Prognosis of ovarian clear cell carcinoma compared to other histological subtypes: a meta-analysis

Objective

To compare the survival outcome between clear cell carcinoma (CCC) and other histological subtypes in epithelial ovarian carcinoma (EOC).

Methods

From January 1974 to February 2011, we identified a total of 31,800 (CCC; 2152, non-CCC; 29648) patients from 12 studies meeting the inclusion criteria.

Results

Heterogeneity tests demonstrated significant between-study variation (I² = 92.1%) with no significant difference in hazard ratio (HR) for death between CCC and non-CCC (HR; 1.16, 95% CI; 0.85-1.57, random-effects model). Comparing the HR based on stage I + II, and stage III + IV, between CCC and non-CCC, showed that CCC patients had a higher hazard rate for death than those with non-CCC of the ovary (stage I + II; HR; 1.17, 95% CI; 1.01-1.36, stage III + IV; HR; 1.65, 95% CI; 1.52-1.79). In a comparison of CCC and serous EOC, advanced stage (III and IV) CCC only showed a poorer hazard rate for death than serous EOC (HR; 1.71, 95% CI; 1.57-1.86).

Conclusion

This analysis suggests that ovarian CCC patients had poorer prognosis than those with other histological subtypes of EOC, especially in advanced EOC stages. Different treatment strategies may be needed for patients with ovarian CCC.     

Novel mechanism of reduced proliferation in ovarian clear cell carcinoma cells: cytoplasmic sequestration of CDK2 by p27

Objective

Ovarian clear cell carcinoma (CCC) carries a poor prognosis because of its insensitivity to chemotherapy. We previously found an association between reduced proliferation of CCC and chemoresistance; here we investigated the mechanism of the reduced proliferation.

Methods

We assessed cell cycle function by measuring the activity of cyclin-dependent kinases (CDKs) and the protein expression of cyclins, the CDK inhibitors, and p53 in 22 ovarian cancer cell lines and 60 human ovarian cancer specimens. We examined the cellular location of p27, p27 phosphorylated at threonine 157 (p27^Thr157), and CDK2 protein by confocal microscopy and western blotting. We tested the effect of the inhibitor of phosphatidylinositol-3-kinase (PI3K) and small interfering RNA against p27 (si-p27) in two CCC cell lines (RMG-I, SMOV-2).

Results

CCC cells had lower CDK2 activity and higher p27 expression than serous adenocarcinoma (SA) cells. Low CDK2 activity correlated with high p27 protein expression. p27^Thr157 sequestered CDK2 in the cytoplasm, but PI3K inhibitor or si-p27 maintained CDK2 in the nucleus and restored its activity. In human specimens, CDK2 was mostly in the cytoplasm and was spatially associated with p27; CDK2 activity was lower in the CCC than in the SA specimens. si-p27 enhanced the cytotoxic effect of cisplatin, doxorubicin, and gemcitabine in both RMG-I cells and SMOV-2 cells.

Conclusions

Reduced CDK2 activity via the cytoplasmic sequestration of CDK2 by p27^Thr157 may contribute to suppression of CCC proliferation. A prospective study is needed to determine whether the cytoplasmic sequestration of CDK2 results in the chemoresistance of CCC.     

nm23 gene polymorphisms are associated with survival of patients with epithelial ovarian cancer but not with susceptibility to disease

Objective

nm23, a tumor metastasis suppressor gene, has been linked to protection against tumorigenesis and tumor metastasis. This study evaluated whether genetic variants in the nm23 gene were associated with susceptibility to epithelial ovarian cancer (EOC) or the clinical outcome of patients.

Methods

A case-control study was performed with 302 patients with epithelial ovarian cancer and 302 control women. According to the genotypes, the outcome in 213 EOC patients was compared. Progression-free survival (PFS) and overall survival (OS) were analyzed with Kaplan-Meier plots and Cox models adjusted for clinical factors.

Results

The case-control analysis showed that the rs16949649 and rs2302254 polymorphisms in the nm23 gene promoter were not associated with the risk of developing EOC. In contrast, survival analysis showed that the rs2302254 C/T polymorphism was related to the prognosis of EOC patients. Compared with patients carrying the C/C genotype, patients carrying the T/T genotype had a shorter median PFS and median OS by Kaplan-Meier plots and Cox models adjusted for clinical factors. For rs16949649 T/C polymorphisms, Kaplan-Meier analysis indicated that patients carrying the homozygous C/C genotype had shorter PFS and OS than those carrying the T allele (T/T + T/C genotype). The Cox proportional hazard model analysis suggested that this relationship was only retained in OS when adjusted for clinical factors.

Conclusion

Our studies suggest that rs16949649 and rs2302254 polymorphisms in the nm23 gene promoter may influence the prognosis of patients with epithelial ovarian cancer.     

Prevalence of cysts in epithelial ovarian cancer

Objective

Ovarian carcinomas mostly appear as large cystic masses. However, the exact prevalence of cysts in epithelial ovarian cancer (EOC) has never been documented as well as the tumor factors that are related to the presence of cysts. Demonstrating the prevalence of cysts in EOC is essential for research focused on predictive and prognostic biomarkers in ovarian cyst fluid.

Study design

From 233 patients with primary EOC who underwent surgery, pathological data were collected from pathology reports. Univariate and multivariate logistic regression were used to analyze the relationship between the presence of cysts and other tumor characteristics.

Results

Cysts in EOC were present in 83.7% of the patients and were mostly (61%) multilocular. The most common histological subtypes (serous, mucinous, endometrioid, clear cell) contained cysts in more than 85% of the cases. In univariate regression analysis, early FIGO stage, low tumor grade and a large tumor size were significantly associated with the presence of cysts (OR (95% CI) = 5.312 (1.81-15.57), 6.906 (2.31-20.66) and 1.169 (1.08-1.27), respectively). In multivariate regression analysis, apart from tumor size, only tumor grade was independently associated with the presence of cysts (adjusted OR (95% CI) = 4.234 (1.36-13.22)).

Conclusions

The large majority of all EOCs contained cysts. Histological subtype, FIGO stage, tumor necrosis and age were not associated with the presence of cystic EOC. In contrast, tumor grade and tumor size were independently related to the presence of cystic EOC. This means that cystic EOCs represent a subgroup of larger and more well-differentiated tumors. The evident relationship between the presence of cysts and differentiation grade is interesting from a clinical point of view as grading is especially important for the prognosis and treatment of patients with stage I EOC.     

Carcinosarcoma of the ovary: a review of the literature

Objective

Carcinosarcoma of the ovary is a rare tumor with a grim prognosis. This article critically reviews the literature pertinent to the pathology, pathogenesis, diagnosis, management, and outcome of patients with ovarian carcinosarcoma (OCS).

Methods

MEDLINE was searched for all research articles published in English between January 1, 1981 and August 30, 2011 which reported on patients diagnosed with carcinosarcoma of the ovary. Given the rarity of this tumor, studies were not limited by design or number of reported patients.

Results

Patients with OCS generally present with advanced stage disease, and symptoms similar to those of patients with epithelial ovarian cancer (EOC). Retrospective studies have shown that cytoreductive surgery improves outcomes in patients with OCS. Similarly, platinum-based chemotherapy appears to be active in the treatment of OCS.

Conclusions

Ovarian carcinosarcomas are rare and aggressive tumors, associated with a poor prognosis. The mainstay of treatment remains cytoreductive surgical effort for metastatic disease followed by platinum-based chemotherapy. The role of targeted therapies may be promising in the treatment of OCS.     

A novel genome-based approach correlates TMPRSS3 overexpression in ovarian cancer with DNA hypomethylation

Objective

In an attempt to analyze more profoundly aberrant DNA hypomethylation in epithelial ovarian cancer (EOC), we applied a novel genome-based approach which includes expression profiling following pharmacologic stimulation of DNA methylation with the methyl donor S-adenosyl-l-methionine (SAM).

Methods

Four different EOC cell lines (OVCAR3, SKOV3, TOV21 and TOV112) were treated with SAM, and gene expression profiling was performed in SAM-treated and control EOC cells. Genes, downregulated upon SAM treatment were considered as potentially hypomethylated in EOC. DNA hypomethylation was independently validated in ovarian tumor and control tissues by bisulfite sequencing PCR (BSP).

Results

Among the genes identified, one of particular interest was the type II serine protease TMPRSS3 gene variants A and D (TMPRSS3-A/D), previously recognized as overexpressed in EOC and representing potential EOC therapeutic targets. Consecutive BSP analysis demonstrated that the common putative promoter region of the TMPRSS3-A/D gene variants was significantly hypomethylated in high-grade serous EOC tumors, compared to low-malignant potential ovarian tumors and normal ovarian tissue.

Conclusions

Our data imply that TMPRSS3-A/D overexpression in EOC is probably due to hypomethylation of their control region thus indicating that TMPRSS3-A/D variants could also represent novel molecular targets for epigenetic therapy of late stages of the disease. Our results also suggest that the frequently observed upregulation of different members of the type II serine proteases gene family in advanced cancer could be due to aberrant DNA hypomethylation. Furthermore, our study introduces a promising discovery approach that could be used for the identification of hypomethylated genes in different experimental cell models.     

Cytoplasmic expression of estrogen receptor beta (ERβ) predicts poor clinical outcome in advanced serous ovarian cancer

Objective

In this study we investigated the prognostic value of estrogen receptor α (ERα), ERβ and progesterone receptor (PR) expression in 58 untreated advanced serous ovarian cancer patients. The study also included 12 macroscopically and histopathologically normal ovaries.

Materials and methods

Protein expression was evaluated by immunohistochemistry, and antibody staining detected in both the nuclear and cytoplasmic compartments was taken into account. Immunopositivity was analyzed in relation to tumor clinicopathological variables, disease-free survival (DFS), and overall survival (OS).

Results

Epithelial cells in ovarian cancer tissue showed significantly lower levels of nuclear ERβ and PR, but not ERα, than in normal ovarian tissue. In the case of ERβ, however, while normal ovarian epithelium exhibited almost exclusively strong nuclear staining, ovarian cancer tissue mostly showed cytoplasmic immunopositivity. Nuclear ERα and ERβ expression were not associated with clinical outcome. Conversely, any cytoplasmic ERβ expression was an independent unfavorable prognostic factor for DFS, a finding approaching statistical significance also for OS. These data suggest that, in advanced serous ovarian cancer, cytoplasmic ERβ signaling may be more important for patient survival than its nuclear signaling. In the case of PR, positivity was an independent favorable prognostic factor for DFS.

Conclusions

These novel findings, that need to be confirmed in a large prospective trial, suggest that additional prognostic, and possibly therapeutic opportunities may be available in advanced serous ovarian cancer.     

Survival impact of capsule rupture in stage I clear cell carcinoma of the ovary in comparison with other histological types

Objective

We analyzed a large number of stage I clear cell carcinoma of the ovary (CCC) patients to estimate the survival impact of the capsule status in stage I CCC patients, particularly in comparison with non-CCC patients.

Methods

Clinicopathologic data on 564 patients with stage I epithelial ovarian cancer (EOC) collected under the central pathological review system were subjected to uni- and multivariable analyses to evaluate the disease-free survival (DFS) and overall survival (OS).

Results

There was no significant difference in both the OS and DFS of CCC patients between IA and IC(ir) (intraoperative capsule rupture) {IA vs. IC(ir); OS: P = 0.1402, DFS: P = 0.2701}. In contrast, CCC patients at IC(non-ir) {IC excluding for IC(ir), such as preoperative capsule rupture, positive ascites/washing, and surface involvement} showed a poorer OS and DFS than those at IC(ir), or those at the corresponding stage in non-CCC. In multivariable analysis, the capsule status was an independent prognostic factor of a poor OS and DFS {OS: HR, 2.832; 95% CI 1.156-6.938; P = 0.023; DFS: HR, 4.327; 95% CI, 1.937-9.667; P = 0.0004)} {In contrast, non-CCC: N.S. (OS/DFS)}. Furthermore, in CCC patients, intraperitoneal recurrences were more frequently observed in IC(non-ir) CCC than IA or IC(ir) CCC (P = 0.0083) {In contrast, non-CCC: N.S.}.

Conclusion

This study suggests that CCC patients other than those with intraoperative capsule rupture show a considerable risk for mortality despite adjuvant chemotherapy.     

Hormonal therapy for recurrent low-grade serous carcinoma of the ovary or peritoneum

Objective

To determine whether hormonal therapies have efficacy in patients with recurrent low-grade serous carcinoma of the ovary or peritoneum.

Methods

We searched departmental databases for patients with histologically-confirmed, evaluable, recurrent low-grade serous ovarian or peritoneal carcinoma who received hormonal therapy at our institution between 1989 and 2009. We retrospectively reviewed patients' medical records for demographic, disease, hormonal therapy, and estrogen receptor and progesterone receptor expression data. We used the Response Evaluation Criteria in Solid Tumors version 1.1 to determine patients' responses to hormonal therapy. Because patients could have received more than one evaluable hormonal therapy regimen, we chose to define the outcome metric as “patient-regimens.” Median time to disease progression (TTP) and overall survival (OS) were also calculated. Regression analysis was also performed.

Results

We identified 64 patients with recurrent low-grade serous carcinoma of the ovary or peritoneum. Patients' median TTP and median OS were 7.4 and 78.2 months, respectively. Patients received 89 separate hormonal patient-regimens, which produced an overall response rate of 9% (6 complete responses and 2 partial responses). Sixty-one percent of the patient-regimens resulted in a progression-free survival duration of at least 6 months. Patient-regimens involving ER +/PR + disease produced a longer median TTP (8.9 months) than patient-regimens involving ER +/PR − disease did (6.2 months; p = 0.053). This difference approached but did not reach statistical significance.

Conclusions

Hormonal therapies have moderate anti-tumor activity in patients with recurrent low-grade serous carcinoma of the ovary or peritoneum. Further study to determine whether ER/PR expression status is a predictive biomarker for this rare cancer subtype is warranted.     

Specificity and prognostic validation of a polyclonal antibody to detect Six1 homeoprotein in ovarian cancer

Objective

The presence of Six1 mRNA gene portends a poor prognosis in ovarian cancer. We describe validation of a Six1 specific antibody and evaluate its association with tumorigenicity and prognosis in ovarian cancer.

Methods

A Six1 antibody (Six1cTerm) was raised to residues downstream of the Six1 homeodomain, representing its unique C-terminus as compared to other Six family members. Cells were transfected with Six1-Six6 and Western blot was performed to demonstrate Six1 specificity. Ovarian cancer cell lines were analyzed for Six1 mRNA and Six1cTerm and tumorigenicity was evaluated. Ovarian cancer tissue microarrays (OTMA) were analyzed for Six1cTerm by immunohistochemistry and scored by two blinded observers. The metastatic tumors of 15 stage IIIC high grade serous ovarian cancers were analyzed with Six1 mRNA and Six1cTerm and expression was compared to clinical factors and survival.

Results

The Six1cTerm antibody is specific for Six1. Cell line tumorigenicity in SCID mice correlates with Six1 levels both by mRNA(p = 0.001, Mann-Whitney U test) and by protein (presence vs. absence, p = 0.05 Fischer's Exact test). Six1 protein was present in up to 54% of OTMA specimens. Six1 protein expression in omental/peritoneal metastases correlated with worsened survival in a sample (n = 15) of high grade serous stage IIIC ovarian cancers (p = 0.001).

Conclusions

The Six1cTerm antibody is specific and able to detect Six1 in cell lines and tumor tissue. Six1 protein detection is common in ovarian cancer and is associated with tumorigenicity and poor prognosis in this group of patient samples. Six1cTerm antibody should be further validated as prognostic tool.     

Myxoma virus-mediated oncolysis of ascites-derived human ovarian cancer cells and spheroids is impacted by differential AKT activity

Objective

We propose that metastatic epithelial ovarian cancer (EOC) is a potential therapeutic target for the oncolytic agent, Myxoma virus (MYXV).

Methods

Primary EOC cells were isolated from patient ascites and cultured as adherent cells or in suspension using Ultra Low-Attachment dishes. MYXV expressing green fluorescent protein was used to infect cells and spheroids. Infection was monitored by fluorescence microscopy, viral titering and immunoblotting for M-T7 and M130 virus protein expression, and cell viability by alamarBlue assay. Akti-1/2 (5 μM) and rapamycin (20 nM) were used to assay the role of PI3K-AKT signaling in mediating MYXV infection.

Results

Ascites-derived EOC cells grown in adherent culture are effectively killed by MYXV infection. EOC cells grown in suspension to form three-dimensional EOC spheroids readily permit MYXV entry into cells, yet are protected from the cytopathic effects of late MYXV infection. Upon reattachment (to model secondary metastasis), EOC spheroids are re-sensitized to MYXV-mediated oncolysis. The critical determinant that facilitates efficient MYXV infection is the presence of an activated PI3K-AKT signaling pathway. Treatment with the specific AKT inhibitor Akti-1/2 reduces infection of monolayer EOC cells and spheroids. Direct infection of freshly-collected ascites demonstrated that 54.5% of patient samples were sensitive to MYXV-mediated oncolytic cell killing. We also demonstrate that factor(s) present in ascites may negatively impact MYXV infection and oncolysis of EOC cells, which may be due to a down-regulation in endogenous AKT activity.

Conclusions

Differential activity of AKT serves as the mechanistic basis for regulating MYXV-mediated oncolysis of EOC spheroids during key steps of the metastatic program. In addition, we provide the first evidence that MYXV oncolytic therapy may be efficacious for a significant proportion of ovarian cancer patients with metastatic disease.     

Expression of 67-kDa laminin receptor was associated with tumor progression and poor prognosis in epithelial ovarian cancer

Objective

67-kDa laminin receptor (67LR) has been identified as a prognostic biomarker for a variety of human cancers. We investigated the clinical significance of 67LR expression and its functional role in epithelial ovarian cancer (EOC).

Methods

67LR expression was evaluated by immunohistochemistry in 62 patients with EOC. We assessed the correlation of 67LR expression with clinical characteristics. In vitro experiment was performed for 67LR with inhibition using siRNA to evaluate its role in cell survival, apoptosis, and invasion in EOC cells.

Results

67LR was predominantly expressed on the cell membrane in the majority of EOC samples (45/62, 73%). 67LR expression was significantly correlated with advanced stage (P = 0.001). Patients with 67LR expression had shorter progression-free survival among all the patients (P = 0.010) and in particular among patients with advanced stages (P = 0.046). When 67LR expression was inhibited by siRNA in EOC cells (HeyA8 and A2780), there was a significant decrease of cell proliferation and invasion as well as increase of apoptosis.

Conclusion

These findings suggest that 67LR expression may play an important role in tumor progression into advanced stage with poor prognosis in EOC and down-regulation of 67LR on tumor cells may be a therapeutic target in those patients.     

Novel nanotechnology approaches to diagnosis and therapy of ovarian cancer

Objective

Ovarian carcinoma is the leading cause of death from gynecologic malignancies, which is a direct outcome of missing its diagnosis at an early stage. Approximately 75% of ovarian cancer patients are initially diagnosed with disseminated intra-abdominal disease (stages III-IV) when ~ 30% of patients have a 5-year survival rate. In addition to the challenge of early detection of ovarian cancer, its therapy presents several challenges including the route of therapy, resistance to therapy with recurrence of cancer, and specific targeting of ovarian cancer to reduce cytotoxic side effects.

Methods

We reviewed recent literature employing nanotechnology approaches to diagnosis and therapy of ovarian cancer.

Results

Recent innovations in nanotechnology with applications in cancer diagnostics and therapy help circumvent many pre-existing problems with conventional chemotherapy and present new ways of diagnosis and therapy.

Conclusions

Nanotechnology has promising potential in enhancing early detection of ovarian cancer and treatment of recurrent disease.     

Is low-grade serous ovarian cancer part of the tumor spectrum of hereditary breast and ovarian cancer?

Objective

To determine whether women with low-grade serous ovarian cancer (LGSOC) have personal and family histories of breast and ovarian cancer that are less suggestive of Hereditary Breast and Ovarian Cancer (HBOC), as compared to women with high-grade serous ovarian cancer (HGSOC).

Methods

A single institution, case-control retrospective review of medical records was conducted. Personal demographics, personal cancer history, and family history of breast and ovarian cancer of women with LGSOC were collected and compared to controls with HGSOC, which is known to be associated with HBOC.

Results

195 cases of LGSOC and 386 controls with HGSOC were included in the analysis. Women with LGSOC were significantly less likely to have a first- or second-degree relative with breast or ovarian cancer (p = 0.0016). Additionally, when the personal and family histories were quantified using the AMyriad BRC mutation prevalence tables, women with LGSOC had lower scores indicative of a less suggestive family history for HBOC (p = 0.027).

Conclusions

In this study, women with LGSOC had family histories that were less suggestive of HBOC compared to women with HGSOC, especially when the degree of relatedness of affected relatives was taken into account. By beginning to determine if LGSOC is part of the tumor spectrum seen in HBOC, this study is an important step towards refining hereditary cancer risk assessment for women with ovarian cancer.     

Tyrosine kinase A receptor (trkA): a potential marker in epithelial ovarian cancer

Objectives

To evaluate the role of trkA receptor as a potential tumor marker in serous epithelial ovarian cancer and its relationship with the angiogenic factors expression as vascular endothelial growth factor (VEGF) and nerve growth factor (NGF). Additionally, to examine whether NGF and VEGF secreted by epithelial ovarian cancer (EOC) explants and from epithelial ovarian cancer cell line (A2780) are involved in the process of angiogenesis, such as cellular proliferation, migration and differentiation of the human endothelial cell line (EA.hy926).

Methods

The mRNA levels of VEGF, NGF and trkA receptors were measured using PCR in 60 ovarian samples. Cellular localization and semi-quantitative estimation of VEGF, NGF, total trkA and p-trkA was performed using IHC in epithelial cells. NGF, total trkA and p-trkA protein were also evaluated in endothelial cells from the same tissues. Human endothelial cell line EA.hy926 was cultured with conditioned media obtained from both EOC explants and from the A2780 cell line, with or without NGF stimulus.

Results

Significantly higher levels of NGF, total trkA and p-trkA protein expressions were observed in epithelial and endothelial cells in poorly differentiated EOC versus normal ovary. Interestingly, the p-trkA receptor expression level showed the most significant difference and its presence was only found in borderline tumor and EOC samples indicating the importance of trkA receptor in EOC as a potential tumor marker.A significant increase in proliferation, migration and differentiation of EA.hy926 cells was observed with NGF, and this effect was significantly reverted when NGF was immuno-blocked and when a trkA inhibitor was used, showing that NGF is an important angiogenic factor in EOC by activating its trkA receptor.

Conclusion

These results indicate that p-trkA may be considered as a new potential tumor marker in EOC, and that NGF may also act as a direct angiogenic factor in EOC.     

"Primary peritoneal" high-grade serous carcinoma is very likely metastatic from serous tubal intraepithelial carcinoma: assessing the new paradigm of ovarian and pelvic serous carcinogenesis and its implications for screening for ovarian cancer

Objective

Primary peritoneal high-grade serous carcinoma is thought to arise from the peritoneum, but recent data suggest that the fallopian tube may be an occult source of many of these tumors. This study was performed to evaluate this hypothesis in an unselected series of cases.

Methods

Fallopian tubes from 51 consecutive cases meeting the GOG criteria for primary peritoneal high-grade serous carcinoma, FIGO stages II-IV, were analyzed.

Results

Serous tubal intraepithelial carcinoma (STIC) was identified in 19 patients (37%). When the fimbriae were examined, STIC was identified in 46%, and when all tubal tissue was examined, 56%. STIC was confined to the fimbriae in 53%, involved fimbriae and nonfimbrial mucosa in 20%, and was confined to nonfimbrial mucosa in 20%. Patients with STIC were significantly older than those without STIC (75 years vs. 67 years, respectively; p = 0.007). Patients with STIC were significantly more likely to have FIGO stage IV disease as compared to those without STIC (42% vs. 12.5%, respectively; p = 0.037).

Conclusions

At least half the cases of primary peritoneal high-grade serous carcinoma are associated with intraepithelial carcinoma of the fallopian tube, usually involving the fimbriae. These findings support the view that, like “primary ovarian carcinoma,” what has been traditionally classified as “primary peritoneal carcinoma” is probably derived from occult high-grade serous carcinoma in the fallopian tube. These findings have important implications for ultrasound screening trials for ovarian cancer which are based on the assumption that an enlarged ovary is a very early manifestation of disease.     

Ovarian sex cord-stromal tumors, pleuropulmonary blastoma and DICER1 mutations: a report from the International Pleuropulmonary Blastoma Registry

Objective

Pleuropulmonary blastoma (PPB) is a childhood cancer arising from pleuropulmonary mesenchyme. This neoplasm is a sentinel disease in a familial tumor syndrome recently found to be associated with germline mutations in DICER1. Observations of ovarian sex cord-stromal tumors (OSCST) in PPB kindreds led to further study. We sought to characterize ovarian tumors seen in probands and families with PPB and PPB-related conditions and define germline DICER1 status.

Methods

Patient and family records of pathology-reviewed PPB cases enrolled in the International PPB Registry (IPPBR) were searched for ovarian tumors. Ovarian tumor pathology specimens were obtained and centrally reviewed. Germline DNA from patients with ovarian tumors was tested for DICER1 mutations. Three additional OSCST patients registered in the IPPBR were also tested for mutations in DICER1.

Results

Among 296 kindreds including 325 children with PPB, we observed three children with both PPB and Sertoli-Leydig cell tumors (SLCT)/Sertoli cell tumors. Among family members of PPB patients, we identified six OSCST (three SLCT, one Sertoli cell tumor, one juvenile granulosa cell tumor, one gynandroblastoma). Age at ovarian tumor diagnosis was youngest in PPB probands and younger in family members than in OSCST in general. Germline DICER1 mutations were identified in four of six patients with OSCST from PPB kindreds and in two of three children with OSCST and no personal or family history of PPB.

Conclusions

Primary ovarian neoplasms, particularly OSCST, are a manifestation of the familial PPB syndrome and may be the initial clinical presentation of DICER1 mutations within a family.     

Carcinosarcoma of the ovary: a case-control study

Introduction

Carcinosarcoma of the ovary is a rare tumor with a grim prognosis. Chemotherapy for these tumors is chosen according to guidelines established for epithelial ovarian cancer (EOC). The purpose of this study is to compare response to chemotherapy and survival in patients with advanced stage carcinosarcoma of the ovary.

Methods

We identified women with advanced carcinosarcoma of the ovary who underwent first-line platinum and taxane-based chemotherapy. Each case was matched to two women with serous EOC. Cases and controls were matched by age, stage, and year of diagnosis. The Kaplan-Meier method was used to generate overall survival (OS) data. Factors predictive of outcome were compared using the log-rank test and Cox proportional hazards model.

Results

Fifty women treated with first line platinum and taxane-based chemotherapy had advanced carcinosarcoma of the ovary and were selected as cases. The response rates to chemotherapy for cases and controls were 62% and 83% (P = 0.03), respectively. Median progression-free survival was 11 months (95% CI, 8 to 14 months) versus 16 months (95% CI, 12 to 21 months; P = 0.02) and median overall survival was 24 months (95% CI, 18 to 29 months) versus 41 months (95% CI, 33 to 49 months; P = 0.002) for cases and controls, respectively.

Conclusion

Patients with advanced carcinosarcoma of the ovary have a poorer response to platinum and taxane-based first-line chemotherapy and worse survival, compared to patients with serous EOC. Aggressive surgical treatment may play an important role. However, other alternative systemic therapeutic approaches should be sought for patients with carcinosarcoma of the ovary.     

Papel de p16 en lesiones preinvasivas e invasivas de cáncer de cuello uterino. Aplicación de la técnica a citología convencional

Introduction

Detection of p16 expression by immunohistochemistry and immunocytochemistry is a good standard for the identification of high-grade cervical epithelial lesions and low-grade lesions with DNA HPV viral integration (with a tendency for progression).

Material and methods

We evaluated p16 expression in 58 HPV-positive cervical biopsies and 53 conventional cytological samples that tested HPV-positive with immunohistochemical and immunocytochemical techniques.

Results

All high-grade lesions were positive for p16 while only some of the low-grade lesions were positive. The results obtained in histological samples could be extrapolated to cytological samples from the same patients.

Conclusions

p16 expression in conventional cytology provides similar results to those in histological samples.     

Risk factors for recurrence of ovarian borderline tumors

Objective

The objective of this study was to identify clinicopathologic features that are associated with an increased risk of recurrence for borderline ovarian tumors (BOT).

Methods

We performed a retrospective review of all patients treated for BOT at our institution from 1979 to 2008. Progression-free survival (PFS) was defined as the time of diagnosis to time of recurrence/death or last follow-up. The Kaplan-Meier method was used to calculate the PFS rate and the Wilcoxon-Gehan test was performed to identify prognostic factors.

Results

A total of 266 patients were identified. The median age was 43 years (range, 15-94 years). The majority of patients (68.4%) had FIGO stage I disease and serous histology (73.7%). Only 23 (8.6%) patients developed recurrent disease. The median PFS was 19 years and the median follow-up was 4 years. Abnormal baseline CA-125 (> 35 U/ml), advanced stage, age at diagnosis, and invasive implants were associated with decreased PFS. Of the 196 patients with serous BOT, those with a micropapillary pattern had a 3-year PFS of 75.9% (95%CI, 55.6-87.8) compared with 94.3% (95% CI, 88.4-97.3) for patients without micropapillary pattern (P < 0.001).

Conclusion

Age at diagnosis, an elevated preoperative CA-125, invasive implants, and micropapillary histology were clinical factors associated with increased risk of recurrence in women with BOT. Including these clinicopathologic features will likely identify patients at higher risk for recurrence, for whom development of new treatment strategies would be appropriate.