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Surveillance for a Family History of Colorectal Cancer
 

Surveillance for a Family History of Colorectal Cancer

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    Surveillance for a Family History of Colorectal Cancer Surveillance for a Family History of Colorectal Cancer Presentation Transcript

    • SURVEILLANCE FOR A FAMILY HISTORY OF COLORECTAL CANCER Andrew Luck Northern Adelaide Colorectal Network Lyell McEwin Hospital South Australia
    • NATURE OR NURTURE?
      • Early studies (cancer mortality) showed CRC in any first degree relative increased risk 3-4 fold
          • Woolf Am J Hum Genet 1958
          • Lovett Br J Surg 1976
        • ? Genetic predisposition
        • ? Shared environment
          • Diet
          • Exercise
          • External factors
    • NATURE OR NURTURE?
      • Later studies (cancer incidence with matched control groups and accurate collection of family history data)
        • Australia RR 1.8 St John et al Ann Intern Med 1993
        • Denmark RR Men 1.9 Women 1.6 Sondergaard et al Int J Cancer 1991
        • USA RR 1.7 Fuchs et al N Engl J Med 1994
      • Differences at least in part explained by non genetic factors
    • AVERAGE RISK If aged Risk over 5 years Risk over 10 years Risk over 15 years Risk over 20 years 30 1 in 7000 1 in 2000 1 in 700 1 in 350 40 1 in 1200 1 in 400 1 in 200 1 in 90 50 1 in 300 1 in 100 1 in 50 1 in30 60 1 in 100 1 in 50 1 in 30 1 in 20 70 1 in 65 1 in 30 1 in 20 1 in 15 80 1 in 50 1 in 25
    • CATEGORY 1
      • Those at or slightly above average risk
        • No personal history of bowel cancer, advanced adenoma or chronic ulcerative or Crohn’s colitis
        • Either no close relatives with bowel cancer or one first or second degreee relative with CRC diagnosed at age 55 or older
    • CATEGORY 1
      • Screening recommendations
        • Confirm asymptomatic
        • Faecal occult blood testing every second year from the age of 50 years
    • MODERATELY INCREASED RISK
      • First degree relative with CRC diagnosed at an early age (below 55)
      • Two first degree relatives (or one first and one second degree relative that are related to each other)
      • RR 3-6
      • Category 2
    • AVERAGE RISK If aged Risk over 5 years Risk over 10 years Risk over 15 years Risk over 20 years 30 1 in 7000 1 in 2000 1 in 700 1 in 350 40 1 in 1200 1 in 400 1 in 200 1 in 90 50 1 in 300 1 in 100 1 in 50 1 in30 60 1 in 100 1 in 50 1 in 30 1 in 20 70 1 in 65 1 in 30 1 in 20 1 in 15 80 1 in 50 1 in 25
    • CATEGORY 2
      • Screening recommendations
        • Complete family history
        • Confirm asymptomatic
        • Colonoscopy every 5 years, starting at age 50 or at an age 10 years younger than the age of first diagnosis of CRC in the family, whichever comes first
    • FH ADENOMA
      • Some studies have shown FH sporadic colorectal adenoma can be a marker for CRC risk
        • Esp if detected at a young age
        • Esp if advanced features
          • >1cm
          • High grade dysplasia
          • Villous change
      • Insufficient data to advise relatives
    • CATEGORY 3
      • Those at potentially high risk (RR 15)
        • Three or more first degree relatives (or a combination of first and second degree relatives from the same side of the family (?HNPCC)
        • Two or more relatives as above with high risk features (?HNPCC)
          • Multiple bowel cancers in the same person
          • CRC before age 50
          • A relative with cancer of the endometrium, ovary, stomach, small bowel, renal pelvis, ureter, biliary tract or brain
    • CATEGORY 3
      • Those at potentially high risk
        • At least one first degree relative with a large number or colorectal adenomas (suspected FAP)
        • A relative in whom the presence of a high risk mutation in the APC gene (FAP) or one of the mismatch repair genes (HNPCC) has been identified
    • CATEGORY 3
      • Screening recommendations
        • Complex
        • Individualised
        • ? Genetic testing
        • Extraintestinal tumours
          • FAP - Periampullary carcinoma, intra-abdominal fibromatosis (desmoids), papillary cancer of thyroid
          • HNPCC – tumours of endometrium, ovary, stomach, small bowel, renal pelvis, ureter, biliary tract and brain
    • FAMILIAL ADENOMATOUS POLYPOSIS (FAP)
      • Autosomal dominant
      • APC gene (Chromosome 5)
      • Phenotype influenced by the site of the mutation
        • Attenuated FAP
          • Less than 100 polyps, often only in proximal colon
    • FAMILIAL ADENOMATOUS POLYPOSIS (FAP)
      • Screening recommendations
        • If no mutation identified
          • Flexible sigmoidoscopy annually from age 12-15 to age 35 or until polyps develop
          • Dye spray chromo-endoscopy or narrow band imaging
          • Attenuated FAP families need colonoscopic surveillance
        • If mutation identified
          • Offer genetic testing to distinguish mutation positive and mutation negative family members
    • FAMILIAL ADENOMATOUS POLYPOSIS (FAP)
      • If mutation negative
        • Same risk as Category 1
      • If mutation positive or diagnosis confirmed
        • Total colectomy/ileorectal anastomosis or proctocolectomy in late teenage years
          • Annual flexible sigmoidoscopy if TC/IRA
        • Duodenoscopy from age 25
    • HEREDITARY NON-POLYPOSIS COLORECTAL CANCER (hnpcc)
      • Autosomal dominant
        • Germline mutation in one of the mismatch repair genes, usually MLH1, MSH2, MSH6 or PMS2
      • Early age of onset
      • Proximal colonic malignancy
      • Multiple colorectal cancers
      • Extracolonic malignancy
    • HNPCC
      • Amsterdam criteria 1991
      • Amsterdam II criteria1999
      • Bethesda guidelines 2001
      • Revised Bethesda guidelines 2004
          • Allows selection of patients for MSI assessment (or immunohistochemistry) to determine who should be tested for germline mutation
    • BETHESDA GUIDELINES
      • Colorectal cancer diagnosed in a patient who is less than 50 years of age
      • Presence of synchronous CRC, metachronous CRC or other HNPCC associated cancers
      • CRC with MSI-H type histology in a patient under 60 years of age
          • Tumour infiltrating leucoctes
          • Crohn’s like lymphocytic reaction
          • Mucinous/signet ring differentiation
          • Medullary growth pattern
      • CRC in a patient under 60 with at least one first degree relative with an HNPCC associated cancer
      • CRC in a patient of any age with 2 or more first or second degree relatives with HNPCC associated cancers
    • MICROSATELLITE INSTABILITY
      • Microsatellites are tandem repeats of short (1-5 bases) sequences of DNA.
      • If errors are made during mitosis there is a change in the size of the microsatellite in the daughter cells – so called microsatellite instability (MSI)
      • This should be corrected by mismatch repair genes, but if these are defective, as in HNPCC, MSI-H (high) status remains.
      • MSI-H is thus a marker of HNPCC
    • MSI-H
      • Almost all HNPCC cancers are MSI-H
      • 70% of adenomas in HNPCC are MSI-H
      • 10-15% of sporadic cancers are MSI-H
        • Must consider MSI-H status in the context of the family history and the age of the patients before diagnosing HNPCC
        • Patients who fit Bethesda criteria and have MSI-H tumours should be considered for genetic testing for germ line mutation in MLH1, MSH2, MSH6 and PMS2
    • HNPCC
      • Screening recommendations
        • Proven germline mutation or HNPCC tumours that fit Bethesda/Amsterdam
          • Colonoscopy (and gastroscopy) annually (or at least 2 yearly) beginning at age 25 or 5 years younger than the age of diagnosis of the youngest member of the family
          • Annual transvaginal ultrasound from age 30
          • Annual urinary cytology and renal ultrasound
    • HNPCC
      • Screening recommendations
        • First degree relatives with unknown mutation status
          • As above
          • 2 yearly rather than annual
        • Relatives negative for known germ line mutation
          • Category 1 recommendations
    • SUMMARY
      • Category 1
        • At or just above average risk
          • No FH or single first degree relative with CRC over 55
      • FOBT ever 2 years from age of 50
    • SUMMARY
      • Category 2
        • Moderately increased risk
          • One first degree relative CRC under age 55
          • Two first or second degree relatives on same side of family with CRC
        • 5 yearly colonoscopy from age 50 or 10 years younger than the age of diagnosis of the youngest family member
    • SUMMARY
      • Category 3
      • At potentially high risk
        • Features of FAP or HNPCC
        • Complex
        • Individualised
        • Genetic testing
        • Extensive - often annual testing