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BackgroundBase of tongue cancer incidence and patient survival is increasing why treatment sequelae becomes exceedingly important. Osteoradionecrosis (ORN) is a late adverse effect of radiotherapy and brachytherapy (BT) could be a risk factor. Brachytherapy is used in three out of six health care regions in Sweden.AimsInvestigate if patients treated in regions using BT show an increased risk for ORN and whether brachytherapy has any impact on overall survival.Material and MethodsWe used data from the Swedish Head and Neck Cancer Register between 2008-2014. Due to the nonrandomized nature of the study and possible selection bias we compared the risk for ORN in brachy vs non-brachy regions.ResultsFifty out of 505 patients (9.9%) developed ORN; eight of these were treated in nonbrachy regions (16%), while 42 (84%) were treated in brachy regions. Neither age, sex, TNM-classification/stage, p16, smoking, neck dissection, or chemotherapy differed between ORN and no-ORN patients. The risk for ORN was significantly higher for patients treated in brachy regions compared to non-brachy regions (HR = 2,63, p = .012), whereas overall survival did not differ (HR = 0.95, p = .782).Conclusions and SignificanceBrachytherapy ought to be used cautiously for selected patients or within prospective randomized studies.

A growing body of evidence suggests that components of the tumor microenvironment, including cancer-associated fibroblasts (CAF), may modulate the treatment sensitivity of tumor cells. Here, we investigated the possible influence of CAFs on the sensitivity of head and neck squamous cell carcinoma (HNSCC) cell lines to cetuximab, an antagonistic epidermal growth factor receptor (EGFR) antibody. Cetuximab treatment caused a reduction in the proliferation rate of HNSCC cell lines, whereas the growth of HNSCC-derived CAF cultures was unaffected. When tumor cells were cocultured with CAFs in a transwell system, the cetuximab-induced growth inhibition was reduced, and a complete protection from growth inhibition was observed in one of the tumor cell lines investigated. Media that had been conditioned by CAFs offered protection from cetuximab treatment in a concentration-dependent manner, suggesting that the resistance to treatment was mediated by CAF-derived soluble factors. The coculture of HNSCC cell lines with CAFs resulted in an elevated expression of matrix metalloproteinase-1 (MMP-1) in both the tumor cells and CAFs. Moreover, the CAF-induced resistance was partly abolished by the presence of an MMP inhibitor. However, CAFs treated with siRNA targeting MMP-1 still protected tumor cells from cetuximab treatment, suggesting that several MMPs may cooperate to facilitate resistance or that the protective effect is mediated by another member of the MMP family. These results identify a novel CAF-dependent modulation of cetuximab sensitivity and suggest that inhibiting MMPs may improve the effects of EGFR-targeted therapy. Mol Cancer Res; 10(9); 1158–68. ©2012 AACR.

PDF file - 91K, PCR array gene list

PDF file - 170K, Protection from cetuximab treatment is provided by cancer-associated fibroblast-derived soluble factors

PDF file - 156K, Cancer-associated fibroblasts induce cetuximab resistance in head and neck squamous cell carcinoma cell lines

Supplemental Figure 2 legend: Shown are age-specific cumulative incidences of tonsillectomies during 1970-2009 in Sweden across the year of birth (i.e. birth cohort).

Background: Rising incidence of oropharyngeal cancers in numerous countries since the 1970s has been attributed to increased oral human papillomavirus (HPV) exposure. However, the contribution of coincidental declines in the surgical removal of the tonsils (tonsillectomy) is unknown. We quantified the association of tonsillectomy with risk of tonsillar, other oropharyngeal, and other head and neck cancers and the contribution of declines in tonsillectomies to cancer incidence trends.Methods: We conducted a nation-wide cohort study in Sweden (1970–2009). Tonsillectomies (N = 225,718) were identified through national patient registers, which were linked with the cancer register. Cancer incidence in the tonsillectomy cohort was compared with Sweden's general population through standardized incidence ratios (SIR).Results: Tonsillectomies were associated with reduced risk of tonsil cancers [SIRs 1+ years post-tonsillectomy = 0.31; 95% confidence interval (CI), 0.08–0.79 and 5+ years post-tonsillectomy = 0.17; 95% CI, 0.02–0.62], but unrelated to other oropharyngeal or other head and neck cancers (SIRs 1+ years post-tonsillectomy = 1.61; 95% CI, 0.77–2.95 and 0.92; 95% CI, 0.64–1.27, respectively). The cumulative incidence of tonsillectomy declined significantly (40%–50%) during 1970–2009. However, tonsil cancer incidence significantly increased during 1970–2009 both without and with corrections for declines in tonsillectomies (relative risks per 5-year periods = 1.23, P < 0.001 and 1.20, P < 0.001, respectively).Conclusions: The reduced tonsil cancer risk with tonsillectomy reflects the removal of most of the relevant tissue. The absence of associations with other head and neck cancers indicates that tonsillectomy may not impact carcinogenesis at other sites.Impact: The significant increases in oropharyngeal cancer incidence since the 1970s in Sweden appear independent of declines in tonsillectomies, reinforcing increased oral HPV exposure as the likely cause. Cancer Epidemiol Biomarkers Prev; 25(6); 944–50. ©2016 AACR.

Supplemental Figure 1: Description of tonsillectomy cohort for the Swedish nation-wide study (1970-2009.)Supplemental Table 1: Clinical indications for tonsillectomy, stratified by calendar period and age at tonsillectomy. Supplemental Table 2: Clinical indications for tonsillectomies conducted as in-patient versus out-patient procedures (2006-2009.) Supplemental Table 3: Association of tonsillectomy with risk of head and neck cancers, stratified by age at tonsillectomy, gender, and calendar era of tonsillectomy.Supplemental Table 4: Sensitivity analyses of the association of tonsillectomy with risk of head and neck cancers.

To better identify patients with human papillomavirus (HPV)-positive oropharyngeal cancer (OPSCC) and a poor prognosis after treatment, we compared the gene expression in tumours from patients with a poor or a favourable prognosis in a case-control setting. The results were thereafter validated in two separate cohorts on the RNA and protein levels. High RNA or protein expression of FGF11 was correlated with a poor patient survival in all three cohorts. Taken together, the data imply that FGF11 may play a major role in the prognosis of patients and that FGF11 could serve as a prognostic marker in HPV-positive oropharyngeal cancer.Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is associated with a favourable prognosis. It has therefore been suggested that treatment should be individualized and separated by HPV status. However, additional prognostic markers are still needed before treatment can be individualized for this patient group. For this purpose, all patients diagnosed with HPV and p16-positive OPSCC in Stockholm 2000-2009, identified as having a partial/nonresponse to treatment and having viable tumour cells in their neck specimen with material available were categorized as cases. These were matched to controls (complete responders), and the differences in the gene expression were analysed. Two separate verification cohorts were identified including patients with HPV- and p16-positive OPSCC, and the data from the case-control study were verified by qPCR and immunohistochemistry (IHC) in the respective cohorts. A separation of gene expression in correlation with survival was observed in the case-control study, and FGF11 expression was identified as significantly differently expressed between the two groups. The prognostic role of FGF11 was validated in the two cohorts on the RNA and protein levels, respectively. Taken together, our findings suggest that FGF11 may indicate a poor prognosis in HPV-positive OPSCC and may serve as a prognostic biomarker.

Ranula is a rare benign cystic lesion in the floor of the mouth, which can herniate through the mylohyoid muscle and become a plunging ranula. Treatment for ranulas is currently surgical excision of the sublingual gland. Sclerotherapy with OK-432 is a well-established treatment of lymphatic malformations, but not yet thoroughly evaluated on ranulas. Objectives: To evaluate sclerotherapy of ranulas with OK-432 in a randomized double-blinded trial.20 patients with plunging or intraoral ranula were randomized to two double-blinded injections with OK-432 or saline. Effect on the ranula and evaluation of symptoms and QOL were investigated.Treatment response differed significantly between OK-432 and placebo,This study suggests that sclerotherapy with OK-432 in ranula is a very effective treatment for intraoral ranulas, but possibly less useful in plunging ranulas.This is a limited study, but we believe that sclerotherapy with OK-432 should be recommended as primary treatment at least for intraoral ranulas.

Anticancer immunotherapies have revolutionized cancer management, yet the effect of systemic anti‐programmed cell death protein 1 (PD‐1) treatment is predominantly studied in tumor‐infiltrating lymphocytes (TILs). Its impact on PD‐1 expressing cells in tumor‐draining lymph nodes (TDLNs) is not well understood and yet to be explored. Thus, further research aiming for better understanding of the PD‐1 pathway not only in tumor tissue but also in TDLNs is warranted. In this study, we investigated the expression of PD‐1, CD69, and HLA‐DR on CD4+ and CD8+ T cells by flow cytometry analysis of peripheral blood mononuclear cells (PBMCs), TDLNs, and tumor samples from patients with oral squamous cell carcinoma (OSCC). Our data showed that both helper and cytotoxic T lymphocytes in OSCC tissue were highly activated and expressed high level of PD‐1 (over 70% positivity). Lymphocytes in TDLNs and peripheral blood expressed significantly lower levels of PD‐1 and other activation markers compared to TILs. Moreover, we demonstrated that a significant fraction of PD‐1 negative TILs expressed high levels of human leukocyte antigen – DR isotype and CD69. In contrast, PD‐1 negative cells in TDLNs and PBMCs scarcely expressed the aforementioned activation markers. Furthermore, we proved that patients with a high percentage of CD3+ PD‐1+ cells in tumor‐draining lymph nodes had significantly lower disease‐free and overall survival rates (log‐rank test P = .0272 and P = .0276, respectively). Taken together, we proved that flow cytometry of lymph nodes in OSCC is feasible and may be used to investigate whether PD‐1 levels in TDLNs correspond with survival and potentially with response to anti‐PD‐1 therapy. Such knowledge may ultimately help guide anti‐PD‐1 treatment., Flow cytometry is a powerful tool that can be used in head and neck cancers to investigate immunological milieu of tumor‐draining lymph nodes. In this project, we provide a characterization of T cells within head and neck cancer tumors, tumor‐draining lymph nodes, and blood.

Background: Occult metastases are common in patients with oral squamous cell carcinoma (OSCC) which is why elective neck dissection, adjuvant radiotherapy or watchful waiting have been treatment options after surgical removal of the primary tumour. Sentinel lymph node biopsy (SLNB) has lately emerged as a novel possibility in treatment planning. Objectives: To establish a reliable and clinically useful protocol for SLNB in staging/elective neck dissection in oral cancer. Methods: Fourteen consecutive patients with T1-T2 N0 oral cancer were enrolled when scheduled for elective neck dissection. Results: This study outlines various techniques for improving SLNB in head and neck cancer. After evaluation, a combination of techniques was found to constitute a reliable, clinically adaptable work concept. The suggested procedure starts with the pre-surgical injection of radioactive technetium 99Tcm carried on tilmanocept (Lymphoseek ®) at the tumour site. The radioactivity in the lymph node is then visualized preoperatively with Single Photon Emission Computed Tomography (SPECT/CT). Intraoperatively, indocyanine green (ICG) is injected and a sentinel node is visualized with near-infrared light. To support the sentinel node detection, the surgeon uses a hand-held gamma detection probe. This approach results in a reproducible and reliable detection of sentinel nodes. Conclusion: This paper presents a novel protocol for the identification of the sentinel node in the head and neck region. The protocol additionally enables the use of flow cytometry analysis of resected lymph nodes.

Background Hypopharyngeal cancer (HPSCC) shows a poor clinical outcome, while HPSCC, caused by human papillomavirus (HPV), presents a better outcome. Here, HPCC, immune proteins, and tumor infiltrating CD8+ lymphocytes (CD8+ TILs) were evaluated in relation to HPV and outcome. Methods Fresh frozen tissue from four HPV-positive HPSCC, 39 HPV-negative HPSCC, and normal samples were analyzed for protein expression by the Proseek immuno-oncology immunoassay. CD8+ TIL numbers evaluated by immunohistochemistry on 144 formalin-fixed biopsies were analyzed in relation to clinical outcome. Results Proteins differing between HPV-positive and negative HPSCC included CD8A, PD-L1, Fas ligand, and chemokines. High CD8+ TIL numbers were correlated to improve clinical outcome in HPV-negative HPSCC. Conclusions High expression of immune proteins in HPV-positive HPSCC may explain the better clinical outcome. CD8+ TILs are of relevance for outcome of HPV-negative HPSCC, while tumors with high immune activity but poor patient survival suggest a role for immune therapy.

Background: The treatment of head and neck cancer is an intensive multimodal treatment that has a great impact on the individual patient. Aims/Objectives: This study aimed to evaluate acute and long-term complications associated with mandibular resections and reconstructions. Material and Methods: We retrospectively retrieved data on complications and recurrences among patients that underwent mandibular resections and reconstructions for treating oral cavity cancer (n = 190 patients) and osteoradionecrosis (ORN, n = 72). Reconstructions included composite grafts (n = 177), soft tissue flaps (n = 61), or primary closure without any graft (n = 24). Results: Forty-two patients that underwent reconstructions with composite grafts displayed serious complications (Clavien–Dindo ≥ IIIa). The complication rates were similar between patients treated for oral cavity cancer and patients treated for ORN. Patients that underwent a primary closure without any graft, had a significantly lower risk of complications compared to patients that underwent the other treatments. After hospitalization, 181 patients (69%) had at least one complication. Conclusions: A majority of patients undergoing resection and reconstruction due to oral cancer/ORN suffered from postoperative complications regardless of indication, comorbidity status or reconstruction technique. The risk of Clavien–Dindo grade IIIa–V events was significantly lower for patients treated with primary closure without grafts. Significance: The results from this study clarifies the importance of in-depth analyse prior to decision of treatment for patients with head and neck cancer.

Simple Summary Long-term survival in patients with oropharyngeal cancer is sparsely studied, but atypical recurrences in human papillomavirus-positive (HPV+) oropharyngeal cancer have been indicated. Furthermore, while the role of HPV is well established in tonsillar and base of tongue cancer, the dominant oropharyngeal subsites, its role in the minor oropharyngeal sites (the oropharyngeal walls, the uvula, and the soft palate) is not fully elucidated. The aim of this retrospective study was therefore to assess long-term outcome in relation to oropharyngeal sub-sites and HPV/p16 status. We confirm the prognostic role of p16+ in tonsillar and base of tongue cancer, but not the other sites. We find that combined HPV/p16-status gives better prognostic information than p16 alone. Lastly, we show that p16− cancer has more locoregional and late recurrences compared to p16+ cancer. Consequently, only combined HPV/p16 positivity in patients with tonsillar and tongue base cancer should be used in future treatment de-escalation trials. Abstract Long-term survival data in relation to sub-sites, human papillomavirus (HPV), and p16INK4a (p16) for patients with oropharyngeal squamous cell carcinoma (OPSCC) is still sparse. Furthermore, reports have indicated atypical and late recurrences for patients with HPV and p16 positive OPSCC. Therefore, we assessed long-term survival and recurrence in relation to oropharyngeal subsite and HPV/p16 status. A total of 529 patients with OPSCC, diagnosed in the period 2000–2010, with known HPVDNA and p16-status, were included. HPV/p16 status and sub-sites were correlated to disease-free and overall survival (DFS and OS respectively). The overexpression of p16 (p16+) is associated with significantly better long-term OS and DFS in tonsillar and base of tongue carcinomas (TSCC/BOTSCC), but not in patients with other OPSCC. Patients with HPVDNA+/p16+ TSCC/BOTSCC presented better OS and DFS compared to those with HPVDNA−/p16− tumors, while those with HPVDNA−/p16+ cancer had an intermediate survival. Late recurrences were rare, and significantly more frequent in patients with p16− tumors, while the prognosis after relapse was poor independent of HPVDNA+/−/p16+/− status. In conclusion, patients with p16+ OPSCC do not have more late recurrences than p16−, and a clear prognostic value of p16+ was only observed in TSCC/BOTSCC. Finally, the combination of HPVDNA and p16 provided superior prognostic information compared to p16 alone in TSCC/BOTSCC.

Hypopharyngeal squamous cell carcinoma (HPSCC) has a very poor prognosis. Local surgery may increase survival, but is often avoided due to significant post-op co-morbidities. Since prognostic markers are lacking, the aim was to find predictive biomarkers that identify patients whose response to oncological treatment is poor and who may benefit from primary surgery to increase survival. Pretreatment biopsies from 23 HPSCC patients, 3 human papillomavirus (HPV) positive and 20 HPV-negative, were analyzed for expression of 750 mRNAs using the Nanostring nCounter IO360 panel in relation to 3-year survival. Validation was performed through immunohistochemistry (IHC) for HLA class I and S100A12 in 74 HPV-negative HPSCC samples. Clustering identified a subset of HPV-negative HPSCC with favorable prognosis and a gene expression signature overexpressing calgranulins and immune genes, distinct from that of HPV-positive HPSCC. Enrichment analysis showed immune signaling, including the tumor inflammation signature, to be enriched in surviving patients. IHC validation confirmed high S100A12 and HLA class I expression to correlate with survival in HPV-negative HPSCC. This shows that immune activity is strongly related to survival in HPV-negative HPSCC. Enrichment of the tumor inflammation signature indicates a potential benefit of immunotherapy. Low expression of both HLA class I and S100A12 could be used to select patients for local surgery.

Background TNM-8 staging separates oropharyngeal squamous cell carcinomas (OPSCC) into human papillomavirus (HPV)-mediated and -unrelated OPSCC based on p16INK4a overexpression (p16+), as surrogate marker for HPV. However, OPSCC is histologically and clinically heterogenous including tonsillar and base of tongue squamous cell carcinomas (TSCC and BOTSCC respectively), and carcinomas of soft palate and walls (otherOPSCC). The significance of HPV is established in TSCC/BOTSCC, while its role in otherOPSCC is unclear, which is not considered in TNM-8. Here, p16+ was therefore evaluated in relation to overall survival (OS) and tumor stage per OPSCC subsite. Patients and methods All 932 patients, treated with curative intent in Stockholm 2000–2016 with OPSCC, previously analyzed for p16 expression, were included. Clinical data, including stage and OS, was collected retrospectively. Results Patients with p16+ otherOPSCC had significantly poorer OS compared to patients with p16+ TSCC/BOTSCC (p = 0.005) and their survival was similar to that of patients with p16-otherOPSCC/TSCC/BOTSCC. Moreover, patients with TNM-8 stage I-II and p16+ otherOPSCC had a significant poorer OS compared to patients with p16+ TSCC/BOTSCC and similar stage (p = 0.02). Lastly, patients with otherOPSCC and low TNM-7 stage had a significant better OS, as compared to those with a high stage (p = 0.019) while no hazard discrimination was observed with TNM-7 in TSCC/BOTSCC. Conclusion Our results indicate a risk of misclassification of patients with otherOPSCC and low TNM-8 stage. We suggest that p16 should only be evaluated in TSCC/BOTSCC and that patients with otherOPSCC should all be staged as patients with HPV-unrelated (p16-) OPSCC.

Distinguishing branchial cleft cysts (BCCs) from cystic metastases of a human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (OPSCC) is challenging. Fine needle aspirates (FNAs) from cystic metastasis may be non-representative, while reactive squamous cells from BCC can be atypic. Based on cytology and with the support of HPV DNA positivity many centers treat cystic metastasis oncological and thus patients are spared neck dissection. To do so safely, one must investigate whether HPV DNA and p16DNA was extracted from formalin fixed paraffin embedded (FFPE) surgically resected BCCs from 112 patients diagnosed 2007-2015 at Karolinska University Hospital and amplified by PCR. A multiplex bead-based assay used to detect 27 HPV-types and p16All 112 BCCs were HPV DNA negative, and of 105 BCCs possible to evaluate for p16HPV DNA and p16

Background: Detection of metastatic spread of head and neck cancer to cervical lymph nodes is essential for optimal design of therapy. Undetected metastases lead to mortality, which can be prevented by better detection methods. Methods: We analysed 41 lymph nodes from 19 patients with oral squamous cell carcinoma (OSCC). Each lymph node was divided in two, one half processed for histopathology and the other half dissociated into single-cell suspension, stained for the carcinoma cell markers cytokeratin 5/8 (CK5/8), epithelial cell adhesion molecule (EpCAM) and epithelial mucin (MUC-1), and analysed with flow cytometry. Flow cytometry data were compared with histopathology performed on serial sections and immunohistochemistry. Six cervical lymph nodes from cancer-free patients were used to establish baseline levels in flow cytometry. Results: Flow cytometry analysis (fluorescence-activated cell sorting; FACS) detected all six metastases confirmed by histopathology as well as the histologically negative nodes. Importantly, among nine sentinel lymph nodes, FACS analysis detected

The concept of functional neutrophil subsets is new and their clinical significance in malignancies is unknown. Our study investigated the role of CD16dim CD62Lhigh , CD16high CD62Lhigh and CD16high CD62Ldim neutrophil subsets in head and neck squamous cell carcinoma (HNSCC) patients. These neutrophil subsets may play different roles in immune-related activity in cancer, based on their profile, activation state and migration ability within a tumor site, which may be important in predicting cancer prognoses. Tumor biopsies and blood were obtained from newly diagnosed untreated HNSCC patients and healthy controls. Neutrophil subsets and their phenotype were characterized using flow cytometry. Isolated granulocytes were assessed for anti-tumor immune functions. Compared to controls HNSCC patients exhibited increased CD16high CD62Ldim neutrophils in blood; this subset displayed a distinct phenotypes with high expression of CD11b and CD18. This subset was prone to migrate into the tumor facilitated by tumor-derived IL-8. Furthermore, IL-8 was also found to activate neutrophils and thereby promoting subset transition. Various assays demonstrated that activated CD16high CD62Ldim neutrophils inhibited migration, proliferation and induced apoptosis of FaDu cancer cells. Neutrophil elastase detected in activated CD16high CD62Ldim neutrophils and tumor biopsies suggested that CD16high CD62Ldim neutrophils impart anti-tumoral activity via neutrophil extracellular traps. Furthermore, increased fraction of CD16high CD62Ldim neutrophils was shown to correlate with an increased survival rate. Our study demonstrates the clinical relevance of the CD16high CD62Ldim neutrophil subset, providing evidence for its increased migration capacity, its anti-tumor activity including increased NET formation and finally its correlation with increased survival in HNSCC patients.

Background: Human papillomavirus (HPV) is a favourable prognostic factor in oropharyngeal cancer. Moreover, we and others reported that HPV-positive cancer of unknown primary in the head and neck region (HNCUP) has better outcome than HPV-negative HNCUP. However, not all studies concord. Here, our previous finding was investigated in a new cohort and additional biomarkers were analyzed. Materials and Methods: A total of 19 HNCUPs diagnosed 2008-2013 were analyzed for HPV DNA by polymerase chain reaction assay (PCR) and p16 by immunohistochemistry (IHC). Thereafter, 69 HNCUPs diagnosed between 2000-2013 were analyzed for HPV16 mRNA by PCR (if HPV16DNA-positive) and cluster of differentiation 8 positive (CD8+) tumour-infiltrating lymphocytes (TILs) and human leukocyte antigen (HLA) class I-expression using IHC. Results: HPV DNA, alone and in combination with p16 overexpression, was validated as a favourable prognostic factor in HNCUP. HPV16 mRNA was present in most HPV16 DNA-positive cases, confirming HPV-driven carcinogenesis in HNCUP. High CD8+ TIL counts indicated favourable prognosis. Conclusion: HPV status is useful for the management of patients with HNCUP and the role of CD8+ TILs should be further explored.

BACKGROUND Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC) has a better outcome than most head neck squamous cell carcinomas (HNSCCs) and an HPV-positive lymph node metastasis likely has an HPV-positive oropharyngeal SCC origin. Determining HPV-status in cervical lymph nodes by fine-needle aspiration cytology (FNAC) may be useful for diagnosis. METHODS FNACs from 66 patients with neck masses were prospectively examined for HPV DNA and HPV16 mRNA by a polymerase chain reaction (PCR)-based assay, and the data correlated to diagnosis and HPV-status obtained from histopathological specimens. RESULTS Aspirates from 17 of 66 patients, later diagnosed with HPV-positive oropharyngeal SCC, were HPV16 DNA-positive. HPV16 mRNA was detected in all cases with extractable RNA. All remaining FNACs, including 18 branchial cleft cysts, were HPV DNA-negative. HPV DNA status in the aspirates showed perfect concordance with corresponding biopsies. CONCLUSION HPV16 DNA detection in fine-needle aspirations from neck masses is reliable and HPV16 DNA in a metastasis is a strong indicator of an HPV-positive oropharyngeal SCC. © 2016 Wiley Periodicals, Inc. Head Neck 39: 419-426, 2017.

Human papillomavirus (HPV), in addition to smoking and alcohol, is a cause of oropharyngeal squamous cell carcinoma (OPSCC), particularly of the tonsils and base of the tongue (TSCC and BOTSCC, respectively). Moreover, HPV-positive TSCC and BOTSCC are associated with a better outcome compared with their HPV-negative counterparts (80 vs. 40% 3-year disease-free survival rate, respectively) and their incidence has increased in several countries. Recently, accumulating evidence of HPV in a considerable proportion of cancers of unknown primary (CUP) in the head and neck region and in a small proportion of hypopharyngeal SCCs has been reported. Furthermore, HPV-positive tumours, particularly cases with HPV DNA positivity in combination with overexpression of p16, also tend to have a better clinical outcome compared with that of the corresponding HPV-negative tumours. This finding is particularly prominent in HPV-positive CUPs of the head and neck region, where the primary tumour likely originates from the oropharynx. Thus, the determination of HPV status and p16 expression may be of value for the diagnosis and treatment of CUP of the head and neck region and may also be of value for hypopharyngeal cancers in the future. However, for hypopharyngeal cancer as well as other non-OPSCCs, additional studies per subsite on the effect of HPV status on survival are required.

Background: Rising incidence of oropharyngeal cancers in numerous countries since the 1970s has been attributed to increased oral human papillomavirus (HPV) exposure. However, the contribution of coincidental declines in the surgical removal of the tonsils (tonsillectomy) is unknown. We quantified the association of tonsillectomy with risk of tonsillar, other oropharyngeal, and other head and neck cancers and the contribution of declines in tonsillectomies to cancer incidence trends. Methods: We conducted a nation-wide cohort study in Sweden (1970–2009). Tonsillectomies (N = 225,718) were identified through national patient registers, which were linked with the cancer register. Cancer incidence in the tonsillectomy cohort was compared with Sweden's general population through standardized incidence ratios (SIR). Results: Tonsillectomies were associated with reduced risk of tonsil cancers [SIRs 1+ years post-tonsillectomy = 0.31; 95% confidence interval (CI), 0.08–0.79 and 5+ years post-tonsillectomy = 0.17; 95% CI, 0.02–0.62], but unrelated to other oropharyngeal or other head and neck cancers (SIRs 1+ years post-tonsillectomy = 1.61; 95% CI, 0.77–2.95 and 0.92; 95% CI, 0.64–1.27, respectively). The cumulative incidence of tonsillectomy declined significantly (40%–50%) during 1970–2009. However, tonsil cancer incidence significantly increased during 1970–2009 both without and with corrections for declines in tonsillectomies (relative risks per 5-year periods = 1.23, P < 0.001 and 1.20, P < 0.001, respectively). Conclusions: The reduced tonsil cancer risk with tonsillectomy reflects the removal of most of the relevant tissue. The absence of associations with other head and neck cancers indicates that tonsillectomy may not impact carcinogenesis at other sites. Impact: The significant increases in oropharyngeal cancer incidence since the 1970s in Sweden appear independent of declines in tonsillectomies, reinforcing increased oral HPV exposure as the likely cause. Cancer Epidemiol Biomarkers Prev; 25(6); 944–50. ©2016 AACR.

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.

Background Tonsillar and base of tongue squamous cell carcinoma (TSCC/BOTSCC) has increased. In Stockholm, the proportion of human papillomavirus (HPV)-positive cases and the incidence of TSCC rose between 1970 and 2006 then stabilized. Here, HPV-prevalence, and TSCC/BOTSCC incidence 2000-2016, in Stockholm and Sweden were followed. Methods Incidence data for 2000-2016 were obtained from the Swedish Cancer Registry. TSCC/BOTSCC biopsies, 2013-2016 from Stockholm, were examined for HPV DNA and p16INK4a , or data obtained from medical reports. For cases 2000-2012, data were available from previous studies. Results The incidence of TSCC/BOTSCC has continued to rise in Stockholm and Sweden 2000-2016, especially after 2008. HPV DNA and p16INK4a analysis was determined for 795 Stockholm cases from 2000 to 2016, with 72% being HPV DNA and p16INK4a positive 2013-2016, and 70% positive 2000-2016. Conclusion During 2000-2016, especially after 2008, the incidence of TSCC/BOTSCC has continued to increase in Stockholm and Sweden, with an HPV-prevalence of approximately 70% in Stockholm.

Objectives Inflammation is known to be associated with the progression of cancer. The study was designed to characterise the systemic inflammation in patients with oropharyngeal squamous cell carcinoma (OPSCC) and investigate its relation to tumour size, ability to metastasise and HPV status. Materials and methods Blood was obtained from 58 patients with OPSCC and 90 healthy controls and analysed with leucocyte differential count. Results The patients with OPSCC displayed an increased number of neutrophils and monocytes, whereas the lymphocytes were suppressed compared to the healthy controls. The neutrophils-to-lymphocyte ratio (NLR) and the monocyte-to-lymphocyte ratio (MLR) were calculated, and patients with large tumours exhibited high NLR and MLR. Further, patients with regional lymph node spread displayed a low NLR and MLR. Patients with HPV-positive tumours (n = 48) had a lower NLR than the patients (n = 8) with HPV-negative tumours. Conclusion This study demonstrates that patients with OPSCC have an increased systemic inflammation that is affected by the HPV status, the size of the tumour and lymph node spread.

Oral tongue squamous cell carcinoma (OTSCC) is associated with poor prognosis. To improve prognostication, we analyzed four gene probes (TERC, CCND1, EGFR and TP53) and the centromere probe CEP4 as a marker of chromosomal instability, using fluorescence in situ hybridization (FISH) in single cells from the tumors of sixty-five OTSCC patients (Stage I, n = 15; Stage II, n = 30; Stage III, n = 7; Stage IV, n = 13). Unsupervised hierarchical clustering of the FISH data distinguished three clusters related to smoking status. Copy number increases of all five markers were found to be correlated to non-smoking habits, while smokers in this cohort had low-level copy number gains. Using the phylogenetic modeling software FISHtrees, we constructed models of tumor progression for each patient based on the four gene probes. Then, we derived test statistics on the models that are significant predictors of disease-free and overall survival, independent of tumor stage and smoking status in multivariate analysis. The patients whose tumors were modeled as progressing by a more diverse distribution of copy number changes across the four genes have poorer prognosis. This is consistent with the view that multiple genetic pathways need to become deregulated in order for cancer to progress.

Human papillomavirus (HPV) is a major etiological factor for tonsillar and the base of tongue cancer (TSCC/BOTSCC). HPV-positive and HPV-negative TSCC/BOTSCC present major differences in mutations, mRNA expression and clinical outcome. Earlier protein studies on TSCC/BOTSCC have mainly analyzed individual proteins. Here, the aim was to compare a larger set of cancer and immune related proteins in HPV-positive and HPV-negative TSCC/BOTSCC in relation to normal tissue, presence of HPV, and clinical outcome. Fresh frozen tissue from 42 HPV-positive and 17 HPV-negative TSCC/BOTSCC, and corresponding normal samples, were analyzed for expression of 167 proteins using two Olink multiplex immunoassays. Major differences in protein expression between TSCC/BOTSCC and normal tissue were identified, especially in chemo- and cytokines. Moreover, 34 proteins, mainly immunoregulatory proteins and chemokines, were differently expressed in HPV-positive vs HPV-negative TSCC/BOTSCC. Several proteins were potentially related to clinical outcome for HPV-positive or HPV-negative tumors. For HPV-positive tumors, these were mostly related to angiogenesis and hypoxia. Correlation with clinical outcome of one of these, VEGFA, was validated by immunohistochemistry. Differences in immune related proteins between HPV-positive and HPV-negative TSCC/BOTSCC reflect the stronger activity of the immune defense in the former. Angiogenesis related proteins might serve as potential targets for therapy in HPV-positive TSCC/BOTSCC.

BACKGROUND: The proxy marker for human papillomavirus (HPV), p16, is included in the new AJCC 8th/UICC 8th staging system, but due to incongruence between p16 status and HPV infection, single biomarker evaluation could lead to misallocation of patients. We established nomograms for overall survival (OS) and progression-free survival (PFS) in patients with oropharyngeal squamous cell carcinoma (OPSCC) and known HPV-DNA and p16 status, and validated the models in cohorts from high- and low-prevalent HPV countries.METHODS: Consecutive OPSCC patients treated in Denmark, 2000-2014 formed the development cohort. The validation cohorts were from Sweden, Germany, and the United Kingdom. We developed nomograms by applying a backward-selection procedure for selection of variables, and assessed model performance.RESULTS: In the development cohort, 1313 patients, and in the validation cohorts, 344 German, 503 Swedish and 463 British patients were included. For the OS nomogram, age, gender, combined HPV-DNA and p16 status, smoking, T-, N-, and M-status and UICC-8 staging were selected, and for the PFS nomogram the same variables except UICC-8 staging. The nomograms performed well in discrimination and calibration.CONCLUSIONS: Our nomograms are reliable prognostic methods in patients with OPSCC. Combining HPV DNA and p16 is essential for correct prognostication. The nomograms are available at www.orograms.org .

Reconstructive surgery for mandibular osteoradionecrosis is increasing; however, evidence regarding the impact on health-related quality of life is lacking. The current exploratory study prospectively investigates whether resection with reconstruction is associated with changes in HRQoL parameters for these patients.Seventeen patients underwent microvascular reconstruction for mandibular osteoradionecrosis between 2012 and 2015, and 16 completed the EORTC quality of life questionnaires QLQ-C30 and QLQ-HN35 1 month before and 1 year after surgery.Increases in emotional (P = 0.01) and social functioning (P = 0.004) were observed, together with improvements in the fatigue (P = 0.04), appetite loss (P = 0.02) and pain (P = 0.02) scores, as evaluated by the QLQ-C30. Pain reduction was further confirmed by the QLQ-HN35 (P = 0.04), which also showed improved scores for feeling ill (P = 0.001) and sexual difficulties (P = 0.04).This exploratory study suggests that microvascular reconstruction after mandibular osteoradionecrosis may improve HRQoL, with an emphasis on pain reduction; however, further studies are needed.

summary Material and methods: Presence of HPV DNA was analyzed in mouthwash and tonsillar swab samples, if indicative of HPV-positive tonsillar or base of tongue cancer in 76 patients, with suspected head neck cancer, undergoing diagnostic endoscopy at Karolinska University Hospital. The diagnosis and tumor HPV status was later obtained from patients’ records. As controls, 37 tumor-free dental visitors were included. Results: Of the 76 patients, 22/29 (76%) and 16/18 (89%) had an HPV-positive tonsillar and base of tongue cancer respectively, with 18/22 (82%) and 8/16 (50%) respectively having tumor concordant HPV-type positive oral samples. Two other HPV-positive oral samples in the base of tongue cancer group did not correlate to the tumor HPV status. Among the remaining patients, 19 with other head neck cancer and 10 with benign conditions, 4/29 (14%) had HPV-positive oral samples. Consequently, of the HPV-positive oral samples, dominated by HPV16 and high signals, 27/32 (84%) were derived from 26 patients with concordant HPV-type positive tonsillar or base of tongue cancer and one patient with an unknown primary head and neck cancer. The other five HPV-positive oral samples, with mainly low signals were derived from two patients with non-concordant HPV-type positive tumor biopsies, two patients with HPV-negative tumor biopsies and a patient with a benign condition. Of the dental patients, 3/37 (8%) had HPV-positive tonsillar swabs with weak signals. Conclusion: In patients with suspected head neck cancer, HPV-positive oral samples, especially HPV16 with high signals, could be indicative of HPV-positive tonsillar or base of tongue cancer.

Patients with cancer of unknown primary (CUP) in the head neck region are generally treated with neck dissection followed by radiotherapy at times combined with chemotherapy, a treatment associated with considerable side effects. Some of these tumors may originate as human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OSCC), with better clinical outcome than head neck squamous cell cancer (HNSCC) in general, and could potentially do well with less treatment. Here, we therefore investigated whether HPV status and p53-expression correlated to clinical outcome in patients with CUP in the head neck region. Fifty metastases were analyzed for presence of HPV DNA, and expression of p16INK4A and p53 and the data were correlated to clinical outcome. Patients with HPV DNA-positive (HPVDNA+) metastases had significantly better 5-year overall survival (OS) compared to those with HPVDNA− metastases (80.0% vs. 36.7%, respectively; P = 0.004), with a similar tendency for disease-free survival (DFS). These survival rates showed excellent concordance with those of HPVDNA+ and HPVDNA− OSCC in Sweden during the same time period, strengthening the hypothesis that HPVDNA+ head and neck CUP may originate from HPVDNA+ OSCC. In addition, having absent/intermediary-low as compared to high expression of p53 correlated to a better prognosis with a 69% as compared to 14% 5-year OS, respectively (P

Background Patients with hypopharyngeal cancer have a 5-year survival of only 15% to 30%. Human papillomavirus (HPV) is a risk factor and a favorable prognostic factor for oropharyngeal carcinoma and p16 has been suggested as a surrogate marker for HPV-induced cancer. However, few studies have been performed on HPV and p16 in hypopharyngeal cancer. Methods One hundred nine pretreatment hypopharyngeal cancer biopsies were analyzed for presence of HPV and p16 overexpression, and the results were correlated to patient survival. Results Of 109 tumors, 7 were HPV-positive (4 HPV16) and 18 overexpressed p16. There was some correlation between survival and HPV status, but not with regard to p16 expression. Notably, all patients with HPV16-positive tumors, also overexpressing p16, lived tumor free for more than 3 years. Conclusion Our results indicate that HPV-induced hypopharyngeal cancer is rare and that p16 is not a suitable biomarker for presence of HPV in this tumor type. © 2013 Wiley Periodicals, Inc. Head Neck 36: 107–112, 2014

Patients with human papillomavirus DNA positive (HPVDNA+) oropharyngeal squamous cell carcinoma (OSCC) have better clinical outcome than those with HPV DNA negative (HPVDNA-) OSCC upon intensive oncological treatment. All HPVDNA+ OSCC patients may not require intensive treatment, however, but before potentially deintensifying treatment, additional predictive markers are needed. Here, we examined HPV, p16(INK4a), and CD44 in OSCC in correlation to clinical outcome. Pretreatment tumors from 290 OSCC patients, the majority not receiving chemotherapy, were analyzed for HPV DNA by Luminex and for p16(INK4a) and CD44 by immunohistochemistry. 225/290 (78%) tumors were HPVDNA+ and 211/290 (73%) overexpressed p16(INK4a), which correlated to presence of HPV (P 95% 3-year DFS and OS. Furthermore, in HPVDNA+ OSCC, p16(INK4a)+ overexpression correlated to a favorable 3-year OS. In conclusion, patients with HPVDNA+ and absent/weak CD44 intensity OSCC presented the best survival and this marker combination could possibly be used for selecting patients for tailored deintensified treatment in prospective clinical trials. Absence of/weak CD44 or presence of human papillomavirus (HPV) DNA was shown as a favorable prognostic factors in tonsillar and tongue base cancer. Moreover, patients with the combination of absence of/weak CD44 and presence of HPV DNA presented a very favorable outcome. Therefore, we suggest that this marker combination could potentially be used to single out patients with a high survival that could benefit from a de-escalated oncological treatment.

Objective Head-neck cancer therapy has become intensified. With radiotherapy alone, 3-year disease-free survival (DFS) is 80% for HPV-positive TSCC/BOTSCC and better for patients with favorable characteristics, suggesting therapy could be tapered for some, decreasing side-effects. Therefore, we built a model to predict progression-free survival for patients with HPV-positive TSCC and BOTSCC. Material and methods TSCC/BOTSCC patients treated curatively between 2000 and 2011, with HPV16 DNA/E7 mRNA positive tumors examined for CD8 + TILs, HPV16 mRNA and HLA class I expression were included. Patients were split randomly 65/35 into training and validation sets, and LASSO regression was used to select a model in the training set, the performance of which was evaluated in the validation set. Results 258 patients with HPV DNA/E7 mRNA positive tumors could be included, 168 and 90 patients in the respective sets. No treatment improved prognosis compared to radiotherapy alone. CD8 + TIL counts and young age were the strongest predictors of survival, followed by T-stage Conclusion CD8 + TIL counts, age, T-stage and E2 expression could predict progression-free survival, identifying patients eligible for randomized trials with milder treatment, potentially reducing side effects without worsening prognosis.

The current treatment recommendation for T2-3N0M0 glottic squamous cell carcinoma (SCC) in the Nordic countries comprises of radiotherapy (RT) and chemoradiotherapy (CRT). Tumor radiosensitivity varies and another option is primary surgical treatment, which underlines the need for predictive markers in this patient population. The aim of the present study was to investigate the relation of the proteins WRAP53 beta, survivin and p16INK4a to RT/CRT response and ultimate outcome of patients with T2-T3N0 glottic SCC. Protein expression was determined using immunohistochemistry on tumors from 149 patients consecutively treated with RT or CRT at Helsinki University Hospital, Karolinska University Hospital, and Linkping University Hospital during 1999-2010. Our results demonstrate a significantly better 5-year relapse-free survival, disease-free survival (DFS), disease-specific survival and overall survival of patients with T3N0 tumors treated with CRT compared with RT alone. Patients with tumors showing a cytoplasmic staining of WRAP53 beta revealed significantly worse DFS compared with those with nuclear staining. For survivin, we observed a trend towards better 5-year DFS in patients with strong nuclear survivin expression compared with those with weak nuclear survivin expression (p=0.091). Eleven (7%) tumors showed p16 positivity, with predilection to younger patients, and this age group of patients with p16-positive SCC had a significantly better DFS compared with patients with p16-negative SCC. Taken together, our results highlight WRAP53 beta as a potential biomarker for predicting RT/CRT response in T2-T3N0 glottic SCC. p16 may identify a small but distinct group of glottic SCC with favorable outcome. Furthermore, for T3N0 patients better outcome was observed following CRT compared to RT alone. Funding Agencies|Swedish Cancer Society [2010/545]; County Council of Ostergotland; Research Funds of Linkoping University Hospital; Finnish Cancer Society; Finnish Medical Foundation; Finnish-Norwegian Medical Foundation; Helsinki University Hospital Research Funds [TYH2015204]

// Cinzia Bersani 1 , Lars Sivars 1 , Linnea Haeggblom 1 , Sebastian DiLorenzo 2,3 , Michael Mints 4,5 , Andreas Ahrlund-Richter 1 , Nikolaos Tertipis 1 , Eva Munck-Wikland 6,7 , Anders Nasman 1 , Torbjorn Ramqvist 1,* and Tina Dalianis 1,* 1 Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden 2 Department of Medical Sciences, Uppsala University, Uppsala, Sweden 3 National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden 4 Department of Medicine, Karolinska Institutet, Stockholm, Sweden 5 Department of Surgical and Perioperative Sciences, Umea University, Umea, Sweden 6 Department of Clinical Science and Technology, Karolinska Institutet, Stockholm, Sweden 7 Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Karolinska University Hospital, Stockholm, Sweden * These authors have contributed equally to this work Correspondence to: Cinzia Bersani, email: // Keywords : HPV, tonsillar cancer, base of tongue cancer, cancer of unknown primary of the head and neck region, FGFR3 mutation Received : December 21, 2016 Accepted : January 24, 2017 Published : February 09, 2017 Abstract BACKGROUND: Human papillomavirus positive (HPV + ) tonsillar cancer (TSCC), base of tongue cancer (BOTSCC) and unknown primary cancer of the head and neck (HNCUP) have better outcome than corresponding HPV - cancers. To find predictive markers for response to treatment, and correlations and differences in mutated oncogenes and suppressor genes between HPV + TSCC/BOTSSCC and HPV + HNCUP and HPV - TSCC/BOTSCC targeted next-generation sequencing was performed of frequently mutated regions in 50 cancer related genes. PATIENTS AND METHODS: DNA from 348 TSCC/BOTSCC and 20 HNCUP from patients diagnosed 2000-2011, was sequenced by the Ion Proton sequencing platform using the Ion AmpliSeq Cancer Hotspot Panel v2 to identify frequently mutated regions in 50 cancer related genes. Ion Torrent Variant Caller software was used to call variants. RESULTS: 279 HPV + TSCC/BOTSCC, 46 HPV - TSCC/BOTSCC and 19 HPV + HNCUP samples qualified for further analysis. Mutations/tumor were fewer in HPV + TSCC/BOTSCC and HNCUP, compared to HPV - tumors (0.92 vs . 1.32 vs . 1.68). Differences in mutation frequency of TP53 and PIK3CA were found between HPV + TSCC/BOTSCC and HNCUP and HPV - TSCC/BOTSCC. In HPV + TSCC/BOTSCC presence of FGFR3 mutations correlated to worse prognosis. Other correlations to survival within the groups were not disclosed. CONCLUSIONS: In HPV + TSCC/BOTSCC mutation of PIK3CA was most frequently observed, while TP53 mutations dominated in HPV - TSCC/BOTSCC. In HPV + TSCC/BOTSCC and HNCUP, mutations/tumor were similar in frequency and fewer compared to that in HPV - TSCC/BOTSCC. Notably, FGFR3 mutations in HPV + TSCC/BOTSCC indicated worse prognosis.

The concept of functional neutrophil subsets is new and their clinical significance in malignancies is unknown. Our study investigated the role of CD16

Today, most oropharyngeal squamous cell carcinoma (OSCC) is human papillomavirus (HPV) positive and HPV alone or in combination with p16 is reported to be a favorable prognostic factor for OSCC. Patients with tumors at other OSCC sites (OOSCC) are often included in the same treatment and study protocols as patients with tonsillar- and base of tongue SCC, even though the prevalence and clinical significance of HPV infection in OOSCC is unknown. Since tonsillar and base of tongue SSC cover roughly 90% of all OSCC, there is an obvious risk that there may be a misinterpretation of the results for OOSCC. Herein, we therefore study the prevalence of HPV and p16 and their impact on survival in OOSCC. A total of 69 patients were included in the study, and 61 were included in the survival analysis. HPV and p16 were present in only 17% (12/69) and 25% (17/69) of the OOSCC cases, respectively, while the majority 69% (48/69) was both HPV and p16 negative. Neither HPV nor p16 had predictive value for clinical outcome in OOSCC in this study. In conclusion, the prevalence of HPV and/or p16 is much lower in OOSCC compared to earlier reports including all OSCC, or tonsillar- and base of tongue cancer alone and HPV and p16 had no impact on clinical outcome in OSCC in this study. Our data highlight the diversity of head neck cancer sub-sites and the importance of taking OSCC sub-sites in consideration in future clinical trials and treatment.

The incidence of tonsillar cancer and the proportion of human papillomavirus (HPV) positive tonsillar cancer cases have increased in the last decades. In parallel, treatment for tonsillar cancer has been intensified e.g., by accelerated radiotherapy, and chemotherapy, resulting in more side effects. Patients with HPV-positive tonsillar cancer have better prognosis than those with HPV-negative tumors, and the former group could hypothetically benefit from reduced, less-toxic treatment without compromising survival. Here, we therefore evaluated possible differences in overall and disease-specific survival after different oncological treatments in 153 patients with HPV DNA- and P16-positive tonsillar cancer who were diagnosed and treated with intent to cure between 2000 and 2007, in Stockholm, Sweden. Of these patients, 86 were treated with conventional radiotherapy, 40 were treated with accelerated radiotherapy and 27 were treated with chemoradiotherapy. There were no significant differences in overall or disease-free survival between the groups. However, there was a trend, implying a beneficial effect of the intensified treatment, with chemoradiotherapy being better than radiotherapy despite that more patients had stage IV disease in the former group; and accelerated radiotherapy being better than conventional radiotherapy. This needs to be followed further in larger more homogenous groups of patients. In conclusion, patients with HPV-positive tonsillar cancer treated with conventional- or accelerated radiotherapy or chemoradiotherapy disclosed similar survival rates. The trend for better survival and less metastasis after intensified treatment underlines the need for large prospective studies comparing less intense to more intense treatment (chemoradiotherapy).

Tonsillar, base of tongue and tongue cancer have similar anatomical and histopathological appearances but present differences in prognosis. Human papillomavirus (HPV) is a known risk factor for tonsillar and base of tongue cancer, and a survival benefit has been shown for these tumors; however, HPV prevalence in tongue cancer is low. Tonsillar, base of tongue and tongue cancer patients registered in the Swedish Cancer Registry between 1960 and 2004 were followed from the date of cancer diagnosis until death, emigration out of Sweden, or the end of a follow-up (5 years since cancer diagnosis), whichever occurred first. The relative survival rate was computed as the ratio of the observed to the expected survival rate, in which the latter was inferred from the survival of the entire Swedish population in the same age, sex and calendar year stratum. The relative survival rate has improved significantly over time for patients with tonsillar and base of tongue cancer although delineated by different patterns. However, the relative survival rate in tongue cancer patients exhibited only a very modest improvement during the same time period. Contrary to the overall improved survival for patients with tonsillar and base of tongue cancer, the patients with tongue cancer show a very modest improvement in Sweden since 1960. Further studies are warranted to elucidate more effective treatment options for tongue cancer patients.