Colorectal Cancer

 

Definition of colorectal cancer

• A malignant neoplasm arising from epithelium anywhere in the large bowel (caecum, ascending, transverse, descending or sigmoid colon, rectum), excluding the appendix and the anus
• The vast majority are adenocarcinoma
  • Squamous and adenosquamous carcinoma can occur in the distal rectum

 

Epidemiology of colorectal cancer

• In the UK, colorectal cancer is the 3rd most common cancer at 12% of all cancers, after breast and prostate
• Worldwide incidence (age-standardised) is 17 per 100,000, but varies markedly with geography:
  • 4 per 100,000 in Western Africa to 38 per 100,000 in Australia/New Zealand
• Generally more common in more economically developed countries
• 59% of cases occur in men
• The median age at diagnosis is approximately 70 in the UK

 

Risk factors for colorectal cancer

• Demographic risk factors
  • Age (colorectal cancer is uncommon below the age of 40)
  • Male sex
  • Ethnicity (in the US, black people have a higher risk but this may be due to confounding variables)
• Family history of colorectal cancer
• Previous history
  • Previous colorectal cancer
  • Previous polyps over 1cm, exhibiting high grade dysplasia or with villous/tubulovillous histology
• Comorbidities
  • Ulcerative colitis and Crohn’s colitis (risk increases with extent and duration of colitis)
  • Abdominal radiation
  • Immunosuppression (e.g. in renal transplant recipients)
  • Diabetes mellitus
• Modifiable risk factors
  • Smoking
  • Obesity
  • Processed meat (and possibly also red meat)
  • Alcohol
• Genetic disorders
  • Hereditary non-polyposis colorectal cancer (HNPCC)
    • Autosomal dominant, due to mutations in various mismatch repair genes
    • Responsible for 3% of colorectal cancers
    • It also increases the risk of endometrial cancer, other GI tract cancers and ovarian cancer
  • Familial adenomatous polyposis (FAP)
    • Autosomal dominant defect in APC gene
    • Causes numerous colonic polyps in childhood and colorectal cancer by the age of 45 in 90% of patients
  • MUTYH-associated polyposis
    • Autosomal recessive condition which may cause polyposis and confers increased colorectal cancer risk

 

Protective factors for colorectal cancer

• Vegetarian and high fibre diet
• Daily aspirin use
• Difluoromethylornithine (DFMO) plus sulindac (an NSAID) reduce recurrence in those with prior adenomata

 

Presentations of colorectal cancer

• Variable, depending heavily on site of tumour
• Symptoms from primary tumour
  • Iron-deficiency anaemia (commonly caecal, ascending colon)
  • Altered bowel habit (anywhere) to more loose stool with or without mucous
  • Abdominal pain (from partial obstruction, or perforation causing acute peritonitis, or a localised abscess)
  • Bowel obstruction (pain, bowels not open, abdomen distension, vomiting)
  • Fresh blood per rectum (descending, sigmoid, rectum)
  • Tenesmus (sensation of incomplete defecation; rectum)
  • Rarely, Streptococcus bovis and Clostridium septicum infections are the first manifestation of a colorectal cancer, and may present as infective endocarditis.
• Symptoms from metastatic spread (20% have metastatic disease at presentation)
  • Jaundice, RUQ pain, early satiety, from hepatic metastases
  • Ascites or pain, from peritoneal metastases
  • Pneumaturia or recurrent UTI, due to a colovesical fistula
  • Weight loss
• Incidental diagnosis
  • Clinical findings (abdominal or rectal mass)
  • Incidental imaging of large bowel or liver
• In a screening programme
  • Positive faecal occult blood test / colonoscopy
• Screening for colorectal cancer
  • Frequent screening with colonoscopy should be undertaken in those with a known hereditary syndrome (FAP, HNPCC, MUTYH-associated polyposis)
  • Screening strategies for average-risk populations include colonoscopy, CT colongraphy, and faecal occult blood (FOB) testing
  • National guidelines vary; in the UK an FOB test is done every 2 years between the ages of 50 and 74, and a single flexible sigmoidoscopy is performed at age 55.
  • In the event of a positive FOB test a colonoscopy is undertaken.

 

Differential diagnosis for a colorectal mass

• Other rare colonic cancers: lymphoma, carcinoid tumours, Kaposi’s sarcoma, invasive prostatecancer
• Benign polyps
• Pseudopolyps in colitis
• Endometriosis
• Lipoma
• Tuberculosis

 

Video on colon cancer, focusing on pathophysiology

Investigation of colorectal cancer

• Blood tests
  • FBC, U&E, LFT, Calcium
  • Clotting, group and save
• Colonoscopy is the best first line test, to identify cancers and co-incident second cancers (synchronous lesions), and obtain tissue for histology: brushings, biopsy or resection
  • Note that flexible sigmoidoscopy is inadequate, even with distal tumours, due to the risk of synchronous lesions
  • CT colonography may be used in those unlikely to tolerate colonoscopy
  • Barium enema should not be used unless the above are not available
• If cancer is confirmed, further imaging for staging should be undertaken
  • CT abdomen-pelvis to assess local invasion of the primary, lymphadenopathy, and hepatic metastases
  • CT chest is usually undertaken, though only 10% of nodules seen are colorectal metastases

 

Staging of colorectal cancer

• Tumour node metastasis (TNM) last revised in 2010. Briefly:
  • T1 invades through the submucosa, and T4 invades through visceral peritoneum
  • N0-N2 depends on number of regional lymph nodes
  • M0-M1 depends on distant metastases
  • The TNM status is combined to give a stage from I to IV, where III is defined by nodal disease, and IV by metastatic disease
• Dukes staging (A-C, based on invasion of primary and node status) is no longer used

 

Histology and genetics of colorectal cancer

• Histological grade is divided into low or high, based on gland formation in the tissue
• Mucinous, signet ring and medullary adenocarcinomas carry a worse prognosis
• High microsatellite instability, due to mutated mismatch repair genes, occurs in 15-20% of cancers and is associated with a better prognosis, if the cancer is localised
• Mutations in RAS or NRAS confer resistance to anti-EGFR therapy

 

Initial surgical management of localised colorectal cancer

• For dysplastic polyps and carcinoma in situ, colonoscopic excision is curative if the margins are clear
• For stage I-III adenocarcinoma, surgical excision is the mainstay of treatment, provided the patient is fit enough for surgery (considering comorbidities and performance status)
• The approach may be determined by urgent complications such as perforation or obstruction; in these instances it may be necessary to create a proximal defunctioning stoma, or an end stoma with an anastamosis formed at a later date
• Elective treatment should be with a right or left hemicolectomy, or sigmoid colectomy, as determined by the site of the primary
• Complete mesocolic excision should be performed, to include the mesentery and regional lymph nodes from the primary site
• In experienced hands, a laparoscopic approach is preferred to an open operation, but with a low threshold for conversion to open in the case of complications
• Patients with FAP, HNPCC or synchronous cancers in the left and right should be managed with a total colectomy
• Locally invasive primary cancer should be resected en bloc to achieve clear margins. If this is not possible neoadjuvant (preoperative) chemotherapy can be considered

 

Adjuvant treatment for localised colorectal cancer

• 6 months of adjuvant oxaliplatin-based chemotherapy should be given in stage III (node positive) disease
  • e.g. oxaliplatin plus 5-FU, or oxaliplatin plus capecitabine
• Rectal cancer should be treated with neoadjuvant chemoradiotherapy if locally invasive or node positive
• All other rectal cancer of stage II or higher should be treated with chemoradiotherapy post-operatively

 

Management of metastatic colorectal cancer

• Limited metastases in liver or lung may be amenable to resection, which may bring long-term cure
• First line chemotherapy for patients unsuitable for curative treatment should be either:
  • FOLFOX (5-FU/leucovorin/oxaliplatin)
  • XELOX (capecitabline/oxaliplatin)
  • FOLFIRI (5-FU/leucovorin/irinotecan)
• Bevacizumab (monoclonal antibody against VEGF) may be added, though it has a poor cost-benefit profile
• Monoclonal antibodies against EGFR (cetuximab; panitumumab) can be added in those with wild-type KRAS

 

Complications of colorectal cancer

• Metastasis
• Obstruction
• Iron deficiency anaemia
• Bleeding
• Colovesical fistula

 

Prognosis of colorectal cancer

• Mortality overall is 50% worldwide
• Over 90% of stage I patients are alive, whereas only 8% of stage IV are, at 5 years after diagnosis.
• The major determinant of prognosis is TNM staging
• Other poor prognosticators include:
  • Perivascular or perineural invasion
  • High carcinoembryonic antigen (CEA) levels
  • Intestinal obstruction at presentation
  • Macroscopic perforation at presentation

 

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Colorectal Cancer

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