HPV-16

Understanding the link between HPV and oropharyngeal cancers

Source: www.jaapa.com (Journal of the American Academy of Physician Assistants, October, 2009)
Authors: Denise Rizzolo, PA-C, PhD, Mona Sedrak, PA-C, PhD

Head and neck cancer is diagnosed in approximately 650,000 patients each year worldwide.1 The term head and neck cancer refers to a group of biologically similar cancers originating from the upper aerodigestive tract, including the lip, oral cavity (mouth), nasal cavity, paranasal sinuses, pharynx, and larynx. Oropharyngeal refers to all the structures of the mouth and pharynx, including the tonsils and tongue. Oral squamous cell carcinoma (OSCC) is the most common form of head and neck cancer.2 Seventy-five percent of all OSCCs are attributable to tobacco and alcohol use.3 People who smoke cigarettes are 4 times more likely to develop oral cancer than nonsmokers. Furthermore, individuals who consume alcohol are 3 times more likely than nondrinkers to develop oral cancer.3 According to the Substance Abuse and Mental Health Services Administration, the prevalence of cigarette smoking has decreased among Americans, and alcohol use has also declined since the 1970s.4,5 However despite this, the incidence of oropharyngeal cancers, including cancer of the base of the tongue and tonsils, has increased, especially in younger patients. These trends have led researchers to investigate other potential risk factors.6-8

New studies suggest that there may be an alternative pathway for the development of oropharyngeal cancers. The high-risk types of human papillomavirus (HPV), especially type 16 (HPV-16), are now thought to be potential etiologic agents.2,3 The concept that HPV plays a role in head and neck cancers is not new. This link has been under investigation for at least 20 years.6 This is a worrisome public-health concern because patients with HPV-positive OSCC are 3 to 5 years younger at diagnosis than those with HPV-negative OSCC, and they have a history of high-risk sexual behavior.9-12 Interestingly, patients with HPV-positive OSCC are also less likely to have a history of alcohol and tobacco abuse.3 Therefore, educating patients regarding the disturbing trend of HPV-positive oropharyngeal cancer is important.

Incidence and Prevalence
In the United States alone, an estimated 34,360 people received a diagnosis of oropharyngeal cancer in 2007; of these, 7,550 (5,180 men and 2,370 women) died.13 On average, more than 25% of people who develop oropharyngeal cancer will die of the disease, with only 60% surviving for more than 5 years.14 In fact, oropharyngeal cancer is as common as leukemia and claims more lives than either melanoma or cervical cancer.13

Since the mid 1970s, oropharyngeal cancer rates have increased approximately 15%, with significant disparities in some population groups. For instance, oropharyngeal cancer prevalence is significantly higher in males than in females.14 Prevalence is also higher in Hispanic and black males than it is in white males.14 The risk of oropharyngeal cancer increases with age, and occurrence is highest in persons older than 50 years and peaks between ages 60 and 70 years.14 However, there has been a startling 5-fold increase in the incidence of oral cancer in patients younger than 40 years, many of whom have no known risk factors.4

HPV is associated with 15% to 35% of head and neck cancers worldwide.11 Fifty percent to 90% of OSCCs in the pharynx, tonsil, and tongue are HPV-positive.11 Chaturvedi and colleagues investigated the impact of HPV on the epidemiology of OSCCs in the United States.9 These researchers reported that HPV-positive OSCCs were diagnosed at younger ages than HPV-negative OSCCs (mean age at diagnosis was 61.0 and 63.8 years, respectively) and the incidence increased significantly for HPV-positive OSCC from 1973 to 2004, particularly among younger white men.

Kreimer and colleagues conducted a systematic review of 60 studies and determined that 25.9% of the 5,046 patients with head and neck squamous cell carcinoma (HNSCC) were HPV-positive.2 Furthermore, these researchers noted that HPV-16 was the most prevalent genotype in these cancers, accounting for 86.7% of cases.

Although there is research that supports the association between HPV and oropharyngeal cancers, some studies dispute that relationship. Specifically, controversy exists over the prevalence and significance of HPV in oral tongue cancers (cancer of the anterior two-thirds of the tongue). In a 2008 Mayo Clinic study, researchers examined fresh-frozen tissues from 51 patients with oral tongue cancers.15 Their findings suggest that the incidence of oral HPV in oral tongue cancer was low and was unlikely to play a significant role in the etiology, pathogenesis, and clinical outcomes of oral tongue cancers.15 The authors admit the study was limited by a small sample size and that more research is needed.

Pathogenesis
The oropharyngeal sites that are most often associated with the HPV infection are the tonsils and the tongue.16,17 Reasons why the oropharynx is more susceptible to the HPV infection remain unclear; however, the similarity in accessibility to infection between the tonsillar tissue and the uterine cervical mucosa is believed to make the oropharyngeal area more vulnerable. Another explanation is that tonsillar tissue contains deep invaginations that may capture the virus and facilitate it into the basal cells.

The mechanism of HPV carcinogenesis was first characterized in cervical cancer. Ninety percent of cervical cancer cases are related to HPV infection, predominantly HPV-16 and HPV-18.18 The viral oncoproteins E6 and E7 of the high-risk HPV types are associated with the malignant process in both anogenital and head and neck cancers.17 These oncoproteins inactivate the p53 and pRb tumor suppressor pathways, which is important to the genetic progression of head and neck cancers. HPV infection may therefore represent an alternate but functional pathway for HNSCC pathogenesis. Yet, despite recent literature confirming that HPV is a risk factor associated with oropharyngeal cancers, the HPV infection is not necessary nor is it sufficient for oropharyngeal carcinoma to develop. Therefore, more research is needed to closely define the link between the acquisition of the virus and the progression to cancer.

The major prognostic factors for head and neck cancer are the presence of local and regional metastasis, vascular or lymphatic invasion, positive surgical margins, and extracapsular spread of tumor cells from the lymph nodes into the soft tissue of the head and neck.19 Thus, understanding the mechanism of tumor progression may help to identify new prognostic and predictive markers that will aid in the development of new therapeutic agents for the treatment of HPV-positive cancer.20

Incidence of HPV Transmission
The association between high-risk sexual behavior and transmission of HPV is well-established.10,21 Certain sexual behaviors are associated with a significantly increased risk of HPV transmission, including engaging in casual sex, young age at first intercourse, and infrequent use of condoms. Specifically, a high number of lifetime sex partners (26 or more vaginal-sex partners, 6 or more oral-sex partners) is associated with an increased risk of oropharyngeal cancer. A study conducted from 2000 to 2006 positively correlated HPV-16-positive cancer of the head and neck with number of oral-sex partners, as well as with marijuana use.22

Diffuse white area on the buccal mucosa

Diffuse white area on the buccal mucosa

The onset of the HIV epidemic has resulted in an increase in oral sex practices among teenagers and young adults, which may be contributing to the increase in the incidence of HPV-positive cancers.23 A common belief among people in these age-groups is that oral sex represents a form of “safe sex,” leading to a worry-free behavior that precludes them from contracting sexually transmitted diseases. These findings emphasize a significant implication to public health. The increase in the incidence of tonsillar and base-of-tongue cancers in the United States may be a result of a higher incidence of oral-sex practices.7,8

Clinical Signs and Symptoms
HPV-positive oropharyngeal cancer manifests in the same manner as HPV-negative oropharyngeal cancer. Therefore, clinicians should be aware of the signs and symptoms that suggest OSCC. Patients present with a variety of signs and symptoms depending on the site of origin, including a sore throat, dysphagia, odynophagia, and hoarseness14 (Table 1). The two precursor lesions clinicians should look for are leukoplakia, white lesions (Figure 1), and erythroplakia, red lesions. Although leukoplakia lesions are more common, erythroplakia and lesions with erythroplakic components have a much greater potential for becoming cancerous. Any white or red lesion that does not resolve within 2 weeks should be reevaluated and considered for biopsy to obtain a definitive diagnosis.14 The following are the four basic steps to early detection and prevention of disease:

• Take a thorough history
• Perform a detailed examination of the head and neck
• Educate patients on the risk factors associated with oral cancers
• Provide adequate follow-up to ensure a definitive diagnosis of any suspicious lesions.14

table-1

A thorough history and physical examination of the head and neck should be a routine part of each patient’s general medical examination. Clinicians should be particularly vigilant when examining patients who have a history of tobacco use or drink excessive amounts of alcohol. The examination is conducted with the patient seated. The patient should remove any intraoral prostheses before beginning the examination. The extraoral assessment includes inspection of the face, head, and neck; note any asymmetry or skin pathology, such as crusts, fissuring, growths, and/or color changes. The regional lymph node areas are bilaterally palpated to detect any enlarged nodes.14 The perioral and intraoral examination follows a detailed, seven-step systematic assessment14 (Table 2).

table-2

Therapeutics
Recent data suggests a better prognosis for those patients with HPV-positive HNSCC than for those with HPV-negative HNSCC; however, there is still intense debate over this theory.20 Treatment is the same for patients, regardless of whether they have HPV-positive or HPV-negative HNSCC. Traditional therapy for patients with stage I or II head and neck cancer consists of radiation and/or surgery, and prognosis is excellent. Unfortunately, most patients present with stage III or IV disease, and treatment consists of a combination of chemotherapy, radiation, and surgery.20 Survival rates are greatly diminished when the disease is diagnosed at a later stage.

An interesting note is that research suggests that HPV-positive tumors behave in a different fashion, have a different response to therapy, and are more sensitive to radiation-based therapies; therefore, HPV-positive HNSCCs may require a different therapeutic approach compared with HPV-negative HNSCCs.24 Fakhry and colleagues found that patients with HPV-positive HNSCC had better overall and progression-free survival rates than did patients with HPV-negative HNSCC.24 These findings raise the question of whether traditional therapy is the best option for HPV-positive disease. Even when HNSCC is diagnosed early, treatment still consists of removal of the diseased tissue and/or weeks of radiation therapy that may leave some patients disfigured or with permanent negative sequela (dry mouth, loss of taste, alteration of speech patterns, etc). If HPV-positive cancers are more sensitive to traditional therapy, can less aggressive and extensive treatment be used thereby minimizing the side effects of current therapeutic regimens on this subset of patients? The study authors interpret their results cautiously, suggesting that more research is needed on treatment response and subsequent survival patterns of patients with HPV-positive cancers. Until further research is conducted, therapeutic treatment strategies are the same for HPV-positive and HPV-negative HNSCC.24

Patient Education: Prevention and Detection
The best way to prevent oropharyngeal cancer is to avoid tobacco and alcohol use. In addition, regular dental checkups, including an examination of the entire mouth, are essential for early detection of cancerous and precancerous conditions. Red or white lesions often precede the development of oropharyngeal cancer; therefore, if patients notice any new lesions in their mouths, they should have them evaluated by their clinicians. Lesions that do not resolve after 2 weeks should be biopsied. Detection of oropharyngeal carcinoma while the disease is still localized can dramatically increase survival rates. The 5-year survival rate for patients with localized disease at diagnosis is 82%, compared with only 28% for those whose cancer has spread to other parts of the body.14

Clinicians should take the time to educate young patients regarding HPV infection, its correlation to oropharyngeal cancer, and safe-sex practices. Some discussions in the literature suggest that the HPV vaccine could be considered for the prevention of HPV-positive HNSCC.6,10,20 The HPV vaccine has become an important strategy in the prevention of cervical cancer because HPV has been shown to cause nearly all cases of female cervical cancer. Ninety-five percent of patients with HPV-positive HNSCC are positive for HPV-16; therefore, researchers are exploring whether the vaccine could provide the same prophylactic effect against HPV-positive HNSCC as it does for HPV-associated anogenital cancers.25 D’Souza and colleagues argue that a rationale for HPV vaccination in both boys and girls is that oropharyngeal cancers occur in both men and women.10 They also suggest that if the vaccine prevents oral disease as effectively as it prevents cervical disease, a substantial reduction in the incidence of oropharyngeal cancer in vaccinated populations would provide the ultimate evidence of causality. However, no definitive recommendations to use the HPV vaccine to prevent HPV-positive HNSCC have been made.

table-4

Conclusion
Cancers of the head and neck are a worldwide concern. The incidence of HPV-related head and neck cancer is increasing. Clinicians should be aware of the risk factors as well as the clinical signs and symptoms of oropharyngeal cancers. The best way to prevent oropharyngeal cancer is to avoid tobacco and alcohol use. However, consistent safe-sex practices are also effective preventive measures because of the strong correlation between HPV infection and oropharyngeal cancers. This association has researchers considering the potential effectiveness of the HPV vaccine in the prevention of HPVpositive head and neck cancers. JAAPA

Authors’ affiliations
Mona Sedrak is an associate professor in the PA program at Seton Hall University, South Orange, New Jersey. Denise Rizzolo works at the Care Station, Springfield, New Jersey, and is faculty assistant professor in the PA program at Seton Hall University. They have indicated no relationships to disclose relating to the content of this article.

References
1. Boyle P, Ferlay J. Cancer incidence and mortality in Europe, 2004. Ann Oncol. 2005;16(3):481-488.
2. Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev. 2005;14(2):467-475.
3. Mork J, Lie K, Glattre E, et al. Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med. 2001;344(15):1125-1131.
4. Schantz SP, Yu GP. Head and neck cancer incidence trends in young Americans, 1973-1997, with a special analysis for tongue cancer. Arch Otolaryngol Head Neck Surg. 2002;128(3):268-274.
5. Substance Abuse and Mental Health Services Administration. Results from the 2006 National Survey on Drug Use and Health: National Findings. Rockville, MD: Substance Abuse and Mental Health Services Administration, US Dept of Health and Human Services; 2006. DHHS publication SMA 07-4293.
6. Syrjanen S. Human papillomaviruses in head and neck carcinomas. N Engl J Med. 2007;356(19):1993-1995.
7. Frisch M, Hjalgrim H, Jaeger AB, Biggar RJ. Changing patterns of tonsillar squamous cell carcinoma in the United States. Cancer Causes Control. 2000;11(6):489-495.
8. Shiboski CH, Schmidt BL, Jordan RC. Tongue and tonsil carcinoma: increasing trends in the U.S. population ages 20-44 years. Cancer. 2005;103(9):1843-1849.
9. Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol. 2008;26(4):612-619.
10. D’Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356(19):1944-1956.
11. Saraiya M, Kawaoka K. Incidence of human papillomavirus (HPV)-related head and neck cancers in the US from 1998-2003: Pre-HPV vaccine licensure. [ASCO abstract 6003] J Clin Oncol. 2007;25(suppl):299s.
12. Schwartz SM, Daling JR, Doody DR, et al. Oral cancer risk in relation to sexual history and evidence of human papillomavirus infection. J Natl Cancer Inst. 1998;90(21):1626-1636.
13. American Cancer Society. Cancer Facts & Figures 2007. Atlanta, GA: American Cancer Society; 2007.
14. National Institute of Dental and Craniofacial Research. Detecting oral cancer: A guide for health care professionals. NIDCR Web site. http://www.nidcr.nih.gov/.
15. Liang XH, Lewis J, Foote R, et al. Prevalence and significance of human papillomavirus in oral tongue cancer: the Mayo Clinic experience. J Oral Maxillofac Surg. 2008;66(9):1875-1880.
16. Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000;92(9):709-720.
17. Haddad RI. Human papillomavirus infection and oropharyngeal cancer. Medscape CME Web site. http://cme.medscape.com/viewarticle/559789. Accessed September 4, 2009.
18. Muñoz N, Bosch FX, de Sanjosé S, et al; International Agency for Research on Cancer Multicenter Cervical Cancer Study Group. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348(6):518-527.
19. Forastiere A, Koch W, Trotti A, Sidransky D. Head and neck cancer. N Engl J Med. 2001;345(26):1890-1900.
20. Haddad RI, Shin DM. Recent advances in head and neck cancer. N Engl J Med. 2008;359(11):1143-1154.
21. Gillison ML, Shah KV. Chapter 9: Role of mucosal human papillomavirus in nongenital cancers. J Natl Cancer Inst Monogr. 2003;(31):57-65.
22. Gillison ML, D’Souza G, Westra W, et al. Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst. 2008;100(6):407-420.
23. Mosher WD, Chandra A, Jones J. Sexual behavior and selected health measures: men and women 15-44 years of age, United States, 2002. Adv Data. 2005;(362):1-55.
24. Fakhry C, Westra WH, Li S, Cmelak A, et al. Improved survival of patients with human papillomavirus—positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100(4):261-269.
25. Devaraj K, Gillison ML, Wu TC. Development of HPV vaccines for HPV-associated head and neck squamous cell carcinoma. Crit Rev Oral Biol Med. 2003;14(5):345-362.

October, 2009|Oral Cancer News|

New evidence supports HPV vaccine

MONDAY, July 6 (HealthDay News) — The human papillomavirus (HPV) vaccine is highly effective at preventing precancerous cervical lesions that can lead to cervical cancer, a new study shows.
The researchers also found that the HPV-16/18 AS04-adjuvanted vaccine also appears to protect against other cancer-causing HPV types closely related to HPV-16/18, most notably HPV-31 and HPV-45.
The study of women aged 15 to 25, who received three vaccine doses over six months, found that it was as much as 98 percent effective against HPV-16/18, and between 37 percent and 54 percent effective against 12 other cancer-causing HPV types.
HPV-16/18 causes about 70 percent of cervical cancer cases, while the remaining 30 percent of cases are caused by other cancer-causing HPV types. The cross-protective effect of the HPV-16/18 vaccine could provide an additional 11 percent to 16 percent protection against cervical cancer.
“Although the importance of continued tests for Pap or HPV in vaccinated and unvaccinated women must be emphasized, HPV vaccination has the potential to substantially reduce the incidence of cervical cancer and precancer, and the numbers of colposcopy referrals and cervical excision procedures,” concluded Dr. Jorma Paavonen, of the University of Helsinki in Finland, and colleagues.
The study, which was funded by GlaxoSmithKline Biologicals, maker of the HPV-16/18 AS04-adjuvanted vaccine Cervarix, appears online July 7 and in an upcoming print issue of The Lancet.
In an accompanying editorial, two experts wrote that men must also be included in efforts to halt the spread of HPV.
“Currently, the targets for HPV vaccination are girls and young women aged 11 to 26 years prior to sexual debut,” noted Karin B. Michels, of Harvard Medical School in Boston, and Dr. Harald zur Hausen, of the German Cancer Research Center in Heidelberg.
“While good utilization of the [vaccine] program will reduce cervical cancer incidence in a couple of decades, this subgroup of the population at risk is too small to limit the spread of the virus,” the researchers wrote. “The only efficient way to stop the virus is to also vaccinate the other half of the sexually active population: boys and men.”

Source: Forbes.com

Author: Staff

Industry-funded study showed high levels of protection against human papillomavirus

MONDAY, July 6 (HealthDay News) — The human papillomavirus (HPV) vaccine is highly effective at preventing precancerous cervical lesions that can lead to cervical cancer, a new study shows.

The researchers also found that the HPV-16/18 AS04-adjuvanted vaccine also appears to protect against other cancer-causing HPV types closely related to HPV-16/18, most notably HPV-31 and HPV-45.

The study of women aged 15 to 25, who received three vaccine doses over six months, found that it was as much as 98 percent effective against HPV-16/18, and between 37 percent and 54 percent effective against 12 other cancer-causing HPV types.

HPV-16/18 causes about 70 percent of cervical cancer cases, while the remaining 30 percent of cases are caused by other cancer-causing HPV types. The cross-protective effect of the HPV-16/18 vaccine could provide an additional 11 percent to 16 percent protection against cervical cancer.

“Although the importance of continued tests for Pap or HPV in vaccinated and unvaccinated women must be emphasized, HPV vaccination has the potential to substantially reduce the incidence of cervical cancer and precancer, and the numbers of colposcopy referrals and cervical excision procedures,” concluded Dr. Jorma Paavonen, of the University of Helsinki in Finland, and colleagues.

The study, which was funded by GlaxoSmithKline Biologicals, maker of the HPV-16/18 AS04-adjuvanted vaccine Cervarix, appears online July 7 and in an upcoming print issue of The Lancet.

In an accompanying editorial, two experts wrote that men must also be included in efforts to halt the spread of HPV.

“Currently, the targets for HPV vaccination are girls and young women aged 11 to 26 years prior to sexual debut,” noted Karin B. Michels, of Harvard Medical School in Boston, and Dr. Harald zur Hausen, of the German Cancer Research Center in Heidelberg.

“While good utilization of the [vaccine] program will reduce cervical cancer incidence in a couple of decades, this subgroup of the population at risk is too small to limit the spread of the virus,” the researchers wrote. “The only efficient way to stop the virus is to also vaccinate the other half of the sexually active population: boys and men.”

July, 2009|Oral Cancer News|

Researchers confirm link between HPV and head and neck cancer but survey shows public ignorance on role of oral sex

Source: Medicalnewstoday.com

Author: Olwen Glynn Owen

Human papillomavirus (HPV) is an important causative agent in squamous cell cancers of head and neck (HNSCC) a new meta-analysis presented at the American Society of Clinical Oncology (ASCO) confirms; but a separate European survey at the same meeting reveals the public is woefully ignorant about it and possible ways to avoid it. Lack of public awareness about the possible link between HPV-related head and neck cancer and oral sex with multiple partners presents a case for making vaccinations against HPV more widely available to boys as well as girls before they become sexually active, commented leading expert Professor Jean-Louis Lefebvre of Centre Oscar Lambret, Lille, France.

Researchers led by Farshid Dayyani at the MD Anderson Cancer Center, Houston, Texas, looked at a total of almost 7000 patients who developed head and neck cancer over the past 20 years to gauge the prevalence of HPV – a possible causative agent. They included studies which had tested for the virus in serum or in tumour tissue by PCR and found almost a quarter of patients (24.2%) had HPV positive tumours. Of these the vast majority (86.8%) were positive for HPV 16, the virus also associated with cervical cancer. Overall, the researchers concluded that being HPV positive increased the risk of developing head and neck cancer by 40 per cent. But being HPV16 positive increased the risk more than fourfold (4.47 times higher) compared to HPV16 negative patients.

However, people with HPV-associated head and neck cancer lived longer than people with other forms of the disease, the researchers point out. Their risk of dying was reduced by 60 per cent and by even more in HPV16-associated cancers of the mouth and pharynx compared to HPV negative HNSCC suggesting the virus produces a less aggressive type of cancer.

Other researchers at ASCO presented results of a pan-European survey of public awareness about head and neck cancers and their associated risk factors. Results showed only 15 per cent of people were aware of the risk of acquiring HPV-related oral cancer by oral sex with multiple partners. A finding described as “potentially worrying” by the survey authors. “Although the risk of HPV infection from oral sex is only an observational finding at this stage of our knowledge, people ought to be made aware of it,” said survey leader Professor Lefebvre.

The survey conducted among more than 7500 members of the public in seven European countries – France, Germany, Italy, Netherlands, Spain, Sweden and UK – revealed an alarming lack of awareness of head and neck cancers in general and how to recognise early symptoms, he said.

Only 23 per cent of survey participants were aware of the term “Head and Neck Cancer”, at all. Despite a link between those recognising the term and personally knowing someone affected, the extent of public awareness at a country by country level bore no relation to the incidence of disease nationally. Awareness was lowest in the UK (11 per cent) where almost 8000 cases are diagnosed per year and highest in Italy (39 per cent) where 12,400 cases were diagnosed. Incidence of head and neck cancer was highest in France (over 20,000 cases per year) where awareness was 20 per cent and in Germany (19,700 cases per year) where awareness was 22 per cent. The lowest incidence of disease was in The Netherlands, with just over 2300 cases per year where awareness was comparatively high at 30 per cent.

More than 60 per cent of participants underestimated the incidence of head and neck cancer by at least a factor of 10. Although the majority knew certain lifestyle factors could affect risk of developing head and neck cancer and correctly identified smoking as a risk factor, only 59 per cent knew alcohol played a major role and only 29 per cent acknowledged the part played by excessive sun exposure.

Commenting on the study Professor Lefebvre said the lack of awareness was worrying because it was likely to delay people affected coming forward for diagnosis and treatment at a stage when the disease was potentially curable. Greater efforts should be made to educate the public about avoiding harmful life-style behaviours that increase risk and about how to recognise symptoms requiring a specialist opinion. “Anyone with a sore throat persisting more than two weeks should see their GP and be referred to an ENT specialist for investigation” he advised. “Should more evidence emerge of the link between HPV infection and oral cancer there will be a case for wider vaccination against HPV with young males as well as females offered vaccination,” he added.

Omnibus Internet interviews for the About Face survey were conducted in September 2008 by TNS Healthcare in conjunction with the European Head and Neck Society.

Olwen Glynn Owen
olwen(at)macline.co.uk
Copyright: Medical News Today

June, 2009|Oral Cancer News|

New broad-spectrum vaccine to prevent cervical cancer induces strong responses in animals

Source: Journal of the National Cancer Institute
Author: Staff

Wednesday, May 27, 2009

 

Mice and rabbits immunized with a multimeric-L2 protein vaccine had robust antibody responses and were protected from infection when exposed to human papillomavirus (HPV) type 16 four months after vaccination, according to a new study published in the May 26 online issue of the Journal of the National Cancer Institute.

Current HPV L1-based vaccines are almost 100% protective against infection by the two HPV types that are responsible for 70% of all cervical cancer cases world wide. However, the existing vaccines provide limited protection against the other HPV types that cause cancer. With that limitation in mind, Richard Roden, Ph.D., of the Johns Hopkins University in Baltimore, and colleagues have been working on an alternate vaccine that is based on the HPV minor capsid protein L2, which is highly conserved between HPV types. Previous experiments showed that the L2 protein induced only a weak antibody response in animals.

In the current study, Roden and colleagues linked together a short segment of the L2 protein from several HPV types to generate a single multimeric L2 fusion protein. They tested the ability of this multimeric-L2 protein to induce antibody responses in animals and its ability to protect them from subsequent infection with HPV type 16.

Mice immunized with the multimeric L2 vaccine developed robust antibody responses against all of the HPV types tested, although the antibody titer was still lower than the type-restricted responses following vaccination with an existing HPV L1-based vaccine. When a multimeric L2 vaccine was delivered with a potent adjuvant to stimulate the immune response, such as alum, the vaccinated animals were able to resist infection by HPV16.

“Clinical studies are warranted to assess the safety and immunogenicity of multitype L2 vaccines in alum and other adjuvant formulations,” the authors write. “If an L2 vaccine were proven effective in people, its simpler manufacturing process could make the local production of such a vaccine highly feasible, which might achieve the goal of producing it at sustainable prices in emerging countries and lead to its widespread implementation in the developing world.”

In an accompanying editorial, F. Xavier Bosch, M.D., Ph.D., of the Catalan Institute of Oncology, in Barcelona, Spain, reviews the strengths of the current HPV vaccines but notes that they are too expensive to be used in much of the world and do not protect against enough HPV types. A broad-spectrum vaccine, such as the one being developed by Roden and colleagues, could solve those problems. The new data represent a meaningful step forward, Bosch says.

“The results open the door to a novel family of second generation HPV vaccines with significant potential value in the public health horizon,” the editorialist writes. “As soon as appropriate, Phase 1 trials in humans should be initiated.”

The clinical evaluation of new products, however, will likely take years. During this time, the currently available vaccines should be used as widely as possible, according to the editorialists.

June, 2009|Oral Cancer News|

What Farrah Fawcett can teach us about anal cancer

Source: health.usnews.com/blogs
Author: Deborah Kotz

As much as I think celebrities should be afforded their privacy—like the rest of us—when they’re battling life-threatening diseases, I sometimes blog about their conditions because I see them as teaching moments. Farrah Fawcett is in the news today with reports that she’s been hospitalized for complications of anal cancer. She was first diagnosed with anal cancer in 2006. Speculation was running wild that she was “close to dying,” but the latest reports say she’s suffering from a blood clot that resulted from an “alternative” cancer treatment she had in Germany to fight the cancer’s recurrence.

Anal cancer is one of those cancers no one likes to talk about because it’s, well, anal cancer. But we really should discuss it as much as, say, cervical cancer. Both are predominately caused by the sexually transmitted human papillomavirus. In fact, a 2004 study of 6,000 anal cancer patients (the majority of whom were women) found that 73 percent of the patients tested positive for the strain HPV-16, one of the strains that the Gardasil vaccine protects against.

What’s worrisome is that unlike cervical cancer, which has dropped dramatically since the advent of the Pap smear, anal cancer is on the rise. Incidence rates over the past 30 years have jumped by 78 percent in women and 160 percent in men, probably because more people now have more sexual partners and more people have anal sex (both among heterosexuals and gay men), says Lisa Johnson, a cancer epidemiologist at the Fred Hutchinson Cancer Research Center in Seattle who led the 2004 study.

Having unprotected sex, either anal or vaginally, raises your risk of becoming infected with HPV. Smoking is also associated with a higher risk of anal cancer, according to information I gleaned from the National Cancer Institute website, possibly because it inhibits immune function.

While anal cancer is far less common than breast cancer—1 in 640 women will be diagnosed during their lifetime, compared with 1 in 8 with breast cancer—only about half of anal cancers are detected in their earliest stage, when they’re most treatable. Partly for this reason, only about 67 percent of people diagnosed with anal cancer survive five or more years.

There are, though, several ways women can protect themselves, says Johnson. Younger women can get the Gardasil vaccine, which is approved for those up to age 27. By blocking the transmission of two common cancer-causing HPV strains, she says, the vaccine presumably protects against anal cancers, throat cancers, and oral cancers that are associated with HPV infections.

And don’t skip those yearly gynecologist visits. As tough as it may seem, be upfront with your doctor if you’ve ever had unprotected anal sex and find out if there’s any extra screening you should have. Anal Pap smears are available, and though they’re mostly used for gay men, women can have them too. Be sure you have an HPV test along with your regular Pap smear. If you test positive for a cancer-causing strain and have had anal sex, talk to your doctor about methods for detecting anal abnormalities before they turn cancerous.

I hope Farrah Fawcett will recover fully from this latest complication. I’m eager to see the documentary she’s working on about her treatment experience. The fact that she has documented and shared her fight with cancer suggests that she, too, recognizes the importance of the teaching moment.

April, 2009|Oral Cancer News|

A fighting partner

Source: RDH Magazine
Author: Donna Marie Grzegorek

Dentists and hygienists should be teaming up to be the first line of defense against oral cancer.

In the United States this year, more than 35,310 new cases of oral and pharyngeal cancer will be diagnosed, with an estimated 7,590 people who will die. Sadly, survival rates for oral cancer have not changed significantly in 40 years, and embarrassingly, dental professionals are alone among health professionals who screen for cancer with their hands and eyes. Under the watchful eye of the dental practitioner, 70% of the lesions found during visual and palpation exams are detected in Stage III and Stage IV, and one–half of those patients (58%) will survive less than five years. It gets worse … a survey conducted by the American Dental Association revealed that only 15% of patients reported having an oral cancer examination during a routine dental appointment. And noteworthy, failure to diagnose oral cancer is the number two cause of dental malpractice in the United States. Oral cancer claims constitute the most expensive malpractice suits and the most difficult to defend, with awards typically exceeding $1 million.

If these statistics are not compelling enough, take note that the face of oral cancer is changing. No longer should we look at the older male patient with a chronic history of tobacco and alcohol abuse as the only high–risk patient. Twenty–seven percent of all new oral cancers are occurring in young adults with no associated risk factors. So I ask you … isn’t it time to increase the “standard of care” and incorporate a comprehensive early oral cancer detection program into your office protocol?

Where to begin
I strongly feel that the dental hygienist should be the first line of defense against this insidious disease. The practice act in many states limits the hygienist’s ability to diagnose. Therefore, an early oral cancer detection protocol must involve a partnership between the dental hygienist and the dentist.

Several years ago, upon approaching my employer and stating my desire to increase the standard of care we provide to our patients regarding early oral cancer detection, we initiated our program. We discussed the benefits of incorporating an adjunctive blue spectrum light screening technology into our examination. Two weeks later, upon formulating an appropriate protocol, we launched our enhanced oral cancer screening program.

We began our new effort by educating our patient base. The preponderance of the hygiene appointment was dedicated to discussing the risks of oral cancer, reviewing statistics, and performing the visual, palpation, and blue light examination.

It is critical that the patient understand an adjunctive screening device is not a definitive diagnostic device, but rather a means of detecting disease early, in asymptomatic people.

Positive results are not diagnostic. They are a way to identify persons at increased risk for the presence of cancer, which warrants further evaluation. I review medical/dental and lifestyle risks that each patient possesses. This includes conversations regarding HPV and oral sex.

HPV and oral cancer
Human papillomavirus is now recognized to play a role in the pathogenesis of a subset of head and neck squamous cell carcinomas (HNSCCs), particularly those that arise from the lingual and palatine tonsils within the oropharynx. HPV cancers are the fastest growing segment of the oral cancer population. Although there are more than 100 different types of HPV identified, HPV 16, 18, 31, and 45 are sexually transmitted.

According to the U.S. Department of Health and Human Services, HPV is transmitted through skin to skin contact. HPV 16 and 18 are implicated in most cervical cancers and are also responsible for anal and penile cancers. It appears that HPV 16 is identified in the overwhelming majority of HPV positive oral tumors.

It is encouraging to note that HPV positive oral cancers have significantly better survival outcomes than the non–HPV–related tumors. It is believed that the HPV–related tumors are more susceptible and vulnerable to radiation treatments than their tobacco and alcohol counterparts. It has recently become understood that HPV affects the cell’s molecular machinery. It interferes with the function of a key gene that would normally cause cells with potentially cancerous mutations to self–destruct.
Given the decline of tobacco use over the past 10 years and the increasing rate of HPV–related oral cancer, much of the blame is cast toward HPV transmission through oral sex. I make it perfectly clear to my patients that “oral sex is not safe sex.”

Foundation takes strong position
The Oral Cancer Foundation has expressed very strongly its position about non–tobacco–related oral cancers. The foundation states: “We strongly believe that in a younger population of nonsmoking oral cancer patients, HPV is presenting itself as the dominant causative factor. Since the historic definition of those who need to be screened is now changed by this newly defined HPV etiology, it is not possible to definitively know who is at risk for development of the disease, and who is not. Today, anyone old enough to have engaged in sexual behaviors which are capable of transferring this very ubiquitous virus needs to be screened annually for oral cancer. For this reason, we are strong promoters of opportunistic annual screenings to catch this disease at its earliest possible stages, when it is most vulnerable to existing treatment modalities and the survival rates are the highest.”
Wow ? need I say more?

Every patient should be screened
As clinicians we must remember that patients don’t walk into the office carrying a sign that states they are at high risk for oral cancer. Oftentimes patients are not truthful with the information they provide on their medical/dental histories.

With hard statistics showing that 27% of all oral cancers occur in young adults ages 18 to 35 who don’t drink and don’t smoke, what parameters can we establish to safely screen our patients? The truth is that EVERY patient should be screened for oral cancer.

I perform a comprehensive oral cancer examination during the hygiene visit on each patient age 17 and older at every recare appointment. An identical examination is repeated by the dentist when he completes his portion of the patient examination.

We believe that having two sets of eyes looking for oral cancer is better than one. This protocol has been well received by our patients. It creates value for the procedure, but most importantly it sends a message of great significance to our patients. We encourage patients to return for a complimentary re-examination if they find any oral lesion that does not resolve in two weeks.
I dispense to each patient a “self examination” visual and palpation instruction sheet. I encourage self–examination of the head and neck on a monthly basis and compare the process to breast self–examination.

Up your game
I assert that any adjunctive screening device will enhance the office “standard of care,” and improve patient health outcomes. Complete your research and choose the methodology that provides the best fit for you, your patients, and your practice. I recommend not offering the oral cancer examination as if it were an option. Present a compelling argument through education and discussion so the patient thanks you for being one of the few offices that offer such a valuable service.

I believe dental hygienists must partner with their supervising dentists to create an effective early detection protocol. The dental professional is the first line of defense against this menacing disease. Together we can make a difference. In the past 29 years, I have observed the profession of dental hygiene mature from one of mechanical tooth debridement to one of veritable health–care provider. We have a unique opportunity and a critical responsibility to counsel our patients on the importance of living healthier lives through meticulous oral health care. It’s wonderful to save a tooth, but as dental health–care providers in 2009, we have many opportunities to save lives.

Genetic signatures of HPV-related and unrelated oropharyngeal carcinoma and their prognostic implications

Source: Clinical Cancer Research 15, 1779, March 1, 200
Author: Jens P. Klussmann et al.

Purpose:
Patients with human papillomavirus (HPV)-containing oropharyngeal squamous cell carcinomas (OSCC) have a better prognosis than patients with HPV-negative OSCC. This may be attributed to different genetic pathways promoting cancer.

Experimental Design:
We used comparative genomic hybridization to identify critical genetic changes in 60 selected OSCC, 28 of which were associated with HPV-16 as determined by HPV-specific PCR and fluorescence in situ hybridization analysis and positive p16INK4A immunostaining. The results were correlated with HPV status and clinical data from patients.

Results:
Two thirds of OSCC harbored gain at 3q26.3-qter irrespective of HPV status. In HPV-negative tumors this alteration was associated with advanced tumor stage (P = 0.013). In comparison with HPV-related OSCC, the HPV-negative tumors harbored: (a) a higher number of chromosomal alterations and amplifications (P = 0.03 and 0.039, respectively); (b) significantly more losses at 3p, 5q, 9p, 15q, and 18q, and gains/amplifications at 11q13 (P = 0.002, 0.03; <0.001, 0.02, 0.004, and 0.001, respectively); and (c) less often 16q losses and Xp gains (P = 0.02 and 0.03). Survival analysis revealed a significantly better disease-free survival for HPV-related OSCC (P = 0.02), whereas chromosome amplification was an unfavorable prognostic indicator for disease-free and overall survival (P = 0.01 and 0.05, respectively). Interestingly, 16q loss, predominantly identified in HPV-related OSCC, was a strong indicator of favorable outcome (overall survival, P = 0.008; disease-free survival, P = 0.01) and none of these patients had a tumor recurrence.

Conclusions:
Genetic signatures of HPV-related and HPV-unrelated OSCC are different and most likely underlie differences in tumor development and progression. In addition, distinct chromosomal alterations have prognostic significance.

Authors:
Jens P. Klussmann1, Jeroen J. Mooren5,6, Martin Lehnen1, Sandra M.H. Claessen5, Markus Stenner1, Christian U. Huebbers1,3, Soenke J. Weissenborn5, Inga Wedemeyer2, Simon F. Preuss1, Jos M.J.A.A. Straetmans6, Johannes J. Manni6, Anton H.N. Hopman5 and Ernst-Jan M. Speel5

Authors’ affiliations:
Departments of 1 Oto-Rhino-Laryngology, Head and Neck Surgery, and 2 Pathology, 3 Jean-Uhrmacher Institute, 4 Institute of Virology, University of Cologne, Cologne, Germany; and Departments of 5 Molecular Cell Biology and 6 Otorhinolaryngology, Head and Neck Surgery, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands

March, 2009|Oral Cancer News|

HPV-16 oncoprotein vaccine protects against head and neck cancer in mice

Source: www.medscape.com
Author: staff

Immunization with a vaccine that targets the E6 and E7 oncoproteins of human papillomavirus-16 (HPV-16) prevents mice with HPV-16-positive head and neck squamous cell cancers (HNSCCs) from expressing these two oncoproteins by mounting a potent immune response.

The vaccine may become part of a treatment regimen, along with surgery, chemotherapy or radiotherapy, in patients with HPV-16-positive HNSCCs, investigators report in the December issue of the Archives of Otolaryngology, Head and Neck Surgery.

Dr. John H. Lee and colleagues at the Veterans Administration Medical Center in Iowa City generated an adenoviral recombinant vaccine expressing HPV-16 E6/E7 oncoproteins (adenovirus 5 (Ad5) E6/E7). Mice inoculated with the vaccine “completely cleared E6/E7-expressing tumor cells implanted 2 weeks after immunization.” (Dr. Lee is now at the Sanford School of Medicine, University of South Dakota, Sioux Falls.)

“A time course of interferon-gamma response showed that E6/E7-specific interferon-gamma production is significantly increased in the first 2 weeks after administration of the vaccine and is substantially maintained for up to 70 days,” the investigators report.

“At all dosages of vaccine, mice inoculated with Ad5 E6/E7 completely cleared E6/E7-expressing tumor cells implanted 2 weeks after either intratracheal or submucosal inoculation, with significant E6/E7-specific interferon-gamma production,” the team reports. “Inoculated mice cleared E6/E7-expressing tumor 70 days after implantation.”

“In accord with this, our data show that immunization with HPV-16 E6/E7 is an effective method for protecting a host from E6/E7-expressing HNSCCs via generation of a potent immune response,” Dr. Lee and colleagues write.

“Therapeutic vaccines may also be a practical option for patients with HPV-associated cancers such as those of the head and neck,” they conclude. “Combining immunotherapy with traditional treatment such as surgery, chemotherapy, or radiotherapy may be another option for improving the prognosis and quality of life of individuals with HPV-16-associated HNSCCs.”

Source:
Arch Otolaryngol Head Neck Surg 2008;134:1316-1323.

January, 2009|Oral Cancer News|

Human Papillomavirus-16 modifies the association between fruit consumption and head and neck squamous cell carcinoma

Source: Cancer Epidemiology Biomarkers & Prevention 17, 3419-3426, December 1, 2008
Author: Mara S. Meyer et al.

Human papillomavirus-16 (HPV-16) is a risk factor for head and neck squamous cell carcinoma (HNSCC). HPV-positive cancers have distinct disease cofactors and improved survival following treatment.

There is conflicting evidence of a protective association of fruit consumption with HNSCC. As HPV-related disease is clinically distinct, we investigated whether the association between fruit consumption and HNSCC risk was modified by exposure to HPV-16. We studied 270 cases and 493 controls with fruit intake information and known HPV-16 antibody status. Cases were identified at nine Boston-area medical facilities between 1999 and 2003. Controls were randomly selected from the greater population and frequency matched to cases by age, gender, and town of residence.

Controlling for age, gender, race, smoking, alcohol, total energy intake, body mass index, and education, the seronegative individuals had a significantly lower risk of HNSCC with increasing total fruit consumption [odds ratio (OR)tertile 2, 0.60; 95% confidence interval (95% CI), 0.38-0.95; ORtertile 3, 0.57; 95% CI, 0.35-0.95] and specifically increasing citrus fruit consumption (ORtertile 2, 0.61; 95% CI, 0.39-0.97; ORtertile 3, 0.59; 95% CI, 0.37-0.96). However, among the seropositive, risk increased with greater fruit consumption (ORtertile 2, 2.27; 95% CI, 0.92-5.58; ORtertile 3, 1.40; 95% CI, 0.55-3.59) and citrus fruit consumption (ORtertile 2, 3.35; 95% CI, 1.36, 8.24; ORtertile 3, 3.15; 95% CI, 1.23-8.08). This interaction was statistically significant (P < 0.05), showing that fruit consumption was associated with a reduced HNSCC risk among HPV-16-seronegative individuals but an increased HNSCC risk among the HPV-16-seropositive individuals. These findings suggest that dietary factors dramatically alter the pattern of occurrence of HPV-associated HNSCC and show that viral-related disease is clinically and etiologically distinct. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3419–26) Auhors: Mara S. Meyer1, Katie M. Applebaum2,4, C. Sloane Furniss3, Edward S. Peters6, Brian G. Luckett6, Judith F. Smith7, Janine Bryan7, Michael D. McClean5, Carmen Marsit9 and Karl T. Kelsey8,9 Authors Affiliations: Departments of 1 Epidemiology, 2 Environmental Health, and 3 Genetics and Complex Diseases, Harvard School of Public Health; Departments of 4 Epidemiology and 5 Environmental Health, Boston University School of Public Health, Boston, Massachusetts; 6 Epidemiology Program, Louisiana State University Health Sciences School of Public Health, New Orleans, Louisiana; 7 Department of Vaccine Biologics Research, Merck and Co., Inc., West Point, Pennsylvania; and Departments of 8 Community Health and 9 Pathology and Laboratory Medicine, Center for Environmental Health and Technology, Brown University, Providence, Rhode Island

December, 2008|Oral Cancer News|

Does Pretreatment Seropositivity to Human Papillomavirus Have Prognostic Significance for Head and Neck Cancers?

Source: Cancer Epidemiology Biomarkers & Prevention 17, 2087-2096, August 1, 2008
Authors: Elaine M. Smith et al.

Background:
Human papillomavirus (HPV) is a risk factor for head and neck cancers (HNC), yet HPV-associated tumors have better prognosis than HPV-negative tumors.

Methods:
We evaluated whether pretreatment presence of antibodies to HPV capsids [virus-like particles (VLP)] or to HPV-16 oncoproteins E6 and E7 was a predictor of HPV-positive HNC and clinical outcomes. Sera from 156 HNC patients were tested for antibodies to HPV-16–derived antigens using ELISA. HPV-16 in tumors was evaluated by PCR and DNA sequencing.

Results:
HPV-16 antibodies were found in 33% with HPV-16 VLP, 21% with HPV-16 E6, and 21% with E7. HPV-16 was detected in 26% of tumors. There was a strong correlation between detection of HPV-16 tumor DNA and antibodies to HPV-16 E6 or E7 ( = 0.7) but not to HPV-16 VLP ( = 0.4). Multivariate analyses showed significantly better disease-specific survival in seropositive HPV-16 VLP [hazard ratio (HR), 0.4; 95% confidence interval (95% CI), 0.1-0.9], HPV-16 E6 (HR, 0.1; 95% CI, 0.02-0.5), and HPV-16 E7 (HR, 0.3; 95% CI, 0.1-0.9) cases. Less disease recurrence occurred among those with antibodies to both E6 and E7 compared with those negative to both (P = 0.003). There was better disease-specific survival in patients who were E6 positive at baseline and remained positive at follow-up compared with individuals who were E6 negative at both time points (P = 0.03; = 0.9).

Conclusions:
The presence of antibodies to HPV-16 E6 and E7 is associated with HPV in tumor cells and with better clinical outcomes. These findings suggest that the presence of E6/E7 antibodies before treatment is predictive of better clinical outcomes and that they may serve as biomarkers for selecting targeted therapeutic modalities developed for HPV-associated tumors. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2087–96)

Authors:
Elaine M. Smith1, Linda M. Rubenstein1, Justine M. Ritchie2, John H. Lee3, Thomas H. Haugen4,5, Eva Hamsikova6 and Lubomir P. Turek4,5

Authors’ affiliations:
Departments of 1 Epidemiology and 2 Biostatistics, College of Public Health, Departments of 3 Otolaryngology and 4 Pathology, College of Medicine, University of Iowa; 5 Veterans Affairs Medical Center, Iowa City, Iowa; and 6 Department of Experimental Virology, Institute of Hematology and Blood Transfusion, Prague, Czech Republic

August, 2008|Oral Cancer News|