Association between tonsillectomy and oropharyngeal cancer risk: a retrospective cohort study.

BACKGROUND: The purpose of this retrospective cohort study is to describe the association between the history of tonsillectomy and the risk of oropharyngeal squamous cell carcinoma (OPSSC), using a large cohort of patients. MATERIALS AND METHODS: We performed a retrospective cohort study with 3620 patients diagnosed with OPٍSCC from 2010 to 2021. We utilized the University of Florida patients' registry i2b2 system. Three subsets of OPSSC were defined, base of tongue(BOT) cancer, tonsillar cancer, and other OPSSC. Tumor demographics and history of tonsillectomy were collected. Odds ratio for OPSSC were assessed utilizing a logistic regression model with adjusting for gender, race, and age. P < 0.05 was deemed significant. RESULTS: Of the 3620 OPSSC patients were BOT cancer (N = 964), tonsillar cancer (N = 995), and other OPSSC (N = 1661). There was a statistically significant reduction in tonsillar cancer and BOT cancer odds ratio in patients with a history of tonsillectomy vs. patients without tonsillectomy (0.086 and 0.117), respectively, with a P value < .0001. The odds ratio of OPSSC in patients with a history of tonsillectomy vs. patients without tonsillectomy is 1.031. CONCLUSION: This study showed that the OPSSC and previous history of tonsillectomy are associated. Our results showed a significant reduction in BOT and tonsillar cancer risk in patients with a history of tonsillectomy and an insignificant decrease in other OPSSC. This study could emphasize the importance of the development of future clinical trials to investigate the role of prophylactic tonsillectomy as a secondary preventive strategy to reduce OPSSC.

Tonsillectomy as Prevention of Tonsil and Base of Tongue Cancer: Systematic Review and Meta-analysis on the Immuno-Oncological Effect of One Among the Most Common Surgeries in the World.

Otorhinolaryngology tradition is that tonsillectomy (TE) is conducted among children and adolescents for obstructive sleep apnea secondary to adenotonsillar hypertrophy and in adults for chronic disease of the tonsils and adenoids (recurrent tonsillitis). Nevertheless, over the last 50 years, we have observed a decline in TE worldwide. As a result, there is an emerging concern of a correlated possible increased risk of tonsil cancer (TC) and other subtypes of oropharyngeal squamous cell carcinoma. Since the available data on such topics are limited and controversial, our aim was to elucidate the impact of TE on the incidence mainly of TC through a systematic review of the literature and a meta-analysis of the studies. After a thorough search, 7 retrospective studies were considered eligible for review and meta-analysis (MA). At MA, patients with a history of TE seem to show a reduced risk of TC but a higher predisposition for base of tongue (BOT) cancer (p<0.001): however, the elevated heterogeneity of the studies hampers drawing firm and convincing conclusions (statistical inconsistency >95%). In future, randomized control trials will be welcome to elucidate the prophylactic role of TE against TC and its real impact on BOT cancer.

Uncommon Sites of Lymphoepithelial Carcinoma in Head and Neck Region.

We present two cases of Lymphoepithelial carcinoma (LEC) which were found in uncommon sites, the first at the right parotid salivary gland and the second at the base of the tongue. Both patients presented with painless neck masses and were diagnosed with histologic analysis. There is an association with Epstein-Barr virus (EBV) infection in the first case, but none was found in the second case. The primary and metastatic LEC are indistinguishable through histological studies. Therefore, examination of nasopharynx and neck imaging is vital to differentiate primary and metastatic LEC in non-nasopharyngeal sites. A collaboration between surgeons and pathologists is essential for accurate diagnosis of LEC. Radiotherapy is the main choice of treatment for LEC, similar to the cases in the nasopharynx.

Surgical Treatment for Advanced Oropharyngeal Cancer: A Narrative Review.

Background and Objectives: to describe current scientific knowledge regarding the treatment options in advanced oropharyngeal cancer. The standard care for advanced oropharyngeal cancer (OPSCC) has been chemoradiotherapy, although surgical approaches followed by adjuvant treatment have been proposed. The best therapy for each patient should be decided by an interdisciplinary tumour-board. Different strategies should be considered for the specific patient's treatment: surgery, chemotherapy and radiation therapy or combinations of them. The treatment choice is influenced by tumour variability and prognostic factors, but it also depends on cancer extension, extranodal extension, nervous invasion, human papilloma virus (HPV) presence, making the decisional algorithm not always clear. HPV-related OPSCC is strongly associated with a favourable overall survival (OS) and disease-free survival rate (DSS); by contrast, HPV-negative OPSCC often flags a worse prognosis. Consequently, the American Joint Committee on Cancer (AJCC) differentiates OPSCC treatment and prognosis based on HPV status. Methods: we carried out a review of current scientific literature to analyze the different indications and limitations of surgical treatment options in OPSCC stage III and IV. Conclusion: robotic surgery or open approaches with reconstructive flaps can be considered in advanced stages, resulting in the de-intensification of subsequent systemic therapy and fewer related side effects. Furthermore, in the event of the primary failure of systemic therapy or disease recurrence, the surgical approach constitutes an additional therapeutic option which lengthens patient survival functions.

Brachytherapy and osteoradionecrosis in patients with base of tongue cancer.

BACKGROUND: Base 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. AIMS: Investigate if patients treated in regions using BT show an increased risk for ORN and whether brachytherapy has any impact on overall survival. MATERIAL AND METHODS: We 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. RESULTS: Fifty 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 SIGNIFICANCE: Brachytherapy ought to be used cautiously for selected patients or within prospective randomized studies.

Targeted Therapy of HPV Positive and Negative Tonsillar Squamous Cell Carcinoma Cell Lines Reveals Synergy between CDK4/6, PI3K and Sometimes FGFR Inhibitors, but Rarely between PARP and WEE1 Inhibitors.

Human papillomavirus positive (HPV+) tonsillar and base of tongue squamous cell carcinoma (TSCC/BOTSCC) have a favorable outcome, but upon relapse, survival is poor and new therapeutical options are needed. Recently, we found synergistic effects by combining the food and drug administration approved (FDA) phosphoinositide 3-kinase (PI3K) and fibroblast-growth-factor-receptor (FGFR) inhibitors BYL719 and JNJ-42756493 on TSCC cell lines. Here this approach was extended and Cyclin-Dependent-Kinase-4/6 (CDK4/6) and Poly-ADP-ribose-polymerase (PARP) and WEE1 inhibitors PD-0332991, and MK-1775 respectively were also examined. HPV+ CU-OP-2, -3, -20, and HPV- CU-OP-17 TSCC cell lines were treated with either BYL719 and JNJ-42756493, PD-0332991 BMN-673 and MK-1775 alone or in different combinations. Viability, proliferation, and cytotoxicity were followed by WST-1 assays and the IncuCyte S3 Live® Cell Analysis System. All inhibitors presented dose-dependent inhibitory effects on tested TSCC lines. Synergy was frequently obtained when combining CDK4/6 with PI3K inhibitors, but only sometimes or rarely when combining CDK4/6 with FGFR inhibitors or PARP with WEE1 inhibitors. To conclude, using CDK4/6 with PI3K or FGFR inhibitors, especially PD-0332991 with BYL719 presented synergy and enhanced the decrease of viability considerably, while although dose dependent responses were obtained with PARP and WEE1 inhibitors (BMN-673 and MK-1775 resp.), synergy was rarely disclosed.

Base of tongue squamous cell carcinomas, outcome depending on treatment strategy and p16 status. A population-based study from the Swedish Head and Neck Cancer Register.

BACKGROUND: The base of tongue squamous cell carcinoma (BOTSCC) is mainly an HPV-related tumor. Radiotherapy (EBRT) ± concomitant chemotherapy (CT) is the backbone of the curatively intended treatment, with brachytherapy (BT) boost as an option. With four different treatment strategies in Sweden, a retrospective study based on the population-based Swedish Head and Neck Cancer Register (SweHNCR) was initiated. MATERIAL AND METHODS: Data on tumors, treatment and outcomes in patients with BOTSCC treated between 2008 and 2014 were validated through medical records and updated as needed. Data on p16 status were updated or completed with immunohistochemical analysis of archived tumor material. Tumors were reclassified according to the UICC 8th edition. RESULTS: Treatment was EBRT, EBRT + CT, EBRT + BT or EBRT + CT + BT in 151, 145, 82 and 167 patients respectively (n = 545). A p16 analysis was available in 414 cases; 338 were p16+ and 76 p16-. 5-year overall survival (OS) was 68% (95% CI: 64-72%), with76% and 37% for p16+ patients and p16- patients, respectively. An increase in OS was found with the addition of CT to EBRT for patients with p16+ tumors, stages II-III, but for patients with tumor stage I, p16+ (UICC 8) none of the treatment strategies was superior to EBRT alone. CONCLUSION: In the present retrospective population-based study of BOTSCC brachytherapy was found to be of no beneficial value in curatively intended treatment. An increase in survival was found for EBRT + CT compared to EBRT alone in patients with advanced cases, stages II and III (UICC 8), but none of the regimes was significantly superior to EBRT as a single treatment modality for stage I (UICC 8), provided there was p16 positivity in the tumor. In the small group of patients with p16- tumors, a poorer prognosis was found, but the small sample size did not allow any comparisons between different treatment strategies.

Targeted Therapy with PI3K, PARP, and WEE1 Inhibitors and Radiotherapy in HPV Positive and Negative Tonsillar Squamous Cell Carcinoma Cell Lines Reveals Synergy while Effects with APR-246 Are Limited.

Human papillomavirus positive (HPV+) tonsillar and base of tongue cancer (TSCC/BOTSCC) is rising in incidence, but chemoradiotherapy is not curative for all. Therefore, targeted therapy with PI3K (BYL719), PARP (BMN-673), and WEE1 (MK-1775) inhibitors alone or combined was pursued with or without 10 Gy and their effects were analyzed by viability, proliferation, and cytotoxicity assays on the TSCC/BOTSCC cell lines HPV+ UPCI-SCC-154 and HPV- UT-SCC-60A. Effective single drug/10 Gy combinations were validated on additional TSCC lines. Finally, APR-246 was assessed on several TSCC/BOTSCC cell lines. BYL719, BMN-673, and MK-1775 treatments induced dose dependent responses in HPV+ UPCI-SCC-154 and HPV- UT-SCC-60A and when combined with 10 Gy, synergistic effects were disclosed, as was also the case upon validation. Using BYL719/BMN-673, BYL719/MK-1775, or BMN-673/MK-1775 combinations on HPV+ UPCI-SCC-154 and HPV- UT-SCC-60A also induced synergy compared to single drug administrations, but adding 10 Gy to these synergistic drug combinations had no further major effects. Low APR-246 concentrations had limited usefulness. To conclude, synergistic effects were disclosed when complementing single BYL719 BMN-673 and MK-1775 administrations with 10 Gy or when combining the inhibitors, while adding 10 Gy to the latter did not further enhance their already additive/synergistic effects. APR-246 was suboptimal in the present context.

Targeted Therapy With PI3K and FGFR Inhibitors on Human Papillomavirus Positive and Negative Tonsillar and Base of Tongue Cancer Lines With and Without Corresponding Mutations.

OBJECTIVES: Human papillomavirus positive (HPV+) tonsillar and base of tongue squamous cell carcinoma (TSCC/BOTSCC), the major subsites of oropharyngeal squamous cell carcinoma (OPSCC) have favorable outcome, but upon relapse, outcome is poor and new therapies needed. Since, phosphatidyl-inositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and fibroblast-growth-factor-receptor-3 (FGFR3) mutations often occur in such tumors, here, we tested targeted therapy directed to such genes in TSCC/BOTSCC cell lines. We also combined the two types of inhibitors with each other, and cisplatin or docetaxel that are used clinically. METHODS: The HPV+ CU-OP-2, -3, -20, UPCI-SCC-154, and HPV- CU-OP-17 and UT-SCC-60A cell lines were first tested for common PIK3CA/FGFR3 mutations by competitive-allele-specific TaqMan-PCR. They were then treated with the food and drug administration (FDA) approved drugs, alpelisib (BYL719) and erdafitinib (JNJ-42756493) alone and in combination with cisplatin or docetaxel. Viability, proliferation, apoptosis and cytotoxicity responses were thereafter followed by WST-1 assays and the IncuCyte S3 Live® Cell Analysis System. RESULTS: HPV+ CU-OP-2 had a pS249C-FGFR3, and like CU-OP-20, a pE545K-PIK3CA mutation, while no other lines had such mutations. Irrespectively, dose dependent responses to all PI3K/FGFR inhibitors were obtained, and upon combining the inhibitors, positive effects were observed. Cisplatin and docetaxel also induced dose dependent responses, and upon combination with the inhibitors, both positive and neutral effects were found. CONCLUSIONS: The data suggest that FDA approved drugs alpelisib and erdafitinib efficiently inhibit TSCC/BOTSCC cell line growth, especially when combined irrespective of presence of corresponding mutations and should be further explored, for use upon recurrent disease.

Whole-Exome Sequencing of HPV Positive Tonsillar and Base of Tongue Squamous Cell Carcinomas Reveals a Global Mutational Pattern along with Relapse-Specific Somatic Variants.

To identify predictive/targetable markers in human papillomavirus positive (HPV+) tonsillar and base of tongue cancer (TSCC/BOTSCC), whole-exome sequencing (WES) of tumours of patients with/without recurrence was performed. Forty primary tumours and adjacent normal tissue were separated by micro-dissection from formalin-fixed paraffin-embedded tissue from patients treated with curative intent 2000-2014 at Karolinska University Hospital. Successful sequencing was obtained in primary tumours of 18 patients without and primaries of 17 with local or distant recurrence, as well as in 10 corresponding recurrences (i.e., five local relapses and five distant metastases) from these 17 patients. One variant-a high-impact deletion in the CDC27 gene-was observed only in primaries of 5/17 patients that had a recurrence after full treatment but in none of those without recurrence. In addition, 3 variants and 26 mutated genes, including CDC27, BCLAF1 and AQP7, were present in at least 30% of all primary tumours independent of prognosis. To conclude, a CDC27 deletion was specific and found in ~30% of samples from patients with a local relapse/distant metastasis and could, therefore, potentially be a prospective marker to predict prognosis. Commonly mutated genes, such as BCLAF1, should be further studied in the context of targeted therapy.

Induction chemotherapy followed by concurrent chemoradiotherapy versus CCRT for locally advanced hypopharynx and base of tongue cancer.

BACKGROUND/AIMS: Clinical trials have not consistently supported the use of induction chemotherapy (IC) for locally advanced head and neck squamous cell cancer. Hypopharynx and base of tongue (BOT) cancer has shown relatively poor survival. We investigated the role of IC in improving outcome over current chemoradiotherapy (CRT) in patients with hypopharynx and BOT cancer. METHODS: Treatment-naïve patients with stage III/IV (M0) hypopharynx or BOT cancer were randomly assigned to receive CRT alone (CRT arm: cisplatin 100 mg/m2 on D1 3-weekly, two times plus radiotherapy 68.4 Gy/30 fractions on weekdays) versus two 21-day cycles of IC with TPF (docetaxel & cisplatin 75 mg/m2 on D1, and fluorouracil 75 mg/m2 on D1-4) followed by the same CRT regimen (IC arm). The primary endpoint was progression-free survival (PFS). RESULTS: This study closed early after enrollment of 36 patients (19 in the CRT arm, 17 in the IC arm). After a median follow-up of 47.2 months, there was no significant difference in PFS: the median PFS was 26.8 months for the CRT arm and was not reached for the IC arm (p = 0.13). However, the survival curves were widely separated with a plateau after 3 years, suggesting a potential survival benefit from IC: 3-year PFS rates were 45% and 68%, and 3-year overall survival rates were 56% and 86%, in the CRT and IC arms, respectively. CONCLUSION: This study failed to demonstrate that induction TPF chemotherapy improves survival in patients with BOT and hypopharynx cancer. However, it suggested a favorable outcome with IC to this population.

Human papilloma virus (HPV) prevalence upon HPV vaccination in Swedish youth: a review based on our findings 2008-2018, and perspectives on cancer prevention.

PURPOSE: Three human papillomavirus (HPV) vaccines are available against up to nine HPV types. In Sweden, from 2012, Gardasil was offered to 10-12 year old girls through the school-based vaccination program, and as catchup vaccination for women up to 26 years. To obtain a baseline, and follow HPV vaccination effects, during 2008-2018, cervical and oral HPV prevalence were followed at a youth clinic in Stockholm, and in 2013 for comparison oral HPV prevalence was examined in high-school youth in a middle-sized county in Sweden. METHODS: In this review, we discuss all our data with cervical and oral mouthwash samples that were collected and tested for 24-27 HPV types by a bead-based multiplex assay from 2008. RESULTS: Compared with 2008-2011, with ~ 35% HPV16 and > 60% high risk (HR) HPV cervical prevalence at the youth clinic, a decrease of vaccine HPV types was observed between 2013 and 2018, with e.g., HPV16 falling to 5% in catchup vaccinated women and 15-18% in nonvaccinated women. Most common cervical HR-HPV types were HPV39, 51, 52, 56, and 59 together accounting for ~ 10% of cervical cancer, and where only HPV52 is included in Gardasil-9. At baseline 2009-2011, oral HPV prevalence was ~ 10% in unvaccinated youth at the youth clinic, but after 2013 it dropped to < 2% at the youth clinic and high schools. CONCLUSION: To conclude, Gardasil HPV types have decreased, but it is still important to follow remaining HR-HPV types and cancer development, since there is an ongoing increase in the incidence of HPV-associated tonsillar and base of tongue cancer, and cervical cancer in Sweden.

A global epidemic increase of an HPV-induced tonsil and tongue base cancer - potential benefit from a pan-gender use of HPV vaccine.

In 2007, human papillomavirus (HPV) type 16 was finally recognized as a risk factor, besides smoking and alcohol, for oropharyngeal squamous cell carcinoma (OPSCC), including tonsillar squamous cell carcinoma (TSCC), by the International Agency for Research against Cancer. Just before, in 2006, the Food and Drug Administration had approved Gardasil, the first vaccine against HPV16, 18, 6 and 11, for preventive vaccination women against cervical cancer. Concurrently, some Western countries, where smoking was decreasing, disclosed an epidemic increase in the incidence of OPSCC, especially of TSCC and base of tongue cancer (BOTSCC), together accounting for 80-90% of all OPSCCs, and mainly affecting men. The epidemic was later revealed to be due to a rise in HPV-positive cases, and scientists in the field suggested HPV vaccination also of boys. Globally, there are roughly 96 000 incident OPSCC cases/year of which 20-24% are caused by HPV, thereby accounting for around 22 000 OPSCC cases annually. Of these cases, 80-90% are due to HPV16 infection and would be prevented with the presently registered HPV vaccines. In Western countries, such as Sweden (with almost 400 TSCC and BOTSCC cases per year) and the United States, HPV prevalence in OPSCC is higher and around 70%. HPV vaccination of girls has been initiated in many countries, and the vaccines have been efficient and their side effects limited. HPV vaccination of boys has, however, been the exception, but should definitely not be delayed any further. It would benefit both girls and boys directly, and result in better and more robust herd immunity. Today, we have the possibility to eliminate several high-risk HPV types in the younger generations and avoid more than 600 000 cancer cases annually worldwide, and this possibility should be embraced by offering global pan-gender HPV vaccination.

In vitro antitumor effects of FGFR and PI3K inhibitors on human papillomavirus positive and negative tonsillar and base of tongue cancer cell lines.

Human papillomavirus positive (HPV+) tonsillar and base of tongue squamous cell carcinoma (TSCC/BOTSCC) have better outcomes than corresponding HPV- negative (HPV-) cancer cases. Our previous study demonstrated that fibroblast growth factor receptor 3 (FGFR3) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit a (PIK3CA) are often mutated in HPV+ cancer. To investigate whether targeted therapy is an option for TSCC/BOTSCC, two HPV+ and one HPV- TSCC/BOTSCC cell lines were tested for their sensitivity towards FGFR and PI3K inhibitors. The HPV+ cell lines UM-SCC-47 and UPCI-SCC-154, and the HPV- cell line UT-SSC-60A were tested by competitive allele-specific TaqMan-PCR for presence/absence of frequently occurring FGFR3 and PIK3CA mutations. All cells were then treated with FGFR inhibitor AZD4547 and PI3K inhibitors BEZ235 and BKM120 alone, or with AZD4547 and BEZ235 in combination. Viability was analyzed using a WST-1 assay, cytotoxicity tested by a CellTox Green cytotoxicity assay, apoptosis analyzed by a Caspase Glo 3/7 assay and proliferation examined with the xCELLigence system. HPV+ UM-SCC-47 and UPCI-SCC-154 cells, and HPV- UT-SSC-60A cells, did not exhibit any common FGFR3 or PIK3CA mutations, but were all sensitive to FGFR inhibitor AZD4547 and PI3K inhibitors BEZ235 and BKM120. Notably, HPV+ UPCI-SCC-154 cells were more sensitive than the other two cell lines. Furthermore, when AZD4547 and BEZ235 treatment was combined in HPV+ UPCI-SCC-154 and HPV- UT-SSC-60A cells, potentiated combination effects were observed. HPV+ UM-SCC-47 and UPCI-SCC-154 cells, and HPV- UT-SSC-60A cells had no common FGFR3 or PIK3CA mutations, but were sensitive to FGFR inhibitor AZD4547, and PI3K inhibitors BEZ235 and BKM120. Furthermore, the latter two cell lines were particularly sensitive to combinations of AZD4547 and BEZ235.

Differences in gene expression between high-grade dysplasia and invasive HPV+ and HPV- tonsillar and base of tongue cancer.

BACKGROUND: Human papillomavirus (HPV) is a causative agent for tonsillar and base of tongue squamous cell carcinoma (TSCC/BOTSCC), as well as for cervical cancer. Premalignant stages in cervical cancer have been studied extensively, while little is known about premalignant stages in TSCC/BOTSCC and the role of HPV. Here we analyzed differences in gene and protein expression between high-grade dysplasia and invasive cancer in both HPV-positive (HPV+ ) and HPV-negative (HPV- ) TSCC/BOTSCC. METHODS: High-grade dysplasia and invasive carcinoma were laser microdissected from HPV+ and HPV- TSCC/BOTSCC tumor sections. Differential gene expression was studied utilizing nanoString RNA-panels and genes of interest were validated on the protein level by immunohistochemistry. RESULTS: Forty genes in the HPV+ tumors showed significantly different expression between high-grade dysplasia and invasive cancer and 33 genes in the HPV- tumors. Five out of the nine most significant pathways showed similar increased activity in invasive cancer as compared to high-grade dysplasia in both HPV+ and HPV- tumors. Lastly, significant differences in protein expression was confirmed for SPARC, psoriasin, type I collagen and galectin-1 in both HPV+ and HPV- tumors. CONCLUSIONS: This is to our knowledge the first study disclosing differences and similarities in gene expression between dysplastic and invasive HPV+ and HPV- TSCC/BOTSCC.

TLR5 and TLR7 are differentially expressed in human papillomavirus-positive and negative base of tongue squamous cell carcinoma, and TLR7 may have an independent prognostic influence.

BACKGROUND: Human papillomavirus-positive (HPV+) base of tongue squamous cell carcinoma (BOTSCC) has a better outcome than corresponding HPV- cancer. TLR5 and TLR7 expression was previously shown to differ depending on HPV - status and correlate with outcome in oropharyngeal squamous cell carcinoma. AIMS/OBJECTIVES: For validation, TLR5 and TLR7 were analyzed in a BOTSCC-cohort for correlation with HPV, survival, CD4+ and CD8+ tumor-infiltrating lymphocyte (TIL) counts, the latter being a well-documented prognostic marker. MATERIALS AND METHODS: BOTSCC biopsies, (49HPV+/28HPV-) were analyzed by immunohistochemistry for TLR5 and TLR7, and correlated with the above parameters. RESULTS: TLR5 expression was more frequently absent/weak than medium/strong in HPV+ compared to HPV- BOTSCC (p < .001). The opposite was observed for TLR7 (p < .007). TLR5 and TLR7 expression did not correlate to survival in either the HPV- or HPV+ cases, or to CD4+ TILs. TLR5, (but not TLR7) expression was correlated to CD8+ TIL counts (p = .023). CONCLUSION AND SIGNIFICANCE: Absent/weak TLR5 and medium/strong TLR7 expression was validated as more frequent in HPV+ compared with HPV- BOTSCC. A correlation between CD8+ TIL counts, and TLR5 expression was disclosed, but not with TLR7. Therefore, it could be useful to investigate TLR7 further as a potential independent prognostic marker.

National Cancer Database Analysis of the effect of brachytherapy on overall survival in patients with base of tongue cancer.

BACKGROUND: We performed an analysis of the National Cancer Database (NCDB) to evaluate overall survival (OS) in patients with base of tongue (BOT) cancer treated with external beam radiation therapy (EBRT) combined with brachytherapy (BT). METHODS: The tongue NCDB Participant User File was used to obtain demographic and clinical patient data. The Kaplan-Meier method was used to determine OS. Significance was determined using univariable and multivariable Cox proportional hazards models. RESULTS: At 3 years, OS was 69.6%, 77.1%, and 63.7% for patients treated with EBRT (n = 27 954), EBRT + BT (n = 209), or BT alone (n = 154), respectively (P = .01). On multivariable analysis, the instantaneous hazard of death for patients receiving EBRT + BT was 25% (Hazard ratio [HR] = 0.75, 95% CI: 0.58-0.98) lower than patients receiving only EBRT (P = .03). CONCLUSIONS: The addition of BT to EBRT in BOT cancer has an OS benefit.

Total Glossectomy With Free Flap Reconstruction: Twenty-Year Experience at a Tertiary Medical Center.

OBJECTIVES/HYPOTHESIS: To characterize the demographics, clinicopathologic characteristics, and treatment and reconstructive outcomes of patients who underwent total glossectomy STUDY DESIGN: Retrospective chart review at an academic tertiary-care medical center. METHODS: All patients who had undergone total glossectomy (as an individual procedure or as part of a more extensive resection) between January 1, 1995 and December 31, 2014 were included in the analysis. Patient characteristics and clinical outcomes were reviewed. RESULTS: Forty-eight patients underwent total glossectomy for oral tongue and base of tongue cancer. The mean age of the patients was 56 (range, 29-92 years). History of tobacco and heavy alcohol use was found in 76% and 11% of patients, respectively. The majority of patients had advanced cancer (91.7% at stage IV), and 60.4% had salvage therapy for recurrent disease. T4 disease comprised 81% of patients. Sixty percent had clinical or radiographic evidence of nodal metastasis. Reconstruction of the defect was performed with free flaps from the rectus abdominus (40%), fibula (25%), anterolateral thigh (23%), and other donor tissues. One- and 5-year survival rates were 42% and 26%, with locoregional and distant recurrence reported at 36% and 25%, respectively. CONCLUSIONS: Total glossectomy for oncologic control is most commonly performed in patients who have stage IV cancers. Despite high reconstructive success rates, the likelihood of locoregional and distance recurrence was high. Most patients can communicate intelligibly and achieve decannulation, but swallowing outcomes remain guarded, especially considering previous irradiation and resection of the base of tongue. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:1087-1092, 2019.

Changes in incidence and prevalence of human papillomavirus in tonsillar and base of tongue cancer during 2000-2016 in the Stockholm region and Sweden.

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.

Overexpression of FGFR3 in HPV-positive Tonsillar and Base of Tongue Cancer Is Correlated to Outcome.

BACKGROUND/AIM: Human papillomavirus-positive (HPV+) tonsillar and base of tongue squamous cell carcinoma (TSCC/BOTSCC) have better outcome than corresponding HPV- cancers. To better individualize treatment, additional predictive markers are needed. Previously, we have shown that mutated fibroblast growth factor receptor 3 protein (FGFR3) was correlated to poorer prognosis and here FGFR3 expression was further analyzed. PATIENTS AND METHODS: One-hundred-fifteen HPV+TSCC/ BOTSCC biopsies were analyzed for FGFR3 by immunohistochemistry (IHC), and 109/115 were analyzed for FGFR3 mutations by Ion Proton sequencing, or by Competitive Allele-Specific Taqman PCR (CAST-PCR). Disease-free survival (DFS) was then calculated according to FGFR3 IHC expression. RESULTS: CAST-PCR was useful for detecting the three most common FGFR3 mutations. Focusing especially on the 98/115 patients with HPV+TSCC/BOTSCC and wild-type FGFR3, high FGFR3 expression correlated to significantly better 3-year DFS, p=0.043. CONCLUSION: In patients with HPV+TSCC/BOTSCC and wild-type FGFR3, overexpression of FGFR3 was correlated with better DFS.