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.