Review Article
Hepatocellular carcinoma in non-cirrhotic liver: A reappraisal

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Abstract

Although not frequently, hepatocellular carcinoma (HCC) can ensue in a non-cirrhotic liver. As compared to cirrhotic HCC, this kind of tumour has some peculiarities, such as: (a) a lower male preponderance and a bimodal age distribution; (b) a lower prevalence of the three main risk factors (hepatitis B and C virus infections and alcohol abuse), with an increased prevalence of other etiologic factors, such as exposure to genotoxic substances and sex hormones, inherited diseases, genetic mutations; (c) a more advanced tumour stage at the time of diagnosis, as it is usually detected due to the occurrence of cancer-related symptoms, outside any scheduled surveillance program; (d) a much higher amenability to hepatic resection, due to the low risk of liver failure even after extended parenchymal mutilation; (e) overall and disease-free survivals after resection of non-advanced tumours (meeting the Milano criteria) comparable to that obtained with liver transplantation in cirrhotic patients carrying an early tumour; (f) overall survival strictly dependent on tumour burden (and its recurrence) and barely influenced by liver function.

Introduction

Hepatocellular carcinoma (HCC), the most frequent type of primary liver cancer, is the sixth most common solid tumour and the third cause of cancer mortality in world population [1].

Liver cirrhosis is the main risk factor for HCC, leading to chronic necroinflammation and hepatocellular regeneration. This is the background for genetic mutations to accumulate and cells to progress to overt malignancy. Nevertheless, a certain number of HCCs arise in non-cirrhotic livers. This kind of hepatic carcinogenesis occurs in a proportion of cases that ranges widely from 7% to 54% across the geographic areas and according to the aetiology of the liver disease [2], [3], [4], [5], [6], [7], [8], [9].

This review describes the epidemiological and clinical features, and the therapeutic management of non-cirrhotic HCCs, which are fairly distinct from those of the same tumour when it occurs in a cirrhotic background.

Section snippets

Demographic characteristics

Some series of non-cirrhotic HCCs reported a lower male preponderance (male/female ratio: 1.3–2:1) as compared with the cirrhotic counterpart, where this ratio ranges from 3.2 to 8:1 [6], [8], [10]. However, this feature was not confirmed by other studies, reporting similar ratios [5], [11], [12].

The mean age is generally less advanced in non-cirrhotic than in cirrhotic patients [6], [8], [12], although there is not full agreement about this feature either [5], [11], [13]. Namely, cirrhotic HCC

Viral infections

As for cirrhotic HCC, hepatitis B virus (HBV) or C virus (HCV) chronic infections are the main risk factors. However, current or occult/past HBV (testified by serum anti-core antibody [HBcAb]) and HCV infections were more commonly found in cirrhotic than non-cirrhotic patients in most series [6]. Table 1, Table 2 report the prevalence of HBV surface antigen (HBsAg) and anti-HCV antibody in these two categories of patients coming from different geographic areas.

HBV infection can trigger hepatic

Hepatocarcinogenetic pathways

Some authors have hypothesised a different hepatocarcinogenetic pathway in HCC with and without cirrhosis. This assumption is based on the detection of a different scenario of genetic alterations found in non-cirrhotic HCC, that is, a trend towards a lower rate of p53 mutation and a higher prevalence of β-catenin mutation, p14 inactivation and global gene methylation [70].

A recent study analysed the presence of microsatellite instability (MSI), a sign of deficiency in DNA mismatch repair

Pathologic findings of HCC and the surrounding non-cirrhotic liver

The non-tumoural liver of these patients ordinarily presents with chronic hepatitis, varying degrees of fibrosis, steatosis, iron overload or other metabolic disorders, so that very few cases show a normal parenchyma [2], [6], [13]. Moreover, cell dysplasia, more often the large cell type, can be found in 27–40% of the cases [2], [18]. These figures decrease to 6–20% in the subgroup of non-fibrotic liver [13], [19].

A single large mass (around 10 cm in many series) is the most common macroscopic

Diagnosis

In developed countries, a growing number of patients with chronic liver diseases evolving to high grade fibrosis or cirrhosis are now being included in scheduled ultrasonographic surveillance, as recommended by the recent international guidelines for HCC management [28], [29]. Surveillance in fact succeeds in achieving an early diagnosis of the tumour, usually before the clinical symptoms become manifest. Instead, in otherwise healthy patients (or with an undiagnosed liver disease),

Treatment and survival

Hepatic resection is the best therapeutic choice for patients with non-cirrhotic HCC. Although data regarding its feasibility in unselected (non-surgical) series are not available, it is likely that the proportion of patients with non-cirrhotic HCC eligible for resection is much greater than the 12–28% reported for those with underlying cirrhosis [80], [81]. In fact, despite a larger tumour burden, the preserved function of non-cirrhotic liver generally offers the chance of performing very

Conclusions

As compared to a tumour developing in a cirrhotic liver, non-cirrhotic HCC presents some peculiarities:

  • (a)

    Lower male preponderance and a bimodal age distribution.

  • (b)

    Lower prevalence of the three main risk factors for HCC, that is, HBV and HCV infections and alcohol abuse.

  • (c)

    More advanced tumour stage at the time of diagnosis, since it is generally detected at a symptomatic stage.

  • (d)

    Much higher amenability to hepatic resection, due to the low risk of liver failure even in the case of extended parenchymal

Conflict of interest

None declared.

Acknowledgment

The authors thank Ms. Susan West for the linguistic revision of the manuscript.

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