Hepatocellular carcinoma | |
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Other names | Hepatoma |
Hepatocellular carcinoma in an individual who was hepatitis C positive. Autopsy specimen. | |
Specialty | Oncology |
Hepatocellular carcinoma (HCC [1] ) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. [2] HCC is the third leading cause of cancer-related deaths worldwide. [3]
The development of HCC is attributed to fibrosis and cirrhosis, which occur in the setting of chronic liver injury and inflammation. The latter being closely linked to chronic viral hepatitis infection (hepatitis B or C) or exposure to toxins such as alcohol, aflatoxin, or pyrrolizidine alkaloids. [4] 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. [5] : 870–873
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 cases and the lowest survival rates after treatment occur 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 than three times as common in males as in females, for unknown reasons. [5] : 870–873
Most cases of HCC occur in people who already have signs and symptoms of chronic liver disease. They may present with worsening symptoms or without symptoms at the time of cancer detection. HCC may present with non-specific symptoms such as abdominal pain, nausea, vomiting, or feeling tired. [6] Some symptoms that are more closely associated with liver disease include yellow skin (also called jaundice), 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. [6]
Since HCC mostly occurs in people with cirrhosis of the liver, risk factors generally include factors which cause chronic liver disease that may lead to cirrhosis. Still, certain risk factors are 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). [7] Recognized risk factors include:
The significance of these risk factors varies globally. In regions where hepatitis B infection is endemic, such as southeast China, hepatitis B is the predominant cause. [16] 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 excessive alcohol use. [17]
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. [17]
Chronic liver disease is rare in children and adolescents; however, congenital liver disorders are associated with an increased the chance of developing HCC. [18] Specifically, children with biliary atresia, infantile cholestasis, glycogen-storage diseases, and other cirrhotic diseases of the liver are predisposed to developing HCC in childhood.[ citation needed ]
Young adults afflicted by the rare fibrolamellar variant of hepatocellular carcinoma may have none of the typical risk factors, such as cirrhosis and hepatitis. [17]
The risk of hepatocellular carcinoma in type 2 diabetics is greater (from 2.5 [11] to 7.1 [19] times the nondiabetic risk) depending on the duration of diabetes and treatment protocol. [20] 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. [11] [19] [21] [22] 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. [19] [21] 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. [23] [24] While there are claims that anabolic steroid abusers are at greater risk [25] (theorized to be due to insulin and IGF exacerbation [26] [27] ), the only evidence that has been confirmed is that anabolic steroid users are more likely to have the benign hepatocellular adenomas transform into the more dangerous hepatocellular carcinoma. [28] [29]
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. [30]
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. [31] 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. [32] Reactive oxygen species also cause epigenetic alterations at the sites of DNA repair. [33]
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. [17]
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. Historically, a biopsy of a tumor was required to prove an HCC diagnosis. However, imaging (especially MRI) findings may be conclusive enough without histopathologic confirmation. [17]
HCC remains associated with a high mortality rate, in part because initial diagnosis commonly occurs at an advanced stage of disease. As with other cancers, outcomes are significantly improved if treatment is initiated earlier in the disease process. Since the vast majority of HCC cases occur 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(AASLD), which recommends ultrasound screenings every six months for people with cirrhosis, with or without measurement of blood levels of tumor marker alpha-fetoprotein (AFP). [34] Elevated levels of AFP are associated with active HCC disease, though their reliability can be inconsistent. At levels >20, sensitivity is 41–65% and specificity is 80–94%. However, at levels >200, sensitivity is 31 and specificity is 99%. [35]
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. [36]
Controversy remains as to the most effective screening protocols. For example, while some data support decreased mortality related to screening 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.” [34]
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), [37] 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. [17] [38]
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:[ citation needed ]
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. [36]
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. [36] The sensitivity is further increased if gadolinium contrast-enhanced and diffusion-weighted imaging are combined.
MRI is more sensitive and specific than CT. [39]
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. [40] A biopsy is not needed to confirm the diagnosis of HCC if certain imaging criteria are met. [17]
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). [17]
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. [41] A fifth form – lymphoepithelioma like hepatocellular carcinoma – has also been described. [42] [43]
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. [44]
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). [44]
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. [45]
Stage | Description | Child-Pugh class | ECOG performance status |
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0 (very early stage) | Single nodule, < 3 cm | A | 0 |
A (early stage) | 1–3 nodule, all < 3 cm | A or B | |
B (intermediate stage) | Multi-nodular tumor | ||
C (advanced stage) | Portal invasion and extra-hepatic spread | 1 or 2 | |
D (terminal stage) | Severe liver damage | C | 3 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. [49]
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. [50] In the case of patients with cirrhosis, alcohol consumption is to be avoided. Also, screening for hemochromatosis may be beneficial for some patients. [51] Whether screening those with chronic liver disease for HCC improves outcomes is unclear. [52]
Treatment of hepatocellular carcinoma varies by the stage of disease, a person's likelihood to tolerate surgery, and availability of liver transplant:
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. [54] 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).[ citation needed ]
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. [55] 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. [56] 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. [57]
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), [17] 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. [58] Studies from the late 2000s obtained higher survival rates ranging from 67% to 91%. [59]
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". [60] In fact, among patients with compensated cirrhosis, transplantation is not associated with improved survival compared to hepatectomy, but instead is significantly more expensive. [61] Patient selection is considered a major key for success. [62]
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. [76] Trials have found modest improvement in overall survival: 10.7 months vs 7.9 months and 6.5 months vs 4.2 months. [77] [76]
The most common side effects of Sorafenib include a hand-foot skin reaction and diarrhea. [77] 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. [78]
A host of additional targeted therapies and immune checkpoint inhibitors have been found to be effective against this disease. For instance, in the recent phase III trial IMBrave 150, the combination of atezolizumab and bevacizumab was found to improve both overall and progression-free survival compared to sorafenib alone. [79]
Tremelimumab (Imjudo) was approved for medical use in the United States in October 2022. [80] It is indicated, in combination with durvalumab, for the treatment of adults with unresectable hepatocellular carcinoma. [80]
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. [83] [ failed verification ] 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 ]
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, [5] : 821–881 Hepatocellular carcinoma causes 662,000 deaths worldwide per year [86] about half of them in China.
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. [17] 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. [87]
The most common malignant tumors in the liver represent metastases (spread) from tumors which originate elsewhere in the body. [5] 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. [88] 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.[ citation needed ]
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.[ citation needed ]
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. [89] [90]
Mipsagargin (G-202), has orphan drug designation as a treatment during chemotherapy for HCC. [91] It is a thapsigargin-based prodrug with cytotoxic activity used to reduce blood flow to the tumor during treatment. Results from Phase 2 trial recommended G-202 as a first-in-class PSMA-targeted prodrug and that it move to clinical trials. [92]
Current research includes the search for the genes that are disregulated in HCC, antiheparanase antibodies, [93] protein markers, [94] non-coding RNAs [95] (such as TUC338) [96] and other predictive biomarkers. [97] [98] 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. [99]
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. [100]
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. [101]
A prospective study found that increased hepatocellular cancer risk is associated with higher levels of major circulating bile acids that were measured in people several years prior to tumor diagnosis. [102] In another study using a mouse model, it was found that dysregulated hepatic bile acids collaboratively promote liver carcinogenesis. [103]
JX-594, an oncolytic virus, has orphan drug designation for this condition and is undergoing clinical trials. [104] Hepcortespenlisimut-L (Hepko-V5), an oral cancer vaccine, also has US FDA orphan drug designation for HCC. [105] Immunitor Inc. completed a Phase II trial, published in 2017. [106] A randomized trial of people with advanced HCC showed no benefit for the combination of everolimus and pasireotide. [107]
Hepatitis is inflammation of the liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), poor appetite, vomiting, tiredness, abdominal pain, and diarrhea. Hepatitis is acute if it resolves within six months, and chronic if it lasts longer than six months. Acute hepatitis can resolve on its own, progress to chronic hepatitis, or (rarely) result in acute liver failure. Chronic hepatitis may progress to scarring of the liver (cirrhosis), liver failure, and liver cancer.
Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection period, people often have mild or no symptoms. Early symptoms can include fever, dark urine, abdominal pain, and yellow tinged skin. The virus persists in the liver, becoming chronic, in about 70% 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.
Liver tumors are abnormal growth of liver cells on or in the liver. Several distinct types of tumors can develop in the liver because the liver is made up of various cell types. Liver tumors can be classified as benign (non-cancerous) or malignant (cancerous) growths. They may be discovered on medical imaging, and the diagnosis is often confirmed with liver biopsy. Signs and symptoms of liver masses vary from being asymptomatic to patients presenting with an abdominal mass, hepatomegaly, abdominal pain, jaundice, or some other liver dysfunction. Treatment varies and is highly specific to the type of liver tumor.
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, sold under the brand name Afinitor among others, is a medication used as an immunosuppressant to prevent rejection of organ transplants and as a targeted therapy in the treatment of renal cell cancer and other tumours.
Viral hepatitis is liver inflammation due to a viral infection. It may present in acute form as a recent infection with relatively rapid onset, or in chronic form, typically progressing from a long-lasting asymptomatic condition up to a decompensated hepatic disease and hepatocellular carcinoma (HCC).
Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.
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.
Transcatheter arterial chemoembolization (TACE) is a minimally invasive procedure performed in interventional radiology to restrict a tumor's blood supply. Small embolic particles coated with chemotherapeutic drugs are injected selectively through a catheter into an artery directly supplying the tumor. These particles both block the blood supply and induce cytotoxicity, attacking the tumor in several ways.
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 three 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.
Sorafenib, sold under the brand name Nexavar, is a kinase inhibitor drug approved for the treatment of primary kidney cancer, advanced primary liver cancer, FLT3-ITD positive AML and radioactive iodine resistant advanced thyroid carcinoma.
Liver cancer, also known as hepatic cancer, primary hepatic cancer, or primary hepatic malignancy, is cancer that starts in the liver. Liver cancer can be primary in which the cancer starts in the liver, or it can be liver 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.
Fibrolamellar carcinoma (FLC) is a rare form of carcinoma that typically affects young adults and is characterized, under the microscope, by laminated fibrous layers interspersed between the tumor cells. It has been estimated that 200 new cases are diagnosed worldwide each year. However, in light of recent advances in our molecular understanding, this has recently been revised to suggest it may be at least ten times more common. FLC, also known as fibrolamellar hepatocellular carcinoma, is different from the more common hepatocellular carcinoma (HCC) in that it afflicts young people with normal liver function and no known risk factors.
Selective internal radiation therapy (SIRT), also known as transarterial radioembolization (TARE), radioembolization or intra-arterial microbrachytherapy is a form of radionuclide 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, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage to the liver leads to repair of liver tissue and subsequent formation of scar tissue. Over time, scar tissue can replace normal functioning tissue, leading to the impaired liver function of cirrhosis. The disease typically develops slowly over months or years. Early symptoms may include tiredness, weakness, loss of appetite, unexplained weight loss, nausea and vomiting, and discomfort in the right upper quadrant of the abdomen. As the disease worsens, symptoms may include itchiness, swelling in the lower legs, fluid build-up in the abdomen, jaundice, bruising easily, and the development of spider-like blood vessels in the skin. The fluid build-up in the abdomen may develop into spontaneous infections. More serious complications include hepatic encephalopathy, bleeding from dilated veins in the esophagus, stomach, or intestines, and liver cancer.Stages of cirrhosis include compensated cirrhosis and decompensated cirrhosis.
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 four-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.The threshold Milan criteria are as follows:
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. Brivanib is no longer in active development.
A liver support system or diachysis is a type of therapeutic device to assist in performing the functions of the liver. Such systems focus either on removing the accumulating toxins, or providing additional replacement of the metabolic functions of the liver through the inclusion of hepatocytes to the device. This system is in trial to help people with acute liver failure (ALF) or acute-on-chronic liver failure.
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, 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 a 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.
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
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
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
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
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.
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.
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.
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
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.
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.
This is the first reported case of hepatic adenoma re-growth with recidivistic steroid abuse, complicated by life-threatening hemorrhage.
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.