Microbiome-derived cobalamin and succinyl-CoA as biomarkers for improved screening of anal cancer.

Human papillomavirus can cause preinvasive, high-grade squamous intraepithelial lesions (HSILs) as precursors to cancer in the anogenital area, and the microbiome is suggested to be a contributing factor. Men who have sex with men (MSM) living with human immunodeficiency virus (HIV) have a high risk of anal cancer, but current screening strategies for HSIL detection lack specificity. Here, we investigated the anal microbiome to improve HSIL screening. We enrolled participants living with HIV, divided into a discovery (n = 167) and validation cohort (n = 46), and who were predominantly (93.9%) cisgender MSM undergoing HSIL screening with high-resolution anoscopy and anal biopsies. We identified no microbiome composition signatures associated with HSILs, but elevated levels of microbiome-encoded proteins producing succinyl coenzyme A and cobalamin were significantly associated with HSILs in both cohorts. Measurement of these candidate biomarkers alone in anal cytobrushes outperformed anal cytology as a diagnostic indicator for HSILs, increasing the sensitivity from 91.2% to 96.6%, the specificity from 34.1% to 81.8%, and reclassifying 82% of false-positive results as true negatives. We propose that these two microbiome-derived biomarkers may improve the current strategy of anal cancer screening.

Human monkeypox virus infection in women and non-binary individuals during the 2022 outbreaks: a global case series.

BACKGROUND: Between May and November, 2022, global outbreaks of human monkeypox virus infection have been reported in more than 78 000 people worldwide, predominantly in men who have sex with men. We describe the epidemiological and clinical characteristics of monkeypox virus infection in cisgender (cis) and transgender (trans) women and non-binary individuals assigned female sex at birth to improve identification and understanding of risk factors. METHODS: International collaborators in geographical locations with high numbers of diagnoses of monkeypox virus infection were approached and invited to contribute data on women and non-binary individuals with confirmed monkeypox virus infection. Contributing centres completed deidentified structured case-report spreadsheets, adapted and developed by participating clinicians, to include variables of interest relevant to women and non-binary individuals assigned female at birth. We describe the epidemiology and clinical course observed in the reported infections. FINDINGS: Collaborators reported data for a total of 136 individuals with monkeypox virus infection who presented between May 11 and Oct 4, 2022, across 15 countries. Overall median age was 34 years (IQR 28-40; range 19-84). The cohort comprised 62 trans women, 69 cis women, and five non-binary individuals (who were, because of small numbers, grouped with cis women to form a category of people assigned female at birth for the purpose of comparison). 121 (89%) of 136 individuals reported sex with men. 37 (27%) of all individuals were living with HIV, with a higher proportion among trans women (31 [50%] of 62) than among cis women and non-binary individuals (six [8%] of 74). Sexual transmission was suspected in 55 (89%) trans women (with the remainder having an unknown route of transmission) and 45 (61%) cis women and non-binary individuals; non-sexual routes of transmission (including household and occupational exposures) were reported only in cis women and non-binary individuals. 25 (34%) of 74 cis women and non-binary individuals submitted to the case series were initially misdiagnosed. Overall, among individuals with available data, rash was described in 124 (93%) of 134 individuals and described as anogenital in 95 (74%) of 129 and as vesiculopustular in 105 (87%) of 121. Median number of lesions was ten (IQR 5-24; range 1-200). Mucosal lesions involving the vagina, anus, or oropharynx or eye occurred in 65 (55%) of 119 individuals with available data. Vaginal and anal sex were associated with lesions at those sites. Monkeypox virus DNA was detected by PCR from vaginal swab samples in all 14 samples tested. 17 (13%) individuals were hospitalised, predominantly for bacterial superinfection of lesions and pain management. 33 (24%) individuals were treated with tecovirimat and six (4%) received post-exposure vaccinations. No deaths were reported. INTERPRETATION: The clinical features of monkeypox in women and non-binary individuals were similar to those described in men, including the presence of anal and genital lesions with prominent mucosal involvement. Anatomically, anogenital lesions were reflective of sexual practices: vulvovaginal lesions predominated in cis women and non-binary individuals and anorectal features predominated in trans women. The prevalence of HIV co-infection in the cohort was high. FUNDING: None.

IL-15/IL-15Rα in SJS/TEN: Relevant Expression of IL15 and IL15RA in Affected Skin.

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a life-threatening hypersensitivity reaction to medications characterized by keratinocyte apoptosis and skin detachment. IL-15 serum levels have been associated with severity and prognosis of SJS/TEN. We have measured IL-15 concentrations in serum and blister fluid (BF) from patients with SJS/TEN by ELISA and used quantitative RT-PCR to analyze the expression of IL15 and IL15RA (encoding for IL-15 Receptor-α chain) genes in peripheral blood and BF cells, including isolated monocytes, and in affected skin. A positive correlation was found between IL-15 serum levels and a percent of detached skin. BF concentrations were higher, but no correlation was found. Higher IL15 and IL15RA gene expression levels were found in skin-infiltrating blister fluid cells compared to peripheral mononuclear cells. Moreover, IL15RA transcripts were barely detected in healthy skin, being the highest expression levels found in samples from two SJS/TEN patients who did not survive. The cutaneous expression of IL-15Rα in SJS/TEN may provide an explanation to the tissue-specific immune cytotoxic response in this clinical entity, and the results suggest that the effects of IL-15 in SJS/TEN patients may be dependent on the expression of its private receptor IL-15Rα in affected skin.

Monkeypox Virus Infection in Humans across 16 Countries - April-June 2022.

BACKGROUND: Before April 2022, monkeypox virus infection in humans was seldom reported outside African regions where it is endemic. Currently, cases are occurring worldwide. Transmission, risk factors, clinical presentation, and outcomes of infection are poorly defined. METHODS: We formed an international collaborative group of clinicians who contributed to an international case series to describe the presentation, clinical course, and outcomes of polymerase-chain-reaction-confirmed monkeypox virus infections. RESULTS: We report 528 infections diagnosed between April 27 and June 24, 2022, at 43 sites in 16 countries. Overall, 98% of the persons with infection were gay or bisexual men, 75% were White, and 41% had human immunodeficiency virus infection; the median age was 38 years. Transmission was suspected to have occurred through sexual activity in 95% of the persons with infection. In this case series, 95% of the persons presented with a rash (with 64% having ≤10 lesions), 73% had anogenital lesions, and 41% had mucosal lesions (with 54 having a single genital lesion). Common systemic features preceding the rash included fever (62%), lethargy (41%), myalgia (31%), and headache (27%); lymphadenopathy was also common (reported in 56%). Concomitant sexually transmitted infections were reported in 109 of 377 persons (29%) who were tested. Among the 23 persons with a clear exposure history, the median incubation period was 7 days (range, 3 to 20). Monkeypox virus DNA was detected in 29 of the 32 persons in whom seminal fluid was analyzed. Antiviral treatment was given to 5% of the persons overall, and 70 (13%) were hospitalized; the reasons for hospitalization were pain management, mostly for severe anorectal pain (21 persons); soft-tissue superinfection (18); pharyngitis limiting oral intake (5); eye lesions (2); acute kidney injury (2); myocarditis (2); and infection-control purposes (13). No deaths were reported. CONCLUSIONS: In this case series, monkeypox manifested with a variety of dermatologic and systemic clinical findings. The simultaneous identification of cases outside areas where monkeypox has traditionally been endemic highlights the need for rapid identification and diagnosis of cases to contain further community spread.

Analysis of the prevalence of human papillomavirus and abnormal anal cytology in women at risk.

Our aim was to analyze the association between anal human papillomavirus (HPV) infection and abnormal anal cytology in women with high-grade cervical intraepithelial neoplasia (CIN 2+). We also analysed what other risk factors might be significant. We carried out a prevalence study from April 2015 to March 2017 at La Paz University Hospital. Genotyping of HPV, anal cytology and high-resolution anoscopy were performed. Of 171 patients recruited, 53 cases (31%) were diagnosed as histological CIN 2+: there were no statistically significant differences in the prevalence of anal HPV (OR = 0.8), nor the prevalence of abnormal anal cytology (OR = 2.15, 95% CI 0.8-5.7) compared to women with CIN 1 or no cervical dysplasia. Immunosuppression (OR = 2.51, 95% CI 1-6.3, p < .05), cervical HPV (OR = 3.9, 95% CI 1.9-8.0, p < .01) and being older than 40 years old (p < .05) were also associated with anomalous anal results.Impact StatementWhat is already known on this subject? Anal HR-HPV and abnormal anal cytology may precede anal intraepithelial neoplasia (AIN): a premalignant lesion that may progress to anal cancer. It is known that there are four populations which present a higher risk of developing anal cancer compared to the general population: human immunodeficiency virus (HIV)-positive patients, other immunocompromised populations, men who have sex with men and women with a history of disease secondary to HPV infection.What do the results of this study add? This study allowed us to compare the prevalence of anal HPV and abnormal anal cytology in women with CIN 2+: it analysed whether these women already presented alterations in anal tests at the moment of the diagnosis of the preneoplastic cervical lesion. It also provides information for the management of the populations at a higher risk of developing anal cancer; specifically, the group of women with a prior history of HPV-associated anogenital disease.What are the implications of these findings for clinical practice and/or further research? Our findings improve the existing evidence on anal HPV infection and anal cytology on the least studied population at risk. Data could be useful for further research in order to clarify the role of anal screening in this population and standardise the clinical practice.

Screening for precancerous anal lesions with P16/Ki67 immunostaining in HIV-infected MSM.

BACKGROUND: Screening of anal cancer in HIV-infected MSM with anal cytology results in high rates of false positive results and elevated burden of high-resolution anoscopies. High-risk HPV up-regulates p16 and Ki67 expression in epithelial cells. We assessed the usefulness of P16/Ki-67 immunostaining cytology for the diagnosis of precancerous anal lesions. METHODOLOGY: Cross-sectional multicenter study. Concomitant anal liquid cytology with p16/Ki-67 immunostaining and HRA with biopsy of acetowhite lugol-negative lesions was performed in HIV-infected MSM. We compared the diagnostic performance of an abnormal anal cytology and p16/Ki-67 immunostaining relative to HRA-guided biopsy by logistic regression and comparison of ROC areas. RESULTS: We included 328 HIV-infected MSM. HSIL was histologically diagnosed in 72 subjects (25.1%), and 2 (0.6%) were diagnosed with anal cancer. An abnormal cytology showed a sensitivity of 95.6% and a specificity of 58.8% for the diagnosis of biopsy-proven HSIL. P16/Ki67 positivity was associated with the presence of biopsy-proven HSIL (P trend = 0.004) but with low sensitivity (41.2%) and specificity (71%). The combination of standard cytology with P16/Ki67 immunostaining did not increment the predictive value of standard cytology alone (AUC 0.685 vs. 0.673, respectively, P = 0.688). CONCLUSION: In HIV-infected MSM P16/Ki67 immunostaining does not improve the diagnostic accuracy of anal cytology, which shows a high sensitivity yet poor specificity. Other approaches aimed at improving the diagnostic accuracy of current techniques for the diagnostic of precancerous HSIL are warranted.

Topical cidofovir to treat high-grade anal intraepithelial neoplasia in HIV-infected patients: a pilot clinical trial.

OBJECTIVE: To evaluate the efficacy of 1% topical cidofovir cream for the treatment of anal high-grade squamous intraepithelial lesions (HSILs) in HIV-infected individuals. DESIGN: Single-arm, open-label, pilot clinical trial. METHODS: The study medication was applied intraanally three times per week for 4 weeks. Lesions were assessed with high-resolution anoscopy and biopsy at weeks 12 and 24. The primary endpoint was complete remission (CR) at week 12, defined as clinical and histological remission. We also evaluated partial remission defined as regression to low-grade squamous intraepithelial lesion. RESULTS: We included 17 HIV-infected patients with intraanal HSIL. Median (interquartile range) age was 36 years (28-41), median (interquartile range) CD4 cell count was 545 cells/µl (358-630), and viral load was less than 50  copies/ml in 93.7%. Two patients were lost to follow-up, one of them did not apply treatment. At 12 weeks, in the intention-to-treat population, 10 out of 16 patients [62.5%; 95% confidence interval (CI), 38.2-85.7%] had achieved CR. At 24 weeks, seven of the 10 patients (70%; 95% CI, 47-93%) remained in CR, but two out of 10 patients (20%; 95% CI, 0-40%) presented HSIL. One patient did not attend the visit at 24 weeks. Three patients with persistent HSIL at 12 weeks improved at 24 weeks (partial response in one and CR in two). The mean number of human papillomavirus genotypes decreased from 5.2 to 2.7 at 12 weeks (P = 0.002). Local adverse effects were frequent (81%), although there were no discontinuations because of adverse events. CONCLUSION: One percent topical cidofovir could be an appropriate alternative therapy in HIV-infected patients with anal HSIL. CLINICAL TRIAL: gov unique identifier: NCT01946009.

Human papillomavirus mRNA testing for the detection of anal high-grade squamous intraepithelial lesions in men who have sex with men infected with HIV.

Currently, screening for anal high-grade squamous intraepithelial lesions (anal HSIL) relies on anal cytology and high-resolution anoscopy. Since this approach has limited sensitivity and specificity for detecting anal HSIL, there is increasing interest in the role of biomarkers for predicting anal HSIL. The aim of this study is to evaluate the diagnostic accuracy of HPV E6/E7-mRNA expression for the detection of anal HSIL in MSM infected with HIV, in comparison to DNA-HR-HPV and anal cytology. This cross-sectional screening study included 101 MSM followed at the HIV-unit of La Paz University Hospital. Intra-anal swabs from patients participating in a screening program including cytology, high-resolution anoscopy and histology were analyzed. HR-HPV-DNA detection was performed by means of the CLART® HPV2 assay (GENOMICA S.A.U., Madrid, Spain). E6/E7-mRNA detection of HR-HPV-types 16, 18, 31, 33, and 45 was performed using the NucliSENS-EasyQ assay (BioMérieux, Marcy lEtoile, France). HR-HPV DNA and HPVE6/E7 mRNA were detected in 82% and 57% of the anal smears respectively. Anal cytology screening was abnormal in 70.3%. For the detection of HSIL sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 71.7%, 55.6%, 57.9%, and 69.8% for E6/E7-mRNA testing, respectively, compared to 100%, 31.5%, 55.4%, and 100% for HR-HPV-DNA testing and to 83%, 40.7%, 54.9%, 73.3% of cytology testing. In comparison with the other tests, HPVE6/E7 mRNA testing yielded a lower clinical sensitivity but a higher clinical specificity and PPV for the detection of anal HSIL in MSM infected with HIV.

Prevalence of abnormal anal cytology and high-grade squamous intraepithelial lesions among a cohort of HIV-infected men who have sex with men.

BACKGROUND: The incidence of anal cancer among HIV-infected patients is higher than that in other populations. Anal high-grade squamous intraepithelial lesions are considered precursors to invasive squamous-cell carcinomas and are strongly associated to high-risk human papillomavirus infection. OBJECTIVE: The aim of this study is to determine the prevalence of anal high-grade squamous intraepithelial lesions through screening based on cytology and high-resolution anoscopy with biopsy in a cohort of HIV-infected men who have sex with men. DESIGN: This investigation is an observational cross-sectional cohort study. SETTING: The study was conducted in the HIV unit of a tertiary hospital in Spain. PATIENTS: Three hundred HIV-infected men who have sex with men participated. Physical examination led to a diagnosis of perianal squamous-cell carcinoma and high-grade squamous intraepithelial lesions in 2 patients who were then excluded. INTERVENTIONS: Anal liquid cytology was performed. Patients with cytological abnormalities underwent high-resolution anoscopy and biopsy. MAIN OUTCOME MEASURE: The primary outcome measured was biopsy-proven high-grade squamous intraepithelial lesions. RESULTS: The median age was 41 ± 10.5 years. The mean and nadir CD4 cell counts were 651 ± 205 cells/mm(3) (interquartile range, 438-800) and 273 ± 205 cells/mm(3) (interquartile range, 131-362). High-risk human papillomavirus was detected in 80.9% of patients, and human papillomavirus 16 was detected in 35.9% of patients. The mean number of human papillomavirus genotypes was 4.6 ± 2.9 (CI, 2-6). Anal cytology was abnormal in 40.9% of patients (n = 122/298; interquartile range, 35.4%-46.6%). High-resolution anoscopy and biopsies were performed in 119 patients. The results of histological analyses were as follows: normal, 7.7% (n = 23); condyloma, 4.3% (n = 13); anal intraepithelial neoplasia 1, 5.7% (n = 17); anal intraepithelial neoplasia 2, 14% (n = 42); and anal intraepithelial neoplasia 3, 8% (n = 24). The overall prevalence of high-grade squamous intraepithelial lesions among patients with abnormal cytology was 54% (95% CI, 45.1%-62.8%). A diagnosis of high-grade squamous intraepithelial lesions was associated with human papillomavirus 16 and human papillomavirus 51 infection, and with detection of a higher number of human papillomavirus genotypes. LIMITATIONS: High-resolution anoscopy was only performed in patients with abnormal cytology. CONCLUSIONS: The prevalence of high-risk human papillomavirus infection and high-grade squamous intraepithelial lesions is high in our cohort. Physical examination enabled straightforward diagnosis of perianal high-grade squamous intraepithelial lesions and squamous-cell carcinoma in 2 patients.

Childhood actinic lichen planus: successful treatment with antimalarials.

Actinic lichen planus (ALP) is a photosensitive variant of lichen planus, affecting mainly young adults of Middle Eastern descent. We report a case of ALP in a 9-year-old Colombian girl with an excellent response to hydroxychloroquine and photoprotection.

Uso de pomada de tacrolimus al 0, 1 por ciento durante un año en niños con vitiligo / Treatment during a year with 0.1 por ciento tacrolimus ointment in young patients with vitiligo

Introducción: El vitiligo es una alteración cutánea con un carácter predominantemente autoinmunitario, caracterizada por despigmentación de la piel y del pelo. En los niños, además de ser un problema estético constituye un reto terapéutico, ya que los tratamientos estándar (fototerapia y corticoesteroides) producen frecuentes efectos adversos. Materiales y métodos: En un estudio retrospectivo se evaluó la respuesta del tacrolimus tópico al 0,1 % durante un año, en 22 niños con vitiligo, en seguimiento en la Unidad de Dermatología Pediátrica del Hospital La Paz, durante el periodo comprendido de 2002 a 2008. Resultados: Se observó algún grado de repigmentación en 81,8 % de los pacientes. La repigmentación fue significativa en cara, cuello y extremidades, a los 9 meses, y en el tronco, a los 12 meses. No se observaron efectos secundarios sistémicos durante el seguimiento. Conclusión: El tacrolimus tópico podría considerarse como una opción terapéutica, en la población pediátrica con vitiligo.

Letter: Umbilical basal cell carcinoma in a 21-year-old man: Report of an exceptional case and dermatoscopic evaluation.

We report an exceptional case of umbilical basal cell carcinoma (BCC) in a 21-year-old man, whose correct diagnosis was suggested by dermoscopy during initial complete body mole mapping. Although BCC is a common skin tumor, only 7 cases of BCC arising within the umbilicus have been reported previously. To the best of our knowledge, our patient is unique because of his age, being the youngest case of umbilical BCC described in the literature. Complete examination and digital dermoscopic monitoring let us identify an asymptomatic, nonpigmented papule at the umbilicus. Dermoscopy images revealed signs of superficial ulceration and several types of vascular structures, which gave us the clue for the diagnosis and helped us differentiate it from other lesions such as Spitz nevus or amelanotic melanoma. The diagnosis was confirmed with histopathology after excision and there was no evidence of relapse in the following four years.

Palmoplantar nonpustular psoriasiform dermatitis in a rhesus macaque.

A case of psoriasiform dermatitis in an adult male rhesus macaque is reported. Appearing spontaneously, the condition presented the clinical and histopathological features of human palmoplantar nonpustular psoriasis. The animal developed multiple scaly plaques on his palms and soles, as well as nail hyperkeratosis and widening of the nail root. Microscopically, the skin lesions showed epidermal hyperkeratosis with multifocal parakeratosis, neutrophil microabscesses in the stratum corneum, a loss of granule cell layer under the microabscesses, acanthosis, and elongation of the rete ridges; the superficial dermis showed a dense inflammatory infiltrate containing lymphocytes, macrophages and neutrophils, as well as dilated and tortuous blood vessels. The lesions improved for 15 days after intramuscular corticosteroid depot therapy and worsened slightly afterwards. Later, a spontaneous, progressive remission coincided with the beginning of spring and lasted until the end of summer; the skin lesions practically disappeared during this period, and the nails looked nearly normal. During the next autumn and winter only nail hyperkeratosis was present. Serum analyses showed hyperproteinaemia and hyperglobulinaemia during the outbreak phase and normal values during remission. The clinical and histopathological features of this case, as well as its evolution, are compared with the three other reported cases of psoriasiform skin lesions in nonhuman primates. To the authors' knowledge, this is the first report of a definite palmoplantar nonpustular psoriasiform dermatitis in a rhesus macaque.

Dermoscopic findings and histological correlation of the acral volar pigmented maculae in Laugier-Hunziker syndrome.

Laugier-Hunziker syndrome (LHS) is an acquired, benign, macular hyperpigmentation of the lips and oral mucosa, often associated with pigmentation of the nails. Volar acral maculae on the palms and fingertips of patients affected by LHS are a typical feature of this rare entity. Dermoscopic examination of these maculae has been described in a previous report, in which authors found a parallel-furrow pattern. We describe two cases in which a parallel-ridge pattern (PRP) was found on the dermoscopic examination of the pigmented acral lesions. Histological examination showed increased melanin in basal keratinocytes, which was most prominent in those located at the crista intermedia profunda, that is, in the epidermal rete ridges underlying the surface ridges. In our study, dermoscopic features of the pigmented maculae found on LHS differed from those previously described. In addition, by means of this case report, the histological features of these lesions are described for the first time, showing an excellent correlation with dermoscopy. The reported cases prove that although the PRP is very specific of melanoma, it is also possible to find it in benign lesions. Therefore, we must be familiar with the differential diagnosis of PRP, and take into consideration the clinical context in which we find it. Further studies are needed to increase our knowledge on the histological and dermoscopic features of acral pigmented maculae of LHS.

Genetic analysis of three important genes in pigmentation and melanoma susceptibility: CDKN2A, MC1R and HERC2/OCA2.

The CDKN2A gene is regarded as the major familial malignant melanoma (MM) susceptibility gene. Human pigmentation is one of the main modulators of individual risk of developing MM. Therefore, the genes involved in the determination of skin colour and tanning response are potentially implicated in MM predisposition and may be useful predictors of MM risk in the general population. The human melanocortin-1 receptor gene (MC1R) plays a crucial role in pigmentation and also appears to be important in MM. The OCA2 gene has emerged as a new and significant determinant of human iris colour variation. We present a case-control study in Spanish population including 390 consecutive patients with melanoma and 254 control subjects. Sequence analysis of the entire coding region and genotyping of 5 tag-SNPs in the genomic region of MC1R was performed. We identified 27 variants, two reaching statistical significance [R160W (OR: 4.18, 95% CI: 1.24-14.04, P = 0.02) and D294H (OR: 3.10, 95% CI: 1.37-7.01, P = 0.01)] and we detected two novel non-synonymous changes: V92L and T308M. Odds ratio for carrying two functional variants was 4.25 (95% CI: 2.30-7.84, P = 3.63 x 10(-6)). Haplotypes of the entire MC1R region have been established, and we observed an enrichment of a rare European haplotype similar to African values carrying variants V92M and I155T. In addition, three potentially functional SNPs were selected in p16/CDKN2A and in the promoter region of OCA2/HERC2. Our data for CDKN2A gene did not reach statistically significant results for any of the two studied alleles. We found that the variant allele A > G of OCA2/HERC2 (rs12913832) was associated with pigmentation features: eye, hair and skin colour; P-values = 1.8 x 10(-29), 9.2 x 10(-16), 1.1 x 10(-3), respectively, validating previous results.

Congenital syphilis, case report and epidemiologic features in Spain.

Congenital syphilis (CS) is a preventable disease. Nevertheless, since the year 2000, there has been an upward trend in incidence in Spain, similar to what has occurred in other European countries. We present a case of early congenital syphilis showing the classical features of the disease, in which skin lesions gave the clue that led to the diagnosis.

Anal carcinoma in an HIV-infected woman.

A 42-year-old HIV-infected woman with an antecedent of HPV-related genital disease is diagnosed with invasive anal carcinoma due to HPV 16. Anal cancer is becoming an increasing problem in HIV-infected woman. In fact, the prevalence of HPV infection-related disease in this population is higher in the anus than in the cervix. Careful follow-up is recommended in HIV-infected women and, above all, in those with an antecedent of genital HPV infection.