Buccoliero, A. M.

Genitori, L.

Giordano, F.

Mussa, F.

Taddei, Antonio

Taddei, Gian Luigi

English

Florence Research

Neuropathology 2006;  26, 206–211 doi:10.1111/j.1440-1789.2006.00674.x© 2006 Japanese Society of NeuropathologyCase ReportPapillary glioneuronal tumor radiologically mimicking a cavernous hemangioma with hemorrhagic onsetAnna Maria Buccoliero,1 Flavio Giordano,3 Federico Mussa,3 Antonio Taddei,2 Lorenzo Genitori3 and Gian Luigi Taddei1Departments of 1Human Pathology and Oncology and 2General Surgery, University of Florence and 3Division of Neurosurgery, ‘Anna Meyer’ Pediatric Hospital, Florence, ItalyPapillary glioneuronal tumor is a recently identifiedlow-grade brain neoplasm classified as variant of gan-glioglioma. Its salient morphological characteristics are thepresence of pseudopapillary structures composed of bloodvessels, often hyalinized, lined by uniform small astrocytesand a proliferation of neurocytic cells, eventually admixedwith ganglioid and ganglion cells. We present a case of pap-illary glioneuronal tumor occurring in a 15-year-old femalewith an unusual hemorrhagic onset. The clinical, morpho-logical and immunohistochemical features are discussedand the published literature is reviewed. This article pro-poses that papillary glioneuronal tumor should be includedin the differential diagnosis of patients with tumoralrelated brain hemorrhage.Key words: central nervous system, immunohistochemis-try, intracerebral hemorrhage, mixed neuronal-glialtumors, papillary glioneuronal tumor.INTRODUCTIONMixed glio-neuronal tumors represent a group of brainneoplasms showing a wide morphological, immuno-histochemical and ultrastructural spectrum of glial andneuronal differentiation. They especially occur in thesupratentorial region of young people and often have anindolent prognosis. Among them, the papillary glioneu-ronal tumor has recently been identified as an infrequentlow-grade tumor and classified as a variant of gan-glioglioma. Typical morphological features are pseud-opapillary structures composed of frequently thickenedhyalinized blood vessels lined by uniform small astrocytesand a proliferation of neurocytic cells eventually admixedwith ganglioid and ganglion cells. Rabdoid, minigemisto-cytic, and Olig2 (a recently established oligodendroglialmarker) positive cells have been recognized too.1–16In this article, we describe the clinical, morphologicaland immunohistochemical features of a new case of papil-lary glioneuronal tumor diagnosed in a young girl.CASE REPORTClinical summaryMB, a previously healthy 15-year-old girl, was admittedto the intensive care unit (ICU) because of a suddenheadache followed by aphasia and coma. First, computedtomography (CT) showed a massive intraparenchymalbrain hemorrhage located in the left basal ganglia and tem-poral lobe with intraventricular bleeding and hydroceph-alus (Fig. 1). Emergency external ventricular drainage wasperformed to treat the hydrocephalus and raised intracra-nial pressure. Cerebral angiography revealed no abnormalvascular circles, while T1–T2-weighed magnetic resonanceimaging (MRI) supported the diagnosis of cavernoushemangioma. Shortly afterwards the brain hemorrhagespontaneously healed without further surgery. The patientwas transferred to the ward and discharged 20 days laterfree of neurological complaints. The lesion was not oper-ated on because of its deep and inaccessible site. Duringthe follow-up, serial CT and MRI revealed a progressivecystic transformation of the hemorrhage cavity into the lefttemporal lobe extending in the region of the homolateralthalamus. The final radiological picture, 2 years later, con-Correspondence: Anna Maria Buccoliero, MD, Dipartimento di Pato-logia Umana e Oncologia, Università degli Studi di Firenze, Viale G.B.Morgagni, 85, 50134 Firenze, Italia. Email: ambuccoliero@unifi.itReceived 25 July 2005; revised and accepted 22 September 2005.Blackwell Publishing AsiaMelbourne, AustraliaNEUNeuropathology0919-65442006 Blackwell Publishing Asia Pty LtdJune 2006263206211Case ReportPapillary glioneuronal tumorAM Buccoliero et al.Papillary glioneuronal tumor 207© 2006 Japanese Society of Neuropathologysisted of a cystic-nodular lesion located in the deep lefttemporal lobe in the paraventricular region; the maximumdiameter of the cystic lesion was about 35 mm, while thenodular one was about 25 mm. Contrast enhancement wasnodular and showed only a small solid circular part of thelesion. The new radiological diagnosis was consistent with abrain tumor or vascular malformation, such as hemangio-blastoma or cavernous hemangioma (Fig. 2).Surgery was computer-assisted by Neuronavigator(Stealth Navigation System, Medtronic, Goleta, California,USA) after a previous brain-map of eloquent areasobtained with functional MRI. Gross total removal wasachieved through a left parieto-occipital transventricularroute. The postoperative period was uneventful. Thepatient was discharged from the ICU to the ward in 1-daysurgery with normal neurological examination. Postopera-tive CT control confirmed radical removal without abnor-mal contrast enhancement. Thirty-two months after thefirst symptoms and 12 months after the surgery the patientis alive and well.Pathological findingsMethodsSurgical samples were routinely fixed in neutral bufferedformol, embedded in paraffin and stained with HEfor histopathological evaluation. Immunohistochemicalstudies (standard Streptavidin-biotin technique) were per-formed. The primary antibodies used were: monoclonalantibody directed against KI-67 (clone Mib-1, 1:80 dilu-tion; IMMUNOTECH, Marseille, France), GFAP (cloneZCG29, prediluted, Zymed Laboratory, San Francisco,California, USA), neuron specific enolase (NSE; cloneMIG-N3, prediluted, BioGenex, San Ramon, California,USA), synaptophysin (SP; clone Snp 88, prediluted, Bio-Genex) and antibody against neurofilaments (NF; PANclone DA2; FNP7; RMb020.11, 1:20 dilution, Zymed Lab-oratory). Microwave antigen enhancement was utilized forall the used antibodies. Immunohistochemical staining wasperformed on NEXES automated immunostainer (Ven-tana Medical Systems, Tucson, Arizona, USA).The proliferation index was determined estimating thepercentage of the Ki-67 positive neoplastic cells in the totaltumoral cells in the most positive areas.Fig. 1 First computed tomography (CT): massive intra-parenchymal brain hemorrhage located in the left basalganglia and temporal lobe with intraventricular bleeding andhydrocephalus.Fig. 2 Axial (right) and coronal (left)MRI of the lesion before its surgicalexcision. The cystic-nodular tumor wasparaventricular, located in the left deeptemporal lobe and posterior thalamus;homogeneous gadolinium enhance-ment is seen in the nodular part.208 AM Buccoliero et al.© 2006 Japanese Society of NeuropathologyFig. 3 Histological and immunohistochemical features: (a–d) double architectural patterns, pseudopapillae composed of thick-ened and hyalinized blood vessels sheathed by a single or multistratified layer of small cells and solid areas consisted of neurocyticcells; (c,d) thin walled vessels; and (d) microcalcifications in the solid areas (HE; original magnification: a ×100; b–d ×200); GFAP(e, pseudopapillary and solid areas) and SP (f, solid areas only) positive immuno-stain (original magnification: e,f ×200).Papillary glioneuronal tumor 209© 2006 Japanese Society of NeuropathologyResultsHistological examination of the tumor revealed twodifferent architectural patterns: pseudopapillary and solid.Pseudopapillae were composed of blood vessels, oftenthickened and hyalinized, sheathed by a single or multi-stratified layer of uniform small cells with ovoid-roundnuclei and scant cytoplasm; solid areas consisted of isomor-phous cells with round nuclei and wide, clear cytoplasmmimicking oligodendroglioma or neurocytoma. Thinwalled vessels were numerous in the solid areas. Lympho-cytic infiltrates, microcalcifications, hemosiderin depositsand microhemorrhagic areas were observed. The lesion didnot show necrosis or mitoses. Reactive pilocytic gliosis withRosenthal fiber and granular bodies, and wide cicatricialfibrous areas were identified along the peritumoral tissue(Fig. 3).Immunohistochemical examination revealed both neu-ronal and glial differentiation. Specifically, the cells liningthe pseudopapillae and the oligodendrocyte-like cellsstained positively for GFAP, NSE and NF whereas theoligodendrocyte-like cells only stained positively for SP(Fig. 3).The Ki-67 index was very low (about 1%).Table 1 Papillary glioneuronal cases reported in the international LiteratureReference Sex/ageSymptoms/duration Site/size (cm)† Neuroimaging characteristics Therapy‡ Follow-up§/monthsLesion Enhancement patternKomori 1998 M/13 Headache, nausea, memory loss, difficultyin comprehension andexpression/8 monthsTemporal left/7 Cystic with muralnodule,calcificationsHeterogeneous GTR NER/45F/30 None Parietal left/3 Solid and cystic Heterogeneous GTR NER/43M/11 Seizure/1 day Temporal left/7 Cystic, calcifications Ring enhancement PR RT NER/12F/27 Seizure/1 day Temporal right/4 Solid and cystic,calcificationsHomogenous GTR NER/18M/36 Headache, transient visual field, impaired speech andcomprehension/1 yearsParietal left/7 Cystic with muralnoduleHomogenous GTR NER/6F/19 Mood swings, impairedcomprehension and expression/2 yearsTemporal left/1.5 Solid Equivocal GTR NER/12F/35 Seizure, headache/1 day Temporal left/4 Solid and cystic,calcificationsRing enhancement GTR NER/12M/52 Headache/6 months Frontal right/3 Cystic with muralnoduleHomogeneous GTR NER/6F/26 Headache, tingling onthe rightside/1 dayFrontal left/5 Cystic with muralnoduleHomogeneous GTR NER/?Bouvier-Labit2000M/23 Headache, visual disturbance,dorsalgias, impairedcomprehension and expression/4 weeksParieto-occipitalleft/6Cystic with muralnoduleHeterogeneous GTR NER/84Prayson 2000 M/18 Headache, visual disturbance/2 monthsParieto-occipitalleft/5.3Cystic Ring enhancement,scattered internalenhancementGTR NER/3Barnes 2002 M/4 Headache/6 months Temporal left/3 Solid Heterogeneous GTR NER/30Broholm 2002 M/16 Consciousness lost, seizures/7 monthsFrontal left/2.8 Cystic with muralnoduleRing enhancement,mural noduleenhancementGTR NER/6Tsukayama 2002F/75 Vertigo, vomiting/unclearFrontal left/5 Cystic with muralnoduleHomogeneous PR NER/20Lamszus 2003 F/24 Seizures/6 months Parieto-occipitalleft/1Cystic Absent GTR NER/3Borges 2004 F/14 Headache, decrease in musclestrength, seizure/18 monthsFronto-parietalleft/5.5Cystic Ring enhancement GTR NER/56Stosic-Opincal2005F/16 Nausea, vomiting, fever,headache/unclearParietal right/3.5 Cystic Ring enhancementand septationsPR NER/36†Greatest dimensionGTR, gross total resection; NER, no evidence of recurrence; PR, partial resection.210 AM Buccoliero et al.© 2006 Japanese Society of NeuropathologyDISCUSSIONPapillary glioneuronal tumor is a low-grade uncommonneoplasm recently listed as a rare variant of gangliogliomain the World Health Organization (WHO) classification oftumors of the nervous system.1 It has been named in thisway because of its papillary feature (due to the dehiscenceof the cells about the vessels) and because of its doubleastrocytic and neuronal differentiation at either the mor-phological, immunohistochemical or ultrastructural level.Papillary glioneuronal tumor was first described byKomori et al. in 1998 as a novel clinico-pathologic entity.2Nevertheless, morphologically similar tumors have beenpreviously reported under many different names, i.e.pseudopapillary neurocytoma with glial differentiation,atypical extraventricular neurocytic neoplasm and pseudo-papillary ganglioneurocytoma.17–24To the best of our knowledge, 17 cases complete withclinical and histopathological data have been documentedto date in the English language literature (one additionalcase lacked exhaustive clinical and histopathological data;six cases were reported in the Polish and Japanese litera-ture).2–12,15,16,24–26 The analysis of these cases supports theproposition that papillary glioneuronal tumor more oftenaffects young people (mean age at the diagnosis: 26 years,range 4–75 years) without gender predominance (female :male ratio about 1:1). The first symptoms, commonly head-ache (59%) and seizures (35%), appear an average of6 months (range 1 day-2 years) before diagnosis. It typi-cally arises in the supratentorial region (all reported cases)primarily involving the left cerebral hemispheres (82%).Common neuroimaging characteristics are a cystic appear-ance (88%) and the presence of contrast enhancement(88%; ring enhancement 35%; homogeneous 29%; heter-ogeneous 24%). Follow-up data indicate a benign outcomewith no evidence of recurrence during intervals rangingfrom 3 months to 7 years (Table 1).2–12,15 Histopathologicalfeatures of papillary glioneuronal tumor are similar in allreported cases, invariably reproducing the first descriptionof this tumor by Komori.2The main peculiarity of our case is the onset with a mas-sive brain hemorrhage.The frequency of intracranial hemorrhage in patientswith intracranial neoplasms varies in the different seriesfrom 2% to 5%. It may occur in all central nervous systemtumors to a varying degree and extent and may even bemassive. These massive ones mostly occur in more malig-nant tumors, such as glioblastoma or metastases. Neverthe-less, benign tumors, such as pituitary adenoma, pilocyticastrocytomas or meningiomas, may also bleed to the extentof a massive hemorrhage.27–31Several mechanisms were advocated to explain thepathogenesis of brain tumor related hemorrhages: endot-helial proliferation with subsequent obliteration of thelumen; thin walled or poorly formed vessels; perivascularnecrosis with subsequent loss of vessel support; presence ofintratumoral arteriovenous fistulae.30,31In the present case, the hemorrhage could have resultedeither from the presence of numerous thin walled vesselsin the solid areas or from the abnormal hyalinized wall ofthe vessels in the papillary zones. Actually, in spite of anabsence of previously reported papillary glioneuronaltumors showing massive brain hemorrhages, signs of pre-vious bleeding (i.e., hemosiderin deposition, hemosiderin-laden macrophages) are often reported.2–5,8 Consequently,we may suppose that hemorrages may occur with variousgravity in papillary glioneuronal tumor.In conclusion, papillary glioneuronal tumor should beincluded in the differential diagnosis of patients withtumoral related brain hemorrhage.REFERENCES1. Kleihues P, Cavenee WK. Pathology and Genetics.Tumor of the Nervous System. World Health Organi-zation Classification of Tumours. Lyon: IARC, 2000.2. Komori T, Scheithauer BW, Anthony DC et al.Papillary glioneuronal tumor. A new variant of mixedneuronal-glial neoplasm. Am J Surg Pathol 1998; 22:1171–1183.3. Bouvier-Labit C, Daniel L, Dufour H, Grisoli F,Figarella-Branger D. Papillary glioneuronal tumor:clinicopathological and biochemical study of one casewith 7-year follow-up. Acta Neuropathol 2000; 99: 321–326.4. Prayson RA. Papillary glioneuronal tumor. ArchPathol Lab Med 2000; 124: 1820–1823.5. Barnes NP, Pollock JR, Harding B, Hayward RD.Papillary glioneuronal tumour in a 4-year-old. PediatrNeurosurg 2002; 36: 266–270.6. Broholm H, Madsen FF, Wagner AA, Laursen H.Papillary glioneuronal tumor – a new tumor entity.Clin Neuropathol 2002; 21: 1–4.7. Tsukayama C, Arakawa Y. A papillary glioneuronaltumor arising in an elderly woman: a case report. BrainTumor Pathol 2002; 19: 35–39.8. Lamszus K, Makrigeorgi-Butera M, Laas R, West-phal M, Stravrou D. A parieto-occipital tumor.Neuropathology case. Available from URL: http://path.upmc.edu/cases/case323.html.9. Borges G, Bonilha L, Menezes AS et al. Long termfollow-up in a patient with papillary glioneuronaltumor. Arq Neuropsiquiatr 2004; 62: 869–872.10. Biernat W, Liberski PP. [Papillary glioneuronaltumor.] Pol J Pathol 2001; 52: 111–112. (In Polish.)Papillary glioneuronal tumor 211© 2006 Japanese Society of Neuropathology11. Kordek R, Henning R, Jacobsen E, Kearney M. [Pap-illary glioneuronal tumor – a new variant of benignmixed brain neoplasm.] Pol J Pathol 2003; 54: 75–78.(In Polish with English abstract.)12. Ebato M, Tsunoda A, Maruki C, Ikeia F, Okada M.[Papillary glioneuronal tumor with highly degenera-tive pseudopapillary structure accompained by specificabortive glial cells: a case report.] No Shinkei Geka2003; 31: 1185–1190. (In Japanese with Englishabstract.)13. McLendon RE, Provenzale J. Glioneuronal tumors ofthe central nervous system. Brain Tumor Pathol 2002;19: 51–58.14. Cenacchi G, Giangaspero F. Emerging tumor entitiesand variants of CNS neoplasms. J Neuropathol ExpNeurol 2004; 63: 185–119.15. Stosic-Opincal T, Peric V, Gavrilovic S, Marcovic Z,Sener RN. Papillary glioneuronal tumor. AJR Am JRoentgenol 2005; 185: 265–267.16. Tanaka Y, Yokoo H, Komori T et al. A distinct patternof Olig2-positive cellular distribution in papillary glio-neuronal tumors: a manifestation of the oligodendro-glial phenotype? Acta Neuropathol 2005; 110: 39–47.17. Kim DH, Suh YL. Pseudopapillary neurocytoma withglial differentiation. Acta Neuropathol (Berl) 1997; 94:167–191.18. Tsuchida T, Matsumoto M, Shirayama Y, Imahori T,Kasai H, Kawamoto K. Neuronal and glial character-istics of central neurocytoma: electron microscopicalanalysis of two cases. Acta Neuropathol (Berl) 1996;91: 573–577.19. von Deimling A, Janzer R, Kleihues P, Wiester OD.Pattern of differentiation in cortical neurocytoma: animmunohistochemical study of eleven biopsies. ActaNeuropathol (Berl) 1990; 79: 473–479.20. Westphal M, Stavrou D, Nausch H, Valldueza JM,Hermann HO. Human neurocytoma cells in cultureshow characteristics of astroglial differentiation. JNeurosci Res 1994; 38: 698–704.21. Biernat W, Zakrzewski K, Liberski PP. Case of themonth. Brain 2000; 10: 313–314.22. Giangaspero F, Cenacchi G, Losi L, Cerasoli S, Bis-ceglia M, Burger PC. Extraventricular neoplasm withneurocytoma features. A clinicopathological study of11 cases. Am J Surg Pathol 1997; 21: 206–212.23. Komory T, Sheithauer BW, Anthony DC, Scott RM,Okazaki H, Kobayashi M. Pseudopapillary ganglion-eurocytoma. J Neuropathol Exp Neurol 1996; 55: 654.24. Shibuya M, Yamazaki H, Sugiyama M. [A case of pap-illary glioneuronal tumor.] Brain Tumor Pathol 2003;20 (Suppl): 73. (In Japanese.)25. Ishizawa T, Komori T, Ishizawa K et al. [A case of pap-illary glioneuronal tumor with rhabdoid cell compo-nents.] Brain Tumor Pathol 2004; 21 (Suppl): 65. (InJapanese.)26. Tanaka Y, Hirato J, Makita Y, Nazato Y. [A case ofpapillary glioneuronal tumor.] Brain Tumor Pathol2004; 21 (Suppl): 66. (In Japanese.)27. Wakai S, Yamakawa K, Manaka S, Takakura K.Spontaneous intracranial hemorrhage caused by braintumor: its incidence and clinical significance. Neuro-surgery 1982; 10: 437–444.28. Schrader B, Barth H, Lang EW et al. Spntaneousintracranial haematomas caused by neoplasms. ActaNeurochir 2000; 142: 979–985.29. Licata B, Turazzi S. Bleeding cerebral neoplasms withsymptomatic hematoma. J Neurosurg Sci 2003; 47:201–210.30. Fujita K, Matsumoto S. [Intracerebral hemarrhage inbrain tumors.] No Shinkei Geka 1980; 8: 929–934. (InJapanese with English abstract.)31. Lieu AS, Hwang SL, Howng SL, Chai CY. Braintumors with hemorrhage. J Formos Med Assoc 1999;98: 365–367.

Papillary glioneuronal tumor radiologically mimicking a cavernous hemangioma withhemorrhagic onset.

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Papillary glioneuronal tumor radiologically mimicking a cavernous hemangioma withhemorrhagic onset.

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