Diagnostic Value of Preoperative uPAR-PET/CT in Regional Lymph Node Staging of Oral and Oropharyngeal Squamous Cell Carcinoma: A Prospective Phase II Trial.

The detection of lymph node metastases is a major challenge in oral and oropharyngeal squamous cell carcinoma (OSCC and OPSCC). 68Ga-NOTA-AE105 is a novel positron emission tomography (PET) radioligand with high affinity to urokinase-type plasminogen activator receptor (uPAR), a receptor expressed on the surfaces of tumor cells. The aim of this study was to investigate the diagnostic value of uPAR-PET/CT (computerized tomography) in detecting regional metastatic disease in patients with OSCC and OPSCC compared to the current imaging work-up. In this phase II trial, patients with OSCC and OPSCC referred for surgical treatment were prospectively enrolled. Before surgery, 68Ga-NOTA-AE105 uPAR-PET/CT was conducted, and SUVmax values were obtained from the primary tumor and the suspected lymph nodes. Histology results from lymph nodes were used as the standard of truth of metastatic disease. The diagnostic values of 68Ga-uPAR-PET/CT were compared to conventional routine preoperative imaging results (CT and/or MRI). The uPAR expression in resected primary tumors and metastases was determined by immunohistochemistry and quantified digitally (H-score). A total of 61 patients underwent uPAR-PET/CT. Of the 25 patients with histologically verified lymph node metastases, uPAR-PET/CT correctly identified regional metastatic disease in 14 patients, with a median lymph node metastasis size of 14 mm (range 3-27 mm). A significant correlation was found between SUVmax and the product of the H-score and tumor depth (r = 0.67; p = 0.003). The sensitivity and specificity of uPAR-PET/CT in detecting regional metastatic disease were 56% and 100%, respectively. When added to CT/MRI, uPAR-PET was able to upstage 2/11 (18%) of patients with occult metastases and increase the sensitivity to 64%. The sensitivity and specificity of 68Ga-NOTA-AE105 uPAR-PET/CT were equivalent to those of CT/MRI. The significant correlation between SUVmax and uPAR expression verified the target specificity of 68Ga-NOTA-AE105. Despite the target specificity, the sensitivity of imaging is too low for nodal staging and it cannot replace neck dissection.

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.

Diagnostic accuracy of combined optical- and radio-guided SNB for neck staging of oral squamous cell carcinoma lesions in the anterior oral cavity.

PURPOSE: The purpose was to investigate the diagnostic performance of bimodal optical and radio-guided sentinel node biopsy (SNB) for oral squamous cell carcinoma (OSCC) sub-sites in the anterior oral cavity. METHODS: Prospective study of 50 consecutive patients with cN0 OSCC scheduled for SNB was injected with the tracer complex Tc99m:ICG:Nacocoll. A near-infrared camera was applied for optical SN detection. Endpoints were modality for intraoperative SN detection and false omission rate at follow-up. RESULTS: In all patients, a SN could be detected. In 12/50 (24%) of cases, the SPECT/CT showed no focus in level 1, but intraoperatively a SN in level 1 was optically detected. In 22/50 cases (44%), an additional SN was identified only due to the optical imaging. At follow-up, the false omission rate was 0%. CONCLUSION: Optical imaging appears to be an effective tool to allow real-time SN identification comprising level 1 unaffected by possible interference of radiation site from the injection.

Dysphagia and QoL 3 Years After Treatment of Oropharyngeal Cancer With TORS or Radiotherapy.

OBJECTIVE(S): To investigate dysphagia and quality of life (QoL) outcomes 3 years after treatment of oropharyngeal cancer with either primary trans oral robotic surgery (TORS) or radiotherapy (RT). METHODS: A prospective cohort study conducted at the Copenhagen University Hospital. Endpoints were objective swallowing function, examined using fiberoptic endoscopic evaluation of swallowing (FEES) and video fluoroscopy (VF). QoL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core (EORTC QLQ-C30), Head & Neck Module (EORTC QLQ-HN35), and MD Anderson Dysphagia Inventory (MDADI). A comparison was made between 1-, and 3-year results. RESULTS: Forty-four patients were included prior to treatment, 31 treated with TORS and 13 with RT. One-year results for this cohort have previously been published (https://doi.org/10.1080/00016489.2020.1836395). Significant improvement on FEES in retention at the piriform sinus was noted in both groups. Patients treated with TORS had improved safety scores as well as dynamic imaging grade of swallowing toxicity (DIGEST) and efficiency scores, whereas patients treated with RT only had improvements in the latter two. Improvement in QoL scores was only noted for patients treated with TORS in composite MDADI scores. CONCLUSION: We found significant improvements in objective swallowing function from one to 3 years after treatment, particularly in patients treated with TORS. However, these improvements were not reflected as clinically meaningful improvements in QoL. LEVEL OF EVIDENCE: 3, cohort follow-up study Laryngoscope, 133:1893-1898, 2023.

Enhanced recovery after microvascular reconstruction in head and neck cancer - A prospective study.

Objectives: Patients undergoing microvascular reconstruction after head and neck cancer typically have several comorbidities, and the procedures are often followed by complications and prolonged hospitalization. Consequently, the application of enhanced recovery after surgery (ERAS) for these patients undergoing microvascular reconstruction has gained attention in recent years. ERAS is a peri- and postoperative care concept that has repeatedly shown beneficial results for a wide variety of surgical procedures, including microvascular reconstruction. This study presents the results after the introduction of our ERAS protocol for head and neck cancer reconstruction. Methods: We prospectively treated 30 consecutive patients according to our ERAS protocol from June 2019 to December 2020 and compared the results of the treated patients with those of patients treated with our traditional recovery after surgery (TRAS) protocol. We are based on our ERAS protocol on the following core elements of recovery: improved patient information, goal-directed fluid therapy, minimally invasive surgery, opioid-sparing multimodal analgesia, early ambulation, and pre-defined functional discharge criteria. Results: The baseline characteristics of the groups were comparable. The ERAS group had a significantly shorter length of stay (13.1 vs. 20.3 days, p < 0.001), significantly shorter time to ambulation (3.0 days vs. 6.4 days, p < 0.001), shorter time to removal of nasogastric tube (13.3 days vs. 22.7 days, p = 0.05), and fewer tracheostomies performed (10% vs. 90%, p < 0.001). There were no differences in complications, flap survival, or 30-day re-admissions between the two groups. Conclusion: The introduction of ERAS in patients with head and neck cancer undergoing microvascular reconstruction seems safe and results in improved recovery. Level of evidence: 3.

[Transoral robotic surgery for the head and neck].

Transoral robotic surgery (TORS) has been utilized in the head and neck field for more than a decade. It is a minimally invasive technique which ensures flexible instrumentation and 3D visualization of the oropharynx. This has led to a paradigm shift in the treatment of early-stage oropharyngeal cancer and in the diagnostic management of unknown primary of the head and neck. Over time, the indications for TORS have broadened. This review discusses the development, current indications, and future perspectives of TORS within head and neck surgery.

Expression patterns of uPAR, TF and EGFR and their potential as targets for molecular imaging in oropharyngeal squamous cell carcinoma.

The clinical introduction of molecular imaging for the management of oropharyngeal squamous cell carcinoma (OPSCC) relies on the identification of relevant cancer­specific biomarkers. The application of three membrane­bound receptors, namely urokinase­type plasminogen activator receptor (uPAR), tissue factor (TF) and EGFR have been previously explored for targeted imaging and therapeutic strategies in a broad range of solid cancers. The present study aimed to investigate the expression patterns of uPAR, EGFR and TF by immunohistochemistry (IHC) to evaluate their potential for targeted imaging and prognostic value in OPSCC. In a retrospective cohort of 93 patients with primary OPSCC, who were balanced into the 45 human papillomavirus (HPV)­positive and 48 HPV­negative groups, the IHC­determined expression profiles of uPAR, TF and EGFR in large biopsy or tumor resection specimens were analyzed. Using the follow­up data, overall survival (OS) and recurrence­free survival were measured. Specifically, associations between survival outcome, biomarker expression and clinicopathological factors were examined using Cox proportional hazards model and log­rank test following Kaplan­Meier statistics. After comparing the expression pattern of biomarkers within the tumor compartment with that in the adjacent normal tissues, uPAR and TF exhibited a highly tumor­specific expression pattern, whereas EGFR showed a homogeneous expression within the tumor compartment as well as a consistent expression in the normal mucosal epithelium and salivary gland tissues. The positive expression rate of uPAR, TF and EGFR in the tumors was 98.9, 76.3 and 98.9%, respectively. No statistically significant association between biomarker expression and survival outcome could be detected. Higher uPAR expression levels had a trend towards reduced OS according to results from univariate analysis (P=0.07; hazard ratio=2.01; 95% CI=0.92­4.37). Taken together, these results suggest that uPAR, TF and EGFR may be suitable targets for molecular imaging and therapy in OPSCC. In particular, uPAR may be an attractive target owing to their high positive expression rates in tumors and a highly tumor­specific expression pattern.

Human papillomavirus testing in metastatic squamous cell carcinoma of the neck with unknown primary using PCR on fine-needle aspiration smears: a prospective clinical study.

PURPOSE: Squamous cell carcinoma metastasis of the head and neck with unknown primary tumor (CUP) comprises a diagnostic challenge. Human papillomavirus (HPV) testing on cytologic specimens is gaining increasing focus as this may facilitate an early diagnosis of HPV-induced oropharyngeal carcinoma. This study aimed to prospectively assess PCR-based HPV-DNA testing on FNA smears in a clinical setting. METHODS: Patients referred to a tertiary Head and Neck Cancer Center with suspected CUP were included from November 2016 to November 2018. Scraped cell material from FNA smears was analyzed for HPV-DNA with PCR using general primers (GP5 + /GP6 +) and correlated with the origin and histology of the primary tumor (oropharynx vs. outside oropharynx or benign tumor). The turn-around time reflecting the workflow for HPV-DNA testing by PCR was also calculated. RESULTS: A total of 93 patients were enrolled in the study. The sensitivity and specificity were 86.7% [95% CI 75.4-94.1%] and 92.0% [95% CI 74.0-99.0%], and the positive and negative predictive values were 96.3% [95% CI 87.3-99.0%] and 74.2% [95% CI 59.9-84.7%], respectively. The turn-around time for HPV testing was a mean four calendar days. CONCLUSION: HPV-DNA testing on FNA smears can be performed within a reasonable timeframe and can guide for the detection of an HPV-positive oropharyngeal primary tumor in the clinical setting for patients presenting with CUP of the head and neck.

Nasal vestibule squamous cell carcinoma: a population-based cohort study from DAHANCA.

BACKGROUND: Cancer of the nasal vestibule is a rare type of malignancy dominated by squamous cell carcinoma (SCC), and with poor survival. The treatment is either radiotherapy, surgery or a combination of both. Previous studies have shown a 5-year disease-specific survival of 74% and overall survival (OS) of 50%.Our objective was to describe the consecutive cohort of patients diagnosed with SCC of the nasal vestibule in Denmark from 2008 until 2018 and evaluate prognostic factors and treatment outcome using locoregional failure (LRF), disease-specific mortality (DSM), and OS as endpoints. METHODS: All patients diagnosed with SCC of the nasal vestibule from 2008 until 2018 were identified in the nationwide clinical database, DAHANCA and were followed for LRF and death (DSM and OS) until March 2021. OS was analysed using Kaplan-Meier estimator, and cumulative incidence of LRF and DSM were analysed using the Aalen-Johansen estimator. Analysis of prognostic factors was performed using Cox proportional hazard models. RESULTS: A total of 162 patients were identified. The median age was 71 years and 54% were male. Disease stage at the time of diagnosis were stage I (70%), II (17%), III (2%) and IV (11%). Curatively intended treatment was performed in 146 patients (90%), of which treatment failure occurred in 42 patients (29%). Most failures occurred at the primary tumour site (64%). Cancer Patient Pathways recommended time to treatment was fulfilled in 71% of patients. The 5-year OS and DSM in patients treated with curative intent were 65% and 11%, respectively. Stage was a significant independent prognostic factor. No difference in LRF, DSM or OS were shown between the applied treatments. CONCLUSIONS: Stage is the main independent prognostic factor, and failure most commonly appear at the primary tumour site.

Days alive and out of hospital following transoral robotic surgery: Cohort study of 262 patients with head and neck cancer.

BACKGROUND: Days alive and out of hospital (DAOH) is a validated outcome in clinical trials, since it reflects procedure-associated morbidity and mortality. Transoral robotic surgery (TORS) has become a widely adopted procedure with increasing demand for knowledge and data on morbidity. METHODS: Retrospective single-center assessment of a prospective TORS database comprising patients treated for malignancy between 2013 and 2018 using DAOH to describe procedure- and disease-related morbidity the first 12-postoperative months. RESULTS: For 262 patients, median DAOH365 was 357 days (IQR 351-360). Indications for TORS were (i) primary curative resection (61%), (ii) salvage resection (15%), and (iii) diagnostic work-up of cancer of unknown primary in the head and neck (24%). Median DAOH365 was 359 days (IQR 351-361 days), 348 days (IQR 233-355), and 357 days (351-361), respectively. Pneumonia had the highest impact in DAOH365 reduction. CONCLUSION: Total median DAOH365 after TORS was 357 days. The main cause leading to DAOH365 reduction was pneumonia.

Nasopharyngeal malignancies in Denmark diagnosed from 1980 to 2014.

OBJECTIVES: Nasopharyngeal malignancies are reported having decreasing incidence and reduced mortality. This study provides a nationwide update of the incidence and survival in Denmark. MATERIALS AND METHODS: The Danish Cancer Registry (DCR) and Central Population Register (CPR) were used to identify all patients registered with nasopharyngeal malignancies between 1980 and 2014 in Denmark. We evaluated the age-adjusted incidence rate (AAIR), average annual percent change (AAPC) and relative survival (RS) and also constructed age-population-cohort (APC) models. RESULTS: 911 patients were identified with a male:female ratio of 2.2:1, a median age of 57.7 years (range 2.8-98.3 years) and an overall median follow-up time of 2.7 years (range 0-37 years). The AAIR was 0.39 cases per 100 000 in 1980 and 0.28 cases per 100 000 in 2014 with an AAPC of -3.2 (95% CI: -7.5; 1.2, p = 0.1). The overall 1-year and 5-year RS rates were 76.3% and 42.1%, respectively. We found a significant age effect in the APC model for the incidence of nasopharyngeal malignancies, but no significant cohort or period effects. CONCLUSION: The incidence of nasopharyngeal carcinomas has slightly decreased over the last four decades, however insignificantly. Meanwhile, the relative survival has increased significantly in Denmark since 1980. The cause of improved relative survival might be attributed to altered treatment practices.

Long-term survival outcomes after primary transoral robotic surgery (TORS) with concurrent neck dissection for early-stage oropharyngeal squamous cell carcinoma.

BACKGROUND: In 2013, transoral robotic surgery (TORS) was implemented as a protocolled treatment alternative to the traditional radiotherapy (RT) in Denmark for oropharyngeal squamous cell carcinoma (OPSCC). In 2017, we published our first prospective feasibility study, showing that TORS with concurrent neck dissection successfully achieved negative margins in 29 out of 30 patients (97%) with early-stage OPSCC. AIMS/OBJECTIVES: This follow-up study aims to evaluate the five-year overall survival (OS), disease-specific survival (DSS) and recurrence-free survival (RFS). METHODS: Retrospective follow-up study including 30 patients treated with TORS for early-stage OPSCC (T1-T2, N0-N1, M0, UICC 7th edition) from September 2014 to January 2016 at a single head and neck cancer centre in Denmark. The five-year OS, DSS and RFS, including a detailed analysis of the recurrences, were addressed. RESULTS: The five-year OS, DSS and RFS was 90%, 93% and 87%, respectively. Median follow-up was 54.5 months. Four patients developed a recurrence, with one regional, one distant metastatic (M) and two locoregional recurrences. The median time to recurrence was 24 months (range 3-42 months). CONCLUSIONS AND SIGNIFICANCE: This follow-up study demonstrates good five-year OS, DSS and RFS in a prospective cohort of patients undergoing TORS and neck dissection for early-stage OPSCC.

[Head and neck ultrasound examination].

Head and neck ultrasound examination is increasingly used as point-of-care imaging among clinicians from different specialities to improve the diagnostic workup and perform ultrasound-guided interventions. Ultrasound can provide immediate information about morphology and anatomic relation of lumps and bumps of the neck and guide treatment of various lesions varying from patients with putative head and neck cancer to patients with acute neck abscess. This review describes the principles of a systematic head and neck ultrasound examination and the most common pathologies diagnoses with benefit by ultrasound.

Manuscript title: the maxillary swing approach - the first Scandinavian experience.

BACKGROUND: The maxillary swing approach was introduced three decades ago in the head and neck field providing optimal surgical exposure for tumors in the nasopharyngeal and/or the retromaxillary space. OBJECTIVES: To report the clinical experience, patient surgical morbidity and survival outcomes following the introduction of the maxillary swing approach in Denmark. MATERIAL AND METHODS: A retrospective study including patients who underwent the maxillary swing approach from January 2012 - January 2020. Baseline and perioperative data, pathology, postoperative morbidity and survival outcomes were registered. RESULTS: Sixteen patients were included of which 15 had a malignant tumor with different histology, while one patient had a benign tumor. Most commonly reported short-term morbidity were trismus, cheek hypoesthesia, nasopalatal fistula, lacrimation and nasal stenosis (<3 months postoperatively) improving markedly at 12 months follow-up. For patients with malignant tumors, the 5-year overall survival and recurrence-free survival rates were 60% and 66.7%, respectively. CONCLUSIONS AND SIGNIFICANCE: The maxillary swing approach was safely implemented by a multidisciplinary team at a high-volume centralized head and neck cancer center in Denmark. The procedure may be considered for salvage surgery of recurrent nasopharyngeal carcinomas and selected malignant and benign tumors located in the nasopharynx and/or retromaxillary space inaccessible by other surgical modalities.

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.

Incidence and survival of salivary gland cancer in children and young adults in Denmark: A nation-wide study for the period 1990-2015.

OBJECTIVES: The aim of this study was to evaluate incidence and survival of children and young adults with salivary gland cancer (SGC) in Denmark during the period 1990-2015. METHOD: We included all patients aged 0-24 years registered with primary SGC in the Danish Cancer Registry, the Danish Pathology Data Bank, or the DAHANCA database during 1990-2015. Patients were divided in two age-groups: children (0-17 years) and young adults (18-24 years). Incidence rates, overall survival (OS), and recurrence free survival (RFS) was evaluated in relation to age-group, sex, tumor location, tumor histology, and T-, N-, and M-classification. RESULTS: A total of 70 SGC patients between 0 and 24 years (67% female, n = 47) were included. Thirty-six were children at time of diagnosis, and 34 were young adults. The incidence was higher among young adults compared to children (0.29 vs. 0.11 per 100.000) and showed no significant change during the study period. There were no differences in the distribution of sex, tumor location, or tumor histology between children and young adults. The total 5 and 15-year survival rates were 97.1% and 91.7% for OS, and 97.1% and 83.1% for RFS. The survival rates showed no significant differences according to age-groups, sex, tumor location, or tumor histology. Patients diagnosed in stage T4 had significantly worse OS and RFS. CONCLUSION: The incidence of SGC among children and young adults in Denmark was low and stable in the period 1990-2015. The overall survival was very high, demonstrating the excellent prognosis for children and young adults with SGC.

Long-term quality of life & functional outcomes after treatment of oropharyngeal cancer.

Functional and QoL outcomes were compared longitudinally in a cohort of patients treated for oropharyngeal squamous cell carcinoma (OPSCC) with primary transoral robotic surgery (TORS) or radiotherapy (RT). Forty-four patients undergoing primary TORS (n = 31) or RT (n = 13) for any stage OPSCC were included. Only low-stage disease was treated with TORS. Functional outcomes were: salivary flow rate, image-based swallowing function, and a self-reported 10-point scale comparing current swallowing function to baseline (CvB scale). QoL was assessed with European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core (EORTC QLQ-C30), Head & Neck Module (EORTC QLQ-HN35), and MD Anderson Dysphagia Inventory (MDADI). Shoulder impairment was assessed with Neck Dissection Impairment Index (NDII) and Oxford Shoulder Score (OSS). In the RT group, salivary flow rates had significantly declined at 12-month follow-up, with the biggest declines in QoL subscale scores recorded in the RT group for dry mouth and sticky saliva. Swallowing function on imaging studies was overall good, with no severe dysphagia within 1 year although, both treatment groups showed significant deterioration relative to baseline at the 12-month follow-up with increased DIGEST scores and pharyngeal retention. Shoulder impairment was rare at 1 year in both groups. A comprehensive examination of this cohort treated for OPSCC showed overall good functional and QoL outcomes 1 year after treatment. However, persistent impairment was seen in both groups with regards to swallowing function. In the TORS group, at 12-months follow-up, the QoL questionnaires showed worse scores in only one subscale (sticky saliva).