Clinicopathological, metastatic and prognostic features of stage IV esophageal adenocarcinoma versus squamous cell carcinoma: a SEER database analysis

Introduction

Esophageal cancer (EC) is the sixth leading cause of cancer death and 50% of cases present with distant metastases at the time of diagnosis (1). In 2020, the global incidence of the disease was 604,000 new cases, with 544,000 deaths (2). EC has a poor prognosis, because it has often progressed into an advanced stage at diagnosis. Advanced EC is prone to distant metastasis, even multiple metastases. About 90% of EC patients in China can be classified into esophageal squamous cell carcinoma (ESCC), which is also a common subtype worldwide (3). A recent retrospective study reporting 23,804 esophageal adenocarcinoma (EAC) cases and 13,919 ESCC cases suggests an increasing incidence of EAC and a decreasing incidence of ESCC in the United States (4).

EC is prone to metastasizing to the liver, lung, bone, and brain (5). Among them, brain metastases carry the worst prognosis. The main treatment strategy for advanced EC is systemic palliative care, assisted by endoscopic therapy and nutritional support (6). Palliative care, including palliative resection or primary tumor chemoradiotherapy, is mainly performed to relieve EC-related symptoms (obstruction or bleeding) and improve the quality of life (7). In previous studies, surgeons have presented conflicting opinions on whether surgery is beneficial for the treatment of primary EC. Some studies found that surgery and non-resection groups had the same prognosis (8,9), while others reported promising outcomes following palliative resection, radiotherapy, and chemotherapy (10,11). Nonetheless, several studies have shown that patients with metastatic EC can benefit from multimodal treatment, which typically includes palliative resection, radiotherapy, and chemotherapy (12). The treatment strategy aims to alleviate symptoms, control disease progression, and improve overall survival (OS) rates. It is important to consider the patient’s characteristics, the stage of his disease, and the response to treatment when evaluating the best approach to managing advanced EC (13).

Based on the data extracted from the Surveillance, Epidemiology, and End Results (SEER) database [2010–2016] and another data treated in our hospital [2014–2016] serving as the external cohort. This study aimed to analyze the clinical and epidemiological characteristics of stage IV ESCC and EAC. Moreover, we compared the survivals of patients with different metastatic patterns, and screened out treatment strategy improving stage IV EAC and ESCC prognosis. We present this article in accordance with the STROBE reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-23-88/rc).

Methods

Data

The data were extracted from the SEER program between 2010 and 2016. The program contains the population-based central cancer registries of 18 geographically defined regions. Furthermore, the clinical data of 217 patients with stage IV ESCC and EAC in the Department of Gastroenterology of the Second Affiliated Hospital of Nantong University between 2014 and 2016 were reviewed. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Ethics Committee of the Second Affiliated Hospital of Nantong University approved the protocol study (No. 2023KT259) and individual consent for this retrospective analysis was waived.

Patients

The inclusion criteria included: (I) there was only one primary tumor; (II) the histological was positive for EAC or ESCC; and (III) American Joint Committee on Cancer (AJCC) 7^th edition stage was IV. The exclusion criteria included: (I) the demographic information (including race) was incomplete; (II) the clinic-pathological information was incomplete, including differentiation, AJCC stage [tumor-node-metastasis (TNM)], histological stage, causes of death and therapy; and (III) the information was just from autopsy or death certificate (Figure 1).

Figure 1 Flowchart of selection of patients with metastatic EC used the SEER database. SEER, Surveillance, Epidemiology, and End Results; EC, esophageal cancer; ICD-O-3, International Classification of Disease for Oncology third edition; AJCC, American Joint Committee on Cancer; UNK, unknown; TNM, tumor-node-metastasis; EAC, esophageal adenocarcinoma; ESCC, esophageal squamous cell carcinoma.

Patients’ primary sites were defined by using the International Classification of Disease for Oncology third edition (ICD-O-3) histopathology codes. According to the age at diagnosis, we divided them into <50, 50–65, and >65 years groups.

Clinical variables

Information on demographic factors (age, race, gender), tumor-related factors (differentiation, histology, and AJCC TNM staging system), treatment methods (surgery, chemotherapy, radiotherapy, none), and follow-up were collected from the database. And follow-up period ended in 2021. According to the SEER program’s surgery codes and information about other treatments, we divided treatment options into categories: no treatment, chemotherapy alone, radiotherapy alone, chemotherapy + radiotherapy, surgery (including only surgery, surgery + radiation, surgery + chemotherapy, and surgery + radiation + chemotherapy). In this study, OS time was the primary endpoint. It was calculated from the date of the first definite diagnosis to the date of death caused by any cause or the most recent follow-up.

Statistical analysis

In this cohort study, patient’s OS was depicted by the Kaplan-Meier curves. Survival was defined as the time from diagnosis to death from any cause. The survival curves were analyzed by the log-rank test. Univariate and multivariate Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs), which indicated the independent prognostic factors associated with OS. Every two groups of variables were compared by χ²/Z test. In all analyses, P<0.05 was considered significant, and all statistical tests were two-sided. All data were analyzed by IBM SPSS Statistics 26 software (IBM Corporation, Armonk, NY, USA).

Results

Basic information of patients

Of the 3,707 enrolled cases, all patients were diagnosed between 2010 and 2016, including 920 cases (24.8%) with ESCC and 2,787 cases (75.2%) with EAC. Stages IV ESCC and EAC were prevalent in the over 65 years age group, and more common in Caucasian men. The most prevalent primary site of ESCC was the middle of 1/3 of the esophagus and that of EAC was the lower 1/3 of the esophagus. Most cancers were in moderately or poorly differentiated. The clinical and demographic characteristics are shown in Table 1. Of the 3,707 cases of distant metastasis, 316 cases (34.3%) of ESCC and 790 cases (28.3%) of EAC received combined chemotherapy and radiotherapy, 16 cases (1.7%) of ESCC and 86 cases (3.1%) of EAC received surgery including only surgery, surgery + radiation, surgery + chemotherapy, surgery + radiation + chemotherapy, and 990 cases (35.5%) of EAC received chemotherapy only.

A total of 217 cases from external cohort were enrolled in this research, including 125 cases (57.6%) with stage IV ESCC and 92 cases (42.4%) with stage IV EAC. The clinical and demographic characteristics are shown in Table 2. Of the 217 cases, 57 cases (45.6%) ESCC and 38 cases (41.3%) treated with chemoradiotherapy, 20 cases (16.0%) ESCC and 17 cases (18.5%) EAC treated with surgery followed by chemoradiotherapy, and all EAC patients did not receive surgery only or surgery combined with radiation. Furthermore, 32 cases ESCC and 12 cases EAC did not receive any treatment.

Metastasis patterns

A total of 2,717 patients presented distant metastases observed in the bone, brain, liver, and lung in the SEER database. There are 15 groups of metastatic EC, divided into single-organ metastases (bone, brain, liver, and lung), two-organ metastases (bone and brain, bone and liver, bone and lung, brain and liver, brain and lung, and liver and lung), three-organ metastases (bone, brain, and liver; bone, brain, and lung; bone, liver, and lung; and brain, liver, and lung), and four-organ metastases (bone, brain, liver, and lung). Of the 655 ESCC cases, the most common metastatic patterns included lung only (n=225, 34.4%), liver only (n=153, 23.4%), and bone only (n=89, 13.6%). Of the 2,062 EAC cases, the most common metastatic patterns included liver (n=844, 40.9%), liver and lung (n=286, 13.9%), and bone (n=270, 13.1%). The possibility of brain metastasis was lower than those of liver, lung, and bone metastases. The difference between the specific metastatic modes of ESCC and EAC is shown in Table 3.

In the external cohort, because of the limited sample size, metastasis patterns were divided into nine groups, single-organ metastases (bone, liver, and lung), two-organ metastases (bone and liver, bone and lung, and liver and lung), three-organ metastases (bone, brain, and liver; bone, liver, and lung), and four-organ metastases (bone, brain, liver, and lung). The most common metastatic patterns in ESCC included lung (n=40, 32.0%), liver and lung (n=30, 24.0%), and liver (n=29, 23.2%). While in EAC group, the most common metastatic patterns included liver (n=39, 42.4%), liver and lung (n=21, 22.8%), lung (n=10, 10.9%), and liver and bone (n=10, 10.9%). The difference between the specific metastatic modes of ESCC and EAC is shown in Table 4.

Survival

A survival analysis was conducted on patients with the above four metastatic patterns, who made up more than 80% of the sample. The median survival was 4 months for metastatic ESCC, and 5 months for metastatic EAC, which may not be clinically significant. The univariate Cox regression analysis revealed treatment mode and metastasis patterns associated with all-cause mortality in patients with stage IV ESCC & EAC patients (P<0.05). The multivariate Cox analysis showed that treatment mode and metastasis patterns were independent risk factors affecting the OS (Tables 5,6). The OS of stage IV EAC patients with lung metastasis was longer than that of the other three metastatic patterns, with an average of 7 months (Figure 2). Additionally, the survival time was relatively longer in EAC patients receiving surgery, with an average of 14 months (Figure 3).

Figure 2 OS rate of ESCC and EAC patients with the common metastasis patterns. (A) ESCC; (B) EAC. OS, overall survival; ESCC, esophageal squamous cell carcinoma; EAC, esophageal adenocarcinoma.

Figure 3 OS rate of different treatment regimens for ESCC and EAC from SEER database. (A) ESCC; (B) EAC. Surgery including only surgery, surgery + radiation, surgery + chemotherapy, and surgery + radiation + chemotherapy. OS, overall survival; ESCC, esophageal squamous cell carcinoma; EAC, esophageal adenocarcinoma; SEER, Surveillance, Epidemiology, and End Results.

In the external cohort, approximately 80% of the sample had the above-mentioned metastasis patterns. It was found that survival rates between ESCC and EAC were not different. The median survival was 4 months for ESCC, and 6 months for EAC. The univariate Cox analysis showed that only treatment mode was related to the prognosis (P<0.05). The multivariate Cox analysis showed that treatment mode was independent risk factor affecting the OS (Tables 7,8). In addition, the median survival time was 11 months, relatively longer in EAC patients receiving surgery combined with chemoradiotherapy than other treatment modes (Figure 4).

Figure 4 OS rate of different treatment regimens for ESCC and EAC from the external cohort. (A) ESCC, (B) EAC. Surgery including only surgery, surgery + radiation, surgery + chemotherapy, and surgery + radiation + chemotherapy. OS, overall survival; ESCC, esophageal squamous cell carcinoma; EAC, esophageal adenocarcinoma.

Discussion

In this study, we found that stage IV EAC and ESCC were more prevalent in males, elderly, or Caucasians. ESCC was more common in the middle 1/3 esophageal segment, and EAC in the lower 1/3 segment. The number of EAC cases was larger than that of ESCC, and poorly differentiated was the most common. The minority patients received surgery (accounting for less than 5%). The SEER database is mainly based on North America, therefore, the epidemiological characteristics of EC inferred from the present study may not be representative globally. According to Lepage C’s epidemiological survey, ESCC is the most common subtype of EC outside the United States, accounting for 90% of cases worldwide, and EAC in North America and Europe (14). According to the results of this study, the prevalence of EAC in the United States is indeed much higher than that of ESCC, which is in line with the characteristics of epidemiological investigation. In addition, due to the absence of a serous layer and abundant lymphatic capillary system in the esophagus, EC metastasis is prone to occurring earlier. Patients with early-stage EC have often no obvious symptoms, and EC has usually progressed into the advanced stage at diagnosis.

Therefore, we conducted a subgroup analysis of stage IV EC patients. In this study, the incidence of EAC metastasis was compared with that of ESCC metastasis (the proportion of stage IV), finding that metastasis was more likely in males, which may be explained by that male hormones can promote the proliferation and metastasis of EC cells, and the likelihood of men drinking alcohol and smoking cigarettes is higher than that of women (15-17). In metastatic ESCC, the proportions of patients with moderately or poorly differentiated were similar, while in metastatic EAC, the proportion of low differentiation was higher (60%), and the degree of differentiation was related to distant metastasis and prognosis. EAC is more likely to be located in the lower esophagus and ESCC in the middle esophagus. EAC generally evolves from Barrett’s esophagus, which is susceptible to reflux esophagitis. The reason why ESCC tends to occur in the middle segment is currently unclear, and it is speculated to be related to physiological stenosis in this part. Due to the loss of surgical opportunities, advanced EC tends to be treated with chemotherapy and radiation therapy. Therefore, in this study, the majority of patients with stage IV ESCC and EAC chose chemotherapy combined with radiation therapy (18,19).

Then, we compared the metastatic patterns of stage IV EAC and ESCC. Overall, the most common metastatic sites were the lung, liver, and bone in EC patients, which is consistent with previous studies (5,20-23). Metastases to the liver are frequently observed in ESCC and EAC, the venous drainage of the distal esophagus drain directly into the portal vein, where the venous drainage of the distal esophagus drain directly into the portal vein. It may explain the high prevalence of liver metastases among EC patients. It is thought that the high frequency of lung metastases may be due to the fact that other parts of the venous drainage system of the distal esophagus, as well as the mid and proximal part of the esophagus, drain directly to the superior vena cava. There are no clear mechanisms behind the differences in metastatic patterns between EC subtypes. however, tumor location can pose a confounding factor as EAC originate from the distal esophagus and ESCC generally from the proximal esophagus (21). Furthermore, esophageal carcinoma had the high rate of bone metastasis. Due to its anatomical proximity to the spine and shared blood supply with it, the middle esophagus may have been affected by this finding. The vertebral vein system is interconnected and its blood flow is slow, so when the pressure increases in the thoracic or abdominal cavity, the tumor embolus can travel directly to the vertebral veins and cause metastasis (5,24).

Analysis of treatments corresponding to the top four metastatic modes found that ESCC patients with lung or bone metastasis preferred radiotherapy combined with chemotherapy, while those with liver or liver & lung metastasis preferred chemotherapy alone. Among the treatment plans corresponding to the first four metastatic modes of EAC, patients with only bone metastasis tended to choose radiotherapy combined with chemotherapy, while others chemotherapy alone. Our survival analysis of the SEER database showed that EAC patients who received surgery had a longer survival time. Most stage IV EC patients often are not even considered for surgery due to perceived high risk, this finding is consistent with our data from the SEER database where only 2.8% of patients received surgery. In response to the question of whether surgery should be considered in patients with stage IV EC, the results of our external validation cohort suggest that when surgery was incorporated into patients’ treatment plans, their survival was improved. Analysis of this cohort showed that surgery followed by chemoradiation therapy, had the most improved survival compared to other modalities. This finding may be because of our limited clinical sample size. But, Del Calvo et al. found that chemoradiation therapy followed by surgery should be considered for octogenarians who are surgically fit (25). However, the treatment paradigm with surgery was rarely used in stage IV EC patients, and most received definitive chemoradiation therapy only. Undoubtedly, there existed an increasing amount of proof indicating that individuals with metastatic tumors can experience advantages from undergoing surgery on the original tumor (13). Surgical intervention can benefit metastatic cancer patients by boosting their immune system, which is compromised by primary tumors that cause immunosuppression. Despite the presence of metastatic tumors, the immune system was restored following surgical resection of the primary tumor. Moreover, surgery can reduce the patient’s tumor burden, allowing systemic therapy to have a more significant effect. Additionally, surgery can benefit patients with advanced EC by treating primary tumors locally. A surgical procedure may alleviate symptoms related to esophageal obstruction, nutrition, and metastasis of the regional lymph nodes, as well as relieve symptoms resulting from compression of the lymph nodes (13).

This study has certain limitations. First, this is a retrospective study based on the SEER database. We only obtained data on liver, lung, bone, and brain metastases, without data on other metastasis sites from the SEER database. Second, although we selected an external cohort for validation, the sample size was limited because of loss to follow-up. Third, only synchronous transfer cases were recorded, lacking data on asynchronous transfer. Fourth, since the vast majority of the samples in this study come from European and American countries, more domestic data are needed for further research.

Conclusions

The present finding is the first large-scale report on clinicopathological, metastatic, and prognostic features of stage IV ESCC versus EAC. Metastatic patterns may differ between patients with EAC and ESCC, but the prognosis may be similar. The distant organ metastasis in EC may contribute to poor outcomes. Stage IV EAC patients treated with surgery combined with chemoradiotherapy may have a better prognosis. Thus, stage IV EAC patients should be considered for surgery probably.

Acknowledgments

We acknowledge the National Cancer Institute, specifically the SEER team, for granting us access to SEER data.

Funding: This work was supported by the Nantong City Health Commission Research Youth Project (No. QA2021011) and the Research Project of Kangda College, Nanjing Medical University (No. KD2022KYJJZD026).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-23-88/rc

Data Sharing Statement: Available at https://cco.amegroups.com/article/view/10.21037/cco-23-88/dss

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-23-88/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-23-88/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). Ethics Committee of the Second Affiliated Hospital of Nantong University approved the protocol study (No. 2023KT259) and individual consent for this retrospective analysis was waived.

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/.

References

1. Mazidimoradi A, Banakar N, Khani Y, et al. Current status and temporal trend in incidence, death, and burden of esophageal cancer from 1990-2019. Thorac Cancer 2023;14:2408-58. [Crossref] [PubMed]
2. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
3. Liu CQ, Ma YL, Qin Q, et al. Epidemiology of esophageal cancer in 2020 and projections to 2030 and 2040. Thorac Cancer 2023;14:3-11. [Crossref] [PubMed]
4. Then EO, Lopez M, Saleem S, et al. Esophageal Cancer: An Updated Surveillance Epidemiology and End Results Database Analysis. World J Oncol 2020;11:55-64. [Crossref] [PubMed]
5. Yuan B, Lu H, Hu D, et al. Predictive models for the risk and prognosis of bone metastasis in patients with newly-diagnosed esophageal cancer: A retrospective cohort study. Front Surg 2023;9:1014781. [Crossref] [PubMed]
6. Wang Y, Yang W, Wang Q, et al. Mechanisms of esophageal cancer metastasis and treatment progress. Front Immunol 2023;14:1206504. [Crossref] [PubMed]
7. Cui C, Wu X, Deng L, et al. Modified Glasgow prognostic score predicts the prognosis of patients with advanced esophageal squamous cell carcinoma: A propensity score-matched analysis. Thorac Cancer 2022;13:2041-9. [Crossref] [PubMed]
8. Tanaka T, Fujita H, Matono S, et al. Outcomes of multimodality therapy for stage IVB esophageal cancer with distant organ metastasis (M1-Org). Dis Esophagus 2010;23:646-51. [Crossref] [PubMed]
9. Saddoughi SA, Reinersman JM, Zhukov YO, et al. Survival After Surgical Resection of Stage IV Esophageal Cancer. Ann Thorac Surg 2017;103:261-6. [Crossref] [PubMed]
10. van der Wilk BJ, Eyck BM, Noordman BJ, et al. Characteristics Predicting Short-Term and Long-Term Health-Related Quality of Life in Patients with Esophageal Cancer After Neoadjuvant Chemoradiotherapy and Esophagectomy. Ann Surg Oncol 2023;30:8192-202. [Crossref] [PubMed]
11. Bardol T, Ferre L, Aouinti S, et al. Survival after Multimodal Treatment Including Surgery for Metastatic Esophageal Cancer: A Systematic Review. Cancers (Basel) 2022;14:3956. [Crossref] [PubMed]
12. Liao F, Yu S, Zhou Y, et al. A machine learning model predicting candidates for surgical treatment modality in patients with distant metastatic esophageal adenocarcinoma: A propensity score-matched analysis. Front Oncol 2022;12:862536. [Crossref] [PubMed]
13. Wei L, Xu J, Hu X, et al. A predictive scoring model to select suitable patients for surgery on primary tumor in metastatic esophageal cancer. Cancer Rep (Hoboken) 2023;6:e1898. [Crossref] [PubMed]
14. Böhme F, Racz K, Sebesta C Jr, et al. Esophageal Cancer. Wien Med Wochenschr 2023;173:209-15. [PubMed]
15. McMenamin ÚC, Liu P, Kunzmann AT, et al. Circulating Sex Hormones Are Associated With Gastric and Colorectal Cancers but Not Esophageal Adenocarcinoma in the UK Biobank. Am J Gastroenterol 2021;116:522-9. [Crossref] [PubMed]
16. Dawsey SM, Duits LC. A substantial advance for screening of oesophageal cancer. Lancet Gastroenterol Hepatol 2023;8:393-5. [Crossref] [PubMed]
17. Zhang S, Guo J, Zhang H, et al. Metastasis pattern and prognosis in men with esophageal cancer patients: A SEER-based study. Medicine (Baltimore) 2021;100:e26496. [Crossref] [PubMed]
18. Guo J, Zhang S, Li H, et al. Lung Metastases in Newly Diagnosed Esophageal Cancer: A Population-Based Study. Front Oncol 2021;11:603953. [Crossref] [PubMed]
19. Liu J, Zeng X, Zhou X, et al. Longer interval between neoadjuvant chemoradiotherapy and surgery is associated with improved pathological response, but does not accurately estimate survival in patients with resectable esophageal cancer. Oncol Lett 2023;25:155. [Crossref] [PubMed]
20. Qiu G, Zhang H, Wang F, et al. Metastasis Patterns and Prognosis of Elderly Patients With Esophageal Adenocarcinoma in Stage IVB: A Population-Based Study. Front Oncol 2021;11:625720. [Crossref] [PubMed]
21. Verstegen MH, Harker M, van de Water C, et al. Metastatic pattern in esophageal and gastric cancer: Influenced by site and histology. World J Gastroenterol 2020;26:6037-46. [Crossref] [PubMed]
22. Takeuchi M, Kawakubo H, Matsuda S, et al. The Usability of Intensive Imaging Surveillance After Esophagectomy in Patients with Esophageal Cancer. Ann Surg Oncol 2023;30:2190-7. [Crossref] [PubMed]
23. Luo P, Wei X, Liu C, et al. The risk and prognostic factors for liver metastases in esophageal cancer patients: A large-cohort based study. Thorac Cancer 2022;13:2960-9. [Crossref] [PubMed]
24. Zhou X, Liu S, Huo Z, et al. Clinical characteristics and surgical treatment of esophageal cancer spinal metastasis - A single center 10-year retrospective study. Clin Neurol Neurosurg 2020;197:106071. [Crossref] [PubMed]
25. Del Calvo H, Nguyen DT, Chan EY, et al. Surgery provides improved overall survival in surgically fit octogenarians with esophageal cancer after chemoradiation therapy. J Thorac Dis 2021;13:5875-86. [Crossref] [PubMed]