The Role of ß1 Integrin/CD29 as a Potential Prognostic Factor for the Risk of Progression to Cervical Carcinoma in HPV-Associated Lesions.

Background and Objectives: Available evidence reports the overexpression of ß1 integrin in dysplastic rather than normal cervical tissue. We aimed to evaluate the involvement of ß1 (CD29) integrin in the progressive pathogenesis of cervical intraepithelial neoplasia (CIN). Materials and Methods: From January 2019 to December 2021, we prospectively enrolled women undergoing a colposcopy with a cervical biopsy for abnormal cervical cytology and/or undefined cytology with a positive HPV DNA test and women with relapsing cervical inflammatory disorders. Based on the histopathological results, women were divided into four groups: group A (CIN1), group B (CIN2), group C (CIN3), and group D (no CIN diagnosis) as a control group. Subsequently, cytofluorimetry and immunohistochemical analysis (based on the identified positive cell ratios as follows: ≤10%, negative; 10-25%, 1+ (weak); 25-50%, 2+ (medium); ≥50%, and 3+ (high)) for ß1 integrin were carried out. Results: In total, 154 women were included. The average fluorescence intensity in the four groups was 2.35 ± 1.37, 2.73 ± 1.56, 3.09 ± 1.56, and 2.13 ± 1.25 UA from groups A to D, respectively; this figure was significantly different for CIN3 (group C) women relative to the other groups (p = 0.0132). Higher ß1 integrin/CD29 concentrations in the CIN groups with HR-HPV 16 and 18 were also detected (p = 0.0292, 0.0367, and 0.0357 respectively for CIN3, CIN2, and CIN1). Immunohistochemistry analysis showed higher results for the CIN3 group compared to controls and all the other groups (p < 0.001). Conclusions: ß1/CD29 integrin expression increased with CIN grade, and it was significantly higher in CIN3 lesions. This could be used as a promising screening tool to identify women prone to developing high-grade cervical lesions. However, additional evidence is needed to strengthen these findings.

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.

Sparing Is Caring: Hormonal Retreatment in Women with Recurrent Endometrial Cancer after Fertility Preservation Management-A Single Centre Retrospective Study.

Fertility-sparing treatment (FTS) of endometrial cancer (EC) has a high rate of remission but also a high rate of relapse (10-88%). Many women still wish to conceive at the time of relapse, but results regarding retreatment are still lacking. This study aims to evaluate the safety, oncological and pregnancy outcomes of repeated FST in women with recurrent EC. This is a retrospective single-center study that recruited patients who had uterine recurrence after achieving a complete response (CR) with FST for FIGO stage IA, well-differentiated (G1), endometrioid EC. All eligible women underwent a second FST. Among 26 patients with recurrence, 6 decided to receive a hysterectomy and 20 received fertility-sparing retreatment. In total, 17 out of 20 women (85%) achieved a CR in a median time of 6 months. A total of 2/20 women showed a stable disease and continued the treatment for a further 6 months and finally achieved a CR. In total, 1/20 women showed disease progression and underwent demolitive surgery. After relapse and a CR, 14 patients attempted to become pregnant, among whom 7 became pregnant (pregnancy rate 50%-life birth rate 29%). Secondary FST is a safe and effective option for women who desire to preserve fertility after the recurrence of early-stage EC.

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.

HPV Tests Comparison in the Detection and Follow-Up after Surgical Treatment of CIN2+ Lesions.

BACKGROUND: HPV tests differ for technology, targets, and information on genotyping of high risk (HR) HPV. In this study, we evaluated the performance of 6 HPV DNA tests and one mRNA test in the detection of cervical intraepithelial lesions (CIN) and as a test-of-cure in the follow-up after surgical conservative treatment. METHODS: One hundred seventy-two women referred to the European Institute of Oncology, Milan, for surgical treatment of pre-neoplastic cervical lesions, were enrolled in this study (IEO S544) from January 2011 to June 2015. For all women, a cervical sample was taken before treatment (baseline) and at the first follow-up visit (range 3 to 9 months): on these samples Qiagen Hybrid Capture 2 (HC2), Roche Linear Array HPV Test (Linear Array), Roche Cobas 4800 HPV test (Cobas), Abbott RealTime High Risk HPV test (RT), BD Onclarity HPV assay (Onclarity), Seegene Anyplex II HPV HR Detection (Anyplex), and Hologic Aptima HPV Assay (Aptima) histology and cytology were performed at baseline, and the same tests and cytology were performed at follow-up. RESULTS: At baseline 158/172 (92%), histologies were CIN2+, and 150/172 (87%) women were recruited at follow-up. Assuming HC2 as a comparator, the concordance of HPV tests ranges from 91% to 95% at baseline and from 76% to 100% at follow-up (PABAK ranging from 0.81 to 0.90 at baseline and PABAK ranging from 0.53 to 1 at follow-up). All HPV showed a very good sensitivity in CIN2+ detection at baseline, more than 92%, and a very good specificity at follow-up, more than 89%. CONCLUSIONS: HPV tests showed a good concordance with HC2 and a very good and comparable sensitivity in CIN2+ detection. Hence, an HPV test represents a valid option as test-of-cure in order to monitor patients treated for CIN2+ lesions during follow-up.

Fertility-Sparing Treatment for Endometrial Cancer: Oncological and Obstetric Outcomes in Combined Therapies with Levonorgestrel Intrauterine Device.

BACKGROUND: The prevalence of reaches up to 5% in women younger than 40 years. Therefore, the fertility preservation should be the goal of the clinical practice in women with desire of pregnancy and low-risk features. The aim of this study is to compare oncological and reproductive outcomes of different hormonal therapies in FST of EC. METHODS: A retrospective single-center study recruiting patients with presumed FIGO STAGE IA endometrioid G1 EC from 2005 to 2020 was performed. We assessed outcomes for three different therapeutic options: GnRHa + LNG-IUD vs. MA + LNG-IUD vs. MA + LNG-IUD + MET. RESULTS: In total, 75 patients were enrolled and followed up for a median of 45 months. Complete response (CR) was achieved in 75% of patients at 12 months. Although not statistically significant, we reported an increasing rate of CR from the regimen with GnRHa to the one with MA + MET (65% vs. 83%). We showed a statistically significant lower risk of recurrence in women treated with MA + LNG-IUD + MET, when compared to GnRHa + LNG-IUD regimen. The pregnancy rate was 74% and live birth rate was 42%, with no differences among regimens. CONCLUSIONS: FST is a safe and effective option in women who desire to preserve fertility.

Human Papillomavirus Same Genotype Persistence and Risk of Cervical Intraepithelial Neoplasia2+ Recurrence.

To evaluate the significance of HPV persistence as a predictor for the development of CIN2+ recurrence and the impact of multiple genotypes and of HPV 16/18 on recurrence risk. A prospective cohort observational study was carried out at the European Institute of Oncology, Milan, Italy, from December 2006 to December 2014. A total of 408 women surgically treated by excisional procedure for pre-neoplastic and neoplastic cervical lesions were enrolled. HPV test was performed at baseline and at first follow-up visit planned at 6 ± 3 months after treatment. Two-year cumulative incidences for relapse were estimated and compared by the Gray's test. Overall, 96 (23.5%) patients were persistent for at least one genotype at three to nine months from baseline and 21 (5.1%) patients relapsed. The two-year cumulative relapse incidence was higher in HPV persistent patients compared to not-persistent (CIF = 27.6%, 95% CI: 16.2-40.2% versus CIF = 1.7%, 95% CI: 0.3-5.8%, p < 0.001), in women with persistent multiple infections (CIF = 27.2%, 95% CI: 7.3-52.3%, p < 0.001), and with the persistence of at least one genotype between 16 and 18, irrespective of the presence of other HR genotypes (CIF = 32.7%, 95% CI: 17.9-48.3%, p < 0.001), but not significantly different from women positive for single infections or any other HR genotype, but not for 16 and 18. The risk of CIN2+ recurrence should not be underestimated when same HPV genotype infection persists after treatment.

Anyplex II HPV test in detection and follow-up after surgical treatment of CIN2+ lesions.

Human papillomavirus (HPV) tests differ for technology, targets, and information on the genotype and viral load. In this study, we evaluated the performance of the Seegene Anyplex II HPV HR (Anyplex) assay in the detection of cervical intraepithelial lesions (CIN) and as a test-of-cure in the follow-up after surgical treatment. One hundred and sixty-seven women referred to the European Institute of Oncology, Milan, for surgical treatment of CIN2+ were enrolled. A cervical sample was taken before treatment and at the first follow-up visit: on these samples, Qiagen Hybrid Capture 2 (HC2), Roche Linear Array HPV Test (Linear Array), cytology and histology were performed at baseline, HC2, and cytology at follow-up. Anyplex genotyping HPV test was performed on a post aliquot from liquid-based cytology specimens when available. The concordance between Anyplex and HC2 was 93.6% at baseline and 76.7% at follow-up (3-9 months after treatment), respectively. The concordance between Anyplex and Linear Array was evaluable only at baseline (92.9%). No recurrence occurred in women without the persistence of the same genotype at follow-up. Seven women relapsed: six had persistence of the same genotypes (five HPV16, one HPV33, and one HPV39), while one tested negative not only with Anyplex but also with HC2 for the persistence of low-risk genotype infection (HPV73 only detected by Linear Array). Anyplex test represents a valid option for HPV detection and genotyping in order to stratify women at risk of high-grade lesions at baseline and to monitor patients treated for CIN2+ lesions during follow-up.

Distribution of High-Risk Human Papillomavirus Genotypes and Multiple Infections in Preneoplastic and Neoplastic Cervical Lesions of Unvaccinated Women: A Cross-sectional Study.

OBJECTIVE: The aim of the study was to investigate the distribution of high-risk (HR) human papillomavirus (HPV) genotypes and the role of multiple infection in preneoplastic and neoplastic cervical lesions, according to histology, age, and the number of genotypes per infection. MATERIALS AND METHODS: Nine hundred eighty-eight women affected by known HPV-related cervical lesions and attending the European Institute of Oncology, Milan, Italy, from December 2006 to December 2014, were selected for a cross-sectional study. Prevalence of HPV genotypes was calculated by histology and the number of genotypes per infection. Univariate and multivariable cervical intraepithelial neoplasia (CIN) 2-3 versus CIN 1 risks were estimated by logistic regression models. RESULTS: Overall, HPV 16 (53.1%), HPV 31 (15.1%), and HPV 58 (6.4%) were the most frequent genotypes in precancerous lesions. At multivariable analysis, HPV 16 (p = .02), 18 (p = .013), and 56 (p = .01) were significantly associated to worsen histology, whereas HPV 39 (p = .03) and 45 (p = .03) were statistically correlated only to the increasing number of genotypes per infections. Human papillomavirus 33 was the only genotype significantly related to both the number of genotypes per infection (p = .005) and age (p = .03). Infections by HR-HPV (odds ratio [OR] = 9.48, 95% CI = 3.77-23.8, p < .001), HPV genotypes covered by current vaccines (OR = 6.28, 95% CI = 4.05-9.75, p < .001), single HPV genotype (OR = 8.13, 95% CI = 4.12-16.0, p < .001), as well as age (OR = 1.13, 95% CI = 1.07-1.19, p < .001) were significantly associated to higher risk of CIN 2-3. CONCLUSIONS: The most of CIN 2+ lesions are sustained by HR-HPV genotypes, especially the ones covered by 9-valent vaccine; therefore, the widespread use of prophylactic HPV vaccines could significantly reduce the incidence of preneoplastic and neoplastic cervical lesions.

Onclarity Human Papillomavirus Extended Genotyping in the Management of Cervical Intraepithelial Neoplasia 2+ Lesions.

OBJECTIVE: Many methods are available today for human papillomavirus (HPV) testing; they differ for technology, targets, and information on the genotypes detected. In this study, we evaluated the performance of the Onclarity HPV assay in detection and follow-up of cervical preneoplastic lesions. MATERIALS AND METHODS: One hundred sixty-seven women referred to the European Institute of Oncology, Milan, for treatment of cervical lesions were enrolled. We investigated the utility of Onclarity extended genotyping HPV test in the management of cervical intraepithelial neoplasia (CIN) 2+ preneoplastic lesion. RESULTS: At baseline, the concordance was 92% (150/163) between Onclarity and Hybrid Capture 2 (HC2) and 93% (142/152) between Onclarity and linear array, respectively. At follow-up, the concordance between Onclarity and HC2 was 80%. Seven women relapsed: 6 had persistence of the same genotypes and 1 patient tested negative not only with Onclarity but also with HC2 for the presence of a low-risk genotype in the sample. CONCLUSIONS: This study showed that the evaluation of the HPV genotype persistence may represent a valid option to monitor patients treated for CIN 2+ lesions, because relapses were detected only in patients with persistence of the same genotype detected at baseline.

The Role of Photodynamic Therapy in the Treatment of Vulvar Intraepithelial Neoplasia.

BACKGROUND: vulvar intraepithelial neoplasia is a non-invasive precursor lesion found in 50-70% of patients affected by vulvar squamous cell carcinoma. In the past, radical surgery was the standard treatment for vulvar intraepithelial neoplasia, however, considering the psychological and physical morbidities related to extensive surgery, several less aggressive treatment modalities have been proposed since the late 1970s. Photodynamic therapy is an effective and safe treatment for cutaneous non-melanoma skin cancer, with favorable cosmetic outcomes. METHODS: in the present paper, the results of selected studies on photodynamic therapy in the treatment of vulvar intraepithelial neoplasia are reported and discussed. RESULTS: Overall, complete histological response rates ranged between 20% and 67% and symptom response rates ranged between 52% and 89% according to different studies and case series. CONCLUSIONS: the real benefit of photodynamic therapy in the setting of vulvar intraepithelial neoplasia lies in its ability to treat multi-focal disease with minimal tissue destruction, preservation of vulvar anatomy and excellent cosmetic outcomes. These properties explain why photodynamic therapy is an attractive option for vulvar intraepithelial neoplasia treatment.

Conization in Early Stage Cervical Cancer: Pattern of Recurrence in a 10-Year Single-Institution Experience.

OBJECTIVE: The main objective of this study was to analyze the pattern of recurrence after conization and pelvic lymphadenectomy in early-stage cervical cancer (CC). METHODS: We retrospectively identified 60 patients with early-stage CC who referred to the European Institute of Oncology (IEO; Milan, Italy) for fertility-sparing surgery. All of them underwent conization and pelvic lymphadenectomy (one received neoadjuvant chemotherapy followed by simple trachelectomy because of the size of the tumor). RESULTS: In total, 54 patients were considered for final analysis; only 23 patients were entirely treated at IEO. Relapse occurred in 7 (13%) of 54 patients, and in 6 cases (86%) it was local. One patient experienced a pelvic lymph node recurrence (in a woman who conceived 4 months after conservative surgery). However, this was an atypical case for site and timing of recurrence with the consistent doubt that the nodal involvement was already present before conization. Thus, analyzing only IEO population, the recurrence rate was lower (9%), becoming 4% excluding the atypical case with nodal involvement. CONCLUSIONS: In our series, the relapse was mainly local (on the cervix). However, the pattern of recurrence and recurrence rates after conization and pelvic lymphadenectomy for early-stage CC are still unclear. Further studies, comparing conization with radical trachelectomy, are necessary to confirm that the adoption of this procedure in clinical practice is safe. Our data highlight that the management of such as a particular condition in dedicated and highly specialized centers is mandatory.

Fertility-Sparing Options in Young Women with Cervical Cancer.

OPINION STATEMENT: Cervical cancer (CC) is the fourth most frequent tumor and the fourth most common cause of cancer death among women worldwide. Furthermore, more than 40 % of women with early CC are affected during reproductive age and wish to remain fertile. Thus, many patients demand a more conservative policy for managing these lesions in order to have an uneventful pregnancy in the near future. For this reason, interest in fertility preservation strategies has been increasing, and the number of published studies on this topic has grown significantly. Conization was the first fertility-sparing surgical procedure tested in stage IA1 CC. However, in recent decades, other strategies have been tested, particularly for more advanced tumors. The aim of this review is to analyze the main techniques performed in patients with CC who are eligible for fertility-sparing surgery, with particular attention paid to open questions and controversies.