PD-L1 Expression in Mismatch Repair-deficient Endometrial Carcinoma and Tumor-associated Immune Cells: Differences Between MLH1 Methylated and Nonmethylated Subgroups.
Mismatch repair (MMR)-deficient endometrial carcinomas show increased programmed cell death-ligand 1 (PD-L1) expression compared with MMR-intact endometrial carcinomas, but there are limited data regarding PD-L1 expression between sporadic and inherited carcinomas exhibiting MMR loss. Most of the studies investigating PD-L1 expression in endometrial carcinoma have used tissue microarrays and did not examine all tumor blocks. In this study, we analyzed the expression of PD-L1 in resection specimens of 176 consecutive endometrial carcinomas using all tumor blocks; we compared PD-L1 expression in MMR-deficient endometrial carcinomas, including the MLH1 and PMS2-loss subgroup, and the other MMR-loss subgroups (MSH2 and MSH6, isolated PMS2, and isolated MSH6), with the MMR-intact subgroup. MLH1 methylation was performed in tumors with MLH1 and PMS2 loss. Tumor cell (TC) and tumor-associated immune cell (IC) PD-L1 positivity with a 1% cutoff was observed in 21% (n=37) and 66.5% (n=117) of cases, respectively, and with a 5% cutoff in 5.1% (n=9) and 39.8% (n=70) of cases, respectively. MMR protein deficiency was a statistically significant parameter associated with IC PD-L1 positivity, with 1% and 5% cutoffs on multivariate analysis [odds ratio (OR)=5.236, 95% confidence interval (CI)=2.075-13.211, P=0.001, and OR=3.702, 95% CI=1.759-7.791, P=0.001, respectively]. The multivariate analysis showed that IC PD-L1 positivity, using both 1% and 5% cutoffs, was significantly associated with the MLH1 and PMS2 loss compared with the MMR protein-intact subgroup (MLH1 and PMS2 loss for 1% cutoff: OR=5.104, 95% CI=1.876-13.881, P=0.001, and for 5% cutoff: OR=3.322, 95% CI=1.540-7.166, P=0.002). Squamous differentiation was an independent predictor for TC PD-L1 positivity, with a 5% cutoff (OR=6.102, 95% CI=1.280-10.096, P=0.026). Larger tumor size was an independent predictive factor for IC PD-L1 positivity with a 1% cutoff (OR=6.757, 95% CI=1.569-29.109, P=0.010). Overall, 48 (92.3%) of 52 MLH1 methylated tumors showed IC PD-L1 positivity with 1% cutoff, and 34 (65.4%) of 52 MLH1 methylated tumors showed IC PD-L1 positivity with 5% cutoff. Our results show a higher rate of IC PD-L1 positivity than in previous studies. This is likely due in part to the use of all tumor blocks. MLH1 and PMS2 loss was an independent predictive factor for IC PD-L1 positivity, with both 1% and 5% cutoffs. Using univariate analysis, we observed decreased disease-free survival for IC PD-L1 positivity ≥5%. Our study results should now be tested and proven in larger cohorts, with longer follow-up data.
Kir G
，Olgun ZC
，Soylemez T
，Aydin A
，Demircan B
，Kaya IA
，McCluggage WG
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Clinicopathologic characteristics and outcomes of endometrial Cancer patients with mismatch repair deficiency in the era of universal Lynch syndrome screening.
To evaluate clinicopathologic characteristics and survival impact associated with mismatch repair (MMR) deficient subgroups of endometrial cancer (EC) in patients undergoing universal screening for Lynch Syndrome.
A retrospective cohort study using a prospectively maintained gynecologic oncology registry of patients who underwent surgery for EC was conducted. All pathology specimens underwent tumor testing using immunohistochemistry for MMR deficiency with reflex MLH1 promotor methylation testing. Tumors were classified as MMR-I (intact MMR expression), MMR-DM (MMR deficient due to MLH1 methylation), and MMR-DU (MMR deficient without MLH1 methylation). Univariate and multivariate analysis performed to determine factors associated with MMR-DM. Progression-free survival (PFS) and overall survival (OS) analyzed by stage and endometrioid subgroup.
From 2012 to 2016, 1018 EC patients were identified and screened. Overall, 71.6% were classified as MMR-I, 23.8% MMR-DM, and 4.6% MMR-DU. In comparison to MMR-DU, MMR-DM tumors were associated with older age, postmenopausal status, lymphovascular space invasion, and pure endometrioid histology. Compared to MMR-I, MMR-DM tumors were associated with older age, endometrioid histology, lymphovascular space invasion, and higher grade on multivariable analysis. There was no difference in PFS and OS between the three groups overall. In patients with endometrioid EC, MMR-DM tumors were associated with lower PFS vs. MMR-I (HR:2.51, CI:1.54, 4.10, P < 0.001). This effect persisted for stage I/II endometrioid EC (HR 2.66, CI:1.34, 5.26 p = 0.005). No difference in PFS or OS was noted among stage III/IV endometrioid tumors.
MMR deficiency is associated with adverse prognostic factors and worse PFS among endometrioid tumors, particularly in early stage EC. MMR testing outside of LS screening has prognostic value, warranting consideration for inclusion as a biomarker in prospective clinical trials.
Carr C
，Son J
，Yao M
，Priyadarshini A
，Marquard J
，Vargas R
，Michener C
，AlHilli MM
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