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Primary peritoneal carcinoma can have multifocal origins: implications for prophylactic oophorectomy.

The clinical entity of primary peritoneal carcinoma has had many different names, including papillary serous carcinoma of the peritoneum (PSCP). First reported in 1959 (1), PSCP refers to the diffuse involvement of peritoneal surfaces with a neoplasm appearing identical to papillary serous carcinoma of the ovary, in the absence of a demonstrable primary ovarian tumor. It can occur in women after oophorectomy for prophylaxis or benign disease or in women with intact ovaries. Clinically, it is indistinguishable from stage III epithelial ovarian cancer (2,3). Historically, there have been two theories about the origin of this cancer. The first is that the tumor develops in the ovarian surface epithelium and subsequently spreads throughout the peritoneal cavity. The primary tumor is postulated to be microscopic, and therefore not detectable, or to have regressed completely. The second theory is that the disease starts de novoin the peritoneal mesothelium, which is of müllerian origin. This theory seems plausible because the cell of origin of epithelial ovarian cancer is the peritoneal reflection on the surface of the ovary, not the underlying stromal or germ cell components. PSCP may be particularly relevant in women with inherited susceptibility to ovarian cancer, where germline mutations create a field defect. In this setting, the entire peritoneal surface, not just that covering the ovary, is at risk for malignant transformation. However, the peritoneal reflection on the surface of the ovary may be particularly vulnerable to malignant transformation as a result of repeated injury following ovulation and/or high levels of local estrogen exposure. The report by Schorge et al. (4) appearing in this issue of the Journal provides evidence for the latter hypothesis. Schorge et al. identified 22 women with PSCP and intact ovaries, 20 of whom were heterozygous at the androgen receptor (AR) locus on the X chromosome and thus informative for their analysis. These investigators demonstrated that, in five of the 20 cases, tumor DNA from multiple sites showed different patterns of loss of heterozygosity (LOH) at the AR locus. These data could be interpreted as evidence for the development of multiple, independent tumor clones or as evidence of tumor heterogeneity. However, two of these five tumors had different patterns of X-chromosome inactivation, a finding that strongly supports a multifocal origin, at least in these two cases. These results support the results obtained in a previous study (5) by the same group, in which they found a different pattern of 17p LOH and p53 gene mutation in four of six women with PSCP. Together, these results suggest that, in at least some cases, PSCP is polyclonal, arising in multiple primary peritoneal sites. Conversely, other investigators(6), using analysis of p53 gene mutations, have provided some evidence for monoclonal disease origin. In that series, nine of 10 patients with stage III ovarian cancer and two patients with PSCP had identical molecular changes at all tumor sites analyzed. While rare, PSCP has attracted attention lately as a cancer that may occur with increased frequency in women who carry inherited mutations in BRCA1 and BRCA2. It is well known that women with germline mutations in BRCA1 and BRCA2 have a markedly increased risk of developing ovarian cancer, with lifetime risk estimates ranging from 16% to 44%, depending on the populations being studied (7,8). The incidence of PSCP, before or after oophorectomy, is not known in these high-risk women. Of course, a major goal in the clinical management of these women is the reduction of cancer risk and related mortality. Strategies to this end have included increased cancer surveillance, risk factor modification, consideration of chemoprevention, and prophylactic surgery. Unfortunately, data from prospective trials of ovarian cancer risk alteration in known BRCA1 and BRCA2 mutation carriers are lacking. However, many women with BRCA1 and BRCA2 mutations are being advised to undergo prophylactic oophorectomy because of the lack of proven means of effective surveillance for ovarian cancer. A subset of these women goes on to develop PSCP, sometimes decades after oophorectomy. For ovarian cancer, secondary prevention efforts within the general population, including clinical examination, transvaginal ultrasound, and determination of CA125 serum levels, have not been shown to improve survival rates. Some investigators (10,11)have shown that intensive surveillance by use of transvaginal ultrasound in women with a family history of ovarian cancer can detect early stage disease with increased frequency, but this has not been confirmed in women with known BRCA1 and BRCA2 mutations. Unfortunately, the modification of life-