There is an emerging shift in the relative frequencies of ovarian and fallopian tube cancer in BRCA+ women that has been generated by studies of women undergoing prophylactic salpingo-oophorectomy.9, 10, 11, 14, 19
In contrast to symptomatic BRCA+ women with ovarian cancer whose tumors have been classified as ovarian in over 90%, early cancers detected in the asymptomatic women have been attributed to the fallopian tubes in up to 100% of studies.19, 20
Supporting this origin has been a recently described entity in the benign tubal mucosa – the p53 signature – that shares several attributes with early serous carcinomas (tubal intraepithelial carcinomas), including strong staining for p53, predominately distal (fimbria) tubal location, involvement of secretory cells, and evidence of DNA damage with frequent p53 mutations.14
However, controversy exists over the magnitude of cases of serous carcinoma deserving assignment to the tube versus ovary. This is the first study to systematically compare the prevalence of this candidate precursor lesion in Müllerian epithelium of the fallopian tube and ovary from the same patient population and to correlate the presence of CICs with p53 signatures in either site.
The frequency of the p53 signature in this series of BRCA+ fallopian tubes was virtually identical to that of consecutively accessioned fallopian tubes from women with neither a strong family history of ovarian cancer nor concurrent ovarian cancer described in an earlier report (). 14
The similarity in frequency of p53 signatures in the two groups suggests that the initiation of DNA damage and p53 accumulation is independent of BRCA mutation status and may serve as a generic early event in the pathogenesis of serous carcinomas arising in the distal fallopian tube.
The degree to which CICs play a role in serous carcinogenesis in BRCA+ women has been controversial. There is no question that the Mullerian epithelium in OSE, CICs or endometriosis is directly or indirectly responsible for a range of mucinous, endometrioid and low grade serous tumors. The degree to which BRCA status plays a role in the pathogenesis of these tumors is unclear, inasmuch as cancer risk in these patients is attributed primarily to the high grade serous carcinomas. 21
However, in a recent study, we found that 2 of 7 presumed primary tubal carcinomas in women with BRCA mutations were of the endometrioid type, suggesting that endometrioid carcinogenesis is enhanced, if to a lesser degree. 19
Investigators have focused principally on p53 mutations in CICs as an early event. A prior report has described p53 positive CICs adjacent to ovarian carcinomas. 5
A recent study has also implicated involvement of ovarian inclusions in this pathway by the discovery of p53 positive benign epithelia, often in concert with ovarian cancers.22
However, p53 positive CICs were not documented in another study of a similar population. 6
The findings in this study are consistent with the last study; only one p53 positive focus was detected on the ovarian surface and it was not associated with immunohistochemical evidence of DNA damage. No CICs contained positive staining.
Although we and others have not demonstrated a compelling scenario of p53 mutations in CICs, the role of the OSE in serous carcinogenesis remains an important, if unproven, concept. Animal models of ovarian epithelial carcinogenesis have focused on genotoxic damage imposed by ovulation, in which OSE cells in the proximity of the ovulatory event undergo DNA damage.23
A similar scenario would explain the localization of p53 signatures and serous carcinomas to the distal fallopian tube, where the potential genotoxic impact of ovulation would be highest.14
In this study, we found only one focus of p53-positive epithelium in the ovarian surface, but the number could be underestimated if OSE were lost during tissue processing, as is often the case. Another report described focally intense p53 staining in the OSE of 14% of prophylactic specimens from BRCA+ women in contrast to none of controls, and linked it to expression of BTAK, which is over-expressed in immortalized human OSE cells and a high percentage of ovarian cancers.24, 25
Whether this staining pattern has biologic significance is unclear, inasmuch as we did not see evidence of DNA damage in the one p53-positive focus identified in the OSE in this study, and the p53 mutational status of these foci is unknown. Nevertheless, the experimental evidence supports a role of the OSE in the development of ovarian cancer. While a distal tubal origin can be implicated in nearly one-half of “ovarian” serous carcinomas, the origin of nearly one fourth of these tumors – surface carcinomas without either an obvious intra-parenchymal ovarian source or endosalpingeal involvement – remains unresolved and could be explained by an origin in the OSE.12
The recent studies implicating the fallopian tube in serous carcinogenesis and the presence of a candidate precursor in this site provide a compelling endorsement for further research to resolve the risk factors involved in this model of serous carcinogenesis. The high frequency of p53 signatures is in keeping with most precursor models, in whichp the early events are far more common than cancer outcomes.26
The overall risk of ovarian cancer has been reported as high as 60% in BRCA+ women, and the odds of detecting an early malignancy in prophylactic specimens approximately 6 percent.27
The high frequency of p53 signatures in fallopian tubes from all women, combined with the much higher risk of cancer in BRCA+ women, suggests that a germline BRCA mutation may serve as a promoter, enhancing the risk of transition from a p53 signature to malignancy. However, further studies are needed to determine if p53 signatures represent more than one biologic entity. In a prior study, we found that 8 of 14 p53 signatures contained p53 mutations, an approach that is complicated by the small amount of target tissue and low recovery of DNA. In this study, immunostaining for γ-H2AX was employed as a surrogate marker for DNA damage, a feature characteristic of serous carcinomas, with 66% of cases scoring positive. We are currently investigating the possible role of immunostaining with this marker to predict the presence of a p53 mutation.
The strength of association between the distal fallopian tube and serous carcinogenesis is a compelling endorsement for an epidemiologic analysis of the p53 signature, in women both with and without genetic risk factors for pelvic serous cancer (). Studies that systematically catalogue the frequency of p53 signatures and divine their epidemiologic correlates in these populations will clarify the role of this entity as a surrogate marker for ovarian cancer risk and shed light on its causation.