Molecular, Pathologic, and Clinical Features of Early-Onset Endometrial Cancer: Identifying Presumptive Lynch Syndrome Patients

Abstract

Purpose: A woman with early-onset endometrial cancer (EC) may represent the ''sentinel''cancer event in a Lynch syndrome kindred.The aim of this study was to determine the incidence of Lynch syndrome in a series of young-onset EC, and to identify molecular, clinical, and pathologic features that may alert clinicians to the presence of this disorder. Experimental Design: Patients with EC, ages V50 years, were identified from the Queensland Centre for Gynaecological Cancer. Tumor sections underwent histopathology review and were immunostained for mismatch repair proteins. Tumor DNA was tested for microsatellite instability and methylation of MLH1. Patients were conservatively classified as presumptive Lynch syndrome if their tumors showed loss of at least one mismatch repair protein and were negative for methylation of MLH1. Personal and family history of cancer was reviewed where available. Results: Presumptive Lynch syndrome was seen in 26 of 146 (18%) tumors. These tumors were more likely to be poorly differentiated, International Federation of Gynecology and Obstetrics stage II and above, have tumor-infiltrating lymphocytes, have higher mitotic rate, and have deeper myometrial invasion (P < 0.05). Lynch syndrome cases were more likely to be associated with a positive family history when analyzed for Amsterdam criteria II, diagnosis of a Lynch syndrome spectrum cancer in at least one first-degree relative, and family history of any cancer (P < 0.05).Conclusion: Presumptive Lynch syndrome was identified in 18% of early-onset EC. A risk of this magnitude would argue for routine immunohistochemical testing of tumors in patients diagnosed with EC at or before the age of 50 years.

Analysis of Lynch Syndrome Mismatch Repair Genes in Women with Endometrial Cancer

“…There is evidence that MSI and immunohistochemical analysis of the MMR genes are techniques with good sensitivity and specificity for identifying patients with LS. A study carried out in 183 women with endometrial cancer [21] found a concordance of 100% between the two techniques, and Walsh et al [22] reported a similar result (97.5%). In contrast, we found less strong concordance (88.31%).…”

Clinical and pathologic features of young endometrial cancer patients with loss of mismatch repair expression

“…Earlier studies on tumors arising in individuals with Lynch syndrome indicate that these cancers tend to be of endometrioid histology, higher grade, and with a higher risk of lymphatic invasion and tumor infiltrating lymphocytes [9]. Shih et al reported that patients under the age of 40 with loss of MMR gene expression demonstrated poor prognostic features and had a worse survival than patients with intact MMR expression [4].…”

Improving identification of lynch syndrome patients: A comparison of research data with clinical records

“…20 Patients exhibiting loss of tumor expression of MMR proteins are prioritized for germline mutation testing: MLPA for genomic rearrangements and exon sequencing of the relevant MMR gene. 21 There were 439 ANECS participants identified as resident in Queensland and for whom family history questionnaire data were available.…”