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.

Ovarian cancer metastatic to the brain: what is the optimal management?

PURPOSE: To better define determinants of survival and optimal management strategies for patients with ovarian cancer and brain metastases. METHODS: A review of literature using Medline identified 15 case series of ovarian cancer patients with brain metastases (OBM). Each article was abstracted for survival data, and in all cases, the intervals between ovarian cancer diagnosis and brain metastasis identification, and between brain metastasis identification and last follow-up were recorded. Cases were categorized by patient characteristics and treatment modality for brain metastases. Estimated survival probabilities were plotted using the Kaplan-Meier method with differences between subgroups analyzed by the log-rank test. Cox proportional hazards model was used to identify independent prognostic factors age, number of metastasis, and treatment modality associated with survival. RESULTS: The median interval from ovarian cancer diagnosis to brain metastasis in 104 identified patients was 19.5 months. Brain metastasis was single in 43%, multiple in 41%, and not reported in 16% of cases. About 81.7% of patients were treated for their brain metastases using external radiation therapy (XRT), chemotherapy, and surgery. XRT was utilized in 76% of 104 patients and in 93% of treated patients. The most commonly used modalities were XRT alone (40%) and craniotomy and XRT (17%). The median survival (MS) for all patients regardless of treatment type was 6 months. Patients who received any treatment lived longer than those not receiving surgery/chemotherapy/XRT (MS; 7 months vs. 2 months, P = 0.0001). Patients with single brain metastasis had a longer median survival (21 months vs. 6 months, P = 0.049) when treated with craniotomy plus radiation and/or chemotherapy compared to treatment regimens that excluded craniotomy. In a multivariate analysis, only treatment type was significant in predicting survival. CONCLUSION: OBM portends a poor prognosis, however, long-term survival is possible. Patients appear to benefit from therapy, especially selected groups of OBM patients with single brain metastasis treated with radiation therapy and surgery.

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.

Cervical cancer with paraaortic metastases: significance of residual paraaortic disease after surgical staging.

Cervical carcinoma frequently metastasizes to the paraaortic region, necessitating extended field radiotherapy to effect a cure. As imaging modalities are unreliable in identifying all cases of paraaortic nodal metastases (PAN), surgical staging is often utilized prior to radiotherapy. This study was aimed at identifying factors predictive of survival in women with cervical carcinoma and paraaortic metastases. In particular, survival based on extent of paraaortic disease was examined. The study group consisted of 43 women (stages IB-IVB) identified between 1982 and 1993 who were treated with extended field radiation for cervical carcinoma with histologically confirmed paraaortic metastases. The estimated 5-year survival for the study population was 24% with a median survival of 18 months. Pelvic tumor size had a significant impact on survival with the median survival being 34 months if the primary lesion was < 6 cm compared to 14 months if > or = 6 cm (P = 0.01). Eight of the 26 (31%) women without residual PAN disease after surgical staging remain alive and disease free (mean follow-up, 74 months). In contrast, only 1 of the 17 (6%) women with gross residual PAN is alive 71 months after treatment (P = 0.05). However, a comparison of Kaplan-Meier survival curves did not show a statistically significant advantage to the surgical excision of grossly involved PAN (P = 0.98). Although long-term survival among women with grossly involved, unresected paraaortic metastases is uncommon, further study is necessary to elucidate the role of surgical excision of bulky aortic disease in women with cervical cancer.

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.

Residual disease in the uterus after preoperative radiotherapy and hysterectomy in stage IB cervical carcinoma.

Sixty-one patients with FIGO IB cervical cancer treated with planned preoperative radiotherapy (dose to point A: 52-93 Gy, mean 73 Gy) and hysterectomy from 1969 to 1993 were retrospectively reviewed. Patient characteristics and treatment parameters and their association with residual tumor in the hysterectomy specimen were analyzed. Glandular (adenocarcinoma and adenosquamous) tumors were smaller than squamous tumors: 6/11 (55%) were < 6 cm in diameter, versus 12/50 (24%) squamous tumors (p = 0.03). Glandular tumors had a higher incidence of residual disease: 10/11 (91%) versus 24/50 (48%) (p = 0.01). There was no association between presence of pathologic residual disease in the hysterectomy specimen and tumor size, morphology (endophytic vs. exophytic), patient age, dose to point A, time to deliver radiotherapy, or interval between radiotherapy and hysterectomy. Overall 34/61 (56%) patients had residual disease in their hysterectomy specimens after planned preoperative radiotherapy. There were significantly more glandular tumors than squamous tumors with residual disease, even though glandular tumors were a group of smaller tumors.

Human papillomavirus type 18: association with poor prognosis in early stage cervical cancer.

BACKGROUND: Cervical carcinoma is a leading cause of mortality from cancer among women worldwide, accounting for approximately 160,000 deaths annually. Prognosis in patients with this disease is dependent on several well-established clinical features (stage of disease and age of patient) and pathologic features (lymph node status, grade of tumor, and depth of invasion). Although the features associated with poor clinical outcome have been well studied, molecular markers such as human papillomavirus (HPV) type that may reflect the underlying biologic basis for clinical behavior are poorly understood. PURPOSE: To test the hypothesis that differences in survival among patients with cervical carcinoma are associated with HPV DNA type, we conducted a historical cohort study of patients treated at our institutions over a 10-year period. METHODS: Fresh primary tumor tissue samples from 291 women with all stages of cervical carcinoma diagnosed from April 1983 through August 1993 were rapidly frozen and stored at -70 degrees C until analysis. High-molecular-weight DNA was extracted and purified by homogenization, proteinase K digestion, phenol extraction, ammonium acetate salt displacement, ethanol precipitation, and ribonuclease treatment. HPV nucleotide sequences were amplified from tumor DNA samples by polymerase chain reaction with the use of both consensus L1 (MY09/MY11) primers that recognize more than 25 HPV types and modifications of type-specific primers developed for HPV types 16, 18, and 6. Clinical data were abstracted from hospital, office, and tumor registry records. Univariate analysis was conducted using Student's t test and chi-squared tests. Survival curves were estimated by use of the Kaplan-Meier method; differences between groups were examined by the logrank test. Multivariate survival analysis was performed according to the Cox proportional hazards model. RESULTS: HPV DNA was detected in 247 (85%) of 291 tumors: HPV16 in 52%, HPV18 in 20%, other HPV types in 13%, and no HPV DNA in 15%. Eighty-eight percent of squamous tumors contained HPV DNA compared with 79% of adenocarcinomas, the latter harboring predominantly HPV18. Women 45 years old or younger with a history of cigarette smoking tended to have HPV DNA in their tumors, but the HPV type was not associated with established prognostic factors such as stage, grade, lymph node metastasis, or depth of stromal invasion. After a median follow-up of 38.9 months, among potential prognostic factors of patient age, histologic cell type, grade, and HPV DNA status, only stage was predictive of survival in the entire study population. However, among the 171 patients treated with type III radical hysterectomy (removal of uterus and upper vagina along with other tissues extending to the pelvic wall) and pelvic lymphadenectomy (removal of all lymphatic tissue in the pelvis), multivariate analysis determined that lymph node status (adjusted risk ratio [RR] = 3.12; 95% confidence interval [CI] = 1.35-7.21), depth of stromal invasion (adjusted RR = 3.14; 95% Cl = 1.05-9.34), and the presence of HPV18 DNA (adjusted RR = 2.59; 95% CI = 1.08-6.22) were statistically significant predictors of survival. CONCLUSION: HPV18 DNA type is an independent prognostic factor in patients with cervical carcinomas treated with radical hysterectomy and pelvic lymphadenectomy. IMPLICATIONS: The use of molecular markers such as HPV DNA type may allow the identification of patients with early stage cervical cancer at high risk for disease recurrence.

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.

Laparoscopically assisted transperineal interstitial brachytherapy with omental flap for locally recurrent endometrial cancer.

In most cases, Syed-Neblett template placement is blind with respect to intraperitoneal structures. We evaluated the feasibility of laparoscopic assistance to add a potentially useful dimension to this technique. Two patients successfully underwent laparoscopic lysis of pelvic adhesions, assisted needle placement and creation of an omental pelvic carpet to protect the small intestine. The procedure resulted in avoidance of direct vascular and bowel injury and more appropriate depth of needle placement at 24 and 26 month follow-up, there is no evidence of radiation induced complications. The technique of laparoscopically assisted Syed-Neblett placement as described is feasible and may decrease operative and radiation associated morbidity.

Ability of visual tests to predict underlying cervical neoplasia. Colposcopy and speculoscopy.

OBJECTIVE: To describe the attributes of colposcopy and a low-power, magnified examination that utilizes chemiluminescent illumination (speculoscopy) in the visualization of cervical epithelium in a predefined, high-risk population and to compare how the two tests predict cervical histology. STUDY DESIGN: During this multicenter, prospective study, 395 women who were referred to our colposcopy clinic underwent a repeat cervical smear and speculoscopy followed immediately by colposcopy. Abnormal colposcopic lesions were biopsied and endocervical curettage performed when indicated. Histologic diagnoses were compared with cytology, speculoscopy and colposcopy results. RESULTS: Colposcopy was more sensitive than speculoscopy in the detection of cervical neoplasia (97% vs. 82%) (P < .001) and was superior in visualizing focal lesions and vascular patterns. An antecedent acetowhite abnormality detected during speculoscopy was highly predictive of subsequent abnormal colposcopy (97% positive predictive value). The "overall" rate of acetowhite lesions during speculoscopy was nearly half the rate during colposcopy (P < .001). CONCLUSION: Colposcopy is better suited than speculoscopy to the follow-up of patients with abnormal cervical cytology because it facilitates lesion grading and assists in directing biopsies. Speculoscopy is best utilized as a dichotomous screening test based on the presence or absence of at least one well-demarcated acetowhite lesion and may be more suitable than colposcopy as an adjunct to cervical cancer screening due to its lower overcall rate. The biophysical properties of blue-white chemiluminescent light as it relates to the diagnosis of cervical neoplasia are discussed.

Prognostic significance of human papillomavirus DNA in vulvar carcinoma.

OBJECTIVE: To determine the histopathologic, epidemiologic, and prognostic significance of human papillomavirus (HPV) DNA in primary invasive vulvar cancer. METHODS: From December 1981 through October 1992, primary tumor tissue from 55 newly diagnosed vulvar cancers was evaluated for the presence of HPV DNA. The DNA was extracted from tumor tissue and subjected to the polymerase chain reaction (PCR) using highly conserved consensus L1 primers that detect 25 different HPV genotypes and primers specific for HPV type 6/E6, type 16/E7, and type 18/E6 gene sequences. All PCR products were hybridized to type-specific radiolabeled probes. The association between the presence of HPV DNA and histologic, epidemiologic, and clinical characteristics was analyzed. RESULTS: Thirty-three (60%) tumors contained HPV DNA. Patients younger than 70 years of age or who smoked were more likely to have HPV-positive vulvar cancers. Twenty-one (95%) of 22 tumors classified as basaloid, warty, or verrucous contained HPV DNA, whereas 12 (39%) of 31 typical squamous tumors contained HPV (P < .001). Two adenocarcinomas were negative for HPV. Tumors with or without HPV DNA did not differ with respect to International Federation of Obstetricians and Gynecologists stage (size and nodal status), tumor grade, or therapy. Using life-table analysis, the absence of HPV DNA and the presence of regional nodal metastasis were predictive of recurrence and death from vulvar cancer. When controlling for lesion size, age, tumor grade, and nodal metastasis using the Cox proportional hazards model, only HPV status remained an independent prognostic factor. CONCLUSION: Human papillomavirus DNA is more common in vulvar cancers of young women who smoke than in older nonsmokers. Patients with HPV-negative tumors are at an increased risk of recurrence and death from vulvar cancer.

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.

Cytogenetic changes in ovarian mucinous cystadenocarcinoma of low malignant potential with persistent pseudomyxoma peritonei.

Minimal cytogenetic data are available for low malignant potential ovarian neoplasms, and none for those complicated by pseudomyxoma peritonei. Cytogenetic analysis was performed on tissue obtained from a patient undergoing repeat evacuation of mucin and mucin-producing implants in pseudomyxoma peritonei originating from an ovarian mucinous cystadenocarcinoma of low malignant potential. Specimens obtained from intraperitoneal implants during one of the cyto/mucin-reductive procedures revealed a mixture of normal female karyotype (46,XX) and an abnormal karyotype with a deletion involving the short arm of chromosome 1, and a balanced translocation involving chromosomes 2 and 6, [46,XXdel(1)(p21p31), t(2;6)(q35;p21)]. The vast majority of the cells from three subsequent cyto/mucin-reductive procedures displayed a normal female karyotype with few cells containing random abnormalities.

A modified incision and technique for total retroperitoneal access and lymph node dissection.

Surgical assessment of aortocaval lymph nodes in patients with unresectable primary cervical cancer helps in planning radiation treatment ports. Removal of enlarged lymph nodes may also serve a therapeutic purpose in reducing the tumor load to be sterilized by radiation. An extraperitoneal dissection is considered to be superior to a transperitoneal approach, and numerous incisions to access either the upper or the lower retroperitoneum have been described. A modified supraumbilical incision and technique that provide wide bilateral exposure of the retroperitoneum from the suprarenal aorta to the obturator fossae were used in six patients.

Comparison of the polymerase chain reaction and Southern blot analysis in detecting and typing human papilloma virus deoxyribonucleic acid in tumors of the lower female genital tract.

To conduct studies on the clinical and pathologic significance of human papilloma virus (HPV) in genital malignancies, accurate detection and typing of the virus in clinical material are essential. Currently, Southern blotting and the polymerase chain reaction (PCR) are two of the most commonly used methods to identify HPV. This study was undertaken to compare these techniques in the detection and typing of HPV in 242 invasive malignancies of the lower female genital tract. BamHI and PstI restriction digests of tumor DNA were hybridized to 32P-labeled probes for HPV types 6, 16, and 18 at TM -20 degrees C after Southern transfer. Blots were then washed at Tm -20 degrees C and Tm -9 degrees C. The DNA was also amplified by PCR using both highly conserved consensus L1 primers that detect 25 different HPV genotypes and primers specific for HPV 6 E6, 16 E7, and 18 E6. All PCR products were hybridized to type-specific radiolabeled probes. In 202 of the 242 (83%) samples, HPV was detected, including 189 of 218 (87%) cervical cancers, 11 of the 20 (55%) vulvar cancers, and two of four tumors from the vagina, urethra, or anus. In 67% of the specimens, there was agreement between the Southern blot technique and both methods of PCR (consensus and type-specific primers), including 121 of the 202 HPV-positive specimens and 40 HPV-negative specimens. Of the 141 tumors with HPV detected by Southern blot analysis, the same HPV type was detected by PCR in 121 (86%).(ABSTRACT TRUNCATED AT 250 WORDS)

Idiopathic CD4+ T-lymphocytopenia and recurrent vulvar intraepithelial neoplasia.

BACKGROUND: CD4+ T-lymphocytopenia immunodeficiency without human immunodeficiency virus (HIV) infection has been reported recently. The association between immunodeficiency and anogenital neoplasia secondary to human papillomavirus infections is well documented. CASE: A woman with recurrent vulvar intraepithelial neoplasia (VIN) had idiopathic CD4+ T-lymphocytopenia without HIV infection. CONCLUSION: Human papillomavirus-related VIN may be associated with idiopathic CD4+ T-lymphocytopenia.

Serum progesterone monitoring in post-molar surveillance.

Serial serum progesterone and beta human chorionic gonadotropin (beta hCG) levels were measured during surveillance of 24 women at risk for development of gestational trophoblastic neoplasia (GTN) following evacuation of complete molar gestations. Six of the 24 patients developed post-molar GTN. The initial median progesterone level of 76 ng/ml in these six patients drawn at evacuation was significantly higher than the median of 18 ng/ml in those not developing GTN (P = 0.026). Additionally, the serum progesterone decreased to < 5 ng/ml within a week of evacuation in 16/18 patients without GTN. In 5/6 GTN cases, levels of progesterone remained > 5 ng/ml for > or = 3 weeks of the surveillance period (P < 0.05). Serum beta hCG levels required 4-11 weeks of surveillance to distinguish between non-persistent cases and GTN. We conclude that serial serum progesterone levels measured during post-molar surveillance parallel beta hCG regression.