High-grade serous carcinoma (HGSC) is a type of tumor 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 localized to the ovary.
HGSC is 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.
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.
There are 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.
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.
More than 20% of ovarian cancer tumors have hereditary origin: majority of these feature mutations in the tumor 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.
Tumor protein 53 (TP53) expression pattern in the Fallopian tube epithelium – the ‘p53 signature’ – is thought to be a precursor marker of HGSC.
TP53 mutations were found in 96% of HGSC cases.
Pelvic HGSC show either a complete absence of P53 expression, or overexpression, suggesting that any aberration of P53 leads to tumor 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 tumor recurrence.
The serous membrane is a type of secretory epithelium which covers organs in body cavities and secretes serous fluid to reduce friction from muscle movement.
The 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.
High-grade serous carcinoma is generally limited to the peritoneal area.
A convincing precursor of HGSC in the ovary has not yet been identified.
It is recognized that HGSC can have variable and complex primary origins, but understanding and determining this will give insight into its pathogenesis.
Assuming a fimbrial origin, as observed in the majority of HGSC cases, the current understanding of HGSC genesis suggests a process by which serous tubal intraepithelial fimbrial cells implant into the ovary as cortical inclusion cysts through the ovulation rupture site.
Diagnosis is precipitated by 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 assesses the abdominal cavity and lymph nodes are examined for malignant tissue, usually via laparoscopy.
Necrosis is common in HGSC and absent in LGSC, as are giant tumor cells.
Psammoma bodies are more frequent in low-grade serous carcinoma.
Tp53 expression is assessed for mutations, overexpression or absence is common features of high-grade serous carcinomas.
The progression of HGSC may also be determined from examining the cadherin expression profile.
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 for an individual deemed at risk of HGSC has been (bilateral or unilateral) removal of both the ovary and the Fallopian tube (salpingo-oophorectomy).
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 tumor and thus reduce the number of chemotherapy cycles needed.
The typical advanced presentation as well as extra-ovarian spread seen in HGSC can require aggressive debulking procedures.
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.
Measurements of blood CA125 levels are used to determine patient response to the treatment.
Between 20% and 30% of patients relapse within six months of treatment.
Poly ADP ribose polymerase (PARP) inhibitors are another possible treatment, with carriers of BRCA1/2 mutations being the most responsive.
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.
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.