T1b esophageal cancer: upstaging, the price of oncological certainty, and personalization

Esophagectomy with lymphadenectomy has traditionally been the standard of care for clinically staged submucosal (cT1b) esophageal cancer (EC). It has the benefit of removing potential lymph node metastases (LNM) and provides high oncological certainty that the EC has been removed. However, it also carries a considerable mortality rate of 0–4% and morbidity rates up to 56%, with severe pulmonary complications and anastomotic leakage with subsequent mediastinitis occurring in 10–20% of patients (1-3). Endoscopic resection (ER) has proven itself as a safe and effective minimally invasive alternative for removing (T1) EC (4-6). ER not only causes less morbidity, but also results in significantly higher quality of life (7). Since the introduction of endoscopic submucosal dissection (ESD), it has also become possible to remove submucosal EC while preserving the integrity of the gastrointestinal anatomy (4-6). However, due to the lack of high quality prospective data on the endoscopic management of T1b EC, the optimal management continues to represent a matter of debate in modern oncologic practice.

In their comprehensive National Cancer Database (NCDB) study, Ayoade and colleagues provide interesting insights regarding this debate (8). The authors assessed survival outcomes of treatment-naïve patients from various types of hospitals across the United States who underwent endoscopic management (n=543) or esophagectomy (n=926) of cT1bN0 EC, diagnosed between 2010 and 2018 (8). They reported a significantly higher 5-year survival after esophagectomy. However, the generalizability of this outcome is questionable, as the endoscopically managed patients were significantly older, and the survival benefit disappeared in the propensity-matched survival analysis of patients with negative resection margins (8). Furthermore, during the inclusion period, ER was still an emerging approach, and ESD in particular was not widely used yet (9,10). Consequently, endoscopists were still on their learning curve, which likely limited the efficacy of the technique (11-13). Outcomes from more recent studies conducted in experienced centers are therefore better suited to guide personalized care. In addition, there was a significant amount of nodal and tumor upstaging after esophagectomy, questioning the reliability of the initial cT1bN0 diagnosis. The authors identified that lymphovascular invasion (LVI), poor tumor differentiation, and tumor size ≥10 mm as prognostic factors were significantly associated with nodal upstaging (8). We think their findings reconfirm that the decision between surgical and endoscopic management cannot be reduced to a binary choice based on a cT1b diagnosis. Instead, it must be guided by three interconnected considerations: the risk of post-treatment upstaging, the balance between oncological radicality and quality of life, and the necessity of individualized treatment.

Upstaging

Ayoade et al. describe that in 15% of patients who underwent esophagectomy, there was nodal upstaging despite being clinically staged as node-negative (cN0). Additionally, within the same treatment group, 12% of patients had tumor upstaging from cT1b to pT2 or higher. It has to be acknowledged that there might be verification bias when interpreting upstaging in registry cohorts of surgical vs. only endoscopically treated patients. As surgical cohorts undergo systematic pathological nodal assessment, endoscopic cohorts typically do not, which can inflate the apparent upstaging and survival contrasts. Nevertheless, the observed upstaging by Ayoade et al. exposes the Achilles’ heel in the successful management of cT1b patients: pre-treatment staging. Staging modalities often used for EC include endoscopic assessment, endoscopic ultrasound (EUS), and positron emission tomography (PET) or computed tomography (CT) scans. Routine pre-ER EUS/(PET-)CT is often unnecessary in clearly early, endoscopically resectable lesions, while EUS/CT should be used selectively when nodal disease is suspected or when diagnostic ER is not feasible. Because histopathological assessment from diagnostic ER more accurately determines invasion depth, current guidelines often advise against routine use of pre-ER EUS or (PET-)CT (4-6,14). Also, diagnostic ER carries no additional (oncological) risk, but potentially safes overtreatment in a substantial amount of patients (15). Both the endoscopic and histological assessment can be challenging and should therefore be performed by experts (6,16). When pathology confirms submucosal invasion, poor tumor differentiation or LVI, subsequent staging with EUS with fine-needle aspiration (FNA) of suspicious nodes should be performed to assess local-regional lymph nodes, and (PET-)CT should be used to assess non-regional lymph nodes and distant metastases (5,6,16). Only after full staging can an adequately informed decision regarding subsequent management be made. Unfortunately, the authors did not report the pre-treatment staging procedures and/or modalities used (8), which hampers assessment of the diagnostic certainty of the cT1bN0 diagnoses in the included patients. If patients had been appropriately staged, the outcomes may have reflected the challenges with the detection of microscopic LNM in T1b tumors with our current staging tools (16,17). However, not all micrometastases found during pathological staging would have subsequently developed as clinically relevant LNMs, and the prognostic significance of nodal micrometastases remains heterogeneous and controversial (17). This further complicates the interpretation and clinical utility of current staging tools. Furthermore, the pathological tumor stage was not provided for the endoscopically managed cohort, which is crucial information to assess the accuracy of clinical staging in these patients. This omission substantially limits the generalizability of the findings and adds further uncertainty to an analysis already subject to a high risk of selection bias due to the retrospective design and the inclusion of data from varying types of institutions.

Oncological certainty vs. quality of life

Once complete staging is accomplished, the focus shifts to balancing oncological certainty with quality of life considerations. Esophagectomy, while offering the highest immediate oncological certainty by also removing locoregional lymph nodes and thus potential LNMs, is among the most invasive and life-altering surgical procedures in gastrointestinal oncology (18). It carries significant risks of perioperative morbidity and mortality, as well as long-term consequences including altered swallowing, reflux, nutritional challenges, and reduced quality of life (18,19). In contrast, endoscopic management offers clear advantages in terms of short-term morbidity, recovery time, and preservation of gastrointestinal function (20). For example, Ayoade et al. report a lower 90-day mortality after endoscopic therapy (2.0%) compared to esophagectomy (4.3%). For older patients or those with significant comorbidities, this difference may be clinically decisive. However, the trade-off is oncological certainty. After diagnostic ER and expert histological assessment, it becomes clear whether a cT1b EC is an actual pT1b EC. However, unlike esophagectomy, which includes systematic lymphadenectomy and allows removal of occult nodal metastasis, endoscopic therapy is limited to local tumor control (20,21). Thus, the advantage of endoscopic management, its local and organ-preserving nature, is also its main limitation. Therefore, clinicians are forced to balance procedural safety and quality of life against long-term cancer-free survival.

Although the authors do not perform subgroup analyses based on EC type, the risks of developing LNM are actually very different. For low-risk T1b esophageal adenocarcinoma (i.e., superficial submucosal invasion, well-moderate differentiation, and absent LVI) the risk of LNM is <2%, which is lower than the mortality rate after esophagectomy (5,16,22). Additional surgical treatment after ER is therefore not advised and strict follow-up with EUS and (PET-)CT is recommended (5,6,16). T1b esophageal adenocarcinoma is considered high-risk in case of deep submucosal invasion (>500 µm), and/or increasing tumor size, and/or poor tumor differentiation, and/or LVI (16,23). These cancers have a reported LNM rate of 0–16% (22,24,25). Due to this higher LNM rate, current guidelines advise to discuss both strict endoscopic follow-up with gastroscopy, EUS and (PET-)CT, and additional non-endoscopic treatment such as esophagectomy and/or chemoradiation (5,6,16). Early-stage esophageal squamous cell carcinoma is more aggressive than adenocarcinoma, resulting in a higher risk of LNM and metachronous lesions (6). For instance, lesions with submucosal invasion greater than 200 µm are already classified as high-risk (4). Therefore, additional non-endoscopic treatments are more frequently considered for high-risk T1b squamous cell carcinoma (4-6). As described, submucosal invasion beyond 200–500 µm (depending on the tumor type) exposes a patient to higher metastatic risks. Unfortunately, the exact submucosal invasion depth was not reported by the authors, leaving an important factor unexplored that could have accounted for the difference in overall survival between both groups.

Irrespective of the cancer subtype, management inevitably involves balancing the risk of LNM after primary treatment against the risk of overtreatment. Following ER, a subset of patients may indeed be at risk of LNM. However, performing surgery on every patient would result in the vast majority undergoing esophagectomy without ever developing LNM, while more than half would experience long term postoperative morbidity. Moreover, metastases can still occur after esophagectomy, indicating that surgery also does not provide absolute safeguard against the development of LNM (26,27).

Personalized care

While nodal upstaging exposes the risks of endoscopic therapy, Ayoade et al. also present compelling evidence that challenges a rigid, surgery-first approach for all T1b tumors. Their data show that some patients with favorable tumor characteristics, particularly those with well-differentiated tumors and negative margins after ER, demonstrate survival outcomes comparable to those who undergo esophagectomy. This finding supports the third key principle: treatment must be personalized. T1b disease is not a uniform entity and treating all T1b tumors as identical will result in overtreatment for some and undertreatment for others.

The study identifies three factors strongly associated with nodal upstaging:

• LVI;
• Poor differentiation;
• Tumor size >1 cm.

These features could help stratify risk and should be taken into consideration in clinical decision-making. A small, well-differentiated tumor without LVI behaves differently from a poorly differentiated lesion with aggressive histology, even if both are technically classified as T1b. Therefore, a broader classification, based not only on invasion depth should be used in determining subsequent policies (4-6). A blank recommendation for esophagectomy fails to acknowledge the heterogeneity of disease biology and the individual circumstances of patients.

Personalization does not mean lowering standards of oncological safety. It means carefully identifying subgroups of patients for whom it is safe to manage endoscopically and for whom it is better to offer additional surgery. Additionally, even if LNMs develop during follow-up, curative treatment options remain available. Baseline staging may fail to detect micrometastatic disease, however, strict follow-up strategies will enable detection of evolving LNM and/or intraluminal recurrences during surveillance (PREFER study, NCT03222635). These strategies consist of periodic endoscopic surveillance, including EUS, and cross-sectional imaging [(PET-)CT), with follow-up intervals gradually extended over time in the absence of recurrence or LNMs. This approach provides a robust safety net for patients while minimizing long-term complications and maintaining quality of life.

And just as ER consists of multiple resection techniques, it may be beneficial for patients to look beyond esophagectomy as the sole surgical option. For certain high-risk patients, it may also be safe to perform a selective lymph node resection using sentinel node-navigated surgery (28). This could solve the problem of untreated and undetected LNM, while preserving the gastrointestinal anatomy. A practical algorithm for treatment of T1b disease can be found in Figure 1.

Figure 1 Practical algorithm for treatment of esophageal cancer. CT, computer tomography; EUS, endoscopic ultrasound; ER, endoscopic resection; FNA, fine needle aspiration; LVI, lymphovascular invasion; MDT, multidisciplinary team; PET, positron emission tomography; R0, tumor free resection margins; R1, margins not free of tumor; Rx, margins not assessable; SM, submucosal.

Interplay between the three core concepts

The three concepts (upstaging, the balance between oncological certainty and quality of life, and personalization) are not separate discussions. They exhibit a high degree of interdependence:

• Nodal upstaging exposes the uncertainty of oncologic pre-treatment staging;
• Quality of life considerations determine how patients value this trade-off;
• Personalization helps identify which patients may safely accept that risk.

In patients with low-risk EC (i.e., well-differentiated tumors, small lesion size, negative margins, absence of LVI), endoscopic management is an appropriate and patient-centered approach, including in older or frail individuals. In contrast, for certain high-risk ECs or younger and non-frail patients, a more invasive treatment strategy may be justified to reduce the risk of recurrence. However, younger age may also argue in favor of minimally invasive treatment, as younger patients also will have to live longer with potentially long-term complications. Therefore, the goal is not to replace surgery with endoscopy or vice versa, but to integrate them within an evidence based, patient-centered framework.

Looking forward

Ultimately, nodal upstaging represents a failure of detection, not just a treatment problem. The real solution lies not solely in choosing esophagectomy or endoscopy, but in improving our ability to discern tumor biology before committing to either. Only when we reduce the uncertainty of nodal status will we truly be able to personalize therapy without compromising oncological safety.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Laparoscopic and Endoscopic Surgery. The article has undergone external peer review.

Peer Review File: Available at https://ales.amegroups.com/article/view/10.21037/ales-2026-1-0008/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://ales.amegroups.com/article/view/10.21037/ales-2026-1-0008/coif). The authors have no conflicts of interest to declare.

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