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Anesthetics

Transoral ultrasound of the tonsils and tongue base under general anesthesia.

The tonsils and tongue base will be scanned transorally using high-frequency intraoperative ultrasound transducers. Direct contact with the tonsils through the mouth is achieved during general anesthesia.

Transoral Ultrasound

Tobias Todsen, MD, PhD

Adult patients suspected of Squamous Cell Carcinoma of Unknown Primary (SCCUP) will be prospectively enrolled at a tertiary head \& neck cancer center at Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark. All patients will undergo Magnetic Resonance Imaging (MRI) and Positron Emission Tomography-Computerized Tomography (PET-CT) prior to examination in general anesthesia. During general anesthesia, Intraoperative Transoral Ultrasound (ITUS) will be performed prior to panendoscopy. Detected tumors will be registered with specified oropharyngeal sub-locations. Blinded to ITUS, a consultant head \& neck surgeon will perform panendoscopy. After examination, the surgeon is unblinded to ultrasound results. Final histopathology results from location-specified biopsies performed will be used as reference standard. The overall detection rate will be compared between ITUS, panendoscopy, PET-CT and MRI with sensitivity and specificity analysis. Oropharynx sub-location specific detection rate of ITUS vs. panendoscopy will be compared with logistic regression analysis.

A prospective diagnostic study examining patients with suspected SCCUP will be performed at the Department of Otorhinolaryngology \& Head \& Neck Surgery, Copenhagen University Hospital - Rigshospitalet, Denmark. This specialized cancer center is responsible for the surgical work-up for approximately half of suspected SCCUP patients in the Danish population of 5.8 million.

Standard work-up of patients with suspected SCCUP in Denmark consists of same-day clinical examination combined with high resolution video endoscopy with NBI, surgeon-performed neck ultrasound and fine-needle aspiration cytology (FNAC) of suspected lymph nodes with same-day results. Cytology results can be further tested for Human Papillomavirus (HPV), and patients are booked for panendoscopic examination under general anesthesia with frozen section biopsy. Pre-operative cross-sectional imaging to locate the primary tumor includes MRI and 18-F Fluordeoxyglucose (FDG) PET-CT.

Intraoperative transoral ultrasound

During general anesthesia and prior to panendoscopy, ITUS will be performed while a consultant head \& neck surgeon performing panendoscopy is blinded. A Fujifilm Arietta 850 or Arietta 65 (Fujifilm, Tokyo, Japan), BK5000 (BK Medical ApS, Herlev, Denmark), or Samsung RS85 (Samsung Medison, Seoul, South Korea) ultrasound machines will be used. Small-footprint, high-frequency transducers such as the Arietta L51K linear-array intraoperative robot transducer attached to a forceps, the BK5000 "flexible hockey-stick" 18XL5s, or the Samsung RS85 LA3-22AI "hockeystick" will be used. A Boyle-Davis gag or laryngoscope will be used to visualize the tonsils (Figure 1), while the transducer is placed onto each tonsil in transverse and sagittal planes. The tongue base will be scanned by pulling the tongue anteriorly by an assistant and placing the transducer directly onto the tongue base. Alternatively, the tongue can be retracted with a video-laryngoscope while revealing the tongue base. The tongue base will be scanned from side to side in the sagittal plane. The tongue can then be pulled to either the left or right side to angle the probe obliquely for transverse imaging. If a tumor is suspected, the tumor location is registered in the following categories, including indication of right or left side:

* Tonsil cranial.
* Tonsil caudal.
* Glossotonsillar sulcus.
* Anterolateral tongue base.
* Anteromedial tongue base.
* Posterolateral tongue base.
* Posteromedial tongue base.
* "Other" oropharynx sub-locations, including anterior \& posterior pharyngeal arches, soft palate, uvula, posterior oropharynx wall, and vallecula.

B-mode video clips of both tonsils and the tongue base will be recorded. Power doppler for suspected tumors and the contralateral side will be performed. If a well-defined lesion is seen, the greatest tumor diameter and if possible, three-dimensional size is measured. The grade of tumor suspicion will be rated on a 5-point Likert scale ranging from 0 (very low) to 5 (very high).

Panendoscopy Following ITUS, the surgeon will perform standard panendoscopy of the pharynx including palpation of the oral cavity and oropharynx, and high-resolution video endoscopy with NBI. If the surgeon suspects a tumor, the location is registered with the same categories as above. Tumor suspicion will be rated on a 5-point Likert scale ranging from 0 (very low) to 5 (very high). The surgeon will categorize visual findings such as ulcers, exophytic tumors, asymmetric tissue, vulnerable/bleeding mucosa, suspect vasculature on NBI, or no suspect visual findings. The surgeon will categorize palpatory findings as soft or firm. The clinically visualized or palpated greatest tumor diameter will be estimated. The surgeon is then unblinded to ultrasound results. After unblinding from ultrasound, the investigators will register whether further directed biopsies from ultrasound suspected location are performed.

If the primary tumor is not located during panendoscopy, patients will tonsillectomied and the tonsils will be sliced in 2mm slices by head \& neck pathologists in search of the primary tumor. If the primary tumor is still unknown and the neck metastasis is HPV+, then patients are offered Transoral Robotic Surgery (TORS) with diagnostic tongue base mucosectomy. These tongue base specimens will also be sliced in 2mm slices and examined by head \& neck pathologists. If the primary tumor is located in final histopathology from either tonsillectomies or tongue base mucosectomy, the location of the tumors will be compared to the initially registered suspected ultrasound locations from panendoscopy.

Medical chart data The patient's age, sex, alcohol, smoking, largest cervical lymph node size, cervical lymph node side (right/left), date of panendoscopy, date of conclusive histopathology results, and date of treatment initiation will be obtained from medical charts.

Surgeon-performed Intraoperative Transoral Ultrasound for Cancer of Unknown Primary

Surgeon-performed Intraoperative Transoral Ultrasound in Patients With Suspected Head and Neck Squamous Cell Carcinoma of Unknown Primary: a Prospective Diagnostic Accuracy Study

Average operative time, including setup with mouth gags, to perform transoral ultrasound in general anesthesia.

The difference in proportion of patients with SCCUP where a primary tumor location is correctly detected by ITUS but not detected with panendoscopy alone.

The echogenicity, shape and doppler flow pattern relative to the normal and contralateral tonsil tissue will be compared in biopsy-verified primary tumors.

The percentage of primary tumors located is compared between all of the above tests.

The Novo Nordic Foundation

Rigshospitalet, Denmark

Principal Investigator

Blood and Lymph Conditions

Immune System Diseases

Mouth and Tooth Diseases

Ear, Nose, and Throat Diseases

Rare Diseases

Lymphoma

Hypertrophy

Oropharyngeal Neoplasms

Tongue Neoplasms

Tonsillar Neoplasms

Pathological Conditions, Anatomical

Pharyngeal Neoplasms

Otorhinolaryngologic Neoplasms

Head and Neck Neoplasms

Pharyngeal Diseases

Stomatognathic Diseases

Otorhinolaryngologic Diseases

Lymphosarcoma

Tongue Cancer

Anti-Arrhythmia Agents

Channel Blockers

Lidocaine

Anesthetics, Local

Transoral and transcervical ultrasound of the oropharynx, including the tonsils and tongue base.

Under local anesthetic with xylocaine spray in the oropharynx, the tonsils and tongue base are scanned with small-footprint, high-frequency ultrasound transducers (such as the 18XL5s hockey-stick from BK Medical)

Transoral ultrasound

The tongue base and tonsils are scanned externally via the neck, where a (preferably low-frequency) transducer is placed onto the skin above the hyoid bone to visualize the tongue base. The tonsils are visualized adjacent to the tongue base on either side and are located deep to the submandibular glands in a oblique coronal plane.

Transcervical ultrasound

The aim of the study was to examine the detection rate and tumor size evaluation in patients with suspected oropharynx cancer using a new technique with transoral ultrasound of the oropharynx. The new technique was compared to Magnetic Resonance Imaging (MRI). The study investigators included patients referred to a tertiary head \& neck cancer center in Copenhagen, Denmark, with suspicion of oropharynx cancer. Patients supplied written informed consent and were included and ultrasound scanned with local anesthesia in the outpatient clinic. Blinded assessment of MRI's was performed for tumor detection and compared to ultrasound with the reference standard being histopathology biopsy results.

An explorative diagnostic study was performed at the Department of Otorhinolaryngology, Head \& Neck Surgery, Copenhagen University Hospital - Rigshospitalet, Denmark from October 1st, 2021, to April 30th, 2022. The study investigators invited adult patients from the outpatient cancer clinic referred with a suspicion of oropharynx cancer to participate in the study. At the study investigators' center, all head \& neck cancer patients receive diagnostic work-up which includes clinical exam, flexible laryngoscopy with narrow-band imaging, surgeon-performed neck ultrasound and biopsy and/or cytology with same-day results. Patients were enrolled after verbal and written consent and were offered an ultrasound examination of the oropharynx as an addition to the standard diagnostic workup in the outpatient clinic. All included patients also received an MRI of the head and neck. Clinical data including age, sex, smoking habits, alcohol consumption, date of MRI scan, and histopathology results were obtained from medical charts after inclusion.

Interventions included transoral ultrasound of the tonsils and base of tongue, conducted with BK5000 ultrasound machines using the X18L5s "hockey stick" transducer. Transcervical ultrasound was also performed in patients where a tongue base cancer was most likely. Standard linear neck transducers (X18L5) or a curved 9C2 transducer was used. The tonsils and tongue base were scanned in two planes if possible, and doppler flow was recorded as well. Ultrasound images were stored as video clips.

The detection of tumors with ultrasound was recorded as "positive" if a well-defined tumor was seen that was clearly visualized compared to the contralateral side. A "negative" result was given if no tumors were suspected on either side. An "inconclusive" result was given if a tumor was not clear, but there was suspicious asymmetry visualized. The anatomical sub-location of tumors were stratified into right and left tonsil, tongue base, overlapping tonsil and tongue base, and "other" sub-locations. "Other" sub-locations included the soft palate, uvula, oropharynx posterior wall, vallecula, anterior pharyngeal arch and posterior pharyngeal arch.

MRI was used as the reference test. An expert neuroradiologist blinded to ultrasound results and histopathology rated all tests for tumor detection in the oropharynx and tumor size in detected tumors.

Statistical analysis:

Tumor detection of oropharynx ultrasound and MRI will be compared using the histopathologic diagnosis (cancer or benign) as reference standard to calculate sensitivity, specificity, positive- and negative predictive values (PPV, NPV).

Inconclusive tests will be analyzed as a positive result due to the clinical consequences often leading to diagnostic tonsillectomy.

McNemar's test for differences between sensitivity, specificity, PPV and NPV between ultrasound and MRI will be calculated.

The greatest tumor diameter will be compared between ultrasound and MRI using scatter plots and the Pearson's R correlation coefficient. Tumor volumes calculated using the formula for an ellipse: π/6 \* craniocaudal \* anteroposterior \* mediolateral will be compared. Statistical analysis will be performed using R software version 4.2.2.

Outpatient Ultrasound for the Diagnostic Work-up of Oropharynx Cancer

Surgeon-performed Outpatient Transoral and Transcervical Ultrasound for the Diagnostic Work-up of Oropharynx Cancer: a Feasibility Study

Patients with cancer (histopathology verified) correctly detected by a positive ultrasound or MRI test result.

Greatest tumor diameter measured in millimeters.

Patients with benign tonsillar asymmetry (histopathology verified) correctly detected by a negative ultrasound or MRI test result.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Surgeon-performed Intraoperative Transoral Ultrasound for Cancer of Unknown Primary	NCT05841966	Cancer of Unkno... Unknown Primary... Unknown Primary...	Transoral Ultra...	18 Years -	Rigshospitalet, Denmark
Surgeon-performed Intraoperative Transoral Ultrasound for Cancer of Unknown Primary	NCT05841966	Cancer of Unkno... Unknown Primary... Unknown Primary...	Transoral Ultra...	18 Years -	Rigshospitalet, Denmark
Outpatient Ultrasound for the Diagnostic Work-up of Oropharynx Cancer	NCT05698667	Oropharynx Canc... Oropharynx Neop... Tonsil Cancer Tonsil Neoplasm Tonsil Hypertro... Tonsil Lymphoma Base of Tongue ... Base of Tongue ...	Transoral ultra... Transcervical u...	18 Years -	Rigshospitalet, Denmark
Outpatient Ultrasound for the Diagnostic Work-up of Oropharynx Cancer	NCT05698667	Oropharynx Canc... Oropharynx Neop... Tonsil Cancer Tonsil Neoplasm Tonsil Hypertro... Tonsil Lymphoma Base of Tongue ... Base of Tongue ...	Transoral ultra... Transcervical u...	18 Years -	Rigshospitalet, Denmark

Spots Global Cancer Trial Database for transoral ultrasound