The Role of Early and Delayed Surgery for Infants with Congenital Brain Tumors

Jong Seok Lee; Ji Yeoun Lee; Kyung Hyun Kim; Sung-Hye Park; Eun Jung Koh; Seung-Ki Kim; Ji Hoon Phi

doi:10.4143/crt.2023.1174

Articles

Page Path: HOME > Cancer Res Treat > Volume 56(3); 2024 > Article

Original Article Pediatric cancer The Role of Early and Delayed Surgery for Infants with Congenital Brain Tumors: Jong Seok Lee¹, Ji Yeoun Lee^1,2, Kyung Hyun Kim¹, Sung-Hye Park³, Eun Jung Koh¹, Seung-Ki Kim^1,4, Ji Hoon Phi^1,4,; Cancer Research and Treatment : Official Journal of Korean Cancer Association 2024;56(3):909-919.
DOI: https://doi.org/10.4143/crt.2023.1174
Published online: December 28, 2023

¹Division of Pediatric Neurosurgery, Seoul National University Children’s Hospital, Seoul National University College of Medicine, Seoul, Korea

²Neural Development and Anomaly Laboratory, Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Korea

³Department of Pathology, Seoul National University Children’s Hospital, Seoul National University College of Medicine, Seoul, Korea

⁴Neuroscience Research Institute, Seoul National University Medical Research Center, Seoul National University College of Medicine, Seoul, Korea

Correspondence: Ji Hoon Phi, Division of Pediatric Neurosurgery, Seoul National University Children’s Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
Tel: 82-2-2072-3639 Fax: 82-2-744-8459 E-mail: phijh@snu.ac.kr

• Received: October 31, 2023 • Accepted: December 26, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2,674 Views
101 Download

prev next

Full Article

Download PDF

Abstract

Purpose
The present study aimed to evaluate the role of early and delayed surgery in congenital brain tumors and analyze the clinical outcomes of infantile brain tumors.
Materials and Methods
We performed a retrospective cohort study on 69 infantile brain tumors at a single institution from January 2008 to June 2023. Outcomes were assessed as early mortality (within 30 days following surgery) to evaluate the risk of early surgery in congenital brain tumors. Outcomes of recurrence and overall survival were analyzed in infantile brain tumors.
Results
Surgery-related early mortality appeared to occur in young and low-body-weight patients. Cut-off values of age and body weight were found to be 1.3 months and 5.2 kg to avoid early mortality. Three patients (3/10, 30%) showed early mortality in the early surgery group, and early mortality occurred in one patient (1/14, 7.14%) in the delayed surgery group, whose tumor was excessively enlarged. Younger age at diagnosis (< 3 months of age; hazard ratios [HR], 7.1; 95% confidence intervals [CI], 1.4 to 35.6; p=0.018) and leptomeningeal seeding (LMS; HR, 30.6; 95% CI, 3.7 to 253.1; p=0.002) were significant independent risk factors for high mortality in infantile brain tumors.
Conclusion
We suggest delaying surgery until the patient reaches 1.3 months of age and weighs over 5.2 kg with short-term imaging follow-up unless tumors grow rapidly in congenital brain tumors. Younger ages and the presence of LMS are independent risk factors for high mortality in infantile brain tumors.
Key words: Brain neoplasms, Infant, Congenital, Mortality, Leptomeningeal seeding, Recurrence, Survival

Introduction

Central nervous system (CNS) tumors are the most common solid tumors in childhood [1,2]. Infantile brain tumors, first identified before the age of 1 year, constitute 6.7% of pediatric brain tumors. They have different biological features from other pediatric brain tumors, challenging diagnosis and treatment [3,4]. Although survival has improved because of advanced surgical techniques and the understanding of molecular biology, infantile brain tumors show the lowest overall survival (OS) rates among the same disease groups [5,6]. The poor outcomes are attributed to biological differences in tumors, challenges in chemotherapy, and the limitation of radiation therapy in young patients [5,7,8]. Surgical resection is the mainstay of treatments for congenital brain tumors, defined as tumors first identified before 2 to 6 months of age [8-11].

On the other hand, risks of surgery in low-body-weight infants with congenital diseases are well-known in cardiac surgeries [12,13] but have never been evaluated in neurological surgeries. Especially for congenital brain tumors, the challenge remains to balance the risk of performing early surgery on newborns with low body weight or delaying surgery for patients to gain body weight with possible tumor growth [12]. Some patients may require emergent surgery due to progressive neurological impairment with rapid tumor growth, and others may be tolerable to delayed surgery. However, in congenital brain tumors, cut-off points of body weight, age, and tumor volume that can minimize surgery-related morbidity and mortality are unclear, requiring the establishment of criteria.

Based on our cohort of infantile brain tumors, we evaluated the risk of low-body-weight surgery in congenital brain tumors and analyzed clinical outcomes of recurrence and survival in infantile brain tumors.

Materials and Methods

1. Study design and population

The database of patients with pathologically confirmed brain tumors aged 1 year and younger was queried retrospectively from January 2008 to June 2023 in the clinical data warehouse at the author’s institution. We found 70 patients with infantile brain tumors. Excluding one patient who underwent the first surgery at another institution, 69 patients were finally included in the analysis. Twenty-eight patients had congenital brain tumors, defined as tumors first identified before 3 months of age in this study.

2. Clinical features and criteria for parameters

The initial diagnosis was the time when brain tumors were first identified on magnetic resonance imaging (MRI). If there was neurological impairment, hydrocephalus, or rapid tumor growth on more than two sequential imaging (ultrasonography or MRI), surgery was performed as soon as possible, and if not, surgery was performed as an elective operation. The age, body weight, and tumor volume were measured before surgery. Tumor volume was measured using the function of volumetric analysis on MRI. Leptomeningeal seeding (LMS) was evaluated on preoperative brain and spinal MRI or microscopic cerebrospinal fluid analysis (n=67).

All patients underwent surgery, and resected tumors were diagnosed according to the 2021 World Health Organization (WHO) classification of tumors of the CNS [14]. Surgery was performed by four skilled pediatric neurosurgeons who were trained at the same institution. The treatment protocol and surgical skills are relatively well-standardized and considered not significantly different among surgeons. Tumor grade was classified according to the CNS WHO (n=52) or Norris (n=10) grading systems [15]. Germ cell tumors (GCTs; n=10) followed the Norris grade. Histiocytic tumors (n=2) and soft tissue tumor (n=1) did not follow both grading systems. Low-grade tumors referred to tumors of CNS WHO grade 1, 2, and Norris grade 0, 1, and high-grade tumors referred to tumors of CNS WHO grade 3, 4, and Norris grade 2, 3. Immature teratoma with Norris grade 2 and 3 were classified as high-grade because they showed low OSs and were warranted for adjuvant therapy [16,17].

The extent of tumor resection was classified as gross total resection (GTR; 100% resection), near-total resection (NTR; 90%-99% resection), subtotal resection (50%-90% resection), and partial resection (PR; < 50% resection) on postoperative MRI (n=68) [18,19]. The postoperative MRI was acquired within 48 hours after surgery.

3. Definition of early and delayed surgery

The delayed surgery referred that the surgeon intended to delay surgery, the interval between the diagnosis and surgery was more than one month, and there were more than two follow-up imaging (ultrasonography or MRI) before surgery (n=14). Others were defined as early surgery (n=55).

4. Outcomes

Outcomes were assessed as in-hospital mortality and early mortality to evaluate the risk of early surgery in congenital brain tumors. In-hospital mortality was defined as expiration occurring during the period of hospitalization following surgery. Early mortality was defined as expiration occurring within 30 days following surgery, which reflected surgery-related mortality. Outcomes of recurrence-free survival (RFS) and OS according to histopathology, tumor grade, location, LMS, and the extent of resection were analyzed for infantile brain tumors.

5. Statistical analysis

Graphs were constructed using the ggplot2 function in R (R Foundation for Statistical Computing, Vienna, Austria). The receiver operating characteristic (ROC) analyses were performed to determine cut-off values of age and body weight to avoid early mortality using the ROC function in R. An area under the curve (AUC) of < 0.50 is considered worthless, 0.60-0.69 poor, 0.70-0.79 fair, 0.80-0.89 good, and 0.90-1 excellent. Kaplan-Meier curves were constructed using survival and survmine functions in R. RFS and OS rates were reported at 1, 2, and 3 years after surgery with 95% confidence intervals. Hazard ratios (HRs) of mortality were estimated from univariate and multivariate Cox proportional hazard survival analyses. Statistical analyses were performed by R, and a p-value less than 0.05 was considered statistically significant.

Results

1. Patients’ characteristics

Among 69 patients with infantile brain tumors, there were 44 males and 25 females (Table 1). The median ages at diagnosis and operation were 5 months and 5.5 months. Increased intracranial pressure (n=23) was the most frequent initial presentation, followed by incidental findings (n=15), increased head circumference (n=11), and seizure (n=10). The median follow-up period was 27 months after the operation.

2. Histopathological diagnosis and tumor characteristics

In infantile brain tumors (Fig. 1, S1 Table), gliomas, glioneuronal, and neuronal tumors (n=22, 31.4%), and embryonal tumors (ETs; n=22) were the most common categories, followed by choroid plexus tumors (CPTs; n=11, 15.7%), and GCTs (n=10, 14.3%). As a single pathology, atypical teratoid/rhabdoid tumor (ATRT) was the most common tumor (n=14, 20%), followed by pilocytic astrocytoma (n=7, 10%), immature teratoma (n=7), medulloblastoma (n=6, 8.6%), and choroid plexus carcinoma (n=6).

As for age distribution (Fig. 2, S1 Table), GCTs were diagnosed at exclusively early ages, which were all diagnosed before six months of age, and 80% were diagnosed before three months of age. ETs (32.1%) were the most common tumors diagnosed before three months of age. Before 3 months of age, ATRT (n=6) was the most common tumor, followed by immature teratoma (n=5), mature teratoma (n=3), circumscribed astrocytic gliomas (n=2), and pediatric-type diffuse high-grade gliomas (n=2). High-grade tumors (n=40) and supratentorial tumors (n=44) accounted for 65% and 63.8%. LMS (n=24) was identified in 35.8% of patients.

3. Risk evaluation of early and delayed surgery

The median age, body weight, and tumor volume at the operation were 5.5 months, 7.9 kg, and 30.4 mL (Table 2). There were six in-hospital mortality (8.7%) and four early mortality (5.8%) following surgery. We constructed scatter plots and curves of body weight (kg) and tumor volume (mL) according to patients’ ages (months) before surgery (S2 Fig.). The body weight tended to increase with age, but the variation in tumor volume was independent of age. Early mortality appeared to occur in low age and body weight, ranging from 1.07 to 1.27 months and from 2.72 to 4.9 kg (S3 Table). Intraoperative estimated blood loss ranged from 3,700 to 4,000 mL, and massive transfusions were performed. All four patients underwent intraoperative cardiopulmonary resuscitation (iCPR). Three patients achieved the return of spontaneous circulation, but they expired shortly after being transferred to the intensive care unit. One patient successfully recovered spontaneous circulation, but the residual tumor progressed rapidly, making it unavoidable to undergo reoperation one month later. Unfortunately, cardiopulmonary resuscitation (CPR) occurred again during reoperation, and the patient succumbed to the bleeding.

The ROC curves were generated based on patients’ age and body weight (S4 Fig.), and the ROC analyses were performed to determine the cut-off values of age and body weight to avoid early mortality (Table 3). Cut-off values were found to be 1.3 months and 5.2 kg, with AUC of 96.9 (p < 0.001) and 95.8 (p < 0.001).

We next constructed scatter plots based on patients’ ages at diagnosis and operation, and intervals between diagnosis and operation (Fig. 3). Categories represented the timing of surgery as early (n=55) or delayed (n=14), and red dotted circles represented the patients corresponding to early mortality. In the delayed surgery group, the latest age for diagnosis was 2 months, and one patient showed early mortality (7.1%). This patient (patient 1 in S3 Table) showed an excessively large and rapidly growing tumor, and surgery could not be delayed any longer than 1 month. He underwent surgery at a weight of 2.9 kg and the age of 1.07 months with a tumor volume of 953.3 mL. On the other hand, early surgery was performed in 55 patients, and 10 patients were ≤ 2 months of age at diagnosis. Three patients showed early mortality (3/10, 30.0%) in the early surgery group (≤ 2 months of age at diagnosis). In the delayed surgery group, early mortality occurred in one exceptional case, and there was no early mortality when the age at surgery was over 1.3 months (Fig. 3B). This suggests the benefit of delayed surgery in congenital brain tumors, except for exceptionally large or rapidly growing tumors.

4. Outcomes of RFS and OS

During follow-up, tumors recurred in 21 patients (30.4%) (Table 2). The mean time to recurrence after surgery was 100.6 months (S5 Fig.). The 1-year and 3-year RFS rates were 68.4% and 63.8%. There were statistically significant associations of histopathology (p=0.037), tumor location (p=0.014), and LMS (p < 0.001) with RFS.

Twenty patients (29.0%) expired during follow-up (Table 2). The mean OS time after surgery was 106.1 months (Fig. 4). The 1-year, 2-year, and 3-year OS rates were 89.6%, 78.3%, and 66.9%. There were statistically significant associations of histopathology (p=0.002), tumor grade (p=0.003), location (p=0.040), and LMS (p < 0.001) with OS. The glioma, glioneuronal, and neuronal tumor group showed no mortality.

Univariable and multivariable Cox proportional hazard survival analyses were performed for infantile brain tumors (Table 4). On univariate analysis, age at diagnosis, tumor grade, location, LMS, and the extent of resection were significantly correlated with mortality. Younger patients (< 3 months of age; HR, 4.1; p=0.002), high-grade tumors (HR, 11.0; p=0.018), infratentorial tumors (HR, 2.5; p=0.048), and tumors with LMS (HR, 10.0; p < 0.001) showed higher mortality. The NTR and PR groups presented higher mortality than the GTR group (HR, 3.7; p=0.026 and HR, 4.1; p=0.027, respectively). On multivariable analysis, age at diagnosis, LMS, and the extent of resection (PR) remained the independent risk factors for mortality. Younger patients (< 3 months of age) with LMS showed higher mortality than older patients (≥ 3 months of age) without LMS (HR, 7.1; p=0.018 for age at diagnosis, and HR, 30.6; p=0.002 for LMS). The PR group presented higher mortality than the GTR group (HR, 14.8; p=0.024).

Discussion

1. Histopathological diagnosis and tumor characteristics

In the American population, gliomas and ETs are the most common in patients who are under 19 years of age [1,7,20,21]. Glioma and ETs are predominant in infants as in the whole pediatric population. However, ETs and CPTs characteristically show peak prevalence in infants [1,21]. Our results also show that gliomas and ETs are the most common. However, there is a relatively higher prevalence of GCTs (10%) compared to that of the United States (less than 4%), demonstrating the well-known characteristics of the East Asian population [1]. Medulloblastoma (6.6%) is over four times more prevalent than ATRT (1.5%) in the whole pediatric population [20,21]. In infantile ETs, ATRT accounts for the highest proportion (63.6%), which is over 2.3 folds of the proportion of medulloblastoma (27.3%). In pediatric intracranial GCTs, germinoma is the most prevalent, which accounts for more than 50% of intracranial GCTs [22-24]. Teratoma and yolk sac tumors are known to be prevalent at infantile ages [25], and our results show that only teratoma is identified, which is the characteristic feature of infantile GCTs.

High-grade tumors are prevalent in ETs, CPTs, and GCTs. All ETs are malignant tumors of CNS WHO grade 4. High-grade tumors account for 54.5% and 70% each in CPTs and GCTs. The high prevalence of ETs and CPTs in infants and the high prevalence of GCTs in East Asian infants contribute to high mortality rates and challenges in treatments for infantile brain tumors.

On the other hand, there were tumors whose diagnoses were unclear according to the latest CNS WHO classification. Although ‘medulloblastoma, histologically defined’ is a still-existing diagnosis, ‘molecularly defined medulloblastoma’ emerged from the previous version of the classification based on methylation and transcriptome profiling. One of the most noticeable changes in the latest classification is the change in the classification of gliomas based on the state of the gene fusion and the methylation profile [14,22]. ‘Glioblastoma’ and ‘anaplastic astrocytoma’ no longer exist as pediatric tumors. Therefore, we revised past diagnoses of infantile brain tumors according to the new classification. ‘Glioblastoma’ was rediagnosed as ‘diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype,’ and ‘anaplastic astrocytoma’ was rediagnosed as ‘infant-type hemispheric glioma’.

The difference in prevalence between pediatric and infantile brain tumors suggests that infantile tumors have different biological features compared to pediatric tumors. Ethnic differences imply differences in genetic backgrounds. Changes in the diagnostic classification over time reflect the importance of genetic and epigenetic features of tumors.

2. The role of early and delayed surgery on congenital brain tumors

We first evaluate the role of early and delayed surgery on congenital brain tumors. In previous reports, the major causes of surgery-related early mortality were massive hemorrhage, myocardial infarction, severe arrhythmia, and pulmonary embolism [26]. Intraoperative bleeding was the most common factor among non-cardiac causes (52.2%). Since body fluid and blood volume are proportional to body weight, patients with low body weight have small amounts of blood volume. If patients with lower body weights experience bleeding during surgery, they are more susceptible to hypovolemia. Estimated mean circulating blood volume in full-term infants is known as 84-91.7 mL/kg [27]. Calculating with Korean standard growth data [28], circulating blood volume is 277.2-302.6 mL for males and 268.8-293.4 mL for females in newborns, and 378-412.7 mL for males and 352.8 -385.1 mL for females in 1-month-old infants. In our study, four patients who showed early mortality were around 1 month of age, and intraoperative blood loss ranged from 3,700 to 4,000 mL, which was almost 10-folds of the estimated circulating blood volume, leading to iCPR. Infants with congenital brain tumors are susceptible to hypovolemic shock while removing hypervascular tumors, and they are prone to coagulopathy and pulmonary edema after massive transfusion, which contributes to the high risk of early mortality.

To avoid this fatal event, our results can guide the timing of surgery on congenital brain tumors. Although the tumor volume showed inconsistent results, it cannot be excluded from the decision-making process for the timing of surgery. If excessively enlarged or rapidly growing tumors involve core structures and pose a risk of severe neurological injury, delayed surgery is not feasible, and the surgeon’s decision on early surgery is necessary. If a tumor does not cause severe neurological impairment without rapid growth, delayed surgery with short-term image follow-up is recommended until the patients’ age and body weight exceed the cut-off values.

3. Outcomes of RFS and OS

In a previous study on pediatric brain tumors (age ≤ 14 years), the 1-year and 2-year OS rates were 89.9%-90.0%, and 79.2%-79.4% [7]. In our study, the 1-year, 2-year, and 3-year OS rates were 89.6%, 78.3%, and 66.9%, which showed comparable results in other reports. In another study, infants exhibited lower OS compared to the other pediatric ages at yearly intervals of up to 5 years [7]. Five-year OS for all tumors were 36.7% (< 3 months), 56.0% (3-5 months), 63.8% (6-11 months), and 74.7% (1-19 years). Patients under 3 months of age especially showed the lowest OS as in our results. Younger patients have a higher proportion of malignant brain tumors [20]. The surgery-related mortality is higher in congenital brain tumors. Chemotherapy and radiotherapy are also limited in young patients.

By multivariable analysis, younger age (< 3 months of age) at diagnosis, the presence of LMS, and the extent of resection (PR) are independent risk factors for the high mortality in infantile brain tumors. Concerning histopathology, glioma, glioneuronal, and neuronal tumors showed better survival than other categories with no mortality. However, there were no differences in survival among ETs, CPTs, and GCTs. Because each histopathological category contains various pathologies with heterogeneous malignancies, the results can be inconsistent. Especially, in the category of glioma, glioneuronal, and neuronal tumors, there are not only various benign glioneuronal tumors but also highly malignant glial tumors. Therefore, individual pathologies rather than categorical diagnosis appear to be more important. Also, among 11 patients with PR, all four patients who underwent iCPR are included, which contributes to a high mortality rate. Tumors could not be properly removed in those patients due to iCPR, and four patients subsequently expired after CPR. Therefore, in this group, the impact on mortality is considerably related to surgery rather than merely the extent of tumor resection. On the other hand, LMS is a classical poor prognostic factor associated with high mortality in brain tumors [29]. Therefore, despite the development of chemotherapy, radiotherapy, and targeted therapy, treatment for younger patients with LMS remains a challenging condition. Conquering these diseases is a lifelong challenge for mankind.

4. Limitations

Our study had some limitations. First, this study was a retrospective analysis. Also, the timing of surgery was not constant among patients, and the number of patients who showed early mortality was small. Further studies require more patients with precise treatment strategies.

Electronic Supplementary Material

Supplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).

crt-2023-1174_S1_Table.pdf

crt-2023-1174_S2_Fig.pdf

crt-2023-1174_S3_Table.pdf

crt-2023-1174_S4_Fig.pdf

crt-2023-1174_S5_Fig.pdf

NOTES

Ethical Statement

The study was approved by the Institutional Review Board of the author’s institution (IRB No. 2308-020-1454). Informed consent was waived by the IRB due to the retrospective design.

Author Contributions

Conceived and designed the analysis: Lee JS, Phi JH.

Collected the data: Lee JS.

Contributed data or analysis tools: Lee JS, Park SH, Phi JH.

Performed the analysis: Lee JS, Phi JH.

Wrote the paper: Lee JS.

Critical review: Lee JY, Kim KH, Park SH, Koh EJ, Kim SK, Phi JH.

Supervision: Phi JH.

Conflicts of Interest

Conflict of interest relevant to this article was not reported.

Acknowledgements

This study was jointly supported by a grant from the Creative-Pioneering Researchers Program through Seoul National University (No. 800-20210571; to Phi JH), and a grant from SNUH Kun-hee Lee Child Cancer & Rare Disease Project, Republic of Korea (No. 22A-003-0100; to Phi JH).

Fig. 1.

Donut and pie charts showing histopathology (A), grade (B), location (C), and leptomeningeal seeding (D) of infantile brain tumors. ATRT, atypical teratoid/rhabdoid tumor; CNS, central nervous system; DIA, desmoplastic infantile astrocytoma; DIG, desmoplastic infantile ganglioglioma; DNET, dysembryoplastic neuroepithelial tumor; ETMR, embryonal tumor with multilayered rosettes; IDH, isocitrate dehydrogenase; SEGA, subependymal giant cell astrocytoma; WHO, World Health Organization.

Fig. 2.

Stacked bar charts showing the age distribution of infantile brain tumors as disease categories (A) and individual pathologies (B). ATRT, atypical teratoid/rhabdoid tumor; ETMR, embryonal tumor with multilayered rosettes.

Fig. 3.

Scatter plots are constructed according to patients’ ages at initial diagnosis (dx, months), ages at operation (op, months), and intervals (days) between initial dx and op. Ages at dx - ages at op (A), and ages at op - intervals between dx and op (B). Categories indicate the timing of surgery as early or delayed surgery. Red dotted circles refer to four early mortality cases. The horizontal dotted line indicates intervals of 30 days, and the vertical dotted line indicates ages of 1.3 months.

Fig. 4.

Kaplan-Meier curves showing the OS (n=69) of tumors (A), and OS according to histopathology (n=64) (B), tumor grade (n=62) (C), location (n=66) (D), leptomeningeal seeding (LMS; n=67) (E), and the extent of resection (n=68) (F). Time was measured from the operation. The mean OS time was 106.1 months. The 1-year, 2-year, and 3-year OS rates were 89.6%, 78.3%, and 66.9%, respectively. There were statistically significant associations of histopathology (p=0.002) (B), tumor grade (p=0.003) (C), location (p=0.040) (D), and LMS (p < 0.001) (E) with OS. ET, embryonal tumor; GCT, germ cell tumor; GNT, glioma, glioneuronal, and neuronal tumor; GTR, gross total resection; NTR, near-total resection; PR, partial resection; STR, subtotal resection.

Table 1.

Demographic and clinical data of patients with infantile brain tumors (n=69)

Parameter	Value
Male:Female	44:25 (1.76:1)
Age at diagnosis (mo)	5 (0-11.75)
Age at operation (mo)	5.5 (0.75-12)
Interval between diagnosis and operation (mo)	0.2 (0-6.93)
Postoperative follow-up periods (mo)	27 (0-154)
Clinical presentations (multiple)	69
Symptoms of IICP^a)	23 (33.3)
Incidental findings	15 (21.8)
Increased head circumference	11 (15.9)
Seizure	10 (14.5)
Developmental delay	7 (10.1)
Poor oral intake	6 (8.7)
Facial palsy	3 (4.4)
Imbalance	2 (2.9)
Respiratory depression	1 (1.5)
Aspiration	1 (1.5)

Values are presented as median (range) or number (%).

^a) Symptoms of increased intracranial pressure (IICP): vomiting, fontanelle bulging, extra-ocular movement limitation, or altered mentality.

Table 2.

Perioperative findings and outcomes of patients with infantile brain tumors (n=69)

Parameter	Value
Age at operation (mo)	5.5 (0.75-12)
Bwt at operation (kg)	7.9 (2.72-12.2)
Tumor volume at operation (mL)	30.4 (0.18-953.3)
Extent of resection	68
GTR	33 (48.5)
NTR	15 (22.1)
STR	9 (13.2)
PR	11 (16.2)
In-hospital mortality	6 (8.7)
Early mortality	4 (5.8)
Recurrence	21 (30.4)
Recurrence interval (mo)	4 (1-34)
Expire	20 (29.0)
Survival period (mo)	5 (0-27)

Values are presented as median (range) or number (%). Bwt, body weight; GTR, gross total resection; NTR, near-total resection; PR, partial resection; STR, subtotal resection.

Table 3.

The cut-off points of age and bwt to avoid early mortality

	Cut-off	Sensitivity	Specificity	AUC (95% CI)	p-value
Age - w/o early mortality	1.3	96.9	100	96.9 (92.6-100)	< 0.001
bwt - w/o early mortality	5.2	88.9	100	95.8 (90.0-100)	< 0.001

Cut-off values of age and bwt are expressed in months and kg. Sensitivities, specificities, and AUCs are expressed in percentage (%). AUC, area under the curve; bwt, body weight; CI, confidence interval; w/o, without.

Table 4.

Univariable and multivariable Cox proportional hazard survival analyses of infantile brain tumors

Variable	Univariable analysis				Multivariable analysis^a)
Variable	No.	HR	95% CI	p-value	Adjusted HR	95% CI	p-value
Sex
Male	44	1.0			1.0
Female	25	0.9	0.36-2.3	0.826	0.95	0.2-4.5	0.953
Age at diagnosis (mo)
≥ 3	53	1.0			1.0
< 3	16	4.1	1.7-9.8	0.002	7.1	1.4-35.6	0.018
Histopathology
CPT	10	1.0			1.0
GCT	10	0.7	0.18-2.9	0.644	0.4	0.05-3.0	0.373
ET	22	1.4	0.45-4.3	0.566	1.2	0.06-23.3	0.915
Grade^b)
Low	22	1.0			1.0
High	40	11.0	1.5-84	0.018	2.1	0.18-24.3	0.560
Location
Supratentorium	44	1.0			1.0
Infratentorium	22	2.5	1.0-6.1	0.048	0.4	0.02-7.4	0.511
Leptomeningeal seeding
No	43	1.0			1.0
Yes	24	10.0	3.3-30.0	< 0.001	30.6	3.7-253.1	0.002
Extent of resection
GTR	33	1.0			1.0
NTR	15	3.7	1.17-11.6	0.026	2.6	0.59-11.2	0.210
STR	9	2.1	0.49-8.7	0.319	0.9	0.14-6.1	0.942
PR	11	4.1	1.17-14.1	0.027	14.8	1.43-152.2	0.024

CI, confidence interval; CNS, central nervous system; CPT, choroid plexus tumor; ET, embryonal tumor; GCT, germ cell tumor; GTR, gross total resection; HR, hazard ratio; NTR, near-total resection; PR, partial resection; STR, subtotal resection; WHO, World Health Organization.

^a) Multivariable analysis: forty-eight data were analyzed due to 21 missing values,

^b) Low grade, CNS WHO 1+2, and Norris 0+1; High grade, CNS WHO 3+4, and Norris 2+3.

REFERENCES

1. Lamba N, Groves A, Torre M, Yeo KK, Iorgulescu JB. The epidemiology of primary and metastatic brain tumors in infancy through childhood. J Neurooncol. 2022;156:419–29. Article PubMed PDF
2. Shekdar KV, Schwartz ES. Brain tumors in the neonate. Neuroimaging Clin N Am. 2017;27:69–83. Article PubMed
3. Buetow PC, Smirniotopoulos JG, Done S. Congenital brain tumors: a review of 45 cases. AJR Am J Roentgenol. 1990;155:587–93. Article PubMed
4. Carstensen H, Juhler M, Bogeskov L, Laursen H. A report of nine newborns with congenital brain tumours. Childs Nerv Syst. 2006;22:1427–31. Article PubMed PDF
5. Jurkiewicz E, Brozyna A, Grajkowska W, Bekiesinska-Figatowska M, Daszkiewicz P, Nowak K, et al. Congenital brain tumors in a series of 56 patients. Childs Nerv Syst. 2012;28:1193–201. Article PubMed PDF
6. Manoranjan B, Provias JP. Congenital brain tumors: diagnostic pitfalls and therapeutic interventions. J Child Neurol. 2011;26:599–614. Article PubMed PDF
7. Hart M, Anderson-Mellies A, Beltrami A, Gilani A, Green AL. Population-based analysis of CNS tumor diagnoses, treatment, and survival in congenital and infant age groups. J Neurooncol. 2022;157:333–44. Article PubMed PMC PDF
8. Viaene AN, Pu C, Perry A, Li MM, Luo M, Santi M. Congenital tumors of the central nervous system: an institutional review of 64 cases with emphasis on tumors with unique histologic and molecular characteristics. Brain Pathol. 2021;31:45–60. Article PubMed PMC PDF
9. Lasky JL, Choi EJ, Johnston S, Yong WH, Lazareff J, Moore T. Congenital brain tumors: case series and review of the literature. J Pediatr Hematol Oncol. 2008;30:326–31. PubMed
10. Mazewski CM, Hudgins RJ, Reisner A, Geyer JR. Neonatal brain tumors: a review. Semin Perinatol. 1999;23:286–98. Article PubMed
11. Mohanty CB, Shukla DP, Devi BI. Brain tumors of infancy: an institutional experience and review of the literature. Pediatr Neurosurg. 2013;49:145–54. Article PubMed PDF
12. Anderson BR, Blancha Eckels VL, Crook S, Duchon JM, Kalfa D, Bacha EA, et al. The risks of being tiny: the added risk of low weight for neonates undergoing congenital heart surgery. Pediatr Cardiol. 2020;41:1623–31. Article PubMed PMC PDF
13. Mehmood A, Ismail SR, Kabbani MS, Abu-Sulaiman RM, Najm HK. Outcome of low body weight (< 2.2 kg) infants undergoing cardiac surgery. J Saudi Heart Assoc. 2014;26:132–7. Article PubMed PMC
14. Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23:1231–51. Article PubMed PMC PDF
15. Norris HJ, Zirkin HJ, Benson WL. Immature (malignant) teratoma of the ovary: a clinical and pathologic study of 58 cases. Cancer. 1976;37:2359–72. Article PubMed
16. O’Connor DM, Norris HJ. The influence of grade on the outcome of stage I ovarian immature (malignant) teratomas and the reproducibility of grading. Int J Gynecol Pathol. 1994;13:283–9. Article PubMed
17. Phi JH, Kim SK, Park SH, Hong SH, Wang KC, Cho BK. Immature teratomas of the central nervous system: is adjuvant therapy mandatory? J Neurosurg. 2005;103:524–30. Article PubMed
18. Hardesty DA, Sanai N. The value of glioma extent of resection in the modern neurosurgical era. Front Neurol. 2012;3:140.Article PubMed PMC
19. Joo JD, Kim H, Kim YH, Han JH, Kim CY. Validation of the effectiveness and safety of temozolomide during and after radiotherapy for newly diagnosed glioblastomas: 10-year experience of a single institution. J Korean Med Sci. 2015;30:1597–603. Article PubMed PMC PDF
20. Ostrom QT, Price M, Neff C, Cioffi G, Waite KA, Kruchko C, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2015-2019. Neuro Oncol. 2022;24:v1–95. Article PubMed PMC PDF
21. Ostrom QT, Price M, Ryan K, Edelson J, Neff C, Cioffi G, et al. CBTRUS statistical report: pediatric brain tumor foundation childhood and adolescent primary brain and other central nervous system tumors diagnosed in the United States in 2014-2018. Neuro Oncol. 2022;24:iii1–38. Article PubMed PMC PDF
22. Gianno F, Giovannoni I, Cafferata B, Diomedi-Camassei F, Minasi S, Barresi S, et al. Paediatric-type diffuse high-grade gliomas in the 5th CNS WHO Classification. Pathologica. 2022;114:422–35. Article PubMed PMC
23. Kaatsch P, Hafner C, Calaminus G, Blettner M, Tulla M. Pediatric germ cell tumors from 1987 to 2011: incidence rates, time trends, and survival. Pediatrics. 2015;135:e136–43. Article PubMed PDF
24. McCarthy BJ, Shibui S, Kayama T, Miyaoka E, Narita Y, Murakami M, et al. Primary CNS germ cell tumors in Japan and the United States: an analysis of 4 tumor registries. Neuro Oncol. 2012;14:1194–200. Article PubMed PMC
25. Oosterhuis JW, Stoop H, Honecker F, Looijenga LH. Why human extragonadal germ cell tumours occur in the midline of the body: old concepts, new perspectives. Int J Androl. 2007;30:256–63. Article PubMed
26. Han F, Wang Y, Wang Y, Dong J, Nie C, Chen M, et al. Intraoperative cardiac arrest: A 10-year study of patients undergoing tumorous surgery in a tertiary referral cancer center in China. Medicine (Baltimore). 2017;96:e6794PubMed PMC
27. Riley AA, Arakawa Y, Worley S, Duncan BW, Fukamachi K. Circulating blood volumes: a review of measurement techniques and a meta-analysis in children. ASAIO J. 2010;56:260–4. Article PubMed
28. Kim JH, Yun S, Hwang SS, Shim JO, Chae HW, Lee YJ, et al. The 2017 Korean National Growth Charts for children and adolescents: development, improvement, and prospects. Korean J Pediatr. 2018;61:135–49. Article PubMed PMC PDF
29. Grossman SA, Krabak MJ. Leptomeningeal carcinomatosis. Cancer Treat Rev. 1999;25:103–19. Article PubMed

Figure & Data

REFERENCES

Citations

Citations to this article as recorded by

PubReader
ePub Link

Cite

CITE: export Copy Download Format; Close

Download Citation

Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

Format:

RIS — For EndNote, ProCite, RefWorks, and most other reference management software
BibTeX — For JabRef, BibDesk, and other BibTeX-specific software

Include:

Citation for the content below
Citation and abstract for the content below

The Role of Early and Delayed Surgery for Infants with Congenital Brain Tumors

Cancer Res Treat. 2024;56(3):909-919. Published online December 28, 2023

DOI: https://doi.org/10.4143/crt.2023.1174

XML Download

Abstract
Introduction
Materials and Methods
Results
Discussion
Electronic Supplementary Material
NOTES
REFERENCES

The Role of Early and Delayed Surgery for Infants with Congenital Brain Tumors

Fig. 1. Donut and pie charts showing histopathology (A), grade (B), location (C), and leptomeningeal seeding (D) of infantile brain tumors. ATRT, atypical teratoid/rhabdoid tumor; CNS, central nervous system; DIA, desmoplastic infantile astrocytoma; DIG, desmoplastic infantile ganglioglioma; DNET, dysembryoplastic neuroepithelial tumor; ETMR, embryonal tumor with multilayered rosettes; IDH, isocitrate dehydrogenase; SEGA, subependymal giant cell astrocytoma; WHO, World Health Organization.

Fig. 2. Stacked bar charts showing the age distribution of infantile brain tumors as disease categories (A) and individual pathologies (B). ATRT, atypical teratoid/rhabdoid tumor; ETMR, embryonal tumor with multilayered rosettes.

Fig. 3. Scatter plots are constructed according to patients’ ages at initial diagnosis (dx, months), ages at operation (op, months), and intervals (days) between initial dx and op. Ages at dx - ages at op (A), and ages at op - intervals between dx and op (B). Categories indicate the timing of surgery as early or delayed surgery. Red dotted circles refer to four early mortality cases. The horizontal dotted line indicates intervals of 30 days, and the vertical dotted line indicates ages of 1.3 months.

Fig. 4. Kaplan-Meier curves showing the OS (n=69) of tumors (A), and OS according to histopathology (n=64) (B), tumor grade (n=62) (C), location (n=66) (D), leptomeningeal seeding (LMS; n=67) (E), and the extent of resection (n=68) (F). Time was measured from the operation. The mean OS time was 106.1 months. The 1-year, 2-year, and 3-year OS rates were 89.6%, 78.3%, and 66.9%, respectively. There were statistically significant associations of histopathology (p=0.002) (B), tumor grade (p=0.003) (C), location (p=0.040) (D), and LMS (p < 0.001) (E) with OS. ET, embryonal tumor; GCT, germ cell tumor; GNT, glioma, glioneuronal, and neuronal tumor; GTR, gross total resection; NTR, near-total resection; PR, partial resection; STR, subtotal resection.

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

The Role of Early and Delayed Surgery for Infants with Congenital Brain Tumors

Parameter	Value
Male:Female	44:25 (1.76:1)
Age at diagnosis (mo)	5 (0-11.75)
Age at operation (mo)	5.5 (0.75-12)
Interval between diagnosis and operation (mo)	0.2 (0-6.93)
Postoperative follow-up periods (mo)	27 (0-154)
Clinical presentations (multiple)	69
Symptoms of IICP^a)	23 (33.3)
Incidental findings	15 (21.8)
Increased head circumference	11 (15.9)
Seizure	10 (14.5)
Developmental delay	7 (10.1)
Poor oral intake	6 (8.7)
Facial palsy	3 (4.4)
Imbalance	2 (2.9)
Respiratory depression	1 (1.5)
Aspiration	1 (1.5)

Parameter	Value
Age at operation (mo)	5.5 (0.75-12)
Bwt at operation (kg)	7.9 (2.72-12.2)
Tumor volume at operation (mL)	30.4 (0.18-953.3)
Extent of resection	68
GTR	33 (48.5)
NTR	15 (22.1)
STR	9 (13.2)
PR	11 (16.2)
In-hospital mortality	6 (8.7)
Early mortality	4 (5.8)
Recurrence	21 (30.4)
Recurrence interval (mo)	4 (1-34)
Expire	20 (29.0)
Survival period (mo)	5 (0-27)

	Cut-off	Sensitivity	Specificity	AUC (95% CI)	p-value
Age - w/o early mortality	1.3	96.9	100	96.9 (92.6-100)	< 0.001
bwt - w/o early mortality	5.2	88.9	100	95.8 (90.0-100)	< 0.001

Variable	Univariable analysis				Multivariable analysis^a)
Variable	No.	HR	95% CI	p-value	Adjusted HR	95% CI	p-value
Sex
Male	44	1.0			1.0
Female	25	0.9	0.36-2.3	0.826	0.95	0.2-4.5	0.953
Age at diagnosis (mo)
≥ 3	53	1.0			1.0
< 3	16	4.1	1.7-9.8	0.002	7.1	1.4-35.6	0.018
Histopathology
CPT	10	1.0			1.0
GCT	10	0.7	0.18-2.9	0.644	0.4	0.05-3.0	0.373
ET	22	1.4	0.45-4.3	0.566	1.2	0.06-23.3	0.915
Grade^b)
Low	22	1.0			1.0
High	40	11.0	1.5-84	0.018	2.1	0.18-24.3	0.560
Location
Supratentorium	44	1.0			1.0
Infratentorium	22	2.5	1.0-6.1	0.048	0.4	0.02-7.4	0.511
Leptomeningeal seeding
No	43	1.0			1.0
Yes	24	10.0	3.3-30.0	< 0.001	30.6	3.7-253.1	0.002
Extent of resection
GTR	33	1.0			1.0
NTR	15	3.7	1.17-11.6	0.026	2.6	0.59-11.2	0.210
STR	9	2.1	0.49-8.7	0.319	0.9	0.14-6.1	0.942
PR	11	4.1	1.17-14.1	0.027	14.8	1.43-152.2	0.024

Table 1. Demographic and clinical data of patients with infantile brain tumors (n=69)

Values are presented as median (range) or number (%).

Symptoms of increased intracranial pressure (IICP): vomiting, fontanelle bulging, extra-ocular movement limitation, or altered mentality.

Table 2. Perioperative findings and outcomes of patients with infantile brain tumors (n=69)

Values are presented as median (range) or number (%). Bwt, body weight; GTR, gross total resection; NTR, near-total resection; PR, partial resection; STR, subtotal resection.

Table 3. The cut-off points of age and bwt to avoid early mortality

Table 4. Univariable and multivariable Cox proportional hazard survival analyses of infantile brain tumors

Multivariable analysis: forty-eight data were analyzed due to 21 missing values,

Low grade, CNS WHO 1+2, and Norris 0+1; High grade, CNS WHO 3+4, and Norris 2+3.