WHO Grade IV glioblastoma multiforme (GBM) with extensive neuronal differentiation.
GBM is the most common primary brain tumor occurring in the United States, accounting for an estimated 13,000 deaths each year (5). GBM is morphologically heterogenous with the histological hallmarks of extensive microvascular proliferation, prominent necrosis, and frequent mitoses. As an astrocytic neoplasm, GBM typically stains positively for GFAP and S-100 protein. In addition to the classic form of glioblastoma, 2 histological variants and several other patterns have been defined including gliosarcoma, giant cell GBM, glioblastoma with lipidized cells, small cell glioblastoma, glioblastoma with oligodendroglioma component, and glioblastoma with heterologous differentiation (1).
Gangliogliomas are typically well-differentiated neoplasms containing both neuronal and glial components. Though rare, several reports have described the malignant transformation of well-differentiated gangliogliomas into a GBM, with tumor microscopy revealing extensive astrocytic proliferation, high mitotic activity, endothelial proliferation, and cellular pleomorphism with multinucleated cells (2, 4). Both p53 mutations and inactivation of p16 have been implicated in the malignant transformation of gangliogliomas (2, 4).
No published reports have described a primary brain neoplasm exhibiting features of both glioblastoma as well as multiple regions of extensive neuronal differentiation. The documented experiences have been limited to case reports involving children and adolescents with malignant conversion of a known, well-differentiated ganglioglioma into GBM, as well as small case series of malignant glioneural tumors (2, 3). The diagnosis of malignant glioneural tumors is dependent on antibody positivity for neurofilament protein, NeuN, synaptophysin, and chromogranin, in addition to frequent mitoses (6). Such tumors pose unique questions regarding their biology and whether the two components reflect a "collision" between two separate neoplastic processes, or if the neuronal component arose from pluripotent precursor cells within the tumor.
In our patient, there was no indication of malignant conversion from ganglioglioma, and negative immunostaining for neurofilament protein and NeuN is inconsistent with the diagnosis of malignant glioneural tumor. The numerous areas of positive staining for synaptophysin or Tuj1 suggested extensive neuronal differentiation within the GBM. As such, following gross total resection, the patient was started on temozolomide followed by focal irradiation and erlotinib. He survived 257 days (8 months, 15 days) after diagnosis.
The authors would like to thank Holly Wagner for providing editorial assistance in preparation of this manuscript.
Contributed by Shawn L. Hervey-Jumper, MD; Anthony C. Wang, MD; Andrea N. Yates, BS; Patricia L. Robertson, MD; Karin M. Muraszko, MD; Hugh J.L. Garton, MD, MHSc; Mila Blaivas, MD, PhD