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Case Reports
. 2022 Feb 19;12(2):539.
doi: 10.3390/diagnostics12020539.

A Rare Case of Hepatic Vanishing Bile Duct Syndrome Occurring after Combination Therapy with Nivolumab and Cabozantinib in a Patient with Renal Carcinoma

Affiliations
Case Reports

A Rare Case of Hepatic Vanishing Bile Duct Syndrome Occurring after Combination Therapy with Nivolumab and Cabozantinib in a Patient with Renal Carcinoma

Karim Gourari et al. Diagnostics (Basel). .

Abstract

Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) significantly improve the outcomes of patients with advanced clear cell renal cell carcinoma (ccRCC); however, high-grade toxicities can occur, particularly during combination therapy. Herein, we report a patient with advanced metastatic ccRCC, who developed grade 4 cholestasis during combined therapy with nivolumab and cabozantinib. After the exclusion of common disorders associated with cholestasis and a failure of corticosteroids (CS), a liver biopsy was performed that demonstrated severe ductopenia. Consequently, a diagnosis of vanishing bile duct syndrome related to TKI and ICI administration was made, resulting in CS discontinuation and ursodeoxycholic acid administration. After a 7-month follow-up, liver tests had returned to normal values. Immunological studies revealed that our patient had developed robust T-cells and macrophages infiltrates in his lung metastasis, as well as in skin and liver tissues at the onset of toxicities. At the same time, peripheral blood immunophenotyping revealed significant changes in T-cell subsets, suggesting their potential role in the pathophysiology of the disease.

Keywords: checkpoint inhibitors; cholestasis; immune related adverse events; severe ductopenia; vanishing bile duct syndrome.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
First liver biopsy performed at presentation. Hematoxylin and eosin-stained sections. (A): Liver parenchyma is characterized by centrilobular necrosis, sometimes confluent. (B): Immune infiltrate predominates around portal areas and is mainly composed of lymphocytes (arrow) and rare eosinophils (arrowhead).
Figure 2
Figure 2
Second liver biopsy performed 5 weeks after cholestasis onset. Immunohistochemical staining with an anti-cytokeratin-7 (CK7) antibody. Large interlobular bile ducts are absent as anti-CK7 staining only reveals the ductular reaction. These findings are suggestive of ductopenia.
Figure 3
Figure 3
Tissue immune infiltration at disease progression and at the onset of toxicities. (A): Representative fluorescent multiplexed IHC images of lung metastasis, skin tissue, and liver tissues before (PRE) and during (ON) immunosuppressive therapy. Tumor-infiltrating lymphocytes were revealed by CD20 (red), CD8 (yellow) and CD4 (green), FOXP3 (blue), CD68 (magenta), and tumor cells by panCK (cyan). (B): Quantification of immune cell (as percentage of total cells) within the stroma, the epithelium, and total area of each tissue.
Figure 4
Figure 4
Peripheral blood immune cell profiling at the onset of toxicities. Immunophenotyping of granulocytes and mononuclear cells during immunosuppressive therapy at two timepoints after the onset of toxicities (visit 1 and 2) using flow cytometry.

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