Comparison of Transoral and Transcervical Ultrasonography with MRI for the Diagnostic Work-Up of Oropharynx Tumors: A Protocol for a Multicenter Clinical Trial (SPOTUS).

This study protocol for a prospective, multicenter, diagnostic, clinical trial describes the integration of transoral and transcervical ultrasonography (US) in the initial clinical work-up of patients referred to tertiary head and neck cancer centers with suspected oropharyngeal cancer. The study evaluates the blinded detection rate of oropharyngeal tumors and their US-estimated size and T-stage before histopathology and cross-sectional imaging are available. Magnetic resonance imaging (MRI) scans will be prospectively rated while blinded to T-site histopathology and US. The primary outcome measures of diagnostic accuracy, including sensitivity, specificity, positive and negative predictive values, and overall accuracy, will be reported for both US and MRI. A sub-analysis of prospectively rated 18F-Fluorodeoxyglucose (FDG) positron emission tomography/computerized tomography (PET/CT) scans in patients with clinically suspected unknown primary tumors will also be compared to US and MRI. Secondary outcome measures, including a comparison of tumor size estimation between US, MRI, and CT, will also be reported. This prospective multicenter study will provide clinically impactful information regarding the use of transoral and transcervical US for the diagnostic work-up of oropharyngeal cancer.

Intraoral Ultrasound versus MRI for Depth of Invasion Measurement in Oral Tongue Squamous Cell Carcinoma: A Prospective Diagnostic Accuracy Study.

Oral squamous cell carcinoma (OSCC) of the tongue is the most common type of oral cavity cancer, and tumor depth of invasion (DOI) is an important prognostic factor. In this study, we investigated the accuracy of intraoral ultrasound and magnetic resonance imaging (MRI) for assessing DOI in patients with OSCC. Histopathological measurement of DOI was used as a reference standard. We conducted a prospective study including patients planned for surgical treatment of OSCC in the tongue. The DOI was measured in an outpatient setting by intraoral ultrasound and MRI, and was compared to the histopathological DOI measurements. Bland-Altman analysis compared the mean difference and 95% limits of agreement (LOA) for ultrasound and MRI, and the Wilcoxon signed-rank test was used to test for significance. The correlation was evaluated using Pearson's correlation coefficient. We included 30 patients: 26 with T1 or T2 tumors, and 4 with T3 tumors. The mean difference from histopathology DOI was significantly lower for ultrasound compared to MRI (0.95 mm [95% LOA -4.15 mm to 6.06 mm] vs. 1.90 mm [95% LOA -9.02 mm and 12.81 mm], p = 0.023). Ultrasound also led to significantly more correct T-stage classifications in 86.7% (26) of patients compared to 56.7% (17) for MRI, p = 0.015. The Pearson correlation between MRI and histopathology was 0.57 (p < 0.001) and the correlation between ultrasound and histopathology was 0.86 (p < 0.001). This prospective study found that intraoral ultrasound is more accurate than MRI in assessing DOI and for the T-staging of oral tongue cancers. Clinical practice and guidelines should implement intraoral ultrasound accordingly.

Transoral Ultrasound in the Outpatient Clinic for the Diagnostic Work-Up of Oropharyngeal Cancer: A Feasibility Study.

Magnetic resonance imaging (MRI) is the preferred imaging modality for oropharyngeal cancers (OPCs), but it has difficulties distinguishing between small OPCs and unilateral tonsil hypertrophy. We hypothesized that surgeon-performed transoral ultrasound (US) could be used to accurately detect T-stage OPCs. We performed a single-center prospective diagnostic accuracy study including patients with suspected or biopsy-verified OPCs during outpatient appointments. All patients were offered transoral US and MRI. If transoral US could not be tolerated by the patient, transcervical US was performed. The primary outcome was the diagnostic accuracy of detecting OPCs with US compared to MRI, using histopathology as the reference standard. The secondary outcome was comparing the primary tumor diameters between US and MRI blinded to each other. Out of the 26 patients included in the study, 21 (81%) had OPCs. Transoral US could be performed in 21/21 and 1/5 patients with suspected palatine and lingual tonsil OPCs, respectively. Overall, US diagnostic accuracy was 92%, compared to 81% with MRI (p = 0.37). US and MRI had a high correlation between tumor diameters in the anteroposterior diameter (R = 0.80, p < 0.001), corresponding to the depth axis on US. In conclusion, this small study showed the promise and feasibility of transoral US to improve the initial clinical evaluations of patients with suspected OPCs.

3D Ultrasound and MRI in Assessing Resection Margins during Tongue Cancer Surgery: A Research Protocol for a Clinical Diagnostic Accuracy Study.

Surgery is the primary treatment for tongue cancer. The goal is a complete resection of the tumor with an adequate margin of healthy tissue around the tumor.Inadequate margins lead to a high risk of local cancer recurrence and the need for adjuvant therapies. Ex vivo imaging of the resected surgical specimen has been suggested for margin assessment and improved surgical results. Therefore, we have developed a novel three-dimensional (3D) ultrasound imaging technique to improve the assessment of resection margins during surgery. In this research protocol, we describe a study comparing the accuracy of 3D ultrasound, magnetic resonance imaging (MRI), and clinical examination of the surgical specimen to assess the resection margins during cancer surgery. Tumor segmentation and margin measurement will be performed using 3D ultrasound and MRI of the ex vivo specimen. We will determine the accuracy of each method by comparing the margin measurements and the proportion of correctly classified margins (positive, close, and free) obtained by each technique with respect to the gold standard histopathology.

Epidemiology, outcomes, and prognostic factors in submandibular gland carcinomas: a national DAHANCA study.

PURPOSE: The aim of this study is to present incidence, histological subtypes, survival rates, and prognostic factors based on a national cohort of patients with salivary gland carcinoma. METHODS: All Danish patients with submandibular gland carcinoma diagnosed from 1990 to 2015 (n = 206) were included and analyzed following histological re-evaluation. Data were collected by the Danish Head and Neck Cancer Group (DAHANCA). Overall, disease-specific and recurrence-free survival were evaluated. Prognostic factors were analyzed with multivariate Cox Hazard Regression. RESULTS: The study population consisted of 109 (53%) men and 97 (47%) women, median age 62 years (range 11-102). Adenoid cystic carcinoma was the most frequent subtype (50%). Tumour classification T1/T2 (75%) and N0 (78%) was most frequent. The mean crude incidence was 0.17/100,000/year. Most patients (n = 194, 94%) were treated with primary surgery, and 130 (67%) received postoperative radiotherapy. The 5- and 10-year survival rates were for overall survival 64% and 41%, disease-specific survival 74% and 61%, and recurrence-free survival 70% and 56%, respectively. Survival rates were higher for adenoid cystic carcinoma compared to other subtypes, but the difference was not significant in multivariate analysis. Recurrence occurred in 69 patients, and 37 (53.6%) of them had recurrence in a distant site. Advanced T-classification and regional lymph-node metastases had significant negative impact on survival rates. CONCLUSION: The incidence of submandibular gland carcinoma in Denmark was 0.17/100,000/year and stable during the time period. The most frequent subtype was adenoid cystic carcinoma. Half of the recurrences presented in a distant site, and multivariate analysis confirmed that advanced stage was independent negative prognostic factor for recurrence and survival.

An HPV-Vaccinated Patient With Human Papillomavirus-Positive Oropharyngeal Squamous Cell Carcinoma.

This case report describes an extremely early-onset case of human papillomavirus­positive oropharyngeal squamous cell carcinoma in a Norwegian woman in her early 20s.

3D Ultrasound versus Computed Tomography for Tumor Volume Measurement Compared to Gross Pathology-A Pilot Study on an Animal Model.

The margin of the removed tumor in cancer surgery has an important influence on survival. Adjuvant treatments, prognostic complications, and financial costs are required when the pathologist observes a close/positive surgical margin. Ex vivo imaging of resected cancer tissue has been suggested for margin assessment, but traditional cross-sectional imaging is not optimal in a surgical setting. Instead, three-dimensional (3D) ultrasound is a portable, high-resolution, and low-cost method to use in the operation room. In this study, we aimed to investigate the accuracy of 3D ultrasound versus computed tomography (CT) to measure the tumor volume in an animal model compared to gross pathology assessment. The specimen was formalin fixated before systematic slicing. A slice-by-slice area measurement was performed to compare the accuracy of the 3D ultrasound and CT techniques. The tumor volume measured by pathological assessment was 980.2 mm3. The measured volume using CT was 890.4 ± 90 mm3, and the volume using 3D ultrasound was 924.2 ± 96 mm3. The correlation coefficient for CT was 0.91 and that for 3D ultrasound was 0.96. Three-dimensional ultrasound is a feasible and accurate modality to measure the tumor volume in an animal model. The accuracy of tumor delineation on CT depends on the soft tissue contrast.

Differences in gene expression despite identical histomorphology in sinonasal intestinal-type adenocarcinoma and metastases from colorectal adenocarcinoma.

Sinonasal intestinal-type adenocarcinoma (sITAC) is histomorphologically indistinguishable from colorectal adenocarcinoma (CRC) leading to diagnostic challenges. Metastases from CRCs to the sinonasal tract have been reported. The aim of the study was to identify a biomarker making it possible to distinguish between sITAC and metastases of colorectal origin. Formalin-fixated paraffin-embedded (FFPE) tissue from 20 consecutive patients with sITAC treated at Rigshospitalet, Denmark from 2005 to 2017, 20 patients with CRC, and second patients with both sinonasal and colorectal carcinomas were included, and RNA-sequencing was performed on all samples. Moreover, a series of 26 samples from metastasizing CRC were included (in-house data). 3139 differentially expressed genes were identified, of these several were deemed as possible biomarkers, including CSDE1, for which immunohistochemical staining was performed. sITAC and CRC differ in genomic expression. CSDE1, previously found upregulated in CRC, was significantly differentially expressed. Using immunohistochemical staining, no sITACs displayed strong and diffuse staining for CSDE1, which represents a potential marker to use in distinguishing sITAC from a metastasis of colorectal origin. This knowledge could improve the diagnostic process and hopefully the outcome in patients with this rare tumor.

Impact of human papillomavirus in sinonasal cancer-a systematic review.

BACKGROUND: Human papillomavirus (HPV) is an established prognostic marker in oropharyngeal squamous cell carcinoma. Currently, the role of HPV in sinonasal carcinoma is being explored. OBJECTIVES: This systematic review addresses the role of HPV in sinonasal cancer, establishing the occurrence of HPV-positive cancers and the influence of HPV-positivity on prognosis in sinonasal cancer as well as the utility of the putative surrogate marker of HPV (p16) in sinonasal cancer. MATERIAL AND METHODS: Studies were identified with searches of Medline via PubMed and Embase via OVID (4 May 2020). Articles on original research concerning sinonasal cancer and HPV in humans written in English were included. Case reports with less than five cases were excluded. RESULTS: Initially, 545 articles were identified; 190 duplicate articles were removed leaving 355 articles for title/abstract screening. Title/abstract screening excluded 243 articles, leaving 112 studies assessed for eligibility. After full-text screening, 57 studies were included. All articles investigated the significance of HPV in sinonasal carcinomas. HPV was reported in approximately 30% of sinonasal squamous cell carcinoma (SNSCC), where it was associated with a better prognosis. In sinonasal cancer, p16 is associated with diagnostic pitfalls and a putative utility of p16 in SNSCC has yet to be established. HPV was not frequently reported in other types of sinonasal carcinomas, besides the recently described subtype, HPV-dependent Multiphenotypic Sinonasal Carcinoma. In other types of sinonasal carcinoma, HPV is not frequently found. CONCLUSION: Approximately 30% of SNSCC are HPV-positive. HPV-positivity in SNSCC is associated with improved survival. HPV occurs only rarely in other sinonasal cancers. There is currently not sufficient evidence for p16 as a surrogate marker of HPV in SNSCC.

Surgical treatment of the neck in patients with salivary gland carcinoma.

BACKGROUND: Elective neck dissection (END) in patients with salivary gland carcinoma is controversial and there are no universally accepted guidelines. METHODS: Patients were identified from the Danish Head and Neck Cancer Group. Between 2006 and 2015, 259 patients with primary salivary gland carcinoma were treated with END. Variables potentially associated with regional metastases were analyzed using logistic regression. Neck recurrence-free survival was calculated using the Kaplan-Meier method. RESULTS: Occult metastases were found in 36 of the patients treated with END (14%) and were particularly frequent among patients with T3/T4 tumors and high-grade histology tumors. In multivariate analyses, high-grade histology and vascular invasion were associated with occult metastases. CONCLUSION: We recommend END of levels II and III for patients with high-grade or unknown histological grade tumors, and for T3/T4 tumors. Levels I, II, and III should be included in END in patients with submandibular, sublingual, or minor salivary gland carcinomas.

Prognostic scoring models in parotid gland carcinoma.

BACKGROUND: The aim was to identify prognostic factors and test three prognostic scoring models that predicted the risk of recurrence in patients with parotid gland carcinoma. METHODS: All Danish patients with parotid gland carcinoma, treated with curative intent, from 1990 to 2015 (n = 726) were included. Potential prognostic factors were evaluated using Cox regression and competing risk analyses. The concordance of each prognostic model was estimated using Harrel's C index. RESULTS: The study population consisted of 344 men and 382 women, with a median age of 63 years. Age above 60 years, high grade histology, T3/T4 tumor, regional lymph node metastases, and involved surgical margins were all associated with a significant reduction in recurrence-free survival. The prognostic model that agreed best with actual outcomes had a C-index of 0.76. CONCLUSION: Prognostic scoring models may improve individualized follow-up strategies after curatively intended treatment for patients with parotid gland carcinoma.

Salivary gland carcinoma in Denmark: a national update and follow-up on incidence, histology, and outcome.

PURPOSE: Salivary gland carcinoma is a rare disease and studies on epidemiology and outcome require data collection over many years. The aim of this study is to present an update of incidence rates, anatomical sites, histological subtypes, and survival rates based on the Danish national cohort of salivary gland carcinoma patients. METHODS: Data from all Danish patients with salivary gland carcinoma diagnosed from 1990 to 2015 (n = 1601) were included and analyzed following histological reevaluation and reclassification. Overall, disease-specific, and recurrence-free survival were evaluated. Prognostic factors were analyzed with multivariate Cox Hazard Regression. RESULTS: The study population consisted of 769 men and 832 women, median age 62 years (range 6-102). The most frequent anatomic site was the parotid gland (51.8%). Adenoid cystic carcinoma was the most common subtype (24.7%). The majority had tumor classification T1/T2 (65.3%). The mean crude incidence was 1.2/100.000/year with an increase of 1.5% per year. There was no increase in age-adjusted incidence. The 5-, 10-, and 20-year survival rates were for overall survival 68, 52, and 35%, for disease-specific survival, 77, 69, and 64%, and for recurrence-free survival, 75, 64, and 51%, respectively. Age, high-grade histological subtype, advanced T-classification, cervical lymph node metastases, vascular invasion, and involved surgical margins had significantly negative impact on survival rates. CONCLUSION: The age-adjusted incidence has been stable for a period of 26 years. Multivariate analysis confirmed that histological grade, advanced stage, involved surgical margins and vascular invasion are independent negative prognostic factors. Survival rates were stationary compared to earlier reports.

Major driver mutations are shared between sinonasal intestinal-type adenocarcinoma and the morphologically identical colorectal adenocarcinoma.

PURPOSE: The purpose of our study was to compare genomic changes in sinonasal intestinal-type adenocarcinoma (sITAC) and colorectal adenocarcinoma (CRC), as they are histomorphologically indistinguishable. This can cause diagnostic difficulties as sinonasal tumours initially diagnosed as sITAC may represent metastasis from CRC, a frequent cancer. Previous studies have not uncovered the underlying mechanism behind the histomorphological resemblance. METHODS/PATIENTS: Tissue samples from all consecutive patients with sITAC at our facility (20 patients) were compared to samples from 20 patients with CRC as well as samples from 2 patients with both CRC and sinonasal tumours. DNA sequencing was performed using Illumina TruSight Oncology 500 panel consisting of 523 cancer-associated genes. Frequent mutations were inspected manually using the Integrative Genomics Viewer. RESULTS: Several well-known cancer-associated genes were mutated in the CRC group, but also in the sinonasal ITAC group. These genes included APC mutated in 65% of the CRC group and 37% of the sinonasal ITAC group, and TP53 mutated in 65% of CRC samples and 58% of ITAC samples. These shared mutations may explain the histomorphological similarities. Successful DNA sequencing was performed on the colorectal sample from one of the two patients with both CRC and sinonasal tumour. Comparing mutations in these samples from one patient we have shown that the sinonasal tumour in all probability was a CRC metastasis. CONCLUSION: We have identified several genetic similarities between sITAC and CRC. This discovery brings us closer to understanding mechanisms behind the development of sITAC-and hopefully in the future targeted therapy.

The current epidemic of HPV-associated oropharyngeal cancer: An 18-year Danish population-based study with 2,169 patients.

BACKGROUND: The objectives of this study were to investigate the incidence of high-risk genotypes of human papillomavirus (HPV) in tumours of patients with oropharyngeal squamous cell carcinoma (OPSCC) during an 18-year period in Eastern Denmark. METHODS: In this population-based, consecutive, semi-national registry study, all patients diagnosed with OPSCC from 2000 to 2017 in Eastern Denmark were evaluated at head and neck oncological departments at public university hospitals. Analyses included tumour characteristics (HPV-positive [HPV+] versus HPV-negative [HPV-]), age-adjusted incidence rates (AAIRs), average annual percentage change (AAPC) of OPSCC, and patient demographics. All HPV+ cases from 2011 to 2017 were genotyped. RESULTS: In total, 55% of 2169 OPSCC cases were HPV+. HPV16, HPV33, HPV35 or other types were found in 86%, 7.4%, 3.4% and 3.2% of cases, respectively. The AAIR per 100,000 of all OPSCCs was 1.8 in 2000, which increased to 5.1 in 2017 (HPV+: threefold increase, HPV-: twofold increase). The AAPC from 2000 to 2017 increased by 7% (HPV+ increased by 10% and HPV- by 4%). The median age at diagnosis for all OPSCC cases increased during the 18-year study period (HPV+: 58-61 years, p < 0.001; HPV-: 60-65 years, p < 0.001). CONCLUSION: We report a threefold increase in OPSCC incidence during the 18-year observation period and a significant increase in median age at diagnosis. Over 93% of HPV genotypes in HPV+ OPSCC are included in current HPV vaccines except for HPV35 (4%). HPV vaccination of both sexes is advised to halt this emerging cancer epidemic.

Incidence and survival of hypopharyngeal cancer: a Danish Nation-Wide Study from 1980 to 2014.

Objectives: To evaluate changes in incidence and survival of patients diagnosed with hypopharyngeal cancer (HPC) in Denmark in the period 1980-2014.Methods: All patients registered with HPC in the Danish Cancer Registry (DCR) in the period 1980-2014 were included. Age-adjusted incidence rates (AAIRs), average annual percentage change in incidence, and overall survival were calculated.Results: Two thousand and nine patients were included (79.7% men). The overall AAIR increased significantly from 0.3 per 100,000 to 1.1 per 100,000 during the study period, corresponding to an increase of 4.1% per year. The most frequent histology was squamous cell carcinoma (SCC) comprising 90.3%. The overall five-year survival increased with 13.5 percentage points from 13.4% in the period 1980-1985 to 26.9% in the period 2010-2014. Women demonstrated better survival compared to men with a hazard ratio of 0.83, and patients with SCC had better survival compared to the remaining histology groups.Conclusions: This nation-wide study, covering nearly four decades, showed a significant increase in incidence and survival of HPC in Denmark.

Incidence and survival of laryngeal cancer in Denmark: a nation-wide study from 1980 to 2014.

Background: The purpose of this registry study was to evaluate trends in incidence and survival of laryngeal cancer in the Danish population from 1980 to 2014. Methods: This study includes all patients with laryngeal cancer registered in the Danish Cancer Registry (DCR) in the period 1980-2014. The age-adjusted incidence rate (AAIR) per 100,000 and average annual percent change (AAPC) were calculated. We evaluated the relative survival at five years in relation to gender, anatomical location, year at diagnosis, and histological type. Further, an age-period-cohort (APC) model of incidence was constructed. Results: A total of 8748 patients (82% males) were included. The median age at diagnosis was 60 years, range 18-101 years. The AAIR decreased from 3.6 per 100,000 in 1980 to 2.3 per 100,000 in 2014 with an AAPC of -0.8% (p < .008). Considering the anatomic location, we found that glottic cancer had a significantly better survival at five years compared to the other locations. We observed no significant difference in survival for supraglottic, subglottic and larynx unspecified cancer during the observation period. During the period 1980-2014, we found no improvement in five year relative survival. Conclusions: This nation-wide study reports a significant decrease in the incidence of laryngeal cancer. Glottic cancer had a significantly better survival at five years compared to other locations.