Studies on the influence of human papillomaviruses (HPV) and other biomarkers on the prevalence of oropharyngeal cancer and clinical outcome

Background. Oropharyngeal squamous cell carcinoma (OSCC), where tonsillar
(TSCC) and base of tongue squamous cell carcinoma (BOTSCC) dominate, is
increasing and is now the most common head and neck squamous cell carcinoma
(HNSCC) in Sweden. Smoking and alcohol are risk factors for HNSCC, but in 2007,
human papillomavirus (HPV) infection was also recognized as a risk factor for OSCC.
Notably, HPV positive OSCC has a much better clinical outcome than and HPV
negative OSCC. The last decade treatment of HNSCC, including OSCC, has been
intensified with chemoradiotherapy, due to the generally poor prognosis of HNSCC.
Such treatment, with more side effects, is likely needless for most HPV positive OSCC,
but since around 20% of the patients do not do well, additional markers are needed to
single out patients with an expected favourable outcome before possible de-escalation
of treatment.



Aims. To follow incidence and HPV prevalence in OSCC over time in order to
understand why OSCC has increased. To search for additional predictive biomarkers in
HPV positive OSCC, to more safely de-escalate treatment.



Results: In papers I-II we showed that the prevalence of HPV in TSCC had increased
significantly in Stockholm from 23% (1970-1979); to 28% 1980-1989; to 57% 1990-
1999; to 79% 2000-2007. Notably, also during the 2000s there was a significant
increase in HPV prevalence, from 68% 2000-2002; to 77% 2003-2005; up to 93%
2006-2007. Likewise, HPV prevalence also increased in BOTSCC, from 58% 1998-
2001 to 84% 2006-2007. The increase in HPV prevalence was paralleled by an increase
in incidence of TSCC and BOTSCC, and when estimating the HPV incidence in TSCC,
the incidence had increased 7-fold from 1970 to 2006. In paper III we found that HPV
positive TSCC had significantly more CD8+ and Foxp3+ tumour infiltrating
lymphocytes (TILs), and that a high CD8+TIL count was correlated with a favourable
clinical outcome in both HPV positive and negative TSCC. In addition, a high CD8+
count and a high CD8+/Foxp3+ ratio were significantly correlated with a favourable 3-
year disease-free survival in HPV positive and negative TSCC respectively. In papers
IV-V, we show that absence of “classical” HLA class I intensity staining was correlated
with a favourable disease-free survival, disease-specific survival, overall survival and
progression-free survival in patients with HPV positive OSCC, and to a worse clinical
outcome in patients with HPV negative OSCC. Moreover in paper V, patients with
HPV positive OSCC with absence of /or weak “classical” HLA class I intensity
staining presented a very high survival that was independent of treatment regime. HLAE,
-G was also analysed in TSCC, but without any outcome correlation. In addition,
HLA class II expression was analysed and found to be more common in HPV positive
than HPV negative OSCC, but correlated to better clinical outcome only in the latter
group.



Conclusion: A parallel increase in incidence as well as HPV prevalence in TSCC and
BOTSCC was demonstrated suggesting HPV infection being responsible for the
epidemic increase in OSCC. Finally, HPV positive TSCC or OSCC with high CD8+
TIL counts or with absent/weak HLA class I intensity staining presented a very good
clinical outcome, suggesting that these markers could potentially be used to select
patients for prospective randomised trials de-escalating oncological treatment