Cholangiocarcinoma

The cholangiocarcinoma ( Medical: cholangiocarcinoma ) is a malignant tumor of the biliary tract. It is a rare tumor with an annual incidence of one to two cases per 100,000 in the Western world where the disease rate has risen in recent decades worldwide. Risk factors for cholangiocarcinoma are primary sclerosing cholangitis ( an inflammatory disease of the bile ducts ), congenital abnormalities of the liver, infection with the liver parasite Opisthorchis viverrini and Clonorchis sinensis and the (now banned ) use of Thorotrast as X-ray contrast agent. The symptoms of bile duct cancer are jaundice, weight loss and itching. The diagnosis is made by a combination of blood tests, imaging, endoscopy and laparotomy.

A surgical removal of the tumor is the only option for treatment with healing views. However, the tumor in most cases will only be discovered and properly diagnosed when patients are already at an advanced stage of the disease. Except surgery and chemotherapy and radiotherapy can improve treatment prospects. Patients in an advanced stage of the disease usually receive chemotherapy or palliative care. Research objectives for cholangiocarcinoma are the so-called targeted therapy with erlotinib and photodynamic therapy.

• 8.1 Adjuvant chemotherapy and radiation
• 8.2 Treatment of advanced disease
• 8.3 Experimental Methods

Epidemiology

The Cholangiocarcinoma is a relatively rare tumor. Each year, in the U.S., about 2,000 to 3,000 new cases, which corresponds to an annual incidence of 1-2 per 100,000. The evaluation of autopsy series showed that the prevalence from 0.01 to 0.46 %. In Asia, the prevalence of cholangiocarcinoma is higher, for which one makes the endemic spread of chronic parasitic diseases responsible. The incidence of cholangiocarcinoma increases with age. Men are affected slightly more often, probably because of the higher incidence rate of primary sclerosing cholangitis in men. In the presence of primary sclerosing cholangitis prevalence increases by a multiple of up to 30%. Numerous studies have demonstrated, which has risen during the last decades in many parts of the world, the incidence of bile duct carcinoma. The reasons for this are unknown. May contribute to improved diagnostic capabilities and an increase of risk factors such as HIV disease on the rise.

Risk Factors

Different risk factors for the development of cholangiocarcinoma have been described. In the Western world, is one of them primarily primary sclerosing cholangitis, an inflammatory disease of the bile ducts, which in turn often occurs together with ulcerative colitis. From epidemiological studies, it was concluded that the lifetime risk of developing a cholangiocarcinoma, in subjects with primary sclerosing cholangitis is 10-15 %, although up to 30% were found in autopsy series installments. The reasons for the association between cholangiocarcinoma and primary sclerosing cholangitis are unclear.

Certain parasitic diseases of the liver are also risk factors for cholangiocarcinoma. The widespread in Thailand, Laos and Malaysia liver fluke Opisthorchis viverrini and be indigenous to, especially in Japan, Korea and Vietnam Clonorchis sinensis relative increase the risk for cholangiocarcinoma. Increase in patients with chronic liver diseases such as viral hepatitis B or C, alcoholic liver disease, or cirrhosis from other causes also the risk of cholangiocarcinoma.

Also, HIV is a potential risk factor for cholangiocarcinoma. However, it is unclear whether HIV are responsible for the relationship itself or with HIV -associated diseases such as hepatitis C. Congenital malformations of the liver such as Caroli 's syndrome or choledochal cysts, lead to a lifetime risk of 15% for the development of cholangiocarcinoma. Rare genetic diseases such as hereditary non- polyposis colorectal carcinoma and papillomatosis of the biliary tract on contact with cholangiocarcinoma. A correlation with the occurrence of gallstones is not safe in use. However, there is a correlation between the incidence of gallstones and bile duct carcinoma, if the gallstones are located within the liver. This is unusual in Western countries, but is more common in parts of Asia. The use of Thorotrast, a form of thorium dioxide as a contrast agent may, even after 30-40 years, leading to a bile duct carcinoma. The use of Thorotrast was banned because of its carcinogenicity.

Pathophysiology

The cholangiocarcinoma can occur in any portion of the bile duct system. Tumors that grow in the past within the liver bile ducts, called " intrahepatic " and tumors that occur in the bile duct system outside the liver are called " extrahepatic ". Tumors that occur at the exit point of the bile duct system, called " perihilar " and those that lie at the junction of the two emerging from the liver bile ducts are called Klatskintumore. Although cholangiocarcinoma is known to be a tumor of the epithelial cells of the bile ducts, so far remained unknown, from which cells the tumor develops. It is believed that he originates from a pluripotent stem cell of the liver.

Presumably passes through the bile duct carcinoma - like colon cancer - a series of stages of development of metaplasia and dysplasia hypoplasia over towards the carcinoma ( adenoma -carcinoma sequence ). Therefore processes play as chronic inflammation and narrowing of the bile ducts associated with a flow obstruction of the bile in the development of this tumor a role. The histological picture of cholangiocarcinoma may vary from undifferentiated to well differentiated tissue. The tumor is often surrounded by a fibrotic or desmoplastic tissue. In the case of a pronounced fibrosis it may be difficult to distinguish a well- differentiated cancer of the bile ducts of a reactive modified only epithelium. There is no entirely specific immunohistochemical staining, which distinguishes malignant from benign bile duct altered tissue. Markers for cytokeratin, carcinoembryonic antigen, and mucins may be helpful in diagnosis. Most tumors ( 90 %) are adenocarcinomas.

Symptoms and signs

The most common physical signs of the presence of a bile duct carcinoma are jaundice, which occurs when the bile ducts are narrowed by the tumor and is typically painless, a generalized (ie the whole body occurring ) itching (66% ), abdominal pain (30-50 % ), weight loss (30-50% ) and fever (20 %). To a certain extent the symptoms of the localization of the tumor depend. Patients with cholangiocarcinoma of the bile ducts outside the liver have more jaundice and patients with a tumor within the liver often have pain without jaundice.

Blood tests in patients with cholangiocarcinoma often show evidence of an obstructive jaundice with elevated bilirubin, alkaline phosphatase ( AP) and γ - glutamyl transferase (GGT ) with normal aminotransferase levels. This constellation of liver values ​​rather suggests a relocation of the biliary tract than for an inflammation or infection of the liver, which are the most common differential diagnoses of jaundice. The tumor marker CA 19-9 is mostly positive.

Diagnostics

The bile duct carcinoma can be clearly diagnosed by a tissue examination. Typically manages the extraction of tissue that is sufficiently suitable for pathological examination, only in the context of an operation. A cholangiocarcinoma may be suspected if a patient shows an obstructive jaundice. In patients with primary sclerosing cholangitis a clarification of the diagnosis of bile duct carcinoma can cause great problems. Such patients have a high risk to get a cholangiocarcinoma, but the symptoms are not easy to distinguish from primary sclerosing cholangitis. Also can be detected in the corresponding patient sometimes neither mass nor a widening of the bile ducts.

Laboratory tests

There are no specific blood tests through which a bile duct carcinoma can be detected. Serum levels of the tumor markers carcinoembryonic Embryonic Antigen ( CEA) and CA 19-9 are often increased, but they are not sensitive and specific enough to be used as a screening procedure. However, they can substantiate the diagnosis in conjunction with imaging techniques.

Ultrasonography and computed tomography of the upper abdomen

For information on what an obstructive jaundice is frequently used as the first imaging method for representation of the biliary tract, the upper abdominal sonography. With this method, the transfer and expansion of the bile ducts can be investigated and in some cases may in this way have the diagnosis of bile duct cancer are provided. The computed tomography plays an important role in the investigation of these patients.

Imaging of the biliary tract

Although the imaging of the upper abdominal organs may be useful for the diagnosis of Gallengangskarzinoma, a representation of the biliary tract is often unavoidable with a contrast agent. For this purpose is the endoscopic retrograde cholangiopancreatography (ERCP), an endoscopic method used as a means of selection by gastroenterologists or surgeon. Although ERCP is an invasive procedure with all the associated risks pass their advantages but is taken from the tissue samples for diagnosis and a tubular implant can be inserted into the bile duct, thereby eliminating the relocation of the biliary tract.

During the ERCP an endoscopic ultrasound may be performed to facilitate removal of tissue samples by means of biopsy. In addition, as a possible lymph node involvement can be better assessed and information is obtained on the question of operability of the tumor. As an alternative to percutaneous transhepatic cholangiography ERCP ( PTC) can be used. Magnetic resonance cholangiopancreatography (MRCP ) is a non - invasive diagnostic alternative to ERCP. Some authors have suggested the diagnosis ERCP generally be replaced for biliary tumors by MRCP, as well as the tumor can be diagnosed and the risks of ERCP be avoided.

Surgical diagnosis

An operation of the abdominal cavity may be necessary in order to obtain enough tissue material and to make a tumor staging. Occasionally, it may be sufficient, especially if more invasive measures are to be avoided laparoscopy. An operation is usually carried out only in patients with a disease at an early stage.

Pathology

Most bile duct cancers are usually histologically differentiated good to moderate. A Immunohistochemistry is helpful in diagnosis when a differentiated cholangiocarcinoma of metastases other gastrointestinal tumors should be distinguished. Tissue smears are rarely diagnostically meaningful.

Staging

Although there are more than three current staging procedures for cholangiocarcinoma ( Bismuth, Blumgart, American Joint Committee on Cancer ), none is suitable for predicting the survival rate well. The most important staging criterion is the question of whether a tumor can be surgically removed. The decision can generally only be taken during an operation.

General guidelines for Operierbarkeit are:

• Absence of lymph node or liver metastases
• Absence of tumor involvement of the portal vein
• Absence of tumor infiltration of adjacent organs
• Absence of distant metastases

Forecast

If surgical removal of the tumor is not possible, because distant metastases are present, the five-year survival rate is zero percent, and less than five percent for all patients. The median survival time is less than six months for patients who are inoperable, untreated and otherwise healthy, if the tumor has spread to the liver either via the biliary tract or the portal vein.

In patients with operable tumors healing prospect depends on the tumor location and from the question of whether it can be removed completely. Distal bile duct carcinomas are usually treated by surgery after Whipple. In these cases, the long-term survival rate is about 15-25 %, although a series of studies has a five-year survival rate of 54 % reported for patients in which there was no lymph node involvement.

Patients with intrahepatic cholangiocarcinoma usually receive a liver resection. The reported survival rate was 22 % to 66 % in different studies and depended on whether lymph nodes were affected and whether complete tumor removal succeeded.

The beyond the perihilar area carcinomas are most frequently inoperable. When an operation is possible, a so-called aggressive therapy is often chosen, which is comprised of a removal of the gallbladder and partial resection of the liver. Of patients with operable carcinoma beyond the perihilar area a five-year survival rate of 20 % to 50 % is reported.

Patients with primary sclerosing cholangitis who develop cholangiocarcinoma secondary, presumably therefore have the worst prognosis because their tumor is usually detected only when it is already advanced. There are indications that an aggressive surgical therapy with adjuvant method can improve the prognosis.

Treatment

The Cholangiocarcinoma is considered incurable and rapidly lead to death if the tumor can not be completely removed. Since the operability of the tumor can usually be assessed only during surgery in most patients an exploratory laparotomy ( opening the abdomen for examination purposes ) is necessary, unless the tumor is inoperable anyway. Adjuvant therapy procedures after liver transplantation play a role only in a small number of cases.

Adjuvant chemotherapy and radiation

If the tumor can be surgically removed, patients may receive adjuvant chemotherapy or radiation therapy to increase the chances of recovery. On the question of the benefit of adjuvant therapy procedure at cholangiocarcinoma, there are positive and negative reports. In no case so far ( March 2007) were conducted prospective and randomized studies. In cases where the tumor has been completely removed ( Gewebsrand negative) is adjuvant chemotherapy, without benefit. The benefits of a combined chemoradiotherapy is not clear. If the tumor could be removed only incompletely ( Gewebsrand positive), but radiochemotherapy is recommended due to the current study area.

Treatment of advanced disease

In the majority of cases, the bile duct carcinoma presenting as an inoperable tumor. In these cases, the patients are treated with palliative chemotherapy with or without radiation. It was shown in randomized trials that when inoperable cholangiocarcinoma chemotherapy improves quality of life and extended life expectancy.

There are no common chemotherapy procedures for cholangiocarcinoma and it is recommended that the appropriate patients should be included in studies, wherever that is possible. The following chemotherapeutic agents in the treatment of cholangiocarcinoma used: fluorouracil with folinic acid, gemcitabine as a single agent, or in combination with cisplatin, irinotecan, or capecitabine.

Experimental Methods

In a small pilot study, a limited benefit to the tyrosine kinase inhibitor erlotinib has been demonstrated. Photodynamic therapy is an experimental procedure in which the patient is a light-sensitive drug is injected, and then the tumor is irradiated with light endoscopy. In a small randomized study could be achieved with this method, first results. Overall, the benefits of the procedure is not yet foreseeable.