The Pleomorphic Xanthoastrocytoma and Its Differential Diagnosis: a Study of Five Cases

The Pleomorphic Xanthoastrocytoma and Its Differential Diagnosis: A Study of Five Cases

JOHAN M. KROS, MD, CHARLES J. VECHT, MD, PHD, AND STANISLAV Z. STEFANKO, MD, PHD

Five brain tumors with the histopathologic features of pleomorphic Despite some atypical clinical features, the histo- xanthoastrocytomas (PXAs) are presented. Computed tomography pathology of the present five cases was compatible with scans showed a remarkable homology. Two cases had atypical lo- the entity of PXA. However, in one of the presented calizations for a PXA, while one 46-year-old patient did not conform tumors, neoplastic neuronal cells were found. The dif- to the normal age distribution of this tumor. Nevertheless, in these ferential diagnosis of PXA and of this case, in particular, cases, the histopathology was always characteristic for PXA, a re- are discussed. markable pleomorphism, in addition to simultaneous expression of glial fibrillary acidic protein and histiocytic markers in the various tumor cells. In one of the presented tumors, however, clusters of MATERIALS AND METHODS neoplastic neuronal cells were also found. In this particular case, differential diagnostic criteria to distinguish between a PXA and a Conventional Staining and desmoplastic infantile ganglioglioma are lacking. HUM PATHOL 22: lmmunohistochemistry 1128-l 135. Copyright 0 1991 by W.B. Saunders Company Pleomorphic tumors with malignant appearance from patients with unexpected benign courses as well as from patients In 1979, Kepes et al described 12 young patients with a primary diagnosis of PXA were reviewed. The paraffin- with superficial brain tumors with extensive involvement embedded material from five selected cases was retrieved from of the leptomeninges.’ In spite of an impressive pleo- the archives and new sections were made. The slides were morphism, necrosis was never found in these tumors, stained with hematoxylin-eosin, periodic acid-Schiff for mu- and mitoses were scanty. The presence of intracyto- copolysaccharides and glycogen, Nissl stain for the Nissl sub- plasmic lipid droplets in part of the tumor cells, as well stance, and Bodian stain for visualization of axon bundles. For immunohistochemistry, the slides were incubated with as a basal lamina around individual cells, supported the antibodies against vimentin, keratin. desmin, epithelial mem- initial view that these highly pleomorphic neoplasms brane antigen, SlOO protein, GFAP, neuron-specific enolase, represented a variant of meningocerebral fibrous xan- lysozyme (muramidase), (Y-1 -antitrypsin, (Y-1 -antichymotrypsin, thomas.’ Once the expression of glial fibrillary acidic neurofilament (monoclonal reacting with 70- and 200-kd pro- protein (GFAP) was found in the tumor cells, however, teins), and synaptophysin. The primary antibodies were ob- these neoplasms were considered to be variants of as- tained from DAK0 (Copenhagen, Denmark). Immunohisto- trocytomas and, subsequently, were termed “pleomor- chemistry on 5 pm-thick sections of the paraffin-embedded phic xanthoastrocytomas” (PXAs).’ In contrast to their material was done with the two-step indirect immunoperoxi- ominous histopathology, the clinical courses appeared dase technique as described previously.” Final visualization to be relatively favorable.’ Therefore, distinction of was achieved by incubation with 0.02% diaminobenzidine in PXAs from other pleomorphic gliomas is important. The phosphate-buffered saline and 0.075% H202. Control slides, in which the primary antibody was replaced by phosphate- presence of necrosis in a pleomorphic intracerebral tu- buffered saline, were always negative. The slides were slightly mor should definitely exclude the diagnosis of PXA, counterstained with hematoxylin to determine the cellular since necrosis is invariably linked with malignancy.“.4 morphology. For keratin staining a mild proteolytic treatment Several cases of PXA have been described.“-‘” Some with pronase (Sigma no. P5147, St Louis, MO) was performed of these had exceptional clinical features. In contrast (0.1% pronase for 15 minutes at room temperature) to demask with the typical young age of incidence of PXAs, a 62- the keratin epitopes. year-old man was described by Mackenzie.” Unusual localizations of PXAs were the suprasellar region and RESULTS the floor of the medial skull fossa.8.‘7 Furthermore, PXAs with extensive recurrences after initial o eration Patients and Computed Tomography Scan and rapid fatal outcomes have been reported. R-21 Findings The clinical data of the five cases are summarized From the Departments of Pathology/Neuropathology and Neu- in Table 1. One patient (case no. 4) was 46 years old. rology/Neurosurgery, Academic Hospital Rotterdam-Dijkzigt, Rot- The tumor in this patient was located in the thalamus. terdam, The Netherlands. Accepted for publication January 28, 1991. Ke! words:pleomorphic xanthoastrocytoma, glioma, immunohis- The patient died after 3 years due to tumor progression. tochemlstry, ganglioglioma, desmoplastic infantile ganglioglioma. Although a stereotactic operation was performed, suf- Address correspondence and reprint requests to Johan M. Kros, ficient material for reliable diagnosis was available. Case MD, Department of Pathology/Neuropathology, Academic Hospital no. 5 presented with a tumor located in the temporal Rotterdam-Dijkzigt, PO Box 1738, 3000 AD Rotterdam, The Neth- lobe with extension into the thalamus. erlands. Copyright 0 1991 by W.B. Saunders Company On a computed tomography (CT) scan, the lesions 0046-8177/91/2211-0009$5,00/O showed uniform intense contrast enhancing (Fig 1). The

1128 PLEOMORPHIC XANTHOASTROCYTOMA (Kros et al)

TABLE 1. Clinical Data of the Five Patients

lesions wertx sharpI) demarcated. with brain edema ex- shaped cells) (Fig 2F). Focal infiltratrs of Ivmphocytes tending into the white matter. In three patients (nos. 1, and plasma cells were found (Fig ?A). 2, and 3) the tumors were located at the convexity, with In case no. 5 clusters of neuronal elements were brain edema extending centrally into the white matter. seen dispersed between the other tumor elements (Fig Two patients (nos. 1 and 5) had centrally located lesions, 2H-1,). The neoplastic nature of the neuronal elements including thr thalamus. with no or only mild develop- was supper-ted by their pleomorphism ad random ori- ment of brain edema (Fig 1). entation: they sometimes formed clusters (Fig ZK). The (IW neuronal nature of these neoplastic cells was proven Histopathologic Features bv the presence of Nissl substance in addition to im- n;unohistc,chemical profiles (see below) (Fig 21). A marked pleomorphism was an invariable tinding in ‘41 five p,atients (Fig PA). Xanthomatous cells as well lmmunohistochemistry as polygonal cells with eosinophilic hyaline granules in the cytoplasm! were seen among irregular bundles of In all tumors a majority of the tumor cells stained spindle-shaped cells (Fig ‘LA, C, D, E, and F). Further- positive for anti-GFAP‘antibody (Table 2; Fig 2s) and more, gemistocvtic cells, giant cells (some of which were for anti-vimentin, as well as for the histioc ytic markers polynuclear), and nude nuclei without recognizable cy- CU-1-antitrypsin and a-1 - ;Inti~hyrllot~psin (Table 2; Fig toplasm were seen (Fig ‘LA and G). Many periodic acid- XI). Furthermore, the tumor cells express4 Sl 00 pro- Schiff-positive. diastase-resistant granules were present tein and neuron-specific enolase (Table I!). In none of‘ in par’ of thie tumor cells (Fig 9E). Only sporadic mitoses the cells was immunostaining acquired for anti-keratin were noted. In AI five cases necrosis was definitely ab- xid anti-Iysozynie (Table 2). sent. Vascular proliferation was not obvious. Keticulin In the neoplastic neuronal cells of c’ase no. :i the staining revealed a fiber network surrounding individual perikaryon and the cell processes wcrc positive for neu- tumor cells (ie. both the polygonal cells and the spindle- rotilament (Fig 2.1). Intense positifit! for anti-svnapto-

FIGURE 1. Computed tomography scan findings. (Left) Case no. 2. Computed tomography idiosyncrasies of a PXA, a parietal located, partly cystic tumor, firmly connected with the dura. (Right) Case no. 5. Cystic tumor with deep temporal location, extending into the thalamus. No connection with the dura is noted.

1129 FIGURE 2. Histopathologic and immunohistochemical pictures. (A) Case no. 1. Low-power magniftcation of a typical PXA: a moderately cellular, marked pleomorphic tumor, without necrosis. (Hematoxylin-eosin stain; magnification X9.) (B) Case no. 1. lmmunopositivity for GFAP of the various tumor cells. Round cells as well as spindle-shaped cells are positive for GFAP. (Peroxidase antiperoxidose [PAP] stain for GFAP: magnification X79.) (C) Case no. I. lmmunopositivity for a-I-antichymotrypsin in the PXA. The expression is variable. (PAP stain for tu-I-antichymotrypsin; magnification x79.) (D) Case no. I. Xanthomatous cell (“lipid-laden cell”): polygonal cell with confluent vacuoles in the cytoplasm. (Hematoxylin-eosin stain; magnification x264.) (E) Case no. 1. Eosinophilic hyaline granular cell: this cell was described in detail OS a constituent of the PXAs by lwaki et al.’ lntracytoplasmatic eosinophilic granules are found, which stain strongly with periodic acid-Schiff. (Magnification x264.) (F) Case no. I. Spindle-shaped cell. Reticulin is not exclusively found around this cell type, but surrounds the lipid-laden cells as well. (Gomori stain; magnification x264.) (G) Case no. 3. Multinuclear giant cell (Touton-like giant cell). A variety of larger cells are seen in the PXA, ranging from gemistocytic cells to monstrous cells. The nuclei of the Touton-like cells have an (almost) circular arrangement. (Hematoxylin-eosin stain; magnification x264.) (H) Case no. 5. Neuronal cell (arrow) in a highly pleomorphic tumor indistinguishable from the PXA. (Hematoxylin-eosin stain; magnification XI 15.) (I) Case no. 5. Among the neuronal cells in case no. 5, several binucleated cells were found. (Nissl stain; magnification x264.) (J) Case no. 5. Neuronol cell (arrow) PAP stained for neuroftlament. (Magnification x264.) (K) Case no. 5. Cluster of neuronal cells (arrows). The random orientation and pleomorphism, in addition to strong positivity for synaptophysin, indicate the neoplostic nature of these cells. (PAP stain for synaptophysin; magnification X79.) (L) Case no. 5. Higher magnification of neuronal cell, stained for synaptophysin. lmmunostaining is seen in the perikaryon as well as in and around the cell processes. (PAP stain for synaptophysin: magnification X264.)

1130 FIGURE 2. (Continued) HUMAN PATHOLOGY Volume 22, No. 11 (November 1991)

FIGURE 2. (Continued)

physin antibody was seen in the cytoplasm and in and surrounding brain tissue, and contrast enhancement was around the cell processes (Fig 2K and L). a constant finding. Cysts were seen in all tumors. The CT scan findings are not specific for PXAs, however, since comparable scans are found in a variety of other DISCUSSION benign as well as malignant brain tumors.“.“‘.‘” Despite a similar histopathology, the presented Comparison of the CT scans of the present five cases had discrepant clinical data. Although one case of patients (Fig 1) with photomicrographs of CT scans in P2L4 has been described before in an elderly patient,” the literature”.I:‘.I7.‘“.” revealed a remarkable similarity. PXAs usually appear in young people. One of our pa- The lesions invariably showed distinct borders with the tients was 46 years old. In this patient and in one other

TABLE 2. lmmunohistochemical Results

ker vim gfa ‘Ys t r p chv nse Ill s 1 00 syn

Spindle-shaped cells + + _ + + + + _ Xanthomatous cells _ + + _ + + + t _ Cells with eosinophilic hyaline granules + + _ + + + + _ Gemistocytic c-ells _ t + _ + + + t _ Giant cells _ + _ + + -+ + -. Touton-type giant cells _ _ + _ + + Newonal cells _ _ _ + + +

Symbols: -, negative; +, positive; *. fXnt immunostaining. Abbreviations: ker, keratin: vim. vimentin; gfa, glial fibrillary acidic protein; lys, lysozyme (murarninidase); trp, a-I-trypsin; thy. a-l -c-hy- nrotrypsin; “se. neuron-specific enolase; nf, new&lament: SlOO, SlOO protein; syn, synaptophysin.

1132 PLEOMORPHIC XANTHOASTROCYTOMA (Kros et al)

(no. 5), the tumor was located in a deep region (ie, the easily explained. Moreover, in our cases, the expression thalamus) (Fig 1, right). These cases and a few others of GFAP was not restricted to nonsuperficial tumor cells in the liter,ature illustrate that PXAs ma be found in (Fig 2b). Whatever histogenesis PXAs Inay have, it should B sites without obvious meningeal contact. .” be kept in mind that expression of any marker could Almost all cell types simultaneously expressed very well be the result of capricious behavior of the GFAP as well as the histiocytic markers a-1-antitrypsin tumor cells rather than the indication of a supposed and cu-1-antichymotrypsin (Table 2; Fig 2B and C). Al- nonneoplastic cell of tumor origin.“’ though int r-acranial localized malignant fibrous histio- Necrosis has been identified as a histopathologic cytomas may show pleomorphism as well, there is defi- feature with independent prognostic significance in nitely no (expression of GFAP in these tumors.“‘-“’ gliomas.“” Based on the strict absence of this feature in Despite morphologic and immunohistochemical simi- PXAs, these tumors should be distinguished from larities between PXAs and meningeal-derived fibrous gliomas with heavily lipidized tumor cells:‘.” (Table 3), histiocytomas, Kepes et al believe that PXAs represent as well as from monstrocellular brain tumors in which primary glial, and not mesenchymal, neoplasms.21 In necrosis invariably heralds a bad prognosis.‘” Although spite of the presence of reticulin, collagen depositions, the lengths of survival in monstrocellular glioblastomas (hemi)desmosomes, and intracytoplasmic lipid droplets, are longer than those in less pleomorphic subtypes, the marked GFAP positivity of the tumor cells was seen they differ considerably from those recorded in cases as a definite sign of the true glial nature of this tumor.” of PXA.’ Paulus and. Peiffer, however, disputed its true glial na- The presence of necrosis in two putative cases of ture because of the positivity of the tumor for mono- PXA presented by Gaskill et al was linked with the cytic-histiocytic markers, in addition to the distinct mes- rapid death of one of the patients,“’ while it was also enchymal features.” According to their observations, the cause of criticism surrounding the a’ccuracy of the the presence of GFAP-positive cells would be limited to histopathologic diagnosis.“’ However, some investi- areas of cortical infiltration and might be explained by gators have suggested that anaplastic evolution of endocytic processes of histiocytic cells or by migration PXAs, associated with necrosis, might occur.‘!‘.” of’reactive astrocytes into the primary mesenchymal tu- Moreover, the transition of a PXA into a glioblastoma mor.” If the PXA indeed represents a meningeal-de- with necrosis as a genuine feature has been inter- rived tumor, the occurrence of this entity in nonsuper- preted as further corroboration of the true glial na- ficial parts of the brain, such as the thalamus, is not ture of the former.“’

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The superficial cerebral astrocytomas that were edged for allowing access to the neurosurgical records. Case found in some very young children by Taratuto et al’” no. 3 was kindly provided by Dr R.A.I. de Vos. T. Zwitser, and Chadarkvian et al”’ may be confused with PXAs, A.M. van Seeters, and P.J.A. Janssen are gratefully acknowl- edged for their skillful technical assistance. M. Hanegraaff for but clinical data and histopathology are distinct from secretarial assistance. the latter. Although superficial cerebral astrocytomas contain spindle-shaped cells and gemistocytic cells, lip- REFERENCES idized cells are sporadic and the degree of pleomorphism is not as pronounced as in PXAs (Table 3). Because of 1. KepesJJ. Rubinstein I,J, Eng 1.F: Pleomorphic xanthoastro- GFAP positivity, the superficial cerebral astrocytomas cytoma: A distinctive meningocerebral glioma of young subjects with relatively favorable prognosis. A study of 12 cases. Cancer 44: I XW- are believed to be glial tumors as well.“” Just as in the 1852, 1979 PXA. the subpial astrocytic subset has been considered 2. Kepes JJ, Kepes M, Slowik F: Fibrous xanthomas and xantho- as a possible ontogenic lineage for these superficial lo- sarcomas of the meninges and the brain. Acta Neuropathol (Bert) 23: calized neoplasms.‘“.“’ 187-199, 1973 Our finding of neoplastic neuronal cells in an 3. Gherardi R, Baudrimont M. Nguyen JP. et al: Monstroc-ellulal heavily lipidized malignant glioma. .4cta Neuropathol (Berl) 69:28- otherwise typical PXA (case no. 5) has not been reported 32, 1986 previously. The neuronal cells presented with several 4. Kepes JJ, Ruhinstein 111: Malignant gliomas with heavily hpid- degrees of maturation. Binucleated neuronal cells were ized (foamy) tumor cells: A report of three cases with immunoprr- frequently seen (Fig 21). The presence of Nissl substance, oxidase study. Cancer 47:245 I-2459, 1981 in addition to the expression of neurofilament and syn- 5. Allegranza A. Migliavacca F. Mariani C: Xantoastrocitonla pleomorfo cerebra-meningeu. Istocitopatologia 2: 137. I4 1, 1980 aptophysin, was a signpost for the true neuronal char- 6. Gomez JC, Garcia JH. Colon IX: A variant of cerebral glioma acter of these cells”“,“” (Fig 21-L), while the random ori- called pleomorphic xarithoastrocytoma: Case report. Neurosurgcly entations and clustering are indicative of their neoplastic 16:703-706, 1985 status (Fig 2K). Their presence had, in this case, led to 7. Grant JW. Gallagher P.J: Pleomorphic x;lnthoastro~yton~a. Inllnunohistochenii~al methods for difterentiation from fibrous his- a primary diagnosis of ganglioglioma (ie, desmoplastic tiocytomas with similar morphology. Am J Surg Pathol 10:336-31I. infantile ganglioglioma [DIG]).“’ Gangliogliomas and 1986 ganglioneuromas may very well be found in the floor of 8. Heyerdahl Strum E, Skullerud K: Pleomorphic xantho;istro- the third ventricle, although they might arise anywhere cvtoma: Report of 5 cases. Clin Neuropathol 2: 188-19 I. I983 else in the brain,““,““-“’ whereas DIGS are only encoun- 0. lwaki T, Fukui M. Kondo A. et al: Epithcli;il propcrtirs of pleomorphic xanthoastl-o~~tc,mas determined in ultrdstruc tur-al and tered in peripheral parts’)’ (Table 3). Although pleo- inlmunohistochenii~al 5tuclles. Arta Neuropathol (Berl) 7-1: 142-l 50. morphism may be present either in the glial or in the 1987 neuronal cell component of gangliogliomas, the glial 10. .Jones M, L)rut R. Kaglia G: Pleomor-phic xanthoastroc-~tolll;l. part would be responsible for occasional malignant A report of two cases. Pediatr Pathol 1 :459-467. I !I,‘(3 11. Kuhajda FP. Mendelsohn C;. Tax? JB. ct XI: Plc(mrorphic transformation of these tumors.“” In exceptional cases, YatlthoastroTvtf)m;l: Report of a case with light and alrc-Iron mic IOS- gangliogliomas transform into glioblastomas.“H-“” The copy. IJltrast&t Path01 2:25-32. 1981 variants of DIGS affect young children and usually pres- 12. Mackenzie JM: Pleomorphic xanthoitstn)c stoma in a ti2-vear- ent as huge tumors affecting more than one cerebral old male. Neuropatiiol Appl Ncurobiol 13:48 l-487. I!)87 13. Maleki M, Rohitaillr Y. Bert]-and (;: Atypical santho,ratro- lobe” (Table 3). cytoma presenting as a meningioma. Surg Neural 90:~:3.5-“:38_ _ , 19x3 Desmoplastic infantile ganglioglioma and PXA do I-I. Palma I.. Celli I’. Maleci .4. et al: Malignant [t~clnstro~ellular share a number of clinical and histopathologic charac- brain tumours. ‘4 study of 42 surgically treated casts. Acta Neurtrchil teristics (Table 3). Both contain GFAP-positive cells, and (Wien) 97: 17-25, 1980 both are preferentially associated with the leptomenin- 15. Pasquier B. Kc!jdc~- 1. Labat F. et al: IX s;lnthc,asrrc,~~t(,Irlc du sujet jeune. Revue de la litterature a propos de dcux ob6crvations ges. The distinction between PXAs and DIGS, however, d’evolution discordante. Ann Pathol 5:20-43, 1985 is based on the finding of xanthomatous cells in the 16. Sakai H. Kuwano N. Okada K. et al: A c asp of pleomtrrphic former, while neoplastic neuronal cells should be ex- xanthoastrocytolna (Kepes). No Shinkei Geka !I: 15IO- 1524. I 9X 1 clusively diagnostic for gangliogliomas (ie, DIGS).‘,“’ 17. Stuart C;, Appleton I)K, Cooke R: Pleomorphic xanthoastt-o- cytoma: Report of two cases. Neurosurgery 22:4P?--l27, 1988 Therefore, the presence of xanthomatous cells in ad- 18. Sugita Y, Shigemori M. Uegaki M, et al: Plecmol-phic s;u~- dition to neoplastic ganglion cells in our case no. 5 thoastrocytoma. Case report. Neural Mecl Chir (Tokyo) 28:X I?-X 15, causes difficulties in the differential diagnosis. Fortu- 1988 nately, the distinction between a PXA with a neoplastic 19. Weldon-Limie CM. Victor TA, (;roothuia I)R. rt aI: 1’1~0. morphic xanthclastro~~toma. Ultrastruc-tur.aI and i,llt,lullohist~)chen~- neuronal component on the one hand and a DIG with iral study of a case with a rapidly f’atal outcome f~&~wing surgcr?. xanthomatous cells on the other appears to be irrelevant (:ancer 52:2055~206~. 1983 with respect to the expected biologic behavior. 20. Gaskill SJ, Marlin AE, Saldivar V: (;lioblastoma multifol-nlr In conclusion, we believe that, due to its relatively masquerading as a pleomorphic xanthoastroc ytoma. Childs NCI-v Svst 4:“37-“40_. _ , 1988 favorable prognosis and characteristic histopathology, 21. Kepes JJ, Rubinatein Id. Ansbac her I.. ct al: Histc~patllol~~gi~al the pleomorphic xanthoastrocytoma definitely repre- features of I-ecurrent pleomorphic xanthoastroc.ytornas. Further (or.- sents a separate entity. If neuronal elements are ac- rohoration of the glial nature of this neoplasm. A study of 3 cases. cepted as a possible constituent of this tumor, its dis- Ac1a Neurcq?athoI (Bcrl) 78:5X5-593, 1989 tinction from DIGS may be impossible. 2?. Kros JM. St&nko S%, de Jong AAW. ct al: ~~ltt.:~st~-1~(.t11r;II and irnmunohistr)chemical segr-egation of gemistocvtic subsets. Hti%r PATHW 2‘~:S‘MO-. 1 199 I Ackrmwl~dpnrr~t. The author would like to thank Dr ?3. Taratuto AI., Monges .J. Lylyk I’. ct al: Superficial tel-ebr,tl 7‘h.H. van der Kwast for critical reading of the manuscript astrocytoma attached to the dui-a. Keport of six cases in infzuits. (:ancel. and fruitful discussion. Professor C.J,J. Avezaat is acknowl- 54:2505-2512. 1984

1134 PLEOMORPHIC XANTHOASTROCYTOMA (Kros et al)

1135