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Biliary Tract Cancer

Disease Details

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Description: Biliary tract cancer is a rare malignancy that originates in the bile ducts, which carry bile from the liver to the small intestine.
Type: Biliary tract cancer, also known as cholangiocarcinoma, is not typically associated with a single type of genetic transmission. While some hereditary conditions, such as Lynch syndrome or BAP1 tumor predisposition syndrome, may slightly increase the risk, most cases are sporadic and arise due to a combination of environmental factors and somatic mutations acquired over a person's lifetime.
Signs And Symptoms: The most common physical indications of cholangiocarcinoma are abnormal liver function tests, jaundice (yellowing of the eyes and skin occurring when bile ducts are blocked by tumor), abdominal pain (30–50%), generalized itching (66%), weight loss (30–50%), fever (up to 20%), and changes in the color of stool or urine. To some extent, the symptoms depend upon the location of the tumor: people with cholangiocarcinoma in the extrahepatic bile ducts (outside the liver) are more likely to have jaundice, while those with tumors of the bile ducts within the liver more often have pain without jaundice.Blood tests of liver function in people with cholangiocarcinoma often reveal a so-called "obstructive picture", with elevated bilirubin, alkaline phosphatase, and gamma glutamyl transferase levels, and relatively normal transaminase levels. Such laboratory findings suggest obstruction of the bile ducts, rather than inflammation or infection of the liver parenchyma, as the primary cause of the jaundice.
Prognosis: Surgical resection offers the only potential chance of cure in cholangiocarcinoma. For non-resectable cases, the five-year survival rate is 0% where the disease is inoperable because distal lymph nodes show metastases, and less than 5% in general. Overall mean duration of survival is less than 6 months in people with metastatic disease.For surgical cases, the odds of cure vary depending on the tumor location and whether the tumor can be completely, or only partially, removed. Distal cholangiocarcinomas (those arising from the common bile duct) are generally treated surgically with a Whipple procedure; long-term survival rates range from 15 to 25%, although one series reported a five-year survival of 54% for people with no involvement of the lymph nodes. Intrahepatic cholangiocarcinomas (those arising from the bile ducts within the liver) are usually treated with partial hepatectomy. Various series have reported survival estimates after surgery ranging from 22 to 66%; the outcome may depend on involvement of lymph nodes and completeness of the surgery. Perihilar cholangiocarcinomas (those occurring near where the bile ducts exit the liver) are least likely to be operable. When surgery is possible, they are generally treated with an aggressive approach often including removal of the gallbladder and potentially part of the liver. In patients with operable perihilar tumors, reported 5-year survival rates range from 20 to 50%.The prognosis may be worse for people with primary sclerosing cholangitis who develop cholangiocarcinoma, likely because the cancer is not detected until it is advanced. Some evidence suggests that outcomes may be improving with more aggressive surgical approaches and adjuvant therapy.
Onset: The onset of biliary tract cancer can vary, but it often occurs later in life, typically affecting individuals over the age of 60. Factors such as genetic predisposition, chronic inflammation of the bile ducts (cholangitis), and lifestyle factors like smoking and obesity can influence the onset. However, the exact cause is often multifactorial and may not be clearly identifiable. Early stages might not show symptoms, making regular check-ups important for early detection.
Prevalence: The prevalence of biliary tract cancer varies geographically. It is relatively rare in most Western countries with an incidence of around 1-2 cases per 100,000 people annually. However, higher rates are observed in certain parts of Asia and South America, where incidence can be as high as 85 cases per 100,000 people in some areas.
Epidemiology: Cholangiocarcinoma is a relatively rare form of cancer; each year, approximately 2,000 to 3,000 new cases are diagnosed in the United States, translating into an annual incidence of 1–2 cases per 100,000 people. Autopsy series have reported a prevalence of 0.01% to 0.46%. There is a higher prevalence of cholangiocarcinoma in Asia, which has been attributed to endemic chronic parasitic infestation. The incidence of cholangiocarcinoma increases with age, and the disease is slightly more common in men than in women (possibly due to the higher rate of primary sclerosing cholangitis, a major risk factor, in men). The prevalence of cholangiocarcinoma in people with primary sclerosing cholangitis may be as high as 30%, based on autopsy studies.Multiple studies have documented a steady increase in the incidence of intrahepatic cholangiocarcinoma; increases have been seen in North America, Europe, Asia, and Australia. The reasons for the increasing occurrence of cholangiocarcinoma are unclear; improved diagnostic methods may be partially responsible, but the prevalence of potential risk factors for cholangiocarcinoma, such as HIV infection, has also been increasing during this time frame.
Intractability: Biliary tract cancer, also known as cholangiocarcinoma, is often considered intractable, particularly if diagnosed at an advanced stage. Early-stage biliary tract cancer might be treatable with surgical resection, but advanced stages are challenging due to the cancer's aggressive nature and the complexity of the biliary anatomy. Treatment options such as chemotherapy, radiation therapy, and targeted therapies can manage the disease to some extent but are usually not curative.
Disease Severity: Biliary tract cancer varies in severity based on its stage at diagnosis. Early-stage biliary tract cancer, which includes intrahepatic and extrahepatic cholangiocarcinoma, may potentially be treated surgically, offering a better prognosis. However, many cases are diagnosed at an advanced stage when the cancer has spread, leading to a poorer prognosis and limited treatment options. The severity is largely influenced by tumor location, size, extent of spread, and the patient’s overall health condition.
Healthcare Professionals: Disease Ontology ID - DOID:4607
Pathophysiology: Cholangiocarcinoma can affect any area of the bile ducts, either within or outside the liver. Tumors occurring in the bile ducts within the liver are referred to as intrahepatic, those occurring in the ducts outside the liver are extrahepatic, and tumors occurring at the site where the bile ducts exit the liver may be referred to as perihilar. A cholangiocarcinoma occurring at the junction where the left and right hepatic ducts meet to form the common hepatic duct may be referred to eponymously as a Klatskin tumor.Although cholangiocarcinoma is known to have the histological and molecular features of an adenocarcinoma of epithelial cells lining the biliary tract, the actual cell of origin is unknown. Recent evidence has suggested that the initial transformed cell that generates the primary tumor may arise from a pluripotent hepatic stem cell. Cholangiocarcinoma is thought to develop through a series of stages – from early hyperplasia and metaplasia, through dysplasia, to the development of frank carcinoma – in a process similar to that seen in the development of colon cancer. Chronic inflammation and obstruction of the bile ducts, and the resulting impaired bile flow, are thought to play a role in this progression.Histologically, cholangiocarcinomas may vary from undifferentiated to well-differentiated. They are often surrounded by a brisk fibrotic or desmoplastic tissue response; in the presence of extensive fibrosis, it can be difficult to distinguish well-differentiated cholangiocarcinoma from normal reactive epithelium. There is no entirely specific immunohistochemical stain that can distinguish malignant from benign biliary ductal tissue, although staining for cytokeratins, carcinoembryonic antigen, and mucins may aid in diagnosis. Most tumors (>90%) are adenocarcinomas.
Carrier Status: Carrier status is not applicable to biliary tract cancer as it is not a hereditary condition passed down through carriers of specific genetic mutations. It primarily arises from genetic mutations acquired during a person's lifetime rather than inherited mutations.
Mechanism: Biliary tract cancer, which includes cholangiocarcinoma and gallbladder cancer, involves multiple mechanisms at both the cellular and molecular levels.

### Mechanism:
1. **Chronic Inflammation:** Chronic inflammation of the biliary tract, often due to conditions like primary sclerosing cholangitis or liver fluke infection, can lead to cellular damage and malignancy.
2. **Genetic Mutations:** Mutations in specific oncogenes and tumor suppressor genes are involved in the uncontrolled growth of biliary tract cells.

### Molecular Mechanisms:
1. **Genetic Alterations:**
- **KRAS Mutations:** Commonly involved in the MAPK pathway, leading to increased cell proliferation.
- **IDH1/IDH2 Mutations:** Affect cellular metabolism and promote oncogenesis.
- **TP53 Mutations:** Loss of function in this crucial tumor suppressor gene, leading to uncontrolled cell growth.
- **FGFR2 Fusions:** These fusions activate the FGFR pathway, playing a significant role in cell division and survival.

2. **Epigenetic Modifications:**
- **DNA Methylation:** Aberrant methylation of promoter regions of tumor suppressor genes can silence these genes and contribute to cancer progression.
- **Histone Modification:** Changes in histone acetylation and methylation can alter chromatin structure and gene expression.

3. **Pathway Dysregulation:**
- **WNT/β-Catenin Pathway:** Abnormal activation can lead to increased cell proliferation.
- **PI3K/AKT/mTOR Pathway:** This pathway, when dysregulated, can lead to enhanced cell survival and growth.
- **Notch Signaling Pathway:** Dysregulation can contribute to biliary tract cancer development through effects on cell differentiation and apoptosis.

Understanding these mechanisms helps in identifying potential targets for therapeutic intervention and in the development of personalized treatment strategies for biliary tract cancer.
Treatment: Cholangiocarcinoma is considered to be an incurable and rapidly lethal disease unless all the tumors can be fully resected (cut out surgically). Since the operability of the tumor can only be assessed during surgery in most cases, a majority of people undergo exploratory surgery unless there is already a clear indication that the tumor is inoperable. However, the Mayo Clinic has reported significant success treating early bile duct cancer with liver transplantation using a protocolized approach and strict selection criteria.Adjuvant therapy followed by liver transplantation may have a role in treatment of certain unresectable cases. Locoregional therapies including transarterial chemoembolization (TACE), transarterial radioembolization (TARE) and ablation therapies have a role in intrahepatic variants of cholangiocarcinoma to provide palliation or potential cure in people who are not surgical candidates.
Compassionate Use Treatment: Compassionate use and off-label or experimental treatments for biliary tract cancer may include:

1. **Immunotherapy**: Drugs like pembrolizumab (Keytruda) are sometimes used off-label for biliary tract cancer, particularly in cases with specific genetic markers (e.g., microsatellite instability-high or mismatch repair deficiency).

2. **Targeted Therapy**: Agents such as FGFR2 inhibitors (e.g., pemigatinib) and IDH1 inhibitors (e.g., ivosidenib) may be used in patients with mutations in these genes.

3. **Chemotherapy Combinations**: Various combinations of chemotherapy agents, beyond standard regimens, may be explored on an off-label basis or under experimental protocols.

4. **Clinical Trials**: Participation in clinical trials testing new drugs, drug combinations, or treatment approaches can be an option.

5. **Radioembolization and Selective Internal Radiation Therapy (SIRT)**: This approach may be used in advanced cases, often as part of a clinical trial or compassionate use protocol.

Each of these options would typically require careful consideration by a treating oncologist, and in many cases, approval through regulatory pathways for compassionate use or participation in clinical trials.
Lifestyle Recommendations: For biliary tract cancer, considered rare and often aggressive, certain lifestyle recommendations might help improve overall health and potentially reduce risk factors:

1. **Healthy Diet**: Focus on a balanced diet rich in fruits, vegetables, whole grains, and lean proteins. Avoid excessive intake of red and processed meats, fried foods, and sugar.

2. **Avoid Tobacco and Limit Alcohol**: Smoking is a significant risk factor for many cancers, including biliary tract cancer. Limiting or avoiding alcohol consumption can also reduce liver stress and related risk.

3. **Healthy Weight**: Maintain a healthy weight through proper nutrition and regular physical activity. Obesity is linked to an increased risk of several types of cancer.

4. **Regular Exercise**: Engage in regular physical activity. Aim for at least 30 minutes of moderate exercise most days of the week.

5. **Prevent Infections**: Infections like hepatitis B and C can increase the risk of biliary tract cancers. Get vaccinated for hepatitis B, and take preventive measures to avoid viral hepatitis.

6. **Limit Exposure to Toxins**: Try to minimize exposure to industrial chemicals and toxins that might contribute to liver and bile duct cancers.

7. **Regular Medical Check-ups**: Regular check-ups and screenings can help catch any abnormalities early. Discuss any history of gallstones or other risk factors with your healthcare provider.

Adhering to these lifestyle recommendations can contribute to overall health and potentially decrease the risk factors associated with biliary tract cancer.
Medication: There is no standard reference for a "medication, nan" in the treatment of biliary tract cancer. However, treatments often include surgery, chemotherapy, radiation therapy, and targeted therapies. Medications like gemcitabine, cisplatin, and targeted agents such as pemigatinib or infigratinib may be used, depending on the specific case and genetic markers of the cancer. Always consult a healthcare professional for personalized treatment options.
Repurposable Drugs: There is no information available regarding repurposable drugs specifically for biliary tract cancer.
Metabolites: Biliary tract cancer involves abnormal cell growth in the bile ducts, which are part of the digestive system. Metabolites associated with biliary tract cancer can include alterations in bile acids, bilirubin, and other metabolic compounds. These changes can reflect disruptions in cellular processes and liver function. Detection and analysis of these metabolites can aid in the diagnosis and understanding of the disease.

Causes of biliary tract cancer are multifactorial, often involving a combination of risk factors including chronic inflammation, primary sclerosing cholangitis, liver flukes, certain genetic mutations, and exposure to certain toxins.
Nutraceuticals: The use of nutraceuticals for biliary tract cancer is not well-established in conventional medical practice. Nutraceuticals are food-derived products that offer health benefits, including the prevention and treatment of disease. However, current evidence on their efficacy specifically for biliary tract cancer is limited and requires more research. It is essential to consult healthcare providers for appropriate treatment options and consider nutraceuticals only as a potential supplementary measure if advised by a professional.
Peptides: Regarding biliary tract cancer and the relevance of peptides:

1. **Diagnostic Biomarkers**: Peptides may serve as biomarkers for the early detection and diagnosis of biliary tract cancer. Specific peptide patterns or profiles in blood or tissue samples can help in identifying the presence of cancer.

2. **Therapeutic Agents**: Peptides can be used as therapeutic agents against biliary tract cancer. Peptides can target specific cancer cell receptors, potentially aiding in the development of targeted therapies that minimize harm to normal cells.

3. **Vaccine Development**: Peptides are involved in the creation of cancer vaccines. These vaccines aim to stimulate the body's immune system to recognize and attack cancer cells more effectively.

As of now, no specific peptide-based nanotechnologies are widely applied in clinical settings for biliary tract cancer, but research in this area is ongoing, exploring their potential for drug delivery, imaging, and treatment enhancements.