Background: Recent studies have shown preliminary evidence that vaccination against human papillomavirus (HPV) could decrease the risk of persistent/recurrent HSIL in women treated for high-grade cervical intraepithelial lesion (HSIL). We aimed to determine the benefits of HPV vaccination in patients undergoing conization for HSIL in real-life conditions and evaluate vaccination compliance associated with different funding policies. Methods: From January 2013 to July 2018, 265 women underwent conization in our center. From January 2013 to July 2017, treated patients (n = 131) had to pay for the vaccine, whereas after July 2017 the vaccine was publicly funded and free for treated women (n = 134). Post-conization follow-up controls were scheduled every six months with a Pap smear, HPV testing, and a colposcopy. Results: 153 (57.7%) women accepted vaccination (vaccinated group), and 112 (42.3%) refused the vaccine (non-vaccinated group). Persistent/recurrent HSIL was less frequent in vaccinated than in non-vaccinated women (3.3% vs. 10.7%, p = 0.015). HPV vaccination was associated with a reduced risk of persistent/recurrent HSIL (OR 0.2, 95%CI: 0.1–0.7, p = 0.010). Vaccination compliance increased when the vaccine was publicly funded (from 35.9% [47/131] to 79.1% [106/134], p < 0.001). Conclusions: HPV vaccination in women undergoing conization is associated with a 4.5-fold reduction in the risk of persistent/recurrent HSIL. Vaccination policies have an important impact on vaccination compliance.

Background: Squamous intraepithelial lesions/cervical intraepithelial neoplasias (SIL/CIN) are high-risk human papilloma virus (hrHPV)-related lesions which are considered as high grade (HSIL/CIN2-3) or low grade (LSIL/CIN1) lesions according to their risk of progression to cervical cancer (CC). Most HSIL/CIN2-3 are considered as transforming hrHPV infections, so truly CC precursors, although some clear spontaneously. hrHPV testing has a high sensitivity for the detection of HSIL/CIN2-3 but a relatively low specificity for identifying transforming lesions. We aimed to determine whether the combination of CADM1, MAL and miR124 promoter methylation status assessed in histological samples can be used as a biomarker in the identification of transforming HSIL/CIN lesions. Design: 131 cervical biopsies, including 8 cases with no lesion and a negative hrHPV test result (control group), 19 low-grade (L)SIL/CIN1, 30 HSIL/CIN2, 60 HSIL/CIN3, and 14 CC were prospectively collected. hrHPV was detected and genotyped using the polymerase chain reaction (PCR)-based technique SPF10 HPV LIPA. A multiplex quantitative methylation-specific PCR (qMSP) was used to identify the methylation status of the CADM1, MAL, and miR124 promoter genes. Results: Significantly higher methylation levels of CADM1, MAL and miR-124 were found in HSIL/CIN2-3 and CC compared with normal and LSIL lesions. DNA methylation of at least one gene was detected in 12.5% (1/8) of normal samples, 31.5% (6/19) of LSIL/CIN1, 83.3% (25/30) of HSIL/CIN2, 81.6% (49/60) of HSIL/CIN3 and 100% (14/14) of CC (p < 0.001). The sensitivity and specificity for HSIL/CIN2-3 and CC of having at least one methylated gene were 84.6% and 74.0%, respectively. The sensitivity and specificity of the combination of at least one methylated gene and a positive hrHPV test were 80.7% and 85.1% for HSIL/CIN2-3 and CC, respectively. Conclusions: The methylation rate of CADM1, MAL and miR124 increases with the severity of the lesion. Further research is warranted to evaluate the usefulness of these biomarkers for the identification of transforming HSIL/CIN.

Penile squamous cell carcinoma (PSCC) is a rare but aggressive neoplasm with dual pathogenesis (human papillomavirus (HPV)-associated and HPV-independent). The development of targeted treatment is hindered by poor knowledge of the molecular landscape of PSCC. We performed a thorough review of genetic alterations of PSCC focused on somatic mutations and/or copy number alterations. A total of seven articles have been identified which, overall, include 268 PSCC. However, the series are heterogeneous regarding methodologies employed for DNA sequencing and HPV detection together with HPV prevalence, and include, in general, a limited number of cases, which results in markedly different findings. Reported top-ranked mutations involve TP53, CDKN2A, FAT1, NOTCH-1 and PIK3CA. Numerical alterations involve gains in MYC and EGFR, as well as amplifications in HPV integration loci. A few genes including TP53, CDKN2A, PIK3CA and CCND1 harbor both somatic mutations and copy number alterations. Notch, RTK-RAS and Hippo pathways are frequently deregulated. Nevertheless, the relevance of the identified alterations, their role in signaling pathways or their association with HPV status remain elusive. Combined targeting of different pathways might represent a valid therapeutic approach in PSCC. This work calls for large-scale sequencing studies with robust HPV testing to improve the genomic understanding of PSCC.

Introduction: Based on their etiological relationship with human papillomavirus (HPV), the 2020 WHO classification has divided vulvar squamous cell carcinomas (VSCC) into two distinct types, HPV‐associated and HPV‐independent, and HPV‐independent tumours have recently been divided according to p53 status. Nevertheless, the clinical and prognostic significance of this classification has not been clearly established. We analysed the differential clinical, pathological, and behavioural characteristics of these three types of VSCC in a large series of patients.Methods and results: VSCC samples from patients who underwent primary surgery at the Hospital Clinic of Barcelona, Spain, during a 47‐year period (January 1975 to January 2022) were analysed (n = 190). HPV detection, p16, and p53 immunohistochemical staining were evaluated. We also analysed recurrence‐free survival (RFS) and disease‐specific survival (DSS). Thirty‐three tumours (17.4%) were HPV‐associated and 157 (82.6%) HPV‐independent. Of these, 20 showed normal and 137 abnormal p53 expression. The two types of HPV‐independent tumours showed worse RFS in the multivariate analysis (hazard ratio [HR] = 3.63; P = 0.023 for the HPV‐independent p53 normal VSCC and HR = 2.78; P = 0.028 for the HPV‐independent p53 abnormal VSCC). Although the differences were not significant, HPV‐independent VSCC had worse DSS than HPV‐associated VSCC. Although patients with HPV‐independent p53 normal tumours had worse RFS than patients with HPV‐independent p53 abnormal tumours, the DSS was better for the former group. Only advanced FIGO stage was associated with worse DSS in multivariate analysis (HR = 2.83; P = 0.010).Conclusion: The association of HPV and p53 status have prognostic implications, reinforcing a three‐tier molecular classification of VSCC (HPV‐associated VSCC, HPV‐independent VSCC with normal p53, HPV‐independent VSCC with abnormal p53).

Human papillomavirus (HPV)-independent vulvar squamous cell carcinomas (VSCC) and its precursors frequently harbour TP53 mutations. Recently, six p53 immunohistochemical (IHC) patterns have been defined, which have shown strong correlation with TP53 mutation status. However, few studies have applied this new six-pattern framework and none of them exhaustively compared p53 IHC positivity and patterns between invasive VSCC and adjacent skin lesion. We performed p53 IHC in a series of 779 HPV-independent VSCC with adjacent skin and evaluated the IHC slides following the newly described classification. Some 74.1% invasive VSCC showed abnormal p53 IHC staining. A skin lesion was identified in 450 cases (57.8%), including 254 intraepithelial precursors and 196 inflammatory/reactive lesions. Two hundred and ten of 450 (47%) VSCC with associated skin lesions showed an abnormal p53 IHC stain, with an identical staining pattern between the VSCC and the adjacent skin lesion in 80% of the cases. A total of 144/450 (32%) VSCC showed wild-type p53 IHC both in the invasive VSCC and adjacent skin lesion. Finally, 96/450 (21%) VSCC showed p53 IHC abnormal staining in the invasive VSCC but a wild-type p53 staining in the skin lesion. Most of the discordant cases (70/96; 73%) showed adjacent inflammatory lesions. In conclusion, the p53 IHC staining and pattern are usually identical in the VSCC and the intraepithelial precursor.

Postmortem studies are crucial for providing insight into emergent diseases. However, a complete autopsy is frequently not feasible in highly transmissible diseases due to biohazard challenges. Minimally invasive autopsy (MIA) is a needle-based approach aimed at collecting samples of key organs without opening the body, which may be a valid alternative in these cases. We aimed to: (a) provide biosafety guidelines for conducting MIAs in COVID-19 cases, (b) compare the performance of MIA versus complete autopsy, and (c) evaluate the safety of the procedure. Between October and December 2020, MIAs were conducted in six deceased patients with PCR-confirmed COVID-19, in a basic autopsy room, with reinforced personal protective equipment. Samples from the lungs and key organs were successfully obtained in all cases. A complete autopsy was performed on the same body immediately after the MIA. The diagnoses of the MIA matched those of the complete autopsy. In four patients, COVID-19 was the main cause of death, being responsible for the different stages of diffuse alveolar damage. No COVID-19 infection was detected in the personnel performing the MIAs or complete autopsies. In conclusion, MIA might be a feasible, adequate and safe alternative for cause of death investigation in COVID-19 cases.