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Purpose: Women with BRCA1/2 gene mutations who have completed their childbearing are strong candidates for risk-reducing prophylactic bilateral salpingo-oophorectomy (PBSO). The aim of the current study was to identify baseline predictors of PBSO versus gynecologic screening (GS) in this group of high-risk women., Patients and Methods: Baseline questionnaires were available from 160 BRCA1/2 carriers who participated in a nationwide, longitudinal, observational study of the psychosocial consequences of prophylactic surgery versus periodic screening. Topics addressed by the questionnaire included generic quality of life, cancer-specific distress, risk perception, knowledge of ovarian cancer, and perceived pros and cons of surgery versus screening. PBSO use during the 12-month period after the first gynecologic consultation was determined on the basis of medical record data., Results: During the 12-month follow-up period, 74% of women had undergone PBSO, and 26% opted for screening. Statistically significant multivariate predictors of PBSO included education, general health perceptions, perceived incurability of ovarian cancer, and perceived benefits of surgery., Conclusion: Women with lower educational levels, with poorer general health perceptions, who view ovarian cancer as an incurable disease, and who believe more strongly in the benefits of surgery are more likely to undergo PBSO. Clinicians should ensure that high-risk women are well informed about the low predictive value of GS techniques and about the lethal threat posed by ovarian cancer because of its limited curability.

Purpose: The aim of this study was to evaluate efficacy of gynecologic examination under general anesthesia with cervical biopsies after (chemo) radiation for cervical cancer to identify patients with residual disease who may benefit from salvage surgery., Methods and Materials: In a retrospective cohort study data of all cervical cancer patients with the International Federation of Gynecology and Obstetrics (FIGO) Stage IB1 to IVA treated with (chemo) radiation between 1994 and 2001 were analyzed. Patients underwent gynecologic examination under anesthesia 8 to 10 weeks after completion of treatment. Cervical biopsy samples were taken from patients judged to be operable. In case of residual cancer, salvage surgery was performed., Results: Between 1994 and 2001, 169 consecutive cervical cancer patients received primary (chemo) radiation, of whom 4 were lost to follow-up. Median age was 56 years (interquartile range [IQR], 44-71) and median follow-up was 3.5 years (IQR, 1.5-5.9). In each of 111 patients a biopsy sample was taken, of which 90 (81%) showed no residual tumor. Vital tumor cells were found in 21 of 111 patients (19%). Salvage surgery was performed in 13 of 21 (62%) patients; of these patients, 5 (38%) achieved long-term, complete remission after salvage surgery (median follow-up, 5.2 years; range, 3.9-8.8 years). All patients with residual disease who did not undergo operation (8/21) died of progressive disease. Locoregional control was more often obtained in patients who underwent operation (7 of 13) than in patients who were not selected for salvage surgery (0 of 8 patients) (p < 0.05)., Conclusions: Gynecologic examination under anesthesia 8 to 10 weeks after (chemo) radiation with cervical biopsies allows identification of those cervical cancer patients who have residual local disease, of whom a small but significant proportion may be salvaged by surgery.

Objective: To analyze patterns and frequency of recurrences of squamous cell carcinoma (SCC) of the vulva after wide local excision (WLE) and superficial inguinal lymphadenectomy with separate incisions and to identify prognostic factors for the development of recurrences., Methods: Between January 1985 and December 1999, all 125 consecutive patients with primary SCC of the vulva, treated with WLE and superficial inguinal lymphadenectomy, were retrospectively analyzed. Recurrences were registered by localization as: local, skin bridge, groin or distant., Results: A local recurrence was diagnosed in 29 (23%) patients, 11 (9%) developed a groin and 4 (3%) a distant recurrence. No skin bridge recurrences were identified. The 5 years local relapse-free survival was 70%. After a first local recurrence, 72% of these patients developed a second local recurrence. Adjusted for other predictors, older age (>74 years) is an independent risk factor for local recurrences (HR: 2.38; 95%-C.I.: 1.08-5.23) and stage III/IV cancer for developing groin/distant recurrences (HR: 3.03; 95%-C.I.: 1.0-9.18)., Conclusion: WLE and superficial inguinal lymphadenectomy with separate incisions result in a high groin recurrence rate in this study; superficial lymphadenectomy should be replaced by deep inguinofemoral lymphadenectomy. After a local recurrence, 72% of the patients developed a second local recurrence. These patients are at high risk and need a close follow-up.

Purpose: Preventive health strategies for women at increased hereditary risk of ovarian cancer include gynecologic screening (GS) and/or prophylactic oophorectomy (PBSO). Hormone replacement therapy (HRT) is often prescribed to compensate for postsurgical endocrine deficiencies. This study examined the impact of HRT use on levels of endocrine symptoms and sexual functioning among premenopausal women who have undergone PBSO. Comparisons were made with similar women undergoing GS., Patients and Methods: Questionnaire data on endocrine symptoms and sexual functioning were obtained from 450 premenopausal, high-risk women who had participated in this nationwide, cross-sectional, observational study., Results: Thirty-six percent of women had undergone PBSO and 64% had opted for GS. In the PBSO group, 47% of the women were current HRT users. They reported significantly fewer vasomotor symptoms than nonusers (P < .05). However, compared with premenopausal women undergoing GS, oophorectomized HRT users were more likely to report vasomotor symptoms (P < .01). HRT users and nonusers reported comparable levels of sexual functioning. Compared with women in the GS group, oophorectomized HRT users reported significantly more sexual discomfort due to vaginal dryness and dyspareunia (P < .01)., Conclusion: Although HRT has a positive impact on surgically induced vasomotor symptoms, it may be less effective than is often assumed. Symptom levels remain well above those of premenopausal women undergoing screening, and sexual discomfort is not alleviated by HRT. Physicians need to provide younger high-risk women considering PBSO with realistic information about both benefits and drawbacks of this preventive strategy, including information about premature menopause and HRT.

Objectives: A literature search was conducted to gather information concerning the pathophysiologic mechanisms leading to hot flushes, their prevalence and severity in breast cancer patients, their influence on quality of life, and the best therapeutic option., Methods: Relevant studies in English were selected from Medline., Results and Conclusion: Pathophysiologic mechanisms leading to hot flushes are poorly understood. Estrogen withdrawal is considered to have a central role. Also, serotonin and norepinephrine seem to be involved in hot flush induction. Menopause induced by chemotherapy or ovarian ablation, is accompanied by an abrupt decrease in estrogen level, causing vasomotor symptoms. Hot flushes are also a side effect of tamoxifen and aromatase inhibitors. Quality of life in breast cancer patients may be negatively influenced by hot flushes, and therefore, adequate treatment is important. Currently, of the several non-hormonal options, the selective serotonin-reuptake inhibitor (SSRI) venlafaxine is the most effective in breast cancer patients. However, studies on interaction between SSRIs and tamoxifen may influence future recommendations.

Purpose: Recommendations for women at high risk of ovarian cancer include periodic gynecologic screening (GS) and prophylactic bilateral salpingo-oophorectomy (PBSO). The aim of the current study was to determine the quality-of-life (QOL) effects of PBSO versus GS., Patients and Methods: Questionnaire data were obtained from 846 high-risk women who had participated in this nationwide, cross-sectional, observational study. Forty-four percent of the women had undergone PBSO, and 56% had opted for GS. Topics addressed by the questionnaire included generic QOL, cancer-specific distress, endocrine symptoms, and sexual functioning., Results: No statistically significant between-group differences were observed in generic QOL (Short Form-36), with women in both the PBSO and GS groups scoring similarly to the general population. Compared with GS, PBSO was associated with fewer breast and ovarian cancer worries (P < .001) and more favorable cancer risk perception (P < .05). However, the PBSO group reported significantly more endocrine symptoms (P < .001) and worse sexual functioning (P < .05) than the GS group. Eighty-six percent of women would choose PBSO again, and 63% would recommend it to a friend with familial risk of ovarian cancer., Conclusion: PBSO had no measurable adverse impact on generic QOL of high-risk women. The favorable effects of PBSO in terms of reduced cancer worries and low perceived cancer risk need to be weighed against the increase in endocrine and sexual symptoms. Balanced information will help clinicians and high-risk women to make informed decisions about the optimal preventive health strategy.

Purpose of Investigation: To evaluate whether lymphvascular space involvement (LVSI) is a risk factor for relapse of disease and lymph node metastasis in endometrial cancer., Methods: From 1978 till 2003, 609 patients with epithelial endometrial cancer were treated at the Groningen University Medical Center. The association of LVSI and relapse of disease was evaluated in the total group of 609 patients and in a 'low' and 'high' risk stage I endometrial cancer group. In 239 surgically staged patients, the relation of LVSI and lymph node metastasis was investigated., Results: The median age at diagnosis was 63 years (range 27-92 years) with a median follow-up of 58 months (range 0-236 months). More than half of the patients (56%) received adjuvant radiotherapy. LVSI was present in 123 patients (25,6%), and a prognostic factor for relapse of disease (multivariate analysis, P < 0.0001). In the 'low' and 'high' risk stage I endometrial cancer patients an increase of 2.6 times in relapse of disease was observed in the presence of LVSI. LVSI positive tumors were more likely to have metastasized to the pelvic lymph nodes (multivariate analysis, P = 0.001). In patients with proven negative nodes, LVSI was a prognostic factor for relapse of disease (univariate analysis, P = 0.02)., Conclusion: LVSI is a predictor of nodal disease and an independent prognostic factor for relapse of disease in all stages of endometrial cancer. Patients with stage I endometrial cancer with positive LVSI are at risk for relapse of disease and might therefore benefit from adjuvant therapy., Content: The presence of lymphvascular space involvement (LVSI) in endometrial cancer is significantly and independently associated with an increased risk of pelvic lymph node metastases and/or relapse of disease.

Purpose: To prevent morbidity associated with double modality treatment, early-stage cervical cancer patients should only be offered surgery when there is a low likelihood for adjuvant radiotherapy. We analyzed whether serum squamous cell carcinoma antigen (SCC-ag) analysis allows better preoperative identification of patients with a low likelihood for adjuvant radiotherapy than currently used clinical parameters., Patients and Methods: In a cohort study, International Federation of Gynecology and Obstetrics (FIGO) stage, tumor size, and preoperative serum SCC-ag levels, as determined by enzyme immunoassay, were related to the frequency of postoperative indications for adjuvant radiotherapy in 337 surgically treated, FIGO stage IB/IIA, squamous cell cervical cancer patients., Results: In patients with normal preoperative SCC-ag, 16% of IB1 and 29% of IB2/IIA had postoperative indications for adjuvant radiotherapy, in contrast to 57% of IB1 and 74% of IB2/IIA patients with elevated (> 1.9 ng/mL) serum SCC-ag (P < .001). Serum SCC-ag was the only independent predictor for a postoperative indication for radiotherapy (odds ratio, 7.1; P < .001). Furthermore, in IB1 patients that did not have indications for adjuvant radiotherapy, 15% of patients with elevated preoperative serum SCC-ag levels recurred within 2 years, compared with 1.6% of patients with normal serum SCC-ag levels (P = .02)., Conclusion: In early-stage cervical cancer, determination of serum SCC-ag levels allows more refined preoperative estimation of the likelihood for adjuvant radiotherapy than current clinical parameters, and simultaneously identifies patients at high risk for recurrence when treated with surgery only. The role of preoperative serum SCC-ag in the management of patients with early-stage cervical cancer deserves further investigation.

Purpose: To determine the frequency of mismatch repair (MMR) gene germline mutations in endometrial cancer patients who were diagnosed at less than 50 years of age; to relate the presence of mutations to family history, histopathologic data, presence of tumor microsatellite instability (MSI), and immunostaining; and to formulate criteria for genetic testing in these patients., Patients and Methods: Endometrial cancer patients (N = 58), who were diagnosed at less than 50 years of age, were included and questioned about their family history. Mutation analysis of the MLH1, MSH2, and MSH6 genes was performed (denaturing gradient gel electrophoresis and sequence analysis to detect small mutations and multiplex ligation-dependent probe amplification to detect large deletions or duplications). For MSI analysis, five consensus markers were used, and immunostaining of the three MMR proteins was performed., Results: In five of 22 patients with a positive first-degree family history for hereditary nonpolyposis colorectal cancer (HNPCC)-related cancers, pathogenic germline mutations were found (one MLH1, three MSH2, and one MSH6). Four mutation carriers belonged to families fulfilling the revised Amsterdam criteria. No mutations were found in the 35 patients without such family history (P =.006). MSI was detected in 20 of 57 cancers, among which four were from mutation carriers. In 23 of 51 cancers, one or more MMR protein was absent; in all five mutation carriers, immunostaining indicated the involved MMR gene., Conclusion: In 23% of the young endometrial cancer patients with at least one first-degree relative with an HNPCC-related cancer, an MMR gene mutation was detected. Therefore, presence of an HNPCC-related cancer in a first-degree relative seems to be an important selection criterion for mutation analysis. Subsequent immunostaining of MMR proteins will point to the gene(s) that should be analyzed.

Objective: In hereditary nonpolyposis colorectal cancer (HNPCC), women with a mismatch repair (MMR) gene mutation have a cumulative lifetime risk of 25-50% for endometrial cancer and 8-12% for ovarian cancer. Therefore, female members of HNPCC families are offered an annual gynecologic and transvaginal ultrasound (TVU) examination and serum level CA 125 analysis. The aim of the present study was to evaluate our 10-year experience with this screening program., Methods: Women who are MMR gene mutation carriers or who fulfil the Amsterdam criteria were identified from our HNPCC database. Information concerning the screening program was retrospectively collected from patient files., Results: Forty-one women, 35 premenopausal and 6 postmenopausal, were enrolled in the program with a median follow-up of 5 years (range 5 months-11 years). In 197 patient years at risk, 17 of 179 TVUs gave reason for endometrial sampling. Three premalignant lesions, with complex atypical hyperplasia, were discovered. One interval endometrial cancer was detected as a result of clinical symptoms. No abnormal CA 125 levels were measured and no ovarian cancers were detected., Conclusions: These results demonstrate that gynecologic screening allows the detection of premalignant lesions of the endometrium but also illustrate that recognition and reporting of clinical symptoms by the women themselves is of utmost importance.

Background: The objective of this study was to determine whether modifications in the treatment of patients with vulvar carcinoma influence the rates of recurrence and survival., Methods: Between 1982 and 1997, 253 patients with T1 and T2 invasive squamous cell carcinoma of the vulva were treated by essentially the same team of gynecologic oncologists, and 168 patients (Group I) underwent radical vulvectomy with en bloc inguinofemoral lymphadenectomy. Standard therapy was changed in 1993, and 85 patients (Group II) underwent wide local excision with inguinofemoral lymphadenectomy through separate incisions. The rates of recurrence and survival were compared between both groups., Results: In Group II, the overall recurrence rate (33.3%) within 4 years was increased compared with Group I (19.9%; P = 0.03). In Group II, 5 of 79 patients (6.3%) developed fatal groin or skin bridge recurrences compared with 2 of 159 patients (1.3%) in Group I (P = 0.029); this did not result in a difference in overall survival. In Group II, 40 of 79 patients had tumor free margins measuring 8 mm, resulting in no local recurrences (P = 0.002)., Conclusions: The current study showed that fatal recurrences in either the groin or the skin bridge were more frequent after wide local excision and inguinofemoral lymphadenectomy through separate incisions; however, probably due to lack of power, this did not result in shorter survival. In 40 of 79 patients, the histologic margins measured

Background: The objective of this study was to evaluate the author's recent, preliminary experience with the sentinel lymph node procedure in patients with vulvar melanoma and to compare this experience with treatment and follow-up of patients with vulvar melanomas who were treated previously at their institution., Methods: From 1997, sentinel lymph node procedure with the combined technique (99mTechnetium-labeled nanocolloid and Patente Blue-V) was performed as a standard staging procedure for patients with vulvar melanoma with a thickness > 1 mm and no clinically suspicious inguinofemoral lymph nodes. For the current study, clinicopathologic data from all 33 patients with vulvar melanoma who were treated between 1978 and 2000 at the University Hospital Groningen were reviewed and analyzed., Results: From January 1997 until December 2000, identification of sentinel lymph nodes was successful in all nine patients who were referred for treatment of vulvar melanoma. Three patients underwent subsequent complete inguinofemoral lymphadenectomy because of metastatic sentinel lymph nodes. In follow-up, groin recurrences (in-transit metastases) occurred in two of nine patients, both 12 months after primary treatment. Both patients had melanomas with a thickness > 4 mm and previously had negative sentinel lymph nodes. There was a trend toward more frequent groin recurrences in patients after undergoing the sentinel lymph node procedure (2 of 9 patients) compared with 24 historic control patients (0 of 24 patients; P = 0.06). Five of 33 patients developed local recurrences: Two patients had groin recurrences, and 11 patients developed distant metastases. Twelve patients died of vulvar melanoma. Seventeen patients with a median follow-up of 66 months (range, 9-123 months) are currently alive (overall survival rate, 52%)., Conclusions: Although the numbers were small, this study showed that the sentinel lymph node procedure is capable of identifying patients who have occult lymph node metastases and who may benefit from lymphadenectomy for locoregional control and prevention of distant metastases. However, the data also suggest that the sentinel lymph node procedure may increase the risk of locoregional recurrences (in-transit metastases), especially in patients with thick melanomas. The potential role of the sentinel lymph node procedure as an alternative method of lymph node staging in patients with vulvar melanoma needs further investigation only within the protection of clinical trials and probably should be restricted to patients with melanomas with intermediate thickness (1-4 mm).