Endometrial cancer, obesity, and body fat distribution.

A case-control study was undertaken to evaluate the roles of obesity and body fat distribution in the etiology of endometrial cancer. The study also included an evaluation of the associations of serum estrone, estradiol, and androstenedione with obesity, body fat distribution, and endometrial cancer risk. The study included 168 cases and 334 control subjects identified at an optometry clinic. A strong, positive relationship between overall obesity and endometrial cancer was found. The relative rate of endometrial cancer for women in the upper 90th percentile of a body mass index compared to those below the median was estimated as 5.5 with 95% confidence limits of 3.2-9.6. There was no association between endometrial cancer and the waist to hip ratio, an index of upper versus lower body fat distribution. A statistical test of trend across the four quartiles of the waist to hip ratio yielded a P value of 0.45 after adjustment for confounding by the body mass index. On the other hand, there was a statistically significant, independent positive effect of a high subscapular to tricep skinfold ratio, a measure of central versus peripheral obesity, on endometrial cancer risk. The relative rates of endometrial cancer for the second, third, or fourth quartile compared to the first quartile of this index were 1.5, 1.9, and 2.7, respectively (P = 0.007), after adjustment for the body mass index. Serum estrone and estradiol, but not androstenedione, were statistically significantly correlated with the body mass index among control subjects (r = 0.37 and 0.40 for estrone and estradiol, respectively). On the other hand, each of the sex hormones was uncorrelated with the waist to hip ratio after adjustment for body mass. The correlations between each of the three hormones and the subscapular to tricep skinfold ratio among controls were weak and were not statistically significant (0.10, 0.10, and 0.14 for estrone, estradiol and androstenedione, respectively). Cases had statistically significantly higher mean serum estrogen and androstenedione levels than did controls and these elevations did not simply reflect a higher prevalence of obesity among them. The findings are equivocal with respect to fat patterns and endometrial cancer. We suggest that future epidemiological studies of cancer and body fat distribution more carefully distinguish among the various types of fat patterns.

Chemotherapy of advanced dysgerminoma: trials of the Gynecologic Oncology Group.

Between 1984 and 1989, 20 assessable patients with incompletely resected ovarian dysgerminoma were treated on two protocols of the Gynecologic Oncology Group (GOG). All patients received cisplatin, bleomycin, and either vinblastine or etoposide. More recent patients also received consolidation chemotherapy with vincristine, dactinomycin, and cyclophosphamide (VAC). Eleven patients had clinically measurable disease, and 10 responded completely. Fourteen second-look procedures were done, and all were negative. Currently, 19 of 20 patients are disease-free with median follow-up of 26 months. Cisplatin-based chemotherapy is highly effective in patients with advanced dysgerminoma.

A randomized comparative trial of carboplatin and iproplatin in advanced squamous carcinoma of the uterine cervix: a Gynecologic Oncology Group study.

A total of 394 patients with advanced, measurable squamous carcinoma of the uterine cervix and no prior chemotherapy were randomized to therapy with either carboplatin or iproplatin. There were 23 patients ineligible for the study and 10 patients who were not evaluable; the remaining 361 patients were evaluable for response and adverse effects. Randomization was well balanced for age, performance status, and prior therapy. Both platinum analogs were given every 28 days with starting doses of 400 mg/m2 for carboplatin (340 mg/m2 if the patient underwent prior radiation) and 270 mg/m2 for iproplatin (230 mg/m2 if the patient underwent prior radiation). These doses are equivalent to cisplatin doses of 75 to 100 mg/m2. Hematologic toxicity was dose-limiting, among which thrombocytopenia was slightly more common than leukopenia. Gastrointestinal toxicity was also prominent with both agents; however, iproplatin was significantly more toxic than carboplatin (P less than .001). Renal, otic, and peripheral nervous system toxicities were absent or infrequent with both analogs. No electrolyte abnormalities were observed. The percentage of planned dosages that were actually administered was 100% of carboplatin doses and 85% of iproplatin doses (P less than .0001). The reduction in iproplatin dose was apparently due to gastrointestinal toxicity. Response rates were similar for both agents (15% for carboplatin, 11% for iproplatin) and appear to be inferior to those noted with the parent compound, cisplatin.

New surgical approaches to treatment of cervical cancer.

PURPOSE: Our goal was to evaluate laparoscopic pelvic lymph node dissection, para-aortic lymph node sampling, and laparoscopic radical vaginal hysterectomy (Schauta) in the treatment of early stage cervical cancer. MATERIALS AND METHODS: In a retrospective study of 37 patients treated in the period between October 1993 and February 1996, we evaluated operative time, blood loss, length of hospital stay, lymph node count, and morbidity. Radical abdominal hysterectomy was compared with laparoscopic pelvic lymph node dissection and para-aortic lymph node sampling. Improvement over time was analyzed. RESULTS: Mean operative time was 225 minutes, blood loss was 525 mL, and the average hospital stay was 3 days. This information was compared with a radical abdominal hysterectomy and pelvic and para-aortic lymph node dissection, where the operative time was 210 minutes, blood loss was 1500 mL, and the hospital stay was 9.7 days. Blood transfusion was required in 11% of patients compared with a range of 35%-95% reported in the literature for radical abdominal hysterectomy. The mean pelvic lymph node count was 35; the mean para-aortic lymph node count was 11. Two patients had cystotomies repaired at surgery without lengthening hospital stay or subsequent complication. Two patients had ureteral vaginal fistulae treated by a ureteral stent, which was removed 6 weeks later without further operative procedures or urinary damage. When the data were correlated with the length of experience using the analysis of variance test and linear regression, operative time, blood loss, and hospital costs significantly improved over time. Patient charges averaged $14,868.00 and estimated hospital costs averaged $6449.00. CONCLUSION: Laparoscopic pelvic lymph node dissection and para-aortic lymph node sampling can be performed with adequate lymph node counts and lower morbidity. Laparoscopic Schauta allows shorter hospital stay than radical abdominal hysterectomy, with significantly less blood loss and markedly fewer blood transfusions. Morbidity is higher early in the surgeon's experience but decreases over time.

Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives.

Forty-seven young women with mild or moderate dysplasia of the uterine cervix (cervical intraepithelial neoplasia) diagnosed by cervical smears, received oral supplements of folic acid, 10 mg, or a placebo (ascorbic acid, 10 mg) daily for 3 months under double-blind conditions. All had used a combination-type oral contraceptive agent for at least 6 months and continued it while returning monthly for follow-up examinations. All smears and a biopsy obtained at the end of the trial period were classified by a single observer without knowledge of treatment status using an arbitrary scoring system (1 normal, 2 mild, 3 moderate, 4 severe, 5 carcinoma in situe). Mean biopsy scores from folate supplemented subjects were significantly better than in folate-unsupplemented subjects (2.28 versus 2.92, respectively; p less than 0.05). Final versus initial cytology scores were also significantly better in supplemented subjects (1.95 versus 2.32, respectively; p less than 0.05), unchanged in patients receiving the placebo (2.27 versus 2.30, respectively). Before treatment the mean red cell folate concentration was lower among oral contraceptive agent users than nonusers (189 versus 269 ng/ml, respectively; p less than 0.01) and even lower among users with dysplasia (161 versus 269 ng/ml, respectively; p less than 0.001). Morphological features of megaloblastosis were associated with dysplasia and also improved in folate supplemented subjects. These studies indicate that either a reversible, localized derangement in folate metabolism may sometimes be misdiagnosed as cervical dysplasia, or else such a derangement is an integral component of the dysplastic process that may be arrested or in some cases reversed by oral folic acid supplementation.

Evaluation of the deoxyuridine suppression test by using whole blood samples from folic acid-supplemented subjects.

We performed the deoxyuridine suppression test (dUST) along with assessment of folate and vitamin B-12 status in blood specimens from 136 normal women and 109 women with cervical dysplasia. All tests were repeated at 2, 4, and 6 mo in subjects with dysplasia during a randomized, double-blind intervention trial in which 50 received a 10-mg daily oral folic acid supplement (F group) and 59 received a placebo (P group). Median folate concentration increased fivefold in plasma and threefold in erythrocytes of F group beginning at the second months and remained elevated whereas concentrations of the P group remained unchanged. Vitamin B-12 values did not vary significantly in either group. The dUST value decreased from 10.4 +/- 4.6% (means +/- SD) pretreatment to 4.5 +/- 4.7% in F group after 2 mo (p less than 0.001). The dUST values had significant negative correlation with plasma and erythrocyte folate concentrations. However, erythrocyte folate had the greatest power to distinguish P group from F group.

Concentrations of carotenoids, tocopherols, and retinol in paired plasma and cervical tissue of patients with cervical cancer, precancer, and noncancerous diseases.

Paired blood (collected after an overnight fast) and cervical tissue (cancerous, precancerous, and noncancerous) samples were obtained from 87 patients (age, 21-86 years) who had a hysterectomy or biopsy due to cervical cancer, precancer (cervical intraepithelial neoplasia I, II, and III), or noncancerous diseases. The samples were analyzed using high-performance liquid chromatography for 10 micronutrients (lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, beta-carotene, cis-beta-carotene, alpha-tocopherol, gamma-tocopherol, and retinol). The results indicated that: (a) among the three patient groups, the mean plasma concentrations of all micronutrients except gamma-tocopherol were lowest in the cancer patients; however, the mean tissue concentrations of the two tocopherols and certain carotenoids were highest in the cancerous tissue; and (b) among the 10 micronutrients, only the concentrations of beta-carotene and cis-beta-carotene were lower in both the plasma and tissue of cancer and precancer patients than in those of noncancer controls. These results suggest that: (a) not all of the micronutrient concentrations in plasma reflect the micronutrient concentrations in cervical tissue; thus, in some cases, it may be necessary to measure the tissue micronutrient concentrations to define the role of the micronutrients in cervical carcinogenesis; and (b) maintaining an adequate plasma and tissue concentration of beta-carotene may be necessary for the prevention of cervical cancer and precancer.

Preinvasive cervical neoplasia.

The HPV has been identified as the causative agent for cervical neoplasia. The transforming mechanisms appear to be through inactivation of p105Rb or p53 by the oncoproteins E6 and E7 of HPV types 16 and 18. Because 2% to 24% of normal women test positive for these viral types and the incidence of neoplasia is less than 1%, co-factors must play an important part in carcinogenesis. A search for these co-factors is underway.

Construction of a neovagina after exenteration using the vulvobulbocavernosus myocutaneous graft.

Construction of a neovagina after exenterative surgery is important for the psychologic adjustment of the patient undergoing exenteration. The bulbocavernosus muscle, fat, and overlying vulvar skin have been used as a pedicle graft to create a neovagina in eight patients undergoing supralevator pelvic exenteration in the past 22 months. The vaginal length and caliber has proved to be excellent with return of normal sexual function among four women who currently have a sexual partner. This graft is easier to construct with less operative time and blood loss than the gracilis myocutaneous graft. The cosmetic results are excellent and there have been no complications.

Comparison of Doppler with two-dimensional sonography and CA 125 for prediction of malignancy of pelvic masses.

OBJECTIVE: To assess the validity of Doppler flow sonography for the prediction of malignancy in adnexal masses and to compare the results with two-dimensional ultrasonographic examination and CA 125 levels. METHODS: In a cross-sectional study, 55 patients with adnexal masses were examined using Doppler sonography to measure the resistance index of tumor-associated blood flow profiles. In addition, abdominal and transvaginal ultrasound examinations were performed and preoperative CA 125 serum levels were assessed. RESULTS: Sixteen patients had malignant tumors and 39 had benign tumors. A resistance index cutoff of less than or equal to 0.8 showed the highest sensitivity (93.8%), with a specificity of 56.4%, a positive predictive value of 46.8%, and a negative predictive value of 95.7%. Compared with two-dimensional sonographic evaluation using either a scoring system or subjective assessment, and with CA 125 levels, the resistance index showed higher sensitivity and negative predictive value but lower specificity and positive predictive value. False-positive resistance index values were prevalent with endometriosis, leiomyomata, and mucinous cystadenoma. The combination of the resistance index with either the sonographic features or CA 125 increased the sensitivity and negative predictive value to 100%, with only a slight decrease in specificity and positive predictive value, but was not superior to the combination of two-dimensional sonography and CA 125. CONCLUSION: Doppler sonographic evaluation of resistance indexes in the vessels of adnexal masses increased the sensitivity of two-dimensional sonography and CA 125. However, 46% of positive Doppler results were false and 37.5% of the benign tumors had low resistance indexes, thus limiting the validity of this technique for screening programs.

Secretory immune system of the female reproductive tract: I. Immunoglobulin and secretory component-containing cells.

We have investigated tissues from the female reproductive tract to determine whether the distribution of cells involved in the formation of secretory immunoglobulin A (IgA) molecules is analogous to that described for intestines, bronchus, and mammary and salivary glands. Fresh tissues from fallopian tube, ovary, uterus, and vagina were obtained, and sections were stained with fluorochrome-labeled polyclonal or monoclonal antibodies specific for IgG, IgA, IgA1, and IgA2 subclasses; IgM; secretory component; and J chain. Subepithelial plasma cells were identified in each specimen of fallopian tube, endocervix, ectocervix, and vagina. Approximately two-thirds of the immunoglobulin-positive cells contained IgA and J chain, indicating that they produced polymeric IgA. In comparison to tissues such as spleen and bone marrow, where IgA1-positive cells are produced, we found a high proportion of IgA2-positive cells in fallopian tube, cervix, and vagina. Epithelial cells in fallopian tube and endocervix contained secretory component. These data indicate that secretory IgA, which provides the first line of defense against invading pathogens, is produced locally in tissues of the female reproductive tract.

Laparoscopic para-aortic lymphadenectomy in gynecologic malignancies.

OBJECTIVE: To determine the feasibility, safety, limiting factors, and advantages of laparoscopic para-aortic lymphadenectomy in a series of patients with gynecologic malignancies. METHODS: During a 2-year period, 61 women underwent laparoscopic para-aortic lymph node dissection as part of their management for invasive gynecologic malignancies. A transperitoneal incision directly over the aorta was used. Initially, only the right-side infra-inferior mesenteric artery nodes were removed. The technique of removal of left-side low para-aortic nodes was then developed, followed by the technique for removal of right- and left-side nodes above the transverse duodenum. A total of 52 right para-aortic lymphadenectomies were performed, 12 of which were combined with left-side lymphadenectomies. A total of 17 left-side lymphadenectomies were performed, 12 of which were bilateral. Four patients had nodes removed above the inferior mesenteric artery. RESULTS: The procedure could not be performed in four instances because of obesity or adhesions. Twenty-four patients had their laparoscopic surgery combined with another procedure, which increased their hospital stays: radical hysterectomy (five), laparoscopy-assisted vaginal hysterectomy (17), transperineal interstitial irradiation (one), and anterior-posterior colporrhaphy (one). The remaining 33 patients had laparoscopic surgical staging only. One patient required laparotomy to control bleeding from the vena cava; however, the others had no short- or long-term complications, and the average hospital stay was 1.3 days. CONCLUSION: Laparoscopic para-aortic lymphadenectomy is a safe, effective procedure that allows a shorter hospitalization than traditional laparotomy.

Cryosurgery of cervical intraepithelial neoplasia.

Nine hundred sixty-eight patients with cervical intraepithelial neoplasia (CIN) were evaluated with colposcopy and treated with cryosurgery; 722 had a pretreatment diagnosis of CIN I or II and 246 had CIN III. Of those patients available for 2 follow-up smears, histologically proved persistence of CIN was found in 10% of patients with CIN I and II and 20% of patients with CIN III. Recurrent disease was detected in 3.2 and 3.8%, respectively. No patients had a recurrence after 5 negative Papanicolaou smears. One patient had invasive carcinoma 30 months after treatment. Failure of patients to return for follow-up was a significant problem. When the present results were compared to those published in the literature, cryosurgery was found to be less effective than conization in treating CIN III.

Intraoperative radiation in the treatment of advanced cervical cancer.

Nineteen patients with invasive cervical cancer were treated with intraoperative radiation and most of the patients subsequently received conventional external radiation therapy and intracavitary applications. The technique, resulting complications, and survival of the patients are discussed.

Abdominal-wall tumor implantation after laparoscopy for malignant conditions.

OBJECTIVE: To determine the incidence of abdominal-wall tumor implantation after laparoscopic procedures in patients with known malignancies. METHODS: We reviewed 557 laparoscopic procedures performed by the Gynecologic Oncology Service between November 1990 and February 1994. In 105 procedures, malignancy was documented cytologically or histologically, 88 with intraperitoneal disease and 17 with retroperitoneal disease. Ovarian cancer represented 80% (70 of 88) of the procedures with intraperitoneal malignancy, and the remaining cases consisted of carcinoma of the fallopian tube (two), endometrium (11), cervix (one), breast (three), and stomach (one). Histologically, ovarian carcinomas ranged from low malignant potential to poorly differentiated. Among 88 patients with intraperitoneal disease, 77 had gross disease and 11 had microscopic disease. Four hundred thirty-seven different abdominal-wall puncture sites were used (38 Veress needle sites and 399 laparoscopic ports). RESULTS: One of the 437 (0.2%) abdominal-wall puncture sites developed implantation, a frequency of 1.0% (one in 105) per procedure; this developed after a second-look laparoscopic procedure for ovarian carcinoma in which only microscopic disease was present. If only intraperitoneal disease is considered, the incidence of implantation was 0.3% (one in 363) per abdominal puncture and 1.1% (one in 88) per procedure. CONCLUSION: Tumor implantation at the abdominal-wall puncture site is an infrequent occurrence after laparoscopy in patients with intraperitoneal and retroperitoneal carcinoma.

Identification of histopathologic risk groups in stage IB squamous cell carcinoma of the cervix.

This study was undertaken to identify histopathologic risk factors in 100 women with stage IB squamous cell carcinoma of the cervix treated surgically. Histologic factors included maximum depth of stromal invasion, presence of lymph-vascular invasion, mitotic activity, nature of the tumor-stromal borders, plasma cell-lymphocyte stromal response, histologic grade, and metastases to regional lymph nodes. Using a multifactorial analysis, the maximum depth of stromal invasion was found to be the most important prognostic indicator (P less than .0001). The depth of invasion also correlated significantly with the presence of nodal metastases (P less than .0001), lymph-vascular space invasion (P = .0003), and "spreading" versus "pushing" borders (P = .0315). The number of mitoses, grade of tumor, or plasma cell-lymphocyte stromal response did not correlate significantly with depth of stromal invasion. Lymph-vascular involvement, although present in 59% of the patients, did not significantly affect survival. Depth of stromal invasion and lesion diameter were combined to constitute three risk groups: Patients with small size cervical tumors (less than 2 cm), regardless of depth of stromal invasion, as well as patients with intermediate size lesions (2.1 to 3 cm) with stromal invasion less than or equal to 1.5 cm, constituted a low-risk group; the intermediate-risk group was comprised of those patients with cervical lesions between 2.1 and 3 cm in size and deep stromal invasion (greater than 1.5 cm), as well as those patients with large cervical lesions (greater than 3.0 cm) and stromal invasion less than or equal to 1.5 cm.2+ (greater than 3 cm) and deep stromal invasion (greater than 1.5 cm).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of endocervical curettage in colposcopy.

Two-thousand three-hundred and four patients with abnormal cervical cytology were evaluated by colposcopy, cervical biopsy, and endocervical curettage. The endocervical curettage was more accurate than the cervical biopsy in 1.2% of patients with satisfactory colposcopic examinations, 15.7% of patients with unsatisfactory examinations, and 30.5% of patients with no lesions observed. The endocervical curettage contained neoplastic epithelium in all 15 of the patients with invasive cancer and in seven patients it was the only diagnostic parameter that indicated invasion. The information from the endocervical curettage, when correlated with the cervical cytology, colposcopic findings, and cervical biopsy, eliminated the need to do a diagnostic conization in 76% of patients with unsatisfactory examinations and 79% of patients with no lesion identified. It is recommended that the endocervical curettage be a part of every colposcopic examination.

Clinical and histopathologic factors predicting recurrence and survival after pelvic exenteration for cancer of the cervix.

Between September 1969 and January 1, 1986, 143 pelvic exenterations for recurrent cervical cancer were performed by the gynecologic oncologists at the University of Alabama at Birmingham. Of this group, 78 patients underwent total pelvic exenteration, 63 patients had anterior exenteration, and two had posterior exenteration. The overall operative mortality rate was 6.3%, mostly associated with total pelvic exenteration. The 5-year survival rates were 50% overall, 63% with anterior exenteration and 42% with total exenteration. Univariate and multivariate analyses were performed to identify clinical and histopathologic factors predictive of prolonged survival. Using three clinical factors (duration from initial radiation therapy to exenteration, size of the central mass, and presence of preoperative sidewall fixation), low-, intermediate-, and high-risk groups were constructed; the 5-year survival rates for these groups were 82, 46, and 0%, respectively. Inclusion of one histopathologic factor (margin status of the surgical specimen) added to the ability to predict 2- and 5-year survival rates. The best candidates for cure by pelvic exenteration were those with recurrent small (less than 3 cm), mobile central masses who were a year or longer from the time of their previous radiation therapy. Attempts to resect bulky pelvic recurrences that impinge on the pelvic sidewall, especially in the case of persistent or early recurrent disease (within 6 months), or continuation of exenterative procedures in women known to have nodal metastases or extrapelvic spread, are generally futile. For those women falling between the two extremes, sound clinical and operative judgment is imperative in regard to selecting the treatment offering the best quality of life.

Cervical intraepithelial neoplasia associated with exposure to diethylstilbestrol in utero: a clinical and pathologic study.

The anatomic, colposcopic, cytologic, and histologic findings of the cervix in 300 women exposed to diethylstilbestrol (DES) in utero are reported. Structural cervical abnormalities were found in 51.7% of these patients and an abnormal colposcopic examination was present in 50.6%. The initial interpretation of the pathologic specimens revealed that 26.6% of patients had cytologic or histologic evidence of cervical dysplasia. A uniform pathologic review demonstrated that 10.8% of the cytologic specimens and 37.5% of the histologic specimens had been overread by the initial pathologist. A correlation of the review cytology and histology revealed that the Papanicolaou smear sensitivity for the prediction of abnormal histology was 83.9% and specificity was 86.3%. The probability of an atypical cytologic finding predicting an abnormal histologic pattern was highly significant (P less than .00001). Colposcopic and structural cervical abnormalities were not predictive of an abnormal histologic diagnosis. Of the 18 patients (6%) with histologic evidence of mild-moderate dysplasia, 12 have been followed with no treatment, and cytologic and colposcopic examination has been normal. Marked dysplasia-carcinoma in situ was found in 14 patients (4.7%). Their therapy is summarized. These data strongly suggest that women exposed to DES may be followed safely with Papanicolaou smears and colposcopic examinations provided that both cytopathologists and colposcopists are cognizant of the metaplastic changes in the DES progeny that distinguish them from patients with cervical intraepithelial neoplasia (CIN) who were not exposed to DES. Biopsy should be performed only if indicated by cytologic atypia, colposcopic evidence of advanced CIN, or the presence of an invasive lesion.

Correlation of perioperative morbidity and conization to radical hysterectomy interval.

Between October 1969 and December 1980, radical hysterectomies were performed on 311 patients at the University of Alabama Medical Center in Birmingham. The hospital records of these patients were reviewed for perioperative morbidity. One hundred twenty-two patients (39.2%) had had previous cold knife conization. The conization to radical hysterectomy interval varied between 48 hours and 8 weeks. An analysis of the perioperative morbidity was performed comparing patients with to those without prior conization. Previous cervical conization, regardless of the interval, was not associated with increased hospital stay, operative time, blood loss, or febrile morbidity in patients undergoing radical hysterectomy. These findings suggest that a radical hysterectomy may be safely performed after cervical conization, regardless of the intervening interval.