Retrospective Study of the Correlation Between Pathological Tumor Size and Survival After Curative Resection of T3 Pancreatic Adenocarcinoma: Proposal for Reclassification of the Tumor Extending Beyond the Pancreas Based on Tumor Size

Pancreatic adenocarcinoma is the most lethal common cancer and the eighth leading cause of cancer-related death in men and the ninth leading cause of death in women throughout the world [1]. It has a very poor prognosis, with a 1-year survival rate of 25% and 5-year survival rate of 5%. Surgical resection is the only potential curative therapy for the tumor; however, only 15–20% of patients are considered to be candidates for resection because of an advanced stage at the time of diagnosis [2]. Many previous studies on the outcomes after curative resection of pancreatic adenocarcinoma have revealed that tumor size is an independent prognostic factor, along with lymph node metastasis and the surgical margin after curative resection of the tumor [3‐13]. In the current TNM classification of the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC), tumors limited to the pancreas are divided into T1 and T2 by tumor size (2 cm). On the other hand, there is no classification for tumor sizes extending beyond the pancreas (T3 and T4), despite the fact that most pancreatic adenocarcinomas that are resected are pathologically staged to T3 after surgery [14, 15].

In the present study, we reviewed all data from patients with pancreatic adenocarcinoma who had undergone pancreatectomy with curative intent to calculate tumor size cutoff values (Tco values) for tumors extending beyond the pancreas. We developed a modified TNM classification that incorporated the Tco values for T3 disease and statistically evaluated the usefulness of our proposed new TNM classification.

Data were collected for a total of 1451 consecutive patients with pancreatic adenocarcinomas who underwent pancreatectomy with curative intent between 2001 and 2012 at seven high-volume surgical institutions in Japan (Tokyo Metropolitan Komagome Hospital, Hiroshima University Hospital, Nara Medical University Hospital, Tohoku University Hospital, Kansai Medical University Hospital, Kobe University Hospital, and Wakayama Medical University Hospital). All patients underwent R0 or R1 pancreatectomy and had a confirmed pathological diagnosis. Of the 1451 patients, we excluded 37 patients with initially unresectable tumors who received pancreatectomy after chemotherapy or chemoradiotherapy, 14 patients with mucinous carcinoma, 13 patients with anaplastic carcinoma, and 257 patients whose pathological tumor size was not recorded. In addition, 283 patients with resectable or borderline resectable tumors who received neoadjuvant therapy were excluded because it was considered difficult to accurately measure tumor size due to the effect of such treatment. The remaining 847 patients were reviewed in this study (Fig. 1). In each patient, pathological TNM classification was performed according to the TNM classification of malignant tumors published by the UICC (7th edition). The longest dimension measured by histopathological examination was defined as the tumor size. Tumor resectability was classified according to the National Comprehensive Cancer Network (NCCN) guideline [16]. Overall survival was defined as the interval from the date of surgery to the last follow-up date or death. Statistical analyses were performed using EZR, which is a graphical user interface for R version 2.13.0 (R Foundation for Statistical Computing, Vienna, Austria) [17], and differences were considered significant at P < 0.05. The ethics review board of each participating hospital approved this study.

Many previous studies have found that tumor size was an independent prognostic factor for pancreatic adenocarcinomas, but the Tco value used to evaluate the significance of tumor size has varied among them. Based on a Tco value of 3 cm, Yeo et al. [3], Benassai et al. [8], and Winter et al. [13] reported that tumor size was an independent prognostic factor in pancreatoduodenectomy patients. Moon et al. [10] also employed 3 cm in a study that identified tumor size as an independent prognostic factor in patients who had undergone resection of pancreatic adenocarcinoma by any mode of pancreatectomy. However, Geer et al. [11] and Lim et al. [9] employed 2.5 cm and 2 cm as the Tco values, respectively, in studies of patients who underwent R0/1 pancreatectomy, while Meyer et al. [12] employed 2 cm as the Tco value to evaluate patients undergoing R0 pancreatectomy. All these studies showed that tumor size was an independent prognostic factor after resection of a pancreatic adenocarcinoma. Thus, a range from 2 to 3 cm has been employed as the Tco value in previous studies. Of these studies, only two described the stage distribution of the patients. In the study of Meyer et al. [12], 10.8% of the patients were in stages IA or IB versus only 4.3% in the study of Moon et al. [11]. In the former study, which recruited a higher percentage of patients with tumors limited to the pancreas, the Tco value was set at 2 cm, while it was 3 cm in latter study. However, the rationale for setting the Tco value was not explained in most of the previous reports. In a few studies, significant differences of survival were found by comparing different candidate Tco values set at regular intervals, and the Tco value with the lowest P value was selected [3, 9, 11]. However, none of the previous studies employed ROC analysis to determine the Tco value as we did this time. ROC curves can be used to statistically detect the optimum Tco value without researcher bias, which is considered to be an advantage of the present study.

In this study, multivariate analysis revealed that tumor size was the most significant independent prognostic factor for patients with tumors limited to the pancreas, but the Tco value distinguishing T1 and T2 was the same as in the current TNM classification, and there was no significant difference in overall survival between stages IA and IB. Because of the small number of patients with tumors limited to the pancreas in this study, it was difficult to assess the correlation of tumor size with their prognosis. Among patients with tumors extending beyond the pancreas, the preoperative serum level of CA19-9 was significantly higher in new stage IIB than new stage IIA. This finding corresponded to previous reports that a high preoperative serum level of CA19-9 is a significant adverse prognostic factor [19, 20]. In addition, the proportion of patients with borderline resectable tumors was significantly larger in new stage IIB than IIA, indicating that tumor size is strongly related to tumor invasion of the main arterial trunks (celiac axis and/or superior mesenteric artery) [21]. These results provide support for our proposed new TNM classification.

Many studies have found that N category status is a significant independent prognostic factor [3, 8, 9, 11, 12], although there have been a few exceptions [7, 10]. The N category status was a significant independent prognostic factor for patients who underwent R0/1 pancreatectomy in this study as well. Therefore, the current stage IIB (T1-3N1M0) was defined as the proposed new stage IIC (T1-3bN1M0), basically maintaining the composition of all three categories. The resulting new TNM classification was considered to be useful because there was a significant difference of survival between stages IIA and IIB as well as between stages IIB and IIC.

According to the NCCN guidelines of 2015, preoperative staging laparoscopy is recommended for high-risk patients (borderline resectable disease, markedly elevated CA19-9, large primary tumors, or large regional lymph nodes) [22]. Since CA19-9 > 150 U/mL and tumor size > 3 cm are considered as surrogate markers for preoperative staging laparoscopy, we insist on the necessity of performing preoperative staging laparoscopy to the patients with our new stage IIB or higher to check for unresectability prior to the surgery [23].

In conclusion, the proposed new TNM classification of pancreatic cancer developed in this study reflects tumor size, which is an important prognostic factor in patients with tumors extending beyond the pancreas (current T3), and they form the largest group undergoing pancreatectomy. The present results require validation by a large-scale study employing ROC analysis in the future.