Bowel cancer

Description

Adenocarcinoma of colon or rectum. ~75% sporadic, ~20% familial clustering, ~5% a defined syndrome

Three molecular pathways

Pathway	Mechanism	Features
Chromosomal instability (~85%)	APC -> KRAS -> TP53 adenoma-carcinoma sequence	Left-sided, polypoid
Microsatellite instability (~15%)	dMMR - sporadic (MLH1 promoter hypermethylation) or Lynch	Right-sided, poorly differentiated, mucinous, lymphocytic infiltrate. Better stage-for-stage prognosis; responds to immunotherapy; less benefit from 5-FU alone in stage II
Serrated / CIMP	BRAF V600E, CpG island methylation	Sessile serrated lesions, right colon, rapid progression

Hereditary syndromes

FAP - germline APC; loss of APC releases beta-catenin from restraint -> unchecked proliferation and accumulating mutations
Lynch (HNPCC) - germline MLH1, MSH2, MSH6, PMS2, or EPCAM deletion silencing MSH2
- MLH1 + MSH2 account for 60-80%
MUTYH-associated polyposis (biallelic, autosomal recessive)
Peutz-Jeghers (STK11), juvenile polyposis (SMAD4/BMPR1A), serrated polyposis

Epidemiology

~15,000 Australian cases/year; the 2nd-3rd commonest cancer and 2nd commonest cancer death
Australia has among the highest incidence rates worldwide
Incidence falling in those >50 (screening) but rising in adults <50 - early-onset CRC
Sporadic median age ~69; Lynch-associated 45-60
M slightly > F

Aetiopathogenesis

Modifiable

Obesity, physical inactivity
Red and processed meat, low fibre
Alcohol, smoking
Type 2 diabetes

Non-modifiable / disease-related

Age; family history
IBD - risk rises with duration, extent and severity of inflammation; equal in UC and Crohn colitis for equivalent extent; PSC multiplies it
Prior adenoma or CRC
Acromegaly; abdominopelvic radiotherapy; ureterosigmoidostomy

Protective

Aspirin (and reduces CRC incidence in Lynch syndrome - CAPP2)
Physical activity, fibre, calcium
5-ASA and thiopurines in IBD

FAP

Hundreds to thousands of colonic adenomas (predominantly tubular), appearing from the late second decade
First symptoms: diarrhoea and rectal bleeding; malignant transformation possible from late childhood
Weight loss and weakness signal established cancer
100% lifetime CRC risk untreated

Lynch

Deficient MMR -> microsatellite instability - variable length of repetitive DNA microsatellites
MSH2 carries the highest extra-colonic cancer risk: endometrial first, then small bowel, ureter/renal pelvis, gastric, hepatobiliary, ovarian
Accelerated adenoma-carcinoma sequence (2-3 years, not 10) - why the surveillance interval is 1-2 years

Diagnosis

Presentation

Right colon - iron deficiency anaemia, weight loss, occult bleeding, a mass (obstruction late - wide lumen, liquid stool)
Left colon - change in bowel habit, obstruction, PR bleeding
Rectum - tenesmus, urgency, fresh PR bleeding, mucus
Emergency: obstruction, perforation, bleeding
*Iron deficiency anaemia in any man, or any postmenopausal woman, is colorectal cancer until proven otherwise*

Lynch-associated CRC - the phenotype

Proximal colon, younger (45-60 vs 69)
Often poorly differentiated, mucinous or signet-ring, medullary growth pattern, tumour-infiltrating lymphocytes
High rate of synchronous and metachronous tumours

Workup for Lynch

1. Tumour tissue: MMR protein immunohistochemistry, or MSI by PCR - do this on every new colorectal cancer

MSI-high = deficient MMR; MSI-low/stable = proficient
Loss of MLH1 -> test BRAF V600E and MLH1 promoter methylation first (positive suggests sporadic, not Lynch)

2. Positive -> germline testing; a confirmed MMR gene mutation = Lynch syndrome

Amsterdam II criteria

>=3 relatives with a histologically verified Lynch-spectrum cancer, one a first-degree relative of the other two
>=2 successive generations
>=1 diagnosed before age 50
(FAP excluded)
Clinical criteria under-detect - universal tumour testing has largely replaced them

Staging

Colonoscopy + biopsy (complete the colon - synchronous lesions in ~5%)
CT chest/abdomen/pelvis
MRI rectum for rectal cancer - T stage, circumferential resection margin, extramural vascular invasion, nodes
CEA baseline (prognostic and for follow-up; not diagnostic)
RAS, BRAF, MMR/MSI, HER2 on metastatic disease
TNM staging; nodal status is the key prognostic variable (>=12 nodes must be examined)

Management

By stage

Localised colon cancer

Segmental resection with en-bloc lymphadenectomy
Stage III -> adjuvant chemotherapy (oxaliplatin-based: FOLFOX/CAPOX; 3 months of CAPOX adequate for low-risk stage III - IDEA)
Stage II -> adjuvant only if high-risk features: T4, perforation, obstruction, <12 nodes examined, poorly differentiated, lymphovascular/perineural invasion
- *dMMR/MSI-high stage II has good prognosis and does not benefit from 5-FU monotherapy - do not give it*
Endoscopic resection for pT1 with favourable histology
Circulating tumour DNA increasingly used to guide adjuvant decisions

Rectal cancer

MRI-defined risk drives neoadjuvant treatment
Total neoadjuvant therapy (TNT) - chemoradiotherapy plus systemic chemotherapy before surgery; improves distant control and rates of organ preservation
Total mesorectal excision
Watch-and-wait for a complete clinical response after chemoradiotherapy - avoids a permanent stoma in selected patients
dMMR/MSI-high locally advanced rectal cancer -> neoadjuvant immunotherapy (dostarlimab) - very high complete response rates, organ preservation

Metastatic

Resect liver or lung oligometastases - potentially curative, ~40% 5-year survival
Systemic: FOLFOX/FOLFIRI +/-
- RAS wild-type, left-sided -> anti-EGFR (cetuximab, panitumumab)
- Anti-EGFR is ineffective and harmful in RAS-mutant disease, and less effective in right-sided tumours
- Bevacizumab (anti-VEGF)
- BRAF V600E -> encorafenib + cetuximab
- dMMR/MSI-high -> checkpoint inhibitor (pembrolizumab) first line
- HER2-amplified -> HER2-directed therapy
Palliative stenting or defunctioning stoma for obstruction

Hereditary syndromes

FAP - prophylactic colectomy (proctocolectomy + IPAA, or colectomy + IRA) in late teens/early twenties
- Upper GI surveillance for duodenal/ampullary adenomas (Spigelman stage), thyroid ultrasound
Lynch - colonoscopy every 1-2 years from age 25 (or 5 years before the youngest family diagnosis)
- Aspirin reduces CRC incidence (CAPP2)
- Consider risk-reducing hysterectomy + BSO after childbearing; gastroscopy; urinalysis
- Extended (subtotal) colectomy at cancer diagnosis given metachronous risk
Genetic counselling and cascade testing of relatives in every confirmed syndrome

Associations

IBD - especially with PSC
Streptococcus gallolyticus (bovis) bacteraemia or endocarditis -> colonoscopy
**Clostridium septicum infection**
Acromegaly
Ureterosigmoidostomy
Turcot syndrome - CNS malignancy (usually glioma) with FAP
Gardner syndrome - FAP + osteomas + epidermoid cysts + desmoids
FAP extracolonic features: congenital hypertrophy of the retinal pigment epithelium (CHRPE), supernumerary teeth, gastric fundic gland polyps (~50%, low malignant potential) and duodenal polyps, desmoid tumours (~10%, often triggered by abdominal surgery), papillary thyroid carcinoma, rare CNS tumours
Peutz-Jeghers - mucocutaneous pigmentation; GI, breast, pancreatic, gonadal tumours
MASLD, type 2 diabetes, obesity

Natural history & complications

5-year survival by stage

Stage	Survival
I	>90%
II	~70-85%
III	~50-70%
IV	~15%; ~40% if oligometastatic disease is resected

Adenoma -> carcinoma over ~10 years sporadically; 2-3 years in Lynch
Liver is the commonest metastatic site (portal drainage); rectal cancer can also metastasise to lung via systemic venous drainage
dMMR/MSI-high: better prognosis stage-for-stage in early disease, worse in stage IV - but exquisitely immunotherapy-sensitive

Poor prognostic markers

Nodal involvement, T4, perforation or obstruction at presentation
Lymphovascular and perineural invasion, poor differentiation
BRAF V600E; raised preoperative CEA; positive circumferential resection margin in rectal cancer
Fewer than 12 nodes examined (under-staging)

Surveillance after curative resection

Colonoscopy at 1 year, then by findings (3 then 5 yearly)
CEA 3-monthly for 3 years, then 6-monthly to 5 years
CT chest/abdomen/pelvis annually for 3 years
Post-polypectomy: 5 years if <3 simple polyps (<10 mm, no high-grade dysplasia or villous change); 3 years if >=3 polyps or any advanced polyp

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