SAGE-Hindawi Access to Research Pathology Research International Volume 2011, Article ID 403929, 15 pages doi:10.4061/2011/403929 Review Article Molecular Pathology of Hepatic Neoplasms: Classiﬁcation and Clinical Signiﬁcance Zenta Walther and Dhanpat Jain Department of Pathology, Yale University School of Medicine, 310 Cedar Street, P.O. Box 208023, New Haven, CT 06520-8023, USA Correspondence should be addressed to Dhanpat Jain, dhanpat.jain@yale.edu Received 23 November 2010; Accepted 14 February 2011 Academic Editor: Alyssa M. Krasinskas Copyright © 2011 Z. Walther and D. Jain. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Recent technological advances have enabled investigators to characterize the molecular genetics and genomics of hepatic neoplasia in remarkable detail. From these studies, an increasing number of molecular markers are being identiﬁed that correlate with clinically important tumor phenotypes. This paper discusses current knowledge relevant to the molecular classiﬁcation of epithelial primary hepatic tumors that arise in adults, including focal nodular hyperplasia (FNH), hepatocellular adenoma (HCA), hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), and combined HCC-CC. Genetic analysis has deﬁned molecular subtypes of HCA that are clinicopathologically distinct and can be distinguished through immunohistochemistry. Gene expression studies have identiﬁed molecular signatures of progression from dysplastic nodules (DNs) to early HCC in cirrhosis. Analyses of the mutational spectra, chromosomal aberrations and instability, transcriptomics, and microRNA proﬁles of HCC have revealed the existence of biologically distinct subtypes of this common malignancy, with prognostic implications. Molecular characterization of biliary and hepatic progenitor cell phenotypes in liver cancer has shed new light on the histogenesis of these tumors and has focused attention on novel therapeutic targets. In coming years, the molecular classiﬁcation of hepatic neoplasms will be increasingly valuable for guiding patient care, as targeted therapies for liver cancer are developed and brought into clinical practice. 1. Introduction Over the past decade, tremendous advances have been made in the technologies available for characterizing the molecular genetics, genomics and epigenetics of neoplasia. These advances have greatly accelerated basic research aimed at elucidating the molecular mechanisms underlying tumori- genesis. In addition, they have led to the identiﬁcation of molecular markers that correlate with important biological characteristics of tumors. Such markers are increasingly valuable in clinical practice as tools for facilitating the diagnosis and categorization of tumors, determining their aggressiveness and, in some cases, predicting their responses to particular forms of therapy. The ideal classiﬁcation system for any group of neoplasms would be based on our under- standing of their ontogeny and would integrate histologic features with molecular data in a clinically meaningful way. In this paper, we will discuss the molecular biology of pri- mary hepatic tumors, with particular emphasis on the roles of molecular characterization in clinical practice. We will focus on primary hepatic neoplasms that arise in adults, including hepatocellular adenoma (HCA), hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), and the rare entity, combined hepatocellular and cholangiocarcinoma (HCC-CC). Focal nodular hyperplasia (FNH), although thought to be a nonneoplastic lesion, is often considered in the diﬀerential diagnosis of other hepatocytic tumors and, therefore, has also been included in this discussion. However, consideration of mesenchymal, hematopoietic and childhood liver tumors is beyond the scope of this review. FNH is the most common of the benign hepatocellular tumors, arising in approximately 3% of adults [1, 2]. Although the other major type of benign hepatocellular tumor, HCA occurs much less frequently, with an esti- mated incidence in Europe and North America of 0.003% [3], its association with hemorrhage, rupture, and risk of malignant transformation necessitates its accurate diagnostic distinction from FNH. This is an area in which molecular