Checkpoint Inhibition Causing Complete Remission of Metastatic Combined Hepatocellular-Cholangiocarcinoma after Hepatic Resection

Abstract

Combined hepatocellular-cholangiocarcinoma (CHC) is a rare type of primary liver cancer, speculated to arise from hepatic progenitor cells, and with a worse prognosis than hepatocellular carcinoma (HCC). Serum alpha-fetoprotein (AFP) levels may be one prognostic factor. It has been suggested that checkpoint inhibition might be useful in the treatment of HCC where there is an increased expression of PD-1 and PD-L1 in the microenvironment. Its effect on CHC is unknown. We report a case with a large CHC, which was radically resected, but the 53-yearold female patient subsequently developed pulmonary metastases. Histology demonstrated low-differentiated CHC without microsatellite instability. Treatment with sorafenib was started but was stopped due to angioedema. Under subsequent gemcitabine/cisplatin treatment, the metastatic disease progressed with rising AFP levels. A third-line treatment with pembrolizumab was then started, 2 mg/kg b.w. i.v. every third week for 6 months. This resulted in a radiologically complete remission of the pulmonary metastases and AFP levels were normalized (<10 μg/L) from a level of 1,790 μg/L before treatment. The patient developed immunerelated adverse events (AEs) including diarrhea and hepatitis. These AEs were successfully treated with prednisolone and mycophenolate mofetil, and they were eventually resolved. There are no signs of cancer recurrence neither in the liver nor in the lungs at 33 months after the start of the checkpoint inhibition treatment, and the patient is doing well. Further study is urgently needed on the role of checkpoint inhibition therapy in liver cancer. are responsible for the surgical care and M.P. and L.N. for the oncologic care of the patient. F.A. and J.S. for conception of the study and drafting the manuscript. L.S. is responsible for the pathology examination of the primary liver tumor and pulmonary metastases including histology, immunohistochemistry analyses of MSI. F.H. is responsible for the radiological examinations of the patient. All authors were involved in writing the final manuscript.

Combined hepatocellular-cholangiocarcinoma: An update

“…32,93,96 Sorafenib, approved as the first-line treatment for advanced HCC, and gemcitabine and cisplatin, the standard of care for unresectable iCCA, do not seem to have significant antitumour efficacy. 95 With the exception of 1 case report, 97 no data are available in the literature concerning immunotherapy. This clearly shows that cHCC-CCA should be considered a distinct entity that potentially requires specific therapeutic strategies.…”

Etiology, Pathogenesis, Diagnosis, and Practical Implications of Hepatocellular Neoplasms

“…Unfortunately, the rarity of these tumors has interfered with the performance of randomized clinical trials. There is a paucity of data regarding immunotherapies [ 90 ], although studies suggest that at least some cHCC–CCA should be responsive to these types of treatment [ 91 , 92 ]. Broad genomic profiling of malignancies for actionable mutations specific to each case is currently the most likely path to any possible clinical benefit [ 93 ].…”

Mycophenolate mofetil for immune checkpoint inhibitor‐related hepatotoxicity relapsing during dose reduction of corticosteroid: A report of two cases and literature review

“…We have summarized 15 articles reporting the clinical course of hepatic irAEs treated with MMF (Table 1 ). 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 The types of liver injury were classified as hepatitis, cholangitis or mixed pattern based on pathological findings or, if unavailable, R‐ratios at diagnosis of immune‐related liver injury. 26 Most patients were primarily refractory to steroids; the efficacy rate of MMF in them was less than half.…”