DICER1 mutation-positive giant botryoid fibroepithelial polyp of the urinary bladder mimicking embryonal rhabdomyosarcoma.

Fibroepithelial polyps of the urinary tract are rare lesions. They occur mainly in the upper urinary tract of children. A high disease prevalence has been reported in families with pleuropulmonary blastoma. Here we present a case of a 46-year-old woman who presented with a giant botryoid fibroepithelial polyp of the urinary bladder. Histologically, the lesion showed prominent botryoid features with an embryonal rhabdomyosarcoma-like cambium layer lacking nuclear or cellular atypia. Immunohistochemical analysis ruled out rhabdomyoblastic differentiation. Next-generation sequencing was performed on the polyp tissue and revealed two pathogenic mutations in the DICER1 ribonuclease III (DICER1) gene (c.[5439G>T]; p.[Glu1813Asp] and c.[1525C>T]; p.[Arg509*]). Truncating DICER1 mutations, accompanied by characteristic "hotspot" mutations affecting the RNase IIIB domain of DICER1 are typically seen in DICER1-related lesions. Our findings indicate a role of DICER1 mutations in the pathogenesis of fibroepithelial polyps of the urinary tract.

Analysis of PIK3CA and Akt/protein kinase B in head and neck squamous cell carcinoma.

PIK3CA, which encodes the catalytic subunit, p110-alpha, of phosphatidylinositol 3-kinase (PI3K), is implicated in the development and progression of numerous neoplasias including head and neck squamous cell carcinoma (HNSCC). In the present study, we investigated the occurrence of PIK3CA hot-spot mutations in exons 9 and 20, the genomic gain and amplification of PIK3CA, the expression of PIK3CA mRNA and the p110 alpha protein, as well as the expression of phosphorylated-Akt (pAkt) in 33 cases of HNSCC and compared the results with the clinicopathological data. No non-synonymous mutations were detected. PIK3CA copy number gain and amplification were found in 36.4 and 9% of the cases, respectively, whereas mRNA overexpression was observed in 48.5% of the cases. No correlations could be stated between DNA gain, DNA amplification and mRNA expression, either between DNA or mRNA status and p110 alpha expression. Direct associations were found between PIK3CA gain and lymph node metastases (p=0.025) and between mRNA expression and tumour stage (p=0.015). A strong correlation was detected between p110 alpha and pAkt expression (p<0.001). Concluding, PIK3CA could be an oncogene implicated in HNSCC development. However, our data suggest that amplifications or mutations of this gene seldom occur in HNSCC and that epigenetic events can play an important role in advanced tumour stages.

Prognostic value of PIK3CA and phosphorylated AKT expression in ovarian cancer.

Disrupted phosphatidylinositol 3-kinase (PI3K) activity and its effect on the downstream target AKT plays an important role in malignant diseases. Gain and/or amplification of PIK3CA gene, encoding the catalytic subunit of phosphatidylinositol 3-kinase (p110 alpha) and its increased expression are associated with enhanced PI3K activity in ovarian cancer cell lines. In this study, ovarian carcinomas with documented clinical outcome were assessed for genetic aberrations at the 3q26.3 locus, including PIK3CA, by fluorescence in situ hybridization. PIK3CA amplification was evaluated by quantitative real-time PCR with respect to a control gene situated at 3q13. The expression of p110 alpha, phosphorylated AKT (pAKT) and the proliferation marker Ki-67 were immunohistochemically investigated. PIK3CA amplification and Ki-67 index were strong predictors for an early tumour-associated death. p110 alpha expression correlated with 3q26.3 gain and Ki-67 index but not with the patient outcome. No relationship could be observed between p110 alpha and pAKT or between pAKT and disease outcome. It is interesting to note that cases with a nuclear pAKT immunoreactivity showed a trend of improved overall survival. Our results underline the prognostic significance of PIK3CA in ovarian carcinoma and argue against a simple linear model of PIK3CA gain/amplification followed by PI3K activation and consecutive AKT phosphorylation in ovarian carcinoma.

Glucocorticosteroid receptors in ovarian carcinomas.

The use of glucocorticoids (GCs) in oncology, including in the treatment of ovarian carcinomas, is controversial. In vitro experiments suggest that GCs negatively influence the response to chemotherapy, but the few available clinical data show only benefits. Glucocorticoid action is mediated via glucocorticoid receptors (GRs). This study aims to define any clinical implications of GR expression in ovarian cancer to further the debate. Archived tissue samples from patients with histologically confirmed ovarian cancer were analyzed for GR expression and evaluated by immunohistochemistry and immunoreactive score. The results were related to the patients' overall survival. Kaplan-Meier survival and residual survival analyses gave no evidence that GR expression had any prognostic value in the 85 cases studied. No evidence of poorer survival was found in a small subset of GR-positive patients who received GC treatment. Glucocorticoid receptor expression had no prognostic impact in our study. However, GC (cortisol) is being produced continuously by the body, which may have stimulated GR-positive ovarian cancer cells. Our finding does not exclude the possibility that long-term GC treatment has adverse effects, and it should also be emphasized that treatment duration, dosage and dosing regimens, as well as the choice of an appropriate GC and the mode of application, determine the risks and benefits. Our study showed no evidence against using GC for antiemetic prophylaxis in ovarian carcinomas.

Cancer of the endometrium: current aspects of diagnostics and treatment.

BACKGROUND: Endometrial cancer represents a tumor entity with a great variation in its incidence throughout the world (range 1 to 25). This suggests enormous possibilities of cancer prevention due to the fact that the incidence is very much endocrine-related, chiefly with obesity, and thus most frequent in the developed world. As far as treatment is concerned, it is generally accepted that surgery represents the first choice of treatment. However, several recommendations seem reasonable especially with lymphadenectomy, even though they are not based on evidence. All high-risk cases are generally recommended for radiotherapy. METHODS: A literature search of the Medline was carried out for all articles on endometrial carcinoma related to diagnosis and treatment. The articles were systematically reviewed and were categorized into incidence, etiology, precancerosis, early diagnosis, classification, staging, prevention, and treatment. The article is organized into several similar subheadings. CONCLUSIONS: In spite of the overall good prognosis during the early stages of the disease, the survival is poor in advanced stages or recurrences. Diagnostic measures are very well able to detect asymptomatic recurrences. These only seem justified if patients' chances are likely to improve, otherwise such measures increases costs as well as decrease the patients' quality of life. To date neither current nor improved concepts of endocrine treatment or chemotherapy have been able to substantially increase patients' chances of survival. Therefore, newer concepts into the use of antibodies e.g. trastuzumab in HER2-overexpressing tumors and the newer endocrine compounds will need to be investigated. Furthermore, it would seem highly desirable if future studies were to identify valid criteria for an individualized management, thereby maximizing the benefits and minimizing the risks.

Loss of heterozygosity at 12p13 and loss of p27KIP1 protein expression contribute to melanoma progression.

Little is known about the mechanisms causing p27KIP1 decrease in melanomas. Therefore, we performed loss of heterozygosity (LOH) analysis with polymerase chain reaction at seven different loci surrounding the p27KIP1/CDKN1B gene at 12p13 and direct DNA sequencing analysis of all exons. Furthermore, the immunohistochemical expression of p27KIP1 and Ki-67 was investigated. Only two mutations in the sequence of p27KIP1/CDKN1B were detected, but the number of tumours showing LOH at 12p13 increased significantly with the parameters of tumour progression (pT level, P=0.018; Breslow index, P=0.01; Clark level, P<0.001), with a more aggressive tumour growth (radial versus vertical growth, P=0.018) and tumour subtype (superficial spreading melanomas versus nodular melanomas versus metastases, P<0.001). p27KIP1 protein expression decreased with the Clark level ( P=0.026) and the pT level ( P=0.045). No correlation between LOH affecting 12p13 and p27KIP1 protein decrease in melanomas was stated. This does not exclude the participation of p27KIP1/CDKN1B in p27KIP1 protein decrease, since protein expression is regulated at various cellular levels; but it could also suggest that other tumour suppressors are situated in the same region as p27KIP1/CDKN1B. Taken together, our data shows that loss of p27KIP1 protein expression and LOH at 12p13 contribute to tumour progression in melanoma.

Expression of PTEN in malignant and non-malignant human prostate tissues: comparison with p27 protein expression.

The role of the putative tumour suppressor PTEN in prostate carcinogenesis is controversial. There are conflicting data regarding the rate of its gene inactivation, the role of transcriptional and post-transcriptional factors, as well as its relationship to tumour progression and to the potential downstream regulator, the cell-cycle inhibitor p27. The present study has assessed the in situ expression of PTEN mRNA and protein in 26 prostate intraepithelial neoplasias (PINs), 58 primary prostate carcinomas, and 15 metastases. Although there was a correlation between PTEN mRNA and protein expression, mRNA detection exceeded detection of protein in 19% of PINs and 30% of all invasive tumours. Using RT-PCR and western blotting on microdissected tissue, this discrepancy was attributed, at least in part, to transcription of the PTEN pseudo-gene, which lacks introns. Total or partial loss of PTEN protein occurred with tumour progression but this association was not statistically significant. Analysing the relationship between PTEN and p27 protein expression on consecutive sections by immunohistochemistry, the results do not support a direct link between the two oncosuppressors, other than an associated loss of expression in advanced tumour stages. However, in the basal cells of prostate glands and in most PINs, an inverse relationship was observed between PTEN and p27. This may reflect the existence of a functional balance that controls the cell cycle in prostatic epithelium and that is probably disturbed in invasive tumour cells.

Genomic gain of PIK3CA and increased expression of p110alpha are associated with progression of dysplasia into invasive squamous cell carcinoma.

PIK3CA, encoding the catalytic subunit p110alpha of phosphatidylinositol 3-kinase (PI3K), is activated in malignant diseases. However, the role of the PIK3CA gene aberrations for tumourigenesis of head and neck squamous cell carcinoma (HNSCC) is to date unclear. The present study was designed to determine the genomic aberration of PIK3CA in invasive HNSCC and dysplastic precursor lesions by fluorescence in situ hybridization (FISH) with a YAC probe, containing the PIK3CA gene, on isolated interphase nuclei from histomorphologically well-defined regions of formalin-fixed tissue sections and to compare these data with protein and mRNA expression of p110alpha. The mRNA and protein levels of p110alpha were assessed, respectively, by in situ hybridization and immunohistochemistry on consecutive tissue sections. Copy number gains at 3q26 were observed in one of six low-to-moderate dysplasias (17%) and in seven of nine high-grade dysplasias (78%), as well as in 11 carcinomas (100%). In addition, one of seven high-grade dysplasias (14%) and 6 of 11 carcinomas (55%) had amplifications of 3q26. The majority of cases with copy number gain in more than 50% of the cells and/or amplification in more than 10% of cells showed increased p110alpha mRNA and protein expression, whereas only two cases (18%) (one high-grade dysplasia and one carcinoma) with no gain or low-level gain displayed increased p110alpha protein expression. These data suggest that 3q26 copy number gain and amplification represent early genomic aberrations in HNSCC carcinogenesis. In addition, p110alpha mRNA and protein expression in HNSCC may be regulated by these genomic aberrations as well as by epigenetic events.