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Neuro Oncol 2006 8(1):79-82; DOI:10.1215/S1522851705000347
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Duke University Press

Neuropathology

Atypical teratoid/rhabdoid tumor evolving from an optic pathway ganglioglioma: Case study1

Jeffrey C. Allen, Alexander R. Judkins, Marc K. Rosenblum and Jaclyn A. Biegel2

Department of Neurology, New York University School of Medicine, New York, NY 10016 (J.C.A.); Departments of Pathology (A.R.J., J.A.B.) and Pediatrics (J.A.B.), The Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10021(M.K.R.); USA

2 Address correspondence to Jaclyn Biegel, Room 1002, Abramson Research Center, The Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA (biegel{at}mail.med.upenn.edu).


   Abstract
Top
 Abstract
Introduction
 Case Material and Results
 Discussion
 References
 
We report an atypical teratoid/rhabdoid tumor arising in a ganglioglioma from an 11-year-old male who had been treated over a nine-year period. A combined histologic, immunohistochemical, and molecular genetic analysis confirmed this diagnosis. Molecular genetic studies demonstrated a mutation in exon 9 of the INI1 gene in the tumor, which was not present in the patient's blood. This report is the first to describe progression of a ganglioglioma to atypical teratoid/rhabdoid tumor.

Key Words: atypical teratoid tumor • ganglioglioma • hSNF5/INI1 • rhabdoid tumor


   Introduction
Top
 Abstract
 Introduction
Case Material and Results
 Discussion
 References
 
A typical teratoid/rhabdoid tumor (AT/RT) is a rare primary brain tumor that most often arises in infants and young children (Rorke et al., 1996). It occurs both in infratentorial locations, especially the cerebellopontine angle, and in supratentorial sites. Before it was recognized as a distinct clinical, pathologic, and genetic entity, AT/RT was most often considered a highly aggressive form of primitive neuroectodermal tumor (PNET), which often failed treatment with different combinations of chemotherapy and radiotherapy. The median survival for children with AT/RT is approximately 17 months (Hilden et al., 2004). Molecular genetic studies identified the hSNF5/INI1 gene as a unique gene locus in chromosome 22q11.2 responsible for the development of pediatric rhabdoid tumors (Biegel et al., 1999; Versteege et al., 1998). Central nervous system, renal, and extrarenal rhabdoid tumors may all arise as the result of homozygous inactivation of the INI1 gene. The most frequent alterations involve deletion of the wild-type allele accompanied by a mutation in the remaining homologue, although homozygous deletions of the INI1 gene and compound heterozygous mutations are also observed (Biegel et al., 1999, 2002). In some instances, a germline mutation in the INI1 gene predisposes infants to the development of rhabdoid tumors, and a limited number of familial cases have been reported (Biegel et al., 1999; Sévenet et al., 1999; Taylor et al., 2000).

We have identified a unique AT/RT arising in a histologically confirmed ganglioglioma. We report the pathology findings and molecular analysis of this tumor.


   Case Material and Results
Top
 Abstract
 Introduction
 Case Material and Results
Discussion
 References
 
Clinical Presentation
This 11-year-old boy developed a dissociative nystagmus at 11/2 years of age. His visual fields appeared normal, his visual acuity was grossly intact, and he had no apparent weakness. An MRI at that time revealed an extensive optic pathway tumor best appreciated on the T2-weighted study, involving the prechiasmatic portion of the right optic nerve, optic chiasm, both optic tracts, right temporal lobe, right midbrain, hypothalamus, and thalamus. Heterogeneous enhancement and intratumoral cysts were identified. He did not have neurofibromatosis, and family history was notable only for a paternal uncle who died of rhabdomyosarcoma at age 13. Stereotactic biopsy of the thalamic component yielded a minute specimen diagnosed as a pilocytic astrocytoma.

The child was initially managed conservatively and monitored with serial MRIs. By age 21/2, he developed a mild left hemiparesis and changes on MRI. He received 18 months of carboplatin/vincristine chemotherapy with a partial response. Over the ensuing eight years, he received multiple chemotherapy regimens that followed a similar pattern: clinical and radiographic response or stability followed by progression after the chemotherapy was stopped. The various chemotherapy regimens included thioguanine, procarbazine, CCNU (lomustine, or N-(2-chloroethyl)-N'-cyclohexyl N-nitrosourea), and vincristine; oral etoposide; and temozolomide.

At age 10, he developed a dramatic increase in his left hemiparesis over a two-month period that was associated with the development of large, enhancing, intratumoral cysts within the optic radiation fields in the right diencephalic region. He underwent radiation therapy to the tumor involving the optic chiasm, optic tracts, and right diencephalon to a total dose of 54 Gy. During treatment, he developed clinical and radiographic progression. He underwent a surgical debulking of the large intratumoral cysts and adjacent solid tumor three months following the completion of radiotherapy. The child succumbed to progressive disease within eight months of completing radiotherapy. Spinal MRIs remained free of disease. An autopsy was not performed.

Pathology
This tumor comprised a biphasic population of neoplastic cells (Fig. 1A-C). In some areas, the principal histologic pattern was that of piloid astrocytes admixed with atypical ganglion cells. Scattered microcalcifications were identified in these areas. These regions showed no necrosis, vascular proliferation, or increased mitotic activity. In other areas of this tumor, a second population of neoplastic cells was seen. These had a distinct histologic appearance and were predominantly made up of small cells with rhabdoid features, for example, distinct cell borders, prominent eosinophilic cytoplasm, and nuclei with vesicular chromatin and prominent nucleoli.



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  		Fig. 1. Recurrent tumor. Regions of tumor with low-grade features had the typical appearance of ganglioglioma with distinct areas showing the glial component with abundant fibrillary neoplastic neuropil (A) as well as areas with numerous atypical neoplastic ganglion cells (arrowhead, B). In other areas, the tumor showed high-grade features and was made up of small cells with distinct cell borders, abundant eosinophilic cytoplasm, and large nuclei with vesicular chromatin and prominent nucleoli (C). Immunohistochemical staining for INI1 demonstrated a loss of nuclear expression throughout areas with high-grade rhabdoid features (D, left side) but retained expression in areas with ganglioglioma features (right side).

 
Immunohistochemical staining of the high-grade tumor demonstrated expression of glial fibrillary acidic protein, smooth-muscle actin, and, focally, cytokeratins (with antibody AE 1.3), epithelial membrane antigen, and synaptophysin. The MIB-1 labeling index was 20% in the high-grade component. Immunohistochemical staining of the ganglioglioma components demonstrated strong chromogranin expression in neoplastic ganglion cells, as well as surface perikaryl labeling with synaptophysin. These cells did not express desmin or cytokeratin. Immunohistochemistry for the INI1 protein was performed as described previously (Judkins et al., 2004) and demonstrated a loss of nuclear expression in the high-grade tumor component, but retained expression in the ganglioglioma component, as well as nonneoplastic vascular and mesenchymal tissue (Fig. 1D).

Molecular Genetics
DNA was isolated from formalin-fixed and paraffin-embedded tissue from the second surgery, as well as a peripheral blood sample from the child, and screened for a deletion or mutation in the nine coding exons of the INI1 gene in chromosome 22q11.2 as previously described (Biegel et al., 1999). Loss of heterozygosity for microsatellite markers in chromosome band 22q11.2 was observed. A mutation in exon 9 of the INI1 gene was determined by sequence analysis of polymerase chain reaction products for this exon, as shown in Fig. 2. A deletion of a single guanine residue in base 1143 or 1144 resulted in a frameshift. The mutation results in elimination of the normal stop codon, with a novel stop codon predicted at codon 482. This frameshift mutation is a common alteration in CNS AT/RT (Biegel et al., 2002). Although sequence analysis suggests that the protein would be 482 instead of 385 amino acids in length, expression is not observed by immunohistochemistry (Fig. 1D). The RNA transcript or protein is thus apparently unstable. The normal sequence for exon 9 was also observed in the tumor DNA consistent with contamination with DNA from normal or ganglioglioma cells. The mutation was not identified in the constitutional DNA and thus appears to be somatic in origin.



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  		Fig. 2. A single base pair deletion within exon 9 of the INI1 gene was detected in the tumor tissue, but not in peripheral blood DNA. The deletion causes a frameshift, which is likely to result in an unstable message or protein.

 

   Discussion
Top
 Abstract
 Introduction
 Case Material and Results
 Discussion
References
 
We present an unusual occurrence of an AT/RT arising in the setting of a ganglioglioma. Initial biopsy of the thalamic region of this widespread tumor led to the diagnosis of pilocytic astrocytoma, because neuronal elements were not represented in this minute specimen. The patient's case was followed by using serial MRIs, and a second surgery was not performed until nine years later. At that time, the tumor comprised two distinct components, including a low-grade ganglioglioma and a highly malignant AT/RT. Although rhabdoid tumors may present in a variety of anatomic locations, we are not aware of any reports describing AT/RT arising in the optic pathway. Rhabdoid tumors in all anatomic sites demonstrate loss of nuclear staining of INI1 in tumor cells, with retention of staining in normal infiltrating lymphocytes and blood vessels. Histologically complex CNS AT/RTs show loss of INI1 in the PNET and rhabdoid components, as well as areas of epithelial and mesenchymal tissue. Given the clinically aggressive nature of most AT/RTs, it is unlikely that this component was present at the time of the initial diagnosis. The long period of stable disease, followed by a period of aggressive tumor growth and ultimate demise of the patient, suggests that the change in clinical course may have been due to acquisition of the INI1 mutation in the tumor, with corresponding histologic evolution to a rhabdoid phenotype. Molecular and immunohistochemical studies demonstrated inactivation and subsequent loss of protein expression of INI1 associated with the rhabdoid tumor component in this tumor. The regions of ganglioglioma demonstrated retained nuclear expression of this protein.

The cell of origin for AT/RT or other rhabdoid tumors of the kidney or extrarenal tissues is not known. However, the complex histologic appearance of these tumors, especially in the CNS, in which rhabdoid cells may be juxtaposed to areas of primitive neuroectodermal, epithelial, or mesenchymal tissue, suggests that they arise from a primitive cell with the capacity to diverge along multiple differentiation pathways. The present case suggests several possibilities, which are not mutually exclusive. The first is that the optic pathway ganglioglioma and rhabdoid tumor were both derived from a common stem cell capable of giving rise to each of these tumors. The acquisition of genetic alterations, possibly due to the therapy, may have resulted in a change in the histologic appearance and biologic aggressiveness of the tumor cells over time. The INI1 mutation, specifically, is likely to account for the rapid clinical progression observed in the latter stages of this child's disease. In contrast to the tightly associated findings of INI1 deletions and mutations and rhabdoid tumor, there is little known regarding the molecular etiology of ganglioglioma. Tissue from the first biopsy specimen was not available for molecular analysis.

Litman et al. (1993) reported a patient with synchronous appearance of rhabdoid tumors in the ileum and lung 20 years after radiation treatment for Wilms' tumor. The locations within the radiation fields and the latency were certainly consistent with the development of a radiation therapy-induced tumor. The rapid progression observed was characteristic of rhabdoid tumor. Neuropathologic evaluation of diagnostic specimens compared with second surgery and autopsy findings has demonstrated that a change in histologic appearance may be seen following treatment. Rhabdoid tumors may arise as secondary tumors, but may be underappreciated, especially because of the low number of autopsies performed in patients with malignant brain tumors. In theory, rhabdoid tumors could arise from differentiated cells, for example, in the piloid astrocytes or neurons observed in the present case. Acquisition of an INI1 mutation would similarly lead to a growth advantage and change in histologic appearance and clinical progression. Finally, the rhabdoid tumor may have arisen as a distinct primary tumor within the field of ganglioglioma, and because of its aggressive clinical nature, resulted in a malignancy that was substantially more refractive to therapy.

We are aware of one case report of a rhabdoid meningioma arising in the setting of a preexisting ganglioglioma (Bannykh et al., 2002) in a 52-year-old male. In contrast to our case, however, deletion of the distal region of chromosome 22 containing the NF2 gene (22q12), and not BCR, which is proximal to INI1 in chromosome 22q11.2, was observed by interphase fluorescence in situ hybridization. This finding, in conjunction with the immunophenotypic profile and histologic appearance, suggested that the secondary tumor was a rhabdoid meningioma, and not an AT/RT as seen in the present case. We have recently examined a large series of composite rhabdoid tumors and rhabdoid meningiomas in adults by immunohistochemistry with the INI1 antibody, and we have shown that these neoplasms retain INI1 expression and are therefore distinct from the classic AT/RT or malignant rhabdoid tumor that is characterized by inactivation of INI1 (Perry et al., 2005).

In summary, we have presented a case of an AT/RT that arose in the setting of a ganglioglioma. Consideration of AT/RT should be entertained in patients whose tumors exhibit highly malignant features and undergo rapid progression following a long period of stable disease.


   Acknowledgments
 
We gratefully acknowledge the technical assistance of Lu Tan and Joanne Mauger.


   Footnotes
 
1 This work was supported in part by NIH grant CA46274 (J.A.B.). Back

3 Abbreviations used are as follows: AT/RT, atypical teratoid/rhabdoid tumor; CCNU, lomustine, or chloroethyl cyclohexylnitrosourea; PNET, primitive neuroectodermal tumor. Back

Received for publication March 24, 2005. Accepted for publication June 7, 2005.


   References
Top
 Abstract
 Introduction
 Case Material and Results
 Discussion
 References
 

Bannykh, S.I., Perry, A., Powell, H.C., Hill, A., and Hansen, L.A. (2002) Malignant rhabdoid meningioma arising in the setting of preexisting ganglioglioma: A diagnosis supported by fluorescence in situ hybridization. J. Neurosurg. 97, 1450-1455.[Medline]

Biegel, J.A., Zhou, J.-y., Rorke, L.B., Stenstrom, C., Wainwright, L.M., and Fogelgren, B. (1999) Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res. 59, 74-79.[Abstract/Free Full Text]

Biegel, J.A., Tan, L., Zhang, F., Wainwright, L., Russo, P., and Rorke, L.B. (2002) Alterations of the hSNF5/INI1 gene in central nervous system atypical teratoid/rhabdoid, renal and extrarenal rhabdoid tumors. Clin. Cancer Res. 8, 3461-3467.[Abstract/Free Full Text]

Hilden, J.M., Meerbaum, S., Burger, P., Finlay, J., Janss, A., Scheithauer, B.W., Walter, A.W., Rorke, L.B., and Biegel, J.A. (2004) Central nervous system atypical teratoid/rhabdoid tumor: Results of therapy in children enrolled in a registry. J. Clin. Oncol. 22, 2877-2884.[Abstract/Free Full Text]

Judkins, A.R., Mauger, J., Ht, A., Rorke, L.B., and Biegel, J.A. (2004) Immunohistochemical analysis of hSNF5/INI1 in pediatric central nervous system neoplasms. Am. J. Surg. Pathol. 28, 644-650.[Medline]

Litman, D.A., Bhuta, S., and Barsky, S.H. (1993) Synchronous occurrence of malignant rhabdoid tumor two decades after Wilms' tumor irradiation. Am. J. Surg. Pathol. 17, 729-737.[Medline]

Perry, A., Fuller, C.E., Judkins, A.R., Dehner L.P., and Biegel, J.A. (2005) INI1 expression is retained in composite rhabdoid tumors, including rhabdoid meningiomas. Mod. Pathol. 18, 951-958.[CrossRef]

Rorke, L.B., Packer, R.J., and Biegel, J.A. (1996) Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: Definition of an entity. J. Neurosurg. 85, 56-65.[ISI][Medline]

Sévenet, N., Sheridan, E., Amram, D., Schneider, P., Handgretinger, R., and Delattre, O. (1999) Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am. J. Hum. Genet. 65, 1342-1348.[CrossRef][ISI][Medline]

Taylor, M.D., Gokgoz, N., Andrulis, L., Mainprize, T.G., Drake, J.M., and Rutka, J.T. (2000) Familial posterior fossa brain tumors of infancy secondary to germline mutation of the hSNF5 gene. Am. J. Hum. Genet. 66, 1403-1406.[CrossRef][Medline]

Versteege, I., Sévenet, N., Lange, J., Rousseau-Merck, M.-F., Ambros, P., Handgretinger, R., Aurias, A., and Delattre, O. (1998) Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394, 203-206.[CrossRef][Medline]




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