Optimizing treatment : tumor markers and sclerotherapy in head and neck lesions

Abstract: Treatment of malignant and benign lesions in the head and neck area is challenging, due to complex anatomy and function. It is thus urgent to find ways to individualize treatment, in order to reduce side-effects, but with preserved efficacy. Human papilloma virus (HPV) and its surrogate marker p16 are well accepted as a prognostic markers in tonsil and base of tongue cancer, and in the latest TNM oropharyngeal tumors are classified based on p16-status. However, the prevalence and impact of HPV and p16 in head- and neck cancer located outside of tonsils and base of tongue is unclear. Hypopharyngeal cancer is the subgroup of head and neck tumors with the worst prognosis, and both surgical and oncological treatment have considerable side-effects. Only a few previous studies have focused on HPV in hypopharyngeal cancer, and the results on prevalence and impact on survival are ambiguous. In oropharyngeal cancer the long-term outcome related to HPV, p16 and subsites is not well studied, but observations have reported late and atypical recurrences in HPV-positive patients. Previous studies have also indicated differences regarding prevalence and outcome related to these markers between the oropharyngeal subsites; tonsil (TSCC), base of tongue (BOTSCC) and otherOPSCC. Ranula is a benign cystic lesion originating from the sublingual gland in the floor of the mouth. Traditional treatment is surgery, with the risk of side-effects such as nerve damage, and need of general anesthesia. Sclerotherapy OK-432 is a less invasive treatment, used since long in patients with lymphatic malformations, and with promising preliminary results also on patients with ranula. The research questions this thesis addresses are: - What is the prevalence of HPV and overexpression of p16, has it changed over time and do these markers have a prognostic value in patients with hypopharyngeal cancer? - Is there an impact on long-term survival and recurrence in patients with OPSCC related to p16, HPV and subsite? - Is sclerotherapy with OK 432 an effective and safe way to treat ranula? In paper 1, 109 patients with hypopharyngeal cancer diagnosed in Stockholm-Gotland region 2000- 2007 and treated with intention to cure were analyzed regarding prevalence of HPV and overexpression of p16, and results were correlated to overall and disease-free survival. In paper 2, 82 patients with hypopharyngeal cancer diagnosed in Stockholm-Gotland region 2008-2013 were analyzed in the same manor. Results from both studies regarding HPV and p16 were compared to assess differences in prevalence over time. Survival analysis of 142 patients from both studies, treated with intention to cure and with a follow-up period of three years, was performed. Prevalence of both markers was low, HPV-DNA was found in 3,7% of the patients in paper 1 and in 6,4% of patients in paper 2, overexpression of p16 in 14,6% and 16,5% respectively. The conclusion is that presence of HPV in hypopharyngeal cancer was rare in Stockholm 2000-2013, only 5%, and did not increase over time in this period. Further, p16 is not a suitable surrogate marker for HPV in hypopharyngeal cancer. In paper 3 529 patients with oropharyngeal squamous cell carcinoma (OPSCC), diagnosed in Stockholm-Gotland 2000-2010, treated with intention to cure and with available data on p16, were included. Clinical data, including localization and time to recurrence, was correlated to HPV and p16. 10-year overall and disease-free survival (OS and DFS) were significantly improved for patients with p16+ TSCC and BOTSCC as compared to p16- cancers (p<0.05 and p<0.05), while in otherOPSCC p16-status had no impact on either. p16+ OPSCC showed a higher frequency of distant metastasis but did not relapse later than p16- OPSCC at any subsite (p<0.05 and p=ns respectively). In TSCC and BOTSCCC, both HPVDNA+/p16+ and HPVDNA-/p16+ correlated to a longer OS in the univariate analysis compared to HPVDNA-/p16- cancer (p=<0.001 and 0.0001 resp.), while in the multivariate analysis only HPVDNA+/p16+ correlated to a better OS and DFS. After recurrence, survival was low (5.9%), and did not differ significantly in relation to p16 or HPVDNA status in TSCC and BOTSCC. In conclusion, we find that p16+ TSCC and BOTSCC did not have a higher frequency of late recurrence compared to corresponding p16- tumors. p16+ TSCC and BOTSCC have better longterm outcome than corresponding p16- cancer, but p16 status did not affect OS or DFS in patients with otherOPSCC. The combination of p16 and HPVDNA-status significantly improves prognostic accuracy for TSCC and BOTSCC, compared to p16 alone. In paper 4 20 patients with a plunging or an intraoral ranula were randomized to two double-blinded injections with OK 432 or saline. Effect on the cystic lesion and evaluation of symptoms and QOL were investigated. 19/20 patients completed the study. 5 patients with intraoral ranulas showed complete response, but only 1/4 of the patients with a plunging ranula. The inflammatory reaction after injection with OK 432 caused a mild to moderate impact on QOL. No serious complications were observed. From these results we conclude that sclerotherapy with OK 432 in ranula is a safe and effective treatment for intraoral ranulas, but possibly less useful in plunging ranulas. The inflammatory reaction after treatment is moderate and well tolerable. In summary, we find that HPV is rare in hypopharyngeal cancer and that overexpression of p16 is not a suitable surrogate marker for HPV in this group of patients. Further, long-term outcome in TSCC and BOTSCC is affected by p16-status, but not in otherOPSCC, p16+ OPSCC did not relapse later than p16- OPSCC at any subsite, and the combination of HPV/p16 increases prognostic accuracy compared to p16 alone in TSCC/BOTSCC. p16+ status TSCC and BOTSCC did not have a higher frequency of late recurrence compared to corresponding p16- tumors and p16 status did not affect survival after recurrence. Finally, we conclude that sclerotherapy with OK 432 can be recommended as primary treatment in intraoral ranulas.