Prognosis determination of endocervical adenocarcinomas morphologically reclassified as HPV associated or HPV independent.

OBJECTIVE: To evaluate the prognosis of endocervical adenocarcinomas after reclassification according to the morphologic type based on the 2020 World Health Organization Classification. METHODS: A retrospective longitudinal study with cases admitted at the University of Campinas, Brazil, from 2013 to 2020. The sample included 140 cases morphologically reclassified: 100 cases as adenocarcinoma HPV-associated (HPVA), 17 as HPV-independent (HPVI), and 23 non-HPVA/HPVI. Clinic and pathologic variables were evaluated. Analyses were performed by χ2 , Fisher exact, and Mann-Whitney U tests, Kaplan-Meier curves, Log-rank test, and Cox regression. RESULTS: Compared with the HPVA group, advanced stage (FIGO Stage II+) was more frequent in the HPVI group (P = 0.009), which also showed older patients (P = 0.032), and a higher proportion of deaths (P = 0.006). The median overall survival (OS) differed between groups: 73.3 months in HPVA and 42.4 months in HPVI (P = 0.005). At the multivariate analysis, the risk of death was 6.7 (95% confidence interval 1.9-23.0) times higher in patients diagnosed in advanced stages. CONCLUSION: HPVI cases were more frequent in older patients, presenting at more advanced stages and with worse OS. The morphology-based approach of the new WHO classification appears to be prognostically valuable and applicable in lower- and middle-income settings.

Adult Granulosa Cell Tumour With Heterologous Adipocytic Differentiation: Report of a Unique Case.

Adult granulosa cell tumor is the most common malignant ovarian sex cord-stromal tumor and heterologous elements, in the form of hepatocytes or mucinous epithelium, have rarely been described in these neoplasms. Here, we report an adult granulosa cell tumor in a 61-year-old woman with classic and luteinized elements and exhibiting a previously unreported feature in the form of foci of mature adipocytes. In reporting this case, we review heterologous adipocytic elements and other heterologous elements in ovarian sex cord-stromal tumors and speculate on the pathogenesis of the adipocytic differentiation.

SOX3 duplication in a boy with 46,XX ovotesticular disorder of sex development and his 46,XX sister with atypical genitalia: Probable germline mosaicism.

Ovotesticular disorders of sex development (OT-DSD) are characterized by ovarian follicles and seminiferous tubules in the same individual, with a wide range of atypical genitalia. We report on two sibs with atypical genitalia and SRY-negative 46,XX DSD, OT-DSD was confirmed only in the boy, while the girl had bilateral ovaries. Chromosome microarray analysis (CMA) showed a 737-kb duplication at Xq27.1 including the entire SOX3 gene in both sibs, which was confirmed by quantitative real time PCR. Also, X chromosome inactivation assay showed random inactivation in both sibs. Whole exome sequencing revealed no pathogenic or likely pathogenic variant. CMA of the parents showed normal results for both, suggesting that germline mosaicism could be the reason of recurrence of this duplication in the siblings. Our results support a pathogenic role of SOX3 overexpression in 46,XX subjects leading to variable DSD phenotypes.

Conservative treatment of microinvasive squamous cell carcinoma of the cervix stage IA1: Defining conization height to an optimal oncological outcome.

OBJECTIVE: This paper searches an ideal cone height for stage definition and safe treatment of cervical microinvasive squamous carcinoma stage IA1 (MIC IA1), avoiding excessive cervix resection, favoring a future pregnancy. METHODS: A retrospective study was performed involving 562 women with MIC IA1, from 1985 to 2013, evaluating cone margin involvement, depth of stromal invasion, lymph vascular invasion, conization height, and residual uterine disease (RD). High-grade squamous lesions or worse detection was considered recurrence. Univariate and multivariate regression analyses were performed, including age, conization technique (CKC, cold-knife, or ETZ, excision of transformation zone), and pathological results. Conization height to provide negative margins and the risk of residual disease were analyzed. RESULTS: Conization was indicated by biopsy CIN2/3 in 293 cases. Definitive treatments were hysterectomy (69.8%), CKC (20.5%), and ETZ (9.7%). Recurrence rate was 5.5%, more frequent in older women (p = 0.030), and less frequent in the hysterectomy group (p = 0.023). Age ≥40 years, ETZ and conization height are independent risk factors for margin involvement. For ages <40 years, 10 mm cone height was associated with 68.6% Negative Predictive Value (NPV) for positive margins, while for 15 mm and 25 mm, the NPV was 75.8% and 96.2%, respectively. With negative margins, the NPV for RD varied from 85.7-92.3% for up to 24 mm cone height and 100% from 25 mm. CONCLUSION: Conization 10 mm height for women <40 years provided adequate staging for almost 70%, with 10% of RD and few recurrences. A personalized cone height and staging associated with conservative treatment are recommended.

Preoperative Differentiation of Benign and Malignant Non-epithelial Ovarian Tumors: Clinical Features and Tumor Markers.

OBJECTIVE: To evaluate the role of clinical features and preoperative measurement of cancer antigen 125 (CA125), human epididymis protein (HE4), and carcinoembryonic antigen (CEA) serum levels in women with benign and malignant non-epithelial ovarian tumors. METHODS: One hundred and nineteen consecutive women with germ cell, sex cord-stromal, and ovarian leiomyomas were included in this study. The preoperative levels of biomarkers were measured, and then surgery and histopathological analysis were performed. Information about the treatment and disease recurrence were obtained from the medical files of patients. RESULTS: Our sample included 71 women with germ cell tumors (64 benign and 7 malignant), 46 with sex cord-stromal tumors (32 benign and 14 malignant), and 2 with ovarian leiomyomas. Among benign germ cell tumors, 63 were mature teratomas, and, among malignant, four were immature teratomas. The most common tumors in the sex cord-stromal group were fibromas (benign) and granulosa cell tumor (malignant). The biomarker serum levels were not different among benign and malignant non-epithelial ovarian tumors. Fertility-sparing surgeries were performed in 5 (71.4%) women with malignant germ cell tumor. Eleven (78.6%) patients with malignant sex cord-stromal tumors were treated with fertility-sparing surgeries. Five women (71.4%) with germ cell tumors and only 1 (7.1%) with sex cord-stromal tumor were treated with chemotherapy. One woman with germ cell tumor recurred and died of the disease and one woman with sex cord-stromal tumor recurred. CONCLUSION: Non-epithelial ovarian tumors were benign in the majority of cases, and the malignant cases were diagnosed at initial stages with good prognosis. The measurements of CA125, HE4, and CEA serum levels were not useful in the preoperative diagnosis of these tumors.

OBJETIVO: Avaliar o papel das características clínicas e a medida pré-operatória dos níveis séricos de CA125, HE4, e CEA em mulheres com tumores de ovário não epiteliais benignos e malignos. MéTODOS: Cento e dezenove mulheres consecutivas com tumores ovarianos de células germinativas, do cordão sexual-estroma, e miomas ovarianos foram incluídas neste estudo. Os níveis pré-operatórios dos biomarcadores foram medidos, a cirurgia e a análise histopatológica foram realizadas. Informações sobre tratamento e recorrência da doença foram obtidas dos prontuários médicos das pacientes. RESULTADOS: Nossa amostra incluiu 71 mulheres com tumores de células germinativas (64 benignos e 7 malignos), 46 com tumores do cordão sexual-estroma (32 benignos e 14 malignos), e 2 com leiomiomas ovarianos. Entre os tumores benignos de células germinativas, 63 eram teratomas maduros, e, entre os malignos, quatro eram teratomas imaturos. Os tumores mais comuns do grupo do cordão sexual-estroma foram fibromas (benignos) e tumores de células da granulosa (malignos). Os níveis séricos dos biomarcadores não diferiram entre os tumores de ovário não epiteliais benignos e malignos. A cirurgia preservadora de fertilidade foi realizada em 5 (71,4%) mulheres com tumores malignos de células germinativas. Onze (78,6%) mulheres com tumores do cordão sexual-estroma malignos foram tratadas com cirurgia preservadora de fertilidade. Cinco (71,4%) mulheres com células germinativas e apenas 1 (7,1%) com tumor do cordão sexual-estroma foram tratadas com quimioterapia. Uma mulher com tumor de células germinativas recidivou e morreu da doença. Uma mulher com tumor do cordão sexual-estroma recidivou. CONCLUSãO: Os tumores de ovário não epiteliais foram benignos na maioria dos casos e os malignos foram diagnosticados em estágios iniciais, com bom prognóstico. A medida dos níveis séricos de CA125, HE4, e CEA não foram úteis no diagnóstico pré-operatório desses tumores.

Three-Dimensional Cell Culture Based on Magnetic Fields to Assemble Low-Grade Ovarian Carcinoma Cell Aggregates Containing Lymphocytes.

There is a limited number of established ovarian cancer cell lines matching the low-grade serous histotype available for research purposes. Three-dimensional (3D) culture systems provide in vitro models with better tissue-like characteristics than two-dimensional (2D) systems. The goal in the study was to characterize the growth of a given low-grade serous ovarian carcinoma cell line in a 3D culture system conducted in a magnetic field. Moreover, the culture system was evaluated in respect to the assembly of malignant cell aggregates containing lymphocytes. CAISMOV24 cell line alone or mixed with human peripheral blood mononuclear cells (PBMC) were cultured using a commercially available 3D culture system designed for 24 well plates. Resulting cell aggregates revealed the intrinsic capacity of CAISMOV24 cells to assemble structures morphologically defined as papillary, and reflected molecular characteristics usually found in ovarian carcinomas. The contents of lymphocytes into co-cultured cell aggregates were significantly higher (p < 0.05) when NanoShuttle-conjugated PBMC were employed compared with non-conjugated PBMC. Moreover, lymphocyte subsets NK, T-CD4, T-CD8 and T-regulatory were successfully retrieved from co-cultured cell aggregates at 72h. Thus, the culture system allowed CAISMOV24 cell line to develop papillary-like cell aggregates containing lymphocytes.

Gonadoblastoma-Associated Mixed Gonadal Germ Cell Tumor with Dysgerminoma and Hepatoid Yolk Sac Tumor Components in 46XY Gonadal Dysgenesis.

BACKGROUND: Disorders of sex development are congenital conditions with atypical chromosomal, gonadal, or anatomical sex development. Gonadal dysgenesis in patients containing a Y chromosome have a high risk of developing germ cell tumors with potential for malignant transformation. CASE: We present the case of a 17-year-old phenotypic female with primary amenorrhea and 46,XY complete gonadal dysgenesis. Pelvic ultrasound showed a solid cystic lesion in the right gonad. Pathology showed a gonadoblastoma-associated mixed gonadal germ cell tumor with dysgerminoma and hepatoid yolk sac tumor. SUMMARY AND CONCLUSION: To our knowledge, this mixed neoplasm association has not been previously reported and this case illustrates the challenges for the diagnosis of gonadal dysgenesis-associated tumors, emphasizing its recognition and prognostic implications.

Stage and histology of cervical cancer in women under 25 years old.

OBJECTIVE: To evaluate the histological and stage characteristics of cervical cancer in women under 25 years old, and to compare them with older women. METHODS: Cross-sectional study of cases from the Hospital Cancer Registry of São Paulo State/Brazil from 2000 to 2015. Variables were age, International Federation of Gynecology and Obstetrics stage and histological type. Prevalence ratio (PR) and its 95% confidence interval (CI) were calculated. RESULTS: Out of 18,423 cervical cancer cases 204 (1.1%) were in women under 25 years old. The most frequent stage was stage I in women under 25 (36.2%) and between 25 and 34 (43.4%), and stage III in older women (31.8%). No statistically significant difference was observed in stages by age group. Squamous carcinomas were the most frequent in 73.5% of women under 25 and 78.5% of older women. In women under 25 the following histological types were more frequent: neuroendocrine carcinomas (PR=6.10, 95% CI=2.03-18.35), malignant germ cell tumors (PR=54.98, 95% CI=26.53-113.95), mesenchymal tumors (sarcomas) (PR=5.67, 95% CI=2.58-12.45) and hematopoietic/lymphoid tumors (PR=0.72, 95% CI=2.90-36.69). CONCLUSION: In women under 25 years old cervical cancer was an uncommon diagnosis and in about one third occurred at early stage. Squamous carcinoma was the most frequent histological type regardless age, but rare histological types were more frequent in young women.

Clinical Features and Management of Women with Borderline Ovarian Tumors in a Single Center in Brazil.

OBJECTIVE: The aim of the present study was to describe and analyze data of 57 women with borderline ovarian tumors (BOTs) regarding histological characteristics, clinical features and treatment management at the Department of Obstetrics and Gynecology of the Universidade Estadual de Campinas (Unicamp, in the Portuguese acronym). METHODS: The present retrospective study analyzed data obtained from clinical and histopathological reports of women with BOTs treated in a single cancer center between 2010 and 2018. RESULTS: A total of 57 women were included, with a mean age of 48.42 years old (15.43-80.77), of which 30 (52.63%) were postmenopausal, and 18 (31.58%) were < 40 years old. All of the women underwent surgery. A total of 37 women (64.91%) were submitted to complete surgical staging for BOT, and none (0/57) were submitted to pelvic or paraortic lymphadenectomy. Chemotherapy was administered for two patients who recurred. The final histological diagnoses were: serous in 20 (35.09%) cases, mucinous in 26 (45.61%), seromucinous in 10 (17.54%), and endometrioid in 1 (1.75%) case. Intraoperative analyses of frozen sections were obtained in 42 (73.68%) women, of which 28 (66.67%) matched with the final diagnosis. The mean follow-up was of 42.79 months (range: 2.03-104.87 months). Regarding the current status of the women, 45 (78.95%) are alive without disease, 2 (3.51%) are alive with disease, 9 (15.79%) had their last follow-up visit > 1 year before the performance of the present study but are alive, and 1 patient (1.75%) died of another cause. CONCLUSION: Women in the present study were treated according to the current guidelines and only two patients recurred.

OBJETIVO: O objetivo do presente estudo foi descrever uma série de 57 mulheres com tumores borderline de ovário (TBO) em relação às características histológicas, clínicas, e ao manejo do tratamento realizado no Departamento de Obstetrícia e Ginecologia da Universidade Estadual de Campinas (Unicamp). MéTODOS: O presente estudo retrospectivo analisou dados obtidos dos registros clínicos e histopatológicos de mulheres com TBO tratadas em um único centro oncológico de 2010 a 2018. RESULTADOS: Um total de 57 mulheres foram incluídas, com uma média de idade de 48,42 anos (15,43­80,77), das quais 30 (52,63%) eram menopausadas, e 18 (31,58%) tinham < 40 anos. Todas as mulheres foram operadas. Um total de 37 mulheres (64,91%) foram submetidas a cirurgia de estadiamento completo para TBO, e nenhuma foi submetida a linfadenectomia pélvica ou paraórtica. O tratamento com quimioterapia foi administrado em duas pacientes que recidivaram. Os diagnósticos histológicos finais foram: seroso em 20 mulheres (35,09%), mucinoso em 26 (45,61%), seromucinoso em 10 (17,54%) e endometrióide em 1 (1,75%). A avaliação histológica intraoperatória foi realizada em 42 (73,68%) das mulheres, das quais 28 (66,67%) foram compatíveis com os diagnósticos finais. O tempo médio de seguimento foi de 42,79 meses (variando de 2,03 a 104,87 meses). Em relação ao status atual das mulheres, 45 (78.95%) estão vivas sem doença, 2 (3,51%) estão vivas com doença, 9 (15.79%) tiveram a última consulta de seguimento há > 1 ano antes da realização do presente estudo, mas estão vivas, e 1 paciente faleceu por outra causa. CONCLUSãO: As mulheres do presente estudo foram tratadas de acordo com as recomendações atuais e apenas duas mulheres apresentaram recorrência.

Clinical features and management of women with borderline ovarian tumors in a single center in Brazil / Características clínicas e manejo de mulheres com tumores borderline de ovário em um hospital no Brasil

Abstract Objective The aim of the present study was to describe and analyze data of 57 women with borderline ovarian tumors (BOTs) regarding histological characteristics, clinical features and treatment management at the Department of Obstetrics and Gynecology of the Universidade Estadual de Campinas (Unicamp, in the Portuguese acronym). Methods The present retrospective study analyzed data obtained from clinical and histopathological reports of women with BOTs treated in a single cancer center between 2010 and 2018. Results A total of 57 women were included, with a mean age of 48.42 years old (15.43- 80.77), of which 30 (52.63%) were postmenopausal, and 18 (31.58%) were < 40 years old. All of the women underwent surgery. A total of 37 women (64.91%) were submitted to complete surgical staging for BOT, and none (0/57) were submitted to pelvic or paraortic lymphadenectomy. Chemotherapy was administered for two patients who recurred. The final histological diagnoses were: serous in 20 (35.09%) cases, mucinous in 26 (45.61%), seromucinous in 10 (17.54%), and endometrioid in 1 (1.75%) case. Intraoperative analyses of frozen sections were obtained in 42 (73.68%) women, of which 28 (66.67%) matched with the final diagnosis. The mean follow-up was of 42.79 months (range: 2.03-104.87 months). Regard ingthe current status of the women, 45(78.95%) are alive without disease, 2(3.51%) arealive with disease, 9 (15.79%) had their last follow-up visit > 1 year beforethe performanceof the present study but arealive, and 1 patient(1.75%) died of another cause. Conclusion Women in the present study were treated according to the current guidelines and only two patients recurred.

Resumo Objetivo O objetivo do presente estudo foi descrever uma série de 57 mulheres com tumores borderline de ovário (TBO) em relação às características histológicas, clínicas, e ao manejo do tratamento realizado no Departamento de Obstetrícia e Ginecologia da Universidade Estadual de Campinas (Unicamp). Métodos O presente estudo retrospectivo analisou dados obtidos dos registros clínicos e histopatológicos de mulheres com TBO tratadas em um único centro oncológico de 2010 a 2018. Resultados Um total de 57 mulheres foram incluídas, com uma média de idade de 48,42 anos (15,43-80,77), das quais 30 (52,63%) eram menopausadas, e 18 (31,58%) tinham < 40 anos. Todas as mulheres foram operadas. Um total de 37 mulheres (64,91%) foram submetidas a cirurgia de estadiamento completo para TBO, e nenhuma foi submetida a linfadenectomia pélvica ou paraórtica. O tratamento com quimioterapia foi administrado em duas pacientes que recidivaram. Os diagnósticos histológicos finais foram: seroso em 20 mulheres (35,09%), mucinoso em 26 (45,61%), seromucinoso em 10 (17,54%) e endometrióide em 1 (1,75%). A avaliação histológica intraoperatória foi realizada em 42 (73,68%) das mulheres, das quais 28 (66,67%) foram compatíveis com os diagnósticos finais. O tempo médio de seguimento foi de 42,79 meses (variando de 2,03 a 104,87 meses). Em relação ao status atual das mulheres, 45 (78.95%) estão vivas sem doença, 2 (3,51%) estão vivas com doença, 9 (15.79%) tiveram a última consulta de seguimento há > 1 ano antes da realização do presente estudo, mas estão vivas, e 1 paciente faleceu por outra causa. Conclusão As mulheres do presente estudo foram tratadas de acordo com as recomendações atuais e apenas duas mulheres apresentaram recorrência.

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.

Immunohistochemistry expression of targeted therapies biomarkers in ovarian clear cell and endometrioid carcinomas (type I) and endometriosis.

Ovarian clear cell and endometrioid carcinomas (type I) are thought to develop from endometriosis. ARID1A loss of expression is known to be related to the promotion of the endometriosis carcinogenesis. Despite the diverse origins and prognosis of type I and type II carcinomas, surgery followed by platinum-based chemotherapy is the mainstay of treatment for both. Limited knowledge about the expression of targeted therapies' biomarkers prevents the use of such markers as potential guides for tailored treatment. This study aimed to evaluate the expression of ARID1A gene and target therapies biomarkers (VEGF, PD-L1, and PARP-1) in ovarian clear cell and endometrioid carcinomas and endometriosis, and its relationship with prognosis. Forty-six ovarian clear cell and endometrioid carcinomas, and 24 endometriosis foci samples retrieved from the same surgical specimens were studied. ARID1A, VEGF, PD-L1, and PARP-1 immunohistochemistry expression was compared in carcinomas and endometriosis with regard to the clinicopathological features and prognosis. We found that endometriosis was associated with increased rates of diagnosis of cancer in the initial stages (P = .008). Different levels of expression of all biomarkers were detected in clear cell and endometrioid carcinomas and endometriosis. However, only the VEGF expression level showed a significant increase in the carcinoma group when compared with endometriosis (P = .0002). PARP-1 overexpression correlated with worse progression-free survival (P = .03) and overall survival (P = .01). In conclusion, endometriosis and ovarian clear cell and endometrioid carcinomas exhibited ARID1A loss of expression, and VEGF, PD-L1, and PARP-1 expression. PARP-1 overexpression in clear cell and endometrioid carcinomas was associated with early recurrence and worse overall survival.

Endometriosis-Associated Ovarian Cancer: Population Characteristics and Prognosis.

OBJECTIVE: The aim of this study was to analyze and compare the clinicopathologic features and prognosis of clear cell ovarian carcinoma (CCOC) and endometrioid ovarian carcinoma (EOC) associated or not with endometriosis. METHODS: This was a reconstituted cohort study from a single-institution Brazilian cancer center approved under review board no. 68150617.7.0000.5404 with 50 patients with CCOC and EOC diagnosed between 1995 and 2016, followed up until 2017. Clinicopathologic characteristics and survival outcomes were analyzed. RESULT(S): There were 23 women (46%) with CCOC and 27 with EOC (54%); 80% of those women had histologic confirmation of endometriosis; 42% were nulliparous, and 42% were premenopausal; and cancer antigen 125 was elevated in both International Federation of Gynecology and Obstetrics stages I-II disease (mean, 614.7 Ui/mL; range, 3-6030 Ui/mL) or International Federation of Gynecology and Obstetrics stages III-IV disease (mean, 2361.2 Ui/mL; range, 8-12771 Ui/mL). Women with EOC were 7 years younger than those with CCOC. When associated with endometriosis, CCOCs were more likely diagnosed at earlier stages. Endometrioid ovarian carcinoma and CCOC at initial stage and EOC at advanced stage share similar good prognosis. Univariate analysis showed that CCOC not associated with endometriosis has worse overall survival (OS). However, multivariate analysis showed that only abnormally elevated levels of cancer antigen 125 and advanced stage at diagnosis were significantly associated with reduced progression-free survival. Tumor stage remains the only prognostic factor for OS. CONCLUSIONS: The presence of coexisting endometriosis did not change the prognosis of EOC but was associated with better OS in patients with CCOC. Patients with CCOC and EOC at initial stages and EOC at advanced stages have a good prognosis; however, CCOC at advanced stages had a sooner recurrence and shorter OS.

Strong SOD2 expression and HPV-16/18 positivity are independent events in cervical cancer.

It is well known that persistent infection with high-risk HPV (hr-HPV), mostly HPV-16 and 18, is the main cause of cervical cancer development. Manganese superoxide dismutase (MnSOD or SOD2) are highly expressed in different neoplasia. The present study investigated SOD2 protein expression and the presence of hr-HPV types in 297 cervical samples including non-neoplastic tissue, cervical intraepithelial neoplasia grade 3 (CIN3), squamous cell carcinoma (SCC) and adenocarcinoma (ADC). Strong SOD2 expression was significantly higher in ADC (82%) than CIN3 (52%) or SCC (64%). There was no association between SOD2 expression and HPV 16 and/or 18 detection for every lesion analyzed. Binary Logist Regression revealed that strong SOD2 expression (OR: 27.50, 6.16-122.81) and HPV 16 and/or HPV 18 (OR: 12.67, 4.04-39.74) were independently more associated with CIN3 than non-neoplastic cervix. Strong SOD2 expression (OR: 3.30, 1.23-8.86) and HPV 16 and/or HPV 18 (OR: 3.51, 1.03-11.87) were independently more associated with ADC than SCC. Similar findings for SOD2 expression were observed by the Cochran Mantel-Haenszel test, controlling for HPV-16 and/or HPV 18. In conclusion, the expression of SOD2 was increased in CIN3 and SCC, and more increased in cervical ADC than in SCC. Strong SOD2 expression was statistically independent of the presence of HPV 16 and/or 18. These findings suggest that the mitochondrial antioxidant system and HPV infection could follow independent pathways in the carcinogenesis of cervical epithelium and in the differentiation to SCC or ADC of the cervix.

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.

CAISMOV24, a new human low-grade serous ovarian carcinoma cell line.

BACKGROUND: The spontaneous immortalization of primary malignant cells is frequently assigned to their genetic instability during in vitro culturing. In this study, the new epithelial ovarian cancer cell line CAISMOV24 was described and compared with its original low-grade serous ovarian carcinoma. METHODS: The in vitro culture was established with cells isolated from ascites of a 60-year-old female patient with recurrent ovarian cancer. The CAISMOV24 line was assessed for cell growth, production of soluble biomarkers, expression of surface molecules and screened for typical mutations found in serous ovarian carcinoma. Additionally, comparative genomic hybridization was employed to compare genomic alterations between the CAISMOV24 cell line and its primary malignant cells. RESULTS: CAISMOV24 has been in continuous culture for more than 30 months and more than 100 in vitro passages. The cell surface molecules EpCAM, PVR and CD73 are overexpressed on CAISMOV24 cells compared to the primary malignant cells. CAISMOV24 continues to produce CA125 and HE4 in vitro. Although the cell line had developed alongside the accumulation of genomic alterations (28 CNV in primary cells and 37 CNV in CAISMOV24), most of them were related to CNVs already present in primary malignant cells. CAISMOV24 cell line harbored KRAS mutation with wild type TP53, therefore it is characterized as low-grade serous carcinoma. CONCLUSION: Our results corroborate with the idea that genomic alterations, depicted by CNVs, can be used for subtyping epithelial ovarian carcinomas. Additionally, CAISMOV24 cell line was characterized as a low-grade serous ovarian carcinoma, which still resembles its primary malignant cells.

45,X/46,XY ovotesticular disorder of sex development revisited: undifferentiated gonadal tissue may be mistaken as ovarian tissue.

BACKGROUND: The 45,X/46,XY karyotype has been associated with mixed gonadal dysgenesis (MGD) and ovotesticular disorder of sex development (DSD). Our aim was to revise the diagnosis of ovotesticular DSD in two patients in the context of a retrospective study of 45,X/46,XY subjects with genital ambiguity. CASE PRESENTATION: Patient 1 had a left streak gonad; the right one was considered an ovotestis. Patient 2 had a right testis; the left gonad was considered an ovary. Revision of the histological sections was performed. Both the "ovarian" part of the right gonad of patient 1 and the left "ovary" of patient 2 contained ovarian-type stroma with clusters of sex-cordlike structures and rare germ cells, compatible with undifferentiated gonadal tissue (UGT). Misdiagnosis of ovarian tissue in patients with 45,X/46,XY mosaicism or its variants could also be found in six published case reports. CONCLUSIONS: A distinction between 45,X/46,XY ovotesticular DSD and MGD should be made on past and future cases keeping in mind that UGT may be mistaken as ovarian tissue.