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Page 2 of 9 Bose et al. Hepatoma Res 2019;5:24 I http://dx.doi.org/10.20517/2394-5079.2019.10

disease (NAFLD) often develop cirrhosis and are at high threat of developing HCC, with a significantly high
annual incidence rates nearing 2% per year . However, cirrhosis may or may not be present in HCC. Studies
[2]
have revealed that NAFLD patients would be at a high risk of developing HCC, even in absence of cirrhotic
transformation. The development of HCC is a complex multi-step process named as “hepatocarcinogenesis”
and characterized by progressive genetic aberrations. Studies of these HCC associated molecular aberrations
have also exposed that this malignancy is orchestrated by accumulation of some key genetic as well as
epigenetic events which in turn lead to anomalous activation or inhibition of diverse cellular signaling
cascades in crucial cellular processes like proliferation, cellular survival, differentiation, and angiogenesis.
Further, the emergent views coming out of different studies suggest that the key cell biological events
including regulation of p53/ARF, RB/INK4A and Wnt/β-catenin pathways are also found to be affected in
most cases of HCCs irrespective of etiology of the disease, indicating the presence of a shared oncogenic
pathway in HCC development that regulates the mentioned biochemical events.

Clinical manifestation of HCC is diverse and significantly heterogeneous; asymptomatic cases are of
suggestively high in incidence while symptoms often encompass from pain in upper right-abdominal
quadrant, weight loss to obstructive jaundice and fatigue that are not strikingly exclusive compared to
other hepatic ailments, viral infections, alcohol abuse associated functional loss of liver, etc. These make the
differential detection, screening and monitoring of this fatal disease highly challenging.

Imaging is one of the gold standard non-invasive methods along with assessment of the biomarker alpha-
fetoprotein (AFP) for diagnosis, staging and follow-up monitoring of HCC patients. Further, in standard
clinical practice, AFP > 10 ng/mL or a composite AFP index ensures satisfactory sensitivity for early HCC
detection . However, there have been limitations often reported in sensitivity and specificity of AFP
[3]
assessment and ultrasound based imaging with regard to clinical correlations with HCC. AFP-L3 and des-γ
carboxy prothrombin (DCP) are also used as important biomarkers for HCC determination . HCC have
[4]
a strong sex dominance in male (2 to 8 times more common) than in female in low - and high incidence
areas. It has also been reported that the incidence of HCC holds a significant correlation with age, but
a tendency of early onset of HCC in high-incidence areas has been observed too. With the continuous
increase in incidence and mortality of HCC, along with the limitations of the current diagnostic strategy,
the development of improved strategy for early detection is of greatest importance. The current review will
discuss the latest clinical practice along with some recently introduced techniques in the early and sensitive
diagnosis of HCC.

METHODOLOGY
Clinical manifestation and image based analysis
Often HCC progresses without prominent clinical symptoms and with no detectable aberration in liver
function escaping early diagnosis. This makes HCC diagnosis usually delayed in developing countries
with limited surveillance resources. On the other hand, clinical symptoms are emphasized in cases with
compromised liver function. In advanced stages, symptoms include right upper quadrant abdominal pain,
hepatomegaly, obstructive jaundice, hemobilia, and persistent fever. Some associated non-specific symptoms
of malignant disease including anorexia, nausea, lethargy and weight loss are often reported. In many cases
patients with unrecognized cirrhosis or known compensated cirrhosis may also present. Regular clinical
practice employs various imaging studies such as ultrasonography (US), contrast enhanced computed
tomography (CT) and magnetic resonance imaging (MRI) etc. for diagnosis, treatment management and
follow up of HCC [Figure 1] . According to the European Association for the Study of the Liver (EASL),
[5]
liver lesions of length 2 cm or more observed on MRI or computed tomograph angiography (CTA), with AFP
> 400 ng/mL or rising within sequential measurements do not require biopsy confirmation . According
[6]
to American Association for the Study of Liver Disease (AASLD) guideline however, liver lesions smaller