The Endoscopic Procedures in Familial Adenomatous Polyposis (FAP): a Critical Review

Introduction

To have a better understanding of the role of endoscopy in familial adenomatous polyposis, it is necessary to clarify some concepts in colon cancer development. Colon cancer (CRC) arises from a dys- plastic precursor lesion called adenomatous polyp (or adenoma). Approximately 30–40% of people over 50 years of age will develop an adenoma, but not all adenomas will progress to CRC. In the general popu- lation some individuals tend to develop one or only a few adenomas and endoscopic polypectomy is often sufficient for removing them, thereby markedly reducing the subsequent development to CRC. Ade- nomas arise when both copies of the APC gene are lost. Indeed, the APC gene is considered the “gate- keeper” of the colon, protecting against the develop- ment of adenomas. The loss of APC gene function permits adenoma formation and sets the stage for subsequent molecular alterations of genes such as k- ras and p53, which promote further progression to CRC (Fig. 1). Some people develop multiple polyps of the colon at a younger age due to inheritance of a germline mutation of a gene that predisposes to CRC.

Since these patients are at increased risk of CRC (and other types of cancer), it is important to recognize these syndromes earlier (Table 1). Therefore, endo- scopic procedures play a crucial role in the diagnosis, staging and follow-up of these conditions.

Familial Adenomatous Polyposis

In these patients, the disease begins at the age of 8–10 years with a small number of colonic polyps, increasing progressively until the colon becomes studded with adenomas. Endoscopy mainly plays a diagnostic role (Fig. 2) since colorectal cancer should be considered an inevitable consequence in the natu- ral history of FAP, appearing approximately 15 years after the onset of the polyps. For this reason prophy- lactic proctocolectomy is the procedure of choice for this condition. After the proctocolectomy, the ileal pouch could develop polyps even if the risk of pouch cancer in FAP is unclear. Therefore, long-term endo- scopic surveillance (pouchoscopy) is recommended [1].

It is known that FAP patients frequently develop

The Endoscopic Procedures in Familial Adenomatous Polyposis (FAP): a Critical Review

Walter Piubello, Fabrizio Bonfante, Morena Tebaldi

Normal mucosa

Early adenoma

Intermediate adenoma

Late adenoma

Carcinoma

APC K-ras

DCC/18q genes

P53

Fig. 1.Steps of colon carcinogenesis

tumours (either benign or malignant) in other organs besides the colon, mainly in the upper GI tract (stomach, small intestine). Gastric polyps occur in 30–100%, but adenomas are uncommon, occurring in approximately 5% of FAP patients usually in the gastric antrum (Fig. 3). The development of gastric

carcinoma in FAP patients is only very high in Japan where the gastric cancer rate in the general popula- tion is higher. In other populations it occurs in less than 5% of the population. Proximal small-bowel cancer is one of the two leading causes of death in FAP patients with previous colectomy [2, 3]. It develops

FAP (autosomal Adenomas Colon, Benign: desmoid APC

dominant) (100s-1000s) duodenum, tumours, osteomas,

jejunum, ileum, epidermoid cysts, stomach, (fundic CHRPE^a

gland polyps) Malignant:

medulloblastoma, hepatoblastoma, thyroid cancer, adrenal cancer

Attenuated FAP Adenomas Colon, Osteomas APC (5’ and 3’)

(autosomal (5–100) duodenum, (mandible) APC E1317Q

dominant) stomach

MYH polyposis Adenomas Colon, Osteomas, CHRPE^a MYH^b

(autosomal (5–100) duodenum,

recessive) stomach

aCHRPE, congenital hypertrophy of the retinal pigment epithelium; ^bMYH, is a gene that repairs DNA damage (if defecting, the resulting loss of APC function causes an increase in multiple adenomas)

Fig. 2.Diffuse polyposis of the colon

from pre-existing adenomas which are present in approximately 100% of these patients in the duode- num (Fig. 4). Duodenal adenomas can be classified through macroscopic and histologic criteria in five stages (0–IV) following the Spigelman’s classification (Table 2) [4, 5].

In all FAP patients submitted to proctocolectomy, screening and surveillance for duodenal and small- bowel polyps are mandatory. Duodenoscopy (side vision) should be performed, taking several biopsies from the duodenal papilla and from all the polyps,

Fig. 4.Duodenal adenoma in FAP

Table 2.Spigelman’s score and classification (modified)

Score No. of duodenal polyps Size (mm) Histology Dysplasia

1 point 1–4 1–4 Tubulous Low grade

2 points 5–20 5–10 Tubulous-villous –

3 points > 20 >10 Villous High grade

Classification Stage 0 Point – (no polyps)

I 1–4

II 5–6

III 7–8

IV 9–12

also by means of chromoendoscopy (Fig. 5). At the first duodenoscopy, the prevalence of duodenal adenomatosis is 58–74% in the major series, and only about 10% of adenomas are diagnosed histo- logically.

The risk of duodenal carcinoma is related to the Spigelman stage (about 7% in stage IV, 0.7% in stage 0–III) [6]. In Spigelman stage III–IV, endoscopic ultrasonography is recommended to ensure that invasive growth has not occurred. The regular endo- scopic surveillance of the duodenum should be offered to all FAP patients (Table 3) [7]. The first upper endoscopy should be carried out at the age of 30 years and include multiple random biopsies taken from the duodenal mucosa in patients without visible polyps. Endoscopic surveillance (included ultra- sonography) is recommended at intervals of 3 months in patients who are not suitable for or refuse surgery.

Screening or surveillance for small-bowel polyps is difficult with current technologies. By means of traditional push enteroscopy (PE), up to only 30% of the small-bowel length can be visualized. A new promising endoscopic method for allowing complete

visualisation, biopsies and treatment in the small bowel is the double balloon enteroscopy (DBE; push and pull; Fig. 6), but the use of this technique in FAP patients is not yet routine [8].

Capsule endoscopy (CE) is another recent tech- nology that allows a non-invasive endoscopic assess- ment of the entire small bowel (Fig. 7) [9]. Published clinical trials have shown that CE carries a high diag- nostic yield in patients suffering from obscure gas- trointestinal bleeding [10–13]. Beyond this role, the value of CE in other small bowel disorders has to be evaluated. CE may also be used to search for tumours or tumour-like lesions in patients that present with a known increased risk of small bowel carcinomas such as familial adenomatous polyposis, Peutz-Jeghers syndrome and familial juvenile poly- posis. The comparison between CE and DBE in detecting small bowel tumours is shown in Table 4 [12–16].

In FAP patients, preliminary results [17] suggest that capsule endoscopy can only be used additional- ly to identify patients with significant distal jejunal polyposis. However, this is suggested to be a rather infrequent situation. The correlation between the findings of capsule endoscopy and conventional endoscopy is reported in Table 5. Active control of the capsule endoscopy, the precise assessment of polyps size and the opportunity to obtain biopsies are important long-term future requirements for extending the indication to FAP patients.

In the first study that compares the value of CE and DBE in the diagnosis of small intestinal polypo- sis [18], the diagnostic yield of DBE was superior in comparison to CE in almost the same area explored.

Even Yamamoto et al. [19] have shown that with this method, total enteroscopy can be achieved by com- bining antegrade and retrograde examinations, how- ever, DBE in comparison with CE is an inconvenient and invasive procedure that requires specialized equipment, sedation of the patients, fluoroscopy and

Table 3.Programme for surveillance and treatment of duo- denal adenomatosis

Spigelman’s stage Frequency of endoscopy

0 5 years^a

I 5 years^b

II 3 years^b

III 1–2 years^b

IV Endoscopic ultrasonography

Consider pancreas sparing and pylorus sparing duodenectomy

aIncluding multiple random biopsies from the mucosal fold in patients without visible polyps; ^bIncluding multiple biopsies from polyps

Fig. 6.Double balloon enteroscopy

a prolonged examination time.

At the end of this report, the role of endoscopic procedures in FAP patients can be summarized as follows (Table 6):

– Conventional colonoscopy should be performed with multiple biopsies and polypectomy, starting at the age of 8–10, considering prophylactic proc-

tocolectomy when the number of polyps are increasing and the risk of carcinoma is very high (10–15 years from the onset of polyps).

– Pouchoscopy, after proctocolectomy, should be per- formed because the ileal pouch could develop polyps even if the real risk of pouch cancer is unclear.

– Gastric endoscopy to show fundic gland polyps (frequent) and adenomas (rare).

– Duodenoscopy with side view to remove all the polyps, particularly near the papilla, and to per- form several random biopsies by using chromoen- doscopy with methylene blue.

– Endoscopic ultrasonography in patients with Spigelman stages III–IV.

Fig. 7.Ileal polyp at capsule endoscopy

Table 4.Comparison between capsule endoscopy (CE) and push enteroscopy (PE) in detecting small-bowel tumours

Author Year No. of patients No. of tumours (%)

Total PE CE

Cosentino et al. [14] 2003 33 4 (10.7) 4 2

Delvaux et al. [15] 2002 57 1 (1.8) 0 1

Ell et al. [12] 2002 32 2 (6.3) 2 2

Mylonaky et al. [16] 2002 38 2 (5.3) 2 2

Pennazio et al. [11] 2002 50 3 (6) 2 2

Table 6.Endoscopic procedures in FAP

GI site Endoscope Findings Time and follow-up

Stomach Conventional Fundic gland polyps At first diagnosis

(adenoma)

Duodenum Side vision Adenomas Spigelman stage (endoscope

(±chromoendoscopy) ultrasonography stages III–IV)

Small bowel Capsule endoscopy, Polyps At first diagnosis?

double balloon Surveillance?

enteroscopy

Colon Conventional Adenomas (100s–1000s) -

Ileal pouch Conventional Polyps ?

Table 5.Correlation of Spigelman’s score (modified) meas- ured by capsule endoscopy and conventional endoscopy Capsule endoscopy Conventional endoscopy

(score) (score)

No. of patients

0 1–2 3–4 5–6

0 5 1 - -

1–2 1 - 1 -

3–4 1 ± 7 -

5–6 - - - 7

References

1. Groves CJ, Beveridge G, Swain DJ et al (2005) Preva- lence and morphology of pouch and ileal adenomas in familial adenomatous polyposis. Dis Colon Rectum 48:816–823

2. Arvanitis ML, Jagelman DG, Fazio VW et al (1990) Mortality in patients with familial adenomatous poly- posis. Dis Colon Rectum 33:639–642

3. Nugent KP, Spigelman AD, Phillips RK (1993) Life expectancy after colectomy and ileorectal anastomosis for familial adenomatous polyposis. Dis Colon Rec- tum 36:1059–1062

4. Spigelman AD, Williams CB, Talbot IC (1989) Upper gastrointestinal cancer in patients with familial adeno- matous polyposis. Lancet 2:783–785

5. Spigelman AD (2004) Extracolonic polyposis in famil- ial adenomatous polyposis: so near and yet so far. Gut 53:322–327

6. Bülow S, Bjiörk J, Christensen IJ et al ( 2004) Duodenal adenomatosis in familial adenomatous polyposis. Gut 53:381–386

7. Saurin JC, Gutknecht C, Napoleon B et al (2004) Sur- veillance of duodenal adenomas in familial adenoma- tous polyposis reveals high cumulative risk of advance disease. J Clin Oncol 22:493–498

8. May A, Nachbar L, Ell C (2005) Double–balloon enteroscopy (push and pull enteroscopy) of the small bowel: feasibility and diagnostic and therapeutic yield in patients with suspected small bowel disease. Gas- trointest Endosc 62:62–70

9. De Franchis R, Rondonotti E, Abbiati C et al (2004) Small bowel malignancy. Gastrointest Endosc Clin N Am 14:139–148

11. Pennazio M, Santucci R, Rondonotti E et al (2002) Capsule endoscopy: diagnostic yield and comparison with push enteroscopy in patients with obscure gas- trointestinal bleeding: the Italian multicentre experi- ence. Endoscopy 34 (suppl II):A91

12. Ell C, Remke S, May A et al (2002) The first prospective controlled trial comparing wireless capsule endoscopy with push enteroscopy in chronic gastrointestinal bleeding. Endoscopy 34:685–689

13. Piubello W, Bonfante F, Tebaldi M et al (2005) Pillcam videocapsule endoscopy and obscure gastrointestinal bleeding: our experience. Dig Liver Dis 37(suppl 1):160 14. Cosentino F, Morandi E, Rubis-Passoni G et al (2003) Wireless capsule endoscopy: limits and complications.

Abstracts of the 2003 Meeting of the Italian Federation for Digestive Disease, Italian Federation for Digestive Disease, Florence, p 41

15. Delvaux M, Saurin JC, Gaudin JC et al (2002) Compar- ison of wireless endoscopic capsule and push- enteroscopy in patients with obscure occult/overt digestive bleeding: results of a prospective, blinded, multicentre trial. Gastrointest Endosc 55:AB88 16. Mylonaky M, Fritscher-Ravens A, Swain PC (2002)

Clinical results of wireless capsule endoscopy. Gas- trointest Endosc 55:AB146

17. Schulmann K, Schmiegel W (2004) Capsule endoscopy for small bowel surveillance in hereditary intestinal polyposis and non-polyposis syndromes. Gastrointest Endosc Clin N Am 14:149–158

18. Matsumoto T, Esaki M. Horiyama T et al (2005) Com- parison of capsule endoscopy and enteroscopy with the double-balloon method in patients with obscure bleeding and polyposis. Endoscopy 37:827–832 19. Yamamoto H, Kita H, Sugano K et al (2004) Clinical

outcomes of double-balloon endoscopy for the diag- nosis and treatment of small intestinal diseases. Clin Gastroenterol Hepatol 2:1010–1016