Author information

¹Department of Pathology, National University Hospital, Singapore.

²Ospedale Pediatrico Bambino Gesu, 00165 Rome, Italy.

³Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.

⁴Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele -Milan, Italy; IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano -Milan, Italy.

⁵Institute of Pathology and Medical Genetics, University Hospital Basel, Basel, Switzerland.

⁶Institute of Pathology, Meduniwien, Medical University of Vienna, 1090 Wien, Austria.

⁷Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, VA 22042, United States of America.

⁸Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario M5G1X8, Canada.

⁹Centre for Liver Disease Research, School of Medicine (Southern), University of Queensland, Princess Alexandra Hospital, Ipswich Rd Woolloongabba 4109, Australia.

¹⁰Department of Pathology and Medical Biology, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.

¹¹Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, United States of America.

¹²Department of Pathology, Yonsei University College of Medicine, Seoul Korea.

¹³Department of Pathology, Yonsei University College of Medicine, Seoul Korea. Electronic address: jtaek0517@yuhs.ac.

¹⁴Institute of Pathology, University Hospital, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.

¹⁵Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Department of Pathology, Aretaieion Hospital, Medical School, National & Kapodistrian University of Athens, Athens, Greece.

¹⁶Department of Pathology, Aretaieion Hospital, Medical School, National & Kapodistrian University of Athens, Athens, Greece.

¹⁷Department of Pathology and Molecular Pathology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.

¹⁸Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America. Electronic address: Torbenson.Michael@mayo.edu.

Abstract

Histological subtyping of hepatocellular carcinoma (HCC) is challenging in the presence of histological heterogeneity, where distinctly different morphological patterns are present within the same tumor. Current approaches rely on percent cut-offs. We hypothesized that morphologic intratumor heterogeneity is a non-random biological feature and that incorporating recurrent patterns would improve histological subtyping of HCC. Resected HCC were studied and the overall frequency of morphologic intratumor heterogeneity was 45% in 242 specimens. Steatohepatitic HCC (SH-HCC) had the highest frequency of morphologic intratumor heterogeneity (91%); this was confirmed in additional cohorts of SH-HCC from different medical centers (overall frequency of 78% in SH-HCC). Morphologic intratumor heterogeneity in SH-HCC showed distinct and recurrent patterns that could be classified as early, intermediate, and advanced. Incorporating these patterns into the definition of SH-HCC allowed successful resolution of several persistent challenges: the problem of the best cut-off for subtyping SH-HCC, the problem of the relationship between SH-HCC and scirrhous HCC, and the classification for HCC with abundant microvesicular steatosis. This approach also clarified the relationship between SH-HCC and CTNNB1 mutations, showing that CTNNB1 mutations occur late in a subset of SH-HCC. In summary, there is a high frequency of morphologic intratumor heterogeneity in HCC. Incorporating this finding into histological subtyping resolved several persistent problems with the SH-HCC subtype.