20) | 89 (17) | |
| III | 268 (5.4) | 27 (4.2) | 30 (5.7) | |
| IV | 996 (20) | 140 (22) | 115 (22) | |
| Unknown | 1,717 (34) | 212 (33) | 184 (35) | |
| Tumor size | ||||
| Median (IQR) | 2.0 (1.0–3.2) | 2.0 (1.1–3.5) | 2.5 (1.5–4.0) | <0.001 |
| Clinical lymph node status | ||||
| Present | 1,191 (24) | 132 (20) | 135 (26) | 0.030 |
| Absent | 2,556 (51) | 371 (57) | 252 (48) | |
| Unknown | 1,232 (25) | 148 (23) | 137 (26) | |
| Pathologic lymph node status | ||||
| Present | 2,133 (43) | 227 (35) | 227 (43) | <0.001 |
| Absent | 1,654 (33) | 214 (33) | 160 (31) | |
| Unknown | 1,192 (24) | 210 (32) | 137 (26) | |
| Distant metastases | ||||
| Present | 366 (7.4) | 70 (11) | 50 (9.5) | 0.014 |
| Absent | 4,507 (91) | 570 (88) | 460 (88) | |
| Unknown | 106 (2.1) | 11 (1.7) | 14 (2.7) | |
| Treatment setting | ||||
| Academic | 2,233 (45) | 289 (44) | 231 (44) | <0.001 |
| Non-academic | 2,078 (42) | 245 (38) | 176 (34) | |
| Unknown | 668 (13) | 117 (18) | 117 (22) | |
| Extent of surgery | ||||
| None | 420 (8.4) | 61 (9.4) | 55 (11) | 0.027 |
| Less than lobectomy | 19 (0.4) | 7 (1.1) | 7 (1.3) | |
| Lobectomy | 245 (4.9) | 36 (5.5) | 25 (4.8) | |
| Total thyroidectomy | 4,152 (83) | 526 (81) | 418 (80) | |
| Unknown | 143 (2.9) | 21 (3.2) | 19 (3.6) | |
| Lymphadenectomy | ||||
| Yes | 3,791 (76) | 442 (68) | 387 (74) | <0.001 |
| No | 1,143 (23) | 201 (31) | 131 (25) | |
| Unknown | 45 (0.9) | 8 (1.2) | 6 (1.2) | |
| Guideline-concordant surgery | ||||
| Yes | 3,455 (69) | 394 (61) | 350 (67) | <0.001 |
| No | 1,404 (28) | 237 (36) | 159 (30) | |
| Unknown | 120 (2.4) | 20 (3.1) | 15 (2.7) | |
| Vital status | ||||
| Alive | 3,730 (75) | 472 (73) | 420 (80) | 0.017 |
| Dead | 838 (17) | 115 (18) | 62 (12) | |
| Unknown | 411 (8.3) | 64 (9.8) | 42 (8.0) | |
Temporal Trends in Treatment
The overall rate of appropriate surgical treatment for MTC between 2010–2020 was 68.2%, with a slightly higher rate of guideline-concordant treatment in the second half of the study period compared to the first half (70.7% vs. 66.0%, p<0.001). On mixed-effects modeling, there was a small but significant trend toward more guideline-concordant surgery with each additional year (OR 1.06, 95% CI 1.03–1.09, p<0.001) (Table 3).
TABLE 3.
Mixed-effects model of factors associated with likelihood of guideline-concordant surgery for medullary thyroid cancer.
| Characteristic | Odds Ratio | 95% Confidence Interval |
p-value |
|---|---|---|---|
| Sex | |||
| Male | Reference | Reference | Reference |
| Female | 0.94 | 0.77–1.14 | 0.533 |
| Race/ethnicity | |||
| Non-Hispanic White | Reference | Reference | Reference |
| Non-Hispanic Black | 0.70 | 0.51–0.95 | 0.022 |
| Hispanic | 0.88 | 0.61–1.26 | 0.482 |
| Age | |||
| Each additional year | 0.97 | 0.96–0.98 | <0.001 |
| Year of diagnosis | |||
| Each additional year | 1.06 | 1.03–1.09 | <0.001 |
| Median household income quartile | |||
| 1st (lowest) | 0.56 | 0.42–0.74 | <0.001 |
| 2nd | 0.68 | 0.52–0.89 | 0.004 |
| 3rd | 0.74 | 0.58–0.94 | 0.014 |
| 4th (highest) | Reference | Reference | Reference |
| Insurance type | |||
| Private | Reference | Reference | Reference |
| Medicare | 0.92 | 0.71–1.19 | 0.543 |
| Medicaid | 0.77 | 0.50–1.17 | 0.224 |
| Other or no insurance | 0.64 | 0.42–0.99 | 0.034 |
| Charlson-Deyo comorbidity score | |||
| Each additional point | 0.99 | 0.86–1.15 | 0.922 |
| Distance from treating facility | |||
| Each additional mile | 1.00 | 1.00–1.00 | 0.061 |
| Tumor size | |||
| ≤1.0 cm | Reference | Reference | Reference |
| 1.1–2.0 cm | 2.61 | 2.02–3.37 | <0.001 |
| 2.1–4.0 cm | 2.48 | 1.95–3.16 | <0.001 |
| >4.0 cm | 2.08 | 1.51–2.88 | <0.001 |
| Clinical lymph node status | |||
| Present | 3.49 | 2.65–4.58 | <0.001 |
| Absent | Reference | Reference | Reference |
| Treatment setting | |||
| Academic | 2.14 | 1.71–2.67 | <0.001 |
| Non-academic | Reference | Reference | Reference |
Differences in Treatment
There were several differences in unadjusted treatment characteristics by sex. First, a greater proportion of men were treated in an academic setting compared to women (47.9% vs. 42.4%, p<0.001). While more female patients underwent total thyroidectomy than male patients (84.6 vs. 80.5%, p<0.001), the rate of lymphadenectomy was higher among men (78.0% vs. 72.9%, p<0.001), as was the overall rate of guideline-concordant surgery (70.0% vs. 66.9%, p=0.039). However, on mixed-effects modeling, there were no longer any significant differences in the likelihood of total thyroidectomy (OR 1.03, 95% CI 0.79–1.35, p=0.826), lymphadenectomy (OR 0.93, 95% CI 0.75–1.15, p=0.501), or overall appropriate surgery (OR 0.94, 95% CI 0.77–1.14, p=0.533) by sex (Table 3). Furthermore, there was no difference between men and women in adjusted time to surgery (HR 1.02, 95% CI 0.93–1.12, p=0.692), as shown in Figure 1A.
Figure 1. Adjusted hazard of undergoing surgical management after diagnosis of medullary thyroid cancer.
There was no significant difference between male and female patients in time to surgery (Panel A). When stratified by race/ethnicity (Panel B), time to surgery was significantly longer for Black patients (HR 0.66, 95% CI 0.56–0.78, p<0.001) and Hispanic patients (HR 0.71, 95% CI 0.60–0.85, p<0.001) compared to White patients.
Important differences in the treatment of MTC according to race/ethnicity emerged. While the unadjusted rate of total thyroidectomy was higher for White patients (83.4%) compared to Black patients (80.8%) and Hispanic patients (79.8%) (p=0.027), this difference did not persist after adjusting for other characteristics (Black: OR 0.84, 95% CI 0.55–1.28, p=0.424; Hispanic: OR 0.73, 95% CI 0.46–1.15, p=0.180). Similarly, there was no difference in likelihood of lymphadenectomy (OR 0.90, 95% CI 0.61–1.34, p=0.609) or guideline-concordant surgery for Hispanic compared to White patients (OR 0.88, 95% CI 0.61–1.26, p=0.482). However, Black patients were less likely to undergo lymphadenectomy (OR 0.63, 95% CI 0.46–0.87, p=0.005) and overall guideline-concordant surgery (OR 0.70, 95% CI 0.51–0.95, p=0.022) compared to White patients in the multivariable model (Table 3). Furthermore, Black patients had the greatest unadjusted median time between diagnosis and surgery (54 days) compared to White (40 days) and Hispanic patients (50 days) (p<0.001). On multivariable Cox regression, time to surgery remained longer for patients with minority racial/ethnic backgrounds than for White patients (Black: HR 0.66, 95% CI 0.56–0.78, p<0.001; Hispanic: HR 0.71, 95% CI 0.60–0.85, p<0.001), as shown in Figure 1B.
Several other factors were also significantly associated with timely, appropriate surgery. Median income in the patient’s home ZIP code was associated with a stepwise increase in the likelihood of guideline-concordant surgery. Treatment at an academic facility doubled the likelihood of guideline-concordant surgery, but increased the wait time between diagnosis and surgery (HR 0.83, 95% CI 0.76–0.91, p<0.001) (Table 3). Time to surgery was also longer for patients with Medicaid insurance (OR 0.72, 95% CI 0.59–0.89, p=0.003) and those with higher comorbidity scores (HR 0.93, 95% CI 0.86–1.00, p=0.040).
Margin Status
Overall, the unadjusted rate of positive margins after surgical resection among patients without distant metastatic disease was 13.2%. Intuitively, when stratified by tumor size, positive margins were significantly less common after resection of tumors ≤1.0 cm (4.1%) compared to larger tumors (1.1–2.0 cm: 9.4%; 2.1–4.0 cm: 16.6%; >4.0 cm: 28.2%; p<0.001). Similarly, positive margins were more frequently observed in node-positive disease (33.8% vs. 6.8%, p<0.001). Additionally, female patients less commonly had positive margins compared to male patients (10.2% vs. 17.7%, p<0.001), but no differences were observed by race/ethnicity (White 13.3%; Black: 11.0%; Hispanic: 15.0%; p=0.181).
On multivariable logistic regression analysis, there was no significant relationship between the receipt of guideline-concordant surgery and the likelihood of positive margin status (OR 1.23, 95% CI 0.86–1.76, p=0.260). Additionally, there was no evidence of a relationship between margin status and sex (OR 0.90, 95% CI 0.71–1.15, p=0.399) or race/ethnicity (Black: OR 0.94, 95% CI 0.62–1.43, p=0.781; Hispanic: OR 0.91, 95% CI 0.57–1.44, p=0.674) after adjustment for other characteristics. Rather, positive margins were predicted by increasing tumor size (OR 1.60, 95% CI 1.40–1.81, p<0.001) and the presence of clinically positive lymph nodes (OR 5.00, 95% CI 3.89–6.44, p<0.001). Furthermore, patients who were treated in academic settings had a lower likelihood of positive margins (OR 0.63, 95% CI 0.49–0.79, p<0.001).
Survival Analysis
Amongst patients without distant metastatic disease, overall survival was predicted by several demographic and clinical characteristics, including receipt of guideline-concordant surgery. A reduced hazard of death was observed for female patients (HR 0.70, 95% CI 0.57–0.85, p<0.001) and Hispanic patients (HR 0.56, 95% CI 0.35–0.89, p=0.015). Conversely, worse survival was predicted by larger tumor size (HR 1.33, 95% CI 1.20–1.47, p<0.001) and the presence of clinically positive lymph nodes at presentation (HR 3.16, 95% CI 2.55–3.93, p<0.001). Patients who underwent appropriate surgery for their medullary thyroid cancer had a reduction in hazard of death by more than one-third compared to those who did not (HR 0.64, 95% CI 0.51–0.81, p<0.001), a finding that remained significant after stratification by race/ethnicity (White: HR 0.71, 95% CI 0.55–0.92, p=0.008; Black: HR 0.29, 95% CI 0.14–0.63, p=0.002; Hispanic: HR 0.28, 95% CI 0.09–0.90, p=0.033). There was no evidence of an independent association between treatment at an academic facility and overall survival (HR 0.91, 95% CI 0.75–1.10, p=0.328).
DISCUSSION
While disparities in the presentation and treatment of other thyroid cancer subtypes have been clearly demonstrated, there is limited research exploring potential disparities in MTC care.16, 19, 20 However, MTC is notably more aggressive than the well-differentiated subtype yet more treatable than the anaplastic subtype of thyroid cancer; thus, treatment decisions arguably carry the most influence in the outcomes of MTC.3, 21 In this study, we conducted a national assessment of contemporary MTC care with attention to potential differences by sex and race/ethnicity. We found that, at presentation, rates of locoregional and distant metastases were significantly higher among male and non-White patients compared to female and White patients. While there were no significant sex-based differences in care, Black and Hispanic patients experienced longer wait times from diagnosis to surgery than White patients, and Black patients were significantly less likely to receive guideline-concordant surgery.
One of the key findings from this study is that men were more likely to present with advanced disease compared to women, with more than half found to have positive lymph nodes at the time of diagnosis. Though less stark, similar sex differences have also been noted in the presentation of well-differentiated and anaplastic thyroid cancers.20, 22 Importantly, in our cohort of patients with MTC, there was no difference in income distribution or time to surgery between sexes, and minimal difference in the distribution of insurance type. Therefore, these traditional proxies for access to care do not seem to explain the difference in presentation. Rather, given the evidence that American men are less likely than women to participate in outpatient healthcare visits and other health-promoting behaviors, men may be less likely to have a thyroid nodule identified on routine physical examination or to seek early evaluation of a self-palpated nodule, thereby delaying diagnosis.23, 24 Alternatively, there may be differences in MTC biology attributable to sex, though there has been little exploration of this hypothesis in the literature.25 Regardless of the underlying reasons, the consequences of this sex difference in the presentation of MTC should be taken seriously. One recent study based on a cohort of patients with MTC from the Surveillance, Epidemiology, and End Results database found that male patients had more than three times the risk of lateral neck metastases compared to female patients, and a single-institution study found that male sex was an independent predictor of worse disease-specific survival.26, 27 While we did not find a significant difference in the likelihood of guideline-concordant surgery by sex according to the definition used in our study, the increased risk of advanced disease in men raises questions about whether there are opportunities to improve earlier disease detection among male patients. Disease detection remains challenging in thyroid cancer, as routine screening ultrasounds are not indicated. However, many thyroid nodules are incidentally identified on other imaging studies, including computed tomography (CT) scans of the chest. Annual CT chest imaging is recommended for lung cancer screening in adults 50–80 years old with a qualifying smoking history, a population which is disproportionately male.28 Automated radiology templates which flag incidental thyroid nodules on CT chest reports for further evaluation might represent an opportunity to identify some thyroid cancer patients at an earlier stage. Notably, implementing such an intervention would be more likely to detect the more common subtypes of thyroid cancer due to the rarity of medullary thyroid cancer. Additionally, increasing awareness among primary care providers regarding the increased risk of more aggressive thyroid cancer in men may help promote earlier diagnosis and treatment.
Another important finding from this study is that non-White patients face disparities in the presentation and management of MTC. This result parallels studies of other thyroid cancer subtypes as well as various non-thyroid cancers, in which patients with racial and ethnic minority backgrounds present with more advanced disease and are less likely to receive guideline-concordant care.15, 16, 19, 20, 22, 29 These racial and ethnic disparities in cancer care are multifactorial and deeply rooted.29 In the present study, we found that Hispanic patients most often presented with MTC tumors >4 cm in size and faced the longest wait times between diagnosis and surgery. This finding is likely related, in part, to ethnic differences in access to care, such as language barriers, patterns of health care utilization, and potentially reduced access to health insurance related to immigration status.30 Ensuring that patients are provided with test results and subsequent recommendations in their native language, and improving access to state-based emergency Medicaid services for patients who otherwise do not meet criteria for health insurance based on immigration status, are two potential strategies that health systems may employ to help ameliorate the disparities in care faced by Hispanic patients with medullary thyroid cancer.
Similarly, there are several potential reasons that Black patients were found to be less likely to receive guideline-concordant surgery for MTC, even after accounting for income and insurance status. Prior studies have demonstrated that Black patients less frequently receive thyroid cancer care from high-volume, high-quality surgeons and hospitals, which may be more likely to adhere to guidelines.31, 32 Other factors such as provider implicit bias or differences in comorbidity burden may contribute to race-based disparities in the extent of surgery performed for MTC.33, 34 Though reoperation for persistent disease or cervical recurrence has been demonstrated to be safe and effective in well-differentiated thyroid cancer, appropriate initial management is still preferable as it provides optimal disease control, avoids opportunities for loss to follow-up, and reduces costs, time, and travel burden for the patient.35, 36 Furthermore, in the present study, receipt of guideline-concordant surgery was associated with a survival benefit. Therefore, national and local strategies to promote guideline-concordant care for all patients are warranted. For instance, professional societies can leverage video conferencing platforms and social media to disseminate guideline updates and supporting literature to ensure that all surgeons treating MTC are aware of contemporary recommendations. Additionally, hospitals can audit their own surgical data to assess for deviation from the management guidelines and identify opportunities to improve concordance.
This study has several limitations. First, the NCDB does not include a number of variables that are relevant to the study of MTC treatment and outcomes, such as calcitonin levels, provider characteristics, recurrence data, and cause of death. The NCDB also does not distinguish between patients with hereditary and somatic disease or provide information regarding access to genetic counseling, which may modify the disparities observed in the present study. Additionally, the NCDB does not provide preoperative fine needle aspiration results, making it impossible to assess whether patients were diagnosed with MTC prior to surgery. However, completion thyroidectomies should be captured in the NCDB even if MTC was only diagnosed on surgical pathology after a thyroid lobectomy. Of note, while total thyroidectomy is the recommended treatment for any known MTC and was used to define guideline-concordant care in this study, recent data suggests that sporadic, small, isolated MTC tumors confined to the thyroid will have similar oncologic outcomes regardless of extent of surgery (unilateral thyroid lobectomy versus total thyroidectomy).37, 38 Another limitation is that the NCDB does not provide information on whether a formal central or lateral lymphadenectomy was performed. Because we used the removal of ≥1 lymph node as the definition of lymphadenectomy, our ability to characterize guideline-appropriate management is imperfect. However, given that 84% of patients who had at least 1 lymph node removed in fact had 4 or more removed, we deemed this measure as a reasonable proxy for intentionality of lymphadenectomy. Finally, the substantial missingness in the NCDB can introduce bias, particularly as prior work demonstrates that patients with racial/ethnic minority backgrounds have more extensive missingness.39
In summary, the presentation and management of MTC is characterized by sex-based differences and racial disparities. As male and Hispanic patients tend to present with more advanced disease, interventions to promote earlier diagnosis warrant exploration in future studies. Additionally, Black patients are significantly less likely to undergo lymphadenectomy, suggesting that efforts to promote high-quality, guideline-concordant care for historically marginalized communities should be a priority for surgeons and hospitals.
HIGHLIGHTS:
We assessed for disparities in the presentation and care of medullary thyroid cancer.
Men were more likely to present with advanced disease than women.
Non-White patients were more likely to have advanced disease than White patients.
Black patients received guideline-concordant surgery less often than White patients.
To optimize MTC outcomes, rates of appropriate surgery should be improved for all.
Financial support:
Research reported in this publication was partially supported by the NIH National Cancer Institute grant #K08 CA270385 to HW.
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Disclosures: The authors have no conflicts of interest to disclose.
Saiesh Kalva, Sara P. Ginzberg, Jesse E. Passman, Jacqueline M. Soegaard Ballester, Caitlin B. Finn, Douglas L. Fraker, Rachel R. Kelz, and Heather Wachtel have no conflicts of interest to disclose.
Meeting information: A portion of the work reported in this manuscript will be presented as a podium presentation at the American College of Surgeons 2023 Clinical Congress in Boston, MA.
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