Hepatocellular carcinoma

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. ==Risk factors==

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. 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). Recognized risk factors include: • Chronic viral hepatitis (estimated cause of 80% cases globally) • Chronic hepatitis B (about 50% cases) • Chronic hepatitis C (about 25% cases) • Toxins: • Alcohol use disorder: the most common cause of cirrhosis • Nonalcoholic fatty liver disease • Type 2 diabetes (probably aided by obesity) • Congenital disorders: • Alpha 1-antitrypsin deficiency • Wilson's disease (controversial; while some theorise the risk increases, case studies are rare and suggest the opposite where Wilson's disease actually may confer protection) • Hemophilia, although statistically associated with higher risk of HCC, this is due to coincident chronic viral hepatitis infection related to repeated blood transfusions over lifetime. 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. 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. 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. 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, such as cirrhosis and hepatitis. 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. 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. While there are claims that anabolic steroid abusers are at greater risk (theorized to be due to insulin and IGF exacerbation), 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. == Pathogenesis ==

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. 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. 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. Reactive oxygen species also cause epigenetic alterations at the sites of DNA repair. Many genes responsible for cell proliferation, apoptosis or cell senescence and differentiation are commonly mutated in HCC and are implicated in tumor formation. Mutations in the telomerase reverse transcriptase (TERT) promoter are seen in 47–60% of HCC cases. The HBV genome commonly inserts into hepatocytes' TERT promoter site contributing to oncogenesis. These mutations in the promoter of TERT lead to a constitutively active telomerase which maintains telomere length and contributes to cell immortality. Mutations in the tumor suppressor gene TP53 are seen in about 30% of cases of HCC. ==Diagnosis==

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. 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% and specificity was 97% as compared with pathologic examination of an explanted or resected liver as the reference standard. The sensitivity increases to 79% with AFP correlation. Hepatic nodules that are less than 1 centimeter in size on surveillance ultrasound require serial imaging to ensure stability and to monitor for potential transformation to HCC. 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. 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 biopsy of the lesion. Imaging 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 single large tumor • Multiple tumors • Poorly defined tumor with an infiltrative growth pattern 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. 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. 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. A biopsy is not needed to confirm the diagnosis of HCC if certain imaging criteria are met. A fifth form – lymphoepithelioma like hepatocellular carcinoma – has also been described. File:Histopathology of well-differentiated hepatocellular carcinoma.jpg|Well-differentiated HCC File:Histopathology of moderately differentiated hepatocellular carcinoma.jpg|Moderately differentiated HCC File:Histopathology of poorly differentiated hepatocellular carcinoma.jpg|Poorly differentiated HCC Staging Barcelona Clinic Liver Cancer (BCLC) Staging System The prognosis of HCC is affected by the staging of the tumor, the liver's function due to the effects of chronic liver disease and cirrhosis as well as the person's physical performance status. 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. Important features that guide treatment include: • size • spread (stage) • involvement of liver vessels • presence of a tumor capsule • presence of extrahepatic metastases • presence of daughter nodules • vascularity of the tumor The most common sites of metastasis are the lung, abdominal lymph nodes, and bone. ==Prevention==

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. In those with chronic hepatitis C infection, treatment of the hepatitis C using medications reduces the risk of developing HCC. HCC surveillance in those with chronic liver disease with cirrhosis is indicated and generally consists of a twice-yearly ultrasound with or without Alpha-fetoprotein lab testing. The utility of HCC surveillance or screening in those with chronic liver disease without cirrhosis is less well established. == Treatment ==

Treatment of hepatocellular carcinoma varies by the stage of disease, a person's likelihood to tolerate surgery, and availability of liver transplantation: • 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. • "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. • "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. 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 Surgical resection of HCC tumors is usually the preferred treatment for BCLC stage 0 or A disease. 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. Surgery on diseased or cirrhotic livers is generally associated with higher morbidity and mortality. The Singapore Liver Cancer Recurrence score can be used to estimate risk of recurrence after surgery. 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), Studies from the late 2000s obtained higher survival rates ranging from 67% to 91%. Other estimates of 5 year survival after liver transplantation range from 60 to 60% with a 50% survival rate at 10 years. Among patients with compensated cirrhosis, transplantation is not associated with improved survival compared to hepatectomy, but instead is significantly more expensive. Ablation • Radiofrequency ablation (RFA) uses high-frequency radio waves to destroy tumors by local heating. The electrodes are inserted into the liver tumor under ultrasound guidance using percutaneous, laparoscopic or open surgical approach. It is suitable for small tumors 2 centimeters or less. Since it is a local treatment and has minimal effect on normal healthy tissue, it can be repeated multiple times. Survival is better for those with smaller tumors. In one series of 302 patients, the three-year survival rates for lesions >5 cm, 2.1 to 5 cm, and ≤2 cm were 59, 74, and 91%, respectively. A large randomized trial comparing surgical resection and RFA for small HCC showed similar four-year survival and less morbidities for patients treated with RFA. Ablation methods (usually RF ablation) or arterial based treatments may be used on those awaiting liver transplantation to lower tumor burden (Milan score) and improve treatment response. It may also be used to reduce tumor burden making one eligible for liver transplantation. Arterial catheter-based treatment • Transcatheter arterial chemoembolization (TACE) may be used in BCLC stage B disease and for un-resectable tumors or as a temporary treatment while waiting for liver transplant ("bridge to transplant"). The median survival after TACE is 26–40 months with a tumor response rate of approximately 52%. • Selective internal radiation therapy (SIRT) can be used to destroy the tumor using selective injection of the artery or arteries supplying the tumor with a radioisotope agent. The agent is typically Yttrium-90 (Y-90) incorporated into embolic microspheres that lodge in the tumor vasculature, causing ischemia and delivering their radiation dose directly to the lesion with the intention of sparing the surrounding liver. Based on limited evidence, SIRT has similar efficacy to TACE. Two products are available, SIR-Spheres and TheraSphere. The latter is an FDA-approved treatment for primary liver cancer which has been shown in clinical trials to increase the survival rate of low-risk patients. SIR-Spheres are FDA-approved for the treatment of metastatic colorectal cancer, but outside the US, SIR-Spheres are approved for the treatment of any nonresectable liver cancer including primary liver cancer. External beam therapy • The role of radiotherapy in the treatment of hepatocellular carcinoma has evolved as technological advancements in treatment delivery and imaging have provided a means for safe and effective radiotherapy delivery in a wide spectrum of HCC patients. In metastatic cases, radiotherapy can be used for palliative care. • Proton therapy for unresectable hepatocellular carcinoma was associated with improved survival relative to photon-based radiation therapy which may be driven by decreased incidence of post-treatment liver decompensation. Systemic Systemic therapy for HCC is indicated in BCLC stage C disease, in which cancer has spread beyond the liver. It is also indicated in BCLC stage B disease with tumor progression after local treatments. Trials have found modest improvement in overall survival: 10.7 months vs 7.9 months and 6.5 months vs 4.2 months. Regorafenib increased survival from 7.8 to 10.6 months in those who had tumor progression while on sorafenib compared to placebo. Cabozantinib, which is an inhibitor of multiple tyrosine kinases including VEGFR, hepatocyte growth factor receptor (MET) and AXL and ramucirumab, an antibody directed against VEGF receptor 2, are second line therapies which have been shown to reduce the risk of death compared to placebo. A host of additional targeted therapies and immune checkpoint inhibitors have been found to be effective. 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. Tremelimumab (Imjudo) was approved for medical use in the United States in October 2022. Other • Portal vein embolization (PVE): This technique is sometimes used to increase the volume of healthy liver, in order to improve chances of survival following surgical removal of diseased liver. For example, embolization of the right main portal vein would result in compensatory hypertrophy of the left lobe, which may qualify the patient for a partial hepatectomy. Embolization is performed by an interventional radiologist using a percutaneous transhepatic approach. This procedure can also serve as a bridge to transplant. • High intensity focused ultrasound (HIFU) (as opposed to diagnostic ultrasound) is an experimental technique which uses high-powered ultrasound waves to destroy tumor tissue. • A systematic review assessed 12 articles involving a total of 318 patients with hepatocellular carcinoma treated with Yttrium-90 radioembolization. Excluding a study of only one patient, post-treatment CT evaluation of the tumor showed a response ranging from 29 to 100% of patients evaluated, with all but two studies showing a response of 71% or greater. ==Prognosis==

The prognosis of hepatocellular carcinoma (HCC) varies dramatically depending on disease stage at diagnosis and treatment approach. According to the Barcelona Clinic Liver Cancer (BCLC) strategy, untreated patients have a dismal outcome, with median survival of approximately 3 months for end-stage disease. With appropriate treatment, prognosis improves significantly: patients with very early (BCLC-0) or early-stage disease (BCLC-A) who receive curative treatments like ablation, resection, or liver transplantation can achieve median survival exceeding 5 years. For intermediate-stage disease (BCLC-B), treatment with transarterial chemoembolization (TACE) yields median survival of more than 2.5 years. Advanced-stage patients (BCLC-C) treated with first-line systemic therapies such as atezolizumab-bevacizumab or sorafenib can expect median survival exceeding 2 years, with second-line options like regorafenib, cabozantinib, or ramucirumab (for patients with AFP >400 ng/ml) further extending survival after disease progression. Prognosis is also influenced by liver function status, with the albumin-bilirubin score and AFP levels serving as important prognostic indicators beyond traditional Child-Pugh classification. HCC associated with hepatitis B and/or hepatitis C has significantly higher mortality than other types of HCC. == Epidemiology ==

death from liver cancer per 100,000 inhabitants in 2004 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, 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.