De-escalation in stage IC epithelial ovarian cancer: adjuvant treatment.

Epithelial ovarian carcinoma (EOC) is the most common form of ovarian cancer and is associated with a poor prognosis. Astrocyte Elevated Gene-1 (AEG-1) is an oncogene implicated in cancer cell growth and progression. The present study examined AEG-1 expression in EOC, specifically comparing high-grade serous ovarian carcinoma (HGSOC) and low-grade serous ovarian carcinoma (LGSOC). The present retrospective analytical study employed a cross-sectional design and included women diagnosed with HGSOC or LGSOC between January 2021 and December 2023. Extracted data included demographic, laboratory and clinicopathological characteristics. In addition to comparing AEG-1 expression in HGSOC and LGSOC, associations between these histological subtypes and the extracted variables, as well as associations between AEG-1 expression and these variables, were assessed. Of the 74 patients initially identified, 24 were excluded, resulting in a final sample of 50 patients 23 with LGSOC and 27 with HGSOC. A statistically significant association was found between residual disease and cancer histopathology [odds ratio: 7.219; 95% confidence interval (CI): 1.399-37.252; P=0.024), whereas no significant associations were observed with other variables. AEG-1 expression was significantly higher in HGSOC compared with LGSOC (relative risk: 3.228; 95% CI: 1.188-8.776; P=0.012), with high AEG-1 expression observed more frequently in HGSOC (65.7%) than in LGSOC (34.3%). In conclusion, AEG-1 expression was significantly elevated in HGSOC compared with LGSOC, suggesting a potential role for AEG-1 in the progression of HGSOC.

Expression of E-Cadherin/β-Catenin, PTEN-PI3K-/Akt and P53 in Low Grade and High Grade Serous Ovarian Carcinoma

In this study, we evaluate a two-tier system for grading ovarian serous carcinoma. This system is based primarily on the assessment of nuclear atypia with the mitotic rate used as a secondary feature. The study included 50 cases of low-grade ovarian serous carcinoma and 50 cases of high-grade ovarian serous carcinoma retrieved from the files of the Department of Pathology at the University of Texas M. D. Anderson Cancer Center from a 28-year period. Cases assigned to the low-grade category were characterized by the presence of mild to moderate nuclear atypia. As a secondary feature, they tended to show up to 12 mitoses per 10 high power fields (HPFs), whereas those in the high-grade category had marked nuclear atypia and as a secondary feature more than 12 mitoses per 10 HPFs. For comparison, the tumors were also graded using the Shimizu/Silverberg and the FIGO grading systems. Patients in the low-grade ovarian serous carcinoma group ranged in age from 19 to 75 years (mean 41.7 years) while patients in the high-grade ovarian serous carcinoma group ranged in age from 27 to 76 years (mean 55 years). All of the cases except one were advanced FIGO stage. Using the Shimizu/Silverberg system, the low-grade ovarian serous carcinoma cases were distributed as follows: grade 1, 47 cases; grade 2, 3 cases. Using the FIGO grading system, 35 cases were grade 1 and 15 cases were grade 2. Regarding the high-grade ovarian serous carcinoma group using the Shimizu/Silverberg system, 14 of the cases were grade 2 and 36 cases were grade 3. Using the FIGO grading system, 1 case was grade 1, 38 cases were grade 2, and 11 cases were grade 3. Most of the patients in both groups were treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy and also received cisplatinum-based chemotherapy. On follow-up, 37 patients in the low-grade ovarian serous carcinoma group had died of disease at a median 4.2 years after diagnosis compared with 46 patients in the high-grade ovarian serous carcinoma group who died of disease at a median of 1.7 years. Eight patients in the low-grade ovarian serous carcinoma group and 4 patients in the high-grade ovarian serous carcinoma group were alive with disease at median follow-ups of 4.3 and 3.85 years, respectively. Four patients with low-grade serous carcinoma were alive without evidence of disease after a follow-up that ranged from 4.4 to 22.6 years (median 6.85 years), and one died of other causes 14 years after the diagnosis of her ovarian tumor. On multivariate analysis, residual tumor and tumor grade based on the M. D. Anderson two-tier system for grading ovarian serous carcinoma were found to be significant independent prognostic factors (P = 0.003 and 0.04, respectively). Of interest, 60% of the low-grade ovarian serous carcinomas in this study were associated with a serous neoplasm of low malignant potential, whereas this association was present in only 2% of the high-grade ovarian serous carcinomas. This finding could reflect a difference in the pathogenesis of ovarian serous carcinomas of different grades. In summary, there is usually a good correlation between the two-tier grading system herein presented and the Shimizu/Silverberg and the FIGO grading systems. Because this system is based on defined criteria that are easy to follow and because it involves only two diagnostic categories, it should provide better reproducibility in the grading of ovarian serous carcinoma. However, additional studies are required to validate these statements.

Characterizing the genomic landscape through the lens of FOLR1 status in low and high grade serous ovarian carcinoma

Despite the fact that ovarian epithelial ovarian cancer is a molecularly and histologically heterogeneous disease, standard treatment is the same for all subtypes. Most high-grade serous ovarian carcinomas (OCs) are responsive to initial platinum/taxane chemotherapy, but low-grade serous OCs and clear cell OCs are relatively chemoresistant with limited treatment options upon recurrence, and most patients succumb to the disease. It is therefore of interest to exploit the molecular differences between high-grade serous OCs and other histological types in order to develop novel therapeutics. Over 90% of high-grade serous OCs harbor p53 mutations, whereas low-grade serous OCs are p53 wild-type but more frequently contain KRAS and BRAF mutations. Similarly, ovarian clear cell carcinomas are p53 wild-type but more frequently contain PI3K mutations. Nutlin-3 functions via inhibition of MDM2, thereby activating wild-type p53 and inducing apoptosis. We therefore sought to validate nutlin-3 as a potential novel therapeutic compound for p53 wild-type ovarian carcinomas. Two low-grade serous OC cell lines (HOC-7, MPSC-1), two clear cell OC cell lines (TOV21G, OVAS), and one high-grade serous OC p53-null cell line (SKOV3) were treated with varying concentrations of nutlin-3 (0-70 µm) for 72 hours, and cellular proliferation assays were performed. The three serous OC cell lines were then treated with nutlin-3 (5 µm), and quantitative reaction real-time polymerase chain reaction (qRT-PCR) and Western blot (WB) were employed to quantify MDM2, p53, and p21 expression at 24, 48, and 72 hours after treatment. The MPSC-1 cell line was then sequenced for p53 mutations in exons 5, 6, 7, and 8. Nutlin-3 inhibited cellular proliferation in a dose-dependent manner in the clear cell and low-grade serous cell lines, but not the p53-null high-grade serous cell line, as expected. Both PI3K-mutant clear cell ovarian cancer cell lines exhibited decreased growth in response to nutlin-3, but to a lesser extent than the low-grade serous cell lines. HOC-7, which bears a KRAS mutation, was more sensitive to inhibition than BRAF-mutated MPSC-1. Sequencing for p53 mutation in MPSC-1 surprisingly revealed a heterozygous p53 40 bp deletion in exon 5, which accounted for the reduced sensitivity of MPSC-1 to nutlin-3. On qRT-PCR and WB, levels of p53 were slightly decreased after nutlin-3 treatment and were absent in SKOV3. MDM2 and p21 were initially upregulated, but returned to near-baseline levels after 72 hours. Nutlin-3 is a novel potential therapeutic agent for low-grade serous ovarian carcinoma, and is dependent on an intact p53 pathway. It appears to function via upregulation of p21 with subsequent cell cycle arrest. Further studies characterizing response to nutlin-3 according to tumor mutation status are underway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2784. doi:1538-7445.AM2012-2784

Ovarian serous carcinoma (OSC) is the most common ovarian epithelial malignancy. Recently, a dualistic pathway of ovarian serous carcinogenesis has been proposed based on morphologic observations and molecular genetic analysis. In this scheme, low-grade OSC arises in a stepwise fashion from a benign serous cystadenoma through a usual serous borderline tumor through a micropapillary variant of serous borderline tumor. In contrast, the more common high-grade OSC arises de novo from the ovarian surface epithelium or the epithelium of cortical inclusion cysts with an as yet unrecognized precursor lesion. Although the division of OSC into low- and high-grade variants is gaining greater acceptance, and although there is accumulating molecular genetic evidence for this, there is little published information regarding a comparison of protein expression between these two types of OSC. In this study, we have investigated the immunohistochemical expression of a wide range of proteins in cases of low-grade (n = 22) and high-grade (n = 47) OSC. Antibodies used were p53, MIB1, BCL2, WT1, HER-2/neu, C-KIT, osteopontin, and survivin. For all antibodies, except MIB1, cases were scored as 0 (negative or occasional positive cells), 1+ (<10% cells positive), 2+ (10%-25% cells positive), 3+ (26%-50% cells positive), 4+ (51%-75% cells positive) or 5+ (>75% cells positive). For MIB1, the percentage of positive nuclei was calculated. There was a statistically significant higher expression of p53, MIB1, BCL2, HER-2/neu, and C-KIT in high-grade compared with low-grade OSC (P < 0.05). Thirty of 47 (64%) cases of high-grade OSC exhibited 5+ staining with p53 compared with 4 of 22 (18%) low-grade neoplasms. Twelve of 47 (26%) high-grade OSCs exhibited 5+ staining with BCL2 compared with 1 of 22 (5%) low-grade OSCs. The mean MIB1 proliferative index in high-grade OSCs was 55.4% compared with 23.0% in low-grade OSCs. Virtually all cases of both low-grade and high-grade OSCs exhibited diffuse nuclear positivity with WT1 and diffuse cytoplasmic positivity with survivin. Osteopontin expression was variable with no significant difference in expression between low-grade and high-grade OSC. Although expression of both HER-2/neu and C-KIT was significantly higher in high-grade compared with low-grade OSC, only rare cases exhibited strong positivity with these antibodies, which could be of therapeutic value in individual cases, although this would require additional molecular investigations. The significant differences in protein expression between low-grade and high-grade OSC provides further support for a different underlying pathogenesis. In particular, the differences in p53 immunoreactivity are in keeping with the observation that p53 gene mutation is more common in high-grade than low-grade OSC.

Early detection and treatment of ovarian cancer: shifting from early stage to minimal volume of disease based on a new model of carcinogenesis

Backgroud: Ovarian carcinoma is the third most common malignancy in Indonesian women after breast and cervical cancer. Serous ovarian carcinoma is the most frequent subtype, divided into low-grade and high-grade types, each with distinct genetic and biological characteristics. Objective:This study aims to compare the clinicopathological features of high-grade and low-grade serous ovarian carcinoma. Methods: A retrospective cross-sectional study was conducted using 77 paraffin-embedded samples of serous ovarian carcinoma. Clinical and pathological data including age, body mass index (BMI), age at menarche, and parity were collected and analyzed using the chi-square test. Results: Patients aged &gt;50 years accounted for most cases, with 64.3% presenting high-grade serous carcinoma (HGSC). Overweight/obesity was observed in 40.3% of cases. Early menarche (&lt;13 years) was reported in 78%, and 42.7% were multiparous. No significant differences were found in clinical variables between HGSC and low-grade serous carcinoma (LGSC). Histopathologically, HGSC showed more pronounced cytologic atypia, necrosis, and metastasis. Conclusion: High-grade serous carcinoma demonstrates greater aggressiveness compared to its low-grade counterpart. Histopathological assessment plays a critical role in diagnosis, treatment decisions, and prognosis evaluation.

Morphological and molecular heterogeneity of epithelial ovarian cancer: Therapeutic implications

Ovarian low grade serous carcinoma: A case report

Introduction: The most common malignancy of the ovary is serous carcinoma, which can be classified as either Low-grade Serous Ovarian Carcinoma (LGSOC) or High-grade Serous Ovarian Carcinoma (HGSOC) and originates from the surface epithelium. However, the overall prognosis for both cancers is very poor. Immunohistochemical analysis of p53 and p16 expression is commonly used to detect mutations. Diffuse and strong mutations (mutant type) are almost always observed in cases of HGSOC, while focal expression (wild type) suggests the absence of mutations in HGSOC. LGSOCs are characterised by a low number or absence of genetic mutations. Aim: To investigate the association between p53 and p16 expression in different grades and stages of Serous Ovarian Carcinoma (SOC). Materials and Methods: This observational cross-sectional descriptive study was conducted on 62 patients diagnosed with ovarian serous carcinoma. The study focused on examining the expressions of p53 and p16 using Immunohistochemistry (IHC) in the Department of Pathology, Nil Ratan Sircar Medical College and Hospital, Kolkata, West Bengal, India, over a period of one and a half years (February 2021 to July 2022). The study parameters included clinical features, histological findings, staging, The Federation of Gynaecology and Obstetrics (FIGO), grading, p53 and p16 expression by IHC in all cases, and the association between p53 and p16 expression with the grade and stage of the cancer. Statistical analysis was performed using Analysis of Variance (ANOVA) and Statistical Package for Social Sciences (SPSS) software. A p-value of less than 0.05 was considered significant. Results: A total of 62 cases were included in the study, with 55 cases (88.70%) classified as LGSOC and 7 cases (11.29%) as HGSOC. The mean age for LGSOC was 53.5 years, while for HGSOC it was 54 years. Among the HGSOC cases (n=55), 45 cases (81.80%) showed diffuse positive results (mutant type) for p53. In contrast, there was no diffuse p53 expression in LGSOC cases (n=7), with 5 cases (71.40%) showing focal positivity (wild type). The p-value for comparing p53 expression in both cases was significant (&lt;0.00001). As for p16 expression, among the HGSOC cases (n=55), 31 cases (56.40%) showed diffuse positivity (mutant type), while among the LGSOC cases (n=7), most of the cases, 5 cases (71.40%), showed focal positivity (wild type). The p-value for comparing p16 expression in both cases was significant (&lt;0.003794). Conclusion: In conclusion, p53 along with p16 are good markers for grading SOC, and p53 is highly effective in differentiating HGSOC from LGSOC based on the positivity pattern (diffuse and strong positive for high-grade/mutant type, and focal positive for low-grade cancers). Thus, p53 has become an attractive target for the development of moleculetargeted therapies for this disease.

A dualistic pathway of ovarian serous carcinogenesis is now well established whereby high-grade serous carcinoma and low-grade serous carcinoma represent two distinct tumour types with a different underlying pathogenesis. The aim of this study was to compare expression of p16 INK4A (p16) in these two tumour types. We also included cases of serous borderline tumour, since these are considered to represent a precursor lesion of low-grade serous carcinoma. Cases of serous borderline tumour (n = 18), low-grade ovarian serous carcinoma (n = 22) and high-grade ovarian serous carcinoma (n = 24) were stained with a monoclonal antibody against p16. Cases were scored both with respect to intensity of immunoreactivity (weak, 1+; moderate, 2+; or strong, 3+) and distribution (0, negative or occasional positive cells; 1+, < 10% cells positive; 2+, 10-25% cells positive; 3+, 26-50% cells positive; 4+, 51-75% cells positive; or 5+, 76-100% cells positive). An immunohistochemical composite score was also calculated (0-15) by multiplying the intensity and distribution scores. There was a statistically significant difference in p16 immunoreactivity with respect to intensity, distribution and composite score between high-grade serous carcinoma and each of the other two groups, with the high-grade neoplasms exhibiting stronger and more diffuse positivity. Most high-grade serous carcinomas exhibited positivity of close to 100% of tumour cells. There was no significant difference in p16 expression between the borderline tumours and low-grade serous carcinomas. The increased expression of p16 in high-grade serous carcinoma compared with low-grade serous carcinoma and serous borderline tumour is in keeping with a different underlying pathogenesis. p16 may be implicated in the development of high-grade serous neoplasia within the ovary and elsewhere within the female genital tract.

Ovarian clear cell carcinoma (OCCC) is a special histological type of epithelial ovarian cancer (EOC) that is not derived from epithelial cells of the ovarian or fallopian tube as the most common type of ovarian cancer, high-grade serous ovarian carcinoma (HGSOC), but is closely related to endometriosis and similar to endometrial clear cell carcinoma (ECCC) at morphologic and phenotypic features. However, limited data was shown in OCCC genomic features and compared with that in OCCC, HGSOC and ECCC. Herein, we utilized next-generation sequencing analysis of a panel of 1,021 genes to profile the mutational alterations in 34 OCCC and compared them to those from HGSOC (402 cases) and ECCC (30 cases). In result, the ARID1A and PIK3CA are high-frequency mutations of OCCC. Clonal architectures showed that all the mutations of genes occur in the later stage in the OCCC progress, whereas KRAS mutation is the earlier event compared with mutation of ARID1A or PIK3CA, which usually occurs in a group of ARID1A or PIK3CA mutations. The mutation frequency of main driver genes is similar between OCCC and ECCC, while TP53 is the main mutation in HGSOC and ECCC. Shared mutational signatures between OCCC and ECCC tissues with commonly observed a C>T change indicated a common carcinogens-exposed between these two carcinomas, but HGSOC and ECCC have common and distinct mutational signatures across cohorts respectively. In addition, we identified some novel CNV gains in NF1, ASXL1, TCF7L2, CREBBP and LRP1B and loss in ATM, FANCM, RB1 and FLT in OCCC. Our study offered a new perspective for OCCC tumorigenesis from two organs, the ovary and uterus, at genomic architectures and revealed novel CNV events for helping to provide theoretical support for OCCC treatment.

Complete macroscopic resection (CMR) is a key factor associated with prolonged survival in ovarian cancer. However, most evidence derives from high grade serous ovarian carcinoma (HGSOC), and the benefit of CMR in other histotypes is poorly characterised. We sought to determine which histotypes derive the greatest benefit from CMR to better inform future decisions on radical cytoreductive efforts. We performed multivariable analysis of disease-specific survival (DSS) across two independent patient cohorts to determine the magnitude of benefit associated with CMR within each histotype. Across both cohorts (Scottish, n = 1622; SEER, n = 18947), CMR was associated with prolonged DSS; this was more marked in the Scottish cohort (multivariable HR 0.44, 95%CI 0.37-0.52 vs 0.59, 95%CI 0.57-0.62 in SEER). In both cohorts, clear cell ovarian carcinoma (CCOC) was among the histotypes to benefit most from CMR (multivariable HR 0.23 and 0.50 in Scottish and SEER cohorts); HGSOC cases demonstrated highly significant and clinically meaningful survival benefit, but this was of lower magnitude than in CCOC and endometrioid ovarian carcinoma (EnOC) across both cohorts. The benefit derived in low grade serous ovarian carcinoma is also high (multivariable HR 0.27 in Scottish cohort). CMR was associated with prolonged survival in mucinous ovarian carcinoma (MOC) patients in the SEER cohort (multivariable HR 0.65), but the associated failed to reach statistical significance in the Scottish cohort. The overall ovarian cancer patient population demonstrates significant survival benefit associated with CMR; however, the magnitude of benefit differs between histotypes.

The two most prevalent subtypes of epithelial ovarian carcinoma (EOC) are ovarian clear cell carcinoma (OCCC) and high-grade serous ovarian carcinoma (HGSC). Patients with OCCC have a poor prognosis than those with HGSC due to chemoresistance, implying the need for novel treatment target. In this study, we applied single-cell RNA sequencing (scRNA-seq) together with bulk RNA-seq data from the GEO (Gene Expression Omnibus) database (the GSE189553 dataset) to characterize and compare tumor heterogeneity and cell-level evolution between OCCC and HGSC samples. To begin, we found that the smaller proportion of an epithelial OCCC cell subset in the G2/M phase might explain OCCC chemoresistance. Second, we identified a possible pathogenic OCCC epithelial cell subcluster that overexpresses LEFTY1. Third, novel biomarkers separating OCCC from HGSC were discovered and subsequently validated on a wide scale using immunohistochemistry. Amine oxidase copper containing 1 (AOC1) was preferentially expressed in OCCC over HGSC, while S100 calcium-binding protein A2 (S100A2) was detected less frequently in OCCC than in HGSC. In addition, we discovered that metabolic pathways were enriched in the epithelial compartment of the OCCC samples. In vitro experiments verified that inhibition of oxidative phosphorylation or glycolysis pathways exerted direct antitumor effects on both OCCC and HGSC cells, while targeting glutamine metabolism or ferroptosis greatly attenuated chemosensitivity only in OCCC cells. Finally, to determine whether there were any variations in immune cell subsets between OCCC and HGSC, data from scRNA-seq and mass cytometry were pooled for analysis. In summary, our work provides the first holistic insights into the cellular and molecular distinctions between OCCC and HGSC and is a valuable source for discovering new targets to leverage in clinical treatments to improve the poor prognosis of patients with OCCC.