Diagnosis of Familial Metastatic Colorectal Cancer


Edward Chu, MD:With respect to this specific patient, this is a young patient with what we would call classic HNPCC (hereditary nonpolyposis colorectal cancer syndrome), also known as Lynch syndrome, because there also is a very strong family history of not only colorectal cancer but also extra colonic cancers that are classically associated with HNPCC and the Lynch syndrome—namely, cancer of the endometrium as well as cancer of the stomach. This patient presents with metastatic colorectal cancer with what appears to be liver-limited disease.

Based on the patient’s young age and no presence of comorbid illnesses, this is the kind of patient where we would want to be very aggressive with respect to offering systemic therapy, which should involve both combination chemotherapy and a biologic agent.

With respect to making the diagnosis of HNPCC, or Lynch syndrome, a classic approach is to assess the presence or absence of microsatellite instability. This is a fairly labor-intensive approach, using very sophisticated PCR-based techniques. Now actually, there are 2 other approaches where we can make the diagnosis of HNPCC. One is to have either the patient’s tumor, or the peripheral blood of an individual patient, undergo sequencing analysis to look for mutations in the 5 different mismatch repair genes. The other approach that has been done is to look at the presence or absence of the expression of 2 of the main mismatch repair proteins: MLH1 and hMS2.

When Dr. Lynch first described the Lynch syndrome—he did this with his wife, who was a nurse, quite some time ago—even before there were any genetic approaches to make the diagnosis, there was Lynch syndrome I and Lynch syndrome II. Lynch syndrome I was purely confined to patients with colorectal cancer, whereas Lynch syndrome II was colorectal cancer plus extra colonic cancers. Those extra colonic cancers include cancers of the stomach, the ovaries, the uterus, the small bowel, the uroepithelium, and the kidneys. So, there is a wide range of other cancers outside the colorectal region that are involved with Lynch syndrome II.

With respect to testing for the Lynch syndrome, probably the definitive approach is to get peripheral blood and to do germline testing to see whether or not there are mutational events in any one of the 5 mismatch repair genes.

Transcript edited for clarity.

  • A 47-year-old male presented to the doctor with abdominal pain and anemia
  • He has a family history of cancer:
    • His brother was diagnosed with colon cancer at age 44
    • His sister was diagnosed with gastric cancer at age 24, and mother was diagnosed with endometrial cancer at age 50
    • He has 2 children, a 15-year old boy and a 10-year old girl
  • Initial lab evaluations showed anemia (Hb 8.0 g/dL) and elevated carcinoembryonic antigen (980 ng/ml)
  • CT-scan showed a large mass in the ascending colon and diffuse liver nodules
  • Biopsy results showed a moderately differentiated adenocarcinoma
    • Microsatellite instability (MSI) testing revealed MSI-high (MSI-H) tumor and IHC confirmed the absence of expression of the MLH1 protein
    • He was referred for genetic testing
  • The patient was diagnosed with hereditary nonpolyposis colorectal cancer syndrome
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