Special Feature
Ovarian Cancer Precursor: Fact or Fiction?
By David M. Gershenson, MD
Ovarian cancer remains the most lethal of gynecologic malignancies. Because no effective screening exists for this cancer, more than 70% of cases are still diagnosed after the tumor has spread beyond the ovary. Consequently, the five-year survival rate for the most common stage of this cancer—stage III—has not risen above 20% in the past three decades. Wouldn’t it be wonderful if we could identify the earliest molecular event in malignant transformation of the ovarian surface epithelium—a preinvasive lesion of the ovary—using an imaging modality, a blood test, or even an ovarian "Pap smear?" For more than 20 years, a number of investigators have searched for this elusive lesion, but without success. Proposed nomenclature has ranged from "ovarian dysplasia" to "ovarian carcinoma-in-situ" to a "premalignant ovarian lesion."
Whether an ovarian cancer precursor lesion exists remains unclear in the year 2000. One of the early proponents of the concept of "ovarian dysplasia" has been Liane Deligdisch from Mount Sinai in New York. Since the early 1980s, Deligdisch and colleagues have published extensively on the proposed entity.1-4 The basis of this classification is nuclear morphology that, they propose, is intermediate between benign and frankly malignant lesions of the ovarian epithelium. However, despite the focus of these many reports, the concept of ovarian dysplasia has not been widely embraced by the scientific community.
Nevertheless, the concept of an ovarian precursor lesion obviously continued to be of great interest for the reasons mentioned above. During the 1990s, several important advances propelled the concept back into the spotlight. Several centers began to study the modalities of transvaginal sonography, serum CA 125, or both, as screening modalities for the general population. In addition, the discoveries of the BRCA1 and BRCA2 genes and their mutations allowed us to refine our understanding of the genetics of ovarian cancer beyond that of mere family history—first popularized by the outstanding work of Henry Lynch. Subsequent investigations and observations indicated that approximately 10% of epithelial ovarian cancers are hereditary. In addition, we now know that certain features—Ashkenazi Jewish descent, family history of breast or ovarian cancer, personal history of breast cancer—place some women at higher risk for having one of these mutations and for ovarian cancer.
Because women with a BRCA1 gene mutation are at an estimated 30-60% lifetime risk of ovarian cancer, and women with a BRCA2 mutation are at an estimated 10-30% lifetime risk of ovarian cancer, by the mid-1990s investigators began to focus on these women for clues to some early genetic alteration. Salazar and colleagues examined histologically the ovaries of 20 women who underwent prophylactic oophorectomy because of their increased risk of ovarian cancer (due to family history or genetic studies).5 Among these 20 women, they found two unanticipated microscopic or near-microscopic malignant lesions. In addition, they reported that 85% presented two or more, and 75% presented three or more of the following histologic features: 1) surface epithelial pseudostratification; 2) surface papillomatosis; 3) deep cortical invaginations of the surface epithelium, frequently with multiple papillary projections within small cystic spaces; 4) epithelial inclusion cysts, frequently with epithelial hyperplasia and papillary formations; 5) cortical stromal hyperplasia and hyperthecosis; 6) increased follicular activity; 7) corpus luteum hyperplasia; or 8) hilar cell hyperplasia. A significantly smaller percentage of ovaries from control subjects contained such features—30% and 10%, respectively. Thus, Salazar et al concluded that the "frequency of these changes in the high-risk ovaries compared with control ovaries suggests a characteristic histologic preneoplastic phenotype defined by an increased frequency and intensity of the above-described histologic features in the high-risk ovaries."
The observation by Salazar et al of two occult ovarian malignancies in their series of 20 prophylactic oophorectomies (10%) was very important. Johannsson et al found that two of eight women (25%) who underwent prophylactic oophorectomy because of BRCA1 mutations had ovarian cancer at the time of surgery.6 More recently, investigators from Boston found four incidental ovarian tumors among 50 women undergoing prophylactic oophorectomy, 33 of whom had a calculated risk of carrying a germline BRCA1 or BRCA2 mutation greater than 25%.7 Two of these cases were borderline tumors, and two were malignant. The latter two apparently turned out to be primary peritoneal cancers involving the ovarian surface. Nevertheless, all three series underscore the fact that meticulous sectioning of ovaries from women who undergo prophylactic oophorectomy is imperative to rule out an occult or microscopic malignancy.
On the other hand, the report by Salazar et al subsequently prompted a firestorm of criticism from other experts in the field who disagreed with their findings. These critics essentially stated that their experience did not confirm the findings of premalignant lesions reported by Salazar et al. One such recent report compared ovaries prophylactically removed from 18 women with BRCA1 mutations with those removed from 20 controls.8 Ovaries were examined histologically in a blinded fashion (unlike in the Salazar study). Barakat and colleagues found no differences in histologic alterations of the ovaries between cases and controls, and they concluded that normal ovaries from BRCA1 heterozygotes do not show evidence of premalignant alterations in histology, molecular markers, cell proliferation, or apoptosis. Another group made observations similar to those of Barakat et al.9 Therefore, the issue of the frequency of so-called premalignant lesions in ovaries of women at high risk for ovarian cancer remains very much unresolved. However, a recent report by Werness et al indicates that BRCA1 and p53 can undergo loss of heterozygosity prior to stromal invasion in BRCA1-associated ovarian cancer, suggesting that "loss of function of these two tumor suppressor genes occurs early in ovarian carcinogenesis in BRCA1 mutation carriers."10
In conclusion, the hunt for a precursor lesion of ovarian cancer remains elusive. I do believe, however, that definitive evidence for such a marker will emerge within the next few years.
References
1. Gusberg SD, Deligdisch L. Cancer 1984;54:1-4.
2. Gil J, Deligdisch L. Pathol Res Pract 1989;185: 680-685.
3. Plaxe SC, et al. Gynecol Oncol 1990;38:367-372.
4. Deligdisch L, et al. Cancer 1993;72:3253-3257.
5. Salazar H, et al. J Natl Cancer Inst 1996;88: 1810-1820.
6. Johannsson OT, et al. J Clin Oncol 1998;16:397-404.
7. Lu K, et al. J Clin Oncol 2000;18:2728-2732.
8. Barakat RR, et al. Cancer 2000;89:383-390.
9. Stratton JF, et al. J Natl Cancer Inst 1999;91:626-628.
10. Werness BA, et al. J Natl Cancer Inst 2000;92:
1088-1091.
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