Focal intrahepatic strictures: a review of diagnosis and management

Abstract

Introduction

Focal intrahepatic strictures are becoming more common owing to more prevalent and accurate cross-sectional imaging. However, data relating to their management are lacking. The purpose of the present review was to synthesize the current evidence regarding these lesions and to formulate a strategy for diagnosis and management.

Methods

A literature search of relevant terms was performed using Medline. References of papers were subsequently searched to obtain older literature.

Results

Focal intrahepatic strictures involve segmental hepatic ducts and/or left and right main hepatic ducts during their intrahepatic course. Most patients are asymptomatic while the minority present with vague abdominal pain or recurrent sepsis and only rarely with jaundice. Investigations used to distinguish benign from malignant aetiologies include blood tests (CEA, Ca19.9), imaging studies [ultrasonography (US), computed tomography (CT), magnetic resonance cholangiopancreatography (MRCP) and fluorodeoxyglucose-positron emission tomography (FDG-PET)], endoscopic modalities [endoscopic retrograde cholangiopancreatography (ERCP)/endoscopic ultrasound (EUS)/cholangioscopy] and tissue sampling (brush cytology/biopsy).

Conclusions

A focal intrahepatic stricture requires thorough investigation to exclude malignancy even in patients with a history of biliary surgery, hepatolithiasis or parasitic infection. If during the investigative process a diagnosis or suspicion of malignancy is demonstrated then surgical resection should be performed. If all diagnostic modalities suggest a benign aetiology, then cholangioscopy with targeted biopsies should be performed.

Introduction

Biliary strictures most commonly involve the extrahepatic biliary tree¹ and usually present with clinical and biochemical evidence of biliary obstruction.² Focal intrahepatic strictures (FIHS) involve the segmental intrahepatic ducts, are much rarer and are often asymptomatic.³ They are often detected as incidental findings after imaging performed for other reasons.⁴ The management of these strictures requires a knowledge of their natural history and appropriate diagnostic evaluation. The available literature regarding management of these lesions is inconsistent and often controversial.⁵ The purpose of this review was to synthesize the current evidence regarding these lesions and to formulate a strategy for diagnosis and management.

Methodology

A literature search of relevant terms was performed using Medline as detailed in Fig. 1. References of papers were subsequently searched to obtain older literature.

Figure 1.

Search strategy for literature review

Incidence

FIHS are often asymptomatic and commonly found incidentally with imaging or at autopsy^3,6 making the incidence difficult to assess. Approximately 10% of patients with no history of primary sclerosing cholangitis (PSC) demonstrate ‘PSC-like’ strictures at autopsy.⁶ Case reports^3,7–13 and two small series collected over decades, at a rate of approximately four patients per year,^4,5 suggest that the true incidence is much lower.

Clinical spectrum

Patients with FIHS fall into two clinical groups. The first, representing 30% of patients, is asymptomatic where the lesion is identified incidentally.⁵ The second, representing the remaining 60% to 70%, present with vague symptoms which predominantly include abdominal pain with occasional transient pyrexia and jaundice.^3,5 Abdominal pain occurring in almost half of these patients⁵ is usually non-specific and tends to precede other symptoms.³ It is hypothesized that the pain is as a result of episodes of cholangitis. Rigors and pyrexia occur in a minority (18%) of patients whereas jaundice is less commonly associated with FIHS (0% in the study by Seo and colleagues) than with other biliary strictures.⁵

Natural history

The natural history of intrahepatic strictures depends on accurate diagnostic evaluation which is often difficult and non-confirmatory.⁴ There is no cohort of patients with FIHS who have been followed over time to determine natural history. Some early publications have suggested that recurrent cholangitis predominates³ whereas others suggest that biliary obstruction involving up to 50% of liver parenchyma can be tolerated very well if there is no associated infection and the remaining liver is unobstructed and functional.¹⁴ A study examining liver transplant patients demonstrated that in eight patients with unifocal intrahepatic strictures all had near normal liver function and none developed biliary symptoms nor required biliary intervention during a median of 21-months follow-up.¹⁵ Although a specific patient cohort, it demonstrates the possibly benign prognosis of such strictures even in an immunocompromised patient group.

Differential diagnosis

Amongst multiple case reports, two series focus on FIHS. The first is a retrospective surgical series involving 24 patients of whom one half had benign pathology.⁴ The second is a prospective cholangioscopic series that examined 17 patients who had FIHS and no hepatolithiasis of whom 29% were found to be benign.⁵ Both studies demonstrate that there are significant proportions of both benign and malignant strictures.

Benign strictures can result from many pathological processes. These include direct damage during biliary or liver surgery, hepatic arterial ischaemia such as occurs during transarterial chemoembolization (0.3%)¹⁶ or radiofrequency ablation (17%),¹⁷ chronic cholangitis (e.g. bacterial, eosinophilic such as IgG4 disease or parasitic) and hepatolithiasis.¹⁸ Diseases that are usually multifocal such as primary sclerosing cholangitis (PSC) and Caroli's disease may be localized and present with a FIHS.^19–21 Benign tumours may also present with localized intrahepatic dilatation and an intraluminal filling defect mimicking a FIHS.²² A history of any of the above features may suggest, but is not conclusive, of a benign aetiology. Almost one-third of patients with malignant intrahepatic strictures have a previous history of biliary surgery⁴ and up to 50% of patients have coexistent hepatolithiasis.²³

The most important malignant cause of FIHS is cholangiocarcinoma representing 50–53% of patients in the current series^4,5 whereas HCC, SCC and metastatic disease occur rarely.^3,7–13 Of the three pathological growth types of intrahepatic cholangiocarcinoma – mass-forming, periductal infiltrating and intraductal growth – only periductal infiltrating and to a lesser extent intraductal growing tumours are relevant as they can produce a FIHS without a mass.²⁴ A list of potential aetiologies for FIHS are detailed in Table 1.

Table 1.

Differential diagnoses for focal intrahepatic strictures

BENIGN
Post-operative	Post-biliary surgery
Inflammatory	Hepatolithiasis, PSC, IgG4 disease
Ischaemic	Post TACE/hepatic arterial injury, RFA
Direct toxicity	Hepatic arterial floxuridine
Congenital	Biliary anomalies e.g. Caroli's disease
Benign tumour	Papillary adenoma
Infective	Chronic cholangitis
	– Bacterial, TB, Parasites
	AIDS cholangiopathy
Idiopathic
Malignant
Cholangiocarcinoma
HCC
SCC
Liver metastases

PSC, primary sclerosing cholangitis; RFA, radiofrequency ablation; TACE, transarterial chemoembolization; SCC, squamous cell carcinoma; HCC, hepatocellular carcinoma.

Diagnostic tests

These can be categorized as shown in Table 2.

Table 2.

Diagnostic modalities for focal intrahepatic strictures

Blood tests	Imaging	Endoscopy	Tissue sampling
LFTs Ca19.9/CEA	Abdominal US	EUS	Aspiration
	CT	Intraductal US	Brush cytology
	MRI/MRCP	Cholangioscopy	Biopsy
	PET
	Cholangiography

US, ultrasonography; CT, computed tomography; MRI/MRCP, magnetic resonance imaging/magnetic resonance cholangiopancreatography; PET, positron emission tomography; EUS, endoscopic ultrasound; LFTs, liver function tests.

Blood tests

Liver function tests

Abnormalities of liver function tests (LFTs) in FIHS tend to be milder compared with those that cause more distal obstruction.⁵ alkaline phosphatase (ALP) and gamma glutamyltransferase levels are elevated in the majority (65%) of patients, whereas bilirubin levels are rarely abnormal.^3,5 Although statistically significant differences between levels of ALP have been associated with malignant vs. benign strictures (>200 U/l, P = 0.036⁴), their ability to distinguish the two groups is limited by poor sensitivity and specificity.

CA19.9/CEA

Ca19.9 has been investigated as a tumour marker to distinguish between malignant and benign biliary strictures in both the presence and absence of PSC. Patients with malignant strictures tend to have statistically higher Ca19.9 levels than those with benign strictures.⁴ In the absence of PSC, a Ca19.9 level >100 U/ml had a sensitivity of 53% and a specificity of 92% for predicting malignancy.²⁵ However, a negative result does not exclude cholangiocarcinoma. In the presence of PSC, the sensitivity of the Ca19.9 level is higher (89%) whereas the specificity is similar (86%) for detecting the presence of malignancy,²⁶ neither of which are altered by the addition of a CEA level.²⁷ It is also important to note that very high Ca19.9 levels may be caused by benign conditions²⁸ particularly in the presence of active bacterial cholangitis.²⁹ These levels, however, return to normal quickly after resolution of the infection.²⁸

Imaging

Ultrasound

Ultrasound may be used to identify dilated intrahepatic ducts (>2 mm)³⁰ proximal to a stricture or vascular involvement. In the absence of a mass, its ability to characterize the stricture is limited.^4,31,32 However, ultrasound may identify other relevant features such as the presence of hepatolithiasis³³ or cirrhosis.

Computed tomography

Computed tomography (CT) imaging offers further information including the location of the stricture, the presence of an enhancing or thickened duct wall, lymph node enlargement, vascular invasion and the degree of intrahepatic biliary dilatation. Certain features have been found to be associated more commonly with malignant strictures compared with benign biliary strictures. These include enhanced wall thickening (≥5 mm),^4,34 lymph node enlargement (≥1 cm)^4,34 and portal vein obliteration³⁴ although this has also been demonstrated with benign pathology.³⁵ CT imaging is unable to differentiate between malignant and benign FIHS in the majority of patients.

Magnetic resonance imaging/magnetic resonance cholangiopancreatography

Magnetic resonance imaging/magnetic resonance cholangiopancreatography (MRI/MRCP) detects the presence of a stricture with a sensitivity of 93.5% and a specificity of 94.4%.³⁶ It can also assess for vascular involvement. However, there is no study that has assessed its ability to distinguish benign from malignant intrahepatic strictures. MRI has been shown to accurately distinguish between 60–80% of hilar strictures.^37–48 The degree to which this can be extrapolated to FIHS is unclear (Fig. 2).

Figure 2.

Magnetic resonance cholangiopancreatography (MRCP) of a focal intrahepatic stricture (FISH)

Fluorodeoxyglucose-positron emission tomography

There is limited information regarding positron emission tomography (PET) scanning in the context of intrahepatic strictures. Wakabayashi²³ demonstrated in a small subset of patients (n = 5) with intrahepatic strictures that PET has a sensitivity of 100% and a specificity of 100% for distinguishing benign from malignant disease. Nishiyama and colleagues assessed the accuracy of PET scanning at identifying infiltrative cholangiocarcinoma (i.e. stricture with no mass).⁴⁹ They found that PET had a sensitivity of 75%.⁴⁹ Apart from size of the lesions, the low sensitivity may also relate to the degree of associated fibrosis⁴⁹; however, little can be concluded from such a small study group.

Cholangiography

Cholangiography of the biliary tree may be performed percutaneously or endoscopically if MRCP proves non-contributory. Endoscopic retrograde cholangiopancreatography (ERCP) is usually attempted before percutaneous cholangiography. EUS-guided cholangiography has been attempted as an alternative to percutaneous transhepatic cholangiography (PTC) facilitating rendezvous procedures with retrograde or antegrade drainage.⁵⁰

Cholangiographic features of intrahepatic strictures include interruption of contrast medium, bile duct separation, tapering, shouldering, mucosal irregularity, a filling defect and/or the absence of opacification of the draining biliary tree segment.⁴ An intrahepatic stricture can be more difficult to identify than an extrahepatic stricture because it is either obscured by overlying opacified ducts or it is not filled with contrast.^51,52 Such a localized stenosis that prevents proximal filling initially may be overcome with higher injection pressure.

Distinguishing malignant from benign strictures is difficult and controversial. Some authors suggest benign biliary strictures are characteristically short and ring-like whereas malignant strictures are generally long and irregular.³ Other authors suggest that only an abrupt cut-off and bile duct separation are the statistically significant distinguishing features.⁴ These appearances may be confusing in the context of inflammation.⁵² Cholangiography also fails to accurately assess the length and depth of bile duct cancers.^53,54

Endoscopy

Endoscopic ultrasound

Endoscopic ultrasound (EUS)-guided cholangiography can facilitate both diagnostic and therapeutic intervention when ERCP has failed which occurs in up to 10% of patients.^50,55–58 The proximity between the stomach, duodenum and the biliary tree allows linear array EUS access to this system⁵⁹ in up to 91% of patients.⁵⁰ There are no data on sensitivity or specificity for intrahepatic strictures.

Intraductal ultrasound

In contrast to EUS, intraductal ultrasound (IDUS) is often better able to image the proximal biliary system and surrounding structures.^60,61 IDUS can be used to detect the extent and longitudinal spread of bile duct carcinomas directing resection margins.^54,61–64 Sensitivity of IDUS in non-PSC patients for distinguishing malignant from benign strictures was 97% with a specificity of 89%.⁶⁵ The above studies examined predominantly hilar strictures; however, there are no specific data for intrahepatic strictures.

Cholangioscopy

Cholangioscopy provides good visualization of intrahepatic duct lesions allowing distinction of benign from malignant pathology, early detection of small and multiple foci along with the ability to perform specific targeting of biopsies.^66–71 It also allows for an accurate assessment of proximal and distal cancer extension^70,72 as the superficial pattern of tumour spread may be more extensive than suggested by the stricture itself.²

Cholangioscopy can be performed endoscopically^67–69 or percutaneously^5,63,73–75 after a transhepatic tract has been dilated to facilitate passage of the cholangioscope. The sensitivity of percutaneous cholangioscopy for identifying malignant disease ranges from 76% to 82%.^63,74,75 Procedure-related morbidity includes cholangitis (11.7%) and haemobilia (5.8%).⁵ Endoscopic cholangioscopy has also been investigated by several groups.^67–70 Disadvantages include difficulty negotiating intrahepatic strictures from the ampulla given their proximal location while proximal cancer extension is also only possible to assess if the miniscope is able to traverse the stricture.⁷⁰ The equipment required is fragile and easy to damage. It also may not be possible in any patient whose ampulla is difficult to access (e.g. Roux-en-Y reconstructions) although access with a double balloon enteroscope is described.⁷⁶ However, endoscopic cholangioscopy is less invasive and does not carry the theoretical risk of tumour seeding that potentially occurs in percutaneous cholangioscopy.⁷⁰ It also avoids the formation of a permanent biliary fistula⁷⁷ when a PTC drains an obstructed segment from above. Potential complications of endoscopic drainage include cholangitis as a result of contamination of a partially drained system – mandating prophylactic antibiotics⁷⁰– and the standards risks of endoscopy.

Several authors have examined the cholangioscopic features that distinguish benign from malignant disease. Malignant strictures such as papillary adenocarcinoma were associated with multiple polypoid mucosal projections whereas adenocarcinoma was associated with irregular ductal mucosal changes with stricturing.⁵ Hepatocellular carcinoma (HCC) causing stricturing appeared as a ‘chicken-fat’ like yellowish intraductal mass with thrombi and the lesions tended to bleed on contact.⁵ Bile duct adenomas appear as an intraductal polypoid mass.⁵ Tsuyuguchi's group combined several diagnostic criteria for malignancy from previous percutaneous cholangioscopic studies^2,78,79 including irregularly dilated and tortuous vessels (‘tumour vessels’), contact bleeding and an irregular surface. This gave a sensitivity of 100%, a specificity of 86.8% and an accuracy of 93% for biliary stricture diagnosis.⁸⁰ Benign strictures by contrast demonstrate a smooth stricture segment with no surface irregularities or abnormal tumour vessels.^5,81

Tissue sampling

There are three techniques available to acquire tissue for examination. The first is aspiration cytology where bile is aspirated via a PTC catheter, ERCP catheter or via a nasobiliary drain yielding a sensitivity of 55% and a specificity of 100%⁸² for malignancy. The second technique is brush cytology whereby a metallic brush is deployed across a stricture. The sensitivity for detection of malignancy ranges from 33% to 58%.^83–89 Poor sensitivity has been attributed to poor sampling possibly owing to submucosal tumour growth or extrinsic compression and techniques to improve yield have included stricture dilation or repeated sampling.⁹⁰ The third technique is biopsy of the stricture which can be facilitated during ERCP, PTC or EUS. Endoscopic transpapillary biopsy of bile duct strictures has a sensitivity of 53–86% for cholangiocarcinoma.^87,91 Fine needle aspiration/biopsy during EUS has been more successful producing a sensitivity for biliary stricture diagnosis of 43–86%.^92–96 The sensitivity of EUS-FNA for diagnosing malignancy within proximal biliary strictures in patients who have had a negative ERCP tissue sampling is 25–83%.^92,95,97

Several additional diagnostic modalities have been explored to improve the low sensitivity of biliary cytology. These include flow cytometry,^98,99 digital imaging analysis,⁶⁵ FISH, detection of K-ras and p53 mutations and measurements of CA-19-9 and CEA⁹⁹ in bile fluid. The following data come from studies examining common bile duct biliary strictures and not intrahepatic strictures for which there are no trials.

The addition of flow cytometry to routine cytology increases the diagnostic yield of brushings from biliary strictures from 42% to 63% at the expense of a higher false-positive rate.⁹⁸ Digital imaging analysis (DIA) allows DNA content quantification, assessment of chromatin distribution and nuclear morphology. It is more sensitive at detecting malignancy in biliary strictures than routine cytology (18% vs. 39% P = 0.014); however the overall accuracy of DIA was no better than routine cytology.¹⁰⁰ FISH techniques have also demonstrated poor sensitivity compared with routine cytology (15% vs. 34%)¹⁰¹ but FISH combined with DIA allowed for a two- to five-fold increase in sensitivity when compared with routine cytology.⁶⁵ Analyses of K-ras codon 12 mutations in brush cytologies have yielded poor results for distinguishing malignant from benign biliary strictures because K-ras mutations are variably associated with bile duct malignancy and are commonly positive in benign pathology, particularly pancreatic and PSC disease.¹⁰² Similarly, immunohistochemistry analyses for p53 aberrations have yielded conflicting results^103–105 and are presently not used in the diagnostic algorithm. Finally, Ca19.9 and CEA levels in bile fluid demonstrated no diagnostic benefit.⁹⁹

While some studies show promising results, these tests have not been widely adopted as a consequence of limited availability and a marginal diagnostic advantage.

A summary of investigation features associated with malignancy has been detailed in Table 3.

Table 3.

Features on pre-operative investigations associated with malignancy

Investigation	Features associated with malignancy
LFTs
ALP	>200 U/L
Tumour markers
Ca19.9	↑Ca19.9
Imaging
Ultrasound	Vascular involvement
CT	Enhancing/thickened wall
	Lymph node enlargement
	Vascular invasion including PV involvement
MRI/MRCP	Vascular involvement
Cholangiography	Abrupt cut-off
	Bile duct separation
	Bile duct tapering/shouldering
	Mucosal irregularity
Endoscopy
Cholangioscopy	Polypoid mucosal projections
	Irregular ductal mucosal changes
	Yellow intraductal mass
	Tumour vessels
	Contact bleeding
	Irregular surface
Tissue sampling	Malignant cells

ALS, alkaline phosphatise; MRI/MRCP, magnetic resonance imaging/magnetic resonance cholangiopancreatography; PV, portal vein; LFTs, liver function tests.

Management strategies

In fit patients, there are several management options available for focal intrahepatic strictures. These include observation, non-surgical treatment (such as endoscopic or percutaneous dilatation/stenting) and surgical resection. The decision depends on the risk of malignancy or the presence of symptoms.

Figure 3 outlines our proposed treatment algorithm. Note there are two levels of investigation: ultrasound, CT and MRCP followed by the more invasive EUS, ERCP and obtaining a tissue diagnosis. The initial tests are used to identify a stricture and the second-line investigations to characterize it.

Figure 3.

Treatment algorithm for focal intrahepatic strictures (FISH)

Given the high incidence of malignancy (50%–70%) found in these strictures, if it is diagnosed or suspected at any point throughout the investigative process, the stricture should be resected allowing definitive diagnosis and management.

Malignancy is proven if biliary brushings or biopsy demonstrate malignant cells whether obtained from ERCP, PTC or cholangioscopy. Findings suspicious for malignancy include CT/MRI findings of a thickened biliary wall (>5 mm), lymph node enlargement (>1 cm), vessel occlusion and/or contrast enhancement of the duct. They also would include cholangiographic findings of an abrupt biliary cut-off or separation of the ducts. Suspicious findings on cholangioscopy include irregular ductal mucosa, an intraductal mass, contact bleeding or the presence of tumour vessels.

Some authors suggest that a formal hepatic resection should be performed on the side of the stenosis because it fulfils the principles of oncological surgery³; however, there are no data to support anatomical vs. non-anatomical resection. Laparoscopic resection for FIHS has been described previously.¹⁰⁶

The approach is different for strictures that have no malignant features. In the past, most authors have argued that they should be resected owing to the inadequacy of the available diagnostic tests.^{8,85,107–109} Our group believes that they warrant further investigation with cholangioscopy performed either endoscopically or percutaneously if it is available. As noted above, the false-negative rate for cholangioscopy is between 0–7%, lowered further if a targeted biopsy is performed.⁴ If strictures appear benign on pre-cholangioscopy investigations and a targeted biopsy does not identify any malignancy then given the already low pre-test probability of malignancy and high sensitivity, there is a very low risk of missing malignancy in such patients after cholangioscopy. If the patient is asymptomatic, observation would be appropriate as there is no evidence that a benign stricture is pre-malignant and it avoids the risks of intervention. These patients should be followed-up and if a suspicious change is noted resection should be the default therapy.

If the patient is symptomatic then some intervention is required. While surgery is sometimes the only available option, endoscopic and/or percutaneous options should be considered for strictures that have no suspicious features on any investigations including cholangioscopy. Endoscopic approaches are limited by their ability to access and traverse intrahepatic strictures which lie distant from the ampulla and stenting if required would need long transampullary stents which are prone to dislodgement. Percutaneous transhepatic therapies are hampered by the need for external drains or permanent stents which can cause futures problems for patients with benign disease. Balloon dilatation remains a viable option in both types of treatment. Biodegradable stents are a potential option.¹¹⁰

Finally, the management of patients with a FIHS and associated hepatolithiasis is controversial,¹¹¹ has been previously explored by previous authors and therefore has not been the focus of the present reviww. Some authors argue for routine resection when a biliary stricture associated with hepatolithiasis is isolated to a single segment.¹¹¹ Other authors suggest that endoscopic, including cholangioscopic clearance and stricture dilatation is a less morbid and anequally effective strategy in such patients.^112–114 In all, 10% of patients with hepatolithiasis have associated cholangiocarcinoma¹¹⁵; however, up to 50% of patients with malignant biliary strictures have coexistent hepatolithiasis.²³ Given the risk of malignancy and the inaccuracy of diagnostic tests, we believe that patients should undergo cholangioscopy at a minimum unless resection is performed as the primary treatment modality.

The above algorithm contradicts the opinion of some previous authors³ which predates both cholangioscopy and endoluminal therapies. However, it does serve as a safe and comprehensive pathway that reflects the currently published literature devoted to this rare condition.

Conclusions

A focal intrahepatic stricture requires thorough investigation to exclude malignancy even in patients with a history of biliary surgery, hepatolithiasis or parasitic infection. If during the investigative process a diagnosis or suspicion of malignancy is demonstrated then surgical resection should be performed. If all diagnostic modalities suggest a benign aetiology, then cholangioscopy with targeted biopsies should be performed if it is available.

Conflicts of interest

None declared.