Malignant gliomas with primitive neuroectodermal tumor-like components: a clinicopathologic and genetic study of 53 cases

Abstract

Central nervous system neoplasms with combined features of malignant glioma and primitive neuroectodermal tumor (MG-PNET) are rare, poorly characterized, and pose diagnostic as well as treatment dilemmas. We studied 53 MG-PNETs in patients from 12 to 80 years of age (median = 54 years). The PNET-like component consisted of sharply demarcated hypercellular nodules with evidence of neuronal differentiation. Anaplasia, as seen in medulloblastomas, was noted in 70%. Within the primitive element, N-myc or c-myc gene amplifications were seen in 43%. In contrast, glioma-associated alterations involved both components, 10q loss (50%) being most common. Therapy included radiation (78%), temozolomide (63%) and platinum-based chemotherapy (31%). Cerebrospinal fluid (CSF) dissemination developed in eight patients, with response to PNET-like therapy occurring in at least three. At last follow-up, 27 patients died, their median survival being 9.1 months. We conclude that the primitive component of the MG-PNET: (i) arises within a pre-existing MG, most often a secondary glioblastoma; (ii) may represent a metaplastic process or expansion of a tumor stem/progenitor cell clone; (iii) often shows histologic anaplasia and N-myc (or c-myc) amplification; (iv) has the capacity to seed the CSF; and (v) may respond to platinum-based chemotherapy regimens.

Figure 1

Kaplan‐Meier curves comparing the survival of 53 MG‐PNET patients (blue curve) with 718 conventional GBMs (red curve). No statistically significant difference in median survival (9.1 vs. 10.3 months, respectively) was evident (log‐rank P = 0.39). Abbreviations: GBM = glioblastoma; MG = malignant glioma; PNET = primitive neuroectodermal tumor.

Figure 2

Examples of high‐grade gliomas with neuroblastic (PNET‐like) foci, including (A): a GBM‐PNET with the diffuse astrocytoma component on the left and the neuroblastic component on the right. The diffuse glioma components of MG‐PNET included: GBM with pseudopalisading necrosis (B), gemistocytic astrocytoma (C) and oligodendroglioma (D). The neuroblastic components resembled classic medulloblastomas with Homer Wright rosettes (E), often with anaplastic/large cell features including enlarged cells, vesicular nuclei, prominent nucleoli and cell wrapping (F). Abbreviations: GBM = glioblastoma; MG = malignant glioma; PNET = primitive neuroectodermal tumor.

Figure 3

Additional representative high‐grade gliomas with neuroblastic (PNET‐like) foci, including (A–C): a GBM‐PNET that developed from progression of a diffuse astrocytoma. A. Diffuse astrocytoma, World Health Organization grade II diagnosed in a 30‐yo woman. B. A recurrence 4 years later showed the emergence of a PNET‐like component with neuroblastic rosettes comprising the majority of the tumor. C. Anaplastic foci were also noted. Two additional examples of the relatively sharp interface between the malignant glioma (left) and the PNET‐like nodules (right) are shown in (D) and (E). Medulloblastoma‐like nodularity from another GBM‐PNET is shown in (F). Abbreviations: GBM = glioblastoma; PNET = primitive neuroectodermal tumor.

Figure 4

Representative ancillary stains: GFAP positivity within a minor fraction of the PNET‐like cells (A). Strong synaptophysin positivity in the neuroblastic component, but a lack of staining in the entrapped islands of glioma (B). Nuclear Neu‐N positivity in a subset of the PNET‐like cells (C). Nearly diffuse immunoreactivity for Ki‐67 (D) and p53 protein in primitive cells, including those forming Homer Wright rosettes (E). Reticulin shows a similar pattern to that of desmoplastic medulloblastoma in this example of GS‐PNET (F). Abbreviations: GFAP = glial fibrillary acidic protein; GS = gliosarcoma; PNET = primitive neuroectodermal tumor.

Figure 5

Representative FISH images. Chromosome 10q deletion was seen in both the glioma and PNET‐like regions of a GBM‐PNET (A. one green PTEN and one red DMBT1 signal per cell). Another GBM‐PNET showed c‐myc gene amplification relatively restricted to the PNET‐like component (B. 2–4 green centromere 8 and numerous red c‐myc signals per cell). Another example showed N‐myc gene amplification in the PNET‐like component (C. centromere 2 in red and N‐myc gene in green), whereas the adjacent glioma (D) showed polysomy 2 (chromosomal gain), but no gene amplification. In the AO‐PNET case, codeletion of chromosome 1p (E. one green 1p32 and two red 1q42 signals in most nuclei) and 19q (F. one red 19q13 and two green19p13 signals in most nuclei) was seen in both components. In contrast, N‐myc gene amplification (G) was confined to the PNET‐like nodules. Abbreviations: GBM = glioblastoma; PNET = primitive neuroectodermal tumor.

Figure 6

In contrast to malignant gliomas with PNET‐like foci, the small cell variant of GBM is characterized by a more infiltrative growth pattern with bland, monomorphic nuclei that superficially resemble oligodendroglioma, but display numerous mitotic figures (A) and abundant, thin GFAP‐positive processes (B). On intraoperative smears, the bland oval nuclei of SC‐GBM (C) contrast with the more hyperchromatic and irregular medulloblastoma‐like nuclei of GBM‐PNET (D), the latter example also suggesting the possibility of a Homer Wright rosette. Abbreviations: GBM = glioblastoma; GFAP = glial fibrillary protein; PNET = primitive neuroectodermal tumor; SC = small cell.