研究目的

分析全球不同国家食管癌、胃癌及其亚型发病率的时间变化趋势，量化其亚型和性别差异的变化规律，为各国制定食管癌和胃癌的针对性防控措施提供科学依据。在此基础上，依托我国上消化道癌高发区男性筛查队列开展前瞻性研究，探讨甾体激素代谢标志物与上消化道癌及癌前病变风险的相关性，为高危人群的早期识别和筛查方案优化提供潜在标志物。

材料与方法

1. 选取《五大洲癌症发病率》（Cancer incidence in five continents, CI5）VIII-XII卷（1993-2017）中40个国家的发病率数据进行食管癌和胃癌发病负担及趋势分析。分别选取具有高质量分型数据的25个和24个国家进行食管癌和胃癌不同亚型的发病负担趋势分析，以Segi's世界标准人口为参照，计算食管癌、胃癌及其亚型年龄标准化发病率（Age-standardized incidence rate, ASIR）、以及ASIR的亚型比值和性别比值，并采用Joinpoint回归模型估计其年度变化百分比。CI5 XII卷（2013-2017）纳入的登记点数显著增加，单独筛选出该卷具有高质量分型数据的53个和48个国家进行食管癌和胃癌亚型发病率性别差异的现况分析，并使用同时报告食管癌和胃癌高质量数据的45个国家开展全球食管癌和胃癌发病率性别差异的现况分析。

2. 选取2007-2012年上消化道癌高发区男性筛查队列中基线经病理诊断为食管高级别上皮内瘤变（High-grade intraepithelial neoplasia, HGIN）或癌52例，低级别上皮内瘤变（Low-grade intraepithelial neoplasia, LGIN）100例，1:2匹配对照组200例；以及胃高级别上皮内瘤变或癌32例，肠上皮化生（Intestinal metaplasia, IM）146例，1:2匹配对照组292例。采用高效液相色谱—串联质谱法检测基线血清中20种甾体激素代谢标志物水平，电化学发光免疫分析检测性激素结合球蛋白水平。随访研究对象至2021年12月，收集食管癌和胃癌的发病和死亡情况。采用Logistic回归分析甾体激素代谢标志物与基线诊断为食管癌或胃癌及癌前病变的相关性；采用Cox比例风险回归评估基线甾体激素代谢标志物与食管癌或胃癌发病风险的关系。

研究结果

1. 1993-2017年，各国胃癌的ASIR普遍高于食管癌，但在津巴布韦、乌干达等非洲国家食管癌的负担更高（ASIR大于10/10万），胃癌则在韩国和日本等亚洲国家负担更重（ASIR大于30/10万）。趋势分析显示食管癌呈现差异性变化：ASIR在韩国、美国、中国等22个国家显著下降，但在白俄罗斯、日本、泰国等13个国家明显上升；胃癌在全球范围内呈下降趋势，其中32个国家的ASIR显著下降，仅津巴布韦明显上升。尽管食管癌和胃癌的发病率变化显著，但其ASIR的性别比值在大多数国家中保持相对稳定状态，男性食管癌和胃癌ASIR长期稳定高于女性。2013-2017年，食管癌ASIR的性别比值在白俄罗斯（13.71:1）和韩国（11.39:1）最显著，而胃癌ASIR的性别差异在日本最显著（2.76:1）。此外，食管癌和胃癌的性别比值随着年龄的增长大体呈现“低—高—低”的变化趋势。

2. 亚型分析结果显示，食管鳞癌（Esophageal squamous cell carcinoma, ESCC）的ASIR在19个国家中显著下降，其中有13个国家的食管腺癌（Esophageal adenocarcinoma, EAC）的ASIR明显上升。相反，丹麦、捷克共和国、拉脱维亚和日本ESCC和EAC的ASIR均呈上升趋势，EAC的ASIR仅在韩国呈下降趋势。此外，大多数国家ESCC与EAC的ASIR比值逐渐缩小，在包括美国在内的10个国家的男性以及菲律宾的女性中，EAC的ASIR已超过ESCC。性别分析显示男性ESCC和EAC的ASIR显著高于女性，且EAC的性别差异更为明显。胃癌亚型分析发现，胃非贲门癌（Gastric non-cardia cancer, GNCC）和胃贲门癌（Gastric cardia cancer, GCC）的ASIR在全球范围内呈下降趋势，仅丹麦、瑞士等8个国家的GCC的ASIR明显上升。GCC的ASIR在全球范围内始终低于GNCC，但二者差异在16个国家显著缩小，而中国人群GCC与GNCC的ASIR比值差异从0.15显著下降至0.06。性别分析显示男性GNCC和GCC的ASIR均显著高于女性，且GCC的性别差异比GNCC更显著。

3. 甾体激素标志物与癌变风险研究发现：1）4种激素代谢物与LGIN病变相关，5种激素代谢物与HGIN或食管癌相关，其中雌酮与食管癌及癌前病变（HGIN/LGIN）均显著相关。11.8年的中位随访期间，在对照组或LGIN患者中发现21例食管癌新发病例，基线血清雄烯二酮（HR_连续值 = 2.76, 95% CI: 1.01-7.55）水平与食管癌发病风险正相关，而16-表雌三醇（HR_连续值 = 0.66, 95% CI: 0.46-0.94）水平与食管癌发病风险负相关。2）胃癌变风险研究中，横断面分析显示4种激素代谢标志物与HGIN或胃癌相关，其中雄烯二酮可能与IM、HGIN及胃癌均相关，且在胃癌及HGIN病变中更显著（OR_连续值 = 2.45, 95% CI: 1.01-5.95）。11.8年的中位随访期间，在对照组或IM患者中发现32例胃癌新发病例，基线血清性激素结合球蛋白（HR_连续值 = 2.57, 95% CI: 1.04-6.36）、表睾酮（HR_连续值 =2.10, 95% CI: 1.07-4.15）和孕烯醇酮（HR_连续值 = 1.30, 95% CI: 1.03-1.63）水平与胃癌发病风险正相关。幽门螺杆菌感染状态分层分析显示亚组分析结果与总体人群基本一致。

结论

1993-2017年，全球不同国家食管癌和胃癌的发病率发生显著变化，亚洲国家仍以ESCC为主导，但欧美国家EAC负担逐渐超过ESCC，且全球范围内GCC和GNCC的发病负担差异逐渐缩小。然而，食管癌和胃癌发病负担的性别差异保持稳定，且男性长期显著高于女性。在男性中发现9种和7种与食管癌或胃癌及癌前病变风险可能相关的甾体激素代谢标志物，部分指标如雄烯二酮与两种癌变进展过程均相关，若经过后续验证，有望为上消化道癌高危人群识别和预警提供新指标。

Objectives

This study aims to analyze the temporal trends in the incidence of esophageal and gastric cancers and their subtypes in different countries worldwide, and quantify pattern of variations in subtype- and sex-specific differences. The findings will provide scientific evidence for countries to formulate targeted prevention and control strategies for esophageal and gastric cancers. In addition, we conducted a prospective study to investigate the associations between sex steroid hormone metabolites and the risk of upper gastrointestinal cancer and precancerous lesions, based on a male screening cohort from high-risk areas of upper gastrointestinal cancer in China. This research is expected to provide potential markers for the early detection of high-risk populations and optimization of screening protocols.

Materials and Methods

1. We analyzed the incidence burden and temporal trends of esophageal cancer (EC) and gastric cancer (GC) using incidence data from 40 countries in Cancer Incidence in Five Continents (CI5) Volumes VIII-XII (1993-2017). In addition, we selected 25 and 24 countries with high-quality subtype data for trend analysis of EC and GC subtypes, respectively. The age-standardized incidence rates (ASIR) of EC and GC, and their subtypes, as well as the ASIR ratios for subtypes and sexes were calculated using Segi's World Standard Population. Annual percentage changes were estimated using Joinpoint regression. A significant increase in the number of registry points was included in CI5 Volume XII (2013-2017). Therefore, 53 and 48 countries with high-quality subtype data were individually selected from this volume for cross-sectional analyses of sex differences in the incidence of EC and GC subtypes, respectively. Additionally, we conducted a cross-sectional analysis of global male-to-female incidence rate ratios for EC and GC using 45 countries that reported high-quality incidence data on both EC and GC.

2. We selected baseline pathologically confirmed esophageal high-grade intraepithelial neoplasia (HGIN) or EC cases (n=52), low-grade intraepithelial neoplasia (LGIN, n=100) cases, and 1:2 matched controls (n=200); gastric HGIN or GC cases (n=32), intestinal metaplasia (IM, n=146) cases, and 1:2 matched controls (n=292) from the male upper gastrointestinal cancer screening cohort from 2007 to 2012. We tested 20 sex steroid hormone metabolites in the baseline serum by liquid chromatography-tandem mass spectrometry and sex hormone-binding globulin (SHBG) by the electrochemical luminescence immunoassay. Participants were followed up until December 2021 for the incidence and mortality of EC and GC. Logistic regression analysis was used to calculate associations between sex steroid hormone metabolites and upper gastrointestinal cancer and precancerous lesions diagnosed at baseline. Cox proportional hazards regression was used to estimate associations between baseline sex steroid hormone metabolites and upper gastrointestinal cancer risk.

Results

1. From 1993 to 2017, the ASIRs of GC were generally higher than those of EC in most countries. However, EC had a higher burden in African countries such as Uganda and Zimbabwe, with ASIRs above 10 per 100,000, while GC showed a markedly higher burden in Asian countries, including Japan and the Republic of Korea, with ASIRs above 30 per 100,000. Trend analyses showed heterogeneous changes in EC: ASIRs significantly decreased in 22 countries including China, the Republic of Korea, and the United States, but significantly increased in 13 countries including Belarus, Japan, and Thailand. Remarkably, GC showed a globally declining trend, with ASIRs significantly decreasing in 32 countries, while only Zimbabwe showed a significant increase. Despite these substantial changes in the ASIRs of EC and GC, the male-to-female ASIR ratios have remained relatively stable in most countries, with persistently higher ASIRs for males than for females. From 2013 to 2017, the most pronounced sex differences in EC ASIRs were found in Belarus (13.71:1) and the Republic of Korea (11.39:1), while in GC, the largest male-to-female disparity was observed in Japan (2.76:1). Furthermore, the male-to-female incidence rate ratios of EC and GC showed “low-high-low” trends with increasing age.

2. For analyses of EC subtypes, esophageal squamous cell carcinoma (ESCC) ASIRs significantly declined in 19 countries, while esophageal adenocarcinoma (EAC) ASIRs increased in 13 of these countries. Conversely, both ESCC and EAC ASIRs increased in Denmark, Japan, Latvia, and the Czech Republic, and EAC ASIRs decreased only in the Republic of Korea. ESCC-to-EAC ASIR ratios gradually narrowed in most countries, with EAC surpassing ESCC among males in 10 countries including the United States, and among females in the Philippines. Sex-specific analysis revealed, males exhibited significantly higher ASIRs than females for both subtypes, with more pronounced sex differences observed for EAC. For analyses of GC subtypes, gastric non-cardia cancer (GNCC) and gastric cardia cancer (GCC) ASIRs generally showed declining trends worldwide, with significant increases in GCC ASIRs only observed in 8 countries, including Denmark and Switzerland. While GCC ASIRs remained consistently lower than GNCC ASIRs worldwide, the difference between the two subtypes significantly narrowed in 16 countries. In China, the GCC-to-GNCC ASIR ratio decreased from 0.15 to 0.06. Sex-specific analysis showed that males had consistently higher ASIRs than females for both subtypes, with more pronounced sex differences observed for GCC.

3. In the study of sex steroid hormone metabolites and cancer risk: 4 metabolites were found to be associated with LGIN, and 5 metabolites were associated with HGIN or EC. Notably, estrone was significantly associated with the risk of both EC and its precancerous lesions (HGIN/LGIN). During a median follow-up of 11.8 years, 21 new cases of EC were identified among the participants diagnosed with control or LGIN. Analysis showed positive associations between serum androstenedione levels and EC risk (HR _continuous = 2.76, 95% CI: 1.01-7.55), but negative associations between 16-epiestriol levels and EC risk (HR _continuous = 0.66, 95% CI: 0.46-0.94). In the study of the risk of gastric carcinogenesis, 4 metabolites were found to be associated with HGIN or GC. Androstenedione levels were potentially associated with IM, HGIN and GC, and significantly associated with the risk of HGIN or GC (OR _continuous = 2.45, 95% CI: 1.01-5.95). 32 new cases of GC were identified among the participants diagnosed with control or IM. Results suggested significant positive associations between GC risk and serum SHBG (HR _continuous = 2.57, 95% CI: 1.04-6.36), epitestosterone (HR _continuous = 2.10, 95% CI: 1.07-4.15) and pregnenolone (HR _continuous = 1.30, 95% CI: 1.03-1.63) levels. Additionally, the subgroup analyses stratified by Helicobacter pylori status revealed similar associations in the overall population and in the subgroup analyses.

Conclusion

From 1993 to 2017, EC and GC ASIRs have changed significantly across countries worldwide. ESCC remains predominant in Asian countries, whereas the burden of EAC has gradually surpassed ESCC in many Western countries, and the difference in the burden of GCC and GNCC has narrowed. However, sex differences in the burden of EC and GC have remained relatively stable, with a persistent male predominance. In addition, we found that 9 and 7 sex steroid hormone metabolites were potentially associated with the risk of EC or GC and precancerous lesions in males, respectively; and several metabolites, such as androstenedione, were associated with the progression of both EC and GC. With further validation, it would provide new biomarkers for the early detection and risk prediction of high-risk populations of upper gastrointestinal cancer.