Bauke de Jong

PATHOGENESIS OF ADULT TESTICULAR GERM-CELL TUMORS - A CYTOGENETIC MODEL

In essence, two models exist of the pathogenetic relationship between seminomas and nonseminomatous germ cell tumors (NSGCTs). In the first model, the histogenesis of seminomas is assumed to diverge from that of the other testicular germ cell tumors (TGCTs) at an early stage. The neoplastic pathway of seminomas and NSGCTs is different, with limited or no crossover. The second model suggests that seminomas and NSGCTs have a common origin with a single neoplastic pathway on which seminomas are an intermediate stage in development of NSGCTs. Our data on the cytogenetics and ploidy of seminomas, combined tumors, and NSGCTs lend support to the model of pathogenesis of seminomas and NSGCTs in which all TGCTs (with the possible exception of spermatocytic seminoma and infantile yolk sac tumor) have a single origin and neoplastic pathway, with seminomas representing an intermediate stage in development of NSGCT components, as opposed to the model in which seminomas and NSGCTs develop separately. The progression of TGCTs probably proceeds from high to lower numbers of chromosomes and is therefore accompanied by a net loss of chromosomal material. This decrease will be the end result of loss of specific chromosomes, gain of some other chromosomes (or part of chromosomes), and development of structural abnormalities.

Cytogenetics of carcinoma in situ of the testis

Carcinoma in situ (CIS) of the testis is the precursor lesion of most testicular germ cell tumors (TGCTs). Karyotyping of CIS is important for a better understanding of the pathogenesis of TGCTs and the progression to invasive cancer. We karyotyped three cases of CIS. All three cases showed a numerical abnormal chromosomal pattern. In one case, two copies of the germ cell tumor marker i(12p) were found.

Comparative genomic hybridization of microdissected samples from different stages in the development of a seminoma and a non-seminoma

Human testicular germ cell tumours (TGCTs) of adolescents and adults, both seminomas and non‐seminomas, originate from intratubular germ cell neoplasia (IGCN). Comparative genomic hybridization (CGH) was applied to microdissected samples from different stages of the development of a seminoma and a mixed non‐seminoma, including IGCN of both. The different stages of the seminoma development, namely IGCN, intratubular and invasive seminoma, showed a very similar pattern of chromosomal imbalances, including gains of parts of 7, 8,12,14, and X, and losses of parts of 3, 4, 5, 10, 11, 12q, 16, 18, 22, and Y. A more heterogeneous pattern was found for the non‐seminoma. Some aberrations were present only in IGCN, or in IGCN and in all invasive components (gains of parts of 1q, 17, 19p, 20q, and 22, and losses of parts of 4, 5, 9p, 13, and 18q), while others were present in a less consistent pattern. These are the first reported CGH data from different stages in the development of TGCTs. Although only two cases were studied, the results suggest that particular numerical changes of (parts of) chromosomes are involved in the early development and progression of this cancer. Copyright

Cytogenetic classification of renal cell cancer

Cytogenetic and molecular genetic investigations in cancer are important tools to address problems of oncogenesis and tumor progression, of classification, and of diagnosis of tumors. A combination of advanced molecular genetic, cytogenetic, and (immuno) histopathologic analysis will contribute significantly to the elucidation of the oncogenic steps that lead to immortalization and subsequent malignant behavior. In this review written on the occasion of Dr. Avery Sandbergs 75th anniversary, we will present a model for the pathogenesis of renal cell tumors based on a new cytomorphologic classification and our (cyto)genetic analysis of about 175 renal cell tumors, together with the accumulated data in the literature.

Karyotyping and DNA flow cytometry of mature residual teratoma after intensive chemotherapy of disseminated nonseminomatous germ cell tumor of the testis: a report of two cases

Karyotyping and DNA flow cytometry was performed on mature residual teratoma cells following intensive chemotherapy of disseminated nonseminomatous germ cell tumor of the testis to study its biology. We report herein a successful method for short-term tissue culture and karyotyping of retroperitoneal residual mature teratoma in two cases. In vitro morphology confirmed that the cultured cells were nonembryonal carcinoma cells. Both mature residual teratomas were highly aneuploid and possessed the i(12p) marker characteristic of testicular germ cell tumors. A clone in the retroperitoneal residual lesion of one of the patients showed a DNA-index different from the primary tumor and might represent a clone unmasked by chemotherapy. In view of these data, which are in agreement with recent reports on secondary non-germ cell malignancies arising in mature residual teratoma, aggressive surgery of mature residual lesions seems justified.

Cytogenetics of 12 cases of renal adenocarcinoma.

The cytogenetics of 12 cases of renal adenocarcinoma are presented. Clonal abnormalities were found in nine patients. Worth mentioning are abnormalities of the X chromosome (1 X) and the chromosomes #1(3 X), #3(3 X), #7(4 X), #8(4 X), and #14(2 X). From our data and data from the literature it appeared that the chromosomal regions 3p11-p21, 1q21, 14q22, and Xp11 are important for the oncogenesis of renal cell carcinoma as well as increased dosage of chromosome #7 and loss or abnormalities of chromosomes #8 and #14.

Chromosomal constitution of human spermatocytic seminomas: comparative genomic hybridization supported by conventional and interphase cytogenetics.

No data on the chromosomal constitution of spermatocytic seminomas are available thus far because of their rarity. Ploidy analysis performed on paraffin‐embedded cases showed varying results from (near‐) diploid to aneuploid. We applied comparative genomic hybridization on four snap‐frozen primary spermatocytic seminomas of three different patients. Conventional cytogenetic analysis was successful in one, and “interphase cytogenetics” with centromeric region‐specific probes was applied to another. The results from comparative genomic hybridization showed almost exclusively numerical chromosomal aberrations, in agreement with the data from karyotyping. Despite the limited number of cases studied, a nonrandom pattern of chromosome imbalances was detected: chromosome 9 was gained in all spermatocytic seminomas. This suggests that that this aberration plays a role in the development of this cancer. Interphase cytogenetics shows that the copy number of most chromosomes ranges from two to four, with an average of near trisomic. This constitutes the first report on the chromosomal constitution of spermatocytic seminomas. Genes Chromosomes Cancer 23:286–291, 1998.

Cytogenetic findings in eleven gastric carcinomas

We describe the results of the cytogenetic study of 10 primary adenocarcinomas of the stomach and one lymph node metastasis of a gastric adenocarcinoma after direct harvesting or short-term in vitro culture. All cases showed a variable number of numerical and/or structural clonal cytogenetic aberrations. Polysomy of chromosomes 2 and 20 were the most common numerical abnormalities. Rearrangements of chromosomes 1, 3, 7, and 13 were each observed in more than half the cases. Chromosomes 3 and 13 were the chromosomes more often exhibiting structural cytogenetic aberrations. In five tumors, rearrangements of chromosome 6 resulting in partial deletion of 6q were noted (common deleted region 6q21-22-->qter). The recurrent markers observed in our series were an i(8q) and an i(17q) in three and two cases, respectively. Double minutes (dmin) or homogeneously staining regions (hsr) were evident in three tumors. Contrary to the recent claim that structural abnormalities affecting 11p13-p15 were specifically involved in gastric cancer, we detected rearrangements of this region in only two cases.

Chromosomal constitution and developmental potential of human germ cell tumors and teratomas

Systematic histologic examination and adoption of a fairly standardized nomenclature for the description of the human germ cell tumors and teratomas (GCT&T) of all anatomical localizations [1-3] has led to the recognition that they contain a limited number of basic histologic components: seminoma (SE), termed dysgerminoma in the ovary, and germinoma in extragonadal localizations, and the nonseminomatous elements (NS): embryonal carcinoma (EC), yolk sac tumor (YST), choriocarcinoma, polyembryoma, immature teratoma, mature teratoma (of which the dermold cyst is a distinct, cystic variant), and spermatocytic seminoma. The GCT&T have different histologic patterns depending on their anatomical localization and the sex and the age of the patient. We propose that they can be clustered into four developmental groups on the basis of their clinical presentation and gross and microscopic morphology (Table 1):

Cytogenetic evidence that carcinoma in situ is the precursor lesion for invasive testicular germ cell tumors

A cytogenetic study of two cases of carcinoma in situ of the testis (CIS) and their adjacent invasive tumors, one a nonseminomatous germ cell tumor (NS) and one a seminoma (SE), revealed similarities in chromosomal pattern between the CIS and the invasive lesion in the same patient. These findings present for the first time cytogenetic evidence that CIS of the testis and its adjacent germ cell tumor are clonally related, which suggests that the CIS is indeed the precursor lesion of the invasive tumor.