Lymph node status is a powerful prognostic factor in patients with pancreatic head cancer after resection as lymph node invasion occurs in a high percentage of these patients indicating poor survival (16–19). Therefore, lymphadenectomy has been recognized as an important and fundamental step during PD. A growing body of evidence shows local recurrence after conventional PD results from incomplete clearance of the lymph nodes suggesting extended lymphadenectomy may improve survival outcomes theoretically. For example, the survival rates after extended lymphadenectomy were reported to be greatly enhanced compared with those after standard lymphadenectomy (7, 20–22). However, recent studies found that extended resection did not have survival advantages over standard resection (8, 23–25). Consequently, it is uncertain whether extended lymphadenectomy is superior to standard lymphadenectomy in PD.
In our study, we found extended lymphadenectomy did not improve the survival in all patients with pancreatic head cancer but to cause an increase in the difficulty of surgery (prolonged operating time) as well as in the postoperative complication (high incidence of diarrhea) due to its nature. Accordingly, the number of harvested lymph nodes was larger after extended lymphadenectomy. When we further analyzed the data merely from the subgroup of patients with resectable disease, there were no difference in survival rates between extended lymphadenectomy and standard lymphadenectomy. Therefore, comparison of the number of metastatic lymph nodes did not favor extended lymphadenectomy in patients with resectable disease.
In contrast, distinguished results with respect to the survival rates were observed in patients with BRPHC. Extended lymphadenectomy improved the disease-free survival and the overall survival greatly in patients with BRPHC compared with standard lymphadenectomy. BRPHC, an intermediate stage between resectable and unresectable disease, invades the mesenteric-portal or arterial axis (26). In case of superior mesenteric-portal vein involvement, venous resection and reconstruction during pancreaticoduodenectomy (PD) can contribute to long-term survival of these patients (27, 28). There has been increasing evidence indicating that patients with BRPHC could reach the survival similar to patients with resectable disease following surgery (29–31). However, few studies are reported concerning lymphadenectomy in patients with BRPHC. Actually, the reasonable extent of surgery is based on the range of lymph node invasion. The number of metastatic lymph nodes increased greatly in addition to the number of total lymph nodes in this study, which meant patients with BRPHC might have a wide range of lymph node invasion. Therefore, extended lymphadenectomy might benefit these selected patients. Since vascular resection and reconstruction can significantly affect the process, operating time was similar between the subgroups.
Currently, the risk factors for extensive lymph node metastasis remain limited. In this study, we determined large tumor size, poor tumor differentiation and BRPHC were the independent predictors favoring extended lymphadenectomy. Tumor size has been repeatedly reported to be a crucial prognostic factor for patients with pancreatic cancer (32–36), in relation to positive peritoneal lavage cytology (37) and recurrence (38, 39). It is thought that cells within the tumor usually acquire mutations, and finally, a sub-clone that is capable of lymph node metastasis may evolve as the primary tumor grows. Feng et ai reported NEAT1 could promote PC cell proliferation and metastasis both in vitro and in vivo associating with tumor size and lymph node (40). Oshima et al found mutations in KRAS, p53 and SMAD4 were significantly associated with tumor size and lymph node metastasis (41). It is possible the extent of lymph node metastases tends to increase with tumor size (42, 43).
Another expected risk factor for extensive lymph node metastasis was the poor tumor differentiation which influenced the clinical outcome of patients. In essence, poor degree of tumor differentiation reflects rapid tumor progression (44), whereas there are rich lymphatic networks around the pancreas including the internal pancreatic lymphatics, extrapancreatic lymphatics and peripancreatic lymphatics, which make lymph node metastasis easier. Actually, differentiation of tumor cells is controlled by complex regulatory networks, which can be explained with molecular mechnism of pancreatic cancer differentiation. Xie et al reported dysregulated KLF4 expression associated with poor differentiation of pancreatic cancer (45). Milan et al determined FOXA2 regulated well- and poorly differentiated pancreatic ductal adenocarcinoma cells via interactions with transcription factors (46). Liang et al found patients with poor tumor differentiation had higher MAP4K4 expression, and consequently increased number of positive lymph nodes (47). All these data support a positive association between lymph node metastasis and poor tumor differentiation.
As borderline resectability is noted as a high risk for a margin-positive status in patients with BRPHC vascular resection and reconstruction is usually required in these patients. Nevertheless, the survival still decreases with the severity of vascular involvement (25). Surprisingly, the disease-free survival and the overall survival improved in patients with BRPHC undergoing extended lymphadenectomy in our study due to a wide range of lymph node invasion. There are two possible reasons for this phenomenon. On one hand, the superior mesenteric-portal vein invasion might occur in patients with higher rates of poor tumor differentiation (48) as well as in patients with a larger tumor size (49, 50), which was also confirmed in our study; on the other hand, invasions of the plexuses around the arteries are the main causes of local recurrence after resection in these patients (51). All these suggest a higher rate of lymph node metastasis. Nevertheless, local tumor control by extended lymphadenectomy cannot overcome the negative aspects of pre-existing lymph node metastasis as well as superior mesenteric-portal vein involvement, which might explain why patients with BRPHC still have lower survival rates.
Taken together, we found that patients with BRPHC tended to have vast lymph node metastasis compared with patients with resectable disease. Extensive surgery for pancreatic carcinoma should be entertained in selected patients as it can improve their long-term survival.
The main limitation of this study is that it represented the experience of a single center. The number of patients in each subgroup is relatively small, which may limit the accuracy of our assessment. Future studies, preferably random clinical trials from multi-centers, are needed to further confirm our preliminary outcomes.