Clues from natural history and results of treatment supporting the monoclonal origin of germ cell tumours.

Recent observations have suggested that a major factor in the development of germ cell tumours may be excessive mitogenic stimulus developed because of failure of feedback suppression of the normal pituitary drive due to atrophic damage to germinal epithelium. With this observation and the increasing recognition that there is a common in situ stage which precedes both seminoma and malignant teratoma/non-seminoma there has been a polarisation of views regarding the relationship between seminoma and malignant teratoma/non-seminoma, with some authors viewing these two entities as separate unrelated transformational events while others hypothesise that seminoma is an interim stage of clonal evolution associated with increased malignant potential towards malignant teratoma/non-seminoma. This chapter reviews the clinical evidence supporting the concept of clonal evolution which arises from the observation that the modal DNA content of seminoma (3.6N) is intermediate between that of in situ carcinoma (4.2N) and malignant teratoma/non-seminoma (2.8N). These observations, taken with the observation that the median age of patients with mixed tumours containing both seminoma and non-seminoma elements (30 years) is intermediate between the slower growing seminoma (35 years) and faster growing malignant teratoma/non-seminoma (25 years), as well as studies of spontaneous regression, tumours in AIDS patients chemo/radio sensitivity and post mortem histology, provide the most convincing evidence supporting clonal evolution. However, these observations cannot explain the fact that some patients have more than one focus of tumour (which can be of different histological type) in a single testis with normal tubules in between, even if they have in situ carcinoma. An extreme manifestation is seen in patients who are treated and cured from metastases arising from one testicle who then die from metastases from a completely different histological type arising from a second transformation event of a germ cell in the contralateral testis. The conclusion from these observations is that it is indeed possible for polyclonal development of tumours to occur, as is seen for bladder and bowel tumours, but they do not detract from the concept that seminoma is an intermediate event in the evolution from in situ carcinoma to malignant teratoma/non-seminoma.