High-grade serous carcinoma (HGSC) is a type of tumour that arises from the serous epithelial layer in the abdominopelvic cavity and is mainly found in the ovary. HGSCs make up the majority of ovarian cancer cases and have the lowest survival rates. HGSC is distinct from low-grade serous carcinoma (LGSC) which arises from ovarian tissue, is less aggressive and is present in stage I ovarian cancer where tumours are localised to the ovary. Although originally thought to arise from the squamous epithelial cell layer covering the ovary, HGSC is now thought to originate in the Fallopian tube epithelium. HGSC is much more invasive than LGSC with a higher fatality rate - although it is more sensitive to platinum-based chemotherapy, possibly due to its rapid growth rate. In rare cases, HGSCs can develop from LGSCs, but generally the two types arise independently of each other.
Risk factors
Environmental risk factors The 'incessant ovulation' theory is suggested by the strong correlation between the number of ovulatory cycles of an individual and their risk of ovarian cancer. This trend is reflected in the protective effects of pregnancy, parity and breastfeeding against ovarian cancer, and similar findings in epidemiological studies that have indicated a reduction of risk associated with use of oral contraceptive pills. Ovulation is accepted as the cause of ovarian cortical inclusion cysts, the precursor lesions of serous carcinomas, and lower numbers of these cortical inclusion cysts are thought to be the mechanism by which reducing lifetime ovulations can lower the risk of developing HGSC. Conversely, a temporal association with menopausal hormone therapy and incidence of HGSC was found, and polycystic ovarian syndrome (PCOS) was shown to contribute to a doubling of the risk of ovarian cancer. Endometriosis can increase risk for other ovarian cancer subtypes, but is not associated with HGSC.
Genetic risk factors More than 20% of ovarian cancer tumours have hereditary origin. The majority of these feature mutations in the tumour suppressor BRCA genes, which tend to give rise to HGSC. A mutation in BRCA1 or BRCA2 can confer a lifetime ovarian cancer risk of 40-50% and 10-20% respectively, with BRCA2 mutations strongly associated with better clinical outcomes. A specific tumour protein 53 (TP53) expression pattern in the Fallopian tube epithelium – the 'p53 signature' - is thought to be a precursor marker of HGSC. TP53-/- mice (in which the TP53 gene has been deleted) do not develop ovarian carcinomas. However, TP53 mutations were found in 96% of HGSC cases. A local abnormal TP53 expression may thus be indicative of HGSC. In women, pelvic HGSC show either a complete absence of P53 expression, or overexpression, suggesting that any aberration of P53 leads to tumour development. Additionally, overexpression of TP53 is associated with better clinical outcome whereas an absence of the p53 protein is linked to an increased risk of HGSC tumour recurrence. A recent mouse model suggest that a p53 mutation may induce HGSC arising from the ovary rather than the Fallopian tube.
Pathophysiology
Cell origin HGSC are further distinguished from LGSC by 'type I/II' ovarian tumour nomenclature; type I referring to tumour types (e.g. LGSCs) where precursor lesions within the ovary have been characterised, and type II referring to tumour types (e.g. HGSCs) without association of such lesions, tumours understood to develop de novo from the tubal and/or ovarian surface epithelium. This classification has more relevance to research rather than to clinical practice. The serous membrane is a particular type of secretory epithelium which covers organs in body cavities and secretes serous fluid to reduce friction from muscle movement. Serous membrane lining the abdominopelvic cavity is called the peritoneum; that lining heart and mediastinum is the pericardium, and that lining the thoracic cavity and lungs is the pleura. Technically a 'serous carcinoma' can occur anywhere on these membranes, but high-grade serous carcinoma is generally limited to the peritoneal area. While until recently HGSC was thought to arise from simple differentiation of cortical inclusion cysts (CICs) of ovarian surface epithelium (OSE), the cell origin of HGSC is now understood to be much more complex, with evidence for other sites of origin, both intra- and extra-ovarian, having come to light.
The common Müllerian origin of the Fallopian tubes, uterus, cervix, and upper vagina has resulted in the proposal that peritoneal high-grade serous carcinoma is a spectrum of a single disease. Relevant animal models of HGSC can only be developed when the cell origin is properly understood. However, as HGSC tends to have the same clinical behaviour, regardless of its primary cell origin, determining cell origin is less important for clinical treatment, but may be of relevance when looking for biomarkers. The specific process by which a HGSC arises may be related to the BRCA mutation status of the individual, as well as the p53 mutation status. A 2007 paper describes the process of determining cell of origin as "Tumour origin is typically assigned to the organ presenting with the dominant tumour mass. The one exception is the peritoneum, which is classified as a primary site only if a candidate origin is not found in the endometrium, tube or ovary". It is recognised that HGSC can have variable and complex primary origins, but understanding and determining this will give insight into its pathogenesis.
Pathogenesis Assuming a fimbrial origin, as observed in the majority of HGSC cases, the current understanding of HGSC genesis suggests a process by which STIC fimbrial cells implant into the ovary as cortical inclusion cysts through the ovulation rupture site. To account for instances where there is no STIC involvement, endosalpingiosis or de novo metaplasia of ovarian surface epithelium inclusions are also possible. A much rarer occurrence is the differentiation of HGSC from LGSC.
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