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1 2017 course #1 self-study course contact us: phone toll free fax web dentistry.osu.edu/sms The Ohio State University College of Dentistry 305 W. 12th Avenue Columbus, OH ABOUT this COURSE READ the MATERIALS. Read and review the course materials. COMPLETE the TEST. Answer the eight question test. A total of 6/8 questions must be answered correctly for credit. SUBMIT the ANSWER FORM ONLINE. You MUST submit your answers ONLINE at: CHECK YOUR for your CE certification of completion. ABOUT your FREE CE TWO CREDIT HOURS are issued for successful completion of this self-study course for the OSDB biennium totals. CERTIFICATE of COMPLETION is used to document your CE credit and is ed to each course participant ALLOW 2 WEEKS for processing of your certificate. The Ohio State University College of Dentistry is an American Dental Association (ADA) Continuing Education Recognized Provider (CERP). The Ohio State University College of Dentistry is a recognized provider for ADA CERP credit. ADA CERP is a service of the American Dental Association to assist dental professionals in identifying quality providers of continuing dental education. ADA CERP does not approve or endorse individual courses or instructors, nor does it imply acceptance of credit hours by boards of dentistry. Concerns or complaints about a CE provider may be directed to the provider or to the Commission for Continuing Education Provider Recognition at The Ohio State University College of Dentistry is approved by the Ohio State Dental Board as a permanent sponsor of continuing dental education. This continuing education activity has been planned and implemented in accordance with the standards of the ADA Continuing Education Recognition Program (ADA CERP) through joint efforts between The Ohio State University College of Dentistry Office of Continuing Dental Education and the Sterilization Monitoring Service (SMS). FREQUENTLY asked QUESTIONS Q: Who can earn FREE CE credits? A: EVERYONE - All dental professionals in your office may earn free CE credits. Each person must read the course materials and submit an online answer form independently. Q: Where can I find my SMS number? A: Your SMS number can be found in the upper right hand corner of your monthly reports, or, imprinted on the back of your test envelopes. The SMS number is the account number for your office only, and is the same for everyone in the office. Q: How often are these courses available? A: FOUR TIMES PER YEAR (8 CE credits).

2 2017 course #1 written by Vimi Mutalik, BDS, MDS edited by Sydney Fisher, BS Nick Kotlar, BS release date February 27, 2017 (8:30am EST) HPV-related Oropharyngeal Carcinoma Learning Objectives: 1. Learn key points about HPV-related OPSCC 2. Describe OPSCC prevalence and routes of acquisition 3. List and describe subtypes of HPV-related OPSCC 4. Identify the warning signs and methods of diagnosis, as well as disease treatment 5. Test knowledge by reviewing the True/False questions This is an OSDB Category B Supervised selfinstruction course INTRODUCTION The purpose of this CE self-study is to review the acquisition, prevalence, diagnosis and treatment of HPV-related oropharyngeal carcinomas, as well as disease subtypes and warning signs/symptoms. This CE self-study will also address prevention methods and the relationship between HPV and OSCC. last day to take the course at no charge March 31, :00pm EST Page 1

3 What is HPV-related OPSCC? The head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of neoplasm originating from various anatomic regions namely the oral cavity, oropharynx, hypopharynx, larynx and nasopharynx. Increased incidence of Human Papilloma Virus (HPV) as a cause of cancer in the head and neck region has made it important to analyze different subsites intraorally with caution. Although we refer to oral cancers in general, anatomically they are divided into oral cavity and the oropharynx. The cancers originating from the two anatomic sites, oral cavity and oropharyngeal region causes oral squamous cell carcinoma (OSCC) and oropharyngeal squamous cell carcinoma (OPSCC) respectively. Table 1: Features differentiating oral (OSCC) and oropharyngeal cancers (OPSCC) Parameters Oral cancer Oropharyngeal cancer Site Anterior oral mucosa Base of tongue, tonsils, posterior oral mucosa Etiology Smoking, alcohol Increased sexual partners, HPV Primary Clinical features White plaque, ulcer Enlarged lymph node in neck, dysphagia Incidence Decreasing Increasing Nodal involvement Present Present and may be the only sign of the disease Sex Males common (3:1) Males (5:1) predilection Social history Smoking (80-90%) Smoking (50-65%) Synergistic Alcohol Alcohol not a significant factor effect Prognosis 40% survival rate 80% survival rate Page 2

4 The cancers originating from these two anatomic sites (OSCC and OPSCC) vary considerably in terms of their statistics, etiologies, clinical signs and symptoms and response to treatment. HPV is now thought to be a risk factor in causation OPSCC (referring to posterior regions of the mouth) and not OSCC (common in anterior regions of the mouth). The discussion in this course is focused mostly on HPV-positive OPSCC which includes cancers from the base of tongue, tonsillar and pharyngeal wall. The OPSCC that are HPV-positive have risk factors related to sexual behavior, whereas HPV-negative cancers are strongly associated with tobacco and alcohol use. What are the key facts about HPV infection? Human papilloma virus (HPV) is the most common cause of sexually transmitted disease in the United States. HPV infection is very well-known in the causation of cervical cancers. However, it has been linked to various other cancers as well. In United States, new cases of cervical cancer have declined over the past 30 years because of increased use of Pap test, cervical smears or Pap smears. These tests enable professionals to identify early alterations in mucosa and are more curable than the invasive cancers. Although the rate of cervical cancer has been decreasing in women, the cancer on the back and sides of the throat, tonsils and base of tongue have increased significantly in men over the past few years. HPV has been thought to infect 90% of the U.S. population. About 12,000 Americans between ages of 15 to 24 are infected with HPV daily and about 26 million Americans have oral HPV infection on a given day. This definitely does not mean that all these patients develop OPSCC. In a vast majority of patients, the infection is cleared away within two years with their immune response and may not cause any health issues. There are nearly 200 strains of HPV; however, most of them do not cause cancers. Hence they are categorized into high-risk and low-risk subtypes. The lowrisk strains are associated most commonly with the causation of benign, noncancerous, genital and nongenital warts and the high-risk strains cause precancerous lesions which subsequently progress to cancer. The high-risk strains like HPV 16 and 18 are most commonly associated with occurrence of oropharyngeal cancers. Among them, HPV 16 is greater than 90% of times associated with oropharyngeal cancer. Page 3

5 HPV facts continued The Human Papilloma Virus (HPV) is a double stranded DNA virus that infects the epithelial cells of the skin and mucosa. These viruses have special affinity towards epithelium and are called epidermo-tropic. The mucosal surfaces that are moist like the throat, tongue, tonsils, vagina, cervix, vulva, penis and anus are more susceptible for development of diseases from this virus. Hence these viruses have also a major role in development of cervical, anal and penile cancers. When the virus contacts the epithelial surface it causes changes (koilocytic or viral induced changes) in the infected cells. The unique nature of transitional mucosa and the invaginations in the mucosal surface in the tonsils enables virus capture and makes it a preferential site for HPV. Moreover, the genetic features of HPV 16 facilitate an ideal environment for survival of these oncogenic (cancer-causing) organisms. Although HPV-positive and HPVnegative subtypes OPSCC exists, HPV is detectable in majority of the patients with oropharyngeal cancers. Therefore, in the oropharyngeal region the HPV-positive cases of OPSCC definitely outnumber the HPV-negative OPSCCs. Table 2: HPV facts sheet HPV is highly associated with oropharyngeal squamous cell carcinoma (OPSCC), but not oral squamous cell carcinoma (OSCC) Oropharyngeal squamous cell carcinoma (OPSCC) can be HPV-positive or HPVnegative. But the prognosis for the HPV-positive cases is better. Not all patients who have high-risk HPV in saliva develop oropharyngeal carcinoma. If you get HPV infection, you may or may not develop a precancerous or cancerous lesion. HPV, a primary cause for oral cancer (OSCC), lacks enough scientific evidence. HPV vaccines are safe and effective. Page 4

6 What is unique about HPV infection and OPSCC? The HPV-induced OPSCC have many unique features that distinguishes them from the conventional OSCC. Some studies indicate that the timing between the first exposure to HPV and the development of oropharyngeal cancer approximately exceeds 19 years. Oropharyngeal cancers (HPVinduced) present with very subtle clinical signs/symptoms and at most times the patient is unaware of it. Even the clinicians may find it hard to discover because the symptoms can be very elusive and painless. This is the main reason why OPSCC are usually identified at a later stage. Hence, it is very important that a very thorough examination is undertaken if the patient reports persisting symptoms of a period greater than two weeks. This is because the clinical signs and symptoms vary considerably from the obvious and classical tobacco-induced OSCC. Because the OPSCC have predilection for posterior regions for the mouth, accessibility to this area can be difficult and the primary lesion can be missed easily. Therefore, the tumor size in OPSCC is usually greater and the incidence of cervical and distant metastasis is also higher compared to OSCC. On the other hand, in a vast majority of patients, the infection is cleared away within two years with their immune response and does not cause any health issues. Some studies report that the infection with high-risk HPV usually last for months and is eventually cleared by the immune system. Persistent high-risk cases are the ones that eventually lead to development of malignancies or cancers. On the other hand, if you get HPV infection, you may or may not develop oral pre-cancer that eventually leads to oral cancer. Also, if you have a high-risk HPV infection, it is a myth to consider that you will definitely get HPV-induced OPSCC. The molecular alterations of HPV-positive head and neck cancer is in sharp contrast with HPV-negative head and neck cancers. p53 mutations, downregulated p16 activity and increased expression of prb is noted in HPV-negative head and neck cancers. These differences in the molecular profile indicate a lot about tumor behavior and its response to treatment. Page 5

7 How common is OPSCC? Head and neck cancers rank as the sixth most common cancer type worldwide. It accounts for nearly 5% of the cancers around the globe. Out of the 650,000 cases diagnosed worldwide each year, the annual mortality is about 300,000. Each year, approximately 263,000 cases of oral cavity cancer and 135,000 cases of pharyngeal cancer are diagnosed worldwide. The national head and neck malignant tumor registries indicate oral cavity to be the most predominant site, followed by larynx, hypopharynx, oropharynx, nose and paranasal sinuses and nasopharynx. It is important to note that the OSCC are associated with smoking and alcohol consumption, but the frequency of these cancers has declined in the US over the past 20 years. Figure 1: Incidence trends for Oral (OSCC) and Oropharyngeal (OPSCC) cancers Source: Chaturvedi AK et al., JCO, 2013 Page 6

8 However, the OPSCC has been on the rise with an increase by 28% during 1998 to In US, there is 225% increase in HPV-positive OPSCC from The annual rise in the number of cases is thought to be 70% and this would surpass the annual numbers of cervical cancers. The incidence of OPSCC is increasing in the economically developed countries like US, UK, Europe and Brazil. By 2020, the overall OPSCC burden in US is predicted to surpass cervical SCC. These changes have prompted recent epidemiological work to study differences between HNSCC related to tumor subsites and research on OPSCC is now taking a central position. How is the disease acquired? HPV usually involves the skin or the mucosal epithelium and causes abnormal changes. In most cases, the body fights off the infection and the cells that are infected get back to normal. When the body is unable to fight back because of other coexisting factors (like systemic illness or comorbidities, immunodeficiency status or habits like smoking), this virus can cause a range of diseases like genital warts, oral squamous papilloma, condyloma accuminatum and OPSCC. HPV is a sexually transmitted disease, which is now thought to be epidemic. Increased number of sex partners, open mouth kissing, practicing oral sex (from mouth to genital) and having sex with a partner who has had multiple sex partners are considered high risk factors. The incidence is greater in males as compared to females. This has been attributed to several reasons like a higher spread of infection through oral sex interaction on a woman. This is also further proved by the fact that an increased incidence of these cancers is seen more often in heterosexual men than homosexual men. Another possibility could be that, men mount a less robust immune response and are unable to protect themselves from the infection. A recent case control study also indicated that a high (>26) number of lifetime vaginalsex partners and 6 or more lifetime oral-sex partners are associated with an increased risk of development of OPSCC. The risk is also high in female partners with HPV-associated anogenital cancers and their male partners. On the contrary, it is interesting to note that the incidence of HPV infection in longterm sexual partners is not increased beyond the level compared to the general population. Page 7

9 Figure 2: Indicating the level of exposure to risk factors. Source: A vast majority of these patients have been current /past smokers, so smoking is thought to have a synergistic effect in the causation of these cancers. Immunodeficiency (HIV) infection is also thought to increase the risk for oral HPV infection. The immunodeficiency status is thought to increase the persistence of the infection thereby leading to development of oral HPVrelated disease. Focusing on the various modes of transmission, the risk of transmission from mother to child through saliva is questionable. The recent increased incidence of this disease mirrors the societal changes in sexual behavior that occurred in the developed world. The incidence of oropharyngeal SCC (OPSCC) in the developed countries is increasing as compared to Oral SCC (OSCC) in the developing countries. It is reported that changes in the sexual behavior in the developed world have led to an increase in the number of these OPSCC cases. Page 8

10 What are the different subtypes? Once acquired, the HPV infection goes through different stages/status in the body which is discussed below: Transient carrier status: Infections clears with no lesions, positive for serum antibody tests. It is the most common phase where the virus is present in mucosa and is identified by advanced molecular tests like in situ hybridization (ISH) or polymerase chain reaction (PCR). In majority of the cases, the virus is cleared within 1-2 years. Chronic carrier status: More frequently seen with high-risk subtypes and long term immunosuppression. This is an uncommon phase. There can be persistence of the high risk virus and this has strongly been implicated in the development of OPSCC. Chronic infection by HPV high-risk types confers to a 6- to 50-time increased risk of developing HPV-positive oropharyngeal cancer. Benign lesions: Papilloma, verruca (warts), condyloma accuminatum. Premalignant lesions: Cases of koilocytic dysplasia or HPV induced dysplasia have been described. However, the best described cases are in cervical dysplasia. Oropharyngeal cancer: Usually caused by HPV 16. About 90% of the patients who have this high-risk type definitely have OPSCC in the appropriate clinical setting. Page 9

11 What are the warning signs /symptoms of this disease? Figure 3: Oropharyngeal squamous cell carcinoma (OPSCC) presenting as an ulcero-proliferative growth in the posterior tonsillar area. Courtesy: Dr. Carl Allen, Department of Oral Pathology, The Ohio State University. Columbus Ohio OPSCC are commonly seen in Caucasian males, years of age, less exposed to tobacco and alcohol and with a relatively high socio-economic status. Patients with these cancers usually present with nonspecific symptoms of throat pain which is commonly seen during swallowing and abnormal sensation in the throat. With advanced disease, there is a neck swelling (lymph node enlargement) and dysphagia. The primary lesion is usually located in the tonsillar fossa or in the base of the tongue. Some patients also present with concern of ulcer on the throat, painless tonsil, alterations in voice and ear ache. In most cases, the neck swelling will be the primary concern since the nodal metastasis is aggressive. If the primary lesion is small or in the absence of throat symptoms, a diagnosis of node metastasis from carcinoma of unknown primary (CUP) is made. Page 10

12 How do we diagnose this condition? Although there are various chairside diagnostic tests to detect oral cancer, HPV-induced OPSCC are best identified by a thorough recording or medical/dental/social history from the patients, accompanied by visual and tactile head/ neck examination. Comprehensive oral examination is a key in establishing the diagnosis. Despite limited data showing improved survival, early detection of oral cancer/ pre-cancer is considered an integral part of a comprehensive hard/soft tissue examination that follows patient history and risk assessment. An ulcer or sore throat that has not healed for 2-3 weeks, difficult or painful swallowing, swollen but painless tonsil, recent change of voice/hoarseness, lump on the neck and an ear ache are the guiding features towards a possible early detection of these cancers. Like any diagnostic kit, this process of visual and tactile examination may not be 100% effective, so it is important to pursue if the symptoms have not resolved in 2-3 weeks time in order to arrive at a final diagnosis. Figure 4: Site predilection for OPSCC Source: Page 11

13 Diagnosis continued OraRisk sm HPV by OralDNA Labs and Quest Labs (2010) are commercially available kits usually indicated if there are traditional risk factors like sexual activity, family history of oral cancer, signs and symptoms of oral cancer and presence of a suspicious oral lesion. It is usually noninvasive and easy to use. The method is to gargle/swish with sterile saline for 30 seconds; expectorate into funneltop tube, ship, report. If the test is positive with no lesion, it is indicated to repeat the test again in six months and if it s positive, refer to oral surgery or the ENT department. On obtaining a biopsy from the primary site or a positive lymph node, these tumors represent an early T and a higher N stage, exhibiting moderate to poor cellular differentiation with basaloid/non-keratinizing morphology of tumor cells. The gold standard for assessing the HPV infections is the molecular techniques: in situ hybridization (ISH) or polymerase chain reaction (PCR). Both these techniques help to detect HPV deoxyribonucleic acid (DNA). cdna probe identifies the HPV DNA sequence, but includes episomal DNA (transitory infections). Several biomarkers have been useful; p16 is thought to be the most useful and reliable surrogate biomarker for this. It is noteworthy to mention that that evidence of both HPV DNA and evidence of viral DNA integration (p16+) are needed to diagnose an OPSCC as HPV-positive. What is the treatment and prognosis for HPV related cancers? The protocol for treatment of OPSCC is mainly determined by the stage of the disease. Single treatment modality, either surgery or radiotherapy is usually recommended for early disease. The HPV-positive tumors have better response to therapy. This is attributed to the presence of fewer genetic alterations, improved immune response contributing to higher radio sensitivity and the absence of filed cancerization effects. Moreover, the young age in association with less comorbidity may also contribute to better treatment outcomes. Comorbidities in the form of immunodeficiency states (HIV infection) or long term history of smoking may alter the prognosis and appropriate response to therapy. Tobacco smoking has been associated with worse prognosis in HPV-associated oropharyngeal cancers. The risk of progression of the disease and an increase death rate was directly proportional to the increased smoking history. Overall, HPV-positive cancers are associated with improved 3-year survival, 80% versus 40% for HPV-negative cancers. These cancers have a 28% reduction in risk of death and a 49% decrease in disease recurrence compared to the OSCC which are treated aggressively and have dismal clinical outcome. Page 12

14 How can we prevent HPV related Oropharyngeal cancers? Currently, two prophylactic vaccines, Gardasil (Merck, USA) and Cervarix (GlaxoSmithKline, UK) are available and recommended for adolescent massimmunization. Recently, Gardasil-9, which is a nanovalent vaccine and protects against nine strains of viruses, has been introduced. Since 2006, the federal drug administration (FDA) has approved these vaccines for HPV, all of which render protection against HPV 16 and 18. They are recommended for preteen girls and boys at age 11 to 12 years. The CDC has also recommended this for candidates who did not receive the vaccines when they were younger; including teen boys and girls, women through age 26 and young men through age 21. Both the vaccines are administered in a volume of 0.3mL intramuscularly. After the initial dose, two more booster doses are given, one within 1 or 2 months and another within 6 months. Although these vaccines have been very well-timed in terms of prevention, some patients receiving these vaccines experience pain, fatigue, redness, swelling, fever, GI symptoms, headache, dizziness, myalgia and arthralgia. One of the most common adverse reactions noted is local erythema at the site of injection. Rare cases of severe headache with hypertension, bronchospasm and gastroenteritis have also been documented. Gardasil has also been known to have caused infection, gastrointestinal disorders, nervous system disorders, reproductive and breast disorders. Although these vaccines have been effective, there is limitation in terms of their cost and expenses, as well as preparation and preservation. These vaccines have been designed specifically to reduce cervical cancer, but their effectiveness in minimizing oropharyngeal cancer (OPSCC) is still debatable. Broader subtype coverage of Gardasil-9 is expected to provide similar protection. Studies have also indicated that a decade after the first vaccine have been introduced, only 1 in 5 boys and 2 in 5 girls have been vaccinated. This number is considered low when compared to the health policy target of 80 percent. In addition to the vaccines, use of condoms, limiting the number of sex partners is also thought to decrease the incidence of causing these cancers. To date, Cervarix and Gardasil are considered very safe vaccines and have not been found to have a causal relationship with any serious health concern in a majority of the patients. Page 13

15 Can HPV cause OSCC in oral cavity? Figure 5: Oral squamous cell carcinoma (OSCC) presenting as an ulcer in the anterolateral and ventral portion of the tongue. Courtesy: Dr. Carl Allen, Department of Oral Pathology, The Ohio State University. Columbus Ohio. Comprehensive studies examining the site-specific prevalence of HPV have indicated that it is present in lip mucosa, floor of mouth, palate, tongue etc., in decreasing order of frequency. Since HPV DNA is present in reasonable subgroup of OSCC, it is important to note that not all HPV-positive tumors can be considered to be etiologically HPV driven. Molecular studies analyzing the HPV DNA status could detect viral oncogenes in only about 6-7% of the cases. This supports the notion that HPV is not biologically active in a majority of these oral cancers and is simply a bystander of this disease process. This separation is due to a different etiological process. This was also proven by the fact that most of these tumors were p16-negative, which indicates that the HPV was not transcriptionally active. The overall estimation is that less than 5% of OSCC are HPV-related. Hence, there is no consistent evidence of HPV as a risk factor for OSCC. Cases of HPV-positive pre-cancer in oral epithelial dysplasia, which is also called koilocytic dysplasia, has not been reported often. Studies also show that they have been both high-risk HPV-positive and p16-positive. A series of 20 cases of koilocytic dysplasia showed that the disease was common in men, and presented as white or papillary lesions and usually on ventral tongue. Among them, one recurred and one of them recurred (three times) in spite of excision with clear surgical margins. Up to 67% of those patients were followed for about 48 months and they had no evidence of disease. Hence the behavior off these lesions is considered identical to the HPV-negative lesion. Page 14

16 Abbreviations used: Head and neck squamous cell carcinoma (HNSCC) Oral squamous cell carcinoma (OSCC) Oropharyngeal squamous cell carcinoma (OPSCC) Human Papilloma Virus (HPV) Polymerase chain reaction (PCR) In-situ hybridization (ISH) Educational Links: Oral Cancer Foundation CDC UpToDate About the Author Vimi Mutalik, BDS, MDS Vimi Mutalik completed undergraduate studies at Rajiv Gandhi University in India, and continued on to receive a Masters in Oral Pathology from the same university. Currently a second year resident in oral pathology at The Ohio State University, Mutalik is studying HPV and its relation to oral pre-cancer. Future career plans are to provide patient care through biopsy service and clinical pathology. Mutalik can be reached at Mutalik.1@buckey .osu.edu Neither I nor my immediate family have any financial interests that would create a conflict of interest or restrict my judgement with regard to the content of this course Page 15

17 References Jayaprakash V, Reid M, Hatton E, Merzianu M, Rigual N, Marshall J, Gill S, Frustino J, Wilding G, Loree T, Popat S, Sullivan M. Human papillomavirus types 16 and 18 in epithelial dysplasia of oral cavity and oropharynx: a meta-analysis, Oral Oncol Nov; 47(11): Liu H, Liu XW, Dong G, Zhou J, Liu Y, Gao Y, Liu XY, Gu L, Sun Z, Deng D. P16 Methylation as an Early Predictor for Cancer Development from Oral Epithelial Dysplasia: A Double-blind Multicentre Prospective Study. EBioMedicine Mar 23; 2(5): Miller CS, Johnstone BM. Human papillomavirus as a risk factor for oral squamous cell carcinoma: a meta-analysis, Oral Surg Oral Med Oral Pathol Oral Radiol Endod Jun; 91(6): Nankivell P, Williams H, Webster K, Pearson D, High A, MacLennan K, Senguven B, McConkey C, Rabbitts P, Mehanna H. Investigation of p16(ink4a) as a prognostic biomarker in oral epithelial dysplasia. J Oral Pathol Med Apr; 43(4):245-9 Rettig EM, D Souza G. Surg Oncol Clin N Am (2015) Termine N, Panzarella V, Falaschini S, Russo A, Matranga D, Lo Muzio L, Campi. HPV in oral squamous cell carcinoma vs head and neck squamous cell carcinoma biopsies: a meta-analysis ( ). Ann Oncol Oct; 19(10): Uddin MN, Kouzi SA and Hussain MD. Strategies for Developing Oral Vaccines for Human Papillomavirus (HPV) Induced Cancer using Nanoparticle mediated Delivery System. J Pharm Sci. 2015; 18(2) More references available on request Page 16

18 Post-Test Instructions Answer each question ONLINE (link provided on SMS website) Answer post-course survey questions and click Finish Deadline is March 31, 2017 (4:00pm EST) 1 T F In developed countries, the incidence of oral squamous cell carcinoma (OSCC) is more than oropharyngeal carcinoma (OPSCC). 2 T F Oropharyngeal squamous cell carcinoma (OPSCC) is commonly seen in males. 3 T F The Human papilloma virus is usually cleared within 1-2 years in a patient with a good immune status. 4 T F The prognosis for HPV-positive cancer is worse than HPV-negative cancer. 5 T F Ulceration and pain on the anterior tongue is the most common presenting sign/symptom in patients with oropharyngeal squamous cell carcinoma (OPSCC). 6 7 T T F F HPV 16 and 18 are the strains associated in development of oropharyngeal squamous cell carcinoma (OPSCC). A patient presenting with swollen lymph nodes on his neck in the absence of any signs of disease in the oral and oropharyngeal region, node metastasis from Carcinoma of Unknown Primary (CUP) may be considered in the differential diagnosis. Director John R. Kalmar, DMD, PhD Kalmar.7@osu.edu Program Manager Sydney Fisher, BS Fisher.1057@osu.edu Program Assistant Nick Kotlar, BS Kotlar.2@osu.edu 8 T F HPV vaccines are 100% effective in preventing oropharyngeal cancers (OPSCC).