Christian Marth, MD, PhD Department of Obstetrics and Gynecology Innsbruck Medical University Innsbruck, Austria
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1 Christian Marth, MD, PhD Department of Obstetrics and Gynecology Innsbruck Medical University Innsbruck, Austria
2 Classification of Ovarian Neoplasms Origin Surface Epithelial Cells Germ Cells Sex Cord Stroma Metastasis to Ovaries Frequency 65%-70% 15%-20% 5%-10% 5% Proportion of malignant ovarian tumors 90% 3%-5% 2%-3% 5% Age group affected All ages Variable
3 Sex Cord-Stromal Tumors - Pure sex cord tumors Adult granulosa cell tumor Juvenile granulosa cell tumor Sertoli cell tumors (benign) Sex cord with anular tubules - Pure stromal tumors Fibroma, thecoma, Leydig cell tumor, steroid cell tumor Mixed Sex Cord Stromal Tumors - Sertoli Leydig cell tumors Well/moderately/poorly differentiated/retiform w/o heterologous elements - Sex cord stromal tumors NOS WHO Classification of Ovarian Neoplasms Surface Epithelial Tumors Serous tumors Mucinous tumors Endometrioid tumors Clear cell tumors Brenner tumors Epithelial-stromal Germ Cell Tumors Dysgerminoma Yolk sac tumor Embryonal carcinoma Nongestational choriocarcinoma Mature teratoma Immature teratoma Mixed germ cell tumors Monodermal teratoma and somatic-type tumors arising from a dermoid cyst WHO, World Health Organization Kurman RJ, et al. WHO Classification of Tumours of Female Reproductive Organs, Fouth Edition/IARC WHO Classification of Tumours. Geneva: World Health Organization; 2014.
4 Sex Cord-Stromal Tumors - Pure sex cord tumors Adult granulosa cell tumor Juvenile granulosa cell tumor Sertoli cell tumors (benign) Sex cord with anular tubules - Pure stromal tumors Fibroma, thecoma, Leydig cell tumor, steroid cell tumor Mixed Sex Cord Stromal Tumors - Sertoli Leydig cell tumors Well/moderately/poorly differentiated/retiform w/o heterologous elements - Sex cord stromal tumors NOS WHO Classification of Ovarian Neoplasms Surface Epithelial Tumors Serous tumors Mucinous tumors Endometrioid tumors Clear cell tumors Brenner tumors Epithelial-stromal Germ Cell Tumors Dysgerminoma Yolk sac tumor Embryonal carcinoma Nongestational choriocarcinoma Mature teratoma Immature teratoma Mixed germ cell tumors Monodermal teratoma and somatic-type tumors arising from a dermoid cyst Kurman RJ, et al. WHO Classification of Tumours of Female Reproductive Organs, Fouth Edition/IARC WHO Classification of Tumours. Geneva: World Health Organization; 2014.
5 Sex Cord Stromal Tumors 5%-10% of all ovarian cancer & peak age 50 years Morphologically intriguing with inherent great variations hampering the diagnosis: Expert pathologist review Endocrine manifestations (estrogen secretion 70%) Endometrial hyperplasia (25%) or endometrial carcinoma (5%-10%) Recent findings on mutated genes : FOXL2 for adult granulosa and DICER1 for juvenile granulosa & Sertoli Leydig
6 70% of Sex Cord Stromal Tumors Endocrine manifestations: Granulosa Cell Tumors Childhood: Isosexual precocious pseudo puberty Reproductive age: Menstrual irregularities/secondary amenorrhea, infertility, rarely virilization Post-menopausal: Abnormal vaginal bleeding Endometrial hyperplasia 25% Endometrial adenocarcinoma 5%-10%
7 Granulosa Cell Tumors: Prognostic Factors FIGO Stage: DFS at five years 95% (I-II) vs 59% (III-IV) Age (more than 50 years old) DFS at five years 93% (<50 years) vs 84% (>50 years) Intra-peritoneal tumor rupture For juvenile granulosa cell tumor (JGCT), stage is the major prognostic factor DFS, disease-free survival; FIGO, International Federation of Gynecology and Obstetrics Zhang M, et al. Gynecol Oncol. 2007;104(2): Schneider BP, et al. J Clin Oncol. 2004;22(7):
8 FOXL2: Fork Head Box Protein L2 Is a marker for ovarian differentiation, and is required for granulosa cell differentiation It will prevent the formation of testes by suppressing expression of SOX9 Females missing the FOXL2 gene (germline mutation) appear male. FOXL2 knockout in mature mouse ovaries cause them to develop into testes; however, oocytes are still formed A missense mutation in the FOXL2 gene C134W is found exclusively in adult granulosa cell tumors, but not in other ovarian cancers nor in JGCT
9 Molecularly Defined Adult Granulosa Cell Tumor of the Ovary: The Clinical Phenotype in a Series of 336 Patients Histopathologic features of AGCTs are relatively nonspecific, resulting in misdiagnosis of other cancers as AGCT FOXL2-mutant molecularly-defined AGCT (MD-AGCT) 76% FOXL2 wildtype (wt) AGCT 5% Misdiagnosed other tumor types 19% 94% AGCT FOXL2-mutant OS and DFS of the misdiagnosed cases was lower than in the MD-AGCTs (P<.001) and accounted for 72% of disease-specific deaths within five years OS of MD-AGCTs was not different from population-based controls AGCT, adult granulosa cell tumor; OS, overall sruvival McConechy MK, et al. J Natl Cancer Inst. 2016;108(11): djw134.
10 Survival Curves of Patients With MD-AGCT, AGCT FOXL2 WT, and Misdiagnosed Other Tumor Types OS DSS OS After the First Recurrence DSS, disease-specific survival McConechy MK, et al. J Natl Cancer Inst. 2016;108(11): djw134.
11 Recommended Diagnostic Algorithm for Accurate Diagnosis of AGCT morphological mimics/ differential diagnosis AGCT diagnosis/differential diagnosis classic AGCT FOXL2 IHC Diagnosis confirmed by expert pathologist review positive negative no/not available yes FOXL2 mutation testing positive negative Not AGCT consider other diagnosis including metastasis AGCT FOXL2 mutation testing positive negative MD-AGCT Other sex cord stromal tumors MD-AGCT AGCT-WT McConechy MK, et al. J Natl Cancer Inst. 2016;108(11): djw134.
12 Surgery, cornerstone of treatment Surgical staging: Granulosa Cell Tumors: Therapy Bilateral salpingo oophorectomy + total hysterectomy Peritoneal washings Omentectomy (infracolic) Peritoneal biopsies (diaphragm, paracolic gutters, pelvis) Lymphadenectomy controversial Young age and early stage IA/IC1: Fertility sparing surgery + uterine curettage for granulosa cell tumors
13 Rare Sex Cord Stromal Tumors Occur in young women: 75% of patients are <30 years of age and only 10% are >50 years of age >50% androgenic manifestations, less common in retiform tumors and those with heterologous elements >95% FIGO Stage I Both ovaries are involved in <2% DICER1 mutations Sertoli-Leydig Cell Tumors
14 74 Years Old, Previous DCIS, No Symptoms Clitoris hypertrophy Ovarian cyst (9 cm x 8 cm x 7 cm) Endometrial polyp (6 cm x 2 cm) Testosterone 4.5 µg/l (0.14 after surgery) Histology: Sertoli-Leydig cell tumor Endometrial poly DCIS, ductal carcinoa in situ
15 DICER1 Mutations Are Consistently Present in Moderately and Poorly Differentiated Sertoli-Leydig Cell Tumors 30 out of the 34 SLCTs (88%) harbored 1 DICER1 mutation(s) All 30 moderately differentiated/poorly differentiated SLCTs contained mutations No deleterious DICER1 mutations in the four well-differentiated SLCTs SLCT, Sertoli-Leydig Cell Tumors de Kock L, et al. Am J Surg Pathol. 2017;41(9):
16 Role of DICER1 in MicroRNA Processing Hairpin Rio Frio T, et al. JAMA. 2011;305(1):68-77.
17 DICER1 Syndrome DICER1 Syndrome: Familial disorder Predisposition to develop different kind of tumors: Ovarian sex cordstromal tumors Cervical embryonal rhabdomyo-sarcoma Choong CS, et al. Trends Molec Med. 2012;18(9):
18 Recommended Strategy for Genetic Testing in the Diagnosis of Sertoli-Leydig Cell Tumors Ovarian SLCT or diagnostically-problematic SCST with SLCT in the differential Additional diagnostic opinion Confirmed SLCT (well-, moderately- or poorly-differentiated) SCST of uncertain type, but with SLCT in the differential Refer patient to genetics service for germ-line DICER1 mutation Perform sequencing of DICER1 Rnase III domains in tumor as part of the pathology work-up Germ-line mutation present Germ-line mutation absent Somatic Rnase IIIb mutation present Somatic Rnase IIIb mutation absent Discuss screening/surveillance Test relatives for mutation Optional RNase III domain sequencing in tumor Perform tumor testing (Full coding region of DICER1) Likely not moderately- or poorlydifferentiated SLCT. Consider alternative diagnosis Additional diagnostic opinion Somatic mutation(s) present No mutations identified Non-syndromic SLCT (likely moderately- or poorly differentiated) de Kock L, et al. Am J Surg Pathol. 2017;41(9):
19 Tumor Markers in Sex Cord Stromal Tumors Tumor AFP Estradiol Androgens Inhibin AMH Pure Stromal Normal Normal Normal Normal Normal Granulosa cell Normal May be elevated May be elevated Elevated Elevated Sertoli-Leydig May be elevated May be elevated May be elevated May be elevated Normal
20 Sex Cord Stromal Tumors: Adjuvant Therapy Chemotherapy: Stage I granulosa cell tumors have a low risk of recurrence (9%) Range of adjuvant therapy in the literature 19%-57% Effect on outcome not proven After conservative surgery no data Option: Adjuvant therapy for patients with stage IC disease (MITO-9 neg!) Stage I Sertoli-Leydig cell tumors Adjuvant therapy for poorly differentiated or with heterologous elements Radiotherapy: Retrospective series no observed benefit Hormonal therapy: No data
21 Summary: Sex Cord Stromal Tumors 1 Initial diagnosis Molecular testing and second opinion: AGCT 95% mut FOXL2, SLCT >90% mut DICER1 Fertility and adjuvant treatment Thinking to rarity before surgery! First-line therapy Radical surgery or conservative surgery in young patients for IA-IC1 Postoperative chemotherapy discussed for Granulosa cell tumor stage II-IV, and for stage IC2/3; no consensus for stage IC1 Sertoli-Leydig tumor stage II-IV or stage I poorly differentiated, with mesenchymal heterologous elements and/or retiform component BEP, bleomycin + etoposide + cisplatin; CAP, cyclophosphamide + Adriamycin + cis-platinum; VAC, vincristine + actinomycin D + cyclophosphamide
22 Relapse Summary: Sex Cord Stromal Tumors 2 Repeat surgical resections whenever feasible Hormonal therapy in selected cases (AGCT: aromatase-inhibitor, LH-RH inhibitor, tamoxifen, progestins) Chemotherapy options: BEP, carboplatin, paclitaxel, CAP, VAC Clinical trial is possible: Alienor! BEP, bleomycin + etoposide + cisplatin; CAP, cyclophosphamide + Adriamycin + cis-platinum; VAC, vincristine + actinomycin D + cyclophosphamide
23 Sex Cord-Stromal Tumors - Pure sex cord tumors Adult granulosa cell tumor Juvenile granulosa cell tumor Sertoli cell tumors (benign) Sex cord with anular tubules - Pure stromal tumors Fibroma, thecoma, Leydig cell tumor, steroid cell tumor Mixed Sex Cord Stromal Tumors - Sertoli Leydig cell tumors Well/moderately/poorly differentiated/retiform w/o heterologous elements - Sex cord stromal tumors NOS WHO Classification of Ovarian Neoplasms Surface Epithelial Tumors Serous tumors Mucinous tumors Endometrioid tumors Clear cell tumors Brenner tumors Epithelial-stromal Germ Cell Tumors Dysgerminoma Yolk sac tumor Embryonal carcinoma Nongestational choriocarcinoma Mature teratoma Immature teratoma Mixed germ cell tumors Monodermal teratoma and somatic-type tumors arising from a dermoid cyst Kurman RJ, et al. WHO Classification of Tumours of Female Reproductive Organs, Fouth Edition/IARC WHO Classification of Tumours. Geneva: World Health Organization; 2014.
24 Heterogeneous tumors reflecting the capacity for multiple lines of differentiation of the main stem cell system 30% of primary ovarian tumors 95% of which are mature cystic teratomas 3% of all ovarian cancers Germ Cell Tumors (GCTs) Median age at presentation is 18 years 60% of ovarian tumors <age of 21 are of germ cell type Up to 1/3 of them may be malignant Etiology of malignant ovarian germ cell tumors unknown
25 Kraggerud SM, et al. Endocr Rev. 2013;34(3):
26 DG, dysgerminoma; IT, immature teratoma; YST, yolk sac tumor Kraggerud SM, et al. Endocr Rev. 2013;34(3): Molecular Characteristics of the Main Histologic Subtypes of GCT The DNA copy number profile identified for YSTs has come unique features, but also some changes in common with DG/TesticularGCT Each of the histologic subtypes DG, YST, and IT shows molecular characteristics of ploidy indices, DNA copy number changes, and specific expression patterns of mrna, mirna, and proteins. Seemingly, there is preferential involvement of the TGFß/bone morphogenetic protein and WNT pathways in YST compared to DG.
27 Tumor Markers in Germ Cell Tumors Tumor AFP ß-hCG Lactic dehydrogenase Pure dysgerminoma Immature teratoma Yolk sac tumor (Endodermal sinus tumor) Normal May be elevated May be elevated Normal Elevated Normal Elevated Normal May be elevated Embryonal carcinoma Elevated Elevated Elevated Choriocarcinoma Normal Elevated Normal GCIG Consensus Review for Ovarian Germ Cell Tumors: Brown J, et al. Int J Gynecol Cancer. 2014;24(9 Suppl 3):S48-S54.
28 Malignant Ovarian Germ Cell Tumors Surgery is the initial step in diagnosing and treating GCT Laparotomy, but if tumor rupture can be avoided and complete staging can be performed, the use of minimally invasive surgery feasible Fertility-sparing surgery appears to be safe with excellent survival In patients who have completed childbearing, a hysterectomy and bilateral salpingo-oophorectomy are warranted NACT has been increasingly used in bulky GCT to increase fertilitypreserving surgery, minimize the extent of surgery, and avoid rapid tumor regrowth during postoperative convalescence The necessity and extent of comprehensive surgical staging is controversial Residual disease at primary surgery and yolk sac histology are independent prognostic factors NACT, neoadjuvant chemotherapy Brown J, et al. Int J Gynecol Cancer. 2014;24(9 Suppl 3):S48-S54.
29 Literature Review of Reproductive Function Following Fertility-Sparing Surgery and Platinum-Based Chemotherapy for Malignant Ovarian Germ Cell Tumors Author Number Patients Number Normal Menses Number Pregnancies Gershenson /40 (68%) 22 in 11 Brewer /14 (93%) 5 in 3 Low /47 (92%) 14 in 19 Zanetta /81 (99%) 41 in 16 Tangir /40 (69%) 47 in 29 Gershenson /77 (77%) 37 in 35 Gershenson DM, et al. J Clin Oncol. 2007;25(19):
30 Fertility and Gonadal Function After Adjuvant Therapy in Women Diagnosed With a Malignant Ovarian Germ Cell Tumor Cumulative Post-Treatment Fertility P =.03 CBCT, cisplatin-based chemotherapy Solheim O, et al. Gynecol Oncol. 2015;136(2):
31 Fertility-Preserving Surgery for Advanced Stage GCT National Cancer Database Analysis 526 patients Hysterectomy 20% Older (age 31 vs 20) More likely bilateral tumors (13% vs 48%) Uterine preservation: 83% FIGO II 80% FIGO III 75% FIGO IV Nasioudis D, et al. Gynecol Oncol. 2017;147(3): Hysterectomy No Yes Aged <40 years Advanced stage (II-IV) HR: 0.59, 95% CI: 0.28, 1.24, P =.19
32 Fertility-Preserving Surgery for Advanced Stage GCT National Cancer Database Analysis 526 patients Hysterectomy 20% Older (age 31 vs 20) More likely bilateral tumors (13% vs 48%) Uterine preservation was not associated with decreased survival and should be considered in women with advanced stage GCTs interested in future fertility Uterine preservation: 83% FIGO II 80% FIGO III 75% FIGO IV Nasioudis D, et al. Gynecol Oncol. 2017;147(3): Hysterectomy No Yes Aged <40 years Advanced stage (II-IV) HR: 0.59, 95% CI: 0.28, 1.24, P =.19
33 Malignant Ovarian Germ Cell Tumors 1 FIGO stage I dysgerminoma and stage IA grade 1 immature teratoma may be safely observed postoperatively without chemotherapy (comprehensive surgical staging!) All others receive chemotherapy, although it may be safe to observe and avoid chemotherapy in all with stage IA GCTs, salvaging them in the event that they recur Combination chemotherapy with bleomycin, etoposide, and cisplatin (BEP) 3 to 4 courses of BEP (4 BEP or 3 BEP + 1 EP, not to exceed a total of 270 mg total bleomycin) GCIG Consensus Review for Ovarian Germ Cell Tumors: Brown J, et al. Int J Gynecol Cancer. 2014;24(9 Suppl 3):S48-S54.
34 Malignant Ovarian Germ Cell Tumors 2 Relapses after primary chemotherapy have a poor prognosis, so any resectable residual disease should be removed Treatment failures are categorized as platinum-resistant (progression 6 weeks) or platinum-sensitive (recurrence >6 weeks) VeIP (vinblastine, ifosfamide, and cisplatin) or TIP (paclitaxel, ifosfamide, and cisplatin), with or without added high-dose chemotherapy GCIG Consensus Review for Ovarian Germ Cell Tumors: Brown J, et al. Int J Gynecol Cancer. 2014;24(9 Suppl 3):S48-S54.
35 Salvage High-Dose Chemotherapy (HDC) in Female Patients With Relapsed/Refractory Germ-Cell Tumors: A Retrospective Analysis of the European Group for Blood and Marrow Transplantation (EBMT) Retrospective analysis of 51 assessable female patients with GCT treated with HDC and registered with the EBMT 17 (33%) achieved a complete response (CR) 8 (16%) achieved a marker-negative PR (PRm-); 5 (10%) a marker-positive (PRm+) 5 (10%) achieved stable disease 13 (25%) had progressive disease 3 toxic deaths (6%) In total, 25 of 60 patients (42%) were progression-free following HDC at a median follow-up of 87 months (range months) Salvage HDC based on carboplatin represents a therapeutic option for female patients with relapsed/refractory GCT De Giorgi U, et al. Ann Oncol. 2017;28(8):
36 Fifth OCCC of the GCIG: Areas of Unmet Needs in Clinical Trial Design for Rare Ovarian Tumors Germ Cell Tumors: Identifying patients with GCTs who could be safely managed with surveillance A robust prognostic scoring system Less toxic alternatives to BEP Defining the optimal extent of surgical staging required for GCT Defining the feasibility and safety of limited biopsies followed by neoadjuvant chemotherapy in stage III/IV GCT Comprehensive molecular characterization of GCTs Sex Cord Stromal Tumors: Improved prognostic algorithm for SCST incorporating histological parameters Effective alternatives to first-line BEP An evaluation of the role of hormonal therapy Novel targeted therapies for relapsed SCST OCCC, Ovarian Cancer Consensus Conference; SCST, sex code stromal tumor Leary AF, et al. Ann Oncol. 2017;28(4):
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