Hepatocellular carcinoma
Encyclopedia : H : HE : HEP : Hepatocellular carcinoma
Hepatocellular carcinoma (HCC, also called hepatoma) is a primary malignancy (cancer) of the liver. Most cases of HCC are secondary to either hepatitis infection (usually hepatitis B or C) or cirrhosis (alcoholism being the most common cause of hepatic cirrhosis). 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.
Outside of the West, the commonly accepted prognosis is a median survival of 3 months from diagnosis. This is partially due to late presentation with large tumours, but also the lack of medical expertise and facilities.
Contents
Epidemiology
The epidemiology of HCC exhibits two main patterns, one in North America and Western Europe and another in Non-Western Countries (regions such as sub-Saharan Africa, central Asia, Southeast Asia, and the Amazon basin).Non-Western Countries
In some parts of the world, such as Sub-Saharan Africa and Southeast Asia (and especially Taiwan and China) HCC is the most common cancer, generally affecting men more than women, and with an age of onset between late teens and 30's. This variability is in part due to the different patterns of Hepatitis B transmission in different populations - infection at or around birth (as in Taiwan) 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. 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.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 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
In patients who have a contrast agent allergy or poor renal function, an MRI scan of the abdomen is a more costly but effective substitute.
Once imaged, diagnosis is confirmed by percutaneous biopsy and histopathologic analysis.
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.[1]
Staging and prognosis
Important features that guide treament 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
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-suppresent post-transplant drugs decrease the chance of survival. [NIH]
- 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. [Medicinenet]
- Percutaneous ethanol injection (PEI)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 perform in the treatment of large tumors (larger than 3 cm and less than 4 cm in diameter) most frequently performed 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.
- 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 used for tumors larger than 4 cm in diameter, although some Italian groups have had success with larger tumours using TACE alone.
- High frequency 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
- Chemotherapy adjuvant: 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.[link] (American Society of Clinical Oncology, 2005 Annual Meeting, Abstracts on Hepatobiliary Cancer).
- 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.
Future directions
Current research includes the search for the genes that are disregulated in HCC[Genetic research in HCC] (Stanford Asian Liver Center), protein [markers], and other predictive biomarkers. [link] (Journal of Clinical Oncology - April 2005, Special Issue on MOLECULAR ONCOLOGY: Receptor-Based Therapy). As similar research is yielding results in various other malignant diseases, it is [hoped] that identifying the abberant genes and the resultant proteins could lead to the identification of pharmacological interventions for HCC.Notes
References
- [link] (Lau et al, "Adjuvant intra-arterial iodine-131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial", Lancet, Vol. 353, pp. 797-801, 1999.)
External links
Research links
- [Asian Liver Center at Stanford University]
- [MD Anderson Liver Cancer Homepage]
- [HCC article by Howard J. Worman, MD, Columbia University]
- [MedlinePlus] article about HCC
- [Atlas of Pathology] (photos)
- [NCI Liver Cancer Homepage]
- [HCC Clinical Trials Search Engine]
- [E-Medicine Article]
Patients' sites
- [Blue Faery: The Adrienne Wilson Liver Cancer Association]
- [Liver Cancer Toolbox -]
- [Liver Cancer Support Group Online]
- [2nd Lt. Andrew Torres, USMC]
- [Yahoo Group Liver Cancer Support]
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