Clinicopathological significance of deficient DNA mismatch repair and MLH1 promoter methylation in endometrioid endometrial carcinoma

Context.— The current College of American Pathologists reporting guideline for mismatch repair protein (MMRP) immunohistochemistry for Lynch syndrome (LS) screening considers the presence of any positive nuclear staining as intact MMRP expression. This would include tumors with combined areas of subclonal retention and loss of MMRP staining. Objective.— To evaluate the clinical significance of reporting subclonal staining patterns of MMRP immunohistochemistry in endometrial carcinoma. Design.— We retrospectively reviewed 455 consecutive MMRP immunohistochemistry results of endometrial carcinoma in hysterectomy specimens from 2012 through 2017 and identified cases with subclonal MMRP staining. These results were correlated with the patient's personal and family history of LS-associated carcinoma, MLH1 promoter methylation status, and LS genetic testing. Results.— Subclonal staining of MMRP was seen in 48 of 455 cases (10.5%) on review. Thirty cases demonstrated isolated subclonal staining and were reported by pathologists as follows: subclonal (n = 5), complete MMRP loss (n = 4), and intact MMRP (n = 21). Eighteen cases had subclonal staining in combination with complete loss of other MMRP. Cases reported as subclonal or complete MMRP loss had appropriate clinical follow-up. Two of 2 cases with isolated subclonal MSH6 loss tested positive for LS. One of 3 cases with isolated subclonal MLH1/PMS2 loss was negative for MLH1 promoter methylation; LS genetic testing was not performed because of cost. Conclusions.— Our study reveals that LS germline mutation can be detected in endometrial carcinoma patients whose tumors display sole subclonal MMRP staining. Our results stress the importance of reporting subclonal staining patterns to ensure appropriate clinical follow-up.

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Clinicopathologic Significance of Defective DNA Mismatch Repair in Endometrial Carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2005.04.1574 ◽

2006 ◽

Vol 24 (11) ◽

pp. 1745-1753 ◽

Cited By ~ 106

Author(s):

Destin Black ◽

Robert A. Soslow ◽

Douglas A. Levine ◽

Carmen Tornos ◽

Shirley C. Chen ◽

...

Keyword(s):

Endometrial Carcinoma ◽

Mismatch Repair ◽

Dna Mismatch Repair ◽

Early Stage ◽

Disease Free Survival ◽

Myometrial Invasion ◽

Hazard Ratio ◽

Histologic Subtype ◽

Dna Mismatch ◽

Tumor Group

Purpose Defective DNA mismatch repair is commonly present in sporadic manifestations of gastrointestinal, endometrial, and other cancers. The pathognomonic molecular manifestation of this repair defect is microsatellite instability (MSI). Here, we test the hypothesis that MSI predicts the clinicopathologic features of endometrial carcinoma. Patients and Methods A retrospective cohort of 473 patients treated for endometrial carcinoma at this institution was identified. All cases were reviewed by a gynecologic pathologist, and clinical information was abstracted from medical records. Using consensus criteria, DNA samples from nontumor and tumor tissue pairs were genotyped for MSI. Associations between MSI status and pathologic and clinical variables were assessed. Results Ninety-three (20%) of 473 tumors were MSI+. In the MSI+ tumor group compared with the MSI− tumor group, the proportion of advanced compared with early-stage tumors was higher (92% v 81%; P = .01), as was the proportion of tumors of endometrioid compared with nonendometrioid histologic subtype (94% v 23%; P = .001), and the proportion of tumors with myometrial invasion compared with those with none (92% v 78%; P = .01). By multivariate analyses, disease-free survival (hazard ratio, 0.3; 95% CI, 0.2 to 0.7) and disease-specific survival (hazard ratio, 0.3; 95% CI, 0.1 to 0.8) were significantly improved in patients with MSI+ tumors. Conclusion In endometrial carcinoma, the presence of MSI was independently associated with a more favorable clinical outcome.

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