Histological Assessment of Gonads in DSD: Relevance for Clinical Management

Spoor, Johannes; Oosterhuis, J. Wolter; Hersmus, Remko; Biermann, Katharina; Wolffenbuttel, Katja P.; Cools, Martine; Kazmi, Zainab; Ahmed, S Faisal; Looijenga, Leendert H. J.

doi:10.1159/000481757

Cited by 37 publications

(27 citation statements)

References 123 publications

(149 reference statements)

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“…In the early developmental stage of type II TGCTs, there is a continuum from a delay in maturation of gonocytes, pre-GCNIS and GCNIS; in the latter stage the neoplastic gonocytes are located in a territory known as spermatogonial niche, and consistently fail to switch off and hence express OCT3/4 (a transcription factor expressed both in normal PGCs and embryonic stem cells as well as in their neoplastic counterparts, SEs and ECs), usually in conjunction with expression of TSPY and presence KITLG (illustrating once again that TGCTs are developmental cancers, not due to accumulation of mutations but instead thanks to deregulation of expression of critical differentiation-related proteins) [72,73]. GCNIS (first discovered in 1972 by Skakkebaek [74]) virtually always progresses to overt TGCT (50% at five years and 70% at seven years [75]), passing through an intermediate stage in the ‘default pathway’ of intratubular SE before turning into a fully invasive SE.…”

Section: Pathobiology Of Germ Cell Tumors and Their Developmental mentioning

confidence: 99%

Human Germ Cell Tumors are Developmental Cancers: Impact of Epigenetics on Pathobiology and Clinic

Lobo

Gillis

Jerónimo

et al. 2019

IJMS

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Current (high throughput omics-based) data support the model that human (malignant) germ cell tumors are not initiated by somatic mutations, but, instead through a defined locked epigenetic status, representative of their cell of origin. This elegantly explains the role of both genetic susceptibility as well as environmental factors in the pathogenesis, referred to as ‘genvironment’. Moreover, it could also explain various epidemiological findings, including the rising incidence of this type of cancer in Western societies. In addition, it allows for identification of clinically relevant and informative biomarkers both for diagnosis and follow-up of individual patients. The current status of these findings will be discussed, including the use of high throughput DNA methylation profiling for determination of differentially methylated regions (DMRs) as well as chromosomal copy number variation (CNV). Finally, the potential value of methylation-specific tumor DNA fragments (i.e., XIST promotor) as well as embryonic microRNAs as molecular biomarkers for cancer detection in liquid biopsies will be presented.

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Section: Pathobiology Of Germ Cell Tumors and Their Developmental mentioning

confidence: 99%

Human Germ Cell Tumors are Developmental Cancers: Impact of Epigenetics on Pathobiology and Clinic

Lobo

Gillis

Jerónimo

et al. 2019

IJMS

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“…Therefore, current recommendations may need to be adjusted based on future insights. With a molecular genetic diagnosis more often reached today, and with systematic registration of pathology results and centralised review of challenging cases, further progress in this matter can be achieved (62).…”

Section: Fertility and Documentation Of Gonadal Cancersmentioning

confidence: 99%

Standardised data collection for clinical follow-up and assessment of outcomes in differences of sex development (DSD): recommendations from the COST action DSDnet

Flück

Nordenström

Ahmed

et al. 2019

European Journal of Endocrinology

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The treatment and care of individuals who have a difference of sex development (DSD) have been revised over the past two decades and new guidelines have been published. In order to study the impact of treatments and new forms of management in these rare and heterogeneous conditions, standardised assessment procedures across centres are needed. Diagnostic work-up and detailed genital phenotyping are crucial at first assessment. DSDs may affect general health, have associated features or lead to comorbidities which may only be observed through lifelong follow-up. The impact of medical treatments and surgical (non-) interventions warrants special attention in the context of critical review of current and future care. It is equally important to explore gender development early and refer to specialised services if needed. DSDs and the medical, psychological, cultural and familial ways of dealing with it may affect self-perception, self-esteem, and psychosexual function. Therefore, psychosocial support has become one of the cornerstones in the multidisciplinary management of DSD, but its impact remains to be assessed. Careful clinical evaluation and pooled data reporting in a global DSD registry will allow linking genetic, metabolomic, phenotypic and psychological data. For this purpose, our group of clinical experts and patient and parent representatives designed a template for structured longitudinal follow-up. In this paper, we explain the rationale behind the selection of the dataset. This tool provides guidance to professionals caring for individuals with a DSD and their families. At the same time, it collects the data needed for answering unsolved questions of patients, clinicians, and researchers. Ultimately, outcomes for defined subgroups of rare DSD conditions should be studied through large collaborative endeavours using a common protocol.

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“…The first major issue is obtaining gonadal samples from DSD patients. In DSD, the risk of malignancy is variable and in order to obtain an accurate risk assessment, a histological analysis of gonadal biopsy or gonadectomy is the recommended procedure [ 194 ]. Gonadectomy should only be performed in patients that have higher risks of developing malignant tumors.…”

Section: Considerationsmentioning

confidence: 99%

Applying Single-Cell Analysis to Gonadogenesis and DSDs (Disorders/Differences of Sex Development)

Estermann

Smith

2020

IJMS

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The gonads are unique among the body’s organs in having a developmental choice: testis or ovary formation. Gonadal sex differentiation involves common progenitor cells that form either Sertoli and Leydig cells in the testis or granulosa and thecal cells in the ovary. Single-cell analysis is now shedding new light on how these cell lineages are specified and how they interact with the germline. Such studies are also providing new information on gonadal maturation, ageing and the somatic-germ cell niche. Furthermore, they have the potential to improve our understanding and diagnosis of Disorders/Differences of Sex Development (DSDs). DSDs occur when chromosomal, gonadal or anatomical sex are atypical. Despite major advances in recent years, most cases of DSD still cannot be explained at the molecular level. This presents a major pediatric concern. The emergence of single-cell genomics and transcriptomics now presents a novel avenue for DSD analysis, for both diagnosis and for understanding the molecular genetic etiology. Such -omics datasets have the potential to enhance our understanding of the cellular origins and pathogenesis of DSDs, as well as infertility and gonadal diseases such as cancer.

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Histological Assessment of Gonads in DSD: Relevance for Clinical Management

Cited by 37 publications

References 123 publications

Human Germ Cell Tumors are Developmental Cancers: Impact of Epigenetics on Pathobiology and Clinic

Human Germ Cell Tumors are Developmental Cancers: Impact of Epigenetics on Pathobiology and Clinic

Standardised data collection for clinical follow-up and assessment of outcomes in differences of sex development (DSD): recommendations from the COST action DSDnet

Applying Single-Cell Analysis to Gonadogenesis and DSDs (Disorders/Differences of Sex Development)

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