The hepatocellular carcinoma (also primary hepatocellular carcinoma , scientifically correct: hepatocellular carcinoma , abbreviated as HCC , or carcinoma hepatocellulare ; not to be confused with liver metastasis ) is a cancer that develops directly from the liver cells . This is usually preceded by chronic damage to the liver cells.
Hepatocellular carcinoma is one of the most common malignant tumors worldwide . About 6% of all cancers in men and about 3% in women are hepatocellular carcinomas.
However, there are pronounced geographical differences: in all countries in which hepatitis B occurs very frequently, hepatocellular carcinoma is also found frequently. This is especially true for Asia and Africa. In Europe, on the other hand, carcinoma is rather rare and it usually develops on the basis of liver cirrhosis . However, the incidence has increased continuously in recent years, even in western countries. The reasons for this are the increase in virus-caused chronic hepatitis (liver inflammation), the persistently high alcohol consumption and the high number of people with pathological fatty liver disease (“fatty liver”).
At the end of 2007 a major molecular cause for the development of liver cancer was found. Cell biological studies, published in the journal Proceedings of the National Academy of Sciences , show that the tumor suppressor gene FHIT is disturbed in around 60% of tumor patients . The FHIT ( fragile histidine triad ) gene in chromosome 3 contains the genetic information for a protein of the same name, which in turn controls catenin , a molecule that is central to cell structure. The change in the gene inhibits the production of a large number of proteins, which can lead to uncontrolled cell growth. In the laboratory, the researchers succeeded in introducing a healthy FHIT gene into cancer cells to inhibit the production of these proteins and to reduce the uncontrolled growth typical of tumor cells.
Etiology and Risk Factors
Risk factors for HCC are:
- Liver cirrhosis : If you already have liver cirrhosis , the risk of developing hepatocellular carcinoma is generally increased. Every year 5% of cirrhotic patients become ill.
- Viral hepatitis B and C: A viral hepatitis type hepatitis B and hepatitis C is considered a carcinogen for hepatocellular carcinoma. The greatest risk is cirrhosis of the liver due to hepatitis. In the case of a congenital infection with HBV or HCV, the risk is further increased.
- Non-alcoholic fatty liver hepatitis (NASH) : These patients have an increased risk of developing HCC even without cirrhosis.
- Hemochromatosis: In cirrhosis of the liver with underlying hemochromatosis , the risk of the disease is increased several times.
- Androgens: The incidence of hepatocellular carcinoma is increased with long-term use of androgens , especially when used improperly ( bodybuilding ) .
- Aflatoxins: The by the fungus Aspergillus flavus formed aflatoxins (B1) are a carcinogen for the liver. They mainly occur in contaminated food (nuts, grain).
- Alpha-1 antitrypsin deficiency , an inherited metabolic disorder.
- Tyrosinemia , a rare inherited disorder of the metabolism of the amino acid tyrosine .
- permanent exposure to carbon tetrachloride .
Chronic hepatitis B virus infection is responsible for around 50% of all cases of HCC worldwide. People who are infected with the hepatitic C virus have a 15 to 20 times higher risk of developing HCC than the normal population. In Western countries, around 30 to 40% of all people with HCC show no serological evidence for hepatitis B or C infection, so that other causes are present in these cases. Obesity and the so-called metabolic syndrome are also considered risk factors. In contrast, according to some case control studies, moderate coffee consumption is considered to be moderately protective against the development of HCC. Although around 90% of all hepatocellular carcinomas result from cirrhosis of the liver, not all cirrhoses carry the same risk of developing into HCC. Patients with cirrhosis of the liver due to hepatitis B or C, hemochromatosis, or tyrosinemia are at a particularly high risk, while cirrhosis due to Wilson's disease , primary biliary cirrhosis (PBC) or primary sclerosing cholangitis rarely leads to HCC . Regular intake of acetylsalicylic acid (ASA) may reduce the risk of HCC. The pooled analysis of two non-randomized US studies of 133,371 healthcare workers revealed a significantly lower risk of developing HCC (relative risk 0.51). When taking ASA for more than 5 years, the risk reduction was higher than when taking it for a shorter period of time.
Macroscopically, liver cell carcinomas appear as nodular or infiltrative tumors. The nodular type can be present individually ( solitary ) or sown in many small tumor nests ( multiple ). The tumor nodules are round to oval, gray or - if the tumor produces bile - also green in color. The diffuse type is poorly defined and often also penetrates blood vessels or biliary tract .
In highly differentiated carcinomas, the tumor cells largely resemble healthy hepatocytes and form an almost normal cytoarchitecture with trabeculae . They often contain droplets of bile in the cytoplasm . Cells with large differences in shape (pleomorphism) and giant cells show more de-differentiated forms. Necrosis can occur inside the tumor mass as the blood supply there becomes insufficient. As a rule, material is taken from the tumor using a needle biopsy to determine the pathological picture .
In the microscopic image, the cytoarchitectonic and cytological patterns of liver cell carcinoma can be distinguished:
- fibrolamellar type: high proportion of collagen fibers in which the carcinoma cells are properly walled in, tumor cells are pleomorphic with a large cytoplasm, no increase in AFP, very rare, 20–40. age
- pseudoglandular (adenoid) type: small tubular glandular structures with a lumen
- pleomorphic type: giant cells
- solid type: cells very uniform, no secondary architecture
- Scirrhous type: high proportion of desmoplastic stromal reaction
- trabecular type: neoplastic cell bars of various widths, separated by sinusoidal blood vessels ("capillarization" by neoplastic endothelium)
- diffuse type
- clear cell type
The hepatocellular carcinoma leads to symptoms late. If pressure pain occurs in the right upper abdomen, this is already an expression of the capsular tension in the liver. In advanced stages, a tumor in the right upper abdomen can be felt, usually accompanied by ascites ( ascites ) and tumor cachexia (emaciation due to a metabolic disorder).
In children, primary hepatocellular carcinoma can lead to symptoms of precocious puberty .
Randomized controlled studies have shown that regular preventive examinations in high-risk patients can lead to early detection of HCC and can significantly reduce mortality. The guidelines (as of January 2014) recommend a six-monthly ultrasound examination of the abdomen in cirrhotic patients with stage Child-Pugh A and patients with chronic viral hepatitis or fatty liver hepatitis. Routine determination of the alpha-1-fetoprotein as a screening test is not recommended due to insufficient sensitivity (~ 55%), but is often done in practice.
Alpha-fetoprotein (alpha-1-fetoprotein) is a useful tumor marker for HCC if it is initially elevated. In healthy people, the concentration of alpha-1 fetoprotein is between 0.1 and 5.8 ng / ml. The alpha-1-fetoprotein level in the blood is increased in about 50 to 90% of HCC patients.
Furthermore, the determination of the extent of liver function damage using the Child-Pugh score is part of the diagnosis, alternatively also the ALBI grade. Further diagnostic steps may be necessary (see guideline).
Surgical and interventional measures
The therapy of choice is a partial liver resection . This must be anatomically feasible (no walling of the portal vein) and physiologically acceptable (sufficient remaining liver function after the procedure). The type of surgical procedure also depends on whether you have cirrhosis of the liver . However , at 60%, recurrence rates within five years after the operation are very high.
In selected cases (size of the tumor, stage of the disease, Milan or Milan criteria ), liver transplantation is the procedure of choice. This is also because the recurrence rates are low and the underlying disease (e.g. hepatitis B or C) can usually be treated successfully.
Laser-induced thermotherapy (LITT), radiofrequency-induced thermotherapy (RFITT) and cryotherapy have proven to be effective as minimally invasive procedures in inoperable patients . With these methods of tumor ablation , the tumor tissue is locally thermally destroyed and left in situ, where it is scarred or resorbed over time. Another minimally invasive method is local ablation with necrotizing substances, e.g. B. Percutaneous Ethanol Injection (PEI). According to the Barcelona criteria (2001), the RFITT and PEI are already among the curative measures in the treatment of inoperable hepatocellular carcinomas.
Other interventional procedures are:
- Radio frequency ablation (RFA)
- Radiofrequency Induced Thermotherapy (RFITT)
- Laser-induced thermotherapy (LITT)
- Selective internal radiotherapy (SIRT)
The medicinal measures available to date are basically palliative, ie a cure for the disease cannot be achieved with them alone. The aim of drug treatments is to delay the progression of the disease and alleviate any symptoms related to the disease. The hepatocellular carcinoma responds poorly to conventional cytostatics and is considered to be largely resistant to chemotherapy. In controlled clinical studies, there was no significant improvement in mean survival time with various chemotherapeutic agents. A real improvement in drug treatment options only came about when tumor-specific, “targeted” therapies were developed.
Since the approval of the tyrosine kinase inhibitor sorafenib for the treatment of inoperable HCC, the first targeted therapy in the form of tablets has been available. Studies have shown an overall survival increase in patients with metastatic or unresectable HCC from 7.9 to about 10.7 months. A phase II study compared lenvatinib with sorafenib in patients with inoperable hepatocellular carcinoma . Lenvatinib inhibits VEGF receptors 1–3, FGF receptors 1–4, the PDGF receptor α, RET and KIT . Lenvatinib was not inferior to sorafenib and was subsequently approved for second-line therapy in HCC for patents who had already received sorafenib or who could not tolerate it. The IMbrave150 study compared sorafenib with a combination of atezolizumab and bevacizumab . This phase III study showed a significantly better overall survival for the combination (after 12 months: 67.2% [95% CI 61.3–73.1] compared to 58% [95% CI 45.2–64 , 0]) and better progression-free survival. Atezolizumab is an immune checkpoint inhibitor that blocks PD-L1 and B7-1 , thereby relieving the suppression of T cells . Bevacizumab is a VEGF inhibitor that blocks the formation of new blood vessels, especially tumor vessels. Both drugs are antibodies and are given intravenously.
The biotechnology company 4SC AG has by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for its oncology drug resminostat the orphan drugs receive status for the treatment of hepatocellular carcinoma (HCC).
Since most HCC are often discovered late and the underlying liver cirrhosis limits the therapeutic options, the treatment of the disease is still difficult and the prognosis is unfavorable. The median survival time without therapy, i.e. H. the survival time after which 50% of the patients are still alive without therapy is around 6 months. Patients diagnosed early and transplanted within the Milan criteria have, according to scientific studies, better long-term survival (75% after four years).
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