Recently, due to improved awareness of physical examination and wide use of cross-sectional imaging, NF-pNETs are being diagnosed increasingly at a small size. According to SEER, the incidence of pNETs with a ≤ 2 cm size has increased by 710.4% (with an annual 12.8% change) over the past 22 years [6]. However, the heterogeneity and uncertainty of pNETs biological behavior pose a dilemma to therapeutic decisions, especially for small tumors (≤ 2 cm). According to some publications, most of NF-pNETs ≤ 2 cm are likely to be benign or indolent. Therefore, in 2012, the European Neuroendocrine Tumor Society (ENETS) Guideline suggested that a observation approach could be advocated in selected cases for NF-pNETs ≤2 cm that are discovered incidentally [7]. Despite this, surveillance or surgery for pNETs ≤2 cm remains controversial. Initially, the concept of observation strategy in pNET was first introduced in the setting of MEN1 syndrome, in which a “field-defect” is thought to present throughout the pancreas and unless total pancreatectomy is performed, the pancreatic remnant is prone to develop new tumors latter[8]. Besides, the concept of surgery in small NF-pNETs is not without risk. Pancreatic surgery remains a high-risk procedure. Postoperative risk of morbidity and mortality is inevitable, especially for tumor located in pancreatic head[9]. Despite parenchyma-sparing pancreatectomy, such as central pancreatectomy and enucleation, could preserve more organ function and minimize long-term complication. However, non-anatomic resections may be associate with higher incidence of pancreatic fistula. Based on this, practices regarding decision for surgery or surveillance may vary differently between institutions depending on the cognition of both physician and patient.
Generally, tumor size has been consistently used to correlate with malignant potential and long-term prognosis. Currently, 2cm has often been suggested as a safe cutoff size to decide surgery or surveillance for NF-pNETs. However, some studies have concluded that small pNETs >0.5 cm already have a malignant potential[4,5]. Likewise, Gratian et al found a rate of lymph node metastases and distant metastases in pNETs of <2 cm of 29% and 10%, respectively[10]. Similarly, Haynes et al from Massachusetts General Hospital reviewed 139 patients with incidental NF-pNETs and reported a 7.7 % rate of distant metastases in resected pNETs <2 cm after a median follow-up of 34 months[11]. While in our study, we also found 4.8% rate of lymph node metastases in 3 out of 62 resected NF-pNETs. Therefore, small diameter at diagnosis (≤2 cm) is not an grantee of a benign or indolent behavior.
Since the existence of potential malignancy of small NF-pNET, observation strategy must be conducted cautiously. Based on a retrospective study, the cutoff of 2 cm of observation or surgery used for small NF-pNETs could be decreased to 1.7 cm to select patients more accurately[12]. Sadot reported a series of 104 patients who were recommended observation. After a median follow-up of 44 months, no patient developed metastases[8]. The observation group was significantly older and tended to shorter follow-up, which was inconsistent with our results. More than half patients in the observation group from SEER database were over 70 years old. According to a observational study of natural history of small sporadic NF-pNETs, overall median tumor growth was 0.12mm per year [13]. Thus, observation strategy for older patients is reasonable.
Notably, in 2016, ENETS updated their Guideline that patients with NF-pNETs ≤2 cm have two options: i) It is recommended to have surveillance approach for the patients with G1 or low G2, asymptomatic, mainly with head lesion, no radiological signs suspicious for malignancy, as well as patient factors such as personal wishes, age, or with comorbidities; ii) while for the patients with G2, symptoms and patient wishes, surgery is recommended. Moreover, during the surveillance time, if the tumor size increase >0.5 cm or to a size of >2 cm, surgery is necessary[14].
Therefore, it is vital to determine pathological Ki67 index before making the appropriate strategy for patients with NF-pNETs ≤2 cm. In 1992, for the first time, endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) was reported to diagnose pNETs [15]. Since then, both its sensitivity and accuracy have improved greatly. Larghi et al reported that acquisition of tissue specimens with EUS-FNTA by using a 19-gauge needle is safe, feasible and highly accurate. Preoperative and postoperative Ki–67 proliferation indexes were 83.3% concordant in 10 patients [16]. More recently, Boutsen et al reported that, compared with preoperative grading, 21 of 22 (95%) pNETs <2 cm had the same grading after surgery [17].
Besides, molecular tests based on EUS-FNA may also be helpful to predict the biological behavior. By performing whole exome sequencing, Jiao et al found that 44 % of sporadic pNET harbored somatic inactivating mutations in MEN–1 and that mutations in the MEN1 gene implied a good prognosis [18]. In addition, loss of DAXX/ATRX proteins was reported to be associated with poor survival in patients with pNETs[19]. Thus, Ki67 combined with these molecular markers, may guide physicians to further subgroup distinct patients for observation or surgery.
In conclusion, for elderly patients with NF-pNETs ≤2cm with G1 or low G2, especially for tumor located in pancreatic head, observation strategy may be recommended. Meanwhile, close follow-up should be guaranteed to monitor the tumor dynamics.