Gonadal Maldevelopment as Risk Factor for Germ Cell Cancer: Towards a Clinical Decision Model

Abstract

Context

A disturbed process of gonadal formation and maintenance may result in testicular dysgenesis syndrome or disorders of sex development (DSDs), with an increased germ cell cancer (GCC) risk. Early diagnosis and treatment requires the identification of relevant risk factors and initial pathologic stages.

Objective

To evaluate current knowledge and novel insights regarding GCC risk in patients with DSDs, with the aim of providing a model for clinical use.

Evidence acquisition

A Medline search was conducted to identify all original and review articles assessing the aetiology of GCC, GCC risk in DSD patients, new predictive markers related to GCC, and possible clinical scenarios related to GCC and DSDs.

Evidence synthesis

Embryonic development is controlled by orchestrated patterns of gene and subsequent protein expression. Knowledge of these networks is essential to understand the mechanisms of disturbed development including GCC formation. GCCs are subdivided into seminomas and nonseminomas, and they all arise from embryonic germ cells that have failed to mature appropriately. The precursor is known as carcinoma in situ (also referred to as testicular intratubular neoplasia and intratubular germ cell neoplasia unclassified) in a testicular microenvironment and gonadoblastoma in a dysgenetic/ovarian microenvironment. GCCs mimic embryonic development, resulting in the identification of diagnostic markers (eg, OCT3/4, SRY [sex determining region Y]-box 2 [SOX2], and [sex determining region Y]-box 17 [SOX17]). Novel insights indicate a subtle interplay of specific single nucleotide polymorphisms, environmental factors, and epigenetic aberrations in the aetiology of GCCs. A genvironmental model combining these factors is presented, proposed as a guideline for clinical management by an experienced multidisciplinary team. The goal is individualised treatment including preservation of gonadal function (if possible) and prevention of malignant transformation.

Conclusions

A hypothesis is presented in which combined interactions of epigenetic and environmental parameters affect embryonic gonadal development, resulting in delayed/blocked germ cell maturation that determines the risk for GCC formation. Current and future possibilities for early detection of GCCs in risk populations and follow-up in a clinical setting are discussed.

Patient summary

This review analyses current knowledge about the underlying networks that relate to the development of a germ cell cancer in the context of a disorder of sex development. A combined effect of epigenetic and environmental factors is identified in the pathogenesis, and a model is proposed to apply this knowledge to clinical practice.

Introduction

A disturbed process of gonadal formation and maintenance, as often found in patients with disorders of sex development (DSDs), can increase the risk of developing a malignant germ cell tumour (GCT), referred to as germ cell cancer (GCC). In the general white adolescent and young male population, GCC is the most common cancer, with the incidence still rising [1], [2]. GCCs are part of a heterogeneous group of neoplasms subdivided into five entities [3]. In the context of DSDs, only GCCs (also known as type II GCTs) are relevant and therefore the focus of this review.

Early diagnosis of a rare cancer requires hallmarks to identify risk populations and subsequently informative markers to demonstrate the presence of the earliest pathologic stages with a high likelihood of progression. The histology of the precursor of GCC depends on the microenvironmental context. Within the testis it is referred to as carcinoma in situ (CIS) and within the ovary/dysgenetic gonad as gonadoblastoma (GB). CIS is also known as intratubular germ cell neoplasia unclassified and testicular intratubular neoplasia [3], [4], [5]. Although not correct based on its cell of origin, the abbreviation CIS is the most widely known and therefore is used in this paper. CIS and GB are composed of germ cells with embryonic characteristics, most likely reflecting their origin from primordial germ cells/gonocytes. These cells are assumed to be blocked in their process of maturation due to disturbances within the gonadal microenvironment during early (intrauterine) development. The GCC precursor lesions, CIS and GB, are known to progress to an invasive GCC in most cases when left untreated [4], [6].

DSD is an umbrella term encompassing a spectrum of phenotypes ranging from normal male, mild undervirilisation, ambiguous genitalia to a normal female phenotype. In patients with DSDs, GCC risk depends on the presence of a defined region of the Y chromosome, the so-called gonadoblastoma region on the Y chromosome (GBY region). This specific genetic fragment promotes GCC development in the context of disturbed gonadal development (ie, a dysgenetic gonad [7]) and possibly also in the normally developed testis, for which a testis-specific protein on the Y chromosome (TSPY) is the assumed responsible candidate [8]. Additional risk factors for CIS/GB include the anatomic position of the gonad (ie, of the testis) and epigenetic and microenvironmental parameters.