Human papillomavirus in tonsillar cancer

Abstract

Human papillomviruses (HPVs) are known to be causative agents for the development of cervical carcinoma. To what extent HPV is associated with head and neck cancer remains to be clarified, but an association to tonsillar cancer has been proposed. Importantly, the oncogenes of HPV-16, namely E6 and E7, are generally expressed in tonsillar cancer. It has been suggested that HPV positive and negative tonsillar cancer differ with respect to histopathology, oncogene profile as well as patient group features.

The aim of this thesis was to examine for the presence of HPV in tonsillar cancer, to study the relation of HPV to p53 immunostaining and DNA aberration, and to study the influence of these markers on clinical outcome in tonsillar cancer.

It was shown that HPV, mainly HPV-16, was commonly found in tonsillar cancer (~ 45%), when assayed by PCR. Furthermore, HPV was found to be of significant prognostic value for patients with tonsillar cancer. HPV positive tonsillar cancer patients were to a higher degree tumor free three years after diagnosis and had a better cause-specific survival than the HPV negative group. We therefore investigated if the response to radiotherapy was influenced by HPV or p53 overexpression (determined by immunohistochemistry (IHC)). P53 overexpression by IHC was common in HPV positive as well as in negative cancer. A correlation between HPV and p53 status and response to radiotherapy was not observed in the initial study, including forty patients. When extending the study material, preliminary data showed that HPV positive tonsillar tumors responded better to radiotherapy, although the results were not statistically significant. Complete response (CR) after radiotherapy seemed to be more crucial for clinical outcome than HPV status. Nevertheless, among the group with a CR after radiotherapy, the HPV positive patients appeared to have the highest survival rate.

The physical state of HPV-16 in tonsillar cancer was analyzed by a method based on restriction enzyme cleavage, ligation and PCR. HPV-16 was found to be mainly episomal. When quantifying HPV-16 positive tonsillar cancers by realtime PCR, it was found that the viral load shows a wide range. Moreover, the clinical outcome appeared to be better when the HPV load was higher.

Using image cytometry, the degree of DNA aberration was investigated. Tonsillar cancer displayed a high degree of aneuploidy. HPV positive tumors had a lower degree of aneuploidy than HPV negative tumors. HPV status had a stronger prognostic value in tonsillar cancer than DNA ploidy.

In conclusion, HPV-16 is common in tonsillar cancer and has a prognostic impact. It could not be determined if the presence of HPV leads to an increased sensitivity to radiotherapy. Furthermore, p53 IHC and HPV varied independently. HPV-1 6 was mainly episomal and the data suggest that a high viral load may be of an advantage for clinical outcome in patients with HPV positive tonsillar tumors. Independently of HPV status, there was a high degree of aneuploidy in tonsillar cancer, although to a lower degree in HPV positive tumors. Future studies may reveal further clinically relevant differences in HPV positive and negative tonsillar cancer.