High-grade serous carcinoma

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. 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. == 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. as well as the p53 mutation status. 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. == Diagnosis ==

Symptoms include persistent bloating, postmenopausal bleeding, and/or appetite loss. Transvaginal ultrasonography as well as cancer marker CA125 level analysis is often used to determine potential malignancy of suspect pelvic masses. Surgical staging is the procedure by which the abdominal cavity and lymph nodes are examined for malignant tissue, usually via laparoscopy. Tissue biopsies may be taken for further analysis. It is not until this histological analysis stage that actual diagnosis of HGSC can be made. • Necrosis is common in HGSC and absent in LGSC, as are giant (multi- or mononucleated) tumour cells. • Psammoma bodies are more frequent in low-grade serous carcinoma. • Tp53 expression is assessed for mutations, overexpression or absence – common features of high-grade serous carcinomas. • LGSCs are generally limited to micropapillary growth patterns, whereas HGSCs can exhibit admixed patterns. Distinction of HGSC from high-grade endometrioid carcinoma is not always possible. Screening As ovarian cancer is rarely symptomatic until an advanced stage, regular pre-emptive screening is a particularly important tool for avoiding the late stage at which most patients present. However, A 2011 US study found that transvaginal ultrasound and cancer marker CA125 screening did not reduce ovarian cancer mortality. In contrast, a more recent UK study found that up to 20% of ovarian cancer deaths could be prevented through annual performance of these procedures. ==Prevention==

Prevention for an individual deemed at risk of HGSC has, up until recently, been (bilateral or unilateral) removal of both the ovary and the Fallopian tube (salpingo-oophorectomy). With hormonal and even morbidity issues resulting from ovary removal, and the increased evidence for the role of the Fallopian tubes HGSC pathogenesis, optimisation of this procedure has been to remove just the Fallopian tube(s) (salpingectomy) with the ovaries remaining until age of menopause - although critics of this argue that a reduced blood supply to the ovaries may induce premature menopause regardless. Prophylactic salpingo-oophorectomy is frequently performed in carriers of BRCA1 or BRCA2 mutations, although the benefits conferred by this procedure may vary dependent on the specific mutation. Tubal ligation is a less invasive prophylactic treatment shown to significantly reduce the risk of HGSC. == Treatment ==

Cytoreductive "debulking" surgery may be performed prior to chemotherapy treatment in order to decrease the physical mass of the tumour and thus reduce the number of chemotherapy cycles needed. In some cases total abdominal hysterectomy will be performed, in other cases where the patient intends to bear children a salpingo-oophorectomy is performed instead. Typical chemotherapy is six cycles of intraperitoneally-delivered platinum-base adjuvant chemotherapy with agents such as carboplatin. Poly ADP ribose polymerase (PARP) inhibitors are another possible treatment, with carriers of BRCA1/2 mutations being the most responsive == Epidemiology ==

A study of incidence rates in the US between 1992 and 1999 found that the age-specific incidence rate for HGSC doubles every 10 years up until age 55, where it plateaus at approximately 20 cases per 100,000 women - before dropping dramatically after age 75. Ovarian cancer incidence rates are low in East Asia and highest in Europe, the United States, and Australia/New Zealand. Since 1975, survival rates for ovarian cancer have steadily improved with a mean decrease of 51% by 2006 of risk of death from ovarian cancer for an advanced stage tumour. The increase has mainly been due to successful extended life expectancy of affected patients rather than an improvement in cure rates. A racial disparity exists between black and white women in the US, where black women experience a higher mortality risk from ovarian cancer. == References ==