Alon D. Altman

Guidelines for postoperative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations — Part II

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Maternal age-related rates of gestational trophoblastic disease.

OBJECTIVE: To estimate the incidence of gestational trophoblastic disease in Nova Scotia and to evaluate the effect of time and maternal age on these rates. METHODS: Information on women with a pathologically confirmed diagnosis of gestational trophoblastic disease was extracted from the Nova Scotia Gestational Trophoblastic Disease Registry between 1990 and 2005. The total numbers of deliveries and pregnancies were determined from the Nova Scotia Atlee Perinatal Database and consensus data derived from Statistics Canada. RESULTS: Four-hundred twenty-eight women were identified with gestational trophoblastic disease. Hydatidiform moles showed rates of 220/100,000 pregnancies, 264/100,000 total births, and 266/100,000 live births. Rates of partial mole were twofold higher than complete mole (P<.001). The rates of hydatidiform mole were highest in both younger (younger than 20 years old, P=.02) and older age groups (30–34 years old, P=.04, and at least 35 years old, P=.02). The rates of hydatidiform mole were highest in both younger (less than 20 years old, P=.02) and older age groups (30–34 years old, P .04, and 35 or more years old P=.02). The rates of partial moles were significantly higher in women older than 20 years of age (P<.001) and increased with increasing age (P<.001); the reverse trend was seen in complete mole (P<.001). There was no temporal change in rates or average age of hydatidiform mole during the study period. CONCLUSION: The rates of hydatidiform mole in Nova Scotia estimated by this population-based study using comprehensive validated information, are higher than most previously reported. Maternal age was a significant factor in the risk for molar pregnancies. LEVEL OF EVIDENCE: II

The diagnostic utility of TP53 and CDKN2A to distinguish ovarian high-grade serous carcinoma from low-grade serous ovarian tumors

Low-grade serous carcinomas and serous borderline tumors, combined herein and referred to as low-grade serous tumors, show distinct molecular alterations and clinical behaviors compared with high-grade serous carcinomas. The discrimination between low-grade serous tumors and high-grade serous carcinomas can be challenging on small tissue samples, such as cell blocks of paracentesis fluid or biopsies from omental disease. The purpose of this study was to test the ability of TP53 and CDKN2A immunohistochemistry to distinguish between high-grade serous carcinomas and low-grade serous tumors on small tissue samples. Tissue microarrays containing 582 high-grade serous carcinomas, 45 low-grade serous carcinomas, and 49 serous borderline tumors, confirmed by contemporary histopathological review, were stained for TP53 and CDKN2A (DO7 and E6H4 antibody clones, respectively). TP53 was scored as completely absent, wild-type pattern or overexpressed (>60%), and CDKN2A was scored as either negative/patchy (<90%) or block expression (>90%). The combination of the two markers, ie, the TP53 wild-type pattern and CDKN2A patchy expression, had sensitivity for low-grade serous tumors of 89%, a specificity of 93%, a positive predictive value of 68%, and a negative predictive value of 98%. These markers can, therefore, be used on small biopsies/cell blocks to refute a diagnosis of low-grade serous tumors. These findings may inform emerging neoadjuvant therapeutic strategies in advanced ovarian cancers and may be crucial for future clinical trials on molecular-based therapies.

Uterine sarcoma and aromatase inhibitors: Tom Baker Cancer Centre experience and review of the literature.

Objectives Uterine sarcomas are a rare group of mesenchymal tumors with a poor prognosis and aggressive biology. Standard treatment involves surgical staging. The role of further adjuvant treatment is unclear. The goals of this study were to determine the response rates to treatment of patients with uterine sarcomas and to review the currently available literature on the use of aromatase inhibitors (AIs). Materials and Methods We performed a retrospective analysis on all patients with uterine sarcoma treated with an AI between 2000 and 2010 at the Tom Baker Cancer Centre in Calgary, Alberta. Results Four patients with endometrial stromal sarcoma and 3 patients with leiomyosarcoma received treatment with an AI. A literature search resulted in 10 case reports and 4 retrospective studies of patients with endometrial stromal sarcoma and 1 case report and 2 retrospective studies of patients with leiomyosarcoma. On the basis of the available literature, combined with the current findings, the overall response rate of endometrial stromal sarcoma to AIs is 67% (complete response of 7% and partial response of 60%), and the partial response rate of leiomyosarcoma to AIs is 11%, with no reported complete responses. Conclusions Aromatase inhibitors are a well-tolerated class of medications that are effective in the treatment of endometrial stromal sarcomas. These medications may also have a role to help stabilize disease progression in the treatment of leiomyosarcoma. More large, prospective, multicentered trials will be needed to clarify this issue.

Canadian high risk endometrial cancer (CHREC) consortium: Analyzing the clinical behavior of high risk endometrial cancers

OBJECTIVES The objective of this study is to analyze the clinical behavior of endometrial carcinomas by high risk(HR) histotype, including stage, overall survival, recurrence free survival and patterns of failure. METHODS This is a retrospective multi-institutional cohort study performed at 7 tertiary care centers across Canada between 2000 and 2012 and included: grade 3 endometrioid (EC3), endometrial serous cancer (ESC), clear cell carcinomas (CCC) and carcinosarcoma (CS). Clinicopathological and outcome data was collected. RESULTS 1260 women with endometrial carcinoma with 1013 having staging procedures were identified; 398 EC3, 449 ESC, 236 CS and 91 CCC. 51.8% had lymphovascular space invasion (LVSI) and 18.5% had omental involvement with a statistically significant difference between tumor types (p=0.0005 and 0.0047 respectively); ESC had a significantly greater rate of omental involvement compared to EC3 (22% to 9%, p=0.0005). Within the entire cohort 49.3% were stage 1, 10.6% were stage 2, 27.4% were stage 3 and 12.7% were stage 4. Overall survival and recurrence free survival were significantly different between histotypes (p<0.0001) with CS having the worst outcome. Overall 31.5% of patients recurred. CS and ESC had a higher distant recurrence rate compared to EC3 (29.6%, 31.0% compared to 16.4%, p=0.0002 and p<0.001). CONCLUSION This study is one of the largest clinical cohorts of HR endometrial cancers. We have further clarified the impact of histotype and stage on recurrence and survival, and the high likelihood of distant recurrence. However, the differences are modest and risk prediction models will require additional molecular markers.

Architectural patterns of ovarian/pelvic high-grade serous carcinoma.

We describe the architectural patterns of advanced ovarian/pelvic high-grade serous carcinomas that have been treated with upfront surgery, followed by adjuvant chemotherapy or neoadjuvant chemotherapy, followed by interval debulking to explore the association with the chemotherapeutic response. For 70 cases of advanced (i.e. stage III/IV) high-grade serous carcinomas (33 platinum resistant/intermediate, 37 platinum sensitive; 24 neoadjuvantly treated, 44 primary surgery), all tumor-containing histologic slides were reviewed by 1 of 3 pathologists. Histologic type was confirmed and the following features were assessed: major architectural pattern and the presence of any of 8 predefined minor architectural patterns (papillary, transitional cell carcinoma-like, micropapillary, microcystic, nested papillary, slit-like, glandular, solid). A semiquantitative assessment of psammoma bodies, histiocytic response, necrosis, nuclear atypia, and single-cell invasion was performed. Mitotic count was performed in 10 HPF and 1 HPF was counted for intraepithelial lymphocytes. The morphologic features were tested for an association with previous neoadjuvant chemotherapy and response to chemotherapy (resistant/intermediate versus chemotherapy-sensitive cases stratified by neoadjuvant chemotherapy), which was carried out using &khgr;2 tests for categorical variables and analysis of variance for continuous data. Combinations of features were analyzed using unsupervised clustering (Wald). Although 8 of 18 features were significantly different when samples from neoadjuvantly treated patients were compared with those not previously treated, no individual histomorphologic feature or a combination of features was associated with response to chemotherapy. Further subtyping of high-grade serous carcinomas will likely need ancillary molecular markers that may have a greater potential to identify cases that will not respond to platinum-based chemotherapy.

Use of Aromatase Inhibitors as First- and Second-Line Medical Therapy in Patients With Endometrial Adenocarcinoma: A Retrospective Study

OBJECTIVES The primary objective of this study was to examine the role of aromatase inhibitors (AIs) as first- or second-line medical treatment in women with endometrial adenocarcinoma who were not candidates for surgical management. The secondary objective was to examine the role of AIs in adjuvant and palliative treatment. METHODS Thirty women with endometrial adenocarcinoma who were treated with aromatase inhibitors between 2000 and 2010 at the Tom Baker Cancer Centre in Calgary, Alberta were assessed in a retrospective analysis. Disease response was based on response evaluation criteria in solid tumours. Kruskal-Wallis test was used to compare non-parametric variables and Fisher exact test was used to compare the health variables. RESULTS Seventeen patients received AIs as first- or second-line medical treatment, five received adjuvant therapy, and eight received palliative treatment. The median age of patients in the first or second line medical treatment group was significantly greater than that of patients in the adjuvant or palliative group (P = 0.042). There was no significant difference in median weight or body mass index. The subjective clinical response rate with medical treatment was 70%. In the first- or second-line medical treatment group, only seven patients had available response data. Our study showed stable disease in 5/7 (71%), partial response in 1/7 (14%), and progression in 1/7 (14%) patients. CONCLUSION This retrospective clinical series examining use of an aromatase inhibitor as first- or second-line medical therapy in women with endometrial carcinoma showed that AIs are a potential treatment for patients who have a contraindication to surgery and who either have failed or cannot use megestrol therapy.

The temporal dynamics of chromosome instability in ovarian cancer cell lines and primary patient samples

Epithelial ovarian cancer (EOC) is the most prevalent form of ovarian cancer and has the highest mortality rate. Novel insight into EOC is required to minimize the morbidity and mortality rates caused by recurrent, drug resistant disease. Although numerous studies have evaluated genome instability in EOC, none have addressed the putative role chromosome instability (CIN) has in disease progression and drug resistance. CIN is defined as an increase in the rate at which whole chromosomes or large parts thereof are gained or lost, and can only be evaluated using approaches capable of characterizing genetic or chromosomal heterogeneity within populations of cells. Although CIN is associated with numerous cancer types, its prevalence and dynamics in EOC is unknown. In this study, we assessed CIN within serial samples collected from the ascites of five EOC patients, and in two well-established ovarian cancer cell models of drug resistance (PEO1/4 and A2780s/cp). We quantified and compared CIN (as measured by nuclear areas and CIN Score (CS) values) within and between serial samples to glean insight into the association and dynamics of CIN within EOC, with a particular focus on resistant and recurrent disease. Using quantitative, single cell analyses we determined that CIN is associated with every sample evaluated and further show that many EOC samples exhibit a large degree of nuclear size and CS value heterogeneity. We also show that CIN is dynamic and generally increases within resistant disease. Finally, we show that both drug resistance models (PEO1/4 and A2780s/cp) exhibit heterogeneity, albeit to a much lesser extent. Surprisingly, the two cell line models exhibit remarkably similar levels of CIN, as the nuclear areas and CS values are largely overlapping between the corresponding paired lines. Accordingly, these data suggest CIN may represent a novel biomarker capable of monitoring changes in EOC progression associated with drug resistance.

Pure Immature Teratoma of the Ovary in Adults: Thirty-Year Experience of a Single Tertiary Care Center.

Objective The aim of this study was to evaluate clinicopathologic characteristics, treatment outcome, and reproductive function in women diagnosed with ovarian immature teratoma (IT). Our standard chemotherapy regime is currently etoposide/cisplatin (EP), creating a unique opportunity to evaluate this protocol in ovarian ITs. Materials and Methods This study is a retrospective analysis. Twenty-seven women older than 18 years with ovarian IT stages IA to IIIC were identified and included in this study. Patients were treated at 1 institution, Health Sciences Center, Women’s Hospital, Winnipeg, Manitoba, Canada, between 1983 and 2013. Results The median age at diagnosis was 27.0 years (range, 18–36 years). Twenty-two (82%) presented with an International Federation of Gynecology and Obstetrics stage I disease, 3 (11%) had stage II, and 2 patients (7%) had stage III disease. The histologic grade distribution was grade I in 9 patients (33%), grade II in 3 patients (11%), and grade III in 15 patients (56%). Initial management was surgical for all patients: 3 (11%) hysterectomy and bilateral salpingo-oophorectomy, 1 (4%) cystectomy only, and 23 (85%) unilateral salpingo-oophorectomy. Twenty-one patients (78%) received adjuvant therapy. The median follow-up was 60 months (range, 36–72 months). One patient recurred (histological grade III) 6 months after surgery and had a complete clinical response to 4 cycles of EP chemotherapy. Twelve patients reported an attempt to conceive resulting in 10 pregnancies (8 after chemotherapy). Conclusions Ovarian IT is a curable disease. Fertility-sparing surgery should be offered. Adjuvant treatment with cisplatinum-based chemotherapy, typically with bleomycin, etoposide, and cisplatin, is still considered the standard in stages greater than stage IA grade I. Etoposide/cisplatin as a primary chemotherapy regime for early- or advanced-stage disease is an effective treatment with minimal adverse effects and high tolerability. This is the first published study examining EP as a primary treatment modality for IT. Further studies are needed to strengthen these findings.

The effects of anemia and blood transfusion on patients with stage III-IV ovarian cancer.

Objectives The objective of this study was to examine the overall and recurrence-free survival in patients with advanced ovarian cancer based on hemoglobin and blood transfusions. Methods A retrospective chart review was performed between 2003 and 2007 on patients with pathologically confirmed stage 3–4 ovarian, fallopian, or peritoneal cancers. Data were collected on date of diagnosis, recurrence and death, stage, grade, age, surgery, estimated blood loss, hemoglobin (nadir and average levels), and number of blood transfusions. Results Two hundred sixteen patients were included in the final analysis. In the perichemotherapy, perioperative, and total time frames, 88%, 81%, and 95% of patients were anemic, and 9%, 22%, and 26% of the patients had severe anemia. After adjusting for age, stage, and optimal debulking status, the perichemotherapy hemoglobin level as a continuous variable was weakly associated with recurrence-free survival (adjusted hazard ratio [AHR], 0.98; P = 0.03), and as a categorical variable with both recurrence-free survival (AHR, 2.49; P = 0.003) and overall survival (AHR, 1.91; P = 0.02). The total number of transfusions was also weakly associated with poor recurrence-free survival (AHR, 1.06; P = 0.03). Conclusions Our study is a retrospective analysis of the effects of anemia and transfusion on ovarian cancer. The rates of anemia in chemotherapy patients are higher than previously reported. Although maintaining average hemoglobin greater than 80 g/L during chemotherapy portends an improved overall survival, blood transfusion does not have any effect. The role of transfusion should therefore be limited to symptomatic patients while giving 1 unit at a time. Further prospective studies will be needed to confirm these results.