Clinical presentation and survival outcomes of well‐differentiated thyroid cancer in Filipinos

Abstract Background Filipinos have higher recurrence rates compared to other racial/ethnic groups, which might suggest a higher propensity for aggressive disease. The goal of this study was to perform a population‐based analysis of disease extent at diagnosis and survival outcomes in Filipino patients with well‐differentiated thyroid cancer relative to other racial/ethnic groups. Methods The study cohort comprised adult patients with well‐differentiated thyroid cancer diagnosed between 2004 and 2015, identified in the California Cancer Registry. Rates of extrathyroidal extension, nodal metastasis, and distant metastasis were compared between Filipinos, Non‐Filipino Asians, and Non‐Asians using multilevel logistic regression models. Survival outcomes were compared using Cox regression models, utilizing a sequential modeling approach. Results Filipino ethnicity was associated with extrathyroidal extension (OR 1.35, 95% CI 1.11–1.63) compared with non‐Asians and non‐Filipino Asians. Filipino ethnicity was also associated with nodal metastasis (OR 1.32, 95% CI 1.18–1.46), and with worse OS (Hazard Ratio [HR] 1.45, 95% CI 1.20–1.75) and DSS (HR 1.51, 95% CI 1.12–2.04). After adjusting for demographic and clinical factors, Filipino ethnicity was no longer associated with OS (HR 1.03, 95% CI 0.84–1.25) or DSS (HR 0.93, 95% CI 0.68–1.28). Conclusion Filipino patients with thyroid cancer are more likely to present with locoregionally advanced disease compared with non‐Filipino Asians and non‐Asians. Furthermore, Filipino patients have worse survival outcomes compared with non‐Filipino Asians and non‐Asians. However, this appears to be driven by the higher rates of locoregionally advanced disease in Filipino patients.


| INTRODUCTION
The incidence of thyroid cancer is rapidly increasing in the United States (US). 1 The incidence increased from 4.56 per 100,000 person-years in 1974-1977 to 14.42 per 100,000 person-years in 2010-2013. [2][3][4][5] Although thyroid cancer is associated with low mortality rates, 6 significant racial disparities exist in thyroid cancer outcomes. African American patients present with more advanced tumors, are less likely to receive appropriate treatment, and have worse survival outcomes than other racial groups, even after adjusting for disease stage and other clinically important factors. [7][8][9][10][11] While there is extensive evidence of poor outcomes in African Americans, racial disparities in outcomes have not been adequately studied for Asians, even though they make up a significant proportion of the US population. Furthermore, the Asian population comprises diverse ethnic groups that are not homogenous.
The incidence of thyroid cancer is high in Southeast and East Asians. Among these, Filipinos have one of the highest incidence rates in the world. 12,13 Filipino patients with thyroid cancer have higher rates of recurrence compared to other racial/ethnic groups, which might suggest a higher propensity for aggressive disease. 14 A recent evaluation of US national mortality records indicated that age-adjusted mortality rates due to thyroid cancer were highest in Filipinos. 15 However, it is not clear if this is due to the overall higher incidence of thyroid cancer in this population, or due to worse survival outcomes compared to other racial/ethnic groups. The goal of this study was to perform a population-based analysis of disease extent at diagnosis and survival outcomes in Filipino patients with well-differentiated thyroid cancer relative to other racial/ethnic groups. We hypothesized that Filipino patients have higher rates of advanced stage disease, and consequently, worse survival compared with non-Filipino Asians and non-Asians.

| MATERIALS AND METHODS
This study was approved by the State of California Committee for the Protection of Human Subjects, and was considered exempt by the Stanford University Institutional Review Board. Data were extracted from the California Cancer Registry (CCR) dataset. The CCR is a statewide population-based cancer surveillance system that also comprises three SEER registries. 16 It is the largest, contiguous-area, populationbased cancer registry system in the country, and has been collecting data under state mandate using uniform, high-quality reporting standards since 1988. The study cohort comprised adult patients with papillary thyroid carcinoma or follicular/ Hurthle cell carcinoma diagnosed between 1 January 2004 and 31 December 2015.
Tumor site and histology were determined according to the ICD-O-3 topography (C73.9 for thyroid gland) and morphology codes available in CCR. 17 The following codes  for papillary, follicular, and Hurthle cell carcinoma were  included: 8050/3, 8260/3, 8340/3, 8342/3, 8343/3, 8344/3,  8330/3, 8331/3, 8332/3, and 8335/3. Information on disease stage was obtained from CCR using the SEER-AJCC stage. This is based on combined clinical and pathological assessments, including all information available within 4 months of diagnosis or through completion of surgery in the first course of treatment. Staging information is based on (in priority order) the pathology report, the surgeon's evaluation at the time of surgery, clinical findings, or radiographic description. 18 Patients were classified according to the AJCC staging 6th edition 19  Race/ethnicity was categorized as Filipino, Non-Filipino Asian, or Non-Asian. Marital status was categorized as "married" (including common law) or "single" (singlenever married, divorced, and widowed). Insurance status was categorized as commercial, Medicare, Medicaid, uninsured, or unknown. Neighborhood-level socioeconomic status (SES) was classified into five quintiles, lowest (SES-1), lower-middle (SES-2), middle (SES-3), higher-middle (SES-4), and highest (SES-5) based on the Yost score. The Yost score is a composite index of SES contained in the CCR that is based on principal component analysis of block group level census variables such as education, income, and occupation. 21 The statistical analysis was performed using SAS system, version 9.4 (SAS Institute, Inc.,). Unadjusted and adjusted logistic regression models were used to assess the association between race/ethnicity and the following measures for extent of disease: extrathyroidal extension, nodal metastasis, and distant metastasis. Unadjusted and adjusted multilevel linear regression models were used to assess the association between race/ethnicity and tumor size. For the linear regression models, tumor size was log transformed to improve model fit because the distribution of tumor size was right skewed. For all adjusted analyses assessing the association between race/ethnicity and extent of disease, the following covariates were entered a priori into the model: age, marital status, sex, Charlson comorbidity score, SES, and insurance status. The association between race/ethnicity and overall survival (OS) and disease-specific survival (DSS) was assessed using Kaplan-Meier survival analysis, and unadjusted and adjusted Cox regression models with robust standard error using sandwich variance estimators. Assumption of proportionality in hazards was evaluated and satisfied. In order to understand the drivers of the racial/ethnic disparities in survival, a sequential modeling approach was applied for the adjusted models. Each stage included the following predictors sequentially: (1) demographic (age, sex, and marital status) and clinical factors (T classification, N classification, M classification, Charlson comorbidity score, histology, and extent of thyroidectomy); (2) neighborhood SES; and (3) insurance status. Cases with missing values were excluded from analysis. An estimate was considered to be statistically significant at α = 0.05.

| RESULTS
We identified 36,573 patients meeting the inclusion criteria: 2065 Filipinos, 4327 non-Filipino Asians, and 30,181 Non-Asians. Patient characteristics are shown in Table 1. Filipino patients were older than non-Filipino Asians and non-Asians at diagnosis (51.3 years vs. 47.3 years and 47.7 years, respectively). Slightly higher proportion of non-Asians (22.3%) were male, compared with Filipino Asians (20.5%) and non-Filipino Asians (20.7%).

| DISCUSSION
Our study shows that Filipino patients with thyroid cancer are more likely to present with locoregionally advanced disease compared with non-Filipino Asians and non-Asians. Filipino ethnicity was associated with higher likelihood of extrathyroidal extension, and nodal metastasis, but not distant metastasis. Filipino patients had worse OS and DSS. However, this association disappeared after adjusting for demographic and clinical variables, including extent of disease, indicating that the difference in survival was due to extent of disease.
The findings are important because Filipinos have one of the highest incidence rates of thyroid cancer in the world, 12,13 and the highest incidence-based thyroid cancer | 5967 MEGWALU Et AL. mortality in the United States. 15 This is the largest study to assess the association between Filipino ethnicity and extant of disease and survival outcomes in patients with thyroid cancer. Only one previous study has evaluated the disease extent and outcomes in Filipinos relative to other racial/ethnic groups. Kus et al. performed a singleinstitution retrospective study comparing thyroid cancer outcomes between 36 Filipino and 463 non-Filipino patients. 14 In contrast to our study, they found no difference in tumor size and disease stage between the two groups. There was also no significant difference in survival on unadjusted and adjusted analyses. However, Filipino patients had higher risk of recurrence. In contrast, our study found that Filipino patients had worse survival than non-Filipino  15 They found that Filipinos had the highest age-adjusted mortality rates due to thyroid cancer compared with non-Filipino Asians and non-Hispanic Whites. Since this study used data based on national death certificates, it is unclear if the high incidence-based thyroid cancer mortality for Filipinos is due to the overall higher incidence of thyroid cancer in this population, or due to an actual difference in the disease process in this group relative to other racial/ethnic groups. Several causes for the higher thyroid cancer mortality rates and recurrence in Filipinos have been suggested. Previous studies have theorized that exposure to carcinogenic volcanic lava, and interference of a high-iodine diet with radioactive iodine treatment may contribute to worse outcomes. 15,22 However, our findings suggest that the worse survival outcomes observed in Filipinos is due to more locoregionally advanced disease in this population. The reasons for this difference in disease presentation remains unclear. The higher risk of locoregionally advanced disease in Filipinos remained, even after adjusting for age, sex, marital status, SES, and insurance status, indicating that these are not the drivers of this disparity. Consequently, the more advanced disease at present is unlikely to be due to difficulty accessing timely care. There may be a molecular basis for differences in extent of disease between Filipinos and non-Filipinos. One possible explanation is that Filipinos may be predisposed to tumors that contain genetic mutations that lead to more locoregionally aggressive disease. Several small studies have examined the rates of BRAF V600E mutation (which is associated with more aggressive disease) in Filipino patients with mixed results. One of the studies reported higher rates of BRAF V600E mutation in Filipinos, while the other reported lower rates compared with reported rates for non-Filipino Asians. 23,24 More robust studies are needed to determine whether there is a molecular cause that leads to more aggressive tumors in Filipinos relative to other racial/ethnic groups. The results of our study suggest that clinicians should have a high index of suspicious for locoregionally advanced disease when managing Filipino patients with thyroid cancer. The higher rates of extrathyroidal extension and lymph node metastasis, and the resulting worse survival, raise the question of whether these patients should be managed differently from other racial/ethnic groups. Kus et al. recommended total thyroidectomy for Filipino patients with thyroid nodules 1 cm or larger, regardless of fine needle aspiration cytology findings. 14 They also recommended more frequent follow-up with imaging and serum thyroglobulin measurements for Filipino patients with thyroid cancer. However, there is currently no data on whether such aggressive management would translate to improved survival or reduced recurrence rates. Furthermore, this approach would most likely lead to unnecessary operations for benign thyroid nodules. Another pertinent question is whether this population may benefit from routine cross-sectional imaging of the neck (computed tomography or magnetic resonance imaging), in order to detect extrathyroidal extension and lymph node metastasis that may not be readily apparent on examination. However, there is currently no evidence to support routine cross-sectional imaging in this patient population.
The main strength of our study is its large sample size and diverse patient characteristics. The CCR is the largest, contiguous-area, population-based cancer registry system in the country, and has been collecting data under state mandate using uniform, high-quality reporting standards since 1988. 16 Since cancer reporting is mandated by California law, CCR data are representative of all cancer cases in California. Our study has several limitations. CCR does not provide information on disease recurrence, therefore, the association between Filipino ethnicity and disease recurrence could not be assessed. Also, this study was limited to patients treated in California. Therefore, it is unclear if the findings are generalizable to the entire United States. However, California has the highest population of Filipinos in the United States, with 45% of the nearly 3 million Filipinos in the United States living in California. 25 Consequently, our findings are likely generalizable to the rest of the United States.

| CONCLUSION
Filipino patients with thyroid cancer are more likely to present with locoregionally advanced disease compared with non-Filipino Asians and non-Asians. Furthermore, Filipino patients have worse survival outcomes compared with non-Filipino Asians and non-Asians. However, this appears to be driven by the higher rates of locoregionally advanced disease in Filipino patients. Further investigation is needed to determine whether there is a molecular basis for the higher propensity of Filipinos to present with locoregionally advanced disease. Furthermore, future studies are needed to determine whether this patient population would benefit from more aggressive work-up and treatment. Clinical factors: T classification, N classification, M classification, Charlson comorbidity score, histology, and extent of thyroidectomy.
T A B L E 4 (Continued)