Hepatocellular carcinoma

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Hepatocellular carcinoma
Classification and external resources
Hepatocellular carcinoma 1.jpg
Hepatocellular carcinoma in an individual who was hepatitis C positive. Autopsy specimen.
ICD-10C22.0
ICD-9155
ICD-O:M8170/3
MedlinePlus000280
eMedicinemed/787
MeSHD006528
 
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Hepatocellular carcinoma
Classification and external resources
Hepatocellular carcinoma 1.jpg
Hepatocellular carcinoma in an individual who was hepatitis C positive. Autopsy specimen.
ICD-10C22.0
ICD-9155
ICD-O:M8170/3
MedlinePlus000280
eMedicinemed/787
MeSHD006528

Hepatocellular carcinoma (HCC, also called malignant hepatoma) is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitis infection (hepatitis B or C) or cirrhosis (alcoholism being the most common cause of hepatic cirrhosis).[1]

Compared to other cancers, HCC is quite a rare tumour in the United States. In countries where hepatitis is not endemic, most malignant cancers in the liver are not primary HCC but metastasis (spread) of cancer from elsewhere in the body, e.g., the colon. Treatment options of HCC and prognosis are dependent on many factors but especially on tumour size and staging. Tumour grade is also important. High-grade tumours will have a poor prognosis, while low-grade tumors may go unnoticed for many years, as is the case in many other organs.

Signs and symptoms[edit]

HCC may present with jaundice, bloating from ascites, easy bruising from blood clotting abnormalities or as loss of appetite, unintentional weight loss, abdominal pain, especially in the right upper quadrant, nausea, emesis, or fatigue.[2]

Risk factors[edit]

The main risk factors for hepatocellular carcinoma are;

The risk factors which are most important varies widely from country to country. In countries where Hepatitis B is endemic, such as China, Hepatitis B will be the predominant cause of Hepatocellular Carcinoma.[8] Whereas in countries, such as the United States, where Hepatitis B is rare because of high vaccination rates, the major cause of HCC is Cirrhosis (often due to alcohol abuse).

The risk of hepatocellular carcinoma in type 2 diabetics is greater (from 2.5[7] to 7.1[9] 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][9][10] 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.[9][10] 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.[11][12] While there are claims that anabolic steroid abusers are at greater risk[13] (theorized to be due to insulin and IGF exacerbation[14][15]), 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.[16][17]

When hepatocellular adenomas grow to a size of more than 6–8 cm, they are considered cancerous and thus become a risk of hepatocellular carcinoma. Although hepatocellular carcinoma most commonly affects adults, children who are affected with biliary atresia, infantile cholestasis, glycogen-storage diseases, and other cirrhotic diseases of the liver are predisposed to developing hepatocellular carcinoma.

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.[18]

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

Pathogenesis[edit]

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.[19] 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. Besides, cirrhosis is commonly caused by alcoholism, chronic hepatitis B and chronic hepatitis C. 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 heptatocellular 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[edit]

Hepatocellular carcinoma (HCC) most commonly appears in a patient with chronic viral hepatitis (hepatitis B or hepatitis C, 20%) or/and with cirrhosis (about 80%). These patients commonly undergo surveillance with ultrasound due to the cost-effectiveness.

In patients with a higher suspicion of HCC (such as rising alpha-fetoprotein and des-gamma carboxyprothrombin levels), the best method of diagnosis involves a CT scan of the abdomen using intravenous contrast agent and three-phase scanning (before contrast administration, immediately after contrast administration, and again after a delay) to increase the ability of the radiologist to detect small or subtle tumors. It is important to optimize the parameters of the CT examination, because the underlying liver disease that most HCC patients have can make the findings more difficult to appreciate.

On CT, HCC can have three distinct patterns of growth:

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

The key characteristics on CT are hypervascularity in the arterial phase scans, washout or de-enhancement in the portal and delayed phase studies, a pseudocapsule and a mosaic pattern. Both calcifications and intralesional fat may be appreciated.

CT scans use contrast agents, which are typically iodine or barium based. Some patients are allergic to one or both of these contrast agents, most often iodine. Usually the allergic reaction is manageable and not life threatening.

An alternative to a CT imaging study would be the MRI. MRI's are more expensive and not as available because fewer facilities have MRI machines. More important MRI are just beginning to be used in tumor detection and fewer radiologists are skilled at finding tumors with MRI studies when it is used as a screening device.[citation needed] Mostly the radiologists are using MRIs to do a secondary study to look at an area where a tumor has already been detected.[citation needed] MRI's also use contrast agents. One of the best for showing details of liver tumors is very new: iron oxide nano-particles appears to give better results.[citation needed] The latter are absorbed by normal liver tissue, but not tumors or scar tissue.[citation needed]

In a review article of the screening, diagnosis and treatment of hepatocellular carcinoma, 4 articles were selected for comparing the accuracy of CT and MRI in diagnosing this malignancy.[20] Radiographic diagnosis was verified against post-transplantation biopsy as the gold standard. With the exception of one instance of specificity, it was discovered that MRI was more sensitive and specific than CT in all four studies.

Pathology[edit]

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, grey 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 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.[21]

Staging[edit]

Important features that guide treatment include: -

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

Prevention[edit]

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.[22]

In the case of patients with cirrhosis, alcohol consumption is to be avoided. Also, screening for hemochromatosis may be beneficial for some patients.[23]

Management[edit]

gross anatomy of hepatocellular carcinoma

Prognosis[edit]

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.[38] This is partially due to late presentation with large tumours, but also the lack of medical expertise and facilities. 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[edit]

Age-standardized death from liver cancer per 100,000 inhabitants in 2004.[39]
  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,[1] Hepatocellular carcinoma causes 662,000 deaths worldwide per year[40] about half of them in China.

Africa and Asia[edit]

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.

North America and Western Europe[edit]

Most malignant tumors of the liver discovered in Western patients are metastases (spread) from tumors elsewhere.[1] In the West, HCC is generally seen as a rare cancer, normally of those with pre-existing liver disease. It is often detected by ultrasound screening, and so can be discovered by health-care facilities much earlier 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.

Research[edit]

Pre-clinical[edit]

Current research includes the search for the genes that are disregulated in HCC,[41] protein markers,[42] non-coding RNAs (such as TUC338)[43] and other predictive biomarkers.[44][45] 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.[46]

Clinical[edit]

JX-594, an oncolytic virus, has orphan drug designation for this condition and is undergoing clinical trials.[47]

HCC treatments in Phase II & Phase III Development at June 2013[48][edit]

Company NameProduct NamesDescriptionPartnersLatest Stage of DevelopmentIndication Details
4SC AG4SC-201 (Compound #), BYK408740 (Former compound #), resminostat (Generic)Oral pan-histone deacetylase (HDAC) inhibitorYakult Honsha Co. Ltd.Phase IIFirst-line treatment of advanced hepatocellular carcinoma (HCC); Second-line treatment of hepatocellular carcinoma (HCC)
Active Biotech ABABR-215050 (Compound #), tasquinimod (Generic), TASQ (Informal)Oral quinoline-3-carboxamide derivative that binds S100 calcium binding protein A9 (S100A9; calgranulin B; MRP14)Ipsen GroupPhase IITreat advanced or metastatic hepatocellular carcinoma (HCC)
Astex Pharmaceuticals Inc.SGI-110 (Compound #), S110 (Former compound #)Hypomethylating agentPhase IITreat advanced hepatocellular carcinoma (HCC)
AstraZeneca plcBAY 86-9766 (Compound #), RDEA119 (Former compound #), Refametinib (Informal)Selective inhibitor of mitogen-activated ERK kinase (MEK)Bayer AGPhase IITreat hepatocellular carcinoma (HCC)
Eli Lilly and Co.LY2157299 (Compound #)Transforming growth factor (TGF) beta receptor 1 (TGFBR1; ALK5) inhibitorPhase IITreat hepatocellular carcinoma (HCC)
GenSpera Inc.G-202 (Compound #)Prodrug of plant-derived cytotoxin 12ADTPhase IITreat advanced, progressive hepatocellular carcinoma (HCC)
GlaxoSmithKline plcTykerb (Brand), Tyverb (Brand), GW572016 (Compound #), lapatinib (Generic), Tykerb (Other), Tyverb (Other)HER1 and HER2 receptor kinase inhibitorEddingpharm Inc.Phase IITreat hepatocellular carcinoma (HCC)
Green Cross Corp.JX594 (Compound #)Engineered oncolytic virusPhase IITreat hepatocellular carcinoma (HCC)
Incyte Corp.INC280 (Compound #), INCB28060 (Former compound #)Oral c-Met receptor tyrosine kinase inhibitorNovartis AGPhase IITreat advanced hepatocellular carcinoma (HCC)
Jennerex Biotherapeutics Inc.JX-594 (Compound #), TG6006 (Compound #), pexastimogene devacirepvec (Generic), Pexa-Vec (Informal), JX-5940TG6006 (Other)Recombinant vaccinia virus (addition of GM-CSF and deletion of thymidine kinase)Transgene S.A.; Green Cross Corp.; Lee's Pharmaceutical Holdings Ltd.Phase IITreat advanced hepatocellular cancer (HCC); Treat hepatocellular carcinoma (HCC); Treat primary liver cancer or cancer metastatic to the liver; Treat unresectable primary hepatocellular carcinoma (HCC)
MolMed S.p.A.NGR-hTNF (Compound #), Arenegyr (Former)Recombinant fusion protein that selectively binds to alanyl membrane aminopeptidase (ANPEP; APN; CD13)Phase IITreat hepatocellular carcinoma (HCC)
Novartis AGSOM230 (Compound #), pasireotide (Generic), Signifor (Informal)Somatostatin analogPhase IITreat metastatic hepatocellular carcinoma (HCC)
Pfizer Inc.CP-675 (Compound #), CP-675,206 (Compound #), CP-675206 (Compound #), ticilimumab (Former), tremelimumab (Informal)Human mAB against CTLA-4AstraZeneca plcPhase IITreat hepatocellular carcinoma (HCC)
Innovus Pharmaceuticals Inc.lansoprazole (Generic), PrevOnco (Informal)Lansoprazole formulated with NexMed's NexACT delivery technologyApricus Biosciences Inc.Phase II/IIITreat hepatocellular carcinoma (HCC)
AbbVie Inc.ABT-869 (Compound #), linifanib (Generic)Inhibitor of vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) receptorPhase IIITreat advanced or metastatic hepatocellular carcinoma (HCC); Treat liver cancer
ArQule Inc.ARQ 197 (Compound #), tivantinib (Generic)Small molecule inhibitor of c-Met receptor tyrosine kinaseDaiichi Sankyo Co. Ltd.; Kyowa Hakko Kirin Co. Ltd.Phase IIITreat hepatocellular carcinoma (HCC); Treat unresectable hepatocellular carcinoma (HCC) in patients who have failed one prior systemic therapy
Astellas Pharma Inc.Tarceva (Brand), R1415 (Compound #), RG115 (Compound #), CP-358,774 (Former compound #), OSI-774 (Former compound #), erlotinib (Generic), Tarceva (Other)Small molecule inhibitor of EGFR tyrosine kinase activityChugai Pharmaceutical Co. Ltd; Genentech Inc.; RochePhase IIITreat hepatocellular carcinoma (HCC)
Bayer AGStivarga (Brand), BAY 73-4506 (Compound #), regorafenib (Generic), DAST Inhibitor (Informal), fluoro-sorafenib (Other)Dual acting signal transduction (DAST) inhibitor of multiple kinasesPhase IIITreat advanced hepatocellular carcinoma (HCC); Treat hepatocellular carcinoma (HCC)
BioAlliance Pharma S.A.BA-003 (Compound #), doxorubicin (Generic), Livatag doxorubicin Transdrug (Other)Nanoparticle formulation of doxorubicinPhase IIITreat advanced hepatocellular carcinoma (HCC); Treat hepatocellular carcinoma (HCC)
Bristol-Myers Squibb Co.BMS-582664 (Compound #), Brivanib (Other)Dual inhibitor of VEGFR-2 and fibroblast growth factor (FGF) receptor 1 (FGFR1; CD331)Phase IIIFirst- and second-line treatment of hepatocellular cancer (HCC); First-line treatment of hepatocellular carcinoma (HCC); Treat hepatocellular carcinoma (HCC)
Celsion Corp.ThermoDox heat-activated liposome (Informal)Doxorubicin encapsulated in a heat-activated liposomeYakult Honsha Co. Ltd.; Zhejiang Hisun Pharmaceutical Co. Ltd.Phase IIITreat colorectal liver metastases; Treat liver cancer; Treat metastatic liver cancer; Treat non-resectable hepatocellular carcinoma (HCC)
Delcath Systems Inc.Chemostat doxorubicin (Informal)Doxorubicin delivered using the Chemosat percutaneous hepatic perfusion systemPhase IIITreat hepatocellular carcinoma (HCC)
Eisai Co. Ltd.E7080 (Compound #), Lenvatinib (Other)Inhibitor of multiple VEGF receptor tyrosine kinasesSFJ Pharmaceuticals Inc.Phase IIITreat hepatocellular carcinoma (HCC)
Eli Lilly and Co.IMC-1121B (Compound #), LY3009806 (Compound #), ramucirumab (Generic)Human IgG1 mAb VEGFR-2 antagonistPhase IIITreat advanced, inoperable liver cancer in treatment-naïve patients; Treat hepatocellular carcinoma (HCC)
Kowa Co. Ltd.K-333 (Compound #), NIK-333 (Compound #), peretinoin (Generic), Ruchiko (Other)Oral acyclic retinoid with a vitamin A-like structurePhase IIIPrevent recurrence after curative treatment of HCV-related hepatocellular carcinoma (HCC); Prevent recurrence of hepatocellular carcinoma (HCC) in patients with HCV; Treat hepatocellular cancer (HCC)
Light Sciences Oncology Inc.Litx (Former), Aptocine talaporfin sodium (Informal)Photodynamic therapy (PDT) using photosensitizing agent talaporfin sodium (LS11)Phase IIITreat hepatoma; Treat liver metastases from colorectal cancer; Treat unresectable hepatocellular carcinoma (HCC)
Progen Pharmaceuticals Ltd.PI-88 (Compound #), muparfostat (Generic)Sulfated mannopentaose phosphate anti-angiogenic agent that inhibits VEGF, FGF and heparanase activityMedigen Biotechnology Corp.Phase IIIAdjuvant treatment of hepatitis virus-related hepatocellular carcinoma (HCC) after surgical resection; Treat hepatocellular carcinoma (HCC) following primary tumor resection; Treat primary liver cancer
Taiho Pharmaceutical Co. Ltd.Teysuno (Brand), S-1 (Compound #), TS-1 (Compound #), tegafur/gimeracil/oteracil potassium (Generic), Teysuno (Informal)Oral combination of 5-fluorouracil (5-FU) plus two enzyme inhibitorsNordic GroupPhase IIITreat hepatocellular carcinoma (HCC); Treat liver cancer
Taiho Pharmaceutical Co. Ltd.TSU-68 (Compound #), orantinib (Generic)Low-molecular-weight anti-angiogenetic agent that inhibits receptor tyrosine kinasePhase IIITreat hepatocellular carcinoma (HCC)

Abbreviations[edit]

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[edit]

References[edit]

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