Incidence and prognosis of brain metastases in esophageal carcinoma: a systematic review and meta-analysis

Introduction

Distant metastasis is a common cause of cancer-related death in esophageal carcinoma, frequently involving sites such as the lung, bone, and liver. Brain metastases (BMs), however, represent a distinct clinical entity compared to metastases in other organs, primarily due to the protective blood-brain barrier. As a devastating complication observed in 25–35% of advanced malignancies, BMs are the most common type of intracranial tumors in adults (1). In the United States, it is estimated that 8% to 10% of cancer patients will develop BMs, with approximately 200,000 new cases of BMs each year (2). BMs mainly originate from primary lung cancer, breast cancer, and melanoma (3,4). In contrast, cerebral metastases originating from esophageal carcinoma (BMECs) are relatively rare. A review published in 2014 summarized some clinical studies and it was found that the incidence of BMECs was only 1.4–3.9% (5). However, the incidence of BMECs has increased in recent years, with some studies reporting rates exceeding 10% (6-8). This increase is likely attributable to prolonged survival in patients with esophageal carcinoma and advancements in neuroimaging detection. Nevertheless, precise incidence estimates and a comprehensive understanding of BMEC epidemiology remain limited, potentially hindering clinical awareness and timely intervention.

The clinical presentation of patients with BMECs is similar to those of patients with BMs originated from other carcinomas. Most BMEC patients present with neurological symptoms, among which the most common symptoms are headache, motor disturbance and dizziness, while symptoms such as seizures, visual disturbance, nausea, emesis, speech difficulty, emotional change, memory deterioration and hypersomnia are relatively rare. A minority of BMEC patients are asymptomatic and incidentally diagnosed BMECs (6,9,10). For patients suspected of having BMEC based on neurological symptoms, a non-contrast computed tomography scan is the preferred method for initial screening because of its short acquisition time, easy accessibility, and ability to identify acute neurological injuries that require immediate attention, such as hemorrhages or hydrocephalus. Magnetic resonance imaging is the gold standard for detecting and monitoring disease progression of BMs. Imaging hallmarks of BMs include contrast enhancement of a lesion on contrast-enhanced T1-weighted imaging sequence and increased capillary permeability on T2-weighted imaging or fluid-attenuated inversion recovery sequences (11).

Compounding this epidemiological uncertainty, the outcomes of patients diagnosed with BMECs were poor and the quality of life was significantly impaired (12,13). Although various intervention measures are available—including surgical resection, stereotactic radiosurgery, chemotherapy, radiotherapy, and their combinations (9,14,15)—the literature on optimal treatment modalities for BMECs remains limited, and a standard of care has yet to be established (16). Crucially, early detection is paramount as it expands therapeutic options. However, current guidelines lack consensus on neuroimaging surveillance for esophageal carcinoma, resulting in predominantly symptomatic diagnosis of BMECs, which results in poor prognosis (17,18).

Given these existing knowledge gaps in BMEC epidemiology and survival determinants, there is a clinical need for rigorous evidence synthesis to better understand this condition. To address this unmet need, we conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review and meta-analysis to quantify disease burden and prognostic associations in BMEC populations. We present this article in accordance with the PRISMA reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1219/rc) (19).

Methods

Search strategy

A comprehensive literature search and systematic review of online databases PubMed/MEDLINE, Embase, and Cochrane Library was performed to identify relevant studies published before 8 January 2025 that included incidence and prognosis data of BMECs. The search key words were: “brain metastasis” (and its synonyms searched in Emtree) AND “esophageal carcinoma” (and its synonyms searched in Emtree). The complete search keywords can be found in Appendix 1. The Medical Subject Headings words “esophageal neoplasms” and “brain neoplasms” were also used in the screening of PubMed. A total of 751 articles were yielded through this search strategy.

Inclusion and exclusion criteria

Eligible articles should meet the following criteria: (I) BMs were predominantly analyzed in relation to primary esophageal carcinoma. (II) Detailed patient information was provided, including (i) BM incidence, or (ii) median overall survival (OS) from diagnosis of BMs with its 95% confidence interval (CI), or (iii) hazard ratio (HR) with 95% CI of OS in different groups, or data were sufficient to calculate the HR with 95% CI. (III) The complete manuscript was accessible in the English language.

Articles were excluded if (I) patients were derived from the surveillance, epidemiology, and end results (SEER) database or (II) articles were review articles, case reports, editorials, expert opinions, non-comparative studies, meeting/conference abstract, trial registry records, unrelated to research topics, or duplicate reports.

Data extraction and quality assessment

Two researchers (H.H. and J.D.) independently performed all of the screening of studies and data extraction. The third researcher (Zhichao Liu) resolved the disagreements. For eligible research, we extract all available information: the first name of the author, year of publication, region, research type, number of patients, gender, age, primary tumor site, follow-up time, primary tumor histology, treatment of primary tumor, number of patients with BMs, risk factors, risk factors for incidence in multivariate analysis, extracerebral metastases before diagnosis of BMs, number of BMs, median time from the diagnosis of primary tumor to BM, treatment of BMs, median OS from diagnosis of BMs with 95% CI, 1-year OS rate, prognostic factors for OS in multivariate analysis. The quality of the included studies was assessed using the Agency for Healthcare Research and Quality Tool. Any disagreements were resolved through discussion and consensus.

Statistical analysis

Except for overall pooled incidence, pooled incidence was also calculated by different regions, gender, primary tumor histology, and clinical stage, and using neoadjuvant therapy and surgery or not respectively. The overall and different regions’ pooled median OS was calculated. The pooled HR between different number of BMs, performance status (PS), treatment of BMs, and extracranial metastasis or not was respectively calculated. Cochran’s Q test and I² were used to estimate the heterogeneity effect among the studies. I² statistics more than 50% was suggestive of statistical heterogeneity between studies, and random effects model was used if heterogeneity existed, while common effects model was used. All tests were two-sided and a P value less than 0.05 was considered statistically significant. Publication bias was assessed by visually examining a funnel plot for the main outcome and Egger’s test and Begg’s test. Sensitivity analyses were conducted by performing a set of leave-1-out diagnostic tests, where individual studies were systematically removed from the meta-analysis and the pooled-effect estimate recalculated. All data were managed using Microsoft Excel version 16 (Microsoft, Redmond, WA, USA) and the analysis was carried out using R version 4.3.3 (R Foundation for Statistical Computing, Vienna, Austria).

Results

The selection and characteristics of studies

Of 751 records identified through the initial literature search, 137 records were removed for duplication and 538 records were excluded with title and abstract screening. After retrieval and full-text assessment for eligibility, a total of 31 articles were included in the final analysis (Figure 1), of which 26 (Table 1), 11 (10,13,23,27-29,34,35,40-42), 11 (7,13,25,28,29,31,34,35,40,43,44) articles were used for meta-analysis of incidence, median OS, and prognostic risk factors.

Figure 1 Flow chart detailing the search strategy and identification of studies. SEER, surveillance, epidemiology, and end results.

Table 1 outlines the 26 eligible studies for the incidence meta-analysis, including one randomized controlled trial and 25 retrospective cohort studies. The pooled cohort included 40,233 histologically confirmed esophageal carcinoma patients from eight geographically diverse regions (the America, Japan, China, India, the Netherlands, Greece, Germany, and Belgium), with 623 cases radiologically confirmed BMs. Among these studies, 10 (38.5%) reported median age distributions (range, 60–68 years); 16 (61.5%) provided gender-specific prevalence data (male-to-female ratio: 8,455:2,119); 17 (65.4%) documented histological subtypes [5,023 adenocarcinomas (39.3%) and 7,772 squamous cell carcinomas (SCCs) (60.7%)]; and 13 (50.0%) provided information on treatment of primary tumor. Only 2 studies (7.7%) provided the risk factors for incidence of BMECs through multivariate analysis, including diabetes and radiotherapy.

Table 2 summarized the characteristics of 16 studies used for the meta-analysis of median OS and different risk factors for OS. All 16 studies were retrospective cohort studies involving 489 BMEC patients from different regions (America, Japan, China, Germany and Belgium). All available data from the 16 studies, including median follow-up time, median age, gender, histology type, treatment of primary tumor, extracerebral metastases before diagnosis of BMs, number of BMs, median time from the diagnosis of primary tumor to BMs, treatment of BMs, median OS from diagnosis of BMs with 95% CI, 1-year OS rate, and prognostic factors for OS in multivariate analysis, were included in our analysis. All 16 studies provided median OS, 12 of which provided its 95% CI, and 10 (62.5%) of studies provided 1-year OS rate, varying from 5.8% to 42.0%. Only 4 (25.0%) studies provided prognostic factors for OS in multivariate analysis, consisting of liver metastasis, treatment modality of BMs, Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA) class, Karnofsky performance status (KPS), surgery for brain lesion, chemotherapy, whole brain radiotherapy (WBRT), and local treatment of BMs.

Incidence of BMECs

The pooled incidence of BMECs was 2.84% (95% CI: 1.92–4.19%, Figure 2). The incidence of BMECs in Asian region, including Japan, China and India, was 1.53% (95% CI: 0.83–2.84%), which was significantly lower compared with the incidence in American and European region [4.54% (95% CI: 3.24–6.37%), P=0.003, Figure 2]. The incidence of BMECs originated from adenocarcinoma and SCC also showed significant difference [5.34% (95% CI: 3.52–8.12%) vs. 1.45% (95% CI: 0.84–2.53%), P<0.001, Figure 3], indicating that esophageal adenocarcinoma was over three times more likely to metastasize to the brain than esophageal SCC. However, there was no significant difference between the incidence of BMECs of male and female patients [3.69% (95% CI: 1.90–6.03%) vs. 1.77% (95% CI: 0.68–3.36%), P=0.12, Figure S1], of extensive clinical stage and limited clinical stage [4.76% (95% CI: 2.49–9.07%) vs. 2.54% (95% CI: 0.74–8.70%), P=0.23, Figure S2], of primary tumor’s treatment with neoadjuvant therapy and without [4.57% (95% CI: 1.89–11.04%) vs. 6.23% (95% CI: 3.99–9.21%), P=0.53, Figure S3], or of primary tumor’s treatment with surgery and without [2.74% (95% CI: 1.37–5.49%) vs. 1.91% (95% CI: 0.45–8.07%), P=0.66, Figure S4]. Therefore, the incidence of BMECs originated from adenocarcinoma and SCC still showed significant difference in patients whose primary tumor’s treatment with surgery [3.29% (95% CI: 2.49–4.35%) vs. 1.02% (95% CI: 0.35–2.92%), P=0.04, Figure 4].

Figure 2 Overall, in Asian region and in American and European region subgroup pooled incidence of brain metastasis from esophageal carcinoma via random effects analysis. Subgroups are divided by different area. CI, confidence interval.

Figure 3 The pooled incidence of brain metastasis from esophageal carcinoma originated from adenocarcinoma and SCC via random effects analysis. Subgroups are divided by different histological types. CI, confidence interval; SCC, squamous cell carcinoma.

Figure 4 The pooled incidence of brain metastasis from esophageal carcinoma originated from adenocarcinoma and SCC subgroups in patients whose primary tumor’s treatment with surgery via random effects analysis. Subgroups are divided by different histological types. CI, confidence interval; SCC, squamous cell carcinoma.

Visual inspection of the funnel plot (Figure S5) suggested no evidence of publication bias in the meta-analysis of the pooled incidence of BMECs. Distribution of effect sizes was fairly symmetrical. Most effect sizes fell in the funnel; effect sizes falling outside the funnel did so symmetrically. Egger’s test and Begg’s test were statistically not significant (P=0.93 and P=0.93, respectively), indicating that publication bias may not influence the observed results. The Leave-1-out meta-analysis of the pooled incidence of BMECs (Figure S6) showed no significant difference in the pooled incidence, regardless of which study was omitted. The pooled prevalence of BMECs ranged from 2.63% to 3.12%, and the I² ranged from 94.7% to 96.5%, suggesting that the results of the original meta-analysis were stable and not significantly affected by the number of studies included.

Prognosis of BMECs

The pooled median OS from the diagnosis of BMECs was 5.62 months (95% CI: 3.98–7.94, Figure 5), demonstrating a poor survival. There was no significant difference between the median OS of Asian region and American and European regions [4.67 (95% CI: 2.82–7.74) vs. 6.66 (95% CI: 4.17–10.65), P=0.31, Figure 5]. Through visual inspection of the funnel plot (Figure S7) in the meta-analysis of the pooled OS, the distribution of effect sizes was not fairly symmetrical. Most effect sizes fell outside the funnel asymmetrically. However, Egger’s test and Begg’s test were not statistically significant (P=0.12 and P=0.12, respectively), indicating that publication bias was unlikely to influence the observed results. The Leave-1-out meta-analysis of the pooled log-transformed OS (Figure S8) showed no significant difference in the pooled log-transformed OS, no matter which study was omitted. The pooled log-transformed OS ranged from 1.644 to 1.842, and the I² ranged from 84.7% to 90.6%. It suggested that the results of the original meta-analysis did not change significantly due to the change in the number of studies, and the results were stable.

Figure 5 Overall, in Asian region and in American and European region subgroup pooled median OS months following diagnosis of brain metastasis from esophageal carcinoma via random effects analysis. Subgroups are divided by different area. CI, confidence interval; OS, overall survival.

To identify factors influencing the prognosis of BMEC patients, we conducted a prognostic risk factor analysis for BMEC patients across 11 studies. In the pooled univariate analysis, the PS (either KPS or PS) (P=0.55, Figure 6A) showed no significant effects on OS. However, the resection of BMs was significantly associated with better OS (HR: 0.45, 95% CI: 0.33–0.61, P<0.001, Figure 6B), indicating that resection of BMs reduced the risk of death by approximately 55% on average. In contrast, multiple BMs (HR: 1.66, 95% CI: 1.27–2.16, P<0.001, Figure 6C) and BMECs presenting with extracranial metastasis (HR: 1.52, 95% CI: 1.11–2.09, P=0.01, Figure 6D) were significantly associated with worse OS.

Figure 6 Analysis of prognostic risk factor for patients with BMEC. (A) Pooled HR for survival in patients with BMEC presenting with poor performance status via random effects analysis. Subgroups are divided by different performance status score standard. (B) Pooled HR for survival in patients with BMEC presenting with surgical resection via common effects analysis. (C) Pooled HR for survival in patients with BMEC presenting with multiple BMs via common effects analysis. (D) Pooled HR for survival in patients with BMEC presenting with extracranial metastases via random effects analysis. BMs, brain metastases; BMEC, brain metastasis from esophageal carcinoma; CI, confidence interval; HR, hazard ratio; KPS, Karnofsky performance status; PS, performance status; WBRT, whole brain radiotherapy.

Discussion

This study provided the first evidence-based evaluation of the epidemiological characteristics and prognostic factors of BMECs, offering valuable insights into this rare but highly fatal condition. Through a comprehensive meta-analysis, this study showed the overall incidence of BMECs (2.84%) and significant histological differences (the incidence of adenocarcinoma was 3.7 times that of SCC), and identified key factors influencing survival outcomes.

BMECs are relatively rare in clinical practice. Previous research by Cheng and colleagues reported an incidence of 1.8% among 34,107 esophageal carcinoma patients from the SEER database diagnosed between 2010 and 2018 (45). In our study, the incidence of BMECs was 2.84%, with incidence in American and European region with incidence 4.54%, higher than the incidence reported by Cheng (45).

Our findings revealed a significantly higher incidence of BMs in patients with esophageal adenocarcinoma (5.34%) than those with SCC (1.45%). A study including patients diagnosed with non-metastatic primary lung cancer from the SEER database between 1973 and 2011 found that the incidence of BMs from lung adenocarcinoma was 11%, higher than the 6% of SCC (46). Similarly, a penalized regression competing risk model using data from 330 lung cancer patients showed that patients with adenocarcinoma or large cell carcinoma have a higher risk of developing BM compared to those with SCC (47). These results suggest that adenocarcinoma may have a greater propensity to metastasize to the brain than SCC. Genomic analysis studies of BMs from non-small cell lung cancer (NSCLC) have shown that alterations in the Kirsten Rat Sarcoma viral oncogene homolog (KRAS), Serine/Threonine Kinase 11 (STK11), and Receptor Tyrosine Kinase-Rat Sarcoma viral oncogene homolog pathways are more frequent in lung adenocarcinoma, while Cyclin-Dependent Kinase inhibitor 2A (CDKN2A) deletion is more frequent in SCC. Compared patients without BMs, NSCLC patients with BMs were enriched for alterations in KRAS, CDKN2A, STK11. Although the specific mechanism remains unclear, these findings suggest differences in the mechanisms of BM between SCC and adenocarcinoma (48,49). These findings and our finding highlight the importance of considering brain imaging at staging for patients with esophageal adenocarcinoma.

Compared with different histology types, several biomarkers are commonly used for the prediction of BMs. Notably, multiple studies found that human epidermal growth factor receptor 2 (HER2) overexpression frequently occurs in gastroesophageal adenocarcinoma, which is associated with an increased risk of BMs (50-52). While the exact biological mechanisms remain uncertain, HER2-positive tumors may have a predilection or selective tropism for the central nervous system (53,54). Preclinical models of HER2-positive breast cancer suggest that this is potentially mediated by chemotaxis via CXC chemokine receptor 4 and its ligand, stromal cell-derived factor-1α or via tropomyosin-related kinase B cooperative signaling (55,56). Moreover, multiple studies have found that the formation of heterodimers of HER2 and human epidermal growth factor receptor 3 (HER3) leads to significant activation of the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway in breast cancer cells. Inhibiting HER3 activity can overcome the resistance to PI3K inhibition in breast cancer BMs, and the PI3K-Akt signaling pathway is also considered to be a major regulator of BMs, which mediates cell motility, invasion, and metastasis (57-62). In addition to HER2, mutations in epithelial growth factor receptor, KRAS, and anaplastic lymphoma kinase are frequently implicated in the prediction of BMs in NSCLC. For breast cancer, breast cancer susceptibility gene 1 mutations are also associated with a high incidence of BMs (63-66). While the role of epithelial-mesenchymal transition in BMs remains debated, several studies, including those by Grinberg-Rashi et al., suggest that N-cadherin, a mesenchymal marker that promotes cell migration during embryogenesis and inflammation, may serve as a predictive marker for BMs in NSCLC (67-70). However, unlike HER2, there is currently no research linking these mutations to BMECs.

BMECs are often diagnosed at advanced stages due to the typical reliance on clinical symptom manifestation. This diagnostic delay not only hinders the timely therapeutic interventions but also contributes to diminished quality of life. These clinical challenges are reflected in the suboptimal survival outcomes, as evidenced by that the pooled median OS ranging from 2.00 to 12.00 months after BM diagnosis (7,10,13,23,25,27-29,31,34,35,40-44), which was only 5.62 months in our study. The poor prognosis of BMECs highlights the urgent need for earlier detection and intervention.

Previous studies with small samples have reported several prognostic factors for BMECs. Yang and Song and their colleagues (10,28) found that local treatment modality of BMs is a significantly independent prognostic factor for patients with BMECs. Similarly, RTOG RPA classification and KPS scores were also found to be independent prognostic factors for patients with BMECs (28). Moreover, Lin and colleagues (33) reported that lower the N stage of esophageal tumors is associated with a better prognosis based on a retrospective analysis of 67 patients with BMECs. Consistent with these findings, our study confirmed that the resection of BMs was significantly associated with better OS, while multiple BMs, and extracranial metastasis were significantly associated with worse OS. However, KPS scores showed no significant effects on OS. Other factors were not included in the analysis because of the lack of sufficient data provided in correlational studies. As awareness of BMEC diagnosis improves, larger-sample studies in the future may further confirm the risk factors affecting BMEC prognosis.

The advent of immune checkpoint inhibitors has revolutionized systemic management of advanced esophageal carcinoma, yet their therapeutic potential in cerebral metastases remains underexplored. While agents targeting programmed death-1/programmed death-ligand 1 axis demonstrate measurable responses in primary lesions, the blood-brain barrier and immunosuppressive tumor microenvironment pose unique challenges for intracranial efficacy (71,72). Recent progress in targeted treatments, coupled with the emergence of innovative approaches for drug delivery aimed at bypassing the blood-brain barrier, offers the potential to enhance the efficacy of chemotherapy in addressing BMECs (73). Furthermore, a rare case of esophageal SCC with asymptomatic BMs was reported, whose BM lesion had a complete response to immune checkpoint inhibitors (74). On the other hand, SCC has a lower incidence compared to adenocarcinoma. Exploring the mechanism for this phenomenon can contribute to the prevention of BM. Therefore, in the future, further research on the BMEC pattern of SCC is needed.

Overall, our findings not only filled the evidence-based gap in current BMEC diagnosis and treatment strategies, but also provided crucial theoretical support for enhancing brain monitoring in high-risk patients and optimizing individualized interventions in clinical practice. However, the existing evidence is still limited by the heterogeneity of retrospective studies. Prospective cohort studies are urgently needed in the future to further validate the risk stratification criteria and explore precise treatment models.

This study had several limitations. First, most studies included were retrospective in design, which may introduce potential patient selection bias. Secondly, due to its retrospective nature, heterogeneous follow-up durations may lead to biases in the reported outcomes. Moreover, the inherent heterogeneity and the small sample sizes in both the systematic review and institutional analysis limit the generalizability of our findings. Notwithstanding these limitations, the present investigation yields important insights into the clinical management of BMECs, while establishing support evidence for subsequent translational and clinical investigations in this currently under-researched oncological domain.

Conclusions

This comprehensive meta-analysis indicates BMECs as uncommon but lethal events in patients with esophageal carcinoma, demonstrating a dismal prognosis of BMECs and a higher prevalence and incidence of BMs in adenocarcinoma. These findings support the regular use of brain imaging at staging and neuroimaging surveillance at follow-up in patients with esophageal carcinoma. Future research directions should focus on developing precise BM risk prediction tools and prospective studies to establish optimal treatment for BMECs.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1219/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1219/prf

Funding: This work was supported by the Shanghai Hospital Development Center (No. SHDC22024225), the National Clinical Key Specialty Construction Project (No. 10000015Z155080000004) and the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine grant (No. 20181816).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1219/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.

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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