T1 bladder carcinoma with variant histology: pathological features and clinical significance

The aim of the study was to stratify high-grade T1 (HGT1) bladder urothelial carcinoma into risk categories based on the presence of variant histology when compared to conventional urothelial carcinoma. The clinicopathological features of 104 HGT1 cases of urothelial carcinoma of the bladder with variant histology present in 34 (37%) were assessed. The endpoint of the study was disease-free survival and cancer-specific survival. Overall, variant histology was identified as a significant predictor of disease-free survival (P = 0.035). The presence of any specific variant histology (squamous, glandular, micropapillary, nested, microcystic, inverted growth, villous-like, basaloid, and lymphoepithelioma-like) was identified as a significant predictor of disease-free survival (P = 0.008) and cancer-specific survival (P = 0.0001) in HGT1 bladder cancer. Therefore, our results support including micropapillary HGT1 urothelial carcinoma within the aggressive high-risk category, as suggested by some recent clinical guidelines, but also favor nested, glandular, and basaloid to be placed in the high-risk category due to their potential of aggressive, life-threatening behavior and their limited response to bacillus Calmette-Guerin therapy. Conversely, the low-risk category would include urothelial carcinomas with squamous, inverted growth, or microcystic morphology, all with limited life-threatening potential and good response to current therapy. A very low-risk category would finally include patients whose tumors present villous-like or lymphoepithelioma-like morphology. In conclusion, our findings support the value of reporting the variant histology as a feature of variable aggressiveness in HGT1 urothelial carcinoma of the bladder

Presence of activating KRAS mutations correlates significantly with expression of tumour suppressor genes DCN and TPM1 in colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Despite identification of the major genes and pathways involved in the development of colorectal cancer (CRC), it has become obvious that several steps in these pathways might be bypassed by other as yet unknown genetic events that lead towards CRC. Therefore we wanted to improve our understanding of the genetic mechanisms of CRC development.</p> <p>Methods</p> <p>We used microarrays to identify novel genes involved in the development of CRC. Real time PCR was used for mRNA expression as well as to search for chromosomal abnormalities within candidate genes. The correlation between the expression obtained by real time PCR and the presence of the <it>KRAS </it>mutation was investigated.</p> <p>Results</p> <p>We detected significant previously undescribed underexpression in CRC for genes <it>SLC26A3</it>, <it>TPM1 </it>and <it>DCN</it>, with a suggested tumour suppressor role. We also describe the correlation between <it>TPM1 </it>and <it>DCN </it>expression and the presence of <it>KRAS </it>mutations in CRC. When searching for chromosomal abnormalities, we found deletion of the <it>TPM1 </it>gene in one case of CRC, but no deletions of <it>DCN </it>and <it>SLC26A3 </it>were found.</p> <p>Conclusion</p> <p>Our study provides further evidence of decreased mRNA expression of three important tumour suppressor genes in cases of CRC, thus implicating them in the development of this type of cancer. Moreover, we found underexpression of the <it>TPM1 </it>gene in a case of CRCs without <it>KRAS </it>mutations, showing that <it>TPM1 </it>might serve as an alternative path of development of CRC. This downregulation could in some cases be mediated by deletion of the <it>TPM1 </it>gene. On the other hand, the correlation of <it>DCN </it>underexpression with the presence of <it>KRAS </it>mutations suggests that <it>DCN </it>expression is affected by the presence of activating <it>KRAS </it>mutations, lowering the amount of the important tumour suppressor protein decorin.</p

CELL CYCLE REGULATING GENES AND THEIR PROTEIN EXPRESSION IN SQUAMOUS CELL CARCINOMA OF THE LARYNX AND HYPOPHARYNX

Background. The major mechanisms involved in genomic instability during tumour progression are loss of heterozygosity (LOH) and microsatellite instability (MSI). The most frequently affected are the tumor suppressor genes (TSG). Alterations of cell cycle proteins contribute to the development and biologic behaviour of malignant tumours.Methods. In a prospective study we evaluated the distribution and prognostic significance of immunohistochemically detected proteins p53, p21, p16, Rb, and cyclin D1 in 101 squamous cell carcinomas of the larynx and hypopharynx (LHSCC). Additionally, non isotopic MSI and LOH analysis was performed with microsatellite markers on chromosomes 3p, 9p, 17p, and 11q. Immunohistochemical and molecular alterations were compared to tumour grade, disease stage and three year patients’ overall and disease free survival.Results. Of 101 patients, there were 94 men and 7 women with 73 laryngeal and 28 hypopharyngeal cancers. Immunohistochemical staining was performed on all tumours and molecular analysis in 77 patients.In LHSCC, varying patterns of protein expression were found. A significant correlation was found between cyclin D1 and p21, cyclin D1 and Rb expression, and Rb expression and tumour grade. p53 and p16 expression did not correlate with other proteins. p16 expression correlated with LOH at 9p21, and LOH at 11q13 (cyclin D1 region) correlated with the tumour grade. We observed a high incidence of LOH at specific chromosomal regions: 3p (61%), 9p (54.4%), 17p (57.1%) and 11q (19.5%). Conversely, MSI was present in 6.5% of cases.In addition to tumour grade and N stage, only cyclin D1 expression revealed independent prognostic value for overall, but not disease free survival after multivariate analysis.Conclusions. In conclusion, our study demonstrated the derailment of the growth promoting and suppressing pathways of cell cycle control in almost all LHSCC. Our results suggest that Rb gene inactivation might also be important in the development of LHSCC.It appears that cyclin D1 has a central role in the regulation of the cell cycle in LHSCC. When over-expressed it is able to override most of the inhibitory action exercised by its antagonists and has an independent prognostic value for patient overall survival.Our study demonstrated that the TSG, involved in the regulation of the cell cycle, are changed significantly in LHSCC. The most important mechanism involved, compared to low MSI, appears to be LOH, indicating a dominant role of the suppressor pathway in LHSCC carcinogenesis.</p

Expression, Mutation, and Amplification Status of EGFR and Its Correlation with Five miRNAs in Salivary Gland Tumours

Malignant salivary gland tumours are rare histologically and clinically heterogeneous group of tumours, missing prognostic factors and therapeutic targets. MicroRNAs (miRNAs), small noncoding RNAs, and posttranscriptional regulators of mRNA are poorly described in different subtypes of salivary gland tumours. Epidermal growth factor receptor (EGFR), an important therapeutic target and target of certain miRNAs (i.e., miR-133b), shows variable degrees of expression in salivary gland tumours. Our study included 70 parotid gland tumours of different histological subtypes. Expression, mutations, and copy number variations (CNVs) of EGFR were determined using immunohistochemistry, single-stranded conformation polymorphism, quantitative polymerase chain reaction (qPCR), and fluorescence in situ hybridization. Expression of miR-99b, miR-133b, miR-140, miR-140-3p, and let-7a was analysed using qPCR. Expression of EGFR was observed in 37% of tumours with low and 40% of tumours with high malignant potential. There were no mutations, with the majority of samples showing polysomy of chromosome 7. Based on histological subtypes, we found differential expression of all five miRNAs. We confirmed association of reactivity of EGFR, miR-133b, miR-140, miR-140-3p, and let-7a with CNV of EGFR and a positive association between miR-133b/let-7a and reactivity of EGFR. Age and need for postoperative radiotherapy were characterized as significant in multivariate survival analysis

A CASE OF EXTRANODAL NK/T-CELL LYMPHOMA PRESENTING WITH EOSINOPHILIA

Background. Eosinophilia can occur in extranodal NK/T-cell lymphoma. Chronic hypereosinophilia from any cause is associated with endomyocardial fibrosis.Methods and material. This report includes on a patient with hypereosinophilia, which was diagnosed and investigated nine months before the diagnosis of extranodal NK/T-cell lymphoma (nasal type) of the larynx was confirmed by biopsy. He died with signs of heart failure 11 months after the first symptoms developed. Post mortem investigation revealed endomyocardial fibrosis as a result of chronic hypereosinophilia.Conclusions. To our knowledge eosinophilia has not previously been reported in extranodal NK/T-cell lymphoma (nasal type). Therefore, this is considered to be a rare feature of the presented case. Investigation of the heart for potential silent complications of prolonged and severe eosinophilia has to be considered at an early stage</p

A case of extranodal NK/T cell lymphoma presenting with eosinophilia

Izhodišča. Eozinofilija se lahko pojavi tudi pri ekstranodalnem limfomu T naravnih ubijalk (T/NU). Če je dolgotrajna, lahko vodi v okvaro srčne mišice. Bolniki in metode. Prikazujemo primer bolnika z eozinofilijo, ugotovljeno devet mesecev pred postavitvijo diagnoze ekstranodalnega limfoma T/NU grla. Bolnik je umrl zaradi srčne odpovedi 11 mesecev po prvih simptomih. Na obdukciji je bila ugotovljena fibroza endomiokarda kot posledica kronične eozinofilije. Zaključki. Eozinofilija pri ekstranodalnem limfomu T/NU še ni bila opisana, zato menimo, da gre za redek primer. Pri bolnikih z izrazito eozinofilijo je pomembno zgodnje odkrivanje okvare srca, ki je lahko asimptomatska.Background. Eosinophilia can occur in extranodal NK/T cell lymphoma. Chronic hypereosinophilia from any cause is associated with endomyocardial fibrosis. Methods and material. This report includes on a patient with hypereosinophilia which was diagnosed and investigated nine months before the diagnosis of extranodal NK/T cell lymphoma (nasal type) of the larynx was confirmed by biopsy. He died with signs of heart failure 11 months after the first symptoms developed. Post mortem investigation revealed endomyocardial fibrosis as a result of chronic hypereosinophilia. Conclusions. To our knowledge eosinophilia has not previously been reported in extranodal NK/T cell lymphoma (nasal type). Therefore, this is considered to be a rare feature of the presented case. Investigation of the heart for potential silent complications of prolonged and severe eosinophilia has to be considered at an early stage