Molecular Characteristics and Immunogenomic Profiling of Cholangioblastic Variant of Intrahepatic Cholangiocarcinoma in a 68-year-old Patient

Discussion

Cholangioblastic variant of intrahepatic cholangiocarcinoma is a rare variant of primary intrahepatic biliary tract tumor, and only a few cases have been reported so far (2-5). It usually occurs in young patients with a mean age of 24.5-year-old. However, the age of the patient should not dissuade the suspicion for this tumor, as we herein report the tumor in a 68-year-old patient.

Morphologically, the tumor displays a variety of growth patterns, including trabecular, nested, microcystic/follicular, organoid as well as angulated glandular architectures. It often shows predominantly monotonous cytologic features, with small and uniform tumor cells with basophilic cytoplasm and a lack of nuclear pleomorphism. Occasionally, islands of large hepatoid cells with abundant eosinophilic cytoplasm are also present. In biopsies, due to the monotonous appearance and immunoreaction to some neuroendocrine markers, it is often mistaken as a metastatic well-differentiated NET of unknown primary site. Indeed, 5 of 7 previously reported cases and our case of this tumor were initially misdiagnosed as metastatic well-differentiated neuroendocrine tumors. Other considerations may include metastatic breast carcinoma with neuroendocrine differentiation and metastatic acinar cell carcinoma of the pancreas, both of which may show patchy labeling for neuroendocrine markers and could be mistaken for a well-differentiated NET.

However, the distinct biphasic cytologic features and patchy immunoreaction to synaptophysin and chromogranin in the tumor should raise concerns for this variant of cholangiocarcinoma. In this scenario, screening with inhibin A immunohistochemistry is the logical step to identify candidate cases. The strong and diffuse immunoreaction to Inhibin A and lack of expression of INSM1, GATA3, and Trypsin A all strongly support the diagnosis.

It is not surprising that the expression of neuroendocrine markers can be found in the primitive epithelial cells that compose the developing ductal plate or other blastomas, including hepatoblastoma, pancreatoblastoma, and pulmonary blastoma. Inhibin A expression can be present in 25% of cholangiocarcinoma with stem cell features and ⅛ of fetal liver tissue (3). It is worthy of mention that Inhibin A is not exclusively expressed in CVICC; it is also reportedly expressed in 13% of metastatic NET. In challenging cases, a NIPBL-NACC1 fusion gene, which was recently reported by Argani et al. (4) to be characteristic of CVICC, should be considered to further support the diagnosis. The possible biological function of the NIPBL-NACC1 fused gene is largely unknown but could be the dysregulation of NACC1 protein, thus promoting neoplastic growth.

In summary, cholangioblastic variant of intrahepatic cholangiocarcinoma is a rare entity with distinct biphasic cytology, a strong immunoreaction to Inhibin A, and novel NIPBL-NACC1 gene fusion. It is often misdiagnosed as a metastatic well-differentiated NET. Increasing awareness of the diagnostic pitfall with NETs and including Inhibin A as a screening immunomarker in candidate cases may facilitate proper classification of these tumors and prevent future mistakes.