Hepatic Precancerous Lesions and Small Hepatocellular Carcinoma

https://doi.org/10.1016/j.gtc.2007.08.010Get rights and content

Precancerous lesions that may be detected in chronically diseased, usually cirrhotic livers, include: clusters of hepatocytes with atypia and increased proliferative rate (dysplastic foci) that usually represent an incidental finding in biopsy or resection specimens; and grossly evident lesions (dysplastic nodules) that may be detected on radiologic examination. There are two types of small hepatocellular carcinoma (HCC) (defined as HCC that measures less than 2 cm): early HCC, which is well-differentiated and has indistinct margins; and distinctly nodular small HCC, which is well- or moderately differentiated, and is usually surrounded by a fibrous capsule. Precise diagnosis of precancerous and early cancerous lesions by imaging methods is often difficult or impossible. Detection of a dysplastic lesion in a biopsy specimen is a marker of increased risk for HCC development, and warrants increased surveillance. High-grade dysplastic nodules and small HCCs should be treated by local ablation, surgical resection, or liver transplantation.

Section snippets

Cytologic Changes in Hepatocarcinogenesis

According to the IWP nomenclature [1], dysplastic foci are defined as clusters of hepatocytes with atypia, measuring less than 1 mm in diameter. Although the size criterion is arbitrary, it is related to the fact that dysplastic foci nearly always are contained within a single hepatic lobule (or cirrhotic nodule, because these lesions usually are detected in the setting of cirrhosis). Of course, these small lesions cannot be recognized grossly or radiologically, but they represent incidental

Dysplastic Nodules

Dysplastic nodules (DNs) are nodular lesions that differ from the surrounding parenchyma with regard to size, color, texture, or the degree to which they bulge from the cut surface of resected specimens (Fig. 2). DNs are usually, but not always, detected in cirrhotic livers [1]. Several comprehensive reviews of the histologic features of these lesions have been published in the previous 5 years [14], [29], [30], [31], [32], [33]. Low-grade DNs have features suggestive of a clonal cell

Small Hepatocellular Carcinoma

According to the consensus nomenclature [1], small HCC is defined arbitrarily as carcinomas that measure less than 2.0 cm in diameter. Studies from Japan [48], [56], [57] have shown that there are two types of small HCC:

  • Vaguely nodular HCC (also known as early HCC, or HCC with indistinct margins), which is well-differentiated, lacks a fibrous capsule, and often contains portal tracts (ie, grows around preexisting portal tracts) (Fig. 4)

  • Distinctly nodular HCC, which is well- or moderately

Molecular Pathogenesis of Hepatocellular Carcinoma

The molecular changes that lead to dysplasia are initiated in chronically diseased livers, before cirrhosis is established. At that stage, alterations in gene expression are mostly quantitative, occurring by epigenetic mechanisms [62]. Alterations include increased expression of growth factors, such as transforming growth factor-α (TGF-α) and insulin-like growth factor-2 (IGF-2), which leads to accelerated hepatocyte proliferation. Promoter hypermethylation, resulting in gene inactivation, is

Stem Cells and Hepatocarcinogenesis

There are two distinct roles that stem cells play in HCC development. The first is that of an HCC initiator, such as a facultative, non-neoplastic, liver stem cell that undergoes malignant transformation. The second is that of an HCC-repopulating stem cell, such as a malignant cell that has all the functional features of a facultative stem cell (eg, self-renewal, slow cycling, production of a rapidly proliferative transit-amplifying progeny that generates the bulk of tumor cells, and resistance

Radiologic Imaging of Nodular Lesions in Cirrhotic Livers

Radiologic detection, and characterization, of nodular lesions in cirrhosis remains challenging. Although ultrasound is used widely for detection of HCC in noncirrhotic livers, it is less useful in patients with cirrhosis unless intravenous contrast agents are used. Furthermore, distinction between benign and malignant nodules is also challenging. The overall detection of DNs in explant studies is poor [100]. CT requires iodinated contrast agents and uses ionizing radiation, but it is widely

Summary

Large nodules detected in cirrhotic livers by imaging include large regenerative nodules, dysplastic nodules (low- or high grade), and small HCCs. The differential diagnosis of these lesions by ultrasound, CT, or MRI may be difficult or impossible. Even biopsies may be difficult to interpret. Nevertheless, histologic evidence of a dysplastic nodule, or cytologic change suggestive of dysplasia (dysplastic focus) indicates an increased risk for carcinoma development and warrants increased

References (105)

  • K. Ueda et al.

    Vascular supply in adenomatous hyperplasia of the liver and hepatocellular carcinoma. A morphometric study

    Hum Pathol

    (1992)
  • M. Arakawa et al.

    Emergence of malignant lesions within an adenomatous hyperplastic nodule in a cirrhotic liver. Observations in five cases

    Gastroenterology

    (1986)
  • M. Sakamoto et al.

    Early stages of multistep hepatocarcinogenesis: adenomatous hyperplasia and early hepatocellular carcinoma

    Hum Pathol

    (1991)
  • T. Takayama et al.

    Malignant transformation of adenomatous hyperplasia to hepatocellular carcinoma

    Lancet

    (1990)
  • S. Terasaki et al.

    Histological features predicting malignant transformation of nonmalignant hepatocellular nodules: a prospective study

    Gastroenterology

    (1998)
  • M. Borzio et al.

    Impact of large regenerative, low-grade and high-grade dysplastic nodules in hepatocellular carcinoma development

    J Hepatol

    (2003)
  • O. Nakashima et al.

    Pathomorphologic characteristics of small hepatocellular carcinoma: a special reference to small hepatocellular carcinoma with indistinct margins

    Hepatology

    (1995)
  • M. Roncalli et al.

    Methylation framework of cell cycle gene inhibitors in cirrhosis and associated hepatocellular carcinoma

    Hepatology

    (2002)
  • S. Lee et al.

    Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis

    Am J Pathol

    (2003)
  • V. Paradis et al.

    Clonal analysis of micronodules in virus C-induced liver cirrhosis using laser capture microdissection and HUMARA assay

    Lab Invest

    (2000)
  • M. Maggioni et al.

    Molecular changes in hepatocellular dysplastic nodules on microdissected liver biopsies

    Hepatology

    (2000)
  • M. Sun et al.

    An early lesion in hepatic carcinogenesis: loss of heterozygosity in human cirrhotic livers and dysplastic nodules at the 1p36-p34 region

    Hepatology

    (2001)
  • Y. Kondo et al.

    Genetic instability and aberrant DNA methylation in chronic hepatitis and cirrhosis—a comprehensive study of loss of heterozygosity and microsatellite instability at 39 loci and DNA hypermethylation on 8 CpG islands in microdissected specimens from patients with hepatocellular carcinoma

    Hepatology

    (2000)
  • L. Tornillo et al.

    Chromosomal alterations in hepatocellular nodules by comparative genomic hybridization: high-grade dysplastic nodules represent early stages of hepatocellular carcinoma

    Lab Invest

    (2002)
  • M. Chuma et al.

    Expression profiling in multistage hepatocarcinogenesis: identification of HSP70 as a molecular marker of early hepatocellular carcinoma

    Hepatology

    (2003)
  • V. Paradis et al.

    Molecular profiling of hepatocellular carcinomas (HCC) using a large-scale real-time RT-PCR approach

    Am J Pathol

    (2003)
  • J.M. Llovet et al.

    A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis

    Gastroenterology

    (2006)
  • N.D. Theise

    Cirrhosis and hepatocellular neoplasia: more like cousins than like parent and child

    Gastroenterology

    (1996)
  • L. Libbrecht et al.

    The immunohistochemical phenotype of dysplastic foci in human liver: correlation with putative progenitor cells

    J Hepatol

    (2000)
  • A. Suetsugu et al.

    Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cells

    Biochem Biophys Res Commun

    (2006)
  • J. Neuzil et al.

    Tumour-initiating cells vs. cancer stem cells and CD133: what's in the name?

    Biochem Biophys Res Commun

    (2007)
  • International Working Party

    Terminology of nodular hepatocellular lesions

    Hepatology

    (1995)
  • S. Watanabe et al.

    Morphologic studies of the liver cell dysplasia

    Cancer

    (1983)
  • Y. Nakanuma et al.

    Unusual hepatocellular lesions in primary biliary cirrhosis resembling but unrelated to hepatocellular carcinoma

    Virchows Arch A Path Anat

    (1993)
  • M. Zhao et al.

    Three types of liver cell dysplasia (LCD) in small cirrhotic nodules are distinguishable by karyometry and PCNA labeling, and their features resemble distinct grades of hepatocellular carcinoma

    Histol Histopathol

    (1994)
  • Y. Makino et al.

    Histological features of cirrhosis with hepatitis C virus for prediction of hepatocellular carcinoma development: a prospective study

    Anticancer Res

    (2000)
  • L. Libbrecht et al.

    Predictive value of liver cell dysplasia for development of hepatocellular carcinoma in patients with noncirrhotic and cirrhotic chronic viral hepatitis

    Histopathology

    (2001)
  • Koo JS, Kim H, Park BK, et al. Predictive value of liver cell dysplasia for development of hepatocellular carcinoma in...
  • P.P. Anthony et al.

    Liver cell dysplasia: a premalignant condition

    J Clin Pathol

    (1973)
  • E. Adachi et al.

    Proliferating cell nuclear antigen in hepatocellular carcinoma and small liver cell dysplasia

    Cancer

    (1993)
  • P. Hytiroglou

    Morphological changes of early human hepatocarcinogenesis

    Semin Liver Dis

    (2004)
  • A. Marchio et al.

    Chromosomal abnormalities in liver cell dysplasia detected by comparative genomic hybridisation

    Mol Pathol

    (2001)
  • S. Natarajan et al.

    Large-cell change of hepatocytes in cirrhosis may represent a reaction to prolonged cholestasis

    Am J Surg Pathol

    (1997)
  • M. Borzio et al.

    Hepatocyte proliferation rate is a powerful parameter for predicting hepatocellular carcinoma development in liver cirrhosis

    Mol Pathol

    (1998)
  • M. Roncalli et al.

    Abnormal DNA content in liver cell dysplasia—a flow cytometric study

    Int J Cancer

    (1989)
  • S.S. El-Sayed et al.

    DNA ploidy and liver cell dysplasia in liver biopsies from patients with liver cirrhosis

    Can J Gastroenterol

    (2004)
  • P.E. Zondervan et al.

    Molecular cytogenetic evaluation of virus-associated and nonviral hepatocellular carcinoma: analysis of 26 carcinomas and 12 concurrent dysplasias

    J Pathol

    (2000)
  • V. Paradis et al.

    Clonal analysis of macronodules in cirrhosis

    Hepatology

    (1998)
  • R.R. Plentz et al.

    Telomere shortening and p21-checkpoint inactivation characterize multistep hepatocarcinogenesis in humans

    Hepatology

    (2007)
  • Y.D. Deugnier et al.

    Preneoplastic significance of hepatic iron-free foci in genetic haemochromatosis: a study of 185 patients

    Hepatology

    (1993)
  • Cited by (0)

    This study was supported in part by a grant from the National R&D Program for Cancer Control of the Ministry of Health and Welfare of the Republic of Korea (no. 0,620,210) to Dr. Young Nyun Park.

    View full text