Assessment and biological significance of JC polyomavirus in colorectal cancer in Tunisia.

PURPOSE: Several reports have indicated the presence of JC polyomavirus (JCV) in many human tumors, including colorectal cancers (CRCs). The presence of JCV infection in CRC patients has not been investigated in African countries. METHODS: We examined the prevalence and the biological significance of JCV in Tunisian CRC patients. The presence of JCV was assessed by polymerase chain reaction (PCR) in a series of 105 CRCs and 89 paired non-tumor colonic mucosa samples from Tunisian patients. Results were correlated with the clinicopathological features and immunohistochemical expression of ß-catenin, p53, and the proliferation marker Ki-67. RESULTS: JCV DNA was detected in 58.1% (61/105) of CRC and in only 14.6% (13/89) of paired non tumor colonic mucosa samples (p=0.03). The presence of JCV was significantly correlated with tumor differentiation (p=0.03). Moreover, JCV presence was significantly correlated with nuclear accumulation of ß-catenin (p=0.008) and p53 accumulation (p=0.0001). Multivariate logistic regression analysis showed that tumor differentiation, ß-catenin and p53 accumulation were independent parameters significantly associated with the presence of JCV in CRC (p=0.04; p=0.05; p=0.001, respectively). CONCLUSION: We support a role of JCV in colorectal carcinogenesis in Tunisian patients, especially of well differentiated morphology.

Adjunctive human papillomavirus DNA testing is a useful option in some clinical settings for disease risk assessment and triage of females with ASC-H Papanicolaou test results.

CONTEXT: Recent guidelines recommend colposcopy for women with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H). objective: To determine whether adjunctive high-risk human papillomavirus (hrHPV) testing is useful for disease risk assessment in females with ASC-H Papanicolaou (Pap) test results. DESIGN: High-risk HPV prevalence and histopathologic follow-up data on 1187 females with ASC-H ThinPrep Pap test (TPPT) and hrHPV test results were analyzed. RESULTS: ASC-H was reported in 1646 (0.59%) [corrected] of 277 400 (270 338 TPPT and 7062 conventional) Pap test results. The difference in ASC-H detection rates between TPPTs and conventional Pap smears was statistically significant (0.60% vs 0.38%; P = .02). High-risk HPV was detected in 589 (49.6%) of 1187 females with ASC-H TPPT and hrHPV testing. The hrHPV DNA-positive rate in females younger than 40 years was 54.7%, significantly higher than the 36.5% in women 40 years and older. Among 505 females with histopathologic follow-up, cervical intraepithelial neoplasia 2/3 was identified in 32.7% of hrHPV-positive females compared with 1.2% in hrHPV-negative females. The sensitivity, specificity, positive predictive value, and negative predictive value of ASC-H cytology in conjunction with hrHPV DNA testing results for detection of cervical intraepithelial neoplasia 2/3 were 96.1% versus 100.0%, 54.0% versus 68.4%, 35.8% versus 20.8%, and 98.1% versus 100.0% in females younger than 40 years and women 40 years and older, respectively. CONCLUSIONS: Our data suggest that reflex hrHPV testing is a highly useful option for women with ASC-H Pap tests. Females with ASC-H and negative hrHPV testing may be more efficiently managed by follow-up with regular Pap and hrHPV testing rather than universal colposcopy, especially for women 40 years and older.

Periodic assessment of urine and serum by cytology and molecular biology as a diagnostic tool for BK virus nephropathy in renal transplant patients.

OBJECTIVE: To investigate the significance of polyomavirus (PV) viruria and viremia by morphologic, immunohistochemical and molecular analysis (multiplex nested-polymerase chain reaction) in renal transplant patients. STUDY DESIGN: Urine (n=328), serum (n= 53) and renal biopsies (n=24) from renal transplant patients (n=106) were studied. RESULTS: Decoy cells were found in 53 samples (16%) from 19 patients (18%); viral DNA was amplified in all urinary samples and disclosed BK virus (BKV) (n=24), JC virus (JCV) (n=16), and JCV and BKV DNA (n=13). BKV was the prevailing genotype in patients with a high frequency of decoy cell excretion (p = 0.001). JCV excretion correlated with a low number (p = 0.01) and BKV with a high number of decoy cells (p=0.003). PV DNA was amplified from 30/53 serum samples (56.6%); BKV was the prevailing genotype (p = 0.04). On 24 renal biopsies (18 from the decoy cell-negative and 6 from the decoy cell-positive group) PV nephropathy (PVN) was identified and BKV DNA amplified in 4 biopsies, all from the group with a high frequency of decoy cell excretion. PVN was not identified in renal biopsies from the decoy cell-negative group. CONCLUSION: PV infection is frequent in renal transplant patients. The BKV genotype in urine and serum is significantly related to a high frequency and high number of decoy cells. PVN occurs only in patients with BKV viremia and a high number and frequency of decoy cell excretion in urine. In the absence of decoy cells, PVN can be excluded. Cytologic analysis of urine is an important diagnostic tool for screening renal transplant patients at risk of PVN.

Potential health and economic impact of adding a human papillomavirus vaccine to screening programs.

CONTEXT: Recently published results suggest that effective vaccines against cervical cancer-associated human papillomavirus (HPV) may become available within the next decade. OBJECTIVE: To examine the potential health and economic effects of an HPV vaccine in a setting of existing screening. DESIGN, SETTING, AND POPULATION: A Markov model was used to estimate the lifetime (age 12-85 years) costs and life expectancy of a hypothetical cohort of women screened for cervical cancer in the United States. Three strategies were compared: (1) vaccination only; (2) conventional cytological screening only; and (3) vaccination followed by screening. Two of the strategies incorporated a vaccine targeted against a defined proportion of high-risk (oncogenic) HPV types. Screening intervals of 1, 2, 3, and 5 years and starting ages for screening of 18, 22, 24, 26, and 30 years were chosen for 2 of the strategies (conventional cytological screening only and vaccination followed by screening). MAIN OUTCOME MEASURES: Incremental cost per life-year gained. RESULTS: Vaccination only or adding vaccination to screening conducted every 3 and 5 years was not cost-effective. However, at more frequent screening intervals, strategies combining vaccination and screening were preferred. Vaccination plus biennial screening delayed until age 24 years had the most attractive cost-effectiveness ratio (44 889 dollars) compared with screening only beginning at age 18 years and conducted every 3 years. However, the strategy of vaccination with annual screening beginning at age 18 years had the largest overall reduction in cancer incidence and mortality at a cost of 236 250 dollars per life-year gained compared with vaccination and annual screening beginning at age 22 years. The cost-effectiveness of vaccination plus delayed screening was highly sensitive to age of vaccination, duration of vaccine efficacy, and cost of vaccination. CONCLUSIONS: Vaccination for HPV in combination with screening can be a cost-effective health intervention, but it depends on maintaining effectiveness during the ages of peak oncogenic HPV incidence. Identifying the optimal age for vaccination should be a top research priority.

Laboratory implementation of human papillomavirus testing.

Human papillomavirus testing is becoming an integral component of cervical cancer screening. Market forces will require most laboratories that perform Papanicolaou tests to develop a system for handling human papillomavirus testing also. Data and information are presented that may facilitate laboratories when addressing the following issues in the process of developing a human papillomavirus testing service: Which methodology is the best fit for the laboratory? Is it better to develop an in-house testing service or to send it out? How do I get started? What are the financial and economic issues, and how should they be managed?

Oncogenic human papillomavirus (HPV) infection and uterine cervical cancer: a screening strategy in the perspective of rural India.

The predominance of cervical cancer in India can mostly be attributed to the lack of early screening. The objective of the present study has been, therefore, to determine a cost-effective oncogenic human papillomavirus (HPV)-based cervical cancer screening plan for rural Indian women. The results showed that in normal women, highest prevalence of HPV 16/18 infection was in the age group < or =23 years and lowest in > or =44 years with an insignificant change in between. HPV 16/18 infection was significantly associated with cervical erosion at age < or =23 years, but not with cytology or visual inspection with acetic acid testing at any age. The low-grade cytological lesions, however, increased only with increase in age. Fourteen per cent of the cervical malignancy was also found to be present in the age group 24-33 years with an 87% HPV infection. Here we proposed a cost-effective screening scheme in which HPV testing must be performed in women (a) < or =23 years with cervical erosion and (b) 24-43 years, as an adjunct to Pap smears (both HPV and cytology were prevalent in this group). For women > or =44 years, HPV testing might not be useful, since abnormal cytology was more prominent over the viral infection. We infer that by not performing HPV test in the group < or =23 years, approximately 76% of the high-risk HPV-infected individuals potentially "at risk" for developing cervical cancer might be missed.

[Precancerous lesions and cervical cancer vs HPV infection in pregnant women--cytological assessment]. / Stany przedrakowe i rak inwazyjny szyjki macicy oraz infekcja hpv u kobiet ciezarnych w materiale cytologicznym.

An effort has been made in order to estimate the relationship between HPV, cervical intraepithelial neoplasia and cervical carcinoma. The authors have been trying also to create a reliable prophylactic scheme as far as precancerous lesions and cervical carcinoma are concerned. 2243 pregnant women have been subjected to cytology and colposcopy examination. In selected cases HPV DNA hybridisation technique examination of cervical smear as well as colposcopy directed punch biopsy have been performed. The results of the study indicate of high efficiency of these methods in cervical cancer prophylaxis.

Signal-amplified colorimetric in situ hybridization for assessment of human papillomavirus infection in cervical lesions.

Detection and typing of human papillomavirus (HPV) infection may have a major impact in cervical-screening and follow-up. In this study various commercially available techniques for the detection of HPV were evaluated. HPV-status was determined in 86 samples of cervical cancer by PCR and direct sequencing, catalyzed signal amplified colorimetric DNA in situ hybridization (CSAC- ISH) (GenPoint system, DAKO), immunohistochemistry (IHC) and in 12 selected cases also by conventional, non-amplified ISH. Twenty-one samples of cervical intraepithelial neoplasias grade III (CIN III) were investigated by CSAC-ISH, conventional ISH and by IHC, in corresponding PAP smears HPV-detection and typing was performed by CSAC-ISH and Hybrid Capture test II (HC). In additional 20 PAP smears HPV typing was performed using HC and a novel immunocytochemical system for HPV detection and-typing. CSAC-ISH showed good correlation with PCR analysis in cervical cancers: In 87% of PCR positive cases, HPV infection was also detected by CSAC- ISH (66/76). HPV 16 was detected in 75% of PCR-positive cases (44/59), HPV 18 in 71% of PCR positive cases (5/7). CSAC-ISH detected HPV 31 in only 29% of PCR positive cases (2/7), and HPV 33 in 64% of PCR-positive cases (23/36). Nevertheless, CSAC-ISH- false negative cases for HPV 31 or 33 were nearly always combined infections with other HPV types, which were detectable by CSAC-ISH in most cases. CSAC-ISH revealed HPV infection in 20 of 21 HC-positive cervical smears, while in corresponding biopsies (CIN III) CSAC-ISH detected 100% of HPV infections. Conventional, non-amplified ISH showed significantly lower sensitivity compared with CSAC-ISH, and immunocyto- and -histochemistry were of very low sensitivity for detection of HPV. CSAC-ISH is an easy-to-handle method for detection and typing of cervical HPV infection, and shows sufficient sensitivity for clinical practice.

Cost-effectiveness of monolayers and human papillomavirus testing compared to that of conventional Papanicolaou smears for cervical cancer screening: protocol of the study of the French Society of Clinical Cytology.

The French Society of Clinical Cytology is conducting a study to compare the cost-effectiveness of monolayers and human papillomavirus (HPV) testing with that of conventional Papanicolaou (Pap) smears for cervical cancer screening. The protocol of this study is presented. It includes 3,000 women who will be evaluated by the three methods (conventional Pap smears, or monolayers with or without HPV testing) and by the reference method: colposcopy followed, in cases with abnormalities, by cervical biopsy. Efficacy or performance of the methods will be compared on the basis of sensitivity. Cost comparisons and cost-effectiveness modeling will be based on the costs associated with methods themselves and also the costs of "false positives." This will require specific collection of data concerning the costs of the three methods, as these costs have not previously been accurately documented. Patient recruiting and data collection started in September 1999 and will be complete in June 2000. The first results are expected to be available in spring 2001.

Prediction of cervical intraepithelial neoplasia grade 2-3 using risk assessment and human papillomavirus testing in women with atypia on papanicolaou smears.

OBJECTIVE: To determine whether human papillomavirus (HPV) DNA testing and risk assessment can predict cervical intraepithelial neoplasia (CIN) 2-3 on biopsies in women with atypia on Papanicolaou smears. METHODS: One hundred ninety-five consenting women were referred for colposcopy because of atypia on Papanicolaou smears between September 1997 and April 1999. Before colposcopy, women completed risk assessments and had cervical swabs collected for HPV testing using the Hybrid Capture-II assay (Digene Corporation, Silver Spring, MD). Associations of demographic and clinical variables were assessed by chi(2) analysis, and logistic regression was used to assess factors associated with CIN 2-3. The cost-effectiveness of routine colposcopy versus reflex HPV testing by either conventional or liquid-based Papanicolaou smear media was compared. RESULTS: Cervical intraepithelial neoplasia was diagnosed in 70 of 195 women (35.9%), 55 (28.2%) with CIN 1 and 15 (7.7%) with CIN 2-3. High-risk HPV types were detected in 31.3% of all subjects, 36.4% of those with CIN 1, and 93.3% of those with CIN 2-3. By logistic regression, CIN 2-3 was associated only with detection of high-risk HPV (odds ratio 110.08, 95% confidence interval 8.35, 999. 00). The sensitivity of high-risk HPV for detecting CIN 2-3 was 93. 3%, specificity 73.9%, positive predictive value 23.0%, and negative predictive value 99.3%. The cost of reflex HPV testing using conventional smear or liquid-based media was less than routine colposcopy ($4809 and $4308, respectively, versus $4875 per case detected). CONCLUSIONS: Triage based on HPV testing would result in referral of approximately 31% of patients to colposcopy and appears to be a sensitive and cost-effective alternative to colposcopy.

Outcome of women referred to colposcopy for persistently inadequate smears.

The outcome of referral to colposcopy of 240 women who had persistently inadequate smears was investigated. Of 232 women who attended colposcopy, 214 (92.2%) had a normal outcome, 12 (5.2%) had low grade abnormalities, and six (2.6%) had high grade abnormalities. This group of women therefore has a negligibly increased risk of harbouring cervical neoplasia. Although not directly comparable, women with a history of previous abnormal cytology did not have a higher risk than those without such a history. Unnecessary colposcopy could have been avoided in the majority of cases if a good quality repeat smear had been taken. Improved smear taker training could decrease the number of referrals. A hospital cytology clinic is proposed as a cost-effective alternative to colposcopy at the first attendance.

Anal squamous intraepithelial lesions: relation to HIV and human papillomavirus infection.

Studies from the era prior to the introduction of highly active antiretroviral therapy (HAART) have shown that the prevalence of anal infection with human papillomavirus (HPV) and anal squamous intraepithelial lesions (ASIL) were high among HIV-positive homosexual men, and to a lesser extent, among HIV-negative homosexual men. The data also show that the incidence of high-grade ASIL (HSIL), the putative invasive cancer precursor lesion, was high in these groups. Early data suggest that at least 75% of those with HSIL lesions do not regress while receiving HAART. Given that progression of HSIL to invasive cancer may require several years, lengthened survival associated with HAART may paradoxically lead to an increased risk of anal cancer. The potential to prevent anal cancer through detection and treatment of anal HSIL suggests a need to screen high-risk individuals with anal cytology, similar to cervical cytology screening to prevent cervical cancer. Cost-effectiveness analyses suggest that anal screening programs may be cost-effective in HIV-positive men. However, barriers to implementation of screening include inadequate numbers of clinicians skilled in diagnosis and treatment of HSIL and lack of medical alternatives to surgical excision. Recent progress in understanding the pathogenesis of ASIL in HIV-positive men points to a role for decreased cell-mediated immunity to HPV antigens as well as the effects of the HIV-1 tat protein in modulating the biology of HPV-infected keratinocytes.

Quality, access, and clinical issues in a nurse practitioner colposcopy outreach program.

From 8/89 to 7/92 a NP-colposcopist performed 593 colposcopy examinations including cervical biopsies, endocervical curettages, and Pap smears. Procedures were performed in selected health departments in north-central Florida. This portable outreach program expanded services to a primarily rural, medically indigent population. Specimen results were 21.1% negative, 5.6% human papilloma virus (HPV) only, 37.3% CIN I, 17.4% CIN II, 11.9% CIN III, 2.4% CIS, 0.3% carcinoma, and 4% other. Many CIN lesions also included HPV, yielding an overall incidence of HPV at 62.7%. Using the Bethesda system, 42.8% were low grade lesions, 32.1% high grade. Fourteen cases of CIS and two of carcinoma (one invasive, one microinvasive) were found. An 87.7% colposcopic diagnostic acumen level is favorable compared with published physician studies. One third of undercalls were due to occult canal lesions. Significant risk factors were smoking (48.6%), first coitus at < 18 years old (74%), history of HPV (49.6%), and life-time sexual partners > 2 (61.3%). Holistic prevention enabled 209 non-colposcopy problems.

Detection of human papillomavirus types 16 and 18 in the exfoliated cervical cells using the polymerase chain reaction.

We applied the polymerase chain reaction (PCR) to detect HPV 16 and 18 in cytological samples obtained from the uterine cervices of Japanese women. HPV infection was detected in 17 (25%) of 67 with CIN and 11 (37%) of 30 with cervical carcinoma. It is notable that 11 (16%) of 69 women with normal cervices were infected with either HPV 16 or 18. The polymerase chain reaction is sensitive and useful for epidemiological studies.

Is routine colposcopic assessment necessary following laser ablation of cervical intraepithelial neoplasia?

The colposcopic and cytological findings at follow-up of 1000 women treated by laser ablation for cervical intraepithelial neoplasia or human papillomavirus infection at the Regional Department of Gynaecological Oncology, Gateshead, were reviewed. Colposcopy detected six of 27 patients with residual disease compared with cytology which was abnormal in 26 of the 27 and detected 21 as abnormal on the first visit after laser treatment. In our unit invasive disease after laser treatment was never detected solely on initial colposcopic review.

Male partners of women with genital human papillomavirus infection. An assessment of colposcopic abnormalities by histological examination and human papillomavirus hybridization.

Men whose female sexual partners showed histological evidence of human papillomavirus infection were examined. Human papillomavirus DNA was identified in 29 of 35 biopsy samples of colposcopically-identified penile lesions. Human papillomavirus strains that were related to human papillomavirus genotypes 6/11 were observed most commonly (seven of eight patients) in the partners of patients with warty atypia or condylomata, while human papillomavirus strains that were related to human papillomavirus genotypes 16/18 were most-commonly (eight of 15 patients) observed in tissue from the partners of patients with cervical intraepithelial neoplasia. Measurement of human papillomavirus DNA in lesions by the filter in-situ hybridization technique more-frequently indicated human papillomavirus infection (29 of 35 lesions) than did conventional histopathological assessment (21 of 35 lesions) in this "high-risk" group. We conclude that colposcopically-identifiable lesions in male sexual partners are likely to contain human papillomavirus DNA, even if is no definite histological evidence of human papillomavirus infection is present, and that such lesions frequently contain strains of human papillomavirus that have been associated with the development of anogenital carcinoma.

Histopathology of skin lesions in renal allograft recipients--an assessment of viral features and dysplasia.

We report the pathology of benign and malignant skin lesions from 13 renal allograft recipients. The 59 lesions included 18 squamous carcinomas, 16 verrucous keratoses, 19 warts with varying dysplasia, three plaque lesions resembling those found in epidermodysplasia verruciformis, two non-specific keratoses and one basal cell carcinoma. We delineate criteria for histological assessment of the presence of human papilloma virus (HPV) and use the term verrucous keratosis for lesions in which there is a putative viral contribution. Our findings emphasize the lack of correlation between clinical and histological assessment of the lesions. We note the variable and significant dysplasia within otherwise typical viral warts and the architectural features suggestive of HPV presence in the dysplastic lesions and in in situ and invasive squamous carcinomas. Parallel virological studies have revealed the presence of HPV 5/8 in over 60% of the invasive and in situ carcinomas probed. These HPV types have previously been isolated from squamous carcinomas of epidermodysplasia verruciformis, a condition whose defective cell-mediated immunity may be compared with that of the immunosuppression in our patients.

The importance of histology. Correlation between direct biopsies and associated methodologies--Panama 1982-1985.

The Author on the basis of his personal experience, underlines the importance of the histological examination on cervical target biopsy performed on cytological and colposcopical indications. With this integrated iter it is possible to reduce false negative and positive findings and consequently to obtain a non correct diagnosis and to plane a more precise therapy.

Morphometric assessment of the biological potential of human papillomavirus infections in the uterine cervix.

A series of 69 punch biopsies derived from 513 women prospectively followed up for cervical human papillomavirus (HPV) infections (including HPV lesions with and without cervical intraepithelial neoplasia; HPV-CIN, HPV-NCIN), and 42 control cases (consisting of normal epithelia, and classical CIN lesions) were analyzed morphometrically, using a semiautomatic image analyzer (IBS I-KONTRON), to assess the value of morphometric measurements in discriminating between HPV lesions and CIN, and to find out whether these methods are useful in predicting the outcome of cervical HPV infections. Nuclear area and the form factors Ell, Ar, and Pe were calculated on fifty nuclei in each of the three layers of epithelium; deep, intermediate and superficial. The reproducibility of the measurements was calculated for intra- and interobserver variation. HPV typing was completed using the in situ hybridization technique with DNA probes for HPV 6, 11, 16, 18 and 31. No significant differences were detected by using the form factors (Ell, Ar, Pe), when HPV lesions were compared with the normal epithelium, or with classical CIN lesions, in any of the epithelial layers. The nuclear area was significantly larger in all the epithelial layers in HPV-CIN I, and HPV-CIN II lesions as compared with CIN I and CIN II cases (p less than 0.001), p less than 0.001, p less than 0.005 and p less than 0.001, for deep, intermediate and superficial layers between HPV-CIN I/CIN I, and for all layers in HPV-CIN II/CIN II comparisons, respectively). This was also true when the values of nuclear area in HPV-NCIN I, HPV-CIN II and HPV-CIN III lesions were compared with the normal epithelium (p less than 0.001 for all layers). In the most severe lesions, no significant differences existed between HPV-CIN III and CIN III cases. Nuclear area measurement could not predict, however, the HPV type found in the lesion, or their natural history established by prospective follow-up.