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.

Six-month mortality has decreased for patients with curative treatment intent for head and neck cancer in Sweden.

BACKGROUND: In general, survival outcomes for patients with Head and Neck Cancer (HNC) has improved over recent decades. However, mortality within six months after diagnosis for curative patients remains at approximately 5%. The aim of this study was to identify risk factors for early death among patients with curative treatment, and furthermore, to analyze whether the risk of early death changed over recent years. MATERIAL AND METHOD: This real-world, population-based, nationwide study from the Swedish Head and Neck Cancer Register (SweHNCR) included all patients ≥18 years diagnosed with HNC with a curative treatment intent at the multidisciplinary tumor board from 2008 to 2020. A total of 16,786 patients were included. RESULTS: During the study period a total of 618 (3.7%) patients with curative-intended treatment died within six months of diagnosis. Patients diagnosed between 2008 and 2012 had a six-month mortality rate of 4.7% compared to 2.5% for patients diagnosed between 2017 and 2020, indicating a risk reduction of 53% (p <0.001) for death within six months. The mean time to radiation therapy from diagnosis in the 2008-2012 cohort was 38 days, compared to 22 days for the 2017-2020 cohort, (p <0.001). The mean time to surgery from diagnosis was 22 days in 2008-2012, compared to 15 days for the 2017-2020 cohort, (p <0.001). Females had a 20% lower risk of dying within six months compared to males (p = 0.013). For every year older the patient was at diagnosis, a 4.8% (p <0.001) higher risk of dying within six months was observed. Patients with a WHO score of 1 had approximately 2.4-times greater risk of early death compared to WHO 0 patients (p <0.001). The risk of early death among WHO 4 patients was almost 28 times higher than for WHO 0 patients (p <0.001). Patients with a hypopharyngeal tumor site had a 2.5-fold higher risk of dying within six months from diagnosis compared to oropharyngeal tumor patients (p <0.001). CONCLUSIONS: We found that the risk of early death decreased significantly from 2008 to 2020. During this period, the mean time to the start of treatment was significantly reduced both for surgery and oncological treatment regimes. Among patients with a curative treatment intention, increased risk of early death was associated with male sex, older age, advanced disease, increased WHO score, and a hypopharyngeal tumor site.

Carcinomas of the minor salivary glands of the oral cavity. A population-based study from the Swedish Head and Neck Cancer Register for 2008-2018.

BACKGROUND AND OBJECTIVES: Carcinomas of the minor salivary glands are rare with a heterogeneous pathology. This study explored the demographics, histology, treatment and survival in the Swedish population over 11 years. MATERIAL AND METHODS: Cases of salivary gland carcinomas in the oral cavity were extracted from the 'Swedish Head and Neck Cancer Register' (2008-2018). Statistical analyses with cross tabulation, age grouping, chi-square, the Kaplan-Meier method and log-rank tests were performed. RESULTS: Three hundred thirty cases were included (62% female; mean age 60 years; 83% were WHO Performance Status 0). The carcinomas were mostly stage I (57%), and the most common site was the palate with 165 tumours (50%). The most common histology was mucoepidermoid carcinoma (30%), followed by polymorphous low-grade adenocarcinoma (25%) and adenoid cystic carcinoma (24%). The distribution of histology differed between age groups. The five-year predicted overall survival rate was 83%. Most patients (89%) were treated with primary surgery. CONCLUSION AND SIGNIFICANCE: The demographics, histology, and survival of minor salivary gland carcinomas in the oral cavity in the Swedish population correspond well with previously published material. The demographics and histology differ from carcinomas of the major salivary glands in the same population.

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.

Radiological imaging of the neck for initial decision-making in oral squamous cell carcinomas--a questionnaire survey in the Nordic countries.

BACKGROUND: Fast and accurate work-up is crucial to ensure the best possible treatment and prognosis for patients with head and neck cancer. The presence or absence of neck lymph node metastases is important for the prognosis and the choice of treatment. Clinical lymph node (N)-staging is done by palpation and diagnostic imaging of the neck. We investigated the current practice of the initial radiological work-up of patients with oral squamous cell carcinomas (OSCC) in the Nordic countries. METHODS: A questionnaire regarding the availability and use of guidelines and imaging modalities for radiological N-staging in OSCC was distributed to 21 Head and Neck centres in Denmark (n = 4), Finland (n = 5), Iceland (n = 1), Norway (n = 4) and Sweden (n = 7). We also asked for a description of the radiological criteria for determining the lymph nodes as clinical positive (cN+) or negative (cN0). RESULTS: All 21 Head and Neck centres responded to the questionnaire. Denmark and Finland have national guidelines, while Norway and Sweden have local or regional guidelines. Seventeen of the 19 centres with available guidelines recommended computed tomography (CT) of the cN0 neck. The waiting time may influence the imaging modalities used. Lymph node size was the most commonly used criteria for radiological cN+, but the cut-off measures vary from 0.8 to 2.0 cm. CONCLUSION: Overall, CT is the most commonly recommended and used imaging modality for OSCC. Despite availability of national guidelines the type and number of radiological examinations vary between centres within a country, but the implementation of a fast-track programme may facilitate fast access to imaging. The absence of uniform criteria for determining the lymph nodes of the neck as cN+ complicates the comparison of the accuracy of the imaging modalities. Well-defined radiological strategies and criteria are needed to optimise the radiological work-up in OSCC.

A national study of health-related quality of life in patients with cancer of the base of the tongue compared to the general population and to patients with tonsillar carcinoma.

BACKGROUND: This exploratory, registry-based, cross-sectional study aimed to evaluate patients' health-related quality of life (HRQOL) in a subsite of oropharyngeal cancer: cancer of the base of the tongue (CBT). METHODS: CBT patients, treated with curative intent, completed the EORTC QLQ-C30 and QLQ-H&N35 questionnaires 15 months after diagnosis. The HRQOL of CBT patients was compared to reference scores from the general population and to that of tonsillar carcinoma patients. RESULTS: The 190 CBT patients scored significantly worse than members of the general population on most scales. CBT patients with human papilloma virus (HPV)-positive tumors had significantly better HRQOL on 8 of 28 scales than HPV-negative patients. Compared to 405 tonsillar carcinoma patients, CBT patients had significantly worse HRQOL on 8 of the 28 scales, the majority local head and neck related problems. CONCLUSION: One year after treatment, CBT patients' HRQOL was significantly worse in many areas compared to that of the general population and slightly worse than that of tonsillar carcinoma patients.

Swedish National Multicenter Study on Head and Neck Cancer of Unknown Primary: Prognostic Factors and Impact of Treatment on Survival.

Introduction Head and neck cancer of unknown primary (HNCUP) is a rare condition whose prognostic factors that are significant for survival vary between studies. No randomized treatment study has been performed thus far, and the optimal treatment is not established. Objective The present study aimed to explore various prognostic factors and compare the two main treatments for HNCUP: neck dissection and (chemo) radiation vs primary (chemo) radiation. Methods A national multicenter study was performed with data from the Swedish Head and Neck Cancer Register (SweHNCR) and from the patients' medical records from 2008 to 2012. Results Two-hundred and sixty HNCUP patients were included. The tumors were HPV-positive in 80%. The overall 5-year survival rate of patients treated with curative intent was 71%. Age ( p < 0.001), performance status ( p = 0.036), and N stage ( p = 0.046) were significant factors for overall survival according to the multivariable analysis. Treatment with neck dissection and (chemo) radiation (122 patients) gave an overall 5-year survival of 73%, and treatment with primary (chemo) radiation (87 patients) gave an overall 5-year survival of 71%, with no significant difference in overall or disease-free survival between the 2 groups. Conclusions Age, performance status, and N stage were significant prognostic factors. Treatment with neck dissection and (chemo) radiation and primary (chemo) radiation gave similar survival outcomes. A randomized treatment study that includes quality of life is needed to establish the optimal treatment.

Health-related quality of life among tonsillar carcinoma patients in Sweden in relation to treatment and comparison with quality of life among the population.

BACKGROUND: The health-related quality of life (HRQOL) of tonsillar carcinoma survivors was explored to investigate any HRQOL differences associated with tumor stage and treatment. The survivors' HRQOL was also compared to reference scores from the population. METHODS: In this exploratory cross-sectional study patients were invited 15 months after their diagnosis and asked to answer two quality of life questionnaires (EORTC QLQ- C30, EORTC QLQ- HN35), 405 participated. RESULTS: HRQOL was associated with gender, with males scoring better than females on a few scales. Patients' HRQOL was more associated with treatment than tumor stage. Patients' HRQOL was worse than that in an age- and sex-matched reference group from the normal population, the largest differences were found for problems with dry mouth followed by problems with sticky saliva, senses, swallowing and appetite loss. CONCLUSIONS: The tonsillar carcinoma patients had a worse HRQOL compared to the general population one year after treatment.

Swedish National Multicenter Study on Head and Neck Cancer of Unknown Primary: Prognostic Factors and Impact of Treatment on Survival

Abstract Introduction Head and neck cancer of unknown primary (HNCUP) is a rare condition whose prognostic factors that are significant for survival vary between studies. No randomized treatment study has been performed thus far, and the optimal treatment is not established. Objective The present study aimed to explore various prognostic factors and compare the two main treatments for HNCUP: neck dissection and (chemo) radiation vs primary (chemo) radiation. Methods A national multicenter study was performed with data from the Swedish Head and Neck Cancer Register (SweHNCR) and from the patients' medical records from 2008 to 2012. Results Two-hundred and sixty HNCUP patients were included. The tumors were HPV-positive in 80%. The overall 5-year survival rate of patients treated with curative intent was 71%. Age (p< 0.001), performance status (p= 0.036), and N stage (p= 0.046) were significant factors for overall survival according to the multivariable analysis. Treatment with neck dissection and (chemo) radiation (122 patients) gave an overall 5-year survival of 73%, and treatment with primary (chemo) radiation (87 patients) gave an overall 5-year survival of 71%, with no significant difference in overall or disease-free survival between the 2 groups. Conclusions Age, performance status, and N stage were significant prognostic factors. Treatment with neck dissection and (chemo) radiation and primary (chemo) radiation gave similar survival outcomes. A randomized treatment study that includes quality of life is needed to establish the optimal treatment.

Laminin-5 gamma 2: a marker to identify oral mucosal lesions at risk for tumor development?

Mucosal lesions of various types are frequently encountered in the oral cavity and a limited proportion of these will eventually progress to invasive cancer. Neither macroscopic nor microscopic evaluation can give reliable information concerning risk for cancer development which is why a marker indicating high risk for tumor progression would be of significant value. Laminins are a family of alpha beta gamma heterotrimeric proteins found in basement membranes and earlier studies have shown that laminin-5 gamma 2 expression is a useful marker of invasiveness in head and neck squamous cell carcinomas. Unique material comprising 36 different oral mucosal lesions from 15 patients, prior to the development of invasive carcinoma (12 cases) or cancer in situ (CIS) (3 cases) on the same site, was investigated. For controls we had mucosal lesions from 15 patients without malignant progression. These 15 lesions matched with the specific site in the oral cavity of the initial patients. The minimum follow-up time for the control group was at least 36 months. We performed immunohistochemical staining with a monoclonal antibody against the recombinant gamma 2 chain of laminin-5 in the archived biopsies of preneoplastic oral lesions. Nine out of 15 cases of preneoplastic lesions which became invasive/CIS were laminin-5-positive (60%) whereas only 3 out of 13 (2 were excluded due to sparse material for laminin-5 analysis) lesions which did not progress were laminin-5-positive (23%) (p = 0.05). The results indicate that oral mucosal lesions expressing laminin-5 show an increased risk for tumor progression.

The gamma2 chain of laminin-5 as an indicator of increased risk for recurrence in T1 stage tongue cancer.

BACKGROUND: Treatment of small, localized tongue cancer is an act of balance between sufficiently extensive surgery and/or radiotherapy for safe cure, and minimizing treatment-related morbidity. The biological aggressiveness of these cancers is variable and conventional histopathology does not give sufficient information concerning the risk for local or regional recurrence. Laminin-5 is an extracellular matrix protein noted to have special importance for epithelial cell invasion. PATIENTS AND METHODS: We investigated 43 diagnostic biopsies from patients with T1 tongue cancer treated with wedge excision only. Immunohistochemical analysis was performed using a polyclonal antibody against the gamma2 chain of laminin-5. RESULTS: Thirty-six specimens were evaluated and 16 patients had a recurrence. A staining pattern of 50% or more was seen in the majority of patients (75%) with tumor recurrence and in fewer patients (45%) without recurrence. CONCLUSION: In order to optimize treatment for the individual T1 tongue cancer patient, immunostaining against laminin-5 appears to be one possible useful tool.

Image cytometry DNA-analysis of fine needle aspiration cytology to aid cytomorphology in the distinction of branchial cleft cyst from cystic metastasis of squamous cell carcinoma: a prospective study.

OBJECTIVE: Frequently, the distinction between branchial cleft cyst and cystic metastases from squamous cell carcinoma is difficult by cytomorphology. In a prospective study, we investigated the need for, and the value of, image cytometry DNA-analysis as a complement to cytologic evaluation of cystic lesions in the neck. STUDY DESIGN: Image cytometry DNA-analysis was performed on the fine needle aspiration cytology smears from 50 patients, referred to our department, with a solitary cystic lesion in the lateral region of the neck. METHODS: Smears from aspirates were Giemsa stained and cytologically evaluated. Ahrens image analysis was used for DNA analysis on smears stained with Schiff reagent, and lymphocytes were used as control cells. Epithelial cells with DNA values exceeding 5c were regarded as aneuploid, indicating malignancy. RESULTS: Nine lesions were diagnosed as squamous cell cancer metastases cytologically. DNA analysis showed aneuploidy in all of them except one. Three of these lesions had earlier been diagnosed as branchial cleft cyst at the referring hospital. Eight lesions were cytologically inconclusive and four of them were revealed as cystic metastasis at histopathologic analysis, and DNA analysis showed aneuploidy in all but one, which could not be analyzed. Two of these lesions were also diagnosed as branchial cleft cysts at the referring hospital. All benign lesions were diploid. Nine lesions were thyroid and salivary gland lesions. CONCLUSION: Image cytometry DNA-analysis was shown to help in the distinction between benign and malignant cystic lesions. Thus, when conventional cytomorphology does not suffice, DNA-analysis is clearly a valuable supplement.

The clinical value of image cytometry DNA analysis in distinguishing branchial cleft cysts from cystic metastases of head and neck cancer.

OBJECTIVES/HYPOTHESIS: A branchial cleft cyst presents as a lump in the neck that, generally, is easily cured by surgical excision. The preoperative diagnosis is based on clinical examination and, especially in the Scandinavian countries, fine-needle aspiration cytology. However, at times, the histopathological analysis of the excised cyst reveals a cystic metastasis of squamous cell carcinoma of the head and neck. If adequate diagnosis could be obtained preoperatively, patients would most likely fare better. The study was performed to investigate whether the diagnostic accuracy for these lesions could be improved preoperatively by image cytometry DNA analysis of the fine-needle aspiration cytology specimen. STUDY DESIGN: Image cytometry DNA analysis was performed on the preoperative fine-needle aspiration cytology specimen and the surgical specimens from 51 patients with solitary cysts in the lateral region of the neck. Thirty-six patients were selected because there was a discrepancy between findings on fine-needle aspiration cytology and the final histopathological diagnosis or an uncertain cytological diagnosis. There were 25 metastatic squamous cell carcinomas and 3 thyroid cancers, there was 1 lymphoma and 1 sialoadenitis, and there were 21 branchial cleft cysts. METHODS: The cytodiagnostic Giemsa-stained slides were destained in Methanol and then stained with Schiff's reagent. The paraffin-embedded material from excised cysts were cut and deparaffinized and then stained with Schiff's reagent. Ahrens image analysis was used for DNA analysis and lymphocytes were used as control cells. DNA valves exceeding 5c was regarded as aneuploid. RESULTS: Image cytometry DNA analysis of the preoperative cytological specimen was possible in 41 of 51 patients. We found that in 53% of the cases with cystic metastasis, image cytometry DNA analysis, when possible, revealed aneuploidy, thus indicating malignancy. DNA analysis showed diploidy in all benign cases. CONCLUSIONS: Aneuploidy is highly specific for malignancy. Image cytometry DNA analysis increases the diagnostic sensitivity for malignant cystic metastasis and therefore is a valuable supplement to conventional cytological study for these lesions.

Human papillomavirus is more common in base of tongue than in mobile tongue cancer and is a favorable prognostic factor in base of tongue cancer patients.

The frequency of human papilloma virus (HPV) and its influence on clinical outcome was analyzed retrospectively in pre-treatment paraffin embedded biopsies from 110 patients with tongue cancer. The presence of HPV DNA was examined in 85 mobile tongue tumors and 25 base of tongue tumors by a polymerase chain reaction (PCR) with 2 general primer pairs, GP5+/6+ and CPI/IIG. When HPV-DNA was found, HPV-type specific primers and direct sequencing were used for HPV sub-type verification. Twelve of 110 (10.9%) samples were HPV-positive; 9 for HPV-16, 1 for HPV-33, 1 for HPV-35 and 1 could not be analyzed because of shortage of DNA. HPV was significantly more common in base of tongue tumors (10/25, 40.0%) compared to tumors of the mobile tongue (2/85, 2.3%). The influence of HPV on clinical outcome in mobile tongue cancer could not be studied, due to that HPV was present in too few cases. Of the 19 patients with base of tongue cancer that were included in the survival analysis, however, 7 patients with HPV-positive base of tongue cancer had a significantly favorable 5-year survival rate compared to the 12 HPV-negative patients. In conclusion, HPV is significantly more common in base of tongue cancer than in mobile tongue cancer, and has a positive impact on disease-specific survival in patients with base of tongue cancer.