• adjuvant chemotherapy
• gallbladder neuroendocrine carcinoma
• neuroendocrine tumors
• prognosis
• surgery

Gallbladder neuroendocrine carcinoma (GB-NEC) has a low incidence rate; therefore, its clinical characteristics, diagnosis, treatment and prognosis are not well explored.

To review recent research and analyze corresponding data in the Surveillance Epidemiology and End Results (SEER) database.

Data of GB-NEC (n = 287) and gallbladder adenocarcinoma (GB-ADC) (n = 19 484) patients from 1975 to 2016 were extracted from the SEER database. Survival analysis was performed using Kaplan–Meier and Cox proportional hazards regression. P < 0.05 was considered statistically significant. We also reviewed 108 studies retrieved from PubMed and Reference Citation Analysis (https://www.referencecitationanalysis.com/). The keywords used for the search were: "(Carcinoma, Neuroendocrine) AND (Gallbladder Neoplasms)".

The GB-NEC incidence rate was 1.6% (of all gallbladder carcinomas), male to female ratio was 1:2 and the median survival time was 7 mo. The 1-, 2-, 3- and 5-year overall survival (OS) was 36.6%, 17.8%, 13.2% and 7.3% respectively. Serum chromogranin A levels may be a specific tumor marker for the diagnosis of GB-NEC. Elevated carcinoembryonic antigen, carbohydrate antigen (CA)-19-9 and CA-125 levels were associated with poor prognosis. Age [hazard ratio (HR) = 1.027, 95% confidence interval (CI): 1.006–1.047, P = 0.01] and liver metastasis (HR = 3.055, 95% CI: 1.839–5.075, P < 0.001) are independent prognostic risk factors for OS. Patients with advanced GB-NEC treated with surgical resection combined with radiotherapy and/or chemotherapy may have a better prognosis than those treated with surgical resection alone. There was no significant difference in OS between GB-NEC and GB-ADC.

The clinical manifestations and prognosis of GB-NEC are similar to GB-ADC, but the treatment is completely different. Early diagnosis and treatment are the top priorities.

• Clinical features
• Diagnosis
• Gallbladder neuroendocrine tumor
• Pathology
• Treatment

Mixed neuroendocrine–non-neuroendocrine neoplasms (MiNENs) of the gallbladder are rare malignancies. Here we presented two cases and reviewed the related literature.

Our two patients were postoperatively diagnosed with gallbladder MiNENs, which pathologically consisted of a large cell neuroendocrine carcinoma and papillary adenocarcinoma. After cholecystectomy, one patient had a survival time of 30 months, while the other remained alive through 12 months of follow-up. In the literature, a total of 72 cases of gallbladder MiNENs were identified, and with our two patients included, we calculated a male-to-female ratio of 0.22 and a mean age of 64.5 years for the 74 reported cases. About one-half of these patients were found to have gallstones and presented with abdominal pain or discomfort in a relatively early stage. The preoperative diagnosis of these 74 cases mainly relied on abdominal ultrasound, contrast-enhanced computed tomography (CT) scanning, and magnetic resonance imaging or positron emission tomography/CT. However, the final diagnosis was established based upon the pathological evidence and expression of synaptophysin (Syn) and/or chromogranin A identified by immunohistochemical staining or neurosecretory granules detected by electron microscopy. Fifty-eight patients (78.4%) underwent various operations including simple cholecystectomy (n = 14), en bloc cholecystectomy (n = 9), standard or non-standard radical cholecystectomy (n = 25), or extended radical cholecystectomy (n = 6). The mean size of the resected gallbladder masses was 50.8 ± 36.1 mm (n = 63) with regional lymph node metastasis in 37 patients (52.1%), liver invasion or staging greater than T3 in 33 patients (45.8%), and hepatic metastasis in 26 patients (35.1%). The postoperative median survival time was 36 ± 11.42 months (95% confidence interval, 13.62 to 58.38 months). The log-rank analysis did not find that postoperative adjuvant chemotherapy contributed to a longer survival time relative to that among the patients who did not receive chemotherapy (numbers of patients, 15 versus 43; survival times, 36 months versus 30 months, p > 0.05).

Our two cases and the cases in the literature suggest that MiNENs of the gallbladder predominantly occur in women; are associated with early lymph node metastasis, local hepatic invasion, and hepatic metastasis; and can be managed by various surgeries as well as chemotherapy combined with somatostatin analogs.

• Case report
• Gallbladder
• Large cell neuroendocrine carcinoma
• Median survival time
• Mixed neuroendocrine–non-neuroendocrine neoplasm
• Papillary adenocarcinoma

• gallbladder
• mixed neuroendocrine-non-neuroendocrine neoplasm
• neuroendocrine carcinoma
• neuroendocrine tumors
• prognosis

• Female
• Fluorodeoxyglucose F18
• Gallbladder Neoplasms
• Humans
• Lymphoma, Large B-Cell, Diffuse
• Middle Aged
• Positron Emission Tomography Computed Tomography
• Radiopharmaceuticals

• adenocarcinoma
• gallbladder cancer
• neuroendocrine carcinoma
• overall survival rate
• propensity score matching

• Gallbladder
• Hepatobiliary
• Large cell
• Neuroendocrine
• North-africa
• Outcomes

• biliary intervention
• endocrine cancer
• endocrinology
• general surgery
• medical management

• clinical features
• diagnosis
• neuroendocrine tumor of the gallbladder
• pathological classification
• treatment

Gallbladder neuroendocrine carcinomas are rare tumors with a prognosis poorer than that of other gallbladder carcinomas. These tumors are often detected late and are difficult to treat. We present the case of a 68-year-old woman with small-cell gallbladder neuroendocrine carcinoma. Abdominal sonography and dynamic contrast-enhanced MRI performed at different points in time showed rapid growth. Treatment with surgical resection and adjuvant chemotherapy was instituted. In view of the rapid growth of these tumors, suspicious cases should at least be considered for close follow-up with appropriate imaging studies.

• Computed tomography
• Gallbladder
• Magnetic resonance imaging
• Neuroendocrine carcinoma
• Ultrasonography

Primary neuroendocrine carcinomas of the gallbladder and biliary tract are rare, with pure large cell neuroendocrine carcinomas (LCNEC) being exceedingly rare and with a particularly poor prognosis.

We performed a review of published data on biliary tract large cell neuroendocrine carcinomas in PubMed.

Preliminary search revealed over 2000 results but we found only 12 cases of pure large cell neuroendocrine carcinomas of biliary tract noted in literature to date. Because it commonly presents with non-specific symptoms of abdominal pain and jaundice, diagnosis is made after resection with histo-pathological and immunohistochemical analysis. These cancers are particularly aggressive with high recurrence rates, most often presenting with metastasis to regional lymph nodes and/or the liver resulting in a poor prognosis. Overall, complete surgical excision with systemic chemotherapy is the treatment mainstay. If the cancer is unresectable due to multiple metastases, medical management with systemic chemotherapy is the primary treatment modality.

The prognosis of hepatobiliary LCNEC remains poor with median survival of only 11 months from initial diagnosis. Studies focusing on high grade neuroendocrine carcinoma are needed to enhance our understanding of biology and therapeutics in this rare but aggressive cancer.

• Biliary tract
• Large cell neuroendocrine carcinomas
• Neuroendocrine

We report a case of rare and aggressive gallbladder neuroendocrine carcinoma (GB-NEC), diagnosed with the help of endoscopic ultrasound (EUS). A 65-year-old asymptomatic male, with a past medical history of hypertension, underwent abdominal ultrasound for the screening of an abdominal aortic aneurysm. He was found to have a mixed echogenicity area near the stomach, an incidental finding on abdominal ultrasound. The patient had an upper gastrointestinal (GI) endoscopy exam, which revealed an antral mass that was biopsied. The tissue specimen showed an epithelioid mesenchymal tumor of unclassified type and, eventually, the patient underwent partial gastrectomy. Surgical pathology reported a low-grade sub-serosal gastrointestinal stromal tumor (GIST) of the resected tissue specimen. He was later discharged and advised to follow up with abdominal computed tomography (CT) every year. Two years later, his abdominal CT revealed a new 3.7 cm x 2.0 cm mass in the posterior gallbladder fundus. Subsequently, the patient underwent laparoscopic cholecystectomy and the excisional biopsy reported a T3NXM1 neuroendocrine small cell carcinoma. Then, he received six cycles of systemic chemotherapy with carboplatin and etoposide, showing excellent response initially. However, a repeat CT abdomen/pelvis with contrast, on his eighth-month follow-up, demonstrated the interval development of an infiltrative mass in the pancreatic head. The gastroenterology team was then consulted, who performed sphincterotomy with temporary stent placement and celiac plexus neurolysis. Also, a transduodenal fine-needle aspiration (FNA) of the pancreatic mass was performed, which revealed metastatic small cell carcinoma. Based on these findings, the patient received an additional three cycles of carboplatin/etoposide chemotherapy, along with one cycle of immunotherapy. However, the patient had a poor response to chemotherapy, and he eventually chose hospice care.

• chemotherapy
• endocrine tumor
• eus
• gallbladder tumor

• Gallbladder tumor
• Liver invasion
• Neuroendocrine carcinoma
• Neuroendocrine tumor

• Carcinoma
• Gallbladder
• Large cell neuroendocrine carcinoma
• Neuroendocrine carcinoma
• Neuroendocrine tumours

Neuroendocrine carcinoma (NEC) of the gallbladder is a rare subtype of gallbladder tumor. Here, we report two cases of NEC in two patients initially suspected to have gallbladder carcinoma. No specific symptoms or abnormal blood test results were observed preoperatively. Abdominal computed tomography scans indicated intraluminal masses in the gallbladder and lymph node enlargement in the hepatic hilum. Radical cholecystectomy and regional lymphadenectomy were performed. The first patient also presented with liver invasion and therefore underwent resection of liver segment IV. A diagnosis of NEC was made upon postoperative pathological examination and immunohistochemical staining according to the WHO Classification of Tumors of the Digestive System (2010). One tumor was identified as poorly differentiated NEC and the other as poorly differentiated mixed adenoneuroendocrine carcinoma. Immunohistochemical staining data from both tumors showed positivity for chromogranin A and synaptophysin. The first patient received 4 cycles of chemotherapy consisting of cisplatin and etoposide. No metastases or recurrence were observed 12 mo following surgery. The second patient refused chemotherapy and presented with tumor recurrence 4 mo after surgery. In conclusion, NEC of the gallbladder is an aggressive tumor and the identification of a standardized optimal treatment still requires further research. Our experience together with published studies suggests that radical surgery and adjuvant chemotherapy may improve the prognosis.

• Neuroendocrine carcinoma
• Tumor
• Gallbladder
• Chemotherapy
• Carcinoid

• Adult
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Biomarkers, Tumor/analysis
• Biopsy
• Carcinoma, Neuroendocrine/chemistry
• Carcinoma, Neuroendocrine/secondary
• Carcinoma, Neuroendocrine/therapy
• Cell Differentiation
• Chemotherapy, Adjuvant
• Cholecystectomy
• Gallbladder Neoplasms/chemistry
• Gallbladder Neoplasms/pathology
• Gallbladder Neoplasms/therapy
• Hepatectomy
• Humans
• Immunohistochemistry
• Liver Neoplasms/chemistry
• Liver Neoplasms/secondary
• Liver Neoplasms/therapy
• Lymph Node Excision
• Male
• Middle Aged
• Neoplasm Recurrence, Local
• Time Factors
• Tomography, X-Ray Computed
• Treatment Outcome