Intrahepatic Cholangiocarcinoma

Overview

Cholangiocarcinoma, commonly known as bile duct cancer, is a cancer that develops in the bile ducts. Abdominal pain, yellowish skin, weight loss, generalized itching, and fever are all symptoms of cholangiocarcinoma. It is also possible to have light-colored feces or dark urine. Gallbladder cancer and carcinoma of the ampulla of Vater are two other biliary tract cancers.

Intrahepatic cholangiocarcinoma (ICC), also known as intrahepatic bile duct cancer, is cancer that arises in the bile ducts within the liver. ICC is an uncommon disease that accounts for roughly 10% of all cholangiocarcinomas.

Primary sclerosing cholangitis (an inflammatory disease of the bile ducts), ulcerative colitis, cirrhosis, hepatitis C, hepatitis B, infection with certain liver flukes, and various congenital liver anomalies are all risk factors for intrahepatic cholangiocarcinoma. However, the majority of persons have no identifiable risk factors. 

A combination of blood testing, medical imaging, endoscopy, and, in certain cases, surgical exploration is used to make the diagnosis. Under a microscope, cells from the tumor are examined to confirm the condition. It is most commonly an adenocarcinoma (a cancer that forms glands or secretes mucin).

Intrahepatic Cholangiocarcinoma is often incurable at diagnosis, which is why early identification is ideal. In these circumstances, palliative therapies may include surgical resection, chemotherapy, radiation therapy, and stenting operations. In around one-third of instances involving the common bile duct, and less frequently in other places, the tumor can be entirely removed by surgery, affording a chance of cure.

Even when surgical removal is successful, chemotherapy and radiation therapy are usually necessary. In some situations, surgery may entail a liver transplantation. Even when surgery is successful, 5-year survival is often less than 50%. 

Worldwide epidemiologic facts of Intrahepatic Cholangiocarcinoma (ICC)

Intrahepatic cholangiocarcinoma (ICC) is a kind of aggressive cholangiocarcinoma, which are cancers that grow from biliary tree cholangiocytes. ICC has several key epidemiologic considerations:

• ICCs are rare, accounting for 20–25 % of all cholangiocarcinomas; perihilar (50–60 %) or distal common bile duct (20–25 %) tumors are more prevalent. They remain the second most frequent primary liver cancer, after hepatocellular carcinoma.

• The incidence rate of ICCs in Americans has risen from 3.2 per 1,000,000 in 1975 to 1979 to 8.5 per 1,000,000 in 1995 to 1999 but this trend has leveled off in the last decade.

• The causes for this rising incidence are unknown, although possible explanations include changes in the classification system or a recent increase in Hepatitis C cases. This higher incidence does not appear to be due to increased tumor identification, as the proportion of early stage or smaller tumors found has not changed over time.

• According to population-based research, men in the United States are 1.5 times more likely than women to develop ICCs.

• The average age of diagnosis is 50 years old worldwide, and individuals are rarely diagnosed before the age of 40.

• ICCs are lethal liver cancers with more aggressive tumor biology than the more prevalent hepatocellular carcinoma. Overall 3-year and 5-year survival rates are dismal at 30% and 18%, respectively.

Risk factors for Intrahepatic Cholangiocarcinoma

Although the majority of patients arrive with no recognized risk factors, a number of risk factors for the development of cholangiocarcinoma have been identified. The most prevalent of them in the Western world is primary sclerosing cholangitis (PSC), an inflammatory disease of the bile ducts that is closely related with ulcerative colitis (UC). Epidemiologic studies have suggested that a person with PSC has a 10–15% lifetime risk of developing cholangiocarcinoma, however autopsy series have found rates as high as 30 % in this population.

Certain parasitic liver infections may also be risk factors. Colonization with the liver flukes Opisthorchis viverrini (found in Thailand, Lao PDR, and Vietnam) or Clonorchis sinensis (found in China, Taiwan, eastern Russia, Korea, and Vietnam) has been linked to cholangiocarcinoma development. In some countries, control efforts (Integrated Opisthorchiasis Control Program) geared at limiting the intake of raw and undercooked food have proven successful in lowering the occurrence of cholangiocarcinoma.

Chronic liver illness, whether caused by viral hepatitis (e.g., hepatitis B or hepatitis C), alcoholic liver disease, or cirrhosis of the liver due to other causes, puts people at a considerably higher risk of cholangiocarcinoma. In one study, HIV infection was identified as a potential risk factor for cholangiocarcinoma, although this was unclear if the link was due to HIV or other connected and confounding factors (e.g., hepatitis C infection).

Biliary carcinoma can be caused by infection with the bacteria Helicobacter bilis and Helicobacter hepaticus.

Congenital liver abnormalities, such as Caroli disease (one of five identified choledochal cysts), have been linked to a 15% lifetime chance of developing cholangiocarcinoma. Lynch syndrome II and biliary papillomatosis, both rare genetic disorders, have also been linked to cholangiocarcinoma.

Gallstones (cholelithiasis) are not definitely connected with cholangiocarcinoma. Intrahepatic stones (called hepatolithiasis), which are uncommon in the West but frequent in regions of Asia, have been significantly linked to cholangiocarcinoma.

Thorotrast, a radiologic contrast medium containing thorium dioxide, has been related to the development of cholangiocarcinoma as late as 30–40 years after exposure; Thorotrast was prohibited in the United States in the 1950s due to its carcinogenicity. 

Symptoms and signs of Intrahepatic cholangiocarcinoma

Abnormal liver function tests, jaundice (yellowing of the eyes and skin caused by tumor blockage of bile ducts), abdominal discomfort (30–50%), widespread itching (66%), weight loss (30–50%), fever (up to 20%), and changes in stool or urine color are the most prevalent physical signs of cholangiocarcinoma.

To some extent, the symptoms are determined by the location of the tumor: people with cholangiocarcinoma in the extrahepatic bile ducts (outside the liver) are more likely to have jaundice, whereas people with cholangiocarcinoma in the bile ducts within the liver are more likely to have pain without jaundice. 

Diagnosis of Intrahepatic Cholangiocarcinoma

The nonspecific, aggressive presentation of ICC, combined with its rarity, makes the initial diagnosis difficult. Cross-sectional imaging, which is also utilized for tumor stage and resectability, is the most often used method for detecting ICCs. Given the distinct tumor biology of these tumors in comparison to others, determining the diagnosis prior to intervention has substantial therapy consequences (hepatocellular carcinoma, metastatic adenocarcinoma).

1. Blood tests:

There are no specific blood tests that can be used to identify cholangiocarcinoma on their own. Carcinoembryonic antigen (CEA) and CA19-9 serum levels are frequently increased, however they are neither sensitive or specific enough to be utilized as a general screening tool. They may, however, be beneficial in conjunction with imaging modalities in supporting a suspected cholangiocarcinoma diagnosis.

2. Abdominal imaging:

In patients with suspected obstructive jaundice, ultrasound of the liver and biliary tree is frequently employed as the initial imaging modality. Ultrasound can detect blockage and ductal dilation and may be used to diagnose cholangiocarcinoma in some circumstances. Computed tomography (CT) scanning may also be useful in the diagnosis of cholangiocarcinoma.

3. Imaging of the biliary tree:

While abdominal imaging can be helpful in diagnosing cholangiocarcinoma, direct imaging of the bile ducts is frequently required. Endoscopic retrograde cholangiopancreatography (ERCP), a gastroenterologist or specifically trained surgeon-performed endoscopic procedure, has been frequently employed for this purpose.

Although ERCP is an invasive treatment with dangers, it has advantages such as the ability to acquire biopsies and put stents or other procedures to ease biliary blockage. Endoscopic ultrasonography can also be used during ERCP to improve biopsy accuracy and provide information on lymph node invasion and operability.

Percutaneous transhepatic cholangiography (PTC) may be used instead of ERCP. Magnetic resonance cholangiopancreatography (MRCP) is a non-invasive alternative to endoscopic retrograde cholangiopancreatography (ERCP). Some writers have proposed that MRCP should be used instead of ERCP in the diagnosis of biliary malignancies since it can more correctly characterize the tumor and avoids the hazards associated with ERCP.

4. Surgical exploration:

A appropriate biopsy and accurate staging of a person with cholangiocarcinoma may necessitate surgical exploration. In some cases, laparoscopy can be used for staging and may eliminate the need for a more invasive surgical procedure, such as a laparotomy.

5. Biopsy and histopathology:

Cholangiocarcinomas are histologically well to moderately differentiated adenocarcinomas. Immunohistochemistry can aid in the diagnosis of cholangiocarcinoma by distinguishing it from hepatocellular carcinoma and metastases of other gastrointestinal malignancies. Because these tumors generally contain a desmoplastic stroma and hence do not yield diagnostic tumor cells with scrapings, cytological scrapings are frequently nondiagnostic.

Is Intrahepatic Cholangiocarcinoma curable?

Cholangiocarcinoma is considered an incurable and rapidly fatal cancer until all tumors are completely removed (cut out surgically). Because the operability of the tumor can usually only be determined after surgery, most people have exploratory surgery unless there is already a clear sign that the tumor is inoperable. 

Certain unresectable cases may benefit from adjuvant therapy followed by liver transplantation. Locoregional therapy, such as transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and ablation therapies, can give palliation or potential cure in persons who are not surgical candidates for intrahepatic cholangiocarcinoma.

• Adjuvant chemotherapy and radiation therapy:

If the tumor can be removed surgically, people may receive adjuvant chemotherapy or radiation therapy after the operation to improve the chances of cure. If the tissue margins are negative (i.e. the tumor has been totally excised), adjuvant therapy is of uncertain benefit. Both positive and negative results have been reported with adjuvant radiation therapy in this setting.

Adjuvant chemotherapy appears to be ineffective in patients who have had their tumors totally removed. In this case, the role of combination chemoradiotherapy is unknown. If the tumor tissue margins are positive, suggesting that the tumor was not entirely removed during surgery, adjuvant therapy with radiation and potentially chemotherapy is generally advised based on the available evidence.

• Treatment of advanced disease:

The vast majority of cholangiocarcinoma cases appear as inoperable (unresectable) cancer, in which case patients are often treated with palliative chemotherapy, with or without radiotherapy. In a randomized controlled trial, chemotherapy was proven to improve quality of life and lengthen survival in persons with inoperable cholangiocarcinoma. There is no single chemotherapy regimen that is universally utilized, and participation in clinical trials is frequently advised when possible.

5-fluorouracil with leucovorin, gemcitabine as a single drug, or gemcitabine plus cisplatin, irinotecan, or capecitabine are all chemotherapy medications used to treat cholangiocarcinoma. A tiny pilot research found that the tyrosine kinase inhibitor erlotinib may be beneficial in persons with advanced cholangiocarcinoma.

Radiation therapy appears to prolong survival in people with resected extrahepatic cholangiocarcinoma, and the few reports of its use in unresectable cholangiocarcinoma appear to show improved survival, but numbers are small.

Outcome of Intrahepatic Cholangiocarcinoma & its Management

In cholangiocarcinoma, surgical excision is the only possible cure. The five-year survival rate for non-resectable cases is 0% when the disease is inoperable due to metastases in distal lymph nodes, and less than 5% in general. In persons with metastatic cancer, the average duration of survival is fewer than 6 months.

In surgical cases, the chances of cure vary depending on the tumor's location and if it can be removed fully or simply partially. Distal cholangiocarcinomas (those emerging from the common bile duct) are often treated surgically with a Whipple technique; long-term survival rates range from 15 to 25%, while one series found a five-year survival rate of 54% for persons with no lymph node involvement.

Partial hepatectomy is typically used to treat intrahepatic cholangiocarcinomas (those that arise from the bile ducts within the liver). Various studies have shown post-surgical survival rates ranging from 22 to 66 percent; the prognosis may be affected by the involvement of lymph nodes and the extent of the surgery. Perihilar cholangiocarcinomas (those that originate close where the bile ducts exit the liver) have the lowest chance of being operated. When surgery is an option, they are usually treated aggressively, with the gallbladder and maybe a portion of the liver removed. 5-year survival rates in patients with operable perihilar malignancies range from 20% to 50%.

People with primary sclerosing cholangitis who develop cholangiocarcinoma may have a worse prognosis, most likely because the cancer is not identified until it is advanced. Some data suggests that more aggressive surgical methods and adjuvant therapy may improve outcomes. 

Complications of Intrahepatic Cholangiocarcinoma's management

Complications arising from chemotherapy, radiotherapy, and/or post-surgical resection of the biliary tract cancer include:

• Chemotherapy Side Effects:

Hematological complications include decreased white-cell count, decreased platelet count, decreased hemoglobin. Non-hematological complications include alopecia, anorexia, nausea, fatigue, vomiting, impaired liver functions, impaired renal functions, infections with or without neutropenia, biliary sepsis, etc.

• Post-surgery Complications:

Sepsis, respiratory failure, liver failure, thromboembolic events, intra-abdominal abscess, wound infection, hemorrhage, deep venous thrombosis, biliary leakage, recurrence of the tumor

• Radiotherapy Complications:

Generalized fatigue, nausea, vomiting, fever, etc.

Conclusion

Cholangiocarcinoma is a cancer that develops in the narrow tubes (bile ducts) that transport the digestive fluid bile. The bile ducts connect the liver to the gallbladder and the small intestine. Cholangiocarcinoma, often known as bile duct cancer, primarily affects persons over the age of 50, but it can occur at any age.

The following are signs and symptoms of cholangiocarcinoma: yellowing of your skin and the whites of your eyes (jaundice), Skin that is extremely itchy, feces that are white in color, Fatigue, right-sided abdominal pain just below the ribs losing weight, Fever, Sweating at night and dark urine.

Factors that may increase your risk of cholangiocarcinoma include:

• Primary sclerosing cholangitis: This disease causes hardening and scarring of the bile ducts.
• Chronic liver disease: Scarring of the liver caused by a history of chronic liver disease increases the risk of cholangiocarcinoma.
• Bile duct problems present at birth: People born with a choledochal cyst, which causes dilated and irregular bile ducts, have an increased risk of cholangiocarcinoma.
• A liver parasite: In areas of Southeast Asia, cholangiocarcinoma is associated with liver fluke infection, which can occur from eating raw or undercooked fish.
• Older age: Cholangiocarcinoma occurs most often in adults over age 50.
• Diabetes: People who have type 1 or 2 diabetes may have an increased risk of cholangiocarcinoma.
• Certain inherited conditions: Some DNA changes passed from parents to children cause conditions that increase the risk of cholangiocarcinoma. Examples of these conditions include cystic fibrosis and Lynch syndrome.

ICCs are aggressive cancers that are becoming more common and lethal with time. Few individuals present with resectable illness, and diagnosis is frequently challenging because to the cryptic nature and anatomic position of ICCs. 

In the therapy and treatment of these individuals, prognostic factors such as multifocality, vascular invasion, lymphatic dissemination, and histology should be evaluated. However, due to the rarity of ICCs, nothing is known about the best treatment plan beyond surgical resection. Prospective data are required to better evaluate the efficacy of minimally invasive methods, transplantation, chemotherapy regimens, and other adjuvant therapies on individuals with this deadly disease.