Clinical Genetics InstituteFor CliniciansGenetic Testing Practice Council Updates

Genetic Testing Practice Council Updates

Lynch Syndrome Screening

November 2009

Intermountain Healthcare Clinical Genetics Institute, Oncology Services and Pathology Services are initiating routine immunohistochemistry staining for four mismatch repair proteins, MLH1, MSH2, MSH6 and PMS2 associated with Lynch Syndrome (LS) on all colorectal cancer resection specimens.

  • LS is responsible for 2 – 5 % of familial colorectal cancer, and increases the risk for endometrial, ovarian, and other cancers.
  • Recognizing Lynch syndrome is important for patient care because it will;
    • 1) identify patients at high risk for a second primary cancer and
    • 2) identify those most likely to have microsatellite instability (MSI) in their tumors which has been shown to be associated with a better prognosis.
  • The MSI result may affect patient treatment regimens in the future (more studies are required to confirm treatment differences).

Several publications document the limited sensitivity of relying on Amsterdam or Bethesda Criteria to identify individuals with LS (also known as HNPCC).

Almost half of individuals were missed when age, pathology or family history were used to identify LS. An exhaustive review of the literature supports that immunohistochemistry screening of the four mismatch repair genes detects at least 91% of patients with LS and directs DNA testing to the specific mismatch repair genes. Knowing the specific DNA mutation allows for testing of unaffected relatives in order to discuss initiating early endoscopic screening to detect and treat patients before they present with cancer. Based on the early and significant cancer risk, screening is recommended to start in the mid-twenties in mutation carriers.

Data also indicate that a tumor with abnormal immunohistochemistry results implies microsatellite instability.

A recent meta-analysis pooled data from 32 studies with 7,642 cases and found the hazard ratio for overall survival in patients whose tumors have high microsatellite instability is 0.65. In this review, two studies were identified that assessed benefit of 5-FU in stage II or III colorectal cancer patients by microsatellite instability status. Patients without microsatellite instability benefited significantly from 5-FU (HR=0.72), while patients with microsatellite instability did not benefit from 5-FU (HR=1.24).

Information about immunohistochemistry screening (Sunquest code MMRSCR) for LS has been presented at surgery rounds and tumor boards.

Several pathologists have been involved in the review of this research. The pathologist involved with the colorectal tumor case will choose a tumor block from each colorectal cancer resection to send to ARUP for MMRSCR: Mismatch Repair Protein Immunohistochemistry screening. ARUP offers a technical bulletin at their website.

The cancer genetic counselor at Intermountain Healthcare will follow-up on all abnormal IHC results with information provided directly to patients and to their healthcare providers. Articles regarding the research referenced above are available if requested.

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