Case-control study of endogenous steroid hormones and endometrial cancer.

BACKGROUND: It has been suggested that identified risk factors for endometrial cancer operate through a single etiologic pathway, i.e., exposure to relatively high levels of unopposed estrogen (estrogen in the absence of progestins). Only a few studies, however, have addressed this issue directly. PURPOSE: We assessed the risk of developing endometrial cancer among both premenopausal and postmenopausal women in relation to the circulating levels of steroid hormones and sex hormone-binding globulin (SHBG). The independent effect of hormones was assessed after adjustment for other known risk factors. METHODS: The data used in the analysis are from a case-control study conducted in five geographic regions in the United States. Incident cases were newly diagnosed during the period from June 1, 1987, through May 15, 1990. The case patients, aged 20-74 years, were matched to control subjects by age, race, and geographic region. The community control subjects were obtained by random-digit-dialing procedures (for subjects 20-64 years old) and from files of the Health Care Financing Administration (for subjects > or = 65 years old). Additional control subjects who were having a hysterectomy performed for benign conditions were obtained from the participating centers. Women reporting use of exogenous estrogens or oral contraceptives within 6 months of interview were excluded, resulting in 68 case patients and 107 control subjects among premenopausal women and 208 case patients and 209 control subjects among postmenopausal women. The hormone analyses were performed on blood samples obtained from case patients or from hysterectomy control subjects before surgery. The odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by use of an unconditional logistic regression analysis after we controlled for matching variables and potential confounders. All P values were two-sided. RESULTS: High circulating levels of androstenedione were associated with 3.6-fold and 2.8-fold increased risks among premenopausal and postmenopausal women, respectively, after adjustment for other factors (P for trend = .01 and < .001, respectively). Risks related to other hormone fractions varied by menopausal status. Among postmenopausal women, a reduced risk was associated with high SHBG levels and persisted after adjustment was made for obesity and other factors (OR = 0.51; 95% CI = 0.27-0.95). High estrone levels were associated with increased risk (OR = 3.8; 95% CI = 2.2-6.6), although adjustment for other risk factors (particularly body mass index) diminished the effect (OR = 2.2; 95% CI = 1.2-4.4). Albumin-bound estradiol (E2), a marker of the bioavailable fraction, also remained an important risk factor after adjustment was made for other factors (OR = 2.0; 95% CI = 1.0-3.9). In contrast, high concentrations of total, free, and albumin-bound E2 were unrelated to increased risk in premenopausal women. In both premenopausal and postmenopausal groups, risks associated with obesity and fat distribution were not affected by adjustment for hormones. CONCLUSION: High endogenous levels of unopposed estrogen are related to increased risk of endometrial cancer, but their independence from other risk factors is inconsistent with being a common underlying biologic pathway through which all risk factors for endometrial cancer operate. IMPLICATIONS: Further research should focus on alternative endocrinologic mechanisms for risk associated with obesity and body fat distribution and for the biologic relevance of the increased risk associated with androstenedione in both premenopausal and postmenopausal disease.

In vivo and in vitro "markers" of human cervical intraepithelial neoplasia.

The human uterine cervix offers a unique opportunity to study the early lesions of squamous cell carcinoma, i.e., carcinoma in situ and dysplasia [combined as cervical intraepithelial neoplasia (CIN)]. In vivo, the patients with CIN have the epidemiological common denominators or "markers" of early onset of coitus, multiple sexual partners, 1st delivery before age 20, and antibodies to herpes simplex virus type 2 more frequently than do controls. The lesions themselves have specific epithelial and vascular changes observable with the colposcope in addition to the usual histological markers from biopsy specimens. The chromosomes and DNA content of cells in these lesions are abnormal. In vitro, the cells from CIN have characteristics somewhat between normal and invasive carcinoma. They lack contact inhibition and may be transferred for several generations, in contrast to normal cervical epithelial cells. The fibroblasts from areas adjacent to DIN are different from normal fibroblasts. The mitotic mechanism in cells cultured from CIN has a significantly prolonged prophase and telophase when compared to similar normal cells. The surface of CIN cells, unlike normal cells, has numerous microvilli when examined by scanning electron microscopy and has characteristic differences from normal cells with numerous elongated, irregular microvilli. With the transmission electron microscope, an increase in microvilli and a decrease in desmosomes and tonofibrils are seen in CIN cells. Some of these markers are being used clinically to manage patients with CIN. Other markers are the basis for further investigation of human carcinogenesis.

Absence of major depressive disorder in female cancer patients.

This investigation evaluated the prevalence of depression in female patients who had cancer in any of five predesignated sites. Five hundred five women aged 17 to 80 (190 with breast cancer, 143 with gynecologic malignancies, 111 with melanoma, 37 with bowel cancer, and 24 with lymphoma) were randomly screened. Assessment included the Hamilton rating scale for depression, the Zung self-rating depression scale, the Karnofsky performance scale, and a 10-cm visual pain analogue line. The results revealed a mean Hamilton of 10.2 (range, 0 to 41; SD, 7.5), a mean Zung score of 35.3 (range, 11 to 68; SD, 9.6), a Karnofsky median score of 80, and a median pain score of 0. Scores on the Zung scale were highly correlated with those of the Hamilton scale (r = .75). Based on cutoff scores accepted as indicating depression (Hamilton greater than or equal to 20 and Zung greater than or equal to 50), patients were depressed. The depressed subgroup was in significantly more pain, experienced greater physical disability, and was more likely to have had prior episodes of depression as compared to the non-depressed women. The two best predictors of current depression were performance status (Karnofsky) and history of depression. No relationship was found between depression and other demographic variables or disease parameters (diagnosis, time since diagnosis, stage or phase of illness, and current treatment). Our findings indicate that the prevalence of major depression in cancer patients is lower than many previous studies have indicated and falls within the range seen in the general population.

Endometrial cancer risk in relation to serum lipids and lipoprotein levels.

Blood lipids are useful biochemical indicators for assessing the risk of a number of chronic diseases, particularly those associated with obesity. In a multicenter case-control study that included 256 cases and 185 controls less than 75 years old, we studied the risk of endometrial cancer in relation to serum cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, and triglycerides. Contrary to expectation, blood lipids were, in general, lower among cases compared with controls. The effects of low blood lipids, specifically cholesterol and low density lipoprotein cholesterol, were limited to older women (> or = 55 years). Risk of the disease in this subgroup of 177 cases and 110 controls was increased 3-4-fold among those with the lowest cholesterol or low density lipoprotein cholesterol values. For example, after adjustment for age, education, smoking status, obesity, and body fat distribution, the relative risks of endometrial cancer across decreasing quartiles of serum cholesterol were 1.0, 2.5, 2.4, and 4.2 (P for trend < 0.01). We examined blood lipid levels by disease stage. The low lipid values of older cases did not appear to be a consequence of the disease. While we cannot rule out the possibility that hypocholesterolemia is a predisposing factor for endometrial cancer, there is no obvious biological explanation for the inverse association.

Relation of endometrial cancer risk to past and contemporary body size and body fat distribution.

In a multicenter case-control study that included 403 cases and 297 controls, we examined the relation of past and contemporary body size, including body fat distribution, to the risk of endometrial cancer. The relative contributions of past and contemporary body size were assessed by examining weight and height histories provided by the subjects. Anthropometric indicators thought to reflect early environmental influences (e.g., height and sitting height), current weight, and fat distribution patterns were measured directly. Height was not a risk factor for endometrial cancer, but inexplicably, sitting height was inversely associated with risk. Weight during early adulthood appeared to be directly related to disease risk, but the association was explained by contemporary weight and thus weight gain during adulthood. While contemporary weight was associated with risk of endometrial cancer, the effect was restricted to those in the top quartile. Women whose measured weight at interview exceeded 78 kg had 2.3 times the risk of those weighing less than 58 kg (95% confidence interval, 1.4 to 3.7). Upper-body obesity (waist-to-thigh circumference ratio) was a risk factor independent of body weight. After adjustment for weight, the relative risks of endometrial cancer across increasing quartiles of upper-body obesity were 1.0, 1.5, 1.8, and 2.6 (P for trend < 0.001). These data indicate that both obesity and the distribution of adipose tissue accumulated during adult life increase endometrial cancer risk substantially.

Analysis of histopathological features of endometrioid uterine carcinomas and epidemiologic risk factors.

A large case-control study was performed to determine whether risk factors for endometrioid carcinoma, the most common type of endometrial cancer, vary according to the histological features of the tumor. Study subjects consisted of 328 women with newly diagnosed endometrioid adenocarcinoma and 320 population-based control subjects. Variables studied included age at menarche, menopausal estrogen use, weight, parity, cigarette smoking, and oral contraceptive use. The risk factor profile for endometrioid carcinomas with and without squamous differentiation was very similar. No striking differences in risk factors were observed between endometrioid cancers with and without adjacent endometrial hyperplasia. Finally, none of the risk factors varied substantially between early-stage and late-stage tumors or low-grade and high-grade tumors. In summary, this study indicates that risk factors for endometrioid carcinomas are not related to the morphological features of the tumor.

Intrauterine device use and endometrial cancer risk.

BACKGROUND: Because intrauterine devices (IUD) invoke acute and chronic inflammatory responses in the endometrium, it is possible that prolonged insertion of an IUD could induce endometrial cancer. METHODS: We examined the relation between use of an IUD and endometrial cancer risk using data from a multicentre case-control study involving 405 endometrial cancer cases and 297 population controls. RESULTS: A total of 20 (4.9%) cases and 34 (11.4%) controls reported any use of an IUD. After adjustment for potential confounders, IUD use was not associated with an increased risk of endometrial cancer (RR = 0.56 for ever use; 95% CI: 0.3-1.0). Little reduction in risk was observed among women who last used an IUD within 10 years of the index date (RR = 0.84; 95% CI: 0.3-2.4) but risk was decreased among women who used an IUD in the more distant past (RR = 0.45; 95% CI: 0.2-1.0). Risk did not vary consistently with number of years of IUD use or with years since first use. Risk was not increased among women who used inert devices (RR = 0.46; 95% CI: 0.3-3.6) or those who used devices containing copper (RR = 1.08; 95% CI: 0.1-3.6). CONCLUSION: These data are reassuring in that they do not provide any evidence of an increased risk of endometrial cancer among women who have used IUD.

PIP: IUDs invoke acute and chronic inflammatory responses in the endometrium. The authors therefore explored whether the prolonged insertion of an IUD increases one's risk of developing endometrial cancer. The relation between the use of an IUD and endometrial cancer risk was examined using data from a multicenter case-control study involving 405 endometrial cancer cases and 297 population controls. 20 cases and 34 controls reported using an IUD. After adjusting for potential confounders, IUD use was not associated with an increased risk of endometrial cancer. A small reduction in risk was observed among women who last used an IUD within 10 years of the index date, with the risk further reduced among women who last used an IUD more than 10 years ago. Risk did not vary consistently with the number of years of IUD use or with years since first use. Furthermore, the level of risk was not increased among women who used inert devices or those who used copper-containing devices.

Case-control study of cancer of the vulva.

A case-control study of 209 vulvar cancer patients and 348 community controls allowed assessment of risk factors for this rare tumor. As with cervical cancer, risk increased with the number of reported lifetime sexual partners, with five or more partners associated with two- to threefold increases in risk compared with zero to one partner. This factor largely explained the associations of risk with early age at first intercourse and low socioeconomic status. An independent association, however, was noted between vulvar cancer and a history of genital warts (relative risk 15.2; 95% confidence interval 5.5-42.1). Women who reported a previous abnormal Papanicolaou smear were at excess risk (relative risk 1.8), as were current smokers (relative risk 2.0). A significant interaction was noted between smoking and genital warts, with women reporting both having 35 times the risk of those with neither factor. Menstrual, reproductive, and hygiene factors were generally unrelated to risk. The relationships with sexual factors and genital warts support a common etiology for cervical and vulvar cancers. Future studies should focus on the etiologic agents for genital warts--the human papillomaviruses--and their enhancement by other factors, especially smoking and/or immune deficiencies.

The human uterotubal junction: a scanning electron microscope study during different phases of the menstrual cycle.

Uterotubal junctions from surgically extirpated human uteri were examined. The specimens were obtained during different phases of the menstrual cycle. The interstitial portions of the tubes together with the cornual areas were dissected, excised, and their luminal surfaces exposed. The specimens were then processed for scanning electron microscopy. The surface epithelium of both the cornual endometrium and interstitial endosalpins. Ciliated cells were more numerous in the endosalpinx. Cyclic changes in ciliated cells were minimal, while cyclic secretory activity was demonstrated, especially in the endometrium. The transitional area between the endometrium and the endosalpinx was characterized by a marked increase in the number of ciliated cells, and a tendency of the secretory cells to assume a flattened, polygonal shape. These morphologic features suggest a possible role in the transport and/or maintenance of spermatozoa and/or ova.

PIP: Uterotubal junctions from hysterectomy specimens, obtained at different phases of the menstrual cycle, were examined by scanning electron microscopy. Ciliated and secretory cells, with common morphologic characteristics, were observed in the surface epithelium of both the cornual endometrium and interstitial endosalpinx, with ciliated cells being dominant in number in the endosalpinx. Changes in ciliated cells were minimal during the menstrual cycle, though secretory cell act ivity was apparent, particularly in the endometrium. A considerable inc rease in the number of ciliated cells was observed in the transitional area between the endosalpinx and the endometrium. There was also a tendency of the secretory cells to assume a flattened, polygonal shape in the same region. The observed changes are suggestive of a possible role of the uterotubal junction in the transport of maintenance of spermatozoa or ova.

Urinary tract injuries in pelvic surgery.

In this article, we have reviewed the scope of surgically induced damage to the lower urinary tract. Preventative and reparative techniques have been presented. As pelvic surgeons become more confident in their efforts to safeguard the urinary tract, the chance of an unrecognized injury causing morbidity will diminish.

Tumor cytotoxicity of peritoneal macrophages and peripheral blood monocytes from patients with ovarian, endometrial, and cervical cancer.

The purpose of this study was to compare the cytotoxic capacity of peritoneal macrophages (PM) and peripheral blood monocytes (PBM) from patients with ovarian, endometrial, and cervical cancers after in vitro activation with gamma interferon (IFN-gamma) and lipopolysaccharide (LPS). Peritoneal macrophages were obtained from ascites or peritoneal washings and peripheral blood monocytes via peripheral venipuncture from 58 patients: 17 with ovarian, 19 with endometrial, and 10 with cervical cancers. PBM and PM from 12 patients with nonmalignant gynecologic conditions served as controls. Cytotoxicity was assessed by the ability of PBM and PM to lyze Cr51-labeled Chang hepatoma cells. Activated peripheral blood monocytes of ovarian and endometrial cancer patients and peritoneal macrophages from ovarian cancer patients were significantly more cytotoxic than those from nonactivated controls. Activated PBM and PM from cervical cancer and PM from endometrial cancer did not demonstrate increased cytotoxicity compared to nonactivated controls. There was no significant correlation of the cytotoxicity with grade, stage, differentiation or age of the cancers. These in vitro data would suggest that ovarian cancer and possibly endometrial cancer should receive further evaluation and consideration of cytokine-based and/or adoptive cellular immunotherapy.

Cisplatin as second-line chemotherapy in the treatment of advanced or recurrent leiomyosarcoma of the uterus. A phase II trial of the Gynecologic Oncology Group.

Twenty patients with advanced or recurrent leiomyosarcoma of the uterus who failed prior chemotherapy were placed on study by the Gynecologic Oncology Group. One patient had insufficient data to permit analysis. Of the remaining 19, there was only one objective response to cisplatin 50 mg/m2 intravenously every 3 weeks. Although toxicity was tolerable, there is little evidence of drug activity in patients with leiomyosarcomas of the uterus when the drug is given as second-line chemotherapy in the dose and schedule tested.

Women-centered care: implementing a philosophy.

Women share many health problems in common with men, and therefore seek guidance from similar health professionals. However, there are biologic, psychological, social, economic, life-style, legal, and ethical issues that affect women and for which women require specialized knowledge and care. The primary goal of improving women's health should continue to be the criterion for evaluating the components of the ideal model for a women's center. A center should be fluid enough to be accepted by patients, economical enough to complement existing clinical settings, and creative enough to improve substantially the health of women through services, education, and research.

Salvage mitomycin/5-fluorouracil after platinum-based therapy for women with advanced ovarian cancer and related gynecologic malignancies.

PURPOSE: to determine response rates, survival, and toxicity of a regimen of mitomycin-C and 5-fluorouracil in patients previously treated with platinum-based combinations for ovarian cancer and related gynecologic malignancies. PATIENTS AND METHODS: retrospective chart review of all cases of persistent or recurrent ovarian, fallopian tube, and peritoneal carcinoma treated with mitomycin-C 7 mg/m2 followed by continuous infusion of 5-fluorouracil 600 mg/m2/day over 4 days. RESULTS: 26 patients were treated after a median of 2 prior platinum-based regimens, 22 with ovarian cancer, 3 with peritoneal cancer, and one with fallopian tube cancer. Only 2 patients completed 6 or more cycles. 2 patients had partial responses (8%); no complete responses were seen. 24 patients died a median of 3 months after the initiation of therapy, while 2 patients were alive 4 and 8 months after beginning therapy. All deaths were attributable to disease, not complications of treatment. 8 patients required dose modification or treatment delay for toxicity. Nine patients required a total of 11 unscheduled admissions. CONCLUSIONS: toxicity attributable to mitomycin-C/5-fluorouracil therapy of ovarian cancer is acceptable, but responses are few. More effective alternative should be sought.

A bleomycin/ifosfamide/cisplatin regimen exhibits poor activity against persistent or recurrent squamous gynecologic cancers.

Persistent or recurrent squamous malignancies of the female genital tract are usually incurable by conventional therapy, and results of single agent chemotherapy have been disappointing. We undertook this study to confirm a previously reported response rate of 69%, using a regimen of bleomycin 30U, ifosfamide 5g/m2 with mesna 6g/m2, and cisplatin 50 mg/m2 (BIP) for recurrent cervical cancer. This regimen was used to treat persistent or recurrent squamous cancers in women with cervical cancer (n = 11), vaginal cancer (n = 1) and vulvar cancer (n = 1). Results were reviewed retrospectively and toxicities graded according to the criteria of the Gynecologic Oncology Group. No complete responses were seen. One patient had a partial response (10%, 95% confidence interval 0-28%). Five patients (50%), exhibiting stable disease during therapy with BIP, progressed after cessation of therapy. Of 9 women with symptoms after one cycle. Significant toxicities included neutropenic fever (3 grade 3, 3 grade 4), emesis (1 grade 3), confusion (2 grade 4), vaginal bleeding (2 grade 3), and renal failure (1 grade 3). Eight patients were transfused with a total of 28 units of red cells. After 23 months of follow-up, all patients were dead of disease. Mean survival was 10 months. Toxicity associated with this regimen can be significant, and results appear no better than those reported with single agent therapy.