Background: Accurate assessment of thyroid cartilage invasion in squamous cell carcinoma (SCC) of the larynx remains a challenge in clinical practice. The aim of this study was to assess the diagnostic performance of contrast-enhanced ultrasound (CEUS), contrast-enhanced computed tomography (CECT), and magnetic resonance imaging (MRI) in the detection of non-ossified thyroid cartilage invasion in patients with SCC. Methods: CEUS, CECT, and MRI scans of 27 male patients with histologically proven SCC were evaluated and compared. A total of 31 cases were assessed via CEUS and CECT. The MR images of five patients and six cases were excluded (one patient had two suspected sites), leaving twenty-five cases for analysis via MRI. Results: CEUS showed the highest accuracy and specificity compared with CECT and MRI (87.1% vs. 64.5% and 76.0% as well as 84.0% vs. 64.0% and 72.7%, respectively). The sensitivity and negative predictive value of CEUS and MRI were the same (100%). CEUS yielded four false-positive findings. However, there were no statistically significant differences among the imaging modalities (p > 0.05). Conclusions: CEUS showed better diagnostic performance than CECT and MRI. Therefore, CEUS has the potential to accurately assess non-ossified thyroid cartilage invasion and guide appropriate treatment decisions, hopefully leading to improved patient outcomes.
Keywords: non-ossified thyroid cartilage; CEUS; CECT; MRI; laryngeal cancer
Imaging of the local spread of laryngeal cancer plays an important role in choosing a suitable treatment strategy, such as organ-sparing therapy, radical surgery, or combined therapy. The decision regarding which treatment strategy to employ affects the effectiveness of treatment and quality of life [[
Both contrast-enhanced computed tomography (CECT) and magnetic resonance imaging (MRI) are the main and most widely used modalities for laryngeal imaging; most guidelines leave the choice between the two techniques up to local protocols and scanner availability. In CECT, one of the most controversial issues in the assessment of the tumor invasion of non-ossified thyroid cartilage is a similar post-contrast density of the tumor and the non-ossified thyroid cartilage [[
Contrast-enhanced ultrasound (CEUS) can be used to assess and quantify microcirculation in normal and pathological conditions with a good acoustic window [[
Therefore, the purpose of this study was to assess the diagnostic value of CEUS, compared with that of CECT and MRI, in the detection of non-ossified thyroid cartilage invasion in SCC of the larynx.
Between 2021 and 2023, a prospective comparative study was carried out at the Hospital of Lithuanian University of Health Sciences Kaunas Clinics. A total of 38 patients with histopathologically proven SCC of the larynx were enrolled in this study. The inclusion criteria were as follows: an available CECT scan demonstrating pathological infiltration adjacent to the non-ossified tract of the thyroid cartilage or its clear infiltration; no history of previous laryngeal–hypopharyngeal surgery or chemoradiation; and having undergone surgery planned after multidisciplinary team discussion. Eleven patients were excluded because they refused surgical treatment or did not attend further consultations or undergo further surgery.
All 27 male patients meeting the inclusion criteria were subjected to CEUS and MRI. Informed consent was obtained from all participants before the study. The study was conducted according to the guidelines of the Declaration of Helsinki. Ethical approval was obtained from Kaunas Regional Biomedical Research Ethics Committee (protocol No. 2021-BE-10-00016; dated 2021).
Multislice CT examinations were performed using an Aquilion ONE TSX-301 scanner (Toshiba, Tokyo, Japan) with the following parameters: 120 kVp; specific effective mAs for each patient based on the patient's size and tissue thickness; collimation, 128 × 0.625 mm; field of view, 260 mm; and matrix, 512 × 512. The patients were asked to assume a supine position, breathe quietly, and avoid coughing and swallowing. The field of view was from the skull base to the aortic arch. Scanning was performed without and with intravenous contrast media (65–100 mL) with a 50 mL saline flush to obtain contrast-enhanced images with a 60–80 s delay after administration; the concentration of iodine in the contrast agent was 320–370 mg/mL. Images were reconstructed for axial (parallel to the plane of the true vocal cords), sagittal, and coronal (perpendicular to the plane of the true vocal cords) planes with soft tissue and bone algorithms (2 mm in thickness).
CEUS examination was performed using a Philips Epiq 7 (expert-class) US system (Philips Healthcare, Best, The Netherlands) with a 5–12-MHz linear transducer. The patients were asked to assume the supine position with their necks extended. The larynx and its surrounding structures were evaluated in the transverse and longitudinal sections. The distance between the area of lesion contact to the non-ossified thyroid cartilage seen via CECT and the upper border of the thyroid lamina was measured via CECT and then used as a reference to target the same area through CEUS.
CEUS examination was performed by administering an intravenous bolus of SonoVue (Bracco SpA, Milan, Italy) (5 mL, followed by saline flush) [[
MRI examination was performed using a Philips Ingenia 3.0T scanner (Philips Healthcare, Best, The Netherlands) with dedicated head–neck 20-channel parallel imaging array coils. The patients were imaged in the supine position and asked to breathe quietly and refrain from swallowing and coughing during the scanning. Axial images were captured parallel to the plane of the true vocal cords; coronal images were obtained perpendicular to this plane. The MRI protocol employed is specified in Table 1.
The analysis of CEUS images was performed by two radiologists with >4 and >20 years of experience, respectively. The findings from the CECT and MRI examinations were interpreted by one head-and-neck radiologist with >20 years of experience in head-and-neck imaging. The radiologists were not blinded to the clinical and CECT information during the analysis of CEUS and MRI images.
CEUS images were evaluated and interpreted by both radiologists during examination and post-processing. The non-ossified thyroid cartilage was considered infiltrated by a tumor when contrast enhancement was observed (Figure 1). When the cases were evaluated, there was no disagreement between the radiologists.
CECT and MRI images were evaluated and interpreted according to previous articles [[
In CECT images, non-ossified thyroid cartilage invasion was positive when the following criteria were met: a focal cartilage defect in close proximity to the tumor was found; replacement of the cartilage by soft tissue with enhancement matching that adjacent to the cartilage occurred; and the lesion was in direct contact with the thyroid cartilage and densities were indistinguishable (Figure 2). Findings obtained via CECT were considered negative if the densities between the tumor/pathologic infiltration and the non-ossified cartilage were distinguishable.
When conducting MRI, thyroid cartilage invasion was diagnosed when the thyroid lamina showed abnormal signal intensity matching the signal of the tumor in T2-weighted image (T2WI), T1-weighted image (T1WI) (before and after contrast administration), DWI, and ADC map (Figure 3). When the thyroid lamina showed a T2WI signal, enhancement, and an ADC value higher than those of the tumor, the abnormal signal was classified as inflammation.
A pathologist with >20 years of experience evaluated the surgical specimens according to the existing guidelines described elsewhere [[
The IBM SPSS Statistics 20.0 (IBM Corp. in Armonk, NY, USA) statistical software package was used in this study. Sensitivity, specificity, accuracy, negative predictive value (NPV), and positive predictive value (PPV) of CEUS, CECT, and MRI in evaluating non-ossified laryngeal cartilage involvement were assessed by comparing results with histopathological findings [[
where TP is true positive; TN denotes true negative; FP denotes false positive; and FN denotes false negative.
McNemar's test was used to compare the accuracy of imaging modalities. A p value of <0.05 was considered statistically significant.
In this prospective study, 27 male patients with a mean age of 63 years (SD, 8.7; range, 46–84 years) were enrolled.
Overall, there were 31 cases, as four patients had two suspected sites of non-ossified thyroid cartilage invasion. All 31 cases were assessed using CEUS and CECT. The MR images of five patients (corresponding to 6 cases, as one patient had two suspected sites) were non-diagnostic due to major artifacts, leaving 25 cases for analysis via MRI.
There were 14 cases (51.9%) of glottic SCC and 13 cases (48.1%) of transglottic SCC with the majority showing a G2 degree of differentiation (85.2%). The patients' distribution by pT staging is shown in Table 2.
In six cases (19.4%), histological proof of non-ossified thyroid cartilage invasion was obtained. The diagnostic performance of imaging studies is shown in Table 3. There were no statistically significant differences among the modalities (p > 0.05). CEUS and MRI showed a NPV of 100%. CEUS had four false-positive findings (Figure 4); however, the PPV was higher than those of CECT and MRI (60% vs. 30.8% and 33.3%, respectively).
There were no statistically significant differences between these imaging modalities (p > 0.05). CEUS, contrast-enhanced ultrasound; CECT, contrast-enhanced computed tomography; MRI, magnetic resonance imaging; TP, true positive; TN, true negative; FP, false positive; FN, false negative; PPV, positive predictive value; NPV, negative predictive value.
In the current study, we aimed at evaluating the diagnostic performance of CEUS, CECT, and MRI in detecting non-ossified thyroid cartilage tumor invasion, taking postoperative histopathological examination as the gold standard. Our results show that based on the presence of enhancement, CEUS allows for the discrimination of invaded (i.e., enhancing) from normal (i.e., non-enhancing) non-ossified thyroid cartilage. CEUS, CECT, and MRI evaluation demonstrated high accuracy (87.1%, 64.5%, and 76%, respectively) with minor differences. Moreover, CEUS was slightly superior to other modalities employed in this study in detecting non-ossified thyroid cartilage tumor invasion.
The detection of laryngeal cartilage invasion can significantly influence the choice of optimal treatment strategy and the prognosis of SCC of the larynx. Currently, the choice of optimal treatment strategy is controversial. However, in the case of thyroid cartilage invasion or its suspicion, transoral laryngeal microsurgery (TOLMS) should be ruled out due to possible non-radical tumor removal, and in such cases, open partial horizontal laryngectomy (OPHL), total laryngectomy, or non-surgical treatments should be considered [[
Cross-sectional imaging with multi-slice CT or MRI is designed to map deep tumor spread to the submucosal soft tissues and cartilaginous framework. CECT examination can be quickly performed, is widely available, and allows volumetric acquisition with a submillimetric voxel size: the short acquisition time minimizes the risk of motion artifacts, while the high spatial resolution allows the detection of subtle areas of tumor invasion of soft tissue spaces and cartilage [[
MRI has higher contrast resolution, which is boosted by the possibility of combining different pulse sequences. In the literature, this potential has mainly been exploited to assess cartilage invasion [[
However, most studies evaluating the diagnostic performance of imaging techniques in the detection of cartilage invasion tend to focus—intentionally or unintentionally—on the ossified cartilage. This occurs for several reasons: first, because, in most cases, invasion involves the ossified parts, and second, because CT and MRI better visualize the invasion of ossified cartilage, manifesting with a panel of findings including sclerosis, erosion, or destruction with cartilage replacement by tumor tissue [[
DECT is another promising imaging modality that has been analyzed in recent years. One research group [[
US was also previously investigated for its possible role in solving the problem of thyroid cartilage invasion. Indeed, US seemed to uniquely take a place among cross-sectional modalities for evaluating non-ossified cartilage invasion, as the larynx is a superficial structure, and because it best visualizes the non-ossified parts, which present the most diagnostic challenges when conducting CT and MRI scans [[
Our study aligns with the study by Hu et al. [[
CEUS showed slightly higher diagnostic values in the detection of non-ossified thyroid cartilage invasion in laryngeal and hypopharyngeal cancer than CECT and MRI. This may result in CEUS being an important problem-solving tool in routine clinical practice that can be used to confidently assess non-ossified thyroid cartilage invasion and guide appropriate treatment decisions, hopefully leading to improved patient outcomes. Further studies are needed to increase the number of observations and confirm the evidence obtained.
Graph: Figure 1 True-positive findings through axial CECT and CEUS. (a) In this CECT image, a partial bilateral ossification of the thyroid cartilage with a similar tissue density between the tumor (T) and the non-ossified thyroid cartilage (red arrow) can be seen; (b) CEUS image taken after intravenous contrast material administration showing the enhancement of the tumor (T) with invasion of the right anterior part of the non-ossified thyroid cartilage (asterisks); the adjacent hypoechogenic cartilage is non-invaded (white arrows).
Graph: Figure 2 Bilateral glottic cancer adjacent to the non-ossified thyroid cartilage lamina. (a) Axial CECT findings on the left side were false-positive for tumor invasion (red arrow). (b) CEUS image of the left side at the same level as (a) in the transverse plane shows true-negative findings, i.e., non-enhanced non-ossified cartilage (white arrows).
Graph: Figure 3 Supraglottic squamous cell carcinoma on the left side. (a) Axial CECT represents two sites, namely, sites that were false-positive anteriorly (yellow arrow) and true-positive posteriorly (red arrow), whereas MRI (b) contrast-enhanced high-resolution T1-weighted turbo spin echo Dixon and CEUS (c) findings were true-negative anteriorly (white arrow) and true-positive posteriorly (red arrows), respectively.
Graph: jcm-13-00891-g003b.tif
Graph: Figure 4 Supraglottic squamous cell carcinoma on the right side anteriorly adjacent to non-ossified cartilage inner lamina. (a) Axial CECT and (c) CEUS findings were false positive (red arrow) for tumor invasion of the thyroid cartilage, whereas MRI findings, as shown in (b), in axial contrast-enhanced high-resolution T1-weighted turbo spin echo Dixon images were true negative (white arrow).
Table 1 MRI protocol.
Sequence Plane Slice Thickness, mm Repetition Time, ms Time to Echo, ms Field of View, mm High-resolution T2-weighted turbo spin echo Dixon Axial, coronal, sagittal 2.5–3 2888 80 190–210 High-resolution T1-weighted turbo spin echo Dixon Axial 2.1–2.5 634 8 190–210 DWI and ADC Axial 2 14,439; 220 66 250 Contrast-enhanced high-resolution T1-weighted turbo spin echo Dixon Axial, coronal 2.1–2.5 634 8 190–210
Table 2 Distribution of the patients according to pT staging.
pT Group n (%) pTis 1 (3.7) pT1 7 (25.9) pT2 7 (25.9) pT3 8 (29.6) pT4 4 (14.8)
Table 3 Diagnostic performance of CEUS, CECT, and MRI in the assessment of non-ossified thyroid cartilage invasion.
Imaging Modality TP, TN, FP, FN, Sensitivity, Specificity, Accuracy, PPV, NPV, CEUS (n = 31) 6 21 4 0 100.0 84.0 87.1 60.0 100.0 CECT (n = 31) 4 16 9 2 66.7 64.0 64.5 30.8 88.9 MRI (n = 25) 3 16 6 0 100.0 72.7 76.0 33.3 100.0
Conceptualization M.P.; methodology, M.P., S.V. and S.R.; statistical analysis, R.T.; investigation, M.P., S.V., D.M., S.R. and E.P.; data curation, M.P. and R.T.; writing—original draft preparation, M.P.; writing—review and editing, D.F. and S.R.; visualization, M.P., S.R. and D.M.; supervision S.V.; consulting, D.F.; project administration, S.L. All authors have read and agreed to the published version of the manuscript.
The current study was conducted according to the guidelines of the Declaration of Helsinki. Ethical approval was obtained from Kaunas Regional Biomedical Research Ethics Committee (protocol No. 2021-BE-10-00016; dated 2021).
Informed consent was obtained from all subjects involved in the study.
The data that support the findings of this study are available from the corresponding author upon reasonable request. The data are not publicly available due to privacy or ethical restrictions.
The authors declare no conflicts of interest.
By Milda Pucėtaitė; Davide Farina; Silvija Ryškienė; Dalia Mitraitė; Rytis Tarasevičius; Saulius Lukoševičius; Evaldas Padervinskis and Saulius Vaitkus
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