Abstract
The cellular nature of the giant eosinophilic cells of tuber and of the cells comprising subependymal giant cell astrocytoma (SEGA) in tuberous sclerosis (TS) remains unclear. To assess the characteristics of these lesions, 13 tubers and 6 SEGA were immunohistochemically studied with glial and neuron-associated antigens. In addition to conventional ultrastructure, 6 tubers and 8 SEGA were fibrillary acidic protein (GFAP) and somatostatin. Eosinophilic giant cells of tubers were positive for vimentin (100%), GFAP (77%) and S-100 protein (92%); such cells were also found to a various extent to be reactive for neuron-associated antigens, including neurofilament (NF) proteins (38%) or class III β-tubulin (77%). SEGA also showed variable immunoreactivity for GFAP (50%) or for S-100 protein (100%); NF epitopes, class III β-tubulin, and calbindin 28-kD were expressed in 2 (33%), 5 (83%) and 4 (67%) cases, respectively. Cytoplasmic staining for somatostatin (50%), met-enkephalin (50%), 6-hydroxytryptamine (33%), β-endorphin (33%) and neuropeptide Y (17%) was noted in SEGA, but not in tubers. Ultrastructurally, the giant cells of tubers and the cells of SEGA contained numerous intermediate filaments, frequent lysosomes and occasional rectangular or rhomboid membrane-bound crystalloids exhibiting lamellar periodicity and structural transition to lysosomes. Some SEGA cells showed features suggestive of neuronal differentiation, including stacks of rough endoplasmic reticulum, occasional microtubules and a few dense-core granules. Furthermore, in one case of tuber, a process of a single large cell was seen to be engaged in synapse formation. Intermediate filaments within a few cells of both lesions were decorated by gold particle-labeled GFAP antiserum. Within the tumor cells of SEGA, irregular, non-membrane-bound, electron-lucent areas often contained somatostatin-immunoreactive particles, whereas the latter could not be detected in tuber. The present study provides further evidence of divergent glioneuronal differentiation, both in the giant cells of tubers and the cells of SEGA. The findings of similar cells at different sites, including the subependymal zone, white matter (“heterotopias”), and cortex indirectly supports the idea that these lesions of TS result from a migration abnormality.
Similar content being viewed by others
References
Altermatt HJ, Shepherd CW, Scheithauer BW, Gomez MR (1991) Das subependymale Riesenzellen-Astrozytom. Zentralbl Pathol 137: 105–116
Altermatt HJ, Lopes MBS, Scheithauer BW, VandenBerg SR (1993) The immunochemistry of subependymal giant cell astrocytoma (SEGA) in tuberous sclerosis (TS) (abstract). J Neuropathol Exp Neurol 52: 326
Arseni C, Alexianu M, Horvat L, Alexianu D, Petrovici A (1972) Fine structure of atypical cells in tuberous sclerosis. Acta Neuropathol (Berl) 21: 185–193
Aydin F, Harlan RE, Sholes AH, Dinh DH, Nadell JM, Harkin JC (1994) Subependymal giant cell astrocytoma: a case report with cell culture, cytogenetic, immunohistochemical, ultrastructural and proliferation studies (abstract). Brain Pathol 4: 408
Bender BL, Yunis EJ (1980) Central nervous system pathology of tuberous sclerosis in children. Ultrastruct Pathol 1: 287–299
Bender BL, Yunis EJ (1982) The pathology of tuberous sclerosis. Pathol Annu 17: 339–382
Bettica A, Johnson AB (1990) Ultrastructural immunogold labeling of glial filaments in osmicated and unosmicated epoxyembedded tissue. J Histochem Cytochem 38: 103–109
Binder LI, Frankfurter A, Kim H, Caceres A, Payne MR, Rebhun LJ (1984) Heterogeneity of microtubule-associated protein 2 during rat brain development. Proc Natl Acad Sci USA 81: 5613–5617
Boesel CP, Paulson GW, Kosnik EJ, Earle KM (1979) Brain hamartomas and tumors associated with tuberous sclerosis. Neurosurgery 4: 410–417
Bonetti F, Chiodera PL, Pea M, Margignoni G, Bosi F, Zamboni G, Mariuzzi GM (1993) Transbronchial biopsy in lymphangiomyomatosis of the lung. HMB45 for diagnosis. Am J Surg Pathol 17: 1092–1102
Bonnin JM, Rubinstein LJ, Papasozomenos SC, Marangos PJ (1984) Subependymal giant cell astrocytoma. Significance and possible cytogenetic implications of an immunohistochemical study. Acta Neuropathol (Berl) 62: 185–193
Burger PC, Scheithauer BW (1993) Tumors of the central nervous system. Atlas of tumor pathology, 3rd series, fascicle 10. Armed Forces Institute of Pathology, Washington, DC
Caccamo DV, Herman MM, Frankfurter A, Katsetos D, Collins VP, Rubinstein LJ (1989) An immunohistochemical study of neuropeptides and neuronal cytoskeletal proteins in the neuroepithelial component of a spontaneous murine ovarian teratoma. Primitive neuroepithelium displays immunoreactivity for neuropeptides and neuron-associated β-tubulin isotype. Am J Pathol 135: 801–813
Chou TM, Chou SM (1989) Tuberous sclerosis in the premature infant: a report of a case with immunohistochemistry on the CNS. Clin Neuropathol 8: 45–52
Davidson M, Yoshidome H, Stenroos E, Johnson WG (1991) Neuron-like cells in culture of tuberous sclerosis tissue. Ann NY Acad Sci 615: 196–210
De Chadarevian J-P, Hollenberg RD (1979) Subependymal giant cell tumor of tuberous sclerosis. A light and ultrastructural study. J Neuropathol Exp Neurol 38: 419–433
DeLellis RA, Dayal Y (1992) Neuroendocrine system. In: Sternberg SS (ed) Histology for pathologists. Raven Press, New York, pp 347–362
Dumas JLR, Escourolle JPR (1973) Etude ultrastructurale des lesions cerebrales de la sclerose tubereuse de Bourneville. Acta Neuropathol (Berl) 25: 259–270
Erlandson RA (1994) Diagnostic transmission electron microscopy of tumors with clinicopathological, immunohistochemical, and cytogenetic correlations. Raven Press, New York, pp 270–274
Ferrer I, Fabregues I, Coll J, Ribalta T, Rives A (1984) Tuberous sclerosis: a Golgi study of cortical tuber. Clin Neuropathol 3: 47–51
Frankfurter A, Binder LI, Rebhun LI (1986) Limited tissue distribution of a novel beta-tubulin isoform (abstract). J Cell Biol 103: 273a
Fukuda Y, Kawamoto M, Yamamoto A, Ishizaki M, Basset F, Masugi Y (1990) Role of elastic fiber degradation in emphysema-like lessions of pulmonary lymphangiomyomatosis. Hum Pathol 21: 1252–1261
Gomez MR (1992) The tuberous sclerosis complex a prototype of hamartiosis and hamartomatosis. J Dermatol 19: 892–896
Hirano A, Tuazon R, Zimmerman HM (1968) Neurofibrillary changes, granulovacuolar bodies and argentophilic globules observed in tuberous sclerosis. Acta neuropathol (Berl) 11: 257–261
Hsu SM, Raine L, Fanger H (1981) Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques. A comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 29: 577–580
Huttenlocher PR, Wollmann RL (1991) Cellular neuropathology of tuberous sclerosis. Ann NY Acad Sci 615: 140–148
Iwaki T, Tateishi J (1991) Immunohistochemical demonstration of B-crystallin in hamartomas of tuberous sclerosis. Am J Pathol 139: 1303–1308
Iwaki T, Iwaki A, Miyazono M, Goldman JE (1991) Preferential expression of αB-crystallin in astrocytic elements of neuroectodermal tumors. Cancer 68: 2230–2240
Iwasaki Y, Yoshikawa H, Sasaki M, Sugai K, Suzuki H, Hirayama Y, Sakuragawa N, Arima M, Takashima S, Aoki N (1990) Clinical and immunohistochemical studies of subependymal giant cell astrocytomas associated with tuberous sclerosis. Brain Dev 12: 478–481
Janssen LAJ, Povey S, Attwood J, Sandkuyl LA, Lindhout D, Flodman P, Smith M, Sampson JR, Haines JL, Merkens EC, Fleury P, Short P, Amos J, Halley DJJ (1991) A comparative study on genetic heterogeneity in tuberous sclerosis: evidence for one gene on 9q34 and a second on 11q22–23. Ann NY Acad Sci 615: 306–315
Jay V, Edwards V, Rutka JT (1993) Crystalline inclusion in a subependymal giant cell tumor in a patient with tuberous sclerosis. Ultrastruct Pathol 17: 503–513
Johnson WG, Yoshidome H, Stenroos ES, Davidson MM (1991) Origin of the neuron-like cells in tuberous sclerosis tissues. Ann NY Acad Sci 615: 211–219
Kwiatkowski DJ, Short MP (1994) Tuberous sclerosis. Arch Dermatol 130: 348–354
Lee MK, Tuttle JB, Rebhun LI, Cleveland DW, Frankfurter A (1990) The expression and posttranslational modification of a neuron-specific β-tubulin isotype during chick embryogenesis. Cell Motil Cytoskeleton 17: 118–132
Lyons JC, Scheithauer BW, Ginsburg WW (1982) Gaucher's disease and glioblastoma multiforme in two siblings. A clinicopathologic study. J Neuropathol Exp Neurol 41: 45–53
Machado-Salas JP (1984) Abnormal dendritic patterns and aberrant spine development in Bourneville's disease: a Golgi survey. Clin Neuropathol 3: 52–58
Mukai M, Torikara C, Iri H, Tamai S, Sugiura H, Tanaka Y, Sakamoto M, Hirohashi S (1992) Crystalloids in angiomyolipoma. I. A previously unnoticed phenomenon of renal angiomyolipoma occurring at a high frequency. Am J Surg Pathol 16: 1–10
Nakamura S, Tsubokawa T (1987) Ultrastructure of subependymal giant-cell astrocytoma associated with tuberous sclerosis. J Clin Electron Microsc 20: 5–6
Nakamura Y, Becker LE (1983) Subependymal giant-cell tumor: astrocytic or neuronal? Acta Neuropathol (Berl) 60: 271–277
Nardelli E, De Benedictis G, La Stilla G, Nicolardi G (1986) Tuberous sclerosis: a neuropathological and immunohistochemical (PAP) study. Clin Neuropathol 5: 261–266
Onodera K, Takahashi T, Watanabe R, Ishibashi Y, Sasaki M, Kimura G (1990) Distribution of glial fibrillary acidic protein (GFAP) in the intermediate filaments of the cultured cells from a patient with tuberous sclerosis. J Dermatol 17: 395–402
Probst A, Ohnacker APH (1977) Sclerose tubereuse de bourneville chez un premature. Ultrastructure des cellules atypiques: presence de microvillosites. Acta Neuropathol (Berl) 40: 157–161
Reagan TJ (1988) Neuropathology. In: Gomez MR (ed) Tuberous selerosis, 2nd edn. Raven Press, New York, pp 63–74
Roach ES (1990) International tuberous sclerosis conference. J Child Neurol 5: 269–272
Scheithauer BW (1992) The neuropathology of tuberous sclerosis. J Dermatol 19: 897–903
Shepherd CW, Scheithauer BW, Gomez MR, Altermatt HJ, Katzmann JA (1991) Subependymal giant cell astrocytoma: a clinical, pathologic, and flow cytometric study. Neurosurgery 28: 864–868
Sima AAF, Robertson DM (1979) Subependymal giant-cell astrocytoma. Case report with ultrastructural study. J Neurosurg 50: 240–245
Stefansson K (1991) Tuberous sclerosis. Mayo Clin Proc 66: 868–872
Stefansson K, Wollmann R (1980) Distribution of glial fibrillary acidic protein in central nervous system lesions of tuberous sclerosis. Acta Neuropathol (Berl) 52: 135–140
Stefansson K, Wollmann R (1981) Distribution of the neuronal specific protein, 14-3-2, in central nervous system lesions of tuberous sclerosis. Acta Neuropathol (Berl) 53: 113–117
Stefansson K, Wollmann RL, Huttenlocher PR (1988) Lineages of cells in the central nervous system. In: Gomez MR (ed) Tuberous sclerosis, 2nd edn. Raven Press, New York, pp 75–87
Trombley IK, Mirra SS (1981) Ultrastructure of tuberous sclerosis: cortical tuber and subependymal tumor. Ann Neurol 9: 174–181
VandenBerg SR, May EE, Rubinstein LJ, Herman MM, Perentes E, Vinores SA, Collins VP, Park TS (1987) Desmoplastic supratentorial neuroepithelial tumors of infancy with divergent differentiation potential (“desmoplastic infantile ganglioglioma”). Report on 11 cases of a distinctive embryonal tumor with favorable prognosis. J Neurosurg 66: 58–71
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hirose, T., Scheithauer, B.W., Lopes, M.B.S. et al. Tuber and subependymal giant cell astrocytoma associated with tuberous sclerosis: an immunohistochemical, ultrastructural, and immunoelectron microscopic study. Acta Neuropathol 90, 387–399 (1995). https://doi.org/10.1007/BF00315012
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00315012