Improving glioma resection with 2D-intraoperative ultrasound: Observational results and systematic literature correlation

Abstract

Background:

Maximizing tumor resection is a key prognostic factor in glioma surgery. Intraoperative cerebral ultrasonography (IOUS) offers real-time, cost-effective guidance that can enhance the extent of resection (EOR) and gross total resection (GTR) rates, but data remain heterogeneous.

Methods:

We conducted a retrospective analysis of a prospective observational database including patients with gliomas undergoing surgery with or without IOUS guidance in one tertiary neurosurgical center. Inclusion criteria were preoperative magnetic resonance imaging-suspected gliomas, intended GTR, and available early postoperative imaging. Outcomes were compared using propensity score matching. In addition, a systematic literature review covering 2018–2024 was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Results:

A total of 38 patients were included after matching, with 19 patients in each group. IOUS use significantly improved the mean EOR (85.0% vs. 66.2%, P = 0.028) and GTR rate (47.4% vs. 10.5%, P = 0.029). Benefits were more pronounced in tumors larger than 10 cm³. A learning curve effect was observed, with increasing resection rates over time. The literature review identified nine relevant studies, with GTR rates ranging from 42% to 91%, and recent studies showing improved outcomes with advanced IOUS techniques. These findings should be interpreted cautiously given the small sample size and single-center design.

Conclusion:

IOUS significantly enhances resection outcomes in glioma surgery and demonstrates a progressive benefit with surgeon experience. Given its versatility, low cost, and growing integration with technologies such as contrast-enhanced ultrasound and artificial intelligence, IOUS remains a fundamental tool in modern neurooncology. Future multicenter prospective studies are needed to standardize its use and assess long-term patient outcomes.

INTRODUCTION

Intraoperative cerebral ultrasonography (IOUS) represents an old asset of neurosurgical armamentarium that is regaining its place in current neurosurgical practice due to cutting-edge technology improvement. Advancements in imaging resolution, 3D reconstructions, and the development of cerebral-dedicated ultrasound probes have successfully revived interest in this technique.[13] One of the major challenges in oncological neurosurgery is achieving complete tumor resection while preserving the patient’s neurological functions. Incomplete resection, defined by the presence of postoperative tumor residue, is associated with an increased risk of recurrence, and reduced overall survival.[9] Therefore, the ability to accurately monitor tumor boundaries and adjust the surgical strategy in real-time becomes essential.

Although the introduction of neuronavigation systems has improved the identification and localization of intraparenchymal lesions, their role in detecting tumor resection margins is limited, primarily due to the “brain shift” phenomenon caused by the opening of the dura mater and progressive tumor excision. Consequently, new methods have been developed to determine the boundaries of the tumor bed infiltrated with residual cancer cells and to assist neurosurgeons in achieving complete resection.[15] In a survey conducted by the European Association of Neurosurgical Societies in 2017, over 70% of respondents acknowledged the use of intraoperative techniques for controlling tumor resection, considering this process crucial in most cases. The main techniques used in such cases include intraoperative magnetic resonance imaging (iMRI), the use of 5-aminolevulinic acid (5-ALA) induced fluorescence, sodium fluorescein (SF), or IOUS.[4]

Recent studies have demonstrated that IOUS can significantly improve the rate of complete resection of brain tumors, especially in cases of glioma, by identifying tumor residues remaining after the initial resection. Compared to other intraoperative imaging techniques, such as magnetic resonance imaging (MRI)-based neuronavigation, IOUS offers the advantage of real-time imaging and superior flexibility in the face of intraoperative changes in brain anatomy. In addition, the lower costs and accessibility of IOUS make it an attractive alternative in many surgical centers.[7,12]

This paper aims to investigate the impact of using IOUS on the gross total resection (GTR) of brain gliomas in one tertiary neurosurgical center and corroborate the results with un updated systematic literature review.

MATERIALS AND METHODS

This was a retrospective, monocentric, observational, and comparative study conducted at a tertiary hospital. The objective of the study was to evaluate the impact of IOUS on extent of resection (EOR) and GTR rates in patients undergoing surgery for primary gliomas.

All consecutive patients operated between 2022 and 2024 were considered. We used the following inclusion criteria: presumptive preoperative diagnosis of glial tumor based on cerebral MRI; preoperative aim of surgery being GTR based on functional-anatomical data; use of intraoperative ultrasonography to guide surgical resection (the decision of using IOUS was made by treating physician based on surgeon’s experience, availability of equipment, and logistical feasibility); and early postoperative contrast enhanced imaging (48 h computed tomography [CT] or MRI) available. The exclusion criteria were pediatric population; tumor located in high eloquent areas; use of intraoperative cerebral mapping and functional boundaries; intended subtotal resection or biopsies; and histopathological results other than low-grade or high-grade gliomas (HGG). The control group consisted of patients operated without IOUS, identified through a retrospective review of the institutional database using a propensity score matching, performed to balance the groups in a 1:1 ratio based on age, sex, preoperative tumor volume, and Karnofsky performance scale (KPS).

Demographic data (age, sex), tumor characteristics (preoperative tumor volume, anatomical location), and functional status (preoperative KPS) were recorded.

EOR was assessed using early postoperative MRI or CT imaging and expressed as EOR% (the percentage of preoperative tumor volume resected) and GTR (defined as EOR >95%). Statistical significance was defined as P < 0.05.

Comparisons between groups included Mann–Whitney U-test for EOR and Fisher’s exact test for GTR. Subgroup analyses were conducted based on preoperative tumor volume thresholds (5 cm³ and 10 cm³) and anatomical location (frontal, parietal, temporal, and occipital, insular regions).

In addition, a learning curve effect was explored by evaluating the evolution of EOR% and GTR rates over time since IOUS started to be used in our institution (2022–2024).

Second, we have conducted a systematic literature review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, searching PubMed Database with the following algorithm: (“ultrasound” OR “ultrasonography” OR “ultra-so*” OR “echo*” OR “eco*”) AND (“brain” OR “nervous”) AND (“tumor” OR “tumor” OR “lesion” OR “mass” OR “glio*” OR “GBM”) AND (“surgery” OR “surgical” OR “microsurg*” OR “neurosurg*”), selecting the time frame from 2018 to 2024.

We identified 1319 publications. After reviewing the abstracts or titles, we selected 102 articles for in-depth evaluation. Following the exclusion of review articles, those with incompletely reported data, case presentations, or those unrelated to our topic, we included 8 studies for analysis. A pooled meta-analysis of effect sizes was not performed due to significant heterogeneity across study designs, definitions of outcomes, and imaging modalities, which would limit the validity of quantitative synthesis.

RESULTS

A total of 38 patients were included after 1:1 propensity score matching, comprising 19 patients in the IOUS group and 19 matched controls. The baseline characteristics of the two groups were generally well balanced. The mean age was 57.4 years (±15.6) in the IOUS group and 52.7 years (±7.1) in the control group. Males were predominant in the IOUS group (68.4%) compared to the control group (47.4%). Headache was the most frequent presenting symptom, affecting 68.4% of IOUS patients and 47.4% of controls. Epileptic seizures were reported in 26.3% of IOUS patients versus 10.5% in the control group, while hemiparesis was more common among controls (47.4% vs. 21.1%).

The mean preoperative tumor volume was comparable between groups (35.5 ± 25.7 cm³ for IOUS vs. 34.7 ± 25.1 cm³ for controls). Preoperative KPS scores were similar (76.3 ± 12.1 in IOUS vs. 78.4 ± 10.1 in controls). Regarding tumor localization, frontal tumors were more frequent in the control group (73.7% vs. 36.8% in IOUS), while parietal, temporal, and insular distributions were similar.

The EOR was significantly higher in the IOUS group compared to the matched controls (85.0% vs. 66.2%, P = 0.028). Furthermore, the GTR rate was significantly improved with IOUS guidance (47.4% vs. 10.5%, P = 0.029). Subgroup analysis based on preoperative tumor volume revealed that the benefits of IOUS became more pronounced with larger tumors. For patients with a tumor volume >10 cm³, IOUS was associated with both a significantly higher mean EOR (83.8% vs. 58.5%, P = 0.005) and a higher GTR rate (41.2% vs. 0%, P = 0.008). However, the relatively small number of patients (n = 38) limits the statistical power, especially for subgroup analyses.

Analysis of outcomes over time suggested the existence of a learning curve in IOUS utilization. Mean EOR progressively increased from 73.3% in 2022, to 74.4% in 2023, and reached 95.0% in 2024 (P = 0.041). Similarly, GTR rates increased from 20–25% in 2022–2023 to 70% in 2024, although without reaching statistical significance (P = 0.127). Finally, the median postoperative hospital stay was slightly longer in the IOUS group (4 days) compared to controls (3 days), but this difference was not statistically significant (P = 0.111).

Following the systematic review, we found 1,319 publications. After reviewing the abstracts or titles, we selected 102 articles for in-depth evaluation. Following the exclusion of review articles, those with incompletely reported data, case presentations, pediatric population, or those unrelated to our topic, we included eight studies for analysis [Table 1].[3,8,10,11,14,16,17,19]

Table 1:

The clinical studies resulting from the selection process according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Altogether they are cumulating 1343 adult patients. Only three of them enrolled more than 100 patients, with the largest series being reported in India with 712 glioma surgeries.[19] Most of the studies are of retrospective nature and all of them are unicentric. There is only one paper describing a prospective design.[14] Regarding the tumoral nature, only two papers focused solely on HGG,[14,17] while the others are including all grades without subdivision analyze.[3,8,10,11] One paper is referring to all tumor types, however, data regarding solely glial tumors are available and therefore was listed in our review.[1]

Regarding the preferred imaging method used, there are many variables between papers. Most of them were using standard 2D B-mode. In four studies, authors used 3D ultrasound while in one paper, contrast-enhanced ultrasound was used (CEUS).[8] There are four studies with a comparative arm [Table 2]. Three studies compare different types of ultrasonography: 2DioUS versus 3DioUS or CUEUS while others compare IOUS with standard neuronavigation resection or SF. A broad heterogeneity has been encountered in the use of ultrasound systems and transducer characteristics as range of frequencies, arrays, or sizes. However, techniques involved were not always reported.

Table 2:

Study design.

Most of the papers have stated the EOR achieved based on intraoperative MRI, early postoperative CT or MRI; however, there is now consensus regarding definition of GTR, ranging from 95% to 100% [Table 3]. In our study, we defined GTR as more than 95% resection measured on postoperative imaging.

Table 3:

Gross total resection rates.

DISCUSSION

Maximizing tumor resection has been identified as a positive prognostic factor in neuro-oncology, leading to increased progression-free intervals as well as overall survival in various subgroups of patients with both low-grade and HGG. While other prognostic factors, such as age, preoperative Karnowski index, histopathology, and tumor molecular subtypes, cannot be modified, total resection, when anatomical and functional limits allow, should be our objective as neurosurgeons.

Therefore, efforts have been made to develop technologies and techniques that assist us in achieving this goal. A systematic review of the literature published by Eljamel and Mahboob in 2016[7] analyzed the role of various intraoperative imaging techniques, such as 5-ALA, FS, IOUS, and iMRI, in achieving higher resection rates compared to neuronavigation. Regardless of the adjunct imaging technique used, significantly better resection rates were achieved compared to the classical technique, although no statistical differences were found among them; however, from a financial/economic perspective, for HGG, the most cost-effective intraoperative resection guidance technologies were SF and IOUS.[7] Recent studies suggest that advanced modalities such as CEUS and navigated 3D ultrasound further bridge the gap with higher-cost technologies. From a cost-effectiveness standpoint, IOUS and fluorescein are the most accessible adjuncts, especially in resource-limited settings.

Trevisi et al.[18] conducted a systematic review of the literature up to 2018, regarding the detection of residual tumors through IOUS. Thus, ten studies (409 diffuse gliomas) that reported data on the evaluation of intraoperative ultrasound and postoperative MRI for the resection of HGG and/ or diffuse low grade glioma (DLGG) were included in the qualitative analysis. Overall, sensitivity varied between 20% and 100%, with a combined estimate of 72.2% (95% CI 48.2–87.9%), while specificity ranged from 55.5% to 100%, with a combined estimate of 93.5% (95% CI 70.9–98.8%).[18]

Building on this data, and considering technological advancements in the recent years, with the emergence of dedicated neurosurgery probes, especially high-frequency “hockey stick” types, as well as software specifically designed for brain tissue analysis, we conducted the present review which might reflect better the use of IOUS in neuro-oncology.

The rates of GTR in glioma surgery for patients where GTR was intended preoperatory based on functional and anatomical limitation are quite sparse ranging from 42 to 91%. Interestingly, studies that are reporting data before 2020s are describing a GTR ranging around 45% while in the more recent studies, we note a median GTR of 75%. This improvement in surgical outcome might be explained in various ways. On one hand, technological advancements and the use of latest generation IOUS devices could be one factor in better visualization of tumoral margins. On the other hand, experience gained in the field of ultrasonography and the ongoing progress in image fusion and 3D navigated ultrasonography as long as the exposure to more and more peers and trainees to this method could impact present results.

Della Peppa et al.[6] retrospectively studied 230 patients with glioblastoma multiforme. They used four different techniques for resection control: 5-ALA and CEUS, 5-ALA, CEUS, and conventional microsurgical approach. Total or supramarginal resection was achieved in 69.8% of cases when both techniques were used. When only 5-ALA or CEUS was utilized, the GTR was 11.6% in both groups, while near-total resection (defined as 90–99% of tumor volume) was achieved in nearly 40% of cases, which is significantly better than the 12.7% obtained in the conventional group.[6]

A summary of the selected studies is provided in Table 1. Most of the included articles were retrospective, single-center analyses, with only one study adopting a prospective design.[14] The number of patients varied widely, from small series of 31 to large cohorts of over 700 cases, reflecting the heterogeneity of current evidence regarding the use of IOUS in glioma surgery. Study design characteristics are detailed in Table 2. It is notable that only four studies included a comparative arm, either comparing 2D versus 3D IOUS, or contrasting IOUS with fluorescence-guided surgery or standard neuronavigation. This underscores the limited availability of high-quality controlled data on the true impact of IOUS compared to other intraoperative adjuncts. GTR rates, as outlined in Table 3, ranged broadly from approximately 41% to over 90%, depending on the imaging modality and study design. Earlier studies generally reported GTR rates around 45%, whereas more recent publications, especially those incorporating advanced techniques such as CEUS or fluorescence agents, achieved GTR rates close to 75% or higher.

These findings support the notion that not only technological advancements but also the cumulative experience and familiarity with IOUS among neurosurgeons, have contributed to improved surgical outcomes over the past decade. Our own experience fits this trend, with an initial GTR rate of 47.4% increasing substantially as proficiency with IOUS increased during the study period.

Although in our review, most patients had HGG studies that have been also carried out to analyze the role of IOUS in low-grade gliomas (LGG) patients. Bø et al.[1] published their experience using IOUS on a cohort of 47 patients with primary LGG. The median EOR was 93.4% (Range 77.6– 100%), with more than half of the patients achieving 90% or more. GTR with no visible tumor on postoperative MRI was achieved in 14 patients (30%). The estimated 5-year survival rate was 84%, and they found significantly better overall survival when the residual tumor was <10 mL (estimated 5-year survival 94% vs. 53%), which further reinforces the current data on the importance of GTR.[1]

In our present observational study, the use of IOUS significantly improved both the EOR and GTR rates compared to neuronavigation-only controls. Specifically, the mean EOR was higher in the IOUS group, and the GTR rate reached 47.4%, consistent with the range reported in recent literature (42–91%). While we observed a progressive improvement in GTR over time, this trend should be considered exploratory and hypothesis-generating. No institutional changes in equipment or formal training protocols occurred during the study period, suggesting that growing surgical experience with IOUS may have contributed. Similarly, learning curve effects were also described by other authors.[2,5]

Furthermore, IOUS proved particularly beneficial in the subgroup of patients with larger tumors (>10 cm³), where it was associated with a significantly higher EOR and GTR rate, reinforcing previous findings that larger lesions benefit more from real-time intraoperative imaging.[8,14] Our study, using exclusively 2D B-mode ultrasound without fluorescence or contrast enhancement adjuncts, highlights the efficiency and accessibility of basic IOUS protocols, although combining IOUS with advanced modalities such as CEUS or SF might further enhance resection outcomes, as suggested by recent studies.[8]

Limitations

This study has several limitations that must be acknowledged. First, its retrospective, single-center design inherently limits the generalizability of the results and may introduce selection bias. The use of IOUS was based on individual surgeon preference and equipment availability, potentially reflecting differences in experience or intraoperative decision-making not fully accounted for by propensity score matching.

Second, although propensity score matching was applied to reduce confounding, residual bias cannot be entirely excluded, particularly regarding unmeasured variables such as tumor texture, degree of infiltration, or intraoperative judgment.

Third, the sample size is relatively small, which may affect the statistical power, especially in subgroup analyses. While a learning curve effect was observed over time, it was not prospectively evaluated or standardized.

In addition, this study exclusively employed 2D B-mode ultrasound without adjunct modalities such as contrast enhancement or fluorescence guidance, which limits direct comparability with more technologically advanced protocols.

Another limitation is the absence of molecular data (IDH status, MGMT methylation), which are known to influence tumor resectability and prognosis. Future prospective studies should integrate molecular parameters to better contextualize the impact of IOUS.

Nevertheless, our findings are consistent with those reported in the recent literature, including the results of our own systematic review. It is worth noting that most of the studies included in the review were also retrospective and single-center in design, with comparable sample sizes, reflecting the current evidence landscape regarding IOUS use in glioma surgery. This supports the relevance and external validity of our results, despite the inherent limitations.

CONCLUSION

Intraoperative ultrasonography remains a valuable and accessible tool in glioma surgery, offering real-time, cost-effective guidance for maximizing tumor resection. Our study demonstrated that the use of 2D IOUS significantly improved EOR and GTR rates compared to neuronavigation alone, particularly in cases with larger tumor volumes. Furthermore, a progressive improvement in surgical outcomes was observed over time, underscoring the existence of a learning curve effect with IOUS implementation.

Our findings align with recent literature data, which suggest that advances in ultrasound technology, improved surgeon experience, and the integration of adjunct techniques such as contrast-enhanced ultrasound and fluorescence have contributed to higher GTR rates in glioma surgery. However, most available studies remain retrospective and single-center, highlighting the need for larger prospective multicenter trials to further validate the role of IOUS, standardize protocols, and optimize patient outcomes.

In the era of precision neurosurgery, IOUS offers a versatile, dynamic intraoperative imaging method that can be easily integrated into the surgical workflow. Its ongoing evolution, including the development of navigated 3D systems and AI-assisted interpretation, holds great promise for further enhancing glioma surgery results in the future.

Ethical approval:

The Institutional Review Board has waived the ethical approval for this study, because the study involved retrospective analysis of fully anonymized data obtained from routine clinical care.

Declaration of patient consent:

The authors certify that they have obtained all appropriate patient consent.

Financial support and sponsorship:

Nil.

Conflicts of interest:

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation:

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

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