Pancreatic neuroendocrine tumors (PNET) account for less than 2% of total pancreatic cancer [1] and about 10% of tumor arising from pancreas [2]. Rare incidence and indolent biologic behavior have made it difficult to understand disease entity and establish staging tools for this disease [3,4]. However, the development of imaging technology in recent decades has led to sharp increase in incidence and prevalence [5]. In fact, a proposal for a TNM classification to help stratify the prognosis was not made until 2006 by Rindi et al. [6]. This proposal was ultimately adopted by European Neuroendocrine Tumors Society (ENETS) and has been validated in the subsequent studies [7-12]. Meanwhile, the American Joint Committee on Cancer (AJCC) staging system for PNET was first isolated from exocrine pancreatic adenocarcinoma staging system in 2010 based on studies by Bilimoria et al. [13]. The same classification criteria as in exocrine pancreatic adenocarcinoma were applied to PNET in this study. After that, numerous studies have evaluated the suitability of the AJCC 7th classification [12,14-16]. Of these, two large cohort studies [7,14] have shown that the proportion of patients in stage III of the AJCC 7th edition, which is classified as unresectable case, is relatively small. In particular, poor discrimination between stage II and III was reported by Rindi et al.’s investigation [7]. Furthermore, many studies have raised questions about whether it is appropriate to apply pancreatic adenocarcinoma staging to PNET with other biological characteristics [7,11,14,17,18]. These findings support the need for revision of the AJCC 7th system for PNET.

As a result, the newly revised AJCC 8th staging system introduces the classification criteria asserted by ENETS and shows several significant changes (Tables 1-3). At first, PNET staging system has come out separate system and applied to the only G1 (ENETS/World Health Organization [WHO] 2010 grade 1), G2 (ENETS/WHO 2010 grade 2), and well-differentiated G3 tumors (ENETS/WHO 2010 grade 3) [19]. The remaining poorly differentiated G3 (ENETS/WHO 2010 grade 3) neuroendocrine carcinoma follows staging of exocrine pancreatic cancer. Second, the size of the tumor has become an important criterion to distinguish the T category and invasion of soft tissue around the pancreas was excluded from staging criteria. Third, adjacent organs invasion has been categorized as T4 category, together with unresectable cases such as major vascular invasion. Fourth, M1 category has been subsided according to metastatic sites.

However, several studies have been published that question whether the ENETS system should be accepted as a new staging system [7,10,11]. In particular, stage IIIB (any T N1 M0) has a relatively better prognosis than IIIA (T4 N0 M0) in these studies. In fact, the AJCC 8th manual does not distinguish between specific substages (IIA vs. IIB and IIIA vs. IIIB) unlike ENETS system. In addition, defining adjacent organ invasion and major vascular invasion as the same T4 has an unnatural aspect in that it may confuse the concept of “resectable” or “unresectable.”

Given these, we aim to validate the AJCC 8th staging system in the present study. For this purpose, survival curves were compared according to AJCC 7th, AJCC 8th system, and ENETS system. In addition, multivariate analysis was performed to determine the effect of each system on prognosis.

To best of our knowledge, this is the first study to validate a new AJCC 8th staging classifications for PNET. In fact, validation of the ENETs system, which is the basis for 8th AJCC staging system, has been carried out in several studies [7-12,21]. Unlike previous studies, the strength of the present study is that it allows accurate assessment of lymph node metastasis. Recent studies have supported lymph node metastasis as a predictor of poor prognosis [22,23]. If accurate assessment of the N category through lymph node sampling or lymphadenectomy is not feasible, accurate TNM staging to predict prognosis becomes difficult. The low lymph node yield rate, including zero percent, is likely to be related to the type of surgery and the individual preference of the operator for PNET. In a single-center study, the rate of no lymph node sampling is higher in patients undergoing enucleation and spleen-preserving distal pancreatectomy compared to patients with other operations [24]. In this regards, previous studies to validate ENETS TNM staging had limitation. In a European multicenter study by Rindi et al. [7] using 1,072 cohorts, the lymph node status could not be assessed in 737 (68.8%) patients. The results of a study conducted by Luo et al. [21] using 2,529 cases from Surveillance, Epidemiology, and End Results data should also be cautious about the proper evaluation of staging system because there is no mention of “Nx”. Besides, in the previous two studies mentioning “Nx”, the ratio of “Nx” in all patients was reported as 51.6% and 68.8%, respectively [8,9]. In the current study, among the 972 patients who underwent resection with PNET, 409 patients (42.1%) had no lymph node retrieval and contrary to previous studies mentioned above, we excluded samples from the survival analysis that were not correctly evaluated for lymph node status. The inclusion criteria of the current study, which reflects our intent to not ignore the prognostic significance of lymph node status, seems to provide more accurate validation of the AJCC 8th TNM staging system.

An important change in 8th edition of AJCC system is that G3 was not included in the PNET staging system unlike the previous ENETS system. This reflects the results of previous studies showing that exocrine tumors and neuroendocrine tumors have different tumor biology and prognosis [7,11,14, 17,18,25]. In the former ENETS validation study, the proportion of G3 ranging from 6.8% to 11.0% was not negligible [7-12,21]. By contrary, we used the cohort excluding G3 in this study. This may have helped to evaluate more elaborately the suitability of the new AJCC staging system for PNET.

The present study largely supports that AJCC 8th edition staging system provides better discrimination when compared to the AJCC 7th edition and the ENETS staging system. As for DFS, survival curves of 8th AJCC classification were well separated between all stages. This seems to be related to some detailed changes in the 8th edition as follows. First, the definition of T4 category expanded to adjacent organ invasion, which affected the increase of T4 case number (Figs. 1A, B, 2A, and B). As a result, four T4 patients increased to 16 followed by the increases in stage III cases. Second, T1-3N1M0 (which had been stage IIB in AJCC 7th system) is classified as stage III in the AJCC 8th staging system, leading to an increase in the proportion of stage III. The two changes described above resulted in an increase in the ratio of stage III in the 8th AJCC and a significant difference in DFS curves between stages (stage II vs. III and stage III vs. IV in 8th AJCC staging system).

Another remarkable result of this study is that it is more reasonable to combine stage IIIA (T4, N0, M0) and IIIB (any T, N1, M0) into one prognostic group than to divide stage III into two subgroups. In fact, the results that stage IIIB has a better prognosis than IIIA has already been reported in previous studies [7,10,11]. Rindi et al. [7] estimated this to be due to poorer prognosis of the unresectable T4 compared with positive N cases, or different surgical techniques and lymph node sampling methods, or small sample size of T4. In the current study, there was also no significant difference in survival rate (both OSR and DFS) between the stage IIIA and IIIB using the ENETS system (p=0.291 and p=0.545), respectively (Figs. 1D and 2D). Given these, the attempt at the AJCC 8th edition, which classifies the existing ENETS stage into four simple stages, is considered acceptable.

Despite a better distribution of prognosis in different stages based on the new AJCC revision, the low stage IV (Any T Any N M1) ratio of this study, which is only 4%, is worth mentioning. In our opinion, the proportion of stage IV should be related to the definition of the subject being analyzed. For studies reporting high rates of stage IV ranging 35%-60% [8,10,11], patients who have undergone palliative surgery or who have been just diagnosed with biopsy or cytology had been included. In contrast, this rate was reported to be relatively low ranging 9%-21% in studies involving only patients with surgery [9,12]. The present study included only patients who underwent surgical treatment. It is rare to perform radical surgery for PNET with distant metastasis. Furthermore, the relatively high curative resection rate and exclusion of G3 are also the cause of the low stage IV ratio in the current study. This is consistent with report of a single-center study that patients with G3 accounts for a high percentage of all patients with ENETS stage IV. Of 53 patients with ENETS stage IV in the study, 27 patients (50.9%) were G3 [26].

Several modalities of adjuvant treatment have been proposed that can be used to reduce tumor burden or inhibit cancer progression after recurrence of PNET [27]. In the case of chemotherapy, Ramirez et al. [28] demonstrated that combination treatment with capecitabine/temozolomide has the benefit of prolonging the survival of patients with metastasis. Although all enteropancreatic neuroendocrine tumors were targeted, a randomized controlled study has suggested the effect of long-acting somatostatin analogues [29]. Unfortunately, just 67 of the 472 patients (14.2%) enrolled in the current study were able to confirm whether they received adjuvant treatment. Of these 67 patients, seven had recurrence, and two of seven patients with recurrence received adjuvant treatment. Two of the patients treated with adjuvant treatment were all diagnosed with G2 and AJCC 8th stage II (T2N0M0), received adjuvant chemotherapy and survived to the last follow-up. The last follow-up point of each patient was 17 months and 4 months after the recurrence. Of the seven patients who had recurred, only one died, and he was one of the five who had not received any adjuvant treatment. He was a male patient with LVI, was diagnosed with G2 and AJCC 8th stage III (T3N1MO), and died 41 months after recurrence. Due to the small number of relapses that could be identified, it was not possible to verify statistically the prognostic factor influencing overall survival after recurrence or metastasis. Therefore, further studies using large samples that statistically demonstrate the role of adjuvant treatment for PNET is needed.

The present study has several limitations. First, we could not analyze the prognosis between functional tumor and nonfunctional tumor. Previous two studies have reported that functional neuroendocrine tumor is a prognostic factor for survival [7,14]. However, our multicenter database is missing a lot of information about these items. Thus, if this factor was included in the multivariate analysis process, more sophisticated and reliable statistical analysis would have been possible. Second, there is a potential for bias in the retrospective multicenter study design itself. In particular, this is relevant to the difference in the operative methods between various institutes. Considering the importance of lymph node metastasis to prognosis as previously mentioned in discussion, it is likely that the diversity of operative methods and lymphadenectomy have had some impact on survival.

In summary, this is the first large-scale validation of the AJCC 8th edition staging system for PNET. The revised 8th system provides better discrimination compared to that of the 7th edition system and ENETS staging system. Therefore, using the current system is expected to help stratify the patient's prognosis and provide clinical information.