Uterine effects of tamoxifen: a prospective study.

The purpose of the study was to evaluate tamoxifen-associated changes in the vagina and uterus in postmenopausal breast cancer patients. Between June 1994 and December 1998, 45 patients enrolled in a prospective study before commencing tamoxifen therapy. Patients with endometrial thickness >5 mm or neoplasia were excluded. Transvaginal ultrasonography, vaginal maturation indexes (VMI), and endometrial biopsy were performed at baseline and repeated at 6 months (n= 42), 1 year (n= 39), 2 years (n= 32), 3 years (n= 26), 4 years (n= 19), and 5 years (n= 15). For the 39 patients followed for 1 year, VMI (% parabasal/intermediate/superficial) was 21/71/8 at baseline compared with 1/90/9 at 1 year (P value = 0.0008/0.001/0.78). At baseline, mean endometrial thickness and uterine volume were 2.6 mm and 64 cm(3), respectively, compared with 5.8 mm and 84 cm(3) at 1 year (P= 0.0002, 0.002). At baseline, 80% of patients had atrophic endometrium and 9% proliferative endometrium compared with 61% and 26% at 1 year, respectively (P= 0.04). No cases of endometrial hyperplasia or adenocarcinoma were detected. Findings observed at 6 months persisted through 5 years of follow-up. Tamoxifen exerts a weak estrogenic effect on the vagina and uterus in highly prescreened postmenopausal women without preexisting endometrial pathology.

The use of continuous infusion topotecan in persistent and recurrent ovarian cancer.

We retrospectively review our experience with continuous infusion topotecan for the treatment of persistent or recurrent ovarian cancer in this paper. Nine patients were identified who were treated at the University of California Los Angeles Medical Center between January 1997 and December 1999 using a 14-21 day continuous infusion schedule (0.3-0.7 mg/m2/d). Dose adjustments were performed for grade 3-4 toxicities and treatment was discontinued for persistent severe toxicity or progressive disease. Response to treatment was analyzed and stratified by platinum refractory, resistant, and sensitive disease. A total of 41 treatment cycles were given to nine patients with a median of five per patient (range 1-11). Median follow-up was 8 months. There were two partial responses (22%) and four patients had stable disease (44%), which included two patients with platinum-refractory tumors. No grade 3 or 4 hematologic toxicities were observed. However, two patients suffered grade 3 gastrointestinal toxicity during the first cycle leading to discontinuation of topotecan administration. There was no cumulative toxicity. Topotecan administered by continuous infusion demonstrated response rates comparable to other dosing schedules with minimal hematologic toxicity. Treatment of patients with persistent or recurrent ovarian cancer with continuous infusion topotecan warrants further investigation.

An experience with estrogen replacement therapy in breast cancer survivors.

OBJECTIVE: To evaluate the outcome of breast cancer patients who elected estrogen replacement therapy (ERT). STUDY DESIGN: Breast cancer survivors who elected ERT received the preferred regimen of conjugated estrogen 0.625 mg/day with medroxyprogesterone acetate 2.5 mg/day. RESULTS: 145 patients received ERT for at least 3 months. Thirteen recurrences (9%) were identified; 10 are alive with disease, 3 are dead of disease. The median interval between diagnosis and commencement of ERT was 41 months. Forty-one percent of the study group initiated ERT within 3 years of their breast cancer diagnosis. The median duration of follow-up on ERT was 30 months. CONCLUSION: The concern that ERT might activate growth in occult metastatic sites and promote a rash of recurrences was not confirmed. It is unreasonable to categorically deny all breast cancer survivors ERT.

Ovarian histopathology in breast cancer patients receiving tamoxifen.

OBJECTIVE: The purpose of this study was to examine ovarian histopathology in tamoxifen-treated breast cancer patients undergoing oophorectomy. METHODS: We reviewed the records and ovarian histopathology of 152 breast cancer patients who underwent oophorectomy at a single institution between January 1980 and October 1996. At the time of oophorectomy, 99 patients had never received tamoxifen, 44 patients were currently receiving tamoxifen, and 9 patients had previously received tamoxifen. Patient demographic and medical data and indication for oophorectomy were examined. Ovarian histopathology was classified as normal, functional ovarian cyst, benign ovarian tumor, endometriosis, ovarian cancer, and metastatic cancer. RESULTS: Patient characteristics and indication for oophorectomy did not differ significantly based on tamoxifen exposure. There was no difference in the occurrence of benign ovarian tumors, functional ovarian cysts, or metastatic breast cancer based on tamoxifen exposure. Tamoxifen-treated patients were less likely to have ovarian cancer, 0 of 53 patients (95% confidence interval (CI): 0.0%, 6.7%) compared with 10 of 99 patients (95% CI: 5.0%, 17.8%) patients not receiving tamoxifen (P = 0.015). Endometriosis was slightly more common in patients currently receiving tamoxifen, but the difference was not statistically significant. CONCLUSIONS: In women undergoing oophorectomy, there was no evidence that tamoxifen exposure was associated with an increase in benign or malignant primary or metastatic ovarian neoplasm or in functional ovarian cysts. Further study is necessary to better define any association between tamoxifen and endometriosis and the effect of tamoxifen on ovarian cancer risk.

Endometrial cancer: recent developments in evaluation and treatment.

Endometrial carcinoma is the most common gynecologic malignancy in the United States. Most cases are diagnosed at an early stage. However, the outcome for women diagnosed with advanced-stage disease remains poor. The etiology of most endometrial carcinomas stems from the effects of excess estrogen, whether this comes from exogenous or endogenous sources. Differences in epidemiology and presentation suggest the existence of two forms of endometrial cancer: those related to and those unrelated to hormonal stimulation. Most women with endometrial cancer present with abnormal uterine bleeding; endometrial sampling is essential to exclude endometrial carcinoma in such patients. Endometrial cancer is surgically staged, and staging usually includes a hysterectomy and bilateral salpingooophorectomy. Lymphadenectomy also should be performed in selective cases to better assess disease spread and to evaluate the need for adjuvant therapy. Adjuvant treatment may include the use of radiation, progestins, or cytotoxic chemotherapeutic agents. Several clinical trials are underway to compare these treatment modalities, as well as to determine the optimal combination of active chemotherapeutic agents, such as doxorubicin, platinum agents, and paclitaxel (Taxol).

Effects of tamoxifen on the cytology of the uterine cervix in breast cancer patients.

Tamoxifen, a nonsteroidal antiestrogen, is the endocrine therapy of choice for all stages of breast cancer. Because tamoxifen is well tolerated and has minimal side effects, it is currently being evaluated in large scale trials as a chemopreventive agent for women at risk for developing breast cancer. The potential adverse effects of tamoxifen, specifically the development of proliferative lesions of the endometrium, coupled with the prospect of its wider use, places new emphasis on recognizing tamoxifen-associated histologic and cytologic changes in the female genital tract. The current study evaluated cervical smears from 52 breast cancer patients treated with tamoxifen compared with 21 smears from breast cancer patients who had not received tamoxifen. Cytologic diagnoses were classified according to the Bethesda system. The presence of blood, inflammation, and hormonal effect were also assessed. No squamous intraepithelial lesions were identified. A total of 21 of 38 smears (55%) from patients receiving tamoxifen alone and 11 of 14 smears (78%) from women who received tamoxifen in combination with adjuvant cytotoxic chemotherapy showed atypias compared with only 6 of the 21 breast cancer patients (28%) who did not have hormonal therapy. The number of smears showing atypia was equally divided into changes interpreted as benign reactive and atypical squamous cells of undetermined significance (ASCUS). Of the 19 patients whose smears were classified as ASCUS, 13 patients had a subsequent cervical biopsy and none showed dysplasia or diagnostic human papilloma virus changes. Tamoxifen therapy was not associated with an increase in the presence of blood or inflammation, and no discernible alteration in the hormonal state was seen in the cervical smears. We conclude that the use of tamoxifen may be associated with benign squamous atypia in cervical smears and that the atypia is not associated with intraepithelial lesions.

Abnormalities detected on transvaginal ultrasonography in tamoxifen-treated postmenopausal breast cancer patients may represent endometrial cystic atrophy.

OBJECTIVE: This study was conducted to examine the histopathologic changes in tamoxifen-treated postmenopausal patients with endometrial thickness > or = 5 mm with transvaginal ultrasonography. STUDY DESIGN: Thirty-five tamoxifen-treated postmenopausal breast cancer patients underwent transvaginal pelvic ultrasonography with endometrial thickness > or = 5 mm followed by either curettage-hysteroscopy (n = 24), or hysterectomy (n = 11). Endometrial histopathologic findings were examined. RESULTS: Overall, endometrial polyps were the most common histopathologic finding (23 of 35 patients). Endometrial cystic atrophy was uncommonly detected in patients undergoing curettage-hysteroscopy (1 of 24 patients) compared with patients undergoing hysterectomy (9 of 11 patients). No cases of endometrial cancer or hyperplasia were detected. CONCLUSIONS: Endometrial polyps were a frequent finding in tamoxifen-treated postmenopausal women who had endometrial thickness > or = 5 mm with the use of transvaginal ultrasonography. Endometrial cystic atrophy may explain "thickened endometrium" on transvaginal ultrasonography in this patient population with no evidence of endometrial polyps, hyperplasia, or adenocarcinoma after surgical evaluation.

Cancer of the endometrium and corpus uteri.

Uterine cancer is often diagnosed at an early stage and is therefore considered one of the most curable gynecologic malignancies. Despite this, a substantial number of women who present at more advanced stage or with unfavorable histologies suffer significant morbidity and death from this disease. Research continues along several fronts in an attempt to improve the prognosis for this group of women. Basic scientific research has continued to evaluate mechanisms of carcinogenesis in the hope that better targets for treatment and prevention of disease will be found. Epidemiologic studies have attempted to further define risk factors as well as elucidate risk in those patients receiving combination estrogen and progestin hormone replacement therapy. Clinical studies have further defined prognostic factors, and examined new surgical staging techniques and the need for adjuvant therapy after primary surgery. However, treatment options for advanced and recurrent disease remain limited.

Extraperitoneal laparoscopic para-aortic lymph node dissection.

Extraperitoneal cervical cancer "staging" is considered superior to a transperitoneal approach. We developed an entirely extraperitoneal laparoscopic technique for para-aortic lymph node dissection in a pig model, followed by human subject application. Using latex balloon dissection technology, the technique is as follows. A retroperitoneal space is created via a 15-mm left flank incision. The collapsed balloon trochar is inserted and the balloon is inflated under direct visualization. Subsequently, a CO2 pneumoretroperitoneum is established with 12-15 mm Hg and dissection is carried out using a total of three to four left flank port sites. For initial technique development and improvement, four pigs were used. Excellent bilateral retroperitoneal exposure was achieved. A complete dissection was performed from the renal to the iliac vessels. Subsequently, a bilateral sampling procedure from the level of the inferior mesenteric artery to the liac vessels was performed in four human subjects. A mean of 5 nodes (range 1-9) was removed with an EBL of <50 cc. Operative times were 120-140 min. There were no intra- or postoperative complications. This initial experience demonstrates that laparoscopic extraperitoneal para-aortic access and node sampling is feasible. Further study is ongoing to determine the extent of dissection possible using this approach. However, since this approach mimics the extraperitoneal laparotomy technique, it may have all the advantages of adhesion avoidance combined with an outpatient procedure.

Histopathologic effects of tamoxifen on the uterine epithelium of breast cancer patients: analysis by menopausal status.

We evaluated the histopathologic changes of the uterine epithelium in 73 breast cancer patients with tamoxifen stratified by menopausal status. Clinicopathologic data at the time of breast cancer diagnosis and endometrial sampling were analyzed and compared with 122 breast cancer patients not receiving the drug. The incidence of endocervical and/or endometrial polyps was increased in tamoxifen-treated postmenopausal patients compared with untreated patients, 43% (25 of 58) and 24% (16 of 68), respectively (odds ratio=2.46, P=0.02). In contrast, there was no increase in polyps in premenopausal tamoxifen-treated patients. This finding suggests that the effects of tamoxifen on the endometrium may vary with menopausal status.

Intestinal peritoneal sling as an adjunct to radical pelvic operation and pelvic irradiation.

BACKGROUND: Pelvic peritoneal surfaces are often denuded extensively during radical pelvic operations, providing raw areas for small bowel adherence and potential obstruction. This hazard is compounded in patients who receive whole pelvic adjuvant irradiation. Omental and synthetic slings or redundant sigmoid colon have been incompletely effective in excluding small bowel from the pelvic area. Furthermore, these exclusion procedures have been associated with significant complications. STUDY DESIGN: Anterior parietal peritoneal flaps were created in ten patients who were undergoing radical hysterectomy and pelvic lymphadenectomy for Stage Ib carcinoma of the cervix. These flaps were sewn to the posterior parietal peritoneum at the pelvic brim or higher and functioned as bowel slings. RESULTS: Small bowel loops were effectively excluded from the pelvic area as documented by oral contrast radiologic evaluation at two weeks and six months, postoperatively. Six patients received adjuvant whole pelvic irradiation. There have been no small bowel complications or obstructions during a follow-up period of six to 28 months (median of 16 months). CONCLUSIONS: This pilot series suggests that a parietal peritoneal sling can be performed safely and may protect the small bowel from complications as a result of adhesion formation or radiation.

Extraperitoneal laparoscopic paraaortic lymph node dissection: development of a technique.

Surgical assessment of cervical cancer spread primarily involves pathologic evaluation of the pelvic and paraaortic lymph nodes. Extended field radiation therapy, which may result in a survival advantage, is often based on such surgical findings, since clinical staging is inaccurate for this purpose. Extraperitoneal lymph node dissection is superior to a transperitoneal laparotomy approach, largely because of the absence of intraperitoneal adhesion formation and resulting bowel complications. Although transperitoneal laparoscopy may reduce adhesion formation when compared with laparotomy, it does not eliminate this problem. We developed an entirely extraperitoneal laparoscopic technique for paraaortic lymph node dissection in a pig model, using latex balloon dissection technology. The technique was quick, had a short learning curve, and eliminated bowel retraction or dissection. Excellent bilateral retroperitoneal exposure was achieved from the level of the renal to the iliac vessels for aortocaval lymph node dissection.

Development of endometrial cancer in women on estrogen and progestin hormone replacement therapy.

The presenting symptoms, hormonal regimens, treatment modalities, tumor pathology, and follow-up of 25 women developing endometrial cancer while receiving postmenopausal estrogen and progestin therapy were investigated retrospectively. Patients were interviewed and hormone therapies were confirmed through medical records. Pathology specimens were reviewed. Patients received conjugated estrogens (n = 20) or another estrogen (n = 5). For those on conjugated estrogens, the mean daily dose was 0.68 mg, monthly duration was 24.9 days, and monthly dose was 17.0 mg. Women also received medroxyprogesterone acetate (n = 23) or norethindrone acetate (n = 2). The most common regimen was sequential medroxyprogesterone acetate, at a mean daily dose of 7.5 mg, monthly duration of 9.3 days, and monthly dose of 68 mg (mean duration = 5.7 years). Most tumors were low stage and grade, with few demonstrating grade 3 disease (n = 2) or greater than 50% myometrial invasion (n = 2). Twenty-three (92%) had disease limited to the uterus, while two had stage IIIA disease. All are alive and disease-free after a median follow-up of 26 months. Estrogen and progestin therapy does not prevent endometrial cancer in all patients. Women who developed this tumor on sequential therapy in general received less than the recommended guidelines for daily dosage and monthly duration of progestin. Most patients had early-stage and low-grade disease. Continued vigilance in the care of women on hormone replacement therapy is necessary even when combination therapy is prescribed.

Ovarian, uterine, and cervical cancer in the elderly woman.

Older women are at a significantly increased risk of developing ovarian, endometrial, and cervical cancers. When an elderly woman develops one of these malignancies, she is more likely to die from it than a younger woman. The increased mortality-to-incidence ratio may be related primarily to the more advanced stage at diagnosis. Data suggest that elderly women in the United States are less likely to undergo routine gynecologic screening examinations than younger women, which often results in malignancies that are diagnosed at a more advanced stage. More aggressive screening programs directed at elderly women would likely result in an improvement of morbidity and mortality. Treatment modalities for the gynecologic malignancies presented include surgery, radiotherapy, and chemotherapy and must be carefully selected, planned, and sometimes modified for the elderly woman with intercurrent medical problems. There is no evidence that radical pelvic surgery is associated with increased morbidity in most elderly women compared with younger women. Treatment options such as radiotherapy may be associated with significant morbidity for elderly women. Most chemotherapeutic regimens are tolerated by elderly women, but modification of dose or agent may be necessary in selected cases. Improved screening and better treatments for gynecologic malignancies are needed for our nation's aging population. Studies specifically directed at the diagnosis, care, and treatment of elderly patients with gynecologic malignancies are necessary to improve the significant morbidity and mortality associated with ovarian, endometrial, and cervical cancers in elderly women.

Endometrioid carcinoma of the ovary presenting with an enlarged inguinal lymph node without evidence of abdominal carcinomatosis.

It is generally recognized that ovarian cancer tends to remain intraabdominal even in advanced cases and that dissemination is usually by invasion of adjacent viscera, diffuse intraperitoneal implantation, and metastatic involvement of aortic and pelvic lymph nodes. Primary ovarian lymphatic drainage occurs via the infundibulopelvic ligament to the paraaortic nodes. The presence of an ovarian tumor extending into adjacent pelvic viscera may allow direct lymphatic continuity with inguinal, external, and common iliac lymph nodes. In the absence of such extension it is traditionally believed that the drainage via the infundibulopelvics is so important that only with its blockage, presumably by tumor emboli, can retrograde drainage to pelvic and inguinal nodes occur. We report a case of a patient presenting with a large metastatic inguinal lymph node from a primary epithelial ovarian cancer without evidence of disseminated intraabdominal disease or gross evidence of pelvic or paraaortic lymph node involvement.

Early-stage squamous cell and adenocarcinoma of the cervix.

Articles on early-stage squamous cell and adenocarcinoma of the cervix published between August 1990 and July 1991 are reviewed. A new monoclonal antibody used to distinguish endocervical from endometrial differentiation is described, as well as a histochemical means of distinguishing in situ from invasive adenocarcinoma. In vitro and in vivo studies of cell lines immortalized with human papillomavirus DNA are described with a discussion of the mechanism of the development of malignancy. An animal model to test and develop an anti-human papillomavirus vaccine is presented. The epidemiology of adenocarcinoma is also reviewed, and the development of invasive carcinoma after conservative therapy or conization for dysplasia is discussed. Computed tomography scanning has been found to be no more accurate than examination for staging of early cervical cancer. Several studies in the review period have evaluated risk factors for recurrent disease in patients treated for early-stage cervical cancer, including a prospective surgical pathologic study by the Gynecologic Oncology Group. The optimal treatment of early stage I adenocarcinoma of the cervix is discussed, comparing the efficacy of primary surgical therapy with the efficacy of radiation therapy. The risk of ovarian metastases in patients with early-stage cervical cancer is very low for both squamous cell and adenocarcinoma. The surgical technique and efficacy of laparoscopic pelvic lymphadenectomy for patients with early-stage cervical cancer are discussed. Lateral transposition of the ovaries at the time of radical hysterectomy for cervical cancer has significant potential benefits but also risks. Finally, surveillance methods that detect recurrent cervical cancer after treatment for early-stage disease are discussed.

Oral contraceptives and breast disease.

Epidemiologic data support the hypothesis that the types of OCs used before the mid-1970s protected against most forms of benign breast disease. It is unclear whether current low-dose progestogen OCs will confer the same protection. Further studies are necessary to clarify this. For breast cancer, the relationship is more complex. It is possible that prolonged use of high-dose OCs exert a small increased risk for breast cancer development in women before age 45. Furthermore, prolonged use before a first term pregnancy may result in a small increase in risk for breast cancer before age 45. Studies evaluating the effect of current low-dose OCs are necessary to elucidate what, if any, effect they may have on breast cancer development. Furthermore, as our population ages, studies will be able to determine what effect, if any, may be present in women over age 60, those women with the highest underlying risk of breast cancer. And finally, more research of basic breast tissue physiology and the effect of endogenous and exogenous hormones on this complex organ is needed.

PIP: This review covers the epidemiology of benign and neoplastic breast disease, the theoretical effects of steroids on the breast, and the effects of oral contraceptives on both. Breast cancer has been increasing since the 1940s in older U.S. women, killing about 44,500 of the 175,000 new cases per year. In addition fibrocystic breast disease may affect up to 50% of premenopausal women, resulting in 500,000 biopsies, of which 10% are cancerous, 33% of those in post-menopausal women. The involvement of steroids in development of the human breast, and in breast cancer, is reviewed. The breast does not complete its development until the end of the 1st pregnancy. The terminal ductal cells, from which breast cancers form, are susceptible to stimulation by progestins in nulliparas. Progestins, at least in the high doses used in early orals, protect against benign breast disease. Inadequate amounts of progesterone, however, as in irregular cycles, seem to predispose to breast cancer. Epidemiologic studies of oral contraceptive use and breast cancer are reviewed under the studies of oral contraceptive use and breast cancer are reviewed under the headings of overall results, age, age 45, parity, use before 1st pregnancy, use at young ages, latent effect, hormone formulation, associated benign breast disease, association with other neoplasms, and receptor status. There are slightly increased risks for cancer before age 45 for long-term use of pills before the 1st term pregnancy, although the data are not wholly consistent, in that the specific sub-groups of women affected differ in different studies. There is no clear evidence for a latent effect, that is, appearance of cancer 20-30 years after stopping the pill. Nor is there evidence of breast cancer linked to any specific pill type, nor with benign breast disease, nor with endometrial cancer. The reason for rising breast cancer rates is still unknown. The absolute number of increased cases related to oral contraceptives is insufficient to affect national rates. It is possible that the inconsistent findings in epidemiological studies reflects use of high-dose pills in the 1960s and early 1970s. The contraceptive and non-contraceptive benefits of the pill are more important for women's health than the potential cases of breast cancer in young women who took them for prolonged durations.

Fetal tissue sampling. The San Francisco experience with 190 pregnancies.

Prenatal diagnosis of genetic defects was done using fetal blood sampling in 167 at-risk pregnancies, by fetal skin biopsy in 15 pregnancies, and by fetal liver biopsy in 8 pregnancies. Fetal blood sampling was done by fetoscopy through January 1985 and by sonographically directed percutaneous umbilical blood sampling since then. In our series, cytogenetics has become the major indication for fetal blood sampling, increasing from 6% of the cases with fetoscopy to 48% with umbilical blood sampling. Fetoscopy provided pure fetal blood in 61% of cases while umbilical blood sampling provided pure fetal blood 97% of the time. The corrected risk of fetal demise after percutaneous umbilical fetal blood sampling was 2% and after fetoscopy was 4%.