Malignancy in disorders of sex development

Abstract

Disorders of sex development (DSD) represent a spectrum of conditions in which chromosomal, gonadal, or anatomic sex are atypical and affect 1 in 4,500–5,000 live births. The diagnosis of DSD raises concerns of tumor risk and treatment as well as future fertility preservation. We review the current understanding of the types of gonadal tumors that arise in DSD patients as well as possible markers and treatment. The goal is to inform the members of the DSD team (urologist, endocrinologist, geneticist, psychologist) of the latest findings regarding malignancy in DSD. PubMed® and Google ScholarTM literature searches were performed of current and past peer-reviewed literature on DSD (intersex) regarding gonadal development and tumor formation/treatment. Relevant reviews and original research articles were examined, including cited references, and a synopsis of the data was generated. DSD patients are at increased risk for the development of testicular carcinoma in-situ (CIS) and germ cell tumors (GCT), including seminoma, non-seminoma, juvenile granulosa cell, gonadoblastoma, and dysgerminoma. Cancer risk factors include Y-chromosomal material and gonadal position, especially for streak gonads. The 46 XX DSD patients [congenital adrenal hyperplasia (CAH)] with no genetic Y-chromosomal material are not at higher risk of cancer. Post-pubertal complete androgen insensitivity syndrome (AIS) patients remain prone to tumor development if the testes remain in the abdomen. Estimates of the risk of GCT in partial AIS for untreated undescended testes may be as high as 50%. The cancer risk of scrotal testes in partial AIS is unknown. CIS occurs almost exclusively in patients with hypovirilization, most notably in AIS. Persistent Mullerian Duct Syndrome (PMDS) confers the usual cancer risk associated with cryptorchidism, but also a possible tumor risk of the Mullerian remnant. Several markers are under investigation for tumor evaluation in the DSD population beyond hCG and AFP (Oct3/4, TSPY, WT-1). The management of patients with DSD is complex and evaluation of tumor risk is aided by advances in genotyping for Y-chromosomal material not evident in traditional karyotyping. More complete genetic screening for DSD patients should increasingly become the standard of care. Developments in pathologic diagnosis will further challenge our traditional understanding of the oncologic management and surveillance of these patients. Future studies utilizing more advanced histologic examination of gonads will improve our understanding of the true incidences of malignancy in this diverse population.

Management of Gonads in Adults with Androgen Insensitivity: An International Survey

“…Nevertheless, from our survey it is clear that, currently, most clinicians from participating centres prefer to postpone gonadectomy until after puberty so that secondary sex characteristics can develop optimally [24, 25]. Eleven percent of the women with CAIS in our study had declined a gonadectomy; the main reasons for declining were concerns about the procedure, inconvenience of planning surgery, not wanting HRT and not having adjusted to the diagnosis.…”

Gonadal dysgenesis is associated with worse outcomes in patients with ovarian nondysgerminomatous tumors: A report of the Children's Oncology Group AGCT 0132 study

“…Gonadal dysgenesis (GD) results from a disorder of sexual development in which chromosomal, gonadal, or anatomic sex are atypical . This condition affects one in 4,500–5,000 live births, and encompasses a wide spectrum of phenotypic presentations including normally virilized males or undervirilized males, patients with ambiguous genitalia, and normal phenotypic females . The diagnosis of GD places the patient at an increased risk (15–60%) for developing gonadal germ cell tumors (GCT), especially gonadoblastoma .…”

“…This condition affects one in 4,500–5,000 live births, and encompasses a wide spectrum of phenotypic presentations including normally virilized males or undervirilized males, patients with ambiguous genitalia, and normal phenotypic females . The diagnosis of GD places the patient at an increased risk (15–60%) for developing gonadal germ cell tumors (GCT), especially gonadoblastoma . The presence of Y‐chromosome material or an intraabdominal gonad position increases the risk of developing a gonadal GCT …”

“…Endocrinology consensus on the management of intersex disorders recommends gonadectomy in all high‐risk groups (patients with Y‐chromosomal material [GBY region] and/or intraabdominal gonads or streak gonads) at diagnosis due to the risk of malignancy (15–60%) . Patients with complete androgen insensitivity syndrome (CAIS) are felt to be a lower risk group with later onset of tumors that may have gonadectomy deferred until puberty to allow for potential beneficial effects of hormonal secretion to occur …”

46,XY-disorder of sex development due to a mutation in the WT1 gene

“…Неповна форма синдрому нечутливості до андрогенів (?). Враховуючі наявність Y хромосоми в каріотипі при жіночому фенотипі та ймовірний ризик злоякісного переродження гонад [22], за рішенням мультидисциплінарного консиліуму, після отримання згоди батьків, дитині у віці 12 років проведено гонадектомію. За результатами гістологічного дослідження видалені гонади мали ознаки дисгенетичних гонад з порушенням дозрівання елементів строми статевого тяжу і диференціюванням за чоловічим та частково жіночим типом.…”