title: The pathogenesis of atypical proliferative Brenner tumor: an immunohistochemical and molecular genetic analysis.
abstract: Brenner tumors are ovarian tumors, usually benign, containing epithelium that resembles transitional epithelium. As with other epithelial tumors there exist frankly malignant tumors and tumors that display greater proliferation than the benign Brenner tumors but lack destructive infiltrative growth, and these have been designated 'atypical proliferative' (borderline) Brenner tumors. There have been no well-documented cases of atypical proliferative Brenner tumors that have exhibited malignant behavior. Based on shared morphologic features it is generally believed that atypical proliferative Brenner tumors develop from benign Brenner tumors. The aim of the present study was to confirm this impression by investigating the immunohistochemical and molecular genetic features of benign and atypical proliferative Brenner tumors. Immunohistochemical staining for p16, fluorescence in-situ hybridization (FISH) for CDKN2A (p16-encoding gene) and mutational analysis of the genes commonly mutated in ovarian tumors were performed. p16 immunostaining was positive in the epithelial component of 12 (92%) of 13 benign Brenner tumors, but completely negative in all 7 atypical proliferative Brenner tumors. FISH identified homozygous deletion of CDKN2A in the epithelial component of all atypical proliferative Brenner tumors, but CDKN2A was retained in all benign Brenner tumors. Two PIK3CA somatic mutations were detected in the stromal component in 1 (5%) of 20 Brenner tumors and 3 somatic mutations (1 in KRAS and 2 in PIK3CA) were identified in the atypical epithelial component of 2 (29%) of 7 atypical proliferative Brenner tumors. In summary, our findings suggest that loss of CDKN2A and, to a lesser extent, KRAS and PIK3CA somatic mutations have a role in the progression of a benign to an atypical proliferative Brenner tumor.
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Kuhn
authors.affiliation: Department of Pathology, Seirei Mikatahara Hospital, Hamamatsu, Japan.
authors.forename: Ayse
authors.initials: A
authors.lastname: Ayhan
authors.affiliation: 1] Department of Pathology, Johns Hopkins Medical Institutions, Johns Hopkins University, Baltimore, MD, USA [2] Department of Gynecology and Obstetrics, and Oncology, Johns Hopkins Medical Institutions, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Ie-Ming
authors.initials: IeM
authors.lastname: Shih
authors.affiliation: Department of Pathology and Laboratory Medicine, Washington Hospital Center, Washington, DC, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Seidman
authors.affiliation: 1] Department of Pathology, Johns Hopkins Medical Institutions, Johns Hopkins University, Baltimore, MD, USA [2] Department of Gynecology and Obstetrics, and Oncology, Johns Hopkins Medical Institutions, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kurman
mesh_terms: D001948:Brenner Tumor / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D061346:Laser Capture Microdissection; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D020133:Reverse Transcriptase Polymerase Chain Reaction; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins