Management of Oral Manifestations of Herpes Simplex Virus, Varicella Zoster Virus, and Human Papillomavirus

Many viral infections are lifelong with recurring lesions and oral manifestations. Human herpes viruses consist of a family of DNA viruses that include herpes simplex virus 1 and 2 (HSV-1 and HSV-2) and varicella zoster virus (VZV). HSV-1 and HSV-2 are similar in structure except they have different antigens, such as glycoprotein G (gG), which has amino acid domains that are unique to each HSV type, 1 and 2.^1,2 Either serotype can cause either oral or genital lesions, but most commonly, HSV-1 is responsible for oral lesions while HSV-2 is primarily responsible for genital or lower-body lesions.¹ A publication from the National Center for Health Statistics has reported on the antibody prevalence of HSV types 1 (HSV-1) and 2 (HSV-2), and according to the findings based on the 2015-2016 National Health and Nutrition Examination Survey, among individuals aged 14 to 49 the prevalence of HSV-1 was recorded at 47.8%, while HSV-2 had a prevalence of 11.9%.³ VZV is also common and is the cause of chicken pox and shingles.¹ Accepted treatments for HSV and VZV include nucleoside analogues acyclovir, penciclovir, and their respective prodrugs valacyclovir and famciclovir, when indicated. Human papillomavirus (HPV) is also a DNA virus with many different types that have oral manifestations, including squamous papilloma, verruca vulgaris, condyloma acuminatum, and multifocal epithelial hyperplasia (MEH).¹ The former three lesions are treated with excision, and MEH is self-resolving.

Mechanism of Nucleoside Analogues

A nucleoside is a nitrogenous base with a cyclic pentose sugar group. In this pentose sugar group, the carbons are numbered from 1' to 5' (1 prime to 5 prime). After a series of phosphorylation events by different kinases, once a nucleoside is triphosphorylated at the 5' carbon, it is named a nucleotide and able to be incorporated into DNA replication. The 3' (3 prime) carbon is also significant because this site of the pentose ring has a hydroxyl group. In DNA replication, an unwound DNA helix serves the original DNA strand as a template, while a new, opposing, and complementary DNA strand is synthesized by DNA polymerase. DNA polymerase catalyzes the joining of a nucleotide to the hydroxyl on the 3' carbon. This reaction liberates two of the three phosphate groups (pyrophosphate), leaving the remaining phosphate joining the two nucleotides via a phosphodiester bond, terming this the sugar-phosphate backbone of DNA.⁴

The nucleoside analogue acyclovir chemically resembles the guanosine DNA nucleoside but lacks the cyclic pentose sugar and is thus named due to its acyclic nature. Specifically, its acyclic chemical structure results in the absence of a 3' hydroxyl group, which is needed for DNA replication. Acyclovir is phosphorylated by viral thymidine kinase, which is present in the lytic phase of a herpes infection, making it specific to the virus and thus limiting host toxicity. Once acyclovir is triphosphorylated, viral DNA polymerase cannot add on another nucleotide due to the missing OH group, resulting in DNA chain termination and the halting of viral DNA replication (Figure 1 and Figure 2). Therefore, nucleoside analogues inhibit viral DNA polymerase activity.⁵ Many oral antiviral medications are nucleoside analogues.

Mechanism of Pyrophosphate Analogue: Foscarnet

Upon the reaction of joining a nucleotide to a newly synthesized DNA strand by DNA polymerase, pyrophosphate is released. Foscarnet is a pyrophosphate analogue that binds to and selectively inhibits viral DNA polymerase (Figure 3).⁶ Thus, foscarnet differs from nucleoside analogues in its mechanism of action because it does not rely on viral kinases for its activation and antiviral activity. It is important to note that foscarnet has been shown to disturb renal function as a side effect, but dose adjustments can reduce the risk of renal failure in susceptible patients.⁷

Herpes Simplex Virus

Primary Herpes: Acute Herpetic Gingivostomatitis and Its Treatment

When an individual is exposed to herpes simplex virus 1 (HSV-1) and the individual does not have any pre-existing antibodies to it, this primary infection is typically asymptomatic and occurs at a young age.¹ On the other hand, the most common symptomatic primary herpes infection is acute herpetic gingivostomatitis (AHGS) and is most common in children, but has been occasionally reported in adults. Dentists may be the first healthcare providers to see patients with AHGS and, thus, it is important that they are able to recognize this infection.

AHGS may first manifest over regions in the posterior oral cavity before extending to the anterior oral cavity.⁸ Research is limited regarding the treatment of AHGS in children with antivirals; however, researchers have suggested treating children with acyclovir within the first 72 hours of symptoms if the child is suffering with pain or dehydration.⁹ A recent symptomatic review on AHGS highlighted that despite its high prevalence, the management of AHGS remains unclear due to diagnostic delay, estimated to be 72 hours. If administered during this time, the efficacy of antiviral drugs, including acyclovir, may be compromised.¹⁰

Secondary Herpes: Recurrent Herpes Labialis and Its Treatment

Secondary or recurrent infections are caused by reactivation of the virus. The most common site of recurrent herpes is the lips, known as recurrent herpes labialis (RHL).¹ People who suffer from these recurring attacks, which are cosmetically unesthetic, may also suffer from societal stigma towards herpes.¹¹ Dentists should provide patients with psychological support and reassure them that treatments are available to relieve the pain and discomfort and make RHL lesions heal faster compared to without treatment.

In terms of medical treatment, most products are aimed at resolving existing lesions in a timely fashion, after the outbreak has already occurred. Reported in 2008, acyclovir and penciclovir topical creams were thought to be the most effective remedies for herpes labialis.¹² A recent study determined that there were no statistically significant differences in healing time for herpes labialis lesions among Zovirax^® cream (5% acyclovir), Herpatch serum, a patch that forms a serum-based transparent film, and Compeed^® patches, which are hydrocolloid-containing patches. The mean healing time for these three medications were 9.67, 9.30, and 9.80 days, respectively.¹³ It is noteworthy that patches without antivirals are almost equally effective at healing RHL. Nine days, however, is still a substantial amount of time for patients to endure such a lesion, thus newer and more effective therapies are warranted.

In a more recent meta-analysis evaluating different treatments for RHL, researchers determined that oral valacyclovir with the addition of topical clobetasol was the most effective at reducing healing time with a 3.5-day mean difference, in comparison to acyclovir, penciclovir, famciclovir, and foscarnet (-0.92, -1.20, -2.09, -0.20 days, respectively).¹⁴ This meta-analysis also examined studies on preventative treatment for RHL and concluded that studies are lacking.¹⁴ Considering the prevalence of RHL and its impact on health and cosmetic concerns, further research in this area is needed to address the existing gaps in the prevention of recurrence and treatment aimed at shortening or eliminating outbreak time.

Alternative and Developing Treatments for Recurrent Herpes Labialis

Numerous advancements in the field of RHL treatment are underway and various studies have compared alternative and developing treatments to current, standard antiherpetic treatments (Table 1). In a large, randomized, controlled study, for example, participants were given kanuka honey or 5% topical acyclovir cream within 72 hours of a RHL breakout. Kanuka honey was chosen because manuka honey, of the same family tree, has been found to have antiviral effects.¹⁵ The study concluded that kanuka honey and acyclovir cream were equally effective in the treatment of herpes labialis, resolving lesions in 8 to 9 days.¹⁶ This study is important because it shows an equally effective and alternative treatment to acyclovir.

Research has also concentrated on creating new formulations of existing oral antivirals in hopes of increasing their bioavailability. To achieve this, new research has examined the development of an oil-phase drug delivery system named self-nano emulsifying drug delivery system (SNEDDS). Lavender oil was chosen because it has shown antiviral properties and has been effective in herpes labialis treatment. Penciclovir cream alone has poor oral bioavailability, but when formulated as an oral gel with lavender oil in the form of a SNEDDS, pharmacokinetic data showed a longer penciclovir release and increased bioavailability.¹⁷ This study highlights the potential for improvements in delivery systems for existing antiviral treatments.

Other studies have aimed at generating new classes of treatments for herpes. Existing case reports and studies have tested photodynamic therapy (PDT), in which a photosensitizing agent is applied to skin followed by the application of bright light, such as a laser or red light from a halogen lamp. A few reports using PDT on RHL with methylene blue as a photosensitizing agent have shown good therapeutic outcomes, calling for the need of a larger clinical study in the future to fully investigate this promising and potential treatment method.¹⁸ Another new class of antiherpetic therapy, low-level lasers, has been researched. Data showed that compared to acyclovir, patients who underwent laser therapy had improved pain symptoms and edema with no side effects. In addition, compared to the control group, healing time was significantly shorter. Interestingly, combining acyclovir and laser treatment resulted in significantly decreased recurrence rates.¹⁹ Developing alternative pharmaceutical approaches to nucleoside analogue antiviral drug regimens is important for those patients who are resistant to them, and such alternatives may be superior to existing treatments.

Many of the treatments for RHL are focused on remedying these oral lesions after they have already developed. However, given the prominent visibility of oral herpes lesions and the potential resulting societal stigma, treatments that block their progression rather than simply reduce healing time may greatly benefit patients. One study induced RHL with ultraviolet (UV) light and treated individuals with low-dose thimerosal, an organomercury antimicrobial treatment. The authors' post hoc analysis showed little antiviral activity in the first 48 hours following UV exposure and the blocking of lesion progression during this time.²⁰ More research in this field, including a larger, more powerful study, is needed before the efficacy of this antimicrobial treatment can be determined.

Varicella Zoster Virus: Varicella and Zoster Treatments

Human herpes virus 4, also known as varicella zoster virus (VZV), is the cause of varicella (chicken pox), which is the primary infection of this virus, and herpes zoster (shingles), which is the recurrent infection.¹ These infections are relevant to dentistry because of their oral manifestations. Oral chicken pox lesions are small vesicles. While vesicles are a nonspecific symptom alone, these are accompanied by chicken pox vesicles on the skin and systemic symptoms, including fever, headache, malaise, and nausea. Chicken pox is a self-limiting disease and antivirals are not used routinely for immunocompetent individuals. Antivirals may be used within the first 24 hours of the manifestation of chicken pox in immunocompromised or older children and adults who develop the rash, because the older patients are when they contract this primary infection, the more at risk they are for pulmonary complications. Between 5% and 14% of adults who acquire chicken pox will have pulmonary involvement, and pregnant women are at risk of life-threatening pneumonitis.²¹

Herpes zoster is symptomatic and begins with prodromal pain typically within a dermatome. Following this, in the acute phase, vesicles may form and extend up to the midline of the dermatomes that the virus affects, which are thoracic, cranial, lumbar, and cervical (in order of most commonly affected to least).²² Generally, these lesions heal within 6 weeks. If there are any ocular manifestations or if the tip of the nose is involved, implying nasociliary branch involvement, dentists must refer the patient to an ophthalmologist. The chronic phase of herpes zoster affects 15% of patients. Of these patients, approximately half of those who are over age 60 may develop postherpetic neuralgia, a painful, burning sensation upon contact with any affected skin.¹ Given that older and immunocompromised individuals are at an increased risk for the aforementioned neurologic and ophthalmic complications, medication is recommended; valacyclovir or famciclovir should be administered within 72 hours of the onset of the rash. These drugs are preferred over acyclovir because they have an increased level of antiviral activity and require a decreased frequency of dosages.²³ An alternative treatment for at-risk individuals with severe infections who are resistant to these nucleoside analogues is foscarnet.²⁴

Regarding vaccines, the US Food and Drug Administration has approved Shingrix, a recombinant zoster vaccine. Shingrix is recommended for preventing herpes zoster (shingles) and its complications, namely, post-herpetic neuralgia (PHN), in all adults aged 50 or older and in immunodeficient or immunocompromised adults aged 19 or older by the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention. The ACIP advises administering a two-dose regimen in these patients. In adults over age 50, Shingrix is 90% and 68% to 91% effective at preventing shingles and PHN in healthy and immunocompromised patients, respectively.²⁵

Antiviral Resistance in Nucleoside Analogues

Some individuals may be on long-term antiviral medications to prevent recurrent genital herpes outbreaks, as this approach has shown to reduce the risk of transmission. Subsequently, people on long-term antivirals may develop resistance to nucleoside analogues. Resistance to acyclovir can occur based on mutations in the enzymes with which it binds. First, if viral thymidine kinase were to mutate to the point of not binding acyclovir, it would not phosphorylate it. Without acyclovir becoming triphosphorylated, it is not a precursor to the growing DNA chain because it will not bind to DNA polymerase and is rendered unusable. Second, if the binding site of viral DNA polymerase is mutated, triphosphorylated acyclovir may not bind to it. Without being incorporated to the newly synthesized DNA strand, acyclovir will not terminate DNA replication. By utilizing antiherpetic therapy that targets sites other than these classic pharmaceutical antivirals, the antiviral resistance that occurs via viral thymidine kinase and DNA polymerase mutations is avoided. Algorithms have been proposed for identifying patients with nucleoside analogue resistance by subjecting them to genotypic testing, which has been successful. If they are found to be resistant, patients may be given foscarnet. If symptoms still do not improve, high-dose acyclovir can be considered.²⁶

The issue of drug tolerance highlights the need for the judicial use of acyclovir. Adequate identification of viral disease by dentists and understanding the indications of prescribing antivirals will result in safer, more efficient use of them.

Human Papillomavirus Lesions of the Oral Cavity

Human papillomavirus (HPV) is a double-stranded DNA virus that is epitheliotropic. Many HPV subtypes have been identified, and they have varied risk in relation to causing cancer. Fortunately, oral HPV lesions are related to low-risk subtypes. These oral epithelial lesions include squamous papilloma, verruca vulgaris, condyloma acuminatum, and multifocal epithelial hyperplasia (MEH).¹

Squamous papilloma lesions are caused mainly by HPV types 6 and 11. A large clinical study found that clinicians describe squamous papilloma lesions mainly as papillary; pedunculated; pink or, if keratinized, white; smaller than 5 mm; and solitary.¹ Common sites, in order of most frequent to least, included the soft palate, border of the tongue, mucosal membrane of the lips, and interdental papillae. These findings are consistent with previous studies.²⁷

Verruca vulgaris lesions are caused by HPV types 2 and 4.¹ Whereby "verruca" means "wart-like," verruca vulgaris is the common wart lesion. Warts are usually found in children on the skin but can also manifest in oral mucosa. These warts can spread to another site in an individual via autoinoculation, and it is important to warn patients of this possibility.¹ Oral lesions of this kind are more than 5 mm in width, may be sessile or pedunculated, are exophytic, papillary, and almost always white.¹

Condyloma acuminatum is most commonly associated with HPV types 6 and 11. High-risk types 16 and 18 have also been found to be associated with it, but this is rare.¹ With condyloma acuminatum being a sexually transmitted disease, in which the lesion manifests 1 to 3 months after sexual contact, it is important for dentists to be able to clearly recognize this, as its presence in young children may be an indication of sexual abuse. Transmission from mothers to newborns is possible as well. Again, patients should be warned of the risk of autoinoculation. Clinically, condyloma acuminatum is pink and sessile with short papillary blunt projections, appearing cauliflower-like and similar to the squamous papilloma. Unlike the squamous papilloma, this lesion may manifest in clusters and is larger in size, ranging between 1 cm and 1.5 cm.¹

MEH, also known as Heck's disease, is mainly associated with HPV types 16 and 32.¹ In addition, people may be genetically predisposed to MEH because many people with it have been positive for the HLA-DR4 (DRB1*0404) allele.²⁸ This disease is common in children and clinically looks like many pink, flat lobules that may coalesce, giving a cobblestone-like appearance.¹

The incidence of HPV-associated oropharyngeal cancer (HSV+OPSCC) is increasing and is highest in high-income countries.²⁹ Cancers within the oropharyngeal region encompass those affecting the base of the tongue, lingual tonsil, unspecified soft palate, uvula, tonsils, oropharynx, and Waldeyer's ring, making screening of OPSCC pertinent during intraoral examinations by dentists. Nodal metastasis is also often found at presentation.³⁰ HPV-16 causes 85% to 96% of HPV+OPSCCs and also may be associated with warts or condyloma acuminatum.³¹ ACIP recommends that HPV vaccination be completed at age 11 to 12.³² Research has shown that HPV vaccination has reduced HPV lesions (including strains 6, 11, 16, and 18) in the oral cavity and is efficacious in preventing OPSCC.³⁰ Recognizing the increasing incidence of HPV-associated oropharyngeal cancer and understanding the effectiveness of HPV vaccination in preventing OPSCC underscores the importance of proactive screening and vaccination strategies for better public health outcomes.

Treatment Methods for HPV Lesions

Cold-knife surgical excision is the main treatment for the HPV lesions squamous papilloma, verruca vulgaris, and condyloma acuminatum and has low recurrence rates if the involved infected tissue is removed.³³ For oral squamous papilloma, a study showed that excising 3 mm of normal mucosa around squamous papilloma lesions resulted in the lowest recurrence rate in comparison to smaller excisions and other treatment methods that included laser protocols³³; however, the practicality of removing this much normal tissue is questionable. In a large clinical study regarding squamous papillomas, very low recurrence rates of 2% were found following surgical excision.²⁷

Lastly, MEH is self-resolving but can be surgically excised if it is causing functional or esthetic/cosmetic complications.³⁴ Other reported treatments for MEH include retinoid, interferon alpha, and imiquimod.³⁵ Other treatment methods for HPV lesions that are currently being researched are surgical excision with a quantic molecular resonance scalpel, laser therapy, and cryotherapy.³⁶ There is little recent current literature in the field of HPV lesions, but perhaps with advancements in treatment technologies more studies will take place.

Conclusion

Viral infections, particularly those caused by human herpes viruses and human papillomavirus, manifest in the oral cavity with recurrent lesions. Antiviral nucleoside analogues like acyclovir play a crucial role in inhibiting viral DNA polymerase activity. Recurrent herpes labialis poses challenges, with emerging treatments such as kanuka honey showing promise. Varicella zoster virus necessitates antiviral intervention in specific cases. Antiviral resistance raises concerns, emphasizing the need for judicious use of medications. Oral manifestations of HPV require varied treatment methods, with surgical excision being primary. Advances in treatment modalities for these viral infections continue, offering hope for improved outcomes and patient care.

About the Authors

Lauren Elkada, BSc
Fourth-year dental student, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada

Aviv Ouanounou, BSc, MSc, DDS
Associate Professor, Department of Clinical Sciences (Pharmacology and Preventive Dentistry), Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada; Fellow, International College of Dentists; Fellow, American College of Dentists; Fellow, International Congress of Oral Implantologists

Queries to the author regarding this course may be submitted to mailto:authorqueries@broadcastmed.com.

References

1. Neville BW, Damm DD, Allen CM, Chi AC. In: Oral and Maxillofacial Pathology. 4th ed. St. Louis, MO: Elsevier; 2016.

2. Grabowksa A, Jameson C, Laing P, et al. Identification of type-specific domains within glycoprotein G of herpes simplex virus type 2 (HSV-2) recognized by the majority of patients infected with HSV-2, but not by those infected with HSV-1. J Gen Virol. 1999;80(Pt 7):1789-1798.

3. McQuillan G, Kruszon-Moran D, Flagg EW, Paulose-Ram R. Prevalence of herpes simplex virus type 1 and type 2 in persons aged 14-49: United States, 2015-2016. NCHS Data Brief. 2018;(304):1-8.

4. Cooper GM. The Cell: A Molecular Approach. 2nd ed. Sunderland, MA: Sinauer Associates; 2000.

5. Elion GB. Mechanism of action and selectivity of acyclovir. Am J Med. 1982;73(1A):7-13.

6. Wagstaff AJ, Bryson HM. Foscarnet. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with viral infections. Drugs. 1994;48(2):199-226.

7. Chrisp P, Clissold SP. Foscarnet. A review of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with cytomegalovirus retinitis. Drugs. 1991;41(1):104-129.

8. Huang CW, Hsieh CH, Lin MR, Huang YC. Clinical features of gingivostomatitis due to primary infection of herpes simplex virus in children. BMC Infect Dis. 2020;20(1):782.

9. Goldman RD. Acyclovir for herpetic gingivostomatitis in children. Can Fam Physician. 2016;62(5):403-404.

10. Coppola N, Cantile T, Adamo D, et al. Supportive care and antiviral treatments in primary herpetic gingivostomatitis: a systematic review. Clin Oral Investig. 2023;27(11)6333-6344.

11. Donigan JM, Pascoe VL, Kimball AB. Psoriasis and herpes simplex virus are highly stigmatizing compared with other common dermatologic conditions: a survey-based study. J Am Acad Dermatol. 2015;73(3):525-526.

12. Opstelten W, Neven AK, Eeekhof J. Treatment and prevention of herpes labialis. Can Fam Physician.2008;54(12):1683-1687.

13. Boes H, Gouliomis V, Wechsler A, et al. Clinical study on the effectiveness of three products in the treatment of herpes simplex labialis. Sci Rep. 2020;10(1):6465.

14. Koe KH, Veettil SK, Maharajan MK, et al. Comparative efficacy of antiviral agents for prevention and management of herpes labialis: a systematic review and network meta-analysis. J Evid Based Dent Pract. 2023;23(1):101778.

15. Watanabe K, Rahmasari R, Matsunaga A, et al. Anti-influenza viral effects of honey in vitro: potent high activity of manuka honey. Arch Med Res. 2014;45(5):359-365.

16. Semprini A, Singer J, Braithwaite I, et al. Kanuka honey versus aciclovir for the topical treatment of herpes simplex labialis: a randomised controlled trial. BMJ Open. 2019:9(5):e026201.

17. Hosny KM, Sindi AM, Alkhalidi HM, et al. Oral gel loaded with penciclovir-lavender oil nanoemulsion to enhance bioavailability and alleviate pain associated with herpes labialis. Drug Deliv. 2021;28(1):1043-1054.

18. Lotufo MA, Horliana AC, Santana T, et al. Efficacy of photodynamic therapy on the treatment of herpes labialis: a systematic review. Photodiagnosis Photodyn Ther. 2020;29:101536.

19. Al-Maweri SA, Kalakonda B, AlAizari NA, et al. Efficacy of low-level laser therapy in management of recurrent herpes labialis: a systematic review. Lasers Med Sci. 2018;33(7):1423-1430.

20. Mamber SW, Hatch T, Miller CS, et al. Low-dose oral thimerosal for the treatment of oral herpes: clinical trial results and improved outcome after post-hoc analysis. J Evid Based Integr Med. 2022;27:2515690X221078004.

21. Tunbridge AJ, Breuer J, Jeffery KJM; British Infection Society. Chickenpox in adults - clinical management. J Infect.2008;57(2):95-102.

22. Schmader K. Herpes zoster. Ann Intern Med. 2018;169(3):ITC19-ITC31.

23. Cohen JI. Clinical practice: herpes zoster. N Engl J Med. 2013;369 (3):255-263.

24. Sauerbrei A. Diagnosis, antiviral therapy, and prophylaxis of varicella-zoster virus infections. Eur J Clin Microbiol Infect Dis. 2016;35(5):723-734.

25. Anderson TC, Masters NB, Guo A, et al. Use of recombinant zoster vaccine in immunocompromised adults aged ≥19 years: recommendations of the Advisory Committee on Immunization Practices - United States, 2022. MMWR Morb Mortal Wkly Rep. 2022;71(3):80-84.

26. Piret J, Boivin G. Antiviral resistance in herpes simplex virus and varicella-zoster virus infections: diagnosis and management. Curr Opin Infect Dis. 2016;29(6):654-662.

27. Frigerio M, Martinelli-Klay CP, Lombardi T. Clinical, histopathological and immunohistochemical study of oral squamous papillomas. Acta Odontol Scand. 2015;73(7):508-515.

28. Garcia-Corona C, Vega-Memije E, Mosqueda-Taylor A, et al. Association of HLA-DR4 (DRB1*0404) with human papillomavirus infection in patients with focal epithelial hyperplasia. Arch Dermatol. 2004;140(10):1227-1231.

29. Faraji F, Rettig EM, Tsai HL, et al. The prevalence of human papillomavirus in oropharyngeal cancer is increasing regardless of sex or race, and the influence of sex and race on survival is modified by human papillomavirus tumor status. Cancer. 2019;125(5):761-769.

30. Lewis JS Jr. Morphologic diversity in human papillomavirus-related oropharyngeal squamous cell carcinoma: catch me if you can! Mod Pathol. 2017;30(s1):S44-S53.

31. Lechner M, Liu J, Masterson L, Fenton TR. HPV-associated oropharyngeal cancer: epidemiology, molecular biology and clinical management. Nat Rev Clin Oncol. 2022;19(5):306-327.

32. Meites E, Szilagyi PG, Chesson HW, et al. Human papillomavirus vaccination for adults: updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2019;68(32):698-702.

33. Nammour S, El Mobadder M, Namour A, et al. Success rate of benign oral squamous papilloma treatments after different surgical protocols (conventional, Nd:YAG, CO2 and diode 980 nm lasers): a 34-year retrospective study. Photobiomodul Photomed Laser Surg. 2021;39(2):123-130.

34. Said AK, Leao JC, Fedele S, Porter SR. Focal epithelial hyperplasia - an update. J Oral Pathol Med. 2013;42(6):435-442.

35. Yasar S, Mansur AT, Serdar ZA, et al. Treatment of focal epithelial hyperplasia with topical imiquimod: report of three cases. Pediatr Dermatol. 2009;26(4):465-468.

36. Orru G, Mameli A, Demontis C, et al. Oral human papilloma virus infection: an overview of clinical-laboratory diagnosis and treatment. Eur Rev Med Pharmacol Sci. 2019;23(18):8148-8157.