Surgeon-performed Outpatient Transoral and Transcervical Ultrasound of the Oropharynx

Study Overview
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Brief Summary
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The purpose of the study is to compare the sensitivity and specificity of transoral ultrasound, transcervical ultrasound, Magnetic Resonance Imaging (MRI) and Positron Emission Tomography-Computerized Tomography (PET-CT) in terms of detecting primary oropharynx tumors.

Detailed Description
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A prospective study will be performed at the head & neck departments at Copenhagen University Hospital - Rigshospitalet, Zealand University Hospital - Køge, and Aarhus University Hospital in Denmark. Patients referred with a suspected cancerous lesion of the oropharynx will be invited to participate in this study. With written informed consent, a surgeon-performed outpatient transoral and transcervical examination of the tonsils and tongue base is conducted as an addition to the clinical workup at the head & neck departments. Clinical work-up includes palpation of the oropharynx, flexible endoscopic exam with narrow-band imaging and neck ultrasound. Ultrasound of the oropharynx will be performed using small-footprint, high-frequency (minimum 15MHz) transducers for transoral ultrasound. A lower-frequency (between 2-9 MHz) curved transducer will be used for transcervical ultrasound. If a suspected tumor is visualized, the location is noted and the surgeon performing clinical examination is informed. MRI will be performed on all patients, and two expert neuroradiologist blinded to ultrasound results will separately assess all images for tumor detection, greatest tumor size and T-stage. Interrater reliability analysis will be performed comparing the tumor detection, greatest tumor size and T-stage between both MRI readers. In case of patients with suspected cervical metastasis with no suspected primary tumor on initial clinical exam, a PET-CT will also be performed and compared blinded to ultrasound and MRI. The ultrasound operator will be blinded to all MRI and PET-CT results. Surgeons performing initial clinical work-up, the ultrasound operators, neuroradiologist and nuclear medicine physician will register tumor detection (sub-location specific) and greatest tumor size immediately and prospectively, blinded to histopathology. Prospective gathered data will be registered on standardized data collection sheets or in REDCap using the same standardized variables. All scanning modalities will be evaluated blinded to each other but not to clinical findings. Tumor detection: Suspected tumor locations from clinical evaluation with narrowband imaging and palpation, ultrasound, MRI, and PET-CT will be categorized according to the following criteria: Right tonsil Left tonsil Right tongue base Left tongue base Right overlapping tonsil and tongue base Left overlapping tonsil and tongue base Other oropharynx (soft palate, uvula, anterior and posterior pharyngeal arches, posterior oropharynx wall, and vallecula) Multiple tumor locations The examiners' tumor suspicion confidence will be rated with a 5-point Likert scale ranging from 0, very low suspicion - 5, very high suspicion. The surgeon will also mark on a pictogram of the oropharynx with the biopsy location(s) numbered according to the histopathology registered biopsy locations. Tumor size and staging: If a tumor is visualized or palpated, the greatest tumor diameter will be measured in three dimensions with clinical palpation, ultrasound, and MRI. T-staging will be estimated according to the Union for International Cancer Control 8th edition TNM-staging system: Tx: Unknown primary tumor. T1: Tumor <20 mm in greatest diameter. T2: Tumor 21-40 mm in greatest diameter. T3: Greatest size >40mm or extension to the lingual surface of the epiglottis T4: Invasion of the extrinsic tongue muscles, larynx, pterygoid muscles, hard palate, mandible, carotids nasopharynx or skull base (yes, no, indeterminate). Additional variables: We will prospectively register the study center, date of outpatient ultrasound, ultrasound machine used, doctor performing the ultrasound scan, patient Mallampati 4-point score, Patient mouth opening measured in millimeters between incisors, patient self-reported discomfort from transoral ultrasound and palpation examinations (Supplementary Figure 2), ultrasound scan quality, MRI scan quality and PET-CT scan quality. Quality will be registered on a 5-point Likert scale (1, Very poor quality - 5, excellent quality). The following data will be registered from medical charts: patient age, sex, tobacco smoking, alcohol consumption, date of first clinical contact, date of MRI scan performed, date of PET/CT scan performed, date of available histopathology results and date of treatment initiation. Ultrasound video clips and B-mode images will be stored for retrospective descriptive evaluation of the following characteristics: Tumor shape (smooth/rounded, irregular/lobular). Tumor border delineation (well-circumscribed, unclear). Tumor heterogeneity (homogeneous, heterogeneous). Doppler flow compared to contralateral side (decreased, equivocal, increased). Doppler flow characteristics (peripheral/circumferential, internal organized, internal chaotic) Reference standard: Final histopathology biopsy results will define the presence of cancer as binary results (no cancer vs. cancer present). An expert head and neck pathologist will re-evaluate biopsies results if inconclusive. The presence of a tumor in a correct sub-location assessed by final Multidisciplinary Team (MDT) conference will be used to define correct tumor location. Greatest tumor size and T-stage will also be determined by final MDT decision, considering the clinical and radiological findings. For patients with available complete tumor resections, a secondary analysis will be performed using the histopathologic reported greatest tumor diameter as reference standard.

Official Title
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Surgeon-performed Outpatient Transoral and Transcervical Ultrasound Compared to MRI for the Diagnostic Workup of Primary Oropharynx Tumors: the SPOT-US Trial

Conditions
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Oropharynx Cancer, Tonsil Cancer, Base of the Tongue Tumor, Tonsil Hypertrophy, Tonsil Ulcer, Tonsil Neoplasm, Tonsil Lymphoma, Base of Tongue Carcinoma

Intervention / Treatment
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* Diagnostic Test: Transoral Ultrasound
* Diagnostic Test: Transcervical Ultrasound


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Initially assessed by a specialist otorhinolaryngologist with clinical suspicion of head and neck cancer and referred to fast-track cancer work-up. Any of the following objective or subjective symptoms: Visible and/or palpable tumors of the oropharynx. Asymmetry of the tonsils or tongue base. Symptoms including dysphagia, throat pain, and/or referred otalgia where an oropharynx tumor is suspected but not clinically visible. Suspected cervical lymph node metastasis with no visible/palpable primary tumor. Lateral neck cysts in patients aged 40+ years. Adult patients aged 18+ years. Understands Danish or English and can give written informed consent. Exclusion criteria: Prior radiotherapy to the oropharynx. Prior oropharynx cancer. MRI of the oropharynx or PET-CT already performed 3 months prior to inclusion.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Interventional Model Description: The intervention (transoral and transcervical ultrasound) is performed on all included patients. All patients will also receive a standard MRI of the oropharynx. All tumors will be biopsy verified.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Outpatient Oropharynx Ultrasound<br>Transoral and/or Transcervical ultrasound of the oropharynx | Diagnostic Test: Transoral Ultrasound<br>* The oropharynx is scanned using high-frequency, small-footprint ultrasound transducers placed onto the suspected oropharynx sub-locations (e.g. tonsils or tongue base). Lidocaine spray or gel will be applied prior to scanning to reduce the gag reflex.<br>Diagnostic Test: Transcervical Ultrasound<br>* Curved low-frequency ultrasound transducers will be placed on the submental region on the skin of the neck, and the tongue base will be visualized in the midline in transverse and sagittal planes. The tonsils will be visualized adjacent to the tongue base on either side in oblique transverse and oblique sagittal planes, deep to the submandibular glands.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumors detected by clinical evaluation, ultrasound, MRI, and PET-CT compared to the reference standard histopathology results. | Sub-location specific detection of tumors in the oropharynx will be assessed blinded to histopathology. The final histopathology diagnosis will typically be available within two weeks. | 2 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Greatest tumor diameter in millimeters estimated with clinical evaluation, ultrasound and MRI. | The greatest tumor diameter is measured in millimeters. | 1 minute | 
| Categorical T-stage estimated with clinical evaluation, ultrasound, and MRI. | Categorized according to the Union for International Cancer Control 8th edition TNM-staging system. Tumors will be categorized double-blinded between ultrasound and MRI. | 1 minute | 
| Tonsil and tongue base tumor volume estimated with clinical evaluation, ultrasound and MRI. | Volume is calculated from three perpendicular greatest tumor diameters if available. The volume formula for an ellipse is used: 3/4 * pi * (height/2) * (width/2) * (length/2). | 1 minute |