Endoscopic retrograde forceps biopsy and brush cytology of biliary strictures: a prospective study

0016-5107/95/4206-052055.00 + 0 GASTROINTESTINAL ENDOSCOPY Copyright © 1995 by the American Society for Gastrointestinal Endoscopy

Endoscopic retrograde forceps biopsy and brush cytology of biliary strictures: a prospective study Vittorio Pugliese, MD, Massimo Conio, MD, Guido Nicolo, MD Sebastiano Saccomanno, MD, Beatrice Gatteschi, MD Genoa, Italy

Background: Nonsurgical pathologic confirmation of malignant bile duct strictures is desirable for defining subsequent treatment and prognosis. Endoscopic retrograde cholangiopancreatography is frequently performed in patients suspected of having pancreaticobiliary obstruction, but there exists no standardized method for defining the nature of obstructing lesions by ERCP, Methods: We prospectively evaluated the yields of endoscopic retrograde brush cytology and biopsy for the diagnosis of malignant bile duct strictures. Fluoroscopically guided endobiliary biopsy and brush cytology (52) or cytology alone (42) were performed during endoscopic retrograde cholangiopancreatography in 94 consecutive patients, 64 with malignant strictures and 30 with benign strictures. A single cytopathologist classified the results of these studies as positive or negative for malignancy. Results: The sensitivities of the two procedures were identical (53%) and the gain achieved by combining the two techniques (61%) was small. Specificity proved excellent for both methods. One major complication that occurred was perforation of the common hepatic duct with leakage of bile, which was managed by surgical oversewing. This complication was ascribed to biopsy and untimely removal of the nasobiliary drain by the patient herself. Conclusions: This study indicates that endoscopic retrograde brush cytology alone may be sufficient in daily practice, at least in centers that have access to experienced cytopathologists. We recommend use of forceps biopsy in selected cases where brush cytology is negative. (Gastrointest Endosc 1995;42: 520-6.)

Nonsurgical tissue diagnosis of strictures affecting the bile ducts is highly desirable to avoid more aggressive diagnostic approaches and to plan surgical or alternative treatments. However, tissue confirmation of malignancy is difficult to obtain. Endoscopic Received September 28, 1994. For revision November 17, 1994. Accepted February 21, 1995. From the Gastrointestinal Unit and Department of Pathology, National Institute for Cancer Research, Genoa, Italy. Reprint requests: Vittorio Pugliese, MD, Servizio di Endoscopia Digestiva e Unit& di Gastroenterologia, Istituto Nazionale per la Ricerca sul Cancro, Viale Benedetto XV, 10, 16132 Genova, Italy. 37/1/65104

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retrograde cholangiopancreatography (ERCP) is regarded as a cornerstone in the diagnosis and treatment of pancreaticobiliary diseases, and it allows tissue sampling by multiple techniques. During the past decade, a number of studies have shown that endoscopic retrograde brush cytology is a safe technique, with sensitivity rates ranging from 30% to 80% and with nearly 100% specificity. Endobiliary forceps biopsy is also considered useful and safe by some authors, but it has not yet been established whether or not it adds to the yield of cytology. Hence, the present study has been done to investigate this subject prospectively.

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METHODS AND PATIENTS To make a tissue diagnosis of cancer, three endoscopists and an experienced cytopathologist used the following protocol over a period of 30 months: 1. Endoscopic retrograde forceps biopsy and brush cytology were performed on all biliary strictures detected during ERCP. St~.ctures associated with common bile duct stones or periampullary tumors (tumor apparent when endoscopicalty viewing the papilla without performance of sphincterotomy), as well as those resulting from recent biliary surgery, were excluded from the study. Endoscopic sphincterotomy (ES) was performed whenever required to gain access to the biliary tree. 2. At the end of each ERCP study, the endoscopist had to classify strictures as benign, malignant, or uncertain according to the following data: clinical histories, blood chemistries, ultrasonographic and/or computer-assisted tomographic scan studies, and endoscopic-radiologic findings obtained by the ERCP examination. For the purposes of this study, strictures classified as uncertain were regarded as malignant strictures. 3. The same independent cytopathologist, provided with limited information such as "biliary strictures," had to reexamine all slides randomly and report them as positive or negative for malignancy. From a cytologic viewpoint, malignancy was reported only ff anisocytosis, nuclear enlargement, and variation in shape were all clearly evident. In particular, the term "atypia" was not used as a synonym with malignancy. The histologic criterion to establish malignancy had to be disruption of the basement membrane by the epithelial cells. All patients were suspected of having pancreaticobiliary diseases on the basis of clinical presentations, blood chemistries, transabdominal ultrasonographies, and/or computer assisted tomographies. ERCP was performed with a standard technique using JF1T-10, TJF-10, or TJF-20 Olympus duodenoscopes (Olympus Optical, Hamburg, Germany). Forceps biopsy was attempted before cytology by employing commercially available forceps (Olympus FB-19K or FB39Q). Selective cannulation of the bile duct was carried out using the forceps with the free-hand technique. Under fluoroscopic guidance, the forceps was advanced as far as possible into the stricture in the closed position. The forceps was then opened and the specimen was obtained. If the forceps could not enter the stricture, the open forceps was gently pushed against the distal edge of the lesion. Attempts were made to direct the forceps toward the wall of the strictured duct by gently maneuvering the endoscope or rotating the patient. On the basis of previous studies, 1-4 it was decided that 3 to 5 biopsy samples had to be obtained from strictures affecting the intra-ampullary duct, whereas 2 or 3 specimens were taken from more proximal strictures. After fixation in 10% buffered formalin solution, the biopsy samples were processed conventionally and stained with hematoxylin and eosin. During the first 6 months of study, a brush cytology specimen was obtained by using a standard sheathed brush (Olympus, BC-19 Q) equipped with a guide wire according to the method of Foutch et al. 5 In the subsequent period, the Geenen brushing system (GBC-200-3-3.5, Wilson-Cook Medical Inc., Winston-Salem, N.C.) became

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Table 1. Characteristics of 94 patients whose biliary strictures were sampled by both endoscopic retrograde forceps biopsy and brush cytology or by brush cytology alone Characteristic

No.

Patients with bile duct strictures Men/women Mean age: yrs (range) Forceps biopsy + brush cytology Brush cytology alone Strictures Malignant Benign

94 44/50 69 (37-99) 52 42 64 30

available and was preferred to the previous device. The strictures were brushed several times with a repeated to-and-fro movement. The brush was retracted into the distal end of its sheath and withdrawn. When using the Geenen system, which involves the risk of losing access to difficult strictures because of the absence of a guide wire, we first cannulated the strictures with the guiding catheter of the Cunningham-Cotton sleeve set (CCS-1, Wilson-Cook Med. Inc,). Then the 9.5F Teflon sleeve, belonging to the same set, was advanced as far as possible into the strictures. The Geenen brushing system and the other catheters needed to decompress the bile ducts were then inserted through the Teflon sleeve. Immediately after brush retrieval, the cytologic material was smeared onto 4 glass slides, fLxed in Delaunay solution (50% ethanol, 50% acetone) and stained by the Papanicolaou method. To evaluate the incidence of complications, patients were observed throughout the third day after ERCP with daily blood chemistries and, if clinically necessary, by imaging techniques. The final diagnosis for each patient was confirmed by additional histocytologic data (if subsequently obtained), laparotomy findings or, in absence of these, clinical and radiologic follow-up studies. Sensitivity, specificity, and positive and negative predictive values, as well as accuracy, were calculated for clinicalradiologic diagnosis and for histologic and cytologic studies, either separate or combined. Failures to traverse the strictures with the brush or to obtain adequate forceps material were all regarded as negative studies.

RESULTS D u r i n g t h e s t u d y period, 103 p a t i e n t s w i t h biliary s t r i c t u r e s initially qualified for entry. Tissue s a m p l i n g w a s not a t t e m p t e d in 9 p a t i e n t s for t h e following reasons: m a l i g n a n c y proved b y previous echo-guided fine needle a s p i r a t i o n cytology (FNAC) (4), E R C P examin a t i o n p r e m a t u r e l y concluded (2), a n d e x t r e m e l y poor clinical condition or c o a g u l o p a t h y (3). T h e s e p a t i e n t s w e r e excluded f r o m t h e study. T a b l e I gives t h e c h a r a c t e r i s t i c s of t h e r e m a i n i n g 94 p a t i e n t s e n t e r e d into t h e study. T h e r e w e r e 44 m e n a n d 50 w o m e n w i t h a m e a n age of 69 y e a r s ( m e d i a n 71, r a n g e 37 to 99). B o t h forceps biopsy a n d b r u s h cy-

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521

Table 2. Final diagnoses and number of true positive results by clinical-radiologic studies in 64 patients with malignant bile duct strictures No. of Final diagnosis

cases

Hepatocarcinoma Cholangiocarcinoma Metastatic tumor Pancreas cancer Pancreas islet cell t. Intra-ampullary adenoca. Total

1 22 4 24 2 11 64

C]inical-radiologic diagnosis: positive

Table 4. Final diagnoses and numbers of positive histologic and positive cytologic studies in 36 patients whose malignant biliary strictures were sampled by both techniques

(n)

Final diagnosis

Patients (n)

Histology: positive

1 20 3 22 1 8 55 (86%)

(n)

(n)

Cholangiocarcinoma Metastatic cancer Pancreatic cancer Malignant islet cell tumor Intra-ampullary carcinoma Total

10 3 12 2 9 36

6 1 4 0 8 19 (53%)

7 1 4 0 7 19 (53%)

Positive, Positive for malignancy.

Cytology: positive

Poshive, Positive for malignancy.

Table 3. Causes of benign biliary strictures and number of negative results by clinical-radiologic diagnoses in 30 patients Cause of benign

No. of

stricture

cases

Primary sclerosing cholangitis Previous surgery Chronic pancreatitis Acute pancreatitis Papillitis Stone passage Intradiverticular papilla Undefined Total

1 3 10 1 7 3 4 1 30

Clinical-radiologic diagnosis: negative

(n) 0 2 4 1 2 1 3 1 14 (47%)

Table 5. Distributions of true positive and false negative results of histologic and cytologic studies in 36 patients whose malignant biliary strictures were sampled by both endoscopic retrograde forceps biopsy and brush cytology Study and result

Cytology: positive

Cytology: negative

Total

Histology: positive Histology: negative Total

16 3 19

3 14 17

19 17 36

Positive, Positive for malignancy; negative, negative for malignancy.

Negative, Negative for malignancy.

tology were attempted up through the fifty-second patient. Biopsy was then discontinued because of the perforation that occurred in this patient. Cytology alone was carried out in the remaining group of 42 consecutive patients. In 64 cases, the final diagnosis of malignant disease was confirmed by histologic or cytologic studies of material obtained by surgery, FNAC, or sampling of ascitic fluid (29), surgical exploration (9), or positive cytology or biopsy carried out dining subsequent ERCP studies (4). In the remaining 22 patients, the final diagnoses were based on the appearance of a malignant stricture shown by cholangiography along with ultrasound and/or computed tomography scan evidence of regional metastases (12 patients) or of spinal and muscular metastases (1 patient); infiltration of large peripancreatic vessels shown by angiography (1 patient); or subsequent hospital course. Sixty-one patients of this subset were dead at the time of writing this report. Only 3 are still alive, all with histologic proof of malignancies. In the other 30 patients, strictures proved benign by histologic diagnosis (3), laparotomy (4), or negative 522

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follow-up studies for a median of 31 months (range 15 to 39 months; mean 28 months) (23). Tables 2 and 3 give the results of clinical-radiologic diagnoses. True positive results were 55 of 64, with a sensitivity value of 86%. True negative results were 14 of 30, with a specificity value of 47%. Thirty-six of the 52 strictures studied by both forceps biopsy and brush cytology were malignant. The remaining 16 were benign. The mean numbers of biopsy specimens obtained were 3.5 from strictures affecting the intra-ampullary tract and 2.6 from lesions located more proximally. Table 4 gives the final diagnoses and the positive results of forceps biopsy and brush cytology in the 36 patients with malignant diseases. Out of the 17 false negative results by biopsy, 5 (14%) were due to failures to obtain adequate biopsy material (2 pancreatic adenocarcinoma, 2 cholangiocarcinoma, 1 metastatic tumor). The standard cytology brush could not be advanced beyond the stricture in one case. The numbers of positive results by biopsy alone and by cytology alone were identical, i.e., 19 of 36 or 53%. Table 5 gives the distributions of true positive and false negative results of histologic and cytologic studies in this subgroup of 36 patients and points out that the combined use of the two sampling techVOLUME 42, NO. 6, 1995

Table 6. Sensitivity (SN), specificity (SP), positive and negative predictive values (PPV, NPV) and accuracy (A) percent values for clinical-radiologic studies, for endoscopic retrograde forceps biopsy alone, for brush cytology alone, and for the two sampling techniques combined in patients with biliary strictures Technique

Patients (n)

SN (%)

SP (%)

PPV (%)

NPV (%)

A (%)

Clinical-radiologic Forceps biopsy B r u s h cytology Combined

94 52 94 52

86 53 54 61

47 100 100 100

77 100 100 100

61 48 50 53

73 67 68 73

niques made it possible to classify 22 of 36 (61%) malignant stenoses correctly. In the subset of 16 patients with benign strictures, the causes were as follows: papillitis (7), previous surgery (2), spontaneous stone delivery (2), diverticulum (2), chronic pancreatitis (2), and undefined (1). The acquisition of biopsy material failed in one case (6%) and brush cytology provided unsatisfactory material in another case. No false positive results were obtained. ES had previously been carried out in 41 (79%) of the 52 patients studied by double sampling. Drainage procedures followed ES in 36 of 41 cases (88%). Previous ES correlated positively with the success rate of forceps biopsy: adequate biopsy material was obtained in 95% of cases after ES (39 successful attempts out of 41) and in 64% of cases without ES (7 successful attempts out of 11). Brush cytology alone was performed in 42 consecutive patients after attempts by forceps biopsy were ended. This group consisted of 28 patients with mal i g n a n t strictures and 14 patients with benign strictures. The 28 malignancies were as follows: hepatocarcinoma (1), cholangiocarcinoma (12), metastatic tumor (1), pancreatic cancer (12), and intra-ampullary adenocarcinoma (2). Brush cytology yielded unsatisfactory material in 3 out of 12 patients with pancreatic cancers. Positive results were obtained in 9 of 12 patients with cholangiocarcinomas (75%), 4 of 12 with pancreatic cancers (33%), and 2 of 2 with intra-ampuUary malignancies (100%), with a sensitivity of 54% (15 of 28). In the remaining 14 of 42 cases that received cytologic study alone, strictures were benign and caused by acute pancreatitis (1), chronic pancreatitis (8), previous surgery (1), spontaneous stone delivery (1), diverticulum (2), and primary sclerosing cholangitis (1). No false positive results were obtained. ES was carried out in 25 of 42 patients (60%) studied by brush cytology alone and was followed by drain or stent insertion in 23 of 25 cases (92%). Table 6 summarizes the sensitivity, specificity, positive and negative predictive values, and accuracy percent values for clinical-radiologic studies and for biopsy and cytology, both alone and combined. V O L U M E 42, NO. 6, 1995

Complications occurred in 8 patients (8.5%). In 7, all of whom had also undergone ES and drainage procedures, complications were mild pancreatitis (2), moderate pancreatitis (1), acute cholangitis (3), and selflimiting hemorrhage (1). They all recovered spontaneously or after medical treatment. None of these complications was attributable to the sampling techniques per se. A serious complication occurred in a 74-year-old female patient referred for investigation of the cause of a previous episode of acute cholangitis. She underwent ES and sampling by both forceps biopsy (two samples taken with the Olympus FB-19K forceps) and brush cytology (with the BC-19Q system). A nasobiliary catheter was inserted to prevent post-ERCP cholangitis, but this was prematurely removed by the patient that same day. She developed acute abdominal symptoms suggestive of peritonitis. Because the patient refused to undergo a second ERCP, an explorative laparotomy was carried out. This confirmed biliary peritonitis and revealed a perforation of the common hepatic duct located on the lower edge of a benign appearing stricture. Cho]ecystectomy and suture closure of perforation were carried out and a small-caliber T-tube was inserted through a choledochotomy. After the operation, the patient recovered. During the following 39 months, two episodes of acute cholangitis occurred. A follow-up ERCP study showed the presence of small concrements in the intrahepatic bile ducts above a benign appearing, otherwise unchanged stricture. Under macroscopic examination of the original biopsy material, one of the two samples turned out to be unusually large, measuring 2 x 4 m m in diameter. The microscopic study had shown acute and chronic inflammation with marked fibrosis and the presence of some muscular fibers. The lesion was classified as a benign stricture of the common hepatic duct of uncertain cause.

DISCUSSION In patients with malignant strictures of the bile ducts, preoperative pathologic confirmation allows more correct diagnosis, which facilitates therapeutic planning and accurate prognosis. 6, 7 This is particuGASTROINTESTINAL ENDOSCOPY

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larly important when imaging techniques do not detect a mass lesion. Also, the specificity of clinicalradiologic diagnosis was low in our study (47%, Table 3), due to false positive or uncertain results, mostly in patients with chronic pancreatitis or papillitis. Even though this low specificity may partly be ascribed to our intent to make a more timely diagnosis of cancer, nonetheless it supports the need for accurate tissue sampling techniques of biliary strictures. Tissue confirmation of malignant strictures of the bile ducts is d i f f i c u l t . 6' 8,9 Indeed, out of the 103 patients considered initially, all of whom had undergone imaging techniques, only four had a pre-ERCP diagnosis by the FNAC technique. We agree with other authors 6, lo that sampling during ERCP is the first-line approach to tissue diagnosis ofbiliary strictures. In the past decade, the yields of different endobiliary cytology techniques have been investigated. Sensitivity values range between 20% and 80% in various reports, 1°-16 depending on the type of technique, the method of calculation used, and the site of origin of the underlying malignancy. Endoscopic retrograde brush cytology is the simplest method and is currently preferred to other approaches. 6, 7 In general, its yield has increased in the last few years, thanks to refinements 5, ! 5 and to the greater expertise of cytopathologists. Current research, aimed at reducing the rate of unsatisfactory samples or at evaluating the yields of cytometry and molecular biology techniques, is expected to lower the rate of false negative r e s u l t s . 14, 17-19 Our present study also points out an increase in the overall sensitivity of brush cytology from 42% and 47% in our previous evaluations 11, 12 to the present 54% (Table 6). We obtained this figure in spite of the strict cytologic criteria adopted to diagnose a malignancy, i.e., without considering atypical cells as an equivalent of malignancy. Others, 13, 20 however, obtained a remarkable gain in sensitivity by regarding the detection of atypical cells as a criterion to diagnose malignant disease. Our overall improvement is the result of a considerable increase in sensitivity in cholangiocarcinoma strictures: from the previous 47% and 60% to the present 73% for all the 22 patients studied by means of brush cytology (Table 4). Unfortunately, the sensitivity of this technique remains low when strictures are caused by extrinsic tumors. Our 33% figure is similar to Ryan's 30% figure, 21 but lower than the 45% to 65% figures reported by others. 1°, 13, 14, 22 To increase this low yield, some researchers performed brushings from within strictures of the main Pancre atic duct and reported sensitivity values between 40% and 85%. 15, 23, 24 In our opinion, the usefulness of endopancreatic sampling is questionable. For example, Sawada et al. 23 and Lee et al. 24 used this procedure in only 72 and 34 patients during 14 and 5 years, respec524 G A S T R O I N T E S T I N A L E N D O S C O P Y

tively. This suggests that the success rate in traversing main pancreatic duct strictures with brushing devices is low. Further uncertainty in this method was recently demonstrated by Ferrari et al., 1° who found that endobiliary and endopancreatic brush cytology in pancreas cancer exhibit the same sensitivity. Interesting results in defining strictures caused by extrinsic tumors were achieved with the endoscopic transmural fine-needle aspiration technique using the Howell needle. 16 This author and his coworkers obtained a sensitivity of 57% in 21 cases of extrinsic malignancies. Similar preliminary results, were obtained by the Indiana University g r o u p , 13, 20 suggesting that fine-needle aspiration alone is more accurate than brush cytology alone in sampling extrinsic tumors. Endoscopic retrograde forceps biopsy has been studied less extensively than brush cytology. Moreover, the investigations comparing forceps biopsy and brush cytology are few and it is still controversial whether the combined use of these two techniques is advantageous. Comparative evaluations are in favor of forceps biopsy, 13 but Kurzawinsky et al. 6 recently pointed out that although forceps biopsy is theoretically more suitable than cytology to sample malignancies that spread submucosally or outside the bile ducts,7, 25 it is a second-line technique because it requires a previous ES and its safety has not yet been completely assessed. The present prospective study is among the largest investigations aimed at comparing the yields of forceps biopsy and brush cytology. The sensitivity of forceps biopsy alone was 53% in the present study, similar to the 60% sensitivity reported by Aabakken et al. 3 but lower than the 80% to 85% sensitivity values in other reports, including o u r s . l , 11, 26 These discrepancies may be explained by differences in several variables, such as method of calculation, origin and pattern of growth of malignancy (i.e., superficial or submucosal), depth of infiltration of the bile duct wall by extrinsic malignancy, type of forceps used, and number of samples taken. As an example, Kubota et al. 26 obtained a sensitivity of 89% by taking at least four biopsy samples from 18 cholangiocarcinoma strictures. Our corresponding figure is 60% (Table 4), possibly because we took a smaller amount of material to save time for subsequent brush cytology and to reduce the risk of losing access to strictures. The sensitivity of biopsy in cases with distal strictures was higher t h a n in cases with proximal strictures (Table 4), confirming the results of previous studies. 2, 11, 27 The little larger amount of biopsy material obtained from intra-ampullary tumors (mean 3.5 samples vs 2.6 samples) could explain this higher sensitivity. However, other factors, such as aiming under direct vision and intraluminal pattern V O L U M E 42, NO. 6, 1995

of growth of intra-ampullary tumors, m a y also play a role. In the present study, forceps biopsy and brush cytology showed almost identical sensitivities (Table 6). When we combined the two procedures, the overall sensitivity rose to 61% (Table 6), which approaches the 64% to 68% values reported by others in abstracts. 4, 13 The gain in overall sensitivity achieved by our method is too small to lead us to advise the use of biopsy together with cytology in daily practice. Biopsy was pagicularly disappointing in our study because it did not aid cytology in attaining the goal of a higher sensitivity in diagnosing extrinsic tumors. This further stresses the need for evaluating techniques other t h a n forceps biopsy for these tumors, such as the aspiration biopsy technique with the Howell needle or, possibly, endopancreatic sampling techniques. However, our conclusion that forceps biopsy does not add to the general yield of brush cytology could be argued in the light of the recent findings by Mohandas et al., 2s who noted that initial dilation of strictures increases the sensitivity of subsequent bile cytology. Actually, in our study, forceps biopsy preceded brush cytology in 52 strictures, some of which were also partially dilated. Therefore, it could be postulated that the t r a u m a provoked by forceps biopsy and, to some extent, by dilation, concurred in increasing the cellular harvesting, thus giving an overestimation of the sensitivity of the subsequent brush cytology. However, this is unlikely, inasmuch as the sensitivity of cytology remained the same in the subset of 28 patients with malignant strictures who underwent brush cytology alone. The specificity values for forceps biopsy and brush cytology were excellent in this study (Table 6), as well as in almost all other published studies. A low negative predictive value (about 50%, Table 6) indicates that a negative study does not exclude a malignant disease. However, as shown by Rabinovitz e t al., 29 repeated negative results minimize the probability of missing a diagnosis of cholangiocarcinoma. This consideration allowed two of our patients to avoid surgical operation; 3 y e a r s a f t e r endoscopic dilation they are now entirely asymptomatic. The bfliary perforation that occurred in one of our patients deserves further comment. We believe that the complication was caused by forceps biopsy rather than other maneuvers. This stricture had not been dilated and it seems very unlikely that brushing caused the perforation. The large specimen obtained and repeated biopsy at the same site m a y have accounted for the complication. The same mechanism m a y account for the perforation that occurred after taking multiple endopancreatic samples, as reported by Seifert et al.30 Also, the use of a stiff forceps m a y have played a key role. A smaller-caliber and softer forceps may be safer, VOLUME 42, NO. 6, 1995

even though the sample size would be smaller and a larger number of specimens would be required. Another reason against the routine use of forceps biopsy is the fact that this technique generally requires an ES to facilitate insertion of the forceps. Actually, our results show that ES was more frequent among the 52 patients who underwent double sampling t h a n among the 42 who underwent brush cytology alone (79% vs 60%). However, it is also evident that nearly all patients undergoing ES also received drainage procedures, irrespective of whether they were eventually studied by the double-sampling or the single-sampling technique (88% and 92%, respectively). Therefore, we agree with the view 1, 26, 30 that, for the great majority of patients undergoing endobiliary sampling, ES is justified by the subsequent treatment and does not actually limit the applicability of forceps biopsy. Moreover, we also agree with o t h e r s 2, 27 that, as an exception to such a general indication, ES should be performed in cases of suspected intra-ampullary tumors, even for diagnostic purposes only; an exhaustive sampling is indeed particularly important in view of the excellent outcome of the surgical treatment of these tumors. On the other hand our study shows that the biopsy material was obtained in 95% of attempts after ES but only in 64% of attempts without previous ES: this difference suggests that lateral biopsy is actually easier after ES. In summary, we believe that in daily practice tissue sampling during ERCP is the first-line approach to tissue diagnosis of biliary strictures. Brush cytology alone is to be preferred, at least in centers that have access to experienced cytologists. Routine forceps biopsy use does not add sufficiently to the yield to justify the added time and risk. Forceps biopsy can be used in cases of complete ductal obstructions (which can be obtained frontally), in strictures located in the intra-ampullary tract, or during subsequent ERCP examinations, ff previous brush cytology was negative. Further studies are required to establish optimal intraductal sampling techniques. ACKNOWLEDGMENT

The authors thank the Maria Piaggio Casarsa Foundation-Genova for technical support and Mrs. Ivana Galeazzo, Mrs. Maria Franca Difonzo, and Mrs. Tiziana Dedone for their valuable assistance. REFERENCES 1. Rustgi AK, KelseyPB, Guelrud M, et al. Malignant tumors of the bile ducts: diagnosisby biopsy during endoscopiccannulation. Gastrointest Endosc 1989;35:248-51. 2. DancygierH. Endoscopictranspapillary biopsy (ETPB) of human extrahepatic bile ducts. Light and electron microscopic findings, clinical significance.Endoscopy1989;21:312-20. 3. Aabakken L, Karesen R, Serck-HanssenA, et al. Transpapillary biopsies and brush cytology from the common bile duct. Endoscopy 1986;18:49-51.

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4. Chang L, French S, Hierro H, et al. A prospective study comparing endobiliary biopsy, brush and aspiration cytology during ERCP in diagnosing biliary obstructive lesions [Abstract]. Am J Gastroeuterol 1992;87:1282. 5. Foutch PG, Harlan JR, Kerr D, et al. Wire-guided brush cytology: a new endoscopic method for diagnosis of bile duct cancer. Gastrointest Endosc 1989;35:243-7. 6. Kurzawinski T, Deery A, Davidson BR. Diagnostic value of~cytology for biliary stricture. Br J Surg 1993;80:414-21. 7. Foutch PG. Diagnosis of cancer by cytologicmethods performed during ERCP. Gastrointest Endosc 1994;40:249-52. 8. Lee M. Tissue diagnosis for carcinoma of the pancreas and periampullary structures. Cancer 1982;49:1035-9. 9. Kurzawinski T, Deery A, Dooley J, et al. A prospective controlled study comparing brush and bile exfoliative cytology for diagnosing bile duct strictures. Gut 1992;33:1675-7. 10. Ferrari AP Jr, Lichtenstein DR, Slivka A, et al. Brush cytology during ERCP for the diagnosis of biliary and pancreatic malignancies. Gastrointest Endosc 1994;40:140-5. 11. Pugliese V, Barone D, Saccomanno S, et al. Tissue sampling from the common bile duct through endoscopic retrograde cholangiopancreatography,endoscopic papillo(sphinctero)tomy and drainage in juxtapapillary malignancies. Surg Endosc 1987;1: 83-7. 12. Pugliese V, Gatteschi B, Saccomanno S, et al. Citologia retrograda endoscopica in 49 pazienti con stenosi delle vie biliari. Giorn Ital End Dig 1993;16:41-4 (abstract in English). 13. Hawes RH, Sherman S, Wiersema M, et al. Tissue sampling of biliary strictures at ERCP [Abstract]. Gastrointest Endosc 1994;40:Pl11. 14. Ryan ME, BaldaufMC. Comparison of flow cytometry for DNA content and brush cytology for detection of malignancy in pancreatobiliary strictures. Gastrointest Endosc 1994;40:133-9. ~[5. Venu RP, Geenen JE, Kini M, et al. Endoscopic brush cytology. \ A new technique. Gastroenterology 1990;99:1475-9. 1~. Howell DA, Beveridge RP, Bosco J, Jones M. Endoscopic needle aspiration biopsy at ERCP in the diagnosis of biliary strictures. Gastrointest Endosc 1992;38:531-5. 17. Baron TH, Lee JG, Wax TD, et al. An in vitro, randomized, prospective study to maximize cellular yield during bile duct brush cytology. Gastrointest Endosc 1994;40:146-9. 18. Lee JG, Leung JWC, Cotton PB, et al. K-ras oncogene muta-

526

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19.

20.

21. 22. 23.

24. 25. 26. 27. 28.

29.

30.

tional analysis by PCR improves the diagnostic yield from bile obtained by ERCP [Abstract]. Gastrointest Endosc 1994;40: Pl16. Miki H, Matsumoto S, Harada H, et al. Detection of c-Ki-ras point mutation from pancreatic juice. A useful diagnostic approach for pancreatic carcinoma. Int J Pancreatol 1993;14: 145-8. Wiersema M, Lehman G, Hawes R, Sherman S, Earle D. Improvement of diagnostic yield of brush cytology in malignant biliary strictures by the use of supplemental tissue sampling techniques [Abstract]. Gastrointest Endosc 1992;38:265. Ryan EM. Cytologic brushing of ductal lesions during ERCP. Gastrointest Endosc 1991;37:139-42. Scudera PL, Koizumi J, Jacobson IM. Brush cytology evaluation of lesions encountered during ERCP. Gastrointest Endosc 1990;36:281-4. Sawada Y, Gonda H, Hayashida Y. Combined use of brushing cytology and endoscopic retrograde pancreatography for the early detection of pancreatic cancer. Acta Cytol 1989;33: 870~4. Lee JG, Schutz SM, Layiield L, et al. A prospective study of endoscopic pancreatic duct cytology in 34 consecutive patients [Abstract]. Gastrointest Endosc 1994;40:Pl16. Terasaki K, Wittich GR, Lycke G, et al. Percutaneous transluminal biopsy of biliary strictures with a bioptome. AJR Am J Roentgenol 1991;156:77-8. Kubota Y, Takaoka M, Tani K, et al. Endoscopic transpapillary biopsy for diagnosis of patients with pancreatobiliary ductal strictures. Am J Gastroenterol 1993;88:1700-4. Seyrig JA, Liguory C, Meduri B, et al. Endoscopie dans les tumeurs de la r~gion oddienne. Possibilit~s diagnostiques et th~rapeutiques. Gastroenterol Clin Biol 1985;9:103-8. Mohandas KM, Swaroop VS, Gullar SU, et al. Diagnosis of malignant obstructive jaundice by bile cytology: results improved by dilating the bile duct strictures. Gastrointest Endosc 1994; 40:150-4. Rabinovitz M, Zajko AB, Hassanein T, et al. Diagnostic value ofbrush cytologyin the diagnosis ofbile duct carcinoma: a study in 65 patients with bile duct strictures. Hepatelogy 1990;12: 747-52. Seffert E, Urakami Y, Elster K. Duodenoscopic guided biopsy of the biliary and pancreatic duct. Endoscopy 1977;9:154-61.

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