Hepatocellular carcinoma

Hepatocellular carcinoma

Hepatocellular carcinoma in an individual who was hepatitis C positive. Autopsy specimen.
Classification and external resources
Specialty Oncology
ICD-10 C22.0
ICD-9-CM 155
ICD-O M8170/3
MedlinePlus 000280
eMedicine med/787
MeSH D006528

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), metabolic toxins (e.g. alcohol, aflatoxin), or endogenous toxins like in hemochromatosis and alpha 1-antitrypsin deficiency) or chronic liver disease due to other causes (e.g. NASH), with or without cirrhosis.[1]

Treatment options for HCC and prognosis are dependent on many factors but especially on tumour size, staging, and extent of liver injury. 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.

HCC is relatively uncommon in the United States and many other developed countries. It occurs most commonly in countries that are prevalent with Hepatitis B infection.[2]

Signs and symptoms

Most cases of hepatocellular carcinoma occur in patients who already have symptoms of chronic liver disease and present either with worsening of symptoms or during surveillance that is used to screen patients who are at risk the most. In other cases, HCC may directly present with yellow skin, bloating from fluid in the abdomen, easy bruising from blood clotting abnormalities, loss of appetite, unintentional weight loss, abdominal pain especially in the right upper quadrant, nausea, vomiting, or feeling tired.[3]

Risk factors

The main risk factors for hepatocellular carcinoma are;

The most important risk factors vary widely from country to country. In countries where Hepatitis B is endemic, such as China, Hepatitis B is the predominant cause of Hepatocellular Carcinoma.[11] 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 hepatitis C, obesity or alcohol abuse).

The risk of hepatocellular carcinoma in type 2 diabetics is greater (from 2.5[9] to 7.1[12] 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.[9][12][13] 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.[12][13] 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.[14][15] While there are claims that anabolic steroid abusers are at greater risk[16] (theorized to be due to insulin and IGF exacerbation[17][18]), 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.[19][20]

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.[21]

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

See also: Carcinogenesis

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.[22] 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 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

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

Surveillance differs 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 US every 6 months. AFP is a marker that is useful if it is markedly elevated. At levels less >20 sensitivity is 41-65% and specificity is 80-94%. However, at levels >200 sensitivity is 31, specificity is 99%.[23]

Ultrasound (US) is often the first imaging and screening modality used. On US, HCC often appears as a small hypo-echoic 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 systemic 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.[24]

In people with a higher suspicion of HCC (such as rising alpha-fetoprotein and des-gamma carboxyprothrombin levels),[25] 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 people with HCC have can make the findings more difficult to appreciate.

Triple phase helical CT improves the detection of these tumors. Due to the increased vascularity of hepatocellular carcinoma, the classic finding on CT imaging is hypervascularity in the arterial phase with washout in the portal and delayed phases. A pseudocapsule, a mosaic pattern and both calcifications and intralesional fat may be appreciated. A systemic review 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.[24]

Classification of HCC on CT: Liver Image Reporting and Data System (LI-RADS): LI-RADs is the new way to standardize/classify the HCC lesions found on CT and MRI. Radiologists use this classification system in their imaging reports in order to further characterize suspicious lesions. As a general introduction, LR1 and LR2 get continued surveillance. LR3 has variable follow up. LR4 gets close follow up, additional imaging or treatment. LR5 gets treatment.[26]

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.

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 Magnetic Resonance Imaging (MRI). MRI has about the same sensitivity for detecting HCC has helical CT. However, MRI has the advantage of delivering high resolution images of the liver without nephrotoxic contrast agents or 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 in 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.[24] The sensitivity is further increased gadoxetic acid-enhanced and diffusion-weighted imaging are combined. Despite the advantages of MRI, helical CT remains the technique of choice among radiologists due to the high cost and long image acquisition time of MRI.

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.[27] 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

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.[28]

Staging

The prognosis of HCC is affected by the staging of the tumour as well as the livers function due to the effects of liver cirrhosis.[29]

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 categorisation 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).[29]

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.[30]

Important features that guide treatment include: -

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

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.[31]

In the case of patients with cirrhosis, alcohol consumption is to be avoided. Also, screening for hemochromatosis may be beneficial for some patients.[32]

It is unclear if screening those with chronic liver disease for hepatocellular carcinoma improves outcomes.[33]

Management

Interventional Radiology (IR) Procedures and Management

Gross anatomy of hepatocellular carcinoma

Complications: The most common complication of both TACE and SIRT is post embolization syndrome occurring in 60-80% of patients in TACE and 20-55% in SIRT.[49] Typical findings of post embolization syndrome are fatigue, constitutional symptoms and abdominal pain. It usually lasts 3–4 days with full resolution in 7–10 days. Other more serious complications from TACE and SIRT include liver failure, hepatic dysfunction and gastric ulceration from non-target embolization of the left gastric. Less than 1% of patients who undergo SIRT develop radiation pneumonitis. Complications of RFA are rare but include abscess formation, subcapsular hematoma and tract seeding.

While surgical resection offers the best chance at a cure for hepatocellular carcinoma, the tumors are often inoperable due to large size or spread into vascular and adjacent structures. Medical management is generally palliative and aimed at reducing liver disease symptoms. Chemotherapy is traditionally ineffective. Interventional radiology offers minimally invasive treatments that can improve quality of life, increase survival, and reduce symptoms in these patients.

Other Management

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.[52] This is partially due to late presentation with large tumours, 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.[53]
  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,[54] Hepatocellular carcinoma causes 662,000 deaths worldwide per year[55] 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.

North America and Western Europe

Most malignant tumors of the liver discovered in Western patients are metastases (spread) from tumors elsewhere.[54] 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

Pre-clinical

Current research includes the search for the genes that are disregulated in HCC, anti-heparanase antibodies,[56] protein markers,[57] non-coding RNAs (such as TUC338)[58] and other predictive biomarkers.[59][60] 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.[61]

Clinical

JX-594, an oncolytic virus, has orphan drug designation for this condition and is undergoing clinical trials.[62]

Hepcortespenlisimut-L, an oral cancer vaccine also has US FDA orphan drug designation for hepatocellular carcinoma.[63]

A randomized trial of people with advanced HCC showed no benefit for the combination of everolimus and pasireotide.[64]

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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  2. ↑ Forner, Alejandro; Llovet, Josep M; Bruix, Jordi (2012-03-31). "Hepatocellular carcinoma". The Lancet 379 (9822). doi:10.1016/S0140-6736(11)61347-0. ISSN 0140-6736.
  3. ↑ http://www.mayoclinic.com/health/liver-cancer/DS00399/DSECTION=symptoms
  4. ↑ Alter, MJ (2007-05-07). "Epidemiology of hepatitis C virus infection.". World journal of gastroenterology : WJG 13 (17): 2436–41. doi:10.3748/wjg.v13.i17.2436. PMID 17552026.
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  6. ↑ Wang, Xin W; S.Perwez Hussain, Teh-Ia Huo, Chuan-Ging Wu, Marshonna Forgues, Lorne J Hofseth, Christian Brechot and Curtis C Harris (2002). "Molecular pathogenesis of human hepatocellular carcinoma". Toxicology. 181-182: 43–47. doi:10.1016/S0300-483X(02)00253-6. PMID 12505283. Recent studies in our laboratory have identified several potential factors that may contribute to the pathogenesis of HCC...For example, oxyradical overload diseases such as Wilson disease and hemochromatosis result in the generation of oxygen/nitrogen species that can cause mutations in the p53 tumour suppressor gene
  7. ↑ Cheng, W; S. Govindarajan, A Redeker (February 1992). "Hepatocellular carcinoma in a case of Wilson's disease". Liver International 12 (1): 42–45. doi:10.1111/j.1600-0676.1992.tb00553.x. PMID 1314321. The patient described here was the oldest and only the third female patient with hepatocellular carcinoma complicating Wilson's disease to be reported in the literature.
  8. ↑ Wilkinson, ML; B Portmann, R Williams (1983). "Wilson's disease and hepatocellular carcinoma: possible protective role of copper". Gut 24 (8): 767–771. doi:10.1136/gut.24.8.767. PMC 1420230. PMID 6307837. As copper has been shown to protect against chemically induced hepatocellular carcinoma in rats, this may be the reason for the extreme rarity of hepatocellular carcinoma in patients with Wilson's disease and possibly in other liver diseases with hepatic copper overload.
  9. 1 2 3 El-Serag, Hashem B.; Howard Hampel, Fariba Javadi (20 Feb 2006). "the association between diabetes and hepatocellular carcinoma: a systematic review of epidemiological evidence". Clinical Gastroenterology and Hepatology 4 (3): 369–380. doi:10.1016/j.cgh.2005.12.007. PMID 16527702. Retrieved 2011-02-02. Diabetes is associated with an increased risk for HCC. However, more research is required to examine issues related to the duration and treatment of diabetes, and confounding by diet and obesity
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  12. 1 2 3 Hassan, Manal M.; Steven A. Curley, Donghui Li, Ahmed Kaseb, Marta Davila, Eddie K. Abdalla, Millind Javie, Dalia M. Moghazy, Richard D. Lozano, Jean-Nicholas Vauthey (17 Feb 2010). "Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma". Cancer (ACS) 116 (8): 1938–1946. doi:10.1002/cncr.24982. PMID 20166205. Diabetes appears to increase the risk of HCC, and such risk is correlated with a long duration of diabetes. Relying on dietary control and treatment with sulfonylureas or insulin were found to confer the highest magnitude of HCC risk, whereas treatment with biguanides or thiazolidinediones was associated with a 70% HCC risk reduction among diabetics.
  13. 1 2 Donadon, Valter; Massimiliano Balbi, Michela Ghersetti, Silvia Grazioli, Antonio Perciaccante, Giovanni Della Valentina, Rita Gardenal, Maria Dal Mas, Pietro Casarin, Giorgio Zanette, Cesare Miranda (28 May 2009). "Antidiabetic therapy and increased risk of hepatocellular carcinoma in chronic liver disease". World Journal of Gastroenterology 15 (20): 2506–11. doi:10.3748/wjg.15.2506. PMC 2686909. PMID 19469001. 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.
  14. ↑ Abby, Siegel; Andrew X. Zhu (15 Oct 2009). "Metabolic Syndrome and hepatocellular carcinoma". Cancer (ACS) 115 (24): 5651–5661. doi:10.1002/cncr.24687. PMC 3397779. PMID 19834957. 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.
  15. ↑ Stickely, Felix; Claus Hellerbrand (21 July 2010). "Non-alcoholic fatty liver disease as a risk factor for hepatocellular carcinoma: mechanisms and implications". Gut 59 (10): 1303–1307. doi:10.1136/gut.2009.199661. PMID 20650925. Retrieved 2011-02-02. Based on the known association of NAFLD with IR and MS, approximately two-thirds of the patients were obese and/or diabetic, 4 and a remarkable 25% of these patients had no cirrhosis... Therefore, it is particularly worrying that the most persuasive evidence for an association between NAFLD and HCC derives from studies on the risk of HCC in patients with metabolic syndrome
  16. ↑ "Hepatocellular Carcinoma and Diseases". Retrieved May 12, 2010.
  17. ↑ Hopfner, Michael; Alexander Huether, Andreas P. Sutter, Viola Baradari, Detlef Schuppan, Hans Scherubl (14 May 2006). "Blockade of IGF-1 receptor tyrosine kinase has antineoplastic effects in hepatocellular carcinoma cells". Biochemical Pharmacology 71 (10): 1435–1448. doi:10.1016/j.bcp.2006.02.006. PMID 16530734. 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.
  18. ↑ Huynh, Hung; Pierce K. H. Chow, London L. P. Ooi, Khee-Chee Soo (March 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. Retrieved 2011-02-02. 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.
  19. ↑ Martin, Nicole M.; Barham K Abu Dayyeh, Ramond T Chung (28 Jul 2008). "Anabolic steroid abuse causing recurrent hepatic adenomas and hemorrhage". World Journal of Gastroenterology 14 (28): 4573–4575. doi:10.3748/wjg.14.4573. PMC 2731289. PMID 18680242. This is the first reported case of hepatic adenoma re-growth with recidivistic steroid abuse, complicated by life-threatening hemorrhage.
  20. ↑ Gorayski, Peter; C H Thompson, H S Subhash, A C Thomas (18 Jun 2007). "Hepatocellular carcinoma associated with recreational anabolic steroid use" (PDF). British Journal of Sports Medicine 42 (1): 74–75. doi:10.1136/bjsm.2007.03932. PMID 18178686. Retrieved 2011-02-02. Malignant transformation to HCC from a pre-existing hepatic adenoma confirmed by immunohistochemical study has previously not been reported in athletes taking anabolic steroids. Further studies using screening programmes to identify high-risk individuals are recommended.
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  28. ↑ Hepatocellular carcinoma (Photo) ATLAS OF PATHOLOGY
  29. 1 2 Duseja, Ajay (2014-08-01). "Staging of Hepatocellular Carcinoma". Journal of Clinical and Experimental Hepatology. Hepatocellular Carcinoma. 4, Supplement 3: S74–S79. doi:10.1016/j.jceh.2014.03.045. PMC 4284240. PMID 25755615.
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  34. ↑ Fan, Jia; Yang,Guang-Shun; Fu, Zhi-Ren; Peng, Zhi-Hai; Xia, Qiang; Peng, Chen-Hong; Qian, Jian-Ming; Zhou, Jian; Xu, Yang; et al. (2009). "Liver transplantation outcomes in 1,078 hepatocellular carcinoma patients: a multi-center experience in Shanghai, China" (PDF). Journal of Cancer Research and Clinical Oncology 135 (10): 1403–1412. doi:10.1007/s00432-009-0584-6. PMID 19381688.
  35. ↑ Vitale, Alessandro; Gringeri, Enrico; Valmasoni, Michele; D'Amico, Francesco; Carraro, Amedeo; Pauletto, Alberto; D'Amico, Francesco Jr.; Polacco, Marina; D'Amico, Davide Francesco; Cillo, Umberto (2007). "Longterm results of liver transplantation for hepatocellular carcinoma: an update of the University of Padova experience". Transplantation Proceedings 39 (6): 1892–1894. doi:10.1016/j.transproceed.2007.05.031. PMID 17692645.
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  38. ↑ Josep M. Llovet; Sergio Ricci; Vincenzo Mazzaferro; Philip Hilgard; Edward Gane; Jean-Frédéric Blanc; Andre Cosme de Oliveira; Armando Santoro; Jean-Luc Raoul; Alejandro Forner; Myron Schwartz; Camillo Porta; Stefan Zeuzem; Luigi Bolondi; et al. (2008). "Sorafenib in Advanced Hepatocellular Carcinoma". N Engl J Med 359 (4): 378–390. doi:10.1056/NEJMoa0708857. PMID 18650514.
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  40. ↑ "Sorafenib in Advanced Hepatocellular Carcinoma". Retrieved May 12, 2010.
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