Subcellular localization of the human papillomavirus 16 E7 oncoprotein in CaSki cells and its detection in cervical adenocarcinoma and adenocarcinoma in situ.

E7 is the major oncoprotein of high-risk human papillomaviruses (HPV) which causes cervical cancer. To date E7 oncoproteins have not been investigated in cervical adenocarcinoma. In this study we generated a rabbit monoclonal anti-HPV-16 E7 antibody, RabMab42-3, which recognizes a conformational epitope in the E7 carboxy-terminal zinc-finger resulting in a strong increase in the sensitivity for the detection of cell-associated HPV-16 E7 protein relative to conventional polyclonal anti-HPV-16 E7 antibodies. Using RabMab42-3, we show that the subcellular localization of endogenous HPV-16 E7 oncoprotein varies during the cell cycle in cervical cancer cells. Moreover, we demonstrate for the first time that the HPV-16 E7 oncoprotein is abundantly expressed in cervical adenocarcinoma in situ and adenocarcinoma, suggesting an important role of HPV-16 E7 for the development of these tumors. Our findings suggest that the HPV-16 E7 oncoprotein could be a useful marker for the detection of cervical adenocarcinoma and their precursors.

Testicular cancer in Luxembourg: incidence and outcome in relation to the different histo-pathological types (1980-2004).

BACKGROUND: Increasing incidence rates of testicular cancer have been reported worldwide over the last three decades. Trends over time in the incidence rates of germ cell tumours (GCTs) in Luxembourg (Western Europe) and the outcome, both in relation to the different histological types, were analysed. METHODS: The population-based files of the Morphologic Tumour Registry collecting at a nation-wide level all testicular cancers diagnosed between 1980 and 2004 in the central department of pathology in Luxembourg were retrospectively reviewed. In addition, the presence of concomitant malignant diseases was investigated. RESULTS: 397 patients with GCT were evaluated. The mean age was 33.7 years (range: 1-72). Most of the patients (58.7%) were between 15 and 34 years of age. The age-standardized incidence rates rose from 4.5 per 10(5) (1980-1984) to 7.7 per 10(5) (2000-2004). Out of 275 (69.3%) pure GCTs, 218 seminomas, 48 embryonal carcinomas, 4 yolk sac tumours, 4 malignant teratomas and 1 choriocarcinoma were identified. 30.7% GCTs were of mixed type with 17 different histological variants. 5.8% of the patients had metachronous concomitant cancers, 2% bilateral GCTs and 3.8% non-testicular neoplasms. In all histological categories, with the exception of the pure seminomas, prognosis was determined within the 24 months following diagnosis; pure seminomas need long time follow-up. Ten-year observed survival rates exceeded mostly 90%. Pure embryonal carcinomas had the worst prognosis with a 10-year observed survival rate of 87.1 +/- 12%. CONCLUSIONS: Testicular germ cell tumours are rare, highly curable neoplasms that generally occur in young patients. In all histological categories, except for pure seminomas, prognosis was determined within the 24 months after diagnosis. Despite better observed survival rates, patients with pure seminomas, without or with metachronous concomitant non-testicular malignancies, need long time followup strategy.

High-risk human papillomavirus E7 oncoprotein detection in cervical squamous cell carcinoma.

PURPOSE: Persistent infections by high-risk human papillomavirus (HPV) types are the main etiologic factor for cervical cancer. The objective of this study was to evaluate whether high-risk E7 oncoprotein is adequate as a marker for the detection of cervical cancer. EXPERIMENTAL DESIGN: HPV typing was done in biopsies from 58 cervical carcinoma and 22 normal cervical squamous epithelia. The HPV-16 E7, HPV-18 E7, and HPV-45 E7 oncoprotein levels were monitored by immunohistochemistry and compared with those of p16(INK4a) and Ki67. RESULTS: Fifty-five (94.8%) tumors were high-risk HPV-DNA-positive (46 HPV-16, 2 HPV-16 and HPV-18, 4 HPV-18, 1 HPV-33, and 2 HPV-45). HPV-DNA could not be detected in three tumors (5.2%). High HPV E7 oncoprotein levels were shown in 57 cervical cancers (98.3%), without correlation between expression levels and tumor stages. CONCLUSION: This is the first study which systematically analyzes the levels of the major HPV oncoproteins in cervical carcinomas demonstrating that the high-risk HPV E7 proteins are regularly expressed in these cancers. This suggests that high-risk E7 oncoproteins are necessary for cervical cancers and apparently essential as tumor marker.

Complete loss of PTEN expression as a possible early prognostic marker for prostate cancer metastasis.

The EGF/IGF growth factors are potent mitogens that regulate cell proliferation and cell survival and are involved in prostate cancer development. Using laser microdissection technology and real-time PCR, together with immunohistochemistry, we have explored the growth factor and integrin dependent PI3-kinase/PTEN/Akt signalling pathway in prostate cell lines and tumour samples by analysing EGF-R, IGF1-R, ILK, beta3 integrin, PTEN and p-Akt protein expression. We provide evidence that loss of PTEN expression rather than upregulated EGF/IGF1 receptor expression was responsible for increased p-Akt in neoplastic prostate cells. We therefore compared PTEN expression in patient biopsies at first time diagnosis recruited prospectively (Study I, 112 patients) and patients with confirmed metastasis recruited retrospectively from the Luxembourg cancer registry (Study II, 42 patients). In Study I, loss of PTEN expression at first time diagnosis was found in 26 of 112 patients (23%). In Study II, 25 of the 42 patients (59%) with lymph node metastasis had complete loss of PTEN expression in both the neoplastic glands of the prostate and the invasive prostate cancer cells in the lymph node, and of these 13 (52%) exhibited already loss of PTEN expression at first diagnosis. These findings demonstrate that loss of PTEN expression is an important factor in progression towards metastatic disease and could potentially serve as an early prognostic marker for prostate cancer metastasis.

Thyroid cancer in Luxembourg: a national population-based data report (1983-1999).

BACKGROUND: Twenty years after the nuclear accident in Chernobyl (Eastern Europe), there is still a controversial debate concerning a possible effect of the radioactive iodines, especially I-131, on the increase of thyroid carcinomas (TCs) in Western Europe. Time trends in incidence rates of TC in Luxembourg in comparison with other European countries and its descriptive epidemiology were investigated. METHODS: The population-based data of the national Morphologic Tumour Registry collecting new thyroid cancers diagnosed between 1983 and 1999 at a nation-wide level in the central division of pathology were reviewed and focused on incidence rates of TC. Data from 1990 to 1999 were used to evaluate the distribution by gender, age, histological type, tumour size and the outcome. RESULTS: Out of 310 new thyroid carcinomas diagnosed between 1990 and 1999, 304 differentiated carcinomas (A: 80% papillary; B: 14.5% follicular; C: 3.5% medullary) and 6 anaplastic/undifferentiated TCs (D: 2%) were evaluated. The M/F-ratio was 1:3.2, the mean age 48.3 years (range: 13-92). The overall age-standardized (world population) incidence rates over the two 5-year periods 1990-1994 and 1995-1999 increased from 7.4 per 100,000 to 10.1 per 100,000 in females, from 2.3 per 100,000 to 3.6 per 100,000 in males. Only 3 patients were children or adolescents (1%), the majority of the patients (50%) were between 45 and 69 years of age. The percentage of microcarcinomas (<1 cm) was A: 46.4%, (115/248); B: 13.3%, (6/45); C: 27.3%, (3/11). The unexpected increase of TCs in 1997 was mainly due to the rise in the number of microcarcinomas. The observed 5-year survival rates for both genders were A: 96.0+/-2%; B: 88.9%; C: 90.9%; D: 0%. Prognosis was good in younger patients, worse in males and elderly, and extremely poor for undifferentiated TCs. CONCLUSION: The increasing incidence rates of TC, especially of the papillary type, seem mainly due to a rise in diagnosed microcarcinomas due to some extent to a change in histologic criteria and to more efficient diagnostic tools. This rise appears to be independent of the number of surgical treatments, the immigration rate, and the Chernobyl fallout as the incidence of TC in children remained stable.

Colon cancer in Luxembourg: a national population-based data report, 1988-1998.

BACKGROUND: Over the last two decades time trends in incidence rates of colorectal cancer, changes in the proportions of stage at diagnosis and changes in the anatomic sub-site distribution of colon cancers have been reported in some European countries. In order to determine a strategy for early detection of colon cancer in the Grand-Duchy of Luxembourg, all consecutive colon adenocarcinomas diagnosed during the period 1988-1998 at a nation-wide level were reviewed. METHODS: The population-based data of the national Morphologic Tumour Registry report all new high-grade adenomas (i.e. high-grade intraepithelial adenomatous neoplasias) and all consecutive new invasive adenocarcinomas of the colon diagnosed in the central department of pathology. Attention has been focused on variations in incidence, stage, anatomical site distribution and survival rates. Rectal cancers were excluded. RESULTS: Over the study period, 254 new colonic high-grade adenomas and 1379 new invasive adenocarcinomas were found; the crude incidence rates of colon adenocarcinomas grew steadily by 30%. Comparing the two 5-year periods 1988-1992 and 1994-1998, the crude incidence rates of high-grade adenomas (stage 0) rose by 190%, that of stage I cases by 14.3%, stage II cases 12.9% and stage III cases 38.5%, whereas the crude incidence rates of stage IV cases decreased by 11.8%. The high-grade adenoma/adenocarcinoma ratio increased. The right-sided colonic adenocarcinomas in elderly patients (>69 years) increased by 76%. The observed survival rates correlated with tumour stages. The overall observed 5-year survival rate (stage I-IV) was 51 +/- 3% (95% confidence interval). CONCLUSION: The increasing incidence rates of colon adenocarcinomas, the persistence of advanced tumour stages (stage III), the mortality rates which remain stable, and the changing trends in the age- and sub-site distribution underline the need for preventive measures at the age of 50 in asymptomatic patients to reduce mortality from colo(rectal) cancer.

Atypical glandular cells in conventional cervical smears: incidence and follow-up.

BACKGROUND: Atypical glandular cells on cervical smears are often associated with clinically significant uterine lesions. The frequency and accuracy of AGC-NOS (i.e. atypical glandular cells, not otherwise specified) diagnoses, regardless of the gland cell type or the degree of suspicion, and their outcome were investigated. METHODS: From January 1, 1990 to December 31, 1999 a total of 261 patients had an AGC-NOS diagnosis made by conventional cervical Papanicolaou smear interpretation representing 0.05% of all Pap-smears analyzed at the national level. 191 (73.2%) patients had a subsequent histological examination, 8 samples were not representative by origin and were excluded. RESULTS: Out of 183 AGC-NOS diagnosed, 56.3% (103/183) were associated with tissue-proven precancerous and/or cancerous lesions, 44% being of endocervical and 56% of endometrial origin. 75% of all AGC-patients were asymptomatic. 66.7% (6/9) of the patients with subsequent invasive endocervical adenocarcinoma (AC) and 56% (28/50) of those patients with invasive endometrial AC were without clinical symptoms. 3 patients out of 9 with an invasive endocervical AC were 35 years of age or less. 10.1% and 12.3% of all 'new' tissue-proven invasive endocervical or endometrial AC respectively recorded by the national Morphologic Tumour Registry (MTR) were first identified by a cytological AGC-NOS diagnosis. CONCLUSION: Our findings emphasize the importance of the cytological AGC-category even in the absence of a precise origin or cell type specification. 56% of the AGC-diagnoses being associated with significant cancerous or precancerous conditions, a complete and careful evaluation is required.

Rectal cancer in Luxembourg : a national population-based data report, 1988-1998.

BACKGROUND: Morphologic criteria which might help to support the need for a preventive strategy for early detection of rectal cancer were analysed. Population-based data on rectal adenomas with high-grade dysplastic changes (n = 199) and invasive adenocarcinomas (n = 912) registered by the national Morphologic Tumour Registry (MTR) and diagnosed in a central department of pathology in Luxembourg between 1988 and 1998 were considered. METHODS: The analysis concerned time trends in frequency, crude incidence, tumour-stage, the rectal "high-grade" adenoma/invasive adenocarcinoma-ratio and the survival rates. Histopathological tumour-stage parameters (UICC/AJCC, 1997) in a consecutive series of 641 resected rectal cancers and their relationship with the observed patient survival are investigated. RESULTS: The majority of invasive adenocarcinomas are diagnosed at a late stage (i.e. Stage II and III) into contrast with the highly significant increase (355 %) in frequency of rectal high-grade adenomas (Stage 0). During the two-time periods 1988-1992 and 1994-1998 Stage I and Stage IV-cases decreased by 11 % and 47 % respectively. Tumour-stage correlates with prognosis. The rectal high-grade adenoma / invasive adenocarcinoma-ratio improved significantly over the last five years. CONCLUSION: Over the study period, there has been a highly significant rise in the incidence of resected rectal adenomas with high-grade intraepithelial neoplasia. The ratio of early tumours to invasive cancers has risen while the numbers of colonoscopies and rectoscopies remained unchanged respectively decreased. As the number of advanced tumour-stages remained stable, mass-screening procedures focusing on the fifty to sixty age group should be reinforced.