NMC Case Report Journal
Online ISSN : 2188-4226
ISSN-L : 2188-4226
CASE REPORT
A Rare Case of Giant Congenital/Infant-type Hemispheric Glioma Harboring Concomitant ALK and EGFR Alteration
Derya KARATASSaygi UYGURIrmak Tekeli BARUTHamide SAYARAhmet DAGTEKINEmel AVCI
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2025 Volume 12 Pages 73-78

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Abstract

Infant-type hemispheric glioma is a subtype of pediatric high-grade glioma that is seen among those under the age of 3-5 years and congenital infant-type hemispheric gliomas are another subtype which is seen among those under 6 months of age. The molecular features and overall survival of infant-type hemispheric gliomas are distinct from those of pediatric and adult high-grade gliomas.

The present study reports a fraternal twin case of a giant hemispheric infant-type hemispheric glioma diagnosed at the age of 2 months and treated with gross total resection. Even though the Ki-67 proliferative index of the tumor was 70%, she has been surviving for 4 years. After molecular analysis, the first case of infant-type hemispheric glioma that had concurrent echinoderm microtubule-associated protein-like 4::anaplastic lymphoma kinase gene fusion and an A269V point mutation on exon 7 in epidermal growth factor receptor gene was identified.

Among echinoderm microtubule-associated protein-like 4::anaplastic lymphoma kinase gene fusion cases, the present study presents a rare twin case of giant infant-type hemispheric glioma that has a long recurrence-free survival without radiation or targeted therapy. In contrast, the neurocognitive test results of this case at the age of 4 years corresponded to 12-15 months of age.

Introduction

Pediatric high-grade glioma (HGG) accounts for 8%-12% of all pediatric brain tumors.1) Among the pediatric HGGs, those developing under the age of 3 or 5 years are referred to as infant-type hemispheric glioma (ITHG), whereas those younger than the age of 6 months are called congenital HGGs. No clear incidence rate was reported for these extremely rare patients.

The clinical course of malignant infantile glioma is clearly distinguishable from gliomas in older children and adults with clinical outcomes and specific molecular findings.2) This study reports a rare twin case of giant hemispheric ITHG harboring echinoderm microtubule-associated protein-like 4::anaplastic lymphoma kinase (EML4::ALK) fusion and epidermal growth factor receptor (EGFR) point mutation (exon 7 p.A289V) which was treated with gross total resection (GTR) and conventional chemotherapy at approximately 2 months of age.

Case Report

The patient is one of the female dichorionic fraternal twins with a normal birth weight. Her twin sister was born healthy, they were both born on term. Her parents and all known relatives are considerably inbred, to the best of our knowledge. Three twins were found in pedigree and the twins presented here are the first twins diagnosed with central nervous system (CNS) cancer. The first twins in the family were the granddaughters of a 6th-degree relative, who had cerebellopontine angle schwannoma, whereas the second twins were the aunts of the case examined in this study.

On day 45 after birth, right frontoparietal swelling and inward deviation of the left eye were noted on the patient. Type 1 (T1)- and type 2 (T2)-weighted magnetic resonance imaging (MRI) sequences revealed a giant multicystic right hemispheric lesion exhibiting a heterogeneous signal. A well-defined huge solid and cystic lesion, in size of 100 × 80 × 75 mm, was causing a midline shift in the right hemisphere (Fig. 1). No tumor was detected in the rest of the neuroaxis. After the GTR, the patient was kept intubated for 5 days due to apnea attacks during the extubation attempts. She was discharged from the intensive care unit on day 17 postoperatively and developed a focal seizure in the left lower extremity, which was taken under control using antiepileptic medication.

Fig. 1

Preoperative (A, B, C, D), and 4th year (E, F, G) radiological images of infantile high-grade glioma. A) At the age of 2 months, preoperative axial contrast-enhanced T1-weighted MRI (magnetic resonance imaging) indicates heterogeneous high gadolinium uptake in a giant hemispheric right-sided tumor (100 × 80 × 75 mm). B) Preoperative axial T2-weighted MRI indicates huge cystic components of the tumor. C) Preoperative coronal contrast-enhanced T1 weighted MRI demonstrates the 13.9 mm midline shift, obstruction of lateral ventricles, and the extent of the tumor. D) Punctate calcifications on the anterior aspect of the tumor can be seen on the preoperative non-contrast-enhanced computed tomography. Correct one: Postoperative 4th-year axial (E) and coronal contrast-enhanced T1-weighted (F) and coronal T2-weighted (G) MRI reveals no sign of tumor recurrence.

MRI: magnetic resonance imaging; T1 (longitudinal relaxation time) T2 (transverse relaxation time)

The patient received 4 cycles of chemotherapy (vincristine, etoposide, carboplatin and vincristine, etoposide, cyclophosphamide, Mesna protocols), but no radiotherapy. Four years follow-up MRI showed no sign of recurrence. The Ankara Developmental Screening Inventory3) was used to assess cognitive, motor, language, and social skills/self-care profiles at the age of 4 years. The developmental level of the child corresponded to 12-15 months of age.

Stratification, fascicular array, focal hemangiopericytoma-like pattern, and perivascular clusters with areas of necrotic foci were observed on the tumor cells during histopathological evaluation. Immunohistochemistry results were positive for glial fibrillary acidic protein, vimentin, p53, alpha thalassemia/mental retardation syndrome X-linked mutation, CD56, and S-100, whereas they were negative for synaptophysin, epithelial membrane antigen, CD34, SAL4, H3K2M, and STAT6 (Fig. 2). INI-1 expression was retained. The Ki-67 proliferative index was found to be 70%. Histopathological and immunohistochemical results indicated the diagnosis of ITHG, and further molecular analysis was performed. Following genomic DNA isolation, an Oncoplus V2 kit covering 709 cancer-related genes, additional hotspot regions, and homopolymeric regions for microsatellite instability was used to study genomic alterations. The generated library was sequenced using DNBSEQ-G400 with default parameters aiming to generate an average of 1000-3000X depth per target region. As a result of DNA sequencing analysis, EML4::ALK fusion breakpoints indicated a fusion between 2 genes at intronic regions 2 and 19 of chromosome 2 (Fig. 3). A known somatic, exon 7 A289V mutation in the EGFR gene was detected at 8% of the allele fraction on both strands (Fig. 4). Analyzing the tumor sample, microsatellites were found to be stable when compared to normal tissue samples of a similar sequencing nature. Tumor mutational burden (TMB) was only higher than that of 8% of the samples of a similar kind and was thus categorized as TMB-Low (0.96 mutations/megabase) status. To classify the tumor's methylation class, DNA was extracted and subjected to analysis using Illumina Human Methylation EPIC BeadChip arrays, which allowed for the profiling of C-phosphate-G, CHH, and CHG (H = A, C, or T) methylation patterns across the entire genome. The resulting intensity data files were then uploaded to the website molecularneuropathology.org, and the Brain Classifier (version 12.8) was used. The analysis yielded a methylation classification of "infant-type hemispheric glioma" with a match score of 0.98. Informed consent was obtained from the participant.

Fig. 2

A) The hematoxylin- and eosin-stained section shows a highly cellular tumor with a spindle fibrillar appearance and oval-round-shaped tumor cells with eosinophilic-clear cytoplasm (100× magnification). B) Tumor cells exhibit positivity for glial fibrillary acidic protein (100× magnification). C) The tumor has a high Ki-67 index (200× magnification).

Fig. 3

Visual representation of the detected EML4::ALK fusion in the sequenced sample. Breakpoints indicate a fusion between 2 genes at intronic regions 2 and 19, respectively. The bottom of the image indicates the fusion points and several chimeric reads supporting the fusion event. (Only some of the reads are shown due to space constraints)

Fig. 4

Detected somatic EGFR mutation visualized by Integrative Genomics Viewer. A known somatic EGFR p. Ala289Val mutation was detected at 8% allele fraction at both strands of reads.

Discussion

ITHG is a subgroup of "pediatric high-grade diffuse gliomas". However, these tumors differ significantly from those observed in the pediatric age group both in terms of molecular features and overall survival (OS). Moreover, many different clinical data on survival among ITHG cases were reported in the literature. Without conducting any molecular analysis, Tauziède-Espariat et al.4) reported a very short OS of 16 months. Brat et al.5) stated that 3 of 6 congenital HGG cases survived more than 5 years after conventional chemotherapy, even though only one case underwent GTR and a hemispheric lesion was sub-totally resected. Macy et al.6) reported that 1 of 5 congenital HGGs, whose molecular analysis, tumor extension, and targeted treatment were not identified, survived for 110 months after GTR. Similarly, a case of ITHG survived for 87 months after GTR and conventional chemotherapy, but the size, recurrence, and molecular characteristics of the tumor were not revealed.7) Demonstration of clinical and molecular features has the utmost importance to understand the differences in surveys and the natural behavior of the tumor, as well as to evaluate the effectiveness of targeted therapies.

From the molecular perspective, ALK, ROS1 (ROS proto-onkojen 1), NTRK (neurotrophin receptor kinase), and MET fusions in congenital ITHG have moderate outcomes compared to fusion negatives as better clinical outcomes and responses to targeted therapies are achieved in kinase fusion-positive ITHG.8) For a small group with these fusions, the 5-year OS of infants with ALK-fused hemispheric gliomas was found to be 53.8% and better than others.2) In the context of ALK fusion-positive ITHGs, the median time to death was reported to be 3 years, and better clinical outcomes were associated with targeted therapies.2,9,10)

Moreover is repeated and could be delated the growing body of evidence supports the distinct clinical outcomes and biological features of ALK fusion partners, as well as their varying responses to ALK inhibitors in ITHG.11-18) The literature on the partial, complete, and near-complete responses to targeted therapy, clinical outcomes, and ALK fusion partners in ITHGs is given in Table 1. In response to lorlatinib (ALK tyrosine kinase inhibitor), a case with QKI::ALK fusion was successfully treated and had complete clinical improvement (recovery) despite lung metastasis.11) Following GTR, the local recurrence of ITHG with ZNF397-ALK fusion was treated with lorlatinib, no evidence of the disease was noted for 15 months,12) but excessive weight reduction was reported. Since ALK inhibitors cause severe side effects on brain development and their use can be limited in congenital cases, the clinical results of GTR and conventional chemotherapy are also valuable. Due to rarity, the literature focused on the efficacy of various treatment modalities such as targeted therapies,8,11,12,14) superiority of conventional chemotherapy, targeted therapies, and/or GTR was not clearly revealed. A PPP1CB::ALK fusion case also survived 3 years without a recurrence after GTR alone.13) A medium-sized and gross totally resected thalamic HGG with EML4::ALK fusion survived for 10 years without recurrence after conventional chemotherapy.14) The case of ITHG harboring an EML4::ALK fusion in the present study survived without a recurrence for 4 years after conventional chemotherapy and GTR. In this particular case with ITHG harboring ALK and EGFR alterations, this study suggests that the combined application of conventional chemotherapy may have a positive effect on the surveillance of gross totally resected tumors that do not show significant invasion into the surrounding brain tissue. Moreover, the present study reports the first known case of ITHG that had concurrent EML4::ALK fusion and an A269V point mutation in the EGFR gene.

Table 1

Congenital/Infant-type hemispheric gliomas harboring specific ALK fusion partners in the literature and their clinical outcomes

Authors ALK fusion partner Age Extention of tumor Location Treatment Resection Follow up Response
CT: Conventional chemotherapy, GTR: Gross Total Resection, STR: Subtotal resection, EGFR: Epidermal growth factor receptor, EML4: Echinoderm microtubule-associated proteinlike 4, ALK: Anaplastic lymphoma kinase
Lai et al.11 QKI::ALK 3 years Moderate Parietooccipital Lorlatinib GTR/metastatic lesion + 15 weeks Complete Response
Greenwell et al.12 ZNF397-ALK 3 months Moderate Frontal CT/
Lorlatinib
GTR/GTR 1 year Complete Response
Aghajan et al.13 PPP1CB::ALK 3 months Giant Hemispheric None GTR 3 years Complete Response
Gilani et al.14 EML4::ALK 8 weeks Moderate Thalamus CT GTR 10 years Complete Response
Sai et al.15 SOX5::ALK Newborn Moderate Lateral ventricle Lorlatinib STR 14 months Partial
Response
Bagchi et al.16 SPECC1L::ALK 3 years Giant Hemispheric Lorlatinib STR none Near Complete
Response
Shahab et al.17 ATIC::ALK 3 months Moderate Parietal Lorlatinib STR 2 years Near Complete
Response
Olaciregui et al.18 PPP1CB::ALK 2 months Moderate Temporal Alectinib and Lorlatinib STR/Near total/Near total 4.5 years Near Complete
Response
Present case EML4::ALK
EGFR p.A289V
2 months Giant Hemispheric CT GTR 4 years Complete Response

Both EML4::ALK fusion and EGFR p.A289V mutation which encodes the amino acid of the extracellular domain increase the cellular receptor tyrosine kinase activity.19) This pathway is also known to be crucial for cancer pathogenesis. EGFR mutation and EML4::ALK fusion are separately related to lung cancer and brain tumors such as glioma. EGFR mutation at alanine 289 is related to tumor invasion and a characteristic feature among de novo adult HGGs. The drugs targeting EGFR are often insufficient to treat brain tumors because of heterogeneity and limited penetration into the blood-brain barrier.20) It was identified in only 7.8% of pediatric HGGs.21) Clinical outcomes among congenital cases are lacking since EGFR expression is extremely low or absent.22) The twins with giant ITHG with concomitant EGFR and EML4::ALK alteration in the present study had a remarkable recurrence-free survival despite non-targeted therapy after GTR although the negative impact of EGFR mutation was known in adult glioblastoma.15,20) Further studies on more clinical cases are needed to reveal the clinical effects of the rare concomitant mutation in this mosaic ITHG.

Twin cases with CNS cancers shed light on the family-based heritability and environmental factors of cancer, as well as whether being a twin increases the predisposition to cancer.23-25) A large two-nation study showed that early-onset glioma carries higher familial risks than late-onset glioma.23) Particularly, the risk of the genetic heritability of ITHGs in siblings or twins could not be clearly demonstrated in the literature because of the rarity of this condition. In the present study, being a fraternal twin was thought to be inherited in her family through the consanguineous match. However, there was no evidence about the inheritance of glioma among twins. However, the identification of ITHG in the fraternal twin sister among 6 siblings was noticeable. Considering the literature, it may suggest that environmental factors have a principal causative role in cancer.25) In contrast, the paucity of data in the literature regarding neurocognitive evaluation for ITHG should be taken into consideration. Besides that, both the OS and the functional outcome of the patients should be further investigated. Neurocognitive test results of this case at the age of 4 years corresponded to 12-15 months of age according to the Ankara Developmental Screening Inventory.3)

Conclusion

There are challenges in the management of giant ITHGs, including the difficulty in GTR of giant tumors, perioperative blood transfusion, postoperative apnea, seizures, and inability to give radiotherapy due to toxicity. Malignant histopathological features in ITHG might not correlate to poor outcomes, and molecular analysis should be conducted to better understand the nature of the tumor. Even though the concomitant EML4::ALK fusion and EGFRp.A289V mutation resulted in long-lasting recurrence-free survival in the present case after GTR and conventional chemotherapy regimens, further investigations on more clinical cases are needed to reveal the clinical effects of the rare heterogeneity. The neurocognitive outcomes of the patient examined in this study were poor and corresponded to 12-15 months of age while at the age of 4 years. Thus, neurocognitive outcomes should be considered while following these patients.

Acknowledgments

We are grateful to Ayça Erşen Danyeli, who is assoc. Prof. in Acıbadem Hospital Pathology Department, for her kind support for the methylation profiling.

Conflicts of Interest Disclosure

All authors have no conflict of interest.

References
 
© 2025 The Japan Neurosurgical Society

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