Reproductive risk factors for epithelial ovarian cancer according to histologic type and invasiveness.

PURPOSE: Differences in histology among the subtypes of epithelial ovarian tumors suggest possible differences in their etiologies. We examined reproductive risk factors for epithelial ovarian cancer according to histologic subtype and tumor invasiveness. METHODS: We conducted a population-based, case-control study of associations between reproductive risk factors and epithelial ovarian cancer in the Delaware Valley from 1994 to 1998. Cases age 20 to 69 years with a recent diagnosis of epithelial ovarian cancer (n = 767) were compared to community controls (n = 1367) frequency matched by age. RESULTS: With few exceptions, we found significant risk reduction for each histologic subtype of epithelial ovarian cancer by using oral contraceptive, bearing children, and having a tubal ligation; for each subtype, there was significant increased risk associated with a family history of the disease. There were no significant differences among histologic subtypes in the magnitude of the odds ratios for OC use, parity, breastfeeding, tubal ligation, hysterectomy, family history of breast or ovarian cancer, use of noncontraceptive estrogens, age at menarche, and age at menopause. There were also few differences between invasive and borderline tumors, except that women with borderline tumors were significantly younger than women with invasive disease (44.7 years vs. 52.0 years, p < 0.001). Among serous tumors only, women with borderline tumors were more likely to use oral contraceptives than women with invasive tumors (OR = 2.28 95% CI 1.20-4.35). CONCLUSION: The results of this study suggest that reproductive risk factors do not differ among histologic subtypes of epithelial ovarian cancers.

Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate.

OBJECTIVE: To determine the endometrial safety of lower doses of continuous combined conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA). DESIGN: Randomized, double-blind, placebo-controlled study (the Women's Health, Osteoporosis, Progestin, Estrogen study). SETTING: Study centers across the United States. PATIENT(S): Healthy, postmenopausal women (n = 2,673) with an intact uterus. INTERVENTION(S): Patients received CEE 0.625 mg/day, CEE 0.625/MPA 2.5 mg/day, CEE 0.45 mg/day, CEE 0.45/MPA 2.5 mg/day, CEE 0.45/MPA 1.5 mg/day, CEE 0.3 mg/day, CEE 0.3/MPA 1.5 mg/day, or placebo for 1 year. Endometrial biopsies were evaluated at baseline, cycle 6, and year 1 using a centralized protocol. MAIN OUTCOME MEASURE(S): Efficacy of lower doses of CEE/MPA in reducing the incidence of endometrial hyperplasia rates associated with unopposed CEE. RESULT(S): Endometrial hyperplasia rates ranged from 0 to 0.37% for all CEE/MPA doses. Twenty-nine of the 32 cases of endometrial hyperplasia developed in women who were administered CEE 0.625 mg or CEE 0.45 mg. The incidence of endometrial hyperplasia increased with age for patients administered CEE alone. As expected, there were some inconsistencies among pathologists' ratings in the numbers of hyperplasias and incidence rates for the CEE-alone regimens. There were too few cases of hyperplasia in the combination groups to evaluate consistency among pathologists. CONCLUSION(S): One year of treatment with lower doses of CEE/MPA provides endometrial protection comparable to commonly prescribed doses. These regimens may be used by clinicians to individualize hormone replacement therapy in postmenopausal women.

Oral contraceptives, other methods of contraception, and risk reduction for ovarian cancer.

Oral contraceptives reduce the risk of ovarian cancer, but the impact of other methods of contraception has not been fully explored. This population-based, case-control study involved women 20-69 years of age who had ever had intercourse. We compared cases with a recent diagnosis of ovarian cancer (N = 727) with community controls (N = 1,360). All methods of contraception evaluated were associated with a reduced risk for ovarian cancer. After adjustment for age, race, pregnancies, and family history of ovarian cancer, the odds ratios for ever-use of each method as compared with never-use were: oral contraceptives for contraception, 0.6 (95% confidence interval = 0.5-0.8); intrauterine device, 0.8 (95% confidence interval = 0.6-1.0); barrier methods, 0.8 (95% confidence interval = 0.6-0.9); tubal ligation, 0.5 (95% confidence interval 0.4-0.7); and vasectomy, 0.8 (95% confidence interval = 0.6-1.1). Nulligravid women were not protected by any of these contraceptive methods. Multigravid women, however, were protected by all methods. We conclude that various methods of contraception reduce ovarian cancer risk. This effect does not appear to result from contraceptive use being a nonspecific marker of fertility. The results imply mechanisms other than hormonal or ovulatory by which ovarian cancer risk is reduced.

An assessment of the value of ultrasonographic screening for endometrial disease in postmenopausal women without symptoms.

OBJECTIVE: Our purpose was to evaluate the use of transvaginal ultrasonography for the detection of endometrial disease in a population of postmenopausal women who were without symptoms. STUDY DESIGN: Postmenopausal women were screened for potential inclusion in 2 multicenter, double-blind, placebo-controlled studies of 2 years' duration to evaluate the safety and efficacy of idoxifene in the prevention of osteoporosis. Baseline endometrial evaluation was performed by transvaginal ultrasonography and aspiration biopsy of the endometrium. RESULTS: A total of 1926 women were screened by transvaginal ultrasonography, and 1833 of them had endometrial thickness < or =6 mm. Five cases of endometrial abnormality (adenocarcinoma [n = 1] and atypical hyperplasia [n = 4]) were detected in the 1750 women from this cohort who underwent biopsy. The negative predictive value was >99%. One case of adenocarcinoma was detected in the 42 women who had endometrial thickness >6 mm and underwent biopsy. However, the sampling rate (45%) of women with endometrial thickness >6 mm was too low for confidence in the positive predictive value of 2%. CONCLUSIONS: Despite a high negative predictive value, transvaginal ultrasonography may not be an effective screening procedure for detection of endometrial abnormality in untreated postmenopausal women who are without symptoms.

Factors related to inflammation of the ovarian epithelium and risk of ovarian cancer.

Previous epidemiologic observations consistently suggest that suppression of ovulation, tubal ligation, and hysterectomy reduce the risk of ovarian cancer and that perineal talc use increases the risk. We examined these and other risk factors in the context of a new hypothesis: that inflammation may play a role in ovarian cancer risk. Ovulation entails ovarian epithelial inflammation; talc, endometriosis, cysts, and hyperthyroidism may be associated with inflammatory responses of the ovarian epithelium; gynecologic surgery may preclude irritants from reaching the ovaries via ascension from the lower genital tract. We evaluated these risk factors in a population-based case-control study. Cases 20-69 years of age with a recent diagnosis of epithelial ovarian cancer (767) were compared with community controls (1,367). We found that a number of reproductive and contraceptive factors that suppress ovulation, including gravidity, breast feeding, and oral contraception, reduced the risk of ovarian cancer. Environmental factors and medical conditions that increased risk included talc use, endometriosis, ovarian cysts, and hyperthyroidism. Gynecologic surgery including hysterectomy and tubal ligation were protective. Tubal ligation afforded a risk reduction even 20 or more years after the surgery. The spectrum of associations provides support for the hypothesis that inflammation may mediate ovarian cancer risk.

Risk of ovarian cancer in relation to estrogen and progestin dose and use characteristics of oral contraceptives. SHARE Study Group. Steroid Hormones and Reproductions.

Although past studies have shown that oral contraceptives with 50 microg or more of estrogen reduce the risk of ovarian cancer, it is not clear whether newer, lower-dose formulations do as well. We conducted a population-based, case-control study in the Delaware Valley to assess the impact of dose of oral contraception on risk of ovarian cancer. Cases aged 20-69 years with a diagnosis of epithelial ovarian cancer ascertained between May 1994 and July 1999 (n = 767) were compared with community controls (n = 1,367). Compared with never users, the adjusted risk of ovarian cancer was reduced by 40% for oral contraceptive users overall, with longer duration of use affording greater protection. The ovarian cancer risk reduction was similar for women who initiated oral contraception before 1972, when high-dose pills dominated the market; between 1972 and 1980; and after 1980, when newer, lower-dose pills dominated. Oral contraceptive estrogen and progestin content were compared for cases and controls after adjustment for current age, number of pregnancies, race, and family history of ovarian cancer. Use of low-estrogen/low-progestin pills afforded an estimated risk reduction (odds ratio = 0.5, 95% confidence interval: 0.3, 0.6) that was identical to that for high-estrogen/high-progestin pills (odds ratio = 0.5, 95% confidence interval: 0.3, 0.7).

Prolonged remission of recurrent, metastatic placental site trophoblastic tumor after chemotherapy.

BACKGROUND: Placental site trophoblastic tumor (PSTT) is a form of gestational trophoblastic neoplasm that is frequently resistant to chemotherapy. In most cases disease is confined to the uterus and can be cured by curettage or simple hysterectomy. Patients with metastases, however, frequently have progression of disease and die despite aggressive multiagent chemotherapy. CASE: A 31-year-old woman was found on review of uterine curettings to have a PSTT. Imaging studies revealed multiple lung lesions, a liver lesion, and an enlarged irregular uterus. Hysterectomy and staging surgery revealed a large tumor in the endometrial cavity and multiple metastases. She was treated with etoposide-methotrexate-dactinomycin and cyclophosphamide-vincristine and had a complete clinical remission. Six months later, however, she had a recurrence. She was then treated with six cycles of etoposide-methotrexate-dactinomycin and etoposide-cisplatin. Three years after completion of the second regimen she is without evidence of disease. CONCLUSION: Treatment with multiagent chemotherapy can produce long-term remission, even in patients with recurrent, metastatic PSTT. Addition of platinum may be helpful in patients who have recurred or progressed after treatment with non-platinum-containing regimens.

Sonographic assessment of the endometrium in osteopenic postmenopausal women treated with idoxifene.

Idoxifene is a novel selective estrogen receptor modulator that has shown beneficial effects on bone turnover and lipid metabolism in clinical studies. Preclinical studies have demonstrated that idoxifene has estrogen antagonist activities on the endometrium. This paper describes the results of a double-blind, placebo-controlled, and dose ranging study involving 331 osteopenic postmenopausal women who were treated with either placebo or idoxifene (2.5, 5, or 10 mg/day) for 12 weeks. In these women, endometrial assessment was carried out by transvaginal sonography and endometrial biopsy on selected patients at baseline and on all women at the end of treatment. Women with an endometrial thickness greater than 10 mm were excluded from the study. Aspiration endometrial biopsy was performed on women with an endometrial thickness between 6 and 10 mm at baseline and on all women after treatment. Of the 298 biopsies performed in the subjects at the end of treatment, 99% of the women were reported to have either a benign or atrophic endometrium (85%) or insufficient tissue for diagnosis (14%). Proliferative histologic features were reported in two cases (1%) (2.5 mg idoxifene) and atypical hyperplasia in one placebo patient. Even though idoxifene use was associated with a dose related increase in endometrial thickness as evaluated by transvaginal sonography, no relationship was established between endometrial histologic features and change in endometrial thickness. On histologic analysis, the increase in endometrial thickness seen on transvaginal sonography was not associated with proliferative or hyperplastic change in the epithelial (glandular) endometrial tissue. In 48 patients (16% of total) transvaginal sonography showed endometrial thickening of 5 mm or more over the study period. The endometrial histologic features were benign in all these patients. Nineteen percent of women developed intraluminal fluid, even though endometrial thickness was normal and unchanged and histologic features were normal. Our data show that after 3 months of treatment, no significant pathologic changes of the endometrium were observed. Our data indicate that measurements of endometrial thickness by transvaginal sonography may falsely suggest the presence of endometrial pathologic changes in some postmenopausal women treated with idoxifene. Additional testing using saline infusion sonohysterography is an important part of the transvaginal sonography protocol in equivocal or abnormal cases to exclude focal lesions such as polyps. In addition, our data indicate that pathologic changes of the endometrium are extremely rare in the treated group, indicative of its short term safety. Continued investigation such as this will be needed to establish long term safety.

Endometrial adenocarcinoma with trophoblastic differentiation.

OBJECTIVE: To report a case of stage IIIc poorly differentiated endometrial adenocarcinoma with trophoblastic differentiation and to review previously reported cases. METHODS: The clinical course and histopathology of the case were reviewed, and a literature search for other reported cases was performed. RESULTS: The tumor contained syncytiotrophoblast-like giant cells that stained positively for the beta subunit of human chorionic gonadotropin (beta-hCG), and the patient's serum beta-hCG level was elevated (95 mIU/ml), but became undetectable after treatment. Beta-hCG was used as a tumor marker during further therapy. At 16 months' survival, she remains without evidence of disease and with a beta-hCG (level < 5 mIU/ml). Nine other cases of trophoblastic differentiation in gynecologic nontrophoblastic tumors have been reported, five in endometrial carcinomas which we review. CONCLUSIONS: Trophoblastic differentiation in gynecologic nontrophoblastic tumors is rare. Beta-hCG may be useful as a tumor marker in these cases. The clinical behavior of these tumors has been aggressive, with advanced stages at diagnosis, early widespread metastases or recurrences and poor patient outcomes. The patient presented in this report, however, remains without evidence of disease 16 months following diagnosis and may be the longest survivor with this tumor reported to date.

Identification of oncofetal fibronectin in patients with advanced epithelial ovarian cancer: detection in ascitic fluid and localization to primary sites and metastatic implants.

BACKGROUND: The mechanisms by which metastatic ovarian cancer adheres to peritoneal surfaces are not well understood. A role for tumor-derived extracellular matrix adhesive molecules such as fibronectin (FN) has been proposed. Because oncofetal fibronectin (onfFN) isoforms function in the adhesion of trophoblasts and have been identified in association with several malignancies, we sought to study onfFN in patients with advanced epithelial ovarian cancer. METHODS: Total FN was identified with the nonspecific anti-FN monoclonal antibody CAF. OnfFN was identified using the specific monoclonal antibodies FDC-6 and X18A4. These antibodies were applied to: 1) ascitic fluid from advanced epithelial ovarian cancer patients and peritoneal fluid from patients without pathologic conditions and 2) tissue sections of primary lesions and metastatic ovarian cancer implants. Comparative histologic specimens included normal ovarian tissue and small bowel implants of endometriosis. RESULTS: When measured by sandwich enzyme-linked immunoadsorbent assay, all peritoneal fluids (32 malignant and 32 benign) contained marked quantities of total (CAF reactive) FN, although malignant ascites had higher concentrations than benign samples (173.2 +/- 36.8 microg/mL vs. 76.4 +/- 31.8 microg/mL; P = 0.001). Malignant ascites also had significantly higher levels of onfFN than benign peritoneal fluid (FDC-6: 3.4 +/- 0.6 vs. 0.9 +/- 0.2 microg/mL; and X18A4: 5.1 +/- 1.3 vs. 1.1 +/- 0.4 microg/mL; P = 0.0001). Immunohistochemical staining of malignant lesions revealed prominent localization of both CAF reactive FN and onfFN to the stroma surrounding epithelial tumor nests. More delicate fibrillar staining within tumor nests also was evident. In contrast, implants of endometriosis revealed strong stromal staining for CAF reactive FN but not for onfFN. CONCLUSIONS: These results demonstrate the presence of onfFN in advanced ovarian malignancies. We speculate that onfFN may participate in tumor-associated peritoneal adhesive interactions.

Surgically documented responses to paclitaxel and cisplatin in patients with primary peritoneal carcinoma.

Intra-abdominal carcinomatosis indistinguishable from ovarian cancer may occur after removal of the ovaries or in association with surface ovarian involvement. Because its histologic pattern and behavior approximate those of ovarian cancer, this entity, known as primary peritoneal carcinoma, has been treated in a similar fashion--cytoreductive surgery followed by systemic chemotherapy. This review was undertaken to assess the efficacy of combination chemotherapy with paclitaxel and cisplatin, the current front-line chemotherapeutic regimen for ovarian cancer, in patients with primary peritoneal carcinoma. Sixteen patients diagnosed between January 1989 and July 1994 with primary peritoneal carcinoma were treated at the Hospital of the University of Pennsylvania. The records of the three patients whose initial chemotherapeutic regimen included paclitaxel and cisplatin were reviewed. An additional case from the Robert Wood Johnson Medical Center, Camden, New Jersey, was included. Pathologic review of all cases was conducted at the time of clinical management and again as part of this study. Reassessment laparotomy was performed in all patients after the completion of chemotherapy. Complete clinical information was available on all patients. All four patients presented with intra-abdominal carcinomatosis, and large volume (> 1 cm) residual disease was present following initial cytoreduction. Following chemotherapy, second-look laparotomy documented one complete pathologic response and three partial (>50% tumor volume reduction), but marked, responses. Combination chemotherapy with paclitaxel and cisplatin produces surgically documented responses in patients with primary peritoneal carcinoma.

Primary ovarian melanoma arising in a dermoid stage IIIc: long-term disease-free survival with aggressive surgery and platinum therapy.

A 20-year-old female with a primary melanoma of the ovary arising from a mature cystic teratoma presented with bulky peritoneal metastases. Following aggressive surgical resection and platinum-based chemotherapy the patient remains disease-free 5 years following diagnosis.

Malignant mixed müllerian tumor of the fallopian tube.

BACKGROUND: Malignant mixed müllerian tumor (MMT) of tubal origin is rare and optimal therapy is unknown. METHODS: Five new cases of MMT of the fallopian tube are presented, and the previous literature is reviewed. RESULTS: Eight of 10 patients disease-free at 36 months had long-term cancer-free survival. Surgery alone was inadequate therapy even for those with apparent Stage I disease. Five of six treated postoperatively with radiation and chemotherapy have lived disease-free for at least 45 months. CONCLUSIONS: Combination radiation and chemotherapy may offer improved outcome.

Histology of the fertile and infertile testis.

This article has reviewed the diagnostic value of testicular biopsy in the evaluation of male infertility. In order to optimize the interpretation of morphologic findings, it is essential that a full medical and occupational history and careful hormonal evaluation be performed. A karyotype may be indicated in some cases. The pathologist has the opportunity to render a diagnostic opinion based on examination of seminiferous tubules and interstitium and correlated with the results of the history, physical examination, and laboratory studies. A rapid quantitative method is available for determining the likelihood that a significant epididymal obstruction exists that may be relieved surgically.

Late recurrence of clear-cell adenocarcinoma of the cervix: case report.

In the last 10 years, new observations have been made of the biologic behavior of clear-cell adenocarcinoma of the cervix and vagina arising in young women exposed to diethylstilbestrol in utero. Of particular note is the tumor's capacity to recur after an extended disease-free interval following initial therapy. We report the case of a woman who had her first recurrence 17 years after initial therapy, presenting with metastatic disease to the lungs and cerebellum. This case represents the longest reported interval between primary therapy and recurrence and supports the conclusion made by others that women who have been treated for clear-cell adenocarcinoma of the cervix and vagina may remain at risk of disease progression for many years after initial therapy. Therefore, these women should continue to be monitored. We also recommend periodic chest x-rays for two reasons: 1) The lungs are the most common site of distant spread of disease; and 2) metastatic nodules may be amenable to curative surgical intervention.

DNA content of juvenile granulosa tumors determined by flow cytometry.

Juvenile granulosa tumors (JGT) often exhibit worrisome morphologic features, yet usually behave in a benign fashion. Thirteen JGT were examined by flow cytometric analysis of paraffin material to determine if DNA content and cell kinetics are related to prognosis. The patients ranged in age from stillborn to 16 years. Unilateral salpingoophorectomy was the most common therapy. Eleven patients with follow-up were free of disease. Marked nuclear atypia was evident in three cases, and high mitotic counts were observed in six, but only marked atypia correlated with DNA content. Flow cytometry revealed that 46% of the JGT had abnormal DNA content and increased average growth fraction. The neoplasms with the highest DNA indices were found predominantly in postmenarchal girls. JGT may exhibit abnormal DNA content, nuclear atypia, and numerous mitoses, yet behave benignly. DNA flow cytometric studies of higher stage JGT are warranted.

Endometrial cytosolic and nuclear progesterone receptors in the luteal phase defect.

Basal body temperature profiles, serial serum progesterone levels, and serial endometrial biopsies were studied in 15 infertile women during 21 ovulatory cycles. Ten cycles (in 9 women) demonstrated luteal phase defects (LPD), diagnosed by a histological lag in endometrial maturation, normal luteal phase length, and normal luteal phase serum progesterone levels. Both normal and LPD cycles had a maximum amount of endometrial cytosolic progesterone receptor (PgR) on days 13-15, with a significant decline thereafter. LPD cycles had significantly lower endometrial nuclear PgR concentrations than did normal cycles during the proliferative phase, but luteal phase endometrial nuclear PgR levels were similar in both groups. In 2 LPD women treated with dydrogesterone, normal endometrial maturation and a decline in endometrial cytosolic PgR concentrations in the late luteal phase were found. Therefore, with the exception of endometrial nuclear PgR concentrations during the proliferative phase, we found no evidence for a major abnormality in endometrial PgR levels in LPD cycles with a lag in endometrial histology.

Postoperative peritoneal cysts.

Peritoneal cysts are an infrequent postoperative complication. Few cases have been reported in the literature. This paper presents four cases seen after gynecologic operations. The cysts occurred 1.5 to 8 months postoperatively. The patients presented with pain and a large pelvic mass. No patient showed clinical or laboratory evidence of acute inflammation. Ovarian neoplasm was the leading diagnosis in three cases; the correct preoperative diagnosis of peritoneal cyst was made in only one case. Three patients were managed successfully with resection. One patient was treated with percutaneous drainage, though nine months was required for complete resolution. There were no recurrences at one-year follow-up.