Utility of MLH1 Methylation Analysis in the Clinical Evaluation of Lynch Syndrome in Women with Endometrial Cancer
A Bruegl, B Djordjevic, D Urbauer, R Luthra, R Broaddus. MD Anderson Cancer Center, Houston, TX; Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada
Background: Immunohistochemistry and microsatellite instability are important screening tools to evaluate endometrial cancer (EC) patients for Lynch Syndrome. A complicating factor is that 15-20% of sporadic EC have immunohistochemical loss of MLH1 and high levels of microsatellite instability due to methylation of MLH1. The PCR-based MLH1 methylation assay resolves this issue, yet many clinical laboratories do not perform this assay. The objective of this study was to determine if clinical or pathologic features help to distinguish sporadic EC with MLH1 loss secondary to MLH1 methylation from Lynch Syndrome-associated EC with MLH1 loss and absence of MLH1 methylation.
Design: For 337 EC, MLH1 immunohistochemistry and PCR-based MLH1 analysis were performed. Clinical and pathological data were collected for all patients.
Results: 54/337 EC (16%) had immunohistochemical loss of MLH1. 40/54 had MLH1 methylation and were designated as sporadic, while 14/54 lacked MLH1 methylation and were designated as probable Lynch Syndrome. Diabetes and deep myometrial invasion were significantly associated with the probable Lynch Syndrome group; no other clinical or pathological variable distinguished the 2 groups. Combining Society of Gynecologic Oncology screening criteria with these 2 features accurately captured all Lynch Syndrome cases, but with very low specificity of 36%.
|Sporadic - Methylated MLH1 (%)||Probable Lynch Syndrome - Unmethylated MLH1 (%)||p-value|
|Median Age (range)||57 (31-92)||52 (42-79)||0.4295|
|Family History Endometrial Cancer||4 (10.5)||3 (21.4)||0.370|
|Family History Colon Cancer||7 (18.4)||3 (21.4)||1.0|
|Diabetes||4 (10)||6 (42.9)||0.013|
|Endometrioid Histology||35 (87.5)||11 (78.6)||0.413|
|FIGO Stage I or II||27 (67.5)||11 (78.6)||0.515|
|Endometrioid Grade 1 or 2||26 (74.3)||9 (81.8)||1.0|
|Deep Myometrial Invasion||15 (37.5)||10 (71.4)||0.035|
|LVSI||24 (60.0)||8 (57.1)||1.0|
|Lower Uterine Segment Tumor Location||3 (7.5)||3 (21.4)||0.173|
|Tumor Size Less Than 4 cm||21 (52.5)||8 (57.1)||1.0|