Human Papillomavirus Genotype Richness and the Biodiversity of Squamous and Glandular Cervical Dysplasias: A Cross-Sectional Study.

The impact of multiple infections on the risk of cervical lesions is a subject of ongoing debate. This study aims to explore whether the richness of HPV genotype infections and the biodiversity of squamous and glandular cervical dysplasias could influence the progression of precancerous lesions. We conducted a cross-sectional analysis involving 469 women who attended the Colposcopy Unit at the European Institute of Oncology in Milan, Italy, from December 2006 to December 2014. HPV type richness was measured as the number of different genotypes per patient. We calculated the associations between richness and age, as well as histologic grade, along with Simpson's biodiversity index for cervical dysplasias. We observed significant inverse relationships between the richness of high-risk (HR) genotypes and both age (p = 0.007) and histologic grade (p < 0.001). Furthermore, as the histologic grade increased, the mean biodiversity index of cervical dysplasias decreased, with exceptions noted in cases of normal histology and adenocarcinoma in situ. Different histologic grades formed five clusters with distinct mean ages and mean biodiversity indices. These findings suggest that HPV genotype richness and the biodiversity of cervical dysplasias may play a crucial role in predicting the risk of high-grade cervical lesions, enabling personalized management of precancers.

Tips and Tricks for Early Diagnosis of Cervico-Vaginal Involvement from Extramammary Paget's Disease of the Vulva: A Referral Center Experience.

Cervico-vaginal (CV) localization of extra-mammary Paget's disease (EMPD) of the vulva is extremely rare. In order to investigate the incidence risk and the pathognomonic clinical and pathological features of this condition, a retrospective analysis was conducted including 94 women treated for vulvar EMPD at the European Institute of Oncology, Milan, Italy, from October 1997 to May 2020. Overall nine patients developed CV involvement from EMPD, with a cumulative incidence of 2.5% (95% CI: 0.5-8.0%) at 5 years, 6.5% (95% CI: 1.9-15.1%) at 10 years and 14.0% (95% CI: 4.8-27.8%) at 15 years, respectively. All cases except one were firstly detected by abnormal glandular cytology. None reported vaginal bleeding or other suspicious symptoms. The colposcopic findings were heterogeneous and could sometimes be misdiagnosed. Cervical and/or vaginal biopsies were always performed for histopathological diagnosis by identification of Paget cells in the epithelium or stroma. Most patients developed invasive EMPD (5/9) of the cervix and/or vagina and underwent hysterectomy with partial or total colpectomy. CV involvement from EMPD should not be underestimated in women with a long-standing history of vulvar Paget's disease. Liquid-based cytology with immunocytochemistry represents a valuable tool for early diagnosis and should be routinely performed during the required lifelong follow-up.

Which Risk Factors and Colposcopic Patterns Are Predictive for High-Grade VAIN? A Retrospective Analysis.

Colposcopic patterns of Vaginal Intraepithelial Neoplasia (VAIN) are not definitively related to histological grade. The aim of the present study was to investigate any correlation between clinical and colposcopic features and the development of high-grade VAIN. Two hundred and fifty-five women diagnosed with VAIN (52 VAIN1, 55 VAIN2 and 148 VAIN3) at the European Institute of Oncology, Milan, Italy, from January 2000 to June 2022, were selected for a retrospective analysis. Multivariate logistic regression was performed to estimate the association of risk factors and colposcopic patterns with VAIN grade. Smoking was associated with the development of VAIN (34.1%, p = 0.01). Most women diagnosed with VAIN3 (45.3%, p = 0.02) had a previous history of hysterectomy for CIN2+. At multivariate analysis, colposcopic grade G2 (OR = 20.4, 95%CI: 6.67−61.4, p < 0.001), papillary lesion (OR = 4.33, 95%CI: 1.79−10.5, p = 0.001) and vascularity (OR = 14.4, 95%CI: 1.86−112, p = 0.01) were significantly associated with a greater risk of VAIN3. The risk of high-grade VAIN should not be underestimated in women with a history of smoking and previous hysterectomy for CIN2+, especially when colposcopic findings reveal vaginal lesions characterized by grade 2, papillary and vascular patterns. Accurate diagnosis is crucial for an optimal personalized management, based on risk factors, colposcopic patterns and histologic grade of VAIN.

The Potential Impact of High-Risk Human Papillomavirus-Negative Cervical Intraepithelial Neoplasia 2+ on Primary Human Papillomavirus Screening.

OBJECTIVES: To investigate the prevalence of high-risk human papillomavirus (HPV)-negative cervical intraepithelial neoplasia (CIN) and invasive cervical carcinoma (ICC) and to analyze the distribution of other genotypes in this subset. METHODS: In total, 431 women who underwent excisional surgical treatment for CIN or ICC at the European Institute of Oncology, Milan, Italy, from January 2016 to December 2017 were retrospectively analyzed. The Linear Array HPV genotyping test (Roche Diagnostics) was performed on a postaliquot from high-risk-HPV-negative liquid-based cervical specimens, when available. Patient characteristics and the prevalence of high-risk-HPV-negative CIN grade 2 or worse (CIN2+) were tabulated. We used t tests to compare age between high-risk-HPV-positive and high-risk-HPV-negative patients. RESULTS: Overall, 8.9% of CIN2+ and 7.5% of ICC cases were high-risk HPV negative. There was no age difference between high-risk-HPV-negative CIN2+ women (mean [SD], 41.3 [8.7] years) and high-risk-HPV-positive women (mean [SD], 39.5 [9.0] years) (P = .28). The Linear Array result was available in 22 cases. Most high-risk-HPV-negative patients were positive for a single other genotype infection (32.6%). HPV 73 was the most prevalent genotype, followed by HPV 53 and HPV 84. HPV 26 was detected in 1 case of ICC. CONCLUSIONS: Our results showed a not-negligible proportion of high-risk-HPV-negative CIN2+, suggesting that cotesting would not miss these cases.

VIN usual type-from the past to the future.

Usual vulvar intraepithelial neoplasia (uVIN) is the most common VIN type, generally related to a human papillomavirus (HPV) infection, predominantly type 16. The incidence of uVIN has been increasing over the last decades, and a bimodal peak is observed at the age of 40-44 and over 55 years. Almost 40% of patients with uVIN have a past, concomitant or future HPV-associated lesion of the lower genital tract. HPV-related malignancies are associated with a persistent HPV infection. The host immune response is of crucial importance in determining clearance or persistence of both HPV infections and HPV-related VIN. About 60% of the patients present with symptoms. Clinical features of uVIN vary in site, number, size, shape, colour, and thickness of lesions. Multicentric disease is often present. Most uVIN lesions are positive at immunohistochemistry to p16(ink4a) and p14(arf), but negative to p53. Irrespective of surgical treatment used, uVIN recurrence rates are high. Positive margins do not predict the development of invasive disease and the need to re-excide the tissue around the scare remains to be demonstrated. Therefore, considering the low progression rate of uVIN and psycosexual sequelae, treatments should be as conservative as possible. Medical treatments available are mainly based on immunotherapy to induce normalisation of immune cell count in uVIN. None are approved by the food and drug administration (FDA) for the treatment of uVIN. If medical treatment is performed, adequate biopsies are required to reduce the risk of unrecognised invasive disease. Some studies suggest that failure to respond to immunotherapy might be related to a local immunosuppressive microenvironment, but knowledge of the uVIN microenvironment is limited. Moreover, our knowledge of the potential mechanisms involved in the escape of HPV-induced lesions from the immune system has many gaps. HPV vaccines have been demonstrated to be effective in preventing uVIN, with 94.9% efficacy in the HPV-naive population, while studies on therapeutic vaccines are limited. The low incidence of VIN requires large multicentre studies to determine the best way to manage affected patients and to investigate the immunological characteristics of the 'vulvar microenviroment' which leads to the persistence of HPV.

Performance of self-sampled HPV test in comparison with liquid based cytology.

OBJECTIVE: Strong evidences shows that HPV testing is more sensitive than cytology in detecting high-grade CIN. HPV test can be performed on samples collected by women themselves by means of self-sampling devices. This study compares the results of self-sampled HPV tests with the results of liquid based cytology (LBC). STUDY DESIGN: Seven hundred women scheduled for cervical cytology self-collected a cervicovaginal sample for HPV testing and then underwent a clinician-collected LBC at the European Institute of Oncology. The HPV and LBC results were compared with the McNemar test. RESULTS: All HSIL (N=5) resulted hrHPV positive. LBC resulted LSIL or worse in 38 (5.4%) women (out of 700). Self-sampled HPV was positive in 96 women (13.7%). A LSIL or worse LBC result was found in 15 (2.5%) patients, out of the 604 hrHPV negative women and in 23 (24%) patients, out of the 96 hrHPV positive women. Positive cytology after a self-sampled HPV positive result had an Odds Ratio of 12.4 (95% CI: 5.8-26.6). CONCLUSION: Self-collected HPV testing identifies a group of women at high risk of positive LBC and high grade SIL.

Self-collected human papillomavirus testing acceptability: comparison of two self-sampling modalities.

BACKGROUND: Human papillomavirus (HPV) testing can be used as a primary test for cervical cancer screening. HPV self-sampling has the potential to replace physician/nurse sampling. Our objective was to compare the acceptability of two self-sampling methods among 205 women undergoing an excisional procedure for cervical intraepithelial neoplasia (CIN) at the European Institute of Oncology (IEO). METHODS: One hundred eleven patients were given a Hybrid Capture (HC) Cervical Sampler™ (Qiagen, Hilden, Germany), and 94 received a self-lavaging device, the Delphi® Screener (Delphi Bioscience, Scherpenzeel, The Netherlands), both with written instructions. Self-sampling was performed just before the clinician-collected cervical sample. Women responded to questions using 5-point ordinal scales on the general acceptability of self-sampling and the physical comfort, embarrassment, pain, and difficulty experienced. Participants were also asked whether they prefer self-sampling or clinician sampling. RESULTS: Both self-sampling methods were generally accepted with a significantly high score (p = 0.005) and significantly lower embarrassment (p = 0.042) in favor of the Delphi Screener. Both self-sampling methods were physically well accepted, not painful, and easy to perform. Most women (n = 117, 68%) preferred the self-sampled compared to the clinician-sampled test, with a significantly higher proportion in the Delphi Screener group (n = 59, 77.6%) compared to those using the HC Sampler (n = 58, 60.4%) (p = 0.021). CONCLUSIONS: The present study shows that self-sampling for HPV testing is favorably received by women. A sampling device specifically developed for self-sampling, such as the Delphi Screener, shows the highest degree of satisfaction. A well-accepted HPV sampling method could be especially useful for women who do not take part in cervical screening or in settings where organized screening is not fully implemented.

Age distribution of HPV genotypes in cervical intraepithelial neoplasia.

OBJECTIVE: Recent data showed that HPV16 infections in young women can lead to CIN3 formation very quickly and questioned the common assumption that invasive cervical cancer develops through slowly progressing pre-cancer lesions, CIN1, CIN2 and CIN3. The aim of the study is to compare the age distribution of HPV 16/18 related and HPV16/18 not related CIN. METHODS: We used the data generated from the clinical use of HPV genotyping (LINEAR ARRAY, Roche Diagnostics). Patients were grouped on the basis of histology, CIN1 vs. CIN2+ and on HR-HPV genotype status. RESULTS: The probability to develop a CIN2+ seemed to decrease with age in patients infected with HR-HPV genotype 16/18 while the inverse effect was observed in CIN2+ patients who were HR-HPV positive but HPV16/18 negative (Chi-square test, p(trend)=0.01). Only in HR-HPV positive but HPV 16/18 negative patients, a relative reduction of CIN1 vs. CIN2+ was observed with increasing age (Cochran-Armitage test, p(trend)=0.01); finally, in HR-HPV non-16/18 infected patients only a statistically significant difference in mean age between CIN1 and CIN2+ patients below age 35 was observed. CONCLUSIONS: Besides the limitations of the present cross-sectional analysis, these data suggest a genotype specific natural history of cervical cancer precursors development: one type, more frequent, HPV16/18 related, which develops quick and early in life; another one, non-16/18 HR-HPV related, which develops later, slowly, through low- to high-grade lesions. If confirmed, this hypothesis could influence screening policies, especially in the vaccinated population.

Typing of human papillomavirus in women with cervical lesions: prevalence and distribution of different genotypes.

Human papillomavirus (HPV) are distributed widely and persistent infection with high-risk (HR) HPV is recognized as a necessary cause of cervical cancer. The aim of this study was to evaluate the distribution of different HR-HPV genotypes in 199 women with cervical pre-invasive lesions undergoing conservative treatment. A Linear Array HPV Genotyping Test was used to identify individual HPV genotypes in cervical samples. It was observed that the most prevalent HPV genotypes were HPV 16 (52.6%), HPV 51 (13.5%), and HPV 31 (10.9%); HPV 18 was found in 7.3% of the patients. Stratifying the different HPV genotypes according to the severity of the cervical lesion, a strong association between the increasing severity of the histological diagnosis and the detection of more carcinogenic HR-HPV type was found, and in all but one cervical intraepithelial neoplasia of grade 3 the presence of at least one HR-HPV could be detected, with more than 70% of cervical intraepithelial neoplasia of grade 3 patients bearing HPV 16. Multiple infections, comprising between 2 and 6 HPV types, were found in 43% of patients; however, the presence of more than 1 HR-HPV type was not associated with an increased risk of high grade lesions. In conclusion, this data show that HPV 16, 51, 31, 52, and 18 were the prevalent types found in patients with cervical lesion undergoing conservative treatment, with a high prevalence of HPV 16 in cervical intraepithelial neoplasia of grade 3 patients. No association between multiple infection and severity of the lesion could be found.

Interobserver variability of colposcopic interpretations and consistency with final histologic results.

OBJECTIVE: To evaluate the interobserver reliability of colposcopy and the prediction of final histologic results. MATERIALS AND METHODS: Visibility of the squamocolumnar junction, presence and grading of atypical transformation zone (ATZ), and presence and grading of cervical intraepithelial neoplasia (CIN) were assessed by nine expert colposcopists in 100 cervigrams. Pairwise kappa, group kappa, and class-specific kappa values were computed. Frequency and degree of interobserver disagreement on CIN and ATZ grading and correlation with histologic results were studied. RESULTS: The median pairwise kappa and the group kappa values were excellent for ATZ detection, acceptable for the squamocolumnar junction, and poor for the other variables; the presence of ATZ had a sensitivity for CIN of 90.2% and a specificity of 48.6%; the colposcopic impression of high-grade CIN had a sensitivity of 54.4% and a specificity of 88%. CONCLUSIONS: Some colposcopic predictions are reproducible between observers, predictive of the histologic results, and can be integrated in the algorithm for the management of patients with abnormal Pap smear results.