The 21st century role of Piver type II hysterectomy in FIGO stage IA, IB cervical cancer: a personal perspective.

Class II modified radical hysterectomy reported in 1974 by Piver, Rutledge and Smith for cervical cancer is an extended hysterectomy that has less dissection of the ureter from the paracervical tissues, ligation of the uterine vessels just medial to the ureter to ensure preservation of the distal ureteral blood supply, and less radical parametrectomy preserving the lateral parametrium. The authors present a 21st century personal perspective on the use of a type II hysterectomy based on the 1994 FIGO changes in classification of Stage IAI, IA2, IBI and IB2.

Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations.

Women with mutations of the genes BRCA1 or BRCA2 are at increased risk of ovarian cancer. Oral contraceptives protect against ovarian cancer in general, but it is not known whether they protect against the disease in carriers of these mutations. We obtained self-reported lifetime histories of oral contraceptive use from 451 women who carried mutations of BRCA1 or BRCA2. We used conditional logistic regression to estimate the odds ratios associated with oral contraceptive use, comparing the histories of 147 women with ovarian cancer (cases) to those of 304 women without ovarian cancer (controls) who were matched to cases on year of birth, country of residence and gene (BRCA1 vs BRCA2). Reference ages for controls had to exceed the ages at diagnosis of their matched cases. After adjusting for parity, the odds-ratio for ovarian cancer associated with use of oral contraceptives for at least 1 year was 0.85 (95 percent confidence interval, 0.53-1.36). The risk decreased by 5% (1-9%) with each year of use (P for trend=0.01). Use for 6 or more years was associated with an odds-ratio of 0.62 (0.35-1.09). These data support the hypothesis that long-term oral contraceptive use reduces the risk of ovarian cancer among women who carry mutations of BRCA1 or BRCA2.

Regular use of analgesic drugs and ovarian cancer risk.

Analgesics have been shown to reduce risk for colorectal cancer. Results from three recent reports (D. W. Cramer et al., Lancet, 351: 104-107, 1998; C. Rodriguez et. al., Lancet, 352: 1354-1355, 1998; L. Rosenberg et al., Cancer Epidemiol. Biomark. Prev., 9: 933-937, 2000) suggest that these drugs might be associated with decreased risk for ovarian cancer. In this hospital-based case-control study, we compared 547 patients with ovarian cancer to 1094 age-matched patients with nonneoplastic conditions. All of the participants received treatment at the Roswell Park Cancer Institute between 1982 and 1998 and completed a comprehensive epidemiological questionnaire that included information on demographics, life-style factors, and reproductive characteristics as well as frequency and duration of aspirin and acetaminophen use. Women who reported that they had used one or more of these agents at least once a week for at least 6 months were classified as analgesic users. Logistic regression was used to compute crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Aspirin users were not at reduced risk of ovarian cancer compared with nonusers (adjusted OR, 1.00; CI, 0.73-1.39). There was also no evidence of a decrease in risk as a function of greater frequency of use or prolonged duration of use. Regular acetaminophen use was associated with a reduced risk (adjusted OR, 0.56; 95% CI, 0.34-0.86), and risk reductions were observed for women with the greatest frequency of use (adjusted OR, 0.32; 95% CI, 0.09-1.08) and longest duration of use (adjusted OR, 0.51; 95% CI, 0.27-0.97). These data suggest that regular use of acetaminophen, but not aspirin, may be associated with lower risk of ovarian cancer.

Epidemiologic differences between women with colorectal cancer and women with ovarian cancer.

BACKGROUND AND OBJECTIVES: The difference between the epidemiologic features of women with colorectal cancer and those with ovarian cancer has not been thoroughly studied. The aim of this study is to review the epidemiologic features of women with colorectal cancer and compare them with those of women with ovarian cancer. METHODS: The epidemiologic features of 705 women with colorectal cancer were compared with those of 503 women with primary epithelial ovarian cancer. Both groups included all women with the confirmed respective histologic diagnoses admitted to Roswell Park Cancer Institute between 1982 and 1996 who returned a voluntary self-administered epidemiologic questionnaire. RESULTS: Women with ovarian cancer were significantly younger, had higher education and income, had fewer children, and were more likely to have never been married and nulligravid than those with colorectal cancer. There was a significant difference in the contraceptive history between both groups among women > or = 45 years of age. More women with ovarian cancer had a family history of ovarian cancer and more women with colorectal cancer had a family history of colorectal cancer. CONCLUSIONS: The epidemiologic features of women with colorectal cancer are different from those with ovarian cancer. The difference between both groups might indicate difference in the environmental or genetic etiology of both cancers.

The use of lymphadenectomy in clinical stage I endometrial adenocarcinoma at a large community hospital.

UNLABELLED: PURPOSE AND MATERIALS AND METHODS: Because of the inaccuracies in clinical staging of endometrial cancer, the International Federation of Gynecology and Obstetrics (FIGO) in 1988 changed the staging of endometrial cancer to surgical staging consisting of intraoperative findings and histologic evaluation of the specimen. A decade later, 1998, the United States Society of Gynecologic Oncologists published Practice Guidelines for the surgical staging of endometrial cancer. The purpose of this study was to review the use of lymph node sampling and peritoneal washings in 100 consecutive cases of clinical stage I endometrial cancer and compare these results to the Practice Guidelines of the Society of Gynecologic Oncologists. RESULTS: The vast majority of patients (86%) had peritoneal washings and frozen section (69%) of the uterus. However, only slightly more than half (52%) had palpitation of the pelvic and/or para-aortic lymph nodes. Most encouraging and consistent with the Society of Gynecologic Oncologists' Guidelines is that 87% of the patients with histologically more aggressive cancers (grade III or deep myometrial invasion), had lymph node sampling as did 90.5% with more aggressive histologic subtypes. CONCLUSION: Notwithstanding these results, there is still the need in the 21st century for more uniform guidelines for the surgical staging of endometrial cancer.

A ten-year remission maintained by 6,272 mg (3,920 mg/m2) cumulative dose of cisplatin-based chemotherapy for recurrent epithelial ovarian cancer.

Since cisplatin is a heavy metal, renal and neurotoxicity is considered to be dose limiting in solid tumors. The current case is unusual in that remission has been maintained in a patient with recurrent epithelial ovarian cancer by cisplatin-based chemotherapy without evidence of renal or neurotoxicity, while receiving a total dose of 6,270 mg (3,920 mg/m2) of cisplatin over 11 1/2 years.

Primary ovarian dysgerminoma in a patient with a germline BRCA1 mutation.

Germline mutations in the BRCA1 tumor suppressor gene are associated with increased risk for the development of ovarian cancer. All such cancers thus far reported have been of the epithelial histologic type. We identified an ovarian dysgerminoma in a 16-year-old woman (proband) with a family history of ovarian cancer during a review of histopathologic characteristics of ovarian cancers from women enrolled in the Gilda Radner Familial Ovarian Cancer Registry. Mutation analysis of DNA from this patient's peripheral blood leukocytes revealed a germline BRCA1 mutation (3312insG). The mutation was also present in the mother with breast cancer, a maternal aunt and a distant cousin with ovarian cancer, and a maternal grandfather and an uncle with skin cancer. The development of the proband's dysgerminoma may be unrelated to her germline BRCA1 mutation. Alternatively, such dysgerminomas may be caused by BRCA1 mutations, but occur so infrequently compared with epithelial cancers that they are seldom identified. Analysis of a larger series of ovarian germ cell tumors may resolve this question.

Histopathology of familial ovarian tumors in women from families with and without germline BRCA1 mutations.

Breast cancers from patients with germline BRCA1 mutations show characteristic histopathologic features. However, similar studies of BRCA1-associated ovarian cancers have reported inconsistent findings. Interobserver differences in histopathologic classification are a significant source of variation, and most studies have obtained histopathologic information from pathology reports rather than from review of histopathology slides. We therefore reviewed the histopathology slides and pathology reports to determine histologic type, grade, and stage for cancers of the ovary or peritoneum in 217 women from 126 families enrolled in the Gilda Radner Familial Ovarian Cancer Registry. Peripheral blood DNA from at least 1 affected member of each family was analyzed for BRCA1 mutations, and tumors from BRCA1 mutation-positive families were compared with those from BRCA1-negative families. Of 66 patients from 36 BRCA1-positive families, 64 had ovarian carcinoma, 1 had an ovarian carcinoma in situ, and 1 had a dysgerminoma. Of 151 patients from 90 BRCA1-negative families, 135 had ovarian carcinoma, 10 had ovarian borderline tumors, 3 had ovarian sex cord/stromal tumors, and 3 had primary peritoneal carcinoma. There were fewer grade 1 (P <.001) and stage I (P =.10) cancers in patients from BRCA1-positive families than in patients from BRCA1-negative families. Neither mucinous nor borderline tumors were found in the BRCA1-positive families. Ovarian cancers arising in women from BRCA1-positive families are more likely to be high grade and nonmucinous than cancers arising in women from BRCA1-negative families. The absence of borderline tumors in patients from BRCA1-positive families adds to accumulating evidence that BRCA1 mutations do not play a role in the development of these tumors. HUM PATHOL 31:1420-1424.

Comparative study of ovarian cancer histopathology by registry pathologists and referral pathologists: a study by the Gilda Radner Familial Ovarian Cancer Registry.

OBJECTIVE: The aim of this study was to evaluate whether there is a significant difference in the pathology diagnoses of women in the Gilda Radner Familial Ovarian Cancer Registry between the two expert Registry pathologists and the referral pathologist. Inaccuracies in verification that ovarian cancer did occur in family members could lead to unnecessary prophylactic surgery or genetic testing. METHODS: A retrospective review was performed of (1) site of malignancy; (2) histopathology of malignancy; (3) grade of malignancy; and (4) the presence or absence of malignancy between the Registry and referral pathologists. RESULTS: There was 95.3% complete agreement between the Registry and the referral pathologist on site of origin with a major difference in only 1.0% of the cases. In comparison of histopathology, there was a 61.7% complete agreement, and only 1.0% were considered major differences. There was 68.8% complete agreement in grade of the malignancy, whereas 2.3% were considered major differences. CONCLUSION: When constructing a family pedigree, it is important to obtain pathology reports to confirm the index case diagnosis of the presence or absence of ovarian cancer. However, because of the small percentage of major differences in diagnosis between the two Registry pathologists and the multiple referral pathologists, we believe genetic counselors and treating physicians can rely, in most instances, on the original histopathology report of verification of ovarian cancer without review of the original histopathology slides when recommending surveillance, genetic testing, and/or prophylactic surgery.

Ovarian carcinoma in situ with germline BRCA1 mutation and loss of heterozygosity at BRCA1 and TP53.

BACKGROUND: The two-hit hypothesis for the genesis of cancer predicts that cancer can develop when the wild-type allele of a tumor suppressor gene is lost in an individual with a germline mutation in that gene. Neither loss of heterozygosity (LOH) for BRCA1 nor mutations of the TP53 (also known as p53) gene have been documented prior to invasion in ovarian cancers arising in women with germline BRCA1 mutations. Such documentation is difficult because lesions are rarely identified in ovarian epithelium. We, therefore, looked for LOH at microsatellite polymorphisms linked to the BRCA1 and TP53 tumor suppressor loci in an incidental carcinoma in situ of the ovary removed prophylactically from a woman with a germline BRCA1 mutation. METHODS: By use of laser-capture microdissection, we obtained pure populations of atypical ovarian epithelial cells and normal stromal cells. DNA was extracted, amplified with primers flanking polymorphic microsatellites linked to BRCA1 (D17S855 and D17S579) and TP53 (TP53 and D17S786), and analyzed for LOH at these microsatellites. We also tested for p53 expression in the abnormal epithelium by immunohistochemistry. RESULTS: Both of the markers linked to TP53 showed LOH, as did an intragenic BRCA1-linked marker (D17S855). The other microsatellite marker for BRCA1 was uninformative. Immunohistochemical staining with an antibody to p53 showed strong immunoreactivity confined to the atypical epithelium. CONCLUSIONS: BRCA1, as well as TP53, can undergo LOH prior to stromal invasion in BRCA1-associated ovarian cancer. Strong immunoreactivity for p53 suggests the presence of mutated p53 in these cells as well. These findings suggest that loss of function of these two tumor suppressor genes occurs early in ovarian carcinogenesis in BRCA1 mutation carriers.

Flt-3 ligand inhibits growth of human ovarian tumors engrafted in severe combined immunodeficient mice.

OBJECTIVE: The current study evaluated the effects of Flt-3 ligand (FL) on the growth of human malignant ovarian tumors engrafted in severe combined immunodeficient (SCID) mice with particular attention directed at FL's effect on the host natural killer (NK) cell response against ovarian cancer xenografts. METHODS: Equal portions of surgical specimen-derived human ovarian carcinomas were engrafted subcutaneously (SC) into SCID mice. Mice were placed into one of two treatment groups 7 days after the day of implantation. Group 1 received placebo injections SC from Day 1 to Day 20 and group 2 received FL at 10 microg/day SC from Day 1 to Day 20. NK cell depletion was performed on three additional mice from group 2 starting on Day 0 using anti-asialo GM1. Serial tumor volumes were measured. On Day 21, mice from each group were sacrificed, and tumors and spleens were evaluated. Data analysis included chi(2) tests, Student t tests, and analyses of variance when appropriate. RESULTS: FL resulted in tumor growth delay compared with control (P = 0.036). When NK cell activity was depleted prior to FL administration, no tumor growth delay was observed. Spleens from FL-treated mice were larger (P < 0.01) with expanded white pulp compared with controls. Histologic examination of tumor sections from FL-treated mice revealed regions of solid tumor growth with glandular architecture similar to that seen in control tumors; however, there was an obvious increase in regions composed largely of dense fibrosis in the FL-treated tumors. NK cells and other infiltrating cells could be detected in clusters among tumors from mice treated with FL whereas these cells were only occasionally detected in sections of control tumors. CONCLUSION: FL treatment resulted in an antitumor response against human ovarian cancer engrafted in SCID mice and this inhibition appears to be largely host NK cell mediated. The tumor inhibition seen in this model is similar to that previously seen using syngeneic tumors grown in an immunocompetent animal model. Results from this model can potentially be extrapolated to treatment of human ovarian cancer patients.

Microsatellite instability in ovarian and other pelvic carcinomas.

Twenty-six cases of ovarian carcinoma and six cases of other pelvic neoplasms were analyzed for microsatellite instability (MSI) using frozen specimens, fluorescence technology, and four selected markers (D2S123 on chromosome 2, D18S58 on chromosome 18, BAT26 on chromosome 2, and BAT40 on chromosome 1). This procedure also allowed the detection of loss of heterogeneity (LOH) at the four selected loci. One of the cases of ovarian carcinoma exhibited MSI and this was evident at three loci. Of 44 informative loci, 7 exhibited LOH representing 3 cases of ovarian carcinoma, 3 of 4 cases of primary peritoneal carcinoma, and one case of unknown primary. These data support other findings that MSI is not a frequent occurrence in ovarian cancer; however, LOH is a more frequent event and may be a target for the development of diagnostic/prognostic procedures for ovarian and primary peritoneal carcinoma.

First-line chemotherapy with paclitaxel and platinum for advanced and recurrent cancer of the cervix--a phase II study.

OBJECTIVE: The aim of this study was to assess the role of first-line chemotherapy with paclitaxel and platinum in the treatment of advanced or recurrent cervix cancer. METHODS: Twenty patients with advanced or recurrent cancer of the cervix with no prior chemotherapy and measurable disease were entered in a phase II trial from September 1995 to September 1998. Seventeen patients were treated with paclitaxel at 135 mg/m(2) over 24 h followed by cisplatin at 75 mg/m(2) every 4 weeks. Three patients with impaired renal function were treated with paclitaxel at 135 mg/m(2) over 3 h with carboplatin at 300 mg/m(2). RESULTS: A clinical response rate of 45% was noted (two complete responses and seven partial responses) with a median duration of 6 months (range: 1.5-9). The median progression-free interval and overall survival in patients with a clinical response was 10.5 and 13 months, respectively, compared to 4 (P = 0.015) and 6 months in the nonresponders (P = 0. 14). Seven of nine patients (77.8%) with a clinical response are alive. Patients with recurrences outside the radiation field had twice the response rate (60%) than that of those within the radiated field. The chemotherapy was well tolerated; the most significant toxicity was grade 3/4 neutropenia (55%). No patient had discontinuation of chemotherapy due to toxicity. CONCLUSIONS: First-line chemotherapy with paclitaxel and platinum for advanced and recurrent cervix cancer is promising and deserves consideration for large phase III trials.

Prognostic significance of p53 and p21(waf1/cip1) immunoreactivity in epithelial cancers of the ovary.

OBJECTIVES: Theprognostic value of p53 expression in epithelial ovarian cancer remains unresolved. We hypothesized that prognosis may relate more to expression of p21(waf1/cip1), the major downstream effector of p53, which can also be induced through p53-independent mechanisms. We therefore studied the relationship of p53 and p21(waf1/cip1) expression in epithelial ovarian cancers to clinicopathological variables and prognosis. METHODS: Fixed, embedded tumors from 85 patients with untreated, primary epithelial ovarian cancer were immunostained with antibodies to p53 and p21(waf1/cip1). Expression was correlated with clinicopathological features and prognosis. Survival curves were calculated by the Kaplan-Meier method and compared using the log-rank test for p53, p21(waf1/cip1), and all combinations of expression of the two markers. RESULTS: Sixty-two percent of tumors expressed p53, and 42% expressed p21(waf1/cip1). There was no correlation between p53 and p21(waf1/cip1) expression. Advanced stage, grade, age >/=50, and p53 expression were associated with worse disease-free survival. Patients whose tumors were p53(+)/waf1(-), however, had a particularly strong association with poorer disease-free survival when compared with other combinations of p53 and p21(waf1/cip1) expression (P = 0.003). Neither p53, nor p21(waf1/cip1), nor combinations of expression were independently related to survival when histology, age, stage, and differentiation were considered. CONCLUSIONS: p53 expression in the absence of p21(waf1/cip1) expression is a better marker of poor prognosis than either p53 or p21(waf1/cip1) expression status alone in univariate analysis. Absence of independent prognostic significance may be related to the paucity of early stage cases in the current study.

Role of salvage chemotherapy with topotecan and cisplatin in patients with paclitaxel- and platinum-resistant recurrent ovarian or primary peritoneal cancer: a phase II pilot study.

BACKGROUND AND OBJECTIVES: We assessed the role of salvage chemotherapy with topotecan and cisplatin in patients with platinum- and paclitaxel-resistant advanced and recurrent ovarian or primary peritoneal cancer, based on the reported in vivo and in vitro synergism between these two drugs. METHODS: Twenty patients were entered in this phase II trial from November 1997 to November 1998. They received cisplatin at 50 mg/m(2) on day 1 with topotecan at 0.6 mg/m(2) from day 1 to 5 every 28 days. In 70% of patients (14/20), this combination represented at least a third line of therapy. RESULTS: A clinical response rate of 13.3% (two partial responses) was obtained in the 15 patients with evaluable disease. Sixty percent of patients (9/15) had stable disease and 26.7% (4/15) had progression. The median progression-free interval and survival were 4 months and 7 months, respectively. The 20 patients evaluable for toxicity received a mean of four chemotherapy cycles. Dose reductions were required in 45% of patients despite the administration of growth factors. The major dose-limiting toxicity was a 50% occurrence (10/20) of grade 4 thrombocytopenia and 30% (6/20) grade 4 neutropenia. There was one septic death. CONCLUSIONS: These data suggest that combination therapy with topotecan and cisplatin has minimal activity in platinum- and paclitaxel-resistant advanced and recurrent ovarian or primary peritoneal cancer at the doses utilized in this trial.

Laparoscopic surgery in obese women.

OBJECTIVE: To assess the feasibility and complications of operative laparoscopy in women with high body mass indices (BMIs). METHODS: Forty-seven consecutive patients with BMIs exceeding 30 who underwent operative laparoscopy were compared with 160 consecutive patients with BMIs of 30 or less who underwent the same procedure. Patient characteristics, ultrasound features of adnexal masses, and details of operative procedures were compared. Operative and postoperative complications, the percentage of failed laparoscopies, and length of hospital stay were compared between groups. RESULTS: There were no significant differences between groups in terms of age, parity, menopausal status, history of laparotomy, ultrasound features of adnexal masses, complexity of laparoscopic procedures, and the presence and degree of adhesions at the time of laparoscopy. Estimated blood loss, operative times, operative and major postoperative complications, and lengths of hospital stay also did not differ significantly between women with high BMIs and those with low BMIs (180.3 versus 151.4 mL, P = .41; 150.5 versus 146.5 minutes, P = .78; 2.1 versus 1.9%, P = .90; 2.1 versus 1.9%, P = .91; and 2.3 versus 1.9 days, P = .51, respectively). However, women with BMIs exceeding 30 had a significantly higher incidence of procedure conversion to laparotomy (14.9 versus 5.6%, P = .04). CONCLUSION: Operative laparoscopy is safe and feasible in women with high BMIs. Although there is an increased chance of procedure conversion to laparotomy in these women, the morbidity and length of hospitalization associated with the procedure are similar to those among women with low BMIs.