Bowel cancer: Pathology and the screening process Flashcards
Describe the epidemiology of bowel cancer
Bowel cancer is the third most common cancer in women after breast and lung cancer
Bowel cancer is the third most common cancer in men after prostate and lung cancer
High incidence of bowel cancer in western world; low incidence in Asia and Central Africa
Bowel cancer affects men and women equally
What are the risk factors of bowel cancer?
- Bowel cancer is believed to be an environmental disease and potentially preventable, thus:
Migration from a low risk population to a high risk population increases the risk in the migrant e.g. Japanese who migrated to the USA acquired the risk of their host country
Foods rich in red meat and fat increase the risk of bowel cancer
Food rich in vegetables, fruit & fibre reduces the risk of bowel cancer by ↑ faecal bulk & reduces transit time
Physical activity and low BMI are associated with low risk of cancer
Longstanding ulcerative colitis
Crohn’s disease – to a lesser extend than UC
Presence of adenoma in the large bowel
Previous history of bowel cancer surgery
Family history of bowel cancer
Old age
How does high fibre diet reduce bowel cancer?
By increasing the formation of short chain fatty acids which promote healthy gut microbes which induce differentiation, arrest growth of cells and cause apoptosis i.e. reduces the proliferation of potentially neoplastic cells
By increasing stool bulk thereby reducing stool transit time →potential carcinogens in the stool have a shorter contact with the bowel mucosa
By reducing secondary bile acid formation which are potentially carcinogenic
What is a polyp?
Polyp is a protrusion into a hollow viscus; can be benign adenoma or malignant
What is dysplasia?
Dysplasia (Greek: dys = bad; plasis = formation); the cells have morphological features of cancer but without invasion
What is the difference between high and low grade dysplasia?
Low grade dysplasia – early precancerous features
High grade dysplasia – advanced precancerous features, high risk of invasion if not removed
What are the pathological features of polyps?
Hyperplastic – more goblet cells than normal mucosa; has a lace - like pattern
Tubular adenoma – has test tube appearance
Villous adenoma – has finger-like appearance
Tubulovillous adenoma – a mixture of the
above
Pathology reporting: Tubular adenoma with low or high grade dysplasia
What is the adenoma carcinoma sequence?
This is a stepwise progression to bowel cancer from normal mucosa to adenoma to cancer
Morphological features i.e. macroscopic and histological features are also mirrored at genetic level where there are stepwise genetic alterations
Carcinoma of the bowel is a classic example of multistep carcinogenesis both phenotypically (morphologically) and genetically
What is the evidence of the adenoma carcinoma sequence?
-Populations that have a high prevalence of adenomas have a high prevalence of cancer
-Distribution of adenomas in the large bowel mirrors the distribution of bowel cancer i.e. 60% of the cancer arise in the left colon and most adenomas arise in this region; this is the rationale for bowel cancer screening using flexible sigmoidoscopy
Peak incidence of polyp predates the cancer e.g. peak age for adenomas is 60, median age for bowel cancer is 71 years
-Residual adenoma is found in early invasive cancer
-Risk of cancer is directly related to the number of polyps e.g. FAP with multiple polyps
-Programmes which follow-up patients and remove adenomas reduce the incidence of bowel cancer
What is Familial Adenomatous Polyposis?
- Patients have hundreds to thousands of polyps in large bowel, 500 – 2500
- Minimum of 100 polyps required to make diagnosis FAP
- The polyps are dysplastic and therefore called adenomas
- 100% risk of development of cancer by age of 30
- Prophylactic colectomy around 20years
- FAP contributes to 1% of bowel cancer
- Risk of cancer in the duodenum
Describe the genetics of FAP in carcinogenesis
- Hereditary autosomal dominant condition
- The defective gene is on Chr 5q21 and called APC gene (Adenomatous Polyposis Coli)
- Patients acquire the first abnormal gene in utero as germ cell mutation (‘first hit’)
- To develop polyps they acquire the second genetic abnormality in the somatic cells (‘second hit’)
- The ‘second hit’ paves the way for the development
of polyps from a young age throughout the
teens - Patients have no polyps at birth and require ‘two hits’ to develop polyps
What is the two hit hypothesis?
In FAP the patient is born with a single genetic abnormal (first hit ) and acquires the second genetic abnormality ( second hit) after birth
In sporadic adenomas the person acquires the two hits in somatic cells
The two hit hypothesis was proposed by Knudson to explain hereditary retinoblastoma, cancer of the eye in children and is applicable to most cancers
What is loss of heterogeneity?
The mutation of the APC gene is important in the initiation of bowel cancer
With one copy of abnormal gene , the cells are heterozygous
The loss of the second set of normal genetic material during the ‘second hit’ is termed loss of heterozyosity and cells will acquire two identical copies of abnormal genes i.e. become homozygous for the cancer gene
After the second hit the cells acquire more genetic abnormalities to progress with adenoma-carcinoma sequence
Describe Hereditary non-Polyposis Colorectal Cancer (HNPCC)/Lynch Syndrome
Familial cancer affecting predominantly the caecum and right colon, before the age of 50
Associated with endometrial, ovarian, small bowel and cancer of the urinary tract. Important when asking about family history of cancer not to concentrate just on large bowel cancer
Accounts for 2-3% of bowel cancer
No precursor polyps hence the name
Important to understand the genetics of HNPCC because this is of practical value
Clinicians can request testing for the presence of genetic mutations in the bowel cancer of someone with suspected family history
What are the genetics of HNPCC?
Very different from FAP
During replication the DNA base pairs can mismatch e.g. G – T instead G – C
There are mismatch repair genes which act as ‘spell checkers’ and correct these mismatches
Without the repairs the errors accumulate and create microsatellite instability
Microsatellites are tandem repeat of nucleotides in the DNA of an individual and are fixed for life
Errors due to mismatch in the DNA causes expansion and contractions of these repeat nucleotides causing what is termed as microsatellite instability – a hallmark of defective mismatch repair
There are several mismatch repair genes
At least four genes are involved in the pathogenesis HNPCC
MSH2 (2p16) and MLH1 (3p21) genes account for 30% of the HNPCC
PMS1 and PMS2 are the other genes involved in HNPCC
Similar to FAP individuals inherit the defective copy of the mismatch repair gene in utero (first hit) and acquire the second copy during life (second hit) and develop cancer
