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PURPOSE Early detection of ovarian cancer, the deadliest gynecologic cancer, is crucial for reducing mortality. Current noninvasive risk assessment measures include protein biomarkers in combination with other clinical factors, which vary in their accuracy. Machine learning can be applied to optimizing the combination of these features, leading to more accurate assessment of malignancy. However, the low prevalence of the disease can make rigorous validation of these tests challenging and can result in unbalanced performance. METHODS MIA3G is a deep feedforward neural network for ovarian cancer risk assessment, using seven protein biomarkers along with age and menopausal status as input features. The algorithm was developed on a heterogenous data set of 1,067 serum specimens from women with adnexal masses (prevalence = 31.8%). It was subsequently validated on a cohort almost twice that size (N = 2,000). RESULTS In the analytical validation data set (prevalence = 4.9%), MIA3G demonstrated a sensitivity of 89.8% and a specificity of 84.02%. The positive predictive value was 22.45%, and the negative predictive value was 99.38%. When stratified by cancer type and stage, MIA3G achieved sensitivities of 94.94% for epithelial ovarian cancer, 76.92% for early-stage cancer, and 98.04% for late-stage cancer. CONCLUSION The balanced performance of MIA3G leads to a high sensitivity and high specificity, a combination that may be clinically useful for providers in evaluating the appropriate management strategy for their patients. Limitations of this work include the largely retrospective nature of the data set and the unequal, albeit random, assignment of histologic subtypes between the training and validation data sets. Future directions may include the addition of new biomarkers or other modalities to strengthen the performance of the algorithm.

Background: Ovarian cancer is the deadliest gynecologic cancer, with no recommended screening test to assist with early detection. Cancer antigen 125 (CA125) is a serum biomarker commonly used by clinicians to assess preoperative cancer risk, but it underperforms in premenopausal women, early-stage malignancies, and several histologic subtypes. OVA1 is a multivariate index assay that combines CA125 and four other serum proteins to assess the malignant risk of an adnexal mass. Objective: To evaluate the performance of OVA1 in a cohort of patients with low-risk serum CA125 values. Study Design: We analyzed patient data from previous collections (N = 2305, prevalence = 4.5%) where CA125 levels were at or below 67 units/milliliter (U/mL) for pre-menopausal women and 35 U/mL for post-menopausal women. We compare the performance of OVA1 to CA125 in classifying the risk of malignancy in this cohort, including sensitivity, specificity, positive and negative predictive values. Results: The overall sensitivity of OVA1 in patients with a low-risk serum CA125 was 59% with a false-positive rate of 30%. OVA1 detected over 50% of ovarian malignancies in premenopausal women despite a low-risk serum CA125. OVA1 also correctly identified 63% of early-stage cancers missed by CA125. The most common epithelial ovarian cancer subtypes in the study population were mucinous (25%) and serous (23%) carcinomas. Despite a low-risk CA125, OVA1 successfully detected 83% of serous, 58% of mucinous, and 50% of clear cell ovarian cancers. Conclusions: As a standalone test, CA125 misses a significant number of ovarian malignancies that can be detected by OVA1. This is particularly important for premenopausal women and early-stage cancers, which have a much better long-term survival than late-stage malignancies. Using OVA1 in the setting of a normal serum CA125 can help identify at-risk ovarian tumors for referral to a gynecologic oncologist, potentially improving overall survival.

Aim: Based on evidence that African–American (AA) women have lower CA125 values than Caucasian (C) women, we investigated this to see if this disparity would have an impact on ovarian cancer detection using CA125 and multivariate index assay (MIA). Materials & methods: Serum from two prospective trials of 1029 (274 malignancies [250 C/24AA]) were analyzed for CA125 and MIA results. Clinical performance was calculated. Results: Sensitivity of MIA in Caucasian women was 93.2%, 74.4% for CA125 at the ACOG approved cut-off level of 200 U/ml cutoff, and 80.4% using the 2007, Dearking 67 U/ml cutoff. In AA American women, MIA sensitivity was 79.2%, 33.3% for CA125 at the ACOG approved cut-off levels and 62.5% at the 2007, Dearking 67 U/ml cutoff. Conclusion: Our results support that CA125 in AA women with adnexal masses has lower sensitivity than MIA no matter what the cutoff value is. Implementation of MIA in evaluation of adnexal masses should increase sensitivity of detection of malignancy compared with CA125, particularly in AA women.

e17553 Background: The baseline risk for ovarian cancer in the general population is 1.2%1. However, women with germline variants in ovarian cancer-associated genes can have a much higher baseline risk for ovarian cancer, up to 54%2. Such a difference in baseline risk presents a triaging challenging for physicians when evaluating adnexal masses. It is well known that identifying pathogenic variants in hereditary cancer syndrome genes often leads to changes in care. Less is known about the utility of negative genetic testing results, specifically in the context of adnexal mass assessment. Methods: An observational, prospective study was designed to examine the clinical impact of multivariate index assay (MIA) and germline genetic testing in patients with a known adnexal mass planned for surgery. Inclusion criteria were: female subjects aged 18-65, presence of an adnexal mass, receiving MIA, and consideration of germline genetic testing. Enrolled physicians selected patients under their care that met inclusion criteria and filled out a short survey describing how the results of each test impacted clinical management. This study was considered IRB-exempt as all information was de-identified. Results: 23 patients were enrolled that received both MIA and germline genetic testing. 21 cases had negative genetic testing and two had positive genetic testing. Both patients with positive genetic testing had low-risk MIA results. Both had risk-reduction surgery with benign findings. Three patients had high-risk MIA results with negative genetic results. All patients had a serial monitoring plan of care. Nine patients with low-risk MIA results and negative genetic results proceeded to surgery. No malignancies were reported. Of the 21 patients with negative genetic results, 17 were not immediately planned for surgery. Conclusions: While not reaching statistical significance, there is a strong association between a negative genetic result and non-immediate surgical intervention. While positive genetic testing results may lead to more aggressive, prophylactic surgical management, negative genetic results may support an expectant management approach. Effectively ruling out the most common hereditary cancer predisposition syndromes may provide physicians with useful insight into a patient's baseline risk. [Table: see text]

Prophylactic human papillomavirus (HPV) vaccines and new HPV screening tests, combined with traditional Pap test screening, provide an unprecedented opportunity to greatly reduce cervical cancer in the USA. Despite these advances, thousands of women continue to be diagnosed with and die of this highly preventable disease each year. This paper describes the initiatives and recommendations of national cervical cancer experts toward preventing and possibly eliminating this disease.In May 2011, Cervical Cancer-Free America, a national initiative, convened a cervical cancer summit in Washington, DC. Over 120 experts from the public and private sector met to develop a national agenda for reducing cervical cancer morbidity and mortality in the USA.Summit participants evaluated four broad challenges to reducing cervical cancer: (1) low use of HPV vaccines, (2) low use of cervical cancer screening, (3) screening errors, and (4) lack of continuity of care for women diagnosed with cervical cancer. The summit offered 12 concrete recommendations to guide future national and local efforts toward this goal.Cervical cancer incidence and mortality can be greatly reduced by better deploying existing methods and systems. The challenge lies in ensuring that the array of available prevention options are accessible and utilized by all age-appropriate women-particularly minority and underserved women who are disproportionately affected by this disease. The consensus was that cervical cancer can be greatly reduced and that prevention efforts can lead the way towards a dramatic reduction in this preventable disease in our country.

The implementation of cytology-based screening programs for precancerous lesions of the cervix has decreased the incidence of and mortality from cervical cancer in much of the developed world. Countries without the resources to install such frequent and laboratory-dependent screening programs have more and more options at their disposal. A screening program based on cytology analysis requires too much training, infrastructure, and repeated screening to be feasible. Visual inspection with acetic acid, often used throughout the world, is inexpensive and both sensitive and specific, but it lacks reproducibility. Although human papillomavirus (HPV) testing is too expensive for widespread use, its negative predictive value and sensitivity make it a promising method of screening. Utilizing HPV vaccines as a primary mode of prevention may not be financially feasible and does not obviate the need for screening. Cervical cancer has been considered an AIDS-defining illness, with HPV and HIV often coexisting, and screening methods have been shown to be as reliable for women with HIV as those without. Ultimately, the most clinically effective and cost-effective methods for reducing cervical cancer incidence are those that limit the number of visits that women are required to attend. Providing immediate cryotherapy for those with a positive screen, whether by visual inspection or HPV testing, is promising to have quite an impact, although the type of program implemented will depend on the needs and expectations of each country.

Objective To review the results of patients who were referred for posthysterectomy of abnormal cytology based on screening indications. Materials and methods We performed a retrospective review of 64 patients who have been referred for posthysterectomy vaginal colposcopy to the gynecologic oncology service. Patients' demographics, clinical features, reason for screening, and final diagnosis were recorded. Patients were divided into 2 groups based on posthysterectomy screening guidelines. Group A was considered to have undergone unnecessary screening based on national guidelines, and group B had risk factors that appropriately called for continued surveillance. The number of colposcopic examinations and the incidence of neoplasia were recorded for each group. Results The mean age of the patients was 65 years (range = 35-95 y). Group A included 22 patients with history of abnormal cytology posthysterectomy for benign disease. Of the 22 abnormal cytology results, 21 were low-grade squamous intraepithelial lesion (n = 14) or atypical squamous cells of undetermined significance (n = 7) with 1 high-grade squamous intraepithelial lesion. After referral and colposcopy of this group, no neoplasia was found. Group B included 42 total patients. Of these 42 patients, 20 (48%) had a history of cervical intraepithelial neoplasia, 12 (28%) had a history of vaginal intraepithelial neoplasia, 6 (14%) had history of cervical cancer, 2 (5%) had history of diethylstilbestrol exposure, and 2 (5%) had a history of radiation therapy. In group B, 8 (9%) and 1 (2%) of the patients had vaginal intraepithelial neoplasia 2/3 and squamous cell carcinoma, respectively. Conclusions Current national guidelines are appropriate. Adherence to these guidelines will decrease intervention and not affect the detection of vaginal neoplasia. Patients with risk factors for lower genital tract neoplasia warrant continued screening after hysterectomy.

Endometrial stromal sarcomas are rare tumors that recur long after initial excision. We report a case of recurrent endometrial stromal sarcoma treated with the aromatase inhibitor letrozole and an overview of research completed to date. A 59-year-old female presented with new abdominal onset pain, fatigue, and nausea. She had a computed tomography that showed a pelvic mass, an enlarged right internal iliac lymph node, an atypical liver hemangioma, and a severe left hydronephrosis. The patient underwent an exploratory laparotomy, and attempted surgical resection of the pelvic mass was attempted. Pathology was consistent with recurrent endometrial stromal sarcoma. Since these tumors are hormonally sensitive, the patient was started on letrozole 2.5 mg daily. The patient had complete clinical and radiographic response by 11 months. After 24 months of therapy, the patient remained free of disease. Endometrial stromal sarcomas are hormonally sensitive tumors. Progestins function to decrease the effects of estrogen on target cells and have been used for primary therapy of endometrial stromal sarcomas. Aromatase inhibitors block peripheral synthesis of estrogen. Letrozole is a type 2 aromatase inhibitor that effectively reduces serum estrogen levels. Letrozole has been described as treatment for endometrial stromal sarcoma. Letrozole is well tolerated and is a good option for long-term management of this disease.

External genital warts are a significant health problem particularly for young adults. This review summarizes the current literature on epidemiology, transmission, diagnosis, and treatment. Efficacy of all treatments is less than optimal, and multiple therapies may be necessary for complete resolution. Data on a new patient-applied therapy are presented. New vaccine therapy for prevention of infection should reduce the incidence of disease.

OBJECTIVE To determine the percentage of patients vaccinated per individual provider and to document attitudes and reasons for the acceptance of the human papillomavirus vaccine. METHODS Computerized records were reviewed for individual practitioners in an urban department of obstetrics and gynecology to determine vaccination rates. Questionnaires filled out by practitioners were used to assess individual attitudes and reasons for the unequal distribution of vaccination. RESULTS Overall vaccination rate was 28% (range 6%-55.8%) for the initial 3-month period when the vaccine became available. Barriers to acceptance included patient concerns, provider concerns over safety, and provider concerns over cost. Experience in practice and self-described attitudes toward early acceptance of new medication were not predictive. CONCLUSIONS Early acceptance of human papillomavirus vaccination was provider dependent and was not related to provider experience or attitude. Concerns over cost and safety may be barriers to increasing vaccination rates by gynecologists.

Minoo Robati, David Holtz, Charles J DuntonDepartment of Obstetrics and Gynecology, Main Line Gynecologic Oncology, Lankenau Hospital, Wynnewood, PA, USAAbstract: Treatment of advanced, recurrent or persistent cervical cancer includes radiotherapy and chemotherapy. Radiation has been the primary treatment modality for locoregionally advanced cervical cancer. Concomitant systemic cisplatin chemotherapy and radiation have shown high response rates with improvements in durable remissions and overall survival. Cisplatin has been the standard medication for the treatment of advanced cervical cancer. Combinations with other chemotherapeutic agents have been the subject of clinical trials with varying results. The toxicity of combination chemotherapy and tolerability of patients are other factors that should be considered in the management of patients with advanced disease. Recently topotecan, in combination with cisplatin, achieved increased response and overall survival rates without further compromising the patients’ quality of life. This review focuses on the mechanism of action and toxicities of topotecan, as well as its role as a radio-sensitizer and chemotherapeutic agent in the management of advanced, recurrent, or persistent cervical cancer. Other combination modalities and dosages are also discussed.Keywords: topotecan, combination chemotherapy, advanced cervical cancer

A group of 146 experts representing 29 organizations and professional societies met September 18-19, 2006, in Bethesda, MD, to develop revised evidence-based, consensus guidelines for managing women with abnormal cervical cancer screening tests. Recommendations for managing atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion (LSIL) are essentially unchanged. Changes were made for managing these conditions in adolescents for whom cytological follow-up for 2 years was approved. Recommendations for managing high-grade squamous intraepithelial lesion (HSIL) and atypical glandular cells (AGC) also underwent only minor modifications. More emphasis is placed on immediate screen-and-treat approaches for HSIL. Human papillomavirus (HPV) testing is incorporated into the management of AGC after their initial evaluation with colposcopy and endometrial sampling. The 2004 Interim Guidance for HPV testing as an adjunct to cervical cytology for screening in women 30 years of age and older was formally adopted with only very minor modifications.

To provide updated consensus guidelines for the management of women with cervical intraepithelial neoplasia (CIN) or adenocarcinoma in situ (AIS).A group of 146 experts including representatives from 29 professional organizations, federal agencies, and national and international health organizations met on September 18-19, 2006, in Bethesda, MD, to develop the guidelines. MAJOR CHANGES IN THE GUIDELINES: The management of women with CIN grade 1 (CIN 1) has been modified significantly. In the earlier guidelines, management depended on whether the colposcopic examination was satisfactory and treatment using ablative or excisional methods was acceptable for women with CIN 1. In the new guidelines, cytological follow-up is the only recommended management option, regardless of whether the colposcopic examination is satisfactory, for women with CIN 1 who have a low-grade referral cervical cytology. Treatment of CIN 1 is particularly discouraged in adolescents. The basic management of women in the general population with CIN 2,3 underwent only minor modifications, but options for the conservative management of adolescents with CIN 2,3 have been expanded. Moreover, management recommendations for women with biopsy-confirmed AIS are now included.Updated evidenced-based guidelines have been developed for the management of women with CIN or AIS. These guidelines reflect recent changes in our understanding of human papillomavirus-associated diseases of the cervix and the potential impact of treatment on future pregnancies.

OBJECTIVES: To determine the usefulness of computerized rescreening for detecting high-grade cervical intraepithelial neoplasia (CIN) in patients with cytological evidence of atypical squamous cells of undertermined significance (ASCUS). METHODS: One hundred and eight patients with ASCUS cytology who had undergone colposcopy had their Papanicolaou smears reviewed using PAPNET, a neural network-based instrument. RESULTS: Twenty (18.5%) of the 108 slides were reclassified to a higher-grade lesion. Analysis showed sensitivity (77.8%), specificity (86.9%), and positive (35%) and negative (97.7%) predictive values for detection of high-grade CIN. CONCLUSIONS: PAPNET neural network-based rescreening of ASCUS smears identifies patients with high-grade cancer precursors. It may be a triage test for ASCUS cytology.

Objectives We sought to determine the safety and efficacy of a bipolar electrosurgical loop excision instrument in the diagnosis and treatment of cervical intraepithelial neoplasia (CIN). Materials and methods Twenty-eight patients underwent treatment for CIN using a 20 x 10-mm bipolar electrosurgical loop device (Valley Forge Scientific, Oaks, PA). A Malis (Valley Forge Scientific) electrosurgical generator unit (60 watts cutting) was used to remove the cervical lesion and transformation zone under colposcopic guidance. Specimens were evaluated for histopathological diagnosis, tissue depth, fragmentation of specimens, mean maximal thermal artifact, and mean maximal endocervical and ectocervical thermal artifact. Results Final pathology from bipolar electrosurgical loop excision revealed CIN3 (8), CIN2 (4), CIN1 (11), human papillomavirus changes (3), and normal findings (2). Mean operating time was less than 15 minutes, and mean estimated blood loss was less than 10 ml. Average number of tissue pieces was 1.6 (range, 1-4). No complications occurred. Mean maximal thermal artifact was 0.318 mm. Mean endocervical mucosal and ectocervical mucosal thermal artifacts were 0.177 mm and 0.176 mm, respectively. Mean tissue depth of the excised specimen was 0.40 cm. Histopathological diagnosis was possible on all specimens. In five specimens (17.9%), evaluation of the cauterized endocervical margin for CIN was not possible, owing to thermal artifact. No correlation was observed between tissue depth and thermal artifact. Conclusion Bipolar electrosurgical loop excision for the treatment of CIN is a safe and effective alternative to the traditional unipolar electrosurgical loop excision. Thermal artifact did not interfere with histopathological diagnosis, and the presence of artifact at cauterized margins was similar to that reported for historically unipolar specimens. A randomized control trial comparing therapeutic effectiveness of bipolar electrosurgical loop excision and unipolar electrosurgical loop excision is planned.

OBJECTIVES Our aim was to determine patient knowledge of cervical dysplasia and colposcopy at an inner-city obstetrics and gynecology clinic and the relationship of this knowledge base to compliance. METHODS One hundred six women presenting for colposcopy at Thomas Jefferson University Hospital's obstetrics and gynecology clinic during an 8-month period were given questionnaires testing their knowledge of Papanicolaou smears, colposcopy, cervical dysplasia, and cervical cancer. Their medical records were reviewed 12 to 19 months later for patient demographics and follow-up compliance. RESULTS Mean patient score on the nine-question test was 3.5 ± 1.7 (score range, 0-8). Answers to individual questions showed that 32.1% of patients understood the purpose of a Papanicolaou smear, 52.8% understood the nature of colposcopy, and 24.4% could identify at least three risk factors for cervical cancer. Overall compliance with planned follow-up was 54.7%. We saw no relationship between test scores and follow-up compliance. Correct answers to individual questions did not correlate with improved compliance. Age, parity, intercurrent pregnancy, and history of previous colposcopy were not predictive of compliance. Follow-up compliance correlated with the colposcopic impression of the severity of disease [79.2% for patients with high-grade lesions versus 46.9% for all others (p = .005)]. A statistical trend was observed in relation to the severity of the initiating cytological diagnosis. CONCLUSIONS Patient knowledge was poor, as demonstrated by our questionnaire. Compliance did not correlate with questionnaire scores but rather correlated with the colposcopic impression of severity of disease. Increased knowledge in patients, therefore, may not necessarily increase compliance.

Endometrial hyperplasia is a precursor to the most common gynecologic cancer diagnosed in women: endometrial cancer of endometrioid histology. It is most often diagnosed in postmenopausal women, but women at any age with unopposed estrogen from any source are at an increased risk for developing endometrial hyperplasia. Hyperplasia with cytologic atypia represents the greatest risk for progression to endometrial carcinoma and the presence of concomitant carcinoma in women with endometrial hyperplasia. Abnormal uterine bleeding is the most common presenting symptom of endometrial hyperplasia. Specific Pap smear findings and endometrial thickness per ultrasound could also suggest the diagnosis. Unopposed estrogen in women taking hormone replacement therapy increases the risk of endometrial hyperplasia. Tamoxifen has demonstrated its efficacy in treating women at risk for breast cancer, but it increases the risk of endometrial hyperplasia. The choice of treatment for endometrial hyperplasia is dependent on patient age, the presence of cytologic atypia, the desire for future childbearing, and surgical risk. Endometrial hyperplasia without atypia responds well to progestins. However, women with atypical hyperplasia should be treated with hysterectomy unless other factors preclude surgery. Target audience Obstetricians & Gynecologists, Family Physicians. Learning objectives After completion of this article, the reader should be able to describe the definition and classification of endometrial hyperplasia, to outline the clinical features of a patient with endometrial hyperplasia, to point out the natural history of endometrial hyperplasia, and to summarize the diagnostic options for patients with endometrial hyperplasia.

Cervical carcinoma is staged clinically by examination and simple radiological procedures. CT and MRI can, however, be used to guide management. Prognosis is best made by tumor size. depth of invasion, parametrial involvement, nodal status, LVSI, and histology. CIN III and CIS can be treated by ablative or excisional procedures. Hysterectomy should not be the primary treatment. Microinvasive (

Learning Objectives After completing this course, the reader will be able to:Recognize the reversible and irreversible toxicities associated with the management of newly diagnosed ovarian cancer.Better manage recurrent ovarian cancer.Identify the range of chemotherapeutic options in managing recurrent ovarian cancer. Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com Recognition of recurrent ovarian cancer as a disease with significant secondary responses and remissions has led to an increase in the need for oncologists to plan for the long-term therapy of patients. However, many of the currently available front-line and salvage agents used in advanced ovarian cancer are associated with cumulative and/or irreversible toxicities that pose challenges in long-term planning. The irreversible effects associated with some of these therapies may render patients less tolerant to subsequent treatments and lead to a cycle of diminishing treatment options with each remission and disease relapse. Additionally, the potential for patients to experience cumulative toxicity must be carefully weighed against the goals of prolonging the disease-free interval and improving patient quality of life. A number of agents are available in the treatment armamentarium (platinum, paclitaxel, gemcitabine, etoposide, liposomal doxorubicin, and topotecan), many, but not all of which are associated with cumulative toxicity. For instance, cumulative neurotoxicity associated with cisplatin as first-line therapy may diminish the option for retreatment with platinum at first relapse. In contrast, the main toxicity associated with topotecan is noncumulative, manageable myelosuppression. In this review, the major toxicities associated with the predominant chemotherapy agents used in advanced ovarian cancer are discussed along with selected management approaches in the context of long-term treatment planning and sequencing.

OBJECTIVE To determine the prognostic value of the diagnostic category CIN 1,2. MATERIALS AND METHODS Computerized pathology records of patients with CIN 1,2 at colposcopically directed biopsy followed by treatment with excision were examined, and we compared the diagnostic biopsy with the final tissue diagnosis. Two pathologists who were blinded to the final diagnosis reviewed the original biopsies independently. The ability of the referee pathologist to predict CIN 2 or 3 lesions and interobserver consistency are described. RESULTS Sixty-nine cases of biopsies with CIN 1,2 were reviewed. Nineteen of these patients were lost to follow-up. Of the 46 cases with either an excisional biopsy or hysterectomy, 12 cases (26.1%) demonstrated CIN 2 or greater. Pathologist A and B correctly predicted the high-grade lesions in 66.7% and 58.3% of cases reviewed. Pathologist A and B agreed with each other in 33 of the 46 cases (71.1%). CONCLUSIONS 1) CIN 1,2 on a colposcopic biopsy is associated with a high-grade lesion in 26.1% of the cases. 2) Experienced gynecologic pathologists can identify these high-grade lesions on review in only two thirds of the cases. 3) CIN 1,2 is a useful diagnostic category to prevent undertreatment.

Atypical polypoid adenomyoma (APA) of the uterus is a rare, benign lesion. Histologically, it is composed of a glandular and squamous cell proliferation with architectural complexity and cytologic atypia of glands, and a hypercellular smooth muscle stroma. APA is difficult to distinguish from well-differentiated adenocarcinoma of the uterus. In the case presented, the diagnosis of APA was confused pathologically, radiographically, and clinically with a cervical adenocarcinoma. A review of the English literature is presented.

Ovarian epithelial tumors are classically divided into benign,malignant, and borderline or of low malignant potential. It is controversial whether this last group of tumors should be considered benign or malignant. Expression of cell cycle markers has recently been linked to tumor behavior and response to treatment. It has been shown that one of the pathways through which the p53 gene controls the cell cycle is by transactivating p21 WAF1/CIP1 a cyclindependent kinase (cdk) inhibitor. By inhibiting cdks, p21 WAFR/CIP1 blocks the Gl to S-phase transition in the cell cycle. p53 can be regulated by MDM2 (murine double minute-2) through direct inactivation or promotion of its cytoplasmic degradation. In an attempt to investigate the cell cycle checkpoint mechanisms of these tumors, we studied the expression of p53, Ki-67, MDM2, and p21 WAF1/CIP1 by immunohistochemistry. We analyzed the expression of these proteins in 19 cystadenomas (8 serous and 11 mutinous), 40 borderline tumors (31 serous and 9 mutinous), and 18 serous carcinomas of the ovary. p21 WAF1/CIP1 was expressed in 7 of 19 (37%) benign cystadenomas, 32 of 40 (80%) borderline tumors (93.5% of serous and 33% of mutinous), and in 9 of 18 (50%) serous carcinomas. Ki-67 was only weakly expressed in 8 of 19 (42%) benign cystadenomas, all borderline tumors showed Ki-67 staining in less than 50% of the cells, and 55% of serous carcinomas stained in more than 50% of tumor cells. p53 was absent in all but 1 of the cystadenomas, was expressed in 9 of 40 (22.5%) borderline tumors (25.8% of serous and 11% of mutinous), and in 10 of 18 (55%) carcinomas. All 11 implants of serous borderline tumors expressed p21 WAF1/CIP1 Most serous borderline tumors expressed higher levels of MDM2 compared with the benign cystadenomas and carcinomas. Four of the serous borderline implants (40%) expressed MDM2. Coexpression of p21 WAF1/CIP1 and MDM2 characterizes serous borderline tumors of the ovary and their implants, which suggests that these cell cycle control proteins are important in these tumors and may be related to tumor progression. Low expression of p53 protein in serous borderline tumors might be in part mediated by MDM2. This suggests that the p53 pathway is intact in most of these tumors, in contrast with carcinomas, in which high expression of p53 has been related to mutations of this gene.

Stereotactic irradiation (radiosurgery) is a method of precisely focusing well-defined beams of radiation at small intracranial targets. The technique has been applied to the treatment of brain lesions that are benign (e.g., arteriovenous malformations, meningiomas, pituitary adenomas) and malignant (e.g., gliomas, metastases). This paper introduces preliminary data suggesting the possible value of radiosurgery in the management of ovarian cancer metastatic to the brain. Among 32 women with ovarian cancer metastatic to the brain treated with whole brain irradiation, nine (29%) experienced a complete radiographic response, compared with two of the five patients (40%) treated with radiosurgery. The 2-year survival rate was 60% among those treated with radiosurgery and 15% among those who received whole brain irradiation without radiosurgical boost. Stereotactic irradiation may be of clinical benefit to select patients with brain metastases resulting from ovarian cancer. A prospective randomized trial has been implemented by the Radiation Therapy Oncology Group (RTOG 95-08) to determine whether such observations are reproducible on a national scale.

The Home Study Course is intended for the practicing colposcopist or practitioner who is seeking to develop or enhance his or hercolposcopic skills. The goal of the course is to present colposcopic cases that are unusual or instructive in terms of appearance, presentation, or management or to present colposcopic cases that demonstrate new and important knowledge in the area of colposcopyor pathology. Participants may benefit from reading and studying the material or from testing their knowledge by answering the questions.The American Society for Colposcopy and Cervical Pathology (ASCCP) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The ASCCP designates this continuing medicaleducation activity for 1 hour category 1 credit of the ASCCP's Program for Continuing Professional Development and the Physician's Recognition Award of the American Medical Association. Credit is available for those who choose to apply. The Home Study Course is planned and produced in accordance with the ACCME's Essential Areas and Elements.Faculty must disclose any significant financial interest or relationship with proprietary entities that may have a directrelationship to the subject matter. For this course, the author had no such relationship to report.

Objective To survey general gynecologists regarding the nature of surgical staging of corpus cancer as practiced in the United States. Methods A survey tool was designed to ascertain issues related to surgical staging of corpus cancer among gynecologists in the United States. The survey elicited data pertaining to the demographics and practice characteristics of the respondents. The questionnaire was sent to 700 practicing gynecologists selected randomly from the ACOG membership list. Results Responses were obtained from 227 physicians; however, only 193 could be analyzed. Most of the respondents classified themselves as general gynecologists (93%) and nonacademicians (90%). In a typical year, 60% evaluated fewer than five patients with corpus cancer. A minority of respondents carry out surgical staging of their patients, which includes total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAHBSO), removal of pelvic and para-aortic lymph nodes, and cytologic evaluation of peritoneal fluid. No uniformity was observed regarding the numeric definition of an appropriate “sampling” (median 5, range 1–25) or “dissection” (median 10, range 1–40) of lymph nodes. Most respondents would not return a corpus cancer patient to the operating room to carry out lymph node dissection if a referring colleague had performed TAHBSO but had not removed the nodes. In such a scenario, private practitioners were approximately three times less likely to reoperate on lymph nodes than academic physicians. Conclusion Complete surgical staging is not performed by most physicians caring for women with corpus cancer. The relatively high proportion of nonresponders and nonevaluable responses suggests that these results should be corroborated by other investigators.

Recently, statistical methods have been developed to rigorously assess the relationship between local and distant failures. Such methodology has successfully been applied to a variety of tumors including those arising in the prostate, breast, and cervix. To date, no published data are available to generate a hypothesis to characterize the relationship between local and distant failure for endometrial cancer. The present analysis was undertaken to determine the effect of locoregional control on subsequent metastatic dissemination among women with pathologically staged endometrial cancer treated by hysterectomy followed by adjuvant radiotherapy.The series consisted of 394 patients with FIGO stages I-III endometrial cancer who were surgically staged prior to irradiation [median external beam dose 45 Gy +/- brachytherapy (median vaginal surface dose, 30 Gy)]. The duration of follow-up ranged from 2 to 151 months, with a median of 62 months. Multiple factors were evaluated to determine the associations with distant relapse including FIGO pathological stage, grade, histopathologic subtype (adeno vs papillary/papillary-serous/clear cell), depth of myometrial penetration, age, and local disease status. Time-dependent survival models were generated to assess the influence of local failure on distant metastases.For the entire series, the 5-year actuarial rates of local and distant failures were 9 and 20%, respectively. Women who failed locally had nearly a fourfold risk of failing distantly compared to those who remained locally controlled (P = 0.02). Moreover, the earlier a local failure developed (e.g., within 1 year vs within 3 years), the more likely it was to be associated with distant metastases (P0. 05). The univariate correlations of other factors with the 5-year rate of freedom from distant relapse also disclosed significant associations for grade, histology (adenoca vs papillary/papillary-serous/clear cell), and FIGO path stage. In multivariate analysis, only local control, low grade (grade 1 and 2), and early pathological stage were independently related to the likelihood of achieving freedom from distant relapse.Distant dissemination of endometrial cancer may develop secondary to local failure. Optimization of local control is therefore necessary if long-term cure is to be achieved. The limits of the current database cannot establish whether local failure is a cause of distant spread or a high-risk marker for metastases; however, ongoing national cooperative trials may resolve this controversy.

Papillary projections are distinctive pathologic features of epithelial ovarian neoplasms. We sought to determine whether these structures have recognizable features on MRI. A search of a database of 125 patients on whom MRI was performed with pelvic phased-array coil and abdominal surgical exploration was performed for suspected gynecologic disease identified 15 patients who had either MRI reports or pathology reports mentioning papillary projections in an adnexal mass. The MR images were reviewed to characterize the size, structure, and signal intensity of papillary projections. Pathologic correlation was performed on these and on four surgical specimens imaged with high resolution technique. Pathologic correlation showed that larger papillary projections had a distinctive structure of a fibrous stalk supporting clumps of edematous papillae with signal intensity similar to that of fluid on T2-weighted images. Smaller papillae showed nondescript intracystic projections of intermediate signal intensity on T2-weighted images. All papillary projections in vivo enhanced after injection of gadopentetate dimeglumine. Papillary projections have an appearance on MRI that reflects their histologic structure.

Ovarian fibromas and cystadenofibromas are neoplasms that share a similar distinctive tissue component of dense fibrous tissue. We sought to describe the MRI features of these neoplasms and to determine if the fibrous component shows distinctive characteristics. Fourteen patients in whom MR images performed with multicoil and fast-spin-echo images and who subsequently underwent surgery for resection of ovarian fibromas or cystadenofibromas were identified from two institutions. Five patients had ovarian fibromas, and nine patients had fourteen cystadenofibromas. 1.5-T MR studies used T1-weighted spin echo and multiplanar T2-weighted fast-spin-echo images, with fat saturation gadolinium-enhanced fast multiplanar gradient-echo images in seven patients. Studies were reviewed for findings of low (approximately equal to skeletal muscle) signal intensity solid components on T2-weighted images, characteristics of gadolinium enhancement, and associated endometrial findings. Images were obtained ex vivo from three adnexal surgical specimens with an 8-cm field of view and correlated with histology. All five of the fibromas showed predominantly very low signal intensity, similar to skeletal muscle, on T2-weighted images. Two of five fibromas were in patients with endometrial polyps and increased amounts of fluid in the pelvis. Thirteen cystadenofibromas were multicystic masses with bands of very low signal intensity ranging from 2 to 20 mm in the wall of the mass, and one was predominantly solid fibrous tissue. Pathologic correlation with specimen images showed that the low signal intensity material was the subepithelial fibrous component of the cystadenofibromas. Fibrous components of ovarian fibromas and cystadenofibromas are demonstrable by MR as solid components representing fibrous tissue of very low signal intensity on T2-weighted images.

The purpose of the work was to determine the feasibility and predictive value of Ki-67 immunostaining of cervical cytology and the detection of cervical dysplasia. Air-dried cervical smears were stained with MIB-1 antibody to identify the Ki-67 antigen. Nuclear decoration in abnormal squamous nuclei determined immunoreactivity. One hundred twenty-four nonpregnant patients underwent colposcopy and directed biopsies for abnormal cytology. Sensitivity (0.89), specificity (0.65), positive predictive value (0.60), and negative predictive value (0.91) were found for Ki-67 immunostaining in detection of high-grade cervical intraepithelial neoplasia (CIN) in 124 patients and positive Ki-67 staining was a significant predictor of high-grade CIN in both univariate (odds ratio 15.5 (95% CI 5.5-43.8) and multivariable (odds ratio 21.5 (95% CI 5.0-92.0) analysis. In 101 patients with ASCUS and LGSIL, Ki-67 immunostaining demonstrated the following in detection of high-grade CIN: sensitivity (0.96), specificity (0.67), positive predictive value (0.49), and negative predictive value (0.98). Ki-67 immunostaining of cervical cytology is a predictor of significant cervical pathology with high sensitivity and negative predictive value. Ki-67 immunostaining of cervical cytology may represent a new and cost-effective triage tool for patients with minor abnormalities on cytology.

Summary The diagnosis of endocervical neoplasia can be difficult as it is sometimes mimicked by proliferative or reactive glands. MIB-1 is a proliferation marker that can aid in the diagnosis of squamous intraepithelial lesions (SIL) of the cervix and vulva, but its potential value in the diagnosis of endocervical lesions has not been fully explored. Ten formalin-fixed, paraffin-embedded cases of each of the following were obtained: morphologically normal endocervical glands from patients with cervical SIL, endocervicitis. microglandular hyperplasia (MGH), and endocervical adenocarcinomas (eight in situ, two invasive). Microwave unmasking of antigens was performed prior to immunohistochemical staining for MIB-1 using the avidin/biotin peroxidase method. Labeling indexes were calculated for 34 specimens (10 adenocarcinoma, 8 each of the other diagnoses) using image analysis (Samba 4000). There was diffuse MIB-1 reactivity in adenocarcinoma (labeling index 57–96%, mean 80%), minimal focal reactivity in normal glands underlying SIL (labeling index 0.8–4.3%. mean 2.4%). moderate spotty reactivity in MGH (labeling index 2.9–18.4%, mean 8.5%). and minimal to focally diffuse reactivity in endocervicitis (labeling index 1.0–13.3%. mean 5.7%). These data indicate that the percentage and distribution of MIB-1-reactive endocervical cells can be of diagnostic utility in distinguishing neoplastic glands from those of endocervicitis and MGH.

Percutaneous abscess drainage (PAD) is regarded as an alternative treatment for the care of the gynecologic cancer patient with a pelvic infection. Four female patients with infected pelvic malignancies were evaluated and treated with PAD at Thomas Jefferson University Hospital over a 4-year period. Abscesses in three of the four patients were drained successfully and the catheters were ultimately removed. Successful drainage was defined as a good clinical response and avoidance of surgical debridement. For the patient with an infected pelvic malignancy, PAD offers an alternative to surgery without associated morbidity. Our experience indicates PAD is associated with expedient clinical recovery and preservation of quality of life for most patients.

The outcome of women treated with either definitive irradiation alone or in combination with cisplatin-based chemotherapy for locally advanced (>IIb) squamous cell carcinoma of the cervix has been disappointing. To improve upon our reported results with irradiation alone, a trial using irradiation plus carboplatin chemotherapy was designed for these patients. Twenty-seven women with unresectable squamous cell carcinoma of the uterine cervix were referred to our institution between July 1991 and September 1994. Seven of these patients were enrolled in a phase I/II protocol combining concurrent irradiation and carboplatin chemotherapy. Megavoltage irradiation was used to deliver 45-50.4 Gy to the pelvis (and paraaortic chain when nodes were involved) through a multiple-field technique followed by the application of Fletcher-Suit-Delclos tandem and ovoids to boost the point A dose to 85 Gy. Chemotherapy consisted of intravenous carboplatin (60 mg/m2) administered in conjunction with irradiation to a total dose of 300 mg/m2. The enrolled patients consisted of six women with stage IIIb disease and one with stage IIa with concomitant paraaortic adenopathy. All seven patients enrolled in the study completed the planned course of treatment and tolerated the treatment without severe acute morbidities. No dose modifications were required for the radiation therapy regimen. For one patient, a dose of carboplatin was withheld to allow recovery from thrombocytopenia. The overall response rate was 100% (four complete response, three partial response). The combination of concurrent irradiation (pelvic or pelvic + paraaortic fields) and carboplatin chemotherapy can be safely administered to patients with locally advanced squamous cell carcinoma of the cervix. The treatment is well tolerated and is associated with a high rate of response. Longer follow-up will be necessary to assess the durability of response. In the meantime, we have elected to escalate the dose of carboplatin (90 mg/m2) in the hope of increasing the rate of complete response without incurring unacceptable toxicity.

This study was designed to compare the effectiveness of loop excision procedures as ablation and conization equivalents, and their use in recurrent cervical high-grade dysplasia patients. We retrospectively reviewed patients undergoing loop procedures between January 1992 and April 1994. Conization equivalents were defined as procedures performed for unsatisfactory colposcopy, positive endocervical curettage, discordant cytology and histology, and cytology suggestive of invasion. Effectiveness in high-grade recurrent lesions was evaluated separately. Therapeutic failure was defined as any recurrence of high-grade dysplasia. One hundred sixty-two patients underwent loop procedures, of which 123 (75.9%) had follow-up examinations and are included. Mean follow-up was 17.9 months. Seventy-six patients (61.8%) had the loop procedure performed as an ablation equivalent, 29 (23.6%) as a conization equivalent, and 18 (14.6%) for recurrent disease. Overall effectiveness was 82.1 % and for ablation and conization equivalent procedures was 82.9 and 82.8%, respectively. There was no significant difference between effectiveness when performed for initial therapy (82.9%) and for recurrent disease (72.2%) (P = 0.46). In conclusion, loop excision procedures are effective as ablation and conization equivalents and as treatment for recurrent high-grade dysplasia.

Three cases of primary carcinoma of the Bartholin gland of different histologie types, including adenocarcinoma, squamous cell carcinoma, and adenoid cystic carcinoma, treated at Thomas Jefferson University Hospital are reported. This experience stresses the need to consider Bartholin gland carcinoma in the differential diagnosis of masses in this location. The need for wide local excision of these masses is necessary, especially in older patients. Because these tumors are very rare, current treatment recommendations are based on limited experience. Management may include wide local excision, radical vulvectomy, inguinal lymph node dissection, and adjunctive radiotherapy and chemotherapy. In adenoid cystic carcinoma, the adjunctive radiotherapy is necessary only if the margins are positive. (J GYNECOL SURG 12:145, 1996)

The Home Study Course is intended for the practicing colposcopist or practitioner who is seeking to develop or enhance his or her colposcopic skills. The goal of the course is to present colposcopic cases that are unusual or instructive in terms of appearance, presentation, or management, or that demonstrate new and important knowledge in the area of colposcopy or pathology. Participants may benefit from reading and studying the material or from testing their knowledge by answering the questions.The American Society for Colposcopy and Cervical Pathology (ASCCP) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The ASCCP designates this continuing medical education activity for 1 hour Category I credit of the Physician's Recognition Award of the American Medical Association. Credit is available for those who choose to apply. The Home Study Course is planned and produced in accordance with the ACCME's Essential Areas and Elements.

OBJECTIVE.: To determine whether liquid-based cytology improves Pap smear adequacy, as defined by the presence of endocervical cells, compared with conventional cytology during pregnancy. MATERIALS AND METHODS.: A randomized pilot study was conducted between May 2001 and May 2002. Patients presenting for their first prenatal visit were randomized to receive either a conventional Pap smear or a liquid-based smear (ThinPrep). Rates of endocervical cell recovery and cytologic results were compared between the groups. RESULTS.: Eighty-one patients were enrolled in the study. There were no differences between the groups in age (p = .40), parity (p = .62), gestational age (p = .14), history of abnormal pap (p = .08), previous treatment of neoplasia (p = 1.00), and tobacco use (p = .67). Adequacy of the standard pap versus the liquid-based smear was not different between the two groups (90.5% vs 82.1%, respectively;p = .34). CONCLUSIONS.: The results of this pilot study show that rates of endocervical cell recovery in a pregnant population are not statistically different using conventional or liquid-based cytology. Further research is indicated to assess the utility of the more expensive ThinPrep technology in this population.

BACKGROUND Thrombospondin is a high molecular weight glycoprotein, originally described as a secretion product of platelets, that functions as an adhesive protein in cell-cell and cell-substratum interactions. It promotes metastases in the murine model. Plasma thrombospondin has been shown to be elevated in patients with disseminated breast, lung, and gastrointestinal malignancies. METHODS Blood samples were collected by venipuncture into cubes containing ethylenediamine tetraacetic acid as anticoagulant. They were placed on ice immediately and centrifuged under refrigerated conditions. Plasma was removed and frozen until thrombospondin was quantitated by a competitive enzyme-linked immunosorbent assay. Wilcoxon's two-sample rank-sum test was used to evaluate differences between the patient and control groups. RESULTS The median plasma thrombospondin level was significantly higher in the patient group compared with the control group, and it was directly correlated with stage of disease. There was no correlation between platelet count and thrombospondin level. CONCLUSIONS Tumor-synthesized thrombospondin could explain the elevated levels in the patent group and also the observation of the correlation between the thrombospondin level and tumor burden. Its function as an adhesive protein may allow it to act as the mediator of metastases. thrombospondin may promote or mediate the metastatic process through its function in cell adhesion.

Objective. The goal of this study was to determine the maximal tolerated dose (MTD) of topotecan given with external-beam radiotherapy in advanced cervical cancer. Methods. A prospective Phase I trial of topotecan given with standard external-beam radiotherapy was performed in patients with advanced squamous cell carcinoma of the cervix. Patients were treated with a starting dose of 0.5 mg/m 2 and escalated by 0.25 mg/m 2 . Nine patients were treated. Hematologic and nonhematologic toxicity were measured. Results. Patients were treated with 1.0 mg/m 2 daily for 5 days on Days 1–5 and 22–26 concomitantly with radiotherapy without significant toxicity. Grade III anemia in one case and Grade II leukopenia in two cases were seen in the three patients at this dose level. Dose-limiting toxicity was not reached. Conclusion. Topotecan can be safely administered at a dose of 1.0 mg/m 2 during external-beam radiotherapy for advanced cervical cancer.