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How many biopsies should be performed during percutaneous transhepatic cholangioscopy to diagnose biliary tract cancer?
How many biopsies should be performed during percutaneous transhepatic cholangioscopy to diagnose biliary tract cancer? Kiichi Tamada, MD, Katsumi Kurihara, MD, Takeshi Tomiyama, MD, Akira Ohashi, MD, Shinichi Wada, MD, Yukihiro Satoh, MD, Takamitsu Miyata, MD, Kenichi Ido, MD, Kentaro Sugano, MD Tochigi, Japan Background: The sensitivity of biopsy in the diagnosis of cholangiocarcinoma using percutaneous transhepatic cholangioscopy is not well defined. Methods: Patients with a biliary tract malignancy (n = 52) underwent directed biopsy during percutaneous transhepatic cholangioscopy using a 1.8 mm diameter forceps. Histologic findings were correlated with endoscopic appearance. Results: A diagnosis of carcinoma was made in all four patients with a tumor of the major duodenal papilla and in all 15 patients with a polypoid bile duct tumor with two biopsies from the mass. In 19 patients with stenotic bile duct cancer, a positive diagnosis was made in 95% of cases when three biopsies were taken from the margin of the stenotic area. When cholangioscopy showed a tortuous, dilated vessel (n = 10), the diagnosis of cancer was made with two biopsies taken from the margin of the stenosis. In 14 patients with metastatic bile duct cancer, the diagnosis was made in only 43% of cases when three biopsies were taken from the margin of the stenosis. When combined with results from the three biopsies taken from within the area of stenosis, the sensitivity for diagnosing pancreatic cancer improved from 20% to 60%. Conclusions: Directed cholangioscopic biopsies are highly sensitive for the diagnosis of cholangiocarcinoma but less sensitive for cancer metastatic to the bile duct. The numbers and locations of the biopsies required to make a diagnosis of carcinoma depend on the origin and cholangioscopic appearance of the tumor. (Gastrointest Endosc 1999;50:653-8.) Although percutaneous transhepatic cholangioscopy (PTCS) is a useful m o d a l i t y for o b t a i n i n g biopsy specimens of the bile duct, 1-11 no r e p o r t has d e l i n e a t e d how m a n y s p e c i m e n s should be t a k e n to confirm or exclude t h e diagnosis of m a l i g n a n c y of t h e biliary tract. Additionally, b e c a u s e a v a r i e t y of different t u m o r s a n d types of t u m o r s develop in t h e p a n c r e a t i c o b i l i a r y tree, biopsy guidelines m a y differ according to t h e clinical p r e s e n t a t i o n . This prospective s t u d y is t h e first to a t t e m p t to define guidelines for p e r f o r m i n g biopsies to diagnose biliary t r a c t cancer b y m e a n s of PTCS. PATIENTS AND METHODS
Between June 1989 and September 1998, a total of 82 patients with biliary tract malignancy underwent PTCS. Of these, 52 (28 men, 24 women) with an average age of 65.7 years (range 36 to 88 years) were enrolled in this prospective study. Diagnoses included bile duct cancer (n = 34), Received October 26, 1998. For revision February 4, 1999. Accepted June 23, 1999. From the Departments of Gastroenterology and Pathology, Jichi Medical School, Yakushiji, Tochigi, Japan. Reprint Requests: Kiichi Tamada, MD, Department of Gastroenterology, Jichi Medical School Yakushiji, Tochigi 3290498, Japan; fax: 81-285-44-8297. Copyright 9 1999 by the American Society for Gastrointestinal Endoscopy 0016-5107/99/$8.00 + 0 37/1/100922 VOLUME 50, NO. 5, 1999
gallbladder cancer (n = 6), pancreatic cancer (n = 5), a tumor of the major duodenal papilla (n = 4), or gastric cancer invading the bile duct (n = 3). Surgical resection was performed in 37 patients. Written informed consent was obtained from all patients before percutaneous transhepatic biliary drainage (PTBD), dilatation of the sinus tract, and PTCS. All procedures were conducted under intravenous conscious sedation (10 mg of diazepam and 15 mg of pentazocine). After performing PTBD, the percutaneous tract was dilated to 5.3 mm using a coaxial dilatation catheter (Cook Co., Ltd., Bloomington, Ind.). After 6 to 10 days, a cholangioscope (CHF-P10, CHFQ10, or BF-P200, Olympus Optical Co., Ltd., Tokyo, Japan; or ECN-1530, Pentax Co., Ltd., Tokyo, Japan) was inserted into the bile duct through the established tract using a 16F or 18F peel-away sheath (Cook). A security guidewire was advanced to the fourth portion of the duodenum through the papilla. Biopsies were performed using forceps with serrated cups without a central needle (FB-52C-1, Olympus; or Radial Jaw 3, Boston Co., Ltd., Watertown, Mass.) or forceps with nonserrated cups without a needle (FB-19SW, Olympus). All forceps were 1.8 mm diameter and could be rotated. During the biopsy procedure, the bile duct was irrigated with normal saline mixed with 0.1% noradrenaline to control bleeding. Study design
Patients who required a target biopsy for initial diagnosis or preoperative mapping biopsies by means of PTCS GASTROINTESTINAL ENDOSCOPY
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Bile duct biopsy using percutaneous transhepatic cholangioscopy
Figure 1. Endoscopy and pathology in 59-year-old man with cancer of the intrapancreatic bile duct. A, Cholangioscopy showing a small polypoid tumor at the intrapancreatic bile duct. B, Photomicrograph of the resection specimen (H&E, orig. mag, xl) showing cancer cells throughout the bile duct mucosa. C, Photomicrograph of a biopsy specimen taken from the polypoid tumor (H&E, orig. mag. xl0) showing the mucosa with adenocarcinoma. were enrolled in this study. During PTCS, the first author recorded the endoscopic findings at each position where a biopsy was obtained, and the biopsy specimens were numbered for later reference. Subjects whose endoscopic findings were not recorded in detail were excluded from data analysis. When cholangiography revealed a unilateral polypoid tumor, three biopsy specimens were obtained at slightly different locations from the mass itself. When the stenosis was symmetrical and no discrete mass was apparent, three biopsies were obtained at the margin of the stenosis and three biopsies were obtained within the stenotic region at different depths. When the endoscopy revealed a tortuous, dilated vessel (tumor vessel) at the margin of the stenosis, the first biopsy was obtained at the vessel site. The second and third biopsies were obtained in neighboring regions. The biopsy specimens were fixed with 10% formalin, stained with H&E, and evaluated by two experienced pathologists. The surgical specimens were fixed with 10% formalin, and the bile ducts were cut transversely into 3 m m slices. Each slice was sectioned, stained with H&E, and analyzed by two experienced pathologists. Correspondence between the surgical resection specimens and the biopsy specimens was confirmed by the pathologist (I~IC) and endoscopist (I~T.). The data were analyzed using Fisher's exact test. A p value < 0.05 was considered significant. 654
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RESULTS Complications The two patients who suffered dislodgement of the catheter after PTBD were successfully treated by a second drainage procedure. Another patient developed acute cholecystitis after the 16F PTCS catheter was advanced into the distal bile duct across the cystic duct. This was successfully treated by percutaneous transhepatic gallbladder drainage. Although intrabiliary bleeding occurred after dilatation of the tract in one patient, it resolved without the need for transfusion or transarterial embolization. None of the patients s u f f e r e d a d i r e c t c o m p l i c a t i o n of P T C S a n d b i o p s y s u c h as p e r f o r a t i o n of t h e s i n u s t r a c t or h e m a t o bilia. O o z i n g f r o m t h e b i l e d u c t w a l l w a s w e l l c o n t r o l l e d in all p a t i e n t s b y i r r i g a t i o n w i t h t h e noradrenaline solution. The overall procedurer e l a t e d m o r b i d i t y a n d m o r t a l i t y r a t e s w e r e 8% (4 of 52) a n d 0% (0 of 52), r e s p e c t i v e l y .
Sensitivity of biopsy, polypoid tumor C h o l a n g i o g r a p h y d e m o n s t r a t e d a polypoid t u m o r VOLUME 50, NO. 5, 1999
Bile duct biopsy using percutaneous transhe_patic cholangioscopy
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A
Figure 2. Endoscopy and pathology in 66year-old woman with cancer of the midportion of the bile duct. A, Cholangioscopy showing a tortuous, dilated vessel at the margin of a stenosis. Photomicrographs of the resection specimen (H&E, orig. mag. x l ) showing the bile duct mucosa and the submucosal tissue containing cancer cells (arrowheads) at the margin of the stenotic area (B), 3 mm within the stenotic area (C), and 6 mm proximal to the margin of the stenosJs (D). E, Photomicrograph of a biopsy specimen taken from the position of the dilated vessel (H&E, orig. mag. x4) showing the submucosal tissue with adenocarcinoma. Table 1. Accuracy of biopsies under percutaneous transhepatic cholangioscopy in the diagnosis of cancer (n = 52)
Table 2. Accuracy of biopsy according to the numbers of biopsies in patients with a unilateral polypoid tumor of the bile duct
Diagnostic rate Tumor at the major papilla Bile duct cancer, polypoid type Bile duct cancer, stenotic type Pancreatic cancer Gallbladder cancer Gastric cancer
4/4 (100%) 15/15 (100%) 18/19 (95%) 315 (60%) 4/6 (67%) 1/3 (33%)
in four patients who had a mass involving the major papilla, and in 15 patients with bile duct cancer. Cancer was identified in two biopsy specimens t a k e n from the polypoid t u m o r in all 19 patients (Tables 1 and 2, Fig. 1). Among the 14 patients who u n d e r w e n t surgical resection, histologic examination revealed papillary adenocarcinoma in 10 patients and well-differentiated tubular adenocarcinoma in the remaining four patients.
Sensitivity of biopsy, stenotic type bile duct cancer Cholangioscopy showed a tortuous, dilated vessel in 10 patients with bile duct cancer of the stenotic type. In VOLUME 50, NO. 5, 1999
No. of biopsies 1 2
Tumor at the major papilla Papillary
WDA
Bile duct cancer Papillary
WDA
2/2 (100%) 1/2 (50%) 11/12 (92%) 2/3 (67%) 2/2 (100%) 2/2 (100%) 12/12 (100%) 3/3 (100%)
Papillary, Papillary adenocarcinoma; WDA, well-differentiated tubular adenocarcinoma.
all cases, the diagnosis of cancer was made on two biopsy specimens taken from the margin of the stenotic area (Tables 1 and 3). Surgical resection was performed in eight of 10 patients. All of the surgical specimens contained tubular adenocarcinoma. The sensitivity of biopsies taken from the margin of the stenotic area was better than that of biopsies taken from within the area of stenosis (p < 0.01) (Table 3, Fig. 2). No dilated vessel was observed on cholangioscopy in nine patients with bile duct cancer of the stenotic type. Cancer was present within three biopsies taken from the margin of the stenosis in 89% of these cases (Tables 1 and 3). Surgical resection was performed in GASTROINTESTINAL ENDOSCOPY
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Figure 3. Endoscopy and pathology in 54year-old man with cancer of the intrapancreatic bile duct. A, Cholangioscopy showing a stenosis without a dilated vessel. B, Photomicrograph of the resection specimen (H&E, orig. mag. x l ) showing cancer cells in a small part of the bile duct mucosa and the submucosal tissue (arrowheads) at the margin of the stenosis. C, The cells were not exposed to the lumen of the bile duct within the area of stenosis. Photomicrograph of a biopsy specimen (H&E, orig. mag. x4) taken from the margin of the stenotic area (D), and within the stenosis (E) showing no cancer cell in either mucosal or submucosal tissue. Table 3. Accuracy of biopsy according to the presence of the tortuous, dilated vessel as a cholangioscopic finding in patients with bile duct carcinoma of the stenotic type Cholangioscopic findings No. of biopsies 1 2 3
With dilated vessel Margin
Within
8/10 (80%) 5/10 (50%) 10110 (100%) 7/10 (70%) 10/10 (100%) 7/10 (70%)
Without dilated vessel Margin
Within
3/9 (33%) 2/9 (22%) 5/9 (56%) 5/9 (56%) 8/9 (89%) 5/9 (56%)
Margin, Margin of stenotic area; Within, within the area of stenosis.
eight of these nine patients, and all resection specimens contained t u b u l a r adenocarcinoma. In one patient, cancer was not found in any of four biopsy specimens taken from the margin of the stenosis or in six biopsy specimens taken from within the stenotic area (Fig. 3). In this patient, histologic examination of the surgical specimen revealed cancer cells in a small area at the margin of the area of stenosis.
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Sensitivity of biopsy, metastatic bile duct cancer In the patients with metastatic bile duct tumors (six gallbladder, five pancreatic, and three gastric), cancer was detected within three biopsy specimens taken from the margin of the stenosis in 43% of cases. When these data were combined with data from three biopsy specimens taken from within the stenosis, the sensitivity in the patients with pancreatic cancer improved from 20% to 60% (Table 1, Fig. 4).
DISCUSSION Bile duct b i o p s y u n d e r P T C S is an excellent m o d a l i t y to d i s t i n g u i s h b e t w e e n m a l i g n a n t and benign bile duct stenoses. 1-1~ We have previously reported t h a t target biopsy u n d e r PTCS is useful in avoiding u n n e c e s s a r y s u r g e r y b e c a u s e m o s t p a t i e n t s w i t h benign bile duct stenosis can be t r e a t e d with interventional radiologic procedures, such as d i l a t a t i o n u s i n g a coaxial c a t h e t e r and t e m p o r a r y p l a c e m e n t of a 16F plastic endoprostheses. 10 O t h e r s also h a v e r e p o r t e d t h e u t i l i t y of PTCS for this purpose. 1-5 PTCS is essential for
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Bile duct biopsy using percutaneous transhepatic cholangioscopy
K Tamada, K Kurihara, T Tomiyama, et al.
Figure 4. Endoscopy and pathology in 70-year-old woman with cancer of the pancreas. A, Cholangioscopy showing a stenosis without a dilated vessel. B, Photomicrograph of the resection specimen (H&E, orig. mag • showing no cancer cell in either the bile duct mucosa or the submucosal tissue at the margin of the stenosis. C, Cancer cells in a small part of the deep portion of the submucosal tissue within the stenotic area (arrowhead). D, Histologic examination of a biopsy specimen (H&E, orig. mag. • taken from the margin of the stenotic area showing no cancer cell. E, Photomicrograph of a biopsy specimen (H&E, orig. mag. x20) taken from within the stenosis showing cancer cells in submucosal tissue
(arrowheads). mapping biopsies to determine longitudinal cancer e x t e n s i o n along the bile duct.l-7,11 Cholangiocarcinoma often extends along the bile duct, and cholangiography cannot adequately determine the e x t e n t of local invasion.l-7,11,12 Therefore, t h e n u m b e r of t a r g e t biopsies t a k e n from t h e m a i n t u m o r should be minimized because multiple mapping biopsies m u s t be obtained to determine the surgical margin within a single session of PTCS. Therefore, one goal of t h e c u r r e n t s t u d y was to e s t a b l i s h the n u m b e r of biopsies t h a t should be taken from the main t u m o r to m a k e the diagnosis of cancer. Sato et al. 6 have reported that the mean sensitivity for detecting bile duct carcinoma in a single biopsy specimen is 74%, and recommend that multiple biopsies be obtained. The mean number of specimens obtained in their study was 2.4, which improved the sensitivity to 96%. These results are similar to ours. The sensitivity of the first biopsy for bile duct cancer was 71% (25 of 35), whereas the overall sensitivity for the bile duct carcinoma was 97% (34 of 35). In previous studies, the sensitivity of fluoroscopically directed biopsies obtained via the t r a n s p a p i l l a r y route during ERCP in patients with bile duct carci-
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noma was 80% to 88%. 13-15 We found the sensitivity of biopsy in the diagnosis of metastatic bile duct cancer (pancreatic, gallbladder, and gastric cancer) was low, as has been reported previously. 1-5 B a s e d on this study, we propose the following guidelines for obtaining biopsies by means of PTCS: 1. When cholangiography shows a polypoid tumor, two target biopsies should be obtained from the mass. Then, mapping biopsies should be taken to define the surgical margin. 2. In patients with bile duct cancer of the stenotic type, in whom cholangioscopy shows a tortuous, dilated t u m o r vessel, 1-7 two biopsies should be obtained from the margin of the stenosis rather than the stenosis; the dilated vessel is used as a landmark for the biopsies. This approach is similar to t h a t used for obtaining gastric biopsies, in which the specimen is taken from the margin of the tumor rather than within the base of the ulcer. 3. In patients with bile duct cancer, stenotic type, in whom cholangioscopy does not show a dilated vessel, three biopsies should be obtained at the margin of the stenosis. In one of our patients, cancer cells were present only in one small area at the
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margin of the stenosis. This case emphasizes the importance of obtaining multiple biopsies from the circumference of the margin of the stenotic area. This can only be accomplished under direct vision using PTCS. Fluoroscopically guided bile duct biopsies obtained via the transpapillary route 13-15 or the transhepatic route 16-18 are inadequate for this purpose. 4. In patients with metastatic bile duct cancer, biopsies should be obtained from within the area of stenosis as well as at the margin of the stenosis. In patients with pancreatic cancer, when the cancer cells are not exposed to the lumen of the bile duct, this method is ineffective. Fluoroscopy is necessary to obtain specimens from different depths within the stenosis. PTCS in the diagnosis of pancreatic cancer has less value than in the diagnosis of cholangiocarcinoma. In this study, longitudinal cancer extension along the bile duct was not found in association with pancreatic cancer. Therefore, mapping biopsies are unnecessary. In previous reports, the sensitivity of fluoroscopically directed biopsies obtained via the transpapillary route in patients with pancreatic carcinoma was reported to be 71%.15,16 This procedure, rather than PTCS, should be used in patients in whom there is a suspicion of pancreatic carcinoma. Since 1996, only two patients with pancreatic cancer have been enrolled in this study. These two patients initially were thought to have bile duct cancer because they had a normal pancreatic duct on endoscopic retrograde pancreatography.
3. Nimura Y Staging of biliary carcinoma: cholangiography and cholangioscopy. Endoscopy 1993;25:76-80. 4. Nimura Y, Kamiya J. Cholangioscopy. Endoscopy 1996;28: 138-46. 5. Nimura Y. Cholangioscopy. Endoscopy 1998;30:182-8. 6. Sato M, Inoue H, Ogawa S, Ohashi S, Maetani I, Igarashi Y, et al. Limitation of percutaneous transhepatic cholangioscopy for the diagnosis of the intramural extension of bile duct carcinoma. Endoscopy 1998;30:281-8. 7. Sato M, Maetani I, Ohashi S. Relationship between percutaneous transhepatic cholangioscopy (PTCS) findings and pattern of carcinomatous spread in the bile duct. Diagn Ther Endosc 1994;1:45-50. 8. Neuhause H. Cholangioscopy. Endoscopy 1994;26:120-5. 9. Ponchon T, Genin G, Mitchell R, Henry L, Bory RM, Bodnar D, et al. Methods, indications, and results of percutaneous choledochoscopy, a series of 161 procedures. Ann Surg 1996; 223:26-36. 10. Tamada K, Ueno N, Tomiyama T, Oohashi A, Wada S, Nishizono T, et al. Characterization of biliary strictures using intraductal ultrasonography: comparison with percutaneous cholangioscopic biopsy. Gastrointest Endosc 1998;47:341-9. 11. Tamada K, Ido K, Ueno N, Ichiyama M, Tomiyama T, Kimura K. Preoperative staging of extrahepatic bile duct cancer with intraductal ultrasonography. Am J Gastroenterol 1995;90: 239-46. 12. Tamada K, u Y, Nagai H, Tomiyama T, Tano S, Kanai N, et al. Limitation of cholangiography in assessing longitudinal spread of extrahepatic bile duct carcinoma to the hepatic side. J Gastroenterol Hepatol 1999;14:691-8. 13. Sugiyama M, Atomi Y, Wada N, Kubota A, Muto T. Endoscopic transpapillary bile duct biopsy without sphincterotomy for diagnosing biliary strictures: a prospective comparative study with bile and brush cytology. Am J Gastroenterol 1996;91: 465-7. 14. Kubota Y, Takaoka M, Tani K, Ognra M, Kin H, Fujimura K, et al. Endoscopic transpapiltary biopsy for diagnosis of patients with pancreaticobiliary ductal strictures. Am J Gastroenterol 1993;88:1700-4. 15. Rustgi AK, Keisey PB, Guelrud M, Saini S, Schapiro RH. Malignant tumors of the bile ducts: Diagnosis by biopsy during endoscopic cannulation. Gastrointest Endosc 1989;35:248-51. 16. Tsai CC, Mo LR, Chou CY, Han SJ, Lin RC, Kuo JY, et al. Percutaneous transhepatic transluminal forceps biopsy in obstructive jaundice. Hepatogastroenterology 1997;44:770-3. 17. Savader SJ, Prescott CA, Lund GB, Osterman FA. Intraductal biliary biopsy: comparison of three techniques. JVIR 1996;7: 743-50. 18. Schechter MS, Doemeny JM, Johnson JO. Biliary ductal shave biopsy with the use of the Simpson atherectomy catheter. JVIR 1993;4:819-24.
In conclusion, the numbers and locations of the biopsies required to make a diagnosis depend on the origin and endoscopic findings of the tumor. REFERENCES 1. Nimura Y, Shionoya S, Hayakawa N, Komiya J, Kondo S, Yasui A. Value of percutaneous transhepatic cholangioscopy (PTCS). Surg Endosc 1988;2:213-9. 2. Nimura Y, Kamiya J, Hayakawa N, Shionoya S. Cholangioscopic differentiation of biliary strictures and polyps. Endoscopy 1989; 21:351-6.
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Between June 1989 and September 1998, a total of 82 patients with biliary tract malignancy underwent PTCS. Of these, 52 (28 men, 24 women) with an average age of 65.7 years (range 36 to 88 years) were enrolled in this prospective study. Diagnoses included bile duct cancer (n = 34), Received October 26, 1998. For revision February 4, 1999. Accepted June 23, 1999. From the Departments of Gastroenterology and Pathology, Jichi Medical School, Yakushiji, Tochigi, Japan. Reprint Requests: Kiichi Tamada, MD, Department of Gastroenterology, Jichi Medical School Yakushiji, Tochigi 3290498, Japan; fax: 81-285-44-8297. Copyright 9 1999 by the American Society for Gastrointestinal Endoscopy 0016-5107/99/$8.00 + 0 37/1/100922 VOLUME 50, NO. 5, 1999
gallbladder cancer (n = 6), pancreatic cancer (n = 5), a tumor of the major duodenal papilla (n = 4), or gastric cancer invading the bile duct (n = 3). Surgical resection was performed in 37 patients. Written informed consent was obtained from all patients before percutaneous transhepatic biliary drainage (PTBD), dilatation of the sinus tract, and PTCS. All procedures were conducted under intravenous conscious sedation (10 mg of diazepam and 15 mg of pentazocine). After performing PTBD, the percutaneous tract was dilated to 5.3 mm using a coaxial dilatation catheter (Cook Co., Ltd., Bloomington, Ind.). After 6 to 10 days, a cholangioscope (CHF-P10, CHFQ10, or BF-P200, Olympus Optical Co., Ltd., Tokyo, Japan; or ECN-1530, Pentax Co., Ltd., Tokyo, Japan) was inserted into the bile duct through the established tract using a 16F or 18F peel-away sheath (Cook). A security guidewire was advanced to the fourth portion of the duodenum through the papilla. Biopsies were performed using forceps with serrated cups without a central needle (FB-52C-1, Olympus; or Radial Jaw 3, Boston Co., Ltd., Watertown, Mass.) or forceps with nonserrated cups without a needle (FB-19SW, Olympus). All forceps were 1.8 mm diameter and could be rotated. During the biopsy procedure, the bile duct was irrigated with normal saline mixed with 0.1% noradrenaline to control bleeding. Study design
Patients who required a target biopsy for initial diagnosis or preoperative mapping biopsies by means of PTCS GASTROINTESTINAL ENDOSCOPY
653
K Tamada, K Kurihara, T Tomiyama, et al.
Bile duct biopsy using percutaneous transhepatic cholangioscopy
Figure 1. Endoscopy and pathology in 59-year-old man with cancer of the intrapancreatic bile duct. A, Cholangioscopy showing a small polypoid tumor at the intrapancreatic bile duct. B, Photomicrograph of the resection specimen (H&E, orig. mag, xl) showing cancer cells throughout the bile duct mucosa. C, Photomicrograph of a biopsy specimen taken from the polypoid tumor (H&E, orig. mag. xl0) showing the mucosa with adenocarcinoma. were enrolled in this study. During PTCS, the first author recorded the endoscopic findings at each position where a biopsy was obtained, and the biopsy specimens were numbered for later reference. Subjects whose endoscopic findings were not recorded in detail were excluded from data analysis. When cholangiography revealed a unilateral polypoid tumor, three biopsy specimens were obtained at slightly different locations from the mass itself. When the stenosis was symmetrical and no discrete mass was apparent, three biopsies were obtained at the margin of the stenosis and three biopsies were obtained within the stenotic region at different depths. When the endoscopy revealed a tortuous, dilated vessel (tumor vessel) at the margin of the stenosis, the first biopsy was obtained at the vessel site. The second and third biopsies were obtained in neighboring regions. The biopsy specimens were fixed with 10% formalin, stained with H&E, and evaluated by two experienced pathologists. The surgical specimens were fixed with 10% formalin, and the bile ducts were cut transversely into 3 m m slices. Each slice was sectioned, stained with H&E, and analyzed by two experienced pathologists. Correspondence between the surgical resection specimens and the biopsy specimens was confirmed by the pathologist (I~IC) and endoscopist (I~T.). The data were analyzed using Fisher's exact test. A p value < 0.05 was considered significant. 654
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RESULTS Complications The two patients who suffered dislodgement of the catheter after PTBD were successfully treated by a second drainage procedure. Another patient developed acute cholecystitis after the 16F PTCS catheter was advanced into the distal bile duct across the cystic duct. This was successfully treated by percutaneous transhepatic gallbladder drainage. Although intrabiliary bleeding occurred after dilatation of the tract in one patient, it resolved without the need for transfusion or transarterial embolization. None of the patients s u f f e r e d a d i r e c t c o m p l i c a t i o n of P T C S a n d b i o p s y s u c h as p e r f o r a t i o n of t h e s i n u s t r a c t or h e m a t o bilia. O o z i n g f r o m t h e b i l e d u c t w a l l w a s w e l l c o n t r o l l e d in all p a t i e n t s b y i r r i g a t i o n w i t h t h e noradrenaline solution. The overall procedurer e l a t e d m o r b i d i t y a n d m o r t a l i t y r a t e s w e r e 8% (4 of 52) a n d 0% (0 of 52), r e s p e c t i v e l y .
Sensitivity of biopsy, polypoid tumor C h o l a n g i o g r a p h y d e m o n s t r a t e d a polypoid t u m o r VOLUME 50, NO. 5, 1999
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K Tamada, K Kurihara, T Tomiyama, et al.
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A
Figure 2. Endoscopy and pathology in 66year-old woman with cancer of the midportion of the bile duct. A, Cholangioscopy showing a tortuous, dilated vessel at the margin of a stenosis. Photomicrographs of the resection specimen (H&E, orig. mag. x l ) showing the bile duct mucosa and the submucosal tissue containing cancer cells (arrowheads) at the margin of the stenotic area (B), 3 mm within the stenotic area (C), and 6 mm proximal to the margin of the stenosJs (D). E, Photomicrograph of a biopsy specimen taken from the position of the dilated vessel (H&E, orig. mag. x4) showing the submucosal tissue with adenocarcinoma. Table 1. Accuracy of biopsies under percutaneous transhepatic cholangioscopy in the diagnosis of cancer (n = 52)
Table 2. Accuracy of biopsy according to the numbers of biopsies in patients with a unilateral polypoid tumor of the bile duct
Diagnostic rate Tumor at the major papilla Bile duct cancer, polypoid type Bile duct cancer, stenotic type Pancreatic cancer Gallbladder cancer Gastric cancer
4/4 (100%) 15/15 (100%) 18/19 (95%) 315 (60%) 4/6 (67%) 1/3 (33%)
in four patients who had a mass involving the major papilla, and in 15 patients with bile duct cancer. Cancer was identified in two biopsy specimens t a k e n from the polypoid t u m o r in all 19 patients (Tables 1 and 2, Fig. 1). Among the 14 patients who u n d e r w e n t surgical resection, histologic examination revealed papillary adenocarcinoma in 10 patients and well-differentiated tubular adenocarcinoma in the remaining four patients.
Sensitivity of biopsy, stenotic type bile duct cancer Cholangioscopy showed a tortuous, dilated vessel in 10 patients with bile duct cancer of the stenotic type. In VOLUME 50, NO. 5, 1999
No. of biopsies 1 2
Tumor at the major papilla Papillary
WDA
Bile duct cancer Papillary
WDA
2/2 (100%) 1/2 (50%) 11/12 (92%) 2/3 (67%) 2/2 (100%) 2/2 (100%) 12/12 (100%) 3/3 (100%)
Papillary, Papillary adenocarcinoma; WDA, well-differentiated tubular adenocarcinoma.
all cases, the diagnosis of cancer was made on two biopsy specimens taken from the margin of the stenotic area (Tables 1 and 3). Surgical resection was performed in eight of 10 patients. All of the surgical specimens contained tubular adenocarcinoma. The sensitivity of biopsies taken from the margin of the stenotic area was better than that of biopsies taken from within the area of stenosis (p < 0.01) (Table 3, Fig. 2). No dilated vessel was observed on cholangioscopy in nine patients with bile duct cancer of the stenotic type. Cancer was present within three biopsies taken from the margin of the stenosis in 89% of these cases (Tables 1 and 3). Surgical resection was performed in GASTROINTESTINAL ENDOSCOPY
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Figure 3. Endoscopy and pathology in 54year-old man with cancer of the intrapancreatic bile duct. A, Cholangioscopy showing a stenosis without a dilated vessel. B, Photomicrograph of the resection specimen (H&E, orig. mag. x l ) showing cancer cells in a small part of the bile duct mucosa and the submucosal tissue (arrowheads) at the margin of the stenosis. C, The cells were not exposed to the lumen of the bile duct within the area of stenosis. Photomicrograph of a biopsy specimen (H&E, orig. mag. x4) taken from the margin of the stenotic area (D), and within the stenosis (E) showing no cancer cell in either mucosal or submucosal tissue. Table 3. Accuracy of biopsy according to the presence of the tortuous, dilated vessel as a cholangioscopic finding in patients with bile duct carcinoma of the stenotic type Cholangioscopic findings No. of biopsies 1 2 3
With dilated vessel Margin
Within
8/10 (80%) 5/10 (50%) 10110 (100%) 7/10 (70%) 10/10 (100%) 7/10 (70%)
Without dilated vessel Margin
Within
3/9 (33%) 2/9 (22%) 5/9 (56%) 5/9 (56%) 8/9 (89%) 5/9 (56%)
Margin, Margin of stenotic area; Within, within the area of stenosis.
eight of these nine patients, and all resection specimens contained t u b u l a r adenocarcinoma. In one patient, cancer was not found in any of four biopsy specimens taken from the margin of the stenosis or in six biopsy specimens taken from within the stenotic area (Fig. 3). In this patient, histologic examination of the surgical specimen revealed cancer cells in a small area at the margin of the area of stenosis.
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Sensitivity of biopsy, metastatic bile duct cancer In the patients with metastatic bile duct tumors (six gallbladder, five pancreatic, and three gastric), cancer was detected within three biopsy specimens taken from the margin of the stenosis in 43% of cases. When these data were combined with data from three biopsy specimens taken from within the stenosis, the sensitivity in the patients with pancreatic cancer improved from 20% to 60% (Table 1, Fig. 4).
DISCUSSION Bile duct b i o p s y u n d e r P T C S is an excellent m o d a l i t y to d i s t i n g u i s h b e t w e e n m a l i g n a n t and benign bile duct stenoses. 1-1~ We have previously reported t h a t target biopsy u n d e r PTCS is useful in avoiding u n n e c e s s a r y s u r g e r y b e c a u s e m o s t p a t i e n t s w i t h benign bile duct stenosis can be t r e a t e d with interventional radiologic procedures, such as d i l a t a t i o n u s i n g a coaxial c a t h e t e r and t e m p o r a r y p l a c e m e n t of a 16F plastic endoprostheses. 10 O t h e r s also h a v e r e p o r t e d t h e u t i l i t y of PTCS for this purpose. 1-5 PTCS is essential for
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Bile duct biopsy using percutaneous transhepatic cholangioscopy
K Tamada, K Kurihara, T Tomiyama, et al.
Figure 4. Endoscopy and pathology in 70-year-old woman with cancer of the pancreas. A, Cholangioscopy showing a stenosis without a dilated vessel. B, Photomicrograph of the resection specimen (H&E, orig. mag • showing no cancer cell in either the bile duct mucosa or the submucosal tissue at the margin of the stenosis. C, Cancer cells in a small part of the deep portion of the submucosal tissue within the stenotic area (arrowhead). D, Histologic examination of a biopsy specimen (H&E, orig. mag. • taken from the margin of the stenotic area showing no cancer cell. E, Photomicrograph of a biopsy specimen (H&E, orig. mag. x20) taken from within the stenosis showing cancer cells in submucosal tissue
(arrowheads). mapping biopsies to determine longitudinal cancer e x t e n s i o n along the bile duct.l-7,11 Cholangiocarcinoma often extends along the bile duct, and cholangiography cannot adequately determine the e x t e n t of local invasion.l-7,11,12 Therefore, t h e n u m b e r of t a r g e t biopsies t a k e n from t h e m a i n t u m o r should be minimized because multiple mapping biopsies m u s t be obtained to determine the surgical margin within a single session of PTCS. Therefore, one goal of t h e c u r r e n t s t u d y was to e s t a b l i s h the n u m b e r of biopsies t h a t should be taken from the main t u m o r to m a k e the diagnosis of cancer. Sato et al. 6 have reported that the mean sensitivity for detecting bile duct carcinoma in a single biopsy specimen is 74%, and recommend that multiple biopsies be obtained. The mean number of specimens obtained in their study was 2.4, which improved the sensitivity to 96%. These results are similar to ours. The sensitivity of the first biopsy for bile duct cancer was 71% (25 of 35), whereas the overall sensitivity for the bile duct carcinoma was 97% (34 of 35). In previous studies, the sensitivity of fluoroscopically directed biopsies obtained via the t r a n s p a p i l l a r y route during ERCP in patients with bile duct carci-
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noma was 80% to 88%. 13-15 We found the sensitivity of biopsy in the diagnosis of metastatic bile duct cancer (pancreatic, gallbladder, and gastric cancer) was low, as has been reported previously. 1-5 B a s e d on this study, we propose the following guidelines for obtaining biopsies by means of PTCS: 1. When cholangiography shows a polypoid tumor, two target biopsies should be obtained from the mass. Then, mapping biopsies should be taken to define the surgical margin. 2. In patients with bile duct cancer of the stenotic type, in whom cholangioscopy shows a tortuous, dilated t u m o r vessel, 1-7 two biopsies should be obtained from the margin of the stenosis rather than the stenosis; the dilated vessel is used as a landmark for the biopsies. This approach is similar to t h a t used for obtaining gastric biopsies, in which the specimen is taken from the margin of the tumor rather than within the base of the ulcer. 3. In patients with bile duct cancer, stenotic type, in whom cholangioscopy does not show a dilated vessel, three biopsies should be obtained at the margin of the stenosis. In one of our patients, cancer cells were present only in one small area at the
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margin of the stenosis. This case emphasizes the importance of obtaining multiple biopsies from the circumference of the margin of the stenotic area. This can only be accomplished under direct vision using PTCS. Fluoroscopically guided bile duct biopsies obtained via the transpapillary route 13-15 or the transhepatic route 16-18 are inadequate for this purpose. 4. In patients with metastatic bile duct cancer, biopsies should be obtained from within the area of stenosis as well as at the margin of the stenosis. In patients with pancreatic cancer, when the cancer cells are not exposed to the lumen of the bile duct, this method is ineffective. Fluoroscopy is necessary to obtain specimens from different depths within the stenosis. PTCS in the diagnosis of pancreatic cancer has less value than in the diagnosis of cholangiocarcinoma. In this study, longitudinal cancer extension along the bile duct was not found in association with pancreatic cancer. Therefore, mapping biopsies are unnecessary. In previous reports, the sensitivity of fluoroscopically directed biopsies obtained via the transpapillary route in patients with pancreatic carcinoma was reported to be 71%.15,16 This procedure, rather than PTCS, should be used in patients in whom there is a suspicion of pancreatic carcinoma. Since 1996, only two patients with pancreatic cancer have been enrolled in this study. These two patients initially were thought to have bile duct cancer because they had a normal pancreatic duct on endoscopic retrograde pancreatography.
3. Nimura Y Staging of biliary carcinoma: cholangiography and cholangioscopy. Endoscopy 1993;25:76-80. 4. Nimura Y, Kamiya J. Cholangioscopy. Endoscopy 1996;28: 138-46. 5. Nimura Y. Cholangioscopy. Endoscopy 1998;30:182-8. 6. Sato M, Inoue H, Ogawa S, Ohashi S, Maetani I, Igarashi Y, et al. Limitation of percutaneous transhepatic cholangioscopy for the diagnosis of the intramural extension of bile duct carcinoma. Endoscopy 1998;30:281-8. 7. Sato M, Maetani I, Ohashi S. Relationship between percutaneous transhepatic cholangioscopy (PTCS) findings and pattern of carcinomatous spread in the bile duct. Diagn Ther Endosc 1994;1:45-50. 8. Neuhause H. Cholangioscopy. Endoscopy 1994;26:120-5. 9. Ponchon T, Genin G, Mitchell R, Henry L, Bory RM, Bodnar D, et al. Methods, indications, and results of percutaneous choledochoscopy, a series of 161 procedures. Ann Surg 1996; 223:26-36. 10. Tamada K, Ueno N, Tomiyama T, Oohashi A, Wada S, Nishizono T, et al. Characterization of biliary strictures using intraductal ultrasonography: comparison with percutaneous cholangioscopic biopsy. Gastrointest Endosc 1998;47:341-9. 11. Tamada K, Ido K, Ueno N, Ichiyama M, Tomiyama T, Kimura K. Preoperative staging of extrahepatic bile duct cancer with intraductal ultrasonography. Am J Gastroenterol 1995;90: 239-46. 12. Tamada K, u Y, Nagai H, Tomiyama T, Tano S, Kanai N, et al. Limitation of cholangiography in assessing longitudinal spread of extrahepatic bile duct carcinoma to the hepatic side. J Gastroenterol Hepatol 1999;14:691-8. 13. Sugiyama M, Atomi Y, Wada N, Kubota A, Muto T. Endoscopic transpapillary bile duct biopsy without sphincterotomy for diagnosing biliary strictures: a prospective comparative study with bile and brush cytology. Am J Gastroenterol 1996;91: 465-7. 14. Kubota Y, Takaoka M, Tani K, Ognra M, Kin H, Fujimura K, et al. Endoscopic transpapiltary biopsy for diagnosis of patients with pancreaticobiliary ductal strictures. Am J Gastroenterol 1993;88:1700-4. 15. Rustgi AK, Keisey PB, Guelrud M, Saini S, Schapiro RH. Malignant tumors of the bile ducts: Diagnosis by biopsy during endoscopic cannulation. Gastrointest Endosc 1989;35:248-51. 16. Tsai CC, Mo LR, Chou CY, Han SJ, Lin RC, Kuo JY, et al. Percutaneous transhepatic transluminal forceps biopsy in obstructive jaundice. Hepatogastroenterology 1997;44:770-3. 17. Savader SJ, Prescott CA, Lund GB, Osterman FA. Intraductal biliary biopsy: comparison of three techniques. JVIR 1996;7: 743-50. 18. Schechter MS, Doemeny JM, Johnson JO. Biliary ductal shave biopsy with the use of the Simpson atherectomy catheter. JVIR 1993;4:819-24.
In conclusion, the numbers and locations of the biopsies required to make a diagnosis depend on the origin and endoscopic findings of the tumor. REFERENCES 1. Nimura Y, Shionoya S, Hayakawa N, Komiya J, Kondo S, Yasui A. Value of percutaneous transhepatic cholangioscopy (PTCS). Surg Endosc 1988;2:213-9. 2. Nimura Y, Kamiya J, Hayakawa N, Shionoya S. Cholangioscopic differentiation of biliary strictures and polyps. Endoscopy 1989; 21:351-6.
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