Malignant germ cell tumors of the ovary

European Journal of Obstetrics & Gynecology and Reproductive Biology 90 (2000) 87–91

www.elsevier.com / locate / ejogrb

Original Article

Malignant germ cell tumors of the ovary Pregnancy considerations a b, c a a Younes N. Bakri MD , Adnan Ezzat MD *, Akhtar MD , Dohami MD , Zahrani MD a

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, King Fahad National Guard Hospital, Riyadh, Saudi Arabia b Division of Gynecologic Oncology, Department of Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia c Division of Gynecologic Oncology, Department of Pathology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia Received 4 January 1999; received in revised form 3 August 1999; accepted 12 August 1999

Abstract Objective: To study the pregnancy association and malignant germ cell tumors of the ovary with regard to its effects on tumor prognosis. Study Design: : Seventy-five patients with malignant germ cell tumors of the ovary treated at the King Faisal Specialist Hospital-Research Center (KFSH–RC) Riyadh, Kingdom of Saudi Arabia between January 1976 and December 1992, were reviewed. Data was retrieved from the medical records and the database of ovarian tumor pathology. Patients with tumor / pregnancy association were identified and correlation with obstetrical outcome and tumor prognosis analyzed. Patients who conceived after treatment were identified and their reproductive outcome described. Results: Malignant germ cell tumor was associated with pregnancy in a group of ten patients. Possible tumor effects upon pregnancy in this group included operative delivery by caesarean section (n53), mid-trimester termination (n52), spontaneous abortion (n51). Four patients had normal vaginal birth with no apparent tumor effects upon pregnancy. Pregnancy did not seem to influence the tumor prognosis of pure dysgerminoma (n56), however, two patients with non-dysgerminomatous germ cell tumor (one endodermal sinus tumor and one immature teratoma) died of rapidly progressive disease during the second trimester. Two patients with advanced (stage IIIC) disease concurrent with pregnancy (one pure dysgerminoma and one mixed germ cell tumor), had normal fetal outcomes and achieved long-term survival. Amongst the 22 patients who planned to conceive after conservative surgery, with or without post-operative adjuvant chemotherapy, 12 conceived (12 / 22) and achieved a total of 20 pregnancies. Their outcomes included normal births (n518) including one set of twins and hydatidiform moles (n52). Conclusions: Our findings suggest that, (1) The association of pure dysgerminoma and pregnancy did not adversely affect the tumor prognosis or fetal outcome. However, the question remains as to whether pregnancy worsened the prognosis of non-dysgerminomatous germ cell tumors. (2) Recent platinum-based regimens of multiagent chemotherapy for germ cell tumors did not seem to affect fertility potential.  2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Pregnancy; Prognosis; Germ cell; Cisplatinum; Ovary

Introduction An ovarian malignancy occurring in association with pregnancy is rare, accounting for only 2–5% of ovarian tumors discovered during pregnancy (an incidence of 1 in 15,000–1 in 32,000 pregnancies) [1]. It is particularly *Corresponding author. Tel.: 1966-1-442-3935; fax: 1966-1-4423941.

important that the management of malignant germ cell tumors be optimized because, with appropriate therapy, many of these tumors are potentially curable [2]. Indeed during the last two decades the remarkable improvement in the therapeutic outcome of patients with these tumors is rivaled only by the almost complete curability of gestational trophoblastic disease [3]. If correctly managed, a young woman with malignant germ cell tumor now has more than a 85% chance of being cured and a reasonable chance of

0301-2115 / 00 / $ – see front matter  2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0301-2115( 99 )00213-4

88

Y.N. Bakri et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 90 (2000) 87 – 91

remaining fertile [4,5]. The purpose of this study is to report our experience with malignant germ cell tumors of the ovary with regard to pregnancy.

Materials and methods Between July 1976 and December 1992, 75 patients with malignant germ cell tumor of the ovary were treated at the King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia (KFSH&RC). Sixtyeight patients were between 14 to 45-year-old at the time of this study or the date of primary surgery. Data were retrieved from hospital medical records and computerized ovarian tumor pathology database, which were available for all subjects (n575). Each patient underwent a complete metastatic workup including history and physical examination, blood chemistry studies, and imaging studies. Tumor markers were measured before therapy and included quantitative beta subunit human chorionic gonadotropin assay (B-HCG), alphafetoprotein (AFP), carcinoembryonic antigen (CEA), and lactic dehydrogenase (LDH) / LDH iso enzymes. Cases of benign cystic teratoma were excluded. To insure adequate study of these neoplasms, one author (M.A.) reviewed the microscopic pathology slides and, when needed, further consultation was initiated with major institutions in USA. All patients with the diagnosis of malignant immature teratoma were histologically graded according to the criteria of Thurlbeck & Scully [6]. The 1988 International Federation of Gynecology and Obstetrics (FIGO) Staging System [7] was retrospectively assigned for each case after reviewing the operative reports and microscopy slides. Patients who did not have an appropriate staging with histological documentation of retroperitoneal lymph nodes, omentum, peritoneum, etc. were labeled ‘‘stage undetermined’’. Cases where the surgeon described ‘‘non-palpable’’ retroperitoneal lymph nodes without histologic confirmation, were labeled as stage ‘‘undetermined’’. Second-look laparotomy was performed on a selective basis. Relaparotomy was performed on inadequately staged patients with pure dysgerminoma for the purpose of identifying those who could be spared the chemotherapy treatment (stage IA dysgerminoma). For the purpose of this study, the antenatal, intrapartum, and postpartum records were reviewed for patients delivered at KFSH&RC, while for patients delivered elsewhere, this information was obtained from the referring hospitals.

Results Seventy-five patients with malignant germ cell tumor represented 14.2% of 526 patients treated for primary ovarian cancer at KFSH–RC between January 1976–December 1992. Histopathologic subtypes of these tumors

were: pure dysgerminoma (n532), immature teratoma (n5 18), endodermal sinus tumor (n510), mixed germ cell tumor (n59), malignant transformation in a dermoid cyst (n54, including three squamous cell carcinomas and one carcinoid tumor), embryonal carcinoma (n51), primary ovarian non-gestational choriocarcinoma (n51). Table 1 shows the clinical / pathological profiles of the ten patients with germ cell tumor of the ovary who had the diagnosis made during pregnancy or postpartum period. In this group histopathologic categories included mixed germ cell tumor (n51), endodermal sinus tumor (n51), dysgerminoma (n56), and immature teratoma (n52). Of the four patients who had the tumor concurrent with pregnancy at third trimester, three underwent caesarean sections, and one had spontaneous vaginal birth. All patients with pure dysgerminoma in this group survived and achieved normal fetal outcome except one patient who had a newborn with spina bifida perhaps unrelated to the presence of tumor. Of the two patients who died, one had endodermal sinus tumor stage IIIC, and one had immature teratoma stage undetermined ?III. Both manifested a rapidly progressive disease and died during the second trimester. Abdominal swelling (with or without pain) was the most common presenting symptom. Among patients with appropriate surgical staging, the disease was stage IA (n51), IC (n52), IIIC (n53). The stage was undetermined because of incomplete initial surgical staging in four patients. Failure to sample the retroperitoneal lymph nodes was common to all ‘‘undetermined’’ stage patients. Among the 68 non-pregnant patients who were 14 to 45-years-old, 22 were included in the evaluation of reproductive performance (married social status plus conservative surgery including unilateral salpingo-oophorectomy without hysterectomy). Forty-six patients were excluded because of unmarried social status (n528), hysterectomy and / or bilateral salpingo oophorectomy (n59), loss to follow-up (n52), or death (n57). Among patients included (n522), 12 conceived (12 / 22). Six of these patients (6 / 12) did not receive post-operative chemotherapy, five (5 / 12) received cis-platinum-based combination chemotherapy, and one (1 / 12) had received methotrexate, 5-fluorouracil and vincristine combination chemotherapy. Table 2 shows the clinical / pathological profiles. Twelve patients gave birth to a total of 18 normal newborns. One patient with stage IC dysgerminoma diagnosed at age 14 years had two consecutive hydatidiform moles after primary surgery, without postoperative chemotherapy. One patient conceived and had normal twins. This patient had stage IIIC dysgerminoma with positive retroperitoneal paraaortic lymph nodes, and received three courses of bleomycin, etoposide and cis-platinum (BEP) combination chemotherapy. None of the patients received chemotherapy with the fetus in-utero. Of the 12 patients who conceived after treatment, seven had undergone wedge biopsy of the contralateral ovary during the initial surgery. One patient

Y.N. Bakri et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 90 (2000) 87 – 91

89

Table 1 Clinical / pathological profiles of patients with germ cell tumor of the ovary diagnosed during pregnancy or postpartum [

Pathology / year dx

Age

Pregnancy period

Presenting symptoms / signs

Fetal outcome

Surgery

FIGO stage

1

Dysgerminoma 1988

28

Concurrent pregnancy 34 weeks

Normal

-Lt oophorec tomy -Staging laparotomy

IC

2

Dysgerminoma 1988 Dysgerminoma 1983

19

Concurrent pregnancy at term Post partum 2 weeks

Normal

-Rt S.O. -Staging laparotomy Rt oophorectomy

IC

4

Dysgerminoma 1988

18

Postpartum 10 weeks

5

Dysgerminoma 1983 Dysgerminoma 1989 Immature teratoma grade II 1989 Mixed germ cell tumor 1988 Endodermal sinus tumor 1990

22 25

Concurrent pregnancy at term Postpartum 6 weeks

-Abdominal swelling large for date -Fever -Asymptomatic -Obstructed labor -Abdominal swelling after childbirth -Rt adnexal mass -Painful abdominal swelling -Ascites -Asymptomatic -Solid pelvic mass Lower abdominal pain

33

Post abortion 10 weeks

Abdominal pain and mass

N /A

17

Concurrent pregnancy at term

-Abdominal mass -Pelvic mass

Normal

-Rt oophoretomy -Staging laparotomy

IIIC1aortic nodes

25

Concurrent pregnancy 16 weeks

N /A

-TAH-BSO -Staging laparotomy

IIIC1aortic nodes

Immature teratoma grade II 1982

21

Concurrent pregnancy 8 weeks

-Weight loss -Dyspnea, fever, and jaundice -Ascites Abdominal pain, fever, sweating and weight loss

N /A

TAH-BSO

Undetermined ?III

3

6 7

8

9

10

17

Normal

Undetermined ?I

Normal

-Lt oophorectomy -Rt ovarian biopsy

Undetermined ?I

Spina bifida

Rt S.O.

Normal

-Lt S.O. -Staging laparotomy -Lt S.O. -Staging laparotomy

Undetermined ?I IIIC1aortic nodes IA

N /A5Non applicable.

received 200 rads whole abdominal radiation after which a decision was made to discontinue treatment, she conceived and had three normal vaginal births.

Discussion Of all ovarian neoplasms associated with pregnancy, estimation of malignancy ranges from 2 to 5%, an incidence similar to that of non-pregnant patients in the corresponding age group [1,8]. Dysgerminomas are the most common malignant germ cell tumors, they also constitute 25–35% of all ovarian cancers coexisting with pregnancy and, [9,10] conversely, 15–20% of dysgerminomas may be discovered during pregnancy or in the immediate postpartum period [11]. Obstetric complications resulting from dysgerminoma were numerous in the collected series of Karlen et al. [8] who noted that 47% of patients had associated complications such as caesarean section, and observed that the management of pregnancy was frequently altered to accommodate for the presence of the ovarian tumor. Adverse effect on the fetus was demonstrated by the 24% fetal death rate presumably attributable to alteration in the obstetrical management. Our findings demonstrate a similar obstetrical complication trend, but the fetal outcome was not adversely affected in 6 / 6 patients who had pure dysgerminoma associated with

pregnancy. Non-dysgerminomatous germ-cell tumors, however, manifested a different biological behavior in pregnancy. Two of our patients (one endodermal sinus tumor and one immature teratoma grade II) died of rapidly progressive disease concurrent with pregnancy, together with fetal loss related to therapeutic mid-trimester pregnancy termination. Endodermal sinus tumor, the second most common germ cell tumor, occurs mostly in children and young adults [12]. Only twelve cases of endodermal sinus tumor concurrent with pregnancy have been described [1,10,13– 18]. These tumors grow rapidly. For example nearly half of the patients in the Kurman and Norris [16] series presented with symptoms of one week or less duration and a number of these patients had symptoms for less than 24 h. Similarly, the tumor became evident during a brief period of observation in a case described by Schwartz et al. [13], who suggested that the rapid growth of the endodermal sinus tumor and specifically that which occurs in pregnancy could be due to the following reasons: torsion with bleeding into the tumor; immunosuppressive effect of the pregnancy; and immunosuppressive effect of the tumor. Mixed germ cell tumor of the ovary constitute one of the subcategories of germ cell tumors as noted in the World Health Organization classification [19]. The term ‘‘mixed germ cell tumor’’ denotes a germ cell tumor composed of

Y.N. Bakri et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 90 (2000) 87 – 91

90

Table 2 Clinical / pathological profiles of patients who conceived after diagnosis of germ cell tumor of the ovary [

Histopathology

Age

Operative Findings

FIGO Stage

Adjuvant Therapy

Pregnancy Date / Outcome

1 2

Dysgerminoma Dysgerminoma

19 23

Stage IC Stage IC

None BEP33

1992-Normal 1989-Normal 1993-Normal

3

Dysgerminoma

14

Stage IC

None

1990-Hydati-diform mole 1991-Hydati-diform mole

4

Dysgerminoma

17

Solid mass 1431335 cm -Lt ovarian tumor 1431437 cm -Bowel adhesions -Lt ovarian mass 1231036 cm -Hemorrhagic ascites -Rupture capsule Mass right ovary 10 cm

Undetermined ?

-Radiation 200 rads -Whole abdomen

5

Dysgerminoma

18

Undetermined ?I

None

6

Dysgerminoma

14

-Mass Lt ovary 16 cm -Ascites -Rupture capsule -Omental adhesions -Rt ovarian mass 20315 cm Recurrence mass 213939 cm Lt ovarian tumor 30325 cm Recurrent disease in the omentum and retroperitoneal nodes Rt ovarian solid mass 2 kg

1984-Normal 1987-Normal 1990-Normal 1990-Normal 1992-Normal

Undetermined ?I

None before recurrence

7

Dysgerminoma

17

8

Dysgerminoma

22

9

Dysgerminoma

25

1 0 1 1 1 2

Immature teratoma grade III Endodermal sinus tumor Choriocarcinoma (nongestational)

32 23 16

-Mass Lt ovary 18.5312 310 cm -aortic nodes metastases -Intact capsule Twisted Rt ovarian mass 14 cm Rt ovarian mass 123933 cm. Intact capsule -Hemorrhagic Rt ovarian cysts 1831439 cm -Adhesions to omentum and intestine

1987-Normal

Recurrence

BEP35 and 5000 R for recurrence in 1988

Undetermined ? Recurrence node and omentum

None before recurrence Radiation pelvis / abdomen mediasti-num 2000–44 000 rads

Undetermined ?I Stage IIIC

None

1993-Normal

BEP33

1990-Normal 1993-Normal twins

BEP34

1993-Normal

BE34

1990-Normal

Methotrexate & 5-FU & Vincristine315

1984-Normal

Undetermined ?I Undetermined ?I Stage IV

None after radiation Rx for recurrence 1977-Normal 1978-Normal

BEP5Bleomycin, etoposide, cis-platinum; 5FU55 Flourouracil; R5rad.

two or more malignant germ cell elements. In the past it was common practice to classify germ cell tumors according to the predominant element present. Recent emphasis on careful sampling and thorough analysis of these tumors has shown that mixed tumors are more common than originally thought. Although much progress in the understanding and treatment of these tumors has transpired in the last 10–15 years [20], only continued meticulous study of these neoplasms will reveal possible differences in biological behavior and / or prognosis in association with pregnancy. Before combination chemotherapy was introduced in the mid-1960’s, the prognosis for patients with malignant germ cell tumors of the ovary, exclusive of dysgerminoma, was dismal [21,22]. Since that time, however, several investigators have reported a high degree of success with a variety of combination chemotherapy regimens [23–26]. Because of

the resultant increasing frequency of long-term survivors, attention has recently focused on a variety of late sequelae, in particular, the effects of chemotherapy on ovarian function and reproductive potential [27]. The primary lesion in women receiving chemotherapy appears to be follicle destruction plus ovarian stromal fibrosis [28,29]. Clinical findings in such patients include anovulatory cycles with irregular bleeding, progressing to oligomenorrhea, and eventually amenorrhea. Premature menopause may also occur [27]. Early reports [30] seemed to emphasize the potentially harmful consequences, including infertility. However, more recent studies of the effects of chemotherapy on female patients with Hodgkin’s disease [31] and leukemias [32] have included several patients with subsequent normal ovarian function and successful pregnancies. Reporting the Yale University experience, Schwartz, et al. [33] suggest that preservation of reproductive function

Y.N. Bakri et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 90 (2000) 87 – 91

in advanced disease is possible, particularly if the contralateral ovary is normal. One such patient in our series conceived and had two normal births. Admittedly, the retrospective nature of our study and the relatively small number of cases make it difficult to draw firm conclusions. However, given the rarity of malignant germ cell tumors, it is perhaps justified, with these limitations in mind, to support the conclusions of other reports [33] that the natural history of these tumors may be different from that of common malignant epithelial tumors, enough to warrant different management recommendations, with conservative surgery applicable for selected advanced stages without jeopardizing the chances of cure.

References [1] Malone JM, Gershenson DM, Creasy RK, Kavanagh JJ, Silva EG, Stringer CA. Endodermal sinus tumor of the ovary associated with pregnancy. Obstet Gynecol 1986;68:86S–9S. [2] Thomas GM, Dembo AJ, Hacker NF, DePetrillo AD. Current therapy for dysgerminoma of the ovary. Obstet Gynecol 1987;70:268–75. [3] Creasman WT, Soper JT. Assessment of the contemporary management of germ cell malignancies of the ovary. Am J Obstet Gynecol 1985;53:828–34. [4] Vergote IB, Abeler VM, Kjorstad KE, Trope C. Management of malignant ovarian immature teratoma-role of Adriamycin. Cancer 1990;66:882–6. [5] Rustin GJS. Managing malignant ovarian germ cell tumors. Br Med J 1987;295:869–70. [6] Thurlbeck WM, Scully RE. Solid teratoma of the ovary: A clinicalpathologic analysis of 9 cases. Cancer 1960;13:804–11. [7] Creasman WT. New gynecologic cancer staging. Obstet Gynecol 1990;75:287–8. [8] Karlen JR, Akbari A, Cook WA. Dysgerminoma associated with pregnancy. Obstet Gynecol 1979;53:331–4. [9] Creasman WT, Rutledge F, Smith JP. Carcinoma of the ovary associated with pregnancy. Obstet Gynecol 1971;38:111–6. [10] Novak ER, Lambrou CD, Woodruff JD. Ovarian tumors in pregnancy. Obstet Gynecol 1975;46:401–6. [11] Krepart G, Smith JP, Rutledge F et al. The treatment of dysgerminoma of the ovary. Cancer 1978;41:986–90. [12] Farahmand SM, Marchetti DL, Asirwatham JE, Dewey MR. Ovarian endodermal sinus tumor associated with pregnancy: Review of the literature. Gynecol Oncol 1991;41:156–60. [13] Schwartz RP, Chatwani AJ, Putong PB. Endodermal sinus tumor in pregnancy: Report of a case and review of literature. Gynecol Oncol 1983;15:434–9. [14] Petrucha RA, Ruffolo E, Prophat H. Endodermal sinus tumor: Report of a case associated with pregnancy. Obstet Gynecol 1980;55:90S–3S.

91

[15] Azoury RS, Nasr MF, Muawwad RF. The endodermal sinus tumor: Special features. Int J Gynecol Obstet 1979;17:164–71. [16] Kurman RJ, Norris HJ. Endodermal sinus tumor of the ovary: A clinico-pathologic analysis of 71 cases. Cancer 1976;38:2404–19. [17] Weed JC, Roh RA, Mendenhall HW. Recurrent endodermal sinus tumor during pregnancy. Obstet Gynecol 1979;54:653–6. [18] Van der Zee AGJ, Bruijin HWA, Bouma J, Vries EGE. Endodermal sinus tumor of the ovary during pregnancy: A case report. Am J Obstet Gynecol 1991;164:504–7. [19] Serov SF, Scully RE, Sobin LH. Histological typing of ovarian tumors. International histological classification of tumors. No. 9, Geneva: World Health Organization, 1973. [20] Gershenson DM, Del Junco G, Copeland LJ, Rutledge FN. Mixed germ cell tumors of the ovary. Obstet Gynecol 1984;64:200–6. [21] Gershenshon DM, Morris M, Cangir A, Kavanagh JJ, Stringer CA, Edwards CL, Silva EG, Wharton JT. Treatment of malignant germ cell tumors of the ovary with bleomycin, etoposide, and cisplatin. J Clin Oncol 1990;18:715–20. [22] Jimerson GK, Woodruff JD. Ovarian extraembryonal teratoma: II Endodermal sinus tumor mixed with other germ cell tumors. Am J Obstet Gynecol 1977;127:302–4. [23] Forney JP, DiSaia PJ, Morrow PC. Endodermal sinus: A report of two sustained remissions treated postoperatively with a combination of actinomycin-D, 5-fluorouracil and cyclosphosphamide. Obstet Gynecol 1975;45:186–9. [24] Creasman WT, Fetter BF, Hammond CB et al. Germ cell malignancies of the ovary. Obstet Gynecol 1979;53:226–30. [25] Malkasian GD, Webb MJ, Jorgensen EO. Observations on chemotherapy of granulosa cell carcinoma and malignant ovarian teratomas. Obstet Gynecol 1974;44:885–8. [26] Slayton RE, Hreshchyshyn MM, Silverberg SG et al. Treatment of malignant ovarian germ cell tumor. Cancer 1978;42:390–8. [27] Gershenson DM. Menstrual and reproductive function after treatment with combination chemotherapy for malignant ovarian germ cell tumors. J Clin Oncol 1988;6:270–5. [28] Schilsky RL, Lewis BJ, Sherins RJ et al. Gonadal dysfunction in patients receiving chemotherapy for cancer. Ann Intern Med 1980;93:109–14. [29] Nicosia SV, Matus-Ridley M, Meadows AT. Gonadal effects of cancer therapy in girls. Cancer 1985;55:2364–72. [30] Sobrinho LG, Levine RA, DeConti RC. Amenorrhea in patients with Hodgkin’s disease treated with antineoplastic drugs. Am J Obstet Gynecol 1971;109:135–9. [31] Horning SJ, Hoppe RT, Kaplan HS et al. Female reproductive potential after treatment for Hodgkin’s disease. N Engl J Med 1981;304:1377–82. [32] Siris ES, Leventhal BG, Vaitukaitis JL. Effects of childhood leukemia and chemotherapy on puberty and reproductive function in girls. N Engl J Med 1976;294:1143–6. [33] Schwartz PE, Chambers SK, Chambers JT, Kohorn E, McIntosh S. Ovarian germ cell malignancies: The Yale University experience. Gynecol Oncol 1992;45:26–31.