Search

Phenotypic identification of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) subtypes using immunohistochemical markers has been developed from their molecular characteristics. Our objective was to evaluate the sensitivity of these markers in the definitive diagnosis of these lesions by core needle biopsies. A total of 239 needle biopsies paired with their surgical resection specimen (group A) or without an associated resection specimen (group B) were reviewed. Using a step-by-step algorithm after standard staining, appropriate immunostaining analyses were performed to determine the certainty of diagnosis of FNH, HNF1α-inactivated HCA, inflammatory HCA, β-catenin-activated HCA, or unclassified HCA. The diagnosis of FNH was certain or probable on routine stains in 53% of needle biopsies of group A, whereas after glutamine synthetase staining, the diagnosis was certain in 86.7% as compared with 100% on the corresponding surgical specimen (P=0.04). In needle biopsies of group A, the diagnosis of HCA was certain on routine stains in 58.6% as compared with 94.3% on surgical specimens. After specific immunostaining, diagnosis was established on biopsies with 74.3% certainty, including all HCA subtypes, with similar distribution in surgical specimens. For each "certain diagnosis" paired diagnostic test (biopsy and surgical specimen), a positive correlation was observed (P<0.001). No significant difference was observed between groups A and B for FNH (P=0.714) or for HCA subtypes (P=0.750). Compared with surgical specimens, immunohistochemical analysis performed on biopsies allowed the discrimination of FNH from HCA and the identification of HCA subtypes with good performance.

Telangiectatic hepatocellular adenoma is a rare, recently recognized subtype of hepatocellular adenoma that is often underrecognized by pathologists. We report a case of hepatocellular carcinoma arising within a pigmented telangiectatic hepatocellular adenoma in a noncirrhotic man with diffuse glutamine synthetase and nuclear β-catenin positivity. This case highlights malignant transformation of telangiectatic adenomas, and describes a previously unreported association between pigment deposition and telangiectatic adenoma. Radiology, gross pathology, and histopathology are shown. Review of the literature with attention to β-catenin and glutamine synthetase staining, malignant transformation, patient characteristics, the presence of Dubin-Johnson-like pigment, and genetic characteristics of telangiectatic adenomas are discussed.

Agrin is a recently identified proteoglycan component of vascular and bile duct basement membranes in the liver. The selective deposition of agrin in hepatocellular carcinoma (HCC) microvessels versus sinusoidal walls prompted us to investigate the utility of agrin immunohistochemistry (IHC) in detecting malignant hepatocellular lesions. We focused on the differential diagnostic problems often presented by hepatocellular adenomas (HCAs) and dysplastic nodules. IHC for agrin was performed on 138 formalin-fixed, paraffin-embedded surgical specimens from 93 patients, including cirrhotic liver tissues (25), focal nodular hyperplasia (10), large regenerative nodules (8), low-grade (23) and high-grade (7) dysplastic nodules, small HCC (8), HCC (27), and HCA (30). Agrin immunostaining was compared with that of CD34 and, in selected cases, to glypican-3. The combination of agrin and CD34 sensitively (0.94) and specifically (0.93) identified lesions judged previously as malignant by histology. The majority of benign lesions were clearly agrin-negative, whereas the strength and extent of agrin IHC faithfully reflected dysplasia in "atypical" HCAs and in high-grade dysplastic nodules. Malignant lesions were uniformly positive. In conclusion, as agrin is highly selective for tumor blood vessels, IHC for agrin facilitates the discrimination of benign and malignant hepatocellular lesions. Moreover, whereas glypican-3 in some HCCs may appear in few scattered cells only, agrin is diffusely deposited in virtually all malignant lesions, which may prove advantageous in the evaluation of small specimens such as core biopsies.

It is often difficult to distinguish hepatocellular adenoma (HCA) from well-differentiated hepatocellular carcinoma (WDHCC) when limited tissue from a needle biopsy is evaluated. The aim of this study was to identify gene expression patterns that can distinguish HCA from WDHCC, with the ultimate goal of discovering novel diagnostic markers. Gene expression profile analysis was performed using Affymetrix U133Plus2 GeneChip microarrays on RNA isolated from frozen tissue of 6 HCA and 8 WDHCC specimens. Statistical analysis of microarray data identified 63 genes whose expression levels were significantly different between HCA and WDHCC. These included 57 genes overexpressed by HCA and 6 overexpressed by WDHCC. Eight genes were chosen for further analysis by quantitative RT-PCR on RNA derived from archived, paraffin-embedded tissue blocks of an independent validation set comprising 9 HCAs and 9 HCCs. Seven of the 8 genes demonstrated average expression differences between HCA and HCC that were concordant with the microarray findings, and their expression pattern correctly classified the 18 tumors into HCA and HCC using unsupervised clustering analysis. Furthermore, immunohistochemical staining performed on a third, independent set of 27 HCAs and 33 HCCs confirmed the expression differences at protein levels for 5 of the genes. Taken together, our data demonstrate significant molecular differences between HCA and WDHCC, despite their morphologic similarity. More importantly, we have identified a unique set of genes whose expression pattern can discriminate between these two types of hepatocellular neoplasms, suggesting the possibility of future development of ancillary molecular and immunohistochemical diagnostic methods.