Malignant Gonadal Germ Cell Tumors (Other Than Pure Germinoma) in Patients With Disorders of Sex Development

Abstract

We describe 21 nonpure germinomatous gonadal germ cell tumors (9 with a germinoma component), all but 1 associated with gonadoblastoma, in patients with disorders of sex development who ranged from 7 to 36 years old (average, 20 y). Twenty patients were clinically described as phenotypic females with ambiguous genitalia/virilization and primary amenorrhea. The most common documented peripheral karyotype was 46,XY (10/12; 83%). Fifteen of 16 tumors with available clinicopathologic data were unilateral. They ranged from 7 to 30 cm (mean, 15.5 cm) and were solid and cystic with frequent necrosis and hemorrhage. Gonadoblastoma, in its classic (70%), dissecting (5%), or combined (25%) forms, was identified in all but 1. The malignant germ cell tumors were typically mixed except for 5 pure yolk sac tumors and 1 expansile gonadoblastoma with syncytiotrophoblast cells. When admixed, the most common component was yolk sac tumor (n=10), followed by germinoma (n=9), embryonal carcinoma (n=5), choriocarcinoma (n=4), immature teratoma (n=3), and teratoma (n=2). Typical morphologic patterns of yolk sac neoplasia, including reticular/microcystic, solid (including blastema-like), and endodermal sinus (Schiller-Duval bodies), were seen, as well as glandular (n=10) and hepatoid (n=6) differentiation, with cystically dilated glands and diffuse hepatoid morphology in 3 and 2 tumors, respectively. Two yolk sac tumors showed a sarcomatoid pattern. Somatic-type malignancies (alveolar rhabdomyosarcoma and low-grade spindle cell sarcoma, not otherwise specified) were identified in 1 case each. This is the first large series of germ cell tumors other than typical pure germinoma associated with gonadoblastoma. The high frequency of yolk sac tumor with glandular (especially cystic glandular) and hepatoid morphologies is noteworthy, and their presence should prompt further evaluation for an associated gonadoblastoma and possible disorder of sex development.

Reflections on Historical and Other Aspects of a Remarkable Gonadal Abnormality on the 70th Anniversary of its Description by Dr Robert E. Scully

“…The above summary of the gonadoblastoma story and brief mention of other works does not really do justice to the remarkable understanding Dr Scully had of the pathology and indeed for that matter clinical aspects of the diverse complicated situations encountered in patients with DSDs. What he has written will be of aid to those studying these disorders for years to come and, indeed, recently, almost a decade after his death (in October, 2012), the material he accumulated provided the basis for a peer-reviewed contribution, namely, the publication already noted of a series of cases in which malignant germ cell tumors other than pure germinomas arose in the clinical setting of interest to us here (9). Furthermore, Dr Scully's consultation files probably contain more cases of a complicated nature in which various clinical disorders and equally varied pathologic abnormalities are seen in patients with abnormal gonads.…”

“…We were also struck by distinctive, cystic glands in these cases (Fig. 6B) and suggested that they or hepatoid differentiation in a yolk sac tumor could indicate derivation from an underlying gonadoblastoma and association with a DSD, which should be sought (9).…”

“…Recently we had occasion to examine many of Dr Scully’s gonadoblastoma cases that were associated with invasive germ cell tumors other than germinoma 9. The most common tumor type was yolk sac tumor (15/21; 71%), with high frequencies of them showing glandular (10/15; 67%) or hepatoid (6/15; 40%) differentiation (Fig.…”

“…This essential characteristic was reiterated almost 70 years later in the definition provided in the World Health Organization's monograph dealing with female genital tumors, which states "gonadoblastoma is a distinctive form of in situ germ cell neoplasia." (27) Recently we had occasion to examine many of Dr Scully's gonadoblastoma cases that were associated with invasive germ cell tumors other than germinoma (9). The most common tumor type was yolk sac tumor (15/21; 71%), with high frequencies of them showing glandular (10/15; 67%) or hepatoid (6/ 15; 40%) differentiation (Fig.…”

“…1, bottom), one that has stood the test of time despite the tendency for the names of many entities to be changed, not always for the better, by subsequent investigators. His work on that entity prompted a dedicated study of the pathology of DSD that continued for his entire career (2)(3)(4)(5)(6)(7)(8), even culminating in a publication after his death that was due in significant part to the observations he had made (9). In this essay we tell the story of his "discovery" and study of gonadoblastoma.…”