Maximum diameter of carotid body tumor as an independent risk factor for a GAPP score of ≥5: an ultrasound study

Introduction

In high altitude areas, carotid body tumor (CBT) is a mass that cannot be ignored. Small CBT can be completely removed, but large ones have significantly increased surgical complications, such as cranial nerve injury, increased intraoperative blood loss (IBL), stroke, and malignant potential (1-4).

Compared with computed tomography (CT), magnetic resonance imaging (MRI), and digital subtraction angiography (DSA), ultrasound (US) is a good choice for CBT screening. It is easy to access, mobile, low-cost, reliable, and is suitable for screening in high-altitude households. Conventional color Doppler US cannot only provide the measurement of the lesion size, but also detect its feeding vessels. Contrast-enhanced US (CEUS) can also display the subtle blood flow signal inside the tumor, and can better investigate the Shamblin type (5,6) and vascularity of CBT lesions than conventional color Doppler US (7).

Grading system for adrenal phaeochromocytoma and paraganglioma (GAPP) is a scoring system to predict metastatic potential in pheochromocytomas and paragangliomas (PCCs/PGLs), which is based on the following aspects: histological pattern, cellularity, comedo-type necrosis, capsular/vascular invasion, Ki67 labelling index, and catecholamine type (8,9). However, it remains unknown whether the GAPP score can be predicted from the ultrasonic characteristics of CBT.

The purpose of our study was to identify whether ultrasonic parameters are risk factors for a higher GAPP score in patients with CBT. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-890/rc).

Methods

Study population

The study was approved by the Human Research Ethics Committee of Qinghai University Affiliated Hospital (No. P-SL-20190057). Written informed consent was provided by all participants prior to enrollment. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Between January 2021 and October 2023, patients who fulfilled the inclusion criteria were enrolled in this study. All participants were from Qinghai University Affiliated Hospital. The patient inclusion criteria included all those with surgically confirmed CBT who underwent preoperative US scans of the neck in Qinghai University Affiliated Hospital. Patients with no pathology reports and GAPP score were excluded.

Data collection

The demographics, comorbidities, lesion location, anatomic characteristics, blood test, intervention (surgery, embolization, or radiotherapy), complications, and pathologic features were retrospectively reviewed from all the patients with CBTs.

US examination

All US examinations were performed by an experienced radiologist (with 20 years of clinical experience in conventional US and CEUS), who was blinded to the patients’ clinical data, using an Acuson S2000 US system (Siemens AG, Erlangen, Germany) with 7.5–12 MHz 9L4 linear transducer, equipped with contrast pulse sequencing imaging software. Each patient underwent a complete baseline two-dimensional and color Doppler US examination of the CBT and the adjacent tissues. The maximum diameter of CBT (D_max) and the blood flow of CBT (Adler grade) (10,11) were documented.

CEUS

After baseline US examination, contrast mode was activated after the optimal cross-section of the target lesion and the adjacent common carotid artery (CCA) was selected. Timing started when the sulfur hexafluoride microbubbles US contrast agent SonoVue™ (Bracco, Milan, Italy) was injected intravenously as a 2.4 mL bolus followed by 5 mL of normal sterile saline flush using a 20-gauge peripheral intravenous cannula, and observed continuously for 5 minutes; dynamic images were stored for subsequent analysis.

Next, the following features were recorded on CEUS: (I) the enhancement level of CBT (hypo-, iso-, or hyper-enhancement) and (II) the enhancement pattern of CBT (homogeneous, heterogeneous without perfusion, heterogeneous with perfusion) compared with the surrounding normal tissues.

Finally, the region of interest (ROI) was placed at the solid part of the tumor and the time-intensity curve (TIC) of the ROI was generated. The following quantitative perfusion parameters of CBT were obtained: peak intensity (PI), defined as the maximal signal intensity measured in the selected ROI (the PI of peripheral CBT or CCA was defined as 100%); time-to-peak (TTP), defined as the time from the starting point to the PI of the curve; area under the curve (AUC), defined as the area under the whole-time intensity curve; mean transit time (MTT, in seconds), defined as the time from the starting point to the PI drop to 50% of the curve. All parameters were measured three times and averaged.

Statistical analysis

Continuous data with normal distribution were presented as mean ± standard deviation (SD) and analyzed using the independent sample t-test. Non-normally distributed variables were reported as median with interquartile range (IQR) and analyzed using the Mann-Whitney U test. Categorical variables were represented by frequencies and percentages and analyzed by the Chi-squared test or Fisher’s exact test. Multivariable logistic regression analyses were constructed to identify independent risk factors for a GAPP score of ≥5 in patients with CBT. The discriminative ability of risk factors was assessed using an AUC. Statistical significance was indicated by P values <0.05. All statistical analyses were processed using the software SPSS 19.0 (IBM Corp., Chicago, IL, USA) and MedCalc version 16.8.4 (MedCalc, Ostend, Belgium).

Results

Characteristics of included patients

A total of 68 patients (74 CBTs) were included in this study. According to the GAPP score, they were divided into two groups: Group 1, GAPP score <5 (n=37) and Group 2, GAPP score ≥5 (n=31). There were no significant differences between the two groups in terms of the altitude, gender, age, nationality, lesion locations, Shamblin grade, hypertension, platelet counts, hemoglobin, preoperative embolization, cranial nerve injury, and length of stay. CBTs in the Group 2 were significantly larger than those in the Group 1 (Figure 1). More IBL was observed in Group 2 than in Group 1.

Figure 1 The D_max and GAPP score of CBTs: (A) D_max =1.03 cm, GAPP score =3 (hematoxylin-eosin staining, magnification: 400×); (B) D_max =3.78 cm, GAPP score =6 (hematoxylin-eosin staining, magnification: 400×). D_max, the maximum diameter of carotid body tumor; GAPP, grading system for adrenal pheochromocytoma and paraganglioma; CBT, carotid body tumor.

A total of 10 patients underwent CEUS, with seven having a GAPP score of <5 and three having a GAPP score of ≥5. There were no significant differences between them in terms of the age, gender, lesion locations and Shamblin type, and Adler grade. CBTs in patients with a GAPP score of ≥5 were significantly larger than those with a GAPP score of <5 (P<0.05). However, they did not significantly differ from each other according to the CEUS enhancement pattern and quantitative perfusion parameters. A detailed overview on patient and CBT characteristics is listed in Tables 1,2.

Correlation analysis

There was a positive correlation between the D_max of CBT and their GAPP scores (r=0.327, P=0.006). The linear regression equation was y = 0.2935x + 3.6106, where x and y represent the D_max of CBT and GAPP scores, respectively. IBL also correlated significantly with GAPP scores (r=0.262, P=0.033). The linear regression equation was y = 0.001078x + 4.2827, where x and y represent IBL and GAPP scores, respectively.

Univariate/multivariate logistic regression analyses

Univariate logistic regression analysis showed that the D_max of CBT [odds ratio (OR) =1.748; 95% confidence interval (CI): 1.145–2.670; P=0.009] and IBL (OR =1.002; 95% CI: 1.000–1.004; P=0.048) were the risk factors for a GAPP score of ≥5 in patients with CBT. However, multivariate logistic regression analysis revealed that only the D_max of CBT (OR =1.693; 95% CI: 1.106–2.592; P=0.015) was the independent risk factor for a GAPP score of ≥5.

ROC curve analysis

ROC analysis showed that the D_max of CBT (AUC =0.677, 95% CI: 0.561–0.815; cutoff value, 1.8 cm; sensitivity, 100.00%; specificity, 40.54%), IBL (AUC =0.652, 95% CI: 0.516–0.788, cutoff value, 150 mL; sensitivity, 53.33%; specificity, 80.56%), and their combination (AUC =0.710, 95% CI: 0.587–0.834, cutoff value, 0.276; sensitivity, 100.00%; specificity, 38.89%) had similar abilities to predict a GAPP score of ≥5 in patients with CBT (P>0.05) (Figure 2). However, the D_max had a greater Youden index (0.405) than that of IBL (0.339) and their combination (0.389).

Figure 2 Receiver operating characteristic curve showing the performance of the D_max of CBT, IBL, and their combination on predicting GAPP score greater than or equal to 5 in patients with carotid body tumor. IBL, intraoperative blood loss; AUC, area under the curve; D_max, the maximum diameter of carotid body tumor; CBT, carotid body tumor; GAPP, grading system for adrenal pheochromocytoma and paraganglioma.

Discussion

To the best of our knowledge, this is the first study assessing the recognition ability of US parameters in CBT patients with a greater GAPP score. Our data, firstly, demonstrated that the D_max is an independent risk factor for a GAPP score of ≥5 in patients with CBT. The D_max measured by US may deviate from the maximum size measured by MRI or CT. If so, it would be beneficial to present that data as well.

GAPP score was categorized as 0–2: well differentiated (WD); 3–6: moderately differentiated (MD); and 7–10: poorly differentiated (PD), based on published cut-points for risk stratification (8,9). Higher GAPP scores were associated with aggressive PCCs/PGLs. GAPP score, and modified GAPP (M-GAPP) score, a combination of some GAPP parameters and the immunohistochemical staining of succinate dehydrogenase type B were useful for the prediction of the metastatic potential of PCCs/PGLs (8,9,12).

CBT is a paraganglioma derived from carotid bifurcation chemoreceptors, accounting for 60% of head and neck paragangliomas and 0.5% of head and neck tumors. The vast majority of CBT is benign, with a malignant rate of only 2–8% (13-16) but with expansive growth, it will compress adjacent tissues and erode blood vessels and nerves.

In this study, we evaluated the size (D_max) and blood flow of CBT using color Doppler US in all patients, and the PI, TP, AUC, and MTT using CEUS in some patients. Only the D_max and IBL were significantly different between the patients with a GAPP score of ≥5 and those with a GAPP score of <5, and there were no significant differences between them in terms of the age, gender, altitude, nationality, lesion locations, Shamblin type, Adler grade, enhancement pattern, and perfusion parameters of CEUS. The D_max correlated significantly with GAPP scores and was an independent risk factor for a GAPP score of ≥5 in patients with CBT from multivariate logistic regression analysis. These findings are consistent with previous studies, in which metabolic tumor volume was significantly correlated with the GAPP score (17) and large tumor size was associated with increased risk of metastatic disease (18,19). Perhaps GAPP score was not enough to reflect the changes of microperfusion of CBTs assessed by CEUS.

Our study was inevitably affected by several factors. First, the sample size was small, especially for the patients who underwent CEUS. It is hard to avoid the deviation of statistical results, which may result in a bias in the assessment of risk factors. Second, we did not use tumor volume as a parameter to evaluate CBT size, which may be more accurate. This was because most of our patients came from out-patient clinics or the homes of residents, where US screening for CBT was performed, and the measurement was relatively simple. Finally, this was a retrospective, single-center study, and prospective validation is needed.

Conclusions

The D_max is an independent risk factor for a GAPP score of ≥5 in patients with CBT. US screening of CBT provides important value for its timely diagnosis and treatment.

There are more directions worth exploring in the future, such as the relationship between vertical diameter, horizontal diameter, and GAPP score, the ability of D_max to predict a GAPP score of ≥7 in patients with CBT, and so on.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-890/rc

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-890/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was approved by the Human Research Ethics Committee of Qinghai University Affiliated Hospital (No. P-SL-20190057). Written informed consent was provided by all participants prior to enrollment. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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