Taymaa May

Low malignant potential tumors with micropapillary features are molecularly similar to low-grade serous carcinoma of the ovary

OBJECTIVE Low-grade serous carcinoma (LGSC) is a chemoresistant ovarian neoplasm thought to potentially arise in a background of low malignant potential tumors (LMP), which are typically non-aggressive. However, LMP with micropapillary features (LMP-MP) have more aggressive clinical behavior and may represent an intermediate in progression to LGSC. The objective of this study was to obtain and compare gene expression profiles of LMP, LMP-MP and LGSC to determine if LMP-MP more closely resembles LGSC, and to identify genes involved in LGSC carcinogenesis. METHODS Epithelial cells from LMP (n=17), LMP-MP (n=9) and LGSC (n=11) were isolated by laser capture microdissection. RNA was extracted, reverse transcribed to cDNA, amplified and hybridized to Affymetrix U133 Plus2 genechip arrays. Gene expression data were checked for quality, filtered and significantly altered genes between subgroups were identified. Differential expression of selected genes was verified by RT-qPCR and immunohistochemistry. RESULTS Gene expression analysis identified differential expression between LMP and LMP-MP, LMP and LGSC but not LMP-MP and LGSC. Integration of differentially expressed genes into the protein interaction database CytoScape highlighted gene products in the MAPK pathway as differentially regulated between LMP and LGSC. Four genes were selected and validated by RT-qPCR performed on microarray samples (n=15) and immunohistochemistry on a representative microarray (n=57). CONCLUSION The gene expression profile of LMP-MP is similar to LGSC and distinct from LMP, reflecting their more aggressive clinical behavior. Candidate genes in the MAPK pathway were highlighted which may play a role in LGSC carcinogenesis and indicate potential therapeutic targets.

Current Chemotherapeutic Management of Patients with Gestational Trophoblastic Neoplasia

Gestational trophoblastic neoplasia (GTN) describes a heterogeneous group of interrelated lesions that arise from abnormal proliferation of placental trophoblasts. GTN lesions are histologically distinct, malignant lesions that include invasive hydatidiform mole, choriocarcinoma, placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT). GTN tumors are generally highly responsive to chemotherapy. Early stage GTN disease is often cured with single-agent chemotherapy. In contrast, advanced stage disease requires multiagent combination chemotherapeutic regimens to achieve a cure. Various adjuvant surgical procedures can be helpful to treat women with GTN. Patients require careful followup after completing treatment and recurrent disease should be aggressively managed. Women with a history of GTN are at increased risk of subsequent GTN, hence future pregnancies require careful monitoring to ensure normal gestational development. This article will review the workup, management and followup of women with all stages of GTN as well as with recurrent disease.

Low-grade, low-stage endometrioid endometrial adenocarcinoma: a clinicopathologic analysis of 324 cases focusing on frequency and pattern of myoinvasion.

Patients with low-stage, low-grade endometrial adenocarcinomas have a favorable prognosis; however, a subset has a risk of recurrence and death. We were interested in evaluating patterns of myometrial invasion and correlating them with clinical outcome to potentially identify patients at increased risk. A total of 324 cases of low-stage Grade 1 endometrial adenocarcinoma were reviewed to identify those with myoinvasion. The myoinvasive cases were classified on the basis of the pattern of invasion: infiltrating glands, microcystic elongated and fragmented (MELF; a distinctive histologic variant of the infiltrative gland pattern), broad front, adenomyosis like, and adenoma malignum. Depth of invasion and lymphovascular invasion were recorded, and a clinical follow-up of at least 2 y was obtained, as most recurrences occur in this time frame. Ninety-eight of 324 (30%) cases were invasive; 75 had >2 y of follow-up, with an average length of follow-up of >7 y (range, 24–154 mo; mean 87 mo). All patients had a hysterectomy and bilateral salpingo-oophorectomy; 39 (52%) also underwent a lymphadenectomy. Twenty-seven (36%) were superficially invasive (<10% myoinvasion), 42 (56%) invaded 10% to 49%, and 6 (8%) invaded >50%. Six (8%) cases exhibited cervical stromal invasion (Stage II); the rest were Stage I (65 IA, 4 IB). The invasive patterns consisted of infiltrative glands (48; 65%), a broad front (16; 21%), MELF (5; 7%), adenomyosis like (5; 7%), and adenoma malignum like (1, 1%). There were 65 Stage 1A cases and, of these, the myoinvasive pattern was as follows: 41 infiltrating glands, 15 broad front, 5 MELF, and 4 adenomyosis like. There were 4 Stage IB cases, of which 2 had infiltrating glands, 1 had adenoma malignum, and 1 displayed adenomyosis-like invasion. Six (8%) cases had cervical stromal invasion (Stage II), of which 5 had an infiltrative pattern of growth and 1 displayed a broad front. Lymphovascular invasion was noted in 6 cases (8%), all of which had infiltrative glands. The majority of Grade 1 endometrioid endometrial adenocarcinomas do not invade the myometrium. In cases with invasion, the infiltrative gland pattern was associated with higher stage, (3/4 Stage IB, 5/6 Stage II), lymphovascular invasion (4/6 cases), and recurrence (2/75 cases), suggesting that this growth pattern may be associated with tumors having other histologic features typically associated with more aggressive behavior.

Ten-year survival after epithelial ovarian cancer is not associated with BRCA mutation status

OBJECTIVES After a diagnosis of ovarian cancer, positive BRCA mutation status confers a transient mortality benefit that diminishes with time. The majority of women who survive for 10-12 years are effectively cured of their disease. Thus, it is important to estimate the probability of long-term survival by BRCA mutation status and treatment-related factors. METHODS We included unselected epithelial ovarian cancers diagnosed in Ontario, Canada from 1995 to 1999 and from 2002 to 2004. Clinical information was obtained from medical records. Survival status was determined by linkage to the Ontario Cancer Registry. We estimated the annual mortality for these patients. We compared women who did and did not survive 10 years for a range of factors including BRCA mutation status and extent of residual disease post-surgery. RESULTS Of the 1421 patients, 109 (7.7%) had BRCA1 mutations and 68 (4.8%) had BRCA2 mutations. A status of no residual disease was achieved by 39% of non-carriers and 19% of mutation carriers (P<0.0001). By 10-years of follow-up, 43% of non-carriers, 57% of BRCA1 mutation carriers and 69% of BRCA2 mutation carriers had died from ovarian cancer. Among women with stage III/IV serous cancers and no residual disease, the 10-year actuarial survival was 42% for non-carriers and 29% for mutation carriers (P=0.40). CONCLUSION The initial survival advantage among women with BRCA mutations may reflect a higher initial sensitivity of BRCA carriers to chemotherapy, but this response does not predict long-term survival. The strongest predictor of long-term survival is status of no residual disease at resection.

Comparison of clinical outcomes of patients with clear cell and endometrioid ovarian cancer associated with endometriosis to papillary serous carcinoma of the ovary

OBJECTIVE The aim of this investigation was to compare outcomes of patients with clear cell carcinoma (CCC) and endometrioid carcinoma (EC) of the ovary associated with endometriosis to patients with ovarian papillary serous carcinoma (PSC). METHODS Patients with CCC and EC of the ovary associated with endometriosis were identified and matched by age and stage to PSC controls. Students t test and chi square test were used to analyze continuous and categorical data. The Kaplan-Meier method was used for survival analysis. RESULTS 67 cases associated with endometriosis were identified, of which 45 were arising in endometriosis. Cases were matched to 134 PSC controls. 27 patients with tumors associated with endometriosis presented at stage I (40.3%), 27 at stage II (40.3%), ten at stage III (14.9%) and three at stage IV (4.5%). There was no difference in rate of optimal cytoreduction or response to chemotherapy in cases vs. PSC controls. There was a significant increase in synchronous endometrial cancer in tumors associated with endometriosis compared to PSC (25.4% vs. 3.7%; P<0.001). 18 cases (26.9%) had recurrent disease vs. 55 (41%) controls (P=0.03). The 5-year disease-free survival (DFS) and overall survival (OS) of patients with tumors associated with endometriosis compared to PSC controls were 75% vs. 55% (P=0.03) and 85% vs. 77% (P=0.2), respectively. CONCLUSIONS Patients with tumors associated with endometriosis had a higher rate of synchronous endometrial cancer. Cases also demonstrated a lower rate of recurrence and improved 5 year DFS; however, this did not translate into a difference in OS.

Genomic aberrations in cervical adenocarcinomas in Hong Kong Chinese women.

Although the rates of cervical squamous cell carcinoma have been declining, the rates of cervical adenocarcinoma are increasing in some countries. Outcomes for advanced cervical adenocarcinoma remain poor. Precision mapping of genetic alterations in cervical adenocarcinoma may enable better selection of therapies and deliver improved outcomes when combined with new sequencing diagnostics. We present whole‐exome sequencing results from 15 cervical adenocarcinomas and paired normal samples from Hong Kong Chinese women. These data revealed a heterogeneous mutation spectrum and identified several frequently altered genes including FAT1, ARID1A, ERBB2 and PIK3CA. Exome sequencing identified human papillomavirus (HPV) sequences in 13 tumors in which the HPV genome might have integrated into and hence disrupted the functions of certain exons, raising the possibility that HPV integration can alter pathways other than p53 and pRb. Together, these provisionary data suggest the potential for individualized therapies for cervical adenocarcinoma based on genomic information.

Evaluation of Two Management Strategies for Preoperative Grade 1 Endometrial Cancer

OBJECTIVE: To compare the practices, adjuvant treatment, and outcomes of patients with preoperatively assessed grade 1 endometrioid endometrial cancer between two academic gynecologic oncology centers that use different treatment strategies. METHODS: A retrospective analysis was performed at Duke University Medical Center (Duke) and the Toronto Sunnybrook Regional Cancer Center (Sunnybrook) between 1991 and 2007. Patients at Duke generally underwent surgical staging unless intraoperative assessment identified a negligible risk of nodal disease. Patients at Sunnybrook generally did not undergo surgical staging. RESULTS: A total of 494 patients (272 from Duke and 222 from Sunnybrook were identified with preoperative, central-review–confirming, grade 1, endometrioid, endometrial cancer. Groups were similar in grade, final histology, type of hysterectomy, and length of hospital stay. Patients from Sunnybrook were older (aged 62 years compared with 59 years, P=.001) and were more likely to have capillary lymphatic space involvement (18.2% compared with 8.3%, P=.003) and cervical involvement (12.2% compared with 3.7%, P<.001). Approximately 2% of cases were upgraded to high grade on final specimen. Lymphadenectomy was performed on 49.4% of patients at Duke compared with 11.7% of patients at Sunnybrook. Overall 3-year survival was 96% at Duke and 96% at Sunnybrook (P=.217). Three-year recurrence-free survival was 96% at Duke and 95% at Sunnybrook (P=.327). CONCLUSION: Despite differences in practice and slight differences in patient populations, the recurrence-free and overall survival of women with preoperative centrally reviewed grade 1 endometrial cancer is excellent and without statistically significant difference between the two centers. LEVEL OF EVIDENCE: III

Low-grade and high-grade serous Mullerian carcinoma: Review and analysis of publicly available gene expression profiles

OBJECTIVE Mullerian low grade serous carcinoma (LGSC) and high grade serous carcinoma (HGSC) have distinct molecular profiles, clinical behavior and treatment response. Our objective was to study the biological profiles of these carcinomas. METHODS This study examines publicly available gene expression profiles of LGSC and HGSC to identify differentially expressed genes and key pathways involved in carcinogenesis and chemotherapy response. RESULTS Our analysis supports the hypothesis that serous mullerian carcinoma develop through two different pathways yielding two distinct malignancies, namely LGSC and HGSC. Furthermore, genes potentially involved in chemotherapeutic resistance of LGSC were identified. Suppressing the levels of these genes/proteins may increase clinical response to standard chemotherapy in patients with LGSC. CONCLUSION In summary, this review shows the molecular profile of LGSC and HGSC through multi-center analysis of gene expression profiles of these tumors. The gene signatures of these neoplasms may potentially be used to develop disease-specific, targeted therapy for LGSC and HGSC.

The optimal time for surgery in women with serous ovarian cancer.

BACKGROUND Advanced high-grade serous ovarian carcinoma (HGSC) is commonly treated with surgery and chemotherapy. We investigated the survival of patients treated with primary or interval surgery at different times following neoadjuvant chemotherapy. Their survival was compared with that of patients treated with primary cytoreductive surgery and adjuvant chemotherapy. METHODS Patients with stage III or IV HGSC were included in this retrospective cohort study. Clinical data were obtained from patient records. Patients were divided into 2 groups based on treatment with neoadjuvant chemotherapy and interval cytoreductive surgery (NAC) or with primary cytoreductive surgery and adjuvant chemotherapy (PCS). Study groups were stratified by several clinical variables. RESULTS We included 334 patients in our study: 156 in the NAC and 178 in the PCS groups. Survival of patients in the NAC group was independent of when they underwent interval cytoreductive surgery following initiation of neoadjuvant chemotherapy (p < 0.001). Optimal surgical cytoreduction had no impact on overall survival in the NAC group (p < 0.001). Optimal cytoreduction (p < 0.001) and platinum sensitivity (p < 0.001) were independent predictors of improved survival in the PCS but not in the NAC group. Patients in the NAC group had significantly worse overall survival than those in the PCS group (31.6 v. 61.3 mo, p < 0.001). CONCLUSION Women with advanced HGSC who underwent PCS had better survival than those who underwent interval NAC, regardless of the number of cycles of neoadjuvant therapy. Optimal cytoreduction did not provide a survival advantage in the NAC group.

Changes in clinical presentation of postterm choriocarcinoma at the New England Trophoblastic Disease Center in recent years

OBJECTIVE To review the last 15 year experience of choriocarcinoma following a term gestation at the New England Trophoblastic Disease Center (NETDC) and compare these results to earlier data to determine any changes in the clinical presentation and outcome of this disease. METHODS Women with postterm choriocarcinoma from 1996 through 2011 followed by the NETDC were identified by diagnosis codes. Twenty charts were identified and reviewed. These data were then compared to published results from the NETDC of 44 women from 1964 to 1996. RESULTS Time from antecedent pregnancy to diagnosis of choriocarcinoma was significantly longer in the current series, 46.1 vs. 19.7 weeks (p = 0.03). Despite this change, patient outcomes remained comparable, with similar overall mortality rates (13% vs. 10%, p = NS). However, patient presentation was notably different. In the early series, five (11%) infants suffered hydrops or stillbirth, while in the recent series there were no adverse infant outcomes (p = 0.08). Six women in the current series presented in the absence of symptoms suspicious for choriocarcinoma (either by an incidental positive pregnancy test without other symptoms or by placental pathology), compared to one woman in the prior series (30% vs. 2%, p = 0.001). CONCLUSIONS In recent years postterm choriocarcinoma is being diagnosed or referred later after the antecedent pregnancy at our regional referral center. Recent patients more commonly have no other symptoms than a question of pregnancy and are less likely diagnosed due to the presence of fetal hydrops or stillbirth. Despite later diagnoses, survival with postterm choriocarcinoma continues to be high.