Colorectal Flashcards
Pathophysiology of diverticular disease is an interaction between?
- High intraluminal pressure
- Disordered motility
- Altered colonic structure
- Low fibre diet
FAP (Familial Adenomatous Polyposis)
Germline mutation in the APC gene (adenomatous polyposis coli)
Tumour suppressor gene, chromosome 5
Autosomal dominant inheritance
3/100,000
Autosomal dominant (AD) mutations of the tumour suppressor APC gene (Chr 5q21-22) are responsible for FAP:
• >300 mutations have been described
• lead to a loss of β-catenin regulation → β-catenin accumulation → activated transcription factor Tcf-4 => activation of Wnt (Wingless-type) pathway => cell division and overgrowth
• somatic APC mutations have been discovered in the majority of sporadic desmoids
• AD inheritance, but near complete penetrance => 100% get CRC
Adenoma to Carcinoma Sequence
Classical Pathway - FAP
(chromosome instability (CIN) pathway)
APC (tumour suppressors, 2 hit, beta catenin pathway) / KRAS (oncogene) / SMAD 2 and 4 (tumour suppressors genes, TGF-beta pathway)/ P53 (tumour suppressor, guardian of genome)
Inherited and sporadic -> Earliest mutation frequently involves the APC gene and is present in ~85% of sporadic tumours
Subsequent mutations commonly occur in K-ras and DCC; p53 mutation is generally a late event
Activation of oncogenes (growth promoting pathways) and inactivation of TS genes or apoptotic pathways from deletions, insertions and loss of heterozygosity
Mismatch repair/Microsatellite Instability (HNPCC)
MLH1, MSH2, BRAF (oncogene), BAX
Genes regulate the mismatch repair system which maintains genomic stability - A defect results in expansion or contraction of microsatellites (MSI)
This results in an accumulation of mutations that promote growth or inhibit tumour suppression
Lynch-related CRC present only with KRAS and NOT BRAF mutations
Inherited and sporadic
Another pathway leading from adenomatous polyps, and probably from serrated adenomas, to invasive ca
MSI pathway is related to MMR genes => accumulation of DNA errors throughout the genome
Characterised by the presence of microsatellite instability (biological “footprint” of defect in MMR as there is accumulation of abnormalities in short sequences of nucleotide bases that are repeated dozens to hundreds of times within the genome)
Found in ~15% of sporadic CRC, likely due to hypermethylation (rather than a specific mutation) affecting MMR expression (usually MLH1) => transcriptional silencing of gene expression
CpG island methylator phenotype (CIMP+) pathway
o Subgroup of sporadic CRCs that develop from serrated polyps
o Epigenetic alterations (e.g. DNA hypomethylation and loss of imprinting) as well as DNA hypermethylation => silencing of MMR genes
o CRCs have particularly high frequency of methylation of some CpG islands (in which a cytosine base is followed immediately by a guanine based that are linked with a phosphodiester bond => called CIMP+ tumours). This leads to hypermethylation of MMR genes like MLH1 => silencing
o High incidence of BRAF mutation (mostly in V600E codon) – these occur almost exclusively in MSI-H, CIMP+ CRCs that do not carry mutations in KRAS
o BRAF mutations are also seen in SMOKERS with sporadic CRCs
o Presence of BRAF mutations remove favourable prognosis typically associated with MSI-H tumours
What is Gardener’s Syndrome?
FAP variant
Colonic polyps
Abdominal and abdominal wall desmoids
epidermal inclusion cysts
osteomas - skull, tibia, mandible
Multiple extraintestinal manifestations → Gardner’s syndrome
-Ectodermal in origin
o Epidermoid cysts
o Tumours of the CNS
o Congenital hypertrophy of the retinal pigment epithelium (CHRPE)
-Endodermal in origin
o Adenomas and carcinomas of duodenum, stomach, SB, liver (hepatoblastoma) biliary tree, thyroid, adrenal cortex
o Fundic gland polyps
o Hepatoblastoma
-Mesodermal in origin
o Desmoid tumours, excessive adhesions
o Osteomas
o Dental abnormalities
What is Turcot Syndrome?
FAP variant
Colonic polyps and brain tumours
What is vogelstein’s Model?
According to the Vogelstein model, germline or somatic mutations are required for malignant transformation, and the accumulation of multiple genetic mutations rather than their sequence determines the biological behavior of the tumor .
Germline mutations underlie the common inherited syndromes (eg, familial adenomatous polyposis [FAP], Lynch syndrome), while sporadic cancers result from the stepwise accumulation of multiple somatic mutations.
Mutations in the adenomatous polyposis coli (APC) gene, a feature common to both inherited and sporadic CRCs, occur early in the process, while p53 tumor suppressor gene mutations generally occur late.
In addition to point mutations, other genetic changes that are implicated in human tumorigenesis include altered DNA methylation, and gene rearrangements, amplifications, overexpression, and deletions.
What is the recommendation for Colonic surveillance after polypectomy?
FOBT age 5–74 every 2 years
1/2 or LOW RISK features -> 5yrs
3/4 or HIGH RISK Features -> 3 years
5-9 -> 1 yearly
>10 -> <1 year
incomplete of large/sessile adenoma -> 3-6months
High risk features = adenoma >10mm, villous features, high grade dysplasia
What are the Bethesda criteria for determining who to test for Lynch?
Pt with CRC with -
• histopathological characteristics of MSI in pts <60 yrs (tumour infiltrating lymphocytes, Crohn’s-like lymphocytic reaction mucinous/signet ring differentiation, or medullary growth pattern)
• extra HNPCC cancers, synchronous, metachronous
• single (≥1) 1st degree relative HNPCC-related cancer <50 yrs
• double (≥2) 1st/2nd degree relative HNPCC cancer
• age <50 yrs
REPEAT…
- Patient <50yo with CRC
- Multiple CR or HNPCC-assoc. tumours occurring synchronously or metachronously
- CRC in a patient <60yo with microscopic features suggestive of MSI-H
- Patients with CRC and 1 or more 1st degree relatives with HNPCC-assoc. tumours, one diagnosed <50yo
-Patients with CRC and 2 or more 1st or 2nd degree
relatives with HNPCC assoc. tumours, any age
Screening and Surveillance in LYNCH
Screening HNPCC
Known mutation carriers: Annual colonoscopy from 25yo or 5yrs earlier than youngest diagnosis if <30y
For families fulfilling Amsterdam criteria, mutation status unknown: 1-2nd yearly colonoscopy
LYNCH
Surveillance colonoscopy every 2 years from age 20 (or 5 years younger than affected relative) + Annually after age 35
Annual TV pelvic ultrasound and Ca125 in females
2 yearly upper GI endoscopy
Annual urinalysis and cytology for blood
Annual abdominal ultrasound
Annual LFTs and tumour markers
Note – surveillance will not always prevent a cancer forming (rapid development can occur in <1 year)
MANAGEMENT OF HNPCC
•Prophylactic colectomy not recommended, but considered if >1 advanced adenoma
•Once cancer identified → oncological resection + surveillance of remaining bowel (risk of metachronous CRC is 15-20%) -Can consider extended resection (balance risk of metachronous cancer vs function)
o Colon cancer -> can consider total colectomy with ileorectal anastomosis
o Rectal cancer -> can consider total proctocolectomy +/- IPAA (reduces risk of metachronous cancer but more functional problems with IPAA)
- If less extensive resection, require annual colonoscopy of remaining bowel
- Referral to gynaecologist in women for consideration of total abdominal hysterectomy + BSO after childbearing is complete or by 40 years
- 2 yearly gastroscopies from age 30
- Urine cytology from after 30-36y
Peutz-Jeghers
•Autosomal dominant condition characterised by multiple gastrointestinal hamartomatous polyps and mucocutaneous pigmentation
• Due to mutation in STK11 in >90% (40-50% have de novo mutation rather than inherited)
•Polyps distinguished from juvenile hamartomas by presence of smooth muscle bundles in the submucosa → “branching tree” appearance
HNPCC Genetics
Germ-line mutation: genetic defect of mismatch repair genes on chromosome 3p, 2p, 7p:
• MLH1 (3p22), MSH2 (2p21), MSH6 (2p16), PMS2 (7p22), EPCAM (deletions in the 3’ end => silencing of neighbouring MSH2 gene)
• NB MLH1 and MSH2 account for 90%.
• The defects occur in the setting of microsatellite instability. ( Microsatellite instability (MSI) is the condition of genetic hypermutability that results from impaired DNA mismatch repair (MMR). The presence of MSI represents phenotypic evidence that MMR is not functioning normally.)
Pathology
Typical histology associated with microsatellite instability:
• presence of tumour infiltrating lymphocytes, Crohn’s-like lymphocytic reaction
• mucinous/signet ring differentiation, or
• medullary growth pattern.
What is melanosis coli
• Colonic pigmentation associated with chronic laxative use
• Associated with use of anthraquinones
`- Bisacodyl (dulcolax)
- Senna
• These laxatives pass into colon unabsorbed and are converted into their active form
• active compounds inhibit mucosa cell function => apoptosis
• ingestion of fragments of apoptotic epithelial cells by macrophages => deposition of lipofuscin (not melanin) in lamina propria => pigmentation
• Benign condition, stop laxatives if not required, no specific treatment required
• Lipofuscin is the name given to fine yellow-brown pigment granules composed of lipid-containing residues of lysosomal digestion
