Although the ENETS system is widely used in Europe, and the AJCC system in the United States, there is still no widely accepted staging system for pNETs as they are heterogeneous neoplasms with different clinical features, biological behaviors, and prognoses. The current study used a large, multicenter database to validate the newly developed AJCC 8th staging system for well-differentiated pNETs.
The TNM staging system is widely used for solid tumor staging guidelines, including pNETs, with the main guidelines currently available being the AJCC 7th and 8th systems, the ENETS system, and the mENETS system. Each of these exhibits both similarities and differences.
Both the AJCC 7th and ENETS systems have been widely used in clinical practice for a long time. The AJCC 7th staging system adopted the staging system of exocrine pancreatic carcinomas for pNETs, T4 was defined as patients with involvement of the celiac axis or superior mesenteric artery (unresectable tumor), which meant that a very low proportion of patients were considered stage III (T4, any N, M0). Consistent with the literature, our multicenter cohort had a low proportion of stage III disease (1.1%). In addition, the presence of extra-pancreatic spread was difficult to assess pathologically due to the expansive growth pattern common to pNETs. Furthermore, some studies found that the AJCC 7th staging system has a poor ability to differentiate between the prognoses of some subgroups. Rindi et al identified 1072 pNETs patients from eight European cancer centers (1990–2007) and found no significant difference in mortality between stages IIA and IIB (death rate per 100 persons per year = 3.4 vs 3.7, respectively; HR of death = 25.2, 95% CI = 5.9 to 106.9, P = 0.84), and stages IIB and III (death rate per 100 persons per year = 3.4 and 3.4, respectively; HR of death = 25.1, 95% CI = 5.4 to 116.5, P = 1.0). Our study also exhibited similar results, where there was no significant difference across stages IIA, IIB, III, and IV when the reference was defined as the earlier stage (P = 0.052, p = 0.128, P = 0.249, and P = 0.138, respectively).
The ENETS system’s ability to predict the prognosis of specific groups of patients was considered to be possibly superior to the AJCC 7th system. However, some studies have suggested that ENETS system cannot appropriately discriminate the prognoses of stage I and stage II patients, and predicted some abnormal survival outcomes between stages IIIA and IIIB. Luo et al. investigated the SEER database (N = 2529 patients) and a multicenter database (N = 1143 patients) and confirmed that patients with stage I disease had a similar prognosis to those with stage IIA disease (with stage I as the reference: SEER series, HR = 0.99, P = 0 .955; multicenter series, HR = 1.41, P = 0.337) using the ENETS staging system. In addition, the HR of death for patients with stage IIIA disease was even higher than that for patients with stage IIIB disease (with stage I as the reference: SEER series, HR of death = 2.87 vs. 2.77, respectively; multicentric series, HR of death = 4.56 vs. 4.25, respectively). In our study, there were no significant differences in stages IIIA, IIIB, and IV when the reference was defined as the previous stage (P = 0.978, P = 0.411, and P = 0.077, respectively).
Maintaining the ENETS’s T, N, and M definitions and adopting the AJCC system’s staging definitions, Luo et al. developed the mENETS, which solved the problem of the low proportion of patients of stage III in the AJCC 7th staging system and the poor differentiation between stages I stage II in the ENETS staging system. However, it became clear that the system showed poor ability to distinguish between the prognoses of stages IA and IB. Meanwhile, the prognostic difference between IIB stage III stage was slightly worse than other subgroups. In the present study, there was also no significant difference across stages IIB, III, and IV when the reference was defined as the previous stage (P = 0.158, P = 0.691 and P = 0.139, respectively). Thus, the use of complex staging methods may not have much added value when considering diagnoses in the clinical setting.
In 2017, the AJCC 8th staging system, which followed the ENETS’s definition of T and simplified the original staging criteria, was introduced by the AJCC specifically for well-differentiated pNETs. The AJCC 8th staging system was no longer suitable for poorly differentiated neuroendocrine carcinoma (G3), which have a significantly worse prognosis, and divided all patients into four stages. In fact, some studies have confirmed that there was no significant difference in survival between patients with stage IIIA or IIIB disease according to the ENETS system. Thus, simplifying and merging some subgroups may be acceptable and may be more practical for determining the clinical prognosis of patients with pNETs. In this study, we confirmed that the AJCC 8th staging system succeeded in classifying patients into 4 significantly different staging groups using our multicenter database, and the relative risk for death was closely correlated with advanced stage disease.
Eschewing the TNM staging system, the World Health Organization published their histologic grade (G) classification based on Ki-67 expression and mitotic counts. The classification was principally to be used for prognostic stratification and determining the adjuvant chemotherapy strategy according to the accurate measurement of proliferation. In the present study, patients with G1 disease exhibited a better estimated 5-year survival rate than patients with G2 (87.1% vs. 81.6%), and histologic grade was found to be associated with overall survival in the univariate analysis (G2: HR = 1.534, 95% CI = 1.126 to 2.091, P = 0.007). The functional status of pNETs also has a significant effect on the prognosis. Studies have confirmed that functional pNETs have better prognoses than non-functional pNETs. Consistent with the literature, the estimated 5-year survival rate of patients with functional and non-functional pNETs in our study were 95.0% and 82.5%, respectively. Functional status was also identified as significant positive prognostic factor in the univariate analysis (HR = 0.272, 95% CI = 0.128 to 0.580, P = 0.001).
Although the AJCC 8th staging system is superior to other TNM staging systems and may bring a unified consensus on TNM staging, it failed to include the histologic grade and functional status, which ultimately lead to its limitations in prognosis prediction. Therefore, a new stage classification combining the TNM staging system and G grade is needed to help guide therapeutic decisions. Furthermore, novel surveillance guidelines need to be developed and trialed.
The major limitation of this study was the retrospective nature of the data analysis. Furthermore, the lack of postoperative course data and postoperative chemotherapy information, among other variables, meant that their significance could not be assessed out. Furthermore, since some patients underwent enucleation, the postoperative lymph node assessment may not be accurate.