Evaluation of the woman with postmenopausal bleeding: Society of Radiologists in Ultrasound-Sponsored Consensus Conference statement.

OBJECTIVES: A panel of 14 physicians practicing medicine in the United States with expertise in radiology, obstetrics and gynecology, gynecologic oncology, hysteroscopy, epidemiology, and pathology was convened by the Society of Radiologists in Ultrasound to discuss the role of sonography in women with postmenopausal bleeding. Broad objectives of this conference were (1) to advance understanding of the utility of different diagnostic techniques for evaluating the endometrium in women with postmenopausal bleeding; (2) to formulate useful and practical guidelines for evaluation of women with postmenopausal bleeding, specifically as it relates to the use of sonography; and (3) to offer suggestions for future research projects. SETTING: October 24 and 25, 2000, Washington, DC, preceding the annual Society of Radiologists in Ultrasound Advances in Sonography conference. PROCEDURE: Specific questions to the panel included the following: (1) What are the relative effectiveness and cost-effectiveness of using transvaginal sonography versus office (nondirected) endometrial biopsy as the initial examination for a woman with postmenopausal bleeding? (2) What are the sonographic standards for evaluating a woman with postmenopausal bleeding? (3) What are the abnormal sonographic findings in a woman with postmenopausal bleeding? (4) When should saline infusion sonohysterography or hysteroscopy be used in the evaluation of postmenopausal bleeding? (5) Should the diagnostic approach be modified for patients taking hormone replacement medications, tamoxifen, or other selective estrogen receptor modulators? CONCLUSIONS: Consensus recommendations were used to create an algorithm for evaluating women with postmenopausal bleeding. All panelists agreed that because postmenopausal bleeding is the most common presenting symptom of endometrial cancer, when postmenopausal bleeding occurs, clinical evaluation is indicated. The panelists also agreed that either transvaginal sonography or endometrial biopsy could be used safely and effectively as the first diagnostic step. Whether sonography or endometrial biopsy is used initially depends on the physician's assessment of patient risk, the nature of the physician's practice, the availability of high-quality sonography, and patient preference. Similar sensitivities for detecting endometrial carcinoma are reported for transvaginal sonography when an endometrial thickness of greater than 5 mm is considered abnormal and for endometrial biopsy when "sufficient" tissue is obtained. Currently, with respect to mortality, morbidity, and quality-of-life end points, there are insufficient data to comment as to which approach is more effective. The conference concluded by identifying several important unanswered questions and suggestions that could be addressed by future research projects.

Vaginal hysterectomy as primary treatment of endometrial cancer in medically compromised women.

OBJECTIVE: To study the survival, rates and patterns of recurrence, and perioperative morbidity in medically compromised women with endometrial cancer treated by primary vaginal hysterectomy. METHODS: Fifty-one patients with endometrial cancer treated initially by vaginal hysterectomy between 1977 and 1999 were identified at the University of California, Irvine Medical Center and affiliated hospitals. Data were retrieved from hospital and office records. Statistical analysis, including Kaplan-Meier methods, was performed and the disease-specific survival rates were estimated. This study has 80% power to demonstrate a greater than 20% improvement in 5-year survival over historical controls. RESULTS: Fifty-one women with uterine carcinoma clinically confined to the uterus underwent primary vaginal hysterectomy with (n = 26) or without (n = 25) salpingo-oophorectomy. Eighty-four percent were obese with a body mass index greater than 27. Additional risk factors for surgical complications included hypertension (57%), diabetes mellitus (27%), and cardiovascular disease (18%). One-third of patients had three or more risk factors. Surgical morbidity included one episode of acute hemorrhage necessitating transfusion and abdominal exploration. Blood transfusions were given to four additional patients. There were no perioperative deaths. Five women recurred and expired at a median of 13 months (range 3--53 months) after surgery. The 3- and 5-year disease-specific survival rates were 91.4% and 88.0%, respectively. CONCLUSION: Vaginal hysterectomy for the initial treatment of early-stage endometrial cancer is associated with a high rate of cure and minimal morbidity. Thus, it may be considered a reasonable alternative to the abdominal approach in medically compromised women.

Chemotherapy for advanced or recurrent carcinoma of the cervix.

The management of early-stage cervical cancer involves primarily surgery and/or chemoradiotherapy. When the disease spreads beyond the cervix but remains confined to the pelvis and draining lymph node basins, the mainstay of management is chemoradiotherapy. The use of primary systemic chemotherapy is related to the management of disease that has recurred or spread beyond the pelvic radiation fields. Although the optimal chemotherapy regimen remains to be determined, current protocols and the associated research to support their use are discussed in this review. Additionally, the rationale for use of chemoradiotherapy in locally advanced disease is presented.

A retrospective study of tamoxifen and endometrial cancer in breast cancer patients.

OBJECTIVE: To assess the relationship between low-dose tamoxifen, usage and endometrial cancer in breast cancer patients. METHODS: In this case-control study, the records of the 1017 patients treated at Wilford Hall Medical Center for primary breast cancer between 1978 and 1989 were reviewed. Dose and duration of tamoxifen therapy were recorded as well as the presence of a uterus. Potential confounding variables including diabetes mellitus, hypertension, age, weight, tobacco use, and family history of breast or gynecologic cancer were recorded. RESULTS: Of the 1017 patients in the study, 56 had inadequate records and 375 had undergone a prior hysterectomy and these patients were excluded from the study, leaving 586 eligible patients. Of these 586 women with primary breast cancer and no previous hysterectomy, 108 patients had received tamoxifen, 10 mg twice a day for greater than 1 year. Four of the 108 patients subsequently developed endometrial adenocarcinoma. Four hundred seventy-eight breast cancer patients did not receive tamoxifen and 4 later developed endometrial adenocarcinoma. The odds ratio for the development of endometrial cancer when exposed to tamoxifen was 15.2 with a 95% confidence interval of 2.8-84.4. The patients exposed and not exposed to tamoxifen were compared for potential confounding variables and after controlling for the potential confounders, tamoxifen was found to be an independent risk factor for the development of endometrial cancer. CONCLUSIONS: Low-dose tamoxifen when given for greater than 1 year is associated with secondary endometrial cancer in patients with primary breast cancer.

A phase II trial of neoadjuvant chemotherapy prior to radical hysterectomy and/or radiation therapy in the management of advanced carcinoma of the uterine cervix.

OBJECTIVE: This prospective trial was designed to access the efficacy and safety of neoadjuvant chemotherapy followed by radical hysterectomy and/or radiation therapy in women with advanced carcinoma of the uterine cervix. METHODS: Thirty women, clinical stages IIb-IVa, were enrolled in this clinical trial. Initial treatment consisted of three cycles of bleomycin, cisplatin, and vincristine administered every 10 days. Depending on the extent of disease after chemotherapy, patients then either underwent radical hysterectomy with bilateral pelvic and periaortic lymphadenectomy or surgical staging. Following review of the surgical findings, tailored radiotherapy was administered. RESULTS: Only 10 women (34%) had tumor regression from neoadjuvant chemotherapy sufficient to allow radical hysterectomy prior to tailored adjuvant radiotherapy; the remainder received primary radiotherapy after surgical staging. Two-year disease-free survival was 68, 43, and 0% for women with clinical stages II, III, and IV, respectively. Four women experienced acute toxicity from chemotherapy requiring medical intervention and eight women suffered chronic toxicities requiring hospitalization and/or surgery. CONCLUSION: The neoadjuvant chemotherapy utilized in this trial was generally ineffective in converting patients from inoperable to operable, had no apparent effect on survival, and was associated with significant toxicity.

The use of electrosurgical techniques in the management of premalignant diseases of the vulva, vagina, and cervix: an excisional rather than an ablative approach.

In recent years electrosurgical excision techniques have been advocated for the evaluation and treatment of premalignant diseases of the vulva, vagina, and cervix. Technologic advances in electrosurgical generators and in fine wire loops have made these techniques feasible in the outpatient setting, and considerable experience has been accumulated in Europe and the United States. This article discusses the advantages and disadvantages of this "new" technology with emphasis on the available scientific literature. In summary, electrosurgical excision offers the benefit of providing tissue for complete histopathologic evaluation without compromising the established convenience, safety, and efficacy of ablative techniques.

Extraovarian peritoneal serous papillary carcinoma: a case-control retrospective comparison to papillary adenocarcinoma of the ovary.

Since the establishment of extraovarian peritoneal serous papillary carcinoma (EPSPC) as a clinical entity in 1959, less than 250 cases have been described and its clinicopathologic features remain obscure. The present series is a retrospective, case-controlled study comparing the response and survival to cytoreductive surgery followed by cisplatin-based multiagent chemotherapy of 33 women with confirmed EPSPC versus 33 cases with papillary serous ovarian cancer (PSOC). Each EPSPC case was matched to a PSOC control for extent and distribution of disease prior to and following cytoreductive surgery, tumor grade, patient age, and treatment. Additionally, the new Gynecologic Oncology Group criteria for the diagnosis for EPSPC are discussed. There were no significant differences in tumor response to therapy, disease-free interval, and actuarial survival between cases and controls. These data suggest that EPSPC is clinically similar to PSOC and support the need for a prospective clinical trial to compare these two entities further.

Bulky stage IB cervical carcinoma managed by primary radical hysterectomy followed by tailored radiotherapy.

The management of bulky, stage IB cervical carcinoma remains controversial. The present study reports the outcome of 84 women treated by radical hysterectomy, in which the surgical specimen revealed a lesion measured to be 4 cm or greater in size following formalin fixation. Of the 84 women, 42 (50%) received postoperative radiotherapy based on additional surgical findings beyond tumor size suggesting a high risk for pelvic recurrence including lymph node metastasis, parametrial spread, and compromised margins. Despite the bulky nature of these lesions, major operative and early postoperative complication rates were low (6%). Delayed complications including fistulae and bowel obstructions occurred in only 2.4% of patients treated with surgery alone and in 14.2% of women treated with combined therapy. Corrected 5-year survival in this series was 70.4% (75.6% in the surgery only group and 65.0% in the surgery plus radiotherapy group). Recurrence and mortality rates were related to lesion size, with most recurrences and deaths occurring in women with lesions measuring 6 cm or greater. Comparison of these data utilizing primary radical hysterectomy followed by tailored radiotherapy with previously published data on similar groups of high-risk patients treated with either radiotherapy alone or with radiotherapy followed by simple hysterectomy suggests comparable survival and morbidity.

Serum CA125 regression in epithelial ovarian cancer: correlation with reassessment findings and survival.

Findings at reassessment laparotomy and disease-free survival are reported for a group of patients with advanced-stage epithelial ovarian cancer who have had a complete clinical response to cytoreductive surgery and multiagent platinum-based chemotherapy. The predictive value of the number of chemotherapy cycles to achieve a serum CA125 of < 35 U/ml is compared to the predictive value of s, the rate of achieving a normal serum CA125. s is generated from an exponential regression model. This study suggests that s accurately predicts which patients have residual disease at reassessment laparotomy, who will be free of disease, and, of those in the latter group, who are at greatest risk to recur, as well as overall survival. If these observations are confirmed, physicians may base further therapeutic intervention on the basis of a calculated parameter following complete clinical response to first-line treatment rather than relying on findings at reassessment laparotomy.

Comparison of adenocarcinoma and squamous cell carcinoma of the uterine cervix: a population-based epidemiologic study.

OBJECTIVE: Our objective was to compare epidemiologic and clinical characteristics of adenocarcinoma with those of squamous cell carcinoma of the cervix, with respect to risk by ethnic group, age at diagnosis, stage of disease at diagnosis, and survival. STUDY DESIGN: All data were obtained from the Cancer Surveillance Program of Orange County, California, from 1984 through 1989. A total of 152 cases of adenocarcinoma and 457 of squamous cell carcinoma of the uterine cervix were included. RESULTS: Adenocarcinoma of the cervix was diagnosed at a younger age and an earlier stage than squamous cell carcinoma. Hispanics have the highest risk for squamous cell carcinoma, whereas Asians have the highest risk for adenocarcinoma compared with whites. No differences were observed between the two histologic types in prognosis and survival. CONCLUSION: Differences between the two histologic types of cervix cancer were found in the age at diagnosis, the extent of disease, and the ethnic distribution. In spite of these differences, prognosis and survival were not affected by histologic type.

Radiation myelitis: a complication of concurrent cisplatin and 5-fluorouracil chemotherapy with extended field radiotherapy for carcinoma of the uterine cervix.

Radiation myelitis is a rare but serious complication of radiation therapy. The total dose of radiation to the spinal cord required to cause myelopathy is greater than 50 Gy when the treatment is administered in 25 or more fractions; however, recent evidence has suggested that the concurrent use of chemotherapy may decrease the tolerance of the spinal cord to radiation. This report describes a case of radiation myelitis in a patient after concomitant fluorouracil/cisplatin chemotherapy and extended field radiotherapy for stage IIA adenosquamous cell carcinoma of the uterine cervix metastatic to the para-aortic lymph nodes.

CA 125 regression: a model for epithelial ovarian cancer response.

The rate of decline of CA 125 in effectively treated epithelial ovarian cancer is described by the exponential regression curve CA 125 = EXP [i - s (days after surgery)]. In this equation i, the y-axis intercept, measures initial tumor burden whereas s, the slope of the regression curve, is determined by the extent of cytoreductive surgery and the subsequent response to chemotherapy. Departure from the regression curve uniformly results in progressive disease. In patients whose cancers had been completely removed, we calculated the mean half-life of CA 125 to be 10.4 days (range 4 to 21). In this case s = 0.0835 and characterizes the ideal regression rate. The model predicts that high-dose cisplatin chemotherapy (s = 0.0671) is more effective than low-dose cisplatin (s = 0.0380) (p less than 0.03) in eliminating residual cancer. Because s can be calculated within 2 to 3 months of treatment and then compared with s for the ideal regression curve and with the values of s reported for standard chemotherapy, evaluation of any new treatment protocol can be facilitated with this method.

Clinical and histologic features of vulvar carcinomas analyzed for human papillomavirus status: evidence that squamous cell carcinoma of the vulva has more than one etiology.

The association between the human papillomavirus (HPV) and malignant neoplasms of the uterine cervix is well established; however, its role in the pathogenesis of vulvar cancer has not been well defined. This study correlates the clinical and histopathologic features of 21 invasive carcinomas of the vulva with the presence of HPV DNA as detected by Southern blot and polymerase chain reaction (PCR) analysis. By one or both techniques, HPV DNA was detected in 10 of the 21 tumors analyzed; all HPVs containing tumors hybridized with HPV-16 probes, although PCR also detected HPV-6 in two of the HPV-16-containing tumors. No HPV-18 DNA was detected in any tumor by PCR or Southern blot hybridization. Both the invasive cancer and the surrounding intraepithelial disease tended to display histopathologic features that usually could distinguish HPV-associated cancers from those without HPV DNA. The intraepithelial lesions associated with HPV-containing tumors were of the bowenoid type with koilocytosis, while tumors lacking HPV generally demonstrated a simplex type of intraepithelial lesion. Invasive tumors with no viral DNA were more frequently keratinizing than the HPV-containing cancers. Race, parity, hormonal therapy, and alcohol use did not affect the HPV status; however, HPV DNA was more prevalent in the tumors of younger women and in those with a history of tobacco use. Human papillomavirus status had no impact on the stage of disease or its prognosis. These findings identify two subsets of vulvar carcinoma cases based on HPV hybridization data and the histopathologic characteristics of the tumor.

Does intraperitoneal CA-125 reflect disease status?

The relationship of serum CA-125 to intraperitoneal (IP) CA-125 was studied in 45 patients with a variety of gynecologic diseases including ovarian carcinoma. In 43 of 45 patients the IP level exceeded the serum level of CA-125. Paracentesis may dramatically alter both levels, thus mimicking surgical debulking. All IP levels of CA-125 measured at second-look coeliotomy for the ovarian cancer patients were within the normal range of IP CA-125 measured at surgery for benign disease. Therefore, intraperitoneal CA-125 is less sensitive than serum CA-125 in predicting intraperitoneal disease status. Likewise it cannot be used to predict the subgroup of ovarian cancer patients with negative second-look coeliotomy who are destined to develop a recurrence of disease.

Use of vaginal hysterectomy for the management of stage I endometrial cancer in the medically compromised patient.

Vaginal hysterectomy was performed on 31 patients with stage I endometrial cancer because of medical problems which placed them at high risk for morbidity and mortality from abdominal surgery. These risk factors included morbid obesity (87%), hypertension (58%), diabetes mellitus (35%), and cardiovascular diseases (26%). The perioperative morbidity was minimal, with only four patients (13%) experiencing complications requiring extended hospital stays and no deaths. Adjuvant radiotherapy was administered in 35% of patients with either deep myometrial invasion or unfavorable histology. The 3- and 5-year disease-free survival rates were 100 and 93%, respectively. The only cancer-related death occurred 4.5 years following surgery. Although the authors are not advocating vaginal hysterectomy as standard treatment of endometrial cancer, this approach provides an acceptable alternative to abdominal surgery in the medically compromised patient.

Hemolytic-uremic syndrome associated with neoadjuvant chemotherapy in the treatment of advanced cervical cancer.

Hemolytic-uremic syndrome (HUS) is a rare but severe complication of neoplastic disease as well as some of its treatments. The pathophysiology of HUS is poorly understood, but it affects multiple organ systems and carries a high mortality rate. The diagnosis of HUS is based on a clinical triad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and renal failure, for which no proven therapies exist. This report describes a case of HUS developing in a patient with stage IVA squamous cell carcinoma of the uterine cervix following treatment with cisplatin/bleomycin/vincristine neoadjuvant chemotherapy prior to radiation therapy.

The use of molecular probes to distinguish new primary tumors from recurrent tumors in gynecologic malignancies.

This is the first report using DNA molecular probe technology to distinguish between recurrent tumor and a second primary malignancy in a patient. Tumor DNA was extracted from squamous cell carcinoma of the cervix at the time of radical hysterectomy. Eighteen months later a squamous cell cancer was found in a vaginal apex biopsy from which DNA was extracted. Tumor DNA from both lesions was subjected to restriction enzyme digestion and DNA molecular hybridization with human papillomavirus (HPV) probes. Although both lesions were positive for HPV 16, their respective restriction enzyme patterns had different HPV genetic arrangements, thereby demonstrating their distinctness.

Human papillomavirus genotype as a prognostic indicator in carcinoma of the uterine cervix.

The clinical implications of specific human papillomavirus (HPV) types in invasive cervical carcinomas are only beginning to be appreciated. In this series of 100 women with cervical cancers analyzed for the presence of HPVs 6, 11, 16, 18, and 31 by Southern blot hybridization, a more aggressive clinical behavior was demonstrated for tumors containing HPV 18 than for those with HPV 16 or those in which no HPV was identified. Among 69 stage Ib tumors, no significant differences were found in the size of tumor, presence of parametrial involvement, or lymph node metastasis among patients whose tumor contained HPV 16, HPV 18, or no HPV DNA; however, 45% of the women with HPV 18-containing tumors (five of 11) had recurrence, as compared with only 16% of those with HPV 16 (five of 31) during the 20-month mean follow-up period. This tendency for HPV 18-containing tumors to recur was seen with all histologic subtypes of cervical cancers and with all grades of tumor. In addition, patients with HPV 18-containing tumors were more likely to give a history of recent normal Papanicolaou smears than were those whose tumors contained HPV 16. Forty-four percent of women with HPV 18 in their tumors had a history of three class I Papanicolaou smears in the 3 years before the diagnosis of cancer, whereas a similar history was elicited in only 16% of those with HPV 16 in their tumors, suggesting that HPV 18-containing tumors might progress to invasion without a prolonged preinvasive period.

The effect of oxytocin infusion on the pharmacokinetics of intramuscular magnesium sulfate therapy.

The effect of oxytocin infusion on the pharmacokinetics of standard intramuscular magnesium sulfate therapy was determined in 18 women with preeclampsia; the results were compared with those in seven women with preeclampsia who did not receive oxytocin. Oxytocin had no significant effects on the maternal serum magnesium and calcium ion concentrations, nor did oxytocin appear to affect the magnesium or calcium concentrations in fetal umbilical cord blood. Urinary excretion of magnesium rose 21-fold and calcium excretion rose threefold in patients receiving intramuscular magnesium sulfate in both the oxytocin and the nonoxytocin groups. Sixty-five percent of the administered magnesium was excreted during the treatment period, again with no significant differences between the oxytocin and the nonoxytocin groups. These results indicate that oxytocin does not affect the pharmacokinetics of intramuscular magnesium sulfate and no dosage adjustment of magnesium sulfate is required when oxytocin is used to induce or augment labor or when it is given during the postpartum period.