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www.elsevier.com/locate/cdip
a
Department of Anatomic Pathology, 113B, VA and UCSF Medical Center, 4150 Clement Street,
San Francisco, CA 94121, USA
b
Anatomic Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
KEYWORDS Summary Biliary hamartoma, bile-duct adenoma (BDA) and mucinous cystadeno-
Biliary tumours; ma are the most common benign biliary tumours. Hamartomas occur sporadically or
Benign; in association with polycystic liver disease. BDAs may represent a localized response
Malignant; to injury rather than true neoplasms. Cystadenomas are multilocular lesions lined by
Hamartoma; mucinous epithelium, often with cellular ovarian-like stroma. Cytologic atypia may
Von Meyenburg suggest malignant transformation, but stromal invasion must be identified for
complex; diagnosis of cystadenocarcinoma. Cholangiocarcinoma (CC) is the most common
Adenoma; malignant neoplasm. Risk factors include primary sclerosing cholangitis, liver flukes,
Cystadenoma; hepatolithiasis and thorotrast exposure. The tumours show mass-forming, periduc-
Cystadenocarcinoma; tal-infiltrating or intraductal growth patterns. Intrahepatic CC presents as a hepatic
Cholangiocarcinoma; mass and can be confused with hepatocellular carcinoma or metastatic adenocarci-
Dysplasia; noma. Immunohistochemistry and albumin in situ hybridization are helpful in this
Intraductal distinction. The diagnosis of extrahepatic CC can often be elusive due to the marked
papillomatosis stromal desmoplasia, and multiple endoscopic biopsies and brushings may be
required. Loss of p53 is common in mass-forming intrahepatic CC, and K-ras
mutations in periductal-infiltrative extrahepatic tumours. Prognosis is poor, with 5-
year survival of o20%. Lymph-node metastasis and surgical margin status are the
most significant prognostic factors.
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0968-6053/$ - see front matter & 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.cdip.2004.10.007
ARTICLE IN PRESS
Tumours of the biliary system 35
Bile-duct adenoma
Clinical features
Bile-duct adenoma (BDA) is a less common lesion
than BH. The designation ‘adenoma’ may be a
misnomer as it may not represent a true neoplasm Figure 2 BDA: uniform round ducts lined by bland
but a localized ductal proliferation at a site of cuboidal epithelium.
previous injury2 or peribiliary gland hamartoma.3
BDAs are usually found incidentally at surgery or chemically, BDA expresses both 1F6 and D10
autopsy, and may be sent for frozen section to (antigens extracted from bile-duct cell cultures),
exclude metastasis. a profile similar to bile ductules and canals of
Hering.3
Pathologic features
BDA is typically small (o2 cm), firm, gray-white, Differential diagnosis
well circumscribed, often subcapsular, and can be The absence of nuclear atypia, mitoses and
single or multiple. The ducts are uniform in size and vascular invasion distinguish BDA from adenocarci-
with less intervening fibrous stroma compared to noma. The uniform round outlines of glands,
hamartomas. The stroma is typically more abun- relatively less stroma, lack of bile, absence of
dant centrally than peripherally. The lesional ducts cystic change, and lack of association with poly-
have round outlines and are lined by bland cuboidal cystic liver disease separate it from BH. In contrast
epithelium without mitotic activity (Fig. 2). Bile is to BDA, BHs express D10 but not 1F6.3
not present, and the ductules do not communicate
with the biliary tree. Mucinous metaplasia, a1- Prognosis
antitrypsin droplets, and neuroendocrine differen- BDA is a benign lesion and malignant change is not
tiation may be seen. The endocrine cell clusters known to occur.
must not be confused with metastatic carcinoid or
islet cell tumour.4 A rare variant with clear cells has
Biliary (hepatobiliary) cystadenoma and
been described which can be mistaken for primary
cystadenocarcinoma
or metastatic clear-cell carcinoma.5 Immunohisto-
Clinical features
Biliary cystadenomas are rare lesions, with a higher
incidence in women and histological counterparts
in the pancreas and ovary. It can be associated with
the development of cystadenocarcinoma, which
occurs equally in men and women. The mean age
for cystadenocarcinoma (59 years) is higher than
that for cystadenomas (45 years).6
Pathologic features
Cystadenomas are 5–15-cm multilocular cysts with
a smooth or somewhat trabeculated inner surface.
The cysts are relatively few in number (oligocystic),
tend to be large (macrocystic) and contain fluid of
variable appearance, including serous, mucinous,
gelatinous, occasionally hemorrhagic, or even
Figure 1 BH: irregularly dilated ductules embedded in a purulent. There is no communication between the
dense fibrous stroma. cysts and the biliary tree. The presence of large
ARTICLE IN PRESS
36 S. Kakar, L.J. Burgart
polypoid projections or solid masses in the cyst wall nodes, peritoneum and lung.8 Cystadenocarcino-
is characteristic of cystadenocarcinoma. The cysts mas with mesenchymal stroma occur exclusively in
are lined by a single layer of mucinous epithelial women and behave indolently. In men, these
cells, and small papillary tufts may be present. The tumours lack ovarian-like stroma and behave more
epithelial nuclei are bland and basally located, aggressively.6
without mitotic activity. In women, the cysts are
essentially always associated with a cellular me-
senchymal component resembling ovarian stroma Other benign biliary tumours or tumour-like
(Fig. 3). Densely hyalinized stroma often separates conditions
the ovarian-like stroma from the adjacent liver.
The cyst wall may also be focally lined by Biliary adenofibroma is a rare entity, with three
macrophages, calcification, or scar-like tissue. reported cases in the literature.9 It consists of
Cystadenocarcinomas arising in this lesion often tortuous and branching ductular elements with
have a tubulopapillary, solid or adenosquamous microcystic dilatation, cuboidal to flattened lining
histology.6 Features such as marked nuclear pleo- epithelium, prominent fibroblastic stroma between
morphism, loss of polarity, mitotic figures, and the glands, and immunohistochemical expression of
multilayering of the epithelium suggest malignant D10 but not IF6. Hence it shows marked resem-
transformation, and can be designated as in situ blance to BH, but is larger and is not associated
adenocarcinoma, but stromal invasion is necessary with any typical von Meyenburg complexes. It
for the diagnosis of cystadenocarcinoma.6 Since differs from BDAs, which usually lack cystic config-
malignant change can be focal, extensive sampling uration, have less stroma, and express both 1F6 and
is recommended.7 The presence of a benign D10. Monosomy 22 has been reported in one case.11
epithelial component in up to one-third of cysta- Biliary adenofibroma is considered a benign lesion,
denocarcinomas supports the view that at least and malignant transformation has not been ob-
some of them arise from cystadenomas. Immuno- served. However, the large size and the reported
histochemically, cystadenomas and cystadenocarci- presence of positive p53 immunostaining and
nomas are identical and mark for cytokeratin, tetraploidy raise the possibility of a premalignant
carcinoembryonic antigen and epithelial membrane lesion.
antigen. Scattered chromogranin-positive cells can Serous cystadenoma is rare in the liver and is
occasionally be present. similar to its pancreatic counterpart, consisting of
multiple microcysts lined by bland glycogen-rich
Prognosis cuboidal epithelium (Fig. 4).6 The cysts lack the
Cystadenomas are benign tumours and can be cellular mesenchymal stroma characteristic of
successfully treated by total excision. Cystadeno- mucinous cystadenoma.
carcinomas can invade the adjacent viscera and Neuromas of the extrahepatic biliary ducts can
may occasionally spread to the regional lymph cause obstructive jaundice. They are often trau-
matic in origin, typically after cholecystectomy.12
Lymph-node metastasis and status of surgical in the extrahepatic biliary tree than in mass-
margins are the most common factors influencing forming intrahepatic CC, while p53 mutations are
outcome. Lymph-node involvement is seen in more more common in the latter.41 Alterations of the p16
than 50% of patients at presentation.16 Lymphovas- gene are also frequent, and promoter hypermethy-
cular or perineural invasion, intrahepatic satellite lation may be the most common cause of inactiva-
nodules, and bilobar distribution have been shown tion in intrahepatic CC. Loss of p16 may be a useful
to predict poor survival.38 Mass-forming tumours diagnostic test for PSC-associated cancer.42 Fre-
have a better outcome compared to tumours with a quent overexpression of human telomerase reverse
periductal-infiltrating pattern.28 Tumours with a transcriptase is seen in dysplasia and invasive
marked desmoplastic response may have a higher carcinoma, indicating that it may be an early event
incidence of lymphatic invasion, higher prolifera- in carcinogenesis. The detection of a telomerase
tive activity and lower survival.24 Poorly differen- ladder in biopsy samples has been shown to be an
tiated tumours and variants such as signet-ring and excellent tool for diagnosis.43 Hepatocyte growth
sarcomatous carcinoma may behave aggressively. factor, c-met, is overexpressed in CC and correlates
with tumour differentiation. Other alterations
Pathogenesis and molecular abnormalities include mutations of E-cadherin, b-catenin and
The risk factors of CC, such as PSC and parasitic DPC-4 genes, HER-2/neu gene amplification and
infestations, have chronic inflammation and cho- microsatellite instability.
lestasis as their common link. Chronic inflammation
leads to production of cytokines such as interleu-
Carcinoma affecting the extrahepatic biliary
kin-1 and -6, and interferon-g, some of which have
potent mitogenic effects on biliary epithelial cells.
tree
The proinflammatory cytokines also lead to the
Clinical features
expression of inducible nitric oxide synthase. This
Extrahepatic CC can be divided into tumours arising
in turn leads to generation of nitric oxide and
reactive oxygen radicals, which can irreversibly close to the hilum of the liver (perihilar CC) or in
the distal portion of the bile duct (distal CC).
damage the DNA of the epithelial cells. Nitric oxide
Perihilar neoplasms (also known as Klatskin tumour)
also inactivates key DNA-repair proteins by nitro-
constitute nearly two-thirds of all CC. Patients
sylation, leading to accumulation of potentially
present with obstructive jaundice, repeated at-
oncogenic mutations.17,36 Nitrosylation of caspase
proteases can inactivate caspase 9 with inhibition tacks of cholangitis, and a cholestatic biochemical
of apoptosis.39 Bile acids can increase the levels of profile. Persistent elevation of tumour markers like
COX-2 and myeloid-cell leukemia protein 1 in CA19-9 in the absence of cholangitis can be useful
cholangiocytes; both these molecules can exert for diagnosis.
potent anti-apoptotic effects.40 Bile composition is
altered in chronic cholestasis, and levels of reduced Pathologic features
glutathione are reduced. This compromises a key The tumours may have an infiltrative (70–80%),
intracellular defense against oxidative injury. nodular (20%) or intraductal (o5%) growth pattern.
Hence chronic inflammation and cholestasis exert The infiltrative and nodular tumours are often
a strong proliferative and mutagenic influence on poorly differentiated, tend to spread along the
the biliary epithelium. mucosa and submucosa, and are accompanied by
Loss of p53 and K-ras mutations are the most striking desmoplastic response. Encasement of the
common molecular alterations observed in CC. Loss right or left portal vein is present in one-third of
of p53 is reported in up to 50% of intrahepatic mass- the patients and leads to ipsilateral lobar atrophy.
forming tumours, and can occur by mutation, LOH Lymph-node metastasis occurs in 30–50% of pa-
at 17p or MDM2 gene amplification.36 Inactivation tients at resection, hilar and pericholedochal lymph
of p53 leads to deregulation of bcl-2, and poten- nodes being the most commonly affected. Tumours
tially causes resistance to apoptosis. Loss of bcl-2 arising in the setting of PSC can be multifocal and
correlates with lymph-node metastasis, vascular associated with dysplasia and carcinoma in situ at
invasion and aberrant p53 expression.36 K-ras multiple sites. Due to the marked stromal desmo-
mutations usually affect codon 12 and vary widely plasia, the pathologic diagnosis can often be
with the geographical location and tumour site. elusive, and multiple endoscopic biopsies and
The incidence is up to 100% in England, 50–56% in brushings may be required. Pathologic diagnosis
Japan and 0–8% in Thailand, possibly reflecting may be possible in only 40–70% of cases. The use of
differences in underlying etiology. K-ras mutations ancillary techniques—including digital image ana-
are more common in periductal-infiltrative tumours lysis and fluorescence in situ hybridization to
ARTICLE IN PRESS
40 S. Kakar, L.J. Burgart
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