Extranodal Extension in Esophageal Cancer: Does It Belong in the TNM System?

This article refers to:

Assessing the Prognostic Value of Extranodal Extension in Esophageal Cancer from the Pathological Staging Perspective

We read with great interest the present retrospective study assessing the value of extranodal extension (ENE) in esophageal cancer [1]. According to standard practice, ENE was defined as a disruption of the lymph node capsule due to the metastatic lesion. Nodes with a completely destructed capsule were excluded since it would be challenging to determine whether this was related to tumor invasion, surgical manipulation, or specimen preparation. Although certain groups have attempted to encompass tumor cell emboli, free neoplastic deposits in surrounding structures, and marginal sinus metastases within the spectrum of ENE, these entities do not accurately reflect the true biology of the condition [2,3].

The authors found that ENE constitutes a risk factor for inferior observed and disease-free survival in the setting of pT3 status, pN1 status, and stage III. In subgroup analyses, extranodal extension continued to predict inferior prognosis only in squamous cell carcinomas (SCC). That said, nearly 95% of the cohort had SCC lesions. The incidence of ENE in esophageal adenocarcinomas has been estimated at approximately 40-60% and has also been shown to negatively influence survival [4,5]. In their landmark publication, Luchini et al meta-analyzed 14 studies including 1437 patients with various histological types of esophageal cancer who were followed for an average of nearly 40 months [6]. All-cause mortality (HR = 2.72, 95% CI 2.03 to 3.64), cancer-specific mortality (HR = 1.97, 95% CI 1.41 to 2.75) and relapse (HR = 2.27, 95% CI 1.72 to 2.90) were all significantly greater in the setting of ENE.

This growing body of literature is making a compelling argument toward incorporating ENE in the TNM staging system of esophageal carcinomas. According to the data herein presented in the Journal of Investigative Surgery, the absolute number of affected lymph nodes did not itself affect survival [1]. Therefore, if ENE was incorporated into the TNM staging system, it should be based on its presence in cases with early pN status, rather than the absolute number of lymph nodes with ENE. We also argue that radiologic evaluation of extranodal extension could provide actionable information to multidisciplinary tumor boards debating whether to administer neoadjuvant chemotherapy or chemoradiation to gray zone lesions such as T1b or T2 [7]. Although no esophageal data are available to date, there is extensive experience in oropharyngeal cancers to draw from [8]. For example, when looking at head & neck SCC (HNSCC), the sensitivity and specificity for computed tomography (CT) were nearly 75% and 85%, respectively compared to 60% and 96% for magnetic resonance imaging. On imaging, infiltration of adjacent fatty tissue constitutes a highly specific marker of ENE, while central node necrosis seems to be highly sensitive [9]. Furthermore, a SUV_max cutoff of 3.0 on positron emission tomography-CT seems to identify ENE in HNSCC with specificity and sensitivity of 94.3% and 81.1%, respectively [10]. Similar imaging performance metrics could be reproducible in esophageal cancer. Additional guidance could be provided using endoscopic ultrasound.

Overall, the authors should be commended for their work. Their findings further reinforce the value of extranodal extension in estimating esophageal cancer prognosis. We strongly support the introduction of ENE in a revised TNM classification and feel that accurate radiologic pretreatment detection of ENE could be instrumental in individualizing the care of certain groups of patients.

Disclosure statement

No potential conflict of interest was reported by the author(s).