Colorectal Adenocarcinoma


Colon cancer is a very common tumour in Australia, with an incidence of 46 per 100,000 in men and 32 per 100,000 in women per year. It is very much a disease of modern Western society and is rare in the developing world. It is most common in those over the age of 50 but cases due to germline genetic mutations occur at a younger age.
The patterns of colorectal cancer have changed (at least in America) in the last 50 years. Incidence as a whole is slowly declining, particularly for distal tumours of the sigmoid and rectum. Conversely, the incidence of proximal large bowel tumours is rising.

Aetiology and Pathogenesis

The most significant factor in Western countries appears to be diet, particularly high-kilojoule foods and animal fats. Minimally active lifestyle is also associated. The exact mechanism through which these factors lead to bowel cancer remains elusive; increased bile secretion (containing potential carcinogens) or breakdown of animal fats into carcinogens has been suggested.
Other factors include:

  • Germline genetic mutations in the APC gene (familial adenomatous polyposis) or mis-match repair genes (Lynch syndrome)
  • Inflammatory bowel disease (ulcerative colitis (4-20x risk) and Crohn's disease (3x risk))
  • Exposure ot ionising radiation

Familial Colorectal Cancers

Familial Adenomatous Polyposis

Familial adenomatous polyposis is a classic form Knudson's "two hit hypothesis". APC is a tumour suppressor gene that inhibits the Wnt signalling pathway by binding to beta-catenin. When unbound, beta-catenin passes into the nucleus where it upregulates the transcription of numerous molecules that promote progression through the cell cycle, avoidance of apoptosis (etc).
For diagnosis, patients must have > 100 polyps or tumours within the large bowel. Known mutation of APC is also diagnostic. Patients develop detectable polyps in the second decade of life. The mean age of cancer diagnosis is 40 but a significant number will develop malignancies by the age of 30.
Patients also develop polyposis of the small bowel, particularly in the duodenum (combination of bile + APC mutation). They have a 4% lifetime risk of periampullary tumours. They are also at higher risk of hepatoblastoma and bile duct tumours. Outside the gastrointestinal system, patients with germline mutation of APC have increased rates of endocrine tumours.
Treatment involves colectomy once polyposis develops. Patients should be screened yearly from the age of 10-15 to detect polyposis. Sigmoidoscopy is usually sufficient to detect the onsent of polyposis as the polyps occur throughout the large bowel.

Lynch Syndrome (Previously Hereditary Non-Polyposis Colon Cancer)

Lynch syndrome is caused by mutation in one of five known (and likely additional) mismatch repair genes. Dysfunction of these genes leads to potential mutations when DNA is replicated, as mismatch (ie. incorrect sequencing of the DNA during replication) may not be detected and repaired appropriately. As well as leading to potential malignancies, mismatch repair causes microsatellite instability. Microsatellites are repeated dinucleotide repeats, the most common of which is cytosine and adenosine (CA). The length of microsatellites varies between people but is always the same in an individual person. Errors in microsatellite length are thought to lead to frameshift mutation in tumour suppressor genes, causing the development of malignancy.
Individuals with Lynch syndrome have an 80% risk of developing colon cancer and an elevated risk of developing several other malignancies, including endometrial (50%), renal pelvis, ovarian, brain, stomach and small bowel (all < 15%).
Importantly, sporadic colorectal cancer can also possess evidence of microsatellite instability but this is not necessarily due to Lynch syndrome (ie. loss of mismatch repair function can occur as a non-germline mutation).
Managmenet of patients with known mutations involves annual colonoscopy from the age of 20. Prophylactic colectomy is usually not done until malignancy has developed. Female patients hould have regular screening for ovarian and endometrial cancers and there is some merit to prophylactice salpingo-oophrectomy after any desired children have been produced. Screening for upper gastrointestinal and urothelial cancers is not standardised but is recommended (eg. yearly urine cytology, 5-year gastroscopy).

Natural History

The development of colon cancer from normal epithelium through to various forms of adenoma and finally malignancy was the initial description of the multi-step nature of carcinogenesis. For each of the stages, various additional mutations have been described. For a description of precursor lesions see here.

Once developed, colorectal adenocarcinoma may:

  • Invade locally through the wall of the bowel
  • Spread to regional lymph nodes. This can occur early in the course of disease but only if the muscularis mucosae is breached (in contrast to most other gastrointestinal malignancies which can metastasise after the lamina propria is breached).
  • Undergo haematogenous spread, most commonly to the liver but potentially to the lungs.

Transcoloemic spread through the peritoneal cavity is also possible but not a defining feature except for T4a tumours.

Clinical Presentation

Symptoms and signs can vary. Early tumours are typically asymptomatic but may be picked up during routine blood with the general practitioner as an iron deficiency anaemia due to chronic blood loss. Larger tumours may cause bowel obstruction, abdominal pain, bloating, rectal bleeding or haematochezia.


On barium enema, the classical appearance is of 'apple coring' where the lumen is narrowed by the tumour.
CT may demonstrate the tumour as well as regional or distant disease.
MRI has an important role in rectal tumour. It is able to detect extramural extension (T3 disease) which is the cut-off between surgery alone and neoadjuvant chemoradiotherapy. It has similar accuracy with regards to tumour invasion as endorectal ultrasound but improved sensitivity at detecting nodes; endorectal ultrasound is performed less frequently in the modern era.

Tumour/Normal Tissue Features


There are four typical growth patterns:

  • Exophytic, which bulge into the lumen
  • Endophytic, which invade into the wall of the bowel but have minimal narrowing of the lumen
  • Diffuse
  • Annular, which grow around the circumference of the bowel wall and narrow the lumen

Mucinous tumours may have visible mucous macroscopically. Other tumours usually homogenous, and haemorrhage is rare.


Most commonly, tumours are well or moderately differentiated with extensive gland formation. The cells lining the glands are tall and the lumen is filled with debris. There are several variants to the typical adenocarcinoma:

  • Mucinous tumours contain large pools of mucin, and are associated with microsatellite instability/mismatch repair problems
  • Signet ring tumour cells have the typical signet ring appearance with a displaced nucelus and clear cytoplasm
  • Other rare types include adenosquamous carcinoma, medullary carcinoma, undifferentiated carcinoma and spindle cell carcinoma



The genetics have discussed above in the natural history and aetiology sections.

Staging / Classification

Colorectal cancers are staged using TNM; in the past the Dukes and Modified Astler-Coller systems were used.

T Stage

T1: Confined to submucosa
T2: Invasion of muscularis propria
T3: Invasion through muscularis propria
T4a: Invasion through serosal surface
T4b: Invasion into adjacent organ or tissue (eg. psoas muscle, kidney)

N Stage

N1a: 1 lymph node involved
N1b: 2-3 lymph nodes involved
N2a: 4-6 lymph nodes involved
N2b: > 6 lymph nodes involved

M Stage

M1a: Metastasis to single distant organ or site
M1b: Metastasis to multiple distant organs

Final Stage

TNM Stage T N M Dukes MAC
I T1-2 N0 M0 A A - B1
IIA T3 N0 M0 B B2
IIB T4a N0 M0 B B2
IIC T4b N0 M0 B B3
M0 C C1
IIIB T3-4a
M0 C C2
M0 C C2
IVA Tany Nany M1a X X
IVB Tany Nany M1b X X