Sentinel report of uniquely paired collision tumors: glioblastoma multiforme and coexistent intraventricular subependymoma. Illustrative case

Abstract

BACKGROUND

The presence of intracranial collision tumors, histologically distinct tumors occurring in anatomical proximity, is quite rare. Herein, the authors describe the sentinel case of a contiguous collision tumor combination consisting of glioblastoma multiforme and intraventricular subependymoma.

OBSERVATIONS

A 67-year-old male presented with several months of progressive fatigue superimposed on more recently noted word-finding difficulty, slight left-sided weakness, and episodic confusion. He was found to have a large right frontal mass abutting the right lateral ventricle with an additional nodular focus of enhancement within the right frontal horn. The patient underwent an awake right frontal craniotomy for gross-total resection of the tumor, noted to be of two distinct histological identities.

LESSONS

Although exceptionally rare, primary glial neoplasms of various histologies can be encountered simultaneously during resection, as in this case of co-occurring glioblastoma of the right frontal lobe and right frontal horn intraventricular subependymoma. Close attention to tumoral locations and the gross appearance of specimens during resection can prime the operative neurosurgeon for success in contributing to accurate diagnoses through sending separate pathological specimens for histological analysis when qualitatively different tissue is suspected.

Collision tumors are defined as two histologically distinct tumors coexisting in the same anatomical location.¹ They are quite rare, even more so within the central nervous system (CNS). Primary brain tumors, including meningioma, schwannoma, glioma, and pituitary adenoma, have been identified as components of intracranial collision tumors.^2–4 Less commonly, metastatic tumors originating from breast, lung, or other extracranial lesions have been found to seed to the site of existing primary brain tumors. The diagnosis of collision tumors is generally established with pathology after resection of the lesions, because it is often difficult to make on the basis of preoperative imaging characteristics alone. Herein, we report the first reported occurrence of a collision tumor combination including both a glioblastoma multiforme (GBM) and subependymoma, diagnosed following a single resective surgery.

Illustrative Case

Presentation

A 67-year-old left-handed male with a remote history of tobacco use as well as some chronic hypertension and hyperlipidemia presented to the emergency department at the urging of family for evaluation of fatigue, scanning speech, slight left-sided weakness, and episodic deficits in executive function culminating in an inability to manipulate his fork and knife to eat dinner on the night of emergency room presentation. On further probing, the patient’s wife reported that he had been exhibiting mild confusion for several months, forgetting what he was doing and getting lost in previously well-traveled areas. The patient otherwise denied any nausea, headache, vision changes, or sensory disturbances. On examination, he demonstrated some word-finding difficulties, left pronator drift, and slight left upper-extremity weakness as compared with the right side.

Initial computed tomography (CT) was remarkable for a large, irregular right frontal lobe mass better characterized on magnetic resonance imaging (MRI; Fig. 1). Given the patient’s left-handedness and reported scanning speech with word-finding difficulties, functional MRI was performed to better understand his speech localization. The functional MRI did reveal activation in Wernicke’s area on the right side during the word-generation paradigm. Hence, the patient was offered awake craniotomy for tumor resection so that intraoperative speech mapping could be performed with the goal of maximally preserving language function.

FIG. 1.

Axial (A) and coronal (B) CT scans without contrast showing a hypodense parenchymal lesion neighboring a hyperdense intraventricular lesion with sample measurements of 15.7 mm × 11.3 mm in the axial view and a unidimensional measurement of 18.2 mm in the coronal view. On postcontrast T1-weighted MRI, axial (C) and coronal (D) sequences revealed a large, peripherally enhancing right frontal lobe mass with areas of central necrosis and surrounding hypodensity consistent with vasogenic edema.

Operation

The patient underwent an awake right frontal craniotomy with both neuronavigation and intraoperative fluorescein administration with the goal of optimal resection and minimal morbidity, specifically aimed at preserving speech and motor function. Conscious sedation was administered so that sedation could be lightened following dural opening and speech mapping could be performed over the cortex in the vicinity of the tumor. Bipolar stimulation was used with systematic stimulation of all cortical areas over and around the tumor site while the patient participated in audible language testing with a trained neurophysiologist. One positive response to stimulation was recorded posteroinferiorly to the tumor site, and this site was noted for future avoidance. No additional positive speech areas were noted in the immediate vicinity of the tumor. Following complete speech mapping over the exposed cortex, the patient’s sedation was deepened for tumor resection.

A corticectomy was performed around the superficial margins of the tumor, and pathological tissue was quickly entered. Samples were sent for frozen and final pathology. Microdissection was performed with the intermittent use of fluorescein microscopy to circumferentially delineate pseudomargins of the tumor. On the posterior edge of the resection, subcortical motor stimulation was employed to determine proximity to motor tracts. Great care was taken to avoid identified areas of motor involvement. At the deep aspect of the resection cavity, tumor tissue tracked all the way to the surface of the frontal horn of the right lateral ventricle and appeared to continue into the ventricle. The ventricular cavity was entered, and an additional nodular lesion was clearly visualized. This mass was carefully dissected off the ependymal surface and sent as a separate pathological specimen, given its intraventricular location and some difference in gross appearance and texture. It was observed to have a firmer, more rubberlike consistency than the tissue previously resected.

After inspection of all cavity margins, it was believed that gross-total resection was achieved. Given entry into the ventricle, an external ventricular drain was left in place. Hemostasis was obtained, and closure was performed in the customary fashion.

Postoperative Course

On waking, the patient was found to be neurologically intact with no new deficits and adequate pain control. Head CT on postoperative day 1 revealed minimal blood within the ventricles and no evidence of ventricular enlargement. Therefore, the external ventricular drain was removed on postoperative day 2, at which time MRI was performed (Fig. 2), showing satisfactory resection. The patient was discharged home with his wife on a Decadron taper while awaiting final surgical pathology results to guide further treatment.

FIG. 2.

Postoperative precontrast (A and B) and postcontrast (C and D) T1-weighted images in the axial and coronal planes show resection of intraparenchymal and intraventricular tumor components without evidence of residual disease.

Final pathology revealed the right frontal parenchymal mass to be most consistent with glioblastoma, isocitrate dehydrogenase wild type, CNS World Health Organization (WHO) grade 4. On the other hand, the intraventricular mass was determined to be most consistent with a diagnosis of subependymoma, CNS WHO grade 1 (Fig. 3). Specifically, examination of the hemispheric component of the tumor showed a high-grade infiltrating glioma consisting of astrocytic tumor cells with high mitotic activity, palisaded necrosis, and microvascular proliferation. Prominent involvement of the overlying leptomeninges was present. Examination of the periventricular component showed a low-cellularity tumor with abundant calcifications and bland round-to-oval tumor cells set in a dense fibrillar matrix, consistent with a diagnosis of subependymoma. Immunohistochemical stains, including glial fibrillary acidic protein, oligodendrocyte transcription factor 2, and Ki-67, confirmed these differing diagnoses (Fig. 3).

FIG. 3.

Hematoxylin and eosin (H&E) examination (A) of the hemispheric component of the tumor shows a high-grade infiltrating glioma consisting of astrocytic tumor cells with scattered neurons (arrow) and mitotic activity (arrowhead). Other areas of the hemispheric tumor show palisaded necrosis (star, B) consistent with a grade 4 glioblastoma. Immunohistochemistry shows the hemispheric tumor is positive for glial fibrillary acidic protein (GFAP) (C) and oligodendrocyte transcription factor 2 (Olig2) (D), with many tumor cells positive for the proliferation marker Ki-67 (E). H&E examination (F) of the periventricular component shows a low-cellularity tumor with abundant calcifications. Higher-power H&E examination (G) shows bland round-to-oval tumor cells set in a dense fibrillar matrix. Immunohistochemistry shows the periventricular tumor component is positive for GFAP (H), whereas in contrast to the hemispheric component, Olig2 is negative in the periventricular tumor cells (I), and only very rare cells are Ki-67 positive (arrow, J) consistent with a diagnosis of subependymoma.

The results were conveyed to the patient, and he and his wife opted to pursue further standard of care, including postoperative temozolomide and radiation therapy. Given the low grade of the ventricular collision tumor, the decision was made to forgo additional radiation to the intraventricular site of the resected subependymoma.

Patient Informed Consent

The necessary patient informed consent was obtained in this study.

Discussion

Observations

The occurrence of coexisting primary brain tumors of unique histology within the same patient is exceptionally rare.⁵ Among these rare cases, the most frequent combination of collision tumors involves GBM and meningioma. Primary CNS tumors can also occur in the setting of brain metastasis.⁶ Combined, there are 103 recorded cases of such collision tumors as of 2021,⁶ although no known combination of GBM and subependymoma precedes this report.

Collision tumors of different histological types most typically occur in the setting of previous radiotherapy or in association with familial tumor syndromes.^7–9 The collision tumors in our patient, with a history of neither radiotherapy nor familial tumor syndromes, represent the first reported combination of GBM and subependymoma. Asma et al.¹⁰ reported a collision tumor that similarly involved a subependymoma. However, the colliding tumor was an oligodendroglioma rather than our patient’s GBM. Their patient also had no history of genetic predisposition or irradiation.

Although the tumors appeared continuous in our patient, the difference in gross tissue appearance and texture observed by the operating surgeon prompted him to send the periventricular tissue as an independent sample for analysis. Tunthanathip et al.¹¹ reported that nearly half of reported intracranial collision tumors appeared contiguous, raising the question whether contiguous collision tumors may be an underdiagnosed entity resulting from a failure to recognize gross differences in tissue quality during resection and thus forgoing the histological analysis of what may be a unique tumor entity compared with that initially sent for pathology.

Although the most described primary CNS collision tumor phenotype (e.g., GBM and meningioma) may result from sheer statistics or an otherwise favorable oncogenic environment, collision tumors in which two tumors arise from a common progenitor stem cell (e.g., subependymoma with an oligodendroglioma or GBM) may represent a genetically similar pathogenesis. Meningiomas arise from arachnoid precursor cells. On the other hand, subependymomas, oligodendrogliomas, and GBMs all arise from glial precursor cells.^12,13 Genetic predispositions and radiation exposure may contribute to the occurrence of intracranial collision tumors. However, cases of adjacent collision tumors invoke the possibility that one tumor may promote oncogenesis in another nearby cell line via direct cell-to-cell signaling pathways.

GBMs near the lateral ventricles portend a worse prognosis, in part because of these tumors’ ability to disrupt the ependymal cell barrier, leading to altered ependymal cell health, increased cerebrospinal fluid (CSF) influx, and enhanced signaling between CSF-contained molecules and tumor cells.¹⁴ Whether it relates to this study and whether this played a role in the development of a subependymal tumor due to GBM infiltration remain uncertain. However, the calcified appearance of the intraventricular subependymoma on preoperative imaging suggests chronicity and favors the theory that the subependymoma predated the occurrence of the GBM.

Some reports have found that adjacent collision tumors do not typically invade one another and that their co-occurrence is purely a product of chance. Other studies have demonstrated one tumor type to directly coalesce with the other, again raising the possibility that one tumor may promote the oncogenesis of another cell line.¹⁵ Given that this case represents a single clinical report, it neither strongly supports nor negates the presented theories on the etiological precipitance of collision tumors. It nonetheless adds to the literature on this rare phenomenon and represents the first documented case of a GBM co-occurring adjacent to a subependymoma.

For a symptomatic primary brain tumor, resection is often the treatment of choice. For contiguous collision tumors, a single resection may occur serendipitously without preoperative awareness of multiple tumor types. However, the decision whether to operate on nonadjacent cranial tumors at the same time is less straightforward.^10,11,16 In the case of two or more spatially separated tumors, one may opt to stage resections and focus on removal of the more aggressive tumor first, with that tumor likely governing the overall prognosis.^11,16 In this case, the direct adjacency of the collision tumors resulted in a single resection, and careful examination of resected tissue prompted separate pathological specimens to be sent for analysis.

Lessons

Care should be taken to assess the gross appearance of tissue removed during a tumor resection. Although rare, even seemingly contiguous lesions can be of variant histological identities and thus change ultimate postoperative treatment plans. Ascertaining the immunohistology of intraoperatively acquired specimens is therefore of paramount importance when the neurosurgeon is faced with an unprecedented collision tumor. This case demonstrates the benefit of intraoperative vigilance and attention to tissue character, leading to the appropriate diagnosis of previously undescribed contiguous collision tumors composed of a GBM and a subependymoma.

Author Contributions

Conception and design: Silveira, Wicks, Thakrar, Delahmetovic, DeWitt, Tranmer, Liebelt. Acquisition of data: Abraham, Delahmetovic, DeWitt, Liebelt. Analysis and interpretation of data: Abraham, Delahmetovic, DeWitt, Tranmer, Liebelt. Drafting the article: Silveira, Abraham, Wicks, Thakrar, Delahmetovic, Callahan, Tranmer, Liebelt. Critically revising the article: Silveira, Abraham, Wicks, Thakrar, Delahmetovic, Callahan, DeWitt, Liebelt. Reviewed submitted version of manuscript: Silveira, Abraham, Wicks, Thakrar, Tranmer, Liebelt. Approved the final version of the manuscript on behalf of all authors: Silveira. Administrative/technical/material support: Silveira, Abraham, Callahan. Study supervision: DeWitt, Liebelt.