Oropharyngeal cancer related to HPV
Human papillomavirus (HPV)-positive oropharyngeal cancer (OPC) also known as HPV16+oropharyngeal cancer or HPV+ OPC is a recognized subtype of Oropharyngeal squamous cell carcinomas (OSCC), associated with the HPV type 16 virus.
Causes
HPV oral infection precedes the development of HPV+ OPC. Slight injuries in the mucous membrane serve as an entry gate for HPV, which thus works into the basal layer of the epithelium. People testing positive for HPV16 oral infection have a 14 times increased risk of developing HPV+ OPC.
Immunosuppression seems to be an increased risk factor for HPV+ OPC. Individuals with TGF-β1 genetic variations, specially T869C, are more likely to have HPV16+ OPC. TGF-β1 plays an important role in controlling the immune system.
A 1999 study has found that patients with human papillomavirus (HPV)-associated anogenital cancers had a 4.3-fold increased risk of tonsillar squamous-cell carcinoma.
Although evidence suggests that HPV16 is the main cause of OPC between non-smokers and not-drinkers, the degree to which tobacco and/or alcohol use may contribute to increase the risk of HPV+ OPC is unclear.
Concomitant human herpesvirus-8 infection can potentiate the effects of HPV-16.
Mechanism
A prospective study has found that increased HPV+ OPC risk was observed more than 15 years after HPV exposure, pointing to a slow development of the disease, like in cervical cancer.
HPV associated cancers are caused by the expression of HPV's E6 and E7 proteins that bind to and inactivate tumor suppressor proteins p53 and retinoblastoma protein (pRB), respectively, leading to malignant transformation of HPV infected cells.
The biology of HPV+ OPC is distinct of HPV- OPC with P53 degradation (inactivated by E6 instead of by genetic mutation), pRB pathway inactivation (by E7 instead of Cyclin D1 amplification), and P16 upregulation (over-expression instead of inactivation).
The tonsils epithelia (palatine and lingual) share similar nonkeratinization characteristic with the cervix, where HPV infection play the major role in cases of cervical cancer.
Diagnosis
HPV+ OPC is usually diagnosed at a more advanced stage than HPV- OPC.
Genetic signatures of HPV+ and HPV- OPC are different.
HPV OPC is associated with expression level of the E6/E7 mRNAs and of p16. Nonkeratinizing squamous cell carcinoma strongly predicts HPV-association.
HPV OPC is not merely characterized by the presence of HPV-16. Only the expression of viral oncogenes within the tumor cells plus the serum presence of E6 or E7 antibodies is unambiguously conclusive.
There's not a standard HPV testing method in head and neck cancers, both in situ hybridization and PCR are commonly used. A 2010 study has concluded that both have comparable performance for HPV detection, however it's important to use appropriate sensitivity controls.
Prevention
Risk factors are high number of sexual parteners,(25% increase >= 6 partners) history of oral-genital sex, (125% >= 4 partners) history of anal–oral sex, female partner had a history of either an abnormal Pap smear or a cervical dysplasia, frequent marijuana use, chronic periodontitis, and, among men, decreasing age at first intercourse and history of genital warts.
A 2010 study concluded that current tobacco users with advanced HPV+ OSCC are at higher risk of disease recurrence compared with never-tobacco users.
HPV vaccines have a theoretical potential to prevent oral HPV infection.
A 2010 review study has found that HPV16 oral infection was rare (1.3%) among the 3,977 healthy subjects analyzed.
Treatment
Currently HPV+ OPC are treated similarly to stage-matched and site-matched unrelated OPC. However less intensive use of radiotherapy or chemotherapy, as well as specific therapy, is under research.
It's hypothesized that HPV+ OPC patients benefit better from radiotherapy and concurrent cetuximab treatment than HPV- OPC patients receiving the same treatment.
Prognosis
Tumor HPV status is strongly associated with positive therapeutic response and survival compared with HPV-negative OPC. A possible explanation is “the lower probability of occurrence of 11q13 gene amplification, which is considered to be a factor underlying faster and more frequent recurrence of the disease”. Presence of TP53 mutations, a marker for HPV- OPC, is associated with worse prognosis.
High grade of p16 staining is thought to be better than HPV PCR analysis in predicting radiotherapy response.
Epidemiology
HPV+ OPC patients tend to be younger than HPV- patients. Currently in the US there is a growing incidence of HPV associated oropharyngeal cancers, perhaps as a result of changing sexual behaviors. Tonsil and oropharyngeal cancers increased in male predominance between 1975 and 2004, despite reductions in smoking. Recently, in the US, HPV associated OPC represent about 60% of OPC cases compared with 40% in the previous decade. By 2007, in the US, incidence of general OPC, including non-HPV associated, is 3.2 cases per 100,000 males/year and 1.9 per 100,000 all-sexes/year.
The higher increase incidence of HPV associated OPC is also seen in other countries, like Sweden, with a 2007 incidence of over 80% for cancer in the tonsils, Finland and Czech Republic.
In Australia incidence of HPV associated OPC is 1.56 cases per 100,000 males/year.
History
In 1983, it was first suggested that HPV might be the agent involved in the development of at least certain special types of oral cancers. In 2007 the World Health Organization stated HPV was a cause for oral cancers.
Discussion and Future Directions
Recent studies have clearly established HPV as a definitive risk for oropharyngeal cancer, and HPV-related oropharyngeal cancer is now a well-defined entity with well-known characteristics that include young age, good performance status, male gender, nonsmoking and nondrinking status, basaloid tumor histology, and high-risk sexual behavior. The prognosis for these patients is believed to be better than that for patients who have the "traditional" type of oropharyngeal cancer.
There have been scattered reports over the years suggesting that HPV infection affects prognosis, but the Fakhrypresentation represented the first prospective look at prognosis for these patients as part of an intergroup study. The results reported are quite significant and the implications are important: HPV-related oropharyngeal cancer behaved in a different fashion, had a different response to therapy, was more sensitive to radiation-based therapies, and thus may require a different therapeutic approach compared with HPV-unrelated oropharyngeal cancer. Future studies will be needed to extend and validate these results, and it will be of paramount importance to start using HPV infection as a measure of stratification in head and neck cancer clinical trials.
Another important aspect of these findings is the potential role of HPV vaccination in the prevention of these cancers going forward.
Oropharyngeal cancer can now be placed in the category of "virally mediated cancers," along with the HPV-related cervical, anal, vulvar, and penile cancers and the Epstein Barr virus-associated nasopharyngeal cancer and lymphomas. As such, the issue of HPV vaccination will need to be revisited, and future studies will have to take into account all of the HPV-related cancers, not only cervical cancer. Men will potentially need to be vaccinated as well. Indeed, the implications are quite significant from the public health perspective.
This year's ASCO (American Society of Clinical Oncology) presentations by Chaturvedi and Saraiya provided more evidence to support our growing sense that the incidence of tonsillar cancer is rising. A rise in incidence is worrisome, and tonsillar cancer is one tumor on a very small list of cancers with such an increase. It is suspected that high-risk sexual behavior may account for the increase in HPV infection and, ultimately, tonsillar cancer. Since the onset of the HIV epidemic, we have seen an increase in oral sex among teenagers and
young adults, probably because this is thought to represent a form of "safe sex" and a worry-free behavior. We now know that this is not the case.
Oral sex is not risk free and can result in HPV-related cancer. Public education is of paramount importance. There is a need to disseminate these findings, placing them in context.
In terms of HPV therapeutics, a major focus of the research community has been E6 and E7 targeting. Indeed, an agent that could target these 2 oncogenes would be ideal. Conceptually, this approach is similar to targeted therapies recently developed for chronic myeloid leukemias (bcr-abl targeting) and lung cancer (epidermal growth factor receptor mutations). Research in this area is still preliminary, and previous experience has proven this field to be quite challenging. Nevertheless, newer technologies might make this possible, and the approach described by Rampias and colleagues is promising. If targeting proves feasible, these findings will have represented a major breakthrough. The ability to
treat these cancers without chemotherapy and radiation, but instead with gene therapy and antiviral therapy, is certainly appealing, but we expect that it will be a long time before we see this work come to fruition. In the meantime, our focus should be on fuller utilization of the HPV vaccine and public education measures.
Conclusion
HPV-related head and neck cancer represents a new entity that is now well defined. The practicing oncologist needs to be aware of these new findings, and HPV testing, with PCR or FISH (Fluorescence In Situ Hybridation), should now be performed routinely. For now, results will have significant prognostic though not therapeutic implications. Still, changes come rapidly in this field, and we expect that different treatments will be available to these patients in the near future.
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