Clinical implications of HPV in oropharyngeal cancer

Tonsillar cancer incidence has been increasing in Sweden and many other western countries in the last decades despite that other head and neck cancers are decreasing. It is now established that Human Papillomavirus (HPV) can be accredited part of that increase. The aims of this thesis were to investigate any change in incidence of base of tongue cancer, any further increase of tonsillar cancer incidence, what role HPV may have, the prognostic value of HPV as well as the outcome of different treatment regimes on tonsillar cancer. Using the Swedish Cancer Registry, we found that the incidence for both tonsillar and base of tongue cancer has increased from 1970 to 2006-2007, for tonsillar cancer from 0.74/100000 person-years 1970-1979 to 1.65/100000 person-years 2000-2006 in Stockholm County and for base of tongue cancer from 0.15/100000 person-years 1970- 1974 to 0.47/100000 person-years 2005-2007 in Sweden. We analyzed pre-treatment, paraffin-embedded diagnostic tumor biopsies for HPV using PCR technique and found that the proportion of HPV in both tonsillar and base of tongue cancer has increased during the last decade, reaching 93% positivity in tonsillar cancer and 83% positivity in base of tongue cancer in 2006-2007. To evaluate if HPV was transcriptionally active in these biopsies, we also tested for HPV E6 and E7 mRNA, which was positive in the vast majority of cases. For base of tongue cancer, HPV was found to be a significant prognostic factor, with improved overall as well as disease free survival compared to patients with HPV-negative tumors, irrespective of patient age, sex and tumor stage. It has been suggested that patients with HPV positive tumors possibly could be cured by less intense treatment and thus reducing side effects. When analyzing all HPV positive tonsillar cancer patients in Stockholm County, Sweden between 2000 and 2007, we compared survival and development of distant metastasis between groups that had received three different treatment regimes. No significant difference in overall or disease free survival was found between the treatment groups, but a trend of improved survival for intensified treatment was seen that needs to be studied further. The vast majority of HPV positive tonsillar- and base of tongue cancers are HPV16, which means that the commercially available vaccines would protect against it. This highlights the discussion if boys/men should be included in the HPV vaccination program

HLA class I and II expression in oropharyngeal squamous cell carcinoma in relation to tumor HPV status and clinical outcome.

HPV-DNA positive (HPVDNA+) oropharyngeal squamous cell carcinoma (OSCC) has better clinical outcome than HPV-DNA negative (HPVDNA-) OSCC. Current treatment may be unnecessarily extensive for most HPV+ OSCC, but before de-escalation, additional markers are needed together with HPV status to better predict treatment response. Here the influence of HLA class I/HLA class II expression was explored. Pre-treatment biopsies, from 439/484 OSCC patients diagnosed 2000-2009 and treated curatively, were analyzed for HLA I and II expression, p16(INK4a) and HPV DNA. Absent/weak as compared to high HLA class I intensity correlated to a very favorable disease-free survival (DFS), disease-specific survival (DSS) and overall survival (OS) in HPVDNA+ OSCC, both in univariate and multivariate analysis, while HLA class II had no impact. Notably, HPVDNA+ OSCC with absent/weak HLA class I responded equally well when treated with induction-chemo-radiotherapy (CRT) or radiotherapy (RT) alone. In patients with HPVDNA- OSCC, high HLA class I/class II expression correlated in general to a better clinical outcome. p16(INK4a) overexpression correlated to a better clinical outcome in HPVDNA+ OSCC. Absence of HLA class I intensity in HPVDNA+ OSCC suggests a very high survival independent of treatment and could possibly be used clinically to select patients for randomized trials de-escalating therapy

Outcome after different treatments for patients with HPV+ tonsillar cancer.

e16048 Background: In the last few years, oncological treatment for tonsillar cancer has intensified with accelerated radiotherapy and chemotherapy, which has resulted in more side effects. Patients with HPV-positive tonsillar cancer have better prognosis than those with HPV-negative tumors, and it is possible that patients with HPV-positive tonsillar cancer may benefit from a reduced, less-toxic treatment without compromising survival. Methods: To evaluate the possible difference in survival after different oncological treatments of patients with HPV-positive tonsillar cancer, we evaluated all 211 patients diagnosed with tonsillar cancer between 2000-2007, in Stockholm, Sweden. Included patients were those with available pretreatment biopsies, and treated with intent to cure. A total of 172 patients had HPV-positive tumors and of those, 98 were treated with conventional radiotherapy, 44 were treated with accelerated radiotherapy and 30 were treated with chemoradiotherapy. Results: No significant differences in overall and disease-free survival were seen between the three treatment groups, but there was a trend, where chemoradiotherapy was better than radiotherapy; and accelerated radiotherapy was better than conventional radiotherapy. This trend needs to be followed further. Conclusions: In this study, patients with HPV-positive tonsillar cancer treated with conventional radiotherapy, accelerated radiotherapy or chemoradiotherapy had similar survival rates. However, there is a trend for better survival and less metastasis after intensified treatment underlining the need for prospective studies, where less intense treatment is compared to more intense treatment. </jats:p

HPV prevalence in the different subsites of the oropharynx.

6037 Background: Oropharyngeal cancer patients are often reported as one group in articles and studies regardless that within the subsites of the oropharynx, there are differences regarding clinical features, treatment and HPV prevalence. To investigate these differences, we wanted to further analyze HPV prevalence in the different subsites of the oropharynx. Methods: We identified all patients diagnosed with oropharyngeal cancer in Stockholm County, Sweden, between 2000 and 2007, using the Swedish Cancer Registry, a registry unique in its reliability. Using the ICD 10 codes C01.9 (base of tongue cancer), C09.0-C09.9 (tonsillar cancer) and C10.0-C10.9 (oropharyngeal cancer) and C50.1-C50.8 (cancer of the soft palate). The two last subsites were grouped together into the group Other Oropharyngeal Cancer (OOC). We retrieved pre-treatment biopsies and tested for HPV-DNA using PCR, both with general primers and HPV16 specific primers. Results: We identified 474 patients diagnosed with oropharyngeal cancer in Stockholm County, Sweden between 2000 and 2007; 290 diagnosed with tonsillar cancer, 109 diagnosed with base of tongue cancer and 75 diagnosed with other oropharyngeal cancer. Of these 474 patients, pre-treatment biopsies for HPV-testing were available for 400 patients (236, 95 and 69, respectively). In the tonsillar cancer group, 185 biopsies were HPV-DNA-positive (79%), in the base of tongue cancer group 71 (75%) and in the other oropharyngeal cancer group 17 were positive (25%) Conclusions: Tonsillar and base of tongue cancer share some similarities and HPV prevalence is similarly high in both groups. Other oropharyngeal cancer (OOC) does not share the high HPV-prevalence and it would then be preferred that the sub-sites of the oropharynx are reported separately. </jats:p

A 4-Year Consecutive Study of Post-Tonsillectomy Haemorrhage

&lt;i&gt;Objective:&lt;/i&gt; To analyse consecutive material over a period of 4 years concerning the incidence and consequences of post-tonsillectomy haemorrhages (PTH). &lt;i&gt;Design:&lt;/i&gt; Prospective study. &lt;i&gt;Setting:&lt;/i&gt; University hospital. &lt;i&gt;Participants:&lt;/i&gt; All non-oncological cases of tonsillectomy (TE) and adenotonsillectomy (TA) performed at the ENT department at the Karolinska University Hospital between March 2000 and April 2004. &lt;i&gt;Main Outcome Measures:&lt;/i&gt; Rate, timing and classification of PTH. &lt;i&gt;Results:&lt;/i&gt; During the study period, 2,813 cases (mean age 13 ± 12.8 years; SD) of TE and TA were included. The majority (62%) were children aged below 12 years, and 69% were performed as day surgery. In total, 212 (7.5%) patients were readmitted due to PTH, of which 98 (3.4%) presented with ongoing haemorrhage. The rates of primary and secondary bleeding were 1.9 and 5.5%, respectively. The PTH occurred in 0–19 days post-operatively, in a typical twin peak mode around the day of surgery and then days 4–7. No case of serious PTH was noted. Multiple bleedings (2–3 times) occurred in 19 patients. Only a minority (31%) of the single PTH patients required active treatment, surgery in the theatre (35 patients) or diathermy under local anaesthesia in the emergency room (24 patients). However, almost all received systemic haemostatic treatment. Three patients required blood transfusion due to repeated PTH. Of the 114 patients that did not present with an active PTH, only 1 returned to the operating theatre due to later bleeding. Almost half (43%) of the patients with multiple episodes of PTH had also experienced primary bleedings. &lt;i&gt;Conclusions:&lt;/i&gt; A primary PTH seems to indicate a risk of further episodes of bleedings, and should necessitate extra post-operative observation. Patients with a history of a single self-limiting PTH showed low risk of developing a haemorrhage requiring return to the theatre.</jats:p

HLA class I and II expression in oropharyngeal squamous cell carcinoma in relation to tumor HPV status and clinical outcome.

HPV-DNA positive (HPVDNA+) oropharyngeal squamous cell carcinoma (OSCC) has better clinical outcome than HPV-DNA negative (HPVDNA-) OSCC. Current treatment may be unnecessarily extensive for most HPV+ OSCC, but before de-escalation, additional markers are needed together with HPV status to better predict treatment response. Here the influence of HLA class I/HLA class II expression was explored. Pre-treatment biopsies, from 439/484 OSCC patients diagnosed 2000-2009 and treated curatively, were analyzed for HLA I and II expression, p16(INK4a) and HPV DNA. Absent/weak as compared to high HLA class I intensity correlated to a very favorable disease-free survival (DFS), disease-specific survival (DSS) and overall survival (OS) in HPVDNA+ OSCC, both in univariate and multivariate analysis, while HLA class II had no impact. Notably, HPVDNA+ OSCC with absent/weak HLA class I responded equally well when treated with induction-chemo-radiotherapy (CRT) or radiotherapy (RT) alone. In patients with HPVDNA- OSCC, high HLA class I/class II expression correlated in general to a better clinical outcome. p16(INK4a) overexpression correlated to a better clinical outcome in HPVDNA+ OSCC. Absence of HLA class I intensity in HPVDNA+ OSCC suggests a very high survival independent of treatment and could possibly be used clinically to select patients for randomized trials de-escalating therapy

Kaplan-Meier curves for disease-free survival (DFS), disease-specific survival (DSS) and overall survival (OS) in patients with HPV positive oropharyngeal squamous cell carcinoma (OSCC) with known HLA class I expression.

<p>(A) DFS stratified for HCA-2 intensity, (B) DSS stratified for HCA-2 intensity, (C) OS stratified for HCA-2 intensity, (D) DFS stratified for HC-10 intensity, (E) DSS stratified for HC-10 intensity, and (F) OS stratified for HC-10 intensity. HPV_DNA+ OSCC with absent HLA class I intensity had a significant better clinical outcome than tumors with strong HLA class I intensity, while weak intensity staining presented an intermediate survival (HCA-2: DFS p<0.001; DSS p=0.060; OS p=0.022; HC-10: DFS p=0.003, DSS p=0.021 and OS p=0.009, with the log-rank test). Notably, the difference observed in the HCA-2 DSS analysis did not reach significance, although the trend was similar.</p