A 47-year old woman presented with right upper quadrant pain for 5 months. She never experienced
jaundice, gastrointestinal bleeding and changes in bowel habits. She had only minimal alcohol use and no
intravenous drug use in the past. She had never received blood products. Abdominal ultrasound and CT
scans, revealed a 16 cm cystic and solid mass with areas of increased echogenicity in the left lobe of
the liver. No retroperitoneal lymphadenopathy was noted. A biopsy was unsuccessful, revealing mostly
inflammatory cells. The patient eventually underwent enucleation of the tumor in segments 4, 5 and 8,
but due to the firm adherence of the mass to the hepatic veins posteriorly, only approximately 80% of the
tumor could be resected. There were no postoperative complications and the patient reported no symptoms
following the surgery. Three years of follow-up revealed no metastasis or significant growth of the
Case 4 - Figure 1 - Low power view showing an area composed of densely compressed small tubules.
Case 4 - Figure 2 - Another area is composed of microcysts with thin fibrous septa.
Case 4 - Figure 3 - Higher magnification showing a staghorn pattern reminiscent of serous cystadenoma
Case 4 - Figure 4 - Small tubules lined by a short cuboidal epithelium showing rare mitoses. Note the inconspicuous surrounding stroma.
The resected tumor measured 16 x 11 x 5 cm and had a smooth, tan-white surface. Cross sections revealed
a honeycomb cut surface with thin fibrous septa delineating small cysts. Approximately 30% of the tumor
showed a solid appearance with the cysts embedded in a more densely fibrotic stroma. No necrosis or
hemorrhage was identified.
The tumor was predominantly composed of acinar, microcystic and tubulo-glandular
elements separated in most areas by thin fibrous bands. The cysts measured up to 0.5 cm in largest
diameter. Other areas consisted mostly of smaller tubules and glands embedded in a denser collagenous
background, in places showing a staghorn pattern reminiscent of a serous cystic pattern. The lumina
contained occasional shed epithelial cells, some red blood cells and in some areas dense amorphous
material, consistent with bile. The tubules and glands were lined by a single layer of flat to cuboidal
epithelial cells without cilia. No goblet cells were present. Apocrine snouts were observed on the
lining epithelium. The centrally located round to oval nuclei had inconspicuous nucleoli. Minimal
atypia and rare mitoses were identified. The stroma consisted of a paucicellular and loose fibrous
tissue with sparse blood vessels. Scattered clusters of plasma cells and lymphocytes were identified
throughout the stroma. Myxoid degeneration was focally present.
The epithelium stained positively for D10, p53 (50-75% of the cells displayed a strong nuclear
staining), Keratin AE.3/Cam 5.2, CK-7, -19, CEA and EMA. Interestingly, the epithelial lining did not
stain for 1F6. Less than 10% of nuclei showed positivity for Ki-67.
The stromal cells exhibited a scattered pattern of positivity for Vimentin and SMA and did not stain
for Desmin. Neither the epithelium nor the intracystic secretory material stained for acid mucins with
Alcian blue (pH 2.5).
Flow cytometry studies yielded a tetraploid cell population with a low S-Phase along with an euploid
Diagnosis: Biliary Adenofibroma
Biliary adenofibroma is an extremely rare benign hepatic neoplasm with only two previously reported
cases. It is characterized by a microcystic and tubuloglandular architecture composed of a biliary
epithelium supported by a fibroblastic stromal scaffolding.8,9,10 The strong immunoreactivity of the
cyst lining for several cytokeratins as well as CEA and EMA in the absence of staining for vimentin and
desmin suggests a biliary origin.
Immunohistochemical staining for D10 and 1F6 has been shown to be of some value in the
subclassification of biliary tumors.3 Normal bile ductules and canals of Hering exhibit positive
staining against 1F6 but not D10, whereas the larger bile ducts may show an occasional D10-positive cell
in 22% but an absence of 1F6.3 A similar pattern was also reported in one bile duct hamartoma. Thus,
while the origin of biliary adenofibroma is unknown, the epithelial expression of D10 but not 1F6
observed in our case, may suggest an origin similar to bile duct hamartoma.10 Parada et al. reported
monosomy 22 in the second case of biliary adenofibroma and suggested a mesenchymal origin because
monosomy 22 as well as partial monosomy 22q is a characteristic finding in meningiomas and schwannomas.9
However, the significance of this finding is unclear since this genetic abnormality has not been
reported in any other biliary proliferation, and fluorescence in situ
hybridization performed in this case did not confirm this finding. Alternatively, we suggest that
the biliary epithelial proliferation induces a reactive fibroblastic and smooth muscle stromal response
with scattered chronic inflammatory cells.
Biliary adenofibroma should be distinguished from other solitary hepatic neoplasms. Bile duct
adenoma, also referred to as peribiliary gland hamartoma, generally shows a more tubular and less cystic
configuration with narrow lumens and very dense collagenous stroma compressing the ductules.1,3
Furthermore, bile duct adenomas display a different D10 and 1F6 immunohistochemical profile (D10 positive
and 1F6 positive, together with acid mucin secretion).3 Giant biliary cystadenoma is a multiloculated
benign hepatic tumor with an arguably premalignant character. It can reach a size of more than 20 cm and
shows a cystic architecture somewhat similar to that of biliary adenofibroma with scattered mucin
secreting cells characteristically lining the cysts.5,6 In contrast, mucin secretion is absent in
biliary adenofibromas.9 Furthermore, the cellular mesenchymal stroma noted in the majority of biliary
cystadenomas has not been observed in biliary adenofibromas. Size not withstanding, the histologic
appearance of biliary adenofibroma most closely resembles that of bile duct hamartomas (von Meyenburg
complexes), a similarity reinforced by the D10 and 1F6 immunostaining pattern and lack of mucin
secretion. Given the size but also the tetraploidy status with a low S phase as well as the positivity
for p53 observed in this biliary adenofibroma might represent a potentially premalignant lesion. Of
note, intermediate stages of cystic biliary proliferation resembling bile duct hamartomas and biliary
adenofibromas have been reported in an animal model of aflatoxin-induced cholangiocarcinoma.4
Furthermore, rare cases of malignant degeneration of bile duct hamartomas have been described.2,7,11
However, the demonstration of malignancy arising in biliary adenofibroma has not been established, as of
yet , but warrants continued evaluation.
Given the natural history of this incompletely resected case with a long unremarkable follow-up, it
will likely continue to behave in a benign fashion. However, complete resection with negative margins as
well as thorough histopathological examination and close clinical follow-up are recommended.
- Allaire GS, Rabin L, Ishak KG, et al. Bile duct adenoma. A study of 152 cases. Am J Surg Pathol 1988;12:708-15
- Blanc JF, Bernard PH, Carles, et al. Cholangiocarcinoma arising in Von Meyenburg complex associated
with hepatocellular carcinoma in genetic haemochromatosis. Eur J Gastroenterol
- Bhathal PS, Hughes NR, Goodman ZD. The so-called bile duct adenoma is a peribiliary gland hamartoma.
Am J Surg Pathol 1996;20:858-64
- Cruikshank AH, Sparshott SM. Malignancy in natural and experimental hepatic cysts: experiments with
aflatoxin in rats and malignant transformation of cysts in liver. J Pathol
- Dixon E, Sutherland FR, Mitchell P, et al. Cystadenomas of the liver: a spectrum of disease. Can J Surg 2001;44:371-6
- Florman SS, Slakey DP. Giant biliary cystadenoma: case report and literature review. Am Surg 2001;67:727-32
- Jain D, Sarode VR, Abdul-Karim FW, et al. Evidence for the neoplastic transformation of Von
Meyenburg complexes. Am J Surg Path 2000;24:1131-9
- Parada LA, Bardi G, Hallen M, et al. Monosomy 22 in a case of biliary adenofibroma. Cancer Genet Cytogenet 1997;93:183-4
- Tsui WMS, Loo KT, Chow LTC, et al. Biliary adenofibroma. A heretofore unrecognized benign biliary
tumor of the liver. Am J Surg Pathol 1993;17:186-92
- Varnholt H, Vauthey JN, Dal Cin P, Marsh RW, Bhathal PS, Hughes NR, Lauwers GY. Biliary Adenofibroma
– A rare neoplasm of bile duct origin with an indolent behavior. Am J Surg Pathol
2003 (in press)
- Yaziji N, Martin L, Hillon P, et al. Cholangiocarcinome développé sur micro-hamartomes biliaires
chez un malade atteint d'hémochromatose.(Article in French) Ann Pathol