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Preoperative Diagnosis of Lynch Syndrome With DNA Mismatch Repair Immunohistochemistry on a Diagnostic Biopsy

Warrier, S. K. M.B.B.S., F.R.A.C.S.1,4; Trainer, A. H. F.R.A.C.P., Ph.D.2; Lynch, A. C. M.B.Ch.B., M.Med.Sci., F.R.A.C.S., F.C.S.S.A.N.Z.1; Mitchell, C. M.B.B.S., F.R.C.P.A.3; Hiscock, R. M.B.B.S., F.A.N.Z.C.A., Grad.Dip.Stat.4; Sawyer, S. B.Sc.2; Boussioutas, A. M.B.B.S., F.R.A.C.P.2,5; Heriot, A. G. M.D., M.B.A., F.R.A.C.S.1

Diseases of the Colon & Rectum:
doi: 10.1097/DCR.0b013e318231db1f
Original Contribution

BACKGROUND: DNA mismatch repair immunohistochemistry on tumor tissue is a simple, readily available, and cost-effective method of identifying patients with Lynch syndrome in the postoperative setting. The aim of the study was to assess whether the mismatch repair status of a colorectal cancer can be confirmed by mismatch repair immunohistochemistry on preoperative biopsy.

DESIGN: Germline positive patients with Lynch syndrome were identified from a prospectively collected Familial Cancer Clinic database. Preoperative colorectal cancer biopsy specimens were obtained from the source pathology provider to generate a cohort of matched preoperative and postoperative specimens. The specimens were sectioned and stained for 4 mismatch repair proteins (MLH1, MSH2, MSH6, PMS2). An age-matched cohort to compare specimens was selected from Bethesda positive but mismatch repair immunohistochemistry negative patients. All slides were reviewed by a single blinded pathologist. The Wilson method was used to calculate a true underlying proportion of patients for whom the preoperative result matched the postoperative test result with a 95% confidence interval.

RESULTS: Of 128 germline positive mutation carriers, 40 patients (mean age 41, SD 11.3) had colorectal resections. Thirty-three preoperative specimens were retrievable and were matched with biopsies from 33 controls. The germline mutations included in the study were 8 MLH1, 19 MSH2, 3 MSH6, and 2 PMS2. In patients where germline positive status was known, sensitivity was 100% (95% CI 89.2–100) and specificity was 100% (95% CI 89.2–100). Identical sensitivity and specificity were observed in 33 age-matched patients. The sensitivity of the endoscopic biopsy in predicting germline status was 94.9% (95% CI 80.4–98.3).

CONCLUSION: The mismatch repair disease status of a colorectal cancer can be reliably confirmed by mismatch repair immunohistochemistry on a diagnostic colorectal cancer biopsy sample before definitive surgery. Ascertaining a diagnosis of Lynch syndrome before definitive surgery can influence surgical planning.

Author Information

1 Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

2 Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

3 Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

4 Epworth HealthCare, Melbourne, Victoria, Australia

5 Department of Medicine (RMH/WH), University of Melbourne, Footscray, Victoria, Australia

Financial Disclosures: None reported.

Presented at the meeting of The American Society for Colon and Rectal Surgeons, Vancouver, BC, Canada, May 14 to 18, 2011.

Correspondence: Alexander Heriot, M.D., M.B.A., F.R.A.C.S., Department of Surgical Oncology, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St, Melbourne, VIC 8006, Australia. E-mail:

© The ASCRS 2011