Tumor location as an indicator of survival in T1 resectable pancreatic ductal adenocarcinoma: a propensity score-matched analysis

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease. It has become the fourth-leading cause of cancer-related deaths and is projected to become the second leading cause of cancer-related deaths in the United States by 2030 [1, 2]. It is refractory to most treatment and exhibits a general 5-year survival rate of 8% [2, 3]. For now, surgical resection is the only potential treatment for PDAC patients [4]. Hence, it is important to assess the extent of tumor progression to determine the suitable surgical procedure. The American Joint Committee on Cancer (AJCC) staging system is the most widely used indicator in malignancies prognosis predictions. In the latest 8th edition of the AJCC staging system, the importance of tumor size for patients’ prognosis is further emphasized in T-staging systems. Resectable PDACs are more likely to have a smaller tumor volume than extensively metastatic tumors, and the selection of appropriate surgical treatment for resectable PDAC, especially T1 tumors, is very urgent.

Different tumor locations have different infiltration periods in blood vessels and the surrounding organs. Due to their anatomical location, pancreatic tumors located in the head and body/tail require very different surgical methods. Several studies suggested that the location of the tumor may have prognostic value for PDAC, but no consensus has been reached [5‐7]. In addition, the 8th edition of the AJCC staging system for PDAC does not consider the impact of the location of the tumor. The aim of our study is to find out the influence of the tumor location on prognosis, and propose modifications for the 8th AJCC T-staging system in PDAC.

In our study, we investigated the prognostic value of tumor location for T1 resectable PDAC patients. The pancreatic head location was associated with the bigger size and had worse survival rates compared with the pancreatic body/tail location. To the best of our knowledge, it is the first indication that the pancreatic head location was an indicator for a bad outcome in T1 resectable PDAC.

The newly-introduced 8th edition of the AJCC staging system highlights the importance of tumor size for T staging systems, and also. In addition, T1 (≤2 cm) patients are a considerable part of the patients who can undergo surgical treatment which is why it is crucial to identify the prognostic factors of these patients. As displayed in Table 2, the year of diagnosis and N stage were well-known prognostic factors. Locations of tumors, which can be evaluated before surgery, have a direct effect on the patients’ prognosis.

For now, the prognostic significance of tumor location in pancreatic cancer is still controversial. Several researches reported that tumors located at the body and tail of the pancreas had higher mortality risks. An explanation for these results is that the timing of diagnosis or lead-time bias may result in the difference between pancreatic head and pancreatic body/tail tumors. Patients with pancreatic head tumors gained additional period from earlier diagnosis, rather than tumor biology or intervention differences [12]. Ling et al. found out that patients with pancreatic body/tail tumors had a higher rate of overall-survival and tumor-free survival [13]. Another study reported that local-stage pancreatic body/tail cancer patients had better survival rates compared with local-stage pancreatic head cancer patients [14]. Pancreatic body and tail tumors, due to the late symptoms, give us a subjective impression that it tends to be more advanced, larger, and worse prognoses for patients [15‐17]. Ruess et al. showed that although the tumor sizes were larger, the prognosis of resectable pancreatic body and tail PDAC patients were similar to that of pancreatic head PDAC [18]. Our result exhibited that pancreatic head PDAC had a bigger tumor size, and in the T1 stage, pancreatic body/tail PDAC patients had better survival rates compared to the pancreatic head group. Several reasons may be a factor of this phenomenon. Firstly, the tumor site is the primary determinant of the surgical approach and different surgical methods have an impact on the patient’s gastrointestinal function which has distinct complications that determined patients’ outcome-especially on short-term survival [19, 20]. Radical antegrade modular pancreatosplenectomy, reported in 2003, may get higher margin-free resection rates which improved the prognosis after distal pancreatic tumor resection [21, 22]. Secondly, according to the Japan Pancreas Society, it is stated that in the nomenclature of peripancreatic lymph nodes, the pancreatic head has a more complex lymphatic drainage system compared with the distal pancreas, and the extent of lymphadenectomy during pancreatectomy for pancreatic head PDAC is still disputed [23, 24]. Several studies also showed that pancreatic body/tail tumors have less frequent nodal involvement, which could explain the better outcome of these patients [25, 26]. In our results after the propensity score matching, two groups had similar number of positive lymph nodes and lymph nodes positive rate. The survival between groups were still different, which showed that the impact of location cannot be ignored. The pancreatic head is adjacent to many important organs and blood vessels. Compared with the resection of pancreatic head tumors which have a greater impact on important structures, multivisceral resection of the distal pancreatic tumor is safer and more feasible [27‐29]. What’s more, pancreatic head PDAC can lead to the malignant biliary obstruction and complications after preoperative biliary drainage which cause the delay or even omission of surgery [30]. Hyoun et al. reported that tumors in proximal locations, although smaller in size, were more dedifferentiated than distal tumors which resulted in poor prognosis [26]. Ling et al. reported that pancreatic body/tail PDAC had remarkably lower expressions of miR-501-3p compared with the pancreatic head one. The in vivo and in vitro experiments proved that miR-501-3p could enhance the invasiveness of PDAC cells and resulted in tumor recurrence [13]. Another Study also showed that pancreatic head and pancreatic body/tail PDAC had distinct genetic and molecular features [31].We also improved the subcategories of T1 staging according to the tumor locations. The modified T-staging system exhibited good patient survival stratification for it had better prognosis-discrimination effect than the 8th AJCC staging system. The significance of AJCC staging system is to accurately stratify the patients’ prognosis. Therefore, we proposed the subgroups of T1 according to the tumor locations to promote the precision of AJCC staging system. Compared with the current AJCC 8th edition system, our modified T-staging and corresponding TNM staging system effectively separated the survival curves between stages, especially for the differentiation of short-term survival of patients. There are some advantages of this modified staging system. From a clinical point of view, the determination of tumor location is relatively easy and has more operability in clinical practice. Moreover, the majority of patients are diagnosed at an advanced stage [32, 33], and patients with < 1 cm tumors account for a very small proportion of total patients which can also be observed in our cohort. Hence, the size-based sub-stage of T1 may not be practical in clinical work.

There are also some limitations of this study: 1) only selected SEER cohort; 2) lacked a validation group; 3) only selected resectable PDAC which occurred in the head and the body/tail of the pancreas (excluding patients with PDAC in the pancreatic neck, overlapping lesion of pancreas and other unclear locations); 4) lacked small-sized tumor patients; 5) Multi-center prospective study needed to be applied for further studies; 6) The SEER database was only able to provide basic clinical information hence our research lacked the exploration of further biological mechanisms.

Tumor location is a predictor of resectable ≤2 cm PDAC. Modification of T1 sub stage according to tumor location is accurate and effective in prognostic prediction of PDAC.