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Capsule endoscopy for small bowel surveillance in hereditary intestinal polyposis and non-polyposis syndromes
Gastrointest Endoscopy Clin N Am 14 (2004) 149 – 158
Capsule endoscopy for small bowel surveillance in hereditary intestinal polyposis and non-polyposis syndromes Karsten Schulmann, MD, Wolff Schmiegel, MD, PhD* Department of Medicine, Ruhr-University Bochum, Knappschaftskrankenhaus, In der Schornau 23-25, Bochum D-44892, Germany
Capsule endoscopy (CE) is rapidly emerging as an accepted sensitive novel modality for the noninvasive assessment of small bowel pathologies [1]. Recently published clinical trials have shown that CE carries a high diagnostic yield in patients suffering from obscure gastrointestinal (GI) bleeding [2– 6]. Beyond the high diagnostic yield in patients suffering from obscure GI bleeding, the value of CE in other small bowel disorders has to be evaluated. Most recently, a high sensitivity in patients with a suspicion of Crohn’s disease was reported [7]. CE may also be of use for the search of tumors or tumor-like lesions in patient groups that present with a known increased risk for small bowel carcinomas (SBC), such as familial adenomatous polyposis (FAP), Peutz-Jeghers Syndrome (PJS), and familial juvenile polyposis (FJP) or hereditary nonpolyposis colorectal cancer (HNPCC). Relative and lifetime risks for SBC in these hereditary colorectal cancer syndromes are shown in Table 1. Patients with hereditary polyposis syndromes such as PJS require regular surveillance of the small bowel to enable early detection of SBC and to prevent benign complications such as bleeding, obstruction intussusception. Screening or surveillance for small bowel polyps is difficult with current technologies. Regular radiograph enteroclysis results in accumulating exposure to ionizing radiation. The sensitivity to detect small lesions is low, and even large polyps can be missed by enteroclysis. An alternative for radiograph enteroclysis is push enteroscopy (PE); however, only up to 30% of the small bowel length
This work was supported by a grant from the German Cancer Foundation (Deutsche Krebshilfe). Electronic database information: the URL for the data in this article is: Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/. The results have been presented in part at Digestive Disease Week (DDW) 2003 [25]. * Corresponding author. E-mail address: [email protected] (W. Schmiegel). 1052-5157/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.giec.2003.10.014
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Table 1 Small bowel cancer risk in hereditary colorectal cancer syndromes
Familial adenomatous polyposis Peutz-Jeghers Syndrome Familial juvenile polyposis Hereditary nonpolyposis colorectal cancer
Cumulative lifetime risk (%)
Relative risk
5 – 12 13 NA 1–4
> 100 520 NA >100
can be visualized by PE. Magnetic resonance (MR) enteroclysis is not yet well established in many radiology units is still experimental. CE is a new technology that allows for the first time a noninvasive endoscopic assessment of the entire small bowel. We report our experiences with CE in the first 35 patients with hereditary polyposis and nonpolyposis syndromes. CE was performed in a standard technique as suggested by Given Imaging Ltd. (Yoqneam, Israel). The localization of small bowel lesions was estimated by analyzing the time scale between identified fix points (pylorus passage and ileocecal valve respective entry in the pouch or ileostoma). For patients investigated after July 1, 2002, an additional software-based localization tool was available. For FAP patients, the results of CE were compared with conventional endoscopy (esophagogastroduodenoscopy [EGD] or PE) of the upper gastrointestinal tract using the Spigelman classification system [8]. Due to the impossibility of obtaining histologic type and grade of dysplasia, the score determined by CE consisted only of number and size of polyps (modified Spigelman score). Severity of polyposis in PJS patients was assessed by counting and size estimation of polyps. Size estimation was re-evaluated in all patients after a learning period by having investigated a number of patients by CE; knowledge of polyp size was measured by intestinoscopy, radiology, or surgery. The results of CE were correlated to reference procedures (PE, enteroclysis, MR enteroclysis, blood tests, surgery).
Familial adenomatous polyposis Approximately 70% of FAP patients (OMIM 175,100) develop adenomatous polyps in the duodenum, and 5% to 10% develop gastric adenomas. The rela-
Fig. 1. CE in FAP. (A) Large polypoid lesion located in the gastric antrum (histology: tubular adenoma with moderate dysplasia). (B) Two large polypoid lesions (gastric antrum, small curvature) (histology: tubulo-villous adenomas with HGD and focal T1 carcinomas in both polyps). (C) Multiple large proximal duodenal adenomas (histology: tubulo-villous adenomas with moderate and high-grade dysplasia). (D) Large flat adenoma located in the distal portion of the duodenum (histology: tubulovillous adenoma with moderate dysplasia). (E) Multiple small distal duodenal adenomas (tubular adenomas with LGD). ( F). Polyp in the distal jejunum. A similar lesion was located further downstream in the small intestine. This patient lacks polyps in the endoscopically accessible parts of the small intestine. The results were not confirmed by intraoperative endoscopy due to the very small size of the lesion (< 3 mm) bearing no significant risk for malignancy at this time, and the patient was subjected to further surveillance. (See also Color Plates 36 – 41).
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tive risk (RR) of gastric cancer is not significantly increased, whereas duodenal cancer (RR > 300) and ampullary cancer (RR > 120) are the major diseaserelated causes of death in FAP patients after colectomy [9]. Clinically, the severity of upper gastrointestinal polyposis is classified by determing the Spigelman score [8]. Severe polyposis (Spigelman IV) is present in about 10%
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of cases. Upper GI cancer formation in FAP patients clearly follows the adenoma-carcinoma sequence similar to colon carcinogenesis. Therefore, regular screening of the upper GI tract is recommended for FAP patients [10 – 14]. Although the polyposis of the duodenum and especially the periampullary region is now recognized as a major issue in these patients, little is known about the incidence and clinical significance of adenomatous polyps of the jejunum and ileum in FAP patients. We examined 21 patients with FAP (12 men, nine women). Median age was 40 years (range 15 to 56). All patients were clinically asymptomatic, if improved stool frequency after proctocolectomy was not considered. EGD or PE was performed as reference examination procedure. CE as well as the reference procedures did not reveal any gastric, duodenal, or small bowel adenomas in five patients. Two patients had major findings in the stomach, demonstrating large adenomas of the gastric antrum (up to 20 mm) (Fig. 1A), which were subsequently confirmed by PE and histology (each tubular adenomas with low grade dysplasia [LGD]). One additional patient had two large gastric adenomas (Fig. 1B) in addition to severe duodenal polyposis (Fig. 1C). In four patients the detection of polyps was restricted to the duodenum, which was confirmed by endoscopy (Fig. 1D, E). In 12 patients duodenal and jejunal polyps could be detected by CE. The jejunal polyps were clearly limited to the duodenum and proximal jejunum in eight patients. Additional polyps of the distal jejunum were identified in only four patients. In all 12 patients, the predominant polyp burden was located in the duodenum. The distal jejunal and ileal polyps were not assessible by reference endoscopy. In four patients the assessment of polyposis by CE and reference endoscopy was distinctly different. In three patients, polyps in the jejunum disclosed by CE could not be identified by EGD (Fig. 1F). In contrast, in the third discordant patient two small duodenal adenomas were missed by CE. In one additional patient an adenoma of the papilla of Vater was missed by CE (6 mm in diameter). However, the severity scores added up to the same category due to detection of the five other polyps (up to 10 mm) by both methods (Table 2). In conclusion, one adenoma of the papilla of Vater and two small duodenal adenomas in a second patient were missed by CE, resulting in a sensitivity of 91% in FAP. In contrast, in 5% of FAP patients examined, isolated distal small
Table 2 Correlation of modified Spigelman-Scores (only size and number) measured by CE and reference endoscopy (including gastric and jejunal pathologies) CE Conventional endoscopy
0
1–2
3–4
5–6
0 1–2 3–4 5–6
5 1 – –
1 – – –
1 1 7 –
– – – 7
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bowel polyps were diagnosed. However, in the majority of FAP patients the main polyp burden was located in the duodenum, within the reach of the duodenoscope. Furthermore, identifying and assessing the papilla of Vater was not possible in any patient, which calls for the mandatory routine use of standard upper GI endoscopy with side-viewing duodenoscopes to control the development of adenomas in FAP patients. CE can only be used additionally to identify patients with significant distal jejunal polyposis. However, this is supposed to be a rather infrequent situation. Active control of the capsule endoscope, the precise assessment of polyp size, and the opportunity to obtain biopsies are important long-term future requirements for CE to extend the indication to FAP patients.
Peutz-Jeghers Syndrome PJS (OMIM 175,200) is characterized by hamartomatous GI polyps and mucocutaneous melanin pigmentations (Fig. 2). PJS polyps occur throughout the alimentary tract with a predilection for the small bowel. Generally, first symptoms occur during adolescence or young adulthood with recurrent abdominal discomfort and cramping due to intussusception of small bowel segments. Severe complications are acute intestinal obstruction and subsequent ileus. Many patients present with occult GI bleeding and iron deficiency anemia. Patients with PJS have a very high risk for developing various malignancies [15,16]. The relative risk for small bowel cancer is significantly increased (RR = 520) resulting in a lifetime risk for small bowel cancer of 13% [16]. Due to the high risk for developing benign intestinal complications and malignant disease, regular screening of the small intestinum is recommended [13,17]. Gastrointestinal screening should be initiated by the age of 10 to 12 years, consisting of gastroduodenoscopy, colonoscopy, enteroclysis, and red blood cell count at regular intervals. In addition, screening for pancreatic, breast, and gynecologic cancers is recommended. We enrolled 10 patients with PJS (two men, eight women). Median age was 35 years (range 23 to 58). In group A (symtomatic, n = 5), CE detected multiple large polyps in all patients. All patients were admitted to surgery after performing CE because of polyps outside the range of the push-enteroscope (n = 3) or high polyp burden (n = 2). In contast in group B (asymptomatic/unspecific symptoms, n = 5), one patient had no polyps and the other four patients had only few polyps, which could be removed by polypectomy. Moreover, in one patient a concomittant Crohn’s disease in addition to PJS was diagnosed by CE. In two patients small polyps of the distal small bowel were diagnosed only by CE. Due to the absence of symptoms, the patients were subjected to further surveillance. Regarding PJS, the surveillance of the small bowel in PJS is currently difficult. Repeated enteroclysis (2- to 3-year intervals) and annual red blood cell counts are currently the first-line small bowel surveillance procedures for PJS patients [13]. However, when starting enteroclysis by age 10, a high radiation dose is accumulated over the lifetime. Our data suggest that CE can be applied as a first-line
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Fig. 2. CE in PJS. (A) Large jejunal polyp with luminal obstruction. (B) Confirmative enteroclysis. (C) Multiple gastric hamatomatous polyps. (D) Large distal jejunal hamartomatous polyps. (E, F) Multiple large (> 30 mm) hamartomatous polyps throughout the entire small bowel with predominant localization in the duodenum and proximal jejunum. The polyps often display superficial erosions consistent with iron-deficiency anemia. (See also Color Plates 42 – 46).
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imaging procedure with high sensitivity and specifity for the surveillance of small bowel hamartomas in patients with PJS. The estimation of number, localization, and size was precise enough to allow a clinical decision based on the CE data in all patients investigated (ie, surgery, push intestinoscopy, surveillance). It is therefore possible that CE might replace enteroclysis in the near future in this patient group. The risk of capsule retention in the gastrointestinal tract may be significantly increased due to polyp formation and could subsequently result in increased numbers of surgical procedures. This should be kept in mind when offering CE to patients with PJS, especially when they are asymptomatic.
Familial juvenile polyposis FJP (OMIM 174,900) is a rare autosomal dominant polyposis disorder characterized by multiple juvenile polyps of the colorectum. Predilection site is the colorectum (98%). The stomach (13%) and small bowel (6%) are affected in 13% and 6%, respectively, based on endoscopic and radiologic studies. The risk of GI malignancies is significantly increased (RR = 16) with an estimated lifetime risk of 20% to 60% for the development of colorectal cancer. The median age at diagnosis is approximately 35 to 40 years [18 –20]. The risk for gastric cancer is also significantly increased. Duodenal and pancreatic cancer may be associated with JPC [18,21,22]. According to the low incidence of the disease, there are no general surveillance recommendations. In proven JPC, yearly colonoscopy beginning in early childhood is necessary to detect and remove polyps. We performed CE in two female patients from one family (9 and 28 years old) with FJP. Both had gastric fundic gland cysts and colonic polyps (Fig. 3A). In
Fig. 3. CE in FJP. (A) Large colonic polyp. (B) Large jejunal polyp. (See also Color Plates 47 and 48).
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Fig. 4. CE in HNPCC. Metastatic adenocarcinoma infiltration in the jejunum presenting with obscure GI bleeding. (See also Color Plate 49).
addition CE identified a small bowel in the jejunum of the mother (Fig. 3B), whereas the daughter had no pathologic findings in the small bowel.
Hereditary nonpolyposis colorectal cancer HNPCC is an autosomal dominant disorder characterizd by a mismatch-repair deficiency due a germline mutation in an mismatch repair (MMR) gene. Germline muation carriers have a high lifetime risk of developing malignancies, especially for colorectal cancer (80%) and endometrial carcinomas (40% to 60%). Among these cancers, small bowel cancer occurs with a cumulative lifetime risk of up to 4% and an elevated RR > 100 compared with the general population [23]. Two HNPCC patients were investigated. One had a personal history of duodenal cancer. CE detected no pathologic findings in this patient. The other patient with a personal history of colon cancer and repeated metastases to the small bowel had recurrent GI bleeding episodes and required repeated blood transfusions. Prior upper and lower endoscopy did not identify a relevant bleeding source. The first CE examination was unsuccessful because the capsule was retained in the stomach for more than 6 hours. The second CE examination was performed with an EGD-assisted capsule insertion in the duodenum [24]. CE disclosed an actively bleeding (oozing) nodule within the proximal jejunum (Fig. 4), which was subsequently identified as a metastatic adenocarcinoma tumor in the wall of the small bowel.
Summary The surveillance of the small bowel in patients with hereditary polyposis syndromes is difficult so far. CE is a promising new approach for the surveillance of the small bowel in patients with polyposis snydromes, especially for patients
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with PJS and FJP. In contrast, the additional diagnostic yield in patients with FAP is low when compared with push-enteroscopy. Regarding HNPCC patients, algorithms for defining an appropriate setting of indications (such as family or personal history of small bowel cancer, obscure GI bleeding) and screening intervals have to be defined.
Acknowledgments We would like to thank Tilman Vogel, MD, and Gabriela Moeslein, MD (University of Dusseldorf, Director: Wolfram T. Knoefel, MD), Frank Hummel, MD (University of Mannheim, Director: Manfred V. Singer, MD) and Bruno Neu, MD (University of Munich, Director: Meinhard Classen, MD).
References [1] Iddan G, Meron G, Glukhovsky A, Swain P. Wireless capsule endoscopy. Nature 2000;405:417. [2] Lewis BS, Swain P. Capsule endoscopy in the evaluation of patients with suspected small intestinal bleeding: results of a pilot study. Gastrointest Endosc 2002;56:349 – 53. [3] Ell C, Remke S, May A, Helou L, Henrich R, Mayer G. The first prospective controlled trial comparing wireless capsule endoscopy with push enteroscopy in chronic gastrointestinal bleeding. Endoscopy 2002;34:685 – 9. [4] Appleyard M, Glukhovsky A, Swain P. Wireless-capsule diagnostic endoscopy for recurrent small-bowel bleeding. N Engl J Med 2001;344:232 – 3. [5] Schulmann K, Hollerbach S, Willert J, Kraus K, Schmiegel W. Detection of occult gastrointestinal bleeding disorders by video capsule endoscopy (M2A) of the small bowel. Gastroenterology 2002;122(Suppl):A-329 [AGA Abstract M1651]. [6] Rossini FP, Pennazio M. Small-bowel endoscopy. Endoscopy 2002;34:13 – 20. [7] Fireman Z, Mahajna E, Broide E, Shapiro M, Fich L, Sternberg A, et al. Diagnosing small bowel Crohn’s disease with wireless capsule endoscopy. Gut 2003;52:390 – 2. [8] Spigelman AD, Williams CB, Talbot IC, Domizio P, Phillips RK. Upper gastrointestinal cancer in patients with familial adenomatous polyposis. Lancet 1989;2:783 – 5. [9] Galle TS, Juel K, Bulow S. Causes of death in familial adenomatous polyposis. Scand J Gastroenterol 1999;34:808 – 12. [10] Groves CJ, Saunders BP, Spigelman AD, Phillips RK. Duodenal cancer in patients with familial adenomatous polyposis (FAP): results of a 10 year prospective study. Gut 2002;50:636 – 41. [11] Dunlop MG. Guidance on gastrointestinal surveillance for hereditary non-polyposis colorectal cancer, familial adenomatous polypolis, juvenile polyposis, and Peutz-Jeghers syndrome. Gut 2002;51(Suppl 5):V21 – 7. [12] Schmiegel W, Adler G, Fru¨hmorgen P, Folsch U, Graeven U, Layer P, et al. Kolorektales Karzinom: Pra¨vention und Fru¨herkennung in der asymptomatischen Bevo¨lkerung - Vorsorge bei Risikopatienten - Endoskopische Diagnostik, Therapie und Nachsorge von Polypen und Karzinomen. Z Gastroenterol 2000;38:49 – 75. [13] Burt RW. Colon cancer screening. Gastroenterology 2000;119:837 – 53. [14] Winawer SJ, Fletcher RH, Miller L, Godlee F, Stolar MH, Mulrow CD, et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997;112:594 – 642. [15] Boardman LA, Thibodeau SN, Schaid DJ, Lindor NM, McDonnell SK, Burgart LJ, et al. Increased risk for cancer in patients with the Peutz-Jeghers syndrome. Ann Intern Med 1998; 128:896 – 9. [16] Giardiello FM, Brensinger JD, Tersmette AC, Goodman SN, Petersen GM, Booker SV, et al.
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K. Schulmann, W. Schmiegel / Gastrointest Endoscopy Clin N Am 14 (2004) 149–158 Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 2000;119: 1447 – 53. Giardiello FM, Welsh SB, Hamilton SR, Offerhaus GJ, Gittelsohn AM, Booker SV, et al. Increased risk of cancer in the Peutz-Jeghers syndrome. N Engl J Med 1987;316:1511 – 4. Giardiello FM, Offerhaus JG. Phenotype and cancer risk of various polyposis syndromes. Eur J Cancer 1995;31A:1085 – 7. Coburn MC, Pricolo VE, DeLuca FG, Bland KI. Malignant potential in intestinal juvenile polyposis syndromes. Ann Surg Oncol 1995;2:386 – 91. Woodford-Richens K, Bevan S, Churchman M, Dowling B, Jones D, Norbury CG, et al. Analysis of genetic and phenotypic heterogeneity in juvenile polyposis. Gut 2000;46:656 – 60. Howe JR, Mitros FA, Summers RW. The risk of gastrointestinal carcinoma in familial juvenile polyposis. Ann Surg Oncol 1998;5:751 – 6. Walpole IR, Cullity G. Juvenile polyposis: a case with early presentation and death attributable to adenocarcinoma of the pancreas. Am J Med Genet 1989;32:1 – 8. Aarnio M, Sankila R, Pukkala E, Salovaara R, Aaltonen LA, de la Chapelle A, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 1999;81:214 – 8. Hollerbach S, Kraus K, Willert J, Schulmann K, Schmiegel W. Endoscopically assisted video capsule endoscopy of the small bowel in patients with functional gastric outlet obstruction. Endoscopy 2003;35:226 – 9. Schulmann K, Hollerbach S, Kraus K, Reiser M, Willert J, Mo¨slein G, et al. Value of capsule endoscopy for the detection of small bowel polyps in patients with hereditary polyposis syndromes. Gastroenterology 2003;124:A550.
Capsule endoscopy for small bowel surveillance in hereditary intestinal polyposis and non-polyposis syndromes Karsten Schulmann, MD, Wolff Schmiegel, MD, PhD* Department of Medicine, Ruhr-University Bochum, Knappschaftskrankenhaus, In der Schornau 23-25, Bochum D-44892, Germany
Capsule endoscopy (CE) is rapidly emerging as an accepted sensitive novel modality for the noninvasive assessment of small bowel pathologies [1]. Recently published clinical trials have shown that CE carries a high diagnostic yield in patients suffering from obscure gastrointestinal (GI) bleeding [2– 6]. Beyond the high diagnostic yield in patients suffering from obscure GI bleeding, the value of CE in other small bowel disorders has to be evaluated. Most recently, a high sensitivity in patients with a suspicion of Crohn’s disease was reported [7]. CE may also be of use for the search of tumors or tumor-like lesions in patient groups that present with a known increased risk for small bowel carcinomas (SBC), such as familial adenomatous polyposis (FAP), Peutz-Jeghers Syndrome (PJS), and familial juvenile polyposis (FJP) or hereditary nonpolyposis colorectal cancer (HNPCC). Relative and lifetime risks for SBC in these hereditary colorectal cancer syndromes are shown in Table 1. Patients with hereditary polyposis syndromes such as PJS require regular surveillance of the small bowel to enable early detection of SBC and to prevent benign complications such as bleeding, obstruction intussusception. Screening or surveillance for small bowel polyps is difficult with current technologies. Regular radiograph enteroclysis results in accumulating exposure to ionizing radiation. The sensitivity to detect small lesions is low, and even large polyps can be missed by enteroclysis. An alternative for radiograph enteroclysis is push enteroscopy (PE); however, only up to 30% of the small bowel length
This work was supported by a grant from the German Cancer Foundation (Deutsche Krebshilfe). Electronic database information: the URL for the data in this article is: Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/. The results have been presented in part at Digestive Disease Week (DDW) 2003 [25]. * Corresponding author. E-mail address: [email protected] (W. Schmiegel). 1052-5157/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.giec.2003.10.014
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Table 1 Small bowel cancer risk in hereditary colorectal cancer syndromes
Familial adenomatous polyposis Peutz-Jeghers Syndrome Familial juvenile polyposis Hereditary nonpolyposis colorectal cancer
Cumulative lifetime risk (%)
Relative risk
5 – 12 13 NA 1–4
> 100 520 NA >100
can be visualized by PE. Magnetic resonance (MR) enteroclysis is not yet well established in many radiology units is still experimental. CE is a new technology that allows for the first time a noninvasive endoscopic assessment of the entire small bowel. We report our experiences with CE in the first 35 patients with hereditary polyposis and nonpolyposis syndromes. CE was performed in a standard technique as suggested by Given Imaging Ltd. (Yoqneam, Israel). The localization of small bowel lesions was estimated by analyzing the time scale between identified fix points (pylorus passage and ileocecal valve respective entry in the pouch or ileostoma). For patients investigated after July 1, 2002, an additional software-based localization tool was available. For FAP patients, the results of CE were compared with conventional endoscopy (esophagogastroduodenoscopy [EGD] or PE) of the upper gastrointestinal tract using the Spigelman classification system [8]. Due to the impossibility of obtaining histologic type and grade of dysplasia, the score determined by CE consisted only of number and size of polyps (modified Spigelman score). Severity of polyposis in PJS patients was assessed by counting and size estimation of polyps. Size estimation was re-evaluated in all patients after a learning period by having investigated a number of patients by CE; knowledge of polyp size was measured by intestinoscopy, radiology, or surgery. The results of CE were correlated to reference procedures (PE, enteroclysis, MR enteroclysis, blood tests, surgery).
Familial adenomatous polyposis Approximately 70% of FAP patients (OMIM 175,100) develop adenomatous polyps in the duodenum, and 5% to 10% develop gastric adenomas. The rela-
Fig. 1. CE in FAP. (A) Large polypoid lesion located in the gastric antrum (histology: tubular adenoma with moderate dysplasia). (B) Two large polypoid lesions (gastric antrum, small curvature) (histology: tubulo-villous adenomas with HGD and focal T1 carcinomas in both polyps). (C) Multiple large proximal duodenal adenomas (histology: tubulo-villous adenomas with moderate and high-grade dysplasia). (D) Large flat adenoma located in the distal portion of the duodenum (histology: tubulovillous adenoma with moderate dysplasia). (E) Multiple small distal duodenal adenomas (tubular adenomas with LGD). ( F). Polyp in the distal jejunum. A similar lesion was located further downstream in the small intestine. This patient lacks polyps in the endoscopically accessible parts of the small intestine. The results were not confirmed by intraoperative endoscopy due to the very small size of the lesion (< 3 mm) bearing no significant risk for malignancy at this time, and the patient was subjected to further surveillance. (See also Color Plates 36 – 41).
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tive risk (RR) of gastric cancer is not significantly increased, whereas duodenal cancer (RR > 300) and ampullary cancer (RR > 120) are the major diseaserelated causes of death in FAP patients after colectomy [9]. Clinically, the severity of upper gastrointestinal polyposis is classified by determing the Spigelman score [8]. Severe polyposis (Spigelman IV) is present in about 10%
152
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of cases. Upper GI cancer formation in FAP patients clearly follows the adenoma-carcinoma sequence similar to colon carcinogenesis. Therefore, regular screening of the upper GI tract is recommended for FAP patients [10 – 14]. Although the polyposis of the duodenum and especially the periampullary region is now recognized as a major issue in these patients, little is known about the incidence and clinical significance of adenomatous polyps of the jejunum and ileum in FAP patients. We examined 21 patients with FAP (12 men, nine women). Median age was 40 years (range 15 to 56). All patients were clinically asymptomatic, if improved stool frequency after proctocolectomy was not considered. EGD or PE was performed as reference examination procedure. CE as well as the reference procedures did not reveal any gastric, duodenal, or small bowel adenomas in five patients. Two patients had major findings in the stomach, demonstrating large adenomas of the gastric antrum (up to 20 mm) (Fig. 1A), which were subsequently confirmed by PE and histology (each tubular adenomas with low grade dysplasia [LGD]). One additional patient had two large gastric adenomas (Fig. 1B) in addition to severe duodenal polyposis (Fig. 1C). In four patients the detection of polyps was restricted to the duodenum, which was confirmed by endoscopy (Fig. 1D, E). In 12 patients duodenal and jejunal polyps could be detected by CE. The jejunal polyps were clearly limited to the duodenum and proximal jejunum in eight patients. Additional polyps of the distal jejunum were identified in only four patients. In all 12 patients, the predominant polyp burden was located in the duodenum. The distal jejunal and ileal polyps were not assessible by reference endoscopy. In four patients the assessment of polyposis by CE and reference endoscopy was distinctly different. In three patients, polyps in the jejunum disclosed by CE could not be identified by EGD (Fig. 1F). In contrast, in the third discordant patient two small duodenal adenomas were missed by CE. In one additional patient an adenoma of the papilla of Vater was missed by CE (6 mm in diameter). However, the severity scores added up to the same category due to detection of the five other polyps (up to 10 mm) by both methods (Table 2). In conclusion, one adenoma of the papilla of Vater and two small duodenal adenomas in a second patient were missed by CE, resulting in a sensitivity of 91% in FAP. In contrast, in 5% of FAP patients examined, isolated distal small
Table 2 Correlation of modified Spigelman-Scores (only size and number) measured by CE and reference endoscopy (including gastric and jejunal pathologies) CE Conventional endoscopy
0
1–2
3–4
5–6
0 1–2 3–4 5–6
5 1 – –
1 – – –
1 1 7 –
– – – 7
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bowel polyps were diagnosed. However, in the majority of FAP patients the main polyp burden was located in the duodenum, within the reach of the duodenoscope. Furthermore, identifying and assessing the papilla of Vater was not possible in any patient, which calls for the mandatory routine use of standard upper GI endoscopy with side-viewing duodenoscopes to control the development of adenomas in FAP patients. CE can only be used additionally to identify patients with significant distal jejunal polyposis. However, this is supposed to be a rather infrequent situation. Active control of the capsule endoscope, the precise assessment of polyp size, and the opportunity to obtain biopsies are important long-term future requirements for CE to extend the indication to FAP patients.
Peutz-Jeghers Syndrome PJS (OMIM 175,200) is characterized by hamartomatous GI polyps and mucocutaneous melanin pigmentations (Fig. 2). PJS polyps occur throughout the alimentary tract with a predilection for the small bowel. Generally, first symptoms occur during adolescence or young adulthood with recurrent abdominal discomfort and cramping due to intussusception of small bowel segments. Severe complications are acute intestinal obstruction and subsequent ileus. Many patients present with occult GI bleeding and iron deficiency anemia. Patients with PJS have a very high risk for developing various malignancies [15,16]. The relative risk for small bowel cancer is significantly increased (RR = 520) resulting in a lifetime risk for small bowel cancer of 13% [16]. Due to the high risk for developing benign intestinal complications and malignant disease, regular screening of the small intestinum is recommended [13,17]. Gastrointestinal screening should be initiated by the age of 10 to 12 years, consisting of gastroduodenoscopy, colonoscopy, enteroclysis, and red blood cell count at regular intervals. In addition, screening for pancreatic, breast, and gynecologic cancers is recommended. We enrolled 10 patients with PJS (two men, eight women). Median age was 35 years (range 23 to 58). In group A (symtomatic, n = 5), CE detected multiple large polyps in all patients. All patients were admitted to surgery after performing CE because of polyps outside the range of the push-enteroscope (n = 3) or high polyp burden (n = 2). In contast in group B (asymptomatic/unspecific symptoms, n = 5), one patient had no polyps and the other four patients had only few polyps, which could be removed by polypectomy. Moreover, in one patient a concomittant Crohn’s disease in addition to PJS was diagnosed by CE. In two patients small polyps of the distal small bowel were diagnosed only by CE. Due to the absence of symptoms, the patients were subjected to further surveillance. Regarding PJS, the surveillance of the small bowel in PJS is currently difficult. Repeated enteroclysis (2- to 3-year intervals) and annual red blood cell counts are currently the first-line small bowel surveillance procedures for PJS patients [13]. However, when starting enteroclysis by age 10, a high radiation dose is accumulated over the lifetime. Our data suggest that CE can be applied as a first-line
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Fig. 2. CE in PJS. (A) Large jejunal polyp with luminal obstruction. (B) Confirmative enteroclysis. (C) Multiple gastric hamatomatous polyps. (D) Large distal jejunal hamartomatous polyps. (E, F) Multiple large (> 30 mm) hamartomatous polyps throughout the entire small bowel with predominant localization in the duodenum and proximal jejunum. The polyps often display superficial erosions consistent with iron-deficiency anemia. (See also Color Plates 42 – 46).
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imaging procedure with high sensitivity and specifity for the surveillance of small bowel hamartomas in patients with PJS. The estimation of number, localization, and size was precise enough to allow a clinical decision based on the CE data in all patients investigated (ie, surgery, push intestinoscopy, surveillance). It is therefore possible that CE might replace enteroclysis in the near future in this patient group. The risk of capsule retention in the gastrointestinal tract may be significantly increased due to polyp formation and could subsequently result in increased numbers of surgical procedures. This should be kept in mind when offering CE to patients with PJS, especially when they are asymptomatic.
Familial juvenile polyposis FJP (OMIM 174,900) is a rare autosomal dominant polyposis disorder characterized by multiple juvenile polyps of the colorectum. Predilection site is the colorectum (98%). The stomach (13%) and small bowel (6%) are affected in 13% and 6%, respectively, based on endoscopic and radiologic studies. The risk of GI malignancies is significantly increased (RR = 16) with an estimated lifetime risk of 20% to 60% for the development of colorectal cancer. The median age at diagnosis is approximately 35 to 40 years [18 –20]. The risk for gastric cancer is also significantly increased. Duodenal and pancreatic cancer may be associated with JPC [18,21,22]. According to the low incidence of the disease, there are no general surveillance recommendations. In proven JPC, yearly colonoscopy beginning in early childhood is necessary to detect and remove polyps. We performed CE in two female patients from one family (9 and 28 years old) with FJP. Both had gastric fundic gland cysts and colonic polyps (Fig. 3A). In
Fig. 3. CE in FJP. (A) Large colonic polyp. (B) Large jejunal polyp. (See also Color Plates 47 and 48).
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Fig. 4. CE in HNPCC. Metastatic adenocarcinoma infiltration in the jejunum presenting with obscure GI bleeding. (See also Color Plate 49).
addition CE identified a small bowel in the jejunum of the mother (Fig. 3B), whereas the daughter had no pathologic findings in the small bowel.
Hereditary nonpolyposis colorectal cancer HNPCC is an autosomal dominant disorder characterizd by a mismatch-repair deficiency due a germline mutation in an mismatch repair (MMR) gene. Germline muation carriers have a high lifetime risk of developing malignancies, especially for colorectal cancer (80%) and endometrial carcinomas (40% to 60%). Among these cancers, small bowel cancer occurs with a cumulative lifetime risk of up to 4% and an elevated RR > 100 compared with the general population [23]. Two HNPCC patients were investigated. One had a personal history of duodenal cancer. CE detected no pathologic findings in this patient. The other patient with a personal history of colon cancer and repeated metastases to the small bowel had recurrent GI bleeding episodes and required repeated blood transfusions. Prior upper and lower endoscopy did not identify a relevant bleeding source. The first CE examination was unsuccessful because the capsule was retained in the stomach for more than 6 hours. The second CE examination was performed with an EGD-assisted capsule insertion in the duodenum [24]. CE disclosed an actively bleeding (oozing) nodule within the proximal jejunum (Fig. 4), which was subsequently identified as a metastatic adenocarcinoma tumor in the wall of the small bowel.
Summary The surveillance of the small bowel in patients with hereditary polyposis syndromes is difficult so far. CE is a promising new approach for the surveillance of the small bowel in patients with polyposis snydromes, especially for patients
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with PJS and FJP. In contrast, the additional diagnostic yield in patients with FAP is low when compared with push-enteroscopy. Regarding HNPCC patients, algorithms for defining an appropriate setting of indications (such as family or personal history of small bowel cancer, obscure GI bleeding) and screening intervals have to be defined.
Acknowledgments We would like to thank Tilman Vogel, MD, and Gabriela Moeslein, MD (University of Dusseldorf, Director: Wolfram T. Knoefel, MD), Frank Hummel, MD (University of Mannheim, Director: Manfred V. Singer, MD) and Bruno Neu, MD (University of Munich, Director: Meinhard Classen, MD).
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