ABSTRACT: 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 müllerian 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 müllerian 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.