Abstract
Morphologic intratumor heterogeneity is well known to exist in hepatocellular carcinoma (HCC), but very few systematic analyses of this phenomenon have been performed. The aim of this study was to comprehensively characterize morphologic intratumor heterogeneity in HCC. Also, taken into account were well-known immunohistochemical markers and molecular changes in liver cells that are considered in proposed classifications of liver cell neoplasms or discussed as molecular therapeutic targets. In HCC of 23 patients without medical pretreatment, a total of 120 tumor areas were defined. Analyzed were cell and tissue morphology, expression of the liver cell markers cytokeratin (CK)7, CD44, α-fetoprotein (AFP), epithelial cell adhesion molecule (EpCAM), and glutamine synthetase (GS) along with mutations of TP53 and CTNNB1, assayed by both Sanger and next-generation sequencing. Overall, intratumor heterogeneity was detectable in the majority of HCC cases (20 of 23, 87%). Heterogeneity solely on the level of morphology was found in 6 of 23 cases (26%), morphologic heterogeneity combined with immunohistochemical heterogeneity in 9 of 23 cases (39%), and heterogeneity with respect to morphologic, immunohistochemical, and mutational status of TP53 and CTNNB1 in 5 of 23 cases (22%). Our findings demonstrate that intratumor heterogeneity represents a challenge for the establishment of a robust HCC classification and may contribute to treatment failure and drug resistance in many cases of HCC.
Highlights
Hepatocellular carcinoma (HCC) generally arises in the context of chronic liver diseases, including chronic viral hepatitis, alcoholinduced liver injury, or other metabolic, dietary, or toxic factors such as fatty liver disease or aflatoxin ingestion [1] and ranks number 3 among the leading causes of cancer mortality worldwide [2]
Overall, intratumor heterogeneity was detectable in the majority of hepatocellular carcinoma (HCC) cases (20 of 23, 87%)
Heterogeneity solely on the level of morphology was found in 6 of 23 cases (26%), morphologic heterogeneity combined with immunohistochemical heterogeneity in 9 of 23 cases (39%), and heterogeneity with respect to morphologic, immunohistochemical, and mutational status of TP53 and CTNNB1 in 5 of 23 cases (22%)
Summary
Hepatocellular carcinoma (HCC) generally arises in the context of chronic liver diseases, including chronic viral hepatitis, alcoholinduced liver injury, or other metabolic, dietary, or toxic factors such as fatty liver disease or aflatoxin ingestion [1] and ranks number 3 among the leading causes of cancer mortality worldwide [2]. Attempts to classify HCC by immunohistochemical markers or molecular genetic characteristics added fundamental knowledge to our understanding of hepatocarcinogenesis but so far have hardly been applied in routine surgical pathology and postoperative management [4, 5]. This stands in contrast to the widely accepted classification of hepatocellular adenoma based on morphology, immunohistochem-. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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