Transoral and Cervical Ultrasound of Patients With Suspected Oropharyngeal Cancer

Surgeon-performed Transoral and Cervical Ultrasound of the Palatine and Lingual Tonsils in Patients With Suspected Oropharyngeal Cancer - a Research Proposal for a Multicenter, Randomized Clinical Trial

Introduction The current diagnostic approach for patients with suspected oropharyngeal cancer involves a combination of clinical examination, tissue sampling, and relevant cross-sectional imaging. Previous studies have shown that transoral and cervical ultrasound (US) of the palatine and lingual tonsils has a better diagnostic accuracy than clinical investigation and magnetic resonance imaging (MRI) in patients with suspected oropharyngeal cancer, but it has not been established whether adding this scan to the diagnostic workup has a clinical impact.

Methods A randomized controlled study, including 170 patients at four different Head and Neck Hospital departments in Denmark. One group receives standard diagnostics (control group), and the other group receives standard diagnostics supplemented by transoral and cervical ultrasound of the lingual and palatine tonsils. The diagnostic accuracy, number of correct biopsies, number of imaging modalities ordered, and time to final diagnosis are noted.

Conclusion This randomized controlled study examines whether the implementation of transoral and cervical ultrasound of the palatine and lingual tonsils in patients with suspected oropharyngeal cancer will improve the diagnostic accuracy and have a clinical impact. This concerns more accurate initial diagnoses, more correct biopsies, fewer unnecessary scans, and fewer visits to the outpatient clinic.

Study Overview

• Status: Recruiting
• Conditions: Ultrasound; Oropharyngeal Carcinoma
• Intervention / Treatment: Diagnostic test: Ultrasound of the oropharynx

Detailed Description

Introduction The incidence of oropharyngeal cancer is rising globally. The diagnostic approach for patients with suspected oropharyngeal cancer includes clinical examination and tissue samples in the outpatient clinic (biopsies), followed by relevant cross-sectional imaging (computed tomography (CT), magnetic resonance imaging (MRI), and sometimes 18F-Fluorodeoxyglucose (FDG) positron emission tomography/CT (PET/CT)).

It can be challenging to distinguish small oropharyngeal cancers from benign unilateral tonsil hypertrophy by clinical examination and relevant cross-sectional imaging. Small tumors of the palatine- or lingual tonsils may appear as normal oropharyngeal lymphoid tissue in the clinic and on CT and MRI scans, and normal tonsillar asymmetry can resemble an oropharyngeal cancer. The enhanced metabolic activity of the lingual and palatine tonsils on a PET-CT can blur abnormal activity from a small tumor, and increased one-sided metabolic activity due to inflammation raises suspicion of malignancy. This results in expensive, and, in some cases, painful additional interventions such as biopsies, diagnostic surgeries, and additional cross-sectional imaging.

By far the most common sublocation of oropharyngeal cancers is the palatine and lingual tonsils. Advances in ultrasound (US) technology and smaller high-frequency (>15 MHz) transducers make the palatine and lingual tonsils more accessible for examination. This is done by using a transoral approach, where the transducer can reach the palatine and lingual tonsil directly with access via the oral cavity. Garset-Zamani et al. describe how transoral and cervical US of the palatine and lingual tonsils have a significantly higher diagnostic accuracy than clinical examination and MRI in patients with suspected oropharyngeal cancer.

Cervical US for oropharyngeal cancer diagnostics is demonstrated in several studies. Coquia et al. describe how cervical US can be used to visualize tumors in the lingual and palatine tonsils, advocating for its possibility to fill a gap in tumor characterization, adding information gathered by MR and CT.

US is a low-cost, easily accessible, radiation-free dynamic imaging modality. No previous randomized trials have investigated whether the addition of cervical and transoral US improves the diagnostic accuracy and has a clinical impact. Possible clinical benefits include more accurate initial diagnoses, improved biopsy accuracy, fewer unnecessary scans, fewer outpatient clinic visits, and fewer diagnostic surgeries. In summary, achieving a more precise diagnosis with fever interventions. Should this research prove successful, it could lead to the implementation of US of the palatine and lingual tonsils in the outpatient cancer clinic and substantial advancements in oropharyngeal cancer management.

Research question In patients referred to the outpatient cancer clinic suspected of oropharyngeal cancer, does a clinical examination including transoral and cervical ultrasound, compared with a standard clinical examination alone, improve diagnostic accuracy and have a clinical impact?

Methods

Study design A prospective multicenter randomized controlled trial investigates transoral and cervical US for detecting primary tumors in patients referred for suspicion of oropharyngeal cancer.

The second Surgeon-Performed Oropharyngeal Transoral UltraSonography (SPOT-US-2) is a randomized controlled study of patients seen in the outpatient cancer clinic on suspicion of oropharyngeal cancer. This study compares the standard diagnostic workup to the standard diagnostic workup supplemented by transoral and cervical ultrasound of the lingual and palatine tonsils.

Patients are included and examined at the Department of Otorhinolaryngology, Head and Neck Surgery, Rigshospitalet, Department of Otorhinolaryngology and maxillofacial Surgery, Køge, Department of Otolaryngology, North Zealand Hospital, Hillerød, and Department of Otorhinolaryngology, Head and Neck Surgery, Aarhus University Hospital.

In Denmark, patients are referred to the head and neck outpatient cancer clinic by their general practitioner, a private head and neck practitioner, or a doctor from another specialty when symptoms or objective findings suggest malignancy. All patients referred with a suspected malignancy in Denmark are entitled to a free diagnostic workup.

Patients aged 18 years or older referred to the outpatient cancer clinic on suspicion of oropharyngeal cancer can be included in the study. The suspicion of oropharyngeal cancer includes relevant symptoms, relevant objective findings, or an incidental finding of a possible oropharyngeal malignancy on a scan. Patients are excluded if they have previously had oropharyngeal cancer or radiation to the head and neck area. Patients will be screened for eligibility before their first clinical workup in the outpatient cancer clinic.

A selected group of ENT surgeons will perform the ultrasound scans. All surgeons participating in US scanning will receive verbal and hands-on education on US of the palatine and lingual tonsils.

To establish valid inclusion criteria and minimize bias, the investigators aim to screen all eligible patients before their inclusion. When screening, the investigators want to obtain information from the medical records of all patients suspected of oropharyngeal cancer.

Information from medical records include

• Central personal registry number
• Age
• Sex

• Clinical diagnosis: suspected oropharynx cancer. Based on what of the following:

  • Tonsil asymmetry
  • Visible tumor tissue
  • Ulcus, erosion, exudative lesions
  • NBI dots
  • A firm tonsil palpated compared to the contralateral side
  • Suspected pathologic lymph node on US of the neck
  • A scan (MR, CT, PET/CT) suggesting oropharyngeal malignancy

• Patient symptoms

  • Pain in the oropharynx
  • A sense of increased amount of tissue in the oropharynx
• The given international classification of diseases (ICD) Code

• Included/ excluded.

  o If not included reasons for this:

• Not offered inclusion.
• Did not wish to participate.
• Inclusion criteria are met.

• Final pathology diagnosis in freeze section, formalin, and cytology

  o Histopathologic tumor type (keratinizing/non-keratinizing squamous cell carcinoma, salivary gland carcinoma, lymphoma, other types), HPV-type, and p16 status of the primary tumor

• Tumor location:

  • Palatine tonsil left/right
  • Lingual tonsil left/right
  • Uvula
  • Ventral soft palate
  • Posterior and lateral pharyngeal walls at the oropharyngeal level
  • Epiglottic vallecula
• Time from the patient is seen at the outpatient clinic until the beginning of treatment
• Number of standard image modalities ordered for diagnostics
• Symptomatology and time to admission
• Alcohol and tobacco consumption
• Imaging results (MRI, CT, PET/CT)
• TNM classification
• Treatment plan
• Previous cancer diagnosis

The tumor type will be specified as benign or malignant, and subtyped according to histological type. The final diagnosis will be the binary histopathology diagnosis, as the presence or absence of an oropharyngeal cancer. The location of the cancer, HPV, P16 status, and T-stage will be noted. All patients diagnosed with the absence of oropharyngeal cancer will have their medical charts reviewed six months after inclusion to confirm their initial benign diagnosis. Clinical T-stage in the control and intervention groups will be compared. The clinical T stage will be compared to MRI. The gold standard in T-stage evaluation is post-surgical histopathology or staging at MDT conferences for non-surgical patients.

Statistics Sample size: A non-randomized study by Garset-Zamani et al. found a diagnostic accuracy of 86% using transoral US compared to 68% by clinical examination. The power calculation is performed in R. The power is 80%, and the significance level is 0.05.

A sample size of 170 (85*2) patients is estimated. The inclusion period for 170 patients is set at three years, as patients will be included only by ENT surgeons with relevant transoral US experience.

The final analysis of the data will be conducted using RStudio. Descriptive statistics for the intervention and control groups will be generated and compared. Descriptive statistics for the medical records of patients screened but not included in the study will also be compared with those of patients included in the study. This includes sex, age, smoking, initial symptoms, reason for referral, final diagnosis, and cancer location. Measures of diagnostic accuracy include sensitivity, specificity, positive and negative predictive values, and overall accuracy. Sensitivity is defined as the true positives divided by the number of patients with a verified histopathologic tumor diagnosis. The true positives are defined as patients with verified histopathologic tumor diagnosis and US with tumor suspicion. Specificity is the number of true negatives divided by the number of patients evaluated to be cancer-free. True negatives are defined as US results in patients assessed as cancer-free without tumor suspicion at six months follow-up. Fisher's exact test will be used for categorical variables, including diagnostic accuracy, sensitivity, specificity, the number of correct diagnoses in the outpatient clinic, the number of patients with initial positive biopsies, the number of patients with standard imaging performed, and the number of patients with diagnostic surgery performed. A two-sample t-test will be used to compare the total number of biopsies performed, the tumor size, and the time from initial examination to confirmed diagnosis.

The investigators will perform a subgroup analysis of patients seen on suspicion of cancer in the palatine tonsils, the lingual tonsil, referrals due to an incidental finding on a scan, and tonsil asymmetry without other suspicious findings.

Ethics US is a non-invasive diagnostic imaging modality and is considered safe. Transoral US may cause momentary discomfort, which is reduced by local anesthetic spray. The study will be conducted in accordance with the Declaration of Helsinki. The protocol is approved by the Medical Ethics Committees (MREC), trial number 2501276.

Conclusion This study examines whether the implementation of transoral and cervical US of the palatine and lingual tonsils in patients with suspected oropharyngeal cancer will have a clinical impact. This concerns more accurate initial diagnoses, more correct biopsies, fewer unnecessary scans, fewer diagnostic surgeries and fewer visits to the outpatient clinic. A key strength is the randomized controlled trial design, which allows us to assess the effects of adding US to the diagnostic workup of patients with suspected oropharyngeal cancer.

If our hypothesis is confirmed, these findings could lead to significant improvements in the diagnostic workup of patients with suspected oropharyngeal cancer. This study can determine if transoral US should be implemented as a routine examination for these patients.

• Study Type: Interventional
• Enrollment (Estimated): 180
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark
    • Not yet recruiting
    • Department of Otorhinolaryngology, Head and Neck Surgery, Aarhus University Hospital
    • Contact: Thomas Kjærgaard, MD, PHD, associate professor; Phone Number: 0045 29915664
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Department of Otorhinolaryngology, Head and Neck Surgery & Audiology
    • Contact: Amalie Posselt, MD; Phone Number: 0045 29915664; Email: amalie.hartvig.pall@regionh.dk
  • Hillerød, Denmark
    • Not yet recruiting
    • Department of Otorhinolaryngology, Head and Neck Surgery & Audiology Northzealand Hospital
    • Contact: Amalie Posselt, MD; Phone Number: 0045 29915664
  • Køge, Denmark
    • Not yet recruiting
    • Department of ORL - Head & Neck Surgery and Audiology, Zealand University Hospital,
    • Contact: Amalie Posselt, MD; Phone Number: 0045 29915664

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Referred to outpatient cancer clinic with one of the following:

• A scan (MR, CT, PET/CT) suggesting malignancy in the oropharynx. This being asymmetric metabolic activity on PET/CT, a tumor or asymmetry of the palatine and lingual tonsils on MR and CT (7).
• Tumor suspicious findings (erosion/ulcus, tonsil asymmetry/hypertrophy).

• Tumor-suspicious symptoms (pain of the oropharynx)

  • > 18 years of age.
  • Ability to understand and give informed consent.

Exclusion Criteria:

• • Prior oropharyngeal cancer

  • Prior radiation to the head and neck area

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Diagnostics with ultrasound of the oropharynx; Diagnosis with ultrasound of the oropharynx. This including transoral ultrasound and transcervical ultrasound of the suspected area. This beeing either the palatine or lingual tonsils or both. 2.4 Transoral and cervical US of the lingual and palatine tonsils In the intervention group, US of the palatine and lingual tonsils will be performed in the outpatient clinic during the standard clinical examination. The scan is needed solely for the area of concern. When suspicion involves the palatine tonsils, scanning is limited to them; the same applies to the lingual tonsils. Always scan the contralateral side as a reference. Transoral US will be performed with small high-frequency transducers. Cervical US will be performed with low-frequency, high-depth penetration transducers. The transoral and cervical US scans will be performed according to the previously published protocol by Garset-Zamani et al. The investigators will utilize various US machines, including the Arietta 850 US Mach	Diagnostic test: Ultrasound of the oropharynx; Ultrasound of the oropharynx in patients with suspected oropharyngeal cancer; Other Names: Transoral ultrasound
No Intervention: Control group; Standard clinical workup All patients will receive a standard clinical examination by a trained senior registrar or consultant ENT surgeon, regardless of trial arm allocation. All diagnostics will be aligned with the national guidelines for oropharyngeal cancer, including an head and neck surgeon-performed clinical examination (including fiberoptic laryngoscopy with narrow-band imaging and neck US), MRI/PET-CT, and biopsies. A biopsy is performed to obtain a diagnosis when the ENT surgeon identifies a suspicious area. The biopsy will be sent for a frozen section histopathological examination. Patients will undergo standard imaging (MR, PET/CT) for further confirmation of diagnosis if deemed relevant by the ENT surgeon. A final diagnosis, TNM stage, and treatment plan (surgery, radiotherapy, radio- and chemotherapy) are determined at the multidisciplinary team conference. Standard diagnostic workup for patients with a suspected oropharyngeal cancer.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnostic accuracy	Diagnostic accuracy (sensitivity and specificity) in the control and intervention groups	The follow-up time is six months from the day of study inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
% Number of positive biopsies	Number of patients recieving a sufficient biopsy during their visit in the outpatient clinic.	On the day of the the first outpatient clinic visit.
Tumor staging	Compare the ultrasound and clinical estimated tumor staging with the final size estimate made at the MDT conference and on MRI	From indclusion untill MDT conference
Tumor size	Comparison of tumor size in three dimensions (APxMLxCC) in mm in both groups and correlation with MRI measurements	From inclusion untill MRI result is present. No later than 2 moths after inclusion
Number of patients needing diagnostic surgery	Comparison of the number of patients needing diagnostic surgery inthe intervention and control groups.	From inclusion untill final diagnosis. No later than four moths after inclusion.
Number of visits to the outpatient clinic	Comparison of the number of visits the the outpatient clinic in the two study groups	From initial visit in the outpatient clinic untill completed diagnostic work-up. No later than 6 months after initial examination in the outpatient clinic
Time from initial examination in the outpatient clinic to confirmed diagnosis	Comparison of the two trial arms in time from initial examination in the outpatient clinic to confirmed diagnosis.	6 moths follow up after the patients first visit to the outpatient clinic
Number of standard imaging modalities (MR, CT, PET/CT) ordered to validate the diagnosis.	Comparison between the two trial arms of the number of standard imaging modalities (MR, CT, PET/CT) ordered to validate the diagnosis. AT first visit in the outpatient clinic and in total.	From first visit in the outpatient clinic until the diagnostic workup completed. No later than 6 months following the initial investigation in the outpatient clinic.

Collaborators and Investigators

• Sponsor: Tobias Todsen
• Collaborators: Aarhus University Hospital; Hillerod Hospital, Denmark; Køge Hospital, Denmark

Study record dates

Study Major Dates

• Study Start (Actual): August 20, 2025
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): May 1, 2027

Study Registration Dates

• First Submitted: January 23, 2026
• First Submitted That Met QC Criteria: April 21, 2026
• First Posted (Actual): April 23, 2026

Study Record Updates

• Last Update Posted (Actual): April 23, 2026
• Last Update Submitted That Met QC Criteria: April 21, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Stomatognathic Diseases; Neoplasms by Site; Neoplasms; Head and Neck Neoplasms; Otorhinolaryngologic Diseases; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Pharyngeal Diseases; Oropharyngeal Neoplasms
• Other Study ID Numbers: VMK2501276

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No