Colorectal Cancer Flashcards
Outline general information of colorectal cancer and functions of the colon
General Information about Colorectal Cancer
- Major cancer in ‘developed’ countries
- 4th most common cancer overall
- 2nd leading cause of cancer death overall (behind lung cancer)
- Environmental (diet) and genetic factors in aetiology • 35,000 cases per year in the UK
- 10% of cancer related deaths (16 000 per year)
- Age range = 50-‐80 yrs (sporadic colonic cancer is rare < 30 years) - risk increases with age
- High in USA, Eastern Europe and Australia
- Low in Japan, Mexico and Africa Colonic
Function
- Extraction of water from faeces (electrolye balance)
- Faecal reservoir (evolutionary advantage)
- Bacterial digestion for vitamins (e.g. vitamin B and K)
Describe Colonic Anatomy
- The mucosa is folded but it is smooth -> Submucosa and muscularis propria
- There is a thick muscle layer (muscularis)
- Cancers in the colon are adenocarcinomas (in the glandular epithelium)
- Cells divide in the crypts where the stem cells are found, then they are shunted up to the top of the villus where they are shed
Turnover of Colonic Epithelium
- 2-‐5 million cells die per minute in the colon
- The high rate of proliferation means that the cells are vulnerable
- APC (adenomatous polyposis coli) gene product reduces the risk of mistakes during replication
• APC gene mutation t mechanisms to eliminate genetically defective cells by:
- Natural loss
- DNA monitors
- Repair enzymes
Polyps and Adenomas
- Polyp = any projection from a mucosal surface into a hollow viscus, and may be hyperplastic, neoplastic, inflammatory, hamartomatous etc.
- Adenoma = benign neoplasm of the mucosal epithelial cells
Describe colonic polyps
Colonic polyp types
- Metaplastic/Hyperplastic
- Adenomas
- Juvenile, Peutz Jeghers, Lipomas (don’t really need to know about these ones)
Hyperplastic Polyps
- Very COMMON
- < 0.5 cm
- 90% of all colonic polyps
- There are often multiple polyps
- NO malignant potential
- 15% have K-‐Ras mutations
Describe colonic adenomas
Colonar adenoma types
- Tubular -‐ 90% (>75% tubular)
- Tubulovillous -‐ 10% (25-‐50% villous)
- Villous (>50% villous)
• IMPORTANT: the more villous it is the worse it is
Shapes of Adenomas
- Pedunculated adenomas are on a stalk -‐ it looks a bit like a tree (easier to resect)
- Sessile adenomas are flat and raised
- Both of these can be tubular, tubulovillous or villous
Discuss the microscopic structures of adenomas (tubular and columnar)
Microscopic Structure of Adenomas
NOTE: adenomas are not malignant but they are heading towards being malignant. They are dysplatic but they haven’t invaded through the basement membrane
Tubular Adenomas
- Columnar cells with nuclear enlargement, elongation, multi-‐layering and loss of polarity
- Increased proliferative activity
- Reduced differentiation
- Complexity/disorganisation of architecture - muschroom like tubular structure
Villous Adenomas
- Mucinous cells with nuclear enlargement, elongation, multi-‐layering and loss of polarity
- Exophytic -‐ frond-‐like extension
- Rarely may have hyper-‐secretory function and result in excess mucus discharge and hypokalaemia
Outline the pathophysiology of APC (Adenomatous Polyposis Coli)
Dysplasia
- Literal meaning = ‘bad growth’
- Abnormal growth of cells with some features of cancer Indefinite -‐ has low grade and high grade
- High grade dysplasia:
- Increased mitosis
- Increased nuclear size
- Increased nucleus cytoplasmic ratio
Adenomatous Polyposis Coli (APC)
NOTE: ulcerative colitis can lead to dysplasia
- There are some conditions that lead to increased numbers of polyps
- The most famous condition that increases the number of polyps is familial adenomatous polyposis (FAP)
- A lot of people have colonic polyps but in FAP there are thousands and thousands of polyps
- 5q21 gene mutation
- Site of mutation determines clinical variants (classic, attenuated, Gardner, Turcot etc.)
- Many patients have prophylactic colectomy
- The link between APC and colon cancer allowed the discovery of the adenoma-‐ carcinoma sequence
Outline the progression of colonic adenoma to carcinoma
Colonic Adenomas
- 25% of adults have adenomas at the age of 50
- 5% of these become cancers if left
- Larger polyps have a higher risk than small ones
- Cancers stay at a curable stage for about 2 years Progression from Adenoma to Carcinoma
- MOST colorectal cancers arise from pre-existing adenomas
- Residual adenoma in about 10-‐30% of colorectal cancers
- Adenomas and cancer have similar distribution
- Adenomas usually precede cancer by 10-15 years
- Endoscopic removal of polyps decreases the incidence of subsequent colorectal cancer
p53 mutations lead to carcinoma
But if there is overproduction of p53 - it means that is it malfunctioning and so again it causes problems 5% of adenoma became carcinomas In cases of polyp removal - chances decrease
Outline potential genetic causes of colorectal cancer
Genetic Pathways in Colorectal Cancer
Adenoma Carcinoma Sequence
- APC = best known gene that is damaged
- Others -‐ K-‐Ras, Smads, p53, telomerase activation
Microsatellite Instability
- Microsatellites are repeat sequences that are prone to misalignment
- Some microsatellites are in coding sequences of genes which inhibit growth or apoptosis (e.g. TGFbR11)
- Mis-‐match repair genes (MSH2, MLH1 + 4 others) -‐ recessive genes requiring two hits -‐ without this, there is a very elevated risk of cancer
- HNPCC (hereditary non-‐polyposis colorectal cancer) -‐ germline mutation in these genes (one of the genes is not working and you can still survive with 1 but in the tumour the second stops working)
Genetic predisposition for colorectal cancer:
- FAP -‐ inactivation of APC tumour suppressor genes
- HNPCC -‐ microsatellite instability (defects in DNA repair)
APC: if APC becomes mutated the moves form the cytoplasm to the nucleus
The base of the crypts you want cells to proliferate - APC normally moves to the base and as we go upwards it stops existing
Outline the effect of dietary deficiencies on CC
Dietary factors make a difference:
- High fat
- Low fibre
- High red meat
- Refined carbohydrates •
NOTE: cooking at high temperatures can alter the chemical structure, producing chemicals that can cause mutagenesis
Heterocyclic Amines (HCAs) include PhIP
- PhIP (is oxidised) -> N-OH-PhIP + deoxyguanosine -> mutagenesis
Dietary Deficiencies and Colorectal Cancer
- Folates
- Folates are important co-‐enzymes for nucleotide synthesis and DNA methylation
- MTHFR
- Deficiency leads to disruption in DNA synthesis causing DNA instability (strand breaks and uracil incorporation) -‐ this leads to mutation
- Decreased methionine synthesis leads to genomic hypomethylation and focal hypermethylation -‐ this can have gene activating and gene silencing effects
Anti-cancer Food Elements
- Vitamin C and E – ROS scavengers.
- Isothiocyanates – cruciferous vegetables.
- Polyphenols – green tea and fruit juice.
-Can activate MAPK pathways -> regulating phase 2 metabolisms to detoxify enzymes as well as other genes and thus reduce DNA oxidation. EGCG-induced telomerase activity. Garlic associated apoptosis.
Discuss the Clinical Presentation of Colorectal Cancer
- CHANGE IN BOWEL HABIT
- PER RECTAL BLEEDING
- UNEXPLAINED IRON DEFICIENCY ANAEMIA
- Other features:
- Per rectal mucus
- Bloating
- Cramps (colic)
- Constitutional (weight loss, fatigue)
NOTE: patients tend to rationalise these symptoms as signs of ‘getting old’, piles or IBS
Name some macroscopic and microscopic features of CRC
Macroscopic Features of Colorectal Carcinoma
- Small carcinomas may be present within larger polypoid adenomas (pedunculated or sessile)
Distribution of Colorectal Cancer
- Caecum/Ascending Colon -‐ 22%
- Transverse Colon -‐ 11%
- Descending Colon -‐ 6%
- RECTOSIGMOID -‐ 55%
Microscopic Structures of Carcinomas Inflammatory reaction shows in histology
- Almost all of them are adenocarcinomas (grade 1-3)
- Mucinous carcinomas (type of adenocarcinoma) -> they cause mucin secretion - when it has infiltrated the muscular proper - worst prognosis
- Signet ring cell (type of adenocarcinoma)
- Neuroendocrine (very rare)
Grading and Duke’s classification
Grading
- Proportion of gland differentiation relative to solid areas or nests and cords of cells without lumina
- 10% are well differentiated
- 70% are moderately differentiated
- 20% poorly differentiated
Dukes Classification
Dukes A
- Growth limited to the wall (muscularis propria)
- Nodes negative
Dukes B
- Growth beyond muscularis propria
- Nodes negative
Dukes C1
- Nodes POSITIVE
- Apical lymph node negative
Dukes C2
- Apical lymph node POSITIVE
- Apical lymph nodes = the highest lymph node that has been removed -‐ if this is positive it means that the cancer could have spread even further in the lymphatics
Prognosis and Screening
There are some CLINICAL features that also affect prognosis:
- Diagnosis of asymptomatic patients (improves prognosis)
- Rectal bleeding as presenting symptom (improves prognosis)
- Bowel obstruction (diminished prognosis)
- Tumour location: left colon might be better than right
- Age < 30 (diminished prognosis)
- Preoperative serum CEA (carcinoembryonic antigen) (diminished prognosis with high CEA)
- Distant metastases (markedly diminished prognosis)
PATHOLOGICAL features that affect prognosis:
- Depth of bowel wall penetration (increased penetration = diminished prognosis)
- Number of regional lymph nodes involved
- Degree of differentiation
- Mucinous (colloid) or signet ring cell (diminished prognosis)
- Venous invasion (diminished prognosis)
- Lymphatic invasion (diminished prognosis)
- Perineural invasion (diminished prognosis)
- Local inflammation and immunologic reaction (improved prognosis)
Treatment
Treatment depends on stage
Either only surgical or radiotherapy and chemotherapy as well
Screening
Screening Prerequisites:
- Previous adenoma.
- 1st degree relative affected by CRC before age 45.
- Two affected 1st degree relatives.
- Evidence of dominant familial cancer trait.
- UC and Crohn’s disease.
- Heritable cancer families.
“Screening is the practice of investigating apparently healthy individuals with the object of identifying previously unknown disease”
Criteria:
- Condition should be important in respect to the seriousness and/or frequency.
- Natural history of the disease must be known – to identify where/if screening and intervention takes place.
- Test must be simple, acceptable, sensitive, selective and cost-effective.
- Screening population should have equal access to the screening procedure.
NHS screening for colon cancer
- They look for Faecal Occult Blood (FOB)
- From 55 years onwards they will send a FOB test kit
- If there is blood then an endoscopy is performed
- 55-‐60 yrs -‐ usually a sigmoidoscopy
- Older -‐ full colonoscopy
- They will look for adenomas that can be removed but in some people they will find cancer
