Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study.

BACKGROUND: Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa. METHODS: Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival. RESULTS: FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94). CONCLUSIONS: FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.

Risk-scoring system for the individualized prediction of lymphatic dissemination in patients with endometrioid endometrial cancer.

OBJECTIVE: To develop a risk-scoring system (RSS) for the prediction of lymphatic dissemination after hysterectomy in endometrioid endometrial carcinoma (EC). METHODS: Patients who underwent surgery from 1/1/1999-12/31/2008 were evaluated. Patients with non-endometrioid histology, stage IV with macroscopic extrauterine disease, or receiving adjuvant therapy (excluding brachytherapy) without pelvic and/or paraaortic (P/PA) lymphadenectomy (LND) were excluded. Lymph node dissemination was defined as nodal metastasis when P/PA LND was performed or P/PA lymph node recurrence after negative LND or when LND was not performed. Logistic regression analysis was used to identify predictors for lymphatic dissemination and develop a RSS and nomogram. The RSS was assessed for calibration and verified for discrimination. RESULTS: Overall, 883 patients were assessed of which 521 (59.0%) underwent P/PA LND and 57 (10.9%) had positive lymph nodes. Of patients who did not undergo P/PA LND (N=362) or had negative nodes (N=464), 10 (1.2%) patients had P/PA lymph node recurrence. Myometrial invasion, tumor diameter (TD), FIGO grade, cervical stromal invasion and lymphovascular space invasion were significant on univariable analysis. All preceding variables were included in a multivariable logistic model. A parsimonious model and an alternative full model not including TD were considered. The full model with TD (illustrated in nomogram) had the highest predictive ability (concordance index 0.88). CONCLUSION: Our RSS allows accurate quantification of the probability of lymphatic dissemination and can be used as an adjunct to clinical decision-making after hysterectomy in the absence of staging. TD is an important component of the RSS and should be routinely assessed.

Risk factors that mitigate the role of paraaortic lymphadenectomy in uterine endometrioid cancer.

OBJECTIVE: Paraaortic lymph node (PA) dissemination in endometrial cancer (EC) is uncommon and a systematic infrarenal PA dissection carries morbidity. Our objective was to identify a subgroup of EC patients who may potentially forego PA lymphadenectomy (LND). METHODS: The study endpoint (PA Metastasis or Recurrence; PAMR) was defined as detection of metastasis to PA nodes (among those with any type of PA LND) or PA recurrence within 2 years (among patients without PA LND or those with negative nodes in the context of an inadequate (<5 nodes) PA LND). Patients with non-endometrioid histology, stage IV disease, synchronous cancers, gross extrauterine or gross adnexal disease, neoadjuvant therapy, or insufficient follow-up were excluded. Multivariable logistic regression analysis identified predictors of PAMR. RESULTS: Of the 946 patients, PAMR was observed in 4% (36/946). Multivariable analysis identified positive pelvic nodes (odds ratio (OR) 24.2; p<0.001), >50% MI (OR 5.3; p<0.001) and lymphovascular space invasion (LVSI) (OR 3.7; p=0.005) as the only three independent predictors of PAMR. When all three factors were absent (77% of study cohort), the predicted probability of PAMR was 0.6%. If intraoperative frozen section is not available on pelvic lymph nodes and LVSI, omitting PA LND in all patients with ≤ 50% MI would affect 84% (792/946) of the total cohort, with a 1.1% risk of PAMR (9/792). CONCLUSION: The majority of patients with endometrioid EC may potentially forgo PA LND with expected reductions in surgical morbidity and cost. This cohort may be identified by a combined absence of: positive pelvic nodes, >50% MI and LVSI.

Prospective assessment of survival, morbidity, and cost associated with lymphadenectomy in low-risk endometrial cancer.

OBJECTIVE: Since 1999, patients with low risk endometrial cancer (EC) as defined by the Mayo criteria have preferably not undergone lymphadenectomy (LND) at our institution. Here we prospectively assess survival, sites of recurrence, morbidity, and cost in this low risk cohort. METHODS: Cause-specific survival (CSS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Complications were graded per the Accordion Classification. Thirty-day cost analyses were expressed in 2010 Medicare dollars. RESULTS: Among 1393 consecutive surgically managed cases, 385 (27.6%) met inclusion criteria, accounting for 34.1% of type I EC. There were 80 LND and 305 non-LND cases. Complications in the first 30 days were significantly more common in the LND cohort (37.5% vs. 19.3%; P<0.001). The prevalence of lymph node metastasis was 0.3% (1/385). Over a median follow-up of 5.4 years only 5 of 31 deaths were due to disease. The 5-year CSS in LND and non-LND cases was 97.3% and 99.0%, respectively (P=0.32). None of the 11 total recurrences occurred in the pelvic or para-aortic nodal areas. Median 30-day cost of care was $15,678 for LND cases compared to $11,028 for non-LND cases (P<0.001). The estimated cost per up-staged low-risk case was $327,866 to $439,990, adding an additional $1,418,189 if all 305 non-LND cases had undergone LND. CONCLUSION: Lymphadenectomy dramatically increases morbidity and cost of care without discernible benefits in low-risk EC as defined by the Mayo criteria. In these low-risk patients, hysterectomy with salpingo-oophorectomy alone is appropriate surgical management and should be standard of care.

Incidence and factors associated with synchronous ovarian and endometrial cancer: a population-based case-control study.

OBJECTIVE: To estimate the incidence of synchronous endometrial cancer (EC) and ovarian cancer (OC) in the female population, among all women with EC, and in women under 50 years of age with EC, and to identify factors associated with synchronous EC/OC. METHODS: All cases of synchronous EC/OC and EC diagnosed in women residing in Olmsted County, Minnesota between 1/1/1945 and 12/31/2008 were identified. Incidence was estimated using the population denominator from decennial census data, corrected for hysterectomy prevalence. A case-control study using 15 identified cases (EC/OC) and 45 controls (EC alone) was performed. RESULTS: The incidence of synchronous EC/OC and EC (age-adjusted to the 2000 US female total and corrected for hysterectomy prevalence) in 1945-2008 was 0.88 and 30.3 per 100,000 person-years, respectively. Among women under 50 years of age, the corrected incidence of EC/OC and EC was 0.51 and 5.1 per 100,000 person-years, respectively. Among all women with EC, 3.1% had a synchronous OC compared to 9.4% of women under 50 years of age with EC. Patients with synchronous EC/OC were more likely than those with EC alone to present with a pelvic mass (57.1% vs. 8.9%, p<0.001). Patients with EC alone were more likely to have used oral contraceptive pills (OCPs) than synchronous EC/OC cases (22.7% vs 0%; Odds ratio, 0.10; 95% CI, <0.01-0.87). CONCLUSION: Although the incidence of synchronous EC/OC in the general population is lower than previously reported, nearly 1 in 10 women diagnosed with EC under 50 years of age will have a synchronous OC.

Referral and ascertainment bias in patients with synchronous and metachronous endometrial malignancy.

The purpose of this study was to evaluate the frequency in patients with endometrial cancer of other malignancies and the influence of referral and ascertainment biases on these associations. Analysis of 1,028 local and referred patients who had a hysterectomy for endometrial cancer was based on residence at the time of diagnosis. Altogether, 208 patients had a history of another malignancy, most frequently breast, colon, and ovary. At the time of surgery for endometrial cancer, the prevalence of lymphoma and breast and ovarian cancers was greater than expected although the higher prevalence of lymphoma was limited to referred patients. During follow-up after hysterectomy, the incidence of lung cancer was lower than expected, whereas the incidence of lymphoma was higher. Breast, colorectal, and bladder cancers were more common than expected although this finding was limited to local patients. We concluded that results of epidemiologic studies from tertiary care centers may be misleading if they do not account for referral and ascertainment biases.

HER2 gene amplification and EGFR expression in a large cohort of surgically staged patients with nonendometrioid (type II) endometrial cancer.

Type II endometrial cancers (uterine serous papillary and clear cell histologies) represent rare but highly aggressive variants of endometrial cancer (EC). HER2 and EGFR may be differentially expressed in type II EC. Here, we evaluate the clinical role of HER2 and EGFR in a large cohort of surgically staged patients with type II (nonendometrioid) EC and compare the findings with those seen in a representative cohort of type I (endometrioid) EC. In this study HER2 gene amplification was studied by fluorescence in situ hybridisation (FISH) and EGFR expression by immunohistochemistry. Tissue microarrays were constructed from 279 patients with EC (145 patients with type I and 134 patients with type II EC). All patients were completely surgically staged and long-term clinical follow up was available for 258 patients. The rate of HER2 gene amplification was significantly higher in type II EC compared with type I EC (17 vs 1%, P<0.001). HER2 gene amplification was detected in 17 and 16% of the cases with uterine serous papillary and clear cell type histology, respectively. In contrast, EGFR expression was significantly lower in type II compared with type I EC (34 vs 46%, P=0.041). EGFR expression but not HER2 gene amplification was significantly associated with poor overall survival in patients with type II EC, (EGFR, median survival 20 vs 33 months, P=0.028; HER2, median survival 18 vs 29 months, P=0.113) and EGFR expression retained prognostic independence when adjusting for histology, stage, grade, and age (EGFR, P=0.0197; HER2, P=0.7855). We conclude that assessment of HER2 gene amplification and/or EGFR expression may help to select type II EC patients who could benefit from therapeutic strategies targeting both HER2 and EGFR.

Comparison of loss of heterozygosity patterns in invasive low-grade and high-grade epithelial ovarian carcinomas.

Loss of heterozygosity (LOH) studies were performed to investigate the genetic differences which separate low-grade (LG), high-grade (HG), and borderline epithelial ovarian carcinomas. Fresh tumor samples and blood were obtained from 58 patients (20 LG, 34 HG, and 4 borderline tumor specimens) undergoing surgery for ovarian carcinoma at Mayo Clinic. Tumors were graded using a modified Broder's classification with invasive grades 1 and 2 considered LG, invasive grades 3 and 4 considered HG, and tumors with no evidence of stromal invasion classified as borderline. Polymorphism analysis was performed using 76 restriction fragment length polymorphisms and variable number of tandem repeats and 59 microsatellite markers representing all chromosome arms. Chromosome arms 6p, 17p, 17q, and 22q were found to be frequently lost in LG as well as HG tumors. Chromosome arms 13q and 15q were lost to a significantly greater extent in HG tumors compared to LG neoplasms (P = 0.003 and P = 0.08, respectively). Conversely, 3p loss was seen more frequently with LG tumors (P = 0.02). The majority of LG tumors (65%) did not show frequent LOH in the allelotype analysis. In fact, a subset of 7 (7 of 20) LG tumors accounted for 76% of the total allelic loss in the LG category. These tumors showed LOH almost identical to that of the HG neoplasms. Borderline tumors showed a low rate of allelic loss. There were no common events found between borderline and invasive tumors. Our data suggest that most HG tumors and a subset of LG tumors share genetic alterations at putative tumor suppressor genes detected by LOH studies. Chromosome 6 and 17 losses appear to be early events while 13q and 15q losses appear to be critical late events. However, a majority of LG tumors appear to develop as a consequence of an alternative mechanism(s) which is not detected by LOH studies. Possibilities include: (a) inactivation of tumor suppressor genes without LOH; (b) dominant negative gene(s) in which only one allele requires mutation; and (c) changes in dominant acting oncogenes. This unidentified phenomenon may be operative in borderline tumors as well.

Evidence of functional RB protein in epithelial ovarian carcinomas despite loss of heterozygosity at the RB locus.

The presence of retinoblastoma (RB) protein was evaluated by immunohistochemical staining and correlated with loss of heterozygosity (LOH) at the RB locus in 52 primary epithelial ovarian carcinomas. Forty-eight tumors were informative at the RB locus by molecular genetic analysis. Twenty-five tumors (52%) showed loss of heterozygosity at the RB locus. RB protein expression was found in 23 of these tumors. The remaining two tumors were negative for RB protein product by immunohistochemical staining. All 23 tumors showing no LOH at the RB locus had a normal RB protein pattern. All but three tumors revealed either no LOH with any marker or, if LOH was found for one chromosome 13 marker, all other informative markers also showed LOH. The three recombinant tumors included two which retained alleles at one or more loci distal and one which retained alleles proximal to the RB locus. LOH at the RB locus was significantly more common in invasive high-grade (grades 3 and 4) tumors as compared to invasive low-grade (grades 1 and 2) tumors (P < 0.001). Our data suggest that while molecular genetic studies reveal frequent LOH at the RB locus, particularly in high-grade tumors, normal RB protein expression is present in the majority (96%) of these tumors. This implies that another, unidentified, gene or genes located on chromosome 13 may be important in the progression of most epithelial ovarian carcinomas. Additionally, it is likely that the specific chromosome 13 alteration(s) associated with sporadic ovarian neoplasms will be extremely difficult to identify using allelic loss and deletion mapping studies.

Prognostic significance of p53 immunostaining in epithelial ovarian cancer.

PURPOSE: To evaluate the prognostic significance of p53 expression in epithelial ovarian cancer, including a subset of stage I patients, and to look for correlations between p53 expression and other disease parameters, including stage, grade, age, histologic subtype, second-look results, ploidy, and percent S phase. PATIENTS AND METHODS: We analyzed p53 expression in 284 patients with epithelial ovarian cancer using immunohistochemical techniques in paraffin-embedded specimens. There were 36 patients with stage I disease, 20 with stage II disease, 186 with stage III disease, and 42 with stage IV disease. RESULTS: p53 immunoreactivity was present in 177 cases (62%). p53 expression was associated with grade 3 to 4 disease (P = .003). The following factors were associated with a decrease in overall survival in a univarate analysis: stage III or IV disease (P = .0001), grade 3 or 4 disease (P = .0001), age above the median (P = .0002), and p53 reactivity (P = .04). In a multivariate analysis, stage, grade, and age retained independent prognostic significance. In the subset of 36 stage I patients, p53 positively approached statistical significance (P = .10) as a negative prognostic factor in a univariate analysis. CONCLUSION: Abnormalities of p53 expression occur commonly in epithelial ovarian cancer. Although associated with decreased survival in a univariate analysis, this biologic marker did not retain independent prognostic significance in a multivariate analysis. p53 expression should be studied in a larger cohort of early-stage patients, where accurate prognostic information is needed to direct therapy.

Sentinel lymph node biopsy with metastasis: can axillary dissection be avoided in some patients with breast cancer?

PURPOSE: Recent studies have suggested that the sentinel lymph node (SLN) biopsy is an accurate alternative staging procedure for women with breast cancer. The goal of this study was to identify a subset of breast cancer patients in whom metastatic disease was confined only to the SLN. MATERIALS AND METHODS: From two institutions, we recruited 222 women with breast cancer for SLN biopsy. A SLN biopsy was performed in each patient, followed by an axillary dissection in 182 patients. Histologic and immunohistochemical cytokeratin stains were used on all SLNs. RESULTS: The SLN was identified in 220 (97. 8%) of the 225 biopsies. Evidence of metastatic breast cancer in the SLN was found in 60 (27.0%) of the 222 patients. Of these patients, 32 (53.3%) had evidence of tumor in the SLN only. By multivariate analysis, two factors were found to be significantly associated with a higher likelihood of tumor involvement in the non-SLNs: primary tumor size larger than 2.0 cm (P =.0004) and macrometastasis (> 2.0 mm) in the SLN (P =.002). Additional analysis revealed that none (0%; 95% confidence interval, 0% to 18.5%) of the 18 patients with primary tumors < or = 2.0 cm and micrometastasis to the SLN had remaining axillary lymph node involvement. CONCLUSION: The primary tumor size and metastasis size in the SLN are independent factors in predicting the incidence of tumor in the non-SLNs. Therefore, the SLN biopsy alone may be adequate for staging and/or therapy decision making in patients with primary breast tumors < or = 2.0 cm and micrometastasis in the SLN.

Oligodendrogliomas: reproducibility and prognostic value of histologic diagnosis and grading.

Prognostic value of histological grading of oligodendroglial tumors is controversial and interobserver reproducibility in grading of these tumors is unknown. Seven neuropathologists and 6 surgical pathologists experienced in brain tumor-diagnosis assessed 124 oligodendroglial tumors operated at the Mayo Clinic (1960-1990). Among histologic parameters upon which current oligodendroglioma grading systems are based, only high cellularity, presence of mitoses, microcalcifications, endothelial hypertrophy, endothelial proliferation, and necrosis appeared to be reproducible. Reproducible histologic features, based on consensus ratings among neuropathologists (defined as > 60%), were evaluated for the association with cause-specific survival by fitting Cox regression models. By univariate analysis, a significant association with survival was found for age, high cellularity, presence of mitoses, endothelial hypertrophy and proliferation and necrosis. On multivariable analysis with a stepwise variable selection method, only age and presence of endothelial proliferation were found to be independently associated with survival with a discriminatory index of the model of 0.68. Mitotic index was significantly associated with survival based on the grading from each separate neuropathologist, but it was not based on consensus, most likely because this was classified as indeterminate in 54% of cases. Alternatively, "models fit" considering the assessment of single neuropathologists, identified a model based on age and on mitotic index with similar discriminatory indices of 0.69-0.7. Our study found few factors independently associated with cause specific-survival among morphological parameters. These findings are consistent with the present WHO stratification of oligodendrogliomas into low- and high-grade variants.

Deciduoid peritoneal mesothelioma. An unusual phenotype affecting young females.

Two cases of malignant peritoneal mesothelioma are reported. These tumors affected young women and displayed an unusual histopathologic pattern that closely simulated exuberant, ectopic decidual reaction or at least a malignant counterpart thereof. The importance of the differential diagnosis from decidual reaction is emphasized because decidua-like mesothelioma appears to be a highly malignant neoplasm. The cause of this lesion is unknown; and, considering the young age of the patients and the failure to demonstrate hormone receptors in the neoplastic cells, it is unlikely that asbestos exposure or hormonal imbalance played any role in the development of the disease.

Polymorphous hemangioendothelioma: a report of two cases, one affecting extranodal soft tissues, and review of the literature.

Polymorphous hemangioendothelioma (PH) is a rare vascular neoplasm occurring in lymph nodes. It has been considered a borderline malignant tumor, mainly because of a local recurrence in one of the three cases described to date. This report adds two additional cases, one in which the tumor was extranodal. An extensive immunohistochemical study and thorough literature review were undertaken. The patients, a 55-year-old man and a 28-year-old man, both asymptomatic, presented with tumors involving a left pulmonary hilar lymph node (3 cm) and the soft tissues of the left paravertebral region (4 cm), respectively. The tumors were composed of an admixture of solid, primitive vascular and ectatic angiomatous components, with both elements formed by uniform, polygonal cells. In one case, the cells marked for CD31 and factor VIII, and the other case was positive for CD34. Neither case marked for epithelial membrane antigen and keratin. One tumor partially replaced a lymph node, and no nodal tissue was identified in the other. Of the three previously reported cases of nodal PH, one had recurring and metastatic behavior. PH is a rare, malignant vascular neoplasm that most frequently involves lymph nodes, but it can also affect extranodal locations.

Serous borderline tumor of the paratestis: a report of seven cases.

We report the clinical, morphologic, immunophenotypic, and ploidy findings of seven cases of serous borderline tumor of the paratestis. Mean patient age was 56 years (range, 14-77 years), and the clinical presentation was that of a testicular mass. Tumors ranged in size from 1 to 6 cm (mean, 3.5 cm). Six tumors arose from the tunica albuginea, and two of these tumors were intratesticular. One tumor arose from the tunica vaginalis. Serous borderline tumor of the paratestis is histologically identical to its ovarian counterpart. The tumors were cystic with numerous intracystic blunt papillae lined by stratified epithelial cells with minimal to mild cytologic atypia. Psammoma bodies were present in two cases. In all cases, the neoplastic cells stained strongly and diffusely for cytokeratin 7, estrogen receptor, and CD15, and six of seven cases were positive for progesterone receptor and MOC-31. The cells did not stain for cytokeratin 20, carcinoembryonic antigen, calretinin, and HER2/neu. Proliferative activity, as assessed by MIB-1 staining, ranged from 1.3% to 10% (mean, 5.5%). Five of six tumors were diploid, and one was tetraploid. Patients were treated by radical orchiectomy and followed up from 4 months to 18 years (mean, 48 months; median, 8.5 months). No recurrences or metastases occurred. Serous borderline tumor of the paratestis is morphologically and immunophenotypically identical to ovarian serous borderline tumor. To date, no serous borderline tumor of the paratestis reported in the literature or in our series has recurred or metastasized after resection.

Endometrial cancer in Olmsted County, MN: trends in incidence, risk factors and survival.

PURPOSE: We updated an earlier study in this community from 1945-1974 in order to assess trends in the incidence of, risk factors for, and survival from endometrial cancer in 1975-1991. METHODS: Incidence rates were based on all new cases of endometrial cancer diagnosed among Olmsted County, Minnesota, women during the years 1975-1991, with the population denominator from decennial census data. Risk factors were assessed with conditional logistic regression comparing the incidence cases to age- and gender-matched controls with intact uteri seen the same year the case was diagnosed. Survival was assessed using the Kaplan-Meier method. RESULTS: The incidence of endometrial cancer (age-adjusted to 1970 United States total) in 1975-1991 was 14.3 per 100,000 person-years, which is slightly increased from 1965-74. The rate was 21.7 per 100,000 person-years after adjustment for hysterectomy prevalence. As in the previous study, conjugated estrogen use for six months or more (odds ratio [OR] 2.71; 95% confidence interval [CI] 1.14-6.46) and body mass index (OR 1.06; 95% CI 1.01-1.11) increased the risk of endometrial cancer. The five-year relative survival rate (82%) was not improved over the earlier study. CONCLUSIONS: A small increase in endometrial cancer incidence was linked to the same risk factors identified in an earlier study in this community. No improvement in survival was seen.

The epidemiology of ovarian cancer: a population-based study in Olmsted County, Minnesota, 1935-1991.

PURPOSE: To determine trends in incidence and survival between 1935 and 1991 and to evaluate risk factors for ovarian cancer among Olmsted County, Minnesota women. METHODS: All newly diagnosed cases of ovarian cancer among Olmsted County women in 1975-1991 were identified using the medical records linkage system of the Rochester Epidemiology Project. In order to assess trends, incidence rates in the subset of Rochester women were compared with Rochester rates for 1935-1974. Survival was evaluated by the Kaplan-Meier product-limit method. A case-control analysis of risk factors compared Olmsted County women with invasive epithelial ovarian cancer and an age-matched group of women from the community by logistic regression. RESULTS: Altogether, 129 Olmsted County women were newly diagnosed with ovarian cancer in 1975-1991. The age-adjusted (to 1970 United States whites) incidence rate was 22.5 per 100,000 person-years. Median survival from initial diagnosis was 3.7 years. Compared to an equal number of controls, the 103 women with invasive epithelial disease were more likely to be nulliparous (odds ratio [OR] 1.9; 95% CI 0.95-3.9) but less likely to have a history of thyroid disease (OR 0.4; 95% CI 0.2-0.8), hypertension (OR 0.4; 95% CI 0.1-0.9) or nonsteroidal estrogen use (OR 0.5; 95% CI 0.2-0.9). Prior hysterectomy (OR 0.5; 95% CI 0.2-0.9) and unilateral oophorectomy (OR 0.2; 95% CI 0.04-0.7) were also associated with reduced risk. CONCLUSION: The incidence of ovarian cancer in this community in 1975-1991 was little changed from rates 20 years earlier. There has been some improvement in survival from ovarian cancer in this population compared to 1935-1974, but still less than 50% survive for 5 years. Prior hysterectomy and unilateral oophorectomy appear protective for ovarian cancer.

Overexpression of p34cdc2 protein kinase in epithelial ovarian carcinoma.

OBJECTIVE: To investigate the role of expression of p34cdc2 protein kinase in normal, benign, and malignant ovarian epithelium. MATERIAL AND METHODS: Tissue sections from 24 patients with epithelial ovarian carcinoma (EOC) along with 6 normal ovarian specimens and 12 benign cystadenomas were incubated with mouse IgG monoclonal antibody to human p34cdc2 protein kinase, followed by detection with use of a standard peroxidase-labeled streptavidin-biotin technique. Immunohistochemical staining was graded and compared. Clinical data were also reviewed. RESULTS: Normal surface epithelium and 10 of 12 benign cystadenomas failed to stain for p34cdc2 protein kinase. Of the 24 EOC specimens, however, 19 (79%) stained positively. The staining pattern or intensity was not associated with the histologic grade or surgical stage. CONCLUSION: Expression of p34cdc2 protein kinase is strongly up-regulated in most cases of EOC but not in normal epithelial ovarian tissue or in most cases of benign epithelial tumors evaluated. Therefore, it may be associated with early events in carcinogenesis. Redundant overexpression of cyclin-dependent kinases such as p34cdc2 may contribute to deranged cell cycle progression and proliferation of EOC. Observation of overexpression of p34cdc2 protein kinase in other malignant lesions suggests a common mechanism.

Intracardiac leiomyomatosis: echocardiographic features.

Intravenous leiomyomatosis is a histologically benign smooth-muscle tumor arising from either a uterine myoma or the walls of a uterine vessel with extension into veins. Echocardiographic features of two cases of intravenous leiomyomatosis with extensive spread into the right-sided cardiac chambers and pulmonary arteries are described. Both patients were middle-aged women, with prior history of hysterectomy 12 and 10 years earlier who presented with cardiac symptoms and signs. Distinctive echocardiographic features include 1) elongated mobile masses extending from the veins of the lower body, including inferior vena cava and azygos vein; 2) multiple venous attachments or metastases; and 3) filling of venous vessels and right-heart chambers. Intracardiac leiomyomatosis should be considered in a female patient presenting with an extensive mass in the right-sided cardiac chambers.

Fluorescence in situ hybridization analysis of trisomy 12 in ovarian tumors.

Conventional cytogenetic studies have suggested that trisomy 12 may be a characteristic nonrandom numerical chromosome anomaly in benign ovarian tumors, particularly sex cord-stromal tumors. To confirm this finding, and to avoid possible culture artifact introduced during cytogenetic analysis, the authors performed fluorescence in situ hybridization (FISH) in paraffin-embedded samples of select ovarian neoplasms. Forty-four ovarian fibromas and granulosa cell tumors and 31 benign and borderline epithelial ovarian tumors were examined for the presence of trisomy 12. Trisomy 12 was detected in 40% (8 of 20) of the fibromas. No evidence of trisomy 12 was present in 24 granulosa cell tumors, although 1 granulosa cell tumor was tetrasomic for chromosome 12. Trisomy 12 was found in 27% (3 of 11) of the serous borderline tumors, but was not observed in any of the benign epithelial tumors (13 serous and 7 mucinous cystadenomas). These results confirm that trisomy 12 occurs in a significant proportion of fibromas. However, the incidence of trisomy 12 in granulosa cell tumors is far lower than suggested by previous studies. These results, in conjunction with those of previous cytogenetic reports, suggest that trisomy 12 is rare in benign epithelial ovarian tumors, but occurs fairly commonly as a sole anomaly in borderline epithelial tumors. Further investigation is necessary to establish the significance of trisomy 12 in the pathogenesis of these tumors.