A 68-years-old male complained with xanthochromia, scleral icterus, and abdominal distension for over 20 days was admitted to our hospital in January 2018. He lost about 10 kg of body weight. Physical examination showed deep jaundice of the patient and the left supraclavicular lymph nodes were palpable. The performance status (PS) score was 3. Laboratory tests showed that total bilirubin (TB) was 707.9 umol/L, and CA19-9 level was over 12,000 U/mL, while AFP level was <20 ug/L (Table 1). Magnetic resonance imaging (MRI) found a 47 x 42 mm space-occupying lesion in Segment 4 (S4) and S5 of the liver and a mass in the common bile duct, suspicious for ICC. Subsequent positron emission tomography (PET) showed multiple distant metastases to lungs, abdominal lymph nodes, and left cervical lymph nodes. Histology of the liver lesion biopsy found numerous tubular structures of adenocarcinoma and a fibrous stoma (Figures 1A,B). Immunohistochemistry (IHC) analysis showed the following: CK(+), CK7(+), CK20(weak +), and Ki-67(3%+). The diagnosis was confirmed as stage IV ICC. The presumed survival time was only 3-5 months.
According to the opinion of the ICC multi-discipline team in our hospital, the patient was not a candidate for conventional treatments including surgery and chemotherapy, considering both tumor and PS status. Then, percutaneous transhepatic cholangial drainage (PTCD) was performed to relieve the jaundice and the patient's appetite recovered and the PS score was still 3. To comprehensively investigate the immune microenvironment, the tumor tissue of the liver lesion was submitted for subsequent tests. Additional IHC analysis found a low expression level of programmed cell death ligand 1 (PD-L1) and a low frequency of CD8+ T cells (Figures 1C-F). The whole-exome sequencing (WES) data showed high levels of both MSI and TMB (16.9 mutations/Mb), which indicated the potential benefit of immunotherapy. Additionally, there were 420 indels (insertions and deletions) and 660 single nucleotide variants (SNVs), with five mutations (including MLH1, SMARCA4, BRCA2, POLE2, and ARID1A) known to be associated with sensitivity to immunotherapy while one gene (B2M) conferred resistance to immunotherapy. We further included another 36 ICC cases in the Cancer Genome Atlas (TCGA) dataset to comparatively analyze the patient's tumor immune microenvironment based on the RNA-seq data. This case was found to have a moderate level of immune infiltration under a comprehensive immune signature (Figures 2A,B). Analysis of immune cell components in the tumor microenvironment using the CIBERSORT algorithm revealed scarce CD8+ cells but a large number of M2 macrophages, which is consistent with the IHC result and indicates an immunodeficient state (Figure 2C). After all, anti-PD-1 immunotherapy (pembrolizumab, at a dose of 200 mg every month) combined with radiotherapy was considered as treatment for the patient, which was initiated in February 2018 (Figure 3A).
After two cycles of immunotherapy, the patient's symptoms relieved and his PS improved. The size of the liver lesion slightly reduced to 38 x 33 mm but CA-199 was still over 12,000 U/mL (Figure 3B; Table 1). After six cycles, PS score was 1 and CA-199 was decreased to 4620.49 U/mL (Table 1). Contrast-enhanced computed tomography (CT) scans showed that the liver lesion reduced to 32 x 23 mm (Figure 3B). However, the number of lung metastases increased, which indicated a mixed response to immunotherapy (Figure 3C). Anti-PD-1 immunotherapy continued while radiotherapy was introduced to control the liver and lung lesions, with doses of 50.0 and 48.0 Gy, respectively. All visible tumors reduced in size gradually in the follow-up and the PTCD was removed 3 months later (Figure 3C). Currently, after 26 months of treatment, the patient is alive with high life quality. There aren't any symptoms and PS score is 1. The patient regained 5 kg of body weight. All tumor biomarkers including CA19-9 level are normal. The latest imaging examinations show invisible signs of the liver lesion, the metastatic lymph nodes, and the lung metastases. CR is achieved in this stage IV ICC case (Figure 3C; Table 1).