Mediastinal germ cell tumors: many questions and perhaps an answer

Oosterhuis, J. Wolter; Looijenga, Leendert

doi:10.1172/jci143884

Cited by 13 publications

(17 citation statements)

References 25 publications

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“…They account for up to 15% of all mediastinal neoplasms in adults and for up to 20% in children 4–6 . They are thought to originate from misrouted migrating primordial germ cells that fail to undergo apoptosis and remain inside the mediastinum during early embryogenesis 7–9 . PMGCTs show morphological (e.g.…”

Section: Introductionmentioning

confidence: 99%

Primary mediastinal germ cell tumours: an immunohistochemical and molecular diagnostic approach

Fichtner¹,

Richter²,

Filmar³

et al. 2021

Histopathology

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Aims: Primary mediastinal germ cell tumours (PMGCTs) are rare mediastinal neoplasms, and their diagnosis can be challenging, owing to small biopsy samples. The aim of this study was to develop a diagnostic algorithm using immunohistochemical staining, with a focus on novel markers, and molecular analysis of isochromosome 12p [i(12p)]. Methods and results: Paraffin-embedded tissues of 32 mediastinal tumours were analysed with immunohistochemical staining for sal-like transcription factor 4 (SALL4), Lin-28 homologue A (LIN28), octamer-binding transcription factor 3/4 (OCT3/4), D2-40, cluster of differentiation 117 (CD117), sex-determining region Y-box 17, sex-determining region Y-box 2 (SOX2), cluster of differentiation 30, the b-subunit of human chorionic gonadotropin (b-hCG), GATA-binding protein 3 (GATA3), forkhead box protein A2 (FOXA2), glypican-3 (GPC3), a-fetoprotein (AFP), terminal deoxynucleotidyl transferase (TdT), nuclear protein of the testis (NUT), and pan-cytokeratin. Quantitative real-time polymerase chain reaction was performed to investigate the i(12p) status. Fifteen seminomas, seven teratomas, one yolk sac tumour, one choriocarcinoma and seven mixed PMGCTs were diagnosed. Each entity had different immunohistochemical staining patterns, which helped to distinguish them: OCT3/4, D2-40, CD117 and TdT for seminoma; OCT3/4 and SOX2 for embryonal carcinoma; FOXA2, GPC3 and AFP for yolk sac tumour; and b-hCG and GATA3 for choriocarcinoma. Mature teratomas stained positively for pan-cytokeratin in epithelial components and focally for SALL4, SOX2, GATA3, D2-40, and FOXA2. Furthermore, a NUT carcinoma mimicking a PMGCT was diagnosed, showing strong nuclear SOX2 staining and speckled nuclear NUT staining. i(12p) was detected in 24 of 27 PMGCTs (89%). Conclusion: A diagnostic algorithm is of great importance for a reliable diagnosis of PMGCT in, usually small, tissue biopsy samples. Therefore, a combination of three to four antibodies to identify the correct histological subtype is usually necessary, in addition to morphological features. The i(12p) status serves as an additional option to indicate a germ cell origin in selected cases.

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Section: Introductionmentioning

confidence: 99%

Primary mediastinal germ cell tumours: an immunohistochemical and molecular diagnostic approach

Fichtner¹,

Richter²,

Filmar³

et al. 2021

Histopathology

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show abstract

“…Although, in this current review, there is not enough data to show a survival difference among histopathological subtypes, the better prognosis of malignant mediastinal GCTs in infants compared to that in adolescents suggests that there may be histopathologic and genetic differences, which are associated with differences in clinical behaviour and which may demand a different treatment strategy. Analysing this further, Oosterhuis and Looijenga discussed original data that mutational and copy number variations analysis of a large cohort of patients with primary mediastinal nonseminomas demonstrated a high prevalence of TP53 mutations, likely explaining why patients with primary mediastinal nonseminomas are frequently resistant to platinum-based chemotherapy [ 57 , 58 ], in line with previous findings [ 59 ]. With mediastinal tumours, as with other extragonadal GCTs, frequently presenting in advanced stages, they are dependent on chemotherapy for survival, unlike stage I disease.…”

Section: Discussionmentioning

confidence: 61%

Treatment and Survival of Malignant Extracranial Germ Cell Tumours in the Paediatric Population: A Systematic Review and Meta-Analysis

Hulsker

Mansori

Fiocco

et al. 2021

Cancers

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Objective: This systematic review and meta-analysis was performed to explore overall survival (OS) and event free survival (EFS) rates internationally over the past two decades and to define specific subgroups with inferior outcomes which may demand different treatment strategies. Methods: The search focused on malignant extracranial germ cell tumours (GCTs) in the paediatric population. The initial database search identified 12,556 articles; 32 articles were finally included in this review, comprising a total of 5095 patients. Results: The studies were heterogeneous, varying from single institution reports to large prospective trials. Older studies, describing eras where non-platinum-based chemotherapy regimens were used, showed clearly worse outcomes. Survival for stage I–II gonadal disease is excellent. On the other hand, patients with an initial alpha-fetoprotein (AFP) > 10,000 ng/mL or kU/L, age > 11 years and stage IV disease confer a survival disadvantage. For testicular disease in particular, lymphovascular invasion and certain histopathological subtypes, such as embryonal carcinoma (EC) and mixed malignant GCTs, survival is poorer. Survival data for sacrococcygeal and mediastinal GCTs show a heterogeneous distribution across studies in this review, independent of year of publication. Patients > 12 years presenting with a mediastinal GCT pose a subpopulation which fares worse than GCTs in other locations or age groups. This is independent of AFP levels, stage of disease or treatment protocol, and these patients may demand a different treatment strategy. Conclusions: This review describes the heterogeneous nature of GCTs in different anatomical locations, impacting on stage at presentation, treatment modalities used and survival data. Despite this heterogeneity, in line with the current developmental biology-based classification system, subpopulations can be defined which have an inferior EFS and OS and where future research and more individualised treatment would help to improve survival.

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“…As reported previously and as part of the International Germ Cell Cancer Collaborative Group (IGCCCG) risk stratification, patients harboring a primary mediastinal GCT have the worst prognosis [40]. One could speculate that the bias for TP53 mutations in mediastinal GCTs could be due to a less favorable niche and more strict selection for these tumors [41]. As mentioned before, the embryonal origin of these tumors is still in favor of genome protection and an intact TP53 signaling pathway [8].…”

Section: Discussionmentioning

confidence: 74%

The Role of TP53 in Cisplatin Resistance in Mediastinal and Testicular Germ Cell Tumors

Timmerman

Eleveld

Gillis

et al. 2021

IJMS

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Germ cell tumors (GCTs) are considered to be highly curable; however, there are major differences in the outcomes related to histology and anatomical localization. GCTs originating from the testis are, overall, sensitive to platinum-based chemotherapy, whereas GCTs originating from the mediastinum show a worse response, which remains largely unexplained. Here, we address the differences among GCTs from two different anatomical locations (testicular versus mediastinal/extragonadal), with a specific focus on the role of the P53 pathway. It was recently shown that GCTs with TP53 mutations most often localize to the mediastinum. To elucidate the underlying mechanism, TP53 knock-out lines were generated in cisplatin-sensitive and -resistant clones of the representative 2102Ep cell line (wild-type TP53 testicular GCT) and NCCIT cell line (hemizygously mutated TP53, mutant TP53 mediastinal GCT). The full knock-out of TP53 in 2102Ep and resistant NCCIT resulted in an increase in cisplatin resistance, suggesting a contributing role for P53, even in NCCIT, in which P53 had been reported to be non-functional. In conclusion, these results suggest that TP53 mutations contribute to the cisplatin-resistant phenotype of mediastinal GCTs and, therefore, are a potential candidate for targeted treatment. This knowledge provides a novel model system to elucidate the underlying mechanism of clinical behavior and possible alternative treatment of the TP53 mutant and mediastinal GCTs.

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Mediastinal germ cell tumors: many questions and perhaps an answer

Cited by 13 publications

References 25 publications

Primary mediastinal germ cell tumours: an immunohistochemical and molecular diagnostic approach

Primary mediastinal germ cell tumours: an immunohistochemical and molecular diagnostic approach

Treatment and Survival of Malignant Extracranial Germ Cell Tumours in the Paediatric Population: A Systematic Review and Meta-Analysis

The Role of TP53 in Cisplatin Resistance in Mediastinal and Testicular Germ Cell Tumors

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