Best Practice & Research Clinical Gastroenterology

Vol. 16, No. 1, pp. 91114, 2002

doi:10.1053/bega.2002.0268, available online at http://www.idealibrary.com on

7
Colonic cancer and polyps
Karsten Schulmann

MD

Fellow, Department of Gastroenterology

Markus Reiser

MD

Attending Physician (Faculty), Department of Gastroenterology

Wol Schmiegel*

MD

Chief, Department of Medicine

Ruhr-Universitat Bochum, Medizinische Klinik, Knappschaftskrankenhaus, In der Schornau 2325, D-44892
Bochum, Germany

Colorectal cancer (CRC) is one of the best studied cancers. It is easily accessible and develops
slowly over several years from premalignant lesions (adenomatous polyps) to invasive cancers.
The key molecular events in this sequence have been characterized. Dierent screening
strategies have proven to be eective in lowering both the mortality and the incidence of
CRC. Nevertheless, CRC is still the second leading cause of cancer-related deaths for both
men and women in the USA and other Western countries. An estimated 130 000 new cases
and more than 50 000 deaths have been diagnosed in the USA in 2000. Surgical resection
remains the only curative treatment, and the likelihood of cure is greater when the disease is
detected at an early stage. Hereditary non-polyposis colorectal cancer (HNPCC) and the
dierent polyposis syndromes such as familial adenomatous polyposis (FAP) or PeutzJeghers
disease are rare causes of CRC but have been a major focus of research in past years, helping
with the understanding of the molecular events in carcinogenesis. This review summarizes our
current knowledge of the pathogenesis and management of colorectal polyps and polyposis
syndromes as well as sporadic CRC.
Key words: colorectal adenoma; colorectal carcinoma; FAP; HNPCC; juvenile polyposis;
PeutzJeghers; polyposis; colonoscopy; FOBT; CRC screening; chemoprevention; APC; MMR
genes.

COLORECTAL POLYPS
A mucosal protuberance into the lumen of the colon is dened as a colon polyp.
Histologically, colorectal polyps can be classied as neoplastic (adenomatous) and nonneoplastic (hyperplastic and hamartomatous). Adenomatous polyps are premalignant
lesions of colorectal cancer (CRC) and, therefore, need treatment and surveillance.
*All correspondence to: Wol Schmiegel. Tel: 49 234 299 3401; Fax: 49 234 299 3409, E-mail: wol.
schmiegel@ruhr-uni-bochum.de
15216918/02/01009124 $35.00/00

c 2002 Harcourt Publishers Ltd.

*

92 K. Schulmann et al

Normal mucosa

Carcinoma
APC-mutation/
COX-2 expression

Aberrant crypt foci

p53 and
other
mutations
Small adenoma

Large adenoma
K-ras mutation

Figure 1. Adenomacarcinoma sequence of colorectal cancer. The gure shows the stepwise accumulation
of genetic alterations during tumour progression.

Hamartomatous polyps bear a smaller risk and hyperplastic polyps bear no risk of
malignant transformation.
Adenomatous polyps are found sporadically in approximately 33% of the general
population by the age of 50 and in approximately 50% by the age of 70. Adenomas can
be further characterized as tubular or villous adenomas according to criteria
established by the World Health Organization. Tubular histology equals the crypt
architecture of normal mucosa and is found in 50% of adenomas. Tubular adenomas
rarely exceed a size of 2 cm in diameter length. Villous adenomas comprise 15% of
adenomatous polyps and show a nger-like stroma covered by a mucus producing
epithelium (Figure 2). They often become larger than 2 cm. The remaining 35% of
adenomas contain both tubular and villous structures.
The National Polyp Study has shown a denite relationship between colorectal
adenomas and carcinomas and has given solid footing to the adenoma-to-carcinoma
sequence (Figure 1). The few studies that have been performed on the natural history
of colorectal adenomas suggest that it takes at least 5 years, and more often 10 years,
for a histologically proven adenomatous polyp to develop into colon cancer. Adenomas
that are larger than 1 cm, show villous histology (i.e. at least 25% villous), or show high
grade dysplasia are dened as `advanced colonic neoplasias' or `adenomas with
advanced pathology'. They carry the greatest risk of malignant transformation.1 A
study from Norway calculated an overall rate of prognosis of adenoma-to-carcinoma of
0.25% per year. For polyps larger than 1 cm this rate was 3%, for villous adenomas 17%
and for adenomas with high grade dysplasia the rate was 37% per year.2 Adenomatous
polyps can already contain malignant lesions that, however, must not exceed the
muscularis mucosae (carcinoma in situ) or muscularis propria (pT1 tumour). A positive
family history for colorectal adenomas is believed to be associated with a higher
prevalence. Environmental factors such as a diet low in bre and high in fat and red
meat, smoking and alcohol consumption have been linked to an increased risk of
colorectal adenomas in several prospective studies.3,4 Sex and race have not been
shown to aect the incidence of adenoma.

Colonic cancer and polyps 93

Figure 2. (A) Endoscopic view of an adenoma of the sigma before polypectomy (diathermal loop in place),
histologically this was a tubulovillous adenoma with high-grade dysplasia. (B) Endoscopic view of a carcinoma
of the caecum (ileocaecal valve in the left upper corner).

The earliest recognized lesions in the adenoma-to-carcinoma sequence consist of

enlarged crypts with thickened layers of epithelial cells, increased pericryptal spaces and
irregular or slit-shaped lumina and named aberrant crypt foci (ACF). Subsequently, ACF
have also been identied in the human colonic mucosa.5 On a molecular level, genetic
alterations especially in the adenomatous polyposis coli gene (APC) have been detected
in these early lesions, supporting the hypothesis that ACF is an early premalignant lesion
in the adenoma-to-carcinoma sequence. With the inactivation of the tumour suppressor
APC (the gatekeeper of colorectal cell homeostasis), additional alterations in tumour
suppressor- and oncogenes may accumulate and lead to the development of an
adenomatous polyp and eventually to a carcinoma (see Figure 1).
Clinical presentation and diagnosis
Colorectal adenomas are rarely symptomatic and are usually incidental ndings at
colonoscopy. Abdominal discomfort or a change in stool are infrequent clinical
presentations. Villous adenomas may, occasionally, be associated with potassium-rich
secretory diarrhoea, while 5% of adenomas cause occult bleeding detected by faecal
occult blood testing (FOBT). This overall low sensitivity of FOBT for colorectal
adenomas can, however, reach as high as 50% for polyps larger than 1 cm. The most
sensitive method for the detection of colorectal polyps is complete colonoscopy, which
also allows direct intervention, i.e. biopsy or polypectomy. Double-contrast barium
enema evaluation is less sensitive, does not allow for polyp biopsy or removal and is
today mainly used when colonoscopy is contraindicated or incomplete.
Treatment
All colorectal polyps should be biopsied or removed in order to characterize their
neoplastic potential. Polyps smaller than 0.5 cm should be biopsied, since diathermic
polypectomy might hinder histological grading due to coagulation. Polyps larger than
0.5 cm should be removed by diathermic polypectomy and recovered individually after
documenting their localization. However, using the length of the endoscope for
localizing a polyp is only accurate in the rectum and sigmoid colon. More proximal
polyps can be localized precisely by radiological imaging. Histological evaluation should
be performed according to the WHO classication6 and should include the histological

94 K. Schulmann et al

type (tubular/villous), grading of dysplasia (low/high grade) and information regarding

resection margins. The latter can be especially dicult due to coagulation artefacts and
no consensus has been reached regarding the necessity for a complete resection
according to histological criteria. Individuals in whom colorectal adenomas have been
removed are at risk for new adenomas: in the National Polyp Study this risk was
estimated to be 32.041.7%. Nevertheless, colonoscopy performed 3 years after the
removal of adenomatous polyps is considered to be safe and is the recommended
follow-up strategy irrespective of the size or histological type of the initial adenoma. If
no adenomas are found in the rst follow-up examination, colonoscopy should be
repeated after another 5 years. If there is any doubt about the complete removal of an
adenomatous polyp according to endoscopic or histological criteria, re-examination
should be performed shortly after the initial colonoscopy.
In the special case of a malignant polyp that has reached the submucosa (pT1
tumour), a thorough histological staging and grading is required to guide further
management: histological grade 1 or 2 with no invasion of lymph vessels is associated
with low risk and allows for endoscopic surveillance (after complete polypectomy) at
6, 24 and 60 months. A high risk T1 tumour (as dened by histological grade 3 or 4) or
invasion of lymph vessels calls for surgical resection and endoscopic follow-up at 24 and
60 months.
Chemoprevention after polypectomy can not be recommended at this point.
Although several cohort studies have shown some protective eects, prospective
randomized intervention trials have not been convincing (Table 1).
SPORADIC COLORECTAL CANCER
Introduction
Colorectal cancers not associated with hereditary cancer syndromes (see below) are
dened as sporadic. The lifetime risk of developing sporadic CRC after age 50 is
approximately 5% for average-risk individuals. The likelihood of developing CRC in
patients with one aected rst-degree relative is doubled. First-degree relatives of
patients who had an adenomatous polyp discovered before age 60 also have a twofold
increase in risk for developing CRC, as shown in the National Polyp Study. In addition
to genetic predisposition, environmental factors, including a diet low in bre,
vegetables and folate but high in fat, red meat and alcohol, sedentary ocupation and
cigarette smoking are believed to be associated with an increased CRC risk.
Clinical presentation
Symptoms develop late in the course of the disease and approximately 40% of cases are
diagnosed with stage IV (Table 2), i.e. distant metastases. Abdominal pain, change in
bowel habits and rectal bleeding are the most frequent symptoms leading to a
diagnosis of CRC (Table 3). About 15% of patients present with obstruction and
emergency surgery is warranted in approximately 10%. Faecal occult blood (FOB) is
observed in up to 65% of cases and this highlights the value of FOB testing.
Genetics of sporadic colorectal cancer
Vogelstein et al7 have proposed a multi-step model for the genetic events in the
progression of sporadic CRC. This adenoma-to-carcinoma model (see Figure 1) is

Prospective cohort
Prospective cohort
Randomized, placebocontrolled, followed by
prospective cohort

CI, condence interval.

Grodstein et al.81

D. Oestrogens
Calle et al.80

C. Calcium
Baron et al.79

Prospective cohort

Prospective cohort

Randomized, placebocontrolled

Giovannucci et al.78 Prospective cohort

B. Folate
Giovannucci et al.77 Prospective cohort

Giovannucci et
Giovannucci et al.74
Gann et al.75
Sturmer et al.76

Prospective cohort

A. Aspirin
Thun et al.72

al.73

Design

Agent/Study

Death from colon

cancer
Colorectal cancer
Colorectal
adenomas

Colorectal
adneomas

Colorectal
adenomas
Colon cancer

Death from colon

cancer
Colon cancer
Colorectal cancer
Colorectal cancer

End point

59 002

422 373

913

88 756

25 474

47 900
89 446
22 071

662 424

No. of
patients
(0.610.97) for men
(0.560.96) for women
(0.520.92)
(0.360.90)
(0.801.65)

0.65 (0.500.83)
0.74 (0.550.99)

0.71 (0.610.83)

0.85 (0.740.98)

0.25 (0.130.51)

0.71 (0.560.89)

0.77
0.73
0.68
0.56
1.15

Relative risk (95% CI)

Table 1. Trials of chemoprevention of colorectal cancer.

Benet greatest for current users (R 0.55) and

continous users (R 0.54)
Benet limited to current users for
adenomas 41 cm only

Eect seen as early as 1 year

Benet seen after 15 years of use

Benet greatest in users of folate supplements

Benet greater with continous aspirin use

Benet signicant after 20 years of consistent use

Benet greatest for more frequent aspirin use

Comment

Colonic cancer and polyps 95

96 K. Schulmann et al
Table 2. Staging of colorectal cancer.
UICC
I
II
III
IV

T1
T2
T3
T4
Any T
Any T
Any T

N0
N0
N0
N0
N1
N2
Any N

M0
M0
M0
M0
M0
M0
M1

UICC, International Union Against Cancer; T, primary tumour; N,

nodal status; M, distant metastosis according to TNM-classication.1

Table 3. Symptoms of colorectal cancer.

% of patients with symptoms
Abdominal pain
Change in bowel habit
Occult bleeding
Rectal bleeding
Malaise
Obstruction
Jaundice

40
35
35
27
18
15
55

based on the assumption that a cell must accumulate a combination of four or ve

defects, including mutational activation of oncogenes and inactivation of tumour
suppressor genes, in order to undergo full malignant transformation. Various genetic
changes have been identied and localized within the progression model (Table 4 and
see Figure 2). In addition, genetic markers have been shown to be of prognostic value
for predicting the clinical course and response to therapy.8
Surveillance, screening programme
Dierent screening strategies for average risk individuals have been proposed (Table 5)
and have been shown to be successful in signicantly reducing CRC mortality. CRC
screening for asymptomatic individuals is recommended beginning at age 50. In the
case of increased familial risk (i.e. rst-degree relative aected), screening should be
initiated at an age 10 years younger than the age of the index case.
Faecal occult blood testing
Three randomized controlled trials have demonstrated a signicant reduction in CRC
mortality (1533%) in patients who were screened compared with unscreened controls.
The benet is mostly attributed to early cancer detection and, to a lesser degree, to the
discovery and removal of adenomatous polyps. Indeed, it was shown only recently that
use of either annual or biennial FOBT signicantly reduces the incidence of colorectal
cancer.9 The sensitivity and specicity have been evaluated in patients who provide stool
from three consecutive days. The predictive value for FOBT obtained during a digital
rectal examination is unknown. Dietary restrictions should be obeyed, but may not

APC

K-ras

APC mutation

K-ras, codon 12, 13

Incidence in CRC

Oncogene

Wnt-signalling, cell adhesion, chromosomal stability

See LOH 17p

Cell cycle regulation, CDK inhibitor

Receptor for TGF-beta signalling

Apoptosis

Repair of nucleotide mismatches during replication

50%

90%

70%

Sporadic: rare
HNPCC: 80%

Sporadic: rare
HNPCC: 50%

Sporadic CRC: 15%

HNPCC: 90%

4550%

Tumour suppression, DNA repair, apoptosis, cell cycle regulation LOH: 75%

Transcription factor in TGF-beta signalling, tumour suppression LOH: 7075%

Netrin-1 receptor, apoptosis, cell adhesion, tumour suppression
Transcription factor in TGF-beta signalling

Function

CRC, colorectal cancer; HNPCC, hereditary non-polyposis colorectal cancer.

WAF1

TGF-beta-R-II

TGF-beta-R-II mutation

P53

BAX

BAX mutation

P53 protein labelling increased

MMR genes

MSI

P21/WAF1 protein labelling increased

P53

LOH 8p

Smad 4 (DPC4)
DCC
Smad 2

LOH 18q

LOH 17p

Related gene

Marker

Table 4. Molecular alterations and prognostic markers in colorectal cancer.

Adverse

None

Adverse

Favourable

None

Adverse

Favourable

Adverse

Adverse

Adverse
Adverse
None

Prognostic value

Colonic cancer and polyps 97

98 K. Schulmann et al
Table 5. Screening strategies for average risk subjects.
Strategy

Evidence

Estimated maximal mortality reduction

Annual FOBT

RCT

4550% rehydrated
3035% non-rehydrated

Flexible sigmoidoscopy

Casecontrol

5060% if colonoscopy performed for any

adenoma found in left colon

Flexible sigmoidoscopy FOBT

Non-random

65%

Colonoscopy

In direct from
FOBT trials

7580%

Barium enema

None

5060%, assuming 50% of adenomas are

detected and followed up with colonoscopy

FOBT, faecal occult blood test.

signicantly aect FOBT reliability. Any positive test should be followed up with colonoscopy. The addition of a drop of water to the test slides (rehydrated FOBT) increased
sensitivity but also resulted in a high rate of positive tests, many of which were falsely
positive, thereby substantially changing the cost-eectiveness ratio of this management
approach. Rehydration of FOBT is, therefore, no longer recommended. The sensitivity
of non-rehydrated FOBT reaches approximately 60%, with a specicity of 90%.
Flexible sigmoidoscopy
Two casecontrol studies have found a signicant reduction in CRC mortality in
patients screened using sigmoidoscopy. Patients who have index adenomas discovered
by sigmoidoscopy must proceed to complete colonoscopy. Nevertheless, the prevalence of advanced proximal neoplasias (not detectable by sigmoidoscopy) in patients
with no distal lesions has been shown to be approximately 1.5%.10,11
Colonoscopy
The use of colonoscopy to screen asymptomatic adults for colorectal cancer is receiving
increasing attention. Colonoscopy is feasible and eective in identifying patients with
adnomatous polyps who may benet from removal of the lesions. Colonoscopy is
currently the test of choice for patients with a higher than average risk of CRC.
However, colonoscopy has the highest cost. It remains to be determined whether a full
colonic examination will lead to a greater reduction in the rate of mortality from
colorectal cancer than other methods of screening in average risk individuals.
HEREDITARY COLORECTAL CANCER SYNDROMES
Hereditary colorectal cancer syndromes account for up to 10% of all CRCs (Table 6).
Two groups of hereditary colorectal cancers are commonly distinguished: the
polyposis syndromes with multiple colorectal polyps and the non-polyposis syndromes
presenting with only a single or a few polyps. The polyposis syndromes comprise the
familial adenomatous polyposis (FAP), PeutzJeghers syndrome and juvenile polyposis
coli. The non-polyposis syndromes include hereditory non-polyposis colorectal cancer

Colonic cancer and polyps 99

Table 6. Hereditary colorectal cancer (CRC) syndromes.
% of CRC

CRC risk
(%)

Mutation detection
rate (%)

510

80

PeutzJeghers syndrome
Juvenile polyposis coli

Hereditary non-polyposis
colorectal cancer (HNPCC)

Familial adenomatous
polyposis (FAP)

Gene

Chromosome

5070{

MLH1{
MSH2{
MSH6
PMS1
PMS2

3p21
2p16
2p16
2q32
7q22

100

7080

APC

5q21

0.1

40

490

STK11

19p13.3

0.1

2060

30
Rare
?

SMAD4
PTEN
BMPR1A

18q21.2
10q23
10q2223

{Positive Amsterdam Criteria.

{90% of all detectable mutations are located in MLH1 or MSH2.
Source: Schulmann & Schmiegel.82

(HNPCC) and familial clustering of colorectal cancers without known susceptibility

genes.1214
Familial adenomatous polyposis
Introduction
FAP is a rare autosomal dominant disease that is chararacterized by a large number of
colorectal adenomas ( 4100) and accounts for approximately 1% of all CRCs. FAP is
caused by inactivating germline mutations of the APC gene leading to truncated
proteins with impaired function.15 Since inactivation of the APC gene is also the rst
molecular event in sporadic CRC, FAP is considered to be an acceleration of the
adenoma-to-carcinoma sequence that was rst described for sporadic colonic
neoplasms.
Clinical presentation
The majority of patients with FAP develop hundreds to thousands of colorectal polyps.
Nearly all patients with untreated FAP present with CRC by the age of 40. The family
history for colon cancers is usually positive with numerous relatives aected at a young
age. However, up to 25% of FAP patients do not have a family history, suggesting
spontaneous germline mutations in these patients. While polyp development starts in
the distal colorectum at an average age of 15 years, most patients become symptomatic
by the age of 2530 years. About 70% of patients with FAP who underwent proctocolectomy develop polyps in the upper gastrointestinal tract with numerous, often at
ademonas of the duodenum (Figure 3). Roughly 3040% of FAP patients develop fundic
gland polyposis (Figure 3) and 510% develop gastric adenomas. The risk of gastric
cancer is not increased, whereas duodenal cancer (relative risk (RR) 4300) and
ampullary cancer (RR 4120) are the major cause of death in colectomized patients with
FAP.16 An increased risk is also observed for hepatoblastoma, thyroid cancer and brain

100 K. Schulmann et al
1

(A)

II
45

35
1

29

32

35

III

IV
15
wt

41
mt
2
1
13
mt

36

37
mt

15

Figure 3. Typical features of familial adenomatous polyposis (FAP). (A) Family pedigree. (B) Flat adenoma of
the proximal jejunum (tubulovillous adenoma with high-grade dysplasia). (C) Numerous small duodenal
polyps (tubular adenoma with low-grade dysplasia). The papilla vateri (arrow) reveals no abnormalities.
(D) Fundic gland polyposis of the stomach. (E) Congenital hypertrophy of the retinal pigment epithelium
(CHRPE). Women s, men h, Red, FAP and carcinoma; green, FAP; Slash, deceased.

tumours (usually medulloblastomas) (Table 7). Extra-intestinal manifestations of FAP are

desmoid tumours (1015%), epidermoid cysts (3050%) and osteomas (7080%, often
located within the mandibula). The combination of polyposis, epidermoid cysts and
osteomas is dened as Gardner's syndrome and a combination of polyposis and tumours

Colonic cancer and polyps 101

Table 7. FAP-associated neoplasms.
Lifetime risk (%)
CRC
Duodenal adenoma
Duodenal/papillary cancer
Pancreatic cancer
Desmoids
CNS tumours (medulloblastoma)
(Papillary) thyroid cancer
Hepatoblastoma

100
8090
515
2
1015
51 (RR 92)
12
1

FAP, familial adenomatous polyposis; CRC, colorectal

cancer; RR, relative risk.

of the CNS is dened as Turcot's syndrome. However, these syndromes only display a
dierent spectrum of FAP. Approximately 80% of FAP patients present with congenital
hypertrophies of the retinal pigment epithelium (CHRPE) (Figure 3).17 Approximately
10% of FAP patients present with an attenuated phenotype (AAPC) characterized by less
than 100 polyps and the predominant development of right-sided colon adenomas,
which are often of the at adenoma type. Attenuated FAP (AFAP, AAPC) is mostly
diagnosed between the age of 5055 years.18 The mutations in families with attenuated
FAP are located at the proximal or distal parts of the APC gene.19,20
Genetics of FAP
FAP is caused by germline mutations within the tumour suppressor gene APC on
chromosome 5. The prevalence is 1:10.000 and the penetrance of FAP is 100%.
Although more than 800 dierent germline mutations in the APC gene have been
published, and most are unique to only one FAP family, a number of close genotype
phenotype correlations have been identied. This is mostly due to the fact that almost
all APC mutations are truncating mutations. Thus, it is not the mutation itself that is of
relevance, but its localization within the gene, since this denes the length of the
mutant APC protein. A deletion of 5 base pairs (bp) at codon 1309 is the most
frequent mutation (18% of all FAP patients). This leads to a severe phenotype, with an
onset of disease 10 years earlier compared to patients with mutations between codons
168 and 1580 (except codon 1309) (20 years versus 30 years).21 Another frequent
mutation is a deletion of 5 bp at codon 1061 (12% of all FAP patients), whereas other
mutations are distributed over the whole gene. Mutations in the 30 region of the APCgene are rarely detected.22 Patients with mutations proximal to codon 168 or distal to
codon 1580 are diagnosed predominantly at an older age ( 4 50 years) and display an
attenuated phenotype.21
CHRPE is associated with mutations in the central portion of the APC gene (codon
4631387), whereas desmoid tumours are more frequently observed in families with
mutations distal to codon 1403.23,24 The localization of the APC germline mutation may
be of clinical value in the surgical management of colorectal polyposis, since mutations
between codon 1250 and 1500 are associated with an increased risk of cancer in the
rectal stump after subtotal colectomy.25,26 However, there is no correlation between
germline mutation and polyposis of the upper gastrointestinal tract.21

102 K. Schulmann et al
Table 8. Spigelman classication of duodenal polyposis.

Number of polyps
Size of largest polyp (mm)
Histological type
Histological grading
Grade
I
II
III
IV

1P

2P

3P

14
14
Tubulary
Low

520
510
Tubulovillous
Intermediate

420
410
Villous
High

Spigelman score
14
56
78
912

Source: Spigelman et al.29

Screening programme
Regular endoscopic screening is recommended, if the carrier-status of persons at risk is
conrmed or DNA testing is not informative. Rectosigmoidoscopy should be initiated at
the age of 1012 years and should be performed at 1 year intervals. When polyps are
diagnosed by rectosigmoidoscopy, a complete colonoscopy must be performed to
investigate the entire colon. Rectosigmoidoscopy should be continued yearly up to the
age of 40 years. Between the age of 40 and 60, screening intervals may vary from
35 years. Screening procedures for polyposis of the upper gastrointestinal tract should
be started at the age of 30. Screening intervals of 3 years are recommended. When
adenomas are observed, screening intervals should be shortened to 1 year.27,28 Polyposis
of the upper gastrointestinal tract is graded according to the Spigelman classication to
allow adequate follow-up of the disease (Table 8).29 For families with an attenuated
familial adenomatous polyposis (FAP) screening procedures may be initiated later
depending on the age of onset in the family. Complete colonoscopy is recommended for
adequate screening of attenuated FAP (Table 9).
Treatment
Adequate options for the treatment of FAP are total colectomy with ileorectal
anastomosis (IRA) or proctocolectomy and ileal-pouch-anal anastomosis (IPAA).
Colectomy with IRA is a simple operative procedure with good functional results
regarding stool frequency and faecal continence. The major disadvantage of IRA is the
remaining risk of rectal cancer that requires adequate follow-up endoscopy once a year.
In up to 50% of patients with IRA, rectal cancer or severe rectal polyposis develops,
making metachronous proctectomy necessary.30 For this reason, an increasing number
of patients are treated by proctocolectomy. Endoscopic assessment of the pouch by
pouchoscopy is recommended once a year. The major draw-back of IPAA is the higher
rate of post-operative complications, with loss of the pouch and ileostoma in up to 5% of
cases. Some authors suggest that the risk of rectal cancer depends on the genotype (see
above). The timing of surgery depends on the individual course of the disease
(i.e. number of polyps, dysplasia, occurrence of desmoids or likelihood of desmoid

Colonic cancer and polyps 103

Table 9. Surveillance programmes for hereditary colorectal cancer syndromes.
Disorder

At age
(years)

Examination

Interval
(years)

HNPCC

25

Colonoscopy
Gynaecological examination, transvaginal ultrasound
Gastroduodenoscopy
Abdominal ultrasound
Cytology urine

1
1
1
1
1

FAP

1012

Rectosigmoidoscopy
Abdominal ultrasound
Ophthalmological examination (CHRPE)
Gastroduodenoscopy:
No adenomas
Adenomas

1
1
Once
3
1

Attenuated FAP 2025

Colonoscopy

12

PJS

Colonoscopy
12
Gastroduodenoscopy
12
Small bowel follow-up (push-enteroscopy, MR-Sellink, wireless 12
capsule endoscopy)
Gynaecological examination, transvaginal ultrasound
1
Breast examination, mammography, breast ultrasound
1
MRCP
2

30

12

18
25
JPC

10?
?
?

Colonoscopy
12?
Gastroduodenoscopy?
?
Small bowel follow-up (push-enteroscopy, MR-Sellink; wireless ?
capsule endoscopy)?

HNPCC, hereditary non-polyposis colorectal cancer; FAP, familial adenomatous polyposis; PJS, PeitzJeghers syndrome; JPC, juvenile polyposis coli; CHRPE, congenital hypertrophy of the retinal pigment
epithelium.
Recommendations for HNPCC, FAP and PJS have been adopted from the German Network Study of
Familial Colorectal Cancer (see www.hnpcc.de) and the German Society of Digestive and Metabolic
Diseases (see www.dgvs.de).

tumours expected by family history or DNA testing). Surgery is performed in almost all
patients before the age of 20 years.
The treatment of polyposis of the upper gastrointestinal tract is a complex problem
because the duodenum can not be resected due to its physiological function. Local
treatment of polyposis consists of endoscopic snaring, which is often limited by the
number of polyps and their sessile formation. Laser ablation or electrocoagulation may
lead to perforation or obstruction by the formation of scarring strictures. Surgical
intervention by duodenotomy and polyp removal is not recommended because of
recurrence in nearly all patients. A proximal pancreaticoduodenostomy carries
signicant morbidity and mortality, which has to be taken into account in the
management of patients with upper gastrointestinal polyposis.
Chemoprevention of duodenal polyposis is a desirable goal, but has not been well
investigated so far. Inhibitors of the cyclo-oxygenase enzymes (COX-1 and -2), such as
sulindac, or the selective COX-2 inhibitors, such as celecoxib, have been shown to
reduce the number and mass of colorectal adenomas.31,32 However, sulindac has failed
to show a signicant eect in the upper gastrointestinal tract and celecoxib has not
been investigated for chemoprevention of upper gastrointestinal adenomas yet.

104 K. Schulmann et al
Table 10. HNPCC-related neoplasms.
Lifetime risk (%)
Colorectal cancer
Endometrial cancer
Ovary cancer
Gastric cancer
Urinary tract cancer (ureter/renal pelvis)
Small bowel cancer
Biliary tract and gallbladder cancer
CNS (glioblastoma, astrocytoma)

80
4060
912
1319
410
14
218
34

HNPCC, hereditary non-polyposis colorectal cancer.

Hereditary non-polyposis colorectal cancer

Introduction
Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant
disease with a high risk for colorectal and endometrial cancer caused by germline
mutations in DNA mismatch-repair genes. HNPCC accounts for approximately 510%
of all colorectal cancers.13,33 The major problem in diagnosing HNPCC is the lack of a
characteristic phenotype. HNPCC must be considered in young patients with CRC,
patients with multiple primary cancers and when family clustering of CRC or
endometrial carcinomas is observed.
Clinical presentation
Mutation carriers from HNPCC families have a high lifetime risk for a variety of
malignancies (Table 10). Characteristics of HNPCC-associated CRC is young age at
diagnosis (mean 44 years), location in the proximal colon (70%) and multiple
colorectal primary tumours (synchronous in 15% and metachronous in 40%).
Microscopic features are not specic, but mucinous dierentiation and marked
occurrence of tumour-inltrating lymphocytes or Crohn's-like reaction in the tumour
margin may suggest HNPCC.14 Several studies have indicated a better prognosis for
patients with HNPCC-related CRC compared to sporadic tumours.34 By analogy to
sporadic and FAP-associated colorectal cancers, HNPCC-associated carcinomas also
develop from adenomas. HNPCC-associated adenomas tend to be more often villous
and to be more dysplastic than sporadic adenomas. Adenomas in HNPCC tend to
develop at an earlier age and accelerated progression to carcinomas is assumed.14 Extracolonic cancers in HNPCC include cancers of the endometrium, stomach, ovary, renal
pelvis/ureter, small bowel and the hepatobiliary tract.13 A combination of brain tumours
and CRC (Turcot's syndrome) or visceral and sebaceous skin tumours (MuirTorre
Syndrome) may also be part of the disease spectrum of HNPCC.3537
Diagnostic criteria
The lack of a pathognomic phenotype underlines the importance of taking an extensive
family history. In 1990 the International Collaborative Group on HNPCC (ICGHNPCC) dened the Amsterdam criteria for clinical diagnosis of HNPCC,38 which
have been extended to include extracolonic malignancies (Table 11).14 Because a

Colonic cancer and polyps 105

Table 11. Diagnosis criteria for HNPCC.
Amsterdam criteria I and II (all criteria should be positive)
1. At least 3 relatives with pathologically veried HNPCC-associated cancer (CRC, endometrium, ovary,
stomach, small bowel, ureter, renal pelvis, hepatobiliary tract)
2. One should be a rst degree relative of the other two
3. At least two successive generations should be aected
4. At least one CRC should be diagnosed before the age of 50
5. FAP should be excluded
Bethesda criteria (one should be positive)
(Dene patients whose tumours should be evaluated for microsatellite instability)
1. Positive Amsterdam criteria I/II
2. Synchronous/metachronous CRC or HNPCC-related malignancies (endometrium, ovary, stomach,
small bowel, ureter, renal pelvis, hepatobiliary tract)
3. CRC and a rst degree relative with CRC and/or HNPCC-related malignancy (before the age of 45)
and/or colorectal adenomas before the age of 40
4. CRC and/or endometrial cancer before the age of 45
5. Right-sided, undierentiated colon cancer before the age of 45
6. Signet cell carcinomas in the colorectum before the age of 45
7. Colorectal adenomas before the age of 40
HNPCC, hereditary non-polyposis colorectal cancer; CRC, colorectal cancer; FAP, familial adenomatous
polyposis.

signicant proportion of HNPCC-families do not meet the Amsterdam criteria, the

Bethesda guidelines have been proposed to dene patients whose tumours should be
tested for microsatellite instability (Table 11), which results from loss of the DNA
mismatch repair system.39

Genetics of HNPCC
The characteristic phenomenon of HNPCC-related malignancies is microsatellite
instability (MSI) caused by a defect in the mismatch-repair system. Patients fullling the
Amsterdam criteria show high-frequency MSI in 90% of cases.40 It is assumed that the
remaining 10% of patients with microsatellite stable tumours belong to families with
clustering of colorectal cancer in an autosomal dominant fashion and an as yet
unidentied underlying genetic defect.
So far ve genes of the mismatch repair (MMR) system display pathogenic mutations
in association with HNPCC (hMLH1, hMSH2, hMSH6, hPMS1 and hPMS2: see the-ICGDatabase at www.nfdht.nl). Germline mutations of hMLH1 and hMSH2 account for 70%
of all HNPCC cases.41 Approximately 510% of HNPCC families carry a germline
mutation in the MSH6 gene.4244 Mutations of the MMR-genes PMS1 and PMS2 are
rare.41,45,46 In 40% of clinically dened HNPCC, germline mutations in the known MMRgenes are not detectable despite detectable MSI, suggesting the existence of further
genes.
The screening for MMR mutations in tumours is simplied by the use of antibodies to
hMLH1, hMSH2 and hMSH6 (see Figure 4). A loss or reduction of immunostaining is
suggestive for an MMR defect.

106 K. Schulmann et al

Figure 4. Expression of MMR proteins in HNPCC. (A) MLH1-expression is lacking in the cancer tissue,
whereas expression in the surrounding normal tissue is retained. Within the tumour, stroma cells and
lymphocytes display positive staining. (B) Normal expression of MSH2 in both the cancer and normal tissue.

Recently, the existence of certain genotype/phenotype correlations according to the

aected gene have been proposed. Most families with mutations of the MSH6 gene are
associated with late-onset disease, an excess of endometrial carcinomas and low-grade
microsatellite instability. Even in these cases, Amsterdam and Bethesda criteria may fail
some of these families. The risk of extra-colonic malignancies seems to be higher in
patients with MSH2 mutations compared to MLH1 mutation carriers.34,47 The lifetime
risk of CRC seems to be signicantly lower for women compared to men (30% versus
70%).48
Screening guidelines
The ICG-HNPCC guidelines for the surveillance of persons at risk for HNPCC consist
of biennial colonoscopy beginning at age 2025 years and a gynaecological examination
with transvaginal ultrasound yearly to twice-yearly beginning at age 3035 years.
Gastroduodenoscopy should be performed if gastric cancer runs in the family; cytology
of urine and abdominal ultrasound should be performed in cases of a family history for
urinary tract cancers.14 Currently, the German Network Study for Familial Colorectal
Cancer (Verbundstudie Familiarer Darmkrebs) is evaluating a surveillance programme
that consists of yearly colonoscopy, abdominal ultrasound, gynaecological examination
with transvaginal ultrasound, cytology of urine and oesophagogastroduodenoscopy if
gastric cancer runs in the family starting at age 25 years (see Table 9).
Screening is recommended for patients with proven HNPCC or a high probability
for HNPCC (colorectal cancer/endometrium carcinoma with MSI) as well as rst
degree relatives of these patients. If the pathogenic mutation has been identied for a
family, screening is not recommended for persons at risk in whom the mutation has
been excluded.
Eectivity of screening. A Finnish study with 15 years follow-up indicated that regular
endoscopic screening at 3-year intervals leads to a more than 50% reduction in CRC
and a 65% reduction in CRC mortality.49 However, even with biennial colonoscopy a
signicant proportion of interval cancers have been detected.50 For this reason many
research groups now recommend an interval of 1 year for colonoscopy.14,27

Colonic cancer and polyps 107

Treatment
Because of the high rate of metachronous CRC, a number of experts recommend
subtotal colectomy with ileorectal anastomosis.13 However, no prospective trials have
shown an advantage for subtotal colectomy versus segmental colectomy and yearly
colonoscopy surveillance. Therefore, the latter screening approach is favoured by the
German Network Study for Familial Colorectal Cancer. Subtotal colectomy is,
without doubt, recommended for patients with synchronous CRCs, for non-compliant
patients regarding yearly colonoscopy and for patients with a technically dicult
colonoscopy procedure (i.e. severe diverticulosis, adhesions, severe sigma elongatum).
Prophylactic colectomy for mutation carriers is not recommended in general but
should be considered in mutation carriers with poor compliance to colonoscopy and
for those with adenomas with advanced pathology. Prophylactic hysterectomy or
oophrectomy is also an option but only for selected patients.
PeutzJeghers syndrome
Introduction
PeutzJeghers syndrome (PJS) is a rare autosomal dominant polyposis disorder that is
characterized by hamartomatous gastrointestinal polyps and mucocutaneous melanin
pigmentations. PJ-polyps occur throughout the whole alimentary tract, with a
predilection for the small bowel. The frequency decreases from jejunum, ileum, colon,
rectum, stomach, duodenum to appendix. The oesophagus is spared. Extra-intestinal
polyps are rare, but may occur in in the ureter, the nose or the gallbladder. Pigment
lesions are detectable in most patients with PJS (95%). Predilection sites are the lips,
the perioral region and the intraoral mucosa (Figure 5).
Clinical presentation
Symptoms occur in adolescence or young adulthood as recurrent colicky abdominal
pain due to intussusception of small bowel segments. Severe complications are acute
intestinal obstruction and paralytic ileus of a small bowel segment. Many patients
present with occult gastrointestinal bleeding and iron-deciency anaemia.
Criteria for diagnosis
The diagnosis of PJS is made if one of the following criteria is fullled:51
. Two or more PJ polyps.
. One or more PJ polyps and mucocutaneous melanin pigment lesions.
. One or more PJ polyps and positive family history of PJS.

Family history is negative in up to 45% of index cases, indicating a high incidence of

spontaneous germline mutations.
Molecular genetics
Recently, germline mutations of the STK11 gene on chromosome 19p have been
identied as the cause of the disease. The STK11 gene was identied in 1998 by two
independent investigators.52,53 A germline mutation of the STK11 gene confers
susceptibility, whereas an alteration of the second allele leads to the development of

108 K. Schulmann et al

Figure 5. Typical features of PeutzJeghers syndrome. (A) Typical melanin pigmentations of the lips and
perioral region. (B) PeutzJeghers polyp.

hamartomatous polyps, suggesting that STK11 is a tumour suppressor gene. The

somatic loss of the second allele is usually caused by a deletion (loss of heterozygosity)
at chromosome 19p.54
Cancer risk
Patients with PJS have a signicantly increased relative risk (RR) for developing certain
malignancies and 90% of PJS patients develop a malignant disease by the age of 65.55,56
The RRs for carcinomas of the stomach, small bowel, colorectum and pancreas have
been estimated as being 213, 520, 84 and 132, respectively. In addition, the risk for
carcinomas of the breast, ovary and endometrium (RR 15, RR 27, RR 16,
respectively) is also increased.56,57 Breast cancer often occurs bilaterally and
premenopausally. The risk of cervical carcinomas is not increased, but female patients
with PJS are at increased risk for the development of an adenoma malignum, which
may show rapid disease progression and early dissemination. Almost all female patients
with PJS develop an otherwise rare potentially malignant ovarian tumour, the sex cord
tumour with anular tubules (SCTAT).58 Malignant transformation is observed in 20% of
all cases. Cancer of the thyroid gland, gallbladder and lung also seem to be associated
with PJS.
Sertoli cell tumours are considered to be the equivalent of SCTAT in male patients
with PJS. The risk of malignancy is estimated to be 1020%.59

Colonic cancer and polyps 109

Surveillance
Due to the high risk for developing intestinal complications and malignant disease
regular screening is recommended (see Table 9). Screening should be initiated by the
age of 12 years with regular gastroduodenoscopy and colonoscopy. Screening for small
bowel polyps is dicult. Having regular X-rays results in accumulating exposure to
ionizing radiation and the low sensitivity for detecting small lesions may lack benet.
Standard procedure for surveillance of the small bowel is regular performance of pushenteroscopy (e.g. every 2 years).60,61 The role of wireless capsule endoscopy for the
screening of small polyps in PJS needs to be determined. Symptomatic patients are
suitable for explorative laparatomy and intra-operative endoscopy. The goal of screening
for polyps is the endoscopic or operative removal of all polyps 410 mm in diameter.
Regular endovaginal ultrasound examination should be initiated at the age of 18. Regular
screening for breast and pancreatic cancer should be started by the age of 25. Regular
clinical examinations of the testes are recommended for young male patients with PJS.
Some investigators propose thyroid ultrasound as a regular screening procedure.12

Juvenile polyposis coli

Introduction
Juvenile polyposis coli (JPC) is a rare autosomal dominant polyposis disorder
characterized by multiple hamartomatous polyps of the colorectum. The predilection
site is the colorectum (98%). The stomach (13%) and small bowel (6%) may also be
aected. In a small number of families predominant polyposis of the stomach has been
observed.62 Family history is positive in only 2050% of patients with JPC suggesting a
high incidence of spontaneous mutations or low penetrance. In addition, a missed
diagnosis of JPC in ancestors of patients may explain these low numbers.31

Clinical presentation
Children and adolescents often present with iron-deency anaemia due to occult
gastrointestinal bleeding or hypoproteinaemia and delay of development. Some
patients present with rectal prolapse of polyps.

Molecular genetics
Germline mutations of the SMAD4-gene can be detected in up to 30% of families with
JPC.63 Mutations of PTEN (phosphate and tensin homologue deleted on chromosome
10) have also been reported for a few patients,64 but re-evaluation of the data
suggested that at least some of the patients suered from Cowden's disease rather than
JPC.65 Most recently, Howe et al66 reported germline mutations of the bone
morphogenetic protein receptor 1A (BMPR1A), a serinethreonine kinase type I
receptor, in four families with JPC in whom germline mutations of SMAD4 and PTEN
had been excluded by direct sequencing. By analogy to FAP and PJS, germline
mutations seen in JPC contribute to susceptibility, whereas functional loss of the
second corresponding allele leads to development of the JPC phenotpype.67

110 K. Schulmann et al

Practice points
1. Polyps
. adenomatous polyps are found sporadically in approximately 33% of the general
population by the age of 50 and in approximately 50% by the age of 70
. after complete polypectomy, follow-up endoscopy is warranted after 3 years
irrespective of size or grade of dysplasia of the removed polyps
. up to 40% of patients have developed new colorectal adenomas 3 years after
polypectomy
2. Sporadic CRC
. faecal occult blood testing (FOBT) reduces CRC mortality by 1533%. Although it
is not very sensitive for premalignant lesions (adenomas), FOBT also signicantly
reduces the incidence of CRC
. colonoscopy is the screening method of choice for patients with a higher than
average risk of CRC
. observational studies suggest that non-steroidal anti-inammatory drugs,
supplemental folate and calcium, and post-menopausal oestrogen replacement
have a chemopreventative benet. However, conrmation by double-blind,
placebo-controlled, randomized studies is required before these prophylactic
strategies can be accepted as standard medical practice.
3. Hereditary syndromes
. up to 10% of colorectal cancers are due to hereditary colorectal cancer syndromes
. cyclo-oxygenase (COX) inhibitors (sulindac and the selective COX-2 inhibitor
celecoxib) have been shown to reduce polyp mass (number and size) in patients
with familial adenomatous polyposis (FAP). However, it is currently unknown
whether these eects are associated with a decreased carcinoma risk or whether
COX inhibitors can delay or even replace total colectomy in FAP patients
. hereditary non-polyposis colorectal cancer (HNPCC), the most frequent
hereditary colorectal cancer syndrome, lacks a pathognomic phenotype and
underlines the fact that an extensive family history is of great importance for
identifying patients with HNPCC
. index patients and rst degree relatives of index patients carry a signicantly
increased risk for a variety of malignancies that dier in each syndrome. Tumours
often develop at young age
. regular screening examinations are recommended for index patients and rst
degree relatives
. the genetic background of hereditary colorectal cancer is known. However, a
causative germline mutation can not be identied in every aected family.
Nevertheless, genetic testing is of major importance in almost all cases, since it
allows the prediction of cancer risk for family members
. results of genetic tests may be of great importance and impact for entire families.
Therefore, predictive genetic testing should not be performed without genetic
counselling

Cancer risk
The risk of gastrointestinal malignancies is signicantly increased (RR 16) with an
estimated lifetime risk of 2060% for the development of CRC. The median age at

Colonic cancer and polyps 111

Research agenda
1. Polyps
. the biology of polyps needs further work with regard to both classical and novel
pathways to adenoma and CRC
. randomized, placebo-controlled trials of chemoprevention of polyps or
recurrence of polyps in average and high-risk groups are needed
2. Sporadic CRC
. further research on prognostic markers for chemotherapy is needed (for
example, what is the benet of adjuvant chemotherapy for patients with stage II
cancer and LOH at chromosome 18q?)
3. Hereditary syndromes
. one of the major future aspects in the management of FAP patients is the optimal
therapy of patients with polyposis of the upper gastrointestinal tract (e.g.
chemoprevention trials)
. in approximately 30% of patients with HNPCC a pathogenic mutation in the
known MMR genes is not detectable. Further genes that are thought to be
responsible need to be identied
. due to the high risk of cancer in HNPCC, chemoprevention is a desirable goal for
the management of such patients
. regarding the management of HNPCC-associated CRC the optimal surgical
treatment has not yet been evaluated in a randomized prospective trial
. screening programmes for hereditary colorectal cancer syndromes such as
HNPCC need further evaluation with regard to safety and cost-eectiveness
. due to the dierent molecular biology of HNPCC-associated CRC, prospective
trials of adjuvant and palliative chemotherapy are necessary to evaluate response
and prognosis in this group of patients. In vitro data suggest a chemoresistance
against 5-FU in cancer cells displaying microsatellite instability. Dierent
chemotherapy schedules may be needed for HNPCC-associated CRC
diagnosis is approximately 3540 years.31,68,69 The risk for gastric cancer is also
signicantly increased. Duodenal and pancreatic cancer may be associated with
JPC.31,70,71
Surveillance
Due to an increased risk of cancer and complications of polyposis (anaemia,
malnutrition) regular screening is necessary. Because of the low incidence of the
disease there are no general recommendations. In proven JPC yearly colonoscopy
beginning in early childhood is necessary to detect and remove polyps (see Table 9).
Genetic screening may exclude family members from regular screening examinations
when a germline mutation can be excluded in a mutation-positive family.
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