Neuroendocrine carcinoma (NEC) is a group of heterogeneous tumors originating from diffuse neuroendocrine cells, accounting for less than 1% of all malignancies, which commonly occurs in the gastrointestinal tract (66.0%) and respiratory tract (31.0%) (1, 2). Gallbladder neuroendocrine carcinoma (GB-NEC) is extremely rare in the clinic. From the data provided by the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute (NCI), the incidence of GB-NEC was less than 0.74/100,000, accounting for 0.5% of all NECs and 2.1% of gallbladder cancers (3, 4). As previously reported, GB−NEC is more aggressive and has a poorer prognosis than gallbladder adenocarcinomas (5–7).

Currently, surgical resection remains the primary and preferred therapeutics for GB-NEC patients (8, 9). However, many patients are in a late stage and lose the opportunity for surgery. For these patients, chemotherapy is a critical treatment. According to the European Neuroendocrine Tumor Society (ENETS) 2023 guidance for digestive neuroendocrine carcinoma, platinum in combination with etoposide is recommended as the first-line treatment for patients with metastatic GB-NEC, and irinotecan with fluoropyrimidines has the best evidence as the second-line treatment. However, the regimen for adjuvant chemotherapy is not specified, although platinum/etoposide was probably used for the majority of patients (10–12). Although immunotherapy was not recommended in the guideline, the rationale for its application was based on a PD-L1 expression between 14% and 50%, a suspected high tumor mutational burden (TMB), and a broad range of multiple immune cells (13). Meanwhile, the therapeutic efficacy of immunotherapy should be thoroughly evaluated.

Herein, we describe the excellent benefits of tislelizumab, an anti-human programmed death receptor-1 (PD-1) monoclonal antibody (mAb), combined with chemotherapy in a patient pathologically diagnosed with GB-NEC with liver metastasis after palliative operation. As of the last follow-up, this patient remains alive with no complaints of discomfort, and the therapeutic response has been assessed as complete response (CR) for more than 10 months.

On 8 November, 2021, a 52-year-old woman was admitted to our hospital (The Third Affiliated Hospital of Navy Medical University, Shanghai, China) with the chief complaint of “almost 1 month after palliative surgery for metastatic gallbladder carcinoma.” On 6 October, 2021, the patient experienced unprovoked pain and discomfort in the upper abdomen, accompanied by nausea, acid reflux, and vomiting. Abdominal ultrasonography revealed cholecystolithiasis, cholecystitis, and choledocholithiasis. On October 9, the patient was admitted to Gaoyou People’s Hospital (Gaoyou, Jiangsu Province, China) for further medical care. The results of the examination after hospitalization showed the following: alanine transaminase (ALT) 161 U/L, aspartate aminotransferase (AST) 97 U/L, γ-glutamyl transferase (GGT) 246 U/L, and alkaline phosphatase (AKP) 200 U/L. No obvious abnormalities were found in the rest. Upper abdomen magnetic resonance imaging (MRI) indicated cholecystolithiasis, cholecystitis, and cholangitis, as well as hemangioma-like changes in the left lobe of the liver (Figure 1). Chest computed tomography (CT) and gastroscopy revealed no abnormalities. The patient had no fever, weight loss, or other complaints during the course of the disease and denied a family history of cancer. Considering the possibility of cholecystolithiasis, cholecystitis, and cholangitis, the patient underwent laparoscopic common bile duct lithotomy, laparoscopic cholecystectomy, common bile duct incision, and liver biopsy under general anesthesia on October 11. The postoperative pathology showed poorly differentiated adenocarcinoma combined with neuroendocrine carcinoma, with the cancer tissues invading the full thickness of the gallbladder wall (Figure 2A). In addition, a poorly differentiated neuroendocrine carcinoma was also found in the liver biopsy, which was considered to be a metastatic malignancy (Figure 2B).

Because there is no distribution of neuroendocrine tissues in the gallbladder, the origin of GB-NEC remains controversial. Considering the fact that NEC was mostly accompanied by cholelithiasis, many researchers believe that GB-NEC originated from the intestinal or gastric metaplasia of gallbladder epithelium caused by chronic inflammation (9, 14). On the other hand, some researchers held the opinion that GB-NEC was derived from undifferentiated multipotent stem cells in the gallbladder tissues (9). Furthermore, other researchers insist that NECs and adenocarcinoma could undergo intertransformation, and GB-NEC possibly originated from the transformation of adenocarcinomas (9).

Clinically, GB-NEC can be divided into functional and non-functional according to whether cancerous cells can secrete peptides, causing typical symptoms such as diarrhea, flushing, edema, and wheezing. However, due to the first-pass effect on the liver, only a small fraction of cases had the secretory symptoms, and the main complaints for most patients were non-specific, such as right epigastric discomfort, poor appetite, jaundice, and weight loss, which had no value for differential diagnosis (15). Furthermore, GB-NEC lacks specific tumor biomarkers and typical imaging features by CT or MRI, making it difficult to distinguish (9). All these are important factors for the unclear preoperative diagnosis of the reported case. The confirmative diagnosis of GB-NEC requires pathological examination and immunohistochemistry, including CgA, Syn, etc., which are regarded as specific biomarkers (16).

GB-NEC is a highly malignant and aggressive disease, for which systemic metastasis is common, with the liver being the commonest site of hematogenous metastasis. Chemotherapy is critical for most patients with metastatic GB-NEC. Platinum plus etoposide chemotherapy was the most recommended first-line regimen according to the ENETS, 2023 guidance (10, 12).

In this study, when GB-NEC was pathologically confirmed after surgery, the patient received 8 cycles of EP chemotherapy plus anti-PD-1 mAb tislelizumab immunotherapy, followed by maintenance therapy using tislelizumab alone every 3 weeks. The tumor response was evaluated as PR before the third cycle of treatment and as CR after half a year of maintenance therapy. Although the NGS results indicate PD-L1 negative for the surgical specimen, the therapeutic efficacy of the tislelizumab-containing regimen remains excellent, indicating that the NGS results cannot effectively predict the efficacy of PD-1 targeted therapy.

The prognosis of GB-NEC is poor. According to previous studies, the median survival time (MST) varies from 3 months to 10 months, with 1-, 2-, and 3-year survival rates of approximately 20%, 10%, and 0% (9, 17). In this study, the treatment response of the reported case was evaluated as CR since 13 February, 2023. Although the employment of checkpoint inhibitors is rarely reported, it seems that the application of PD-1 mAb-based therapeutics following palliative operation might be a potentially effective option. However, this scheme needs validation by further clinical studies. If this information is widely available, it will accurately guide the clinical treatment of GB-NEC in the future. Moreover, although the tumor was classified as clinical stage pT3N1M1 (IVB) in this case, according to the perioperative examination results, the intrahepatic tumor and lymph nodes were the metastatic sites only found. Thus, the limited extent of metastasis might also be the reason for the excellent therapeutic efficacy.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

HFL: Conceptualization, Data curation, Formal analysis, Funding acquisition, Writing – original draft, Writing – review & editing. JMQ: Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review & editing. XK: Writing – original draft. CW: Data curation, Formal analysis, Investigation, Writing – review & editing. HYL: Investigation, Methodology, Project administration, Resources, Supervision, Visualization, Writing – review & editing. JRQ: Conceptualization, Data curation, Formal analysis, Investigation, Project administration, Resources, Visualization, Writing – review & editing.