Germ cell neoplasia in situ (<scp>GCNIS</scp>): evolution of the current nomenclature for testicular pre‐invasive germ cell malignancy

Berney, Daniel M.; Looijenga, Leendert H. J.; Idrees, Muhammad T.; Oosterhuis, J. Wolter; Meyts, Ewa Rajpert‐De; Ulbright, Thomas M.; Skakkebæk, Niels E.

doi:10.1111/his.12958

Cited by 132 publications

(91 citation statements)

References 15 publications

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“…The evolution of the new terminology from historical terms recently was reviewed by Berney and colleagues. 139 In short, there are numerous advantages to the change: It acknowledges that GCNIS is a precursor to both seminomas and NSGCTs without the confusing ''unclassified'' term in the name, it allows distinction from other more differentiated forms of intratubular germ cell neoplasia (intratubular seminoma and intratubular embryonal carcinoma, discussed further below in the Histologic Features of GCNIS section), the ''in situ'' component more accurately refers to the specific area where this type of GCT arises (the spermatogonial niche), and lastly, it is more consistent with the nomenclature of other precursor lesions in human malignancies. 8,139 The epidemiology and clinical ramifications of GCNIS, as well as the histologic features and molecular pathogenesis of this entity, will be briefly reviewed in this section.…”

Section: Testismentioning

confidence: 99%

Precursor Lesions of Urologic Malignancies

Khani¹,

Robinson²

2017

Archives of Pathology &Amp; Laboratory Medicine

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Context.— Precursor lesions of urologic malignancies are established histopathologic entities, which are important not only to recognize for clinical purposes, but also to further investigate at the molecular level in order to gain a better understanding of the pathogenesis of these malignancies. Objective.— To provide a brief overview of precursor lesions to the most common malignancies that develop within the genitourinary tract with a focus on their clinical implications, histologic features, and molecular characteristics. Data Sources.— Literature review from PubMed, urologic pathology textbooks, and the 4th edition of the World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs. All photomicrographs were taken from cases seen at Weill Cornell Medicine or from the authors' personal slide collections. Conclusions.— The clinical importance and histologic criteria are well established for the known precursor lesions of the most common malignancies throughout the genitourinary tract, but further investigation is warranted at the molecular level to better understand the pathogenesis of these lesions. Such investigation may lead to better risk stratification of patients and potentially novel treatments.

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Section: Testismentioning

confidence: 99%

Precursor Lesions of Urologic Malignancies

Khani¹,

Robinson²

2017

Archives of Pathology &Amp; Laboratory Medicine

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“…SE and the various forms of NSE originate from a common pathologic germ cell precursor, historically referred to as Carcinoma In Situ (CIS) (Skakkebaek 1972), Intratubular Germ Cell Neoplasia Unclassified (IGCNU), or, most recently, Germ Cell Neoplasia In Situ (GCNIS) according to the World Health Organization classification 2016 (Berney et al 2016). This progenitor shares many characteristics of a primordial germ cell (PGC)/ gonocyte, such as mRNA/miRNA/protein expression (including the coexpression of POU5F1 [also known as OCT3/4] and SOX17) (Looijenga et al 2003;de Jong et al 2008), as well as global CpG methylation erasure, features also found in invasive SE (Port et al 2005;Netto et al 2008;Wermann et al 2010;Al-Hussain et al 2015).…”

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confidence: 99%

Imprints and DPPA3 are bypassed during pluripotency- and differentiation-coupled methylation reprogramming in testicular germ cell tumors

et al. 2016

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Testicular germ cell tumors (TGCTs) share germline ancestry but diverge phenotypically and clinically as seminoma (SE) and nonseminoma (NSE), the latter including the pluripotent embryonal carcinoma (EC) and its differentiated derivatives, teratoma (TE), yolk sac tumor (YST), and choriocarcinoma. Epigenomes from TGCTs may illuminate reprogramming in both normal development and testicular tumorigenesis. Herein we investigate pure-histological forms of 130 TGCTs for conserved and subtype-specific DNA methylation, including analysis of relatedness to pluripotent stem cell (ESC, iPSC), primordial germ cell (PGC), and differentiated somatic references. Most generally, TGCTs conserve PGC-lineage erasure of maternal and paternal genomic imprints and DPPA3 (also known as STELLA); however, like ESCs, TGCTs show focal recurrent imprinted domain hypermethylation. In this setting of shared physiologic erasure, NSEs harbor a malignancy-associated hypermethylation core, akin to that of a diverse cancer compendium. Beyond these concordances, we found subtype epigenetic homology with pluripotent versus differentiated states. ECs demonstrate a striking convergence of both CpG and CpH (non-CpG) methylation with pluripotent states; the pluripotential methyl-CpH signature crosses species boundaries and is distinct from neuronal methyl-CpH. EC differentiation to TE and YST entails reprogramming toward the somatic state, with loss of methyl-CpH but de novo methylation of pluripotency loci such as NANOG. Extreme methyl-depletion among SE reflects the PGC methylation nadir. Adjacent to TGCTs, benign testis methylation profiles are determined by spermatogenetic proficiency measured by Johnsen score. In sum, TGCTs share collective entrapment in a PGC-like state of genomic-imprint and DPPA3 erasure, recurrent hypermethylation of cancer-associated targets, and subtype-dependent pluripotent, germline, or somatic methylation.

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“…A gonadoblastoma is regarded as the carcinoma in situ of the dysgenetic ovary, now referred to as germ cell neoplasia in situ (GCNIS) [Berney et al, 2016], with potential to undergo malignant transformation into invasive germ cell tumors (GCT). Most commonly, a gonadoblastoma progresses to a dysgerminoma, less frequently to tumors such as yolk sac tumor, teratoma, and embryonal carcinoma [Bai et al, 2013;Ulbright, 2014].…”

Section: Discussionmentioning

confidence: 99%

A Rare Case of Embryonal Carcinoma in a Patient with Turner Syndrome without Y Chromosomal Material but Mutations in KIT, AKT1, and ZNF358 Demonstrated Using Exome Sequencing

Gravholt¹,

Dollerup²,

Duval³

et al. 2017

Sex Dev

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Gonadoblastoma and malignant transformations thereof can occur in females with Turner syndrome (TS) and Y chromosomal material. However, in females with TS and no Y chromosomal material, this is rarely seen. We report a female with an apparent 45,X karyotype (in blood and tumor) who was diagnosed with a metastatic embryonal carcinoma. Exome sequencing of blood and the tumor was done, and no Y chromosomal material was detected, while predicted deleterious mutations in KIT (likely driver), AKT1, and ZNF358 were identified in the tumor. The patient was treated with chemotherapy (first-line: cisplatin, etoposide, and bleomycin; second-line: paclitaxel and gemcitabine), and after that surgical debulking was performed. She is currently well and without signs of relapse. We conclude that embryonal carcinoma can apparently occur in 45,X TS without signs of Y chromosomal material.

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Germ cell neoplasia in situ (GCNIS): evolution of the current nomenclature for testicular pre‐invasive germ cell malignancy

Cited by 132 publications

References 15 publications

Precursor Lesions of Urologic Malignancies

Precursor Lesions of Urologic Malignancies

Imprints and DPPA3 are bypassed during pluripotency- and differentiation-coupled methylation reprogramming in testicular germ cell tumors

A Rare Case of Embryonal Carcinoma in a Patient with Turner Syndrome without Y Chromosomal Material but Mutations in <b><i>KIT</i></b>, <b><i>AKT1</i></b>, and <b><i>ZNF358</i></b> Demonstrated Using Exome Sequencing

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