Risk Analysis Stratification of CIN 2+ Development in a Cohort of Women Living with HIV with Negative Pap Smear and HR-HPV Test during a Long-Term Follow-Up.

BACKGROUND: Women living with Human Immunodeficiency Virus are at higher risk of cervical cancer and precancer compared to women without HIV infection. The aim of the study is to evaluate the risk factors for the development of CIN2+ in a cohort of WLWH with negative colposcopy and cytology during a long follow-up period. METHODS: We enrolled, in a multicentric retrospective cohort study, WLWH who attended the colposcopic services from 1999 to 2019. Patients with a normal Pap smear, a negative HR-HPV test, and at least one year of follow-up were considered for the anlysis. RESULTS: The five-year cumulative incidence of histologically confirmed HSIL was 8.3% (95% CI = 2.6-13.6) among subjects with a CD4+ cell count of <200 cells/µL at any visit and 2.1% (95% CI = 0.7-3.4, p = 0.001) in women with a CD4+ cell count of persistently >200 cells/µL. In women with persistent HR-HPV infection, the five-year cumulative incidence of CIN 2+ was 6% (95% CI = 1.6-10.2) versus 2% (95% CI = 0.4-3.6, p = 0.012) in women without HPV infection. An HIV viremia of >200 copies/mL, a CD4+ cell count of <200 cells/µL, persistent HR-HPV infection, and smoking ≥10 cigarettes/day were all independent and statistically significant risk factors associated with the development of CIN2+ during follow-up. CONCLUSIONS: WLWH with good immune status and negative Pap smear and HR-HPV test have a low risk for CIN2+.

High-risk HPV positivity is a long-term risk factor for recurrence after cervical excision procedure in women living with HIV.

OBJECTIVE: To evaluate the risk factors for recurrence of high-grade disease after cervical excision in women living with HIV (WLWH), with a specific interest in the role of high-risk (HR-) HPV positivity. METHODS: Multicentric retrospective study conducted on WLWH who underwent cervical excision between January 1987 and June 2017 in six Italian institutions. The rate of high-grade recurrence was determined. Risk factors for recurrence and HR-HPV positivity were determined with the Log-rank test and Cox proportional hazards regression models. RESULTS: A total of 271 WLWH were included in the final analysis. A high-grade recurrence was found in 58 (21.4%) patients. Age 41 years or more at inclusion and HR-HPV positivity during follow up were independently associated with a higher risk of disease recurrence with relative risks of 4.15 (95% confidence interval [CI] 2.01-8.58, P < 0.001) and 5.18 (95% CI 2.12-12.67, P < 0.01), respectively. Age 41 years or more (relative risk 1.75, 95% CI 1.01-3.04, P = 0.047) resulted as a risk factor for HR-HPV positivity during follow up. CONCLUSION: HR-HPV positivity is a risk factor for recurrence after cervical excision in WLWH. Women older than 41 years may benefit from a long-term yearly follow up. Future studies regarding HPV vaccination after treatment in WLWH may be useful, considering the protective role of the higher probability of HPV negativity in vaccinated women.

Clinical Characteristics and Long-Term Follow-up of Patients Treated for High-Grade Vaginal Intraepithelial Neoplasia: Results From a 20-Year Survey in Italy.

OBJECTIVES: The aim of this survey was to evaluate the different surgical approaches for women with high-grade vaginal intraepithelial neoplasia (HG-VaIN) used in 8 hospitals in central and northern Italy in the last 20 years. In particular, the baseline characteristics of the patients and factors potentially leading to excisional treatment rather than ablation were considered. Moreover, the clinical outcome of patients treated for HG-VaIN (disease persistence or recurrence and progression toward invasive vaginal cancer) was analyzed. MATERIALS AND METHODS: The medical records of all women initially diagnosed with HG-VaIN and subsequently treated in 8 Italian hospitals from January 1996 to December 2016 were analyzed in a multicenter retrospective case series. RESULTS: Among the 226 women included, 116 (51.3%) underwent ablative procedures and 110 underwent excisional surgery (48.7%). An ablative procedure was preferred in cases where multiple lesions were found on colposcopic examinations. Physicians decided more frequently to perform excisional procedures in women with menopausal status, high-grade referral cervical cytology, previous hysterectomy for human papillomavirus-related disease, or VaIN 3 on colposcopic-guided biopsy. CONCLUSIONS: The surgical treatment of HG-VaIN should be tailored according to the clinical characteristics of each woman and each lesion. However, in potentially high-risk cases (VaIN 3, previous hysterectomy for human papillomavirus-related disease, and menopausal women) or in those cases in which an occult invasive disease cannot be ruled out, an excisional approach should be preferred.In any case, long-term follow-up is advisable in women treated for HG-VaIN.

Leiomyomatosis peritonealis disseminata: A case report of recurrent presentation and literature review.

INTRODUCTION: Leiomyomatosis peritonealis disseminata (LPD) is an uncommon disease featured by the presence of multiple nodules of smooth muscle cells scattered in the abdominal cavity. To date only about 150 cases have been reported in literature. We report a case of recurrent LPD after laparotomy. CASE PRESENTATION: In March 2016 a 36-year-old female, with a history of multiple previous laparoscopic myomectomies, consulted her gynaecologist complaining abdominal pain; a MRI was performed and reported multiple pelvic masses, subsequently excised during laparotomy. The patient refused a total hysterectomy with bilateral salpingo-oopherectomy so a close follow-up was recommended. In November 2017 when a new MRI revealed recurrency of the disease, a second laparotomy is performed and all visible nodules are excised. The histological exam confirms LPD diagnosis. On follow-up after three months the patients is completely asymptomatic. DISCUSSION: Differential diagnosis of LPD is challenging due to its similarity to carcinomatosis and to other benign abdominal disorders. Malignant transformation is rare, but it may occur, so a close follow-up is necessary. Even if there is no consensus regarding the treatment, hormonal therapy is probably the best first line approach, while surgery should be the second choice. CONCLUSIONS: LPD is an uncommon but potentially severe disease. In our opinion larger studies are necessary to improve our diagnostic effectiveness and to define the best therapeutic strategy.

Colposcopic patterns of vaginal intraepithelial neoplasia: a study from the Italian Society of Colposcopy and Cervico-Vaginal Pathology.

The aim of this study was to evaluate the colposcopic patterns observed in women with a histopathological diagnosis of vaginal intraepithelial neoplasia (VaIN). The medical charts and the colposcopy records of women diagnosed with VaIN from January 1995 to December 2013 were analysed in a multicentre retrospective case series. The abnormal colposcopic patterns observed in women with VaIN1, VaIN2 and VaIN3 were compared. The vascular patterns and micropapillary pattern were considered separately. A grade II abnormal colposcopic pattern was more commonly observed in women with a biopsy diagnosis of VaIN3 rather than with VaIN1 or VaIN2 (P<0.001). Vascular patterns were also more common in women with VaIN3 rather than with VaIN1 or VaIN2 (P<0.001). Moreover, in women with grade I colposcopy, the rate of VaIN3 was significantly higher when a vascular pattern was observed (62.5 vs. 37.5%; P=0.04). The micropapillary pattern was more common in women with grade I colposcopy and it was more frequently observed in women with VaIN1 rather than in those with VaIN2 or VaIN3 (P<0.001). Grade II abnormal colposcopic pattern was more commonly observed in women with VaIN3. Moreover, the detection of vascular patterns appeared to be associated with more severe disease (VaIN3) even in women with grade I colposcopy, whereas the micropapillary pattern should be considered an expression of a less severe disease (VaIN1 and VaIN2).

Knowledge of HPV infection and vaccination among vaccinated and unvaccinated teenaged girls.

OBJECTIVE: To assess the knowledge of teenaged girls on human papillomavirus (HPV) infection and vaccination 12 months after the start of a vaccine administration and information campaign. METHODS: Between May 15 and June 15, 2009, an anonymous questionnaire was given to 629 girls attending a secondary school in a northeastern Italian city (286 were vaccinated against HPV, 343 were unvaccinated) to investigate their knowledge on HPV infection, transmission, prevention, vaccination, and post-vaccination behaviors. The responses were evaluated with respect to the vaccination status of the participants. RESULTS: Vaccinated teenaged girls had no more knowledge than unvaccinated ones about the route of HPV transmission, and the relationship between HPV and AIDS. Vaccinated girls had less knowledge than unvaccinated girls about preventing transmission by condom (P=0.003) and about the correlation between HPV and penile cancer (P=0.034) and warts (P=0.001). Furthermore, compared with unvaccinated girls, more vaccinated girls believed that contraceptive pills might prevent HPV-related disease (P=0.001). Vaccinated girls better understood the importance of performing regular Pap smears after vaccination (P=0.021). CONCLUSION: Knowledge on HPV infection and vaccination remains suboptimal, especially among vaccinated teenaged girls, despite a broad information campaign. Misconceptions about the utility of secondary prevention may increase risky sexual behaviors.

Prevalence and type distribution of high-risk human papillomavirus infection in women undergoing voluntary cervical cancer screening in Italy.

The aim of this survey was to assess the prevalence and distribution of oncogenic human papillomavirus (HPV) genotypes in women who underwent screening for cervical cancer in Italy. The correlation of genotypes with the cytological results was also evaluated. Cervical samples were collected from 9,947 self-referring women for cervical cancer screening. Participants were screened by liquid-based cytology and high-risk HPV testing using the Hybrid Capture 2 test. Positive samples were genotyped by PCR. Samples (1,474; 14.8%) were positive for high-risk HPV. The prevalence was 29.4% in the 15-19 years-group, decreasing progressively to 6.1% at 50-54 years of age and increasing to 12.2% in those aged over 65 years. HPV 16 was the genotype detected most frequently followed by HPV 31, HPV 18, HPV 56, and HPV 51. HPV 16 or 18 were present in 4% of women with normal cytology and both were detected contemporarily in only 14 women. Twenty-two percent of atypical squamous cells, 26% of low-grade and 56% of high-grade squamous intraepithelial lesions at cytology were positive for HPV 16 and/or 18. The prevalence of HPV infection in Italy is in agreement with that reported worldwide. HPV 16 was the prevalent genotype. The concomitant infection with HPV 16 and HPV 18 (vaccine targets) was found rarely. Apart from HPV 16 and 18, there was a substantial presence of HPV genotypes against which the vaccines available currently have shown cross-protection efficacy. The findings of this study may contribute to reliable predictions on the potential efficacy of an HPV vaccine in clinical practice.

Clinical and epidemiological correlates of antibody response to human papillomaviruses (HPVs) as measured by a novel ELISA based on denatured recombinant HPV16 late (L) and early (E) antigens.

BACKGROUND: At present, seroreactivity is not a valuable parameter for diagnosis of Human Papillomavirus (HPV) infection but, it is potentially valuable as marker of viral exposure in elucidating the natural history of this infection. More data are needed to asses the clinical relevance of serological response to HPV. OBJECTIVES: The objective was to assess the clinical and epidemiological correlates of HPV-seroreactivity in a cohort of HIV-negative and HIV-positive women. METHODS: Seroreactivity of 96 women, evaluated in an ELISA test based on denatured HPV16 late (L) and early (E) antigens, was correlated with their clinical and epidemiological data previously collected for a multi-centre Italian study, HPV-PathogenISS study. RESULTS: No significant correlation was found between HPV DNA detection and seroreactivity. Women, current smokers showed significantly less seroreactivity to L antigens as compared with the non-smokers. HIV-positive women showed significantly less (66.7%) antibody response as compared with HIV-negative women (89.3%), with particularly impaired response to L antigens. Women, HIV-positive and current smokers, showed by far the lowest seroprevalence (33.3%) as compared to 75.9% among all other women (OR = 0.158; 95%CI 0.036-0.695, p = 0.014; Fisher's exact test). Importantly, this association did not loose its significance when controlled for confounding from age (continuous variable) in multivariate analysis or using Mantel-Haenszel test for age-groups. CONCLUSION: It is tempting to speculate that HIV-positive current smokers comprise a special high-risk group, with highly impaired immunological response that could prevent eradication of persistent HPV infections and thus contribute to development of CIN3/CC.

Colposcopy is not necessary to assess the risk to the cervix in HIV-positive women: an international cohort study of cervical pathology in HIV-1 positive women.

The objectives of this prospective multicentre international cohort study are to describe the characteristics of a cohort of HIV-1 positive women and determine the best management system by comparing cervical pathology according to results of cytology, colposcopy and human papillomavirus (HPV) testing at baseline and throughout follow-up. A. Cohorts of known HIV-positive women were recruited from 6 hospital-based European centres and a community-based South African centre. Following registration, women were reviewed every 6 months to undergo cervical surveillance including cytology, colposcopy, histopathology and HPV testing, using the HPV hybrid capture assay. Independent risk factors for the incidence of cytological abnormality and acquisition/clearance of HPV infection during follow up were identified. A total of 1,534 women were recruited, 400 of which were from South Africa. At baseline, among European women, 66% had normal cytology and half were HPV negative and among South African women, 45% had normal cytology and one third (32%) were HPV negative. The sensitivity of cytology (>/=ASCUS) matched with that of colposcopy to detect CIN2+. Rate of detection of high grade CIN at 2 years was similar in European and South African women (11 and 9.3%, respectively). Cytology and HPV testing alone were each sufficiently sensitive as a screening test at 2 yearly intervals. Our data confirm the high prevalence of low-grade cytological abnormalities and high-risk HPV infection. Cytology appears to be sufficient for cervical surveillance, with HPV testing being less specific with poor positive predictive value. There appears to be no additional benefit from routine colposcopy.

Serum antibody response to Human papillomavirus (HPV) infections detected by a novel ELISA technique based on denatured recombinant HPV16 L1, L2, E4, E6 and E7 proteins.

BACKGROUND: Human papillomaviruses (HPVs) are the primary etiological agents of cervical cancer and are also involved in the development of other tumours (skin, head and neck). Serological survey of the HPV infections is important to better elucidate their natural history and to disclose antigen determinants useful for vaccine development. At present, the analysis of the HPV-specific antibodies has not diagnostic value for the viral infections, and new approaches are needed to correlate the antibody response to the disease outcome. The aim of this study is to develop a novel ELISA, based on five denatured recombinant HPV16 proteins, to be used for detection HPV-specific antibodies. METHODS: The HPV16 L1, L2, E4, E6 and E7 genes were cloned in a prokaryotic expression vector and expressed as histidine-tagged proteins. These proteins, in a denatured form, were used in ELISA as coating antigens. Human sera were collected from women with abnormal PAP smear enrolled during an ongoing multicenter HPV-PathogenISS study in Italy, assessing the HPV-related pathogenetic mechanisms of progression of cervical cancer precursor lesions. Negative human sera were collected from patients affected by other infectious agents. All the HPV-positive sera were also subjected to an avidity test to assess the binding strength in the antigen-antibody complexes. RESULTS: Most of the sera showed a positive reactivity to the denatured HPV16 proteins: 82% of the sera from HPV16 infected women and 89% of the sera from women infected by other HPV genotypes recognised at least one of the HPV16 proteins. The percentages of samples showing reactivity to L1, L2 and E7 were similar, but only a few serum samples reacted to E6 and E4. Most sera bound the antigens with medium and high avidity index, suggesting specific antigen-antibody reactions. CONCLUSION: This novel ELISA, based on multiple denatured HPV16 antigens, is able to detect antibodies in women infected by HPV16 and it is not genotype-specific, as it detects antibodies also in women infected by other genital HPVs. The assay is easy to perform and has low cost, making it suitable for monitoring the natural history of HPV infections as well as for detecting pre-existing HPV antibodies in women who receive VLP-based HPV vaccination.

Activation of the ERK/MAP kinase pathway in cervical intraepithelial neoplasia is related to grade of the lesion but not to high-risk human papillomavirus, virus clearance, or prognosis in cervical cancer.

We subjected 302 archival samples (150 squamous cell carcinomas [SCCs] and 152 cervical intraepithelial neoplasia [CIN] lesions) to immunohistochemical staining with extracellular signal-regulated kinase-1 (ERK1) antibody and human papillomavirus (HPV) testing with 3 primer sets. Follow-up data were available for all SCC cases and 67 CIN cases. High-risk (HR) HPV types were associated with CIN (odds ratio [OR], 19.12; 95% confidence interval [CI], 2.31-157.81) and SCC (OR, 27.25; 95% CI, 3.28226.09). There was a significant linear relationship between lesion grade and ERK1 staining intensity (P = .0001). ERK1 staining was a 100% specific indicator of CIN, with a 100% positive predictive value, but a poor predictor of HR HPV. ERK1 expression did not predict clearance or persistence of HR HPV after CIN treatment. ERK1 staining did not significantly predict survival in cervical cancer in univariate (P = .915) or multivariate analysis. After adjustment for HR HPV, stage, age, and tumor grade in the Cox regression model, only stage (P = .0001) and age (P = .002) remained independent prognostic factors. ERK1 expression seems to be an early marker of cervical carcinogenesis. ERK1 overexpression is not a specific marker of HR-HPV in CIN and cervical cancer, nor does it predict virus clearance after CIN treatment or disease outcome in cervical cancer.

Vulvar neoplasia in HIV positive women: a review.

Among genital malignancies, vulvar cancer and its precursor, Vulvar Intraepithelial Neoplasia (VIN), is less commonly encountered than cervical neoplasia. According to R.W. Jones (2001) vulvar cancer represents about 3-5% of all genital neoplasms and its peak of incidence is between 60 and 80 years of age. Risk factors for vulvar carcinoma are: smoking and immune depression, which expose to a higher risk of vulvar HPV infection caused by high risk strains. In recent years, increased prevalence and incidence of high grade VIN and vulvar invasive carcinoma in young patients (below 45 years of age) have been reported. The main group of affected cases is represented by HIV infected women. Data about the severity of immune depression, expressed by CD4 cell count, as an adjunctive risk factor for persistence, recurrence or progression, are conflicting and scanty. Moreover, information about the effect of Highly Active Antiretroviral Therapy (HAART) on the natural history of VIN are inconclusive. So far, a thorough examination of the vulvar region, associated with colposcopy and biopsy when indicated, should be considered a routine procedure in the gynaecological surveillance of HIV positive women.

Mucosal immune response to Human Papilloma Virus (HPV) infection in HIV positive women.

Mucosal immunity plays a central role in the control of genital human papilloma virus (HPV) infection. HIV infection is associated with higher risks of HPV-induced neoplasias. Prevalence, incidence and evolution of genital HPV lesions are correlated with the level of immunodepression. Several changes of the local immune response in the genital tract of HIV infected women have been demonstrated. The influence of HIV on the production of some immunoregulatory cytokines appears of particular interest. The shift from the helper T cells type 1 (Th1) to the helper T cells type 2 (Th2) immune response, which determines the downregulation of the cell-mediated immunity, may explain the frequent loss of immunologic control of HPV and its oncological complications