Apolipoprotein concentrations are elevated in malignant ovarian cyst fluids suggesting that lipoprotein metabolism is dysregulated in epithelial ovarian cancer.

SELDI-TOF MS analysis of ovarian cyst fluids revealed that peaks m/z 8696 and 8825 discriminate malignant, borderline, and benign tumors. These peaks correspond to isoforms of apoA2. ELISA demonstrates that apoA1, A2, B, C2, C3, and E cyst fluid concentrations are uncorrelated and higher in malignant ovarian tumors, but only apoA2, apoE, and age are independent classifiers of malignant ovarian tumors, yielding 55.1% sensitivity, 95% specificity, and 88.1% accuracy to discern malignant from benign and borderline tumors. These data suggest that lipoprotein metabolism is dysregulated in ovarian cancer and that apoA2 and apoE warrant further investigation as ovarian tumor biomarkers.

Ovarian cyst fluids are a cache of tumor biomarkers that include calgranulin A and calgranulin B isoforms.

SELDI-TOF MS analysis of cyst fluids identified 95 peaks that discriminate malignant, borderline, and benign ovarian tumors. Three prominent peaks, which correspond to calgranulin A (m/z 10847) and two isoforms of calgranulin B (m/z 12717 and 13294), have higher concentrations in borderline and malignant cyst fluids. Together, calgranulin A and B distinguish borderline and malignant tumors from benign tumors with 28.6% and 63.6% sensitivity for early stage disease, respectively, at 95% specificity and with 74.8% accuracy. Ovarian cyst fluids are useful for discovering discriminatory biomarkers, such as calgranulin, which may have utility for detecting, diagnosing, and biochemically classifying ovarian tumors.

Concordance of gross surgical and final fixed margins in vulvar intraepithelial neoplasia 3 and vulvar cancer.

OBJECTIVE: To prospectively evaluate the concordance of initial surgical vulvar margins and final fixed margins and to determine the amount of microscopic pathology of grossly negative margins in women with vulvar intraepithelial neoplasia (VIN) 3 or vulvar carcinoma. STUDY DESIGN: Women with VIN 3 or vulvar carcinoma undergoing surgical excision were identified. Prior to excision, acetic acid was used to highlight the lesions, and 2 sutures were placed, 1 at the edge of gross disease and another 1 cm distal from the first. After specimen removal and fixation, the distance between sutures and microscopic involvement of VIN was determined. RESULTS: Twenty-seven women were enrolled; however, only 19 had final fixed specimens that could be accurately measured. The median fixed distance of the vulvar margin was 0.85 cm (mean, 0.83; SD, 0.19) as compared to the gross, 1-cm margin (p = 0.001). Three subjects (16%) had microscopic involvement by VIN 3 in the grossly negative epithelium between the 2 sutures, but none had a positive peripheral margin. CONCLUSION: The gross surgical margin after vulvar resection is reduced by 15% when measured in its final fixed state, and a grossly negative 1-cm margin will seldom harbor significant disease.

Risk of malignancy in unilocular ovarian cystic tumors less than 10 centimeters in diameter.

OBJECTIVE: To determine the natural history and to estimate the risk of malignancy of unilocular ovarian cystic tumors less than 10 cm in diameter followed conservatively by transvaginal ultrasound. METHODS: From 1987 to 2002, 15,106 asymptomatic women at least 50 years old entered the University of Kentucky's Ovarian Cancer Screening Program and underwent initial transvaginal ultrasonography. If the screen revealed nothing abnormal, women were asked to repeat transvaginal ultrasonography yearly. If the screen revealed abnormalities, transvaginal ultrasonography was repeated in 4 to 6 weeks, along with Doppler flow ultrasonography and CA 125 testing. RESULTS: Of the 15,106 women at least 50 years old, 2763 women (18%) were diagnosed with 3259 unilocular ovarian cysts. A total of 2261 (69.4%) of these cysts resolved spontaneously, 537 (16.5%) developed a septum, 189 (5.8%) developed a solid area, and 220 (6.8%) persisted as a unilocular lesion. During this time, 27 women received a diagnosis of ovarian cancer, and ten had been previously diagnosed with simple ovarian cysts. All ten of these women, however, developed another morphologic abnormality, experienced resolution of the cyst before developing cancer, or developed cancer in the contralateral ovary. No woman with an isolated unilocular cystic ovarian tumor has developed ovarian cancer in this population. CONCLUSION: The risk of malignancy in unilocular ovarian cystic tumors less than 10 cm in diameter in women 50 years old or older is extremely low. The majority will resolve spontaneously and can be followed conservatively with serial transvaginal ultrasonography.

Predicting risk of malignancy in adnexal masses.

OBJECTIVE: To estimate the accuracy of preoperative ultrasonography, serum CA 125, and patient demographics as a means of predicting risk of malignancy in women with a ultrasonographically confirmed adnexal mass. METHODS: Tumor morphology derived from ultrasonographic images, tumor size, tumor bilaterality, serum CA 125, and patient demographics were evaluated preoperatively in 395 patients undergoing surgery from 2001 to 2008. Tumor morphology was classified as complex, solid, or cystic. Preoperative findings were compared with tumor histologic findings at the time of surgery. Multivariable classification and regression tree analysis were used to identify a group of patients at high risk of ovarian malignancy. RESULTS: One hundred eighteen patients had ovarian cancer, 13 patients had ovarian tumors of borderline malignancy, and 264 had benign ovarian tumors. Multivariable classification and regression tree analysis defined women at high risk of ovarian malignancy as those with an adnexal mass having complex or solid morphology and a serum CA 125 value greater than 35 units/mL. This definition had a positive predictive value of 84.7% and a negative predictive value of 92.4% and correctly identified 77.3% of patients with stage I and stage II ovarian cancer and 98.6% of patients with stage III and stage IV ovarian cancer. CONCLUSION: Patients with solid or complex ovarian tumors and an elevated serum CA 125 level (greater than 35 units/mL) are at high risk of ovarian malignancy. LEVEL OF EVIDENCE: II.

The search for meaning-Symptoms and transvaginal sonography screening for ovarian cancer: predicting malignancy.

BACKGROUND: The mortality rate of ovarian cancer is greater than that of all other major gynecologic malignancies. Detecting ovarian cancer at an early and curable stage long has been an objective of oncologists. Recently, it was reported that certain symptom patterns are informative for the presence of ovarian malignancy. In this article, the authors report on how symptoms and ultrasound predict ovarian malignancy. METHODS: Two hundred seventy-two women who were participating in annual transvaginal sonography (TVS) screening were selected from among 31,748 women who were enrolled. Symptom results were correlated with ultrasound and surgical pathology findings. RESULTS: TVS performed better than symptoms analysis for detecting malignancies (sensitivity, 73.3% vs 20%), and symptoms analysis performed better for distinguishing benign tumors (specificity, 91.3% vs 74.4%). The use of TVS and symptoms analysis in series resulted in poorer identification of malignancy (sensitivity, 16.7%) but improved the ability to distinguish benign tumors (specificity, 97.9%). Decisions using either symptoms or TVS combined in parallel had small increases in sensitivity (+3.3%) and had coordinated, small decreases in specificity (-5.8%). CONCLUSIONS: Symptoms did identify ovarian malignancies, but not as well as TVS. The current findings indicated that: 1) tumors that are negative by both ultrasound and a symptoms index are likely to be benign (specificity, >97%), and 2) adding symptoms information that has weight equal to the weight of ultrasound only slightly improves the discrimination of malignancy (sensitivity increase, +3.3%). Thus, a major benefit in discriminating malignancy was achieved through ultrasound, whereas the absence of symptoms in conjunction with an abnormal ultrasound (characterized by a low morphology index) indicated that the mass was benign and that surgery may not be required. Finally, informative symptoms can be expected to be absent in 80% of patients with ovarian malignancies.

The treatment of lateral T1 and T2 squamous cell carcinomas of the vulva confined to the labium majus or minus.

OBJECTIVE: To determine the pattern of lymph node metastases, recurrence rate, and survival of patients with lateral T1 and T2 squamous cell cancer (SCC) of the vulva treated by radical vulvectomy or hemivulvectomy and inguinal lymphadenectomy. METHODS: An institutional review was performed to identify lateral T1 and T2 SCC of the vulva confined to the labium majus and minus. RESULTS: Sixty-one patients with lateral T1 and 61 patients with lateral T2 SCC of the vulva were treated from 1963 to 2003. Radical vulvectomy (RV) was performed in 60 patients, and radical hemivulvectomy (RHV) in 62 patients. Seven of 61 patients (11%) with T1 lesions had ipsilateral superficial inguinal lymph node (SIL) metastases, but none had deep inguinal lymph (DIL) node metastases. Nineteen of 61 patients (31%) with T2 lesions had ipsilateral SIL metastases, and 8 had ipsilateral DIL metastases. No patient had contralateral SIL or DIL metastases. Six patients (10%) with T1 lesions and seven patients (11%) with T2 lesions developed recurrence to the ipsilateral vulva and were treated by re-excision. All patients are alive with no evidence of disease 10-195 months after treatment. One patient with T1 and three patients with T2 SCC developed distant recurrence and died of disease (DOD) 10-15 months after surgery. Disease-free survival of patients with T1 lesions was 98% at 2 years and 98% at 5 years, and with T2 lesions was 95% at 2 years and 93% at 5 years. Local or distant recurrence was not more common in patients treated by RHV than in those treated by RV. CONCLUSION: Lateral T1 and T2 squamous cell cancers of the vulva spread to the ipsilateral inguinal lymph nodes and can be treated effectively with RHV and ipsilateral SIL dissection. Deep inguinal lymphadenectomy is indicated only when the SIL are positive.

Ovarian cancer screening with annual transvaginal sonography: findings of 25,000 women screened.

BACKGROUND: Ovarian cancer has the highest mortality rate of all gynecologic malignancies, and most women present with advanced-stage disease. The current investigation was performed to determine the efficacy of annual transvaginal sonography (TVS) as a screening method for ovarian cancer. METHODS: Annual TVS screening was performed on 25,327 women from 1987 to 2005. Asymptomatic women aged>or=50 years and women aged>or=25 years who had a family history of ovarian cancer were eligible for participation in this trial. RESULTS: Among 364 patients (1.4%) with a persisting ovarian tumor on TVS who underwent exploratory laparoscopy or laparotomy with tumor removal, 35 primary invasive ovarian cancers, 9 serous ovarian tumors of low malignant potential, and 7 cancers metastatic to the ovary were detected. Stage distribution was as follows: 28 patients had stage I disease, 8 patients had stage II disease, and 8 patients had stage III disease. Four patients died of disease, 2 patients died of other causes, and 38 patients were alive and well from 0.5 years to 15.8 years after diagnosis (mean, 5.3 years). Nine women developed ovarian cancer within 12 months of a negative screen (false-negative results), and 3 of these patients died of disease. TVS screening had a sensitivity of 85.0%, specificity of 98.7%, positive predictive value of 14.01%, and negative predictive value of 99.9%. After 107,276 screening years, there have been 7 ovarian cancer deaths in the annually screened population and 3 ovarian cancer deaths among women who were noncompliant. Excluding patients with nonepithelial or borderline ovarian malignancies, the survival of patients with ovarian cancer in the annually screened population was 89.9%+/-10.1% at 2 years and 77.2%+/-22.8% at 5 years. CONCLUSIONS: TVS screening, when it was performed annually, was associated with a decrease in disease stage at detection and with case-specific ovarian cancer mortality, but it was not effective in detecting ovarian cancers in women who had normal ovarian volume.

The accuracy of examination under anesthesia and transvaginal sonography in evaluating ovarian size.

OBJECTIVE: To compare pelvic examination under anesthesia to transvaginal sonography (TVS) as a method for ovarian detection and measurement. METHODS: Two hundred and eighty-nine ovaries from 151 women were evaluated. After induction of anesthesia, a complete pelvic examination and TVS were performed, and the ovaries were removed surgically. Ovarian dimensions generated sonographically and estimated on clinical examination were compared to those obtained from the measured surgical specimen. RESULTS: Forty-four percent of ovaries were palpable clinically whereas 85% were visualized sonographically (P < 0.001). Right ovaries were palpable more frequently than left ovaries (P < 0.01). Ovaries were detected clinically in 30% of women > or = 55 years of age versus 51% of women <55 years of age (P < 0.05), in 9% of women weighing > or = 200 lb versus 55% of women weighing <200 lb (P < 0.001), and in 12% of women with a uterine weight > or = 200 g versus 51% of women with a uterine weight <200 g (P < 0.001). TVS was significantly more accurate than clinical examination in detecting ovaries in women with these high risk characteristics. CONCLUSIONS: TVS is significantly more accurate than clinical examination in detecting ovaries and in defining their dimensions. Ovaries frequently are not palpable in women > or = 55 years of age, women who weigh > or = 200 lb, or women with an enlarged uterus (> 200 g). The addition of TVS to annual pelvic examination may be beneficial in women > or = 55 years of age who are overweight and therefore at high risk to develop ovarian cancer.

Ultrasound screening for the early detection of ovarian cancer.

Ovarian cancer screening in the general population has been performed using ultrasound examination of the female pelvis and serum tumor marker determinations. Ultrasound examinations, particularly transvaginal sonography (TVS), have been advocated as potentially useful modalities. Investigators from the University of Kentucky (Lexington, KY) and Hirosaki University (Hirosaki, Japan) have recently published results from ultrasound-based ovarian cancer screening studies. The Kentucky trial screened 14,469 women using TVS on an annual basis. One hundred eighty women underwent surgery, and 17 ovarian cancers were detected, 11 of which were invasive epithelial lesions. The Hirosaki trial reported the results of an ultrasound-based screening study among 51,550 women who were first-time participants. Three hundred twenty-four women underwent surgery, and 22 ovarian cancers were detected. In each of these trials, the positive predictive value of gray-scale sonography was low. Morphologic tumor indexing and Doppler examinations have both been proposed as potential second-line studies, which could increase the positive predictive value of gray-scale ultrasound. A review of these techniques is presented. At present, ovarian cancer screening in the general population using ultrasound examinations is an experimental technique. Further studies are needed to determine whether second-line testing can improve the positive predictive value of gray-scale sonography such that asymptomatic women do not undergo unnecessary surgery for benign masses.

Clinical implications of a rising serum CA-125 within the normal range in patients with epithelial ovarian cancer: a preliminary investigation.

OBJECTIVE: The goal of this study was to determine the clinical implications of a progressively rising serum CA-125 level in the normal (< 35 U/ml) range in ovarian cancer patients with complete response to therapy. METHODS: A multi-institutional investigation was undertaken to identify patients with CA-125-producing epithelial ovarian cancers who experienced progressively rising antigen levels in the normal (<35 U/ml) range after completion of therapy. All patients had (1) histologic documentation of epithelial ovarian cancer and (2) complete clinical remission (CR) as defined by negative imaging studies, normal clinical examination, and a normal (<35 U/ml) serum CA-125 value. All patients had serum CA-125 determinations at 1- to 3-month intervals after treatment. A rising serum CA-125 level was defined as a progressive increase in at least three CA-125 values above the coefficient of variation (CV) for the assay. No patient had a known episode of pelvic or gastrointestinal inflammatory disease during the period when the progressive rise in serum CA-125 took place. RESULTS: Eleven patients with rising serum CA-125 levels in the normal range were identified. Original stage of disease was as follows: stage IIA, 1; stage IIIC, 10. Cell type was as follows: endometrioid adenocarcinoma, 4; serous adenocarcinoma, 6; clear cell carcinoma, 1. Of the 11 patients identified, all developed recurrent ovarian cancer. Tumor recurrence was documented either by new lesions appearing on imaging studies (6/11) or by histologic confirmation (5/11). The mean time from CR to recurrence was 21 months (median = 22, range = 12-33). The mean time from the third early rising serum CA 125 value to clinical or radiographic confirmation of recurrence was 189 days (range = 84-518). All recurrences were intraabdominal with the exception of one axillary recurrence. CONCLUSION: In patients with a history of ovarian cancer, three progressively rising serum CA-125 values in the normal range (< 35 U/ml) at 1- to 3-month intervals are associated with a high likelihood of tumor recurrence. Patients with such a pattern should undergo immediate investigation to rule out and/or identify recurrent cancer.

Outcome of reproductive age women with stage IA or IC invasive epithelial ovarian cancer treated with fertility-sparing therapy.

OBJECTIVES: The purpose of this study was to determine the recurrence rate, survival, and pregnancy outcome in patients with Stage IA and Stage IC invasive epithelial ovarian cancer treated with unilateral adnexectomy. METHODS: A multi-institutional retrospective investigation was undertaken to identify patients with Stage IA and IC epithelial ovarian cancer who were treated with fertility-sparing surgery. All patients with ovarian tumors of borderline malignancy were excluded. Long-term follow-up was obtained through tumor registries and telephone interviews. The time and sites of tumor recurrence, patient survival, and pregnancy outcomes were recorded for every patient. RESULTS: Fifty two patients with Stage I epithelial ovarian cancer treated from 1965 to 2000 at 8 participating institutions were identified. Forty-two patients had Stage IA disease, and 10 had Stage IC cancers. Cell type was distributed as follows: mucinous, 25; serous, 10; endometrioid, 10; clear cell, 5; and mixed, 2. Histologic differentiation was as follows: grade 1, 38; grade 2, 9; and grade 3, 5. Twenty patients received adjuvant chemotherapy (mean 6 courses, range 3-12 courses). Patients received the following chemotherapeutic agents: cisplatin/taxol or carboplatin/taxol, 11; melphalan, 5; cisplatin and cyclophosphamide, 3; and single-agent cisplatin, 1. Eight patients had second-look laparotomies and all were negative. Duration of follow-up ranged from 6 to 426 months (median 68 months). Five patients developed tumor recurrence 8-78 months after initial surgery. Sites of recurrence were as follows: contralateral ovary, 3; peritoneum, 1; and lung, 1. Nine patients underwent subsequent hysterectomy and contralateral oophorectomy for benign disease. At present, 50 patients are alive without evidence of disease and 2 have died of disease 13 and 97 months after initial treatment. The estimated survival was 98% at 5 years and 93% at 10 years.Twenty-four patients attempted pregnancy and 17 (71%) conceived. These 17 patients had 26 term deliveries (no congenital anomalies noted) and 5 spontaneous abortions. CONCLUSION: The long-term survival of patients with Stage IA and IC epithelial ovarian cancer treated with unilateral adnexectomy is excellent. Fertility-sparing surgery should be considered as a treatment option in women with Stage I epithelial ovarian cancer who desire further childbearing.