Oral Human Papillomavirus Benign Lesions and HPV-Related Cancer in Healthy Children: A Systematic Review

Simple Summary The present systematic review aimed to gain deeper insight into the epidemiology, clinical presentation, and histopathology of HPV-related benign and malignant lesions of the oral mucosa in pediatric patients to improve the multidisciplinary preventive and therapeutic management of oral and general healthcare. The emerging role of HPV in oral carcinogenesis in pediatric subjects, along with benign oral mucosal lesions and asymptomatic infections, brings HPV vaccination to the forefront specifically for this age group. Abstract The present systematic review aimed to assess the prevalence of oral HPV-related lesions, categorized as benign (verruca vulgaris “VV”, squamous cell papilloma “SP”, condyloma acuminata “CA”, and focal epithelial hyperplasia “FEH”) and malignant (oral squamous cell carcinoma “OSCC”), in descending order of occurrence in pediatric subjects (≤18 years of age). The secondary objectives were to evaluate the frequency and types of oral lesions described in relation to HPV genotypes and the HPV vaccine type (if any). The study protocol, compliant with the PRISMA statement, was registered at PROSPERO (CRD42022352268). Data from 60 studies, of which quality was assessed using the ROBINS-I tool, were independently extracted and synthesized. Along with seven poorly described benign HPV-related oral lesions that could not be categorized, a total of 146 HPV-related oral lesions, namely 47.26% (n = 69) VV, SP, and CA, 51.37% (n = 75) FEH, and 1.37% (n = 2) OSSC, were diagnosed in 153 pediatric subjects (M:F ratio = 1:1.4) with a mean age of lesion onset of 8.46 years. The viral genotypes detected were HPV-13 (30.61%), -6 (20.41%), -11 (16.33%), HPV-2 (12.24%), -32 (10.20%), -57 (6.12%), and -16 (4.08%). No HPV vaccination was reported in any case. Further studies should be conducted to evaluate the prevalence of HPV-related benign and malignant lesions and the potential role of HPV and associated vaccination in oral carcinogenesis in pediatric subjects.


Introduction
Human papillomavirus (HPV) is associated with benign and malignant diseases of various locations, mainly affecting the skin and genital and oral mucosa [1]. In detail, the benign HPV-related lesions of the oral mucosa recognized by the World Health Organization are squamous cell papilloma (SP), condyloma acuminatum (CA), verruca vulgaris (VV), and focal epithelial hyperplasia (FEH) [2].

Data Extraction and Collection
Two reviewers (M.P.D.P., F.D.S.) extracted data independently, and a third reviewer (G.P.) was consulted in cases of discrepancies. A standardized data extraction form was used, developed under models proposed for intervention reviews of RCTs and non-RCTs [13].
The following data meeting eligibility criteria were collected from each study included in this systematic review: I First author, year, journal, funding, study quality; I Design and number of studies reported; sample size, gender ratio, mean age, comorbidities of the population investigated; HPV vaccine (if any; targeted HPV genotypes); I Total number or prevalence of pediatric subjects with oral HPV-related lesions diagnosed through a clinical examination confirmed based on histopathologic analysis (except for FEH) with/without PCR confirmation; I Macroscopic and microscopic features of oral lesions categorized as benign and malignant oral lesions [15]; Data from 60 studies describing oral HPV-related lesions diagnosed through clinical examination and confirmed based on histopathologic analysis in pediatric subjects were extracted and synthesized.
Of the 60 included studies, 36 were case reports, 19 were case series, 3 were retrospective, and 2 were prospective studies involving a total of 153 cases diagnosed with HPV-related oral lesions in pediatric (≤18 years of age) subjects.
The sources, methods, and qualitative synthesis of oral outcomes from the included studies were pooled. Only data that met eligibility criteria were extracted and analyzed; therefore, data from individuals who were >18-years-old were not detailed. Table 1 summarizes data from included studies describing pediatric (≤18 years of age) cases diagnosed with oral papilloma, verruca vulgaris, or condyloma acuminata. The sources, methods, and qualitative synthesis of oral outcomes from the included studies were pooled. Only data that met eligibility criteria were extracted and analyzed; therefore, data from individuals who were >18-years-old were not detailed. Table 1 summarizes data from included studies describing pediatric (≤18 years of age) cases diagnosed with oral papilloma, verruca vulgaris, or condyloma acuminata. Table 1. Data extracted and collected from studies reporting pediatric cases diagnosed with oral papilloma, verruca vulgaris, or condyloma acuminata. Study characteristics: first author, year, and journal of publication; study design; the reference number; funding. Study methods: sample size (n.), mean age (y.o.), gender ratio (M/F), country, comorbidities and associated ongoing treatments, relatives with similar lesions, HPV exposure (if any), time to onset of oral lesions, type of HPV vaccine administered (if any). Oral HPV-related lesions: macroscopic and microscopic features, number (single/multiple), distribution (unilateral/bilateral, asymmetric or symmetric), location, extra-oral involvement, HPV genotype. Diagnosis: definitive diagnosis, diagnostic procedure(s) performed, therapy, progression.
The study population included 35 males and 33 females between the ages of 1.5 and 18 years, with a mean age of 8.9. However, the gender and age of six subjects were not reported [40].
Country of origin or ethnicity was reported for 28 patients, as follows:  [41].
The mean time to the onset of oral lesions was 11.4 months and ranged from 14 days to 7 years. Only one study [28] reported that the patient had not received an HPV vaccine.

Focal Epithelial Hyperplasia: Case Characteristics
Seventy-five pediatric subjects were diagnosed with focal epithelial hyperplasia [2,18,21,29,. Two studies [56,62] included in this systematic review described cases of FEH in adult patients who reported having the condition since childhood; data from these two studies are shown in Table 2 but were not included in the data analysis. The study population included 18 males and 45 females aged 0-18 years, with a mean age of 9.97 years. However, gender was not specified for 10 subjects [21].
The median time to onset of oral lesions was 19.9 months and ranged from 1 month to 8 years. No study reported whether or not patients were vaccinated against HPV.
Regarding the progression of oral FEH lesions: in 14 cases, lesions healed after an average of 15.95 months, ranging from 14 days to 3 years; in 17 cases, no recurrence occurred after an average of 11 months, with a follow-up ranging from 1.5 months to 1 year. Improvement was noted in seven cases after an average of 18.4 months, ranging from 1 month to 5 years. Recurrence occurred in two cases, after six months in 1 case, while deterioration was declared in 1 case and no improvement occurred in 9 cases with an average follow-up time of 27 months. Table 3 summarizes data from identified studies characterizing pediatric (≤18 years of age) cases diagnosed with oral squamous cell carcinoma.

Oral Squamous Cell Carcinoma: Case Characteristics
A total of two pediatric subjects were diagnosed with oral malignant HPV-related lesions categorized as oral squamous cell carcinoma (OSCC) [1,20].
The study population included two males aged 5 to 8 years, with a mean age of 6.5 years, one of whom was of Caucasian origin [20], and both were without comorbidities.
In one case, HPV exposure through self-vaccination was suspected [18], which was supported by evidence that his two brothers also had HPV-related lesions [18].

Oral Squamous Cell Carcinoma: Macroscopic and Microscopic Features, Extra-Oral Involvement, HPV Genotype
Macroscopic and microscopic features were reported in both studies [1,18], and in two cases, the lesions appeared to be solitary [1,18] and unilateral [1,18] and involved the maxillary ridge [1,18].
Extra-oral involvement was described in one case [18] as warts on the hands, chin, philtrum, and commissures.
The HPV genotype involved was not reported, but p16 positivity was noted in both cases; HPV association with pediatric OSCC was therefore reported based on the p16 status of the lesions.
In one case, the patient healed after 24 months [1] since the partial maxillectomy, while in one case, the patient had two recurrences [18] and one exacerbation [18] and healed only 4 weeks after the partial maxillectomy [18].
On average, patients visited a physician 15.65 months after the appearance of oral lesions, and in no case was HPV vaccination indicated.
The most frequently affected sites were as follows, in descending order: lips (36.6%) in 74 cases (upper lip was reported in 29 and lower lip in 24 cases), followed by cheeks (17.3%) in 35 cases, tongue (13.9%) in 28 cases, palate (8.9%) in 18 cases, labial commissures (7.4%) in 15 cases, gingiva in 14 cases, vermilion (2.5%) in 5 cases, anterior faucial columns (1.5%), uvula (1.5%), and floor of mouth (1.5%) in 3 cases, tonsils (0.99%), the vestibule (0.99%) and alveolar ridge (0.99%) in 2 cases; N\D oral mucosa in 1 (0.5%). Table 3. Extracted and collected data from studies reporting pediatric cases diagnosed with oral squamous cell carcinoma. Study characteristics: first author, year, and journal of publication; study design; the reference number; funding. Study methods: sample size (n.), mean age (y.o.), gender ratio (M/F), country, comorbidities and associated ongoing treatments, relatives with similar lesions, HPV exposure (if any), time to onset of oral lesions, type of HPV vaccine administered (if any). Oral HPV-related lesions: macroscopic and microscopic features, number (single/multiple), distribution (unilateral/bilateral, asymmetric or symmetric), location, extra-oral involvement, HPV genotype. Diagnosis: definitive diagnosis, diagnostic procedure(s) performed, therapy, progression. Microscopic features: sheets of proliferative squamous epithelium and occasional keratin formation, with bland cytology and absence of atypia or cellular pleomorphism; anastomosing channels lined by squamous epithelium with hyperkeratosis and microcystic structures resembling "rabbit burrows" and areas with prominent nuclear pleomorphism, hyperchromasia, and numerous atypical mitotic figures, as well as diffuse p16 positivity HPV genotype detected: N\A but positivity for p16 Diagnosis OSCC (n.1) Diagnostic procedure(s) Periapical radiograph: radiolucency apical to #E and a mesiodens between the 2 permanent central incisors CBCT: palatal soft tissues swelling and impacted mesiodens Biopsy PCR analysis Therapy First step: antibiotics Second step: extraction of #D and #E Third step: biopsy Fourth step: excisional biopsy Fifth step: marginal resection of the anterior emi-maxilla with removal of #8, #7, #6 and #C Progression No response after the first step of therapy Worsening after the second step Recurrence after the third step Healed after 4 weeks since the fifth step Table 3. Cont. Diagnostic procedure(s) Biopsy CBTC: osteolytic lesion with destruction of the buccal cortex; the floor of maxillary sinus was displaced superiorly and there was a thin smooth layer of periosteal new bone over the tumor mass; the roots of the first molar were medially displaced, but there was no evidence of root resorption Incisional biopsy CT: tumor mass displacing the facial artery and the buccal fat plane laterally; the bony crypts of the developing second premolar and the second molar were mostly intact, except for defects adjacent to the lesion, and the follicular spaces of these teeth appeared uniform MRI: no evidence of disease in the regional lymph nodes In situ hybridization for HBV: negative Therapy Partial maxillectomy Progression Healed after 24 months Abbreviations: number, "n.", years old, "y.o."; missing data, "MD"; not available "N\A"; not defined, "N\D"; human papillomavirus, "HPV"; focal epithelial hyperplasia, "FEH"; oral squamous cell carcinoma, "OSCC"; human immunodeficiency virus, "HIV"; human hepatitis B virus, "EBV"; polymerase chain reaction, "PCR"; computed tomography, "CT"; computed tomography cone beam, "CBCT"; magnetic resonance imaging, "MRI"; trichloroacetic acid, "TCA". On average, patients visited a physician 15.65 months after the appearance of or lesions, and in no case was HPV vaccination indicated.

Quality Assessment
The risk of bias of the non-randomized studies included in the present systematic review is reported in Table 4.

Quality Assessment
The risk of bias of the non-randomized studies included in the present systematic review is reported in Table 4.     Puranen et al., 1996 [42] PY

Discussion
The present systematic review aimed to assess the prevalence of oral HPV-related lesions in pediatric subjects (≤18 years of age), categorize them as benign and malignant, and rank them in descending order of occurrence. The secondary objectives were to evaluate the frequency and types of oral lesions described in relation to HPV genotypes and the HPV vaccine type (if any).
Sixty studies were considered, and along with seven poorly described benign HPVrelated oral lesions that could not be categorized, a total of 146 HPV-related oral lesions, The pediatric cases diagnosed with benign oral HPV lesions had a mean age of 8.9 years, slightly lower than the mean age found for FEH (9.97 years), as described later, and lower than the range reported for the highest incidence of verruca vulgaris, between 12 and 16 years of age [74].
In general, HPV-related oral benign lesions are more common in adults [78], similar to the rate of detectable oral HPV infection, which also increases in adulthood [79]. More specifically, detectable oral HPV infection has two peaks in prevalence at ages 30-34 and 60-64 years [79]. It has been hypothesized that the peak at older ages may be related to the normal process of immunosenescence [80], leading to the possible reactivation of latent HPV infections [81]. Nevertheless, benign HPV-related oral lesions have also shown a similar bimodal peak, with condylomata acuminata showing a higher incidence between the third and fourth decades of life and squamous cell papillomas between the third and seventh decades of life [78].
The main transmission route for HPV is skin-to-skin or skin-to-mucosa contact [82]. Sexual transmission has also been adequately documented [80]. Accordingly, in the present systematic review, three cases were sexually abused [40,45] and three cases were investigated for suspected sexual abuse [28,36,48]. Horizontal transmission can occur via fomites, fingers, mouth, and skin contact [82]. Most skin warts in children result from horizontal transmission [15]. For oral mucosal lesions, few studies in the present review also investigated the presence of potentially HPV-related lesions on the body in the patient's family members, and only three cases [28,39,45] were found in at least one family member, suggesting presumed horizontal transmission. In two patients in the present study, self-inoculation was suspected in virgin women and children with genital warts without suspected sexual abuse [82]. Self-inoculation is typical of vulvar warts in children who suck their thumbs or carry their fingers in their mouths [78]. Simultaneous evidence of lesions in the genital area and oral cavity may indicate sexual transmission [78]. Another route of transmission is vertical mother-to-child transmission [82], which is the main route of HPV infection in newborns [15]. Finally, several studies have suggested the possibility of viral transmission through the amniotic fluid or placenta or through contact with the genital mucosa of the mother during delivery [82]. The results of the present study do not suggest a higher prevalence of one route of transmission than the other. However, most of the included studies did not investigate this aspect of infection.
Squamous papillomas are estimated to be the most common benign oral epithelial le-sions in both pediatric and adult populations [78], which is consistent with the present results (n = 37).
Second, in overall frequency, verrucae vulgaris is the predominant cutaneous manifestation of HPV infection, with a total incidence of 10% in children and young adults [74]. Although considered uncommon in the oral cavity [74], VV cases have currently been observed in 19 cases, accounting for 12.42% of all diagnoses.
Condyloma acuminata is more common anogenitally and is the most common manifestation of sexually transmitted infections in the United States and the United Kingdom [74]. It is also estimated that CA cases are not common in the oral cavity [74], which is consistent with the present results showing that CA is the least frequently reported oral manifestation in pediatric subjects (n = 13).
Rarely, multiple verrucae vulgaris occurs together in the oral cavity or clusters [74]; the same is true for SPs. Indeed, in the study by Frigerio et al. [83], which examined 205 oral SPs, only four patients had more than two lesions simultaneously.
Despite the fact that CAs are the benign HPV-related oral lesions that most commonly occur as multiple lesions and tend to coalesce and although Panici et al. [84], examining 101 oral Cas, found 61% of patients with more than five lesions, the retrieved data revealed a higher prevalence of single (22 cases) compared with multiple lesions (10 cases), most of which were represented by CA [2,36,39,40,45,46].
The palate and tongue are considered the sites most commonly affected by SPs [78]. VV, on the other hand, occurs most frequently on the labial mucosa and palate [74], whereas CA occurs on the tongue and upper lip [74]. In line with these findings, the results of the present systematic review showed that benign HPV-related oral lesions most frequently affected the lips (n = 23; 31.08%), with apparently no preference for the upper or lower lip, palate (n = 13; 17.57%), and tongue (n = 9; 12.16%).
Only one study [30] reported that the child had not received HPV vaccination, whereas such information was not detailed elsewhere. Especially, in this pediatric population, dentists should make patients and their parents and caregivers aware of the importance of HPV vaccination, even in children who already have infections, regardless of their HPV status. The American Cancer Society (ACS) has developed new recommendations for HPV vaccination that should be routinely administered between the ages of 9 and 12 to achieve the greatest vaccine efficacy and increase the number of cancers prevented [11]. Healthcare providers should encourage vaccination as early as 9 to 10 years of age and if appropriate, advise those who have not been vaccinated or have not completed vaccination that vaccine administration is less effective in reducing cancer risk at an older age [9]. It is therefore crucial that the pediatric population is encouraged to receive HPV vaccination, as vaccines are critical prevention measures, as was also demonstrated during the COVID-19 pandemic, in which vaccines significantly reduced the risk of virus transmission and infection and prevented severe forms of the disease [85].

Oral Benign HPV-Related Lesions in Pediatric Subjects: Focal Epithelial Hyperplasia
Focal Epithelial Hyperplasia (FEH), also known as Heck's disease, is an asymptomatic and benign condition caused by HPV-13 and/or -32 genotypes [56,86] that presents in the oral cavity as multiple, well-circumscribed, raised, soft papules, and nodules with the same color as the surrounding oral mucosa [56,87].
FEH can affect children and adults [15] but generally shows a higher prevalence in younger individuals, with the first and second decades of life being most commonly affected [87]. Accordingly, the mean age currently calculated was 9.97 years. These data are consistent with those of Sethi et al. [88], who studied a broader age range and included subjects aged 3 to 92 years with a mean age of 23.1.
The same study [88] recorded a male-to-female ratio of 3:4. The higher prevalence of FEH in females has also been described in other studies [86,88,89] with a ratio of 3:4 to 1:5, which is consistent with the findings of the present systematic review that recorded a male-to-female ratio of 2:5. The reason for the higher incidence of FEH in females is still unclear and may be due to the poor hygienic conditions in which women live in certain ethnic groups [90], especially in some regions with a higher FEH prevalence.
In fact, there are no accurate data on the prevalence of FEH in the general population, but it is considered a rare condition [15]. According to initial studies, it occurs most frequently in Native Americans, Mexican Indians, South Americans, and Eskimos [15,89]. Accordingly, the data extracted in this systematic review showed that the country of origin from which most cases of FEH were reported in pediatric patients was Venezuela (n = 9) [24], followed by Iran (n = 8) [57,64], Brazil, and Ghana (n = 6) [53,63,66]. Overall, 20 (26.7%) of the 75 FEH cases were registered in South America, an epidemiological finding consistent with the initial estimate of the geographic distribution of FEH [13]. The involvement of the African continent also seems consistent, with 10 (13.3%) of the cases included in this systematic review (Morocco (n = 1) [61], Libya (n = 1) [58], Algeria (n = 1) [59], Africa (n = 1) [51]; Ghana (n = 6) [66]). In addition, data from the present study also show a high incidence of FEH in Iran, where 8 (10.7%) of the 75 cases occurred [57,64]. This suggests that Heck's disease is generally rare and likely more common in certain ethnic and racial groups [89] living in more densely populated and developing countries. These contexts are even referred to as 'prisons', underscoring the restricted living conditions that place them at high risk for infection [NO_PRINTED_FORM]. Coherently, fewer cases have been diagnosed with oral FEH in Europe and North America, although they have slightly increased between 2001 and 2019 (20 published cases) compared to numbers in 1966-2005 (9 published cases) [86].
The mean time to the appearance of oral lesions was 19.9 months, ranging from 1 to 8 years, as on average, more than 1.5 years elapsed before patients saw a specialist for control. In two cases [56,62], a specialist was even not seen until 10 to 25 years after the lesions appeared. These data suggest that the surveyed population lacks knowledge about Heck's disease and awareness and concern about oral mucosal changes. In addition, it can be assumed that the cases of FEH probably waited an average of one and a half years after the appearance of the lesions before seeing a specialist because the lesions were asymptomatic and did not affect oral functions and esthetics [60]. Consequently, it seems necessary to make the population aware of the importance of regular oral and dental checkups, even more so in the case of oral mucosal changes. These findings can be a more comprehensive alarm signal, even if they are associated with a benign pathology, such as FEH. Indeed, oral lesions, even if asymptomatic, should never be underestimated, as they can be an early sign of other systemic diseases or malignancies. Thus, raising awareness of this issue goes hand in hand with encouraging patients to be vaccinated against HPV.
In this regard, no study reported whether patients with manifestations of Heck's disease received the vaccine. This may be in part because FEH is associated with low-risk HPV-13 and -32 genotypes, whereas HPV vaccines target high-risk HPV genotypes [91].
However, although FEH is a benign condition caused by low-risk HPV genotypes, diagnosed cases may be at higher risk for infection with other viral genotypes. Of note, coinfection with multiple HPV genotypes is recognized as a risk factor for invasive cervical cancer (ICC) and high-grade squamous intraepithelial lesions (HSILs) [92], as is HPV-HIV coinfection for various squamous cell carcinomas [93]. Therefore, awareness, particularly of pediatric patients, who are preferentially targeted by HPV vaccination, remains critical to curbing coinfection, which can further increase the risk of malignancies.
Moreover, HPV vaccination also plays an essential role because Highly Active Antiretroviral Therapy (HAART) has been shown to be less effective for HIV-HPV coinfectionrelated malignancies, and to date, no vaccine against HIV is available [92].
Furthermore, the rate of migration from areas at a higher risk of infection to highincome countries has generally increased, proportionally increasing the number of potentially underdiagnosed cases.
Because oral FEH lesions often regress spontaneously [89] and have no cosmetic or functional consequences [84], treatment is often unnecessary [87]. However, it may be considered if the lesions become painful, interfere with occlusion, or present esthetic complications or social stigma [89,94]. Possible therapies include traditional surgery, laser surgery, electrocautery, cryotherapy, and trichloroacetic acid, excision of the lesion(s), or drug therapy with interferon, podophyllin, vitamin A, levamisole, or imiquimod [49,52,54,55,61,63,65,69,75,95]. These techniques, heterogeneously applied and associated with different success and recurrence rates, were also recorded in this systematic review [94], probably due to the lack of guidelines.
The surgical approach of excising lesions should be limited to single and limited lesions. However, in most cases, FEH occurs as multiple nodulo-papular lesions involving large and diverse mucosa and perilabial tissue areas.
Coherently, in this systematic review, single lesions accounted for 5.3% of cases, while the remaining 94.7% had multiple lesions, predominantly with bilateral and asymmetric patterns. In cases with greater mucosal involvement and considering the often young age of patients (first to second decade of life), conservative and atraumatic approaches may be preferred to preserve esthetics and functions.
From this perspective, a new therapeutic approach using nano-pulse stimulation (NPS) has shown promising results [94]. This technique uses ultrashort electrical pulses to induce localized cell death [94], in contrast to cryotherapy, electrodesiccation, or laser techniques, which produce less precise and effective thermal necrosis [94]. In addition, postoperative complications were minimal [94]. However, further studies on FEH cases treated with NPS are needed to confirm the true efficacy for lesions in the oral cavity, but this technique has already shown optimal safety and efficacy in the treatment of other non-genital warts.

Oral Malignant HPV-Related Lesions in Pediatric Subjects: Oral Squamous Cell Carcinoma
Oral squamous cell carcinoma is a malignant epithelial neoplasm of the head and neck and ranks seventh in worldwide cancer prevalence [96]. However, it remains rare in the pediatric population [20], often associated with congenital syndromes correlated with an increased cancer risk, such as Fanconi anemia, Li-Fraumeni syndrome, Bloom syndrome, ataxia telangiectasia, and xeroderma pigmentosum [97,98], but not others associated with various oral mucosal changes. According to a recent literature review by Lee et al. [18], there were 25 reported cases of OSCC in non-syndromic patients under 16 years of age, while the review by Magalhaes et al. [1] listed a total of 42 cases of OSCC in individuals under 20 years of age in the literature since 1976.
Although its oncogenic role is still not well understood [5], HPV appears to be responsible for 3% of oral carcinomas in adults [6]. To our knowledge, two pediatric cases of OSCC [1,18] have been identified in which HPV, although the viral genotype was not reported, or HPV-positive predictive proteins have been detected. In detail, p16 positivity was detected in both cases [1,18]. The overexpression of p16 is induced by the E7 viral protein of high-risk HPV [99], such as HPV-16 and HPV-18, which are most commonly associated with OSCC [6]. Consequently, detecting high levels of p16 predicts high-risk HPV infection [5]. However, on the one hand, elevated p16 levels were also found in HPV-negative tumors, and on the other hand, many HPV-positive OSCCs were negative for p16 [4], revealing a discrepancy between HPV DNA positivity and oncogenic activity [4]. Given these considerations, although the HPV association with pediatric oral cancer has been reported based on the p16 status of the tumors, the role of HPV in oral carcinogen-esis in these cases is unknown, and HPV-associated OSCC would be extremely rare in a pediatric population.
The two young subjects with HPV-related OSCC were both males, which is consistent with other studies reporting a higher prevalence of OSCC in pediatric male patients [1,18] and of HPV-OSCC in adult males (70% of cases) [100], likely related to the higher rate of oral HPV infection in males, who usually experience oral rather than anogenital infections, compared with those in females [101].
In those two cases [1,18], lesions occurred in the maxillary alveolar ridge region, similar to 12 of 42 OSCC pediatric cases with the involvement of the gingival alveolar ridge described by Magalhaes et al. [1], probably due to embryonic tissue and increased stem cell activity implicated in odontogenesis until tooth eruption [1,98].
In both studies reporting HPV-related OSCC in pediatric subjects [1,18], information about possible HPV vaccination was not reported. Nevertheless, raising awareness of HPV vaccination among children and their parents and caregivers may be of even greater importance, especially in patients exposed to high-risk HPV [102]. In fact, persistent highrisk-HPV infections are associated with more than 90% of cervical cancers and several vaginal, anal, vulvar, penile, and oropharyngeal cancers [103].
Overall, these findings and the possible independent role of HPV in oral carcinogenesis underscore the importance of HPV vaccination. The currently available vaccines (bivalent, quadrivalent, and nonavalent) are the primary means of protection against HPV infection. Since the COVID-19 pandemic abruptly halted the HPV vaccination campaign, it is advisable to revive and exceed the vaccination schedule in time for the first pandemic peak.
Oral healthcare providers, who frequently encounter benign HPV-related lesions, should also take a leading role in this scenario, both in the early diagnosis and treatment of oral HPV-related lesions and in raising awareness of HPV vaccination among pediatric patients and their parents and caregivers.

Conflicts of Interest:
The authors declare no conflict of interest.