Case #3Case #3

USCAP Neuropathology Evening USCAP Neuropathology Evening Seminar/Companion MeetingSeminar/Companion Meeting

Clinical HistoryClinical History

A 71A 71--yearyear--old man presented with a 4old man presented with a 4--week history of word finding difficulty. An week history of word finding difficulty. An initial screening head CT followed by an initial screening head CT followed by an MRI scan revealed a large ringMRI scan revealed a large ring--enhancing enhancing mass of the left temporal lobe that mass of the left temporal lobe that abutted the dura. The patient was abutted the dura. The patient was referred to a tertiary care hospital where referred to a tertiary care hospital where craniotomy and surgical resection of the craniotomy and surgical resection of the mass were performed.mass were performed.

GFAP

Synaptophysin

GFAP

Synaptophysin

Diagnosis?Diagnosis?

Malignant glioneuronal tumorMalignant glioneuronal tumor

Histologic FeaturesHistologic Features

Features of a high grade malignant Features of a high grade malignant neoplasm with nuclear pleomorphism, neoplasm with nuclear pleomorphism, mitotic activity, vascular proliferation and mitotic activity, vascular proliferation and necrosisnecrosisBoth glial and neuronal differentiation as Both glial and neuronal differentiation as characterized by GFAP and synaptophysin characterized by GFAP and synaptophysin immunoreactivityimmunoreactivity

Glioneuronal TumorsGlioneuronal Tumors

““New entitiesNew entities””RosetteRosette--forming glioneuronal tumorforming glioneuronal tumorGlioneuronal tumor with neuropilGlioneuronal tumor with neuropil--like islandslike islandsPapillary glioneuronal tumorPapillary glioneuronal tumor

““TraditionalTraditional””Dysplastic gangliocytoma of the cerebellum (LhermitteDysplastic gangliocytoma of the cerebellum (Lhermitte--Duclos)Duclos)Desmoplastic infantile astrocytoma and ganglioglioma Desmoplastic infantile astrocytoma and ganglioglioma Dysembryoplastic neuroepithelial tumor (DNET)Dysembryoplastic neuroepithelial tumor (DNET)Gangliocytoma/gangliogliomaGangliocytoma/gangliogliomaCentral neurocytoma and extraventricular neurocytomaCentral neurocytoma and extraventricular neurocytomaCerebellar liponeurocytomaCerebellar liponeurocytoma

““MalignancyMalignancy”” in in neuronal/gangliocytic tumorsneuronal/gangliocytic tumors

Most often seen in tumors with both glial and Most often seen in tumors with both glial and neuronal/gangliocytic differentiationneuronal/gangliocytic differentiation““MalignantMalignant”” cells are often felt to be of glial cells are often felt to be of glial originoriginHowever, mixed glioneuronal phenotypic However, mixed glioneuronal phenotypic expression in this category is increasingly expression in this category is increasingly recognized and under intense investigation.recognized and under intense investigation.

Differential Diagnosis and PitfallsDifferential Diagnosis and Pitfalls

The clinical differential diagnosis of a solitary contrastThe clinical differential diagnosis of a solitary contrast--enhancing mass in an older adult patient is broad, but enhancing mass in an older adult patient is broad, but the most common etiologies are the most common etiologies are metastatic carcinoma, metastatic carcinoma, glioblastoma, glioblastoma, andand primary central nervous system large primary central nervous system large BB--cell lymphomacell lymphoma; other entities to keep in mind are ; other entities to keep in mind are demyelinating pseudotumor demyelinating pseudotumor andand cerebral abscess.cerebral abscess.The The misdiagnosis of demyelinating pseudotumor as misdiagnosis of demyelinating pseudotumor as diffuse glioma is one of the most common serious diffuse glioma is one of the most common serious diagnostic errors in surgical neuropathologydiagnostic errors in surgical neuropathology, which can , which can lead to the inappropriate administration of CNS lead to the inappropriate administration of CNS irradiation and/or chemotherapeutic intervention, both of irradiation and/or chemotherapeutic intervention, both of which can have deleterious side effects.which can have deleterious side effects.

Varlet et al Varlet et al -- New Variants of Malignant New Variants of Malignant Glioneuronal Tumors: A study of 40 casesGlioneuronal Tumors: A study of 40 cases

All tumors coexpressed glial fibrillary acidic protein and NFPAll tumors coexpressed glial fibrillary acidic protein and NFPOther neuronal markers tested were inconstantly expressedOther neuronal markers tested were inconstantly expressedNo recurrence was observed at the primary site in 36.4% of patieNo recurrence was observed at the primary site in 36.4% of patients who nts who underwent gross total resectionunderwent gross total resectionTwelve patients Twelve patients (33.3%)(33.3%) developed developed intraintra--axial and/or systemic metastasesaxial and/or systemic metastases, , and 4 were free of disease at 39 to 184 months. and 4 were free of disease at 39 to 184 months. Gross total surgical resectionGross total surgical resection (P = 0.001) and a (P = 0.001) and a long duration of symptomslong duration of symptoms(symptoms > 1 yr; P = 0.013) proved to be (symptoms > 1 yr; P = 0.013) proved to be independent and statistically independent and statistically significant prognostic factors in the multivariate analysissignificant prognostic factors in the multivariate analysis..CONCLUSIONS: CONCLUSIONS: NFP immunostaining is required to identify MGNTs NFP immunostaining is required to identify MGNTs accuratelyaccuratelyTheir distinction from malignant gliomas is of paramount clinicaTheir distinction from malignant gliomas is of paramount clinical l importance, particularly for neurosurgeons, because gross total importance, particularly for neurosurgeons, because gross total surgical surgical resection may be curative in some cases. resection may be curative in some cases. MGNTs may account for the longMGNTs may account for the long--term survival and/or occurrence of term survival and/or occurrence of metastases demonstrated in a subset of malignant gliomas.metastases demonstrated in a subset of malignant gliomas.

Vajtai et al Vajtai et al -- Malignant glioneuronal tumor of the Malignant glioneuronal tumor of the adult cerebrum with neuropiladult cerebrum with neuropil--like islands involving like islands involving

““proliferating nodulesproliferating nodules””: confirmatory report of : confirmatory report of unusual variantunusual variant

Left frontal lobe mass in 59 year old womanLeft frontal lobe mass in 59 year old woman70% was conventional GBM70% was conventional GBMSeveral discrete aggregates of nonSeveral discrete aggregates of non--descript round cells descript round cells with a primitive appearance were present with smudged with a primitive appearance were present with smudged contourscontoursWithin individual clusters there were delicate processes Within individual clusters there were delicate processes but the round cells cells stained but the round cells cells stained strongly for strongly for synaptophysinsynaptophysin and were and were surrounded by GFAP positive surrounded by GFAP positive astrocytesastrocytesMIBMIB--1 staining positive 1 staining positive 99--11%11% in in astrocytic componentastrocytic component, , the the round cellround cell nodules stained postively in approximately nodules stained postively in approximately 40% 40%

Rodriguez et al Rodriguez et al -- Unusual malignant glioneuronal Unusual malignant glioneuronal tumors of the cerebrum of adults: a tumors of the cerebrum of adults: a

clinicopathologic study of three casesclinicopathologic study of three cases

2 men and 1 woman, ages ranging from 35 2 men and 1 woman, ages ranging from 35 –– 8383Epithelioid cells in 3, spindle cells in 1 and Epithelioid cells in 3, spindle cells in 1 and undifferentiated small cells in 1undifferentiated small cells in 1Necrosis, nonNecrosis, non--pallisading was present in all 3 with brisk pallisading was present in all 3 with brisk mitotic activitymitotic activityAll immunoreactive for GFAP, SAll immunoreactive for GFAP, S--100, synaptophysin100, synaptophysin, , chromogranin and chromogranin and 2 were positive for Neu2 were positive for Neu--N and N and neurofilament proteinsneurofilament proteinsEM showed convincing neurosecretory granules in one EM showed convincing neurosecretory granules in one case, and some in filament containing cells were case, and some in filament containing cells were immunogold labeled for GFAPimmunogold labeled for GFAP

Shibahara et al Shibahara et al –– Secondary Secondary glioblastoma with advanced glioblastoma with advanced

neuronal phenotypeneuronal phenotype35 year old man with a partially resected astrocytoma 35 year old man with a partially resected astrocytoma ((immunoreactive for GFAP with a MIBimmunoreactive for GFAP with a MIB--1 labeleing index of 1 labeleing index of approximately 2%approximately 2%) and treated with post) and treated with post--op radiation and op radiation and chemotherapychemotherapyResidual/regrowth resected 5 months and then again 8 months lateResidual/regrowth resected 5 months and then again 8 months later r with death at 11 months with subarachnoid and intraventricular with death at 11 months with subarachnoid and intraventricular disseminationdisseminationRecurrences showed a small blue cell tumor with occasional largeRecurrences showed a small blue cell tumor with occasional largemultinucleated giant cellsmultinucleated giant cellsRecurrences showed high Recurrences showed high MIBMIB--11 labeling index labeling index (80%)(80%) and and extensive extensive positivity for both synaptophysin and NeuNpositivity for both synaptophysin and NeuN but but NOT for GFAPNOT for GFAPAlthough initially diagnosed as GBM, may be better classified asAlthough initially diagnosed as GBM, may be better classified as a a malignant glioneuronal tumormalignant glioneuronal tumor

SummarySummary

A wide range of diverse morphologies can be seen in A wide range of diverse morphologies can be seen in highhigh--grade diffuse glioma, and mixed glioneuronal grade diffuse glioma, and mixed glioneuronal phenotypic expression in this category is increasingly phenotypic expression in this category is increasingly recognized and under investigation.recognized and under investigation.The evaluation of CNS neoplasms increasingly relies on The evaluation of CNS neoplasms increasingly relies on the interpretation and integration of panels comprised of the interpretation and integration of panels comprised of several phenotypic markers rather than on single several phenotypic markers rather than on single antibodies.antibodies.Oncologic neuropathology remains a dynamic, evolving Oncologic neuropathology remains a dynamic, evolving field in which novel tumor types and subtypes of clinical field in which novel tumor types and subtypes of clinical importance continue to be recognized and characterized.importance continue to be recognized and characterized.

ReferencesReferences1.1. Biernat WBiernat W, , Zakrzewski KZakrzewski K, , Polis LPolis L, , Liberski PPLiberski PP. . GlioneuronalGlioneuronal--mesenchymal tumour with malignant mesenchymal tumour with malignant

transformation. Folia Neuropathol. 2007;45(3):140transformation. Folia Neuropathol. 2007;45(3):140--3.3.2.2. Barbashina VBarbashina V, , Salazar PSalazar P, , Ladanyi MLadanyi M, , Rosenblum MKRosenblum MK, , Edgar MAEdgar MA. Glioneuronal tumor with neuropil. Glioneuronal tumor with neuropil--like islands like islands

(GTNI): a report of 8 cases with chromosome 1p/19q deletion anal(GTNI): a report of 8 cases with chromosome 1p/19q deletion analysis. Am J Surgical Path August 2007 ysis. Am J Surgical Path August 2007 31(8): 119631(8): 1196--20022002

3.3. Vajtai IVajtai I, , Reinert MMReinert MM. Malignant glioneuronal tumor of the adult cerebrum with neurop. Malignant glioneuronal tumor of the adult cerebrum with neuropilil--like islands involving like islands involving "proliferating nodules": confirmatory report of an unusual varia"proliferating nodules": confirmatory report of an unusual variant. Acta Neuropathologica (Berlin) 2007 June nt. Acta Neuropathologica (Berlin) 2007 June 113 (6):711113 (6):711--13 Epub April 11 200713 Epub April 11 2007

4.4. Edgar MA, Rosenblum MK.Edgar MA, Rosenblum MK. Mixed glioneuronal tumors. Recently described entities. Arch Mixed glioneuronal tumors. Recently described entities. Arch Pathol Lab Med Pathol Lab Med 2007 131:2282007 131:228--233.233.

5.5. Rodriguez FJ, Scheithauer BW, Robbins PD, Burger PC, Hessler RB,Rodriguez FJ, Scheithauer BW, Robbins PD, Burger PC, Hessler RB, Perry A, AbellPerry A, Abell--Aleff PC, Mierau GW.Aleff PC, Mierau GW.Ependymomas with neuronal differentiation: morphologic and immunEpendymomas with neuronal differentiation: morphologic and immunohistochemical spectrum. Acta ohistochemical spectrum. Acta Neuropathol 2007. 113:313Neuropathol 2007. 113:313--324.324.

6.6. Rodriguez FJRodriguez FJ, , Scheithauer BWScheithauer BW, , Port JDPort JD. Unusual malignant glioneuronal tumors of the cerebrum of adult. Unusual malignant glioneuronal tumors of the cerebrum of adults: a s: a clinicopathologic study of three cases. Acta Neuropathol. 2006 Dclinicopathologic study of three cases. Acta Neuropathol. 2006 Dec;112(6):727ec;112(6):727--37. Epub 2006 Sep 737. Epub 2006 Sep 7

7.7. Shibahara J, Fukayama M.Shibahara J, Fukayama M. Secondary glioblastoma with advanced neuronal immunophenotype. Secondary glioblastoma with advanced neuronal immunophenotype. Virchows Virchows Arch 2005. 447:665Arch 2005. 447:665--668.668.

8.8. Varlet PVarlet P, , Soni DSoni D, , Miquel CMiquel C, , Roux FXRoux FX, , Meder JFMeder JF, , Chneiweiss HChneiweiss H, , DaumasDaumas--Duport CDuport C. New variants of malignant . New variants of malignant glioneuronal tumors: a clinicopathological study of 40 cases. Neglioneuronal tumors: a clinicopathological study of 40 cases. Neurosurgery. 2004 Dec;55(6):1377urosurgery. 2004 Dec;55(6):1377--9191

9.9. Cenacchi GCenacchi G, , Giangaspero FGiangaspero F. Emerging tumor entities and variants of CNS neoplasms. J Neuro. Emerging tumor entities and variants of CNS neoplasms. J Neuropathol Exp pathol Exp Neurol. 2004 Mar;63(3):185Neurol. 2004 Mar;63(3):185--9292

10.10. Rushing EJ, Thompson LD, Mena H.Rushing EJ, Thompson LD, Mena H. Malignant transformation of a dysembryoplastic neuroepithelialMalignant transformation of a dysembryoplastic neuroepithelial tumor tumor after radiation and chemotherapy. Ann Diagn Pathol 2003 Aug; 7(4after radiation and chemotherapy. Ann Diagn Pathol 2003 Aug; 7(4):240):240--4.4.

11.11. Perry A, Scheithauer BW, Macaulay RJB, Raffel C, Roth KA, Kros JPerry A, Scheithauer BW, Macaulay RJB, Raffel C, Roth KA, Kros JM.M. Oligodendrogliomas with neurocytic Oligodendrogliomas with neurocytic differentiation. A report of 4 cases with diagnostic and histogdifferentiation. A report of 4 cases with diagnostic and histogenetic implications. J Neuropathol Exp Neurol enetic implications. J Neuropathol Exp Neurol 2002. 61:9472002. 61:947--955.955.

12.12. Keyvani K, Rickert CH, von Wild K, Paulus W.Keyvani K, Rickert CH, von Wild K, Paulus W. Rosetted glioneuronal tumor: a case with proliferating Rosetted glioneuronal tumor: a case with proliferating neuronal nodules. Acta Neuropathol 2001. 101:525neuronal nodules. Acta Neuropathol 2001. 101:525--528.528.

13.13. Hammond RRHammond RR, , Duggal NDuggal N, , Woulfe JMWoulfe JM, , Girvin JPGirvin JP. Malignant transformation of a dysembryoplastic . Malignant transformation of a dysembryoplastic neuroepithelial tumor. Case report. J Neurosurg. 2000 Apr;92(4):neuroepithelial tumor. Case report. J Neurosurg. 2000 Apr;92(4):722722--5.5.

14.14. Prayson RA, Abramovich CM.Prayson RA, Abramovich CM. Glioneuronal tumor with neuropilGlioneuronal tumor with neuropil--like islands. Hum Pathol 2000. 31:1435like islands. Hum Pathol 2000. 31:1435--1438.1438.

15.15. Teo J, Gultekin SH, Bilsky M, Gutin P, Rosenblum MKTeo J, Gultekin SH, Bilsky M, Gutin P, Rosenblum MK. A distinctive glioneuronal tumor of the adult cerebrum . A distinctive glioneuronal tumor of the adult cerebrum with neuropilwith neuropil--like (including like (including ““rosettedrosetted””) islands: Report of 4 cases. Am J Surg Pathol 1999. 23:502) islands: Report of 4 cases. Am J Surg Pathol 1999. 23:502--510.510.

16.16. McLendon RE, Bentley RC, Parisi JE, Tien RD, Harrison JC, TarbelMcLendon RE, Bentley RC, Parisi JE, Tien RD, Harrison JC, Tarbell NJ, Billitt AL, Gualtieri RJ,l NJ, Billitt AL, Gualtieri RJ, Friedman HS.Friedman HS.Malignant supratentorial glialMalignant supratentorial glial--neuronal neoplasms. Report of two cases and review of the literaneuronal neoplasms. Report of two cases and review of the literature. Arch ture. Arch Pathol Lab Med 1997. 121:485Pathol Lab Med 1997. 121:485--492.492.