Familial Adenomatous
Polyposis (FAP)
DEFINITION
A familial disease associated with many colonic polyps, and high
risk of colorectal and other cancers.
D E A B M I M
EPIDEMIOLOGY
AD inheritance
- but 25% may present de novo.
D E A B M I M
AETIOLOGY
Pathogenesis
Germline mutation of the APC gene in >90% (on long arm ch5)
--> truncated APC protein
This protein normally acts a tumour suppressor, functions to control
cell proliferation (wnt-signaling pathway) & controls
intracellular adhesions (beta-catenin production).
D E A B M I M
BIOLOGICAL BEHAVIOUR
Pathophysiology
>100 adenomas; or fewer with a positive family history.
Classically, start in teenage years and 100% chance of Ca by mean
age ~40.
- 'attenuated FAP' = fewer polyps (mean 25), diagnosed 10-15y later.
100% risk for cancer relates to multiplicity of polyps, each has
moderately low risk but cumulatively = certain risk
Associated with extra-GI disease
- esp. desmoid tumours
- also duodenal / peri-ampullary, pancreatic, papillary thyroid,
CNS, hepatobiliary, others.
- congenital hypertrophy of retinal pigment epithelium, oesteoma,
cutaneous lesions (epidermoid cysts, fibromas).
Genotype-Phenotype
Correlations
Tends to be that certain APC gene deletions associated with
specific variants of FAP
- eg attenuated type, or desmoid-associated, or Gardner's, or
thyroid tumour associated etc.
Gardner's syndrome - colonic polyposis with oesteomas,
soft-tissue desmoid, cutaneous lesions
Turcot syndrome - colonic
polyposis with CNS tumours.
Desmoid Tumours
Differentiated fibroblasts and myofibroblasts within collagenous
stroma.
10-20% of FAP
Major cause of morbidity and mortality after CRC risk addressed.
Risks:
- familial specific phenotype / genotypic deletion.
--> relates to mutation location beyond codon 1400 of APC gene
- prior surgery
- hormone exposure (estrogens)
80% intra-abdominal; else abdo wall, trunk of limbs.
Vary from sheet-like plaques infiltrating along mesentery to large
masses causing obstruction and fistula.
Staging of Desmoids
0 = minimal lesion, doubling rate unknown
1 = <5cm, >24m doubling rate, extra-abdominal
2 = 5-10cm, 12-24m doubling, abdo wall
3 = 10-20cm, 6-12m doubling, mesentery without obstruction
4 = >20cm, 1-6m doubling, mesentery with obstruction.
Ampullary / Peri-ampullary Disease
Nearly all FAP pts get duodenal adenoma
- but risk of duodenal Ca is only 5-10% by 60y
--> so surveillance not prophylactic surgery.
Risk depends on polyp numbers, size and histology
Spigelman Staging System
Rates duodenal polyps by number, max size, histology and dysplasia
Categories (points 1-3)
- number: 1-4, 5-20, >20
- max size: 1-4, 5-10, >10
- histo: tubular, tubulovillous, villous
- dysplasia: mild, mod, severe
Score >7 = high risk for invasive cancer (2%); particularly 9-12
points --> risk 36%.
D E A B M I M
MANIFESTATIONS
Patients will present symptomatic or asymptomatic with
family history for management
- most common symptoms are bleeding and diarrhoea.
D E A B M I M
INVESTIGATIONS
See above / CRC
D E A B M I M
MANAGEMENT
Surveillance
Patients commonly present
surgically when:
i) polyps develop advanced histology
ii) endoscopic management no longer feasible or adequate
iii) patient wants surgery.
When suspect or large (>1cm) lesions appear, pt should be managed
according to oncologic principles.
Operative
Options:
1. Total proctocolectomy with end ileostomy. (TPC)
2. Total abdominal colectomy with ileorectal anastomosis (IRA)
3. Total proctocolectomy and ileo-anal pouch anastomosis (IAPA)
Laparoscopic procedures are probably preferable.
Principles
* Optimal therapy and
surgical option depends on patient and disease factors.
1. IRA vs IAPA
Depends on number, size, status of rectal polyps, genotype, family
history and extracolonic phenotype
IRA leaves rectum at risk.
- risk increases with multiple adenomas, advancing age (30% by 60y)
and genotype.
--> IRA favoured for young patients with personal and family hx
of low rectal polyp burden and attenuated phenotype
Relative contraindications to IRA:
- polyps >3cm, severe dysplasia, any colorectal cancer.
2. IAPA eliminates rectal cancer
risk.
But patients should still be surveyed endoscopically; pouch polyp
rate up to 75% after 15y
- malignant transformation of these is rare, however.
- treatment is by i) endoscopic removal, ii) trans-anal excision,
iii) pouch excision.
IPAA also preferred for pts at risk of duodenal or desmoid disease
- alters bile salt absorption; less secondary bile acid production,
reduced duodenal exposure to carcinogens.
3. Oncologic requirement is to
remove all at-risk mucosa.
- can't do a pouch after an ileocolic tie.
- also reluctance to form a pouch in an irradiated field.
- Intra-abdo desmoids or UGI malignancy precludes IPAA.
--> desmoids contract mesentery, limiting its reach.
4. Indications for TPC and
end-ileostomy
Poor sphincter function
Locally advanced rectal cancer
Preclusion of IPAA as above
Morbidity and QOL
Colectomy and IRA is simple, does not require an ileostomy; leak
rate is low.
- ileus rate 25%
IPAA is technically demanding with pelvic dissection and high
morbidity (>30%)
- 5-10% risk of abscess and leak
TPC does require a pelvic dissection but obviously no leak.
Functional outcome
IRA vs IPAA:
- no difference in urgency or incontinence
- mean daytime stool: 5 after IRA, 6 after IPAA
- mean nighttime stool: 1 after IRA, 2 after IPAA
Female fecundity reduced after pelvic dissection, vs unaffected by
IRA
IPAA worse short term QOL but ~same after 1 year.
--> Surgeon must understand patients comorbidities, potential to
withstand complications and sexual fx / fertility prior to surgery.
Timing of Surgery
Obviously urgent for patients with dysplasia or malignancy.
For the rest, it depends on patient and disease factors
- disruption to life, interference with fertility
- best delayed until after growth, emotional maturity
- minimize effects on schooling or social life
Operating may increase desmoid tumour risk by 2x
Need to inform females that:
- after IAPA, fertility may be affected
- will need a Caesar; or high risk they will be incontinent.
Concerns have led to a staged approach option: IRA first, then IAPA.
- this is very reasonable when possible.
Technical Considerations
IRA colonic resection usually uncomplicated.
In malignant cases:
- oncologic principles of en-bloc resection, high vascular
ligation and adequate nodal harvest.
Anastomosis in rectum
- convergence of tinea, transition to rectal mucosa by endoscopy
Rectal stump <10-15cm bad for reservoir.
Anastomosis considerations:
- end-to-end reasonable, avoids blind ends
- want very low; anal transition zone dysplasia reduced from 18.5 to
7.5% with mucosectomy
--> i.e. complete removal of rectal mucosa.
IPAA with J-pouch; difficult in obese or tall young men.
- need tension-free reach; e.g. transversely score peritoneum over
SMA
- avoid twisting of mesentery, bowel loops sneaking behind the join.
Desmoids
Technically difficult
Serious perioperative morbidity
High recurrence (90%)
--> General reluctance to operate.
Staged Approach
I - observation, COX-2 inhibitors
II - hormone therapy (tamoxifen)
III - cytotoxic agents (methotrexate, vinblastine, adriamycin),
imatinib
IV - as for III
Operative indications
Pain, fistula, obstruction, perforation.
Failed medical management.
Abdo wall desmoids
Operate with more enthusiasm; better outcomes
May need reconstructive colleagues help with abdo wall.
Adjunctive radiation.
Periampullary Disease
Low risk
Scope 1-3 yearly.
Medical therapy = Cox-2 inhibitors
Endoscopic options = snare, EMR, argon-beam plasma coagulation,
photodynamic therapy.
High risk
Operative intervention for 9-12 Spigelman pts
Process
If lesion >1 cm or severe dysplasia
--> work up with EUS and abdo imaging to complete staging.
Operation with pancreaticoduodenectomy (PD) or pancreas-sparing
duodenectomy (PSD)
- comparative mortality and morbidity, although PSD demanding (small
cuff of at-risk duodenal mucosa may be left around ampulla)
- danger with PD is 2cm of duodenum left beyond pylorus and altered
anatomy, making surveillance difficult.
--> much depends on local expertise; i.e. generally PD performed.
D E A B M I M
REFERENCES
Cameron 10th