Clinical relevance of urokinase-type plasminogen activator, its receptor, and its inhibitor type 1 in endometrial cancer.

OBJECTIVE: Tumor invasion involves degradation of extracellular matrix. The urokinase plasminogen activation system participates in this process. Urokinase-type plasminogen activator (uPA), its receptor (uPAR), and its inhibitor, plasminogen activator inhibitor type 1 (PAI-1), are proposed to be prognostic factors in some cancers. There are conflicting data regarding the prognostic role of this system in endometrial cancer. METHODS: To determine the prognostic value of the urokinase plasminogen activation system, contents of uPA, uPAR, and PAI-1 were measured in extracts of endometrial cancer tissue using ELISAs. uPA, uPAR, and PAI-1 levels were determined in 91, 54, and 92 extracts, respectively, and correlated with tumor histology, stage, grade, lymph node involvement, prevalence of metastasis, and recurrence as well as with estrogen (ER), progesterone (PR), epidermal growth factor (EGFR) receptor and HER-2/neu contents. RESULTS: Patients with cancers exhibiting advanced stage, high grade, unfavorable tumor histology, nodal involvement, recurrence, and lower PR levels determined by ligand binding had significantly higher uPA content than others. PAI-1 was significantly elevated in patients with advanced stage, high-grade tumor, recurrence, decreased ER content, and lower PR levels determined by ligand binding. uPAR did not show any relation to any of clinical and laboratory parameters. Elevated expression of PAI-1 was associated with significantly shorter disease-free (P = 0.005) and overall (P = 0.0003) survival. Multivariate analysis revealed that PAI-1 was a predictor of survival although stage was the strongest independent factor. CONCLUSION: Elevated uPA and PAI-1 levels appear to correlate with unfavorable prognosis in endometrial cancer.

Clinical relevance of urokinase-type plasminogen activator, its receptor and inhibitor type 1 in ovarian cancer.

Urokinase-type plasminogen activator (uPA), its receptor (uPAR) and inhibitor, plasminogen activator-type 1 (PAI-1) are proposed to be of prognostic significance in some cancers. To determine the prognostic value of the urokinase plasminogen activation system in ovarian cancer, levels of uPA, uPAR, and PAI-1 were measured in extracts of ovarian cancer tissue using ELISA tests. uPA and PAI-1 were determined in 70 tumor extracts and uPAR in 43 extracts. Levels were correlated with age, tumor histology, stage, grade, lymph node and metastatic status, residual disease, risk of recurrence, epidermal growth factor receptor (EGFR) expression, cathepsin D (Cath-D), and c-erbB-2 levels. uPA and uPAR did not exhibit correlation with any of these parameters. However, patients with high grade tumor, recurrence, and lower EGFR and Cath-D had significantly higher PAI-1 levels compared to those of others (P < 0.05). Kaplan-Meier plots of survival were compared. uPA and uPAR were not related to disease-free or overall survival. Although low PAI-1 appeared to predict a longer overall survival, the difference was not statistically significant. Multivariate analysis revealed that PAI-1 was a predictor for overall survival although it was not as strong as stage. These results suggest that elevated PAI-1 seems to be correlated with an unfavorable prognosis in ovarian cancer.

Metastatic dermatofibrosarcoma protuberans of the vulva.

Dermatofibrosarcoma protuberans (DFSP) of the vulva is a rare, low- to intermediate-grade sarcoma of dermal origin. This case report represents the 13th reported patient with vulvar DFSP and the first reported patient with metastatic vulvar DFSP. Although metastasis is rare, the possibility remains that the frequent recurrence of DFSP will eventually metastasize. Therefore, patients must be followed up on a long-term basis to monitor the progress of this potentially lethal cancer.

Apoptosis as a measure of chemosensitivity to cisplatin and taxol therapy in ovarian cancer cell lines.

OBJECTIVE: Cisplatin- and Taxol-induced apoptosis was studied in four human ovarian cancer cell lines to evaluate apoptosis as a measure of chemosensitivity. METHODS: In vitro sensitivities of OVCAR-3, SKOV-3, UL-1, and UL-2 cells to cisplatin or Taxol were determined by the sulforhodamine B assay. Induction of apoptosis was studied by DNA fragmentation following treatment with cisplatin and/or Taxol after 24- and 48-hr exposure. DNA fragmentation was further quantitated by the diphenylamine assay and the proportion of cells in the G1, G2/M, and S phase of the cell cycle was determined by flow cytometry. Presence of the p53 gene product was examined by Western blotting. RESULTS: The four cell lines represent various sensitivities to cisplatin and Taxol (LD50 range for cisplatin, 5-30 microg/ml; Taxol, 30-1000 nM). UL-2 represents a resistant cell line which was 10-30 times resistant to Taxol and 6 times resistant to cisplatin when compared to the others. Demonstration of apoptosis correlated with the sensitivity of the cell lines to both cisplatin and Taxol for OVCAR-3 and UL-2. DNA fragmentation of OVCAR-3 was uniformly present when treated with cisplatin or Taxol, at 24 or 48 hr. UL-2 demonstrated no apoptosis after 24 or 48 hr of treatment with either cisplatin or Taxol. When sequencing experiments were performed with cisplatin and Taxol, DNA fragmentation correlated with the cytotoxicity assays, except in UL-1 cells where no significant difference was observed in different interactions of cisplatin and Taxol. Pretreatment with Taxol generally resulted in enhanced cytotoxicity in a schedule-dependent manner, and increased fragmentation was demonstrated; cisplatin pretreatment consistently resulted in decreased fragmentation. Quantitation of the fragmented DNA correlated with that seen on gel electrophoresis. OVCAR-3 and UL-1 demonstrated the greatest change from baseline at 24 hr (3.8 and 3.7 times baseline, respectively), whereas UL-2 had little change from the baseline following treatment. G1 arrest occurred more readily in OVCAR-3 and SKOV-3 cells. UL-2 cells had very little change in the proportion of cells entering G1 arrest, but had a significant increase in the G2/M proportion. In OVCAR-3, UL-1, and UL-2 cells, we demonstrated the presence of an aberrantly expressed p53 gene product, while no p53 was detected in the SKOV-3 cells. CONCLUSIONS: Our findings indicate that the ability to achieve significant cytotoxicity by cisplatin and Taxol may be directly related to the induction of apoptosis; however, cellular and genetic characteristics determine the eventual outcome of these treatments.

Vulvar eccrine porocarcinoma.

A rare case of a slowly growing vulvar tumor in a 75-year-old woman is presented. This vulvar neoplasm was an eccrine porocarcinoma with left inguinal nodal metastases. This is believed to be only the second reported case of a vulvar eccrine porocarcinoma. Treatment included a left hemivulvectomy, bilateral inguinal-femoral lymphadenectomy, and postoperative radiation therapy. A review of the literature regarding this unusual malignancy is included.

Quantitative analyses of epidermal growth factor receptors, HER-2/neu oncoprotein and cathepsin D in nonmalignant and malignant uteri.

BACKGROUND: Hormone receptors and oncoproteins are receiving increased attention as possible prognostic factors in different carcinomas. Few data are available regarding quantification of their levels of expression in gynecologic malignancies. METHODS: Epidermal growth factor (EGF) receptor specific binding capacities and affinities were measured by ligand binding assay using [125I]EGF in a competition mode with Accufit software (Lundon Software, Inc., Middlefield, OH). HER-2/neu oncoprotein was extracted from membranes and measured using an enzyme-linked immunosorbent assay. Cathepsin D was measured by an immunoradiometric assay using cytosols for steroid receptor analyses. RESULTS: EGF receptors in 23 nonmalignant uteri ranged from undetectable to 50 fmol/mg membrane protein (median, 0), with dissociation constant values of 1.2 x 10(-9) M to 8.5 x 10(-10) M, compared with EGF receptors in 76 endometrial cancers that ranged from undetectable to 7674 fmol/mg (median, 52). HER-2/neu oncoprotein ranged from undetectable to 2.9 HER-2/neu units (HNU)/microg protein (median, 0.6) in 41 nonmalignant uteri and from undetectable to 5.8 HNU/microg protein (median, 2.5) in endometrial cancers (n = 53). Cathepsin D ranged from 5 to 32 pmol/mg cytosol protein (median, 11) in 42 nonmalignant uteri and 18 to 144 pmol/mg protein (median, 42) in 29 endometrial cancers. CONCLUSIONS: Determination of the frequency and levels of EGF receptors, HER-2/neu protein, and cathepsin D in uteri with and without cancer and the availability of reference materials developed in our laboratory, will allow evaluation of their prognostic value in cancers of the uterus.

Aberrations in normal systemic lipid metabolism in ovarian cancer patients.

Numerous investigations have demonstrated altered systemic lipid metabolism in cancer patients, as well as aberrant lipid utilization by tumor cells. The most common measure of altered systemic lipid metabolism in these individuals has been hyperlipidemia. Although cachexia is not generally considered to be associated with gynecologic cancers, this study demonstrates the presence of lipolysis-promoting activity, detectable in sera and ascites of ovarian cancer patients and indices of altered systemic lipid metabolism. Elevated lipolysis promoting activity was detectable in the sera of 7/9 patients and in the ascites of 5/5 patients. Since previous studies have indicated that cancer patients exhibit a 2.5-fold enhancement in hormone-sensitive lipase (HSL) versus normal controls, as a potential mechanism for elevated lipolysis, the ability of ascites-derived factors to induce HSl was examined. The addition of three of four ascites fluids increased the level of HSL in normal adipocytes. All of the patients' samples exhibited elevated lipid levels versus normal peritoneal fluid. Isolation and analysis of lipids from three ovarian cancer patients revealed four consistent altered lipid parameters compared to normal peritoneal fluid: elevated monoglycerides, diglycerides, and free fatty acids and decreased triacylglycerides. While "classical" cachexia is not a common feature of ovarian cancer, the presence of circulating lipolysis-promoting activity and altered lipid metabolism, generally observed in cachectic individuals, can be demonstrated in these ovarian cancer patients. Based on recent evidence indicating a role of lipids in carcinogenic initiation or promotion, the presence of tumor-derived lipolysis-promoting factor and lipid metabolism alterations may provide a mechanism for the epidemiologically observed association between lipids and certain cancers, including ovarian cancer.

Comparison of cathepsin D determinations in human carcinomas by enzyme immunoassay and immunoradiometric assay.

Overexpression of cathepsin D in several types of carcinoma in women appears to be associated with a poor clinical course. In this prospective investigation, cathepsin D levels in 170 specimens of normal and neoplastic human tissues were determined simultaneously by enzyme immunoassay (EIA) and immunoradiometric assay (IRMA) to allow comparisons in multicentric studies, such as cooperative clinical trials. Nonmalignant uteri and specially prepared reference powders were also evaluated. Linear regression analysis between the two assays for all specimens [EIA = 0.87(IRMA)-3.18] demonstrated a correlation coefficient (r) of 0.99 (P < 0.001). When malignancies were categorized by the tissue origin (i.e., breast, uterus, ovary, lymph node, and colon), highly significant correlations were also observed (regressions slopes ranged from 0.58 to 1.02). Intra- and interassay controls conducted for the new EIA procedure gave CV% ranging from 4.4 to 10.2, which was similar to the IRMA test for cathepsin D. The results of both assays correlated well and were highly reproducible. Either assay may be used with confidence that comparable cathepsin D values will be obtained in a wide range of tissue biopsies.

Squamous cell carcinoma antigen: clinical utility in squamous cell carcinoma of the uterine cervix.

This study further defines the clinical utility of squamous cell carcinoma antigen (SCC-Ag) in initial squamous carcinoma of the cervix, response to treatment, and in the detection of recurrence. Serum specimens were drawn and analyzed from patients with squamous cell carcinoma. Charts were reviewed on 272 patients with 1053 samples evaluated. Treatment of patients prior to the availability of the assay and patients lost to follow-up resulted in lower total numbers of initial and recurrent values. Data were analyzed to detect trends during and after treatment. All values at or above the lowest detectable level of antigen were included; that is, 1.5 ng/ml and above. A SCC-Ag value > or = 2.0 ng/ml drawn at any time during the disease process has a 96.3% positive predictive value, while a value < 2.0 ng/ml is 97.2% specific for absence of disease. Fifty-three percent of 103 patients had elevated SCC-Ag levels prior to treatment, with the proportion increasing accordingly with advancing stage at diagnosis. In 70 patients with recurrence, 81% had elevated values. Squamous cell carcinoma antigen predicted recurrence an average of 6.9 months prior to detection of clinically evident disease. Patients with initially negative SCC-Ag levels may demonstrate elevated values with tumor recurrence. This marker accurately reflects the response to treatment in patients who have elevated levels prior to treatment. Squamous cell carcinoma antigen is a useful tumor marker in the management of patients with squamous cell carcinoma of the uterine cervix.

Small cell neuroendocrine carcinoma of the vagina.

A 65-year-old woman with a history of recurrent vaginal intraepithelial neoplasia was found to have small cell carcinoma (SCC). Exfoliative cytology was instrumental in the discovery of each episode of vaginal neoplasia. Thorough examination of the patient established the tumor as being primary to the vagina, and immunohistochemistry confirmed it to be a neuroendocrine SCC. Eleven patients with neuroendocrine SCC of the vagina have been reported previously. Morphologic characteristics and histogenesis are discussed within the context of the embryology and natural history of extrapulmonary-genital SCC. They have been classified in the amine precursor uptake and decarboxylation family of neoplasms. Originally, a neuroectodermal origin was proposed, but derivation now is thought to be from multipotential epithelial stem cells of the genital tract. Neuroendocrine SCC tends to be an aggressive neoplasm with a propensity for early spread. Long-term survival for patients with vaginal SCC has not been documented. Therapeutic decisions regarding SCC from this site have been based on information gained from the treatment of these tumors elsewhere. Combined modality therapy using initial surgery and adjuvant treatment, including systemic chemotherapy and local exposure to radiation, has produced an apparent complete response in our patient.

Intraoperative evaluation of depth of myometrial invasion in stage I endometrial adenocarcinoma.

In patients with stage I endometrial adenocarcinoma, the incidence of pelvic and para-aortic lymph node metastasis is related to the grade of the tumor and the depth of myometrial invasion. Although the grade of the tumor may be predicted preoperatively by endometrial sampling, the depth of myometrial invasion cannot be determined until after the uterus has been removed. Although complications have been attributed to lymph node sampling, failure to perform the procedure in patients at risk for nodal metastasis may result in underdiagnosis of extrauterine disease, leading to inadequate therapy. Gross visual examination of the cut surface of the tumor at the time of hysterectomy accurately determined the depth of myometrial invasion in 135 of 148 prospectively studied patients (91%) (P less than .001). The sensitivity of the test was 0.71, the specificity was 0.96, and the positive predictive value was 0.80. Intraoperative assessment of the depth of myometrial invasion is a simple, inexpensive, and useful technique for selecting those patients with stage I endometrial adenocarcinoma who might benefit from selective para-aortic lymphadenectomy.