Liver cancer

Liver cancer, also known ashepatic cancer,primary hepatic cancer, orprimary hepatic malignancy, iscancerthat starts in theliver.Liver cancer can be primary in which the cancer starts in the liver, or it can beliver metastasis, or secondary, in which the cancer spreads from elsewhere in the body to the liver. Liver metastasis is the more common of the two liver cancers.Instances of liver cancer are increasing globally.
Primary liver cancer is globally the sixth-most frequent cancer and the fourth-leading cause of death from cancer.In 2018, it occurred in 841,000 people and resulted in 782,000 deaths globally.Higher rates of liver cancer occur where hepatitis B and C are common, including Asia andsub-Saharan Africa.Males are more often affected withhepatocellular carcinoma(HCC) than females.Diagnosis is most frequent among those 55 to 65 years old.
The leading cause of liver cancer iscirrhosisdue tohepatitis B,hepatitis C, oralcohol.Other causes includeaflatoxin,non-alcoholic fatty liver diseaseandliver flukes.The most common types are HCC, which makes up 80% of cases andintrahepatic cholangiocarcinoma.The diagnosis may be supported byblood testsandmedical imaging, with confirmation bytissue biopsy.
Given that there are many different causes of liver cancer, there are many approaches to liver cancer prevention. These efforts includeimmunization against hepatitis B,hepatitis B treatment, hepatitis C treatment, decreasing alcohol use,decreasing exposure toaflatoxinin agriculture, and management ofobesityanddiabetes.Screeningis recommended in those withchronic liver disease.For example, it is recommended that people with chronic liver disease who are at risk forhepatocellular carcinomabe screened every 6 months using ultrasound imaging.
Because liver cancer is anumbrella termfor many types of cancer, the signs and symptoms depend on what type of cancer is present. Symptoms can be vague and broad. Cholangiocarcinoma is associated withsweating,jaundice,abdominal pain,weight loss, andliver enlargement.Hepatocellular carcinoma is associated withabdominal mass,abdominal pain,vomiting,anemia,back pain,jaundice,itching,weight lossandfever.
Treatment options may includesurgery,targeted therapyandradiation therapy.In certain cases,ablation therapy,embolization therapyorliver transplantationmay be used.
Liver cancer can come from the liverparenchymaas well as other structures within the liver such as thebile duct,blood vesselsandimmune cellsThere are many sub-types of liver cancer, the most common of which are described below.
The most frequent liver cancer, accounting for approximately 75% of all primary liver cancers, ishepatocellular carcinoma(HCC).HCC is a cancer formed by liver cells, known ashepatocytes, that become malignant. In terms of cancer deaths, worldwide HCC is considered the 3rd most common cause of  cancer mortalities.
In terms of HCC diagnosis, it is recommended that people with risk factors (including knownchronic liver disease,cirrhosis, etc.) should receive  screening ultrasounds. If the ultrasound shows a focal area that is larger than 1 centimeter in size, patients should then get a triple-phase contrast-enhancedCTorMRIscan.HCC can then be diagnosed radiologically using the Liver Imaging Reporting and Data System (LI-RADS).There is also a variant type of HCC that consists of both HCC and cholangiocarcinoma.
Cancer of the bile duct (cholangiocarcinomaand cholangiocellularcystadenocarcinoma) account for approximately 6% of primary liver cancers.Intrahepatic cholangiocarcinoma (CCA) is an epithelial cancer of the intra-hepatic biliary tree branches.Intrahepatic CCA is the second leading cause of primary liver cancer.It is more common in men and usually is diagnosed in 60-70 year olds.Risk factors for development of intrahepatic CCA includeopisthorchus viverriniinfection,Clonorchis sinensisinfection,sclerosing cholangitis,choledochal cysts, past procedures of the biliary tree, exposure tothorotrastanddioxins, andcirrhosis.This cancer is usually asymptomatic until the disease has progressed. Symptoms include abdominal pain, night sweats, weight loss, and fatigue.Liver markers that can be increased with intrahepatic CCA arecarcinoembryonic antigen (CEA),CA19-9, andCA-125.
These are rare and aggressive liver cancers, yet are the third most common primary liver cancer making up 0.1-2.0% of primary liver cancer.Angiosarcomaandhemangiosarcomaof the liver come from the blood vessel'sendothelial layer. These tumors have poor outcomes because they grow rapidly andmetastasiseeasily. They are also hard to diagnose but are typically suspected onCTorMRIscans that show focal lesions with differing amounts of signal intensity (these tumors have a lot ofbleeding or hemorrhageand subsequent dying of tissue (necrosis)).Biopsy with histopathological evaluation yields the definitive diagnosis.While the cause is often never identified (75% areidiopathic), they are associated with exposures to substances such asvinyl chloride,arsenic,thorotrast(e.g. occupational exposure).Radiationis also a risk factor.In adults, these tumors are more common in males; however, in children they are more common in females.
Even withsurgery,prognosisis poor with most individuals not living longer than six months after diagnosis. Only 3% of individuals live longer than two years.
Another type of cancer formed by liver cells ishepatoblastoma, which is specifically formed by immature liver cells.It is a rare malignant tumor that primarily develops in children, and accounts for approximately 1% of all cancers in children and 79% of all primary liver cancers under the age of 15.Most hepatoblastomas form in the right lobe.
Many cancers found in the liver are not true liver cancers but are cancers from other sites in the body that have spread to the liver (known asmetastases). Frequently, the site of origin is thegastrointestinal tract, since the liver is close to many of these metabolically active, blood-rich organs near toblood vesselsand lymph nodes (such aspancreatic cancer,stomach cancer,colon cancerandcarcinoid tumorsmainly of theappendix), but also frombreast cancer,ovarian cancer,lung cancer,renal cancer,prostate cancer.
The Children's Oncology Group (COG) has developed a protocol to help diagnose and manage childhood liver tumors.
Viral infection withhepatitis Cvirus (HCV) orHepatitis Bvirus (HBV) is the chief cause of liver cancer in the world today, accounting for 80% of HCC.Men with chronic HCV or HBV are more likely to develop HCC than women with chronic HCV or HBV; however, the reasons for this gender difference is unknown.  HBV infection is also linked tocholangiocarcinoma.The role of viruses other than HCV or HBV in liver cancer is much less clear, even though there is some evidence that co-infection of HBV andhepatitis Dvirus may increase the risk for HCC.
HBV and HCV can lead to HCC, because these viral infections cause massiveinflammation,fibrosis, and eventualcirrhosisoccurs within the liver.In addition, manygeneticandepigeneticchanges are formed in liver cells during HCV and HBV infection, which is a major factor in the production of the liver tumors. The viruses induce malignant changes in cells by alteringgene methylation, affecting gene expression, and promoting or repressing cellularsignal transduction pathways. By doing this, the viruses can prevent cells from undergoing a programmed form of cell death (apoptosis) and promote viral replication and persistence.
HBV and HCV also induce malignant changes by causing DNA damage andgenomic instability. This involves the generation ofreactive oxygen species, expression of proteins that interfere with DNA repair enzymes, and HCV induced activation of amutator enzyme.
In addition to virus-relatedcirrhosisdescribed above, other causes of cirrhosis can lead to HCC. Alcohol intake correlates with risk of HCC, and the risk is far greater in individuals with an alcohol-induced cirrhotic liver.There are a few disorders that are known to cause cirrhosis and lead to cancer, including hereditaryhemochromatosisandprimary biliary cirrhosis.
Aflatoxinexposure can lead to the development of HCC.The aflatoxins are a group of chemicals produced by the fungiAspergillus flavus(the name comes fromA. flavustoxin) andA. parasiticus. Food contamination by the fungi leads to ingestion of the chemicals, which are very toxic to the liver. Common foodstuffs contaminated with the toxins are cereals, peanuts, and other vegetables. The amount (dose) and how long (duration) that a person is in contact with aflatoxin is associated with HCC.Contamination of food is common in Africa, South-East Asia, and China. The mechanism by which aflatoxins cause cancer is throughmutationsandepigenetic alterations.  Aflatoxins induce a spectrum of mutations,including in thep53tumor suppressorgene, which is a mutation seen in many types of cancers.Mutation in p53, presumably in conjunction with other aflatoxin-induced mutations andepigeneticalterations,is likely a common cause of aflatoxin-inducedcarcinogenesis.
NASH and NAFL is beginning to be called a risk factor for liver cancer, particularly HCC.In recent years, there has been a noted increase in liver transplantations for HCC that was attributable to NASH.More research is needed in this area and NASH/NAFL.
Childhood liver cancer is uncommon.The liver cancer sub-types most commonly seen in children arehepatoblastoma,hepatocellular carcinoma, embryomal sarcoma of liver, infantile choriocarcinoma of liver, and biliary rhabdomyosarcoma.Increased risk for liver cancer in children can be caused byBeckwith–Wiedemann syndrome(associated with hepatoblastoma),familial adenomatous polyposis(associated with hepatoblastoma),low birth weight(associated with hepatoblastoma),Progressive familial intrahepatic cholestasis (associated with HCC)andTrisomy 18(associated with hepatoblastoma).
Manyimaging modalitiesare used to aid in the diagnosis of liver cancer. For HCC these includemedical ultrasound,computed tomography(CT) andmagnetic resonance imaging(MRI). When imaging the liver with ultrasound, large lesions are likely to be HCC (e.g., a mass greater than 2 cm has more than 95% chance of being HCC).Given theblood flow to the liver, HCC would be most visible when the contrast flows through the arteries of the liver (also called the arterial phase) rather than when the contrast flows through the veins (also called the venous phase).Sometimes doctors will get aliver biopsy, if they are worried about HCC and the imaging studies (CT or MRI) do not have clear results.The majority of cholangiocarcimas occur in thehilarregion of the liver, and often present as bile duct obstruction. If the cause of obstruction is suspected to be malignant,endoscopic retrograde cholangiopancreatography(ERCP), ultrasound, CT, MRI andmagnetic resonance cholangiopancreatography(MRCP) are used.
Tumor markers, chemicals sometimes found in the blood of people with cancer, can be helpful in diagnosing and monitoring the course of liver cancers. High levels ofalpha-fetoprotein(AFP) in the blood can be found in many cases of HCC and intrahepatic cholangiocarcinoma.Of note, AFP is most useful for monitoring if liver cancers come back after treatment rather than for initial diagnosis.Cholangiocarcinoma can be detected with these commonly used tumor markers:carbohydrate antigen 19-9(CA 19–9),carcinoembryonic antigen(CEA) and cancer antigen 125 (CA125). These tumor markers are found in primary liver cancers, as well as in other cancers and certain other disorders.
Prevention of cancers can be separated into primary, secondary, and tertiary prevention. Primary prevention preemptively reduces exposure to a risk factor for liver cancer. One of the most successful primary liver cancer preventions isvaccination against hepatitis B.Vaccination against thehepatitis Cvirus is currently unavailable.Other forms of primary prevention are aimed at limiting transmission of these viruses by promoting safe injection practices, screeningblood donationproducts, and screening high-risk asymptomatic individuals.Aflatoxinexposure can be avoided by post-harvest intervention to discourage mold, which has been effective inwest Africa. Reducingalcohol use disorder,obesity, anddiabetes mellituswould also reduce rates of liver cancer. Diet control inhemochromatosiscould decrease the risk ofiron overload, decreasing the risk of cancer.
Secondary prevention includes both cure of the agent involved in the formation of cancer (carcinogenesis) and the prevention of carcinogenesis if this is not possible. Cure of virus-infected individuals is not possible, but treatment with antiviral drugs can decrease the risk of liver cancer.Chlorophyllinmay have potential in reducing the effects of aflatoxin.
Tertiary prevention includes treatments to prevent the recurrence of liver cancer. These include the use of surgical interventions, chemotherapy drugs, and antiviral drugs.
Like many cancers, treatment depends on the specific type of liver cancer as well as stage of the cancer. The main way cancer is staged is based on theTMN stagingsystems. There are also liver cancer specific staging systems, each of which has treatment options that may result in a non recurrence of cancer, or cure.For example, for HCC it is common to use the Barcelona Clinic Liver Cancer Staging System.
Treatments include surgery, medications, and ablation methods. There are many chemotherapeutic drugs approved for liver cancer including:atezolizumab,nivolumab,pembrolizumab,regorafenib.Increasingly,immunotherapyagents (also called targeted cancer therapies orprecision medicine) are being used to treathepatobiliary cancers.
Recent advances in liver cancer treatment are exploring T cells engineered withchimeric antigen receptors(CARs) targeting glypican-3 (GPC3), such as GAP T cells, showing potential in addressing GPC3-positive tumors, especially in pediatric liver cancers.
Partialsurgical resectionis the recommended treatment forhepatocellular carcinoma(HCC) when patients have sufficient hepatic function reserve.5-year survival ratesafter resection have massively improved over the last few decades and can now range from 41 to 74%.However, recurrence rates after resection can exceed 70%, whether due to spread of the initial tumor or formation of new tumors .Liver transplantationcan also be considered in cases of HCC where this form of treatment can be tolerated and the tumor fits specific criteria (such as theMilan criteria). In general, patients who are being considered for liver transplantation have multiple hepatic lesions, severe underlying liver dysfunction, or both.
Percutaneous ablation is the only non-surgical treatment that can offer cure. There are many forms of percutaneous ablation, which consist of either injecting chemicals into the liver (ethanoloracetic acid) or producing extremes of temperature usingradio frequency ablation,microwaves,lasersorcryotherapy. Of these, radio frequency ablation has one of the best reputations in HCC, but the limitations include inability to treat tumors close to other organs and blood vessels due to heat generation and the heat sink effect, respectively.In addition, long-term of outcomes of percutaneous ablation procedures for HCC have not been well studied. In general, surgery is the preferred treatment modality when possible.
Systemicchemotherapeuticsare not routinely used in HCC, although local chemotherapy may be used in a procedure known astransarterial chemoembolization(TACE). In this procedure, drugs that kill cancer cells and interrupt the blood supply are applied to the tumor. Because most systemic drugs have no efficacy in the treatment of HCC, research into the molecular pathways involved in the production of liver cancer producedsorafenib, atargeted therapydrug that prevents cell proliferation andblood cell growth. Sorafenib obtained FDA approval for the treatment of advanced hepatocellular carcinoma in November 2007.This drug provides a survival benefit for advanced HCC.
Transarterial radioembolization (TRACE) is another option for HCC.In this procedure, radiation treatment is targeted at the tumor. TRACE is still considered an add on treatment rather than the first choice for treatment of HCC,as dual treatments of radiotherapy plus chemoembolization, local chemotherapy, systemic chemotherapy or targeted therapy drugs may show benefit over radiotherapy alone.
Ablation methods (e.g.radiofrequency ablationormicrowave ablation) are also an option for HCC treatment.This method is recommended for small, localized liver tumors as it is recommended that the area treated with radiofrequency ablation should be 2 centimeters or less.
Resection is an option in cholangiocarcinoma, but fewer than 30% of cases of cholangiocarcinoma are resectable at diagnosis. The reason the majority of intrahepatic cholangiocarcinomas are not able to be surgically removed is because there are often multiple focal tumors within the liver.After surgery, recurrence rates are up to 60%.Liver transplant may be used where partial resection is not an option, and adjuvantchemoradiationmay benefit some cases.
60% of cholangiocarcinomas form in theperihilarregion andphotodynamic therapycan be used to improvequality of lifeand survival time in these un-resectable cases.Photodynamic therapy is a novel treatment that uses light activated molecules to treat the tumor. The compounds are activated in the tumor region by laser light, which causes the release of toxic reactive oxygen species, killing tumor cells.
Systemic chemotherapies such asgemcitabineandcisplatinare sometimes used in inoperable cases of cholangiocarcinoma.
Radio frequency ablation,transarterial chemoembolizationand internal radiotherapy (brachytherapy) all show promise in the treatment of cholangiocarcinomaand can sometimes improvebile flow, which can decrease the symptoms a patient experiences.
Radiotherapymay be used in the adjuvant setting or for palliative treatment of cholangiocarcinoma.
Removing the tumor by eithersurgical resectionorliver transplantcan be used in the treatment of hepatoblastoma. In some cases surgery can offer a cure. Chemotherapy may be used before and after surgery and transplant.
Chemotherapy, includingcisplatin,vincristine,cyclophosphamide, anddoxorubicinare used for the systemic treatment of hepatoblastoma. Out of these drugs, cisplatin seems to be the most effective.
Many of these tumors end up not being amenable to surgical treatment.Treatment options include surgically removing parts of the liver that are affected.Liver transplantationandchemotherapyare not effective for angiosarcomas and hemangiosarcomas of the liver.
Globally, liver cancer is common and increasing.Most recent epidemiological data suggests that liver cancer is in the Top 10 for both prevalence and mortality (noted to be the sixth-leading cause of cancer and fourth most-common cause of death).The Global Burden of Disease Liver Cancer Collaboration found that from 1990 to 2015 the new cases of liver cancer per year increased by 75%.Estimates based on most recent data suggest that each year there are 841,000 new liver cancer diagnoses and 782,000 deaths across the globe.Liver cancer is the most common cancer inEgypt,the Gambia,Guinea,Mongolia,Cambodia, andVietnam.In terms of gender breakdown, globally liver cancer is more common in men than in women.
Given that HCC is the most-common type of liver cancer, the areas around the world with the most new cases of HCC each year are Northern and Western Africa as well as Eastern and South-Eastern Asia.China has 50% of HCC cases globally, and more than 80% of total cases occur in sub-Saharan Africa or in East-Asia due tohepatitis Bvirus.In these high disease burden areas, evidence indicates the majority of the HBC and HCV infections occur via perinatal transmission (also called mother-to-child transmission).However, it is important to note that the risk factors for HCC varies by geographic region. For example, inChina,chronic HBV infectionandaflatoxinare the largest risk factors; whereas, inMongolia, it is a combination ofHBV and HCV co-infectionand high levels ofalcohol usethat are driving the high levels of HCC.
In terms of intrahepatic cholangiocarcinoma, we currently do not have sufficient epidemiological data because it is a rare cancer. According to the United States National Cancer Institute, the incidence of cholangiocarcinoma is not known. Cholangiocarcinoma also has a significant geographical distribution, with Thailand showing the highest rates worldwide due to the presence of liver fluke.
In the United States, there were 42,810 new cases of liver and intrahepatic bile duct cancer in 2020, which represents 2.4% of all new cancer cases in the United States.There are about 89.950 people who have liver and intrahepatic liver cancer in the United States.In terms of mortality, the 5-year survival rate for liver and intrahepatic bile duct cancers in the United States is 19.6%.In the United States, there is an estimated 1% chance of getting liver cancer across the lifespan, which makes this cancer relatively rare.Despite the low number of cases, it is one of the top causes of cancer deaths.