Background and Importance
Medulloblastoma (MB) is regarded as an aggressive embryonal primitive neuroectodermal neoplasm of the cerebellum of the World Health Organization (WHO) grade IV, arising from germinal matrix cells of the primitive neural tube. The exact reason behind this malignancy is not well identified, but numerous familial cancer syndromes and John Cunningham polyomavirus infections can play a crucial role in the tumor’s physiopathology [1, 2,  3, 4, 5]. MB frequently occupies the midline of the cerebellum, and cerebellar hemispheres are known as the conventional origin for MBs in adults. MBs can be observed either in the midline of the cerebellum or intra-cerebellar hemispheric or even in the Cerebellopontine Angle (CPA) area, and approximately 80% of childhood MBs tend to arise at the vermis and the apex of the fourth ventricle [2, 6, 7]. Among the molecular subtypes of MBs, group 3 and group 4 mainly involve the fourth ventricle, notwithstanding sonic hedgehog (SHH) MB primarily occupying the cerebellar hemispheric [6].
More importantly, Gross Total Resection (GTR) is preferred for CPA MBs, as it is associated with a significant risk of degenerative impacts on cranial nerve seven (CN-VII) and adjacent components, while the maximal extent of surgical resection is regarded as a standard approach for managing this malignancy [6]. Herein, we sought to outline the general features of CPA MB, its diagnostic dilemma, significant correlated prognostic factors, and multidisciplinary procedure for its management. 
Case Presentation
A 23-year-old man presented to our center complaining of a generalized pulsatile headache, imbalance, swallowing impairment, and right-sided hearing loss for the past 20 days. Physical examination showed a bilateral gag reflex impairment, right-sided hemifacial paresis, and right-sided sensory neural hearing loss. The rest of the physical examination was normal.
The patient initially underwent a computed tomography CT scan of the brain to investigate intracranial lesions. The CT scan of the brain showed a hyper-dense extra-axial mass lesion (41×37 mm) in the right CPA with a significant compression effect on the fourth ventricle, causing three-ventricular obstructive hydrocephalus (Figure 1). Magnetic Resonance Imaging (MRI) depicted a well-defined heterogeneous extra-axial, lobulated, dural-based mass lesion in the right CPA, hypointense on the T1 sequence, and hyperintense on the T2 sequence compared with adjacent parenchyma, which has a bright heterogeneous enhancement during gadolinium injection. A significant mass effect was observed on the adjacent parenchyma, brain stem, and fourth ventricle without evidence of parenchymal edema (Figures 2, 3, 4, 5, 6 & 7). The patient underwent emergent surgery the next day due to the mass effect and hydrocephalus. In a lateral position, his head was fixed using a Mayfield fixator. Concerning the hydrocephalus, we initially placed a posterior external ventricular drainage to control and decrease intracranial pressure during surgery. Under the Electroencephalography (EEG) monitoring of cranial nerves, we approached the patient via the retrosigmoid sub-occipital lateral craniectomy toward the CPA. We drained Cerebrospinal Fluid (CSF) from cisterna magna, then gently dissected the CPA adhesion bands where the tumor presented. At first look, the lesion was creamy and soft. We initially obtained tumor tissue fragments for the frozen section, which revealed large anaplastic cells in favor of MB. The tumor adhered to the VII-VIII cranial nerve complex. It was completely resected with the preservation of the VIII cranial nerve. VII cranial nerve was repaired using a sural nerve graft. All other cranial nerves were intact on direct vision and EEG neuromonitoring.
In the postoperative examination in the intensive care unit, no new neurological deficit was detected, and swallowing significantly improved as well as gag reflex. Histopathologic evaluation revealed hypercellular neoplasm with round cell morphology, frequent mitosis, and areas of necrosis. Areas of large cell transformation with vehicular nuclei and prominent nucleoli are evident. Immunohistochemical (IHC) stain is diffusely positive for synaptophysin, focally positive for Glial Fibrillary Acidic Protein (GFAP) and Epithelial Membrane Antigen (EMA), and negative for cytokeratin (CK), Leukocyte Common Antigen (LCA), and Olig2. KI67 showed a high proliferative index. The final diagnosis was MB, a large cell variant, WHO grade IV (Figure 7). In the histologic and immunohistochemistry evaluation of the tumoral tissue, GFAP was positive, EMA was focally positive, synaptophysin was patchy positive, and Ki-67 was 60% positive in large anaplastic cells, while Olig-2 was reported negative. The above markers and histologic re-evaluation confirmed the diagnosis of MB grade VI. The patient underwent a radiochemotherapy regimen and was discharged in good clinical condition on the sixth postoperative day. 
In the histologic and immunohistochemistry evaluation of the tumoral tissue, GFAP was positive, EMA was focally positive, synaptophysin was patchy positive, and Ki-67 was 60% positive in large anaplastic cells, while Olig-2 was reported negative. The above markers and histologic re-evaluation confirmed the diagnosis of MB grade IV. Table 1 provides more details regarding the previously reported CPA-MBs in the literature.




Discussion
MB is among the posterior fossa’s most common childhood malignant tumors, accounting for 16%-20% of all pediatric tumors [8]. It also represents approximately one-fourth of all neoplasms of central nervous systems and 40% of posterior fossa tumors and is known as the second most prevalent inter-cranial tumor after pilocytic astrocytoma [6, 9]. The CPA MB is more common in adults, with a male sex ratio (1, 3:1) [6, 10, 11]. Six to eight-year-old juveniles consist of most case reports of this malignancy [6, 11, 12]. MB predominantly occurs as an intra-axial phenomenon arising from the subependymal matrix or external granular layer of the inferior medullary vellum of the vermis with an intrinsic proclivity to leptomeningeal diffusion [13, 14, 15]. The most common variant in the adult group of MB is SHH. It accounts for approximately 60% of all patients in adulthood [16]. Classic and desmoplastic have higher incidence rates among the histological subgroups of CPA MBs [7]. Despite growing bodies of literature justifying the exact cause and origin of MB tumors, it remained controversial among investigators. In this regard, some researchers emphasize that CPA MBs can arise from proliferating remnants in the posterolateral medullary velum or residue of the external granular layer of the flocculus hemispheres. Others accentuate the assumption that is based on the upward and lateral migration of germinal cells from the roof of the fourth ventricle during the formation of the external granular layer of the cerebellum, a theory that confirms the CPA localization of MB. Albeit 80% of MBs are located in the cerebellar midline at the inferior vermis and typically project into the fourth ventricle, they can also be present in the sidewall of the cerebellum’s hemisphere or disseminate exophytically into the C.P. angle zone [3, 4, 6, 9, 14, 15, 17, 18, 19, 20]. The extra-axial manifestation of MB in other sites is regarded as a very unexpected phenomenon [4]. Extra-axial incidence of the MBs can probably be attributed to residues of the neural crest cells, which persisted particularly from where MB arose.
The lateral recess of the fourth ventricle contains a portion of the Lower Rhombic Lip (LRL), which is strongly susceptible to Wingless Tumors (WNT) expression. Subsequent empirical investigations clarified the hypothesis that WNT MB may originate from the midline of the fourth ventricle; thereby, they potentially tend to lateralize in the CPA [5, 21].
Paul Gibson et al. compared genes expression, marking human WNT and SHH MBs in the Upper Rhombic Lip (URL) and LRL, and their investigations bring SHHMBs tumor up as a neoplasm originating from the glutamatergic granule neural precursor cells (GNPCs, cells forming the external granular layer of cerebellum)of the URL whereby they are often present in the convexity of cerebella’s hemispheres and vermis; however, WNT-MBs tumors developed from cells of the dorsal brainstem demonstrating that brainstem could be regarded a potential source of WNT MBs by infiltrating of WNT to the embryonic brainstem leading to the high incidence of WNT-MBs genes expression in LRL and embryonic dorsal and lateral brainstem [21]. The inability of SHH MBs to engage the fourth ventricle floor in the CPA region is consistent with recent findings of Tao Wu et al. [6]. Several lines of literature identify SHH MBs as the only type among all MBs subgroups in which the tumors are located in the intra-hemispherical position. Hence, to the best of the authors’ knowledge, the first reported case of extra-axial midline tentorial adult MB followed by a dural-tail sign by Doan NB et al. suggests an unconventional inter-hemispheric SHH MBs [2].
In contrast to midline MBs in most pediatric populations, almost half of MBs in adult groups are located laterally in the cerebellar hemispheres, reflecting miscellaneous etiology and pathogenesis pathways [1]. In this respect, desmoplastic MBs are much more common in the adult population, with approximately 71% of them accompanied by the lateral cerebellar hemisphere manifestation, contrary to 12.5% occurrences of the mostly midline-restricted characteristics of the classical MBs variant [2]. The non-specific triad of vomiting, lethargy, and headache is observed in most pediatric patients with MB [14]. 
Rapid progressive intracranial hypertension-related symptoms (headache, nausea, vomiting, and papilledema), cerebellar ataxia and diplopia, and nystagmus due to cranial nerve involvement are the most common clinical presentations of MBs. Other manifestations, such as gait problems, backache, and bowel and bladder failures, can include spinal metastatic MBs [8, 10, 11, 22].
Generally, trigeminal, abducens, facial, and vestibule-cochlear impairments, lower cranial nerve problems, and symptoms of cerebellar malfunction often highlight CPA neoplasms. Insofar as an initial and aggressive behavior of cerebellar tumor symptoms and gait disorders, including progressing gait ataxia propose the probable presence of the CPA MB lesions, early impairment of facial and vestibule-cochlear nerve, and positional nystagmus reflect an early sign of a probable existing vestibular-acoustic schwannoma, respectively [15]. Despite the intrinsic microscopic appearance of pink or gray MBs observed either in calcified or hemorrhaged regions, histopathological characteristics of the tumor in the CPA region and lateral cerebellar cortex include heterogonous isomorphic sheets of densely round to oval hyperchromatic cells surrounded by scanty cytoplasm along with the dramatically nucleocytoplasmic ratio [4, 8]. Regretfully, neither a reliable pathognomonic nor radiographic approach is recommended as an assistant for different MBs from other subjects with a high probability of developing in the CPA, including vestibular schwannoma and meningioma, which collectively account for 85%-90% of all CPA tumors in adults followed by the meningioma, primary cholesteatomas, and epidermoid tumors [6, 9, 22, 23]. Notably, CT characteristics of CPA MBs include prominent hyperdense homogeneous mass in most assessments and in 10% of cases, it may show calcification [10]. Despite MBs, often presenting as poor-demarcated soft friable mass and central compacted lesions, other tumors of postcranial fossa, including epidermoid cysts, are attenuated on non-enhanced CT due to sufficient cytoplasm and less dense matrix, and they demonstrate well-demarcated lesions concerning their high lipid content, such as cholesterol [8, 14, 24]. No exclusive radiological features exist that favor a definitive diagnosis of CPA MBs malignancies.
MBs arising either from CPA or intraventricular region characterized by iso-hypointense to gray matter on T1-Weighted Images (T1W1) with a predominantly heterogeneous contrast enhancement paradigm after the addition of gadolinium, most likely due to excessive tumors cellularity, inadequate blood supplies, or necrosis, howbeit their appearance ranges from hypointensity to hyperintensity to gray matter on T2-weighted (T2W2) sequences due to the incremented nucleus to cytoplasm ratio of neoplasms cells or diminished free water [9]. Although most MRI assessments reveal heterogeneous Gd-enhancement agents, MBs may vary from uniform to patchy enhancements, and 10%-15% of cases are not allocated to heterogeneous aspects, which canaled to misdiagnosis [5, 9, 20]. Normal integrity and symmetry of the internal auditory canals rather than other CPA lesions, particularly schwannoma, confirm MBs. However, the dural-tail-sign regrades as an unspecific hallmark mostly denoting meningioma, Ninh Ba Doan et al. represented an extra-axial midline tentorial MBs in adults who were associated with this indicator [2, 4, 10]. To the best of the authors’ knowledge, only 12 prior cases of extra-axial CPA-MBs have been reported in the English-written literature [12].
Abbreviations: CPA, cerebellopontine angle; MB, medulloblastoma; CN, cranial nerve; MRI, magnetic resonance imaging; WHO, World Health OrganizationIt is well established that MBs have a marked propensity to metastasize to the leptomeninges, spinal canal, and supratentorial section via CSF and subarachnoid space, with an overall incidence of 38%-60% of all patients and a range of 20% to 40% of pediatrics populations. The spinal canal is the most common pathway at approximately 58%. Moreover, to the best of our knowledge, spinal metastasis from CPA MB has been reported just in one patient, followed by refusing postoperative radiotherapy. Recently, 2 patients suffering MB type SHH (desmoplastic and anaplastic) have been reported, manifesting leptomeningeal tumor dissemination [4, 10,  15, 18, 25, 26, 27, 28, 29]. The total survival chance of CPA MBs is similar to other regions, and with timely surgery and radiotherapy, the 5-year survival rate for MBs is 25%-70% [9, 22]. In almost half of the cases, recurrence occurs, and they survive for about 15 months after relapse [22]. Our patient did not observe residue or recurrences during the first postoperative year.
Microsurgery for total gross resection using the retro mastoid approach accompanied by craniospinal irradiation and chemotherapy is recommended as a safe and effective mainstay in children and adults to prohibit tumor growth [9, 10]. The operation aims to determine the histological diagnosis and deal with probable hydrocephalus. Approximately 10% to 30% of patients with MBs require postoperative ventricular shunting [14, 22].
Chemotherapy is less endured in adults and seemingly did not provide complete and valuable outcomes compared with the pediatric groups. Due to the lack of subsisting randomized control trials, a good understanding of differentiation between radiotherapy with or without adjuvant chemotherapy remained uncovered; consequently, chemotherapy is strongly recommended for adults in the high-risk group. In that respect, our patient underwent radiochemotherapy and was discharged in good clinical condition on the sixth day after the operation. Supplementary immunological procedures that have recently gathered momentum in adult cranial neoplasms represent Programmed Death-1 (PD-1) and the Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4) as the agents, diminishing immune responses in both MBs and gliomas [12]. 
Conclusion
Regardless of the rare presentation of extra-axially CPA, neurosurgeons should be aware of this scarce entity. Clinical considerations and early radiologic evidence should be considered in subjects with suspected MB. A total tumor excision approach followed by aggregative chemotherapy/radiotherapy is designed to hinder tumor relapse.

Ethical Considerations
Compliance with ethical guidelines
Written informed consent was obtained from the patients for publication of their clinical details and clinical evidence.

Funding
This research did not receive any grant from funding agencies in the public, commercial, or non-profit sectors. 

Authors' contributions
Conception and design: Kaveh Ebrahimzadeh; Data Analysis and Interpretation: Hesameddin Hoseini Tavassol; Drafting the article: Mohammad Mirahmadi Eraghi; Critically revising the article: Omidvar Rezaeimirghaed, Mohammad Hallajnejad; Reviewing the submitted version of the manuscript and approving the final version of the manuscript: All authors. Kaveh Ebrahimzadeh and Mohammad Mirahmadi Eraghi contributed equally to this work.

Conflict of interest
The authors declared no conflict of interest.

References

1. De Oliveira F, Landeiro JA, De Castro I. Adult hemispheric cerebellar medulloblastoma. Surgical Neurology International. 2018; 9. [DOI:10.4103/sni.sni_341_17] [PMID] [PMCID]
2. Doan N, Patel M, Nguyen H, Janich K, Montoure A, Shabani S, et al. A rare extra-axial midline tentorial adult medulloblastoma with dural-tail sign mimicking a meningioma. Asian Journal of Neurosurgery. 2018; 13(02):475-7.[DOI:10.4103/1793-5482.228563] [PMID] [PMCID]
3. Kalamarides M, Dewolf E, Couvelard A, Shahidi A, Bouccara D, Cyna-Gorse F, et al. Extraaxial primitive neuroectodermal tumor mimicking a vestibular schwannoma: diagnostic and therapeutic difficulties: Report of two cases. Journal of Neurosurgery. 2001; 94(4):612-6. [DOI:10.3171/jns.2001.94.4.0612] [PMID]
4. Pant I, Chaturvedi S, Gautam VK, Pandey P, Kumari R. Extra-axial medulloblastoma in the cerebellopontine angle: Report of a rare entity with review of literature. Journal of Pediatric Neurosciences. 2016; 11(4):331. [DOI:10.4103/1817-1745.199477] [PMID] [PMCID]
5. Xia H, Zhong D, Wu X, Li J, Yang Y, Sun X. Medulloblastomas in cerebellopontine angle: epidemiology, clinical manifestations, imaging features, molecular analysis and surgical outcome. Journal of Clinical Neuroscience. 2019; 67:93-8. [DOI:10.1016/j.jocn.2019.06.013] [PMID]
6. Wu T, Qu PR, Zhang S, Li SW, Zhang J, Wang B, et al. The clinical treatment and outcome of cerebellopontine angle medulloblastoma: a retrospective study of 15 cases. Scientific Reports. 2020; 10(1):9769. [DOI:10.1038/s41598-020-66585-7] [PMID] [PMCID]
7. Batista KM, de Eulate-Beramendi SA, Rico M, Rodrigo V, Batista YE, Reyes KY. Atypical bilateral cerebellopontine angle medulloblastoma: differential diagnosis, immunohistochemical features and radiological presentation. Contemporary Oncology/Współczesna Onkologia. 2017; 21(3):249-53. [DOI:10.5114/wo.2017.69593] [PMID] [PMCID]
8. Presutto E, Chappell M, Fullmer J, Ezhapilli S. Posterior fossa medulloblastoma in an atypical extra-axial location: A case report. Radiology Case Reports. 2018; 13(2):365-70. [DOI:10.1016/j.radcr.2018.01.007] [PMID] [PMCID]
9. Noiphithak R, Yindeedej V, Thamwongskul C. Cerebellopontine angle medulloblastoma with extensive nodularity in a child: case report and review of the literature. Child's Nervous System. 2017; 33:839-42. [DOI:10.1007/s00381-016-3325-6] [PMID]
10. Spina A, Boari N, Gagliardi F, Franzin A, Terreni MR, Mortini P. Review of cerebellopontine angle medulloblastoma. British Journal of Neurosurgery. 2013; 27(3):316-20. [DOI:10.3109/02688697.2012.741733] [PMID]
11. Northcott PA, Robinson GW, Kratz CP, Mabbott DJ, Pomeroy SL, Clifford SC, et al. Medulloblastoma. Nature Reviews Disease Primers. 2019; 5(1):11. [DOI:10.1038/s41572-019-0063-6] [PMID]
12. Singh S, Kumar N. Extraaxial cerebellopontine angle medulloblastoma with multiple intracranial metastases in adult: A rare case report with a review of literature. Asian Journal of Neurosurgery. 2020; 15(03):695-8. [DOI:10.4103/ajns.AJNS_120_20] [PMID] [PMCID]
13. Aljoghaiman M, Taha MS, Abdulkader MM. Cerebellar medulloblastoma in middle-to-late adulthood. Case Reports in Pathology. 2018; 2018. [DOI:10.1155/2018/5425398]
14. Faleiro RM, de Souza Moraes VV, de Seixas Alves MT, Pedrosa MS, Garcia LA, et al. Extra-axial cerebello-pontine angle medulloblastoma. Arquivos Brasileiros de Neurocirurgia: Brazilian Neurosurgery. 2016; 35(03):234-8. [DOI:10.1055/s-0036-1584552]
15. Bahrami E, Bakhti S, Fereshtehnejad SM, Parvaresh M, Khani MR. Extra-axial medulloblastoma in cerebello-pontine angle: A report of a rare case with literature review. Medical Journal of the Islamic Republic of Iran. 2014; 28:57. [PMCID] [PMID]
16. Majd N, Penas-Prado M. Updates on management of adult medulloblastoma. Current Treatment Options in Oncology. 2019; 20:1-24. [DOI:10.1007/s11864-019-0663-0] [PMID]
17. Furtado SV, Venkatesh PK, Dadlani R, Reddy K, Hegde AS. Adult medulloblastoma and the “dural-tail” sign: rare mimic of a posterior petrous meningioma. Clinical Neurology and Neurosurgery. 2009; 111(6):540-3. [DOI:10.1016/j.clineuro.2009.02.002] [PMID]
18. Kumar R, Achari G, Banerjee D, Chhabra D. Uncommon presentation of medulloblastoma. Child’s Nervous System. 2001; 17:538-42. [DOI:10.1007/s003810100446] [PMID]
19. Chung EJ, Jeun SS. Extra-axial medulloblastoma in the cerebellar hemisphere. Journal of Korean Neurosurgical Society. 2014; 55(6):362-4. [DOI:10.3340/jkns.2014.55.6.362] [PMID] [PMCID]
20. Bhaskar MK, Jaiswal M, Ojha BK, Singh SK, Chandra A, Meel M, Faheem M. Extra-axial cerebellopontine angle medulloblastoma in an infant. Pediatric Neurosurgery. 2017; 52(2):122-6. [DOI:10.1159/000455921] [PMID]
21. Gibson P, Tong Y, Robinson G, Thompson MC, Currle DS, Eden C, et al. Subtypes of medulloblastoma have distinct developmental origins. Nature. 2010; 468(7327):1095-9. [DOI:10.1038/nature09587] [PMID] [PMCID]
22. Akay KM, Erdogan E, Izci Y, Kaya A, Timurkaynak E. Medulloblastoma of the cerebellopontine angle—case report—. Neurologia Medico-Chirurgica. 200343(11):555-8. [DOI:10.2176/nmc.43.555] [PMID]
23. Goudihalli SR, Pathak A, Brar R, Mundi I. Reappraisal of cerebellopontine angle medulloblastomas: Report of a fatal case and lessons learned. Interdisciplinary Neurosurgery. 2018; 12:20-3. [DOI:10.1016/j.inat.2017.12.001]
24. Barkovich AJ. Normal development of the neonatal and infant brain, skull, and spine. Pediatric Neuroimaging. 2002:13-71. [Link]
25. Mohan M, Pande A, Vasudevan MC, Ramamurthi R. Pediatric medulloblastoma: A review of 67 cases at a single institute. Asian Journal of Neurosurgery. 2008; 2(2):63-9. [Link]
26. MacDonald TJ, Rood BR, Santi MR, Vezina G, Bingaman K, Cogen PH, et al. Advances in the diagnosis, molecular genetics, and treatment of pediatric embryonal CNS tumors. The Oncologist. 2003; 8(2):174-86. [DOI:10.1634/theoncologist.8-2-174] [PMID]

27. Singh M, Cugati G, Symss NP, Pande A, Vasudevan MC, Ramamurthi R. Extra axial adult cerebellopontine angle medulloblastoma: An extremely rare site of tumor with metastasis. Surgical Neurology International. 2011; 2:25. [DOI:10.4103/2152-7806.77178] [PMID] [PMCID]
28. Mata-Mbemba D, Zapotocky M, Laughlin S, Taylor MD, Ramaswamy V, Raybaud C. MRI characteristics of primary tumors and metastatic lesions in molecular subgroups of pediatric medulloblastoma: a single-center study. American Journal of Neuroradiology. 2018; 39(5):949-55. [DOI:10.3174/ajnr.A5578] [PMID] [PMCID]
29. Quaranta R, Pelullo M, Zema S, Nardozza F, Checquolo S, Lauer DM, et al. Maml1 acts cooperatively with Gli proteins to regulate sonic hedgehog signaling pathway. Cell Death & Disease. 2017; 8(7):e2942. [DOI:10.1038/cddis.2017.326] [PMID] [PMCID]