Tumor risk in disorders of sex development (DSD)

Abstract

Disorders of sex development (DSD), previously referred to as intersex disorders, comprise a variety of anomalies defined by congenital conditions in which chromosomal, gonadal, or anatomical sex is atypical. Besides issues such as gender assignment, clinical and diagnostic evaluation, surgical and psychosocial management, and sex steroid replacement, the significantly increased risk for developing specific types of malignancies is both clinically and biologically relevant. This relates to germ-cell tumors specifically in DSD patients with hypovirilization or gonadal dysgenesis. The presence of a well-defined part of the Y chromosome (known as the GBY region) is a prerequisite for malignant transformation, for which the testis-specific protein on the Y chromosome (TSPY ) is a likely candidate gene. The precursor lesions of these cancers are carcinoma in situ (CIS)/intratubular germ-cell neoplasia unclassified (ITGCNU) in testicular tissue and gonadoblastoma in those without obvious testicular differentiation. Most recently, undifferentiated gonadal tissue (UGT) has been identified as the likely precursor for gonadoblastoma. The availability of markers for the different developmental stages of germ cells allows detailed investigation of the characteristics of normal and (pre)malignant germ cells. Although informative in a diagnostic setting for adult male patients, these markers -such as OCT3/4 -cannot easily distinguish (pre)malignant germ cells from germ cells showing delayed maturation. This latter phenomenon is frequently found in gonads of DSD patients, and may be related to the risk of malignant transformation. Thus, the mere application of these markers might result in over-diagnosis and unnecessary gonadectomy. It is proposed that morphological and histological evaluation of gonadal tissue, in combination with OCT3/4 and TSPY double immunohistochemistry and clinical parameters, is most informative in estimating the risk for germ-cell tumor development in the individual patient, and might in future be used to develop a decision tree for optimal management of patients with DSD.

Changes Over Time in Sex Assignment for Disorders of Sex Development

“…Boys with gonadal dysgenesis and retained gonads may show an age-related deterioration of testicular function, 19,20 have a higher risk of tumorigenesis, 21 and suffer from suboptimal growth and pubertal development during adolescence. 22 If more infants with 46,XY DSD are being raised as boys and retain their testes with an expectation of normal pubertal development and optimal long-term outcome including fertility, the need for long-term detailed clinical and biochemical surveillance as well as a reevaluation of the genetic etiology will become increasingly important in these affected boys.…”

Polymorphic variation in the androgen receptor gene: Association with risk of testicular germ cell cancer and metastatic disease

“…Subjects with AR gene mutations leading to androgen insensitivity are at significantly higher risk of developing TGCC (7), this risk being most pronounced in those subjects having mutations leading to partial but not complete insensitivity to the male sex hormones (8). Furthermore, since the AR was found to be expressed in CIS cells (9), looking for genetic variants modifying the function of the AR is an obvious strategy when searching for candidate genes involved in the aetiology and pathogenesis of TGCC.…”

Androgen Insensitivity Syndrome (AIS)

“…Specifi c analyses in large sample groups suggest a germ-cell tumour risk as low as 0·8-2%, especially before puberty. 74,75 Benign tumours of non-germ-cell origin include Sertoli cell adenoma and hamartomas.…”