On October 7, 2020, a 56-year-old woman admitted to our hospital due to right upper abdominal pain of 3 days duration. Abdominal computed tomography (CT) revealed space-occupying lesions at the bottom of the gallbladder, and space-occupying lesions in the hilar bile duct with intrahepatic bile duct dilatation, indicating malignant lesions. Multiple enlarged lymph nodes were mainly detected in the hepatic hilar and retroperitoneum. The levels of tumor markers were as follows: carcinoembryonic antigen (CEA), 34.1 mug/L, and carbohydrate antigen CA199, 7527 U/ml. Due to jaundice, the patient planned to undergo cholecystojejunostomy and R1 resection. The patient underwent exploratory laparotomy under general anesthesia on October 12, 2020. However, the patient had extensive lymph node metastasis and was not suitable for operation, then the patient underwent percutaneous transhepatic cholangial drainage (PTCD). The postoperative pathology showed that the tumor adjacent to the gallbladder was poorly differentiated adenocarcinoma with intrahepatic metastasis, classified as clinical stage T3N2M0 according to the tumor-node-metastasis (TNM) staging of the American Joint Committee on Cancer (AJCC) ( Figure 1 ). Next-generation sequencing (NGS) revealed that these mutations were STK11, RB1, CTNNA3, KEAP1, RBM10, and TCF7L2; moreover, PD-L1 positivity was observed. The patient refused chemotherapy, therefore, considering the high positive score, Combined Proportion Score (CPS 98) and Tumor Proportion Score (TPS 90%), sintilimab was given 200 mg every 3 weeks for eight cycles from November 2, 2020, and no adverse reactions were observed. Two weeks after the first administration, the level of tumor markers decreased: CEA, 16.6 mug/L, and CA199, 1,270 U/ml ( Figure 2 ). The patient reexamined after three cycles of treatment. CT showed that the size of tumor and lymph node significantly reduced ( Figure 3 ). Moreover, the patient's jaundice subsided and PTCD was removed. Meanwhile, CEA and CA199 decreased significantly to 3.83 mug/L and 114 U/ml, respectively ( Figure 2 ). However, on March 11, 2021, CT indicated disease progression after six cycles of sintilimab treatment, accompanied by elevation of CA199 to 173 U/ml and CEA to 6.35 mug/L. The combination therapy consisting of sintilimab and Tegafur (chemotherapeutic drug) administered 3 days later. After eight treatment cycles, the patient's CA199 level increased to 222 U/ml on April 13, 2021. One week later, CT revealed local liver metastasis, and the levels of CEA and CA 199 were 14.5 mug/L and 333 U/ml, respectively. Considering the progress of the disease, the entire liver metastasis and gallbladder were removed, and the lymph node dissection in the first porta hepatis was performed ( Figure 4A ). Postoperative pathology showed a poorly differentiated malignant tumor of the gallbladder, consistent with mixed neuroendocrine-nonneuroendocrine tumors (poorly differentiated adenocarcinoma accounted for 60%, small cell neuroendocrine carcinoma accounted for about 40%) ( Figure 4B ). Considering the difference from the first pathological diagnosis, the second NGS (liver metastasis, small cell neuroendocrine carcinoma) revealed that the mutations were PIK3CA, CDKN2A, CDKN2B, TP53, RB1, CCNE1, CEBPA, CTNNA3, GRM3, KEAP1, PBX1, PRKDC, RASA1, RBM10, and TBX3. Furthermore, PD-L1 positivity was also observed (CPS 10; TPS 8%). Different pathological diagnosis showed different mutation profiles. At present, the patient has been in a stable state with better life quality and is still in continuous sintilimab and chemotherapy.