Pancreatic cancer is one of the most aggressive human tumors. Complete surgical resection is the only known curable way for pancreatic cancer, but even patients who have undergone successful surgery often die of the disease due to metastases or relapses, which can be partly attributed to nerve invasion. Peripheral nerve invasion can be attributed to different mechanisms, and to date, three theories have been proposed to explain this finding. (i) Jin et al. identified lymphatic vessels in the superior mesenteric artery peripheral nerve plexus by immunohistochemical staining, providing factual evidence for the theory that tumor cell infiltration in neurogenic PNI was transmitted through lymphatic channels . (ii) The "low resistance theory" proposed in the 1930s identified three weak points in the fascialis—the nerve endings, the blood vessels entering the nerve, and the reticular fibers entering the nerve—and suggested that cancer cells could easily invade and grow along the interfascialis space . (iii) In 1994, Dale Bockman et al. observed high expression levels of transforming growth factor α (TGF-α) in nerve cells and high expression levels of epidermal growth factor receptor (EGFR) in cancer cells by electron microscopy, indicating the possibility of interactions between tumor cells and nerves . Subsequently, numerous basic experiments gradually led to the theory of the neural microenvironment. This theory proposed that cells stimulated by cancer cells in the microenvironment could influence the occurrence of PNI-related processes through autocrine or paracrine mechanisms [14–16]. For example, pancreatic cancer releases colony-stimulating factor (CSF-1) to recruit macrophages, and cancer cells stimulate macrophages to secrete glial cell-derived neurotrophic factor (GDNF) to enhance the invasive ability of cancerous cells .
Pancreatic cancer with nerve invasion has been reported to significantly reduce progression-free survival and overall survival. Recent imaging studies focusing on preoperative determination of nerve invasion in pancreatic head cancer have confirmed the accuracy of MSCT in the diagnosis of EPNI and its effect on prognosis [18–22]. However, even in pancreatic head cancer with nerve invasion, individual patients show distinct differences in prognoses. Therefore, the present study attempted to further investigate the invasion of different pathways of the nerve plexus by pancreatic head cancer.
Although the surgical methods for Whipple surgery have continued to improve over decades of development, screening patients who are eligible for resection is more important to ensure greater patient benefits in the long run. Some scholars have proposed that surgical treatment is not recommended for patients who have been preoperatively diagnosed with EPNI/duodenal invasion of pancreatic cancer. However, since the peripheral nerve plexus invasion rate of pancreatic cancer can be as high as 53%-100% [23, 24], categorization of all patients with peripheral nerve invasion as unresectable may deprive some patients of the opportunity to undergo essential surgery. Therefore, we tried to group pancreatic head cancers involving different nerve plexuses on the basis of the findings of preoperative MSCT examinations, and preliminarily investigated the differences in prognosis among these groups to provide a theoretical basis for the subsequent exploration of treatment options for different groups.
From the embryological point of view, the pancreas originates from the ventral and dorsal pancreatic primordia, and a single pancreas is formed through the development and fusion of both primordia. The ventral pancreatic primordium forms the dorsal part of the head of the pancreas and the uncinate process of the pancreas, while the dorsal pancreatic primordium gradually develops into the ventral part of the head of the pancreas as well as the neck, body, and tail of the pancreas. The boundary between the ventral and dorsal pancreas, i.e., the line connecting the portal/superior mesenteric vein and the anterior edge of the intrapancreatic bile duct, can be roughly defined on CT images (Fig. 4). The ventral pancreas lies on the dorsal side of this boundary, while the dorsal pancreas occupies the ventral region [25, 26]. Pancreatic head cancer originating from the dorsal pancreas often invades the anterior nerve pathway. In contrast, pancreatic head cancer originating from the ventral pancreas often shows cancer cells invading PLX1, PLX2, and ROM. In addition, since the three pathways of nerve plexuses cross at the uncinate process of the pancreas and are located close to each other, pancreatic head cancers are prone to multi-pathway invasion of these nerve plexuses. On the basis of the differences in the anatomical locations of the four pathways of nerve plexus and the growth locations of pancreatic head cancer, this study divided pancreatic head cancers invading different pathways of the nerve plexus into two groups: pancreatic head cancers that invaded AN (group A), and those that invaded PLX1, PLX2, and ROM (group B).
Wang et al  found that the clinicopathological features of pancreatic head cancer arising from dorsal or ventral pancreas were different. The frequencies of some regional lymph node metastasis were different too. Tumors arising from dorsal pancreas were more likely to invade the common bile duct and duodenum than the others. Finally, their findings indicated that the pancreatic head cancer arising from ventral pancreas had a better survival outcome, which is consistent with our results. The weakness of their study  is that it is often difficult to accurately classify the primary tumor location on preoperative CT imaging, and some patients could not be grouped. Differently, we speculate that it is feasible to divide the pancreatic head cancer into anterior and posterior groups according to the preoperative CT diagnosis of nerve invasion. Our study preliminarily confirmed the difference in prognosis between the two groups: group A, pancreatic head cancer anteriorly invading AN, showed worse prognosis than group B, pancreatic head cancer posteriorly invading PLX1/ PLX2/ROM.
The limitations of this study need to be acknowledged. First, this was a retrospective study, and the prognosis of patients with pancreatic head cancer with nerve plexus invasion in different groups still needs to be confirmed by further prospective studies. Second, the small sample size precluded adequate stratified studies. Third, traditional observation indicators such as lymph node invasion and surgical margin were not included in the evaluation criteria, because these indicators need to be confirmed by postoperative pathology and cannot be accurately diagnosed by preoperative CT. Fourthly, multivariate analysis of factors affecting postoperative survival of pancreatic head cancer was not conducted in this study, because EPNI is an independent prognostic factor affecting postoperative survival time of pancreatic head cancer.