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Placement of Covered Self-Expanding Metallic Stents in the Common Bile Duct: A Feasibility Study
Placement of Covered Self-ExpandingMetallic Stents in the Common Bile Duct: A Feasibility Study1 Kotaro Yasumori, MD2 Nagui Mahmoudi, MD Kenneth C. Wright, PhD Sidney Wallace, MD Cesare Gianturco, MD
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Index terms: Bile ducts, neoplasms, 76.32 Bile ducts, prostheses, 766.1268, 766.1299 Bile ducts, stenosis or obstruction, 766.32 Stents and prostheses, 76.1229
JVIR 1993;4:773-778 Abbreviations: PCL = polycaprolactone, SPP = segmented polyether polyurethane
From the Department of Diagnostic RadiUniversity of Texas M.D. Anderson Cancer Center, 1515 Holcombe B I V ~B~~ , 057, Houston, TX 77030. Received May 12, lgg3; revision requested May 20; revision received June 7; accepted June 21. Supported in part by grants from the John S. Dunn Research Foundation and the George A. Cook Memorial Fund and by grant NIHNCIC.4-16672 fromthe National Cancer Institute. Address reprint requests to K.C.W. 2 current address: Department ofRadiology, Faculty of Medicine, K ~ U SUniver~U sity, Fukuoka 812, Japan. SCVIR, 1993
PURPOSE: Gianturco self-expandingmetallic stents have been useful in cases of benign biliary stenoses; however, the stents have not worked well in the presence of intraluminal tumor because of tumor growth between the wire struts. Stents were covered with polymeric membranes, which may prevent tumor ingrowth, and the feasibility of using these covered stents in the common bile duct was studied in healthy adult dogs. MATERIALS AND METHODS: Initially, stents (10 x 6 mm) covered with polycaprolactone (PCL),segmented polyether polyurethane (SPP),and silicone were placed in the common bile duct of dogs and were followed up for 3-12 months. Subsequently, four types of modified silicone-covered stents were evaluated. Rough-surface,small-diameter (3-mm),halfcovered, and tapered stents were placed and followed up for 3 months. RESULTS: In the initial study, the SPP and silicone membranes remained intact, but the PCL covering broke in all dogs. In all but two dogs, luminal narrowing caused by varying degrees of papillary mucosal hyperplasia at both ends of the stent was observed. In the subsequent study, mucosal hyperplasia was considerably reduced by using half-covered stents and was virtually eliminated with tapered stents. All smalldiameter stents migrated into the bowel. CONCLUSION: These studies suggest that tapered Gianturco self-expanding stents covered with silicone may be useful in the biliary tract in cases of intraluminal tumor.
SELF-EXPANDING metallic stents have been successfully applied in the treatment of benign bile duct strictures (1-3). But tumor ingrowth into the stent lumen, which causes restenosis or obstruction, has been reported in malignant stenoses caused by the presence of intraluminal tumor (1,2,4-8). To prevent tumor growth through the gaps between the wire framework of the stent, Gianturco self-expanding stents were covered with polymeric membranes. These stents were evaluated in the common bile duct of healthy dogs with regard to dilatation, stability, membrane durability, patency, and biocompatibility. The study was divided into two parts: first, the evaluation of three different polymeric materials as stent covers; and second, the evaluation of modified silicone-covered stents.
MATERIALS AND METHODS Part I: Stents Stents were constructed of 0.010inch stainless steel wire formed into a cylindrical zigzag configuration with five bends at each end. The stents were 10 mm in length and 8 mm in fully expanded diameter. They were then covered with one of three polymeric compounds: polycaprolactone (PCL) (Polysciences, Warrington, Pa), segmented polyether polyurethane (SPP) (Ethicon, Somerville, NJ), or silicone (Dow Corning, Midland, Mich). When covered, the stents were 5-6 mm in fully expanded diameter (Fig 1). Part I: Animal Studies All experimentation involving animals was approved by the Institu-
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tional Animal Care and Use Committee. Animals were maintained in facilities approved by the American Association for Accreditation of Laboratory Animal Care and in accordance with current U.S. Department of Agriculture, Department of Health and Human Services, and National Institutes of Health regulations and standards. Eighteen adult mongrel dogs (20-30 kg) were used. Anesthesia was induced with intravenous thiopental sodium (18 mglkg) and maintained with halothane (1.5%),nitrous oxide (0.3 Ltmin), and oxygen (0.8 Llmin). A systemic blood sample was drawn for baseline hepatic and renal function tests. A laparotomy was performed, the gallbladder was isolated and punctured with a 16-gauge intravenous Catholon needle (Critikon, Tampa, Fla), and a cholangiogram was obtained. A 0.038-inch wire guide was inserted through the needle and into the duodenum via the common bile duct. The needle was then exchanged for a 10-F Teflon catheter system (Cook, Bloomington, Ind) that was advanced over the wire into the common bile duct under fluoroscopic guidance. A covered stent was pushed through the catheter and released in the bile duct. The catheter was withdrawn, and a postdeployment cholangiogram was obtained. The catheter was removed, the gallbladder puncture site was closed with a pursestring " suture. and the abdominal incision was closed in layers. Postprocedural abdominal radiographs were obtained. s collected to Blood s a m ~ l e were check hepati; and renal function, and abdominal plain radiographs were obtained at 1week and then monthly after stent placement. The stent diameter and position were checked on the plain radiographs. Seven dogs (three with PCL-covered stents, one with an SPP-covered stent, and three with silicone-covered stents), eight dogs (three with PCLcovered, two with SPP-covered, and three with silicone-covered stents), and three dogs with SPP-covered
stents were killed 3,6, and 12 months after stent placement, respectively. Abdominal radiographs and direct cholangiograms were obtained before death to document stent position, stent diameter, and the luminal appearance and patency of the common bile duct. A complete necropsy was performed, and the liver, gallbladder, common bile duct, and duodenum were excised en bloc. The common bile duct was opened longitudinally, and the ductal mucosa and stent were examined grossly. Samples of the common bile duct wall above, below, and within the stented segment were obtained for histologic evaluation.
Part 11: Stents Four types of modified siliconecovered Gianturco self-expanding stents were used (Fig 1). These included stents 6 mm in diameter with the exterior membrane surface roughened, small-diameter (3-mm) stents, stents constructed in a tapered shape with a diameter of 6 mm in the center and 3.5 mm at each end, and stents 6 mm in diameter with only their midportion covered. All stents were 10 mm long, constructed of 0.010-inch stainless steel wire, and contained five bends at each end. Part 11: Animal Studies Four rough-surface stents and three half-covered stents were placed in three dogs each, while four smalldiameter and four tapered stents were placed in two dogs each. Anesthesia, stent placement, and follow-up examinations were performed in the same manner as described in part I. All dogs were killed 3 months after stent placement. RESULTS Part I All dogs tolerated the procedures well, and no clinical symptoms such as jaundice were noted during followup. Serum alkaline phosphatase levels were elevated in all dogs 1week after stent placement, but these lev-
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Figure 1. Photograph of the covered
stents used in this study. Stents in the left column were used in part I and were covered with PCL (top),SPP (middle), and silicone (bottom).The silicone-covered stents shown in the right column were used in part I1 and are small diameter (top),half-covered (middle),and tapered (bottom).
els never exceeded normal limits and returned to baseline by 1month. All other results of hepatic and renal function tests were normal. One dog with a silicone-covered stent died of causes unrelated to the stent 3 days before the 6-month follow-up. Radiographically, the stents reached 25%-92% of their fully expanded diameter immediately after placement, and 100% expansion was seen on all images obtained at 1 week. This diameter was maintained during the remaining follow-up period in all dogs except one. In one dog, the stent diameter was larger on the 4-month image because the PCL covering had broken. No stent migration was seen. Cholangiograms obtained at the time the animals were killed showed localized dilatation of the common bile duct within segments in which the stents were placed. No change in the luminal appearance of the bile
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a. b. Figure 2. Cholangiograms obtained 6 months after placement of stents covered with (a)SPP and (b)silicone. Luminal narrowing is seen at both ends of the stents. Note that the narrowing associated with the silicone-covered stent appears less severe than that associated with the stent covered with SPP.
Figure 3. Crosssectional photomicrograph of common bile duct bridged by silicone-covered stent shown in Figure 2b a t 6 months after stent placement. The epithelium appears flattened or cuboidal, and the perimucosal connective tissue is stretched. (Hematoxylin-eosin stain; original magnification, x 5.)
duct was seen in two dogs, one with a SPP-covered stent followed up for 6 months and one with a silicone-covered stent that died 3 days before the 6-month follow-up of causes unrelated to the stent. In the remaining 16 animals, filling defects and luminal narrowing of varying degrees were noted at both ends of the covered stents (Fig 2) on all follow-up cholangiograms. Stenoses associated with the silicone cover appeared less severe than those associated with the other polymers. With regard to each
polymeric covering, some difference was noted in the degree of stenosis seen at 3 months and that seen at 6 and 12 months. At necropsy, the stented portions of the common bile duct were dilated, but no other abnormality was noted on the external surface of the duct. When the duct was opened, no concretions were found in any of the dogs. All silicone-covered and SPPcovered stents were intact. The mucosal surface beneath these polymeric covers was flat and smooth. All PCL
coverings were found to have separated from the stent wire at some point on the framework. Mild mucosal proliferation was seen in association with the break in the stent cover. In all but the two dogs in which no cholangiographic luminal changes were seen, small villouslike projections arose from the mucosal surface of the bile duct at the proximal and distal ends of the stents. These projections were coincident with the filling defects seen on the cholangiograms. Some projections were pedunculated, while others appeared sessile. They exhibited a cauliflowerlike appearance with a fine granular surface. Microscopically, the epithelium beneath the stent appeared cuboidal or flattened. Perimucosal connective tissue was stretched, with minimal inflammatory cell infiltration (Fig 3). The villouslike projections were found to be fibrovascular stalks lined by tall columnar epithelium arising from the mucosal surface and extending outward into the lumen of the bile duct (Fig 4). These findings are compatible with mucosal hyperplasia. The histologic changes associated with each of the three polymeric coverings were similar.
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a. b. Figure 4. Cross-sectionalphotomicrographsof common bile duct at distal end of covered stents show severe mucosal hyperplasia
composed of fibrovascular stalks lined by tall columnar epithelium arising from the mucosal surface and extending into the ductal lumen. (a)Bile duct shown in Figure 2a 6 months after placement of the SPP-covered stent. (b) Bile duct shown in Figure 2b at 6 months after placement of silicone-coveredstent. Note mucosal reaction associated with silicone covering appears less severe than that associated with SPP. (Hematoxylin-eosinstain; original magnification, ~ 5 . )
Part I1 All dogs tolerated the procedures well, and clinical results were the same as those for the dogs in part I. In two dogs with one rough-surface stent each, moderate stenoses caused by mucosal hyperplasia were seen cholangiographically at each end of the stents. In the other dog with two stents of this type, moderate stenoses developed at the ends of the distal stent, but no stenosis was found at either end of the proximal stent. This observation was confirmed at necropsy. None of the small-diameter stents were found on any of the plain radiographs obtained 1week after stent placement. All had migrated into the duodenum and were passed in the stool. All three dogs with half-covered stents showed minimal stenoses of the common bile duct on the follow-up cholangiograms (Fig 5a). These lesions were less prominent than those associated with stents fully covered by silicone (Fig 2b). Microscopically, moderate mucosal hyperplasia was noted at the ends of the stent covering (Fig 5b). In both dogs with tapered stents,
no stenoses were seen at the ends of the stents on the follow-up cholangiograms (Fig 6a). Mild mucosal hyperplasia, which was less pronounced than that seen with the half-covered straight stents, was observed microscopically (Fig 6b).
DISCUSSION Since the initial experimental evaluation of self-expanding metallic stents in the bile duct by Carrasco et al(9), many reports have been published on use of the stents to treat obstructive jaundice (1,2,4-8). Relatively good results have been reported in cases of benign strictures, but the results in cases of malignant strictures are not encouraging. In these cases, recurrent jaundice is routine because of tumor growth between the wire struts of the stent, tumor growth around the distal and/or proximal ends of the stent, sludge within the stent associated with cholangitis, and occasionally mucosal hyperplasia in the stented segment (1,2,4-8).
Since the Gianturco self-expanding stent is composed of widely spaced stainless steel struts, tumors can easily grow through the gaps between the wire struts. Because this ingrowth could be prevented by the presence of an impermeable membrane, we covered the stents with a thin polymeric sleeve. A report concerning polymer-coated balloon-expandable stents has been published (lo),but to our knowledge, the use of covered self-expanding stents has not been reported. Covered metallic stents have some advantages over conventional plastic endoprostheses. They can be delivered through relatively smaller caliber catheters, which may be less traumatic and may decrease the chance of bile leakage and pain caused by manipulation. These stents achieve a large luminal diameter, which reduces encrustation and keeps the stent patent (11). We used three biocompatible polymers as covering materials. PCL was easy to use, but it was found to be fragile and therefore not considered suitable as a cover. SPP has a low
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6a. 6b. Figures 5,6. (5) Follow-up images obtained 3 months after placement of stent half covered with silicone. (a)Cholangiogram shows minimal luminal narrowing at both ends of stent covering (arrows). (b) Cross-sectional photomicrograph of common bile duct at proximal end of stent covering shows moderate mucosal hyperplasia. (Hematoxylin-eosin stain; original magnification, x 5.) ( 6 ) Follow-up images obtained 3 months after placement of two tapered stents fully covered with silicone. (a) Cholangiogram shows no luminal narrowing associated with either stent (arrows). (b) Cross-sectional photomicrograph of common bile duct at proximal end of proximal stent shows mild mucosal hyperplasia. (Hematoxylin-eosin stain; original magnification, x 5.)
coefficient of friction, and it was found to be durable, as was silicone. The elevated serum alkaline phosphatase levels seen in all dogs at 1 week were probably caused by biliary trauma associated with the catheterization procedure. The bile duct wall of the stented segment showed smooth focal dilatation, and only minimal changes were seen in the wall beneath the stent. These results
suggested that SPP and silicone possess the durability and biocompatibility needed for a biliary stent covering. Since we have found that the luminal diameter of the common bile duct measured cholangiographically in 20-30-kg dogs is 3-4 mm, a standard stent diameter of 6 mm was chosen in an effort to prevent stent migration. Also, this is the same diameter as that of the covered balloon-ex-
panded stents placed in dogs by Alvarado et a1 (10). Three-millimeter stents were placed in two animals because they approximated the exact diameter of the duct. Development of the papillary mucosal hyperplasia seen at both ends of the stents in this study may be species-specificand/or due to the normal nature of the bile duct wall. Similar hyperplastic changes have been noted
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in dogs following placement of bare self-expanding stents (9) and bare and covered balloon-expanded stents (10). However, recurrent stenosis caused by mucosal hyperplasia is uncommon in clinical practice, possibly because of species specificity or the fact that the stent is in contact with fibrotic or neoplastic tissue. Aside from species specificity, multiple factors are probably responsible for the development of mucosal hyperplasia. These may include, but are not limited to, tension applied to the bile duct mucosa by the stent, compromise of peribiliary blood and lymphatic flow resulting from dilation pressure exerted by the stent, polymer biocompatibility, the surface character of the stent, and trauma a t the time of stent insertion. Although some difference in the degree of stenosis was found associated with the same polymeric covering a t different times, nothing definite can be said about progression of the mucosal hyperplasia because serial cholangiograms were not obtained in any of the dogs during follow-up. However, Alvarado et a1 (10) did report progression of the hyperplastic reaction in their canine study. In an attempt to decrease or prevent the severe mucosal hyperplasia encountered in part I of this study, the silicone-covered stents were modified. Silicone was selected because, cholangiographically and microscopically, changes associated with this polymer cover appeared less severe than those associated with SPP. Rough-surface stents were created to increase the coefficient of friction and prevent any stent movement within the bile duct. However, the ductal changes associated with these stents were similar to those seen in part I. Small-diameter, half-covered, and tapered stents were constructed to decrease the tension and any endrelated mechanical process on the
bile duct wall a t the ends of the stents. All small-diameter stents migrated into the duodenum, indicating that for stability, even covered stents need to be larger than the diameter of the duct. The dogs with half-covered stents exhibited only mild changes cholangiographically and moderate mucosal hyperplasia histologically. The dogs with tapered stents showed no changes cholangiographically and mild mucosal hyperplasia microscopically. These results, as well as those of Alvarado et al (lo), indicate that both tension and mechanical stress on the bile duct wall a t the ends of the stent have some role in the development of mucosal hyperplasia. It is also possible that these modified stents could be associated with a more delayed mucosal reaction. Further investigation is needed to evaluate this possibility. Based on the results of this study, we believe that silicone-covered, selfexpanding stents may be used clinically. However, additional research is needed in tumor-bearing bile ducts to determine whether covered stents stimulate a mucosal hyperplasia in humans. If so, stents tapered at the ends to decrease tension and mechanical stress on the bile duct wall may be useful. Since the cause of mucosal hyperplasia does not seem to be simple, another method, such as that used to suppress intimal hyperplasia in vessels (121, may also be worth evaluating. Acknowledgments: We thank Raquel Collins and Irene Szwarc for technical assistance, Peggy Bergmanson for secretarial help, and Bob Czimmy for photographic expertise. References 1. Coons H. Self-expanding stainless steel biliary stents. Radiology 1989; 170:979-983. 2. Irving JD, Adam A, Dick R, Dondelinger RF, Lunderquist A, Roche A. Gianturco expandable metallic
biliary stents: results of a European clinical trial. Radiology 1989; 172: 321-326. Rossi P, Bezzi M, Salvatori, Maccioni R, Porcaro ML. Recurrent benign biliary strictures: management with self-expanding metallic stents. Radiology 1990; 175:661665. Gillams A, Dick R, Dooley JS, Wallsten H, El-Din A. Self-expandable stainless steel braided endoprosthesis for biliary strictures. Radiology 1990; 174:137-140. Lammer J , Klein GE, Kleinert R, Hausegger K, Einspieler R. Obstructive jaundice: use of expandable metal endoprosthesis for biliary drainage. Radiology 1990; 177:789792. Yoshioka T, Sakaguchi H, Yoshimura H, et al. Expandable metallic biliary endoprostheses: preliminary clinical evaluation. Radiology 1990; 177:253-257. Lameris JS, Stoker J , Nijs HGT, et al. Malignant biliary obstruction: percutaneous use of self-expandable stents. Radiology 1991; 179:703707. Adam A, Chetty N, Roddie M, Yeung E, Benjamin IS. Self-expandable stainless steel endoprostheses for treatment of malignant bile duct obstruction. AJR 1991; 156:321325. Carrasco CH, Wallace S, Charnsangavej C, et al. Expandable biliary endoprosthesis: an experimental study. AJR 1985; 145:1279-1281. Alvarado R, Palmaz JC, Garcia OJ, Tio FO, Rees CR. Evaluation of polymer-coated balloon-expandable stents in bile ducts. Radiology 1989; 170:975-978. Lammer J, Stoffler G, Petek WW, Hofler H. In vitro long-term perfusion of different materials for biliary endoprostheses. Invest Radio1 1986; 21:329-331. Forrester JS, Fishbein M, Helfant R, Fagin J . A paradigm for restenosis based on cell biology: clues for the development of new preventive therapies. J Am Coll Cardiol1991; 17:758-769.
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Index terms: Bile ducts, neoplasms, 76.32 Bile ducts, prostheses, 766.1268, 766.1299 Bile ducts, stenosis or obstruction, 766.32 Stents and prostheses, 76.1229
JVIR 1993;4:773-778 Abbreviations: PCL = polycaprolactone, SPP = segmented polyether polyurethane
From the Department of Diagnostic RadiUniversity of Texas M.D. Anderson Cancer Center, 1515 Holcombe B I V ~B~~ , 057, Houston, TX 77030. Received May 12, lgg3; revision requested May 20; revision received June 7; accepted June 21. Supported in part by grants from the John S. Dunn Research Foundation and the George A. Cook Memorial Fund and by grant NIHNCIC.4-16672 fromthe National Cancer Institute. Address reprint requests to K.C.W. 2 current address: Department ofRadiology, Faculty of Medicine, K ~ U SUniver~U sity, Fukuoka 812, Japan. SCVIR, 1993
PURPOSE: Gianturco self-expandingmetallic stents have been useful in cases of benign biliary stenoses; however, the stents have not worked well in the presence of intraluminal tumor because of tumor growth between the wire struts. Stents were covered with polymeric membranes, which may prevent tumor ingrowth, and the feasibility of using these covered stents in the common bile duct was studied in healthy adult dogs. MATERIALS AND METHODS: Initially, stents (10 x 6 mm) covered with polycaprolactone (PCL),segmented polyether polyurethane (SPP),and silicone were placed in the common bile duct of dogs and were followed up for 3-12 months. Subsequently, four types of modified silicone-covered stents were evaluated. Rough-surface,small-diameter (3-mm),halfcovered, and tapered stents were placed and followed up for 3 months. RESULTS: In the initial study, the SPP and silicone membranes remained intact, but the PCL covering broke in all dogs. In all but two dogs, luminal narrowing caused by varying degrees of papillary mucosal hyperplasia at both ends of the stent was observed. In the subsequent study, mucosal hyperplasia was considerably reduced by using half-covered stents and was virtually eliminated with tapered stents. All smalldiameter stents migrated into the bowel. CONCLUSION: These studies suggest that tapered Gianturco self-expanding stents covered with silicone may be useful in the biliary tract in cases of intraluminal tumor.
SELF-EXPANDING metallic stents have been successfully applied in the treatment of benign bile duct strictures (1-3). But tumor ingrowth into the stent lumen, which causes restenosis or obstruction, has been reported in malignant stenoses caused by the presence of intraluminal tumor (1,2,4-8). To prevent tumor growth through the gaps between the wire framework of the stent, Gianturco self-expanding stents were covered with polymeric membranes. These stents were evaluated in the common bile duct of healthy dogs with regard to dilatation, stability, membrane durability, patency, and biocompatibility. The study was divided into two parts: first, the evaluation of three different polymeric materials as stent covers; and second, the evaluation of modified silicone-covered stents.
MATERIALS AND METHODS Part I: Stents Stents were constructed of 0.010inch stainless steel wire formed into a cylindrical zigzag configuration with five bends at each end. The stents were 10 mm in length and 8 mm in fully expanded diameter. They were then covered with one of three polymeric compounds: polycaprolactone (PCL) (Polysciences, Warrington, Pa), segmented polyether polyurethane (SPP) (Ethicon, Somerville, NJ), or silicone (Dow Corning, Midland, Mich). When covered, the stents were 5-6 mm in fully expanded diameter (Fig 1). Part I: Animal Studies All experimentation involving animals was approved by the Institu-
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tional Animal Care and Use Committee. Animals were maintained in facilities approved by the American Association for Accreditation of Laboratory Animal Care and in accordance with current U.S. Department of Agriculture, Department of Health and Human Services, and National Institutes of Health regulations and standards. Eighteen adult mongrel dogs (20-30 kg) were used. Anesthesia was induced with intravenous thiopental sodium (18 mglkg) and maintained with halothane (1.5%),nitrous oxide (0.3 Ltmin), and oxygen (0.8 Llmin). A systemic blood sample was drawn for baseline hepatic and renal function tests. A laparotomy was performed, the gallbladder was isolated and punctured with a 16-gauge intravenous Catholon needle (Critikon, Tampa, Fla), and a cholangiogram was obtained. A 0.038-inch wire guide was inserted through the needle and into the duodenum via the common bile duct. The needle was then exchanged for a 10-F Teflon catheter system (Cook, Bloomington, Ind) that was advanced over the wire into the common bile duct under fluoroscopic guidance. A covered stent was pushed through the catheter and released in the bile duct. The catheter was withdrawn, and a postdeployment cholangiogram was obtained. The catheter was removed, the gallbladder puncture site was closed with a pursestring " suture. and the abdominal incision was closed in layers. Postprocedural abdominal radiographs were obtained. s collected to Blood s a m ~ l e were check hepati; and renal function, and abdominal plain radiographs were obtained at 1week and then monthly after stent placement. The stent diameter and position were checked on the plain radiographs. Seven dogs (three with PCL-covered stents, one with an SPP-covered stent, and three with silicone-covered stents), eight dogs (three with PCLcovered, two with SPP-covered, and three with silicone-covered stents), and three dogs with SPP-covered
stents were killed 3,6, and 12 months after stent placement, respectively. Abdominal radiographs and direct cholangiograms were obtained before death to document stent position, stent diameter, and the luminal appearance and patency of the common bile duct. A complete necropsy was performed, and the liver, gallbladder, common bile duct, and duodenum were excised en bloc. The common bile duct was opened longitudinally, and the ductal mucosa and stent were examined grossly. Samples of the common bile duct wall above, below, and within the stented segment were obtained for histologic evaluation.
Part 11: Stents Four types of modified siliconecovered Gianturco self-expanding stents were used (Fig 1). These included stents 6 mm in diameter with the exterior membrane surface roughened, small-diameter (3-mm) stents, stents constructed in a tapered shape with a diameter of 6 mm in the center and 3.5 mm at each end, and stents 6 mm in diameter with only their midportion covered. All stents were 10 mm long, constructed of 0.010-inch stainless steel wire, and contained five bends at each end. Part 11: Animal Studies Four rough-surface stents and three half-covered stents were placed in three dogs each, while four smalldiameter and four tapered stents were placed in two dogs each. Anesthesia, stent placement, and follow-up examinations were performed in the same manner as described in part I. All dogs were killed 3 months after stent placement. RESULTS Part I All dogs tolerated the procedures well, and no clinical symptoms such as jaundice were noted during followup. Serum alkaline phosphatase levels were elevated in all dogs 1week after stent placement, but these lev-
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Figure 1. Photograph of the covered
stents used in this study. Stents in the left column were used in part I and were covered with PCL (top),SPP (middle), and silicone (bottom).The silicone-covered stents shown in the right column were used in part I1 and are small diameter (top),half-covered (middle),and tapered (bottom).
els never exceeded normal limits and returned to baseline by 1month. All other results of hepatic and renal function tests were normal. One dog with a silicone-covered stent died of causes unrelated to the stent 3 days before the 6-month follow-up. Radiographically, the stents reached 25%-92% of their fully expanded diameter immediately after placement, and 100% expansion was seen on all images obtained at 1 week. This diameter was maintained during the remaining follow-up period in all dogs except one. In one dog, the stent diameter was larger on the 4-month image because the PCL covering had broken. No stent migration was seen. Cholangiograms obtained at the time the animals were killed showed localized dilatation of the common bile duct within segments in which the stents were placed. No change in the luminal appearance of the bile
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a. b. Figure 2. Cholangiograms obtained 6 months after placement of stents covered with (a)SPP and (b)silicone. Luminal narrowing is seen at both ends of the stents. Note that the narrowing associated with the silicone-covered stent appears less severe than that associated with the stent covered with SPP.
Figure 3. Crosssectional photomicrograph of common bile duct bridged by silicone-covered stent shown in Figure 2b a t 6 months after stent placement. The epithelium appears flattened or cuboidal, and the perimucosal connective tissue is stretched. (Hematoxylin-eosin stain; original magnification, x 5.)
duct was seen in two dogs, one with a SPP-covered stent followed up for 6 months and one with a silicone-covered stent that died 3 days before the 6-month follow-up of causes unrelated to the stent. In the remaining 16 animals, filling defects and luminal narrowing of varying degrees were noted at both ends of the covered stents (Fig 2) on all follow-up cholangiograms. Stenoses associated with the silicone cover appeared less severe than those associated with the other polymers. With regard to each
polymeric covering, some difference was noted in the degree of stenosis seen at 3 months and that seen at 6 and 12 months. At necropsy, the stented portions of the common bile duct were dilated, but no other abnormality was noted on the external surface of the duct. When the duct was opened, no concretions were found in any of the dogs. All silicone-covered and SPPcovered stents were intact. The mucosal surface beneath these polymeric covers was flat and smooth. All PCL
coverings were found to have separated from the stent wire at some point on the framework. Mild mucosal proliferation was seen in association with the break in the stent cover. In all but the two dogs in which no cholangiographic luminal changes were seen, small villouslike projections arose from the mucosal surface of the bile duct at the proximal and distal ends of the stents. These projections were coincident with the filling defects seen on the cholangiograms. Some projections were pedunculated, while others appeared sessile. They exhibited a cauliflowerlike appearance with a fine granular surface. Microscopically, the epithelium beneath the stent appeared cuboidal or flattened. Perimucosal connective tissue was stretched, with minimal inflammatory cell infiltration (Fig 3). The villouslike projections were found to be fibrovascular stalks lined by tall columnar epithelium arising from the mucosal surface and extending outward into the lumen of the bile duct (Fig 4). These findings are compatible with mucosal hyperplasia. The histologic changes associated with each of the three polymeric coverings were similar.
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a. b. Figure 4. Cross-sectionalphotomicrographsof common bile duct at distal end of covered stents show severe mucosal hyperplasia
composed of fibrovascular stalks lined by tall columnar epithelium arising from the mucosal surface and extending into the ductal lumen. (a)Bile duct shown in Figure 2a 6 months after placement of the SPP-covered stent. (b) Bile duct shown in Figure 2b at 6 months after placement of silicone-coveredstent. Note mucosal reaction associated with silicone covering appears less severe than that associated with SPP. (Hematoxylin-eosinstain; original magnification, ~ 5 . )
Part I1 All dogs tolerated the procedures well, and clinical results were the same as those for the dogs in part I. In two dogs with one rough-surface stent each, moderate stenoses caused by mucosal hyperplasia were seen cholangiographically at each end of the stents. In the other dog with two stents of this type, moderate stenoses developed at the ends of the distal stent, but no stenosis was found at either end of the proximal stent. This observation was confirmed at necropsy. None of the small-diameter stents were found on any of the plain radiographs obtained 1week after stent placement. All had migrated into the duodenum and were passed in the stool. All three dogs with half-covered stents showed minimal stenoses of the common bile duct on the follow-up cholangiograms (Fig 5a). These lesions were less prominent than those associated with stents fully covered by silicone (Fig 2b). Microscopically, moderate mucosal hyperplasia was noted at the ends of the stent covering (Fig 5b). In both dogs with tapered stents,
no stenoses were seen at the ends of the stents on the follow-up cholangiograms (Fig 6a). Mild mucosal hyperplasia, which was less pronounced than that seen with the half-covered straight stents, was observed microscopically (Fig 6b).
DISCUSSION Since the initial experimental evaluation of self-expanding metallic stents in the bile duct by Carrasco et al(9), many reports have been published on use of the stents to treat obstructive jaundice (1,2,4-8). Relatively good results have been reported in cases of benign strictures, but the results in cases of malignant strictures are not encouraging. In these cases, recurrent jaundice is routine because of tumor growth between the wire struts of the stent, tumor growth around the distal and/or proximal ends of the stent, sludge within the stent associated with cholangitis, and occasionally mucosal hyperplasia in the stented segment (1,2,4-8).
Since the Gianturco self-expanding stent is composed of widely spaced stainless steel struts, tumors can easily grow through the gaps between the wire struts. Because this ingrowth could be prevented by the presence of an impermeable membrane, we covered the stents with a thin polymeric sleeve. A report concerning polymer-coated balloon-expandable stents has been published (lo),but to our knowledge, the use of covered self-expanding stents has not been reported. Covered metallic stents have some advantages over conventional plastic endoprostheses. They can be delivered through relatively smaller caliber catheters, which may be less traumatic and may decrease the chance of bile leakage and pain caused by manipulation. These stents achieve a large luminal diameter, which reduces encrustation and keeps the stent patent (11). We used three biocompatible polymers as covering materials. PCL was easy to use, but it was found to be fragile and therefore not considered suitable as a cover. SPP has a low
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6a. 6b. Figures 5,6. (5) Follow-up images obtained 3 months after placement of stent half covered with silicone. (a)Cholangiogram shows minimal luminal narrowing at both ends of stent covering (arrows). (b) Cross-sectional photomicrograph of common bile duct at proximal end of stent covering shows moderate mucosal hyperplasia. (Hematoxylin-eosin stain; original magnification, x 5.) ( 6 ) Follow-up images obtained 3 months after placement of two tapered stents fully covered with silicone. (a) Cholangiogram shows no luminal narrowing associated with either stent (arrows). (b) Cross-sectional photomicrograph of common bile duct at proximal end of proximal stent shows mild mucosal hyperplasia. (Hematoxylin-eosin stain; original magnification, x 5.)
coefficient of friction, and it was found to be durable, as was silicone. The elevated serum alkaline phosphatase levels seen in all dogs at 1 week were probably caused by biliary trauma associated with the catheterization procedure. The bile duct wall of the stented segment showed smooth focal dilatation, and only minimal changes were seen in the wall beneath the stent. These results
suggested that SPP and silicone possess the durability and biocompatibility needed for a biliary stent covering. Since we have found that the luminal diameter of the common bile duct measured cholangiographically in 20-30-kg dogs is 3-4 mm, a standard stent diameter of 6 mm was chosen in an effort to prevent stent migration. Also, this is the same diameter as that of the covered balloon-ex-
panded stents placed in dogs by Alvarado et a1 (10). Three-millimeter stents were placed in two animals because they approximated the exact diameter of the duct. Development of the papillary mucosal hyperplasia seen at both ends of the stents in this study may be species-specificand/or due to the normal nature of the bile duct wall. Similar hyperplastic changes have been noted
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in dogs following placement of bare self-expanding stents (9) and bare and covered balloon-expanded stents (10). However, recurrent stenosis caused by mucosal hyperplasia is uncommon in clinical practice, possibly because of species specificity or the fact that the stent is in contact with fibrotic or neoplastic tissue. Aside from species specificity, multiple factors are probably responsible for the development of mucosal hyperplasia. These may include, but are not limited to, tension applied to the bile duct mucosa by the stent, compromise of peribiliary blood and lymphatic flow resulting from dilation pressure exerted by the stent, polymer biocompatibility, the surface character of the stent, and trauma a t the time of stent insertion. Although some difference in the degree of stenosis was found associated with the same polymeric covering a t different times, nothing definite can be said about progression of the mucosal hyperplasia because serial cholangiograms were not obtained in any of the dogs during follow-up. However, Alvarado et a1 (10) did report progression of the hyperplastic reaction in their canine study. In an attempt to decrease or prevent the severe mucosal hyperplasia encountered in part I of this study, the silicone-covered stents were modified. Silicone was selected because, cholangiographically and microscopically, changes associated with this polymer cover appeared less severe than those associated with SPP. Rough-surface stents were created to increase the coefficient of friction and prevent any stent movement within the bile duct. However, the ductal changes associated with these stents were similar to those seen in part I. Small-diameter, half-covered, and tapered stents were constructed to decrease the tension and any endrelated mechanical process on the
bile duct wall a t the ends of the stents. All small-diameter stents migrated into the duodenum, indicating that for stability, even covered stents need to be larger than the diameter of the duct. The dogs with half-covered stents exhibited only mild changes cholangiographically and moderate mucosal hyperplasia histologically. The dogs with tapered stents showed no changes cholangiographically and mild mucosal hyperplasia microscopically. These results, as well as those of Alvarado et al (lo), indicate that both tension and mechanical stress on the bile duct wall a t the ends of the stent have some role in the development of mucosal hyperplasia. It is also possible that these modified stents could be associated with a more delayed mucosal reaction. Further investigation is needed to evaluate this possibility. Based on the results of this study, we believe that silicone-covered, selfexpanding stents may be used clinically. However, additional research is needed in tumor-bearing bile ducts to determine whether covered stents stimulate a mucosal hyperplasia in humans. If so, stents tapered at the ends to decrease tension and mechanical stress on the bile duct wall may be useful. Since the cause of mucosal hyperplasia does not seem to be simple, another method, such as that used to suppress intimal hyperplasia in vessels (121, may also be worth evaluating. Acknowledgments: We thank Raquel Collins and Irene Szwarc for technical assistance, Peggy Bergmanson for secretarial help, and Bob Czimmy for photographic expertise. References 1. Coons H. Self-expanding stainless steel biliary stents. Radiology 1989; 170:979-983. 2. Irving JD, Adam A, Dick R, Dondelinger RF, Lunderquist A, Roche A. Gianturco expandable metallic
biliary stents: results of a European clinical trial. Radiology 1989; 172: 321-326. Rossi P, Bezzi M, Salvatori, Maccioni R, Porcaro ML. Recurrent benign biliary strictures: management with self-expanding metallic stents. Radiology 1990; 175:661665. Gillams A, Dick R, Dooley JS, Wallsten H, El-Din A. Self-expandable stainless steel braided endoprosthesis for biliary strictures. Radiology 1990; 174:137-140. Lammer J , Klein GE, Kleinert R, Hausegger K, Einspieler R. Obstructive jaundice: use of expandable metal endoprosthesis for biliary drainage. Radiology 1990; 177:789792. Yoshioka T, Sakaguchi H, Yoshimura H, et al. Expandable metallic biliary endoprostheses: preliminary clinical evaluation. Radiology 1990; 177:253-257. Lameris JS, Stoker J , Nijs HGT, et al. Malignant biliary obstruction: percutaneous use of self-expandable stents. Radiology 1991; 179:703707. Adam A, Chetty N, Roddie M, Yeung E, Benjamin IS. Self-expandable stainless steel endoprostheses for treatment of malignant bile duct obstruction. AJR 1991; 156:321325. Carrasco CH, Wallace S, Charnsangavej C, et al. Expandable biliary endoprosthesis: an experimental study. AJR 1985; 145:1279-1281. Alvarado R, Palmaz JC, Garcia OJ, Tio FO, Rees CR. Evaluation of polymer-coated balloon-expandable stents in bile ducts. Radiology 1989; 170:975-978. Lammer J, Stoffler G, Petek WW, Hofler H. In vitro long-term perfusion of different materials for biliary endoprostheses. Invest Radio1 1986; 21:329-331. Forrester JS, Fishbein M, Helfant R, Fagin J . A paradigm for restenosis based on cell biology: clues for the development of new preventive therapies. J Am Coll Cardiol1991; 17:758-769.