This study is a comprehensive research for metastatic patterns in the two predominant subtypes of esophageal cancer (ESCC and EAC). Major differences between ESCC and EAC were observed, such as frequencies of single-site metastasis, patterns of combination of metastatic sites. These findings may help physicians implement better tailored screening modalities and follow-up strategies in future clinical settings.
Compared with ESCC, EAC had a higher rate of liver or brain metastasis and a lower rate of lung metastasis, with a similar trend in metastasis to bone. These results are partially consistent with findings from two previous SEER studies. Ai et al. found EAC was more likely to have liver, bone, or brain metastasis but had a lower rate of lung metastasis compared with ESCC [10]. The other study of SEER data from 2010 through 2014 reported that patients with EAC had a higher rate of liver or brain metastasis and those with ESCC were more likely to have lung metastasis, with similar proportions of bone metastasis among the two groups [9]. Diverse outcomes might partly be attributable to different sample sizes and confounding clinical variables adjusted in the analysis. In addition, this discrepancy could also be the result of the transition of esophageal histology in the recent decades, which is an increase in the incidence of EAC because of the growing prevalence of obesity and the decline in ESCC incidence after promotion of smoking cessation [2, 11, 12].
Of note, the proportion of liver metastasis in EAC far outweighs that of in ESCC. This may in part be explained by differences in histological type and tumor location as well as pattern of lymphatic spread, as most cases of EAC are present in the lower esophagus where lymphatic flow tends to be downward, while ESCC is more common in the upper two thirds of the esophagus where lymphatic flow is inclined to be upward [13]. Furthermore, the relative short-distance from lower esophagus to liver might also facilitate the spread of esophageal cancer cells to this organ through the venous drainage of the gastrointestinal tract to the portal vein.
A concerning observation was that a large number of patients with metastatic disease exhibited multi-organ metastases. Among all combined metastases, the most frequent multi-organ metastatic pattern was the liver and lung in both ESCC and EAC groups. In concert with some published literatures, liver and lung are the two main drainage regions frequently colonized by a variety of cancers, targeting these sites of high vascular flow [7, 14]. Another observation is that liver or brain metastasis was commonly observed in combination with other organ metastases in EAC. These findings highlight the essential of regular imaging of chest and liver for all esophageal cancer patients and early PET-CT assessment of patients with EAC, especially in cases suspected with liver or brain metastasis. The mechanism of the propensity for a metastatic cell to spread to several anatomically distinct locations, either sequentially or synchronously, has not been demonstrated explicitly in previous literatures. In some extent, this phenomenon could be explained by the ‘seed and soil’ hypothesis that the microenvironment of two host organs bear a resemblance to each other thereby facilitating metastasis to the same degree [15].
To our best knowledge, this is the largest population-based study summarizing the metastatic patterns in ESCC and EAC by analyzing the recently released US SEER-18 cancer registry data. Nevertheless, our study is subject to a number of limitations. The first limitation is the retrospective nature of this study. Second, even though several studies have described molecular changes contributing tumor cells of esophageal cancer to a more aggressive biological behavior [16–19], the underlying mechanism for differences in metastatic patterns between histological subtypes remains unclear. Additionally, most metastatic lesions were clinically diagnosed without histologically confirmed, which might have resulted in misclassification.