Hepatocellular carcinoma


Hepatocellular carcinoma is the most common type of primary liver cancer in adults, and is the most common cause of death in people with cirrhosis.
It occurs in the setting of chronic liver inflammation, and is most closely linked to chronic viral hepatitis infection 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.
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.

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.

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. 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. 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. 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 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 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 show risk levels low enough to be indistinguishable from the general population. 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 and again evidence of greater risk exists here, too. While there are claims that anabolic steroid abusers are at greater risk, the only evidence that has been confirmed is that anabolic steroid users are more likely to have 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.
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.

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. Although historically a biopsy of the tumor was required to prove the diagnosis, imaging findings may be conclusive enough to obviate histopathologic confirmation.

Screening

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. 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%.
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% compared with pathologic examination of an explanted or resected liver as the reference standard. The sensitivity increases to 79% with AFP correlation.
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 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.”

Higher risk people

In a person where a higher suspicion of HCC exists, such as a person with symptoms or abnormal blood tests, 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.

Imaging

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% and specificity was 93% 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% and specificity was 85% compared with pathologic examination of an explanted or resected liver as the reference standard. The sensitivity is further increased if gadolinium contrast-enhanced and diffusion-weighted imaging are combined.
MRI is more sensitive and specific than CT.
Liver image reporting and data system 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 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.

Pathology

Macroscopically, liver cancer appears as a nodular or infiltrative tumor. The nodular type may be solitary or multiple. Tumor nodules are round to oval, gray or green, well circumscribed but not encapsulated. The diffuse type is poorly circumscribed and infiltrates the portal veins, or the hepatic veins.
Microscopically, the four architectural and cytological types of hepatocellular carcinoma are: fibrolamellar, pseudoglandular, pleomorphic, 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. A fifth form – lymphoepithelioma like hepatocellular carcinoma – has also been described.

Staging

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.
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 and general health status of the patient.
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.
StageDescriptionChild-Pugh classECOG performance status
0 Single nodule, < 3 cmA0
A 1-3 nodule, all < 3 cmA or B0
B Multi-nodular tumorA or B0
C Portal invasion and extra-hepatic spreadA or B1 or 2
D 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.

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 the case of patients with cirrhosis, alcohol consumption is to be avoided. Also, screening for hemochromatosis may be beneficial for some patients.
Whether screening those with chronic liver disease for HCC improves outcomes is unclear.

Treatment

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 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.
  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.
  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 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. 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, or arterial catheter-based therapies.

Surgical resection

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. 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 overall recurrence rate after resection is 50-60%. The Singapore Liver Cancer Recurrence score can be used to estimate risk of recurrence after surgery.

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, 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. Studies from the late 2000s obtained higher survival rates ranging from 67% to 91%.
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". In fact, among patients with compensated cirrhosis, transplantation is not associated with improved survival compared to hepatectomy, but instead is significantly more expensive. Patient selection is considered a major key for success.

Ablation

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. Trials have found modest improvement in overall survival: 10.7 months vs 7.9 months and 6.5 months vs 4.2 months.
The most common side effects of Sorafenib include a hand-foot skin reaction and diarrhea. 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.

Other

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. 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 for advanced HCC.

Epidemiology

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, Hepatocellular carcinoma causes 662,000 deaths worldwide per year 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 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 which produces aflatoxins pose another risk factor for HCC.

North America and Western Europe

The most common malignant tumors in the liver represent metastases from tumors which originate elsewhere in the body. 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. 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 and tyrosinemia type I are risk factors for hepatocellular carcinoma. The diagnosis of an acute hepatic porphyria 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.

Research

Preclinical

Mipsagargin, has orphan drug designation as a treatment during chemotherapy for HCC. 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.
Current research includes the search for the genes that are disregulated in HCC, antiheparanase antibodies, protein markers, non-coding RNAs and other predictive biomarkers. 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.
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.
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.

Clinical

, an oncolytic virus, has orphan drug designation for this condition and is undergoing clinical trials.
Hepcortespenlisimut-L, an oral cancer vaccine, also has US FDA orphan drug designation for HCC. Immunitor Inc. completed a Phase II trial, published in 2017.
A randomized trial of people with advanced HCC showed no benefit for the combination of everolimus and pasireotide.