Molecular pathology of testicular germ cell tumours: an update for practicing pathologists

Testicular tumours are a diverse group of tumours, but most cases fall into the category of testicular germ cell tumours (TGCT). TGCTs are classified as either derived from a germ cell neoplasia in situ (GCNIS) or unrelated to GCNIS. Based on the development, molecular alterations and onset of development, TGCTs can further be divided into three groups. Type I TGCTs include prepubertal-type teratoma and yolk-sac tumour. Type II TGCTs are the only GCNIS-related tumours in this classification and include seminomas, embryonal carcinoma, choriocarcinoma, yolk-sac tumour and teratoma of postpubertal type. Type III TGCTs only include spermatocytic tumours. While genetic alterations are helpful in the diagnostic routine, they have not yet been useful in determining treatment options, as targetable alterations are very rare. Type I TGCTs most commonly exhibit chromosomal aberrations and rarely display alterations related to the Wnt signalling pathway. A common molecular alteration in type II TGCTs is the presence of an isochromosome 12p or gain of 12p material. It is thought that the isochromosome 12p develops during the progression of a GCNIS to an invasive TGCT. Seminomas can also exhibit c-Kit mutations or KRAS mutations. Alterations associated with the formation of a somatic-type malignancy and/or the development of cisplatin resistance include TP53 mutations or MDM2 gene amplifications as well as epigenetic alterations. In advanced cases, some of these genes might be useful as targeted therapies (e.g. KRAS G12C or BRAF V600E), but as these mutations are rare, studies on larger groups of patients are not possible. Amplification of chromosome 9 including the DMRT1 gene, or Ras mutations is common in spermatocytic tumours. Overlapping molecular alterations, including those on chromosome 12, have recently been discovered in some type III TGCT. Tumour serum markers (e.g. alpha-fetoprotein, beta-subunit of human gonadotropin and microRNAs) are helpful in the diagnosis and for follow-up analysis to detect recurrent disease or disease progression. This review article provides an overview of the current classification of testicular tumours and their molecular classification. Furthermore, it provides information on biomarkers that are helpful in the diagnostic setting. Additionally, we will provide guidance on how to examine a testicular tumour specimen histopathologically to reach an accurate diagnosis. Finally, we will outline the importance of the content of a histopathological report for the urologists and oncologists.