Lynch Syndrome

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Lynch Syndrome

• Mary Ellen Groshart, M3

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Quest-ce que cest?, and why is it important?

• Another name for HNPCC (autosomal dominant)
• Most common form of hereditary colorectal cancer
  (CRC).
• 90 of cases result from mutation of one of
  several mismatch repair genes
• most commonly MSH2, MLH1, and MSH6.
• Provided a detailed family history, it predicts
  the lifetime risk for CRC as well as many other
  non-colon cancers including endometrial, ovarian,
  small bowel, brain, and others.
• After diagnosis, targeted surveillance can
  significantly decrease patient morbidity and
  mortality.

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Historyune petite déviation

• 1925Michigan pathologist Aldred Scott Warthin
  studied the family history of his seamstress who
  first developed colon cancer, but later died of
  endometrial cancer.
• Her pedigree became known as Family G and
  illustrated a long line of CRC and endometrial
  cancer.
• Henry Lynch continued to study this phenomenon
• In 1993 he extended the range of cancers to
  include ovarian, transitional-cell cancer of the
  renal pelvis, stomach, small bowel, and
  pancreatic cancers.

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Epidemiology

• CRC is the 3rd most common cancer in the US, and
  the 2nd most common cause of cancer death in the
  US.
• 10 of CRC is hereditary
• Lynch syndrome accounts for 2-7 of all CRC
  cases.
• Women with Lynch syndrome have
• 40-60 lifetime risk of developing colon cancer
• 40-60 lifetime risk for endometrial cancer
• 10-12 lifetime risk for ovarian cancer.

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Diagnosis

• Lynch syndrome lacks overt phenotypic markers,
  therefore, accurate family history is crucial.
• If the clinical pattern of disease in the family
  is positive, molecular studies are performed to
  detect microsatellite instabilities and germline
  mutations (MSH2, MLH1, MSH6) that segregate in
  affected family members.
• MSH6 accounts for 10 of Lynch syndrome mutations
  and is associated with milder disease, but an
  excess of endometrial cancer.
• Patients must meet the Amsterdam criteria to be
  diagnosed, and the Bethesda criteria to undergo
  microsatellite testing

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Amsterdam criteria and Bethesda criteria
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What is the sentinel cancer?

• Out of 117 women, 51 presented with gynecologoic
  cancer first.
• median age 45
• median age of 2nd cancer 50

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To screen or not to screen current debate

• Sequencing mismatch repair genes is diagnostic,
  but expensive and takes much time.
• Detecting mismatch repair genes in patients with
  Lynch syndrome can dramatically impact the
  management of that patients cancer, BUT.
• Should a patient with colon cancer automatically
  be screened? What implications does it have on
  his insurance, family, job?
• Can the patient be properly treated simply by
  evaluating family history and follow up with
  targeted surveillance such as regular
  colonoscopies?

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Prevention and treatment outside of genetic
testing/screening

• Colonoscopy beginning at age 25, repeated
  annually
• Endometrial aspiration biopsy annually and
  transvaginal ultrasound with serum CA-125
  measurements once or twice per year
• Prophylaxis
• Prophylactic colectomy offered to patients with
  high-risk mutations or to patients who may not be
  compliant
• Prophylactic hysterectomy with bilateral
  salpingo-oophorectomy.

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Fini
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References

• 1. Lynch HT, Lynch JF. What the Physician Needs
  to Know About Lynch Syndrome an Update.
  Oncology. April 2005. Vol. 19. No. 4.
  pp.455-469.
• 2. Hampel, et al. Screening for the Lynch
  Syndrome N.Engl J Med 352181851-60.
• 3. Lu KH, Dinh M, et al. Gynecologic Cancer as
  a Sentinel Cancer for Women With HNPCC
  syndrome. Obs Gyn 1053 569-574.
• 4. Offit, Kauff. Reducing the Risk of
  Gynecologic Cancer in the Lynch Syndrome N Engl
  J Med 3543 293-295.