2 Pathology Research International FNH (mixed FNH-HCA)? Polyclonal/monoclonal I-HCA HCA with (formerly “T-FNH”) rare ductules monoclonal HCA with no ductules Figure 1: Schematic illustration of the histologic spectrum of benign hepatocellular proliferations. Polyclonal FNH is at one end of the spectrum and nontelangiectatic HCA is at the other; inﬂammatory HCA (I-HCA), formerly classiﬁed as telangiectatic FNH (T-FNH), has overlapping features and is shown in the middle. Gray areas indicate ﬁbrosis; green and red dots represent bile ductules and arterioles, respectively. characterization has become very informative and clinically useful. The most common primary hepatic malignancy is HCC, which constitutes 80–85% of all malignant epithelial neoplasms originating in the liver. HCC often arises in a background of cirrhosis and presents a global public health problem far greater than that of HCA. In the United States, the annual incidence of HCC has been rising over the past three decades [4]. The second most common primary hepatic malignancy is CC, constituting 15–20% of the total, and its incidence has also been rising. There has been an explosion of basic research in the ﬁeld of primary hepatic epithelial cancers in recent years, and we are just beginning to understand their molecular pathogenesis. We anticipate rapid advancements over the next several years in personalized medical approaches to the treatment of liver cancer, as the molecular mechanisms of hepatic tumorigenesis are elucidated and molecular classiﬁcation of these lesions is integrated into clinical study design [5]. 2. Focal Nodular Hyperplasia Focal nodular hyperplasia (FNH) is a common, benign hepatocellular lesion that is believed to arise in response to localized hyperperfusion of the liver parenchyma, typically in association with a microscopic arterial malformation [6, 7]. FNH frequently presents as an incidental hepatic mass noted in imaging studies, and it can often be diagnosed on the basis of its radiographic appearance alone. However, sometimes the diagnosis requires histologic conﬁrmation. Although the gross morphology and microscopic appearance of FNH in resection specimens are usually characteristic and easily recognized, distinguishing FNH from HCA in needle biopsies can be diﬃcult. The distinction is, however, of great importance because of the diﬀering clinical management of these entities. Traditionally, FNH has been considered nonneoplastic and, accordingly, it is thought to have no malignant poten- tial. However, molecular analyses of the clonality of FNH have yielded conﬂicting results, with some studies ﬁnding that up to 50% show X chromosome inactivation patterns suggestive of monoclonality [7, 8]. In general, polyclonality argues strongly against neoplasia, but the implications of monoclonality are less clear, since it may be inﬂuenced by factors such as variability in X-inactivation patterns, tissue architecture and turnover rate. Thus, the question of whether classic FNH is sometimes neoplastic remains controversial. Atypical forms of FNH have been described, including mixed lesions with both FNH-like and HCA-like areas, as well as lesions with histologic features intermediate between FNH and HCA [9]. The latter tumors were originally designated “telangiectatic FNH” (T-FNH), but subsequent molecular analyses have led to their reclassiﬁcation as a variant of HCA (see below). Mixed FNH-HCA have not been subjected to molecular analysis and, indeed, have not been described in recent publications. Therefore, their existence as a distinct entity is uncertain. Although FNH and variants of HCA comprise a histologic spectrum (Figure 1), there is no compelling evidence that they are biologically related in the sense of one being the precursor of another. Given the uncertainty surrounding the issue of neoplasia in FNH, several investigators have searched for genetic alterations that might deﬁne these lesions. If a genetic abnormality characteristic of FNH were found, it would greatly support its neoplastic nature, and the ﬁnding could be diagnostically useful in clinical practice. However, the results of such studies thus far have been uniformly negative, with no mutations detected in the APC, axin, β-catenin, HNF1α, or p53 genes in classic FNH [8, 10–12]. Both FNH and HCA consist predominantly of well- diﬀerentiated hepatocytes. In FNH, there are intervening ﬁbrous bands that radiate from a central scar and contain abundant, proliferating bile ductules. In contrast, HCA have only rare bile ductules, if any, and typically show much less ﬁbrosis. However, the regions of ﬁbrous scar in FNH are variable in abundance and are not always adequately sampled in needle biopsies, sometimes making the histologic distinction from HCA diﬃcult. We have found that the expression patterns of biliary markers, as determined by immunohistochemistry, are frequently diﬀerent in FNH and HCA, not only within regions containing bile ductules, but also in hepatocellular areas [13]. Antibodies against cytokeratin 19 (CK19) and neuronal cell adhesion molecule (NCAM, also known as CD56), which are markers of hepatic progenitor cells as well as biliary epithelium, clearly stain the proliferating ductules within ﬁbrous tracts in FNH and rare, isolated ductules in HCA. Cytokeratin 7 (CK7), which is known to be a marker of immature hepatocytes