Hepatocellular carcinoma

Hepatocellular carcinoma
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 male than females for unknown reasons.[2]

Signs and symptoms

Most cases of HCC occur in people who already have 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 abdomen, 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. There is limited evidence 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, however, if they suffer from congenital liver disorders, this fact increases the chance of developing hepatocellular carcinoma.[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 non diabetic 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 non alcoholic fatty liver disease or NAFLD is present) and again there is evidence of greater risk 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]

Pathogenesis

Hepatocellular carcinoma, like any other cancer, develops when there is a mutation to the cellular machinery that causes the cell to replicate at a higher rate and/or results 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.[25] 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 non-cirrhotic 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 fungus 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 like 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 and thus are not related to hepatocellular carcinoma.

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 (especially MRI) findings may be conclusive enough to obviate histopathologic confirmation.

Screening

Due to the fact that HCC most commonly occurs in the setting of chronic liver disease (e.g. viral hepatitis) and cirrhosis (about 80%), screening by ultrasound (US) is commonly advocated in this population. Surveillance recommendations vary, but the American Association of Liver Diseases recommends screening Asian men over the age of 40, Asian women over the age of 50, people with HBV and cirrhosis, and African and North American blacks. These people are screened with ultrasound every 6 months. Additional evaluation may include measurement of blood levels of AFP, which is a tumor marker. Elevated levels of AFP are associated with active HCC disease. At levels >20 sensitivity is 41-65% and specificity is 80-94%. However, at levels >200 sensitivity is 31, specificity is 99%.[26]

Ultrasound (US) is often the first imaging and screening modality used. On US, 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 percent (95% CI 44-76%) and specificity was 97 percent (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.[27]

Higher risk people

In a person where there is higher suspicion of HCC, such as a person with symptoms or abnormal blood tests (i.e. alpha-fetoprotein and des-gamma carboxyprothrombin levels),[28] 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 in order 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 percent (95% CI 55-80%) and specificity was 93 percent (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 90% or higher, but this data has not been confirmed with autopsy studies.[27]

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 is has improved sensitivity and specificity when compared to US 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 percent (95% CI 70-91%) and specificity was 85 percent (95% CI 77-93%) compared with pathologic examination of an explanted or resected liver as the reference standard.[27] The sensitivity is further increased if gadolinium contrast-enhanced and diffusion-weighted imaging are combined.

MRI is more sensitive and specific than CT.[29]

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.[30] A biopsy is not needed to confirm the diagnosis of HCC if certain imaging criteria are met.

Pathology

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, there are four architectural and cytological types (patterns) of hepatocellular carcinoma: 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, giant. The tumor has a scant stroma and central necrosis because of the poor vascularization.[31]

Staging

The prognosis of HCC is affected by the staging of the tumor as well as the liver's function due to the effects of liver cirrhosis.[32]

There are a number of staging classifications for HCC available; however, due to the unique nature of the carcinoma in order 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).[32]

Out of all the staging classification systems available the Barcelona Clinic Liver Cancer (BCLC) staging classification encompasses all of the above characteristics. This staging classification can be used in order to select people for treatment.[33]

Important features that guide treatment include the following:

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.[34]

Prevention

Since hepatitis B or C is one of the main causes of hepatocellular carcinoma, prevention of this infection is key to then prevent hepatocellular carcinoma. Thus, childhood vaccination against hepatitis B may reduce the risk of liver cancer in the future.[35]

In the case of patients with cirrhosis, alcohol consumption is to be avoided. Also, screening for hemochromatosis may be beneficial for some patients.[36]

It is unclear if screening those with chronic liver disease for hepatocellular carcinoma improves outcomes.[37]

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 (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.[38]
  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.[38]
  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.[39] 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, such as microwave or cryoablation, or arterial catheter-based therapies, such as chemoembolization and radioembolization.

Surgical resection

Gross anatomy of hepatocellular carcinoma

Surgical resection to remove the tumor while preserving enough remaining healthy liver to maintain normal physiologic function. Surgical removal results in favorable prognosis, but only 10-15% of patients are suitable for surgical resection. This is often because of extensive disease or poor underlying liver function. For example, resection in cirrhotic patients is associated with higher morbidity and mortality. Preoperative evaluation for resection must include imaging of the liver in order to estimate the amount of residual liver remaining after surgery; in order to preserve normal function, the residual liver volume should be more than 25% of the total size in a non-cirrhotic liver, and more than 40% of the total size for a cirrhotic liver.[40] The overall recurrence rate after resection is 50-60%. The Singapore Liver Cancer Recurrence (SLICER) score can be used to estimate risk of recurrence after surgery.[41]

Liver transplantation

Liver transplantation to replace the diseased liver with a cadaveric liver or a living donor graft has historically low survival rates (20%-36%). During 1996–2001 the rate had improved to 61.1%, likely related to adoption of the Milan criteria at US transplantation centers. Expanded Shanghai criteria in China resulted in overall survival and disease-free survival rates similar to the Milan criteria.[42] Studies from the late 2000 obtained higher survival rates ranging from 67% to 91%.[43] If the liver tumor has metastasized, the immuno-suppressant post-transplant drugs decrease the chance of survival. Considering this objective risk in conjunction with the potentially high rate of survival, some recent studies conclude that: "LTx can be a curative approach for patients with advanced HCC without extrahepatic metastasis".[44] For those reasons, and others, it is considered nowadays that patient selection is a major key for success.[45]

Ablation

Arterial catheter based treatment

Systemic

Systemic therapy is considered in people with advanced HCC which has spread beyond the liver to other areas of the body. Currently, the multikinase inhibitor sorafenib is the only chemotherapy shown to be effective against HCC.[52]

Other

Prognosis

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.[55] 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 will survive much longer than 6 months. The prognosis for metastatic or unresectable hepatocellular carcinoma has recently improved due to the approval of sorafenib (Nexavar®) for advanced hepatocellular carcinoma.

Epidemiology

Age-standardized death from liver cancer per 100,000 inhabitants in 2004.[56]
  no data
  less than 7.5
  7.5-15
  15-22.5
  22.5-30
  30-37.5
  37.5-45
  45-52.5
  52.5-60
  60-67.5
  67.5-75
  75-110
  more than 110

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 age of 30 to 50,[57] Hepatocellular carcinoma causes 662,000 deaths worldwide per year[58] 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 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. Food infected with Aspergillus flavus (especially peanuts and corns stored during prolonged wet seasons) which produces aflatoxin poses another risk factor for HCC.

In the Eastern Asian hemisphere, hepatocellular carcinoma (HCC) is the most common type of cancer. The common risk factor for HCC in Asia is the high diagnosis of Hepatitis B. However, in Japan the common risk factor is hepatitis C. Another factor is that causes HCC is a mycotoxin called aflatoxin. This mycotoxin is found among many areas in Asia with Southern China being the Asian country with the highest amount of aflatoxin. Thus, China is the country with the highest diagnosis of HCC in Eastern Asia.[59][60]

North America and Western Europe

The most common malignant tumors in the liver represent metastases (spread) from tumors which originate elsewhere in the body.[57] Among cancer that originate from liver tissue, HCC is the most common primary liver cancer. In the United States, the US surveillance, epidemiology, and end results (SEER) database program, shows that HCC accounts for 65% of all cases of liver cancers.[61] As there are screening programs 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 hepatocellular carcinoma 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 hepatocellular carcinoma.

The incidence of HCC is relatively lower in the Western hemisphere than in Eastern Asia. However, despite the statistics being low, there is an increase of HCC in the West. The diagnosis of HCC has increased since the 1980s and it is continuing to increase, making it one of the rising cause of death due to cancer. The common risk factor for HCC is hepatitis C, along with other health issues.[59][60]

Research

Pre-clinical

Current research includes the search for the genes that are disregulated in HCC, anti-heparanase antibodies,[62] protein markers,[63] non-coding RNAs (such as TUC338)[64] and other predictive biomarkers.[65][66] 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.[67]

Clinical

JX-594, an oncolytic virus, has orphan drug designation for this condition and is undergoing clinical trials.[68]

Hepcortespenlisimut-L, an oral cancer vaccine also has US FDA orphan drug designation for hepatocellular carcinoma.[69]

A randomized trial of people with advanced HCC showed no benefit for the combination of everolimus and pasireotide.[70]

Abbreviations

HCC, hepatocellular carcinoma; TACE, transarterial embolization/chemoembolization; PFS, progression-free survival; PS, performance status; HBV, hepatitis B virus; PEI, percutaneous ethanol injection; RFA, radiofrequency ablation; RR, response rate; MS, median survival.

See also

References

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  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. PMC 2686909 Freely accessible. PMID 19469001. doi:10.3748/wjg.15.2506. 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. PMC 2686909 Freely accessible. PMID 19469001. doi:10.3748/wjg.15.2506.
  18. ↑ Siegel A, Zhu AX (2009). "Metabolic Syndrome and hepatocellular carcinoma". Cancer. 115 (24): 5651–5661. PMC 3397779 Freely accessible. PMID 19834957. doi:10.1002/cncr.24687. 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 2 diseases ultimately should lead to improved screening and treatment options for patients with HCC.
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  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. PMID 16530734. doi:10.1016/j.bcp.2006.02.006. 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 and 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.
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  30. ↑ http://www.acr.org/Quality-Safety/Resources/LIRADS
  31. ↑ Hepatocellular carcinoma (Photo) ATLAS OF PATHOLOGY
  32. 1 2 Duseja, Ajay (2014-08-01). "Staging of Hepatocellular Carcinoma". Journal of Clinical and Experimental Hepatology. 4: S74–S79. PMC 4284240 Freely accessible. PMID 25755615. doi:10.1016/j.jceh.2014.03.045.
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