Genetic Ovarian Cancer Syndromes

There are three well-recognized genetic syndromes that account for the vast majority of familial ovarian cancer and approximately 10% of all ovarian cancers. These are breast ovarian cancer syndrome (BOCS), site-specific ovarian cancer syndrome (SSOCS), and hereditary nonpolyposis colorectal cancer (HNPCC) syndrome (or Lynch syndrome). Both BOCS and SSOCS are caused by inherited mutations in the BRCA-1 and BRCA-2 genes. In fact, although often described as separate entities, these two syndromes are most likely phenotypic variants of the same genetic mutations. BRCA-1 and BRCA-2 function as classic tumor suppressor genes and are inherited in an autosomal dominant fashion. Lynch syndrome is caused by mutations in DNA mismatch repair genes responsible for repairing errors in DNA replication. Inactivation of these genes result in a high incidence of right-sided colon cancer, endometrial cancer, and ovarian cancer. Hereditary ovarian cancers associated with BRCA-1 and BRCA-2 mutations will be discussed first, followed by Lynch syndrome–related ovarian cancer.

Breast Ovarian Cancer Syndrome and Site-Specific Ovarian Cancer Syndrome

Germline mutations in the BRCA-1 and BRCA-2 tumor suppressor genes account for approximately 90% of cases of hereditary ovarian epithelial cancers and confer a risk of ovarian carcinoma by age 70 of 40% to 50% and 10% to 20%, respectively. BRCA-1 and BRCA-2 are located on chromosomes 17q21 and 13q12-13, respectively, and are inherited in an autosomal dominant fashion. They encode nuclear proteins that are functionally similar. Both proteins participate in the repair of double-stranded DNA damage, as well as the regulation of gene expression at a transcriptional level. Loss of BRCA protein function leads to failure to repair DNA damage, resulting in the activation of p53, with subsequent initiation of cell cycle arrest or apoptosis. In the absence of functional p53, however, the cell continues to proliferate, DNA damage accumulates, and the likelihood of ensuing malignancy increases.

The lifetime risk of developing ovarian cancer in the United States is about 1.4%, but among women with BRCA-1 and BRCA-2 mutations, the risk has been estimated to be about 40% and 20%, respectively. These genes also impart a significant lifetime risk of breast cancer in women and, in the case of BRCA-2, in men as well. Less than 0.3% of those in the general population are carriers of BRCA-1 or BRCA-2 mutations; however, the carrier rate is dependent on ethnic background.

Founder mutations have been identified among multiple unrelated families in Iceland, the Netherlands, Sweden, and among Jews of Central or Eastern European (Ashkenazi) descent. The best-described founder mutations are the 185delAG and 5382insC mutations in BRCA-1 and the 6174delT mutation in BRCA-2, occurring in Ashkenazi Jews at a carrier rate of 2%. Although women of Ashkenazi Jewish descent do not have an overall increased rate of ovarian cancer, if an Ashkenazi Jewish woman develops ovarian cancer, it is far more likely to be genetic rather than sporadic. Consequently, if a woman of Ashkenazi Jewish descent develops ovarian cancer, there is a 40% chance she carries a mutation in one of these two genes. The implications for her first-degree relatives (mother, sisters, daughters) are that they have a 20% risk for being gene carriers (given autosomal dominant transmission). Therefore, a woman of Ashkenazi Jewish heritage needs only one first-degree relative with ovarian cancer to be considered for further genetic counseling. Routine screening of Ashkenazi women has been proposed given the high likelihood missing carriers based on family history alone.

In contrast to hereditary breast cancers, in which BRCA-1 and BRCA-2 mutations are found with equal frequency, BRCA-1 mutations are found more commonly than BRCA-2 mutations in patients with familial ovarian carcinoma. The mean age of developing ovarian cancer in the setting of a BRCA-1 mutation is younger than in the women without a mutation (53 vs. 63 in the latter group). Although BRCA-1 carriers have a 2% to 3% risk of ovarian carcinoma by age 40, for BRCA-2 carriers, this risk is not until age 50. Mutations in BRCA genes are rare in the setting of sporadic ovarian tumors, but loss of function of their encoded proteins may play a role in tumor development. Inactivation of BRCA-1 in sporadic ovarian tumors has been attributed to promoter hypermethylation.

The Society of Gynecologic Oncologists (SGO) has issued recommended criteria for referral of women to genetic counselors and consideration for genetic testing for BRCA-1 and BRCA-2 genes. These risk variables are summarized in Box 24.1 . Because women with high-grade serous carcinoma probably have a higher rate of underlying germline mutations in BRCA (16% to 20%) than other ovarian tumors, testing should be considered for all women with this type of tumor. Some have argued for population-based testing, independent of history, given the feasibility of such testing, risk associated with missing carriers, and variability in assessment of family history and referral to genetic counselors. In addition, it is currently far more common to obtain expanded panel testing to include other lower penetrance genes.

Most ovarian malignancies diagnosed in women with BRCA mutations are high-grade serous carcinomas of advanced stage. These tumors tend to have morphologic features known as SET, referring to more than 50% solid, pseudoendometrioid, or transitional. Other histologic types have less frequently been described in patients with BRCA-1 mutations, including endometrioid, clear cell, transitional, and undifferentiated carcinomas; carcinosarcoma; and dysgerminoma. Borderline tumors and mucinous tumors do not appear to be associated with BRCA mutations. The overwhelming majority of malignancies identified in the fallopian tube in women with BRCA mutations are also high-grade serous carcinomas.

Lynch Syndrome

Mutations in mismatch repair genes (Lynch syndrome) account for only a small percentage of hereditary ovarian cancer; these women have a lifetime risk of up to 12% for ovarian cancer. Mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) most frequently lead to loss of function and, therefore, to microsatellite instability (MSI). Mismatch repair proteins function to DNA base-pair mismatches. Microsatellites are repetitive DNA sequences that are prone to replication errors, such as base-pair mismatches. Loss of mismatch repair protein function results in an inability to repair these mismatches with resultant MSI. MSI is characterized by these repetitive DNA areas retracting or expanding and causing frameshift mutations. Tumors presumably form when the frameshift mutations occur within the coding region of genes involved in tumor development. Not all mismatch repair gene mutations bear an equivalent risk for ovarian cancer; mutations in PMS2 are associated with the lowest overall risk.

Most ovarian cancers in Lynch syndrome are non-serous histology, specifically endometrioid, clear cell, or undifferentiated carcinomas. Up to 10% of ovarian carcinomas in patients less than or equal to 50 years old are associated with Lynch syndrome. There is a strong association between Lynch syndrome and clear cell carcinoma of the ovary, with mismatch repair protein mutations in 14% or 17% of clear cell carcinomas.

Guidelines for Lynch syndrome in ovarian cancer are not well defined. The Amsterdam and Bethesda criteria primarily focus on colorectal carcinoma, but the SGO has also outlined guidelines for gynecologic tumors. In general, testing for Lynch syndrome should be considered in woman with non-serous ovarian epithelial carcinoma. Because most women with Lynch syndrome who present with ovarian cancer are younger than 50 years old, many age-based algorithms must take this into account. Molecular analysis of the DNA mismatch repair genes is the gold standard for definitive diagnosis of Lynch syndrome, but it is not routinely employed as a screening method due to cost and is used mostly for confirmation. Various algorithms for using mismatch repair protein immunohistochemistry, MSI analysis, and MLH1 methylation studies have been employed. In our institution, we screen all non-serous ovarian epithelial carcinomas by mismatch repair protein immunohistochemistry, with reflex to MLH1 methylation studies in cases where MLH1 expression is lost. This information is directly forwarded to our genetic counseling department to determine the need for further assessment and potential germline testing. Parenthetically, all women with ovarian cancers at the Dana Farber Cancer Institute/Brigham and Women’s Hospital are referred for genetic counseling and undergo expanded panel testing if consenting. We no longer use family history to guide us.

Hereditary Predisposition to Ovarian Cancer: Beyond BRCA and Mismatch Repair Genes

Given that there are still families with strong histories of ovarian cancer with no identifiable mutations in BRCA-1, BRCA-2, or mismatch repair genes, current efforts are focused on identification of other inherited genetic mutations, which might account for the increased risk. Analysis of the large genomic library of single nucleotide repeats in large populations of cases and controls has been performed with the intent to identify loci that segregate with malignancy. This has been successful to a degree, identifying potentially predictive genomic markers for ovarian cancer. The downside has been the relatively low overall risk imposed by individual changes (less than twofold), which are too small to justify their use in a clinical setting, but combined risk models are emerging. Multigene panel testing for cancer risk has become available to patients complicating management recommendations and further stressing the invaluable role of genetic counselors in the process. The risk associated with the genes is highly variable with about 20% of mutations considered to be variants of uncertain significance.

Although BRCA-1, BRCA-2, and mismatch repair genes are certainly the most well-known and studied genes associated with a hereditary disposition to ovarian cancer, recent advances have identified other genes associated with potential increased risk. Mutations in BRIP1, RAD51C, and RAD51D confer a lifetime risk of 10% to 15%. A multi-gene profile (BROCA) is also in use. PALB2 gene mutations have been identified in some families with strong breast and ovarian cancer histories, but the actual risk of ovarian cancer with this gene is currently unknown. Some recently identified mutations are associated with particular types of ovarian tumors. For example, DICER1 mutations are associated with increased risk for the development of Sertoli-Leydig cell tumors, and SMARCA4 gene mutations confer risk for ovarian small cell carcinoma.

Demographic Risk Factors for Ovarian Cancer

Endometriosis

Endometriosis increased ovarian cancer risk with a RR of 1.3 to 1.8. Such cancers are more often low stage and of low-grade endometrioid and clear cell histology. The risk is higher with increasing age and cyst complexity on ultrasound.

Oral Contraceptives

Oral contraceptive pills (OCPs) significantly reduce the risk of developing ovarian cancer. A number of studies have demonstrated a 10% per year risk reduction up to 5 to 7 years of use. This effect seems to persist for at least 10 years after OCPs are discontinued. This protective effect has also been observed in patients known to be carriers of the BRCA-1 and BRCA-2 genes and is the basis for recommending OCPs as a chemoprophylactic agent in known carriers who wish to retain their fertility. There has recently been some controversy about the protective effects of OCPs in BRCA patients. An Israeli population-based study of OCPs and ovarian cancer demonstrated a protective effect of pregnancy but not of OCPs. It is unclear why the Israeli data are inconsistent with prior published reports.

Tubal Ligation

Tubal ligation reduces risk by more than half and may be effective in subsets of women with BRCA mutations and family history of ovarian cancer. The mechanism by which this procedure reduces risk is unknown, but the popular theory is that the transfer of growth factors or carcinogens is interrupted.

Risk Reduction Surgery

Women with inherited mutations in BRCA-1 or BRCA-2 genes carry a sizable risk of “pelvic” (ovarian/fallopian tube/peritoneal) cancer. This risk is attenuated as much as 80% to 90% in those who elect to undergo risk reduction surgery. Following the increased attention to the fallopian tube as a source of high-grade serous cancer over the past 10 years, opportunistic salpingectomy has emerged as a recommended approach to reducing cancer risk in women undergoing sterilization or hysterectomy for benign disease. This involves the removal of fallopian tubes for primary prevention of epithelial carcinoma of the fallopian tube, ovary, or peritoneum in a woman undergoing pelvic surgery for another indication. Based on retrospective population studies, the reduction in ovarian cancer risk is estimated at about 50% with a hazard ratio of 0.65. Although not universal, this practice is being employed in many centers and more precise estimates as to the effectiveness of this technique should be forthcoming over the next one or two decades. Professional societies in several countries now recommend considering salpingectomy at the time of hysterectomy when convenient. Opportunistic salpingectomy with temporary preservation of the ovaries is also being explored in women with BRCA mutations who refuse oophorectomy but there are no outcome data at present. Table 24.1 provides a summary of the risk reduction for ovarian cancer provided by these potential preventative measures.

Pelvic Examination

Pelvic examination is a central component of gynecologic care and permits the evaluation of potential abnormalities throughout the reproductive tract. However, the sensitivity of pelvic examination for the detection of ovarian cancer is only about 44%. A 15-year study of pelvic examination alone uncovered six ovarian cancers in more than 18,000 examinations of 1319 women.

Biomarker Screening Alone

Since the discovery of CA-125 in the 1980s, there has been little progress in the development of a molecular screening tool that promised to make a measurable impact on the death rate for ovarian epithelial cancer. The reasons for this are several:

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  CA-125 is a high molecular weight glycoprotein that is elevated above 35 IU/mL in 85% of all epithelial carcinomas but in only 50% of women with stage I disease.

  
  
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  CA-125 elevations are associated with a range of other intra-abdominal disorders, cutting into the specificity of this marker.

  
  
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  A test with 99% specificity will still necessitate as many as 25 invasive procedures to identify a single malignancy. This level of precision has not been attained, even when multiple biomarkers have been used, including osteopontin and HE4. One study proposed six biomarkers: leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, and CA-125, claiming both high sensitivity and specificity, but it was challenged as unduly optimistic.

Another highly challenging variable in reducing the ovarian cancer death rate by conventional serologic screening lies in the nature of the disease itself. One-fourth of ovarian cancers are associated with a pathogenesis that would favor screening—that is, tumors arising in the ovary that have a lag period prior to developing and metastasizing, specifically endometrioid, mucinous, and clear cell carcinomas. Clearly, these tumors would benefit from screening. Accordingly, when detected in stage I, they all have a good to excellent prognosis. Unfortunately, two-thirds or more ovarian cancers are high-grade serous (or high-grade endometrioid) and have spread to the pelvic organs by the time of diagnosis. A recent report estimated the lead time that could be expected for serologic detection. Based on a longitudinal study with serologic biomarker analysis, the study concluded that levels of CA-125, HE4, and mesothelin began to rise as early as 3 years before the clinical presentation with malignancy; however, significant elevations were not seen until the last 12 months before presentation. The efforts to develop diagnostic biomarkers the past two decades have come face to face with the stark implications of this reality if not the profound significance of understanding the origins and precursors of ovarian cancer. At present, the failure of biomarker detection to alter the disease has resulted in recommendations by every society and task force that routine screening for ovarian cancer not be performed.

Combining Biomarkers With Ultrasound and Other Imaging Techniques

There is evidence that transvaginal sonography (TVS) improves early detection of ovarian cancer and possibly influences mortality in some instances, but at a significant trade-off in specificity ( Fig. 24.1 ). Van Nagell et al. scored ovaries as abnormal if they exceeded 10 and 20 cm ³ from post- and premenopausal women, respectively. In a study of 8500 women who underwent TVS, 121 were abnormal and underwent surgery. A total of 57 had serous cystadenomas, and eight had ovarian cancers, six of which were stage IA. Only one each had an enlarged ovary by palpation or an elevated CA-125. The implication from studies of this type is that TVS will downstage a proportion of tumors and permit improved survival. Despite these results, this group found that TVS had a sensitivity of 98.7% but a positive predictive value (PPV) of only 6.8%. Partridge and Barnes summarized five studies of 11,283 women, noting a PPV of only 3.1% for ovarian cancer. In a study of TVS encompassing 42,113 screening years, van Nagell et al. defined an ovarian volume exceeding 10 cm in postmenopausal women or 20 cm in premenopausal women, or papillary or complex architecture as abnormal. Some 17 of 180 patients with persisting TVS abnormalities who underwent exploratory laparoscopy or laparotomy had cancer, 11 of which were stage I. Eight of the 11 did not have a palpable mass. TVS screening in this setting had a PPV of 9.4% with a negative predictive value of 99.97%. When nonepithelial tumors were excluded, the survival of ovarian cancer patients in the annually screened population was 92.9% at 2 years and 83.6% at 5 years. The authors cautioned that although the improved detection and reduced mortality were associated with screening, this benefit did not apply to women whose cancers occurred in the setting of a normal ovarian volume. Additional studies have echoed the low PPV (1% to 27%) and false positive/true positive ratios of over 30, while reporting a small number of tumors diagnosed at stage I.

Ultrasound evaluation of benign and malignant ovarian cysts. A, Hemorrhagic smooth-walled cyst. B, Ovarian cancer with irregular wall thickness, lining surface, and septation.

(Courtesy of Beryl Bennaceraf, Boston, MA.)

A recent report summarized sequential screening with a baseline and three follow-up CA-125 and TVS assessments. The PPVs were 1.4% to 1.8%, respectively. The ratio of surgical procedures to cancers detected was 31 : 1 at the initial screening and 14 : 1 on the subsequent three testing events. Similar to the studies described, 67% to 83% were stage III or IV, respectively, when diagnosed. Most of the surgeries were prompted by a positive TVS event. An important caveat is that these studies targeted ovarian enlargement, a strategy that ignores the early phases of serous carcinogenesis in the distal fallopian tube, ovarian, and pelvic surfaces. The same limitations apply to the use of ultrasound and biomarkers in combination. The Prostate, Lung, Colorectal and Ovarian (PLCO) trial show that screening with both CA-125 and transvaginal ultrasound compared with standard care did not reduce ovarian cancer mortality.

A recent trial garnering considerable attention was the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKTOCS) that compared yearly CA-125 (using an algorithm) and transvaginal ultrasound (multimodality screening [MMS]) to ultrasound alone and no screening. Over 200,000 women were enrolled. Although the primary analysis did not appear to show a reduction in mortality for MMS, there was a 20% mortality reduction at 7 to 14 years. The authors concluded that this was due to removal of prevalent cases (years 1 to 7). Caveats include the following:

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  The notion that the differences in mortality between early and later years of the study are due to prevalent versus incident disease is unproven.

  
  
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  Estimates of ovarian cancer mortality were based on death certificate data in the compared populations, and the precise reason for reduced mortality estimates is not known.

  
  
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  There is no evidence that this screening algorithm will alter mortality in women with BRCA-1 or BRCA-2 mutations, where the ovarian cancer outcome estimation would be far less prone to error.

This management algorithm is currently not recommended by the U.S. Food and Drug Administration (FDA). Various other algorithms which combine imaging, biomarkers, and clinical signs have been proposed but have not yet been widely adopted.

Molecular Screening for Ovarian Cancer

With the emergence of highly sensitive molecular assays for gene mutations, a few studies have explored the possibility that ovarian or tubal cancers could be detected via analysis of lower genital tract fluids. In theory, these “molecular Papanicolaou (Pap) tests” would detect mutations by sequence analysis targeting common mutations associated with gynecologic cancers. Kinde et al. successfully identified mutations in liquid-based Pap tests from 9 of 22 ovarian carcinomas. It remains to be seen whether this approach will detect early ovarian or tubal carcinomas in their curable stages or will encounter problems with “background mutations” in the genital tract mucosa of healthy women.

Prophylactic Surgery and Detection of Early Malignancy

Bilateral salpingo-oophorectomy in women with BRCA mutations reduces the risk of developing pelvic serous cancers by greater than 90%. Laparoscopy (whenever possible this is the preferred modality) and laparotomy (almost never) are the surgical modalities of choice to allow inspection of the peritoneal surfaces at the time of prophylactic salpingo-oophorectomy and collect fluid for cytologic evaluation. Performing a hysterectomy in addition to removing the adnexa does not appear to improve the efficacy of the procedure. Paradoxically, women with BRCA -associated cancers have a better clinical outcome following treatment than those without BRCA mutations, even though the former tend to present at a higher stage. Presumably, this is due in part to BRCA -associated tumors being more susceptible to chemotherapeutic agents, such as cisplatin, that induce double-stranded DNA damage.

Prophylactic surgery may reduce, but not completely eliminate, the risk of ovarian cancer in high-risk individuals. Bilateral salpingo-oophorectomy in BRCA carriers reduces ovarian cancer risk by over 90% and breast cancer risk by over 50%. The operation should be reserved for women with known mutations in BRCA-1 or BRCA-2 (or other lower penetrance genes with deleterious mutations) or those who have a family history consistent with one of the genetic syndromes associated with ovarian cancer, and it should include an evaluation by a genetic counselor. The addition of hysterectomy does not appear to increase the efficacy of the operation and should be performed only for concurrent gynecologic indications or if the patient has HNPCC. Patients should be informed that prophylactic surgery does not protect them against the subsequent development of high-grade serous carcinoma of the peritoneum. They should also be warned that about 7% of prophylactic operations detect occult ovarian or tubal carcinoma and that these lesions may not be appreciated until final pathology reports are available. Pathologists should be instructed to submit the entire specimen for sectioning to reduce the risk of missing a microscopic occult malignancy. Finally, the patient should be prepared for the consequences of surgical menopause.

An additional risk that has been addressed recently is that of a subsequent uterine serous adenocarcinoma. One study computed an odds ratio of 22 for women with BRCA-1 and 6.4 for those with BRCA-2 germ line mutations. These estimates were based on a very small number of cancer cases across multiple institutions; however, three of three did show loss of wild type BRCA-1 gene. Thus this risk, albeit small, will enter into the discussion when counseling women with these mutations.

In studies of women undergoing prophylactic salpingo-oophorectomy for BRCA-1 or BRCA-2 mutations (BRCA+), the risk of uncovering an early cancer has been estimated to be about 5% to 10%, a figure that may vary both as a function of the age of the population and the thoroughness with which the specimen is examined. Many of these early cancers have been identified in the distal fallopian tube, the earliest malignancy being a tubal intraepithelial carcinoma. In a review of nearly 20 cases in our institution, the frequency of a tubal intraepithelial carcinoma was over 80%. In the largest study to date (GOG-0199), clinically occult cancers were detected in 15 of 326 (4.6%) BRCA-1 carriers and 8 of 231 (3.5%) BRCA-2 carriers undergoing prophylactic salpingo-oophorectomy; about half of these tumors were more than stage II. With these figures in mind, the following points must be stressed:

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  Early malignancies can be both serous (STIC, 80%) and rarely, endometrioid (ETIC, 20%).

  
  
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  Twenty percent of these early serous cancers are not associated with an intraepithelial lesion in the fallopian tube; more extensive tubal sampling might uncover some, but most of the time it will not.

  
  
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  Advanced pelvic serous cancers in BRCA+ women are virtually identical in tumor distribution to the general population with this disease (i.e., less than half will have evidence of a tubal origin). Although it may be tempting to attribute this to obliteration of the tubal mucosal origin by expanding tumor or some other sampling artifact, the reader is strongly cautioned that salpingectomy alone may not rid the patient of risk, and leaving the ovary might even place her at a substantial risk of an eventual pelvic serous cancer .

  
  
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  Prophylactic specimens from women with a family history of cancer but without a documented BRCA mutation are unlikely to contain an early malignancy. Virtually all genetically related pelvic serous cancers are linked to BRCA+.

  
  
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  As mentioned earlier, STICs are also rarely reported in fallopian tubes removed as part of surgery for indications other than serous carcinoma.

The SEE-FIM Protocol

Prophylactic salpingo-oophorectomies from women with mutations in BRCA or strong family histories of ovarian carcinoma should be submitted entirely and examined histologically. Most of the early cancers described in the preceding sections occur in grossly unremarkable specimen, so it is imperative that all the tissue be evaluated in order to properly treat the individual and to further understand the pathogenesis of this disease.

The fallopian tubes and ovaries should be submitted entirely and be evaluated in serial sections by a pathologist with expertise in gynecologic malignancies. At Brigham and Women’s Hospital, the goal is to ensure sectioning and extensive examination of the fimbria (SEE-FIM protocol), because the majority of early serous tumors occur in this area, which is as follows ( Fig. 24.2 ):

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  The entire tube is initially fixed for at least 4 hours to minimize loss of epithelium during manipulation.

  
  
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  The distal 2 cm of the fimbriated end is amputated.

  
  
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  The fimbrial mucosa is sectioned longitudinally into four pieces. The remainder of the tube is sectioned transversely every 2 to 3 mm into cross sections.

  
  
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  The tubal segments combined with the fully sectioned fimbriated end are submitted in toto.

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