Gallbladder neuroendocrine tumors (GB-NETs) are rare, accounting for <0.5% of all NETs, and little is known about somatostatin receptor expression (SSTR) and its response to SSTR-targeted treatment such as Lutetium-177 ( 177 Lu) DOTATATE. 68 Ga DOTATATE PET/CT is a valuable imaging modality for SSTR expression and 177 Lu DOTATATE treatment planning. We present a case of a 74-year-old man with recurrent WHO grade 3 GB-NET. 177 Lu DOTATATE failed to control hepatic metastases despite high DOTATATE uptake, which led to treatment discontinuation. This case highlights the fact that positive SSTR imaging in GB-NETs does not always lead to a favorable response to 177 Lu DOTATATE.

Neuroendocrine neoplasm (NENs) make up approximately 2-3 % of gallbladder malignancies, while only 0.5 % of all NENs develop in the gallbladder. Most Gallbladder neuroendocrine neoplasms (GB-NENs) are discovered incidentally during pathological examinations post-cholecystectomy. 70-year-old male presents with an incidentally discovered 2.2 cm enhancing intraluminal soft tissue mass on abdominal CT scan. The mass demonstrates restricted diffusion on MR imaging, concerning for gallbladder malignancy. Radical cholecystectomy, confirms primary gallbladder neuroendocrine tumor (GB-NET). No adjuvant therapy was recommended at multidisciplinary cancer conference review. The patient is currently disease free at 18 months follow up. The management of GB-NEN remains challenging, due to the lack of specific clinical manifestations and typical imaging features preoperatively. GB-NENs are usually asymptomatic, and the paucity of reported imaging characteristics makes prospective diagnosis of GB-NENs challenging. GB-NEN tend to be larger in size, demonstrating well defined, intact mucosa, with a thick rim of hyperintensity on diffusion weighted images (DWI). Distinguishing between gallbladder neuroendocrine carcinoma (GB-NEC) and gallbladder neuroendocrine tumor (GB-NET) on pathologic evaluation is essential in developing a treatment plan. GB-NETs have superior survival compared to GB-NECs. GB-NETs can be managed utilizing a cholecystectomy with portal lymphadenectomy +/- segment 4b/5 liver resection. GB-NETs may achieve curative resection, if identified at an early disease stage.

Gallbladder mixed neuroendocrine-non-neuroendocrine neoplasm generally consists of a gallbladder neuroendocrine tumor and a non-neuroendocrine component. The World Health Organization (WHO) in 2019 established a guideline requiring each component, both neuroendocrine and non-neuroendocrine, to account for a minimum of 30% of the tumor mass. Patients after surgery resection and diagnosed at microscopy evaluation with pure gallbladder neuroendocrine carcinoma (GBNEC), gallbladder mixed adeno-neuroendocrine carcinoma (GBMANEC, GBNEC≥30%), and gallbladder carcinoma mixed with a small fraction of GBNEC (GBNEC <30%) between 2010 and 2022 at West China Hospital of Sichuan University were collated for the analyses. Demographic features, surgical variables, and tumor characteristics were evaluated for association with patients' overall and recurrence-free survival (OS and RFS). The study included 26 GBNEC, 11 GBMANEC, 4 gallbladder squamous-cell carcinoma (GBSCC), and 7 gallbladder adenocarcinoma (GBADC) mixed with a small fraction of GBNEC. All patients had stage III or higher tumors (AJCC8th edition). The majority of included patients (79.17%) underwent curative surgical resection (R0), with only ten patients having tumoral resection margins. In the analysis comparing patients with GBNEC percentage (GBNEC≥30% vs. GBNEC<30%), the basic demographics and tumor characteristics of most patients were comparable. The prognosis of these patients was also comparable, with a median OS of 23.65 months versus 20.40 months (P=0.13) and a median RFS of 17.1 months versus 12.3 months (P=0.24). However, patients with GBADC or GBSCC mixed with GBNEC <30% had a statistically significant decreased OS and RFS (both P<0.0001)) compared with GBNEC and GBMANEC. Patients with GBNEC who exhibited advanced tumor stages and lymphovascular invasion had a higher risk of experiencing worse overall survival (OS) and recurrence-free survival (RFS). However, a 30% GBNEC component was not identified as an independent risk factor. Patients with GBNEC were frequently diagnosed at advanced stages and their prognosis is poor. The 30% percentage of the GBNEC component is not related to the patient's survival.

Primary gallbladder neuroendocrine tumor (GB-NET) is extremely rare. Therefore, tumor behavior and adequate treatment in GB-NETs are still unclear. A 74-year-old man without any specific complaints was referred to our hospital cause of gallbladder tumor. Abdominal ultrasonography examination revealed a 22-mm non-pedunculated tumor in the gallbladder body. Contrast-enhanced computed tomography showed a polyp that was enhanced in the arterial phase. The patient underwent gallbladder bed resection and radical lymphadenectomy with a diagnosis of gallbladder carcinoma. Macroscopically, the resected specimen showed a nodular expanding tumor measuring 32×15 mm in the gallbladder body. From the pathological findings, a grade 3 GB-NET was diagnosed. Only cystic lymph node metastasis was observed. The patient was discharged uneventfully, but bone and lymph node metastasis were detected eight months after surgery. We conclude that grade 3 GB-NET shows occasionally malignant biological behavior although NET G3 is distinguished from neuroendocrine carcinoma in the current WHO 2019 classification of NET.

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.