Research ArticleClinical Studies
Open Access

Heterogeneity of Tumor Glucose Metabolism in Schwannomas Between Trunk and Extremities: An Imaging Study

YUTA MIYASHI, HIROMICHI OSHIRO, YOSHIRO YOSHIKAWA, RYO KATSUKI, YASUNORI TOME and KOTARO NISHIDA
In Vivo November 2025, 39 (6) 3428-3436; DOI: https://doi.org/10.21873/invivo.14140

Abstract

Background/Aim: Positron emission tomography/computed tomography with 18F-fluorodeoxyglucose (18F-FDG PET/CT) is frequently used to differentiate schwannomas from malignant peripheral nerve sheath tumors. Schwannomas exhibit pathological heterogeneity, with highly cellular (Antoni A) and hypocellular (Antoni B) areas, but current PET/CT methods do not adequately reflect this heterogeneity. This study aimed to compare imaging characteristics of schwannomas in the trunk versus the extremities, with emphasis on metabolic heterogeneity.

Patients and Methods: This retrospective study included patients with solitary schwannomas who underwent MRI and 18F-FDG PET/CT before surgical excision (June 2013-September 2023). Exclusion criteria were plexiform, multiple, biopsy-only lesions, and tumors originating from internal organs. Tumors were classified as trunk or extremity lesions. MRI was used to determine size and volume, while PET/CT measured SUVmax, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Heterogeneity was assessed using three indices: MTV-to-volume ratio (MTV/volume), SUV-based heterogeneity index (HISUV), and metabolic region-adjusted SUV-based heterogeneity index (MRA-HISUV).

Results: Fifty-six patients were included. Trunk schwannomas were larger than extremity tumors in diameter (4.33 cm vs. 2.77 cm; p<0.05) and volume (27.71 cm3 vs. 6.25 cm3; p<0.05). SUVmax (4.09 vs. 3.71) and SUVmean (2.47 vs. 2.22) did not differ significantly. MTV (18.43 cm3 vs. 6.19 cm3, p<0.05) and TLG (58.41 vs. 14.40, p<0.05) were higher in trunk tumors. MTV/volume ratio was lower (0.77 vs. 1.12, p<0.05), while HISUV and MRA-HISUV were higher in trunk schwannomas (1.79 vs. 1.65 and 2.36 vs. 1.49, p<0.05).

Conclusion: Trunk schwannomas were larger and exhibited higher metabolic activity and heterogeneity. Novel parameters such as MTV/volume and MRA-HISUV may enhance the characterization of schwannoma heterogeneity.

Keywords:

Introduction

Schwannomas, which frequently occur in the head, neck, trunk, and extremities, are benign peripheral nerve sheath tumors (1, 2). Schwannomas contain spindle-shaped Schwann cells and present as Antoni A areas with highly cellular regions or Antoni B areas with loose microcystic tissue (3). Magnetic resonance imaging (MRI) is commonly used to differentiate benign peripheral nerve sheath tumors (BPNST), such as schwannomas, from malignant tumors. However, distinguishing benign from malignant neurogenic tumors is often challenging (4).

18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET/CT) is occasionally performed to distinguish schwannomas from soft-tissue sarcomas. Some reports have demonstrated high uptake of 18F-FDG based on the maximum standardized uptake value (SUVmax) in schwannomas; however, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) parameters remain unclear in schwannomas.

Therefore, in this study, we aimed to assess the imaging characteristics of tumor glucose metabolic activity in solitary schwannomas of the trunk or extremities using 18F-FDG PET/CT.

Patients and Methods

Study design and patient selection. This single-institution, retrospective observational study included patients pathologically diagnosed with solitary schwannoma who underwent both MRI and 18F-FDG PET/CT prior to tumor excision or enucleation between June 2013 and September 2023. Patients with plexiform schwannomas, multiple occurrences, biopsy-only procedures, or tumors originating in an organ were excluded. Patients were categorized into trunk and extremity groups. This study was approved by the Institutional Review Board of the University of the Ryukyus Hospital (IRB No. 24-2386-00-00-00) on November 26, 2024. Data collection was conducted between December 2024 and January 2025. Patients who opted out via the designated institutional posters were excluded. Written informed consent was obtained for the use of representative images. The study adhered to the principles of the Declaration of Helsinki and followed the STROBE reporting guidelines.

Image acquisition. 18F-FDG PET/CT was performed using Biograph mCT (Siemens Healthcare, Tokyo, Japan). Detailed PET/CT imaging protocols have been described previously (5-7). All patients fasted for at least 6 h prior to scanning to standardize blood glucose and insulin levels. Imaging was performed 60 min following intravenous administration of 18F-FDG. Whole-body PET/CT images were acquired from the skull to the lower limbs. Preoperative MRI was conducted for all patients with schwannoma.

Image analysis. Maximum tumor diameters were measured in the anteroposterior, mediolateral, and craniocaudal directions using sagittal, coronal, and axial MRI planes. The maximum tumor diameter was defined as the largest of these three measurements. Tumor volume was estimated using the ellipsoid formula {V=4/3 π height/2 width/2 depth/2} based on the same measurements (8).

Tumor glucose metabolic activity in schwannoma. SUVmax was defined as the highest FDG uptake within the tumor (9). The region of interest (ROI) threshold was set at 40% of SUVmax. SUVmean represented the average FDG uptake within the ROI. MTV was calculated as the total ROI volume, and TLG was computed as the product of SUVmean and MTV (10, 11). SUV-based heterogeneity index (HISUV) was calculated by dividing SUVmax by SUVmean to assess intratumoral metabolic heterogeneity (12). The MTV to tumor volume ratio (MTV/volume) was also calculated. The metabolic region-adjusted SUV-based heterogeneity index (MRA-HISUV) was defined as HISUV divided by MTV/volume.

Statistical analysis. All statistical analyses were performed using the JMP software version 17.2 (JMP Statistical Discovery LLC, Cary, NC, USA). Group comparisons between trunk and extremity were conducted using the Mann-Whitney U-test, as the data were not normally distributed. Values are reported as medians with corresponding ranges. A two-sided p-value <0.05 was considered statistically significant.

Results

Patient characteristics. Sixty-two patients who underwent 18F-FDG PET/CT for the diagnosis of schwannoma and were pathologically confirmed with schwannoma between June 2013 and September 2023 at our institution were screened using electronic medical records. Patients with multiple schwannomatosis (n=2), plexiform schwannoma (n=1), tumors originating within an organ (n=1), or those without excision (n=2) were excluded. A total of 56 patients were included in the final analysis (Figure 1), comprising 21 males and 35 females. The mean age of patients undergoing 18F-FDG PET/CT was 56.3 years (range=12-83 years). Twelve patients were categorized into the trunk group and 44 into the extremity group.

Figure 1.
Figure 1.

Flowchart of the study design.

Tumor size of schwannomas. The median maximum diameters for the overall, trunk, and extremity groups were 3.15 cm (range=0.86-11.33), 4.33 cm (range=1.56-6.75), and 2.77 cm (range=0.86-11.33), respectively. Maximum diameter was significantly larger in the trunk group compared with the extremity group (p<0.05) (Figure 2A). Median total tumor volumes for the overall, trunk, and extremity groups were 7.48 cm3 (range=0.17-253.52), 27.71 cm3 (range=1.31-95.99), and 6.25 cm3 (range=0.17-253.52), respectively. Total tumor volume was significantly higher in the trunk group than in the extremity group (p<0.05) (Figure 2B).

Figure 2.
Figure 2.

Tumor size, glucose metabolic activity, and heterogeneity in schwannomas. Figure 2A and B show tumor size. The median maximum diameter (A) and tumor volume (B), measured using MRI, were both larger in the trunk group than in the extremity group. Figure 2C-F illustrates tumor glucose metabolic activity. SUVmax (C) and SUVmean (D) did not differ significantly between groups. However, the median MTV (2E) and TLG (2F) were significantly higher in the trunk group. Figure 2G-I presents tumor heterogeneity. The median MTV-to-volume ratio (G) was lower in the trunk group, while the median HISUV (H) and MRA-HISUV (I) were higher. These findings suggest that glucose metabolic heterogeneity was greater in the trunk group than in the extremity group.

Tumor glucose metabolic activity in schwannomas. Median SUVmax values for the overall, trunk, and extremity groups were 3.85 (range=1.80-10.06), 4.09 (range=2.87-10.06), and 3.71 (range=1.80-6.01), respectively. No significant difference was observed in SUVmax between the trunk and extremity groups (Figure 2C). Median SUVmean values for the overall, trunk, and extremity groups were 2.29 (range=0.98-5.61), 2.47 (range=1.39-5.61), and 2.22 (range=0.98-3.60), respectively, with no significant difference between the trunk and extremity groups (Figure 2D). Median MTV values for the overall, trunk, and extremity groups were 7.64 cm3 (range=1.33-246.23), 18.43 cm3 (range=1.89-77.90), and 6.19 cm3 (range=1.33-246.23), respectively. MTV was significantly higher in the trunk group than in the extremity group (p<0.05) (Figure 2E). Median TLG values for the overall, trunk, and extremity groups were 18.97 (range=1.30-430.90), 58.41 (range=3.27-173.72), and 14.40 (range=1.30-430.90), respectively. TLG was significantly higher in the trunk group compared with the extremity group (p<0.05) (Figure 2F). Median MTV/volume ratios for the overall, trunk, and extremity groups were 1.06 (range=0.16-13.54), 0.77 (range=0.16-1.71), and 1.12 (range=0.54-13.54), respectively. The MTV/volume ratio was significantly higher in the extremity group than in the trunk group (p<0.05) (Figure 2G). Median HISUV values for the overall, trunk, and extremity groups were 1.66 (range=1.48-2.06), 1.79 (range=1.53-2.06), and 1.64 (range=1.48-2.00), respectively. HISUV was significantly higher in the trunk group than in the extremity group (p<0.05) (Figure 2H). MRA-HISUV values for the overall, trunk, and extremity groups were 1.55 (range=0.13-11.43), 2.36 (range=0.95-11.43), and 1.49 (range=0.13-3.05), respectively. MRA-HISUV was significantly higher in the trunk group than in the extremity group (p<0.05) (Figure 2I).

Representative 18F-FDG PET/CT images: A 61-year-old female patient with schwannoma of the right calf underwent preoperative MRI (Figure 3A), 18F-FDG PET/CT (Figure 3B), and subsequent surgical enucleation. Maximum tumor diameter was 2.5 cm, volume was 7.9 cm3, SUVmax was 5.1, and SUVmean was 3.6. MTV and TLG were 5.8 cm3 and 18.4, respectively. MTV/volume was 0.74, HISUV was 1.60, and MRA-HISUV was 2.18.

Figure 3.
Figure 3.

Representative case of a 61-year-old female patient with a schwannoma in the right calf. (A) Axial T2-weighted MRI section. (B) PET/CT fused image.

Discussion

In this study, maximum diameter, total tumor volume, MTV, TLG, HISUV, and MRA-HISUV were significantly higher in the trunk group. SUVmax and SUVmean did not differ significantly between the trunk and extremity groups. However, the MTV/volume ratio was significantly higher in the extremity group.

Glucose metabolism in cancers plays a crucial role in tumor plasticity and microenvironment (13). Glucose metabolism can be altered by cancer treatment, such as chemoradiation (14). 18F-FDG PET is applied to visualize glucose uptake in the human body. Therefore, 18F-FDG PET/CT is frequently used for staging and classification of malignant tumors, including soft-tissue sarcomas (15). Glucose metabolism on FDG-PET/CT can predict not only diagnosis but also prognosis in soft-tissue sarcoma (5). High SUVmax values have been reported in soft-tissue sarcomas compared to benign tumors (6, 16). Schwannomas are BPNST characterized by Antoni A (hypercellular) and Antoni B (myxoid) areas (17). In schwannomas, SUVmax is significantly higher in Antoni A areas than in Antoni B areas (18). Because schwannomas demonstrate SUVmax values similar to soft-tissue sarcomas, distinguishing tumors with high SUVmax from schwannomas and other malignant tumors, such as malignant peripheral nerve sheath tumors (MPNST), can often be less reliable (19).

The maximum diameter of schwannomas ranges from 1 cm to 20 cm. Those originating in the extremities are generally smaller than 5 cm, while larger lesions are relatively common in the mediastinum and retroperitoneum (20, 21). In this study, tumor diameter and volume were greater in the trunk group than in the extremity group, consistent with previous reports (21). Larger tumor size in the trunk may be attributed to reduced anatomical constraints or delayed clinical recognition due to less prominent symptoms. Maximum diameters in this cohort fell within the previously reported range. The median diameter of MPNST is 6 cm (22), which exceeds the median maximum diameter observed in the present study. However, several cases in this study exceeded 6 cm, indicating that tumor size alone is not sufficient for differential diagnosis. Higher MTV and TLG values in the trunk group were consistent with tumor size and suggest greater total tumor metabolic activity in this group.

Previous studies reported mean SUVmax values for schwannomas at 4.1±2.1, with higher values observed in lesions of visceral origin (23). One study found that mean SUVmax of soft-tissue sarcomas varies by FNCLCC grade, with the high-grade group showing a higher median SUVmax (8.8) than the low-grade group (3.3) (24). Therefore, SUVmax values in schwannomas may exceed those in low-grade sarcomas. In the present study, the overall median SUVmax was 3.85, aligning with prior reports (23). However, the mechanisms underlying high FDG uptake in schwannomas remain unclear. Miyake et al. reported associations between high uptake and peritumoral lymphoid infiltration, as well as GLUT1 and GLUT3 expression (25). Hamada et al. noted higher SUVmax in schwannomas ≥5 cm compared to smaller ones (26). In this study, median SUVmax values were 4.09 in the trunk group and 3.71 in the extremity group. Although the difference was not statistically significant, a trend toward higher SUVmax in the trunk group was observed. Another study proposed a cutoff SUVmax of 6.1 for differentiating benign from malignant peripheral nerve sheath tumors, achieving high sensitivity and specificity (AUC=0.91), with no false-positive cases exceeding 8.1 (27). In this study, two patients (3.6%) had SUVmax values >6.1 and >8.1, suggesting that schwannoma cannot be ruled out even when SUVmax exceeds 8.1, as noted by Benjamin et al. (28).

MTV represents the total volume of the ROI, defined as the area with an SUV exceeding a predefined threshold. At our institute, this threshold is set at 40% of the SUVmax. Accordingly, MTV does not represent the true tumor volume, and only a limited number of studies have compared MTV with actual tumor volume. Lai et al. reported that when MTV was calculated using an ROI threshold of 30% SUVmax, there was no significant difference from the actual tumor volume. However, at thresholds above or below 30%, significant discrepancies were observed between MTV and the tumor volume in cervical cancer (29). That study did not address cases where the MTV-to-volume ratio exceeded 100% in the 20% or 25% SUVmax groups. In the present study, the MTV-to-volume ratio was significantly higher in the extremity group than in the trunk group. This may be attributed to increased peritumoral activity in the extremity group or greater tumor heterogeneity in the trunk group. This index may be useful in characterizing tumors and assessing malignancy potential. Although not directly evaluated here, schwannomas frequently exhibit heterogeneous pathological features, such as Antoni A and B areas, which may influence the MTV-to-volume ratio. Compared to other soft-tissue tumors, a more detailed understanding of the biological features of schwannomas may offer clinical value. To date, no study has examined the relationship between the MTV-to-volume ratio and schwannomas or investigated differences in this ratio based on tumor location. Several factors may explain the findings in this study. First, glucose metabolic activity per unit volume may be higher in schwannomas, and the surrounding tissues may exhibit increased metabolic activity in the extremities compared with the trunk. Second, schwannomas in the trunk often contain large regions of low metabolic activity, potentially corresponding to extensive Antoni B areas. Third, intrinsic tissue characteristics may differ between schwannomas originating in the trunk versus the extremities. Finally, a 100% or greater MTV value may indicate prominent peritumoral inflammation (Figure 4A). Overall, the MTV-to-volume ratio appeared to reflect tumor nonuniformity (Figure 4B). A previous study proposed the use of HISUV to assess heterogeneity in schwannomas (12), and the mean HISUV was significantly higher in MPNST (2.1±0.6) than in benign peripheral nerve sheath tumors (1.7±0.3). However, HISUV demonstrated lower specificity than SUVmax. In this study, the median HISUV was significantly higher in the trunk group than in the extremity group. The lower MTV-to-volume ratio observed in the trunk group did not contradict the higher HISUV values in the same group. These findings suggest that the MTV-to-volume ratio may reflect intratumoral heterogeneity. Although statistically significant, the median HISUV difference between the two groups was only 0.15. Given that the range extended from 1.48 to 2.06, with substantial overlap between groups, HISUV alone may offer limited specificity in distinguishing these tumors. To address this, a novel metric–MRA-HISUV– was developed, combining HISUV with the reciprocal of the MTV-to-volume ratio [1/(MTV/volume)], to enhance the sensitivity and specificity of heterogeneity assessment. MRA-HISUV was significantly higher in the trunk group than in the extremity group, showing a trend consistent with the MTV-to-volume ratio (Figure 4C). Since both the MTV-to-volume ratio and MRA-HISUV are relatively easy to calculate, they can be incorporated into daily medical practice and have the potential to be a convenient tool for predicting the degree of uniformity or inflammation before surgery. Furthermore, they probably contribute to more accurate pre-operative diagnosis if a sufficient number of cases are collected.

Figure 4.
Figure 4.

Conceptual illustration of MTV-to-volume ratio, HISUV, and MRA-HISUV. (A, B) Schematic representation showing the distinction between MTV (yellow circle) and tumor volume measured by MRI (blue circle). MTV was identical in both panels, while the MTV-to-volume ratio was higher in the right tumor due to smaller tumor volume. (C) Visualization of SUV distribution and tumor heterogeneity. The red point indicates SUVmax, the green point denotes SUVmean, the blue circle represents MTV, and the light blue circle indicates MRI-derived tumor volume. Wavy lines depict metabolic distribution. The lower panel shows a smaller high-activity ROI, resulting in a higher SUVmean and HISUV. HISUV reflects intratumoral heterogeneity and does not incorporate the MTV-to-volume ratio. MRA-HISUV combines SUVmax, SUVmean, MTV, and tumor volume, with higher values indicating greater heterogeneity.

Study limitations. First, this was a retrospective analysis conducted at a single institution. The sample size was small, the evaluated cases involved patients with schwannomas, and tumor size measurements were performed by the investigator. Tumor growth rate was not assessed. The threshold for MTV calculation was set at 40% of the SUVmax, which corresponds to the default value provided by the imaging system. SUV values varied across samples. Pathological reports were reviewed to confirm the accuracy of the pathological diagnoses. Despite these limitations, this study is the first to report on the MTV-to-volume ratio, the MRA-HISUV metric, and location-specific differences in schwannoma heterogeneity. Future studies involving larger cohorts and varied analytical conditions may yield further insights.

Conclusion

Schwannomas located in the trunk were significantly larger and exhibited higher overall glucose metabolism, whereas those in the extremities showed higher MTV-to-volume ratios and lower HISUV and MRA-HISUV values. These findings suggest that glucose metabolic activity in trunk-origin schwannomas differs from that in extremity-origin tumors. The MTV-to-volume ratio and MRA-HISUV may serve as useful indicators of tumor characteristics, particularly heterogeneity.

Acknowledgements

We wish to thank Dr. Gyo Iida (Department of Radiology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan) for useful discussions and Editage (www.editage.com) for the English language editing.

Footnotes

  • Authors’ Contributions

    YM, HO, YY, RK, YT, and KN conceived the study design. YM and YT contributed to data acquisition. YM, HO, YY, RK, and YT wrote and edited the manuscript. YT and KN revised the manuscript for the intellectual content. YM and YT confirmed the authenticity of the raw data. All Authors have read and approved the final version of the manuscript.

  • Conflicts of Interest

    YT is on the editorial board of Cancer Diagnosis and Prognosis. KN is on the editorial board of the Journal of Orthopaedic Research and a board member of the International Society for the Study of the Lumbar Spine.

  • Funding

    This work was supported in part by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant-in-Aid for Scientific Research (C) (21K09207 and 25K12529) and a Grant-in-Aid for Early-Career Scientists (23K15718). Any recommendations, findings, conclusions, or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the authors’ organization or JSPS.

  • Artificial Intelligence (AI) Disclosure

    No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.

  • Received July 9, 2025.
  • Revision received July 30, 2025.
  • Accepted August 19, 2025.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Heterogeneity of Tumor Glucose Metabolism in Schwannomas Between Trunk and Extremities: An Imaging Study
YUTA MIYASHI, HIROMICHI OSHIRO, YOSHIRO YOSHIKAWA, RYO KATSUKI, YASUNORI TOME, KOTARO NISHIDA
In Vivo Nov 2025, 39 (6) 3428-3436; DOI: 10.21873/invivo.14140
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