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Objective: New commercial HPV RNA assays require further validation studies in population-based cervical cancer screening settings. To assess the performance of (FDA-approved) APTIMA® HPV Assay (AHPV), Hybrid Capture 2 (HC2), in-house PCR genotyping, and ThinPrep LBC in population-based screening, stratified by three histological gold standards., Study Design: A multi-center trial in 5006 women undergoing routine screening in France was designed to compare the absolute and relative risks of diagnosing CIN3+ and CIN2+ lesions by different diagnostic tests., Results: Reproducibility between the primary and second pathology reading was excellent for CIN3+ and CIN2+ endpoints (Cohen's kappa 0.948 and 0.854). Absolute risks (PPV) of different tests (AHPV, HC2, PCR genotyping, LBC) in diagnosing CIN2+ (15-20%) and CIN3+ (4-6%) were similar for the first, second, and consensus pathology readings. The relative risks of diagnosing these lesions by the four tests were also similar when the first, second or third pathology readings were employed. AHPV had the highest absolute risk of both histological endpoints, and detects 5% to 15% more CIN3+ and CIN2+ lesions, respectively, than LBC. Compared with HC2 assay, the relative risk of AHPV is 24% to 29% higher, with a significant difference in CIN2+ detection. With LBC as reference, AHPV had the best sensitivity/specificity balance measured by AUC (area under ROC curve) comparison test (significant for CIN2+), and the colposcopy referral rate (9.2%) comparable to that of LBC (8.7%)., Conclusions: These data corroborate the suitability of AHPV for the primary cervical cancer screening., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The APTIMA HPV Assay (AHPV) allows detection of 14 high-risk human papillomavirus (HPV) RNA types in cervical specimens. Until present, the assay has been compared to HPV DNA tests only in triage settings. Herein, we compare AHPV with a DNA assay (Hybrid Capture 2; HC2) and liquid-based cytology (LBC; using PreservCyt ThinPrep liquid Pap) in a screening setting (French APTIMA screening evaluation [FASE] study). Women (N = 5,006) aged 20-65 were screened by gynecologists in 17 private practices in Paris, France. One cervical specimen was collected and tested with LBC, AHPV and HC2 assays. Women were referred to colposcopy if they were ASC-US+ in LBC or HPV positive in either HPV assay. To control for verification bias, a random group (14%) with normal LBC and dually HPV negative tests underwent colposcopy. Data from 4,429 women were analyzed. Sensitivity, specificity and predictive values were calculated for the three tests. AHPV and HC2 were highly sensitive for CIN2+ (92.0% and 96.7%) and CIN3+ (95.7% and 95.3%) detection and much more sensitive than LBC (69.1% for CIN2+ and 73.3% for CIN3+). Specificity of AHPV was higher than that of HC2, but similar to that of LBC (p < 0.001). Combining LBC with either HPV test slightly increased sensitivity but compromised specificity. AHPV assay is both specific and sensitive for the detection of high-grade precancerous lesions and may be considered as an option for routine cervical cancer screening for women over 20 years of age., (Copyright © 2010 UICC.)

The EUROGIN 2010 roadmap represents a continuing effort to provide and interpret updated information on cervical cancer screening and vaccination against the cause of the disease, high-risk human papillomavirus (HPV). Contrary to the two previous reports in 2008 and 2009, the present roadmap gives equal room to HPV-based screening and HPV vaccination, as a result of the recent strengthening of the evidence on the efficacy and feasibility of both approaches. The superiority of HPV testing in primary screening compared to cytology (in more developed countries) and to cytology or visual inspection methods (in less developed countries) has been demonstrated in several randomised trials. High vaccine efficacy has been confirmed up to 7 years after vaccination; school-based programmes in some countries have been able to reach over 70% coverage among adolescent girls. Demonstration projects have indicated that the delivery of HPV vaccines in less developed countries is feasible and favourably received by populations where cervical cancer is very common. HPV-based screening can diminish cervical cancer incidence more quickly than HPV vaccination, but vaccination can eventually facilitate screening efforts, especially if new vaccines against a greater number of HPV types are introduced. The availability of two highly complementary prevention tools such as HPV testing and HPV vaccination makes it possible to conceive integrated strategies for the elimination of cervical cancer that have no precedent in the cancer field. HPV tests and HPV vaccines remain, however, too expensive, and large-scale financing of screening and vaccination in less developed countries is sorely lacking., (Copyright © 2011 UICC.)

The vaccinology landscape has changed, with national authorities now being increasingly accountable to new stakeholders such as health insurers, regional regulatory bodies, the media, and civil society. Here, we discuss how civil society organisations (CSOs), such as patient and women's groups, have become important drivers in the introduction and sustainability of new vaccination programs. This shift in public implication in vaccine policy has been well illustrated in the recent introduction of human papillomavirus (HPV) vaccination in Europe. Patient and women's groups which were traditionally focused on advocacy of treatments have also become advocates for prevention with the advent of HPV vaccination. Civil society advocacy at the European level supported key resolutions and white papers which in turn informed national recommendations on cervical cancer vaccination. CSOs were also active at the national level, supporting national policy makers. These organisations may bring innovative and effective new approaches to communication on vaccination benefits, using public events, celebrities and various social media. Working with experts, CSOs can also be an important bridge from the science to the lay public. This may provide a vital counterbalance to media hype and antivaccination groups, although CSOs may also be active and vocal opponents of immunization. The successful implementation and sustainability of future vaccination programs against infections such as HIV will be dependent upon the active participation of civil society to inform, to reassure and to maintain public trust., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Human papillomavirus (HPV) DNA testing is widely used in conjunction with Papanicolaou (Pap) testing in cervical cancer screening programs to improve the detection of high-grade lesions. While HPV DNA test sensitivity is good, an improvement in specificity is desired. Detection of HPV mRNA may improve specificity. The APTIMA HPV Assay detects the mRNA of 14 high-risk HPV types in liquid-based cytology specimens., Objective: To evaluate APTIMA HPV Assay performance for detection of high-risk HPV and high-grade cervical intraepithelial neoplasia (CIN) compared to Qiagen's Hybrid Capture 2 HPV DNA (HC2) test., Study Design: Liquid Pap specimens were collected from 800 women referred to colposcopy and tested with the APTIMA HPV Assay and the HC2 test. Complete results were available for 753 subjects. A subset of samples (n = 393) were typed using Roche's Linear Array HPV Genotyping Test., Results: Sensitivity and specificity for detection of high-risk HPV were >92% and 99% for the APTIMA HPV Assay and 93% and 82% for the HC2 test. Clinical sensitivity and specificity were 91% and >55% for detection of CIN 2+, and 98% and 53% for detection of CIN 3+ for the APTIMA HPV Assay; values for the HC2 test were 95% and 47% for CIN 2+, and 99% and 44% for CIN 3+., Conclusions: The APTIMA HPV Assay is sensitive and very specific for detection of high-risk HPV. The APTIMA HPV Assay had similar clinical sensitivity for disease detection but higher clinical specificity than the HC2 test, which may improve patient management and reduce the cost of care.

Objective: To test whether p1l6(INK4a) immunocytochemistry (ICC) in liquid-based cytology (LBC) is useful with colposcopy in abnormal Pap smears., Study Design: A series of 248 women with abnormal Pap smear were analyzed for oncogenic (HR) human papillomavirus (HPV) types using the Hybrid Capture II assay and for p16(INK4a) expression using ICC on cervical samples in PreservCyt liquid media. Colposcopic and loop electrosurgical excision procedure (LEEP) cone biopsy were the gold standard., Results: p16(INK4a) ICC did best as predictor of high-grade squamous intraepithelial lesion, with OR 12.18 (2.72-54.57) (p = 0.0001), showing 88.2% sensitivity (SE), 61.9% specificity (SP), 14.6% positive predictive value (PPV) and 98.6% negative predictive value (NPV). In sorting discrepant cases, p16(INK4a) ICC results in 100% SE and 100% NPV in detecting cervical intraepithelial neoplasia (CIN) 2 lesions among Pap+/biopsy- women. In atypical squamous cells undetermined significance (ASCUS) cytology, adding p16(INK4a) ICC improves specificity of colposcopy from 27.3% to 81.8% and PPV from 42.8% to 71.4%. Best performance is obtained with p16(INK4a) ICC and colposcopy: 83.3% SE, 81.8% SP, 71.4% PPV and 90.0% NPV. CONCLUSION p16(INK4a) is useful in sorting clinically relevant discrepant cases, and p16(INK4a) ICC significantly improves SP and PPV of colposcopy in management of ASCUS cytology.

Despite the considerable success of early screening for prevention of cervical cancer, Pap smears have not fulfilled the hopes that it would lead to a large-scale reduction of this cancer's incidence. Screening appears to be useful for a tiny portion of the world population, although a relatively large portion must put up with its limitations and disadvantages. Human papilloma viruses (HPV) 16 and 18 are responsible for two thirds of all cervical cancers worldwide. The condylomata (condyloma acuminatum), or genital warts, induced by HPV 6 and 11 are frequent among the young and difficult to manage. The extent and burden of HPV infection are considerable, as is the psychological and emotional impact of the diseases associated with it. Because cancer of the cervix is the final consequence of chronic HPV infection, it can be prevented by vaccination. A prophylactic vaccine to protect against the precancerous and cancerous lesions associated with HPV should save lives, reduce expensive diagnostic and therapeutic interventions, and have substantial individual and collective benefits. Clinical trials of anti-HPV vaccines for the prevention of cervical cancer and condyloma have shown remarkable results and an efficacy unequaled in the history of vaccination against infectious diseases. Vaccine efficacy has been shown only in young girls never exposed to the virus and only for the lesions associated with the specific viral types in the vaccine. Preliminary data indicate that the vaccination is effective in women who have previously eliminated naturally the virus. It has no therapeutic effects on existing lesions or in healthy virus carriers. Practical questions remain to be resolved. If the vaccination is left to individual initiative and vaccination coverage is insufficient, there will be no perceptible reduction in the frequency of cervical cancer. Vaccination policies will not be identical in poor countries, where the disease represents one of the leading causes of mortality among women, and in the rich countries, where screening programs have considerably reduced the frequency of this cancer. Current planning calls for the introduction of systematic vaccination of young girls aged 9-15 years, with progressive "catch-up" vaccination of the cohorts of young women aged 16-26 years. Nonetheless mathematical models and immunogenicity results indicate a possible benefit for individual vaccination of adults. This approach must still be assessed in the clinical trials underway. Because the vaccine does not protect against all types of HPV associated with cervical cancer, screening must be continued according to the conditions currently set. Vaccination and screening, which are complementary and synergistic, now constitute the new standards for prevention of this disease.

Cervical screening seems to benefit a minor part of the world female population, and yet women who benefit from it still prove its weaknesses. The fact that these genital lesions are the consequence of a chronic genital infection with HPV opens new and extraordinary opportunities for prevention through vaccination. The highest efficacy is demonstrated in young women naive to the virus types associated with the vaccines. The effectiveness of HPV vaccines are limited by two factors: all genital cancers and precancerous lesions are not induced exclusively by HPV types 16 and 18, and the optimal benefit is demonstrated in adolescents and young women before they have encountered these viruses. Vaccination and screening act complementarily and synergistically, and constitute to date the new standards of disease prevention.

Worldwide, cervical cancer is diagnosed annually in more than 500,000 women and accounts for 270,000 deaths, making it the second leading cause of cancer in women. In Europe, where many countries have set up screening program, cervical cancer ranks third among cancers in women. In France, cervical cancer is diagnosed in 3400-4500 women each year and kills 1000-1600. Since its introduction, Pap smear screening has transformed cervical cancer from a fatal disease into a rare condition. Despite the considerable success of this cytologic screening, Pap smears have not, as was first hoped, reduced incidence on a large scale. The principal reasons are related to the difficulties in ensuring optimum coverage of the population to be screened and in maximizing women's adherence: the success of screening depends on strict compliance with the calendar from 25 to 65 years of age. In 1/3 of cases, invasive cancers are found in women who undergo regular screening, because Pap smears are insufficiently sensitive. In 5% of cases, cancers are observed in women who were inappropriately managed after an abnormal Pap smear finding. The contribution of the HPV test to primary screening opens up promising perspectives of optimum protection. The test's sensitivity for high-grade lesions exceeds 95% and its negative predictive value exceeds 99%. The HPV test is the only test available for which a negative result provides instantaneous assurance that there is no risk of cervical cancer. The Pap smear alone, with its sensitivity of less than 70%, cannot provide this certainty. European and American guidelines recommend screening strategies based on a combined test using the Pap smear and HPV test after the age of 30 years. The impending availability of prophylactic HPV vaccines, which are expected to provide 70% protection against cervical cancer, will not affect the practice of screening, which must continue.

In January 2004 the European Surveillance of Sexually Transmitted Infections Network (ESSTI) issued an international alert regarding an outbreak of Lymphogranuloma venereum (LGV) in Rotterdam in a sexual network of men who have sex with men (MSM). Further to this alert, a retrospective survey was set up by the Institut de Veille Sanitaire and the reference laboratories for N.gonorrhoeae and Chlamydia in France. Our STI clinic in Paris carried out a clinico-biological retrospective study involving 154 MSM screened for anorectal sexually transmitted infections (STIs) between January 2002 and May 2004 and a prospective study between May 2004 and August 2004. Out of 216 swabs of rectal discharge from homosexual or bisexual males, a total of 32 were positive for C. trachomatis (14.8%) (3 patients in 2002, 11 in 2003 and 18 in 2004). C. trachomatis-positive rectal strains were genotyped to detect the specific C. trachomatis serovars and revealed serovars L(2) for 22 patients (respectively 1 in 2002, 9 in 2003 and 12 in 2004). Serum antibody titers for Chlamydia trachomatis were determined among 14 subjects and revealed strongly positive in 13 cases (1/512 to 1/16384) titers of IgG. These 22 patients with clinico-biologically confirmed anorectal lymphogranuloma venereum (ARLGV) were all homosexual men. They ranged from 28 to 52 years (mean age 39.2 years). 12 of 21 (57.1%) subjects with an ARLGV diagnosis were seropositive for human immunodeficiency virus (HIV) (one not done). Although rare, anorectal lymphogranuloma venereum (ARLGV) still exists in France and should not be forgotten in the differential diagnosis of rectal problems in male homosexuals.

Objectives: To assess the performance of a novel PCR-based assay (Roche AMPLICOR HPV test) in detection of cervical pathology as a part of management for abnormal PAP smear (MAPS) and in women participating in cervical cancer screening., Study Design: Altogether, 504 women comprising 270 patients referred for colposcopy due to an abnormal Pap smear and another 234 women participating in cervical cancer screening (tested for comparison) were analyzed for oncogenic (HR) Human papillomavirus (HPV) types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 using the Roche AMPLICOR HPV test in cervical samples collected in PreservCyt liquid media. Colposcopic biopsy and/or LEEP cone biopsy was used as the gold standard in the triage group, while liquid-based cytology (LBC) was the reference test in the screening group., Results: The prevalence of HPV was significantly higher in the MAPS group (65.9%) than in the screening group (31.2%) (P = 0.0001). There was a poor concordance between the referral PAP and the current LBC, being only moderate in the screening series, ICC (weighted kappa) = 0.291 (95%CI 0.070-0.459) (P = 0.007), and almost poor in the MAPS Series, with ICC = 0.217 (95%CI 0.04-0.384) (P = 0.023). AMPLICOR HPV positivity increased linearly with the increasing grade of cervical lesions. In detecting high-grade (CIN2-3), colposcopy was the most sensitive test (96.5%), very similar to AMPLICOR (95.2%) (P = 0.731), while LBC with HSIL cutoff was by far the most specific test (99.5%) and showed the highest PPV (96.1%). NPV of colposcopy (97.2%) and AMPLICOR (96.7%) were similar (P = 0.839). Together with abnormal colposcopy and HSIL cytology, the AMPLICOR HPV test is a powerful independent predictor of high-grade CIN2-3, and as such suitable to replace cervical cytology in management of women with abnormal PAP test (MAPS)., Conclusions: The Roche AMPLICOR HPV test is comparable to other HPV tests (HCII, PCR) in detecting CIN in MAPS. However, more data are clearly needed on the performance of AMPLICOR test in management of abnormal PAP and particularly as a screening tool.

Objectives: For the National health scheme, to compare the costs and the efficacy of treatment of external anogenital warts with imiquimod and podophyllotoxin and laser therapy in the case of failure or relapse., Patients and Methods: A model simulating the two successive treatments was built. In the first phase, the two topical treatments applied by the patients: podophyllotoxin for 4 weeks and imiquimod for 16 weeks were compared. In the case of failure or relapse, laser therapy that is widely used in France in this indication and, was applied. The efficacy of the topical treatments was assessed after reanalysis of the results of two controlled clinical trials versus placebo. These two trials were retained because they were comparable in method and had been recently published at the same time. A review of the literature assessed the results of laser therapy. A survey was conducted to collect the medical resources consumed by the different treatments., Results: Imiquimod provided a clearance rate of 49.5 p. 100, i.e., the disappearance of the lesions at 16 weeks, greater than that of podophyllotoxin (28.3 p. 100) at 4 weeks. The relapse rate was lowest with imiquimod (13.3 p. 100) than with podophyllotoxin (30.9 p. 100). The remission rate without relapse 3 months after the end of treatment was, including the laser, of 62 p. 100 following imiquimod and of 47 p. 100 following podophyllotoxin. The costs per patient cured was of 668 Euros for imiquimod and of 689 Euros for podophyllotoxin., Conclusion: Imiquimod, because of its greater initial efficacy, is at least as cost-effective as podophyllotoxin the treatment of external genital warts.

The objective was to assess the efficacy of the lidocaine 2. 5%/prilocaine 2.5% combination cream during CO2 laser vaporisation treatment of human papillomavirus-related anogenital lesions. The cream was applied 1 to 30 min beforehand. Patients assessed pain using a visual analogue scale. Regardless of the site and lesion surface area, anaesthesia was greatest when the cream was applied 5 to 15 min before treatment. Extra-cervical lesions (vagina, vulva, perineum, anus) were globally less painful than cervical lesions. Lesion surface area is a decisive factor in pre-operative anaesthesia. Small surface-area lesions (< 1 cm2) had significantly greater anaesthesia than larger surface area-lesions (> 5 cm2) (p<0.00001). The study cream proved particularly useful for complete anaesthesia in ambulatory treatment of anal (70%) and urethral (60%) mucosa lesions compared to the uterine cervix (p = 0.03). In terms of anaesthetic efficacy and cost-related benefits, the lidocaine/prilocaine cream is an effective and interesting alternative to locoregional intra-lesional anaesthesia or even to general anaesthesia, for excision and destruction of human papillomavirus-related anogenital lesions.

Human papilloma virus type 16 (HPV-16) is the HPV most frequently associated with cervical carcinoma in humans. For the prevention or treatment of cervical carcinoma, the E6 and E7 oncoproteins appear to be good targets for vaccine-induced cytotoxic T lymphocytes (CTL). Lipopeptide vaccination is an efficient way of stimulating cellular responses. However, to synthesize effective lipopeptides, it is necessary to define which epitopes are immunogenic. In this study we first determined that peptide 80 - 88 of the E6 protein was recognized by CTL from a healthy donor in association with the HLA-B18 molecule. We then defined the HLA-B18 anchoring peptide motif by testing the binding of various short peptides with the HLA-B18 molecule and showed that it was related to the HLA-A1-specific peptide motif. Furthermore, in analyzing the potential E7 epitopes susceptible to associating with HLA-B18, we demonstrated that peptide E7 44 - 52 gave the strongest binding. It could also be recognized by CTL from peripheral blood mononuclear cells (PBMC) of the same healthy donor. Finally, with PBMC from a patient with a cervical intraepithelial neoplasia grade 3, we found CTL which recognized the E6 80 - 88 epitope. We have hence identified two peptides encoded by the E6 and E7 proteins which are presented by the HLA-B18 molecule and could be included in a vaccine against HPV-16.

Objective: To evaluate the performance of HPV testing in identifying cervical neoplasia., Materials and Methods: Minor cytologic atypia of the uterine cervix, particularly atypical squamous cells of undetermined significance (ASCUS) represent a vast group, at least three times more frequent than cytologic high-grade squamous intraepithelial lesions (HGSIL). Even though, individually, ASCUS smears correspond to a normal cervix in nearly 80% of cases, their marked prevalence in the screened population suggests that this category of smear is one of the main sources of histologically confirmed high-grade SIL.The recent recommendations by the National Agency of Accreditation and Evaluation (ANAES) for managing ASCUS smears indicate that it is possible to advise a follow-up smear at regular intervals or immediate colposcopy. The follow-up smear option has limitations related to its incomplete sensitivity (25-40% of existing high-grade SIL can go unrecognized). Colposcopy has optimal sensitivity in recognizing high-grade lesions, but falls short due to lack of specificity.The Hybrid Capture (HC II) (Digene, Silver Spring, MD) test is an objective and reproducible test that makes it possible to detect nononcogenic and oncogenic types of human papillomavirus (HPV) and the DNA viral load, thereby increasing the probability that significant cervical lesions will not go unrecognized., Results: The Hybrid Capture test is simple to perform and positive results for high-risk HPV strongly correlate with the presence of high-grade CIN (sensitivity of approximately 98%). The test's nearly 100% negative predictive value makes it possibly to fully reassure patients who have had an ASCUS smear, freeing them from regular cytologic follow-up, colposcopy, and biopsy. A Hybrid Capture II test that is positive for oncogenic HPV significantly increases the probability of recognizing significant, precancerous cervical lesions. When the reference smear has been done in a liquid suspension, the Hybrid Capture test can be done on the residual cells in the suspension, thereby avoiding an additional visit., Conclusion: Recent French and international evaluations and publications should encourage the ANAES task force to propose the HPV test as a possible option for managing smears with minor atypia.▪.

Objective: To investigate whether ploidy and oncogenic human papillomavirus types can be correlated with the histological grade of cervical intraepithelial neoplasia (CIN) in the same tissue sections., Design: Histological data were obtained from 292 dysplastic lesions of the cervix and classified according to the CIN and the Bethesda terminologies. The samples were analysed using Feulgen-stained image analysis cytometry for ploidy and Human papillomaviruses DNA typing by in situ hybridisation, respectively., Setting: Colposcopy Clinic at Alfred Fournier Institute, Paris., Population: Three hundred and forty women referred for an abnormal cervical smear., Results: The ploidy data strongly segregate high grade from low grade squamous intraepithelial lesions (aneuploidy 78% versus 21%; P < 0.0001). There was a significant association between aneuploidy and the severity of the lesions (94% for CIN 3, 55% for CIN 2 and 14% for CIN 1; P < 0.0001). Both classifications showed a significant association of histological grade with oncogenic human papillomavirus types (HPV 16-18-33; 20% in low grade and 78% in high grade squamous intraepithelial lesions, 31% and 75% in CIN 1 and CIN 3, respectively; P < 0.0001). The simultaneous effects of these viruses and ploidy demonstrate an association in aneuploid cells between the presence of oncogenic human papillomavirus types and histological grade (76% and 18% in high and low grade squamous intraepithelial lesions, respectively; P < 0.0001). Such an association was not observed in diploid cells (20% in both low and high grade squamous intraepithelial lesions)., Conclusions: High risk human papillomavirus types do not exert and an independent effect on the histological grade of cervical intraepithelial neoplasia.

Papillomaviruses have naturally a strict tropism to epithelial cells in which they replicate during the cell differentiation. There is no histological evidence of any inflammatory reaction. No leucocyte recruitment is observed and thus, the role of macrophages during the early infectious process in the epithelium remains unknown. This silent, subacute or chronic infectious disease is characterized fundamentally by a dual pathogenic process, including an infectious process leading to the production of infective virus particles during the differentiation of infected epithelial cells, on the one hand, and an oncogenic process due to interactions of viral oncogenes with host cell regulatory proteins after integration of the virus to the cellular genome. The role of activated macrophages on the oncogenic process is clearly established. They contribute to regulate negatively the transcription of the non structural E6 E7 viral oncogenes and have cytotoxic effects to transformed cells by a direct intercellular contact without evidence of an effect due to a soluble factor such as tumor-necrotizing factor (TNF). Macrophages have, hence, a prominent role as cellular effectors of protective immunity against lesions due to papillomaviruses and particularly against the oncogenic process complicating these infections.

There is now substantial evidence that specific human papillomavirus (HPV) types are probably an etiological factor of cervical cancer and its precursors. Virus infection, viral genes expression emerge as necessary but not sufficient for the cells transformation. The E6-E7 oncoproteins of "high risk" (HPV 16-18) papillomaviruses bind specifically, and with high affinity, to cellular tumor suppressor gene products p53 and pRb, in contrast to "low risk" (HPV 6-11) types. This bond disturbs the cell cycle and results in chromosomal instability, aneuploidy and is the probably starting point of the integration of viral DNA to the host genome. These endogenous modifications are reported to the morphological and colposcopical events of cervical intraepithelial neoplasia and seem to be most important in the pathogenesis of cervical cancer precursors lesions and tumor progression.

According to recent studies showing that human papillomavirus (HPV) infections can be influenced by sex steroid hormones, we performed estrogen (ER) and progesterone (PgR) receptor assays in fresh frozen biopsies of genital-HPV-related lesions. Seventy-three women with normal cervix, condyloma, low- and high-grade CIN and squamous carcinoma were evaluated in comparison with 15 persons with vulvar and 9 with penile papillomavirus-associated lesions. HPV genotypes were determined by dot-blot hybridization. Non-cervical lesions did not express HR. Condyloma on squamous metaplasia of the cervix and high-grade CIN expressed high levels of HR, particularly PgR (mean 4,086 and 4,518 fmoles/g tissue, respectively). Cervical squamous carcinoma expressed very low concentrations of PgR in a limited number of cases. High levels of PgR were correlated with high-grade CIN (p less than 0.05), HPV16-18-associated lesions (p less than 0.01) and ER were correlated to HPV6-11-related lesions (p less than 0.01). The levels were independent of age, cycle stage and oral contraception. Morphological localization of PgR, using an immunocytochemical method using a monoclonal antibody (MAb) (PR-ICA), showed intense homogeneous staining in the nuclei of the stromal fibroblasts underlying dysplastic epithelium and condyloma on squamous metaplasia. These results suggest that, under in vivo conditions, sex steroid hormones, particularly progesterone, may act indirectly on HPV-infected epithelial cells and be implicated as co-factors in HPV-related cervical neoplasia. They could explain the relative predisposition to malignant transformation of the cervix as compared with vulvar and penile mucosa.

Sixty-six patients with fibrocystic mastopathy were enrolled in the trial after being selected according to clinical, radioultrasonographic, and histologic criteria. No characteristic hormonal profile was noted in most patients (52%). Estrogen receptors or progesterone receptors, or both, were found in 57% of patients. Hormone receptor levels were correlated with atypical proliferative mastopathy (87.5%). Mastopathy was associated with a uterine fibroma or a fibromatous uterus in 73% of cases. All patients received intramuscular injections of a sustained delivery system (microcapsules) of luteinizing hormone releasing hormone agonist [D-Trp6]-LHRH, Ipsen-Biotech, Paris) for 3 to 6 months. In case of partial response at 3 months, an antiestrogen (tamoxifen, 40 mg/day, for estrogen receptor-predominant lesions) or a progestin (cyproterone acetate, 50 mg/day, for progesterone receptor-predominant lesions) was added to the luteinizing hormone releasing hormone agonist. A complete response was observed in more than half of the patients (n = 35, 53%) treated by [D-Trp6]-LHRH alone (n = 29) or associated with tamoxifen (n = 4) or cyproterone acetate (n = 2). A significant partial response was observed in 30 other patients (45%). Additionally, half of them received inhibitory drugs. The best responses were seen with cyst reformation (complete response, 100%) and fibrous block. Clinical responses to treatment with [D-Trp6]-LHRH alone were independent of hormone receptor status, but synergistic effects occurred with concomitant use of the corresponding inhibitory drugs. We conclude that chronic mastopathy, particularly when associated with uterine fibroma, can be successfully treated by luteinizing hormone releasing hormone analogs in premenopausal women.