HPV: Here, There, Everywhere Denise Rizzolo, PhD, PA-C HPV Overview

• Human papillomavirus (HPV) is the most common sexually transmitted infection (STI). • According to the CDC the prevalence of genital infection with any HPV type was 42.5% among United States adults aged 18–59 years during 2013–2014. • The CDC states that HPV is so common that nearly all men and women who have sex will get it at some point in their lives. • However, many infections remain asymptomatic and resolve spontaneously. HPV Virology

• Papillomavirus • Infection limited to basal cells of stratified epithelium. • Infects epithelial tissues through micro-abrasions that expose portions of the basement membrane. • HPV lesions are thought to arise from the proliferation of infected basal keratinocytes. Oncogenic Strains of HPV

• 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, 82

• Probable oncogenic strains: 26, 53, 66, 73, 822 HPV as Causative Agent in…

• • • • Vaginal/ • Recurrent Respiratory Papillomatosis*

• *Caused most commonly by HPV types 6 + 11 (non-oncogenic) and rarely by HPV types 16/18 The History of HPV Viruses as Emerging Cause of Cancer • As early as 1842 an association was found between sexual activity and cervical cancer • By the 1990 a definitive link between HPV and cancer was determined • What about HPV and ? • 1983 researchers found HPV structural proteins via immunohistochemistry in 6 out of 8 oral HPV and Oral Cancer—The stats

• HPV has been detected in 45% to 90% of head and neck squamous cell carcinomas (HNSCC), most commonly in the lingual and palatine tonsils or base of the tongue.

• Incidence rates of HPV-positive oropharyngeal cancer have been increasing among white men and women. Age is usually 10 years younger than that of cancer of the oral cavity; roughly seen as early as 40.

• The age at sexual debut is decreasing with oral sex being performed more by men and women that are aged 30 to 49 years compared to older generations. Clinical Case #1

• HPI: A 42 year old Caucasian female presents to your office stating he was referred by his dentist for a tonsillar lesion. She has no significant past medical history and is currently on no medications.

• Social & Sexual Hx: She is married with one child. Sexual history is not disclosed. She denies alcohol or smoking tobacco history, but does admit to daily marijuana use for the past 10 years.

• PE & Diagnostic Testing: Results of a thorough PE and laboratory evaluation are normal except for a 1.5 cm tonsillar lesion. reveals a well- differentiated squamous cell carcinoma, HPV positive. What is the most likely causative strain of the HPV positive squamous cell carcinoma in our case study? A. HPV – 2 B. HPV – 6 C. HPV – 16 D. HPV - 18 HPVHigh Virology Risk Types: and Oncogenesis • 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82 Low Risk Types: • 6, 11, 40, 42, 43, 44, 53, 54, 61, 72, 81 • Associated with about 85 to 95% of HPV- HPV-16 Positive oropharyngeal cancers.

• Verruca vulgaris (occur on lips, hard palate, HPV-2 or HPV-4 and gingiva)

• Condyloma acuminata (occur as genital HPV -6 or HPV – 11 or in the oral mucosa. Commonly found on keratinized mucosa.) ❑ History of sexual activity at a young age ❑ Having multiple sexual partners ❑ History of genital warts Researchers conducted a study in ❑ History of oral sex which they stratified risk factors ❑ History of oral and anal contact according to HPV-16 tumor status ❑ History of marijuana use and found that HPV-16 positive ❑ HIV infection tumors were associated strongly with specific sexual behaviors and marijuana smoking – not with tobacco smoking, alcohol, or poor RISK FACTORS oral hygiene. TRUE or FALSE? The physical exam of a patient with known HPV-positive oral squamous cell carcinoma is typically unremarkable? Signs and Symptoms *Some patients ❑ Persistent sore throat may have no ❑ Non-healing sore in mouth ❑ Earaches signs or ❑ Hoarseness symptoms!* ❑ Enlarges lymph nodes ❑ Pain with swallowing ❑ Unexplained weight loss Physical Exam Findings

• High risk clinical presentations:

• Sharply defined, leukoplakic lesions (especially those > 1 centimeter in size) • Non-homogenous or mixed red-white lesions • Erythroplakic lesions • Areas of persistent ulceration and indurated lesions Clinical Case #2

• HPI: A 45 year old Hispanic female with PMH of anxiety and seasonal allergies who requests screening for oral HPV

• FH: Mother has type 2 diabetes and HTN, Father with high cholesterol

• Meds: Valium PRN, OTC antihistamines and nasal corticosteroid spray for seasonal allergies

• Social & Sexual Hx: She is divorced, but recently started dating. She has two children. She was monogamous with her husband of 16 years and has not been sexually active since her divorce 1 year ago. She used oral birth control pills as contraception during her marriage. She denies alcohol or smoking tobacco history. Clinical Case #2

• ROS: She denies any suggestive symptoms of oral cancer or HPV, such as persistent sore throat, hoarse voice, oral ulcer or sore that does not heal within 2-3 weeks, dysphagia, pain when chewing, ear pain, or a painless lump on the outside of the neck.

• Screenings: Her last dental exam was 5 months ago, no issues. Last PAP 1 year ago, normal.

• PE: Overall unremarkable. The oral cavity is thoroughly examined and found to be free of any suspicious lesions. Is there a test to find out if I have oral HPV?

Screening for HPV……….. Of the following statements, which one is TRUE?

A. Saliva can be used for accurate HPV detection and genotyping PCR to detect the presence of HPV DNA

B. Viral antigen detection through blood is a simple way to detect HPV

C. Tissue fluorescence visualization is a widely used tool for early detection

D. There is no FDA-approved test to diagnose HPV in the mouth or throat

Screening for HPV Oral HPV Testing Pitfalls

• Acetic staining: May become diluted with saliva, detects trauma • Rinsing: May be positive, but does not indicate where the lesion is • Swab: Must brush non keratinized surface such as buccal mucosa, the vestibule, the floor of the mouth, the border of the tongue (until the oropharynx), under the surface of the tongue. **Keratinized surfaces are resistant to collection) • Biopsy of the lesion is most accurate Prognosis and Treatment Options

• Prognosis depends on : • The stage and grade of cancer • Location of tumor • Association of tumor with HPV

• Treatment options depend on: • Stage and grade of cancer • Location of tumor • Maintaining patient speech and swallowing functions • General health of patient Staging

Stage 0 (): Abnormal cells found in lining of oropharynx Stage I: Cancer is 2 cm or smaller and found in oropharynx only

Stage II: Cancer is larger than 2 cm but not larger than 4 cm and is found in oropharynx only

Stage III: Cancer is either ▪ 4 cm or smaller, spread to one lymph node on same side and node is 3 cm or smaller, or; ▪ larger than 4 cm, spread to epiglottis, spread to one lymph node on same side and node is 3 cm or smaller Stage IV: ▪ IVA: Cancer has spread to larynx, front part of roof of mouth, lower jaw or muscles that move the Stagingtongue or are used for chewing. Cancer has spread to one lymph node on same side and is 3 cm or smaller, or: ▪ Cancer has spread to one lymph node on the same side, lymph node is larger than 3 cm but not larger than 6 cm, and one of following is true: ▪ Tumor in oropharynx is any size and may have spread to epiglottis, or: ▪ Tumor has spread to larynx, front part of roof of mouth, lower jaw, or muscles that move the tongue or are used for chewing ▪ IVB: ▪ Tumor surrounds the carotid artery or has spread to the muscle that opens the jaw, the bone attached to the muscles that move the jaw, nasopharynx, or base of skull. Spread to one or more lymph nodes which can be any size, or: ▪ Tumor may be any size and has spread to one or more lymph nodes that are larger than 6 cm ▪ IVC: Tumor may be any size and has spread beyond the oropharynx to other parts of the body such as the lung, bone or liver. Treatment is stage dependent

❑Surgery

❑Radiation Therapy

❑Chemotherapy Stage I and II: ❑Radiation may be preferred where functional deficit will be great, such as the tongue or base of tonsil ❑Surgery may be preferred where functional deficit will be minimal such as tonsillar pillar

Treatment Treatment Stage III: ❑Combination of surgery with postoperative radiation or chemoradiation therapy ❑Radiation therapy for patients with cancer of the tonsil ❑Chemoradiation therapy Treatment

Stage IV: ❑ Combination of surgery with postoperative radiation therapy plus chemotherapy in high risk patients ❑ Radiation therapy alone for patients with stage IVA cancer of tonsil that does not deeply invade the tongue base Stage Lip Tongue Floor of Mouth Oropharynx and Tonsils I 96% 71% 73% 56%

II 83% 59% 60% 58%

III 57% 47% 36% 55%

IV 48% 37% 30% 43%

Five Year Survival Rate for Oropharyngeal Cancer Prognosis for HPV positive OSCC HPV positive OSCC is associated with a significant overall survival rate when compared to patients with HPV negative tumors. Various studies reveal statistics between 40% and 50% increased overall survival rate. Who is talking about Oral HPV with our patients ??? The Dentist ? The Family Practice Provider? HPV Health Literacy

• Focus group of 33 dentists was done in 2016 • HPV Infection • Most knew it was a sexually transmitted infection – but only a few knew which types were virulent • HPV • Few discussed with patients or new the strains it covered. Thought it was removed from market because of “birth defects” • Connection between HPV and Oropharyngeal Cancer • Most knew HPV caused cancer but uncertain of the risk factors • Screening • Some had lack of knowledge of symptoms and most had questions on best way to screen. Vázquez-Otero C, Vamos CA, Thompson EL, Merrell LK, Griner SB, Kline NS, Catalanotto FA, Giuliano AR, Daley EM. Assessing dentists’ human papillomavirus–related health literacy for oropharyngeal cancer prevention. JADA 2018 Jan 1;149(1):9-17. HPV Health Literacy

• Discussing HPV with patients • Most felt uncomfortable, sensitive subject, specifically did not want to discuss with underage patients • Practice Barriers • Many stated their office set up was not conducive to having the conversation with their patients. • MANY PARTICIPANTS STATED THEY DID NOT DISCUSS HPV WITH THEIR PATIENTS! Lets take a look at ….. Anal HPV Anal Cancer

• Statistics: • About 8,200 new cases (5,250 in women and 2,950 in men) • About 1,100 deaths (650 in women and 450 in men) • The risk of being diagnosed with anal cancer during one’s lifetime is about 1 in 500 • Rare in people younger than 35 and is found mainly in older adults, with an average age being in the early 60s. • Incidence of anal cancer increasing past 30 years (women, blacks, immunocompromised); risk factors are multifactorial (HPV has a high link to development) Risk Factors

• HPV • History of anal sex • History of cervical high grade dysplasia • Multiple Sexual Partners • Older Age • Most commonly detected and diagnosed in their 6th decade • Immunosuppression • HIV/AIDS • Organ transplant recipients • Corticosteroids HPV and Anal Cancer

• High-risk HPV is detected in 90% of individuals with Anal Squamous Cell Carcinoma. • HPV subtype 16 and/or 18 (considered high-risk HPV subtypes) • HPV 16 is seen more often Symptoms

• Anal Itch (anal pruritus). • A mass or swelling in the anal canal, around the anal opening, perineum, or in the intragluteal cleft. • Bleeding from the rectum/anus. • Pain in the area of the anus. Physical Examination Findings

• External Evaluation • Plaques – hyperkeratosis, erythema, leukoplakia, foci of ulceration, excoriation, hyper/hypopigmentation • Masses – fixed, scaly, ulcerated, raised • DRE (digital rectal examination) • Masses – mobile or fixed • Nodules – multiple, or solitary • Gross blood, fragments of lesions • Standard Anoscopy • Visualization of plaques • Abnormal surface vessels • Condyloma • Pedunculated masses Screening

• No set guidelines • Anal cytology • are accepted methods to screen for anal dysplasia. • performed by moistening a Dacron swab with tap water and inserting it three to four centimeters into the anus. • The swab is removed by applying gentle pressure while withdrawing it in a circular motion. • The sample can be smeared onto a slide or processed using a liquid-based medium. ****Can have a margin of error- not directly visualizing like a pap smear (higher sensitivity if anoscope is used) High Resolution Anoscopy

• HRA with biopsy is recommended for any cytology results showing ASCUS, ASCUS-H, LSIL or HSIL. • HRA uses a high-magnification colposcope with a transparent anoscope covered in 5% lidocaine lubricating gel to examine the entire anal canal and perianal skin under close visual inspection. • Application of 3-5% acetic acid is applied to the anal canal using a cotton tip swab applied for one-minute in order to identify areas of rapid cell turnover. • Lugol’s solution can also be applied to improve biopsy yield and accuracy. • Higher grade lesions will not uptake Lugol’s solution and the tissue remains unstained as compared to the normal tissue. • Abnormal areas are biopsied. ASCUS=atypical squamous cells of undetermined significance, LSIL= Low-grade squamous intraepithelial lesion HSIL= High-grade squamous intraepithelial lesion Lugol’s = aqueous iodine and strong iodine solution MUST TEST FOR HPV Diagnosis

• The is used to report cytologic findings for both anal and cervical pap smears; • Normal • Atypical Squamous Cell of Undetermined Significance (ASCUS) • Atypical Squamous Cell of Undetermined Significance-cannot exclude HSIL (ASCUS–H), • Low-grade Squamous Intraepithelial Lesions (LSIL) and High-grade Squamous Intraepithelial Lesions (HSIL) Diagnosis continued

• When are taken, the histologic nomenclature of HPV associated squamous proliferations of the lower genital tract are classified as: • Low-grade Squamous Intraepitheial Lesion • High-grade Squamous Intraepitheial Lesion • However, the histologic terms can be further classified as; • AIN, grades 1, 2 or 3. • AIN 1 corresponds to anal LSIL or Low-Grade anal intraepithelial neoplasia (LGAIN) • AIN 2 and 3 as anal HSIL or High-grade anal intraepithelial neoplasia (HGAIN) Treatment

• There is no standard treatment for AIN, but several options are available to treat localized lesions. • The decision to treat should not be based on cytology, but rather on histology (biopsies). • HGAIN should be treated • LGAIN can be monitored with repeat HRA examination annually Topical Treatments

• Imiquimod 5% cream is an immunomodulatory drug • Cream is applied to the perianal region at bedtime and washed off in the morning. • Cream is applied three times a week for up to 16 weeks. • Complete resolution of AIN in 48% of patients and a partial response in 34% of patients with a recurrence rate of 34% in a follow-up period of 11 to 39 months. • Topical 5-fluorouricil (5-FU) • Applied for nine to 16 weeks. • A small open-label study of 5-FU found that 26 of 46 patients (56.5%) had complete or partial response, but 25% had recurrence at 6 months. Treatment continued

• Wide local excision to remove the areas of dysplasia is not longer done due to the morbidity and recurrence rates associated with this procedure. • Cure can be achieved with minimally invasive surgery in 85 to 90%. • The more commonly accepted treatment includes the directed destruction of HGAIN aimed at destroying lesions using: • electrocautery, • infrared coagulation, • or cryotherapy. Biopsy Findings Treatment Options • Monitor with HRA examination every 6 months. If two consecutive exams normal, monitor LGAIN (AIN 1) annually • Topical treatment maybe indicated for symptomatic patients (itching, bleeding, etc. ) Topical Therapy HGAIN (AIN 2 or 3) For small lesions (< 1cm2 at the base): • Local application of bichloroacetic or 80-90% trichloroacetic acid (well tolerated but can be painful) • Liquid nitrogen Other topical, self-applied options (can be used to treat diffuse lesions) • Topical imiquimod applied for 6-10 hours then washed off, three times a week for 16 weeks. • Topical 5% 5-fluorouracil applied BID for 16 weeks Infrared Coagulation (office based) • For lesions too large for topical treatment • Followed by debridement for destroyed tissue using biopsy forceps

Surgery and CO2 Laser Ablation • For large (>1 cm2) or extensive lesions, or for patients unable to receive infrared coagulation • Surgical excision with a scalpel for discrete lesions with or without laser ablation • Large lesions may require multiple, staged procedures to reduce risk of bleeding, anal stenosis, sphincter compromise and infection • Referrals should be made to surgical centers or colorectal surgeons with experience in treating anal dysplasia.

Follow-up HRA should be done every 6 months. Recurrence/Surveillance

• Rates seem to be equivalent regardless of treatment modality. • Rates vary from 10 – 75%. • Rates higher in immunocompromised patients. • The American Society of Colon and Rectal Surgeons recommends that patients with AIN be monitored with digital rectal exam, standard anoscopy plus or minus HRA and application of acetic acid or Lugol’s solution every four to six months. And Finally A Brief Review of …… Cervical Cancer Statistics

• About 12,820 new cases of invasive cervical cancer will be diagnosed. • About 4,210 women will die from cervical cancer. • Most cases are found in women younger than 50. It rarely develops in women younger than 20. • Infection by the HPV is the most important risk factor for cervical cancer. • About two-thirds of all cervical cancers are caused by HPV 16 and 18. Signs and Symptoms

• Usually asymptomatic • Abnormal vaginal bleeding • An unusual discharge from the vagina pain during sex Screening

• The USPSTF recommends screening for cervical cancer in women age 21 to 65 years with cytology (Pap smear) every 3 years or, • For women age 30 to 65 years who want to lengthen the screening interval, screening with a combination of cytology and human papillomavirus (HPV) testing every 5 years. • Not recommended: • Women younger than 30 years, HPV testing • Women younger than 21 (pap smear) • Women Older than 65, who have had adequate prior screening Treatment

• Primary goal is removal of symptomatic warts • If left untreated, genital warts may regress spontaneously or persist with or without proliferation • In most patients, treatment can induce -free periods • In the absence of lesions, treatment is not recommended for subclinical genital HPV infection • Effect of current treatment on future transmission is unclear • Up to 2/3 of patients will experience recurrences of warts within 6- 12 weeks of therapy; after 6 months most patients have clearance • This is important when you think about treatment Treatment

• Patient applied treatment:

• Imiquimod 3.75% or 5% cream (Aldara™) • Podofilox 0.5% solution or gel (Condylox™)

• 40-50% of women will have complete clearance of warts and remainder will have partial clearance- 30% will have recurrence within 12 weeks. Treatment

• Recommended Regimen for Cervical Warts • For women who have exophytic cervical warts, a biopsy evaluation to exclude high-grade SIL must be performed before treatment is initiated • Management of exophytic cervical warts should include consultation with a specialist • Recommended Regimens for Vaginal Warts (provider administered) • Cryotherapy with liquid nitrogen- used weekly until wart resolves OR • Trichloroacetic acid (TCA) or bichloroacetic acid (BCA) 80%–90% solution applied to warts- with a cotton swab- • CAUTION – can cause burns to area- only 70% response reate Case

• Anne Drew is a 34-year-old woman who comes in stating that she wants to get "checked out" because Jonathan, her sex partner, has small solid "bumps" on the skin on the shaft of his penis. Jonathan told her that he was diagnosed and treated for genital warts about a year ago and his health care provider told him they could recur. Recent pap screen 4 months ago was normal. What should be included in Ms. Drew’s evaluation? • Acetic acid evaluation of external genitalia • Pelvic exam with visual inspection of genitalia • Pap smear screening • HPV DNA test • Ms. Drew’s pelvic exam is normal. However, visual inspection of her genitalia reveals multiple small (<0.5 cm) flesh-colored, papular lesions in the perineal area. What is the differential diagnosis for the papular genital lesions? (select all that apply) • Secondary syphilis (condyloma lata) • Molluscum contagiosum • Genital warts • Skin tags Which laboratory tests should be ordered or performed? (select all that apply) • Serologic test for syphilis (e.g., RPR—STAT if available) • Test for Chlamydia trachomatis • Test for Neisseria gonorrhoeae • Counseling and testing for HIV • Screening for other STDs including HIV should be considered for all persons newly diagnosed with genital warts. Serologic test for syphilis should be performed to rule out secondary syphilis. You discuss the following genital warts management options with Ms. Drew: Patient-applied therapy Podofilox 0.5% solution or gel Imiquimod 5% cream Sinecatechins 15% ointment Provider-administered therapy Cryotherapy with liquid nitrogen or cryoprobe Podophyllin resin 10%-25% in compound tincture of benzoin Trichloroacetic acid (TCA) or bichloroacetic acid (BCA) 80%-90% No intervention Which of the following statements is accurate with regard to treatment options? • Recurrence of genital warts after treatment is uncommon. • Most patients require only a single treatment. • The effect of treatment on future transmission is unknown. • Complications occur frequently with wart treatment. Thoughts

• Because of uncertainty about the effect of treatment on future transmission and the possibility of spontaneous resolution, some patient may choose to forgo treatment and await spontaneous resolution. What condition could cause a substantial increase in the number and size of Ms. Drew’s genital warts? • • Exposure to sunlight • Immunodeficiency

• Exposure to sunlight is not known to increase the number and size of genital warts. HPV

• (quadrivalent) • Prevents HPV types 16 and 18, as well as 6 and 11 which cause 90% of genital warts • Protects against cancers of anus, vagina and vulva • Only vaccine licensed for use in males along with Gardasil 9

• Gardasil 9 • Prevents HPV types 6, 11, 16, 18, 31, 33, 45, 52 and 58

• (bivalent)*** • Prevents HPV types 16 and 18 which cause 70% of cervical cancers

*******Taken off the market roughly September 2017 HPV Vaccines

• Recommended for 13 – 26 year old females and 13 – 21 year old males who have not completed the series • Recommended for gay and bisexual men and immunocompromised persons through age 26 if they were not previously vaccinated • Vaccines do NOT treat existing conditions caused by HPV HPV Rates of Vaccination

• Fall well below National Goal of 80% of population • In 2015, 63% of girls aged 13–17 years had received at least 1 dose of the HPV vaccine, and 42% had received all recommended doses in the series. • Lower among boys; 50% of those aged 13–17 years received at least 1 dose, but only 28% received all recommended doses. • Higher rates of vaccination with Medicaid insurance and living below the poverty line compared to those with commercial insurance and living above the poverty line. How many members of the audience recommend the vaccination? Health care provider barriers

• Some providers stated they have limited knowledge of the vaccine or conflicting information on what strains it covers. • Difficulty with approaching parents about the vaccine. • Some stated they simply forgot to mention it. • Hesitant to administer the vaccine before onset of sexual activity because the suggested age (11 to 12 years ) seemed to young. • Providers have the biggest influence on whether patients will accept vaccination!

Muncie HL, Lebato AL, HPV vaccination; overcoming parental and physician impediments Am Fam Physician. 2015;92(6)-449-454 Questions???? References

• Schiller, J. T.; Day, P. M.; Kines, R. C. (2010). Current understanding of the mechanism of HPV infection. Gynecologic Oncology 118 (1 Suppl): S12. • Muñoza N, Castellsaguéb X, Berrington de Gonzálezc A, Gissmann L (2006). Chapter 1: HPV in the etiology of human cancer. Vaccine 24 (3): S1–S10. • Altekruse SF, Kosary CL, Krapcho M, Neyman N, Aminou R, Waldron W, Ruhl J, Howlader N, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Cronin K, Chen HS, Feuer EJ, Stinchcomb DG, Edwards BK (eds). SEER Cancer Statistics Review, 1975- 2007, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2007/, based on November 2009 SEER data submission, posted to the SEER web site, 2010. • Mayeaux EJ Jr, Harper MB, Barksdale W, Pope JB. Noncervical human papillomavirus genital infections. Am Fam Physician 1995 Sep 15;52(4):1137-46, 1149-50 • Morasse, L., Davidov, A., Castellanos, M.R.(2009). The role of human papillomavirus testing in cervical cancer screening. JAAPA: 22(11), 20-23. • Ostor, A.G. (1993). Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol. 12(2): 186-92. • Wright, T.C., Schiffman, M. (2003). Adding a Test for Human Papillomavirus DNA to Cervical-Cancer Screening. NEJM;348(6):489-490 • Wright, T.C., Massad, L.S., Dunton, C.J., Spitzer, M., Wilkinson, E.J., Solomon, D. (2007). 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. American Journal of Obstetrics & Gynecology, Available at: http://download.journals.elsevierhealth.com/pdfs/journals/0002-9378/PIIS0002937807009301.pdf References

• Zandberg DP, Bhargava R, Badin S, Cullen KJ. The Role of Human Virus in Non Genital Cancers. CA Cancer J Clin 2013;63:57-81. • Gayar O H et al. Otolaryngology -- Head and Neck Surgery 2014;0194599813519738. • Cleveland JL, Junger ML, Saraiya M, Markowitz LE, Dunne EF, Epstein JB.The connection between human papillomavirus and oropharyngeal squamous cell carcinomas in the United States Implications for dentistry. The Journal of the American Dental Association, 2011; 142(8);915-924. • American Cancer Society http://www.cancer.org/cancer/oralcavityandoropharyngealcancer/detailedguide/oral- cavity-and-oropharyngeal-cancer-survival-rates • Cole T, et al. How to increase HPV Vaccination Rates. Clinician Reviews. 2017;40-46 • Vázquez-Otero C, Vamos CA, Thompson EL, Merrell LK, Griner SB, Kline NS, Catalanotto FA, Giuliano AR, Daley EM. Assessing dentists’ human papillomavirus–related health literacy for oropharyngeal cancer prevention. JADA 2018 Jan 1;149(1):9-17.