Pathway to cancer

The malignant transformation to the ITGCN cell is believed to take place in utero during the early development of the germline stem cell. It is believed that this cell would have ultimately differentiated into a gonocyte and has very similar morphologic characteristics [13]. Further immu-nohistochemical studies have confirmed the presence of proteins in both primordial germ cells and ITGCN cells that are not present in normal adult testes (KIT, OCT3/4, and AP-2g) (Fig. 3) [14]. Almstrup and colleagues [15] recently published their results describing the expression pattern of TFAP2C in neoplastic adult and fetal testes. This protein encodes for the transcription factor AP-2g, which is almost exclusively produced by cells that are not fully differentiated, such as gonocytes and was found to be elevated in ITGCN cells but not in normal germ cells of the adult testis.

Fig. 3. ITGCN nuclei stained with antibodies to OCT-3, which is specific for ITGCN and embryonal carcinoma.

Various chromosomal abnormalities have been described in ITGCN cells, with polyploidization (DNA index 1.5) and gain of chromosomal material at 12p (as an isochromosome) and 17q being the most common defects [16-18]. Other chromosomes (7, 8,14, and X) can gain or lose genetic material, but the gain at 12p seems to occur first and correlates with the invasive capability of ITGCN cells [19]. Many other genes that are important to invasive testicular tumors are present on the 12p chromosome (NANOG, STELLA, and CCND2) when studying these tumors via fluorescent in situ hybridization (FISH) or comparative genomic hybridization [20]. Controversy exists concerning the exact role that 12p plays in ITGCN; however, gain of 12p material has been associated with survival of ITGCN cells outside of the seminiferous tubules [6]. The common denominator is that the expression of ITGCN cells is a combination of increased transcriptional activity at some loci and or the loss of silencing of other loci [8]. The exact mechanism of neoplastic transformation of germ cells remains poorly understood. Answering this question has been difficult because of the difficulty of growing ITGCN cells in cell culture, and the lack of an animal model [4]. Research has focused on the observations of increased risk of TGCTs in patients with testicular dysgenesis and the hypothesis that inadequate stimulation of the testes by reproductive hormones during development could disturb normal differentiation and lead to malignant transformation [8]. Another hypothesis suggests that in developed countries exposure to environmental agents leads to an estrogenic effect in utero and could disrupt normal development [21]. Current theory is that once transformed into malignant cells, the tumor cells directly migrate through the basement membrane like other invasive in situ tumors (breast, skin), although recent studies by Donner and colleagues [22] have described a different manner of invasion. Instead of direct extension through the basement membrane, they support the theory of tumor cell proliferation within the tubule and degeneration of the Sertoli cells, followed by conversion of the tubule wall to connective tissue.

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