Survivors of gynecologic malignancies: impact of treatment on health and well-being.

PURPOSE: While overall survival from gynecologic malignancies has greatly improved over the last three decades, required treatments can lead to multiple health issues for survivors. Our objective was to identify health concerns that gynecologic cancer survivors face. METHODS: A systematic, stratified sample of women with gynecologic malignancies was surveyed for 18 health issues occurring before, during, or after treatment. The impact of clinical features and treatment modality on health issues was assessed through multivariate logistic regression models. RESULTS: Of 2,546 surveys mailed, 622 were not received by eligible subjects secondary to invalid address, incorrect diagnosis, or death. Thus, 1924 survivors potentially received surveys. Of the 1,029 surveys (53.5%) completed, median age was 59 years; diagnoses included 29% cervical, 26% endometrial, 26% ovarian/primary peritoneal/fallopian tube, 12.1% vulvar, and 5.4% vaginal cancers. The most frequently reported health issues included fatigue (60.6%), sleep disturbance (54.9%), urinary difficulties (50.9%), sexual dysfunction (48.4%), neurologic issues (45.4%), bowel complaints (42.0%), depression (41.3%), and memory problems (41.2%). These rankings were consistent with patients' self-reported rankings of "highest impact" personal issues. After controlling for demographic and clinical variables, multivariate analyses revealed that treatment modality impacted the odds of experiencing a given health issue. CONCLUSIONS: Our study demonstrates that gynecologic cancer survivors experience a high frequency of health conditions and highlights the association between treatment modality and specific health concerns. IMPLICATIONS FOR CANCER SURVIVORS: The study findings highlight the multiple health concerns experienced by gynecologic cancer survivors and suggest the potential for developing interventions to mitigate these concerns in survivorship.

Neuroendocrine tumors in the ovary: histogenesis, pathologic differentiation, and clinical presentation.

OBJECTIVE: Primary neuroendocrine tumors in the ovary are rare. These tumors arise from the neuroendocrine cell system of ovarian stroma and surface epithelium, and may also arise from teratoma. We present four primary ovarian neuroendocrine tumors and compare clinicopathologic findings based on tumor histogenesis and site of origin. DESIGN: Four primary ovarian neuroendocrine tumors were identified from our 10-year departmental archives. H&E slides and immunostains were reviewed and the diagnoses were confirmed. Clinical history, imaging studies, and follow-up data were obtained from medical records. RESULTS: Patients' ages ranged from 26 to 63. All patients presented with abdominal discomfort and unilateral or bilateral ovarian masses. MRI and CT scans from cases 1 and 2 revealed a solid ovarian mass with no extra-ovarian extension. In case 1, the patient also had a cystic mass in the opposite ovary and an elevated urine 5-HIAA. Microscopically, case 1 revealed a well-differentiated carcinoid tumor with no surface epithelial involvement, and a mature teratoma in the contralateral ovary. Case 2 revealed a stromal carcinoid within the ovarian parenchyma. Imaging studies from cases 3 and 4 showed large complex masses with peritoneal implants and ascites. In both cases 3 and 4, tumor grossly involved both ovarian parenchyma and surface epithelium with multiple pelvic implants. In addition, liver metastases were present in case 4. Microscopically, these tumors were poorly differentiated carcinoma with neuroendocrine differentiation. Histologic sections revealed extensive necrosis, and both cases showed positivity for neuroendocrine markers. CONCLUSIONS: Primary neuroendocrine tumors in the ovary are rare and consist of a group of heterogeneous malignancies that express similar immunohistochemical markers. Primary neuroendocrine tumors that are limited to the ovarian parenchyma often arise from ovarian stroma and teratoma, and are carcinoid tumors with a good prognosis. Neuroendocrine tumors that arise from surface epithelium or dedifferentiate from de novo carcinoma often involve both ovarian stroma and surface epithelium and clinically present as aggressive malignancies with poor prognoses.

Satisfaction with ovarian carcinoma risk-reduction strategies among women at high risk for breast and ovarian carcinoma.

BACKGROUND: Women who are at high risk for breast and ovarian cancer have 2 major management options to reduce their risk of ovarian cancer: periodic screening (PS) or risk-reducing salpingo-oophorectomy (RRSO). Little is known regarding patient satisfaction levels with risk-reduction strategies. Thus, the authors sought to determine levels of patient satisfaction with PS versus RRSO and to identify factors that may influence satisfaction. METHODS: As part of a larger study, women who received testing for the breast cancer genes BRCA1 and BRCA2 were sent a follow-up questionnaire packet to explore issues related to cancer risk reduction. The authors report on the results from a variety of validated instruments, including the Satisfaction With Decision (SWD) scale, focused on the choice between PS and RRSO. RESULTS: In total, 544 surveys were mailed, and 313 responses were received (58%). The overall satisfaction rate among respondents was high. The median SWD score was significantly higher in the RRSO group compared with the PS group (P < .001). BRCA mutation carriers had higher median SWD scores regardless of management type (P = .01). Low satisfaction scores were associated with high levels of uncertainty and the perception that the decision between PS and RRSO was difficult to make (P = .001). Satisfaction was unrelated to demographics, clinical factors, or concerns of cancer risk. CONCLUSIONS: In the current study, the majority of women who were at high risk for breast and ovarian cancer were satisfied with their choice of risk-reduction strategy. Difficulty with decision making was associated with lower satisfaction levels. Improved education and support through the decision-making process may enhance overall levels of satisfaction.

A phase II trial of paclitaxel and carboplatin in women with advanced or recurrent uterine carcinosarcoma.

BACKGROUND: Systemic therapy for advanced uterine carcinosarcoma (CS) has been disappointing. The most widely studied regimen is ifosfamide and cisplatinum. Moderate success has been documented using paclitaxel in ovarian CS. The purpose of this study was to evaluate carboplatin/paclitaxel in advanced and recurrent uterine CS. METHODS: A single-arm, prospective, phase II trial opened in October 2001. Primary end points were time to progression (TTP) and response rate (RR). Quality-of-life data were obtained. Patients treated adjuvantly received 6 cycles of carboplatin/paclitaxel every 21 days. Patients with disease at study entry were treated until response, progression, or toxicity. RESULTS: Of 23 patients enrolled, 9 received adjuvant treatment, 13 had documented disease, 1 was inevaluable. Eight of 13 patients with measurable disease had a complete or partial response (62% RR). Overall, median TTP was 9.5 months. In the adjuvant group, median TTP was 15 months. With measurable disease, median TTP was 7.9 months. Median overall survival was 21.1 months. There was no difference in survival between patients with or without measurable disease. For patients having prior radiation, median TTP with recurrence in the radiated field was 13.3 months, and 14.5 months if outside the field (P = 0.71). Two patients (9%) had treatment-limiting toxicity. Quality-of-life scores improved from baseline over time. CONCLUSIONS: Carboplatin and paclitaxel have improved tolerability and RR (62%) compared with previous reports of ifosfamide/cisplatin or ifosfamide/paclitaxel in treating uterine CS. This regimen seems promising and should be considered in combined therapies with targeted agents.

Improved survival in non-Ashkenazi Jewish ovarian cancer patients with BRCA1 and BRCA2 gene mutations.

OBJECTIVES: Previous studies report a survival advantage in ovarian cancer patients with Ashkenazi Jewish (AJ) breast cancer gene (BRCA) founder mutations. The purpose of this study was to determine if this association exists in patients with non-Ashkenazi Jewish (non-AJ) BRCA mutations. We also sought to account for "survival bias" by minimizing lead time that may exist between diagnosis and genetic testing. METHODS: Patients with stage III/IV ovarian cancer and a non-AJ BRCA mutation, seen between January 1996 and July 2007, were identified from eight institutions. Patients with sporadic ovarian cancer were compared to similar cases, matched by age, stage, year of diagnosis, and vital status at time interval to BRCA testing. Progression-free (PFS) and overall survival (OS) were calculated by the Kaplan-Meier method. Multivariate Cox proportional hazards models were calculated for variables of interest. Fisher's exact test and chi-square were also used for analysis. RESULTS: Ninety-five advanced stage ovarian cancer patients with non-AJ BRCA mutations and 183 sporadic controls were analyzed. Compared to sporadic ovarian cancer patients, non-AJ BRCA patients had longer PFS (27.9 months vs. 17.9 months, HR 0.61 [95% CI 0.43-0.86]) and OS (101.7 months vs. 54.3 months, HR 0.43 [95% CI 0.27-0.68]). BRCA status was an independent predictor of PFS and OS. CONCLUSIONS: This multicenter study demonstrates a significant survival advantage in advanced stage ovarian cancer patients with non-AJ BRCA mutations, confirming the previous studies in the Jewish population. This improved survival was evident when accounting for the "survival bias" that coincides with genetic testing.

Evaluating women with ovarian cancer for BRCA1 and BRCA2 mutations: missed opportunities.

OBJECTIVE: To estimate the incidence of genetic counseling referral for ovarian cancer patients who are at substantial risk for a BRCA1 or BRCA2 mutation. METHODS: An analysis was performed of new ovarian cancer patients who were seen at a comprehensive cancer center from January 1, 1999, through December 31, 2007. Patients at substantial (more than 20-25%) risk for a BRCA1 or BRCA2 mutation were identified and records reviewed for referral to genetic counseling. Time to referral was estimated using the Kaplan-Meier method. RESULTS: A total of 3,765 epithelial ovarian cancer patients were seen during the 9-year period. On average, 23.8% of patients met substantial-risk criteria for BRCA mutations. In 1999, only 12% of patients at substantial-risk were referred. Referral improved over time with 48% referred in 2007 (P<.001). Newly diagnosed patients were more often referred for genetic counseling than new patients with recurrent disease or those seen as second opinions. African-American women meeting substantial-risk criteria were less likely to be referred than were white or Hispanic women (P=.009). CONCLUSION: Although dictated family history was accurate, interpretation of risk for BRCA1 or BRCA2 mutations and subsequent referral to genetic counseling was poor. Although there was significant improvement over time, 50% of substantial-risk patients still were missed. Systematic efforts to identify those ovarian cancer patients at substantial risk for a BRCA1 or BRCA2 are necessary.

Molecular clustering of endometrial carcinoma based on estrogen-induced gene expression.

Identification of biomarkers potentially provides prognostic information that can help guide clinical decision-making. Given the relationship between estrogen exposure and endometrial cancer, especially low grade endometrioid carcinoma, we hypothesized that high expression of genes induced by estrogen would identify low risk endometrioid endometrial cancers. cDNA microarray and qRT-PCR verification were used to identify six genes that are highly induced by estrogen in the endometrium. These estrogen-induced biomarkers were quantified in 72 endometrial carcinomas by qRT-PCR. Unsupervised cluster analysis was performed, with expression data correlated to tumor characteristics. Time to recurrence by cluster was analyzed using the Kaplan-Meier method. A receiver operating characteristic (ROC) curve was generated to determine the potential clinical utility of the biomarker panel to predict prognosis. Expression of all genes was higher in endometrioid carcinomas compared to non-endometrioid carcinomas. Unsupervised cluster analysis revealed two distinct groups based on gene expression. The high expression cluster was characterized by lower age, higher BMI, and low grade endometrioid histology. The low expression cluster had a recurrence rate 4.35 times higher than the high expression cluster. ROC analysis allowed for the prediction of stage and grade with a false negative rate of 4.8% based on level of gene expression in endometrioid tumors. We have therefore identified a panel of estrogen-induced genes that have potential utility in predicting endometrial cancer stage and recurrence risk. This proof-of-concept study demonstrates that biomarker analysis may play a role in clinical decision making for the therapy of women with endometrial cancer.

Enhanced estrogen-induced proliferation in obese rat endometrium.

OBJECTIVE: We tested the hypothesis that the proliferative estrogen effect on the endometrium is enhanced in obese vs lean animals. STUDY DESIGN: Using Zucker fa/fa obese rats and lean control, we examined endometrial cell proliferation and the expression patterns of certain estrogen-regulated proproliferative and antiproliferative genes after short-term treatment with estradiol. RESULTS: No significant morphologic/histologic difference was seen between the obese rats and the lean rats. Estrogen-induced proproliferative genes cyclin A and c-Myc messenger RNA expression were significantly higher in the endometrium of obese rats compared with those of the lean control. Expression of the antiproliferative gene p27Kip1 was suppressed by estrogen treatment in both obese and lean rats; however, the decrease was more pronounced in obese rats. Estrogen more strongly induced the antiproliferative genes retinaldehyde dehydrogenases 2 and secreted frizzled-related protein 4 in lean rats but had little or no effect in obese rats. CONCLUSION: Enhancement of estrogen-induced endometrial proproliferative gene expression and suppression of antiproliferative gene expression was seen in the endometrium of obese vs lean animals.

Carcinoma of the lower uterine segment: a newly described association with Lynch syndrome.

PURPOSE: Endometrial carcinoma in the lower uterine segment (LUS) is a poorly described cancer that can be clinically confused with endocervical carcinoma. We performed a case-comparison study to document the clinicopathologic characteristics of LUS tumors and their association with risk factors for endometrial cancer. PATIENTS AND METHODS: The clinical records and pathology reports from women who underwent hysterectomy at our institution for endometrial or endocervical adenocarcinoma over an 11-year interval were reviewed. The LUS group consisted of women with endometrial tumors that clearly originated between the lower uterine corpus and the upper endocervix. Immunohistochemistry and microsatellite instability and MLH1 methylation assays were performed. RESULTS: Thirty-five (3.5%) of 1,009 women had endometrial carcinoma of the LUS. Compared with patients with corpus tumors, LUS patients were younger, had higher stage tumors, and had more invasive tumors. Preoperative diagnosis of the LUS tumors more frequently included the possibility of endocervical adenocarcinoma. Seventy-three percent of the LUS tumors had an immunohistochemical expression pattern typical of conventional endometrioid adenocarcinoma. Ten (29%) of 35 women with LUS tumors were confirmed to have Lynch syndrome or were strongly suspected to have Lynch syndrome on the basis of tissue-based molecular assays. CONCLUSION: The prevalence of Lynch syndrome in patients with LUS endometrial carcinoma (29%) is much greater than that of the general endometrial cancer patient population (1.8%) or in endometrial cancer patients younger than age 50 years (8% to 9%). On the basis of our results, the possibility of Lynch syndrome should be considered in women with LUS tumors.

What women with ovarian cancer think and know about genetic testing.

OBJECTIVES: Few women with ovarian cancer undergo genetic testing for the Breast and Ovarian Cancer susceptibility genes, BRCA1 and BRCA2. With the prospect of BRCA-directed therapeutics, we investigated ovarian cancer patients' knowledge and willingness to undergo genetic testing. METHODS: All ovarian cancer patients seen in the Gynecology Center of a cancer center and a private clinic were asked to complete an anonymous questionnaire regarding knowledge and willingness to undergo BRCA testing. Women who had prior genetic testing were asked not to participate. Data was analyzed using Fisher's exact test. RESULTS: Two-hundred and thirty seven ovarian cancer patients voluntarily completed the questionnaire. Fifty-five percent (131/237) of participants had not heard of BRCA testing. Of Caucasian respondents, 51% were unaware of BRCA testing, compared to 70% of Hispanic and 88% of African American respondents (p=0.008). Awareness was correlated with education (p<0.001). Eighty-nine percent of participants were willing to be tested if it would directly affect their therapy and 86.9% would be tested to benefit their family. Seventy-four percent of patients would pay 20% of the cost of testing, only 25.1% would pay in full. CONCLUSIONS: A majority of women with ovarian cancer are not aware of the availability of BRCA testing. This lack of awareness is more profound in minorities. Despite lack of knowledge, most patients would undergo testing if it would impact their care. However, cost may be a barrier. Given the willingness of patients to undergo testing and the possibility of targeted therapy, clinicians who care for these patients should work to make appropriate genetic counseling referrals.

STK15 F31I polymorphism is associated with increased uterine cancer risk: a pilot study.

OBJECTIVE: STK15 is a serine threonine kinase which assists chromosomal separation and mitotic spindle stability through interaction with the centrosome during mitosis. We hypothesized that STK15 polymorphisms might modulate the risk of uterine cancer. METHODS: We used a hospital-based case-control study to assess the association between STK15 polymorphisms and risk of uterine cancer. Cases and controls were matched on age, race, and smoking status. Two common STK15 single nucleotide polymorphisms (SNPs), F31I (T/A), and V57I (G/A), were genotyped. Odds ratios (OR) and 95% confidence intervals (CI) were obtained using unconditional logistic regression analysis. RESULTS: A total of 193 women with uterine cancer and 218 controls were genotyped for both SNPs. After adjustment for age, race, and smoking status for the F31I SNP, the homozygous variant genotype (AA) was associated with a significantly increased uterine cancer risk (OR 10.2; 95% CI 2.23-46.5). Individuals with the heterozygous genotype (TA) and a history of tobacco use also exhibited an increased risk for uterine cancer (OR 2.63; 95% CI 1.20-5.76). For the V57I SNP, neither the homozygous (AA) nor the heterozygous (GA) variant genotypes were associated with significantly altered risk for uterine cancer (OR 0.76; 95% CI 0.18-3.25 and OR 0.88; 95% CI 0.52-1.49). CONCLUSION: Our study demonstrates that STK15 F31I SNP is associated with an increased risk for uterine cancer. Confirmation of this pilot study is needed in a larger case-control population to evaluate this genetic variant with other known risk factors for uterine cancer.

Management of cervical adenocarcinoma in situ during pregnancy.

OBJECTIVE: Adenocarcinoma in situ (AIS) is a precursor of invasive disease that is being more frequently diagnosed during the reproductive years. Few reports have described the treatment of this condition in gravid women. The purpose of this study was to review our collective experience managing cervical AIS during pregnancy. STUDY DESIGN: Retrospective medical record review of all women diagnosed with AIS during pregnancy from 1995 to 2004 at 3 academic institutions. RESULTS: Eleven women with a median age of 32 years were identified. Five who received a diagnosis in the early second trimester underwent uncomplicated cold knife conization (CKC) at 14 to 19 weeks' gestation. Six patients underwent postpartum CKC. All 11 women delivered at term. One patient undergoing postpartum CKC required radical hysterectomy for stage IB1 cervical adenocarcinoma. Four subsequent pregnancies occurred among patients having fertility-sparing surgery. CONCLUSION: Management of cervical AIS during pregnancy by early second trimester CKC is safe for mother and fetus.