How common is liver cancer and what are the risk factors :
It is very common, the incidence has increased over time and there are scientifically well-established risk factors.
Liver cancer is 5th most common cancer comprising 7% of all cancers and 2nd most frequent cause of cancer-related death globally(854,000 new cases and 810,000 deaths per year)
HCC (hepatocellular carcinoma) accounts for approximately 90% of primary liver cancers.
Between 1990 and 2015 newly diagnosed HCC cases increased by 75%, mainly due to changing age structures and population growth
Cirrhosis precedes HCC in 80%-90% of patients, and one-third of all patients with cirrhosis will develop HCC.
The incidence of HCC is 1%-8% per year in all patients with cirrhosis
The major causes of cirrhosis, and hence HCC are HBV, hepatitis C virus (HCV), alcohol(20-30% of HCC, heavy drinkers may not survive long enough to develop HCC thus underestimating risk)), and nonalcoholic fatty liver disease (NAFLD), but less-prevalent conditions, such as hereditary hemochromatosis, primary biliary cholangitis (PBC), and Wilson’s disease, have also been associated with HCC development.
As the obesity epidemic progresses, the number of patients developing HCC on the background of NAFLD may increase.
The age at which HCC appears varies according to sex, geographical area, and risk factor associated with cancer development. In high-risk countries with major HBV prevalence, the mean age at diagnosis is usually below 60 years.
Sex differences (M:F-2:1-4:1 with age at diagnosis higher in females) due to sex hormones appear to be important as a risk factor for HCC.
HCC in Non-Cirrhotic:
Although not as common, HCC can occur without cirrhosis. Hepatitis B infection without cirrhosis(0.3-0.6%/yr) , Hepatitis C infection with advanced fibrosis(0.8%/yr) and nonalcoholic steatohepatitis (NASH=0.1%/yr) have been associated with non-cirrhotic HCC.
HBV is a DNA virus that integrates into the host genome and produces HBV X protein, which may play a key regulatory role in HCC development by promoting cell proliferation(oncogenic virus)
Risk factors associated with increased development of HCC in HBV-infected individuals are:
– Cirrhosis(from 0.8 per 100 person-years in non -cirrhotics to 2.2 to 4.3 per 100 person-years in cirrhotics)
-The multiplicative effect of heavy smoking and alcohol drinking increases the risk of HCC 9-fold
-Persistent HBV e antigen and elevated serum HBV DNA viral load
-HBV genotype – Risk of HCC appears to be higher with HBV genotypes C and F
-HBV mutations – Such as in preS, basic core promoter ( BCP), or HBx regions
-Family history
NAFLD (Non-alcoholic fatty liver disease)
The prevalence of nonalcoholic fatty liver disease (NAFLD) is 25% and NASH is 3%, with 40% of all patients with NASH progressing to advanced stages of fibrosis.
Although it is clear that NAFLD portends a lower risk {(0.1 non-cirrhotic and 1%/yr for cirrhotic)}for HCC than HBV or HCV, the high prevalence and increasing incidence of NAFLD in the population underlies the importance of NAFLD in the development of HCC
Genetic factors, such as the presence of PNPLA3, also are associated with a high susceptibility to NASH and thus a risk for HCC
HCV
HCC risk sharply increases after cirrhosis develops in HCV, from an annual incidence of less than 1% to between 2% and 8%.
After SVR with treatment, the risk decreases by 71% but is not completely eliminated
HCC in children
Second-most common hepatic malignancy in this population and often occurs in the absence of cirrhosis. HCC has been detected in pediatric patients with HBV, biliary atresia, primary sclerosing cholangitis, Fanconi’s syndrome, hereditary tyrosinemia, and glycogen storage disease type IA. However, the annual incidence in these patients appears to be low and contrary to adults has remained stable over the decades
What are the Symptoms:
There are no specific symptoms and the ones are mostly due to underlying background liver disease
Patients with HCC generally present with signs and symptoms of advancing cirrhosis, as follows:
- Pruritus
- Jaundice
- Splenomegaly
- Variceal bleeding
- Cachexia
- Increasing abdominal girth (portal vein occlusion by thrombus with the rapid development of ascites)
- Hepatic encephalopathy
- Right upper quadrant pain (uncommon)
What is the role of surveillance :
Because of non-specific symptoms, late presentation at the same time well-established risk probabilities, surveillance becomes must to catch at an early stage for a cure.
The need for surveillance by cost-effective analysis is:
-in patients who are eligible for HCC-related treatments.
– all cirrhotics and stage 4 PBC( incidence 1.5%/yr)
-non-cirrhotic HBV carriers{ incidence 0.2%/yr, high-risk group-Asian male >40yr Asian female>50 and African, North American black and those with a family history )
-patients with cirrhosis and treated HCV as risk continues
-patients on the waiting list for liver transplantation in order to detect and manage tumour occurrence or tumour response, and to help define priority policies for transplantation
Surveillance is not recommended in:
-HCV or NAFLD and no cirrhosis as the risk of HCC is significantly lower
-advanced cirrhosis (child C) with low anticipated survival not eligible for curative treatment
USG (ultrasonography) alone or the combination of USG plus AFP(alfa fetoprotein), at 6 monthly intervals is the modality for surveillance
A 10-mm size on USG and AFP >20 ng/mL is the threshold for a positive result. Longitudinal changes in AFP may increase sensitivity and specificity than AFP interpreted at a single threshold of 20 ng/mL
CT and MRI are not recommended as the primary modality for surveillance
20% of USG are classified as inadequate for surveillance, as in obesity, alcohol, and NAFLD-related cirrhosis and alternative surveillance modalities may be needed
Can liver cancer be prevented:
Yes as we are well aware of risk factors
1. Vaccination against hepatitis B for all newborns and high-risk groups
Since the perinatal or early postnatal transmission is an important cause of chronic HBV infections globally, the first dose of hepatitis B vaccine should be given as soon as possible after birth even in low-endemic countries (those with the prevalence of hepatitis B surface antigen carriers <2%).
Vaccination is also recommended in age-specific cohorts (young adolescents) and people with risk factors for acquiring HBV infection (i.e. health workers, travelers to areas where HBV infection is endemic, injecting drug users, and people with multiple sex partners).
2. Antiviral treatment for patients with chronic hepatitis B and C infection to maintain HBV suppression and SVR(sustained viral response) in HCV
In HCV there is a more than 70% reduction in HCC incidence (absolute risk reduction: 4.6%) after SVR independently of the grade of fibrosis.
3. Health agencies should implement policies to:
-prevent HBV/HCV transmission
-counteract chronic alcohol abuse
-promote a lifestyle that prevents obesity and metabolic syndrome
Diagnosis
Biopsy is not needed for diagnosis, imaging suffices
Unlike most solid cancers, the diagnosis of HCC can be established, and treatment rendered, based on noninvasive imaging without biopsy confirmation.
Multiphase CT and MRI exams should be performed, interpreted, and reported through its CT/MRI Liver Imaging Reporting And Data System (CT/MRI -LI-RADS)
In LI-RADS system, observations (i.e., lesions or pseudolesions) >10 mm visible on multiphase exams are assigned category codes reflecting their relative probability
LI-RADS 1 and LI-RADS 2 indicate definitely and probably benign, respectively thus needing only routine surveillance
LI-RADS 3 indicates a low probability of HCC, needing close longitudinal to follow up imaging
LI-RADS 4 indicates probable HCC needing biopsy to confirm
LI-RADS 5 indicates definite HCC.
LI-RADS M is assigned to observations with features highly suggestive or even diagnostic of malignancy, but not specific for HCC needing a biopsy
FDG-PET is not recommended for diagnoses due to the high false-negative rate.
A biopsy is needed when:
Suspicion of HCC without cirrhosis
LI-RADS 4-high but not conclusive suspicion of HCC on imaging
LI-RADS M like intrahepatic cholangiocarcinoma
Biopsy should not be performed if it is not going to alter management
What is the Treatment-
Multimodality with Surgery mainstay of treatment Multidisciplinary team, the liver surgeon remains the hub of team wheel
Treatment allocation is guided by staging systems which includes:
1. Tumour burden (number and size)
2. Liver function as
a) Child-Pugh score graded as A,B and C in ascending order of severity of derangement includes prothrombin time(INR ), albumin level, bilirubin level ,ascites and encephalopathy
b) Model for End-Stage Liver Disease(MELD) score which includes the level of bilirubin ,INR and Creatinine
c)portal hypertension as Platelet count(<1000,00) and oesophageal varices on upper GI endoscopy
3.performance status of the patient
Available therapeutic options can be divided into curative and noncurative interventions.
Curative therapies offers the chance of long-term response and improved survival include
Surgical resection,
Orthotopic Liver Transplantation(LT),
Ablative techniques such as thermal ablation.
Non-curative therapies, which attempt to prolong survival by slowing tumour progression, include
Transarterial chemoembolization (TACE),
Transarterial radioembolization (TARE),
Stereotactic body radiation therapy (SBRT),
Systemic chemotherapy
Surgery is the mainstay of HCC treatment as it offers best outcomes of any treatment in well-selected candidates(5-year survival of 60−80%)
Ablative and non-curative treatment modalities are sometimes supplanted to surgical treatments to allow waiting period or downstage diseases
Surgical resection:
Is the treatment of choice for resectable HCC occurring in patients without cirrhosis and in the setting of cirrhosis with intact liver function(Child A) and absence of CSPH(clinically significant portal hypertension).
For patients with single tumour, well-preserved liver function, and no evidence of PH (normal bilirubin and hepatic venous pressure gradient <10 or platelet count >100,000) surgical resection offers a low perioperative mortality and is associated with survival rates of nearly 70% at 5 years. 
There is technically no size cutoff, and large tumours can be safely resected if there is sufficient functional liver remnant.
In cases where a large volume of resection is anticipated such as with greater than three segments, portal vein embolization(PVE) can be utilized to increase the size of the contralateral lobe and thus reduce the risk of hepatic insufficiency. An increase of 20%-25% in the contralateral lobe may be anticipated 4-6 weeks following bland embolization
Lobar TARE has been shown to simultaneously treat the tumour and lead to hypertrophy of the opposite lobe
Laparoscopic/Robotic liver resection may offer benefits in terms of shorter length of hospitalization, and potentially decreased risk of postoperative decompensation and other complications.
The risk of recurrence following resection is up to 70% at 5 years so regular followup CT/MR imaging is a must.
There are currently no other adjuvant therapies which have been demonstrated to be effective in the postresection or post-ablation setting to prevent a recurrence
Liver Transplantation:
LT is a highly effective, efficient therapy for early-stage HCC because it offers optimal treatment of both the underlying liver disease and the tumour
Transplantation is the treatment of choice for patients with early-stage HCC occurring in the setting of CSPH and/or decompensated cirrhosis.
LT is associated with excellent long-term survival rates(60-80% 5yr) for HCC within Milan criteria(1 tumour of up-to 5cms or up-to 3 nodules, with the largest being < 3cms, with no vascular involvement) occurring in the setting of decompensated liver disease.
Recurrence of HCC following LT has been estimated to be 11%-18%.
LT can be Deceased donor or Living donor.
DDLT:
Because of a scarcity of the available organ donors, the organs are offered only to really eligible/suitable patients, in good condition. (within Milan Criteria)
Although MELD exception points to expedite allocation is given to HCC on a waitlist but the policy is not universal.
Bridging is defined as the use of LRT—such as TACE, Y90, ablative therapy, or a combination of different types of LRT such as TACE and ablation—to induce tumour death and deter tumour progression beyond the Milan criteria
Downstaging is a reduction in tumor burden to within Milan criteria for DDLT using LRTs. The optimal form of liver-directed therapy for the purposes of downstaging cannot be determined based on the available data.
There is no standard, agreed-upon waiting period following downstaging to determine the efficacy of downstaging and subsequent optimal timing for LT.
LDLT:
LDLT is voluntary, controlled (both timing and quality of graft) and overcomes the problem of organ shortage
Extending criteria beyond Milan is followed by centres across the globe like UCSF, Tokyo, Asan criteria etc
Tumour vascular invasion and extrahepatic spread are the absolute contraindications
Surveillance for HCC recurrence in posttransplant patients should include abdominal and chest CT scan for better evaluation of the soft tissue, though optimal timing and duration, as well as the impact of surveillance, is not certain
Ablation:
Destruction or ablation of tumor cells can be achieved by the injection of chemical substances (ethanol, acetic acid, and boiling saline) or by modifying local tumour temperature (radiofrequency[RFA], microwave, laser, cryotherapy).
The procedure can be done percutaneously with minimal invasiveness or during laparoscopy and is currently considered the best option early-stage HCC who are not candidates for surgical intervention
RFA Microwave Cryoablation Electroporation
SBRT is a developing form of LRT. SBRT had complete and partial responses of 15% and 45%, respectively, for small HCC and can be considered an alternative to thermal ablative techniques
Thermal ablation is superior to ethanol injection. Thermal ablative techniques have the best efficacy in tumours with a maximum diameter less than 3 cm, although microwave ablation potentially provides better tumoral response than RFA.
Patients post-ablation are at high risk for recurrence and surveillance should be performed with contrast-enhanced CT or MRI every 3-6 months
Noncurative Therapies
LRT should be considered for patients with intermediate-stage HCC who are not eligible for curative treatments.
TACE
The chemotherapeutic drug(doxorubicin, Cisplatin), along with lipoidal is injected into the artery supplying the tumour. Tumour cells absorb the lipoidal, very well and in the process, absorb the chemotherapeutic drugs too. After this injection, small gel foams or biodegradable products are injected to block the small arteries, supplying the tumour and to cut their nutrient and oxygen supply to the tumour.
Drug-eluting beads (DEBs) may offer advantages over conventional TACE, including a greater standardization of therapy, increased/sustained tumoral concentration, and lower systemic absorption of chemotherapy
TACE should not be used in:
Decompensated liver disease
Advanced liver and/ kidney dysfunction
Macro-vascular invasion extrahepatic spread
TARE
TARE has emerged as an alternative therapy to TACE. In contrast to TACE, radioembolization ismicroembolic and therefore the hepatic artery maintains its patency.
The therapeutic action of TARE is predominately radiation with ytrium 90 as opposed to embolization.
The use of TARE over TACE by some centres has included patients who are advanced stage and poor candidates for TACE, larger tumours (>2 segments) with portal vein invasion, and progressive disease post-TACE.
Systemic Chemotherapy
HCC is recognised as among the most chemo-resistant tumour types. Sorafenib is currently the standard of care for patients with advanced tumours.
It is indicated for patients with well-preserved liver function (Child-Pugh A) and with advanced tumours
Patients who are ineligible for or progress after TACE/TARE should be considered for systemic therapy.
Current data do not demonstrate the benefit of TARE compared to sorafenib in patients with advanced HCC.
Dr. Sanjay Goja | Program Director and Clinical Lead – Liver Transplant, HPB Surgery and Robotic Liver Surgery – Liver Transplant & HPB Surgery | Mazumdar Shaw Medical Center, Bommasandra, Bangalore and Narayana Superspeciality Hospital, Gurugram