Intraductal papillary neoplasm of the bile duct: Radiologic findings in a new disease

Abstract

Intraductal papillary neoplasm of the biliary tract (B-IPN) is a scarcely known entity in our daily practice due to its low prevalence. Until its new definition in the fourth edition of the WHO classification of the digestive tract tumors of 2010 the disease was grouped under a heterogeneous and imprecise terminology. In addition, in recent years there has been progress in the knowledge of its etiopathogenesis, its natural history and its findings in image. The purpose of this paper is to review these data underlining the radiological findings of the disease and its differential diagnosis.

Resumen

La neoplasia papilar intraductal de la vía biliar (NPI-VB) es una entidad poco conocida en nuestro medio por su baja prevalencia. Hasta su nueva definición en la cuarta edición de la clasificación de la Organización Mundial de la Salud de los tumores del aparato digestivo publicada en 2010, la enfermedad se agrupaba bajo una terminología heterogénea y poco precisa. Además, en los últimos años se ha avanzado en el conocimiento de su etiopatogenia, su historia natural y sus hallazgos en imagen. El propósito de este artículo es repasar estos datos subrayando los hallazgos radiológicos de la enfermedad y su diagnóstico diferencial.

Introduction

Intraductal papillary neoplasm of the bile duct (IPNB) is considered to be a new type of tumour that affects the bile duct. It is an umbrella term for a group of pre-existing, sometimes confusing terms,^1–9 such as intrahepatic biliary mucinous neoplasm of the biliary tract, since not all IPNBs produce mucin,^3,5–7,10 or biliary papillomatosis. It also clarifies erroneous terms, such as mucinous pancreatic duct ectasia cystadenocarcinoma, as IPNB and cystadenocarcinoma are different diseases.^1,5,6,8–13

IPNBs can manifest as recurrent, intermittent and self-limited episodes of acute cholangitis, either due to mucin production or desquamation of the tumour epithelium, which in both cases involves bile duct obstruction and can mimic hepatolithiasis.^{3,4,6,8,12–14} It can also be asymptomatic, and be diagnosed incidentally.^{6,8,11,13–15} It is more common in men between the fifth and seventh decades of life,^3,5,6,8,15 and in South-east Asia,^{3,5–8,13,15} probably due to the higher prevalence of hepatolithiasis and clonorchiasis in these regions, both of which are risk factors for the disease.^{3–6,8,15,16}

Embryology and anatomy

The development of the hepato-biliopancreatic system plays an important role in the pathogenesis of IPNB (Fig. 1).^{3,5,11,17–19} The common bile duct and ventral pancreatic duct share an embryological origin, because both originate from an endodermal evagination of the rudimentary duodenum. This is why they show common histological and immunohistochemical characteristics: a flat columnar epithelium, and expression of cytokeratins 7 And 19.^5,11,18 In addition, the peribiliary glands are reservoirs for pluripotent stem cells for differentiation towards pancreatic epithelium, and the final expression of one or the other is controlled by the expression and inhibition of different genes.^5,18,19 Thus, any alteration in gene expression could lead to the persistence of pancreatic remains within the biliary epithelium, and partly explain the origin of IPNB.⁵ This aetiopathogenic mechanism also explains the pancreatic acinar metaplasia occasionally observed in peribiliary glands^3,5,11,18, the similarity between the IPNB and intraductal papillary neoplasm of the pancreas (IPNP),^2–14,20 and the possible coexistence of these neoplasms^20,21 (Fig. 2).

Figure 1.

Embryological development of the hepato-biliopancreatic system. Endodermal ventral (blue arrow) and dorsal (red arrow) evagination of the rudimentary duodenum. The ventral bud (or “hepatic diverticulum”) differentiates to form, on the one hand, the hepatic primordium (yellow arrow), which will also give rise to the intrahepatic bile duct, and, on the other hand, the gallbladder, the extrahepatic bile duct (green arrow), and ventral pancreas (brown arrow).^{3,5,11,17–19} The dorsal bud is the precursor of the pancreas and the dorsal pancreatic duct. The common bile duct and ventral pancreas surround the second portion of the duodenum and join the dorsal pancreas. The common bile duct, as it encircles the duodenum, extends towards the hepatic hilum and finally joins the intrahepatic bile duct, thus completing the biliopancreatic system.^5,17,18

Adapted from: Katabathina et al.⁵ and Mortelé et al.¹⁷.

Figure 2.

A 66-year-old man in a pre-transplant study for liver cirrhosis. A) Axial T2-TSE showing signs of hepatic cirrhosis and more marked intrahepatic bile duct dilation in the left hepatic lobe, where it becomes multiloculated and replaces virtually the entire parenchyma. B) Thick-slice magnetic resonance cholangiopancreatography showing beaded cystic images associated with intra- and extrahepatic bile duct dilation. Small cystic image is also seen in the head of the pancreas, together with dilatation of the lateral branch and main pancreatic duct. C) Post-gadolinium T1-THRIVE scan in the portal phase, showing biliary tract dilation with no intrabiliary enhancement foci. Examination of the explanted liver showed that the findings corresponded to innumerable cystic lesions filled with mucinous material, which communicated with the dilated bile duct. The histological study showed a papillary mucinous bile duct tumour (IPMN), with low-grade dysplasia. The patient is in follow-up for the pancreatic lesion, classified as IPMN by endoscopic ultrasound, and for the involvement of the unresectable distal bile duct.

Classification

IPNB can manifest in various ways^{3,5,6,11,13–16,22}: it is more often a multifocal rather than a solitary lesion, with an intraluminal location and the appearance of a pedunculated or sessile fungating or polypoid mass or “fern leaf” pattern (Fig. 3). IPNB can also show a pattern of “cast-like” or tubular lesions, in which the tumour reduces ductal lumen in a long segment of the bile duct. Finally, a pattern of superficial involvement can also be observed, in which the lesion is barely visible on imaging techniques. This pattern gives the surface of the bile duct an irregular or “sawtooth” pattern that is sometimes visible on ultrasound or endoscopic retrograde cholangiopancreatography (ERCP), and is caused by numerous neoformative papillary outgrowths present in the bile duct mucosa. This pattern is known as “coral reef” when viewed directly by cholangioscopy.

Figure 3.

A 72-year-old man under study for obstructive jaundice. A) T2-TSE-SPAIR MRI showing intra- and extrahepatic biliary duct dilation and a polypoid filling defect inside the left hepatic duct (yellow arrows in A-C). B) Post-gadolinium T1-THRIVE scan in the portal phase showing the intracanalicular filling defect with discrete enhancement less than the parenchyma. C) Diffusion-weighted sequence (b = 1000) showing hyperintense focus on the intrabiliary lesion. D) ADC (apparent diffusion coefficient) map with hypointense intraductal lesion, indicating diffusion restriction. The patient underwent cephalic duodenopancreatectomy for ampullary adenocarcinoma. Histology also showed intraductal papillary neoplasm in the resected bile duct (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).

Another important factor in the classification of IPNBs is mucin production, which only occurs in one third of these tumours^3,5–7,10 (Fig. 4), unlike IPNPs, where mucin production is close to 100%.³ An alternative system^{5,6,11–13,23} of classifying intraductal papillary mucinous neoplasm of the bile duct (IPMN-B) has been proposed, initially by Sakamoto et al.,²³ which divides these tumours into three subtypes: ductectatic, cystic and intermediate (Fig. 5):

• 1

  Ductectatic tumours are characterised by the presence of papillary tumours that proliferate inside a diffusely dilated bile duct (Figs. 2 and 4).

• 2

  Cystic tumours are characterised by the existence of a large cystic lesion that communicates with the intrahepatic bile duct (Fig. 6).

  
  

  Figure 6.

  A 36-year-old woman with episodes of repeated cholangitis. A) Coronal reconstruction of intravenous contrast-enhanced computed tomography (CT). B) MIP reconstruction of magnetic resonance cholangiopancreatography. C) Axial T2-TSE showing cystic lesion at the junction of segments II and IV (arrows) communicating with dilated bile duct (arrowhead). In the magnetic resonance sequences, a heterogeneous intracystic content and “thread sign” (asterisk) are observed. Normal size bile duct (hollow arrows). The lesion corresponded to a cystic intraductal papillary mucinous neoplasm communicating with the bile duct.
• 3

  Intermediate tumours are also characterised by a cystic lesion that communicates with the intrahepatic bile duct, but involve a detectable solid tumour content that secretes mucin into the intrahepatic and/or extrahepatic bile ducts (Fig. 7).

  
  

  Figure 7.

  A 50-year-old man with obstructive jaundice and constitutional symptoms. A) Axial intravenous contrast-enhanced computed tomography (CT). B) Coronal reconstruction showing generalised dilatation of the intrahepatic bile duct in both lobes and in the common bile duct. Content with greater attenuation than the bile (black arrows) is observed inside some bile ducts and in the common bile duct lumen extending to the left liver. A solid lesion that enhances less than the parenchyma (white arrows), with intratumoral cystic areas, is also observed. Fine needle aspiration of the lesion gave a diagnosis of intraductal cholangiocarcinoma.

Figure 4.

A 70-year-old man under study for colon carcinoma staging. A) Computed tomography (CT) performed in 2012 showing slightly dilated biliary ducts in segment II (arrow). B) CT performed in 2015 showing greater progression of intrahepatic bile duct dilatation and small peripheral calcifications not seen in the previous scan (arrows). C) Thick-slice magnetic resonance cholangiopancreatography. D) Coronal T2-TSE-SPAIR performed in 2015 showing dilatation of the bile duct in segments II and III and the common bile duct; curvilinear hypointense striations (arrows) or “thread sign” are observed in the most severely dilated segments. Left hepatectomy showed mucin in the bile duct and diffuse intraductal papillary mucinous neoplasm of the bile duct with mucinous adenocarcinoma.

Figure 5.

Sakamoto’s classification. A) Ductectatic: papillary tumours that proliferate inside a diffusely dilated bile duct. B) Cystic: presence of a large cystic lesion that communicates with the intrahepatic bile duct. C) Intermediate: cystic lesion that communicates with the intrahepatic bile duct, but with a detectable solid tumour content that secretes mucin into the intrahepatic bile ducts and sometimes into the extrahepatic bile ducts.

Adapted from: Takanami et al.¹²

Some experts have suggested that the ductectatic, cystic and intermediate IPMN-B subtypes are the bile duct equivalents of the main duct, lateral branch and mixed type IPMNs of the pancreas, respectively.^5,6,11,12

IPMN-Bs can rupture the bile duct due to high pressure, and give rise to pseudomyxoma peritonei or fistulas with adjacent structures.^3,13

Imaging findings

Detection of IPNB using imaging techniques will depend on the size of the lesion. Although the tumour cannot be identified, the bile duct is often dilated and obstructed, either by mucin production or by fragmentation of the tumour epithelium. Since tumour localisation is important for surgical planning, direct cholangioscopy can be performed if suspected IPNB is not detected using radiological techniques.¹³ Cholangioscopy and histopathological study are the gold standard tests, as they permit real-time visualisation and histological confirmation of the tumour.^6,8,12–16

The tumour

On ultrasound, dilation of the bile duct and occasionally intraluminal masses of variable echogenicity are usually seen,^8,14 or nodular or irregular thickening of the ductal wall.^6,12

It is important to remember that when large intraductal masses are detected on dynamic computed tomography (CT) and magnetic resonance imaging (MRI) studies, they usually show hyper-enhancement in the late arterial phase with contrast washout during the portal or late phases.^4,7,8 The presence of peritumoural parenchymal enhancement or protruding edges on the margins of the lesion are indicative of invasion of the adjacent hepatic parenchyma,^7,10 although the degree of invasion is often overestimated.⁷

In these cases, dynamic MRI with hepatobiliary contrast may be useful, because normal hepatocytes capture the contrast during the hepatobiliary phase, but the tumour cells do not.

It is important to remember that this detail allows the clinician to distinguish between inflammatory changes in the peritumoral hepatic parenchyma and true tumour invasion.²² These findings correlate well with increased fluorodeoxyglucose (FDG) uptake on PET/CT scan.^6,8,12,22

The T2-weighted fast spin-echo (FSE) MRI sequence is sometimes useful to identify the papillary pattern of the tumour, due to the high resolution of contrast provided by the high-intensity signal from bile in this sequence.³ The use of diffusion-weighted sequences and ADC (Apparent Diffusion Coefficient) improve the definition of the lesion and are related to the invasive potential of the tumour.^3–6

It is important to remember that the most severely dilated biliary ducts are usually the ones that contain the tumour lesions, even those that are not radiologically visible.^3,11,13

Mucin

The capacity of ultrasound, CT and MRI to detect mucin is limited, because mucin has the same echogenicity, attenuation and signal intensity, respectively, as bile.^3,6,10,13

It is important to remember that the presence of mucin in the bile duct should be suspected when there is a mismatch between the hyperintense bile content visualised on magnetic resonance cholangiopancreatography (MRCP) and the amorphous, elongated cordlike filling defects observed on ERCP.^3,13 ERCP also allows biopsies and therapeutic manoeuvres to be performed, such as decompression by papillotomy or stent placement in inoperable cases.^4,6,14

A recent study described a highly specific finding for the diagnosis of intrabiliary mucin on MRI, called the “thread sign”,¹⁰ which consists of curvilinear hypointense striations in the dilated bile duct in T2-FSE and MRCP sequences (Figs. 4 and 6). Hepatobiliary-specific gadolinium is also effective at showing mucin as filling defects during the hepatobiliary excretion phase.^6,10,12,22 The disadvantage, however, is that biliary excretion of contrast is diminished in these patients due to impaired liver function caused by bile duct obstruction.^12,22

Pathology and prognosis

In the fourth edition of the 2010 World Health Organization (WHO) classification, IPNB is described as a new neoplasm.¹ Since then, numerous issues have arisen concerning the classification of IPNB as a single entity or a group of different neoplasms.²

A group of expert pathologists recently proposed a new provisional classification (Table 1)² that divides IPNB into two groups: Type 1 IPNB (Fig. 8) and type 2 IPNB (Fig. 7).

Table 1.

Provisional histopathological classification of intraductal papillary neoplasms of the bile duct (IPNB).²

	Location	Histopathology	Histological phenotype	IPMN-P	Dysplasia	Invasive
Type 1 or “classic” IPNB	Intrahepatic bile duct	Uniform, regularly arranged papillary proliferation	1. Gastric, followed by oncocytic	Shared similarities:	Coexisting foci of low- to high-grade dysplasia, or even adenoma	Both types (especially type 2) are invasive
		Thin fibrovascular stalks	2. Sometimes: more or less disorganised tubulopapillary elements.	● Structural: fibrovascular stalks surrounded by oedematous stroma
				● Physiological: mucin production
Type 2 (papillary cholangiocarcinoma) IPNB	Extrahepatic and hilar bile duct	Complex papillary proliferation	1. Pancreatobiliary and/or intestinal	No shared similarities	Predominantly high-grade dysplasia
		Thick fibrovascular stalks	2. The gastric type is uncommon, and the oncocytic is very rare
		Irregular branching
		Mixed tubulopapillary or cribriform pattern, ± necrosis

Figure 8.

A 60-year-old man under study for abdominal pain in the right hypochondrium, jaundice and fever. A) Thick-slice magnetic resonance cholangiopancreatography. B) Axial T2-TSE showing focal dilatation of intrahepatic bile ducts in segment VII and small hypointense filling defects (arrows) in the wall of the dilated ducts in both sequences. Segmentectomy showed intraductal papillary neoplasm of the bile duct with non-infiltrating in situ cholangiocarcinoma.

Some pathologists insist that both groups have the same invasive potential, and constitute a single pre-invasive pathological condition. The only difference between them is their location.^1,2

Other experts suggest that each group is different: type 2 IPNB is most likely an extreme papillary variant of conventional cholangiocarcinoma, since its fibrous/nodular component would be expected to coexist with an intraductal papillary tubulopapillary growth pattern.² Therefore, further studies are needed to clarify the significance of this provisional classification.²

The difference between the IPNB and biliary intraepithelial neoplasia (BilIN) is that the first shows papillary projections of more than 5 mm, while the second consists of a flat or micropapillary lesion with a growth of less than 3 mm², making it undetectable using conventional imaging techniques.⁴ BilIN is also found in surgical specimens of patients diagnosed with hepatolithiasis.⁴

IPNB extends superficially through the mucosa,^{3,4,6–8,11–14} giving it a better overall prognosis than conventional cholangiocarcinomas (mass formation and periductal infiltration).^{3–8,10–12,16}

IPNB has a worse postoperative prognosis than IPMN-P.^3,24 Although both variants of IPNB are associated with invasive growth, this is more frequent in type 2 or “papillary cholangiocarcinoma”,² hence its poor prognosis.¹⁰

Differential diagnosis

The following are the main mimickers of IPNB:

Periductal infiltrating cholangiocarcinoma

Unlike IPNB, the tumour extends submucosally, causing thickening of the bile duct wall, hyperenhanced with respect to the hepatic parenchyma, and visualised on dynamic studies. It often causes stenosis and dilatation of the proximal bile duct. It also differs from IPNB in terms of its location: while IPNB can affect both the intra- and extrahepatic bile ducts, infiltrating cholangiocarcinoma usually occurs at the confluence of the common hepatic duct.⁴

Hepatolithiasis

On MRCP and T2-TSE, hepatolithiasis is shown as single or multiple filling defects in the intra- and/or extrahepatic bile duct, which can be confused with multifocal intraductal neoplasms (Fig. 9).

Figure 9.

A 44-year-old man diagnosed with Caroli disease, with recurrent cholangitis. A) axial T2-TSE. B) Thick-slice magnetic resonance cholangiopancreatography showing saccular dilations of some intrahepatic ducts and dilatation of the common bile duct. The areas of dilation contain multiple, hypointense, faceted filling defects, corresponding to hepatolithiasis. The finding was confirmed in the explanted liver after liver transplantation.

It is important to remember that dynamic CT and/or MRI studies should be performed to differentiate between these entities, assessing the presence or absence of enhancement. They do not restrict diffusion.

Mucinous cystic neoplasia

This is a new disease included in the fourth edition of the WHO classification, and includes both cystadenoma and cystadenocarcinoma.

It is important to remember that the differential diagnosis of mucinous cystic neoplasia (MCN) is established with the cystic subtype of IPMN-B.^13,22 IPMN, unlike MCN, communicates with the bile duct, and no ovarian stroma are found in the cyst wall^1,5,6,8,13 (Fig. 10). MCN is not associated with extrahepatic bile duct dilation.^3,10,13,14

Figure 10.

A 28-year-old woman under study for epigastric pain of several days of evolution that does not improve. A complex cystic lesion was identified on ultrasound (not shown). A) Thick-slice magnetic resonance cholangiopancreatography showing a polylobulated cyst with thin internal septa (arrowheads) superimposed on the confluence of both hepatic ducts (arrows) and on the proximal common hepatic bile duct, which is of normal diameter and does not communicate with the lesion. B) Intravenous contrast-enhanced computed tomography scan showing a cystic lesion in segment IV, with internal septa in its posterior portion (white arrow). After left hepatectomy, histology showed mucinous cystic neoplasm.

Choledochal cysts

These are uncommon congenital anomalies of the bile duct that are a risk factor for onset of cholangiocarcinoma^4,17 and IPNB.^3,16 The presence of a “mass-forming” cholangiocarcinoma associated with a choledochal cyst should be distinguished from all forms of IPMN-Bs.^4,12 (Fig. 11).

Figure 11.

Fine-slice MIP magnetic resonance cholangiopancreatography showing choledochal cyst (arrow) associated with an abnormal pancreaticobiliary junction (arrowhead).

Ciliated hepatic foregut cyst

This is an extremely rare disease than can progress to squamous malignancy. It manifests as a unilocular cyst, typically located in the hepatic segment 4a. Its appearance on imaging studies is complex, with no enhancement in dynamic CT or MRI studies. Differential diagnosis is made mainly with MCN, hydatid cyst and simple liver cyst.^25–29

Other

Other diagnostic possibilities are intraductal metastasis or invasive hepatocarcinoma. In both cases, a parenchymal mass is usually seen: in the case of hepatocarcinoma, with its own characteristics in the dynamic study and with indicative findings of cirrhosis, while in the case of metastasis there is usually a history of cancer, more commonly colorectal cancer.^3,4

Conclusion

IPNB is a recently diagnosed disease that may share pathogenesis with another well-known neoplasm, IPMN-P. However, no standardised pathological diagnostic criteria have yet been developed, and it is unclear whether it is a single tumour or a group of tumour subtypes. Radiologists need to be familiar with the possible manifestations of IPNB on different imaging techniques, because prognosis improves with early diagnosis.

Authorship

• 1

  Responsible for the integrity of the study: BVS, MJP, DRV.

• 2

  Study conception: BVS, DRV, MJP.

• 3

  Study design: BVS, DRV, MJP.

• 4

  Data collection: BVS, DRV, MJP.

• 5

  Data analysis and interpretation: BVS, DRV, MJP.

• 6

  Statistical processing: Not applicable.

• 7

  Literature search: BVS, DRV, MJP.

• 8

  Drafting of the article: DRV, BVS, MJP.

• 9

  Critical review of the manuscript with intellectually relevant contributions: MJP, BVS, DRV.

• 10

  Approval of the final version: MJP, BVS, DRV.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Acknowledgements

The authors of the article would like to thank Dr Rafael Rodríguez Romero for contributing to the graphic editing of Figs. 1 and 5.