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issn:1048-891
2.  Staging Lymphadenectomy in Patients with Clear Cell Carcinoma of the Ovary 
Objective
The purpose of this study was to assess the rate of lymph node (LN) metastasis in comprehensively staged ovarian clear cell carcinoma (OCCC) clinically confined to the ovary and determine factors associated with LN metastasis.
Methods
We identified all cases of OCCC treated at four institutions from January 1994 through December 2011. We included cases with disease grossly confined to the ovary that had surgical staging performed, including at least 10 LNs sampled. Clinical and pathologic data were abstracted from electronic medical records and a de-identified data set was compiled and processed at a single institution. Factors potentially associated with LN metastasis were tested. Appropriate statistical tests were performed.
Results
We identified 145 eligible cases that met the criteria for this analysis. Median age was 52.9 years (range, 30–81), and median total LN count was 19 (range, 10–74). Seven (4.8%) of 145 comprehensively staged cases had LN metastasis; 6 of these cases (4.1%) were isolated metastasis. Cytologic washings, peritoneal, omental and fallopian tube involvement were not associated with nodal metastasis. Cases with ovarian surface involvement and positive cytology had a 37.5% incidence of LN positivity, which was statistically meaningful when compared with all other cases (p=0.003).
Conclusion
Women who underwent comprehensive staging for clinical stage I OCCC had a LN metastasis rate of 4.8%. The subgroup of cases with both ovarian surface involvement and positive cytology had the highest incidence of LN metastasis. This may influence clinical decision making on whether to perform lymphadenectomy in patients with incidental OCCC found after salpingo-oophorectomy.
doi:10.1097/IGC.0000000000000559
PMCID: PMC4891809  PMID: 26509849
ovarian cancer; lymph node; metastasis; staging
3.  Differentiating Squamous Cell Carcinoma of the Cervix and Epithelioid Trophoblastic Tumor 
Background
Epithelioid trophoblastic tumor (ETT) is a recently described subtype of gestational trophoblastic neoplasia (GTN). Its diagnosis requires a high level of suspicion because it is often mistaken for more common cervical or uterine corpus epithelial neoplasms.
Case
This is a 39-year-old woman who presented with a cervical mass and positive human chorionic gonadotropin and was diagnosed with both locally advanced squamous cell cervical carcinoma and nonmetastatic GTN. She was treated unsuccessfully with concurrent intravenous cisplatin plus pelvic radiation and single-agent intravenous methotrexate. A retrospective review of the cervical biopsy using immunohistochemistry as well as genotyping of the tumor changed the original diagnosis to ETT. It is known that ETT is relatively unresponsive to chemotherapy compared with most other types of GTN; therefore, surgery would have been the optimal treatment. She died despite multiple salvage chemotherapies.
Conclusions
Malignant GTN is one of the most curable gynecologic malignancies; however, its correct diagnosis is critical for the appropriate treatment. It can be easily misdiagnosed as a carcinoma because of their morphologic similarity. Genetic finger-printing and immunohistochemistry are potentially valuable tools to confirm the diagnosis of ETT.
doi:10.1097/IGC.0b013e31821a278d
PMCID: PMC5109971  PMID: 21697681
Epithelioid trophoblastic tumor; Gestational trophoblastic neoplasm; Immunohistochemistry
4.  Metastasis-Associated in Colon Cancer-1 Associates With Poor Prognosis and Promotes Cell Invasion and Angiogenesis in Human Cervical Cancer 
Supplemental digital content is available in the text.
Objective
The aim of this study is to investigate the clinicopathologic significance and potential role of metastasis-associated in colon cancer-1 (MACC1) in the progression of cervical cancer.
Methods
MACC1 expression was examined in cervical cancer cell lines, 6 matched cervical cancer tissues, and adjacent noncancerous tissues using Western blotting and real-time reverse transcriptase polymerase chain reaction. MACC1 protein expression and localization were determined in 181 paraffin-embedded archived cervical cancer samples using immunohistochemistry. Statistical analyses were applied to evaluate the clinicopathologic significance. The effects of MACC1 on cell migration, invasion, and angiogenesis were examined using migration assay, wound healing assay, 3-dimensional morphogenesis assay, and chicken chorioallantoic membrane assay. Western blotting was performed to examine the impact of MACC1 on the Akt and nuclear factor κB signaling pathways.
Results
Both protein and messenger RNA levels of MACC1 was up-regulated in cervical cancer cell lines and cervical cancer tissues, as compared with normal tissues. High MACC1 expression was detected in 96 (53%) of 181 of the cervical cancer tissues. In addition, high MACC1 expression correlated significantly with aggressiveness of cervical cancer, including International Federation of Gynecology and Obstetric stage (P = 0.001), pelvic lymph node metastasis (P = 0.004), recurrence (P = 0.037), and poor survival (P = 0.001). Moreover, enforced expression of MACC1 in cervical cancer cell lines significantly enhanced cell migration, invasion, and angiogenesis. Conversely, knockdown of MACC1 caused an inhibition of cell migration, invasion, and angiogenesis. Up-regulation of MACC1 increased, but knockdown of MACC1 decreased the expression of matrix metalloproteinase-2 and matrix metalloproteinase-9. Furthermore, enforced expression of MACC1 could enhance, but knockdown of MACC1 could reduce AKT and nuclear factor κB pathway activity.
Conclusions
Our findings suggest that MACC1 protein, as a valuable marker of cervical cancer prognosis, plays an important role in the progression of human cervical cancer cells.
doi:10.1097/IGC.0000000000000524
PMCID: PMC5106080  PMID: 26332389
Cervical cancer; MACC1; Invasion; Angiogenesis; Akt; NF-κB
5.  Should the Optimal Adjuvant Treatment for Patients With Early-Stage Endometrial Cancer With High-Intermediate Risk Factors Depend on Tumor Grade? 
Objectives
To explore whether the optimal adjuvant treatments for patients with early-stage endometrial cancer with high-intermediate risk (HIR) factors should depend on tumor grade.
Methods
A retrospective analysis of patients with HIR endometrial cancer from 1999 to 2012 was conducted. The adjuvant treatments and survival were evaluated.
Results
A total of 129 patients with HIR were identified, of which 71 had grade 1–2 tumor and 58 had grade 3 tumor. The adjuvant treatment chosen differed significantly between patients with grade 1–2 and grade 3 tumors (P < 0.001). Most of the patients (76.1%) with grade 1–2 tumors received no adjuvant treatment; however, chemotherapy alone was the most frequent (75.9%) adjuvant treatment for patients with grade 3 tumors. In the grade 1–2 group, no significant differences in the 5-year progression-free survival (94.1% vs 96.3%; P = 0.857) and overall survival (OS) rates (94.1% vs 98.1%; P = 0.401), respectively, were observed between patients who received adjuvant treatment (radiation and chemotherapy with or without radiation) and those who did not. For grade 3 disease, patients undergoing adjuvant chemotherapy alone had a favorable outcome with the 5-year progression-free survival rate of 84.4% and the OS rate of 95.5%.
Conclusion
It is logical to speculate that surgery followed by observation might be sufficient for patients with HIR with grade 1–2 tumor. Further prospective trials are required to confirm the issue owing to the limited number of this population. More studies are warranted to clarify the feasibility and efficacy of adjuvant chemotherapy alone in patients with HIR with grade 3 tumor.
doi:10.1097/IGC.0000000000000572
PMCID: PMC5106082  PMID: 26397067
Endometrial cancer; High-intermediate risk; Adjuvant chemotherapy; Adjuvant radiotherapy
6.  Understanding Lymphatic Drainage Pathways of the Ovaries to Predict Sites for Sentinel Nodes in Ovarian Cancer 
Supplemental digital content is available in the text.
Objective
In ovarian cancer, detection of sentinel nodes is an upcoming procedure. Perioperative determination of the patient’s sentinel node(s) might prevent a radical lymphadenectomy and associated morbidity. It is essential to understand the lymphatic drainage pathways of the ovaries, which are surprisingly up till now poorly investigated, to predict the anatomical regions where sentinel nodes can be found. We aimed to describe the lymphatic drainage pathways of the human ovaries including their compartmental fascia borders.
Methods
A series of 3 human female fetuses and tissues samples from 1 human cadaveric specimen were studied. Immunohistochemical analysis was performed on paraffin-embedded transverse sections (8 or 10 μm) using antibodies against Lyve-1, S100, and α-smooth muscle actin to identify the lymphatic endothelium, Schwann, and smooth muscle cells, respectively. Three-dimensional reconstructions were created.
Results
Two major and 1 minor lymphatic drainage pathways from the ovaries were detected. One pathway drained via the proper ligament of the ovaries (ovarian ligament) toward the lymph nodes in the obturator fossa and the internal iliac artery. Another pathway drained the ovaries via the suspensory ligament (infundibulopelvic ligament) toward the para-aortic and paracaval lymph nodes. A third minor pathway drained the ovaries via the round ligament to the inguinal lymph nodes. Lymph vessels draining the fallopian tube all followed the lymphatic drainage pathways of the ovaries.
Conclusions
The lymphatic drainage pathways of the ovaries invariably run via the suspensory ligament (infundibulopelvic ligament) and the proper ligament of the ovaries (ovarian ligament), as well as through the round ligament of the uterus. Because ovarian cancer might spread lymphogenously via these routes, the sentinel node can be detected in the para-aortic and paracaval regions, obturator fossa and surrounding internal iliac arteries, and inguinal regions. These findings support the strategy of injecting tracers in both ovarian ligaments to identify sentinel nodes.
doi:10.1097/IGC.0000000000000514
PMCID: PMC5106084  PMID: 26397066
Lymphatic drainage ovaries; Sentinel node detection
7.  Cytokeratin 5 positive cells represent a therapy resistant subpopulation in epithelial ovarian cancer 
Objective
Cytokeratin 5 (CK5) is an epithelial cell marker implicated in stem and progenitor cell activity in glandular reproductive tissues and endocrine and chemotherapy resistance in estrogen receptor (ER)+ breast cancer. The goal of this study was to determine the prevalence of CK5 expression in ovarian cancer and the response of CK5+ cell populations to cisplatin therapy.
Materials and Methods
CK5 expression was evaluated in two ovarian tissue microarrays, representing 137 neoplasms, and six ovarian cancer cell lines. Cell lines were treated with IC50 cisplatin and the prevalence of CK5+ cells pre- and post-treatment determined. Proliferation of CK5+ vs. CK5− cell populations was determined using bromodeoxyuridine (BrdU) incorporation. Chemotherapy induced apoptosis in CK5+ vs. CK5− cells was measured using immunohistochemical staining for cleaved caspase-3.
Results
CK5 was expressed in 39.3% (42/107) of epithelial ovarian cancers with a range of 1-80% positive cells. Serous and endometrioid histologic subtypes had the highest percentage of CK5+ specimens. CK5 expression correlated with ER positivity (38/42 CK5+ tumors were also ER+). CK5 was expressed in 5/6 overall and 4/4 ER+ epithelial ovarian cancer cell lines ranging from 2.4-52.7% positive cells. CK5+ compared to CK5− cells were slower proliferating. The prevalence of CK5+ cells increased following 48 hour cisplatin treatment in 4/5 cell lines tested. CK5+ compared to CK5− ovarian cancer cells were more resistant to cisplatin induced apoptosis.
Conclusions
CK5 is expressed in a significant proportion of epithelial ovarian cancers and represents a slower proliferating, chemoresistant subpopulation that may warrant co-targeting in combination therapy.
doi:10.1097/IGC.0000000000000553
PMCID: PMC4635519  PMID: 26495758
epithelial ovarian cancer; cytokeratin 5; cisplatin; drug resistance; estrogen receptor.
8.  Oral Contraceptive Use and Reproductive Characteristics Affect Survival in Patients With Epithelial Ovarian Cancer 
Objectives
Prognostic risk factors influencing survival in patients with epithelial ovarian cancer (EOC) include tumor stage, grade, histologic subtype, debulking, and platinum status. Little is known about the impact of hormonal milieu and reproductive factors before cancer diagnosis on clinical outcome. We sought to evaluate whether oral contraceptive (OC) use carries any prognostic significance on overall survival (OS) in patients with EOC.
Methods
Newly diagnosed patients with EOC, fallopian tube, and primary peritoneal cancers between 1982 and 1998 were prospectively evaluated with a comprehensive epidemiologic questionnaire. A retrospective chart review was performed to abstract clinicopathologic data, including OS. A Kaplan-Meier analysis was performed to compare survival across various exposures. A Cox regression model was used to compute adjusted hazards ratios (aHRs) and 95% confidence intervals (CIs).
Results
We identified 387 newly diagnosed cancers with evaluable information in this cohort. Decreased risk of death was observed in women who reported prior use of OC (aHR, 0.79; 95% CI, 0.58–1.09), previous pregnancy (aHR, 0.77; 95% CI, 0.57–1.04), or a live birth (aHR, 0.81; 95% CI, 0.60–1.08) after adjusting for age at diagnosis, stage, and histologic subtype. Oral contraceptive use was associated with a crude reduced risk of death (HR, 0.55; 95% CI, 0.42–0.72), with reported median OS of 81 months in OC users versus 46 months in nonusers. Patients who reported a single live birth experienced the largest potential survival advantage (aHR, 0.61; 95% CI, 0.39–0.94). Oral contraceptive use and prior pregnancy were associated with improved survival across all strata.
Conclusions
Oral contraceptive use may have lasting effects on epithelial ovarian tumor characteristics conferring favorable prognosis. Putative mechanisms that affect tumor biology include complex interactions between ovarian cells, host immune cells, and hormonal microenvironment during carcinogenesis. Future efforts should be directed to determine the role of reproductive factors in antitumor immunity.
doi:10.1097/IGC.0000000000000540
PMCID: PMC4665090  PMID: 26273932
Reproductive characteristics; Oral contraceptives; Parity; Ovarian cancer survival
9.  Dysregulated Expression of Long Noncoding RNAs in Ovarian Cancer 
Abstract
Ovarian cancer is the leading cause of death among women with gynecologic malignancies. The development and progression of ovarian cancer are complex and a multiple-step process. New biomarker molecules for diagnostic and prognostic are essential for novel therapeutic targets and to extend the survival time of patients with ovarian cancer. Long noncoding RNAs (lncRNAs) are non–protein-coding transcripts longer than 200 nucleotides that have recently been found as key regulators of various biological processes and to be involved in the development and progression of many diseases including cancers. In this review, we summarized the expression pattern of several dysregulated lncRNAs (HOTAIR, H19, XIST, and HOST2) and the functional molecular mechanism of these lncRNAs on the initiation and progression of ovarian cancer. The lncRNAs as biomarkers may be used for current and future clinical diagnosis, therapeutics, and prognosis.
doi:10.1097/IGC.0000000000000828
PMCID: PMC5084630  PMID: 27603915
lncRNA; Ovarian cancer; HOTAIR; H19; XIST; HOST2; OC - ovarian cancer; lncRNA - long noncoding RNA; EOC - epithelial ovarian cancer; SOC - serous ovarian cancer; ORF - open reading frame; ncRNAs - noncoding RNAs; HOTAIR - HOX transcript antisense intergenic RNA; XIST - X inactive-specific transcript; Xi - X chromosome inactivation; MALAT1 - metastasis-associated lung adenocarcinoma transcript 1; MEG3 - maternally expressed gene 3; HOST2 - human ovarian cancer-specific transcript 2; ICR - imprinting control region; PRC2 - polycomb-repressive complex 2; EMT - epithelial-mesenchymal transition; IGFII - insulin-like growth factor II; UCA1 - urothelial cancer associated 1; MMP2 - matrix metallopeptidase 2; MMP9 - matrix metallopeptidase 9; NEAT - 1-nuclear paraspeckle assembly transcript 1; PSPC1 - protein-coding gene paraspeckle component 1
10.  Does the Type of Surgical Approach and the Use of Uterine Manipulators Influence the Disease-Free Survival and Recurrence Rates in Early-Stage Endometrial Cancer? 
Objective
The purpose of this study was to compare the long-term safety, disease-free survival, and recurrence rate of total laparoscopic hysterectomy using uterine manipulator and abdominal hysterectomy in the surgical treatment in early-stage endometrial cancer.
Study Design
This was a cohort study of 147 patients with clinical endometrial cancer (laparoscopic surgery group, 77 women; laparotomy group, 70 women). Data were evaluated and analyzed by intention-to-treat principle, and survival data of stage I endometrial cancer (129 patients; 66 from laparoscopic surgery group and 60 from laparotomy group) were estimated by using the Kaplan-Meier curves.
Results
After a follow-up period of 60 months for both laparoscopic surgery and laparotomy groups, no significant difference in the cumulative recurrence rates (7.4% and 13.1%, P = 0.091) and overall survival (97.1% and 95.1%, P = 0.592) was detected between both groups of stage I endometrial cancer. Conversion to laparotomy occurred in 10.4% (8/77) of the laparoscopic procedures. Laparoscopic hysterectomy was associated with less use of pain medication (P = 0.001) and a shorter hospital stay (P < 0.001), but the procedure took longer than laparotomic hysterectomy (P < 0.001). The proportion of patients with intraoperative and long-term complications was not significantly different between both groups. The use of uterine manipulators did not have increased recurrence rate in patients treated with laparoscopic approach.
Conclusions
The laparoscopic surgery approach to early-stage endometrial cancer using uterine manipulators is as safe and effective as the laparotomic approach.
doi:10.1097/IGC.0000000000000808
PMCID: PMC5084631  PMID: 27518143
Disease free survival; Overall survival; Endometrial cancer; Hysterectomy; Laparoscopy; Laparotomy; Surgery; Uterine manipulator
11.  Evaluation of Metachronous Breast and Endometrial Cancers 
Background
The time interval between diagnoses of breast cancer (BC) and endometrial cancer (EC) is not well established in women with metachronous primary tumors. We sought to examine this interval and identify associations with treatment-related and clinicopathologic factors.
Methods
We identified 141 patients who developed both cancers during 1966 to 2013. Patients were divided into 2 groups: group 1, BC first, and group 2, EC first. Subanalysis performed of group 1 (59 patients) stratified around adjuvant tamoxifen use: pre-1990 BC diagnosis and post.
Results
Fifty-nine and 82 patients were in groups 1 and 2, respectively. The mean time interval was comparable (76 vs 74 months, P = 0.861). Subanalysis divided group 1 into pre- (n = 27) and post- (n = 32) 1990 and resulted in different mean time intervals between diagnosis of metachronous cancers (106 vs 50 months, respectively [P = 0.042]). Median progression-free survival (PFS) and overall survival (OS) for EC were longer in the pre group (PFS, 51 vs 26 months [P = 0.169]; OS, 59 vs 27 months [P = 0.190]). Median PFS and OS for BC were also longer in this group (PFS, 147 vs 109 months [P = 0.005]; OS, 166 vs 114 months [P < 0.001]).
Conclusions
Our data indicate the mean time interval between the diagnosis of EC and BC was approximately 6 years. Disease-specific EC survival was worse for patients with a previous diagnosis of BC. Stratification around implementation of tamoxifen use shows comparable grade and stage but different time interval and survival, suggesting resulting effects from adjuvant therapy for BC. These results are useful in counseling women at risk.
doi:10.1097/IGC.0000000000000785
PMCID: PMC5064444  PMID: 27648713
Metachronous endometrial and breast cancer; Tamoxifen
12.  Expression Patterns of the Wnt Pathway Inhibitors Dickkopf3 and Secreted Frizzled-Related Proteins 1 and 4 in Endometrial Endometrioid Adenocarcinoma 
Objective
The aim of the study was to determine the differential expression patterns of the wingless-type (Wnt) pathway inhibitors Dkk3 (Dickkopf 3), SFRP1 (secreted frizzled-related protein 1), and SFRP4 in normal müllerian tissue and endometrial endometrioid adenocarcinoma specimens.
Methods
Messenger RNA (mRNA) and protein levels of the Wnt pathway inhibitors Dkk3, SFRP1, and SFRP4 were evaluated by real-time reverse transcription–polymerase chain reaction and Western blot analysis. A total of 87 human tissue specimens were obtained from 60 women who participated in Gynecologic Oncology Group protocol 210. Twenty-seven normal müllerian tissues, 32 early-stage, and 28 advanced-stage endometrial endometrioid cancer specimens were analyzed.
Results
Median age for this cohort was 60 years, with median body mass index of 32 kg/m2. There was a difference in Dkk3 protein expression between normal müllerian tissues and primary endometrial endometrioid adenocarcinoma samples (P = 0.05). There was down-regulation of Dkk3, SFRP1, and SFRP4 mRNA expression in patients with high-grade disease (P = 0.08, 0.06, and 0.05, respectfully). Furthermore, a decrease in SFRP1 and SFPR4 mRNA expression was noted in patients with a diagnosis of locoregional and distant disease recurrence. Lastly, a trend toward decreased progression-free survival in patients with low Dkk3, SFRP1, and SFRP4 mRNA expression levels was noted.
Conclusions
Wnt pathway inhibitor (Dkk3, sFRP1, and/or sFRP4) expression was down-regulated in patients with high-grade disease and was associated with locoregional and distant disease recurrence. Despite sample size (power) limitations, these results support previous preclinical studies and may suggest a therapeutic role for Wnt signaling in endometrial cancer.
doi:10.1097/IGC.0000000000000563
PMCID: PMC5061499  PMID: 26397159
Dkk3; SFRP1; SFRP4; Uterine cancer; Wnt pathway
13.  Impact of lymph node ratio and adjuvant therapy in node-positive endometrioid endometrial cancer 
Objectives
To determine if the ratio of positive to negative lymph nodes, or lymph node ratio (LNR), is a prognostic variable in patients with node-positive endometrial cancer and the impact of adjuvant therapy on survival.
Methods
After IRB approval, a retrospective review of patients diagnosed with stage IIIC endometrioid or mixed endometrioid endometrial cancer at a single institution from January 2000 through October 2011 was performed. Clinicopathologic and adjuvant treatment data was collected. Univariate and multivariate analysis were used to identify prognostic factors for progression-free (PFS) and overall survival (OS).
Results
One hundred twenty-four patients with stage IIIC1 (n=64) and IIIC2 (n=60) endometrial cancer were included in the analysis. Median age was 60 years (range 25-84) and median follow-up was 49.4 months (range 0.1-301.6). Age >70 years was identified as a prognostic factor for worse PFS (p=0.0002) and OS (p=0.0002) on multivariate analysis. Patients in this cohort receiving any adjuvant radiotherapy showed improved PFS (HR 0.34, 95% CI 0.13-0.90, p=0.03) compared to those receiving any adjuvant chemotherapy (HR 2.33, 95% CI 1.16-4.65, p=0.02). In a subgroup analysis, patients with ≥ 10 nodes removed (n=81) with a LNR >50% had a PFS of 25.2 months compared to 135.6 months with a LNR ≤50% (HR 3.87, 95% CI 1.15-13.04, p=0.03).
Conclusions
LNR may define a subgroup of stage IIIC endometrial cancers at increased risk for recurrence. Adjuvant radiotherapy was associated with decreased recurrence risk.
doi:10.1097/IGC.0000000000000510
PMCID: PMC4581897  PMID: 26332387
14.  Complementary prognostic value of pelvic MRI and whole-body FDG PET/CT in the pretreatment assessment of patients with cervical cancer 
Objective
To evaluate the incremental prognostic value of pelvic magnetic resonance imaging (MRI) and whole-body 18F-fluorodeoxyglucose (FDG) positron-emission tomography/computed tomography (PET/CT) findings compared to clinical-histopathologic factors in patients with newly-diagnosed cervical cancer.
Methods
The institutional review board approved this retrospective study of 114 patients (median age 40.6 years) with International Federation of Gynecology and Obstetrics (FIGO) stage I-IVB cervical cancer who underwent pre-treatment MRI and PET/CT. All scans were reviewed for locoregional tumor extent, pelvic or/and paraaortic lymphadenopathy, and distant metastases. Univariate Cox proportional hazard regression was performed to evaluate associations between clinical-histopathologic factors, imaging findings and progression-free survival (PFS). Multivariate models were built using independent predictors for PFS. Harrell’s C was used to measure concordance (C-index).
Results
Forty patients progressed within a median time of 10.4 months (range: 0.4–40.3 months). At univariate analysis, age, FIGO stage, tumor histology, tumor grade and all MRI and PET/CT features were significantly associated with PFS (p<0.0001-p=0.0474). A multivariate model including clinical and imaging parameters (parametrial invasion on MRI and paraaortic lymphadenopathy/distant metastases on PET/CT) had significantly higher concordance for predicting PFS than a model including clinical parameters only (C-index: 0.81 [95%CI: 0.75–0.87] vs. 0.68 [95% CI: 0.59–0.78], p<0.001). The comparison of C-indices for the combined clinical and imaging model approached significance when compared to a FIGO stage model (C-index: 0.81 [95%CI: 0.75–0.87] vs. 0.75 [95% CI: 0.69–0.82, p=0.058).
Conclusion
In patients with newly-diagnosed cervical cancer, a prognostic model including combined MRI and PET/CT findings provides information that complements clinical and histopathologic factors.
doi:10.1097/IGC.0000000000000519
PMCID: PMC4998040  PMID: 26397068
15.  Oxaliplatin Is a Safe Alternative Option for Patients With Recurrent Gynecologic Cancers After Hypersensitivity Reaction to Carboplatin 
Objective
The aim of this study was to determine the tolerability and efficacy of oxaliplatin in patientswith recurrent gynecologic malignancies after carboplatin hypersensitivity reactions in comparison with conventionally used cisplatin.
Methods
Forty-six patients were treated with platinum-based chemotherapy from 2006 to 2011 and developed hypersensitivity reactions to carboplatin. Oxaliplatin was administered to 27 patients; 19 patients received cisplatin. Clinicopathologic variables, toxicity, and time-to-failure were analyzed retrospectively using descriptive statistics, Fisher exact, and independent sample permutation t tests.
Results
The median number of carboplatin cycles and cumulative dose before reaction were similar in the oxaliplatin and cisplatin groups, respectively (6 vs 7.5 cycles, P = 0.93; 980 [662] mg vs 686 [579.6] mg, P = 0.49). Non–life-threatening hypersensitivity reaction to oxaliplatin developed in 2 of 27 patients. No reactions to cisplatin occurred. The median number of oxaliplatin/cisplatin cycles was 6 in both groups. Complete response to therapy was 34.6% (oxaliplatin) and 31.6% (cisplatin); stable disease was seen in 50.0% and 36.8% of oxaliplatin- and cisplatin-treated patients, respectively (P = 0.46). Exposure to oxaliplatin resulted in less neurotoxicity than cisplatin (25.9% vs 68.4%, P = 0.01). The median number of prior chemotherapy lines in both groups was 2. The median time-to-failure was 10.8 months in oxaliplatin group and 9.8 months in cisplatin group (P = 0.86).
Conclusions
Salvage therapy with oxaliplatin after hypersensitivity reaction to carboplatin is associated with excellent tolerability and time-to-failure comparable to cisplatin. When further administration of carboplatin is precluded, oxaliplatin represents a safe and effective treatment strategy in the platinum-sensitive relapse setting. The significantly lower neurotoxicity profile makes it an attractive alternative to cisplatin.
doi:10.1097/IGC.0000000000000307
PMCID: PMC5042199  PMID: 25356535
Carboplatin hypersensitivity; Oxaliplatin; Cisplatin
16.  Lymphovascular space invasion portends poor prognosis in low-risk endometrial cancer 
Objective
The prognostic significance of lymphovascular space invasion (LVSI) in patients with early-stage endometrial cancer is not established. We sought to determine if LVSI status in patients with early-stage low-risk endometrial cancer correlates with recurrence and survival.
Methods
The records of all women who underwent hysterectomy for primary treatment of endometrial cancer from January 2006 through January 2011 at one academic institution were reviewed. Patients with grade 1 or 2 endometrioid histology, myometrial invasion less than 50%, and disease confined to the uterus (clinical FIGO stage IA) were analyzed. Fisher’s exact test and the Wilcoxon rank-sum test were applied to compare patients with and without LVSI. Recurrence-free survival (RFS) and overall survival (OS) were calculated using the Kaplan-Meier method.
Results
Two hundred forty patients met the inclusion criteria. Forty (16.7%) had LVSI. Ninety-one patients (37.9%) underwent lymphadenectomy. Median tumor size was 30 mm in patients with and 26 mm in patients without LVSI (p=0.150). Thirty patients (12.5%) received adjuvant therapy. Site of recurrence did not differ between patients with and without LVSI. Patients with LVSI were more likely to have myometrial invasion (p<0.001), postoperative pathologic grade 2 disease (p<0.001), to undergo lymphadenectomy (p=0.049) and receive adjuvant therapy (p<0.001). The 5-year cumulative incidence of recurrence was 3.8% in the no-LVSI group and 14.2% in the LVSI group (p=0.053). The presence of LVSI was significantly associated with worse RFS (p=0.002) and OS (p=0.013).
Conclusion
Patients with low-risk endometrial cancer and LVSI have worse RFS and OS despite being more likely to undergo lymphadenectomy and adjuvant therapy.
doi:10.1097/IGC.0000000000000490
PMCID: PMC4549160  PMID: 26067863
17.  Clinical Outcome of Isolated Serous Tubal Intraepithelial Carcinomas (STIC) 
Objective
Risk-reducing salpingo-oophorectomy (RRSO) is recommended for women with BRCA mutation due to increased risk of pelvic serous carcinoma. Serous tubal intraepithelial carcinoma (STIC) is a pathologic finding of unknown clinical significance. This study evaluates the clinical outcome of patients with isolated STIC.
Materials/Methods
We retrospectively reviewed the medical records of consecutive patients with a germline BRCA1/2 mutation or a high-risk personal or family history of ovarian cancer who underwent RRSO between January 2006 and June 2011. All patients had peritoneal washings collected. All surgical specimens were assessed using the sectioning and extensively examining the fimbria protocol, with immunohistochemistry when indicated. p53 signature lesions and secretory cell outgrowths were excluded.
Results
Of 593 patients who underwent RRSO, isolated STIC was diagnosed in 12 patients (2%). Five patients (42%)were BRCA1 positive, 5 patients (42%)were BRCA2 positive, and 2 patients (17%) had high-risk family history. Preoperatively, all patients with STIC had normal CA-125 levels and/or pelvic imaging results. Seven patients underwent hysterectomy and omentectomy, 6 patients (46%) had pelvic node dissections, and 5 patients (39%) had para-aortic node dissections. With the exception of positive peritoneal washings in 1 patient, no invasive or metastatic disease was identified. No patient received adjuvant chemotherapy. At median follow-up of 28 months (range, 16–44 months), no recurrences have been identified.
Conclusions
Among the cases of isolated STIC after RRSO reported in the literature, the yield of surgical staging is low, and short-term clinical outcomes are favorable. Peritoneal washings are the most common site of disease spread. Individualized management is warranted until additional data become available.
doi:10.1097/IGC.0b013e3182a80ac8
PMCID: PMC4979072  PMID: 24172097
Serous tubal intraepithelial carcinoma; Prophylactic salpingo-oophorectomy; Ovarian carcinoma
18.  Expanding the indications for radical trachelectomy: A report on 29 patients with stage IB1 tumors measuring 2–4 centimeters 
Objectives
Radical trachelectomy has enabled select women with stage I cervical cancer to maintain fertility after treatment. Tumor size ≥2 cm has been considered a contraindication and those patients denied trachelectomy. We report our trachelectomy experience with tumors measuring 2–4 cm.
Methods
We retrospectively reviewed the medical records of all patients planned for fertility-sparing radical trachelectomy. Largest tumor dimension was determined by physical exam, preoperative MRI, or pathology. No patient received neoadjuvant chemotherapy.
Results
Twenty-nine of 110 (26%) patients had stage IB1 disease with tumors 2–4 cm. Median age was 31 years (range, 22–40) and 83% were nulliparous. Thirteen (45%) had squamous cell carcinoma, 12 (41%) adenocarcinoma, and 4 (14%) adenosquamous. Thirteen of 29 (45%) patients had positive pelvic nodes. All paraortic nodes were negative. Due to intraoperative frozen section, 13 (45%) patients underwent immediate hysterectomy and 1 (3%) definitive chemoradiation. Due to high-risk features on final pathology, 6 (21%) patients who had retained their uterus received chemoradiation. Nine (31%) patients underwent a fertility-sparing procedure. At median follow-up 44 months (range, 1–90) there was one recurrence.
Conclusions
Expanding radical trachelectomy inclusion criteria to women with 2–4 cm tumors allows for a fertility-sparing procedure in 30% of patients who would otherwise have been denied the option, with no compromise in oncologic outcome.
doi:10.1097/IGC.0b013e318296034e
PMCID: PMC4973580  PMID: 23714706
19.  Cervical conization and sentinel lymph node mapping in the treatment of stage I cervical cancer: is less enough? 
Objective
To determine the feasibility of cervical conization and sentinel lymph node (SLN) mapping as a fertility-sparing strategy to treat stage I cervical cancer and estimate the tumor margin status needed to achieve no residual carcinoma in the cervix.
Methods
We identified all patients who desired fertility-preservation and underwent SLN mapping with cervical conization for stage I cervical cancer from 9/2005–8/2012. Relevant demographic, clinical, and pathological information was collected.
Results
Ten patients were identified. Median age was 28 years (range,18–36). None of the patients had a grossly visible tumor. The initial diagnosis of invasive carcinoma was made either on a loop electrosurgical excision procedure (LEEP) or cone biopsy. All patients underwent preoperative radiologic evaluation (MRI and PET-CT). None of the patients had evidence of gross tumor or suspicion of lymph node metastasis on imaging. Stage distribution included: IA1 with lymphovascular invasion, 7(70%); and microscopic IB1, 3(30%). Histology included: squamous cell carcinoma, 8(80%); adenocarcinoma, 1(10%); and clear cell carcinoma, 1(10%). Nine patients underwent repeat cervical conization with SLN mapping, and 1 patient underwent post-conization cervical biopsies and SLN mapping. None of the patients had residual tumor identified on the final specimen. The median distance from the invasive carcinoma to the endocervical margin was 2.25mm, and the distance from the invasive carcinoma to the ectocervical margin was 1.9mm. All collected lymph nodes were negative for metastasis. After a median follow-up of 17 months (range,1–83), none of the patients were diagnosed with recurrent disease and 3 patients (30%) achieved pregnancy.
Conclusion
Cervical conization and SLN mapping appears to be an acceptable treatment strategy for selected patients with small-volume stage I cervical cancer. Tumor clearance of ≥2mm appears to correlate well with no residual on repeat conization. A larger sample size and longer follow-up is needed to establish the long-term outcomes of this procedure.
doi:10.1097/IGC.0000000000000034
PMCID: PMC4972180  PMID: 24335661
stage I cervical cancer; conization; sentinel lymph node mapping
20.  Chemotherapy Response Rates among Endometrial Cancer Patients with Elevated Serum Platelets 
Objective
This retrospective study evaluates the influence of serum platelet count on chemotherapy response rates among women with endometrial cancer.
Methods
From three separate cancer centers, a total of 318 patients with endometrial cancer who received post-operative chemotherapy between June 1999 and October 2009 were retrospectively identified. Endometrioid, serous, clear cell, and carcinosarcoma histologies were included. Subjects were classified as having an elevated platelet count if their serum platelet count was greater than 400 × 109/L at the time of initial diagnosis. Primary outcome was chemotherapy response, classified as either complete or partial/refractory. Secondary outcomes were disease free and disease specific survival (DFS, DSS). Chi-square and Student t-tests were performed as appropriate. Kaplan-Meier curves and Cox proportional hazards models were used to assess serum platelet effect on survival.
Results
There were 125 deaths, 76 recurrences, and 48 disease progressions. Of the total group, 53 (16.7%) were categorized as having an elevated platelet count. An elevated platelet count was associated with a lower chemotherapy response rate in univariate analysis (HR 2.8; 95% CI 1.46, 5.38; p <0.01). Multivariate analysis showed elevated platelets to be independently associated with decreased DFS (HR 2.24; 95% CI 1.26, 3.98; p<0.01) but not DSS (HR 1.03, 95%CI 0.56, 1.88, p=0.93).
Conclusions
Endometrial cancer patients with an elevated serum platelet count > 400 × 109/L may have lower chemotherapy response rates and are at increased risk for recurrence when compared to patients with a count within normal range.
doi:10.1097/IGC.0000000000000453
PMCID: PMC4477286  PMID: 26098089
21.  Make new friends but keep the old: Minimally invasive surgery training in gynecologic oncology fellowship programs 
Objectives
To evaluate the role of minimally invasive surgery (MIS) in gynecologic oncology fellowship training and fellows’ predictions of their use of MIS in their future practice.
Methods
All fellows-in-training in American Board of Obstetrics and Gynecology-approved training programs were surveyed in 2012 through an online or mailed-paper survey. Data were analyzed and compared to results of a similar 2007 survey.
Results
Of 172 fellows, 69 (40%) responded. Ninety-nine percent of respondents (n=68) indicated that MIS was either very important or important in gynecologic oncology, a proportion essentially unchanged from 2007 (100%). Compared to 2007, greater proportions of fellows considered laparoscopic radical hysterectomy and node dissection for cervical cancer (87% vs 54%, p<0.0001) and trachelectomy and staging for cervical cancer (83% vs 32%, p<0.0001) appropriate for MIS. Of respondents, 92% believed that maximum or some emphasis should be placed on robotic-assisted surgery(RAS) and 89% on traditional laparoscopy during fellowship training. Ten percent rated their fellowship training in laparoendoscopic single-site surgery as very poor; 44% said that the question was not applicable. Most respondents (60%) in 2012 performed at least 11 procedures per month, whereas most respondents (45%) in 2007 performed 6 to 10 procedures per month (p=0.005). All respondents at institutions where robotic surgery was used were allowed to operate at the robotic console, and 63% of respondents reported that in RAS cases when a fellow sat at the robot, the fellow performed more than 50% of the case at the console.
Conclusions
These findings indicate that MIS in gynecologic oncology is here to stay. Fellowship programs should develop a systematic approach to training in MIS and in individual MIS platforms as they become more prevalent. Fellowship programs should also develop and apply an objective assessment of minimum proficiency in MIS to ensure that programs are adequately preparing trainees.
doi:10.1097/IGC.0000000000000466
PMCID: PMC4478093  PMID: 26067857
22.  Role of minimally invasive surgery in gynecologic oncology: An updated survey of members of the Society of Gynecologic Oncology 
Objectives
To evaluate the current patterns of use of minimally invasive surgical procedures, including traditional, robotic-assisted, and single-port laparoscopy, by Society of Gynecologic Oncology (SGO) members and to compare the results to those of our 2004 and 2007 surveys.
Methods
SGO members were surveyed through an online or mailed-paper survey. Data were analyzed and compared with results of our prior surveys.
Results
Four hundred six (32%) of 1279 SGO members responded. Eighty-three percent of respondents (n = 337) performed traditional laparoscopic surgery (compared to 84% in 2004 and 91% in 2007). Ninety-seven percent of respondents performed robotic surgery (compared to 27% in 2007). When respondents were asked to indicate procedures that they performed with the robot but not with traditional laparoscopy, 75% indicated radical hysterectomy and pelvic lymphadenectomy for cervical cancer. Overall, 70% of respondents indicated that hysterectomy and staging for uterine cancer was the procedure they most commonly performed with a minimally invasive approach. Only 17% of respondents who performed minimally invasive surgery performed single-port laparoscopy, and only 5% of respondents indicated that single-port laparoscopy has an important or very important role in the field.
Conclusions
Since our prior surveys, we found a significant increase in the overall use and indications for robotic surgery. Radical hysterectomy or trachelectomy and pelvic lymphadenectomy for cervical cancer and total hysterectomy and staging for endometrial cancer were procedures found to be significantly more appropriate for the robotic platform in comparison to traditional laparoscopy. The indications for laparoscopy have expanded beyond endometrial cancer staging to include surgical management of early-stage cervical and ovarian cancers, but the use of single-port laparoscopy remains limited. We also found that, since our 2007 survey, robotic surgical training significantly increased with a greater percentage of fellows completing more than 50% of the surgical cases.
doi:10.1097/IGC.0000000000000450
PMCID: PMC4478101  PMID: 25860841
23.  Sentinel Lymph Node Biopsy in Vulvar Cancer using Combined Radioactive and Fluorescence Guidance 
Objective
Near-infrared (NIR) fluorescence imaging using Indocyanine Green (ICG) has recently been introduced to improve the SLN procedure. Several optical tracers have been successfully tested. However, the optimal tracer formulation is still unknown. This study evaluates the performance of ICG–99mTc-nanocolloid in relation to two most commonly used ICG-based formulas during SLN biopsy of vulvar cancer.
Methods/materials
12 women planned to undergo SLN biopsy for stage I vulvar cancer were prospectively included. SLN mapping was performed using the dual-modality radioactive and NIR fluorescence tracer ICG-99mTc-Nanocolloid. All patients underwent combined SLN localization using NIR fluorescence, and the (current) gold standard using blue dye and radioactive guidance.
Results
In all 12 patients at least one SLN was detected during surgery. A total of 21 lymph nodes (median 2, range 1 – 3) were resected. Median time between skin incision and first SLN detection was 8 (range 1 – 22) minutes. All resected SLNs were both radioactive and fluorescent, though only 13 of 21 SLN (62%) stained blue. Median brightness of exposed SLNs, expressed as SBR, was 5.4 (range 1.8 – 11.8). Lymph node metastases were found in 3 patients.
Conclusions
NIR fluorescence guided SLN mapping is feasible and outperforms blue dye staining. Premixing ICG with 99mTc-nanocolloid provides real-time intra-operative imaging of the SN and appears the optimal tracer combination in terms of intraoperative detection rate of the SN (100%). Moreover, ICG-99mTc-Nanocolloid allows administration of a 5-times lower injected dose of ICG (compared to ICG and ICG:HSA) and can be injected the up to 20h before surgery.
doi:10.1097/IGC.0000000000000419
PMCID: PMC4478233  PMID: 25768079
Vulvar cancer; Image-Guided Surgery; Near-Infrared Fluorescence; Sentinel Lymph Node Mapping; Multimodal Imaging
24.  Prior Tubal Ligation Might Influence Metastatic Spread of Nonendometrioid Endometrial Carcinoma 
Objective
The exfoliation of endometrial carcinoma might intraperitoneally spread through the fallopian tube. We analyzed the influence of prior tubal ligation (TL) in endometrial carcinoma to evaluate whether it can prevent the process and improve patients’ survival.
Methods
A total of 562 patients with a diagnosis of endometrial carcinoma at the Peking University People’s Hospital between July 1995 and June 2012 were enrolled in this study. The patients were divided into 2 groups based on the presence or absence of prior TL. International Federation of Gynecology and Obstetrics stage distributions, recurrence rates, survival status, and histopathological findings were compared between the 2 groups. Kaplan-Meier estimates and log-rank tests were used to compare the survival status based on TL in the overall population and stratified by histopathological subtypes and International Federation of Gynecology and Obstetrics stages. Cox models analysis was used to estimate the hazard ratios and 95% confidence intervals for associations between TL and carcinoma-specific mortality. All statistical tests were 2-sided.
Results
Of the 562 patients, 482 (85.7%) had a diagnosis of endometrioid and 80 patients (14.2%) with nonendometrioid carcinoma. Tubal ligation was associated with negative peritoneal cytology in the total population (P = 0.015) and in patients with endometrioid carcinomas (P = 0.02) but not help to reduce carcinoma-specific mortality (P = 0.095 and P = 0.277, respectively). In the nonendometrioid group, TL was not only associated with negative peritoneal cytology (P = 0.004) but also with lower stage (P < 0.001) and lower recurrence rate(P < 0.005), resulting in improved prognosis (P = 0.022). In Cox models analysis adjusted for covariates, TL was inversely associated with lower endometrial carcinoma-specific mortality (hazard ratio, 0.47; 95% confidence interval, 0.14–2.6).
Conclusion
Tubal ligation was associated with lower positive peritoneal cytology, stages, and recurrence rate, and improved prognosis among patients with nonendometrioid carcinoma. Tubal ligation might influence metastatic spread of nonendometrioid endometrial carcinoma. It could also help to reduce positive peritoneal cytology among patients with endometrioid carcinoma, but lacked prognostic significance.
doi:10.1097/IGC.0000000000000727
PMCID: PMC4920272  PMID: 27104940
Tubal ligation; Endometrial carcinoma; Nonendometrioid carcinoma
25.  Survivorship as an Element of Clinical Trials in Ovarian Cancer 
doi:10.1097/IGC.0b013e31821bb717
PMCID: PMC4920476  PMID: 21543942
Survivorship; Ovarian cancer; Clinical trials; Quality of life; Cancer care continuum; Care plan

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