HPV is the most common cause of sexually-transmitted infections the world over. The aim of this study was to assess the impact of a healthcare quality improvement strategy designed to increase the rate of vaccination against HPV in women diagnosed with cervical lesions graded as CIN2 or higher (CIN2+) during routine screening. The Veneto Regional Health Service developed a 22-item questionnaire to measure the gap between ideal procedure and real practice regarding the offer of vaccination against HPV for women undergoing routine cervical screening. The questionnaire was administered to nine expert doctors, one at each of the region’s Local Health Units (LHUs). An additional specific assessment concerned the quality of the related web pages available on the LHU websites. Strategies to close the gap between ideal procedure and real practice were decided collegially, and a checklist to support good practices was developed and shared with operators at the LHUs. Changes in practice were measured using data relating to women diagnosed with CIN2+ lesions extracted from the regional oncological screening database before and after the publication of a Regional Procedure on the topic. The LHUs differed considerably in how they managed each step, in terms of training for healthcare personnel, organization and assessment of the pathway from cervical screening to HPV vaccination, and in dedicated website communication. After implementing the quality improvement strategy, the proportion of women given a first dose of HPV vaccine within 3 months of being diagnosed with CIN2+ lesions at 1st-level screening rose to 50% (compared with 30.85% beforehand), and the median time elapsing between a diagnosis of CIN2+ lesion and a first dose of HPV vaccine dropped from 158 to 90 days. These findings underscore the importance of providing training to promote vaccination for general practitioners and other clinicians. The study also confirms the need for more efforts in communication to ensure that any citizen has the opportunity to access preventive healthcare. Human papillomavirus (HPV) is the most common cause of sexually-transmitted infection everywhere in the world and basically the sole cause of cervical cancer . AccordiHPV malignant cytological lesions are divided into L-SIL , including CIN-1  and H-SIL  including CIN- 2 and -3 . In most cases, the infection causes mild cellular abnormalities that regress spontaneously. On the contrary, the persistence of the virus in epithelial cells is a predictive factor of evolution, over the years, into cervical cancer.For the treatment of cervical precancerous lesions caused by oncogenic HPVs, surgery  is recommended. Moreover, therapeutic vaccines and genome-editing therapies (such as the CRISPR/Cas platform) targeting HPV E6 and E7 oncoproteins have recently shown promising results in preclinical and clinical trials to control the progression of HPV-related cervical precancerous and cancerous diseases .Vaccination against HPV has proved highly effective (>90%) in preventing infection in women under 25 years old who have never previously been infected with the virus . CervicaNowadays, there is global consensus on the recommendation of HPV vaccination for women who undergo conization after being diagnosed with CIN2+ cervical lesions because it has been demonstrated that vaccination is effective in preventing relapses, especially in cases of CIN2-3 ,9,10,11.Despite the evidence in the literature on the efficacy of prevention strategies, the degree to which they are adopted in healthcare practice remains uncertain, and it is worth taking action to promote their implementation. An iterative process consisting of several steps is recommended. This includes: adapting guidelines to local contexts; identifying barriers to their use; selecting and implementing tailored interventions to promote their adoption; monitoring and assessing the associated outcomes, and the sustainability of the recommendations. Quality improvement (QI) in the provision of healthcare is described as a systematic, information-driven, change-focused activity . QI provThe aim of this study was to examine the impact of a QI strategy to increase the uptake of HPV vaccination by women diagnosed with cervical lesions graded as CIN2 or higher (CIN2+) during routine cervical screening.The Italian National Health Service (NHS) is a public system financed mainly by general taxation and organized essentially on a regional basis . Its polIn the Veneto Region, immunization against HPV is offered actively and free of charge to all children in their twelfth year of life. It remains available free of charge at a patient’s request for people up to 25 years old and for other at-risk subgroups of the population, such as men who have sex with men, patients with HIV, and women diagnosed with precancerous cervical lesions graded CIN2+ .In November 2020, the Veneto Regional Health Service adopted an evidence-based procedure called “HPV vaccination for women treated for high-grade HPV-related cervical lesions” , /;/.The resulting dataset was divided into four, based on the time to the provision of care : less than 3 months, 3–6 months, 6–12 months, and more than 12 months.The data extracted were:Data extracted were represented as a distribution of both absolute and relative frequencies of a discrete quantitative variable. The median and 5th, 25th, 75th, and 95th percentiles of time to the provision of care were calculated.Data deriving from the questionnaire were represented as a radar chart. The radar chart was depicted as a sequence of equiangular spokes, with each spoke representing one of the variables. The data length of a spoke is proportional to the magnitude of the variable for the data point relative to the maximum magnitude of the variable across all data points. A line is drawn connecting the data values for each spoke.No ethical approval was required, and data was communicated by Local Health Units in aggregated form.A framework of the QI strategy adopted by the Veneto Region to analyze and improve the healthcare provider regarding HPV immunization for women with CIN2+ lesions is represented in strategies to improve the training of healthcare personnel: at two LHUs, they involved webinars or face-to-face meetings held by an expert (the doctor in charge of 2nd-level screening or an oncologist); the other LHUs engaged in active training and in-house meetings (of gynecologists) to discuss the procedure; the various LHUs also arranged for the proper storage and availability of printed copies of the procedure for easy consultation;strategies to develop effective communications: explanatory videos and video interviews were prepared and broadcast via social channels in two cases, and television interviews were used in another ; in one case, printed information sheets were produced and distributed at most of the LHUs’ vaccination clinics;strategies to develop an organized and proactive patient involvement: immunization was recommended in letters notifying patients that their cervical screening had revealed CIN2+ lesions; one LHU established a routine procedure for booking a vaccination within 30 days after surgery for CIN2+ lesions and, if the patient failed to attend, vaccination was recommended again at the time of her gynecological follow-up.After the quality improvement strategies were implemented, one in every two women (as opposed to 30.85% beforehand) was given a first dose of HPV vaccine within 3 months of being diagnosed with CIN2+ lesions at 1st-level cervical screening, and the median time to the provision of care dropped from 158 to 90 days.The present analysis revealed an initially heterogeneous application by LHUs in Veneto of the regional procedure regarding the offer of HPV vaccination to women treated for CIN2+ cervical lesions. A quality improvement program produced a marked reduction in the time elapsing between a diagnosis of CIN2+ lesions on cervical screening and the administration of a first dose of the HPV vaccine.The present study was conducted by the Prevention Directorate of the Veneto Region to improve the quality of the HPV vaccine provision to the specific at-risk population of women who have not undergone vaccination and can be compared with other experiences in Italy and Europe. For example, in Catalonia, Del Pino, and colleagues  analyzedThe current analysis can be compared with the picture emerging from a recent review by Pereira et al. , who anaOur findings suggest that—for the training of general practitioners and other physicians involved in the pathway investigated here —it is essential to conduct at least one active training event. This can be a meeting or a webinar, possibly with scheduled subsequent update sessions. This is because various studies showed that, even among healthcare professionals, there are often prejudiced attitudes or knowledge gaps regarding vaccines, or their importance is simply underestimated ,30. A reAs concerns communication aspects for health service users, the checklist drawn up in the light of the present analysis proposes the production of ad hoc information materials aimed at women diagnosed with CIN2+ cervical lesions in the present case. These materials should be prepared jointly by healthcare personnel with expertise on the topic (who decide the content) and personnel experts in communication (who decide how to present it). The information should be disseminated using all currently-available communication channels  to reach as much of the population as possible. Considering the growing attention paid to the issue of vaccinations for individuals who are at higher risk due to their clinical and/or social conditions (an issue brought to the fore by the COVID-19 vaccination campaign), it is now high time to update healthcare service web pages. They should be designed to be straightforward and accessible, and the contents easy to maintain and revise. Digital and traditional formats should be used, complying with the recommendations and best communication practices. A plentiful body of literature confirms that targeted communication strategies increase awareness among service users and consequently help to increase adherence to the vaccination offer ,34,35.As for evaluating the service provided, none of the LHUs considered had yet devised indicators or corrective actions to improve their vaccination offer process. This is a work in progress for all Vaccination Services. Process indicators are key to monitoring the pathway and implementing any active calls or catch-up actions.All these considerations are confirmed in the US standards and recommendations for adult vaccination ,37. TheiIn conclusion, although further efforts will be needed to consolidate good practices and offer solutions endorsed by a larger number of experts, this study confirmed the importance of standard operating procedures as part of efforts to provide more efficient and patient-centered healthcare. The present study focused on the offer of HPV vaccination to women revealing CIN2+ lesions on routine cervical screening, but most of the good practices and considerations that emerged could be equally applicable to other vaccinations aimed at other at-risk sub-populations.Increasing the adherence of a specific target population to a recommended vaccination is not only proof of quality and efficacy for a healthcare system but also has a profound impact in terms of lives saved and cost-effectiveness. Indeed, according to an Italian health technology assessment on HPV vaccination in women treated for HPV-related precancerous lesions, adjuvant vaccination is cost-effective in general and especially from the second year after surgery and can reduce the risk of recurrence by up to 80% compared to no vaccination after surgery ,25. It iThis study has both strengths and limitations that need to be mentioned. The main strengths lie in its originality and the novel nature of the data: to our knowledge, it is the first study to have taken a quality improvement approach to preventive medicine and to have examined the timing of steps in an integrated pathway leading from cervical screening to HPV vaccination.The main pitfall is that the data of time to the provision of care are not perfectly comparable between the two cohorts considered since 43% of women in the “after-operating-procedure” cohort had less than 364 days (or sometimes less than 180 days) passed since the CIN2+ diagnosis at the time of writing. For this reason, further evidence will be needed to consolidate our findings. Moreover, the present study has a predominantly methodological approach and did not analyze the specific immunization status of the minority of CIN2+ women who had already been vaccinated before : this may be a hint for future research.


Sufficient prognostic parameters are still lacking in penile cancer. In this study, we sought to evaluate the current TNM classification in terms of its ability to estimate prognosis and to identify additional independent prognostic parameters. We found that lymph node metastasis—as well as lymphovascular invasion in node-negative patients—had the strongest impact on prognosis, whereas HPV did not show an influence on outcome. Furthermore, the pT1b stage seems questionable, and a revision of the current TNM classification is advised.p = <0.001), while lymphovascular invasion was a significant parameter for reduced CS and OS . Concerning the primary tumor stage, a significant difference in MFS was found only between pT1b and pT1a (p = 0.017), whereas CS and OS did not significantly differ between T categories. In patients without lymph node metastasis at the time of primary diagnosis, lymphovascular invasion was a significant prognostic parameter for lower MFS (p = 0.032). Histological subtypes differed in prognosis, with the worst outcome in basaloid carcinomas, but without statistical significance. HPV status was not associated with prognosis, either in the total cohort or in the usual type alone. Conclusion: Lymphatic involvement has the highest impact on prognosis in penile cancer, whereas HPV status alone is not suitable as a prognostic parameter. The pT1b stage, which includes grading, as well as lymphovascular and perineural invasion in the T stage, seems questionable; a revision of the TNM classification is therefore required.Background: Advanced penile carcinoma is characterized by poor prognosis. Most data on prognostic factors are based on small study cohorts, and even meta-analyses are limited in patient numbers. Therefore, there is still a lack of evidence for clinical decisions. In addition, the most recent TNM classification is questionable; in line with previous studies, we found that it has not improved prognosis estimation. Methods: We evaluated 297 patients from Germany, Russia, and Portugal. Tissue samples from 233 patients were re-analyzed by two experienced pathologists. HPV status, p16, and histopathological parameters were evaluated for all patients. Results: Advanced lymph node metastases  were highly significantly associated with reductions in metastasis-free (MFS), cancer-specific (CS), and overall survival (OS) rates ( Penile carcinoma (PC) is a rare tumor disease with an incidence of 1/100,000 men in western Europe, while the estimated incidence in developing countries is much higher with up to 10% of all malignant diseases in men ,3. Due tINK4a immunohistochemistry because p16INK4a is the established surrogate marker for HPV-driven transformation [Active expression of functional hrHPV viral oncoproteins is causally linked to the malignant transformation of proliferating cells . Detectiormation ,10,11. Tormation ,12.The majority of PCs are penile squamous cell carcinomas (PSCCs) with different histological subtypes. Histological subtyping of penile carcinomas is based on their HPV status, so that there are HPV-associated and non-HPV-associated subtypes. The most common histological subtype is the usual PSCC, which accounts for about 75% of all cases and is mostly HPV negative, followed by warty-basaloid, basaloid, and warty PSCCs, the latter being strongly associated with HPV-induced carcinogenesis . The hisThe TNM classification is used to estimate prognosis. Because the previous version was found to be inadequate, an adjustment of the TNM classification was made in its eighth edition ; howeverFor this reason, in this study, we investigated the current TNM classification as well as other putative risk factors with the aim of providing a more accurate prognosis estimation and thus reducing the risk of over- or undertreatment.A total of 297 patients from multiple centers in Germany , Russia , and Portugal (40 from the Portuguese Oncology Institute of Porto), who had been treated for penile carcinoma between 1989 and 2018, were included in this cohort. The Saarland ethical committee confirmed analyses of patient data and tumor samples. Representative formalin-fixed and paraffin-embedded tissue samples from 233 patients were analyzed. Experienced uropathologists from two German university centers reviewed all tissue samples and re-examined the respective histological subtypes, as well as lymphovascular, vascular, and perineural invasions, according to the 2016 WHO classification . All tumINK4a were performed, as previously reported, using a monoclonal antibody against p16INK4a , with 1:4000 dilution [Tissue microarray construction and immunohistochemistry with an evaluation of p16dilution . Tumor sDNA was isolated from FFPE tissue sections using a QIAamp DNA FFPE Tissue Kit  according to the manufacturer’s protocol. HPV PCR  was perf®, Armonk, NY, USA).Statistical analyses were performed using SPSS Statistics 28 . Thus, 31.1% of the specimens displayed an HPV-positive status based on DNA detection and p16 staining . The median patient age was 63 years (range 24–93), with mean ages of 58, 67, and 77.5 years among Russian, German, and Portuguese patients, respectively. HPV status could be evaluated in 222 patients. Among these, 79 tumor samples (35.6%) were positive for hrHPV-DNA. In addition, HPV subtype 16 was found in 72 tumor samples, subtypes 18 and 35 in 2 samples, and subtype 59 in 1 sample. In two tumor samples, the exact subtype could not be identified. p16Comparing histological subtypes , we founAfter comparing the seventh and eighth editions of the TNM classification systems, one patient was shifted from the pT1a to the pT1b stage due to the inclusion of perineural invasion in the pT1b stage  in the ep = 0.14 for CSS; p = 0.133 for OS).The median follow-up time was 27 months (range 3–253 months). Warty tumors had the best MFS, CSS, and OS  rates. IAnalysis of HPV-positive and HPV-negative tumors did not reveal any significant differences in MFS, CSS, and OS between the two groups, either in the total cohort a–c or inp = 0.003), CSS , and OS . The pT1b stage had the worst five-year survival rate (44%) even when compared with pT2 (78%), pT3 (56%), and pT4 (50%) tumors. Five-year CSS and OS survival rates significantly decreased with increasing T stages   a–c.p = 0.017; CSS: log rank, p = 0.034; OS: log rank, p = 0.025), but outcomes did not differ between G2 and G3 (Higher grades (G2–3) were associated with a significantly decreased MFS, CSS, and OS compared with G1  and advanced lymph node metastasis stages  were independent parameters to predict MFS. pN2  and pN3 stages , as well as lymphovascular invasion  and the age at diagnosis, were independent prognostic parameters concerning CSS and OS. In the next step, Cox regression analysis was performed. In univariate analysis, multiple parameters correlated significantly with MFS, CSS, and OS  values tp = 0.032), whereas other prognostic factors included in the pT1b stage such as grading, vascular invasion, or perineural invasion did not show any significant differences in survival , survival a–c.Penile cancer remains a poorly studied tumor entity; as a result, prognosis in advanced stages also remains poor. Due to the low incidence of the disease, reliable systematic data on prognostic markers and systemic therapy are limited. Most studies have been based on small numbers of patients from single centers. In this study, we succeeded in recruiting an international multicenter patient cohort with a high number of patients to evaluate prognostic parameters; these are important when determining individualized therapeutic approaches, especially those with curative intention in the early stages of the disease. In brief, we found that HPV has no influence on prognosis, whereas lymph node metastasis and lymphovascular invasion are both significant independent prognostic parameters.The frequency of HPV-related tumorigenesis was lower in our cohort than in several published data . This miINK4a analysis; in such studies, therefore, the involvement of viral oncoproteins in tumorigenesis was not proved [The prognostic role of HPV status has not yet been clarified. In head and neck cancers, the data clearly demonstrate a better survival rate for HPV-induced tumors ,22; howet proved . On the t proved . This coOur analysis did not reveal any association of HPV with prognosis, either in the total cohort or in the usual type alone. The latter analysis was performed to eliminate the bias of the deviating prognoses between histological subtypes. We may say, therefore, that HPV is not suitable as an independent prognostic parameter. However, histological subtypes differ in prognosis regardless of HPV status and should therefore be reported by pathologists and considered when making decisions concerning therapy. In our study, the number of other histological subtypes was too small to perform a meaningful analysis of the role of HPV. However, such an analysis, involving larger study cohorts, may be seen as a necessary future task.Nevertheless, HPV status should still be determined, as future HPV-positive PC patients may benefit not only from targeted therapies but also from immunotherapies, as shown in the recently published study by de Vries et al. .In line with the results of various previous studies, we found that the advanced lymph node metastasis stage  was the most important prognostic factor ,32. ThesSimilarly, lymphovascular invasion was a significant parameter for shorter MFS in patients without proven lymph node metastases at the time of surgery. In line with previous studies, we found that the risk of distant metastasis significantly increases in the presence of lymphovascular invasion because infiltration of tumor cells into the lymphatic system is known to be a prerequisite for tumor spread ,35,36. TBased on our results, the inclusion of lymphovascular invasion, grading, and, starting from the eighth edition of TNM, perineural invasion into the classification of the primary tumor for the discrimination between pT1a and pT1b can be seen as unique within tumor staging guidelines and should be critically discussed. pT1b showed the worst outcome concerning MFS, such as non-organ-confined tumors. A better differentiation of risk factors in the TNM classification is necessary, considering lymphovascular invasion as an independent prognostic parameter to avoid overtreatment in low-malignant tumors, while aggressive tumors, especially with LVI, benefit from early aggressive therapy and a close follow-up. As the current TNM classification only partially improved its prognostic value, compared with the previous version ,38,39, fIn addition to the retrospective character of this study, the low frequency of some histological subtypes may be seen as another limitation that prevented a more detailed analysis concerning prognostic evaluation. Further studies with higher patient numbers that focus on histological subtypes are therefore needed. Moreover, patients were evaluated over a period of almost 30 years; therefore, a wide variety of therapy concepts were applied that could not be considered in this study. Additional research is required to evaluate whether patients with lymph node metastases or lymphovascular infiltration may benefit from a more aggressive therapy.HPV status plays an important role in the etiology of penile carcinoma; however, it is not associated with prognosis or metastatic potential. Additional markers beyond HPV status that more accurately reflect the underlying tumor biology may help improve prognostic estimates. In contrast, histological subtypes exert a major influence on prognosis; therefore, these should always be reported, with consequent impact upon therapy decisions.Advanced lymph node metastasis and lymphovascular invasion in node-negative patients are the most important independent prognostic parameters. Therefore, an aggressive lymph node management is suggested for LVI-positive patients. Furthermore, the combination of lymphovascular invasion, grading, and perineural invasion into a single T category is arguably beneficial, and a more detailed discrimination of the risk factors in the TNM system appears to be urgently needed.


Adolescence and pregnancy are considered to be risk factors for human papillomavirus (HPV) infection. The relationship between this infection in the uterine cervix and oral HPV infection is controversial. This report describes a case of a pregnant 16-year-old adolescent who presented HPV infection in the uterine cervix and the mouth. Smears were collected from the cervix and the tongue/palate. Dental biofilm samples were also collected. The microarray technique was used to detect HPV. The HPV 56 subtype was observed in the cervical smear and HPV 6 in dental biofilm. In this pregnant adolescent, HPV infection was present in both the cervix and the mouth, but the HPV subtypes infecting these two areas were different. The reported risk factors for HPV infection are multiple partners, oral contraceptive and an early start to sexual activity.In order to promote the health of both mother and child, pregnant women need to adhere to primary healthcare measures. Cervical screening and health education strategies are powerful tools for gaining knowledge about HPV. The treatment for the induced lesions ranges from home-based therapy to surgical therapy. The present case report describes a 16-year-old patient who was diagnosed with cervical and oral HPV infection.A 16-year-old pregnant adolescent attended a routine prenatal consultation at the Maternity School of the Federal University of Rio de Janeiro . According to her medical records, she had a history of syphilis and bacterial vaginosis that had been adequately treated at the same health clinic. In the clinical examination performed during the first trimester of pregnancy, she presented cervical lesions diagnosed as HPV-induced lesions in the cytopathological evaluation. The patient received guidance regarding her HPV infection and for periodic monitoring of the cervical lesions. Moreover, aspects of STD prevention, including oral sex, and family planning issues were addressed.At the time of the clinical appointment, she was 31 weeks pregnant with her first child. She had been using an oral contraceptive method, which failed due to incorrect use, and resulted in an unwanted pregnancy. When interviewed, she reported that her active sex life started when she was 13 years old and that she had had 10 sexual partners since her first sexual intercourse, but that at that moment, she had only one sexual partner. During the interview, she also reported having vaginal intercourse and oral sex at weekly frequency. The last vaginal and oral intercourse had been on the previous day and four days earlier, respectively. She stated that she had never used alcohol, marijuana or cocaine.In the genital examination, white stained areas were identified in the uterine cervix, after applying acetic acid. Local smears for cytopathological analysis were collected from these areas. The slides were sent to the laboratory at the same clinic. An oral examination was performed, including a complete periodontal examination. The patient did not present any oral lesions and her teeth were healthy. The gingival bleeding index, dental plaque index and the mean probing depth of the gingival sulcus were recorded. The patient presented bleeding in 9% of the gingival sites and dental biofilm in 65% of the tooth sites. The mean probing depth was 2.24 mm, with no attachment loss.The slides sent to the laboratory were processed using the Papanicolaou (Pap) test. The cytological data were evaluated by means of the Bethesda criteria and the cells were found to present koilocytosis, nuclear enlargement, nuclear hyperchromasia, irregular nuclear outlines and perinuclear halos .Swab samples for HPV identification were collected from the cervix and the mouth . Samples of dental biofilm were also collected using a sterile periodontal curette, from the teeth with deeper sulci. The samples collected were subjected to DNA purification  and the microarray reaction for DNA HPV genotyping .The cervical smear showed the presence of DNA from HPV56, which is a high-risk subtype. No HPV DNA was detected in the tongue/palate smear. DNA from HPV 6 was detected in one of the four samples of dental biofilm. HPV was present in the periodontal sulcus of the lower left canine. The depth of the gingival sulcus at this site was 4 mm, and it did not present bleeding on probing.Preventive measures were reaffirmed and a clinical monitoring approach was implemented in relation to the cervix HPV-induced lesions, which consisted of cervical screening every 12 months. The lesions presented a self-healing course within the first year of observation.,The presence of HPV-infected lesions is sometimes only shown through screening techniques.The HPV56 viral subtype detected in this pregnant adolescent is among the high-risk oncogenic subtypes that might be found in adolescents.The protocol for monitoring low-grade squamous intraepithelial lesions in adolescents (≤ 20 years) consists of performing cytological tests every 12 months, for a period of two years.Presence of HPV DNA has been observed under some pathological conditions that affect the mouth. This virus has been identified in abscesses of endodontic origin; in gingivitis and periodontitis; and in malignant tumors, such as oral squamous cell carcinoma.Some human viruses have been implicated in facilitating establishment of periodontal pathogenic bacteria in the gingival sulcus. HPV may infect deeper layers and reach the basal cell layer without necessarily causing any type of lesion, because the junctional epithelium connects the gingival sulcus with the connective tissue through a gap in the epithelial barrier.Even though the patient reported a recent history of oral sex, she did not present HPV in the cells collected from the mouth smears. The oral site from which HPV DNA was observed in this pregnant adolescent was in dental biofilm from a periodontal sulcus of an anterior tooth that did not present any clinical signs of inflammation or deep sulci. Detection of HPV at this site may suggest that the anterior sites of the mouth were exposed to HPV during oral intercourse. Other authors did not believe that periodontal tissues were able to act as a reservoir for HPV, because they were unable to observe the virus in any sample of gingivitis, periodontitis or healthy gingival tissue in their study.,Little is known about the prevalence of this infection in the mouth. The practice of oral sex is currently suggested to be a risk factor for HPV infection in the mouth.,,Some studies have attempted to find evidence of an association and/or relationship between HPV infection in the mouth and genitalia of pregnant women.In this pregnant adolescent, there were different subtypes of HPV infection affecting the uterine cervix and the mouth. Further clinical studies with data on individual characteristics and behavior are needed, in order to determine the real risk factors for HPV infection in the mouth.


Human papilloma viruses (HPV), that are causative for most squamous cell cervical cancers (SCC), have a simple structure with only a few genes (six early and two late genes). Two of the early HPV genes (E6 and E7) are capable of transforming normal squamous epithelium into cancer. In the last 10 years, a controversial discussion arose as to which cells are primarily involved in cervical carcinogenesis. Virologists traditionally use a research model of stratified squamous epithelium, a permissive environment for completion of a full HPV-life cycle. Basic insights on HPV tropism, HPV life cycle, HPV-uptake, HPV-replication, HPV-gene expression were gained from this model. Stratified squamous epithelium, however, is a low-risk area for SCC. Most SCC develop in an area of endocervical columnar epithelium that undergoes squamous metaplasia. SCC arise after infection of immature squamous metaplasia, proliferating reserve cells/reserve cell hyperplasia and reserve cells of the endocervical columnar epithelium. Study models investigating this pathway of carcinogenesis do not exist and therapeutic consequences deduced from this knowledge are lacking. This review describes in detail cervical carcinogenesis after HPV infection of subcolumnar reserve cells and discusses new intervention strategies for patients. The WHO-launched global strategy to eliminate HPV-associated cervical cancer builds primarily on prophylactic vaccination, screening and treatment. New insights in cervical pathogenesis, may assist in reaching this ambitious WHO goal. They have a simple structure and are built of only a few genes (six early and two late genes). The late genes (L1 and L2) encode the major capsid proteins. The early genes  are involved in replication control. Two of the early HPV genes (E6 and E7) are able to transform normal squamous epithelium into cancer due to their ability to immortalize cells. Virologists traditionally use a research model of stratified squamous epithelium, a permissive environment for completion of the HPV-life cycle. Basic insights on HPV associated disease including viral tropism, viral life cycle, HPV-uptake, HPV-replication, HPV-gene expression, the concept of transforming HPV infection in the development of HPV-associated squamous cell cancers (SCC) and immune control of HPV-infection are based on a study model consisting of this stratified squamous epithelium.stratified squamous epithelium model” is suitable for research on HPV-associated carcinogenesis in stratrified squamous epithelium of the skin, penis, vulva, vagina, and oral cavity. By contrast, this model has short comings when explaining cervical carcinogenesis, because most cervical SCC originate in an area initially covered by non-squamous endocervical epithelium consisting of tall columnar epithelium with subcolumnar reserve cells capable of squamous metaplasia. The area in which most cervical SCC develop is called transformation zone, and features several maturation levels of metaplastic squamous epithelium bordering tall columnar epithelium with subcolumnar epithelium.In fact, this “In the last 10 years a controversial discussion arose as to which cells are primarily involved in cervical carcinogenesis. It is well accepted that reserve cells give rise to metaplastic squamous epithelium and that high-grade squamous intraepithelial lesions (HSIL)/SCC develop after HPV-infection of metaplastic squamous epithelium of different maturation levels. Reserve cells develop from two different embryonic structures: Urogenital sinus derived p63/CK17-positive cells are the primary precursor cells for the squamous epithelium/HSIL/SCC, and Müllerian-derived CK7-positive reserve cells for the columnar epithelium/adenocarcinoma in situ (AIS)/adenocarcinoma (AC). Reserve cells extend from the squamocolumnar junction (SCJ) throughout the entire cervical columnar epithelium to the isthmic border  Figs. 1. These o2Cervical cancer is one of the most common causes of cancer deaths in women globally. In 2020, the WHO launched a global strategy to accelerate the elimination of cervical cancer that focusses on prophylactic vaccination, screening and treatment of women at risk for invasive disease . The ris3Retrospective analyses show that women with treated HSIL are at increased risk of recurrent HSIL and even invasive squamous cervical cancer (SCC) . Followi4The observation that most cervical precancerous lesions develop within the area of squamous metaplastic epithelium was an important milestone in understanding cervical oncogenesis and is credited to Hans Hinselmann (1884–1959). He presented a completely new view of cervical oncogenesis based on his colposcopic and histologic findings. He described two different types of cervical squamous epithelia. The first type was the (preexisting) original squamous epithelium, and the second type was a newly formed squamous metaplastic epithelium. He called this zone (area) of metaplastic epithelium “Umwandlungszone” . This seOne of the current misconceptions about stem cells of cervical cancer is based on recent studies on embryos and fetal tissues before development of adult-type epithelia and before definitive positioning of reserve cells has occured. This theory postulates that cuboidal stem cells at the SCJ identified by the “stem cell marker” CK7 give rise to HSIL/SCC . However5Current recommendations for HSIL/AIS treatment are based on expert opinions and lack rigorous evidence-based support. In 2011, the IFCPC approved a revision of colposcopic terminology . To stan6The risk of recurrent or new HSIL post-treatment mainly depends on presence of residual endocervical columnar epithelium. CK17/p63 and / or CK7 expressing reserve cells will undergo new squamous differentiation, and thus are ultimately responsible for new immature/mature squamous metaplasia, recurrent HSIL and SCC . This exCountries with limited medical access: Women in low income and middle income countries have the highest risk of cervical cancer/cervical cancer deaths . Positive margins, however, are reported in 44% after LEETZ and 29% after cold knife conization requiring re-excision or hysterectomy (AIS originates from CK7 expressing reserve cells of Müllerian origin, the stem cell for glandular lesions and renewal . Colposcerectomy . Regardierectomy .8Prophylactic vaccines and screening programmes have successfully reduced the burden of HPV infections and cervical pre/cancer. HPV vaccination, however, does little for those women who are infected by non-vaccine HPV types. Current efforts in management focus on treatment of the precancerous lesions only without offering prevention of recurrent and invasive disease post-treatment. Treatment of the whole area of risk for HSIL/SCC with targeted intervention strategies opens the way for future reducing the incidence and mortality from cervical cancer.


The epidemiology of human papillomavirus (HPV)-associated cancers has changed since the development of the multivalent vaccine. This is evidenced by the decline in incidence of cervical cancers in the post-vaccine era. By contrast, studies have reported the rise in incidence of these cancers in males. Though little is known regarding HPV-associated cancers in males, Hispanic males have been largely excluded from research on these cancers.The purpose of this study was to examine the differences in late-stage diagnosis of HPV-associated cancers  among subgroups of Hispanic males in the U.S.We performed a population-based retrospective cohort study using the 2005–2016 North American Association of Central Cancer Registries Cancer in North America Deluxe data file (n = 9242). Multivariable logistic regression modeling was used in studying late-stage diagnosis.There were no differences in late-stage diagnosis of oropharyngeal cancer between Hispanic subgroups. Higher odds of late-stage penile cancers were observed among Mexican and Puerto Rican males relative to European Spanish males. Lower odds of late-stage anorectal cancers were observed among Central or South American and Puerto Rican males. Having Medicaid or no insurance were associated with late-stage diagnosis for all cancers.Certain subgroups of Hispanic males have higher odds of late-stage HPV-associated cancer diagnosis based on country of origin and insurance status. These findings call for improved efforts to increase HPV vaccination, particularly among these subgroups of Hispanic males. Efforts to improve health care access and early detection from health care providers are also needed. Most of the literature on HPV-associated cancers have focused on females and the virus’ link to cervical cancers, despite it being associated with 72% of squamous cell carcinomas (SCCs) of the oropharynx, 91% of anorectal SCCs, and 63% of penile SCCs. HPV-associated cancers are preventable, and vaccination remains the best strategy in mitigating adverse health outcomes since there are currently no routine screening recommendations for HPV-associated cancers among males. Furthermore, despite studies demonstrating that males have a 3-fold higher prevalence of HPV positivity and are less likely to clear HPV infections, HPV vaccination campaigns have primarily targeted females. Although the Advisory Committee on Immunization Practices (ACIP) recommended the HPV vaccine as protection for females in 2006, the recommendation did not extend to males until 2011. Since October 2011, ACIP recommends the HPV vaccine to 11- to 12-year-old males, with 9- to 21-year-old males also considered age-eligible. More recently, the HPV 9-valent vaccine  was approved by the FDA for both men and women through 45 years of age in preventing HPV associated malignancies affecting the oropharynx, cervix, anorectal tract, and penis.In the United States, human papillomavirus (HPV) is the most common sexually transmitted infection (STI) and is purported to cause an estimated 19,925 cases of HPV-associated cancers among males annually. A study based on the 2013 National Immunization Survey Teen (NIS-Teen) found that 34.6% of boys between the ages of 13–17 had one dose of the HPV vaccine while series completion (≥3 doses) was only 13.9%. Completion rates were significantly higher among Hispanics (20.3%) compared to Non-Hispanic (NH) black (15.7%) and white males (11.1%). Despite this improvement, Hispanic adolescent males continue to have lower rates of HPV vaccination initiation and completion than Hispanic females (21% vs 39% respectively).11Although studies have suggested that HPV vaccine initiation has increased among males, completion rates continue to lag behind females.12 However, there have been very few studies that include Hispanics and/or males when examining health outcomes of HPV-associated cancers. For instance, Hispanic males have the highest age-adjusted incidence rate of HPV-associated penile cancer compared to non-Hispanic males. In addition, Hispanic males are over 4 times more likely to develop HPV-associated oropharyngeal cancer than Hispanic females, with lower socioeconomic status and education being major risk factors. This is particularly concerning given that Hispanics have higher HPV-associated oropharyngeal cancer mortality compared to NH Whites, which is further reflected when stratifying by lower socioeconomic status. Most of the existent literature on HPV-associated cancers has predominantly focused on understanding NH White-Black disparities.19 Furthermore, few studies pertaining to HPV-associated cancers have included Hispanics/Latinos as distinct groups, particularly among males. If Hispanics were included, researchers focused only on a certain state, one type of cancer, or Medicare beneficiaries.21 Given the heterogeneity within the broader category of Hispanics, it is important to analyze the data among the different subgroups based on country of origin, such as European Spanish, Cuban, Mexican, Dominican, Central/South American, and Puerto Rican. In doing so, the preventative and treatment efforts can be better targeted within this diverse population and in geographic regions where larger numbers of Hispanic males reside. To the best of our knowledge, this is the first study to examine differences in late-stage diagnosis of HPV-associated cancers  among Hispanic males by country of origin.Several studies have examined factors associated to HPV vaccination uptake and knowledge about HPV among Hispanic males.This is a population-based retrospective cohort study of Hispanic males in the U.S. diagnosed with invasive  oropharyngeal, anorectal, or penile cancers from 01/01/2005-12/31/2016 in the North American Association of Central Cancer Registries (NAACCR) Cancer in North America (CiNA) Deluxe data file. NAACCR CiNA is the most comprehensive cancer incidence database, given its coverage of approximately 93% of the population living in the U.S. This database contains de-identified demographic, cancer type, and treatment information from population-based cancer registries across the U.S. and Canada. At the time the study was conducted (2019–2020), the full data file from NAACCR was available through 2016. We included 12 years of data to have a sufficient number of cases for each HPV-associated cancer in Hispanic males. The Surveillance, Epidemiology, and End Results (SEER)*Stat software program was used to access the data, which was then exported into the Statistical Package for the Social Sciences (SPSS) version 27  for advanced analyses. This study was approved and determined exempt from review by the Institutional Review Boards at NAACCR and Rutgers University. we used CDC definitions of HPV-associated cancers with the aforementioned ICD-O-3 site codes as well as histological codes for squamous cell carcinoma (SCC) . HPV-associated cancers were restricted to microscopically confirmed cases.Cases identified in the NAACCR CiNA file were downloaded onto a Microsoft Excel document, where data cleaning was performed based on inclusion and exclusion criteria. We included Hispanic males with known tumors in anatomic sites under the International Classification of Diseases for Oncology (ICD-O)-3. Cases were considered to be oropharyngeal cancers if they were located at the base of tongue (C01.9); lingual tonsil (C02.4); overlapping lesion of tongue (C02.8); soft palate (C05.1); uvula (C05.2); tonsillar fossa (C09.0); tonsillar pillar (C09.1); overlapping lesion of tonsil (C09.8); tonsil (C09.9); vallecula (C10.0); anterior surface of epiglottis (C10.1); lateral wall of oropharynx (C10.2); posterior wall of oropharynx (C10.3); branchial cleft (C10.4); overlapping lesion of oropharynx (C10.8); oropharynx (C10.9); pharynx (C14.0); Waldeyer’s ring (C14.2); overlapping lesion of lip, oral cavity, and pharynx (C14.8). The anorectal cancer category was determined by malignancies in the rectum (C20.9); anus (C21.0); anal canal (C21.1); cloacogenic zone (C21.2); overlapping lesion of rectum, anus, and anal canal (C21.8). Penile cancers were classified by those found at the prepuce (C60.0); glans penis (C60.1); body of penis (C60.2); overlapping lesion of penis (C60.8); and penis (C60.9). We included the following demographic covariates: age at diagnosis; health insurance; county level attributes of residence ; and geographic region of the U.S. The NAACCR CiNA Research file categorizes age in 5-year intervals . We grouped age into 3 categories: <54, 55–64, 65+ years. Health insurance categories included: private, Medicare, Medicaid, Other , and no insurance or self-pay. Metropolitan/Non-metropolitan county designations were broadly based on population size (metropolitan has 50 000 persons or more). Percent of persons below poverty was categorized as: <9.99%, 10%–19.99%, and 20% or more below federal poverty levels. The 4 geographic regions of the U.S. were based on the U.S. Census Bureau: Northeast , South , Midwest , and West/Pacific .Our main outcome of interest, stage at diagnosis, was classified as local, regional, distant, or unknown, based on the SEER Summary Stage 1977/2000/Derived variable. We dichotomized stage as “early” if the tumor was identified as local disease at diagnosis and “late” stage if the tumor was regional or distant to the respective anatomic site. Approximately 60% of cases were classified as “Hispanic Not Otherwise Specified (NOS).” We conducted sensitivity analyses including and excluding Hispanic NOS group. Results differed; therefore, this group was included in the analysis to avoid selection bias in our results.We used the SEER Spanish/Hispanic Origin variable in identifying the Hispanic subgroups based on country of origin. The subgroups identified by this variable included European Spanish, Cuban, Mexican, Dominican, Central/South American, and Puerto Rican. European Spanish included males identified as being born in Spain, including the Canary Islands, Balearic Islands, and Andorra.2 tests were used to examine bivariate associations of country of origin with age, insurance status, county level attributes of residence and poverty, geographic region, stage at diagnosis, and anatomic site. Associations between demographic characteristics and late-stage diagnosis were evaluated using χ2 tests and univariate logistic regression. Odds ratios and corresponding 95% confidence intervals (CIs) of late-stage diagnosis compared with early stage were calculated for each category of Hispanic subgroup, with European Spanish as the reference group because preliminary analyses showed that European Spanish was similar to NH Whites (data not shown). Covariates in multivariable logistic regression models included: age at diagnosis, health insurance status, residential characteristics , and geographic region. Reference groups for covariates were chosen following other similar research and were generally the groups with the lowest cancer mortality.15 Lastly, interaction terms were added in the final adjusted model to examine the modification effect of Hispanic subgroup on all other variables in predicting late-stage diagnosis. No significant interactions were found (data not presented). Cases with unknown disease stage at diagnosis, health insurance status, county of residence, or unknown percent persons below poverty were excluded from the final multivariable models.The number of new cases of HPV-associated cancers from 2005 to 2016 among Hispanic males was extracted from SEER*Stat and stratified by country of origin. χ2 tests of these bivariate relationships were significant at P-values <.01.Compared with the other subgroups, a significantly higher proportion of Cubans were greater than 65 years of age (38.8%) and had Medicaid insurance (22.8%). A higher proportion of Mexicans had private insurance (27%) and lived in the Western/Pacific region of the country (59.7%). Central/South Americans composed a larger proportion of individuals with no insurance (15%) and living in counties with <9.9% poverty (18.4%). Higher proportions of oropharyngeal cancers were observed among Cubans (75.3%), Dominicans (72.7%), and European Spanish (72%), while a higher percentage of penile cancers were in Mexicans (26.7%). χThere were no differences in late-stage diagnosis of oropharyngeal cancers by Hispanic country of origin . Similar28 These findings are consistent with the estimated population level circumcision rates among the country of origin subgroups included in this study, whereby Puerto Rican males have a lower proportion of male circumcision (.14%) relative to European Spanish males (6.6%). Although males from Mexico have a larger proportion of circumcision rates (15.4%), we found higher odds of late-stage diagnosis in Mexicans compared with European Spanish. This may be due to European Spanish males in the U.S. to have circumcision rates more similar to NH White males in the US (71.2%). In fact, regression modeling with NH White males as the control group found no difference in late-stage diagnosis of penile cancers with European Spanish males . This suggests that including European Spanish with other Hispanic subgroups in epidemiological cancer research may mask finding of disparities among Hispanics.To the best of our knowledge, this is the first study to examine late-stage diagnosis of HPV-associated penile, anorectal, and oropharyngeal cancers among Hispanic males by country of origin. While relatively rare compared with other HPV-associated cancers, penile cancer was the only malignancy type where significant differences in stage at diagnosis by Hispanic subgroup were observed, with Mexican and Puerto Rican males having higher late-stage diagnosis compared with their European Spanish counterparts. Previous research has demonstrated that lack of circumcision and higher number of lifetime sexual partners are independent risk factors for reduced clearing of HPV and increased viral detection.Our study also found approximately 32% lower odds of late-stage diagnosis of penile cancers among Hispanic males >65 years of age. This finding is consistent with previous research that has reported higher incidence of oncogenic and more aggressive strains of genital HPV infections among younger males relative to their older counterparts, likely due to differences in sexual risk factors. Additionally, HPV-associated malignancies in males has been reported to be proportionally higher in Europe than in Latin America. HPV-associated cancers of the anorectum are associated with behavioral risk factors that are more localized, such as receptive anal intercourse, higher lifetime sexual partners, prior history of sexually transmitted infections. Our findings suggest that European Spanish males may have more of these risk factors relative to Puerto Rican and Central or South American males.The findings from this study suggest that Central or South American as well as Puerto Rican males had lower odds of late-stage anorectal cancers compared to their European Spanish counterparts. This observation is supported by previous research reporting a higher burden of age-adjusted incidence of anal cancer in Western Europeans  relative to males from the Caribbean , as well as Central  or South  America. Our observations of lower odds of late-stage diagnosis of oropharyngeal cancers in Hispanic males living in more impoverished areas can be partially explained by higher vaccine initiation and completion among males living in households with incomes below the poverty line as a result of safety-net health services. HPV-positive oropharyngeal cancers have also been reported to be more likely in younger persons, with higher SES and education, and lower exposures to tobacco and alcohol.37Hispanic males were found to have lower odds of late-stage diagnosis of oropharyngeal cancers among individuals with >65 years of age and living in more impoverished counties. Older age and lower odds of late-stage disease is consistent with our findings for penile cancers where younger males made up a higher proportion of HPV infections with aggressive viral strains.15 and probably due to lack of access to health care services as a barrier to receiving care throughout the cancer control continuum, including screening and prevention, diagnosis, treatment, survivorship, and end-of life care. Lack of insurance has been found to have a strong association with patients being diagnosed with cancer at later disease stages and having poorer survival. Similarly, existent literature identified that patients with Medicaid insurance experience advanced disease at diagnosis and worse survival.41 This may be explained by the fact that many previously uninsured patients qualify to enroll in Medicaid at or after being diagnosed with cancer, at which point available treatment modalities provide lower rates of disease eradication or control in the context of advanced disease.Among all HPV-associated cancers among Hispanic men, having Medicaid and no insurance were significantly associated with higher odds of late-stage diagnosis. These results are consistent with previous research43 Although Hispanic parents have positive attitudes about the HPV vaccine, they were less likely to receive a recommendation from a provider and also had a slower rate of HPV vaccination uptake compared to NH Whites.46 Provider recommendation has previously been reported to be significantly associated with vaccine initiation and completion among males. Vaccination in men who have sex with men increased from 22.5% to 37.6% between 2014 and 2017 according to the American Men’s Internet Survey; however, this was only in men who had seen a PCP within the past 12 months, and had disclosed sexual preference and previous STI (both risk factors for HPV associated cancers) to their PCP. Evidence suggests geographic variations in vaccination rates, with HPV coverage being higher among adolescents living below the federal poverty level and those living in metropolitan areas. However, another study found completion of HPV vaccination was lower in low-income neighborhoods.48 It has also been reported that receipt of other vaccinations such as the meningitis vaccine was a strong indicator for likelihood of initiating and completing the HPV vaccines, which may be a potential strategy to increase HPV vaccinations among young males.Research has suggested that lack of knowledge regarding HPV transmission, misperceptions about the vaccine, and lack of primary care provider (PCP) recommendation may influence parents’ decision to not vaccinate their sons. Therefore, our classification of HPV-associated cancers based on SCC histological type may have included cancers associated with alcohol consumption and/or smoking history, but the misclassification would be expected to be similar among the different country of origin subgroups.Although this is the first study to assess late-stage diagnosis of male HPV-associated cancers among Hispanics by country of origin, there are a few limitations to note in interpreting the results. First, this study was limited to the data within the NAACCR CiNA Deluxe file, which has a large amount of missing data pertaining to country of origin. Our analyses were conducted on cases of Hispanic males whose country of origin was known/confirmed through the NAACCR CiNA Deluxe file, and we included 12 years of data to have a sufficient number of cases for each HPV-associated cancer. We included the Hispanic NOS group in the final analyses to avoid selection bias, since this was a large proportion of cases (59.8%). Results may have differed if Hispanic country of origin were known. Second, the database also lacks details regarding other comorbidities , individual behaviors , or other demographic characteristics  that could affect stage at diagnosis for these cancers. Lastly, HPV status was not diagnostically confirmed using molecular testing for each of the cases, but instead based on the assumption that cancers from specific anatomic sites and histologies are highly associated with HPV. While penile cancer remains a rare malignancy in the U.S., the physical and psychological burdens can be significant, so it is clinically important to identify populations at higher risk based on their country of origin and/or cultural practices, for example, lower rates of circumcision. Additionally, since approximately 63% of penile cancers are related to HPV and vaccinations can potentially prevent these malignancies, there is strong support to target HPV vaccinations in these specific subgroups, as well as in the larger Hispanic community. Our findings additionally suggest benefit for increasing vaccination efforts among younger Hispanic males that meet eligibility for vaccination.Mexican and Puerto Rican males had higher odds of late-stage penile cancer relative to European Spanish males, which is significant because organ preservation is less likely at late disease stage. there is a strong suggestion that interventions to increase HPV vaccination can provide benefit among Hispanic males despite our findings not demonstrating higher odds of late-stage disease at diagnosis. Other cancer-specific health outcomes can be mitigated through vaccination particularly survival and mortality, especially when considering that Hispanics of lower SES have been previously reported to have worse outcomes relative to non-Hispanic Whites of higher SES. Our findings suggest that Hispanic males of higher SES may benefit from interventions to increase vaccination due to presenting at significantly later stages of oropharyngeal cancers relative to males of lower SES.When considering that 72% of oropharyngeal cancers are attributable to HPV,Because there are currently no recommended screening tests for HPV-associated cancers in males, increasing awareness of symptoms and signs of anorectal, oropharyngeal, and penile cancers are needed in the general public as well as in health care providers  to increase early detection of these cancers soon after presentation. Additionally, health insurance and access to health care are needed to decrease late-stage diagnosis of these preventable cancers among Hispanic males. When considering that a large proportion of the cases were categorized as Hispanic NOS within the registry, this study calls for better identification methods of Hispanic country of origin. Improved identification of these subgroups would allow for better understandings of cancer outcomes among Hispanics. Finally, more research is needed to expand the limited knowledge regarding HPV-associated cancers in this population. Inclusion of additional risk factors  and health outcomes in future research will allow greater specificity in clinical risk assessments and its implications for outreach to particular communities.


Cervical cancer is the most common Human Papilloma Virus (HPV)-related disease among women. Since 2008, HPV vaccination has been routinely recommended for pre-adolescent and adolescent girls in Uganda as the primary preventive measure for cervical cancer. However, in Uganda, most especially in Lira district, there is limited literature on HPV vaccination uptake and associated factors among girls aged 9-14years. This study assessed the uptake of HPV vaccine and associated factors among in-school girls aged 9–14 years in Lira City, northern Uganda.A cross-sectional study was conducted among 245 primary school girls aged 9–14 years in Lira City, northern Uganda. Multistage sampling technique was used to sample eligible participants and data was collected using interviewer administered questionnaire. Data was analysed using SPSS version 23.0. Descriptive statistics and multivariate logistic regression at 95% level of significance were used to identify the level of HPV vaccine uptake and predictors respectively.P ≤ 0.001], taught about cervical cancer at school , and exposure to outreach clinics .HPV vaccination uptake was at 19.6%  among the school girls aged 9–14 years in Lira City, northern Uganda. The mean age of the girls was 12.11 (± 1.651) years. Predictors that were independently associated with HPV vaccine uptake included; recommendation from health worker [aOR 9.09, 95% CI (3.19–25.88), The study found that one in five of the school girls in Lira City, northern Uganda. received HPV vaccine. Girls who were taught about cervical cancer at school, exposure to outreach clinics and received health worker recommendation had more odds of receiving HPV vaccine than their counter parts. The Ministry of Health should strengthen school based cervical cancer education, awareness raising about HPV vaccination and health worker recommendations to improve HPV vaccine uptake among school girls in Uganda. Genital human papillomavirus (HPV) infection is the most common sexually transmitted infection worldwide, estimated at 75% and 80% among men and women of all ages respectively . HPV is Global HPV immunization coverage as of 2018 was estimated at 12.2% , despiteIn Uganda, cervical cancer is the number one cause of death among women with cancer-related deaths estimated at 40.5 per 100,000 . HPV vacDespite the concerted efforts, previous secondary data analysis study showed that the uptake of HPV vaccine among girls aged 10–14 years was as low as 22% across Uganda . In addiThis was a cross-sectional study employing quantitative methods of data collection and analysis. This study was conducted among six schools in Lira City, northern Uganda. Lira City is the main, administrative, and commercial centre of the Lira District. It is located approximately 100 km (62 miles), southeast of Gulu City the largest city in northern Uganda, and approximately 337 km (209 miles), by road, north of Kampala the capital city of Uganda.This study was conducted among 245 girls aged 9–14 years in selected primary schools located in Lira City, northern Uganda. All girls aged 9-14years who were available at the time of data collection studying in selected schools and had assented were included in the study. Written informed consent was obtained from the parents/guardians of the participants/adolescent school girls. Girls who were ill, those whose parents had not consented, and girls who did not assent to participate in the study were excluded from the sample frame before the participant level sampling procedure. This study focused on girls aged 9–14 years because they are the target age group for the HPV vaccine and are also less likely sexually exposed .2pq/d2 with the assumptions, the confidence interval was taken at 95%., the level of uptake of HPV vaccine taken (p) was 0.1761 , ever taught about cervical cancer at school , and exposure to community outreach clinics , p = 0.013] as shown in (Table .19–25.88Our study found that just about one in five 19.6%) of the school girls aged 9–14 years in Lira city northern Uganda had received HPV vaccine. Our finding conforms with the result of a previous similar study conducted in Lira District, northern Uganda where uptake of the HPV vaccine was found to be 17.61% . The low.6% of thAs a cost-effective and easy to implement strategy to ensure girls aged 9–14 year old are reached with the HPV vaccine, the current policy of the Ugandan Ministry of Health recommends that, HPV vaccination be administered to school girls in primary school grade five regardless of their age . HoweverFurthermore, our study found that school girls who were taught about cervical cancer at school had thirteen odds of receiving HPV vaccination compared to their counterparts. This association could be due to the increased awareness and knowledge on cervical cancer, HPV vaccine to prevent cervical cancer and related health impact of cervical cancer on one’s life following the learning about cervical cancer in school , 27. TheOur study also found that school girls aged 9–14 years in Lira City northern Uganda, who received a recommendation for HPV vaccination from health workers had nine odds of receiving the HPV vaccine compared to their counterparts. These findings conform to results from a previous study carried out in Mulago Hospital, Central Uganda where health worker recommendation was one of the factors associated with the timely completion of the HPV vaccination among girls aged 9–14 years . This asOur study also found that school girls who were exposed to outreach clinics were having four odds of receiving HPV vaccine compared to their counterparts. This association could be due to synergies built between HPV vaccination and the existing health programs such as other immunization services, deworming, and HIV testing services, which are widely accepted by the community and the in schools , 32, 33.This study used a small sample size of 245 school-going adolescent girls. This could have affected statistical power thus impacting on the reliability of this study. However, the results are comparable with one of the previous cross-sectional study conducted in Lira District with a sample size of 460 female adolescents which also found a low 17.61%) uptake of HPV vaccine among female adolescents [.61% uptaThe study found that one in five of the school girls in Lira City, northern Uganda received HPV vaccine. Girls who were taught about cervical cancer at school, exposure to outreach clinics and received health worker recommendation were more likely to receive HPV vaccine than their counter parts. The Ministry of Health should strengthen school based cervical cancer education, awareness raising about HPV vaccination and health worker recommendations to improve HPV vaccine uptake among school girls in Uganda.There is also need to empower the teachers with the information about HPV and cervical cancer such that they can easily pass it on to girls in school and also be champions in their communities to ease dissemination of information.


To determine the value of low-risk human papillomavirus (HPV) PCR to screen for “high-grade anal squamous intraepithelial lesion and anal cancer” (HSIL-plus), rate of patients with low-grade anal squamous intraepithelial lesion (LSIL) progressing to HSIL-plus, and progression-related factors. Prospective, longitudinal study of consecutive MSM-LHIV attended between May 2010 and December 2021 and followed for 43 months (IQR: 12–76). HIV-related variables were gathered at baseline, performing anal cytology for HPV detection/genotyping, thin-layer cytological study, and high-resolution anoscopy (HRA). Follow-up was annual when HRA was normal or LSIL, and post-treatment in cases of HSIL-plus, re-evaluating sexual behavior, viral-immunological status, and HPV infection of anal mucosa. The 493 participants had mean age of 36 years: CD4 nadir < 200 cells/uL in 23.1%, virological failure in 4.1%, and tetravalent HPV vaccine > 5 years earlier in 15%. HSIL-plus was ruled out in patients with monoinfection by low-risk HPV genotype and normal cytology . Progression from LISL to HSIL-plus occurred in 4.27% of patients within 12 months (IQR: 12–12): risk factors were acquisition of high-risk  and low-risk (HR: 3.68 95% CI: 1.04–12.94) HPV genotypes, specifically genotype 6 , and history of AIDS (HR: 5.81 95% CI: 1.78–18.92). Monoinfection by LR-HPV genotypes in patients with normal cytology is not associated with anal cancer or precursor lesions. Progression from LSIL to HSIL-plus, observed in <5% of patients, was related to acquisition of HR and LR HPV genotypes, especially 6, and a history of AIDS. Anogenital infection by human papillomavirus (HPV) is the most common sexually transmitted infection (STI) worldwide . It has Immunosuppression is a risk factor for HPV acquisition and is produced by infection with the human immunodeficiency virus (HIV). The degree of immunodepression has been related to the incidence of anal dysplasia from chronic infection by HPV genotypes ,4. This Research to date has established a relationship between high-risk (HR) genotypes and a greater likelihood of precursor lesions of anogenital or oropharyngeal cancer/carcinomas ,8. MSM lInadequate data are available on the presence/absence of HSIL or anal cancer in patients with monoinfection by LR HPV genotype. The objectives of this study were to verify the sensitivity (S), specificity (Sp), and negative (NPV) and positive (PPV) predictive value of the presence of anal mucosal infection by LR HPV genotypes to screen for HSIL and/or anal cancer (HSIL-plus) in MSM-LHIV; to determine the percentage of these patients progressing from LSIL to HSIL-plus; and to analyze the factors related to this progression. The study included 493 MSM-LHIV aged 36 years (±10.36), 48.6% were university students, 48.1% smoked a mean of 1.65 packs/year (IQR: 0–15), 15% had received the full course of tetravalent HPV vaccine; and 39.8% had another STI; the median number of partners to date was 50 sexual partners (IQR: 20–200), and the median number in the previous 12 months was 2 (IQR 1–8). The mean age at HIV diagnosis was 31 years, and the mean CD4 count was 444.6 cells/uL, with 23.1% of participants having CD4 nadir < 200 cells/uL. At study enrolment, the CD4 count was 689.8 cells/uL and CD4/CD8 ratio 0.7 (0.46–0.98), 10.8% were naïve, and 4.1% were in virological failure. They had received antiretroviral treatment (ART) for a median of 20 months (IQR: 7–73): 32.9% with non-nucleoside analog reverse transcriptase inhibitor (NNRTI), 26.2% with protease inhibitor (PI), and 38.5% with integrase strand transfer inhibitors (INSTI). Infection by oncogenic genotypes was detected in 74%, with a median of 1 genotype (IQR:1–3); infection by non-oncogenic genotypes in 71.2%, with a median of 1 genotype (IQR:0–2); and coinfection in 56%. HR genotypes 16 (26.4%) and 31 (13.6%) were the most frequently isolated, followed by LR genotypes 6 (18.9%) and 42 (17.8%). Baseline cytology results showed LSIL in 46.7%, normal mucosa in 40.8%, atypical squamous cells of uncertain significance (ASCUS) in 7.7%, and HISL in 2.6%. High-resolution anoscopy (HRA) results were normal in 52.3% of participants, LSIL (AIN1) in 38.5%, HSIL (AIN2/3) in 11%, and ASCC in 0.6% .LR-HPV PCR achieved 79.6% sensitivity (S), 27.9% specificity (Sp), 12.7% positive predictive value (PPV), and 91.6% negative predictive value (NPV) for the diagnosis of HSIL-plus, while cytology demonstrated 72.7% S, 43.7% Sp, 14.2% PPV, and 82.4% NPV for this diagnosis. HSIL-plus could be ruled out in all patients with anal mucosa monoinfection by LR-HPV genotypes and normal cytology  . CorrelaThe median follow-up period was 43 months (IQR: 12–76). After a mean follow-up of 12 months, progression from LSIL (AIN1) to HSIL-plus was observed in 23 participants (4.7%) (IQR: 12–12), with 1 progressing to invasive anal cancer (ASCC) and 22 to HSIL (AIN2/AIN3), while spontaneous regression of LSIL (AIN1) was recorded in 150 (30.4%) (IQR: 12–24). p = 0.016]), AIDS stage , non-retired , the presence of condylomas , a history of condylomas , the acquisition of HR  and LR  genotypes, and anal mucosa infection by genotypes 6  and 84 . Infection by HPV-62 genotype emerged as a protective factor against progression   . In the multivariate analysis, progression from LSIL to HSIL-plus was related to the acquisition of HR  and LR (HR 3.68 95% CI: 1.04–12.94) HPV genotypes, including infection by genotype 6 (HR 4.47 95% CI: 1.34–14.91) and a history of AIDS (HR: 5.81 95% CI: 1.78–18.92) .In the study of factors favoring progression from AIN1 to HSIL-plus in patients with AIDS, no statistically significant association was found in bivariate analyses, which considered age, age at start of sexual relations, number of sexual partners in previous 12 months, VPH vaccination, time since HIV diagnosis, CD4 count, CD8 count, viral load, and number of HR and LR HPV genotypes and of all genotypes.The participants in this study were followed for a median of 43 months. One-third were aged under 30 years, and three-fifths between 30 and 50 years; around one-half of them smoked, and one-fifth reported a history of >300 sexual partners throughout life. In regard to HIV infection, their viroimmunological status was excellent, with only 4.1% in virologic failure and a median CD4 count of 698.9 cells; 71.2% were infected with LR genotypes, 74% with HR genotypes, and 56% were coinfected with LR and HR genotypes. Less than half of the participants had normal anal mucosa, around one-tenth had HSIL at enrolment, and three (0.6%) had anal cancer, a similar profile to that of other European cohorts , and eveWith respect to the value of LR-HPV PCR as the sole screening test for HSIL or anal cancer, it achieved S and NPV values that were higher than obtained with anal cytology and very similar to those observed with HR-HPV PCR. HSIL-plus could be ruled out in all participants with monoinfection by LR-HPV genotypes and normal cytology. This is the first report on the value of LR-HPV PCR in the diagnosis of these lesions in MSM-LHIV, showing that the combination of LR-HPV PCR and anal cytology ruled out HSIL-plus with 100% S and 100% NPV. These findings are in line with previously published results supporting the combination of HR-HPV PCR with anal cytology to screen for anal cancer and precursor lesions in HIV-positive MSM ,13LSIL progressed to HSIL-plus (1 ASCC and 22 AIN2/3) in less than 5% of participants during the follow-up period, largely within one year of follow-up, lower than the progression rates of 16.4%  and 36% par excellence in anal mucosa and responsible for both precursor lesions and anal cancer [The degree of immunosuppression, defined by current CD4 count and CD4 nadir < 200 cells/uL, has been associated with the risk of lesion progression ,17. A rel cancer . Furtherl cancer .The results of this study are limited to a specific population of HIV-positive MSM and cannot be extrapolated to other types of subjects. Study strengths include the prospective and longitudinal design, large sample size, and systematic long-term follow-up. Notably, this is the first published report on monoinfection by LR-HPV genotypes in the anal canal of MSM-LHIV. In conclusion, monoinfection due to LR-HPV genotypes is not associated with anal cancer or precursor lesions in patients with normal cytology. The progression rate from LSIL to HSIL-plus was <5% and was related to the acquisition of HR- and LR-HPV genotypes  and a history of AIDS. These findings are directly relevant to the care of anal dysplasia in MSM-LHIV, because the presence of LR-HPV genotypes alone with normal cytology rules out precancerous lesions and anal cancer, allowing for a longer interval between anoscopy examinations. Furthermore, given that only a very small percentage of patients with low-grade AIN1 progress, and over a prolonged period, these can be monitored by HRA every year rather than every three or six months. This prospective, longitudinal, single-center study included consecutive MSM-LHIV who participated between May 2010 and December 2021 in a program for the screening, diagnosis, treatment, and follow-up of anal mucosa dysplastic lesions. All participants were attended at Virgen de las Nieves University Hospital (HUVN) of Granada, after referral from Infectious Disease Units of the HUVN of Granada and Hospital Complex of Jaen . This study was approved by the ethical committee of the coordinating center. All patients had given consent to the use of their data for research purposes, and all data were gathered in accordance with Spanish personal data protection legislation (Organic Law 3/5 December 2018).The inclusion criterion was to be MSM-LHIV aged over 17 years. Exclusion criteria were being a heterosexual man or woman living with HIV and having a history of anal canal neoplasm in the previous five years.At the baseline visit (V0), patients were informed about the conditions and objectives of this investigation, and data were gathered on their age, history of perianal-genital condylomas, number of sexual partners throughout life, number of sexual partners over past 12 months, age at onset of sexual relations, utilization of condoms and their percentage utilization, smoking (yes/no and packs/year), alcohol consumption , injection drug use (IDU), ex-IDU, nationality, schooling, months with HIV diagnosis, CDC-classified HIV stage, months under antiretroviral treatment (ART) and lines used, virological failure (RNA ≥ 50 copies/mL in ≥2 determinations during previous 6 months), CD4 nadir, CD4 and CD8 lymphocyte counts, viral load at HIV diagnosis, and the presence of other infections, including chronic hepatopathy by hepatitis B virus (HBV) or hepatitis C virus (HCV), syphilis, other sexual transmitted infections (STIs), perianal-genital warts, and latent, treated, or active tuberculous infection. Information was also collected on CD4 and CD8 cell counts, CD4/CD8 ratio, and viral load at V0. At the same visit, cotton swabs impregnated with physiological saline were used to take two anal canal mucosal samples: one for HPV detection and genotyping by qualitative polymerase chain reaction (PCR) (Linear Array HPV Genotyping Test) with a “GeneAmp PCR System 9700” thermocycler , and the other for thin-layer cytological study with a ThinPrep 2000 Processor . Both samples were immersed in thin-layer liquid and sent to the hospital pathology laboratory for analysis. Genotypes 16, 18, 26, 31, 33, 35, 39, 45, 51–53, 56, 58, 59, 66, 68, 73, and 82 were considered high risk (HR-HPV), and genotypes 6, 11, 34, 40, 42–44, 54, 55, 57, 61, 70–72, 81, 83, 84, and 89 low risk (LR-HPV). Genotypes 39, 45, 59, and 68 were classified as subspecies of genotype HPV 18 and genotypes 31, 33, 35, 52, 58, and 67 as subspecies of HPV 16 .© colposcope , introducing a transparent disposable anoscope through which 5 mL acetic acid was instilled and left for around 3 min, removing it for examination of the mucosa. Next, 5% Lugol’s iodine was instilled for 1 min and the anoscopic examination was repeated. Samples were taken from quadrants of apparently normal mucosa and from areas with Lugol-negative aceto-white lesions. Biopsies were performed with endoscopic retrograde cholangiopancreatography (ERCP). After an interval of 4–12 weeks, participants underwent rectal inspection and digital rectal examination followed by high-resolution anoscopy (HRA) with a Carl Zeiss 150 fc Patients with normal anoscopy or LSIL(AIN1) were followed up at one year with cytology, HPV PCR, and anoscopy studies. Patients with HSIL either underwent mucosectomy by electrical scalpel (offered from May 2010 onwards) in the Coloproctology Unit of the General Surgery Department or self-administered 5% imiquimod three times a week for 16 weeks (offered from 2014 onwards). Anoscopy was performed in these patients at the end of their treatment, scheduling a follow-up at one year if the outcome was normal/LSIL or retreatment if HSIL, and referring the patient to the hospital oncology department if anal cancer was detected. Information was gathered at the follow-up visit on the number of sexual partners in the previous 12 months, the emergence of STIs , genital/anal condylomas, ART experience , CD4 and CD8 lymphocyte counts, CD4/CD8 ratio, and HIV viral load. In the cytology study, the Bethesda classification  was usedt-test for independent samples was applied for quantitative variables when normally distributed according to the Kolmogorov–Smirnov test and the Mann–Whitney U test when non-normally distributed. Qualitative variables were analyzed with Pearson’s chi-square test or, when application criteria were not met, Fisher’s test. Multiple logistic regression analysis was then performed, entering variables that were significant in bivariate analyses or considered relevant in the literature. SPSS 21.0  was used for data analyses, and the level of significance was 0.05 in all tests. In descriptive analysis, means, standard deviations, medians, and percentiles were calculated for quantitative variables and absolute and relative frequencies for qualitative variables. In bivariate analyses, the Student’s