Atypical teratoid/rhabdoid tumors with multilayered rosettes in the pineal region

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare, highly malignant tumor of the central nervous system (CNS) that typically occurs during infancy. These tumors exhibit morphologic heterogeneity and differentiate along multiple lineages, thus posing a diagnostic challenge. Here, we present two cases of AT/RT with a primitive neuroectodermal component and histological pattern resembling an embryonal tumor with multilayered rosettes (ETMR), a rare but distinctive embryonal entity with different therapeutic implications. Patient 1, a 23-month-old girl, presented with a history of gait unsteadiness and headache; cranial computed tomography (CT) identified a mass in the pineal and third ventricular regions. Patient 2, a 26-month-old girl, presented with headache and vomiting; CT revealed a mass in the posterior third ventricle. Both patients were treated via gross total tumor resection. Although histologically, AT/RT cases variably comprise primitive neuroectodermal, mesenchymal, and classic rhabdoid cells, the most striking feature of both cases was the presence of multilayered rosettes with a few Homer Wright rosettes and occasional primitive neuroepithelial tubes in focal primitive component areas. Immunohistochemistry revealed considerable heterogeneity within the tumors. We further present our findings in the context of the relevant literature.     

A fourth ventricle atypical teratoid/rhabdoid tumor in an infant

Atypical teratoid/rhabdoid tumor (AT/RT), a recently established central nervous system tumor entity, occurs in children and is more malignant than medulloblastoma/primitive neuroectodermal tumors (PNET). We report here a case of AT/RT in a male infant who was 9 months old at the time of diagnosis. Magnetic resonance imaging revealed that the tumor occupied the fourth ventricle, and at surgery it was found to adhere to the floor of the fourth ventricle. After subtotal removal of the tumor mass, chemotherapy and radiotherapy were performed, but the patient died about 8 months after the diagnosis following rapid regrowth of the residual tumor. Light-microscopically, the tumor was composed mainly of nests of rhabdoid cells with fields of PNET. Occasional mesenchymal and epithelial fields were also evident. Immunohistochemically, these rhabdoid cells were positive for vimentin, epithelial membrane antigen, smooth-muscle actin, cytokeratin, and S-100 protein, and less frequently for glial fibrillary acidic protein. Electron-microscopically, the typical rhabdoid cells contained whorled bundles of intermediate filaments in their cytoplasm. Occasionally, such rhabdoid cells were covered partially by basal lamina at their stromal interface. These findings are typical of AT/RT. Although it is well known that AT/RT often arises in the posterior fossa, detailed reports of cases affecting the fourth ventricle are rare. In this case, the ultrastructural relationship between rhabdoid cells and the basal lamina, which has not so far been described in AT/RT, was of great interest when the nature of the rhabdoid cells was considered. Presented at the 20th annual meeting of the Japan Society of Brain Tumor Pathology in Hiroshima, May 10–11, 2002     

A rare astrocytic tumor with rhabdoid features

We report an extremely rare tumor presenting with rhabdoid features in the left temporoparietal lobe near the trigone in an 18-year-old Japanese man. This tumor mainly consisted of medium to large round cells that proliferated diffusely and incoherently with a scant extracellular matrix. These tumor cells had an eccentric nucleus and an eosinophilic cytoplasm containing inclusion bodies and bundles of intermediate filaments. The nuclei of these cells were vesicular with prominent nucleoli. This tumor had an area appearing to be diffuse astrocytoma peripherally and lacked a primitive neuroectodermal tumor component, a mesenchymal component, and epithelial differentiation. INI expression, which is not observed in atypical teratoid/ rhabdoid tumor (AT/RT), was found in this tumor. From these findings, we concluded that this tumor was not AT/RT but an astrocytic tumor with rhabdoid features. We also concluded that the tumor cells exhibiting rhabdoid features had secondarily arisen from the peripheral area presenting an appearance of diffuse astrocytoma.     

Atypical Teratoid/Rhabdoid Tumors of the Central Nervous System

Summary Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant central nervous system neoplasm that usually affects very young children and is typically deadly despite very aggressive treatment. Considered rare, the tumor was not recognized as a distinct entity until the 80’s, due to its similar features with other primitive tumors. Although AT/RT has become increasingly recognized, published data has been based on small series and are retrospective. Based on these data, there are occasional long-term survivors, most of whom received intensive multi-modal therapy. AT/RT is the first pediatric brain tumor for which a candidate tumor suppressor gene has been identified. A mutation or deletion in the INI1 gene occurs in the majority of AT/RT tumors. The function of the gene is not yet understood. Prospective clinical and biologic trials are greatly needed to understand the efficacy of therapeutic interventions, as well as the role of the gene.     

Disulfiram modulates stemness and metabolism of brain tumor initiating cells in atypical teratoid/rhabdoid tumors

Background

Atypical teratoid/rhabdoid tumors (AT/RT) are among the most malignant pediatric brain tumors. Cells from brain tumors with high aldehyde dehydrogenase (ALDH) activity have a number of characteristics that are similar to brain tumor initiating cells (BTICs). This study aimed to evaluate the therapeutic potential of ALDH inhibition using disulfiram (DSF) against BTICs from AT/RT.

Methods

Primary cultured BTICs from AT/RT were stained with Aldefluor and isolated by fluorescence activated cell sorting. The therapeutic effect of DSF against BTICs from AT/RT was confirmed in vitro and in vivo.

Results

AT/RT cells displayed a high expression of ALDH. DSF demonstrated a more potent cytotoxic effect on ALDH⁺ AT/RT cells compared with standard anticancer agents. Notably, treatment with DSF did not have a considerable effect on normal neural stem cells or fibroblasts. DSF significantly inhibited the ALDH enzyme activity of AT/RT cells. DSF decreased self-renewal ability, cell viability, and proliferation potential and induced apoptosis and cell cycle arrest in ALDH⁺ AT/RT cells. Importantly, DSF reduced the metabolism of ALDH⁺ AT/RT cells by increasing the nicotinamide adenine dinucleotide ratio of NAD⁺/NADH and regulating Silent mating type Information Regulator 2 homolog 1 (SIRT1), nuclear factor-kappaB, Lin28A/B, and miRNA let-7g. Animals in the DSF-treated group demonstrated a reduction of tumor volume (P < .05) and a significant survival benefit (P = .02).

Conclusion

Our study demonstrated the therapeutic potential of DSF against BTICs from AT/RT and suggested the possibility of ALDH inhibition for clinical application.     

Epigenetic repression of RASSF1A but not CASP8 in supratentorial PNET (sPNET) and atypical teratoid/rhabdoid tumors (AT/RT) of childhood

Supratentorial primitive neuroectodermal tumors (sPNET) and atypical teratoid/rhabdoid tumors (AT/RT) of the CNS represent a biological and clinical enigma, despite advances in both molecular techniques and clinical management for these two rare embryonal brain tumors of childhood. Epigenetic changes hold great potential as possible disease mechanisms and may be manipulated therapeutically. We thus studied aberrant methylation of the genes RASSF1A and CASP8 and its consequence on expression in cell lines and primary tumors using a combination of semiquantitative methylation specific PCR (MSP), bisulfite sequencing and RT-PCR. In all, 17 samples of autopsy-derived normal appearing brain served as controls. Opposed to control tissues 19/24 sPNET and 4/6 AT/RT demonstrated aberrant methylation for the RASSF1A promoter region. Treatment of cell lines using 5-Aza-2'-deoxycytidine (5AZA) alone or in combination with trichostatin A (TSA) succeeded in re-establishing expression of RASSF1A in cell lines derived from a renal rhabdoid, an AT/RT and a medulloblastoma. A 5' CpG-rich region of CASP8 was methylated in normal tissues and in tumors. However, CASP8 showed inconsistent expression patterns in normal and tumor tissues. Our results indicate that aberrant methylation of the RASSF1A promoter region may be of importance in the origin and progression of sPNET and AT/RT while the analysed 5'-CpG rich region of the CASP8 gene does not seem to play an important role in these tumors. Further studies of epigenetic changes in these rare tumors are warranted as their biology remains obscure and treatment efforts have been rather unsuccessfull.     

Differential Expression of Bikunin (HAI-2/PB), A Proposed Mediator of Glioma Invasion,by Demethylation Treatment

This report describes the clinical, pathological, immunohistochemical and genetic data of two rare malignant neoplasms of the central nervous system (CNS) – a cerebral atypical teratoid/rhabdoid tumor (AT/RT) in a 5-month-old girl and a spinal canal primitive neuroectodermal tumor (PNET) in her father. Despite aggressive treatment, both tumors were fatal, displaying extensive local recurrence and diffuse neoplastic dissemination. The paraffin-embedded tumor tissue samples were analyzed using a dual-color FISH with a locus specific LSI22q (BCR) probe. In the AT/RT tissue, a loss of BCR locus was observed in a significant proportion of the cells in contrast to the PNET specimen where the majority of nuclei did not reveal any loss of the BCR region. No mutations in exon 5 and no changes in SNP of intron 5 of hSNF/INI1 gene were found. In addition, analysis of loss of heterozygosity (LOH) was performed using a panel of 15 microsatellite markers of chromosome 22. No LOH were found in both tumor tissues. In both cases no constitutional mutations of gene TP53 were found. Analysis of the TP53 mutations in the tumor tissues revealed that the PNET, not the AT/RT tumor, was homozygous for a missense mutation at codon 175 (CGC CAC). Thus, our findings emphasize the genetic differences between the two specimens and suggest that the occurrence of these two aggressive tumors of CNS in one family could be coincidental.     

Cyclin D1 is overexpressed in atypical teratoid/rhabdoid tumor with <Emphasis Type="Italic">hSNF5/INI1</Emphasis> gene inactivation

Object: Although atypical teratoid/rhabdoid tumor (AT/RT) is known to generate through inactivation of the hSNF5/INI1 gene on chromosome 22q, the downstream molecular mechanism remains unclear. We histologically and molecularly reviewed our pediatric brain tumors for unrecognized AT/RTs and evaluated the role of cyclin D1, a potential molecular target of hSNF5/INI1. Methods: We analyzed 16 tumors under three years of age: seven medulloblastomas, three anaplastic ependymomas (E IIIs), two each of supratentorial primitive neuroectodermal tumors (sPNETs) and choroid plexus carcinomas (CPCs), and one each of neuroblastoma and pineoblastoma. Immunohistochemistry for glial fibrillary acidic protein, vimentin, epithelial membrane antigen, smooth muscle actin and cyclin D1 was performed. Polymerase chain reaction (PCR)-single-strand conformation polymorphism analysis with direct sequencing, differential PCR and microsatellite analysis were conducted for hSNF5/INI1mutation, homozygous deletion and loss of heterozygosity (LOH) on 22q, respectively. Because of the presence of rhabdoid cells and the polyimmunophenotypic features, the diagnosis was revised to AT/RT in five (31%) tumors, namely, two E IIIs and one each of medulloblastoma, CPC and pineoblastoma. Three of them harbored such hSNF5/INI1 aberrations as germline single base deletion (492/6 delC) and missense mutation (C157T) together with LOH 22q or homozygous deletion. Cyclin D1 was overexpressed in those three tumors but not in the two that lacked hSNF5/INI1 inactivation. Conclusion: AT/RT can be misdiagnosed as a variety of tumors, including ependymoma that potentially harbors LOH 22q. Our data indicate that cyclin D1 is a target of hSNF5/INI1in primary tumors.     

Atypical teratoid/rhabdoid tumor of the spine in an adult: case report and review of the literature

Atypical teratoid/rhabdoid tumors (AT/RTs) are rare, malignant brain tumors which occur almost exclusively in infants and young children. There have been only 17 cases of AT/RT in adults reported in the medical literature and the rarity of this tumor makes the diagnosis in adults difficult. We describe a case of an AT/RT of the spinal cord in an adult. A 43-year old woman presented with neck and left upper extremity pain. An MRI demonstrated a mass lesion in the dorsal spinal cord extending from C4 to C6. The patient underwent a C3 through C7 laminectomy. In consultation with senior pathologists at other institutions, the lesion was initially diagnosed as a rhabdoid meningioma. Molecular genetic studies revealed monosomy 22 and loss of expression of the INI1 gene in 22q11.2. Subsequently, immunohistochemical studies revealed the absence of INI1 gene expression in the malignant cells, supporting the diagnosis of AT/RT. The patient underwent three additional surgical procedures for recurrent disease throughout the neuraxis secondary to leptomeningeal spread of the tumor. Despite aggressive surgical resection, adjuvant chemotherapy and radiation therapy, the patient succumbed to the disease two and a half years after her initial presentation. An unrestricted autopsy was performed. To our knowledge, this is the first case of a spinal atypical teratoid/rhabdoid tumor in an adult fully documented with molecular, immunohistochemical, cytogenetic and autopsy findings.     

Evaluation of osteopontin as a potential biomarker for central nervous system embryonal tumors

Osteopontin (OPN) is a protein linked to tumor growth, progression and metastasis of cancers. However, its role in the progression of central nervous system (CNS) embryonal tumors such as atypical teratoid/rhabdoid tumor (AT/RT), medulloblastoma (MB) and primitive neuroepithelial tumors (PNET) remains elusive. In this study, we investigated the value of OPN staining in differential diagnosis of AT/RT from MB and PNET, and assessed the correlation between OPN expression and patients’ prognosis. This retrospective study was conducted on tissue sections obtained from children cases with CNS embryonal tumors treated in Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine from 2006 to 2012 by immunohistochemistry (IHC). 49 cases were collected (11 AT/RTs, 25 MBs, and 13 PNETs), with a median follow-up time of 28.9 months. OPN expression in AT/RT was significantly higher than MB and PNET with the positive rates of 100, 32, and 23 %, respectively (P < 0.01). The specificity and sensitivity of OPN staining in diagnosing AT/RT are 97.4 and 90.9 %, respectively, as judged by strong OPN IHC staining level (+++). Patients who had positive OPN staining have increased risks of poorer median overall survival (hazard risk 5.54, 95 % CI 1.87–16.38) and tumor progression (hazard risk 14.47, 95 % CI 4.47–46.85). OPN is a valuable biomarker to aid in the differential diagnosis between AT/RT and MB/PNET. Moreover, OPN is a potential novel prognostic marker for CNS embryonal tumors.     

Clinicopathologic prognostic factors in childhood atypical teratoid and rhabdoid tumor of the central nervous system: a multicenter study

BACKGROUND:

The objective of this study was to describe the clinical and pathologic features and to identify prognostic factors in patients with atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system (CNS).

METHODS:

Patients aged <18 years with newly diagnosed CNS AT/RT who were treated in France between 1998 and 2008 were retrospectively identified. The study included all patients who had a diagnosis of AT/RT confirmed by pathologic review, including immunostaining for INI 1, tumor protein 53 (p53), β‐catenin, claudin‐6, and Ki‐67 and analysis for SMARCB1/hSNF5/INI1 mutation.

RESULTS:

Fifty‐eight patients with confirmed AT/RT were eligible for the current analysis. The median age at diagnosis was 1.4 years (range, 14 days to 8.5 years). The site of the primary tumor was supratentorial in 26 patients, infratentorial in 28 patients and spinal in 4 patients. Loss of INI1 nuclear expression was observed in 49 of 50 evaluable tumors. Positive claudin‐6 was observed in 37 of 42 assessed tumors and, in 12 of those tumors, the staining was strong and diffuse. Positive nuclear immunoreactivity for β‐catenin was observed in 24 of 44 tumors, and P53 was overexpressed in 31 of 44 tumors. Primary adjuvant therapy included chemotherapy in 47 patients and radiotherapy in 16 patients. The median follow‐up was 58 months (range, 9‐125 months), and the median survival was 9 months. Multivariate analysis identified age <2 years (P = .01), metastasis at diagnosis (P = .03), and strong immunopositivity for claudin‐6 (P = .03) as prognostic factors for the risk of death.

CONCLUSIONS:

AT/RT tumors in children carry a dismal prognosis. Age <2 years, metastasis at diagnosis, and strong claudin‐6 positivity appeared to be independent prognostic factors for outcome. Cancer 2012. © 2011 American Cancer Society.     

An immunohistochemical and electron microscopic study of atypical teratoid/rhabdoid tumor

We report two infant cases with atypical teratoid/rhabdoid tumor (AT/RT) located in the cerebellar vermis and spinal cord. MRI showed the tumors were isointense on T₁-weighted images and mixed intensity of isointense and slight high intensity on T₂-weighted images. Postcontrast MRI demonstrated clear margin of tumor and heterogeneous strong enhancement. It was difficult to differentiate the tumor from medulloblastoma by hematoxylin and eosin staining. However, immunohistochemical staining showed that these tumor cells react positively for cytokeratin, smooth muscle actin (SMA), and epithelial membrane antigen (EMA) and helped us with the differentiation. Electron microscopic study has confirmed the presence of mesenchymal components, such as filaments and desmosome junctions in the rhabdoid cells, but no neuronal components. The tumors rapidly increased in size, showing high MIB-1 index, and the prognosis was gave.     

Salvage re-irradiation for recurrent high-grade glioma and comparison to bevacizumab alone

Embryonal tumors are a heterogeneous group of central nervous system (CNS) tumors whose subgroups have varying incidence and outcome. Despite these differences, they are often grouped as a single entity for study purposes. To date, there are no Canadian multi-institutional studies examining the incidence and outcome of all embryonal subtypes. The current study is an observational study reviewing embryonal tumors in all patients less than 36 months of age diagnosed with a CNS tumor in Canada from 1990 to 2005. Embryonal tumors accounted for 26.9% of all CNS tumors. Medulloblastomas were the highest proportion of the embryonal tumors at 61.5%. Atypical teratoid/rhabdoid tumors (AT/RT) had the second highest proportion of embryonal tumors at 18%. The proportion of primitive neuroectodermal tumors (PNET) was 16%, with 2.6 and 1.9% for congenital medulloepithelioma and ependymoblastoma tumors, respectively. AT/RT and PNET were more common in younger age groups. Medulloblastoma became more prevalent with increasing age, with its highest prevalence in the 25 to 36 month age group. Survival rates for our Canadian population at 18 and 24 months were 0.74 and 0.68 for medulloblastoma, 0.64 and 0.60 for PNET, and 0.36 and 0.29 for AT/RT, respectively. Overall, our data are comparable with published international rates for embryonal tumors. These incidence and outcome figures can guide future research into these rare tumors.     

Atypical Teratoid/ Rhabdoid Tumor of Brain: a Clinicopathologic Study of Eleven Patients and Review of Literature

Background: Atypical teratoid/ rhabdoid tumor (AT/RT) is a rare aggressive embryonal central nervous system(CNS) tumor of infancy and early childhood. Majority of the cases arise in the posterior fossa, and remaining in thecerebrum. Aims: To analyze the clinicopathologic features of AT/RT on a cohort of cases. Materials and methods:All reported cases of AT/RT at the Department of Pathology and Laboratory Medicine, Aga Khan University Hospital(AKUH) from 2007 to 2016 were reviewed for clinical and pathological features. Immunohistochemical stain for INI-1was performed in all 11 cases. Follow up was obtained. Results: A total of 11 cases were identified. Seven patients weremales and 4 were females. The ages ranged from 1 month to 48 months (mean 26.6 months). Six tumors were locatedin the cerebrum and 3 in the posterior fossa. Exact Location was not known in 2 cases. Histologically, rhabdoid cellswere present in sheets in variable proportions in five cases, Medulloblastoma and PNET like areas were seen in 2 caseseach. Immunohistochemical stains EMA (10/10), vimentin (7/7), CKAE1/AE3 (8/9), and CD99 (3/4), GFAP (6/10),ASMA (3/4) and synaptophysin (3/4) were positive in varying proportions while desmin was negative in all 6 cases inwhich it was performed. All 11 tumors lacked immunoreactivity for INI-1 protein. Four patients died of disease witha follow up ranging from 5 to 24 months. Conclusions: AT/RT is a rare highly aggressive embryonal tumor of CNS.A male predominance was noted in our series. We report the first and largest series from Pakistan.     

Atypical teratoid rhabdoid tumor located in the pineal region following prophylactic irradiation for acute lymphoblastic leukemia

Atypical teratoid rhabdoid tumor (AT/RT) is a rare entity. In the central nervous system, AT/RT generally arises from the posterior fossa of infants and behaves aggressively. AT/RT is reported to arise from the infratentorial region (63%) and other sites, such as the suprasellar region, cerebellopontine angle, and spinal cord. The pineal region is rare (6%) as a site of origin. Radiation-induced brain tumors are well known. In this report, we present a case of a pineal region tumor causing acute hydrocephalus that could be pathologically diagnosed as AT/RT following prophylactic cranial irradiation for acute lymphoblastic leukemia.     

Aspiration cytopathology of epithelioid angiosarcoma

BACKGROUND: Epithelioid angiosarcoma (EA) is an uncommon neoplasm readily mistaken for carcinoma. In contrast to the histopathology of this tumor, the cytopathology as obtained using fine-needle aspiration (FNA) biopsy has rarely been described. METHODS: Three patients with histologically and immunohistochemically proven EA each underwent FNA using standard technique before surgical resection. RESULTS: Aspirate smears were obtained from 3 males (ages 47, 63, and 15 years) each of whom presented with a solitary palpable soft tissue mass, 1 from the left calf and 2 from the right popliteal region. No patient had a history of malignancy or had been exposed to prior radiation therapy. Smears were relatively hypocellular due to the dilutional effects of abundant blood. Cells were scattered on slides primarily in a single cell dissociated pattern; small aggregates were present in a fraction of the slides. Malignant cells generally monotonous in size and averaging three to four times the dimension of a mature lymphocyte had a rounded so-called epithelioid configuration. Cells possessed primarily rounded, single nuclei often eccentrically placed, with some anisokaryosis, and smooth nuclear borders. Binucleated cells with mirror-image nuclei were much less frequent, and cells with three or four nuclei were even more scarce. Cells contained large single nucleoli or more often multiple misshapen smaller nucleoli. Cytoplasm was abundant and finely granular in virtually all cells. In some, the cytoplasm acquired a central spheric density thus producing a "rhabdoid" appearance that was only seen with air-dried Diff-Quik (Fisher Scientific, Biochemical Sciences, Inc., Swedesboro, NJ) stained smears. Mitoses were readily found. Immunostaining of the cell block in one case permitted a specific diagnosis of EA before subsequent surgical excision. CONCLUSIONS: Epithelioid angiosarcoma may display a rhabdoid morphology in FNA biopsy smears, and this cytopathology can closely mimic that of nonsmall carcinoma, malignant melanoma, and other epithelioid types of soft tissue tumors. Immunophenotyping is essential for definitive diagnosis. Cancer (Cancer Cytopathol) Copyright 2000 American Cancer Society.     

Oncolytic measles virus efficacy in murine xenograft models of atypical teratoid rhabdoid tumors

BackgroundAtypical teratoid rhabdoid tumor (AT/RT) is a rare, highly malignant pediatric tumor of the central nervous system that is usually refractory to available treatments. The aggressive growth, propensity to disseminate along the neuroaxis, and young age at diagnosis contribute to the poor prognosis. Previous studies have demonstrated the efficacy of using oncolytic measles virus (MV) against localized and disseminated models of medulloblastoma. The purpose of this study was to evaluate the oncolytic potential of MV in experimental models of AT/RT.MethodsFollowing confirmation of susceptibility to MV infection and killing of AT/RT cells in vitro, nude mice were injected with BT-12 and BT-16 AT/RT cells stereotactically into the caudate nucleus (primary tumor model) or lateral ventricle (disseminated tumor model). Recombinant MV was administered either intratumorally or intravenously. Survival was determined for treated and control animals. Necropsy was performed on animals showing signs of progressive disease.ResultsAll cell lines exhibited significant killing when infected with MV, all formed syncytia with infection, and all generated infectious virus after infection. Orthotopic xenografts displayed cells with rhabdoid-like cellular morphology, were negative for INI1 expression, and showed dissemination within the intracranial and spinal subarachnoid spaces. Intratumoral injection of live MV significantly prolonged the survival of animals with intracranial and metastatic tumors.ConclusionThese data demonstrate that AT/RT is susceptible to MV killing and suggest that the virus may have a role in treating this tumor in the clinical setting.     

Molecular analysis of the rhabdoid predisposition syndrome in a child: a novel germline hSNF5/INI1 mutation and absence of c-myc amplification

The authors report a case of the rhabdoid predisposition syndrome (RPS) secondary to a germline hSNF5/INI1 mutation, whose brain tumor was originally unclassified but finally diagnosed as an atypical teratoid/rhabdoid tumor (AT/RT) by molecular analysis. A 7-month-old infant presented with hydrocephalus secondary to a huge pineal tumor and subsequently developed a renal rhabdoid tumor. The histology of the brain tumor was initially undetermined; however, an AT/RT was strongly suspected because of her clinical course. Mutational screening of the hSNF5/INI1 gene by heteroduplex and direct sequence analysis detected a missense mutation at codon 53 (CGATGA, argininestop) in both tumors, as well as in normal tissue of the kidney. Polymerase chain reaction (PCR)-based microsatellite analysis showed in both tumors allelic loss on chromosome arm 22q to which the hSNF5/INI1 gene maps. c-myc amplification was examined by differential PCR but not detected. Histologic review of the brain tumor by immunohistochemistry confirmed focal expression of epithelial membrane antigen and smooth muscle actin. These findings suggest that the brain tumor was really an AT/RT as a component of RPS secondary to a germline hSNF5/INI1 mutation. The present mutation has never been reported in the literature.     

Mutations of the INI1 rhabdoid tumor suppressor gene in medulloblastomas and primitive neuroectodermal tumors of the central nervous system.

Germ-line and somatic mutations of the hSNF5/INI1 gene have been reported in atypical teratoid/rhabdoid tumors (AT/RTs) of the brain, consistent with its role as a tumor suppressor gene. In the present study, we determined the frequency of deletions and mutations of INI1 in 52 children whose original diagnosis was medulloblastoma (MB) or primitive neuroectodermal tumor (PNET) of the central nervous system. Mutations were detected in DNA isolated from four tumors, all from children less than 3 years of age at diagnosis. Two of the four were reviewed and reclassified as atypical teratoid tumor, whereas there was insufficient material to establish this diagnosis in the two remaining cases. The relatively low frequency of mutations, even in a large series of infants, suggests that loss of sequences from chromosome 22 and/or mutations of INI1 do not account for the poor prognosis of children with MB or PNET who are less than 3 years of age at diagnosis. Nevertheless, chromosome 22 deletion and INI1-mutation analysis of infants with MB/PNET should be considered for all children who are less than 1 year of age. Detection of these mutations suggests that the child has an AT/RT, rather than a MB/PNET, a finding with important prognostic value.     

Atypical teratoid rhabdoid tumor (AT/RT) in adults: review of four cases

Atypical teratoid/rhabdoid (AT/RT) tumor is a rare, highly malignant tumor of the central nervous system (CNS) most commonly found in children less than 5 years of age. Although the vast majority of cases are diagnosed in young children, there have been isolated case reports in adults. Since its histological appearance can be confused with other tumors, especially in adults, separating AT/RT from other neoplasms may be difficult. In many instances, a reliable diagnosis is not possible without demonstrating the lack of nuclear INI1 protein expression by immunohistochemical methods. The patients (three males and one female) ranged in age from 23 to 42 years (mean age, 32 years). Radiographically, two tumors were localized in the right fronto-parietal region, one was frontal and the other was found in the left temporal lobe. Varying degrees of hydrocephalus and heterogeneous enhancement were present on MRI. In all cases, diagnosis during intraoperative consultation and preliminary diagnosis was different from the final diagnosis after immunohistochemical analysis. Immunohistochemical staining showed that the tumor cells were positive for vimentin and reacted variably for keratin, epithelial membrane antigen (EMA), synaptophysin, neurofilament protein, CD34, and smooth muscle actin (SMA). All were negative for GFAP, S-100, desmin and CD99. Three of the four cases lacked nuclear expression of INI1. One patient is alive with no evidence of disease 17 years after the diagnosis. In adult examples of AT/RT, the diagnosis requires a high index of suspicion, with early tissue diagnosis and a low threshold for investigation with INI1 immunohistochemistry to differentiate this entity from other morphologically similar tumors. Although the prognosis is dismal in pediatric population, long term survival is possible in adult AT/RT cases after surgery and adjuvant radiotherapy and chemotherapy.