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

risk group. In a real clinical surveillance protocol a combination of ultrasound based analysis and serological
determination of biomarkers: AFP, AFP-L3 and DCP increases the diagnostic accuracy to a significant level
compared to only image based study. However, ultrasound is reported to be precision compromised in
visualizing the liver in patients with morbid obesity, therefore, in next level of confirmation triple phase CT
or MRI is recommended. However, ultrasound positive, MRI negative cases are further cross-checked and
confirmed either by biopsy or MRI with liver specific contrast agent under this HCC surveillance guidance.
Based on 85-171 days of median doubling time in HCC volume, a 6-month interval in the surveillance
protocol is currently recommended. However, the JSH guidelines propose a 3-4 month interval for HBV and
HCV associated liver cirrhosis patients.

The widely approved strategy for the surveillance of HCC as mentioned above is a combination of image
based and serological analysis with varied stand alone and combined sensitivity and diagnostic accuracy
which provide impetus for the clinical assessment of new biomarker for HCC.

A recent study on the diagnostic performance of serum aldo-keto reductase family 1 member B10 (AKR1B10)
in hepatitis B virus/hepatitis C virus (HBV/HCV)-related liver diseases demonstrated a crucial correlation
in detection of HCC. Significant and stage dependent elevation of serum levels of AKR1B10 were recorded
in patients with HCC compared to liver disorder cases. Importantly, comparison of advanced and terminal
of HCC cases, a crucial increase in AKR1B10 levels was reported in early and intermediate HCC stages. The
reported sensitivity (81.0%) and specificity (60.9%) for AKR1B10 based HCC diagnosis were significantly high
at a cutoff value of 1.51 ng/mL. Further, conjoint measurement of serum AKR1B10 and AFP significantly
increased sensitivity and specificity of the combined diagnostic parameters [21,22] .

Cell secreted small membrane-enclosed spheres, present in biological fluids are known as extracellular
vehicles (EVs). EVs contain diverse types of biomolecules, including proteins, RNA, DNA, various
metabolites and lipids, etc. that often carries the signature of the ailing conditions of the tissues of their
origin. Thus, EVs are often potential source of biomarkers for different human pathobiology. Several lines of
different diagnostic reports suggested that HCC cell-derived EVs carries the key effectors for autocrine and/
or paracrine cellular communications, chemoresistance, angiogenesis, and tumor dissemination. A study
has been successful in identifying EVs secreted by sorafenib-treated HCC cells rich in long intergenic non-
coding RNA regulator for reprogramming (linc-ROR) that enables them to escape chemotherapy-induced
apoptosis by the mechanism of p53 repression, upregulating the expression of CD133 marker and the
stimulation of the signaling pathway for hepatocyte growth factor (HGF)/c-Met/Akt in liver cancer cells .
[23]
The notable abundance of EVs in biological fluids and their varied molecular payload has recently upgraded
EVs as a key source of non-invasive biomarkers in liver diseases. Diagnostic studies have demonstrated the
significantly elevated levels of different micro-RNAs in serum EVs of HCC patients (miRs 18a, 221, 222, and
224) as compared to cirrhosis or HCB patients, whereas a prominent drop in the concentration of miR-21
was consistently observed in the serum EVs of HCC patients as compared to HBV or healthy controls .
[24]
Another important molecular cargo of EVs isolated from HCC has been miR-665, whose concentration has
found to be positively correlated with tumor size, and clinical stages along with local invasion . Reduced
[25]
expression of another EV cargo, miR-718 is highly correlated with increasing tumor size, recurrence and
poor histological differentiation of HCC cells . Furthermore, low concentrations of serum EV packed miR-
[26]
125b have found to be associated to advanced TNM staging parameters, which is a suggestive of miR-125b
as a potential prognostic biomarker for recurrence and overall survival of HCC . Further, recent studies
[27]
suggest that apart from miRNAs, serum EVs has been the delivery mode of diverse set of HCC associated
proteins such as LG3BP, polymeric immunoglobulin receptor (PIGR) and alpha-2-macroglobulin (A2MG).
These proteins were found to be over expressed in HCC patients compared to healthy individuals and serum
EV concentrations of these proteins provided even better diagnostic value than AFP in early diagnosis of
HCC . Serum EV concentration itself is an implicative of HCC progression; it has been demonstrated that
[28]
stage I and II HCC patients recorded higher serum EV abundance compared to liver cirrhosis patients .
[29]