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\begin{document}

\title{Consensus Recommendations from EXPeRT/PARTN-ER Groups for the Diagnosis
and Therapy of Sex Cord Stromal Tumors in Children and Adolescents}



\author[1]{Dominik T. Schneider}%
\author[2]{Daniel Orbach}%
\author[3]{Tal Ben-Ami}%
\author[4]{Ewa Bien}%
\author[5]{Gianni Bisogno}%
\author[6]{Ines Brecht}%
\author[7]{Giovanni Cecchetto}%
\author[8]{Andrea Ferrari}%
\author[9]{Jan Godziński}%
\author[10]{Dragana Janic}%
\author[11]{Ricardo Lopez}%
\author[12]{Apostolos Pourtsidis}%
\author[13]{Jelena  Roganovic}%
\author[14]{Kris Ann Schultz}%
\author[15]{Teresa Stachowicz-Stencel}%
\author[16]{Brice Fresneau}%
\affil[1]{Klinikum Dortmund}%
\affil[2]{Institut Curie}%
\affil[3]{Kaplan Medical Center}%
\affil[4]{Medical University, Gdansk}%
\affil[5]{Division of Hematology/Oncology}%
\affil[6]{University of Tübingen}%
\affil[7]{Universita degli Studi di Padova Scuola di Medicina e Chirurgia}%
\affil[8]{Istituto Nazionale Tumori, Milano }%
\affil[9]{Marciniak Hospital}%
\affil[10]{University of Belgrade, University of Children's Hospital}%
\affil[11]{Cruces University Hospital}%
\affil[12]{Panagiotis and Aglaia Kyriakou Children's Hospital}%
\affil[13]{Clinical Hospital Center Rijeka}%
\affil[14]{University of Minnesota}%
\affil[15]{Medical University of Gdansk}%
\affil[16]{GUSTAVE ROUSSY}%


\vspace{-1em}



  
  \date{May 08, 2024}


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\selectlanguage{english}
\begin{abstract}
As part of the European Union-funded project designated PARTN-ER, the
European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) is
continuously developing consensus recommendations in order to harmonize
standard care for very rare solid tumors of children and adolescents.
This paper presents the internationally recognized recommendations for
the diagnosis and treatment of sex cord stromal tumors (SCST). The
clinical approach to sex cord stromal tumors of the testis (TSCST) and
ovary (OSCST) depends on histological differentiation and tumor stage.
Virtually all TSCSTs present as localized non-metastatic tumors, with
excellent prognosis after complete resection. In contrast, the prognosis
of OSCSTs may be adversely affected by tumor spillage during surgery or
presence of metastases. In these cases, cisplatin-based chemotherapy is
recommended. Of note, some SCSTs may develop in the context of tumor
predisposition syndromes e.g. DICER-1, so that specific follow-up is
indicated. SCSTs should be diagnosed and treated according to
standardized recommendations that include reference pathology, genetic
testing for tumor predisposition syndromes in selected cases, and
stratified adjuvant chemotherapy in patients with unfavorable risk
profile. To ensure high quality of diagnosis and therapy, patients
should be enrolled into prospective registries.%
\end{abstract}%



\sloppy


\textbf{Consensus Recommendations from EXPeRT/PARTN-ER Groups for the
Diagnosis and Therapy of Sex Cord Stromal Tumors in Children and
Adolescents}

Authors:

Dominik T. Schneider\textsuperscript{1}, Daniel
Orbach\textsuperscript{2}\textsubscript{,} Tal Ben
Ami\textsuperscript{3}, Ewa Bien\textsuperscript{4}, Gianni
Bisogno\textsuperscript{5}, Ines B. Brecht\textsuperscript{6}, Giovanni
Cecchetto\textsuperscript{7}, Andrea Ferrari\textsuperscript{8}, Jan
Godzinski\textsuperscript{9}, Dragana Janic\textsuperscript{10}, Ricardo
Lopez Almaraz\textsuperscript{11}, Apostolos
Pourtsidis\textsuperscript{12}, Jelena Roganovic\textsuperscript{13},
Kris Ann P. Schultz\textsuperscript{14}, Teresa
Stachowicz-Stencel\textsuperscript{4}, Brice
Fresneau\textsuperscript{15,16}

Affiliations:

\begin{enumerate}
\tightlist
\item
  Clinic of Pediatrics, Dortmund Municipal Hospital, Dortmund, Germany
\item
  SIREDO Oncology Center (Care, Innovation and Research for Children,
  Adolescents and Young Adults with cancer), Institut Curie, PSL
  University, Paris, France
\item
  Pediatric Hematology Unit, Kaplan Medical Center, Rehovot, Israel;
\item
  Department of Pediatrics, Hematology and Oncology, Medical University,
  Gdansk, Poland
\item
  Clinic of Pediatric Hematology and Oncology, University of Padova,
  Italy
\item
  Clinic of Pediatric Hematology and Oncology, University of T\selectlanguage{ngerman}übingen,
  Germany
\item
  Clinic of Pediatric Surgery, University of Padova, Italy
\item
  Istituto Tumori, Milan, Italy
\item
  Department of Pediatric Surgery, Marciniak Hospital, Wroclaw, Poland
  and Department of Pediatric Traumatology and Emergency Medicine,
  Medical University, Wroclaw, Poland
\item
  Department of Hematology and Oncology, University Children's Hospital,
  University of Belgrade, Belgrade, Serbia
\item
  Pediatric Hematology Oncology Department, Hospital Universitario de
  Cruces, Barakaldo-Bizkaia, Spain
\item
  Pediatric Oncology Unit, Aglaia Kyriakou Children's Hospital, Athens,
  Greece
\item
  Department of Pediatrics, Clinical Hospital Center Rijeka, University
  of Rijeka, Croatia
\item
  International Ovarian and Testicular Stromal Tumor Registry,, Cancer
  and Blood Disorders, Children's Minnesota, Minneapolis, MN,U.S.A.
\item
  Gustave Roussy, Université Paris-Saclay, Department of Pediatric
  Oncology, Villejuif, F-94805, France
\item
  Paris-Saclay University, Paris-Sud University
\end{enumerate}



\textbf{Correspondence to:}

Professor Dr. Dominik T. Schneider,

Klinik für Kinder- und Jugendmedizin, Beurhausstr. 40, D-44137 Dortmund,
Germany

T: +49-231-95321680;

F: +49-231-95321047;

E: dominik.schneider@klinikumdo.dedominik.schneider@klinikumdo.de

\textbf{Short running title:} Recommendations for sex cord stromal
tumors

\textbf{Key words:} rare tumors, sex cord stromal tumors, ovary, testis,
guidelines

\textbf{Conflict of interest:} All the authors have no conflicts of
interest to disclose.

\textbf{Funding source:} The PARTN-ER project (ERN-PAEDCAN Partner
Paediatric Rare Tumours Network -- European Registry) is financed and
co-funded by the Health Program of the European Union which did not take
part in the writing of these guidelines (3\textsuperscript{rd} Health
Programme Call: HP-PJ-06-2016: Rare diseases -- support for New
Registries. CHAFEA Grant Nr: 777336 --- HP-PJ-06-2016).

\textbf{Financial disclosure:} All the authors have no financial
relationships relevant to this article to disclose.\selectlanguage{english}
\begin{figure}[H]
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\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

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\textbf{Text word count} : 3051

\textbf{Abstract word count} : 188

\textbf{Number of tables} : 5

\textbf{Number of figures:} 0

\textbf{Supplemental files:} 0



\textbf{List of Abbreviations:}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
AFP & Alpha fetoprotein\tabularnewline
\midrule
\endhead
CT & Computerized tomography\tabularnewline
DHEAS & Dehydroepiandrosterone\tabularnewline
ERN PaedCan & European Reference Network for Paediatric
Cancer\tabularnewline
EXPeRT & European Cooperative Study Group for Pediatric Rare
Tumors\tabularnewline
FIGO & International Federation of Gynecology and
Obstetrics\tabularnewline
GCT & Germ Cell Tumor\tabularnewline
GrCT & Granulosa Cell Tumor\tabularnewline
FSH & Follicle Stimulating Hormone\tabularnewline
LH & Luteinizing Hormone\tabularnewline
MRI & Magnetic Resonance Imaging\tabularnewline
PARTN-ER & Paediatric Rare Tumours Network - European
Registry\tabularnewline
SLCT & Sertoli-Leydig Cell Tumor\tabularnewline
SCSTs & Sex cord stromal tumors\tabularnewline
HPLAP & Human alkaline placenta like phosphatase\tabularnewline
VRT & Very rare tumor\tabularnewline
\bottomrule
\end{longtable}

\subsection*{Abstract}

{\label{abstract}}

As part of the European Union-funded project designated PARTN-ER, the
European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) is
continuously developing consensus recommendations in order to harmonize
standard care for very rare solid tumors of children and adolescents.
This paper presents the internationally recognized recommendations for
the diagnosis and treatment of sex cord stromal tumors (SCST).

The clinical approach to sex cord stromal tumors of the testis (TSCST)
and ovary (OSCST) depends on histological differentiation and tumor
stage. Virtually all TSCSTs present as localized non-metastatic tumors,
with excellent prognosis after complete resection. In contrast, the
prognosis of OSCSTs may be adversely affected by tumor spillage during
surgery or presence of metastases. In these cases, cisplatin-based
chemotherapy is recommended. Of note, some SCSTs may develop in the
context of tumor predisposition syndromes e.g. \emph{DICER-1} , so that
specific follow-up is indicated.

SCSTs should be diagnosed and treated according to standardized
recommendations that include reference pathology, genetic testing for
tumor predisposition syndromes in selected cases, and stratified
adjuvant chemotherapy in patients with unfavorable risk profile. To
ensure high quality of diagnosis and therapy, patients should be
enrolled into prospective registries.



\section*{Introduction}

{\label{introduction}}

Sex cord stromal tumors (SCSTs) represent a heterogeneous group of rare
gonadal tumors that represent approximately 10\% of all gonadal tumors
during childhood.\textsuperscript{1} SCSTs develop from the non-germ
cell component of the gonads. Physiologically, these cells support germ
cell maturation in their microenvironment. Furthermore, they may produce
sex hormones, and so may the corresponding tumors. The rarity and
heterogeneity of SCSTs, and the difficulty in the correct
histopathologic classification leave a significant uncertainty with
regard to the optimal clinical. Of note, some subtypes are associated
with constitutional genetic aberrations (e.g. \emph{DICER1} mutations)
and thus, they may be part of an underlying cancer predisposition and
require specific follow-up.\textsuperscript{2--4}

This paper presents the internationally harmonized recommendations for
the diagnosis and treatment of children and adolescents with SCSTs,
established by the EXPeRT within the EU-funded project called PARTN-ER -
Paediatric Rare Tumours Network - European Registry. The methodology of
the process -- development under the auspices of the European Reference
Network for Paediatric Cancer (ERN PaedCan) - has been already described
(Orbach et al, PBC 2021)

\section*{Testicular Sex Cord Stromal Tumors
(TSCST)}

{\label{testicular-sex-cord-stromal-tumors-tscst}}

Patients with TSCSTs typically present with indolent intra-testicular
mass. Apart from benign disorders such as varicocele, cysts etc.,
malignant germ cell tumors (GCT) and teratomas are the most relevant
differential diagnosis.\textsuperscript{1} Beyond infancy, malignant
GCTs are almost exclusively yolk sac tumors, characterized by serum
secretion of alpha-fetoprotein (AFP). After the onset of puberty, other
histological types such as seminoma, embryonal carcinoma and
choriocarcinoma may develop, being clinically categorized into seminoma
and non-seminoma.

Most of TSCSTs present as painless testicular swelling. The only
specific clinical manifestation that distinguishes TSCSTs from other
testicular tumors of different histological origin is its hormonal
secretion. However hormonal activity is mostly observed in Leydig cell
tumors, a very rare type of pediatric SCSTs in which testosterone
secretion is responsible of isosexual precocious pseudopuberty in
prepubertal boys or gynecomastia due to aromatization of testosterone to
estradiol in Leydig cells or adipose
tissue.\textsuperscript{5}Large-cell calcifying Sertoli cell tumors are
another histological subtype of TSCSTs encountered in prepubertal boys,
teenagers and young adults, which could be revealed by endocrine signs,
in particular gynecomastia due to aromatase activity in Sertoli tumor
cells. The main other pediatric TSCST is juvenile granulosa cell tumor
(GrCT), mostly diagnosed in the first year of life as painless
testicular swelling. All these pediatric TSCSTs have a benign course
after curative total orchiectomy. A genetic susceptibility syndrome is
rare but has to be explored in cases of large-cell calcifying Sertoli
cell tumors which are associated with Peutz-Jeghers syndrome
(\emph{STK11} mutations) and Carney complex (\emph{PRKAR1A} mutations).

\subsection*{Diagnostic work-up}

{\label{diagnostic-work-up}}

\textbf{Anamnesis}

Standard anamnesis {[}Level I, Grade A{]}.

Specific query regarding tumor predisposition syndromes (e.g.
Peutz-Jeghers syndrome) {[}Level V, Grade B{]}.

\textbf{Physical examination}

Palpation of both testes, determination of pubertal stage according to
the Tanner scale {[}Level I, Grade A{]}.

Complete physical examination, focussing on abdominal palpation {[}Level
I, grade A{]}.

\textbf{Laboratory investigation}

\begin{itemize}
\tightlist
\item
  All patients: Serum AFP (correlate to age-related reference levels) to
  exclude malignant secreting yolk sac tumor {[}Level I, Grade A{]}.
\item
  Adolescents: Serum \selectlanguage{ngerman}ß-HCG and total HCG to exclude secreting GCTs
  {[}Level I, Grade A{]}.
\item
  Serum inhibin, estrogen, testosterone, DHEAS, FSH and LH in cases of
  endocrinological symptoms such as precocious puberty or gynecomastia
  {[}Level I, Grade B{]}.
\item
  Routine genetic testing for cancer predisposition in all patients is
  not recommended. However, based on family and individual history and
  exam, genetic testing of individual patients can be considered in the
  evaluation for tumor predisposition. In large cell calcifying Sertoli
  tumors, Peutz-Jeghers syndrome should be excluded. Single cases of
  pediatric testicular stromal tumors have been described in children
  with germline DICER1 pathogenic variation (one Sertoli and one Leydig
  cell tumor) (L. Golmard et al, in press) {[}Level V, Grade B{]}.
\end{itemize}

\textbf{Imaging}

\begin{itemize}
\tightlist
\item
  Ultrasound of both testes, measurement of tumor size, exclusion of
  paratesticular tumor {[}Level I, Grade A{]}.
\item
  Testicular MRI is currently used more frequently to distinguish
  between benign lesions, Leydig cell tumors, other SCSTs and GCTs
  {[}Level III, Grade C{]}.
\item
  Pelvic-abdominal ultrasound focussing on paraaortal lymph nodes in
  case of right-sided and renal lymph nodes in case of the left-sides
  tumors is recommended {[}Level II, Grade A{]}.
\item
  TSCSTs are most commonly detected as small tumors, limited to the
  testis, and they extremely rarely
  metastasize.\textsuperscript{6--8}Thus, more intensive staging is not
  recommended in case of SCSTs in prepubertal patients {[}Level IV,
  Grade A{]}.
\item
  Pelvic-abdominal MRI is recommended only if ultrasound does not allow
  assessment of the retroperitoneal lymph nodes {[}Level III, Grade
  A{]}. CT can also be used but bears the disadvantage of radiation
  exposure in children {[}Level III, Grade B{]}.
\item
  Chest X-ray can be done, however is not recommended to avoid radiation
  exposure, as lung metastases are not expected {[}Level III, grade
  D{]}. In particular, chest CT is not recommended {[}Level II, Grade
  E{]}.
\end{itemize}

\subsection*{Therapy}

{\label{therapy}}

\begin{itemize}
\tightlist
\item
  Orchiectomy after high inguinal incision and first ligation of the
  spermatic cord constitutes the gold standard and constitutes the only
  treatment for most patients {[}Level III, Grade
  A{]}.\textsuperscript{6, 7}
\item
  Considering the patient's potential wish, a testicular prosthesis can
  be inserted during the same surgical session {[}Level IV, Grade B{]}.
\item
  Considering the overall favourable prognosis, there has been some
  debate as to whether tumor excision after scrotal excision or organ
  sparing surgery (e.g. enucleation of the tumor) may also be
  appropriate. These strategies have not yet been validated
  prospectively, and it is unclear whether organ sparing surgery may
  indeed contribute to further reproductive function and increase
  quality of life {[}Level IV, Grade C{]}.\textsuperscript{9}
\item
  In case of complete but organ sparing enucleation of a testicular SCST
  with an inguinal approach, a second look surgery and orchiectomy is
  not mandatory, at least in prepubertal children with non-metastatic
  tumors {[}Level IV, Grade D{]}. Moreover, in the same group of
  patients a second look surgery in case of transscrotal surgery is not
  considered mandatory, either {[}Level IV, Grade D{]}.
\item
  Organ sparing surgery should be attempted as an individual approach in
  non-metastatic bilateral tumors {[}Level IV, Grade B{]}{]}.
\item
  Biopsy of a contralateral testis, which is not suspicious on palpation
  and/or ultrasound, is not required {[}Level IV, Grade D{]}.
\item
  Retroperitoneal lymph node dissection is recommended only in rare
  cases of suspicious lymph node spread detected by ultrasound and/or
  MRI {[}Level IV, Grade B{]}.
\item
  The extremely rare metastatic tumor should be treated according to the
  corresponding concept for metastatic OSCST {[}Level V, Grade
  B{]}.\textsuperscript{1}
\end{itemize}

\subsection*{Follow-up (FU)}

{\label{follow-up-fu}}

\begin{itemize}
\tightlist
\item
  Despite the excellent prognosis, regular follow-up is recommended at
  least for the first two years {[}Level III, Grade A{]}. As up to 5\%
  of patients may develop metachronous contralateral tumors, long-term
  follow-up may be offered, in particular in patients with suspected
  genetic predisposition (\textbf{Table I} ) {[}Level IV, Grade B{]}.
\item
  Follow-up investigations include anamnesis, physical examination and
  measurement of serum tumor markers only, if these have been elevated
  peri-operatively {[}Level IV, Grade A{]}.
\item
  Imaging follow-up includes pelvic, abdominal and scrotal ultrasound
  {[}Level IV, Grade A{]}.
\item
  Abdominal and pelvic MRI is recommended in case of equivocal findings
  on US during follow-up {[}Level IV, Grade A{]}.
\item
  Routine chest X-ray is not recommended for follow-up {[}Level IV,
  Grade E{]}.
\end{itemize}

\section*{Ovarian Sex Cord Stromal Tumors
(OSCSTs)}

{\label{ovarian-sex-cord-stromal-tumors-oscsts}}

Patients with OSCSTs characteristically present with abdominal
distension and may often suffer from abdominal discomfort and
pain\textsuperscript{1}. Hormone secreting tumors may present with signs
of precocious puberty such as breast swelling, pubic hair, vaginal
bleeding -- characteristic of estrogen-secreting GrCTs -- or
virilisation and hirsutism -- characteristic of androgen-secreting
SLCTs.\textsuperscript{8} Some patients may present with symptoms of
acute abdomen, caused by adnexal/ovarian torsion. Malignant GCTs and
small cell carcinomas of the ovary, hypercalcemic type (SMARCA4
deficient) present the two most relevant differential diagnoses of
OSCSTs. OSCSTs are different from GCTs in terms of their clinical
presentation and their biology including associated genetic tumor
predisposition syndromes.\textsuperscript{10}

OSCSTs are histologically heterogeneous and include GrCTs, SLCTs, pure
Sertoli cell and Leydig cell tumors, as well as theca and
granulosa-theca tumors, sclerosing stromal tumors, sex cord-stromal
tumors with annular tubules, and gynandroblastomas with simultaneous
Sertoli and granulosa cell differentiation. They may arise in the
context of several defined hereditary disorders. Juvenile GrCTs may be
associated with multiple enchondromatosis, syn. Ollier's
disease.\textsuperscript{11, 12} Otherwise, no pathognomonic genetic
aberration has been defined for juvenile GrCTs, but approximately one
third may show point mutations of stimulatory G
proteins.\textsuperscript{13}

SLCTs are consistently associated with mutations of the
\emph{DICER1}gene.\textsuperscript{3, 14, 15} A report from the
International Ovarian and Testicular (OTST) Registry found germline
\emph{DICER1} mutations in approximately half of patients with SLCTs
\textsuperscript{4}. In this group, a spectrum of other cancers has been
reported, of which thyroid cancer was seen in 4/25 patients. These
findings have significant impact on long-term follow-up of these
patients and the surveillance of potentially affected family members.
\textsuperscript{16}

Last, there is a pronounced association of Peutz-Jeghers syndrome with
sex cord stromal tumors with annular tubules (SCTAT) of both the testis
and ovary.\textsuperscript{12, 17} Approximately one third of SCTAT
appear to develop in the context of Peutz-Jeghers syndrome. These tumors
usually develop at a younger age than in otherwise healthy patients and
may develop bilaterally.

\subsection*{Diagnostic work-up (Table
III)}

{\label{diagnostic-work-up-table-iii}}

\textbf{Anamnesis}

\begin{itemize}
\tightlist
\item
  Standard anamnesis {[}Level I, Grade A{]}
\item
  Gynaecological and pubertal development according to Tanner scale
  {[}Level I, Grade A{]}
\item
  Query for thyroid disease such as multinodular goitre in the patient
  and her family (\emph{DICER1} syndrome) {[}Level II, Grade
  B{]}.\textsuperscript{3}
\item
  Specific query regarding tumor predisposition syndromes in the family,
  including tumors which may be associated with \emph{DICER1} pathogenic
  variation (e.g. pleuropulmonary blastoma, pineoblastoma etc.) {[}Level
  II, Grade A{]}.\textsuperscript{14}
\end{itemize}

\textbf{Physical examination}

Complete physical examination, focussing on abdominal palpation,
pubertal status, signs of virilisation and hirsutism {[}Level I, Grade
A{]}.

\textbf{Laboratory investigation}

\begin{itemize}
\tightlist
\item
  Serum AFP may be elevated in \textgreater{}10\% of SLCTs, in
  particular in retiform subtype.\textsuperscript{18} Tumor markers are
  completed by HCG/ß-HCG to exclude secreting GCT. Serum CA125 can serve
  as a sensitive ovarian tumor marker during
  follow-up.\textsuperscript{19} Elevated calcium may indicate ovarian
  small cell carcinoma, hypercalcemic type, but may occasionally be seen
  in other ovarian tumors. {[}Level II, Grade A{]}
\item
  Serum Inhibin and anti-Mullerian hormone, Estradiol, Testosterone,
  DHEAS / LH /FSH {[}Level II, Grade A{]}.
\item
  \emph{DICER1} testing should be offered to patients with SLCTs or
  gynandroblastoma -- after prior genetic counselling {[}Level II, Grade
  A{]}.\textsuperscript{20}
\item
  Testing of thyroid hormones and thyroid ultrasound in cases of SLCTs,
  suspected or proven for \emph{DICER1} mutation - at diagnosis, and at
  regular intervals (e.g. every two years) during follow-up {[}Level II,
  Grade B{]}.\textsuperscript{3}
\item
  Prior to start of chemotherapy, hepatic, hematologic and renal
  functions must be evaluated and audiometry should be performed
  {[}Level II, Grade A{]}.
\end{itemize}

\textbf{Imaging}

\begin{itemize}
\tightlist
\item
  Abdominal ultrasound focussing on the pelvis, ovaries, para-aortal
  lymph nodes (right ovarian tumor) and renal lymph nodes (left ovarian
  tumor) {[}Level II, Grade A{]}.
\item
  Abdominal and pelvic MRI {[}Level IV, Grade A{]}.
\item
  Chest X-ray or low-dose chest CT. Comment: OSCST extremely rarely
  metastasize at distant sites, almost never beyond the diaphragm. Most
  metastases occur within the abdominal cavity, leading to peritoneal
  tumor spread, or to the locoregional pelvic or retroperitoneal lymph
  nodes {[}Level IV, Grade B{]}.\textsuperscript{8, 21--23}
\end{itemize}

\textbf{Pathology and staging}

\begin{itemize}
\tightlist
\item
  Ovarian biopsy is strongly discouraged at diagnosis {[}Level III,
  grade E{]}.
\item
  Pathological assessment should include evaluation for capsule rupture,
  capsular invasion, subtyping of OSCSTs, grading (grade of immaturity
  in SLCTs), and description of prognostic histologic factors such as
  heterologous elements in SLCTs, mitotic rate in GrCTs {[}Level II,
  Grade A{]}. Pathologic samples should be evaluated by an experienced
  gyneco-/pediatric pathologist, a central reference pathologist review
  is recommended {[}Level IV, Grade A{]}.\textsuperscript{21}
\item
  \emph{FOXL2} genetic assessment could be performed in GrCTs to
  distinguish juvenile and adult types.
\item
  SCSTs should be staged according to the updated staging system of the
  International Federation of Gyneco-oncology (FIGO) for epithelial
  ovarian cancer {[}Level IV, Grade B{]} (Table II).\textsuperscript{18,
  24, 24, 25}
\end{itemize}

\subsection*{Therapy}

{\label{therapy-1}}

\textbf{Surgery}

\begin{itemize}
\tightlist
\item
  Since most tumors present as localized, stage FIGO Ia tumors,
  fertility sparing surgery, i.e. tumor resection by oophorectomy or
  adnexectomy will constitute the only therapy of these tumors {[}Level
  IV, Grade A{]}.\textsuperscript{8, 22, 23, 25}
\item
  Tumor resection with oophorectomy or adnexectomy should be the first
  surgical care {[}Level III; grade A{]}. Prior biopsy is discouraged
  {[}Level II, grade E{]}.
\item
  Median laparotomy constitutes the standard surgical approach in adults
  {[}Level II, Grade A{]}, but in children also a sub-umbilical
  transverse incision or a Pfannenstil laparotomy can be accepted
  (depending on the size of the tumor and the initial tumor spread),
  which both allow for a good tumor exposure and a better cosmetic
  result {[}Level III, Grade B{]}. In case of small tumors, laparoscopic
  resection may be performed by experienced surgeons {[}Level IV, grade
  C{]}. However, oncologic criteria must be respected also with
  minimally invasive procedures {[}Level II, grade A{]}. Tumor rupture,
  puncture or any other violation of the tumor capsule have to be
  avoided stringently {[}Level IV, Grade E{]}.\textsuperscript{26}
\item
  Staging includes cytological evaluation of ascites and/or peritoneal
  washings in absence of ascites, ideally before tumor mobilisation
  {[}Level IV, Grade B{]}.\textsuperscript{25}
\item
  Staging includes inspection and palpation of the contralateral ovary,
  inspection of the peritoneal cavity, focussing on the pelvis, pouch of
  Douglas and diaphragmatic cupola, with biopsy of any suspicious
  lesions, inspection and biopsy of any suspicious lymph nodes {[}Level
  IV, Grade B{]}.\textsuperscript{25}
\item
  Tumors confined to the ovary should be resected via ovariectomy; in
  cases of pelvic adhesion/infiltration, ipsilateral adnexectomy has to
  be performed {[}Level IV, Grade B{]}.\textsuperscript{25}
\item
  In cases of adhesions to the omentum, omentectomy is recommended;
  routine omentectomy is not required, if unsuspicious {[}Level IV,
  Grade B{]}.
\item
  In cases of bilateral tumors, ovary sparing tumor resection may be
  considered as an individual approach by an experienced surgeon and
  with appropriate equipment {[}Level V, Grade B{]}.\textsuperscript{25}
\item
  Routine retroperitoneal lymph node dissection is not recommended, if
  unsuspicious {[}Level IV, Grade B{]}.
\item
  Biopsy of an unsuspicious (in palpation and by ultrasound)
  contralateral ovary is not required {[}Level IV, Grade B{]}.
\item
  There is no role for debulking surgery (apart from palliative
  surgery). Hysterectomy as well as contralateral ovariectomy or other
  mutilating surgery should never be performed as an upfront surgery.
  Instead, inoperable tumors should be cautiously biopsied in order to
  assure the pathological diagnosis, and upfront chemotherapy should be
  initiated followed by delayed tumor resection {[}Level IV, Grade
  A{]}.\textsuperscript{25}
\end{itemize}

\textbf{Adjuvant Therapy including Chemotherapy} (Table IV)

\begin{itemize}
\tightlist
\item
  Stage IA/IB tumors do not require any adjuvant chemotherapy, in
  particular if histology shows good to intermediate differentiation; in
  selected patients with specific histologic criteria e.g. sarcomatous
  elements within SLCT, adjuvant chemotherapy can be discussed after
  individual consultation {[}Level III, Grade E{]}.\textsuperscript{1,
  8, 22, 23}
\item
  In stage IC juvenile GrCTs, chemotherapy is certainly recommended in
  case of pre-operative spontaneous tumor rupture (FIGO IC2) and/or
  malignant ascites (FIGO IC3) {[}Level IV, Grade A{]}. The indication
  for chemotherapy is disputable in stage IC1 juvenile GrCTs if
  intraoperative tumor spread occurs and appropriate surgical management
  (peritoneal washings) has been performed (FIGO Stage IC1) {[}Level IV,
  Grade C{]}.\textsuperscript{26}
\item
  Adjuvant chemotherapy is recommended in all stage IC SLCTs,
  irrespective of the time of the tumor rupture {[}Level IV, Grade
  A{]}.\textsuperscript{18}
\item
  Adjuvant chemotherapy is recommended in all tumors with locoregional
  spread or distant metastases (FIGO stage II, III, IV) {[}Level III,
  Grade A{]}.\textsuperscript{1, 8, 22, 23, 25}
\item
  In unresectable tumors, up-front chemotherapy may be considered
  followed by delayed tumor resection {[}Level IV, Grade C{]}.
\item
  All other histologic subtypes of SCSTs (different from juvenile GrCTs
  and SLCTs) rarely present beyond stage IA and rarely require adjuvant
  chemotherapy {[}Level IV, Grade D{]}.\textsuperscript{21}
\item
  Chemotherapy is chosen in analogy to GCT protocols and commonly
  includes cisplatin-based regimen (e.g. bleomycin-etoposide-cisplatin
  or etoposide-ifosfamide-cisplatin) {[}Level III, Grade A{]} (Table
  V).\textsuperscript{1, 25}
\item
  In stage IC tumors, (three to) four cycles of chemotherapy and in
  stage II, III, IV tumors four cycles of chemotherapy are recommended,
  with second look surgery in case of initial macroscopic incomplete
  resection or residual disease {[}Level IV, Grade B{]}. Some study
  groups recommend a minimum of four cycles of chemotherapy, with
  escalation to up to six cycles in metastatic tumors {[}Level IV, Grade
  C{]}.
\item
  Radiotherapy is not routinely recommended {[}Level IV, Grade E{]}
\item
  In case of insufficient response or tumor progression, therapy
  intensification can be considered on an individual basis, after
  discussion with national and international experts. Prognosis of these
  patients is poor. Therapeutic options include addition of bevacizumab,
  HIPEC (hyperthermic intraperitoneal chemotherapy with cytoreductive
  surgery), regional deep hyperthermia in combination with platin-based
  chemotherapy, high dose chemotherapy with autologous hematopoietic
  stem cell transplantation, and radiotherapy {[}Level V, Grade
  C{]}.\textsuperscript{27, 28}
\end{itemize}

\subsection*{Follow-up}

{\label{follow-up}}

\begin{itemize}
\tightlist
\item
  Regular follow-up is recommended, at least for the first five to ten
  years {[}Level IV, Grade B{]}.
\item
  As up to 10\% of patients may develop metachronous contralateral
  tumors, long-term follow-up may be offered {[}Level IV, Grade
  B{]}.\textsuperscript{16, 18}
\item
  In adult GrCTs, longer follow-up is recommended, because these tumors
  may recur after more than ten years {[}Level IV, Grade
  B{]}.\textsuperscript{12}
\item
  In \emph{DICER1} positive tumors, life long surveillance is
  recommended, because \emph{DICER1} associated tumors may develop even
  at older age {[}Level IV, Grade A{]}.\textsuperscript{16}
\item
  Follow-up investigations include anamnesis, physical examination, and
  measurement of serum tumor markers only if these have been elevated
  perioperatively {[}Level IV, Grade A{]}.
\item
  In SLCTs with \emph{DICER1} pathogenic variant, thyroid function and
  structure should be monitored with ultrasound and laboratory
  investigations (association with multinodular goitre) at diagnosis and
  then at least every two years {[}Level IV, Grade
  B{]}.\textsuperscript{3, 16}
\item
  Radiographic follow-up includes pelvic and abdominal ultrasound, in
  three-monthly intervals during the first three years after diagnosis
  and in increasing intervals thereafter {[}Level IV, Grade B{]}.
\item
  Abdominal MRI is recommended in case of equivocal findings and in
  (adolescent) patients with poor visibility on ultrasound {[}Level IV,
  Grade B{]}.
\item
  Routine chest X-ray is not recommended for follow-up {[}Level IV,
  Grade E{]}.
\end{itemize}

\section*{Open questions to be addressed in the
future}

{\label{open-questions-to-be-addressed-in-the-future}}

The standardization of diagnostic assessment, risk stratification and
therapy as well as participation in international registries will
advance the knowledge of the biology and the clinical behaviour of
SCSTs. However, due to rarity and heterogeneity of these tumors,
randomized therapeutic studies will be impossible, even at the
international level. Thus, research will have to focus on biological
studies that may reveal the genetic basis of tumor development and risk
constellations within tumor predisposition syndromes. Moreover, for
testicular SCSTs, the evaluation of surgical data may address whether
testis sparing may be feasible and safe. In contrast, the focus in
OSCSTs will remain in the optimal risk stratification in tumors with
high-risk histology and stage IC tumors. Last, effective salvage
strategies must be developed in the context of the growing genetic and
biological data on the rare cases of recurrent ovarian SCSTs, which have
a very unfavourable prognosis.

\emph{}

\subsection*{Legends:}

{\label{legends}}

\textbf{Table 1:}Histologic differentiation of testicular and ovarian
sex cord stromal tumors in children and adolescents, their relative
frequencies, characteristic age at presentation and associated genetic
aberrations\textsuperscript{1, 7, 21, 23}

\textbf{Table 2:} Staging according to the revised International
Federation of Gynecologic Oncology (FIGO)/WHO staging
system\textsuperscript{29--31}

\textbf{Table 3:} Specific diagnostic strategy in testicular or ovarian
sex cord stromal tumors (from Schneider et al, 2012\textsuperscript{1})

\textbf{Table 4:} Proposed therapeutic algorithm in testicular and
ovarian sex cord stromal tumors (from Schneider et al,
2012\textsuperscript{1})

\textbf{Table 5:} Cisplatin-based chemotherapy regimen currently in use
for the treatment of malignant germ cell tumors and sex cord stromal
tumors (from Schneider et al, 2012\textsuperscript{1})

\section*{References:}

{\label{references}}

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2. Bauer AJ, Stewart DR, Kamihara J, Harris AK, Turner J, Shah R,
Schneider KW, Schneider K, Carr AG, Harney LA, Frazier AL, Orbach D,
Schneider DT, Malkin D, Dehner LP, Messinger YH, Hill DA, Schultz KAP.
DICER1 and Associated Conditions: Identification of At-risk Individuals
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D, Arseneau J, Schultz KA, Priest JR, Nguyen VH, Harach HR, Livingston
DM, Foulkes WD, Tischkowitz M. DICER1 mutations in familial multinodular
goiter with and without ovarian Sertoli-Leydig cell tumors.\emph{JAMA}
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Young RH, Field A, Yu W, Turner J, Cost NG, Schneider DT, Stewart DR,
Frazier AL, Messinger Y, Hill DA. DICER1-related Sertoli-Leydig cell
tumor and gynandroblastoma: Clinical and genetic findings from the
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M, Boldrini R, D'Onofrio V, Ferrari A, Bernini G. Sex cord-stromal
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Hill DA. Ovarian tumors related to intronic mutations in DICER1: a
report from the international ovarian and testicular stromal tumor
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11. Clement PB, Young RH, Scully RE. Clinical syndromes associated with
tumors of the female genital tract.\emph{SeminDiagnPathol}
.1991;8:204-233.

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similarities and differences with consideration of selected
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13. Kalfa N, Ecochard A, Patte C, Duvillard P, Audran F, Pienkowski C,
Thibaud E, Brauner R, Lecointre C, Plantaz D, Guedj AM, Paris F, Baldet
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Barfoot R, Burke A, Chisholm J, Hewitt M, Jenkinson H, King D, Morland
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P, Futreal PA, Vujanic G, Nicholson AG, Sebire N, Turnbull C, Priest JR,
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N. DICER1 syndrome: clarifying the diagnosis, clinical features and
management implications of a pleiotropic tumour predisposition
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15. Whitcomb RW, Calkins JW, Lukert BP, Kyner JL, Schimke RN.
Androblastomas and thyroid disease in postmenopausal
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16. Schultz KAP, Williams GM, Kamihara J, Stewart DR, Harris AK, Bauer
AJ, Turner J, Shah R, Schneider K, Schneider KW, Carr AG, Harney LA,
Baldinger S, Frazier AL, Orbach D, Schneider DT, Malkin D, Dehner LP,
Messinger YH, Hill DA. DICER1 and Associated Conditions: Identification
of At-risk Individuals and Recommended Surveillance Strategies
.\emph{Clin Cancer Res} .2018;24:2251-2261.

17. Young RH, Welch WR, Dickersin GR, Scully RE. Ovarian sex cord tumor
with annular tubules: review of 74 cases including 27 with Peutz-Jeghers
syndrome and four with adenoma malignum of the cervix.\emph{Cancer}
.1982;50:1384-1402.

18. Schneider DT, Orbach D, Cecchetto G, Stachowicz-Stencel T, Brummel
B, Brecht IB, Bisogno G, Ferrari A, Reguerre Y, Godzinski J, Bien E,
Calaminus G, Göbel U, Patte C. Ovarian Sertoli Leydig cell tumours in
children and adolescents: an analysis of the European Cooperative Study
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19. Schneider DT, Calaminus G, Göbel U. Diagnostic value of alpha
1-fetoprotein and beta-human chorionic gonadotropin in infancy and
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20. Schultz KA, Harris A, Williams GM, Baldinger S, Doros L, Valusek P,
Frazier AL, Dehner LP, Messinger Y, Hill DA. Judicious DICER1 testing
and surveillance imaging facilitates early diagnosis and cure of
pleuropulmonary blastoma. \emph{Pediatr Blood Cancer}
.2014;61:1695-1697.

21. Schneider DT, Jänig U, Calaminus G, Göbel U, Harms D. Ovarian sex
cord-stromal tumors--a clinicopathological study of 72 cases from the
Kiel Pediatric Tumor Registry. \emph{Virchows Arch} .2003;443:549-560.

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Urban C. Long-term Remission in a Female With Multiple Relapsed Juvenile
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31. Rosendahl M, Høgdall CK, Mosgaard BJ. Restaging and Survival
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