Intrahepatic Cholangiocarcinoma with High Microsatellite Instability and Tumor Mutation Burden That Responded Significantly to Pembrolizumab but Perforated within a Short Period

Abstract

Cholangiocarcinoma has a poor prognosis, and resection is the only curative treatment. Pembrolizumab, a programmed death receptor 1 inhibitor, has proven effective against unresectable or metastatic solid tumors with high microsatellite instability (MSI-H) or a high tumor mutation burden (TMB-H). In the present case, pembrolizumab treatment was initiated after standard chemotherapy for MSI-H and TMB-H unresectable intrahepatic cholangiocarcinoma. Intrahepatic tumor necrosis perforated the abdominal cavity. Emergency surgery was performed, but the patient died 36 days after admission. A pathological autopsy revealed that the intrahepatic tumor had almost completely disappeared.

Keywords: microsatellite instability-high; pembrolizumab; tumor mutation burden-high; unresectable cholangiocarcinoma.

Figure 1.

Imaging findings before and after percutaneous transhepatic portal vein embolization. (a, b) Intrahepatic cholangiocarcinoma invaded the second part of the duodenum (arrowheads). (c) Computed tomography (CT) before PTPE showed that intrahepatic cholangiocarcinoma had not invaded the middle hepatic artery (arrow). (d) CT after PTPE showed that intrahepatic cholangiocarcinoma had invaded the middle hepatic artery (arrow). (e, f) Hepatoduodenal ligament lymph node metastases appeared (arrows). The analyses were performed by computed tomography (a, c-e), esophagogastroduodenoscopy (b), or fluorine-18 fluorodeoxyglucose positron emission tomography (f).

Figure 2.

(a) Clinical course of treatment and changes in serum CA19-9 levels. CA19-9: cancer antigen 19-9, PTPE: percutaneous transhepatic portal vein embolization, NGS: next-generation sequencing. (b) CT showed that the tumor was clearly larger after GS treatment than before treatment. Left panel: Before GS treatment. Right panel: After GS treatment.

Figure 3.

CT findings before and after pembrolizumab therapy. (a, b) Following pembrolizumab therapy, the intrahepatic tumor decreased in size from 63 mm×72 mm to 38 mm×40 mm, and the tumor contained air, which suggested tumor necrosis. (c) CT showed Douglas’ pouch ascites. (d, e) CT (sagittal section) revealed perforation of the necrotic tumor into the abdominal cavity (arrow), and penetration of the tumor and duodenum was observed (arrowhead). Upper abdominal free air and ascites were documented.

Figure 4.

(a) Clinical course after surgery and changes in serum WBC and CRP levels. (b) CT showed no ascites or intra-abdominal abscess. (c) An examination of the upper gastrointestinal seven days after surgery showed fistula with the intrahepatic cavity, but passage through the GI tract was uneventful. (d) An examination of the upper gastrointestinal 21 days after surgery illustrated that duodenal obstruction and the intrahepatic bile duct and cavity were contrasted through the perforation.

Figure 5.

Macroscopic findings at the autopsy. (a) The necrotic tumor was exposed in the duodenal lumen (arrowhead). The asterisk indicates the antrum, and the sharp sign indicates the duodenum. (b) Fistulas with tumor were observed on the liver surface (arrows).

Figure 6.

Pathological findings at the autopsy. (a) Intrahepatic tumor. (b) Perforation of the liver. (c) Lungs. The upper panels present macroscopic findings, and the middle and lower panels present microscopic findings. (a) Upper panel: Residual carcinoma (red lines). Middle panel: Carcinoma (arrow), necrosis (arrowhead). Lower panel: carcinoma. (b) Upper panel: perforated site (arrow). Middle and lower panel: No remnants of carcinoma. (c) Lower panel: No findings of alveolar loss or fibrosis, indicative of drug-related interstitial pneumonia.