DOI: 10.1111/tog.

12755 2021;23:177–86
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Nonepithelial ovarian cancers

BMBS BSc (Hons), *
a b
Holly Baker-Rand Katharine Edey MBChB MRCOG PGDip
a
Specialist Registrar, Department of Obstetrics and Gynaecology, Royal Devon and Exeter NHS Foundation Trust, Exeter, Devon EX2 5DW, UK
b
Consultant Gynaecological Oncologist, Clinical Leadership Mentor and Gynaecology Governance Lead, Royal Devon and Exeter NHS Foundation
Trust, Exeter, Devon EX2 5DW, UK
*Correspondence: Holly Baker-Rand. Email: hbaker-rand@nhs.net

Accepted on 24 September 2020. Published online 24 June 2021.

Key content regimen of bleomycin, etoposide and cisplatin being most

 Nonepithelial ovarian cancers (NEOCs) are rare forms of ovarian
cancer, including malignant ovarian germ cell tumours
(MOGCTs), sex cord-stromal tumours (SCSTs) and
ovarian sarcoma.
 Tumour markers including alpha-fetoprotein, human chorionic
gonadotrophin, lactate dehydrogenase and inhibin can be useful in
aiding preoperative diagnosis of malignant ovarian masses.
 NEOCs are staged using a similar classification to epithelial ovarian
tumours; however, the staging system for male germ cell tumours
is considered a more useful prognostic tool.
 These tumours can occur at any age; however, many present in the
reproductive years, and fertility-sparing treatments are
often required.
 Advanced-stage MOGCTs and SCSTs are managed with debulking
surgery and platinum-based adjuvant chemotherapy, with the
widely used.
Learning objectives
 To understand the classification and pathology of NEOCs.

To describe the role of tumour markers in diagnostic criteria and
to be aware of the FIGO staging classifications and their
prognostic use.
 To understand management protocols and follow-up regimens.
Ethical issues
 Patients of reproductive age risk infertility if preoperative diagnosis
is incorrect and more extensive surgery involving bilateral
salpingo-oophorectomy is performed.
Keywords: nonepithelial / ovarian cancer / pathology

Please cite this paper as: Baker-Rand H, Edey K. Nonepithelial ovarian cancers. The Obstetrician & Gynaecologist 2021;23:177–86. https://doi.org/10.1111/tog.
12755

dense capsule, the tunica albuginea, and the surface is covered

Introduction
In the UK, ovarian cancer is the sixth commonest cancer in
women and is responsible for over 4000 deaths annually.1
Nonepithelial ovarian cancers (NEOCs) are uncommon forms
of ovarian tumour, accounting for approximately 10% of all
ovarian malignancies.2 The classification includes malignant
ovarian germ cell tumours (MOGCTs), sex cord-stromal
tumours (SCSTs) and very rare primary cancers, such as
ovarian sarcoma and small cell carcinoma of the ovary.3,4
NEOCs can present at any age, including in women of
reproductive age. This Review aims to provide an
understanding of the classification, diagnosis and
management of all NEOCs, focusing on MOGCTs and SCSTs.
Pathophysiology
The ovaries originate from intermediate mesoderm and
develop within the mesonephric ridge, descending through
the pelvis to lie in the ovarian fossae.5 The ovary is divided into
the cortex and medulla.6 The cortex is composed of ovarian
follicles, interstitial gland cells and stroma. It is surrounded by a
with surface epithelium of coelomic origin.7 Epithelial ovarian
tumours, which account for most ovarian malignancies, are
attributed to neometaplasia of surface epithelial cells.8 The
medulla of the ovary is formed from embryonic mesenchyme
and contains the lymphovasculature of the ovary.6 SCSTs arise
from various cell types from the primitive sex cords and
stromal cells.9 Stromal cells include theca cells, fibroblasts and
Leydig cells.9 Granulosa cells and Sertoli cells are present in
gonadal primitive sex cords.3 Germ cells arise in the
endodermal layer of the yolk sac. They migrate via the
hindgut epithelium through the dorsal mesentery and are
incorporated into the developing gonads.3 Most nonepithelial
ovarian tumours arise from these specific cells: germ cells,
granulosa cells, theca cells, stromal fibroblasts and steroid cells.
Less common tumours can arise from nonspecific ovarian cells;
for example, mesenchymal cells.
Clinical presentation
The commonest presenting symptoms include persistent
abdominal distension, pelvic or abdominal pain, urinary

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 Nonepithelial ovarian cancers

urgency or frequency and menstrual irregularities. However, perimenopausal and postmenopausal women, while Sertoli–
as with other ovarian masses, many women are Leydig cell tumours occur in young women.11 The incidence
asymptomatic and tumours are incidental findings.10 An of SCSTs is 2.1 per 1 000 000 women. For small cell
NEOC is an important differential diagnosis to consider in carcinoma of the ovary, hypercalcaemic type (SCCOHT),
premenopausal and postmenopausal women, as well as in the mean age at diagnosis is approximately 24 years.12
adolescent girls, who present with a complex ovarian mass.
Malignant germ cell tumours
Dysgerminomas microscopically exhibit nests of polygonal
Classification of nonepithelial ovarian
cells with prominent nucleoli and clear glycogen-filled
cancers
cytoplasm.4,12 Most show isochromosome 12p and, as with
Box 1 lists the main classifications and subdivisions of all MOGCTs, they express the transcription factor Sal-like
NEOCs.2,4 MOGCTs usually occur in premenopausal women protein 4 (SALL4).12,13 Immature teratomas demonstrate
and represent 80% of preadolescent ovarian malignancies.2 elements from all three germ cells, with the addition of
The yearly adjusted incidence rate of MOGCTs is 3.7 per immature embryonal tissues – usually neuroepithelial or
1 000 000 women. SCSTs can present at any age, with adult- glandular.8 These MOGCTs also express SALL4.
type granulosa cell tumours mainly occurring in Macroscopically, yolk sac tumours are large, with extensive
areas of necrosis and haemorrhage. They resemble the
endoderm and primitive yolk sac mesenchyme, with
Box 1. Adapted World Health Organization (WHO) 2014 intestinal and hepatic embryonal tissue. The presence of
classification of nonepithelial ovarian neoplasms Schiller–Duval bodies is pathognomonic.12
1. Sex cord-stromal tumour
a. Pure sex cord tumours Sex cord-stromal tumours
i. Granulosa cell tumour Granulosa cell tumours are large tumours, with focally cystic
1. Adult-type and solid areas.8 Granulosa cell tumours are associated with
2. Juvenile type
mutations in the Forkhead box L2 (FOXL2) gene.8,12 Sertoli–
ii. Sertoli cell tumour
iii. Sex cord tumour with annular tubules Leydig tumours resemble embryonic testis and cause
b. Pure stromal tumours virilisation.8 Of these, 22% have heterologous elements in
i. Fibroma the form of mucinous glands and – occasionally – skeletal
ii. Thecoma
iii. Fibrosarcoma
muscle or cartilage.2,12 Of all Sertoli–Leydig tumours, 60%
iv. Leydig cell tumour exhibit a DICER1 mutation.8
v. Sclerosing stromal tumour
vi. Signet ring tumour
vii. Steroid (lipid) cell tumour Diagnosis and tumour markers
viii. Leydig cell tumour
c. Mixed sex cord-stromal tumours (Sertoli–Leydig tumours) The Royal College of Obstetricians and Gynaecologists’
2. Germ cell tumour (RCOG) Green-top Guidelines have made clear
a. Teratoma
recommendations for the investigation of ovarian
i. Immature
ii. Mature masses.10,14 Computerised tomography (CT) and magnetic
b. Embryonal carcinoma resonance imaging (MRI) are no more sensitive or specific than
c. Nongestational choriocarcinoma transvaginal ultrasound in detecting malignancy. However, CT
d. Dysgerminoma
is used in the staging of disease and MRI can be useful for
e. Yolk sac tumour (endodermal sinus tumour)
f. Mixed germ cell tumour characterising cysts when ultrasound is inconclusive (see
3. Monodermal teratoma and somatic-type tumours arising Figure 1).14 CT should not be the first-line investigation in girls
from a dermoid cyst – including malignant struma ovarii, and adolescents because of the risk of radiation exposure, as
malignant neuroectodermal tumours and sebaceous well as the good sensitivity and specificity of ultrasound.10
carcinomas Serum CA125, lactic dehydrogenase (LDH),
4. Miscellaneous tumours – including small cell carcinoma,
alphafetoprotein (a-FP) and human chorionic
hypercalcaemic type and small cell carcinoma, pulmonary gonadotrophin (hCG) levels should be measured in all
type women under 40 years of age, with complex ovarian
5. Soft tissue tumours
a. Myoxma masses.10 Serum CA125 should be measured in
b. Others (including angiosarcoma, leiomyosarcoma, liposarcoma, postmenopausal women; carcinoembryonic antigen (CEA)
osteosarcoma) and CA19-9 levels can aid diagnosis and indicate the
Note: Full classification available in WHO Classification of Tumour of
Female Reproductive Organs4
likelihood of mucinous or endometrioid epithelial ovarian
tumours or Krukenberg tumours (e.g. lower or upper

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 Baker-Rand and Edey

gastrointestinal tract).14 This recommendation is to aid the
diagnosis of NEOCs because these proteins and hormones are
secreted by some types of germ cell tumours. Although they
Figure 1. Magnetic resonanance image of an ovarian yolk sac
tumour. Yolk sac tumours are complex ovarian masses with solid
and cystic components.
are nonspecific markers, their levels correlate with staging
and survival statistics.2 Table 1 demonstrates the secreted
proteins of pure malignant germ cells. Serum CA125 levels
(units per millilitre) are usually raised in epithelial ovarian
cancers; however, it is only raised in 50% of early disease and
can be raised secondary to endometriosis, fibroids and pelvic
infections.10 The RCOG does not recommend taking serum
CA125 levels for premenopausal women with simple ovarian
cysts. Where a level has been taken, premenopausal women
with assays greater than 200 U/mL should be discussed with
a gynaecological oncologist. In postmenopausal women, a
risk of malignancy index should be calculated and, for any
score ≥200, a CT scan of the abdomen and pelvis should be
arranged. Referral to the gynaecological oncology
multidisciplinary team (MDT) should also be made.
SCSTs can present with hormone-mediated syndromes
based on whether they are formed from hyperestrogenic
ovarian cells (granulosa and theca cells) or hyperandrogenic
testicular cell types (Sertoli and Leydig cells).
Hyperestrogenic SCSTs may present with precocious
puberty in children, abnormal uterine bleeding or
endometrial hyperplasia.11 Hyperandrogenic SCSTs may
present with defeminisation (loss of hip fat and breast
atrophy), hirsutism, irregular menstruation, hoarse voice or
male-pattern baldness.8,9,15 Inhibin B is secreted by granulosa
cell tumours. It is not routinely measured to aid with
diagnosis because it is an expensive assay to perform;

Table 1. Secreted tumour markers and associated nonepithelial ovarian cancers (modified from Gershenson, UpToDate)36

Tumour type a-FP hCG LDH Inhibin T A4 DHEA AMH

Germ cell tumours

Dysgerminoma – + – – – – –

Embryonal +/ + +/ – – – – –

Immature teratoma +/ – +/ – – – +/ –

Choriocarcinoma – + +/ – – – – –

Yolk sac tumour (endodermal sinus tumour) + – + – – – – –

Sex cord-stromal tumours

Thecoma – – – +/ – – – –

Granulosa cell – – – + +/ – – +

Sex cord tumour with annular tubules – – – – – – – –

Sertoli–Leydig +/ – – +/ +/ +/ +/ –

Abbreviations: a-FP = alphafetoprotein; A4 = androstenedione; AMH = anti-m€ ullerian hormone; DHEA = dehydroepiandrostenedione; E2 =
estradiol; hCG = human chorionic gonadotrophin; LDH = lactic dehydrogenase; T = testosterone.

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 Nonepithelial ovarian cancers

Table 2. FIGO staging classification for cancer of the ovary, fallopian tube and peritoneum16

Stage I: Tumour confined to ovaries or fallopian tube(s)

IA: Tumour limited to one ovary (capsule intact) or fallopian tube; no tumour on ovarian or fallopian tube surface; no malignant cells
in the ascites or peritoneal washings

IB: Tumour limited to both ovaries (capsule intact) or fallopian tubes; no tumour on ovarian or fallopian tube surface; no malignant
cells in the ascites or peritoneal washings

IC: Tumour limited to one or both ovaries or fallopian tubes, with any of the following:

IC1: Surgical spill

IC2: Capsule ruptured before surgery or tumour on ovarian or fallopian tube surface

IC3: Malignant cells in the ascites or peritoneal washings

Stage II: Tumour involves one or both ovaries or fallopian tubes with pelvic extension (below pelvic brim) or peritoneal
cancer

IIA: Extension and/or implants on uterus and/or fallopian tubes and/or ovaries

IIB: Extension to other pelvic intraperitoneal tissues

Stage III: Tumour involves one or both ovaries or fallopian tubes, or peritoneal cancer, with cytologically or histologically
confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes

IIIA1: Positive retroperitoneal lymph nodes only (cytologically or histologically proven):

IIIA1(i): Metastasis up to 10 mm in greatest dimension

IIIA1(II): Metastasis more than 10 mm in greatest dimension

IIIA2: Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes

IIIB: Macroscopic peritoneal metastasis beyond the pelvis up to 2 cm in greatest dimension, with or without metastasis to the
retroperitoneal lymph nodes

IIIC: Macroscopic peritoneal metastasis beyond the pelvis more than 2 cm in greatest dimension, with or without metastasis to the
retroperitoneal lymph nodes (includes extension of tumour to capsule of liver and spleen without parenchymal involvement of
either organ)

Stage IV: Distant metastasis excluding peritoneal metastases

IVA: Pleural effusion with positive cytology

IVB: Parenchymal metastases and metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside of
the abdominal cavity)

however, it is commonly used as part of follow-
up protocols.2,8
Staging and prognosis
The International Federation of Gynaecology and Obstetrics
(FIGO) staging classification for cancers of the ovary,
fallopian tube and peritoneum is used to stage all NEOCs
(see Table 2). FIGO recognises that the classification used
for male germ cell tumours may provide better prognostic
information than its own classification; this is because the
FIGO classification focuses predominantly on epithelial
ovarian cancers, in which prognosis is poorer for distant
disease.16 Full staging is achieved through a surgical
approach and includes omentectomy, biopsies of the
peritoneum and pelvic/para-aortic lymph nodes along
with pelvic washings.2,13 However, with a suspected
NEOC, fertility-conserving surgery should be the initial
approach in girls, adolescents and women wishing to retain
fertility. Before surgical staging, preoperative investigations

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 Baker-Rand and Edey

Table 3. IGCCCG stratified risk model for germ cell tumours, adapted by Meisel et al.

Type of cancer Good Intermediate Poor

Dysgerminoma No metastases other than lung, Metastases beyond lung, lymph N/A
lymph nodes or peritoneum nodes and peritoneum

All other subtypes of malignant No metastases other than lung, No metastases other than lung, Metastases beyond lung, lymph
ovarian germ cell tumour lymph nodes, or peritoneum lymph nodes, or peritoneum nodes and peritoneum
AND AND ≥1 of the following OR

 a-FP <1000 ng/L  a-FP 1000–10 000 ng/mL  a-FP >10 000 ng/mL
 hCG <5000 mIU/mL  hCG 5000–50 000 mIU/mL  hCG >50 000 mIU/mL
 LDH <1.59N  LDH 1.5–109N  LDH >109N

5-year overall survival (%) 91 80 50

Abbreviations: a-FP = alphafetoprotein; hCG = human chorionic gonadotrophin; IGCCCG = international germ cell cancer collaborative group; LDH =
lactic dehydrogenase; N = upper limit of normal.

should include a transvaginal pelvic ultrasound scan; a CT
of the thorax, abdomen and pelvis;, a chest x-ray and blood
tests, including appropriate tumour markers.2,16 Fluoro-
deoxyglucose positron emission tomography (PET) is highly
sensitive and is used in selected cases with germ cell
tumours, either after inadequate surgical staging or for
restaging following adjuvant chemotherapy.17 In women
with granulosa cell tumours, endometrial curettage should
be performed owing to the risk of endometrial
abnormalities from the hyperestrogenic effects of
granulosa cell tumours.2
Because MOGCTs and SCSTs are highly sensitive to
chemotherapy,2,8 even advanced disease can be successfully
treated. Five-year overall survival rates are in excess of 80%,
despite metastases to the lungs or lymph nodes.18,19 The
International Germ Cell Cancer Collaborative Group
(IGCCCG) created a stratified risk model for germ cell
tumours based on the spread of disease and the levels of
serum tumour markers. This model was initially created for
testicular tumours and provides information about the risk
of recurrence.20 The information has been extrapolated and
used for female germ cell tumours to provide prognostic
information (see Table 3).18
The American Cancer Society uses information from the
Surveillance, Epidemiology, End Results (SEER) database to
calculate survival statistics for different types of ovarian
cancer. The SEER database organises cancers into the
following groups: localised, regional and distant, instead of
grouping by FIGO stage.19 The 5-year survival rates are
shown in Table 4.

Table 4. SEER survival statistics

5-year relative survival rates for ovarian

cancer

Type of ovarian cancer

SEER stage Invasive epithelial Stromal Germ cell

Localised – no sign that the cancer has spread outside of the ovaries (%) 92 98 98

Regional – the cancer has spread outside the ovaries to nearby structures or lymph nodes (%) 76 89 94

Distant – the cancer has spread to distant parts of the body such as liver or lungs (%) 30 54 74

All SEER stages combined (%) 47 88 93

Abbreviation: SEER = surveillance, epidemiology, and end results.

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 Nonepithelial ovarian cancers

Management Table 5. Management of malignant ovarian germ cell tumours

(adapted from ESMO Clinical Practice Guidelines 2018)2
Surgery and chemotherapy form the pillars of treatment for
NEOCs.2,16 The aim of any surgical intervention is to achieve Type of
cancer
macroscopic cytoreduction of the tumour, as removal of all (Stage) Management
visible deposits is associated with improved survival.2

Fertility-conserving surgery Dysgerminoma

Given the high incidence of NEOCs in young women of or
IA
before reproductive age, fertility-sparing surgery in the form
of unilateral salpingo-oophorectomy has become common
practice.21 Full surgical staging is considered the gold IB-IC
standard of management13 and this has previously been
described. The surgical approach is often carried out through IIA-IV
an open route, usually via a midline laparotomy, which
allows for adequate access and the ability to carefully examine
the abdominal cavity. A laparoscopic approach to NEOCs
Immature teratoma
may be appropriate in some cases; however, the use of
laparoscopy in ovarian cancers remains controversial. IAG1
Concerns about the use of a laparoscopic approach are
related to the possibility of tumour spillage and therefore IAG2-3
upstaging of tumours, the possibility of inadequate staging
and the risk of metastasis at port sites.22 A 2016 Cochrane
review23 comparing laparoscopy and laparotomy for early-
stage ovarian cancer found no high-quality evidence to help
quantify the risks and benefits of a minimally invasive
approach. However, a 2018 literature review by Tantitamit IB-IC
and Lee22 concluded that a laparoscopic approach for the
Fertility-sparing surgery or full surgical staging with
active surveillance
Fertility-sparing surgery or full surgical staging
If fully staged: active surveillance
Full staging/debulking surgery with adjuvant
chemotherapy (fertility sparing surgery may be
indicated)
Fertility-sparing surgery or full surgical staging with
active surveillance
Fertility-sparing surgery or full surgical staging
 If fully staged and negative postoperative tumour
markers: active surveillance
 If not fully staged or positive postoperative tumour
markers: adjuvant chemotherapy
Fertility-sparing surgery or full surgical staging and
adjuvant chemotherapy

treatment of early-stage ovarian cancers is feasible, safe IIA-IV
and effective.
Concerns about reduced fertility and premature
menopause following unilateral salpingo-oophorectomy
have been investigated. There is good evidence to state that
although the quantity of the ovarian reserve is affected, the
rate of successful pregnancies, from both spontaneous Yolk sac tumour
conception and assisted reproduction following unilateral
IA-IB
oophorectomy, are comparable with women who have both
ovaries intact.24,25 For women concerned with early
menopause following unilateral oophorectomy, the HUNT2
population study demonstrated that women who had
undergone unilateral oophorectomy entered menopause
1 year earlier than women with two ovaries; this effect is IC-IV
similar to that of smoking.26
Full staging/debulking surgery with adjuvant
chemotherapy (fertility-sparing surgery may be
indicated)
 Further cytoreductive surgery for residual disease may
be appropriate
Fertility-sparing surgery or full surgical staging
 If fully staged and negative postoperative tumour
markers: active surveillance
 If not fully staged or positive postoperative tumour
markers: adjuvant chemotherapy
Full staging/debulking surgery with adjuvant
chemotherapy (fertility sparing surgery may be
indicated)

Management of malignant germ cell tumours

Malignant germ cell tumours account for 1.5% of ovarian
cancers in Europe, with approximately 100 diagnosed each
year in the UK.27 Of all MOGCTs, 60–70% are diagnosed in
the early stage and are treated with surgery followed by active and testicular germ cell tumours. As most patients presenting
surveillance or adjuvant chemotherapy.2,21 MOGCTs are with MOGCTs are adolescents or young women, the focus of
more sensitive to chemotherapy than SCSTs; this is management is chemotherapy, alongside fertility-conserving
supported by data from the management of both ovarian surgery. Although full surgical staging is the gold standard of

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management, it can be associated with higher morbidity if
full lymphadenectomy is performed. Therefore, more recent
focus has been on the lesser degree of surgical staging
described by Billmire et al.28 This suggests that full pelvic and
para-aortic lymphadenectomy can no longer be justified.28 In
women who have completed their family or who are beyond
childbearing age, more radical surgery, including total
hysterectomy and bilateral salpingo-oophorectomy, is the
most appropriate management. Management of MOGCTs is
detailed in Table 5.
The common adjuvant chemotherapy regimens for the
treatment of NEOCs are etoposide and cisplatin (EP), or
bleomycin, etoposide and cisplatin (BEP). Three to four
cycles of adjuvant chemotherapy with EP or BEP is the
standard treatment regimen for MOGCTs.2,3,13 BEP is used
in patients under the age of 40 years and for those over 40
years old, the EP regimen is used. There are considerable
short and long-term complications from the BEP
chemotherapy regimen, including ototoxicity and hearing
loss, nephrotoxicity, pulmonary dysfunction, Raynaud’s
phenomenon, avascular necrosis and secondary
malignancies – in particular, acute myeloid leukaemia.2,29
There is a risk of gonadal dysfunction leading to iatrogenic
menopause and sterility; therefore, women have the option of
oocyte cryopreservation before chemotherapy. However, the
rate of premature ovarian failure after chemotherapy is low at
3%.27 Successful pregnancies have been reported following
treatment with these chemotherapeutic agents.30
Adequately staged stage 1 cancers can potentially be
managed without chemotherapy to avoid toxicity. Indeed,
this is now the standard of care in stage 1 testicular cancers.
An oncologist with expertise in management of these rare
cancers should discuss the advantages and disadvantages of
chemotherapy with women. Relapse in stage 1a
dysgerminoma is around 20% and most women will be
cured with salvage chemotherapy.
National centres (Charing Cross London, Sheffield and
Dundee) exist for the management of trophoblastic ovarian
tumours. Women with these tumours, although often
managed locally, should be referred to the nearest national
centre for surveillance. The registration and treatment
programme offered by these specialist centres achieves cure
rates >98% and low chemotherapy rates (5–8%).31
Management of sex cord-stromal tumours
Of all SCSTs, 60–95% are diagnosed in the early stage and the
focus of treatment is surgery with adjuvant chemotherapy.2,21
This is the same for advanced SCSTs, which are managed
with more extensive surgery and adjuvant chemotherapy.2,13
Most women presenting with SCSTs are perimenopausal or
postmenopausal and this, combined with SCSTs being
less chemosensitive than MOGCTS, means full staging
surgery, including hysterectomy and bilateral salpingo-
ª 2021 Royal College of Obstetricians and Gynaecologists
Baker-Rand and Edey
oophorectomy, is recommended. Fertility-sparing surgery
may be indicated and is usually considered on an individual
case basis. Chemotherapy regimens for SCSTs are like those
used for MOGCTs and consist of three to four cycles of
adjuvant chemotherapy with EP or BEP, with the same age-
related divisions. However, SCSTs can also be treated with
carboplatin and paclitaxel combination chemotherapy.2,3
Management of SCSTs is detailed in Table 6.
Small cell carcinoma of the ovary,
hypercalcaemic type
SCCOHTs are aggressive ovarian tumours, characterised as
malignant rhabdoid tumours. They are associated with
deleterious mutations of the SMARCA4 (SWI/SNF-related,
matrix associated, actin dependent regulator of chromatin
subfamily A, member 4) remodelling gene.12,13 The median
age at presentation is 24 years old.3 Serum calcium levels are
elevated in approximately two-thirds of patients.32 Most
Table 6. Management of sex cord-stromal tumours
Type of
cancer
(Stage) Management
Granulosa cell tumour
IA Fertility-sparing surgery or full surgical staging with
standard follow-up
IC1 Full staging/debulking surgery including TAH and BSO
(fertility-sparing surgery may be indicated)
IC2-3 Full staging/debulking surgery including TAH and BSO
and adjuvant chemotherapy (fertility-sparing surgery
may be indicated)
IIA-IV Full staging/debulking surgery including TAH and BSO
and adjuvant chemotherapy
Sertoli–Leydig tumour
IA In young patients: fertility-sparing surgery or full
surgical staging
In older patients: full staging surgery including TAH
and BSO
If the tumour is poorly differentiated or has
heterologous elements then adjuvant chemotherapy
is required
>IA Full staging/debulking surgery including TAH and BSO
and adjuvant chemotherapy (fertility sparing surgery
may be indicated)
Abbreviations: TAH = total abdominal hysterectomy; BSO = bilateral
salpingo-oophorectomy
183
 Nonepithelial ovarian cancers
tumours are unilateral and 50% of tumours demonstrate
extraovarian spread at diagnosis.3,32 SCCOHTs are
chemosensitive at the outset, but there is a high risk of
relapse.2,12 There is a lack of evidence to provide clear
recommendations for management. The consensus is for
complete surgical staging followed by adjuvant chemotherapy
and/or pelvic radiotherapy.2 Cisplatin and etoposide are the
chemotherapeutic agents of choice. Recently, autologous
stem cell transplants have been performed as an adjuvant
treatment and these are associated with better survival.2 Five-
year survival is 10%, with most patients dying within 2 years
of diagnosis.3,13
Ovarian sarcoma
Sarcomas of the ovary are exceedingly rare. Adenosarcoma
and carcinosarcoma are mixed epithelial and mesenchymal
tumours, which are managed as epithelial ovarian cancers.
Carcinosarcoma (also known as malignant mixed
mesodermal tumour) is the most common subtype.33
Nonepithelial types of ovarian sarcoma include
angiosarcoma, leiomyosarcoma, liposarcoma and
osteosarcoma.4,13 Of all nonepithelial ovarian sarcomas,
80% occur in postmenopausal women, with the mean age
at diagnosis being 63 years old.3,33 Ovarian sarcomas are
aggressive tumours and most present with distant disease.13
They commonly spread to the liver, lungs and retroperitoneal
lymph nodes. Guidance published by the National Institute
of Health and Care Excellence (NICE)34 recommends that
patients with sarcoma are managed in specialist sarcoma
units, as this has been shown to improve outcomes. The
guidance recognises the limitations of these centres in the
management of gynaecological sarcoma. It also recognises
that, although nonepithelial ovarian sarcomas should be
referred to sarcoma units, management is shared with – and
Table 7. Active surveillance programme for management of malignant ovarian germ cell tumours (modified from ESMO Clinical Practice Guidelines
2018)
Time period Examination Pelvis US
1st year Monthly 2-monthly
2nd year 2-monthly 4-monthly
3rd year 3-monthly 6-monthly
4th year 4-monthly
5th to 10th year 6-monthly
Abbreviations: CTAP = computed tomography abdomen and pelvis; CXR = chest X-ray; US = ultrasound
184
guided by – the gynaecological oncology MDT. The rare
prevalence of these tumours means there is a lack of data and
no clear consensus on treatment regimens. Localised disease
is usually managed with aggressive surgery. Metastatic disease
is managed with chemotherapy, often palliative.
Chemotherapeutic agents that have been used in the
management of ovarian sarcoma include cisplatin,
doxorubicin and ifosfamide.3,33 Secondary cytoreductive
surgery has not been found to be feasible or effective.33
Prognosis is poor and long-term survival is uncommon.3,13,33
Active surveillance and follow-up
Germ cell tumours
Recurrence of MOGCTs usually occurs early, with the highest
risk of relapse being in the first 2 years after treatment.
Therefore, women undergoing fertility-sparing surgery in
early-stage disease are recommended to follow an active
surveillance plan post-treatment according to the RCOG and
European guidelines. This active surveillance programme,
described by Vasquez and Rustin,2 has a demanding visiting
schedule designed to detect recurrence over a 10-year period
(see Table 7). Women wishing to conceive are usually advised
to avoid doing so within the first 2 years post-treatment,
when risk of relapse is greatest.
Sex cord-stromal tumours
After treatment with surgery and adjuvant chemotherapy,
SCSTs follow standard follow-up regimens (see Box 2), which
combine history, examination and evaluation of serum
tumour markers to assess possible recurrence. Physical
examination should include pelvic examination. As SCST
relapse tends to occur late, regular follow-up commences in
the third year and continues indefinitely.3 Serum tumour
marker levels (hCG, a-FP, LDH, CA125 and inhibin B,
Tumour markers CXR CTAP
Every 2 weeks (first 2-monthly 1 month
6 months) and then monthly 3 months
12 months
2-monthly 4-monthly
3-monthly 6-monthly
4-monthly 8-monthly
6-monthly Annually
ª 2021 Royal College of Obstetricians and Gynaecologists

Box 2. ESMO follow-up recommendations for ovarian sex cord-
stromal tumours
History, examination and tumour markers:
 From third year and continued indefinitely, 6-monthly
 Plus 6-monthly pelvic ultrasound for women treated with fertility-
sparing surgery
measured depending on the type of NEOC) are used to assess
response to chemotherapy and subsequently to assess
relapse.2,3 Clinicians should be aware of hyperestrogenic
symptoms, particularly in the absence of ovaries. In such
cases, women may present with an absence of menopausal
symptoms, which may suggest recurrence of granulosa cell
tumours. Virilisation may suggest recurrence of androgenic
Sertoli–Leydig tumours. If lung metastases are suspected in
NEOC recurrence, then a CT of the chest, abdomen and
pelvis should be obtained. The use of PET scan for this
purpose has not been recommended. For any patient who has
undergone fertility-sparing surgery, six-monthly pelvis
ultrasound scan should be performed.2
Hormone replacement
Women made menopausal through radical surgery or
because of adjuvant chemotherapy may request hormone
replacement therapy (HRT). It is recognised that iatrogenic
menopause causes greater prevalence and greater severity of
menopausal symptoms.35 These symptoms, which can
considerably reduce quality of life for women affected,
include low mood; vasomotor symptoms, including
flushing; and sexual dysfunction, including loss of libido.
There are no robust data to evaluate the safety of HRT for
NEOCs. However, given the hormone-dependent nature of
SCSTs, HRT is not recommended and should be avoided in
these patients. In the case of MOGCTs, HRT is usually
considered to be safe and hormonal contraceptives are
not contraindicated.2
Psychological support
The importance of a holistic approach to care and early
psychological support should not be underestimated for young
women who are diagnosed with cancer. Early involvement of
Teenage and Young Adult (TYA) services and specialist nurses,
and joint pathways with paediatric and gynaecological
surgeons, can offer the best care for young patients.
Conclusion
NEOCs are a broad group of malignancies. It is important to
consider them as differential diagnoses, particularly in girls and
young women with a complex ovarian mass. Involvement of
the multidisciplinary gynaecological oncology team is
ª 2021 Royal College of Obstetricians and Gynaecologists
Baker-Rand and Edey
essential. This team should include surgeons, oncologists,
cancer nurse specialists, histopathologists, radiologists and
psychologists. Pathways for involvement of paediatric
surgeons and fertility specialists should be clear.
In girls, adolescents and women of reproductive age,
surgery should be fertility conserving whenever possible. For
premenopausal women receiving chemotherapy, the risk of
premature ovarian failure should be discussed. Referral to
fertility specialists for oocyte preservation should be
considered and discussed with the patient or parents at an
early stage.
Disclosure of interests
There are no conflicts of interest.
Contribution to authorship
HBR researched and wrote the article. KE provided clinical
expertise and edited the article. All authors approved the
final version.
Acknowledgements
Thank you to Dr Surabhi Agrawal, Consultant
Histopathologist, Musgrove Park Hospital, Taunton, for
providing advice on cellular pathology and classification of
nonepithelial ovarian tumours.
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ª 2021 Royal College of Obstetricians and Gynaecologists