Do Glioblastomas with Syndromic Association Have Better Prognosis? A Case of Supratentorial Glioblastoma with Embryonal Tumor Differentiation in a Child with Multiple Enchondromatosis.

Glioblastoma (GBM) is an aggressive cancerous neoplasm of the brain that has numerous morphological subtypes. Primitive neuroectodermal differentiation (hereafter, referred to as embryonal tumor [ET] differentiation) in GBM is one of them and is known to occur in adults. Their presentation in pediatric population is rare and can be a source of diagnostic confusion. The dual pathology leads to doubts where one could ask whether it is ET differentiation in GBM specimen or glial differentiation in ET specimen. This histological discrimination has a bearing on the treatment regimens and prognosis. We report a case of a 10-year-old boy presenting with a supratentorial GBM, isocitrate dehydrogenase wild type with ET differentiation, and multiple benign bony lesions of both extremities. He underwent surgical excision for the brain neoplasm followed by radiotherapy and has shown prolonged survival with no recurrence. In this article, we discuss prognostic factors associated with long-term survival of these tumors. Copyright:

Introduction

Morphologic subtypes of Glioblastoma (GBM) include gliosarcoma, giant cell GBM and epithelioid GBM as well as rarer variants such as GBM associated with oligodendroglioma (GBM-O) and GBM associated with primitive neuroectodermal tumor (PNET).[12] GBM-PNET tumors (i.e., GBM with embryonal tumor [ET] differentiation) usually present in adults and have similar prognosis to pure GBMs alone.[1] We report a case of a 10-year-old boy presenting with an insular neoplasm along with multiple bony lesions of both extremities suggestive of a syndromic association. He underwent surgical excision followed by chemoradiotherapy with good outcomes and a progression-free survival of more than three years. We hypothesize that syndromic association can lead to long-term survival in GBMs.

Case Report

A 10-year-old boy was admitted in the department of neurosurgery for complaints of seizures for 1.5 months and holocranial headache for one month. The seizures were of generalized tonic–clonic semiology with no localizing features and they were controlled on tablet levetiracetam. On examination, he was neurologically intact except for his vision, which was 6/9 in both eyes with Grade 2 papilledema. General physical examination revealed multiple lesions in both right and left leg, right shoulder, and left wrist [Figure 1]. These lesions appeared to be arising from bone, free from overlying skin, non-tender, and bony hard in consistency. There were no other neurocutaneous markers present. A gadolinium-enhanced contrast magnetic resonance imaging (MRI) of brain revealed a large space occupying lesion in left insular area, which appeared hypointense on T1-weighted (T1W) and hyperintense on T2-weighted (T2W) images with heterogeneous peripheral contrast enhancement [Figure 2]. Significant mass effect was noted and a portion of the lesion encased distal branches of middle cerebral artery. There was no restriction on diffusion-weighted imaging or blooming on gradient echo images. The differential diagnosis following MRI was high-grade glioma, supratentorial ET, and ependymoma. X-rays of the limbs revealed well-defined expansile lucent lesions arising at the metaphysis with a sclerotic border, suggestive of non-ossifying fibromas or enchondromas. Biopsy of the lesion revealed enchondroma, and orthopedic opinion was taken. Chest X-ray and the whole spine screening revealed no other lesion.

Figure 1

(A) Clinical photograph showing multiple bony lesions in upper aspect of both lower limbs. (B, C) X-ray of lower limb and right humerus showing expansile radiolucent lesion arising at metaphysis

Figure 2

(A) Preoperative Non contrast Computerized Tomography head axial view showing large left frontotemporal hyperdense lesion with areas of hypodensity with mass effect. (B–D) Preoperative gadolinium-enhanced MRI brain axial view showing left frontotemporal lesion, hypointense on T1W, and hyperintense on T2W with heterogeneous-contrast enhancement

The child underwent a left frontoparietal craniotomy and the tumor was almost completely excised except for the part encasing middle cerebral artery. Owing to excess bleeding, he was shifted on ventilator and slowly weaned off. He made a full recovery with no neurological deficit. On histology, sheets of atypical glial cells with predominant small cell morphology were found, and these glial cells were arranged in perivascular pseudorosettes [Figure 3]. Immunohistochemistry (IHC) reported that the predominant part of the tumor was positive for Glial fibrillary acidic protein (GFAD) and negative for Cluster of differentiation, Leucocyte common antigen, and synaptophysin. However, the perivascular pseudorosettes were positive for synaptophysin and negative for GFAP. Molecular analysis was negative for isocitrate dehydrogenase (IDH)-1 and IDH-2. On the basis of this, the final diagnosis was reported as GBM, IDH-wild type with ET differentiation, and the patient received radiotherapy with concomitant temozolomide. He is currently on follow-up three years after surgery and is doing well with the last MRI scan showing no evidence of recurrence.

Figure 3

(A) Histopathology showing cellular sheets of atypical glial cells with predominant small cell morphology (×40). (B) Histopathology showing focal necrosis and rosette-like arrangement of cells. (C) Perivascular pseudorosette of the glial cells, some with gemistocytic morphology (×400). (D) IHC for lesion showing GFAP positivity, synaptophysin negativity, whereas pseudorosettes were positive for synaptophysin

Discussion

In the largest series on supratentorial GBM-ET tumors by Perry et al.,[1] the median age of presentation was 54 years with a range of 12–80 years. They have been rarely described in the pediatric population and when they do occur, it is important to carefully review the histology. This is carried out to discriminate these tumors from pure ETs that usually present at this age as they have different adjuvant therapy. The presence of distinct nodules (or in our case, micronodules represented by perivascular pseudorosettes) is mandatory to make a diagnosis of GBM-ET.

In our case, immunohistochemistry helped clinch the diagnosis. The GBM component was identified by the presence of predominant glial tissue, which was GFAP positive and synaptophysin negative, whereas the ET corresponded to the perivascular pseudorosettes with synaptophysin positivity.

The accepted theory for the origin of these tumors is the presence of common stem cells within gliomas that later on differentiate. Singh et al.[3] have shown the presence of neural stem cell surface markers (CD113 and Nestin) within gliomas to further provide credence to this theory. Recent evidence states that these tumors occur in younger age, have higher frequency of p53 mutations, and often have a history of low-grade glioma indicating secondary GBM.[14]

Though the survival rate for these tumors is the same as that of pure GBMs, younger age of presentation in the former probably confers some survival advantage. Song et al.[4] described the presence of IDH-1 mutation to be a favorable prognostic factor as both patients in their series with positive mutation showed survival >12 months.[4] Other studies confirm these findings in GBM-O tumors.[2] In our case, IHC being negative for both suggests that some other factors could have been responsible.

Syndromic association with GBM-ET has not yet been described and could be one of the main factors responsible in our patient. Enchondromatosis including Ollier disease and Maffucci syndrome are caused by somatic mutations of IDH-1 or 2, and therefore can be associated with Central nervous system gliomas. Achiha et al.[5] described an adult patient with enchondromatosis and oligodendroglioma (IDH-1 mutant and 1p/19q co-deleted), who was tumor free for more than 18 months.[5] Similarly, Amlashi et al.[6] have observed better outcomes for syndromic medulloblastomas, whereas Huttner et al.[7] found increased survival in children with GBM and type-1 neurofibromatosis.[6]

Treatment is maximal safe surgical excision followed by radiotherapy and concomitant temozolomide. Careful histological review allowed us to avoid unnecessary spinal irradiation. Although platinum-based chemotherapeutic agents can be reserved for treatment failures, Prelaj et al.[8] stated that early introduction of PNET-like platinum-based chemotherapy prevents recurrence.

Conclusion

GBM with ET differentiation is a rare histological variant of GBM that needs to be carefully differentiated from pure GBMs. Although the aforementioned case report in isolation cannot form definite conclusion, it does add evidence to the theory that syndromic GBMs have better prognosis and when coupled with completed Stupp regimen can have excellent long-term outcomes.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.