Discussion
Primary GB-neuroendocrine tumors (NET) account for 0.5% of all NET and 2.1% of all GB cancers[9]. The most common primary tumor sites are the gastrointestinal and respiratory tracts [2] ,and GB-NEC is very rare. Although there is no comprehensive epidemiological information on gallbladder NEC, there is a report that the median age of patients is 58.4 years (range 26-75), with an M:F ratio of 7:8. Median overall patient survival is 26 months for those without lymph node metastasis and 10.4 months for patients with it [10].
Cisplatin and Etoposide (EP therapy) or Cisplatin and Irinotecan (IP therapy) is widely recommended for NEC, but the response rate and median overall survival (OS) are unfavorable (EP: response rate, 12%; median OS 6.9 months , IP: response rate, 39%; median OS 10.1 months) [11].
In the present case, considering the patient’s age and medical history, we started nivolumab monotherapy. As a result of image examination, though the paraaortic lymph node swelled, the GB tumor clearly shrank and swelling of hepatic duct lymph node disappeared. A tumor marker against NEC, NSE turned negative.
These findings suggest that nivolumab can be effective against GB-NEC. Nevertheless, PD-L1 28-8 immunohistochemistry (IHC) was positive in less than 10% of cancer cells. This suggests the following two possibilities: 1. PD-L1 positive cells were killed by nivolumab, leaving only colonies of negative cells. 2. Nivolumab activates T cells, which kill PD-L1 negative cells. Drug sensitivity of cancer cells varies from cell to cell because each cancer cell has a different genetic background. Therefore, although ICIs are very effective for cancer cells with high PD-L1, ICIs may also be effective against subgroups with low or undetectable PD-L1. Actually, it has been reported that in lung cancer, ICIs respond even when the expression rate of PD-L1 is extremely low [12]. Recent studies suggest that PD-L1 inhibitors themselves may activate tumor-reactive T cells and enhance anti-tumor immunity [13]. Further studies on the correlation between the PD-L1 expression rate and the ICI response rate in gallbladder cancer are awaited.
EUS-FNA is quite useful because its sensitivity to GB cancer is 96% [14]. In this case, we detected NEC using the EUS-FNA technique for lymph nodes in the hepatoduodenal ligament. However, in cases in which primary tumors have both NET and non-neuroendocrine components, so-called mixed neuroendocrine-nonneuroendocrine neoplasms (MiNEN), EUS-FNA may not be able to detect all of them. NEC is highly malignant and readily metastasizes to other tissues. Therefore, even if an NEC component is detected by biopsy of metastatic lymph nodes, the primary tumor may contain nonneuroendocrine components such as adenocarcinoma.
It is necessary to choose an effective chemotherapy regimen for all tumor components. Multiple EUS-FNA enables collection of multiple samples, which can facilitate correct diagnosis and selection of an appropriate chemotherapy regimen, but dissemination and bile leakage are problematic [15]. Furthermore, NEC is located deep within an area of vascular or perineural invasion [16]. As a result, most MiNEN are diagnosed from surgical specimens [17]. Therefore, it is important to diagnose using serum tumor markers, imaging tests, or EUS-FNA. Ultimately, it may be useful to collect samples surgically.
In conclusion, EUS-FNA is useful for diagnosis of GB-NEC. However, because the primary tumor may be MiNEN rather than NEC, it is better to perform a biopsy when selecting a chemotherapy regimen. Nivolumab may enhance the immune function of T cells by some means other than inhibition of PD-1, and it may be effective against GB-cancer involving NEC despite the low expressionof PD-L1.