Peritoneal High-grade Serous Carcinoma Research Articles

Genomic Catastrophe (Chromothripsis and Polyploidy) Correlates With Tumor Distribution in Extrauterine High-grade Serous Carcinoma.

Most extrauterine high-grade serous carcinomas (HGSCs) are thought to develop first in the distal fallopian tube. Most models of HGSC assume origin from relatively stable, noninvasive serous tubal intraepithelial carcinomas. However, widespread tumor involvement in the absence of a serous tubal intraepithelial carcinoma could occur after catastrophic genomic events (CGEs; such as chromothripsis or polyploidy). Twenty-six HGSCs assigned to fallopian tube (n = 9, group 1) and/or ovary (n = 9, group 2), and primary peritoneal (n = 8, group 3) were assessed by microarray (Oncoscan). CGEs were identified in 15/26 (57.7%); chromothripsis-like pattern in 13/26 (50.0%) and polyploidy in 6/26 (23.1%). CGE was seen in 4/9 (44.4%), 9/9 (100%), and 2/8 (25%) cases in groups 1. 2, and 3, respectively. Overall, CGEs were seen in 9/9 (100%) cases with grossly evident ovarian parenchymal involvement versus 6/17 (35.3%) without ( P = 0.0024). Ovarian size (measured on the long axis) correlated with CGE positivity ( P = 0.016). CGEs are significantly more common in HGSCs with ovarian parenchymal involvement compared with those limited to the fallopian tube and/or extraovarian tissues. These associations suggest geographically different tumor growth patterns and support the subdivision of HGSCs according to not only the stage but also tumor distribution. They have implications for clinical and pathologic presentation, trajectory of tumor evolution, and in the case of primary peritoneal HGSCs, potentially unique precursors to tumor transitions that could inform or influence cancer prevention efforts.

The prognostic value of the chemotherapy response score in tubo-ovarian or primary peritoneal high-grade serous carcinoma (466)

<b>Objectives:</b> The purpose of the study was to evaluate the prognostic value of a two-tiered chemotherapy response score (CRS) system on progression-free and overall survival in high-grade serous ovarian cancer patients using traditional survival type analysis. <b>Methods:</b> Retrospective chart data were collected from all patients aged 18 and older with FIGO stage III or IV tubo-ovarian high-grade serous carcinoma undergoing neoadjuvant chemotherapy (NACT) at a single institution from January 2017 to January 2021. A two-tier scoring system was used in which patients were stratified to either CRS 1-2 (no or minimal response to neoadjuvant chemotherapy) or CRS 3 (appreciable or near-complete response). These data were used to compare progression-free and overall survival between the patients in each subgroup using survival analysis (log-rank test). Survival data were adjusted for covariates as appropriate with a Cox regression model. <b>Results:</b> We identified 80 women who met the inclusion criteria above; 97% (<i>n</i>=78) were Caucasian, and the mean age was 66 years (range: 25-87). Baseline demographic data were similar between patients with CRS 1-2 (<i>n</i>=58) and patients with CRS 3 (<i>n</i>=22). More women with CRS 3 underwent an aborted attempt at cytoreduction or surgery for bowel obstruction at the time of diagnosis (<i>n</i>=3 compared to none in the CRS 1-2 cohort). Overall, 74% (<i>n</i>=58) of patients achieved a partial response on platinum-based NACT. About 23% (<i>n</i>=5) of patients with CRS 3 had a complete response compared to only 12.5% (<i>n</i>=7) of CRS 1-2. Overall a greater percentage of patients in the CRS 3 group (95%, <i>n</i>=21) achieved optimal cytoreduction compared with patients in CRS 1-2 (74%, <i>n</i>=43). <i>BRCA1</i> or <i>2</i> mutation frequencies were similar in both CRS subgroups. The majority of women recurred (73%, <i>n</i>=59) regardless of the CRS subgroup. Ultimately five patients were excluded from the analysis of progression-free and overall survival due to pertinent missing information such as documented CRS or missing vital statistics. The mean time from diagnosis to recurrence was 16 months versus 19 months for CRS 1-2 compared to CRS 3, but this difference was not significant. Median time from interval debulking to recurrence was not different between groups (11 months for CRS 1-2 vs 13 months for CRS 3, p=0.21). There was no difference in overall survival between the two groups; mean survival was 35 months in CRS 1-2 versus 34 months in CRS 3 (p=0.86). <b>Conclusions:</b> Previous studies have suggested a difference in progression-free survival for women who had CRS 1-2 versus CRS 3, indicating that this scoring system can inform disease prognosis and may help to guide adjuvant treatment strategies. Our preliminary analysis revealed no statistically significant difference in progression-free or overall survival for patients with CRS 1-2 versus CRS 3 and did not replicate the findings of other studies, a discrepancy that warrants further investigation.

TP53 variant allele frequency correlates with the chemotherapy response score in ovarian/fallopian tube/peritoneal high-grade serous carcinoma

Molecular findings in ovarian, fallopian tube, and peritoneal high-grade serous carcinoma (HGSCa) are emerging as potential prognostic indicators. The chemotherapy response score (CRS) has been proposed as a histologic-based prognostic factor in patients with HGSCa treated with neoadjuvant chemotherapy (NACT). No study details the relationship between the mutational landscape of HGSCa and the CRS. This study addresses this issue using next-generation sequencing (NGS). We retrospectively identified 25 HGSCas treated with NACT and pathology material available to calculate the CRS. All cases had NGS on the primary debulking specimen post-NACT. The three-tier Böhm CRS was applied to the omentum or adnexa and calculated as a combined score. Tumor mutation burden (TMB) and TP53 variant allele frequency (VAF) were calculated and used in correlative analysis. All cases had at least one mutation, most commonly TP53 (25 cases, 100%). Other mutations were BRCA2 (one case, 4%), ARID1A (two cases, 8%), and 1 (4%) of each of the following: ERBB2, NTRK3, STK11, NTRK2, TSC1, PIK3CA, NF1, NOTCH3, CDK2, SMAD4, and PMS2. TMB ranged from 2.58 to 7.75 (median 3.84). There was no statistically significant relationship between the TMB and omental CRS, R-squared=0.011 (P=0.62); adnexal CRS, R-squared=0.005 (P=0.74); or with the combined CRS, R-squared=0.009 (P=0.65). Statistically significant correlation was found between the TP53 VAF and the omental CRS (R-squared=0.28, P=0.007), adnexal CRS (R-squared=0.26, P=0.01), and the combined CRS (R-squared=0.33, P=0.0026). The TP53 VAF was adjusted for percent of tumor present on the slide resulting in an average per cell TP53 mutational load, resulting in similar results with a statistically significant correlation between the average per cell TP53 mutational load and the omental CRS (R-squared=0.27, P=0.02), adnexal CRS (R-squared=0.16, P=0.05), and the combined CRS (R-squared=0.23, P=0.02). In summary, NGS confirmed TP53 mutations in all cases of HGSCa. TMB showed no correlation with the CRS. TP53 VAF and average per cell TP53 mutational load showed significant correlation with the CRS, whether graded on the adnexa or omentum or as a combined score, indicating concordance between molecular and histological findings following NACT.

Efficacy and safety results from neopembrov study, a randomized phase II trial of neoadjuvant chemotherapy (CT) with or without pembrolizumab (P) followed by interval debulking surgery and standard systemic therapy ± P for advanced high-grade serous carcinoma (HGSC): A GINECO study.

5500 Background: To investigate whether adding Pembrolizumab (P) to neoadjuvant carboplatin-paclitaxel chemotherapy (CP) may increase the optimal debulking rate, assessed by Complete Resection Rate (CRR) after Interval Debulking Surgery (IDS) in patients (pts) with initially unresectable International Federation of Gynecology and Obstetrics (FIGO) stage IIIC/IV ovarian, tubal or peritoneal HGSC. Methods: Multicenter, open-label, non-comparative randomized phase II trial. Pts were randomized (2:1) to receive 4 cycles of CP ± P before IDS. After IDS, all patients received post-operative chemotherapy (2 to 4 cycles) and optional bevacizumab for 15 months in total ± P as maintenance therapy for up to 2 years. Randomization was stratified on center, FIGO stage, Bev planned after IDS and disease volume (&lt;5cm/&gt;5cm). Primary endpoint was the centrally reviewed CRR at IDS. 60 pts were planned in the CP+P arm (A'Hern's single-stage design P0=50%, P1=70%). Safety (particularly due to P addition), surgical morbidity, ORR, PFS and OS were secondary endpoints. Results: 91 pts were randomized from 02/18 to 04/19 with a median Peritoneal Cancer Index at 24 (range 7-39). 80 pts (88%) received Bev in combination with CP followed by bev ± P in maintenance. In the CP+P group (n=61), 58 (95%) pts had IDS and 78% achieved complete resection. The CRR in this group was 74%, statistically superior to the pre-defined hypothesis. In the CP group, CRR was 70% (29/30 pts underwent IDS). Complete resection after strictly 4 cycles of CP±P was obtained for 41 pts (71%) and 17 (58%) pts in CP+P and CP group, respectively (sensitivity analysis). For CP+P group, numerically higher ORRs were observed before IDS compared to CP group (76% vs 61%). Grade ≥3 adverse events (AE) occurred in 75% of the CP+P group and 67% in the CP group: mainly blood and lymphatic, gastrointestinal and vascular disorders. Postoperative AE (mainly infectious, vascular and gastrointestinal) occurred in 20% and 13% of the pts in CP+P and CP arm, respectively. No difference in the number of fatal events between the two arms: 2 in the experimental arm vs 1 in the control arm. Progression free survival rate at 18 months was 61% (95CI% [47-73]) and 57% (95CI% [37-72]) in CP+P and CP arm, respectively. Conclusions: P may be safely added to preoperative treatment in pts deemed non-optimally resectable. The primary objective was met with an improved CRR on CP+P arm. The CRR in the control group was higher than expected. Survival data and translational research including PDL1 status are ongoing to better define P as treatment option in this setting. Clinical trial information: 2016-004-163-39. Clinical trial information: NCT03275506.

Magnetic resonance imaging findings of extrauterine high-grade serous carcinoma based on new pathologic criteria for primary site assignment.

There has been no study that has reported magnetic resonance imaging (MRI) findings of extrauterine high-grade serous carcinomas (HGSCs) that have been histologically determined by the new criteria. To assess MRI findings of extrauterine HGSCs based on new pathologic criteria. Fifty patients with histopathologically proven extrauterine HGSCs, who underwent pretreatment gadolinium-enhanced MRI, were included in this study. After surgery, the primary sites were histopathologically determined based on new criteria for primary site assignment in extrauterine HGSCs as follows: fallopian tube (n = 34); ovary (n = 9); primary peritoneal HGSC (n = 1); and tubo-ovarian (n = 6). We retrospectively reviewed MR images and compared the MR findings between tubal and ovarian primaries. MRI patterns with tubal primaries were classified as ovarian cancer (62%), peritoneal cancer (35%), and fallopian tube cancer (3%). MRI patterns with ovarian primaries were classified as ovarian cancer (78%) and peritoneal cancer (22%). The frequency of the involvement of the fallopian tube, ovary, peritoneum, uterus, and lymph node was not significantly different between the two pathologies. There was no significant difference in the abnormal amount of ascites, hemorrhagic ascites, or characteristics of the ovarian lesions between the two pathologies. On MR images, tubal primaries almost always exhibited ovarian or peritoneal cancer pattern, but rarely exhibited fallopian tube cancer pattern. MR findings could not accurately differentiate between tubal and ovarian primaries; therefore, histopathologic investigation is essential for determination of the primary site of extrauterine HGSCs.

Novel, genetically induced mouse model that recapitulates the histological morphology and immunosuppressive tumor microenvironment of metastatic peritoneal carcinomatosis

BackgroundPeritoneal carcinomatosis is a hallmark of advanced peritoneal tumor progression, particularly for tubal/ovarian high-grade serous carcinomas (HGSCs). Patients with peritoneal carcinomatosis have poor survival rates and are difficult to treat...

Case Report: Borderline tumor and primary peritoneal carcinoma - a rare synchronism

Ovarian borderline serous tumors present with peritoneal involvement in 20% of cases, either as non-invasive or invasive implants, the latter also known as extraovarian low-grade serous carcinoma. The coexistence of high-grade serous carcinoma is rare, suggesting a synchronous neoplasia with a distinct and independent tumor biology and behavior. We aim to describe a case of a synchronous ovary-peritoneum neoplasia: serous borderline tumor and primary peritoneal high-grade serous carcinoma. A discussion and literature review concerning the optimal diagnostic and therapeutic approach is provided.

Case Report: Borderline tumor and primary peritoneal carcinoma - a rare synchronism

Ovarian borderline serous tumors present with peritoneal involvement in 20% of cases, either as non-invasive or invasive implants, also known as extraovarian low-grade serous carcinoma. The coexistence of high-grade serous carcinoma is rare, suggesting a synchronous neoplasia with a distinct and independent tumor biology and behavior. We aim to describe a case of a synchronous ovary-peritoneum neoplasia: serous borderline tumor and primary peritoneal high-grade serous carcinoma. A discussion and literature review concerning the optimal diagnostic and therapeutic approach is provided.

Bilateral serous tubal intraepithelial carcinoma associated with high-grade serous carcinoma of the peritoneum

Serous tubal intraepithelial carcinoma (STIC) is now considered a putative precursor lesion of most extrauterine high-grade serous carcinomas (HGSC). It is frequently reported in high-risk women and women with advanced-stage serous carcinoma. This case study reports a serous high-grade carcinoma (HGSC) consisting of a bilateral STIC with a focus of stromal invasion in the left tube, and a peritoneal HGSC. The grossly normal-appearing tubes including the fimbriated ends were sectioned following the SEE-FIM protocol. In both tubes, tumor aggregates were exfoliated extensively to the tubal lumens. The neoplastic epithelia in any location were diffusely positive for p53 in strong nuclear patterns. Pelvic lymph nodes were negative for tumor on serial sections and keratin 7 immunohistochemistry, and there was no evidence of lymphatic vessel involvement. The lack of any evidence of lymphovascular invasion and regional lymph node metastases supports the interpretation of intraluminal and transcoelomic spread, and may be taken as evidence of dissemination of tubal neoplastic cells by exfoliation in this case. The biology of transcoelomic spread is reviewed in this manuscript.

Prognostic impact of intraoperative peritoneal cytology in interval debulking surgery for pelvic high-grade serous carcinoma.

Background and ObjectivesThe aim of this study was to determine whether peritoneal washing cytology (PWC) during interval debulking surgery (IDS) could predict the prognosis of patients with pelvic high‐grade serous carcinoma (HGSC) achieving R0 status.MethodsBetween January 2007 and May 2018, 110 patients with ovarian/tubal/primary peritoneal HGSC received platinum‐based neo‐adjuvant chemotherapy, followed by IDS at National Cancer Center Hospital, Japan. All the patients achieved R0 debulking status, defined as no macroscopic residual tumor in the peritoneal cavity at the completion of IDS. PWC was performed before debulking during IDS. The survival outcomes were compared between the PWC‐positive and PWC‐negative groups.ResultsThe median progression free survival (PFS) for the entire cohort was 17 months (range, 5‐133 months). The median PFS for the PWC‐positive group was significantly shorter than that of the PWC‐negative group (16 vs 19 months, HR 2.04, 95% CI 1.22‐3.41, P‐value < 0.01). Increased risk of progression was observed on both univariate and multivariate analyses, including age and FIGO stage (HR 2.28; 95% CI 1.35‐3.84, P < 0.01).ConclusionsThe positive PWC during IDS was found to predict earlier disease recurrence in patients with pelvic HGSC achieving R0 status. As performing PWC during IDS becomes standard practice, prospective validation should be conducted in the future.

Survival differences in gynecologic high-grade serous carcinomas based on site of origin: Material or semantic?

Objective: The primary origin of most nonuterine (NU) gynecologic high-grade serous carcinomas (HGSC) is likely the fallopian tube (FT). Over time, the diagnosis of FT cancers has increased with a corresponding decrease in ovarian cancers. Prior studies have shown that women with FT-HGSC have improved survival compared to those with ovarian or peritoneal HGSC. We sought to determine whether survival outcomes differ for women with HGSC based on site of origin using updated 2014 guidelines for classification of gynecologic malignancies.

Referral patterns for genetic counselling of women diagnosed with tubo-ovarian or peritoneal high-grade serous carcinoma (HGSC) within the Auckland Gynaecological Oncology Centre.

Germline BRCA1/2 mutations account for approximately 15% of invasive ovarian carcinomas. Referral of all women with non-mucinous epithelial tubo-ovarian and peritoneal cancer, especially high-grade serous carcinoma (HGSC) to genetic services for genetic counselling and subsequent BRCA testing, has become standard of care in many countries. Publicly funded BRCA testing was restricted to women ≤70 years old with HGSC in New Zealand for most of our study period. Referral rates of women with HGSC for BRCA mutation testing in New Zealand have not previously been reported. To determine the proportion of eligible patients with tubo-ovarian or peritoneal HGSC referred to Auckland Gynaecologic Oncology Centre who were referred for genetic counselling. To determine the number of patients who underwent BRCA1/2 genetic testing and the rate of germline BRCA mutations. Eligible cases were identified from Auckland Gynaecologic Oncology multidisciplinary meetings database from 1 January 2012 to 31 December 2014. Genetic referrals sent were checked against the genetic services database to ensure that referrals were received. Genetic counselling clinic attendance, uptake and results of genetic testing were also collected. One hundred and four eligible patients were identified with 58 patients referred. Referral rates increased from 37.5% in 2012 to 64.3% in 2014. Of the 58 patients referred, 53 attended genetic counselling, and 49 underwent BRCA mutation testing, of whom 10 (20.4%) tested positive for a germline BRCA mutation. Overall, 55.8% of eligible patients were referred for genetic testing; however, referral rates increased with time. This BRCA mutation-positive rate is comparable with current international data.

A simple high-throughput approach identifies actionable drug sensitivities in patient-derived tumor organoids

Tumor organoids maintain cell–cell interactions, heterogeneity, microenvironment, and drug response of the sample they originate from. Thus, there is increasing interest in developing tumor organoid models for drug development and personalized medicine applications. Although organoids are in principle amenable to high-throughput screenings, progress has been hampered by technical constraints and extensive manipulations required by current methods. Here we introduce a miniaturized method that uses a simplified geometry by seeding cells around the rim of the wells (mini-rings). This allows high-throughput screenings in a format compatible with automation as shown using four patient-derived tumor organoids established from two ovarian and one peritoneal high-grade serous carcinomas and one carcinosarcoma of the ovary. Using our automated screening platform, we identified personalized responses by measuring viability, number, and size of organoids after exposure to 240 kinase inhibitors. Results are available within a week from surgery, a timeline compatible with therapeutic decision-making.

Targeted Sequencing of Tubo-ovarian and Peritoneal High-grade Serous Carcinoma With Wild-type p53 Immunostaining Pattern.

We aimed to demonstrate the use of next-generation sequencing (NGS) to confirm the presence of tumor protein 53 (TP53) mutations in tubo-ovarian and peritoneal high-grade serous carcinoma (HGSC) with a wild-type p53 immunostaining pattern and investigate whether the TP53 mutational status is altered by chemotherapy. A commercial NGS panel comprising 171 genes was used to analyze the genetic profiles of 15 HGSC samples. Paired specimens obtained before and after chemotherapy were available for four patients. All examined samples exhibited TP53 mutations. For all the patients who underwent neoadjuvant or postoperative adjuvant chemotherapy, TP53 mutations identified in samples obtained after chemotherapy were the same as those detected in pre-chemotherapeutic samples. HGSCs exhibit TP53 mutations even though a subset of HGSCs displayed a wild-type p53 immunostaining pattern. Chemotherapy does not affect the TP53 mutational status in HGSC.

Disease Distribution in Low-stage Tubo-ovarian High-grade Serous Carcinoma (HGSC): Implications for Assigning Primary Site and FIGO Stage.

The latest FIGO and TNM (eighth edition) staging systems for ovarian, tubal, and peritoneal neoplasms require primary site assignment as tubal/ovarian/peritoneal, but provide no guidance or criteria. Fewer than 10% of extrauterine high-grade serous carcinoma (HGSC) cases present at low stage (stage I/II). Low-stage cases offer a unique opportunity to understand the pattern of disease early in its evolution prior to wide dissemination and provide valuable evidence for guiding specimen handling and tumor staging. This study aimed to examine disease distribution in low-stage tubo-ovarian HGSC. Anonymized pathology reports of 152 stage I/II extrauterine HGSCs from 6 teaching hospitals were analyzed: group 1 (n=67) comprised cases with complete tubal examination by Sectioning and Extensively Examining the FIMbriated end of the tube (SEE-FIM) and group 2 (n=85) consisted of cases without documentation of both tubes being fully examined by the SEE-FIM or a SEE-FIM-like protocol. The stage, site/pattern of involvement, site/size of largest tumor focus and laterality of tubal and ovarian involvement were recorded. Tubal mucosal involvement was present in 95% of optimally examined cases and many factors influenced detection of tubal disease. Bilateral involvement, suggestive of metastasis, was significantly more frequent in the ovaries (35%) than the tubes (9%) (P<0.0001, Fisher exact test). No case showed a complete absence of tubal/ovarian involvement, questioning the biological existence of primary peritoneal HGSC. Disease distribution in low-stage cases supports a tubal origin for most HGSCs. Detailed tubal sampling upstages some apparent stage I cases through detection of microscopic tubal involvement.

TP53 Mutation Status of Tubo-ovarian and Peritoneal High-grade Serous Carcinoma with a Wild-type p53 Immunostaining Pattern.

Diffuse and strong nuclear p53 immunoreactivity and a complete lack of p53 expression are regarded as indicative of missense and nonsense mutations, respectively, of the TP53 gene. Tubo-ovarian and peritoneal high-grade serous carcinoma (HGSC) is characterized by aberrant p53 expression induced by a TP53 mutation. However, our experience with some HGSC cases with a wild-type p53 immunostaining pattern led us to comprehensively review previous cases and investigate the TP53 mutational status of the exceptional cases. We analyzed the immunophenotype of 153 cases of HGSC and performed TP53 gene sequencing analysis in those with a wild-type p53 immunostaining pattern. Immunostaining revealed that 109 (71.3%) cases displayed diffuse and strong p53 expression (missense mutation pattern), while 39 (25.5%) had no p53 expression (nonsense mutation pattern). The remaining five cases of HGSC showed a wild-type p53 immunostaining pattern. Direct sequencing analysis revealed that three of these cases harbored nonsense TP53 mutations and two had novel splice site deletions. TP53 mutation is almost invariably present in HGSC, and p53 immunostaining can be used as a surrogate marker of TP53 mutation. In cases with a wild-type p53 immunostaining pattern, direct sequencing for TP53 mutational status can be helpful to confirm the presence of a TP53 mutation.

Morphologic features of fallopian tubal epithelium in pelvic high-grade serous carcinoma

Objective: To study the pathologic features of fallopian tubal epithelium in patients with pelvic high-grade serous carcinoma (HGSC), to investigate its role in pelvic serous carcinogenesis and to reclassify the primary site of HGSC based on recently proposed criteria. Methods: The fallopian tubes in 58 cases of pelvic HGSC (54 cases of ovarian primary, 3 cases of tubal primary, 1 case of peritoneum) and 25 cases of pelvic non-HGSC (5 cases of ovarian low-grade serous cancer, 9 cases of endometrioid cancer, and 11 cases of clear cell ovary carcinoma) were collected from June 2015 to December 2016, and serially examined under light microscope (SEE-FIM protocol). Immunostaining for p53 and Ki-67 was performed to evaluate the presence of p53 signature, serous tubal intraepithelial lesion (STIL), serous tubal intraepithelial carcinoma (STIC) and invasive carcinoma in these fallopian tubes. Meanwhile, primary site of HGSC based on the recently proposed diagnostic criteria were also reclassified. Results: Among the study group, the frequencies of p53 signature, STIL, STIC and invasive HGSC were 27.6% (16/58), 43.1% (25/58), 36.2% (21/58) and 67.2% (39/58), respectively, while in control group, the proportions were 24.0% (6/25), 0, 0 and 8.0% (2/25), respectively. The continuum of epithelial changes in the process of serous neoplasia including p53 signature, STIL, STIC and invasive carcinoma was identified in 8 cases of pelvic HGSC. The proportions of STIL, STIC and invasive carcinomas in HGSC group were higher than that in non-HGSC group (P<0.01). About 80.0% (20/25) of STIL and 85.7% (18/21) of STIC were present unilaterally. Diagnostically, the study group contained the 17 cases of ovarian HGSC, 40 cases of tubal HGSC, and 1 case of peritoneal HGSC after reclassification of the cancer primary. Conclusions: Continuous changes of tubal epithelium including p53 signature, STIL, STIC and invasive carcinomas are identified in patients with HGSC, supporting the current understanding that the fallopian tube is likely the cellular source of the majority HGSC. STIL and STIC may be specific to pelvic HGSC and may act as a target for future research on the early detection and prevention of this disease. The newly proposed diagnostic criteria for pelvic HGSC will lead us to more accurate classification of cancer primary sites. Correct classification of HGSC may have potential impacts for cancer prevention and improve our understanding of ovarian serous carcinogenesis.

Similar protein expression profiles of ovarian and endometrial high-grade serous carcinomas.

Background:Ovarian and endometrial high-grade serous carcinomas (HGSCs) have similar clinical and pathological characteristics; however, exhaustive protein expression profiling of these cancers has yet to be reported.Methods:We performed protein expression profiling on 14 cases of HGSCs (7 ovarian and 7 endometrial) and 18 endometrioid carcinomas (9 ovarian and 9 endometrial) using iTRAQ-based exhaustive and quantitative protein analysis.Results:We identified 828 tumour-expressed proteins and evaluated the statistical similarity of protein expression profiles between ovarian and endometrial HGSCs using unsupervised hierarchical cluster analysis (P<0.01). Using 45 statistically highly expressed proteins in HGSCs, protein ontology analysis detected two enriched terms and proteins composing each term: IMP2 and MCM2. Immunohistochemical analyses confirmed the higher expression of IMP2 and MCM2 in ovarian and endometrial HGSCs as well as in tubal and peritoneal HGSCs than in endometrioid carcinomas (P<0.01). The knockdown of either IMP2 or MCM2 by siRNA interference significantly decreased the proliferation rate of ovarian HGSC cell line (P<0.01).Conclusions:We demonstrated the statistical similarity of the protein expression profiles of ovarian and endometrial HGSC beyond the organs. We suggest that increased IMP2 and MCM2 expression may underlie some of the rapid HGSC growth observed clinically.

Intact PTEN Expression by Immunohistochemistry is Associated With Decreased Survival in Advanced Stage Ovarian/Primary Peritoneal High-grade Serous Carcinoma.

Ovarian high-grade serous carcinoma is an aggressive malignancy with poor prognosis. Optimal surgical debulking and tumor sensitivity to platinum-based chemotherapy are 2 well-established prognostics for this tumor type. Molecular markers that identify more clinically aggressive tumors would potentially allow for the development of individualized treatment options. PTEN is a key negative regulator of the PI3K signaling pathway. Loss of PTEN expression in endometrial carcinoma is associated with endometrioid histology; women with endometrioid tumors have a better prognosis than those with nonendometrioid tumors. The prognostic and predictive value for PTEN has not been effectively explored in ovarian/peritoneal high-grade serous carcinoma. PTEN immunohistochemistry was assessed in 126 women with Stage III, high-grade serous carcinoma of the ovary/peritoneum treated with surgery and then a platinum-based regimen. Compared with PTEN-negative or PTEN-reduced tumors, positive PTEN immunohistochemistry, detected in 58% of tumors, was associated with decreased pS6 and increased PTEN mRNA levels. Positive PTEN expression was independent of surgical debulking status or platinum sensitivity. PTEN-positive tumors were associated with significantly decreased recurrence-free survival. Importantly, the devised PTEN immunohistochemistry scoring system was reproducible among pathologists.

Early detection of ovarian and fallopian tube cancer by examination of cytological samples from the endometrial cavity

Background:Accumulating evidence suggests that many ovarian high-grade serous carcinomas (HGSCs) originate in the fallopian tube. Malignant cells shed by tubal lesions can be detected by examination of cytological samples from the endometrial cavity (endometrial cytological testing). To evaluate the use of this method for detecting HGSC, we examined epithelial ovarian, fallopian tube, and primary peritoneal cancer patients.Methods:Endometrial cytological testing was performed for endometrial cancer screening in asymptomatic women and for pre-treatment evaluation in symptomatic suspected ovarian, tubal, and peritoneal cancer patients.Results:Of the 122 ovarian, tubal, and peritoneal cancer patients, malignant cells were identified in 5 patients who did not show detectable abnormalities on imaging studies. Cervicovaginal cytology was positive in only one of these five patients. Four patients were asymptomatic and one was symptomatic. Three asymptomatic patients had early-stage HGSCs, and the other asymptomatic patient had positive peritoneal cytology findings but no detectable tumour. HGSC patients were significantly more likely to have positive findings on endometrial cytology than patients with other histological types (23% vs 6%, P=0.02).Conclusion:Endometrial cytological testing can detect early-stage ovarian, tubal, and peritoneal HGSCs without detectable pelvic masses and may be useful for ovarian cancer screening.