Cholangiolar pattern and albumin in situ hybridisation enable a diagnosis of intrahepatic cholangiocarcinoma

Abstract

<jats:sec><jats:title>Aims</jats:title><jats:p>The histological distinction of intrahepatic cholangiocarcinoma (ICC) from metastatic adenocarcinoma remains a challenge. The primary goal was to evaluate the diagnostic value of morphology and albumin expression in the diagnosis of ICC.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We evaluated morphological patterns in 120 ICCs and 677 non-hepatic adenocarcinomas and performed in situ hybridisation (ISH) stain for albumin in the former cohort (retrospective cohort). We also identified 119 samples from primary and metastatic lesions, the validation cohort, in which albumin ISH was performed as part of the diagnostic workup. Targeted sequencing was performed on selected cases. We also mined existing expression profiling data including cases from The Cancer Genome Atlas (TCGA) (41 760 unique samples).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>In the retrospective cohort, 45% of ICCs and &lt;1% of non-hepatic adenocarcinomas showed a cholangiolar pattern; albumin ISH was positive in 93% of ICCs with significant intratumorous heterogeneity. In the validation cohort, 29% of ICCs showed a cholangiolar pattern and 88% expressed albumin, while all metastatic non-hepatic neoplasms were negative (n=37) (sensitivity 88% and specificity 100%). Targetable genetic alterations (<jats:italic>IDH</jats:italic> mutations and <jats:italic>FGFR2</jats:italic> fusions) were identified in 31% of ICCs (10 of 32). An analysis of the TCGA data validated the specificity of the albumin assay.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>The cholangiolar pattern and albumin RNA ISH distinguishes ICC from metastatic adenocarcinoma with high specificity. Given the high prevalence of targetable mutations in ICC, albumin RNA ISH is an essential component in the workup of tumours of uncertain origin. A specific diagnosis of ICC could trigger molecular testing and uncover targetable genetic alterations.</jats:p></jats:sec>

Quantitative proteomic analysis of bile in extrahepatic cholangiocarcinoma patients

“…Cholangiocarcinoma cell arising from cell proliferation after bile duct injury could be a form of undifferenciated cholangiocyte producing albumin. There are several reports on aberrant expression of albumin; it could be used to distinguish bile duct neoplasm from other metastatic adenocarcinoma [46][47][48].…”

Optimizing the Diagnosis and Biomarker Testing for Patients with Intrahepatic Cholangiocarcinoma: A Multidisciplinary Approach

“…To establish the diagnosis of iCCA and distinguish it from other tumors, it is recommended that specific imaging observations are considered and analyzed [ 46 , 52 ]. HCC may be distinguished from iCCA based on radiological features on a contrast-enhanced imaging study; while HCC lesions show hyperenhancement in the arterial phase and contrast washout in the venous phase, iCCA shows progressive contrast uptake throughout both arterial and venous phases without a washout pattern [ 46 , 47 , 48 ].…”

“…Importantly, albumin in situ hybridization assays may aid pathologists in the diagnosis of iCCA and should be considered in the workup when iCCA is suspected. Research has shown that non-hepatic primary cancers are largely negative for albumin and that positive albumin in cancer cells has high sensitivity for iCCA [ 52 , 53 , 54 ]. While the assays can differentiate iCCA from liver metastases, it should be noted that it may not be useful in differentiating iCCA from HCC or pancreatic acinar cell carcinoma lesions; therefore, HCC and pancreatic acinar-specific markers should be used to rule out these tumors.…”

“…While the assays can differentiate iCCA from liver metastases, it should be noted that it may not be useful in differentiating iCCA from HCC or pancreatic acinar cell carcinoma lesions; therefore, HCC and pancreatic acinar-specific markers should be used to rule out these tumors. Additionally, a negative result should not be exclusionary for iCCA diagnosis as the sensitivity of the assay has ranged from 64 to 99% and large duct iCCA is commonly negative for albumin staining [ 52 ].…”

“…Other diagnostic clues include the cholangiolar pattern, which comprises well-formed ducts with angular profiles that mimic antler horns [ 52 ]. Although the cholangiolar pattern can be used to distinguish iCCA, it is not present in most cases [ 51 , 52 ].…”