Pathologic and clinical tumor size discordance in early-stage cervical cancer: Does it matter?

OBJECTIVE: The objective of this study was to assess the rate of discordance between clinical and pathologic tumor size for women with stage IB1 cervical cancer (FIGO 2009 criteria), assess risk factors for discordance, and determine the impact of discordance on oncologic outcomes. METHODS: This was a secondary analysis of a prior multi-institutional retrospective review of patients diagnosed with stage IB1 (FIGO 2009 staging) cervical cancer undergoing radical hysterectomy between 2010 and 2017. Demographic, clinicopathologic, and oncologic data were collected. Pathologic upstaging was defined as having a preoperative diagnosis of stage IB1 cervical cancer with pathology demonstrating a tumor size >4 cm. Demographic and clinicopathologic data was compared using chi-square, fisher exact or 2-sided t-test. Survival was estimated using the Kaplan-Meier method. RESULTS: Of the 630 patients, 77 (12%) were upstaged. Patients who were upstaged had lower rates of preoperative conization (p < .001) or preoperative tumor sizes ≤2 cm (p < .001). Upstaged patients had increased odds of deep stromal invasion, lymphovascular space invasion, positive margins and positive lymph nodes. Almost 88% of upstaged patients received adjuvant therapy compared to 29% of patients with tumors ≤4 cm (odds 18.49, 95% CI 8.99-37.94). Finally, pathologic upstaging was associated with an increased hazard of recurrence (hazard ratio [HR] 1.95, 95% CI 1.03-3.67) and all-cause death (HR 2.31, 95% CI 1.04-5.11). CONCLUSIONS: Pathologic upstaging in stage IB1 cervical cancer is relatively common. Upstaging is associated with an 18-fold increased risk of receipt of adjuvant therapy. Patients undergoing preoperative conization and those with tumors <2 cm had lower risks of upstaging. Improvement in preoperative assessment of tumor size may better inform primary treatment decisions.

Gender differences in how physicians access and process information.

There is an absence of information on how physicians make surgical decisions, and on the effect of gender on the processing of information. A novel web based decision-matrix software was designed to trace experimentally the process of decision making in medical situations. The scenarios included a crisis and non-crisis simulation for endometrial cancer surgery. Gynecologic oncologists, fellows, and residents (42 male and 42 female) in Canada participated in this experiment. Overall, male physicians used more heuristics, whereas female physicians were more comprehensive in accessing clinical information (p < 0.03), utilized alternative-based acquisition processes in the non-crisis scenario (p = 0.01), were less likely to consider procedure-related costs (p = 0.04), and overall allocated more time to evaluate the information (p < 0.01). Further experiments leading to a better understanding of the cognitive processes involved in medical decision making could influence education and training and impact on patient outcome.

Para-aortic and pelvic extended-field radiotherapy for advanced-stage uterine cancer: dosimetric and toxicity comparison between the four-field box and intensity-modulated techniques.

BACKGROUND: In patients with advanced-stage endometrial carcinoma (eca), extended-field radiotherapy (efrt) is traditionally delivered by the 3-dimensional conformal (3d-crt) 4-field box technique. In recent years, the use of intensity-modulated radiotherapy (imrt) in gynecologic cancers has increased. We compared the delivery of efrt by the 3d-crt and contemporary imrt techniques. METHODS: After surgical staging and adjuvant chemotherapy in 38 eca patients, efrt was delivered by either imrt or 3d-crt. Doses to the organs at risk, side effects, and outcomes were compared between the techniques. RESULTS: Of the 38 eca patients, 33 were stage iiic, and 5 were stage ivb. In the imrt group, maximal doses to rectum, small intestine, and bladder were significantly higher, and mean dose to bladder was lower (p < 0.0001). Most acute gastrointestinal, genitourinary, and hematologic side effects were grade i or ii and were comparable between the groups. In long-term follow-up, only grade 1 cystitis at 3 months was statistically higher in the imrt patients. No grade iii or iv gastrointestinal or genitourinary toxicities were observed. No statistically significant differences in overall and disease-free survival or recurrence rates were observed between the techniques. CONCLUSIONS: In advanced eca patients, imrt is a safe and effective technique for delivering efrt to the pelvis and para-aortic region, and it is comparable to the 3d-crt 4-field box technique in both side effects and efficacy. For centres in which imrt is not readily available, 3d-crt is a valid alternative.

Comparing indocyanine green, technetium, and blue dye for sentinel lymph node mapping in endometrial cancer.

BACKGROUND AND AIMS: With the debate over extent of lymphadenectomy in endometrial cancer, sentinel lymph node (SLN) mapping may provide a focused approach to evaluate the most relevant lymph nodes (LN) while minimizing the complications. We evaluated SLN mapping using filtered technetium(99), indocyanine green (ICG), and blue dye. METHODS: Prospective evaluation of 100 patients who underwent SLN mapping by using submucosal and deep stromal cervical injections of technetium(99), ICG, and blue dye as part of the staging for endometrial cancer. RESULTS: 286 SLNs were mapped (2.9 per patient) in 92% of patients. The bilateral detection rate was 76%. ICG had a significantly higher SLN detection rate than blue dye in both overall (87% vs 71%, respectively; p=0.005) and bilateral (65% vs 43%, respectively; p=0.002) detection, but similar SLN detection rates compared to technetium(99) in both overall (87% vs 88%, respectively; p=0.83) and bilateral (65% vs 71%, respectively; p=0.36) detection. In eight cases, the SLN was in the para-aortic area and in 14 cases in the pre-sacral, hypogastric vein, or parametrial area. In nine cases, the SLN was positive for metastasis, and in seven cases the SLN was the only positive node. One SLN was falsely negative. No complications or anaphylactic reactions occurred. CONCLUSION: Intra-operative SLN mapping using cervical injection is feasible in patients with endometrial cancer and yields adequate detection rates. It allows mapping of SLNs in areas (pre-sacral, hypogastric vein, parametrial) not routinely sampled. Given the poorer performance of blue dye, surgeons may omit its use if a combination of ICG and technetium(99) is used.

Anti-proliferative and pro-apoptotic actions of a novel human and mouse ovarian tumor-associated gene OTAG-12: downregulation, alternative splicing and drug sensitization.

In studying the age dependence and chronology of ovarian tumors in follicle stimulating hormone receptor knockout mice, we identified a novel ovarian tumor associated gene-12 (OTAG-12), which is progressively downregulated and maps to Chr. 8B3.3. OTAG-12 protein overexpression in mouse ovarian and mammary tumor cells suggested powerful anti-proliferative effects. In human epithelial ovarian cancers (OCs) and OC cell lines, OTAG-12 mRNA expression is downregulated in comparison with normal ovaries. Cloning and identification revealed that human OTAG-12 mapping to gene-rich Chr. 19p13.12 is expressed in three spliced forms: hOTAG-12a, hOTAG-12b and hOTAG-12c, of which b is predominant in the normal ovary. Functionally active hOTAG-12b is a simple protein with no disulfide bonds and a nuclear localization signal is present in all variants. Transfection of OTAG-12 variants in OC and tumorigenic HEK293 cells confirmed nuclear localization. hOTAG-12b overexpression in OC and HEK293 cells effectively suppressed cell growth, anchorage-dependent and independent colony formation followed by apoptosis, whereas hOTAG-12a and hOTAG-12c had no such effects. Deletion mutants identified the critical importance of carboxyl terminus for hOTAG-12b function. Doxycycline-inducible growth inhibition of HEK293 cells by hOTAG-12a was associated with effects on G2 cell cycle arrest and apoptosis induction. hOTAG-12b expression rendered tumorigenic cells more sensitive to four apoptotic stimuli including etoposide-a topoisomerase-II inhibitor. Doxycycline-induced hOTAG-12b expression blocked xenograft tumor growth in nude mice, whereas hOTAG-12a was ineffective. Although p53-pathway-dependent apoptotic agents could upregulate endogenous hOTAG-12b and p53 in UCI-101/107 OC cells, hOTAG-12b could also induce apoptosis in p53-null and platinum-resistant SKOV3 OC cells and Doxycycline-induced hOTAG-12b did not alter p53. Further study showed that hOTAG-12b increases mRNAs of pro-apoptotic genes such as BAD, GADD45α and CIEDB, while inhibiting anti-apoptotic NAIP and Akt1 expression, suggesting that hOTAG-12b-induced apoptosis might be p53-independent. These results indicate that hOTAG-12b is a putative ovarian tumor suppressor gene warranting further studies.

HPV-related vulvar intraepithelial neoplasia: outcome of different management modalities.

OBJECTIVE: To evaluate the outcome of various management schemes for HPV-related vulvar intraepithelial neoplasia (VIN, usual type). METHODS: Retrospective chart review of patients with histologically diagnosed grade 2/3-VIN who had at least one year of follow-up. The variables that were collected included patient characteristics, management modalities, and clinical outcome. RESULTS: Fifty patients with a median age of 45 years old were evaluated. The median duration of follow-up was 43.5 months (12-186). Complete response (CR) and partial response occurred in 28 (56%) and 4 (8%), respectively. Nineteen of 28 patients with CR recurred with VIN. Surgical excision yielded higher CR (77%) than did either ablational techniques (21-33%) or topical immunotherapy (33%). CONCLUSION: In this experience, surgical excision for VIN, usual type, resulted in better therapeutic success rates than other treatment modalities. Management schemes should be individualized based on extent of disease and patient compliance.

Doxorubicin levels in the serum and ascites of patients with ovarian cancer.

AIMS: To investigate the diffusion and accumulation of doxorubicin metabolites in the ascites of patients with ovarian cancer following intravenous injection, as a model for intraperitoneal accumulation of drugs. METHODS: The concentrations of doxorubicin and its metabolites [Doxorubicinol (Dox-ol), 7-deoxydoxorubicinolone (7d-Dox-ol-on) and 7-deoxydoxorubicinone (7d-Dox-on)] were measured using high-performance liquid chromatography in the serum and in the ascites of seven patients with recurrent ovarian carcinoma suffering from symptomatic ascites and treated with intravenous doxorubicin. RESULTS: Doxorubicin metabolites accumulated in the peritoneal cavity. The concentrations of the doxorubicin metabolites were initially higher in the serum compared to the ascitic fluid, but following several hours the doxorubicin metabolites became higher in the ascites, and remained detectable in the ascites for up to 168h, long after disappearance from the serum. CONCLUSIONS: Doxorubicin metabolites accumulate in the ascites and are cleared more slowly from the peritoneal compartment than from the serum. Accumulation in the peritoneal cavity with prolonged half-life should be considered when administering medication in patients with ascites.

Malignancies following bilateral salpingo-oophorectomy (BSO).

AIMS: Prophylactic bilateral salpingo-oophorectomy (BSO) is an effective risk reducing measure in ovarian cancer susceptible women. Yet, a small subset of women develop primary peritoneal carcinomatosis (PPC) after BSO. The rates of PPC following non-risk reducing BSO have sparingly been reported. METHODS: Women who underwent BSO for non-cancer reasons from 1/1/1984 to 12/31/2000 were crossed with the list of cancer diagnoses reported to the Israel National Cancer Registry until 12/31/2001. RESULTS: Overall, 4128 women at a mean age of 58+/-12 years were analyzed. After a mean of 7.2+/-4 years following BSO, 147 women (3.6%) were diagnosed with cancer: breast cancer in 50 women 62+/-50 months after BSO, and one patient developed PPC, whereas the expected was 0.15 cases. The Standardized Incidence Ratio (SIR) of developing breast cancer was statistically significant lower than expected (SIR 0.71, 95% C.I. 0.44-0.78). CONCLUSION: The rate of post-oophorectomy PPC in average risk population is low, and BSO appears to lower the rate of breast cancer in average risk women.

Importance of accurate preoperative diagnosis in the management of aggressive angiomyxoma: report of three cases and review of the literature.

BACKGROUND: Aggressive angiomyxoma is a benign but locally aggressive tumor that occurs mostly in young women. Because excision is often incomplete, the risk of local recurrence is high. This report describes differences in presentation and the importance of accurate preoperative diagnosis of this rare neoplasm. METHODS AND RESULTS: We describe three cases with different presentations. Two were initially misdiagnosed, and local recurrence necessitated reoperation. Accurate diagnosis in the third case was followed by complete excision, with no recurrence. CONCLUSION: Aggressive angiomyxoma should be considered in the differential diagnosis of young women who present with a well-defined mass in the pelvic tissue. Accurate preoperative diagnosis should alert the surgeon to the need for wide excision, which is essential for prevention of local recurrence.

Alphav integrin expression is a novel marker of poor prognosis in advanced-stage ovarian carcinoma.

PURPOSE: To analyze the possible correlation between expression of the alphav and beta1 integrin chains and survival in advanced-stage ovarian carcinomas, studying two patient groups with extremely different disease outcome. EXPERIMENTAL DESIGN: Sections from 56 primary ovarian carcinomas and metastatic lesions from 34 patients diagnosed with advanced-stage ovarian carcinoma (Fédération Internationale des Gynaecologistes et Obstetristes stages III-IV), divided into long-term (16) and short-term (18) survivors, were evaluated for expression of alphav and beta1 integrin chains using mRNA in situ hybridization. Protein expression was additionally studied in 52 specimens using immunohistochemistry. RESULTS: The mean values for disease-free survival and overall survival were 115 and 132 months for long-term survivors, as compared with 4 and 23 months for short-term survivors, respectively. Expression of alphav integrin mRNA was observed in carcinoma (18 of 56; 32%) and stromal (17 of 56; 30%) cells. beta1 integrin mRNA was similarly detected in carcinoma (25 of 56; 47%) and stromal (19 of 56; 34%) cells. No significant differences were observed when primary and metastatic lesions were compared (P > 0.05). Alphav integrin mRNA was present more often in carcinoma cells in tumors of short-term survivors (P = 0.017 for carcinoma cells). In univariate survival analysis for all cases, alphav integrin mRNA expression in tumor cells correlated with poor survival (P = 0.012). This finding retained its predictive power in a multivariate survival analysis, in which all of the molecules studied previously in this patient cohort were included (P = 0.031). Immunohistochemistry confirmed the differences in alphav integrin expression in tumor cells of short-term as compared with long-term survivors, whereas beta1 integrin protein expression was comparable in the two groups. CONCLUSIONS: To our best knowledge, this is the first evidence associating integrin expression with poor survival in ovarian carcinoma. Alphav integrin is, thus, a novel prognostic marker in advanced-stage ovarian carcinoma.

The Tyr978X BRCA1 Mutation in Non-Ashkenazi Jews: Occurrence in High-Risk Families, General Population and Unselected Ovarian Cancer Patients.

Background: In Jewish individuals of Ashkenazi (East European) decent, three predominant mutations, 185 delAG and 5382insC (BRCA1) and 6174delT (BRCA2), seem to account for a substantial portion of germline mutations in high-risk breast/ovarian cancer families. Among non-Ashkenazi Jews, the 185delAG and the Tyr978X mutations, as well as several 'private' mutations have been reported within the BRCA1 gene. Objective: Assessing the occurrence rate of the Tyr978X BRCA1 germline mutation in Jewish non-Ashkenazi individuals: high-risk familial cases, unselected ovarian cancer patients and the general average risk Jewish Iraqi population. In addition, finding proof that this is a founder mutation. Methods: PCR amplification of the relevant fragment of the BRCA1 gene from constitutional DNA followed by restriction enzyme digest that differentiates the wild type from the mutant allele. In addition, BRCA1-linked markers were used for haplotype analysis. Results: The Tyr978X BRCA1 mutation was detected in 3/289 (1%) of the average-risk Jewish Iraqi population, in 7/408 (1.7%) high-risk Jewish non-Ashkenazi individuals (representing 332 unrelated families) and in 1/81 (1.2%) of unselected Jewish non-Ashkenazi ovarian cancer patients. Allelotyping using BRCA1-linked markers revealed an identical allelic pattern in all mutation carriers with the intragenic markers. Conclusions: Our findings suggest that this mutation is prevalent in Iraqi Jews, represents a founder mutation, and should be incorporated into the panel of mutations analyzed in high-risk families of the appropriate ethnic background. Copyright 2001 S. Karger AG, Basel

Infertility treatment after conservative management of borderline ovarian tumors.

BACKGROUND: Young patients with ovarian tumors of low malignant potential usually undergo conservative surgery because of the excellent prognosis of these tumors. Patients wishing to conceive after diagnosis occasionally require ovulation induction, but data regarding the safety of assisted reproductive technologies in this situation remains anecdotal. The current study analyzes the outcome of a group of patients who received infertility treatment after the conservative management of borderline ovarian tumors. METHODS: The clinical and pathologic records of 104 patients with a borderline tumor of the ovary who were treated and followed over a 20-year period (1979--1999) were reviewed. Forty-three patients who underwent conservative management were the subjects of the current study. RESULTS: Follow-up was available for 95% of the patients, giving a total of 270 women-years of follow-up. Nine of the 43 patients developed a local recurrence, 8 of which occurred in patients with serous tumors. Five of these 9 patients underwent cystectomy only at the time of recurrence, and all were without evidence of disease at a mean follow-up of 75 months (range, 25--93 months). Nineteen patients delivered a total of 25 healthy children after diagnosis of a borderline ovarian tumor; 7 of these patients were treated with in vitro fertilization (IVF) after diagnosis. Four of these patients developed a recurrence, two patients before the IVF treatment and two patients after the IVF treatment. The latter two patients were without evidence of disease at the time of last follow-up (15 months and 26 months, respectively, after the recurrence). CONCLUSIONS: The results of the current study suggest that ovulation induction may be considered after the diagnosis of a borderline ovarian tumor. Recurrences were observed in two of seven patients, all of which remained histologically borderline.

Topoisomerase II immunostaining as a prognostic marker for survival in ovarian cancer.

OBJECTIVE: This study aimed to evaluate topoisomerase II compared to Ki-67 expression as a marker for tumor behavior and for prognosis of patients with ovarian cancer. METHODS: In order to screen for potential prognostic markers, two groups of patients with advanced stage (FIGO stages III and IV) epithelial ovarian carcinoma were selected based on differences in survival (mean survival, 11 years versus 2 years). Pathology slides were reviewed, and immunohistochemistry using antibodies to topoisomerase II and Ki-67 was performed on the original cell blocks. No patients were lost to follow-up. RESULTS: Detectable expression of topoisomerase II was present in 70.0 +/- 30.3% of cells in patients with rapidly progressing disease, compared to only 12.3 +/- 12.4% of cells in long-term survivors (P = 0.0001). Ki-67 expression was also more frequent in short-term survivors compared to long-term survivors, but the difference was less prominent than with topoisomerase II (P = 0.01). Specificity and sensitivity as prognostic factors reached 88.2 and 93.8% for topoisomerase II, compared to 55.6 and 88.2% for Ki-67. CONCLUSIONS: Topoisomerase II expression as detected by immunohistochemistry in tumor samples emerged as a promising clinically relevant biomarker for survival in advanced epithelial ovarian cancer.

Caveolin-1 expression in advanced-stage ovarian carcinoma--a clinicopathologic study.

OBJECTIVE: The aim of this study was to analyze the correlation among the expression of caveolin-1, the protein constituent of caveolae, and disease outcome in advanced-stage ovarian carcinomas. METHODS: Sections from 76 primary ovarian carcinomas and metastatic lesions from 45 patients diagnosed with advanced-stage ovarian carcinoma (FIGO stages III-IV) were evaluated for caveolin-1 expression using immunohistochemistry. Patients were divided into long-term survivors and short-term survivors based on disease outcome. Twenty nonneoplastic fallopian tubes and ovaries were additionally studied. RESULTS: The mean follow-up period was 70 months. The mean values for disease-free survival and overall survival were 109 and 125 months for long-term survivors, compared to 3 and 21 months for short-term survivors, respectively. Caveolin-1 expression was localized to the cell membrane in 24/76 (32%) specimens and was detected in the cytoplasm in 52/76 (68%) cases. Both patterns were more often detected in metastases, when compared with primary tumors. In addition, membrane immunoreactivity was more often seen in tumor of short-term survivors. These differences did not reach statistical significance (P > 0.05). Combined membrane and cytoplasmic immunoreactivity was seen in 17/20 (85%) nonneoplastic lesions. Despite its role in tyrosine-kinase-mediated signal transduction in vitro studies, caveolin-1 expression in carcinomas showed no association with the protein expression of c-erbB-2 and epidermal growth factor receptor, evaluated in a previous study of this patient cohort. CONCLUSIONS: This study provides the first in vivo evidence of caveolin-1 membrane expression in human malignancies. Caveolin-1 is often expressed in advanced-stage ovarian carcinoma, but does not appear to be a powerful predictor of disease outcome in these tumors. The reduced expression level in carcinomas compared to nonneoplastic epithelium may point to a role for caveolin-1 as a tumor suppressor gene.

Ets-1 messenger RNA expression is a novel marker of poor survival in ovarian carcinoma.

Ets-1 proto-oncogene is a transcription factor involved in several cellular functions, including the activation of several proteases participating in tumor invasion and metastasis. The objective of this study was to analyze the possible correlation between Ets-1 mRNA expression and survival in advanced-stage ovarian carcinomas, studying two patient groups with extremely different disease outcome. Sections from 66 primary ovarian carcinomas and metastatic lesions from 41 patients diagnosed with advanced-stage ovarian carcinoma (International Federation of Gynecologists and Obstetricians stages III and IV) were evaluated for expression of Ets-1 using mRNA in situ hybridization. Patients were divided into long-term (n = 17) and short-term (n = 24) survivors. The mean values for disease-free survival and overall survival were 116 and 133 months for long-term survivors, as compared to 3 and 21 months for short-term survivors, respectively. Expression of Ets-1 mRNA was detected in carcinoma cells and stromal cells in 28 of 66 (42%) and 22 of 66 (33%) lesions, respectively. Ets-1 expression showed an association with mRNA expression of vascular endothelial growth factor (P = 0.001 for carcinoma cells; P = 0.004 for stromal cells), basic fibroblast growth factor (P = 0.049 for carcinoma cells), and membrane type-1 matrix metalloproteinase (P = 0.045), which were previously studied in this patient cohort. Ets-1 mRNA was detected more often in both carcinoma and stromal cells in tumors of short-term survivors (P = 0.038 for carcinoma cells). In univariate survival analysis for all cases, Ets-1 expression in both tumor (P = 0.018) and stroma (P = 0.026) correlated with poor survival. These findings were reproduced in an analysis of primary tumors alone (P = 0.039 for tumor cells; P < 0.001 for stromal cells). Ets-1 mRNA expression in stromal cells retained its predictive power in a multivariate survival analysis in which all molecules studied previously in this patient cohort were included (P = 0.007). To our knowledge, this is the first evidence associating Ets-1 mRNA expression and poor survival in human epithelial malignancy. Ets-1 is thus a novel prognostic marker in advanced-stage ovarian carcinoma. The association between Ets-1 mRNA expression and the expression of membrane type-1 matrix metalloproteinase and angiogenic genes, first documented here in a study of patient material, points to the central role of this transcription factor in tumor progression in ovarian carcinoma.

E-Cadherin complex protein expression and survival in ovarian carcinoma.

OBJECTIVE: The aim of this study was to analyze the correlation between expression of E-cadherin complex proteins, epidermal growth factor receptor (EGFR), and c-erbB-2 and disease outcome in advanced-stage ovarian carcinomas. METHODS: Sections from 75 primary ovarian carcinomas (=37) and metastatic lesions (=38) from 45 patients diagnosed with advanced-stage ovarian carcinoma (FIGO stage III-IV) were immunostained and evaluated for staining pattern, extent, and intensity. Patients were divided in two groups based on disease outcome. Long-term survivors (21 patients) and short-term survivors (24 patients) were defined using a double cutoff of 36 months for disease-free survival (DFS) and 60 months for overall survival (OS). Mean follow-up period was 70 months. The mean values for DFS and OS were 109 and 125 months for long-term survivors, as compared to 3 and 21 months for short-term survivors, respectively. RESULTS: Comparison of all primary and metastatic lesions showed upregulation of gamma-catenin protein expression in the latter (P = 0.05). When segregated according to disease outcome, the expression of all studied proteins, with the exception of EGFR, was more diffuse in tumors of short-term survivors. The presence of cytoplasmic staining for c-erbB-2 was associated with poor survival in the entire cohort (P = 0.007), as well as in primary tumors alone (P = 0.003), in survival analysis. Similar results were seen in the evaluation of primary tumors for gamma-catenin (P = 0.002). CONCLUSIONS: gamma-Catenin, and possibly c-erbB-2, are valid markers of poor survival in advanced-stage ovarian carcinoma.

CA 125 measurement and ultrasonography in borderline tumors of the ovary.

OBJECTIVES: Our goal was to perform an analysis of ultrasonographic characteristics and CA 125 levels in ovarian tumors of borderline malignancy. STUDY DESIGN: We performed a retrospective analysis of CA 125 levels and ultrasonographic parameters in 91 patients with borderline tumors. RESULTS: Serous tumors of borderline malignancy were associated with elevated CA 125 levels in 75% of patients before surgery (mean, 156 IU/mL) compared with 30% of mucinous tumors (mean, 28 IU/mL; P =.004). CA 125 was elevated in 35% of stage IA serous tumors (mean, 67 IU/mL) compared with 89% of tumors with spread beyond the ovary (mean, 259 IU/mL; P =.001). Mucinous tumors tended to be bigger (13.1 +/- 7 cm) on ultrasonography than serous tumors (9.3 +/- 6.2 cm, P =.016). Mucinous tumors were multilocular in half the patients and contained papillations in 40% of the patients. Serous tumors were multilocular in 30% of the patients but presented with solid or papillary patterns in 78% of the patients (P =.001). A resistance index of <0.4 was found in 36% of mucinous tumors and half the cases of serous tumors. In 13% of patients, ultrasonographic characteristics were compatible with a simple cyst only, including 1 patient with microinvasion and 1 patient with stage IIIB disease. Sensitivity of gray-scale ultrasonography was 87%, that of CA 125 measurement was 62%, and that of flow was 55%. At least 1 diagnostic test result was abnormal in 93% of patients, 2 were abnormal in 69% of patients, and all 3 were abnormal in 21% of patients. CONCLUSIONS: A high proportion of borderline tumors of the ovary, particularly of the serous type, were associated with elevated CA 125 levels and abnormal ultrasonographic characteristics, although some tumors presented as simple cysts.

Comparative genomic hybridization in inherited and sporadic ovarian tumors in Israel.

To gain an understanding of the molecular mechanisms of ovarian cancer, we analyzed 16 ovarian tumors from Jewish Israeli patients by comparative genomic hybridization: 12 invasive epithelial tumors (including three BRCA1 and one BRCA2 mutation carriers), 2 primary peritoneal carcinomatosis, 1 pseudomyxoma peritoneii tumor, and 1 sertoli cell tumor. We similarly analyzed 1 normal ovary from a BRCA1 mutation carrier, and 3 metastases. The most common abnormalities in epithelial tumors were amplification of 8q22.1-ter (8/12, 66.6%), 1q22-32.1 (5/12, 41.6%), 3q, 10p (4/12, 33.3% for each), and deletions of 9q (5/12, 41.6%) and 16q21-24 (4/12, 33.3%). All 3 BRCA1 mutation carriers and 2 of 8 sporadic cases displayed 9q deletion, and 2 of 3 BRCA1 mutation carriers, but none of the sporadic cases, had deletion of chromosome 19. The range of genetic changes in primary peritoneal tumors and epithelial ovarian cancers was similar, though the mean number of alterations in the former was less (3.5/tumor versus 8/tumor). Our preliminary results may indicate that inherited predisposition to ovarian cancer possibly entails preferential somatic deletions of chromosomes 9 and 19.

p53 and WAF1 polymorphisms in Jewish-Israeli women with epithelial ovarian cancer and its association with BRCA mutations.

OBJECTIVE: To investigate whether polymorphic p53 and WAF1 alleles are associated with clinical, demographic and histopathological features and BRCA mutation in women with ovarian cancer. DESIGN: A cross-sectional study. POPULATION: Two hundred and twenty-one nonselected Israeli women with epithelial ovarian cancer. METHODS: DNA was analysed for known polymorphisms in intron 3 (a 16 nucleotide single repeat) and intron 6 (a G to A change at nucleotide 13,494) of the p53 gene, the S31R polymorphism in the WAF1 gene, and for three predominant Jewish mutations in the BRCA genes (185delAG and 5382insC in BRCA1, and 6174delT in BRCA2). MAIN OUTCOME MEASURE: The rate of polymorphic p53 and WAF1 alleles and their association with BRCA mutation, ethnic origin, age and stage at diagnosis, and family history of cancer. RESULTS: Of the tested women, 72 (32.6%) were either BRCA1 (n = 57) or BRCA2 (n = 15) mutation carriers. Sixty-eight of 213 (31.9%) were heterozygous for intron 3 polymorphism, 67/193 (34.7%) for intron 6 polymorphism, and 22/154 (14.3%) for S31R of the WAF1 gene. The p53 and WAF1 polymorphism rate did not differ between BRCA mutation carriers and noncarriers. No significant association between specific p53 or WAF1 genotypes, and clinical, histopathological or demographic variables was observed. CONCLUSION: In Jewish-Israeli women with sporadic and familial ovarian cancer, p53 or WAF1 polymorphisms do not seem to affect the phenotype.