Malignant ovarian germ cell tumors

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GYNECOLOGY 81OBSTETRICS International Journal of Gynecology& Obstetrics53 (1996)151-158

Article

Malignant ovarian germ cell tumors S.-N. Chow*a9b,J.-H. Yanga, Y.-H. Lin”, Y.-P. Chena, J.-I. Laia, R.-J. Chen”, C.-D. Chen” ‘Department of Obstetrics and Gynaecology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan b Laser Medicine Research Center, College of Medicine. National Taiwan University, Taipei, Taiwan

Received27 June 1995;revised10December1995;accepted14December1995

Objectives: Fifty patients with malignant ovarian germ cell tumors, which accounts for 10.8% of all ovarian malignancies, were treated from 1977 through 1994. Their casesare reviewed. Met/r&r: The histology includes endodermal sinus tumor (EST) in 15patients, immature teratoma in 14, dysgerminoma in 13, and mixed germ cell tumor in eight. The mean ageat presentation was 21.5 years and mean primary tumor diameter was 16cm. All patients underwent surgery as the initial treatment, and 10 received more than one operation. Postoperative adjuvant chemotherapy was not given to caseswith stage la immature teratoma and dysgerminoma. VAC (vincristine, actinomycin D, cyclophosphamide) and BVP (bleomycin, vinblastine, cisplatin) regimenswere utilized in early 1980sfor EST and advancedstagetumors of immature teratoma and dysgerminoma. BEP (bleomycin, etoposide, cisplatin) and EP (etoposide, cisplatin) regimens were applied in advanced-stagediseaseand some stage I diseasesince 1990.VIP (VP-16, ifosfamide, cisplatin) regimen was employed as salvage regimen in caseswhere other combinations failed. Results: a-Fetoprotein (AFP) was elevated in every tumor containing endodermal sinus element, and AFP servedas a good indicator for prediction of tumor recurrence. The follow-up time ranged from 5 to 144months with the mean of 54.5 months. Conclusions: The survival rate for EST was 54%, that for immature teratoma and dysgerminoma was 85% and 90%, respectively. Keywords: Malignant ovarian germ cell tumor; Endodermal sinus tumor; Immature teratoma; Dysgerminoma

1. Introdwtion Malignant

ovarian germ cell tumor is a rare

disease,and accounts for about 5% of all ovarian malignancies. It can be subdivided into dysgerminoma, endodermal sinus tumor (EST), eml Corresponding author, Tel.: +886 2 3970800Ext. 5165; Fax: +8862 3211683.

bryonal carcinoma, polyembryoma, choriocarcinoma, immature teratoma (Imm T), and mixed germ cell tumor (MGCT). The prognosis of nondysgerminomatous ovarian germ cell malignancy was poor before the advent of modem chemotherapeutic management in the 1970s. Multipleagent chemotherapy has dramatically improved the survival rate of germ cell malignancies since then. Smith and Rutledge [l] described the effec-

0020-7292/9W$15.00 0 1996International Federationof Gynecologyand Obstetrics PII 0020-7292(96)02657-l

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tiveness of vincristine, actinomycin D, and cyclophosphamide (VAC) in 1975. Creasman et al. [2] used methotrexate, actinomycin D and chlorambucil and obtained 89% 2-year survival in 26 patients with germ cell tumors (dysgerminoma excluded). Einhom and Donahue [3] achieved prolonged complete remission without relapse using bleomycin, vinblastine, and cisplatin (BVP). Wong et al. [4] reported 3/SVAC-failed malignant ovarian germ cell tumors which were cured and remained diseasefree 24-79 months after completion of bleomycin, etoposide, and cisplatin (BEP). This report reviews the experience of ovarian germ cell malignancies from 1977through 1994in National Taiwan University Hospital (NTUH). 2. Materials and methods

We reviewed medical records of female patients who were pathologically proven to have malignant ovarian germ cell tumors. In total, 50 caseswere collected from 1977 through 1994, which accounted for 10.8% of all ovarian malignancies in the past 18years in NTUH. The tumors were staged according to the International Federation of Gynecology and Obstetrics (FIGG) staging system [5]. Thirty-one patients completed their treatment course at our hospital and were then regularly followed up. The other 19 patients received initial

surgery at other institutes and were referred to our hospital for further management such as chemotherapy and radiotherapy. The follow-up time ranged from 5 to 144months (mean, 54.5 months). Six patients were lost to follow-up and their present condition is unknown. 3. Results

FIG0 stageand histology of the entire seriesof patients are summarized in Table 1. Histologic grades of immature teratoma are according to the criteria of Thurlbeck and Scully [6]. Twenty-eight of 50 (56%) patients had stage I disease,four (8%) had stage II disease, 15 (30%) had stageIII disease,and three (6%) had stage IV disease. The age distribution was from 6 to 36 years (mean, 21.5 years). Abdominal pain, abdominal distension, and palpable abdominal mass are the leading complaints. Other complaints such as abdominal fullness, urinary symptoms (urinary difficulty and urinary frequency) are also recorded. Tumor markers were measuredinitially in 40 of the 50 patients. AFP (ol-fetoprotein) and LDH (lactic dehydrogenase) were elevated (20/20 and 818,respectively) in pure endodermal sinus tumors and mixed germ cell tumors containing component of EST. AFP also served as a good indicator for

Table I Stage, cell types, and histologic grades of malignant ovarian germ cell tumors EST

InUIlT

Dy%

MGCT

Total

Grade 1

Grade 2

Grade 3

IIa IIb IIC IIIa IIIb IIIC IV

2 0 5 0 0 0 0 1 4 3

6 0 1 0 0 0 0 0 0 0

3 0 I 0 0 0 0 I 1 0

0 0 0 0 0 0 0 0 1 0

4 1 1 2 1 0 1 0 3 0

4 0 0 I 0 0 0 0 3 0

19 1 8 3 1 0 1 2 12 3

Total

15

7

6

1

13

8

50

la Ib IC

EST, endodermal sinus tumor; Imm T, immature teratoma; Dysg, dysgerminoma; MGCT, mixed germ cell tumor.

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Table 2 Summary of patients with endodermal sinus tumor (EST) of ovary Patient

Histology

Age (YeW

sw3e

SWWY

Further management

current status (months)

1

EST

36

Ia

VAC x 9

DOD 16

2 3 4 5 6 7 8 9 10

EST EST EST EST EST EST EST EST EST

34 18 26 11 21 11 28 34 15

+, unknown regimen VAC x 8, BVP x 4 VAC x 5 EP x 4 EP x 4 BEP x 9, EP x 3, VIP x 6 -b BVP x 4 BVP x 6

NED 31 LosttoFlLl 18 NED 103 NED 55 NED 57 DOD 32 Lost to F&J NED 45 NED 113

11

EST

21

IIIC

VAC x 5

DOD 12

12

EST

16

IIIC

VAC x lb

DOD 15

13

EST

24

IV

VAC x 6

DOD 52

14 15

EST EST

17 33

IV IV

us0 TAH, USO, Oms TAH, BSO TAH, BSO TAH, BSO, Om USO, 0~ APP USO, Om, APP TAH, BSO, Om, Deb TAH, BSO, Om TAH, BSO us0 TAH, USO, Onis us0 TAH, USO, Deb” us0 Deba us0 TAH, USO, Deb’ TAH, BSO, Om, App, Deb us0 TAH, USO, Om, Debs

BEP x 3, EP x 4 BEP x 2, VIP x 2

NED 38 DOD8

Ia IC

Ic Ic Ic Ic IIIb IIIC IIIC

USO, unilateral salpingo-oophorectomy; TAH, total abdominal hysterectomy; Om, omentectomy; BSO, bilateral salpingooophorectomy; App, appendectomy; Deb, debulking operation; VAC, vincristineJactinomycin D/cyclophosphamide; BVP, bleomycin/vinblastine/cisplatin; EP, etoposide/cisplatin; BEP, bleomycin/etoposide/cisplatin; VIP, VP-16/ifosfamide/cisplatin; DOD, dead of disease;NED, no evidence of disease;F/u, follow up. aRepeated operation. bPatient rejected further chemotherapy.

post-treatment prognosis prediction. In our series, nine patients had post-treatment AFP elevation: six had persisting AFP elevation and three had reelevation of AFP 3-6 months after completion of initial chemotherapy. Further managements, either re-operation or chemotherapy, were therefore applied. Two out of nine resumed disease-freestatus, while sevendied of the disease. CA-125 (carcinoma antigen- 125), hCG (human chorionic gonadotropin), and CEA (carcinoembryonic antigen) were also used as tumor markers of germ cell tumors, but the sensitivity was not as satisfactory as for AFP. Thirteen out of 28 (46%) patients had CA-125 elevation, five out of 17 (29%) patients had hCG elevation, and five out of 26 (19%) patients had CEA elevation. All patients in our series underwent surgery as

initial treatment and the tumor size ranged from 4 to 28 cm (mean, 16 cm) in its maximal diameter. Ten out of 50 patients (6 EST, 3 Imm T, 1 MGCT) received more than one surgical intervention. Eight of nine (except one lost to follow up) reoperated patients died of disease 8-52 months after diagnosis even under maximal debulking operation and adjuvant chemotherapy. Since most of the neoplasm occurred in young women, preservation of reproductive function in early stagediseaseis important. Thirteen out of 19 (68%) stage Ia patients (stage Wgrade 1 in immature teratoma) received unilateral salpingooophorectomy (Tables l-5), and adjuvant chemotherapy was added if necessary.The prognosis in patients of stage Ia immature teratoma and dysgerminoma treated with unilateral salpingo-

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Table 3 Summary of patients with immature teratoma (Imm T) of ovary Patient

Histology

Age (years) Stage/grade

Surgery

Further management

Current status (months)

16 17 18 19 20 21 22 23

ImmT ImmT ImmT ImmT BmliT ImmT ImltlT ImmT

11 23 28 14 27 26 33 31

WI Ia/l Ia/l Ia/1 Ia/l la/l Ia/2 Ia/

EP x 4 EP x 6

NED 61 NED 49 NED 48 NED 19 NED 64 NED 32 NED 5 Lost to F/u 5

24 25 26 27 28

ImmT ImmT ImmT ImmT IrMiT

27 33 34 19 IO

W2 ICI1 k/2 IIIb/2 IIIc/2

us0 us0 us0 us0 us0 us0 TAH, BSO us0 TAH, USO, Om, Deb* us0 USO, Om TAH, USO, Om TAH, BSO, Om, App us0 Deba

EP x 1 EP x 4 BVP x 3 EP x 4

NED 47 NED 35 NED 75 NED 49 DOD5

29

ImmT

8

IIW3

us0 Debs

BEP x I

DOD 11

USO, unilateral salpingo-oophorectomy; TAH, total abdominal hysterectomy; BSO, bilateral salpingo-oophorectomy; Om, omentectomy; Deb, debt&icingoperation; EP, etoposidekisplatin; BVP, bleomycin/vinblastine/cisplatin; BEP, bleomycin/etoposide/cisplatin; NED, no evidence of disease; F/U, follow up; DOD, dead of disease. ‘Repeated operation.

Table 4 Summary of patients with dysgerminoma (Dysg) of ovary Patient 30 31 32 33 34 35 36 37 38 39 40 41 42

Histology

Age (years) Stage

Surgery

Further management

Current status (months)

2:;

20 11

2::

i

2:;

13 31 6 10 14 24 18 18

TAH, BSO, Om us0 USQ APP us0 USO, Om, App us0 us0 TAH, BSO TAH, US0 USO, Om TAH, BSO, Om, PALND USO, PLND USO, Om, PLND

EP x 2 EP x 4 BVP x 3 BVP x 2, R/T 4OOOcGy BEP x 4 EP x 6 EP x 2a --a R/T 4OOOcGy

Lost to F/U NED 62 NED 48 NED 20 NED 29 NED 73 Lost to FiU 28 NED 134 NED 19 NED 8 NED 144 DOD 15 Lost to F/U 2

2:: 2: 2:; Dyso

Ia Ia Ia Ia Ib IC

IIa IIa IIb IIIa IIIC Ilk

IIIC

TAH, total abdominal hysterectomy; BSO, bilateral salpingo-oophorectomy; Om, omentectomy; USO, unilateral salpingooophorectomy; App, appendectomy; PALND, para-aortic lymph node dissection; PLND, pelvic lymph node dissection; EP, etoposidekisplatin; BVP, bleomycinkinblastinekisplatin; R/T, radiotherapy; BEP, bleomycin/etoposidekisplatin; FKJ, follow up; NED, no evidence of disease;DOD, dead of disease. sPatient rejected further chemotherapy.

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S-N. Chow et al. /International Journal of Gynecology & Obstetrics 53 (19%) 151-158 Table 5 Summary of patients with mixed germ cell tumor (MGCT) of ovary Patient

Histology

Age

s=w

Surgery

Further management

Current status (momhs)

43 44 45 46 47 48 49 50

EST + Dysg EST + Dysg EST+ImmT+Germ EST+ImmT EST+ImmT EST+ImmT EST + Dysg EST + Dysg

20 17 27 33 15 24 23 15

Ia Ia Ia Ia IIa IIIC IIIC IIIC

us0 us0 us0 TAH,BSO,Om, App uso,om TAH,BSO,PLND TAH,BSO us0 USO,Deb*

BEP x 6, EP x 3 EP x 4 EP x 4 BVP x 4 BEP x 5, EP x 1 BEP x 4

NED 135 DOD 14 DOD 17 NED 42 NED 40 NED 10 DOD1 DOD 32

DOD 32 EST= endodermal sinus tumor; Dysg= dysgerminoma; Imm T = immature teratoma; Germ = germinoma; US0 = unilateral salpingo-oophorectomy; TAH = total abdominal hysterectomy; BSO = bilateral salpingo-oophorectomy; Om = omentectomy; App = appendectomy; PLND = pelvic lymph node dissection; Deb = debulking operation; BEP = bleomycin, etoposide, cisplatin; EP = etoposide, cisplatin; BVP = bleomycin, vinblastine, cisplatin; NED = no evidence of disease;DOD = dead of disease. l repeated operation.

oophorectomy (patient nos. 16-21 in Table 3, 3l-33 in Table 4) is good with all the patients alive (9/g). In contrast to the above result, patients of stage Ia EST and MGCT treated with unilateral salpingo-oophorectomy (patient no. 1 in Table 2, 43-45 in Table 5) had a poorer outcome; only one patient survived and the other three died of disease 14-17 months after diagnosis.

The usage of post-operative adjuvant chemotherapy was mainly based on the FIG0 stage and tumor histology of the disease. Generally speaking, chemotherapy was not used in stageIa disease of immature teratoma and dysgerminoma. VAC and VBP regimens were utilized in early 1980sfor EST and advanced-stagetumors of immature teratoma and dysgerminoma. BEP and EP regimens

Table 6 Chemotherapy regimens Regimen

Drugs

Dose

Schedule

Treatment courses

VAC

Vincristine Actinomycin D Cyclophosphamide Bleomycin Vinblastine Cisplatin Bleomycin Etoposide Cisplatin Etoposide Cisplatin VP- I6 (Etoposide) Ifosfamide Cisplatin

1.5 mg/m2 0.5 mg 150 ms/m2 20 mplm* 6 mg/m* 20 mg/m’ 25 mg/m2 100 mg/m* 100 mg/m* 100 mg/m* 100 mglm* 100 mg/m* 1.2 g/m* 20 mg/m*

IV on Dl every 2 weeks IV on Dl-5 every 4 weeks IV on Dl-5 every 4 weeks IV on Dl every 3 weeks IV on DI-2 every 3 weeks IV on Dl-5 every 3 weeks 24 h IV infusion on Dl-3 every 3 weeks IV on Dl-3 every 3 weeks IV on Dl every 3 weeks IV on Dl-3 every 3 weeks IV on Dl every 3 weeks IV on Dl-5 every 3 weeks 24 h IV infusion on Dl-5 every 3 weeks 24 h IV infusion on Dl-5 every 3 weeks

6 3 3 4

BVP BEP EP VIP

3-4 4-6 variable

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were applied in advanced-stagediseaseand some stage I diseasesince 1990 as their efficacies were proved [4,7l. VP-16 (etoposide), ifosfamide, and cisplatin (VIP) were put to use as salvagemanagement after all other trials failed. Chemotherapy was strictly given as scheduled in Table 6 except for neutropenia. A white count < 3000/~1or platelet c 100 OOO/plprior to chemotherapy required a l-week delay until these levels were reached. If the parameters were still below requirements 1 week later, etoposide, vincristine, actinomycin D, and cyclophosphamide will be 25% off if the white count is > 2000/~1, granulocytes are > lOOO/$, and platelets are > 50 OOO/~l.The regimens used are summarized in Table 6. Patient no. 15, a 33-year-old, gravida 2, para 2, was a case of EST stage IV who received laparoscopic left oophorectomy at another institute. Histology revealed EST and she was referred to our hospital. Laparotomy was performed 1 month 19 days later and showed diffuse implantation of cancerous mass in abdominal and pelvic cavity. Maximal debulking, including total abdominal hysterectomy, right salpingo-oophorectomy, omentectomy, hepatic lobectomy, splenectomy, resection of colon, ileum, and pancreatic tail, was done as much as possible. The patient died of disease 8 months after diagnosis even though chemotherapy was given with BEP regimen for rwo courses and VIP regimen for two courses. Except for six patients that were lost to follow up, 31144 (70%) patients are currently alive without evidence of disease. Immature teratoma (1 l/13, 85%) and dysgerminoma (g/10, 90%) ap peared to have the better prognosis, while EST (7113,54%) and MGCT (418,50%) had the poorer outcome. Histology, age, stage,management, and current status of all 50 cases are summarized in Tables 2-5.

4. Dl!seudoo

The results presented in this report demonstrate our experiencein the past 18 years. The treatment policy in the seriesis mainly surgical intervention exclusively, followed by adjuvant chemotherapy,

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dependending on the contemporary treatment principles [81. Endodermal sinus tumor remains the most virulent germ cell tumor. Six out of 13 died of disease 8-52 months later, even under adjuvant chemotherapy after surgery (Table 2). Slayton et al. [9] reported VAC as an effective regimen in 16123 surgically resected tumors (stage I-IIa). In more advanced disease (stage II-IV), platinum-based chemotherapy should be used exclusively in view of the high failure rate of VAC. BVP and BEP are both effective, but the former is more toxic with possible neuromuscular damage. AFP servesas a good indicator in evaluating chemotherapy effectivenessand we used 20 rig/ml as the cut-off point. Treatment of immature teratoma is based on FIG0 stageand histologic grade of the tumor. In our experience, patients with stage Is/grade 1 immature teratoma can be safely treated with unilateral oophorectomy, and no more chemotherapy is required. Stage Wgrade 2 or 3 as well as stage Ib through IIc disease require short-term chemotherapy of VAC or platinum-based regimen for three to six courses. Long-term chemotherapy, perhaps 1 year with combination therapy, might be more effective for advanced-stageimmature teratoma than the short-term therapy [lo]. Dysgerminoma is the only germ cell malignancy that may occur bilaterally. Patients who are suspectedto have dysgerminoma at surgery should receive wedge resection of the normal-appearing contralateral ovary. Early-stage dysgerminoma can usually be treated with unilateral oophorectomy if preservation of reproductive function is considered. For patients with advanced-stage disease, chemotherapy and/or radiotherapy may serve as an adjuvant therapy. The advantage of chemotherapy over radiotherapy in young women is preservation of reproductive function. Both VAC and platinum-based chemotherapy are efficacious in treating advanced-stage dysgerminoma [ 111. Schwartz [12] recommended that dysgerminoma patients who are under VAC treatment defer pregnancy for 1 year after combination chemotherapy, becausethey will ovulate, and the malignancy may recur within a short time after completion of treatment. The management of mixed germ cell tumors

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should be based on the histology of the tumor as well as on the FIG0 stage.If the tumor is composed of immature teratoma and dysgerminoma, treatment of stage I diseasecan be VAC or BEP chemotherapy. Therapy for more advanced stage disease should be long-term chemotherapy to make sure that any immature teratomatous elements have been adequately exposed to the therapy. For advanced-stage tumors that contain endodermal sinus elements, the treatment should be BEP chemotherapy [ 121. Only nine of 18 stageIII and IV patients appear to have been cured with our management. We reanalyzed the clinical data: three patients were treated in 1979-1984 with VAC regimen which is supposedto be lesseffective for malignant ovarian germ cell tumors; four patients had diffuse cancerousinvasion and received suboptimal surgical resection; one patient rejected adjuvant chemotherapy. All the above may be reasonsfor the poor survival rate of advanced-stage patients in our series. Generally, a chemotherapeutic agent, if used to treat a given neoplasm after failure of another drug, has a smaller chance of successthan the sameagent used as primary treatment [ 141.Jacobs et al. [ 151explained the possible causesas follows: a failed regimen may select for more virulent class of tumor; the patient is less able to tolerate an additional therapeutic regimen after having received the initial chemotherapeutic agents; and host resistance of patients to tumors may be weakened by prolonged illness and rigorous treatment. The EP regimen is lesstoxic than BEP and BVP. A report of EORTC (European Organization for Researchand Treatment of Cancer) noted no therapeutic difference between BEP and EP in goodprognosis patients [ 131. So EP is generally the first-line of therapy for early stage diseasein our series. The volume of residual tumor has an impact on survival in our series, and inability to tolerate chemotherapy does not. Twenty-seven out of 31 patients with < 1 cm residual tumor diameter are alive at present, while four out of 13 with > 1 cm residual tumor diameter are alive (P < 0.05, Fisher’s exact test); 19/27patients who can tolerate chemotherapy well are alive presently, and three

157

out of seven who cannot tolerate chemotherapy well are alive (P > 0.05, Fisher’s exact test). Tumor markers, including AFP, are checked at the initiation of each chemotherapy as the guide of treatment. If tumor markers persist abnormally high after completion of chemotherapy, further chemotherapy will be given and we may change to a more effective regimen. For those without tumor markers available, we will arrange computed tomography or second-look laparotomy as treatment guidance. The significance of second-look laparotomy in patients with ovarian germ cell malignancies have yet to be established. The monitoring of serum tumor markers is an alternative to second-look laparotomy. The procedure should only be indicated in patients without detectable tumor markers. Gershenson et al. [16] suggested that second-look laparotomy should be considered for those patients entering clinical trials in new agents or study regimens, and for those patients with advanced disease. An EST patient in our series suffered from diffuse cancerous implantation in abdominal cavity after laparoscopic oophorectomy. Maiman et al. [ 171concluded that attempted laparoscopic excision of adnexal masses that are subsequently found to be malignant are not uncommon. Potential problems with this approach include inappropriate surgical procedures, incomplete surgical staging, inadequate patient preparation and delay in definitive therapy. He suggestedthat if there is suspicion of ovarian cancer upon laparoscopic evaluation, the ovarian capsule should not be violated and laparotomy should be initiated. Laparoscopic ovarian surgery should be performed using strict criteria to reduce the likelihood that a malignancy will be disrupted. About 70-80% of patients with disseminated germ cell tumors will achieve a durable complete remission (CR) with modem cisplatin-based chemotherapy [7,18]. Ifosfamide in combination with cisplatin and either etoposide (VIP) or vinblastine (VeIP) was investigated as salvage therapy, and induced a durable CR in one-third of patients [19,20]. More recently, high dose carboplatin, etoposide, and ifosfamide followed by autologous bone marrow transplantation achieved

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a 23-3 1%CR rate [21,22]. This is still under investigation and is hopeful for patients with poor prognostic fkatures. References

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