The biliary tract comprises of gallbladder and intra and extrahepatic biliary tree. Bile is directed through these ducts to the second part of duodenum at major duodenal papilla. The epithelium of the biliary tract is lined with cells called cholangiocytes. Carcinoma of the biliary tract arises from the malignant transformation of the epithelium of the bile ducts which is made up of these cholangiocytes, and is categorized on the basis of its anatomical location as; 1) Intrahepatic cholangiocarcinoma 2) Extrahepatic cholangiocarcinoma, which includes; perihilar tumor also known as Klatskin tumor (originating from the epithelium of the bile duct at the junction of right and left hepatic ducts with the cystic duct where it forms the common bile duct) and distal cholangiocarcinoma outspreading to encompass the gallbladder, ampulla of Vater and pancreatic biliary ducts. [1][2]
Although both intrahepatic and extrahepatic cholangiocarcinoma arises from the same epithelium of the bile duct, the pathogenesis and clinical outcomes of extrahepatic cholangiocarcinoma differs from that of intrahepatic cholangiocarcinoma on the basis of different anatomical location. [2]
Cholangiocarcinoma is considered as one of the rare but most aggressive tumors with a very poor prognosis because mostly, it is advanced and unresectable by the time it is diagnosed. Late presentation of the tumor in many cases has already caused the extensive involvement of the blood vessels and the regional lymph nodes that curative surgical resection becomes a challenge. Although rare, it represents the second most common type of primary liver malignancy following hepatocellular carcinoma. [3]
Chronic inflammatory conditions predispose the biliary tract epithelium to modify under stress and undergo transformation that give rise to the cancer of the biliary tract. The most established chronic inflammatory condition associated with biliary tract cancer is primary sclerosing cholangitis (PSC), which is associated with chronic inflammatory bowel disease, particularly ulcerative colitis. Besides primary sclerosing cholangitis, other conditions that carries a high risk for the development of cholangiocarcinoma by causing chronic inflammation and cholestasis are 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 infection withand some congenital biliary tract malformations (e.g. caroli’s disease, choledochal cysts) are also associated with the risk of developing cholangiocarcinoma. [4] The most common etiological factors associated with gallbladder cancer are chronic inflammation of the gallbladder, cholelithiasis, porcelain gallbladder, gallbladder polyps, congenital gallbladder cysts. Other factors that may be associated with cholangiocarcinoma are obesity, smoking, alcohol, and type 2 diabetes. [4] [5]
Cholangiocarcinoma has an annual incidence ranging from 0.72 to 1.62 per 100,000 individuals recorded in the U.S. Although this incidence varies in different countries, as an increase in the number of cases is reported worldwide. With a rate of more than 80 per 100,000 individuals, Northeast Thailand (Asia) is noted to have the highest incidence of the disease, most likely due to chronic infection with hepatobiliary flukes. [4] [2]
Over the past several decades, multiple studies have documented a steady growth in the incidence of intrahepatic cholangiocarcinoma. Multiple factors have been recorded as to the reason for this rise, preceding the chronic inflammation and irritation of the biliary tract epithelium. The incidence also increases with age, and it is slightly more common in men than in women, possibly because of the higher rate of primary sclerosing cholangitis in men at age 40 or even younger, which is documented as a risk factor to developing cholangiocarcinoma. [2]
The epithelium of the biliary tract under chronic irritation and inflammation goes through a series of changes that are similar to the changes predisposing to other gastrointestinal cancers, i.e., from hyperplasia to metaplasia and dysplasia, finally to carcinoma, which involves mutations in different oncogenes and tumor suppressor genes. [6]
Studies have shown that up to 20% of intrahepatic bile duct tumors express Isocitrate dehydrogenase (IDH) genes – IDH1 and IDH2 genes mutations. Fibroblast growth factor receptor (FGFR) gene fusion and translocation have also been found in about 13% to 17% of intrahepatic bile duct tumors. [7]
In contrast, perihilar and distal cholangiocarcinoma (pCCA and dCCA) have shown to express fusion genes involving PRKACA and PRKACB and catalytic subunits of the protein kinase A. On the other hand, 8-9% of cholangiocarcinoma exhibit ROS1 gene fusions. The tumor suppressor gene Tumor protein 53 (Tp53) mutation, has been found to occur in about 40% of perihilar (pCCA) and distal cholangiocarcinoma (dCCA) while in 25% of intrahepatic cholangiocarcinoma (iCCA). Alteration in the proto-oncogene e.g. KRAS have been identified with more prevalence in distal and perihilar cholangiocarcinoma as compared to intrahepatic cholangiocarcinoma. i.e. 42% and 22% respectively. Overexpression and mutation of epidermal growth factor receptor (EGFR) have been studied to occur in both intrahepatic (iCCA) and extrahepatic cholangiocarcinoma (dCCA/pCCA), with overexpression of EGFR more prevalent in intrahepatic cholangiocarcinoma i.e., 11-27% as compared to distal and perihilar type i.e., 5-19%. Furthermore, most of the epithelial tumors, including cholangiocarcinoma (CCA) are frequently reported to have a defective signaling pathway involving RAS/RAF/MEK and the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway. [5]
Cyclin dependent kinase inhibitor 2A (CDKN2A) have been reported recently in a considerable quantity of intrahepatic cholangiocarcinoma (iCCA), i.e. 45%. [8]
Traditionally, cholangiocarcinoma was histologically classified as poorly differentiated or well-differentiated adenocarcinoma: gland forming or tubular, squamous, mucinous, signet cells, and some other rare variants of the tumor.
The American Joint Committee for Cancer (AJCC) modified this classification from simply well-differentiated to poorly differentiated carcinoma on the histological basis to:
Cholangiocarcinoma is generally asymptomatic in the early stages. It can present with obstruction of the biliary tract by malignant cellular growth as:
Keeping in sight the clinical manifestations, it is essential to carry out a thorough physical examination, blood tests and imaging to look for the cause 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 help monitor the liver disease or damage otherwise known as liver function tests which includes; Aspartate aminotransferase (AST), alanine aminotransferase (AST), bilirubin, as well as biliary tract excreted products as bile salts, gamma glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP). [10]
Imaging
Abnormal liver function tests are not specific to biliary tract carcinoma as it is present in a wide range of diseases involving the liver. Therefore, imaging plays a vital role in the diagnosis, staging and management of the patients having cholestatic pattern on the initial laboratory tests. [10]
Ultrasonography and CT scan remains the initial imaging modality performed in patients with symptoms of biliary tract obstruction to determine the anatomy and location of the tumor. Direct bile duct visualization is often necessary, which is carried out with an invasive procedure called endoscopic retrograde cholangiopancreatography (ERCP) or a non-invasive magnetic resonance cholangiopancreatography (MRCP). Endoscopic ultrasonography (USG) can also be performed during endoscopic retrograde cholangiopancreatography. Endoscopic retrograde cholangiopancreatography (ERCP) allows both diagnostic and therapeutic interventions like taking of a biopsy sample and stent placement, respectively. For tissue diagnosis, a biopsy sample is taken while performing endoscopic ultrasonography via fine-needle aspiration, or a percutaneous biopsy could be performed.[11]
The two most common tumor markers that differentiate cholangiocarcinoma from other gastrointestinal tumors and are positive in both extrahepatic and intrahepatic cholangiocarcinoma are CK7 and CK19. [4] Although the most frequently used immunohistochemical stains such as carcinoembryonic antigen (CEA) and cancer antigen (CA) 19-9 are often elevated in malignant biliary disease, but they are neither sensitive nor specific enough to be used as a general screening tool in the diagnosis of cholangiocarcinoma. [6]
Resectable (Localized) Bile Duct Cancer
Surgical resection remains the only possible chance of cure for the localized intrahepatic and extrahepatic bile duct tumors. Assessment of the patient on the basis of physical and radiological examination should be carried out prior to surgery, which includes the size and anatomic location of the tumor, vascular, and lymph nodes involvement and the presence of metastatic disease. [12]
For the purpose of staging the tumor adequately, surgical exploration via laparoscopy may be necessary. Extrahepatic cholangiocarcinoma can be treated effectively with surgical resection. The perihilar cholangiocarcinoma is a subtype of extrahepatic cholangiocarcinoma, also known as Klatskin tumor may need extensive surgical resection, which may involve the resection of a part of the liver and extrahepatic bile duct. The goal is to render the margins tumor-free. [3] 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 follow the surgical removal of the intrahepatic cholangiocarcinoma in some patients for a better outcome, but a series of studies showed that the 5-year survival rate only increased in a subset of patients with hepatic cirrhosis and early intrahepatic cholangiocarcinoma. [13]
Post-treatment surveillance in patients with resected tumors includes imaging with CT-scan to assess for any biliary tract abnormality following surgery. [3]
The National Comprehensive Cancer Network (NCCN) guidelines for a negative margin R0 and negative regional nodes resected tumor recommends no chemotherapy or radiation therapy, alone or in combination. In patients with resected cholangiocarcinoma but positive margins or lymph node involvement, adjuvant 5-fluorouracil (5-FU) based chemoradiation therapy is suggested. [14] [7]
Advanced and Unresectable Tumors
Advanced tumor stage at the time of diagnosis, including metastatic and recurrent bile duct cancers, or in patients who do not fit as surgical candidate, the following treatment options are considered.
Chemotherapy is considered in patients with advanced tumor stage or unresectable tumors. Studies based on phase III and phase II clinical trials, involving gemcitabine alone and in combination with cisplatin have shown better results in gemcitabine/cisplatin combination as compared to gemcitabine monotherapy. [15]
In most individuals who are not surgical candidates for tumor resection, palliative treatments such as; systemic chemotherapy with first line medical therapy involving gemcitabine and cisplatin, other gemcitabine based-regimen, second line medical therapy supported by clinical trials involving fluoropyrimidine FOLFOX chemotherapy associated with better 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 studies in recent years have shown fluorouracil (FU) based combination therapies with better outcomes. [15] Other non-surgical treatment options include radiofrequency ablation, radioembolization, photodynamic therapy (PDT), proton beam therapy (PBT), hepatic arterial infusion chemotherapy (HAIC), trans-arterial chemoembolization and stereotactic radiotherapy. The goal is to improve the quality of life in such patients. [15] [7]
Patients with unresectable advanced stage tumors should consider molecular testing for microsatellite instability or a deficient mismatch repair system. Those with deficient mismatch repair system (dMMR) or high microsatellite instability (MSI-H) tumors can be considered for treatment with pembrolizumab therapy, which is directed against the programmed cell death protein 1 (PD1). [7]
Staging of the tumor is necessary to address issues like the surgical resectibility of the tumor, which depends upon the size and anatomical location of the tumor, the extent of the tumor, structures such as blood vessels and lymph nodes involvement, assessment of the direct involvement of the surrounding organs and whether the tumor is advanced enough for surgical treatment.
Previously, for intrahepatic cholangiocarcinoma, the Union for International Cancer Control (UICC)-TNM classification system of malignant liver tumors was applied, which differed from the UICC-TNM classification of the extrahepatic cholangiocarcinoma and gallbladder carcinoma. However, with the rise in the incidence of intrahepatic cholangiocarcinoma and given the fact that it arises from the malignant transformation of the cholangiocytes or progenitor cells which in either case have distinct histological and biological characteristic features from hepatocellular carcinoma, the American Joint Union on Cancer/Union for International Cancer Control (AJCC/UICC) recognized intrahepatic cholangiocarcinoma as a separate entity and was assigned a different TNM staging than malignant liver tumors.
According to the American joint committee of cancer (AJCC), the intrahepatic cholangiocarcinoma (IHCC) TNM classification and staging include:[10][7]
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.
The AJCC staging and classification for extrahepatic (EHCC) includes;
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
Due to late diagnosis and limited therapeutic options, biliary tract cancer has the worst prognosis with a median survival less than 2 years and a survival rate less than 10%. [5]
Although various chemotherapeutic agents are used in the treatment of unresectable tumors, the overall median survival remains only one year indicating the lethal nature of the tumor. Surgery provides the only potential cure for early-stage cancer, with post-surgery survival depending on factors as; margin status, the involvement of the surrounding structures, and metastasis.[5]
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. [19][20][21]
Health care professionals dealing with patients of the biliary tract cancer must keep in mind that educating the patient and family regarding the physical and medical status of the patient is very necessary. Patient and family should be provided information about the diagnosis, disease progression, prognosis, status of the patient, both preoperatively and postoperatively. Complications of the surgery should be explained as well.
In the event that the tumor is advance enough to be unresectable or the patient is not a candidate for surgery, details must be provided by the health care professionals about the disease, its prognosis, its effects on the mental and physical health of the patient, details of the treatments other than surgery, their complications and how to manage these complications. A comprehensive approach that covers the patient's emotional, social, physical, and mental health should be taken. [22]
An interprofessional approach is needed to deal with patients with biliary tract cancer, which includes a team of oncologists, radiologists, gastroenterologists, and experienced surgeons to manage such challenging tumors. Tumors that are not advanced can be treated with surgical resection. For unresectable tumors, multiple treatment approaches are available such as chemotherapy, radiation therapy, palliative treatment, targeted molecular therapy, and immunotherapy. Recent clinical studies and data suggests promising results of immunotherapy and targeted molecular therapy. [7][15]
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