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52
duct
Sphinct
common bile duc
Duodenal wall
Submucosal layer
H. Ohtsuka and M. Unno
Fig. 6.2 Anatomy of the
sphincter of Oddi and ampulla
of Vater
er of
Sphincter
of ampulla
Common bile duct
Pancreas
t
Pancreatic
Sphincter of
pancreatic duct
Muscle of duodenal wall
duct and the pancreatic duct in the duodenum form the
ampulla of Vater. In approximately 80% of individuals, the
common bile duct joins the pancreatic duct in the duodenal
wall and forms the common channel [3]. The sphincter of
Oddi is located in the ampulla of Vater and it serves to prevent regurgitation of both bile and pancreatic juice in the
common bile and pancreatic ducts, respectively (Fig.6.2).
The function of the biliary tract is controlled by the autonomic nervous system, specically the celiac ganglia of the
sympathetic nervous system and the vagus nerve of the parasympathetic nervous system. Branches from the hepatic
plexus, which is formed by the sympathetic nerves and the
vagus nerve, are distributed across the gallbladder, bile ducts,
and papilla to control the biliary tract [4].
6.2 The Functions oftheBiliary Tract
6.2.1 Gallbladder
The efux of bile into the duodenum is controlled via the
functional integration of the gastrointestinal and neuroendocrine systems. The gallbladder, which is contracted by muscular tissue, and the sphincter of Oddi at the duodenal papilla
play important roles in the control of the efux of bile.
lial cells, a lamina propria layer, a muscularis propria layer,
The gallbladder is comprised of a single layer of epithe-
a layer of perimuscular connective tissue, and a serosa layer
[5]. The epithelium of the gallbladder absorbs water and
electrolytes and concentrates the gallbladder bile, which
contains bile acids. The epithelium is also involved in the
uptake of bile acid and cholesterol [6]. Bile acid is the main
component of bile and is made of several different specic
acids. Hydrophobic bile acids are cytotoxic. The epithelium
of the gallbladder and bile ducts secrete mucin, which protects the epithelial cells by inactivating free radicals produced by the hydrophobic bile acids.
The contraction and relaxation of the gallbladder are controlled by the vagus nerve, visceral nerves, and cholecystokinin (CCK), a gastrointestinal hormone. Between periods of
digestion, the sphincter of Oddi is contracted and the gallbladder is relaxed. This leads to the secretion of bile from the
liver into the gallbladder via the hepatic ducts. Approximately
90% of bile ows into the gallbladder and is stored there.
The gallbladder maintains a moderate level of tonic contraction between periods of digestion. It repeatedly relaxes and
contracts with the cycle of the migrating motor complex
(MMC) in the upper gastrointestinal tract [7]. The concentrated bile tends to precipitate in the fundus and the body of
the gallbladder. The repeated contraction and relaxation
improves the concentration efciency of the bile by replacing precipitated bile with a relatively lower concentration of
bile in the upper gallbladder. The repeated contraction and
relaxation also prevents cholesterol deposition, which can
6 Biliary Tract Functions andImpairment
53
lead to the formation of insoluble bile components, including
gallstones [8]. When food reaches the duodenum, CCK is
secreted from the duodenum and jejunum. CCK induces the
contraction of the gallbladder and the relaxation of the
sphincter of Oddi, leading to the excretion of the stored bile
into the duodenum. As in the other parts of the gastrointestinal tract, the motility of the gallbladder during digestion is
affected by the cephalic phase, antral phase, and duodenal
phase of digestion [9]. The cephalic phase is initiated by
stimulation from the central nervous system, such as olfactory and taste sensations. The gallbladder contracts upon
stimulation from the vagus nerve system, and approximately
30–40% of bile is released from the gallbladder at this stage.
When food reaches the stomach, a reex is induced in the
area from the pyloric antrum to the gallbladder (the antral
phase). During the duodenal phase, when food reaches the
duodenum, CCK is released from the duodenum and proximal jejunum and almost all of the remaining content of the
gallbladder is excreted [10].
6.2.2 Sphincter ofOddi
The sphincter of Oddi is a smooth muscle structure that is
approximately 1cm long. It regulates the junction of the bile
duct and pancreatic duct at the duodenum, preventing regurgitation of bile and pancreatic uid as well as contents of the
duodenum (Fig.6.2). The functions of the sphincter of Oddi
are regulated by the neuroendocrine system [11]. Between
periods of digestion, the sphincter of Oddi contracts in a
peristaltic manner, which regulates the outow of bile into
the duodenum and helps store the bile in the gallbladder.
During digestion, CCK and autonomic nerves relax the
sphincter of Oddi and the adjacent segment of the duodenum
in a coordinated manner. This helps excrete bile into the duodenum efciently. The relaxation of the sphincter of Oddi by
autonomic nerves involves stimulation mediated by nonadrenergic inhibitory neurons from the vagus nerve and the
neurospinal reex with visceral nerves as afferent and efferent pathways. Morphine and pentazocine contract the sphincter of Oddi and increase the internal pressure of the biliary
tract. In contrast, atropine, butylscopolamine bromid, nitroglycerin, and calcium channel blockers relax muscles, leading to reduced tension and inhibited motility [12].
caused by metabolic abnormalities or a direct motility disturbance of the gallbladder, though this condition has not been
clearly dened. Gallbladder dysfunction causes pain similar
to chronic cholecystitis [13]. According to the Rome IV criteria, a set of diagnostic criteria used to diagnose functional
gastrointestinal disorders, gallbladder motility disorders
should be diagnosed when moderate-to-severe pain persists
for 30min or longer in an area from the epigastric region to
the right hypochondrium region [14]. Furthermore, gallstones and other organic abnormalities need to be ruled out
via imaging examinations (such as an abdominal ultrasonography) before motility disorders can be diagnosed. A reduced
gallbladder ejection fraction is observed on provocative cholescintigraphy in patients with gallbladder motility disorders
when CCK is administered intravenously. A laparoscopic
cholecystectomy relieves the symptoms of gallstones and
gallbladder motility disorders.
6.3.2 Dysfunction oftheSphincter ofOddi
The sphincter of Oddi regulates the excretion of bile and
pancreatic juice and prevents the regurgitation of duodenal
juice into the bile ducts and pancreatic duct. In papillary dysfunction, the sphincter of Oddi is excessively contracted,
which inhibits the excretion of bile and pancreatic juice [14,
15]. This leads to increased internal pressure of the bile ducts
and the pancreatic duct, causing various symptoms.
Dysfunction of the sphincter of Oddi can be broadly classied into pancreatic and biliary types. The pancreatic type is
characterized by an increase in the blood pancreatic enzymes,
amylase, and lipase, accompanied by symptoms such as
abdominal pain. The biliary type is frequently observed in
patients who have developed persistent or recurrent abdominal pain after a cholecystectomy and is characterized by elevations of alanine transaminase (ALT) and alkaline
phosphatase (ALP), as well as dilation of the bile ducts.
Nifedipine and nitroglycerin can be administered to treat
dysfunction of the sphincter of Oddi. An endoscopic papillotomy can be performed if the drugs are ineffective, and
surgery is performed if the papillotomy is ineffective.
6.3.3 Pancreaticobiliary Maljunction
6.3 Impairment ofBiliary Tract
6.3.1 Gallbladder Dysfunction
The gallbladder and sphincter of Oddi contain muscle bers.
Dysfunctions of these organs can occur when their motility
is inhibited. Gallbladder dysfunction is a motility disorder
Pancreaticobiliary maljunction is a congenital malformation
in which the pancreatic duct and the bile duct join outside the
duodenal wall, forming a long common channel. In patients
with pancreaticobiliary maljunction, the sphincter of Oddi
does not regulate the conuence of the pancreatic duct and
bile duct, resulting in bidirectional regurgitation of bile and
pancreatic juice. Due to the reciprocating ow of pancreatic
juices and bile, various complications may develop in the
>
Secreti
54
bile duct and the pancreas. Reux of pancreatic juice into the
biliary tract is associated with a high incidence of cholangitis
and cholangiocarcinoma. Congenital biliary dilatation,
which is also known as “congenital choledochal cyst,” is a
disease in which the extrahepatic bile duct, or both the extra
and intrahepatic bile ducts, is dilated in various ways and
involves pancreaticobiliary maljunction. In cases with congenital biliary dilatation, because there is an increased incidence of extrahepatic bile duct cancer or gallbladder cancer,
prophylactic resection of the dilated extrahepatic biliary duct
and gallbladder followed by hepaticojejunostomy is considered as a standard treatment [16].
6.4 The Functions ofBile
6.4.1 The Physiology ofBile
Bile is weakly alkaline (pH: 7.1–7.3) and the total amount
of bile produced and secreted per day is 600–1200mL.The
main components of bile include bile acids, phospholipids,
cholesterols, and bilirubin. Bile also contains proteins,
inorganic salts, and metabolized or detoxied drugs.
Hepatic bile is excreted into the bile canaliculi and stored
in the gallbladder via the bile ducts. Water and electrolytes
are reabsorbed in the gallbladder by the epithelium and
concentrated 5- to 10-fold to form gallbladder bile. Bile
can be divided into bile in the canaliculi, which is produced by hepatocytes, and bile secreted from the cholangiocytes of the epithelium. The secretion of bile in the
canaliculi consists of bile acid- dependent bile ow and
bile acid-independent bile ow [17]. These two types of
bile ow lead to the excretion of sodium ions and water
into the bile ducts. Bile acid-dependent bile ow uses bile
acid, which is actively excreted from the hepatocytes; bile
acid-independent bile ow uses glutathione, which is also
excreted from the hepatocytes. Bile secreted from the
cholangiocytes contains a large amount of bicarbonate and
is secreted via Cystic brosis transmembrane conductance
regulator (CFTR), a chloride ion channel [18] (Fig.6.3).
Secretin, a digestive hormone, facilitates the secretion of
bile in the bile ducts via cyclic adenosine monophosphate
(cAMP); in contrast somatostatin, gastrin, and insulin
block secretin receptors and suppress the secretion of bile
in the bile ducts [19, 20].
6.4.2 Enterohepatic Circulation
Bile is secreted from hepatocytes into the bile canaliculi. It is
eventually excreted into the duodenum after passing through
the biliary system. Bile contains biological substances and
drugs that are metabolized in the liver. Some of these sub-
H. Ohtsuka and M. Unno
<Bile duct lumen
<Apical><Basolateral>
H
O
2
CFTR
-
PKA
cAMP
n
Secretin
receptor
<Cholangiocyte>
Fig. 6.3 Regulation of cholangiocyte bicarbonate secretion by secre-
tin. AQP aquaporin, AE2 Cl
exchanger, PKA protein kinase A
CI
AE2
AQP1
+
Na
NHE
−
−
/HCO
anion exchanger 2, NHE Na+/H+
3
CI
HCO
H
2
H
H
2
–
–
3
O
+
O
stances are reabsorbed in the intestine and returned to the
liver via the portal vein to be secreted second time, a cycle
termed enterohepatic circulation. Enterohepatic circulation
involves bile acid that is synthesized in the liver and physiologically active substances, including vitamin D3, vitamin
B12, and folic acid, and ensures the effective use of these
substances. Drugs such as morphine, warfarin, and digoxin
are metabolized in the liver and enter the enterohepatic circulation. These drugs are excreted into bile after being conjugated with glucuronide in the hepatocytes. Glucuronide
conjugates are highly polar and not easily absorbed in the
small intestine. However, they are hydrolyzed by
β-glucuronidase from the enteric bacteria and metabolized to
parent compounds. This increases the lipid solubility and
intestinal absorption of the compounds.
6.4.3 Bile Acids
Bile acid consists of primary bile acids (cholic acid and chenodeoxycholic acid) and secondary bile acids (deoxycholic
acid and lithocholic acid). Primary bile acids are synthesized
from cholesterol in the hepatocytes, and secondary bile acids
are produced through the biotransformation of primary bile
acid by the enteric bacteria. Bile acid is amphiphilic, containing both hydrophilic and hydrophobic parts within its
molecules. Therefore, bile acid acts as a biological surfactant, forming micelles that have an outer hydrophilic part and
an inner hydrophobic part. Human bile acid contains a large
number of conjugated amino acids, such as glycine and tau-
Uptak
bile acids
<Sinusoid>
6 Biliary Tract Functions andImpairment
rine. Compared to free bile acid, conjugated bile acid is
highly polar with increased solubility. Bile acid is excreted
into the intestine, and the majority of bile acid is reabsorbed
in the small intestine through enterohepatic circulation.
Uptake in the sinusoidal membrane and the excretory system
in the canalicular membranes of hepatocytes play an important role in this mechanism. Sodium-dependent taurocholate
co-transporting polypeptide (NTCP), a sodium-dependent
transport carrier, and organic anion transporting polypeptide
(OATP), a sodium-independent transport carrier, are involved
in the uptake of bile acids in the sinusoidal membrane [21].
While NTCP has a high substrate-specicity for bile acid,
OATP is also involved in the uptake of hydrophobic organic
compounds, such as bilirubin and indocyanine green. The
excretion of bile acid from hepatocytes is regulated by drug
transporters, such as bile salt export pump (BSEP) and multidrug resistance-associated proteins 2 and 3 (MRP2 and
MRP3). BSEP and MRP2 are expressed in the bile canaliculi, and MRP3 is expressed in the sinusoidal membrane of
hepatocytes [20]. These efux transporters are considered to
perform ATP-dependent primary active transport.
6.4.4 Cholesterol andBile Pigments
55
Oxysterol
LXR
e of
NTCP
OATPs
MRP3
Fig. 6.4 Cholesterol and bile acid metabolism in the hepatocyte
Cholesterol
CYP7A1
FXR
Bile acids
Primary BAs
Secondary BAs
Phospholipids
ABC G5/8
Bile acid
synthesis
BSEP
MRP2
<Hepatocyte>
<Canaliculus>
MDR3
hydroxylase (CYP7A1). FXR is activated by the ligand bile
acid. FXR inhibits CYP7A1 and reduces the expression of
NTCP and OATP. Together, these regulatory mechanisms
lead to increased or decreased hepatic cholesterol levels. The
synthesis of bile acid increases when hepatic cholesterol levels are high. In contrast, when bile acid levels are high, bile
acid synthesis decreases.
The cholesterol in the bile is in the hydrophobic free form
rather than the hydrophilic ester form. Cholesterol is one of
the hydrophobic substances that are dissolved by the mixed
micelles formed by bile acids and phospholipids. Cholesterol
precipitates as crystals and forms gallstones when the cholesterol content in bile is higher than the number of bile acids
and phospholipids.
The color of bile and stool is affected by bile pigments.
One of the most important bile pigments is bilirubin. Bilirubin
is derived from heme proteins, such as hemoglobin, catalase,
and cytochrome. It is taken up by OATPs, which are expressed
in the cell membrane on the vascular side of hepatocytes.
Bilirubin is secreted into bile by the efux transporter MRP2
after being conjugated with glucuronide. Conjugated bilirubin is reduced and metabolized to urobilinogen by the enteric
bacteria and excreted in the feces. Part of the bilirubin is reabsorbed through enterohepatic circulation.
6.4.5 Nuclear Receptors andBile Acid
Metabolism
The metabolism of cholesterol and bile acid is primarily regulated by the nuclear receptors Liver X Receptor (LXR) and
Farnesoid X Receptor (FXR) [22] (Fig.6.4). LXR is activated by the ligand oxysterol. LXR facilitates the synthesis
of bile acid by upregulating the activity of cholesterol-7α-
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plasma cholecystokinin (CCK), duodenal release of CCK, diurnal
variation of plasma CCK, and immunoreactive plasma CCK components in man. Hepato-Gastroenterology. 1980;27:300–9.
11. Peeters TL, Vantrappen G, Janssens J. Bile acid output and the
interdigestive migrating motor complex in normals and in cholecystectomy patients. Gastroenterology. 1980;79:678–81.
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16. Kamisawa T, Kaneko K, Itoi T, etal. Pancreaticobiliary maljunction
and congenital biliary dilatation. Lancet Gastroenterol Hepatol.
2017;2:610–8.
17. Nathanson MH, Boyer JL. Mechanisms and regulation of bile
secretion. Hepatology. 1991;14:551–66.
18. Kanno N, LeSege G, Glaser S, et al. Secretin regulation of Cholangiocyte bicarbonate secretion. Am J Phys.
2001;281:G612–25.
19. Glaser SS, Rodgers RE, Phinizy JL, etal. Gastrin inhibits secretininduced ductal secretion by interaction with specic receptors on
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20. Lesage GD, Marucci L, Alvaro D, etal. Insulin inhibits secretininduced ductal secretion by activation of PKC alpha and inhibition
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21. Paumgarter G. Biliary physiology and disease: reactions of a
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22. Calkin AC, Tontonoz P. Transcriptional integration of metabolism
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Mol Cell Biol. 2012;13:213–24.
Preinvasive Intraductal Biliary
Neoplasm: Biliary Intraepithelial
Neoplasm andIntraductal Papillary
Neoplasm ofBile Duct
YasuniNakanuma, KatsuhikoUesaka, andTakuroTerada
7
Abstract
Biliary intraepithelial neoplasm (BIlIN) and intraductal
papillary neoplasm of the bile duct (IPNB), an intraductal
non-invasive neoplasm, are being established pathologically as precursor lesions of invasive cholangiocarcinoma
(CCA). These premalignant lesions are found in the extrahepatic and intrahepatic large bile duct but not in the
intrahepatic small bile duct. BilINs are a microscopical
lesion and can be classied into low-grade and highgrade. High-grade BilIN was previously called “in situ
carcinoma” of the bile duct. This lesion is presumed to be
followed by periductal nodular/sclerosing growth of
CCA. The preoperative detection of high-grade BilIN
may be an important step in the determination of the risk
of CCA. In contrast, IPNB shows grossly exophytic
growth in a dilated bile duct lumen, with histologically
villous/papillary neoplastic epithelia with tubular components covering ne brovascular stalks. Interestingly,
approximately half of IPNBs show stromal invasion
(IPNB associated with invasive carcinoma) at the time of
surgical resection. IPNBs are classied into low-grade
and high-grade dysplasia. The recent subclassication of
IPNB into types 1 (low-grade dysplasia and high-grade
dysplasia with regular architecture) and 2 (high-grade
dysplasia with irregular architecture) may be more practically applicable in the clinical eld than two-tiered sys-
Y. Nakanuma (*)
Department of Diagnostic Pathology, Shizuoka Cancer Center,
Shizuoka, Japan
Department of Diagnostic Pathology, Fukui Prefecture Saiseikai
Hospital, Fukui, Japan
K. Uesaka
Department of Hepatobiliary Pancreatic Surgery, Shizuoka Cancer
Center, Shizuoka, Japan
T. Terada
Department of Gastrointestinal Surgery, Fukui Prefecture Saiseikai
Hospital, Fukui, Japan
tem (low- and high-grade dysplasia). The outcome of
postoperative IPNBs is more favorable in IPNBs than in
CCA via BilIN processes. The recent recognition of two
preinvasive biliary neoplasms may facilitate further clinical and basic studies of CCA.
7.1 Introduction
The concept of epithelial tumors arising from non-invasive
intraepithelial dysplasia or neoplasm is well-established in
various human cancers [1]. Recent studies have shown that
there are at least two types of preinvasive neoplasms of the
bile ducts preceding cholangiocarcinoma (CCA): biliary
intraepithelial neoplasm (BilIN) and intraductal papillary
neoplasm of bile duct (IPNB) [2–5]. BilINs are microscopically identiable epithelial neoplasm, while IPNBs are
grossly visible epithelial neoplasms covering ne brovascular stalks (Figs.7.1, 7.2). BilIN may be the most common
precursor in nodular-sclerosing, perihilar and distal CCA (p/
dCCA) and large-duct intrahepatic CCA (iCCA). IPNBs
present unique pathological features, and about half of
IPNBs present stromal invasion at the time of surgical resection. Recently, the World Health Organization (WHO) published the Classication of Digestive System Tumours fth
edition (2019), in which BilIN and IPNB were introduced in
separate chapters [3, 4].
We herein review the pathological features of BilIN and
IPNB, based on this WHO classication, with reference to
the clinical and molecular and genetic features.
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022
M. Makuuchi et al. (eds.), The IASGO Textbook of Multi-Disciplinary Management of Hepato-Pancreato-Biliary Diseases,
https://doi.org/10.1007/978-981-19-0063-1_7
57
58
ab
Fig. 7.1 Biliary intraepithelial neoplasm (BilIN) of bile duct. (a) Low-grade BilIN showing mild nuclear stratication and hyperchromasia.
H&E.(b) High grade BilIN showing disordered nuclear polarity and pleomorphism. H&E
Y. Nakanuma et al.
a
b
c
Fig. 7.2 Intraductal papillary neoplasm of bile duct (IPNB). (a)
Grossly, papillary tumorous lesion (→) is found in the extrahepatic bile
duct. (b) Type 1 IPNB.Regular papillary neoplasm is found in the bile
duct. H&E. (c) Type 2 IPNB.Irregular papillary neoplasm with tubular
component and widened stroma is found in the bile duct. H&E
7 Preinvasive Intraductal Biliary Neoplasm: Biliary Intraepithelial Neoplasm andIntraductal Papillary Neoplasm ofBile Duct
59
7.1.1 Clinical Features, Risks,
andBackground Lesions andImaging
Findings ofBIlINs andIPNBs
7.1.1.1 Clinical Features, Risks, andBackground
Lesions
BilINs
There have been no reports on the clinical or laboratory features characteristic to BilINs. In the background in cases not
associated with invasive CCAs, BilINs, particularly highgrade ones, are occasionally found in patients with hepatolithiasis, primary sclerosing cholangitis (PSC), liver uke
infection, and anomalous union of the pancreatic biliary duct
and can also be found incidentally in bile duct and gallbladder specimens that are resected for other reasons [5, 6]. In
addition, BilIN is often encountered in the mucosa adjacent
to nodular/sclerosing CCA.BilINs are generally not associated with excessive mucin secretion.
IPNBs
IPNBs typically affect middle-aged to elderly adults and
show a male predominance [7]. Intermittent or recurrent,
right-upper-quadrant abdominal pain and acute cholangitis
or jaundice are the most common clinical manifestations, but
a certain percentage of patients have no symptoms at the
diagnosis [7]. Elevated levels of alkaline phosphatase and
CEA and CA19-9 have been reported, although they are
unlikely to have high sensitivity or specicity for the diagnosis of IPNB [7].
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 [8]. Hepatolithiasis and liver
uke infection (Clonorchiasis sinensis [CS] or Opisthorchis
viverrini [OV] infection) are major risk factors of IPNB in
Far Eastern countries [8]. IPNBs also reportedly develop in
PSC and congenital biliary tract disease. Interestingly,
these etiologic factors are also known as major risk factors
for nodular- sclerosing p/dCCA and large-duct iCCA [2],
suggesting that these factors may be causally related to the
development of IPNB and also of CCA via the BilIN process [9].
Recently, an outbreak of IPNB was reported among
young adult workers in the offset color proof-printing
department at a printing company in Japan [10]. They were
chronically exposed to chlorinated organic solvents, including dichloromethane and 1,2-dichloropropane. Interestingly,
IPNB or IPNB associated with invasive carcinoma was predominantly observed in the dilated intrahepatic and perihilar bile ducts.
7.1.1.2 Imaging Findings
BilINs
BilIN lesions cannot be accurately identied preoperatively
by existing imaging modalities. Occasionally, they are
detected as focal bile duct stenosis or dilatation in cases not
associated with CCA [11].
IPNB
The most important morphological changes are the presence
of (a) bile duct dilatation, (b) intraductal mass(es), (c) cystic
lesion(s), and (d) macro-invasion of the liver [12, 13]. The
patterns of bile duct dilatation are diffuse duct ectasia, localized duct dilatation, and cystic dilatation. IPNB lesions were
found more commonly at the right than left intrahepatic
ducts and had more peripheral than central locations in
patients with OV [11]. On US, IPNB was more variable with
hyperechoic nodules (37.5%), focal bile duct dilatation
(37.5%), and diffuse bile duct dilatation with intraductal
nodules (25%) [11]. Magnetic resonance imaging (MRI)
reveals IPNB as isointense to hypointense masses on
T1-weighted images and hyperintense masses on
T2-weighted images. On computed tomography (CT), the
enhancement pattern of IPNB is isodense or hyperdense during the late arterial phase and not hyperdense during the
portal-venous and delayed phase. Other ndings obtained by
CT are inltration of the neoplasm along the duct wall and
intense rim enhancement at the base of the lesion.
7.1.2 Pathologies ofBIlINs andIPNBs
7.1.2.1 Gross
BilIN
While BilIN lesions cannot be accurately identied grossly,
they may be recognized as subtle and nonspecic granular or
rough bile duct mucosa, particularly around invasive CCA
[5, 6]. As for the anatomical location, the majority of BilIN
cases not associated with CCA arose from the right intrahepatic duct, specically from a peripheral branch of the inferoposterior and superoposterior segments in cases with OV
infection [11].
IPNB
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
or hepatic hilum [12–14]. Some cases simultaneously
involved the intrahepatic and extrahepatic bile ducts. When
60
Y. Nakanuma et al.
IPNB exists in the intrahepatic bile ducts, it tends to be found
in the left-sided biliary ductal system [7]. However, IPNB in
OV-infected patients was found more commonly at the right
than left intrahepatic ducts and had more peripheral than
central locations [11].
Generally, IPNBs present papillary or villous or polypoid,
exophytic growth (range, 1–6cm) (Fig.7.2a) [2, 3, 5]; height,
at least 5mm from the adjacent biliary mucosa in the dilated
bile ducts is typical; however, some papillary neoplasms
with a similar histopathology that are <5mm but >3mm in
height are occasionally encountered [15]. These exophytic
lesions are usually conglomerates of smaller or higher polypoid lesions, but single or isolated polypoid lesions are also
encountered. IPNBs located in the intrahepatic bile ducts
tend to be larger in both mass and length than those in the
extrahepatic bile ducts.
The gross features of IPNBs depend on their anatomical
location, state of excessive mucin secretion, and macroinvasion of the liver [3, 12]. Some IPNBs, particularly those
arising in the extrahepatic bile ducts, are associated with cylindrical or fusiform morphology with moderate dilatation of the
affected bile ducts and appear as cast-like structures, while
other IPNBs, particularly those in the intrahepatic bile duct,
present with marked macroscopic dilatation or unilocular or
multilocular cystic changes. These cystic changes represent
cystic dilatation of the bile ducts and usually show luminal
communication with the adjacent bile duct. The internal surfaces of the cystic lesions are smooth or nely granular, and
papillary mural nodules are commonly observed. IPNBs may
present separate multiple lesions of various stages along the
biliary tree, both synchronously and dyssynchronously [7].
Some may represent multiple occurrences of IPNB in the bile
duct mucosa with a neoplastic predisposition, while others are
due to intraluminal implantation or dissemination of neoplastic cells of the main papillary tumor along the biliary tree [16].
Excessive mucin hypersecretion is more frequently observed
in intrahepatic IPNBs than in extrahepatic IPNBs. Bile ducts
with excessive mucin secretion located upstream and downstream from IPNBs are signicantly dilated due to the large
amount of mucin in the duct lumen.
A variable proportion of the mucosa around the main papillary conglomerate lesions shows visible granular or small
papillary lesions, suggesting neoplastic mucosal changes
that are continuous with the main lesion [3].
Controversial Cases: BilIN or IPNB
Some intraductal preinvasive biliary neoplasms present diffuse dilatation of the bile ducts without visible intraductal
tumors on imaging and macroscopic observation because of
their microscopic size [17]. Indeed, several case reports have
described extensive bile duct dilatation lled with mucin and
lined by a supercially spreading, microscopically identiable, non-invasive biliary neoplasm despite no grossly visible identiable papillary neoplasms [18]. Whether these
cases correspond to a variant of BilIN with bile duct dilatation
and mucin hypersecretion or should be regarded as a variant
of IPNB with microscopic neoplastic size remains unclear.
7.1.2.2 Histologies
BilINs
BilINs show a at or micropapillary, intraepithelial biliary
neoplasm occasionally with glandular formation and are
composed of enlarged columnar or cuboidal epithelial cells
with stratied hyperchromatic nuclei and a high nucleus/
cytoplasm ratio (Fig. 7.1a, b) [2, 4, 5]. Nuclear pleomorphism and nucleoli may be also found. The intramural
peribiliary glands may be continuously involved. BilINs usually occur in the extrahepatic and intrahepatic large bile
ducts but are also found in the gallbladder. While a majority
of BIlINs are of pancreatobiliary phenotype, the gastric and
intestinal phenotypes are also encountered.
Grading and Invasion A two-tiered grading system of
“low” versus “high” is applied to BilINs in order to delineate
the clinically signicant examples from the insignicant
ones. High-grade BilIN was previously called “in situ carci-
noma” of the bile duct. The main differential features are
shown in Table7.1 [2, 4]. High-grade BilIN usually forms a
eld of lesional spread of neoplastic epithelial cells on the
biliary mucosa. Immunohistologically, high-grade BilINs
are constantly diffusely and strongly positive for S100P, a
differential point from low-grade BilIN or reactive changes
[5]. High-grade BilINs express CEA and MUC1 [19] and
also selectively stain for insulin-like growth factor II mRNA
binding protein (IMP3) [19].
High-grade BilINs are frequently found in the bile duct
mucosa around nodular-sclerosing CCAs [2, 5, 16], with
Table 7.1 Comparison between low-grade BilIN and high-grade BilIN
Characters Low-grade BilIN (BilIN-1/2) High-grade BilIN (BilIN-3)
Histology Flat/pseudopapillary/micropapillary
Hyperchromatic nuclei
Increased N/C ratio
Stratied or multi-layered nuclei
Reserved nuclear polarity
Distribution in biliary mucosa Relatively small foci or area Relatively extensive area or spread
S-100P expression Weakly or scattered expression Strongly and diffusely positive
Flat/pseudopapillary/micropapillary
Hyperchromatic and irregular nuclei
Increased N/C ratio, pleomorphic, bizarre nuclei
Single layered or stratied nuclei
Disturbed nuclear polarity
7 Preinvasive Intraductal Biliary Neoplasm: Biliary Intraepithelial Neoplasm andIntraductal Papillary Neoplasm ofBile Duct
61
high-grade BilINs likely being a preceding lesion of these
CCAs. Indeed, microscopic stromal invasion of tubular adenocarcinoma is occasionally found beneath high-grade
BilINs in patients without grossly visible CCA, suggesting
the actual development of invasion from high-grade BilIN
resulting in conventional CCA.
IPNB.
IPNBs are a preinvasive, papillary/villous biliary neoplasm
with variable tubular components covering ne brovascular
stalks or with brous stroma in dilated bile ducts (Fig.7.2b,
c). Some cases of IPNB, particularly oncocytic subtype,
show mildly widened stroma due to edema with inammatory cell inltration [3]. The histology of IPNB is heterogeneous, depending on the subtypes and grade of atypia.
Four Subtypes IPNBs are histologically classiable into
four subtypes based on their cell lineages: intestinal IPNB
(iIPNB), gastric IPNB (gIPNB), pancreatobiliary IPNB (pbIPNB), and oncocytic IPNB (oIPNB) [2, 3]. While many
cases are predominantly composed of an individual subtype,
admixtures of foci of other subtypes and cases with controversial subtyping are sometimes observed. This subtyping is
facilitated by immunohistochemistry to detect mucus core
proteins and cytokeratins. As for the incidence, iIPNB is the
most common subtype, followed by gIPNB, pbIPNB, and
oIPNB. There are no apparent differences in sex or age
among the four subtypes of IPNB.
Grading of Atypia
IPNBs are traditionally classied into
low-grade and high-grade, mainly based on the cellular
atypia and structural alterations, particularly nuclear atypia
and alteration [2, 3, 20]. For example, the high-grade IPNBs
show hyperchromatic nuclei, nucleoli, nuclear and cellular
pleomorphism, and a loss of polarity, while the low-grade
IPNBs do not. Some IPNBs are low-grade, while others are
high-grade or high-grade with low-grade foci.
IPNBs show structural changes or alterations: some cases
show regular papillary, villous or tubular structures, and a
relatively homogeneous appearance (type 1), while others
show irregular papillary, villous or tubular structures, and a
heterogeneous appearance (type 2). Mainly based on these
structural alterations, Japan–Korea biliary pathologists propose a new subclassication of IPNB into types 1 and 2 [15].
IPNBs with a low-grade (about 10% of all IPNBs) and those
with a high-grade with regular structures (30%) belong to
type 1, while the remaining IPNBs with a high grade and
irregular structures (60%) belong to type 2. In type 1, papillary brovascular stalks are generally thin (depending on the
subtype), while brovascular stalks are variably widened at
the basal side in some cases. In addition, type 2 does not
Table 7.2 Type 1 and 2 subclassication of intraductal papillary neo-
plasms of bile duct (IPNB)
Type 1 IPNB Type 2 IPNB
Structures * Regular villous,
Atypia of intraepithelial
neoplasm
Location at the biliary tree *Usually
Mucin overproduction * Frequent * Infrequent
Stromal invasion * Rare * Common
Subtypes
• Intestinal subtype
• Gastric subtype
• PB subtype
• Oncocytic subtype
Similarities to prototypic
subtypes of IPMN
Poor differentiation such
as solid or cribriform
pattern, coagulative
necrosis, overt malignant
features, cystic changes
Highly atypical cellular
and nuclear changes
Fibrovascular stalks * Thin (depending
papillary, or
tubular structures
* Homogeneous
appearance
* Low-grade
dysplasia
*High-grade
dysplasia with
regular
histologies
intrahepatic bile
duct
* Infrequent
* Equal
* Infrequent
* Frequent
* Similar
(depending on
subtypes)
* Almost absent * Frequent
* Absent * Infrequent
on subtype)
* Irregular and
complicated villous,
papillary or tubular
structures
* Heterogeneous
appearance
* High-grade
dysplasia with
irregular histologies
*Intrahepatic and
extrahepatic bile
duct
* Frequent
* Equal
* Frequent
* Infrequent
* Different variably
(depending on
subtype)
* Thin to widened
(depending on
subtype)
infrequently show foci of complicated lesions, such as cribriform and solid components, and relatively large cystic
changes and foci of bizarre cells and nuclear changes.
Coagulative necrosis is also experienced in type 2.
Neuroendocrine differentiation has been reported in type 2
IPNB.The main differential features between types 1 and 2
are shown in Table7.2.
As for other characteristics, type 1 tends to arise in the
intrahepatic bile ducts, while type 2 develops similarly in the
extrahepatic and intrahepatic bile ducts. Furthermore,
according to recent studies, types 1 and 2 show other clinicopathological and molecular-genetic differences [21–23]:
Type 1 IPNBs were frequently associated with a noninvasive, intestinal and oncocytic subtypes, development in
the intrahepatic bile ducts, mucin hypersecretion, a relatively
good prognosis and old age, while type 2 IPNBs were associated with an invasive, pancreatobiliary subtype, frequent
development within the extrahepatic bile ducts and a worse
prognosis than type 1 IPNBs.