Esophageal cancer (EC) is a devastating disease with an increasing incidence worldwide, especially in the Western white population (1, 2). Surgery with or without radiotherapy and/or chemotherapy remains the treatment of choice for resectable EC. Nonetheless, even after en-bloc resection of the tumor, the loco-regional recurrence rates of EC are reported to be as high as 52% (3, 4). The TNM staging of EC defined by the American Joint Committee on Cancer (AJCC) is widely used for prognostication and therapeutic decision-making. In addition, various criteria have been suggested as independent prognostic factors after resection, including tumor size (5–8), tumor grade (6, 8), nodal involvement, lymph node ratio (9–13), and degree of tumor regression after neoadjuvant therapy (14).

The significance of the circumferential radial margin (CRM) status in EC has gained attention after the discovery of the association between CRM positivity and the incidence of local recurrence in colorectal and pancreatic cancer (15–17). Sagar et al. (18) first described the role of CRM in EC, showing that CRM involvement is associated with an increased risk of local recurrence. Further studies by the same group also showed that the presence of malignant cells within 1 mm of the CRM reduces median survival (19). Currently, there are two definitions of CRM involvement commonly used in clinical practice. The Royal College of Pathologists (RCP) defines a positive CRM as a tumor at or within 1 mm of the cut margin (20), whereas the College of American Pathologists (CAP) considers only the presence of a tumor at the cut margin as CRM-positive (21).

Neoadjuvant concurrent chemoradiotherapy (CCRT) before esophagectomy has been shown to improve R0 resection local control and survival compared to surgery alone (22) and is accepted as a standard of care for patients with locally advanced disease. However, the role and definition of CRM positivity after CCRT and esophagectomy remain unclear in the literature.

The purpose of the present study was to investigate the significance of CRM status in patients with EC undergoing esophagectomy after neoadjuvant CCRT and to examine the prognostic impact of CRM status according to the RCP and CAP criteria for overall and disease-free survival.

A total of 299 patients with EC were enrolled in the current study. There were 102 (34.1%) and 40 (13.3%) patients with a positive CRM according to the RCP and CAP criteria, respectively. Patient and disease characteristics are summarized in Table 1 .

The survival impact of each clinical and pathological variable in the univariate analysis is shown in Table 2 . Among patients with a positive CRM as defined by the RCP and CAP criteria, significantly more patients had an advanced T and N staging status and underwent adjuvant chemoradiation than among those with a negative CRM (P < 0.05). The presence of T3 disease and lymph node metastasis increased the risk of mortality and disease progression (P = 0.001 for OS and T3 status, and P < 0.005 for other variables both in OS and PFS).

The risk of mortality and disease progression was higher in patients with CAP-defined CRM positivity, with HRs of 4.45 (2.90-6.82; P = 0.001) and 2.89 (2.57-5.88; P = 0.001) for OS and PFS, respectively. The survival disadvantage of RCP-defined CRM positivity was also significant, with HRs of 2.93 (2.90-4.10; P = 0.001) and 2.73 (1.99-3.75; P = 0.001) for OS and PFS, respectively. Table 3 shows the multivariate analysis for patient survival.

In addition to T and N staging, the presence of a CAP-defined positive CRM strongly disadvantaged survival, with HRs of 2.82 (1.70-4.66; P < 0.001) and 2.36 (1.44-3.87; P = 0.001) for OS and PFS, respectively. When the CRM was defined by the RCP criteria, the difference became insignificant with HRs of 1.62 (0.95-2.78; P = 0.078) and 1.46 (0.89-2.40; P = 0.135) for OS and PFS, respectively ( Supplementary Table 1 ). Figure 1 shows the survival curves according to CRM status based on the CAP criteria, with CRM positivity correlating with significantly lower OS and PFS (adjusted P < 0.05).

When we further classified the patients into three groups with circumferential margin uninvolvement, less than 1 mm, and involvement the significant survival difference persisted only between the patients with and without CRM involvement, although the survival curve of patients with a clear CRM of less than 1 mm was between the above-mentioned two groups of patients. Table 4 shows the results of the multivariate analysis, which includes the CRM status classified as CRM negativity, a clear CRM of less than 1 mm, and CRM involvement. Patients with CRM involvement showed significantly lower chances of survival, with adjusted HRs of 3.35 (1.73-6.48; P < 0.001) and 2.63 (1.42-4.86, P = 0.002) for OS and PFS respectively. This correlation was not seen in patients with a clear CRM of less than 1 mm, with adjusted HRs of 1.62 (0.95-2.78; P = 0.078) and 1.46 (0.89-2.40; P = 0.135) for OS and PFS, respectively.

Thus far, the literature has been contradictory on the significance of CRM status after esophagectomy, a fact largely attributed to the heterogeneity of the study populations (25). In addition, the different pathologic classification systems (RCP and CAP criteria) also make the prognostic effect of CRM difficult to evaluate (20, 21). Our study demonstrates that a CAP-defined positive CRM is a strong prognostic factor for patients with EC undergoing CCRT followed by radical esophagectomy and three-field lymph node dissection. However, although a similar trend was observed for RCP-defined CRM positivity in the multivariate analysis, it did not reach statistical significance.

The first study on CRM status in EC was published by Sagar et al. in 1993 (18), showing a possible association between a higher local recurrence rate and CRM involvement. In 2001, Dexter et al. (19) reported the first large-scale study on the impact of CRM involvement on the OS of 135 patients with EC. A meta-analysis by Wu et al. (26) found that the results of these studies were influenced by the heterogeneity of the patient populations, including varying T staging and the use of neoadjuvant therapy. A subgroup analysis by Khan et al. showed that CRM involvement yielded a statistically significant survival disadvantage only in T3 tumors (6). A later study by Griffiths et al. (27) revealed that the CRM status affects prognosis in patients with a low ratio of involved metastatic lymph nodes, whereas it is not a prognosticating factor in patients with a high metastatic lymph node ratio. The role of CRM status is also influenced by neoadjuvant therapy. As the above-mentioned study by Khan etal, the prognosticating significane of CRM for T3 disease was less evident once the patient received neoadjuvant chemoradiation (6). However, Shah et al. (28) reported that CRM involvement is an independent prognostic factor after deoadjuvant chemotherapy. Chao et al. (29) also reported an association between CRM status and local recurrence and survival rates in patients with ypT3 disease status after neoadjuvant CCRT.

Neoadjuvant CCRT has been adopted as a standard of care for improving the survival of patients with surgically treated locally advanced EC (22). The presence of a positive CRM after neoadjuvant therapy, especially after CCRT, represents poor response to neoadjuvant therapy and failure of complete surgical resection, leading to poor survival outcomes. However, CRM positivity, as defined by the RCP criteria, has previously been demonstrated to be 36 to 55% (18, 19, 28).

Three-field radical lymph node dissection with a mean of 41 dissected lymph nodes was performed. The association between CRM positivity and lymph node metastasis was significant in our patients. After adjusting for T and N staging status, CAP-defined CRM positivity remained a significant prognosticating factor, in contrast with RCP-defined CRM positivity. Furthermore, when patients were classified into three groups, that is, those with a clear CRM, those with a clear CRM of less than 1 mm, and those with CRM involvement, a significant survival difference was observed only between patients with and without CRM involvement. These results were compatible with the findings of Brac et al., indicating that CAP-defined CRM positivity was a significant prognostic factor for OS and PFS in patients receiving upfront esophagectomy without neoadjuvant therapy (30). Similarly, Depypere et al. reported that CAP-defined CRM positivity can precisely predict the OS and PFS in patients with ypT3 tumors after neoadjuvant CCRT and esophagectomy (31). Histologically, most of these patients had adenocarcinoma (118/163, 72.4%), and two-field lymph node dissection was performed. In contrast, all our patients had squamous cell carcinoma and underwent three-field lymph node dissection during esophagectomy following neoadjuvant CCRT.

After adjusting for other significant prognostic factors, including T and N staging, CAP-defined CRM positivity remained prognostic for the entire patient population in our study. The prognostic value of CRM involvement is, therefore, greater after radical lymph node dissection and neoadjuvant chemoradiation (32). Adjuvant therapy might therefore be prescribed on the basis of CAP-defined CRM positivity rather than the RCP criteria. What is new in our work compared to the present literature is that, in addition to pathological T and N staging of the tumor, only CAP-defined CRM positivity was a significant prognostic factor with adjusted hazard ratios of 2.64 (1.56-4.46) and 2.25 (1.34-3.78) for overall and progression-free survival, respectively (P < 0.001).

Recently, a global prospective randomized trial, CheckMate 577, demonstrated that the use of nivolumab, an adjuvant immune-checkpoint inhibitor, improves the PFS of patients with EC after neoadjuvant chemoradiation and complete esophagectomy (R0 resection) (33). It must urgently be determined whether this strategy provides a survival advantage even in CRM-positive patients, where the prognosis is poor.

This was a large cohort study conducted by a single surgical team on patients with squamous cell carcinoma after neoadjuvant chemoradiation with long-term follow-up. However, this study is limited by potential selection bias, varying surgical treatment methods, and the neoadjuvant protocol used. Further studies are required to determine whether these findings can be applied to patients with other tumor cell types, two-field lymph node dissection, and after neoadjuvant chemotherapy or immunotherapy.

The CRM status, defined by CAP criteria, plays a vital role in OS and PFS in patients with EC after neoadjuvant CCRT and radical esophagectomy. Further adjuvant treatment may improve the currently poor survival outcomes of patients with CAP-defined CRM involvement after neoadjuvant CCRT and esophagectomy.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by the Research Ethics Committee review board of the Taiwan University Hospital (202202085RINA). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

AP wrote the first draft of the manuscript. K-CC, S-WK, M-WL, H-CL, P-MH, Y-HL, H-PW, M-LH, C-HC, C-HH, T-CH, F-MH and S-LL collected data, reviewed and edited. J-ML contributed to design of the study and edit. All authors contributed to the article and approved the submitted version.