Pathogenesis of ovarian, fallopian tubal, and peritoneal serous carcinomas
- Christopher P Crum, MD
Christopher P Crum, MD
- Department of Pathology
- Brigham and Women's Hospital
- Jonathan Bijron, MD
Jonathan Bijron, MD
- University Medical Center Utrecht, The Netherlands
- Section Editors
- Barbara Goff, MD
Barbara Goff, MD
- Section Editor — Gynecologic Oncology
- Department Chair, Gynecologic Oncology
- University of Washington Medical Center
- Rochelle L Garcia, MD
Rochelle L Garcia, MD
- Section Editor — Obstetric and Gynecologic Pathology
- Professor of Pathology
- Adjunct Professor of Obstetrics & Gynecology
- University of Washington Medical Center
The term epithelial ovarian carcinoma has been used to refer to a large group of malignant neoplasms that typically present as ovarian tumors with involvement of the fallopian tube and peritoneum. Accumulating evidence suggests that these epithelial neoplasms can be divided into two groups in terms of probable site of origin: either ovarian or tubal .
The first group of carcinomas, which have a plausible origin in the ovary, include those with the following histologies: endometrioid, mucinous, clear cell, borderline, and low grade serous. Some of these appear to arise from endometriosis, a benign condition that may involve the ovaries. This is the case for endometrioid and clear cell carcinomas.
Müllerian inclusions in the ovarian cortex are another potential source of primary ovarian carcinomas. These have been implicated in the development of mucinous and lower grade serous neoplasms. The evidence for this is morphologic evidence of a gradual spectrum of changes seen in the ovary, potentially proceeding from cortical inclusions to cystadenofibromas to borderline and low grade serous carcinomas.
The fallopian tubes, uterus, cervix, and upper vagina derive from Müllerian (paramesonephric) tissue, while the ovary develops from the primordial germ cells and surrounding surface epithelium . Primary Müllerian neoplasms of the ovary likely originate from cells acquired during the reproductive years, with possibilities including transport of epithelial cells from the fallopian tubes or endometrium (lining of the uterus). An older theory is Müllerian metaplasia of ovarian surface epithelium.
The second group consists of extrauterine pelvic serous carcinomas, particularly those that are high grade and are associated with a poor prognosis. These have traditionally been thought to be primary ovarian carcinomas, with a few designated as fallopian tube carcinoma (if the bulk of disease was in a fallopian tube) or peritoneal carcinoma (if little or no ovarian or fallopian tube disease was present). The consistent features of these carcinomas have been rapid progression, extra-ovarian disease at the time of diagnosis, and the absence of a known precursor lesion. Evidence suggests that many of these neoplasms may originate in the fallopian tube. Based upon this theoretical framework, we will use the term "extrauterine pelvic serous carcinoma" to refer to these carcinomas, implying a possible origin in the ovary, tube, or Müllerian epithelium elsewhere in the peritoneal cavity.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Tone AA, Salvador S, Finlayson SJ, et al. The role of the fallopian tube in ovarian cancer. Clin Adv Hematol Oncol 2012; 10:296.
- Blaustein's Pathology of the Female Genital Tract, 6th ed, Kurman RJ, Ellenson LH, Ronnett RM. (Eds), Springer, New York 2011.
- Wiegand KC, Shah SP, Al-Agha OM, et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med 2010; 363:1532.
- Kurman RJ, Visvanathan K, Roden R, et al. Early detection and treatment of ovarian cancer: shifting from early stage to minimal volume of disease based on a new model of carcinogenesis. Am J Obstet Gynecol 2008; 198:351.
- Kindelberger DW, Lee Y, Miron A, et al. Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship. Am J Surg Pathol 2007; 31:161.
- Alvarado-Cabrero I, Cheung A, Caduff R. Tumours of the fallopian tube. In: Tumours of the Breast and Female Genital Organs: WHO Classification of Tumours, Tavassoli FA, Devilee P (Eds), IARC Press, Lyon, France 2003. p.206.
- Colgan TJ. Challenges in the early diagnosis and staging of Fallopian-tube carcinomas associated with BRCA mutations. Int J Gynecol Pathol 2003; 22:109.
- HU CY, TAYMOR ML, HERTIG AT. Primary carcinoma of the fallopian tube. Am J Obstet Gynecol 1950; 59:58.
- SEDLIS A. Primary carcinoma of the fallopian tube. Obstet Gynecol Surv 1961; 16:209.
- Yoonessi M. Carcinoma of the fallopian tube. Obstet Gynecol Surv 1979; 34:257.
- Mehrad M, Ning G, Chen EY, et al. A pathologist's road map to benign, precancerous, and malignant intraepithelial proliferations in the fallopian tube. Adv Anat Pathol 2010; 17:293.
- Colgan TJ, Murphy J, Cole DE, et al. Occult carcinoma in prophylactic oophorectomy specimens: prevalence and association with BRCA germline mutation status. Am J Surg Pathol 2001; 25:1283.
- Leeper K, Garcia R, Swisher E, et al. Pathologic findings in prophylactic oophorectomy specimens in high-risk women. Gynecol Oncol 2002; 87:52.
- Powell CB, Kenley E, Chen LM, et al. Risk-reducing salpingo-oophorectomy in BRCA mutation carriers: role of serial sectioning in the detection of occult malignancy. J Clin Oncol 2005; 23:127.
- Finch A, Shaw P, Rosen B, et al. Clinical and pathologic findings of prophylactic salpingo-oophorectomies in 159 BRCA1 and BRCA2 carriers. Gynecol Oncol 2006; 100:58.
- Callahan MJ, Crum CP, Medeiros F, et al. Primary fallopian tube malignancies in BRCA-positive women undergoing surgery for ovarian cancer risk reduction. J Clin Oncol 2007; 25:3985.
- Carcangiu ML, Peissel B, Pasini B, et al. Incidental carcinomas in prophylactic specimens in BRCA1 and BRCA2 germ-line mutation carriers, with emphasis on fallopian tube lesions: report of 6 cases and review of the literature. Am J Surg Pathol 2006; 30:1222.
- Hirst JE, Gard GB, McIllroy K, et al. High rates of occult fallopian tube cancer diagnosed at prophylactic bilateral salpingo-oophorectomy. Int J Gynecol Cancer 2009; 19:826.
- Reitsma W, de Bock GH, Oosterwijk JC, et al. Support of the 'fallopian tube hypothesis' in a prospective series of risk-reducing salpingo-oophorectomy specimens. Eur J Cancer 2013; 49:132.
- Schmeler KM, Daniels MS, Soliman PT, et al. Primary peritoneal cancer after bilateral salpingo-oophorectomy in two patients with Lynch syndrome. Obstet Gynecol 2010; 115:432.
- Piek JM, van Diest PJ, Zweemer RP, et al. Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer. J Pathol 2001; 195:451.
- Conner J, Crum C, Feltmate C, Brigham and Women's Hospital, Harvard Medical School, unpublished data.
- Medeiros F, Muto MG, Lee Y, et al. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol 2006; 30:230.
- Lee Y, Miron A, Drapkin R, et al. A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J Pathol 2007; 211:26.
- Kuhn E, Kurman RJ, Vang R, et al. TP53 mutations in serous tubal intraepithelial carcinoma and concurrent pelvic high-grade serous carcinoma--evidence supporting the clonal relationship of the two lesions. J Pathol 2012; 226:421.
- Carlson JW, Miron A, Jarboe EA, et al. Serous tubal intraepithelial carcinoma: its potential role in primary peritoneal serous carcinoma and serous cancer prevention. J Clin Oncol 2008; 26:4160.
- Roh MH, Kindelberger D, Crum CP. Serous tubal intraepithelial carcinoma and the dominant ovarian mass: clues to serous tumor origin? Am J Surg Pathol 2009; 33:376.
- Przybycin CG, Kurman RJ, Ronnett BM, et al. Are all pelvic (nonuterine) serous carcinomas of tubal origin? Am J Surg Pathol 2010; 34:1407.
- Seidman JD, Zhao P, Yemelyanova A. "Primary peritoneal" high-grade serous carcinoma is very likely metastatic from serous tubal intraepithelial carcinoma: assessing the new paradigm of ovarian and pelvic serous carcinogenesis and its implications for screening for ovarian cancer. Gynecol Oncol 2011; 120:470.
- Leonhardt K, Einenkel J, Sohr S, et al. p53 signature and serous tubal in-situ carcinoma in cases of primary tubal and peritoneal carcinomas and serous borderline tumors of the ovary. Int J Gynecol Pathol 2011; 30:417.
- Vicus D, Finch A, Cass I, et al. Prevalence of BRCA1 and BRCA2 germ line mutations among women with carcinoma of the fallopian tube. Gynecol Oncol 2010; 118:299.
- Gilks CB, Irving J, Köbel M, et al. Incidental nonuterine high-grade serous carcinomas arise in the fallopian tube in most cases: further evidence for the tubal origin of high-grade serous carcinomas. Am J Surg Pathol 2015; 39:357.
- Morrison JC, Blanco LZ Jr, Vang R, Ronnett BM. Incidental serous tubal intraepithelial carcinoma and early invasive serous carcinoma in the nonprophylactic setting: analysis of a case series. Am J Surg Pathol 2015; 39:442.
- Semmel DR, Folkins AK, Hirsch MS, et al. Intercepting early pelvic serous carcinoma by routine pathological examination of the fimbria. Mod Pathol 2009; 22:985.
- Fathalla MF. Incessant ovulation--a factor in ovarian neoplasia? Lancet 1971; 2:163.
- Hutson R, Ramsdale J, Wells M. p53 protein expression in putative precursor lesions of epithelial ovarian cancer. Histopathology 1995; 27:367.
- Oral E, Ilvan S, Tustas E, et al. Prevalence of endometriosis in malignant epithelial ovary tumours. Eur J Obstet Gynecol Reprod Biol 2003; 109:97.
- Dehari R, Kurman RJ, Logani S, Shih IeM. The development of high-grade serous carcinoma from atypical proliferative (borderline) serous tumors and low-grade micropapillary serous carcinoma: a morphologic and molecular genetic analysis. Am J Surg Pathol 2007; 31:1007.
- Salani R, Kurman RJ, Giuntoli R 2nd, et al. Assessment of TP53 mutation using purified tissue samples of ovarian serous carcinomas reveals a higher mutation rate than previously reported and does not correlate with drug resistance. Int J Gynecol Cancer 2008; 18:487.
- Carlson J, Roh MH, Chang MC, Crum CP. Recent advances in the understanding of the pathogenesis of serous carcinoma: the concept of low- and high-grade disease and the role of the fallopian tube. Diagn Histopathol (Oxf) 2008; 14:352.
- Geyer JT, López-García MA, Sánchez-Estevez C, et al. Pathogenetic pathways in ovarian endometrioid adenocarcinoma: a molecular study of 29 cases. Am J Surg Pathol 2009; 33:1157.
- Madore J, Ren F, Filali-Mouhim A, et al. Characterization of the molecular differences between ovarian endometrioid carcinoma and ovarian serous carcinoma. J Pathol 2010; 220:392.
- Köbel M, Kalloger SE, Boyd N, et al. Ovarian carcinoma subtypes are different diseases: implications for biomarker studies. PLoS Med 2008; 5:e232.
- Finch A, Beiner M, Lubinski J, et al. Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 Mutation. JAMA 2006; 296:185.
- Holschneider CH, Berek JS. Ovarian cancer: epidemiology, biology, and prognostic factors. Semin Surg Oncol 2000; 19:3.
- Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361:123.
- Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12:852.
- Press JZ, De Luca A, Boyd N, et al. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. BMC Cancer 2008; 8:17.
- Singer G, Stöhr R, Cope L, et al. 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: a mutational analysis with immunohistochemical correlation. Am J Surg Pathol 2005; 29:218.
- O'Neill CJ, Deavers MT, Malpica A, et al. An immunohistochemical comparison between low-grade and high-grade ovarian serous carcinomas: significantly higher expression of p53, MIB1, BCL2, HER-2/neu, and C-KIT in high-grade neoplasms. Am J Surg Pathol 2005; 29:1034.
- Laury AR, Ning G, Quick CM, et al. Fallopian tube correlates of ovarian serous borderline tumors. Am J Surg Pathol 2011; 35:1759.
- Kurman RJ, Vang R, Junge J, et al. Papillary tubal hyperplasia: the putative precursor of ovarian atypical proliferative (borderline) serous tumors, noninvasive implants, and endosalpingiosis. Am J Surg Pathol 2011; 35:1605.
- Kurman RJ, Shih IeM. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol 2010; 34:433.
- Singer G, Kurman RJ, Chang HW, et al. Diverse tumorigenic pathways in ovarian serous carcinoma. Am J Pathol 2002; 160:1223.
- Singer G, Oldt R 3rd, Cohen Y, et al. Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst 2003; 95:484.
- Sieben NL, Macropoulos P, Roemen GM, et al. In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low-grade serous tumours. J Pathol 2004; 202:336.
- Mayr D, Hirschmann A, Löhrs U, Diebold J. KRAS and BRAF mutations in ovarian tumors: a comprehensive study of invasive carcinomas, borderline tumors and extraovarian implants. Gynecol Oncol 2006; 103:883.
- Wong KK, Tsang YT, Deavers MT, et al. BRAF mutation is rare in advanced-stage low-grade ovarian serous carcinomas. Am J Pathol 2010; 177:1611.
- Taylor HS, Vanden Heuvel GB, Igarashi P. A conserved Hox axis in the mouse and human female reproductive system: late establishment and persistent adult expression of the Hoxa cluster genes. Biol Reprod 1997; 57:1338.
- Cheng W, Liu J, Yoshida H, et al. Lineage infidelity of epithelial ovarian cancers is controlled by HOX genes that specify regional identity in the reproductive tract. Nat Med 2005; 11:531.
- International Collaborative Ovarian Neoplasm Group. Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. Lancet 2002; 360:505.
- Markman M, Rothman R, Hakes T, et al. Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol 1991; 9:389.
- Dizon DS, Dupont J, Anderson S, et al. Treatment of recurrent ovarian cancer: a retrospective analysis of women treated with single-agent carboplatin originally treated with carboplatin and paclitaxel. The Memorial Sloan-Kettering Cancer Center experience. Gynecol Oncol 2003; 91:584.
- Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet 2003; 361:2099.
- Schmeler KM, Sun CC, Bodurka DC, et al. Neoadjuvant chemotherapy for low-grade serous carcinoma of the ovary or peritoneum. Gynecol Oncol 2008; 108:510.
- Gershenson DM, Sun CC, Bodurka D, et al. Recurrent low-grade serous ovarian carcinoma is relatively chemoresistant. Gynecol Oncol 2009; 114:48.
- Bodurka DC, Deavers MT, Tian C, et al. Reclassification of serous ovarian carcinoma by a 2-tier system: a Gynecologic Oncology Group Study. Cancer 2012; 118:3087.
- Paley PJ, Swisher EM, Garcia RL, et al. Occult cancer of the fallopian tube in BRCA-1 germline mutation carriers at prophylactic oophorectomy: a case for recommending hysterectomy at surgical prophylaxis. Gynecol Oncol 2001; 80:176.
- Agoff SN, Mendelin JE, Grieco VS, Garcia RL. Unexpected gynecologic neoplasms in patients with proven or suspected BRCA-1 or -2 mutations: implications for gross examination, cytology, and clinical follow-up. Am J Surg Pathol 2002; 26:171.
- Agoff SN, Garcia RL, Goff B, Swisher E. Follow-up of in situ and early-stage fallopian tube carcinoma in patients undergoing prophylactic surgery for proven or suspected BRCA-1 or BRCA-2 mutations. Am J Surg Pathol 2004; 28:1112.
- Manchanda R, Abdelraheim A, Johnson M, et al. Outcome of risk-reducing salpingo-oophorectomy in BRCA carriers and women of unknown mutation status. BJOG 2011; 118:814.
- Powell CB, Swisher EM, Cass I, et al. Long term follow up of BRCA1 and BRCA2 mutation carriers with unsuspected neoplasia identified at risk reducing salpingo-oophorectomy. Gynecol Oncol 2013; 129:364.
- Wethington SL, Park KJ, Soslow RA, et al. Clinical outcome of isolated serous tubal intraepithelial carcinomas (STIC). Int J Gynecol Cancer 2013; 23:1603.
- Conner JR, Meserve E, Pizer E, et al. Outcome of unexpected adnexal neoplasia discovered during risk reduction salpingo-oophorectomy in women with germ-line BRCA1 or BRCA2 mutations. Gynecol Oncol 2014; 132:280.
- POTENTIAL PRECURSOR LESIONS
- Serous tubal intraepithelial neoplasia
- Ovarian cortical inclusion cysts
- CHARACTERISTICS OF PELVIC SEROUS NEOPLASMS
- High grade pelvic serous carcinoma
- - Origins
- - High grade endometrioid carcinoma
- Histologic diagnosis
- Evaluation of rrBSO specimens
- Assigning primary tumor site
- - Targeted therapy (PARP inhibitors)
- Low grade serous neoplasms
- - Origins
- CLINICAL ISSUES
- Classification and chemoresponsiveness
- Treatment of STIC found at rrBSO