There are considerable discrepancies about the predilection sites of the NETs according to the database of various countries which may due to the different race [1, 5]. Though gastroenteropancreatic NETs are the most common type in the NETs representing 65-75% of all cases , they also occur in other organs such as ovary, testis and hepatobiliary system and so on. Gallbladder neuroendocrine tumors (GB-NETs) are extremely rare which only represent 2% in all gallbladder tumors .
The average onset age of GB-NETs is 64 years old with a female preponderance  , which is very similar with primary colorectal NEC that is reported to have a median age of 60 years and a female to male ratio of 2:1 . NETs are divided into functional and nonfunctional depending on whether the tumor cells can produce hormones and induce endocrine syndromes. Up to now 13 types of neuroendocrine cells have been found, which could release different types of bioactive molecules . Most of the primary colorectal NEC patients have no carcinoid syndrome, so as the majority of the GB-NETs leading to it’s easily to be omitted in the earlier stage [8–10]. Patients often complain with nonspecific symptoms such as abdominal pain, epigastric discomfort and jaundice, with only 3.3%-3.7% in all cases presenting hormone-related syndromes . As in our case, the patient complained about mild epigastric discomfort, without any hormone-related clinical manifestation.
Gallbladder carcinomas are believed to originate from malignant transformation of epithelial atypical hyperplasia which often occurs during the chronic inflammation . The origin of GB-NETs remains uncertain because neuroendocrine cells do not naturally exist in the mucosa of the gallbladder. One of the theories proposed that neuroendocrine cells could be generated from the stem cells deviating from their original differentiation during metaplastic process especially intestinal type . As reported by Sakamoto , 10.7% of intestinal metaplasia was found in 103 cholecystolithiasis cases who had received cholecystectomy. Cholecystolithiasis and cholecystitis were also found in most cases of GB-NETs, which suggested GB-NETs might relate to chronic inflammation of the gallbladder  , while only two of ten cases of colorectal NEC have related inflammatory diseases such as ulcerative colitis and Crohn's disease. This difference may indicate that the origination and mechanism of GB-NETs is quite different from colorectal NEC . As in our case, the patient also had history of chronic cholecystitis. Proliferation and aggregation of these cells in the metaplastic epithelium could be an early sign for the gallbladder neuroendocrine tumors. Very few cases of concurrent adenocarcinoma and neuroendocrine tumor in the gallbladder were reported [16–18]. In our case, both glandular and neuroendocrine differentiations were observed and no transitional region between the two parts was found, which suggested the tumor might arise independently from two different precursor cells in a synchronous fashion or arise from a multipotent stem cell. Another theory postulate heterotopic pancreas in the gallbladder may play a role in origin of GB-NETs. The enzyme secreted by the heterotopic pancreas would damage the gallbladder mucosa and lead to metaplasia, which was believed as a possible etiology for GB-NETs [19, 20].
The diagnosis of GB-NETs is rarely made preoperatively because there is no specific symptoms and imageological change. Ultrasound, CT scan, MRI, PET-CT and somatostatin receptor scintigraphy (SRS) can provide useful information of NETs, but confirmed diagnosis can only be made by pathological examination. Endoscopic ultrasonography with fine needle aspiration can increase the diagnostic sensitivity from 74% to 90%, compare to the endoscopic ultrasonography only . Definite diagnosis relies on diffuse and intensive expression of marker proteins such as chromogranin A (CgA), neuron-Specific Enolase (NSE) and synaptophysin (Syn). Because of the extremely rareness of the primary NETs of the gallbladder, metastasis from other organs such as lung should be excluded carefully . Recent grading system suggested by WHO and ENETS depend mainly on Ki-67 index and mitotic count . Mixed adenoneuroendocrine carcinoma is diagnosed only when both portions are more than 30% in the pathological examination. In our case, adenocarcinoma was not detected in the biopsy but in the surgical specimen. We believe that it’s because of the specimen taken by the biopsy is limited so that the adenocarcinoma was omitted unintentionally. Another reason might be the curative effect of neo-adjuvant chemotherapy and somatostatin treatment, which killed majority of the tumor neuroendocrine cells and made the NEC portion less predominant.
Personalized and comprehensive therapy is preferred in treatment of NETs. Surgery, radiotherapy, peptide receptor mediated radionuclide therapy, chemotherapy and biological target treatment are all optional in NETs. Different surgical procedures such as mere cholecystectomy and cholecystectomy plus liver segment resection and lymph node dissections were reported according to different cases . It is estimated that 74% of the GB-NETs patients will suffer from recurrence and metastasis after mere cholecystectomy . Laparoscopic cholecystectomy is not preferred because it may cause intraperitoneal dissemination of the GB-NETs [26, 27]. For early stage of GB-NETs such as T1N0, cholecystectomy is suggested. For advanced stage, cholecystectomy plus liver segment resection and lymph node dissection could increase the 5-year overall survival rate . In some cases, chemotherapy was reported to increase the median survival time (4-31 months) and relief the symptoms in GB-NETs . The objective response rate (ORR) of EP regimen in GEP-NETs is 53-67%, while its median survival time is shorter than 16 months . Somatostatin analogues can inhibit the secretion of a broad range of hormones by binding to the somatostatin receptors on the NETs cell membrane. Recently, studies also found that somatostatin analogues can inhibit tumor cell growth directly by modulating the signal transduction of proliferation and apoptosis. Long-acting octreotide or lanreotide could prolong the overall survival rate of in metastatic mid-gut NET patient .
The prognosis of GB-NETs is related to the tumor size, invasion depth, differentiation degree and metastasis state, with a 60.4% 5-year overall survival rate . Poor differentiation and accompanied with adenocarcinoma predict a worse prognosis, while tumor limited to the gallbladder wall is a good prognostic indicator. For GB-NETs with local invasion and lymph node metastasis, patients who received extended lymph node dissection would still suffer from recurrence and metastasis and the median survival time is only 30.3 months . Extended operation including cholecystectomy, liver segment resection and lymph node dissection could increase the 5-year survival rate from 21.3% to 60.4% . NCCN guideline indicated patients with the unresectable neuroendocrine tumor could receive palliative operation, adjuvant chemotherapy and somatostatin analogue treatment . In our case, neo-adjuvant chemotherapy and somatostatin treatment successfully transformed the unresectable neoplasm and made radical operation available. Although at this stage it is hard to judge whether the radical operation could bring any long term advantage to patient of this kind, it does provide valuable experience in the management strategy of advanced gallbladder neuroendocrine tumors.