BACKGROUND
Epidermoid cysts are rare lesions in the central nervous system, representing 1–2% of all intra-cranial tumours.(1)
These mass lesions are typically found in the parasellar region or cerebellopontine angle. Only 15 such cases have been reported in the paediatric population to date.(1) We present a case of an intrinsic brainstem epidermoid in an 8-year-old male that was misdiagnosed and treated as a diffuse midline glioma.
CASE REPORT
An 8-year-old male child was referred to our institution for a second opinion. He had received empiric brainstem radiation at another institution for what was presumed to be a diffuse midline glioma. The child had presented to the index hospital with progressive facial weakness. An MRI scan (Figure 1) demonstrated a well-circumscribed complex cystic lesion centred in the pons. The lesion was predominantly hypointense on T1-weighted imaging (T1WI) and hyperintense on T2-weighted imaging (T2WI) with a small solid component located anteriorly within the cyst. The lesion measured 14 mm 20 mm × 21 mm and demonstrated enhancement of the nodular component post gadolinium administration. The fluid-attenuated inversion recovery (FLAIR) sequence demonstrated incomplete signal suppression. Diffusion-weighted imaging (DWI) demonstrated high signal intensity with corresponding low signal on the apparent diffusion coefficient (ADC) map, indicating restricted diffusion of the lesion. Based on these findings, the index hospital diagnosed a diffuse midline glioma and administered empiric radiotherapy.
Index MRI performed prior to empiric radiotherapy
Top left: T1 weighted imaging (T1WI) demonstrating hypointense mass lesion within brainstem. Top right: T2 weighted imaging (T2WI) revealing hyperintense cystic lesion with a small solid component located anteriorly. Bottom left: Diffusion weighted imaging (DWI) demonstrating high signal intensity. Bottom right: Corresponding low signal on the apparent diffusion coefficient (ADC) map, indicating restricted diffusion of the lesion.
When the child failed to respond to treatment, the parents sought assistance from our institution. On examination, the only clinical sign was that of a complete right-sided seventh cranial nerve lesion. A repeat MRI scan was not significantly different to the original scan. It was felt that this lesion was not a classic diffuse midline glioma and warranted surgical intervention.
The lesion was approached via a standard midline posterior fossa craniotomy. Neuronavigation (STEALTH, Medtronic, Minneapolis, USA) was used for surgical planning and tumour localization. Intra-operative neurophysiological monitoring (Medtronic NIM® Eclipse, Minneapolis, USA) was used for intra-operative mapping and neuromonitoring. The floor of the fourth ventricle was entered through the supra-facial triangle. The lesion was found to be a cyst containing liquefactive, creamy fluid. This was entirely evacuated. There were no perioperative complications and the child had an uneventful recovery.
Histopathology revealed abundant nucleated and anucleated squamous cells, in keeping with an epidermoid tumour. Clinical follow-up at 3 months post-surgery showed significant improvement with only a mild residual cranial nerve VII palsy (House and Brackmann grade 3). Follow-up MRI at 3 months and a year post-surgery revealed that the lesion is stable following near total resection.
DISCUSSION
Lesions of the brainstem involve the entire spectrum of neuropathology including demyelinating, inflammatory, infective and neoplastic conditions.(2) Pooled pathological diagnoses reveal neoplastic disease to account for approximately 92% of brainstem space occupying lesions (SOLs), with gliomas accounting for 84% of these.(2)
The largest group of neoplasms are the glioma group, which are not a distinct entity, but a heterogeneous collection of tumour types.(2) Broadly speaking, gliomas can be classified as either focal or diffuse. The focal group, accounting for about 20%, are considered low grade, are often amenable to surgery and portend a relatively good prognosis. The remaining 80% make up the diffuse group, have a poor prognosis and were previously termed diffuse intrinsic pontine gliomas (DIPG).(2) In 2016, the WHO classification of tumours of the Central Nervous System removed the term DIPG and replaced it with the term diffuse midline glioma.(3) This was based on genetic alterations in addition to histo-pathological features. Approximately 75% of these midline tumours harbour a specific genetic aberration namely the histone H3 K27M mutation. The focal group are further subclassified, with several classification systems having been proposed for these lesions, incorporating features such as size, location and imaging characteristics.(4)
Although there are no sanctioned radiological guidelines for the diagnosis of a diffuse midline glioma,(3,5) the classic features used to describe a typical diffuse midline glioma are: (1) an intrinsic, central location involving more than 50% of the axial diameter of the pons; (2) diffuse infiltration with indistinct tumour margins; (3) hypointensity on T1-weighted MR imaging sequences; (4) hyperintensity on T2-weighted sequences; (5) no or minimal contrast enhancement after the administration of gadolinium; (6) the absence of cystic or exophytic components and (7) encasement of the basilar artery.(5)
Although making a diagnosis based on radiographic evidence alone represents a well-established management paradigm in the treatment of children with a suspected diffuse midline glioma,(6) considerable interobserver variability exists between radiologists in interpreting the MRIs of diffuse midline gliomas.(7)
In contrast to diffuse midline gliomas, which have a fulminant clinical course, epidermoid cysts of the brainstem are rare congenital, slow growing tumours that grow by accumulation of epithelial cell debris and cholesterol crystals from desquamation of the inner epithelial lining of the tumour capsule.(8) They are derived from ectodermal remnants, which remain within the developing neural tube within the 3rd and 5th weeks of gestation.(8)
The key to the radiological diagnosis of these exceedingly rare lesions lies in a high index of suspicion. Brainstem epidermoids are typically hypointense on T1WI and hyperintense on T2WI with some internal heterogeneity. Occasionally, the lesion can be hyperintense on T1WI reflecting a high protein or cholesterol content, the so called “white epidermoid”. Brainstem epidermoids characteristically demonstrate restricted diffusion on the DWI/ADC map. Contrast enhancement is rare and if seen, it is of the cyst wall only. Epidermoids typically do not have perilesional oedema or haemorrhagic components. A review of the radiological findings of the current case was entirely in keeping with features of a typical epidermoid in all aspects and should not have been mistaken for a diffuse midline glioma.
If doubt exists as to the exact nature of these lesions, we argue that at the very least, a stereotactically directed biopsy should be performed. Historically, given the presumed risk of performing a brainstem biopsy, its use was generally condemned.(9) In a meta-analysis of 753 cases reviewing the diagnostic value and safety of stereotactic biopsy of brainstem tumours, Hamisch et al.(2) found a 0.6% risk for overall morbidity, a 0.6% risk of mortality and a 96.1% diagnostic success rate. Together with this mounting evidence regarding the safety of brainstem biopsies, it has become compelling to attain tissue specimens of brainstem gliomas in order to better understand the biology of these lesions such that in future more effective therapies can be offered.(10) In the recent past, because the diagnosis of diffuse midline glioma was largely made on MRI findings rather than on tissue diagnosis, biological advances in diffuse midline glioma treatment have been challenging. Given the lack of tissue biopsies, some centres have relied on post-mortem specimens from diffuse midline glioma patients for genomic analysis.(11) In 2011, a multi-disciplinary consensus statement was released justifying biopsies of typical diffuse midline gliomas as part of clinical trials to investigate tumour biology further, and recommended biopsy of atypical lesions to confirm the diagnosis and guide therapy.(12) In addition to confirming the histological diagnosis of a diffuse midline glioma, whole genome sequencing and analysis of specific altered signalling pathways in a given tumour could allow targeted therapies with molecular inhibitors. Trials are currently underway investigating this.(13)
If a diagnosis can confidently be made based on MRI alone, or if a histopathological diagnosis has confirmed an epidermoid cyst (or other focal brainstem tumour), these lesions need to be tackled surgically. Neurophysiological monitoring is mandatory for the resection of brainstem lesions. Neurophysiological monitoring allows for brainstem mapping, thus providing anatomical identification of neural structures and identifying “safe entry zones” into the brainstem.(14) In the present case, the floor of the fourth ventricle was entered through the well-described(15) “safe zone” of the supra-facial triangle. Ideal management of brainstem epidermoids is cyst aspiration along with complete resection of the cyst wall. Complete resection of the cyst wall may not always be feasible as the capsule is frequently firmly adherent to the brainstem and gross total resection should not be pursued at the expense of neural injury. Aspiration alone unfortunately carries an increased recurrence rate.(1) Neurophysiological monitoring is required throughout the procedure to provide real time information about the functional integrity of the brainstem. Efforts to avoid intra-operative spillage of the epidermoid cyst contents into the subarachnoid cisterns should be made as it may result in an aseptic meningitis. Intra-operative cyst spillage has been described in up to 50% of the reported cases.(1) Perioperative use of steroids and copious irrigation is recommended to prevent aseptic meningitis should inadvertent cyst spillage occur.
The recurrence rate following surgical resection is variable, reported as ranging between 1% and 54%.(1) Reoperation should be offered to all who present with recurrence. Historically, the perioperative mortality following surgery for these lesions was high, but with the advent of modern micro-neurosurgical techniques, neuronavigation and intra-operative neurophysiological monitoring, the rate of post-operative morbidity has declined, and long-term survival is now anticipated following surgery for these lesions. These lesions do not respond to radiotherapy or other adjuvant treatment and surgery remains the only effective management strategy for these lesions.
CONCLUSIONS
Intra-axial epidermoid cysts are rare lesions, but with a high index of suspicion should be included in the differential diagnosis of brainstem tumours that appear atypical on MRI. Given the increasing safety profile of brainstem biopsies, it may be prudent to consider biopsies in all atypical brainstem lesions. With modern-day neurosurgical techniques, including neuronavigation and intra-operative neurophysiological monitoring, the resection of intrinsic brainstem lesions is no longer forbidden and should be considered for focal lesions.