BRCA1 expression in a large series of sporadic ovarian carcinomas: a Gynecologic Oncology Group study.

BRCA1 is a tumor suppressor gene that, when mutated, is associated with the development of hereditary ovarian cancer. A role for BRCA1 in the pathoetiology of sporadic ovarian epithelial cancer (OEC) development has been suggested, although spontaneous mutations of the BRCA1 gene in this disease are uncommon. Loss of gene function by epigenetic alteration is observed more commonly, while other means of gene inactivation have not been intensively investigated. We examined expression and localization of the BRCA1 gene product by immunohistochemistry and sought to clarify the relationship between protein expression and tumor stage, grade, histopathologic subtype, and outcome. Among 230 spontaneous OEC tumors, we found a statistically significant decrease in BRCA1 protein expression with advancing stages of OEC. There was no relationship between expression and tumor grade. There was a statistically significant relationship between the pathologic subtypes of OEC and BRCA1 expression. Minimal BRCA1 expression was protective for survival. These findings confirm a high rate of loss of BRCA1 protein expression in sporadic OEC and suggest a role of BRCA1 in the progression of sporadic ovarian carcinoma.

BRCA1 germline mutations and polymorphisms in a clinic-based series of ovarian cancer cases: a Gynecologic Oncology Group study.

OBJECTIVE: The aims of this study were to determine the frequency of BRCA1 gene alterations in an unselected, clinic-based series of ovarian cancer cases; to evaluate the usefulness of family history in predicting the likelihood of a disease-causing mutation; and to document the occurrence of polymorphic variants in BRCA1 and to determine their distribution among families accordingly to history of breast and/or ovarian cancer. METHOD: Two hundred fifty-eight women with primary epithelial ovarian cancer, entered onto a nonclinical protocol of the Gynecologic Oncology Group, were analyzed for BRCA1 germline alterations by single-strand conformation polymorphism analysis. RESULTS: Protein-truncating mutations in BRCA1 were identified in 12 patients (4.6%). The median age of cancer diagnosis in BRCA1 mutation carriers was 47 years compared to 57 years in patients without mutations (P = 0.02). All but 1 of the patients with BRCA1 mutations reported a family history of breast and/or ovarian cancer and 8 had a first-degree relative with cancer. Twelve mutations of unknown significance were also identified. An association was also noted between the presence of common polymorphisms in BRCA1 and family history of cancer. Polymorphisms were present at higher frequency among women without a family history of cancer compared to women with positive family histories, suggesting they are associated with reduced risk. CONCLUSION: In a clinic-based series of ovarian cancer patients, germline BRCA1 mutations were detected in 12 of 258 (4.6%) patients. A strong correlation was noted between the presence of mutations and family history of breast and/or ovarian cancer, indicating that these women are most likely to benefit from genetic susceptibility testing.

The efficacy of transvaginal sonographic screening in asymptomatic women at risk for ovarian cancer.

OBJECTIVE: The purpose of this study was to determine the efficacy of annual transvaginal sonography (TVS) as a screening method for ovarian cancer. METHODS: Annual TVS screening was performed on 14, 469 asymptomatic women from 1987 to 1999. Eligibility criteria included (1) all women >/= 50 years of age and (2) women >/= 25 years of age with a family history of ovarian cancer. Ovarian volume was calculated using the prolate ellipsoid (length x height x width x 0.523). An abnormal sonogram was defined by (1) an ovarian volume >10 cm(3) in postmenopausal women or >20 cm(3) in premenopausal women or (2) a papillary or complex tissue projection into a cystic ovarian tumor. All women with abnormal TVS had a repeat sonogram in 4-6 weeks. Patients with a persistently abnormal second screen had a serum CA-125 determination, tumor morphology indexing, and Doppler flow sonography, and were advised to have surgical tumor removal. RESULTS: One hundred eighty patients with persisting TVS abnormalities underwent exploratory laparoscopy or laparotomy. Seventeen ovarian cancers were detected: 11 Stage I, 3 Stage II, and 3 Stage III. Only three patients with Stage I cancers had a palpable ovarian mass on clinical examination. All patients with Stage I and II ovarian cancer are alive without recurrence 1.8-9.8 years (median, 4.5 years) after diagnosis. Two of the three Stage III patients have died of disease: one at 4.3 years and one at 7.7 years after detection. Four patients developed ovarian cancer within 12 months of a negative scan (FN): 2 Stage II, 2 Stage III. Three of these patients are alive with no evidence of disease 0.4, 1.9, and 5.5 years after diagnosis, and 1 patient has died of disease 0.7 years after diagnosis. Four patients developed ovarian cancer more than 12 months following a normal screen. All 4 presented clinically with Stage III disease. Two of these patients have died of disease and two patients are alive 1.5 and 2.1 years after diagnosis. TVS screening was associated with the following statistical variables: sensitivity, 81%; specificity, 98.9%; positive predictive value (PPV), 9.4%; and negative predictive value (NPV), 99.97%. After 46, 113 screening years, there have been 3 ovarian cancer deaths in the annually screened population and 2 ovarian cancer deaths in women receiving less than annual screening. The survival of ovarian cancer patients in the annually screened population was 95.0 +/- 4.9% at 2 years and 88.2 +/- 8.0% at 5 years. Excluding all cases of nonepithelial or borderline epithelial malignancies, the survival of patients with ovarian cancer in the annually screened population was 92.9 +/- 6.9% at 2 years and 83.6 +/- 10.8% at 5 years. CONCLUSIONS: (1) TVS screening, when performed annually, is associated with a decrease in stage at detection and a decrease in case-specific ovarian cancer mortality. (2) TVS screening does not appear to be effective in detecting ovarian cancer in which ovarian volume is normal.

Ovarian volume related to age.

OBJECTIVE: The goal of this study was to determine the relationship of ovarian volume to age, height, and weight in women undergoing transvaginal sonography. METHODS: Thirteen thousand nine hundred sixty-three women 25-91 years of age undergoing annual transvaginal sonography as part of the University of Kentucky Ovarian Cancer Screening Program were the subjects for this investigation. Each ovary was measured in three dimensions, and ovarian volume was calculated using the prolate ellipsoid formula (L x H x W x 0.523). Mean ovarian volume according to age was calculated for each decade of life. RESULTS: Data were obtained from 58,673 observations of ovarian volume. Mean ovarian volume was 6.6 +/- 0.19 cm(3) in women less than 30 years of age; 6.1 +/- 0.06 cm(3) in women 30-39; 4.8 +/- 0.03 cm(3) in women 40-49; 2.6 +/- 0.01 cm(3) in women 50-59; 2. 1 +/- 0.01 cm(3) in women 60-69; and 1.8 +/- 0.08 cm(3) in women >/=70. Mean ovarian volume was 4.9 +/- 0.03 cm(3) in premenopausal women and 2.2 +/- 0.01 cm(3) in postmenopausal women (P < 0.001). The use of exogenous estrogens was associated with a significant reduction in ovarian volume in women 40-59 years of age, but not in women >/= 60. Ovarian volume was unrelated to patient weight but was greater in tall women (>68 in.) than in short women (<58 in.). CONCLUSION: There is a statistically significant decrease in ovarian volume with each decade of life from age 30 to age 70. Mean ovarian volume in premenopausal women is significantly greater than that in postmenopausal women. The upper limit of normal for ovarian volume is 20 cm(3) in premenopausal women and 10 cm(3) in postmenopausal women.

BRCA1-related and sporadic ovarian cancer in the same family: implications for genetic testing.

OBJECTIVE: The aim of this study was to present a family with both BRCA1-related and sporadic ovarian cancer and address current difficulties in genetic testing. METHODS: BRCA1 mutation detection was performed on a family having four confirmed cases of ovarian cancer, two cases of breast cancer, and one case each of colon, stomach, and prostate cancer. The incidence and types of cancer were consistent with a BRCA1 mutation although previous linkage analysis had excluded this family as being due to BRCA1. RESULTS: A protein-truncating mutation in BRCA1, denoted 2799delAA, was identified in the germline DNA of each of the women affected with breast and ovarian cancer in this family except the proband, who was diagnosed with ovarian cancer at age 65. CONCLUSIONS: In an earlier study, which sought to determine the proportion of site-specific ovarian cancer due to BRCA1, the family described in this report was wrongly identified as not being due to BRCA1 when, in fact, all but one of the breast and ovarian cancer cases carry a deleterious BRCA1 mutation. Our analysis suggests that the proband, who was the first of the women in this family to seek genetic counseling, developed ovarian cancer by chance and not as the result of an inherited mutation. We describe the results of our analysis in light of current issues that face clinicians who may be involved in genetic testing for breast and ovarian cancer predisposition.

The malignant potential of small cystic ovarian tumors in women over 50 years of age.

OBJECTIVE: The aim of this study was to determine the risk of malignancy in cystic ovarian tumors < 10 cm in diameter in asymptomatic postmenopausal women or women >or =50 years of age. METHODS: All cystic ovarian tumors detected by transvaginal sonography screening in asymptomatic postmenopausal women or women > or =50 years of age were evaluated with respect to size and morphology. Histology was recorded on all tumors removed surgically. Follow-up data were available both on patients undergoing surgery and on those who elected to be followed without operative intervention. RESULTS: Unilocular cystic tumors were detected in 256 of 7705 patients (3.3%). All tumors were < 10 cm in diameter and 90% were < 5 cm in diameter. One hundred twenty-five of these cysts (49%) resolved spontaneously within 60 days and 131 (51%) persisted. Forty-five patients with persisting ovarian cysts underwent operative removal of these tumors. Thirty-two patients had ovarian serous cystadenomas, and the remainder had a variety of benign lesions. There were no cases of ovarian carcinoma in this group. Eighty-six patients with unilocular cystic ovarian tumors were followed at 3- to 6-month intervals without surgery, and none have developed ovarian cancer. Complex cystic ovarian tumors were detected in 250 patients (3.2%). All tumors were < 10 cm in diameter and 89% were < 5 cm in diameter. One hundred thirty-five (55%) resolved spontaneously within 60 days, and 115 (45%) persisted. One hundred fourteen of these patients underwent operative tumor removal. Seven patients had ovarian carcinoma, 1 had primary peritoneal cancer, and 1 had metastatic breast cancer to the ovary. CONCLUSION: Unilocular ovarian cysts < 10 cm in diameter in asymptomatic postmenopausal women or women > or =50 years of age are associated with minimal risk for ovarian cancer. In contrast, complex ovarian cysts with wall abnormalities or solid areas are associated with a significant risk for malignancy. These data are important in determining optimal strategies for operative intervention in these patients.

Transvaginal sonography as a screening method for the detection of early ovarian cancer.

From December 1987 to December 1993, 6470 women underwent screening with transvaginal sonography (TVS) as part of the University of Kentucky Ovarian Cancer Screening Project. Two groups of women were eligible to participate in this investigation: (i) asymptomatic postmenopausal patients or patients >50 years of age, and (ii) asymptomatic women >30 years of age with a family history of ovarian cancer. Ovarian volume was calculated using the prolate ellipsoid formula (length x height x width x 0.523). An abnormal sonogram was defined by (1) an ovarian volume >10 cm3 in postmenopausal women or >20 cm3 in premenopausal women, and (2) a papillary or complex tissue projection into a cystic ovarian tumor. All women with an abnormal TVS had a repeat sonogram in 4-6 weeks. Patients with persistently abnormal scans had a serum CA-125 determination, tumor morphology indexing, and color Doppler sonography. Ninety patients (1.4%) with a persisting abnormality on TVS underwent exploratory laparotomy or laparoscopy for tumor removal. Thirty-seven patients had serous cystadenomas and six had primary ovarian cancers. Five patients had Stage IA ovarian cancer and one patient had Stage IIIB disease. Only one of the ovarian cancer patients had a palpable abnormality on pelvic examination, and none had an elevated (>35 u/ml) serum CA-125. All these patients are presently alive and well 1-5 years after conventional therapy. There was one false negative in this study, a 38-year-old white female who was noted to have a small ovarian cancer at the time of laparoscopic prophylactic oophorectomy 11 months after a normal scan. Over 17,000 screening years have been accrued and there have been no deaths from primary ovarian cancer in the screened population. A cost analysis of TVS screening is presented.

Lymph node metastases and prognosis in patients with stage IA2 cervical cancer.

Ninety-four patients with squamous cell carcinoma invading the cervical stroma to a depth of >3.0-5.0 mm with 7 mm or less in horizontal spread (FIGO Stage IA2) were evaluated. Depth and lateral extent of stromal invasion were verified using an ocular micrometer. Cell type and lymph vascular space invasion (LVSI) were recorded in each case. Patients were treated primarily by radical hysterectomy with pelvic lymphadenectomy, and those with lymph node metastases were offered postoperative radiation. Following treatment, patients were seen at 3-month intervals for 2 years, and every 6 months thereafter. The mean duration of follow-up was 6.9 years (range 0.4-23.5 years). Seven of 94 patients (7.4%) had lymph node metastases. Five patients had 1 positive node, 1 patient had 2 positive nodes, and 1 patient had 3 positive nodes. Five patients developed recurrent cancer and 4 died of disease. LVSI was present in 31 cases (33%). Tumor recurrence was significantly increased in patients with positive LVSI (9.7% vs 3.2%). The 5-year survival rate of patients with LVSI was 89% vs 98% in patients without this finding (P = 0.058). The 5-year survival rate of all Stage IA2 cervical cancer patients was 95%. Patients with Stage IA2 cervical cancer have a significant risk of lymph node metastases and should be treated by radical hysterectomy with pelvic lymphadenectomy. LVSI is an important prognostic variable in these patients and should be recorded in all cases.

Carboplatin and paclitaxel in ovarian carcinoma: a phase I study of the Gynecologic Oncology Group.

PURPOSE: To develop a tolerable, dose-intense regimen of carboplatin and paclitaxel for the treatment of primary epithelial ovarian carcinoma. PATIENTS AND METHODS: Patients underwent initial surgical assessment and tumor debulking. Patients with stage III/IV disease received six cycles of chemotherapy on a planned 21-day cycle. Carboplatin dose was calculated based on projected area under the curve (AUC) for concentration over time (mg. mL-1.min) and escalated to determine the maximum-tolerated dose (MTD). Paclitaxel dose was also escalated as a 3-, 24-, or 96-hour infusion. Granulocyte colony-stimulating factors (G-CSFs) were required at selected dose levels or could be added based on hematologic toxicity. RESULTS: Thirty-nine patients were enrolled and assessable for toxicity and response. Dose-limiting toxicity (DLT) was hematologic, primarily neutropenia. Less than 2% of all cycles with paclitaxel as a 3- or 24-hour infusion were associated with either grade 4 thrombocytopenia or febrile neutropenia. The carboplatin MTD was AUC 7.5 (equivalent to a median dose of 471 mg/m2). The MTD for paclitaxel was 135 mg/m2 over 24 hours and 175 mg/m2 over 3 hours without initial G-CSF. A 96-hour infusion of paclitaxel at a dose of 120 mg/m2 was associated with excessive single-cycle and cumulative myelosuppression, and was not further evaluated. Measured carboplatin AUC agreed well with the calculated AUC. The overall complete (n = 16) and partial (n = 2) response rate among 24 patients with measurable disease was 75%, with a median progression-free survival time of 15 months. CONCLUSION: Carboplatin could be safely combined with paclitaxel using a dose formula based on projected renal clearance. The recommended outpatient regimen is carboplatin AUC 7.5 and paclitaxel 175 mg/m2 over 3 hours without initial G-CSF. This treatment safely achieved a greater dose-intensity of carboplatin than would have been achieved with conventional dosing based on body-surface area.

Evidence for a unifocal origin in familial ovarian cancer.

OBJECTIVE: The purpose of this investigation was to determine the pattern of loss of heterozygosity in multiple tumor sites from familial ovarian cancer cases. If ovarian cancer arises focally in one ovary and then metastasizes to other sites, a similar pattern should be seen in all tumor sites. However, if ovarian cancer arises multifocally throughout the peritoneal cavity, a different pattern of loss would be expected among the different sites. STUDY DESIGN: The presence or absence of loss of specific alleles for 9 loci on chromosomes 1, 6, 11, 13, 16, and 17 was determined in multiple tumor sites from 12 familial ovarian cancer cases. RESULTS: The frequency of loss of heterozygosity was as follows: chromosome 17 (100%), chromosome 13 (82%), chromosome 6 (80%), chromosome 16 (73%), chromosome 1 (57%), and chromosome 11 (22%). In every case an identical pattern was present for at least one locus. In four cases loss of the same allele was present in tumor from the ovary and all metastatic sites for all informative loci. In the remaining eight cases loss of the same allele for one to five (mean three) loci was detected. CONCLUSIONS: The pattern of loss of heterozygosity in the 12 familial ovarian cancers included in this investigation favors a unifocal origin of disease. A dual primary origin could not be absolutely excluded in 3 cases. High frequencies on chromosomes 17q and 13 suggest that loss of whole or part of these chromosomes is important in ovarian carcinogenesis.

Genetic alterations distinguish different types of ovarian tumors.

Seventy-four sporadic ovarian tumors were studied for loss of heterozygosity (LOH) and microsatellite instability (MI) with 20 polymorphic markers on chromosome 17 and at least I marker on every other chromosome. Additionally, activation of the K-ras oncogene was examined through mutation analysis of codon 12. A majority of the tumors analyzed were low grade and/or of the mucinous histologic type. A negative correlation between LOH on chromosome 17 and K-ras activation was observed, with the former alteration present in the majority of high grade serous and endometrioid tumors and the latter most commonly found in the mucinous and low malignant potential (LMP) tumors. In 60% of cases where LOH on chromosome 17 was present, it was observed at all informative markers, indicating chromosome loss. In these cases, frequent events of LOH were observed on the other chromosomes. When confined events of LOH were observed on chromosome 17, fewer events of LOH were observed on the other chromosomes. In the absence of LOH on chromosome 17, LOH on other chromosomes was rare. K-ras activation was most commonly observed in tumors with no LOH events. Two endometrioid tumors and 2 mucinous tumors demonstrated MI. Our data support the involvement of different molecular pathways in the development of different types of ovarian tumors.

The molecular basis of ovarian cancer.

BACKGROUND: Molecular genetic studies of ovarian cancer have been limited by the inaccessible location of the ovary, the advanced stage of tumors available for analysis, and the lack of a well-defined precursor lesion. However, genetic alterations important in ovarian tumorigenesis have been identified recently. METHODS: Molecular genetic evaluation of ovarian cancer primarily has utilized mutation analysis, immunohistochemical techniques, and loss of heterozygosity (LOH) studies. RESULTS: Overexpression of the HER-2/neu oncogene is present in approximately one third of ovarian cancers and is associated with poor prognosis. Mutations of the K-ras oncogene have been identified in a similar proportion of mucinous ovarian tumors, including borderline tumors. The study authors as well as others have frequently detected LOH on chromosome 17, including the p53 and BRCA1 loci, and at 17p3.3 and 1717q22-23. Genetic linkage analysis indicates that the majority of inherited ovarian cancers are caused by mutations in the BRCA1 gene. Mutations in mismatch repair genes have been identified in ovarian cancers that occur as part of the hereditary nonpolyposis colon cancer syndrome. CONCLUSIONS: Sporadic ovarian tumors are the end result of a complex pathway involving multiple oncogenes and tumor suppressor genes, including HER-2/neu, K-ras, p53, BRCA1, and additional tumor suppressor genes on chromosome 17. The majority of inherited ovarian cancers are due to mutations in the BRCA1 gene, which appears to be a tumor suppressor gene. It is hoped that an increased understanding of the molecular basis of ovarian cancer will lead to advances in prevention, diagnosis, and treatment.

Ovarian cancer screening.

BACKGROUND: The three most extensively evaluated screening methods for ovarian cancer are pelvic examination, serum CA 125, and transvaginal sonography (TVS). The lack of sensitivity of pelvic examination and serum CA 125 has limited their use in ovarian cancer screening. Currently, the most effective screening method for ovarian cancer is TVS. METHODS: Transvaginal sonography was performed with a standard ultrasound unit and a 5.0 MHz vaginal transducer. Each ovary was measured in three dimensions and ovarian volume was calculated using the prolate ellipsoid formula (L x H x W x 0.523). An ovarian volume greater than or equal to 20 cm3 in premenopausal women and greater than or equal to 10 cm3 in postmenopausal women was considered abnormal. Also, any internal papillary projection from the tumor wall was considered abnormal. A patient with an abnormal screen had a repeat TVS in 4-6 weeks. Women with a persisting abnormality on TVS underwent pelvic examination, serum CA 125 determination, Doppler flow sonography, and tumor morphologic indexing before operative tumor removal. RESULTS: Eighty-five hundred asymptomatic women underwent TVS screening. One hundred twenty-one of these women had a persisting abnormality and underwent tumor removal. Fifty-seven patients had serous cystadenomas and eight had primary ovarian cancers. Six patients had Stage IA ovarian cancer, one had Stage IIC ovarian cancer, and one had Stage IIIB ovarian cancer. Only one of these patients had palpable ovarian enlargement on clinical examination and one had an elevated serum CA 125. All patients are alive and well 4-61 months after conventional therapy. The direct cost of TVS screening was highest during the initial years of the program and fell progressively to $30/screen during the 4th year of the study. Worldwide, more than 14,000 women have been screened using ultrasonography, and 19 ovarian cancers have been detected. More than 20,000 patient-screening-years have been accrued, and there have been no deaths from primary ovarian cancer in the screened population. CONCLUSIONS: Transvaginal sonography screening causes a decrease in stage at detection and a decrease in case-specific mortality. Further study is needed to determine if annual TVS screening will significantly reduce ovarian cancer mortality. The cost for TVS screening is reasonable and is well within the range of that reported for other screening tests.

Loss of heterozygosity and genomic instability in synchronous endometrioid tumors of the ovary and endometrium.

BACKGROUND: The unknown etiology of endometrioid carcinomas of the ovary and the relatively high frequency of a concomitant carcinoma of the endometrium in these patients warrants study of such tumors. The aim of this study was to identify the genetic alterations involved in endometrioid ovarian cancer development, and to determine whether primary tumors of the endometrium and synchronous primary endometrioid tumors of the ovary could be distinguished based on differing patterns of genetic alterations. The distinction of metastatic carcinoma of the ovary from other synchronous primary tumors is often difficult but has important therapeutic and prognostic implications. METHODS: This study examined the genetic alterations at 28 polymorphic DNA markers in the DNA of tumors of 17 patients with endometrioid carcinoma of the ovary, including 5 nonmetastatic ovarian tumors, 5 ovarian tumors metastatic to the uterus, and 7 endometrioid ovarian tumors with a synchronous primary endometrial tumor. RESULTS: Chromosomes 17 and 22 were found to be the most common sites of loss of heterozygosity (LOH) in the 17 patients studied. Loss of heterozygosity on chromosome 17 was associated with advanced stage ovarian tumors. In 96% of LOH events in the metastatic tumors, LOH was observed in the primary tumor and in the metastatic site. Conversely, in four of seven synchronous tumors in which LOH was observed, LOH was confined to the ovarian tumor. Genomic instability was identified in two of seven patients with synchronously occurring tumors that did not demonstrate LOH. A positive family history was noted for these two patients. CONCLUSIONS: A lack of shared genetic alterations and in synchronously occurring endometrial and endometrioid ovarian tumors indicates independent developmental pathways for these tumors. Loss of heterozygosity on chromosome 17 in endometrioid ovarian carcinoma may indicate transition to a more aggressive tumor.

Genetic alterations on chromosome 17 distinguish different types of epithelial ovarian tumors.

Epithelial tumors of the ovary are the most common ovarian tumors of adult women. They exist in several different histological patterns and exhibit varying degrees of aggressiveness. Molecular genetic studies in epithelial ovarian cancer have shown that loss of heterozygosity (LOH) for regions of chromosome 17 is a common event, probably reflecting the inactivation of one or more tumor suppressor genes present on this chromosome. We examined 87 sporadic epithelial ovarian tumors of different grade and histological type at 16 loci on this chromosome and found that 35% of them showed LOH for chromosome 17. Of these, 84% showed LOH for all informative markers, suggesting that loss of the entire chromosome 17 homologue may have occurred. Interestingly, chromosome 17 loss was observed frequently in serous tumors (49%), was less common in endometrioid tumors (15%), and was rare in mucinous tumors (4%) (P = .01 and P = .0002, respectively). Our findings support the concept that the histological subtypes of epithelial ovarian cancer may be the result of different molecular genetic events.

Hypermethylation at a chromosome 17 "hot spot" is a common event in ovarian cancer.

Alterations of normal DNA methylation patterns have been reported in various types of human tumors. These alterations are represented by genome wide hypomethylation and by region specific hypermethylation. One commonly hypermethylated region is 17p13.3 (D17S5), the putative site of a tumor suppressor gene. In this study we report that hypermethylation at this locus occurs frequently (33%) in ovarian tumors. We reported previously that loss of chromosome 17 is a common event in serous epithelial ovarian tumors. A correlation of the methylation event and chromosome 17 loss suggests that hypermethylation at D17S5 precedes chromosome 17 loss.

Developing intervention/prevention strategies for individuals at high risk of developing hereditary ovarian cancer.

In 1994, an estimated 24,000 new cases of ovarian cancer will be diagnosed in the United States. Most of these patients will have disease spread beyond the ovary at the time of diagnosis; despite tumor debulking and aggressive platinum-based chemotherapy, their long-term prognosis is poor. In view of the advanced stage of disease at the time of diagnosis and the poor results of conventional therapy, advances in early detection and/or prevention are desperately needed. The recent recognition that a family history of the disease is perhaps the strongest risk factor for the development of ovarian cancer offers a unique opportunity to identify women at high risk for ovarian cancer and to develop effective screening methods and prevention/intervention strategies for these high-risk women. The results of the breakout session "Developing Strategies for Intervention/Prevention Trials for Individuals at Risk of Hereditary Ovarian Cancer" are summarized here. The majority of the discussion in this session focused on three major issues: 1) identification of moderate- and high-risk individuals who would potentially benefit from screening, prevention, and intervention efforts; 2) assessment of the effectiveness of current screening modalities and the usefulness of current intervention/prevention strategies; and 3) recommendations for clinical trial design.

Familial site-specific ovarian cancer is linked to BRCA1 on 17q12-21.

In a study of nine families with "site-specific" ovarian cancer (criterion: three or more cases of epithelial ovarian cancer and no cases of breast cancer diagnosed at age < 50 years) we have obtained evidence of linkage to the breast-ovarian cancer susceptibility gene, BRCA1 on 17q12-21. If the risk of cancer in these families is assumed to be restricted to the ovary, the best estimate of the proportion of families linked to BRCA1 is .78 (95% confidence interval .32-1.0). If predisposition to both breast and ovarian cancer is assumed, the proportion linked is 1.0 (95% confidence interval .46-1.0). The linkage of familial site-specific ovarian cancer to BRCA1 indicates the possibility of predictive testing in such families; however, this is only appropriate in families where the evidence for linkage to BRCA1 is conclusive.

Therapeutic implications of lymph nodal spread in lateral T1 and T2 squamous cell carcinoma of the vulva.

From 1963 to 1993, 157 patients with primary squamous cell carcinoma of the vulva were treated by radical surgery at the University of Kentucky Medical Center. There were 84 unilateral lesions confined to the labium majus or labium minus. Thirty-seven patients had T1 lesions, median diameter 1.5 cm (range 0.5-2.0 cm), and 47 patients had T2 lesions, median diameter 3.4 cm (range 2.2-9.0 cm). Radical vulvectomy with bilateral inguinal lymphadenectomy was performed in 56 patients and radical hemivulvectomy with selective inguinal lymphadenectomy in 28 patients. An average of 8 nodes was removed with superficial inguinal lymphadenectomy and 13 nodes with superficial and deep inguinal lymphadenectomy. Deep inguinal lymph node metastases occurred only in patients with positive superficial inguinal lymph nodes. There were no contralateral inguinal lymph node metastases in any lateral T1 or T2 lesion. Following surgery, patients were followed 1-15 years (mean 5.0 years) and none have been lost to follow-up. Nine patients developed ipsilateral recurrences, but no contralateral recurrences were noted. Seven of these patients developed local recurrences to the ipsilateral vulvar skin and were cured by reexcision. Two patients (2.4%), both of whom had positive ipsilateral superficial and deep inguinal lymph node metastases at the time of initial surgery, developed distant metastases and died of disease 10 and 11 months after treatment. These data suggest that deep inguinal lymph nodal metastases occurred only in patients with superficial inguinal node involvement. Contralateral inguinal lymph nodal metastases are extremely rare in lateral T1 and T2 vulvar squamous cell carcinomas. Radical hemivulvectomy is as effective as radical vulvectomy in the treatment of lateral T1 and T2 vulvar squamous cell cancers.