Germ Cell Tumors in the Intersex Gonad

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The development of germ cell tumors in patients with disorders of sex development (DSD) is an important complication. The so-called “type II germ cell tumors of the testis and the gonad “are by far the most frequent and feared tumors in these patients: seminoma if the gonad is considered a testis, dysgerminoma (DG) if it is considered an ovary. These invasive tumors are always preceded by the presence of an in situ neoplastic lesion: intratubular germ cell neoplasia (also called carcinoma in-situ [CIS], or gonadoblastoma [GB]). Progress has been made in identifying gene products related to the germ cell tumor development, of which 2 are major immunohistochemical markers. The in-situ neoplatic lesions of intersex gonads (CIS and GB) are unambiguously characterized by a consistent expression of 2 proteins: OCT3/4 and TPSY, a protein testis specific Y-encoded. There are transitional changes of the germ cells during development. In all DSD conditions, as compared with male and female fetuses throughout pregnancy, a subpopulation of germ cells is affected by maturation delay. In patients with gonadal dysgenesis, the increased risk of GB is related to the extremely retarded or blocked maturation of the germ cells and stroma cells that fail to differentiate properly. The authors discussed and proposed several criteria to allow distinguishing between maturation delay and CIS.

This article presented the prevalence of germ cell tumors, revisiting the terminology of intersex disorders, and the confusing criteria for the diagnosis of malignant germ cells at an early age, opposing maturation delay vs. early steps in malignant transformation. Criteria for a correct diagnosis of neoplastic lesions are provided with a new classification system for patients with DSD. Some conclusions for prevalence are presented. Germ cell tumors occur in 12% of patients with gonadal dysgenesis. The prevalence is low, with a conservative figure of 2.3% in undervirilized patients, with essentially CIS arising in well-differentiated testicular tissue. In contrast, nearly all in-situ lesions in patients with gonadal dysgenesis are gonadoblastomas. An estimated risk is presented in the table.

Recent studies have suggested the pathogenetic mechanism leading to malignancy within the dysgenetic gonad; which is dicussed at length in this paper. The normal maturation of germ cells is interrupted with prolonged OCT3/4 expression (increased survival of the primordial germ cells) and a maintained or erased genomic imprinting. This may lead to immortalization of the cells with an increased TSPY expression, causing proliferation. The authors propose a classification of patients with DSD, based on the differentiation type of the gonad, which is directly related to the risk of tumor development. It is proposed as a tool to refine our insight into the prevalence of germ cell tumors.

Cools M, Drop SL, Wolffenbuttel KP, Oosterhuis JW, Looijenga LHJ. Germ cell tumors in the intersex gonad: Old paths, new directions, moving frontiers. Endocr Rev. 2006;27:468-84.

Editor’s Comment

This is a major review on a complex issue. The authors have also published a recent paper on the gonadoblastoma,¹ which compared their extensive experience in pathology of the dysgenetic gonads in keeping with the hypothesis that Skakkebeak et al² proposed.The data presented have limitations, as they are exclusively based on gonadal pathology. As a matter of fact, bilateral gonadal biopsy or, preferably, removal is presently required for full relevant information. Future evidence-based protocols are needed for a better management of these patients. The issue also adds new perspective because of the pressure of advocacy groups and the tendency to preserve gonads and rearing more of these patients as males. Follow-up will require noninvasive techniques such as ultrasound assessments. More information is needed to prevent carcinoma in-situ progression towards invasiveness. At present, it is mandatory to search for the presence of TSPY protein and/or gene in dysgenetic gonads, even if the karyotype does not reveal a Y-bearing cell line. This approach is also a valuable addition to the recent consensus group statement on intersex disorders.³ In pediatric patients with gonadal dysgenesis, gonadectomy is mostly performed prophylactically, and malignant lesions are less often observed. However, there is a need for more information in each condition on the risk of developing malignancy, including serum markers for early detection of tumors. I agree with the authors when they urge for “an intense and multicenter collaboration to answer all questions in a restricted time period.”

Raphaël Rappaport, MD

References - (linked to )

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Last Updated: 04/30/2008