Biliary Tract Cancer

Overview

The biliary tract is made up of the gallbladder as well as the intra and extrahepatic biliary tree. Bile is directed to the second half of the duodenum by these ducts at the main duodenal papilla. The biliary tract epithelium is lined by cells known as cholangiocytes.

Biliary tract cancers, including intrahepatic, perihilar, and distal cholangiocarcinoma, as well as gallbladder cancer, are uncommon in most high-income nations but are a serious health concern in endemic regions; however, the prevalence of intrahepatic cholangiocarcinoma is increasing internationally.

The ideal method relies on the anatomical position of the initial tumor, and the greatest outcomes are attained through therapy by professional interdisciplinary teams. Unfortunately, the majority of patients come with locally progressed or metastatic illness.

Biliary Tract Cancer

Tumors that form from epithelial cells lining the biliary tract, which includes the intrahepatic bile duct, extrahepatic bile duct, gall bladder, and ampulla of Vater, are classified as biliary tract cancer. Gallbladder cancer is the most frequent biliary tract cancer and the third most common gastrointestinal tract malignancy. Tumors commonly spread by vascular, lymphatic, intraperitoneal, neural, and intraductal pathways. The liver, lymph nodes, and surrounding organs are frequent sites of metastasis.

Carcinoma of the biliary tract develops from the malignant transformation of the bile duct epithelium, which is made up of these cholangiocytes, and is classified according to its anatomical location as;

Intrahepatic cholangiocarcinoma
Extrahepatic cholangiocarcinoma, which includes perihilar tumor, also known as Klatskin tumor (originating from the bile duct epithelium at the junction of the right and left hepatic ducts with the cystic duct where it forms the common bile duct) and distal cholangiocarcinoma, which spreads to encompass the gallbladder, ampulla of Vater, and pancreatic

Although both intrahepatic and extrahepatic cholangiocarcinoma emerge from the same bile duct epithelium, the pathophysiology and clinical consequences of extrahepatic cholangiocarcinoma differ due to anatomical location.

Cholangiocarcinoma is an uncommon but aggressive malignancy with an extremely bad prognosis since it is usually advanced and unresectable by the time it is identified. In many cases, the tumor's late manifestation has already caused substantial involvement of the blood arteries and nearby lymph nodes, making curative surgical removal difficult. Although uncommon, it is the second most prevalent kind of primary liver cancer after hepatocellular carcinoma.

Epidemiology

In the United States, the yearly incidence of cholangiocarcinoma ranges from 0.72 to 1.62 per 100,000 people. Although the frequency varies by country, a rise in the number of cases has been documented globally. Northeast Thailand (Asia) has the greatest incidence of the illness, with a rate of more than 80 per 100,000 people, most likely due to chronic infection with hepatobiliary flukes.

Multiple investigations have shown that the incidence of intrahepatic cholangiocarcinoma has been steadily increasing over the last several decades. Multiple variables have been identified as the cause of this increase, which occurred prior to the persistent inflammation and irritation of the biliary tract epithelium.

It is also somewhat more prevalent in males than in women, presumably due to a greater occurrence of primary sclerosing cholangitis in men at age 40 or younger, which is recorded as a risk factor for developing cholangiocarcinoma.

Etiology

Chronic inflammatory circumstances predispose the biliary tract epithelium to change under stress and undergo metamorphosis, giving birth to biliary tract cancer. Primary sclerosing cholangitis (PSC), which is associated with chronic inflammatory bowel illness, particularly ulcerative colitis, is the most well-established chronic inflammatory disorder related with biliary tract malignancy.

Aside from primary sclerosing cholangitis, other conditions that increase the risk of cholangiocarcinoma development by causing chronic inflammation and cholestasis include colonization with liver flukes such as Clonorchis sinensis (endemic in southern China, Hong Kong, and Korea) or Opisthorchis viverrini (endemic in north-eastern Thailand, western Malaysia, and Laos), hepatolithiasis

Chronic gallbladder inflammation, cholelithiasis, porcelain gallbladder, gallbladder polyps, and congenital gallbladder cysts are the most prevalent etiological factors linked with gallbladder cancer. Obesity, smoking, alcohol, and type 2 diabetes are all risk factors for cholangiocarcinoma.

Pathophysiology

Under chronic irritation and inflammation, the biliary tract epithelium undergoes a series of changes similar to those that predispose to other gastrointestinal cancers, namely, hyperplasia, metaplasia, dysplasia, and finally carcinoma, which involves mutations in various oncogenes and tumor suppressor genes.

According to research, up to 20% of intrahepatic bile duct cancers display Isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 mutations. Fibroblast growth factor receptor (FGFR) gene fusion and translocation has also been discovered in around 13% to 17% of intrahepatic bile duct cancers.

Changes in the proto-oncogene, such as KRAS, have been shown to be more prevalent in distal and perihilar cholangiocarcinoma than in intrahepatic cholangiocarcinoma, at 42 percent and 22 percent, respectively. Overexpression and mutation of the epidermal growth factor receptor (EGFR) have been observed in both intrahepatic (iCCA) and extrahepatic cholangiocarcinoma (dCCA/pCCA), with EGFR overexpression being more common in intrahepatic cholangiocarcinoma (11-27%) compared to distal and perihilar type (5-19%).

Furthermore, most epithelial cancers, including cholangiocarcinoma (CCA), have a faulty signaling pathway including RAS/RAF/MEK and the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK).

Cyclin dependent kinase inhibitor 2A (CDKN2A) has recently been identified in a significant amount of intrahepatic cholangiocarcinoma (iCCA), i.e. 45 percent.

Symptoms

Cholangiocarcinoma is generally asymptomatic in the early stages. It can present with obstruction of the biliary tract by malignant cellular growth as:

Abdominal pain or heaviness (typically in the right upper quadrant)
Jaundice
Generalized itching
Fever
Weight loss
Generalized malaise
Changes in the color of stool and urine.

Diagnosis

Keeping the clinical manifestations in mind, it is critical to do a complete physical examination, blood testing, and imaging to determine the origin of the sign and symptoms.

Diagnostic evaluation is dependent both on laboratory and imaging tests, which includes:

Blood Tests

Serum levels of certain enzymes and proteins that aid in the monitoring of liver disease or damage, also known as liver function tests, include aspartate aminotransferase (AST), alanine aminotransferase (AST), bilirubin, as well as biliary tract excreted products such as bile salts, gamma glutamyl transpeptidase (GGT), and alkaline phosphatase (ALP).

Imaging

Abnormal liver function tests are not unique to biliary tract cancer since they are found in a wide spectrum of liver disorders. As a result, imaging is critical in the diagnosis, staging, and therapy of individuals who have a cholestatic pattern on first laboratory testing.

Ultrasonography and CT scans are still the first imaging modalities used in patients with biliary tract obstruction symptoms to evaluate the architecture and location of the tumor. Direct bile duct imaging is frequently required, which can be accomplished by an invasive surgery known as endoscopic retrograde cholangiopancreatography (ERCP) or a non-invasive magnetic resonance cholangiopancreatography (MRCP) (MRCP).

Endoscopic retrograde cholangiopancreatography (ERCP) can also include endoscopic ultrasonography (USG). Endoscopic retrograde cholangiopancreatography (ERCP) enables for both diagnostic and therapeutic measures such as biopsy sample collection and stent insertion. A biopsy sample is collected during endoscopic ultrasonography through fine-needle aspiration for tissue diagnosis, or a percutaneous biopsy might be done.

CK7 and CK19 are the two most prevalent tumor markers that distinguish cholangiocarcinoma from other gastrointestinal cancers and are positive in both extrahepatic and intrahepatic cholangiocarcinoma. Although the most commonly used immunohistochemical stains, such as carcinoembryonic antigen (CEA) and cancer antigen (CA) 19-9, are frequently elevated in malignant biliary disease, they are neither sensitive nor specific enough to be used as a general screening tool for cholangiocarcinoma diagnosis.

Management

Respectable (Localized) Bile Duct Cancer

The only way to treat localized intrahepatic and extrahepatic bile duct cancers is by surgical excision. Prior to surgery, a physical and radiological examination should be performed to determine the size and anatomic position of the tumor, the involvement of vascular and lymph nodes, and the existence of metastatic illness.

Surgical exploration by laparoscopy may be required to appropriately stage the tumor. Surgical resection can effectively cure extrahepatic cholangiocarcinoma. Perihilar cholangiocarcinoma, also known as Klatskin tumor, is a subtype of extrahepatic cholangiocarcinoma that may necessitate significant surgical resection, including excision of a portion of the liver and extrahepatic bile duct. The objective is to remove all tumors from the margins.

The extent of liver resection depends upon the extent of involvement of the liver parenchyma. The distal subtype of extrahepatic cholangiocarcinoma, which may involve the pancreatic duct can be surgically managed with a pancreaticoduodenectomy (Whipple's procedure). Liver transplantation in the setting of cholangiocarcinoma is controversial.

Traditionally, liver transplantation would be performed after surgical removal of the intrahepatic cholangiocarcinoma in some patients for a better outcome, but a series of studies revealed that the 5-year survival rate increased only in a subset of patients with hepatic cirrhosis and early intrahepatic cholangiocarcinoma.

In patients with resected tumors, post-treatment monitoring involves CT-scan imaging to look for any biliary system abnormalities that may have occurred after surgery.

The National Comprehensive Cancer Network guidelines for a resected tumor with a negative margin R0 and negative regional nodes advocate no chemotherapy or radiation treatment, either alone or in combination. Adjuvant 5-fluorouracil (5-FU)-based chemoradiation treatment is recommended for patients with resected cholangiocarcinoma but positive margins or lymph node involvement.

Advanced and Unresectable Tumors

Advanced stage of tumor The following treatment options are evaluated at the time of diagnosis, including metastatic and recurring bile duct malignancies, or in patients who do not qualify for surgery.

Chemotherapy
Palliative therapy
Immunotherapy
Molecular targeted therapy

Chemotherapy may be considered for patients with advanced tumor stages or unresectable tumors. According to studies based on phase III and phase II clinical trials utilizing gemcitabine alone and in combination with cisplatin, the gemcitabine/cisplatin combination outperformed gemcitabine monotherapy.

Palliative treatments such as systemic chemotherapy with first line medical therapy involving gemcitabine and cisplatin, other gemcitabine-based regimens, second line medical therapy supported by clinical trials involving fluoropyrimidines are used in the majority of patients who are not surgical candidates for tumor resection. FOLFOX chemotherapy has been associated with improved survival outcomes, biliary drainage with endoscopic or percutaneously placed stents to relieve symptoms associated with cholestasis, and in patients who have persistent symptoms of biliary tract obstruction despite stent placement, fluoropyrimidine plus oxaliplatin is a treatment option, while recent studies have shown fluorouracil (FU) based combination therapies with improved outcomes.

Radiofrequency ablation, radioembolization, photodynamic therapy (PDT), proton beam therapy (PBT), hepatic arterial infusion chemotherapy (HAIC), trans-arterial chemoembolization, and stereotactic radiation are further non-surgical therapeutic options. The objective is to improve these patients' quality of life.

Recent research suggests that medicines targeting targetable mutations should be evaluated in people with incurable malignancies. With the passage of time, more information regarding these targeted molecular medicines has become available. As previously stated, intrahepatic bile duct tumors express isocitrate dehydrogenase (IDH) genes – IDH1 and IDH2 gene mutations; however, a phase I clinical trial of ivosidenib, a selective and reversible MIDH1 inhibitor drug, has demonstrated anti-oncogenic properties with a better outcome and safety profile.

Cholangiocarcinoma has also been reported to contain fusion and translocation of the fibroblast growth factor receptor (FGFR) gene. In individuals with advanced unresectable malignancies, fibroblast growth factor inhibitor techniques can increase survival chances. Such medications are still being evaluated for targeted treatment against biliary tract cancer, with positive findings predicted. A therapeutic experiment employing valproic acid yielded encouraging benefits in a group of 12 individuals, but additional research is required.

In a group of 28 patients with unresectable biliary tract cancer, ongoing clinical studies employing target treatment against the downstream effectors of KRAS mutation RAF and MEK have exhibited anti-tumor effectiveness. BRAF and RAF inhibitor combinations are still being studied. Bevacizumab, an anti-vascular endothelial growth factor receptor (VEGF) antibody, has been studied in conjunction with GEMOX (gemcitabine plus oxaliplatin) and has showed encouraging results. Clinical studies are required for further assessment. Furthermore, erlotinib, a tyrosine kinase inhibitor that inhibits the epidermal growth factor receptor by attaching to its ATP binding site, has demonstrated clinical efficacy when combined with bevacizumab (anti-VEGF).

Patients with unresectable advanced-stage cancers may undergo molecular testing for microsatellite instability or a malfunctioning mismatch repair mechanism. Those with malignancies with a defective mismatch repair system (dMMR) or high microsatellite instability (MSI-H) may be candidates for pembrolizumab therapy, which targets the programmed cell death protein 1. (PD1).

Differential Diagnosis

Hepatocellular carcinoma
Metastatic liver cancer
Gallbladder adenomas
IgG4 related sclerosing cholangitis
Gallbladder polyps
Gallbladder adenomyomatosis
Pancreatic cancer

Staging

Staging the tumor is necessary to address issues such as surgical resectibility, which is determined by the tumor's size and anatomical location, the extent of the tumor, the involvement of structures such as blood vessels and lymph nodes, assessment of the direct involvement of the surrounding organs, and whether the tumor is advanced enough for surgical treatment.

The TNM classification and staging of intrahepatic cholangiocarcinoma (IHCC) are as follows, according to the American Joint Committee on Cancer (AJCC):

Primary tumor

pTx - Primary tumor cannot be assessed

pT0 - No evidence of primary tumor

pTis - Carcinoma in situ (intraductal tumor)

pT1 - Solitary tumor without vascular invasion, ≤5 cm or >5cm

pT1a - Solitary tumor ≤5 cm without vascular invasion

pT1b - Solitary tumor >5 cm without vascular invasion

pT2 - Solitary tumor with intrahepatic vascular invasion, or multiple tumors with or without vascular invasion

pT3 - Tumor perforating the visceral peritoneum

pT4 - Tumor involving local extrahepatic structures by direct invasion

Regional Lymph Nodes

Nx - Regional lymph nodes cannot be assessed

N0 - No regional lymph nodes metastasis

N1 - Regional lymph nodes metastasis present

Distant metastasis

M0 - No distant metastasis

M1 - Distant metastasis present

Stage 0: Tis, N0, M0:
Stage IA: T1a, N0, M0:
Stage IB: T1b, N0, M0: =
Stage II: T2, N0, M0:
Stage IIIA: T3, N0, M0:
Stage IIIB: T4, any N, M0; or any T, N1, M0;
Stage IV: Any T, Any N, M1

For extrahepatic cholangiocarcinoma, several staging systems including Bismuth-Corlette system, American joint committee for cancer (AJCC), and Memorial Sloan-Kettering cancer center clinical staging system (MSKCC) have been proposed all of them with some modifications in the T-staging.

For Perihilar (Klatskin tumor) cholangiocarcinoma:

Primary tumor (T)

pTx - Primary tumor cannot be assessed

pT0 - No evidence of primary tumor

pTis - Carcinoma in situ / high-grade dysplasia

pT1 - Tumor confined to the bile duct, with extension up to the muscle layer or fibrous tissue

pT2 - Tumor invades beyond the wall of the bile duct to surrounding adipose tissue, or tumor invades adjacent hepatic parenchyma

pT2a - Tumor invades beyond the wall of the bile duct to surrounding adipose tissue

pT2b - Tumor invades adjacent hepatic parenchyma

pT3 - Tumor invades unilateral branches of the portal vein or hepatic artery

pT4 - Tumor invades the main portal vein or its branches bilaterally or the common hepatic artery; or unilateral second-order biliary radicals with contralateral portal vein or hepatic artery involvement

Regional lymph nodes (N)

Nx - Regional lymph nodes cannot be assessed

N0 - No regional lymph node metastasis

N1 - One to three positive lymph nodes typically involving the hilar, cystic duct, common bile duct (choledochal), hepatic artery, posterior pancreatoduodenal and portal vein lymph nodes

N2 - Four or more positive lymph nodes from the sites described for N1

Distant metastasis (M)

M0 - No distant metastasis

M1 - Distant metastasis

Stage 0: Tis N0 M0;
Stage I: T1 N0 M0;
Stage II: T2a-b N0 M0;
Stage IIIA: T3 N0 M0;
Stage IIIB: T4 N0 M0;
Stage IIIC: any T N1 M0;
Stage IVA: any T N2 M0;
Stage IVB: any T any N M1

For distal cholangiocarcinoma:

Primary tumor

pTx: Primary tumor cannot be assessed

pTis: Carcinoma in situ/high-grade dysplasia

pT1: Tumor invades the bile duct wall with a depth less than 5 mm

pT2: Tumor invades the bile duct wall with a depth of 5-12 mm

pT3: Tumor invades the bile duct wall with a depth greater than 12 mm

pT4: Tumor involves the celiac axis, superior mesenteric artery, and/or common hepatic artery

Regional lymph nodes

Nx - Regional lymph nodes cannot be assessed

N0 - No regional lymph nodes metastasis

N1 - Regional lymph nodes metastasis present

Distant metastasis

M0 - No distant metastasis

M1 - Distant metastasis present

Stage 0: Tis N0 M0;
Stage I: T1 N0 M0;
Stage II: T1, N0, M0;
Stage IIA: T1 N1 M0 or T2 N0 M0;
Stage IIB: T2 N1 M0 or T3 N0-1 M0;
Stage IIIA: T1-3 N2 M0;
Stage IIIB: T4 N0-2 M0;
Stage IV: Any T, Any N, M1

Prognosis

Biliary tract cancer has the poorest prognosis due to late detection and limited therapy choices, with a median survival of less than 2 years and a survival rate of fewer than 10%.

Despite the use of several chemotherapeutic medicines in the treatment of unresectable tumors, the overall median survival remains one year, showing the tumor's fatal character. Surgery is the sole viable therapy for early-stage cancer, with post-surgery survival influenced by criteria such as margin status, involvement of adjacent tissues, and metastasis.

Complications

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

Chemotherapy Side Effects

Hematological problems include low white-cell count, low platelet count, and low hemoglobin. Alopecia, anorexia, nausea, lethargy, vomiting, impaired liver functions, decreased renal functions, infections with or without neutropenia, biliary sepsis, and other non-hematological problems might occur.

Post-surgery Complications

Sepsis, respiratory failure, hepatic failure, thromboembolic events, intra-abdominal abscess, wound infection, hemorrhage, DVT, biliary leakage, tumor recurrence.

Radiotherapy Complications

Generalized fatigue, nausea, vomiting, fever.

Conclusion

Biliary tract cancer is a kind of cancer that develops in the cells of the bile ducts, gallbladder, or Vater's ampulla. Cholangiocarcinoma of the bile ducts is classed as intrahepatic (affects bile ducts within the liver), hilar (occurs at the intersection of the left and right hepatic ducts), and extrahepatic (affects bile ducts outside the liver) (affects the common bile duct outside the liver).

Gallbladder cancer begins in the gallbladder's cells. Ampullary cancer begins in the ampulla of Vater, which connects the bile ducts of the liver and pancreas and enters the duodenum.