Is There a Role for Cholangioscopy in Patients with Primary Sclerosing Cholangitis?

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1 American Journal of Gastroenterology ISSN C 2006 by Am. Coll. of Gastroenterology doi: /j x Published by Blackwell Publishing Is There a Role for Cholangioscopy in Patients with Primary Sclerosing Cholangitis? Nida S. Awadallah, B.S., Yang K. Chen, M.D., Cyrus Piraka, M.D., Mainor R. Antillon, M.D., and Raj J. Shah, M.D. Division of Gastroenterology, Department of Internal Medicine, University of Colorado Health Sciences Center, Denver, Colorado OBJECTIVES: METHODS: Assess the role of cholangioscopy in primary sclerosing cholangitis for 1) detection of cholangiocarcinoma using cholangioscopy-assisted biopsy 2) detection of stones not seen on cholangiography 3) stone removal with cholangioscopy-directed lithotripsy. Prospective cohort of consecutive patients referred for cholangioscopy to evaluate dominant strictures or stones. A data collection sheet was employed. Follow-up was by chart review/phone contact. Clinical improvement was defined as resolution of jaundice or 50% reduction in pain or cholangitis episodes requiring hospitalization. RESULTS: 41 patients (30M, 11F) had 60 cholangioscopy procedures (55 per oral, 5 percutaneous). 33/41 (80%) patients underwent 44 tissue sampling events. Histology: positive for extrahepatic cholangiocarcinoma (N = 1), negative/atypical (N = 31), and inadequate (N = 1). Stones were found in 23/41 (56%) patients, of which 7/23 (30%) were missed on cholangiography and detected only by cholangioscopy. 9/23 (39%) underwent cholangioscopy-directed lithotripsy. Stone clearance: complete (N = 10, 7 by cholangioscopy-directed lithotripsy after failed conventional stone extraction); partial (N = 7); and not attempted (N = 6). Median follow-up was 17.0 months (range 1 56). Clinical improvement was achieved in 25/40 (63%). Eight patients have undergone transplant and cholangiocarcinoma was present in the explant of two at 1 and 12 months post-cholangioscopy, respectively. CONCLUSIONS: This is the first series of patients with primary sclerosing cholangitis undergoing cholangioscopy for the evaluation of dominant strictures and cholangioscopy-directed stone therapy with demonstrable clinical benefits. Stones detected by cholangioscopy were missed by cholangiography in nearly one of three patients. Cholangioscopy-directed lithotripsy may be superior to conventional ERCP for achieving complete stone clearance. Despite the use of cholangioscopy, diagnosis of cholangiocarcinoma remains technically challenging. (Am J Gastroenterol 2006;101: ) INTRODUCTION Primary sclerosing cholangitis (PSC) is a syndrome of unknown etiology and is characterized by diffuse periductular inflammation resulting in stricturing of the intrahepatic and/or extrahepatic biliary tree. Progressive stricturing leads to cholestasis and calculi formation, and the chronic inflammatory condition likely contributes to an increased risk for cholangiocarcinoma (CCA). Although medical and endoscopic therapy in PSC remains controversial, liver transplantation is the last resort and considered to be the treatment of choice for patients with end stage liver disease (1 3). For patients with progressive PSC that results in frequent cholangitis episodes or sustained jaundice, retrospective and uncontrolled studies have suggested that endoscopic treatment of dominant strictures with dilation and/or stenting can result in transient clinical and biochemical improvement and a decrease in Mayo risk score, thus allowing postponement of transplantation in selected patients (4 6). The incidence of CCA in patients with PSC is higher than in the general population. Estimates have ranged from 6 to 18% at long-term follow-up and up to 36% in those undergoing liver transplantation (7 16). Previous studies assessing the use of endoscopic retrograde cholangiopancreatography (ERCP) with brush cytology and biopsy or tumor markers such as CA19-9, carcinoembryonic antigen (CEA), CA50, CA242, and CA125 have shown variable success in detecting CCA prior to liver transplant (16 22). A definitive diagnosis of CCA, however, can only be established by positive cytology or histology. Cholangioscopy (CP) permits direct visualization of the biliary tree during ERCP (23). Currently available therapeutic cholangioscopes (10 F) can be passed through the operating channel of a standard therapeutic duodenoscope obviating the 284

2 Is There a Role for Cholangioscopy in Patients 285 need for a cumbersome mother-daughter system. CP with intraductal lithotripsy is an established treatment modality for patients with difficult biliary stones, and can be an alternative to surgery (24 28). In a preliminary report, patients with indeterminate biliary strictures were shown to benefit from cholangioscopic visualization with directed tissue sampling to confirm or exclude malignancy (29). Whether CP is useful in patients with PSC is unknown. The authors hypothesized that CP may offer an advantage over conventional biopsy techniques by helping to visually select and direct the sites to biopsy in patients with diffuse biliary pathology such as PSC. The objectives of our study were to assess the role of CP in PSC for (1) the detection of CCA using CP-directed or CPassisted biopsy, (2) the detection of biliary stones not seen at cholangiography, and (3) stone removal with CP-directed lithotripsy. PATIENTS AND METHODS Consecutive patients with PSC referred to the University of Colorado Hospital between March 2000 and November 2004 for cholangioscopic evaluation of dominant biliary strictures or stones were included. Institutional Review Board approval was obtained for the collection of patient data (exempt status). PSC patients who had already been diagnosed with CCA or who had undergone liver transplantation were excluded. A data collection sheet was employed to record the following: patient demographics, imaging studies, previous attempts at tissue sampling, previous endoscopic interventions, presence of inflammatory bowel disease, cholangitis episodes requiring hospitalization or outpatient antibiotics, method of stone therapy, dilation or stenting of strictures, cholangiographic detection of stones, cholangioscopic visualization of stones not seen at cholangiography, cholangioscopic visualization of epithelial lesions, and cholangioscopic biopsies obtained. Endoscopic complications were defined using published consensus criteria (30). Methods of stone therapy were CP-directed lithotripsy (electrohydraulic lithotripsy (EHL) and mechanical lithotripsy utilizing the Segura Nitinol tipless basket (Cook Medical, Winston-Salem, NC)), balloon or basket sweep, and flushing. Dominant strictures were defined as those located in the main duct or right/left hepatic ducts. The following lesions were biopsied at CP: intraductal masses, infiltrative or ulcerated strictures, and papillary or villous mucosal projections (31). Tissue acquisition was performed after cholangioscopic visualization. CP-directed biopsies (CDB) were performed under direct visualization using a miniature biopsy forceps passed through the working channel of the cholangioscope. CP-assisted biopsies (CAB) were performed with fluoroscopic guidance using conventional biopsy forceps passed through the working channel of the duodenoscope, after initial localization by CP (documented by a spot film of the cholangioscope position during CDB). Follow-up was attempted in all patients by chart review and patient phone calls until liver transplant, death, or study termination. A standard data collection sheet was utilized for follow-up. Follow-up inquiries included additional ERCP procedures, percutaneous transhepatic cholangiograms (PTC), imaging studies, hepatobiliary surgery or biopsies, complications of ERCP and CP, and episodes of cholangitis requiring hospitalization or outpatient antibiotics. Clinical improvement was defined as resolution of jaundice or a 50% reduction in pain or cholangitis episodes requiring hospitalization or outpatient antibiotics. Cholangioscopy Technique All procedures were performed by an experienced endoscopist (R.S., Y.C., M.A.). The cholangioscopes used during the 60 procedures included Olympus (Olympus America, Melville, NY) CHF BP30 (fiber optic, N = 50); Olympus CHF B160 (video, N = 4); and Pentax (Pentax, Montvale, NJ) FCP 9P (fiber optic, N = 6). The cholangioscope diameter ranged from 3.1 to 3.4 mm with a 1.2 mm operating channel that accommodates the miniature biopsy forceps or EHL fiber. The Olympus videoscopes had a slightly smaller two-way tip deflection (90 up and down) when compared to the fiber-optic instruments (160 up and 130 down). All of the patients received prophylactic antibiotics (Levofloxacin 500 mg IV followed by 5 10 days of oral antibiotics). Following cholangiography and placement of a guidewire, the cholangioscope was advanced through the operating channel (4.2 mm) of a standard therapeutic duodenoscope over the guidewire and into the biliary ducts. Sphincterotomy and stricture dilation were performed as needed to facilitate scope passage across the papilla or stricture, respectively. If a percutaneous transhepatic drain was present, then CP was performed utilizing the established tract and passed through a 12 F sheath. To enhance visualization and permit use of the operating channel of the cholangioscope for biopsy or EHL, the guidewire was removed and intermittent flushing with sterile saline was performed while the cholangioscope was slowly withdrawn to inspect the biliary system. Stricture dilation was followed by stenting at the discretion of the endoscopist. Stones and stone fragments following lithotripsy were extracted using standard methods. CP-directed mechanical lithotripsy was performed under direct vision by passing a 3.2 F, 2.0 cm 2.5 cm Segura Nitinol tipless basket (Part number TSB-1, Cook Medical, Winston-Salem, NC) through the operating channel of the cholangioscope, capturing the stone and mechanically crushing it through a combination of closing and pulling the basket against the tip of the cholangioscope. RESULTS Forty-one consecutive patients (30 males, 11 females) with a median age of 52 yr (range: yr) had a total of 60 (range: 1 3 per patient) CP procedures (55 per oral and 5 percutaneous). The index CP procedure was for the evaluation of dominant strictures noted on a previous cholangiogram (N =

3 286 Awadallah et al. Table 1. Patient Characteristics Patient Characteristics N = 41 patients Duration of PSC Median 6 yr (range: yr) Coexisting inflammatory N = 21 bowel disease Presenting symptoms Cholangitis episodes (N = 30) Jaundice (N = 2) Pain (N = 1) Worsening LFTs (N = 8) Indication for index CP Evaluation of dominant strictures (N = 35) Stone removal (N = 1) Evaluation of PSC strictures and stone removal (N = 5) From the time of initial abnormal ERCP or the onset of signs/symptoms including elevated liver function tests (LFTs), jaundice and cholangitis episodes until index CP procedure. Of these, nine had colectomy. 35), stone removal (N = 1), both (N = 4), and suspected PSC (N = 1). Nineteen repeat procedures were for additional stricture evaluation (N = 15) or stone removal (N = 4). Patient characteristics are summarized in Table 1. Evaluations performed prior to the index CP: 39 of 41 (95%) patients had a mean of 2.9 ERCPs (range: 1 13), 8 of 41 (20%) patients had a mean 5.3 PTCs (range: 1 16), and 30 of 41 (73%) patients had one or more abdominal CT scans that did not identify a mass. Twenty-five of 41 (61%) patients had prior tissue sampling including ERCP biopsy and/or cytology (N = 17), ERCP biopsy and endoscopic ultrasound (EUS) fine needle aspiration cytology (N = 4), PTC biopsy (N = 3), and surgical biopsy (N = 1). Thirty-seven of 41 (90%) patients had sphincterotomy performed prior to or during the index CP, and the remaining four patients did not require sphincterotomy due to percutaneous CP (N = 3) and previous choledochoduodenostomy (N = 1). Evaluation of Biliary Stones Stone location and interventions are described in Table 2 and stone clearance is described in Table 3. Biliary stones were identified in 23 of 41 (56%) patients and clearance was complete (N = 10), partial (N = 7), and not attempted (N = 6). Of the 17 patients with complete/partial clearance, 9 had CPdirected lithotripsy and 8 underwent conventional methods of stone extraction alone (see Fig. 1). Complete clearance was achieved in 7 of 9 (78%) patients who were treated with CP-directed lithotripsy (EHL or mechanical lithotripsy) and 3 of 8 (38%) patients treated with conventional methods of stone extraction alone. In 7 of 23 (30%) patients, the stones were missed on cholangiography and detected only by CP. Of the 10 patients with complete stone clearance, stones recurred in 6 (60%) at the median follow-up of 17.0 months (range: 1 56 months). Stone removal was not attempted in a few selected patients for the following reasons: the stones were small enough to spontaneously pass through the biliary sphincterotomy performed for CP, small intrahepatic stones that were not associated with significant clinical symptoms, Table 2. Stone Location and Interventions in 23 PSC Patients with Biliary Stones Missed by Location Patients Cholangiography Intervention Intrahepatics 9 3 Two CP-EHL One CP-mechanical lithotripsy One balloon sweep only Five not attempted Extrahepatics 10 4 Two CP-EHL One CP-mechanical lithotripsy Four balloon/basket sweep only Two flushing One not attempted Intrahepatics and 4 0 Three CP-EHL extrahepatics One balloon sweep only Total 23 7 Nine CP-directed lithotripsy Six balloon/basket sweep only Two flushing Six not attempted Mechanical basket lithotripsy through the working channel of the cholangioscope. or stones in tertiary biliary radicles with downstream strictures that were beyond the reach of the cholangioscope. Evaluation of Dominant Strictures Stricture location and therapeutic interventions are described in Table 4. Lesions visualized by the cholangioscope that warranted biopsy were taken in 33 of 41 (80%) patients, of which 11 patients had a repeat cholangioscopic biopsy for a total of 44 tissue sampling events: CP-directed biopsy (CDB, N = 15); CP-assisted biopsy (CAB, N = 8); both CDB and CAB (N = 21). CAB only was performed if the cholangioscopic biopsy forceps could not be passed through its operating channel due to acute angulation of the cholangioscope. CAB may not have been performed if tissue acquired by CDB was deemed to be adequate by visual inspection. Fifteen patients had concomitant brush cytology, and three others had brush cytology only. Biopsies were taken from the intrahepatic bile ducts in 15 procedures, extrahepatic bile ducts in 22 procedures, and both intra- and extrahepatic bile ducts in 7 Table 3. Results of Stone Removal Using Conventional ERCP Methods or CP Stone Clearance (N = 17) Technique Complete Partial CP-directed lithotripsy (N = 9) 7 (78%) 2 (22%) Conventional methods only (N = 8) 3 (38%) 5 (63%) Total (N = 17) 10 (59%) 7 (41%) Stone removal was not attempted in 6 of 23 (26%) patients with stones.

4 Is There a Role for Cholangioscopy in Patients 287 COLOUR FIG. Table 4. Location and Interventions of Strictures Evaluated by CP Number of Procedures Location (N = 60) Intervention Intrahepatic 13 Three dilation and stenting Two dilation only Two stenting only Six no dilation or stenting Extrahepatic 10 Six dilation and stenting Zero dilation only One stenting only Three no dilation or stenting Intra- and 37 Seventeen dilation and stenting extrahepatic Eight dilation only Two stenting only Ten no dilation or stenting Total 60 Twenty-six dilation and stenting Ten dilation only Five stenting only Nineteen no dilation or stenting Biopsies without stricture dilation or stenting in 13 of 19 procedures. procedures (see Fig. 2). Of the total 60 CP procedures, the stricture of interest could not be completely traversed by the 10 F cholangioscope during 14 examinations (intrahepatic, N = 6 and extrahepatic, N = 8), however CDB, CAB, or brushings were taken in 9 of these 14 (64%). Histology was positive for extrahepatic CCA in one patient, negative or atypical in 31 patients, and inadequate in the remaining 1 patient (see Fig. 3). Eighteen of 41 (44%) patients had brush cytology that was either negative/atypical (N = 13), suspicious (N = 2), or inadequate (N = 3). Figure 1. (A) Cholangiogram suspicious for intraductal polyps. (B) Cholangioscopic view of adherent stones treated with mechanical lithotripsy using a Nitinol basket through the cholangioscope. (C) Cholangioscopic view following fragmentation of stones. Follow-Up Follow-up was obtained in 40 (98%) patients for a median of 17.0 months (range: 1 56 months). Patients had a mean of 1.9 (range: 0 11) ERCPs after the index CP. Seven of 40 (18%) patients had subsequent negative EUS, CT, or PTC biopsies. Eight patients had liver transplantation. CCA was in the explant of two of the eight patients at the hilum and right anterior lobe at 1 and 12 months post-cp, respectively. Percutaneous CP in the patient with hilar CCA revealed a suspicious nodule in the left main hepatic duct. CDB was negative and visualization of the common hepatic duct and right main hepatic duct was limited due to the presence of a right intrahepatic drain. This patient is alive without cancer recurrence at 15 months follow-up. Percutaneous CP in the patient with right anterior lobe CCA revealed a suspicious intrahepatic stricture, but both CDB and CAB were negative. This patient died at 29 months posttransplant. Overall, clinical improvement was noted in 25 of 40 (63%) patients (see Fig. 4). Complications occurred in 3 of 60 (5%) procedures: mild pancreatitis (N = 2) and mild perforation managed nonoperatively (N = 1).

5 288 Awadallah et al. COLOUR FIG. COLOUR FIG. Figure 2. (A) Cholangiogram reveals a dominant stricture of the upstream common bile duct. (B) Fluoroscopic view of cholangioscopydirected biopsy. (C) Cholangioscopy view of a biopsy proven benign stricture. The patient is without cancer at 21 months of follow-up. Figure 3. (A) Cholangiogram of a benign-appearing stricture. (B) Cholangioscopic view of biopsy proven cholangiocarcinoma. (C) Cholangioscopy-assisted biopsy after cholangioscopic localization of the stricture.

6 Is There a Role for Cholangioscopy in Patients 289 Figure 4. Clinical improvement after cholangioscopy. DISCUSSION The diagnosis of PSC is based on clinical, histological, and radiographic features. Historical criteria suggested the diagnosis should be excluded if the patient had a history of biliary tract stones, previous biliary surgery, or had been diagnosed with CCA (32 34). In 1992, Pokorny et al. reviewed selected PSC patients and found that nearly half had bile duct stones on ERCP either at the time of diagnosis or that were subsequently discovered (35). They also found that the patients with stones were approximately 50% more likely to have ascending cholangitis than those without stones. Attempts at stone removal, however, led to a reduction in ascending cholangitis in only 25% of patients, and of those who had stone clearance, stones recurred uniformly. A subsequent study by Kaw et al. revealed similar findings (36). Our study also found a 50% prevalence of stones, however, these were discovered at index CP whereas the previous studies identified stones at initial evaluation in only 6 23% of patients. Our higher rate of stone detection may be explained by enhanced visualization of the biliary tree with CP over fluoroscopy alone. Cholangiography missed nearly one out of every three patients with stones. These stones likely contribute to the chronic inflammation, stricturing, cholestasis and cholangitis seen in PSC patients. Further, our study showed that among the 17 patients with complete or partial stone clearance, 13 (77%) experienced clinical improvement (Fig. 4). This reduction in ascending cholangitis and/or pain may be attributable to earlier and superior detection of stones by CP and the benefits of CPdirected lithotripsy. However, randomized studies comparing conventional ERCP techniques for stone extraction with CP visualization and directed lithotripsy are needed to confirm that CP significantly contributes to clinical improvement. CP-directed mechanical lithotripsy has not previously been reported and, although it was performed in only two patients, it is a promising new technique for removing difficult intrahepatic stones. Of the patients who underwent CPdirected lithotripsy (both EHL and mechanical lithotripsy), two-thirds experienced clinical improvement. Ancillary interventions such as stricture dilation and stenting may also have contributed to the positive clinical outcome. In our 10 patients with complete clearance of stones, 60% developed recurrence at a median follow-up of 17.0 months. The wide range of previously reported stone recurrence in PSC patients of 7 100% is likely related to variations in the duration of follow-up (35 36). PSC patients are at an increased risk of developing CCA and several surveillance strategies have been proposed (14, 16, 18, 19). The limitation of all current surveillance strategies using tumor markers and imaging modalities is that tissue sampling is required to confirm suspected malignancy. Other than monitoring hepatic enzymes, CA19-9, and noninvasive imaging, CCA is being assessed in PSC patients largely with cholangiography and brush cytology (37). Brush cytology has been widely employed for dominant or suspicious strictures, but the methodology is fraught with false negative and occasionally false positive results (19 22). Although direct visualization of the biliary tree using CP has been available for many years, this approach has not been systematically applied to evaluate consecutive PSC patients for detection of CCA. Caldwell et al. found that a small caliber cholangioscope could traverse intrahepatic strictures but was not pursued due to difficulties in maneuvering and the inability to perform directed tissue sampling (38, 39). We have successfully performed CP-directed or assisted biopsies in 44 sessions, 22 of which were from intrahepatic strictures, with only one inadequate biopsy sample. Given the diffuse inflammatory stricturing seen in PSC patients, direct visual inspection of the strictures alone without biopsy could be misleading, and may not reliably differentiate benign from malignant disease. Thus, the authors recommend directed sampling of any epithelium if it looks ulcerated or has mass-like projections (31).

7 290 Awadallah et al. Our study cohort contains a small number of PSC patients with a diagnosis of CCA and this limits our ability to report the true sensitivity of CP for detecting cancer in PSC patients. However, CP excluded cancer in the majority of patients, which is an important consideration in pre-transplant PSC patients. Cholangioscopic biopsies detected cancer in one patient and we have thus far excluded cancer in 31 patients at a median follow-up of 17.0 months (ranged 1 56 months). Of the remaining nine patients, eight underwent transplantation and one was lost to follow-up. Two cancers discovered in the explant that were not detected on CP were located at the hilum and right anterior lobe at 1 and 12 months following CP, respectively. Pre-existing percutaneous tracts were utilized in these two patients and likely limited the examination to only one liver segment. Despite advances in cholangioscope technology, one-fourth of the desired strictures to be evaluated in our study could not be completely traversed. Nevertheless, whether incidental CCA found on explant is clinically important has been challenged in a study by Goss et al. who found the 5-yr survival in these PSC patients to be similar to those without cancer in the explant (3). In conclusion, this is the first reported series of consecutive PSC patients undergoing CP for evaluation of dominant strictures and CP-directed stone therapy. Detection and treatment of stones by CP in patients with PSC contributes, in part, to clinical improvement by relief of pain and by reducing jaundice and cholangitis episodes. In addition, CPdirected lithotripsy may be superior to conventional ERCP for achieving complete stone clearance. Directed tissue sampling via the cholangioscope using miniature biopsy forceps yields adequate tissue samples, but detection of intrahepatic CCA in patients with PSC remains challenging. Access to small intrahepatic ducts and CDB are hampered by the relatively large caliber of current cholangioscopes and by the limitations of two-way tip deflection. Further miniaturization, improvements in optical technology and introduction of four-way scope tip deflection are desirable features. The concept of concentrating tissue sampling efforts on dominant strictures in PSC patients should be reassessed and screening for CCA may require a more thorough cholangioscopic inspection including nondominant or subtle strictures in the biliary system. Controlled studies to evaluate and compare diagnostic and therapeutic maneuvers of ERCP with and without CP will enhance our understanding of the benefits of CP in patients with PSC. STUDY HIGHLIGHTS What Is Current Knowledge Patients with primary sclerosing cholangitis are at higher risk of developing cholangitis and cholangiocarcinoma than the general population. Current screening strategies for cholangiocarcinoma miss a significant proportion of cholangiocarcinomas subsequently found in the explant. What Is New Here Conventional ERCP interventions such as stricture dilation and stenting along with cholangioscopy-directed lithotripsy of stones resulted in clinical improvement in the majority of PSC patients. Most patients with primary sclerosing cholangitis have biliary stones, however, cholangiography missed one out of every three patients with stones detected by cholangioscopy. Directed tissue sampling via the cholangioscope using miniature biopsy forceps yielded adequate tissue samples, but the diagnosis of intrahepatic cholangiocarcinoma in patients with PSC still remains challenging. Reprint requests and correspondence: Raj J. 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