Human papillomavirus in recurrent respiratory papillomatosis, tonsillar cancer and mobile tongue cancer

Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.

Dissertation date: 21-10-2016 (English).

Doctoral thesis.

Main supervisor: Dr. Katarina Olofsson

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Abstract [en]

This thesis focuses on the effects of the human

papillomavirus (HPV) in tonsillar cancer, mobile

tongue cancer, and recurrent respiratory

papillomatosis (RRP). The purpose was to

characterize patients with RRP in northern Sweden

in order to identify more care-intensive RRP

patients and to describe the voice and quality of

life aspects that follow RRP. Further aims were to

confirm the expected increase of HPV-positive

tonsillar cancer cases in northern Sweden, and

to study the correlation between HPV, its surrogate

marker p16 and HPV receptor syndecan-1 in both

tonsillar cancer and mobile tongue cancer.

A total of 27 consecutive patients with RRP were

evaluated at 3 months postoperatively using the

voice handicap index (VHI) and SF-36 questionnaires

to assess the impact on life and voice in a RRP

population. The values were compared to

normative data. This report was further extended by

examining consecutive data from 21 new patients in

order to characterize RRP patients in northern

Sweden. In order to study HPV DNA in tonsillar

(n= 65) and mobile tongue cancer (n=109), HPV DNA

was extracted from paraffin-embedded biopsies and detected by polymerase chain reaction using general primers Gp5+/6+ and CpI/IIG. Expression of HPV surrogate marker p16 and the HPV receptor syndecan-1 was analysed by immunohistochemistry.

Patients that underwent more than one RRP surgery per year were younger than those treated less frequently and they had significantly impaired voice quality as compared to normal subjects. Females, patients with frequent surgical treatment sessions, and patients with the high-risk HPV subtypes scored significantly lower in several domains of the quality of life assessment as compared with normal subjects. Forty-eight RRP patients had a median age of 44.5 years; 71% were men and 29% females, preferentially infected with HPV6. Patients with high surgical treatment frequency/year showed more widespread RRP in the larynx compared to the patients treated less frequently.

A total of 214 tonsillar cancer cases were identified. The vast majority were men. They had a median age of 58 years at diagnosis and expressed HPV as well as p16. The incidence of tonsillar cancer revealed a 2,7-fold increase in men between the years 1990 and 2013. The study demonstrates a strong association between p16 and HPV infection in tonsillar malignancies. These findings are in contrast to the mobile tongue cancer cases, where no evidence of HPV DNA could be detected although one-third showed p16 staining. This demonstrated a poor correlation between HPV and p16 in mobile tongue cancer. There was no difference in the expression of the primary HPV receptor, syndecan-1, between tonsillar and mobile tongue cancer.

In conclusion, the frequency of RRP operations, age at onset, gender and subtype of the HPV may be used as factors to predict voice disability. RRP patients with high surgical treatment frequency were significantly younger and had a more widespread laryngeal disease compared to the low-frequency treated group. This study confirms the existence of a clinical RRP group, not primarily related to HPV subtype, but to a more care-intensive RRP population. Our findings identify a 2,7-fold increase in the incidence of tonsillar cancer, HPV and p16 in men between 1990-2013. We can use p16 to detect HPV in tonsillar cancer but not in tongue cancer.

The introduction of vaccination against HPV may have a role in the prevention of specific HPV-subtype positive head and neck malignancies and recurrent respiratory papillomatosis since the current vaccine protects against HPV6, 11, 16, 18, 31, 33, 45, 52 and 58. Males will definitely benefit indirectly from vaccination of females, though males will still remain at risk of cancers associated with HPV. This highlights the need for sex-neutral vaccination strategy. Our intention is that this thesis will provide scientific data to support a gender-neutral vaccination and to develop simple tools to detect HPV in tonsillar cancer.

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