Preclinical evaluation of olaparib and metformin combination in BRCA1 wildtype ovarian cancer.

OBJECTIVES: BRCA mutated ovarian cancers show increased responsiveness to PARP inhibitors. PARP inhibitors target DNA repair and provide a second hit to BRCA mutated tumors, resulting in "synthetic lethality". We investigated a combination of metformin and olaparib to provide "synthetic lethality" in BRCA intact ovarian cancer cells. METHODS: Ovarian cancer cell lines (UWB1.289, UWB1.289.BRCA, SKOV3, OVCAR5, A2780 and C200) were treated with a combination of metformin and olaparib. Cell viability was assessed by MTT and colony formation assays. Flow cytometry was used to detect cell cycle events. In vivo studies were performed in SKOV3 or A2780 xenografts in nude mice. Animals were treated with single agent, metformin or olaparib or combination. Molecular downstream effects were examined by immunohistochemistry. RESULTS: Compared to single drug treatment, combination of olaparib and metformin resulted in significant reduction of cell proliferation and colony formation (p<0.001) in ovarian cancer cells. This treatment was associated with a significant S-phase cell cycle arrest (p<0.05). Combination of olaparib and metformin significantly inhibited SKOV3 and A2780 ovarian tumor xenografts which were accompanied with decreased Ki-index (p<0.001). Metformin did not affect DNA damage signaling, while olaparib induced adenosine monophosphate activated kinase activation; that was further potentiated with metformin combination in vivo. CONCLUSION: Combining PARP inhibitors with metformin enhances its anti-proliferative activity in BRCA mutant ovarian cancer cells. Furthermore, the combination showed significant activity in BRCA intact cancer cells in vitro and in vivo. This is a promising treatment regimen for women with epithelial ovarian cancer irrespective of BRCA status.

Risk of postoperative venous thromboembolism after minimally invasive surgery for endometrial and cervical cancer is low: a multi-institutional study.

OBJECTIVE: To determine the 30-day prevalence of venous thromboembolism (VTE) after minimally invasive surgery (MIS) for endometrial (EC) and cervical cancers (CC). METHODS: A retrospective cohort study at two large tertiary care centers between 2006 and 2011. Patients having MIS for EC or CC were included. Cases converted to laparotomy were excluded. The primary outcome measure was clinically diagnosed VTE within 30 days of operation. RESULTS: Of the 558 patients, 90% had EC and 10% had CC. Modalities of hysterectomy included robotic (88%), vaginal (9%), and laparoscopic (3%). A total of 66% had pelvic and 35% had paraaortic lymphadenectomy. The VTE prophylaxes were sequential compression devices (100%) and heparin (39%). There were no VTE events during hospital stay (95% CI, 0.0%-0.7%). The 30-day prevalence of VTE was (0.5%; 95% CI, 0.1%-1.6%). The hitherto recommended risk criteria for giving extended 30-day thromboprophylaxis by the American College of Obstetrics and Gynecologists (ACOG) or by the American Society of Clinical Oncology (ASCO) did not predict risk of VTE in our population. CONCLUSIONS: The prevalence of VTE in EC and CC undergoing MIS is very low. The existing 30-day risk prediction models proposed by the ACOG and ASCO stem from open surgery patients and do not appear to apply to MIS patients. Certainly, we found no evidence supporting the use of extended prophylactic heparin in this setting. Further research is urgently needed to define the role of any duration of thromboprophylaxis in MIS patients with endometrial or cervix cancer.

Prognostic impact of lymphadenectomy in uterine serous cancer.

OBJECTIVE: To estimate the survival impact of lymphadenectomy in women diagnosed with uterine serous cancer. DESIGN: Women with a diagnosis of uterine serous cancer were identified from the Surveillance, Epidemiology and End Results Program (SEER) from 1988 to 2007. Only surgically treated women were included. SETTING: The Surveillance, Epidemiology and End Results Program database provided data from 17 registries. POPULATION: The study population comprised 4178 women. METHODS: Statistical analyses using Student's t-test, Kaplan-Meier survival methods and Cox proportional hazards regression were performed. MAIN OUTCOME MEASURE: Overall survival. RESULTS: Three thousand, one hundred and ninety-four (67.7%) women underwent lymphadenectomy. Older women (≥65 years) and Caucasian women (relative to Asian) were less likely to have lymphadenectomy (P < 0.001). The prevalence of nodal metastasis in women having lymphadenectomy was 32%. Of the 1997 women who had disease grossly confined to the uterus and underwent lymphadenectomy, 387 (19%) were found to have nodal metastasis. Lymphadenectomy was associated with improved survival; women who underwent lymphadenectomy were 41% (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.54-0.64; P < 0.001) less likely to die than women who did not have the procedure. Moreover, more extensive lymphadenectomy correlated positively with survival. Compared with women with 1-10 nodes removed, those with more extensive lymphadenectomy (>10 nodes removed) were 26% (HR, 0.74; 95% CI, 0.67-0.83; P < 0.001) less likely to die. The impact of the extent of lymphadenectomy on survival was significant in both node-negative and node-positive women. CONCLUSION: Age and race influenced the prevalence of lymphadenectomy in our cohort. This study suggests that the extent of lymphadenectomy is associated with significant improvement in survival of women with uterine serous cancer.

Correlation of tumor size with other prognostic factors in uterine serous carcinoma: a large multi-institutional study.

OBJECTIVE: Uterine serous carcinoma (USC) constitutes 10% of uterine cancers but ~40% of deaths. Tumor size is a known prognostic factor in other solid tumors. In endometriod cancers it is one element used to identify the need for complete staging, while its significance in USC is debated. Therefore tumor size was examined as an independent prognostic factor. METHODS: Clinical and pathologic variables were recorded for 236 institutional patients, and those patients in the SEER database with USC. Chi-square and Fisher exact t-tests were utilized and survival data generated via Kaplan-Meier method; multivariate analysis was performed via cox-regression. RESULTS: The patients' mean age was 67.2 years (range 40-91). Survival ranged from 0 to 184 months (mean 42.8). We used a tumor size cut-off of 1cm and noted significant associations with myometrial invasion (p<0.0001), angiolymphatic invasion (p<0.0001), peritoneal washings (p=0.03), stage (p=0.015) and positive lymph nodes (p=0.05). Furthermore, recurrence was associated with larger tumors (p=0.03). In multivariate analysis, extra-uterine disease was the only factor associated with both recurrence and survival. Review of the SEER database noted association of larger tumors with lymph node involvement and a significant survival advantage with tumors <1cm in both univariate and multivariate analysis. CONCLUSIONS: Treatment options for USC are often predicated on the surgical stage and therefore components of the staging are vitally important. The 1cm tumor-size cut-off should be studied prospectively as a prognostic indicator of survival and recurrence in USC and considered for inclusion in USC staging.

Clinical outcomes of adjuvant chemotherapy and vaginal brachytherapy with or without pelvic radiation for surgical stage I-II uterine serous carcinoma.

OBJECTIVE(S): To evaluate the benefit of adding pelvic radiation treatment (EBRT) to vaginal cuff brachytherapy (VB) for women with early stage uterine serous carcinoma (USC) treated with adjuvant chemotherapy. MATERIALS AND METHODS: After institutional review board (IRB) approval, the authors retrospectively identified 56 patients with 2009 International Federation of Gynecology and Obstetrics (FIGO) Stage I-II USC treated with hysterectomy, bilateral oophorectomy +/- lymphadenectomy, adjuvant chemotherapy, and radiation therapy with either VB alone (n = 33) or VB + EBRT (n = 23) between July 1998 and August 2009. RESULTS: Median age and follow-up were 68.5 years and 54 months respectively. Median VB alone surface dose was 37.5 Gy and median pelvic EBRT dose was 45 Gy. The prevalence of lower uterine segment involvement, > 50% myometrial invasion, and Stage II disease were higher for patients receiving VB + EBRT. Overall, only one vaginal recurrence was observed. Pelvic recurrence rate was 26% for VB + EBRT compared to 12% for VB alone (p = 0.179). The five-year recurrence-free survival (RFS) was 80.5% for VB vs 67.3% for VB + EBRT (p = 0.3847), and the five-year overall survival (OS) was 65.9% for VB vs 66.7% for VB + EBRT (p = 0.7159). On univariate and multivariate analysis, radiation treatment modality was not a predictor for local control or survival. CONCLUSIONS: In this cohort, there was no significant clinical benefit of adding pelvic EBRT to the adjuvant management of early stage uterine serous carcinoma. The higher prevalence of high-risk features in the VB + EBRT group may underestimate the value of this treatment. Further investigation is warranted to identify the optimal radiation treatment regiment for early stage USC treated with surgery and adjuvant chemotherapy.

Prognostic impact of lymphadenectomy in clinically early stage malignant germ cell tumour of the ovary.

BACKGROUND: The aim of this study was to determine the impact of lymphadenectomy and nodal metastasis on survival in clinical stage I malignant ovarian germ cell tumour (OGCT). METHODS: Data were obtained from the National Cancer Institute registry from 1988 to 2006. Analyses were performed using Student's t-test, Kaplan-Meier and Cox proportional hazard methods. RESULTS: In all, 1083 patients with OGCT who have undergone surgical treatment and deemed at time of the surgery to have disease clinically confined to the ovary were included 590 (54.48%) had no lymphadenectomy (LND-1) and 493 (45.52%) had lymphadenectomy. Of the 493 patients who had lymphadenectomy, 441 (89.5%) were FIGO surgical stage I (LND+1) and 52 (10.5%) were upstaged to FIGO stage IIIC due to nodal metastasis (LND+3C). The 5-year survival was 96.9% for LND-1, 97.7% for LND+1 and 93.4% for LND+3C (P=0.5). On multivariate analysis, lymphadenectomy was not an independent predictor of survival when controlling for age, histology and race (HR: 1.26, 95% CI: 0.62-2.58, P=0.5). Moreover, the presence of lymph node metastasis had no significant effect on survival (HR: 2.7, 95% CI: 0.67-10.96, P=0.16). CONCLUSION: Neither lymphadenectomy nor lymph node metastasis was an independent predictor of survival in patients with OGCT confined to the ovary. This probably reflects the highly chemosensitive nature of these tumours.

The racial disparity in outcomes in endometrial cancer: could this be explained on a molecular level?

OBJECTIVE: The racial disparities among patients with endometrial carcinoma have been previously reported. The objective of this study is to analyze and compare the molecular profiles in endometrial cancer in Caucasian and African American patients using a number of known molecular markers. MATERIALS AND METHODS: 147 patients diagnosed with endometrial cancer between 1995 and 2001 were included in the study. Patients' demographics, clinical and pathological data were reviewed. Immunohistochemical staining for p53, VEGF, Ki-67 and HIF-1alpha was performed on tissue micro array sections. Tumors' expression of p53, VEGF, Ki-67, and HIF-1alpha was compared based on ethnicity and tumor type (Type I = endometrioid carcinomas and Type II = non-endometrioid carcinomas). Spearman's correlation and Fisher's Exact Tests were used for statistical analysis and Kaplan-Meier, log-rank and Cox regression were used for survival analysis. RESULTS: 97 patients were Caucasian and 50 patients were African American. The mean age was 62 (33-91) years for Caucasian patients and 63.5 (24-89) years for the African American patients. African American patients had more Type II carcinoma than Caucasian patients (P = 0.055). High p53 expression was statistically significant among the African American patients (49% vs. 30%, P = 0.035) versus Caucasian patients. There was no significant difference demonstrated when comparing the VEGF, Ki-67, and HIF-1alpha expression between the racial groups. Survival analysis showed a trend toward a shorter survival in the African American patients compared to the Caucasian patients; median survival 62 versus 77 months (P = 0.061). On the other hand, we did not find a significant difference in survival by ethnicity when we adjusted for tumor histology. CONCLUSION: While African American patients with endometrial cancer seem to show a trend toward a shorter survival, this seems to be mainly due to the fact that they have a higher proportion of Type II tumors. The molecular profiles for p53, Ki-67, VEGF and HIF-1alpha expression of histologically matched tumors were similar between the two ethnic groups.

Maspin expression and localization impact on angiogenesis and prognosis in ovarian cancer.

INTRODUCTION: The goal of this study is to evaluate the relation of maspin expression and its cellular localization to markers of angiogenesis in epithelial ovarian serous carcinoma (OSC). MATERIALS AND METHODS: We identified 118 patients with high-grade advanced stage OSC who were treated at our institution. Clinical data were collected, and immunohistochemistry (IHC) with antibodies to VEGF, CD34, COX-2, and maspin was performed on paraffin-embedded tumor blocks. CD34 immunostaining was used to determine microvessel density. The correlation between the various molecular markers was assessed using the Chi-square test. Survival analysis was computed using the Kaplan-Meier model, and various prognostic variables were compared using Cox regression analysis. RESULTS: Maspin expression was noted in 81.4% (96/118) of tumors. Expression was localized to the nuclear compartment in 21.2% of cases, whereas 60.2% of cases showed evidence of cytoplasmic +/- nuclear expression. Tumors that exhibited nuclear maspin expression had lower VEGF and COX-2 expression than tumors with negative or cytoplasmic expression. Tumors with high nuclear maspin expression had lower mean MVD than those with low or negative expression. The median survival based on localization of maspin was 1146 days for those with negative tumors, 1803 days for those with nuclear maspin, and 637 days for those with cytoplasmic maspin (P < 0.001). In a Cox regression analysis, maspin localization was an independent prognostic factor. CONCLUSION: Maspin expression and localization seem to play a role in ovarian cancer angiogenesis and progression. High nuclear expression was associated with reduced markers of angiogenesis and prolonged survival.

Critical evaluation of secondary cytoreduction in recurrent ovarian cancer.

OBJECTIVE: The optimal strategy for salvage therapy in patients who suffer from ovarian cancer recurrence after a disease-free interval is not established. The objective of this paper is to analyze the existing published data on salvage surgery in this setting. METHODS: A retrospective review of the English literature was done looking at studies addressing the role of secondary cytoreductive surgery in recurrent ovarian cancer. A number of parameters were collected from these studies and analyzed, including patients' characteristics, outcome of secondary cytoreduction, perioperative complications, postoperative therapy, and survival. In a parallel analysis, we reviewed the outcome of patients treated with salvage chemotherapy without surgery in similar clinical settings. RESULTS: Optimal cytoreduction was achievable in 38-87% of the study populations reviewed with acceptable perioperative complications and mortality. The attempt to analyze the impact of secondary cytoreduction on survival was limited by (1) the inter-investigator differences in defining optimal cytoreduction, (2) the heterogeneity of the patients included, (3) and the lack of information on postoperative therapy. All the studies suggest that patients left with no gross residual disease after secondary cytoreduction seem to benefit from prolonged survival in the range of 44-60 months. Current data reveal that the use of combination chemotherapy without surgery for salvage treatment of recurrent ovarian cancer can be associated with prolonged median survival reaching up to 35 months. CONCLUSION: The available data suggest a benefit for secondary surgical cytoreduction in recurrent ovarian cancer. This needs to be considered in the light of recent data reporting prolonged survival with the use of combination salvage chemotherapy without surgery. Currently, it is not known if a salvage strategy combining surgery and multiagent chemotherapy regimens will have a survival benefit over chemotherapy alone. Hopefully, current ongoing prospective trials will answer this question.

Inhibition of paclitaxel-induced apoptosis by the specific COX-2 inhibitor, NS398, in epithelial ovarian cancer cells.

OBJECTIVE: In vitro studies have revealed that treatment of various human cancer cell lines with specific cyclo-oxygenase 2 (COX-2) inhibitors induces apoptotic cell death. It is currently proposed that the combination of COX-2 inhibitors with chemotherapeutic agents improves the efficacy of cancer treatment. MATERIALS AND METHODS: In this study we sought to determine the effects of combining paclitaxel and the COX-2 inhibitor NS398 on apoptosis of epithelial ovarian cancer (EOC) cells. Two EOC cell lines, SKOV3 and MDAH2774, were exposed to increasing concentrations of paclitaxel (0.1, 10, and 100 microM) and NS398 (10, 100 microM) as well as a combination of both drugs. Apoptosis was evaluated by the Tunel assay. The fluorescein-labeled DNA was visualized directly by fluorescence microscopy and quantitated by flow cytometry. RESULTS: While NS398 did not significantly alter apoptosis of either EOC cell lines after 24 h of continuous exposure, treatment of both cell lines with paclitaxel resulted in a significant increase in the rate of apoptosis (60-70%). Concomitant treatment of both SKOV3 and MDAH2774 cells with paclitaxel and NS398 resulted in marked impairment of paclitaxel-induced apoptosis. Similarly, sequential treatment during which both cell lines were treated with NS398 for 4 h, triple-washed, and then exposed to paclitaxel for 24 h resulted in a significant inhibition of paclitaxel-induced apoptosis. Similar inhibition was seen when NS398 was replaced by aspirin. CONCLUSIONS: Combining COX-2 inhibitors and paclitaxel does not have an additive or synergistic tumoricidal effect. On the contrary, NS398 treatment markedly inhibited the apoptotic effects of paclitaxel in each of these two EOC cell lines.

Utility of lymphangiography in the prediction of lymph node metastases in patients with cervical cancer.

Our objective was to assess the value of lymphangiography in selecting patients for surgical staging of locally advanced cervical cancer. We reviewed our computerized database to identify patients with cervical cancer who had abnormal findings on lymphangiography and underwent retroperitoneal lymph node dissection between September 1991 and January 1996. The records of these patients were retrospectively reviewed, and the following data were retrieved: clinical tumor stage and findings on lymphangiography at surgery, and on pathologic examination of resected lymph nodes. The lymphangiograms were reviewed and reinterpreted in blinded fashion by two of the authors. The positive and negative predictive values of lymphangiography for the presence of lymph node metastases were calculated, with findings on pathologic examination of lymph nodes used as the gold standard. The positive and negative predictive values of surgeons' clinical assessments at surgery were also calculated. Fifty patients met the selection criteria and constituted the study population. Fourteen patients (28%) had histologically negative nodes, and 36 patients (72%) had lymph node metastases. Thirty-three patients had metastases to pelvic nodes, 1515 patients had metastases to common iliac nodes, and 1616 patients had metastases to para-aortic nodes. The positive predictive value of lymphangiography for lymph node metastases was 74% for pelvic nodes, 73% for common iliac nodes, and 88% for para-aortic nodes. The negative predictive value of lymphangiography for lymph node metastasis was 76% for common iliac nodes and 77% for para-aortic nodes. Overall, 46% of the patients selected for surgical exploration had histologic findings of either common iliac or para-aortic lymph node metastases; these findings led clinicians to extend radiation fields to cover the para-aortic lymph nodes. Lymphangiography is helpful in selecting patients with cervical cancer who have a high risk of common iliac or para-aortic lymph node metastasis. However, more accurate and more readily available noninvasive methods of evaluating cervical patients for the presence of regional disease continue to be needed.

Effects of prostaglandin E(2) on proliferation and apoptosis of epithelial ovarian cancer cells.

OBJECTIVE: There is strong evidence indicating that prostaglandins (PG) and their synthesizing enzyme cyclooxygenase-2 (COX-2) play an important role in tumorigenesis. The purposes of the present study were to determine the pattern of expression of COX-2 and the effect of PG treatment on proliferation and apoptosis in epithelial ovarian cancer cells. METHODS: Two epithelial ovarian cancer cell lines, MDAH-2774 and SKOV3, were grown in flasks to confluence. Cells were then treated with exogenous dimethyl prostaglandin E(2) (dmPGE(2)) at increasing concentrations of 0-10 microg/mL. Total RNA was extracted from cells at different treatment doses and subjected to reverse transcriptase-polymerase chain reaction for the semiquantitative analysis of COX-2, Bcl-2, and bax expression. Flow cytometry was performed to assess effect of treatment on the cell cycle. The TUNEL assay was used to assess apoptosis. RESULTS: We found that COX-2 was constitutively expressed in the MDAH-2774 and SKOV3 epithelial ovarian cancer cells as determined by detection of a 304-bp amplified fragment using specific primers for the COX-2 gene. Treatment of both cell lines with dmPGE(2) resulted in dose-dependently higher expression of COX-2, Bcl-2, and bax mRNA compared with untreated cells. These changes were associated with an increase in the proliferative fraction and with a simultaneous reduction in apoptosis. CONCLUSIONS: Prostaglandin E(2) stimulated proliferation and reduced apoptosis in epithelial ovarian cancer cells. These effects were associated with overexpression of COX-2 and an increase in the ratio of Bcl-2:bax mRNA.

Spontaneous malignant transformation of human ovarian surface epithelial cells in vitro.

PURPOSE: Epithelial ovarian cancer has no reliable marker for early detection and no known specific premalignant changes. Human ovarian surface epithelial (HOSE) cells expressing human papillomavirus type 16 (HPV-16) E6/E7 genes undergo crisis, and surviving cells exhibit an immortalized phenotype. Cells show an increasingly invasive phenotype on collagen rafts over time. To ascertain the nature of this aberrant growth, we characterized this spontaneous progression of HOSE cells from a benign to an invasive phenotype using histopathology, immunophenotyping, and tumorigenesis assays. EXPERIMENTAL DESIGN: At various passages, cells were monitored for growth on collagen, response to tumor necrosis factor alpha and daunorubicin, immunohistochemistry and Western blot analysis of E-cadherin and beta-catenin, growth in soft agar, and tumor formation in immunodeficient mice. RESULTS: As passage number increased, cells became increasingly aggressive on collagen, with more pronounced focal stratification and invasion. Furthermore, late-passage cells were more resistant to the apoptotic effects of TNF-alpha and daunorubicin than earlier-passage cells. E-cadherin expression was limited to early-passage cells, whereas beta-catenin was expressed regardless of passage. Cells invading collagen formed colonies in soft agar at low efficiency but were not tumorigenic in immunodeficient mice. Some cultures recovered from colonies grew in soft agar at high efficiencies, and one was tumorigenic. CONCLUSIONS: HOSE cells expressing E6/E7, over time, develop characteristics of malignant cells and produce tumors consistent with an ovarian surface epithelium lineage. Progression of HOSE cells from a benign to an invasive phenotype in vitro may provide a model to dissect the progression of ovarian cancer.

Secondary cytoreductive surgery for localized intra-abdominal recurrences in epithelial ovarian cancer.

OBJECTIVE: The aim of this study was to evaluate the role of secondary cytoreductive surgery in patients with recurrent epithelial ovarian cancer with an apparent solitary intra-abdominal focus. METHODS: We conducted a retrospective review of patients with epithelial ovarian cancer who underwent secondary cytoreduction for recurrence at the University of Texas M. D. Anderson Cancer Center between 1985 and 1994. Eligible patients included those who had a laparotomy to resect a tumor that was apparently solitary. Cytoreductive surgery was defined as optimal if the diameter of the largest residual tumor was < or =2 cm and suboptimal if >2 cm. RESULTS: Twenty-five patients met our eligibility criteria. Their mean age was 55 years (range, 35-73 years). The median time from primary diagnosis to recurrence was 37.6 months. Tumor was found to be confined to a solitary site in 15 patients (60%), to two sites in 6 (24%), and to three or more sites in 4 (16%). Surgical procedures included cytoreduction in 10 patients, intestinal resection in 8, splenectomy in 3, and limited biopsies in 4. Secondary cytoreduction was optimal in 18 of 25 patients (72%). The median postsecondary cytoreduction survival was 25.1 months for patients who had suboptimal secondary cytoreduction compared with 56.9 months for those who had optimal cytoreduction (P = 0.08). CONCLUSIONS: Secondary cytoreductive surgery for recurrent ovarian cancer at an apparently solitary intra-abdominal site resulted in optimal residual tumor in a high proportion of patients. Although there was no survival advantage for patients whose tumor was optimally debulked, there was a trend toward improved survival. A large prospective randomized trial of secondary cytoreduction for recurrence is recommended.

[Chemotherapy in metastatic or recurrent endometrial carcinoma]. / Chemotherapie beim metastasierenden oder rezidivierenden Korpuskarzinom.

Endometrial cancer is the fourth most common malignancy in women with an estimated 36,100 new cases diagnosed in the United States. The major treatment is surgical staging with hysterectomy, lymph node assessment and possible adjuvant irradiation. Systemic hormonal and chemotherapy has been reserved for women with disseminated primary disease or extrapelvic recurrence. Recent data showed that oral medroxyprogesterone, 200 mg/day, produced a 25% overall response for patients with well-differentiated histology and positive receptor status. In those patients especially if they are asymptomatic, endocrine therapy may be a reasonable initial approach. Patients with advanced or recurrent endometrial cancer should be considered for clinical trials using new agents or randomized trials designed to answer important questions. For patients not eligible for clinical trials, treatment with a platinum compound and paclitaxel or doxorubicin in combination should be considered.

Conservative surgery in a young patient with peritoneal psammocarcinoma.

Psammocarcinoma is a rare epithelial neoplasm of the ovary and peritoneum. The reported management of patients with this tumor includes radical surgery and chemotherapy. We report the case of a young woman with metastatic psammocarcinoma treated with conservative surgery who is alive 6.5 years following positive second-look laparotomy.

Tumor angiogenesis in vulvar squamous cell carcinoma.

OBJECTIVE: Angiogenesis has been shown to correlate positively with the presence of metastatic disease in some tumors, but has not been studied in invasive vulvar squamous cell carcinoma. Fifty cases of invasive vulvar squamous cell carcinoma were studied in an effort to correlate angiogenesis with stage, survival, and pattern of invasion. METHODS: These patients were diagnosed between 1987 and 1993. Microvessels were identified immunohistochemically using antibody to Factor VIII, and areas of greatest microvessel density associated with tumor were counted. The pattern of invasion was categorized as "spray," "pushing," or "mixed." The mean microvessel count was correlated with surgical and clinical stage, pattern of invasion, and survival. RESULTS: Mean microvessel counts in surgical stage I/II cases (31.1 +/- 7.3) were not significantly different from stage III/IV cases (26.3 +/- 8.6) (P = 0.089). Similarly mean microvessel counts in clinical stage I/II cases (31.6 +/- 11.9) were not significantly different from stage III/IV cases (27.0 +/- 8.7) (P = 0.198). Seventeen patients who died of disease had mean counts of 26.1 +/- 6.4, while 21 patients alive with or without evidence of disease had counts of 31.1 +/- 10.8 (P = 0.087). Mean microvessel counts did not vary significantly with the spray pattern (30.1 +/- 8. 7), pushing pattern (31.4 +/- 12.9), or mixed pattern of invasion (31.4 +/- 12.9) (P = 0.920). CONCLUSIONS: Tumor angiogenesis in vulvar squamous cell carcinoma does not correlate positively with stage, survival, or pattern of invasion and cannot be used as a prognostic indicator.