Oropharyngeal Cancer

See ((oral cancer)).

Composed of the tonsils, base of tongue, soft palate, and oropharyngeal wall.

Located between oral cavity and larynx.

Tumors in this location are squamous cell carcinomas in over 90% of cases.

In 2008 estimated 35,000 new cases of oral cavity/oral pharyngeal cancer.

HPV-attributable oropharyngeal cancer has surpassed cervical cancer as the most prevalent type of HPV-related cancer in the US.

Annual incidence of base of tongue and tonsil cancers increased by 2.1 and 3.9%, respectively from 1972 to 2001 among white men and women ages 20-44, while the incidence of other sites have declined (Shiboski).

Oropharyngeal cancers in men involving tonsils, base of tongue now outnumber that of cervical cancer in women, and among white men is rising 10% each year.

Incidence of tonsil cancer among African-Americans and white men younger than 60 years has increased 2-3% per year through 1998.

Almost always detected at advanced stage.

The overall incidence of HPV positive oropharynx cancer is increasing whereas the incidence of HPV negative – primarily tobacco and alcohol related cancer,  is decreasing.

HPV 16 infection increases the risk of oropharynx cancer and accounts for approximately 90% of cases, and HPV 18, 33, and 35 are responsible for the vast majority of the remaining fraction.

The prevalence of HPV 16 is higher in oropharyngeal cancer than in cervical cancer where it is about 50%.

Expression of the HPVE6 and E7 oncogenes inactivate the tumor suppressor proteins p53 and pRb, respectively, which are frequently mutated in tobacco related mucosal squamous cell carcinomas.

Inactivation of p53 and pRb promotes genomic instability in the development of cancer and is responsible for the upregulation of p16 protein expression, a reliable surrogate marker of the presence of HPV DNA in these tumors.

Metanalysis show the patients who’s tumors are both HPV positive and P 16 positive have a better five-year overall survival and five year disease free survival than patients with tumors that were HPV negative/P 16 negative.

Smoking is associated with decreased overall in progressive free survival regardless of the P 16 status.

Never smokers have a 51% reduction in risk of cancer progression compared with former and current smokers with HP positive squamous cell cancer of the head and neck.

Staging requires an assessment of HPV status, which involves insitu hybridization or polymerase chain reaction techniques for determining  HPV DNA or the viral load, or immunohistochemical testing to detect P16 expression, which is a surrogate marker for HPV positivity.
Patients with HPV-P16-positive, oral pharyngeal cancers are younger, more likely to be white, have fewer smoking pack year history, small primary tumors, and significantly better outcomes than in patients with HPV negative disease, as well as a higher eight year overall survival rate.
HPV vaccination is associated with the reduced vaccine type oral HPV infections.
Interferon gamma has a role in HPV positive head and neck cancer pathogenesis as a deficiency of interferon-gamma allows escape from detection of cancer cells by cytotoxic T cells.

Advanced oropharyngeal cancer has locoregional failure rates of 30-70% and progression free survival rates of 30-50% with either combined surgery and radiotherapy or radiotherapy alone.

Strongly associated with HPV infection with or without risk factors of tobacco and alcohol use.

HPV positive tumors have an increased expression of PD-L1.

Incidence of HPV negative oropharyngeal cancer has declined in the US from 1988-2004 from 2 cases per hundred thousand population to 1 per hundred thousand, while the incidence of HPV positive oropharyngeal cancer has increased by 225% from 0.8 per 100,000 to 2.6 per 100,000 population, predominantly among young individuals, man, and white persons.

In a study of 5579 participants age 14- 69 years who provided a 30 second oral rinse for HPV DNA polymerase chain reaction and type specific hybridization: overall prevalence of oral HPV infection of 6.9% (Gillison ML et al).

In the above study prevalence of HPV oral infection keep for ages 30-34 years and 60-64 years in men, and men have a higher overall prevalence of HPV 10.1% versus 3.6%.

In the above study and overall HPV-16 oral prevalence of 1%.

85% of HPV related oral pharyngeal cancers are positive for HPV-16.

Patients with HPV16 positive oropharyngeal cancer have markedly improved survival.

HPV positive oropharyngeal tumors are increasing in incidence and exceed such lesions caused by the more traditional risk factors of tobacco and alcohol.

The increased incidence among young is consistent with sexual behavioral changes, But the reasons for increases among men is unclear.

Oral HPV infection is a cause of a subset of oropharyngeal squamous cell carcinoma and is associated sexual behavior in contrast to HPV negative oro- pharyngeal squamous cell cancer which is associated with chronic tobacco and alcohol use.

At least 90% of HP positive oral pharyngeal squamous cell carcinoma is are associated with HPV types 16 and oral infection confers an approximate 50 fold increase in the risk of HPV positive moral pharyngeal squamous cell carcinoma (Gillison ML et al).

Associated with lifetime number of vaginal sex partners.

Type 16 HPV involved in such lesions.

90-95% of oral oropharyngeal tumors associated with HPV or type 16.

Type 16 HPV integrates into oropharyngeal tumor cell nuclei.

Most oropharyngeal squamous cell cancers produce specific HPV proteins.

Nonsmokers disproportionately infected with HPV.

HPV positive oral frontal tumors account for 20-75% of all oropharyngeal tumors(Fakhry C).

HPV positive head and neck tumors have a risk of death half of HPV negative tumors.

More than 86% of HPV-positive tumors over express p16, a cyclin dependent kinase inhibitor, and only 3% of HPV-negative tumors over express p16 (Reimers N).

The p16 tumor suppressor protein is associated with better outcomes.

Patients with HPV positivity and squamous cell cancer of the oropharynx have multiple sex partners and frequently engage in oral-genital relations.

The percentage of HPV-associated oropharyngeal cancers have steadily increased, and in many countrie this type of disease represents the majority of new cases.

HPV associated oropharyngeal cancer is associated with wild type P 53, down regulation of cyclin D and the retinoblastoma protein pRb.

The E7 viral oncoprotein of HPV inactivates pRb leading to upregulation of CDKN2A and increased expression of p16.

p16 over expression correlates with HPV expression.

Patients with HPV associated oropharyngeal cancer frequently present with a small T1-T-2 lesions and advanced nodal stage (Kies M).

HPV associated oropharyngeal cancer patients have a superior survival after chemo-radiation, compared with those patients who are HPV negative.

HPV associated oropharyngeal cancer pattern of failure indicates a lower rate of local regional relapse, second malignancies and death from other causes.

Patients with HPV positive oral pharyngeal cancer have a significantly better three-year survival of 82.4% vs. 57.1% for those with HPV negative tumors (Ang KK).

Docetaxel, cisplatin and 5FU improves overall survival compared with Cisplatinum and fluorouracil was followed by radiation alone, or radiation and weekly low-dose carboplatin(Posner MR, Vermorken JB).

A clinical trial of patients with human papillomavirus (HPV)-positive oropharyngeal cancer demonstrated worse overall survival with cetuximab plus radiation therapy than with cisplatin plus radiation, the current standard treatment (NCI).

Induction chemotherapy with oropharyngeal cancer decreases distant metastases(Pignon JP).

Reducing radiation doses by 15-20% is associated with high progression free survival and improved toxicity profile compared with standard doses (ChenA).

The addition of concurrent chemoradiotherapy has a treated related mortality risk of up to 3%.

Trans oral laser micro surgery and trans oral robotic surgery have been increasingly used for early oral pharyngeal squamous cell carcinoma, suggesting faster recovery, lower incidence of late morbidity such as swallowing dysfunction and xerostomia and better quality of life in comparison with intensity modulated radiation therapy.

In a randomized controlled trial comparing functional outcome of radio therapy with her without chemotherapy, versus trans oral robotic surgery and neck dissection for the treatment of T1 or T2, N0-2 oral pharyngeal squamous cell carcinoma concluded radiotherapy resulted in less dysphagia with similar overall survival and progression free survival (Nichols).

Neoadjuvant neither nivolumab with and without ipilimubab have significant pathological response and in patients with oral pharyngeal cancer: response rate greater than 90%.
Pembrolizumib approved for refractory with metastatic head neck squamous cell carcinoma (16% response rate  in refractory disease).
Nivolumab as a single agent compared with standard treatment resulted in an overall survival of 7.5 months compared with 5.1 months.

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