GI cancers Flashcards
Colorectal cancer - epidemiology
Disease of westernised societies
2nd Commonest cause of cancer death
Survival improved but still only 55% chance of being alive in 5 years
15% of all male cancers, 12% of all female cancers
- 3rd commonest incident male cancer (after lung & prostate)
- 3rd commonest incident female cancer (after breast & lung)
Colon F>M
Rectum M>F
(BUT rectum more common than colon)
Distribution – Most common rectum -> sigmoid -> colon -> caecum
Peak age 75-79 yrs (age-specific mortality increases exponentially with age)
Colorectal cancer - aetiology
Age
Western diet
- Diet high in fat, red meat
- Low in fibre, fruit and green vegetables (brassica vegetables protect)
- High stool pH
Lifestyle factors - Smoking, lack of exercise, beer (rectal cancer)
Inflammatory bowel disease
- Pan-Ulcerative colitis 30% risk at 30 yrs, 40% risk if <15yrs at dx
- Crohn’s disease RR 2.5
Genetic predisposition
- Overall genetic contribution 35%
- Dominant gene disorders 2 - 5% (HNPCC, FAP, Others - PJS, JPS)
FH
Defined syndromes: HNPCC 2-5% or FAP 0.07%
Lifetime risk - 5.1
Colorectal cancer presentation
- emergency
- elective
Emergency
- Obstruction or Perforation
- > May lead to peritonitis, localized abscess or fistula formation
- Bleeding
- Localized pain
Elective
- Altered bowel habit
- Rectal bleeding
- Colicky pain
- Unexplained anaemia
- Anorexia/ weight loss/ malaise
- Flatulence
Symptoms - Change in bowel habits Frequency & consistency Diarrhoea more likely to be cancer than constipation - Abdominal pain = Generally not present unless big
Left colon cancer symptoms
Fresh rectal bleeding, mucus Altered bowel habit Tenesmus Mass Obstruction occurs early
Right colon cancer symptoms
Present with anaemia from occult bleeding or with altered bowel habit
Weight loss
Abdominal pain
Obstruction = late feature
Colorectal cancer diagnosis
Bloods - FBC, CRP , UandEs
Digital rectal exam
1st line = colonoscopy
- biopsy any polyps
- if high risk of complications - consider CT colonoscopy
Emergency operation (20-25%)
Surveillance
- HNPCC, FAP, Inflammatory bowel disease, prior cancer
Population FOBT screening
Colonic polyp
Excrescence of colonic mucose
Does not indicate nature of lesion
- Neoplastic
- Non-neoplastic (Hamartomas; Metaplastic (hyperplastic); Inflammatory)
70% of people aged 65-75 will have a polyp
Bigger polyps more likely to become cancerous
Dysplasia -> higher chance of adenocariconoma in future
Most common type of rectal cancer
- metastasis site
mostly adenocarcinoma
Mets to liver and lung
FAP
1.8 new patients per million
Uncommon - 1% of all colorectal cancers
Autosomal dominant with ~100% penetrance
Inactivating mutations of the tumour suppressor APC (5q21) gene
Germline mutation - > 1400 mutations reported; most = loss-of-function mutations resulting in truncated APC protein
APC normally binds to and sequesters beta-catenin. Cant do this when mutated – allowing beta-catenin to translocate to nucleus -> upregulates expression of many genes
20% - new mutations, no FH
100s polyps develop in 80% of patients by age 15, symptoms e.g. rectal bleeding begin few years later
Cancer will develop within 10-15 years of appearance of adenomas, 90% develop colorectal cancer by 50 years
Extra-intestinal manifestations: CHRPE – congenital hypertrophy of retinal pigment epithelium, epidermoid cysts (extremities, face, scalp – 50%), benign osteomas – esp. skull and angle of mandible, dental abnormalities, desmoid tumours (mesentery, abdominal wall, benign but may cause compression of organs. Difficult to remove, may respond to tamoxifen)
Diagnosis
- Early identification of affected individuals before symptoms develop
- Can be excluded if sigmoidoscopy normal
- In new cases – genetic testing should be carried out to confirm diagnosis & identify causal mutation
- All 1st degree relatives should undergo testing
- Known FAP – offered mutation testing at 13-14, if have mutation offered colectomy at 18
Operation of choice = total proctocolectomy with ileal pouch-anal anastomosis (prophylactically done)
Periodic upper GI endoscopy every 1-3 years to detect and monitor duodenal and periampullary adenomas – large may be removed
What does APC do in cell?
APC normally binds to and sequesters beta-catenin. Cant do this when mutated – allowing beta-catenin to translocate to nucleus -> upregulates expression of many genes
Cells unaware that joined together so divide uncontrollably
Extra-intestinal manifestation of FAP
CHRPE – congenital hypertrophy of retinal pigment epithelium
epidermoid cysts (extremities, face, scalp – 50%)
benign osteomas – esp. skull and angle of mandible
dental abnormalities
desmoid tumours (mesentery, abdominal wall, benign but may cause compression of organs. Difficult to remove, may respond to tamoxifen)
Peutz-Jeghers syndrome
AD – most commonly from truncating mutations in serine-threonine kinase gene on chromosome 19
Multiple hamartomatous polyps occur in small intestine & colon
Melanin pigmentation of lips, mouth and digits
Most asymptomatic BUT may have chronic bleeding, anaemia or intussusceptino
Risk of small bowel or colonc adenocarcinoma and cancer of lung, pancreas, testis, ovary, breast and endometrium
HNPCC
- definition criteria
HNPCC
Definition criteria:
(1) >3 family member with histologically proven colorectal cancer
(2)One relative a first degree relative of the other two
(3) >2 generations affected
(4) Age at onset <50yrs in at least one family member
Uterine cancer in one or more relatives acceptable as part of a 3 member family
Not as many polyps
Mutations in DNA mismatch repair genes
MSH2 40%; MLH1 40%; MSH6 20%
Colorectal cancer surgery
Only treatment modality offering potential cure
Emergency (obstructed, perforated - unprepared bowel)
- Segmental excision and on-table colonic lavage
- Colectomy and ileorectal anastomosis
- Hartmann’s procedure -> Bowel obstruction, perforation or palliation
Elective (low rectal cancer require mechanical bowel preparation)
- Segmental resection (eg R-hemicolectomy, ant. resection etc)
- Restorative rectal excision +/- colonic pouch
- Transanal excision of rectal cancer
- Colonoscopic polypectomy
Endoscopic removal
- Small/moderate adenomas
Sigmoid + rectum = anterior resection
Right hemicolectomy = caecal, ascending or proximal transverse colon tumours
Left hemicolectomy = distal transverse or descending colon
Left hemicolectomy
distal transverse or descending colon
Right hemicolectomy
caecal, ascending or proximal transverse colon tumours
Colorectal cancer - adjuvant chemotherapy
Locally advanced rectal cancer
- Neoadjuvant radiotherapy or chemoradiotherapy to increase chance of complete surgical resection
- Continuity should be restored with direct anastomosis
5-fluorouracil based regimens – now capecitabine (TS inhibitor)
- 30% reduction in mortality for Dukes’ C
- 5% overall increase in absolute survival for Dukes’ C
- 3% overall increased survival Dukes B
Combination therapy (CAPOX)
Capecitabine (thymidylate synthase inhibitor) + oxaliplatin
2nd line agents
- Cetuximab –mab to epidermal growth factor receptor
- Bevacizumab - mab to vascular endothelial growth factor
- Temozolomide
Duke’s staging
A Limited to bowel wall B Through full thickness bowel wall C1 Regional lymph nodes involved C2 Apical lymph node involved D – cancer spread to another part of body
APC/Beta-catenin pathway
Inactivation of APC (Adenomatous Polyposis Coli) tumour suppressor gene seen in about 80% of colorectal carcinomas
Genetic basis of the inherited condition FAP
Early event in the adenoma-carcinoma sequence
Subsequent accumulation of multiple mutations and chromosomal instability
Microsatellite instability pathway
10-15% of sporadic colorectal carcinomas (R>L)
Inactivation of DNA mismatch repair genes
MSH2, MLH1 (90% of cases involve one of these)
Others - MSH6, PMS1, PMS2
Inherited mutation in one of these genes is the basis of Hereditary Non-Polyposis Colorectal Carcinoma (HNPCC) syndrome (Lynch syndrome)
Loss of one of these genes increases mutation rate by up to 1000-fold
Not associated with typical adenoma-carcinoma sequence
Colorectal cancer Screening
Scotland
- FIT test – keyring swab poo
- Age 50-74 – every 2 years
- 50-60% sensitivity so lots of false positives
20% survival benefit in 50-75 years old
England → 60-74 year olds
Anal carcinoma
- incidence
- aetiology
- pathology
- clinical presentation
- treatment
UK incidence: 300 cases annually (1.5% of all malignant colorectal disease)
Aetiology
- Human papilloma virus type 6, 11 and 16
- Anoreceptive intercourse
- Immunosuppression (HIV, pharmacological, haematological)
Pathology
- AIN (anal intra-epithelial neoplasia)
- Squamous
- Adenocarcinoma
- Basiloid
- Small cell carcinoma
- Malignant melanoma
Clinical presentation:
Ulcer, warty lesion, pruritis, pain, bleeding
Treatment
- AIN1&2 - Observe, often settles
- AIN3 - Surveillance with magnifying anoscopy and biopsy
- Local excision for invasive carcinoma T1/T2 tumours
- Combined chemo-radiation for invasive carcinoma
5FU
- Enters reactions in place of uracil
- Inhibits thymidylate synthetase and interferes with DNA & RNA synthesis
- SE: nausea, diarrhea, stomatitis, myelosuppresion
Mitomycin C and radiotherapy
Abdomino-perineal excision - salvage procedure
Outcome: 65-80% 5yr survival
Most common type of gastric cancer
adenocarcinoma
- incidence falling
- arises from mucus secreting cells in base of gastric crypts
- most develop on background of chronic atrophic gastritis with intestinal metaplasia and dysplasia
GISTs
Gastro-intestinal stromal tumours
- Arise from interstitial cells of Cajal
- Express c-kit proto-oncogene – encodes tyrosine kinase receptor
- Mostly benign leiomyomas but can bleed
Histology – “spindle-cell” or “epitheliod “pattern
IHC – C-kit
Treatment
Metastatic – imatinib (Glivec) → bonds to C-kit (CD117), a tyrosine kinase, where adenosine phosphate normally binds preventing phosphorylation and c-kit activated signalling is abolished
