E. Fekaj. Surg Chron 2014; 19(2): 65-67.

A prognostic value of biomarkers in hepatocellular carcinoma

Enver Fekaj
Department of Abdominal Surgery, University Clinical Center of Kosovo, Pristine, Republic of Kosovo

Abstract
Hepatocellular carcinoma (HCC) is the predominant histological type, accounting for 70-85% of total liver cancers. Chronic HBV infection is the most prevalent cause of HCC, following by chronic HCV infection. Despite many treatment options for patients with HCC,
the mortality rate remains high making HCC the third leading cause of cancer-related death worldwide. Prognostic algorithms, such
as the Barcelona Clinic Liver Cancer (BCLC) classification, have been introduced in routine clinical care. Although current clinical staging systems provide a rough framework of prognostic classification and treatment decision for HCC, identification of prognostic biomarkers could further enhance outcome prediction and treatment selection. A high level of C-reactive protein (CRP) at the time of
diagnosis predicts poor long-term survival of patients with HCC. The neutrophil:lymphocyte ratio (NLR) is an independent predictor
for prognosis in patients with HCC. The elevation of NLR indicates that host immunity remains low. A decrease in the number of CD4
cytotoxic T lymphocytes (CTLs) is closely associated with progressive stages of HCC and poor survival. A high expression level of
SALL4, an oncofetal gene, has a worse prognosis in patients with HCC. Future studies, based on large prospective cohorts, are required to validate their prognostic value before they can be translated into clinical use.
Key words: Hepatocellular carcinomas, Biomarkers, Serum markers, Liver cell carcinoma, Adult liver cancers

Introduction
Primary liver cancer is the fifth most frequently diagnosed
cancer worldwide in men and the seventh in women. Hepatocellular carcinoma (HCC) is the predominant histological type,
accounting for 70-85% of total liver cancers (1). Chronic HBV
infection is the most prevalent cause of HCC, following by
chronic HCV infection. HCC is a typical example of a virusrelated cancer, but, it is also strongly associated with chronic
alcoholism as a risk factor. Obesity is also recognized to
strongly affect HCC development compared with other malignancies (2). Despite many treatment options for patients with
early-stage HCC, the mortality rate remains high making HCC
the third leading cause of cancer-related death worldwide (3).
This high mortality rate reflects the poor prognosis for patients with advanced-stage HCC, the pattern of presentation,
and the poor outcome associated with cirrhosis. Most patients present with advanced-stage disease, only 30% of patients present with resectable disease, and up to 80% have
underlying cirrhosis (4).The treatment options in advancedstage disease are limited, and the survival rate is dismal. Despite advances in surgical and nonsurgical treatments, the
prognosis for patients with HCC remains unsatisfactory compared with many other common human cancers (5).
Advances in early detection, imaging techniques and novel
therapies have improved patient selection and enabled evidence-based treatment approaches. Consequently, prognostic algorithms, such as the Barcelona Clinic Liver Cancer

(BCLC) classification, have been introduced in routine clinical

care. The BCLC system is widely accepted, being currently
endorsed by US and European associations for the study of
liver diseases and oncology (6).
Although current clinical staging systems provide a rough
framework of prognostic classification and treatment decision
for HCC, identification of prognostic biomarkers could further
enhance outcome prediction and treatment selection (5).
The aim of this review was to analyze the prognostic value
of biomarkers for patients with hepatocellular carcinoma.
C- reactive protein
Sieghart et al. (7) reported that high levels of C-reactive protein (CRP) at the time of diagnosis predict poor long-term
survival of patients with HCC. CRP is an acute-phase protein
produced by the liver in inflammatory conditions and it has a
role in linking innate immunity and inflammation (8). Sieghart
et al. studied the prognostic importance of serum levels of
CRP in patients with HCC undergoing nonsurgical treatment.
They used a training cohort of 466 patients in one institution
to identify the optimum cut-off CRP level (1mg/dl, equivalent
to 95.2 nmol/l), and then evaluated the influence on prognosis of high versus low CRP levels according to this cut-off value
in a validation cohort of 252 patients treated at another institution (7). The study showed that raised levels of CRP were a
predictor of poor survival in multivariate analysis independent of other clinical factors. More importantly, CRP level was
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E. Fekaj. Surg Chron 2014; 19(2): 65-67.

demonstrated to have independent prognostic value after

stratification by the Barcelona Clinic Liver Cancer (BCLC) classification, suggesting that CRP level can be added to the clinical staging system to further subcategorize patients in term of
prognosis (7,8).
CD4cytotoxic T cells
Fu et al. (9) showed that impairment of CD4 cytotoxic T lymphocytes (CTLs) predicts poor outcome. They studied circulating and tumor-infiltrating CD4CTLs in patients with HCC and
observed that a decrease in the number of CD4CTLs was
closely associated with progressive stages of HCC and poor
survival (5,9). The authors investigated the potential regulatory mechanism involved in the decrease in CD4CTLs and
showed that the number of CD4CTLs was negatively correlated with the number of T-regulatory cells. In this study,
prognostic importance of circulating and tumor CD4CTLs was
studied in two different cohorts of patients over different
time periods: circulating CD4CTLs were evaluated in 232 patients with HCC between 2005 and 2012; and tumor CD4CTLs
were evaluated in 315 patients undergoing resection for HCC
between 2001 and 2004.Although both circulating and tumor
CD4CTLs were shown to be independent prognostic factors
in multivariate analysis in the respective cohorts, it remained
unclear whether circulating and tumor-infiltrating CD4CTLs
were correlated with each other, and which cell type might
provide the best prognostic information (9).
Neutrophil- Lymphocyte ratio
The idea that inflammation has a decisive role in tumor initiation, promotion, invasion and metastasis, and affects immune
surveillance and response to treatment has been proposed
(10). Therefore, the use of inflammation markers seems a
reasonable approach to predict HCC metastasis (11). Neutrophils are the most abundant type of leucocytes and constitute
the first line of defense against invading microbes; therefore
neutrophil count is a sensitive marker of host inflammation.
Several lines of evidence suggest that neutrophils can be recruited by cancer cells to facilitate proangiogenic and proinvasive effects (11). A study by Bertuzzo et al. (12) has found
that neutrophil: lymphocyte ratio (NLR), a simple laboratory
marker, predicted survival and disease recurrence in patients
who underwent orthotopic liver transplantation (OLT) for
HCC. Lymphocytes are comprised of T cells, B cells and natural
killer cells. A reduction in lymphocyte number, especially
CD4T cells, is a sign of host immunodeficiency. The elevation
of NLR in patients with HCC or other cancers might indicate
that inflammation is exacerbated and host immunity remains
low. Elevated pretransplantation NLR was associated with
high disease recurrence and mortality rates. Furthermore,
elevated NLR was associated with the invasiveness of tumors,
manifested by a high incidence of microvessel invasion, increased serum -fetoprotein levels, and poor differentiation
in tumor cells. Halazum et al. (13) showed that patients with
elevated NLR have a poor prognosis after OLT for HCC. NLR

has been reported to be of prognostic value in patients with

various types of cancer who have undergone curative surgery
(14). In Bertuzzo et al.s study, NLR was an independent predictor for prognosis, whereas the Milan criteria were not - a
result that further justifies the addition of NLR into widely
used staging system for patient selection. It seems likely, that
NLR reflects inflammation and immune disturbance in the
host (12).
The oncofetal gene SALL4
The oncofetal gene, SALL4, has an important role in a subtype
of aggressive HCC. SALL4 is one of the key regulators in
charge of the self-renewal property of human and mouse
embryonic stem cells. The expression of this gene decreases
as development progresses, to the point that it is absent in
most adult normal tissues. However, it is reactivated in some
cancers, including HCC. In patients with HCC with a high expression level of SALL4 had a worse prognosis than patients
with a low expression level of the gene, independent of baseline liver function or the type of treatment the patient received. Global gene-expression data revealed that HCC that
express SALL4 have progenitor-like gene signatures; cancers
with these stem-like gene signatures are often associated
with poor prognosis. Patients with various cancers will be
screened for SALL4 expression at time of diagnosis; the ones
who are positive for SALL4 will be offered a SALL4-specific
treatment regimen, which will lead to longer survival and better quality of life for these patients. In the near future SALL4
can be used as a targetable marker for patients with cancer
(15).
Conclusions
A high level of CRP at the time of diagnosis predicts poor
long-term survival of patients with HCC. CRP is a predictor of
poor survival independent of other clinical factors. The neutrophil-lymphocyte ratio (NLR) predicts survival and disease
recurrence in patients who underwent orthotopic liver transplantation for HCC. The elevation of NLR in patients with HCC
indicates that inflammation is exacerbated and host immunity
remains low. NLR is an independent predictor for prognosis in
patients with HCC. The impairment of CD4 cytotoxic T lymphocites predicts poor outcome. A decrease in the number of
CD4CTLs is closely associated with progressive stages of HCC
and poor survival. The oncofetal gene, SALL4, has an important role in a subtype of aggressive HCC. A high expression
level of SALL4 has a worse prognosis in patients with HCC.
However, future studies on large prospective cohorts are required to validate their prognostic value before they can be
translated into clinical use.
Abbreviations
HBV: Hepatitis B virus; HCV: Hepatitis C Virus; CD4: Surface protein of mature T helper cells
Conflict of interest
The author declare no conflict of interest.

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Corresponding author:
Enver Fekaj, MD, MSc, PhD candidate, Department of Abdominal Surgery,
University Clinical Center of Kosovo, Rrethi i Spitalit, str: p.n., 10000, Pristine, Republic of Kosovo,
tel.: +38649639494
e-mail: enverfekaj@hotmail.com

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