Policy Review

ESGO–SIOPE guidelines for the management of adolescents

and young adults with non-epithelial ovarian cancers
Cristiana Sessa, Dominik T Schneider, François Planchamp, Katja Baust, Elena Ioana Braicu, Nicole Concin, Jan Godzinski, W Glenn McCluggage,
Daniel Orbach, Patricia Pautier, Fedro A Peccatori, Philippe Morice, Gabriele Calaminus

The European Society of Gynaecological Oncology and the European Society for Paediatric Oncology jointly developed Lancet Oncol 2020; 21: e360–68
clinically relevant and evidence-based guidelines for the management of adolescents and young adults aged Oncology Institute of Southern
15 to 25 years with non-epithelial ovarian cancers, including malignant ovarian germ cell tumours, sex cord-stromal Switzerland, Bellinzona,
Switzerland (C Sessa MD);
tumours, and small cell carcinoma of the ovary of hypercalcaemic type. The developmental process of these guidelines
Paediatric Oncology, Klinikum
is based on a systematic literature review and critical appraisal process involving an international multidisciplinary Dortmund, Dortmund,
developmental group consisting of experts from relevant disciplines (paediatric oncology, paediatric surgery, medical Germany (D T Schneider MD);
oncology, pathology, psycho-oncology, gynaecological oncology, and reproductive endocrinology). Given the specific Institut Bergonié, Bordeaux,
France (F Planchamp MSc);
and often complex issues involved in treating this group of patients, fertility sparing surgery and decrease of acute Paediatric Oncology, University
and long-term toxicities from treatment were important criteria for guidelines definition. Prior to publication, the Hospital Bonn, Bonn, Germany
guidelines were reviewed by 54 independent international practitioners in cancer care delivery. (K Baust DPsy, G Calaminus MD);
Gynaecologic Oncology,
Charité-Universitätsmedizin
Introduction to avoid different therapeutic approaches that are used Berlin, Humboldt-
The European Society of Gynaecological Oncology depending on the medical background of the treating Universitätzu Berlin, Berlin
(ESGO) and the European Society for Paediatric Oncology physician. This joint initiative aims to foster the exchange Institute of Health, Institute of
(SIOPE) jointly developed clinically relevant and of experience and specialist opinion between involved Gynecology, Berlin, Germany
(E I Braicu MD); Gynaecologic
evidence-based guidelines in order to improve the quality disciplines, including specialist pathologists, to result in Oncology, Medical University
of care for adolescents and young adults (AYAs) with the broadest possible perspective on these rare tumours. of Innsbruck, Innsbruck,
non-epithelial ovarian cancers, including malignant The international development group for the ESGO– Austria (N Concin MD);
ovarian germ cell tumours, sex cord-stromal tumours, SIOPE guidelines is well aware that the general principles Paediatric Surgery, Marciniak
Hospital, Medical University,
and small cell carcinoma of the ovary of hypercalcaemic discussed in these guidelines are not always fully trans­ Wroclaw, Poland
type across Europe and worldwide. The definition of ferable to adults with these neoplasms. Any clinician (J Godzinski MD); Pathology,
AYAs used in these guidelines includes women aged applying or consulting these guidelines is expected to Belfast Health and Social Care
15 to 25 years, although this definition is arbitrary. use independent medical judgment in the context of Trust, Belfast, UK
(W G McCluggage MD); Medical
Germ cell tumours comprise a heterogeneous group of individual clinical circumstances to determine any Oncology, Institut Curie, Paris,
benign and malignant neoplasms and are subdivided patient’s care or treatment. These guidelines make no France (D Orbach MD); Medical
by their anatomical location: gonadal (ovary or testis) representations or warranties of any kind regarding their Oncology (P Pautier MD) and
Gynaecologic Oncology
and extragonadal. They are heterogeneous with respect content, use, or application, and disclaim any respon­
(P Morice MD) Institut Gustave
to clinical, histopathological, immunophenotypic, and sibility for their application or use in any way. Roussy, Villejuif, France; and
molecular characteristics.1 Sex cord-stromal tumours Gynaecologic Oncology,
might also occur in the ovary or testis and rarely arise Data collection European Institute of Oncology
IRCCS, Milan, Italy
at extragonadal sites;2 they also constitute a hetero­ Search strategy and selection criteria
(F A Peccatori MD)
geneous group of tumours. Sex cord-stromal tumours The ESGO–SIOPE guidelines were developed using a
Correspondence to:
are categorised into pure stromal, pure sex cord, and five-step process including the creation of a multi­ Dr Cristiana Sessa, Department
mixed.1 The most common malignant (or potentially disciplinary international development group, use of of Medical Oncology, Oncology
malignant) ovarian sex cord-stromal tumours are scientific evidence and international expert con­sensus to Institute of Southern
Switzerland, Ospedale San
granulosa cell tumours, which include juvenile and adult support the guidelines, use of an inter­national external
Giovanni, 6500 Bellinzona,
types based on different histological and molecular review process, and management of potential conflicts of Switzerland
characteristics, and Sertoli-Leydig cell tumours. Small interests (figure). The ESGO–SIOPE nomi­nated practi­ cristiana.sessa@eoc.ch
cell carcinoma of the ovary of hypercalcaemic type is an cing clinicians (from paediatric oncology, paediatric
extremely rare ovarian malignancy that most commonly surgery, medical oncology, pathology, psycho-oncology,
affects women younger than 40 years, but very rarely gynaecological oncology, and repro­ductive endocrinology)
those younger than 10 years.3–10 that are involved in the management of AYAs with non-
These ESGO–SIOPE guidelines specifically focus on epithelial ovarian cancers to serve on the international
the management of female AYAs with these types of expert panel (appendix p 1). To ensure that the recom­ See Online for appendix
neoplasm, an age group which has different needs and mendations were evidence-based on the highest possible
faces the challenge of transitioning from childhood to level of evidence, a systematic liter­ature review of relevant
adolescence, receiving care from a primary paediatric studies published between January, 1998, and May, 2018,
care setting to care in adult medicine, including oncology was done using the Medline database. The main search
and gynaecological oncology. An important principle is terms were “adolescent and young adults”, “adjuvant
that patients should receive the best possible care, trying chemo-radiation therapy”, “advanced stage”, and “salvage

www.thelancet.com/oncology Vol 21 July 2020 e360

 Policy Review
Nomination of multidisciplinary international development group
Identification of scientific evidence
Formulation of guidelines
External evaluation of guidelines (international review)
Integration of international reviewers’ comments
Figure: Guideline development process
Grade description
A At least one meta-analysis, systematic review, or RCT rated as 1++,* and directly applicable to the
target population; or a body of evidence consisting principally of studies rated as 1+,† directly
applicable to the target population, and demonstrating overall consistency of results
B A body of evidence including studies rated as 2++,‡ directly applicable to the target population,
and demonstrating overall consistency of results; or extrapolated evidence from studies rated as
1++ or 1+
C A body of evidence including studies rated as 2+,§ directly applicable to the target population and
demonstrating overall consistency of results; or extrapolated evidence from studies rates as 2++
D Evidence level 3¶ or 4||; or extrapolated evidence from studies rated as 2+
Recommended best practice based on the clinical experience of the guideline development
 group
RCT=randomised controlled trial. *A level 1++ rating is for high quality meta-analyses, systematic reviews of RCTs,
or RCTs with a very low risk of bias. †A level 1+ rating is for well conducted meta-analyses, systematic reviews, or RCTs
with a low risk of bias. ‡A level 2++ rating is for high quality systematic reviews of case control or cohort studies or
high quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the
relationship is causal. §A level 2+ rating is for well conducted case control or cohort studies with a low risk of
confounding or bias and a moderate probability that the relationship is causal. ¶A level 3 rating is for non-analytic
studies—eg, case reports, case series. ||A level 4 rating is for expert opinion.
Table 1: Scottish Intercollegiate Guidelines Network grading system for recommendations
treatment.” Priority was given to meta-analyses and
randomised controlled trials but lower levels of evidence
were also evaluated because of the rarity of these
diagnoses. Full search criteria are stated in the appendix
(pp 2–4). The search was critically appraised, a list of
abstracts of the papers of potential interest were sent to
the international development group, who then selected
the full papers to be analysed and could propose
additional papers.
Guideline development
The international development group developed guide­
lines for pathological diagnosis, staging, work-up,
management (early and advanced stages, and refractory
and recurrent disease), and follow-up for each tumour
type included. General principles of management and
general principles of pathological evaluation were also
defined. The guidelines were adopted if they were
supported by sufficient high-level scientific evidence or
when a broad consensus among experts was obtained, or
both. The level of evidence and grade of each guideline
were defined according to the Scottish Intercollegiate
e361 www.thelancet.com/oncology Vol 21 July 2020
Guidelines Network grading system (table 1). The ESGO–
SIOPE also established a large multidisciplinary panel of
practising clinicians that provide care to AYAs with non-
epithelial ovarian cancers to act as expert reviewers for the
guidelines developed. The reviewers selected were still
involved in clinical practice, had competence in a relevant
specialty, and were from different European countries or
non-European countries to ensure a global perspective.
The 54 international reviewers were inde­pendent from
the development group (appendix p 5). International
reviewers were asked to evaluate the guidelines according
to their relevance and feasibility in clinical practice.
Reviewers were asked whether they agreed with the
guidelines and to provide comments if they did not agree.
Responses of the 54 external reviewers were pooled and
discussed by the international development group to
finalise the guidelines. In the case of disagreement by the
reviewers, a concerted reply and proposal had to be
provided by the development group.
Findings
Unless otherwise indicated, the recommendations below
are recommended best practice on the basis of professional
experience and consensus of the development group.
General principles of management and pathological
evaluation
Because of the rarity of the various non-epithelial ovarian
tumours covered in these guidelines, patients should be
referred to a specialised centre with a multidisciplinary
setting that includes adult and paediatric expertise.
Therapy should be adequately monitored by trained
oncologists. Patients should be staged according to the
International Federation of Gynecology and Obstetrics
2014 staging system. In patients with suspected ovarian
tumours, the preoperative diagnostic work-up should
include, in addition to abdominal and pelvic ultrasound,
an abdomino-pelvic MRI with thoracic CT scan, and the
serum tumour markers α-fetoprotein, β-human chorionic
gonadotropin (β-HCG), inhibin B, anti-Müllerian hormone
and lactate dehydrogenase (grade D). A serum calcium
level should also be measured. In cases where immediate
surgery has been done before these investigations, the
investigations should be done as soon as possible after
surgery; however, no optimal timeframe was recom­
mended. Abdominal and pelvic MRI is preferred to
CT scan when­ever possible to reduce radiation exposure.
Preoperative pelvic MRI is helpful to assess potential
bilateral ovarian involvement (eg, in dysgerminoma and
teratoma) and to better characterise the mass to guide the
surgical strategy (choice of approach; grade D). There is no
indication for PET-CT because of low negative predictive
value. In the case of a cystic component within the
suspicious tumour mass, diagnostic puncture is to be
avoided. The surgical approach should be carefully selected
on the basis of initial imaging to avoid intraoperative
rupture of the tumour. Oophorectomy should be preferred

to cystectomy or tumourectomy. Biopsies of the tumour
are contraindicated, except in patients with extraovarian
spread. Median laparotomy is the preferred option in
suspected malignant tumours. A minimally invasive
approach is an acceptable option only if (1) the surgeon is
trained in laparoscopic oncological surgery, (2) the removal
of the tumour can be done without rupture, (3) no
morcellation of the specimen occurs during the removal,
and (4) full exploration of the peritoneal cavity can be done.
Before manipulating the tumour, peritoneal fluid
should be sent for cytological examination. If there is no
fluid in the abdominal cavity, peritoneal washing should
be done. Staging of tumours also includes examination
of the peritoneal surfaces; biopsy of diaphragmatic
peritoneum, paracolic gutters, and pelvic peritoneum;
examination and palpation of pelvic and para-aortic
lymph nodes; excision of enlarged lymph nodes;
inspection, palpation and large biopsy of the omentum,
if normal; removal of adherent or abnormal omentum;
and inspection of the contralateral ovary with biopsy of
abnormal appearing areas. Fertility sparing surgery
saving the uterus and at least a part of one adnexa) is the
first surgical option when awaiting definitive pathological
results (grade D). In the case of macroscopic extraovarian
disease, a precise description of the spread (location and
size) should be clearly documented and at least biopsies
of the extraovarian disease should be done.
Supportive care should take into consideration acute
and delayed side-effects of chemotherapy. The use of
steroids should be avoided, if possible. Oncofertility
counselling has to be offered to all AYA patients before
therapy. Psycho-oncological support tailored to the
specific needs of AYA patients should be offered to all
patients and their relatives at each step of the initial
treatment and follow-up (grade D). If tumour markers
are elevated at diagnosis, they should be measured after
surgery and before the start of surveillance therapy or
any adjuvant treatment. In the case of chemotherapy,
tumour markers should be measured before each
treatment cycle. The decrease of tumour markers should
be in line with the marker’s expected half-life. AYAs with
malignant ovarian germ cell tumours, sex cord-stromal
tumours, and small cell carcinoma of the ovary of
hypercalcaemic type should be treated, whenever
feasible, within clinical trials. The aims of clinical trials
for patients at high-risk should be to improve efficacy
while maintaining the degree of safety already accepted.
The aims of clinical trials in patients who are low to
medium risk should be to maintain the efficacy while
decreasing toxicity. In cases where no standard treatment
options are available, participation in clinical trials
evaluating new therapeutic approaches should be
considered. When no clinical trials are open, clinical data
should be reported to clinical registries.
Tumours should be classified according to the 2014
WHO classification. Confirmation of diagnosis by
an experienced specialist gynaecological or paediatric
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Policy Review
pathologist is strongly advised given the rarity of these
neoplasms and the substantial risk of misdiagnosis.
Exchange of specimens between experts is strongly
encouraged (grade D). Immunohistochemistry and
molecular tests are often necessary for diagnosis and
these are not available in many pathology laboratories
(grade D). With certain tumour types, discussed later
case by case, a familial tumour syndrome should be
considered and genetic counselling including psycho­
logical consultation service and germline mutation
analysis are advised. These should be done in case of
bilateral germ cell tumour, unilateral germ cell tumour
with streak gonad or pubertal retardation, Sertoli-Leydig
cell tumours, and small cell carcinoma of the ovary of
hypercalcaemic type (grade D).
Malignant ovarian germ cell tumours
Diagnosis, pathology, staging, and work-up
Clinical staging follows the recommendations provided
in the general principles of management within this
guideline. Malignant ovarian germ cell tumours comprise
dysgerminoma, yolk sac tumour, immature teratoma,
embryonal carcinoma (extremely rare within the ovary),
and non-gestational choriocarcinoma. The presence or
absence of lymphovascular space involvement should be
reported. These neoplasms might be difficult to diagnose
and immunohistochemical markers can be of value
(grade C): Sal-like protein 4 is typically positive in all
malignant ovarian germ cell tumours, including the
immature neuroepithelium in immature teratomas;
OCT3/4, Alkaline phosphatase, placental type (PLAP),
D2-40, NANOG, and SCFR are commonly positive in
dysgerminoma; PLAP can be positive in yolk sac tumours;
α-fetoprotein and glypican-3 are commonly positive in
yolk sac tumours; OCT3/4, tumour necrosis factor
receptor superfamily member 8, NANOG, and SOX10 are
usually positive in embryonal carcinoma; and non-
gestational choriocarcinomas are typically immuno­
reactive with β-HCG and inhibin.
In general, because of overlap between the various
immunohistochemical markers and unexpected aberrant
staining patterns, it is best to use panels of markers
rather than rely on individual markers. There are a
number of incompletely characterised chromosomal and
genetic abnormalities in malignant ovarian germ cell
tumours, the clinical significance of which have not yet
been determined. The most frequent chromosomal
aberration is isochromo­some 12, with a gain of the p arm
of chromosome 12. As malignant ovarian germ cell
tumours might arise in the context of gonadal dysgenesis
(eg, Swyer syndrome), genetic evaluation for sex chromo­
somal aberrations should be recommended (grade D).
Management of early-stage disease
In the case of the presence of a solid or partially solid
ovarian mass on ultrasound, an additional MRI should be
done (grade D). If a solid component is present on MRI,
 Policy Review
surgery is the initial treatment of early-stage malignant
ovarian germ cell tumours (grade C). The choice of the
approach should be carefully evaluated to avoid any
rupture during intervention. In the case of bilateral
tumours, bilateral salpingo-oophorectomy is strongly
discouraged and the preservation of at least a part of one
ovary should be promoted (grade C). In the case of a solid
unilateral tumour, total en-bloc oophorectomy is the
treatment of choice. In cystic tumours, cystectomy should
be avoided. Fertility sparing surgery is now considered
the standard surgical treatment for young patients with
malignant ovarian germ cell tumours (grade C). With a
contralateral macroscopically normal ovary and negative
imaging, ovarian biopsy is not necessary (grade C). In the
case of macroscopic bilateral ovarian disease (mainly
dysgerminoma), preservation of at least a healthy part of
one ovary (unilateral salpingo-oophorectomy and contra­
lateral partial oophorectomy) and the uterus should be
encouraged unless genetic analysis reveals dysgenetic
gonads. For dysgenetic gonads, removal of the remaining
ovary is encouraged (grade C).
In case of bilateral tumours, genetic analysis for sex
chromosomal aberrations should be done in combination
with genetic counselling and psychological support.
Because of the risk of gonadoblastoma and dysgermi­
noma, in case of dysgenetic gonad, bilateral salpingo-
oophorectomy could be done. If an initial cystectomy or
tumorectomy has been done with no indication for
adjuvant treatment on the basis of the final pathology
report and serum tumour markers have normalised,
additional surgery to remove the residual ovary is
required to reduce the risk of recurrence. When adjuvant
medical treatment is required, such additional surgery
could be avoided. For dysgerminoma and teratoma, there
is a risk of bilateral involvement and postoperative ultra­
sound monitoring of the remaining ovary is recom­
mended. If a tumour is considered likely to be malignant
(secreting, imaging of tissular or mixed, or important
extraovarian spread), a laparotomic approach is appro­
priate for removal of the tumour for staging and to
minimise the risk of intraperitoneal spillage (grade C).
For masses where the risk of malignancy is low or
uncertain, a minimally invasive approach (laparoscopy or
robotic) could be discussed. If the diagnosis is made
postoperatively, reoperation for comprehensive surgical
staging with lymphadenectomy is to be avoided. Nodal
removal should be done only where there is evidence of
nodal abnormalities during surgical exploration, MRI, or
CT scan (lymphadenopathy; grade C). In completely
resected stage IA neoplasms with normalising or
negative postoperative tumour markers, active surveil­
lance is the preferred approach (grade C). In stage IA
yolk sac tumours and non-compliant patients, adjuvant
chemotherapy (maximum two cycles) is an option. The
management of stage IB neoplasms (rare cases) is
complex and should be discussed according to the
histotype of the tumours in both ovaries. In stage IC1
e363 www.thelancet.com/oncology Vol 21 July 2020
malignant ovarian germ cell tumours, the situation is
equivocal. Both options (chemotherapy [maximum
two cycles] or active surveillance) could be considered.
Patients with stage IC2 and IC3 malignant ovarian germ
cell tumours of all types should receive adjuvant
chemotherapy (maximum three cycles; grade C).
Management of advanced-stage disease
Fertility sparing surgery should be considered even in the
case of advanced disease because of the high chemo­
sensitivity of malignant ovarian germ cell tumours
(grade C). Because of this high chemosensitivity, extensive
cytoreductive surgery should be avoided during initial
management. Surgical resection is only required in
rare cases of residual disease after chemotherapy (in
peritoneum, remaining ovary, or lymph nodes). A careful
close surveillance could be discussed for patients with
dysgerminoma with minimal residual disease on imaging
following treatment because these residues are usually
non-viable. Standard chemotherapy for stage III–IV
disease is used as in adult protocols, with bleomycin,
etoposide, and platinum for three to four cycles with
bleomycin omitted after cycle three (maximum total
cumulative dose 270 IU) to avoid lung toxicity (grade C).
In adolescent patients, other options are: cisplatin,
etoposide, and ifosfamide; cisplatin, etoposide, and dose-
reduced bleomycin; or carboplatin, etoposide, and
bleomycin as used in paediatric protocols, for three to
four cycles (grade C). Patients with raised tumour
markers at presentation who do not have negative
markers after cycle four are considered non-responders to
the treatment. Patients with raised tumour markers at
presentation in whom tumour markers are not falling
according to their expected half-life after the second cycle
of treatment should be considered high-risk, and
intensification of therapy should be discussed. In cases of
immature teratoma with extra ovarian disease that
comprises gliomatosis peritonei (morphologically benign
glial tissue with no immature elements), complete
surgical resection of the peritoneal disease is not required
(if the surgery is too invasive). However, large and
multiple biopsies should be done to ensure that all tissues
are mature and glial.
Management of refractory or recurrent disease
The need for and the type of treatment including
chemotherapy and irradiation has to be discussed in a
multidisciplinary team decision-making setting. In
cases of immature teratoma or mixed tumours with
a component of immature teratoma and subsequent
recurrence and normal serum markers following
chemotherapy, a growing teratoma syndrome should be
suspected (presence of exclusively mature elements in
extraovarian sites [peritoneal or nodal, or both] following
chemo­therapy). In this situation, treatment is exclusively
surgical resection provided that on histological exami­
nation all tissues (all of which should be examined
 Policy Review

Clinical Abdominal or pelvic Tumour Chest x-ray or Abdomen or pelvic PROs‡

examination* ultrasound markers low-dose CT MRI or CT†
First 6 months
Surgery only Monthly§ Monthly§ Monthly§ Every 6 months Every 6 months Yes¶
Other treatments Every 2 months Every 2 months Every 2 months Every 6 months Every 6 months Yes¶
6–12 months Every 2 months Every 2 months Every 2 months Every 6 months Every 6 months ··
Year 2 Every 3 months Every 3 months Every 3 months Every 6 months Every 6 months Yes
Year 3 3–6 months 3–6 months 3–6 months ·· .. ··
Years 4–5 Every 6 months Every 6 months ·· ·· .. Yes
Years 6–10 Yearly Yearly ·· ·· .. ··

PRO=patient-reported outcome. *Monitoring of potential long-term toxicities (organ, endocrine, and hearing function) should be done. †MRI should be preferred whenever
possible to avoid radiation exposure. ‡Age-appropriate self-report questionnaires should be used to screen for psychological late effects. §Until tumour markers are
normalised, then every 2 months. ¶At the beginning of treatment.

Table 2: Follow-up strategy of malignant ovarian germ cell tumours

in total) are mature. Surgical resection should be
conservative, preserving the uterus and a part of one
ovary if technically feasible. In the other situations, a
biopsy is essential to have histological confirmation of
recurrence before starting additional treatment. All
specimens should be carefully histologically examined to
confirm or exclude only pure mature tissues. There is no
defined treatment strategy for patients who relapsed after
completion of chemotherapy. Treatment options to be
considered can include platinum-based combinations
and should take into account previous lines of therapy
and the delay between initial tumour and relapse. In pure
dysgerminoma, radiotherapy could also be discussed
(grade D). Intensified chemotherapy with stem cell
support can be considered (grade D). The role of salvage
surgery in recurrent disease is not well defined (grade D).
Follow-up
The surveillance programme in the management of
malignant ovarian germ cell tumours is based on clinical
examination, tumour markers, and imaging (table 2).
Sex cord-stromal tumours
Diagnosis, pathology, staging, and work-up
Serum α-fetoprotein, β-HCG, CA-125, inhibin, anti-
Müllerian hormone, calcium, and lactate dehydrogenase
values are required. Oestrogen, dehydroepi­androsterone,
testosterone, luteinising hormone, and follicle stimu­
lating hormone levels are also required with signs of
hormonal production. Clinical staging follows the
recommendations provided in the general principles
of management within this guideline. A variety of
immuno­ histochemical markers are of value in the
diagnosis of ovarian sex cord-stromal tumours, these
include inhibin (the most specific), calretinin, NCAM-1,
MART-1, CD99 antigen-like protein 2, steroidogenic
factor-1, Forkhead box protein L2, and Wilms tumour
protein. Because all of these markers have problems
regarding sensitivity and specificity, they should be
used in combination rather than relying on a single
marker. These markers, while of value in diagnosing
sex cord-stromal tumours, are of low value in
distinguishing between the various neoplasms in this
group (grade C). Pathological evaluation of Sertoli-
Leydig cell tumours should include a description of the
grade (well, moderate, or poorly differentiated) and
the presence of specific histological features, such as
retiform pattern or presence of heterologous elements
(most commonly mucinous glandular, skeletal muscle,
or cartilage). In all Sertoli-Leydig cell tumours or
gynandroblastomas, patients should be screened for
other disorders that might be associated with DICER1
syndrome, in particular thyroid disease and a variety of
uncommon neoplasms. A family history should be
taken into consideration, and genetic analysis of
DICER1 should be initiated along with genetic
counselling (grade C). Given the risk of endometrial
associated proliferative lesions (hyperplasia and endo­
metrioid carcinoma) due to hormonal production,
endo­metrial sampling is conventionally recommended
in adult patients with granulosa cell tumour (grade D).
There are no data to support the need for endometrial
sampling in AYAs. However, endometrial imaging
should be done to assess the thickness of the endo­
metrium. In the absence of data, the role of PET-CT
cannot be defined.
Management of early-stage disease
Comprehensive staging includes submission of peri­
toneal fluid or peritoneal washings, examination of the
contralateral ovary, random blind peritoneal sampling
and resection of any suspicious lesions, large omental
biopsy, or infracolic omentectomy. Systematic lymph
node dissection is not recommended. Resection of lymph
nodes should be done only in cases of suspicious nodes
on imaging or intraoperative examination (grade C).
After comprehensive staging, if confirmed as stage IA,
most tumours should be managed with surgical resection
alone. Exceptions are poorly differentiated Sertoli-Leydig
cell tumours or Sertoli-Leydig cell tumours with
hetero­logous elements or retiform patterns, where
adjuvant treatment could be considered (grade C).

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 Policy Review

Stage IA Stage IC Stage II–III

Clinical examination*
Blood markers‡
Abdominal or pelvic ultrasound
Abdominal or pelvic MRI
PROs§
Every 4 months for 2 years,
then yearly†
Every 4 months for 2 years,
then yearly†
Every 4 months for 2 years,
then yearly†
No
Yes (at the beginning of treatment,
at 2 years, and at 5 years)
Every 4 months for 2 years, then every
6 months for 5 years, then yearly†
Every 4 months for 2 years, then every
6 months for 5 years, then yearly†
Every 4 months for 2 years, then every
6 months for 5 years, then yearly†
Every 6 months for 2 years
Yes (at the beginning of treatment, at
2 years, and at 5 years)
Every 2–4 months for 2 years, then every
6 months for 5 years, then yearly†
Every 4 months for 2 years, then every
6 months for 5 years, then yearly†
If FSS, every 4 months for 2 years, then
every 6 months for 5 years, then yearly†
Every 6 months for 5 years
Yes (at the beginning of treatment,
at 2 years, and at 5 years)

FSS=fertility sparing surgery. PRO=patient-reported outcome. *Monitoring of potential long-term toxicities (organ, endocrine, or hearing function) should be done.
†Minimum of 10 years. ‡If elevated at diagnosis. §Age-appropriate self-report questionnaires should be used to screen for psychological (late) effects.

Table 3: Follow-up strategy of sex cord-stromal tumours

Tumours that are staged higher than IA might require
chemotherapy (grade C). Surgery alone is an option in
stage IC1 granulosa cell tumours. All stages IC2 and IC3
juvenile granulosa cell tumours and all stages IC Sertoli-
Leydig cell tumours should receive adjuvant chemo­
therapy. Most patients receive three to four cycles of
cisplatin-based chemotherapy (grade C).
Management of advanced-stage disease
The decision on surgical management is to be taken
in a multidisciplinary team decision-making setting.
Chemotherapy is recommended. Most commonly used
regimens are bleomycin, etoposide, and platinum for at
least four cycles; and cisplatin, etoposide, and ifosfamide
for at least four cycles depending on response (grade D).
If cisplatin is contraindicated, carboplatin or paclitaxel
is an option (grade D). In case of incomplete initial
macroscopic resection for stage III disease and residual
disease after chemotherapy, a delayed surgical attempt
should be considered after neoadjuvant chemotherapy.
Management of refractory or recurrent disease
The need for and the type of treatment including
chemotherapy and irradiation has to be discussed in
a multidisciplinary team decision making setting.
Management of recurrent disease is dependent on the
site of recurrence, dissemination, tumour-free interval,
previous therapy, and histological subtype. Re-surgery
aiming for maximum cytoreduction is the best option for
manage­ment of recurrent disease (grade D). Additional
treatment options to be considered preferentially within
clinical trials are hormone therapy and treatment with
antiangiogenetic or targeted drugs alone or in combi­
nation (grade D).
Follow-up
Follow-up is based on clinical examination, tumour
markers, and imaging (table 3). Patients with Sertoli-
Leydig cell tumours and who have a germline DICER1
mutation should be screened for other associated
diseases, including thyroid disease (multi­nodular goitre,
thyroid carcinoma).
Small cell carcinoma of the ovary of hypercalcaemic type
Diagnosis, pathology, staging, and work-up
When the diagnosis is suspected before surgery, pre­
operative staging includes abdominal or chest CT scan,
serum CA-125, calcaemia, chromogranin-A, and neuron
specific enolase. In the absence of data, the role of
preoperative PET-CT cannot be defined. Surgery should be
done by a team trained in nodal and peritoneal debulking
surgery. The surgical approach is more extensive compared
to other histotypes, similar to epithelial ovarian cancer.
Establishing a diagnosis of small cell carcinoma of the
ovary of hypercalcaemic type might be difficult given the
wide differential diagnosis, including a variety of small
round cell tumours. Immunohistochemical protein
staining for BRG1 (SMARCA4) might be extremely useful
because over 95% of these neoplasms exhibit loss of
nuclear immunoreactivity with this marker while there is
retention of nuclear immunoreactivity in almost all
histological mimics. Dual loss of SMARCA4 (BRG1) and
SMARCA2 (BRM) expression might also be useful in
diagnosis (grade C). Because in a substantial proportion of
cases there is a germline SMARCA4 mutation present, all
females with small cell carcinoma of the ovary of hyper­
calcaemic type should undergo genetic counselling and
SMARCA4 sequencing in germline (grade C). The efficacy
of regular follow-up visits with abdominal ultrasound and
MRI for SMARCA4 mutation carriers is undetermined.
Prophylactic oophorectomy should be discussed with
healthy SMARCA4 mutation carriers. However, the
optimal age for this oophorectomy is undetermined,
because of the lack of penetrance data.
Management of early-stage disease
When the pathological diagnosis is ensured, surgical
treatment includes total abdominal hysterectomy and
bilateral salpingo-oophorectomy with peritoneal staging
and full pelvic and para-aortic lymphadenectomy also
for macroscopically stage I patients, because of poor
prognosis, the high risk of extraovarian spread, and the
loss of function of the remaining ovary after intensive
adjuvant treatment (grade D). A conservative approach
is not recommended. Adjuvant chemotherapy with

e365 www.thelancet.com/oncology Vol 21 July 2020


combinations including platinum (usually, cisplatin
and etoposide) is indicated (grade D). The inclusion of
paclitaxel in platinum combination can be considered
(grade D). Radiotherapy can be used in a multimodality
approach following chemotherapy. However, its role is
still not well defined (grade D). In patients without
evidence of disease after initial chemotherapy, dose-
intensive chemotherapy with stem cell support can be
used in a multimodality approach for consolidation
(grade D).
Management of advanced-stage disease
Removal of peritoneal disease (debulking surgery)
including omentectomy and pelvic and para-aortic
lymphadenectomy, if complete removal of the peritoneal
disease can be achieved, is recommended (as initial
surgery or after three to six cycles of chemotherapy;
grade D). Six cycles of chemotherapy with platinum or
etoposide combinations are recommended (grade D).
For patients in complete remission after initial surgery
and chemotherapy, dose-intensive regimen followed by
high-dose chemotherapy with stem cell support and
pelvic radiotherapy can be considered (grade D).
Management of refractory or recurrent disease
There is no standard treatment for patients with refractory
or recurrent disease (grade D). Clinical trials with new
drugs tailored to the biology of the tumour are strongly
recommended.
Follow-up
Oncofertility counselling should be proposed. There is
no defined follow-up strategy. Because of the aggressive
course of the disease, close follow-up is recommended in
a multidisciplinary setting according to patient condition,
status of disease, and therapeutic resources available.
Discussion
These evidence-based guidelines, developed by a group of
international experts and reviewed by a large international
panel of practising clinicians that provide care to AYAs
with non-epithelial ovarian cancers, are relevant for any
clinician dealing with a patient with these rare tumour
types and will help in clinical decision making. Optimal
diagnostic and pathological investigations and risk
stratification are essential to avoid over-treatement or
under-treatment. In these patients, any chemotherapy
might be associated with the risk of developing late
sequelae such as infertility or impairment of organ
functions, as well as the development of subsequent new
neoplasms elsewhere. The absolute risk of subsequent
new neoplasms in AYA survivors is higher than in children
and adults.11 In the largest study12 to date that includes
200 945 AYAs (aged 15–39 years at diagnosis), survivors of
cancer in England and Wales, the absolute risk of specific
subsequent primary neoplasms after each of 16 types of
AYA cancer was increased with years from diagnosis in
www.thelancet.com/oncology Vol 21 July 2020 e366
Policy Review
survivors of breast, cervical, and testicular cancer, and
Hodgkin’s disease in both sexes. Data on modalities of
treatment and intensity were not available and indications
on how to select or adapt chemotherapy and radiotherapy
regimens could not be provided. Overall, a less frequent
schedule of radiological investigations, with replacement
of CT scan by MRI or ultrasound whenever feasible, less
therapeutic interventions in favour of an active surveillance
policy in early high-risk cases, and a shorter duration of
chemotherapy, are features important in the management
of AYA patients with cancer to reduce the likelihood of
developing subsequent new neoplasms.
The different approach in the management of
malignant ovarian germ cell tumours between AYAs and
older adults is evident in the present guidelines, in
particular in yolk sac tumours stage IA and stage IC1 and
dysgerminoma stage IC1, where surveillance is the
preferred approach in selected compliant patients. For all
other stages of malignant ovarian germ cell tumours
and in all sex cord-stromal tumours but granulosa
stage IC2–3, the recommended modalities of treatment
are the same in AYAs and older adults. In granulosa
stage II, IC2–3, we recommend chemotherapy. The
manage­ ment in IC1–2 granulosa is different in both
populations. Active surveillance or adjuvant chemo­
therapy is recommended for adults and adjuvant chemo­
therapy is the sole option for juvenile subtype.13
Moderate and severe symptoms of anxiety or depres­
sion, or both, are reported in more than a quarter of AYA
patients with cancer.14–18 This age group are more prone to
various mental disorders than adult patients with cancer.
Not getting counselling needs met was observed to be
substantially associated with distress over time.19 AYAs
with cancer experience disrupted educational trajectories
and there is a need for assistance with returning to
school or work. Moreover, AYAs with cancer report
feeling isolated and missing out on important normative
social activities during their treatment. There are some
specific challenges for patients with gynaecological
cancer in adolescence and young adulthood, including
those related to psychosexual development, changes in
body image, fertility and long-term family-planning or
life-planning, building up stable intimate relationships,
and autonomy from parents or families.
The first important means of maintaining fertility in
AYAs with non-epithelial ovarian cancer is to preserve at
least one ovary (or part of one ovary in those rare cases of
bilateral disease) and the uterus at first surgery. Special
care should be taken to reduce the risk of peritoneal
adhesions that might hamper future fertility because of
tubal obstruction or distortion. By contrast to small
cell carcinoma of the ovary of hypercalcaemic type, all
malignant ovarian germ cell tumours and sex cord-
stromal tumours can generally be treated with a fertility
sparing surgical approach, thus allowing subsequent
conception. Even patients with bilateral ovarian involve­
ment or advanced malignant ovarian germ cell tumours
 Policy Review
or sex cord-stromal tumours might undergo fertility
sparing surgery, because cisplatin-based chemo­therapy
might be curative in this setting.20 If fertility sparing
surgery is used, AYAs with non-epithelial ovarian cancer
have a high probability of subsequent spontaneous
pregnancy. Data including more than 100 patients from
different series report a pregnancy rate of 75–90% after
fertility sparing surgery with or without subsequent
cisplatin-based chemotherapy.21–23
Nonetheless, the risk of chemotherapy-induced ovarian
insufficiency cannot be underestimated. Cisplatin is con­
sidered a moderately gonadotoxic agent, but a clinically
relevant association between total dose of cisplatin and
premature ovarian insufficiency has been described.22,24
The reduction of anti-Müllerian hormone and the
recovery rate after completion of chemotherapy is sub­
stantially correlated to patient age, with young patients
having a more rapid recovery of pre-chemotherapy anti-
Müllerian hormone concentrations than in patients older
than 30 years (premenopausal and outside the definition
of young adults). The mechanisms underlying ovarian
gonadotoxicity could be different in younger and older
patients, confirming the clinical observation that recovery
of ovarian function after chemotherapy is more efficient
in young women than women aged 30–40 years
(premenopausal).25
To reduce the risk of chemotherapy-induced ovarian
insufficiency, oocyte cryopreservation, ovarian tissue
cryopreservation, and pharmacological protection with
luteinising hormone-releasing hormone (LHRH) ana­
logues during chemotherapy could be considered.24
LHRH analogues might potentially have an additional
anti-tumour effect by reducing the endocrine stimul­
ation of tumour cells.26 Ovarian cryopreservation is con­
tra­indicated in patients with ovarian tumours because
of the risk of tumour cell contamination, and the only
data available for LHRH analogues protection are
for breast cancer,27 oocyte cryopreservation remains
theoretically the only possibility to preserve fertility in
patients undergoing chemotherapy. Age at diagnosis,
potential risks, and benefits of oocyte cryopreservation
and timing should be evaluated and discussed for each
individual patient. Of note, oocyte cryopreservation
cannot be proposed before surgery or chemotherapy in
the majority of patients with non-epithelial ovarian
cancer. The ovarian involvement, the rapid growth of
malignant ovarian germ cell tumours and the need
for a precise diagnosis hamper the possibility of
harvesting oocytes before surgery. In patients who are
in remission after surgery and chemotherapy, thorough
counselling regarding the possibility of earlier meno­
pause or earlier onset of infertility should be done
when appropriate. Patients should be informed that
delaying pregnancy can be associated with worse repro­
ductive outcomes and that prophylactic oocyte cryo­
preservation during follow-up could be considered even
after chemotherapy.25
e367 www.thelancet.com/oncology Vol 21 July 2020
Some subgroups of children and adolescents with
cancer—mainly those who received chemotherapy—are
more vulnerable and have a higher risk of experiencing
adverse health outcomes than their peers.28–31 Some
adverse effects can appear months after treatment, but
many develop several years after treatment completion.32,33
An additional important point is that a substantial pro­
portion of patients with non-epithelial ovarian tumours
might have developed their tumour in the context of
genetic predisposition—eg, sex chromosomal aberrations
(malignant ovarian germ cell tumours), DICER1 muta­
tions (Sertoli-Leydig cell tumours, gynandro­blastomas)
or SMARCA4 mutations (small cell carcinoma of the
ovary of hypercalcaemic type). All patients with bilateral
tumours, Sertoli-Leydig cell tumours, gynandroblastoma,
and small cell carcinoma of the ovary of hypercalcaemic
type are recommended to be referred for germline
mutation testing. The presence of these germline genetic
alterations makes these patients, as well as family
members with germline mutations, at considerable risk
of developing other disorders, which are part of the
particular predisposition syndrome. Long-term follow-up
well beyond the end of the AYA age is crucial.34,35 Studies
to identify the best psychosocial and long-term follow-up
care, including prevention and screening for early
detection of late side-effects, should be included in
clinical research programmes in AYA patients.36 Partici­
pation in clinical trials including AYAs with malignant
ovarian germ cell tumours (MOGCT), sex cord-stromal
tumours, or small cell carcinoma of the ovary of hyper­
calcaemic type is strongly encouraged. A first intergroup
phase 3 randomised trial (MAKEI V) between paediatric
oncology and gynaecological oncology to compare
cisplatin and carboplatin in patients with malignant
ovarian germ cell tumours opened at the end of 2019 for
patients aged 29 years and younger.
Contributors
The development group, which includes all authors, is collectively
responsible for the development of the guidelines, the preparation of the
manuscript, and the decision to submit for publication.
Declaration of interests
All costs relating to the development process were covered by ESGO
and SIOPE funds. There was no external funding of the development
process or manuscript production. EIB is an advisory board member
for Tesaro, Clovis, AstraZeneca, Seattle Genetics, Roche Pharma,
Incyte, and Merck Sharp & Dohme; has received personal fees from
AstraZeneca, Tesaro, Clovis, and Roche Pharma for travel expenses;
has received personal fees from Merck Sharp & Dohme (steering
committee); and grants from Roche Diagnostics, outside the submitted
work. NC is an advisory board member for Seattle Genetics and
AstraZeneca; and has recieved travel expenses from Amgen, Roche,
and Genmab, outside the submitted work. All remaining authors
declare no competing interests.
Acknowledgments
The authors thank ESGO and SIOPE. The authors also thank the
54 international reviewers for their participation (appendix p 5).
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