title: Ovarian low-grade and high-grade serous carcinoma: pathogenesis, clinicopathologic and molecular biologic features, and diagnostic problems.
abstract: 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.
authors.affiliation: Department of Pathology (Division of Gynecologic Pathology), The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. rvang1@jhmi.edu
authors.forename: Russell
authors.initials: R
authors.lastname: Vang
authors.forename: Ie-Ming
authors.initials: IeM
authors.lastname: Shih
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kurman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018284:Cystadenocarcinoma, Serous / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis / Q000378:metabolism; D009154:Mutation; D009363:Neoplasm Proteins / Q000032:analysis; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; C413364:ERBIN protein, human; C117307:KRAS protein, human; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
references.citation: Am J Surg Pathol. 2008 Nov;32(11):1667-74
references.pmid: 18769340
references.citation: Gynecol Oncol. 2003 Jun;89(3):447-52
references.pmid: 12798710
references.citation: J Clin Oncol. 2008 Sep 1;26(25):4160-5
references.pmid: 18757330
references.citation: Cancer. 2000 Nov 15;89(10):2076-84
references.pmid: 11066048
references.citation: Am J Surg Pathol. 2008 Dec;32(12):1800-6
references.pmid: 18779727
references.citation: Am J Pathol. 2004 May;164(5):1511-8
references.pmid: 15111296
references.citation: Am J Obstet Gynecol. 1950 Jan;59(1):58-67, illust
references.pmid: 15399626
references.citation: Surg Clin North Am. 1978 Feb;58(1):121-9
references.pmid: 644422
references.citation: Am J Surg Pathol. 2003 Jun;27(6):725-36
references.pmid: 12766576
references.citation: Am J Surg Pathol. 2005 Feb;29(2):218-24
references.pmid: 15644779
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18739-44
references.pmid: 17130457
references.citation: Am J Surg Pathol. 2005 Nov;29(11):1482-9
references.pmid: 16224215
references.citation: Gynecol Oncol. 1993 Sep;50(3):347-51
references.pmid: 8406199
references.citation: Gynecol Oncol. 2001 Feb;80(2):201-6
references.pmid: 11161860
references.citation: Int J Gynecol Cancer. 2008 May-Jun;18(3):487-91
references.pmid: 17692090
references.citation: J Natl Cancer Inst. 2002 Sep 18;94(18):1396-406
references.pmid: 12237285
references.citation: Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):5944-50
references.pmid: 17062665
references.citation: Am J Surg Pathol. 2009 Oct;33(10):1504-14
references.pmid: 19623034
references.citation: Cancer Res. 2004 Oct 1;64(19):6915-8
references.pmid: 15466181
references.citation: Am J Surg Pathol. 2004 Apr;28(4):496-504
references.pmid: 15087669
references.citation: J Pathol. 2004 Mar;202(3):336-40
references.pmid: 14991899
references.citation: Br J Cancer. 2008 Dec 16;99(12):2020-8
references.pmid: 19018267
references.citation: Int J Gynecol Pathol. 2001 Oct;20(4):323-8
references.pmid: 11603214
references.citation: Mod Pathol. 2006 Aug;19(8):1091-100
references.pmid: 16648864
references.citation: Am J Surg Pathol. 2007 Feb;31(2):161-9
references.pmid: 17255760
references.citation: Mod Pathol. 1997 Jul;10(7):663-7
references.pmid: 9237175
references.citation: Am J Surg Pathol. 2006 Feb;30(2):230-6
references.pmid: 16434898
references.citation: Int J Gynecol Pathol. 2004 Jul;23(3):265-72
references.pmid: 15213603
references.citation: Hum Pathol. 2005 Oct;36(10):1049-54
references.pmid: 16226103
references.citation: Gynecol Oncol. 2006 Nov;103(2):703-8
references.pmid: 16828848
references.citation: Am J Surg Pathol. 2009 Jul;33(7):1037-41
references.pmid: 19238079
references.citation: Virchows Arch. 1999 Feb;434(2):117-20
references.pmid: 10071245
references.citation: Cancer Res. 2009 May 1;69(9):4036-42
references.pmid: 19383911
references.citation: Cancer. 1998 Mar 1;82(5):893-901
references.pmid: 9486579
references.citation: Int J Gynecol Cancer. 2007 May-Jun;17(3):601-6
references.pmid: 17504374
references.citation: Hum Pathol. 2004 Aug;35(8):918-33
references.pmid: 15297960
references.citation: Int J Gynecol Cancer. 2006 Jan-Feb;16 Suppl 1:123-8
references.pmid: 16515579
references.citation: Obstet Gynecol. 2006 Aug;108(2):361-8
references.pmid: 16880307
references.citation: Annu Rev Pathol. 2009;4:287-313
references.pmid: 18842102
references.citation: Cancer Biol Ther. 2006 Jul;5(7):779-85
references.pmid: 16721043
references.citation: Cancer. 1994 Apr 1;73(7):1859-64
references.pmid: 8137211
references.citation: Cancer Res. 2005 Mar 1;65(5):1994-2000
references.pmid: 15753399
references.citation: Gynecol Oncol. 2006 Dec;103(3):883-7
references.pmid: 16806438
references.citation: Hum Pathol. 2008 Aug;39(8):1239-51
references.pmid: 18602670
references.citation: Gynecol Oncol. 1996 Mar;60(3):393-6
references.pmid: 8774644
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):14004-9
references.pmid: 16172393
references.citation: Am J Pathol. 2002 Apr;160(4):1223-8
references.pmid: 11943707
references.citation: Int J Cancer. 2004 Oct 20;112(1):14-25
references.pmid: 15305371
references.citation: Am J Surg Pathol. 2007 Aug;31(8):1168-74
references.pmid: 17667538
references.citation: Cancer Res. 2005 Nov 15;65(22):10602-12
references.pmid: 16288054
references.citation: Clin Cancer Res. 2004 Oct 1;10(19):6432-6
references.pmid: 15475429
references.citation: Gynecol Oncol. 2007 Dec;107(3):398-403
references.pmid: 17997146
references.citation: Int J Gynecol Pathol. 2008 Jan;27(1):1-9
references.pmid: 18156967
references.citation: Int J Gynecol Pathol. 2005 Oct;24(4):363-8
references.pmid: 16175083
references.citation: J Natl Cancer Inst. 2000 Jul 5;92(13):1088-91
references.pmid: 10880552
references.citation: Am J Surg Pathol. 2005 Aug;29(8):1034-41
references.pmid: 16006797
references.citation: Histopathology. 2007 May;50(6):773-9
references.pmid: 17493241
references.citation: J Natl Cancer Inst. 2002 Jan 2;94(1):61-7
references.pmid: 11773283
references.citation: Int J Gynecol Cancer. 2006 Mar-Apr;16(2):484-9
references.pmid: 16681715
references.citation: Int J Gynecol Pathol. 2000 Jan;19(1):7-15
references.pmid: 10638449
references.citation: Am J Surg Pathol. 2009 Aug;33(8):1220-4
references.pmid: 19461510
references.citation: Am J Clin Pathol. 2007 Jan;127(1):103-13
references.pmid: 17145637
references.citation: Hum Pathol. 2002 Jan;33(1):47-59
references.pmid: 11823973
references.citation: Mod Pathol. 2005 Feb;18 Suppl 2:S19-32
references.pmid: 15761464
references.citation: Int J Gynecol Pathol. 2003 Jan;22(1):37-41
references.pmid: 12496696
references.citation: J Natl Cancer Inst. 2003 Mar 19;95(6):484-6
references.pmid: 12644542
references.citation: Gynecol Oncol. 2007 Jun;105(3):625-9
references.pmid: 17320156
references.citation: Am J Surg Pathol. 2007 Jul;31(7):1007-12
references.pmid: 17592266
references.citation: Am J Surg Pathol. 2007 May;31(5):653-63
references.pmid: 17460447
references.citation: Gynecol Oncol. 2003 Apr;89(1):148-54
references.pmid: 12694669
references.citation: Am J Surg Pathol. 2005 Jun;29(6):707-23
references.pmid: 15897738
references.citation: Eur J Surg Oncol. 2004 Nov;30(9):976-81
references.pmid: 15498644
references.citation: Am J Hum Genet. 2001 Mar;68(3):700-10
references.pmid: 11179017
references.citation: J Pathol. 2007 Jan;211(1):26-35
references.pmid: 17117391
references.citation: J Surg Oncol. 2000 Mar;73(3):148-52
references.pmid: 10738268
references.citation: Histopathology. 2008 Aug;53(2):127-38
references.pmid: 18298580
references.citation: Int J Gynecol Pathol. 2004 Apr;23(2):162-9
references.pmid: 15084845
references.citation: Am J Surg Pathol. 1996 Nov;20(11):1319-30
references.pmid: 8898836
references.citation: Gynecol Oncol. 2008 Mar;108(3):510-4
references.pmid: 18155273
references.citation: Am J Obstet Gynecol. 2004 Apr;190(4):1039-45
references.pmid: 15118638
references.citation: Am J Surg Pathol. 2006 Oct;30(10):1209-21
references.pmid: 17001150
references.citation: Am J Surg Pathol. 2008 Oct;32(10):1566-71
references.pmid: 18724243
references.citation: Hum Pathol. 2004 Aug;35(8):934-48
references.pmid: 15297961
references.citation: Curr Oncol Rep. 2008 Nov;10(6):519-23
references.pmid: 18928667
references.citation: Cancer. 2005 Dec 15;104(12):2807-16
references.pmid: 16284991