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Ovarian Germ-Cell Malignant Tumors

Ovarian Germ-Cell Malignant Tumors

Ovarian germ- malignant tumors

Author: Doctor Isabelle Ray-Coquard1 Creation Date: August 2002 Update: March 2004

Scientific Editor: Professor Thierry Philippe

1Département de médecine carcinologique, Centre Léon Bérard, 28 rue Laënnec, 69373 Lyon Cedex 8, France. [email protected]

Abstract Keywords Definition Frequency Diagnostic methods Disease progression Management Etiology References

Abstract Ovarian germ-cell tumors represent 15-20% of all ovarian tumors. They are rapidly growing that arise from primordial germ cells derived from the embryonal . Malignant germ-cell tumors represent 5% of ovarian tumors. Their annual incidence in France is 0.5/100.000 . The diagnosis, suspected on physical examination, relies on pelvic or transvaginal ultrasonography detection of a voluminous ovarian mass responsible for abdominal discomfort and/or swelling, but is only confirmed during the initial surgical intervention (). Dosage of tumor markers -human chorionic gonadotropin (hCG), (LDH) and alpha-fetoprotein (αFP)- also contribute to the diagnosis, the prognosis and follow-up of the disease. Surgery is the main therapeutic modality; it consists of excision of the tumor masses and preservation of reproductive function should be attempted. Among non-hematological , malignant germ-cell tumors can be curable with cytotoxic and the introduction of into therapeutic regimens constituted a decisive advancement. Malignant ovarian germ-cell tumors share a common cytogenetic characteristic with all ovarian, testicular or extragonadal germ-cell tumors of children and adults: the presence of an isochromosome of the short arm of 12 [i(12p)], which is not found in any other type of .

Keywords Ovarian germ-cell tumors, embryonal gonad, chorionic gonadotropin (hCG), lactate dehydrogenase (LDH), alpha-fetoprotein (αFP), isochromosome 12 [i(12p)]

Definition encountered, particularly for tumors associating Germ-cell tumors of the represent 15–20% several histological types. of all ovarian tumors. These rapidly growing Two histological groups are distinguished: neoplasms arise from primordial germ cells (45%), equivalent to testicular derived from the embryonal gonad and can , and non-dysgerminomatous (non- reach impressive dimensions in a short period of seminomatous) tumors. The latter include: time. Approximately 95% of germ-cell tumors 1. -sac tumors or endodermal sinus tumors are represented by benign cystic and (20%); are relatively easy to diagnose. The remaining 2. teratomas (20%) classified into three grades 5% are malignant germ-cell tumors and are according to the extension of the immature responsible for most of the diagnostic difficulties

Ray-Coquard I, Ovarian tumors of cord–stromal origin. Orphanet Encyclopedia. March 2004. http://www.orpha.net/data/patho/GB/uk-OVARI.pdf 1

neuroectodermal component (the present Type of tumor αFP hCG LDH tendency is to combine grades II and III); - +/- + 3. rare pure embryonal (< 5%); Endodermal sinus tumor + - +/- 4. pure (< 1%); Immature teratoma +/- - +/- 5. composite tumors (10%), including mature Embryonal +/- + +/- and immature teratomas and/or yolk-sac tumors, - + +/- and associated with a +/- +/- +/- predominantly dysgerminomatous component Table 1. Serum markers of malignant ovarian germ-cell (Scully, 1979). tumors

Frequency When an ovarian germ-cell tumor is suspected, Malignant germ-cell tumors represent 5% of these markers should systematically be tested ovarian tumors. The annual incidence in France before surgical intervention, and even before any is 0.5/100.000 females and the number of new surgery for a pelvic mass in a young woman. cases/year is estimated to be around 100 (Williams and Gershenson, 1993). Disease progression Dosage of tumor markers — hCG, LDH and αFP Diagnostic methods — is also informative in terms of prognosis and The diagnosis, suspected based on physical follow-up of disease progression. Even though examination, relies on pelvic or transvaginal their prognostic values have not been clearly ultrasonographic demonstration of a voluminous established, an increased concentration signals ovarian mass responsible for abdominal a tumor relapse. Although the specificities of discomfort and/or swelling. For certain these markers are very high, their sensitivities histological subtypes, notably embryonal are not definitive, as clinical progression can carcinoma, signs of precocious are occur in the absence of increased sometimes the factors motivating consultation. concentrations of tumor markers (Bidart et al., But it is the first surgical intervention 1992; Droz et al., 1992). (laparotomy) that establishes the diagnosis. The Patient’s age (above 22 years) has also been latter can also be made based on dosage of the described a negative prognostic factorto be following tumor markers (see Table 1): taken into consideration (Mayordomo et al., 1994). Human chorionic gonadotrophin (hCG) Other tumor markers have been evaluated hCG, a glycoprotein with molecular mass of 33 (CA125, CA19.9, neuron-specific enolase (NSE), kDa and a half- of 3 days, can be measured angiotensin, macrophage–colony-stimulating by radioimmunoassay. It is secreted by mixed or factor (MCSF)) (Kawai et al., 1991). However, pure choriocarcinomas and by individual their concentrations have only been measured in cells. The hCG level can be a small number of patients, so their contribution moderately elevated in patients with pure outside a therapeutic trial has not yet been dysgerminomas. hCG is comprised of two determined (Suzuki et al., 1998). subunits: an alpha-subunit, common with Several studies have attempted to identify hypophyseal hormones, and a beta-subunit prognostic factors able to establish metastatic specific to hCG. risk. Frequently described factors include: tumor size (> 10 cm), histological type (endodermal Alpha-fetoprotein (αFP) sinus, choriocarcinoma) and a high histological αFP, a glycoprotein with molecular mass of 130 grade (for immature teratomas) (Kurman and kDa and a half-life of 7 days, can be measured Norris, 1976a; Norris et al., 1976). Residual by radioimmunoassay. It is secreted by yolk-sac tumor after surgery appears to be a determinant tumors and some embryonal carcinomas. Its negative prognostic factor (Slayton, 1984; level is often elevated in patients with mixed Williams et al., 1989). tumors and is never above normal in those with pure dysgerminomas. Management Treatment of rare ovarian tumors is currently as Lactate dehydrogenase (LDH) follows. Measurement of LDH concentrations is Surgery is the same as that for ovarian particularly informative for patients with , with one major difference: dysgerminomas for whom they are often conservation of reproductive function in women elevated (Sheiko and Hart, 1982). of reproductive age is usual case for this type of tumor. Chemotherapy, based on data reported in the literature, is the same as that prescribed for testicular germ-cell tumors.

Ray-Coquard I, Ovarian tumors of sex cord–stromal origin. Orphanet Encyclopedia. March 2004. http://www.orpha.net/data/patho/GB/uk-OVARI.pdf 2

Surgery, chemotherapy and possible surgical has benefited from the therapeutic intervention for residual lesions is highly advancements made against testicular germ-cell complex. tumors. The inclusion of cisplatin in therapeutic regimens constituted a decisive step forward that Surgical management radically prolonged patient survival (Einhorn, The initial surgery is primordial for these rare 1981). Studies that have been published mainly ovarian tumors because it provides the considered the association of PVB (cisplatin, diagnosis, determines the extent of disease vinblastine and ). Since 1987, dissemination and is also the first therapeutic vinblastine has been replaced by , modality. because the BEP (bleomycin, etoposide and Although many patients underwent initial surgery cisplatin) regimen was shown to be as effective to excise ‘all’ tumor masses (total as PVB against testicular tumors and less toxic with bilateral adnexectomy, omentectomy, (Williams et al., 1987). Chemotherapy should be complete abdominal exploration and lymph-node adapted to the histological type and the tumor dissection), some were able to have stage (Culine et al., 1997b). Because of the conservative surgery (preserving the rapid tumor growth, it should be started shortly contralateral ovary and the uterus) associated after surgery (1 week to 10 days) (Herrin and with a complete abdominal exploration) (Culine Thigpen, 1999). et al., 1997a). The acute toxicities observed, especially Exploratory surgery after chemotherapy is not hematological, are the same as those reported indicated for pure dysgerminomas, even if during chemotherapy for testicular germ-cell retroperitoneal masses persist, because they tumors (Einhorn, 1990). often do not contain viable tumor cells and can continue to regress; endodermal sinus tumors Treatment of relapses and choriocarcinomas secrete sufficiently Among patients who had been in relapse after reliable tumor markers (aFP and bhCG, first-line surgery and/or radiotherapy, 69% respectively); patients with early stage disease treated with a cisplatin-containing regimen and for whom the initial surgery was complete. achieved long-term complete remissions Surgical reintervention is necessary in the (Williams et al., 1989). Concerning salvage following situations. When only were therapy after the failure of chemotherapy, the taken during the first surgery, reintervention indications for surgery at relapse are still being consists of excising the ovary where the primary discussed and the results of second-line tumor was located. For embryonal carcinomas chemotherapy have been difficult to analyze. As or mixed non-secretory germ-cell tumors, it is regards relapse treatment, sensitivity to platinum essential to remove residual lesions after has appeared, only recently, to be an important chemotherapy because neither imaging nor element. Indeed, patients relapsing more than 6 tumor markers are sufficiently reliable to weeks after the end of cisplatin therapy are determine their histological nature (Gershenson, defined as being platinum-sensitive, whereas 1993, 1994). Certain components of teratomas, those whose disease progressed in less that 6 especially neuroectodermal, can, by losing all weeks after the end of the chemotherapy their malignant potential, evolve towards regimens are considered to be platinum-resistant maturation. This mature can become (Loehrer et al., 1988; Motzer et al., 1991; voluminous (growing ) and be Gershenson, 1993). responsible for functional complications (Gershenson et al., 1985, 1986; Williams and Etiology Gershenson, 1993; Geisler et al., 1994). Malignant ovarian germ-cell tumors share a Simple monitoring after surgery is classically common cytogenetic characteristic with all recommended only for stage I dysgerminomas ovarian, testicular, extragonadal germ-cell or immature stage I and grade I teratomas which tumors of adults or children: the presence of an carry an extremely low risk of relapse (Norris et isochromosome of the short arm of chromosome al., 1976; Thomas et al., 1987; Dark et al., 12 [i(12p)], which is not found in any other type 1997). As far as the other tumors are concerned, of cancer (Kurman and Norris, 1976b). notably embryonal carcinomas or yolk-sac tumors and those discovered at stage II, III or IV, References adjuvant chemotherapy after surgery is Bidart JM, Troalen F, Lazar V, Berger P, prescribed because of the high risk of relapse. Marcillac I, Lhomme C, Droz JP, Bellet D Monoclonal antibodies to the free beta-subunit of Chemotherapy human chorionic gonadotropin define three Among non-hematological cancers, malignant distinct antigenic domains and distinguish germ-cell tumors can be curable by cytotoxic between intact and nicked molecules. chemotherapy. Too rare to be included in Endocrinology 131: 1832–1840 randomized studies, treatment of these tumors

Ray-Coquard I, Ovarian tumors of sex cord–stromal origin. Orphanet Encyclopedia. March 2004. http://www.orpha.net/data/patho/GB/uk-OVARI.pdf 3

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Ray-Coquard I, Ovarian tumors of sex cord–stromal origin. Orphanet Encyclopedia. March 2004. http://www.orpha.net/data/patho/GB/uk-OVARI.pdf 4

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