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

^{1 1}Familial Cancer Laboratory and ²Molecular Cancer Epidemiology Laboratory, Queensland Institute of Medical Research; ³Departments of Gastroenterology and Hepatology and ⁴Gynaecological Oncology, Royal Brisbane and Women's Hospital; ⁵Queensland Clinical Genetics Service, Royal Childrens' Hospital; ⁶Faculty of Health Sciences and ⁷School of Medicine, University of Queensland, Herston, Australia; ⁸Queensland Medical Laboratory, Murarrie, Australia; ⁹Nijmegen Medical Centre, Radboud University, the Netherlands; and ¹⁰Department of Cellular Pathology, St. Marks Hospital, Harrow, United Kingdom

^* To whom correspondence should be addressed. E-mail: Joanne.Young{at}qimr.edu.au.

	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 50 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.

Key Words: Gynecologic cancers: other