Diagnosis and Management of Cholangiocarcinoma: A Multidisciplinary Approach

Part IAnatomy and Histology of the Biliary Tree and Cholangiocarcinoma

© Springer Nature Switzerland AG 2021

J. H. Tabibian (ed.)Diagnosis and Management of Cholangiocarcinomahttps://doi.org/10.1007/978-3-030-70936-5_1

1. Anatomy of the Biliary Tree: Normal, Anomalous, and Relationship to Cholangiocarcinoma

Jad Abou-Khalil¹  

(1)

Department of Surgery, Division of General Surgery – Hepatobiliary and Pancreatic Surgery Unit, The Ottawa Hospital, Ottawa, ON, Canada

Jad Abou-Khalil

Email: jaboukhalil@toh.ca

Keywords

Biliary anatomyCholangiocarcinomaBile ductsCommon bile ductGallbladder

Abbreviations

CBD

Common bile duct

CCA

Cholangiocarcinoma

CHD

Common hepatic duct

LHD

Left hepatic bile duct

LLS

Left lateral section

RAD

Right anterior bile duct

RHD

Right hepatic bile duct

RPD

Right posterior bile duct

Overview

Cholangiocarcinoma (CCA), a malignancy of the biliary epithelium, can arise anywhere within the biliary system, from the intrahepatic ducts to the hepatopancreatic ampulla. Understanding biliary anatomy and the breadth of its variation finds particular importance in the treatment of CCA. This chapter will describe standard configurations of the left and right biliary tree, their confluence, the gallbladder, and common bile duct (CBD) and identify common variations on this standard anatomy as they relate to the treatment of CCA, especially surgical.

Anatomy of the Left Biliary System

The left bile duct (LHD) is formed by the confluence of segments 2, 3, 4a, and 4b. Four common anatomical variants of its formation are described [1]. In the most common configuration, the segments 2 and 3 bile ducts join to form a left lateral section (LLS) [2] duct close to the umbilical fissure. 55% of individuals share this configuration. This confluence occurs at the umbilical fissure, medial to the fissure, or lateral to it 5%, 50%, and 45% of the time, respectively, joining a single segment 4 duct to form the left hepatic duct (LHD). The second most common configuration, seen 30% of the time, finds two separate ducts from 4a and 4b, respectively, joining the LLS duct. In the third most common variant, the segments 3 and 4 ducts join to the right of the umbilical fissure and are joined by the segment 2 duct closer to the hilum; this occurs 10% of the time. In the fourth configuration, seen in 5% of individuals, segments 2, 3, and 4 join together at the umbilical fissure. Of note, in the second and fourth configuration, the segment 4 duct can join the LHD to the left of the umbilical fissure, exposing this duct to a risk of injury whenever a transection plane runs through the umbilical fissure, for example, during segments 2 and 3 resection for an intrahepatic CCA in segments 2 and 3 (Fig. 1.1).

Fig. 1.1

Four common anatomical variants of the left viliary drainage system: (a) the segment 2 and 3 bile ducts join to form a left lateral section (LLS) duct close to the umbilical fissure, joining a single segment 4 duct to form the left hepatic duct (LHD). (b) two separate ducts from 4a and 4b, respectively, joining the LLS duct. (c) the segment 3 and 4 ducts join to the right of the umbilical fissure and are joined by the segment 2 duct closer to the hilum. (d) segments 2,3, and 4 join together at the umbilical fissure

Using corrosion casting , surgical anatomists of the mid-twentieth century, from Rex to Couinaud, described the anatomical relationship of the biliary tree to the portal vein and its segmental branches [3]. The LHD always lies superiorly (cephalad) to the portal vein, a relationship that allows access to the left hepatic duct during a Hepp-Couinaud maneuver, wherein the hilar plate is lowered to reveal the left hepatic duct behind the portal vein. This universal configuration is variably termed epiportal or supraportal. More distally towards the segmental branches of the biliary tree, this relationship is mostly maintained, except for a described hypoportal configuration of the segment 3 branches, occurring in 3.6% and up to 8% of livers [3, 4]. The presence of a parenchymal or fibrous bridge over the Rex’s recess is a surface clue to the presence of a hypoportal segment 3 duct. This does not occur with segment 2 branches, due to the embryological origin of the ducts – with segments 3 and 4 arising together as an anteriomedial sector within the left lobe and segment 2 arising separately as a left posterior-lateral sector.

The LHD is longer than the right hepatic duct (RHD), measuring 2–5 cm, and courses more horizontally. The RHD, if present at all, usually measures 1 cm before it bifurcates into its anterior and posterior tributaries.

Anatomy of the Right Bile Ducts and the Biliary Confluence

Similarly to the left liver, the bile ducts draining segments 5, 6, 7, and 8 in the right liver join together in four commonly recognizable configurations [5, 6]. The most common configuration finds the right anterior bile duct (RAD) draining segments 5 and 8 meeting with the right posterior bile duct (RPD) draining segments 6 and 7 to become the RHD. This configuration, termed type 1, is found in 56% of livers (Fig. 1.2). Unlike in the left liver where the LHD is universally epiportal, the RHD can be hypoportal 20% of the time. Specifically, the RPD can lie in a hypoportal configuration, hooking behind the right anterior portal vein branch – a configuration described by Hjortsjö and eponymously named Hjortsjö’s hook. The type 2 configuration (14% of livers) presents as a triple confluence of the LHD with the RAD and the RPD, with no distinct RHD. In types 3a and 3b, the RAD and RPD join the LHD, respectively, in 5% and 15% of livers. In types 4a and 4b, the RAD and RPD, respectively, join the CHD below the confluence – a pattern termed convergence etagée. The long-held belief that small bile ducts connect the gallbladder lumen to intrahepatic bile ducts, so-called ducts of Luschka, is disproven. There are nonetheless bile ducts lying in close proximity to the cystic plate which can be injured in the course of a cholecystectomy.

Fig. 1.2

Anatomic variation of the biliary confluence according to the Nakamura classification. (a) Type 1; (b) type 2; (c) type 3a; (d) type 3b; (e) type 4a; (f) type 4b. LHD, left hepatic duct; RAD, right anterior duct; RPD, right posterior duct. (Reproduced with permission from Elsevier. Source: https://​doi.​org/​10.​1016/​j.​suc.​2018.​12.​005)

Every effort must be made to delineate biliary anatomy prior to embarking on a liver resection for the treatment of a CCA. Particular attention must be drawn to the anatomical variants mentioned above in planning hepatectomies for hilar CCA, as the anatomy determines the number and location of bile ducts that will be encountered at the planned transection line and that will need to be reconstructed. For example, a CCA involving the LHD may present with dilatation of both the LHD and the RPD if the RPD inserts into the LHD (Fig. 1.2).

Embryologically, the intrahepatic bile ducts form from the ductal plate, a thin layer of cells that surrounds the portal vein branches and that follow its branching pattern within the developing liver [7]. Therefore, biliary anatomy typically tracks portal venous anatomy, and variants of portal venous anatomy should consequently raise suspicion of biliary ductal anatomical variation.

The Caudate Ducts

The Spigelian lobe (i.e., Couinaud’s segment 1), the caudate process, and the paracaval caudate (described by Couinaud as a 9th segment but rarely referred to as such in contemporary nomenclature) form the caudate lobe. Each of these portions of the caudate lobe is drained by at least one duct, with up to five ducts draining the caudate. The Spigelian lobe drains into the LHD, with the remainder of the caudate draining into the left-right confluence, the RHD, or the RPD. But as elsewhere in the liver, this drainage pattern is highly variable, and this laterality is not universal. A third of Spigelian lobes drain into the RHD or the RPD, especially when the RPD inserts into the LHD. Conversely, a third of the paracaval and caudate process ducts insert into the LHD [8]. This explains the oncologic benefit observed when performing a caudate resection as part of the treatment of hilar CCAs; caudate resection in this context is associated with margin-negative resection and improved long-term survival [9]. Particular attention to dilatation of the caudate ducts in the context of hilar CCA can yield important clues as to their insertion in relationship to the obstructing tumor.

The Gallbladder and Extrahepatic Bile Ducts

The gallbladder lies at the equator between the right and left hemiliver, an imaginary line known as Cantlie’s line or the Rex-Cantlie line coursing between segments 4b and 5, through the bed of the gallbladder towards the vena cava posteriorly. The gallbladder is mostly peritonealized, except for its posterior surface which lies on the cystic plate, a fibrous area on the underside of the liver. The proportion if its circumference varies, from a pedicled gallbladder with little to no contact with the cystic plate to a mostly intrahepatic gallbladder surrounded by liver parenchyma. The gallbladder carries no muscularis mucosa, no submucosa, and a discontinuous muscularis and only carries a serosa on the visceral peritonealized surface. These anatomical specificities facilitate the direct invasion of gallbladder cancer into the liver. This is why the surgical treatment of gallbladder cancer mandates a radical cholecystectomy, which includes resection of a wedge of segments 4b and 5, when the T stage is higher or equal to T1b [10].

From the body of the gallbladder, a conical infundibulum becomes a cystic duct that extends as the lower edge of the hepatocystic triangle towards the porta hepatis and joins with the common hepatic duct (CHD) to form the CBD. As in the rest of the biliary system, variation is the rule when it comes to the cystic duct confluence with the CHD. It can variably run parallel to it for a distance prior to inserting or spiral behind it and insert on its medial aspect. It can variably insert into the RHD or the RPD, the latter in 4% of livers and particularly when the RPD inserts into the CHD (i.e., below the left-right ductal confluence). This configuration is notorious for exposing the RPD to a risk of injury at the time of cholecystectomy. Rare variations of gallbladder anatomy, including gallbladder duplication and gallbladder agenesis, are also described but are rare [2, 11, 12].

The CBD courses anterolaterally within the hepatoduodenal ligament, usually to the right of the hepatic artery and anterolaterally to the portal vein. However, hepatic arterial anatomy can vary, and when an accessory or replaced hepatic artery is present arising from the superior mesenteric artery , the accessory or replaced vessel courses lateral to the CBD. In its conventional configuration, the right hepatic artery crosses posteriorly to the RHD as it heads towards the right liver, but 25% of the time it crosses anteriorly. These anatomical variants are all relevant to developing a sound surgical strategy to treat hilar CCA. Of note, while left hepatic artery anatomy can also be quite variable, rarely does it affect surgical decision-making in CCA to the same degree as right hepatic artery anatomy.

Distally, the CBD enters the head of the pancreas, joining the pancreatic duct to form the hepatopancreatic ampulla. Just distal to this is the sphincter of Oddi, which controls emptying of ampullary contents into the second portion of the duodenum. The treatment of CCAs of the distal, intrapancreatic portion of the bile duct involves a pancreaticoduodenectomy (Chap. 14, Judge et al.). When the junction of the CBD and the pancreatic duct occurs before the sphincter complex, reflux of pancreatic enzymes into the biliary tree can lead to chronic inflammatory changes and anatomical distortion resulting in choledochal cysts, known risk factors for the development of CCA (Chap. 5, Chaiteerakij).

Arterial Supply of the Biliary Tree and Its Implications for Resectability of Cholangiocarcinoma and Bilioenteric Reconstruction

Unlike the rest of the liver parenchyma, which receives dual supply from the arterial and portal venous circulation, the biliary tree is exclusively alimented by the arterial system. The LHD and RHD are alimented respectively by the left hepatic artery and right hepatic artery, which can frequently display replaced, accessory, and aberrant origins – the left artery arising conventionally from the hepatic artery proper but alternatively from the left gastric artery and the right hepatic artery arising from the hepatic artery proper but also variably from the superior mesenteric artery. In hilar CCA, variable combinations of hepatic arterial anatomy and tumor location can either favor resectability or make a tumor unresectable. For example, a CCA involving the confluence of the right and left bile ducts might have a higher chance of being resectable if the right liver is alimented by a replaced right hepatic artery distant from the tumor than if the right hepatic artery coursed in its conventional location in close proximity to the hilum, where it risks being involved by tumor.

Within the hilum of the liver, a plexus of arteries connects the right and left hepatic arteries. Termed the hilar epicholedochal plexus, this vascular network provides collateral circulation that can maintain arterial supply to one side of the liver if the ipsilateral vessel is damaged [13]. The preservation of arterial blood supply to the liver remnant is crucial, particularly when creating an enterobiliary anastomosis. Its absence leads to ischemic cholangiopathy and liver abscesses that can be difficult to treat [14].

The CBD receives arterial supply inferiorly from paired arterioles arising from the gastroduodenal artery and the posterior superior pancreaticoduodenal artery, the most important and constant arterial supply to the distal CBD. Proximally the CBD is alimented by paired arterioles of the right hepatic artery. These vessels, known as the marginal arteries, run in parallel to the CBD, laterally and medially to it. Denuding the CBD of this arterial supply risks stricture formation after choledochoenteric anastomosis.

Conclusion

CCA can arise anywhere along the biliary tree. A thorough understanding of the anatomy of the bile ducts, its common variant configurations, and its relationship to correspondingly variable vascular anatomy is necessary to allow for the safe surgical treatment of CCA.

References

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Darnis B, Mohkam K, Cauchy F, Cazauran JB, Bancel B, Rode A, et al. A systematic review of the anatomical findings of multiple gallbladders. HPB (Oxford). 2018;20(11):985–91. PubMed PMID: 29887260. Epub 2018/06/12. eng.Crossref

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Kitamura H, Mori T, Arai M, Tsukada K, Numata M, Kawasaki S. Caudal left hepatic duct in relation to the umbilical portion of the portal vein. Hepato-Gastroenterology. 1999;46(28):2511–4. PubMed PMID: 10522029. Epub 1999/10/16. eng.PubMed

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Nakamura T, Tanaka K, Kiuchi T, Kasahara M, Oike F, Ueda M, et al. Anatomical variations and surgical strategies in right lobe living donor liver transplantation: lessons from 120 cases. Transplantation. 2002;73(12):1896–903. PubMed PMID: 12131684. Epub 2002/07/20. eng.Crossref

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Van Eyken P, Sciot R, Callea F, Van der Steen K, Moerman P, Desmet VJ. The development of the intrahepatic bile ducts in man: a keratin-immunohistochemical study. Hepatology. 1988;8(6):1586–95. PubMed PMID: 2461337. Epub 1988/11/01. eng.Crossref

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Kitami M, Murakami G, Ko S, Takase K, Tuboi M, Saito H, et al. Spiegel’s lobe bile ducts often drain into the right hepatic duct or its branches: study using drip-infusion cholangiography-computed tomography in 179 consecutive patients. World J Surg. 2004;28(10):1001–6.Crossref

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Birgin E, Rasbach E, Reissfelder C, Rahbari NN. A systematic review and meta-analysis of caudate lobectomy for treatment of hilar cholangiocarcinoma. Eur J Surg Oncol. 2020;46(5):747–53. PubMed PMID: 31987703. Epub 2020/01/29. eng.Crossref

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Hickman L, Contreras C. Gallbladder cancer: diagnosis, surgical management, and adjuvant therapies. Surg Clin North Am. 2019;99(2):337–55. PubMed PMID: 30846038. Epub 2019/03/09. eng.Crossref

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© Springer Nature Switzerland AG 2021

J. H. Tabibian (ed.)Diagnosis and Management of Cholangiocarcinomahttps://doi.org/10.1007/978-3-030-70936-5_2

2. Anatomic and Morphologic Classifications of Cholangiocarcinoma

Michael A. Mederos¹   and Mark D. Girgis¹  

(1)

Department of Surgery, University of California, Los Angeles, Los Angeles, CA, USA

Michael A. Mederos

Email: mmederos@mednet.ucla.edu

Mark D. Girgis (Corresponding author)

Email: mdgirgis@mednet.ucla.edu

Keywords

IntrahepaticPerihilarMorphologyGrowth patternMass-formingPeriductal infiltrating

Abbreviations

AJCC

American Joint Committee on Cancer

CCA

Cholangiocarcinoma

dCCA

Distal cholangiocarcinoma

iCCA

Intrahepatic cholangiocarcinoma

IG

Intraductal growing

LCSGJ

The Liver Cancer Study Group of Japan

MF

Mass-forming

MSKCC

Memorial Sloan Kettering Cancer Center

pCCA

Perihilar cholangiocarcinoma

PI

Periductal infiltrating

TNM

Tumor, lymph node, metastases

Introduction

Cholangiocarcinoma (CCA) originates from the bile duct epithelium at any aspect of the biliary tree. Contemporary anatomic classification separates CCA into three entities based on the location of origin: intrahepatic, perihilar, and distal CCA (Figs. 2.1, and 2.2). These three categories have different and sometimes overlapping risk factors, presentation, and outcomes. For example, while distal CCA often presents with jaundice and pruritus due to biliary obstruction, intrahepatic CCA might present with vague abdominal pain and sometimes jaundice often due to the mass effect of the tumor on other structures and ducts. Each anatomic category can be further subdivided by the tumor morphology and growth pattern (Fig. 2.2).

Fig. 2.1

Anatomic classification of cholangiocarcinoma. (Illustration by Hannah Bryce Ely, CMI)

Fig. 2.2

Imaging of cholangiocarcinoma. (a) Computed tomography (CT) of mass-forming intrahepatic cholangiocarcinoma. The yellow arrow demonstrates the peripheral enhancement of the large tumor. The white arrows highlight associated biliary dilation; (b) MRI of perihilar cholangiocarcinoma (yellow arrow); (c) CT of distal cholangiocarcinoma. The yellow arrow demonstrates an abrupt filling defect of the dilated common bile duct

Intrahepatic Cholangiocarcinoma

Morphology

Intrahepatic CCA (iCCA) may originate anywhere from the microscopic bile ducts in the liver periphery to the second-order bile ducts. It is the least common of the three anatomic types of CCA (5–10% of all CCA) [1]; however, the incidence of this anatomic subtype has steadily increased in the USA from roughly 1200 new cases in 2004 to 3800 new cases in 2015 [2]. The Liver Cancer Study Group of Japan (LCSGJ) classifies iCCA into three distinct morphologic subtypes based on gross appearance: mass forming, periductal infiltrating, and intraductal growing. A 4th category includes tumors with more than one component of the three morphologic subtypes (e.g., mass forming + periductal infiltrating) (Fig. 2.3) [3]. These macroscopic growth patterns are likely associated with differences in risk factors, cellular origin, and biological progression [4]. The relationship between the morphologic subtype and prognosis has been debatable [5]. Previously, the 7th edition of the American Joint Committee on Cancer (AJCC 7) staging manual stipulated that iCCAs with a periductal-infiltrating component are designated as T4 lesions due to a perceived worse prognosis. This characterization was excluded in the 8th edition of the AJCC staging manual (AJCC 8) with the recommendation that morphology continues to be documented for data collection [6]. However, new data suggest morphologic subtype might indeed have long-term prognostic significance in those undergoing curative-intent resection [5, 7].

Fig. 2.3

Morphologic classification of intrahepatic cholangiocarcinoma. (Illustration by Hannah Bryce Ely, CMI)

Mass Forming

The purely mass-forming (MF) growth pattern is the most common morphology of iCCA (60%) [6]. MF iCCA appears as a mass within the hepatic parenchyma, arising from small intrahepatic bile ducts or hepatic progenitor cells with no discernible invasion of a major branch of the portal triad [3]. Tumors of this morphologic subtype can grow to large sizes and are often greater than 5 cm in those who undergo surgical resection [8]. The tumor cells are typically at the periphery of the lesion, and the center is characterized by necrosis and scarring. Because of this radial growth configuration, peripheral arterial enhancement is a common imaging finding (Fig. 2.2a). Multiple intrahepatic lesions are common in MF iCCA, but it is difficult to distinguish if multiple tumors represent multifocal disease (multiple primary tumors) or intrahepatic metastasis from an index lesion (satellite lesions) [9]. Nevertheless, the presence of more than three lesions is associated with significantly worse disease-free and overall survival in those undergoing hepatic resection with curative intent [10].

Periductal Infiltrating

In contrast to the distinct borders of the MF subtype, periductal-infiltrating (PI) iCCA arises from large bile duct epithelium and peribiliary glands and is characterized by a diffuse longitudinal growth pattern along large intrahepatic bile ducts on both gross and microscopic examination [1]. This growth pattern often causes intrahepatic biliary dilatation due to stricture or obstruction, and there are no distinct borders or apparent invasion of the surrounding liver parenchyma. Often included in this subtype is the MF + PI mixed variant, which exhibits features of both subtypes (Fig. 2.3). Tumors with a PI component represent approximately 40% of iCCAs [6]. Compared to the mass-forming and intraductal growing subtypes, patients with PI or MF + PI tumors have more major vascular invasion, lymphovascular invasion , and perineural invasion [7].

Intraductal Growing

The intraductal-growth (IG) subtype of iCCA is characterized by the tumor’s papillary growth toward or within the bile duct lumen (Fig. 2.3) [3]. The precursor lesion associated with intraductal growing tumors is termed intraductal papillary neoplasm of the bile duct and is discussed in detail elsewhere in this book (Chap. 3, Nakanuma et al. and Chap. 4, Fathizadeh et al.). On computed tomography (CT) imaging, this growth pattern often appears as biliary ectasia due to dilation of the bile duct proximal to the lesion. Because this morphology is intraductal, it may be confused for hepatolithiasis. The IG subtype of iCCA has been associated with a better prognosis compared to the MF and PI subtypes. However, data suggest that IG more frequently demonstrates adverse pathologic features, such as lymphovascular invasion, perineural invasion, and poor/undifferentiated tumors when compared to MF iCCA. Nevertheless, despite these features, the overall prognosis of the IG subtype appears more favorable than MF and PI iCCA [5].

Staging

The preferred system for staging CCA is the AJCC tumor, lymph node, and metastases (TNM) classification. Intrahepatic, perihilar, and distal CCA are staged independently [11]. Staging of iCCA has been significantly modified over the past two decades. Prior to 2010, the AJCC staged iCCA using data derived from HCC. However, iCCA has since been recognized as a separate entity given the several differences in clinical features, biology, and growth patterns, and a new staging system separate from HCC was developed in AJCC 7 (Table 2.1) [12]. In AJCC 7, the T stage focused on vascular invasion, number of tumors, and extension beyond the visceral peritoneum and/or penetration of other surrounding structures. Tumor size was initially excluded as it was not considered a significant adverse prognostic indicator for iCCA [12, 13]. However, size was included in the current edition (AJCC 8) after several studies, and a meta-analysis demonstrated an association with tumor size and survival that was likely not seen in prior studies due to the limited number of patients with small tumors [8]. Additionally, tumors with a periductal-infiltrating growth pattern were classified at T4 lesions in AJCC 7 because this was thought to beget a worse prognosis. However, morphologic classification was omitted in AJCC 8 because the data regarding growth type and prognosis was inconsistent and no clear conclusion could be drawn [14, 15]. The AJCC 8 does recommend to document growth patterns for data collection.

Table 2.1

AJCC 7 and 8 staging of intrahepatic cholangiocarcinoma

Altogether, the T stage in AJCC 8 is now classified by tumor size, number of tumors, vascular invasion, extension beyond the visceral peritoneum, and invasion of extrahepatic structures. High-grade dysplasia that does not extend beyond the basement membrane are in situ tumors (Tis). Tumors that are ≤5 cm or >5 cm without vascular invasion are classified as T1a and T1b, respectively. This translates to a 5-year overall survival of 51.7% and 32.6% (P < 0.001), respectively. T2 tumors include solitary tumors with vascular invasion or multiple tumors with or without vascular invasion. Approximately one fifth of patients with iCCA have multiple tumors at the time of surgery [16, 17]. T3 tumors include any iCCA that perforates the visceral peritoneum, and T4 tumors directly invade extrahepatic structures (Table 2.1).

Lymph node metastasis is an important prognostic indicator and is common in iCCA, reported as high as 40% in those who underwent resection with regional lymphadenectomy. For right-sided tumors, the AJCC defines regional lymph nodes as hilar (common bile duct, hepatic artery, portal vein, and cystic duct), periduodenal, and peripancreatic lymph node areas. For left-sided tumors, these lymph node sites include the inferior phrenic, hilar, and gastrohepatic lymph nodes. Spread to these regional lymph nodes is associated with a worse overall survival compared to those with no nodal disease (median 18.0 vs. 45.0 months, P < 0.001) [18]. Anatomically, lymph node metastasis was identified in 38.4% of patients who had a lymphadenectomy of the hepatoduodenal ligament (lymph node station 12) compared to 57.8% in those who had a lymphadenectomy beyond station 12 (P < 0.001). AJCC 8 classifies nodal disease as N0 (no regional lymph node metastasis) or N1 (regional lymph node metastasis present) (Table 2.1). Spread to extra-regional lymph nodes (celiac, periaortic, and pericaval nodes) is considered M1 disease, however. M1 classification also includes extrahepatic sites, which most commonly includes the bone, peritoneum, lungs, and pleura.

Since the release of AJCC 8, several studies have challenged the current staging criteria and suggest that growth pattern should be reintroduced into the staging system. A multi-institutional study across 14 centers analyzed 1083 patients who underwent curative-intent resection of iCCA and found that patients with the PI or mixed (MF + PI) subtypes had higher rate of invasion of adjacent organs, positive margins, major vascular invasion, lymphovascular invasion, and perineural invasion. Overall 5-year survival in patients with a PI component was significantly worse, even after propensity matching for clinicopathologic variables (26.2% vs. 35.7%, respectively; p = 0.03) [7]. Further, the timing and pattern of disease recurrence seem to differ between the growth types.

Perihilar Cholangiocarcinoma

Perihilar CCA (pCCA) is the most common category among bile duct cancers (50–70%) [19]. In 1965, Gerald Klatskin published his series of 13 patients with adenocarcinoma of the hepatic duct confluence, outlining in great deal the distinctive manifestation of the disease [20]. These tumors eventually became known as the eponymous Klatskin tumor. By definition these tumors involve the extrahepatic bile ducts distal to the segmental hepatic ducts and proximal to the cystic duct (Figs. 2.1, and 2.2b). Risk factors associated with pCCA include male gender, advanced age, choledochal cysts, and inflammatory conditions that result in a high cellular turnover (e.g., primary sclerosing cholangitis, inflammatory bowel disease, and gallstone disease).

Perihilar CCA tends to have a sclerosing histologic growth pattern, which makes these tumors characteristically fibrotic and infiltrative, particularly along the ducts and surrounding structures. In contrast, the papillary histologic subtype is usually well-differentiated and characterized by an intraductal growth pattern [21].

Staging Systems

Bismuth-Corlette

Henri Bismuth and Marvin Corlette introduced a classification for pCCA in 1975 with modification in 1992 [22, 23]. The Bismuth-Corlette classification is frequently used to this day and focuses on the level and extension of tumor invasion along the proximal extrahepatic biliary tree (Table 2.2, Fig. 2.4). Type I lesions involve the common hepatic duct below the confluence of the right and left hepatic ducts, while type II lesions involve the confluence but does not extend to the right or left hepatic ducts. Type III tumors involve the confluence and extend to the right or left hepatic ducts, designated IIIa and IIIb, respectively. Type IV tumors involve the confluence and extend to both the right and left hepatic ducts. Although commonly used to classify pCCA tumors and help guide the surgical approach, the Bismuth-Corlette classification does not provide information on vessel involvement, lymph node or distant metastases, or liver atrophy [24]. Hepatic atrophy in the setting of pCCA is associated with locally advanced disease and likely involvement of the portal venous system.

Table 2.2

Bismuth-Corlette classification of perihilar cholangiocarcinoma

Fig. 2.4

Bismuth-Corlette classification of perihilar cholangiocarcinoma. (Illustration by Hannah Bryce Ely, CMI)

MSKCC Classification

Blumgart and colleagues at the Memorial Sloan Kettering Cancer Center (MSKCC) devised and subsequently modified a classification system that expanded on the Bismuth-Corlette classification by including hepatic atrophy and portal venous involvement (Table 2.3) [21, 25, 26]. T1 lesions involve the confluence with or without unilateral extension to second-order biliary radicals; T2 lesions are T1 lesions with ipsilateral portal vein involvement or ipsilateral hepatic lobar atrophy; and T3 lesions either have bilateral extension to second-order radicals, unilateral extension with contralateral portal vein involvement or lobar atrophy, or main or bilateral portal venous involvement. In this staging system, the T stage correlated with resectability, attaining a margin-negative specimen, and likelihood of metastatic disease. However, the MSKCC staging system was less useful for predicting survival [21].

Table 2.3

Memorial Sloan Kettering Cancer Center (MSKCC) classification of perihilar cholangiocarcinoma [21]

AJCC TNM

Previously, AJCC 7 incorporated elements of the Bismuth-Corlette and MSKCC classification systems into T staging (Table 2.4). However, AJCC 8 eliminated any Bismuth-Corlette definitions; T4 lesions correlated with a Bismuth-Corlette type IV tumor in the previous edition. The AJCC has shifted to an emphasis on tumor invasion through the bile duct wall and vascular involvement. In addition to portal vein involvement, as described in the MSKCC classification, AJCC 8 includes hepatic artery involvement but does not incorporate hepatic atrophy into T stage [19]. T1 tumors are confined to the bile duct with extension up to the muscle layer or fibrous tissue. Tumors that invade beyond the bile duct to surrounding adipose tissue are T2a, and those that invade the hepatic parenchyma are T2b. Tumors that invade branches of the portal vein and hepatic artery unilaterally are T3. Perihilar tumors are T4 when there is invasion of the main portal vein and common hepatic artery or if there is unilateral extension to second-order biliary radicals with contralateral portal vein or hepatic artery involvement. In a multi-institutional study analyzing actual 5-year survival in patients who underwent resection with curative intent, none with T3 or T4 tumors were 5-year survivors [27].

Table 2.4

AJCC 7 and8 staging of perihilar cholangiocarcinoma

pCCA frequently metastasizes to regional lymph node basins (hilar, cystic duct, choledochal, portal, hepatic arterial, and posterior pancreaticoduodenal lymph nodes) due to the extensive periductal lymphatics. Nodal metastases are as high as 50% in some series and are directly related to T stage. Furthermore, multiple positive lymph nodes is adversely related to survival (RR 1.61; 1.01–2.56) [28]. Accordingly, AJCC 8 updated the N stage and incorporated the number of positive lymph nodes: one to three regional lymph node metastases are designated N1 and greater than four lymph nodes is N2. Extra-regional lymph node metastases (outside the hepatoduodenal ligament) are considered distant and are designated M1. Other common sites of metastasis include the peritoneum, liver, lung, bone, brain, and skin.

Distal Cholangiocarcinoma

CCA that develops in common bile duct (between the ampulla of Vater and the confluence of the common hepatic duct and cystic duct) is categorized as distal CCA (dCCA) and comprises 20–30% of bile duct cancers (Figs. 2.1 and 2.2c) [29]. The distal most aspect of the common bile duct (CBD) sits within the pancreatic parenchyma at the head of the pancreas and is the most common site of dCCA. At this location, dCCA frequently presents with biliary obstructive symptoms: painless jaundice, pruritus, and acholic stools. Pancreatic ductal dilatation and evidence of pancreatitis may also be encountered during the workup. Tumors at this location are positioned near, and frequently involve, important structures, which confers prognostic significance and impacts surgical planning. Nearby organs that may be invaded directly include to the pancreas, stomach, duodenum, gallbladder, colon, and omentum. Arteries that may be involved include the superior mesenteric, celiac, splenic, and hepatic arteries. Veins involved include the portal, splenic, splenoportal confluence, and the superior mesenteric vein and its branch vessels. Differentiating dCCA from other periampullary tumors such as ampullary carcinoma and pancreatic neoplasms is often difficult to discern on imaging and endoscopic evaluation.

Staging

Unlike pCCA, which has multiple staging systems, dCCA is only staged by the AJCC TNM system and is used for both clinical and pathologic staging of dCCA. For clinical locoregional staging, high-quality cross-sectional imaging and/or evaluation via endoscopic ultrasound (EUS) is critical to delineate depth of invasion and involvement of surrounding structures and to identify pathologic lymph nodes. Previously, T stage was stratified by histologic invasion (i.e., confined to the bile duct or extends beyond the wall of the bile duct) (Table 2.5). This method for T staging was problematic, however, because of the variable thickness along the common bile duct and the characteristic and marked desmoplastic reaction that often obscures the boundaries of the bile duct wall and the extent of tumor invasion from the basal lamina [30]. Further, this T-stage classification was not associated with survival outcome. Instead, the measured depth of invasion demonstrated a better correlation with survival [31]. Accordingly, AJCC 8 defines T stage by a measured depth of invasion into the bile duct wall: T1, <5 mm; T2, 5–12 mm; and T3, >12 mm. T4 is defined by invasion of the celiac axis, superior mesenteric artery, or common hepatic artery (Table 2.5). Unfortunately, for reasons listed above, dCCA is often misclassified as pancreatic adenocarcinoma or ampullary carcinoma, which have different staging classifications, tumor biology, and patient outcomes [29, 32]. Even after resection of a periampullary tumor, dCCA is often misdiagnosed on pathologic evaluation [33].

Table 2.5

AJCC 7 and 8 staging of distal cholangiocarcinoma

Lymph node metastasis occurs in approximately 40% of patients with dCCA who undergo surgical resection. Regional lymph nodes include those along the common bile duct and hepatic artery, the posterior and anterior pancreaticoduodenal nodes, and the nodes along the right lateral wall of the superior mesenteric artery. Similar to pCCA, the number of metastatic lymph nodes in dCCA appears to be useful in predicting patient outcomes. One study evaluating lymph node metastasis in 370 patients who underwent resection for dCCA found that patients with 4 or more involved nodes had a significantly shorter median survival compared to patients with only 1 to 3 involved nodes (1.3 vs. 2.2 years; p = 0.001) [34]. Accordingly, the N stage has been modified to reflect these outcomes (N1, one to three positive lymph nodes; N2, four or more positive nodes). Regarding distant metastases, the most common sites include the liver, peritoneum, and lungs [29].

Conclusion

CCA is a malignant tumor that can arise from any part of the biliary tree, anatomically separated into three categories based on the site of origin: intrahepatic, perihilar, and distal. The morphologies, risk factors, presentation, treatment, and outcomes for each anatomic category of CCA are often variable but sometimes overlap. The anatomic location of CCA is used to determine staging, as assessed by the AJCC, and is critical to deciding on treatment and determining prognosis for patients afflicted with these malignancies.

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© Springer Nature Switzerland AG 2021

J. H. Tabibian (ed.)Diagnosis and Management of Cholangiocarcinomahttps://doi.org/10.1007/978-3-030-70936-5_3

3. Intraductal Tumors of the Biliary Tract: Precursor Lesions and Variants

Yasuni Nakanuma¹, ²  , Katsuhiko Uesaka³  , Masayuki Ohtsuka⁴  , Koushiro Ohtsubo⁵  , Dai Inoue⁶   and Kazuto Kozaka⁶

(1)

Department of Diagnostic Pathology, Shizuoka Cancer Center, Shizuoka, Japan

(2)

Department of Diagnostic Pathology, Fukui Prefecture Saiseikai Hospital, Fukui, Japan

(3)

Department of Hepatobiliary Pancreaetic Surgery, Shizuoka Cancer Center, Shizuoka, Japan

(4)

Department of Hepatobiliary Pancreatic Surgery, Chiba University Hospital, Chiba, Japan

(5)

Division of Medical Oncology, Cancer Institute, Kanazawa University Hospital, Kanazawa, Japan

(6)

Department of Radiology, Kanazawa University Hospital, Kanazawa, Japan

Katsuhiko Uesaka

Email: k.uesaka@scchr.jp

Masayuki Ohtsuka

Email: otsuka-m@faculty.chiba-u.jp

Koushiro Ohtsubo

Email: ohtsubo@staff.kanazawa-u.ac.jp

Dai Inoue

Email: d-inoue@lake.ocn.ne.jp

Keywords

Intraductal papillary neoplasm of the bile ductCholangiocarcinomaIntraductal papillary mucinous neoplasm of the pancreasBiliary anatomyBiliary intraepithelial neoplasm

Abbreviations

AUS

Abdominal ultrasonography

BilIN

Biliary intraepithelial neoplasm

CA19-9

Carbohydrate antigen 19-9

CCA

Cholangiocarcinoma

CEA

Carcinoembryonic antigen

CT

Computed tomography

ERC

Endoscopic retrograde cholangiography

EST

Endoscopic sphincterotomy

EUS

Endoscopic ultrasonography

gIPNB

Gastric intraductal papillary neoplasm of the bile duct

HE staining

Hematoxylin and eosin staining

iCCA

Intrahepatic cholangiocarcinoma

ICPN

Intracholecystic papillary neoplasm

IDUS

Intraductal ultrasonography

iIPNB

Intestinal intraductal papillary neoplasm of the bile duct

IPMN

Intraductal papillary mucinous neoplasm

IPNB

Intraductal papillary neoplasm of bile duct

ITPN

Intraductal tubulopapillary neoplasm of the bile duct

MCN

Mucinous cystic neoplasm

MDCT

Multidetector computed tomography

MR

Magnetic resonance imaging

MRC

Magnetic resonance cholangiography

MUC

Mucin core protein

NBI

Narrow-band imaging

oIPNB

Oncocytic intraductal papillary neoplasm of the bile duct

PanIN

Pancreatic intraepithelial neoplasm

pbIPNB

Pancreatobiliary intraductal papillary neoplasm of the bile duct

POCS

Peroral cholangioscopy

WHO

World Health Organization

Introduction

In our experience, there are generally at least two types of tumors involving the biliary tree. One is characterized by a nodular or sclerosing lesion affecting the bile duct wall and periductal tissue and the other by tumors that mainly grow in the intraductal lumen and usually show no or slight stromal invasion [1–3]. In the latter type, several diseases are included (Table 3.1), and they present unique clinicopathological features that differ from nodular sclerosing cholangiocarcinoma (CCA) [4, 5]. Among them, intraductal papillary neoplasms of the bile duct (IPNBs) are a representative intraductal neoplasm. The affected bile ducts are dilated and filled with a grossly visible exophytic tumor and histologically neoplastic biliary epithelia [2, 6–8].

Table 3.1

Intraductal tumors of the biliary tract, related lesions, and mimickers

IPNBs have been studied in comparison to intraductal papillary mucinous neoplasms (IPMNs) of the pancreas, which are also a preinvasive intraductal papillary neoplasm associated with invasive carcinoma and intramucosal spread of neoplastic epithelia [9–14].

Another well-known intraductal tumor of the biliary tract is biliary intraepithelial neoplasm (BilIN) [1, 2, 8, 15–20]. This lesion is microscopically identifiable as a flat or micropapillary lesion. BilINs are reportedly an important precursor or preinvasive lesion of conventional nodular/sclerosing CCA, and there are also other categories of intraductal neoplasms [8, 21–23]. Metastatic carcinoma growing in the bile duct lumen also shows similar gross and imaging characteristics [24].

Recently, the World Health Organization (WHO) published the Classification of Digestive System Tumours 5th edition (2019), in which the new term, benign and precursor lesions, was proposed based on recent progress in this field [4, 7, 10, 15, 25]. We herein review the pathological features of benign and prcursor lesions of the bile duct, particularly IPNB, based on this WHO classification, with reference to the molecular and genetic features, imaging, diagnosis, and management. Other types of benign and precursor lesions of the bile duct are also briefly reviewed.

Intraductal Papillary Neoplasms of the Bile Duct (IPNBs)

IPNB is characterized by intraductal neoplastic growth of biliary epithelia covering fine fibrovascular stalks that lack an ovarian-mesenchymal-type stroma, mainly involving the extrahepatic and intrahepatic bile ducts [7]. IPNBs are associated with variable intramucosal (lateral) spread of neoplastic epithelia around the main papillary tumor, and multifocal occurrence is also reported [2, 3, 7, 21, 26, 27]. The cell of origin of a majority of IPNBs is believed to be the biliary lining cells, while some IPNBs might be derived from the cells in peribiliary glands, which are distributed along the extrahepatic and intrahepatic bile ducts [28–31]. IPNBs are thought to be premalignant lesions with the potential to progress invasive tumors. IPNBs may develop through a multistep process or sequence, eventually followed by invasion [27, 32]. Consequently, IPNBs, particularly those without invasion, usually progress slowly, and patients appear to have better survival in comparison to patients with conventional CCA [27, 33].

Since the first report of IPNBs in the English literature [6], IPNBs have been further studied, and data are now accumulating [12, 27]. IPNBs show variable gross and histopathological features, molecular and genetic features, and biological behavior [6, 32–42]. IPNBs are regarded as preinvasive biliary lesions that are not frequently associated with stromal invasion (IPNB associated with invasive carcinoma) [7]. The incidence of invasion and the histological features in fact differ among several proposed subcategories (or several synonymous names) of IPNB [39, 42, 43]. This heterogeneity and complexity lead to controversy in relation to the clinicopathological recognition and diagnosis of IPNB, suggesting that IPNBs are not a homogeneous disease [44–46]. Several nomenclatures have previously been applied to these tumors according to the dominant feature(s) [36, 45–49]; however, the use of these obsolete terms is not recommended at the present time (Table 3.2) [7].

Table 3.2

Proposed, accepted, and unrecommended terms for intraductal tumors and related lesion by WHO Classification of Tumours (2019)

Epidemiology and Risks

Epidemiology

IPNBs are reported worldwide and affect typically middle-aged to elderly adults (50–80 years of age) and show a male predominance [7, 27, 40, 50–56]. IPNBs account for 9–38% of all bile duct carcinomas [33, 40, 46, 53, 57]. The highest incidence of IPNB is reported in Far Eastern countries [46, 50, 51, 55, 58].

The pathobiology of IPNB may present geographic variation between Asian and Western populations. Cordon-Weeks et al. reported that IPNBs identified in centers from Asia were more likely to be intrahepatic and were less frequently invasive in comparison to those from Western centers [27, 32, 33, 52]. IPNBs account for 10–38% of all bile duct tumors in East Asian populations but only 7–12% of all bile duct tumors in Western populations [32, 33, 50, 51, 55]. The pooled prevalence in Asian populations was more than twice that in Western populations [27], and IPNBs in Western centers showed higher rates of invasive disease and were less frequently associated with mucus production and more frequently of the pancreatobiliary subtype [7, 27, 32, 33].

Risk Factors

Hepatolithiasis and liver fluke infection (Clonorchis sinensis in Korea or Opisthorchis viverrini infection in South East Asia) are believed to be major risk factors for IPNB [50, 51, 53–56, 59]. In addition, approximately 30% of patients have a previous history or concomitant existence of biliary stones, as shown in the reports from Far Eastern countries [36, 60, 61], but not from Western countries [32, 33]. IPNBs also reportedly develop in primary sclerosing cholangitis [62] and congenital biliary tract disease [63]. Interestingly, these etiologic factors are also known as major risk factors for nodular sclerosing perihilar/distal CCA and mass-forming and periductal intrahepatic cholangiocarcinoma (iCCA) [1, 4, 5], suggesting that chronic biliary tract irritation and inflammation may be causally related to the development of IPNB in addition to other types of CCA. Recently, an outbreak of IPNB was reported among young adult workers in the offset color proof-printing department at a printing company in Japan [64]. They were chronically exposed to chlorinated organic solvents, including dichloromethane and 1,2-dichloropropane. Interestingly, IPNB or IPNB associated with invasive carcinoma was observed in various sites of the intrahepatic large bile ducts, perihilar bile ducts and distal bile ducts in these patients [65].

A significant proportion of IPNB cases are completely asymptomatic in endemic and non-endemic areas [27]. Imaging modalities (see below) appear to have some value in screening and detecting IPNB in asymptomatic patients who are at a high risk of developing IPNB [62, 63, 66].

Pathology

Gross Features

Location Along the Biliary Tree

While the locations of IPNBs have varied in several reports, the majority of IPNBs (67%) were located at the intrahepatic bile ducts in Asian countries, while in Western countries, they were more common in the extrahepatic bile ducts [8, 27, 54, 55] or hepatic hilum [32, 33] (Table 3.3). Some cases simultaneously involved the intrahepatic and extrahepatic bile ducts [27, 67, 68]. Despite these variable locations, when IPNB exists in the intrahepatic bile ducts, it tends to be found in the left-sided biliary ductal system [27, 46, 61], for reasons which remain uncertain.

Table 3.3

Pathologic characteristics of intraductal papillary neoplasm of the bile duct (IPNB)

aIncluding perihilar bile duct

bPancreatobiliary, cited from Refs. [4, 27]

Main Tumors and the Surrounding Bile Duct Mucosa

Generally, IPNBs present as papillary or villous, exophytic growth (range, 1–6 cm) (Fig. 3.1) [13, 27, 46, 69]; height, at least 5 mm from the adjacent biliary mucosa) in the dilated bile ducts are typical; however, some papillary neoplasms with a similar histopathology that are <5 mm but >3 mm in height are occasionally encountered [42]. These exophytic lesions are usually conglomerates of smaller or higher polypoid lesions but are not infrequently single or isolated.

Fig. 3.1

Gross features of intraductal papillary neoplasm of bile duct. (a) Papillary lesion in the distal bile duct. Two parts (*) are from a single lesion. (b) Congromelate polypoid lesions (→) in the perihilar bile duct. (c) Single polypoid tumor (→) in the perihilar bile duct. (d) Conglomerate polypoid lesions (→) and surrounding granular or rough mucosa (*) in the perihilar and distal bile duct. (e) Papillary lesions in the wall of cystically dilated intrahepatic bile ducts (*) and invasion (→)

Gross features and anatomical location

The gross features of IPNBs depend on their anatomical location, state of excessive mucin secretion, or macro-invasion of the liver [7, 50, 51]. IPNBs located in the intrahepatic bile ducts tend to be larger inboth mass and length than those