Human papillomavirus-related basaloid squamous cell carcinoma of the bladder associated with genital tract human papillomavirus infection.

Basaloid squamous cell carcinoma is a biologically aggressive neoplasm mainly found in the head and neck region. Recently, four cases of basaloid squamous cell carcinoma of the bladder have been reported, and three of them occurred in patients with neurogenic bladder, repeated catheterizations and human papillomavirus infection of the urinary tract. To the best of our knowledge, none of the patients affected by basaloid squamous cell carcinoma of the bladder described in the literature had documented genital involvement by human papillomavirus. Herein, we describe the case of a woman with neurogenic bladder affected by basaloid squamous cell carcinoma of the bladder and by a concomitant genital tract human papillomavirus infection.

Unusual presentation of primary T-cell lymphoblastic lymphoma: description of two cases.

BACKGROUND: T-cell lymphoblastic lymphoma comprises approximately 85-90% of all lymphoblastic lymphomas. It often arises as a mediastinal mass, and with bone marrow involvement. Presentation at other sites without nodal or mediastinal localization is uncommon. CASE REPORT: We describe clinical, histologic, immunohistochemical, and molecular features of two cases of primary T-cell lymphoblastic lymphoma arising respectively in uterine corpus and testis. The tumors were composed by medium to large cells, exhibiting a diffuse pattern of growth but sometimes forming indian files or pseudo-rosettes. The neoplastic cells strongly expressed TdT and T-cell markers in both uterine corpus and testis. However, the testis case also showed aberrant expression of B-cell markers, thus molecular biology was necessary to achieve a final diagnosis. T-cell receptor gene rearrangement analysis identified a T-cell origin. CONCLUSIONS: To the best of our knowledge, only one doubtful previous case of primary uterine T-cell lymphoblastic lymphoma and no previous cases of primary testicular T-cell lymphoblastic lymphoma have been reported. Due to the morphology of neoplastic cells, a challenging differential diagnosis with all the tumors belonging to the so-called small round blue cell tumor category is mandatory. In ambiguous lineage cases, molecular biology may represent an adequate tool to confirm diagnosis. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1559880973128230.

Correlation of EGFR, pEGFR and p16INK4 expressions and high risk HPV infection in HIV/AIDS-related squamous cell carcinoma of conjunctiva.

BACKGROUND: Squamous cell carcinoma of conjunctiva has increased tenfold in the era of HIV/AIDS. The disease pattern has also changed in Africa, affecting young persons, with peak age-specific incidence of 30-39 years, similar to that of Kaposi sarcoma, a well known HIV/AIDS defining neoplasm. In addition, the disease has assumed more aggressive clinical course. The contributing role of exposure to high risk HPV in the development of SCCC is still emerging. OBJECTIVE: The present study aimed to investigate if immunohistochemical expressions of EGFR, pEGFR and p16, could predict infection with high risk HPV in HIV-related SCCC. METHODS: FFPE tissue blocks of fifty-eight cases diagnosed on hematoxylin and eosin with SCCC between 2005-2011, and subsequently confirmed from medical records to be HIV positive at the department of human pathology, UoN/KNH, were used for the study. Immunohistochemistry was performed to assess the expressions of p16INK4A, EGFR and pEGFR. This was followed with semi-nested PCR based detection and sequencing of HPV genotypes. The sequences were compared with the GenBank database, and data analyzed for significant statistical correlations using SPSS 16.0. Ethical approval to conduct the study was obtained from KNH-ERC. RESULTS: Out of the fifty-eight cases of SCCC analyzed, twenty-nine (50%) had well differentiated (grade 1), twenty one (36.2%) moderately differentiated (grade 2) while eight (13.8%) had poorly differentiated (grade 3) tumours. Immunohistochemistry assay was done in all the fifty eight studied cases, of which thirty nine cases (67.2%) were positive for p16INK4A staining, forty eight cases (82.8%) for EGFR and fifty one cases (87.9%) showed positivity for p-EGFR. HPV DNA was detected in 4 out of 40 SCCC cases (10%) in which PCR was performed, with HPV16 being the only HPV sub-type detected. Significant statistical association was found between HPV detection and p16INK4 (p=0.000, at 99% C.I) and EGFR (p=0.028, at 95% C.I) expressions, but not pEGFR. In addition, the expressions of these biomarkers did not show any significant association with tumor grades. CONCLUSION: This study points to an association of high risk HPV with over expressions of p16INK4A and EGFR proteins in AIDS-associated SCCC.

Lymphoepithelioma-like carcinoma of the ovary.

Only one case of lymphoepithelioma-like carcinoma of the ovary has been reported so far. A new case is herein illustrated in a 69-year-old woman: an ovarian mass adherent to urinary bladder dome with peritoneal carcinomatosis. Histologically, undifferentiated carcinomatous areas were intermingled with abundant lymphoid tissue. Epstein-Barr virus has not been detected either in neoplastic or in lymphoid cells.

Rare lymphoid neoplasms coexpressing B- and T-cell antigens. The role of PAX-5 gene methylation in their pathogenesis.

We report 3 cases of lymphoid neoplasms with mixed lineage features of T-, NK-, or B-cell marker expression and clonal gene rearrangement for both T-cell receptor and immunoglobulin light chain IgK. A characteristic of our cases was the lack of expression of the specific B-cell transcription factor, Pax5, which is essential for maintaining the identity and function of mature B cells during late B lymphopoiesis. In the absence of Pax5, B cells in vitro can differentiate into macrophages, dendritic cells, granulocytes, and T/NK cells. Methylation analysis of the Pax5 gene in our cases suggests that its inactivation by this epigenetic event in a committed or mature B cell, before plasma cell differentiation, may well be a common pathogenetic mechanism in mature lymphoid neoplasms with expression of multilineage antigens. In particular, case 1 may represent a mixed NK- and B-cell lineage; and cases 2 and 3 may represent mixed T and B-cell lineage, respectively. Aberrations in the DNA methylation patterns are currently recognized as a hallmark of human cancer. Cases with aberrant phenotypes require molecular analysis for lineage assignment. Studies of such cases may be helpful to better elucidate whether they represent a distinct entity with clinical, immunophenotypic, and molecular characteristics or an incidental phenomenon during malignant transformation. Interestingly, these cases were all characterized by poor clinical outcome.

Age at menarche is not an independent risk factor for high-risk human papillomavirus infections and cervical intraepithelial neoplasia.

Data are controversial as to the role of menarche age as a risk factor of high-risk human papillomavirus (HR-HPV) infections. The objective of this study was to analyse the risk estimates for age at menarche as determinant of cervical intraepithelial neoplasia (CIN) and HR-HPV infections. A cohort of 3187 women were stratified into three groups according to their age at menarche: (i) women <13 years of age; (ii) those between 13 and 14 years and (iii) women >15 years of age. These groups were analysed for predictors of (a) HR-HPV, (b) high-grade CIN and (c) outcome of HR-HPV and cytological abnormalities during prospective follow-up. All the three groups had identical prevalence of HR-HPV, Papanicolaou smear abnormalities and CIN grades. In contrast to menarche age itself, the time from menarche to the first intercourse (TMI), to the first pregnancy (TMP) and to the first delivery (TMD) were all significant (P = 0.0001) predictors of HR-HPV (but not CIN2) in univariate analysis, but lost their significance in a multivariate model. Outcome of cervical disease and HR-HPV infection was unrelated to menarche age, the latter and the three intervals being not predictors of CIN2 in a multivariate model. In conclusion, age at menarche and the intervals between menarche and (i) onset of sexual activity, (ii) first pregnancy and iii) first delivery, are not independent predictors of HR-HPV infections and CIN2 in multivariate analysis.

Smoking is an independent risk factor for oncogenic human papillomavirus (HPV) infections but not for high-grade CIN.

BACKGROUND: Recent evidence implicates smoking as a risk factor for cervical cancer (CC), but the confounding from high-risk human papillomavirus (HPV) infections is not clear. OBJECTIVES: To analyse the role of smoking as an independent predictor of CIN2+ and HR-HPV infections in a population-based prospective (NIS, New Independent States of former Soviet Union) cohort study. STUDY DESIGN AND METHODS: A cohort of 3,187 women was stratified into three groups according to their smoking status: (i) women who never smoked; (ii) those smoking in the past; and (iii) women who are current smokers. These groups were analysed for predictors of (a) HR-HPV; (b) high-grade CIN, and (c) outcome of HR-HPV infections and cytological abnormalities during prospective follow-up (n = 854). RESULTS: The three groups were significantly different in all major indicators or risk sexual behaviour (or history) implicating strong confounding. There was no increase in HSIL/LSIL/ASC-US cytology or CIN1+/CIN2+/CIN3+ among current smokers. Only few predictors of HR-HPV and CIN2+ were common to all three groups, indicating strong interference of the smoking status. There was no difference in outcomes of cervical disease or HR-HPV infections between the three groups. In multivariate model, being current smoker was one of the five independent predictors of HR-HPV (P = 0.014), with adjusted OR = 1.52 (95%CI 1.09-2.14). In addition to age, HR-HPV was the only independent predictor of CIN2+ in multivariate model (OR = 14.8; 95%CI 1.72-127.31). CONCLUSIONS: These data indicate that cigarette smoking is not an independent risk factor of CIN2+, but the increased risk ascribed to smoking is mediated by acquisition of HR-HPV, of which current smoking was an independent predictor in multivariate model.

Cell cycle regulators p105, p107, Rb2/p130, E2F4, p21CIP1/WAF1, cyclin A in predicting cervical intraepithelial neoplasia, high-risk human papillomavirus infections and their outcome in women screened in three new independent states of the former Soviet Union.

BACKGROUND: The growth-controlling functions of the high-risk human papillomaviruses (HPV) depend on their ability to interact with several cellular proteins, including the key regulatory proteins of the cell cycle. We have examined the value of cell cycle regulatory proteins as predictors of the intermediate end point markers in cervical carcinogenesis: (a) grade of cervical intraepithelial neoplasia (CIN), (b) high-risk HPV type, (c) clearance/persistence of high-risk HPV, and (d) disease outcome in women participating in a multicenter follow-up study in three New Independent States countries. METHODS: Totally, 232 biopsy samples tested high-risk HPV-positive and/or Papanicolaou smear-positive women were immunohistochemically stained for the following cell cycle markers: p105, p107, p130, E2F4, p21(CIP1/WAF1/SDI1), cyclin A, and Ki-67. In addition, apoptotic index (AI) and mitotic index (MI) were determined in H&E-stained sections. Prospective follow-up data were available to disclose the clinical and virological outcome of the lesions. RESULTS: The expression of Ki-67, p21(CIP1/WAF1/SDI1), and cyclin A and AI and MI values were markedly increased in high-grade lesions, but only MI was an independent predictor of CIN3 in multivariate analysis. Cyclin A was the only independent predictor of high-risk HPV (odds ratio, 1.09; 95% confidence interval, 1.01-1.18; P = 0.021), exceeding the predictive power of CIN grade and high-grade squamous intraepithelial lesion Papanicolaou smears. None of these markers provided any useful predictive information as to the clinical and virological outcomes during the follow-up. Highly significant correlations (P = 0.0001) were found between AI and MI as well as between MI and cyclin A, Ki-67 and p21(CIP1/WAF1/SDI1), Ki-67 and cyclin A, and p21(CIP1/WAF1/SDI1) and cyclin A followed by that between p105 and cyclin A (P = 0.001) and p105 and p130 (P = 0.002). CONCLUSIONS: All tested factors related to cell cycle were increased, but only MI and cyclin A was an independent predictor of CIN3 and high-risk HPV carriage, respectively.

Urocortin expression is downregulated in human endometrial carcinoma.

Urocortin (UCN) is a 40-amino acid neuropeptide sharing 45% sequence homology with corticotropin-releasing factor (CRF). The human endometrium expresses both UCN and CRF, and CRF/UCN receptors type-1 (CRF-R1) and -2 (CRF-R2). CRF-R1 activation inhibits cell growth and proliferation of a tumor cell line derived from the human endometrium, and the UCN signaling pathway has been implicated in tumorigenesis of several tissues. Therefore, we investigated whether UCN mRNA and peptide are expressed by human endometrial adenocarcinoma, and whether their expression changes compared to controls. Samples of well (grade 1; n = 6 endometrioid adenocarcinoma, of whom n = 1 with squamous differentiation, and n = 1 clear-cell carcinoma) and poorly differentiated (grade 3; n = 3 endometrioid adenocarcinoma) endometrial adenocarcinoma were collected from nine women (age range 61-79 years) enrolled at the time of diagnosis. Healthy endometrium was collected from postmenopausal women (controls; n = 13; age range 64-78 years), who underwent hysterectomy for uterine prolapse. Immunohistochemistry was used to evaluate cellular UCN localization, with the intensity of immunostaining scored on a subjective scale. Quantitative real-time reverse transcriptase (RT)-PCR analysis was used to estimate mRNA expression changes and restriction analysis was used to confirm PCR products identity. UCN mRNA expression was significantly reduced (P < 0.0001) in endometrial adenocarcinoma than in healthy controls. Immunoreactive UCN was found in luminal and glandular epithelial cells in healthy, but not in neoplastic samples. UCN mRNA and peptide expressions are decreased in endometrial adenocarcinoma. These data and the evidence that endometrial cancer expresses UCN receptors and UCN is involved in tumorigenesis of several tissues together suggest a role for UCN in endometrial tumoral cell growth and proliferation.

pRb2/p130 and VEGF expression in endometrial carcinoma in relation to angiogenesis and histopathologic tumor grade.

PURPOSE: Endometrial cancer is the most common gynecologic malignancy. Established prognostic factors are histologic grade, depth of myometrial invasion, and extrauterine spread including retroperitoneal lymph node metastases. Tumorigenesis is a multistep process involving different genetic changes resulting in uncontrolled cellular proliferation, inhibition of apoptosis, and enhanced vascular proliferation among other events. Angiogenesis, the formation of new blood vessels from a preexisting vascular network, is necessary for invasive tumor growth and metastasis and constitutes an important point in the control of cancer progression. The pathogenesis of the angiogenetic phenotype may involve the inactivation of different tumor suppressor genes. EXPERIMENTAL DESIGN: We investigated the relationship between the expression levels of VEGF and the retinoblastoma family member pRb2/p130 in endometrial carcinoma in relation to histopathologic tumor grade in a cohort of 50 patients. RESULTS: We found that VEGF and pRB2/p130 expression were inversely correlated. Additionally, high grade tumors presented a significantly lower number of cells expressing pRb2/p130 when compared to low grade tumors. A significant positive correlation was found, by means of the Spearman coefficient, between VEGF expression and binary grading (0.450, p-value < 0.005) which is an architectural grading system that uses low-magnification assessment of amount of solid growth, pattern of invasion, and presence of necrosis to divide endometrioid carcinomas into low- and high-grade tumors. Additionally, we also found a negative correlation between pRb2/p130 expression levels and binary grading (-0.595, p-value < 0.005). Interestingly, we also found that VEGF and pRb2/p130 expression levels were not related to staging (p-value > 0.005). CONCLUSIONS: These results open up a new perspective including novel markers that, combined together, may be useful in patient screening for endometrial cancer aggressiveness.

Oral contraceptives are not an independent risk factor for cervical intraepithelial neoplasia or high-risk human papillomavirus infections.

BACKGROUND: Oral contraception (OC) has been proclaimed by the IARC as a risk factor of cervical cancer (CC), on prolonged use by high-risk human papillomavirus (HPV) positive women. However, the available data are far from complete, and more evidence is necessary on the potential confounding effects of sexual behavior and HPV infection. The aim of the present was study to analyse the risk estimates for OC users in order to develop several intermediate end-point markers in cervical carcinogenesis. PATIENTS AND METHODS: A cohort of 3,187 women, enrolled in a multi-center screening trial in three New Independent States (NIS) of the former Soviet Union (the NIS Cohort Study), was stratified into three groups according to their contraception modes: i) non-users of contraception, ii) non-OC users and iii) OC users. These groups were analysed forpredictors of three outcome measures: a) exposure to HR-HPV; b) progression to high-grade cervical intraepithelial neoplasia (CIN2/3 and HSIL); and c) persistence/clearance of HR-HPV and cytological abnormalities during a prospective follow-up. RESULTS: All three groups had an identical prevalence of HR-HPV (HCII and PCR), Pap smear abnormalities and CIN histology, but differed significantly (p=0.0001) with regard to all key variables of sexual behaviour, known as risk factors for CC. Predictors of HR-HPV, CIN2/3 and HSIL were different in the three groups, reflecting these different sexual preferences. Use of OC was not a significant predictor of CIN2/3 or HSIL in HPV-positive or HPV-negative women. Outcomes of cervical disease and HR-HPV infection were unrelated to contraception. In a multivariate regression model mode of contraception was of no predictive value for either HR-HPV or high-grade CIN. CONCLUSION: Sexual behaviour is different among OC users, non-OC users and in nonusers of contraception; these risk factors predispose women to HR-HPV, high-grade CIN, and determine the outcome of their cervical disease/HR-HPV infection. The use of OC is not an independent risk factor for any of these intermediate end-point markers of cervical carcinogenesis. Failure to record these epidemiological data inevitably leads to erroneous conclusions about the role of OC as an independent risk factor of cervical cancer.

Inhibin alpha-subunit and the inhibin coreceptor betaglycan are downregulated in endometrial carcinoma.

OBJECTIVE: In the present study we evaluated the protein distribution and mRNA levels of inhibin alpha-subunit and its coreceptor betaglycan in endometrial adenocarcinoma. DESIGN: Two groups of postmenopausal women were studied: the first group had recently diagnosed endometrial adenocarcinoma (n = 16; age range 61-79 years), and the second group (n = 12; age range 64-78 years) had undergone hysterectomy for uterine prolapse and served as control. METHODS: Inhibin alpha-subunit and betaglycan gene expression and tissue distribution were evaluated by semiquantitative RT-PCR and immunohistochemistry respectively. RESULTS: Inhibin alpha-subunit and betaglycan mRNAs were expressed by both healthy and tumoral endometria, but their expression was significantly lower in endometrial carcinoma (P < 0.001, based on Student's t test). Inhibin alpha-subunit expression was much weaker in the glands of tumours than in non-neoplastic specimens. Betaglycan protein was identified in the epithelial cells lining non-tumoral endometrium, and in endothelial cells of both normal and tumoral endometria. Well-differentiated neoplastic cells had a faint and scarce betaglycan staining, and poorly differentiated cells did not express betaglycan at all. CONCLUSIONS: The lower inhibin alpha and betaglycan expression in endometrial adenocarcinoma suggests that the inhibin action may be disrupted. However, the expression of betaglycan in the endothelia of the tumour vasculature suggests that a selective vascular response to inhibin may be possible in these tumours.

Acquisition of high-risk human papillomavirus infections and pap smear abnormalities among women in the New Independent States of the Former Soviet Union.

The rates of acquisition and the times of incident high-risk (HR) human papillomavirus (HPV) infections and Pap smear abnormalities and their predictive factors were analyzed in women participating in a multicenter screening study in three countries of the New Independent States of the former Soviet Union. The 423 patients were prospectively monitored for a mean of 21.6 months. At the baseline, 118 women were HR HPV DNA negative (Hybrid Capture II assay) and Pap smear negative (group 1), 184 were HPV DNA positive and Pap smear negative (group 2), and 121 were HPV DNA negative and Pap smear positive (group 3). The time to the acquisition of an incident abnormal Pap smear (19.4 months) was significantly longer in group 1 than in group 2 (9.2 months) (P = 0.0001). The times of acquisition of incident HR HPV infection were 16.6 and 11.0 months in group 1 and group 3, respectively (P = 0.006). The monthly rates of acquisition of incident HR HPV infections were very similar in group 1 (1.0%) and group 3 (0.8%), whereas the rate of acquisition of an abnormal Pap smear was significantly higher in group 2 (3.1%) than in group 1 (1.5%) (P = 0.0001). The acquisition of HR HPV infection (but not a positive Pap smear result) was significantly (P = 0.0001) age dependent. The only significant independent (P = 0.001) predictor of the incidence of an abnormal Pap smear result was a high HR HPV load of >20 relative light units/control value (CO) (rate ratio, 2.050; 95% confidence interval, 1.343 to 3.129). Independent predictors of incident HR HPV infection were patient category (a sexually transmitted disease) and ever having been pregnant. The time of acquisition of HR HPV infection was 3 months shorter than that of an abnormal Pap smear. At the baseline the high load of a particular HR HPV type is the single most important predictor of an incident Pap smear abnormality, whereas young age and having a sexually transmitted disease predict incident HR HPV infections.

An ovarian mucinous adenocarcinoma arising from mature cystic teratoma associated with respiratory type tissue: a case report.

Mature cystic teratoma (dermoid cyst) is the most common benign germ cell tumor of the ovary, accounting for approximately 30% of all ovarian tumors. Malignant transformation is rare; the most frequent transformation reported is to squamous-cell carcinoma in 80% of cases, whereas transformation to adenocarcinoma is described in about 7% of cases. We report a case of malignant transformation to mucinous adenocarcinoma arising from respiratory-like epithelium in a mature teratoma of the ovary.

Expression of betaglycan in pregnant tIssues throughout gestation.

BACKGROUND: Betaglycan is a membrane-anchored proteoglycan involved in mediating the passage of transforming growth factor-beta (TGF-beta), inhibin and activin activities into cells. TGF-beta and inhibin-related proteins are growth factors that are expressed by several tIssues and in pregnancy. They have a function in modulating the growth, differentiation and invasion of the placental trophoblast. OBJECTIVE: To evaluate whether betaglycan is expressed by intrauterine tissues throughout gestation. DESIGN AND METHODS: Expression of betaglycan mRNA and protein was evaluated (by RT-PCR and immunohistochemistry, respectively) in trophoblast, decidua and fetal membranes collected during the first (n=6 elective terminations of pregnancy, between 8 and 12 gestational weeks) and third (n=6 elective caesarean sections, between 39 and 40 weeks) trimesters of pregnancy. RESULTS: Betaglycan mRNA was expressed by all gestational tIssues, independently of gestational age. Immunoreactive protein was found in decidual cells and in some chorionic, but not epithelial, amniotic cells. With respect to the placental localization, syncytiotrophoblast, but not cytotrophoblast, cells were intensively stained both in the placental bed and in the villous trophoblast, and in some cells within the stroma of terminal villi, of the first and third trimesters of pregnancy. Immunoreactive betaglycan was demonstrated in the endothelial cells of decidual vessels in both the first and third trimesters of pregnancy, whereas endothelial cells of fetal blood vessels in the villous were clearly represented only in first trimester samples, not in those of term placenta. CONCLUSIONS: Betaglycan mRNA and peptide are expressed by the trophoblast, the decidua and the fetal membranes, but the localization of the peptide in vessel walls is dependent on gestational age.

Sexual habits and human papillomavirus infection among females in three New Independent States of the former Soviet Union.

BACKGROUND: On a global scale, the New Independent States (NIS) of the former Soviet Union have an intermediate incidence of cervical cancer, the main etiologic factor of which is human papillomavirus (HPV), a major sexually transmitted disease (STD). Recently, the prevalence of all STDs has exploded in these countries. GOAL: The goal of this study was to examine the sexual habits and HPV prevalence among females in three NIS countries. STUDY DESIGN: In this multinational (European Community-funded) trial, a series of 3,175 consecutive female patients were examined for HPV status (by Hybrid Capture II) at six clinics in Russia, Belarus, and Latvia. A meticulous survey of their sexual habits and other potential risk factors of HPV infections was made by structured questionnaire. RESULTS: Three categories of patients were examined: those attending STD clinics (n=722), gynecological patients (n=761), and those who participated in cervical cancer screening (n=1,692). These three categories were significantly differentiated by a large number of key variables, including the HPV detection rate (44.9% of STD patients, 39.8% of gynecological patients, and 24.5% of those who were screened). A wide variety sexual habits of these subjects were predictors of the HPV status in univariate analysis. Binary logistic regression analysis found that six different variables remained as independent predictors of HPV status. Patient category (STD) and (young) age were two highly significant predictors of increased risk (P<0.0001), whereas having a nonsmoking partner and having zero or one partner during the past 2 years were significant protective factors (P=0.004 and P=0.007, respectively). CONCLUSION: The results of this study indicate that women and girls in these NIS countries are conservative in many key characteristics of "high-risk" sexual behavior, such as age at onset of sexual activity, number of partners, and casual sex partners. HPV-positive and HPV-negative groups are clearly distinguished by the same variables identified as the key risk factors of HPV infection and cervical intraepithelial neoplasia in Western countries.

Evaluation of MDR1, LRP, MRP, and topoisomerase IIalpha gene mRNA transcripts before and after interferon-alpha, and correlation with the mRNA expression level of the telomerase subunits hTERT and TEP1 in five unselected human melanoma cell lines.

Intrinsic and acquired multidrug-resistance (MDR) and the activity of the enzyme telomerase have been demonstrated in human melanoma. A direct regulation of the MDR pathways and of telomerase by interpheron-alpha (IFN-alpha), which is currently used in the therapy of advanced cutaneous melanoma, has also been hypothesized. In this study, we used five melanoma cell lines not selected in vitro for drug resistance (Me665/2/21, Me665/2/60, HT-144, SK-MEL-28, and SK-MEL-5), which in a previous study, had shown different responses to IFN-alpha in terms of proliferation, apoptosis, telomerase activity and expression of mRNA for the human telomerase reverse transcriptase (hTERT). We investigated the expression of the multidrug resistance (MDR1) gene, multidrug resistance protein (MRP), lung resistance protein (LRP), topoisomerase IIalpha (Topo IIalpha), hTERT, and telomerase-associated protein (TEP1), which is shared by telomerase and vault MDR proteins at the mRNA expression level, using the reverse transcription-PCR (RT-PCR). All cell lines showed an intrinsic expression of hTERT, TEP1, and MDR gene transcripts (only MDR1 mRNA was under the detection level in SK-MEL-28 cells). After IFN-alpha exposure, we observed either no effect, a trend towards a decrease of hTERT, MRP, and Topo IIalpha, or an increase of TEP1, MDR1, and LRP mRNA expression in some cell lines. Effects were usually temporary and not always significant. No correlation was found between hTERT and TEP1 mRNA expression, whereas significant positive correlations were found between TEP1 and MDR1 mRNA, and between TEP1 and LRP mRNA. IFN-alpha modulates differently MDR gene transcripts in human melanoma cell lines. Positive correlation between TEP1 and LRP also seems to identify them as common targets of IFN-alpha effects.

Ovarian psammocarcinoma with peritoneal implants.

A case of ovarian psammocarcinomas with omental and peritoneal implants in a 48-year-old woman was treated with total hysterectomy, bilateral oophorectomy and omentectomy. Two years later there was no sign of recurrent disease.

Human papillomavirus testing and conventional pap smear cytology as optional screening tools of women at different risks for cervical cancer in the countries of the former soviet union.

OBJECTIVES: Human papillomavirus (HPV) infection is a sexually transmitted disease (STD) and the single most important etiological agent of cervical cancer. In parallel with the increase of STDs and because of the lack of any organized cancer screening in the new independent states of the former Soviet Union, the incidence and mortality rates of cervical cancer are rapidly rising. This is the first report from an ongoing European Commission-funded (INCO-Copernicus Program) cross-sectional and cohort study (focused on the key issues of this major health problem in the new independent states) analyzing the performance of the HPV DNA (Hybrid Capture II) test as a potential screening tool for cervical cancer in these countries. MATERIALS AND METHODS: A series of 3,175 women (screening, gynecological, or STD patients) from six clinics in Russia, Belarus, and Latvia received routine cytology and HPV testing with Hybrid Capture II (HCII). All women with HPV-positive results or abnormalities in cytology were subjected to colposcopy and biopsy. The sensitivity, specificity, receiver operating characteristics, as well as positive (PPV) and negative predicting values (NPV), were determined for HCII and quality-controlled cytology in detecting significant pathology (cervical intraepithelial neoplasia [CIN] 3 and cancer). RESULTS: Significant pathology was strongly associated with high-grade cytology (odds ratio [OR] = 8.5; 95% confidence interval [CI] = 4.1-17.8; chi-square, p < .0001). Pap smear cytology detected high-grade lesions with a sensitivity of 64.0% (44.8-83.2), specificity of 89.1% (84.5-93.7), PPV of 44.4% (28.8-61.0), and NPV of 94.8% (91.2-98.4). Of the 3,086 samples analyzed by HCII, 33.0% were positive for oncogenic HPV types, with a wide variation (from 23% to 45%) between the three patient groups (p < .0001). The presence of high-grade cytology was significantly associated with HCII positivity at all cutoff levels (OR = 14.4; 95% CI = 8.4-24.5; chi-square, p < .0001; 1 pg/mL threshold). In the receiver operating characteristics curve, the HCII cutoff point most closely balancing sensitivity (83.1%) and specificity (75.6%) was 2 pg/mL. The presence of high-grade histology was associated with HCII positivity (cutoff 1 pg/mL; OR = 4.8; 95% CI = 0.7-34.2;p = .047). At the cutoff (1 pg/mL), sensitivity of the HCII test was 96.6% (90.0-100), specificity was 15.9% (10.6-21.2), PPV was 15.1% (9.9-20.3), and NPV was 96.8% (90.3-100). Changing the cutoff significantly affected sensitivity at 20 pg/mL and NPV at 500 pg/mL. CONCLUSIONS: HCII assay is a sensitive tool in detecting significant pathology, but less specific than the Pap test. A negative HCII test practically precludes high-grade CIN (NPV, >95%). Because the performance characteristics of the HCII test depend on the prevalence of HPV and CIN in the study population, the cost-benefit issues in different settings will be the limiting factor for the application of this test as a screening tool.