Multifocal cancer is associated with better survival than solitary cancer in non-Hispanic White patients with thyroid carcinoma
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Key findings
• First, multifocal disease was significantly associated with better cancer-specific survival (CSS) and overall survival (OS) in non-Hispanic White patients with thyroid carcinoma, but not in other ethnicities.
• Second, multifocal disease was an independent protective factor of thyroid carcinoma regardless of tumor stage and treatment.
What is known and what is new?
• Ninety percent of the thyroid cancer cases may have regional lymph node invasion where multifocal disease is the most common risk factor. However, direct evidence between multifocal thyroid carcinoma and cancer survival was rarely reported.
• This study is to demonstrate an ethnicity-specificity regarding multifocal disease in relation to better CSS and OS in patients with thyroid carcinoma.
What is the implication, and what should change now?
• The findings of this study would inform a personalized management for ethnicity-specific patients with thyroid multifocal cancer in clinical practice.
Introduction
Thyroid cancer is one of the most common malignancies in both male and female worldwide, with an estimated 586,202 new cases and 43,646 deaths every year (1). In the United States, the incidence ranks in the seventh place among women population (2). Although the incidence in female is approximately three times higher than in male, the mortality is similar in both genders (2).
The most common type of thyroid cancer is adenocarcinoma, and its incidence has been increasing rapidly for the past decades (3,4). It is relatively indolent compared with other types of thyroid cancer; however, up to 90% of the cases may have regional lymph node invasion, and ~3% of the patients may have distant metastasis, which are lethal phenotypes indicating a poorer prognosis (3,5,6). One of the risk factors for regional lymph node invasion is multifocal diseases, which have been reported to be commonly found in post-operational specimens (3,7,8). However, direct evidence between multifocal thyroid carcinoma and cancer survival is rarely reported. The impact of multifocality on cancer-specific survival (CSS) and overall survival (OS) remains unclear. Furthermore, there is limited evidence on whether this relationship varies across ethnic groups, which has motivated us to explore this question.
Therefore, we conducted the present study using the nationwide cancer registration data via the Surveillance, Epidemiology, and End Results (SEER) database. Our objective is to evaluate whether multifocal disease is associated with cancer outcomes in different ethnicities. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2024-523/rc).
Methods
Study population
The study population was obtained from the SEER 18 Registries Custom database between 2000 and 2016, which covered nearly 30% of the total population of the United States (9). The inclusion criteria were: (I) cases with pathological confirmation [International Classification of Disease for Oncology, Third Edition (ICD-O-3) code 8140–8389]; (II) behavior code of ICD-O-3 is marked as “malignant” to exclude the benign adenoma; and (III) cases under active follow-up. We excluded the cases with multiple primary cancers. Finally, we identified 123,771 individuals diagnosed with primary “thyroid adenocarcinoma” (the thyroid cancer was the first malignant and only primary tumor that the patients had). Here, “thyroid adenocarcinoma” in the SEER database indicates differentiated thyroid carcinoma including papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC). The study was approved by the Institutional Review Board of Shanghai General Hospital, Shanghai, China. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).
Outcomes assessment
The primary outcome in the present study was time to cancer-specific death. The secondary outcome was time to all causes of death. CSS was defined as time to death, and the primary cause of death was thyroid papillary adenocarcinoma. OS was defined as time to any cause of death.
Statistical analysis
Mean and standard deviation (SD) were used to describe normally distributed variables. Number of count and percentage were used to describe categorical variables. Univariable and multivariable Cox regressions were performed to evaluate the association between variables and outcomes with time effect. A two-tailed P<0.05 is considered as statistically significant. All statistics were performed using R software (ver 4.1.3) (10).
Results
A total of 82,217, 8,551, 13,445, and 19,558 non-Hispanic White (NHW), non-Hispanic African American (AA), Non-Hispanic Asian or Pacific Islander (AP), and Hispanic White (HW) patients were enrolled in this study, respectively. Characteristics of the study population are described in Table 1. The highest male-to-female ratio was observed in NHW with 24.25% of male and 75.75% of female patients (~1:3), while the lowest male-to-female ratio was found in AA with 16.61% of male and 83.39% (~1:5) of female patients (Table 1). About 45–55% of patients received only surgical treatment, 41–52% of patients received both surgical and radiation treatment, while about 2–3% of patients did not receive any treatment.
Table 1
| Characteristics | NHW | Non-Hispanic AA | Non-Hispanic AP | HW |
|---|---|---|---|---|
| Number of patients | 82,217 | 8,551 | 13,445 | 19,558 |
| Age at diagnosis (years) | 48.86±15.22 | 49.27±14.37 | 47.73±15.00 | 44.54±15.06 |
| Gender | ||||
| Male | 19,934 (24.25) | 1,420 (16.61) | 2,745 (20.42) | 3,412 (17.45) |
| Female | 62,283 (75.75) | 7,131 (83.39) | 10,700 (79.58) | 16,146 (82.55) |
| Stage | ||||
| I | 31,819 (38.70) | 3,497 (40.90) | 5,234 (38.93) | 8,318 (42.53) |
| II | 3,388 (4.12) | 429 (5.02) | 423 (3.15) | 615 (3.14) |
| III | 5,493 (6.68) | 548 (6.41) | 1,148 (8.54) | 1,465 (7.49) |
| IV | 2,503 (3.04) | 221 (2.58) | 633 (4.71) | 873 (4.46) |
| Unknown | 39,014 (47.45) | 3,856 (45.09) | 6,007 (44.68) | 8,287 (42.37) |
| Solitary or multifocal | ||||
| Solitary | 41,711 (50.73) | 5,013 (58.62) | 6,685 (49.72) | 9,869 (50.46) |
| Multifocal | 27,939 (33.98) | 2,187 (25.58) | 4,907 (36.50) | 7,159 (36.60) |
| Ectopic or unknown | 12,567 (15.29) | 1,351 (15.80) | 1,853 (13.78) | 2,530 (12.94) |
| Treatment | ||||
| No treatment | 2,010 (2.44) | 291 (3.40) | 500 (3.72) | 620 (3.17) |
| Surgical treatment | 41,356 (50.30) | 4,745 (55.49) | 5,990 (44.55) | 8,985 (45.94) |
| Both surgical and radiational treatment | 38,851 (47.25) | 3,515 (41.11) | 6,955 (51.73) | 9,953 (50.89) |
| Outcomes | ||||
| All death | 4,514 (5.49) | 641 (7.50) | 616 (4.58) | 870 (4.45) |
| Disease-specific death | 1,556 (1.89) | 168 (1.96) | 307 (2.28) | 389 (1.99) |
| Alive | 77,703 (94.51) | 7,910 (92.50) | 12,829 (95.42) | 18,688 (95.55) |
Data are presented as number, mean ± SD, or number (%). AA, African American; AP, Asian or Pacific Islander; HW, Hispanic White; NHW, non-Hispanic White; SD, standard deviation; SEER, Surveillance, Epidemiology, and End Results.
By the end of the latest follow-up, 1,556 (1.89%), 168 (1.96%), 307 (2.28%), and 389 (1.99%) patients died from thyroid carcinoma in NHW, AA, AP, and HW, respectively. In terms of all causes of death, 4,514 (5.49%), 641 (7.50%), 616 (4.58%), and 870 (4.45%) records were observed respectively (Table 1). In univariable analysis, an 11% reduction of cancer-specific death was observed in NHW who had multifocal cancer compared with those who had solitary cancer [hazard ratio (HR) =0.89, 95% confidence interval (CI): 0.77–1.02, P=0.09, Table 2]. Combined analysis with all the ethnicities suggested an 18% reduction of cancer-specific death among who had multifocal cancer compared with those who had solitary cancer (HR =0.72, 95% CI: 0.66–0.78, P<0.001, Table 2). Such reduction of cancer-specific death became more significant in multivariable analysis after adjusting for age, gender, stage, and treatment (in NHW: HR =0.63, 95% CI: 0.50–0.79, P<0.001, Table 3; in all ethnicities: HR =0.64, 95% CI: 0.56–0.73, P<0.001).
Table 2
| Race | CSS | OS | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Solitary | Multifocal | HR (95% CI) | P value | Solitary | Multifocal | HR (95% CI) | P value | ||
| NHW (n=82,217) | 550/41,617 (1.32) | 326/27,921 (1.17) | 0.89 (0.77–1.02) | 0.09 | 1,698/41,617 (4.08) | 939/27,921 (3.36) | 0.83 (0.77–0.90) | <0.001 | |
| Non-Hispanic AA (n=8,551) | 54/4,978 (1.08) | 26/2,185 (1.19) | 1.08 (0.68–1.73) | 0.74 | 238/4,978 (4.78) | 109/2,185 (4.99) | 1.03 (0.82–1.29) | 0.80 | |
| Non-Hispanic AP (n=13,445) | 113/6,672 (1.69) | 71/4,903 (1.45) | 0.88 (0.66–1.19) | 0.41 | 214/6,672 (3.21) | 146/4,903 (2.98) | 0.96 (0.78–1.19) | 0.72 | |
| HW (n=19,558) | 139/9,842 (1.41) | 92/7,158 (1.29) | 0.93 (0.72–1.21) | 0.60 | 313/9,842 (3.18) | 206/7,158 (2.88) | 0.93 (0.78–1.11) | 0.43 | |
| Combined analysis | – | – | 0.72 (0.66–0.78) | <0.001 | – | – | 0.79 (0.76–0.83) | <0.001 | |
Data are presented as event/total number (%), unless otherwise stated. AA, African American; AP, Asian or Pacific Islander; CI, confidence interval; CSS, cancer-specific survival; HR, hazard ratio; HW, Hispanic White; NHW, non-Hispanic White; OS, overall survival.
Table 3
| Characteristics | NHW | Non-Hispanic AA | Non-Hispanic AP | HW | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | ||||
| Age at diagnosis | 1.05 (1.04–1.06) | <0.001 | 1.02 (0.99–1.05) | 0.29 | 1.06 (1.04–1.09) | <0.001 | 1.05 (1.04–1.07) | <0.001 | |||
| Gender | |||||||||||
| Male | Ref. | Ref. | Ref. | Ref. | |||||||
| Female | 0.93 (0.74–1.16) | 0.50 | 0.86 (0.36–2.06) | 0.73 | 0.70 (0.41–1.20) | 0.19 | 0.70 (0.47–1.05) | 0.088 | |||
| Stage | |||||||||||
| I | Ref. | Ref. | Ref. | Ref. | |||||||
| II | 2.71 (1.28–5.79) | 0.009 | 2.58 (0.26–25.23) | 0.42 | 8.91 (1.95–40.73) | 0.005 | 1.32 (0.28–6.08) | 0.72 | |||
| III | 6.18 (3.53–10.82) | <0.001 | 9.98 (2.23–44.59) | 0.003 | 8.90 (2.37–33.36) | 0.001 | 2.18 (0.81–5.88) | 0.13 | |||
| IV | 100.12 (62.34–160.82) | <0.001 | 104.78 (27.11–404.91) | <0.001 | 46.47 (13.40–161.19) | <0.001 | 35.39 (17.13–73.13) | <0.001 | |||
| Treatment | |||||||||||
| No treatment | Ref. | Ref. | Ref. | ||||||||
| Surgical treatment | 0.18 (0.12–0.25) | <0.001 | 0.19 (0.06–0.58) | 0.003 | 0.20 (0.09–0.43) | <0.001 | 0.19 (0.10–0.35) | <0.001 | |||
| Both surgical and radiational treatment | 0.13 (0.09–0.17) | <0.001 | 0.10 (0.04–0.30) | <0.001 | 0.13 (0.06–0.28) | <0.001 | 0.14 (0.08–0.24) | <0.001 | |||
| Solitary or multifocal | |||||||||||
| Solitary | Ref. | Ref. | Ref. | Ref. | |||||||
| Multifocal | 0.63 (0.50–0.79) | <0.001 | 0.86 (0.39–1.89) | 0.70 | 0.83 (0.48–1.43) | 0.50 | 0.75 (0.49–1.13) | 0.20 | |||
AA, African American; AP, Asian or Pacific Islander; CI, confidence interval; HR, hazard ratio; HW, Hispanic White; NHW, non-Hispanic White; ref., reference.
A significant better OS was also observed in NHW who had multifocal cancer compared with those who had solitary cancer (HR =0.83, 95% CI: 0.77–0.90, P<0.001, Table 2). The results were stronger in the combined analysis with all the ethnicities cancer (HR =0.79, 95% CI: 0.76–0.83, P<0.001, Table 2). This remains significant after multivariable adjustment (in NHW: HR =0.73, 95% CI: 0.63–0.84, P<0.001, Table 4; in all ethnicities: HR =0.81, 95% CI: 0.75–0.87, P<0.001). Similar trends of reduction (although not statistically significant) of cancer-specific death or all-cause death were also found in AP or HW who had multifocal disease compared with those who had solitary disease (Tables 2-4). Such a trend was not found in AA.
Table 4
| Characteristics | NHW | Non-Hispanic AA | Non-Hispanic AP | HW | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | ||||
| Age at diagnosis | 1.07 (1.06–1.07) | <0.001 | 1.06 (1.04–1.07) | <0.001 | 1.07 (1.06–1.09) | <0.001 | 1.06 (1.05–1.07) | <0.001 | |||
| Gender | |||||||||||
| Male | Ref. | Ref. | Ref. | Ref. | |||||||
| Female | 0.66 (0.58–0.76) | <0.001 | 0.69 (0.45–1.05) | 0.09 | 0.60 (0.41–0.89) | 0.01 | 0.66 (0.49–0.90) | 0.008 | |||
| Stage | |||||||||||
| I | Ref. | Ref. | Ref. | Ref. | |||||||
| II | 1.26 (0.97–1.63) | 0.08 | 0.78 (0.35–1.72) | 0.54 | 2.94 (1.37–6.31) | 0.006 | 0.81 (0.39–1.72) | 0.59 | |||
| III | 1.59 (1.28–1.97) | <0.001 | 1.90 (1.15–3.12) | 0.01 | 2.77 (1.52–5.06) | 0.001 | 1.35 (0.84–2.16) | 0.21 | |||
| IV | 7.87 (6.52–9.49) | <0.001 | 4.50 (2.58–7.84) | <0.001 | 7.69 (4.37–13.52) | <0.001 | 6.76 (4.63–9.87) | <0.001 | |||
| Treatment | |||||||||||
| No treatment | Ref. | Ref. | Ref. | ||||||||
| Surgical treatment | 0.22 (0.17–0.28) | <0.001 | 0.17 (0.09–0.33) | <0.001 | 0.27 (0.15–0.48) | <0.001 | 0.20 (0.13–0.31) | <0.001 | |||
| Both surgical and radiational treatment | 0.14 (0.11–0.18) | <0.001 | 0.09 (0.05–0.18) | <0.001 | 0.14 (0.08–0.26) | <0.001 | 0.12 (0.08–0.18) | <0.001 | |||
| Solitary or multifocal | |||||||||||
| Solitary | Ref. | Ref. | Ref. | Ref. | |||||||
| Multifocal | 0.73 (0.63–0.84) | <0.001 | 1.08 (0.73–1.59) | 0.71 | 0.87 (0.59–1.29) | 0.49 | 0.85 (0.64–1.15) | 0.29 | |||
AA, African American; AP, Asian or Pacific Islander; CI, confidence interval; HR, hazard ratio; HW, Hispanic White; NHW, non-Hispanic White; ref., reference.
In addition to tumor foci, multivariable analyses also showed several risk factors for CSS and OS. Tumor stage was a strong predictor for CS and OS as expected in different ethnicities (all P values below 0.05, Tables 3,4). Surgical treatment only, as well as the combination treatment of surgical and radiational treatment were both effective treatment methods to promote CSS and OS; however, the combination treatment would provide a slightly better survival (Tables 3,4).
Discussion
Unlike other well-investigated risk factors for thyroid carcinoma such as lymph node invasion, tumor size, unilateral or bilateral disease, etc., the association between multifocal diseases and cancer outcomes was poorly studied. Possible reasons include the relatively low report rate in the pathological reports in terms of multifocal or solitary disease compared with other risk factors, as well as duplication information among tumor size, tumor burden, and multifocal diseases. The present study provided direct evidence on this topic. Firstly, multifocal disease was significantly associated with better CSS and OS in NHW patients with thyroid carcinoma, but not in other ethnicities. Secondly, multifocal disease was an independent protective factor of thyroid carcinoma regardless of tumor stage, and treatment. These interesting results are straight forward and critical for clinical practice. Consistent trends are observed in other ethnicities, although the results did not reach statistical significance.
The association between multifocal thyroid carcinoma and disease outcomes are long controversial. A retrospective study with more than 600 patients from Greece suggested that multifocal disease was associated with lymph node spreading and T3/T4 cancers (11). Another study based on a Chinese population with similar sample size indicated similar results, which suggested a significant association with disease recurrence (12). A systematic review reported that multifocality was associated with increased recurrence risks in patients with thyroid carcinoma, whereas no significant difference was shown in CSS. However, several recently well-designed prospective studies demonstrated non-significant difference of cancer outcomes between multifocal and solitary diseases (13,14). Aside from the contradictory results from different studies, limitations in these studies were obvious. For example, the number of observed outcomes were small, which made the statistical power questionable. On the other hand, the effects of different treatment methods were unable to evaluate. For instance, surgeons tend to dissect more lymph nodes in patients with multifocal cancer than solitary cancers. In our study, with the largest sample size so far, could provide stronger evidence that patients with multifocality would have better survival than those with unifocality. Such associations remained significant after adjusting for treatment methods.
Biological mechanism underneath the results from the present study is unclear. In an early study, researchers believed that multifocal diseases were associated with heredity thyroid cancer and heredity syndromes such as multiple endocrine neoplasm (MEN) diseases (15). Multiple mutations in BRAF, RAS, RET/PTC were found in multifocal thyroid carcinoma (16,17). However, another study using whole-exome sequencing in 8 multifocal cancers did not report any significant findings (18). In addition to genetic factors, a recent study indicated that chronic lymphocytic thyroiditis (CLT) was highly coexistent with multifocal thyroid carcinoma (19). While the concurrent CLT was repeatedly shown related to lower recurrence and better prognosis (20-23). The protective effect of multifocality on survival is likely attributable to the protective effect of CLT against tumors spread via immunological and genetic mechanisms, such as the FAS/FAS ligand pathway, interleukin-1, interleukin-8, chemokine ligand 20, and recruitment of lymphocyte subtypes (24,25). Therefore, further research using bioinformatic and experimental approaches is warranted to interpret the causal relationship between multifocality and cancer outcomes.
Several limitations should be noted. First, we were only able to observe a significant association between multifocal disease and cancer survival in NHW patients. Similar trends were observed in other ethnicities; however, the results did not reach statistical significance. The relatively small sample size and the limited number of observed outcomes in these ethnicities could not provide enough statistical power in the present analysis. These trends need to be further tested in the future. Second, the missing rates of some clinical information were high, such as tumor stage. Although imputation is an optional way to provide simulation results for the missing data, it is not necessary for the current research. For example, treatment information was completed, and it was highly correlated with the tumor stages (patients with higher tumor stage would be more likely to receive combination treatment). A retrospective study is currently being conducted by our team to further investigate this topic. Finally, given the nature of the SEER database, we were unable to incorporate other important factors such as lymphovascular invasion, macroscopic extracapsular extension, and lymph node positivity in the analysis. These should be comprehensively evaluated in our future study.
Conclusions
Multifocal thyroid carcinoma is associated with better CSS and OS than solitary cancer in NHW races. The findings of this study may inform personalized management for ethnicity-specific patients with thyroid multifocal cancer in clinical practice.
Acknowledgments
We thanked the SEER program for approving our protocol and providing the custom datasets.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2024-523/rc
Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2024-523/prf
Funding: This work was supported by grants from
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2024-523/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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