Gallbladder cancer is the most common anatomic subtype of biliary tract cancer (BTC), arising from the epithelial lining of the gallbladder [MS-3]. The vast majority of gallbladder cancers are adenocarcinomas [MS-3]. The disease is characterized by local and vascular invasion, regional lymph node metastasis, and distant metastases [MS-3]. Gallbladder cancer is frequently diagnosed at an advanced stage due to its asymptomatic early course and presentation mimicking benign biliary conditions; it is often discovered incidentally at cholecystectomy for presumed benign disease or on pathologic review [MS-4]. Clinically, patients may present with biliary obstruction and jaundice, chronic right upper quadrant pain, or a suspicious mass on imaging. The presence of jaundice portends a poor prognosis, with advanced disease in 96% of such cases and significantly lower disease-specific survival [MS-4]. Embryologically, the gallbladder derives from the foregut endoderm, and the cancer typically arises in the fundus, body, or neck of the gallbladder. Anatomically, the gallbladder is a pear-shaped organ beneath the liver; its proximity to the liver and biliary tree facilitates direct invasion and spread. Staging is based on tumor depth (T1–T4), nodal involvement (N0–N2), and distant metastasis (M0–M1) per AJCC 8th edition [ST-1].

The predominant histologic type of gallbladder cancer is adenocarcinoma, accounting for the vast majority of cases [MS-3]. Other rare histologies include neuroendocrine tumors, sarcomas, and squamous cell carcinomas; however, these are not staged as gallbladder carcinoma and should be managed according to relevant NCCN Guidelines for those tumor types [GALL-B]. Within adenocarcinoma, there are no standardized molecular subtypes recognized for routine clinical use, but molecular profiling reveals distinct genomic alterations (see molecular pathogenesis). Pathologic staging parameters include carcinoma in situ/high-grade dysplasia, tumor depth of invasion (T stage), number of regional lymph nodes involved (N stage), and distant metastasis (M stage) [GALL-B]. Histologic differentiation (well, moderate, poorly differentiated) is reported but not subtype-specific. The incidence of microsatellite instability-high (MSI-H) is approximately 1%–3% [BIL-B 3/8]. Gallbladder cancers with MSI-H are more prevalent in patients with chronic cholecystitis or pancreaticobiliary maljunction [MS-3].

Genomic analysis of gallbladder cancer has identified clinically relevant alterations, though the landscape is less well characterized than that of cholangiocarcinoma. HER2 (ERBB2) overexpression/amplification is present in approximately 15%–30% of gallbladder cancers [BIL-B 3/8; MS-30]. Activating mutations in BRAF V600E occur in 1%–5% of cases [BIL-B 3/8]. FGFR2 gene fusions and IDH1 mutations are rare in gallbladder cancer but testing may be considered in select cases [BIL-B 2/8]. NTRK1/2/3 gene fusions are exceedingly rare (<1%) [BIL-B 3/8]. MSI-H/dMMR is found in 1%–3% of tumors, and TMB-H in <5% [BIL-B 3/8]. KRAS G12C mutations occur in approximately 1% of gallbladder cancers [BIL-B 3/8]. RET gene fusions are also rare (<1%) [BIL-B 3/8]. The genomic profile suggests potential for targeted therapy with agents approved in other tumor types, such as trastuzumab-based combinations for HER2-positive disease, dabrafenib/trametinib for BRAF V600E, and immune checkpoint inhibitors for MSI-H/dMMR or TMB-H tumors [BIL-C 3/5]. Germline pathogenic variants (e.g., BRCA2, BRCA1, MLH1, MSH2) are found in approximately 9%–11% of BTC patients, with gallbladder cancer included in these studies [BIL-B 1/8].

In the United States, an estimated 12,610 new cases of gallbladder cancer and other biliary tract cancers are expected in 2025, with approximately 4,400 deaths [MS-2]. Gallbladder cancer is the most common anatomic subtype of BTC [MS-3]. Incidence increases steadily with age, and females are more likely to be diagnosed than males [MS-3]. Incidence and mortality rates are highest among American Indian, Alaska Native, and Asian/Pacific Islander populations [MS-3]. From 1973 to 2015, the incidence of gallbladder cancer decreased in both sexes, and in white, American Indian/Alaska Native, and Asian/Pacific Islander individuals, but showed a small trend toward increase in Black individuals [MS-3]. Globally, there are pockets of elevated incidence in Korea, Japan, parts of Eastern Europe, South America (especially Bolivia, Chile, Spain), and in females in India, Pakistan, and Ecuador [MS-3]. The 5-year overall survival for all stages is poor; median survival for the entire cohort of 435 patients at a single center was 10.3 months, with 12.9 months for stage IA–III and 5.8 months for stage IV [MS-3–MS-4]. Tumor stage is the strongest prognostic factor [MS-3].

The most prevalent risk factor for gallbladder cancer is cholelithiasis with chronic inflammation; risk increases with stone size [MS-3]. Calcification of the gallbladder wall (porcelain gallbladder), a consequence of chronic inflammation, has historically been associated with elevated risk, with cancer present in 7%–15% of such patients [MS-3]. Other established risk factors include anomalous pancreaticobiliary duct junction, gallbladder polyps >1 cm, chronic typhoid infection, primary sclerosing cholangitis (PSC), inflammatory bowel disease (IBD), and adenomyomatosis of the gallbladder [MS-3]. Prophylactic cholecystectomy is considered beneficial for high-risk patients (e.g., porcelain gallbladder, polyps >1 cm) [MS-3]. Patients with a history of chronic cholecystitis or pancreaticobiliary maljunction have a greater prevalence of MSI-H gallbladder cancers [MS-3]. Risk factors are largely inflammatory in nature, and most gallbladder cancers are sporadic; however, up to 10%–15% of BTCs may be associated with an inherited cancer predisposition syndrome (e.g., BRCA2, BRCA1, Lynch syndrome) [BIL-B 1/8].

Intrahepatic cholangiocarcinoma (iCCA) is a primary liver cancer arising from the epithelium of the intrahepatic bile ducts within the hepatic parenchyma, also referred to as peripheral cholangiocarcinoma [MS-9; Figure 1]. It is a highly lethal malignancy, and its incidence has been rising dramatically in recent decades [MS-9]. iCCA accounts for approximately 10%–20% of primary liver cancers and is the second most common primary hepatic malignancy after hepatocellular carcinoma. More than 90% of iCCAs are adenocarcinomas [MS-9]. Morphologically, iCCA is classified into three growth patterns: mass-forming (most common), periductal-infiltrating, and intraductal-growing [MS-9; INTRA-C]. Histologically, iCCA is further categorized as small duct type or large duct type based on differentiation and cell morphology [INTRA-C]. The diagnosis is based on histologic confirmation demonstrating cholangiocyte differentiation, supported by immunohistochemistry and albumin in situ hybridization when necessary [INTRA-C]. iCCA typically presents with nonspecific symptoms such as fever, weight loss, abdominal pain, and is often detected as an isolated hepatic mass on imaging [MS-11]. Biliary obstruction is uncommon unless the tumor involves the hepatic hilum. Staging follows the AJCC 8th edition classification for intrahepatic bile duct tumors, which considers tumor number, size, vascular invasion, lymph node involvement, and distant metastasis [ST-2].

Intrahepatic cholangiocarcinoma is classified morphologically into mass-forming, periductal-infiltrating, and intraductal-growing types [MS-9]. The mass-forming type appears as a multinodular distinct mass with malignant glands in a sclerotic stroma and well-demarcated borders. Periductal-infiltrating type is characterized by poorly defined borders and a linear growth pattern along an intermediate or larger native bile duct [INTRA-C]. Intraductal-growing type is less common. Histologically, iCCA is divided into small duct type and large duct type based on differentiation and cytokeratin expression [INTRA-C]. Molecular subtypes are increasingly recognized: approximately 9%–15% of iCCAs harbor FGFR2 fusions/rearrangements, and 10%–20% have IDH1 mutations [BIL-B 3/8]. Other subtypes include those with BRAF V600E mutations (1%–5%), HER2 alterations (5%–20%), MSI-H (1%–3%), TMB-H (<5%), and rare NTRK fusions (<1%) [BIL-B 3/8]. Mixed HCC-CCA is a distinct entity (1%–10% of primary liver tumors) with both hepatocellular and cholangiocytic components [INTRA-B]. The subtype classification has therapeutic implications, as FGFR2 fusions and IDH1 mutations are actionable targets with approved therapies.

Intrahepatic cholangiocarcinoma harbors a distinct genomic landscape with frequent alterations in IDH1 (10%–20% of cases) and FGFR2 gene fusions/rearrangements (9%–15% of cases) [BIL-B 3/8]. These alterations are relatively specific to iCCA and rare in other biliary tract subsites. BRAF V600E mutations occur in 1%–5% of iCCA [BIL-B 3/8]. HER2 (ERBB2) overexpression/amplification is present in 5%–20% of iCCA [BIL-B 3/8]. Microsatellite instability-high (MSI-H) is found in 1%–3%, and TMB-high in <5% [BIL-B 3/8]. NTRK1/2/3 gene fusions are exceedingly rare (<1%) [BIL-B 3/8]. RET gene fusions are also rare (<1%) [BIL-B 3/8]. KRAS G12C mutations occur in approximately 1% of iCCA [BIL-B 3/8]. NRG1 gene fusions are identified in <1% of iCCA [BIL-B 3/8]. For mixed HCC-CCA, genomic profiling reveals a higher prevalence of TP53 and TERT promoter mutations, more commonly associated with HCC, particularly in patients with underlying hepatitis C virus infection [INTRA-B 1/2]. IDH1 mutations in iCCA most commonly occur at codon 132 (R132X) [BIL-B 5/8]. These genomic alterations define potential targets for therapy, including FGFR inhibitors (pemigatinib, futibatinib, erdafitinib), IDH1 inhibitor (ivosidenib), and others [BIL-C 3/5].

In the United States, intrahepatic cholangiocarcinoma (iCCA) is estimated to account for a significant proportion of the 42,240 new liver and intrahepatic bile duct cancer cases expected in 2025, with approximately 30,090 deaths attributed to liver/intrahepatic bile duct cancer [MS-2]. From 2001 to 2017, the incidence of iCCA increased dramatically by 148.8%, while extrahepatic CCA increased at a slower rate of 7.5% [MS-9]. The increase in incidence may be partly attributable to improved diagnostic accuracy [MS-9]. Five-year overall survival rates for iCCA improved from 1973 to 2008, likely due to advances in treatment [MS-9]. The median survival for patients with unresectable disease is poor; the ABC-02 trial showed median overall survival of 11.7 months with gemcitabine/cisplatin [MS-23]. iCCA occurs more frequently in patients with underlying liver disease, including cirrhosis, hepatitis B and C, and metabolic dysfunction-associated steatotic liver disease (MASLD) [MS-9–MS-10]. Racial and ethnic variation exists but specific incidence rates by demographic for iCCA alone are less commonly reported. The disease often presents at an advanced stage, with only 20%–30% of patients eligible for curative resection at diagnosis.

Risk factors for intrahepatic cholangiocarcinoma are associated with chronic inflammation and are similar to those for hepatocellular carcinoma. Strong risk factors include primary sclerosing cholangitis (PSC), hepatolithiasis (calculi of intrahepatic bile ducts), choledochal cysts, and liver fluke infections (Opisthorchis viverrini, Clonorchis sinensis) [MS-9]. Hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, cirrhosis, diabetes, obesity, alcohol use, and tobacco smoking are established risk factors for iCCA [MS-9]. A systematic review and meta-analysis identified biliary cysts/stones, cirrhosis, HBV, and HCV as the strongest risk factors for both intrahepatic and extrahepatic CCA [MS-9]. Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with increased incidence of iCCA (pooled adjusted OR 2.09; 95% CI 1.49–2.91) [MS-10]. Unlike gallbladder cancer, cholelithiasis is not considered a risk factor for iCCA [MS-9]. Inflammatory bowel disease may increase risk, although this association is confounded by PSC [MS-9].

Extrahepatic cholangiocarcinoma (eCCA) encompasses malignant tumors arising from the epithelium of the extrahepatic bile ducts, extending from the junction of the right and left hepatic ducts to the ampulla of Vater. It is subclassified into perihilar (hilar) and distal cholangiocarcinoma [MS-9]. Perihilar cholangiocarcinoma, also known as Klatskin tumor, occurs at or near the confluence of the right and left hepatic ducts and the common hepatic duct; distal cholangiocarcinoma arises in the common bile duct above the ampulla of Vater [MS-9]. Perihilar tumors are the most common type of eCCA [MS-9]. More than 90% of eCCAs are adenocarcinomas [MS-9]. Patients typically present with obstructive jaundice, pruritus, and sometimes abdominal pain. Diagnosis is confirmed by histology demonstrating cholangiocyte differentiation, supported by immunohistochemistry and albumin in situ hybridization [EXTRA-B]. Anatomically, perihilar tumors are staged using the AJCC perihilar bile duct classification, while distal tumors use the distal bile duct staging system [ST-3, ST-4]. The modified Bismuth-Corlette and Blumgart staging systems are also used for perihilar tumors to assess resectability and prognosis [MS-10–MS-11]. Complete surgical resection with negative margins is the only potentially curative treatment, but many patients present with advanced disease [MS-17].

Extrahepatic cholangiocarcinoma is anatomically divided into perihilar (hilar) and distal subtypes. Perihilar tumors arise in the main lobar ducts proximal to the cystic duct; distal tumors arise in the extrahepatic biliary tree between the cystic duct confluence and the ampulla of Vater [EXTRA-B]. These two subtypes differ in surgical approach: perihilar tumors require major hepatic resection with caudate lobectomy, while distal tumors are managed by pancreaticoduodenectomy [EXTRA-A]. Histologically, both are predominantly adenocarcinomas. Growth patterns may be mass-forming, periductal-infiltrating, or intraductal, though classification by growth pattern is less commonly applied in eCCA. Pathologic parameters include depth of invasion (for distal tumors: <5 mm, 5–12 mm, >12 mm), lymph node involvement (N1: 1–3 positive nodes; N2: ≥4 positive nodes), and margin status [EXTRA-B]. Rare histologies such as neuroendocrine tumors or sarcomas are staged separately and should be managed according to relevant NCCN Guidelines [EXTRA-B]. Molecularly, eCCA has a lower frequency of FGFR2 fusions and IDH1 mutations compared to iCCA, but HER2 alterations (5%–20%) and other markers occur [BIL-B 2/8, 3/8].

Extrahepatic cholangiocarcinoma (eCCA) has a distinct molecular profile from intrahepatic CCA. FGFR2 gene fusions/rearrangements and IDH1 mutations are rare in eCCA but testing is recommended due to potential therapeutic implications [BIL-B 2/8, 5/8]. HER2 (ERBB2) overexpression/amplification occurs in 5%–20% of eCCA [BIL-B 3/8]. BRAF V600E mutations are found in 1%–5% [BIL-B 3/8]. MSI-H/dMMR is present in 1%–3%, and TMB-H in <5% [BIL-B 3/8]. NTRK1/2/3 gene fusions are very rare (<1%) [BIL-B 3/8]. RET gene fusions occur in <1% [BIL-B 3/8]. KRAS G12C mutations are found in approximately 1% [BIL-B 3/8]. NRG1 gene fusions are rare (<1%) and have been reported in eCCA [BIL-B 2/8, 3/8]. Comprehensive genomic profiling is recommended for unresectable or metastatic eCCA to identify actionable alterations [BIL-B 1/8]. The genomic landscape also includes alterations in TP53, CDKN2A, and SMAD4, though these are not included in Table 1 of the guideline. Germline pathogenic variants (e.g., BRCA2, BRCA1, MLH1, MSH2, PALB2, RAD51D, BAP1, ATM) are present in approximately 9%–11% of BTCs including eCCA [BIL-B 1/8].

Extrahepatic cholangiocarcinoma (eCCA) is more common than intrahepatic CCA in the United States [MS-9]. From 2001 to 2017, the incidence of eCCA increased at a slower rate of 7.5% [MS-9]. SEER data analysis indicates that perihilar cholangiocarcinoma is the most common type of eCCA [MS-9]. The median overall survival for patients with unresectable eCCA is short; with supportive care it is measured in months, and with systemic therapy, median survival is approximately 1 year (11.7 months in the ABC-02 trial for advanced BTC including eCCA) [MS-23]. Five-year survival rates following complete resection range from 20%–42% for hilar CCA and 16%–52% for distal CCA [MS-17]. Surgical margin status, lymph node involvement, and depth of tumor invasion are independent predictors of survival [MS-17]. eCCA tends to present at a stage where resectability is often limited. Racial/ethnic variations are less well studied, but risk factors such as primary sclerosing cholangitis and parasitic infections contribute to geographic differences in incidence. The overall prognosis remains poor, and most patients ultimately die of their disease.

Established risk factors for extrahepatic cholangiocarcinoma include primary sclerosing cholangitis (PSC), hepatolithiasis, choledochal cysts, and liver fluke infections [MS-9]. PSC is a particularly strong risk factor, and patients with PSC should be considered for surveillance. Chronic calculi of the bile duct (hepatolithiasis) are also well-established. Choledochal cysts, congenital dilations of the bile ducts, confer a significantly increased risk. Inflammatory bowel disease (IBD) may be a risk factor, though this is often confounded by PSC [MS-9]. Other risk factors include hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, cirrhosis, diabetes, obesity, alcohol use, and tobacco smoking, although these are more strongly linked to intrahepatic CCA [MS-9]. Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with increased incidence of eCCA (pooled adjusted OR 2.05; 95% CI 1.59–2.64) [MS-10]. Unlike gallbladder cancer, cholelithiasis is not thought to be linked with eCCA [MS-9]. Most patients diagnosed with eCCA have no identifiable predisposing factors [MS-9].

Mixed hepatocellular-cholangiocarcinoma (HCC-CCA) is a rare primary liver malignancy that contains histologic components of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). It is estimated to represent 1% to 10% of primary liver tumors [INTRA-B 1/2]. The diagnosis is made on pathologic review, which may reveal either separate foci of HCC and CCA within the same tumor (combined type) or biphenotypic cells that coexpress immunohistochemical markers of both hepatocellular and cholangiocytic differentiation [INTRA-B 1/2]. Due to the dual histology, the clinical behavior of mixed HCC-CCA is often aggressive, and treatment strategies are evolving. The NCCN Guidelines emphasize that liver resection is the standard treatment for resectable disease [INTRA-B 1/2]. For unresectable disease, liver-directed locoregional therapies may be considered, similar to those used for HCC and iCCA [INTRA-B 1/2]. Liver transplantation may be evaluated in selected patients with limited tumor burden based on center-specific criteria [INTRA-B 1/2]. At advanced stages, biopsy at recurrence is recommended to determine the dominant histology, which may guide systemic therapy selection [INTRA-B 1/2].

Mixed HCC-CCA is broadly divided into two histologic patterns: 1) Tumors with separate foci of HCC and CCA in discrete areas (combined type), and 2) Biphenotypic tumors where individual cells coexpress immunohistochemical markers of both HCC (e.g., Hep Par1, GPC3, AFP) and CCA (e.g., CK7, CK19) [INTRA-B 1/2]. This distinction has implications for diagnosis, as molecular profiling may show a predominance of HCC-associated genomic alterations (TP53, TERT promoter mutations) in tumors from patients with underlying hepatitis C virus infection [INTRA-B 1/2]. The identification of a targetable alteration associated with CCA (e.g., FGFR2 fusion, IDH1 mutation) should prompt consideration of appropriate targeted therapy [INTRA-B 2/2]. The subtype may change during disease progression; therefore, repeat biopsy at recurrence is recommended to reassess dominant histology, especially if there are discordant responses [INTRA-B 1/2].

Genomic profiling of mixed HCC-CCA suggests a higher prevalence of mutations typically associated with HCC, including TP53 and TERT promoter mutations, particularly in patients with hepatitis C virus infection [INTRA-B 1/2]. These findings are based on small sample sizes and may not be generalizable to all mixed HCC-CCA cases. The presence of CCA-associated genomic alterations (e.g., FGFR2 fusions, IDH1 mutations, BRAF V600E, HER2 amplification) is less well characterized but could be identified using multigene panel testing (MGPT) [INTRA-B 2/2]. Because the tumor may harbor targetable aberrations, MGPT is recommended for all patients with advanced mixed HCC-CCA [INTRA-B 1/2]. At progression, molecularly targeted therapies directed against identified alterations (e.g., FGFR inhibitors, IDH1 inhibitor, BRAF/MEK inhibitors, HER2-directed agents) should be considered [INTRA-B 2/2; BIL-C 3/5]. In the absence of a targetable alteration, regimens with demonstrated activity in both HCC and CCA are options, including nivolumab plus ipilimumab or regorafenib [INTRA-B 1/2]. The genomic complexity and dual lineage contribute to the challenging management of this entity.

Mixed HCC-CCA is a rare primary liver tumor, estimated to represent 1% to 10% of all primary liver cancers [INTRA-B 1/2]. There are limited large-scale epidemiological data specific to this entity, as it is often grouped with either HCC or CCA in population-based studies. The incidence may be higher in patients with underlying chronic liver disease, particularly hepatitis C, where genomic profiling reveals more HCC-like alterations [INTRA-B 1/2]. A retrospective multicenter study including 101 patients reported a median overall survival of 15.5 months for those receiving chemotherapy, with a trend toward better survival compared to non-chemotherapy regimens [INTRA-B 1/2]. The 5-year overall survival after surgical resection varies, but recurrence is common and long-term outcomes are poor. Due to its rarity, standardized reporting and clinical trials are lacking, and most data come from small retrospective series. The diagnosis is often made incidentally at pathology review of a resected liver mass that was initially suspected to be either HCC or CCA.

Specific risk factors for mixed HCC-CCA are not well defined, but likely overlap with those for HCC and intrahepatic CCA. Underlying cirrhosis from any cause (viral hepatitis, alcohol, metabolic dysfunction) is a plausible risk factor. Hepatitis C virus (HCV) infection appears to be particularly associated with mixed HCC-CCA that harbors a higher prevalence of TP53 and TERT promoter mutations [INTRA-B 1/2]. Hepatitis B virus (HBV) infection is also a risk factor. Metabolic dysfunction-associated steatotic liver disease (MASLD) may contribute. Other risk factors that are classic for CCA (e.g., primary sclerosing cholangitis, hepatolithiasis, liver flukes) have not been specifically confirmed for mixed HCC-CCA. Given its rarity, no large-scale epidemiological studies have identified unique risk factors. Patients with known chronic liver disease who develop a primary liver tumor with atypical imaging features should be considered for biopsy to evaluate for mixed histology.

Gallbladder cancer is commonly diagnosed at an advanced stage because it is often asymptomatic in its early stages and has an aggressive nature that can spread rapidly. Another factor contributing to late diagnosis is a clinical presentation that mimics biliary colic or chronic cholecystitis. Hence, it is common for a diagnosis of gallbladder cancer to be an incidental finding at cholecystectomy for presumed benign gallbladder disease or, more frequently, on pathologic review following cholecystectomy for symptomatic cholelithiasis. In a retrospective review of 435 patients diagnosed and treated with curative resection at a single center from 1995 to 2005, 123 patients (47%) were diagnosed with gallbladder cancer as an incidental finding after cholecystectomy [23]. Other possible clinical presentations include a suspicious mass detected on ultrasound or biliary tract obstruction with jaundice or chronic right upper quadrant abdominal pain. The presence of jaundice in patients with gallbladder cancer is associated with a poor prognosis; patients with jaundice are more likely to have advanced-stage disease (96% vs. 60%; P < .001) and significantly lower disease-specific survival (6 vs. 16 months; P < .0001) than those without jaundice [25]. In a sample of 82 patients with gallbladder cancer who presented with jaundice, the resectability rate was low (7%), with even fewer having negative surgical margins (5%) and no disease-free survivors at 2 years [25].

AJCC 8th edition (2017), TNM system

Patients with intrahepatic cholangiocarcinoma (iCCA) often present with nonspecific symptoms due to late diagnosis. Early-stage iCCA may manifest as mild changes in serum liver function tests, particularly alkaline phosphatase. Common symptoms include fever, weight loss, and/or abdominal pain; symptoms of biliary obstruction are uncommon because these tumors do not necessarily involve the common hepatic/bile duct. iCCA may be detected incidentally as an isolated intrahepatic mass on imaging performed for other reasons [85]. In a retrospective analysis, the 5-year survival rate after complete resection ranged from 20% to 40% depending on stage [75,77]. The incidence of iCCA has increased dramatically (148.8% from 2001 to 2017) likely due to improved diagnostic capabilities [65].

AJCC 8th edition (2017), TNM system for intrahepatic bile duct tumors

Extrahepatic cholangiocarcinoma (eCCA) includes perihilar (Klatskin) and distal subtypes. Patients typically present with jaundice, which is the most common symptom, followed by evidence of biliary obstruction or abnormality on imaging. Pain, abnormal liver function tests, and pruritus are also common. Perihilar tumors often present with obstructive jaundice and may be associated with pruritus and dark urine. Distal cholangiocarcinomas also present with jaundice and may cause pancreatic duct obstruction leading to pancreatitis. Most CCAs (>90%) are adenocarcinomas [63]. Extrahepatic CCA is more common than intrahepatic CCA [64]. The 5-year survival rates following complete resection range from 20% to 42% for hilar and 16% to 52% for distal CCAs [198,199].

AJCC 8th edition (2017), separate TNM for perihilar and distal bile duct tumors

Mixed hepatocellular-cholangiocarcinoma (HCC-CCA) is a rare primary liver tumor, estimated to occur in 1% to 10% of patients with primary liver tumors [181-184]. Tumors may contain separate foci of both HCC and CCA histology in discrete areas, or be biphenotypic with coexpression of markers. Patients often present with features of both HCC and CCA, such as a liver mass with elevated alpha-fetoprotein (AFP) and CA 19-9, and may have underlying chronic liver disease (hepatitis B/C, cirrhosis, MASLD). The presentation can overlap with either pure HCC or CCA; diagnosis is made on pathology (biopsy or resection). Genomic profiling shows higher prevalence of TP53 and TERT promoter mutations similar to HCC, especially in HCV infection [3,5].

No dedicated AJCC staging for mixed HCC-CCA; typically staged as intrahepatic bile duct tumor (iCCA) or HCC depending on dominant histology. NCCN recommends staging per appropriate component.