What’s new?

C Screening programmes are increasing the numbers of ‘polyp

cancers’

C

COLORECTAL CANCER

Colorectal cancer: featuresand investigationNigel Hall

Genetic analysis of individual tumours is feasible and will

impact on future therapy

AbstractColorectal cancer is a common malignancy affecting 35,000 people a year

in the UK. Most cancers are sporadic but a few, occurring at young age,

have a clear genetic basis. The majority are in the rectum or rectosigmoid

and give rise to symptoms of rectal bleeding, often with a looser or more

frequent stool. Right-sided cancers typically give rise to anaemia, because

the blood in the stool is occult and unnoticed by the patient. Almost all the

symptoms of malignancy can also be caused by benign disease. Diagnosis

relies on luminal imaging, with colonoscopy being the gold standard. Pre-

operative staging should include imaging of the liver and chest with

computed tomography. For rectal cancers, magnetic resonance scanning

of the pelvis provides accurate information about the local tumour and

nodal status, and is used to inform decisions regarding pre-operative che-

moradiotherapy. All colorectal cancers should be discussed at multidisci-

plinary meetings to enable optimum treatment to be determined.

Keywords colonoscopy; colorectal neoplasms; colorectal surgery;

neoplasm staging; virtual colonoscopy

Colorectal cancer, often known simply as bowel cancer, is

a common solid organ malignancy affecting 35,000 patients

a year in the UK,1 about half of whom will die from it. At all ages

it is more common in males (especially rectal cancer) but

because of the greater longevity of women the overall sex

distribution is equal. It is generally a disease of advancing years,

with a peak age at diagnosis of 70 years; the lifetime risk by the

age of 80 years is about 5e10%.

Epidemiology

Colorectal cancer is common in ‘Westernized’ populations,

probably due largely to dietary factors. Europe, the USA and

Japan have high rates compared to Africa and Asia. Bowel

cancers are thought to arise through a combination of hereditary

predisposition, exposure to environmental agents (e.g. diet),

lifestyle, and chance. Dominantly inherited strongly penetrant

syndromes, such as familial adenomatous polyposis (FAP) and

hereditary non-polyposis colorectal cancer (Lynch syndrome),

are responsible for a small percentage of colorectal cancers, often

developing before the age of 40 years.2 A much greater propor-

tion may be the result of weakly penetrant but more common

susceptibility genes, which are yet to be identified.3 Other known

risk factors include diets high in red meat and low in fibre, lack of

exercise, obesity, alcohol and (probably) smoking, personal

history of adenomatous polyps or previous colorectal cancer, and

Nigel Hall BA DM FRCS is Consultant Colorectal Surgeon at Adden-

brooke’s Hospital, Cambridge, UK. Competing interests: none declared.

MEDICINE 39:5 250

long-standing colonic inflammatory bowel disease.4,5 Aspirin

and non-steroidal anti-inflammatory drugs are thought to be

protective against polyps and cancer but their use as chemo-

preventative agents is not currently recommended.6

Pathology and pathogenesis

Adenomaecarcinoma sequence

Analysis of the histological and molecular changes of colorectal

polyps and malignancies has led to the adenomaecarcinoma

hypothesis that now underpins our understanding of carcinogenesis

in many other malignancies.7 There are two common molecular

pathways e the ‘classical’ or chromosomal instability pathway and

the microsatellite instability pathway. The majority of sporadic

cancers follow the classical pathway in which large segments or

whole chromosomesmaybe lost orduplicated; but about 15%follow

the other pathway in which small changes in DNA, often at repeated

nucleotide sequences (microsatellites), result in cancer-causing

genetic mutations. These pathways have their counterparts in

hereditary syndromes e FAP cancer follows the classical pathway

whereas Lynch syndrome follows the microsatellite instability

pathway.8,9 Detailed genetic analysis of individual tumours is

becoming a reality with ever-decreasing costs and improved tech-

nology. This will help to predict behaviour and response to therapy.

The large majority of colorectal cancers are adenocarcinomas

arising from the mucosa. Rare tumours include carcinoids,

lymphoma and melanoma.

Distribution

About two-thirds of sporadic cancers arise distal to the splenic

flexure, with about 40% arising in the rectum. In patients with

Lynch syndrome, this proportion is reversed with caecal cancer

being the most common site.10

Spread

Like many cancers, colorectal carcinoma spreads locally, via

lymphatics and through the bloodstream. The liver is the most

common metastatic site, via the portal venous system, followed

next by pulmonary seedlings. Rarer sites include the skin, brain

and bone. Trans-coelomic spread leads to the development of

multiple peritoneal nodules, though ascites is usually minimal.

Pathological staging

Histological staging of colorectal cancers is performed post-

operatively. Dukes’ and TNM staging (Figure 1) are widely used

to inform decisions about adjuvant therapy.

Dukes’ staging: node-negative tumours are staged A if they have

not penetrated the muscularis propria, B if they have. If there is

lymph node spread, the tumour is automatically a Dukes’ C.11 A

C2 tumour is one in which there is lymphatic invasion at the

� 2011 Elsevier Ltd. All rights reserved.

Histological staging of colorectal cancers

Muscularis

mucosa

Muscularis

propria

Peritoneum

This illustrates the two common staging methods – Dukes’ (stage A to D) and TNM (T1-4, N0-2, M0-1). T1 and T2 are Dukes’ A cancers and do not invade past the muscularis propria. T3 and T4 are Dukes’ B tumours: they penetrate the muscularis and T4 disease extends either beyond the peritoneum or into adjacent organs. N status depends on the number of involved lymph nodes as shown.

N1: 1-3 nodes

N2 4+ nodes

C2

C1

A B

T1T2

T3 T4

Distant

disease

‘D’

M1

Figure 1

Criteria for referral to fast-track colorectal clinic

C A change in bowel habit (looser and/or more frequent stools)

persisting >6 weeks without rectal bleeding in a person aged

60 years or older

C Rectal bleeding persisting >6 weeks without a change in bowel

habit and without anal symptoms, in a person aged 60 years or

older

C Rectal bleeding with a change of bowel habit towards looser

stools and/or increased stool frequency persisting for 6 weeks

or more, in a person aged 40 years or older

C A palpable right lower abdominal mass or a palpable rectal

mass (intraluminal and not pelvic)

C Iron-deficiency anaemia with a haemoglobin of 11 g/dL or less in

a man, or of 10 g/dL or less in a non-menstruating woman

Table 1

COLORECTAL CANCER

node furthest away from the tumour e at the ‘high tie’. Although

not described by Dukes, it is now conventional to label any

metastatic spread as stage D.

TNM staging is more precise than Dukes’ staging but clinically

less useful because there are so many subgroups.

Malignantpolyps:with theadventof screeningprogrammes, earlier

detection of cancers has led to an increased detection of ‘polyp

cancers’, which are T1 lesions. Many of these are cured by poly-

pectomy alone. Use of other staging methods that take into account

the depth of penetration, such as the Haggitt12 and Kikuchi13 clas-

sifications, is helpful in judging the risk of lymph node metastasis

and thus in deciding whether a formal resection is indicated.

Circumferential margin: for surgery to be potentially curative,

especially for rectal cancers, it is important to remove a margin of

normal tissue around a cancer. Measurement of whether the

circumferential resectionmargin (CRM) is involvedwith cancer can

be a very useful predictor of local and even distant recurrence.14,15

Diagnosis

Symptoms

Gastrointestinal symptoms are common, even in the absence of

pathology, and there is a wide overlap of symptomatology for

malignant and benign causes. Based on a large clinical database

in Portsmouth, referral criteria have been developed that identify

patients with colorectal cancer most reliably (Table 1),16 but only

about 10e14% of patients meeting such criteria harbour

a malignancy.

Obstructive symptoms: as tumours enlarge they tend to narrow

the bowel lumen. This commonly leads to a looser more frequent

stool rather than constipation, though any persistent change in

bowel habit should be investigated. Distal tumours are more

MEDICINE 39:5 251

likely than proximal tumours to lead to an alteration in bowel

habit, as the stool consistency is more solid. Proximal tumours

may produce no symptoms at all until they obstruct completely.

In the rectum, the mass effect of a cancer leads to tenesmus

(a feeling of incomplete evacuation).

Bleeding: rectal bleeding, especially if associated with a change

in bowel habit, is a worrying symptom. Low rectal tumours can

bleed bright blood just like haemorrhoids; bleeding from left-

sided tumours may be darker red and mixed in with the stool.

Although right-sided tumours bleed, this is not visible in the

stools and so these cancers classically present with iron-defi-

ciency anaemia because there is no warning sign to the patient.

Symptoms not usually associated with colorectal malignancy:

bowel cancers are biologically inert and do not display para-

neoplastic features. Weight loss and anorexia are very

uncommon unless there is widespread metastatic disease. Pain is

also unusual unless a tumour is so advanced that it is nearly

obstructing the bowel lumen or invading bone or nerves.

Acute presentation: about 20% of patients with colorectal

cancer present as emergencies e usually with obstruction but

occasionally with perforation or abscess formation. Most of these

will require emergency surgery.

Signs

Patients with symptoms suggestive of colorectal pathology

should undergo abdominal examination, rectal examination and

a rigid sigmoidoscopy in the clinic.

Palpable mass: many colorectal cancers are palpable e typically,

a right colon cancer gives rise to a firmmass in the right iliac fossa.

Rectal cancers can often be felt on digital examination, and a rolled

edge or circumferential nature can easily be appreciated. If

a tumour is found, the surgeon will be greatly helped by infor-

mation about the height of tumour from the anal verge, whether it

is mobile, tethered or fixed, and which quadrants are involved.

Sigmoidoscopic findings: a rigid sigmoidoscope will be able to

examine most of the rectum and sometimes the distal sigmoid, so

� 2011 Elsevier Ltd. All rights reserved.

Figure 2 a, b This polyp in the descending colon was removed by endoscopic mucosal excision (EMR) after raising it off the muscularis propria by injecting

gelofusine and methylene blue in the submucosal plane. c The site of the polyp was marked with a black tattoo ink either side of the polyp. Histological

analysis revealed it to be a malignant polyp and the patient subsequently underwent a laparoscopic colectomy; the tattoo was essential for the surgeon

to know exactly which part of the colon to remove.

COLORECTAL CANCER

it can easily identify rectal tumours in the clinic. Equally

important, it may reveal bleeding and inflamed mucosa from

inflammatory bowel disease as an alternative explanation of the

patient’s symptoms. The presence of streaks of blood in

the lumen of the rectum is strongly indicative of pathology in the

sigmoid above the reach of the rigid scope e usually a large

polyp or cancer.

Differential diagnosis

There is a wide differential diagnosis: alteration in bowel habit

may be caused by irritable bowel syndrome, diverticular disease,

infections, thyroid dysfunction, coeliac disease or inflammatory

bowel disease (IBD); rectal bleeding may be caused by haemor-

rhoids, anal fissure, IBD or polyps; iron-deficiency anaemia may

be caused by gastric or small bowel pathology, poor diet, coeliac

disease or bleeding from other organ systems (e.g. renal or

genital tract).

Investigations

Diagnosis

Bladder

Mesorectal

Biochemical tests: no blood test will confirm or refute the

diagnosis of colorectal cancer. A full blood count is useful to

detect anaemia. Although carcino-embryonic antigen (CEA) is

commonly assayed, its value is more in follow-up than diagnosis.

Faecal occult blood testing is a screening tool and is not indicated

in persons with colorectal symptoms e such individuals need full

colonic evaluation as described below.

Lumen of rectum

Lymphnode

Sacrum

fascia

Rectal tumour encroaching mesorectal fascia

Figure 3 MRI scan of a locally advanced rectal cancer. This transverse

section clearly demonstrates the mesorectal fascial envelope, which is the

boundary of surgical excision. The tumour is extending through the full

thickness of the bowel wall and is very close to the edge of the meso-

rectum. One of many enlarged lymph nodes is shown on this image. This

patient had pre-operative chemoradiotherapy to downstage the tumour

and then underwent a potentially curative resection of his rectal

carcinoma.

Colonoscopy: it is the gold-standard investigation for colorectal

cancer and polyps. Completion rates should be over 90% in good

centres with a perforation rate less than 0.1%. Colonoscopy will

identify cancers and enable biopsy, and has therapeutic potential

for removing polyps distant from the cancer to prevent meta-

chronous malignancy developing during follow-up. A tattoo can

be placed to allow the site of a tumour to be recognized at

subsequent laparoscopic resection (Figure 2). Even if a rectal

cancer is diagnosed in the clinic, luminal imaging is still required

to rule out synchronous disease. Barium enema is rapidly and

rightly becoming obsolete because it is inaccurate and consis-

tently both over-diagnoses and misses cancers.17

MEDICINE 39:5 252

CT scans: particularly for elderly patients, a CT of the abdomen

and pelvis is a useful diagnostic tool and is non-invasive.18

Occasionally spasm on the right side of the abdomen can

mimic the appearances of cancer on CT: if there is no clinically

palpable mass in this situation, a colonoscopy is required to

visualize the right colon and corroborate the CT findings.

CT colography: with multislice volume acquisition CT, excellent

views can be obtained by insufflating air into a prepared colon.

CT colonography is almost as accurate as colonoscopy and can

visualize bowel proximal to an obstructing tumour.19

Biopsy: all rectal cancers require biopsy proof of malignancy

before treatment is decided. For colonic disease this is less

important as the endoscopic appearances usually indicate the

need for surgery.

Pre-operative clinical staging

Once a colorectal cancer has been diagnosed, clinical staging

investigations should be performed to detect synchronous

polyps and cancer, local spread and metastatic disease. CT of the

chest, abdomen and pelvis is used for all patients to detect

� 2011 Elsevier Ltd. All rights reserved.

COLORECTAL CANCER

distant spread. Rectal cancers should be discussed at a multi-

disciplinary meeting before surgery; all tumours are discussed

postoperatively.

Practice points

C Colorectal cancer is common; the majority are distal and may

be within the reach of the examining finger or rigid

sigmoidoscope

C Typical symptoms include rectal bleeding and a looser or more

frequent bowel habit

C Right-sided cancers are a common cause of iron-deficiency

anaemia

C Staging of most bowel cancers is best provided by CT scans of

chest, abdomen and pelvis along with a colonoscopy. Barium

enema is becoming obsolete

C Pelvic MRI is useful for staging rectal cancers and is used to

direct pre-operative therapy

Rectal cancer: the extent of local spread determines pre-opera-

tive therapy and so pelvic imaging is very important. Transrectal

ultrasound can accurately stage bowel wall invasion but is less

good at detecting lymph node involvement.20 MRI is probably the

most useful method for determining tumour invasion and nodal

status (Figure 3). More importantly, it is the best way of

assessing whether the tumour is close to the edge of the meso-

rectal envelope: this has implications for the surgeon and informs

decisions regarding pre-operative chemoradiotherapy (see Colo-

rectal Cancer: management on pp 254e258 of this issue).21 A

REFERENCES

1 Toms JR, ed. CancerStats monograph 2004. London: Cancer Research

UK, 2004.

2 Fearnhead NS, Wilding JL, Bodmer WF. Genetics of colorectal cancer:

hereditary aspects and overview of colorectal tumorigenesis. Br Med

Bull 2002; 64: 27e43.

3 Bodmer WF. Cancer genetics: colorectal cancer as a model. J Hum

Genet 2006; 51: 391e6.

4 Bingham SA, Day NE, Luben R, et al. Dietary fibre in food and

protection against colorectal cancer in the European Prospective

Investigation into Cancer and Nutrition (EPIC): an observational

study. Lancet 2003; 361: 1496e501.

5 Boyle P, Langman JS. ABC of colorectal cancer: epidemiology.

Br Med J 2000; 321: 805e8.

6 Elwood PC, Gallagher AM, Duthie GG, Mur LA, Morgan G. Aspirin,

salicylates, and cancer. Lancet 2009; 373: 1301e9.

7 Fearon ER, Vogelstein B. A genetic model for colorectal tumorigen-

esis. Cell 1990; 61: 759e67.

8 Hall NR, Madoff RD. Genetics and the polyp-cancer sequence. In:

Edelstein PS, ed. Colon and rectal cancer. Wilmington, DE: Wiley-Liss,

2000.

9 Hardy RG, Meltzer SJ, Jankowski JA. ABC of colorectal cancer:

molecular basis for risk factors. Br Med J 2000; 321: 886e9.

10 Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR.

Review of the Lynch syndrome: history, molecular genetics,

screening, differential diagnosis, and medicolegal ramifications. Clin

Genet 2009; 76: 1e18.

11 Dukes CE. The classification of cancer of the rectum. J Pathol Bac-

teriol 1932; 35: 323e32.

12 Haggitt RC, Glotzbach RE, Soffer EE, Wruble LD. Prognostic factors in

colorectal carcinomas arising in adenomas: implications for lesions

removed by endoscopic polypectomy. Gastroenterology 1985; 89:

328e36.

13 Kikuchi R, Takano M, Takagi K, et al. Management of early invasive

colorectal cancer. Risk of recurrence and clinical guidelines. Dis Colon

Rectum 1995; 38: 1286e95.

MEDICINE 39:5 253

14 Adam IJ, Mohamdee MO, Martin IG, et al. Role of circumferential

margin involvement in the local recurrence of rectal cancer. Lancet

1994; 344: 707e11.

15 West NP, Hohenberger W, Weber K, Perrakis A, Finan PJ, Quirke P.

Complete mesocolic excision with central vascular ligation produces

an oncologically superior specimen compared with standard surgery

for carcinoma of the colon. J Clin Oncol 2010; 28: 272e8.

16 Thompson MR. Referral guidelines for colorectal cancer. Colorectal

Dis 2002; 4: 287e97.

17 Winawer SJ, Stewart ET, Zauber AG, et al. A comparison of colono-

scopy and double-contrast barium enema for surveillance after pol-

ypectomy. National Polyp Study Work Group. N Eng J Med 2000; 342:

1766e72.

18 Fink M, Freeman AH, Dixon AK, et al. Computed tomography of the

colon in elderly people. Br Med J 1994; 308: 1018.

19 Halligan S, Altman DG, Taylor SA, et al. CT colonography in the

detection of colorectal polyps and cancer: systematic review, meta-

analysis, and proposed minimum data set for study level reporting.

Radiology 2005; 237: 893e904.

20 Brown G, Davies S, Williams GT, et al. Effectiveness of preoperative

staging in rectal cancer: digital rectal examination, endoluminal

ultrasound or magnetic resonance imaging? Br J Cancer 2004; 91:

23e9.

21 Brown G, Radcliffe AG, Newcombe RG, Dallimore NS, Bourne MW,

Williams GT. Preoperative assessment of prognostic factors in rectal

cancer using high resolution magnetic resonance imaging. Br J Surg

2003; 90: 355e64.

FURTHER READING

Cunningham D, Atkin W, Lenz HJ, et al. Colorectal cancer. Lancet 2010;

375: 1030e47.

National Institute for Health and Clinical Excellence. Guidance on cancer

services: improving outcomes in colorectal cancers e manual update.

London: NICE, 2004.

� 2011 Elsevier Ltd. All rights reserved.