General Information About Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer
This PDQ summary covers the staging and treatment of ovarian epithelial, fallopian tube, and primary peritoneal cancer.
Epithelial carcinoma of the ovary is one of the most common gynecologic malignancies and the fifth most frequent cause of cancer death in women, with 50% of all cases occurring in women older than 65 years. Findings from risk-reducing surgeries in healthy women with BRCA1 or BRCA2 mutations have reinforced the hypothesis that many high-grade serous cancers—the most common histologic subtype of ovarian cancer—may arise from precursor lesions that originate in the fimbriae of the fallopian tubes. In addition, histologically similar cancers diagnosed as primary peritoneal carcinomas share molecular findings, such as loss or inactivation of the tumor-suppressors p53 and BRCA1 or BRCA2 proteins. Therefore, high-grade serous adenocarcinomas arising from the fallopian tube and elsewhere in the peritoneal cavity, together with most ovarian epithelial cancers, represent "extrauterine adenocarcinomas of Müllerian epithelial origin" and are staged and treated similarly to ovarian cancer; since 2000, they usually have been included in ovarian cancer clinical trials. On the other hand, clear cell and endometrioid ovarian cancers that are linked to endometriosis have different gene-expression signatures, as do mucinous subtypes.
Stromal and germ cell tumors are relatively uncommon and comprise fewer than 10% of cases. (Refer to the PDQ summaries on Ovarian Germ Cell Tumor Treatment and Ovarian Low Malignant Potential Tumor Treatment for more information.)
Incidence and Mortality
Estimated new cases and deaths from ovarian cancer in the United States in 2014:
- New cases: 21,980.
- Deaths: 14,270.
The most important risk factor for ovarian cancer is a family history of a first-degree relative (e.g., mother, daughter, or sister) with the disease. Approximately 20% of ovarian cancers are familial, and although most of these are linked to mutations in the BRCA1 or BRCA2 genes, several other genes have been implicated in familial ovarian cancers.[6,7] The highest risk appears in women who have two or more first-degree relatives with ovarian cancer. The risk is somewhat less for women who have one first-degree and one second-degree relative (grandmother or aunt) with ovarian cancer.
In most families affected with the breast and ovarian cancer syndrome or site-specific ovarian cancer, genetic linkage has been found to the BRCA1 locus on chromosome 17q21.[9-11] BRCA2, also responsible for some instances of inherited ovarian and breast cancer, has been mapped by genetic linkage to chromosome 13q12. The lifetime risk for developing ovarian cancer in patients harboring germline mutations in BRCA1 is substantially increased over that of the general population.[13,14] Two retrospective studies of patients with germline mutations in BRCA1 suggest that these women have improved survival compared with BRCA1 mutation-negative women.[15,16][Level of evidence: 3iiiA] Most women with a BRCA1 mutation probably have family members with a history of ovarian and/or breast cancer; therefore, these women may have been more vigilant and inclined to participate in cancer screening programs that may have led to earlier detection.
For women at increased risk, prophylactic oophorectomy may be considered after age 35 years if childbearing is complete. In a family-based study among women with BRCA1 or BRCA2 mutations, of the 259 women who had undergone bilateral prophylactic oophorectomy, 2 of them (0.8%) developed subsequent papillary serous peritoneal carcinoma, and 6 of them (2.8%) had stage I ovarian cancer at the time of surgery. Of the 292 matched controls, 20% who did not have prophylactic surgery developed ovarian cancer. Prophylactic surgery was associated with a higher-than-90% reduction in the risk of ovarian cancer (relative risk [RR], 0.04; 95% confidence interval [CI], 0.01–0.16), with an average follow-up of 9 years; however, family-based studies may be associated with biases resulting from case selection and other factors that may influence the estimate of benefit. (Refer to the Description of the Evidence section in the PDQ summary on Ovarian Cancer Prevention for more information.)
After a prophylactic oophorectomy, a small percentage of women may develop a primary peritoneal carcinoma, similar in appearance to ovarian cancer.
Ovarian cancer usually spreads via local shedding into the peritoneal cavity followed by implantation on the peritoneum and via local invasion of bowel and bladder. The incidence of positive nodes at primary surgery has been reported to be as high as 24% in patients with stage I disease, 50% in patients with stage II disease, 74% in patients with stage III disease, and 73% in patients with stage IV disease. In this study, the pelvic nodes were involved as often as the para-aortic nodes. Tumor cells may also block diaphragmatic lymphatics. The resulting impairment of lymphatic drainage of the peritoneum is thought to play a role in development of ascites in ovarian cancer. Also, transdiaphragmatic spread to the pleura is common.
For patients with stage I disease, the most important prognostic factor is grade, followed by dense adherence, and large-volume ascites. The use of DNA flow cytometric analysis of stage I and stage IIA patients may identify a group of high-risk patients. Patients with clear cell histology appear to have a worse prognosis. Patients with a significant component of transitional cell carcinoma appear to have a better prognosis. Stage I tumors have a high proportion of low-grade serous cancers and have a distinctly different derivation than high-grade serous cancers, which usually present in stages III and IV. Many high-grade serous cancers originate in the fallopian tube and other areas of extrauterine mullerian epithelial origin.
- Younger age.
- Good performance status.
- Cell type other than mucinous and clear cell.
- Lower stage.
- Well-differentiated tumor.
- Smaller disease volume prior to any surgical debulking.
- Absence of ascites.
- Smaller residual tumor following primary cytoreductive surgery.
For patients with stage I disease, the most important prognostic factor is grade, followed by dense adherence and large-volume ascites. DNA flow cytometric analysis of stage I and stage IIA patients may identify a group of high-risk patients. Patients with clear cell histology appear to have a worse prognosis. Patients with a significant component of transitional cell carcinoma appear to have a better prognosis.
Although the ovarian cancer-associated antigen, CA-125, has no prognostic significance when measured at the time of diagnosis, it has a high correlation with survival when measured 1 month after the third course of chemotherapy for patients with stage III or stage IV disease. For patients whose elevated CA-125 normalizes with chemotherapy, more than one subsequent elevated CA-125 measurement is highly predictive of active disease, but this does not mandate immediate therapy.[31,32]
Case-control studies suggest that BRCA1 and BRCA2 mutation carriers have improved responses to chemotherapy when compared with patients with sporadic epithelial ovarian cancer. This may be the result of a deficient homologous DNA repair mechanism in these tumors, which leads to increased sensitivity to chemotherapy agents.[33,34]
Survival and Follow-up
Most patients with ovarian cancer have widespread disease at presentation. This may be partly explained by relatively early spread (and implantation) of high-grade papillary serous cancers to the rest of the peritoneal cavity. Conversely, symptoms such as abdominal pain and swelling, gastrointestinal symptoms, and pelvic pain often go unrecognized, leading to delays in diagnosis. Screening procedures such as gynecologic assessment, vaginal ultrasound, and CA-125 assay have had low predictive value in detecting ovarian cancer in women without special risk factors.[36,37] Efforts have been made to enhance physician and patient awareness of the occurrence of these nonspecific symptoms.[38-42] (Refer to the PDQ summaries on Pain and Gastrointestinal Complications for more information.) As a result of these confounding factors, yearly mortality in ovarian cancer is approximately 65% of the incidence rate.
Long-term follow-up of suboptimally debulked stage III and stage IV patients showed a 5-year survival rate lower than 10% with platinum-based combination therapy prior to the current generation of trials, including taxanes. By contrast, optimally debulked stage III patients treated with a combination of intravenous taxane and intraperitoneal platinum plus taxane achieved a median survival of 66 months in a Gynecologic Oncology Group trial.
Numerous clinical trials are in progress to refine existing therapy and test the value of different approaches to postoperative drug and radiation therapy. Patients with any stage of ovarian cancer are appropriate candidates for clinical trials.[44,45] Information about ongoing clinical trials is available from the NCI Web site.
Other PDQ summaries containing information related to ovarian epithelial, fallopian tube, and primary peritoneal cancer include the following:
- Yancik R: Ovarian cancer. Age contrasts in incidence, histology, disease stage at diagnosis, and mortality. Cancer 71 (2 Suppl): 517-23, 1993. [PUBMED Abstract]
- Levanon K, Crum C, Drapkin R: New insights into the pathogenesis of serous ovarian cancer and its clinical impact. J Clin Oncol 26 (32): 5284-93, 2008. [PUBMED Abstract]
- Birrer MJ: The origin of ovarian cancer—is it getting clearer? N Engl J Med 363 (16): 1574-5, 2010. [PUBMED Abstract]
- Dubeau L, Drapkin R: Coming into focus: the nonovarian origins of ovarian cancer. Ann Oncol 24 (Suppl 8): viii28-viii35, 2013. [PUBMED Abstract]
- American Cancer Society: Cancer Facts and Figures 2014. Atlanta, Ga: American Cancer Society, 2014. Available online. Last accessed November 24, 2014.
- Lynch HT, Watson P, Lynch JF, et al.: Hereditary ovarian cancer. Heterogeneity in age at onset. Cancer 71 (2 Suppl): 573-81, 1993. [PUBMED Abstract]
- Pennington KP, Swisher EM: Hereditary ovarian cancer: beyond the usual suspects. Gynecol Oncol 124 (2): 347-53, 2012. [PUBMED Abstract]
- Piver MS, Goldberg JM, Tsukada Y, et al.: Characteristics of familial ovarian cancer: a report of the first 1,000 families in the Gilda Radner Familial Ovarian Cancer Registry. Eur J Gynaecol Oncol 17 (3): 169-76, 1996. [PUBMED Abstract]
- Miki Y, Swensen J, Shattuck-Eidens D, et al.: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266 (5182): 66-71, 1994. [PUBMED Abstract]
- Easton DF, Bishop DT, Ford D, et al.: Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet 52 (4): 678-701, 1993. [PUBMED Abstract]
- Steichen-Gersdorf E, Gallion HH, Ford D, et al.: Familial site-specific ovarian cancer is linked to BRCA1 on 17q12-21. Am J Hum Genet 55 (5): 870-5, 1994. [PUBMED Abstract]
- Wooster R, Neuhausen SL, Mangion J, et al.: Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265 (5181): 2088-90, 1994. [PUBMED Abstract]
- Easton DF, Ford D, Bishop DT: Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet 56 (1): 265-71, 1995. [PUBMED Abstract]
- Struewing JP, Hartge P, Wacholder S, et al.: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336 (20): 1401-8, 1997. [PUBMED Abstract]
- Rubin SC, Benjamin I, Behbakht K, et al.: Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N Engl J Med 335 (19): 1413-6, 1996. [PUBMED Abstract]
- Aida H, Takakuwa K, Nagata H, et al.: Clinical features of ovarian cancer in Japanese women with germ-line mutations of BRCA1. Clin Cancer Res 4 (1): 235-40, 1998. [PUBMED Abstract]
- Rebbeck TR, Lynch HT, Neuhausen SL, et al.: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346 (21): 1616-22, 2002. [PUBMED Abstract]
- Klaren HM, van't Veer LJ, van Leeuwen FE, et al.: Potential for bias in studies on efficacy of prophylactic surgery for BRCA1 and BRCA2 mutation. J Natl Cancer Inst 95 (13): 941-7, 2003. [PUBMED Abstract]
- Piver MS, Jishi MF, Tsukada Y, et al.: Primary peritoneal carcinoma after prophylactic oophorectomy in women with a family history of ovarian cancer. A report of the Gilda Radner Familial Ovarian Cancer Registry. Cancer 71 (9): 2751-5, 1993. [PUBMED Abstract]
- Burghardt E, Girardi F, Lahousen M, et al.: Patterns of pelvic and paraaortic lymph node involvement in ovarian cancer. Gynecol Oncol 40 (2): 103-6, 1991. [PUBMED Abstract]
- Dembo AJ, Davy M, Stenwig AE, et al.: Prognostic factors in patients with stage I epithelial ovarian cancer. Obstet Gynecol 75 (2): 263-73, 1990. [PUBMED Abstract]
- Schueler JA, Cornelisse CJ, Hermans J, et al.: Prognostic factors in well-differentiated early-stage epithelial ovarian cancer. Cancer 71 (3): 787-95, 1993. [PUBMED Abstract]
- Young RC, Walton LA, Ellenberg SS, et al.: Adjuvant therapy in stage I and stage II epithelial ovarian cancer. Results of two prospective randomized trials. N Engl J Med 322 (15): 1021-7, 1990. [PUBMED Abstract]
- Gershenson DM, Silva EG, Mitchell MF, et al.: Transitional cell carcinoma of the ovary: a matched control study of advanced-stage patients treated with cisplatin-based chemotherapy. Am J Obstet Gynecol 168 (4): 1178-85; discussion 1185-7, 1993. [PUBMED Abstract]
- Omura GA, Brady MF, Homesley HD, et al.: Long-term follow-up and prognostic factor analysis in advanced ovarian carcinoma: the Gynecologic Oncology Group experience. J Clin Oncol 9 (7): 1138-50, 1991. [PUBMED Abstract]
- van Houwelingen JC, ten Bokkel Huinink WW, van der Burg ME, et al.: Predictability of the survival of patients with advanced ovarian cancer. J Clin Oncol 7 (6): 769-73, 1989. [PUBMED Abstract]
- Neijt JP, ten Bokkel Huinink WW, van der Burg ME, et al.: Long-term survival in ovarian cancer. Mature data from The Netherlands Joint Study Group for Ovarian Cancer. Eur J Cancer 27 (11): 1367-72, 1991. [PUBMED Abstract]
- Hoskins WJ, Bundy BN, Thigpen JT, et al.: The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 47 (2): 159-66, 1992. [PUBMED Abstract]
- Thigpen T, Brady MF, Omura GA, et al.: Age as a prognostic factor in ovarian carcinoma. The Gynecologic Oncology Group experience. Cancer 71 (2 Suppl): 606-14, 1993. [PUBMED Abstract]
- Mogensen O: Prognostic value of CA 125 in advanced ovarian cancer. Gynecol Oncol 44 (3): 207-12, 1992. [PUBMED Abstract]
- Högberg T, Kågedal B: Long-term follow-up of ovarian cancer with monthly determinations of serum CA 125. Gynecol Oncol 46 (2): 191-8, 1992. [PUBMED Abstract]
- Rustin GJ, Nelstrop AE, Tuxen MK, et al.: Defining progression of ovarian carcinoma during follow-up according to CA 125: a North Thames Ovary Group Study. Ann Oncol 7 (4): 361-4, 1996. [PUBMED Abstract]
- Vencken PM, Kriege M, Hoogwerf D, et al.: Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients. Ann Oncol 22 (6): 1346-52, 2011. [PUBMED Abstract]
- Safra T, Borgato L, Nicoletto MO, et al.: BRCA mutation status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin. Mol Cancer Ther 10 (10): 2000-7, 2011. [PUBMED Abstract]
- Hogg R, Friedlander M: Biology of epithelial ovarian cancer: implications for screening women at high genetic risk. J Clin Oncol 22 (7): 1315-27, 2004. [PUBMED Abstract]
- Partridge E, Kreimer AR, Greenlee RT, et al.: Results from four rounds of ovarian cancer screening in a randomized trial. Obstet Gynecol 113 (4): 775-82, 2009. [PUBMED Abstract]
- van Nagell JR Jr, Miller RW, DeSimone CP, et al.: Long-term survival of women with epithelial ovarian cancer detected by ultrasonographic screening. Obstet Gynecol 118 (6): 1212-21, 2011. [PUBMED Abstract]
- Goff BA, Mandel L, Muntz HG, et al.: Ovarian carcinoma diagnosis. Cancer 89 (10): 2068-75, 2000. [PUBMED Abstract]
- Friedman GD, Skilling JS, Udaltsova NV, et al.: Early symptoms of ovarian cancer: a case-control study without recall bias. Fam Pract 22 (5): 548-53, 2005. [PUBMED Abstract]
- Smith LH, Morris CR, Yasmeen S, et al.: Ovarian cancer: can we make the clinical diagnosis earlier? Cancer 104 (7): 1398-407, 2005. [PUBMED Abstract]
- Goff BA, Mandel LS, Melancon CH, et al.: Frequency of symptoms of ovarian cancer in women presenting to primary care clinics. JAMA 291 (22): 2705-12, 2004. [PUBMED Abstract]
- Goff BA, Mandel LS, Drescher CW, et al.: Development of an ovarian cancer symptom index: possibilities for earlier detection. Cancer 109 (2): 221-7, 2007. [PUBMED Abstract]
- Armstrong DK, Bundy B, Wenzel L, et al.: Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354 (1): 34-43, 2006. [PUBMED Abstract]
- Ozols RF, Young RC: Ovarian cancer. Curr Probl Cancer 11 (2): 57-122, 1987 Mar-Apr. [PUBMED Abstract]
- Cannistra SA: Cancer of the ovary. N Engl J Med 329 (21): 1550-9, 1993. [PUBMED Abstract]