Spectrum of Biliary Lesions/Neoplasms in Hepatic Parenchyma with Reference to a Precursor of Small Duct-Type...

Intrahepatic cholangiocarcinomas (iCCAs) are histologically subdivided into small duct-type (SD-iCCA) and large duct-type (LD-iCCA). LD-iCCA versus SD-iCCA may differ in the molecular/genetic profiles and oncogenesis, including precursor lesions. While several precursors, such as high-grade biliary intraepithelial neoplasm (BilIN) and intraductal papillary neoplasm of bile duct (IPNB), have been proposed for LD-iCCA, the potential SD-iCCA precursors remain to be identified. Amid growing interests in the precursors of SD-iCCA, benign "biliary lesions/neoplasms developing in the hepatic parenchyma (BLNP)" such as von Meyenburg complexes (VMCs), bile duct adenomas (BDAs), and biliary adenofibroma (BAF), have been noted to determine whether they have the potential for precursor of SD-iCCA. Herein, these BLNPs were reviewed. BLNP can be classified into three categories. First, traditional VMC and BDA in normal livers which lack atypical features are categorized as "traditional BLNP". Second, a constellation of several lesions such as VMC and BDA detectable in the background livers of SD-iCCA and in chronic liver disease (unusual VMC and BDA), VMC with dysplastic features, BDA located in the deep hepatic parenchyma, multiple BDA, BDA presenting the BRAF V600E mutation, and BAF harboring variable dysplasia or in situ carcinomas, which may include neoplastic lesions but do not show invasive growth, are categorized as "unusual/dysplastic BLNP". Third, tubulocystic carcinoma with BAF-like features (AI-TCC) and SD-iCCA with ductal plate malformation (DPMP) which share overlapping features and show relatively good post-operative outcomes and retained features of VMC or DPM, and BDA and BAF, are categorized as "low-grade malignant BLNP". While the first category is benign and may not be related to SD-iCCA, some of the second category may be related to SD-iCCA, and the third category is malignant and shows invasive growth. The latter two categories may form a common biliary tumorigenic spectrum involving BLNP. Precursors of SD-iCCA, if they exist, may be included in the second category, and the third category may represent unique carcinomas possibly associated with or followed by conventional SD-iCCA. In conclusion, this novel approach to categorize BLNPs into three categories guarantees further studies of precursors of and their progression to conventional SD-iCCA.