4 neoplasia, Chen et al. performed directed LOH analysis and genomic sequencing of several Wnt pathway genes [10]. Three of ten HCA were found to bear small, in-frame deletions in one allele of the β-catenin gene, and to express truncated forms of the protein that are predicted to be constitutively activated. The French group that had originally identiﬁed HNF1 inactivation in HCA next expanded their study to include assessment of β-catenin mutation status as well as genotype- phenotype correlations in these tumors [26]. In a collection of 96 HCA, 44 were found to have HNF1 gene inactivation and to display a characteristic histology, including marked hepatocellular steatosis, a lack of cytologic atypia, and an absence of inﬂammatory inﬁltrates in the lesion. Beta- catenin mutation was identiﬁed in 12 of the 96 tumors and was frequently associated with histologic features suggestive of malignancy, including nuclear atypia and pseudoacinar formation. Importantly, β-catenin mutation and HNF1 inactivation were mutually exclusive in these tumors, indi- cating the existence of at least two distinct, nonoverlapping molecular subtypes of HCA. In the 1990s, a class of histologically unusual hepatic tumors was described and termed “telangiectatic FNH” (T-FNH) [9]. These lesions lacked a central scar, but because they displayed focal ductular reaction and a nodular architecture, they were categorized as an atypical variant of FNH. However, the sinusoidal dilatation, naked arterioles, and frequent intralesional hemorrhage that typiﬁed T-FNH were recognized as being similar to HCA (Figure 1). These peculiar features of T-FNH invited molecular characteriza- tion and comparison with both classic FNH and HCA. Two groups performed clonality assays and found a much higher rate of monoclonality in T-FNH than in classic FNH [11, 20]. The angiopoietin mRNA expression pattern, which had been shown to diﬀer between FNH and HCA, was found in T- FNH to resemble that of HCA, and a global proteomic proﬁle of T-FNH matched that of HCA while distinguishing both T-FNH and HCA from classic FNH [20]. Together, these ﬁndings strongly suggest that so-called telangiectatic FNH is actually a variant of HCA. In the genotype-phenotype study described above, HCA that were found not to harbor genetic alterations in either HNF1 or β-catenin were further subdivided into two groups on the basis of the presence or absence of inﬂammatory inﬁltrates. The subgroup showing inﬂammation, named inﬂammatory HCA (I-HCA), was found to include all lesions formerly classiﬁed as T-FNH. Thus, four subtypes of HCA were proposed: (1) HNF1-inactivated HCA (H-HCA), (2) β-catenin-mutated HCA (β-HCA), (3) I-HCA, and (4) nonmutated, noninﬂammatory HCA [26]. A subsequent study of 93 HCA (47 of which had been previously analyzed) supported this classiﬁcation system in general, except that β- catenin mutation was discovered to occur in a fraction of I- HCA as well as in noninﬂammatory HCA [27]. The hypothesis that I-HCA represents a biologically distinct entity was greatly strengthened with the ﬁnding of a marked overexpression of acute-phase reactants by the hepatocytes of these lesions [27]. At both the mRNA Pathology Research International and the protein level, serum amyloid A (SAA) and C- reactive protein (CRP) are signiﬁcantly overexpressed in I-HCA relative to nonneoplastic liver. When all types of hepatocellular adenoma are examined, the sensitivity and speciﬁcity of SAA overexpression by immunohistochemistry for identifying I-HCA was found to be 94%. The degree of SAA overexpression did not correlate with the extent of inﬁl- tration by inﬂammatory cells, which suggested that acute- phase protein expression might be an intrinsic feature of the neoplastic hepatocytes, whereas inﬂammatory inﬁltration might be secondary. To explore this possibility, Rebouissou et al. undertook a genome-wide mRNA expression study, comparing I-HCA to normal liver, and identiﬁed a pro- nounced activation of acute-phase inﬂammatory signaling in I-HCA [28]. Further inquiry into the potential causes of this inﬂammatory gene expression signature led to the discovery of mutations in the IL6ST gene, which encodes gp130, a component of the IL-6 receptor, in 60% of I-HCA [28]. These IL6ST mutations lead to ligand-independent activation of the IL-6 receptor, which promotes STAT3 sig- naling and induces the acute-phase inﬂammatory response within hepatocytes. The recruitment of inﬂammatory cells into I-HCA appears to be secondary to gp130-mediated hepatocellular production of the chemokine, CCL20, which attracts immune cells. In this study, all 43 I-HCA were found to show expression signatures indicative of IL-6 pathway activation, even those tumors in which no IL6ST mutation was identiﬁed. In I-HCA lacking IL6ST mutation, no other genetic alterations could be identiﬁed in various components of the STAT3 signaling pathway. However, gp130 protein levels were elevated in most of these lesions, suggesting that posttranslational control of gp130 was aberrant, perhaps due to occult mutation of a gene that normally regulates gp130’s protein abundance. In summary, HCA can be assigned to one of four categories [3]. The ﬁrst is H-HCA and is deﬁned by HNF1 inactivation. This variety accounts for 35–40% of all HCA and occurs almost exclusively in women. Rarely, these tumors arise in the context of familial diabetes (MODY3) and can be multiple. H-HCA can be identiﬁed through immunohistochemical staining for liver fatty acid binding protein (LFABP), which is a transcriptional target of HNF1 and is completely absent in the hepatocytes of these lesions. Histologically, H-HCA usually displays marked steatosis but no inﬂammation, and it lacks cytologic atypia. The second category, I-HCA, comprises over 50% of all HCA. It is characterized by the presence of inﬂammatory inﬁltrates, focal ductular reaction, sinusoidal dilation, and dystrophic arterioles. I-HCA almost invariably shows dramatic over- expression of acute-phase reactants, including SAA and CRP, which can be demonstrated by immunohistochemistry (Figure 3). Although the HNF1 gene is never inactivated in I-HCA, β-catenin mutations are sometimes found [29]. This type of HCA is associated with obesity, smoking, and alcohol consumption and is the most common variety of HCA in men. The third category of HCA is somewhat controversial and consists of lesions that harbor activating mutations of β-catenin but are noninﬂammatory; it has been reported