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 ].…”

Component with abundant immune‐related cells in combined hepatocellular cholangiocarcinoma identified by cluster analysis

“…Contrastingly, for iCCA, immunotherapy has resulted in antitumor responses, but only in a select group of patients; consequently, the introduction of suitable indications has been delayed 15,16 . However, patients with cHCC‐CCA are mostly excluded from clinical trials on immunotherapies because of the rarity and specific features of this disease 6 ; there is only one case report on using immune therapy for treating cHCC‐CCA 17 …”

“…15,16 However, patients with cHCC-CCA are mostly excluded from clinical trials on immunotherapies because of the rarity and specific features of this disease 6 ; there is only one case report on using immune therapy for treating cHCC-CCA. 17 Interpretation of the tumor immune microenvironment (TIME) is important for exploring the therapeutic indication of immunotherapy. 18 Recent studies have shown that high expression of PD-L1 19,20 and abundant tumor-infiltrating lymphocytes [21][22][23] are correlated with the treatment effectiveness of immunotherapy.…”

“… 15 , 16 However, patients with cHCC‐CCA are mostly excluded from clinical trials on immunotherapies because of the rarity and specific features of this disease 6 ; there is only one case report on using immune therapy for treating cHCC‐CCA. 17 …”