Malignancies in Disorders of Sexual Development

The evolution of malignancies in DSD (Disorders of Sexual Differentiation) is rare and multifactorial. Aberrant germ cell development usually leads to the development of a malignancy. The gonads of children with DSD often have insufficiently differentiated supporting cells which hinders complete maturation of germ cells. Delayed gonadal development increases the risk of tumorigenesis due to the prolonged state of gonocyte immaturity. The immature germ cells abundantly express TSPY (testis-specific protein Y-encoded), which further promotes survival and proliferation. Presence of gonadal dysgenesis along with surviving germ cells places the child at a high malignant risk that increases with age. The exact risk of malignancies in each subtype of DSD is not known. The lowest risk is seen in those with Turner Syndrome without Y chromosome, complete AIS (Androgen Insensitivity Syndrome), and ovotesticular DSD. The highest risk is seen with gonadal dysgenesis, partial AIS, and syndromic associations such as Denys Drash and Frasier syndromes. Imaging is not very sensitive to identify masses in this population as the gonads are often aberrantly located, of heterogenous size and appearance, and maldeveloped or dysgenetic. Monthly self-examination is recommended for patients with palpable gonads, as a screening tool for testicular cancer. Tumor markers are another option for screening, but there is a lack of evidence and no set cut-offs for DSD patients. One of the latest advances in screening for Germ cell Tumor (GCT) is the development of microRNA (miRNA) testing. There are no consensus guidelines regarding the decision and timing of gonadectomy. Although ideal for the prevention or cure of an early stage invasive GCT, it has its drawbacks in the form of permanent infertility and hypogonadism. The final decision depends not only on the predicted risk of GCT but on the child’s gender identity as well as desire for fertility.