IHC Testing for MMR Deficiency Sufficient in Endometrial Cancer

October 17, 2016

Microsatellite instability analysis and immunohistochemistry analysis are highly concordant with regard to testing for mismatch repair deficiency in endometrial cancer.

Microsatellite instability (MSI) analysis and immunohistochemistry (IHC) analysis are highly concordant with regard to testing for mismatch repair (MMR) deficiency in endometrial cancer, according to a new study. This suggests that the IHC approach is sufficient in this malignancy.

“Recent studies have suggested that tumor molecular features, including MMR deficiency, may improve prognostication and help guide adjuvant therapy for endometrial cancer patients,” wrote study authors led by Tjalling Bosse, MD, PhD, of Leiden University Medical Center in the Netherlands. “Second, accurate assessment of MMR deficiency is essential to identify patients with endometrial cancer caused by Lynch syndrome.”

There was previously no agreement on the best way to test for MMR deficiency in endometrial cancer. The new study included 696 patients with endometrial cancer who were screened using both MSI testing (using a pentaplex panel) and IHC analysis. The results were published in Annals of Oncology.

MSI analysis showed microsatellite-stable (MSS) endometrial cancers in 74% of patients, MSI-high endometrial cancers in 24%, and MSI-low endometrial cancers in 2%. Of the 566 endometrial cancers deemed MSS, almost all (96%) retained expression of all four MMR proteins. Most of the MSI-high cases had complete loss of expression of two of the proteins: MLH1 and PMS2 (77%).

In total, the concordance between MSI and IHC analysis was very strong, observed in 655 of 696 cases (94%), for a correlation coefficient (using Cohen’s Kappa analysis) of 0.854 (95% CI, 0.811–0.897; P < .001).

The 41 discordant cases (6%) included subclonal loss of MMR expression in 18 cases, MSS or MSI-low cases with loss of MMR expression in 20 cases, and MSI-low or MSI-high cases that retained MMR protein expression in 3 cases. The authors noted that most discordant cases could be explained by MLH1 promoter methylation. Two cases deemed MSI-high but with retained MMR protein expression also carried a POLE exonuclease domain variant, which could explain that discordance, they wrote.

“Our study shows high agreement between IHC and MSI analysis, but not 100%,” the investigators wrote. Assessment of protein expression by IHC is preferred, though, for several reasons: the technique is widely available and carries a lower cost, and allows for determination of the affected MMR gene. “Pathologists should be aware of the MMR protein expression patterns, including subclonal loss, to ensure correct classification in daily diagnostic pathology.”