Linda R. Duska

A model for predicting surgical outcome in patients with advanced ovarian carcinoma using computed tomography.

A reliable model for predicting the outcome of primary cytoreductive surgery may be a useful tool in the clinical management of patients with advanced epithelial ovarian carcinoma.

Clinicopathologic analysis of 187 high-grade endometrial carcinomas of different histologic subtypes: similar outcomes belie distinctive biologic differences.

The clinical and histopathologic features of 187 high-grade endometrial cancers [FIGO grade 3 endometrioid (EC-3), serous (SC), and clear cell (CC)] were studied to determine whether clinicopathologic differences between these various histologic subtypes existed. The study group consisted of 89 EC-3s, 61 SCs, and 37 CCs. Treatment regimens were individualized. SCs and CCs were significantly more likely than EC-3s to occur in patients older than 65 years (P=0.03), and SCs tended to occur more frequently in patients of African descent than EC-3s and CCs (P=0.07), although this was not statistically significant. EC-3s had the highest rate of associated endometrial hyperplasia (P=0.05). SCs were most likely to have high-stage disease at presentation (≥stage IIB; P=0.01), with peritoneal dissemination at diagnosis being much more common compared with EC-3s and CCs (P=0.004). Median follow-up was 39 months, and median overall survival was 47 months. Five-year survivals were 45% (EC-3), 36% (SC), and 50% (CC)—differences that were not statistically significant. In contrast, the impact of stage on survival was significant (P<0.001). Among all other factors evaluated, only age greater than 65 years was a negative predictor (risk ratio, 2.23; P<0.001), whereas a family history of cancer reduced the risk of death when controlling for stage (risk ratio, 0.54; P=0.005). When controlling for stage, race, reproductive history, personal history of cancer, histologic subtype, depth of myometrial invasion, lymphovascular invasion, presence of an endometrial polyp, presence of hyperplasia, or staging adequacy did not affect prognosis. High-grade endometrial cancers of different histologic subtypes treated in an individualized manner are associated with similar clinical outcomes, but differences in age at presentation, race distribution, association with hyperplasia, stage, and sites of tumor dissemination support the idea that these represent distinct disease entities as defined by traditional histopathologic classification of endometrial cancers.

Borderline tumors of the ovary: correlation of frozen and permanent histopathologic diagnosis

Objective To evaluate the correlation between the diagnosis of borderline tumor of the ovary by frozen and permanent pathology. Methods All pathology reports with diagnoses of borderline tumor of the ovary between 1980 and 1998 at Massachusetts General Hospital were reviewed. Univariate and multivariable logistic regression models were constructed for patient age, tumor size, histology, presence of bilateral or extraovarian disease, and concurrent diagnosis of endometriosis or endosalpingiosis. Results We reviewed 140 cases. The average age of patients was 52.3 years. Eighty tumors were serous, 47 mucinous, 11 mixed, and two endometrioid. The mean diameter overall was 13.7 cm (range 1–70 cm), 10.2 cm for serous, and 20.1 cm for mucinous. Diagnoses of borderline tumors by frozen and permanent pathology were consistent in 60% of cases. Frozen section interpreted a benign lesion as malignant (overdiagnosed) in 10.7% of cases, and interpreted a malignant lesion as benign (underdiagnosed) in 29.3%. No variable was a significant predicator of overdiagnosis. In univariate analysis, underdiagnosis was more likely for other types of tumors than serous (P < .001), tumors larger than 20 cm (P = .039), and tumors confined to the ovaries (P = .009). When all variables were included in a multiple regression model, only histology was a significant predictor of underdiagnosis (P = .039). Conclusion Frozen or permanent pathology reports of diagnoses of borderline tumor were consistent 60% of the time, whereas the positive predictive value of borderline by frozen section was 89.3%. Tumors other than serous are more likely to be misinterpreted.

SGO White Paper on Ovarian Cancer: Etiology, Screening and Surveillance☆

Ovarian cancer is a heterogeneous, rapidly progressive, highly lethal disease of low prevalence. The etiology remains poorly understood. Numerous risk factors have been identified, the most prominent involving an inherited predisposition in 10% of cases. Women with germline mutations associated with Hereditary Breast/Ovarian Cancer and Lynch syndromes have dramatically elevated risks (up to 46% and 12%, respectively). Risk-reducing salpingo-oophorectomy is the best method to prevent ovarian cancer in these high-risk women. Significant risk reduction is also seen in the general population who use oral contraceptives. Since up to 89% patients with early-stage disease have symptoms prior to diagnosis, increased awareness of the medical community may facilitate further workup in patients who otherwise would have had a delay. Despite enormous effort, there is no proof that routine screening for ovarian cancer in either the high-risk or general populations with serum markers, sonograms, or pelvic examinations decreases mortality. Further evaluation is needed to determine whether any novel biomarkers, or panels of markers, have clinical utility in early detection. Prospective clinical trials have to be designed and completed prior to offering of any of these new diagnostic tests. CA125 is currently the only biomarker recommended for monitoring of therapy as well as detection of recurrence. This commentary provides an overview on the background, screening and surveillance of ovarian cancer.

Clinical evaluation of Atypical glandular cells of undetermined significance on cervical cytology

Abstract Objective: To determine the incidence of and identify risk factors for clinically significant diagnoses associated with the diagnosis on Papanicolaou test of atypical glandular cells of undetermined significance. Methods: A computer search was initiated of diagnoses of atypical glandular cells of undetermined significance at the Massachusetts General Hospital from January 1993 through December 1996. Seventy-three patients with 81 smears were identified that were seen in the Colposcopy Clinic. All cytology was reviewed. A clinically significant lesion was defined as high-grade squamous intraepithelial lesion (SIL) or worse, endocervical glandular atypia or worse, or carcinoma. Results: The rate of diagnoses of atypical glandular cells of undetermined significance was 0.167%. All patients underwent colposcopy, and 88% underwent endocervical curettage. A clinically significant diagnosis was made in 34.2% of patients, including cancer in 8.2%. A concurrent squamous diagnosis carried a risk of clinically significant lesion of 50%, compared with a risk of 25.5% for atypical glandular cells of undetermined significance alone (P = .043). Premenopausal and postmenopausal patients were both at risk for clinically important lesions, but premenopausal patients were more likely to have a high-grade SIL (30.4% versus 7.4%, P = .04). The subtype “suggestive of reactive” was a significant negative predictor of significant lesion (odds ratio = 0.09, 95% confidence interval 0.018, 0.482) in a logistic regression model controlling for age, menopausal status, and concurrent squamous diagnosis. Conclusion: Atypical glandular cells of undetermined significance is an important Papanicolaou test diagnosis that needs appropriate and careful evaluation. Further studies are required to clarify areas of risk and to make triage algorithms.

Phase 1–2 study of docetaxel plus aflibercept in patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer

BACKGROUND Biologically targeted therapies have been postulated as a viable strategy to improve outcomes for women with ovarian cancer. We assessed the safety, tolerance, pharmacokinetics, relevant circulating and image-derived biomarkers, and clinical activity of combination aflibercept and docetaxel in this population. METHODS For the phase 1 (pharmacokinetic) study, eligible patients had measurable, recurrent or persistent epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with a maximum of two prior chemotherapy regimens. Aflibercept was administered intravenously over three dose levels (2, 4, or 6 mg/kg; one dose every 21 days) to identify the maximum tolerated dose for the phase 2 study. Pharmacokinetics were assessed and dynamic imaging was done during a lead-in phase with single-agent aflibercept (cycle 0) and during combination therapy with intravenous docetaxel (75 mg/m(2)). Eligibility for the phase 2 study was the same as for phase 1. Patients were enrolled in a two-stage design and given aflibercept 6 mg/kg intravenously and docetaxel 75 mg/m(2) intravenously, every 3 weeks. The primary endpoint was objective response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors version 1.0. The trial has completed enrolment and all patients are now off study. The trial is registered at ClinicalTrials.gov, number NCT00436501. FINDINGS From the phase 1 study, the recommended phase 2 doses of aflibercept and docetaxel were found to be 6 mg/kg and 75 mg/m(2), respectively. Log-linear pharmacokinetics (for unbound aflibercept) were observed for the three dose levels. No dose-limiting toxicities were noted. 46 evaluable patients were enrolled in the phase 2 trial; 33 were platinum resistant (15 refractory) and 13 were platinum sensitive. The confirmed ORR was 54% (25 of 46; 11 patients had a complete response and 14 had a partial response). Grade 3-4 toxicities observed in more than two patients (5%) were: neutropenia in 37 patients (80%); leucopenia in 25 patients (54%); fatigue in 23 patients (50%); dyspnoea in ten patients (22%); and stomatitis in three patients (7%). Adverse events specifically associated with aflibercept were grade 1-2 hypertension in five patients (11%), and grade 2 proteinuria in one patient (2%). INTERPRETATION Combination aflibercept plus docetaxel can be safely administered at the dose and schedule reported here, and is associated with substantial antitumour activity. These findings suggest that further clinical development of this combination in ovarian cancer is warranted. FUNDING US National Cancer Institute, US Department of Defense, Sanofi-Aventis, Gynecologic Cancer Foundation, Marcus Foundation, and the Commonwealth Foundation.

Comparison of the quality of life of early and advanced stage ovarian cancer survivors

OBJECTIVE The objective of this study was to compare the long-term adjustment and QOL of early and advanced stage ovarian cancer survivors (OCS). METHODS Early and advanced OCS >3 years from diagnosis with no evidence of recurrent cancer were interviewed. The following surveys were administered: EORTC QLQ-C30 (overall QOL) and QLQ-OV28 (ovarian specific issues), MHI-17 (anxiety, depression and global well-being), CALGB sexual functioning, FACT Fatigue, Becks Hopelessness Scale, Fear of Recurrence (FOR), PCL-C post-traumatic stress disorder (PTSD), Unmet Needs, FACT-Spirituality (FACT-Sp), complementary therapy (CAM use), and MOS Social Support Survey (MOS). The results of the surveys were compared between the early and advanced stage groups. RESULTS 42 advanced and 58 early stage patients were interviewed. The majority of survivors scored above the medical outpatient norm for emotional status (71% of early stage and 64% of advanced stage survivors). Overall QOL, fatigue, hopelessness, spirituality, social support, degree to which unmet needs were met and use of complementary therapy, did not differ between the two groups. No advanced stage OCS had diagnosable PTSD scores, while 6.9% of early stage survivors had scores indicative of PTSD. Decreased sexual interest attributed to cancer and anxiety when getting CA-125 testing were of concern for both groups. OCS used on average 5 CAM to improve their QOL. CONCLUSION Regardless of staging, OCS experience similarly overall positive QOL and adjustment, though PTSD, sexual problems and fear of recurrence are still important for some survivors.

An international series on abdominal radical trachelectomy: 101 patients and 28 pregnancies.

Objectives Abdominal radical trachelectomy (ART) is a type C resection (uterine vessels ligated at origin from the hypogastric vessels). Questions arise as to whether fertility is maintained after ART, particularly when uterine vessels are sacrificed. We report an international series on ART to describe fertility and oncologic outcomes. Methods Databases at 3 institutions were queried to identify patients planned for ART from 1999 to 2011. Clinical and demographic data were gathered. Results One hundred one patients underwent ART. Mean age was 31 years (range, 19–43 years). Histologic classifications were adenocarcinoma (n = 54), squamous cell carcinoma (n = 40), adenosquamous carcinoma (n = 6), and clear cell carcinoma (n = 1). Twenty patients (20%) required conversion to hysterectomy (10 margins and 10 nodes). Eight patients underwent completion hysterectomy owing to the following: positive margins on final pathology (n = 3), patient’s choice (n = 4), or recurrence (n = 1). Postoperatively, 20 patients (20%) received adjuvant chemotherapy and/or radiation (4 final pathology margins and 16 nodes). Four patients (4%) had recurrence and lived 22 to 35 months after diagnosis. Of the 70 women who had neither hysterectomy nor adjuvant therapy, 38 (54%) attempted pregnancy and 28 (74%) achieved pregnancy. Thirty-one pregnancies resulted in 16 (52%) third trimester deliveries. Six patients are currently pregnant with outcomes pending. Conclusions These data demonstrate that ART preserves fertility and maintains excellent oncologic outcomes. Most women (74%) attempting pregnancy after ART are able to achieve pregnancy and deliver in the third trimester (52%). Preservation of the uterine vasculature is not necessary for fertility; obstetrical outcomes are similar to those of the historical vaginal radical trachelectomy cohorts.

Frailty: An outcome predictor for elderly gynecologic oncology patients☆

OBJECTIVES The objective of this pilot study was to determine if frailty predicts surgical complications among elderly women undergoing gynecologic oncology procedures. METHODS A cohort of gynecologic oncology patients age ≥ 65, undergoing surgery between March and December 2011 was identified. Frailty was evaluated using a validated assessment tool. The primary outcome measure was 30 day postoperative complication rate. RESULTS Forty women were approached for study entry and 37 (92%) enrolled. The mean age was 73 years (range 65-95). The majority of women had a malignancy and underwent a major abdominal surgical procedure. Twenty-one women (57%) were not frail, 10 (27%) were intermediately frail and 6 (16%) were frail. There was no difference in age or prevalence of medical comorbidities between groups. Frail women had a significantly higher BMI compared to intermediately frail and not frail women, (36.0, 31.5 and 26.1 kg/m(2), p=0.02). The rate of 30-day surgical complications increased with frailty score and was 24%, versus 67% for women who were not frail as compared to the frail (p=0.04). CONCLUSIONS Pre-operative frailty assessment is well accepted by gynecologic oncology patients and feasible in a clinic setting. Frail women had a higher BMI, indicating that low body weight is not a marker for frailty, and had a significantly higher rate of 30-day postoperative complications in this pilot study. Initial findings support the concept of measuring frailty as a possible predictor for postoperative morbidity that will allow for improved patient counseling and decision making.

Molecular profile of grade 3 endometrioid endometrial carcinoma: is it a type I or type II endometrial carcinoma?

Two types of endometrial carcinoma (EC) have been delineated on the basis of clinicopathologic studies. Low-grade endometrioid carcinoma (EEC) is the prototype of type I EC and is characterized by microsatellite instability and PTEN, K-ras, and/or &bgr;-catenin gene mutations, whereas type II EC is typically represented by serous and clear cell carcinomas (SCs/CCCs), the former frequently showing p53 mutations and c-erb-2 overexpression; however, the molecular profile of grade 3 EEC has not yet been well characterized. The goal of this study was to define the immunohistochemical and molecular profile of grade 3 EEC. We studied 25 patients with grade 3 EEC ranging in age from 35 to 87 (mean 61) years. At the time of initial diagnosis, 16 patients had stage I tumors, whereas 3, 5, and 1 had stages II, III, and IV tumors, respectively. Only 1 patient with stage IV tumor had disease in the peritoneum because of direct extend of tumor through the uterine wall. Two tissue microarrays were constructed from paraffin-embedded blocks and stained for MLH-1, MSH-2, p16, cyclin D1, C-erb-B2, WT-1, and p53. Loss of MLH-1 and MSH-2 was seen in 3 of 25 and 1 of 24 tumors, respectively; none showed loss of both. Diffuse p16 nuclear expression was found in 7 of 23 cases; diffuse and strong nuclear immunostaining for p53, cyclin D1, and Her-2 was seen in 9 of 24 neoplasms, 9 of 25, and 3 of 25 carcinomas, respectively. WT-1 was negative in all 25 tumors. One of the 3 grade 3 EECs with Her-2 overexpression showed gene amplification by fluorescence in situ hybridization analysis. No gene amplification for cyclin D1 was found. Follow-up information was available for all patients. Sixteen had stage I tumors. Of these patients, 11 were alive and well (AW), 3 died of disease (DOD), and 2 died of unrelated causes (DUC), with a mean follow-up time of 56 months (range, 24 to 96 mo); 2 of 3 patients with stage II tumors DOD, and 1 was AW with a mean follow-up time of 81 months (range, 6 to 66 mo); of the 5 patients with stage III tumors, 2 DOD, 1 was AW, 1 was alive with lung metastases, and 1 DUC [mean follow-up of 29 months (range, 12 to 74 mo)]; the only patient who had a stage IV tumor DOD 12 months later. Interestingly, patients with grade 3 EECs showing loss of MLH-1/MSH-2 had stage I tumors, and all were AW (60 to 84 mo). Seventy-seven percent (7 of 9) of patients with tumors showing cyclin D1 overexpression were stage I, and none died of disease, whereas 85% (6 of 7) of patients with p16-positive tumors were high stage (2 stage II, 3 stage III, and 1 stage IV), and 5 DOD. All but one of these patients had tumors that also had p53 overexpression. All 3 patients with Her-2 overexpression DOD (stages I, III, and IV). In conclusion, this study shows that grade 3 EEC shares with low-grade EEC the overexpression but not amplification of cyclin D1 and low frequency of Her-2 overexpression and amplification. Grade 3 EEC shares with SC the relatively common p53 and p16 overexpression and low frequency of loss of mismatch repair genes. However, in contrast to SC ECs, which often show WT-1, cyclin D1 amplification, and Her-2 overexpression and/or amplification, grade 3 EECs rarely overexpressed any of these markers. Moreover, in this study, patients with tumors showing loss of MLH-1/MSH-2 or cyclin D1 overexpression were more likely to have low-stage tumors (stage I), whereas patients with tumors that overexpressed p53, p16, or Her-2 were frequently associated with high-stage tumors.