GermGerm CellCell anandd StromalStromal TTuumorsmors ofof thethe OvaryOvary

FredFred UelanUelandd,, MMDD UniversiUniversityty ofof KentucKentuckkyy GynGynecolecoloogicgic OncolOncolooggyy ClinicalClinical ProfProfiilele andand ClassifClassifiicaticatioonn

GeGerrmm CelCelll TTumumororss OvarianOvarian NNeeoplasmsoplasms

 Coelomic 50-70%  Germ 15-20%  Specialized gonadal 5-10% stroma  Nonspecific 5-10% mesenchyme  Metastatic tumors 5-10%

GermGerm CellCell TumorsTumors

 20%20% ofof allall ovarianovarian ttuumorsmors  22--3%3% ofof oovarianvarian mmalignanciesalignancies  PresentationPresentation atat youngyoung ageage  TTuummoorr mamarkerkerrss – hCG – αFP – LDH GermGerm CellCell TumorsTumors WHOWHO ClassifiClassificcationation  DysgeDysgerrmmininomomaa  ChoriocarcinChoriocarcinomomaa  EndodeEndodermrmalal sinussinus  EmEmbbrryonalyonal ccaarcinorcinomama ttuumormor  PolyPolyemembbrryyomomaa  TeratTeratoommaa  MixedMixed GCTGCT – Immature  CCoombombo GGCCT/StrT/Stromaomall – Mature Mature – Gonadoblastoma – Struma ovarii – Other –

Dysgerminoma

Embryonal Morula

Embryo sac Endodermal sinus tumor Blastula Endodermal sinus tumor OvarianOvarian GeGerrmm CellCell TuTummorsors SpecificSpecific TTuumormor TypesTypes

GeGerrmm CelCelll TTumumororss DysgerminDysgerminoomama

 It’s Not About the Bike  Incidence – 1-2% of ovarian tumors – 3-5% of ovarian – 40% of all GCT – Peak incidence age 19 – 67% stage IA  10-15% bilaterality – 20% in “normal appearing opposite” DysgerminDysgerminoomama OvarianOvarian DyDyssgerminomagerminoma DysgerminDysgerminoomama

 Presentation – Solid, lobulated, and can be large – 15% associated with MCT – Associated with and gonadoblastoma – High growth fraction, lymphatic spread  Tumor markers – LDH, placental  Survival – Overall =86% – Stage I =90% DysgerminDysgerminoomama

 FertilityFertility--sparingsparing surgerysurgery – 85% of patients are younger than 35 yo – Consider uterine preservation (IVF)  RadiosensitiveRadiosensitive  ChCheemothmotheerapyrapy – Combination, dose-intense regimen DysgerminDysgerminoomama

 Large, round, ovoid or polygonal cells  Pure or mixed stromal infiltration  Lymphatic space invasion is common DysgerminDysgerminoomama

Incidence Survival Stage IA 70% 92% 10-year Stage IB 10% >90% 5-year Stage II, III 15% >90%

Stage IV 5% 80% EndodermaEndodermall SinusSinus TuTummoror

 Presentation – 20% of all GCT – Median age 19 yo – , large mass – 10-30 cm common – Very rapid growth, intra-abdominal and hematological spread

= αFP, α1 antitrypsin  Synonyms – tumor, Mesonephroma  Survival – Overall survival =70% – Stage I =90% EndodermaEndodermall SinusSinus TuTummoror

 Solid tumor with hemorrhage and gelatinous  Microscopy – Hyaline globules – Schiller-Duval bodies

 Single vessel surrounded by neoplastic cells EndodermaEndodermall SinusSinus TuTummoror

Hyaline globules → α1 anti-trypsin EndodermaEndodermall SinusSinus TuTummoror

Schiller-Duval bodies TeratomaTeratoma CCllassifassifiicationcation

 IImmmamatureture  MatureMature  SpecializedSpecialized – Struma ovarii – Carcinoid ImmaturImmaturee TTeratomaeratoma

 Presentation – 20% of all GCT – 75% in first 2 decades of – 12-15% bilateral – 60-70% are Stage I  Rarely produce tumor markers- αFP and CA-125  Grade is determined by % neural  Stage IA grade 1 → no  Survival – Overall =63% – Stage I =75% ImmaturImmaturee TTeratomaeratoma ImmaturImmaturee TTeratomaeratoma

Primitive neural elements ImmaturImmaturee TTeratomaeratoma GradingGrading Grade Scully Norris 0 Well differentiated All mature; rare mitoses 1 Well differentiated; rare Some immature and embryonal tissue neuroepithelium 2 Moderate embryonal; Immature and atypia and mitoses neuroepithelium ≤ 3 lpf 3 Large embryonal; atypia Immature and and mitoses neuroepithelium in ≥ 4 lpf ImportanceImportance ofof GradingGrading

Grade Number Tumor

1 22 4 (18%)

2 24 9 (37%)

3 10 7 (70%) MatureMature CCysystticic TeratomaTeratoma

 5-25% of all ovarian tumors – 10-20% bilateral  Most common of young women  Sonography – Complex, cystic and solid – Fat/fluid or /fluid level, calcifications – High MI score  1-2% with malignant degeneration – Rokitansky’s protuberance – Squamous cell possible

MatureMature CCysystticic TeratomaTeratoma MatureMature CCysystticic TeratomaTeratoma MatureMature CCysystticic TeratomaTeratoma

Sebaceous glands MatureMature CCysystticic TeratomaTeratoma

Intestinal gland formation SpecializedSpecialized TeratomasTeratomas

 Struma ovarii – 2-3% of all – 25-35% have symptoms of – Usually benign, but may undergo malignant transformation  Follicular type  Carcinoid tumors – Associated with GI or respiratory epithelium – Primary ovarian tumors are rare (N=50) – Often PMP – 1/3 have carcinoid syndrome from serotonin – Symptoms resolve with excision – 5-hydroxyindoleacetic acid in urine StrumaStruma OOvvaariirii

 Follicles contain vividly eosinophilic, acellular colloid  Variation in follicular size is typical  Can have rich vascularity OvarianOvarian CaCarrcinoidcinoid

 Insular pattern  Round uniform cells  Fibroconnective tissue background  80% with neurosecretory granules ChoriocarcChoriocarciinomanoma

 PresentationPresentation – Uncommon, aggressive tumor – Often part of mixed GCT – Consider met from gestational chorioCA – Mean age 20 yo, children common – Half of premenarchal → precocious  TTuummoorr mamarkerrker – hCG ChoriocarcChoriocarciinomanoma

Cytotrophoblast – Smaller cells – Smaller nuclei  Syncitiotrophoblast – Larger cells – Eosinophilic cytoplasm – Bizarre nuclei  Hemorrhage Syncitiotrophoblast EmbEmbrryonalyonal CarcinomaCarcinoma

 Presentation – Mean age < 30 yo – Only 4% of GCT and often part of – 60% Stage IA – Poorly differentiated – Aggressive, intra-abdominal spread and mets common  Tumor markers: hCG, αFP  Survival – Overall =40% – Stage I =75% EmbEmbrryonalyonal CellCell CancerCancer

 Large, primitive cells  Papillary or gland-like formation, occasional  Sheets and ribbons PolyePolyemmbrybryoomama

 BestBest ccllassifiedassified asas aa mmixedixed ttumumoror – Never found in pure form – fewer than 50 cases – All under age 40  ResReseembmblleses eemmbbrryonalyonal cacarrcincinomomaa – days 13-15  TreaTreatteded likelike otherother mmiixxeded GCTGCT  TTuummoorr mamarkerkerrs:s: hhCG,CG, ααFPFP MixedMixed GCTGCT EmbryonalEmbryonal aandnd ChChooririooCACA GonadoblaGonadoblasstomatoma

 Combined Germ Cell / Cord Stromal Tumor  Presentation – Age 1-38 – Small tumors – Phenotypic ♀ with  90% have Y  22% from streak – Bilaterality 30-50%  Check for dysgenic gonads – BSO if Y – If TFS, await puberty before BSO GonadoblaGonadoblasstomatoma

 Large germ cells, clear cytoplasm  Nests of primordial germ cells surrounded by specialized stromal cells  Associated sex chord stromal cells

Gonadoblastoma GCTGCT TTuumormor MarkersMarkers

Histology AFP hCG LDH PLAP CA-125 Dysgerminoma - + + + + Endodermal + - + - + sinus tumor Immature + - - - + teratoma Embryonal CA + + - + - ChorioCA - + - + - TreatmentTreatment

GeGerrmm CelCelll TTumumororss SurgerySurgery

 ImImportancportancee ofof stagingstaging inin earlearlyy diseadiseassee  FertilityFertility--sparingsparing surgersurgeryy oftenoften requiredrequired – Can preserve uterus for future IVF, even if BSO  DebulkingDebulking iimprovesmproves outcoutcomomee ChemotherChemotheraapypy forfor GCTGCT

 BEP – 20 U/m2 weekly x 9 – 100 mg/m2 days 1-5 q 3 weeks x 3 – 20 mg/m2 days 1-5 q 3 weeks x 3  VAC – 105 mg/m2 weekly x 12 – Act D 0.5 mg days 1-5 q 4 weeks – Cytoxan 5-7 mg/kg days 1-5 q 4 weeks  VBP – Vinblastine 12 mg/m2 q 3 weeks x 4 – Bleomycin 20 U/m2 weeks x 7, 8 on week 10 – Cisplatin 20 mg/m2 days 1-5 q 3 weeks x 3 ClassifClassifiicaticatioonn

StrStromomalal TTuummoorsrs OvarianOvarian StStrromalomal TumoTumorrss

 Granulosa cell tumors – Inhibin, CA-125  Sertoli-Leydig tumors – CA-125, αFP, sTest  Steroid cell tumors – sTest as 50-75% virilized  Gynandroblastoma – ♀ and ♂ components OvarianOvarian FibFibrromaoma GranulosaGranulosa CellCell TumorTumor

 Presentation – Adult (95%) and juvenile types – Solid and/or cystic- variable – , occasional – 80% palpable on examination – Hemoperitoneum in 15% – 80-90% Stage I – Low grade, late relapse  Estrogen excess and the endometrium – 25% proliferative – 55% hyperplastic – 13% GranulosaGranulosa CellCell TumorTumor TreatmentTreatment

 JuvenileJuvenile – High cure rate  AdultAdult – Resection –

 BEP

and Taxol

 GnRH analogs GranulosaGranulosa CellCell TumorTumor GranulosaGranulosa CellCell TumorTumor GranulosaGranulosa CellCell TumorTumor GranulosaGranulosa CellCell TumorTumor GranulosaGranulosa CellCell TumorTumor

Call-Exner bodies SertoliSertoli--LeydigLeydig CellCell TumTumoorsrs

 Benign – tumors→ no hormones – Leydig tumors→ testosterone  Potentially Malignant Grade % – Sertoli-Leydig tumors – Arrhenoblastoma, androblastoma 1 0 – Grade 3 2 10  44% five-year survival 3 60 SertoliSertoli--LeydigLeydig TumorTumor

Well-differentiated tubules TreatmentTreatment SSummaummarryy

GeGerrmm CelCelll andand StStromromaa TTuummoorsrs Dysgerminoma USO staging if BEP x 3 cycles if possible stage II-IV Endodermal Debulk but BEP x 3-4 cycles sinus tumor preserve fertility Embryonal As above BEP x 3-4 cycles carcinoma Malignant As above BEP or VAC teratoma x 3-4 cycles Granulosa cell USO if young BEP x 3-4 cycles tumor o/w TAH/BSO GnRH agonists for advanced ds. Sertoli-leydig As above BEP or VAC cell x 3-4 cycles ConclusionConclusionss

1. Common in young women 2. Tumor markers 3. Treatment • Fertility-sparing surgery • Chemosensitive→ BEP for 3-6 cycles • Radiosensitive 4. No adjuvant chemo for: • Stage I pure dysgerminoma • Stage IA grade 1 IT