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Page 8 of 18 Galicia-Moreno et al. Hepatoma Res 2020;6:20 I http://dx.doi.org/10.20517/2394-5079.2019.36

Histopathology
This diagnostic method can only be considered when evaluating nodules greater than 2 cm, or if radiological
[51]
findings are not compatible with HCC. However, liver biopsies can yield false negative results . Histological
evaluation is considered positive if the sample is positive for at least two of glypican 3, heat shock protein 70
[52]
and glutamine synthase, which represents a sensitivity of 72% and a specificity of 100% .

Finally, we will review two novel, unconventional, diagnostic methods of HCC.

Gut microbiota analysis
The gut microbiota has an important role in the maintenance of homeostasis in humans. Evidence
[53]
demonstrates connections between gut microbiota and HCC development. Ponziani et al. demonstrated
that translocated bacterial elements from the gut to the liver can start an inflammatory process through
toll-like receptors (TLRs). Lipopolysacharides from Gram (-) bacteria can bind TLR-4; TLR-2 recognizes
the bacterial triacylated lipopeptide, and TLR-5 can recognize flagellin, a protein component of bacterial
flagella [54,55] . In all cases, the final effect is the production of inflammatory cytokines such as TNF-a, IL-1b
[56]
and IL-6 from the NF-kB pathway . The gut microbiota and the development of HCC is also linked directly
[57]
via the JAK or STAT3 pathway, which are mainly activated by IL-6 . Due to this, gut microbiota evaluation
could improve diagnostic reliability. Pre- clinical and clinical trials have shown a direct correlation between
Gram (-) bacteria and inflammatory changes related to the development of HCC. All these observations
suggest that evaluation of the proportion of harmful and beneficial bacteria could be considered as a
promising tool for the early diagnosis of HCC. Some limitations have been considered for these purposes
as sometimes, HCC patients are subjected to antibiotic treatment, which may alter the composition and
function of their microbiota, limiting diagnostic use.

Nanotechnology for HCV diagnosis
HCV infection is the main etiologic agent of hepatic cirrhosis and HCC. There are 8 main genotypes and
[58]
86 subtypes described in the last few years . These antiviral agents are effective in reducing the probability
of developing cirrhosis and HCC. However, these are highly expensive drugs and inaccessible to most
patients, especially in low-income countries. Another important aspect to consider is that only a few highly-
specialized laboratories perform molecular diagnosis for HCV, which is essential for the best diagnosis and
[59]
treatment .
Nanotechnology is a new, interesting and promising diagnosis tool for infectious diseases that uses
[59]
nanoparticles and specific nanoscale tests directed at the pathogen genome . There are different types
of nanoparticles and gold is suitable for efficient diagnosis. It has been used to identify pathogens such as
[62]
[63]
[61]
[60]
Mycobacterium tuberculosis , Helicobacter pylori , the dengue virus , and influenza A . On the other
hand, RNA aptamers are single-stranded RNA oligonucleotides that specifically bind to a target molecule,
[59]
which makes them good alternatives for the development of HCV serological tests . Nanoparticles and
aptamers, can be used as biosensors for diagnosis as the fusion of both can be bound to the HCV core
[64]
protein, enabling easy detection of this protein .
There are several reasons that can lead to diagnostic failure in early HCC and as a consequence, failure in
the correct selection of therapies. First, the absence of early identification of the at-risk population; second,
no application of routine surveillance (e.g., performance of ultrasound twice a year); and finally, mistakes in
[1]
the interpretation of screening tests . There is no evidence to suggest that HCC screening improves survival
in high-risk groups, although many medical professionals do use several diagnostic strategies such as AFP
[65]
and liver ultrasonography for HCC screening . Nevertheless, screening tests for HCC are very important
to increase survival and quality of life. For example, when detected early, 5-year survival is greater than 50%
but when diagnosed late and patients are symptomatic or the cancer is late stage, 5-years survival is less than
[18]
10% .