Case Report
Non-functioning well-differentiated
neuroendocrine tumor of the extrahepatic
bile duct: an unusual suspect?
Harsheet Sethi, Mansoor Madanur, Parthi Srinivasan, Bernard Portmann,
Nigel Heaton and Mohamed Rela
London, UK
BACKGROUND:  Neuroendocrine tumors (NETs) arising
in the biliary tree are extremely rare, and 37 cases were
identified in the English literature.
METHODS: A well-differentiated NET was found arising
from the junction of the cystic and common hepatic ducts,
in a 51-year-old male presenting with pedal edema and
weight loss with abnormal liver enzymes and a normal
serum bilirubin level. No mass was seen on radiological
imaging and biopsy of the liver was suggestive of an early
cholangiopathy. A bile leak complicating the liver biopsy
led to an ERCP that demonstrated a filling defect suggestive
of a mass in the common bile duct (CBD).
RESULTS: He underwent a successful excision of the tumor
with a Roux-en-Y hepaticojejunostomy. The diagnosis of
NET was made on histological and immunohistochemical
analysis of the resected specimen. He remains well and
disease free 22 months after surgery.
CONCLUSIONS: Recognition of biliary NET continues to
be a challenge and an increased awareness of these tumors
in rare sites will result in optimal management of these
tumors.
(Hepatobiliary Pancreat Dis Int 2007; 6: 549-552)
KEY WORDS: carcinoid;
 neuroendocrine tumor;
 biliary;
 common bile duct
Author Affiliations:  Department of Hepatobiliary and Transplant
Surgery (Sethi H, Madanur M, Srinivasan P, Heaton N and Rela M); and
Department of Histopathology (Portmann B), Kings College Hospital,
Denmark Hill, London SE5 9RS, UK
Corresponding  Author:  Mohamed Rela, FRCS, Institute of Liver
Studies, Kings College Hospital, Denmark Hill, London SE5 9RS, UK (Tel:
0044-2032999000ext4801; Fax: 0044-2073463575; Email: Mohamed.rela@
kcl.ac.uk)
© 2007, Hepatobiliary Pancreat Dis Int. All rights reserved.
Hepatobiliary Pancreat Dis Int，Vol 6，No 5 • October 15，2007 • www.hbpdint.com • 549
Introduction
C
arcinoma of the extrahepatic bile ducts
accounts for less than 2% of all cancers, and
these are predominantly cholangiocarcinomas
(80%).[1] Bile ducts remain one of the rarest primary
sites for neuroendocrine tumors (NETs) accounting
for 0.2% to 2.0% of all such tumors.[1]
NETs (previously known as carcinoid tumors)
arise from embryonal neural crest cells (Argentaffin
or Kulchitsky cells), which migrate to the respiratory
and gastrointestinal tracts during development. The
paucity of these cells in the biliary tree explains the
rarity of NET in this site. Familiarity with unusual
sites of origin facilitates early recognition and
characterization of these tumors, allowing for timely
intervention.
A review of the published literature since the first
reported case in 1959[2] identified 52 cases of well-
differentiated NET of the extrahepatic bile ducts. We
present the second case of a tumor arising at the
junction of the cystic and common hepatic ducts.[3]
Case report
A 51-year-old man presented with swelling of both
legs and weight loss over one year. There was no
history of jaundice. He was a heavy smoker. Clinical
examination revealed clubbing and pedal edema with
extensive varicosities in both lower limbs. Abdominal
examination showed nothing abnormal. Laboratory
tests showed elevated levels of aspartate transaminase
145 U/L (normal: less than 70), alkaline phosphatase
227 U/L (normal: 42 to 128), gamma-glutamyl
transferase 1399 U/L (normal: 10 to 66), serum
bilirubin of 9 μmol/L (normal: 0 to 17) and albumin
of 42 g/L (normal: 35 to 50). The level of CA19-9

Fig. 1. Cholangiogram revealing a filling defect in the proximal
CBD with non-visualisation of the gallbladder.
Fig. 2. At completion of the procedure with a plastic stent
placed in the CBD across the obstruction.
was elevated at 298 kU/L (normal <37), however
carcinoembryonic antigen and alpha-fetoprotein were
normal. Liver ultrasound scan showed normal results.
Hepatitis serology and autoantibodies were negative
with the exception of anti smooth muscle antibody,
which was weakly positive (1∶20).
He underwent a liver biopsy, which was
complicated by a bile leak and perihepatic collection
and led to his referral to our centre. Abdominal CT
revealed a perihepatic collection with mild bilobar
intrahepatic duct dilatation and significantly enlarged
portal, para-aortic and aortocaval lymph nodes. No
lesion could be seen in the extrahepatic bile duct. An
ultrasound guided percutaneous drainage of the
perihepatic collection was performed. Subsequent
ERCP demonstrated a filling defect suggestive of a
mass at the proximal end of the common bile duct
(CBD) (Figs. 1, 2). Brush cytology was negative
for malignancy and a plastic stent was inserted.
Endoscopic ultrasound (EUS) confirmed the findings
of a dilated CBD with a 3×2 cm mass obstructing the
mid CBD consistent with cholangiocarcinoma. There
was no evidence of vascular invasion or involvement
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Hepatobiliary & Pancreatic Diseases International
Fig. 3. HE staining. Tumor consisting of nests and glandular
elements is seen to the left of the field adjacent to a bile duct
branch (right of the field).
Fig. 4. Same field as Fig 3. immunostained for chromogranin.
of the pancreas.
At laparotomy, a hard tumor was palpable within
the CBD with no evidence of metastases. Excision of the
extrahepatic biliary tree with portal lymphadenectomy
and a Roux-en-Y hepaticojejunostomy reconstruction
was completed with minimal blood loss. There were
no perioperative complications and he was discharged
home in a week. The patient is well on 22 months with
no evidence of disease on CT and MRI scans. The liver
function and chromogranin A and B levels remain
normal.
Pathological findings
Histological examination revealed a well-differen-
tiated, 2.5×2.2×2.8 cm papillary neuroendocrine
neoplasm with a very thin fibro-vascular stroma,
arising at the union of the cystic and common hepatic
duct. There was evidence of infiltration of the duct
wall and periductal soft tissue. Mitotic figures were
not visible. There was no evidence of necrosis or
vascular invasion. Resection margins and resected
lymph nodes were free of tumor (pT2 N0 M0).
Immunohistochemical analysis showed neoplastic
Non-functioning well-differentiated NET of the extrahepatic bile duct: an unusual suspect?
cells diffusely positive for chromogranin A and focally
reactive for synaptophysin (Figs. 3, 4).
Discussion
NETs have characteristic histological, clinical, and
biological properties and were first described by
Lubarsch in 1888. Oberndofer coined the term
karzinoide (carcinoma like) in 1907 to establish
a distinct identity from adenocarcinoma. Ciaccio
introduced the theory of endocrine origin of these
tumors in 1906, which was further reinforced by
the work of Gosset and Masson in 1914.[4] Pernow
and Waldenstrom[5] first described the "carcinoid
syndrome" in 1954. In 1959, Davies[2] described a
carcinoid of the distal CBD and pancreatic duct. Pilz[6]
reported a carcinoid tumor arising from within the
CBD in 1961. The term "carcinoid" was replaced with
"endocrine tumor" by the World Health Organisation
in 2000.[7]
Extrahepatic bile ducts remain the rarest primary
sites for NET accounting for 0.2%-2.0% of all
gastrointestinal NETs. Since 1959, we found 113 cases
of CBD and pancreatic duct carcinoids and 52 cases of
primary extrahepatic bile duct carcinoids. The most
common anatomical locations were the CBD (58%),
perihilar (28%), cystic duct (11%) and common
hepatic duct (3%). The present patient presents
with a tumor arising at the junction of the cystic and
common hepatic ducts. Rugge et al[3] reported a similar
case of a 64-year-old woman with jaundice and biliary
colic.
Overall, there is a female predominance with the
female-to-male ratio ranging from 1.05[8, 9] to 2.2.[1]
No predisposing factors have been identified though it
has been postulated that chronic inflammation within
the bile ducts leads to metaplasia of the scattered
endocrine cells, the precursors to endocrine tumors.[10]
The incidence peaks in the fifth decade (range from 12
to 79 years).[11]
Biliary NETs can be hormonally active and
many immunohistochemically stain positive for
somatostatin, serotonin, and gastrin. None of the
reported cases have shown evidence of carcinoid
syndrome or symptoms linked to hormone secretion.
Most patients present with features related to the
effect of the tumor with obstructive jaundice, biliary
colic and pruritis.[12, 13] The identification of bile duct
obstruction is often difficult on imaging. The incidence
of false negative brush cytology is high owing to the
submucosal location of these tumors. Chamberlain
et al[1] highlighted the clinical differences between
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biliary NET and cholangiocarcinoma, suggesting that
young females with localized, surgically resectable
tumors are more likely to have NET. In most cases,
the decision to proceed to surgical exploration is based
on suspicion of cholangiocarcinoma. The diagnosis of
a NET is made postoperatively after histological and
immunohistochemical analysis of the specimen.[12-14]
Biliary NETs have an indolent biological behavior
and exhibit limited propensity for both metastatic
and local spread. Only one-third of these tumors
present with metastases, making an aggressive
surgical approach mandatory. Concurrent partial
hepatectomy or non-anatomical resection of liver
metastases may be performed in a curative attempt,
although there are no evidence-based guidelines
available. Complete surgical resection is associated
with a more favourable prognosis and long-term
survival (20 years) has been reported even in the
presence of distant metastases.[2] In most cases
adequate clearance can be achieved by excision of the
extrahepatic bile ducts with portal lymphadenectomy
and Roux-en-Y hepaticojejunostomy reconstruction,
but some distal CBD tumors are best treated by
pancreaticoduodenectomy.
The role of adjuvant therapy remains
controversial and most studies have failed to
demonstrate survival advantage.[15] Although size of
tumor, presence of lymphovascular invasion and the
quantitative assessment of Ki-67 reactive cells help to
determine prognosis, there are no absolute criteria for
judging the malignant potential of biliary endocrine
tumors.[16-18] Among patients with localized tumors,
the 5-year survival ranges from 60% to 100%.[8, 19]
While NETs of the gastrointestinal tract have
become a more recognised entity, idiosyncratic
features of biliary neuroendocrine lesions pose a
significant challenge and awareness of these tumors
will facilitate preoperative diagnosis and result in
optimal management.
Funding: None.
Ethical approval: Not needed.
Contributors: SH proposed the study and wrote the first draft.
MM helped with literature search. HN and RM reviewed and
corrected the manusript. SH is the guarantor.
Competing interest: No benefits in any form have been received
or will be received from a commercial party related directly or
indirectly to the subject of this article.
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Received March 30, 2007
Accepted after revision May 15, 2007