Abstract
Diagnosis of biliary strictures remains challenging because of the low sensitivity of conventional transpapillary sampling using endoscopic retrograde cholangiopancreatography. New devices and tips have been developed to increase the diagnostic yield of conventional transpapillary sampling. However, additional endoscopic procedures are often necessary for indeterminate biliary strictures. Two major approaches for indeterminate biliary strictures are endoscopic ultrasonography-guided sampling and peroral cholangioscopy (POCS)-guided biopsy. The selection of modalities should be considered based on the stricture location. Although endoscopic ultrasound is the preferred approach for distal biliary strictures, POCS is preferred for perihilar biliary strictures. Endoscopic ultrasonography-guided sampling is highly sensitive in cases with a mass, but the sensitivity of POCS-guided biopsies is unsatisfactory, and discrepancy with the visual diagnosis of POCS is common. Whether these advanced techniques should be performed as the initial procedure or as a rescue after a failed diagnosis by conventional transpapillary sampling needs to be clarified in terms of diagnostic yield and cost-effectiveness.
Keywords: Biliary strictures, Cholangioscopy, Endoscopic retrograde cholangiopancreatography, Endosonography
INTRODUCTION
Despite recent advancements in radiological and endoscopic procedures, biliary strictures still pose diagnostic challenges for clinicians despite the recent advancement of radiological and endoscopic procedures.1 In general, most biliary strictures are malignant; however, accurate and timely diagnosis is mandatory for appropriate management of biliary strictures. While delayed diagnosis of malignancy leads to disease progression, surgical resection without confirmation of malignancy poses a risk for benign conditions, with reported rates of unnecessary surgical resection ranging from 3.1% to 14% in cases of benign hilar biliary strictures.2,3 To make things more complex, malignancy can occur in the background of benign inflammatory conditions, such as primary sclerosing cholangitis.
Endoscopic retrograde cholangiopancreatography (ERCP) with transpapillary sampling is the standard of care for biliary strictures; however, its diagnostic yield is unsatisfactory. In cases with indeterminate biliary strictures, additional procedures such as peroral cholangioscopy (POCS) and endoscopic ultrasonography (EUS) are often necessary; however, a strategy for the workup of biliary strictures has not been fully established. In this review, we discuss the current status of the management of indeterminate biliary strictures.
DEFINITION OF INDETERMINATE BILIARY STRICTURES
Differential diagnoses of biliary strictures vary widely (Table 1), and an accurate diagnosis of biliary strictures is mandatory for appropriate management but can be difficult. Indeterminate biliary strictures were defined as those of uncertain etiology with inconclusive/negative imaging or tissue diagnosis.4 The initial non-invasive workup involves high-resolution cross-sectional imaging, such as dynamic computed tomography (CT) and magnetic resonance imaging (MRI) with MR cholangiopancreatography (MRCP). When diagnosis remains unconfirmed even after ERCP with transpapillary tissue sampling, the stricture is categorized as indeterminate.
Table 1.
Differential diagnoses of biliary strictures
| Differential diagnoses of biliary strictures |
|---|
| 1. Malignant |
| Biliary tract cancer |
| Pancreatic cancer |
| Hepatocellular carcinoma |
| Metastatic cancer |
| Malignant lymphoma |
| 2. Benign |
| (1) Inflamatory |
| Chronic pancreatitis |
| Primary sclerosing cholangitis |
| IgG4-related sclerosing cholangitis |
| Eosinophic cholangitis |
| Immune checkpoint inhibitor-related cholangitis |
| (2) Vascular |
| Vasculitis |
| Intra-arterial chemotherapy/embolization |
| Portal hypertensive biliopathy |
| (3) Infectious |
| Acquired immune deficiency syndrome cholangiopathy |
| Tuberculosis |
| Recurrent pyogenic cholangitis |
| (4) Pust-surgical |
| Cholecystectomy |
| Liver transplantation |
Ig, immunoglobulin.
Table 2.
Indication, tips, and characteristics of each diagnostic modality for biliary strictures
| Indications | Tips | Advantages | Disadvantages | |
|---|---|---|---|---|
| Transpapillary brush cytology | All biliary strictures | - 30 Passes | - Low cost | - Low sensitivity |
| - Combined with biopsy and bile aspiration | - Technical easiness | |||
| Transpapillary biopsy | All biliary strictures | - 3 Biopsies | - Low cost | - Low sensitivity |
| - Sheath-assisted biopsies | - Technical difficulty in perihilar strictures | |||
| POCS | Intrinsic stricture except in the distal end of the bile duct | - 3 Biopsies | - Direct visualization | - High cost |
| - Rapid on-site evaluation | - Target biopsies | - Small samples | ||
| - Possible discrepancy between visual and pathological diagnoses | ||||
| EUS-guided sampling | Distal extrinsic stricture with mass | - Sampling prior to biliary stenting | - High sensitivity | - Risk of bile leakage and dissemination |
POCS, peroral cholangioscopy; EUS, endoscopic ultrasonography.
Biliary strictures are classified as either intrinsic or extrinsic. Extrinsic biliary strictures are defined as strictures caused by compression by a mass outside the bile duct. Intrinsic strictures are defined as biliary strictures without discrete extrinsic masses.
THE DIAGNOSTIC YIELD OF CONVENTIONAL TRANSPAPILLARY SAMPLING
Brush cytology and intraductal biopsy have been performed as conventional transpapillary sampling methods, with a reported sensitivity of 43% for brush cytology and 52% for transpapillary biopsy under fluoroscopic guidance. The sensitivity remained at 66%, even with the combination of these two techniques.5 The technical hurdles of conventional transpapillary sampling are the small sample size obtained using small devices and indirect visualization under fluoroscopic guidance. Attempts to increase sample size have also been reported. A retrospective study showed that the number of transpapillary biopsies was associated with sensitivity. The sensitivity increased from 60.0% for one sample to 77.8% for two samples and 100.0% for three or more samples.6 A randomized controlled trial (RCT) showed that the sensitivity of brush cytology increased from 38% to 57% by simply increasing the number of brush passes from 10 to 30 passes.7 The addition of bile aspiration during transpapillary tissue sampling is also a simple method to improve diagnostic yield. Cytology of the aspirated bile showed higher cellular adequacy (92.8% vs. 35.7%) and sensitivity (66.6% vs. 17.6%) than brush cytology alone.8 Thus, in conventional transpapillary sampling, a combination of brushing with 30 passes, intraductal biopsies with >3 samplings, and bile aspiration is recommended to increase diagnostic yield.
New devices have been developed to improve the diagnostic yield of transpapillary samples. A dense cytology brush was designed to increase the cellularity of the cytology specimens. Despite promising results in preliminary studies,9,10 recent two RCTs have shown conflicting results. While one study showed more cellularity with the dense cytology brush,11 another study showed no superiority over a conventional cytology brush and was early terminated.12 The use of a basket catheter to grasp the tissue was also evaluated for the diagnosis of biliary strictures and compared with the cytology brush. The sensitivity of the basket group was 80%, which was significantly higher than 48% of the conventional brush group.13 Recently, a new scraper-type device that can obtain both cytological and histological specimens was reported. In a retrospective study, the sensitivities of cytology and histology were 91.6% and 72.6%, respectively, and as high as 93.7% when cytology and histology were combined.14-16 Rapid on-site evaluation (ROSE), which is often used in EUS-guided sampling, has been reported in transpapillary brush cytology.17 However, the cost-effectiveness of ROSE in this setting requires further evaluation.
In addition to the limited sample size, access to perihilar biliary strictures can be technically difficult. Targeted biopsy for POCS, which will be discussed later, is a diagnostic option but is not available in all centers. Furthermore, cost is also an issue with the POCS. New devices or tips have been reported to increase accessibility to the perihilar regions. Sheath-assisted biopsies,18 which allow easy and repeated transpapillary access, show a higher adequate sampling rate (88.2% vs. 66.4%) within a shorter time (3.7 vs. 7.7 min) than conventional transpapillary sampling. The rate of adverse events, mostly post-ERCP pancreatitis, was significantly lower (6.4% vs. 21.6%) in sheath-assisted biopsy, which was also attributable to the avoidance of repeated transpapillary insertion of the biopsy forceps. The zipline technique,19 which allows wire-guided insertion of biopsy forceps by a looped nylon thread passed through the holes of the biopsy forceps, is also a cheap and helpful method for easy access to the targeted bile duct.
Despite the development of these new techniques and devices, the diagnostic yield of transpapillary sampling remains unsatisfactory, and the next steps to indeterminate biliary strictures are necessary after inconclusive transpapillary sampling.
NEXT STEPS TO INDETERMINATE BILIARY STRICTURE
There are two major diagnostic approaches for indeterminate biliary strictures: an intraductal approach using POCS and an extraductal and intraductal approach using EUS. POCS allows for direct visualization and targeted biopsy. EUS can visualize both intraductal and extraductal imaging as well as EUS-guided sampling.
Recently, new modalities have been developed, including confocal laser endomicroscopy (CLE)20 and fluorescence in situ hybridization (FISH). CLE allows in vivo visualization, so called “virtual biopsy.” Probe-type CLE (pCLE) is used to evaluate indeterminate biliary strictures. A probe with a diameter of <1.0 mm can be advanced either through an ERCP catheter or POCS and is positioned in direct contact with the biliary mucosa. There are two pCLE classifications for indeterminate biliary strictures: the Miami and Paris classifications. In the Miami classification,21 the criteria for malignancy include thick dark bands, thick white bands, dark clumps, epithelium, and fluorescein leakage. To further differentiate inflammation from malignancy, the Paris classification defines pCLE findings of inflammation as a dark granular pattern in scales, thickened reticular structures, roughness, vascular congestion, increased interglandular space, and thickened reticular stricture.22 In a recent meta-analysis of pCLE for indeterminate biliary strictures,23 the sensitivity and specificity were 88% and 79%, respectively. Despite its high diagnostic yield, pCLE for biliary strictures is not widely used in clinical practice because of its high cost and limited availability.
FISH is an adjunctive technique of biliary brush cytology to evaluate chromosomal abnormalities.24 The sensitivities of cytology and FISH were previously reported to be 15% and 34%, respectively, for the detection of malignancy in bile duct brush specimens (p<0.01). In a recent meta-analysis, the sensitivity and specificity of FISH were 57.6% and 87.8%, respectively.25 More recently, methylated DNA markers have been reported to be useful in the diagnosis of biliary malignancies. When combined as a panel, the sensitivity and specificity were 73.4% and 92.9%, respectively, compared with sensitivity and specificity of 20.6% and 100% by cytology and 65.6% and 96.2% by FISH.26 However, the new modalities of FISH and methylated DNA markers have not been widely utilized in clinical practice.
EUS-GUIDED SAMPLING
EUS-guided sampling for biliary strictures is reported to have a higher sensitivity than transpapillary sampling. A systematic review revealed a sensitivity of 75% for EUS-guided sampling compared to 49% for transpapillary sampling.27 Despite its high sensitivity, the sensitivity of EUS-guided sampling varies among studies from 33% to 96%.28 The reasons for this variation in the diagnostic yield of EUS-guided sampling can be multifactorial, such as needle size and type, suction, and lesion size (or the presence of a mass rather than wall thickening alone). EUS-guided sampling using new fine-needle biopsy needles can improve the diagnostic yield compared to conventional fine-needle aspiration needles.29 The diagnostic yield of EUS-guided sampling depends on a target size, too.30 Furthermore, it is difficult to visualize perihilar regions using EUS. Forward-viewing EUS might provide better visualization and help with EUS-guided sampling in this region,31 but this echoendoscope is not widely available. Thus, EUS-guided or transpapillary sampling can be selected based on the location and nature of biliary strictures. In cases of extrinsic biliary strictures, the accuracy of transpapillary sampling was 67.8%; however, EUS-guided sampling as a second step provided an accuracy of 90.9%, resulting in an overall accuracy of 96.6%.32 In contrast, in intrinsic biliary strictures, the accuracy of the initial transpapillary sampling was 81.8%, and the additional second transpapillary sampling provided an accuracy of 84.2%, with an overall accuracy of 96.7% in two sessions of transpapillary sampling. Similarly, in cases with distal biliary strictures, EUS-guided sampling as a second step provided a sensitivity of 96.0%. POCS-guided biopsy as a second step provided a sensitivity of 92.3% for perihilar biliary strictures.33 In general, pancreatic cancers with a discrete mass present with extrinsic distal biliary strictures,34 and EUS-guided sampling is more diagnostic than transpapillary sampling.
Notably, EUS-guided sampling for biliary strictures has a potential risk of bile leakage or peritoneal dissemination and should be avoided in potentially resectable biliary tract cancers. Although biliary stent placement may reduce the risk of bile leakage, an indwelling biliary stent can impair EUS visualization and decrease the diagnostic yield of EUS-guided sampling.35 Thus, EUS-guided sampling may be better performed in the initial procedure, if necessary.
PERORAL CHOLANGIOSCOPY
As briefly discussed above, POCS is another diagnostic modality for indeterminate biliary strictures that allows direct visualization and targeted biopsies. The sensitivity and specificity of POCS are 67% to 100% and 49% to 100% by visual impression and 38% to 100% and 75% to 100% by targeted biopsies.4 Various diagnostic criteria for POCS36,37 have been reported, but consensus guidelines4 suggest four items for the diagnosis of malignancy: tumor vessels, papillary projections, nodules/masses, and infiltrative lesions. The sensitivity of visual diagnosis by POCS is often higher than that of targeted biopsies, but interobserver agreement was only fair to moderate with kappa values of 0.12 to 0.54, even using those diagnostic criteria. It is also well known that dilated vessels can be observed in immunoglobulin (Ig) G4 sclerosing cholangitis and the clinical context, including serum IgG4 levels, should be considered in the diagnosis of indeterminate biliary strictures.38
The use of image-enhanced cholangioscopy, such as narrowband imaging39 and I-scan,40 could potentially improve the diagnostic yield by better visualization of surface structures and tumor vessels. However, image enhancement is not possible with the SpyGlass system, which is widely used in clinical practice. To overcome this limitation, artificial intelligence (AI)-based approaches have been intensively investigated in the field of POCS. Marya et al.41 reported accuracy of the convolutional neural network model was 90.6%, compared with that of brush cytology (62.5%) or forceps biopsy sampling (60.9%). Zhang et al.42 also reported an AI model of POCS with an accuracy of 93.0%, compared to 84.5% by novices and 88.6% by experts. However, the study results need further validation before the intraprocedural AI diagnosis of indeterminate biliary strictures during POCS becomes commercially available.
Despite these advancements in image-based diagnosis of POCS, pathological diagnosis remains the gold standard for the diagnosis of malignancy. Although POCS visualization was more sensitive than POCS-guided biopsies (93% vs. 82%), it was also associated with lower specificity (86% vs. 98%).43 The low sensitivity of POCS-guided biopsies can be attributed to the small number of specimens obtained using the microforceps. The use of ROSE has been reported to increase the diagnostic yield of targeted biopsies, the use of ROSE was reported,44 similar to EUS-guided sampling. In an RCT of on-site and off-site evaluation,45 the diagnostic yield was similar, with a sensitivity of 76.9% and 75.0%, respectively. However, the median number of biopsies necessary for diagnosis was one in the on-site group, while three or four biopsies showed a similar diagnostic yield in the off-site group. This study suggests that ROSE is helpful in achieving adequacy of biopsy specimens during POCS, and three biopsies are recommended if on-site evaluation is not available. The diagnostic yield of POCS is inferior in distal biliary strictures because of the unstable position of the POCS.46 In distal biliary strictures without discrete masses, percutaneous transhepatic cholangioscopy can be helpful if the lesion is not amenable to EUS-guided sampling.47
In summary, POCS with targeted biopsies is useful as a next step in cases of perihilar biliary strictures; however, the diagnostic yield of targeted biopsies still needs further improvement.
WHAT IS THE BEST DIAGNOSTIC ALGORITHM FOR BILIARY STRICTURES?
As previously discussed, EUS-guided sampling is preferred for distal biliary strictures, while POCS-guided biopsy is recommended for evaluating intrinsic lesions; both serve as essential next steps for indeterminate biliary strictures. The proposed algorithm for biliary strictures is illustrated in Figure 1.
Fig. 1.
Proposed algorithm for biliary strictures. CT, computed tomography; EUS, endoscopic ultrasonography; ERCP, endoscopic retrograde cholangiopancreatography; BD, biliary drainage; POCS, peroral cholangioscopy.
Whether these advanced EUS and POCS techniques should be performed as the initial procedure or only after inconclusive ERCP remains debatable. EUS-guided sampling of distal biliary strictures is often selected as the salvage technique after inconclusive ERCP with biliary stenting. However, the diagnostic yield of EUS-guided sampling can be impaired by an indwelling biliary stent; the accuracy was 77.5% vs. 94.5%, and the sensitivity was 71.0% vs. 91.7% in cases with and without biliary stents.35 Furthermore, comprehensive genome profiling (CGP) for matched therapy is increasingly utilized in clinical practice, and EUS-guided sampling was more applicable to CGP than ERCP: 34.9% vs. 8.6% by EUS-guided sampling and transpapillary sampling.48 Given the low sensitivity of transpapillary sampling, EUS-guided sampling, followed by ERCP with stenting, can be performed in a single session. In a multicenter retrospective study,49 same session EUS-guided and transpapillary sampling had a higher sensitivity (85.8%, compared to 73.6% in EUS-guided sampling alone and 56.5% in transpapillary sampling. However, in cases with large (>4 cm) pancreatic masses, EUS-guided sampling alone was comparable to a combination of EUS-guided and transpapillary sampling. Thus, EUS-guided sampling is recommended prior to ERCP in cases of distal biliary strictures, if available.
The timing of the POCS is also under debate. Because an indwelling stent in cases of indeterminate biliary strictures causes inflammation or sloughing of the bile duct mucosa, the diagnostic yield of POCS might be impaired if performed in a second session or later after inconclusive conventional ERCP. One RCT50 demonstrated that POCS-guided biopsies in the first ERCP showed higher sensitivity than ERCP-guided brushing (68.2% vs. 21.4%) for indeterminate biliary strictures on MRCP. However, indeterminate biliary strictures are defined as those with an inconclusive diagnosis based on ERCP with transpapillary tissue sampling. Given the cost of POCS, especially single-use cholangioscopy, routine use of POCS for biliary strictures during initial ERCP may not be recommended. The only cost-effective analysis of POCS for indeterminate biliary strictures was reported as a salvage procedure after inconclusive ERCP, which suggested that POCS with its high sensitivity could reduce the number of procedures by 31% and the total cost by 5%.51 In addition to concerns regarding the cost of POCS, it is associated with the potential risk of adverse events, including cholangitis.52,53 The risk of cholangitis or bacteremia may further increase if POCS for biliary strictures is performed before biliary drainage. Thus, whether POCS should be performed after inconclusive conventional ERCP or during the first ERCP should be further evaluated.
FOLLOW-UP AFTER INCONCLUSIVE WORKUP
As previously discussed, the sensitivity of various diagnostic modalities is still low, and false negativity is present in the evaluation of indeterminate biliary strictures. Tissue sampling of lesions other than biliary strictures, such as EUS-guided sampling of swollen lymph nodes or metastatic lesions, should be performed whenever possible. As the cause of biliary strictures is more often malignant than benign, repeat procedures are recommended after inconclusive procedures. However, there is no evidence for an appropriate interval after inconclusive pathological findings when malignancy is clinically suspected. In clinical practice, follow-up procedures are often performed a few months later, but it is also unclear whether radiological images of CT or MRI/MRCP are sufficient or whether advanced procedures of EUS-guided sampling and/or POCS should be performed. Another option is a percutaneous approach. The diagnostic yield of percutaneous transluminal forceps biopsy had a sensitivity of 81% and a specificity of 100% in a meta-analysis.54 However, this approach requires percutaneous transhepatic biliary drainage, which is associated with an impaired quality of life due to an indwelling external drainage tube, as well as a risk of tumor seeding in case of malignancy.55 Another option is surgical exploration with possible resection. However, surgical resection without a preoperative pathological diagnosis should always be considered with caution because it is potentially associated with complications. The potential diagnostic benefits of surgical exploration should always be balanced against its invasiveness.
CONCLUSIONS
Pathological diagnosis of biliary strictures still poses challenges in conventional ERCP-based tissue sampling. In patients with indeterminate biliary strictures, POCS and EUS with tissue sampling should be selected according to the location (perihilar and distal) and nature (intrinsic and extrinsic) of the strictures. Indications, tips, advantages and disadvantages of each diagnostic modality are summarized in Table 2. A structured approach for biliary strictures should be established to further improve the diagnostic yield and cost-effectiveness. There remain unanswered questions and unmet needs for the diagnosis of biliary strictures (Table 3), and further research is warranted to increase the diagnostic yield of indeterminate biliary strictures.
Table 3.
Unanswered questions and unmet needs for indeterminate biliary strictures
| Unanswered questions and unmet needs |
|---|
| Devices or tests to improve conventional transpapillary sampling |
| Should EUS be performed prior to ERCP in all cases? |
| Should POCS be performed in all cases and during the first session? |
| Biomarkers for malignancy |
| What are the appropriate intervals for re-evaluation after inconclusive results? |
| Which tests should be performed for re-evaluation? |
ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasonography; POCS, peroral cholangioscopy.
Footnotes
Conflicts of Interest
Yousuke Nakai received research grants from Boston Scientific Japan Century Medical Inc., Gadelius Medical KK and HOYA Corporation and honoraria from Boston Scientific Japan, Gadelius Medical KK, and Olympus Corporation. The other authors have no potential conflicts of interest.
Funding
None.
Author Contributions
Conceptualization: YN, RH, YT; Data curation: YN, RH, YS, NO; Methodology: YN; Supervision; YN; Writing–original draft: YN; Writing–review & editing: all authors.
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