Advances in the molecular characterization of biliary tract and gallbladder cancer

Biliary tract cancers

First described by Durand-Fardel in 1840, biliary tract tumors arise from cholangiocytes residing in the biliary tree. The biliary tract cancers include intrahepatic cholangiocarcinoma (IHCC, within the liver; see Chapter 50 ), extrahepatic cholangiocarcinoma (EHCC, within the extrahepatic biliary tree; see Chapter 51 ), and gallbladder cancer (GBCA, within the gallbladder; see Chapter 49 ). Recently, it has been recognized that some subtypes of IHCC can arise from hepatic progenitor cells or have stem cell features (see Chapter 9C ). Thus combined or mixed hepatocellular cholangiocarcinoma (C-HCC), which has cells with a phenotype that is intermediate between hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), is occasionally seen and considered to be a subtype of IHCC (see Chapters 47 , 50 , and 89 ). These biliary tract cancers constitute a rare set of malignancies and mostly present as locally advanced or metastatic disease. Because of their rarity, as well as their common cell of origin, systemic treatment for all these tumor types has been identical, but chemotherapeutic regimens lack significant response rates. In patients with advanced disease, goals of systemic chemotherapy are still palliative in nature (see Chapters 47 and Chapter 49, Chapter 50, Chapter 51 ). With fairly recent developments in next-generation sequencing (NGS) and other molecular techniques; however, comprehensive molecular profiling now enables the identification of unique genetic signatures among these cancers and is important in clinical trial design using drugs to target specific pathways.

Classification

The vast majority of biliary tract tumors are adenocarcinomas, and they most often arise at or near the biliary confluence. The latter fall under the general category of EHCCs (see Chapter 51 ), which are further subcategorized into hilar CCA (also known as Klatskin tumor ) and distal CCA, with the transition occurring proximal to the cystic duct in the current American Joint Committee on Cancer TNM Classification and National Comprehensive Cancer Network (NCCN) guidelines. ^, These are further categorized as perihilar CCA by their precise location with reference to the biliary bifurcation and the hepatic lobar ducts. This classification is most useful for descriptive purposes and for operative planning. In contrast to the perihilar tumors, the distal CCAs account for a relatively small fraction of all bile duct tumors. Mid-bile duct tumors are even less common and often turn out to represent tumors of the gallbladder or cystic duct. Diffuse involvement of the entire biliary tree is a very rare condition, affecting a very small fraction of patients with biliary tract cancer. CCA may also arise from the intrahepatic bile ducts, giving rise to the subgroup known as IHCC (or peripheral CCA; see Chapter 50 ). IHCCs can also be subcategorized by their growth characteristics into three groups: mass-forming , periductal-infiltrating , or intraductal growing types. Until recently, International Classification of Disease (ICD) codes combined IHCC with HCC under the code for primary liver tumor, ^, but these are clearly different entities, and the second and third editions of the ICD for Oncology (ICD-O-2/3) have attempted to correct for this issue. In ICD-O-2, hilar tumors were assigned a unique histology code, but this was cross-referenced to the topography code for intrahepatic rather than extrahepatic tumors. Under the third ICD-O-3 edition, hilar tumors are cross-referenced to either location. In addition to the aforementioned coding issues, many tumors previously referred to as liver adenocarcinoma of unknown primary site were likely unrecognized IHCCs. Together, these changes in ICD classification have influenced observed changes in the incidence rates of IHCC and EHCC.

Epidemiology

Although rare, biliary tract cancer has a distinctly higher incidence in certain demographic groups and geographic regions (see Chapters 49 , 50 , and 51 ). GBCA has a higher incidence among females and in South America, whereas IHCC is more common in Asia. The peak incidence of the biliary tract cancers is the seventh decade of life, with a slightly higher male predilection. In the United States, an estimated 6,300 new IHCC cases were diagnosed, whereas 12,360 new EHCC or GBCA cases were diagnosed in 2019. Outside of the United States, the incidence rates vary globally, presumably reflecting differences in infectious causes, environmental risk factors (i.e., sedentary lifestyles, alcohol, smoking, and diet), exposure to toxic chemicals, and genomics. The highest incidence rate is in Northeast Thailand (age-standardized incidence rate [ASIR]: 85/100,000 population), where it occurs approximately 100 times more often than in the West. High prevalence of carcinogenic liver flukes is associated with the high incidence rates of biliary tract cancers. Nevertheless, in the United States, IHCC and EHCC incidence rates have steadily increased from 1999 to 2013 across sex and racial/ethnic groups (estimated annual percent change [eAPC]: 3.2% for IHCC and 1.8% for EHCC). Also, in other countries (e.g., Japan, Australia, and many European countries), increased rates for IHCC are widely reported. In contrast, the overall GBCA incidence rate has been stable or declining, although it increased among African Americans (eAPC: 1.8%) and people aged less than 45 years (eAPC: 1.8%). ^, The increased incidence of IHCC and EHCC may be attributable, in part, to the fact that several risk factors (e.g., cirrhosis and obesity) have increased globally over recent decades. The increased detection of early stage or smaller tumors may also be considered a reason, as would be expected if the increase were only because of an improvement in diagnostic modalities, such as magnetic resonance imaging (MRI) and computed tomography (CT). ^{, ,}

Epidemiologic data over the last few decades have also shown that the mortality rate of IHCC is rising globally, whereas the mortality rates of EHCC and GBCA have decreased in most countries. ^, The GBCA mortality rates declined after the increase of cholecystectomy. Despite recent imaging modality developments, most patients presenting with unresectable or metastatic disease still typically die within 12 months of diagnosis. In addition to a lack of highly efficacious systemic therapies, sepsis from cholangitis, frequently related to interventions performed for biliary obstruction and progressive liver failure, contribute to the high mortality. Although biliary tract tumors remain relatively rare, there has been increased interest in studying the biology of these diseases in recent years.

Chronic biliary inflammation and cholestasis

Molecular pathogenesis

The molecular pathogenesis of biliary tract tumors has recently become an area of vigorous investigation (see Chapters 9A and 9C ). In the era of advanced molecular analyses, including NGS, rapid progress is being made in our understanding of the genomic basis of these malignancies. Tumor profiling of biliary tract cancers has revealed that molecular profiles differentiate IHCC, EHCC, and GBCA and that every tumor has both biologically complex and individually unique molecular alterations, suggesting individualized therapeutic options. It is beyond the scope of this chapter to document every known molecular alteration reported or associated with biliary tract cancers. Instead, we focus on recurrent themes in altered signaling pathways that together result in the pathogenic phenotypes and potential drug targets ( Fig. 9E.1 ).