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Page 2 of 17 Rastogi. Hepatoma Res 2020;6:47 I http://dx.doi.org/10.20517/2394-5079.2020.35

INTRODUCTION
Hepatocellular carcinoma (HCC) usually arises in a cirrhotic liver and is characterized by tremendous
[1]
phenotypic and molecular heterogeneity . Around 20% of HCCs arise in non-cirrhotic livers [2-5] . The
underlying etiologies, risk factors, pathogenetic mechanisms, gross specimen features, histological variants
and the differential diagnosis of non-cirrhotic HCCs is quite distinct from HCCs arising in cirrhotic
backgrounds. However, these aspects have not been adequately studied and further analysis of the
molecular genetics and pathological characteristics in non-cirrhotic HCCs is necessary. In this article, an
overview of the clinical, etiological and etiopathogentic, patho-molecular characteristics and differential
diagnosis of HCCs arising in non-cirrhotic backgrounds, are presented.

DEMOGRAPHIC AND CLINICAL CHARACTERISTICS
HCC is the most common primary malignant liver tumor and usually arises in cirrhotic livers. The
occurrence of HCC in non-cirrhotic livers varies across different geographic regions of the world with a
[6]
prevalence ranging from 7% to 54% . Most series, however, have reported a prevalence of around 15%-
[2-5]
20% .
The existence of HCC in non-cirrhotic livers has a bimodal age distribution, with peaks in the second and
seventh decades. Non-cirrhotic HCCs have a lower male to female sex ratio (1.3-2.1) in comparison to
[6]
cirrhotic HCCs where the ratio is 3.2 to 8:1 . HCC in non-cirrhotic patients manifest with non-specific
symptoms or a clinically silent course in the initial period. This is due to the lack of surveillance imaging
and higher hepatic reserves, leading to a delay in diagnosis until an advanced stage with a larger tumor
burden has been reached . Extrahepatic metastasis is already present in more than 25% of these patients at
[7]
[8]
the time of presentation .
Non-cirrhotic HCCs usually display similar imaging features to cirrhotic HCCs on computed tomography
(CT) and MRI, with arterial phase hyper-enhancement followed by washout on portal venous and/or
delayed phase imaging [9,10] . However, due to the non-prototypical background, the development of HCCs in
non-cirrhotic livers is one of the most important indications for tissue diagnosis. Imaging features illustrate
[11]
a solitary mass with or without satellite lesions . Similar to imaging, serum α-fetoprotein measurements
[7]
are similar for HCCs arising from both cirrhotic and non-cirrhotic backgrounds .
[7]
The prognosis for non-cirrhotic HCCs is usually better than that for cirrhotic HCCs . Non-cirrhotic HCCs
are more amenable to hepatic resection due to the lower risk of liver failure. Patients without cirrhosis have
longer survival (postoperative overall survival and recurrence-free survival) than patients with cirrhosis [7,12] .
However, the recurrence rate of HCC in non-cirrhotic livers is very high after surgical resection [11,13,14] .

ETIOLOGIC CONSIDERATIONS
A variety of conditions can be a risk factor for developing non-cirrhotic HCC.

Infections
Hepatitis B virus (HBV) infection is one of the most common underlying etiologies, especially in high
incidence areas. Up to 30% of HBV-related HCCs arise in non-cirrhotic livers [15,16] . HBV infection can
directly trigger liver carcinogenesis by integration of the HBV genome into the host hepatocyte DNA. This
can cause secondary chromosomal rearrangement and genomic instability, or produce genototoxins such
as the HBx protein, resulting in HCC development in non-cirrhotic backgrounds [7,17] . In addition, the X
protein of HBV, through its interaction with p53, interferes with tumor-suppressor activity. This oncogenic
impact of HBV can remain even in treated cases or after seroconversion and resolution of HBV [18,19] .