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Germ cell tumours (GCT) are the most common testicular tumours and form a heterogenous group of tumours with different biological behaviour. Based on differences regarding patient age at first manifestation, morphological characteristics and molecular changes, they are divided into three different groups of GCTs (type I-III). For treatment and prognosis, an exact histopathological analysis of an orchiectomy resection specimen is very important, including the specification of all different histological subtypes with their proportional distribution. This article describes the approach of the preparation of a resection specimen and the histopathological analysis of a testicular tumour. In addition, it describes cases in which additional tools like immunohistochemical and molecular analyses are necessary. Furthermore, the current WHO classification of testicular GCT is discussed., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Approximately 30% of seminoma (SEM) patients present with moderately elevated human chorionic gonadotropin (hCG) levels at first diagnosis. In case of high hCG serum levels, the presence of a non-SEM component, i.e. choriocarcinoma (CC), may be assumed. To characterize cases described as pure seminoma with high serum hCG levels, tissue samples and DNA were analyzed. Patient files from an international registry were screened for patients with SEM and extraordinarily high hCG serum levels. IHC and qRT-PCR analysis was performed for markers of SEM, embryonal carcinoma (EC) and CC/trophoblast cells. The cell lines TCam-2 (SEM), 2102EP, NCCIT, NT2/D1 (EC) and JAR, JEG3 and BeWo (CC) were included for comparison. Of 1031 SEM patients screened, 39 patients (3.7%) showed hCG serum levels > 1000 U/l. Of these, tumor material for IHC and RNA for qRT-PCR was available from n = 7 patients and n = 3 patients, respectively. Median pre-orchiectomy serum hCG level was 5356 U/l (range: 1224-40909 U/L). Histopathologically, all investigated samples were classified as SEM with syncytiotrophoblast sub-populations. SEM cells were SALL4 + / OCT3/4 + / D2-40 + , while syncytiotrophoblast cells were hCG + / GATA3 + / p63 + and SOX2 - /CDX2 - . qRT-PCR analysis detected trophoblast stem cell markers CDX2, EOMES and TFAP2C as well as the trophectoderm-specifier TEAD4, but not GATA3. Additionally, SOX17 and PRAME, but not SOX2, were detected, confirming the pure SEM-like gene expression signature of the analyzed samples. In conclusion, excessively increased hCG serum levels can appear in patients with pure SEM. To explain detectable hCG serum levels, it is important to diagnose the subtype of a SEM with syncytiotrophoblasts., (© 2023. The Author(s).)

In germ cell tumors (GCT), a growing teratoma during chemotherapy with decreasing tumor markers was defined as 'growing teratoma syndrome' (GTS) by Logothetis et al. in 1982. So far, its pathogenesis and specific treatment options remain elusive. We aimed at updating the GTS definition based on molecular and epigenetic features as well as identifying circulating biomarkers. We selected 50 GTS patients for clinical characterization and subsequently 12 samples were molecularly analyzed. We further included 7 longitudinal samples of 2 GTS patients. Teratomas (TER) showing no features of GTS served as controls. GTS were stratified based on growth rates into a slow (<0.5 cm/month), medium (0.5-1.5) and rapid (>1.5) group. By analyzing DNA methylation, microRNA expression and the secretome, we identified putative epigenetic and secreted biomarkers for the GTS subgroups. We found that proteins enriched in the GTS groups compared to TER were involved in proliferation, DNA replication and the cell cycle, while proteins interacting with the immune system were depleted. Additionally, GTS rapid seem to interact more strongly with the surrounding microenvironment than GTS slow . Expression of pluripotency- and yolk-sac tumor-associated genes in GTS and formation of a yolk-sac tumor or somatic-type malignancy in the longitudinal GTS samples, pointed at an additional occult non-seminomatous component after chemotherapy. Thus, updating the Logothetis GTS definition is necessary, which we propose as follows: The GTS describes a continuously growing teratoma that might harbor occult non-seminomatous components considerably reduced during therapy but outgrowing over time again., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The most common group of testicular tumours comprises germ cell tumours. Other primary testicular tumours are rare, but it is important to be aware of the wide variety of other, much rarer testicular tumours for the differential diagnosis. These tumours include sex cord stromal tumours and testicular adnexal tumours, which must be distinguished from metastases or somatic-type malignancies in germ cell tumours. Immunohistochemical markers and molecular alterations can help to correctly diagnose these tumours., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

The fibroblast growth factor receptors comprise a family of related but individually distinct tyrosine kinase receptors. Within this family, FGFR2 is a key regulator in many biological processes, e.g., cell proliferation, tumorigenesis, metastasis, and angiogenesis. Heterozygous activating non-mosaic germline variants in FGFR2 have been linked to numerous autosomal dominantly inherited disorders including several craniosynostoses and skeletal dysplasia syndromes. We report on a girl with cutaneous nevi, ocular malformations, macrocephaly, mild developmental delay, and the initial clinical diagnosis of Schimmelpenning-Feuerstein-Mims syndrome, a very rare mosaic neurocutaneous disorder caused by postzygotic missense variants in HRAS, KRAS, and NRAS. Exome sequencing of blood and affected skin tissue identified the mosaic variant c.1647=/T > G p.(Asn549=/Lys) in FGFR2, upstream of the RAS signaling pathway. The variant is located in the tyrosine kinase domain of FGFR2 in a region that regulates the activity of the receptor and structural mapping and functional characterization revealed that it results in constitutive receptor activation. Overall, our findings indicate FGFR2-associated neurocutaneous syndrome as the accurate clinical-molecular diagnosis for the reported individual, and thereby expand the complex genotypic and phenotypic spectrum of FGFR-associated disorders. We conclude that molecular analysis of FGFR2 should be considered in the genetic workup of individuals with the clinical suspicion of a mosaic neurocutaneous condition, as the knowledge of the molecular cause might have relevant implications for genetic counseling, prognosis, tumor surveillance and potential treatment options., (© 2024. The Author(s).)

Localized jawbone invasion is a milestone in the progression of oral squamous cell carcinoma (OSCC). The factors that promote this process are not well understood. Sclerostin is known to be involved in bone metabolism and there are preliminary reports of its involvement in bone tumors and bone metastasis. To identify a possible involvement of sclerostin in the bone invasion process of OSCC, sclerostin expression was analyzed in vitro in two different human OSCC tumor cell lines by quantitative real-time polymerase chain reaction (qRT-PCR), and the effect of recombinant human (rh)-sclerostin treatment on tumor cell capabilities was evaluated using proliferation, migration, and invasion assays. Undifferentiated human mesenchymal stem cells (hMSCs) were osteogenically differentiated and co-cultured with OSCC tumor cells to demonstrate potential interactions and migration characteristics. Sclerostin expression was evaluated in clinical cases by immunohistochemistry at the OSCC-jawbone interface in a cohort of 15 patients. Sclerostin expression was detected in both OSCC tumor cell lines in vitro and was also detected at the OSCC-jawbone interface in clinical cases. Tumor cell proliferation rate, migration and invasion ability were increased by rh-sclerostin treatment. The migration rate of tumor cells co-cultured with osteogenically differentiated hMSCs was increased. The results presented are the first data suggesting a possible involvement of sclerostin in the bone invasion process of OSCC, which deserves further investigation and may be a potential approach for drug-based tumor therapy.

This article will review current aspects of the histopathological, immunohistochemical and molecular analysis of primary mediastinal germ cell tumours (PMGCTs) as well as their aetiological, epidemiological, clinical and therapeutic features. PMGCTs represent an important differential diagnosis in the spectrum of mediastinal tumours, and their diagnosis is usually made on small tissue samples from core needle biopsies in combination with diagnostic imaging and serum tumour markers. As in lymphomas, a small biopsy is often the only viable tumour sample available from these patients, as they receive chemotherapy prior to eventual surgical resection. Pathologists therefore need to apply an efficient combination of immunohistochemical markers to confirm the diagnosis of a PMGCT and to exclude morphological mimics., (© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.)