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Page 4 of 17 Rojas et al. Hepatoma Res 2018;4:31 I http://dx.doi.org/10.20517/2394-5079.2018.60

However, in patients with early stage of HCC, AFP showed the best AUC (0.80, 95% CI: 0.77-0.84) followed by
DCP (0.72, 95% CI: 0.68-0.77) and then AFP-L3 (0.66, 95% CI: 0.62-0.70). Intermediate-advanced stage of HCC
compared to cirrhotic controls showed a highest AUC of DCP (0.89, 95% CI: 0.86-0.92) compared to total
AFP (0.84, 95% CI: 0.81-0.88) (P = 0.01), indicating that DCP could be a more useful marker in advanced
[9]
stages . The cut off points used were 20 ng/mL for AFP, 10% for AFPL3 and 150 mAU/mL for DCP.

Nevertheless, there are some important differences between DCP and AFP; DCP is more specific for HCC
because the underlying liver disease (e.g., chronic hepatitis C) can lead to an elevation of AFP but not of
DCP. The DCP-positive and AFP-negative tumors show greater aggressiveness, larger size, less differentiation
and vascular invasion, and in short, an early recurrence after curative treatments [22,23] .

[24]
Along these lines, Hamamura et al. compared survival among four groups of similar patients diagnosed
with HCC based on AFP and DCP levels (A: AFP below 100 ng/mL and DCP below 0.0625 AU/mL; B:
AFP greater than 100 ng/mL and DCP below 0.0625 AU/mL; C: AFP below 100 ng/mL and DCP above
0.0625 AU/mL; D: AFP greater than 100 ng/mL and DCP above 0.0625 AU/mL). The survival rates obtained
after 3 years were 73.4%, 48.3%, 42.7% and 0%, respectively, while those values at 5 years were 53.5%, 25.9%, 0%
and 0%, respectively, in a statistically significant way. Therefore, it can be concluded that patients with high
levels of AFP and DCP have a lower survival, as well as those with high DCP only have a worse prognosis
than those who do not.

Several studies have suggested that DCP may be involved in cell proliferation of neoplasic cells by acting as
a growth factor. This may have important prognostic implications in the future, especially if combined with
AFP [25,26] .

Glypican-3
Glypican-3 (GPC3) is a member of the glypican family of glycosyl-phosphatidylinositol-anchored cell-surface
heparan-sulfate proteoglycans. Its levels increase considerably in patients with HCC, while GPC3 is not
[27]
detected in healthy liver tissue, so it has been identified as an useful tumor marker for HCC diagnosis .
Thus, in a recently published meta-analysis, sensitivity and specificity observed were of 0.53 (95% CI: 0.49-
[28]
0.57) and 0.77 (95% CI: 0.74-0.81), respectively, with an AUC of 0.82 . In addition, it seems to have a higher
[29]
sensitivity than AFP, with similar specificity , whereas their combination notably increase both sensitivity
[30]
and specificity (98.5% and 97.8%, respectively) . On the other hand, GPC3 is detectable in approximately
[16]
one third of patients with HCC with normal AFP levels .
[31]
With regard to early diagnosis, Libbrecht et al. studied the expression of GPC3 in histopathological
samples of HCC with less than or equal to 3 cm of diameter present in the cirrhotic liver (also analysing
non-lesional tissue), low-grade and high-grade dysplastic nodules, and focal nodules of hyperplasia.

Immunohistochemical studies and real time reverse transcriptase-polymerase chain reaction for GPC3 were
performed. The expression of GPC3 by both techniques was much higher in small HCC than in cirrhosis
and other types of small focal lesions, with a sensitivity and specificity for the diagnosis of HCC in small
focal lesions of 0.77 and 0.96, respectively, in resected cases, and 0.83 and 1, respectively, for needle biopsies.
This may be due to the stimulation of growth induced by GPC3, which upregulates the autocrine/paracrine
canonical Wnt signaling, with a strong increase in its expression in the transition from premalignant lesions
[32]
to small HCC .

Since GPC3 acts as a growth factor in HCC, it could be a potential therapeutic target. Codrituzumab (GC33)
is a recombinant, humanized monoclonal antibody that binds to human GPC3 with high affinity. The