Colorectal cancer Flashcards
Colorectal cancer epidemiology
- major cancer in developed countries
- 4th most common cancer worldwide
- 2nd leading cause of cancer death overall (behind lung cancer)
- aetiology includes environmental factors (diet) and genetic factors
Colon function
- Extraction of water from faeces (electrolyte balance)
- Faecal reservoir (evolutionary advantage)
- Bacterial digestion for vitamins (eg: B and K)
Colonic anatomy
-smooth folded mucosa with thick muscle layer
Turnover of colon cells
- 2.5 million cells die per minute in colon=high proliferation rate
- proliferation renders cells vulnerable to mutation
- APC mutation prevents cell loss
Normal protective mechanisms to eliminate genetically defective cells:
- natural loss
- DNA monitors
- repair enzymes
Polyp
- any projection from a mucosal surface into a hollow viscus
- may be hyperplastic, neoplastic, inflammatory, hamartomatous etc
Adenoma
-benign neoplasm of mucosal epithelial cells
Colonic polyp types
- metaplastic/ hyperplastic
- adenomas
- juvenile
- Peutz Jeghers
- lipomas
- others (essentially any circumscribed intramucosal lesions)
Hyperplastic polyps
- very common growth
- <0.5cm
- constitute 90% of all colon polyps
- often come in multiples
- no malignant potential
- 15% have K-Ras mutation
Colonic adenoma types
- Tubular (>75% tubular)
- Tubulovillous (25-50% villous)
- Villous (>50% villous)
- Flat
- Serrated
Colonic adenoma anatomy
- adenomas on a stalk=pedunculated
- flat and raised adenoma=sessile
Microscopic structure of adenomas (tubular)
- columnar cells with nuclear enlargement, elongation, multilayering and loss of polarity
- increased proliferative activity
- reduced differentiation
- complexity/ disorganisation of architecture
Microscopic structure of adenomas (villous)
- mucinous cells with nuclear enlargement, elongation, multilayering and loss of polarity
- exophytic, frond-like extensions
- rarely may have hypersecretory function resulting in excess mucus discharge and hypokalemia
Dysplasia
- abnormal growth of cells with some features of cancer
- subjective analysis
- given indefinite, low grade and high grade classification
Adenomatous Polyposis Coli (APC/FAP)
- 5q21 gene mutation
- site of mutation determines clinical variants (eg: classical, attenuated, Gardner, Turcot etc)
- many patients have a prophylactic colectomy
Colonic adenoma
- 25% of adults have adenomas at age 50=5% of these become cancers if left
- large polyps have higher risk of becoming cancerous than smaller polyps
- cancers stay at curable stage for about 2 years
Progression from adenoma to carcinoma
- most colorectal carcinomas arise from adenoma with 10-30% of colorectal carcinomas having a residual adenoma
- adenomas and carcinomas have a similar distribution
- adenomas typically precede cancers by 15 years
- endoscopic polyp removal decreases incidence of subsequent colorectal carcinomas
Dysplasia associated lesion
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Adenoma carcinoma sequence
-APC, K ras, Smads, p53, telomerase activation
Microsatellite instability
- microsatellites=repeat sequences prone to misalignment
- some microsatellites are in coding gene sequences which inhibit growth or apoptosis
- mismatch repair genes (MSH2) are recessive and require 2 hits for loss
Genetic predisposition to colorectal cancer
1) FAP=inactivation of APC TSG
2) HNPCC=microsatellite instability
Colonic carcinoma epidemiology
- 35k cases per annum in UK
- contribute 10% of cancer deaths
- age range=50-80 (sporadic rare <30)
- high incidence in US, Eastern Europe and Australia
- low incidence in Japan, Mexico and Africa
- Dietary factors predisposing to colonic carcinoma include high fat, low fibre, high red meat and refined carbs
Diet and colorectal cancer
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Dietary deficiencies with colorectal carcinoma
- Folates (co-enzyme for nucleotide synthesis and DNA methylation)
- MTHFR=deficiency leads to DNA synthesis disruption causing DNA instability leading to mutations. Decreased methionine synthesis also leads to genomic hypomethylation and focal hypermethylation leading to gene activation and silencing effects
Anticancer food elements
- Vitamin C and E=ROS scavengers
- Isothiocyanates in cruciferous vegetables (broccoli, cauliflower etc)
- Polyphenols in green tea and fruit juice=activate MAPK pathway which regulates phase 2 detoxifying enzymes and other genes and reduces DNA oxidation
- Garlic associated apoptosis
- EGCG-induced telomerase activity
Clinical presentation of colorectal carcinoma
- change in bowel habit
- pre-rectal bleeding
- unexplained iron deficiency anaemia
- pre-rectal mucus production
- bloating
- cramps (‘colic’)
- weight loss and fatigue (constitutional symptoms)
OFTEN SYMPTOMS RATIONALISED AS GETTING OLD, PILES OR IRRITABLE BOWEL
Macroscopic features of colorectal carcinoma
-small carcinomas may be present with larger polypoid adenomas (pedunculated or sessile)
Distribution of colorectal carcinoma
- caecum/ascending colon=22%
- transverse colon=11%
- descending colon=6%
- rectosigmoid=55%
Microscopic structure of colonic carcinomas
- adenocarcinomas grade 1 to 3
- mucinous carcinomas
- signet ring cell carcinoma
- neuroendocrine carcinoma
Grading of colonic carcinomas
- defined by proportion of gland differentiation relative to solid areas or nests and cords of cell without lumina
- ~10% of carcinomas=well differentiated
- ~70% of carcinomas=moderately differentiated
- ~20% of carcinomas=poorly differentiated
Dukes classification
- Dukes A=growth limited to wall, nodes negative
- Dukes B=growth beyond muscularis propria, nodes negative
- Dukes C1=nodes positive, apical lymph node negative
- Dukes C2=apical lymph node positive
Clinical features affecting prognosis
- diagnosis in asymptomatic patients
- rectal bleeding as presenting symptom
- bowel obstruction/perforation
- tumour location
- age <30
- preoperative serum CEA
- distant metastases
Diagnosis in asymptomatic patients prognosis
POSITIVE
-improved diagnosis
Rectal bleeding as presenting symptom prognosis
POSITIVE
-improved prognosis
Bowel obstruction/perforation prognosis
NEGATIVE
-diminished prognosis
Tumour location prognosis
POSITIVE AND NEGATIVE
- colon better than rectum
- left colon better than right colon
Age <30 prognosis
NEGATIVE
-diminished prognosis
Preoperative serum CEA (high levels=carcinoembryonic antigen) prognosis
NEGATIVE
-diminished prognosis with high CEA level
Distant metastases prognosis
NEGATIVE
-markedly diminished prognosis
Pathologic features affecting prognosis
- depth of bowel wall penetration
- number of regional lymph nodes involved
- degree of differentiation
- mucinous (colloid) or signet ring cell type
- venous invasion
- lymphatic invasion
- perineural invasion
- local inflammation and immunologic reaction
Depth of bowel wall penetration prognosis
-NEGATIVE if increased penetration (diminished prognosis)
Number of regional lymph nodes involved prognosis
POSITIVE AND NEGATIVE
-1 to 4 nodes better than >4 nodes involved
Degree of differentiation prognosis
- NEGATIVE if poorly differentiated
- POSITIVE if well differentiated
Mucinous (colloid) or signet ring cell type prognosis
NEGATIVE
-diminished prognosis
Venous invasion prognosis
NEGATIVE
-diminished prognosis
Lympathic invasion prognosis
NEGATIVE
-diminished prognosis
Perineural invasion prognosis
NEGATIVE
-diminished prognosis
Local inflammation and immunologic reaction prognosis
POSITIVE
-improved prognosis
Treatment options for grading
- Grade I= surgery
- Grade II=surgery, 5FU
- Grade III=surgery, 5FU/Leucovorin
- Grade IV=surgery, metastatectomy, chemotherapy, pallative RT
Screening criteria for high risk colon cancer
- previous adenoma
- first degree relative affected by colorectal cancer before 45 years old
- 2 affected first degree relatives
- evidence of dominant familial cancer trait (including colorectal, uterine and other cancers)
- Ulcerative colitis and Crohn’s disease
- heritable cancer families (includes other sites)
Population screening for cancer
-practice of investigating apparently healthy individuals with object of detecting unrecognised disease or people with an exceptionally high risk of developing disease, and of intervening in ways to prevent occurrence of disease or improve prognosis upon development
Criteria for screening programme
- condition should be important in respect to seriousness and/or frequency
- known natural history of disease (to identify where screening can take place and enable effects of any intervention to be assessed)
- test characteristics=simple and acceptable to patient, sensitive and selective
- cost-effective
- screening population should have equal access to screening procedure
NHS screening for colon cancer
- look for faecal occult blood (FOB)
- FOB test kit sent to over 55 year olds
- if positive result for FOB, endoscopy offered (sigmoidoscopy for 55-60 years old and colonoscopy for 60-75 years old)
