15018752330
发表时间:2015-11-03 浏览次数:401次
Introduction
Liver
cancer, primary hepatocellular carcinoma (HCC) or hepatoma has become
the third leading cause of death from cancer worldwide. [1],[2]
In 2008, the GLOBOCAN reported 746,300 new cases of HCC diagnosed
worldwide with 695,900 HCC-related deaths and a 1.07 incidence to
mortality ratio making it the third most fatal cancer world-wide with
the vast majority (84%) of cases concentrated in the developing
countries in Asia and Africa. [2],[3] HCC is a disparate cancer preferentially afflicting the middle to lower socio-economic segment of the world. [4]
The economic cost of HCC is staggering with global expense estimated at
$895.2 billion a year only followed by cardiac ($753.2 billion) and
cerebrovascular disease ($298.2 billion).
Hepatoma Research (Hepatoma Res,
ISSN 2394-5079, http://www.hrjournal.net/), this new open access online
journal, has been created to improve and promote the international
exchange of clinical and academic information about HCC. We invite our
peers, clinical and research collaborators alike to contribute to this
new journal to improve the international exchange of information in real
time to meet this global challenge. Our journal will address all aspect
of HCC, including cell biology, pathophysiology, genetics, immunology,
pharmacology, medical management as well as radiological and surgical
interventions.
Etiology
Currently, HCC predominately (78%) arises from two chronic liver
infections: hepatitis B virus (HBV) and hepatitis C virus (HCV). HBV
represents the etiologic factor in 50% of world-wide HCC cases and was
recognized in 1994 by the WHO/IARC with a relative risk ranging from 5
to 98. [5],[6]
Inactive HBV is also an established risk for HCC with a hazard ratio of
4.6. HBV in Asia, especially in China and Korea, has shown a steady
decline through HBV immunization programs. Alternatively, the United
States and Japan witnessed a rise in HCV acquired from intravenous drug
abuse in the 60's and 80's, which was associated with 80-90% of HCC
cases in Japan and 40-60% of cases in Italy and the United States with
an odds ratio of 1.3-134. [7],[8],[9]
After decades of frustration treating HCV introduction of new protease
inhibitors are achieving 80-100% viral eradication, which is associated
with a decreased the relative risk for the development of HCC. [10],[11],[12] Unfortunately complete virologic response does not eradicate the risk of HCC in established HCV-related cirrhosis.
Unfortunately,
the progress in viral hepatitis has not addressed the looming cloud of
obesity, nonalcoholic fibrotic liver disease (NAFLD) and nonalcoholic
steatohepatitis (NASH) on our horizon. In a world of advancing
technology, the standard of living including food stores has
dramatically increased and subsequently the mean body mass index and
incidence of obesity. NAFLD/NASH as an etiologic factor results in
excess fatty acids, and hepatocellular steatosis, which elicits fatty
acid oxidation and reactive oxidative stress thought to produce
epigenetic changes. [13],[14]
Carcinogenesis
No matter what the agent viral hepatitis, fatty liver or diabetes
the principle risk factor in HCC is the presence of a pre-neoplastic
liver. [15],[16]
In HBV-related HCC, the presence of serum HBV DNA has been shown to be a
predictor of HCC development synergistic with inflammation. [17]
Viral DNA replication and hepatitis B core antigen expression are
halted in HBV HCC, while 20% of cells persist production of hepatitis B
surface antigen triggering an immune responses and the secretion of
cytokines tumor necrosis factor-a, interferon and interleukin-2, which
can down regulate the accumulation of HBV RNAs. [18],[19],[20]
Development of HCV-related HCC is a multistep process including the up
regulation of inflammatory cytokines and induction of oxidative stress
from chronic hepatitis, fibrosis, liver regeneration, and cirrhosis. [21]
The intermediate step is represented by dysplastic nodules with the
coexistence of epigenetic and genetic changes that develop into HCC.
Multiple pro-inflammatory states appear to be synergistic with HCV
including: alcohol, HBV and HIV co-infection, diabetes mellitus, older
age, African American race, thrombocytopenia, and smoking. [21],[22],[23],[24]
Nonalcoholic fibrotic liver disease and NASH is an entity previously
classified with cryptogenic cirrhosis with a high relative risk for HCC.
Pro-inflammatory states from fatty acids release cytokines,
pro-oncogenic signals and stimulate epigenetic changes even in the
absence of cirrhosis. [18] Subsequently obese type II diabetics are at twice the risk to develop HCC. [25],[26],[27]
Alternatively, African Americans are at a lower relative risk for HCC
compared to Caucasians based on fat distribution and metabolism. The
estimated yearly incidence of HCC development in NASH-cirrhosis (2.6%)
is similar to HCV-cirrhosis (4%). [28]
Genes involved in hepatocarcinogenesis include p53, PIKCA, and β-catenin . In addition, there are two signaling pathways for cellular differentiation that are frequently disrupted: (1) Wnt-β-catenin and (2) Hedgehog. WNT signaling appears to be associated with a higher incidence of transformation and pre-neoplastic adenomas. [29]
Surveillance
The American Association for the Study of Liver Diseases advocates bi-annual ultrasound surveillance for high-risk patients. [30] Cost-effectiveness is meet with two criteria: (1) annual incidence > 1.5% per year and (2) threshold of $50,000 per quality-adjusted life year (QALY). Several economic analyzes confirm Child-Pugh Class A patients increase life expectancy with cost effectiveness of $26,000 and $55,000 per QALY. The best data on surveillance comes from a prospective Chinese trial. [31],[32],[33],[34],[35] Surveillance is recommended for all cirrhotics, HBV carriers if they are Africans older than age 20 years, Asians older than 40 years or have a family history of HCC. However, debate on the utility of AFP continues. Unfortunately ultrasound is highly operator dependent with a variable sensitivity of 30-70%, and most importantly < 20% of patients compliant with biannual exams. [36],[37],[38]
Diagnosis
Hepatocellular carcinoma is diagnosed by contrast-enhanced
computerized tomography (CT) or magnetic resonance imaging (MRI). Early
arterial phase enhancement is seen in the tumor followed by venous phase
dropout. These characteristics carry result in 90% sensitivity and 95%
specificity for lesions greater than one centimeter. [39]
In 2013, the American College of Radiology introduced the Liver Imaging
Reporting and Data System to standardize the reporting and data
collection of CT and MRI for HCC. [40]
In efforts to improve lower cost technology, contrast-enhanced
ultrasound was introduced with a 90% sensitivity, 99% specificity and
89% diagnostic accuracy. [41] The diagnostic accuracy of MRI has been improved by dual contrast agents like Eovist® , which is a hepatobiliary excretion and vascularization markers used to diagnosis HCC. [42]
Despite these advances in technology, diagnostics are still encumbered
by operator variability and inadequate diagnostic resolution in tumors
under 2 cm. The deficiencies in diagnostic screening and sensitivity are
seen by the mean tumor size of HCC with the state of Louisiana being
6.5 cm well above Milan Criteria.
Staging and prognosis
Multiple staging systems exist for HCC, but the Barcelona Clinic Liver
Cancer (BCLC) staging, and prognostic system appear to be the most
widely accepted. BCLC incorporates tumor stage, cirrhosis stage, and
functional performance status and links stage with a treatment
algorithm. [43],[44],[45]
Despite multiple valid staging systems, the most attractive system
would be the staging of HCC on genomic finger printing directing therapy
and resource allocation such as liver transplants.
Very early
stage HCC (Stage 0) are tumors < 2 cm have the best prognosis but are
hard to identify on imaging. Early stage HCC (Stage A) is solitary
lesions or up to three lesions < 3 cm with preserved liver function
(Child-Pugh Class A or B) and reasonable functional status (PS 0-2)
with. Their 5-year survivals reach 50-75%. Intermediate stage HCC (Stage
B) is multi-nodular with preserved liver function (Child-Pugh Class A
or B) and good functional status (PS 0), and no cancer-related symptoms
or evidence of vascular invasion. Advanced stage HCC (Stage C)
demonstrates vascular invasion or extra-hepatic spread with compromise
of functional status (PS 1 or 2) due to HCC. Terminal stage HCC (Stage
D) have tumor marked with vascular invasion and extra-hepatic spread
with decompensated cirrhosis (Child-Pugh Class C), poor functional
status (PS > 2).
Treatment options
Surgical resection is an excellent option but has a limited utility due
to advanced cirrhosis and is employed in < 5% of patients. [46]
Candidates for resection include: (1) Child-Pugh Class A; (2) hepatic
venous pressure gradient < 10 mmHg; (3) platelet count > 100,000;
(4) future remnant > 25% (non-cirrhotic); and (5) 50% (cirrhotic)
resulting in a 70% 5-year survival. [47],[48]
The future remnant can be augmented by pre-operative portal vein
embolization. Unfortunately, the majority of patients develop either new
HCC or recurrent tumor within 5-year exceeding 70% but if the tumor
burden remains within Milan they are candidates for salvage transplant. [49],[50]
Liver transplantation is reserved for unresectable or decompensated
cirrhotics with HCC within the Milan criteria: (1) One lesion ≤ 5 cm and
(2) three lesions ≤ 3 cm could provide a > 70% 5-year survival. [51]
Current organ allocation in the United States is performed utilizing
Model for End-stage Liver Disease with HCC receiving exception point
varying from 22 to 34 points while patients that exceeding Milan are
required to be downstaged by pre-transplant locoregional to reduce
dropout and potentially post-operative recurrence. [52],[53]
European centers take an alternative approach whereby laparoscopic
resection is liberally employed, and those patients with the highest
risk for recurrence are sent for the liver transplant. These factors
include lymphovascular invasion and nonencapsulated tumors.
Locoregional
therapies include: (1) percutaneous ethanol injection; (2) cryotherapy;
(3) radiofrequency ablation; (4) microwave therapy; (5) irreversible
electroporation (IEP); and (6) yttrium. Percutaneous ethanol is the
least expensive and frequently performed in the office with ultrasound.
Thermal ablation is more complex but very effective in smaller tumors
(2-3 cm): 70-80% and intermediate tumors (3-5 cm): 50%. Radiofrequency
ablation, microwave ablation, and IEP all result in thermal injury,
tissue necrosis and apoptosis propagation. [54],[55]
Several drug delivery systems have been introduced including ThermoDox® and Delcath® a percutaneous intrahepatic, hepatic perfusion device. ThermoDox® is a liposomal delivery system for doxorubicin triggered by heat delivered by an ablation device. [56] The Delcath® device delivers high doses of chemotherapy to the liver in an isolated circuit under hyperthermic conditions.
Radioembolization
or Y-90 is the radiation delivered through microembolization beads. Two
versions of Y-90 exist, smaller beads for end capillary embolization
and the larger for arterial embolization both designed to deliver up to
150 Gy of beta radiation. [57]
Both have relative complications related to their size, embolization
stasis methods and radiation intensity. Elevated bilirubin and portal
vein thrombosis have become relative contraindications using selective
and super-selective approaches. Y-90 has a median survival of 17.2
months in Child-Pugh A cirrhotics and 7.7 months in Child-Pugh B
cirrhotics. [58]
Trans-arterial chemoembolization (TACE) is a widely adopted therapy for
HCC embolizing tumor's arterial supply with or without doxorubicin.
TACE has a survival advantage at 1 year (82% vs. 63%) and 2 years (63% vs. 27%) compared to controls. [59],[60]
Increased bilirubin (> 2.5 mg/dL) and portal vein thrombosis are no
longer an absolute contraindications utilizing a selective or
super-selective approach to tumors. [61]
Drug-eluting beads have been developed to provide stable and prolonged
delivery to decrease doxorubicin toxicity resulting in higher rates of
complete response. [62],[63]
Chemoembolization results in the tumor ischemia and hypoxia, which
stimulate angiogenic growth factors including vascular endothelial
growth factor (VEGF), which potentially-induce tumor angiogenesis and
tumor recurrence. [64]
Sorafenib is a tyrosine kinase inhibitor that was shown to have a
survival benefit over best supportive care in two pivotal studies: (1)
sorafenib in patients with advanced HCC and Asian Pacific trials in
patients with Child-Pugh Class A cirrhosis, and (2) advanced HCC
compatible with Stage C. [65],[66]
Sorafenib is currently the primary chemotherapeutic agent for the
treatment of unresectable or recurrent HCC. Multiple adjuvant trials are
under way to evaluate the synergistic effects of sorafenib
post-resection and ablative therapies. Brivanib is an oral selective
dual inhibitor of the fibroblast growth factor and the VEGF pathway,
which is being evaluated as a second-line therapy for the management of
VEGF stimulation. [67] Other agents under investigation include: erlotinib, bevacizumab, lapatinib, gefitinib and cetuximab.
Conclusion
Hepatocellular carcinoma is the third leading cause of cancer mortality
world-wide preferentially afflicting lower socioeconomic patients.
Dramatic advances have been made to reduce the incidence of HBV and HCV
including HBV immunization strategies and the introduction of new direct
acting antiviral drugs for the treatment of HCV. With eradication
strategies for HBV and HCC, NAFLD and NASH will become the principle
etiology for HCC. HCC will become a disease of the obese.
Obesity
itself will complicate HCC management particularly surgical
interventions including resection and liver transplantation.
Concentrated efforts should be placed on early diagnosis. Early
diagnosis not only improves patient survival and is far more cost
effective than any late intervention. Several diagnostic strategies lie
in the future with the potential identification of circulating tumor
cells or identification of a premalignant signature like epigenetic
changes. Despite our best efforts to diagnose HCC in earlier stages,
this will not be feasible in most. Therapeutic efforts should be
redoubled into the development of new drug delivery systems and
platforms to improve chemotherapeutic monotherapy or platform assisted
surgery with agents such as nanoparticle and liposomal delivery systems.
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