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Endoscopic resection of Peutz-Jeghers polyps throughout the small intestine at double-balloon enteroscopy without laparotomy
Endoscopic resection of Peutz-Jeghers polyps throughout the small intestine at double-balloon enteroscopy without laparotomy Naoki Ohmiya, MD, PhD, Ayumu Taguchi, MD, Kennosuke Shirai, MD, Nobuyuki Mabuchi, MD, Daigo Arakawa, MD, Hironobu Kanazawa, MD, Masayasu Ozeki, MD, Masahiro Yamada, MD, Masanao Nakamura, MD, Akihiro Itoh, MD, PhD, Yoshiki Hirooka, MD, PhD, Yasumasa Niwa, MD, PhD, Tetsuro Nagasaka, MD, PhD, Masafumi Ito, MD, PhD, Shinji Ohashi, MD, PhD, Shozo Okamura, MD, PhD, Hidemi Goto, MD, PhD
Background: Small-bowel enteroscopy with the double-balloon method was developed to improve access to the small intestine. This study evaluated the usefulness of this method for the resection of small-intestinal PeutzJeghers polyps. Methods: Two patients with Peutz-Jeghers syndrome underwent nonsurgical double-balloon enteroscopic resection of polyps throughout the small intestine. Observations: Multiple polyps in the jejunum were successfully resected via the oral route, as were the polyps in the ileum via the anal route. All 18 polyps (10-60 mm in size) were resected without subsequent bleeding or perforation. Histopathologically, 3 large polyps (>30 mm diameter) were hamartomas with adenomatous components. Conclusions: Double-balloon enteroscopy was safe and useful for the diagnosis and the treatment of PeutzJeghers polyps throughout the small intestine. Double-balloon enteroscopic polypectomy might preclude complications of Peutz-Jeghers syndrome, including intussusception, bleeding, and tumorogenesis, thereby obviating the need for multiple laparotomies.
The principle features of the Peutz-Jeghers syndrome (PJS) are GI polyps and melanin spots on the oral mucosa, the lips, and the digits.1,2 PJS is transmitted as an autosomal dominant trait. The Peutz-Jeghers polyps (PJP) occur in the stomach and throughout the small and the large intestine but are most common and numerous in the jejunum and the ileum (at least 90% of cases). The polyps are mostly hamartomas, but, in a few polyps, adenomatous changes and foci of adenocarcinoma are present.3,4 For patients with PJS, Reid5 calculated the lifetime occurrence of small-intestinal adenocarcinoma at 2.4%. The most frequent complications of PJS are intussusception and bleeding because of ulceration or infarction of a polyp.6 The natural history of patients with PJS usually includes multiple laparotomies with intestinal resections that can ultimately result in short-bowel syndrome. To control the small-intestinal polyposis, combined endoscopic and surgical treatment generally is advocated, i.e., intraoperative enteroscopy with endoscopic and/or surgical resection of polyps, with or without resection of short segments of intestine.7-14 The polyposis, however, may progress by intermittent periods of growth, with the appearance of new lesions or the growth of existing Copyright ª 2005 by the American Society for Gastrointestinal Endoscopy 0016-5107/2005/$30.00 + 0 PII: S0016-5107(04)02457-5
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polyps.15 New ‘‘crops’’ of polyps may appear in different segments of the bowel even though a ‘‘clean’’ small intestine had been achieved by combined endoscopic/ surgical treatment. Thus, patients with PJS often undergo operations repeatedly, and complications related to adhesions are common. Tada et al.16 removed 4 large polyps (>1 cm in size) from the ileum and the jejunum with a two-channel enteroscope; a guide string was inserted through one channel and a polypectomy snare through the other. With this ‘‘ropeway’’ method, it may take several days for the guide string to pass from mouth to rectum.17 Stretching the string can damage the small-bowel mucosa and cause tremendous pain that necessitates use of general anesthesia. Thus, this method is seldom used. Yamamoto et al.18,19 and Yamamoto and Sugano20 developed a novel insertion technique of enteroscopy, the double-balloon method, to improve access to the small intestine within a relatively short period of time. This method uses two balloons, one attached to the tip of the enteroscope and the another balloon at the distal end of an overtube. By using these balloons to grip the intestinal wall, the endoscope can be inserted further without forming redundant loops of small intestine.18 Moreover, the enteroscope can be inserted via either the oral or the anal approach. The double-balloon method enables not only endoscopic visualization of the small intestine but also tissue sampling and interventional therapies, www.mosby.com/gie
Ohmiya et al
Peutz-Jeghers polyps: resection at double-balloon enteroscopy without laparotomy
including balloon dilation of benign strictures and polypectomy.19 This report describes the usefulness of doubleballoon enteroscopy for endoscopic resection of PJPs throughout the small intestine without laparotomy.
(Nichirei, Tokyo, Japan). Demonstration of binding sites with the peroxidase reaction was achieved with 3,3#diaminobenzidine tetrahydrochloride. Faint nuclear staining, sufficient to aid in orientation but not enough to influence judgment of positivity, was performed with Mayer’s hematoxylin solution.
PATIENTS AND METHODS Enteroscopic polypectomy The double-balloon enteroscopy system (Fujinon Toshiba ES Systems Co., Ltd., Tokyo, Japan) consists of a highresolution videoendoscope (EN-450P5/20) (working length 200 cm; accessory channel diameter 2.2 mm), a flexible overtube (140 cm long), and a balloon controller for inflation/deflation of the latex balloons on the enteroscope and overtube, and monitoring of the air pressure within the balloons. Enteroscopy was performed via both oral and anal approaches to remove polyps from the entire small intestine as described by Yamamoto et al.18,19 and Yamamoto and Sugano20 No specific preparation is required for the oral approach. Patients were instructed to fast beginning at least 12 hours before the examination. For the anal approach, bowel cleansing is required as for colonoscopy. Patients were instructed to drink an aqueous solution of dimethicone (200 mg/200 mL) 2 hours before the examination to eliminate air bubbles in the small intestine. Enteroscopy was performed with the patient under conscious sedation and analgesia (drip infusions of midazolam and morphine). Before polypectomy, a hypertonic saline-epinephrine solution (HSE solution: 4.7% sodium chloride, 0.005% epinephrine, 0.2% indigo carmine)21 was injected into the submucosal layer of the stalk and the base of the PJP to avoid postpolypectomy bleeding and thermal injury of the deeper tissue layers. PJPs were endoscopically resected and retrieved with a polypectomy snare (maximum diameter 5 cm). The procedures were performed under fluoroscopic guidance.
RESULTS Case 1
Sections from formalin-fixed paraffin-embedded blocks were stained with H&E and immunostained with p53 (mouse monoclonal antibody, clone DO-1; Immunotech, Marseille, France) and Ki-67 (mouse monoclonal antibody, clone MIB1; Immunotech), as previously described.22 Slides were microwaved at 95 C for 7 cycles of 5 minutes to enhance antigen retrieval. Endogenous peroxidase activity was blocked by incubation with 0.3% hydrogen peroxide for 20 minutes. Then the specimens were treated with 10% normal rabbit serum for 10 minutes at room temperature. Primary antibodies were incubated with tissue sections for 18 hours at 4 C. After washing, they were incubated with biotin-conjugated antimouse immunoglobulin for 10 minutes at room temperature and then were incubated with peroxidase-conjugated streptavidin for 5 minutes at room temperature with a Histofine kit
A 29-year-old man presented to his primary care physician 9 years earlier (in August 1994) with a 2-month history of intermittent lower abdominal pain, diarrhea, and weight loss. Barium contrast radiography of the colon demonstrated multiple polyps. The patient had noticed the presence of melanin spots on his lips and digits in early childhood. The family history was positive for PJS (father); two siblings were not affected. With a diagnosis of PJS, the patient was admitted to our hospital for polypectomy. Several colonic polyps were endoscopically resected, except for two polyps (3-4 cm in diameter) in the transverse colon that were regarded as too large for polypectomy. The patient, therefore, underwent surgery with polypectomy through an enterotomy. Histopathologic evaluation revealed that all polyps were hamartomas except for a surgically removed 4-cm hamartomatous polyp with an adenomatous component. No polyp was noted on doublecontrast radiography of the jejunum and the ileum. During follow-up at a local hospital, barium contrast radiography, performed 4 years later, revealed two jejunal polyps (1-2 cm). Five years after that study, another barium contrast study disclosed that these polyps had increased to 3-4 cm in size, as well as the presence of an additional 1-cm ileal polyp. Although the patient was asymptomatic, he was referred to us for nonsurgical enteroscopic polypectomy with the double-balloon method to avoid intussusception and bleeding. On admission (November 2003), the examination was unremarkable and standard laboratory tests detected no abnormality. Two double-balloon enteroscopies were performed, one via the oral route, the other via the anal approach (Table 1). At enteroscopy via the oral approach, two pedunculated polyps were resected after injection of HSE solution. Both specimens, one 30 mm in diameter and the other 45 ! 20 mm in size were retrieved (Fig. 1). Six days later, a 10 ! 8-mm pedunculated polyp was resected after submucosal injection of HSE solution at per anal enteroscopy; the resection specimen was retrieved (Fig. 2). Several small polyps (!5 mm) were observed in the terminal ileum but were not resected. There was no complication of either enteroscopy. The patient was discharged 6 days later. Histopathologically, all of the polyps were hamartomas except the 45 ! 20-mm polyp, which had adenomatous
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TABLE 1. The approach, duration of examination, results of polypectomy, and complications
Patient 1
Patient 2
Approach
Duration
Results of polypectomy
Complications
Oral
2 h 10 min
Two pedunculated polyps in jejunum one 30 mm and one 45 mm
None
Anal
1 h 40 min
One 10 mm pedunculated polyp in ileum
None
Oral
4h
Six pedunculated polyps, ranging from 10-60 mm in size in jejunum
None
Anal
3 h 30 min
Five pedunculated polyps, ranging from 10-30 mm in size in ileum
Fever, abdominal tenderness
Anal
1h
Four pedunculated polyps, ranging from 10-20 mm in size in ileum
None
A 28-year-old woman presented (August 1981) 23 years earlier with complaints of intermittent hematochezia without abdominal pain. The medical history included emergent partial enterectomies because of intussusception of polyps at 6 and 16 years of age. A diagnosis had been made of PJS because of intestinal polyposis and melanin spots on the lips and digits. Several polyps (2-3 cm) were resected colonoscopically from the descending and the sigmoid colon. On histopathologic evaluation, all of the colonic polyps were hamartomas. Double-contrast radiography of the small intestine revealed 3 polyps (1-3 cm) in the ileum. Attempts to resect the largest polyp (3 cm in diameter) proximal to the ileocecal valve at colonoscopy were unsuccessful. Barium contrast radiography of the small intestine performed 17 years later because of a decrease in Hb level to 9.8 g/dL (female normal: 11-16 g/dL) (December 1998) revealed 7 polyps ranging from 1 to 4 cm in size in the jejunum and the ileum. Although combined endoscopic/ surgical treatment was recommended to the patient, she was reluctant to undergo laparotomy. Her subsequent course was characterized by relapsing anemia (Hb, 6.7-9.9 g/dL) that responded to oral administration of iron. Four years later (January 2003), there was the third episode of intussusception in the small bowel. At emergent laparotomy at a local hospital, a 20-cm length of intussuscepted ileum was resected. Eight months after surgery (October 2003), the patient was admitted to our hospital for endoscopic resection of all polyps in the small intestine by means of doubleballoon enteroscopy. At this time, the family history was positive for PJS: a 25-year-old daughter had PJS but a 22year-old son did not. The patient’s mother had died of disseminated intravascular coagulation of unknown cause at age 43 years.
Double-contrast radiography of the small bowel revealed 9 pedunculated to semipedunculated polyps ranging in size from 15 to 60 mm. Two days later, doubleballoon enteroscopy was performed via the oral approach, with the intent of resecting all polyps larger than 10 mm (Table 1). All polyps were resected after submucosal injection of HSE solution. Only the 60-mm polyp was retrieved. Polypectomies were performed from distal to proximal without complication. The patient was discharged 6 days later. The patient was rehospitalized (December 2003) 2 months later for enteroscopic polypectomy via the anal approach. A group of 3 polyps was found that had a mass-like appearance, with occlusion of the narrowed lumen of the proximal ileum. A 20-mm pedunculated polyp (undetected radiographically) was resected first (without injection of HSE solution). A 30 ! 25-mm pedunculated polyp was resected next, after submucosal injection of HSE solution; the specimen was retrieved (Fig. 3). Then, a 20-mm pedunculated polyp and a 10-mm semipedunculated polyp close to this polyp were resected. A 20-mm semipedunculated polyp in the mid ileum also was resected after submucosal injection of HSE solution. Although all of these polyps were resected successfully, removal of the clump of 3 polyps was technically difficult and prolonged. Further attempts to remove more polyps, therefore, were deferred. On the day after polypectomy, the patient was asymptomatic, but examination revealed mild direct and rebound tenderness in the left periumbilical region and fever (38.1 C). The patient continued to fast for 2 days and fosfomycin was administered intravenously for 3 days. The fever resolved after 24 hours, and, at 3 days, there was no abdominal tenderness. A second enteroscopy via the anal route was performed 5 days after the first (December 10). A 15-mm pedunculated polyp (7-mm-diameter stalk), a 20-mm pedunculated (6-mm-diameter stalk) polyp, and two 10-mm pedunculated polyps that formed a mass-like cluster in the intrapelvic ileum were endoscopically resected without complication. These polyps were removed from proximal to distal. The patient was discharged 2 days later.
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components. Immunohistochemically, sporadic intranuclear overexpression of the p53 oncoprotein was observed in atypical cells in this large polyp. Ki-67-positive proliferative cells extended to the luminal surface of the mucosa.
Case 2
Ohmiya et al
Peutz-Jeghers polyps: resection at double-balloon enteroscopy without laparotomy
Figure 1. A, Double-contrast roentgenogram showing 45 ! 20-mm polyp (arrow) in jejunum. B, Roentgenogram showing enteroscope inserted via mouth with open polypectomy snare. C, Enteroscopic view of polyp with long, thick stalk. D, Snared polyp after injection of stalk with HSE solution.
A 60-mm diameter polyp retrieved from the duodenum and a 30 ! 25-mm pedunculated polyp removed from the ileum contained several adenomatous foci positive for p53 and Ki-67 at the luminal surface.
Endoscopically, the small intestine is relatively inaccessible,20 and abnormalities deep within this organ, here-
tofore, were untreatable endoscopically, except by laparotomy with surgeon-assisted interoperative endoscopy. In patients with PJS, hamartomatous polyps are most numerous in the jejunum and the ileum.6 These patients often are referred for surgery to remove these lesions, even if they are asymptomatic. Thus, patients with PJS usually (and reluctantly) undergo repeated enterectomy or polyp resections at emergent or planned laparotomies, as occurred in both of our patients. However, in both cases, PJPs throughout the jejunum and the ileum were
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DISCUSSION
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Figure 1. Continued. E, Stump after polypectomy. F, Resection specimen.
resected with relative ease by double-balloon enteroscopy, thereby obviating the need for further surgery. Videocapsule endoscopy has the potential for visualization of the entire small bowel in all patients without bowel strictures, provided the battery and the recorder function properly and the intestine is clean. Although there is no comparative study, it is reasonable to question whether a complete exploration of the small bowel can be achieved with double-balloon enteroscopy. In patient 2, almost the entire small bowel was inspected, and all polyps demonstrated in the jejunum and the ileum by double-contrast radiography were resected. However, the entire small bowel is rarely intubated when doubleballoon enteroscopy is performed via the oral or the anal approach alone. However, it has the potential for complete small-intestinal exploration when the two approaches are combined. One way to document that the combined approach inspects the entire small intestine is to mark the deepest point of insertion by application of a mucosal clip or injection of sterilized Indian ink or indigo carmine. Then, when double-balloon enteroscopy is performed via the opposite approach, visualization of the mark confirms that the entire small intestine has been inspected. We performed 66 doubleballoon enteroscopies in 40 patients between June 2003 and April 2004. There were no serious complications, including perforation and massive hemorrhage. Of these 66 examinations, deep insertion of the small bowel was impossible in two patients because of adhesions. One had a history of pancolectomy for familial polyposis, and the enteroscopy was limited by a postoperative adhesion approximately 40 cm from the ligament of Treitz. The other patient had a history of appendectomy with the adhesion being located approximately 30 cm from the ileocecal valve. As with capsule endoscopy, intraabdominal adhesions also are problematic for doubleballoon enteroscopy.
Evidence of a minor complication (abdominal tenderness and fever) was noted in patient 2 on the day after polypectomy. Mathus-Vliegen and Tytgat7 noted that PJPs that are bulky, locally concentrated in large numbers, invaginated, thick stalked, and those with serosal retraction into the stalk, are unsuitable for polypectomy, even if performed intraoperatively, and recommended that such lesions be removed by enterectomy. Radiographically, some of the polyps in our second patient were retracted into a narrowed intestinal lumen. This appearance may indicate the presence of transmural fibrosis or subclinical invagination. These polyps probably would be considered unsuitable for polypectomy according to the criteria of Mathus-Vliegen and Tytgat.7 Thus, resection of one or more of these lesions may have resulted in transmural thermal injury with mild localized peritonitis, the so-called postpolypectomy syndrome. The patient remained asymptomatic, and the fever and abdominal tenderness resolved with conservative treatment. Almost all PJPs are easy to resect, because they are pedunculated. Enteroscopic resection of even bulky and retracted PJPs is possible and preferable to surgery, as long as patients do not have symptoms that warrant operative treatment. Ideally, double-balloon enteroscopic polypectomy should be performed when PJPs are relatively small and thereby avoid the technically more difficult endoscopic resection of large polyps at a later stage. Another complication of PJS is the development of intestinal adenoma and adenocarcinoma. Intranuclear expression of p53 in GI adenocarcinomas in PJS has been demonstrated by immunohistochemistry.23–25 In our two patients, p53 with topographical expression of Ki-67 was demonstrated immunohistochemically, specifically in adenomatous components of all polyps larger than 30 mm in diameter. Thus, double-balloon enteroscopic polypectomy also may be useful for prevention of carcinogenesis.
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Figure 2. A, Double-contrast roentgenogram (with compression) showing 10 ! 8-mm polyp in ileum. B, Roentgenogram showing enteroscope inserted via anus with snare open. C, Chromoendoscopic image (indigo carmine) of pedunculated polyp. D, Excised polyp and stump. E, Resection specimen.
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Figure 3. A, Barium contrast roentgenogram (with compression) showing polyp with multiple bosselations. B, Roentgenogram showing enteroscope inserted via anus with injection needle. C, Enteroscopic image showing snared polyp. D, Resection specimen.
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Peutz-Jeghers polyps: resection at double-balloon enteroscopy without laparotomy
In conclusion, experience in two patients with PJS indicates that double-balloon enteroscopy is useful for treatment of PJPs throughout the small intestine. This enteroscopic method has the potential to change the conventional management of patients with PJS.
14.
15.
16.
ACKNOWLEDGMENT The authors thank Hironori Yamamoto MD, PhD, Jichi Medical School, for technical advice and John Cole for proofreading.
17. 18.
19.
REFERENCES
the small intestine in Peutz-Jeghers syndrome: a case report. Surg Laparosc Endosc Percutan Tech 2000;10:409-11. Seenath MM, Scott MJ, Morris AI, Ellis A, Hershman MJ. Combined surgical and endoscopic clearance of small-bowel polyps in PeutzJeghers syndrome. J R Soc Med 2003;96:505-6. Fenoglio-Preiser CM, Lantz PE, Listrom MB, Davis M, Rilke FO. Gastrointestinal pathology: an atlas and text. New York: Raven Press; 1989. Tada M, Misaki F, Akasaka Y, Kawai K. Endoscopic polypectomy for the removal of polyps of the small intestine. Gastroenterol Jpn 1982;17: 177-81. Lewis BS, Waye JD. Total small bowel enteroscopy. Gastrointest Endosc 1987;33:435-8. Yamamoto H, Sekine Y, Sato Y, Higashizawa T, Miyata T, Iino S, et al. Total enteroscopy with a nonsurgical steerable double-balloon method. Gastrointest Endosc 2001;53:216-20. Yamamoto H, Yano T, Kita H, Sunada K, Ido K, Sugano K. New system of double-balloon enteroscopy for diagnosis and treatment of small intestinal disorders [comment]. Gastroenterology 2003;125:1556; author reply 1556–7. Yamamoto H, Sugano K. A new method of enteroscopy: the double-balloon method. Can J Gastroenterol 2003;17:273-4. Shirai M, Nakamura T, Matsuura A, Ito Y, Kobayashi S. Safer colonoscopic polypectomy with local submucosal injection of hypertonic saline-epinephrine solution. Am J Gastroenterol 1994;89:334-8. Niimi C, Goto H, Ohmiya N, Niwa Y, Hayakawa T, Nagasaka T, et al. Usefulness of p53 and Ki-67 immunohistochemical analysis for preoperative diagnosis of extremely well-differentiated gastric adenocarcinoma. Am J Clin Pathol 2002;118:683-92. Gruber SB, Entius MM, Petersen GM, Laken SJ, Longo PA, Boyer R, et al. Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome. Cancer Res 1998;58:5267-70. Entius MM, Keller JJ, Westerman AM, van Rees BP, van Velthuysen ML, de Goeij AF, et al. Molecular genetic alterations in hamartomatous polyps and carcinomas of patients with Peutz-Jeghers syndrome. J Clin Pathol 2001;54:126-31. De Leng WW, Westerman AM, Weterman MA, De Rooij FW, Dekken Hv H, De Goeij AF, et al. Cyclooxygenase 2 expression and molecular alterations in Peutz-Jeghers hamartomas and carcinomas. Clin Cancer Res 2003;9:3065-72.
1. Dormandy TL. Gastrointestinal polyposis with mucocutaneous pigmentation (Peutz-Jeghers syndrome). N Engl J Med 1957;256:1093-103 contd. 2. Zegarelli EV, Kutscher AH, Mercadante J, Kupferberg N, Piro JD. Atlas of oral lesions observed in the syndrome of oral melanosis with associated intestinal polyposis (Peutz-Jeghers syndrome). Am J Dig Dis 1959;4:479-89. 3. Perzin KH, Bridge MF. Adenomatous and carcinomatous changes in hamartomatous polyps of the small intestine (Peutz-Jeghers syndrome): report of a case and review of the literature. Cancer 1982;49:971-83. 4. Narita T, Eto T, Ito T. Peutz-Jeghers syndrome with adenomas and adenocarcinomas in colonic polyps. Am J Surg Pathol 1987;11:76-81. 5. Reid JD. Intestinal carcinoma in the Peutz-Jeghers syndrome. JAMA 1974;229:833-4. 6. Berk EJ, Haubrich WS, Kalser MH, Roth JLA, Schaffner F. Bochus gastroenterology. Philadelphia: W.B. Saunders; 1985. 7. Mathus-Vliegen EM, Tytgat GN. Intraoperative endoscopy: technique, indications, and results. Gastrointest Endosc 1986;32:381-4. 8. van Coevorden F, Mathus-Vliegen EM, Brummelkamp WH. Combined endoscopic and surgical treatment in Peutz-Jeghers syndrome. Surg Gynecol Obstet 1986;162:426-8. 9. Spigelman AD, Thomson JP, Phillips RK. Towards decreasing the relaparotomy rate in the Peutz-Jeghers syndrome: the role of peroperative small bowel endoscopy. Br J Surg 1990;77:301-2. 10. Eugene C, Tennenbaum R, Fingerhut A, Etienne JC. Treatment of tumors of the small intestine in Peutz-Jeghers’ syndrome. Value of a combined endoscopic and surgical approach. Apropos of 2 familial cases, one of which with a 15-year follow-up [French]. Gastroenterol Clin Biol 1992;16:604-7. 11. De Luca N, Chia Y, Gorard DA. Total gastrointestinal endoscopy in the management of Peutz-Jeghers syndrome. Postgrad Med J 1998;74: 745-7. 12. Lin BC, Lien JM, Chen RJ, Fang JF, Wong YC. Combined endoscopic and surgical treatment for the polyposis of Peutz-Jeghers syndrome. Surg Endosc 2000;14:1185-7. 13. Taira K, Matsubara H, Isa T, Miyazato H, Hiroyasu S, Shiraishi M, et al. Combined endoscopic and surgical treatment for multiple polyps of
20.
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21.
22.
23.
24.
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Received June 7, 2004. For revision August 8, 2004. Accepted September 27, 2004. Current affiliations: Division of Gastroenterology, Department of Therapeutic Medicine, Department of Laboratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan, Department of Endoscopy, Department of Pathology, Nagoya University Hospital, Nagoya, Japan, Division of Gastroenterology, Department of Internal Medicine, Toyohashi Municipal Hospital, Aichi, Japan. Reprint requests: Naoki Ohmiya, MD, PhD, Division of Gastroenterology, Department of Therapeutic Medicine, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan.
Background: Small-bowel enteroscopy with the double-balloon method was developed to improve access to the small intestine. This study evaluated the usefulness of this method for the resection of small-intestinal PeutzJeghers polyps. Methods: Two patients with Peutz-Jeghers syndrome underwent nonsurgical double-balloon enteroscopic resection of polyps throughout the small intestine. Observations: Multiple polyps in the jejunum were successfully resected via the oral route, as were the polyps in the ileum via the anal route. All 18 polyps (10-60 mm in size) were resected without subsequent bleeding or perforation. Histopathologically, 3 large polyps (>30 mm diameter) were hamartomas with adenomatous components. Conclusions: Double-balloon enteroscopy was safe and useful for the diagnosis and the treatment of PeutzJeghers polyps throughout the small intestine. Double-balloon enteroscopic polypectomy might preclude complications of Peutz-Jeghers syndrome, including intussusception, bleeding, and tumorogenesis, thereby obviating the need for multiple laparotomies.
The principle features of the Peutz-Jeghers syndrome (PJS) are GI polyps and melanin spots on the oral mucosa, the lips, and the digits.1,2 PJS is transmitted as an autosomal dominant trait. The Peutz-Jeghers polyps (PJP) occur in the stomach and throughout the small and the large intestine but are most common and numerous in the jejunum and the ileum (at least 90% of cases). The polyps are mostly hamartomas, but, in a few polyps, adenomatous changes and foci of adenocarcinoma are present.3,4 For patients with PJS, Reid5 calculated the lifetime occurrence of small-intestinal adenocarcinoma at 2.4%. The most frequent complications of PJS are intussusception and bleeding because of ulceration or infarction of a polyp.6 The natural history of patients with PJS usually includes multiple laparotomies with intestinal resections that can ultimately result in short-bowel syndrome. To control the small-intestinal polyposis, combined endoscopic and surgical treatment generally is advocated, i.e., intraoperative enteroscopy with endoscopic and/or surgical resection of polyps, with or without resection of short segments of intestine.7-14 The polyposis, however, may progress by intermittent periods of growth, with the appearance of new lesions or the growth of existing Copyright ª 2005 by the American Society for Gastrointestinal Endoscopy 0016-5107/2005/$30.00 + 0 PII: S0016-5107(04)02457-5
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polyps.15 New ‘‘crops’’ of polyps may appear in different segments of the bowel even though a ‘‘clean’’ small intestine had been achieved by combined endoscopic/ surgical treatment. Thus, patients with PJS often undergo operations repeatedly, and complications related to adhesions are common. Tada et al.16 removed 4 large polyps (>1 cm in size) from the ileum and the jejunum with a two-channel enteroscope; a guide string was inserted through one channel and a polypectomy snare through the other. With this ‘‘ropeway’’ method, it may take several days for the guide string to pass from mouth to rectum.17 Stretching the string can damage the small-bowel mucosa and cause tremendous pain that necessitates use of general anesthesia. Thus, this method is seldom used. Yamamoto et al.18,19 and Yamamoto and Sugano20 developed a novel insertion technique of enteroscopy, the double-balloon method, to improve access to the small intestine within a relatively short period of time. This method uses two balloons, one attached to the tip of the enteroscope and the another balloon at the distal end of an overtube. By using these balloons to grip the intestinal wall, the endoscope can be inserted further without forming redundant loops of small intestine.18 Moreover, the enteroscope can be inserted via either the oral or the anal approach. The double-balloon method enables not only endoscopic visualization of the small intestine but also tissue sampling and interventional therapies, www.mosby.com/gie
Ohmiya et al
Peutz-Jeghers polyps: resection at double-balloon enteroscopy without laparotomy
including balloon dilation of benign strictures and polypectomy.19 This report describes the usefulness of doubleballoon enteroscopy for endoscopic resection of PJPs throughout the small intestine without laparotomy.
(Nichirei, Tokyo, Japan). Demonstration of binding sites with the peroxidase reaction was achieved with 3,3#diaminobenzidine tetrahydrochloride. Faint nuclear staining, sufficient to aid in orientation but not enough to influence judgment of positivity, was performed with Mayer’s hematoxylin solution.
PATIENTS AND METHODS Enteroscopic polypectomy The double-balloon enteroscopy system (Fujinon Toshiba ES Systems Co., Ltd., Tokyo, Japan) consists of a highresolution videoendoscope (EN-450P5/20) (working length 200 cm; accessory channel diameter 2.2 mm), a flexible overtube (140 cm long), and a balloon controller for inflation/deflation of the latex balloons on the enteroscope and overtube, and monitoring of the air pressure within the balloons. Enteroscopy was performed via both oral and anal approaches to remove polyps from the entire small intestine as described by Yamamoto et al.18,19 and Yamamoto and Sugano20 No specific preparation is required for the oral approach. Patients were instructed to fast beginning at least 12 hours before the examination. For the anal approach, bowel cleansing is required as for colonoscopy. Patients were instructed to drink an aqueous solution of dimethicone (200 mg/200 mL) 2 hours before the examination to eliminate air bubbles in the small intestine. Enteroscopy was performed with the patient under conscious sedation and analgesia (drip infusions of midazolam and morphine). Before polypectomy, a hypertonic saline-epinephrine solution (HSE solution: 4.7% sodium chloride, 0.005% epinephrine, 0.2% indigo carmine)21 was injected into the submucosal layer of the stalk and the base of the PJP to avoid postpolypectomy bleeding and thermal injury of the deeper tissue layers. PJPs were endoscopically resected and retrieved with a polypectomy snare (maximum diameter 5 cm). The procedures were performed under fluoroscopic guidance.
RESULTS Case 1
Sections from formalin-fixed paraffin-embedded blocks were stained with H&E and immunostained with p53 (mouse monoclonal antibody, clone DO-1; Immunotech, Marseille, France) and Ki-67 (mouse monoclonal antibody, clone MIB1; Immunotech), as previously described.22 Slides were microwaved at 95 C for 7 cycles of 5 minutes to enhance antigen retrieval. Endogenous peroxidase activity was blocked by incubation with 0.3% hydrogen peroxide for 20 minutes. Then the specimens were treated with 10% normal rabbit serum for 10 minutes at room temperature. Primary antibodies were incubated with tissue sections for 18 hours at 4 C. After washing, they were incubated with biotin-conjugated antimouse immunoglobulin for 10 minutes at room temperature and then were incubated with peroxidase-conjugated streptavidin for 5 minutes at room temperature with a Histofine kit
A 29-year-old man presented to his primary care physician 9 years earlier (in August 1994) with a 2-month history of intermittent lower abdominal pain, diarrhea, and weight loss. Barium contrast radiography of the colon demonstrated multiple polyps. The patient had noticed the presence of melanin spots on his lips and digits in early childhood. The family history was positive for PJS (father); two siblings were not affected. With a diagnosis of PJS, the patient was admitted to our hospital for polypectomy. Several colonic polyps were endoscopically resected, except for two polyps (3-4 cm in diameter) in the transverse colon that were regarded as too large for polypectomy. The patient, therefore, underwent surgery with polypectomy through an enterotomy. Histopathologic evaluation revealed that all polyps were hamartomas except for a surgically removed 4-cm hamartomatous polyp with an adenomatous component. No polyp was noted on doublecontrast radiography of the jejunum and the ileum. During follow-up at a local hospital, barium contrast radiography, performed 4 years later, revealed two jejunal polyps (1-2 cm). Five years after that study, another barium contrast study disclosed that these polyps had increased to 3-4 cm in size, as well as the presence of an additional 1-cm ileal polyp. Although the patient was asymptomatic, he was referred to us for nonsurgical enteroscopic polypectomy with the double-balloon method to avoid intussusception and bleeding. On admission (November 2003), the examination was unremarkable and standard laboratory tests detected no abnormality. Two double-balloon enteroscopies were performed, one via the oral route, the other via the anal approach (Table 1). At enteroscopy via the oral approach, two pedunculated polyps were resected after injection of HSE solution. Both specimens, one 30 mm in diameter and the other 45 ! 20 mm in size were retrieved (Fig. 1). Six days later, a 10 ! 8-mm pedunculated polyp was resected after submucosal injection of HSE solution at per anal enteroscopy; the resection specimen was retrieved (Fig. 2). Several small polyps (!5 mm) were observed in the terminal ileum but were not resected. There was no complication of either enteroscopy. The patient was discharged 6 days later. Histopathologically, all of the polyps were hamartomas except the 45 ! 20-mm polyp, which had adenomatous
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TABLE 1. The approach, duration of examination, results of polypectomy, and complications
Patient 1
Patient 2
Approach
Duration
Results of polypectomy
Complications
Oral
2 h 10 min
Two pedunculated polyps in jejunum one 30 mm and one 45 mm
None
Anal
1 h 40 min
One 10 mm pedunculated polyp in ileum
None
Oral
4h
Six pedunculated polyps, ranging from 10-60 mm in size in jejunum
None
Anal
3 h 30 min
Five pedunculated polyps, ranging from 10-30 mm in size in ileum
Fever, abdominal tenderness
Anal
1h
Four pedunculated polyps, ranging from 10-20 mm in size in ileum
None
A 28-year-old woman presented (August 1981) 23 years earlier with complaints of intermittent hematochezia without abdominal pain. The medical history included emergent partial enterectomies because of intussusception of polyps at 6 and 16 years of age. A diagnosis had been made of PJS because of intestinal polyposis and melanin spots on the lips and digits. Several polyps (2-3 cm) were resected colonoscopically from the descending and the sigmoid colon. On histopathologic evaluation, all of the colonic polyps were hamartomas. Double-contrast radiography of the small intestine revealed 3 polyps (1-3 cm) in the ileum. Attempts to resect the largest polyp (3 cm in diameter) proximal to the ileocecal valve at colonoscopy were unsuccessful. Barium contrast radiography of the small intestine performed 17 years later because of a decrease in Hb level to 9.8 g/dL (female normal: 11-16 g/dL) (December 1998) revealed 7 polyps ranging from 1 to 4 cm in size in the jejunum and the ileum. Although combined endoscopic/ surgical treatment was recommended to the patient, she was reluctant to undergo laparotomy. Her subsequent course was characterized by relapsing anemia (Hb, 6.7-9.9 g/dL) that responded to oral administration of iron. Four years later (January 2003), there was the third episode of intussusception in the small bowel. At emergent laparotomy at a local hospital, a 20-cm length of intussuscepted ileum was resected. Eight months after surgery (October 2003), the patient was admitted to our hospital for endoscopic resection of all polyps in the small intestine by means of doubleballoon enteroscopy. At this time, the family history was positive for PJS: a 25-year-old daughter had PJS but a 22year-old son did not. The patient’s mother had died of disseminated intravascular coagulation of unknown cause at age 43 years.
Double-contrast radiography of the small bowel revealed 9 pedunculated to semipedunculated polyps ranging in size from 15 to 60 mm. Two days later, doubleballoon enteroscopy was performed via the oral approach, with the intent of resecting all polyps larger than 10 mm (Table 1). All polyps were resected after submucosal injection of HSE solution. Only the 60-mm polyp was retrieved. Polypectomies were performed from distal to proximal without complication. The patient was discharged 6 days later. The patient was rehospitalized (December 2003) 2 months later for enteroscopic polypectomy via the anal approach. A group of 3 polyps was found that had a mass-like appearance, with occlusion of the narrowed lumen of the proximal ileum. A 20-mm pedunculated polyp (undetected radiographically) was resected first (without injection of HSE solution). A 30 ! 25-mm pedunculated polyp was resected next, after submucosal injection of HSE solution; the specimen was retrieved (Fig. 3). Then, a 20-mm pedunculated polyp and a 10-mm semipedunculated polyp close to this polyp were resected. A 20-mm semipedunculated polyp in the mid ileum also was resected after submucosal injection of HSE solution. Although all of these polyps were resected successfully, removal of the clump of 3 polyps was technically difficult and prolonged. Further attempts to remove more polyps, therefore, were deferred. On the day after polypectomy, the patient was asymptomatic, but examination revealed mild direct and rebound tenderness in the left periumbilical region and fever (38.1 C). The patient continued to fast for 2 days and fosfomycin was administered intravenously for 3 days. The fever resolved after 24 hours, and, at 3 days, there was no abdominal tenderness. A second enteroscopy via the anal route was performed 5 days after the first (December 10). A 15-mm pedunculated polyp (7-mm-diameter stalk), a 20-mm pedunculated (6-mm-diameter stalk) polyp, and two 10-mm pedunculated polyps that formed a mass-like cluster in the intrapelvic ileum were endoscopically resected without complication. These polyps were removed from proximal to distal. The patient was discharged 2 days later.
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components. Immunohistochemically, sporadic intranuclear overexpression of the p53 oncoprotein was observed in atypical cells in this large polyp. Ki-67-positive proliferative cells extended to the luminal surface of the mucosa.
Case 2
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Peutz-Jeghers polyps: resection at double-balloon enteroscopy without laparotomy
Figure 1. A, Double-contrast roentgenogram showing 45 ! 20-mm polyp (arrow) in jejunum. B, Roentgenogram showing enteroscope inserted via mouth with open polypectomy snare. C, Enteroscopic view of polyp with long, thick stalk. D, Snared polyp after injection of stalk with HSE solution.
A 60-mm diameter polyp retrieved from the duodenum and a 30 ! 25-mm pedunculated polyp removed from the ileum contained several adenomatous foci positive for p53 and Ki-67 at the luminal surface.
Endoscopically, the small intestine is relatively inaccessible,20 and abnormalities deep within this organ, here-
tofore, were untreatable endoscopically, except by laparotomy with surgeon-assisted interoperative endoscopy. In patients with PJS, hamartomatous polyps are most numerous in the jejunum and the ileum.6 These patients often are referred for surgery to remove these lesions, even if they are asymptomatic. Thus, patients with PJS usually (and reluctantly) undergo repeated enterectomy or polyp resections at emergent or planned laparotomies, as occurred in both of our patients. However, in both cases, PJPs throughout the jejunum and the ileum were
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Figure 1. Continued. E, Stump after polypectomy. F, Resection specimen.
resected with relative ease by double-balloon enteroscopy, thereby obviating the need for further surgery. Videocapsule endoscopy has the potential for visualization of the entire small bowel in all patients without bowel strictures, provided the battery and the recorder function properly and the intestine is clean. Although there is no comparative study, it is reasonable to question whether a complete exploration of the small bowel can be achieved with double-balloon enteroscopy. In patient 2, almost the entire small bowel was inspected, and all polyps demonstrated in the jejunum and the ileum by double-contrast radiography were resected. However, the entire small bowel is rarely intubated when doubleballoon enteroscopy is performed via the oral or the anal approach alone. However, it has the potential for complete small-intestinal exploration when the two approaches are combined. One way to document that the combined approach inspects the entire small intestine is to mark the deepest point of insertion by application of a mucosal clip or injection of sterilized Indian ink or indigo carmine. Then, when double-balloon enteroscopy is performed via the opposite approach, visualization of the mark confirms that the entire small intestine has been inspected. We performed 66 doubleballoon enteroscopies in 40 patients between June 2003 and April 2004. There were no serious complications, including perforation and massive hemorrhage. Of these 66 examinations, deep insertion of the small bowel was impossible in two patients because of adhesions. One had a history of pancolectomy for familial polyposis, and the enteroscopy was limited by a postoperative adhesion approximately 40 cm from the ligament of Treitz. The other patient had a history of appendectomy with the adhesion being located approximately 30 cm from the ileocecal valve. As with capsule endoscopy, intraabdominal adhesions also are problematic for doubleballoon enteroscopy.
Evidence of a minor complication (abdominal tenderness and fever) was noted in patient 2 on the day after polypectomy. Mathus-Vliegen and Tytgat7 noted that PJPs that are bulky, locally concentrated in large numbers, invaginated, thick stalked, and those with serosal retraction into the stalk, are unsuitable for polypectomy, even if performed intraoperatively, and recommended that such lesions be removed by enterectomy. Radiographically, some of the polyps in our second patient were retracted into a narrowed intestinal lumen. This appearance may indicate the presence of transmural fibrosis or subclinical invagination. These polyps probably would be considered unsuitable for polypectomy according to the criteria of Mathus-Vliegen and Tytgat.7 Thus, resection of one or more of these lesions may have resulted in transmural thermal injury with mild localized peritonitis, the so-called postpolypectomy syndrome. The patient remained asymptomatic, and the fever and abdominal tenderness resolved with conservative treatment. Almost all PJPs are easy to resect, because they are pedunculated. Enteroscopic resection of even bulky and retracted PJPs is possible and preferable to surgery, as long as patients do not have symptoms that warrant operative treatment. Ideally, double-balloon enteroscopic polypectomy should be performed when PJPs are relatively small and thereby avoid the technically more difficult endoscopic resection of large polyps at a later stage. Another complication of PJS is the development of intestinal adenoma and adenocarcinoma. Intranuclear expression of p53 in GI adenocarcinomas in PJS has been demonstrated by immunohistochemistry.23–25 In our two patients, p53 with topographical expression of Ki-67 was demonstrated immunohistochemically, specifically in adenomatous components of all polyps larger than 30 mm in diameter. Thus, double-balloon enteroscopic polypectomy also may be useful for prevention of carcinogenesis.
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Peutz-Jeghers polyps: resection at double-balloon enteroscopy without laparotomy
Figure 2. A, Double-contrast roentgenogram (with compression) showing 10 ! 8-mm polyp in ileum. B, Roentgenogram showing enteroscope inserted via anus with snare open. C, Chromoendoscopic image (indigo carmine) of pedunculated polyp. D, Excised polyp and stump. E, Resection specimen.
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Figure 3. A, Barium contrast roentgenogram (with compression) showing polyp with multiple bosselations. B, Roentgenogram showing enteroscope inserted via anus with injection needle. C, Enteroscopic image showing snared polyp. D, Resection specimen.
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Peutz-Jeghers polyps: resection at double-balloon enteroscopy without laparotomy
In conclusion, experience in two patients with PJS indicates that double-balloon enteroscopy is useful for treatment of PJPs throughout the small intestine. This enteroscopic method has the potential to change the conventional management of patients with PJS.
14.
15.
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ACKNOWLEDGMENT The authors thank Hironori Yamamoto MD, PhD, Jichi Medical School, for technical advice and John Cole for proofreading.
17. 18.
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Received June 7, 2004. For revision August 8, 2004. Accepted September 27, 2004. Current affiliations: Division of Gastroenterology, Department of Therapeutic Medicine, Department of Laboratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan, Department of Endoscopy, Department of Pathology, Nagoya University Hospital, Nagoya, Japan, Division of Gastroenterology, Department of Internal Medicine, Toyohashi Municipal Hospital, Aichi, Japan. Reprint requests: Naoki Ohmiya, MD, PhD, Division of Gastroenterology, Department of Therapeutic Medicine, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan.