Surveillance for a Family History of Colorectal Cancer

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Surveillance for a Family History of Colorectal Cancer

  1. 1. SURVEILLANCE FOR A FAMILY HISTORY OF COLORECTAL CANCER Andrew Luck Northern Adelaide Colorectal Network Lyell McEwin Hospital South Australia
  2. 2. NATURE OR NURTURE? <ul><li>Early studies (cancer mortality) showed CRC in any first degree relative increased risk 3-4 fold </li></ul><ul><ul><ul><li>Woolf Am J Hum Genet 1958 </li></ul></ul></ul><ul><ul><ul><li>Lovett Br J Surg 1976 </li></ul></ul></ul><ul><ul><li>? Genetic predisposition </li></ul></ul><ul><ul><li>? Shared environment </li></ul></ul><ul><ul><ul><li>Diet </li></ul></ul></ul><ul><ul><ul><li>Exercise </li></ul></ul></ul><ul><ul><ul><li>External factors </li></ul></ul></ul>
  3. 3. NATURE OR NURTURE? <ul><li>Later studies (cancer incidence with matched control groups and accurate collection of family history data) </li></ul><ul><ul><li>Australia RR 1.8 St John et al Ann Intern Med 1993 </li></ul></ul><ul><ul><li>Denmark RR Men 1.9 Women 1.6 Sondergaard et al Int J Cancer 1991 </li></ul></ul><ul><ul><li>USA RR 1.7 Fuchs et al N Engl J Med 1994 </li></ul></ul><ul><li>Differences at least in part explained by non genetic factors </li></ul>
  4. 4. 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
  5. 5. CATEGORY 1 <ul><li>Those at or slightly above average risk </li></ul><ul><ul><li>No personal history of bowel cancer, advanced adenoma or chronic ulcerative or Crohn’s colitis </li></ul></ul><ul><ul><li>Either no close relatives with bowel cancer or one first or second degreee relative with CRC diagnosed at age 55 or older </li></ul></ul>
  6. 6. CATEGORY 1 <ul><li>Screening recommendations </li></ul><ul><ul><li>Confirm asymptomatic </li></ul></ul><ul><ul><li>Faecal occult blood testing every second year from the age of 50 years </li></ul></ul>
  7. 7. MODERATELY INCREASED RISK <ul><li>First degree relative with CRC diagnosed at an early age (below 55) </li></ul><ul><li>Two first degree relatives (or one first and one second degree relative that are related to each other) </li></ul><ul><li>RR 3-6 </li></ul><ul><li>Category 2 </li></ul>
  8. 8. 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
  9. 9. CATEGORY 2 <ul><li>Screening recommendations </li></ul><ul><ul><li>Complete family history </li></ul></ul><ul><ul><li>Confirm asymptomatic </li></ul></ul><ul><ul><li>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 </li></ul></ul>
  10. 10. FH ADENOMA <ul><li>Some studies have shown FH sporadic colorectal adenoma can be a marker for CRC risk </li></ul><ul><ul><li>Esp if detected at a young age </li></ul></ul><ul><ul><li>Esp if advanced features </li></ul></ul><ul><ul><ul><li>>1cm </li></ul></ul></ul><ul><ul><ul><li>High grade dysplasia </li></ul></ul></ul><ul><ul><ul><li>Villous change </li></ul></ul></ul><ul><li>Insufficient data to advise relatives </li></ul>
  11. 11. CATEGORY 3 <ul><li>Those at potentially high risk (RR 15) </li></ul><ul><ul><li>Three or more first degree relatives (or a combination of first and second degree relatives from the same side of the family (?HNPCC) </li></ul></ul><ul><ul><li>Two or more relatives as above with high risk features (?HNPCC) </li></ul></ul><ul><ul><ul><li>Multiple bowel cancers in the same person </li></ul></ul></ul><ul><ul><ul><li>CRC before age 50 </li></ul></ul></ul><ul><ul><ul><li>A relative with cancer of the endometrium, ovary, stomach, small bowel, renal pelvis, ureter, biliary tract or brain </li></ul></ul></ul>
  12. 12. CATEGORY 3 <ul><li>Those at potentially high risk </li></ul><ul><ul><li>At least one first degree relative with a large number or colorectal adenomas (suspected FAP) </li></ul></ul><ul><ul><li>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 </li></ul></ul>
  13. 13. CATEGORY 3 <ul><li>Screening recommendations </li></ul><ul><ul><li>Complex </li></ul></ul><ul><ul><li>Individualised </li></ul></ul><ul><ul><li>? Genetic testing </li></ul></ul><ul><ul><li>Extraintestinal tumours </li></ul></ul><ul><ul><ul><li>FAP - Periampullary carcinoma, intra-abdominal fibromatosis (desmoids), papillary cancer of thyroid </li></ul></ul></ul><ul><ul><ul><li>HNPCC – tumours of endometrium, ovary, stomach, small bowel, renal pelvis, ureter, biliary tract and brain </li></ul></ul></ul>
  14. 14. FAMILIAL ADENOMATOUS POLYPOSIS (FAP) <ul><li>Autosomal dominant </li></ul><ul><li>APC gene (Chromosome 5) </li></ul><ul><li>Phenotype influenced by the site of the mutation </li></ul><ul><ul><li>Attenuated FAP </li></ul></ul><ul><ul><ul><li>Less than 100 polyps, often only in proximal colon </li></ul></ul></ul>
  15. 15. FAMILIAL ADENOMATOUS POLYPOSIS (FAP) <ul><li>Screening recommendations </li></ul><ul><ul><li>If no mutation identified </li></ul></ul><ul><ul><ul><li>Flexible sigmoidoscopy annually from age 12-15 to age 35 or until polyps develop </li></ul></ul></ul><ul><ul><ul><li>Dye spray chromo-endoscopy or narrow band imaging </li></ul></ul></ul><ul><ul><ul><li>Attenuated FAP families need colonoscopic surveillance </li></ul></ul></ul><ul><ul><li>If mutation identified </li></ul></ul><ul><ul><ul><li>Offer genetic testing to distinguish mutation positive and mutation negative family members </li></ul></ul></ul>
  16. 16. FAMILIAL ADENOMATOUS POLYPOSIS (FAP) <ul><li>If mutation negative </li></ul><ul><ul><li>Same risk as Category 1 </li></ul></ul><ul><li>If mutation positive or diagnosis confirmed </li></ul><ul><ul><li>Total colectomy/ileorectal anastomosis or proctocolectomy in late teenage years </li></ul></ul><ul><ul><ul><li>Annual flexible sigmoidoscopy if TC/IRA </li></ul></ul></ul><ul><ul><li>Duodenoscopy from age 25 </li></ul></ul>
  17. 17. HEREDITARY NON-POLYPOSIS COLORECTAL CANCER (hnpcc) <ul><li>Autosomal dominant </li></ul><ul><ul><li>Germline mutation in one of the mismatch repair genes, usually MLH1, MSH2, MSH6 or PMS2 </li></ul></ul><ul><li>Early age of onset </li></ul><ul><li>Proximal colonic malignancy </li></ul><ul><li>Multiple colorectal cancers </li></ul><ul><li>Extracolonic malignancy </li></ul>
  18. 18. HNPCC <ul><li>Amsterdam criteria 1991 </li></ul><ul><li>Amsterdam II criteria1999 </li></ul><ul><li>Bethesda guidelines 2001 </li></ul><ul><li>Revised Bethesda guidelines 2004 </li></ul><ul><ul><ul><li>Allows selection of patients for MSI assessment (or immunohistochemistry) to determine who should be tested for germline mutation </li></ul></ul></ul>
  19. 19. BETHESDA GUIDELINES <ul><li>Colorectal cancer diagnosed in a patient who is less than 50 years of age </li></ul><ul><li>Presence of synchronous CRC, metachronous CRC or other HNPCC associated cancers </li></ul><ul><li>CRC with MSI-H type histology in a patient under 60 years of age </li></ul><ul><ul><ul><li>Tumour infiltrating leucoctes </li></ul></ul></ul><ul><ul><ul><li>Crohn’s like lymphocytic reaction </li></ul></ul></ul><ul><ul><ul><li>Mucinous/signet ring differentiation </li></ul></ul></ul><ul><ul><ul><li>Medullary growth pattern </li></ul></ul></ul><ul><li>CRC in a patient under 60 with at least one first degree relative with an HNPCC associated cancer </li></ul><ul><li>CRC in a patient of any age with 2 or more first or second degree relatives with HNPCC associated cancers </li></ul>
  20. 20. MICROSATELLITE INSTABILITY <ul><li>Microsatellites are tandem repeats of short (1-5 bases) sequences of DNA. </li></ul><ul><li>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) </li></ul><ul><li>This should be corrected by mismatch repair genes, but if these are defective, as in HNPCC, MSI-H (high) status remains. </li></ul><ul><li>MSI-H is thus a marker of HNPCC </li></ul>
  21. 21. MSI-H <ul><li>Almost all HNPCC cancers are MSI-H </li></ul><ul><li>70% of adenomas in HNPCC are MSI-H </li></ul><ul><li>10-15% of sporadic cancers are MSI-H </li></ul><ul><ul><li>Must consider MSI-H status in the context of the family history and the age of the patients before diagnosing HNPCC </li></ul></ul><ul><ul><li>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 </li></ul></ul>
  22. 22. HNPCC <ul><li>Screening recommendations </li></ul><ul><ul><li>Proven germline mutation or HNPCC tumours that fit Bethesda/Amsterdam </li></ul></ul><ul><ul><ul><li>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 </li></ul></ul></ul><ul><ul><ul><li>Annual transvaginal ultrasound from age 30 </li></ul></ul></ul><ul><ul><ul><li>Annual urinary cytology and renal ultrasound </li></ul></ul></ul>
  23. 23. HNPCC <ul><li>Screening recommendations </li></ul><ul><ul><li>First degree relatives with unknown mutation status </li></ul></ul><ul><ul><ul><li>As above </li></ul></ul></ul><ul><ul><ul><li>2 yearly rather than annual </li></ul></ul></ul><ul><ul><li>Relatives negative for known germ line mutation </li></ul></ul><ul><ul><ul><li>Category 1 recommendations </li></ul></ul></ul>
  24. 24. SUMMARY <ul><li>Category 1 </li></ul><ul><ul><li>At or just above average risk </li></ul></ul><ul><ul><ul><li>No FH or single first degree relative with CRC over 55 </li></ul></ul></ul><ul><li>FOBT ever 2 years from age of 50 </li></ul>
  25. 25. SUMMARY <ul><li>Category 2 </li></ul><ul><ul><li>Moderately increased risk </li></ul></ul><ul><ul><ul><li>One first degree relative CRC under age 55 </li></ul></ul></ul><ul><ul><ul><li>Two first or second degree relatives on same side of family with CRC </li></ul></ul></ul><ul><ul><li>5 yearly colonoscopy from age 50 or 10 years younger than the age of diagnosis of the youngest family member </li></ul></ul>
  26. 26. SUMMARY <ul><li>Category 3 </li></ul><ul><li>At potentially high risk </li></ul><ul><ul><li>Features of FAP or HNPCC </li></ul></ul><ul><ul><li>Complex </li></ul></ul><ul><ul><li>Individualised </li></ul></ul><ul><ul><li>Genetic testing </li></ul></ul><ul><ul><li>Extensive - often annual testing </li></ul></ul>

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