Pretracheal (No. 106pre) lymph node metastasis, considered an oligometastatic disease, may achieve long-term survival when treated with modern neoadjuvant therapy combined with surgical resection

Esophageal cancer is the 11th most common cancer globally and the 7th leading cause of cancer-related deaths, primarily due to its poor prognosis (1). Esophageal cancer is prone to lymph node metastasis, and its oligometastatic lesions include metastases to distant organs and extra-regional lymph nodes. Pretracheal lymph node metastasis (No. 106pre in the Japanese classification) is classified as an M1 lymph node metastasis. Traditionally, patients with pretracheal lymph node metastasis have had an extremely poor prognosis, with a reported 3-year survival rate of 0% (2). In the management of esophageal cancer, metastasis to the pretracheal lymph nodes (No. 106pre) remains a subject of ongoing clinical debate. The controversy arises from the fact that while pretracheal lymph node metastasis is pathologically classified as advanced disease, it may present with relatively limited spread in some patients, resulting in a distinct clinical scenario of “pathologically advanced-stage disease with regionally confined metastasis”. Categorizing all such cases as incurable advanced disease could lead to the denial of potentially curative surgery for patients who might benefit from a combination of local and systemic therapies. On the other hand, overly aggressive surgical intervention may result in unnecessary operative trauma and complications. However, limited case numbers and a focus on earlier, heterogeneous patient cohorts have left the pathological characteristics of this site underexplored. Advances in intensive neoadjuvant therapy and the introduction of promising new drugs for esophageal cancer warrant reevaluating the significance of resecting pretracheal lymph node metastases.

Igaue’s paper “Pretracheal (No.106pre) lymph node metastasis in esophageal carcinoma: A sign of widespread disease progression, but potentially treatable as oligometastatic disease through neoadjuvant chemotherapy followed by surgery - A multicenter cohort study” aims to validate whether 106pre metastasis represents an “oligometastatic” state, an intermediate between locally advanced and widely metastatic disease. It evaluates whether long-term survival can be achieved through modern neoadjuvant therapy combined with surgical resection of pretracheal lymph nodes (3).

This study included patients with esophageal cancer who were diagnosed with pretracheal lymph node metastasis and underwent esophagectomy following neoadjuvant chemotherapy (NAC). Among the 110 esophageal cancer patients, 94 had pathologically negative pretracheal lymph nodes, while 16 were positive. The 106pre(+) group had more advanced disease and a higher average number of metastatic lymph nodes (10.0). The 3-year overall survival (OS) rate was 66.6% for the pretracheal 106pre(−) group and 29.9% for the 106pre(+) group (3). Although the positive group demonstrated a significantly lower survival rate, it was still substantially higher than the historical data of 0%. More importantly, on multivariable analysis, pretracheal lymph node (No. 106pre) metastasis itself was not an independent prognostic factor, whereas ypN3 emerged as a more decisive indicator of poor prognosis. The results indicate that a high nodal burden is associated with adverse outcomes (3). This finding suggests that although 106pre metastasis often coincides with a high nodal burden, it may not inherently represent uncontrollable systemic disease. Within a multimodal treatment framework, the pretracheal (106pre) lymph node could still represent a potential therapeutic target in the context of oligometastatic disease. However, this possibility requires methods to clarify systemic response to chemotherapy, warranting further research. For example, circulating tumor DNA (ctDNA) assays may predict response to systemic therapy or help select patients for local treatment by detecting micrometastatic disease with high sensitivity (4). Similarly, the ongoing NCT04931420 trial has already selected patients with oligometastatic cancer for local therapy based on ctDNA clearance after induction chemotherapy (5). Such trials are likely to become increasingly important in the future.

The core strength of this study lies in its rigorous and clinically relevant design. The authors established clear, well-defined inclusion criteria focusing on a specific nodal station—the pretracheal (No. 106pre) lymph nodes. All enrolled patients were clinically diagnosed with 106pre lymph node metastasis and uniformly underwent esophagectomy following NAC. This approach ensured a highly homogeneous study cohort and mitigated bias arising from widely divergent treatment strategies or heterogeneous disease stages. It is the first large-sample, multicenter retrospective study conducted in the context of modern NAC. Moreover, the survival outcomes were better than those previously reported: the 3-year OS in p106pre(+) patients reached 29.9%, which, although significantly lower than that of the negative group (66.6%), was markedly superior to the nearly absent long-term survival noted in earlier literature (2). The study suggests that 106pre metastasis is not necessarily an “absolute terminal stage”, and some patients can achieve long-term survival with comprehensive treatment, supporting its consideration as an oligometastatic state. The study also has clinical significance: for patients clinically diagnosed with 106pre metastasis, NAC combined with radical resection and lymphadenectomy may still offer benefits. A blanket refusal of surgical opportunity should be avoided. Despite these novel insights, the findings of this study are subject to several key limitations. First, the most prominent issue is the severe imbalance in sample distribution. The pathologically confirmed 106pre-positive group [p106pre(+)] contained only 16 patients, compared to 94 in the negative group [p106pre(−)]. Second, the study is limited by inadequate follow-up depth. The median follow-up time was not reported, and only 3-year survival data were provided. Furthermore, the already mentioned limitation of “insufficient diagnostic accuracy” warrants deeper analysis. The root cause lies in the inherent limitations of contrast-enhanced computed tomography (CT), the primary diagnostic tool used in the study, for assessing mediastinal lymph node metastasis, as it offers suboptimal sensitivity and specificity. This directly led to a high proportion (85.5%) of clinically positive patients being “downstaged” to pathologically negative after surgery.

In the era of modern NAC, although 106pre metastasis indicates widespread progression, some patients can achieve long-term survival (3-year OS 29.9%) through NAC combined with radical surgery. Prognosis depends mainly on ypN3 status rather than the 106pre metastasis itself. These findings support the classification of isolated 106pre metastasis as a form of “oligometastasis”, providing a rationale for local therapy and offering guidance to the conceptual debate within the current esophageal cancer staging system. They strongly suggest that, following effective systemic therapy such as NAC, prognosis may be determined not by the anatomic location of metastases, but by their biological behavior, concretely reflected in the post-treatment residual tumor burden (e.g., ypN3 status). This provides empirical evidence for integrating the more biologically relevant concept of “oligometastasis” into the esophageal cancer staging system. Furthermore, this study also supports, or even strongly advocates for, the use of postoperative ypN stage as a core prognostic stratifier in esophageal cancer. This is based on the finding that ypN3 was the strongest independent prognostic factor, with a hazard ratio substantially higher than other variables. The prognostic significance of ypN3 is also observed in gastric cancer, where its status serves as a predictor of poor outcome (6). Furthermore, the most significant implication of this study is that it challenges the traditional notion that “106pre positivity equals no surgical value”. Under modern comprehensive treatment modalities, long-term survival data from some patients suggest that for cases with radiologically indicated 106pre metastasis, NAC combined with thorough surgical dissection is not futile but may be a key pathway to cure for selected patients. This promotes the development of individualized multimodal therapy, though future efforts should integrate precise staging (e.g., ctDNA) and prospective trials to optimize patient selection, maintaining academic rigor while ensuring clinicians can quickly grasp the key points.

Acknowledgments

None.

Footnote

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

Peer Review File: Available at https://aoe.amegroups.com/article/view/10.21037/aoe-25-24/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aoe.amegroups.com/article/view/10.21037/aoe-25-24/coif). The authors have no conflicts of interest to declare.

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