Malignant rhabdoid tumor of the central nervous system

Perspectives in Pathology Malignant Rhabdoid Tumor of the Central Nervous System PAULJ. BIGGS, MD,* PAULD. GAREN, MD,t JAMESM. POWERS,MD} AND A. JULIAN GARVIN, MD, PHDt Originally described and most frequently reported in association with the kidney, the malignant rhabdoid tumor (MRT) is a highly aggressive neoplasm with distinctive morphologic features. Extrarenal sites reported for this n e o p l a s m include the liver, thymus, and various soft tissue sites. Young infants are affected with rare exceptions. We report the case of a 3-month-old boy who presented with hyperirritability and increasing head size over several weeks. The patient died following a two-week hospital stay marked by development of seizures, paralysis, and apnea. At autopsy, significant findings were limited to the central nervous system. The subarachnoid space contained neoplasm throughout, with multiple areas of parenchymal invasion. A predominating intraparenchymal mass was present in the inferior cerebellum contiguous with the neoplasm in the subarachnoid space and probably represented the site of origin. Microscopically, the neoplasm was composed of a highly cellular monomorphic population of polygonal cells with roughly ovoid vesicular nuclei and conspicuous nucleoli. Variable amounts of cytoplasm were present, and many ceils contained a single, welldemarcated eosinophilic hyaline globule adjacent to the nucleus. Ultrastructurally, the cytoplasmic globules were composed of whorled aggregates of intermediate filaments. Immunoperoxidase studies confirmed that the filaments were composed, at least in part, of vimentin. The morphologic and immunohistochemical features are diagnostic of MRT, an entity of unknown histogenesis that has not been reported previously as a primary neoplasm of the CNS. HUM PATHOL 18:332--337, 1987.

cytoplasmic cross striations and ultrastrnctural features associated with skeletal muscle differentiation, such as h e x a g o n a l arrays o f a l t e r n a t i n g thick a n d t|fin filaments, Z bands, and basement membranes. 1-4 I n addition, i m m u n o h i s t o c h e m i c a l studies f o r the p r e s e n c e o f cytoplasmic myoglobin were negative. 5 A l t h o u g h g i R T s were originally and most freq u e n t l y r e p o r t e d as arising in the kidney, 1-3,6,7 similar neoplasms have b e e n seen in the thymus, s liver, 4 and various soft tissue sites. 4,9,1~ An interesting association between M R T o f the kidney and a variety o f e m b r y o n a l p r i m a r y t u m o r s o f the central n e r v o u s system has b e e n r e p o r t e d . H We are u n a w a r e o f any unequivocal reports o f M R T occurring as a p r i m a r y neoplasm o f the CNS.

REPORT OF A CASE

T h e t e r m malignant r h a b d o i d t u m o r (MRT) was i n t r o d u c e d in 1981 to specify a highly aggressive n e o p l a s m having distinctive m o r p h o l o g i c features by light microscopy. ~ T h e s e features include the presence o f polygonal cells with r o u g h l y ovoid vesicular nuclei; p r o m i n e n t , usually single and fairly central nucleoli; variable a m o u n t s o f eosinophilic cytoplasm, a n d hyaline globular cytoplasmic inclusions in scatt e r e d cells. T h e neoplastic cells usually have a diffuse g r o w t h p a t t e r n , a l t h o u g h a focal t r a b e c u l a r o r alveolar p a t t e r n may be seen. T h e growth pattern and the p r e s e n c e o f variable a m o t m t s o f eosinophilic cytoplasm were believed to be reminiscent o f r h a b d o myoblastic differentiation; however, the cells lacked Received from the Department of Pathology, *Baptist Medical Centers, Birmingham, Alabama; and the tMedical University of South Carolina, Charleston, South Carolina. Accepted for publication September 15, 1986. Presented at the 62nd Annual Meeting of the American Association of Neuropathologists, J u n e 19, 1986, Minneapolis, Minnesota. Address correspondence and reprint requests to Dr. Biggs: Department of Pathology, Baptist Medical Center-Princeton, 701 Princeton Avenue, S.W., Birmingham, AL 35211. 0046-8177/87 $0.00 + .25

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A 3-month-old boy was healthy until 6 weeks o f age, when increasing irritability was noted. This soon was followed by decreased feeding and constipation. For one to two weeks prior to admission, additional problems became evident including apathy, hypotonia, urinary retention, and increasing head size. Physical examination on admission revealed lack of spontaneous movements in the extremities with loss of sensation in the lower extremities. Right facial weakness was present. The abdomen and urinary bladder were distended. A computed tomography scan of the head revealed moderate hydrocephalus. Cerebrospinal fluid (CSF) examination revealed no abnormalities. -Two days after admission, motor seizures began, involving the upper extremities, head, and neck. These increased in frequency and duration during the remainder of the hospital course. The onset of apneic spells necessitated mechanical respiratory assistance. A repeat CSF examination revealed neoplastic cells of uncertain type. Respiratory assistance was discontinued approximately two weeks after admission, and tile patient died. A complete autopsy study was performed. Abnormal findings were limited to the CNS. The brain was formed normally and weighed 620 grams. Tan-white tissue of variable consistency was present throughout the subarachnoid space of the brain and spinal cord, with concentration of this tissue within sulci and over the base of the brain (fig. I). This tissue surrounded the cranial and spinal nerves along their extents within the subarachnoid space. Variable CNS parenchymal invasion was present up to a maximum depth of 0.8 cm. Additionally, a predominating intraparenchymal mass was present in the inferior cerebellum contiguous with the tissue in the subarachnoid space (fig. 2).

MALIGNANT RHABDOID TUMOR OF THE CNS [Biggs et al.)

FIGURE 1. Gross view of brain showing neoplasm, probably originating in inferior cerebullum (arrow). It infiltrates the subarachnoid space and extends into the basilar surface of the brainstem and frontal lobes. FIGURE 2. A closer view of the neoplasm shows the extensive involvement of the cerebellum with extension into subarachnoid space and brainstem [arrow).

b u f f e r e d formaldehyde solution and were stained with h e m a t o x y l i n - e o s i n . Selected sections were stained additionally with periodic acid-Schiff (PAS) with a n d w i t h o u t p r e t r e a t m e n t with d i a s t a s e , Wilder's method for reticulin, and phosphotungstic acid-hematoxylin (PTAH) Additional sections from representative tissue blocks were stained using an i m m u n o p e r o x i d a s e avidin-biotin-peroxidase complex (ABC) method, 12

There were no gross abnormalities of tile dura mater or pituitary gland.

MATERIALSAND METHODS

Multiple sections were taken from all levels of the CNS for light microscopy. These were embedded in paraffin after being fixed in 4 per cent neutral 333

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with antibodies to vimentin (monoclonal antibody MA 074, BioGenex Laboratories, Dublin, California); glial fibrillary acidic protein (polyclonal antibody A561, Accurate Chemical Corporation, Westbury, N e w York); neurofilament protein (monoclonal antibody MA73-5C, BioGenex Laboratories); cytokeratin (monoclonal antibody M A 71-5C, BioGenex Laboratories); keratin (polyclonal antibody A575, Accurate Chemical Corporation); desmin (monoclonal antibody MA72-5C, BioGenex Laboratories); epithelial m e m b r a n e antigen (monoclonal antibody M613, Dako Corporation, Santa Barbara, California); S-100 protein (polyclonal antibody Z311, Accurate Chemical Corporation); myoglobin (polyclonal antibody A324, Accurate Chemical Corporation); and smooth muscle myosin (polyclonal antibody obtained from National Institutes of Health, Bethesda, Maryland). Portions of the formaldehyde-fixed tissue from the cerebellar mass were water rinsed, post-fixed in 2 per cent osmium tetroxide, dehydrated, and emb e d d e d in epoxy resin. U l t r a t h i n sections were stained with uranyl acetate-lead citrate and examined with an electron microscope. Additional ultrathin sections were stained with silver proteinate. 13

specializations except for occasional intercellular junctions of the zonula adherens type. Nuclei were ovoid with occasional indentations and contained prominent nucleoli. Within the cytoplasm of many cells were circumscribed, but not membrane-bound, filamentous conceiatric whorls (fig. 6). These whorls were composed of 8- to 10-nm filaments and corresponded to the eosinophilic cytoplasmic inclusions n o t e d on light microscopy. Mitochondria, lipid droplets, and ribosomes, which were also present in surrounding cytoplasm, often were incorporated into the whorls. Within occasional cells, the filaments composing the whorl displayed focal dense thickenings (fig. 7). An occasional tubulovesicular profile was noted adjacent to the whorls. Scattered clusters of 10- to 12-rim filaments also were present in the cytoplasm but were separate from the whorls. No evidence of hexagonal arrays o f thick and thin filaments, Z-band formation, or basement membranes was present. Silver proteinate stains showed no evidence of carbohydrate moieties within the filamentous whorls.

RESULTS

T h e malignant rhabdoid tumor is characterized by light microscopic features that include all o f the following: a diffnse growth pattern of predominantly polygonal cells (may be focally alveolar or trabecular), vesicular nuclei with prominent nucleoli, and scattered cells that contain a cytoplasmic hyaline globular inclusion adjacent to the nucleus. 1-11 This neoplasm can be characterized further by the presence o f vimentin within the cytoplasmic hyaline inclusions in all cases in which appropriate immunohistochemical staining has been done. 6,7,1~A n u m b e r of immunohistochemical studies have been performed with negative results and have included staining for myoglobin, 3,5,l~ desmin, l~ actin, 6 neurofilament prot e i n , 7.1~ k e r a t i n , 3,7 S-IO0 p r o t e i n , l~ a - l - a n t i trypsin, 3A~ a-l-antichymotrypsin, 3'1~ and lysozyme.3 One group of investigators 4 reported variably positive results for lysozyme in three of their four cases of MRTs; however, they could not rule out infiltration of these neoplasms by benign histocytes as an explanation for this staining pattern. Results of immunohistochemical staining for cytokeratin have been reported as negative in one study 6 and as positi~;e in others. 7,1~ In the studies showing positive staining, a minority of the neoplastic cells stained, and the distribution of staining included the entire cytoplasm as opposed to distinctive staining of the cytoplasmic hyaline inclusions. Additionally, immunohistochemical staining for epithelial membrane antigen has been reported by Tsuneyostfi et al. 1~in their series of tumors occurring in soft tissue sites. T h e present neoplasm, although occurring in a previously unreported anatomic site, fulfills the morphologic criteria for MRT. Additionally, the immunohistochemical staining profile--including staining for vimentin and no staining for neurofilament pro-

Light microscopic examination of hematoxylineosin-stained sections of the brain and spinal cord revealed neoplastic tissue within the subaraclmoid space and invading adjacent parenchyma (fig. 3). A diffuse growth pattern was present throughout the neoplasm. The cells were generally polygonal with occasional foci of tadpole- and spindle-shaped cells. T h e eosinophilic cytoplasm was variable in amount, and cytoplasmic borders were easily visualized. The nuclei were rouglfiy ovoid and vesicular and contained p r o m i n e n t , single, fairly central nucleoli. Many cells contained a single well-demarcated hyaline globular inclusion within the cytoplasm adjacent to the nucleus (fig. 4). Mitotic figures and areas of necrosis were n u m e r o u s . Some PAS-positive, diastase-resistant material was present within the globular cytoplasmic inclusions. The reticulin stains demonstrated the presence o f reticulin s u r r o u n d i n g groups of neoplastic cells. The PTAH stains failed to demonstrate the presence of glial fibrils within the neoplasm, but reactive astrocytosis was p r e s e n t a r o u n d foci of parenchymal invasion. Sections o f dura mater and pituitary gland showed no abnormalities. Immunoperoxidase staining of sections of the neoplasm revealed cytoplasmic staining for vimentin corresponding to the globular hyaline inclusions (fig. 5). Stains for glial fibrillary acidic protein, S100, neurofilament protein, epithelial membrane antigen, cytokeratin, keratin, desmin, myoglobin, and smooth muscle myosin were negative. Electron microscopic examination revealed that the majority of tumor cells were large, with relatively abundant cytoplasm. These cells were free of surface 334

DISCUSSION

MALIGNANTRHABDOIDTUMOR OF THE CNS (Biggs et aL)

FIGURE 3. FIGURE 4, eosin stain, FIGURE 5.

Thisphotomicrograph illustrates infiltration of brain parenchyma by large polygonal cells. (Hematoxylin-eosTn stain, x 80.) Higher magnification of neoplastic cells with prominent nucleoli and cytoplasmic gTobular inclusions (arrows). (Hematoxylinx 400.) Inset, globular inclusion. (I-lematoxylin-eosin stain, x 800.) Immunoperoxidase stain for vimentin showing cytoplasmic staining corresponding to cytoplasmic globules (arrows). (x 400.)

tein, desmin, keratin, and myoglobin--is consistent with previous reports o f M R T as outlined earlier. T h e lack of glial fibrillary acidic and S-100 protein staining also s u p p o r t s a diagnosis o f M R T and renders unlikely a glial origin for our patient's neoplasm. We were unable to obtain staining for cytoo keratin or epithelial membrane antigen in our case. As n o t e d e a r l i e r c y t o k e r a t i n staining has b e e n present variably in reported cases. This may be the result of variable expression of cytokeratin in these neoplasms or of differences in the antisera to cytokeratin in these studies. The uhrastructural features found in our case are consistent with previous reports. 1-4 Well-demar335

cated, nonmembrane-bound, whorled aggregates of cytoplasmic intermediate filaments were identified in all cases, including our own. These aggregates correspond to the hyaline globular inclusions seen on light microscopy and are c o m p o s e d primarily or completely of vimentin. Whorled filamentous intracytoplasmic eosinophilic inclusions a r e not specific for MRT and may occur in a variety of epithelial, neuroendocrine, and mesenchymal neoplasms. 14 Other ult r a s t r u c t u r a l f e a t u r e s i n c l u d e d s c a t t e r e d lipid droplets, mitochondria, and ribosomes, as well as rare primitive cell junctions. Scattered cytoplasmic clusters of larger filaments were noted in our case and in one previous r e p o r t J Focal thickening of cyto-

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FIGURE 6. Large neoplastic cells have irregular nuclear outlines and prominent nucleoli. Filamentous inclusions [arrows], frequently with globular shapes, are present in a perinuclear location. The cells contain a normal complement of cytoplasmic organelles and lipid droplets [Li). (x 16,500.) FIGURE 7, A closer view of the cytoplasmic inclusions demonstrates that they are composed of 8- to 10-nm filaments that occasionally display focal densities. Endoplasmic reticulum [er] and other cytoplasmic components may be incorporated into the inclusions. [ x 49,500.]

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type arise in the cerebellum, including rhabdomyosarcoma, m e d u l l o m y o b l a s t o m a , and neuroblast o m a ) 7 T h e paucity of focal cerebellar signs in our patient does not exclude a cerebellar primary site. is Alternately, origin of the neoplasm within the leptomeninges cannot be excluded. The histogenesis of MRT remains a source of speculation. A myogenous origin has been ruled out on the basis of the ultrastructural and immunohistochemical features described earlier. A histiocytic origin has been suggested on the basis of focal positive immunohistochemical staining for lysozyme in one report 4 and the presence of lysosome-like structures within tumor cells in another, s As discussed earlier, infiltrating histiocytes may account for staining for lysozyme. A mesenchymaI origin for this neoplasm is attractive based on the variety of primary sites reported for MRTs as well as on the ultrastructural and immunohistochemical findings o f aggregated vimentin filaments and r a r e primitive cell junctions. Vimentin, however, is found in many types of cells, especially cultured cells, and may represent a marker

plasmic filament aggregates, as seen in our case, is a feature not previously emphasized in reports o f M R T but is a fairly nonspecific finding, as it is seen in a variety of cell types ]5 including smooth muscle cells, myoepithelial cells, myofibroblasts, and endothelial cells) 6 Clinically, MRT is a highly aggressive neoplasm with frequent and early hematogenous metastases. T h e r e is no sex predominance, and, with the exception of three of five cases reported arising in various soft tissue sites by Tsuneyoshi et al., l~ the neoplasms presented in young children, many under 1 year of age. 1-11 Prolonged survival is rare but is reported in some cases of MRT o f the kidney following surgery and subsequent combination c|lemotherapy. 1 O u r patient presented at an early age, having manifested a variety of nonspecific findings beginning at 6 weeks of age. T h e patient was diagnosed as having a CNS neoplasm at 3 months of age and died 2 weeks later. T h e determination of a specific site of origin in our case is not possible. T h e predominating intraparenchymal mass of the inferior cerebellum is the most likely primary site. Other neoplasms of nonglial 336

MALIGNANTRHABDOIDTUMOR OF THE CNS (Biggs et al.)

of immaturity, rather than of mesenchymal derivation. t5 T h e reports o f coexpression of cytokeratin and vimentin in MRT are intriguing, as this finding suggests early epithelial differentiation. Other reports of MRT involving the CNS have appeared recently in the literature. Beckwith 19 makes brief mention o f having encountered tumors morphologically similar to gIRT within the CNS in addition to other sites; however, it is unclear whether he is referring to one or more cases with tumors limited to the CNS or to cases with tumors in the CNS as well as within the kidney. No case histories or photographs are available to clarify this statement, de Chadardvian and Russo 2~ report two cases in which MRTs were found in both the kidney and CNS. Because the CNS neoplasms clinically preceded discovery of the renal neoplasms in these patients, an implication of independent origins of the neoplasms in the two sites was made. We believe that it is just as likely that the CNS lesions represent metastases from the renal neoplasms, as MRT has been shown to be a highly aggressive t u m o r producing relatively early h e m a t o g e n o u s metastases. It certainly is not uncommon for a metastasis to tlm brain from a malignant neoplasm to be the presenting clinical feature. Finally, Briner et al. ~l report an infant with MRT of the CNS diagnosed by biopsy who died two and one half months later. This probably represents a case of p r i m a r y gIRT o f the CNS; however, no autopsy findings are r e p o r t e d , thus a n o t h e r primary site cannot be excluded. Our case included a complete autopsy study that revealed neoplasm restricted to the CNS. This case, therefore, represents the first well-documented report of gIRT unequivocally originating in the CNS.

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4. Gonzalez-Crussi F, Goldschmidt RA, Hsueh W, et al: Infantile sarcoma with intracytoplasmic filamentous inclusions: distinctive t u m o r o f possible histiocytic origin. Cancer 49:2365, 1981 5. RutledgeJ, BeckwithJB, Benjamin D, et al: Absence o f i m m u noperoxidase staining for myoglobin in the malignant rhabdoid t u m o r of the kidney. Pediatr Pathol 1:93, 1983 6. Rousseau-Merck M-F, Nogues C, Nezelof C, et al: Infantile renal tumors associated with hypercalcemia: characterization o f intermediate-filament clusters. Arclt Pathol Lab Med 107:31 I, 1983 7. Vogel AM, Gown AM, Caughlan J, et al: Rhabdoid tumors of the kidney contain mesenchymal-specific and epithelial-specific i n t e r m e d i a t e filament proteins. Lab Invest 50:232, 1984 8. Lemos LB, Hamoudi AB: Malignant thymic t u m o r in an inf a n t ( m a l i g n a n t lfistiocytoma). A r c h P a t h o l Lab Med 102:84, 1978 9. Lynch HT, Sknrin SB, Dahms BB, et al: Paravertebral malignant rhabdoid t u m o r in infancy: in vitro studies of a familial tumor. Cancer 52:290, 1983 I0. Tsuneyoshi M, Daimaru T, Hashimoto H, et al: Malignant soft tissue neoplasms with the histologic features of renal rhabdoid tumors: an uhrastructural and immunohistochemical stud),. HUM PATHOL 16:1235, 1985 11. Bonnin JM, Rubinstein LJ, Palmer NF, et al: T h e association of embryonal tumors originating in the kidney and in the brain: a report o f seven cases. Cancer 54:2137, 1984 12. Hsu SM, Raine L, Fanger H: T h e use o f antiavidin antibody and avidin-biotin-peroxidase complex in immunoperoxidase technics. Am J Clin Pathol 75:816, 1981 13. Thiery JP: Mise en dvidence des polysaccharides sur coupes fines en microscopic dlectronique. J Microscopic 6:987, 1967 14. W a r n e r TFCS, Seo IS: Aggregates o f cytofilaments as the cause of the appearance of hyaline t u m o r cells. Uhrastruct Pathol 1:395, 1980 15. Ghadially FN: Diagnostic Electron Microscopy of Tumonrs, ed 2. London, Butterworths, 1985, pp 344-361 16. NewsteadJ, Munkacsi I: Electron microscopic observations on the juxtamedullary efferent arterioles and arteriole rectae in kidneys of rats. Z Zellforsch 97:465, 1969 17. Biggs PJ, Powers JM: Neuroblastic medulloblastoma with a b u n d a n t cytoplasmic actin filaments. Arch Pathol Lab Med 108:326, 1984 18. Crosley CJ, Mishkin M, Rorke LB: Congenital sarcoma of the brain. A m J Dis Child 128:523, 1974 19. Beckwith JB: Wihns' t u m o r and other renal tumors of childhood: a selective review from the National Wilms' T u m o r Stud)' Pathology Center. HUM PATHOL 14:481, 1983 20. de Chadarfvian J-P, Russo P: Central nervous system-renal neoplasia: a puzzling emerging association in young child r e n (abstract). Lab Invest 50:2P, 1984 21. Briner J, Bannwart F, Kleihues P: Malignant small cell tumor of the brain with intermediate filaments--a case of a primary cerebral r h a b d o i d t u m o r (abstract). Pediatr Pathol 3:117, 1985