Estimating risk of metastatic disease in T1b esophageal adenocarcinoma: incremental progress but gaps remain

The presence of lymph node metastasis (LNM) is a crucial determinant of long-term prognosis in patients with early esophageal adenocarcinoma (EAC). Presence of nodal disease typically precludes curative endoscopic resection, and requires induction chemoradiotherapy followed by surgical resection [1] [2]. While T1a EAC is associated with a low nodal metastasis rate of 0–2 %, T1b has a much higher rate of 16 %–22 % [2] [3]. Although selective use of endoscopic therapy for superficial disease limited to the upper third of the submucosa has been advocated, many centers perform surgery for all patients with T1b EAC. Hence, there is an unmet clinical need to reliably stratify patients for the most suitable therapy.

“...it is notable that the vast majority of metastasis occurred within the first year, which suggests that the metastatic spread may have already occurred at the time of resection, and that our ability to assess for early metastatic spread is limited.”

Multiple factors including lymphovascular invasion, degree of differentiation, tumor grade, and depth of submucosal invasion have been utilized to stratify the risk of LNM in patients with T1b EAC [3]. However, we do not currently have reliable scoring tools that can accurately quantify this risk in T1b EAC and hence guide management for endoscopic versus surgical intervention. Efforts have been made to create scoring systems based on nationwide [4] or single-institution [3] [5] databases, but their adoption in guidelines and clinical use has been limited.

In this issue of Endoscopy, Gotink et al. report the results of a nationwide, retrospective, multicenter cohort study from the Netherlands Cancer Registry of 248 patients with T1b EAC who underwent endoscopic or surgical resection without neoadjuvant chemoradiation [6]. The goal was to identify risk factors that are associated with the risk of nodal disease or metastasis after endoscopic or surgical resection, and then use those risk factors to develop a predictive scoring system for clinical use. Three expert gastrointestinal pathologists reviewed histological parameters including size of tumor, depth of invasion, differentiation, and lymphovascular invasion. Notably, this scoring system relied solely on histological parameters and did not employ any demographic factors, or clinical/endoscopic features.

The authors predicted that the risk of developing metastatic disease was highest with lymphovascular invasion, followed by large-sized tumors, and then the depth of submucosal invasion. Using different combinations of these criteria, the authors developed a risk calculator to predict the risk of metastasis at 5 years. Using this large sample size, the scoring system estimated the 5-year metastases rate for T1b EAC to range from 5.9 % to 70.1 % [6]. This study reaffirms that the risk of nodal or metastatic disease in patients with T1b EAC remains high. Furthermore, it is notable that the vast majority of metastasis occurred within the first year, which suggests that the metastatic spread may have already occurred at the time of resection, and that our ability to assess for early metastatic spread is limited. These features suggest that close surveillance and a high degree of suspicion for metastatic disease are crucial in the post-resection time period, especially within the first year. These data are also useful to keep in mind when counseling patients about the disease prognosis and competing risks and benefits of therapy. Interestingly, the grade of differentiation did not alter the outcomes in this study and hence was excluded from the risk-scoring calculator. This is in contrast to other scoring systems where poor and moderately differentiated EAC led to higher risk scores and were associated with worse outcomes [3] [4] [5]. Indeed, the recently published 2021 National Comprehensive Cancer Network (NCCN) guidelines for esophageal cancers also include poorly differentiated histology as a marker of poor prognosis and note a higher risk of lymph node involvement [1]. In our clinical practice, we continue to use grade of differentiation in assessing risk of metastatic disease.

Unlike a previous study by Weksler et al., which used an administrative database to perform statistical analysis [4], Gotink et al. had access to specimens and were able to accurately reassess the histology and evaluate the high-risk parameters [6]. Two other scoring systems, which relied on single-center retrospective analyses, were based solely on primary esophagectomies [5], whereas the current study incorporated surgical as well as endoscopic interventions. Beyond the limitations inherent in retrospective analyses, some aspects of the study need to be kept in mind while interpreting the data. Only four patients underwent endoscopic submucosal dissection. This is presumably a reflection of the practice patterns prevalent prior to 2016, which is the time-period assessed in the study. Emerging data suggest that endoscopic submucosal dissection provides accurate histological staging, and curative potential in selected patients with T1b EAC [7]. Moving forward, this scoring system will need to withstand scrutiny during external validation, preferably in a prospective study. In a prior validation study of two scoring systems by Nobel et al., 32 patients with T1b EAC and LNM were assessed [8]. Overall, the Lee and Weksler scores demonstrated high predictive and discriminatory capabilities with area under the curve values of 0.832 and 0.824, respectively [4] [5]. However, the false-positive rate (compared with pathologic LNM status) was 73 % and 56 %, respectively, for the two scores [4] [5] [8]. This is critical information as overestimating the risk of metastatic cancer may misguide therapy and potentially lead to an unwarranted overuse of surgical resection instead of endoscopic therapy.

It remains to be seen whether the use of these scoring systems actually impacts clinical care or leads to a refinement in prediction models or management algorithms. Understanding the risk of nodal disease will be crucial in eventually working toward identifying the subset of patients with T1b EAC who can safely undergo endoscopic resection instead of esophagectomy. In addition to histological features, the decision making for therapy also needs to include endoscopic and patient-related factors. At this time, there is no well-validated and reliable scoring system that can encompass all the above factors and guide decision making. Hence, we continue to advocate for multidisciplinary decision making that involves the patient and individualizes care based on disease characteristics as emphasized by this study, as well as patient preference, presence of comorbidities, and availability of expertise.

Publication History

Article published online:
17 August 2021

• References

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