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11-SEPTEMBER-2008 12:20:15 - Hepatocellular carcinoma Hepatocellular carcinoma Classification and external resources Hepatocellular carcinoma in an individual that was hepatitis C positive. Autopsy specimen. ICD-10 C22.0 ICD-9 155 ICD-O: 8170/3 MedlinePlus 000280 eMedicine med/787 MeSH D006528 Hepatocellular carcinoma HCC, also called hepatoma is a primary malignancy cancer of the liver. Most cases of HCC are secondary to either a viral hepatitide infection hepatitis B or C or cirrhosis alcoholism being the most common cause of hepatic cirrhosis.1 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 tumor size and staging. Tumor grade is also important. High-grade tumors will have a poor prognosis, while low-grade tumors may go unnoticed for many years, as is the case in many other organs, such as the breast, where a ductal carcinoma in situ or a lobular carcinoma in situ may be present without any clinical signs and without correlate on routine imaging tests, although in some occasions it may be detected on more specialized imaging studies like MR mammography it should be stated, however, that the sensitivity of this technique remains, even with current state-of-the-art technology, below 50%. 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.2 This is partially due to late presentation with large tumours, but also the lack of medical expertise and facilities. This is a rare tumor in the United States. A new receptor tyrosine kinase inhibitor, sorafenib has been shown in a Spanish phase III clinical trial to double the lifespan of late stage HCC patients. Contents 1 Epidemiology 1.1 Non-Western Countries 1.2 North America and Western Europe 2 Pathogenesis 3 Diagnosis, screening and monitoring 4 Pathology 5 Staging and prognosis 6 Treatment 7 Awareness 8 Future directions 9 Additional images 10 References 11 External links 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 more common between the 3rd and 5th decades of life1 Hepatocellular carcinoma causes 662,000 deaths worldwide per year3, about half of them in China. Non-Western Countries 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 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. 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.1 In the West, HCC is generally seen as 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, herary 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. Pathogenesis Main article: 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. 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. In Hepatitis B, however, the integration of the viral genome into infected cells is the most consistently associated factor in malignancy. 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 countries like China and western 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, screening and monitoring Hepatocellular carcinoma HCC most commonly appears in a patient with chronic viral hepatitis hepatitis B or hepatitis C, 20% or 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 single large tumor Multiple tumors Poorly defined tumor with an infiltrative growth pattern Once imaged, diagnosis is confirmed by percutaneous biopsy and histopathologic analysis. 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. Mostly the radiologists are using MRIs to do a secondary study to look at an area where a tumor has already been detected. 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. The latter are absorbed by normal liver tissue, but not tumors or scar tissue. Pathology 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.4 Staging and prognosis Important features that guide treatment include: - size spread stage involvement of liver vessels presence of a tumor capsule presence of extrahepatic metastases presence of daughter nodules vascularity of the tumor MRI is the best imaging method to detect the presence of a tumor capsule. Treatment Liver transplantation to replace the liver with a cadaver liver or a live donor lobe. Historically low survival rates 20%-36% recent improvement 61.1%; 1996-2001, likely related to adoption of Milan criteria at US transplantation centers. If the tumor disease has metastasized, the immuno-suppressant post-transplant drugs decrease the chance of survival. Surgical resection to remove a tumor to treat small or slow-growing tumors if they are diagnosed early. This treatment offers the best prognosis for long-term survival but unfortunately is possible in only 10-15% of cases. Resection in cirrhotic patients carries high morbidity and mortality. Percutaneous ethanol injection PEI well tolerated, high RR in small 3 cm solitary tumors; as of 2005, no randomized trial comparing resection to percutaneous treatments; recurrence rates similar to those for postresection. Transcatheter arterial chemoembolization TACE is usually performed in the treatment of large tumors larger than 3 cm and less than 4 cm in diameter, most frequently by intraarterially injecting an infusion of antineoplastic agents mixed with iodized oil such as Lipiodol. As of 2005, multiple trials show objective tumor responses and slowed tumor progression but questionable survival benefit compared to supportive care; greatest benefit seen in patients with preserved liver function, absence of vascular invasion, and smallest tumors. Sealed source radiotherapy can be used to destroy the tumor from within thus minimizing exposure to healthy tissue. TheraSphere is an FDA approved treatment which has been shown in clinical trials to increase survival rate of low-risk patients. This method uses a catheter inserted by a radiologist to deposit radioactive particles to the area of interest. Radiofrequency ablation RFA uses high frequency radio-waves to ablate the tumour. Intra-arterial iodine-131-lipiodol administration Efficacy demonstrated in unresectable patients, those with portal vein thrombus. This treatment is also used as adjuvant therapy in resected patients Lau at et, 1999. It is believed to raise the 3-year survival rate from 46 to 86%. This adjuvant therapy is in phase III clinical trials in Singapore and is available as a standard medical treatment to qualified patients in Hong Kong. Combined PEI and TACE can be used for tumors larger than 4 cm in diameter, although some Italian groups have had success with larger tumours using TACE alone. High intensity focused ultrasound HIFU not to be confused with normal diagnostic ultrasound is a new technique which uses much more powerful ultrasound to treat the tumour. Still at a very experimental stage. Most of the work has been done in China. Some early work is being done in Oxford and London in the UK. Hormonal therapy Antiestrogen therapy with tamoxifen studied in several trials, mixed results across studies, but generally considered ineffective Octreotide somatostatin analogue showed 13-month MS v 4-month MS in untreated patients in a small randomized study; results not reproduced. Adjuvant chemotherapy: No randomized trials showing benefit of neoadjuvant or adjuvant systemic therapy in HCC; single trial showed decrease in new tumors in patients receiving oral synthetic retinoid for 12 months after resection/ablation; results not reproduced. Clinical trials have varying results.5 Palliative: Regimens that included doxorubicin, cisplatin, fluorouracil, interferon, epirubicin, or taxol, as single agents or in combination, have not shown any survival benefit RR, 0%-25%; a few isolated major responses allowed patients to undergo partial hepatectomy; no published results from any randomized trial of systemic chemotherapy. Cryosurgery: Cryosurgery is a new technique that can destroy tumors in a variety of sites brain, breast, kidney, prostate, liver. Cryosurgery is the destruction of abnormal tissue using sub-zero temperatures. The tumor is not removed and the destroyed cancer is left to be reabsorbed by the body. Initial results in properly selected patients with unresectable liver tumors are equivalent to those of resection. Cryosurgery involves the placement of a stainless steel probe into the center of the tumor. Liquid nitrogen is circulated through the end of this device. The tumor and a half inch margin of normal liver are frozen to -190°C for 15 minutes, which is lethal to all tissues. The area is thawed for 10 minutes and then re-frozen to -190°C for another 15 minutes. After the tumor has thawed, the probe is removed, bleeding is controlled, and the procedure is complete. The patient will spend the first post-operative night in the intensive care unit and typically is discharged in 3 - 5 days. Proper selection of patients and attention to detail in performing the cryosurgical procedure are mandatory in order to achieve good results and outcomes. Frequently, cryosurgery is used in conjunction with liver resection as some of the tumors are removed while others are treated with cryosurgery. Patients may also have insertion of a hepatic intra-arterial artery catheter for post-operative chemotherapy. As with liver resection, your surgeon should have experience with cryosurgical techniques in order to provide the best treatment possible. There is a new drug Sorafenib which was originally used for Renal Cell Cancer that has shown promising results when used with Hepatocellular Cancer Interventional radiology Abbreviations: HCC, hepatocellular carcinoma; TACE, transarterial embolization/chemoembolization; PFS, progression-free survival; PS, performance status; HBV, hepatitis B virus; PEI, percutaneous ethanol injection; RR, response rate; MS, median survival. Awareness The Jade Ribbon Campaign is used for awareness of liver cancer and hepatitis B in the Pacific Islands, where such illnesses are more widespread than elsewhere. Future directions Current research includes the search for the genes that are disregulated in HCC,6 protein markers,7 and other predictive biomarkers.89 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.10 Additional images References ^ a b c Kumar V, Fausto N, Abbas A ors 2003. Robbins Cotran Pathologic Basis of Disease, 7th, Saunders, pp. 914-7. ISBN 978-0-721-60187-8. ^ Hepatocellular carcinoma MedlinePlus, Medical Encyclopedia ^ Cancer. World Health Organization February 2006. Retrieved on 2007-05-24. ^ Hepatocellular carcinoma Photo ATLAS OF PATHOLOGY ^ American Society of Clinical Oncology, 2005 Annual Meeting, Abstracts on Hepatobiliary Cancer ^ Genetic research in HCC Stanford Asian Liver Center ^ Huntington Medical Research Institute News, May 2005 ^ Journal of Clinical Oncology, Special Issue on Molecular Oncology: Receptor-Based Therapy, April 2005 ^ Lau W, Leung T, Ho S, Chan M, Machin D, Lau J, Chan A, Yeo W, Mok T, Yu S, Leung N, Johnson P 1999. Adjuvant intra-arterial iodine-131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial. Lancet 353 9155: 797-801. doi:10.1016/S0140-67369806475-7. PMID 10459961. ^ Thomas M, Zhu A 2005. Hepatocellular carcinoma: the need for progress. J Clin Oncol 23 13: 2892-9. doi:10.1200/JCO.2005.03.196. PMID 15860847. External links NCI Liver Cancer Homepage Blue Faery: The Adrienne Wilson Liver Cancer Association v d e Digestive system - Digestive disease - Gastroenterology primarily K20-K93, 530-579 Upper GI tract Esophagus Esophagitis Candidal - Boerhaave syndrome - UES Zenker's diverticulum - LES Barrett's esophagus, Mallory-Weiss syndrome - Esophageal motility disorder Nutcracker esophagus, Achalasia, Diffuse esophageal spasm, GERD - Esophageal stricture - Megaesophagus Stomach Gastritis Atrophic, Ménétrier's disease, Gastroenteritis - Peptic gastric ulcer/Dieulafoy's lesion - Dyspepsia - Pyloric stenosis - Achlorhydria - Gastroparesis - Gastroptosis - Portal hypertensive gastropathy - Gastric antral vascular ectasia - Gastric dumping syndrome - Gastric volvulus Intestinal/ enteropathy Small intestine/ duodenum/jejunum/ileum Enteritis Duodenitis, Jejunitis, Ileitis Peptic duodenal ulcer Malabsorption: Coeliac - Tropical sprue - Blind loop syndrome - Whipple's - Short bowel syndrome - Steatorrhea Large intestine appendix/colon Appendicitis - Colitis Pseudomembranous, Ulcerative, Ischemic Functional colonic disease IBS, Intestinal pseudoobstruction/Ogilvie syndrome Megacolon/Toxic megacolon - Diverticulitis/Diverticulosis Large and/or small Enterocolitis Necrotizing - IBD Crohn's disease vascular: Abdominal angina - Mesenteric ischemia - Angiodysplasia Bowel obstruction: Ileus - Intussusception - Volvulus - Fecal impaction Constipation - Diarrhea Rectum/anus Proctitis Radiation proctitis - Proctalgia fugax - Rectal prolapse - Anal fissure/Anal fistula - Anal abscess Accessory Liver Hepatitis Viral hepatitis, Autoimmune hepatitis, Alcoholic hepatitis - Cirrhosis PBC - Fatty liver NASH - vascular Hepatic veno-occlusive disease, Portal hypertension, Nutmeg liver - Alcoholic liver disease - Liver failure Hepatic encephalopathy, Acute liver failure - Liver abscess - Hepatorenal syndrome - Peliosis hepatis Gallbladder Cholecystitis - Gallstones/Cholecystolithiasis - Cholesterolosis - Rokitansky-Aschoff sinuses - Postcholecystectomy syndrome Bile duct/ other biliary tree Cholangitis PSC, Ascending - Cholestasis/Mirizzi's syndrome - Biliary fistula - Haemobilia - Gallstones/Cholelithiasis common bile duct Choledocholithiasis, Biliary dyskinesia Pancreatic Pancreatitis Acute, Chronic, Herary - Pancreatic pseudocyst - Exocrine pancreatic insufficiency - Pancreatic fistula Hernia Diaphragmatic: Congenital diaphragmatic - Hiatus Abdominal hernia: Inguinal Indirect, Direct - Umbilical - Incisional - Femoral Obturator hernia - Spigelian hernia Peritoneal Peritonitis Spontaneous bacterial peritonitis - Hemoperitoneum - Pneumoperitoneum GI bleeding Upper Hematemesis, Melena - Lower Hematochezia See also congenital, neoplasia v d e Tumors: digestive system neoplasia C15-C26/D12-D13, 150-159/211 Tract Upper Esophagus: Adenocarcinoma - Squamous cell carcinoma Stomach: Gastric carcinoma - Signet ring cell carcinoma - Gastric lymphoma Lower Small intestine: Appendix Carcinoid, Pseudomyxoma peritonei Colon/rectum: Herary nonpolyposis colorectal cancer - Polyp Colorectal polyp, Peutz-Jeghers syndrome, Juvenile polyposis syndrome, Familial adenomatous polyposis, Cronkhite-Canada disease Anus Upper and lower Gastrointestinal stromal tumor Accessory Liver tumor malignant: Hepatocellular carcinoma Fibrolamellar - Hepatoblastoma benign: Hepatocellular adenoma - Cavernous angioma hyperplasia: Focal nodular hyperplasia - Nodular regenerative hyperplasia Biliary tract neoplasm bile duct: Cholangiocarcinoma - Klatskin tumor gallbladder: Gallbladder cancer Pancreas exocrine pancreas: Adenocarcinoma - Pancreatic ductal carcinoma Pancreatoblastoma Peritoneum Primary peritoneal cancer see also noncongenital, congenital v d e Epithelial neoplasms ICD-O 8010-8799 Papilloma/carcinoma 8010-8139 Small cell carcinoma - Verrucous carcinoma - Squamous cell carcinoma - Basal cell carcinoma - Transitional cell carcinoma - Inverted papilloma Adenomas/adenocarcinomas 8140-8429 Linitis plastica pancreas Insulinoma, Glucagonoma, Gastrinoma, VIPoma, Somatostatinoma - Neuroendocrine tumors Cholangiocarcinoma - Hepatocellular adenoma/Hepatocellular carcinoma - Adenoid cystic carcinoma - Familial adenomatous polyposis - Prolactinoma - Oncocytoma - Hurthle cell - Clear cell adenoma/adenocarcinoma - Renal cell carcinoma - Multiple endocrine neoplasia - Endometrioid tumor - Apudoma - Klatskin tumor - Carcinoid - Cylindroma Adrenocortical adenoma/Adrenocortical carcinoma Papillary hidradenoma Adnexal And Skin appendage 8390-8429 sweat gland Hidrocystoma, Syringoma Cystic, Mucinous And Serous 8440-8499 Mucoepidermoid carcinoma - Cystadenoma/Cystadenocarcinoma/Pseudomyxoma peritonei - Signet ring cell carcinoma/Krukenberg tumor Ductal, Lobular And Medullary 8500-8549 Ductal carcinoma - Comedocarcinoma - Paget's disease of the breast/Extramammary Paget's disease Acinar cell 8550-8559 Acinic cell carcinoma Complex epithelial 8560-8589 Warthin's tumor - Thymoma Gonadal 8590-8679 Sex cord-stromal tumour: Thecoma - Granulosa cell tumour - Luteoma - Sertoli-Leydig cell tumour Paragangliomas And Glomus tumors 8680-8719 Paraganglioma - Pheochromocytoma - Glomus tumor Nevi and melanomas 8720-8799 Melanocytic nevus - Dysplastic nevus - Halo nevus Nodular melanoma - Lentigo maligna melanoma - Superficial spreading melanoma - Acral lentiginous melanoma Retrieved from http://en..org/wiki/Hepatocellular_carcinoma Categories: Gastroenterology | Types of cancer | Hepatology Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages Deutsch Español Français Hrvatski Italiano Latina Magyar Nederlands 日本語 Norsk bokmål Polski Português Suomi Svenska This page was last modified on 6 September 2008, at 07:00
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