Frameless Robot-Assisted Stereotactic Biopsy is Superior to Microsurgical Biopsy for Pediatric Diffuse Intrinsic Pontine Gliomas

doi:10.21203/rs.3.rs-1886446/v1

Purpose: Diffuse intrinsic pontine gliomas are prone to high surgical risks , and they could even lead to death due to their specific sites. To determine the value of frameless robot-assisted stereotactic biopsies of DIPGs, when compared with microsurgical biopsies.

Methods: We conducted a retrospective study of 71 pediatric patients who underwent biopsies from January 2016 to January 2021. (i) group 1: microsurgical biopsies, (ii) group 2: frameless robot-assisted stereotactic biopsies. Demographic information, neuroimaging characteristics, pathological diagnoses, operation time, postoperative intensive care unit (ICU) stay time, postoperative hospitalization time, complications, cost, and perioperative mortality rate (POMR) were collected for analysis.

Results: 32 cases underwent microsurgical biopsies (group 1) and 39 cases underwent frameless robot-assisted stereotactic biopsies(group 2). All cases were accurately diagnosed after surgery. There was no significant difference in gender, age, symptom times and tumor volumes between the two groups (p > 0.05); operation time, postoperative ICU, stay time and postoperative hospitalization time were longer in group 1 than in group 2 (p < 0.001); the intraoperative bleeding volumes and cost were higher in group 1 than in group 2 (p < 0.001). Group 1 patients required more perioperative blood transfusion than group 2 (p = 0.001), and the new neurological impairments were more frequent in group 1 than in group 2 (p = 0.003). The POMR was 9.38% (3/32) in group 1 and 0 in group 2 (p = 0.087).

Conclusions: Frameless robot-assisted stereotactic biopsy was superior to microsurgical biopsy for pediatric DIPGs.

pediatric

diffuse intrinsic pontine glioma

robot

stereotactic biopsy

diagnosis

Tumors located within the brainstem comprise approximately a tenth of all pediatric brain tumors[1]. More than 50% of pediatric brainstem tumors are gliomas, and diffuse intrinsic pontine gliomas (DIPGs), accounts for > 75% of pediatric brainstem gliomas[2]. DIPG is a devastating central nervous system tumor in children with no significant therapeutic progress made in the last 50 years[3]. The survival percentage for DIPG remains very low, with a median survival of less than 1 year. Since the 1990s, diagnosis has usually been based on typical radiological characteristics using magnetic resonance imaging (MRI), without biopsy[4, 5]. But the current standard of treatment, radiotherapy, unfortunately cannot improve the prognosis of DIPG[6]. In recent years, with the progress of neuromolecular pathology[7] and the concept of personalized treatment of tumors, clinicians have gradually realized that biopsy plays an important role in the diagnosis and treatment of pediatric DIPG, which is of great significance for the determination of disease prognosis and the study of potential treatment options[8, 9]. Hence, a biopsy which combines histopathological diagnosis with molecular-genetic analysis, will become increasingly important for patients with DIPGs, and it can help develop new treatments for DIPGs, including identifying new targets and improving DIPG treatments[6].

The accepted techniques for DIPG biopsies include frame-based or frameless stereotactic biopsy, robotic biopsy, endoscopic biopsy, and microsurgical biopsy[2]. With the advancement of medical equipment, minimally invasive and precise biopsy（such as robotic biopsy）has been increasingly adopted, but a microsurgical approach is still widely used in many clinics. However, comparison and evaluation of the different surgical techniques has not been reported. This study compared microsurgical biopsy and frameless robot-assisted stereotactic biopsy to determine the relevance of robotic biopsy for diagnosing DIPG in children, and to provide evidence for its further clinical application.

Patients

A total of 71 consecutive patients (36 boys and 35 girls) with a confirmed diagnosis of DIPG who underwent biopsy at our center between January 2016 to January 2021 were enrolled in this retrospective study. The inclusion criteria were that children whose preoperative MRI indicated DIPG and resective surgery were not suitable, thus a biopsy was performed. Exclusion criteria included: 1. other types of brainstem tumors that were not DIPG; 2. DIPGs who underwent partial resection; 3. multiple lesions involving the brainstem, but the brainstem was not taken for biopsy; and 4. ≥ 18 years of age. Data collected were patient demographics (age and gender), neuroimaging characteristics, tumor volumes (these volumes were calculated based on the modified ellipsoidal formula: tumor volume = length×width²×0.5[10]), the type of biopsy, histopathological results, surgical time, postoperative intensive care unit (ICU) stay time, postoperative hospitalization time, complications, costs, and postoperative mortality rate (POMR). In our hospital, microsurgical biopsy was used for DIPG before 2019, and frameless robot-assisted stereotactic biopsy was usually performed after 2019. Here we divided the patients into two groups according to the biopsy methods: (i) group 1: microsurgical biopsies, and (ii) group 2: frameless robot-assisted stereotactic biopsies. This study was approved by the Medical Ethics Committee of Children’s Hospital of our center(IRB [2020]32). Written informed consent to participate in this study was obtained from all legal guardians.

Presurgical Examination and Surgery

All children underwent a preoperative thin-sliced computed tomography (CT) scanning and contrast enhanced MRI. In group 1, the retrosigmoid approach was conducted in 31 cases, and subtemporal approach in one case. After the dural incision, a microsurgical biopsy was conducted and the contrast-enhancing areas of the tumors were targeted for biopsy, if possible. The minimum biopsy volume of approximately 1–1.5 cm³ was considered as meeting the requirements of histopathology and genetic testing.

Patients in group 2 underwent a 3.0 T MRI with a three-dimensional (3D) T1-weighted sequence (1 mm, including no contrast and double contrast sequences) and a 3D coronal FLAIR sequence (1 mm) with fat suppression. Preoperative planning of electrode implantation was conducted using Sinoplan software (Sino-Precision, Beijing, China). The infratentorial transcerebellar approach was typically used, and the contrast-enhancing area of the tumor was targeted during biopsies, when present. The trajectory was designed to avoid the ventricles and vessels that could be observed in MRI. The surgical procedure consists mainly of the following steps: (i) settlement of fiducial markers: five stereoelectroencephalography guidance screws (Sino-Precision) were inserted in the skull; (ii) intraoperative CT and preoperative MRI images were co-registered; and (iii) patient registration and biopsy. The patient was then placed in the Mayfield-Kees head fixation under anesthesia. The ipsilateral shoulder was elevated with a shoulder roll, and the head was flexed slightly and rotated approximately 45º toward the contralateral shoulder. The degree of rotation was adjusted on the basis of the surgical target. The robot-assisted stereotactic system (Sino-Precision) was used and registered using the fiducials, and a registration error in measurement of less than 0.5 mm was defined as acceptable. The robotic arm was able to automatically reach the designated position according to preoperative planning (Fig.1). Using the robotic guiding instrument, a drill was used to enter the skull after a 1 cm incision was made in the scalp, and the dura mater was opened with a coagulation probe. Afterwards, 2−3 pieces of tissues were removed from the same trajectory in different directions using a side-cutting biopsy needle (Elekta Instruments, Stockholm, Sweden), then stepped-back 5−10 mm to remove another two tissues in different directions.

Intra- and Post-operative Evaluation

Surgical information, including surgical times, intraoperative blood losses, and perioperative blood transfusions were collected. After surgery, the patient was transferred to ICU and a CT examination was performed within postoperative 6 hours. The histopathological diagnosis success rates, perioperative mortality rates (POMR), postoperative ICU stay times, postoperative hospitalization times, and complications and costs were investigated after biopsies for brainstem tumors. The POMR was measured at two time periods: death on the day of surgery and death before discharge from hospital or within 30 days of the procedure, whichever was sooner[11].

Statistical Analysis

Statistical analysis was conducted using SPSS statistical software for Windows, version 22.0 (SPSS, Chicago, IL, USA). The Shapiro-Wilk test was used to determine the normal distribution of all continuous variables before analysis. The mean and standard deviation were calculated for parametric variables, and group comparisons were conducted using t-test; the median and interquartile ranges(IQR) calculated for non-parametric variables, and group comparisons were conducted using the Wilcoxon rank‐sum test for continuous variables, and the chi-square test or Fisher’s exact test for categorical variables. The results were considered to be statistically significant at p < 0.05.

Demographics

There were a total of 71 children; the male-to-female ratio was 1.03 (36 boys, and 35 girls). The mean age at diagnosis was 6.39 years, ranging from 1.3−13 years of age. The most common presenting signs and symptoms were ataxia or gait disturbance (n = 27, 35.03%), cranial neuropathies (n = 25, 35.21%), intracranial hypertension (n = 15, 21.13%), and hemiparesis (n = 12, 16.90%). A total of 49 patients (69.01%) presented with symptoms lasting less than 1 month, and two patients (2.82%) were asymptomatic at the time of diagnosis. A total of 32 patients underwent microsurgical biopsies (group 1) and 39 cases underwent frameless robot-assisted stereotactic biopsies (group 2). Table 1 shows the patient demographics and tumor characteristics. No significant difference was observed in gender, age, and symptom persistence time between the two groups (p > 0.05, Table1). The lesions were contrast enhanced in 23 (71.88%) patients and contrast nonenhanced in nine (28.12%) patients in group 1; similarly, the lesions were contrast enhanced in 20 (51.28%) patients and contrast nonenhanced in 19 (48.72%) patients in group 2, with no significant difference between the two groups (p = 0.092; Table 1).

Table1 Comparison of the two groups with regard to demographic information, symptom and neuroimaging characteristics

	Group 1	Group 2	P value
Gender(n)			0.914^a
Boy	16 50%)	20 (51.28%)
Girl	16 (50%)	19 (48.72%)
Age(years)	6（4.5-8.0）	7（4.0-8.0）	0.981^b
Symptoms			/
Intracranial hypertension	6 (18.75%)	9 (23.08%)
Cranial neuropathy	14 (43.75%)	11 (28.21%)
Hemiparesis	5 (15.63%)	7 (17.95%)
Ataxia or gait disturbance	11 (34.37%)	16 (41.03%)
Asymptomatic	1 (3.13%)	1 (2.56%)
Symptoms persistence time(d)	20.5（7.75-37.5）	21（8-35）	0.785^b
MRI(n)			0.092^a
Contrast enhanced	23 (71.88%)	20 (51.28%)
Contrast nonenhanced	9 (28.12%)	19 (48.72%)
Tumor volumes(mm³)	18410.96(87500.00-37869.63)	25600(16111.20-32645.41)	0.503^b
Extrapontine extension(n)			0.989^a
Yes	18	22
No	14	17
Hydrocephalus(n)			0.204^c
Yes	7	4
No	25	35
Tumor margin(n)			0.978^a
Ill defined	27	33
Well defined	5	6

MRI: magnetic resonance imaging.

Tumor volumes(mm³) were calculated based on the modified ellipsoidal formula: tumor volume = length×width²×0.5

Values are expressed as number (%), or median (interquartile range)

a CMH χ2.

b Wilcoxon rank-sum.

c Fisher’s exact.

Operative and Postoperative Parameters

The intraoperative bleeding volume was 100 (IQR 80−150) mL in group 1 and 6 (IQR 5−6) mL in group 2, thus, group 1 patients showed more intraoperative bleeding volume than group 2 patients (p < 0.001). In group 1, nine children required perioperative blood transfusions, while none required a transfusion in group 2 (p = 0.001). The surgical time, postoperative ICU stay time, and postoperative hospitalization time were longer in group 1 than in group 2 (p < 0.001), and the cost was also higher in group 1 than in group 2 (p < 0.001; Table 2).

Table2 Comparison of the two groups with regard to operative, postoperative and complications

	Group 1	Group 2	P value
Operation time(mins)	199.69±50.90	80.13±26.86	＜0.001^a
Intraoperative bleeding（ml）	100 (80-150)	6 (5-6)	＜0.001^b
Perioperative blood transfusion(n)			0.001^c
Yes	9 (28.12%)	0
No	23 (71.88%)	39 (100%)
Postoperative ICU stay times(d)	8 (5.00-12.75)	2 (1-2)	＜0.001^b
Postoperative hospitalization times (d)	18 (13-27.5)	7 (5-8)	＜0.001^b
Cost (yuan)	91052.86 (83987.43-124349.05)	30239.78 (27243.73-35694.27)	＜0.001^b
New neurological impairment	7 (21.88%)	0	0.003^c
POMR	9.38% (3/32)	0	0.087^c

ICU: intensive care unit.

POMR: Perioperative mortality rate，which was measured at two time periods: death on the day of surgery and death before discharge from hospital or within 30 days of the procedure, whichever is sooner.

Values are expressed as number (%), or median (interquartile range)

a t-test

b Wilcoxon rank-sum.

c Fisher’s exact.

Histopathology

The histopathological diagnosis success percentage was 100%, both in groups 1 and 2. All cases were diagnosed accurately after one biopsy, and no repeated surgery was performed. Postoperative pathological results were as follows (supplemental table): 71 patients (100%) had diffuse midline gliomas, 60 of them carry missense mutations in the Histone H3 genes, including 7 cases with the HIST1H3B/C (H3.1), 21 case with H3F3A(H3.3). And there were 32 cases with H3K27M mutations, but the specifics are unknown. 11 patients had a histone 3 wild-type DIPGs.

Complications and POMR

The POMR was 9.38% (3/32) in group 1 and 0 in group 2, and the difference was not statistically significant (p = 0.087, Table 2). In group 1, one patient died of respiratory failure and heart arrest on the second day after microsurgical biopsy(Fig. 2).

One patient died in the fifth day after surgery due to postoperative cerebellum and tumor edema, resulting in increased hydrocephalus, secondary diabetes insipidus, and electrolyte disorders. Another patient developed central nervous system infection and died 23 days after microsurgical biopsy. In group 2, 15% (n = 6) relevant postoperative hemorrhages occurred, but there was no associated symptom. New neurological impairment occurred in seven patients in group 1 and none in group 2, with a statistical significance (p = 0.003). The follow-up was 8 (IQR 4-12.75)months. However, the median survival time for group1 was 7.5 months, and it was 9.0 months for the group2, with the difference not statistically significant (p = 0.187) (Fig. 3).

The brainstem is one of the most complex structures in the human body and contains the most complex intracranial anatomy. All motor, sensory, sympathetic, and parasympathetic brain functions are integrated and travel through the brainstem[12]. The structural complexity of the brainstem makes surgical procedures extremely difficult. Brainstem tumors are more common in children and represent up to 10%−20% of childhood brain tumors and 25% of posterior cranial fossa tumors[8], with the most common of these tumors being DIPG. DIPG is a fatal disease and the main cause of child mortality from neoplasms of the central nervous system. So far, no effective therapy has been found for this disorder. Over the past few decades, the treatment of DIPG has progressed as a result of gradual advancements in microsurgical techniques, sophisticated imaging technologies, and most importantly, the availability of MRI. The option of DIPG biopsy at diagnosis has been used to identify molecular alterations, perform biological-based research, and evaluate new treatment options[2]. In addition, biopsies can provide further information to guide the development of pre-clinical models, which may lead to targeted therapies for DIPG[13].

Techniques for biopsies involve microsurgery, endoscopy, frame-based stereotaxy, frameless stereotaxy, and frameless robot-assisted stereotactic biopsies. Microsurgery and endoscopy biopsies of DIPG are technically challenging and have been historically associated with considerable risk[4]. If maximum accuracy is needed, skull-mounted stereotactic frames are still widely preferred[14, 15]. However, high accuracy stereotactic frames are time-consuming, complex, an inconvenient procedural workflow, and often restrict access to the surgical field, especially in pediatric cases[16–19]. Frameless stereotactic biopsy was considered to have low accuracy[14, 18, 19]. Frameless robot-assisted stereotactic biopsy combines the advantages of frameless and frame-based techniques into a highly accurate, safe, and rapid stereotactic procedure[20].

The first report of a robot-assisted stereotactic brain biopsy was in 1985 when a modified PUMA industrial robot was used to define the trajectory[21]. Robotic devices overcome limitations of frame-based and frameless techniques in terms of accuracy and usability[22]. Carai et al[3] reported their experience in DIPG stereotactic needle biopsy using the robotic stereotactic-assisted system in seven pediatric patients, in which the specimens were diagnosed and used for molecular analysis for all patients. No surgical complications were observed. One child showed a transient neurological worsening related to the biopsy that resolved within 2 weeks. Dawes et al[23] reported their experience using the Neuromate robot to perform robot-assisted stereotactic biopsy in children with tumors located within brainstems. Eleven consecutive children were identified with brain tumors located within the brainstem and related structures, who underwent 12 robot-assisted stereotactic brain biopsies, with no reported surgical complications.

The most frequent complication of stereotactic biopsy is intracranial hemorrhaging[24]. Taweesomboonyat et al[25] analyzed 85 cases of frameless stereotactic biopsies, with the incidence of postoperative intracranial hemorrhage being 19%. The incidence of hemorrhage after robot-assisted biopsy was 6.0%−13.64%[26–28]. Yasin et al[27] retrospectively analyzed 102 consecutive stereotactic biopsies using the neuromate robotic device, with the diagnosis rate being 94% and the incidence of postoperative bleeding being 12.7%. In our study, all patients were definitively diagnosed using one biopsy, and 15% relevant mild postoperative hemorrhages occurred after frameless robot-assisted stereotactic biopsies, but there was no associated symptom. Moreover, no new neurological impairment, and no perioperative deaths in children who underwent frameless robot-assisted stereotactic biopsy were observed in our cohort. Therefore, robot-assisted stereotactic biopsy in children appears to be an effective, feasible, and safe diagnostic approach.

The advantage of microsurgical biopsy is that more tumor tissue can be obtained, but the surgery is more invasive. Stereotactic biopsies are less invasive, but because less tissue is obtained, a definitive diagnosis is sometimes elusive and even repeated surgery is required. According to our findings, compared to microsurgical biopsies, frameless robotic-assisted stereotactic biopsies could provide a definitive diagnosis using a single operation with shorter surgical time, shorter postoperative ICU stay time, and postoperative hospitalization times, and less cost. Movever, there was no perioperative deaths among children who underwent frameless robotic-assisted stereotactic biopsies, whereas 3 children in the microsurgical biopsy group died. However, because of the small sample size, we could not definitvely conclude that frameless robotic-assisted stereotactic biopsy had less POMR than microsurgical biopsy.

In summary, this study described a series of patients who underwent microsurgical and frameless robotic-assisted stereotactic biopsies for pediatric DIPG. The findings suggested that safe and effective diagnoses of DIPG were possible using robotic biopsies. More importantly, frameless robot-assisted stereotactic biopsies were superior to microsurgical biopsies in pediatric DIPG, which can provide the basis for individualized treatments of children, and is an ideal strategy for precise treatment of children with DIPG.

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No competing interests reported.

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Frameless Robot-Assisted Stereotactic Biopsy is Superior to Microsurgical Biopsy for Pediatric Diffuse Intrinsic Pontine Gliomas

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Abstract

Figures

Introduction

Patients And Methods

Results

Discussion

Conclusions

References

Additional Declarations

Supplementary Files

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