Squamous cell carcinoma arising in mature cystic teratoma of the ovary: report of two cases with molecular analysis.

Mature cystic teratoma (MCT) is the most frequent ovarian tumor and it is generally composed of well-differentiated elements which, nevertheless, have the potential for malignant transformation. The authors report two cases of squamous cell carcinoma (SCC) arising on ovarian MCT. In the present study, no mutation of the CDKN2A gene, whose impairment may deeply affect either the p16(CDKN2A)-CyclinD1-pRb cascade or the p14(CDKN2A)-mdm2-p53 cascade, was observed in tumour tissues from our cases' collection. This suggests that changes in the protein levels for the above-described candidate effectors may be somehow due to epigenetic alterations into the mechanisms controlling their expression. Analogously, no genetic modification among the two main genes (EGFR and KRAS) upstream the MAPK signalling pathway, which has been widely reported to play a major role in both development and progression of vast majority of malignant tumours, was detected in this series. Additional genes and pathways should be therefore investigated in order to identify genomic impairments underlying the MCT malignant transformation.

Immunoreactivity for Ca 125 and INI 1 loss of expression are useful markers in the diagnosis of vulvar proximal-type epithelioid sarcomas: report of two cases.

Epithelioid sarcomas (ES) are rare soft tissue tumours of obscure histogenesis. Diagnosis is often difficult as specific morphological and immunohistochemical patterns do not exist. Two distinct clinico-pathological entities have been identified: the classic or distal type and the proximal type. Recently, immunohistochemical detection of Ca 125 was described in ES, as well as loss of INI 1 expression. The authors describe in this paper the morphological and immunohistochemical features of two cases of proximal ES of the vulva. Immunoreactivity for Ca 125 and loss of INI 1 expression were present in both cases. These results confirm previous observations in Asian reports showing that these markers can be used as immunohistochemical markers for the diagnostic assessment of ES.

Chromosomal abnormalities and microsatellite instability in sporadic endometrial cancer.

Defective DNA mismatch repair and nonfunctional mechanisms controlling the proper progression of the cell cycle have been proposed as being responsible for the genomic instability and accumulation of karyotypic alterations in endometrial cancer (EC). To assess whether numerical chromosomal anomalies (aneuploidy) and microsatellite instability (MSI) might be representative of distinctive tumour behaviour, paraffin-embedded tissue samples from 86 patients with sporadic EC were evaluated by both fluorescence in situ hybridisation (FISH) and microsatellite analysis, using free nuclei and genomic DNAs (respectively). Approximately one-third of the tumours analysed (24/74; 32%) exhibited MSI, whereas 38/86 (44%) of the EC samples displayed aneuploidy. The majority of the unstable cases (15/24; 63%) were from advanced-stage patients. Conversely, 23 (61%) out of the 38 tumours with aneuploidy were from early-stage patients. No apparent correlation was found between MSI and aneuploidy, whereas the immunohistochemical (IHC) analysis revealed that inactivation of the MLH1 mismatch repair gene may be involved in the majority of the MSI+ sporadic ECs. No genetic or cytogenetic alteration analysed here seems to add any significant predictive value to the stage of disease.

Genotoxic effects of cadmium chloride on human amniotic fluid cells cultured in vitro.

In this study we report the results of cytogenetic tests, namely a search for chromosome aberrations (CA) and sister chromatid exchanges (SCEs), performed on human amniotic fluid cells cultured and treated with Cadmium chloride. The cells from primary cultures were exposed to CdCl2 at 1 microM and 10 microM for 24 h. At the higher dose, no metaphases were scored and at the lower dose (1 microM) no effects were evident on cell proliferation, and no chromosome aberrations were found. In the subsequent experiments we used cells from subcultures exposed to 1 microM and 5 microM CdCl2. At the 5 microM dose was evident the induction of chromatid breaks, while the frequency of sister chromatid exchanges shows a small increase, not statistically significant at the dose of 1 microM. In this study we positively demonstrated that amniotic fluid cells grown in vitro are reliable for testing various mutagenic or teratogenic substances. With regard to cadmium treatment results, it is evident a clastogenic effect of cadmium chloride but not a significant induction of SCEs.

Molecular alterations at chromosome 9p21 in melanocytic naevi and melanoma.

BACKGROUND: The chromosome 9p21 and its CDKN locus, with the p16 tumour suppressor gene (CDKN2A), are recognized as the genomic regions involved in the pathogenesis of melanoma. OBJECTIVES: To elucidate further the role of such regions during the different phases of melanocytic tumorigenesis. METHODS: Tissue sections from naevi, primary and metastatic melanomas were investigated by fluorescence in situ hybridization for allelic loss at the 9p21 chromosome and by immunochemistry for p16CDKN2A expression. RESULTS: Dysplastic naevi and primary or secondary melanomas were found to carry hemizygous deletions within the entire 9p21 region at similar frequencies (varying from 55% to 62%). Allelic deletion spanning the CDKN locus was observed at significantly increased rates moving from early (7%) to advanced (28%) primary melanomas and to secondary melanoma lesions (37%) (P=0.018). Also, inactivation of the p16 gene (CDKN2A) was absent in naevi and present at steadily increasing rates moving from primary melanomas (7% early lesions to 17% advanced lesions) to melanoma metastases (62%) (P=0.004). CONCLUSIONS: Our findings indicate that, in a model of sequential accumulation of genetic alterations, 9p21 deletions may play a role in melanocytic transformation and tumour initiation whereas rearrangements at the CDKN locus, and p16 gene (CDKN2A) inactivation may contribute to tumour progression.

Issues affecting molecular staging in the management of patients with melanoma.

Prediction of metastatic potential remains one of the main goals to be pursued in order to better assess the risk subgroups of patients with melanoma. Detection of occult melanoma cells in peripheral blood (circulating metastatic cells [CMC]) or in sentinel lymph nodes (sentinel node metastatic cells [SNMC]), could significantly contribute to better predict survival in melanoma patients. An overview of the numerous published studies indicate the existence of several drawbacks about either the reliability of the approaches for identification of occult melanoma cells or the clinical value of CMC and SNMC as prognostic factors among melanoma patients. In this sense, characterization of the molecular mechanisms involved in development and progression of melanoma (referred to as melanomagenesis) could contribute to better classify the different subsets of melanoma patients. Increasing evidence suggest that melanoma develops as a result of accumulated abnormalities in genetic pathways within the melanocytic lineage. The different molecular mechanisms may have separate roles or cooperate during all evolutionary phases of melanocytic tumourigenesis, generating different subsets of melanoma patients with distinct aggressiveness, clinical behaviour, and response to therapy. All these features associated with either the dissemination of occult metastatic cells or the melanomagenesis might be useful to adequately manage the melanoma patients with different prognosis as well as to better address the different melanoma subsets toward more appropriate therapeutic approaches.