Hepatocellular carcinoma

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Hepatocellular carcinoma
Hepatocellular carcinoma 1.jpg
Hepatocellular carcinoma in an individual who was hepatitis C positive. Autopsy specimen.
Specialty Oncology

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults, and is the most common cause of death in people with cirrhosis. [1]


It occurs in the setting of chronic liver inflammation, and is most closely linked to chronic viral hepatitis infection (hepatitis B or C) or exposure to toxins such as alcohol or aflatoxin. Certain diseases, such as hemochromatosis and alpha 1-antitrypsin deficiency, markedly increase the risk of developing HCC. Metabolic syndrome and NASH are also increasingly recognized as risk factors for HCC. [2]

As with any cancer, the treatment and prognosis of HCC vary depending on the specifics of tumor histology, size, how far the cancer has spread, and overall health.

The vast majority of HCC occurs in Asia and sub-Saharan Africa, in countries where hepatitis B infection is endemic and many are infected from birth. The incidence of HCC in the United States and other developing countries is increasing due to an increase in hepatitis C virus infections. It is more common in males than females for unknown reasons. [2]

Signs and symptoms

Most cases of HCC occur in people who already have signs and symptoms of chronic liver disease. They may present either with worsening of symptoms or may be without symptoms at the time of cancer detection. HCC may directly present with yellow skin, abdominal swelling due to fluid in the abdominal cavity, easy bruising from blood clotting abnormalities, loss of appetite, unintentional weight loss, abdominal pain, nausea, vomiting, or feeling tired. [3]

Risk factors

HCC mostly occurs in people with cirrhosis of the liver, and so risk factors generally include factors which cause chronic liver disease that may lead to cirrhosis. Still, certain risk factors are much more highly associated with HCC than others. For example, while heavy alcohol consumption is estimated to cause 60–70% of cirrhosis, the vast majority of HCC occurs in cirrhosis attributed to viral hepatitis (although there may be overlap). [4] Recognized risk factors include:

The significance of these risk factors varies globally. In regions where hepatitis B infection is endemic, such as southeast China, this is the predominant cause. [13] In populations largely protected by hepatitis B vaccination, such as the United States, HCC is most often linked to causes of cirrhosis such as chronic hepatitis C, obesity, and alcohol abuse.

Certain benign liver tumors, such as hepatocellular adenoma, may sometimes be associated with coexisting malignant HCC. Evidence is limited for the true incidence of malignancy associated with benign adenomas; however, the size of hepatic adenoma is considered to correspond to risk of malignancy and so larger tumors may be surgically removed. Certain subtypes of adenoma, particularly those with β-catenin activation mutation, are particularly associated with increased risk of HCC.

Children and adolescents are unlikely to have chronic liver disease, but if they suffer from congenital liver disorders, this fact increases the chance of developing HCC. [14] Specifically, children with biliary atresia, infantile cholestasis, glycogen-storage diseases, and other cirrhotic diseases of the liver are predisposed to developing HCC in childhood.

Young adults afflicted by the rare fibrolamellar variant of hepatocellular carcinoma may have none of the typical risk factors, i.e. cirrhosis and hepatitis.

Diabetes mellitus

The risk of hepatocellular carcinoma in type 2 diabetics is greater (from 2.5 [7] to 7.1 [15] times the nondiabetic risk) depending on the duration of diabetes and treatment protocol. A suspected contributor to this increased risk is circulating insulin concentration such that diabetics with poor insulin control or on treatments that elevate their insulin output (both states that contribute to a higher circulating insulin concentration) show far greater risk of hepatocellular carcinoma than diabetics on treatments that reduce circulating insulin concentration. [7] [15] [16] [17] On this note, some diabetics who engage in tight insulin control (by keeping it from being elevated) show risk levels low enough to be indistinguishable from the general population. [15] [16] This phenomenon is thus not isolated to diabetes mellitus type 2, since poor insulin regulation is also found in other conditions such as metabolic syndrome (specifically, when evidence of nonalcoholic fatty liver disease or NAFLD is present) and again evidence of greater risk exists here, too. [18] [19] While there are claims that anabolic steroid abusers are at greater risk [20] (theorized to be due to insulin and IGF exacerbation [21] [22] ), the only evidence that has been confirmed is that anabolic steroid users are more likely to have hepatocellular adenomas (a benign form of HCC) transform into the more dangerous hepatocellular carcinoma. [23] [24]


Hepatocellular carcinoma, like any other cancer, develops when epigenetic alterations and mutations affecting the cellular machinery cause the cell to replicate at a higher rate and/or result in the cell avoiding apoptosis. [25]

In particular, chronic infections of hepatitis B and/or C can aid the development of hepatocellular carcinoma by repeatedly causing the body's own immune system to attack the liver cells, some of which are infected by the virus, others merely bystanders. [26] Activated immune-system inflammatory cells release free radicals, such as reactive oxygen species and nitric oxide reactive species, which in turn can cause DNA damage and lead to carcinogenic gene mutations. [27] Reactive oxygen species also cause epigenetic alterations at the sites of DNA repair. [28]

While this constant cycle of damage followed by repair can lead to mistakes during repair, which in turn lead to carcinogenesis, this hypothesis is more applicable, at present, to hepatitis C. Chronic hepatitis C causes HCC through the stage of cirrhosis. In chronic hepatitis B, however, the integration of the viral genome into infected cells can directly induce a noncirrhotic liver to develop HCC. Alternatively, repeated consumption of large amounts of ethanol can have a similar effect. The toxin aflatoxin from certain Aspergillus species of fungi is a carcinogen and aids carcinogenesis of hepatocellular cancer by building up in the liver. The combined high prevalence of rates of aflatoxin and hepatitis B in settings such as China and West Africa has led to relatively high rates of hepatocellular carcinoma in these regions. Other viral hepatitides such as hepatitis A have no potential to become a chronic infection, thus are not related to HCC.


Methods of diagnosis in HCC have evolved with the improvement in medical imaging. The evaluation of both asymptomatic patients and those with symptoms of liver disease involves blood testing and imaging evaluation. Although historically a biopsy of the tumor was required to prove the diagnosis, imaging (especially MRI) findings may be conclusive enough to obviate histopathologic confirmation.


HCC remains associated with a high mortality rate, in part related to initial diagnosis commonly at an advanced stage of disease. As with other cancers, outcomes are significanty improved if treatment is initiated earlier in the disease process. Because the vast majority of HCC occurs in people with certain chronic liver diseases, especially those with cirrhosis, liver screening is commonly advocated in this population. Specific screening guidelines continue to evolve over time as evidence of its clinical impact becomes available. In the United States, the most commonly observed guidelines are those published by the American Association for the Study of Liver Diseases, which recommends screening people with cirrhosis with ultrasound every 6 months, with or without measurement of blood levels of tumor marker alpha-fetoprotein (AFP). [29] Elevated levels of AFP are associated with active HCC disease, although inconsistently reliable. At levels >20 sensitivity is 41-65% and specificity is 80-94%. However, at levels >200 sensitivity is 31, specificity is 99%. [30]

On ultrasound, HCC often appears as a small hypoechoic lesion with poorly defined margins and coarse, irregular internal echoes. When the tumor grows, it can sometimes appear heterogeneous with fibrosis, fatty change, and calcifications. This heterogeneity can look similar to cirrhosis and the surrounding liver parenchyma. A systematic review found that the sensitivity was 60% (95% CI 44–76%) and specificity was 97% (95% CI 95–98%) compared with pathologic examination of an explanted or resected liver as the reference standard. The sensitivity increases to 79% with AFP correlation. [31]

Controversy remains as to the most effective screening protocols. For example, while some data support decreased mortality related to screening in people with hepatitis B infection, the AASLD notes. “there are no randomized trials [for screening] in Western populations with cirrhosis secondary to chronic hepatitis C or fatty liver disease, and thus there is some controversy surrounding whether surveillance truly leads to a reduction in mortality in this population of patients with cirrhosis.” [29]

Higher risk people

In a person where a higher suspicion of HCC exists, such as a person with symptoms or abnormal blood tests (i.e. alpha-fetoprotein and des-gamma carboxyprothrombin levels), [32] evaluation requires imaging of the liver by CT or MRI scans. Optimally, these scans are performed with intravenous contrast in multiple phases of hepatic perfusion to improve detection and accurate classification of any liver lesions by the interpreting radiologist. Due to the characteristic blood flow pattern of HCC tumors, a specific perfusion pattern of any detected liver lesion may conclusively detect an HCC tumor. Alternatively, the scan may detect an indeterminate lesion and further evaluation may be performed by obtaining a physical sample of the lesion.


Triphasic contrast CT of hepatocellular carcinoma. Triphasic CT scan of hepatocellular carcinoma.jpg
Triphasic contrast CT of hepatocellular carcinoma.

Ultrasound, CT scan, and MRI may be used to evaluate the liver for HCC. On CT and MRI, HCC can have three distinct patterns of growth:

A systematic review of CT diagnosis found that the sensitivity was 68% (95% CI 55–80%) and specificity was 93% (95% CI 89–96%) compared with pathologic examination of an explanted or resected liver as the reference standard. With triple-phase helical CT, the sensitivity was 90% or higher, but these data have not been confirmed with autopsy studies. [31]

However, MRI has the advantage of delivering high-resolution images of the liver without ionizing radiation. HCC appears as a high-intensity pattern on T2-weighted images and a low-intensity pattern on T1-weighted images. The advantage of MRI is that it has improved sensitivity and specificity when compared to ultrasound and CT in cirrhotic patients with whom it can be difficult to differentiate HCC from regenerative nodules. A systematic review found that the sensitivity was 81% (95% CI 70–91%) and specificity was 85% (95% CI 77–93%) compared with pathologic examination of an explanted or resected liver as the reference standard. [31] The sensitivity is further increased if gadolinium contrast-enhanced and diffusion-weighted imaging are combined.

MRI is more sensitive and specific than CT. [33]

Liver image reporting and data system (LI-RADS) is a classification system for the reporting of liver lesions detected on CT and MRI. Radiologists use this standardized system to report on suspicious lesions and to provide an estimated likelihood of malignancy. Categories range from LI-RADS (LR) 1 to 5, in order of concern for cancer. [34] A biopsy is not needed to confirm the diagnosis of HCC if certain imaging criteria are met.


Micrograph of hepatocellular carcinoma. Liver biopsy. Trichrome stain. Hepatocellular carcinoma intermed mag.jpg
Micrograph of hepatocellular carcinoma. Liver biopsy. Trichrome stain.

Macroscopically, liver cancer appears as a nodular or infiltrative tumor. The nodular type may be solitary (large mass) or multiple (when developed as a complication of cirrhosis). Tumor nodules are round to oval, gray or green (if the tumor produces bile), well circumscribed but not encapsulated. The diffuse type is poorly circumscribed and infiltrates the portal veins, or the hepatic veins (rarely).

Microscopically, the four architectural and cytological types (patterns) of hepatocellular carcinoma are: fibrolamellar, pseudoglandular (adenoid), pleomorphic (giant cell), and clear cell. In well-differentiated forms, tumor cells resemble hepatocytes, form trabeculae, cords, and nests, and may contain bile pigment in the cytoplasm. In poorly differentiated forms, malignant epithelial cells are discohesive, pleomorphic, anaplastic, and giant. The tumor has a scant stroma and central necrosis because of the poor vascularization. [35] A fifth form – lymphoepithelioma like hepatocellular carcinoma – has also been described. [36] [37]


BCLC Staging System

The prognosis of HCC is affected by the staging of the tumor and the liver's function due to the effects of liver cirrhosis. [38]

A number of staging classifications for HCC are available; however, due to the unique nature of the carcinoma to fully encompass all the features that affect the categorization of the HCC, a classification system should incorporate tumor size and number, presence of vascular invasion and extrahepatic spread, liver function (levels of serum bilirubin and albumin, presence of ascites, and portal hypertension) and general health status of the patient (defined by the ECOG classification and the presence of symptoms). [38]

Of all the staging classification systems available the Barcelona Clinic Liver Cancer staging classification encompasses all of the above characteristics. This staging classification can be used to select people for treatment. [39]

Barcelona Clinic Liver Cancer classification [40] [41] [42]
StageDescription Child-Pugh classECOG performance status
0 (very early stage)Single nodule, < 3 cmA0
A (early stage)1-3 nodule, all < 3 cmA or B
B (intermediate stage)Multi-nodular tumor
C (advanced stage)Portal invasion and extra-hepatic spread1 or 2
D (terminal stage)Severe liver damageC3 or 4

Important features that guide treatment include:

MRI is the best imaging method to detect the presence of a tumor capsule.

The most common sites of metastasis are the lung, abdominal lymph nodes, and bone. [43]


Since hepatitis B and C are some of the main causes of hepatocellular carcinoma, prevention of infection is key to then prevent HCC. Thus, childhood vaccination against hepatitis B may reduce the risk of liver cancer in the future. [44] In the case of patients with cirrhosis, alcohol consumption is to be avoided. Also, screening for hemochromatosis may be beneficial for some patients. [45] Whether screening those with chronic liver disease for HCC improves outcomes is unclear. [46]


Treatment of hepatocellular carcinoma varies by the stage of disease, a person's likelihood to tolerate surgery, and availability of liver transplant:

  1. Curative intention: for limited disease, when the cancer is limited to one or more areas of within the liver, surgically removing the malignant cells may be curative. This may be accomplished by resection the affected portion of the liver (partial hepatectomy) or in some cases by orthotopic liver transplantation of the entire organ.
  2. "Bridging" intention: for limited disease which qualifies for potential liver transplantation, the person may undergo targeted treatment of some or all of the known tumor while waiting for a donor organ to become available. [47]
  3. "Downstaging" intention: for moderately advanced disease which has not spread beyond the liver, but is too advanced to qualify for curative treatment. The person may be treated by targeted therapies in order to reduce the size or number of active tumors, with the goal of once again qualifying for liver transplant after this treatment. [47]
  4. Palliative intention: for more advanced disease, including spread of cancer beyond the liver or in persons who may not tolerate surgery, treatment intended to decrease symptoms of disease and maximize duration of survival.

Loco-regional therapy (also referred to as liver-directed therapy) refers to any one of several minimally-invasive treatment techniques to focally target HCC within the liver. These procedures are alternatives to surgery, and may be considered in combination with other strategies, such as a later liver transplantation. [48] Generally, these treatment procedures are performed by interventional radiologists or surgeons, in coordination with a medical oncologist. Loco-regional therapy may refer to either percutaneous therapies (e.g. cryoablation), or arterial catheter-based therapies (chemoembolization or radioembolization).

Surgical resection

Gross anatomy of hepatocellular carcinoma HepatoCellular Ca.JPG
Gross anatomy of hepatocellular carcinoma

Surgical removal of the tumor is associated with better cancer prognosis, but only 5–15% of patients are suitable for surgical resection due to the extent of disease or poor liver function. [49] Surgery is only considered if the entire tumor can be safely removed while preserving sufficient functional liver to maintain normal physiology. Thus, preoperative imaging assessment is critical to determine both the extent of HCC and to estimate the amount of residual liver remaining after surgery. To maintain liver function, residual liver volume should exceed 25% of total liver volume in a noncirrhotic liver, greater than 40% in a cirrhotic liver. [50] Surgery on diseased or cirrhotic livers is generally associated with higher morbidity and mortality. The overall recurrence rate after resection is 50-60%. The Singapore Liver Cancer Recurrence score can be used to estimate risk of recurrence after surgery. [51]

Liver transplantation

Liver transplantation, replacing the diseased liver with a cadaveric or a living donor liver, plays an increasing role in treatment of HCC. Although outcomes following liver transplant were initially poor (20%–36% survival rate[ medical citation needed ]), outcomes have significantly improved with improvement in surgical techniques and adoption of the Milan criteria at US transplantation centers. Expanded Shanghai criteria in China have resulted in overall survival and disease-free survival rates similar to those achieved using the Milan criteria. [52] Studies from the late 2000s obtained higher survival rates ranging from 67% to 91%. [53]

The risks of liver transplantation extend beyond risk of the procedure itself. The immunosuppressive medication required after surgery to prevent rejection of the donor liver also impairs the body's natural ability to combat dysfunctional cells. If the tumor has spread undetected outside the liver before the transplant, the medication effectively increases the rate of disease progression and decreases survival. With this in mind, liver transplant "can be a curative approach for patients with advanced HCC without extrahepatic metastasis". [54] Patient selection is considered a major key for success. [55]


Arterial catheter-based treatment


In disease which has spread beyond the liver, systemic therapy may be a consideration. In 2007, Sorafenib, an oral multikinase inhibitor, was the first systemic agent approved for first-line treatment of advanced HCC. [62] Trials have found modest improvement in overall survival: 10.7 months vs 7.9 months and 6.5 months vs 4.2 months. [63] [62]

The most common side effects of Sorafenib include a hand-foot skin reaction and diarrhea. [63] Sorafenib is thought to work by blocking growth of both tumor cells and new blood vessels. Numerous other molecular targeted drugs are being tested as alternative first- and second-line treatments for advanced HCC. [64]



The usual outcome is poor, because only 10–20% of hepatocellular carcinomas can be removed completely using surgery. If the cancer cannot be completely removed, the disease is usually deadly within 3 to 6 months. [67] This is partially due to late presentation with tumors, but also the lack of medical expertise and facilities in the regions with high HCC prevalence. However, survival can vary, and occasionally people survive much longer than 6 months. The prognosis for metastatic or unresectable HCC has improved due to the approval of Sorafenib (Nexavar®) for advanced HCC.[ citation needed ]


Age-standardized death from liver cancer per 100,000 inhabitants in 2004.
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Age-standardized death from liver cancer per 100,000 inhabitants in 2004.
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Liver tumor types by relative incidence in adults in the United States, with hepatocellular carcinoma at left. Liver tumor types in adults by relative incidence.png
Liver tumor types by relative incidence in adults in the United States, with hepatocellular carcinoma at left.

HCC is one of the most common tumors worldwide. The epidemiology of HCC exhibits two main patterns, one in North America and Western Europe and another in non-Western countries, such as those in sub-Saharan Africa, Central and Southeast Asia, and the Amazon basin. Males are affected more than females usually, and it is most common between the ages of 30 and 50, [70] Hepatocellular carcinoma causes 662,000 deaths worldwide per year [71] about half of them in China.

Africa and Asia

In some parts of the world, such as sub-Saharan Africa and Southeast Asia, HCC is the most common cancer, generally affecting men more than women, and with an age of onset between the late teens and 30s. This variability is in part due to the different patterns of hepatitis B and hepatitis C transmission in different populations – infection at or around birth predispose to earlier cancers than if people are infected later. The time between hepatitis B infection and development into HCC can be years, even decades, but from diagnosis of HCC to death, the average survival period is only 5.9 months according to one Chinese study during the 1970-80s, or 3 months (median survival time) in sub-Saharan Africa according to Manson's textbook of tropical diseases. HCC is one of the deadliest cancers in China, where chronic hepatitis B is found in 90% of cases. In Japan, chronic hepatitis C is associated with 90% of HCC cases. Foods infected with Aspergillus flavus (especially peanuts and corns stored during prolonged wet seasons) which produces aflatoxins pose another risk factor for HCC.

North America and Western Europe

The most common malignant tumors in the liver represent metastases (spread) from tumors which originate elsewhere in the body. [70] Among cancers that originate from liver tissue, HCC is the most common primary liver cancer. In the United States, the US surveillance, epidemiology, and end results database program, shows that HCC accounts for 65% of all cases of liver cancers. [72] As screening programs are in place for high-risk persons with chronic liver disease, HCC is often discovered much earlier in Western countries than in developing regions such as sub-Saharan Africa.

Acute and chronic hepatic porphyrias (acute intermittent porphyria, porphyria cutanea tarda, hereditary coproporphyria, variegate porphyria) and tyrosinemia type I are risk factors for hepatocellular carcinoma. The diagnosis of an acute hepatic porphyria (AIP, HCP, VP) should be sought in patients with HCC without typical risk factors of hepatitis B or C, alcoholic liver cirrhosis, or hemochromatosis. Both active and latent genetic carriers of acute hepatic porphyrias are at risk for this cancer, although latent genetic carriers have developed the cancer at a later age than those with classic symptoms. Patients with acute hepatic porphyrias should be monitored for HCC.

The incidence of HCC is relatively lower in the Western Hemisphere than in Eastern Asia. However, despite the statistics being low, the diagnosis of HCC has increased since the 1980s and it is continuing to increase, making it one of the rising causes of death due to cancer. The common risk factor for HCC is hepatitis C, along with other health issues. [73] [74]



Current research includes the search for the genes that are disregulated in HCC, antiheparanase antibodies, [75] protein markers, [76] non-coding RNAs [77] (such as TUC338) [78] and other predictive biomarkers. [79] [80] As similar research is yielding results in various other malignant diseases, it is hoped that identifying the aberrant genes and the resultant proteins could lead to the identification of pharmacological interventions for HCC. [81]

The development of three-dimensional culture methods provides a new approach for preclinical studies of cancer therapy using patient-derived organoids. These miniaturized organoid 'avatars' of a patient's tumor recapitulate several features of the original tumor, rendering them an attractive model for drug-sensitivity testing and precision medicine for HCC and other types of primary liver cancer. [82]

Furthermore, HCC occurs in patients with liver disease. A biomarker named six-miRNA signature allows effective treatment of patients with HCC and is able to predict its recurrence in the liver. [83]


JX-594, an oncolytic virus, has orphan drug designation for this condition and is undergoing clinical trials. [84]

Hepcortespenlisimut-L (Hepko-V5), an oral cancer vaccine, also has US FDA orphan drug designation for HCC. [85] Immunitor Inc. completed a Phase II trial, published in 2017. [86]

A randomized trial of people with advanced HCC showed no benefit for the combination of everolimus and pasireotide. [87]

See also

Related Research Articles

Hepatitis inflammation of the liver tissue

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Hepatitis C Human viral infection

Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver. During the initial infection people often have mild or no symptoms. Occasionally a fever, dark urine, abdominal pain, and yellow tinged skin occurs. The virus persists in the liver in about 75% to 85% of those initially infected. Early on chronic infection typically has no symptoms. Over many years however, it often leads to liver disease and occasionally cirrhosis. In some cases, those with cirrhosis will develop serious complications such as liver failure, liver cancer, or dilated blood vessels in the esophagus and stomach.

Alcoholic liver disease

Alcoholic liver disease (ALD), also called alcohol-related liver disease (ARLD), is a term that encompasses the liver manifestations of alcohol overconsumption, including fatty liver, alcoholic hepatitis, and chronic hepatitis with liver fibrosis or cirrhosis.

Everolimus chemical compound

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Alcoholic hepatitis hepatitis (inflammation of the liver) due to excessive intake of alcohol

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Liver disease Human disease

Liver disease is a type of damage to or disease of the liver. Whenever the course of the problem lasts long, chronic liver disease ensues.

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Cholangiocarcinoma, also known as bile duct cancer, is a type of cancer that forms in the bile ducts. Symptoms of cholangiocarcinoma may include abdominal pain, yellowish skin, weight loss, generalized itching, and fever. Light colored stool or dark urine may also occur. Other biliary tract cancers include gallbladder cancer and cancer of the ampulla of Vater.

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In oncology, AFP-L3 is an isoform of Alpha-fetoprotein (AFP), a substance typically used in the triple test during pregnancy and for screening chronic liver disease patients for hepatocellular carcinoma (HCC). AFP can be fractionated by affinity electrophoresis into 3 glycoforms: L1, L2, and L3 based on the reactivity with the lectin Lens culinaris agglutinin (LCA). AFP-L3 binds strongly to LCA via an additional α 1-6 fucose residue attached at the reducing terminus of N-acetylglucosamine; this is in contrast to the L1 isoform. It is the L1 isoform which is typically associated with non-HCC inflammation of liver disease condition. The L3 isoform is specific to malignant tumors and its detected presence can serve to identify patients whom need increased monitoring for the development of HCC in high risk populations. AFP-L3% is now being considered as a tumor marker for the North American demographic.

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Non-alcoholic fatty liver disease Excessive fat build-up in the liver not caused by alcohol use

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Liver cancer gastrointestinal system cancer, located in the liver

Liver cancer, also known as hepatic cancer and primary hepatic cancer, is cancer that starts in the liver. Cancer which has spread from elsewhere to the liver, known as liver metastasis, is more common than that which starts in the liver. Symptoms of liver cancer may include a lump or pain in the right side below the rib cage, swelling of the abdomen, yellowish skin, easy bruising, weight loss and weakness.

Fibrolamellar hepatocellular carcinoma A hepatocellular carcinoma characterized microscopically by laminated fibrous layers interspersed between the tumour cells. The polygonal, deeply eosinophilic tumor cells arise in non-cirrhotic livers.

Fibrolamellar hepatocellular carcinoma (FHCC) is a rare form of hepatocellular carcinoma (HCC) that typically affects young adults and is characterized, under the microscope, by laminated fibrous layers interspersed between the tumour cells. Approximately 200 new cases are diagnosed worldwide each year.

Selective internal radiation therapy

Selective internal radiation therapy, also known as transarterial radioembolization (TARE), radioembolization or intra-arterial microbrachytherapy is a form of radiation therapy used in interventional radiology to treat cancer. It is generally for selected patients with surgically unresectable cancers, especially hepatocellular carcinoma or metastasis to the liver. The treatment involves injecting tiny microspheres of radioactive material into the arteries that supply the tumor, where the spheres lodge in the small vessels of the tumor. Because this treatment combines radiotherapy with embolization, it is also called radioembolization. The chemotherapeutic analogue is called chemoembolization, of which transcatheter arterial chemoembolization (TACE) is the usual form.

Cirrhosis Chronic disease of the liver, characterized by fibrosis

Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, is a condition in which the liver does not function properly due to long-term damage. This damage is characterized by the replacement of normal liver tissue by scar tissue. Typically, the disease develops slowly over months or years. Early on, there are often no symptoms. As the disease worsens, a person may become tired, weak, itchy, have swelling in the lower legs, develop yellow skin, bruise easily, have fluid build up in the abdomen, or develop spider-like blood vessels on the skin. The fluid build-up in the abdomen may become spontaneously infected. Other serious complications include hepatic encephalopathy, bleeding from dilated veins in the esophagus or dilated stomach veins, and liver cancer. Hepatic encephalopathy results in confusion and may lead to unconsciousness.

In transplantation medicine, the Milan criteria are set of criteria applied in consideration of patients with cirrhosis and hepatocellular carcinoma (HCC) for liver transplantation with intent to cure their disease. Their significance derives from a landmark 1996 study in 48 patients by Mazzaferro et al which showed that selecting cases for transplantation according to specific strict criteria led to improved overall and disease-free survival at a 4-year time point. These same criteria have since been adopted by the Organ Procurement and Transplantation Network (OPTN) in the evaluation of patients for potential transplantation.

Brivanib alaninate chemical compound

Brivanib alaninate (INN/USAN) also known as BMS-582664 is an investigational, anti-tumorigenic drug for oral administration. The drug is being developed by Bristol-Myers Squibb for the treatment of hepatocellular carcinoma or HCC, the most common type of liver cancer.

This is a timeline of liver cancer, describing especially major discoveries and advances in treatment of the disease.


The Liver Imaging Reporting and Data System is a quality assurance tool created and trademarked by the American College of Radiology in 2011 to standardize the reporting and data collection of CT and MR imaging patients at risk for hepatocellular carcinoma (HCC), or primary cancer of the liver cells. It provides a standardized framework for classification of liver lesions by a radiologist, and only applies in patients with chronic liver disease, the main risk factor for liver cancer. The hierarchical classification, from LR1 to LR5, is based on specific imaging features of the lesion in question, and corresponds to the degree of suspicion for malignancy. For example, a lesion with features corresponding to the highest category, LR5, is "definitely" HCC. Importantly, the increasing acceptance of the LI-RADS system of reporting by referring clinicians has reduced the need for tissue biopsy confirmation of cancer in patients with chronic liver disease.

Transarterial bland embolization is a catheter-based tumor treatment of the liver. In this procedure, a variety of embolizing agents can be delivered through the tumor’s feeding artery in order to completely occlude the tumor’s blood supply. The anti-tumor effects are solely based on tumor ischemia and infarction of tumor tissue, as no chemotherapeutic agents are administered. The rationale for the use of bland embolization for hepatocellular carcinoma(HCC) and/or other hyper-vascular tumors is based on the fact that normal liver receives a dual blood supply from the hepatic artery (25%) and the portal vein (75%). As the tumor grows, it becomes increasingly dependent on the hepatic artery for blood supply. Once a tumor nodule reaches a diameter of 2 cm or more, most of the blood supply is derived from the hepatic artery. Therefore, bland embolization and transarterial chemoembolization (TACE) consist of the selective angiographic occlusion of the tumor arterial blood supply with a variety of embolizing agents, with or without the precedence of local chemotherapy infusion. The occlusion by embolic particles results in tumor hypoxia and necrosis, without affecting the normal hepatic parenchyma.


  1. Forner A, Llovet JM, Bruix J (2012). "Hepatocellular carcinoma". The Lancet. 379 (9822): 1245–1255. doi:10.1016/S0140-6736(11)61347-0. PMID   22353262.
  2. 1 2 Kumar V, Fausto N, Abbas A, eds. (2015). Robbins & Cotran Pathologic Basis of Disease (9th ed.). Saunders. pp. 870–873. ISBN   978-1455726134.
  3. "Liver cancer overview". Mayo Clinic.
  4. 1 2 Heidelbaugh, Joel J.; Bruderly, Michael (2006-09-01). "Cirrhosis and chronic liver failure: part I. Diagnosis and evaluation". American Family Physician. 74 (5): 756–762. ISSN   0002-838X. PMID   16970019.
  5. Alter MJ (2007). "Epidemiology of hepatitis C virus infection". World Journal of Gastroenterology. 13 (17): 2436–41. doi:10.3748/wjg.v13.i17.2436. PMC   4146761 . PMID   17552026.
  6. White DL, Kanwal F, El-Serag HB (2012). "Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review". Clinical Gastroenterology and Hepatology. 10 (12): 1342–59. doi:10.1016/j.cgh.2012.10.001. PMC   3501546 . PMID   23041539.
  7. 1 2 3 El–Serag HB; Hampel H; Javadi F (2006). "the association between diabetes and hepatocellular carcinoma: a systematic review of epidemiological evidence". Clinical Gastroenterology and Hepatology. 4 (3): 369–380. doi:10.1016/j.cgh.2005.12.007. PMID   16527702. Diabetes is associated with an increased risk for HCC. However, more research is required to examine issues related to the duration and treatment of diabetes, and confounding by diet and obesity
  8. Wang XW, Hussain SP, Huo TI, Wu CG, Forgues M, Hofseth LJ, Brechot C, Harris CC (2002). "Molecular pathogenesis of human hepatocellular carcinoma". Toxicology. 181–182: 43–47. doi:10.1016/S0300-483X(02)00253-6. PMID   12505283. Recent studies in our laboratory have identified several potential factors that may contribute to the pathogenesis of HCC...For example, oxyradical overload diseases such as Wilson disease and hemochromatosis result in the generation of oxygen/nitrogen species that can cause mutations in the p53 tumour suppressor gene
  9. Cheng W, Govindarajan S, Redeker A (1992). "Hepatocellular carcinoma in a case of Wilson's disease". Liver International. 12 (1): 42–45. doi:10.1111/j.1600-0676.1992.tb00553.x. PMID   1314321. The patient described here was the oldest and only the third female patient with hepatocellular carcinoma complicating Wilson's disease to be reported in the literature
  10. Wilkinson ML, Portmann B, Williams R (1983). "Wilson's disease and hepatocellular carcinoma: possible protective role of copper". Gut. 24 (8): 767–771. doi:10.1136/gut.24.8.767. PMC   1420230 . PMID   6307837. As copper has been shown to protect against chemically induced hepatocellular carcinoma in rats, this may be the reason for the extreme rarity of hepatocellular carcinoma in patients with Wilson's disease and possibly in other liver diseases with hepatic copper overload
  11. Huang YC, Tsan YT, Chan WC, Wang JD, Chu WM, Fu YC, Tong KM, Lin CH, Chang ST, Hwang WL (2015). "Incidence and survival of cancers among 1,054 hemophilia patients: A nationwide and 14-year cohort study". American Journal of Hematology. 90 (4): E55–E59. doi:10.1002/ajh.23947. PMID   25639564.
  12. Shetty, Shrimati; Sharma, Nitika; Ghosh, Kanjaksha (2016-03-01). "Epidemiology of hepatocellular carcinoma (HCC) in hemophilia". Critical Reviews in Oncology/Hematology. 99: 129–133. doi:10.1016/j.critrevonc.2015.12.009. ISSN   1040-8428. PMID   26754251.
  13. Tanaka M, Katayama F, Kato H, Tanaka H, Wang J, Qiao YL, Inoue M (2011). "Hepatitis B and C virus infection and hepatocellular carcinoma in China: A review of epidemiology and control measures". Journal of Epidemiology. 21 (6): 401–416. doi:10.2188/jea.JE20100190. PMC   3899457 . PMID   22041528.
  14. "Pathophysiology". 2019-11-10. Retrieved May 12, 2010.Cite journal requires |journal= (help)
  15. 1 2 3 Hassan MM, Curley SA, Li D, Kaseb A, Davila M, Abdalla EK, Javle M, Moghazy DM, Lozano RD, Abbruzzese JL, Vauthey JN (2010). "Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma". Cancer. 116 (8): 1938–1946. doi:10.1002/cncr.24982. PMC   4123320 . PMID   20166205. Diabetes appears to increase the risk of HCC, and such risk is correlated with a long duration of diabetes. Relying on dietary control and treatment with sulfonylureas or insulin were found to confer the highest magnitude of HCC risk, whereas treatment with biguanides or thiazolidinediones was associated with a 70% HCC risk reduction among diabetics.
  16. 1 2 Donadon, Valter (2009). "Antidiabetic therapy and increased risk of hepatocellular carcinoma in chronic liver disease". World Journal of Gastroenterology. 15 (20): 2506–11. doi:10.3748/wjg.15.2506. PMC   2686909 . PMID   19469001. Our study confirms that type 2 diabetes mellitus is an independent risk factor for HCC and pre-exists in the majority of HCC patients. Moreover, in male patients with type 2 diabetes mellitus, our data shows a direct association of HCC with insulin and sulphanylureas treatment and an inverse relationship with metformin therapy.
  17. Donadon V, Balbi M, Ghersetti M, et al. (2009). "Antidiabetic therapy and increased risk of hepatocellular carcinoma in chronic liver disease". World Journal of Gastroenterology. 15 (20): 2506–11. doi:10.3748/wjg.15.2506. PMC   2686909 . PMID   19469001.
  18. Siegel A, Zhu AX (2009). "Metabolic Syndrome and hepatocellular carcinoma". Cancer. 115 (24): 5651–5661. doi:10.1002/cncr.24687. PMC   3397779 . PMID   19834957. The majority of 'cryptogenic' HCC in the United States is attributed to nonalcoholic fatty liver disease (NAFLD), a hepatic manifestation of the metabolic syndrome... It is predicted that metabolic syndrome will lead to large increases in the incidence of HCC over the next decades. A better understanding of the relation between these two diseases ultimately should lead to improved screening and treatment options for patients with HCC.
  19. Stickely F, Hellerbrand C (2010). "Non-alcoholic fatty liver disease as a risk factor for hepatocellular carcinoma: mechanisms and implications". Gut. 59 (10): 1303–1307. doi:10.1136/gut.2009.199661. PMID   20650925. Based on the known association of NAFLD with IR and MS, approximately two-thirds of the patients were obese and/or diabetic, 4 and a remarkable 25% of these patients had no cirrhosis... Therefore, it is particularly worrying that the most persuasive evidence for an association between NAFLD and HCC derives from studies on the risk of HCC in patients with metabolic syndrome
  20. "Hepatocellular Carcinoma and Diseases" . Retrieved May 12, 2010.
  21. Höpfner M, Huether A, Sutter AP, Baradari V, Schuppan D, Scherübl H (2006). "Blockade of IGF-1 receptor tyrosine kinase has antineoplastic effects in hepatocellular carcinoma cells". Biochemical Pharmacology . 71 (10): 1435–1448. doi:10.1016/j.bcp.2006.02.006. PMID   16530734. Inhibition of IGF-1R tyrosine kinase (IGF-1R-TK) by NVP-AEW541 induces growth inhibition, apoptosis and cell cycle arrest in human HCC cell lines without accompanying cytotoxicity. Thus, IGF-1R-TK inhibition may be a promising novel treatment approach in HCC.
  22. Huynh H, Chow PK, Ooi LL, Soo KC (2002). "A possible role for insulin-like growth factor-binding protein-3 autocrine/paracrine loops in controlling hepatocellular carcinoma cell proliferation". Cell Growth & Differentiation. 13 (3): 115–122. PMID   11959812. Our data indicate that loss of autocrine/paracrine IGFBP-3 loops may lead to HCC tumor growth and suggest that modulating production of the IGFs, IGFBP-3, and IGF-IR may represent a novel approach in the treatment of HCC.
  23. Martin NM, Abu Dayyeh BK, Chung RT (2008). "Anabolic steroid abuse causing recurrent hepatic adenomas and hemorrhage". World Journal of Gastroenterology. 14 (28): 4573–4575. doi:10.3748/wjg.14.4573. PMC   2731289 . PMID   18680242. This is the first reported case of hepatic adenoma re-growth with recidivistic steroid abuse, complicated by life-threatening hemorrhage.
  24. Gorayski P, Thompson CH, Subhash HS, Thomas AC (2007). "Hepatocellular carcinoma associated with recreational anabolic steroid use". British Journal of Sports Medicine. 42 (1): 74–75. doi:10.1136/bjsm.2007.03932. PMID   18178686. Malignant transformation to HCC from a pre-existing hepatic adenoma confirmed by immunohistochemical study has previously not been reported in athletes taking anabolic steroids. Further studies using screening programmes to identify high-risk individuals are recommended.
  25. Shibata T, Aburatani H (2014). "Exploration of liver cancer genomes". Nat Rev Gastroenterol Hepatol. 11 (6): 340–9. doi:10.1038/nrgastro.2014.6. PMID   24473361.
  26. Chien-Jen Chen; Hwai-I. Yang; Jun Su; Chin-Lan Jen; San-Lin You; Sheng-Nan Lu; Guan-Tarn Huang; Uchenna H. Iloeje (2006). "Risk of Hepatocellular Carcinoma Across a Biological Gradient of Serum Hepatitis B Virus DNA Level". JAMA. 295 (1): 65–73. doi:10.1001/jama.295.1.65. PMID   16391218.
  27. Yang SF, Chang CW, Wei RJ, Shiue YL, Wang SN, Yeh YT (2014). "Involvement of DNA damage response pathways in hepatocellular carcinoma". Biomed Res Int. 2014: 1–18. doi:10.1155/2014/153867. PMC   4022277 . PMID   24877058.
  28. Nishida N, Kudo M (2013). "Oxidative stress and epigenetic instability in human hepatocarcinogenesis". Dig Dis. 31 (5–6): 447–53. doi:10.1159/000355243. PMID   24281019.
  29. 1 2 Heimbach, Julie K.; Kulik, Laura M.; Finn, Richard; Sirlin, Claude B.; Abecassis, Michael; Roberts, Lewis R.; Zhu, Andrew; Murad, M. Hassan; Marrero, Jorge (2017-01-01). "Aasld guidelines for the treatment of hepatocellular carcinoma". Hepatology. 67 (1): 358–380. doi:10.1002/hep.29086. ISSN   1527-3350. PMID   28130846.
  30. "Clinical features and diagnosis of primary hepatocellular carcinoma". UptoDate. Retrieved 4 February 2014.
  31. 1 2 3 Colli, A; Fraquelli, M; Casazza, G; Massironi, S; Colucci, A; Conte, D; Duca, P (March 2006). "Accuracy of ultrasonography, spiral CT, magnetic resonance, and alpha-fetoprotein in diagnosing hepatocellular carcinoma: a systematic review". The American Journal of Gastroenterology. 101 (3): 513–23. doi:10.1111/j.1572-0241.2006.00467.x. PMID   16542288.CS1 maint: multiple names: authors list (link)
  32. Ertle, JM; Heider, D; Wichert, M; Keller, B; Kueper, R; Hilgard, P; Gerken, G; Schlaak, JF (2013). "A combination of α-fetoprotein and des-γ-carboxy prothrombin is superior in detection of hepatocellular carcinoma". Digestion. 87 (2): 121–31. doi:10.1159/000346080. PMID   23406785.
  33. El-Serag HB, Marrero JA, Rudolph L, Reddy KR (May 2008). "Diagnosis and treatment of hepatocellular carcinoma". Gastroenterology. 134 (6): 1752–63. doi:10.1053/j.gastro.2008.02.090. PMID   18471552.
  34. "Li-Rads". Archived from the original on 2017-07-11. Retrieved 2014-02-04.
  35. Hepatocellular carcinoma (Photo) ATLAS OF PATHOLOGY
  36. Chan AW, Zhang Z, Chong CC, Tin EK, Chow C, Wong N (2019). "Genomic landscape of lymphoepithelioma-like hepatocellular carcinoma". J Pathol. 249: 166–172. doi:10.1002/path.5313.CS1 maint: multiple names: authors list (link)
  37. Chan AW, Tong JH, Pan Y, Chan SL, Wong GL, Wong VW, Lai PB, To KF (2015). "Lymphoepithelioma-like hepatocellular carcinoma: an uncommon variant of hepatocellular carcinoma with favorable outcome". Am J Surg Pathol. 39 (3): 304–312. doi:10.1097/pas.0000000000000376.CS1 maint: multiple names: authors list (link)
  38. 1 2 Duseja, Ajay (2014-08-01). "Staging of Hepatocellular Carcinoma". Journal of Clinical and Experimental Hepatology. 4 (Suppl 3): S74–S79. doi:10.1016/j.jceh.2014.03.045. PMC   4284240 . PMID   25755615.
  39. Llovet JM, Brú C, Bruix J (1999). "Prognosis of hepatocellular carcinoma: the BCLC staging classification". Seminars in Liver Disease. 19 (3): 329–38. doi:10.1055/s-2007-1007122. PMID   10518312.
  40. "BCLC staging system and the Child-Pugh system ;Liver cancer ; Cancer Research UK". www.cancerresearchuk.org.
  41. "What is the Barcelona Clinic Liver Cancer (BCLC) system for hepatocellular carcinoma (HCC) staging?". www.medscape.com.
  42. Kinoshita, A; Onoda, H; Fushiya, N; Koike, K; Nishino, H; Tajiri, H (27 March 2015). "Staging systems for hepatocellular carcinoma: Current status and future perspectives". World Journal of Hepatology. 7 (3): 406–24. doi:10.4254/wjh.v7.i3.406. PMC   4381166 . PMID   25848467.
  43. Katyal, Sanjeev; Oliver, James H.; Peterson, Mark S.; Ferris, James V.; Carr, Brian S.; Baron, Richard L. (2000). "Extrahepatic Metastases of Hepatocellular Carcinoma". Radiology. 216 (3): 698–703. doi:10.1148/radiology.216.3.r00se24698. PMID   10966697.
  44. "Hepatitis B: Prevention and treatment". Archived from the original on 24 July 2013. Retrieved 28 August 2013. "WHO aims at controlling HBV worldwide to decrease the incidence of HBV-related chronic liver disease, cirrhosis, and hepatocellular carcinoma. by integrating HB vaccination into routine infant (and possibly adolescent) immunization programs."
  45. "Prevention" . Retrieved May 12, 2010.
  46. Kansagara, Devan; Papak, Joel; Pasha, Amirala S.; O'Neil, Maya; Freeman, Michele; Relevo, Rose; Quiñones, Ana; Motu'apuaka, Makalapua; et al. (17 June 2014). "Screening for Hepatocellular Carcinoma in Chronic Liver Disease". Annals of Internal Medicine. 161 (4): 261–9. doi:10.7326/M14-0558. PMID   24934699.
  47. 1 2 Pompili, Maurizio (2013). "Bridging and downstaging treatments for hepatocellular carcinoma in patients on the waiting list for liver transplantation". World Journal of Gastroenterology. 19 (43): 7515–30. doi:10.3748/wjg.v19.i43.7515. PMC   3837250 . PMID   24282343.
  48. Gbolahan, Olumide B.; Schacht, Michael A.; Beckley, Eric W.; LaRoche, Thomas P.; O'Neil, Bert H.; Pyko, Maximilian (April 2017). "Locoregional and systemic therapy for hepatocellular carcinoma". Journal of Gastrointestinal Oncology. 8 (2): 215–228. doi:10.21037/jgo.2017.03.13. ISSN   2078-6891. PMC   5401862 . PMID   28480062.
  49. Marrero, JA; Kulik, LM; Sirlin, CB; Zhu, AX; Finn, RS; Abecassis, MM; Roberts, LR; Heimbach, JK (August 2018). "Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases" (PDF). Hepatology. 68 (2): 723–750. doi:10.1002/hep.29913. PMID   29624699.
  50. Ma, Ka Wing; Cheung, Tan To (December 2016). "Surgical resection of localized hepatocellular carcinoma: patient selection and special consideration". Journal of Hepatocellular Carcinoma. 4: 1–9. doi:10.2147/JHC.S96085. PMC   5207474 . PMID   28097107.
  51. Ang, Soo Fan; Ng, Elizabeth Shu-Hui; Li, Huihua; Ong, Yu-Han; Choo, Su Pin; Ngeow, Joanne; Toh, Han Chong; Lim, Kiat Hon; Yap, Hao Yun; Tan, Chee Kiat; Ooi, London Lucien Peng Jin; Chung, Alexander Yaw Fui; Chow, Pierce Kah Hoe; Foo, Kian Fong; Tan, Min-Han; Cheow, Peng Chung (2015). "The Singapore Liver Cancer Recurrence (SLICER) Score for Relapse Prediction in Patients with Surgically Resected Hepatocellular Carcinoma". PLOS ONE. 10 (4): e0118658. Bibcode:2015PLoSO..1018658A. doi: 10.1371/journal.pone.0118658 . PMC   4382157 . PMID   25830231.
  52. Fan, Jia; Yang, Guang-Shun; Fu, Zhi-Ren; Peng, Zhi-Hai; Xia, Qiang; Peng, Chen-Hong; Qian, Jian-Ming; Zhou, Jian; Xu, Yang; et al. (2009). "Liver transplantation outcomes in 1,078 hepatocellular carcinoma patients: a multi-center experience in Shanghai, China". Journal of Cancer Research and Clinical Oncology. 135 (10): 1403–1412. doi:10.1007/s00432-009-0584-6. PMID   19381688.
  53. Vitale, Alessandro; Gringeri, Enrico; Valmasoni, Michele; D'Amico, Francesco; Carraro, Amedeo; Pauletto, Alberto; D'Amico, Francesco Jr.; Polacco, Marina; D'Amico, Davide Francesco; Cillo, Umberto (2007). "Longterm results of liver transplantation for hepatocellular carcinoma: an update of the University of Padova experience". Transplantation Proceedings. 39 (6): 1892–1894. doi:10.1016/j.transproceed.2007.05.031. PMID   17692645.CS1 maint: multiple names: authors list (link)
  54. Obed, Aiman; Tsui, Tung-Yu; Schnitzbauer, Andreas A.; Obed, Manal; Schlitt, Hans J.; Becker, Heinz; Lorf, Thomas (2009). "Liver Transplantation for Hepatocellular Carcinoma: Need for a New Patient Selection Strategy: Reply". Langenbeck's Archives of Surgery. 393 (2): 141–147. doi: 10.1007/s00423-007-0250-x . PMC   1356504 . PMID   18043937.
  55. Cillo, Umberto; Vitale, Alessandro; Bassanello, Marco; Boccagni, Patrizia; Brolese, Alberto; Zanus, Giacomo; Burra, Patrizia; Fagiuoli, Stefano; Farinati, Fabio; Rugge, Massimo; d'Amico, Davide Francesco (February 2004). "Liver transplantation for the treatment of moderately or well-differentiated hepatocellular carcinoma". Annals of Surgery. 239 (2): 150–9. doi:10.1097/01.sla.0000109146.72827.76. PMC   1356206 . PMID   14745321.
  56. Tanabe, KK; Curley, SA; Dodd, GD; Siperstein, AE; Goldberg, SN (February 1, 2004). "Radiofrequency ablation: the experts weigh in". Cancer. 100 (3): 641–50. doi:10.1002/cncr.11919. PMID   14745883.CS1 maint: multiple names: authors list (link)
  57. Tateishi, R; Shiina, S; Teratani, T; Obi, S; Sato, S; Koike, Y; Fujishima, T; Yoshida, H; Kawabe, T; Omata, M (15 March 2005). "Percutaneous radiofrequency ablation for hepatocellular carcinoma. An analysis of 1000 cases". Cancer. 103 (6): 1201–9. doi:10.1002/cncr.20892. PMID   15690326.CS1 maint: multiple names: authors list (link)
  58. Chen, Min-Shan; Li, Jin-Qing; Zheng, Yun; Guo, Rong-Ping; Liang, Hui-Hong; Zhang, Ya-Qi; Lin, Xiao-Jun; Lau, Wan Y (2006). "A Prospective Randomized Trial Comparing Percutaneous Local Ablative Therapy and Partial Hepatectomy for Small Hepatocellular Carcinoma". Annals of Surgery. 243 (3): 321–8. doi:10.1097/01.sla.0000201480.65519.b8. PMC   1448947 . PMID   16495695.
  59. Yamamoto, Junji; Okada, Shuichi; Shimada, Kazuaki; Okusaka, Takushi; Yamasaki, Susumu; Ueno, Hideki; Kosuge, Tomoo (2001). "Treatment strategy for small hepatocellular carcinoma: Comparison of long-term results after percutaneous ethanol injection therapy and surgical resection". Hepatology. 34 (4): 707–713. doi:10.1053/jhep.2001.27950. PMID   11584366.
  60. "Interventional Radiology Treatments for Liver Cancer". Society of Interventional Radiology. Archived from the original on 8 February 2014. Retrieved 4 February 2014.
  61. Kooby, DA; Egnatashvili, V; Srinivasan, S; Chamsuddin, A; Delman, KA; Kauh, J; Staley CA, 3rd; Kim, HS (February 2010). "Comparison of yttrium-90 radioembolization and transcatheter arterial chemoembolization for the treatment of unresectable hepatocellular carcinoma". Journal of Vascular and Interventional Radiology. 21 (2): 224–30. doi:10.1016/j.jvir.2009.10.013. PMID   20022765.CS1 maint: multiple names: authors list (link)
  62. 1 2 Llovet, Josep M.; Ricci, Sergio; Mazzaferro, Vincenzo; Hilgard, Philip; Gane, Edward; Blanc, Jean-Frédéric; de Oliveira, Andre Cosme; Santoro, Armando; Raoul, Jean-Luc (2008-07-24). "Sorafenib in Advanced Hepatocellular Carcinoma". New England Journal of Medicine. 359 (4): 378–390. CiteSeerX . doi:10.1056/nejmoa0708857. ISSN   0028-4793. PMID   18650514.
  63. 1 2 Cheng, Ann-Lii; Kang, Yoon-Koo; Chen, Zhendong; Tsao, Chao-Jung; Qin, Shukui; Kim, Jun Suk; Luo, Rongcheng; Feng, Jifeng; Ye, Shenglong (January 2009). "Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial". The Lancet. Oncology. 10 (1): 25–34. doi:10.1016/S1470-2045(08)70285-7. ISSN   1474-5488. PMID   19095497.
  64. Kudo, Masatoshi (2017). "Systemic Therapy for Hepatocellular Carcinoma: 2017 Update". Oncology. 93 (1): 135–146. doi:10.1159/000481244. ISSN   0030-2414. PMID   29258077.
  65. Madoff, DC; Hicks, ME; Vauthey, JN; Charnsangavej, C; Morello FA, Jr; Ahrar, K; Wallace, MJ; Gupta, S (September–October 2002). "Transhepatic portal vein embolization: anatomy, indications, and technical considerations". Radiographics. 22 (5): 1063–76. doi:10.1148/radiographics.22.5.g02se161063. PMID   12235336.CS1 maint: multiple names: authors list (link)
  66. Vente MA, Wondergem M, van der Tweel I, et al. (April 2009). "Yttrium-90 microsphere radioembolization for the treatment of liver malignancies: a structured meta-analysis". European Radiology. 19 (4): 951–9. doi:10.1007/s00330-008-1211-7. PMID   18989675.
  67. Hepatocellular carcinoma MedlinePlus, Medical Encyclopedia
  68. "WHO Disease and injury country estimates". World Health Organization. 2009. Retrieved November 11, 2009.
  69. Table 37.2 in: Sternberg, Stephen (2012). Sternberg's diagnostic surgical pathology. Place of publication not identified: LWW. ISBN   978-1-4511-5289-0. OCLC   953861627.
  70. 1 2 Kumar V, Fausto N, Abbas A (editors) (2015). Robbins & Cotran Pathologic Basis of Disease (9th ed.). Elsevier/Saunders. pp. 821–881. ISBN   9780323266161.CS1 maint: multiple names: authors list (link) CS1 maint: extra text: authors list (link)
  71. "Cancer". World Health Organization. February 2006. Retrieved 2007-05-24.
  72. Rowe, JulieH; Ghouri, YezazAhmed; Mian, Idrees (2017-01-01). "Review of hepatocellular carcinoma: Epidemiology, etiology, and carcinogenesis". Journal of Carcinogenesis. 16 (1): 1. doi:10.4103/jcar.jcar_9_16. PMC   5490340 . PMID   28694740.
  73. Choo, Su Pin; Tan, Wan Ling; Goh, Brian K. P.; Tai, Wai Meng; Zhu, Andrew X. (15 November 2016). "Comparison of hepatocellular carcinoma in Eastern versus Western populations". Cancer. 122 (22): 3430–3446. doi:10.1002/cncr.30237. PMID   27622302.
  74. Goh, George Boon-Bee; Chang, Pik-Eu; Tan, Chee-Kiat (December 2015). "Changing epidemiology of hepatocellular carcinoma in Asia". Best Practice & Research Clinical Gastroenterology. 29 (6): 919–928. doi:10.1016/j.bpg.2015.09.007. PMID   26651253.
  75. Yang, Jian-min; Wang, Hui-ju; Du, Ling; Han, Xiao-mei; Ye, Zai-yuan; Fang, Yong; Tao, Hou-quan; Zhao, Zhong-sheng; Zhou, Yong-lie (2009-01-25). "Screening and identification of novel B cell epitopes in human heparanase and their anti-invasion property for hepatocellular carcinoma". Cancer Immunology, Immunotherapy. 58 (9): 1387–1396. doi:10.1007/s00262-008-0651-x. PMID   19169879.
  76. Huntington Medical Research Institute News, May 2005 Archived 2005-12-10 at the Wayback Machine
  77. Klingenberg, Marcel; Matsuda, Akiko; Diederichs, Sven; Patel, Tushar (September 2017). "Non-coding RNA in hepatocellular carcinoma: Mechanisms, biomarkers and therapeutic targets". Journal of Hepatology. 67 (3): 603–618. doi:10.1016/j.jhep.2017.04.009. ISSN   1600-0641. PMID   28438689.
  78. Braconi, C; Valeri, N, Kogure, T, Gasparini, P, Huang, N, Nuovo, GJ, Terracciano, L, Croce, CM, Patel, T (2011-01-11). "Expression and functional role of a transcribed noncoding RNA with an ultraconserved element in hepatocellular carcinoma". Proceedings of the National Academy of Sciences of the United States of America. 108 (2): 786–91. Bibcode:2011PNAS..108..786B. doi:10.1073/pnas.1011098108. PMC   3021052 . PMID   21187392.CS1 maint: multiple names: authors list (link)
  79. "Journal of Clinical Oncology, Special Issue on Molecular Oncology: Receptor-Based Therapy, April 2005". Archived from the original on 2005-11-30. Retrieved 2005-08-31.
  80. Lau W, Leung T, Ho S, Chan M, Machin D, Lau J, Chan A, Yeo W, Mok T, Yu S, Leung N, Johnson P (1999). "Adjuvant intra-arterial iodine-131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial". The Lancet. 353 (9155): 797–801. doi:10.1016/S0140-6736(98)06475-7. PMID   10459961.
  81. Thomas M, Zhu A (2005). "Hepatocellular carcinoma: the need for progress". Journal of Clinical Oncology. 23 (13): 2892–9. doi:10.1200/JCO.2005.03.196. PMID   15860847. Archived from the original on 2005-11-05. Retrieved 2005-08-29.
  82. Broutier L, Mastrogiovanni G, Verstegen MM, Francies HE, Gavarró LM, Bradshaw CR, Allen GE, Arnes-Benito R, Sidorova O, Gaspersz MP, Georgakopoulos N, Koo BK, Dietmann S, Davies SE, Praseedom RK, Lieshout R, IJzermans JNM, Wigmore SJ, Saeb-Parsy K, Garnett MJ, van der Laan LJ, Huch M (2017). "Human primary liver cancer-derived organoid cultures for disease modeling and drug screening". Nat Med. 23: 1424–1435. doi:10.1038/nm.4438. PMC   5722201 . PMID   29131160.CS1 maint: multiple names: authors list (link)
  83. Fumao, B; Zhou, H; Ma, M; Guan, C; Lyu, J; Meng, QH (2 May 2018). "A novel RNA-sequencing-based miRNA signature predicts with recurrence and outcome of hepatocellular carcinoma". Molecular Oncology. 12 (7): 1125–1137. doi:10.1002/1878-0261.12315. PMC   6026871 . PMID   29719937.
  84. ennerex Granted FDA Orphan Drug Designation for Pexa-Vec in Hepatocellular Carcinoma (HCC) Archived March 25, 2014, at the Wayback Machine
  85. FDA Orphan Drug database
  86. Tarakanovskaya, M. G; Chinburen, J; Batchuluun, P; Munkhzaya, C; Purevsuren, G; Dandii, D; Hulan, T; Oyungerel, D; Kutsyna, G. A; Reid, A. A; Borisova, V; Bain, A. I; Jirathitikal, V; Bourinbaiar, A. S (2017). "Open-label Phase II clinical trial in 75 patients with advanced hepatocellular carcinoma receiving daily dose of tableted liver cancer vaccine, hepcortespenlisimut-L". Journal of Hepatocellular Carcinoma. 4: 59–69. doi:10.2147/JHC.S122507. PMC   5396941 . PMID   28443252.
  87. Sanoff, Hanna K.; Kim, Richard; Ivanova, Anastasia; Alistar, Angela; McRee, Autumn J.; O’Neil, Bert H. (2015). "Everolimus and pasireotide for advanced and metastatic hepatocellular carcinoma". Investigational New Drugs. 33 (2): 505–509. doi:10.1007/s10637-015-0209-7. PMC   4487887 . PMID   25613083.

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