Familial Adenomatous Polyposis (FAP)

DEFINITION
A familial disease associated with many colonic polyps, and high risk of colorectal and other cancers.

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EPIDEMIOLOGY

AD inheritance

- but 25% may present de novo.
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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).

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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%.


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MANIFESTATIONS

Patients will present symptomatic or asymptomatic with family history for management
- most common symptoms are bleeding and diarrhoea.


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INVESTIGATIONS

See above / CRC

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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.

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REFERENCES
Cameron 10th