Infratentorial medulloepithelioma with divergent differentiation: Possibly a predictor of poor outcome.

Medulloepitheliomas (WHO grade IV) are rare, malignant embryonal tumors of pediatric population, classified under the central nervous system (CNS) primitive neuroectodermal tumors (PNET). Histologically, these tumors are characterized by neoplastic neuroepithelium recapitulating the embryonic neural tube. We describe a rare case of infratentorial medulloepithelioma with divergent differentiation in a 1-year-old male child who presented with headache, vomiting, and seizures. Histopathologic examination of the excised tumor revealed the characteristic neuroepithelium, along with other areas showing primitive neuroectodermal (blastemal) cells in sheets, ependymoblastic rosettes, and nodular areas of neuronal differentiation. Possibly, this proliferating immature neuroepithelium is the cause of poor outcome in medulloepitheliomas. Due to the rarity of these tumors, it remains to be established whether infratentorial location or tumors with divergent differentiation are also predictors of adverse prognosis.

Introduction

First described by Bailey and Cushing in 1926,[1] cerebral medulloepitheliomas are extremely rare and highly aggressive embryonal brain tumors affecting the pediatric population, with only 37 published cases.[2] Histologically, these lesions are composed of papillary, tubular, or trabecular arrangements of neoplastic neuroepithelium reminiscent of the structure of embryonic neural tube.[23] Classified under the group of central nervous system (CNS) primitive neuroectodermal tumors (PNET), medulloepitheliomas may also show differentiation along neuronal, astrocytic, ependymoblastic, oligodendroglial, or mesenchymal lines.[2] These tumors correspond to World Health Organization (WHO) grade IV and carry a dismal prognosis with a median survival of 5 months.[2] Here, we report a case of 1-year-old child with posterior fossa medulloepithelioma displaying multiple lineages of differentiation.

Case Report

A 1-year-old male child presented to the out-patient department with symptoms of headache, nausea, and vomiting for the last 2½ months. The patient suffered a bout of seizure 4 days back. He had no significant medical or family history. Computed tomography (CT) scan revealed an isodense, well-circumscribed tumor mass in the posterior fossa with contrast enhancement. A radiological suggestion of medulloblastoma was made. The patient underwent debulking of the tumor; multiple tissue pieces received were irregular, grayish pink, with tiny foci of cystic change and hemorrhage, and size ranging from 1 cm diameter to 3 × 2.5 × 2 cm. Microscopic examination showed well-defined ribbons and strands of pseudostratified neuroepithelium arranged in papillary and tubular patterns, recapitulating the primitive neural tube [Figure 1]. External limiting membrane as described was seen on the outer surface of the stratified epithelium; few cystically dilated spaces lined by the epithelium and containing homogeneous eosinophilic material were also observed [Figure 2]. Mitotic figures were prominent in the pseudostratified strands of neuroepithelium, particularly near the luminal surface (2–3/high-power field). In other areas of the tumor, sheets of primitive neuroectodermal cells, with hyperchromatic nuclei, scanty cytoplasm, and nuclear molding were seen [Figure 1], along with interspersed ependymoblastic rosettes [Figure 1, inset, above left]. These are true rosettes having central lumina, surrounded by cells dispersed in multiple concentric layers, with the outermost cellular layer characteristically intermingling with the surrounding undifferentiated small round cells. Extensive areas of neuronal differentiation [Figures 3 and 4] were also observed. In addition, focal astrocytic [Figures 4 and 5] and ependymal [Figure 6] differentiation was also noted. A morphological diagnosis of medulloepithelioma with differentiation along neuronal, astrocytic, ependymal, and ependymoblastic lineages was considered. The patient was treated with postoperative radiotherapy and chemotherapy (with vincristine, cisplatin, and cyclophosphamide). Unfortunately, the child had a rapid downhill course and died after 3 months of surgery.

Figure 1

Photomicrograph showing ribbons of primitive neuroepithelium (above left, arrow) mimicking embryonic neural tube; in other areas of the tumor, sheets of undifferentiated neuroectodermal cells (lower right, thin arrow) with interspersed ependymoblastic rosettes (arrow head) (H & E stain, 40× magnification). (Inset, below right) Sheets of undifferentiated neuroectodermal cells at higher magnification (H & E stain, 400× magnification). (Inset, above right) Characteristic multilayered ependymoblastic rosette, with outer cell layer merging with the undifferentiated cells (H & E stain, 400×)

Figure 2

Epithelium-lined cystic space filled with eosinophilic material; tubular strands of hyperchromatic neuroepithelium seen in far right and far left (H & E stain, 100×)

Figure 3

Photomicrograph showing well-demarcated islands of pale staining areas representing neuronal differentiation (arrow heads); neuroepithelium seen in this illustration also (arrows) (H & E stain, 100×)

Figure 4

Ribbon of primitive neuroepithelium (arrow head) in the left, with adjacent focus of astrocytic differentiation; a nodule of neuronal differentiation (arrow) in the right and neuroectodermal (blastemal) cells in sheets at the center (H & E stain, 400×)

Figure 5

Another focus of astrocytic differentiation in a fibrillary background; note the stratified neuroepithelium (arrow head) in the lower left (H & E stain, 400×)

Figure 6

Focus of ependymal differentiation (area under the left of arc) (H & E stain, 400×)

Discussion

Medulloepitheliomas are extremely rare embryonal tumors which affect children mostly between the ages of 6 months and 5 years with an equal sex distribution.[2] The rarity of this tumor in CNS can be estimated by the fact that around 37 cases have been reported to the best of our literature search.[24] Contrary to medulloblastomas, which are infratentorial tumors, medulloepitheliomas more commonly have supratentorial location. The cerebrum appears to be the most favored site accounting for nearly 30% of all medulloepitheliomas – with the most common site being periventricular, and involving in order of frequency, the temporal, parietal, occipital, and frontal lobes.[4] Cases occurring in the intraorbital region, cauda equina, presacral area, and sciatic nerve have been reported.[2] In one series of eight cases, Molloy et al.[5] found the tumors equally distributed in supratentorial and infratentorial locations. In our case, the tumor was present in the posterior fossa, with a radiological impression of medulloblastoma.

In addition to the primitive neuroepithelium, the tumor displayed sheets of undifferentiated blastemal (neuroectodermal) cells having small round cell morphology. Histogenetically, presence of characteristic neuroepithelium recreating embryonic neural tube led to the concept that these tumors are probably derived from the neoplastic transformation of a periventricular or subependymal precursor cell.[2] The primitive neuroectodermal cells may have undergone maturation arrest at an intermediate stage of differentiation, resulting in the formation and subsequent proliferation of the immature neuroepithelium. Cases showing differentiation toward neuronal, glial, or even mesenchymal tissues have been reported.[2] This explains the multipotent nature of the primitive neuroectodermal cells. The present case morphologically showed focal astrocytic, ependymal, and extensive neuronal differentiation, with well-formed ependymoblastic rosettes. Immunohistochemical confirmation of divergent differentiation, along with assessment of proliferative activity could have been more useful.

The concept of ependymoblastoma has been recently questioned, and the cells in “ependymoblastic rosettes” may not be primarily ependymal or glial precursors.[67] Instead, such multilayered true rosettes with central lumen, described as “ependymoblastic rosettes,” have now been shown to occur also in supratentorial CNS PNETs, medulloepitheliomas, and a newly described variant referred to as “Embryonal Tumor with Abundant Neuropil and True Rosettes” (ETANTR).[27] Medulloepitheliomas may also share a histogenetic overlap with teratoma owing to the occasional mesenchymal differentiation. Henceforth, the differential diagnoses include medulloblastoma, choroid plexus carcinoma, and immature teratoma.[2] ETANTR does not usually occur in the posterior fossa. Immature teratomas, in addition to primitive neuroectodermal component, also contain tissue of fetal appearance from other germ layers.[2]

Due to relatively less number of cases encountered, the optimal course of management for these high-grade tumors is yet to be standardized, and they are usually associated with rapid progression and dismal prognosis. Only three reported cases till date have survived beyond 5 years.[4] Gross total resection followed by radiotherapy and high-dose chemotherapy is the most accepted treatment protocol. Our case with infratentorial location and histological evidence of divergent differentiation had undergone surgical debulking followed by chemo-radiotherapy, but unfortunately died after 3 months of surgery. Moftakhar et al.,[4] after a thorough review of the reported cases of cerebral medulloepitheliomas, did not find any prognostic implication of age or gender. However, they noted that supratentorial tumors and negative cerebrospinal fluid were associated with better prognosis, while the well-differentiated medulloepitheliomas were associated with recurrence, consistent with that observed in PNETs with differentiation.[4] This higher recurrence rate may be due to resistance to chemotherapy and radiation in tumors with differentiation.

A study involving stratification of medulloblastomas on the basis of histopathologic grading showed no evidence of association between nodularity and anaplasia or outcome.[8] In medulloepitheliomas, it remains to be confirmed through larger case series, whether primitive neuroectodermal cells displaying differentiation along divergent cell lineages have a different outcome and proliferative activity. In addition, like medulloblastomas, grading of this primitive neuroectodermal component (small round cells) on the basis of anaplasia and apoptosis[8] can also be attempted in medulloepitheliomas. Fan et al.[9] observed that there is increased amplification of hTERT gene and increased mRNA expression in CNS embryonal tumors, which may play an important role in the evolution of a molecular prognostic marker in years to come.