Ovarian Low-grade and High-grade Serous Carcinoma: Pathogenesis, Clinicopathologic and Molecular Biologic Features, and Diagnostic ProblemsVang, Russell MD; Shih, Ie-Ming MD, PhD; Kurman, Robert J. MDAdvances in Anatomic Pathology: September 2009 - Volume 16 - Issue 5 - p 267-282 doi: 10.1097/PAP.0b013e3181b4fffa Review Articles Abstract Author Information Ovarian serous carcinomas have been graded using various systems. Recently, a 2-tier system in which tumors are subdivided into low grade and high grade has been proposed. This approach is simplistic, reproducible, and based on biologic evidence indicating that both tumors develop via different pathways. Low-grade serous carcinomas exhibit low-grade nuclei with infrequent mitotic figures. They evolve from adenofibromas or borderline tumors, have frequent mutations of the KRAS, BRAF, or ERBB2 genes, and lack TP53 mutations (Type I pathway). The progression to invasive carcinoma is a slow step-wise process. Low-grade tumors are indolent and have better outcome than high-grade tumors. In contrast, high-grade serous carcinomas have high-grade nuclei and numerous mitotic figures. Identification of a precursor lesion in the ovary has been elusive and therefore the origin of ovarian carcinoma has been described as de novo. More recently, studies have suggested that a proportion seem to originate from intraepithelial carcinoma in the fallopian tube. The development of these tumors is rapid (Type II pathway). Most are characterized by TP53 mutations and lack mutations of KRAS, BRAF, or ERBB2. Although both types of serous carcinomas evolve along different pathways, rare high-grade serous carcinomas seem to arise through the Type I pathway. Immunohistochemical stains for p53, p16, and Ki-67 for distinction of low-grade from high-grade tumors are of limited value but can be helpful in selected instances. This review provides an update on the pathogenesis and clinicopathologic features of these 2 types of serous carcinomas and addresses some of the diagnostic problems that are encountered in routine practice. Departments of Pathology (Division of Gynecologic Pathology) and Gynecology & Obstetrics, The Johns Hopkins University School of Medicine, Baltimore, MD Supported by Grants from NIH/NCI RO1CA116184 (R.J.K.) and RO1CA129080 and RO1CA103937 (I.-M.S.). Reprints: Russell Vang, MD, Department of Pathology, Division of Gynecologic Pathology, The Johns Hopkins Hospital, Weinberg Building, Rm. 2242, 401 North Broadway, Baltimore, MD 21231 (e-mail: firstname.lastname@example.org). © 2009 Lippincott Williams & Wilkins, Inc.