INTRODUCTION

Cholangiocarcinoma (CCA) is an uncommon and severe cancer originating from the epithelial cells of the bile ducts, which transport bile from the liver to the gallbladder and small intestine [1]. The disease is marked by a difficult diagnosis, frequently identified in advanced stages, and typically has a dismal prognosis. The tumor can arise in any segment of the biliary route, resulting in specific clinical symptoms dependent on its location. Intrahepatic cholangiocarcinomas are occasionally categorized as a form of liver cancer [2-4]. Perihilar and distal cholangiocarcinomas are sometimes known as extrahepatic bile duct malignancies. Histologically, about 90% of cholangiocarcinomas are classified as adenocarcinomas [5]. They may range from well-differentiated to undifferentiated tumors. Cholangiocarcinomas are frequently enclosed in a fibrotic or desmoplastic tissue response, complicating the differentiation between well-differentiated tumors and typical reactive epithelium [6]. Cholangiocarcinoma is an uncommon malignancy, impacting around 8,000 individuals annually in the United States. It predominantly occurs in elderly persons, with peak prevalence at approximately 70 years of age. Cholangiocarcinoma exhibits greater prevalence in Southeast Asia, where it is linked to persistent liver fluke infections [7-10].

Cholangiocarcinoma, a neoplasm originating from the bile ducts, is categorized according to its anatomical site, histological properties, and molecular attributes. The principal categories consist of the following:

Anatomical Categorization

The anatomical categories of cholangiocarcinoma are provided as follows: Intrahepatic cholangiocarcinoma (iCCA): It arises from the bile ducts located within the liver.

Perihilar cholangiocarcinoma (pCCA): It arises at the confluence of the left and right hepatic ducts, sometimes referred to as Klatskin tumors.

Distal cholangiocarcinoma (dCCA): It originates from the bile ducts external to the liver, next to the small intestine [11].

Histological Categorization

The histological categorization of the disease is described as follows:

Adenocarcinoma: It is the predominant form, characterized by glandular features or mucin-secreting cells.

Other variations: These include squamous cell carcinoma, adenosquamous carcinoma, and sarcomatoid variations [12-14] (Fig. 1).

Molecular and Genetic Classification

Cholangiocarcinomas can be categorized according to their molecular profiles, which may inform targeted therapy [15]. Illustrations encompass IDH1 and IDH2 mutations that are prevalent in intrahepatic cholangiocarcinoma, FGFR2 fusions, mutations in the KRAS gene and BRAF mutations [16].

TNM Staging

The dimensions and scope of the primary neoplasm are classified under tumor (T), which describes the size and extent of the tumor. The involvement of regional lymph nodes is categorized under node (N), indicating the presence or absence of lymph node metastasis. Metastasis (M) refers to the dissemination of cancer cells to distant organs, assessing whether the cancer has spread beyond the original site. Every classification provides an insight into prognosis, therapeutic approach, and possible reaction to specific treatments [17].

Intrahepatic cholangiocarcinoma (ICC) is an uncommon, yet increasingly identified primary liver malignancy, representing 10-20% of all cholangiocarcinomas [18]. A systematic review and meta-analysis of data from various countries indicated a global increase in the incidence rates of ICC and extrahepatic cholangiocarcinoma (ECC) over the last two decades. Significant increases were observed in countries with historically low incidence rates, including various European nations and Australia. In contrast, countries, such as Thailand, demonstrated a nonsignificant reduction in ICC incidence [19]. Numerous meta-analyses have pinpointed significant risk factors for CCA. A study indicated that obesity correlates with an increased risk of developing CCA. Furthermore, viral hepatitis is recognized as a notable risk factor, supported by a meta-analysis demonstrating an elevated risk of CCA in individuals with chronic hepatitis B or C infections [20]. Extensive research has been conducted on prognostic factors influencing overall survival in patients with resected hilar cholangiocarcinoma. A meta-analysis of 24 studies encompassing 4,599 patients revealed several significant prognostic indicators: age, tumor category (T stage), lymph node involvement, microvascular invasion, perineural invasion, and tumor differentiation. These studies emphasize the global burden of CCA and the necessity of identifying modifiable risk factors and prognostic indicators to enhance patient outcomes. The global prevalence has increased over the past few decades, especially in Southeast Asia, where liver fluke infections, such as Opisthorchis viverrini and Clonorchis sinensis, are endemic and recognized as risk factors. Additional significant risk factors for intrahepatic cholangiocarcinoma (ICC) encompass chronic liver diseases, including cirrhosis, hepatitis B and C infections, and non-alcoholic fatty liver disease (NAFLD). Conditions that induce chronic biliary inflammation, including primary sclerosing cholangitis (PSC), choledochal cysts, and hepatolithiasis, further elevate the risk. Moreover, environmental exposures to toxins, such as thorotrast, and genetic alterations in IDH1, IDH2, and FGFR2, have been associated with its development. The diagnosis of intrahepatic cholangiocarcinoma (ICC) generally necessitates a combination of imaging studies, laboratory analyses, and histopathological verification. Preliminary imaging techniques, such as ultrasound, computed tomography (CT), or contrast-enhanced magnetic resonance imaging (MRI), are employed to assess the tumor's features and scope [21]. The MRI with MRCP (magnetic resonance cholangiopancreatography) is especially effective in elucidating the biliary tree. Tumor markers, such as increased serum CA 19-9 and carcinoembryonic antigen (CEA), can assist in diagnosis, but they are not specific. A conclusive diagnosis typically necessitates a biopsy, frequently conducted with imaging guidance [22-25]. Clinical staging adheres to the TNM (tumor-node-metastasis) approach, which evaluates tumor dimensions and extent (T), lymphatic node involvement (N), and distant metastasis (M). ICC is often classified as localized, locally progressed (including nearby organs or blood vessels), or metastatic, with prognosis being worse as the stage progresses [26].