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.     

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.     

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.     

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.     

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.     

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.     

Cisplatin-selected resistance is associated with increased motility and stem-like properties via activation of STAT3/Snail axis in atypical teratoid/rhabdoid tumor cells

Atypical teratoid/rhabdoid tumor (ATRT) is a malignant pediatric brain tumor with great recurrence after complete surgery and chemotherapy. Here, we demonstrate that cisplatin treatment selects not only for resistance but also for a more oncogenic phenotype characterized by high self-renewal and invasive capabilities. These phenomena are likely due to STAT3 upregulatoin which occurred simultaneously with higher expression of Snail, an activator of epithelial–mesenchymal transition (EMT), in ATRT-CisR cells. STAT3 knockdown effectively suppressed Snail expression and blocked motility and invasion in ATRT-CisR cells, while overexpressing Snail reversed these effects. Chromatin immunoprecipitation assay indicated that STAT3 directly bound to Snail promoter. Moreover, STAT3 knockdown effectively suppressed cancer stem-like properties, synergistically enhanced the chemotherapeutic effect, and significantly improved survival rate in ATRT-CisR-transplanted immunocompromised mice. Finally, immunohistochemistrical analysis showed that STAT3 and Snail were coexpressed at high levels in recurrent ATRT tissues. Thus, the STAT3/Snail pathway plays an important role in oncogenic resistance, rendering cells not only drug-resistant but also increasingly oncogenic (invasion, EMT and recurrence). Therefore, the STAT3/Snail could be a target for ATRT treatment.     

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.     

The tyrosine kinase c‐Abl promotes proliferation and is expressed in atypical teratoid and malignant rhabdoid tumors

BACKGROUND:

Atypical teratoid/rhaboid tumors (AT/RTs) and extracranial malignant rhabdoid tumors are highly malignant neoplasms with a dismal prognosis. These tumors predominantly affect infants and targeted, adjuvant treatment approaches would be highly desirable.

METHODS:

In the current study, the authors investigated the expression and functional role of tyrosine kinases in 2 malignant rhabdoid tumor cell lines (A204 and G401) and in a series of 5 AT/RTs and 18 malignant rhabdoid tumors (13 rhabdoid tumors of the kidney and 5 extrarenal rhabdoid tumors).

RESULTS:

Both cell lines consistently expressed the tyrosine kinase c‐Abl, which promoted proliferation as assessed by small interfering RNA knockdown. Blockage of c‐Abl using the tyrosine kinase inhibitor imatinib resulted in reduced cellular growth in both cell lines. Furthermore, c‐Abl was expressed in all rhabdoid tumors, whereas expression of platelet‐derived growth factor receptor subtypes alpha and beta was infrequent and c‐Kit expression was absent.

CONCLUSIONS:

The current data pointed toward a role for c‐Abl in the biology of malignant rhabdoid tumors and provided a rationale for the investigation of tyrosine kinase inhibitors that target c‐Abl for the treatment of these aggressive tumors. Cancer 2010. © 2010 American Cancer Society     

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.     

Clinicopathologic characteristics and prognostic factors in 420 metastatic breast cancer patients with central nervous system metastasis

BACKGROUND: Breast cancer is the second most common cause of central nervous system (CNS) metastases. Several risk factors for CNS metastases have been reported. The objective of the current study was to describe clinicopathologic characteristics and prognostic factors in breast cancer patients with CNS metastases. METHODS: The authors retrospectively evaluated clinical data from 420 patients who had been diagnosed with breast cancer and CNS metastasis between 1994 and 2004 at the University of Texas M. D. Anderson Cancer Center. RESULTS: The median age of the patients at the time of diagnosis of breast cancer was 45 years (range, 25-77 years). Premenopausal and postmenopausal patients were distributed equally. Most patients had invasive ductal histology (91.2%), grade 3 tumors (81.4%) (using the modified Black nuclear grading system), T2 tumor classification (40.1%), and N1 lymph node status (59.7%) diagnosis. Forty percent of patients had estrogen receptor (ER)-positive disease, and 34% had progesterone receptor-positive disease. HER-2/neu status was recorded for only 248 patients, and 39% of the patients in that group had HER-2/neu-positive disease. The most common sites of first metastasis were liver, bone, and lung. CNS metastasis was the site of first recurrence in 53 patients (12%). In total, 329 patients had received either neoadjuvant treatment (113 patients) or adjuvant chemotherapy (216 patients). The majority of those patients (74.4%) had received anthracycline-based regimens. Metastasis was solitary in 111 patients (26.4%), and 29 patients had only leptomeningeal metastases. The median time from breast cancer diagnosis to CNS metastasis was 30.9 months (range, from -5 months to 216.7 months). The median follow-up after a diagnosis of CNS metastasis was 6 months (range, 7-95.9 months). In all, 359 patients died, and the overall median survival was 6.8 months. Only age at diagnosis and ER status were associated significantly with overall survival in the multivariate analysis. CONCLUSIONS: The current results indicated that the prognosis remains patients with breast cancer metastatic to the CNS. More effective treatment approaches are needed for patients with CNS metastases, even for those with favorable prognostic factors, such as ER-positive tumors or younger age.     

Atypical Teratoid/rhabdoid Tumors in Adult Patients: Case Report and Review of the Literature

Atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system are rare and extremely aggressive malignancies of early childhood. We report a case of AT/RT in an adult patient.A 30-year-old woman presented with headache, vomiting and ataxia during the second trimester of pregnancy. Magnetic resonance imaging revealed a posterior fossa mass. A gross total resection was performed. Pathological examination revealed an AT/RT. Despite the dismal prognosis the patient decided not to undergo an abortion. For this reason postoperative accelerated hyperfractionated radiotherapy was limited to the tumor region. Six months later the woman delivered a healthy baby. One week postpartum, a central nervous system recurrence localized apart from the primary lesion was treated with radiosurgery. Two months later a diffuse progression was noted. Despite a 6 week course of oral temozolomide, the tumor progressed and the patient died 11 months after diagnosis.Although survival was short, surgery and involved field radiotherapy yielded a progression-free interval of 9 months. This allowed the patient to carry pregnancy to term. Radiosurgery resulted in a complete remission of the first recurrence. Oral chemotherapy was not effective in controlling diffuse tumor spread.     

A multimodal strategy based on surgery,radiotherapy, ICE regimen and high dose chemotherapy in atypical teratoid/rhabdoid tumours: a single institution experience

Purpose Atypical Teratoid/Rhabdoid Tumour is a rare and aggressive childhood tumour. The outcome of a series treated with the same multimodal strategy was reported. Patients The patients were treated with surgery, 2 courses of ifosfamide/carboplatin/etoposide(ICE), 2 courses of cyclophosphamide/etoposide/carboplatino/thiotepa (CECAT) or 2 other ICE courses, high dose chemotherapy (HDC) and radiotherapy. Results Eight patients underwent primary surgery achieving a complete removal in 3. Progressive disease (PD) occurred in 2/8 patients during ICE courses and in 3/4 during CECAT courses. After 4 courses 5 patients presented a PD. HDC was performed in 3 patients followed by local radiotherapy. The Kaplan Meier OS and EFS probability at 5 years are, respectively, 50% (CI 11–80%) and 33% (CI 6–66%). Conclusion A strategy based on surgery, including a second surgical look, and on radiotherapy appears the best option. ICE regimen and HDC correlate with good prognosis in some patients but this approach needs further evaluation.