Based on these observations, we hypothesize that gonadoblastomas originate from surviving OCT3/4-positive germ cells in areas of undifferentiated gonadal tissue within the dysgenetic gonad. Supportive evidence was obtained that carcinoma in situ arises in regions with testicular differentiation.

The dimorphic expression of OCT3/4 allows distinction between maturation delay and CIS. Studies in larger patient series are essential before a biopsy to evaluate the neoplastic risk can eventually be proposed as an alternative for gonadectomy.

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Most cervical carcinomas appear to arise from cervical intraepithelial neoplasia (CIN) lesions. In addition to infection with high‐risk human papilloma viruses, which is indicative of an increased risk of progression, alterations of oncogenes and tumor suppressor genes play a role. Genetic studies of CIN lesions, primary cervical carcinoma, and metastases may shed light on the relative importance of various genetic alterations involved in the progression of CIN to invasive carcinoma. We examined tumor material from 10 patients with squamous cell carcinoma of the uterine cervix and synchronous CIN lesions and lymph node metastases. The CIN component, invasive carcinoma, and lymph node metastases were analyzed separately for loss of heterozygosity (LOH) on the following loci: VHL (3p21), HLA region (6p22–23), PGL (11q 22–24), E6 associated protein (15q11–13), TP53 (17p13), DCC (18q21.1), and chromosomes 1, 2, 4, 9, 20, and X. Using immunohistochemistry, the expression of the EGF receptor, ERBB2, and TP53 was determined. In CIN lesions, frequent LOH was found at chromosome arms 3p, 6p, and 11q. Primary invasive carcinoma showed additional LOH at chromosome arms 6q, 17p, and 18q. In lymph node metastases, an additional locus on the X chromosome displayed LOH. All carcinomas and synchronous lesions but one showed high expression levels of the EGF receptor. TP53 staining, when present, was found in all synchronous lesions. Focal staining of ERBB2 was found in one CIN lesion, two invasive carcinomas, and four metastases. The molecular alterations accumulated in a fashion that paralleled the progression of the tumors. These results indicate that cervical tumorigenesis occurs in a stepwise fashion, including infection and integration of oncogenic HPV and several specific genetic alterations. Genes Chromosomes Cancer 26:346–354, 1999. © 1999 Wiley‐Liss, Inc.

Cervical carcinomas develop as a result of multiple genetic alterations. As the genetic alterations are the cause of malignant transformation, it is likely that specific genetic alterations lead to specific clinical behaviour. The aim of this study was (i) to localise chromosome arms that harbour likely tumour-suppressor genes, by analysing loss of heterozygosity (LOH) and (ii) to study the association of LOH with clinicopathological parameters. To define the regions of interest, we studied the presence of loss of heterozygosity at all chromosomes in 67 cervical carcinomas (stages IB and IIA) with 81 polymorphic markers. In addition, all frequent allelic imbalances were correlated with HPV status and clinicopathologic parameters including survival, FIGO-stage, lymph-node metastasis, tumour size, number of mitoses, vaso-invasion and histologic type. LOH at a frequency over 25% was observed at sites on 9 chromosome arms: 3p21, 4p16. The involvement of human papilloma virus (HPV) in the development of carcinoma of the uterine cervix has been firmly established. Since HPV infection does not always lead to cervical cancer, other genetic alterations must also play a role in tumour development. These include activation of oncogenes and inactivation of tumour-suppressor genes. The genetic changes in a tumour are an important determinant for the behaviour of the tumour cells. The pattern of genetic alterations can therefore be expected to be associated with important clinical features, including prognosis, histologic tumour type and response to therapy. Inactivation of a tumour-suppressor gene is the result of inactivation of both alleles of such a gene. Usually one allele is lost by a small inactivating mutation or deletion and the second by complete loss of the allele (Knudson, 1971). Loss of one allele results in loss of heterozygosity (LOH) and indicates the possible presence of a tumour-suppressor gene in that region. Such chromosomal losses can be detected by cytogenetic studies or by the analysis of LOH with polymorphic markers. Only a limited number of tumour-suppressor genes has been identified to date. Given the large number of regions with frequent LOH, several tumour-suppressor genes remain to be identified.Cytogenetic studies on carcinoma of the uterine cervix have shown the non-random involvement of a number of chromosomes, particularly chromosomes 1, 3, 5, 11 and 17. With the exception of chromosome 5, where a short-arm isochromosome is the commonest derivative, these chromosomes most often undergo short-arm deletions (Atkin, 1997).Studies of LOH in cervical carcinomas have reported a high frequency of LOH at chromosomes 3p, 4, 5, 6, 11p and 17p (Kisseljov et al., 1996;Mitra et al., 1994;Rader et al., 1996;Mullokandov et al., 1996;Hampton et al., 1996;Kersemaekers et al., 1998). We have now addressed the correlation between clinicopathologic parameters and LOH. Clinicopathologic parameters known to be of prognostic value in cervical cancer are lymph-node metastases, maximum depth of invasion, lymphvascular ...

Intercellular contacts, mediated by E-cadherin, are essential for germ cell migration and maturation. Furthermore, it has been suggested that decrease or loss of E-cadherin correlates with tumour progression and invasive behaviour. beta-catenin is involved in a number of different processes, including cell--cell interaction when bound to cadherins, and determination of cell fate in pluripotent cells when activated via the Wnt signal-transduction pathway. To shed more light on the role of these factors in normal fetal germ cell development and the pathogenesis of germ cell tumours (GCTs), the present study investigated the presence and localization of E-cadherin and beta-catenin by immunohistochemistry. E-cadherin was only weakly expressed in or absent from fetal germ cells of the second and third trimesters, and was not expressed in carcinoma in situ/intratubular germ cell neoplasia unclassified (CIS/ITGCNU) and gonadoblastoma, the precursor of an invasive GCT in dysgenetic gonads. In GCTs, it was generally not expressed in seminoma and dysgerminoma, but was found in the vast majority of non-seminoma cells. beta-catenin was found in the cytoplasm of fetal germ cells at all gestational ages and in spermatogenesis in post-pubertal testes. It was also present in CIS/ITGCNU and gonadoblastoma. Whereas seminomas and dysgerminoma were negative, non-seminoma cells were frequently found to express beta-catenin. Expression of both factors therefore reflects the degree of differentiation of these tumours. No differences for either E-cadherin or beta-catenin were observed between samples of tumours resistant or sensitive to chemotherapy, and E-cadherin expression did not correlate with vascular invasion. E-cadherin and beta-catenin therefore play a role in both normal and malignant germ cell development and differentiation that warrants further investigation, but they seem to be of limited value as predictive or prognostic factors in GCTs.

Although our results are in line with previous findings of the presence of wild-type P53 in TGCTs, they show that a high level of P53 does not relate directly to treatment sensitivity of these tumors, and inactivation of P53 is not a common event in the development of cisplatin resistance.

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