3.1. Ovarian GrCT
GrCT account for up to 5% of overall ovarian cancers. There is an incidence of 0.61 cases per 100,000 women per year, accounting for around 2–5% of all ovarian cancers
[43][31]. Adult GrCT are the most common form, comprising around 95% of GrCT. The majority of these present at an early stage, in an indolent fashion.
The most common presenting complaints with SCST are the presence of an adnexal mass, abdominal pain and distention. Some of these tumours are termed “functioning” and can release hormones, including androgens and oestrogens. As such, patients may have evidence of oestrogen excess, including abnormal vaginal bleeding, precocious puberty, or androgen excess, including hirsutism
[44,45][32][33].
The presence of some tumour markers can be of diagnostic benefit. Inhibin A and B, oestradiol and MIH (Müllerian inhibiting substance) are hormones secreted by GrCT. MIH levels can also be elevated, and the combination of inhibins and MIH is useful for monitoring disease status.
Adult GrCT have been found to have an association with a somatic
c.402C >
G missense point mutation in the
FOXL2 gene. This is pathognomonic for adult GrCT and may have a causative role
[48][34]. In addition, genetic studies can be used to differentiate between early stage and advanced stage adult GrCT.
Due to oestrogen production by GrCT, there can be an associated finding of endometrial hyperplasia, and endometrial carcinoma can be seen in up to 10% of patients with GrCT. These are often at an early stage, and thus carry a good prognosis
[49][35].
Surgical management is used to treat GrCT. Patients who present in their reproductive years are managed with a USO. For patients who are postmenopausal or have no desire of childbearing, they are treated with a total abdominal hysterectomy and bilateral salpingo-oophorectomy (BSO)
[45][33]. For patients with stage IA GrCT, surgery alone provides an excellent prognosis, with no adjuvant therapies used. Around 97% of GrCT are unilateral
[50][36]. For stage IB, i.e., involving both ovaries, a total abdominal hysterectomy with BSO is used. FSS can be attempted in selected cases. For stage IC, surgery alongside adjuvant platinum-based chemotherapy is used. For advanced or metastatic disease, cytoreductive surgery is the most effective treatment. Additional chemotherapy courses can be used in these patients, as the prognosis is poor, with a high recurrence rate
[2].
Hormone therapy has been shown to have a role in GrCT which express steroid hormone receptors. No corroboration between hormonal therapy and hormone receptor expression has been established. Aromatase inhibitors have been found to be the most responsive hormone therapy, though data is limited
[51][37].
GrCT have a good prognosis as they are usually diagnosed at an early stage. There are numerous significant prognostic factors related to GrCT, including the stage of the tumour, size of the tumour, whether or not it has ruptured, the mitotic index, and the presence of residual disease following surgical resection and grading. The most accurate prognostic factor in GrCT is the staging of the tumour at the time of diagnosis
[52][38]. An early stage is also associated with reduced recurrence rates
[45][33].
3.2. Sertoli-Leydig Cell Tumours
SLCT are rare; they account for less than 0.5% of ovarian tumours. The majority occur in women aged between 20 and 40. Their specific incidence is not easily determined. They often present with a unilateral mass. The tumours are usually hormone-secreting; the majority secrete testosterone but some may produce oestradiol. Up to 85% of patients experience virilisation. Patients may have pure Sertoli cell tumours which can secrete renin, which can cause hypertension
[40][39].
SLCT are formed of varying proportions of Sertoli cells and Leydig cells, and may have other heterogeneous elements
[56][40]. These cells are normally found around the seminiferous tubules of the testicles, and are involved in androgen production. SLCT are classified into well-differentiated, moderately differentiated and poorly differentiated tumours. Both moderately- and poorly-differentiated SLCT express at least mutation in the
DICER1 gene, whilst well-differentiated SLCT can be
DICER1-independent. The association between the
DICER1 mutation and SLCT has been shown to be around 88%
[57][41]. The
FOXL2 missense mutation, which is associated with GrCT can also be found in SLCT, but the sensitivity is only around 50%. As such,
FOXL2 is generally used with serum inhibins to distinguish SCST from non-SCST, rather than to compare different SLCT
[58][42].
For young patients who have stage IA SLCT and are of reproductive age, FSS is offered. Those with poorly differentiated malignancy are offered adjuvant chemotherapy. Patients who have no desire of childbearing are offered a total abdominal hysterectomy and BSO. For SLCT staging greater than IA, surgery and adjuvant chemotherapy are offered irrespective of tumour differentiation. The chemotherapy regimens are platinum-based
[2].
SLCT carry a good prognosis since most patients at time of diagnosis have a disease stage of I; nevertheless, advanced stages carry an extremely poor prognosis
[59][43].
4. Small Cell Ovarian Carcinomas
Small cell carcinomas of the ovary hypercalcaemic type (SCCOHT) typically occur in adolescents and young women with a peak incidence in the third decade of life. Serum calcium levels may serve as a marker for treatment response and recurrences. The pathophysiology of hypercalcemia is unclear, it has been postulated that the parathyroid hormone or parathyroid hormone-related protein (PTHrP) appear to be crucial
[40][39]. The prognosis of SCCOHT is very poor and the risk of extra-ovarian spread high
[2].
A germ cell origin for SCCOHT has been suggested. However, more recently, SCCOHT have been sequenced and confirmed to be a malignant rhabdoid tumour by virtue of consistent deleterious mutations in
SMARCA4, a chromatin-remodelling gene encoding protein BRG1. These tumours resemble high grade neuroendocrine histological features; nevertheless, they are now recognised to be a distinct clinical and pathological entity. They are predominantly characterised by variable numbers of larger cells with a luteinised or rhabdoid appearance
[40][39].
There is currently no consensus as far as the treatment of the SCCOHT is concerned. A combination of treatment modalities, consisting of debulking surgery, followed by chemotherapy and possibly radiotherapy is recommended. FSS is reasonable, as the disease is mostly unilateral
[40][39]. A combination of a cisplatin and etoposide-based therapy is generally considered most appropriate. SCCOHT are particularly chemosensitive at the outset but the relapse is usually rapid.
Small cell carcinomas of the ovary, pulmonary type (SCCOPT) affect older, peri- or postmenopausal patients. In contrast with SCCOHT, they are not correlated with hypercalcemia. SCCOPT are predominantly unilateral and have dismal prognosis even when diagnosed early. Histopathologically, they have solid growth of small cells arranged in sheets and closely packed nests. The tumour cells are pleomorphic, round to spindle-shaped, with scanty cytoplasm and hyperchromatic and elongated nuclei. Pre-existing endometrioid carcinomas and Brenner tumours are predisposition factors for the development of the SCCOPT. Neuroendocrine markers (chromogranin, synaptophysin and NSE) are diffusely positive by immunohistochemistry
[40][39].
Conventional surgical treatment includes radical surgery (hysterectomy and BSO), followed by adjuvant platinum-etoposide chemotherapy. The evidence for the potential role of the immunotherapy is extrapolated from the small-cell lung cancers. It seems that there is a promising activity of the anti-PD1 antibodies in this context
[2].