Role of discoidin domain receptor 2 (DDR2) and microRNA-182 in survival of women with high-grade serous ovarian cancer.

The objective of this study is to evaluate the relationship between discoidin domain receptor 2 (DDR2) and miR-182 expression with response to platinum-based chemotherapy and survival in women with high-grade serous ovarian cancer (HGSOC). We evaluated 78 women with HGSOC stages I-IV, diagnosed between 1996 and 2013, and followed up until 2016. DDR2 expression was assessed using immunohistochemistry on tissue microarray slides. The microRNAs were evaluated by qRT-PCR. DDR2 expression was high in 11 (14.1%) women. PFS was significantly lower in women with FIGO stage I/II - versus III/IV, post-surgery residual disease and high expression of DDR2. Women with postsurgery residual disease, FIGO stage I/II - versus III/IV and DDR2 expression had worse OS, but only post-surgery residual disease remained an independent prognostic factor for worse OS in multivariable analysis. miR-182 expression levels were significantly lower in patients harboring tumors with higher expression of DDR2 (p < 0.001). In this relatively large cohort of women with HSGOC, higher DDR2 expression was associated with lower miR-182 levels and worse PFS, suggesting that these molecules may be associated with mechanisms of HGSOC progression.

WT1, p53 and p16 expression in the diagnosis of low- and high-grade serous ovarian carcinomas and their relation to prognosis.

OBJECTIVE: To evaluate the diagnostic and prognostic value of the immunohistochemical expression of WT1, p53 and p16 in low- (LGSOCs) and high-grade serous ovarian carcinomas (HGSOCs). RESULTS: HGSOC had a significantly higher proportion of advanced stage disease, higher CA125 levels, higher proportion of post-surgery residual disease and higher recurrence or disease progression. WT1 was expressed in 71.4% of LGSOCs and in 57.1% of HGSOCs (p = 0.32). Focal and/or complete absence of p53 expression with negative p16 expression was found in 90.5% of LGSOCs, in contrast to the 88.1% of HGSOCs with diffuse or complete absence of p53 expression with positive p16 expression (<0.001). The IHC p53/p16 index and the morphological classification were closely matched (k = 0.68). In the univariate analysis, FIGO stage, post-surgery residual disease and histological grade were significantly associated with progression-free survival (PFS) and overall survival (OS). The IHC p53/p16 index was associated only with PFS. WT1 was not associated with PFS or OS. According to the multivariate analysis, advanced FIGO stage and presence of post-surgery residual disease remained independent prognostic factors for worst PFS, however these features had only a trend association with OS. METHODS: 21 LGSOC and 85 HGSOC stage I-IV cases were included. The morphological classification was assessed according to the World Health Organization (WHO) criteria. Immunohistochemistry (IHC) was performed in tissue microarray slides. IHC p53/p16 index was compared with the morphological classification. CONCLUSIONS: The IHC p53/p16 index was a good marker for the differentiation of LGSOC and HGSOC, but the morphologic classification showed a better association with survival. FIGO stage and post-surgery residual disease remained the only independent prognostic factors for survival.

BRCA1, Ki67, and ß-Catenin Immunoexpression Is Not Related to Differentiation, Platinum Response, or Prognosis in Women With Low- and High-Grade Serous Ovarian Carcinoma.

OBJECTIVE: The purpose of this study was to compare the immunohistochemical expression of BRCA1, Ki67, and ß-catenin in women with low-grade (LGSOC) and high-grade serous ovarian carcinomas (HGSOC) and their relationship with clinicopathological features, response to platinum-based chemotherapy, and survival. METHODS: For this study, 21 LGSOC and 85 HGSOC stage I to IV cases, diagnosed and treated from 1996 to 2013 and followed-up until December 2016, were included. BRCA1, Ki67, and ß-catenin expression was assessed using tissue microarray-based immunohistochemistry. RESULTS: Women with HGSOC were significantly more likely to have advanced-stage disease (P < 0.001), higher CA125 levels (P < 0.001), postsurgery residual disease (P < 0.01), and higher rates of disease progression and recurrence (P = 0.001). The percentage of women with HGSOC whose tumors expressed Ki67 was significantly higher compared with women with LGSOC (P < 0.001). The expression of BRCA1 and ß-catenin did not differ between LGSOC and HGSOC (P = 0.12 and P = 1.00, respectively). The clinicopathological features and the response to platinum-based chemotherapy did not differ according to the BRCA1, Ki67, and ß-catenin expression in either group. In HGSOC, only International Federation of Gynecology and Obstetrics stage was independently associated with poor survival (PFS and OS). CONCLUSIONS: Ki67 expression was significantly higher in HGSOC. BRCA1 and ß-catenin expression did not differ between LGSOC and HGSOC samples. BRCA1, Ki67, and ß-catenin expression was neither related to clinicopathological features, response to platinum-based chemotherapy, nor survival. Only International Federation of Gynecology and Obstetrics stage remained associated with poor survival in women with HGSOC.

Criteria for selection of laparoscopy for women with adnexal mass.

OBJECTIVES: We compared the indication of laparoscopy for treatment of adnexal masses based on the risk scores and tumor diameters with the indication based on gynecology-oncologists' experience. METHODS: This was a prospective study of 174 women who underwent surgery for adnexal tumors (116 laparotomies, 58 laparoscopies). The surgeries begun and completed by laparoscopy, with benign pathologic diagnosis, were considered successful. Laparoscopic surgeries that required conversion to laparotomy, led to a malignant diagnosis, or facilitated cyst rupture were considered failures. Two groups were defined for laparoscopy indication: (1) absence of American College of Obstetrics and Gynecology (ACOG) guideline for referral of high-risk adnexal masses criteria (ACOG negative) associated with 3 different tumor sizes (10, 12, and 14 cm); and (2) Index of Risk of Malignancy (IRM) with cutoffs at 100, 200, and 300, associated with the same 3 tumor sizes. Both groups were compared with the indication based on the surgeon's experience to verify whether the selection based on strict rules would improve the rate of successful laparoscopy. RESULTS: ACOG-negative and tumors≤10 cm and IRM with a cutoff at 300 points and tumors≤10 cm resulted in the same best performance (78% success=38/49 laparoscopies). However, compared with the results of the gynecology-oncologists' experience, those were not statistically significant. DISCUSSION: The selection of patients with adnexal mass to laparoscopy by the use of the ACOG guideline or IRM associated with tumor diameter had similar performance as the experience of gynecology-oncologists. Both methods are reproducible and easy to apply to all women with adnexal masses and could be used by general gynecologists to select women for laparoscopic surgery; however, referral to a gynecology-oncologist is advisable when there is any doubt.

[Laparoscopy for diagnosis and treatment of adnexal masses]. / Laparoscopia na abordagem inicial de tumores anexiais.

PURPOSE: To assess clinical factors, histopathologic diagnoses, operative time and differences in complication rates between women undergoing laparoscopy or laparotomy to diagnose and treat an adnexal mass and their association with laparoscopy failure. METHODS: In this prospective study, 210 women were invited to participate and 133 of them were included. Eighty-eight women underwent laparotomy and 45 underwent laparoscopy. Fourteen of the 45 laparoscopies were converted to laparotomy intraoperatively. We assessed whether age, body mass index (BMI), previous abdominal surgeries, CA-125, Index of Risk of Malignancy (IRM), tumor diameter, histological diagnosis, operative time and surgical complication rates differed between the laparoscopy group and the group converted to laparotomy and whether those factors were associated with conversion of laparoscopy to laparotomy. We also assessed surgical logs to evaluate the reasons, as stated by the surgeons, to convert a laparoscopy to laparotomy. RESULTS: In this research, 30% of the women had malignant tumors. CA-125, IRM, tumor diameter and operative times were higher for the laparotomy group than the laparoscopy group. Complication rates were similar for both groups and also for the successful laparoscopy and unsuccessful laparoscopy groups. The surgical complication rate in women with benign tumors was lower for the laparoscopy group than for the laparotomy group. The factors associated with conversion to laparotomy were tumor diameter and malignancy. During laparoscopy, adhesions a large tumor diameter were the principal causes of conversion. CONCLUSION: This study suggests that laparoscopy for the diagnosis and treatment of adnexal masses is safe and does not increase complication rates even in patients who need conversion to laparotomy. However, when doubt about the safety of the procedure and about the presence of malignancy persists, consultation with an expert gynecology-oncologist with experience in advanced laparoscopy is recommended. A large tumor diameter was associated with the necessity of conversion to laparotomy.

Laparoscopia na abordagem inicial de tumores anexiais / Laparoscopy for diagnosis and treatment of adnexal masses

OBJETIVO: Avaliar o uso da laparoscopia como método diagnóstico e terapêutico na abordagem inicial de tumores anexiais em população de risco para malignidade, bem como fatores clínicos associados à falha do método e conversão para laparotomia, e comparar taxas de complicação com pacientes cuja abordagem inicial se deu por laparotomia. MÉTODOS: Estudo prospectivo com 210 mulheres com exames de imagem prévios constando tumor anexial, das quais 133 foram incluídas. Destas, 45 foram submetidas à laparoscopia e 88, à laparotomia. Catorze das 45 cirurgias iniciadas por laparoscopia foram convertidas a laparotomia no intraoperatório. Foi avaliado se idade, índice de massa corporal (IMC), número de cirurgias abdominais prévias, CA-125, índice de risco de malignidade (IRM), diâmetro do tumor, duração da cirurgia e número de complicações cirúrgicas diferiram entre os grupos laparoscopia, laparoscopia com conversão à laparotomia e laparotomia. Foi também avaliado o motivo reportado pelos cirurgiões como falha da laparoscopia e a razão da conversão para laparotomia. RESULTADOS: A taxa de tumores malignos neste estudo foi de 30%. Houve diferença nos valores de CA-125, IRM e diâmetro do tumor entre os grupos laparoscopia e laparotomia. A duração da cirurgia foi maior no grupo de laparoscopias convertidas à laparotomia, porém as taxas de complicação cirúrgica foram semelhantes entre os grupos e, quando isolados os tumores benignos, as taxas de complicação cirúrgica da laparoscopia se mostraram inferiores à laparotomia. Dentre os fatores em estudo, apenas o tamanho do tumor esteve relacionado à conversão para laparotomia. CONCLUSÃO: Este estudo sugere que a abordagem inicial de pacientes com tumores ...

PURPOSE: To assess clinical factors, histopathologic diagnoses, operative time and differences in complication rates between women undergoing laparoscopy or laparotomy to diagnose and treat an adnexal mass and their association with laparoscopy failure. METHODS: In this prospective study, 210 women were invited to participate and 133 of them were included. Eighty-eight women underwent laparotomy and 45 underwent laparoscopy. Fourteen of the 45 laparoscopies were converted to laparotomy intraoperatively. We assessed whether age, body mass index (BMI), previous abdominal surgeries, CA-125, Index of Risk of Malignancy (IRM), tumor diameter, histological diagnosis, operative time and surgical complication rates differed between the laparoscopy group and the group converted to laparotomy and whether those factors were associated with conversion of laparoscopy to laparotomy. We also assessed surgical logs to evaluate the reasons, as stated by the surgeons, to convert a laparoscopy to laparotomy. RESULTS: In this research, 30% of the women had malignant tumors. CA-125, IRM, tumor diameter and operative times were higher for the laparotomy group than the laparoscopy group. Complication rates were similar for both groups and also for the successful laparoscopy and unsuccessful laparoscopy groups. The surgical complication rate in women with benign tumors was lower for the laparoscopy group than for the laparotomy group. The factors associated with conversion to laparotomy were tumor diameter and malignancy. During laparoscopy, adhesions a large tumor diameter were the principal causes of conversion. CONCLUSION: This study suggests that laparoscopy for the diagnosis and treatment of adnexal masses is safe and does not increase complication rates even in patients who need conversion to laparotomy. However, when doubt about the safety of the procedure and about the presence of malignancy persists, consultation with an expert gynecology-oncologist ...

Analysis of the contribution of immunologically-detectable HER2, steroid receptors and of the "triple-negative" tumor status to disease-free and overall survival of women with epithelial ovarian cancer.

We assessed associations between steroid receptors including: estrogen-alpha, estrogen-beta, androgen receptor, progesterone receptor, the HER2 status and triple-negative epithelial ovarian cancer (ERα-/PR-/HER2-; TNEOC) status and survival in women with epithelial ovarian cancer. The study included 152 women with primary epithelial ovarian cancer. The status of steroid receptor and HER2 was determined by immunohistochemistry. Disease-free and overall survival were calculated and compared with steroid receptor and HER2 status as well as clinicopathological features using the Cox Proportional Hazards model. A mean follow-up period of 43.6 months (interquartile range=41.4 months) was achieved where 44% of patients had serous tumor, followed by mucinous (23%), endometrioid (9%), mixed (9%), undifferentiated (8.5%) and clear cell tumors (5.3%). ER-alpha staining was associated with grade II-III tumors. Progesterone receptor staining was positively associated with a Body Mass Index≥25. Androgen receptor positivity was higher in serous tumors. In stand-alone analysis of receptor contribution to survival, estrogen-alpha positivity was associated with greater disease-free survival. However, there was no significant association between steroid receptor expression, HER2 status, or TNEOC status, and overall survival. Although estrogen-alpha, androgen receptor, progesterone receptor and the HER2 status were associated with key clinical features of the women and pathological characteristics of the tumors, these associations were not implicated in survival. Interestingly, women with TNEOC seem to fare the same way as their counterparts with non-TNEOC.

HE4 can help discriminate women with malignant ovarian tumors only if CA125 levels are elevated.

Objective: To evaluate the performance of mesothelin, CA125, HE4 and ROMA index in the detection of malignant ovarian tumors. 
Study Design: This is a cross-sectional study including 199 women with adnexal masses (67 with malignant tumors and 132 with benign tumors) and 150 healthy women (controls). We used a recursive multivariate partitioning algorithm to assess the contribution of each of the serum markers and the ROMA index to the discrimination of women with malignant tumors. Also, the areas under the ROC curves (AUC) for each of the serum markers and for the ROMA index were compared using the Venkatraman's projection-permutation test. 
Results: In the recursive model, CA125 had the best performance in discriminating women with malignant tumors. In women with normal-range CA125 levels, none of the other markers contributed to the discrimination of women with malignant tumors. In women with elevated CA125 levels, elevated HE4 levels were associated with an increased risk of harboring a malignant tumor. The AUC for mesothelin was smaller than that for all the other curves, and both the ROMA index and CA125 had better AUC than HE4. 
 Conclusion: In women with normal CA125 levels, neither mesothelin nor HE4 contributed to discriminate women with malignant ovarian tumors; however, for women with elevated CA125 levels HE4 may help discriminating those who have a malignant ovarian tumor.

Survival of women with ovarian carcinomas and borderline tumors is not affected by estrogen and progesterone receptor status.

OBJECTIVE: To examine the patterns of estrogen receptor (ER) and progesterone receptor (PR) expression in borderline ovarian tumors (BOTs) and ovarian carcinomas. We also assessed the disease-free survival (DFS) and overall survival (OS) in women with ovarian carcinoma, in relation to ER and/or PR expression. METHODS: We examined ER/PR expression in 38 BOTs and 172 ovarian carcinomas removed from patients treated at the State University of Campinas-UNICAMP (Brazil), from 1993 to 2008 and followed for up to 60 months using tissue microarray-based immunohistochemistry. RESULTS: Twenty-eight (73.7%) mucinous and 10 (26.3%) serous BOTs were included. Ovarian carcinomas consisted mainly of 79 (46.0%) serous, 44 (25.5%) mucinous, 17 (9.8%) endometrioid, 10 (5.8%) clear-cell types. There was no significant difference of the ER/PR expression between BOT and ovarian carcinoma (p=0.55 for ER alone, 0.90 for PR alone, and 0.12 for combined expression). The level of ER/PR expression in BOTs was significantly higher in serous than in mucinous tumors (p<0.01). In carcinomas, ER/PR was higher in serous tumors than in mucinous (p<0.01) and clear cell tumors (p=0.02), and higher in endometrioid tumors than in mucinous tumors (p<0.01). DFS was affected neither by the clinical characteristics nor by combined steroid receptor status. OS was found to be significantly worse (p<0.01) only in women with stages II-IV tumors and those with residual disease after surgery (p<0.01). CONCLUSION: Overall, serous and endometrioid tumors were predominantly ER/PR positive, whereas mucinous and clear-cell tumors were preponderantly ER/PR negative. DFS and OS were not affected by ER/PR expression.

[Serous and non-serous ovarian carcinoma: histological tumor type as related to the grade of differentiation and disease prognosis]. / Carcinoma de ovário seroso e não seroso: tipo histológico em relação ao grau de diferenciação e prognóstico.

PURPOSE: To compare the clinical-pathological features of women with serous and non-serous ovarian tumors and to identify the factors associated with survival. METHODS: In this reconstructed cohort study, 152 women with ovarian carcinoma, who attended medical consultations between 1993 and 2008 and who were followed-up until 2010 were included. The histological type was clearly established for all women: 81 serous carcinomas and 71 non-serous tumors (17 endometrioid, 44 mucinous and 10 clear cell carcinomas). The crude and adjusted odds ratios (OR), with the respective 95% confidence intervals (95%CI), were calculated for the clinical and pathological features, comparing serous and non-serous histological types. The Hazard Ratios (HR) with 95%CI was calculated for overall survival, considering the clinical and pathological features. RESULTS: Comparison of serous to non-serous tumor types by univariate analysis revealed that serous tumors were more frequently found in postmenopausal women, and were predominantly high histological grade (G2 and G3), advanced stage, with CA125>250 U/mL, and with positive peritoneal cytology. After multivariate regression, the only association remaining was that of high histological grade with serous tumors (adjusted OR 15.1; 95%CI 2.9-77.9). We observed 58 deaths from the disease. There was no difference in overall survival between women with serous carcinoma and women with non-serous carcinoma (HR 0.4; 95%CI 0.1 - 1.1). It was observed that women aged 50 years or less (HR 0.4; 95%CI 0.1-0.9) and those who were in menacne (HR 0.3; 95%CI 0.1-0.9) had a longer survival compared respectively to those above 50 years of age and menopaused. High histological grade (G2 and G3) (p<0.01), stages II-IV (p<0.008) and positive cytology (p<0.001) were significantly associated with worse prognosis. CA125 and the presence of ascites did not correlate with survival. Survival was poor when the disease was diagnosed in stages II to IV and compared to stage I (log-rank p<0.01) regardless of histological type (serous and non-serous). CONCLUSIONS: The proportion of high histological grade (G2 and G3) was significantly higher among serous than non-serous carcinomas. Serous and non-serous histological types were not related to overall survival.

Carcinoma de ovário seroso e não seroso: tipo histológico em relação ao grau de diferenciação e prognóstico / Serous and non-serous ovarian carcinoma: histological tumor type as related to the grade of differentiation and disease prognosis

OBJETIVO: Comparar as características clinicopatológicas de mulheres com carcinoma seroso e não seroso de ovário e identificar os fatores associados à sobrevida. MÉTODOS: Foram incluídas, neste estudo de coorte reconstituída, 152 mulheres com carcinoma de ovário, atendidas entre 1993 e 2008 e seguidas até 2010, nas quais o tipo histológico foi claramente estabelecido: 81 pacientes com carcinoma seroso e 71 pacientes com tumores não serosos (17 com carcinoma endometrioide, 44 com carcinoma mucinoso e 10 com carcinoma de células claras). Foram calculados os odds ratios (OR) brutos e os OR ajustados com os respectivos intervalos de confiança (IC95%) para as características clínicas e patológicas, comparando tumores serosos e não serosos. Foram calculados os Hazard Ratios (HR) com os respectivos IC95% em relação à sobrevida geral, para as variáveis clínicas e patológicas. RESULTADOS: Comparando os tipos seroso e não seroso, na análise univariada, os tumores serosos foram mais frequentes na pós-menopausa e eram preponderantemente carcinomas de alto grau histológico (G2 e G3), em estádios avançados, com CA125>250 U/mL e citologia peritoneal positiva. Após regressão múltipla, apenas o alto grau histológico se manteve associado com tumores serosos (OR ajustado 15,1; IC95% 2,9-77,9). Observamos 58 óbitos pela doença. O tipo histológico (seroso ou não seroso) não esteve associado com a sobrevida (HR 0,4; IC95% 0,1-1,1). Mulheres com idade de 50 anos ou menos (HR 0,4; IC95% 0,1-0,9) e aquelas que estavam em menacme (HR 0,3; IC95% 0,1-0,9) tiveram maior sobrevida quando comparadas, respectivamente, àquelas com idade acima de 50 anos e na menopausa. Carcinomas de alto grau histológico (G2 e G3) (p<0,01), estádio II a IV (p<0,008) e citologia peritoneal positiva (p<0,001) estiveram significativamente relacionados com pior prognóstico. O nível sérico de CA125 e a presença de ascite não se relacionaram com a sobrevida. A sobrevida foi menor quando a doença foi diagnosticada em estágios II a IV em comparação àquela das mulheres diagnosticadas no estádio I (log-rank p<0,01) independentemente do tipo histológico (seroso ou não seroso). CONCLUSÕES: A proporção de carcinomas de alto grau histológico (G2 ou G3) foi significativamente maior entre os carcinomas serosos comparados com não serosos. O tipo histológico seroso ou não seroso não esteve associado à sobrevida total.

PURPOSE: To compare the clinical-pathological features of women with serous and non-serous ovarian tumors and to identify the factors associated with survival. METHODS: In this reconstructed cohort study, 152 women with ovarian carcinoma, who attended medical consultations between 1993 and 2008 and who were followed-up until 2010 were included. The histological type was clearly established for all women: 81 serous carcinomas and 71 non-serous tumors (17 endometrioid, 44 mucinous and 10 clear cell carcinomas). The crude and adjusted odds ratios (OR), with the respective 95% confidence intervals (95%CI), were calculated for the clinical and pathological features, comparing serous and non-serous histological types. The Hazard Ratios (HR) with 95%CI was calculated for overall survival, considering the clinical and pathological features. RESULTS: Comparison of serous to non-serous tumor types by univariate analysis revealed that serous tumors were more frequently found in postmenopausal women, and were predominantly high histological grade (G2 and G3), advanced stage, with CA125>250 U/mL, and with positive peritoneal cytology. After multivariate regression, the only association remaining was that of high histological grade with serous tumors (adjusted OR 15.1; 95%CI 2.9-77.9). We observed 58 deaths from the disease. There was no difference in overall survival between women with serous carcinoma and women with non-serous carcinoma (HR 0.4; 95%CI 0.1 - 1.1). It was observed that women aged 50 years or less (HR 0.4; 95%CI 0.1-0.9) and those who were in menacne (HR 0.3; 95%CI 0.1-0.9) had a longer survival compared respectively to those above 50 years of age and menopaused. High histological grade (G2 and G3) (p<0.01), stages II-IV (p<0.008) and positive cytology (p<0.001) were significantly associated with worse prognosis. CA125 and the presence of ascites did not correlate with survival. Survival was poor when the disease was diagnosed in stages II to IV and compared to stage I (log-rank p<0.01) regardless of histological type (serous and non-serous). CONCLUSIONS: The proportion of high histological grade (G2 and G3) was significantly higher among serous than non-serous carcinomas. Serous and non-serous histological types were not related to overall survival.