Case 4 -

Medulloblastoma Timothy Smith and Cynthia Welsh

The name 'medulloblastoma' was created by a committee as the name for a cerebellar tumor that can show both glial and neuroblastic differentiation. The imaginary medulloblast is never mentioned in embryology courses. It is a 'small blue cell tumor' that occurs in the cerebellum as the second most common brain tumor in children, usually boys, occurring less commonly in adults. It is included as the most common member of the primitive neuroectodermal tumors (PNETs). Others include pineoblastoma, cerebral PNET, cerebral neuroblastoma, and ependymoblastoma. There is an association with the p53 germline mutations, LiFraumeni and Gorlin syndromes. Clinical symptoms include irritability, ataxia, gaze palsies, and nystagmus. MRI shows a contrast enhancing mass in the cerebellar vermis in children or the lateral cerebellar hemisphere in adults. T1 weighted images show a hypodense mass compressing or invading the fourth ventricle. MRI can identify CSF downstream wash metastases. Rare skeletal metastases can be identified on plain x-rays, but must be distinguished from the more common bone infarcts associated with chemotherapy. The other PNETs occur in the cerebral hemispheres and pineal in children and young adults. Small cell neoplasms (medulloblastoma differential diagnosis) Medulloblastoma PNETs (medulloblastoma, ependymoblastoma, pineoblastoma, cerebral neuroblastoma) Small cell metastases Lymphoma Small cell glioblastoma Germinoma Rhabdomyosarcoma, Ewing sarcoma Esthesioneuroblastoma, SNUC (sinonasal undifferentiated carcinoma) The surgeon sees the tumor as a pink mass in the cerebellum or as a white frosting-like area if the tumor invades the subarachnoid space. Hemorrhage and cystic degeneration are common findings. The tumor is soft, contributing to good smears and frozen sections. Both smears and sections show a small cell tumor forming variably sized sheets separated by blood vessels or fibrovascular septae. In squash preparations, the cells separate distinctly from the thin blood vessels. Even though the pink fibrillary background is common for neuroglial tumors, fibrillary background is minimal in medulloblastomas although fine fluffy cytoplasmic material may be seen between nuclei. Nuclei are described as oval, oblong, or carrot shaped with even, soft chromatin punctuated by randomly placed nucleoli (not the regularly placed nucleoli of lymphomas). Frozen sections show a tumor composed of small cells arranged back-to-back with crossing fibrous septae and nuclear molding. Tumor cells form imperfect irregular rosettes, meaning they rarely make well defined Homer-Wright rosettes. Tumors containing rosettes Medulloblastomas have imperfect Homer Wright rosettes Neuroblastomas of the adrenal have the best Homer Wright rosettes Retinoblastomas have Flexner-Wintersteiner rosettes Ependymomas have perivascular rosettes Mitoses and apoptotic cells are everywhere. Many tumors display amorphous sheets with few random cells showing neuronal differentiation, but more show islands of larger cells showing glial differentiation (i.e. having pink fibrillar processes). Rare tumors have a pattern of rows and ribbons in fibrous stroma or in cerebellar white matter. The desmoplastic medulloblastoma occurs in the lateral cerebellum of adults. It is characterized by abundant reticulin and often linear patterns of tumor cells. The large cell medulloblastoma is composed of cells larger than usual. It is diffusely synaptophysin positive, while EMA, keratin negative. The large cell medulloblastoma resembles the atypical teratoid rhabdoid tumor but this tumor is positive for EMA, keratins and smooth muscle actin. Very rare medulloblastomas have rhabdomyoblastic strap cells (medullomyoblastoma) or melanin. These last two elements if present can be confirmed on permanents. Other considerations: Medulloblastomas are densely cellular small cell tumors with little glial fibrillarity and are therefore distinctly different from pilocytic astrocytomas, glioblastoma multiforme, anaplastic astrocytomas, and ependymomas. Small cell glioblastomas possess much more fibrillarity, and endothelial hyperplasia than medulloblastoma. Small cell glioblastoma will have areas that are equally densely cellular to medulloblastoma and it will have less cellular areas with larger cells. Distinction from lymphoma can be based on the striking variability (ovals and carrot shapes) of medulloblastoma nuclei, a feature lacking in lymphoma nuclei. The imperfect rosettes of medulloblastoma are not seen in lymphomas. If occurring in adults, they must be distinguished from metastatic small cell carcinoma of lung, a task best approached on permanent sections. Similarly, distinction from other PNETs can be impossible on frozen sections, but cerebral neuroblastoma occurs in the cerebral hemispheres. Ewing's sarcoma, when affecting the CNS, occurs in the bone and meninges. Medulloepithelioma is an extremely rare tumor of epithelioid cells forming ribbons and tubules occurring in either cerebellum or cerebrum. The atypical teratoid rhabdoid tumor is a primitive large cell medulloblastoma-like tumor with divergent differentiation identified by scattered larger keratin, EMA, and actin positive cells. It deserves recognition because of treatment differences from medulloblastoma. Diagnosis of this very rare entity must also wait for permanent sections.