Ovarian carcinomas: five distinct diseases with different origins, genetic alterations, and clinicopathological features

Jaime Prat1
1Department of Pathology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Sant Quinti 87-89, 08041, Barcelona, Spain

Tóm tắt

Từ khóa


Tài liệu tham khảo

Prat J (2004) Pathology of the ovary. Saunders, Philadelphia

Lee KR, Tavassoli FA, Prat J et al (2003) Surface epithelial-stromal tumours (Ch 2: tumours of the ovary and peritoneum). In: Tavassoli FA, Devilee P (eds) World Health Organization classification of tumours: pathology and genetics of tumours of the breast and female genital organs. IARC Press, Lyon, pp 117–145

Shvartsman HS, Sun CC, Bodurka CC, Mahajan V, Crispens M, Lu KH, Deavers MT, Malpica A, Silva EG, Gershenson DM (2007) Comparison of the clinical behavior of newly diagnosed stages II–IV low-grade serous carcinoma of the ovary with that of serous ovarian tumors of low malignant potential that recur as low-grade serous carcinoma. Gynecol Oncol 105:625–629

Stewart BW, Kleihues P (2003). World Cancer Report (IARC Press)

Jass JR (2006) Colorectal cancer: a multipathway disease. Crit Rev Oncog 12:273–287

Gilks CB, Prat J (2009) Ovarian carcinoma pathology and genetics: recent advances. Hum Pathol 40:1213–1223

Takano M, Kikuchi Y, Yaegashi N, Kuzuya K, Ueki M, Tsuda H, Suzuki M, Kigawa J, Takeuchi S, Tsuda H, Moriya T, Sugiyama T (2006) Clear cell carcinoma of the ovary: a retrospective multicentre experience of 254 patients with complete surgical staging. Br J Cancer 94:1369–1374

du Bois A, Lück HJ, Meier W, Adams HP, Möbus V, Costa S, Bauknecht T, Richter B, Warm M, Schröder W, Olbricht S, Nitz U, Jackisch C, Emons G, Wagner U, Kuhn W, Pfisterer J (2003) A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 95:1320–1329

Fountain J, Trimble E, Birrer MJ (2006) Summary and discussion of session recommendations. Gynecol Oncol 103:S23–S25

Köbel M, Kalloger SE, Boyd N, McKinney S, Mehl E, Palmer C, Leung S, Bowen NJ, Ionescu DN, Rajput A, Prentice LM, Miller D, Santos J, Swenerton K, Gilks CB, Huntsman D (2008) Ovarian carcinoma subtypes are different diseases: implications for biomarker studies. PLoS Med 5:e232

Kurman RJ, Shih IM (2010) The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol 34:433–443

Piek JM, van Diest PJ, Zweemer RP, Jansen JW, Poort-Keesom RJ, Menko FH, Gille JJ, Jongsma AP, Pals G, Kenemans P, Verheijen RH (2001) Dysplastic changes in prophylactically removed fallopian tubes of women predisposed to developing ovarian cancer. J Pathol 195:451–456

Piek JM, van Diest PJ, Zweemer RP, Kenemans P, Verheijen RH (2001) Tubal ligation and risk of ovarian cancer. Lancet 358:844

Medeiros F, Muto MG, Lee Y, Elvin JA, Callahan MJ, Feltmate C, Garber JE, Cramer DW, Crum CP (2006) The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol 30:230–236

Kindelberger DW, Lee Y, Miron A, Hirsch MS, Feltmate C, Medeiros F, Callahan MJ, Garner EO, Gordon RW, Birch C, Berkowitz RS, Muto MG, Crum CP (2007) Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: evidence for a causal relationship. Am J Surg Pathol 31:161–169

Lee Y, Miron A, Drapkin R, Nucci MR, Medeiros F, Saleemuddin A, Garber J, Birch C, Mou H, Gordon RW, Cramer DW, McKeon FD, Crum CP (2007) A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J Pathol 211:26–35

Folkins AK, Jarboe EA, Saleemuddin A, Lee Y, Callahan MJ, Drapkin R, Garber JE, Muto MG, Tworoger S, Crum CP (2008) A candidate precursor to pelvic serous cancer (p53 signature) and its prevalence in ovaries and fallopian tubes from women with BRCA mutations. Gynecol Oncol 109:168–173

Jarboe E, Folkins A, Nucci MR, Kindelberger D, Drapkin R, Miron A, Lee Y, Crum CP (2008) Serous carcinogenesis in the fallopian tube: a descriptive classification. Int J Gynecol Pathol 27:1–9

Obata K, Morland SJ, Watson RH, Hitchcock A, Chenevix-Trench G, Thomas EJ, Campbell IG (1998) Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors. Cancer Res 58:2095–2097

Sato N, Tsunoda H, Nishida M, Morishita Y, Takimoto Y, Kubo T, Noguchi M (2000) Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst of the ovary: possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary. Cancer Res 60:7052–7056

Singer G, Oldt R 3rd, Cohen Y, Wang BG, Sidransky D, Kurman RJ, IeM S (2003) Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Nat Cancer Inst 95:484–486

Singer G, Stöhr R, Cope L, Dehari R, Hartmann A, Cao DF, Wang TL, Kurman RJ, IeM S (2005) Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis. Am J Surg Pathol 29:218–224

Laury AR, Ning G, Quick CM, Nucci MR, Parast MM, McKeon FD, Xian W, Crum CP (2011) Fallopian tube correlates of serous borderline tumors. Am J Surg Pathol 35:1759–1765

Kurman RJ, Vang R, Junge J, Hannibal CG, Kjaer SK, Shih Ie M (2011) Papillary tubal hyperplasia: the putative precursor of ovarian atypical proliferative (borderline) serous tumors, noninvasive implants, and endosalpingiosis. Am J Surg Pathol 35:1605–1614

Malpica A, Deavers MT, Lu K, Bodurka DC, Atkinson EN, Gershenson DM, Silva EG (2004) Grading ovarian serous carcinoma using a two-tier system. Am J Surg Pathol 28:496–504

Gilks CB, Ionescu DN, Kalloger SE, Köbel M, Irving J, Clarke B, Santos J, Le N, Moravan V, Swenerton K (2008) Tumor cell type can be reproducibly diagnosed and is of independent prognostic significance in patients with maximally debulked ovarian carcinoma. Hum Pathol 39:1239–1251

Al-Hussaini M, Stockman A, Foster H, Mc Cluggage WG (2004) WT-1 assists in distinguishing ovarian from uterine serous carcinoma and in distinguishing between serous and endometrioid ovarian carcinoma. Histopathology 44:109–105

Köbel M, Kalloger SE, Carrick J, Huntsman D, Asad H, Oliva E, Ewanowich CA, Soslow RA, Gilks CB (2009) A limited panel of immunomarkers can reliably distinguish between clear cell and high-grade serous carcinoma of the ovary. Am J Surg Pathol 33:14–21

Karst AM, Levanon K, Duraisamy S, Liu JF, Hirsch MS, Hecht JL, Drapkin R (2011) Stathmin 1, a marker of PI3K pathway activation and regulator of microtubule dynamics, is expressed in early pelvic serous carcinomas. Gynecol Oncol 123:5–12

Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Fan I, Tang J, Li S, Zhang S, Shaw PA, Narod SA (2006) Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J Natl Cancer Inst 98:1694–1706

Venkitaraman AR (2009) Linking the cellular functions of BRCA genes to cancer pathogenesis and treatment. Annu Rev Pathol 4:461–487

Geisler JP, Hatterman-Zogg MA, Rathe JA, Buller RE (2002) Frequency of BRCA1 dysfunction in ovarian cancer. J Natl Cancer Inst 94:61–67

Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Prat J, Harkes I, Repasky EA, Gabrielson E, Schutte M, Baylin SB, Herman JG (2000) Promoter hypermethylation is a cause of BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst 92:564–569

Bowtell DD (2010) The genesis and evolution of high-grade serous ovarian cancer. Nat Rev Cancer 10:803–808

Levanon K, Ng V, Piao HY, Zhang Y, Chang MC, Roh MH, Kindelberger DW, Hirsch MS, Crum CP, Marto JA, Drapkin R (2010) Primary ex vivo cultures of human fallopian tube epithelium as a model for serous ovarian carcinogenesis. Oncogene 29:1103–1113

Powell CB, Kenley E, Chen LM, Crawford B, McLennan J, Zaloudek C, Komaromy M, Beattie M, Ziegler J (2005) Risk-reducing salpingo-oophorectomy in BRCA mutation carriers: role of serial sectioning in the detection of occult malignancy. J Clin Oncol 23:127–132

Pothuri B, Leitao MM, Levine DA, Viale A, Olshen AB, Arroyo C, Bogomolniy F, Olvera N, Lin O, Soslow RA, Robson ME, Offit K, Barakat RR, Boyd J (2010) Genetic analysis of the early natural history of epithelial ovarian carcinoma. PLoS One 5:e10358

Norquist BM, Garcia RL, Allison KH, Jokinen CH, Kernochan LE, Pizzi CC, Barrow BJ, Goff BA, Swisher EM (2010) The molecular pathogenesis of hereditary ovarian carcinoma: alterations in the tubal epithelium of women with BRCA1 and BRCA2 mutations. Cancer 116:5261–5271

Espinosa I, Catasus L, Canet B, D’Angelo E, Muñoz J, Prat J (2011) Gene expression analysis identifies two groups of ovarian high-grade serous carcinomas with different prognosis. Mod Pathol 24:846–854

Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC, Ashworth A (2005) Targeting the DNA repair defectin BRCA mutant cells as a therapeutic strategy. Nature 434:917–921

Tutt AN, Lord CJ, McCabe N, Farmer H, Turner N, Martin NM, Jackson SP, Smith GC, Ashworth A (2005) Exploiting the DNA repair defectin BRCA mutant cells in the design of new therapeutic strategies for cancer. Cold Spring Harb Symp Quant Biol 70:139–148

Gershenson DM, Sun CC, Lu KH, Coleman RL, Sood AK, Malpica A, Deavers MT, Silva EG, Bodurka DC (2006) Clinical behavior of stage II–IV low-grade serous carcinoma of the ovary. Obstet Gynecol 108:361–368

Malpica A, Deavers MT, Tornos C, Kurman RJ, Soslow R, Seidman JD, Munsell MF, Gaertner E, Frishberg D, Silva EG (2007) Inter-observer and intraobserver variability of a two-tier system for grading ovarian serous carcinoma. Am J Surg Pathol 31:1203–1208

Ayhan A, Kurman RJ, Yemelyanova A, Vang R, Logani S, Seidman JD, IeM S (2009) Defining the cut-point between low- and high-grade ovarian serous carcinomas: a clinicopathologic and molecular genetic analysis. Am J Surg Pathol 33:1220–1224

Jones S, Wang T-L, Kurman RJ, Nakayama K, Velculescu VE, Vogelstein B, Kinzler KW, Papadopoulos N, Shih I-M (2012) Low-grade serous carcinomas of the ovary contain very few point mutations. J Pathol 226:413–420

Bell DA, Longacre TA, Prat J, Kohn EC, Soslow RA, Ellenson LH, Malpica A, Stoler MH, Kurman RJ (2004) Serous borderline (low malignant potential, atypical proliferative) ovarian tumors: workshop perspectives. Hum Pathol 35:934–948

Sieben NL, Roemen GMJM, Oosting J, Fleuren GJ, van Engeland M, Prat J (2006) Clonal analysis favours a monoclonal origin for serous borderline tumours with peritoneal implants. J Pathol 210:405–411

Crispens MA, Bodurka D, Deavers M, Lu K, Silva EG, Gershenson DM (2002) Response and survival in patients with progressive or recurrent serous ovarian tumors of low malignant potential. Obstet Gynecol 99:3–10

Rodriguez IM, Prat J (2002) Mucinous tumors of the ovary: a clinicopathologic analysis of 75 borderline tumors (of intestinal type) and carcinomas. Am J Surg Pathol 26:139–152

Lee KR, Scully RE (2000) Mucinous tumors of the ovary—A clinicopathologic study of 196 borderline tumors (of intestinal type) and carcinomas, including an evaluation of 11 cases with “pseudomyxomaperitonei”. Am J Surg Pathol 24:1447–1464

Silverberg SG, Bell DA, Kurman RJ, Seidman JD, Prat J, Ronnett BM, Copeland L, Silva E, Gorstein F, Young RH (2004) Borderline ovarian tumors: key points and workshop summary. Hum Pathol 35:910–917

Hoerl HD, Hart WR (1998) Primary ovarian mucinous cystadenocarcinomas: a clinicopathologic study of 49 cases with long term follow-up. Am J Surg Pathol 22:1449–1462

Riopel MA, Ronnett BM, Kurman RJ (1999) Evaluation of diagnostic criteria and behavior of ovarian intestinal-type mucinous tumors. Atypical proliferative (borderline) tumors and intraepithelial, microinvasive, invasive and metastatic carcinomas. Am J Surg Pathol 23:617–635

Provenza C, Young RH, Prat J (2008) Anaplastic carcinoma in mucinous ovarian tumors: a clinicopathologic study of 34 cases emphasizing the crucial impact of stage on prognosis, their histologic spectrum, and overlap with sarcoma-like mural nodules. Am J Surg Pathol 32:383–389

Heinzelmann-Schwarz VA, Gardiner-Garden M, Henshall SM, Scurry JP, Scolyer RA, Smith AN, Bali A, Vanden Bergh P, Baron-Hay S, Scott C, Fink D, Hacker NF, Sutherland RL, O’Brien PM (2006) A distinct molecular profile associated with mucinous epithelial ovarian cancer. Br J Cancer 94:904–91353

Cuatrecasas M, Villanueva A, Matias-Guiu X, Prat J (1997) K-ras mutations in mucinous ovarian tumors. A clinicopathologic and molecular study of 95 cases. Cancer 79:1581–1586

Park SY, Kim HS, Hong EK, Kim WH (2002) Expression of cytokeratins 7 and 20 in primary carcinomas of the stomach and colorectum and their value in the differential diagnosis of metastatic carcinomas to the ovary. Hum Pathol 33:1078–1085

Vang R, Gown AM, Wu LS, Barry TS, Wheeler DT, Yemelyanova A, Seidman JD, Ronnett BM (2006) Immunohistochemical expression ofCDX2 in primary ovarian mucinous tumors and metastatic mucinous carcinomas involving the ovary: comparison with CK20 and correlation with coordinate expression of CK7. Mod Pathol 19:1421–1428

Ji H, Isacson C, Seidman J, Kurman RJ, Ronnett BM (2002) Cytokeratins 7and 20, Dpc4, and MUC5AC in the distinction of metastatic mucinous carcinomas in the ovary from primary ovarian mucinous tumors: Dpc4assists in identifying metastatic pancreatic carcinomas. Int J Gynecol Pathol 21:391–400

Ronnett BM, Yemelyanova AV, Vang R, Gilks CB, Miller D, Gravitt PE, Kurman RJ (2008) Endocervical adenocarcinomas with ovarian metastases: analysis of 29 cases with emphasis on minimally invasive cervical tumors and the ability of the metastases to simulate primary ovarian neoplasms. Am J Surg Pathol 32:1835–1853

Irving JA, Catasús L, Gallardo A, Bussaglia E, Romero M, Matias-Guiu X, Prat J (2005) Synchronous endometrioid carcinomas of the uterine corpus and ovary: alterations in the beta-catenin (CTNNB1) pathway are associated with independent primary tumors and favorable prognosis. Hum Pathol 36:605–619

Tothill RW, Tinker AV, George J, Brown R, Fox SB, Lade S, Johnson DS, Trivett MK, Etemadmoghadam D, Locandro B, Traficante N, Fereday S, Hung JA, Chiew YE, Haviv I, Australian Ovarian Cancer Study Group, Gertig D, DeFazio A, Bowtell D (2008) Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clin Cancer Res 14:5198–5208

Sainz de la Cuesta R, Eichhorn JH, Rice LW, Fuller AF Jr, Nikrui N, Goff BA (1996) Histologic transformation of benign endometriosis to early epithelial ovarian cancer. Gynecol Oncol 60:238–244

Jiang X, Morland SJ, Hitchcock A, Thomas EJ, Campbell IG (1998) Allelotyping of endometriosis with adjacent ovarian carcinoma reveals evidence of a common lineage. Cancer Res 58:1707–1712

Dinulescu DM, Ince TA, Quade BJ, Shafer SA, Crowley D, Jacks T (2005) Role of K-ras and PTEN in the development of mouse models of endometriosis and endometrioid ovarian cancer. Nat Med 11:63–70

Wiegand KC, Shah SP, Al-Agha OM, Zhao Y, Tse K, Zeng T, Senz J, McConechy MK, Anglesio MS, Kalloger SE, Yang W, Heravi-Moussavi A, Giuliany R, Chow C, Fee J, Zayed A, Prentice L, Melnyk N, Turashvili G, Delaney AD, Madore J, Yip S, McPherson AW, Ha G, Bell L, Fereday S, Tam A, Galletta L, Tonin PN, Provencher D, Miller D, Jones SJ, Moore RA, Morin GB, Oloumi A, Boyd N, Aparicio SA, Shih Ie M, Mes-Masson AM, Bowtell DD, Hirst M, Gilks B, Marra MA, Huntsman DG (2010) ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med 363:1532–1543

Lemon B, Inouye C, King DS, Tjian R (2001) Selectivity of chromatin-remodelling cofactors for ligand-activated transcription. Nature 414:924–928

Birrer MJ (2010) The origin of ovarian cancer—is it getting clearer? N Engl J Med 363:1574–1575

Palacios J, Gamallo C (1998) Mutations in the beta-catenin gene (CTNNB1) in endometrioid ovarian carcinomas. Cancer Res 58:1344–1347

Catasús L, Bussaglia E, Rodriguez I, Gallardo A, Pons C, Irving JA, Prat J (2004) Molecular genetic alterations in endometrioid carcinomas of the ovary: similar frequency of beta-catenin abnormalities but lower rate of microsatellite instability and PTEN alterations than in uterine endometrioid carcinomas. Hum Pathol 35:1360–1368

Gamallo C, Palacios J, Moreno G, Calvo de Mora J, Suárez A, Armas A (1999) Beta-catenin expression pattern in stage I and II ovarian carcinomas: relationship withbeta-catenin gene mutations, clinicopathological features, and clinical outcome. Am J Pathol 155:527–536

Campbell IG, Russell SE, Choong DY, Montgomery KG, Ciavarella ML, Hooi CS, Cristiano BE, Pearson RB, Phillips WA (2004) Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 64:7678–7681

Catasus L, Gallardo A, Cuatrecasas M, Prat J (2008) PIK3CA mutations in the kinase domain (exon 20) of uterine endometrial adenocarcinomas are associated with adverse prognostic parameters. Mod Pathol 21:131–139

Willner J, Wurz K, Allison KH, Galic V, Garcia RL, Goff BA, Swisher EM (2007) Alternate molecular genetic pathways in ovarian carcinomas of common histological types. Hum Pathol 38:607–613

Gras E, Catasus L, Argüelles R, Moreno-Bueno G, Palacios J, Gamallo C, Matias-Guiu X, Prat J (2001) Microsatellite instability, MLH-1 promoter hypermethylation, and frameshift mutations at coding mononucleotide repeat microsatellites in ovarian tumors. Cancer 92:2829–2836

Moreno-Bueno G, Gamallo C, Perez-Gallego L, Calvo de Mora J, Suarez A, Palacios J (2001) Beta-catenin expression pattern, beta-catenin gene mutations, and microsatellite instability in endometrioid ovarian carcinomas and synchronous endometrial carcinomas. Diagn Mol Pathol 10:116–122

Sugiyama T, Kamura T, Kigawa J, Terakawa N, Kikuchi Y, Kita T, Suzuki M, Sato I, Taguchi K (2000) Clinical characteristics of clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum based chemotherapy. Cancer 88:2584–2589

Komiyama S, Aoki D, Tominaga E, Susumu N, Udagawa Y, Nozawa S (1999) Prognosis of Japanese patients with ovarian clear cell carcinoma associated with pelvic endometriosis: clinicopathologic evaluation. Gynecol Oncol 72:342–346

Press JZ, De Luca A, Boyd N, Young S, Troussard A, Ridge Y, Kaurah P, Kalloger SE, Blood KA, Smith M, Spellman PT, Wang Y, Miller DM, Horsman D, Faham M, Gilks CB, Gray J, Huntsman DG (2008) Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. BMC Cancer 8:17

Kato N, Sasou S, Motoyama T (2006) Expression of hepatocyte nuclear factor-1beta (HNF-1beta) in clear cell tumors and endometriosis of the ovary. Mod Pathol 19:83–89

Kobayashi H, Yamada Y, Kanayama S, Furukawa N, Noguchi T, Haruta S, Yoshida S, Sakata M, Sado T, Oi H (2009) The role of hepatocyte nuclear factor-1beta in the pathogenesis of clear cell carcinoma of the ovary. Int J Gynecol Cancer 19:471–479

Horiuchi A, Imai T, Wang C, Ohira S, Feng Y, Nikaido T, Konishi I (2003) Upregulation of small GTPases, RhoA and RhoC, is associated with tumor progression in ovarian carcinoma. Lab Invest 83:861–870

Canet B, Pons C, Espinosa I, Prat J (2011) Ovarian clear cell carcinomas: RHO GTPases may contribute to explain their singular biologic behavior. Hum Pathol 42:833–839

Itamochi H, Kigawa J, Sugiyama T, Kikuchi Y, Suzuki M, Terakawa N (2002) Low proliferation activity may be associated with chemoresistance in clear cell carcinoma of the ovary. Obstet Gynecol 100:281–287