**1. Introduction**

Ovarian cancer is the most lethal malignancy of gynaecological cancer representing 23% of gynaecological neoplasms and the 5th most common leading cause of death in women. Most ovarian malignant neoplasms are diagnosed at an advanced stage with high recurrence rates and an overall 5-year survival rate of around 50% [1–3].

Ovarian tumours originate from ovarian or fallopian tube tissue and are divided into epithelial tumours (benign, border-line and malignant), germ cell tumours, sex cord-stromal tumours and mesenchymal tumours [4].

In this chapter, we will focus on the epithelial ovarian malignant tumours and will present an overview of the recent advances in the ovarian tumours classification along with their histopathological, immunophenotypic and molecular features.

Epithelial ovarian malignant tumours comprise a heterogeneous neoplastic disease with distinct histomorphologic features, pathogenesis, precursor lesions, immunophenotypic and molecular profiles, different biological behaviour and clinical

outcomes [4]. According to the recent 2020 WHO classification based on histomorphology, immunophenotypic features and molecular alterations, epithelial ovarian malignant tumours are classified into five main types with different incidences: high-grade serous carcinoma (HGSC—70%), low-grade serous carcinoma (LGSC—5%), endometrioid (EC—10%), mucinous (MC—3%) and clear cell carcinomas (CCC—10%) [3–6].

Rare histopathologic entities are seromucinous carcinoma, malignant Brenner tumour, mesonephric-like carcinoma, undifferentiated and dedifferentiated carcinomas, carcinosarcoma and mixed cell carcinoma [5]. Seromucinous carcinoma as a distinct entity, characterised by serous and endocervical-type mucinous epithelium with foci of clear cells and areas of endometrioid and squamous differentiation, has been removed from the recent 2020 WHO classification. It is now considered a subtype of endometrioid carcinoma based on immunohistochemical and molecular studies [5].

Traditional concepts of ovarian carcinogenesis assumed that ovarian cancer pathogenesis is due to Müllerian or non-Müllerian metaplasia of ovarian surface epithelium leading progressively to malignant transformation [7] or due to malignant transformation of endometriosis lesions and/or inclusion cysts [8]. Recent pathological observations and molecular studies have revealed that the majority of the high-grade serous carcinomas arise from a precursor dysplastic lesion in the fimbria of fallopian tubes, designated as STIC (Serous Tubal Intraepithelial Carcinoma), whereas low-grade serous carcinomas arise within the ovarian parenchyma from benign or borderline serous tumours [9–11]. In addition, the presence of genomic alterations in the *BRCA1* and *BRCA2* tumour suppressor genes and gene mutations in *p53, p16, CCNE1, BRD4* and *RSF1,* and centrosome copy number abnormalities, in STIC and high-grade serous carcinoma, suggest a clonal histogenetic relationship between this precursor lesion and HGSC [12–15]. A clonal histogenetic relationship has also been observed among endometriosis, precursor ovarian surface epithelium lesions and endometrioid and clear cell carcinomas based on mutations found in *ARID1A, PIK3CA, KRAS* and *MET* genes among these pathologic entities [16–18].

It is now well established that ovarian carcinogenesis is based on a dualistic model of pathogenesis that divides ovarian epithelial malignant tumours into two main categories, designated as type I and type II ovarian tumours [7].

Type I ovarian epithelial tumours arise from precursor lesions in the ovary such as cystadenoma or adenofibroma. These lesions can undergo malignant transformation through atypical proliferation or transformation to borderline tumours and eventually into invasive ovarian neoplasms. Type I ovarian epithelial tumours include low-grade serous carcinoma, endometrioid carcinoma, mucinous carcinoma, clear cell carcinoma and malignant Brenner tumour. They have a relatively indolent clinical course and are characterised by genomic stability, distinctive molecular profile for each histotype and low incidence of p53 mutations (10–13%), except of mucinous carcinoma, which displays high incidence of p53 mutations (64%) [19, 20].

Type II ovarian epithelial tumours arise from distal fallopian tube fimbria epithelium through dysplastic lesions (STIC) and finally towards invasive carcinomas. They show aggressive biological behaviour and comprise high-grade serous carcinoma, carcinosarcoma and dedifferentiated and undifferentiated carcinomas [6, 21]. They are characterised by genomic instability, high incidence of p53 mutations and abnormal function of tumour suppressor genes *BRCA1* and *BRCA2* due to mutations or gene promoter hypermethylation [19, 20].

*Recent Advances in Classification and Histopathological Diagnosis of Ovarian Epithelial… DOI: http://dx.doi.org/10.5772/intechopen.106545*

In the following sections, we are going to present the morphologic, immunophenotypic and molecular alterations that can be found in the five main histotypes of ovarian epithelial malignant tumours and the putative implications that may have in the clinical outcomes and targeted therapeutic interventions.