Introduction
The latest cancer statistics revealed that lung cancer and thyroid cancer are common malignancies worldwide, with high incidence rates ranking second and eleventh among cancers, respectively.[1-4] Based on advances in diagnostic techniques, such as low-dose computed tomography and ultrasound,[5,6] the detection rates of the two cancers have increased substantially, which partially contributes to the elevated incidence, especially for female patients.[2,7] Moreover, the mortality rate of lung cancer is high, with a 5-year survival rate of <20%.[2] In contrast, the mortality rate of thyroid cancer has remained low or even steadily declined, ranging from 0.20 to 0.40 per 100,000 men and 0.20 to 0.40 per 100,000 women.[8]
The abnormal epidemiological pattern of thyroid cancer may be partly attributed to the nature of the tumor, with low malignant papillary thyroid cancer accounting for most cases,[3] while an increasing number of early-stage diseases have been discovered by disease screening, which may lead to overdiagnosis while also resulting in lower mortality.[9]
Nevertheless, the low mortality of thyroid cancer does not correspond to a low disease burden considering that a prolonged life may allow the development of subsequent primary malignancies (SPMs), which should not be underestimated. Previous studies emphasized the risk of antitumor therapy for SPMs in thyroid cancer patients since many sequential therapies exist, such as iodine-131 and external irradiation,[10] which may have carcinogenic effects, while routine computed tomography scans during follow-ups may also increase radiation exposure.[11] Some studies demonstrated that approximately 7.7% of patients with thyroid cancer developed a second primary carcinoma within 2 years of follow-up, and lung cancer accounted for 3.9% of cases, suggesting that the management of these patients should be as careful as that of high-risk patients.[12,13] For thyroid cancer patients with newly appearing lung nodules, no systematic understanding for distinguishing second primary lung cancer (SPLC) from metastatic lesions has been reached. Thus, SPLC in some patients with a thyroid cancer history may not be pathologically confirmed. Given the significant disease burden and high mortality of lung cancer, which may seriously shorten the survival of thyroid cancer patients, early identification of SPLC should be prioritized to ensure a good long-term prognosis. A previous study comprehensively described the risk of SPLC in breast cancer patients,[14] but this risk has not yet been systematically understood in thyroid cancer.
Therefore, our study aimed to analyze the risk of SPLC among thyroid cancer patients and to explore the relative risk factors for SPLC after the diagnosis and treatment of thyroid cancer.
Methods
Protocol and registration
The present meta-analysis was conducted according to the Preferred Reporting Items for Systematic Review and Meta-analyses statement (PRISMA)[15] and was registered at the International Prospective Register of Systematic Reviews: No. CRD42021285399.
Search strategy
We systematically retrieved relevant publications in the PubMed, Web of Science, Scopus, and Embase databases up to November 24, 2021. The following keywords were applied: “lung”, “pulmonary”, “cancer”, “tumor”, “neoplasm”, “carcinoma”, “malignancy”, “thyroid”, and “second primary”. In addition, the reference lists in relevant articles were carefully reviewed to identify additional studies. The language of the included studies was restricted to English. The detailed search strategy for PubMed is presented in Supplementary File 1, https://links.lww.com/CM9/B319.
Eligibility criteria
The inclusion criteria were as follows: (1) thyroid cancer and lung cancer were diagnosed by pathological examination; (2) discrepancies in the risk for SPLC between thyroid cancer patients and the general population were analyzed; (3) standardized incidence ratios (SIRs) with corresponding 95% confidence intervals (95% CIs) were provided; (4) full-text versions written in English were available; and (5) the most novel or comprehensive study was selected when duplications or even considerable overlaps were identified.
The exclusion criteria were as follows: (1) reviews, conference abstracts, case reports, letters, or comments; (2) experimental studies not evaluating the risk of SPLC; (3) insufficient data for SIRs and corresponding 95% CIs; and (4) studies lacking a control group.
Data extraction
Data were extracted from the included studies by two independent investigators (H. Wang and R. Yang). The following information was collected: the first author, publication year, study design, study region, databases, period, follow-up (years), sample size, and SIRs with their corresponding 95% CIs. Disagreements were carefully evaluated and then resolved by discussion and consensus. The dataset needed to replicate our findings is presented in Supplementary File 2, https://links.lww.com/CM9/B320.
Risk of bias assessment
The risk of bias was assessed using the Newcastle-Ottawa quality assessment scale (NOS),[16] and studies assigned ≥6 points were regarded as high-quality studies.
Statistical analysis
SIRs and 95% CIs were merged to explore the risk of developing SPLC in thyroid cancer patients. Pooled SIRs and 95% CIs were combined through the random effects or fixed effects model according to heterogeneity, which was evaluated by Q tests and I2 statistics. If the P value was <0.1 and I2 was >50%, we considered that the result had significant heterogeneity and thus selected the random effects model. Otherwise, the fixed effects model was selected. Subgroup and sensitivity analyses were performed to explore potential confounding factors and the possibility of overrepresentation of each study. Funnel plots, Begg's test,[17] and Egger's test[18] were utilized to assess publication bias. A trim and fill method was applied to modify our results if a significant publication bias existed.[19] A P value <0.05 was considered statistically significant. All statistical analyses and visualizations were performed by R (version 4.1.0, R Foundation for Statistical Computing, Vienna, Austria) and R Studio (1.3.1), and the package was ‘meta’ (version 5.5).
Results
Literature search
Through our systematic search in various databases, 2690 publications were identified. After removing 1212 duplications, 1478 studies were further screened by titles and abstracts. Subsequently, 98 studies were selected for full-text assessments, and 14 studies were ultimately included.[12,20-32] The PRISMA flow diagram and checklist are presented in Figure 1 and Supplementary File 3, https://links.lww.com/CM9/B321.
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Figure 1: PRISMA flow diagram of this meta-analysis. PRISMA: Preferred Reporting Items for Systematic Review and Meta-analyses statement.
Risk of bias assessment
The NOS scores of all included articles ranged from 6 to 9, suggesting a low risk of bias. The NOS assessment for each study is presented in Supplementary File 4, https://links.lww.com/CM9/B322.
Characteristics of the included studies
As shown in Table 1, a total of 14 retrospective studies were enrolled in our primary analysis. For the study region, Asia accounted for six studies,[12,25-29] whereas five and two studies were performed in Europe[20,21,24,31,32] and the USA,[22,30] respectively. The sample sizes ranged from 282 to 355,966, with more than half of the studies having a large sample size (>10,000). Since the studies by Berthe et al[21] and Izkhakov et al[29] provided the SIRs and 95% CIs of males and females separately without results for the combined population, we regarded these studies as two cohorts for analysis.
Table 1 -
Main characteristics of the included studies.
| Authors |
Year |
Country/Region (database) |
Sample size |
Gender (M/F) |
Period |
Follow-up (years) |
NOS |
| Dottorini et al
[20]
|
1995 |
Italy (GHBA) |
931 |
237/694 |
1960–1993 |
7.44∗
|
7 |
| Berthe et al
[21]
|
2004 |
France (FBCCC) |
875 |
146/729 |
1960–1998 |
8.0 |
6 |
| Ronckers et al
[22]
|
2005 |
USA (SEER) |
29,456 |
7406/22,050 |
1973–2000 |
8.0 |
7 |
| Sandeep et al
[23]
|
2006 |
Europe, Canada, Australia, and Singapore (CI5) |
39,002 |
9972/29,030 |
1975–2000 |
0–10+ |
8 |
| Verkooijen et al
[24]
|
2006 |
Netherland (LUMC) |
282 |
63/219 |
1985–1999 |
10.6∗
|
7 |
| Tabuchi et al
[25]
|
2012 |
Japan (OCR) |
355,966 |
NA |
1985–2004 |
2.5 |
7 |
| Lu et al
[26]
|
2013 |
Taiwan, China (TCR) |
19,068 |
4205/14,863 |
1979–2006 |
7.06∗
|
8 |
| Cho et al
[27]
|
2014 |
Korea (KCCR) |
178,844 |
27,089/151,755 |
1993–2010 |
3.3 |
8 |
| Teng et al
[28]
|
2016 |
Taiwan, China (NHI) |
20,235 |
4116/16,119 |
1997–2010 |
5.91 |
8 |
| Izkhakov et al
[29]
|
2017 |
Israel (INCR) |
11,538 |
2696/8842 |
1980–2009 |
1.0–30.0 |
9 |
| Wu et al
[30]
|
2017 |
USA (SEER) |
271,106 |
152,767/118,339 |
1992–2012 |
5.0 |
6 |
| Bright et al
[31]
|
2019 |
UK (ONS and WCR) |
7809 |
1594/6215 |
1971–2006 |
16.8 |
9 |
| Crocetti et al
[32]
|
2021 |
Italy (ICR) |
276,100 |
59,669/216,431 |
1998–2012 |
0–15.0 |
7 |
| Ho et al
[12]
|
2021 |
Korea (HIRA) |
269,604 |
51,003/218,601 |
2008–2018 |
2.34–6.84 |
7 |
∗Reported as the mean. Results in other studies were reported as the medians or ranges.CI5: Cancer Incidence in Five Continents; F: Female; FBCCC: François Baclesse Comprehensive Cancer Centre; GHBA: General Hospital in Busto Arsizio; HIRA: Health Insurance Review and Assessment database; ICR: Italian cancer registries; INCR: Israel National Cancer Registry; KCCR: Korea Central Cancer Registry; LUMC: Leiden University Medical Center; M: Male; NA: Not available; NHI: Taiwan National Health Insurance database; NOS: Newcastle-Ottawa quality assessment scale; OCR: Osaka Cancer Registry; ONS: Office for National Statistics; SEER: Surveillance, Epidemiology and End Results dataset; TCR: Taiwan Cancer Registry; WCR: Welsh Cancer Registry.
The risk of developing SPLC
A total of 1480,816 cases based on 16 cohorts were included in the primary analysis, and the pooled result demonstrated that patients with first primary thyroid cancer had a higher risk of developing SPLC than the general population (SIR = 1.21, 95% CI: 1.07–1.36, P < 0.01, I2 = 81%, P < 0.01) [Figure 2].
Figure 2: Forest plot showing the risk for subsequent primary lung cancer in thyroid cancer patients. CI: Confidence interval; IV: Interval; SE: Standard error of treatment effect; SIR: Standardized incidence ratio; TE: Treatment effect.
Subgroup analyses
Subgroup analyses were performed to detect potential influencing factors for the association between thyroid cancer and SPLC [Table 2]. The results showed that sex can be an important influencing factor, as female patients (SIR = 1.65, 95% CI: 1.40–1.94, P < 0.01, I2 = 75%, P < 0.01) were more likely to be affected than males (SIR = 1.04, 95% CI: 0.94–1.14, P = 0.4618, I2 = 33%, P = 0.1733). In addition, Asian individuals (SIR = 1.42, 95% CI: 1.21–1.66, P < 0.01, I2 = 81%, P < 0.01) seemed to have a higher risk of SPLC than European or American individuals. No difference was found between the young (≤50 years) and elderly (>50 years) patient subgroups.
Table 2 -
Results of the subgroup analyses.
|
|
Association |
Heterogeneity |
Difference |
|
|
|
|
|
| Variable |
N
|
SIR (95% CI) |
P values |
I
2 (%) |
P values |
P values |
| Sample size |
|
|
|
|
|
0.48 |
| ≤10,000 |
7 |
1.30 (1.07–1.59) |
<0.01 |
0 |
0.51 |
|
| >10,000 |
9 |
1.19 (1.04–1.37) |
<0.01 |
89 |
<0.01 |
|
| Region |
|
|
|
|
|
<0.01 |
| Asia |
7 |
1.42 (1.21–1.66) |
<0.01 |
81 |
<0.01 |
|
| Europe |
6 |
1.05 (0.86–1.26) |
0.65 |
8 |
0.37 |
|
| USA |
2 |
0.97 (0.79–1.20) |
0.79 |
83 |
0.01 |
|
| Mixed |
1 |
0.93 (0.80–1.08) |
0.34 |
/ |
/ |
|
| Sex |
|
|
|
|
|
<0.01 |
| Female |
7 |
1.65 (1.40–1.94) |
<0.01 |
75 |
<0.01 |
|
| Male |
7 |
1.04 (0.94–1.14) |
0.46 |
33 |
0.17 |
|
| Age (years) |
|
|
|
|
|
0.94 |
| ≤50 |
3 |
1.29 (0.96–1.73) |
0.10 |
0 |
0.82 |
|
| >50 |
2 |
1.26 (0.79–1.99) |
0.33 |
88 |
<0.01 |
|
| Overall |
16 |
1.21 (1.07–1.36) |
<0.01 |
81 |
<0.01 |
|
95% CI: 95% Confidence interval; N: Number of cohorts; SIR: Standardized incidence ratio.
Sensitivity analysis
We then performed a sensitivity analysis to further explore the potential source of heterogeneity by removing each study from the meta-analysis independently. As shown in Figure 3, the pooled SIRs demonstrated that our results were robust and credible. However, after omitting the study by Teng et al[28], the heterogeneity decreased substantially (SIR = 1.15, 95% CI: 1.03–1.28, P = 0.01, I2 = 74%, P < 0.01), suggesting that this publication might be the main source of heterogeneity.
Figure 3: Results of the sensitivity analysis. CI: Confidence interval; IV: Interval; SIR: Standardized incidence ratio.
Publication bias
Funnel plots, Begg's test, and Egger's test were applied to assess publication bias. The funnel plots were basically symmetrical [Figure 4]. In addition, the results of Begg's test and Egger's test also showed no significant bias (Begg: P = 0.93, Egger: P = 0.63), suggesting that our results are reliable.
Figure 4: The funnel plot for detecting publication bias.
Discussion
Thyroid cancer ranks as the 11th most common type of malignancy worldwide, with approximately 0.6 million new cases and relatively low mortality, and more frequently occurs in females.[2] Due to advances in early diagnostic and therapeutic approaches, the prognosis of thyroid cancer patients appears to be good, with cancer-specific survival approaching 100%.[33] Previous studies have shown that the risk of second primary malignancies (SPMs) may be higher in thyroid cancer survivors due to their prolonged lives.[34,35] Lung cancer remains the main cause of tumor-related death, with the highest mortality and second-highest morbidity,[1,2] suggesting that the development of SPLC in these patients should be monitored more closely by both oncologists and thyroid surgeons.
In the present study, we comprehensively determined the risk of SPLC in patients with thyroid cancer. The results demonstrated that a former history of thyroid cancer may result in a markedly higher risk of developing lung cancer (SIR = 1.21, 95% CI: 1.07–1.36, P < 0.01, I2 = 81%, P < 0.01). Further analysis of influencing factors revealed that female patients (SIR = 1.65, 95% CI: 1.40–1.94, P < 0.01, I2 = 75%, P < 0.01) were more susceptible than males (SIR = 1.04, 95% CI: 0.94–1.14, P = 0.46, I2 = 33%, P = 0.17), whereas Asian individuals (SIR = 1.42, 95% CI: 1.21–1.66, P < 0.01, I2 = 81%, P < 0.01) may be at a higher risk than American or European individuals.
A previous meta-analysis performed by Subramanian et al[34] initially confirmed that thyroid cancer survivors are at a higher risk of developing SPMs, although their results for SPLC might lack credibility because of the few studies that they enrolled and inconsistency with clinical observations (n = 6, SIR = 0.84, 95% CI: 0.75–0.92, P < 0.05).[35] Our study constructed stricter inclusion and exclusion criteria and ultimately enrolled more studies with results indicating the adverse impact of a thyroid cancer history on SPLC, suggesting that our study was more convincing and accurate.
Previous studies have reported many consistent risk factors for lung cancer and thyroid cancer patients, such as smoking, obesity, family history, and radiation exposure.[36,37] We aimed to further explore the impact of these factors, but the included studies lacked these data. Moreover, in terms of genetic mechanisms, many driver genes have been described in both lung cancer and thyroid cancer. Ret proto-oncogene (RET) mutation or rearrangement has been demonstrated to be a critical driver in thyroid and pulmonary malignancies, and some novel tyrosine kinase inhibitors targeting such mutations, such as pralsetinib and selpercatinib, seem to be effective.[38-40] In addition, Braf proto-oncogene[41] mutations, which contribute to the key signaling pathways regulating cell growth, proliferation, and other tumorigenic processes, also contribute to the development and progression of these two diseases. Thus, these factors might be one of the reasons for the elevated SPLC risk.
Radiotherapy, especially radioactive iodine treatment (RAI), may also serve as a prognostic factor in thyroid cancer. The study by Wu et al[30] revealed that radiation status might be associated with SPLC; nevertheless, their result was not statistically significant (SIR: 1.13, 99% CI: 0.91–1.38, P > 0.05).[30] Based on two meta-analyses by Sawka et al[35] and Yu et al[42], the risk of SPMs but not SPLC increases among RAI recipients. Likewise, studies focusing on the role of RAI with either positive or negative results were subsequently carried out.[43-45] Nevertheless, the analytical approaches varied substantially among studies, while the patients partly overlapped; thus, we could not merge them to conduct another meta-analysis. However, studies till date have been few in number and insufficiently credible, and thus further exploration is needed to ascertain whether RAI can affect the risk of SPLC. Some mechanisms regarding the RAI might contribute to SPLC in thyroid cancer survivors. Radiotherapy often results in pulmonary injuries in clinical practice, which is called radiation-induced lung injury (RILI) and is especially observed during tumor treatment.[46] Radiation-induced pulmonary or systemic inflammation and malnutrition may lead to the appearance and development of lung cancer,[47,48] whereas pulmonary fibrosis, the most severe form of RILI, also increases the risk and worsens the prognosis of lung cancer because of a decline in lung function and activation of some tumor-associated pathways.[49,50] In addition, radiation itself can also induce novel genomic alterations irrespective of the type of primary tumor, suggesting that the genetic impact could be another contributing factor.[51]
Interestingly, our findings indicated that females are the main population affected. Based on previous studies, we may infer that the thyroid gland is a common endocrine organ that can be easily affected by systemic hormone levels; for instance, estrogen can promote the growth and proliferation of tumor cells in the thyroid gland, which might be regulated by the estrogen receptor and downstream mitogen-activated protein kinase and phosphoinositide-3-kinase/AKT pathways.[52] Furthermore, estrogen also plays a crucial role in lung cancer, which is related to epidermal growth factor receptor, the common driver gene of lung adenocarcinoma.[53] Thus, we hypothesized that female patients with thyroid cancer may initially have sex hormone disturbances that males do not have, which is not caused by thyroid cancer or its treatment, and could increase the risk of both thyroid cancer and lung cancer. Therefore, these patients may develop thyroid cancer first, and have a higher risk of SPLC than males due to some common carcinogenesis mechanisms of both thyroid and lung cancer mediated by female hormones.
Certainly, our study has some limitations. The most obvious limitation is the high heterogeneity among studies; thus, we conducted a further analysis to determine the possible origin. Second, most of our included studies were retrospective, while some of them lacked baseline patient characteristics, such as smoking, body mass index, family history, and radiation exposure, which may introduce bias to the results. Additionally, although we attempted to adjust our results and determine potential risk factors for SPLC, most factors were not analyzed due to a deficiency of relevant data.
In general, thyroid cancer patients are at higher risk of developing lung cancer, and females and Asian individuals might be predominantly affected. However, future prospective studies with higher quality or exploring potential risk factors, especially RAI, are needed to confirm our findings, which would facilitate decision-making and high-risk patient identification for follow-up in clinical practice. Moreover, novel medications or therapeutic strategies targeting the two diseases or even pan-cancer could also be prioritized to not only treat tumors precisely but also prevent disease progression or recurrence.
Funding
This study was supported by grants from the National Natural Science Foundation of China (Nos. 92159302, 81871890, 91859203 to W. Li).
Conflicts of interest
None.
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