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The large amount of literature published over the last two decades on human papillomavirus (HPV)-DNA testing has definitely demonstrated the association between high-risk viral genotypes (hrHPV) and cervical cancer. Moreover, hrHPV-DNA testing has shown excellent performance in several clinical applications, from screening settings to the follow-up of treated patients, compared to conventional cytology or colposcopy options. On the other hand, when a huge number of reports are published on the same subject in a relatively short period of time, with many variations in settings, study designs and applications, the result is often confusion and decreased comprehension by readers. In daily office practice, several different situations (in symptomatic or asymptomatic women) can be positively managed by the correct use of hrHPV-DNA testing. Validated hrHPV-DNA testing and, specifically, the HC2® assay, due to its excellent sensitivity and negative predictive value together with optimal reproducibility, currently represent a powerful tool in the clinician's hands to optimally manage several situations related to HPV infection and the potential development of cervical cancer. [ABSTRACT FROM AUTHOR]

Objective: The present study aimed to assess long-term follow-up outcomes in women with in situ/microinvasive adenocarcinoma (AC) of the uterine cervix treated conservatively., Methods: Retrospective multi-institutional study including women with early glandular lesions and 5-year follow-up undergoing fertility-sparing treatment. Independent variables associated with recurrence were evaluated. Logistic regression analysis and Kaplan-Meier survival analysis with Logrank test were performed., Results: Of 269 women diagnosed with in situ/microinvasive AC, 127 participants underwent conservative treatment. During follow-up, recurrences were found in nine women (7.1%). The only factor associated with recurrence during follow-up was positive high-risk Human Papillomavirus (hr-HPV) testing (odds ratio 6.21, confidence interval 1.47-26.08, p = 0.012). HPV positivity in follow-up showed a recurrence rate of 21.7% against 3.8% in patients who were HPV-negative ( p = 0.002, Logrank test). Among women with negative high-risk HPV tests in follow-up, recurrences occurred in 20.0% of non-usual-type histology vs. 2.1% of usual-type cases ( p = 0.005)., Conclusion: HPV testing in follow-up is of pivotal importance in women with early glandular lesions undergoing conservative treatment, given its recurrence predictive value. However, women who are high-risk HPV-negative in follow-up with non-usual-type histopathology may represent a sub-population at increased risk of recurrences. Further studies should confirm these findings.

The World Health Organization (WHO) set the goal of 90% HPV vaccination coverage in the population to eliminate cervical cancer. Opportunistic vaccination is performed outside the free vaccination or catch-up programs. Both free and opportunistic HPV vaccination programs experienced slowdowns during the COVID-19 pandemic. In this retrospective study, we aimed to identify the benefits and the obstacles of opportunistic vaccination among male and female individuals who took advantage of the "on-demand" service offered by San Raffaele Hospital in Milan from April 2018 to May 2023. The impact that the COVID-19 pandemic had on vaccination adherence was also analyzed. Data on a total of 527 subjects were collected from an in-house database and through personal interviews. Women in the cohort of older patients (over 25) adhered to the vaccination schedule more than younger women. Opportunistic vaccination request is influenced by the need of a gynecologist, a general practitioner, or public health clinic availability. Women also showed good adherence to screening, demonstrating awareness of the importance of cervical cancer secondary prevention despite vaccination. Opportunistic vaccination offers the possibility of including individuals excluded from the free vaccination campaigns, often already affected by lesions caused by HPV, providing increased viral clearance and faster lesion regression. The main limit remains the economic burden.

Quality Control (QC) and Quality Assurance (QA) principles are essential for effective cervical cancer prevention. Being a crucial diagnostic step, colposcopy's sensitivity and specificity improvements are strongly advocated worldwide since inter- and intra-observer differences are the main limiting factors. The objective of the present study was the evaluation of colposcopy accuracy through the results of a QC/QA assessment from a survey in Italian tertiary-level academic and teaching hospitals. A web-based, user-friendly platform based on 100 colposcopic digital images was forwarded to colposcopists with different levels of experience. Seventy-three participants were asked to identify colposcopic patterns, provide personal impressions, and indicate the correct clinical practice. The data were correlated with a panel of experts' evaluation and with the clinical/pathological data of the cases. Overall sensitivity and specificity with the threshold of CIN2+ accounted for 73.7% and 87.7%, respectively, with minor differences between senior and junior candidates. Identification and interpretation of colposcopic patterns showed full agreement with the experts' panel, ranging from 50% to 82%, in some instances with better results from junior colposcopists. Colposcopic impressions correlated with a 20% underestimation of CIN2+ lesions, with no differences linked to level of experience. Our results demonstrate the good diagnostic performance of colposcopy and the need for improving accuracy through QC assessments and adhesion to standard requirements and recommendations.

It is unknown whether human papillomavirus (HPV) status impacts the prognosis of early stage cervical glandular lesions. This study assessed the recurrence and survival rates of in situ/microinvasive adenocarcinomas (AC) according to HPV status during a 5-year follow-up. The data were retrospectively analyzed in women with available HPV testing before treatment. One hundred and forty-eight consecutive women were analyzed. The number of HPV-negative cases was 24 (16.2%). The survival rate was 100% in all participants. The recurrence rate was 7.4% (11 cases, including four invasive lesions (2.7%)). Cox proportional hazards regression showed no difference in recurrence rate between HPV-positive and HPV-negative cases ( p = 0.148). HPV genotyping, available for 76 women and including 9/11 recurrences, showed a higher relapse rate for HPV-18 than HPV-45 and HPV-16 (28.5%, 16.6%, and 9.52%, p = 0.046). In addition, 60% and 75% of in situ and invasive recurrences, respectively, were HPV-18 related. The present study showed that most ACs were positive for high-risk HPV, and the recurrence rate was unaffected by HPV status. More extensive studies could help evaluate whether HPV genotyping may be considered for recurrence risk stratification in HPV-positive cases.

Objective: To evaluate the impact of healthcare reorganization during the severe acute respiratory syndrome coronavirus 2 pandemic on Italian colposcopy clinic activities, focusing on cervical excision procedures, follow-ups for conservative management of low-grade lesions, and follow-ups post cervical excision., Methods: Retrospective study conducted in 14 Italian colposcopy clinics. The number and clinical characteristics of cervical excisions, follow-ups for conservative management of low-grade lesions, and follow-ups after cervical excision were compared between the period March 1, 2019 to February 29, 2020 (pre-pandemic) and March 1, 2020 to February 28, 2021 (pandemic) with a Poisson regression analysis., Results: In the pandemic period, the number of cervical excisions was reduced by 8.8% (95% confidence interval [CI]=-15.6% to -2%; p=0.011). Excisions were less frequently performed in the operating room (-35.1%; 95% CI=-47.6% to -22.6%; p<0.001), the number of patients from spontaneous screening was reduced by -14.0% (95% CI=-23.4% to -4.6%; p=0.003), and the CO2-laser technique was used less frequently (-30%; 95% CI=-45.1% to -15.0%; p<0.001). As compared to the pre-pandemic period, the number of follow-ups for conservative management of low-grade lesions was reduced by -26.7% (95% CI=-39.0% to -14.4%; p<0.001), and the follow-up appointments after cervical excision were reduced by -51.0% (95% CI=-58.1% to -43.9%; p<0.001)., Conclusion: The most significant impact of the healthcare reorganization during the coronavirus disease 2019 pandemic was on follow-ups after cervical excision. The resumption of disrupted activities should follow a risk-based prioritization, starting from women in follow-up after cervical excision. It is advisable that the trend of performing cervical excision as an outpatient procedure is maintained in the post-pandemic period., Competing Interests: No potential conflict of interest relevant to this article was reported., (© 2023. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Objective: The objective of the present study was to investigate the potential prognostic role of neutrophil-lymphocyte ratio (NLR) in comparison with known parameters of prediction for the detection of recurrences of cervical intraepithelial neoplasia (CIN) after treatment., Methods: We retrospectively evaluated patients who underwent surgical treatment for CIN2, CIN3, and carcinoma in situ (CIN2+) between 2010 and 2019. NLR was recorded before surgery, and the follow-up records of patients were analyzed. Cases were splitted into two subgroups according to baseline NLR-low-NLR for <2 and high-NLR for ≥2 values of the index-and correlated with recurrences., Results: 428 cases fulfilled the criteria and were included in the study. Recurrence rate in patients with NLR <2.0 and NLR ≥2.0 was 15.2% and 27.3%, respectively, being the odd ratio for recurrence significantly higher in patients with NLR ≥2 (OR = 2.09; 95% CI 1.28-3.41; p = 0.003). A highly significant statistical difference in recurrence rate was demonstrated, in both univariate and multivariate, for surgical margins, follow-up HPV-DNA status, and NLR values., Conclusion: Preoperative NLR categorization is a strong independent prognostic factor for recurrences after surgical excision of CIN. NLR evaluation is a simple, reproducible, and cost-effective clinical instrument that could optimally be introduced in clinical practice in every setting., Competing Interests: The authors declare no potential conflict of interests and nothing to disclose., (Copyright © 2022 Massimo Origoni et al.)

Persistent positivity of HPV-DNA testing is considered a prognostic index of recurrent disease in patients treated for CIN2+. HPV detection, and particularly genotyping, has an adequate high rate of sensitivity and specificity (along with an optimal reproducibility), for accurately predicting treatment failure, allowing for an intensified monitoring activity. Conversely, women with a negative HPV-test 6 months after therapy have a very low risk for residual/recurrent disease, which leads to a more individualized follow-up schedule, allowing for a gradual return to the normal screening scheme. HPV testing should be routinely included (with or without cytology) in post-treatment follow-up of CIN2+ patients for early detection of recurrence and cancer progression. HPV genotyping methods, as a biological indicator of persistent disease, could be more suitable for a predictive role and risk stratification (particularly in the case of HPV 16/18 persistence) than pooled HPV-based testing. However, it is necessary to be aware of the performance of the system, adhering to strict standardization of the process and quality assurance criteria.

Background: Over the last two decades it has become clear that distinct types of human papillomavirus (HPV), the so-called high-risk types (hrHPV), are the major cause of cervical cancer. The hrHPV-DNA testing has shown excellent performance in several clinical applications from screening to the follow-up of conservatively treated patients., Methods: We conducted a systematic review of the recent literature on the performance of HPV DNA testing in follow-up after treatment of high-grade cervical lesions, adenocarcinoma in situ, and microinvasive carcinoma compared to Pap smear cytology., Results: Observational studies have demonstrated that the high risk hrHPV-DNA test is significantly more sensitive (95%) compared to follow-up cytology(70%) in detecting post-treatment squamous intraepithelial high-grade lesions. Moreover, in patients treated conservatively for cervical adenocarcinoma in situ, the hrHPV-DNA test is the most significant independent predictor of recurrent disease or progression to invasive cancer, and the combination of viral DNA testing and cytology reaches 90% sensitivity in detecting persistent lesions at the first follow-up visit and 100% at the second follow-up visit. The cause of microinvasive squamous cervical carcinoma is increasingly treated with conservative therapies in order to preserve fertility, and an effective strategy allowing early detection of residual or progressive disease has become more and more important in post-treatment follow-up. Primary results seem to indicate that the median time for viral clearance is relatively longer compared with patients treated for CIN and suggest a prolonged surveillance for these patients. However, the potential clinical value of HPV-DNA testing in this clinical setting needs to be confirmed by further observations., Conclusions: The excellent sensitivity, negative predictive value, and optimal reproducibility of the hrHPV DNA testing, currently is considered a powerful tool in the clinicians' hands to better manage post-treatment follow-up either in cervical squamous lesion or in situ adenocarcinoma.

Since the introduction of biomolecular testing for the identification of high-risk human papillomavirus DNA (hrHPV-DNA) in cervical cancer preventive strategies, many interesting aspects have emerged in this field; firstly, HPV-DNA testing has been demonstrated to have better sensitivity than conventional cytology in several settings: screening, triage of ASC-US and in follow-up after treatment. Despite this, some limitations of these new technologies have also been underlined: the major issue is the low specificity of the tests, which cannot discriminate between regressive and progressive infections. Thus, recent research has moved the attention towards novel markers of progression that could more precisely detect cases at real risk of cancer development. In view of the fact that progression to cancer is dependable of the E6/E7 proteins integration and transforming action, the overexpression of E6/E7 transcripts has been seen as a valuable marker of this risk. This review aims to summarise the literature data on this topic and to provide a clear view of the emerging perspectives.

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.

Pelvic pain is a common condition which significantly deteriorates health-related quality of life. The most commonly identified causes of pain in the pelvic region are gynaecologic, urologic, gastrointestinal, neurological, and musculoskeletal. However, in up to 33% of patients the source of this symptom is not identified, frustrating both patients and health-care professionals. Pelvic pain may involve both the somatic and visceral systems, making the differential diagnosing challenging. This paper aimed to review the mechanisms involved in pelvic pain perception by analyzing the neural plasticity and molecules which are involved in these complex circuits.

Strong evidence exists that the host's immune system plays a crucial role for the development of human papillomavirus-related cervical premalignant and malignant lesions. In particular, effective cell-mediated immunity (CMI) promotes spontaneous infection clearance and cancer precursors regression in healthy subjects, while immunosuppressed individuals are more likely to experience infection persistence, cervical intraepithelial neoplasia (CIN) lesions, and cervical cancer. In this study, the prognostic significance of immunohistochemical profiling of CD4+ T-cells, CD8+ T-cells, dendritic cells (CD11c+), T-bet+, and GATA-3+ transcription factors has been studied in surgical specimens of 34 consecutive women affected by high-grade cervical intraepithelial neoplasia (CIN2-3) submitted to cervical conization. Results have been correlated with the clinical outcomes at 24 months after treatment and statistically analyzed. Higher rates of CD4+ T-cells, CD11c+ dendritic cells, and T-bet+ transcription factor positivity showed a strong statistically significative correlation with favourable clinical outcomes (P ≤ 0.0001). These data reinforce the evidence of the relevance of the host's immune status in the natural history of HPV-related cervical disease and add a prognostic significance of the cervical immunological profile in terms of predicting significant lower recurrence rates.

Cervical neoplastic lesions are associated with infection by high-risk human papilloma-viruses (HPV). The two genotypes most frequently found in the lesions are HPV-16 and HPV-18 with a prevalence of 50-60% and 15-18%, respectively. The E6 and E7 viral oncoproteins are involved in the transformation process and represent foreign antigens for the host. We previously reported that anti-HPV-18 E6 CD4(+) T cells are present in patients with high-grade HPV-18-expressing cervical lesions but also in 50% of the total consecutive patients tested, independently of the HPV type carried. These results indicated that HPV-18 E6 is immunogenic and suggested that all responsive patients, irrespective of the HPV expressed, had encountered HPV-18 and cleared the infection. Here, we investigated anti-HPV-18 E7 CD4(+) T-cell immunity in a cohort of 23 HPV-18 E6-responsive patients. We found that, although E7-specific CD4(+) T cells were present in all women, a robust T helper type (Th1)/Th2 type response against E7 was associated with HPV-18-negative status, suggesting that indeed these patients might have cleared the virus. In agreement with this hypothesis, we found strong anti-E7 CD4(+) T-cell immunity in 20% of 24 healthy donors without evidence of disease. In contrast, a robust Th1/Th2 type response against E6 but not E7 correlated with a lack of disease relapse and/or infection recurrence but did not discriminate between HPV-18-positive and HPV-18-negative patients. Collectively, our data suggest different roles for anti-HPV-18 E6 and E7 CD4(+) T cells in anti-viral and anti-tumour immunity.

To determine the effect of highly active antiretroviral therapy (HAART) on high-risk human papillomavirus (HR-HPV) infections and related cervical lesions, the virologic and cytologic markers of HPV infection were prospectively studied in 163 human immunodeficiency virus (HIV)-infected women, including 27 untreated, 62 treated with reverse transcriptase inhibitors, and 74 treated with HAART. A high prevalence of both infections with HR-HPV types (68%) and squamous intraepithelial lesions (SILs; low grade, 20.2%; high grade, 6.2%) was observed. The risks of infection and disease were inversely correlated with CD4 cell counts (P=.015 and P=.022, respectively). During the observation period (mean, 15.4 months; range, 6-24 months), CD4 cell counts increased significantly only in subjects receiving HAART (P<.001). Persistence of HR-HPV infection and progression of SILs were comparable in the 3 groups. These results indicate that, even in the era of HAART, HIV-infected women should be monitored carefully for the emergence of high-grade SILs and cervical cancer.