High-grade serous carcinoma of the ovary

Ovarian cancer
Diagram showing fimbrial end of the fallopian tube and spread to the ovarian surface epithelium
SpecialtyOncology, gynecology
Usual onsetAge 65-years[1]
CausesUnknown[1]
Diagnostic methodRaised CA125[1]

High-grade serous carcinoma of the ovary (HGSC) is a type of ovarian cancer.[1][2] It typically occurs in early postmenopausal females, and frequently presents in the late stage of the condition, usually with a large tummy or mass.[3]

It is a type of serous tumor of the ovary that typically occurs in women aged over 60-years, who have a family history of ovarian or breast cancer and who have never had children.[1] Having multiple births and fewer menses in life, breastfeeding, and taking the oral contraceptive pill, appear to give protection.[1] Although originally thought to arise from the squamous epithelial cell layer covering the ovary, it is now established that most HGSCs originate in a precursor lesion called serous tubal intraepithelial carcinoma, found in the finger-like projections of the fallopian tube.[1]

They account for around 70% of ovarian cancers.[1]

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.[4]

This trend is reflected in the protective effects of pregnancy, parity and breastfeeding against ovarian cancer,[5][6] and similar findings in epidemiological studies that have indicated a reduction of risk associated with use of oral contraceptive pills.[7][4]

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.[8]

Conversely, a temporal association with menopausal hormone therapy and incidence of HGSC was found,[9] and polycystic ovarian syndrome (PCOS) was shown to contribute to a doubling of the risk of ovarian cancer.[10]

Endometriosis can increase risk for other ovarian cancer subtypes, but is not associated with HGSC.[11]

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.[12] A mutation in BRCA1 or BRCA2 can confer a lifetime ovarian cancer risk of 40-50% and 10-20% respectively,[13] 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.[14] However, TP53 mutations were found in 96% of HGSC cases.[15] A local abnormal TP53 expression may thus be indicative of HGSC.[16] In women, pelvic HGSC show either a complete absence of P53 expression, or overexpression, suggesting that any aberration of P53 leads to tumour development.[17] 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.[17]

A recent mouse model suggest that a p53 mutation may induce HGSC arising from the ovary rather than the Fallopian tube.[18]

Diagnosis

Symptoms include persistent bloating, postmenopausal bleeding, and/or appetite loss.[19]

Transvaginal ultrasonography as well as cancer marker CA125 level analysis is often used to determine potential malignancy of suspect pelvic masses.[20]

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.[20]

If glands are seen to fuse with intricate, extensive papillae featuring epithelial tufting with solid nests surrounded by a space alongside irregular slit-like spaces, then serous carcinoma is suspected.

Distinguishing between LGSC and HGSC:[21]

  1. Necrosis is common in HGSC and absent in LGSC, as are giant (multi- or mononucleated) tumour cells.
  2. Psammoma bodies are more frequent in low-grade serous carcinoma.
  3. Tp53 expression is assessed for mutations, overexpression or absence – common features of high-grade serous carcinomas.
  4. 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.[21]

The progression of HGSC may also be determined from examining the cadherin expression profile.[22]

Screening

As ovarian cancer is rarely symptomatic until an advanced stage,[23] 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.[24] 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.[25]

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 [26][27] - although critics of this argue that a reduced blood supply to the ovaries may induce premature menopause regardless.[28]

Prophylactic salpingo-oophorectomy is frequently performed in carriers of BRCA1 or BRCA2 mutations,[29] although the benefits conferred by this procedure may vary dependent on the specific mutation.[30]

Tubal ligation is a less invasive prophylactic treatment shown to significantly reduce the risk of HGSC.[31]

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.[20] The typical advanced presentation as well as extra-ovarian spread seen in HGSC can require aggressive debulking procedures.[32] 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.[20] 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.[33]

Poly ADP ribose polymerase (PARP) inhibitors are another possible treatment, with carriers of BRCA1/2 mutations being the most responsive [34][35]

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.[36]

Ovarian cancer incidence rates are low in East Asia[37] and highest in Europe, the United States, and Australia/New Zealand.[38]

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.[39] 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.[39][40]

References

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