Extraovarian primary peritoneal carcinoma (EOPPC), a relatively newly defined disease that develops only in women, accounts for approximately 10% of cases with a presumed diagnosis of ovarian cancer. Characterized by abdominal carcinomatosis, uninvolved or minimally involved ovaries, and no identifiable primary, EOPPC has been reported following bilateral oophorectomy performed for benign disease or prophylaxis. Most cases are of serous histology; however, nonserous tumors have been observed. Although EOPPC is similar to serous ovarian carcinoma with respect to clinical presentation, histologic appearance, and response to chemotherapy, molecular and epidemiologic studies have indicated that it may be a separate entity. This review explores the clinical presentation, management, prognosis, and survival of EOPPC.
Extraovarian primary peritoneal carcinoma (EOPPC) is an adenocarcinoma that develops from the peritoneum lining the pelvis and abdomen and is characterized by abdominal carcinomatosis, uninvolved or minimally involved ovaries, and no identifiable primary tumor. This relatively newly defined disease entity occurs exclusively in women and has been reported following bilateral oophorectomy performed for benign disease or prophylaxis. It accounts for approximately 10% of cases with a presumed diagnosis of ovarian cancer.
Although most cases of EOPPC are of serous histology, nonserous tumors have been reported. Different investigators have referred to EOPPC as serous surface papillary carcinoma,[1,4,5] primary peritoneal carcinoma, peritoneal mesothelioma, multiple focal extraovarian serous carcinoma, primary peritoneal papillary serous adenocarcinoma, serous surface carcinoma of the peritoneum, extraovarian peritoneal serous papillary carcinoma,[10,11] extraovarian mllerian adenocarcinoma, normal-sized ovary carcinoma syndrome, papillary serous carcinoma of the peritoneum,[14-16] and peritoneal papillary carcinoma.
Extraovarian primary peritoneal carcinoma is similar in clinical presentation, histologic appearance, and response to serous ovarian carcinoma. However, molecular and epidemiologic studies[18,19] suggest that EOPPC may be a separate entity. This review examines the current literature on EOPPC, with an emphasis on its clinical presentation, management, prognosis, and survival.
The first case of EOPPC was reported by Swerdlow in 1959. He described a 27-year-old woman experiencing pelvic pain, who, upon examination, was found to have an adnexal mass. Exploratory laparotomy revealed a friable pelvic tumor and normal fallopian tubes and ovaries. On microscopic examination, the tumor exhibited a papillary architecture and was most remarkable for large deposits of psammoma bodies.
Two years later, Rosenbloom and Foster reported a case of pelvic peritoneal tumor, which they referred to as diffuse papillary mesothelioma. In 1974, Parmley and Woodruff demonstrated that pelvic peritoneum had the potential to differentiate into a mllerian type of epithelium, and in 1977, Kannerstein et al and Kannerstein and Churg pointed out the importance of distinguishing EOPPC from peritoneal malignant mesothelioma, a condition that predominantly affects men and is associated with exposure to asbestos.
Two theories have been proposed to explain the development of EOPPC. Some authors believe that embryonic germ cell rests remain along the gonadal embryonic pathway and that EOPPC develops from a malignant transformation of these cells. Other authors contend that field carcinogenesis occurs, with the celomic epithelium lining the abdominal cavity (peritoneum) and the ovaries (germinal epithelium) manifesting a common response to an oncogenic stimulus.
Muto et al demonstrated that four of six cases of EOPPC had different patterns of allelic loss at various anatomic sites, and one of these cases also had a p53 mutation present in some, but not all, anatomic sites. These findings are consistent with a multifocal origin for primary peritoneal carcinoma.
The same authors had previously shown that, in advanced-stage epithelial ovarian cancer, the pattern of allelic loss, X chromosome inactivation, and p53 mutation was consistent with a unifocal origin. Contrary to Muto et al, Kupryjanczyk et al, using p53 mutation analysis, identified identical mutations in tumors obtained from different sites in two patients with primary peritoneal carcinoma. Again, these findings are consistent with a unifocal origin.
Role of BRCA1 Mutations?
Mutations of the tumor-suppressor gene BRCA1 have been implicated in the development of familial ovarian and breast cancer.[26,27] The role of BRCA1 gene mutations in the development of EOPPC is uncertain. In the only molecular study reported to date, BRCA1 germ-line mutations were identified in 3 (17.6%) of 17 EOPPC patients. If these findings are confirmed by further studies, EOPPC should be considered a malignancy expressed in the familial breast-ovarian cancer syndrome.
To date, ~500 cases of EOPPC have been reported in the literature. The relatively small number of reported cases is due to the facts that (1) EOPPC is a relatively newly defined disease entity and (2) most EOPPC cases are misdiagnosed as epithelial ovarian cancer.
Some authors believe that the incidence of EOPPC is increasing. Centers that document the relative frequency of EOPPC and epithelial ovarian cancer report a ratio of approximately 1:10.[17,19,29] An autopsy study by Rothacker et al demonstrated that EOPPC accounts for 8% of all autopsies with the final diagnosis of serous ovarian cancer. These authors estimated an incidence of 1 case per 150,000 women per year in their geographic area.
The risk factors for EOPPC are unknown. Unlike peritoneal mesothelioma, EOPPC has no association with exposure to asbestos.
An epidemiologic study that compared EOPPC patients with patients with epithelial ovarian cancer discovered some similarities and differences between the two groups. Compared with women with epithelial ovarian cancer, those with EOPPC were significantly older, had later menarche, and were less likely to have used perineal talc powder. On the other hand, there were no significant differences between the two groups with regard to race; education; income; marital status; smoking; history of the use of birth control pills or hormone replacement; history of tubal ligation or infertility; family history of ovarian, colorectal, or endometrial cancers; and personal history of breast or uterine cancers.
The clinical presentation of EOPPC is indistinguishable from that of advanced-stage epithelial ovarian cancer.[9-11,14-17] Most reported cases of EOPPC have been in white women, with a median age of 57 to 66 years.
The most common presenting symptoms include abdominal distention, pain, and gastrointestinal symptoms (nausea, vomiting, dyspepsia, or change in bowel habits). The most common presenting finding on physical examination is ascites, reported in approximately 85% of cases.
On exploratory laparotomy, a widespread intraperitoneal malignancy has been found, which usually involves the omentum and upper abdomen with minimal or no ovarian involvement. The operative findings of EOPPC are similar to those of advanced-stage epithelial ovarian cancer or peritoneal carcinomatosis from metastatic gastrointestinal cancers, except that the ovaries show minimal or no involvement and no primary can be found in the gastrointestinal tract or other organs. Because the ovaries look normal, EOPPC has sometimes been referred to as normal-sized ovary carcinoma syndrome.
Approximately 3.2% to 21.2% of EOPPC patients have a history of bilateral oophorectomy for benign disease or prophylaxis.[10,14,30] Extraovarian primary peritoneal carcinoma spreads mainly transperitoneally; however, lymphatic and blood-borne metastases have been suggested.[10,14,31] Metastasis to different groups of lymph nodes,[10,14] the liver parenchyma, and the brain have been reported.
Levels of the tumor marker CA 125 were elevated (> 35 U/mL) in most of the EOPPC patients in whom preoperative CA 125 values were known.[3,15,32] Some authors have found that CA 125 levels correlate with the clinical status of the disease and response to therapy. In a group of 29 EOPPC patients, mean CA 125 values were similar to those of a group of 27 women with epithelial ovarian cancer matched for age, stage, and grade.
1. Tobacman JK, Tucker MA, Kase R: Intraabdominal carcinomatosis after prophylactic oophorectomy in ovarian cancer prone families. Lancet 2:795-797, 1982.
2. Rothacker D, Mobius G: Varieties of serous surface papillary carcinoma of the peritoneum in Northern Germany: A thirty-year autopsy study. Int J Gynecol Pathol 14:310-318, 1995.
3. Altras MM, Aviram R, Cohen I, et al: Primary peritoneal papillary serous adenocarcinoma: Clinical and management aspects. Gynecol Oncol 40:230-236, 1991.
4. Gooneratne S, Sassone M, Blaustein A, et al: Serous surface papillary carcinoma of the ovary: A clinicopathologic study of 16 cases. Int J Gynecol Pathol 1:241-249, 1981.
5. Mulhollan TJ, Silva EG, Tornos C, et al: Ovarian involvement by serous surface papillary carcinoma. Int J Gynecol Pathol 13:120-126, 1994.
6. Moll UM, Valea F, Chumas J: Role of p53 alteration in primary peritoneal carcinoma. Int J Gynecol Pathol 16:156-162, 1997.
7. Swerdlow M: Mesothelioma of the pelvic peritoneum resembling papillary cystadenocarcinoma of the ovary: Case report. Am J Obstet Gynecol 77:200, 1959.
8. August CZ, Murad TM, Newton M: Multiple focal extraovarian serous carcinoma. Int J Gynecol Pathol 4:11-23, 1985.
9. Truong LD, Maccato ML, Awalt H, et al: Serous surface carcinoma of the peritoneum: A clinicopathologic study of 22 cases. Hum Pathol 21:99-110, 1990.
10. Dalrymple JC, Bannatyne P, Russell P, et al: Extraovarian peritoneal serous papillary carcinoma: A clinicopathologic study of 31 cases. Cancer 64:110-115, 1989.
11. Bloss JD, Liao SY, Buller RE, et al: Extraovarian peritoneal serous papillary carcinoma: A case-control retrospective comparison to papillary adenocarcinoma of the ovary. Gynecol Oncol 50:347-351, 1993.
12. Kowalski LD, Kanbour AI, Price FV, et al: A case-matched comparison of extraovarian vs primary ovarian adenocarcinoma. Cancer 79:1587-1594, 1997.
13. Feuer GA, Shevchuk M, Calanog A: Normal-sized ovary carcinoma syndrome. Obstet Gynecol 73:786-792, 1989.
14. Fromm GL, Gershenson DM, Silva EG: Papillary serous carcinoma of the peritoneum. Obstet Gynecol 75:75-89, 1990.
15. Killackey MA, Davis AR: Papillary serous carcinoma of the peritoneal surface: Matched-case comparison with papillary serous ovarian carcinoma. Gynecol Oncol 51:171-174, 1993.
16. Ransom DT, Shreyaskmar RP, Keeney GL, et al: Papillary serous adenocarcinoma of the peritoneum. Cancer 66:1091-1094, 1990.
17. Lele SB, Piver MS, Matharu J, et al: Peritoneal papillary carcinoma. Gynecol Oncol 31:315-320, 1988.
18. Muto MG, Welch WR, Mok SCH, et al: Evidence for a multifocal origin of papillary serous carcinoma of the peritoneum. Cancer Res 55:490-492, 1995.
19. Eltabbakh GH, Piver MS, Natarajan N, et al: Epidemiological differences between women with extra-ovarian primary peritoneal carcinoma and women with epithelial ovarian cancer. Obstet Gynecol 91:254-259, 1998.
20. Rosenbloom MA, Foster RB: Probable pelvic mesothelioma: Report of a case and review of literature. Obstet Gynecol 18:213-222, 1961.
21. Parmley TH, Woodruff JD: The ovarian mesothelioma. Am J Obstet Gynecol 120:234-241, 1974.
22. Kannerstein M, Churg J, McCaughey WTE, et al: Papillary tumors of the peritoneum in women: Mesothelioma or papillary carcinoma. Am J Obstet Gynecol 127:306-314, 1977.
23. Kannerstein M, Churg J: Peritoneal mesothelioma. Hum Pathol 8:83-84, 1977.
24. Tsao SW, Mok SCH, Knapp RC, et al: Molecular genetic evidence of a unifocal origin for human serous ovarian carcinomas. Gynecol Oncol 48:5-10, 1993.
25. Kupryjanczyk J, Thor AD, Beauchamp R, et al: Ovarian, peritoneal, and endometrial serous carcinoma: Clonal origin of multifocal disease. Mod Pathol 9:166-173, 1996.
26. Miki Y, Swensen J, Shattuck-Eidens D, et al: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66-71, 1994.
27. Shattuck-Eidens D, McClure M, Simrad J, et al: A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene. JAMA 273:535-541, 1995.
28. Bandera CA, Muto MG, Berkowitz RS, et al: Germline BRCA1 mutations in women with papillary serous carcinoma of the peritoneum (abstract). Gynecol Oncol 64:297, 1997.
29. White PF, Merino MJ, Barwick KW: Serous surface papillary carcinoma of the ovary: A clinical, pathological, ultrastructural and immunohistochemical study of 11 cases. Pathol Annu 20:403-418, 1995.
30. Piver MS, Eltabbakh GH. Hempling RE, et al: Two sequential studies for primary peritoneal carcinoma: Induction with weekly cisplatin followed by either cisplatin-doxorubicin-cyclophosphamide or paclitaxel-cisplatin. Gynecol Oncol 67:141-147, 1997.
31. Eltabbakh GH, Piver MS, Werness BA: Primary peritoneal adenocarcinoma metastatic to the brain. Gynecol Oncol 66:160-163, 1997.
32. Mills SE, Andersen WA, Fechner RE, et al: Serous surface papillary carcinoma: A clinicopathologic study of 10 cases and comparison with stage III-IV ovarian serous carcinoma. Am J Surg Pathol 12:827-834, 1988.
33. Cancer Committee of the International Federation of Gynecology and Obstetrics: Staging Announcement, FIGO Cancer Committee. Gynecol Oncol 25:383-385, 1986.
34. Resta L, Maiorano E, Zito FA, et al: Multifocal extraovarian serous carcinoma: A histochemical and immunohistochemical study. Eur J Gynecol Oncol 9:474-478, 1988.
35. Raju U, Fine G, Greenwald KA, et al: Primary papillary serous neoplasia of the peritoneum: A clinico-pathologic and ultrastructural study of eight cases. Hum Pathol 20:426-436, 1989.
36. Clark JE, Wood H, Jaffurs WJ, Fabro S: Endometrioid-type cystadenocarcinoma arising in the mesosalpinx. Obstet Gynecol 54:656-658, 1979.
37. Lee KR, Verma U, Belinson JL: Primary clear cell carcinoma of the peritoneum. Gynecol Oncol 41:259-262, 1991.
38. Banerjee R, Gough F: Cystic mucinous tumors of the mesentery and retroperitoneum: Report of three cases. Histopathology 12:527-532, 1988.
39. Hampton HL, Hufman HT, Meeks GR: Extraovarian Brenner tumors. Obstet Gynecol 79:844-846, 1992.
40. Mirc JL, Fenoglio-Preiser CM, Husseinzadeh N: Malignant mixed mullerian tumor of extraovarian secondary mullerian system: Report of two cases and review of the literature. Arch Pathol Lab Med 119:1044-1049, 1995.
41. Menzin AW, Aikins JK, Wheeler JE, et al: Surgically documented responses to paclitaxel and cisplatin in patients with primary peritoneal carcinoma. Gynecol Oncol 62:55-58, 1996.
42. Foyle A, Al Jabi M, McCaughey WTE: Papillary peritoneal tumors in women. Am J Surg Pathol 5:241-249, 1981.
43. Chen KTK, Flam MS: Peritoneal papillary serous carcinoma with long-term survival. Cancer 58:1371-1373, 1986.
44. Eltabbakh GH, Werness BA, Piver MS, et al: Prognostic factors in extra-ovarian primary peritoneal carcinoma (abstract). Gynecol Oncol 68:112, 1998.
45. Gilks CB, Bell DA, Scully RE: Serous psammocarcinoma of the ovary and peritoneum. Int J Gynecol Pathol 9:110-121, 1990.