Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood

Summary Clinical and morphological features of an apparently unique, biologically aggressive central nervous system tumor in 32 infants and children are presented. This neoplasm is formed wholly or partly by rhabdoid cells, areas resembling typical primitive neuroectodermal tumor, and, less frequently, malignant mesenchymal and/ or epithelial tissue. The tumor has been named atypical teratoid/rhabdoid tumor (ATT/RhT) and is regarded as a unique class of primary central nervous system (CNS) tumors. It occurs most commonly in infants less than two years of age, has often metastasized throughout the CNS at presentation, does not respond to therapy and causes death less than a year after diagnosis. These tumors may occur in any CNS site but almost 60% are located in the cerebellum. The most common chromosomal abnormality involves chromosome 22.     

Extraneural metastasis in a child with atypical teratoid rhabdoid tumor of the central nervous system

Atypical teratoid rhabdoid tumor is a distinctive brain tumor appearing in infancy and early childhood. Leptomeningeal dissemination is common, both at presentation and relapse. Extracranial metastases of the central nervous system tumors are rarely seen. To our knowledge there is only one report with an atypical teratoid rhabdoid tumor metastasizing via a ventriculoperitoneal shunt. We describe the first case of atypical teratoid rhabdoid tumor of the central nervous system who developed lung metastasis without the presence of a shunt.     

中枢神经系统非典型畸胎样/横纹肌样瘤临床病理观察

目的:探讨中枢神经系统非典型畸胎样/横纹肌样瘤(CNS AT/RT)的临床病理特征。方法:分析9例外科治疗的中枢神经系统AT/RT患者临床病理和影像学检查资料,对手术切除的肿瘤标本进行常规病理组织学和免疫组织化学检查,并结合相关文献,探讨其临床病理特征。结果:9例患者中,<15岁者7例(77.8%),>15岁者2例(22.2%),中位年龄6岁。临床表现为头痛、呕吐或对侧肢体麻木;肿瘤位于幕上者8例,幕下者1例;影像学检查显示,肿瘤多数呈囊实性改变,在肿瘤周围有明显的水肿征象,其中1例肿瘤周围有环形壁;病理上,肿瘤具有特征性的横纹肌样细胞分化以及其他细胞分化特征,包括上皮样、PNET样、黏液样或胶质瘤样。免疫组织化学标记显示,肿瘤细胞表达GFAP、CKpan、EMA和Vimentin,缺乏INI1、CD117和PLAP的表达;肿瘤Ki-67增殖指数>40%。患者平均生存期5个月。结论:AT/RT是中枢神经系统罕见的高度恶性肿瘤,好发于幼儿;临床表现为颅内占位性病变的相关症状或体征,病理上肿瘤细胞具有多能分化组织形态和免疫表型;该肿瘤的诊断依赖病理组织学及免疫组织化学检查,预后较差。     

Continuous remission of newly diagnosed and relapsed central nervous system atypical teratoid/rhabdoid tumor

Atypical teratoid/rhabdoid tumors (AT/RT) are highly malignant lesions of childhood that carry a very poor prognosis. AT/RT can occur in the central nervous system (CNS AT/RT) and disease in this location carries an even worse prognosis with a median survival of 7months. In spite of multiple treatment regimens consisting of maximal surgical resection (including second look surgery), radiation therapy (focal and craniospinal), and multi-agent intravenous, oral and intrathecal chemotherapy, with or without high-dose therapy and stem cell rescue, only seven long-term survivors of CNS AT/RT have been reported, all in patients with newly diagnosed disease. For this reason, many centers now direct such patients, particularly those under 5years of age, or those with recurrent disease, towards comfort care rather than attempt curative therapy. We now report on four children, two with newly diagnosed CNS AT/RT and two with progressive disease after multi-agent chemotherapy who are long term survivors (median follow-up of 37months) using a combination of surgery, radiation therapy, and intensive chemotherapy. The chemotherapy component was modified from the Intergroup Rhabdomyosarcoma Study Group (IRS III) parameningeal protocol as three of the seven reported survivors in the literature were treated using this type of therapy. Our four patients, when added to the three reported survivors in the literature using this approach, suggest that patients provided this aggressive therapy can significantly alter the course of their disease. More importantly, we report on the first two survivors after relapse with multi-agent intravenous and intrathecal chemotherapy treated with this modified regimen.     

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.     

Oncolytic measles virus prolongs survival in a murine model of cerebral spinal fluid-disseminated medulloblastoma

Medulloblastoma is the most common malignant brain tumor of childhood. Although the survival rate of afflicted children has improved considerably over the past several years, a subset of these patients will present with disseminated disease and face a much bleaker prognosis. In addition, patients may present with disseminated disease at recurrence. We previously demonstrated the efficacy of a recombinant oncolytic measles virus (MV) to treat localized medulloblastoma in a mouse xenograft model. In the present study, we sought to extend our findings to the treatment of disseminated disease. To this end, we developed and characterized a mouse xenograft model of disseminated medulloblastoma using serial bioluminescent imaging techniques in combination with histopathological examination. Mice injected with medulloblastoma cells into their right lateral ventricle showed tumor growth in their ventricles and in both intracranial and spinal subarachnoid spaces, closely recapitulating the human disease. Subsequent intraventricular administration of MV resulted in stabilization and shrinkage of the tumor, significantly prolonging the survival of the treated animals, compared with those treated with an inactivated virus. These data demonstrate that oncolytic MV may be of use in treating disseminated medulloblastoma. In addition, our protocol of intraventricular tumor cell injection, followed by bioluminescent imaging coupled with histopathological examination, provides a model for use in evaluating future recombinant oncolytic viruses and other preclinical therapeutic approaches for disseminated medulloblastoma.     

Survival outcomes in atypical teratoid rhabdoid tumor for patients undergoing radiotherapy in a Surveillance, Epidemiology, and End Results analysis

BACKGROUND:

Atypical teratoid rhabdoid tumor (ATRT) is a rare central nervous system malignancy with a poor prognosis that affects mostly young children. Although radiotherapy (RT) historically has been delayed in patients aged <3 years, emerging evidence suggests a role for RT to achieve long‐term survivorship. Clinical features and age‐dependent trends of RT use were evaluated for patients with ATRT.

METHODS:

The National Cancer Institute's Surveillance, Epidemiology, and End Results database was used to identify 144 patients with ATRT from 1973 to 2008. The primary endpoint was median overall survival (OS). Clinical and treatment variables were assessed for an association with OS using Cox proportional hazards models. Landmark analysis was used to correct for immortal time bias of adjuvant RT.

RESULTS:

The median age at diagnosis was 1 year (range, 0‐67 years). Gross total resection of the primary tumor was achieved in 39% of patients, and 33% of patients received RT. From 1992 to 2008, RT use increased 2.4‐fold in patients aged ≤3 years. The median OS for was 10 months. In multivariate analyses, metastatic disease (hazard ratio, 2.83; 95% confidence interval, 1.53‐5.23; P = .001) and RT (hazard ratio, 0.10; 95% confidence interval, 0.01‐0.73; P = .02) were identified as independent predictors of survival. Landmark analysis confirmed a robust association between RT use and survival, which was attenuated in patients ages 4 to 17 years compared with younger patients.

CONCLUSIONS:

The current results indicated that RT may offer a significant survival benefit for patients with ATRT and that patients aged ≤3 years may derive more benefit from initial RT compared with older children. The authors concluded that prospective clinical trials are needed to examine the role of RT in the initial management of ATRT in patients aged <3 years. Cancer 2012. © 2011 American Cancer Society.     

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     

High expression of BMP pathway genes distinguishes a subset of atypical teratoid/rhabdoid tumors associated with shorter survival

Molecular profiling of tumors has proven to be a valuable tool for identification of prognostic and diagnostic subgroups in medulloblastomas, glioblastomas, and other cancers. However, the molecular landscape of atypical teratoid/rhabdoid tumors (AT/RTs) remains largely unexplored. To address this issue, we used microarrays to measure the gene expression profiles of 18 AT/RTs and performed unsupervised hierarchical clustering to determine molecularly similar subgroups. Four major subgroups (clusters) were identified. These did not conform to sex, tumor location, or presence of monosomy 22. Clusters showed distinct gene signatures and differences in enriched biological processes, including elevated expression of some genes associated with choroid plexus lineage in cluster 4. In addition, survival differed significantly by cluster, with shortest survival (mean, 4.7 months) in both clusters 3 and 4, compared with clusters 1 and 2 (mean, 28.1 months). Analysis showed that multiple bone morphogenetic protein (BMP) pathway genes were upregulated in the short survival clusters, with BMP4 showing the most significant upregulation (270-fold). Thus, high expression of BMP pathway genes was negatively associated with survival in this dataset. Our study indicates that molecular subgroups exist in AT/RTs and that molecular profiling of these comparatively rare tumors may be of diagnostic, prognostic, and therapeutic value.     

Impact of radiotherapy for pediatric CNS atypical teratoid/rhabdoid tumor (single institute experience)

PURPOSE: To assess outcomes and prognostic factors in radiotherapy of pediatric central nervous system atypical teratoid/rhabdoid tumor (AT/RT). METHODS AND MATERIALS: Seventeen patients with central nervous system AT/RT were retrospectively reviewed after curative radiotherapy as primary or adjuvant therapy between January 1990 and December 2003. Overall and failure-free survival rates were calculated using the Kaplan-Meier method. The log-rank method was used to compare the effects of dosage (>50 Gy or < or =50 Gy) and treatment duration (>45 days or < or =45 days). Multivariate analysis was performed for prognostic factors. RESULTS: Median overall survival and failure-free survival were 17 and 11 months, respectively. The 3 longest-surviving patients were older, underwent gross tumor removal, and completed both craniospinal and focal boost irradiation. Multivariate analysis revealed a significant relationship between the following: overall survival and performance status (p = 0.019), failure-free survival and total irradiation dose (p = 0.037), time interval between surgery and radiotherapy initiation (p = 0.031), and time interval between surgery and radiotherapy end point (p = 0.047). CONCLUSION: Radiotherapy is crucial in the treatment of AT/RT. We recommend initiating radiotherapy immediately postoperatively and before systemic chemotherapy in pediatric patients > or =3 years of age.     

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.     

Atypical teratoid/rhabdoid tumor: the controversy behind radiation therapy

To date, approximately 200 cases of atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system have been described in the literature. This CNS tumor tends to present at an age of less than 3 years, and most patients succumb to their disease within 1 year of diagnosis. Prior to the rise in utilization of immunohistochemical (IHC) testing in the late 1990s, this tumor was likely mistaken as medulloblastoma and treated as such. However, lessons learned from regimens based upon medulloblastoma have revealed that AT/RT requires more aggressive treatment. A significant portion of patients die of local recurrence in spite of aggressive surgery and chemotherapy. As most patients with AT/RT present as infants or young children, radiation therapy has been a less than standard treatment option. However, recent evidence suggests that long-term survival can occur with use of more aggressive treatment approaches including dose-intense chemotherapy as well as adjuvant radiation therapy. A standardized and effective approach to treating this usually fatal tumor remains elusive, and the role of radiation therapy presents a particular dilemma as young patients with this disease may experience devastating late effects of therapy if they achieve a long-term survival. Review of the literature reveals an association between initial radiation therapy and the ability to achieve a prolonged survival. Our review underscores the importance or enrolling patients in multi-institutional prospective studies to further investigate the value of radiation to treat this pediatric neoplasm.     

Treatment of medulloblastoma with a modified measles virus

Although treatment of medulloblastoma has improved, at least 30% of patients with this tumor die of progressive disease. Unfortunately, many of the children who survive suffer long-term treatment-related morbidity. Previous studies have demonstrated the efficacy of using oncolytic viruses to eradicate brain tumors. The objective of this study was to test the efficacy of measles virus in treating medulloblastoma. To determine whether medulloblastoma cells are susceptible, 5 different human medulloblastoma cell lines were analyzed for the expression of the measles virus receptor CD46. Fluorescence-activated cell-sorting analysis confirmed expression of CD46 on all cell lines tested, with UW288-1 having the most prominent expression and D283med displaying the lowest expression. CD46 expression was also demonstrated, using immunohistochemistry, in 13 of 13 medulloblastoma tissue specimens. All 5 medulloblastoma cell lines were examined for their susceptibility to measles virus killing in vitro. A measles virus containing the green fluorescent protein (GFP) gene as a marker for infection (MV-GFP) was used. All cell lines exhibited significant killing when infected with MV-GFP, all formed syncytia with infection, all showed fluorescence, and all allowed viral replicaton after infection. In an intracerebral murine xenograft model, a statistically significant increase in survival was seen in animals treated with the active measles virus compared with those treated with inactivated virus. These data demonstrate that medulloblastoma is susceptible to measles virus killing and that the virus may have a role in treating this tumor in the clinical setting.