scholarly journals The Evolution of Ovarian Carcinoma Subclassification

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 416
Author(s):  
Martin Köbel ◽  
Eun Young Kang
Keyword(s):  
Ovarian Carcinoma ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Expression Profiles ◽  
Model Systems ◽  
Serous Carcinoma ◽  
Molecular Profile ◽  
Low Grade ◽  
Ovarian Carcinomas ◽  
Immunohistochemical Markers

The phenotypically informed histotype classification remains the mainstay of ovarian carcinoma subclassification. Histotypes of ovarian epithelial neoplasms have evolved with each edition of the WHO Classification of Female Genital Tumours. The current fifth edition (2020) lists five principal histotypes: high-grade serous carcinoma (HGSC), low-grade serous carcinoma (LGSC), mucinous carcinoma (MC), endometrioid carcinoma (EC) and clear cell carcinoma (CCC). Since histotypes arise from different cells of origin, cell lineage-specific diagnostic immunohistochemical markers and histotype-specific oncogenic alterations can confirm the morphological diagnosis. A four-marker immunohistochemical panel (WT1/p53/napsin A/PR) can distinguish the five principal histotypes with high accuracy, and additional immunohistochemical markers can be used depending on the diagnostic considerations. Histotypes are further stratified into molecular subtypes and assessed with predictive biomarker tests. HGSCs have recently been subclassified based on mechanisms of chromosomal instability, mRNA expression profiles or individual candidate biomarkers. ECs are composed of the same molecular subtypes (POLE-mutated/mismatch repair-deficient/no specific molecular profile/p53-abnormal) with the same prognostic stratification as their endometrial counterparts. Although methylation analyses and gene expression and sequencing showed at least two clusters, the molecular subtypes of CCCs remain largely elusive to date. Mutational and immunohistochemical data on LGSC have suggested five molecular subtypes with prognostic differences. While our understanding of the molecular composition of ovarian carcinomas has significantly advanced and continues to evolve, the need for treatment options suitable for these alterations is becoming more obvious. Further preclinical studies using histotype-defined and molecular subtype-characterized model systems are needed to expand the therapeutic spectrum for women diagnosed with ovarian carcinomas.

MOLECULAR AND GENETIC SUBTYPES OF OVARIAN CANCER: PROSPECTS FOR FURTHER STUDIES

2019 ◽  
Vol 65 (1) ◽  
pp. 56-62
Author(s):  
Alisa Villert ◽  
Larisa Kolomiets ◽  
Natalya Yunusova ◽  
Yevgeniya Fesik
Keyword(s):  
Ovarian Cancer ◽  
Ovarian Carcinoma ◽  
Molecular Subtypes ◽  
Survival Rates ◽  
Consensus Algorithm ◽  
Histopathological Diagnosis ◽  
Low Grade ◽  
High Grade ◽  
Ovarian Carcinomas ◽  
Genetic Subtypes

High-grade ovarian carcinoma is a histopathological diagnosis, however, at the molecular level, ovarian cancer represents a heterogeneous group of diseases. Studies aimed at identifying molecular genetic subtypes of ovarian cancer are conducted in order to find the answer to the question: can different molecular subgroups influence the choice of treatment? One of the achievements in this trend is the recognition of the dualistic model that categorizes various types of ovarian cancer into two groups designated high-grade (HG) and low-grade (LG) tumors. However, the tumor genome sequencing data suggest the existence of 6 ovarian carcinoma subtypes, including two LG and four HG subtypes. Subtype C1 exhibits a high stromal response and the lowest survival. Subtypes C2 and C4 demonstrate higher number of intratumoral CD3 + cells, lower stromal gene expression and better survival than sybtype C1. Subtype C5 (mesenchymal) is characterized by mesenchymal cells, over-expression of N-cadherin and P-cadherin, low expression of differentiation markers, and lower survival rates than C2 and C4. The use of a consensus algorithm to determine the subtype allows identification of only a minority of ovarian carcinomas (approximately 25%) therefore, the practical importance of this classification requires additional research. There is evidence that it makes sense to randomize tumors into groups with altered expression of angiogenic genes and groups with overexpression of the immune response genes, as in the angiogenic group there is a comparative superiority in terms of survival. The administration of bevacizumab in the angiogenic group improves survival, while the administration of bevacizumab in the immune group even worsens the outcome. Molecular subtypes with worse survival rates (proliferative and mesenchymal) also benefit most from bevacizumab treatment. This review focuses on some of the advances in understanding molecular, cellular, and genetic changes in ovarian carcinomas with the results achieved so far regarding the formulation of molecular subtypes of ovarian cancer, however further studies are needed.

scholarly journals Immunohistochemical Biomarkers as a Surrogate of Molecular Analysis in Ovarian Carcinomas: A Review of the Literature

Diagnostics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 199 ◽  
Author(s):  
Giacomo Santandrea ◽  
Simonetta Piana ◽  
Riccardo Valli ◽  
Magda Zanelli ◽  
Elisa Gasparini ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Molecular Analysis ◽  
Immunohistochemical Analysis ◽  
Cost Effective ◽  
Mucinous Carcinoma ◽  
Serous Carcinoma ◽  
Malignant Neoplasms ◽  
Low Grade ◽  
Ovarian Carcinomas ◽  
Novel Target

The term “ovarian carcinoma” encompasses at least five different malignant neoplasms: high-grade serous carcinoma, low-grade serous carcinoma, endometrioid carcinoma, mucinous carcinoma, and clear cell carcinoma. These five histotypes demonstrated distinctive histological, molecular, and clinical features. The rise of novel target therapies and of a tailored oncological approach has demanded an integrated multidisciplinary approach in the setting of ovarian carcinoma. The need to implement a molecular-based classification in the worldwide diagnostic and therapeutic setting of ovarian cancer demanded a search for easy-to-use and cost-effective molecular-surrogate biomarkers, relying particularly on immunohistochemical analysis. The present review focuses on the role of immunohistochemistry as a surrogate of molecular analysis in the everyday diagnostic approach to ovarian carcinomas.

Low-grade serous ovarian carcinoma: an evolution toward targeted therapy

2019 ◽  
Vol 30 (10) ◽  
pp. 1619-1626 ◽  
Author(s):  
Ioannis A Voutsadakis
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Ovarian Carcinoma ◽  
Molecular Profile ◽  
Low Grade ◽  
High Grade ◽  
Novel Therapies ◽  
Precursor Lesions ◽  
Molecular Defects ◽  
Serous Ovarian Carcinoma

Low-grade serous ovarian carcinoma and its high-grade serous ovarian carcinoma counterpart differ in their precursor lesions, molecular profile, natural history, and response to therapies. As such, low-grade serous ovarian carcinoma needs to be studied separately from high-grade serous ovarian carcinoma, despite challenges stemming from its rarity. A deeper understanding of the pathogenesis of low-grade serous ovarian carcinoma and the most common molecular defects and pathways involved in the carcinogenesis of the ovarian epithelium from normal to serous borderline ovarian tumors to low-grade serous ovarian carcinoma will help develop better therapies. By adopting targeted approaches there may be an opportunity to integrate novel therapies without the need for robust numbers in clinical trials. This manuscript will discuss low-grade serous ovarian carcinoma and focus on the arising treatments being developed with an improved understanding of the pathogenesis of this disease.

scholarly journals Gynecologic Serous Carcinoma: An Immunohistochemical Analysis of Malignant Body Fluid Specimens

2018 ◽  
Vol 143 (6) ◽  
pp. 677-682
Author(s):  
Shuyue Ren ◽  
William Klump
Keyword(s):  
Body Fluid ◽  
Germ Cell Tumors ◽  
Immunohistochemical Analysis ◽  
Serous Carcinoma ◽  
Low Grade ◽  
High Grade ◽  
Gynecologic Malignancy ◽  
Immunohistochemical Markers ◽  
Immunohistochemical Studies ◽  
Positive Results

Context.— Evaluation of fluid specimens involved by serous carcinoma might potentially include PAX8, GATA3, Uroplakin II, SOX2, and SALL4 antibodies. Those markers are commonly employed for diagnosing carcinomas of various types, including urothelial malignancies and germ cell tumors. There have been no comprehensive immunohistochemical studies, to our knowledge, for those markers on fluid specimens involved by serous carcinoma. Objective.— To evaluate immunohistochemical markers PAX8, GATA3, SOX2, uroplakin II, and SALL4 in the diagnosis of high-grade serous carcinoma in fluid specimens. Design.— We examined 113 fluids (96 ascites specimens and 17 pleural fluid specimens) that were positive for carcinoma. Most (94 cases; 83.2%) consisted of high-grade serous carcinoma of Müllerian origin. Nineteen cases of non–high-grade serous carcinoma (including one case of low-grade serous carcinoma) of gynecologic origin were also included as anecdotal data. Results.— In 113 fluid specimens with positive results for carcinoma, including nonserous types, 99 (87.6%) had positive results for PAX8, 19 (16.8%) for GATA3; 19 (16.8%) for SOX2, 23 (20.4%) for uroplakin II, and 8 (7.1%) for SALL4. Of 94 fluids (83.2%) involved with high-grade serous carcinoma, 84 (89.4%) had positive results for PAX8, 18 (19.1%) for GATA3, 17 (18.1%) for SOX2, 22 (23.4%) for uroplakin II, and 8 (8.5%) for SALL4. Some of these specimens showed reactivity for more than one immunohistochemical marker. Conclusions.— Most fluids involving high-grade serous carcinoma showed positive results for PAX8, and some cases expressed GATA3, SOX2, uroplakin II, and SALL4. Serous carcinoma in fluids may be positive for immunohistochemical markers not thought of traditionally as associated with gynecologic malignancy, an important consideration in avoiding misdiagnosis.

scholarly journals Ultrasound, macroscopic and histological features of serous epithelial ovarian carcinomas

2020 ◽  
pp. ijgc-2020-001473
Author(s):  
Paola Romeo ◽  
Damiano Arciuolo ◽  
Maria Cristina Moruzzi ◽  
Francesca Moro
Keyword(s):  
Ovarian Carcinoma ◽  
Low Grade ◽  
High Grade ◽  
Ovarian Carcinomas ◽  
Histological Features ◽  
Serous Ovarian Carcinoma ◽  
Epithelial Ovarian Carcinomas

We present a video showing two cases of serous epithelial ovarian carcinomas. The first video shows clinical, ultrasound, macroscopic, and histological features of a patient with high grade serous ovarian carcinoma. The second video presents clinical, ultrasound, macroscopic, and histological features of a patient with low grade serous ovarian carcinoma.

scholarly journals Clinicopathological Spectrum of Surface Epithelial Ovarian Carcinoma and its Association with Serum CA-125 Levels: A Cohort Study

2021 ◽  
Author(s):  
Nisha Singla ◽  
Sarita Nibhoria ◽  
Kanwardeep Kaur Tiwana ◽  
Prince Gupta
Keyword(s):  
Cohort Study ◽  
Ovarian Carcinoma ◽  
World Health ◽  
Serous Carcinoma ◽  
Ca 125 ◽  
Categorical Variables ◽  
Low Grade ◽  
High Grade ◽  
History Of ◽  
Epithelial Tumours

Introduction: The ovaries are the primary female reproductive organs and endocrine glands. Ovarian carcinoma has often been called as the silent killer because the symptoms may develop so late that the chances of cure are very poor. According to World Health Organisation (WHO) ovarian tumours are classified based upon their most probable tissue of origin: surface epithelial (65%), germ cell (15%), sex cord-stromal (10%), metastases (5%) and miscellaneous. The malignant surface epithelial tumours are further classified by cell type into serous, mucinous, endometrioid, clear cell, brenner, seromucinous and undifferentiated carcinoma. The most widely used tumour marker in ovarian carcinoma is CA-125 which is considered as gold standard. Aim : To find the utility of serum CA-125 levels in histopathological variants of malignant surface epithelial tumours, degree of differentiation and their distribution according to clinical data pertaining to age, parity, history of use of oral contraceptive pills/ovulation inducing drugs and family history of carcinoma ovary/breast or colon. Materials and Methods: A prospective study (cohort study) was done at Guru Gobind Singh Medical College and Hospital, Faridkot over a period of 1.5 year (April 2017-oct 2018) on 50 ovarian masses which were diagnosed as ovarian carcinoma. Data was represented as frequencies and percentages for categorical variables and as means and standard deviations for continuous variables. Analysis was done using Statistical Package for Social Sciences (SPSS) v 20.0.0. Results: Serous carcinoma (80%) topped among all the histological variants. Serous high grade carcinoma was more common than serous low grade carcinoma. Maximum rise of serum CA-125 levels were seen in serous carcinoma. Among serous carcinomas, mean serum CA-125 levels were more in high grade serous carcinoma than low grade serous carcinoma and the results were statistically significant. conclusion: Serum CA-125 level is a great tool for diagnosis, follow-up and prognosis of ovarian carcinomas.

scholarly journals Characterization of an Aging-Based Diagnostic Gene Signature and Molecular Subtypes With Diverse Immune Infiltrations in Atherosclerosis

2022 ◽  
Vol 8 ◽  
Author(s):  
Lei Zhao ◽  
Fengfeng Lv ◽  
Ye Zheng ◽  
Liqiu Yan ◽  
Xufen Cao
Keyword(s):  
Western Blotting ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Expression Profiles ◽  
Macrophage Polarization ◽  
Differential Expression Analysis ◽  
Gene Signature ◽  
Immune Checkpoints ◽  
Foam Cell Formation ◽  
Diagnostic Model

Objective: Advancing age is a major risk factor of atherosclerosis (AS). Nevertheless, the mechanism underlying this phenomenon remains indistinct. Herein, this study conducted a comprehensive analysis of the biological implications of aging-related genes in AS.Methods: Gene expression profiles of AS and non-AS samples were curated from the GEO project. Differential expression analysis was adopted for screening AS-specific aging-related genes. LASSO regression analysis was presented for constructing a diagnostic model, and the discriminatory capacity was evaluated with ROC curves. Through consensus clustering analysis, aging-based molecular subtypes were conducted. Immune levels were estimated based on the expression of HLAs, immune checkpoints, and immune cell infiltrations. Key genes were then identified via WGCNA. The effects of CEBPB knockdown on macrophage polarization were examined with western blotting and ELISA. Furthermore, macrophages were exposed to 100 mg/L ox-LDL for 48 h to induce macrophage foam cells. After silencing CEBPB, markers of cholesterol uptake, esterification and hydrolysis, and efflux were detected with western blotting.Results: This study identified 28 AS-specific aging-related genes. The aging-related gene signature was developed, which could accurately diagnose AS in both the GSE20129 (AUC = 0.898) and GSE43292 (AUC = 0.685) datasets. Based on the expression profiling of AS-specific aging-related genes, two molecular subtypes were clustered, and with diverse immune infiltration features. The molecular subtype–relevant genes were obtained with WGCNA, which were markedly associated with immune activation. Silencing CEBPB triggered anti-inflammatory M2-like polarization and suppressed foam cell formation.Conclusion: Our findings suggest the critical implications of aging-related genes in diagnosing AS and modulating immune infiltrations.

scholarly journals Pan-cancer machine learning predictors of primary site of origin and molecular subtype

2018 ◽  
Author(s):  
William F. Flynn ◽  
Sandeep Namburi ◽  
Carolyn A. Paisie ◽  
Honey V. Reddi ◽  
Sheng Li ◽  
...  
Keyword(s):  
Machine Learning ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Expression Profiles ◽  
Metastatic Cancer ◽  
Gene Expression Profiles ◽  
Primary Site ◽  
Cancer Types ◽  
Tissue Of Origin ◽  
Pan Cancer

ABSTRACTBackgroundIt is estimated by the American Cancer Society that approximately 5% of all metastatic tumors have no defined primary site (tissue) of origin and are classified as cancers of unknown primary (CUPs). The current standard of care for CUP patients depends on immunohistochemistry (IHC) based approaches to identify the primary site. The addition of post-mortem evaluation to IHC based tests helps to reveal the identity of the primary site for only 25% of the CUPs, emphasizing the acute need for better methods of determination of the site of origin. CUP patients are therefore given generic chemotherapeutic agents resulting in poor prognosis. When the tissue of origin is known, patients can be given site specific therapy with significant improvement in clinical outcome. Similarly, identifying the primary site of origin of metastatic cancer is of great importance for designing treatment.Identification of the primary site of origin is an import first step but may not be sufficient information for optimal treatment of the patient. Recent studies, primarily from The Cancer Genome Atlas (TCGA) project, and others, have revealed molecular subtypes in several cancer types with distinct clinical outcome. The molecular subtype captures the fundamental mechanisms driving the cancer and provides information that is essential for the optimal treatment of a cancer. Thus, along with primary site of origin, molecular subtype of a tumor is emerging as a criterion for personalized medicine and patient entry into clinical trials.However, there is no comprehensive toolset available for precise identification of tissue of origin or molecular subtype for precision medicine and translational research.Methods and FindingsWe posited that metastatic tumors will harbor the gene expression profiles of the primary site of origin of the cancer. Therefore, we decided to learn the molecular characteristics of the primary tumors using the large number of cancer genome profiles available from the TCGA project. Our predictors were trained for 33 cancer types and for the 11 cancers where there are established molecular subtypes. We estimated the accuracy of several machine learning models using cross-validation methods. The extensive testing using independent test sets revealed that the predictors had a median sensitivity and specificity of 97.2% and 99.9% respectively without losing classification of any tumor. Subtype classifiers achieved median sensitivity of 87.7% and specificity of 94.5% via cross validation and presented median sensitivity of 79.6% and specificity of 94.6% in two external datasets of 1,999 total samples. Importantly, these external data shows that our classifiers can robustly predict the primary site of origin from external microarray data, metastatic cancer data, and patient-derived xenograft (PDX) data.ConclusionWe have demonstrated the utility of gene expression profiles to solve the important clinical challenge of identifying the primary site of origin and the molecular subtype of cancers based on machine learning algorithms. We show, for the first time to our knowledge, that our pan-cancer classifiers can predict multiple cancers’ primary site of origin from metastatic samples. The predictors will be made available as open source software, freely available for academic non-commercial use.

Low grade serous ovarian carcinoma: identifying variations in practice patterns

2019 ◽  
Vol 29 (1) ◽  
pp. 174-180 ◽  
Author(s):  
John Siemon ◽  
David M Gershenson ◽  
Brian Slomovitz ◽  
Matthew Schlumbrecht
Keyword(s):  
Ovarian Carcinoma ◽  
Practice Patterns ◽  
Gynecologic Oncology ◽  
Braf Inhibitor ◽  
Primary Treatment ◽  
Treatment Modalities ◽  
Serous Carcinoma ◽  
Low Grade ◽  
Serous Ovarian Carcinoma ◽  
Platinum Resistant

ObjectivesLow grade serous ovarian carcinoma is a rare subtype of ovarian cancer with an indolent and chemorefractory course. As such, treatment strategies among practitioners are not uniformly known. The primary objective of this study was to identify differences in practice patterns among physicians who treat low grade serous carcinoma.Methods MaterialsA de novo survey was distributed to members of the Society of Gynecologic Oncology. Questions about demographics, management of primary and recurrent disease, and use of consolidation therapy were included. Statistical analyses were performed using χ2 and Fisher’s exact tests.Results194 gynecologic oncologists completed the survey. Approximately two-thirds of respondents practiced in a university based setting and treated a high volume of ovarian cancers, including low grade serous carcinoma. 82% recommended somatic testing during treatment and 84% routinely sent patients for genetic counseling. Treatment preferences for primary disease varied by debulking status. 48% of practitioners used hormone antagonism as consolidation after primary treatment. Secondary cytoreduction was preferred for patients with platinum sensitive recurrence and a long disease free interval following primary treatment (P<0.001). Hormone antagonism was the preferred treatment for the first platinum resistant recurrence (54%), while a BRAF inhibitor was the preferred agent in platinum resistant recurrence in the presence of a known BRAF mutation (56%).ConclusionsThere was significant variation in the preferred management of low grade serous carcinoma among practitioners. Further efforts to improve knowledge of this disease, identify optimal treatment modalities, and provide guidelines for management should be encouraged.

scholarly journals Current ideas about molecular genetic subtypes of ovarian cancer: a personalized approach and a new platform for further research

2021 ◽  
Vol 11 (11) ◽  
pp. 157-168
Author(s):  
A. Rybin
Keyword(s):  
Ovarian Cancer ◽  
Molecular Subtypes ◽  
Molecular Genetic ◽  
Consensus Algorithm ◽  
Histopathological Diagnosis ◽  
Low Grade ◽  
Ovarian Carcinomas ◽  
Altered Expression ◽  
Ovarian Cancers ◽  
Genetic Subtypes

Highly malignant ovarian cancers are a histopathological diagnosis, but can be multiple diseases at the molecular level. Research aimed at identifying molecular genetic subtypes of ovarian cancer is being conducted to find an answer to the question: can different molecular subgroups influence the choice of treatment? One of the achievements of this direction is the recognition of the dualistic theory of the origin of ovarian carcinomas with their division into High-grade and Low-grade subtypes. However, the data of sequencing of the tumor genome suggest the existence of 6 subtypes of carcinoma, including two LG and four HG subtypes. Patients of subtype C1 are characterized by a high stromal response and have the lowest survival, tumors of C2 and C4 subtypes have a higher rate of intratumoral CD3 + cells, lower stroma gene expression and better survival than C1. The mesenchymal subtype C5 is widely represented by mesenchymal cells, characterized by overexpression of N-cadherins and P-cadherins, low expression of differentiation markers and lower survival than C2 and C4. The use of a consensus algorithm to determine the subtype allows the identification of only a minority of ovarian cancers (approximately 25%). In this regard, the practical significance of this classification still requires additional research, and today it is permissible to talk about the existence of only 2-3 reproducible subtypes. It is thought that it makes sense to randomize tumors into groups with altered expression of angiogenic genes and with overexpression of immune response genes, as in the angiogenic group there is a comparison of the advantage in survival (prescribing bevacizumab improves it, and in the immune group even increases bevacizumab). Molecular subtypes with poorer survival rates (proliferative and mesenchymal) also benefit most from bevacizumab treatment. The review focuses on some advances in understanding molecular, cellular, and genetic changes related to ovarian cancers with the results achieved so far in describing molecular subtypes of ovarian cancer. The available information is the basis for planning further research.

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