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Diagnosis of malignant biliary strictures
Diagnosis of Malignant Biliary Strictures Anthony Lin, MD, Sreeni Jonnalagadda, MD, and Steven A. Edmundowicz, MD
It is important to determine the benign or malignant nature of a biliary stricture, and a tissue diagnosis is usually desirable. This article discusses methods for diagnosis of malignant biliary strictures, including bile cytology, biliary brush cytology, intraductal forceps biopsy, needle aspiration, scraping devices, and endoscopic ultrasound-guided aspiration. Ki-ras analysis and the u s e of flow cytometry are also reviewed. In most cases a combination of tissue sampling techniques will result in the highest diagnostic yield. Copyright 2002, Elsevier Science (USA). All rights reserved.
t is essential to determine the benign or malignant nature of
I .a biliary stricture to plan appropriate therapy. This can
sometimes be a daunting task given the nature of the disease processes that lead to biliary strictures. Some common origins of malignant biliary strictures are listed in Table 1. The most commonly encountered causes of malignant bile duct strictures include cancers of the ampulla, bile duct, and pancreas. These account for more than 75% of all patients presenting with extrahepatic bile duct obstruction. 1 A few biliary strictures can be correctly (and simply) classified as benign by their clinical presentation and appearance (for example, a smooth stricture in the region of the cystic duct following biliary surgery with a normal preoperative cholangiogram). Other more "indeterminate" strictures require further testing and analysis of the clinical scenario, as many benign diseases can mimic malignancy, including primary sclerosing cholangitis (PSC), postoperative stricture, Mirizzi syndrome, bile duct adenomas, chronic pancreatitis, and inflammation from stone disease. Malignant and benign strictures of the bile duct may appear identical on abdominal ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and even direct cholangiography. Abdominal ultrasonography, CT and MRI may show biliary ductal dilation and reveal the level of the obstruction, but may not show a tumor mass responsible for the obstruction. The patient's history and presentation (jaundice, pruritis, abdominal pain, anorexia, and weight loss) can be nonspecific findings for many disease processes. Because of this, a tissue diagnosis is desirable for all but the most obvious benign lesions. However, it is important to determine what treatment options would be available to a given patient before an aggressive program to obtain tissue is undertaken. If surgical therapy is planned regardless of the results of diagnostic imaging then securing a tissue diagnosis may not be From the Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis, MO. Address reprint requests to Steven A. Edmundowicz, MD, Campus Box 8124, 660 S. Euclid Ave, St. Louis, MO 63110; e-mail: [email protected]. Copyright 2002, Elsevier Science (USA). All rights reserved. 1096-2883/02/0403-0002535.00/0 doi:10.1053/tgie.2002.34138
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necessary. Alternatively, if the patient is not a candidate for any aggressive therapy then palliation with a stent may be all that is required. In other patients, even those that are not candidates for surgical resection, confirming the malignant diagnosis could still be useful in establishing a prognosis and planning a course of chemotherapy or radiation therapy while providing palliative biliary decompression during the same procedure. The definitive method for tissue sampling and staging is surgical exploration. The invasiveness of this procedure and the predominance of comorbidities in the population which develop malignant bile duct strictures have somewhat limited this approach to only the best operative candidates. If a tumor mass is visualized on imaging studies, fine needle aspiration (FNA) for cytology may be the most direct approach to a diagnosis. One should be aware that there is a small but reported risk (1 in 20,000) t of seeding tumor along the needle tract while using the percutaneous approach. With advances in endoscopic techniques and accessories and its relatively lower morbidity and mortality compared to surgery, endoscopic retrograde cholangiopancreatography (ERCP) has become the initial modality in identifying and treating biliary strictures. Numerous devices are available at the time of ERCP to obtain samples of tissues for analysis. These include catheters for aspiration cytology, wire guided brushes, biopsy forceps, needle catheters for fine needle aspiration, and scraping devices. In addition, the nature of the stricture can be further evaluated by standard endoscopic ultrasound (EUS) with and without FNA, miniprobe endoscopic ultrasound, and direct cholangioscopy. It is clear that these endoluminal techniques are far from perfect in securing a diagnosis of malignancy. This is not only due to the disease processes that cause biliary strictures but also with problems inherent to the sampling device(s) used. The extrabiliary origin of many cancers responsible for bile duct strictures (ie, gallbladder, pancreatic) affects the sensitivity of sampling. A cytologic diagnosis is dependent on some degree of tumor invasion into bile duct epithelium that can be sampled with endoluminal devices. If no penetration into the lumen is present, endoluminal sampling techniques, such as brushing, will have a low yield. Tumors may replace the normal epithelium, but be fibrotic or scirrhous making it difficult to obtain tissue. Cholangiocarcinomas are often well differentiated and hard to distinguish from benign ductal epithelium at cytology. The determination between cholangiocarcinoma and primary sclerosing cholangitis may be very difficult. There may be the presence of morphologically low-grade or benign epithelium overlying a malignancy. Dysplastic cells might occur in the absence of malignancy especially in chronic inflammatory conditions. Tumors may be located at a difficult site to sample, present with tight strictures that prevent the use of some sampling devices, and be hard to visualize making sampling of the exact area of tumor infiltration difficult. Material obtained may be insufficient for analysis and samples can be small, superfi-
Techniques in Gastrointestinal Endoscopy, Vol 4, No 3 (July), 2002: pp 102-112
TABLE 1. Common Causes of Malignant Biliary Strictures Cholangiocarcinoma Ampullary carcinoma Metastatic disease Pancreatic carcinoma Enlarged porta hepatis malignant lymph nodes Mass lesions in the liver Right renal mass Data from ref 1.
cial, and lack architecture to help secure a diagnosis. Unless a cytopathologist is present for the procedure, there is no way to assess whether an adequate sample has been obtained. Despite all of these potential problems, endoluminal sampling at the time of ERCP remains one of the easiest and effective methods to evaluate biliary strictures, and palliation of biliary obstruction can also be done at the time of ERCP. Each biliary sampling method has its own inherent advantages and disadvantages. Some of the more commonly used devices and techniques will be discussed in this article.
tumor cells exfoliating into the biliary tree by the aspiration of bile through a catheter after cannulation of the ampulla. Aspiration of anywhere from 5 to 30 mL of bile has been reported to be sufficient. 4-8 These later studies involving direct aspiration from the biliary system showed that it was a convenient and noninvasive method, but its sensitivity for malignancy was as low as 30% to 50%. ~-s Several studies were then performed comparing bile aspiration to brush cytology and/or forceps biopsies. 9,1~These studies showed that bile cytology alone was inferior in sensitivity to brushing (26% v 69%) 9 and to forceps biopsy (32% v 88%). l~ Specificity in these studies was 100%. The cellular material and debris from removed stents has
Endoluminal Sampling Techniques Bile Cytology The role of bile cytology has decreased over recent years as technology for more direct means of sampling biliary pathology has developed. Early studies 2,3 attempted to use duodenal fluid for the detection of malignancy; however, a significant false positive rate was found. This was thought to be from degenerative changes caused by duodenal juice. Because of this, duodenal aspirates are no longer used for biliary cytodiagnosis. The next evolution for bile aspiration cytology was to try to recover
c
Fig 1. Biliary brushing device (Courtesy of Wilson-Cook Medical, Winston-Salem, NC). DIAGNOSIS OF MALIGNANT BILIARY STRICTURES
D
Fig 2. Brushing technique. (A) Achieve cannulation and pass wire past biliary stricture. (B) Exchange cannula with wire guided brush system and pass brush system beyond stricture. This will help dilate stricture somewhat. (C) Pull brush catheter to distal extent of stricture then deploy brush. Agitate brush through stricture 10-15 times. Do not pull brush all the way back into catheter, especially if brush system has a leading tip. (D) Retrieve brush catheter, process brush for cytology, leaving wire in place for other biliary maneuvers.
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Fig 3. Biliary stricture brushing. (A) A malignant distal common bile duct stricture with guidewire in place. (B) The double lumen biliary cytology brush is passed over the guidewire with the distal tip fluoroscopically visible tip above the stricture. (C) The brush is advanced beyond the tip of the catheter. (D) The brush is repositioned flouroscopically and cellular material is obtained from the stricture by moving the brush in a to and fro motion, The brush is then recaptured and the catheter exchanged maintaining the guidewire in place,
been studied as a potential source of additional cytologic specimens. Use of this technique has been studied with mixed results, usually slightly inferior when compared to bile duct brushings. 3r Diagnosis is also delayed until the time for stent removal/exchange. Given this data on bile cytology, other methods to obtain material for the diagnosis of malignant bile duct strictures are routinely used.
Biliary Brush Cytology Bile duct brushing for cytology is one of the more routinely used methods of sampling biliary strictures. Different types of commercially available brushes exist and all seem comparable in efficacy. Most endoscopists prefer double lumen brushes that can be passed over a guidewire that is left in place during the sampling procedure. A rigid material is used to make the bristles of the brush, which cause mucosal disruption and capture cells for cytological analysis. Biliary sphincterotomy is not required to obtain brushings. An example of a typical double lumen brush device is shown in Figure 1. Technique. Figure 2 (line drawing) and Figure 3 (fluoroscopic images) show how to obtain biliary stricture brushings.
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After cannulation is achieved, a guidewire is passed through the stricture. The cytology brush system is then passed over the wire and the brush deployed into the stricture. The brush is agitated to and fro, gathering cells from the stricture, and then recaptured into the device. There is no standard number of times the brush should be passed through the stricture, though the increased mucosal disruption by more passes may increase yield. Care should be taken not to agitate the brush through areas of normal mucosa as this may fill the available brush with normal cells. The brush tip is then withdrawn into the protective catheter and removed from the patient while the guidewire is kept in place. The recovered material is then processed for cytologic review per local protocol. This process can be repeated as required. There have been reports that dilation of the stricture with a balloon or catheter before brushing can increase the yield of the sampling procedure~l; this has not been confirmed in other studies. 1~ Many studies have been done analyzing the diagnostic sensitivity and specificity of biliary brush cytology, as outlined in Table 2. The sensitivity in these studies ranged anywhere from 30% to 100%. Possible reasons this variation between studies include: difference in the prevalence of malignancies and beLIN, JONNALAGADDA, AND EDMUNDOWICZ
TABLE 2. Brush Cytology Studies of Bile Duct Strictures Author
Number (n)
Sensitivity (%)
Specificity (%)
Trent et a133 Layfield et a134 Lee et a135 Foutch et a136 Foutch et a[37 Glasbrenner et a138 Ferrari et a]39 Stewart et al4~ Rabinovitz et a141 Ryan et a142 Yap et a143 Kurzawinski et a144 Ryan et aDs Scudera et a146 Venu et a147
31 108 149 39 18 86 74 406 65 48 52 39 69 19 53
71 44 37 100 33 56.1 56,2 59.8 40 30 75 60 44 100 80
100 98 100 100 100 90.5 100 98.1 100 92 92 100 100 100 100
nign disease in the study population, differences in classification of cytologic dysplasia, the use of blinded observers/analysis, and differences in the rates of tumors causing extrinsic compression (pancreatic, gallbladder, or metastatic disease). Of note, there is no standardized method of handling the brush after the specimens have been obtained. In the past, the material from the brushes have been smeared onto slides and fixed with preparative material. Currently, most processing methods include the whole brush being immersed in preservative material with extraction of cells by the cytologic technician in the laboratory. One in vitro study to determine an optimal processing method with maximization of cellular yield was performed by Baron et al. 12 They used an animal model to compare pulling the brush from the sheath versus pushing the brush from the end of the sheath. Pulling the brush out through
PPV
NPV
Accuracy (%)
100
100
84
100
58
72
94.1 100
43.2 51
65.4 70
the entire catheter significantly decreased the amount of cellular material obtained. Ultimately, the requirements of the local cytology department will be the most important determinant in the handling of specimens. Brushings, despite their variable reported yield, are a relatively easy method of sampling. Brushings can take less than 5 minutes to perform, can be wire-guided, and do not require biliary sphincterotomy to perform. The relative ease of the procedure makes brushings a recommended method of sampling.
Biliary Forceps Biopsy Forceps biopsies have a theoretical advantage over brushings since forceps have the potential to obtain deeper and larger tissue samples. In reality, forceps can be more cumbersome to
Fig 4. Forceps biopsy technique. (A) Achieve cannulation with closed forceps. This may require sphincterotomy to achieve. This may be done alongside a previously placed wire. (B} Maneuver scope to where the forceps can be opened and turned into the midportion of the stricture. Close forceps and recover specimen. (C) If a tight stricture is present, the forceps can be opened in such a fashion to impact into and sample the distal end of the stricture. DIAGNOSIS OF MALIGNANT BILIARY STRICTURES
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creased yield of diagnosis--if they can be performed. Combined sampling appears to have an increased yield of diagnosis over single sampling methods; it is not clear whether this is just an effect of taking more samples versus some effect on the mucosa of the first sampling technique that increases the yield for the subsequent technique.
Endoscopic Needle Aspiration
Fig 5. Forceps biopsy technique.
use and may require greater endoscopic expertise. The forceps are stiffer than the brushing devices and require careful maneuvering to avoid perforation. Endoscopic sphincterotomy is sometimes required to pass the forceps. The stricture may be hard to access (especially left hepatic strictures) and maneuvering the forceps into the area of interest may not be possible. Some newer design forceps may be passed over a wire to help alleviate this problem. Occasionally, because of the size of the lumen, a forceps may not be able to be opened in the stricture. There is also a theoretical increased risk of bile duct injury and bleeding because of the deeper biopsies taken. Technique. A forceps sampling technique is outlined in Figure 4 (line drawing) and Figure 5 (fluoroscopic image). After completion of the cholangiogram and demonstration of a stricture, a guidewire can be placed into the intrahepatic ducts and sphincterotomy preformed if necessary. The guidewire is left in place and the biliary biopsy forceps passed alongside and into the bile duct. Using fluoroscopic guidance and the guidewire as a guide, the forceps device is positioned at the downstream edge of the stricture, opened, and a sample entrapped in the forceps cups. The biopsy forceps are then withdrawn into the endoscope leaving the guidewire in place. In some settings, particularly if an endoscopic sphincterotomy has been previously performed, the forceps may be used without a guidewire. Some endoscopists prefer to use a sleeve or sheath to introduce the biliary forceps into the duct. Others use the Howell introducer system (HBIN-35 Wilson Cook Medical, Winston-Salem, NC, described later) to place the forceps device and a cytology brush into the area of the stricture. There are two main types of forceps, a side opening forceps (L-configuration) and a forward opening forceps (Y-configuration). This is shown in Figure 6. The side opening forceps are useful in cases where the forceps can be driven into the midst of the stricture and the forceps opened into the bile duct wall for sampling. The forward opening forceps is useful when it can be impacted with jaws open into the distal most portion of a stricture and samples taken from that end. Several studies have been performed examining the sensitivity and specificity of forceps biopsies alone and in combination/ comparison to biliary brushings. These studies are summarized in Table 3. From these studies, it appears that biopsies do have an in106
Howell et al t3 described the development and use of a retractable 22-gauge 7-mm long needle in a ball-tipped catheter in 1992 (see Fig 7). The device was designed to sample the deep mucosa and submucosa of the bile duct. They studied 31 patients (26 with known malignant bile duct strictures) with needle aspiration and brushings. By using fluoroscopic guidance, the needle-containing catheter was positioned directly below the stricture. The needle was then extended into the tumor and aspirations obtained. They found cytology positive for malignancy in needle aspirates in 16 of the 26 known positives and positive brushings in 2 of them. When two cases of "suspicious cytology biopsies" were considered positive for malignancy, the combination of the needle aspirations and the brushings were 73% sensitive with a specificity of 100%. One patient with cholangiocarcinoma had a positive brushing but a negative needle aspiration. The authors recommended needle aspiration as an adjunct to brushing. Despite the reported experience, endoscopic needle aspiration has not gained as widespread usage as brushings and/or forceps.
Other Devices Used for Diagnosis of Malignant Biliary Strictures The search for better devices and/or techniques for sampling biliary strictures is an ongoing process. Use of a ropeway-type bile duct forceps with a side slit for a guidewire was studied by Tamada et al. 14 This device is a prototype 1.8-mm diameter forceps from Olympus that has a side slit present for passage of a 0.025 inch guidewire and the ability to be passed into the
d
!. ,,
.
.
.
.
.
f
Front Opening
Side Opening
Fig 6. Front-opening versus side-opening forceps designs. LIN, JONNALAGADDA, AND EDMUNDOWICZ
TABLE 3. Studies Comparing Forceps Biopsies and/or Brushings of Bile Duct Strictures Author Sugiyama et a148 (biopsies) (brushings) Ponchon et a149 (biopsies) (brushings) (combined) Schoefl et aP~ (biopsies) (brushings) (combined) Pugliese et a151 (biopsies) (brushings) (combined) Kubota et a152 (biopsies)
Number (n)
Sensitivity (%)
Specificity (%)
PPV
NPV
Accuracy (%)
43 43
81 48
100 100
100 100
43 67
63 86
128 210 115
43 35 63
97 97 97
97 96 98
41 44 53
58 56 73
106 59 48
64.9 46.7 70.4
100 100 100
100 100 100
69.2 61.9 71.4
68.9 61.5 76.5
52 94 52
53 54 61
100 100 100
100 100 100
48 50 53
67 68 73
41
88
100
3.2-mm accessory channel of a conventional duodenoscope. The forceps could be passed into the biliary tree without a sphincterotomy, and samples were obtained Dom the middle of the biliary strictures. In their study, the authors found that the guidewire was able to maneuver the forceps into the appropriate area for sampling in 12 patients, 1 of which was not able to be sampled by conventional nonwire guided forceps. One of the problems with the conventional forceps was difficulty accessing the left hepatic ducts, as there was preferential entry of the right hepatic system. The authors felt that the samples obtained from the new forceps was equivalent (in their small study) to the conventional forceps and that because of ability to leave the wire in place, stenting and other subsequent maneuvers were accomplished more readily. However, careful technique is required to prevent displacement o[ the wire and conventional forceps are still effective to biopsy the margins of strictures. Further use and/or modifications of this device may lead to its routine use. Modifications to the standard brush used for cytologic sampiing have also been explored, on the observation that increased disruption of the affected biliary mucosa may lead to
Fig 7. The Howell biliary aspiration needle. (Courtesy of Wilson Cook Medical, Winston-Salem, NC) DIAGNOSIS OF MALIGNANT BILIARY STRICTURES
increased sensitivity of diagnosis of malignancy. Modifications include cutting flaps into dilation catheters (n = 15, sensitivity 60%) ~5 and a combination 10 French dilator and an abrasive Velcro pad with semi-rigid mushroom shaped bristles (n = 15, sensitivity for malignancy 100%). 76 These modifications have not reached widespread usage. In an attempt to obtain deeper and greater amounts of tissue in a non-surgical fashion, several different scraping devices have been studied and developed. The percutaneous application of the 9 French Simpson atherectomy catheter was studied by Schechter et al. 17 The catheter is a device originally used for removal of peripheral arterial atheroma. Nineteen bile duct shave biopsies were obtained with the device in 19 patients total, 18 patients with symptomatic biliary obstruction. The sensitivity for a histiologic diagnosis was 79% (14 malignancies, 1 primary sclerosing cholangitis). The authors noted the ability to obtain relatively large amounts of tissue for study and the potential for sampling of the extramucosal space. However, the authors noted that the high expense of the catheter and the risk of complications (2 patients had transient but significant hemorrhages) limit the widespread application of the device. Another study by Kaufman et al is looked retrospectively at their experience in the percutaneous use of the Simpson atherectomy catheter. Their sensitivity for diagnosis was 97%, a specificity of 100%, a positive predictive value of 100% and a negative predictive value of 93%. The complication rate in their series was 2%. The tissue samples obtained were 0.5 to 2.0 cm in length, which was felt to contribute to the high sensitivity rate. The authors felt that in the right hands and through proper selection of patients undergoing percutaneous drainage of biliaiy tract strictures, the Simpson atherectomy catheter would be of clinical utility. Garcia-Vila et a119studied biliary sampling through the use of a biliary manipulation catheter percutaneously through a drain. A 6.5 French biliary manipulation catheter (Wilson Cook) was passed through a 7-8 French introducer sheath, then the catheter tip was angled 110 degrees, then aspiration, rotation, and brushing movements were used to obtain material for analysis. 37 patients were examined; the sensitivity for detection of malignancy was 76%, specificity 100%, positive predictive value 100%, negative predictive value 53%. Four cases of spontaneous hemobilia were described, but no other complication arose. The authors felt that this was a less
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expensive and comparable alternative to the Simpson atherectomy catheter with fewer complications. Recently, a scraping device that can be passed through the accessory channel of a therapeutic duodenoscope, the Zimmon Lateral Biopsy Cup or Mighty Bite device, has been developed by Wilson Cook (Fig 8). The use of this device is similar to that of the atherectomy catheter and reportedly with less risk. The 7 French Mighty Bite device uses a cone shaped tip with a backward facing 360 degree cutting blade. The blade closes onto a catheter terminating in an anvil. The device allows for multiple biopsies, which are retrieved in a batch. The advantage of the 360 degree blade is that it allows circumferential biopsies within strictures and facilitates orientation for free biopsies. The cutting blade is also thought to minimize artifact that can be cause by squeezing of tissue by standard sampling techniques. The device is able to accept a 0.025 inch guidewire. Studies are now underway to determine the clinical utility of this device. Technique. Figure 9 (line drawing) and Figure 10 (fluoroscopic images) show the Mighty Bite sampling technique. Cannulation is achieved and a 0.025 inch guidewire is placed through the stricture with its end in one of the larger intrahepatic systems. The Mighty Bite device is then advanced past the stricture, then maneuvered so that when deployed, the cone shaped tip with cutting blade is just within the stricture. The device is then pulled through the area of stricture with the tip deployed, then the tip is captured and the device removed from the patient with the guidewire remaining behind. The tissue is removed from the tip, and the process repeated as needed. Howell et al 2~ described a combination device, the HBIN-35 (Wilson Cook Medical) (Fig 11), which allows the endoscopist to perform fine needle aspiration, forceps biopsy and brush cytology with just one wire guided device that does not require a sphincterotomy for biliary access. The device consists of a 10 French double lumen catheter, with a 0.035 inch guide wire channel from the distal tip and a 5 French second channel with a 45 degree ramp positioned one centimeter below the shoulder of the dilating tip. A 22-gauge biopsy needle mounted in a 3 French metal ball-tipped catheter is also provided with the device.
Fig 8. The Mighty Bite Device. (Courtesy of Wilson Cook Medical, Winston-Salem, NC)
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,f
Fig 9. Mighty Bite Sampling Technique. (A) Achieve cannulation and pass wire past biliary stricture. The Mighty Bite device requires no larger than a 0.025 inch wire. (B) Exchange cannula with wire guided Mighty Bite system and pass system beyond stricture. This will help dilate stricture somewhat. (C) Open tip of Mighty Bite catheter in the stricture, then keeping the scraping cap deployed, pull the entire device into the scope thus pulling the scraping cap through the length of the stricture. (D) Once the scraping cap has reached the distal extent of the stricture, close the device and withdraw the whole device back into the scope for recovery. Device can be used for multiple passes.
Technique. Once a biliary stricture has been identified, a guide wire is placed above the stricture and the catheter passed through the stricture, thus dilating it (Fig 12). The ball-tipped catheter with the needle is then passed through the 45 degree ramp channel, the needle deployed, and fine needle aspiration samples obtained. A 5 French biopsy forceps can then be passed and biopsies obtained. Finally after repositioning of the device, a spring tipped brush can be passed and brushings obtained. In the authors hands, this whole sequence added only 12 to 15 minutes to the entire ERCP procedure time. Twenty-eight patients with obstructive jaundice were studied. By using the device needle, biopsies were positive for malignancy in 12% and suspicious in 15%, forceps biopsies were positive in 15% and suspicious in 15%, brush cytology was positive in 42% and suspicious in 15%. Combining the yields resulted in a 69% LIN, JONNALAGADDA, AND EDMUNDOWICZ
Fig 10. The Mighty Bite device in use during ERCP. (A) Mighty Bite device advanced over the 0.25 inch guidewire and positioned beyond the stricture. (B) The tip of the Mighty Bite catheter is opened above stricture. (C) The device is pulled through the stricture to obtain a sample. (D) The device is withdrawn through the stricture, closed, and exchanged through the endoscope leaving the guidewire in place.
sensitivity and specificity of 95-100%. Farrell et a121 used the HBIN-35 and compared the combination of stricture dilation, fine needle aspiration, and subsequent brushings to the conventional brushing technique. In their study, the sensitivity of conventional brushings (n = 24) was 57%, specificity of up to 100%, positive predictive value 80%, negative predictive value 57% and diagnostic accuracy of 67%. This is compared to the combined sampling (n = 22) sensitivity of 85%, specificity of
Fig 11. Howell ramp catheter. (Courtesy of Wilson Cook Medical, Winston-Salem, NC) DIAGNOSIS OF MALIGNANT BILIARY STRICTURES
100%, positive predictive value of 100% negative predictive value of 40% (low number of benign lesions in study group) and an overall diagnostic accuracy of 86%. The differences were statistically significant. The authors felt that the order of the diagnostic modalities as well as the different sampling methods contributed to the increased rate of diagnosis, and that this device would be of clinical benefit. Direct visualization of the lesion and direct biopsy by cholangioscopy has also been explored as a means of diagnosis. Hwang et a122studied the role of percutaneous cholangioscopy guided forceps in patients suspected of intrabiliary ductal diseases. Twenty-seven patients were studied, and a histologic diagnosis was made in 24 patients, resulting a sensitivity of 89%. The main drawback was the need to have a 16 French tract to perform the procedure. Seo et a123 examined the usefulness of cholangioscopy in patients with focal stricture of the intrahepatic duct unrelated to intrahepatic stones. They also used percutaneous cholangioscopy in 17 patients and were able to obtain a histologic diagnosis in all patients (sensitivity 100%). Dilation of the tract to 18 French was required to pass the larger choledochoscope. Certain mucosal abnormalities were noted to be potentially characteristic for specific pathology. The authors do note that the procedure helped in staging in these cases, but
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with the mother-daughter scope and newer smaller diameter retrograde cholangioscopes has also been described. While this may be a useful additional approach in some lesions the additional time and effort to complete retrograde cholangioscopy has prevented it from being used as a standard approach in all patients. There is no published literature that shows a higher sensitivity for tumor detection with retrograde cholangioscopy.
Endoscopic Ultrasound EUS can be useful in the evaluation of malignant strictures of the bile ducts. High resolution examination of the region may detect a tumor mass or disruption of the typical wall layers of the bile duct by an infiltrating process. Vascular invasion and adjacent lymphadenopathy may also be identified for staging purposes. EUS imaging may increase the suspicion of a malignant etiology of a stricture. EUS instruments can also be used to guide FNA to secure a diagnosis by sampling the tissue surrounding the stricture, an adjacent mass or regional lymph nodes. EUS of biliary strictures can be completed with two general techniques, miniprobe EUS and standard endoscopic devices.
Miniprobe EU5 The use of intraductal ultrasound in the evaluation of biliary disease has been recently reviewed. 25 These devices are of high frequency (12.5 to 30 MHz) and provide detailed imaging of the bile duct wall and some surrounding tissue. They do not currently have tissue acquisition capabilities and therefore can suggest a malignant diagnosis by sonographic criteria only. If the equipment is available at the time of ERCP, intraductal EUS can be completed in a relatively short time providing useful information regarding the type and extent of the stricture.
EUS With FNA Fig 12. Howell Ramp Catheter Technique. (A) Achieve cannulation and place wire past area of stricture. (B) Insert Howell catheter device through stricture over wire. The wire exits the distal port of the catheter. The tip of the device serves to dilate the stricture. {C) Insert the sampling device through the side port. The side port exits at an angle, allowing guidance of the sampling device into the stricture. Sampling devices must be compatible with the Howell device and include needle for FNA, forceps, and brushes. (D) The side port of the device can also be used to achieve cannulation of the right hepatic system, or any other biliary system that is more difficult to access. A wire is place through the side port and the angle of the device sideport exit will allow guidance of the wire into the system of interest.
was somewhat invasive and time consuming. Sato et a124 e x a m i n e d the thickness of the specimens obtained from percutaneous cholangioscopy and attempted to assess the sensitivity for intramural invasive carcinoma. Their conclusions were that percutaneous cholangioscopy with biopsy can only detect invasive carcinoma in the superficial layers of the bile duct, such as the mucosal layer and the shallowest fibromuscular layer. Multiple biopsies are also required as the sensitivity of a single specimen for invasive carcinoma is low. Vascular dilation on examination may be characteristic of extension beyond the adventitia. The use of percutaneous cholangioscopy is not routine in the United States due to its more invasive nature, time requirements, and cost. Endoscopic retrograde cholangioscopy
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A more common approach in patients with biliary obstruction is to obtain cholangiography and an attempt at tissue diagnosis during the initial ERCP. If unsuccessful at securing a diagnosis, then standard EUS with one of the linear systems that allows EUS guided FNA is a useful next step in the evaluation. EUS with FNA allows detailed imaging of the region of the stricture and real time EUS guided FNA if a lesion or abnormality is seen. If no associated mass or lymphadenopathy is identified, the region of the stricture can still be sampled without signif~cam morbidity. This technique has been described to evaluate biliary strictures and secure a diagnosis of both pancreatic malignancy 26 and cholangiocarcinomaY
Other Types of Analysis of Samples Obtained by ERCP With the advent of improved methods in molecular biology, there has been interest in DNA tumor marker analysis of cells obtained from the biliary tree. For example, K-ras oncogene mutations are present in 75% to 100% of pancreatic adenocarcinomas, 41% to 100% of cholangiocarcinomas, and in 55% of gallbladder carcinomas. Lee et al as examined the utility of K-ras mutational analysis on aspirated bile. In their study, PCR products were amplified from the bile of 8 of 12 patients with malignancy and 3 of 8 with benign disease. K-ras oncogene products were present in 4 of the 8 from malignant samples and LIN, JONNALAGADDA, AND EDMUNDOWICZ
absent in all 3 from benign samples. The authors stated that this resulted in a sensitivity of 33%, a specificity of 100% and a positive predictive value of 100% for the diagnosis of malignancy. Laethem et a129 examined Ki-ras gene analysis of brushings from either pancreatic or biliary duct strictures in comparison to brush cytology in the diagnosis of strictures. The authors found that the sensitivity, specificity and accuracy of Ki-ras analysis versus brush cytology was 25% v 42%, 100% v 100%, and 35% v 43%, respectively. They felt that the low rates of detected Ki-ras mutations may have been due to the variable presence of the mutations, or potentially because only a fraction of the tumor cells contained the mutations (sampling variability). Their conclusion was that other means of stricture sampling like brush cytology appear to be more useful on a routine basis for the diagnosis of biliary strictures, but that further study may be warranted. Telomerase activity has been noted in 95% to 100% of surgically resected pancreatic adenocarcinomas. 3~Stable telomerase length is highly correlated with immortalization that characterizes most models of tumor formation. Morales et aP ~ studied the role of in situ hybridization for telomerase RNA in ERCP brushings from 18 patients, 8 of whom had malignancy. The combination of cytology and in situ hybridization lead to a sensitivity for malignancy of 100%. Larger studies would be needed to confirm these findings. The use of flow cytometry has also been studied to see if it would increase the sensitivity of conventional light microscopy examination of cytological samples obtained from the biliary tree. Ryan et aP 1 used DNA staining and flow cytometry on brushing specimens to determine aneuploidy, which in some pancreatobiliary cancers has been reported as a feature of malignant cells. The sensitivity of routine cytology or flow cytometry was 42%. Specificity for malignancy for routine cytology was 92% and 77% for flow cytometry. With the combination of the techniques sensitivity for malignancy rose to 63%, but sensitivity fell to 63%. Flow cytometry had a higher false positive rate than routine cytology. The lack of a sufficient amount of cells for analysis may also be a problem. The authors felt that flow cytometry was able to increase diagnosis of malignancy, but because of the high false positive rate that the clinical scenario should play an important role in interpreting the resuits. Image cytometry has also been studied to assess the role of determining cell DNA contents, using the same rationale as flow cytometry. Imaging has the additional benefit of studying the location and amounts of nuclear material as well as requiring fewer cells. Sears et aP 2 examined brushings from patients with chronic pancreatitis, pancreatic carcinoma, primary sclerosing cholangitis, and cholangiocarcinoma. A specific attempt was made to distinguish between primary sclerosing cholangitis and cholangiocarcinoma. Nuclear size, heterogeneity of chromatin clumps, and percent cell nuclei with hyperdiploid DNA content were some of the parameters studied. Malignancy was able to be distinguished from primary sclerosing cholangitis, sensitivity and specificity was estimated to be 82% and 85%, respectively. Although somewhat promising, the authors caution that larger prospective trials would be required to assess the predictive ability of image cytometry.
DIAGNOSIS OF MALIGNANT BILIARY STRICTURES
Conclusion Malignant bile duct strictures remain a significant diagnostic challenge. The techniques discussed above provide options for the endoscopist to secure a diagnosis of malignancy. While no one technique is sensitive enough to detect all malignant strictures a combination of techniques will hopefully allow the endoscopist to provide a tissue diagnosis in most situations. In the future, additional devices will be available to sample strictures in an attempt to delineate their etiology. In the meantime, repeat sampling and the liberal use of EUS with FNA will hopefully lead to a successful diagnosis in most patients.
References 1. Yamada T, AIpers D, Laine L, et al: Textbook of Gastroenterology. Lippincott, Williams and Wilkins, 1999 2. Kline TS, Joshi LP, Goldstein F: Preoperative diagnosis of pancreatic malignancy by the cytologic examination of duodenal secretions. Am J Clin Pathol 70:851-854, 1978 3. Dreiling DA, Nieburgs HE, Janowitz HD: The combined secretin and cytology test in diagnosis of pancreatic and biliary tract cancer. Cancer Med Clin North Am 44:801-815, 1960 4. Harell GS, Anderson MF, Berry PF: Cytological bile examination in the diagnosis of biliary duct neoplastic strictures. AJR 137:11231126, 1981 5. Cobb CJ, Floyd WN: Usefulness of bile cytology in the diagnostic management of patients with biliary tract obstruction. Acta Cytol 29:93-100, 1985 6. Cohan RH, Illescas FF, Newman GE, et al: Biliary cytodiagnosis. Bile sampling for cytology. Invest Radiol 20:177-179, 1985 7. Dessa LA, Akosa AB, Lazzara S, et al: Cytodiagnosis in the management of extrahepatic biliary strictures. Gut 32:1188-1191, 1991 8. Davidson BR, Varsamidakis N, Dooley JS, et al: The value of exfoliative cytology for investigating bile duct strictures. Gut 33:14081411, 1992 9. Kurzawinski TR, Deery A, Dooley JS, et al: A prospective study of biliary cytology in 100 patients with bile duct strictures. Hepatology 18:1399-1405, 1993 10. Sugiyama M, Atomni Y, Wada N, et al: Endoscopic transpapillary Bile duct biopsy without sphincterotomy for diagnosing biliary strictures: A prospective comparative study with bile and brush cytology. Am J Gastroenterol 91:465-467, 1996 11. Mohandas KM, Swaroop VS, Gullar SU, et al: Diagnosis of malignant obstructive jaundice my bile cytology: Results improved by dilating the bile duct stricture. Gastrointest Endosc 40:150-154, 1994 12. Baron T, Lee J, Wax T, et al: An in vitro randomized, prospective study to maximize cellular yield during bile duct brush cytology. Gastrointest Endosc 40:146-149, 1994 13. Howell D, Beveridge R, Bosco J, et al: Endoscopic needle aspiration biopsy at ERCP in the diagnosis of biliary strictures. Gastrointest Endosc 38:531-535, 1992 14. Tamada K, Higashizawa T, Tomiyama T, et al: Ropeway-type bile duct forceps with a side slit for a guidewire. Gastrointest Endosc 53:89-92, 2001 15. Yip C, Leung M, Chan KM, et al: Scrape biopsy of malignant biliary stricture through percutaneous transhepatic biliary drainage tracts. AJR 152:529-530, 1989 16. Parasher VK, Huibregtse K: Endoscopic retrograde wire-guided cytology of malignant biliary strictures using a novel scraping brush. Gastrointest Endosc 48:288-290, 1998 17. Schechter M, Doemen J, Johnson J: Biliary ductal shave biopsy with the use of the Simpson atherectomy catheter. SCIR 4:819-824, 1993 18. Kaufman D, Widlus D, Lazinger M, et al: Diagnostic accuracy of Simpson atherectomy catheter biopsy in detecting pancreaticobiliary malignancy. Am J Gastro 96:1054-1058, 2001 19. Garcia-Vila J, Bordon F, Gonzalez-Anon M, et al: Endoluminal biopsy
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of the bile duct with a biliary manipulation catheter. JVIR 10:13941396, 1999 Howell D, Parsons W, Jones M, et al: Complete tissue sampling of biliary strictures at ERCP using a new device. Gastrointest Endosc 43:498-502, 1996 Farrell R, Jain A, Brandwein S, et al: The combination of stricture dilation, endoscopic needle aspiration, and biliary brushings significantly improves diagnostic yield from malignant bile duct strictures. Gastrointest Endosc 54:587-594, 2001 Hwang M, Tsai C, Chou C, et al: Percutaneous cholangiofiberscopic endoluminal forceps biopsy of intrabile duct diseases. Hepato-Gastroenterology 45:2073-2078, 1998 See D, Kim M, Lee S, et al: Usefulness of cholangioscopy in patients with focal stricture of the intrahepatic duct unrelated to intrahepatic stones. Gastro Endosc 49:204-209, 1999 Sate M, Inoue H, Ogawa S, et al: Limitations of percutaneous transhepatic cholangioscopy for the diagnosis of the intramural extension of bile duct carcinoma. Endoscopy 30:281-288, 1998 Levy MJ, Bazquez-Sequeiros E, Wiersema MJ: Evaluation of pancreaticobiliary ductal systems by intraductal US. Gastrointest Endosc 55:397-408, 2002 Gress F, Gottleib K, Sherman S, et al: Endoscopic ultrasonographyguided fine needle aspiration biopsy of suspected pancreatic cancer. Ann Intern Med 134:459-464, 2001 Fritscher-Ravens A, Broering DC, Sriram PV, et al: EUS-guided fine-needle aspiration cytodiagnosis of hilar cholangiocarcinoma: A case series. Gastrointest Endosc 52:534-540, 2000 Lee LG, Leung J, Cotton P, et al: Diagnostic utility of K-ras mutational analysis on bile obtained by endoscopic retrograde cholangiopancreatography. Gastrointest Endosc 42:317-320, 1995 Laethem JL, Bourgeois V, Parma J, et al: Relative contribution of Ki-ras gene analysis and brush cytology during ERCP for the diagnosis of biliary and pancreatic diseases. Gastrointest Endosc 47: 479-485, 1998 Morales CP, Brudick JS, Saboorian MH, et al: In situ hybridization for telomerase RNA in routine cytologic brushings for the diagnosis of pancreaticobiliary malignancies. Gastrointest Endosc 48:402-405, 1998 Ryan M, Baldauf M: Comparison of flow cytometry for DNA content and brush cytology for detection of malignancy in pancreaticobiliary strictures. Gastrointest Endosc 40:133-139, 1994 Sears R, Duckworth C, Decaestecker C, et al: Image Cytometry as a discriminatory tool for cytologic specimens obtained by endoscopic retrograde cholangiopancreatography. Cancer Cytopath 84: 119-126, 1998 Trent V, Khurana K, Pisharodi L: Diagnostic accuracy and clinical utility of endoscopic bile duct brushing in the evaluation of biliary strictures. Arch Pathol Lab Med 123:712-715, 1999 Layfield L, Wax T, Lee J, et al: Accuracy and morphologic aspects of pancreatic and biliary duct brushings. Acta Cyologica 39:11-18, 1995 Lee J, Leung J, Baillie J, et al: Benign, dysplastic, or malignantmaking sense of endoscopic bile duct brush cytology: Results in 149 consecutive patients. Am J Gastroent 90:722-726, 1995
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36. Foutch P, Kerr DM, Harlan JR, et al: Endoscopic retrograde wireguided brush cytology for diagnosis of patients with malignant obstruction of the bile duct. Am J Gastroent 85:791-795, 1990 37. Foutch O, Kerr D, Harlan J, et al: A prospective controlled analysis of endoscopic cytotechniques for diagnosis of malignant biliary strictures. Am J Gastroent 86:577-580, 1991 38. Glassbrenner B, Ardan M, Boeck W, et al: Prospective evaluation of brush cytology of biliary strictures during endoscopic retrograde cholangiopancreatography. Endoscopy 31:712-717, 1999 39. Ferarri A, Lichtenstein D, Slivka A, et al: Brush cytology during ERCP for the diagnosis of biliary and pancreatic malignancies. Gastro Endo 40:140-145, 1994 40. Stewart C, Mills P, Carter R, et al: Brush cytology in the assessment of pancreatico-biiiary strictures: A review of 406 cases. J Clin Path 54:449-455, 2001 41. Rabinovitz M, Zajko A, Hassaein T, et al: Diagnostic value of brush cytology in the diagnosis of bile duct Carcinoma: A study in 65 patients with bile duct Strictures. Hepatology 12:747-752, 1990 42. Ryan ME, Baldauf MC: Comparison of flow cytometry DNA content and brush cytology for detection of malignancy in pancreaticobiliary strictures. Gastrointest Endosc 40:133-140, 1994 43. Yap CK, ten Kate FJW, Ramsoekh B, et al: A retrospective analysis of brush cytology in biliary tract strictures: Sensitivity, specificity, atypia and the effect of indwelling biliary stents. Endoscopy (in press) 44. Kurzawinki T, Deery A, Dooley J: A prospective study of biliary cytology in 100 patients with bile duct strictures. Hepatology 18: 1399-1403, !993 45. Ryan ME: Cytologic brushings of ductal lesions during ERCP. Gastrointest Endosc 37:139-142, 1991 46. Scudera PL, Koizumi J, Jacobsen IM: Brush cytology evaluation of lesions encountered during ERCP. Gastrointest Endosc 36:281-284, 1990 47. Venu RP, Geenen JE, Kini M, et al: Endoscopic retrograde brush cytology: A new technique. Gastroenterology 99:1475-1479, 1990 48. Sugiyama M, Atomi Y, Wada N, et al: Endoscopic transpapillary bile duct biopsy without sphincterotomy for diagnosing biliary strictures: A prospective comparative study with bile and brush cytology. Am J Gastroenterol 91:465-467, 1996 49. Ponchon T, Gagnon P, Berger F, et al: Value of endobiliary brush cytology and biopsies for the diagnosis of malignant bile duct stenosis: Results of a prospective study. Gastro Endosc 42:565-572, 1995 50. Schoefl R, Haefner M, Wrba F, et al: Forceps Biopsy and brush cytology during endoscopic retrograde cholangiopancreatography for the diagnosis of biliary stenoses. Scand J Gastroenterol 32:363368, 1997 51. Pugliese V, Conlo M, Nicolo G, et al: Endoscopic retrograde forceps biopsy and brush cytology of biliary strictures: A prospective study. Gastrointest Endosc 42:520-526, 1995 52. Kubota Y, Yakaoka M, Tani K, et al: Endoscopic transpapillary biopsy for diagnosis of patients with pancreaticobiliary ductal strictures. Am J Gastroenterol 88:1700-1704, 1993
LIN, JONNALAGADDA, AND EDMUNDOWICZ
It is important to determine the benign or malignant nature of a biliary stricture, and a tissue diagnosis is usually desirable. This article discusses methods for diagnosis of malignant biliary strictures, including bile cytology, biliary brush cytology, intraductal forceps biopsy, needle aspiration, scraping devices, and endoscopic ultrasound-guided aspiration. Ki-ras analysis and the u s e of flow cytometry are also reviewed. In most cases a combination of tissue sampling techniques will result in the highest diagnostic yield. Copyright 2002, Elsevier Science (USA). All rights reserved.
t is essential to determine the benign or malignant nature of
I .a biliary stricture to plan appropriate therapy. This can
sometimes be a daunting task given the nature of the disease processes that lead to biliary strictures. Some common origins of malignant biliary strictures are listed in Table 1. The most commonly encountered causes of malignant bile duct strictures include cancers of the ampulla, bile duct, and pancreas. These account for more than 75% of all patients presenting with extrahepatic bile duct obstruction. 1 A few biliary strictures can be correctly (and simply) classified as benign by their clinical presentation and appearance (for example, a smooth stricture in the region of the cystic duct following biliary surgery with a normal preoperative cholangiogram). Other more "indeterminate" strictures require further testing and analysis of the clinical scenario, as many benign diseases can mimic malignancy, including primary sclerosing cholangitis (PSC), postoperative stricture, Mirizzi syndrome, bile duct adenomas, chronic pancreatitis, and inflammation from stone disease. Malignant and benign strictures of the bile duct may appear identical on abdominal ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and even direct cholangiography. Abdominal ultrasonography, CT and MRI may show biliary ductal dilation and reveal the level of the obstruction, but may not show a tumor mass responsible for the obstruction. The patient's history and presentation (jaundice, pruritis, abdominal pain, anorexia, and weight loss) can be nonspecific findings for many disease processes. Because of this, a tissue diagnosis is desirable for all but the most obvious benign lesions. However, it is important to determine what treatment options would be available to a given patient before an aggressive program to obtain tissue is undertaken. If surgical therapy is planned regardless of the results of diagnostic imaging then securing a tissue diagnosis may not be From the Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis, MO. Address reprint requests to Steven A. Edmundowicz, MD, Campus Box 8124, 660 S. Euclid Ave, St. Louis, MO 63110; e-mail: [email protected]. Copyright 2002, Elsevier Science (USA). All rights reserved. 1096-2883/02/0403-0002535.00/0 doi:10.1053/tgie.2002.34138
102
necessary. Alternatively, if the patient is not a candidate for any aggressive therapy then palliation with a stent may be all that is required. In other patients, even those that are not candidates for surgical resection, confirming the malignant diagnosis could still be useful in establishing a prognosis and planning a course of chemotherapy or radiation therapy while providing palliative biliary decompression during the same procedure. The definitive method for tissue sampling and staging is surgical exploration. The invasiveness of this procedure and the predominance of comorbidities in the population which develop malignant bile duct strictures have somewhat limited this approach to only the best operative candidates. If a tumor mass is visualized on imaging studies, fine needle aspiration (FNA) for cytology may be the most direct approach to a diagnosis. One should be aware that there is a small but reported risk (1 in 20,000) t of seeding tumor along the needle tract while using the percutaneous approach. With advances in endoscopic techniques and accessories and its relatively lower morbidity and mortality compared to surgery, endoscopic retrograde cholangiopancreatography (ERCP) has become the initial modality in identifying and treating biliary strictures. Numerous devices are available at the time of ERCP to obtain samples of tissues for analysis. These include catheters for aspiration cytology, wire guided brushes, biopsy forceps, needle catheters for fine needle aspiration, and scraping devices. In addition, the nature of the stricture can be further evaluated by standard endoscopic ultrasound (EUS) with and without FNA, miniprobe endoscopic ultrasound, and direct cholangioscopy. It is clear that these endoluminal techniques are far from perfect in securing a diagnosis of malignancy. This is not only due to the disease processes that cause biliary strictures but also with problems inherent to the sampling device(s) used. The extrabiliary origin of many cancers responsible for bile duct strictures (ie, gallbladder, pancreatic) affects the sensitivity of sampling. A cytologic diagnosis is dependent on some degree of tumor invasion into bile duct epithelium that can be sampled with endoluminal devices. If no penetration into the lumen is present, endoluminal sampling techniques, such as brushing, will have a low yield. Tumors may replace the normal epithelium, but be fibrotic or scirrhous making it difficult to obtain tissue. Cholangiocarcinomas are often well differentiated and hard to distinguish from benign ductal epithelium at cytology. The determination between cholangiocarcinoma and primary sclerosing cholangitis may be very difficult. There may be the presence of morphologically low-grade or benign epithelium overlying a malignancy. Dysplastic cells might occur in the absence of malignancy especially in chronic inflammatory conditions. Tumors may be located at a difficult site to sample, present with tight strictures that prevent the use of some sampling devices, and be hard to visualize making sampling of the exact area of tumor infiltration difficult. Material obtained may be insufficient for analysis and samples can be small, superfi-
Techniques in Gastrointestinal Endoscopy, Vol 4, No 3 (July), 2002: pp 102-112
TABLE 1. Common Causes of Malignant Biliary Strictures Cholangiocarcinoma Ampullary carcinoma Metastatic disease Pancreatic carcinoma Enlarged porta hepatis malignant lymph nodes Mass lesions in the liver Right renal mass Data from ref 1.
cial, and lack architecture to help secure a diagnosis. Unless a cytopathologist is present for the procedure, there is no way to assess whether an adequate sample has been obtained. Despite all of these potential problems, endoluminal sampling at the time of ERCP remains one of the easiest and effective methods to evaluate biliary strictures, and palliation of biliary obstruction can also be done at the time of ERCP. Each biliary sampling method has its own inherent advantages and disadvantages. Some of the more commonly used devices and techniques will be discussed in this article.
tumor cells exfoliating into the biliary tree by the aspiration of bile through a catheter after cannulation of the ampulla. Aspiration of anywhere from 5 to 30 mL of bile has been reported to be sufficient. 4-8 These later studies involving direct aspiration from the biliary system showed that it was a convenient and noninvasive method, but its sensitivity for malignancy was as low as 30% to 50%. ~-s Several studies were then performed comparing bile aspiration to brush cytology and/or forceps biopsies. 9,1~These studies showed that bile cytology alone was inferior in sensitivity to brushing (26% v 69%) 9 and to forceps biopsy (32% v 88%). l~ Specificity in these studies was 100%. The cellular material and debris from removed stents has
Endoluminal Sampling Techniques Bile Cytology The role of bile cytology has decreased over recent years as technology for more direct means of sampling biliary pathology has developed. Early studies 2,3 attempted to use duodenal fluid for the detection of malignancy; however, a significant false positive rate was found. This was thought to be from degenerative changes caused by duodenal juice. Because of this, duodenal aspirates are no longer used for biliary cytodiagnosis. The next evolution for bile aspiration cytology was to try to recover
c
Fig 1. Biliary brushing device (Courtesy of Wilson-Cook Medical, Winston-Salem, NC). DIAGNOSIS OF MALIGNANT BILIARY STRICTURES
D
Fig 2. Brushing technique. (A) Achieve cannulation and pass wire past biliary stricture. (B) Exchange cannula with wire guided brush system and pass brush system beyond stricture. This will help dilate stricture somewhat. (C) Pull brush catheter to distal extent of stricture then deploy brush. Agitate brush through stricture 10-15 times. Do not pull brush all the way back into catheter, especially if brush system has a leading tip. (D) Retrieve brush catheter, process brush for cytology, leaving wire in place for other biliary maneuvers.
103
Fig 3. Biliary stricture brushing. (A) A malignant distal common bile duct stricture with guidewire in place. (B) The double lumen biliary cytology brush is passed over the guidewire with the distal tip fluoroscopically visible tip above the stricture. (C) The brush is advanced beyond the tip of the catheter. (D) The brush is repositioned flouroscopically and cellular material is obtained from the stricture by moving the brush in a to and fro motion, The brush is then recaptured and the catheter exchanged maintaining the guidewire in place,
been studied as a potential source of additional cytologic specimens. Use of this technique has been studied with mixed results, usually slightly inferior when compared to bile duct brushings. 3r Diagnosis is also delayed until the time for stent removal/exchange. Given this data on bile cytology, other methods to obtain material for the diagnosis of malignant bile duct strictures are routinely used.
Biliary Brush Cytology Bile duct brushing for cytology is one of the more routinely used methods of sampling biliary strictures. Different types of commercially available brushes exist and all seem comparable in efficacy. Most endoscopists prefer double lumen brushes that can be passed over a guidewire that is left in place during the sampling procedure. A rigid material is used to make the bristles of the brush, which cause mucosal disruption and capture cells for cytological analysis. Biliary sphincterotomy is not required to obtain brushings. An example of a typical double lumen brush device is shown in Figure 1. Technique. Figure 2 (line drawing) and Figure 3 (fluoroscopic images) show how to obtain biliary stricture brushings.
104
After cannulation is achieved, a guidewire is passed through the stricture. The cytology brush system is then passed over the wire and the brush deployed into the stricture. The brush is agitated to and fro, gathering cells from the stricture, and then recaptured into the device. There is no standard number of times the brush should be passed through the stricture, though the increased mucosal disruption by more passes may increase yield. Care should be taken not to agitate the brush through areas of normal mucosa as this may fill the available brush with normal cells. The brush tip is then withdrawn into the protective catheter and removed from the patient while the guidewire is kept in place. The recovered material is then processed for cytologic review per local protocol. This process can be repeated as required. There have been reports that dilation of the stricture with a balloon or catheter before brushing can increase the yield of the sampling procedure~l; this has not been confirmed in other studies. 1~ Many studies have been done analyzing the diagnostic sensitivity and specificity of biliary brush cytology, as outlined in Table 2. The sensitivity in these studies ranged anywhere from 30% to 100%. Possible reasons this variation between studies include: difference in the prevalence of malignancies and beLIN, JONNALAGADDA, AND EDMUNDOWICZ
TABLE 2. Brush Cytology Studies of Bile Duct Strictures Author
Number (n)
Sensitivity (%)
Specificity (%)
Trent et a133 Layfield et a134 Lee et a135 Foutch et a136 Foutch et a[37 Glasbrenner et a138 Ferrari et a]39 Stewart et al4~ Rabinovitz et a141 Ryan et a142 Yap et a143 Kurzawinski et a144 Ryan et aDs Scudera et a146 Venu et a147
31 108 149 39 18 86 74 406 65 48 52 39 69 19 53
71 44 37 100 33 56.1 56,2 59.8 40 30 75 60 44 100 80
100 98 100 100 100 90.5 100 98.1 100 92 92 100 100 100 100
nign disease in the study population, differences in classification of cytologic dysplasia, the use of blinded observers/analysis, and differences in the rates of tumors causing extrinsic compression (pancreatic, gallbladder, or metastatic disease). Of note, there is no standardized method of handling the brush after the specimens have been obtained. In the past, the material from the brushes have been smeared onto slides and fixed with preparative material. Currently, most processing methods include the whole brush being immersed in preservative material with extraction of cells by the cytologic technician in the laboratory. One in vitro study to determine an optimal processing method with maximization of cellular yield was performed by Baron et al. 12 They used an animal model to compare pulling the brush from the sheath versus pushing the brush from the end of the sheath. Pulling the brush out through
PPV
NPV
Accuracy (%)
100
100
84
100
58
72
94.1 100
43.2 51
65.4 70
the entire catheter significantly decreased the amount of cellular material obtained. Ultimately, the requirements of the local cytology department will be the most important determinant in the handling of specimens. Brushings, despite their variable reported yield, are a relatively easy method of sampling. Brushings can take less than 5 minutes to perform, can be wire-guided, and do not require biliary sphincterotomy to perform. The relative ease of the procedure makes brushings a recommended method of sampling.
Biliary Forceps Biopsy Forceps biopsies have a theoretical advantage over brushings since forceps have the potential to obtain deeper and larger tissue samples. In reality, forceps can be more cumbersome to
Fig 4. Forceps biopsy technique. (A) Achieve cannulation with closed forceps. This may require sphincterotomy to achieve. This may be done alongside a previously placed wire. (B} Maneuver scope to where the forceps can be opened and turned into the midportion of the stricture. Close forceps and recover specimen. (C) If a tight stricture is present, the forceps can be opened in such a fashion to impact into and sample the distal end of the stricture. DIAGNOSIS OF MALIGNANT BILIARY STRICTURES
105
creased yield of diagnosis--if they can be performed. Combined sampling appears to have an increased yield of diagnosis over single sampling methods; it is not clear whether this is just an effect of taking more samples versus some effect on the mucosa of the first sampling technique that increases the yield for the subsequent technique.
Endoscopic Needle Aspiration
Fig 5. Forceps biopsy technique.
use and may require greater endoscopic expertise. The forceps are stiffer than the brushing devices and require careful maneuvering to avoid perforation. Endoscopic sphincterotomy is sometimes required to pass the forceps. The stricture may be hard to access (especially left hepatic strictures) and maneuvering the forceps into the area of interest may not be possible. Some newer design forceps may be passed over a wire to help alleviate this problem. Occasionally, because of the size of the lumen, a forceps may not be able to be opened in the stricture. There is also a theoretical increased risk of bile duct injury and bleeding because of the deeper biopsies taken. Technique. A forceps sampling technique is outlined in Figure 4 (line drawing) and Figure 5 (fluoroscopic image). After completion of the cholangiogram and demonstration of a stricture, a guidewire can be placed into the intrahepatic ducts and sphincterotomy preformed if necessary. The guidewire is left in place and the biliary biopsy forceps passed alongside and into the bile duct. Using fluoroscopic guidance and the guidewire as a guide, the forceps device is positioned at the downstream edge of the stricture, opened, and a sample entrapped in the forceps cups. The biopsy forceps are then withdrawn into the endoscope leaving the guidewire in place. In some settings, particularly if an endoscopic sphincterotomy has been previously performed, the forceps may be used without a guidewire. Some endoscopists prefer to use a sleeve or sheath to introduce the biliary forceps into the duct. Others use the Howell introducer system (HBIN-35 Wilson Cook Medical, Winston-Salem, NC, described later) to place the forceps device and a cytology brush into the area of the stricture. There are two main types of forceps, a side opening forceps (L-configuration) and a forward opening forceps (Y-configuration). This is shown in Figure 6. The side opening forceps are useful in cases where the forceps can be driven into the midst of the stricture and the forceps opened into the bile duct wall for sampling. The forward opening forceps is useful when it can be impacted with jaws open into the distal most portion of a stricture and samples taken from that end. Several studies have been performed examining the sensitivity and specificity of forceps biopsies alone and in combination/ comparison to biliary brushings. These studies are summarized in Table 3. From these studies, it appears that biopsies do have an in106
Howell et al t3 described the development and use of a retractable 22-gauge 7-mm long needle in a ball-tipped catheter in 1992 (see Fig 7). The device was designed to sample the deep mucosa and submucosa of the bile duct. They studied 31 patients (26 with known malignant bile duct strictures) with needle aspiration and brushings. By using fluoroscopic guidance, the needle-containing catheter was positioned directly below the stricture. The needle was then extended into the tumor and aspirations obtained. They found cytology positive for malignancy in needle aspirates in 16 of the 26 known positives and positive brushings in 2 of them. When two cases of "suspicious cytology biopsies" were considered positive for malignancy, the combination of the needle aspirations and the brushings were 73% sensitive with a specificity of 100%. One patient with cholangiocarcinoma had a positive brushing but a negative needle aspiration. The authors recommended needle aspiration as an adjunct to brushing. Despite the reported experience, endoscopic needle aspiration has not gained as widespread usage as brushings and/or forceps.
Other Devices Used for Diagnosis of Malignant Biliary Strictures The search for better devices and/or techniques for sampling biliary strictures is an ongoing process. Use of a ropeway-type bile duct forceps with a side slit for a guidewire was studied by Tamada et al. 14 This device is a prototype 1.8-mm diameter forceps from Olympus that has a side slit present for passage of a 0.025 inch guidewire and the ability to be passed into the
d
!. ,,
.
.
.
.
.
f
Front Opening
Side Opening
Fig 6. Front-opening versus side-opening forceps designs. LIN, JONNALAGADDA, AND EDMUNDOWICZ
TABLE 3. Studies Comparing Forceps Biopsies and/or Brushings of Bile Duct Strictures Author Sugiyama et a148 (biopsies) (brushings) Ponchon et a149 (biopsies) (brushings) (combined) Schoefl et aP~ (biopsies) (brushings) (combined) Pugliese et a151 (biopsies) (brushings) (combined) Kubota et a152 (biopsies)
Number (n)
Sensitivity (%)
Specificity (%)
PPV
NPV
Accuracy (%)
43 43
81 48
100 100
100 100
43 67
63 86
128 210 115
43 35 63
97 97 97
97 96 98
41 44 53
58 56 73
106 59 48
64.9 46.7 70.4
100 100 100
100 100 100
69.2 61.9 71.4
68.9 61.5 76.5
52 94 52
53 54 61
100 100 100
100 100 100
48 50 53
67 68 73
41
88
100
3.2-mm accessory channel of a conventional duodenoscope. The forceps could be passed into the biliary tree without a sphincterotomy, and samples were obtained Dom the middle of the biliary strictures. In their study, the authors found that the guidewire was able to maneuver the forceps into the appropriate area for sampling in 12 patients, 1 of which was not able to be sampled by conventional nonwire guided forceps. One of the problems with the conventional forceps was difficulty accessing the left hepatic ducts, as there was preferential entry of the right hepatic system. The authors felt that the samples obtained from the new forceps was equivalent (in their small study) to the conventional forceps and that because of ability to leave the wire in place, stenting and other subsequent maneuvers were accomplished more readily. However, careful technique is required to prevent displacement o[ the wire and conventional forceps are still effective to biopsy the margins of strictures. Further use and/or modifications of this device may lead to its routine use. Modifications to the standard brush used for cytologic sampiing have also been explored, on the observation that increased disruption of the affected biliary mucosa may lead to
Fig 7. The Howell biliary aspiration needle. (Courtesy of Wilson Cook Medical, Winston-Salem, NC) DIAGNOSIS OF MALIGNANT BILIARY STRICTURES
increased sensitivity of diagnosis of malignancy. Modifications include cutting flaps into dilation catheters (n = 15, sensitivity 60%) ~5 and a combination 10 French dilator and an abrasive Velcro pad with semi-rigid mushroom shaped bristles (n = 15, sensitivity for malignancy 100%). 76 These modifications have not reached widespread usage. In an attempt to obtain deeper and greater amounts of tissue in a non-surgical fashion, several different scraping devices have been studied and developed. The percutaneous application of the 9 French Simpson atherectomy catheter was studied by Schechter et al. 17 The catheter is a device originally used for removal of peripheral arterial atheroma. Nineteen bile duct shave biopsies were obtained with the device in 19 patients total, 18 patients with symptomatic biliary obstruction. The sensitivity for a histiologic diagnosis was 79% (14 malignancies, 1 primary sclerosing cholangitis). The authors noted the ability to obtain relatively large amounts of tissue for study and the potential for sampling of the extramucosal space. However, the authors noted that the high expense of the catheter and the risk of complications (2 patients had transient but significant hemorrhages) limit the widespread application of the device. Another study by Kaufman et al is looked retrospectively at their experience in the percutaneous use of the Simpson atherectomy catheter. Their sensitivity for diagnosis was 97%, a specificity of 100%, a positive predictive value of 100% and a negative predictive value of 93%. The complication rate in their series was 2%. The tissue samples obtained were 0.5 to 2.0 cm in length, which was felt to contribute to the high sensitivity rate. The authors felt that in the right hands and through proper selection of patients undergoing percutaneous drainage of biliaiy tract strictures, the Simpson atherectomy catheter would be of clinical utility. Garcia-Vila et a119studied biliary sampling through the use of a biliary manipulation catheter percutaneously through a drain. A 6.5 French biliary manipulation catheter (Wilson Cook) was passed through a 7-8 French introducer sheath, then the catheter tip was angled 110 degrees, then aspiration, rotation, and brushing movements were used to obtain material for analysis. 37 patients were examined; the sensitivity for detection of malignancy was 76%, specificity 100%, positive predictive value 100%, negative predictive value 53%. Four cases of spontaneous hemobilia were described, but no other complication arose. The authors felt that this was a less
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expensive and comparable alternative to the Simpson atherectomy catheter with fewer complications. Recently, a scraping device that can be passed through the accessory channel of a therapeutic duodenoscope, the Zimmon Lateral Biopsy Cup or Mighty Bite device, has been developed by Wilson Cook (Fig 8). The use of this device is similar to that of the atherectomy catheter and reportedly with less risk. The 7 French Mighty Bite device uses a cone shaped tip with a backward facing 360 degree cutting blade. The blade closes onto a catheter terminating in an anvil. The device allows for multiple biopsies, which are retrieved in a batch. The advantage of the 360 degree blade is that it allows circumferential biopsies within strictures and facilitates orientation for free biopsies. The cutting blade is also thought to minimize artifact that can be cause by squeezing of tissue by standard sampling techniques. The device is able to accept a 0.025 inch guidewire. Studies are now underway to determine the clinical utility of this device. Technique. Figure 9 (line drawing) and Figure 10 (fluoroscopic images) show the Mighty Bite sampling technique. Cannulation is achieved and a 0.025 inch guidewire is placed through the stricture with its end in one of the larger intrahepatic systems. The Mighty Bite device is then advanced past the stricture, then maneuvered so that when deployed, the cone shaped tip with cutting blade is just within the stricture. The device is then pulled through the area of stricture with the tip deployed, then the tip is captured and the device removed from the patient with the guidewire remaining behind. The tissue is removed from the tip, and the process repeated as needed. Howell et al 2~ described a combination device, the HBIN-35 (Wilson Cook Medical) (Fig 11), which allows the endoscopist to perform fine needle aspiration, forceps biopsy and brush cytology with just one wire guided device that does not require a sphincterotomy for biliary access. The device consists of a 10 French double lumen catheter, with a 0.035 inch guide wire channel from the distal tip and a 5 French second channel with a 45 degree ramp positioned one centimeter below the shoulder of the dilating tip. A 22-gauge biopsy needle mounted in a 3 French metal ball-tipped catheter is also provided with the device.
Fig 8. The Mighty Bite Device. (Courtesy of Wilson Cook Medical, Winston-Salem, NC)
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,f
Fig 9. Mighty Bite Sampling Technique. (A) Achieve cannulation and pass wire past biliary stricture. The Mighty Bite device requires no larger than a 0.025 inch wire. (B) Exchange cannula with wire guided Mighty Bite system and pass system beyond stricture. This will help dilate stricture somewhat. (C) Open tip of Mighty Bite catheter in the stricture, then keeping the scraping cap deployed, pull the entire device into the scope thus pulling the scraping cap through the length of the stricture. (D) Once the scraping cap has reached the distal extent of the stricture, close the device and withdraw the whole device back into the scope for recovery. Device can be used for multiple passes.
Technique. Once a biliary stricture has been identified, a guide wire is placed above the stricture and the catheter passed through the stricture, thus dilating it (Fig 12). The ball-tipped catheter with the needle is then passed through the 45 degree ramp channel, the needle deployed, and fine needle aspiration samples obtained. A 5 French biopsy forceps can then be passed and biopsies obtained. Finally after repositioning of the device, a spring tipped brush can be passed and brushings obtained. In the authors hands, this whole sequence added only 12 to 15 minutes to the entire ERCP procedure time. Twenty-eight patients with obstructive jaundice were studied. By using the device needle, biopsies were positive for malignancy in 12% and suspicious in 15%, forceps biopsies were positive in 15% and suspicious in 15%, brush cytology was positive in 42% and suspicious in 15%. Combining the yields resulted in a 69% LIN, JONNALAGADDA, AND EDMUNDOWICZ
Fig 10. The Mighty Bite device in use during ERCP. (A) Mighty Bite device advanced over the 0.25 inch guidewire and positioned beyond the stricture. (B) The tip of the Mighty Bite catheter is opened above stricture. (C) The device is pulled through the stricture to obtain a sample. (D) The device is withdrawn through the stricture, closed, and exchanged through the endoscope leaving the guidewire in place.
sensitivity and specificity of 95-100%. Farrell et a121 used the HBIN-35 and compared the combination of stricture dilation, fine needle aspiration, and subsequent brushings to the conventional brushing technique. In their study, the sensitivity of conventional brushings (n = 24) was 57%, specificity of up to 100%, positive predictive value 80%, negative predictive value 57% and diagnostic accuracy of 67%. This is compared to the combined sampling (n = 22) sensitivity of 85%, specificity of
Fig 11. Howell ramp catheter. (Courtesy of Wilson Cook Medical, Winston-Salem, NC) DIAGNOSIS OF MALIGNANT BILIARY STRICTURES
100%, positive predictive value of 100% negative predictive value of 40% (low number of benign lesions in study group) and an overall diagnostic accuracy of 86%. The differences were statistically significant. The authors felt that the order of the diagnostic modalities as well as the different sampling methods contributed to the increased rate of diagnosis, and that this device would be of clinical benefit. Direct visualization of the lesion and direct biopsy by cholangioscopy has also been explored as a means of diagnosis. Hwang et a122studied the role of percutaneous cholangioscopy guided forceps in patients suspected of intrabiliary ductal diseases. Twenty-seven patients were studied, and a histologic diagnosis was made in 24 patients, resulting a sensitivity of 89%. The main drawback was the need to have a 16 French tract to perform the procedure. Seo et a123 examined the usefulness of cholangioscopy in patients with focal stricture of the intrahepatic duct unrelated to intrahepatic stones. They also used percutaneous cholangioscopy in 17 patients and were able to obtain a histologic diagnosis in all patients (sensitivity 100%). Dilation of the tract to 18 French was required to pass the larger choledochoscope. Certain mucosal abnormalities were noted to be potentially characteristic for specific pathology. The authors do note that the procedure helped in staging in these cases, but
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with the mother-daughter scope and newer smaller diameter retrograde cholangioscopes has also been described. While this may be a useful additional approach in some lesions the additional time and effort to complete retrograde cholangioscopy has prevented it from being used as a standard approach in all patients. There is no published literature that shows a higher sensitivity for tumor detection with retrograde cholangioscopy.
Endoscopic Ultrasound EUS can be useful in the evaluation of malignant strictures of the bile ducts. High resolution examination of the region may detect a tumor mass or disruption of the typical wall layers of the bile duct by an infiltrating process. Vascular invasion and adjacent lymphadenopathy may also be identified for staging purposes. EUS imaging may increase the suspicion of a malignant etiology of a stricture. EUS instruments can also be used to guide FNA to secure a diagnosis by sampling the tissue surrounding the stricture, an adjacent mass or regional lymph nodes. EUS of biliary strictures can be completed with two general techniques, miniprobe EUS and standard endoscopic devices.
Miniprobe EU5 The use of intraductal ultrasound in the evaluation of biliary disease has been recently reviewed. 25 These devices are of high frequency (12.5 to 30 MHz) and provide detailed imaging of the bile duct wall and some surrounding tissue. They do not currently have tissue acquisition capabilities and therefore can suggest a malignant diagnosis by sonographic criteria only. If the equipment is available at the time of ERCP, intraductal EUS can be completed in a relatively short time providing useful information regarding the type and extent of the stricture.
EUS With FNA Fig 12. Howell Ramp Catheter Technique. (A) Achieve cannulation and place wire past area of stricture. (B) Insert Howell catheter device through stricture over wire. The wire exits the distal port of the catheter. The tip of the device serves to dilate the stricture. {C) Insert the sampling device through the side port. The side port exits at an angle, allowing guidance of the sampling device into the stricture. Sampling devices must be compatible with the Howell device and include needle for FNA, forceps, and brushes. (D) The side port of the device can also be used to achieve cannulation of the right hepatic system, or any other biliary system that is more difficult to access. A wire is place through the side port and the angle of the device sideport exit will allow guidance of the wire into the system of interest.
was somewhat invasive and time consuming. Sato et a124 e x a m i n e d the thickness of the specimens obtained from percutaneous cholangioscopy and attempted to assess the sensitivity for intramural invasive carcinoma. Their conclusions were that percutaneous cholangioscopy with biopsy can only detect invasive carcinoma in the superficial layers of the bile duct, such as the mucosal layer and the shallowest fibromuscular layer. Multiple biopsies are also required as the sensitivity of a single specimen for invasive carcinoma is low. Vascular dilation on examination may be characteristic of extension beyond the adventitia. The use of percutaneous cholangioscopy is not routine in the United States due to its more invasive nature, time requirements, and cost. Endoscopic retrograde cholangioscopy
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A more common approach in patients with biliary obstruction is to obtain cholangiography and an attempt at tissue diagnosis during the initial ERCP. If unsuccessful at securing a diagnosis, then standard EUS with one of the linear systems that allows EUS guided FNA is a useful next step in the evaluation. EUS with FNA allows detailed imaging of the region of the stricture and real time EUS guided FNA if a lesion or abnormality is seen. If no associated mass or lymphadenopathy is identified, the region of the stricture can still be sampled without signif~cam morbidity. This technique has been described to evaluate biliary strictures and secure a diagnosis of both pancreatic malignancy 26 and cholangiocarcinomaY
Other Types of Analysis of Samples Obtained by ERCP With the advent of improved methods in molecular biology, there has been interest in DNA tumor marker analysis of cells obtained from the biliary tree. For example, K-ras oncogene mutations are present in 75% to 100% of pancreatic adenocarcinomas, 41% to 100% of cholangiocarcinomas, and in 55% of gallbladder carcinomas. Lee et al as examined the utility of K-ras mutational analysis on aspirated bile. In their study, PCR products were amplified from the bile of 8 of 12 patients with malignancy and 3 of 8 with benign disease. K-ras oncogene products were present in 4 of the 8 from malignant samples and LIN, JONNALAGADDA, AND EDMUNDOWICZ
absent in all 3 from benign samples. The authors stated that this resulted in a sensitivity of 33%, a specificity of 100% and a positive predictive value of 100% for the diagnosis of malignancy. Laethem et a129 examined Ki-ras gene analysis of brushings from either pancreatic or biliary duct strictures in comparison to brush cytology in the diagnosis of strictures. The authors found that the sensitivity, specificity and accuracy of Ki-ras analysis versus brush cytology was 25% v 42%, 100% v 100%, and 35% v 43%, respectively. They felt that the low rates of detected Ki-ras mutations may have been due to the variable presence of the mutations, or potentially because only a fraction of the tumor cells contained the mutations (sampling variability). Their conclusion was that other means of stricture sampling like brush cytology appear to be more useful on a routine basis for the diagnosis of biliary strictures, but that further study may be warranted. Telomerase activity has been noted in 95% to 100% of surgically resected pancreatic adenocarcinomas. 3~Stable telomerase length is highly correlated with immortalization that characterizes most models of tumor formation. Morales et aP ~ studied the role of in situ hybridization for telomerase RNA in ERCP brushings from 18 patients, 8 of whom had malignancy. The combination of cytology and in situ hybridization lead to a sensitivity for malignancy of 100%. Larger studies would be needed to confirm these findings. The use of flow cytometry has also been studied to see if it would increase the sensitivity of conventional light microscopy examination of cytological samples obtained from the biliary tree. Ryan et aP 1 used DNA staining and flow cytometry on brushing specimens to determine aneuploidy, which in some pancreatobiliary cancers has been reported as a feature of malignant cells. The sensitivity of routine cytology or flow cytometry was 42%. Specificity for malignancy for routine cytology was 92% and 77% for flow cytometry. With the combination of the techniques sensitivity for malignancy rose to 63%, but sensitivity fell to 63%. Flow cytometry had a higher false positive rate than routine cytology. The lack of a sufficient amount of cells for analysis may also be a problem. The authors felt that flow cytometry was able to increase diagnosis of malignancy, but because of the high false positive rate that the clinical scenario should play an important role in interpreting the resuits. Image cytometry has also been studied to assess the role of determining cell DNA contents, using the same rationale as flow cytometry. Imaging has the additional benefit of studying the location and amounts of nuclear material as well as requiring fewer cells. Sears et aP 2 examined brushings from patients with chronic pancreatitis, pancreatic carcinoma, primary sclerosing cholangitis, and cholangiocarcinoma. A specific attempt was made to distinguish between primary sclerosing cholangitis and cholangiocarcinoma. Nuclear size, heterogeneity of chromatin clumps, and percent cell nuclei with hyperdiploid DNA content were some of the parameters studied. Malignancy was able to be distinguished from primary sclerosing cholangitis, sensitivity and specificity was estimated to be 82% and 85%, respectively. Although somewhat promising, the authors caution that larger prospective trials would be required to assess the predictive ability of image cytometry.
DIAGNOSIS OF MALIGNANT BILIARY STRICTURES
Conclusion Malignant bile duct strictures remain a significant diagnostic challenge. The techniques discussed above provide options for the endoscopist to secure a diagnosis of malignancy. While no one technique is sensitive enough to detect all malignant strictures a combination of techniques will hopefully allow the endoscopist to provide a tissue diagnosis in most situations. In the future, additional devices will be available to sample strictures in an attempt to delineate their etiology. In the meantime, repeat sampling and the liberal use of EUS with FNA will hopefully lead to a successful diagnosis in most patients.
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