Chapter 12 Germ cell, stromal, and Other ovarian tumors

Germ cell tumors Classification

Clinical profile Relatively small proportion of all ovarian tumor(~20%) Occur in young women Recent developments of in chemotherapy -> prognosis 변화 Initial symptoms

Dysgerminoma Uncommon tumor - 1-2% of primary ovarian neoplasms - 3-5% of ovarian malignancies Occur at any age from infancy to old age : 7 Mo-70years - most cases occur in adolescence and early adulthood Present at a relatively early stage - Ia 65-75% - Ib 10-15% - II+III 15% - IV 5%

Stroma - infiltrated with lymphocytes - often contains granulomas similar to sarcoid - occasionally, contains isolated gonadotropin producing syncytiotrophoblastic giant cells

Gross finding - firm or flesh and cream colored or pale tan - both external and its cut surfaces may be lobulated

Sexually abnormal females : a few dysgerminoma - pure or mixed gonadal dysgenesis or testicular feminization. - develops in a previously existing gonadoblastoma Symptoms - not distinctive - similar to other solid ovarian neoplasms - duration of Sx : usually short - abdominal enlargement and presence of a mass in the lower abdomen(m/c) One of the two most common malignant ovarian neoplasm in pregnancy - serous cystadenoca. of low maliganant potential - nonspecific finding - relates to the age rather than to the pregnant states

the opposite ovary may be involved with the tumor process - only germ cell tumor (10-15%) Metastatic spread - lymphatic spread - hematogenous spread : occur later - any organ can affected : liver, lungs, bone

Treatment Historically, surgery followed by radiation Recently, the use of multiple-agent chemotherapy Chemotherapy  Recently appears to have become the treatment of choice  Success rate : as good as that of radiation  Preservation of fertility  used more frequently with significant success in patients who advanced disease  Optimal drug combination : not yet been determined  Doxorubicin and cyclophosphamide or cisplatin, vinblastin, and bleomycin (VBP)  Today, the treatment of choice after surgery in patients with advanced disease

Conservative management - in the young woman with a unilateral encapsulated tumor - who desirous of future childbearing Conservative surgery without radiation in stage Ia results

In patient whom unilateral salpingo-oophoretomy is performed –careful inspection of the other ovary –rule out disseminated disease –assessment of the retroperitoneal lymph nodes –should be followed closely and have periodic examinations : 90% of recurrences appear in the first 2 years –most recurrences can be successfully eradicated by radiation therapy or chemotherapy Several prognostic factors 1.Tumor size (>10cm) 2.Patient age : older than 40 years or younger than 20 years 3.Presence of other germ cell elements

Report Schwartz : 4 patients with metastasis to the contralateral ovary and preservation of ovary with subsequent CTx –All patients were alive and had no disease Mo after diagnosis De palo …. : 56 patients who had pure dysgerminomas - 5 year relapse-free survival rates Stage Ia, Ib, Ic : 91% Stage III retorperitoneal disease :74% Stage III peritoneal disease : 24% peritoneal involvement of any kind was associated a poor prognosis

Recurrences  Should be treated aggressively with reexploration and tumor reduction  Removed tissue : examined carefully for evidence of germ cell elements other than dysgerminoma Tx of Dysgerminoma associated with gonadoblastoma  Radical because of the frequent occurrence of bilateral tumors and the absence of normal gonadal function  Investigation of the genotypes and karyotypes of all patients  Preserve the uterus : IVF can be utilized Tx of dysgerminoma contain small areas of more malignant histology(embryonal ca or EST)  The prognosis and therapy are determined by the more malignant germ cell elements

Endodermal Sinus Tumor (Yolk Sac Tumor) second most common form of malignant germ cell tumor 22% of germ cell lesions ¾ of the patients : combination of abdominal pain and abdominal or pelvic mass Median age : 19years Sx  Acute pain : torsion Almost always unilateral Size : cm

Cut surface : gray yellow with areas of hemorrhage and cystic gelatinous changes Consist of  scattered tubules or spaces lined by single layers of flattened cuboidal cells  loose reticular stroma  Numerous scattered para- amnosalicylic-positive globules  Characteristic invaginated papillary structure with a central blood vessel

Highly malignant  Metastasize early and invade the surrounding structures  Intraabdominal spread : extensive involvement of abdominal structures with tumor deposits  Metastases also occur via the lymphatic system  AFP level are often elevation  Characterized by extreme rapid growth and extensive intra- abdominal spread

prognosis Historically : Unfavorable, died within 12-18MO of diagnosis Treatment In the past : frustrating  Kurman and Norris : no logn-term survirors in 17 pts with stage I tumor who were receiving adjuvant RTx and single alkylating agents, dactinomycin or MTX  Gallion : review the literature in only 27% of 96 patients with stage I EST were alive at 2 years  not sensitive to radiation therapy  Optimal surgical extirpation of the disease : advocated

In later years : optimistic reports of sustained remission in some pts treated by surgery and multiple agent chemotherapy

GOG : VAC, pure EST 31 pts –15(48%) failed, including 11 of 24(46%) who had complete resection GOG : VAC, mixed germ cell tumors containing EST 15 pts –8(53%) failed GOG : VAC, stage I-III completely resected EST 48 pts –35(73%) pts were free of disease with a median follow time of 4 years Gershenson and associates : VAC, pure EST –18 of 26(69%) pts were free Gallion and associates : VAC, stage I disease –17 of 25(68%) pts were alive and well 2 years or more after Sessa … : VBP, pure EST –13 pts, unilateral oophorectomy(12) –All received VBP and are alive at 20 months to 6 years

Schwartz … : used VAC for stage I disease but prefer VBP for stage II-IV –12 of 15 pts are alive and have no evidence of disease. –treat at least one course beyond a normal AFP titer –one recurrence was treated successfully with BEP GOG : evaluated VBP in stage III and IV –16 of 29(55%) ESTs were long-term disease-free survivor –Induced a substantial number of durable complete responses, even in Pts with prior CTx –Toxicity was significant Smith ….: disease were resistant to MAC and VBP –complete remission with VP-16 and cisplatin contained regimen Williams –In disseminated germ cell tumors, BEP was more effective and had less neuromuscular toxicity than had VBP

Williams : reported the GOG experience –93 patients who were given BEP postoperatively in an adjuvant setting for malignant germ cell cancers of the ovary –Immature teratomas(42), EST(25), mixed germ cell tumors(24) –91 of 93 had no evidence of disease after three course of BEP with median follow-up of 39 months Dimopoulos –40 pts with nondysgerminomatous tumor were treated BEP or PVB –Median follow-up of 39 months –5 pts developed progressive disease and died Fujita –41 pts with EST, either pure or mixed –More aggressive surgery did not increase survival –Survival was similar whether VAC or PBV –All stage I pts given either VAC or PBV following surgery survived without evidence of recurrence

Serum AFP –Useful diagnostic tool in patients who have EST –Ideal tumor marker –Can be useful when monitoring the results of therapy and for detecting metastasis and recurrences after therapy Levels of hCG and its b subunit –Normal

Embryonal carcinoma One of the most malignant cancer in the ovary Only 4% of the malignant ovarian germ cell tumors A mean age : 15 years More than half of the pts have hormonal abnormalities –Precocious puberty, irregular uterine bleeding, amenorrhea, or hirsutism

Consist of large primitive cells with occasional papillary or gland-like formations(f12-7) The cell have eosinophilic cytoplasm with distinct borders and round nuclei with prominent nucleoli Numerous mitotic figures, many atypical multinucleated giant cells

Contain hCG, syncytiotrophoblast-like cells and AFP in the large primitive cells Kurman and Norris –Actual survival rate of 30% for the entire group –Stage I tumor, survival rate was 50% With modern therapy, survival rates should greatly improved EST vs Embryonal ca

Optimal therapy –Not yet established –Probably similar to that for EST VAC –Definitely active in this disease –Not appear to be as reliable for advanced cases as VBP VBP –Can be used at that point in the hope of salvage Total number of courses of VAC therapy –Really not known GOG : evaluated the effectiveness of the VBP in stage III, IV, recurrent malignant germ cell tumors –Overall progression-free interval at 24 months : 55% hCG and AFP : progression monitor

Polyembryoma Rare ovarian germ cell neoplasm In most cases, associated with other neoplastic germ cell elements(immature teratoma) Highly malignant germ cell neoplasm Invasion of adjacent structures and organs Not sensitive to RTx Response to CTx : unknown

Choriocarcinoma Rare Highly malignant tumor May be associated with sexual precocity Arise in one of three ways 1)Primary gestational choriocarcinoma associated with ovarian pregnancy 2)Metastatic choriocarcinoma form a primary gestational choriocarinoma arising in other parts 3)A germ cell tumor differentiating in the direction of trophoblastic structures In the most cases, the tumor is admixed with other neoplastic germ cell elments Occurs in children and young adults

Secrete hCG Precocious puberty –Mammary development, growth of pubic and axillary hair, and uterine bleeding Adult patients : signs of ectopic pregnancies –Associated with an increased production of hCG Estimation of urinary or plasma hCG levels –useful diagnostic test Prognosis –Historically : unfavorable –Modern CTx regimen : effective Creasman ….: MAC –Prolonged remissions Combination CTx using MTX or dactinomycin and alkylating agent

Mixed Germ Cell Tumors Contain at least two malignant germ cell elements –Dysgerminoma(m/c, 65-80%) MD anderson Hospital –9 pts(surgery alone), 6 pts(RTx) : all recurrences –Of 17 pts (VAC) : 9 were placed into remission –5 pts (VBP after surgery) : 4 are alive and well –20 pts are alive and well –14 pts who had stage I disease and were treated with combination CTx after surgery : 11(79%) survived Creasman … : treated 5 pts stage I lesion, MAC –3 pts also received RTx –All 5 were long-term survivors GOG –10 completely resected tumor, VAC : 7 are long-term survivors –5 incompletely resected disease, VAC : 4 recurrence

Schwartz –8 pts, VAC –7 long-term survivors