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Volume 7 Issue 1

Year 2008

VHJOE Editor:

John Deutsch, MDSt. Mary’s Duluth Clinic

International Editor:

Manoop S. Bhutani, MDMD Anderson Cancer Center, Houston TX

Editorial Board:

William R. Brugge, MDMassachusetts General

Hospital

Peter R. McNally, DODenver, CO

Thomas J. Savides, MDUniversity of California,

San Diego

C. Mel Wilcox, MDUniversity of Alabama,

Birmingham

Visible Human Project® is a registered trademark of

the U.S. National Library of Medicine. The National Library of Medicine is not affilated with the publication of this journal.

V i s i t u s o n l i n e a t w w w . v h j o e . o r g

The Visible Human Journal of Endoscopy (VHJOE) is a PEER REVIEWED journal, featuring EMBEDDED

VIDEO CLIPS and IMAGE-RICH articles. VHJOE publishes EXPERT REVIEWS from leading gastroenterologists as well

as interesting CASE REPORTS. Additionally, VHJOE features the VISIBLE HUMAN INTERACTIVE ATLAS, a powerful,

web-based application, developed by the Center for Human Simulation, which provides unparalleled views of human

anatomy.

Above: View of Interactive Atlas, showing selected anatomical structures (left) and corresponding oblique section (right).


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E D I T O R I A L

Table of Contents

Editor’s Column: Two New Sections John C. Deutsch, M.D.......................................................................................................1

A R T I C L E SAppendicitis Complicated by Appendiceal-Sigmoid Fistula LTC Bradley Bute, M.D., COL Frank Jahns, M.D.Amanda McNally, COL Peter R. McNally, D.O. ...........................................................2

L I T E R AT U R E R E V I E WLiterature Review - (1) Evaluation of postsurgical recurrence in Crohn’s . . . ;(2) Peroral cholecystoscopy with electrohydraulic lithotripsy for treatment . . . ;(3) High Dose Rifaximin for Treatment of Small Intestinal Bacterial OvergrowthPeter R. McNally, DO, FACG, FACP.............................................................................10

Guest Commentary Leslie H. Sobin, M.D. ...................................................................................................14

Role of EUS in Defining Extent of Disease and Guiding Therapy in Eosinophilic Gastritis with Pyloric Stenosis Bhavani Moparty, M.D., Karen Szauter, M.D.Manoop S. Bhutani, M.D., FASGE, FACG, FACP..........................................................5

CASES FROM THE ARMED FORCES INSTITUTE OF PATHOLOGY

Familial Small Intestinal Carcinoid Tumors Discovered by Capsule EndoscopyJohn C. Deutsch, M.D., Steven C. Teng .........................................................................7

Gastrointestinal stromal tumors, endocrine tumors, and neurofibroma involving the gastrointestinal tract of a patient with neurofibromatosis-1Janet C. Shaw, LtCol, USAF, MC, Angela Levy, COL, MC, USAAnupamjit K. Mehrotra, M.D., Lucas Sheldon, Maj, UDAF, MC,Leslie H. Sobin, M.D. ....................................................................................................16

V i s i t u s o n l i n e a t w w w . v h j o e . o r g V i s i t u s o n l i n e a t w w w . v h j o e . o r g

Volume 7 Issue 1

Year 2008

Editor’s Column || John C. Deutsch, M.D.

Two New Sections

11

A R T I C L E S

F E AT U R E D M O V I EFeatured Movie: Visible Human Splenic Vein John C. Deutsch, M.D.....................................................................................................26

I N F L A M M AT O R Y B O W E L D I S E A S EGuest Commentary: Bret Lashner, M.D. ........................................................................................................20

This issue of VHJOE features two new sections: “Cases from the Armed Forces of Pathology (AFIP)” and “Inflammatory Bowel Disease.” Dr. Sobin is a master educator in the field

of GI pathology and will direct his staff at the AFIP in the publication of this new and permanent new section in the journal. Dr. Bret Lashner is a national leader in the field of Inflammatory Bowel Disease and he will guide his staff from the Cleveland Clinic in the development of

a series of clinically relevant articles on IBD. We are certain that the readers of the Journal will find the materials presented in these new sections of Journal clinically helpful in the care and evaluation of their patients.

As usual, we will continue to publish case reports, literature reviews and anatomy based imaging. We are interested in having a repository of

Colon Cancer Surveillance Strategies in Inflammatory Bowel Disease Ahmed Kandiel, M.D., M.P.H. ......................................................................................21

Figure 1a: Anatomy models of the pancreas, duodenum and biliary tree

from the Visible Human data as derived from the VH Dissector Program.

Figure 1b: Anatomy models of the pancreas, duodenum and biliary tree from the Visible Human data as derived from the VH Dissector Program. This image shows the

pancreatic duct and biliary tree after removal of the other organs.


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V i s i t u s o n l i n e a t w w w . v h j o e . o r g22

Article || LTC Bradley Bute, M.D., COL Frank Jahns, M.D., Amanda C. McNally COL® Peter R. McNally, D.O.

Appendicitis Complicated by Appendiceal-Sigmoid Fistula

Figure 2: Labeled: Abdominal radiograph of a patient in the process of developing toxic megacolon from an inflammatory process in the abdomen. The descending colon lacks haustra, and thumbprinting is evident near the hepatic flexure and across the

transverse colon. In general, a 10 cm cecum or an 8 cm transverse colon is

at risk for complications.

pictures and articles for our readers to be able to refer to such as the posterior view of the pancreas (Figures

1a & b), or an example of an abdominal radiograph showing the development of toxic megacolon (Figure 2), and we encourage the submission of articles, images and video clips.

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official policy or reflecting the views of the Army or Department of Defense.

Key Words:

Appendicitis, fistula, and abdominal abscess

Introduction:

Delayed diagnosis of appendicitis can result in the complications of suppuration, rupture, and localized abscess formation.1,2 The fixation of the inflamed appendix to an adjacent structure or hollow organ with spontaneous fistulous drainage is an uncommon occurrence.3 Persistence of the fistulous communication, may resolve spontaneously or require surgical correction.4,5 We report a case of appendiceal abscess complicated by spontaneous fistulous decompression into the sigmoid colon. CT scan was helpful

in defining the nature of the abscess and the degree of fistulous communication. Antibiotic therapy was successful in acute management followed by elective laparoscopic appendectomy.

Case Report

An 18 year old male was admitted to our hospital for evaluation of a four day illness characterized by nausea, vomiting, and fever with associated diarrhea and abdominal pain. On physical examination the patient appeared toxic with a temperature of 104 degrees F. The abdomen was diffusely tender, but without guarding or signs of peritoneal irritation. Rectal examination was non tender and stool guaiac negative. Leukocyte count was 11,500 with 10% band forms. The remainder of the screening biochemical blood tests was unremarkable. Plain x-rays of the abdomen showed a nonspecific bowel gas pattern. Ultrasound of the appendix was reported to be normal. Pancultures of bodily fluids were obtained and antibiotic therapy initiated


Volume 7 Issue 1

Year 2008for suspected intra-abdominal sepsis. The patient rapidly and completely resolved all findings within 24 hours and antibiotics were stopped. Complete clinical resolution of symptoms, normalization of bowel habits off antibiotics for 3 days lead to the presumptive diagnosis of viral gastroenteritis.

Seven days after hospital discharge, the patient experienced acute onset of sharp lower abdominal pain, increased by defecation. This was followed by fecal urgency of numerous small bowel movements. Stools were initially formed, but progressed to a loose and watery consistency. There was no associated

hematochezia. The abdominal pain with defecation was excruciating and localized to the left lower quadrant and suprapubic area. The patient had experienced mild fever and was re-admitted for further evaluation. Directed inquiry was negative for recent travel, exposure to other ill individuals, rectal trauma, or family history of inflammatory bowel disease. The patient had a core temperature 101.4 F. Physical examination was remarkable for a soft abdomen with mild tenderness in both lower quadrants. Screening

blood chemistries were normal except for a leukocyte count of 23,600 with 90% PMN forms. An un-prepped s i g m o i d o s c o p i c examination was performed to evaluate for possible infections, idiopathic or antibiotic related colitis. Examination to the splenic flexure showed no evidence of colitis. Endoscopic findings were remarkable for a focal 5 cm mound of

friable mucosa with extrinsic compression of the sigmoid colon about 18 cm from the anal verge. Within the center of this friable mass was an 8 mm hole in the colon with free flow of fibrinous white strands and brown-white mucopurulent material, Figure 1. Histologic examination of mucosal biopsies showed colonic mucosa with ulceration, acute inflammation and crypt abscesses, but no granulomas.

Rapid clinical and laboratory improvement occurred after initiation of antibiotic therapy. Computerized tomography (CT), Figure 2a of the abdomen identified thickening of sigmoid colon and a contained parasigmoid fluid collection. No changes suggestive of inflammatory bowel disease were identified with a dedicated contrast examination of the small bowel. After 10 days of intravenous antimicrobial therapy, CT imaging was repeated, Figure 2b. The sigmoid fistulous communication was closed and the paracolonic fluid collection resolved. Six weeks later, sigmoidoscopy showed complete healing of the fistulous communication, Figure 3. At laparoscopy the appendix was adherent to the sigmoid colon, Figure 4. Adhesions were lysed and the appendix successfully removed. After four months of follow up the patient remained well.

Discussion

The diagnosis of appendicitis and its complications is usually straight forward. In our case, the patient initially presented with clinical signs of appendicitis and an Alvarado score

33

Figure 1: Endoscopic view of the appendiceal-sigmoid fistula (0600

o’clock position, yellow arrow), with white pus streaming from the fistula.

Figure 2a: Computerized tomography of the pelvis shows appendix (red

arrows), a para colonic fluid collection (red circle) and sigmoid wall thickening (yellow arrow).

Figure 2b: Computerized tomography of the pelvis after antibiotic therapy

shows resolution in para-colonic fluid collection. Appendix is fixed to thickened sigmoid bowel wall (red

arrows).

Figure 3: Endoscopic view of the healed appendiceal-sigmoid fistula

(0800 o’clock position, yellow arrow), after effective antibiotic treatment and prior to laparoscopic appendectomy.


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of 5, but a negative abdominal ultrasound (See Table 1).6,7,8,9,10 Additionally, his complete and rapid resolution of symptoms promoted a conservative approach. The failure of abdominal ultrasound to help in the diagnosis of appendicitis in this patient is not surprising, since sensitivity for

diagnosis of appendicitis drops significantly in cases of retrocecal and perforated appendicitis. 11,12 As evidenced in later evaluation of this patient, computerized tomography is the most accurate radiologic test for acute appendicitis.12

Table 1. Alvarado score6

The perforation of the appendiceal abscess into the adjacent hollow organ (sigmoid colon), served to decompress the primary lesion and give rise to the atypical presentation of our patient. Appendicitis complicated by vesico-, cutaneous- and enteral-enteral fistulae have been previously reported in literature. 8,9,10 Urinary urgency and multi-organism urinary infection should alert the clinician of the possibility of entero-vesicular fistulae.13 Compensated chronic entero-appendiceal fistulae have been reported.3 Though some patients have been reported as asymptomatic, others present with diarrhea, obstruction, abdominal mass, or lower abdominal pain. Once a fistula is diagnosed, surgical intervention in the form of appendectomy and simple closure of the fistula is recommended.4,5

Sigmoid stricture may also complicate appendiceal-colonic fistula.1,4 In our patient there was luminal narrowing due to extrinsic mass effect which in the older patient may be misinterpreted as a neoplastic process.17,18 In the elderly, complicated sigmoid diverticulitis has been shown to fistulize to the normal appendix. 19,20

In our patient, spontaneous internal drainage and decompression of the appendix by fistulous communication with the sigmoid obviated the need for emergent surgery or percutaneous catheter drainage.21,22 In fact, emergent surgical intervention may have resulted in much more moribund two stage open surgical procedure.23 This case demonstrates that acute antibiotics, followed by elective, interval laparoscopic appendectomy can be an effective management option for the contained appendiceal abscess with spontaneous enteral decompression.

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References: 1. Paulson EK, Kalady MF, Pappas TN. Suspected Appendicitis. New Engl J Med. 2003;348;236-242.

2. Maxwell JM and Ragland JJ. Appendicitis: Improvements in diagnosis and treatment. Am Surg 1991; 57: 282-285.

3. Dent TL and Harrison TS. Persistent appendiceal-sigmoid fistula. Arch Surg 1968; 96: 309-311.

4. Kim SW, Ahn BK, Park HS, Lee SH, Baek SU. Appendico-Sigmoid Fistula Due to Appendicitis. J Korean Soc Coloproctol. 2004;20:225-227.

5. Walker LG, Rhame DW, and Smith RB. Enteric and cutaneous appendiceal fistulae. Arch Surg 1969, 99: 585-588.

6. Alvarado A. A practical score for the early diagnosis of acute appendicitis. Ann Emerg Med 1986; 15:557-564.

Figure 4: Artistic illustration of the findings at laparoscopic surgery with appendix adherent to sigmoid colon.

Symptom ScoreMigration of pain 1Anorexia 1Raised temperature T>37.3C 1Rebound pain 1Tenderness in right iliac FOSSA 2Nausea, vomiting 1Differential WBC > 75% PMN 1Leucoyte count 2Total 10Alvarado score > 7 predictive of appendicitis: sensitivity of 95% and specificity 46%; with PPV 87% (95% CI 74–99%), and NPV 72.4% (95% CI 61–83%).7


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Article || Bhavani Moparty M.D., Karen Szauter M.D. Manoop S Bhutani M.D.FASGE,FACG,FACP

Role of EUS in defining extent of disease and guiding therapy in eosinophilic gastritis with pyloric stenosis

5

Abstract:

We describe a case of eosinophilic gastritis (EG) presenting as pyloric stenosis. A 62 year woman presented with vomiting and weight loss. Upper endoscopy revealed pyloric stenosis. Biopsies revealed severe chronic antral gastritis with eosinophilia. EUS showed pyloric wall thickening to 7mm

with loss of five layer echopattern. Patient was treated with slow steroid taper with improvement. Her prior episodes of EG were treated with 4-6 weeks of steroids, but had symptom recurrence. She declined surgical full thickness biopsy, so EUS was a less invasive method compared to surgery for evaluating disease extent. The findings provided useful information and guided management.

7. Denizbasi, A and Unluer, EE. The role of the emergency medicine resident using the Alvarado score in the diagnosis of acute appendicitis compared with the general surgery resident. European Journal of Emergency Medicince. 10(4), December 2003, pp 296-301.

8. Bundy DG, Byerley JS, Liles AE, Perrin EM, Katznelson J, Rice HE. Does this child have appendicitis. JAMA. 2007;298:438-451.

9. Wang LT, Prentiss KA, Simon JZ, Doody DP, Ryan DP. The use of white blood cell count and left shift in the diagnosis of appendicitis in children. Pediatric Emergency Care. 2007;23:69-768.

10. Humes DJ and Simpson J. Acute appendictitis: Clinical Review. BMJ. 2006;333:530-534.

11. Friday JH. Update on appendicitis: diagnosis and presurgical management. Current Opinion in Pediatrics. 2006;18:234-238.

12. Terasawa T, Blackmore C, Bent S, Kohlwes RJ. Systematic Review: Computed tomography and ultrasonography to detect acute appendicitis in adults and adolescents. Ann Intern Med. 2004;141:537-546.

13. Abu-Dalu J, Urca I, Meiraz D. Appendico-vesical fistula-A rare complication of acute appendicitis. Br J Urol 1974; 46:586.

14. Skaane P. Spontaneous appendicocutaneous fistula: Report of a case and review of the literature. Dis Colon Rectum 1981; 24: 55-554.

15. Pairolero PC, Judd ES, Hodgson JR. Appendicoenterosigmoid fistula. Surgery 1969; 66: 695-697.

16. Maas LC, Gelzayd EA, Treisman E. Sigmoid stricture: An unusual presentation of perforated appendicitis with abscess formation. Am J Gastroenterol 1978; 70: 191-193.

17. Bailey AD and Goldner F. Appendicitis as an unusual cause of progressive sigmoid narrowing. J Clin Gastroentrol 1987; 9: 705-707.

18. Halls JM and Meyers HI. Acute appendicitis with abscess simulating carcinoma of the sigmoid. Am J Roentgenol 1977; 129: 1057-1059.

19. Marshak RH, Maklansky D, and Lindner AE. Sigmoid-appendiceal fistula in diverticulitis. Am J Gastroenterol 1976; 66: 292-296.

20. Van Hillo M, Fazio VW, and Lavery IC. Sigmoidoappendiceal fistula- An unusual complication of diverticulitus. Dis Colon Rectum 1984; 27: 618-620.

21. Livingston EH, Woodward WA, Sarosi GA, Haley RW. Disconnect between incidence of nonperforated and perforated appendicitis: Implications for pathophysiology and management. Annals of Surgery. 2007;245:886-892.

22. Nicolaou S, Talsky A, Khashoggi K, Venu V. Ultrasound-guided interventional radiology in critical care. Critical Care Medicien. 2007;35[Suppl.]:S186-S197.

23. Andersson RE and Petzold MG. Nonsurgical treatment of appendiceal abscess or phlegmon: A systematic Review and Meta-analysis. Annals of Surgery. 2007;246:741-748.


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Key words:

Endoscopic ultrasound (EUS), eosinophilic gastritis, pyloric stenosis

Introduction:

Eosinophilic gastritis may be difficult to diagnose since the exact disease mechanism is not clearly understood.1 The diagnosis of eosinophilic gastritis is based on clinical history and biopsy findings of increased eosinophils, after exclusion of other etiologies of eosinophilic disorders.2, 3 We describe a case of eosinophilic gastritis presenting as pyloric stenosis. Endoscopic ultrasound (EUS) was used to aid in assessing the extent of disease infiltration and guiding further management.

Case report:

A 62-year-old woman presented with vomiting solids and liquids immediately after eating. She reported a 40 pound weight loss. Her only medication was sertraline. Physical exam was unremarkable. Laboratory tests including a CBC with differential, electrolytes, liver panel, IgE were normal; stool studies revealed no ova or parasites. Upper endoscopy revealed pyloric stenosis (Figure 1) and a TTS balloon dilation to 10mm for 60 seconds was done with some heme

in the pyloric area post dilation. Biopsies revealed severe chronic antral gastritis with eosinophilia without Helicobacter pylori. No eosinophils were noted on small bowel or esophageal biopsies. Her symptoms persisted despite multiple pyloric dilations; therefore treatment with 4-6 weeks of

tapering doses of oral steroids was started. Initially she responded to the treatment, but had recurrence of symptoms once steroids were tapered.

Patient declined surgical full thickness biopsy to evaluate extent of disease but agreed to EUS. A 2.4 mm 12 MegaHertz EUS miniprobe was passed through the channel of an upper endoscope and was inserted into the stenotic pyloric channel for high frequency ultrasound imaging. No dilation of the pylorus was performed immediately prior to the EUS so

that dilation would not affect EUS findings. EUS demonstrated hypoechoic pyloric wall thickening to 7mm with loss of layer echopattern as well as loss of definition of the muscularis propria(the muscularis propria was distinctly visible only in 1/4th of the circumference of the pylorus) that would be consistent with full thickness involvement of the pylorus with eosinophilic gastritis (Figure 2). The wall of the body and antrum appeared normal with an intact layer pattern. Based on the EUS findings, patient was treated with a slow but longer steroid taper (over 6 months instead of over 4-6 weeks) with gradual but persistent improvement in symptoms.

Discussion:

Eosinophilic gastrointestinal diseases include a spectrum of illnesses including esophagitis, gastritis, gastroenteritis, enteritis and colitis. The presentation can vary based on location of symptoms. Eosinophilic gastritis is even more complex to diagnose due to the presence of baseline eosinophils. Eosinophilic gastritis can involve the mucosa, muscularis or serosa. Patients with mucosal involvement can present with vomiting, pain, anemia, and malabsorption symptoms. Infiltration of eosinophils into the muscularis can cause wall thickening, resembling pyloric stenosis. Serosal involvement presents with ascites.1 Eosinophilic gastritis is generally treated with a short course of steroids.4 Our patient’s prior episodes of pyloric stenosis had been treated with 4-6 weeks of steroids. She presented with recurrence of symptoms; therefore we wanted to assess extent of eosinophilic involvement. Since she declined surgical full thickness biopsy, EUS in our patient served as a less invasive method compared to surgery for evaluating the extent of disease infiltration. The findings provided us useful information regarding disease extent, guiding further management. There may be a role for EUS in eosinophilic gastrointestinal disorders for evaluating the extent of disease.5 As illustrated in the above case, EUS may be a less invasive alternative to full thickness surgical biopsy in patients with difficult to manage eosionophilic gastrointestinal disorders.

Figure 1: Upper endoscopy revealing pyloric stenosis.

Figure 2: A 12 MegaHertz EUS miniprobe image of the stenotic

pyloric channel showing pyloric wall thickening to 7mm(calipers) with loss of layer echopattern. The muscularis

propria is intact in only 1/4th of the circumference of the pylorus

(arrowhead).


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References

1. Rothenberg ME. Eosinophilic gastrointestinal disorders (EGID). J Allergy Clin Immunol 2004;113:11-28; quiz 29.

2. Klein NC, Hargrove RL, Sleisenger MH, Jeffries GH. Eosinophilic gastroenteritis. Medicine (Baltimore) 1970;49:299-319.

3. Talley NJ, Shorter RG, Phillips SF, Zinsmeister AR. Eosinophilic gastroenteritis: a clinicopathological study of patients with disease of the mucosa, muscle layer, and subserosal tissues. Gut 1990;31:54-8.

4. Lee CM, Changchien CS, Chen PC, Lin DY, Sheen IS, Wang CS, et al. Eosinophilic gastroenteritis: 10 years experience. Am J Gastroenterol 1993;88:70-4.

5. Andriulli A, Recchia S, Valente G, Pera A, Verme G. Endoscopic ultrasonography in eosinophilic infiltration of gastric wall. Ital J Gastroenterol 1990;22:129-32.

Article || John C. Deutsch, M.D., Steven C. Teng

Familial Small Intestinal Carcinoid Tumors Discovered by Capsule Endoscopy

Abstract:

A patient was evaluated for recurrent blood loss/iron deficiency anemia. Capsule endoscopy identified several abnormalities in the small bowel which at surgery were found to be carcinoid tumors. The patient’s father had died from metastatic carcinoid tumors 25 years previously. The inheritability of small intestinal carcinoid disease is discussed. Introduction:

A 56-year-old gentleman had a history of severe iron deficiency anemia, but no signs of intestinal bleeding. Eighteen months prior to evaluation, the patient had unexplained severe anemia with a hemoglobin of 8 and MCV of 58 fl. This appears to recover following transfusion and 3 months his hemoglobin was 15. A source of bleeding was not identified on endoscopy at an outside institution. One month later, he presented with a hemoglobin of 7, an elevated TIBC, 678 (normal less than 400) and a low ferritin level, 4 mcg/L (normal greater than 15 mcg/L). EGD and colonscopy performed at an outside institution were relatively unremarkable.

His past medical history was unremarkable. He was without any symptoms of any disease process, and was working full time without difficulties. His family history was significant in that his father had died from metastatic carcinoid tumor, with a presumptive ileal origin 25 years earlier. No other familial neoplastic or endocrine diseases were identified. The patient’s physical exam was completely normal for age. Rectal examination revealed brown stool that was hemoccult positive on 2/3 cards. At our institution, evaluation included a small bowel capsule endoscopy (Pill Cam SB, Given Imaging Ltd). This showed several nodular areas including some with lymphangiectasia. Figures 1-3, Video 1. No active intra-luminal bleeding or mucosal changes of celiac disease were identified. Due to a concern for potential carcinoid tumor,

Figure 1: Selected image from the small bowel endoscopy showing

nodules.


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a chromogranin A level was obtained and revealed a marked elevation at 6850ng/ml (normal 225 ng/ml). A 5-HIAA level was slightly elevated at 8.2 (nl less than 6). CT of the abdomen was normal.

Based on the capsule endoscopy and supporting

laboratory evaluation the patient underwent exploratory surgery. Two nodules were palpated in a short section of ileum and 20 cm of mid-ileum was resected. A liver biopsy of a small nodule was also done. Four discrete mucosal and submucosal tan-yellow tumor nodules were identified in

the ileum ranging from 0.3 to 0.5 cm in greatest dimension (Figure 4,5). No tumor was found in 12 lymph nodes. The small liver lesion revealed a bile duct hamartoma. The patient has not had recurrent anemia in the 6 months following surgery. His MCV is now 98 fl. A repeat chromogranin A level at 6 months was 1600 (Normal less than 225).

Discussion

Carcinoid tumors are small neuroendocrine neoplasms which can

occur throughout the body, and commonly in the gastrointestinal tract.1 Intestinal carcinoid tumors are characterized by location: foregut, midgut and hindgut, Table 1.2-4 Familial neuroendocrine tumor syndromes of the foregut and pancreas which can include carcinoid tumors, seem to be associated with the MEN1 syndrome.5,6 MEN1 Syndrome does not appear to be related to the development of midgut (ileal) carcinoids2,4

Table 1: Location of Intestinal Carcinoid Tumors

Familial carcinoid tumors of the ileum (midgut) and hindgut consist of case reports.6-12 Mutations in the tumor-suppressor gene succinate-ubiquinone oxidoreductase subunit D (SDHD) gene have been detected in midgut carcinoid tumors, it is unclear if there are inherited cases with this mutation due to the rarity of the event. Two recent reviews indicate that for an individual with one affected first degree relative, the risk of carcinoid is four times greater than the general population.4,13

Foregut Midgut HindgutEsophagus Jejunum Descending colonStomach Ileum Sigmoid colonDuodenum Appendix RectumLiver Right colonGallbladder Transverse colconBile ductsPancreas


nodules.


nodules.

Figure 4: Histology overview showing carcinoid tumor.

Figure 5: Histology showing benign carcinoid tumor.

Video Clip 1: Small bowel capsule endoscopy showing nodules in the

ileum.


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Our patient presented with an apparent blood loss anemia. The cause was not identified during upper and lower endoscopies. Further assessment lead to small bowel capsule endoscopy. An active bleeding site was not found, but findings worrisome for carcinoid tumor were identified. Following clinical assessment which revealed both a family history of carcinoid tumor, and elevated chromogranin A levels14,15 with a marginal 5HIAA level, surgical exploration was pursued, and four carcinoid tumors were uncovered. It is important to emphasize that nodal (40-85%) and liver metastasis (10-60%) are commonly associated with midgut carcinoids. Risk for metastasis correlates with size of the primary tumor. In our case, preoperative abdominal CT scan was negative, but careful surgical exploration identified a

solitary hepatic lesion histology consistent with incidental hamartoma, emphasizing the need for careful preoperative staging for midgut carcinoid. The findings at capsule endoscopy can be subtle. However, capsule endoscopy has been reported to be effective in identifying tumors of the small bowel, including carcinoid tumors.16,17 Still, the decision to pursue further evaluation of a potential carcinoid tumor by either double balloon endoscopy or surgery can be difficult. In our case, the findings at capsule endoscopy, supportive laboratory work, and a family history of carcinoid tumors helped us to pursue a surgical option. This patient is obviously at risk for reoccurrence and will require close, lifelong follow up.

References

1. Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD. Current status of gastrointestinal carcinoids. Gastroenterology. 2005 128:1717-51.

2. Sutton R, Doran HE, Williams EMI, Vora J, Vinjamuri S, et al. Neuroendocrine tumors: Surgery for midgut carcinoid. Endocrine-Related Cancer. 10:469-481, 2003.

3. Debelenko, L. V.; Brambilla, E.; Agarwal, S. K.; Swalwell, J. I.; Kester, M. B.; Lubensky, I. A.; Zhuang, Z.; Guru, S. C.; Manickam, P.; Olufemi, S.-E.; Chandrasekharappa, S. C.; Crabtree, J. S.; Kim, Y. S.; Heppner, C.; Burns, A. L.; Spiegel, A. M.; Marx, S. J.; Liotta, L. A.; Collins, F. S.; Travis, W. D.; Emmert-Buck, M. R. Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung. Hum. Molec. Genet. 6: 2285-2290, 1997.

4. Babovic-Vuksanovic D, Costantinou CL, Rubin J, Rowland CM, Schaid DJ, Karnes PS. Familial occurrence of carcinoid tumors and association with other malignant neoplasms. Cancer Epidemiology, Biomarkers & Prevention. 8:715-719, 1999.

5. Leotlela PD, Jauch A, Holtgreve-Grez H, Thakker RV. Genetics of neuroendocrine and carcinoid tumours. Endocr Relat Cancer. 2003;10:437-50.

6. Anderson, R. E. A familial instance of appendiceal carcinoid. Am. J. Surg. 111: 738-740, 1966.

7. Eschbach, J. W.; Rinaldo, J. A., Jr. Metastatic carcinoid: a familial occurrence. Ann. Intern. Med. 57: 647-650, 1962.

8. Moertel, C. G.; Dockerty, M. B. Familial occurrence of metastasizing carcinoid tumors. Ann. Intern. Med. 78: 389-390, 1973.

9. Katdare MV, Fichera A, Heimann TM. Familial rectal carcinoid: report of two first-degree relatives with rectal carcinoid and review of the literature. Tech Coloproctol. 2006 10:143-6.

10. Pal T, Liede A, Mitchell M, Calender A, Narod SA. Intestinal carcinoid tumours in a father and daughter. Can J Gastroenterol. 2001 15:405-9.

11. Wale RJ, Williams JA, Beeley AH, Hughes ES. Familial occurrence in carcinoid tumours. Aust N Z J Surg. 1983 Aug;53(4):325-8.

12. Kytola, S.; Nord, B.; Elder, E. E.; Carling, T.; Kjellman, M.; Cedermark, B.; Juhlin, C.; Hoog, A.; Isola, J.; Larsson, C. Alterations of the SDHD gene locus in midgut carcinoids, Merkel cell carcinomas, pheochromocytomas, and abdominal paragangliomas. Genes Chromosomes Cancer 34: 325-332, 2002.

13. Hemminki K and Li X. Familial carcinoid tumors and subsequent cancers: a nationwide epidemiologic study from Sweden. International Journal of Cancer. 94;444-448, 2001.

14. Woltering EA, Hilton RS, Zolfoghary CM, Thomson J, Zietz S, Go VL, Vinik AI, Vinik E, O’Dorisio TM, Mamikunian G. Validation of serum versus plasma measurements of chromogranin a levels in patients with carcinoid tumors: lack of correlation between absolute chromogranin a levels and symptom frequency. Pancreas. 2006 33:250-4.

15. Kölby L, Bernhardt P, Swärd C, Johanson V, Ahlman H, Forssell-Aronsson E, Stridsberg M, Wängberg B, Nilsson O. Chromogranin A as a determinant of midgut carcinoid tumour volume. Regul Pept. 2004 Aug 15;120(1-3):269-73.

16. Nathan SR, Biernat L, Tang D. Multifocal small-bowel carcinoid tumor causing obscure recurrent gastrointestinal bleeding diagnosed by capsule endoscopy. Endoscopy. 2007 Oct 24.

17. van Tuyl SA, van Noorden JT, Timmer R, Stolk MF, Kuipers EJ, Taal BG. Detection of small-bowel neuroendocrine tumors by video capsule endoscopy. Gastrointest Endosc. 2006 Jul;64(1):66-72.


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Literature Review || Peter R. McNally, DO, FACG, FACP.

Beltran, et al, demonstrated the utility of capsule endoscopy (CE), as they evaluated patients with Crohn’s for post operative disease relapse in the neoileum. It is likely that CE will become the non-invasive standard for the evaluation of post operative Crohn’s patients. Early detection of disease relapse will guide the institution of disease modifying treatment strategies.

Introduction

• Postoperative relapse of Crohn’s disease is common. 1

- Neoileum relapse is 73 & 85% and symptomatic relapse is 20 & 34% at 1 and 3 yr Post Op. 1

• Prophylactic post operative immunosuppressant therapy is recommended for the High Risk to Relapse Group. 2

- Fistulizing Disease - Ileocolonic location - Smoker• Post Operative endoscopic surveillance at 6-12 mo is

recommended for the Average Risk to Relapse Group.3

• Wireless capsule endoscopy (CE) has recently been shown to be more accurate than Ileocolonoscopy in detecting small bowel activity among patients with Crohn’s.4

• “Gold Standard” for the monitoring Post Op Crohn’s Disease for relapse has been Ileocolonoscopy.

• This study examined safety and utility of CE to monitor for post operative relapse when compared to the “Gold Standard.”

Aim

• To test the safety and accuracy of CE to detect post operative relapse of Crohn’s in the neoileum.

• Compare the safety, patient tolerance, accuracy of CE

to Ileocolonoscopy to detect relapse among clinically asymptomatic post operative Crohn’s patients.

Study Design

• Prospectively enrolled Crohn’s patients after ileocolonic anastomosis between Oct 2003 and Oct 2005.

• Demographics– N=24 (13 ♀ and 11 ♂) – All Asymptomatic– None on prophylactic treatment to prevent relapse

• Exclusion Criteria: – History Dysphagia– Pregnancy– Lactation– Life-threatening conditions– Nonsteroidal anti-inflammatory drug intake

Study Evaluations

• Study Evaluations (all within 2 wk):– M2A Patency Capsule (Given Imaging Ltd,

Yoqneam,Isreal),– Ileocolonoscopy (CF-VL, Olympus, Tokyo, Japan)– CE (M2A Given Imaging Ltd, Yoqneam,Isreal).

• Rutgeerts’ Index1 > 2 used to defined recurrence• 0: no changes• 1: < 5 aphathous lesions• 2: > 5 aphathous lesions, with nl “skip” mucosa• 3: diffuse aphathous ileitis• 4: diffuse inflammation: ulcers, nodules &/or narrowing

Materials and Methods

• Evaluations: M2A Patency Capsule • Capsule passage: Patient confirmation or X-ray location

in colon or patency scanner• Transit “normal” < 40hrs

Evaluation of postsurgical recurrence in Crohn’s disease: a new indication for capsule endoscopy?

Beltran PV, Nos P, Bastida G, Beltran, B, Arguello L, Aguas M, Rubin A, Pertejo V, Sala T. Gastrointestinal Endoscopy. 2007;66:533-40

PatencyCapsule


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• Examination Neoileum– Ileocolonoscopy (CF-VL, Olympus, Tokyo, Japan)– CE (M2A Given Imaging Ltd, Yoqneam,Isreal).

• Evaluations: Ileocolonoscopy– Fosfosoda (Casen Fleet) bowel prep 45 ml X2– Conscious Sedation: medazolam (2-3 mg) or Fentanyl

(50 microgram)– Neoileum examined as far as possible (10-30 cm)– Findings Graded by Rutgeerts’ Index1

• Evaluations: Patient Comfort Survey– Completed after CE and Ileocolonoscopy

CE Showing Ileal Ulceration

Patient Characteristics: Gender: 11/13 (M/F) Age: 38 (18-71 yr)

Clinical Characteristics

Smokers 50% ∆ time from surgery 254 days Perianal Disease 88% Surgery Ileo-Ascending anastamosis 67% Ileo-Transverse anastamosis 33% Length resection (cm) 34 (13-60)

Disease Activity Markers Erythrocyte sedimentation 19 (7-24) C-reactive protein (0-8mg/L) 1.2 (0-6) Crohn’s Disease Activity Index 56 (23-168)

Results: CE vs.. Ileocolonoscopy

N = 24 ProcedureFailure

Crohn’s (+)

Patency M2A 22/24 2/24 (8.3%)Non passage

CE 21/22 1/22 (4.5%)Fail to transmit

15/22 (62%)13 proximal

Ileocolonoscopy 24/24 3/24 (12%)Fail to intubate

6/21 (25%)

PatencyCapsuleScanner


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Results: Patient Comfort

• All patients preferred CE to endoscopy• Bowel prep for endoscopy disrupted daily activity

more than liquid diet for CE (83% vs. 20%)• 50% of the pts considered the endoscopy

uncomfortable• 8/24 (33%) pts required additional conscious sedation

during the neoileal exploration

Reviewer Comments

Beltran, et al, have clearly shown the following:• 2/24 (8.3%) non passage of patency capsule suggests

the need to evaluate luminal patency before CE in asymptomatic post op Crohn’s

• CE is superior to endoscopy (62% vs. 25%) in the detection of active post operative Crohn’s disease.

• CE is preferred by pts over endoscopy for evaluation of post operative Crohn’s

Beltran, et al, do not answer the question:• Does detection of post operative Crohn’s disease by

either method (endoscopy or CE) make a difference in managing this disease?

• However, the authors will certainly have an answer in the future. Those patients in this study with Rutgeerts’ score > 2 were offered therapeutic modification with 2.5 mg/kg/day azathioprine.

Chen and Antillon, have illustrated a novel “high tech” endoscopic intervention for ESLD patients with symptomatic cholelithiasis can bridge these patients until liver transplantation is performed. Dr. Antillon has kindly contributed a video of the peroral cholecystoscopy and lithotripsy procedure for your review.

Introduction:

Cholelithiasis is a common medical condition seen in ~20 of Americans aged 65 yrs and when symptoms arise cholecystectomy is recommended.1,2 Among healthy persons

without liver disease the laparoscopic cholecystectomy is safe with very low procedure related mortality (< 0.5%)3,4. Persons with ESLD have increased morbidity with any surgery, but especially when it involves the biliary tract. Portal hypertension causes anatomic challenges for even the experienced laparoscopic surgeon. Engorgement of portal vessels, excessive bleeding of “ordinary” vessels, can make identification and dissection within Calot’s triangle very difficult, Figure 1.

Cirrhosis is a significant risk factor for gallstone formation with reported gallstone prevalence of 29-34%.5,6,7 Gallstones associated with cirrhosis are usually mixed-pigmented type and not responsive to per oral ursodiol dissolution therapy. Fortunately, most cirrhotic patients with gallstones are asymptomatic, but when symptoms arise gallbladder decompression or removal is required. Surgical mortality associated with cholecystectomy for symptomatic gallstones in ESLD patients is reported to be as high as 30%.8 Alternative treatment options have included percutaneous cholecystotomy and transpapillary endoscopic stenting of the cystic duct.9,10,11,12

Chen and Antillon report a case of a 52 year old male awaiting liver transplantation for hepatitis C related ESLD.13 The patient had multiple large, symptomatic gallstones. Surgical cholecystectomy was felt to be a high risk due to Childs-Pugh Class C cirrhosis. Percutaneous cholecystotomy was not performed because of concerns related to ascites and coagulopathy. This group performed a total of four ERCP’s to stent, decompress and dilate the cystic duct, and finally lithotripsy and rinse clear gallstones. Mild pancreatitis occurred with one of the ERCP procedures. Once stones where clear the patient was maintained on ursodiol and remained symptom free. Twenty-five months later the patient received a living donor right lobe.

Chen and Antillon have described and illustrated a “high tech” alternative to surgery and interventional radiologic

Peroral cholecystoscopy with electrohydraulic lithotripsy for treatment of symptomatic cholelithiasis in end-stage liver disease

Chen YK, Nichols MT, Antillon MR Gastrointestinal Endoscopy. 2008;67:132-135

Figure 1: Calot’s triangle is formed by the cystic duct, cystic artery and the common hepatic duct. Surgical

definition of this anatomy is essential for safe dissection and laparoscopic cholecystectomy. With Permission

GI/Liver Secrets 3rd Edition, Elsevier, Philadelphia 2005.


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that may serve as an important bridge for ESLD patients with symptomatic gallstones that are awaiting liver transplantation, see Video 1. Of greater importance, is that Chen and Antillon have demonstrated that there is a peroral t r a n s p a p i l l a r y “window” to see into the gallbladder. In the future, this “window” into the gallbladder may provide an opportunity to evaluate and treat gallbladder polyps, right upper quadrant abdominal pain, and cholelithiasis in selected patients.

References

1. Russo MW, Wei JT, Thiny MT, et al. Digestive and liver disease statistics. Gastroenterology. 2004;126:1448-1453.

2. Urbach DR and Stukel TA. Rate of elective cholecystectomy and the incidence of severe gallstone disease. CMAJ. 2005 Apr 12;172(8):1015-9.

3. Benvegnu L, Noventa F, Chemello, L, et al. Prevalence and incidence of cholelithiasis in cirrhosis and relation to the etiology of liver disease. Digestion 1997;58:293-8.

4. Elzouki AN, Nilsson S, Nilsson P, et al. The prevalence of gallstones in chronic liver disease is related to degree of liver dysfunction. Hepatogastroenterology. 1999;46:2946-50.

5. Conte D, Fraquelli M, Fornari F, et al. Close relation between cirrhosis and gallstones: Cross-sectional and longitudinal survey. Arch Intern Med. 1999;159:49-52.

6. McSherry CK, Glenn F. The incidence and causes of death following surgery for nonmalignant biliary tract disease.Ann Surg. 1980;191:271-5.

7. Bloch R, Allaben R, Walt A. Cholecystectomy in patients with cirrhosis: a surgical challenge. Arch Surg. 1985;120:669-72.

8. Befeler AS, Palmer DE, Hoffman M, Longo W, Solomon H, DiBisceglie AM. The safety of Intra-abdominal surgery in patients with cirrhosis. Archives of Surgery. 2005;140:650-654.

9. Silberfein EJ, Zhou W, Kougias P, El Sayed HF, Huynh TT, Albo D, Berger DH, Brunicardi FC, Lin PH. Percutaneous

cholecystostomy for acute cholecystitis in high-risk patients: experience of a surgeon-initiated interventional program. Am J Surg. 2007 194(5):672-7.

10. Conway JD, Russo MW, Shrestha R. Endoscopic stent insertion into the gallbladder for symptomatic gallbladder disease in patients with end-stage liver disease. Gastrointest Endoscopy. 2005;61:32-6.

11. Schlenker C, Trotter JF, Shah RJ, et al. Endoscopic gallbladder stent placement for treatment of symptomatic cholelithiasis in patients with end-stage liver disease. AM J Gastroenterol. 2006;101:278-83.

12. Hixson LJ, Fennerty MB, Jaffee PE, et al. Peroral cholangioscopy with intracorporeal electrohydralic lithotripsy for cholelithiasis. AM J Gastroenterol. 1992;87:296-9.

13. Chen YK, Nichols MT, Antillon MR. Peroral cholecystoscopy with electrohydraulic lithotripsy for treatment of symptomatic cholelithiasis in end-stage liver disease. Gastrointestinal Endoscopy. 2008;67:132-135.

Lastly, the entity of small intestinal bacterial overgrowth (SIBO) and its recent association with irritable bowel disease (IBS) has lead to the examination of a series of antibiotic treatments for this disorder. The placebo, controlled study, by Pimentel, et al,1 showing that rifaximin 1200 mg per day for 10 days is effective in improving global symptoms of IBS has spurred clinical interest in the treatment of this disease. The report of a dose ranging trial by Scarpelli, et al, showed that a higher dose of rifaximin (1600mg per day) is a safe and more effective in the treatment for these patients. It is likely that future treatment trials with rifaximin for IBS will incorporate higher dosing regimens of this compound to improve on currently demonstrated treatment response rates.

Introduction

• Small intestinal bacterial overgrowth (SIBO) is a burgeoning field of study in the etiology of Irritable Bowel Syndrome (IBS).

13

Video Clip 1: Video clip of peroral transpapillary cholecystoscopy

using Fiberoptic Choledocoscope (Olympus, Corp). Video clip provided

by Mainor R. Antillon, MD, MBA, MPH, Professor of Medicine and Surgery, Director of Endoscopy,

Vice-Chairman of Internal Medicine- Clinical Programs Division of

Gastroenterology & Hepatology, University of Missouri-Columbia.

High Dose Rifaximin for Treatment of Small Intestinal Bacterial Overgrowth

Scarpellini E, Gabrielli M, Lauritano C, Lupascu A, Merra G, Cammarota G, Cazzato IA, Gasbarrini G, Gasbarrini A.Alimentary Pharmacology & Therapeutics. 2007;25:781-786


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• Many antibiotics have been examined in the treatment of SIBO. (Lin HC. JAMA 2004;292:852-858.)

– Metrinodizole– Ciprofloxacin– Tetracycline– Neomycin– Rifaximin

• Rifaximin is a non absorbed, intra-luminal antibiotic that appears to have the best efficacy in treatment of this disorder.

Aim

• Scarpellini et al, conducted a dose ranging trial of Rifaximin at doses of 1600 mg/day vs. 1200 mg/day to assess efficacy, safety and tolerability in the treatment of SIBO.

Study Design

• 80 consecutive pts with SIBO were enrolled.• Diagnosis of SIBO based upon clinical history and

positive Glucose Breath Test (GBT), defined as > 20 ppm rise in H2/CH4.

• Treatment randomized to 7- days of Rifaximin 1600 mg/d (Group 1) or 1200 mg/d (Group 2).

• Objective measurements: – GBT 1 month after treatment– Compliance– Side effects

Results

• Drop outs: 1 patient in group 1• GBT normalization

– Group 1 > Group 2 (80% vs. 58%; p < 0.05 ITT model) and (82% vs. 61%; p<0.05 PP).

• Compliance: NS difference• Side effect profile: NS difference.

Conclusions

• This study demonstrates that Rifaximin 1600 mg/d had significantly higher efficacy for treatment of SIBO than 1200mg/d.

• Compliance rates and side effects with Rifaximin 1600 mg/d compared favorably with 1200 mg/d.

Reviewer Comments

• This is a simple dose ranging trial to evaluate efficacy, compliance and safety of Rifaximin at 1600 mg/d vs. 1200 mg/day.

• It is likely that future studies examining treatment of IBS patients with SIBO will be conducted using this higher dose of Rifaximin that appears to be safe and more effective.

Cases From The Armed Forces Institute of PathologyLeslie H. Sobin, M.D. Introduction by Peter Peter R. McNally, DO, FACP, FACGGuest Commentary

Leslie H. Sobin, M.D. Chief, Division of Gastrointestinal Pathology Department of Hepatic and Gastrointestinal Pathology Armed Forces Institute of Pathology

The Editorial Board of VHJOE is extremely excited to introduce a new section to the journal entitled, “Cases From the Armed Forces Institute of Pathology (AFIP).” Dr. Sobin and his faculty at the AFIP provide expert pathology consultation on exotic and difficult cases referred from across the globe. As they share their most fascinating case materials with us, the readers of VHJOE, will surely


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come to understand why Dr. Sobin and his faculty are an invaluable and irreplaceable intellectual treasure to the field of Medicine and Gastrointestinal Pathology.

Dr. Leslie H. Sobin was born in New York City, received his Bachelor of Science degree from Union College in 1955 and his medical degree from the State University of New York at N.Y.C. in 1959. He did his residency in Anatomic Pathology at the New York Hospital-Cornell Medical Center where he rose to Assistant Professor. From 1965 to 1968 he served as WHO Professor of Pathology at the University of Kabul, Afghanistan after which he returned to Cornell as Associate Professor of Pathology. He rejoined WHO in 1970 as Pathologist and was responsible for the WHO International Histological Classification of Tumors.

In 1981 he joined the staff of the Armed Forces Institute of Pathology, Washington, DC where he rose to Chief of Gastrointestinal Pathology, Co-chair of the Department of Hepatic and Gastrointestinal Pathology and Director of Scientific Publications. He continued his work on the WHO tumor classification series as head of a WHO Collaborating Center at the AFIP. He has been co-editor of the third and fourth series of the AFIP Atlas of Tumor Pathology. As Chairman of the TNM Prognostic Factors Project of the International Union Against Cancer (UICC) for over 20 years, he co-edited the TNM Classification of Malignant Tumors in its 4th, 5th and 6th editions.

Dr. Sobin is author or coauthor of over 300 scientific articles, chapters, and books among which were the AFIP Atlas of Intestinal Tumors and the Atlas of Endoscopy and Endoscopic Biopsies of the Gastrointestinal Tract. Among his publications are: articles on staging of cancer, classification of tumors, epidemiology of gastrointestinal cancer, and pathology of GISTs; chapters on the appendix, gastrointestinal polyps and tumors. He published three books of verse on pathology: A Pathology Primer- in verse, Tales of the Ampulla of Vater, and The Prosector’s Guide to the Autopsy.

He has been the Director of the AFIP’s annual course on Endoscopic Biopsies of the Gastrointestinal Tract for over 15 years.

Peter R. McNally, DO, FACP, FACG Editorial Board, VHJOE UCHSC, Center for Human Simulation

Guest Commentary Editor of Cases from the Armed Forces Institute of Pathology, Dr. Sobin

The Armed Forces Institute of Pathology (AFIP) was founded in 1862 as the Army Medical Museum. It is located in Washington, DC on the grounds of the Walter Reed Army Medical Center. Its primary mission is second opinion diagnostic consultations on pathologic specimens that are usually difficult to diagnose due to their rarity or their variation from the ordinary. These cases have resulted in a unique repository of lesions, numbering over three million, that have been the basis of major pathological studies.

The AFIP’s diagnostic departments are based mainly on organ sites, e.g. skin, liver, gastrointestinal, genitourinary, pulmonary, soft tissue, bone, hematological, neurological, endocrine and gynecological pathology. In addition, there are specialty departments dealing with infectious and parasitic diseases, molecular techniques and environmental pathology. As all of these specialties are located in one institution, there is close interaction between its departments in analyzing complex cases.

The educational mission of the Institute consists of formal courses and “hands-on” study of materials in courses as well as in specialty departments where one to two year fellowships are available as are one month visits.

Unique to the AFIP is the Department of Radiologic Pathology, pursuing the interface between diagnostic radiology and anatomic pathology. This department is responsible for a course attended by virtually all North American radiologists in their training. A by-product is an unmatched repository of cases having extensive radiological images and pathological slides, a great source for studies in this field and the origin of the cases that will be presented in this series.

http://www.afip.org/Departments/HepGastr_dept/index.html


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The opinions and assertions contained herein are the private views of the authors, and are not to be construed as official, or as reflecting the view of the Department of the Air Force, Army, or Defense.

Key Words: Neurofibromatosis, von Recklinghausen disease, gastrointestinal stromal tumor, carcinoid, neuroendocrine tumor

Introduction:

Neurofibromatosis-1 (NF1), also known as von Recklinghausen disease, is an autosomal dominant disorder with high penetrance, but variable expression resulting from mutations in the NF1 gene located on chromosome 17. Many types of abdominal tumors have been found in these patients. Here we report a case of a patient with NF1 and three separate types of abdominal tumors - a duodenal / periampullary psammomatous somatostatinoma, a gastrointestinal stromal tumor, and a neurofibroma.

History:

A 48-year-old man with a history of neurofibromatosis-1 presented with abdominal pain, nausea, vomiting, weight loss, and symptoms of gastroesophageal reflux.

Physical Exam:

On physical examination, he was noted to be cachectic, but was in no acute distress and his vital signs were within normal limits. No palpable abdominal masses were noted and he was not jaundiced.

Laboratory Studies:

The patient was reported to have had an increased gastrin level in the past (value not available).

Radiology Studies:

CT scan of the abdomen showed a partially obstructing 4.0 cm heterogeneously enhancing mass arising from the medial wall of the second portion of the duodenum that was causing dilatation of the stomach and first portion of the duodenum. The adjacent pancreas was normal. There was no evidence of biliary dilatation. A second 2.0 mass was present adjacent to the uncinate process of the pancreas. The scan also demonstrated ascites within the peritoneal cavity and scoliosis of the spine.

16

Cases From The Armed Forces Institute of PathologyJanet C. Shaw, LtCol, USAF, MC, Angela Levy, COL, MC, USA Anupamjit K. Mehrotra, MD, Lucas Sheldon, Maj, USAF, MC,Leslie H. Sobin, MD Gastrointestinal stromal tumors, endocrine tumors, and neurofibroma involv-ing the gastrointestinal tract of a patient with neurofibromatosis-1

Figures 1&2: Selected CT scans of the pancreas show a 4 cm mass within the duodenum (asterisk in 1 and 2). The mass appears to arise

along the medial duodenal wall and partially obstructs the duodenum. It is heterogeneous in CT attenuation.

There is a second mass adjacent to the uncinate process of the head of the pancreas (arrow in 1). It is oval, sharply marginated, and

hypoattenuating with respect to the adjacent pancreas. It appears to be separate from the pancreas because there is an intervening fatty plane.

The differential diagnosis for the obstructing duodenal mass includes periampullary adenoma, adenocarcinoma, gastrointestinal stromal

tumor, and carcinoid. The second mass is located in the retroperitoneum and is separate from the pancreas. It may represent an enlarged lymph

node that is related to the duodenal mass. Alternatively, it may represent a neurofibroma or gastrointestinal stromal tumor since the patient is

known to have Neurofibromatosis type 1.


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Endoscopy:

At endoscopy, severe gastroesophageal reflux with esophagitis was found. Approximately 1500 cc of fluid was suctioned from his stomach, and he was found to have a nearly obstructing duodenal stricture with a massively dilated duodenal bulb. Endoscopic ultrasound identified pancreatic head and peripancreatic masses without ductal dilatation or evidence of biliary obstruction.

Other studies:

Octreotide study reportedly showed uptake in the patient’s right arm, consistent with a neurofibroma, but no increased uptake in his abdomen.

Procedure and Findings:

At exploratory laparotomy, a large duodenal mass, as well as multiple peripancreatic, periaortic, and mesenteric lymph nodes / masses found. A Whipple resection was performed to remove the duodenal mass and multiple lymph nodes / masses in the mesentery were biopsied or removed.

Pathology:

The mass obstructing the duodenum was removed at operation separate from the Whipple resection, measured 2.5 x 1.5 x 1.3 cm, and had a bulging fleshy tan cut surface. By histology, this lesion and a separate lesion

removed from the root of the superior mesenteric vein were gastrointestinal stromal tumors with spindled cells arranged in intersecting fascicles and whorls. Areas of nuclear palisading were present as well as occasional perinuclear halos. Because the lesion was greater than 2 cm, but less than 5 cm in maximal dimension and had fewer than 5 mitoses per 50 high powered (40X) fields, it was identified as having a low risk for progressive disease or uncertain malignant potential.

Gross examination of the Whipple resection specimen showed multiple periduodenal and peripancreatic mass lesions as well as submucosal lesions in the duodenum proximal to the ampulla of Vater causing polypoid mucosal lesions. On histology, the polypoid duodenal

areas were morphologically consistent with a psammomatous somatostatinoma with nests and tubuloglandular structures comprised of cells with round central nuclei containing dispersed “salt and pepper” chromatin, abundant pink cytoplasm, and foci of psammoma bodies (concentric lamellated calcifications) in the gland-like spaces. Microscopic sections showed the tumor was centered in the region of the ampulla of Vater and infiltrated both the duodenum and head of the pancreas. Significant cellular atypia,

17

Figure 3: Intraoperative photo of surgeon identifying one of the

periduodenal masses.

Figure 4: Gross photo of Whipple resection specimen. Probe is in

ampulla of Vater. Cut sections show the white tan glistening submucosal duodenal lesion within the yellow

lobulated periduodenal adipose tissue .

Figure 5: Gastrointestinal stromal tumor. Spindled cells arranged in

intersecting fascicles and whorls. There are scattered dilated, but thin walled

blood vessels.

Figure 6: Gastrointestinal stromal tumor. The spindle cells are relatively

bland and uniform. A perinuclear halo (clear vacuole) is present. The

cytoplasm of the cells is vaguely fibrillar, reminiscent of neural tissue.

Video Clip 1: Video file of pancreatic CT scan performed with oral and

intravenous contrast material. There is marked dilatation of the stomach and first portion of the duodenum. There is a partially obstructing mass in the second portion of the duodenum that originates on the medial wall of the

duodenum near the ampulla of Vater. A second, separate, well-defined,

oval mass is located adjacent to the uncinate process of the pancreas. It is lower in CT attenuation than the

adjacent pancreas. The remainder of the scan is remarkable for the presence

of ascites and scoliosis of the spine.


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numerous mitoses, and tumor necrosis were not present. Despite the absence of significant atypia, tumor was present in sections taken from the periduodenal and transverse mesocolon lymph nodes, indicative of metastasis.

A small neurofibroma with delicate thin spindle cells admixed with fibrous tissue, neural elements, and a slightly myxoid stroma in continuity with a large peripheral nerve was present adjacent to the bile duct margin of the Whipple specimen.

Discussion:

Neurofibromatosis-1 (NF1), also known as von Recklinghausen

disease, is an autosomal dominant disorder with high penetrance, but variable expression resulting from mutations in the NF1 gene located on chromosome 17. This gene plays a role in controlling cell proliferation via regulation of the activity of the p21 product of the ras oncogene.1 Patients with the disorder have hamartomatous lesions as well as varied benign and malignant tumors. The diagnosis of NF1 is based primarily on physical manifestations of the disease to include

café-au-lait spots, Lisch nodules of the iris, neurofibromas (plexiform neurofibromas are a diagnostic finding alone), and freckling in the intertriginous areas.

Abdominal masses in patients with NF1 have been categorized

into based on the “cell of origin” of the tumor - neurogenic, neuroendocrine, non-neurogenic mesenchymal, embryonal, and adenocarcinomas. Some neoplasms, such as a plexiform neurofibroma, are pathognomonic of the disease. Other neoplasms, such as duodenal carcinoid tumors (which would include the psammomatous somatostatinoma) have been reported to occur more frequently in NF1 patients than the general population.2 Psammomatous somatostatinomas are found exclusively in the duodenal / periampullary region and have fairly unique histology of a neuroendocrine tumor with tubuloglandular architecture and psammoma bodies. However, if the psammoma bodies are infrequent, the tumor can be histologically confused with a well differentiated pancreaticobiliary adenocarcinoma, which would have a significant impact on patient prognosis. While immunoreactive for somatostatin, the tumors usually do not secrete hormones and are not associated with symptoms of increased somatostatin such as diabetes mellitus, steatorrhea, or cholelithiasis.3 These lesions have been described as occurring more frequently in African-American patients with NF1 than in other races.4 Up to a quarter of these tumors have been metastatic to lymph nodes at time of operation. However, death is not usually directly attributable to the tumor.5

Gastrointestinal stromal tumors (GIST’s) also have been well described in patients with NF1 and are different from sporadic GIST’s. Most sporadic GIST’s have mutations

Figure 7: Duodenum. Psammomatous somatostatinoma extending from the duodenal submucosa into the mucosa

and encroaching on the Brunner glands with overlying hyperplasia of

the mucosa. The dark purple structures are psammoma bodies.

Figure 8: Pancreas. Somatostatinoma on the right is infiltrating into the

pancreatic parenchyma on the left. This figure also demonstrates the

tubuloglandular architecture of the somatostatinoma.

Figure 9: Somatostatinoma. The nuclei are bland and have neuroendocrine

features-they are round, regular, and have dispersed chromatin. The cells have abundant pink granular cytoplasm. Some of the cells are

arranged in solid clusters and some form pseudoglands.

Figure 10: Somatostatinoma. Psammoma bodies present in

pseudoglands.

Figure 11: Neurofibroma. Thin spindle cells present in fibrous tissue on the right and wavy neural type spindle

cells on the left.


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of the KIT or PDGFRA genes which encode for tyrosine kinase receptors involved in cell signal transduction. Gastrointestinal stromal tumors occurring in patients with NF1 are frequently multiple and located in the small intestine, particularly the jejunum.6 In addition, despite being immunoreactive for CD117 (c-kit), and morphologically indistinguishable from sporadic GIST’s, many GIST’s in patients with NF1 have been found not to have KIT or PDGRFA mutations.6,7,8,9 Many NF1 patients also have foci of hyperplasia of interstitial cells of Cajal, the cell of origin of GIST’s. GIST’s in patients with NF1 usually have spindle cell morphology and have a relatively low risk for progressive disease based on size and mitotic activity of the lesions.

Neurofibromas are well described in patients with NF1 with the skin and gastrointestinal tract as the two most frequently described locations for tumors. Plexiform neurofibromas occur exclusively in patients with NF1, although this patient did not have a plexiform neurofibroma discovered at operation. Despite having multiple tumors, many patients

with NF1 have nonspecific physical complaints and the tumors are not infrequently discovered incidentally during a workup or operation performed for other reasons. Some patients will present with intermittent gastrointestinal bleeding and pain secondary to erosions, intussusception, obstruction, or volvulus.

Patients with NF1 have a variety of intra-abdominal lesions to include neuroendocrine tumors, particularly in the duodenum / ampullary region, and gastrointestinal stromal tumors. Patients can present with symptoms related to obstruction or can be asymptomatic. The patient in this report had significant weight loss, as well as nausea and vomiting secondary to gastric outlet obstruction secondary to the mass effect from the duodenal psammomatous somatostatinoma. Preoperative evaluation for endocrine tumors was negative in this patient, although an octreotide study would only identify functioning or secreting tumors. A high index of suspicion for unusual intra-abdominal lesions is needed when evaluating patients with NF1 who have gastrointestinal complaints.

References

1. Martin GA, Viskochil D, Bollag G, McCabe PC, Crosier WJ, Haubruck H, et al. The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 1990;63:843-849.

2. Dayal Y, Tallberg KA, Nunnemacher G et al. Duodenal carcinoids in patients with and without neurofibromatosis. Am J Surg Pathol 1986;10:348-357.

3. William GT. Endocrine tumours of the gastrointestinal tract-selected topics. Histopathology 2007;50:30-41.

4. Burke AP, Sobin LH, Federspiel BH, Shekitka KM, Helwig EB. Somatostatin producing carcinoids in patients with von Recklinghausen’s neurofibromatosis: a predilection for Black patients? Cancer 1990;65:1591-1595.

5. Bettini R, Falconia M, Crippa S, Capelli P, Boninsegna L,Pederzoli P. Ampullary somatostatimomas and jejunal gastrointestinal stromal tumor in a patient with Von Recklingausen’s disease. World J Gastroenterol 2007; 13(19):2761-2763.

6. Kang DY, Park CK, Choi JS, Jin SY, Kim HJ, Joo M, et al. Multiple gastrointestinal stromal tumors: Clinicopathologic and genetic analysis of 12 patients. Am J Surg Pathol 2007:31(2):224-232.

7. Stewart DR, Corless CL, Rubin BP, Heinrich MC, Messiaen LM, Kessler LJ, et al. Mitotic recombination as evidence of alternative pathogenesis of gastrointestinal stromal tumours in neurofibromatosis type 1. J Med Genet 2007:44(1):e61.

8. Maertens O, Prenen H, Debiec-Rychter M, Wozniak A, Sciot R, Pauwels P, et al. Molecular pathogensis of multiple gastrointestinal stromal tumors in NF1 patients. Hum Mol Genet 2006;15(6):1015-1023.

9. Miettinen M, Fetsch JF, Sobin LH, Lasota J. Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a Clinicopathologic and molecular genetic study of 45 cases. Am J Surg Pathol 2006:30(1):90-96.


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The Editorial Board of VHJOE is very excited to have Bret A. Lashner, MD, join the journal as Guest Editor, Inflammatory Bowel Disease. Dr. Lashner is one of the leaders in the field of Inflammatory Bowel Disease and possesses a wealth of clinical and research experience with these disorders. This brief Biographical Sketch will serve as our introduction of Dr. Lashner, to you, the readers of VHJOE.

Dr. Lashner is a Professor of Medicine and the Director of the Center for Inflammatory Bowel Disease at the Cleveland Clinic. He is a graduate of Haverford College and New York University School of Medicine, and completed a residency in internal medicine at Temple University Hospital, a fellowship in gastroenterology at the University of Chicago, and a Masters degree in Public Health at the University of Illinois at Chicago. After 7 years on the faculty of the University of Chicago involved with a busy clinical practice and IBD clinical research Dr. Lashner joined the Cleveland Clinic in 1993.

Dr. Lashner has conducted numerous clinical studies in IBD on such topics as cancer prevention with folic acid, optimization of cancer surveillance techniques, risk factors for malignancy, IBD risk in families, and epidemiologic determinants of disease. Dr. Lashner is an Associate Editor of The American Journal of Gastroenterology and Inflammatory Bowel Diseases. He is the Department of Gastroenterology Fellowship Program Director and the Co-chair of the Cleveland Clinic General Clinical Research Center Advisory Committee. He is serving on the grant review committee of the American College of Gastroenterology and the Crohn’s and Colitis Foundation of America.

Peter R. McNally, DO, FACP, FACG Editorial Board, VHJOE UCHSC, Center for Human Simulation

Comments from the Editor of Inflammatory Bowel Disease, Dr. Lashner

There are exciting recent advances in our understanding of inflammatory bowel diseases that we would like to present to you over the coming 12 months in VJHOE.

Ahmed Kandiel, M.D. has been asked to review cancer surveillance strategies in patients with inflammatory bowel disease. He will include his work with chromoendoscopy, narrow band imaging, and autofluorescence that may directly impact on your practice.

Jean-Paul Achkar, M.D. has been invited to review tricks in the use of biologic therapies in Crohn’s disease. How to select among the 3 available biologic agents (infliximab, adalimumab, and natalizumab), how to avoid complications, and how to maximize effectiveness should be of interest.

Jeffry Katz, M.D. has been asked to comment on the use of probiotics and other complementary and alternative medical therapies that are being use more and more often in our patients.

For the last review in this series, Aaron Brzezinski, M.D. has been asked to review the extraintestinal manifestations of inflammatory bowel disease, and how to recognize and treat them.

In all, information from this series should be of great interest, and should directly impact on your clinical care of inflammatory bowel disease patients.

20

Inflammatory Bowel DiseaseBret Lashner, M.D. Introduction by Peter Peter R. McNally, DO, FACP, FACGGuest Commentary

Bret Lashner, M.D. Director of the Center for Inflammatory Bowel Disease Cleveland Clinic Foundation


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Introduction

Colorectal cancer complicating ulcerative colitis (UC) was first recognized in 1925 by Crohn and Rosenberg. Colorectal cancer in UC accounts for only 1% of all cases of colorectal cancer seen in the general population1, but it accounts for 3-17% of all UC deaths.2,3 In a meta-analysis by Eaden et al.4, the overall prevalence of colorectal cancer in UC was 3.7%, and increased to 5.4% in cases of pancolitis. This study also determined that the cumulative risk of colorectal cancer in UC increased with longer duration of disease, resulting in a 2% risk after 10 years, an 8% risk after 20 years, and an 18% risk after 30 years of disease. It is important to note, however, that more recent studies have found a much lower risk of colorectal cancer in UC, with crude annual incidence rates ranging from 0.06% to 0.2%5.

The colorectal cancer risk in Crohn’s disease approximates the risk in UC patients when matched for a similar anatomic extent and duration of disease6. Among patients with longstanding, unresected extensive Crohn’s colitis, the relative risk for developing colorectal cancer ranges from 5.6 to 23.8.6 Even without adjustments for disease location or duration, the largest population-based study of cancer risk in inflammatory bowel disease (IBD) showed a relative risk of developing colorectal cancer of 2.64 for Crohn’s disease patients, as compared to a relative risk of 2.75 for UC patients.7

Although there have not been any randomized clinical studies to determine whether current surveillance colonoscopy techniques prolong survival in IBD, the bulk of evidence seems to suggest a benefit.8,9 In this article, current guidelines for colon cancer surveillance in IBD will be reviewed, including pitfalls of current recommendations. In addition, the evolving role of new techniques for cancer surveillance in IBD will be addressed, including chromoendoscopy, narrow band imaging (NBI) and auto-fluorescence imaging (AFI).

Current Guidelines for Colon Cancer Surveillance in IBD

Current guidelines recommend annual or biannual surveillance colonoscopy after 8 to 10 years of colitis (including left-sided colitis), or at time of diagnosis of concurrent primary sclerosing cholangitis (PSC). Multiple biopsies at regular distances should be performed, usually in four quadrant fashion every 10 cm and, in addition, any abnormal lesions or strictures should be biopsied as well.10- 13 A prior study has shown that 33 biopsies throughout the colon are required for 90% confidence of detection of dysplasia and 56 biopsies are required for 95% confidence of detection of dysplasia.14

There are, however, significant potential limitations and pitfalls with conventional colonoscopy for dysplasia surveillance in IBD. Although recent improvements in colonoscopic technology and more careful withdrawal can lead to increased detection of dysplastic lesions with conventional techniques15, a significant proportion of dysplastic lesions occur in flat, normal appearing mucosa that cannot be visually detected by conventional light colonoscopy.16 It is also important to realize that 10 random surveillance biopsies only cover an estimated 0.05% of the total colonic mucosal surface area.17 This fact is especially concerning when results of a survey of gastroenterologists revealed that 57% took 10 or fewer biopsies when performing IBD dysplasia surveillance, and only 2% took more than 20 biopsies.18 Given that most IBD dysplasia is flat and that there have been problems with physician adherence to the rigorous biopsy protocols required to maximize accurate dysplasia detection, new techniques that would better detect flat lesions and possibly minimize or abolish the need for numerous random mucosal biopsies of normal appearing mucosa could be of great benefit.

Inflammatory Bowel DiseaseAhmed Kandiel M.D., M.P.H.Colon Cancer Surveillance Strategies in Inflammatory Bowel Disease


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Chromoendoscopy

Chromoendoscopy has experienced a resurgence of interest as a potential superior technique for dysplasia surveillance in IBD. Chromoendoscopy was first described in 197619, and involves the topical application of stains or pigments to improve tissue localization, characterization, and diagnosis during endoscopy (Figures 1-4). There are three main types of stains that are used: absorptive stains such as methylene blue and Lugol’s solution, reactive stains such as congo red or phenol red, and contrast stains such as indigo carmine.20 The two main types of dye that have been used in the colon are methylene blue and indigo carmine.

Methylene blue is taken up by actively absorbing tissues in the colon, and is not absorbed by abnormal colonic tissue that is inflamed or dysplastic. A mucolytic such as N-acetylcysteine is first sprayed, followed by a 0.1 to 2% methylene blue spray. The mucosa

is then washed until the staining pattern is stable. It is important to note that some safety concerns have been raised regarding the use of methylene blue. Photosensitization of DNA with methylene blue, visible light, and oxygen results in oxidative damage and single strand breaks in plasmid DNA.21 When methylene blue was combined with white light, it also led to DNA damage in Barrett’s mucosa as well as in colonic epithelium.22,23 The clinical relevance

of this DNA damage remains unclear, but it is somewhat reassuring that a recent pilot study revealed that UC patients who had been exposed to methylene blue chromoendoscopy did not have a higher rate of colonic dysplasia during follow-up.24 Of note is the fact that these patients were only followed for 20 months, so it is unclear whether there will be additional risk for these patients in the future.

Indigo carmine is a combination of a blue plant dye and a red coloring agent. In contrast to methylene blue, it is not absorbed by the colon, and simply pools in the crevices between epithelial cells, thus highlighting small or flat lesions as well as mucosal irregularities. It can be administered via an oral capsule or oral lavage solution, but is usually applied as a 0.1 to 0.4% spray - no preceding mucolytic is required. There have been no reported safety issues with indigo carmine, and in contrast to methylene blue, there is no DNA damage to colonic epithelium when it is exposed to indigo carmine in combination with white light.23

There have been five major published studies from Europe and Japan evaluating the use of chromoendoscopy in UC (Table 1). Four of the five studies used indigo carmine, and four of the five studies used magnification or high resolution colonoscopes. Two additional studies from the United States have recently been presented in abstract form, evaluating the utility of chromoendoscopy for dysplasia detection in IBD.25,26

22

Lesions detected with 0.1% indigo carmine chromoendoscopy (white arrows) that were not seen with

conventional white light colonoscopy. Lesions in Figures 1 and 2 are dysplastic, lesion in Figure 3 is

hyperplastic, and lesion in Figure 4 is normal mucosa. Biopsy and

pathologic evaluation were needed to determine which lesions were

dysplastic

Figure 1

Figure 2

Figure 3

Figure 4


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All of these studies showed that chromoendoscopy increases the number of detected dysplastic lesions in UC patients as well as the number of patients with detected dysplasia. Although these studies showed a statistically significant increase in the number of dysplastic lesions detected, the increase in the number of patients with dysplasia was not always statistically significant in these studies, though statistical significance likely would have been reached with larger sample sizes. This is an important point as finding more patients with dysplasia, who would not have otherwise been identified, is a more relevant clinical outcome that simply finding more dysplastic lesions in a single patient who already had a visible dysplastic area that was detected with conventional white light colonoscopy.

Indigo carmine chromoendoscopy can be carried out with a conventional colonoscope, a spray catheter, and commercially available indigo carmine dye. A 5 ml ampule of 0.8% indigo carmine is added to 35 ml of water in a 60 cc luer lock syringe and attached to the spray catheter. Once cecal intubation is achieved, the spray catheter can be inserted and segmental spraying of the colon can be performed during colonoscope withdrawal with careful

examination of the mucosa for any highlighted lesions. Approximately 120 to 160 ml of the diluted dye is used per procedure (3 to 4 ampules of 0.8% indigo carmine).

Narrow Band Imaging (NBI)

NBI highlights the colonic mucosal surface and microvasculature by using special filters that narrow the respective red, green, and blue bands while simultaneously increasing the relative intensity of the blue band.27 Dysplastic areas with increased hemoglobin concentrations due to hypervascularity may appear brownish or dark with NBI,28, 29 and an irregular, disrupted mucosa with an abnormal mucosal capillary configuration, such as a tortuous capillary pattern, may be apparent.29 Results from an initial case report30 as well as a pilot study29 evaluating the efficacy of NBI for neoplasia detection in UC were promising, but a recent prospective randomized study comparing NBI to white light colonoscopy for dysplasia surveillance revealed that the first generation NBI system was not superior to white light colonoscopy for dysplasia detection.28 A new NBI system was recently released, however, and the efficacy of this newer system needs to be evaluated.

Table 1: Summary of Published Studies Evaluating Chromoendoscopy for UC Dysplasia Surveillance.

Study Dye Scope N Total #Patients

withDysplasia

# Patientsw/VisibleDysplasiaw/WhiteLight

# Patientsw/VisibleDysplasiaw/Chromo

RelativeRate of

DysplasiaDetectionw/Chromo

P -Value

# Patientsw/Dysplasia

Onlyw/Random

Biopsy

Matsumotoet al. 2003

0.2%Indigo

Carmen

HighRes 57 12 7 11* 1.6 NS 1

Kiesslichet al. 2003

0.1%Methylene

BlueMag 165 19 6 13 2.2 NS NR

Rutteret al. 2004

0.1%Indigo

CarmenStand 100 7 2 7* 3.5 NS 0

Hurlstoneet al. 2004

0.5%Indigo

CarmenMag 324 35 NR NR -- -- NR

Hurlstoneet al. 2005

0.5%Indigo

CarmenMag 700 81 19 62 3.3 NR NR

* Since both conventional examination and chromendoscopy were performed on the same patient in this study, this number includes total visible lesions seen with both procedures. ** NS: not significant; NR: not reported; High Res: high resolution colonoscope; Mag: magnification colonoscope; Stand: standard colonoscope.


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References

1. Choi PM, Zelig MP. Similarity of colorectal cancer in crohn’s disease and ulcerative colitis: Implications for carcinogenesis and prevention. Gut 1994;35:950-4.

2. Gyde S, Prior P, Dew MJ, et al. Mortality in ulcerative colitis. Gastroenterology 1982;83:36-43.

3. Lashner BA, Provencher KS, Bozdech JM, et al. Worsening risk for the development of dysplasia or cancer in patients with chronic ulcerative colitis. Am J Gastroenterol 1995;90:377-80.

4. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: A meta-analysis. Gut 2001;48:526-35.

5. Loftus EV, Jr. Epidemiology and risk factors for colorectal dysplasia and cancer in ulcerative colitis. Gastroenterol Clin North Am 2006;35:517-31.

6. Ullman TA. Dysplasia and colorectal cancer in crohn’s disease. J Clin Gastroenterol 2003;36:S75-8; discussion S94-6.

7. Bernstein CN, Blanchard JF, Kliewer E, et al. Cancer risk in patients with inflammatory bowel disease: A population-based study. Cancer 2001;91:854-62.

8. Friedman S, Rubin PH, Bodian C, et al. Screening and surveillance colonoscopy in chronic crohn’s colitis. Gastroenterology 2001;120:820-6.

9. Mpofu C, Watson AJ, Rhodes JM. Strategies for detecting colon cancer and/or dysplasia in patients with inflammatory bowel disease. Cochrane Database Syst Rev 2004;(2)(2):CD000279.

10. Kornbluth A, Sachar DB. Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults (update): American college of gastroenterology, practice parameters committee.

NBI is now available on many new high resolution colonoscopes. The colonoscopic view can be toggled between the NBI mode and the conventional white light mode by simply pressing a button adjacent to the control wheel on the instrument shaft.

Auto-fluorescence Imaging (AFI)

When tissue is exposed to light of short wavelength, such as blue light, certain tissue components called fluorophores, such as mitochondria, lysosomes, and submucosal collagen, will autofluoresce, and other tissue molecules called chromophores, predominantly hemoglobin in the gastrointestinal tract, will absorb both the excitation and the autofluorescent light.27, 31 Since neoplastic tissue will contain more fluorophores and chromophores than the surrounding normal mucosa, the neoplastic tissue will appear red or purple on AFI, while normal tissue will appear green.31,32 There have been no published studies on the use of AFI for neoplasia surveillance in IBD, but studies evaluating this technology in Barrett’s esophagus have shown increased detection rates of high grade dysplasia when compared to conventional white light endoscopy.31 Trials are needed to evaluate the efficacy of AFI for colon cancer surveillance in IBD. Some colonoscopes now come equipped with both NBI and AFI modes.

Conclusions:

In summary, a significant proportion of dysplastic lesions in IBD are flat or very small and can be missed with conventional white light colonoscopy, though the advent of more advanced high resolution instruments is likely

decreasing the number of these missed lesions. The number of random biopsies needed to detect this flat dysplasia can be cumbersome and there have been problems with adherence to recommended surveillance protocols.

Chromoendoscopy has been proposed as a better alternative, resulting in the detection of small, subtle, and flat dysplastic lesions with a decreased number of biopsies. Chromoendoscopy studies have revealed a 1.6 to 3.5 fold increase in the number of patients with detected dysplasia with chromoendoscopy as compared to conventional colonoscopy, but this technique can also be cumbersome and time consuming and has not yet been adopted on a wide scale. NBI and AFI are very promising techniques that seem to have the advantages of chromoendoscopy without the disadvantages of exogenous dye administration and the repeated insertion and withdrawal of a spray catheter, but more data is needed on the efficacy of these technologies in colon cancer surveillance in IBD.

Some have advocated doing away with random non-targeted biopsies and performing only dye or NBI targeted biopsies, as well as biopsies of any lesions visible with conventional white light. Although the yield is usually greater with targeted biopsies, dysplasia has still been found on random, non-targeted biopsies in most studies evaluating this issue. Several studies have found cases where patients were found to have dysplasia detected only by random biopsies without any other visible lesions.25, 26, 28, 33 It would be prudent to continue the random biopsy protocol until more effective techniques are developed and verified for colon cancer surveillance in IBD.

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Am J Gastroenterol 2004;99:1371-85.

11. Winawer S, Fletcher R, Rex D, et al. Colorectal cancer screening and surveillance: Clinical guidelines and rationale-update based on new evidence. Gastroenterology 2003;124:544-60.

12. Leighton JA, Shen B, Baron TH, et al. ASGE guideline: Endoscopy in the diagnosis and treatment of inflammatory bowel disease. Gastrointest Endosc 2006;63:558-65. 13. Itzkowitz SH, Present DH. Crohn’s and Colitis Foundation of America Colon Cancer in IBD Study Group. Consensus conference: Colorectal cancer screening and surveillance in inflammatory bowel disease. Inflamm Bowel Dis 2005;11:314-21.

14. Rubin CE, Haggitt RC, Burmer GC, et al. DNA aneuploidy in colonic biopsies predicts future development of dysplasia in ulcerative colitis. Gastroenterology 1992;103:1611-20.

15. Rutter MD, Saunders BP, Wilkinson KH, et al. Most dysplasia in ulcerative colitis is visible at colonoscopy. Gastrointest Endosc 2004;60:334-9.

16. Tytgat GN, Dhir V, Gopinath N. Endoscopic appearance of dysplasia and cancer in inflammatory bowel disease. Eur J Cancer 1995;31A:1174-7.

17. Rosenstock E, Farmer RG, Petras R, et al. Surveillance for colonic carcinoma in ulcerative colitis. Gastroenterology 1985;89:1342-6.

18. Eaden JA, Ward BA, Mayberry JF. How gastroenterologists screen for colonic cancer in ulcerative colitis: An analysis of performance. Gastrointest Endosc 2000;51:123-8.

19. Tada M, Katoh S, Kohli Y, et al. On the dye spraying method in colonofiberoscopy. Endoscopy 1976;8:70-4.

20. Canto MI. Staining in gastrointestinal endoscopy: The basics. Endoscopy 1999;31:479-86.

21. Kumar SS, Ghosh A, Devasagayam TP, et al. Effect of vanillin on methylene blue plus light-induced single-strand breaks in plasmid pBR322 DNA. Mutat Res 2000;469:207-14.

22. Olliver JR, Wild CP, Sahay P, et al. Chromoendoscopy with methylene blue and associated DNA damage in Barrett’s oesophagus. Lancet 2003;362:373-4. 23. Davies J, Burke D, Olliver JR, et al. Methylene blue but not indigo carmine causes DNA damage to colonocytes in vitro and in vivo at concentrations used in clinical chromoendoscopy.Gut 2007;56:155-6.

24. Kiesslich R, Burg J, Kaina B, et al. Safety and efficacy of methylene blue-aided chromoendoscopy in ulcerative colitis: A prospective pilot study upon previous chromoendoscopies. Gastrointestinal Endoscopy 2004;59:97.

25. Kandiel A, Lashner B, Achkar J, et al. Chromoendoscopy for colonic dysplasia surveillance in inflammatory bowel disease. Gastroenterology 2007;132:S66.

26. Marion JF, Waye JD, Present DH, et al. Methylene blue dye-spray targeted biopsies are superior to standard colonoscopic surveillance biopsies for detecting dysplasia in patients with ulcerative colitis and crohn’s colitis: A prospective endoscopic trial. Gastroenterology 2007;132;S:67.

27. Kiesslich R, Hoffman A, Neurath MF. Colonoscopy, tumors, and inflammatory bowel disease - new diagnostic methods. Endoscopy 2006;38:5-10.

28. Dekker E, van den Broek FJ, Reitsma JB, et al. Narrow-band imaging compared with conventional colonoscopy for the detection of dysplasia in patients with longstanding ulcerative colitis. Endoscopy 2007;39:216-21.

29. Matsumoto T, Kudo T, Jo Y, et al. Magnifying colonoscopy with narrow band imaging system for the diagnosis of dysplasia in ulcerative colitis: A pilot study.Gastrointest Endosc 2007;66:957-65.

30. East JE, Suzuki N, von Herbay A, et al. Narrow band imaging with magnification for dysplasia detection and pit pattern assessment in ulcerative colitis surveillance: A case with multiple dysplasia associated lesions or masses. Gut 2006;55:1432-5.

31. Kara MA, Bergman JJ. Autofluorescence imaging and narrow-band imaging for the detection of early neoplasia in patients with barrett’s esophagus. Endoscopy 2006;38:627-31.

32. Haringsma J, Tytgat GN, Yano H, et al. Autofluorescence endoscopy: Feasibility of detection of GI neoplasms unapparent to white light endoscopy with an evolving technology. Gastrointest Endosc 2001;53:642-50.

33. Matsumoto T, Nakamura S, Jo Y, et al. Chromoscopy might improve diagnostic accuracy in cancer surveillance for ulcerative colitis. Am J Gastroenterol 2003;98:1827-33.

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Featured Movie || John C. Deutsch, MD

Featured Movie: Visible Human Splenic Vein

26

The splenic vein is an important structure for gastroenterologist. For example, thrombosis of the splenic vein from inflammatory disease or tumors in the pancreas can lead to life threatening bleeding from gastric varicies. The varicies can be cured with splenectomy. With the advent of EUS, the splenic vein has taken on a role as an important landmark when evaluating the pancreas. The vein runs just caudal to the pancreas and can be readily identified as an anechoic structure by ultrasound.

This issue’s featured movie shows images of the splenic vein from the Visible Human Male and Visible Human Female data sets. The first part of the video shows a coronal cross section of the Male and the relation of the spleen and splenic vein to various anatomical structures. The stomach is empty and away from the vessels. The second part of the video shows a magnified view of the anatomy using the Female. This image is more trans axial in orientation. The pancreas in the Female appears to have undergone some degradation,

and the stomach is filled with debris, moving it closer to the pancreas and splenic vein. This then leads into a radial array EUS exam of the pancreas and splenic vein.

Hopefully the viewer can become comfortable with the regional anatomy after watching the different perspectives and orientations.

Video Clip 1: Images of the splenic vein from the Man and Woman data

sets. The first part of the video shows a coronal cross section of the Man and the relation of the spleen and splenic vein to various anatomical structures. The second part of the video shows a magnified view of the anatomy using

the Woman.

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