Original Article Imaging Findings of Bile Duct Hamartomas: a Case Report and Literature Review

Int J Clin Exp Med 2015;8(8):13145-13153 www.ijcem.com /ISSN:1940-5901/IJCEM0012001

Original Article Imaging findings of bile duct hamartomas: a case report and literature review

Qiu-Sheng Shi1*, Ling-Xi Xing1*, Li-Fang Jin1, Han Wang2, Xiu-Hong Lv3, Lian-Fang Du1

1Department of Ultrasound, Shanghai First People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; 2Department of Radiology, Shanghai First People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China; 3Department of Pathology, Shanghai First People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China. *Co-first authors. Received June 27, 2015; Accepted August 11, 2015; Epub August 15, 2015; Published August 30, 2015

Abstract: Bile duct hamartomas (BHs), also called von Meyenburg complex (VMC), are benign biliary malformations that originate from disorganization of the small intrahepatic bile ducts. This disorganization is often associated with the abnormal involution of embryonic ductal end plates in the liver. This is clinically significant, as the development of BHs can cause diagnostic confusion with liver metastases and small hepatocellular carcinoma (SHCC). Currently, we report a specific case of BHs and review the literature to better define and diagnose BHs. In the following case, a 37 year-old male bearing a lesion in his liver is presented and undergoes both radiological and pathological diagnosis. The lesion is preliminarily suspected to be a hepatic hemangioma by examination of conventional ultrasound (US), contrast enhanced ultrasound (CEUS), computerized tomographic scanning (CT) and magnetic resonance imaging (MRI). However, SHCC is suspected by follow-up analysis of US and CEUS, due to the patient’s background history of hepatitis B and growth of the lesion and a tumor-feeding vessel in BHs via CEUS. However, BHs are finally diagnosed by biopsy pathology under the guidance of ultrasound. Therefore, we believe pathology is imperative for correct diagnosis of BHs over other similar diseases when the imaging findings are atypical. Here we report the novel and unique detection of a tumor-feeding vessel, which mimicked SHCC strongly, during the course of CEUS. We also present a comprehensive review of the previous reported radiological examination related to BHs.

Keywords: Bile duct hamartomas (BHs), pathology, ultrasound (US), contrast enhanced ultrasound (CEUS), computerized tomographic (CT), magnetic resonance imaging (MRI)

Introduction 5.6% in adults in a large series of autopsy samples [4, 6, 7]. Macroscopically, BHs can be char- Bile duct hamartomas (BHs), also known as von acterized by the visualization of many grayish- Meyenburg complex (VMC), were initially whitish or yellow small nodules scattered described by the Swiss pathologist Hanns von throughout the liver, either intraparenchymally Meyenburg [1] in 1918. BHs have been previ- or subcapsularly [6, 8-10]. BHs may be detect- ously described as benign liver malformations ed as single or multiple hamartomas, with a resulting from maldevelopment of the ductal diameter ranging from 1 to 15 mm [11]. During end plates, which remain in a persistent dou- diagnosis, its characteristics can mimic that of ble-layered cylindrical structure similar to the liver metastases, especially when the patient fetal ductal plate [2, 3]. Therefore, pathologi- has previously suffered a primary malignancy cally, BHs can be defined by examining dilated [9, 11]. intrahepatic bile ductules and the surrounding fibrous stroma [4, 5]. Patients with BHs are usually symptomatic. Jaundice, epigastralgia, and fever can occur. BHs are typically detected during laparotomy or Jaundice, a major symptom, is caused by autopsy, and the prevalence of BH formation is obstruction of the biliary tract owing to the age-dependent, varying from 1% in children to mucus secreted by biliary papillomas [4, 6, 12]. Bile duct hamartomas

Figure 1. Imaging of patient findings via US and CEUS. (A) At initial examination, a heterogeneous hypoechoic nodule was located in the liver parenchyma via US (red arrow). (B) At initial examination, there was no blood flow in the interior of the nodule (red arrow). (C) The result of a second examination shows a similar heterogeneous nodule located in the liver parenchyma (red arrow). (D) The results of a second examination show sporadic internal blood flow in the interior of the nodule (red arrow). (E-H) At first CEUS examination, enhancement of the hypervascular nodule is earlier than the surrounding liver parenchyma. The arrival time, peak time and regression time of Sonovue® are (E) 12 seconds, (F) 19 seconds and (G) 24 seconds, respectively (red arrows). (H) A tumor-feeding vessel connecting the branch of hepatic artery and the lesion (red arrow). (I-L) At second CEUS examination, enhancement of the hypervascular nodule is also earlier than the surrounding liver parenchyma. The arrival time, peak time and regression time of Sonovue® are (I) 10 seconds, (J) 17 seconds, and (K) 24 seconds, respectively. (L) The tumor-feeding vessel is again detected (red arrows).

However, these symptoms are nonspecific. A disappearance in the delay phase in CEUS. close relationship has been reported to exist Additionally, we believe imaging strategies are between BHs and the following congenital dis- not sufficient to achieve a most definitive diag- orders: Caroli’s disease, polycystic liver dis- nosis of BHs in the absence of typical imaging ease, congenital hepatic fibrosis, mesenchymal findings. hamartomas, bile duct atresia and autosomal recessive polycystic kidney disease [5, 8, 13, Case report 14]. While VMC is a benign condition, there is an ongoing debate as to whether BHs have the Here, we report the occurrence of a hypoechon- potential to induce malignant degeneration to ical solid nodule in the right liver lobe detected cholangiocarcinoma and hepatocellular carci- by B-mode ultrasonography in a 37 year-old noma [6, 8, 11, 13-15]. Here, we report a case male. Our study had been approved by the eth- of VMC diagnosed through several radiological ics committee of Shanghai First People’s examinations, including ultrasound (US), con- Hospital and the informed consent had been trast-enhance ultrasound (CEUS), computer- waived. Considering that the patient had a his- ized tomographic scanning (CT) and magnetic tory of Hepatitis B, development of a malignant resonance imaging (MRI). We present novel tumor could not be ruled out. At the initial results via CEUS that suggest the occurrence of screening, CT scanning missed the nodule a tumor-feeding vessel. The imaging is because it was imaged in only one frame, which enhanced in the arterial phase without early was reluctantly discovered in a later retrospec-

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Figure 2. Imaging of patient findings via CT and MRI. (A, B) CECT examination displayed no enhancement in both of hepatic arterial phase and portal venous phase (red arrows). (C-E) Conventinal MRI examination. (C) T1WI, the lesion is hypointense (red arrow). (D) T2WI, the lesion is hyperintense (red arrow). (E) DWI, the lesion shows free diffusion (red arrow). (F-H) Gadolinium-enhanced T1WI. (F) The lesion displays rim enhancement in the hepatic arterial phase, and marginal tuberculiform enhancement in both (G) portal venous phase and (H) hepatic vein (red arrows). tive analysis of the CT imaging. Additionally, the (Figure 1B). The ultrasound findings at the six- patient refused to undergo a MRI examination. month follow-up were roughly consistent with CEUS was further implemented, with the pri- that of the first time, with a slightly increased mary consideration being liver benign lesion. lesion size of 13.5×13.8 mm (Figure 1C). Six months later, follow-up with US, CEUS and However, we additionally detected an internally MRI showed that the lesion had slightly sporadic blood flow Figure ( 1D), which was increased in size (on US and CEUS) and indi- initially suggestive of a malignant transforma- cated the presence of a tumor-feeding vessel. tion. The MRI findings suggested that the lesion was benign. Because SHCC could not be ruled out Contrast enhanced ultrasound (CEUS) on US and CEUS, considering the patient’s history of hepatitis B, a biopsy was indispensable During the first examination, a 2.5 ml solution in order to identify the final diagnosis. The of the microbubble contrast agent Sonovue® patient had suffered right abdominal discom- was injected into the median cubital vein. fort, but did not present with other clinical Twelve seconds later, the dye began to delin- symptoms such as fever, nausea or vomiting, eate the lesion outline (Figure 1E), and reached cough and expectoration, gastrointestinal dys- peak contrast at 19 seconds (Figure 1F). The function, jaundice, hematemesis or melena. contrast lasted 24 seconds and then began to Laboratory examination found no abnormal subside (Figure 1G). In the retrospective analy- results, including α-FP and other tumor-related sis six months later, a tumor-feeding vessel was index. Next, we present the strategies used for observed during the contrast enhancement diagnosis: course, which was not detected at first examination of the CEUS data (Figure 1H). Conventional ultrasound (US) At the six-month follow-up, both the arrival and The first ultrasound examination was conduct- peak contrast times were two seconds earlier ed at initial screening. A solid non-homoge- than that of the first examination, 10 seconds neous hypoechoic lesion was detected in the (Figure 1I) and 17 seconds (Figure 1J), respec- liver, measuring 8.9×13.6 mm (Figure 1A). This tively. Similar to the initial screening, imaging lesion was located in the upper segment of the started to subside at 24 seconds (Figure 1K). right anterior hepatic lobe, and was considered Again, the tumor-feeding vessel was also a benign lesion due to its clear boundary, regu- detected (Figure 1L). By CEUS examination, the lar shape and the missing internal blood flow lesion demonstrated a slight increase in size,

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Figure 3. Lesion biopsy under ultrasound guidance and pathological examination. (A) The lesion is clearly presented by two-dimensional sonogram. (B) The biopsy needle is inserted into the lesion through the liver parenchyma. (C-F) Pathological examination. (C, D) The lesion displays hyperplasia of the fibrocollagenous stroma and bile ducts ((H) and (E) staining, (C) ×100, (D) ×400). (E, F) The bile duct epithelia is positive for CK (Immunohistochemistry of CK, (E) ×100, (F) ×400). which was an 11×15 mm in measurement, as slightly lower and non-homogeneous. There compared to the initial measurement of was no enhancement in either hepatic arterial 8.9×13.6 mm. CEUS of the nodule displayed an phase or in portal venous phase of iohexol- enhancement in the arterial phase, similar to enhanced imaging (Figure 2A, 2B). the majority of liver cancers. However, the malignant liver lesions on CEUS typically disap- Magnetic resonance imaging (MRI) pear earlier than the surrounding liver parenchyma in the delay phase, but that trait did not A MRI examination was performed at the six- emerge in our patient. Thus, valid conclusions month follow-up. A round lesion measuring 15 could not be drawn to differentiate BHs and mm in diameter was found in the upper seg- liver metastases via US and CEUS alone. ment of the right anterior hepatic lobe, with Because of the changes in size and hemody- hypo-intense signals on T1-weighted images namics of lesion, a malignant lesion (SHCC or (T1WI) (Figure 2C), hyper-intense signals on liver metastasis) was initially suspected. T2-weighted images (T2WI) (Figure 2D), and high diffusion on diffusion-weighted imaging Contrast enhanced computed tomographic (DWI) (Figure 2E), respectively. After Magnevist (CECT) was injected intravenously, the lesion was clearly imaged with rim enhancement in the To perform CECT, the arterial phase scanning hepatic arterial phase (Figure 2F) of enhanced and the porto-venous phase scanning were T1WI, and marginally nodular enhancement respectively started at 8 s and 35 s after a was detected in portal venous phase (Figure bolus of Ultravist 370 was injected. At the initial 2G) and delayed phase (Figure 2H). Therefore, screening, CT imaging did not recognize the a liver hemangioma was suggested via the MRI liver nodule as it was detected in only one results. cross-section. However, the nodule was detected in the following retrospective study of CT Biopsy under ultrasound guidance imaging by improving the brightness and contrast. Compared with the surrounding liver Due to inconclusive diagnosis by the imaging parenchyma, the density of the lesion was studies, a biopsy was performed with a dispos-

13148 Int J Clin Exp Med 2015;8(8):13145-13153 Bile duct hamartomas able core tissue biopsy needle, MN1820, lagenous stroma with little vascular prolifera- Bard® Magnium®, USA, under the guidance of tion. Furthermore, the dilated bile ducts may ultrasound instrument equipped with a punc- have some bile in their lumina [6, 10]. ture probe, Hitachi, Japan (Figure 3A, 3B). Three strips of tissue samples measuring 1 cm Two kinds of classification methods for BHs in diameter and 21 mm in length were obtained. have been mentioned in the literature. Based The sample strips were placed on sterilized on the degree of biliary tract dilatation within glass and turned over to prepare smear glass. the lesions, BHs can be divided into three Next, the strips were dipped in absolute alcohol classes: (i) predominantly solid, (ii) predomi- to fix the specimens for pathological exami- nantly cystic and (iii) intermediate lesions [4, 8, nation. 16, 17]. The connections between the abnormal dilated cysts and the draining bile ducts The resulting pathological sections were BHs are also divided in two types: (i) draining or reviewed by specialists in hepatobiliary pathol- (ii) non-draining [8, 18]. However, it is also ogy. It was determined that the morphology and strongly believed that there is no communica- structure of the hepatic cells had no obvious tion either among the deformed bile ducts or abnormalities. However, the small bile duct between them and the normal biliary system cells were in an irregular arrangement sur- [19]. rounded by plenty of fibrocollagenous stroma. In addition, the bile duct epithelia were signifi- Sonographic findings of BHs detect hypoecho- cantly hyperplastic without cellular heteromor- ic, hyperechoic, or mixed non-homogeneous phism (Figure 3C, 3D). The results of the immu- echoic lesions [10, 11, 13, 20, 21]. A specific nohistochemistry demonstrated that cytoke- ultrasonic characteristic of BHs is the so-called ratins (CK) CK8, CK18 and CK19 staining were “multiple comet-tail echoes” that have been all positive, while hepatocyte staining was neg- inferred to be strong diagnostic evidence ative (Figure 3E, 3F). Due to this staining, the towards BHs [10, 11, 21]. However, this finding histological origin of the lesion was considered was not significant in our case study. Instead, to be bile duct epithelium. Therefore, bile duct CEUS was used to evaluate the microcircula- hamartoma was finally defined by pathology. tion inside the lesion. Recently, Murphy- Lavallee et al. [11, 22] have suggested a unique The patients were additionally followed-up both phenomenon wherein all metastases display four months and nine months after the biopsy. degrees of enhancement in the arterial phase At these times, the size of the lesion was on CEUS, no matter the appearances on con- 13.6×14.9 mm and 13.7×15.7 mm, respective- trast enhanced CT and contrast enhanced MRI ly. The nodule increased one to two mm in nine [11]. There has been no contrast enhancement months. Due to the benign results of biopsy reported in most cases of CEUS examination before, BHs were considered the correct patho- for BHs, but this finding is currently being dis- logic results. puted [10, 13]. For example, Berry et al. [11, Discussion 23] and Phillip et al. [11] reported cases of multiple BHs that did not demonstrate any As mentioned above, BHs are considered enhancement in all three phases of the pro- benign liver malformations resulting from cess (arterial, portal venous, and delayed derangement of brephic bile duct cells, which is phase) via CEUS. On the other hand, Hohmann proposed to be triggered by a disruptive or isch- et al. [11, 24] highlighted the presence of con- emic factor during bile duct lamina remodeling trast enhancement on CEUS in a BH measuring [8, 13]. These nodules typically measure less 5 mm in size. Imaging of the lesion was syn- than 1 cm on gross observation, strongly simu- chronized and consistent with that of the nor- lating liver metastases on macroscopical mal liver parenchyma in arterial phase and por- inspection and in imaging studies [9, 10]. tal venous phase, and ‘washout’ in the delayed Microscopically, BHs consist of a variable num- phase [11]. Our results of CEUS roughly agree bers of dilated, tortuous or branching intrahe- with the findings of Hohmann et al. The imaging atic bile ducts surrounded by monoptychial of the lesion displayed enhancement in arterial columnar or cubical bile duct epithelium. The phase, similar to imaging in liver malignancies. background is composed of abundant fibrocol- These differences may vary based on lesion

13149 Int J Clin Exp Med 2015;8(8):13145-13153 Bile duct hamartomas size. Typically, liver malignancies on CEUS show mal biliary system, also known as the ‘starry that the lesion disappears earlier than the sur- sky’ phenomenon. The dilated bile ducts of BHs rounding liver parenchyma in the delay phase. are hyper intense isolated nodules scattered in In our case, they are synchronous in portal both of the liver lobes, and may or may not com- venous phase and delay phase. Innovatively, municate with the draining bile ducts [6, 10, we have also found a tumor-feeding vessel dur- 13, 21, 27, 28]. MRCP can facilitatefacilitate ing the course of CEUS, which has never been the differential diagnosis of BHs and other bile reported. Thus, valid conclusions cannot be duct anomalies such as Caroli disease by ana- drawn between imaging differences in BH and lyzing the association with the draining bile liver malignancies. ducts [13]. However, based on whether there are connections between the abnormal dilated BH lesions are always low-density on CT scan- cysts and the draining bile ducts, some believe ning images. In the published literature, no that BHs can be divided in two types, existence enhancement of BHs has been captured in all or absence of the communication [8, 13]. phases of CECT after intravenous injection of iodine contrast medium [13], as in our case. The most important differential diagnosis of However, exceptions exist in two cases [13, 25] BHs would be to rule out liver metastases, in which the imaging of lesions was homoge- which would interfere with different treatment neously enhanced on post-contrast imaging of strategies [29], especially when the patient has CECT. a history of malignancy [2, 28]. Other similar diseases include primary hepatocellular carci- The typical imaging features of BHs on MRI are noma, intrahepatic cholangiocarcinoma and hypo signal on T1WI and hyper signal on T2WI circumscribed inhomogeneous fatty liver [2, [11, 19]. However, controversy exists when con- 28], simple hepatic cyst, small liver abscess, sidering enhancement of gadolinium-enhanced and lymphoma. To our knowledge, CEUS of BHs T1WI [11]. Both enhancement [13, 18, 21, 26, 27] and non-enhancement [11, 13] have been has been reported in few papers, and the accu- reported. In our case, rim enhancement was racy of CEUS in the diagnosis of BHs has not detected in the hepatic arterial phase, and been reported. CT helps slightly in differentiat- marginal tuberculiform enhancement was ing BHs from liver metastasis but has poor tis- detected in both the portal venous phase and sue contrast resolution [21]. Comparatively, if the delayed phase of enhanced T1WI. This was accompanied with typical imaging, MRI may be speculated to be resulting from the compressed of the greatest value in the differential diagno- liver parenchyma surrounding the lesion and sis of BHs and liver metastasis, although it inflammatory cell infiltration [21, 27]. As a remains controversial, as described above. In promising part of MRI, diffusion-weighted imag- addition, the dilated bile ducts of BHs can dis- ing (DWI) has attracted a lot of attention in dif- play the characteristic “starry sky” appearance ferentiating benign lesions from malignant in some cases on MRCP [6, 10, 13, 21]. We lesions, due to diffusion rate. It is thought that believe that pathological examination is benign lesions display free diffusion on DWI, required in those lesions with atypical radiologi- while malignant lesions show restricted diffu- cal performance, such as solitary lesions or sion [11]. According to this theory, the lesion in enhanced post-gadolinium during MRI [21], as our case could be inferred to be benign. in our case. Additionally, it has been suggested that the false negative rate of CT and MRI remains high BHs may also be confused with peribiliary gland for liver metastasis less than 1.5 cm in size, hamartoma (PGH), also known as intrahepatic which may also explain the discrepancies in the bile duct adenoma, originating from peribiliary T2W1 enhancement. This size coincides with glands. Microscopic examination of PGH the vast majority of BHs, so the differential reveals disordered peribiliary gland acini diagnosis would be difficult and may vary with embedded in fibrotic tissue which causes lesion size [28]. chronic inflammation [8, 30]. Microscopical examination of BHs shows small irregular and Magnetic resonance cholangiopancreatogra- dilated bile ducts embedded in fibrocollage- phy (MRCP) imaging has the ability to identify nous stroma without inflammation [8, 10, 31, the communication between BHs and the nor- 32]. Part of the dilated bile ducts turn into small

13150 Int J Clin Exp Med 2015;8(8):13145-13153 Bile duct hamartomas cysts and maybe contain inspissated bile in Disclosure of conflict of interest them [8, 30, 33]. However, it is difficult to distinguish BHs from PGH by macroscopical exam- None. ination or imaging methods. The only difference is that PGH has been considered to have Abbreviations delayed or prolonged enhancement on contrast enhanced CT and MRI [8]. The most precise BHs, Bile duct hamartomas; VMC, Von Meyen- identifying method to distinguish BH and PGH burg complex; US, Ultrasound; CEUS, Contrast should be immunohistochemistry. The serous enhanced ultrasound; CT, Computerized tomo- and mucous cells comprised in acini and graphic scanning; MRI, Magnetic resonance tubules of PGH express D10 and 1F6, which imaging; T1WI, T1-weighted images; 2WI, are also secreted by the intrahepatic peribiliary T2-weighted images; DWI, Diffusion-weighted glands [30, 34, 35]. Another related investiga- imaging; CK, Cytokeratin; MRCP, Magnetic res- tion demonstrates that PGH can be marked onance cholangiopancreatography; PGH, specifically by five foregut antigens (D10, 1F6, Peribiliary gland hamartoma. MUC6, MUC5AC, and TFF2) as well as the exo- Address correspondence to: Dr. Lian-Fang Du, crinosity of acid mucin [35]. Therefore, imaging Department of Ultrasound, Shanghai First People’s examination may help somewhat in indicating Hospital Affiliated to Shanghai Jiao Tong University the most likely differential diagnosis of BHs and School of Medicine, 85 Wu Jin Road, Shanghai PGH, with the final diagnosis depending on 200080, China. Tel: +86-13386259562; Fax: pathology. (0086) 021-37798276; E-mail: du_lianfang2013@ Conclusion 163.com References BHs are benign liver malformations, with an extremely low probability of malignant transfor- [1] H vM. Über die Zyztenleber. Beitr Pathol mation. Recently, they have attracted a lot of Anatom 1918; 64: 47-532. attention because they simulate the perfor- [2] Michalakis K, Coppack SW and Koak Y. Von mance of liver metastasis on gross observation Meyenburg complex in a bariatric patient. J and imaging examination. As mentioned, it is Gastrointestin Liver Dis 2011; 20: 120. difficult with imaging studies alone to differenti- [3] Terada T and Moriki T. Monolobar ductal plate ate BH from similar disease. However, when malformation disease of the liver. Pathol Int imaging, we believe MRI is most important for 2010; 60: 407-412. differential diagnosis. Pathological examina- [4] Karahan OI, Kahriman G, Soyuer I and Ok E. Hepatic von Meyenburg complex simulating tion is necessary when a history of primary biliary cystadenocarcinoma. Clin Imaging malignancy exists or the patient has atypical 2007; 31: 50-53. appearance on radiological images. In addition, [5] Hettinger M, Klotz M, Bolay L and Weber P. we present diagnosis of BHs from a small lesion [Multiple bile duct hamartomas of the liver--a in the liver of a young patient with hepatitis. We rare differential diagnosis to liver metastasis]. also present a novel association between BHs Ultraschall Med 2005; 26: 150-153. and tumor-feeding vessels that has never been [6] van Vlerken LG, van Leeuwen MS, Schipper reported, potentially creating a new link ME and van Erpecum KJ. The “Von Meyenburg between benign lesions and tumor vasculature. complex”: an unusual cause of cholangitis? Of course, we cannot rule out that our case may Clin Res Hepatol Gastroenterol 2011; 35: 762- be an individual phenomenon. 764. [7] Redston MS and Wanless IR. The hepatic von Acknowledgements Meyenburg complex: prevalence and association with hepatic and renal cysts among 2843 This project was carried out with financial sup- autopsies [corrected]. Mod Pathol 1996; 9: 233-237. port from the National Natural Science [8] Ioannidis O, Iordanidis F, Paraskevas G, Foundation of China (Grant Nos. 30332369/ Ntoumpara M, Tsigkriki L, Chatzopoulos S, Ko- H1205 and 81171352/H1805) and the tronis A, Papadimitriou N, Konstantara A, Science and Technology Support Projects of Makrantonakis A, Sakkas A and Kakoutis E. the Science and Technology Commission of Incidentally discovered white subcupsular liver Shanghai (Grant No. 124119a5300). nodules during laparoscopic surgery: biliary

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