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

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

Requests for reprints: Joanne Young, Familial Cancer Laboratory, Queensland Institute of Medical Research, Herston Q4006, Australia. Phone: 61-7-3362-0490; Fax: 617-3362-0108; E-mail: Joanne.Young{at}qimr.edu.au.

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.