Non-epithelial ovarian cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Authors: I. Ray-Coquard, P. Morice, D. Lorusso, J. Prat, A. Oaknin, P. Pautier, N. Colombo
Journal: Annals of Oncology (2018)

Non-epithelial ovarian tumours account for approximately 10% of all ovarian cancers. Malignant germ cell tumours (GCTs) occur mainly in young women whereas the most common type of sex cord-stromal tumours (SCSTs), i.e. granulosa cell tumour, occurs more often in middle age and in postmenopausal women [1.Gatta G. van der Zwan J.M. Casali P.G. et al.Rare cancers are not so rare: the rare cancer burden in Europe.Eur J Cancer. 2011; 47: 2493-2511http://dx.doi.org/10.1016/j.ejca.2011.08.008Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar]. Malignant GCTs represent 5% of all ovarian cancers and 80% of the preadolescent malignant ovarian tumours. SCSTs are rare neoplasms that account for approximately 3%–5% of ovarian malignancies and the majority of ovarian tumours with endocrine manifestations. The yearly-adjusted incidence rate is 3.7/1 000 000 and 2.1/1 000 000 women for GCTs and SCSTs, respectively [1.Gatta G. van der Zwan J.M. Casali P.G. et al.Rare cancers are not so rare: the rare cancer burden in Europe.Eur J Cancer. 2011; 47: 2493-2511http://dx.doi.org/10.1016/j.ejca.2011.08.008Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar]. Small cell carcinoma of the ovary (SCCO) usually affects young women and children [2.Young R.H. Oliva E. Scully R.E. Small cell carcinoma of the ovary, hypercalcemic type. A clinicopathological analysis of 150 cases.Am J Surg Pathol. 1994; 18: 1102-1116http://dx.doi.org/10.1097/00000478-199411000-00004Crossref PubMed Scopus (354) Google Scholar] with a very low incidence (less than 1% of ovarian cancers) [1.Gatta G. van der Zwan J.M. Casali P.G. et al.Rare cancers are not so rare: the rare cancer burden in Europe.Eur J Cancer. 2011; 47: 2493-2511http://dx.doi.org/10.1016/j.ejca.2011.08.008Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar]. Unlike GCTs, SCSTs and steroid cell tumours are unilateral and occur over a wide range of age; for instance, granulosa cell tumours and thecomas are found mainly in peri- and postmenopausal women, whereas juvenile granulosa cell tumours, Sertoli cell tumours and Sertoli–Leydig cell tumours (SLCTs) usually develop in adolescents and young females in whom maintenance of fertility is important [3.Prat J. Pathology of the Female Reproductive Tract.in: Mutter G.L. Prat J. Ovarian sex cord-stromal and steroid cell tumors (Chapter 28). 3. Churchill Livingstone (Elsevier, Edinburgh2014Google Scholar]. The initial symptoms and signs of non-epithelial ovarian cancers are usually a subacute pelvic pain, feeling of pelvic pressure because of a pelvic mass and menstrual irregularities. Diagnostic work-up should include pelvic ultrasound, abdomino-pelvic computed tomography (CT) scan, chest X-ray and positron emission tomography (PET) scan in selected cases (GCTs) [III, B]. In young patients, serum human chorionic gonadotropin (hCG), alpha-foetoprotein (α-FP) and lactate dehydrogenase (LDH) levels, full blood count and liver and renal function tests should be carried out. Inhibin B is secreted by granulosa cell tumours and could be a useful marker for the disease. Serum anti-Müllerian hormone (AMH) may be a marker of ovarian reserve and granulosa cell tumours in postmenopausal or post-oophorectomy women [4.Lane A.H. Lee M.M. Fuller Jr, A.F. et al.Diagnostic utility of Müllerian inhibiting substance determination in patients with primary and recurrent granulosa cell tumors.Gynecol Oncol. 1999; 73: 51-55http://dx.doi.org/10.1006/gyno.1998.5290Abstract Full Text PDF PubMed Scopus (74) Google Scholar]. While these markers are nonspecific, they can provide prognostic information, so quantitative hCG, α-FP, LDH and cancer antigen 125 (CA 125) should be measured preoperatively [5.Gershenson D.M. Current advances in the management of malignant germ cell and sex cord-stromal tumors of the ovary.Gynecol Oncol. 2012; 125: 515-517http://dx.doi.org/10.1016/j.ygyno.2012.03.019Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar]. If gonadoblastoma is suspected, a preoperative karyotype should be obtained on all premenarche girls because of the propensity of these tumours to arise in dysgenetic gonads. Most non-epithelial ovarian tumours arise from cells specific to the ovary (germ cells, granulosa cells, theca cells, stromal fibroblasts and steroid cells); other less common gonadal tumours arise from non-specific ovarian cells (mesenchymal cells). The World Health Organization (WHO) classification of GCTs is presented in Table 1 [6.Prat J. Cao D. Carinelli S. et al.WHO Classification of Tumours of Female Reproductive Organs.in: Kurman R.J. Carcangiu M.L. Herrington C.S. Young R.H. Teratoma (Chapter 1: Tumours of the ovary). 4. Lyon, IARC2014: 57-62Google Scholar, 7.Prat J. Cao D. Carinelli S. et al.WHO Classification of Tumours of Female Reproductive Organs.in: Kurman R.J. Carcangiu M.L. Herrington C.S. Young R.H. Monodermal teratomas and somatic-type tumours arising from a dermoid cyst (Chapter 1: Tumours of the ovary). 4. Lyon, IARC2014: 63-66Google Scholar]. GCTs recapitulate steps of development, from undifferentiated germ cells to adult tissues. Primitive GCTs composed of undifferentiated germ cells and GCTs with extraembryonic differentiation are all malignant. Teratomas are the most common GCTs; most are composed of mature tissues and are benign (dermoid cysts). In immature teratomas, embryonic tissues indicate the malignant potential and grading is prognostically relevant [7.Prat J. Cao D. Carinelli S. et al.WHO Classification of Tumours of Female Reproductive Organs.in: Kurman R.J. Carcangiu M.L. Herrington C.S. Young R.H. Monodermal teratomas and somatic-type tumours arising from a dermoid cyst (Chapter 1: Tumours of the ovary). 4. Lyon, IARC2014: 63-66Google Scholar]. Grade 1 tumours show rare foci of immature neuroepithelial tissue that occupy < 1 low power field (40×) in any slide (low grade); grade 2 tumours show similar elements, occupying 1–3 low power fields (40×) in any slide (high grade); grade 3 tumours exhibit large amounts of immature neuroepithelial tissue occupying > 3 low power fields (40×) in any slide (high grade). A two-tiered (low and high grades) system is now more commonly used [8.O'Connor D.M. Norris H.J. The influence of grade on the outcome of stage I ovarian immature (malignant) teratomas and the reproducibility of grading.Int J Gynecol Pathol. 1994; 13: 283-289Crossref PubMed Scopus (128) Google Scholar]. Other rare malignant GCTs constitute a heterogeneous group including somatic cancers arising in dermoids and monodermal teratomas [7.Prat J. Cao D. Carinelli S. et al.WHO Classification of Tumours of Female Reproductive Organs.in: Kurman R.J. Carcangiu M.L. Herrington C.S. Young R.H. Monodermal teratomas and somatic-type tumours arising from a dermoid cyst (Chapter 1: Tumours of the ovary). 4. Lyon, IARC2014: 63-66Google Scholar]. In the elderly, non-dysgerminoma GCTs arise from epithelial ovarian cancer, usually endometrioid and clear cell carcinomas. Primitive GCTs and immature teratomas are chemosensitive and susceptible to fertility-sparing surgery. Because of their chemosensitivity and the increasing adoption of fertility-sparing surgery, correct pathological diagnosis is essential and these cases should be examined by gynaecological pathologists [V, B]. Diagnosis can be made on conventional histological material; given the multiplicity of morphological features, immunohistochemical markers (Table 2) and chromosome 12p fluorescent in situ hybridisation (FISH) can be used to confirm the diagnosis in difficult cases. SALL4 and OCT4 are widely used; more recently, it has been recognised that SOX2 is expressed in embryonal carcinoma and primitive neuroectodermal tumours of teratomatous origin.Table 1WHO 2014 classification of GCTs [6.Prat J. Cao D. Carinelli S. et al.WHO Classification of Tumours of Female Reproductive Organs.in: Kurman R.J. Carcangiu M.L. Herrington C.S. Young R.H. Teratoma (Chapter 1: Tumours of the ovary). 4. Lyon, IARC2014: 57-62Google Scholar]DysgerminomaYolk sac tumourEmbryonal carcinomaNon-gestational choriocarcinomaMature teratomaImmature teratoma Mixed germ cell tumourGCT, germ cell tumour; WHO, World Health Organization. Open table in a new tab Table 2Immunohistochemistry of primitive GCTsSall4OCT3/4SOX2Dys++–YST+––EC+++Dys, dysgerminoma; EC, embryonal carcinoma; GCT, germ cell tumour; YST, yolk sac tumour. Open table in a new tab GCT, germ cell tumour; WHO, World Health Organization. Dys, dysgerminoma; EC, embryonal carcinoma; GCT, germ cell tumour; YST, yolk sac tumour. SCSTs and steroid cell tumours constitute a heterogeneous group of tumours (Table 3) and vary in their capacity to produce clinically significant amounts of steroid hormones. Granulosa cell tumours are typically oestrogenic and may be associated with various clinical syndromes, depending upon the age of the patient. SLCTs typically produce androgens, and clinical virilisation is observed in 70%–85% of patients. Those with sex cord elements may be malignant, with granulosa cell tumours being the most frequent histological type. Neoplasms of pure ovarian stroma are mostly benign, with > 50% of them being fibromas. In morphologically ambiguous cases, an immunopanel of inhibin alpha, calretinin and FOXL2, together with FOXL2 (402C-G) mutational analysis, is useful to confirm the diagnosis of adult granulosa cell tumours (AGCTs) [V, B] [9.Al-Agha O.M. Huwait H.F. Chow C. et al.FOXL2 is a sensitive and specific marker for sex cord-stromal tumors of the ovary.Am J Surg Pathol. 2011; 35: 484-494http://dx.doi.org/10.1097/PAS.0b013e31820a406cCrossref PubMed Scopus (132) Google Scholar]. Chang et al. demonstrated that another molecule involved in the tumourigenesis of AGCTs is activin A [10.Chang H.M. Cheng J.C. Taylor E. Leung P.C. Oocyte-derived BMP15 but not GDF9 down-regulates connexin43 expression and decreases gap junction intercellular communication activity in immortalized human granulosa cells.Mol Hum Reprod. 2014; 20: 373-383http://dx.doi.org/10.1093/molehr/gau001Crossref PubMed Scopus (58) Google Scholar]. A subset of SCSTs is typically negative for FOXL2 on immunostaining (retiform or poorly differentiated SLCT), but these tumours usually express inhibin alpha and/or calretinin. Another recent finding has been the occurrence of DICER1 mutations in SCST [V, C].Table 3WHO 2014 classification of SCSTs and steroid cell tumours [7.Prat J. Cao D. Carinelli S. et al.WHO Classification of Tumours of Female Reproductive Organs.in: Kurman R.J. Carcangiu M.L. Herrington C.S. Young R.H. Monodermal teratomas and somatic-type tumours arising from a dermoid cyst (Chapter 1: Tumours of the ovary). 4. Lyon, IARC2014: 63-66Google Scholar]Pure stromal tumoursFibroma Cellular fibroma ThecomaLuteinized thecoma associated with sclerosing peritonisisFibrosarcomaSclerosing stromal tumourSignet-ring stromal tumourMicrocystic stromal tumourLeydig cell tumourSteroid cell tumourSteroid cell tumour, malignantPure sex cord tumoursAdult granulosa cell tumourJuvenile granulosa cell tumourSertoli cell tumoursSex cord tumour with annular tubulesMixed sex cord-stromal tumoursSertoli–Leydig cell tumoursWell differentiatedModerately differentiatedWith heterologous elementsPoorly differentiatedWith heterologous elementsRetiformWith heterologous elementsSex cord-stromal tumours, NOSNOS, not otherwise specified; SCST, sex cord-stromal tumour; WHO, World Health Organization. Open table in a new tab NOS, not otherwise specified; SCST, sex cord-stromal tumour; WHO, World Health Organization. Small cell carcinomas of the ovary hypercalcaemic type (SCCOHTs) are the most common form of ovarian undifferentiated carcinomas in women < 40 years old and the most common ovarian tumour associated with hypercalcaemia (70%). This tumour is typically unilateral and should be distinguished from primitive GCTs and granulosa cell tumours (mainly juvenile). Although its histogenesis is unknown, recent reports suggest that it may represent an ovarian malignant rhabdoid tumour [11.Foulkes W.D. Clarke B.A. Hasselblatt M. et al.No small surprise—small cell carcinoma of the ovary, hypercalcaemic type, is a malignant rhabdoid tumour.J Pathol. 2014; 233: 209-214Crossref PubMed Scopus (106) Google Scholar]. Recent studies have identified mutations in the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodelling gene, SMARCA4 encoding BRG1. These mutations represent a frequent event occurring in 76%–100% of SCCOHTs [12.Jelinic P. Mueller J.J. Olvera N. et al.Recurrent SMARCA4 mutations in small cell carcinoma of the ovary.Nat Genet. 2014; 46: 424-426http://dx.doi.org/10.1038/ng.2922Crossref PubMed Scopus (233) Google Scholar, 13.Ramos P. Karnezis A.N. Craig D.W. et al.Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4.Nat Genet. 2014; 46: 427-429http://dx.doi.org/10.1038/ng.2928Crossref PubMed Scopus (228) Google Scholar, 14.Karnezis A.N. Wang Y. Ramos P. et al.Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type.J Pathol. 2016; 238: 389-400http://dx.doi.org/10.1002/path.4633Crossref PubMed Scopus (128) Google Scholar]. Germline mutations in SMARCA4 or SMARCB1 were already known to predispose to the development of paediatric tumours, namely atypical teratoid/rhabdoid tumours [15.Hasselblatt M. Gesk S. Oyen F. et al.Nonsense mutation and inactivation of SMARCA4 (BRG1) in an atypical teratoid/rhabdoid tumor showing retained SMARCB1 (INI1) expression.Am J Surg Pathol. 2011; 35: 933-935http://dx.doi.org/10.1097/PAS.0b013e3182196a39Crossref PubMed Scopus (174) Google Scholar, 16.Schneppenheim R. Frühwald M.C. Gesk S. et al.Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome.Am J Hum Genet. 2010; 86: 279-284Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar]. SMARCA4 immunohistochemistry is highly sensitive and specific for a diagnosis of SCCOHT [loss of SMARCA4 (BRG1) protein expression] and is now useful in the differential diagnosis of poorly differentiated ovarian tumours [17.Karanian-Philippe M. Velasco V. Longy M. et al.SMARCA4 (BRG1) loss of expression is a useful marker for the diagnosis of ovarian small cell carcinoma of the hypercalcemic type (ovarian rhabdoid tumor): a comprehensive analysis of 116 rare gynecologic tumors, 9 soft tissue tumors, and 9 melanomas.Am J Surg Pathol. 2015; 39: 1197-1205http://dx.doi.org/10.1097/PAS.0000000000000475Crossref PubMed Scopus (64) Google Scholar]. SCCOHTs usually react diffusely for WT1, making the interpretation difficult. Differential diagnosis includes juvenile or adult granulosa tumours, metastatic melanoma, dysgerminoma, Ewing tumour and undifferentiated carcinoma. The staging system for non-epithelial ovarian cancers is generally adopted from the one for epithelial ovarian cancer originally defined by the International Federation of Gynecology and Obstetrics (FIGO) (Table 4) [18.Prat J. FIGO Committee on Gynecologic Oncology. Staging classification for cancer of the ovary, fallopian tube, and peritoneum.Int J Gynaecol Obstet. 2014; 124: 1-5Crossref PubMed Scopus (847) Google Scholar]. Outcomes appear to be superior when patients are treated in a large cancer centre, likely due to the rare nature and infrequent presentation of these cancers [19.Solheim O. Kærn J. Tropé C.G. et al.Malignant ovarian germ cell tumors: presentation, survival and second cancer in a population based Norwegian cohort (1953-2009).Gynecol Oncol. 2013; 131: 330-335Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar].Table 42014 FIGO ovarian cancer staging system and corresponding TNMTNM stagingFIGO stagingDescriptionT1a-N0-M0Stage IATumour limited to one ovary (capsule intact), no tumour on ovarian surface; no malignant cells in ascites or peritoneal washings; no regional lymph node metastasis; no distant metastasisT1b-N0-M0Stage IBTumour limited to both ovaries (capsules intact), no tumour on ovarian surface; no malignant cells in ascites or peritoneal washings; no regional lymph node metastasis; no distant metastasisT1c-N0-M0Stage IC1Tumour limited to one or both ovaries with capsule ruptured (surgical spill); no regional lymph node metastasis; no distant metastasisT1c-N0-M0Stage IC2Tumour limited to one or both ovaries with capsule ruptured before surgery or tumour on ovarian surface; no regional lymph node metastasis; no distant metastasisT1c-N0-M0Stage IC3Tumour limited to one or both ovaries with malignant cells in ascites or peritoneal washings; no regional lymph node metastasis; no distant metastasisT2a-N0-M0Stage IIAExtension and/or implants on the uterus and/or tube(s); no malignant cells in ascites or peritoneal washings; no regional lymph node metastasis; no distant metastasisT2b-N0-M0Stage IIBExtension to and/or implants in other pelvic tissues; no malignant cells in ascites or peritoneal washings; no regional lymph node metastasis; no distant metastasisT1/T2-N1-M0Stage IIIA1Stage IIIA1 (i)Stage IIIA1 (ii)Tumour limited to the ovaries (one or both) (T1) or tumour involves one or both ovaries with pelvic extension (T2); regional lymph node metastasis; no distant metastasisMetastasis up to 10 mm in greatest dimensionMetastasis more than 10 mm in greatest dimensionT3a-N0/N1-M0Stage IIIA2Microscopic peritoneal metastasis beyond the pelvis (no macroscopic tumour); no regional lymph node metastasis (N0) or regional lymph node metastasis (N1); no distant metastasisT3b-N0/N1-M0Stage IIIBMacroscopic peritoneal metastasis beyond the pelvis up to 2 cm in greatest dimension; no regional lymph node metastasis (N0) or regional lymph node metastasis (N1); no distant metastasisT3c-N0/N1-M0Stage IIICMacroscopic peritoneal metastasis beyond the pelvis > 2 cm in greatest dimension and/or regional lymph node metastasis; no regional lymph node metastasis (N0) or regional lymph node metastasis (N1); no distant metastasisany T-any N-M1Stage IVAPleural effusion with positive cytologyany T-any N-M1Stage IVBParenchymal metastases and metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside of the abdominal cavity)FIGO, International Federation of Gynecology and Obstetrics; TNM, tumour, node, metastasis.Modified from [22.Reed N.S. Pautier P. Avall-Lundqvist E. et al.Gynecologic Cancer InterGroup (GCIG)consensus review for ovarian small cell cancers.Int J Gynecol Cancer. 2014; 24: S30-S34http://dx.doi.org/10.1016/j.ijgo.2013.10.001Crossref PubMed Scopus (32) Google Scholar] and [57.Champion V. Williams S.D. Miller A. et al.Quality of life in long-term survivors of ovarian germ cell tumors: a Gynecologic Oncology Group study.Gynecol Oncol. 2007; 105: 687-694http://dx.doi.org/10.1016/j.ygyno.2007.01.042Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. Open table in a new tab FIGO, International Federation of Gynecology and Obstetrics; TNM, tumour, node, metastasis. Modified from [22.Reed N.S. Pautier P. Avall-Lundqvist E. et al.Gynecologic Cancer InterGroup (GCIG)consensus review for ovarian small cell cancers.Int J Gynecol Cancer. 2014; 24: S30-S34http://dx.doi.org/10.1016/j.ijgo.2013.10.001Crossref PubMed Scopus (32) Google Scholar] and [57.Champion V. Williams S.D. Miller A. et al.Quality of life in long-term survivors of ovarian germ cell tumors: a Gynecologic Oncology Group study.Gynecol Oncol. 2007; 105: 687-694http://dx.doi.org/10.1016/j.ygyno.2007.01.042Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. Outcomes may depend on the age at diagnosis. Premenarche girls and women > 45 years who develop GCTs may have different tumour biology and a worse prognosis than postadolescent females in the reproductive years. Patients with testicular cancer are stratified as having good, intermediate or high risk for recurrence based on clinical, pathological and serological markers. Compared with testicular cancer, clinical prognosticators are less well defined for ovarian GCTs. Adverse factors include age > 45 years, stage > I, incomplete surgical resection and yolk sac tumour (YST) histology [20.Mangili G. Sigismondi C. Gadducci A. et al.Outcome and risk factors for recurrence in malignant ovarian germ cell tumors: a MITO-9 retrospective study.Int J Gynecol Cancer. 2011; 21: 1414-1421http://dx.doi.org/10.1097/IGC.0b013e3182236582Crossref PubMed Scopus (80) Google Scholar, 21.de la Motte Rouge T. Pautier P. Genestie C. et al.Prognostic significance of an early decline in serum alpha-fetoprotein during chemotherapy for ovarian yolk sac tumors.Gynecol Oncol. 2016; 142: 452-457http://dx.doi.org/10.1016/j.ygyno.2016.07.005Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar]. Stage is also an important prognostic factor for SCSTs, although advanced-stage diseases can also have a good prognosis because of their sensitivity to chemotherapy (ChT). The FIGO stage [18.Prat J. FIGO Committee on Gynecologic Oncology. Staging classification for cancer of the ovary, fallopian tube, and peritoneum.Int J Gynaecol Obstet. 2014; 124: 1-5Crossref PubMed Scopus (847) Google Scholar] and the intraperitoneal tumour rupture are the most often reported prognostic factors. Patient age (> 50 years) and the size of the tumour (> 5 cm) have a less certain prognostic value [5.Gershenson D.M. Current advances in the management of malignant germ cell and sex cord-stromal tumors of the ovary.Gynecol Oncol. 2012; 125: 515-517http://dx.doi.org/10.1016/j.ygyno.2012.03.019Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar]. The majority of these tumours can be cured, but around 20% relapse or give rise to metastases that can be fatal [III, A]. Prognosis of SCCOHT is poor with only 30%–40% long-term survivors with standard treatment [2.Young R.H. Oliva E. Scully R.E. Small cell carcinoma of the ovary, hypercalcemic type. A clinicopathological analysis of 150 cases.Am J Surg Pathol. 1994; 18: 1102-1116http://dx.doi.org/10.1097/00000478-199411000-00004Crossref PubMed Scopus (354) Google Scholar]. Potential favourable prognostic factors, in addition to disease stage (stage IA versus others) are: age > 30 years; normal pre-operative calcium level; a tumour size < 10 cm; the absence of large cells; and complete surgical resection including bilateral oophorectomy [22.Reed N.S. Pautier P. Avall-Lundqvist E. et al.Gynecologic Cancer InterGroup (GCIG)consensus review for ovarian small cell cancers.Int J Gynecol Cancer. 2014; 24: S30-S34http://dx.doi.org/10.1016/j.ijgo.2013.10.001Crossref PubMed Scopus (32) Google Scholar, 23.Bristow R.E. Tomacruz R.S. Armstrong D.K. et al.Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis.J Clin Oncol. 2002; 20: 1248-1259http://dx.doi.org/10.1200/JCO.2002.20.5.1248Crossref PubMed Scopus (1960) Google Scholar]. A surgical approach can be carried out through open route or, in selected cases, by minimally invasive approaches—laparoscopy and robotics—to avoid tumour rupture during surgery. A careful examination of the abdominal cavity is required. The staging procedure includes infracolic omentectomy, biopsy of the diaphragmatic peritoneum, paracolic gutters, pelvic peritoneum and peritoneal washings in macroscopic stage I disease. There is no consensus about the role of systematic lymphadenectomy, but the omission of staging peritoneal procedures seems to increase the recurrence rate [24.Mangili G. Sigismondi C. Lorusso D. et al.The role of staging and adjuvant chemotherapy in stage I malignant ovarian germ cell tumors (MOGTs): the MITO-9 study.Ann Oncol. 2017; 28: 333-338Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar], though without impact on overall survival [25.Billmire D. Vinocur C. Rescorla F. et al.Outcome and staging evaluation in malignant germ cell tumors of the ovary in children and adolescents: an Intergroup study.J Pediatr Surg. 2004; 39: 424-429http://dx.doi.org/10.1016/j.jpedsurg.2003.11.027Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar]. GCTs, particularly dysgerminoma, have a high risk of nodal spread. On the other hand, given the very high chemosensitivity of such tumours, potential nodal metastasis should be cured by adjuvant ChT in these patients [III, A]. Thus, nodal debulking surgery is only required in rare cases of residual disease after ChT. In early-stage disease that does not require adjuvant ChT because of favourable prognostic factors, nodal dissection should be carried out only where there is evidence of nodal abnormalities during surgical exploration and/or initial CT scan (lymphadenopathy) [III, A]. Patients not undergoing initial nodal staging surgery can be safely cured with ChT at the time of the potential nodal recurrence [26.Matei D. Brown J. Frazier L. Updates in the management of ovarian germ cell tumors.Am Soc Clin Oncol Educ Book. 2013; : e210Crossref Google Scholar]. Unilateral salpingo-oophorectomy with preservation of the contralateral ovary and the uterus is now considered as the standard surgical treatment for young patients with GCTs [III, A]. This conservative management should be considered even in the case of advanced disease because of the sensitivity of the tumour to ChT [IV, B] [27.Low J.J. Perrin L.C. Crandon A.J. Hacker N.F. Conservative surgery to preserve ovarian function in patients with malignant ovarian germ cell tumors. A review of 74 cases.Cancer. 2000; 89: 391-398Crossref PubMed Scopus (195) Google Scholar]. Systematic ovarian biopsy is not necessary when the contralateral ovary is macroscopically normal [III, A]. In case of macroscopic bilateral ovarian diseases (particularly dysgerminoma or immature teratoma), preservation of at least a healthy part of one ovary (unilateral salpingo-oophorectomy and contralateral cystectomy) and the uterus should be encouraged [IV, B] [28.Brown J. Friedlander M. Backes F.J. et al.Gynecologic Cancer Intergroup (GCIG) consensus review for ovarian germ cell tumors.Int J Gynecol Cancer. 2014; 24: S48-S54Crossref PubMed Scopus (87) Google Scholar]. In postmenopausal women and in patients with advanced-stage disease or with bilateral ovarian involvement, abdominal hysterectomy and bilateral salpingo-oophorectomy could be carried out with careful surgical staging [III, A]. The place of conservative treatment in child-bearing age patients affected by SCSTs is somewhat different. Preservation of the uterus and contralateral ovary seems to be safe in macroscopic stage IA disease but should not be carried out in stages > I. Conservative surgery is also an acceptable approach in young patients with stage I SCSTs [IV, B]. In the case of juvenile granulosa cell tumours, the safety of this management approach in stage IC disease remains controversial, particularly in stage IC2 or IC3 disease [V, C]. In case of conservative treatment, an endometrial curettage (or hysterectomy in case of radical management) must be carried out to rule out concomitant uterine cancers in patients with granulosa cell tumour [IV, B]. For SCSTs, retroperitoneal evaluation is not mandatory because of the very low incidence of retroperitoneal metastases in early-stage disease [III, A]. Recent publications on incidence of lymph node metastases in SCST support the position that lymphadenectomy is not needed in these patients [29.Nasioudis D. Kanninen T.T. Holcomb K. et al.Prevalence of lymph node metastasis and prognostic significance of lymphadenectomy in apparent early-stage malignant ovarian sex cord-stromal tumors.Gynecol Oncol. 2017; 145: 243-247http://dx.doi.org/10.1016/j.ygyno.2017.03.005Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar]. SLCTs frequently have low-grade malignancy, although occasionally a retiform or poorly differentiated (sarcomatoid) form may be malignant. In postmenopausal women and in patients with advanced-stage disease or with bilateral ovarian involvement, abdominal hysterectomy and bilateral salpingo-oophorectomy should be carried out with careful surgical staging for SCST [III, A]. The prognosis of SCCOHT is very poor and the risk of extra-ovarian spread high. All suspected cases should benefit from a review by an expert pathologist and be discussed in a specialised tumour board [V, A]. Efforts should be made to treat patients in a more homogeneous way through national and international networks [V, A]. Conventional surgical treatment includes radical surgery (bilateral salpingo-oophorectomy and hysterectomy) combined with peritoneal and nodal staging surgery, even for macroscopically stage I disease [IV, A] [2.Young R.H. Oliva E. Scully R.E. Small cell carcinoma of the ovary, hypercalcemic type. A clinicopathological analysis of 150 cases.Am J Surg Pathol. 1994; 18: 1102-1116http://dx.doi.org/10.1097/00000478-199411000-00004Crossref PubMed Scopus (354) Google Scholar]. The largest series to date reported a decline in survival in patients treated conservatively [2.Young R.H. Oliva E. Scully R.E. Small cell carcinoma of the ovary, hypercalcemic type. A clinicopathological analysis of 150 cases.Am J Surg Pathol. 1994; 18: 1102-1116http://dx.doi.org/10.1097/00000478-199411000-00004Crossref PubMed Scopus (354) Google Scholar]. As a result of the adjuvant treatment after surgery combining high-dose ChT (HDCT) and radiotherapy (RT), the potential preservation of gonadal function is considered to be only conceptual even if one ovary and the uterus are preserved [2.Young R.H. Oliva E. Scully R.E. Sm