Keywords ependymoma - cerebellopontine angle - chondro-osseous metaplasia - posterior fossa
- vestibular schwannoma
Introduction
Ependymomas are rare neuroepithelial neoplasms that are driven by oncogenetic events
in tumor cells that result in ependymal differentiation and comprise a mere 1.6 to
1.8% of all primary central nervous system (CNS) tumors. They are relatively well-circumscribed
neoplasms composed of ependymal differentiated tumor cells that usually arise in close
vicinity of the ventricular system of the brain, commonly in the fourth ventricle
(i.e., in the posterior fossa [PF]), supratentorial region, and in the spinal cord,
where they are frequently related to the conus or filum terminale.[1 ]
Ependymomas show a bimodal pattern of age distribution, the first peak occurring in
childhood with the mean age of presentation being 4 years where they preferentially
occur intracranially with the majority of the neoplasms occurring in the PF (ependymal-lined
ventricular system) followed by a supratentorial location. The second peak is observed
in adults, usually presenting between 20 and 40 years of age, where they typically
arise as intramedullary spinal tumors. However, an ependymoma occurring at the cerebellopontine
(CP) angle is an extremely uncommon sight, which poses diagnostic and management dilemmas
to neurosurgeons, radiologists, and neuropathologists alike.
The most recent Fifth Edition of World Health Organization (WHO) Classification of
Central Nervous System Tumors 2021 recognizes myxopapillary ependymoma and subependymoma
as distinct histopathological subtypes, which are well described in the literature.[2 ] However, the occurrence of extensive chondro-osseous metaplasia in ependymoma is
an exceptionally rare pathological finding and there is an extreme scarcity of literature
elucidating its clinicopathological spectrum and prognostic significance.
Herein, we illustrate an intriguing clinical tale of a 7-year-old male child with
PF ependymoma, not otherwise specified (NOS), CNS WHO grade 3, arising at the right
CP angle and masquerading as a vestibular schwannoma, which in itself is a rare presentation
and additionally exhibiting extensive chondro-osseous metaplastic elements, which
is an extremely infrequent histopathological manifestation. To the best of the authors'
knowledge and after a comprehensive literature search, the coexistence of these two
rare observations has merely been described once in international literature.
Case Presentation
A 7-year-old boy presented to the pediatric emergency department of a tertiary hospital
with chief complaints of projectile vomiting, headache, lethargy, and inability to
feed for the last 2 days following a trivial fall while playing outside. There was
no history of associated fever, drowsiness, altered sensorium, blurring of vision,
seizures, or behavioral change. Also, there was no long-standing history of any chronic
ailments or medications. On examination, the child was hemodynamically stable with
only mild dehydration present and there were no signs of any neurological deficits.
The evaluated Glasgow Coma Scale (GCS) score was 15 (eye-opening: 4; best verbal response:
5; best motor response: 6). There were no signs of papilledema and the rest of the
systemic examination was unremarkable as well.
He was advised a noncontrast computed tomography scan, which revealed the presence
of a well-defined soft-tissue lesion in the right CP angle with multiple foci of calcification
within the space-occupying lesion (SOL). It was seen causing compression over the
pons and the fourth ventricle and upstream minimal dilation of the third and bilateral
lateral ventricles. There was no evidence of bony hyperostosis. He subsequently underwent
a gadolinium contrast-enhanced magnetic resonance imaging (MRI) scan, which showed
a well-defined mass lesion of size 57 × 30 mm in the right CP angle cistern appearing
as hypointense on T1-weighted (T1W) and hyperintense on T2W and fluid-attenuated inversion
recovery (FLAIR) sequence with moderate heterogeneous enhancement on the postcontrast
study (as shown in [Fig. 1 ]). The lesion was abutting the basilar artery, encasing the right vertebral artery,
and compressing upon underlying pons, medulla oblongata, and fourth ventricle resulting
in upstream obstructive hydrocephalus with mild periventricular ooze. Radiological
features were indicative of a right CP angle SOL, likely to be a vestibular schwannoma.
Fig. 1 Radiological findings. Magnetic resonance imaging (MRI) scan showing a well-defined
mass lesion of size 57 × 30 mm in the right cerebellopontine (CP) angle cistern with
moderate heterogeneous enhancement on the postcontrast study. (a ) T1 axial and (b ) coronal views.
The child underwent right retromastoid-suboccipital (RMSO) craniotomy under general
anesthesia and gross total resection of the tumor was done. Intraoperatively, it was
a reddish-brown tumor, and soft to firm in consistency. The excised tumor was entirely
submitted for histopathological examination and confirmatory diagnosis.
The excised tumor mass was received in the histopathology department in 10% neutral
buffered formalin and was entirely processed. Five-micron thick, hematoxylin and eosin–stained
sections were prepared from formalin-fixed and paraffin-embedded tissue. Multiple
sections examined from the tumor tissue exhibited the presence of a cellular, well-circumscribed
tumor composed of uniform and monotonous round to oval small cells with indistinct
cellular outlines embedded in a fibrillary matrix. They had round nuclei with speckled
chromatin and inconspicuous nucleoli. The tumor was heterogeneous in composition with
the presence of nodules with a higher cellular density as compared with surrounding
syncytial areas. Characteristic perivascular pseudorosettes were present with tumor
cells arranged in a radial fashion surrounding the vascular lumina creating an intervening
anucleate zone. Numerous true ependymal rosettes were also appreciated comprising
cuboidal to columnar cells surrounding a central lumen. A striking histopathological
feature observed was the presence of extensive areas of mature cartilage and bony
trabeculae with mineralization, as metaplastic elements within the tumor proper. Large
areas of tumor necrosis were present along with dense acute inflammatory infiltrate
and atypical mitoses were frequently observed with mitotic count of 8 to 10 per high-power
field. Hyalinization of blood vessels was seen as well. However, no areas of nuclear
pleomorphism or areas of cystic or myxoid degeneration were seen (as shown in [Fig. 2 ]).
Fig. 2 Histopathological findings. (a ) Numerous true ependymal rosettes comprising cuboidal to columnar cells surrounding
a central lumen, hematoxylin and eosin ×400. (b ) Characteristic perivascular pseudorosettes with tumor cells arranged in a radial
fashion surrounding the vascular lumina creating an intervening anucleate zone, hematoxylin
and eosin ×400. (c ) Section showing the presence of large areas of mature cartilage (red asterisk ), bony trabeculae with mineralization (black arrow ), and true ependymal rosettes (red arrow ), hematoxylin and eosin ×100. (d ) Extensive areas of mature cartilage within tumor proper, hematoxylin and eosin ×400.
(e ) Extensive areas of formation of bony trabeculae within tumor proper along with true
ependymal rosettes (red arrow ), hematoxylin and eosin ×100. (f ) Large areas of necrosis within the tumor along with dense acute inflammatory infiltrate
and presence of atypical mitotic figures (inset ), hematoxylin and eosin ×400.
Immunohistochemistry (IHC) was performed on 2-µm thick sections taken on poly-L-lysine
coated slides. An extensive panel of immunohistochemical antibodies was applied to
clinch an accurate diagnosis. On IHC, the tumor cells showed diffuse immunoreactivity
for glial fibrillary acidic protein (GFAP), perinuclear dotlike and ringlike immunostaining
for epithelial membrane antigen (EMA), strong nuclear and cytoplasmic positivity for
S100, focal positivity with pancytokeratin (AE1/AE3), and membranous immunostaining
with CD 99. Ki-67 proliferation index was around 75%. The tumor cells were negative
for synaptophysin, chromogranin, IDH1, OLIG2, and neurofilament (as shown in [Fig. 3 ]).
Fig. 3 Immunohistochemistry findings. (a ) Tumor cells showing diffuse immunoreactivity for glial fibrillary acidic protein
(GFAP), immunohistochemistry ×400. (b ) Perinuclear dotlike and ringlike immunostaining for epithelial membrane antigen
(EMA), immunohistochemistry ×400. (c ) Strong nuclear and cytoplasmic positivity for S100, immunohistochemistry ×400. (d ) Focal positivity with pancytokeratin (AE1/AE3), immunohistochemistry ×400. (e ) High Ki-67 proliferation index of around 75%, immunohistochemistry ×400. (f ) Negative immunostaining with IDH1, immunohistochemistry ×400.
Based on the corroborative radiological, histopathological, and immunohistochemical
findings, a final impression of PF ependymoma, NOS, CNS WHO grade 3 with extensive
chondro-osseous metaplasia, at right CP angle was rendered.
The child was clinically stable post-surgical excision of the tumor and had been kept
on close follow-up in the pediatric neurosurgery outpatient department. He had shown
no signs of recurrence of the tumor at the previous location or elsewhere in the brain
parenchyma or spinal cord for 8 months post excision. However, after that his parents
had taken him to his native village, due to which he could not attend his regular
follow-up visits. On telephonic follow-up at the 10th postoperative month, his father
informed that his condition had rapidly deteriorated in the ninth month post-surgical
excision and had started experiencing severe headache and recurrent bouts of projectile
vomiting and had ultimately succumbed to the illness.
Discussion
Ependymomas comprise a rare group of neuroepithelial neoplasms that constitute a mere
1.6 to 1.8% of all primary CNS tumors and are relatively commonly seen in children
as compared with adults. As per the statistical figures from the Central Brain Tumor
Registry of the United States, the incidence of ependymoma varies between 0.29 and
0.6 per 100,000 persons annually.[3 ] They are composed of ependymal differentiated tumor cells arising in close association
with the ependymal-lined ventricular system, central canal of the spinal cord, or
originate from the cortical ependymal rests. They show a slight male predilection
with a male-to-female ratio of 1.3:1.[4 ] The preponderance of ependymomas to occur at a specific site vastly depends on the
age group of the affected patient. A majority (around 90%) of pediatric ependymomas
typically occur intracranially, of which most of them typically occur in or around
the fourth ventricle, whereas 65% of adult neoplasms characteristically occur in the
spinal cord.[5 ]
The most recent Fifth Edition of WHO Classification of CNS Tumors 2021 recommendations
regarding the classification of ependymal tumors have led to a paradigm transition
in prognostication and risk stratification for the patients. It has guided neurosurgeons
in refining treatment and follow-up management plans as well. It suggests that wherever
feasible, ependymomas should be subtyped using a holistic approach considering key
histopathological and molecular findings, in adjunct with the anatomic location of
the tumor. The application of DNA methylation studies helps classify ependymal neoplasms
into three main categories including the following: (1) supratentorial ependymomas,
which are characterized by two molecular subgroups involving ZFTA (previously known as C11orf95 ) and YAP1 fusion genes, with ZFTA fusions having a worse prognosis in contrast to ependymomas with YAP1 fusions, which have a favorable prognosis. (2) PF ependymomas, which are further
subclassified into Posterior fossa group A (PFA) and Posterior fossa group B (PFB)
based on the DNA methylation profile alignment. Moreover, PFA ependymomas show a globally
reduced nuclear expression of H3 p.K28me3 (K27me3) in the tumor nuclei and are characterized
by genomic stability in genome-wide copy number analysis studies. PFB ependymomas,
on the other hand, demonstrate retained nuclear immunoexpression of H3 p.K28me3, while
exhibiting chromosomal instability and aneuploidy in genetic studies. (3) Spinal ependymomas,
which can either have a classic or myxopapillary histopathology with relatively favorable
outcome or can display aggressive high-grade morphology and behavior with MYCN (MYCN
Proto-Oncogene, BHLH Transcription Factor) amplification. Additionally, one molecular
subgroup at each anatomical location comprises of tumors with histomorphological characteristics
of subependymoma. Moreover, the WHO also suggests defining ependymomas by their anatomic
location without molecular classification in those cases where molecular analysis
reveals a different alteration from that defined at the particular location, where
the term “NEC” (not elsewhere classified) is recommended. Furthermore, where molecular
studies fail or are not feasible, the term “NOS” is applied, which is especially implemented
in resource-poor countries where molecular cytogenetics are yet to be incorporated
into routine clinical practice. Although myxopapillary ependymoma and subependymoma
continue to be listed as ependymoma subtypes, papillary, tanycytic, and clear cell
histopathological variants are no longer regarded as subtypes. Another important implication
of the updated classification negates the application of the term “anaplastic ependymoma.”
However, in an integrated final diagnosis, CNS WHO grade 2 or 3 can be assigned depending
on histopathological features.[6 ] Therefore, in the present case, a final diagnosis of posterior fossa ependymoma,
NOS, CNS WHO grade 3 was rendered owing to the anatomical site of occurrence of the
tumor, which was CP angle, suggesting a posterior fossa ependymoma. Moreover, a WHO
grade 3 was attributed accounting for the high-grade histopathological features including
large areas of tumor necrosis, high mitotic count, high Ki-67 proliferation index,
and the presence of numerous atypical mitoses.
Posterior fossa ependymomas usually occur in and around the fourth ventricle. They
can arise from its floor, roof, and/or the lateral aspect. However, the CP angle is
an extremely rare site for the occurrence of ependymoma, which has been infrequently
described in limited reports by Salunke et al,[7 ] Lan et al,[8 ] Ebrahimi et al,[9 ] and Dibs et al[10 ] and, when present, poses significant diagnostic and management challenges. It can
easily masquerade as a vestibular schwannoma on imaging, which is typically known
to occur at the CP angle. Other possible mimickers at this site could be a meningioma,
vascular aneurysm or ectasia, or less commonly epidermoid cyst, arachnoid cyst, or
even metastasis from malignant primaries elsewhere. Moreover, this peculiar location
of the tumor also enhances the operative difficulties of a neurosurgeon as they can
alter the posterior fossa anatomical landmarks as they grow. However, diligent effort
should be made in distinguishing and arriving at an accurate diagnosis as they have
diverse management and follow-up protocols, with varying prognostic outcomes for the
patients. The pivotal role of histopathology along with the ancillary technique of
IHC cannot be emphasized enough and is crucial for precise diagnosis and timely formation
of appropriate management plans.
Another exceptionally uncommon and intriguing histopathological finding observed in
the present case was extensive chondro-osseous metaplasia within the tumor proper.
Quite a few theories have been proposed to explain this rare observation in ependymomas.
The most accepted postulate remains that they arise from the metaplastic transformation
of either the glial or mesenchymal component of the neoplasm.[11 ] Another interesting hypothesis suggested for glial tumors is the production of basement
membrane–like material by the neoplastic cells, which on condensation may convert
into chondroid mesenchyme.[12 ] Wang et al[13 ] concluded that the presence of chondro-osseous metaplastic elements in ependymoma
was associated with a worse outcome for the patient despite aggressive management,
indicating that their presence confers an aggressive behavior to the neoplasm. However,
due to the seldom-seen nature of this histomorphological feature, there is no definite
consensus regarding its etiopathogenesis and clinical consequences. Larger studies
with long-term follow-up of patients need to be undertaken to comprehensively elucidate
their characteristics and establish robust guidelines on their clinical implications.
The clinicopathological features of the previously described cases of ependymoma exhibiting
both chondroid and osseous metaplasia are summarized in [Table 1 ].[14 ]
[15 ]
[16 ]
[17 ]
Table 1
The clinicopathological features of the previously described cases of ependymoma exhibiting
both chondroid and osseous metaplasia
Sl. no.
Study
Age (y)
Sex
Site of occurrence
Histologic variant of ependymoma
CNS WHO grade
Follow-up and outcome
1
Bannykh and Baehring[14 ]
61
Male
Left frontal lobe
Anaplastic
3
Death at 6 mo
2
Mridha et al[15 ]
9
Male
Left cerebellopontine angle cistern
Anaplastic
3
NA
3
Gessi et al[16 ]
2
Female
Fourth ventricle
Anaplastic
3
NA
3
Female
Fourth ventricle
Ependymoma
2
NA
53
Female
Fourth ventricle
Subependymoma/ependymoma
1
NA
4
Wang et al[13 ]
5
Male
Fourth ventricle
Ependymoma
2
Death at 18 mo
5
Alkhaibary et al[17 ]
3
Male
Fourth ventricle
Anaplastic
3
No recurrence at 2 y
6
Present study
7
Male
Right cerebellopontine angle cistern
Posterior fossa ependymoma
3
Death at 9 mo post-surgical excision
Ependymomas are treated by gross total resection with/without adjuvant radiotherapy.[18 ] Several novel therapeutic drugs targeting ALK (Anaplastic lymphoma kinase), VEGF
(Vascular endothelial growth factor), mTOR (Mammalian target of rapamycin), EGFR (Epidermal
growth factor receptor), ErbB2 (Erb-B2 receptor tyrosine kinase 2) pathways are under
clinical trial for neurofibromatosis 2–associated neoplasms and offer a promising
future.[19 ]
Conclusion
This unique case report elucidates the clinical, radiological, and neuropathological
features of a scarcely described presentation of posterior fossa ependymoma occurring
at the CP angle, which itself is challenging to diagnose, and, additionally, with
concurrent presence of extensive chondro-osseous metaplasia, making it an exceptionally
uncommon occurrence. Moreover, histopathological and immunohistochemical evaluation
plays a pivotal role in distinguishing challenging masqueraders. Long-term clinical
follow-up and diligent and detailed assessment of similar rare presentations in the
future are mandatory for the establishment of robust guidelines on the clinical and
prognostic impact of this rare co-occurrence and consequently refining treatment guidelines
for the patients.
