Biliary tract cancer

from Wikipedia, the free encyclopedia
Classification according to ICD-10
C22.1 Intrahepatic bile duct carcinoma
C24.0 Extrahepatic bile duct
common bile duct
cystic duct
hepatic duct
common hepatic duct
C24.1 Ampulla hepatopancreatica Father's papilla
C24.8 Biliary tract, overlapping several areas
C24.8 Malignant neoplasm involving both intra- and extrahepatic bile ducts
C24.9 Biliary tract, unspecified
ICD-10 online (WHO version 2019)

The bile duct carcinoma (medical cholangiocarcinoma or cholangiocellular carcinoma ) is a malignant tumor of the biliary tract . It is a rare tumor with an annual incidence of one to two cases in 100,000 in the western world, with the incidence rate increasing worldwide over the past few decades. Risk factors for bile duct carcinoma are primarily sclerosing cholangitis (an inflammatory disease of the bile ducts), congenital malformations of the liver , in East Asia also infections with the liver parasite Opisthorchis viverrini and the Chinese liver fluke as well as the (now prohibited) use of Thorotrast as an X-ray contrast medium . The symptoms of biliary tract cancer are jaundice , weight loss, and itching . The diagnosis is made by a combination of blood tests , imaging tests , endoscopy, and laparatomy .

Surgical removal of the tumor is the only option for treatment with a prospect of recovery. However, in most cases, the tumor is only discovered and properly diagnosed when the patient is at an advanced stage of the disease. In addition to surgery, chemotherapy and radiation can also improve treatment prospects. Patients in an advanced stage of the disease usually receive chemotherapy or palliative care. Research goals on biliary tract cancer are so-called targeted therapy with Erlotinib and photodynamic therapy .

Epidemiology

Age-corrected mortality rates for intrahepatic (IH) and extrahepatic (EH) bile duct carcinomas, differentiated by gender and country. Source: Khan et al., 2002.
country IH (men / women) EH (men / women)
United StatesUnited States United States 0.60 / 0.43 0.70 / 0.87
JapanJapan Japan 0, 23/0, 10 5, 87/5, 20
AustraliaAustralia Australia 0.70 / 0.53 0, 90/1, 23
EnglandEngland England / WalesWalesFlag of Wales (1959 – present) .svg  0.83 / 0.63 0.43 / 0.60
ScotlandScotland Scotland 1, 17/1, 00 0.60 / 0.73
FranceFrance France 0, 27/0, 20 1, 20/1, 37
ItalyItaly Italy 0.13 / 0.13 2, 10/2, 60

Bile duct carcinoma is a rather rare tumor. About 2,000 to 3,000 new people are diagnosed with the disease in the United States each year, an annual incidence of 1–2 in 100,000. The evaluation of autopsy series showed that the prevalence is between 0.01 and 0.46%. In Asia, the prevalence of biliary tract cancer is higher, which is attributed to the endemic spread of chronic parasitic diseases. The incidence of biliary tract cancer increases with age. Men get the disease somewhat more often, probably because of the higher incidence rate of primary sclerosing cholangitis in men. In the presence of primary sclerosing cholangitis, the prevalence increases many times over to up to 30%. Numerous studies have shown that the incidence of biliary tract cancer has increased in large parts of the world over the past few decades. The reasons for this are unknown. Improved diagnosis options and an increase in risk factors such as HIV disease may contribute to the increase.

Risk factors

Reproduction cycle of Clonorchis sinensis

Various risk factors for developing biliary tract cancer have been described. In the western world, this primarily includes primarily sclerosing cholangitis , an inflammatory disease of the biliary tract, which in turn often occurs together with ulcerative colitis . From epidemiological studies it was concluded that the lifetime risk of developing bile duct carcinoma in persons with primary sclerosing cholangitis is 10–15%, although rates of up to 30% have been found in autopsy series. The causes of the association between bile duct carcinoma and primary sclerosing cholangitis are unclear.

Certain parasitic diseases of the liver are also risk factors for biliary tract cancer. The liver fluke Opisthorchis viverrini, which is widespread in Thailand , Laos and Malaysia , and its relative Clonorchis sinensis , which is mainly native to Japan , Korea and Vietnam, increase the risk of developing bile duct carcinoma. Patients with chronic liver disease, such as hepatitis B or C virus , alcoholic liver disease , or liver cirrhosis from other causes also increase the risk of biliary tract cancer.

HIV is also a potential risk factor for biliary tract cancer. However, it is unclear whether HIV itself or HIV-associated diseases such as hepatitis C are responsible for the link. Congenital malformations of the liver, such as Caroli's syndrome or common bile duct cysts, lead to a lifetime risk of 15% for the development of biliary tract cancer. Rare hereditary diseases such as hereditary non-polypous colorectal carcinoma and papillomatosis of the biliary tract are associated with biliary tract cancer. A connection with the occurrence of gallstones has not been proven. However, there is a link between the frequency of gallstones and bile duct cancer 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 medium , can lead to bile duct carcinoma even after 30–40 years. The use of Thorotrast has been banned because of its carcinogenicity .

Pathophysiology

Positional relationship of bile ducts and upper abdominal organs

Bile duct carcinoma can occur in any section of the bile duct system. Tumors that grow in the bile ducts within the liver are 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 biliary system are called "perihilar" and those that lie at the junction of the two emerging from the liver bile ducts, are as Klatskintumore designated. Although bile duct carcinoma is known to be a tumor of the epithelial cells of the bile ducts, it has so far remained unknown from which cells the tumor develops. It is believed that it originates from a pluripotent stem cell in the liver.

Like colon cancer , bile duct carcinoma presumably goes through a series of developmental steps from hypoplasia to metaplasia and dysplasia to carcinoma ( adenoma-carcinoma sequence ). Therefore, processes such as chronic inflammation and narrowing of the biliary tract, which are associated with an obstruction of the flow of the bile, play a role in the development of this tumor. The histological picture of biliary tract cancer can vary from undifferentiated to well-differentiated tissue. The tumor is often surrounded by fibrotic or desmoplastic tissue. In the case of pronounced fibrosis, it can be difficult to distinguish a well-differentiated carcinoma of the bile ducts from a reactive epithelium. There is no completely specific immunohistochemical staining that distinguishes malignant from benign biliary tissue. Markings for cytokeratin , carcinoembryonic antigen, and mucins can be helpful in diagnosis. Most tumors (over 90%) are adenocarcinomas .

Symptoms and signs

Yellowing of the skin and eyes

The most common physical signs of the presence of bile duct carcinoma are jaundice , which occurs when the bile ducts are narrowed by the tumor and is typically painless, generalized itching ( that is, occurring over the whole body) (66%), abdominal pain (30– 50%), weight loss (30-50%) and fever (20%). To some extent, the symptoms depend on the location of the tumor. Patients with bile duct cancer of the biliary tract outside of the liver are more likely to have jaundice, and patients with a tumor within the liver are more likely to experience pain without jaundice.

Blood tests in patients with biliary tract cancer often show evidence of obstructive jaundice with increased bilirubin , alkaline phosphatase ( AP ), and γ-glutamyltransferase ( GGT ) with normal transaminase levels . This constellation of liver values suggests an obstruction of the biliary tract rather than an inflammation or infection of the liver , which are the most common differential diagnoses of jaundice . The tumor marker CA 19-9 is usually positive.

Diagnosis

Bile duct carcinoma can only be clearly diagnosed by examining the tissue. Tissue that is sufficiently well suited for a pathological examination can usually only be removed as part of an operation. Bile duct carcinoma can be suspected if a patient has obstructive jaundice. In patients with primary sclerosing cholangitis , clarifying the suspected diagnosis of biliary tract cancer can be very difficult. Such patients are at high risk of developing bile duct cancer, but symptoms are not easily distinguishable from primary sclerosing cholangitis. In addition, sometimes neither a mass nor a widening of the bile ducts can be detected in the corresponding patients.

Laboratory tests

There are no specific blood tests that can detect biliary tract cancer. The serum levels of the tumor markers Carcino-Embryonic Antigen ( CEA ) and CA 19-9 are often elevated, but they are not sensitive and specific enough to be used as a screening method. However, in connection with imaging tests, they can support the suspected diagnosis.

Sonography and computed tomography of the upper abdomen

Bile duct carcinoma in the liver ( tumor outlined in yellow)

If there is evidence of obstructive jaundice, the first imaging method used to visualize the biliary tract is often upper abdominal sonography . With this method the obstruction and widening of the bile ducts can be examined and in individual cases the diagnosis of bile duct carcinoma can be made in this way. The computed tomography plays an important role in the study of these patients.

Imaging of the biliary tract

ERCP image of bile duct carcinoma; a narrowing of the bile duct with a proximal widening (to the liver) is shown

Although imaging of the upper abdominal organs can be helpful in diagnosing bile duct carcinoma, imaging of the bile ducts with a contrast agent is often unavoidable. For this purpose, endoscopic retrograde cholangiopancreatography (ERCP), an endoscopic procedure, is the method of choice for gastroenterologists or surgeons. While ERCP is an invasive procedure with all of its associated risks, its advantages are that it can take tissue samples for diagnosis and insert a tubular implant into the bile duct to clear the bile duct obstruction.

Endoscopic ultrasound can be performed during ERCP to simplify the removal of tissue samples using a biopsy . In addition, a possible lymph node involvement can be better assessed and information about the operability of the tumor can be obtained. As an alternative to ERCP, percutaneous transhepatic cholangiography (PTC) can be used. The magnetic resonance cholangiopancreatography (MRCP) is a noninvasive diagnostic alternative to ERCP. Some authors have suggested that ERCP should generally be replaced by MRCP when diagnosing biliary tumors, as this can also be used to diagnose the tumor and avoid the risks of ERCP.

Surgical diagnostics

A surgery of the abdominal cavity may be necessary to gain sufficient fabric material and a tumor staging to make. Occasionally, a laparoscopy may be sufficient, especially if more invasive measures are to be avoided. Surgery is usually only done on patients with early-stage disease.

pathology

Microfoto of a bile duct carcinoma (right in the picture), HE staining

Bile duct cancers are adenocarcinomas and are usually well to moderately differentiated histologically. Immunohistochemistry is helpful in diagnosing differentiated biliary tract cancer from metastases from other gastrointestinal tumors. Tissue smears are rarely diagnostically meaningful.

Staging

Although there are more than three current staging methods for biliary tract cancer (Bismuth, Blumgart, American Joint Committee on Cancer), none are well suited to predict survival. The most important staging criterion is the question of whether a tumor can be surgically removed. The decision about this can usually only be made during an operation.

General guidelines for operability are:

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 invaded the liver through either the biliary tract or the portal vein.

In patients with operable tumors, the chances of recovery depend on the location of the tumor and whether it can be completely removed. Distal biliary tract cancer is usually treated with Whipple surgery . In these cases, the long-term survival rate is around 15-25%, although one series of studies has reported a five-year survival rate of 54% for patients with no lymph node involvement.

Patients with intrahepatic bile duct cancer usually receive a partial liver resection . In various studies, the reported survival rate was 22% to 66% and depended on whether lymph nodes were involved and whether complete tumor removal was successful.

Perihilar carcinomas are most often inoperable. If surgery is possible, so-called aggressive therapy is often chosen, which consists of removing the gallbladder and partially resecting the liver. A five-year survival rate of 20% to 50% has been reported for patients with operable perihilar carcinoma.

Patients with primary sclerosing cholangitis who develop secondary bile duct carcinoma probably have the poorest prognosis because the tumor is usually only detected when it has progressed. There is evidence that aggressive surgical therapy, along with adjuvant procedures, can improve the prognosis.

treatment

Bile duct carcinoma is considered incurable and can quickly lead to death if the tumor cannot be completely removed. Since the operability of the tumor can usually only be assessed during an operation, a trial aparatomy (opening of the abdominal cavity for examination purposes) is necessary in most patients, unless the tumor is inoperable anyway. Adjuvant therapy methods after liver transplantation only play a role in a small number of cases.

Adjuvant chemotherapy and radiation

If the tumor can be surgically removed, patients can receive adjuvant chemotherapy or radiation therapy to increase the chances of recovery. There have been positive and negative reports on the question of the benefit of adjuvant therapy methods for biliary tract cancer. In no case have prospective and randomized studies been carried out to date (March 2007) . In those cases in which the tumor has been completely removed (tissue margin negative), adjuvant chemotherapy is of no use. The benefit of combined chemoradiotherapy is not clear. If the tumor could only be removed incompletely (tissue margin positive), based on the current study situation, chemoradiotherapy is recommended.

Treatment of advanced disease

In the majority of cases, bile duct carcinoma presents as an inoperable tumor. In these cases, patients are treated with palliative chemotherapy with or without radiation . It could in randomized shown studies that chemotherapy in unresectable cholangiocarcinoma quality of life improves and prolongs life expectancy.

There is no generally binding chemotherapy regimen for biliary tract cancer and it is recommended that such patients should be included in studies wherever possible. The following chemotherapeutic agents are used in the treatment of biliary tract cancer: fluorouracil together with folinic acid , gemcitabine as a single preparation, or in combination with cisplatin , irinotecan or capecitabine . A combination therapy with gemcitabine and cis-platinum (also oxaliplatin, "GEMOX", if kidney function is impaired ) is currently (2015) the standard therapy for first-line therapy .

Experimental procedure

A small pilot study demonstrated limited use for the tyrosine kinase inhibitor Erlotinib . The photodynamic therapy is an experimental method in which the patient a light-sensitive drug is injected, and then the tumor is irradiated with light endoscopically. In a small randomized study, the first results were obtained with this method. Overall, however, the benefits of the process cannot yet be foreseen.

Web links

Individual evidence

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