Esophageal cancer is one of the most aggressive cancers worldwide, and its incidence rate has increased significantly in recent years [1, 2]. As the dominant type of esophageal cancer in China, esophageal squamous cell carcinoma (ESCC) has a generally poor prognosis due to the lack of effective clinical methods for its early detection. Recently, improvements in diagnostic modalities and the development of a combination treatment of surgery, radiation and chemotherapy have improved the outcomes for this cancer [3]. Despite these advances, the prognosis in patients with ESCC remains poor, with an overall 5-year survival of 15-34% [4, 5]. Given the poor prognosis of ESCC and its high incidence, it is increasingly important to understand the initiation and progression of ESCC and to identify the prognostic factors most associated with it.

An appropriate risk-stratified selection for adjuvant treatment trials is paramount, considering the high cost and toxic side effects of chemotherapeutic drugs. A variety of prognostic characteristics, including tumor location, size, differentiation, infiltration depth, lymph node involvement and distant metastasis, have been proposed as relevant factors for predicting the outcomes of patients with ESCC [6]. These characteristics have been incorporated into a proposed prognostic monogram designed to predict patients’ survival [7]. Although the currently proposed TNM system shows conformable prognostic accuracy, a demand remains for increasing the accuracy of the existing system for predicting outcomes.

Perineural invasion (PNI) involves cancer cells surrounding nerve fibers and entering the perineurium, spreading local infiltration and metastasis [8]. Cancer cells found in the perineurium are indicative of neural invasion [9]. PNI is regarded as a prominent characteristic of ESCC, as PNI is frequently observed in ESCC [10]. The PNI status has been found to be significantly correlated with poor survival in ESCC patients, as evidenced by univariate analysis [11]. However, Ochiai et al. reported that PNI was not a significant prognostic parameter in esophageal cancer [12]. Moreover, PNI in N0 esophageal cancer was found to have no association with cancer-specific survival following curative esophagectomy in a univariate statistical analysis [13]. Although PNI has been investigated in both esophageal SCC and adenocarcinoma, its incidence and prognostic value based on ESCC in high prevalence in a region, with a focus on PNI, has not been clarified. To address these issues, we employed a large cohort of patients with ESCC in a region in where it has a high prevalence to determine the association between PNI status and clinical outcomes.

PNI is the process of neoplastic invasion of the nerves, and it is also an important pathway by which tumor’s progress and spread to the adjacent tissues or organs. It is commonly detected in human cancers of the pancreas and biliary tract [16–18]. It has been found to be a crucial route for the local spread of tumors that are associated with poor outcomes in various types of human cancers. However, the role of PNI status in ESCC and its utility to clinicians continue to be debated. In our study, we assessed a retrospective collection of data to determine the prognostic value of PNI for the survival of patients with ESCC who underwent curative esophagectomies. Moreover, our particular interest is in determining the potential effects of PNI in node-negative ESCC patients.

Our results demonstrated that the presence of PNI was observed in 47.7% of patients with ESCC as evaluated on H&E-stained slides. However, less than 30% of the PNI-positive tumors were detected in esophageal cancer (including SCC and adenocarcinoma) in previous studies [10, 12]. Differences in the histological types and PNI definitions may contribute to this discrepancy. In the current study, we utilized a broader definition inclusive of both of the circumstances: cancer cells surrounding at least one-third of the nerve without invading through the nerve sheath, as well as tumor cells within any of the 3 layers of the nerve sheath [19–22]. Furthermore, the increased detection rate observed in our study is most likely because the pathologic analysis was performed by pathologists with expertise in PNI who were blinded to the follow-up data in this study. Consistent with our study, PNI has been recognized in many series as a prevalent pathological characteristic of gastric cancer and is reported in up to 73% of this tumor at the time of resection [23]. PNI rates were much higher in pancreatic cancer (70-100%) and in biliary tract cancer (75-85%) [16, 24]. Our findings suggest that PNI is a common pathologic feature of ESCCs removed by radical esophagectomy.

A further correlation analysis revealed that the presence of PNI in ESCCs was significantly associated with tumor differentiation, infiltrate depth, pN status and stage. Studies in other cancers have led to similar conclusions. For instance, Ochiai et al. reported that the presence of PNI in esophageal cancer was closely correlated with the depth of invasion [12]. Liebig et al. found that PNI was associated with a more advanced stage and poor tumor differentiation in colorectal cancer [20]. Previous studies also showed that evidence of PNI on a prostate needle biopsy is predictive of a higher T stage and extracapsular invasion at resection [25, 26]. Furthermore, the presence of PNI was found to be correlated with tumor size, margin status, lymph node metastasis and AJCC stage in patients with pancreatic ductal adenocarcinoma [14]. Taken together, these data suggest that PNI plays an important role in the development and/or progression of human cancers.

Our findings of the PNI status and its correlation with ESCC patients’ outcomes are consistent with the results of other groups. In 1999, Torres et al. showed a significant association between the presence of PNI and the poor survival of patients with ESCC as evidenced by a univariate analysis [11]. Other groups have reported similar results [27–29], in which PNI was a significant pathologic parameter in head and neck cancers, heralding decreased survival, increased locoregional recurrence rates and a shorter time to relapse. In a more recent study, Liegig et al. suggested that PNI is correlated with decreased survival on a multivariate analysis and established that PNI is an independent predictor of outcomes in colorectal cancer patients [20]. Importantly, PNI in pT3N0 rectal cancer is also found to be an independent risk predictor of a local recurrence [30]. Notably, other published reports show no significant prognostic value for PNI to predict the outcomes in patients with esophageal squamous cell carcinoma and adenocarcinoma [12, 13]. Taken together, differences in the clinicopathologic characteristics among cohorts, geographic backgrounds, definition of PNI, patient heterogeneity, small sample sizes and different definitions of end points (disease-free, cancer specific or overall survival) may contribute to the controversial results. In our study, the findings of a significant association between the PNI status and clinical outcome in esophageal cancer may be strengthened by the single histological type and large sample size.

Generally, our results support the idea that the presence of PNI may improve the ability to discriminate among ESCC patients’ outcomes, especially for patients who are node-negative. It is well known that the pTNM stage and tumor differentiation are the best-established risk predictors for important aspects affecting the outcomes of patients with ESCC. These two variables, based on specific clinicopathologic features and the extent of the disease, may have reached their limits in providing critical information influencing patient prognosis and treatment strategies at the pN0 stage. Moreover, the outcomes of patients with the same stages following surgery are substantially different, and such large discrepancies have not been well understood [31, 32]. Thus, there is a need for new objective strategies that can more effectively distinguish between patients with favorable and unfavorable outcomes. In the present study, our data support the concept that PNI, as detected by H&E staining, can identify ESCC patients with or without an aggressive clinical course and/or poor outcome at the pN0 stage. Thus, the evaluation of PNI may become a factor for predicting the prognosis and rendering a more tailored treatment strategy in patients with ESCC.

The retrospective nature of this study may be considered its major limitation, and it may have influenced these results. However, the study was strengthened by the fact that all of the histopathological slides were re-evaluated by the same gastrointestinal pathologists. Although our findings should be confirmed by prospective studies, we believe that our results contribute to the literature because it includes only patients with ESCC. To our knowledge, this is the first report to investigate the prognostic ability of PNI in an area of high ESCC prevalence; however, further external validation of our findings using pooled multicenter data is needed.

In conclusion, the presence of PNI was a strong and independent predictor of a poor outcome, as indicated by the univariate and multivariate analyses. Adding the PNI model could improve the ability to discriminate ESCC patients’ outcomes. Our data suggest that PNI could function as an independent prognostic factor of outcomes in ESCC and support the consideration of the PNI status in primary ESCC specimens for therapy stratification. In particular, we advocate for the consideration of node-negative ESCC patients who are PNI positive for treatment with the effective adjuvant therapies that are currently available.