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Behaviour and epidemiology of differentiated thyroid cancer among filipinos in and outside the Philippines: Comparison between Qatar, Canada and Philippines

Background No study assessed the behaviour/epidemiology of differentiated thyroid cancer (DTC) among Filipinos in the Middle East/north Africa; or compared such behaviour with Filipino DTC patients in and outside the Philippines. Materials and methods Retrospective review of all adult Filipinos with DTC diagnosed between 2015 and 2020 at our institution [papillary TC (PTC, n = 110); follicular TC (FTC, n = 4)]. Chi-square or t-test compared the frequency, demography, history, ultrasound, laboratory and histopathology of PTC vs FTC; and compared the epidemiology of DTC among Filipinos in Qatar vs Canada (1 study) vs the Philippines (3 studies). Results DTC frequency was ≈43.84 cases/100,000 Filipinos in Qatar. Males had more aggressive disease in terms of lymphovascular invasion, number of nodules, stage IV disease and metastases. PTC and FTC were similar, but more PTC patients presented with solid tumors and higher number of involved lymph nodes. DTC behaviour among Filipinos in Qatar vs Canada was fairly homogenous. Conversely, DTC among Filipinos in Qatar vs Philippines exhibited many dissimilarities: Qatar had significantly younger patients, less hyperthyroid/thyrotoxicity symptoms and neck swelling at presentation, fewer solid nodules, micro-calcifications, and multi-nodular disease; smaller tumors; more stage I and less stage IV disease; and no distant metastasis (P 0.01 to < 0.0001). Conclusions DTC epidemiology among Filipinos in Qatar and Canada was fairly homogenous. Conversely, DTC in Qatar vs the Philippines was dissimilar. DTC among Filipinos in Qatar has presentations that could be misinterpreted as non-suspicious. This warrants additional practices for earlier detection among Filipinos.


Introduction
Papillary thyroid cancer (PTC) is the most common type of differentiated thyroid cancer (DTC), accounting for >80% of thyroid cancers, whereas follicular thyroid cancer (FTC) is the second most common (10-15%) [1][2][3]. The frequency of DTC has risen in the past decades [2]. Generally, thyroid cancer has low mortality rates and favorable prognosis [4,5]. However, some racial/ethnic populations display a higher likelihood e.g., Filipinos exhibit one of the highest thyroid cancer rates [6]. An important focus of thyroid cancer research has been to ascertain the factors associated with poor disease outcomes [7][8][9].
Generally, the distribution of health of different ethnic groups varies by region of origin, region of destination and their combination [10]. Despite this, most studies of thyroid cancer among Filipinos examined those living in the Philippines [2,11,12]. The very few studies that appraised thyroid cancer among Filipinos living outside the Philippines were mostly in USA or Canada [7,13,14]. To our knowledge, no studies assessed thyroid malignancy among Filipinos living in the Middle East and North Africa (MENA) region, despite that countries of the Arabian Gulf are among the top 10 destinations for Filipinos [15]. There is a lack of thyroid cancer studies that assessed the association between thyroid cancer and country, with calls for analysis of thyroid cancer across different regions of the world [16].
Therefore, the current study bridges this knowledge gap to examine the epidemiology, clinical presentation, features and characteristics of DTC among Filipinos in Qatar. The specific objectives were to assess the: • Frequency of PTC and FTC; • Demographic, history and surgical characteristics; and, • Ultrasonographic, pre-op laboratory, post-op histopathology, and management features.
In addition, we compared the above findings with those of Filipino patients with DTC living in the Philippines and elsewhere outside the Philippines using published articles identified after a literature search.
To the best of our knowledge, the current study is the first to undertake such a task. The findings add to the thin evidence base on the subject.

Study design, ethics and procedures
Filipinos represent the third largest group of expatriates in Qatar [17]. Hamad General Hospital is the largest tertiary care facility in Qatar and receives all the thyroid cancer cases in the country. The Medical Research Center (IRB) of Hamad Medical Corporation approved this retrospective study (#MRC-01-20-983). The inclusion criteria included all Filipinos ≥18 years diagnosed with DTC between May 2015-June 2020 (N = 114). Using patients' hospital case numbers, we retrieved three sets of pre-and post-operative data from the electronic records database. These included demographic, history and surgical characteristics; ultrasonographic and FNA (fine needle aspiration) findings, pre-op laboratory, and histopathology data; and the use/doses of radioactive iodine ablation (RAI) or external beam radiotherapy, recurrence, and survival. Staging of thyroid cancer used the AJCC-8 staging system for patients diagnosed during 2018-2020; and AJCC-7 for patients diagnosed during 2015-2017 [18,19]. The AJCC/TNM system predicts survival among patients with cancer [9,20].

Literature search for articles to compare with the current study
Using PubMed, MEDLINE, Scopus, and Google scholar electronic databases, we searched the literature for studies of Filipino patients with DTC living in and outside the Philippines published between January 2005 to March 2022. Additional searches were performed employing the reference lists of studies. After examining the abstracts and full texts, the research team selected 4 suitable papers, 3 in the Philippines [11,21,22] and 1 in Canada [7]. Data pertaining to three sets of pre/post-operative variables under examination were extracted from the 4 selected articles, tabulated and compared to the findings from Qatar. We report the current study in line with the STROCSS 2021 criteria [23], with research registry unique identifying number [24].

Statistical analysis
Data were presented as mean ± standard deviation (SD) or frequency and percentage as appropriate. Using chi-square for categorical variables and t-test for continuous, PTC was compared FTC; and findings of the present study were compared to other studies in the Philippines and Canada. Data analysis used the Statistical Package for Social Sciences version 21 (SPSS Inc., Chicago, IL), and online statistical package OpenEpi [25], with significance set at P < 0.05.

Results
Across our 114 patients, PTC and FTC comprised 96.5% and 3.5% respectively. Common PTC variants included classic (74.6%) and follicular (13.2%) variants. The 114 diagnosed cases divided by the 260,000 Filipinos in Qatar during the study period [17] generated an incidence of ≈43.84 DTC cases per 100,000 Filipinos living in Qatar.  Table 1 shows that mean age was 40.15 years, and females were overrepresented (83.3%). The only significant differences between PTC vs FTC patients was that surgically, PTC was associated with more total thyroidectomy + lymph node dissection or right hemi-thyroidectomy; and for ultrasound (US), more PTC patients presented with solid tumors, while FTC patients presented more with mixed solid/cystic tumors. PTC and FTC patients displayed significantly different Bethesda scores ( Table 2), but did not significantly differ across the laboratory characteristics (Table 3).

Histologic profile, staging, management, and outcomes
PTC and FTC patients did not differ across the histopathological characteristics except that PTC cases had a slightly higher mean number of involved nodes (P = 0.004) ( Table 4). PTC and FTC did not differ in the disease stages (Table 5) or in the management, recurrence and survival features ( Table 6).

DTC among filipinos by sex
We compared the characteristics of DTC among Filipinos by sex. No significant sex differences were observed across the clinical, ultrasonographic, FNA, recurrence and survival features, as well as across most laboratory variables (data not presented). Most histologic variables did not show sex differences. However, more males displayed positive tumor lymphovascular invasion (52.6% ♂ vs 18.9% ♀ , P = 0.002); presented with >1 tumor nodule (63.2% ♂ vs 40.7% ♀ , P = 0.03); had stage 4 disease (10.5% ♂ vs 0% ♀ P = 0.005); and metastases (11.1% ♂ vs 1.1% ♀ , P = 0.02). These findings suggested that in Qatar, Filipino males encountered a more aggressive disease than females.   of Filipinos with DTC living in Canada [7]. DTC behaviour among both patient populations was very similar, with the exception that in Canada, significantly more patients received radiotherapy (EBRT) after the initial surgery compared to Qatar. This suggested that DTC among Filipinos in both countries appeared to be fairly homogenous.

DTC among filipinos living outside vs in the Philippines: Qatar vs Philippines
The above picture differed when we compared our findings with three studies of Filipino DTC patients in mainland Philippines [11,21,22]. Table 7 (Section B) suggests that although sex distribution was similar between Qatar vs the Philippine studies [11,21,22]; the epidemiology appeared to be quite dissimilar.
As for age at presentation, Qatar patients were slightly younger than those of two Philippine studies [11,22]. In connection with clinical and laboratory findings, the Philippines exhibited more family history of thyroid disease, and history of thyrotoxicity and neck swelling at presentation, supporting that in the same study [21], mean preop TSH was significantly lower, while mean T4 level was significantly higher than in Qatar (although all levels were within normal range). The Philippines had also higher prevalence FTC [11], solid nodules [11,21], micro-calcifications [21], larger tumors and multi-nodular disease [11]. Histopathology confirmed that in the Philippines, tumors were significantly larger, and displayed lower prevalence of AJCC stage I, as well as higher prevalence of stage IV disease [11,22]. Similarly, TNM classification showed significant differences in the N categories [11,22], and significantly more M1 patients in the Philippines vs Qatar (4.7% vs 0%) [11]. Tumor multifocality was significantly more in Qatar [11,21,22], and there were significant differences in FNA findings between Qatar and Philippines [11].

Discussion
DTC is the most common endocrine malignancy [26]. To the best of our knowledge, the current study is the first to appraise DTC among Filipinos living in the MENA region and the first to undertake in-depth comparisons of such findings to Filipino patients diagnosed with DTC living in and outside the Philippines. The main findings were that the behaviour and epidemiology of DTC among Filipinos living Qatar vs Canada appears to be homogenous, with considerable similarities and overlap. Conversely, DTC among Filipinos living Qatar vs the Philippines appears to be heterogenous: Qatar had younger patients, less thyrotoxicity, neck swellings, solid nodules, micro-calcifications, multi-nodularity; smaller tumors; more stage I and less stage IV disease; and no distant metastasis (P 0.01 to < 0.0001). The mean follow up of our patients was 2.61 ± 1.82 years, with the maximum follow up being 6.84 years.
During the study period, DTC incidence was ≈43.84 cases/100,000 Filipinos living in Qatar. Thyroid cancer incidence among Filipino patients aged ≥20 years in the USA was 19.57/100,000 Filipinos [27]. Our  observed higher rate might be due to that: thyroid cancer affects young/middle-aged persons, and Filipino expats in Qatar are middle aged [28]; we examined Qatar during 2015-2020 while the US study [27] reported on 2004-2014, and the frequency of DTC has risen in the past decades [2]; and, Qatar offers free healthcare coverage (higher likelihood that all cases would be identified early). Globally, TC incidence based on population-based cancer registries (26 countries) was 47 per 100,000 women and 14 per 100,000 men [4]. Across our Qatar sample, relatively more females had DTC, supporting others [29]. However, DTC among our males exhibited relatively more aggressive features (lymphovascular invasion, number of tumors, stage 4 disease, metastases) than among females. Such higher aggressiveness among males is congruent with other studies [30] and propositions of sex difference in TC pathogenesis [31].
We then compared the DTC characteristics amongst Filipinos living in Qatar and elsewhere. Table 7 (Section A) compares Qatar vs Canada and suggests that DTC epidemiology among Filipinos in Qatar appeared to be fairly homogenous to that in Canada. While it is difficult to speculate the reasons for the observed similarities, a common feature between the Filipino patients with DTC in Qatar and Canada is their immigrant status. Generally, most persons who leave their native country to immigrate or reside in another country for economic betterment are usually healthy individuals (healthy migrant effect). For instance, immigrants were relatively healthier on arrival in Canada compared to native-born Canadians, and immigrant health converged with years in Canada to native-born levels [32]. Commonly, at immigration, migrants have better health status than the remaining population in their native country of birth, and to some extent, better health than the population in the host country [33]. Table 7 (Section B) compares Qatar with three studies of Filipino DTC patients living in mainland Philippines [11,21,22]. Contrary to the similarities we noticed above in DTC behaviour among Filipinos in Qatar and in Canada, the emerging picture was different. With the exception of the sex distribution, DTC epidemiology among Filipinos in Qatar vs the Philippines appeared to be quite heterogenous as discussed below.
Females were more represented in Qatar and in the three Philippine studies, supporting a ratio of 4.5:1 reported by other thryoid cancer research in the Philippines [29,34]. Over-representation of females is well illustrated in our sample, despite that Qatar's demography has high male proportion [17]. As for age at presentation, mean age of the Qatar sample was slightly younger than in the Philippine studies [11,22], probably due to the young/middle-aged demography of expats in Qatar [17].
Clinically, the Philippines had more family history of thyroid disease, hyperthyroid symptoms and neck swelling at presentation than Qatar [21]. Whilst it is difficult to speculate why, the prevalence of iodine deficiency might offer clues. Iodine deficiency is not a health concern in Qatar [35]; while many regions in the Philippines remain iodine deficient [36], although some reports maintain that the Philippines had overcome its iodine deficiency [22]. Lack of dietary iodine is a cause of thyroid disorders, but excess iodine, genetics, geographical and dietary factors also trigger thyroid disorders [37]. Hence, others proposed environmental effects due to exposure to a carcinogenic agent in volcanic lava [38]. If this was the case, Filipinos living outside the Philippines (e.g., Qatar) might be less exposed. Such lack of exposure to environmental effect leading to a decreased risk of thryoid cancer is recognized [39]. Still others suggested that genetic profiles might be the cause [40].
In addition, some of our findings suggested that DTC in the Philippines is more advanced at presentation: ultrasound showed more solid nodules, micro-calcifications, larger tumors, and multi-nodular disease than observed in Qatar, features that suggest thryoid cancer risk or development of multiple recurrences [8,41]; patients presented with higher tumor burden (less stage I, more stage IV disease) [11,22]; and TNM classification showed that 4.7% of patients in the Philippines had distant metastasis (M1) [11] vs 0% in Qatar. Collectively, the above clinical, ultrasound and histopathology findings suggested that DTC among Filipinos in Qatar appears to behave in a quite dissimilar manner compared to that in the Philippines.

Clinical implications
The less suspicious disease presentation and initial ultrasonographic findings in Qatar compared to the Philippines might sometimes lead the unsuspecting health worker to erroneously misinterpret it as nonmalignant disease. DTC in Qatar displayed significantly higher   proportions of multifocal tumors not readily detected by initial US. Hence, a high index of suspicion is required among Filipinos living in Qatar with thyroid nodules, even with small nodules. This warrants the implementation of additional multi-fold opportunistic strategies for earlier detection among this population group: education of Filipinos on thyroid self-examination; raising awareness/training of primary/health care professionals to undertake thorough thyroid examination during routine checkups of Filipinos; and to assess any suspicion of thyroid nodules or malignancy when Filipinos have routine imaging scans for other health problems.

Limitations and strengths of study
This study has limitations. A larger sample size would have beneficial to test differences between PTC and FTC patients. Retrospective medical record reviews have limitations of data quality. For about 17.5% of the sample, we had no information on survival, probably because they left Qatar. Comparisons based on specific genetic and molecular markers would have been beneficial. The comparisons of our sample with three Philippine studies [11,21,22] or the study in Canada [7] were limited by the different reporting of the disease characteristics across the published papers; consensus and standardization of the reporting of thyroid cancer would benefit similar comparisons across different countries. Unpacking the reasons behind the differences between Filipino patients with DTC living in Philippines vs outside the Philippines is not a straightforward one. Future research could benefit from exploring such limitations.
Nevertheless, the study has many strengths. To our knowledge, it is the first to appraise DTC among Filipinos living in the MENA region, employing many variables. In addition, it is representative of the Filipino population living in Qatar as our institution receives all cases across the country. We undertook the rare detailed comparison of Filipino patients with DTC in Qatar and the Philippines, employing three suitable and different studies undertaken in the Philippines involving data stretching over more than two decades (24 years, 1990-2014), and including a large number of (1373) of DTC patients seen at 3 different main tertiary care hospitals at various locations in Manila. We are not aware of any previous study that undertook such analysis.

Conclusion
The epidemiology of DTC among Filipinos living Qatar vs Canada appears to be homogenous, with considerable similarities and overlap. Conversely, DTC among Filipinos living Qatar vs the Philippines appears to be heterogenous. It appears that DTC among Filipinos living in Qatar has presentations that could erroneously be misinterpreted as nonmalignant by the unsuspecting health worker, and seemingly lower tumor load compared to those living in the Philippines. Hence, thyroid lesions among Filipinos in Qatar should be taken very seriously. These characteristics warrant the implementation of additional opportunistic practices for earlier detection among this population group. Data on DTC among Filipinos living in the MENA region are scarce; surgeons and endocrinologists should be encouraged to publish such data.

Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.