CASE REPORT

Ultrasonography of intrahepatic bile duct adenoma with renal cellcarcinoma: correlation with pathology

Manabu Watanabe • Kazue Shiozawa • Takashi Ikehara • Miue Ichimori •

Mie Shinohara • Yoshinori Kikuchi • Koji Ishii • Tetsuo Nemoto •

Kazutoshi Shibuya • Yasukiyo Sumino

Received: 18 May 2012 / Accepted: 5 December 2012 / Published online: 14 February 2013

� The Japan Society of Ultrasonics in Medicine 2013

Abstract Intrahepatic bile duct adenoma (BDA) is a

relatively rare benign tumor. Most cases are incidentally

discovered during surgery or autopsy. We report here the

co-existence of renal cell carcinoma and BDA mimicking

metastasis in a 30-year-old female. An isoechoic nodule

with a hypoechoic rim sized 10 9 9 mm was observed by

ultrasonography in S2 of the liver. On contrast-enhanced

ultrasonography (CEUS), the mass was enhanced in the

early vascular phase and a defect with a clear border

appeared in the post-vascular phase. We present the

ultrasonography findings of BDA, including those yielded

by CEUS using Sonazoid, along with the gross and

microscopic pathological correlation.

Keywords Bile duct adenoma � Contrast-enhanced

ultrasonography � Sonazoid

Introduction

Bile duct adenoma (BDA) is a relatively rare benign

intrahepatic tumor. It is often detected and diagnosed

incidentally during surgery or at autopsy. There are no

abdominal computed tomography (CT) or magnetic reso-

nance (MRI) findings characteristic of BDA, and its dif-

ferentiation from metastatic liver cancer, if it is

complicated by cancer of other organs, and from liver

cancer, if it is complicated by chronic liver disease, poses

problems. In this study, we evaluated intrahepatic BDA

complicated by renal cell carcinoma (RCC). Ignee et al. [1]

and Hohmann et al. [2] reported findings on contrast-

enhanced ultrasonography (CEUS) using Sonovue, but

those using Sonazoid (Daiichi-Sankyo, Tokyo, Japan) have

not been reported to date. We primarily present the ultra-

sonography (US) findings in a BDA patient, including

those yielded by CEUS using Sonazoid, with a review of

the literature.

Case report

The patient was a 30-year-old female. She had undergone

living donor right kidney transplantation at the age of

24 years due to chronic renal failure and had since received

cyclosporine and steroids. There was no rejection, and the

course was uneventful. On a scheduled examination

4 years after kidney transplantation, a cystic mass about

40 mm in diameter was detected by abdominal CT in the

left native kidney, but it was considered a complicated cyst

and was observed. After 2 years, abdominal CT showed

enlargement of the mass in the left native kidney to 45 mm

and a nodular lesion about 10 mm in diameter in S2 of the

liver, and the patient was admitted for close examination.

No abnormality was noted on blood chemistry tests or in

tumor markers such as CEA, AFP, and SCC or viral

markers. The tumoral lesion of the left native kidney was

considered from US and CT findings to be an elliptical

cystic lesion containing solid components, and Doppler US

M. Watanabe (&) � K. Shiozawa � T. Ikehara � M. Ichimori �M. Shinohara � Y. Kikuchi � K. Ishii � Y. Sumino

Division of Gastroenterology and Hepatology,

Department of Internal Medicine, Toho University Medical

Center, Omori Hospital, 6-11-1 Omorinishi, Ota-ku,

Tokyo 143-8541, Japan

e-mail: manabu62@med.toho-u.ac.jp

T. Nemoto � K. Shibuya

Department of Surgical Pathology,

Toho University Medical Center, Omori Hospital,

6-11-1 Omorinishi, Ota-ku, Tokyo 143-8541, Japan

123

J Med Ultrasonics (2013) 40:251–256

DOI 10.1007/s10396-012-0428-x

demonstrated pulsatile blood flow signals in the solid part,

suggesting RCC. Also, a lesion 10 9 9 mm in size with the

appearance of an isoechoic nodule nearly equal to that of

the surrounding liver parenchyma with a hypoechoic rim

(so-called ‘‘bull’s eye’’ pattern) was observed by US in S2

of the liver (Fig. 1). On CEUS, the mass was markedly

enhanced compared with the surrounding liver paren-

chyma, including the hypoechoic rim, in the early vascular

phase 11 s after Sonazoid administration (Fig. 2a). The

contrast diminished in the late vascular phase 20–30 s after

Sonazoid administration (Fig. 2b), and a defect with a clear

border appeared in the post-vascular so-called Kupffer

phase (Fig. 2c). On dynamic CT, the mass in S2 of the

liver, which was a low density area on plain CT (Fig. 3a),

was slightly enhanced in the arterial phase (Fig. 3b),

showed a slightly lower density than the surrounding liver

parenchyma in the portal phase (Fig. 3c), and was isodense

in the equilibrium phase (Fig. 3d). Retrospectively, plain

abdominal CT images obtained 3 years earlier suggested a

low density area about 10 mm in diameter in S2 of the

liver, and, by comparison with images obtained in the latest

examination, the mass showed no tendency toward

enlargement. MRI delineated the liver mass as a low-

intensity area on T1-weighted imaging, but the mass was

unclear on T2-weighted imaging. On CT, the liver mass

showed no progressive enlargement, but, as the possibility

of liver metastasis of RCC could not be excluded by US,

nephrectomy and partial hepatectomy were carried out.

Histologically, the mass in the left native kidney was

diagnosed as clear cell RCC. The cut surface of the

resected specimen showed a well-circumscribed, firm,

yellowish-white mass, 11 9 11 9 11 mm, located 8 mm

below the liver capsule (Fig. 4a). Microscopically, the

mass had no capsule and showed a proliferation of

columnar to cuboidal cells having eosinophilic and rich cell

bodies and forming small glandular ducts. The ductal

lumens were relatively even in size and were interposed by

stroma accompanied by the infiltration of inflammatory

cells, primarily monocytes. There were portal tracts in the

mass. The cuboidal cells were uniform and lacked nuclear

pleomorphism as well as hyperchromasia without definite

mitosis (Fig. 4b). The background liver parenchyma

showed no fibrosis or fatty change. An immunohisto-

chemical examination demonstrated positive staining for

CK7 and CK19 as well as negative staining for CK20.

Also, Hep par 1 was negative, suggesting that hepatocel-

lular carcinoma was unlikely, and the positive rate of MIB-

1 was 5 % or less. A diagnosis of intrahepatic BDA was

Fig. 1 Gray-scale US (a longitudinal axis, b transverse axis) showed

a 10 9 9-mm isoechoic nodule with a hypoechoic rim in S2 of the

liver (arrow)

Fig. 2 CEUS (left side) and gray-scale US as baseline images (right

side). On CEUS performed with 0.5 ml of Sonazoid, the mass (arrow)

was enhanced in the early vascular phase (a), the contrast diminished

in the late vascular phase 20–30 s after Sonazoid administration (b),

and a marked wash-out with a clear border appeared in the post-

vascular phase (c)

252 J Med Ultrasonics (2013) 40:251–256

123

made based on these findings. On examination of the H&E-

stained resected specimen through a magnifying glass, the

center was pale pink, and the peripheries were slightly

purplish. Comparison between the findings on gray-scale

US and the histopathological specimen suggests that the

purplish peripheries correspond to the hypoechoic rim

(Fig. 5a). Pathological findings were the same in the center

and peripheries, but the amount of stroma was smaller, and

infiltration of inflammatory cells such as lymphocytes was

more notable, in the peripheries than in the center

(Fig. 5b).

Discussion

BDA is a proliferative lesion consisting of cholangiole-like

glandular ducts and occurring as single or multiple nodules

anywhere within the liver. It is a rare disease classified by

the WHO as a benign tumor of the bile duct epithelium

[3, 4]. Although the pathogenesis of BDA is still subject to

debate, it has been reported to be a reactive process to a

focal bile ductular injury caused by inflammation, trauma,

etc. [5], or regarded as a hamartomatous change of perib-

iliary accessory glands [6, 7]. It shows no particular pref-

erence concerning age or gender [8], but it is often

discovered in adulthood. The size of BDA is often 1 cm or

smaller [5], clinical symptoms are rare, and the lesion is

usually a clearly circumscribed, round, grayish-white, non-

Fig. 3 Unenhanced CT showed a low density mass (arrow) measur-

ing about 10 mm in S2 of the liver (a). Dynamic CT showed slight

enhancement in the arterial phase (b), a slightly lower density than the

surrounding liver parenchyma in the portal phase (c), and isodensity

in the equilibrium phase (d)

Fig. 4 The cut surface of the resected specimen showed a well-

circumscribed and yellowish-white nodule, 11 9 11 9 11 mm,

located 8 mm below the liver capsule (a). Microscopically, the mass

consisted of densely packed proliferation of simple tubular ducts. The

cuboidal epithelium resembled that of interlobular bile ducts without

cell atypia or mitotic activity (b) (H&E 9100)

J Med Ultrasonics (2013) 40:251–256 253

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encapsulated nodular lesion that develops under the hepatic

capsule. It may be detected incidentally during surgery or

autopsy and is often resected when a metastatic malignant

tumor or hepatocellular carcinoma cannot be excluded by

imaging examination. BDA has frequently been reported to

be complicated by chronic liver disease or liver cirrhosis

due to alcohol or viruses [9]. However, this is probably

because patients with chronic liver disorders more often

undergo screening for liver cancer by imaging techniques,

and not because chronic liver disorders frequently underlie

BDA.

In our patient, BDA was detected during a search for

metastasis of RCC. It showed a hypoechoic rim, a so-called

‘‘bull’s eye,’’ on gray-scale US, and was located 8 mm

below the hepatic capsule, while BDA is generally located

immediately under the hepatic capsule, so we strongly

suspected intrahepatic metastasis. To this day, there has

been no report showing US findings in a sufficient number

of patients with BDA. The literature in Japanese or English

concerning US findings of BDA is summarized in Table 1.

Ten nodules including the one in our patient are listed, and

their mean size is 12.5 (5–20) mm. The interior of the mass

was hyperechoic in three cases, hypoechoic in six cases,

and isoechoic only in our patient. The echogenicity of

masses is generally low, but it is considered to be affected

not only by the condition of the surrounding liver paren-

chyma such as fatty liver, as well as calcification and

hyalinization, but also by intratumoral hemorrhage

[10, 11]. Also, a hypoechoic rim was observed around the

mass in four (40 %) cases including our patient. There is no

literature discussing the cause of this hypoechoic rim, but

the pathological findings in our patient suggest that find-

ings on gray-scale US reflect components of the stroma and

degree of inflammatory cell infiltration at the peripheries of

the tumor corresponding to the hypoechoic rim. However,

discussion of causes of the decrease in stromal components

or marked inflammatory cell infiltration in the peripheries

observed in our patient is beyond the scope of this study.

Reports on the hemodynamics of BDA observed by

dynamic CT vary from enhancement in the arterial phase to

delayed or prolonged enhancement in the portal or equili-

bration phase, but, at the very least, the contrast of the

Table 1 Summary of cases

presented by ultrasonography

and reported previously

CH chronic hepatitis, BC breast

cancer, DM diabetes mellitus,

LC liver cirrhosis,

EC esophageal carcinoma,

RCC renal cell carcinoma

References Age Sex Tumor size (mm) Echogenicity Hypoechoic rim Complications

Kobayashi et al. [11] 62 F 15 High Yes None

Miyazaki et al. [16]. 64 M 17 High Yes CH

Tajima et al. [9] 75 M 5 High No CH

Otani et al. [17]. 61 M 11 Low No CH

Fukano et al.[18] 55 F 17 Low No BC

Ignee et al. [1] 25 F 9 Low No DM

59 F 20 Low No LC

51 F 15 Low No BC

Hohmann et al. [2] 49 M 5 Low Yes LC, EC

Our case 30 F 11 Iso Yes RCC

Fig. 5 Comparison between the findings on gray-scale US and a

histopathological specimen suggested that the purplish peripheries

corresponded to the hypoechoic rim (a) (H&E 940). Pathological

findings were the same in the center and peripheries, but the amount

of stroma was smaller, and infiltration of inflammatory cells such as

lymphocytes was more notable, in the peripheries than in the center

(b) (H&E 9200)

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tumor is considered to be enhanced despite differences in

the phase of its occurrence [9, 12]. Also, defects are con-

sidered to have been reported often on CT during ante-

rioportography, reflecting the pathological finding of

narrowing or collapsing of the portal vein in the nodules

[8].On MRI, BDA shows hypointensity on T1-weighted

images and hyperintensity on T2-weighted images.

According to previous reports from different institutions,

various imaging techniques have been used, but most

BDAs show hypervascular characteristics consisting of

prolonged enhancement on dynamic MRI like CT imaging

[12]. CEUS, on the other hand, is superior to dynamic CT

and MRI in temporal resolution, allows more detailed

evaluation of the hemodynamics of masses, and may be

useful for the differentiation of benign and malignant dis-

eases [13]. CEUS using Sonazoid, in particular, has been

reported to be useful for the diagnosis and differentiation of

liver masses as it clarifies the characteristic hemodynamic

features of masses such as the processes of multistep

hepatocarcinogenesis from a dysplastic nodule to hepato-

cellular carcinoma in the early vascular phase and the

presence or absence of Kupffer cells in the post-vascular

phase [14]. Metastasis can demonstrate rim-like enhance-

ment or homogeneous dense hyperperfusion in the early

vascular phase and a defect in the post-vascular phase [15].

Ignee et al. [1], who observed the hemodynamics of BDA

using Sonovue as the contrast agent, reported that all three

patients with BDA showed contrast enhancement in the

early vascular phase, and a clearly bordered defect in the

late vascular and post-vascular phases, and that differen-

tiation of the disease from intrahepatic malignant tumors is

difficult. We performed CEUS using Sonazoid, the uptake

of which by Kupffer cells in the tumor can be evaluated in

the post-vascular phase 10 min or more after the injection,

unlike Sonovue [14]. The tumor was markedly enhanced

compared with the surrounding liver parenchyma, includ-

ing the hypoechoic rim in the early vascular phase 11 s

after Sonazoid administration through the cubital vein, but

the enhancement gradually diminished after a peak, which

occurred 20 s after the Sonazoid injection. In the Kupffer

phase about 10 min after the injection, the mass was

delineated as a clearly bordered defect, indicating that the

tumor lacked Kupffer cells. While these findings differed

from those in benign tumors such as liver hemangioma,

focal nodular hyperplasia, and hepatic adenoma, the dif-

ferentiation of BDA from malignant tumors such as

hepatocellular carcinoma, intrahepatic bile duct carcinoma,

cholangiocellular carcinoma, and metastatic tumor was

difficult, as also reported by Ignee et al. [1]. Unfortunately,

BDA cannot be definitively differentiated from other

malignant tumors by CEUS using Sonazoid or Sonovue

alone, and a larger case series is needed. Based on CEUS or

dynamic CT findings in cases reported to date including

ours, however, BDA is considered to be a relatively

hypervascular mass, and its hemodynamics are thought to

be determined by the cellularity and amount and density of

fibrous stroma in the tumor. On CEUS, BDA was delin-

eated in the post-vascular phase as a defect clearly distinct

from the surrounding liver parenchyma in the reports from

Ignee et al. [1] and Hohmann et al. [2] as well as in our

case. Benign liver masses that show contrast enhancement

in the early vascular phase decrease in contrast in the late

vascular phase, and a clear defect in the post-vascular

phase on CEUS may be due to inflammatory pseudotu-

mors, but these findings may also be useful for the diag-

nosis of BDA.

Regarding the intrahepatic mass that was detected

1 year before the RCC appeared on the kidney, the size of

which had not changed for 3 years on CT, it may be

enough just to monitor the patient closely without per-

forming an operation, or it may be necessary to perform a

needle biopsy for diagnosis. Pathological differential

diagnoses to be discussed include metastasis, cholangio-

carcinoma, bile duct hamartoma, hepatic abscess, inflam-

matory pseudotumor, and hepatic granuloma. The

difficulty of the pathological diagnosis of BDA has been

suggested in reports showing that rapid cytodiagnosis has

often led to a mistaken diagnosis [9]. In this case, there was

concern about whether a definite diagnosis could be made

even with needle biopsy of the liver tumors. The patient

had a strong desire to undergo hepatic surgery.

BDA is thought to have been detected more frequently

in recent years due to improvements in imaging diagnostic

techniques such as multidetector-row CT, MRI, and high-

end US imaging. The difficulty of diagnosis of BDA is

thought to derive from the following facts: they are rela-

tively small, they are located at the peripheries of the liver

and are susceptible to the partial volume effect, and they

present hemodynamic features resembling those of malig-

nant tumors by imaging techniques including CEUS. If a

mass is detected in a patient with chronic hepatitis, liver

cirrhosis, or cancer in other organs, as in our patient, BDA

as well as malignant tumors must be considered as differ-

ential diagnoses. The accumulation of data on each imag-

ing modality is awaited.

Conflict of interest None.

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