Esophageal and EGJ AC have shown the highest rates of increase in incidence of any cancer over the past four decades, especially in high-income countries [2]. In recent years, EGJ AC has also increased in Japan [3, 4]. On the other hand, esophageal SCC accounts for up to 90% of cases of esophageal cancer worldwide; however, it is decreasing in Western countries [5, 10]. These two distinct tumors tend to be considered to share similar characteristics and their differences have rarely been investigated. However, in addition to the previously observed greater male predominance of esophageal AC than esophageal SCC, other differences may also exist [11].
Regarding differences in the post-therapeutic outcomes, Siewert et al. reported a worse long-term survival among esophageal SCC patients compared to AC patients in patients undergoing surgery alone at the beginning of the twenty-first century [12]. Thereafter, the CROSS trial demonstrated similar LRR rates between the two histology groups of esophageal or EGJ cancer, in patients who received neoadjuvant CRT followed by surgery, whereas a higher risk of LRR for SCC was observed in patients who only underwent surgery [13]. As for systemic failure, conflicting outcomes regarding its likeliness in relation with histology, brought by varied protocols of trimodality therapy, have been reported [14, 15]. Concerning treatment modalities other than surgery-based treatment, Xi et al. retrospectively compared esophageal cancer cases by definitive CRT and reported significantly more favorable hematogenous failure-free survival in SCC patients and significantly higher rates of distant failure in AC patients [16]. However, the locational distributions of the two histological subtypes can vary, and previous studies present a bias in terms of tumor location between the two histological subtypes.
This study is the first to compare postoperative recurrence patterns and timing between histological subtypes in an EGJ-limited-cancer cohort and identify differences. As a result, a significantly worse postoperative non-lymphogenous failure-free survival and significantly longer period from surgery to recurrence was observed in the AC group compared to the SCC group. In contrast, a relatively higher recurrence rate at LN was observed in the SCC group, even though the SCC group showed a larger number of harvested LNs and a smaller number of metastatic LNs. Studies involving lager cohorts that focused on individual histological subtypes have shown that the primary cause of postoperative failure in esophageal SCC was often LN metastasis [17]. Conversely, LN metastasis was a less common factor contributing to postoperative failure in EGJ AC [18]. The findings of the present study agree with those of previous studies, suggesting that assessing tumor-spreading appearance based on a viewpoint lymphogenous or non-lymphogenous, rather than focusing solely on locoregional or systemic aspects, may provide more informative insights.
Concerning recurrence timing, median time-to-recurrence after surgery in esophageal and EGJ AC has been reported within a range of between 11 and 26 months [19–21]. In esophageal SCC, Kurogochi et al. reported that over 70% of postoperative recurrence occurred within one year [22]. To the best of our knowledge, there have been no direct comparisons of the timing of postoperative recurrence between histological subtypes in esophageal or EGJ cancer. Yun et al. directly compared the timing of recurrence after surgery for non-small cell lung cancer and found varied peaks of recurrence hazard depending on tumor histology; 9 months in SCC and 15 months in AC [23]. These findings closely resemble our results, suggesting that longer periods until recurrence in AC than in SCC may be a common tumoral characteristic across primary organs, considering findings in the field of lung cancer.
Treatment strategies for esophageal and EGJ AC have mainly been developed in Western countries. In the CROSS trial, conducted in a cohort among which 75% of patients had esophageal or EGJ AC, the effect of neoadjuvant chemoradiotherapy tended to be lower for AC than for SCC. Furthermore, the ten-year outcomes did not show significant survival superiority in the AC group [24, 25]. A high ratio (28.6%) of hematogenous recurrence after the neoadjuvant chemoradiotherapy was also noted.13 The FLOT4-AIO trial demonstrated a significantly enhanced outcome with perioperative FLOT (docetaxel, oxaliplatin, leucovorin, and 5-FU) therapy for EGJ and gastric AC, compared with perioperative ECF/ECX (MAGIC regimen) therapy [26]. For esophageal or EGJ cancer after neoadjuvant CRT, significantly longer disease-free survival for both AC and SCC were associated with adjuvant nivolumab therapy in the Checkmate 577 trial [27]. In the Neo-AEGIS trial, trimodality therapy was directly compared with perioperative chemotherapy for AC of the esophagus and EGJ [28]. This study ended in equipoise, with significantly fewer liver and lung metastases in the perioperative chemotherapy group.
The current study indicates that EGJ AC may exhibit a stronger tendency for non-lymphogenous progression compared to EGJ SCC. This may be a favorable factor for treatment emphasizing systemic control since non-lymphogenous progression is more challenging to manage through surgical resection or by radiation therapy than progression through the lymphatic system. Comprehensively, both the findings reported in the literature and the results of the present study suggest that perioperative systemic treatment would be promising for EGJ AC.
This study has some limitations, including its retrospective, single-center design. Possibility of selection bias cannot be excluded. Second, variations of treatments could have influenced the results. Surgical approach and the extent of LN dissection, where a consensus has not made, varied between the subgroups while R0 was secured in all cases, and both the incidence of postoperative complication and the distribution of LN metastasis site were comparable. Differences in perioperative treatments also might have affected the result. Third is the small number of the cases. Nevertheless, given the rarity of EGJ SCC, we believe this study is valuable in terms of the study of aspects that have rarely been investigated before. Furthermore, this study is the first to note the different pattern and varied timing of postoperative recurrence in EGJ cancers. Future research with larger and characteristically well-matched cohorts to verify these findings will be desirable and beneficial.