Colorectal Cancer

 

• Background

  Pathophysiology

  • 95% are adenocarcinomas, the rest lymphoma or squamous cell.
  • Often the result of a mutation in the WNT/β-catenin pathway. Includes sporadic mutations of APC which reduce its inhibition of β-catenin, an activator of protein synthesis.
  • Usually develop from adenomatous polyps.
  • Commonest sites are rectum (25%), sigmoid (25%), and caecum (15%).

  Staging

  • TNM. T refers to depth, not size.
  • Dukes': A confined to mucosa; B through muscle; C lymph nodes; D distant mets.

  Epidemiology

  4th commonest cancer in UK, after breast, prostate, and lung: 1/15 (men) or 1/20 (women) lifetime risk.

• Signs and symptoms

  • PR bleeding, anaemia.
  • Mass felt PR or abdominally.
  • Distal cancer: blood and mucous PR, altered bowel habits (especially diarrhoea), tenesmus. More likely than proximal cancer to present with obstruction as the stool is more solid here and thus the flow more easily blocked.
  • Proximal cancer (up to splenic flexure): weight loss, anaemia, right iliac fossa pain.

• Risk factors

  DIAPERS MD:

  • Diet: ↓fibre, ↑cured meat.
  • IBD
  • ↑Age: mean onset at 65.
  • Polyps (adenomatous).
  • Ethanol
  • Relatives (family history).
  • Smoking
  • Male sex.
  • Diabetes and obesity.

  Genetic syndromes:

  • GI-specific: hereditary non-polyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome, hereditary flat adenoma syndrome.
  • Other syndromes: BRCA, Turcot's (mismatch repair cancer syndrome), Cowden's (PTEN mutation).

  Associated cancers which are risk factors for CRC:

  • Small bowel.
  • Endometrial
  • Breast
  • Ovarian

• Screening and prevention

  UK screening programme:

  • Fecal immunochemical test (FIT) and follow on flexible sigmoidoscopy offered to everyone age 60-74.
  • Requires 3 stool samples, before they touch the water, within 2 weeks.
  • Results by post in 2 weeks.
  • Repeated every 2 years. After 74, patients can request the test.

  Prevention in high risk individuals (e.g. HNPCC):

  • Lifelong daily aspirin.

• Urgent referral criteria

  Refer to secondary care for investigation of possible colorectal cancer for any of:

  • If under age 55, PR bleed and persistent (>6 weeks) change in bowel habit towards diarrhoea (loose or frequent stools). If over age 55, either is sufficient (provided PR bleed doesn't have other anal symptoms).
  • Palpable right abdo mass.
  • Unexplained iron-deficiency anaemia in men or post-menopausal women.

• Investigations

  Bloods:

  • Basics: FBC (microcytic anaemia), U&E (baseline), LFT (liver mets).
  • Carcinoembryonic antigen (CEA) is only 60% sensitive, so not useful for diagnosis, but should be ordered as a baseline to compare in follow up.

  GI investigation:

  • Faecal occult blood (FOB), used for screening.
  • Endoscopy is usually diagnostic: flexible sigmoid if only fresh red blood, otherwise colonoscopy.

  Imaging:

  • Staging: contrast CT chest-abdo pelvis. Other options are MRI and liver US.
  • CT can also be used for non-invasive virtual endoscopy (CT colography), but its use is limited as it doesn't allow biopsy.
  • Double-contrast (air and contrast) barium enema: may show apple core lesion.

• Management

  General approach:

  • Surgical resection ± chemo and radiotherapy.
  • Even in metastatic disease, surgery can still be considered, depending on the extent.
  • MDT, especially post op: dietician, stoma nurse, physio.

  Surgery

  Ascending, transverse, and descending colonic tumours:

  • Right hemicolectomy, with ileocolic anastomosis, for ascending colon tumours. The right colic artery and superior mesenteric nodes are also removed.
  • Extended right hemicolectomy, going beyond the midtransverse colon, for transverse colon tumours.
  • Left hemicolectomy, with anastomosis of transverse and sigmoid colon, for descending colon tumours or high sigmoid tumours. Inferior mesenteric and left colic arteries, and inferior mesenteric nodes, are also removed.
  • In an acute obstruction, resection or stenting.

  Sigmoid and rectal tumours:

  • Anterior resection for low sigmoid and upper rectal tumours. Can be high anterior resection – for the segment covered by peritoneum – or low anterior resection. Anastomosis of colon and remaining rectal stump, with defunctioning loop ileostomy while it heals. Inferior mesenteric and left colic arteries also removed.
  • Sigmoid colectomy is a more limited procedure for sigmoid tumours in frailer patients.
  • Abdominoperineal (AP) resection if tumour <6 cm from anal margin. Surgical access via laparotomy and perineal opening. Removes rectum and anus – with opening sewn shut – and leaves permanent end colostomy. Less extensive techniques such as transanal resection or total mesorectal excision are preferred for early stage tumours.
  • Hartmann's procedure: emergency resection of obstructed or perforated rectosigmoid. Also used in IBD and diverticular disease. Followed by temporary end colostomy, and an oversewn rectal stump from which secretions can still pass through anus. Primary anastomosis is not possible due to inflammation and faecal contamination, but can be anastomosed later if desired.
  • Loop colostomy with follow up resection is an alternative for acute obstruction.

  Limited lung or liver mets:

  • Consider surgical metastasectomy.

  Good anastomosis requires:

  • Good blood supply.
  • Mucosal apposition.
  • Low tension.

  Many of these procedures can be done laparoscopically:

  • Pros: shorter ileus, ↓pain, ↓length of stay and earlier return to work.
  • Cons: longer, technically harder, more expensive, risk of off camera injury.
  • 20% convert to open, but this isn't a 'failure'.

  Less invasive approaches:

  • Colonic stents for obstructing tumours: emergency bridge to definitive surgery, and a colostomy-free alternative to Hartmann's. Risk of perforation, so initially need regular obs and CXR.

  Chemotherapy

  • Neoadjuvant: downstaging of T3-4 rectal (along with radiotherapy).
  • Adjuvant if there is high recurrence risk: T3-4 or poorly-differentiated tumor, lymph node (Dukes' C) or vascular invasion. Folinic acid, fluorouracil and oxaliplatin (FOLFOX) is a commonly regimen.
  • Metastatic: FOLFOX.

  Radiotherapy

  • Neoadjuvant and adjuvant radiotherapy added to chemotherapy for T3-4 rectal tumours.
  • Causes too much damage if used elsewhere.

  Follow up

  • 2 x CT chest-abdo-pelvis in first 3 years.
  • CEA every 6 months in first 3 years.
  • Colonoscopy at 1 year, and repeat at 5 if normal.

• Complications and prognosis

  • Perforation, fistula.
  • Mets: commonly liver and lung.
  • 5 year survival by Dukes' grade: A (90%), B (70%), C (50%), D (10%). 50% overall.

• Colon polyps

  Epidemiology

  • 30% of people have 1-2 colon polyps by age 70.
  • 0.1% have >2 and are at increased risk of colon cancer.

  Types

  90% are hyperplastic polyps:

  • Usually in the rectosigmoid.
  • Confer very little cancer risk.

  10% are adenomatous polyps (aka adenomas):

  • 10% risk of malignant transformation.
  • Classically, 3 histological sub-types: tubular (commoner, usually pedunculated), villous (usually rectal and sessile i.e. flat), and tubulovillous. Villous generally larger and thus have the greatest malignant potential.
  • Sessile serrated polyps are a recently recognised group of adenomas, mainly right colon, with similar appearance to hyperplastic polyps but with malignant potential.

  Presentation

  Often asymptomatic, and detected incidentally or through screening colonoscopy.

  Symptomatic disease includes:

  • PR bleeding
  • PR mucus
  • Tenesmus
  • Intussusception

  Management

  • Polypectomy via colonoscopy, for histological diagnosis, symptom relief, and/or cancer prevention.
  • For adenomatous or multiple polyps, repeat surveillance colonoscopy will be needed.

• Hereditary non-polyposis colorectal cancer (HNPCC)

  Aka Lynch syndrome. Causes 1-2% of all colorectal cancer (CRC).

  Pathophysiology

  • Autosomal dominant loss of mismatch repair gene (MMR) – e.g. MSH2, MLH1, MSH6 – leading to improperly matched DNA base pairs (i.e. not A-T, C-G).
  • Leads to microsatellite instability (MSI) i.e. repeats of mono/dinucleotides.
  • Microsatellite instability is seen in 15% of all CRC, so is more often sporadic than due to HNPCC.

  Clinical features

  • 80% develop CRC, mean age 44, with ⅔ in proximal colon.
  • Less likely to metastasize than most CRC.
  • Other cancers in those with HNPCC: endometrium (80% of female carriers), gastric, small bowel, ovary, pancreas, brain, hepatobiliary tract, urinary tract.

  Screening and diagnosis

  All CRC patients should be screened for Lynch syndrome by histology of their tumours:

  • Check for MSI with PCR, and/or for MMR proteins with immunohistochemical staining.
  • Refer for genetic testing if either is +ve.

  For asymptomatic individuals, all of the Amsterdam criteria must be satisfied for genetic referral:

  • ≥3 relatives on same side of family with HNPCC-related cancer, across ≥2 generations.
  • ≥1 cancer must occur <50 years old.
  • Familial adenomatous polyposis excluded.
  • Tumours in relatives must have been pathologically verified as having changes consistent with HNPCC.

  Management

  • Colonoscopy every 1-2 years from age 20-25.
  • Prophylactic hysterectomy post-childbirth.
  • Lifelong daily aspirin.

• Familial adenomatous polyposis (FAP)

  Pathophysiology

  • Autosomal dominant APC mutation.
  • 95% penetrance.
  • There is also an autosomal recessive MUTYH gene version.

  Signs and symptoms

  • >100 colonic polyps, or 'attenuated FAP' with 3-99 polyps.
  • Inevitably leads to cancer, mean onset 39 years.

  Management

  • Genetic testing for all 1st degree relatives aged >10.
  • Annual sigmoidoscopy if genetic test +ve.
  • Prophylactic resection with ileal-anal anastomosis recommended if many polyps found. Offer from age 16 onwards.

• Peutz-Jeghers syndrome (PJS)

  Pathophysiology

  • Autosomal dominant mutation in STK11, a tumour suppressor gene.

  Presentation

  • Freckles around and inside mouth.
  • Hamartomatous GI polyps: benign but disorganised mass of local tissue.
  • >90% risk of developing cancer: CRC (40%), gastric (30%), pancreatic (40%), small bowel, breast (50%), gonadal, uterine, lung.
  • Non-cancer complications include bowel obstruction and intussusception.

  Management

  • Upper and lower GI endoscopy.
  • Large polyp removal.
  • Breast, gynae, and pancreatic surveillance.