Medulloblastoma demonstrating multipotent differentiation: case report

We report a 6-year-old boy who presented with a medulloblastoma demonstrating classic, myoblastic, neuronal, glial, and melanotic differentiation and manifesting as severe morning headache. Magnetic resonance imaging revealed a mass lesion with cystic components in the cerebellar vermis. He underwent suboccipital craniotomy and total resection of the tumor. The specimen consisted of three morphologically distinct components. The first component consisted of densely packed cells with round-to-oval highly hyperchromatic nuclei surrounded by scanty cytoplasm. Immunohistochemical staining revealed diffuse expression of neurofilament protein and focal expression of desmin and myoglobin. The second component consisted of long spindle-shaped cells with elongated nuclei and eosinophilic cytoplasm. Immunohistochemical staining revealed diffuse expression of neurofilament protein, desmin, and myoglobin. The third component consisted of cells with small, densely hyperchromatic nuclei and scanty cytoplasm in a fine fibrillary background. Mature ganglion cells and melanotic tumor cells were also observed. Immunohistochemical staining revealed diffuse expression of synaptophysin and neurofilament protein, and focal expression of glial fibrillary acidic protein, S-100 protein, desmin, and myoglobin. The diagnosis was medulloblastoma with myoblastic, neuronal, astrocytic, and melanotic differentiation. Medulloblastoma demonstrating multipotent differentiation is rare, but the features observed in this case support the idea that medulloblastoma originates from multipotent stem cells.     

Medulloblastoma with melanotic differentiation: case report and review of the literature

Medulloblastoma with melanotic differentiation, a rare variant of medulloblastoma, often carries a poor prognosis. We present such a case of a 4 year male with this rare, aggressive tumor. Additionally, we have reviewed the literature and report on the features important in the pathologic and radiologic diagnosis in this type of tumor, as well as review clinical outcomes. This subtype of medulloblastoma occurs more frequently in males, at a younger median age than the other subtypes of medulloblastoma. The prognosis is generally very poor. However, it is important to note, that a subset of patients with M0 disease who can achieve a gross total resection followed by radiation and platinum based chemotherapy can become long term survivors of this aggressive subtype of medulloblastoma.     

Medulloblastoma with focal divergent/teratoid differentiation

Medulloblastomas with myogenic differentiation, previously termed medullomyoblastomas, form rare variants of medulloblastomas. Occasional tumors showing combined myogenic differentiation and melanotic tubular structures have also been described. On studying the records of a tertiary-care super specialty hospital, of 80 cases of medulloblastoma in a 5-year period, 36 showed nodular islands of neuronal, three myogenic, two glial, and one melanotic differentiation. Of the three cases of medulloblastomas with myogenic differentiation, we came across an extremely rare variant of medulloblastoma showing, in addition to the predominant primitive neuroectodermal component, a single minute nodular focus of 0.8 cm diameter, with divergent differentiation into mainly myogenic, epithelial, cartilaginous, and osseous lineages. Two ependymoblastic rosettes were also identified at different foci. In conclusion, a medulloblastoma with a small nodular island of divergent differentiation into various lineages has been seldom documented in literature. Microscopic foci of multilineage differentiation may be explained by the teratoid potential of medulloblastoma, or pluripotent nature of the neural crest cells, and requires extensive sampling for detection. It remains to be confirmed through more reports whether medulloblastomas with differentiation respond to a treatment protocol similar to that of medulloblastomas.     

Calmodulin-kinases regulate basal and estrogen stimulated medulloblastoma migration via Rac1

Medulloblastoma is a highly prevalent pediatric central nervous system malignancy originating in the cerebellum, with a strong propensity for metastatic migration to the leptomeninges, which greatly increases mortality. While numerous investigations are focused on the molecular mechanisms of medulloblastoma histogenesis, the signaling pathways regulating migration are still poorly understood. Medulloblastoma likely arises from aberrant proliferative signaling in cerebellar granule precursor cells during development, and estrogen is a morphogen that promotes medulloblastoma cell migration. It has been previously shown that the calcium/calmodulin activated kinase kinase (CaMKK) pathway promotes cerebellar granule precursor migration and differentiation during normal cerebellar development via CaMKIV. Here we investigate the regulatory role of the CaMKK pathway in migration of the human medulloblastoma DAOY and cerebellar granule cells. Using pharmacological inhibitors and dominant negative approaches, we demonstrate that the CaMKK/CaMKI cascade regulates basal medulloblastoma cell migration via Rac1, in part by activation of the RacGEF, βPIX. Additionally, pharmacological inhibition of CaMKK blocks both the estrogen induced Rac1 activation and medulloblastoma migration. The CaMKK signaling module described here is one of the first reported calcium regulated pathways that modulates medulloblastoma migration. Since tumor dissemination requires cell migration to ectopic sites, this CaMKK pathway may be a putative therapeutic target to limit medulloblastoma metastasis.     

Quick diagnosis of malignant melanoma with the touch-fluorescence method during operation

Nine cases of primary melanotic melanoma, three cases of metastatic amelanotic melanoma, and 26 cases of pigmented and unpigmented tumors other than melanoma were examined with the touch-fluorescence method using preparations from the cut surface of the lesions. Fluorescent melanoma cells were easily detected with a fluorescence microscope in all the cases of malignant melanoma whether the melanoma was melanotic or amelanotic. The fluorescent melanoma cells could be divided into three types by configuration: round, spindle-shaped, and pleomorphic. The main cell type of superficial spreading melanoma was round and that of nodular melanoma and acral lentiginous melanoma was chiefly pleomorphic. Fluorescent tumor cells were not seen in pigmented and unpigmented tumors other than melanoma, except in pigmented basal cell epithelioma; this fact made it possible to apply this method routinely for quick diagnosis of malignant melanoma during operation.     

Melanotic primitive neuroectodermal (neuroepithelial) tumor of medulla

A 69-year-old man had a melanotic primitive neuroectodermal tumor of the medulla displaying various neuroepithelial elements including undifferentiated neuroepithelial cells forming Homer Wright's rosettes as well as neoplastic neuroglia resembling those seen in medulloblastoma. The neuroglial tumor cells were verified by demonstrating glial fibrillary acidic protein (GFAP) in the cells. These findings support the concept that the primitive neuroectodermal tumor and medulloblastoma are similar neoplasms. They have been described by such diverse names as melanotic medulloblastomas and progonomas. Review of 18 reported cases of intracranial melanotic primitive neuroectodermal tumors, including the present one, reveals that they have common pathologic features, are most frequent in the cerebellum and fourth ventricle, often metastasize widely within the neuraxis or even systemically, occur more frequently in children than adults, and strike males more often than females.     

The modulation of astrocytic differentiation in cells derived from a medulloblastoma surgical specimen

Medulloblastomas are cerebellar tumors which are primarily composed of sheets of uniform, small malignant cells and may have astrocytic, neuronal or no features typical of these cell types. The assessment of astrocytic differentiation in medulloblastoma rests largely on the detection in malignant cells of glial fibrillary acidic protein (GFAP), a marker present in the later stages of normal astrocyte differentiation. It is still not known whether cells that do not contain GFAP in medulloblastomas with astrocytic differentiation correspond to highly proliferative astrocyte progenitors in maturation arrest at earlier stages of differentiation. The purpose of the current study was to examine whether cells in short term culture derived from a medulloblastoma tumor specimen with astrocytic differentiation were of the astrocytic lineage and if so, whether they represented proliferative astrocyte progenitors which would morphologically and antigenically mature in response to differentiating agents. A portion of tumor specimen from a 10-month-old child with recurrent posterior fossa medulloblastoma (RB2) that contained GFAP focally in tumor cells was grown in monolayer culture. We examined cellular structure and appearance of western immunoblotting and immunohistochemical studies for GFAP and neuron-specific enolase (NSE) in RB2 cells before and after treatment with retinoic acid (RA) and dibutyryl cyclic AMP (dBcAMP). RB2 in culture consisted of small polygonal cells (93%), large flat cells (3%), and polygonal cells with cytoplasmic processes (4%). In untreated RB2, 30% of cells expressed GFAP and staining for NSE was negative. RA treatment produced flattened cells and decreased GFAP. DBcAMP reversibly induced fine cytoplasmic processes containing GFAP in 85% of cells within 96h. Neither agent induced NSE. The results suggest that cultured cells which are derived from a medulloblastoma with astrocytic differentiation do not spontaneously differentiate but that treatment with dBcAMP suppresses proliferation, enhances cytoplasmic process formation and increases cytoplasmic GFAP. Cells in culture and in medulloblastoma tumor specimens which do not contain GFAP may represent astrocyte progenitors in maturation arrest.     

Medulloblastoma in an adult suggestive of external granule cells as its origin: A histological and immunohistochemical study

We describe a rare case of medulloblastoma in an adult woman with histological findings suggesting an origin for this neoplasm in the external granular layer or its remnants. The patient presented with cerebellar dysfunction, and neuroimaging revealed a right cerebellar mass lesion. Pathological examination of the operative specimen revealed a medulloblastoma with occasional areas of neuronal or glial differentiation. Zic protein was also detected immunohistochemically in the tumor cells. The tumor cells were mainly distributed in the subarachnoid space and extended to the cerebellar parenchyma through the perivascular space to form tumor nodules. A suggestive finding, as concerns the origin of this neoplasm, was that the tumor cells were also spread evenly along the subpial zone of the molecular layer, reminiscent of the cellular architecture of the fetal external granular layer.     

High dose chemotherapy with autologous stem cell rescue for patients with medulloblastoma

Summary High-dose chemotherapy with autologous stem cell rescue (ASCR) is a promising strategy for patients with poor prognosis cerebellar medulloblastoma. For this strategy to be effective, it must be shown that the medulloblastoma tumor cells are sensitive to the chemotherapeutic agents whose dose-limiting toxicity is hematopoietic, and stem cells must be available that are free of contaminating tumor. Several protocols for high-dose chemotherapy followed by ASCR are presented in this chapter. Initial encouraging evaluations of this technique in patients with recurrent disease has prompted testing of its feasibility in infants and young children. In a reasonably short time, the role of high-dose chemotherapy with ASCR will be determined for subgroups of patients with medulloblastoma.     

Expression of major histocompatibility complex on human medulloblastoma cells with neuronal differentiation

Medulloblastomas are among the most common malignant brain tumors in children. These tumors consist of immature bipotential cells that may differentiate into neuronal and glial cells. We have established two cell lines for human medulloblastoma. One was derived from a 2-year-old girl with a cerebellar tumor (designated as ONS-76) and another from a 9-year-old girl with a metastatic tumor in the right frontal lobe (ONS-81). The in vitro population-doubling times were 18.6 and 19.2 h, respectively. Immunohistochemical studies showed that both cells possessed neurofilament protein (Mr 145,000 and 200,000) and neuron-specific enolase, without glial fibrillary acidic protein or S-100 protein. Human gamma-interferon enhanced class I major histocompatibility complex antigens on these medulloblastoma cells. Class II major histocompatibility complex antigens were also induced by human interferon-gamma. We here report for the first time the expression of class II major histocompatibility antigens, which play an important role in immune response, on human medulloblastoma cells with neuronal differentiation.     

Valproic Acid prolongs survival time of severe combined immunodeficient mice bearing intracerebellar orthotopic medulloblastoma xenografts.

PURPOSE: To develop novel orthotopic xenograft models of medulloblastoma in severe combined immunodeficient mice and to evaluate the in vivo antitumor efficacy of valproic acid. EXPERIMENTAL DESIGN: Orthotopic xenografts were developed by injecting 10(3) to 10(5) tumor cells from four medulloblastoma cell lines (D283-MED, DAOY, MHH-MED-1, and MEB-MED-8A) into the right cerebellum of severe combined immunodeficient mice. Animals were then examined for reproducibility of tumorigenicity, cell number-survival time relationship, and histopathologic features. Tumor growth was monitored in vivo by serially sectioning the xenograft brains at 2, 4, 6, and 8 weeks postinjection. Valproic acid treatment, administered at 600 microg/h for 2 weeks via s.c. osmotic minipumps, was initiated 2 weeks after injection of 10(5) medulloblastoma cells, and treated and untreated animals were monitored for differences in survival. Changes in histone acetylation, proliferation, apoptosis, differentiation, and angiogenesis in xenografts were also evaluated. RESULTS: Tumorigenicity was maintained at 100% in D283-MED, DAOY, and MHH-MED-1 cell lines. These cerebellar xenografts displayed histologic features and immunohistochemical profiles (microtubule-associated protein 2, glial fibrillary acidic protein, and vimentin) similar to human medulloblastomas. Animal survival time was inversely correlated with injected tumor cell number. Treatment with valproic acid prolonged survival time in two (D283-MED and MHH-MED-1) of the three models and was associated with induction of histone hyperacetylation, inhibition of proliferation and angiogenesis, and enhancement of apoptosis and differentiation. CONCLUSION: We have developed intracerebellar orthotopic models that closely recapitulated the biological features of human medulloblastomas and characterized their in vivo growth characteristics. Valproic acid treatment of these xenografts showed potent in vivo anti-medulloblastoma activity. These xenograft models should facilitate the understanding of medulloblastoma pathogenesis and future preclinical evaluation of new therapies against medulloblastoma.     

Primitive pineal tumor with retinoblastomatous and retinal/ciliary epithelial differentiation: an immunohistochemical study

A one year old boy was found to have a large tumor encompassing the pineal region and extending towards the third and lateral ventricles and quadrigeminal plate. The tumor was composed mostly of small, undifferentiated cells. Some small cells were arranged in Flexner-Wintersteiner rosettes and a few displayed fleurettes. The tumor contained immature cartilage and skeletal muscle and numerous clusters of pigmented epithelial-like cells which, histologically, resembled those found in melanotic neuroectodermal tumors of infancy (retinal anlage tumors) and retinal or ciliary epithelium. Immunologic stains demonstrated neurofilaments, synaptophysin and retinal S-antigen in some of the small cells and transthyretin in some of the epithelial-like cells. The findings indicate that certain primary pineal parenchymal tumors have features in common with tumors of the ocular medullary epithelium.     

A molecular fingerprint for medulloblastoma

Medulloblastoma is the most common malignant pediatric brain tumor. In mice, Ptc1 haploinsufficiency and disruption of DNA repair (DNA ligase IV inactivation) or cell cycle regulation (Kip1, Ink4d, or Ink4c inactivation), in conjunction with p53 dysfunction, predispose to medulloblastoma. To identify genes important for this tumor, we evaluated gene expression profiles in medulloblastomas from these mice. Unexpectedly, medulloblastoma expression profiles were very similar among tumors and also to those of developing cerebellum. However, 21 genes were specifically up-regulated in medulloblastoma, including sFrp1, Ptc2, and Math1, members of signaling pathways that regulate cerebellar development. Coordinated deregulation of these same genes also occurred in a large subset of human medulloblastomas. These data identify a group of genes that is central to medulloblastoma tumorigenesis.     

Melanotic neuroectodermal tumor of infancy. A review of seven cases

The melanotic neuroectodermal tumor of infancy (MNTI) is a rare, usually benign, pigmented neuroectodermal tumor which most often involves the maxilla. The authors reviewed seven cases of MNTI, with patient ages of our patients ranged from nine weeks to 18 months; six of the seven were less than six months old at initial diagnosis. Four patients were males, and all were white. One tumor each was located in the femur, the temporal bone, and the epididymis; the remaining lesions occurred in the maxilla. Three of the four maxillary tumors recurred locally; the epididymal and femoral tumors metastasized. Two of these cases had unique clinical or pathologic features. The case of the femoral tumor is remarkable in that it is the first reported one of MNTI presenting in a long bone. This tumor was aggressively malignant; within two months after its discovery, a large mass of similar tumor was formed in the pelvis, and the tumor resulted in the patient's death. To the authors' knowledge, the case of the temporal bone tumor is the first one of MNTI in which neuronal differentiation of the neuroblastic cells is convincingly demonstrated. This finding provides additional evidence in support of the neuroectodermal theory of origin of these neoplasms.     

Inhibition of NF-κB signaling commits resveratrol-treated medulloblastoma cells to apoptosis without neuronal differentiation

Resveratrol promotes differentiation and apoptosis of medulloblastoma cells by suppressing STAT3 signaling and a range of cancer-associated gene expression. However, Bcl-2, a common target of STAT3 and NF-κB signaling, is distinctly up-regulated in resveratrol-treated medulloblastoma cells, indicating potential effects of NF-κB in Bcl-2 expression and anti-medulloblastoma efficiency of resveratrol. To clarify this point, the status of NF-κB signaling and the consequence of NF-κB inhibition in UW228-2 and UW228-3 medulloblastoma cells without and with resveratrol treatment were evaluated by several experimental approaches. The results revealed that resveratrol activated NF-κB signaling in both cell lines at the 4-h treatment point, and the treated cells sequentially exhibited Bcl-2 up-regulation, neuronal-like phenotype with synaptophisin expression, and, eventually, apoptosis. Pyrrolidine dithiocarbamate (PDTC) treatment inhibited NF-κB activation and Bcl-2 expression and committed resveratrol-treated cells to apoptosis at the 8-h time point without the step of neuron-oriented differentiation. On the other hand, a single 50 μg/ml lipopolysaccharide (LPS) treatment activated NF-κB signaling accompanied with sustained proliferation and neuron-like differentiation. Tissue microarray-based immunohistochemical staining showed significantly different (P < 0.001) p65 nuclear translocation between the neurons of tumor-surrounding cerebella (10/10; 100%) and medulloblastoma tissues (20/117; 17.09%). Additionally, synaptophysin production was found in 83.64% of p65-positive and in 40.35% of p65-negative medulloblastoma cases. Our in-vitro and in-vivo results thus demonstrate the dual effects of NF-κB signaling on medulloblastoma cells by delaying resveratrol-induced apoptosis by up-regulating Bcl-2 expression or by involvement in neuronal-like differentiation in the absence of resveratrol. Therefore, appropriate inhibition of NF-κB activation may enhance the anti-medulloblastoma efficacy of resveratrol.     

MicroRNA profiling in human medulloblastoma

Medulloblastoma is an aggressive brain malignancy with high incidence in childhood. Current treatment approaches have limited efficacy and severe side effects. Therefore, new risk-adapted therapeutic strategies based on molecular classification are required. MicroRNA expression analysis has emerged as a powerful tool to identify candidate molecules playing an important role in a large number of malignancies. However, no data are yet available on human primary medulloblastomas. A high throughput microRNA expression profiles was performed in human primary medulloblastoma specimens to investigate microRNA involvement in medulloblastoma carcinogenesis. We identified specific microRNA expression patterns which distinguish medulloblastoma differing in histotypes (anaplastic, classic and desmoplastic), in molecular features (ErbB2 or c-Myc overexpressing tumors) and in disease-risk stratification. MicroRNAs expression profile clearly differentiates medulloblastoma from either adult or fetal normal cerebellar tissues. Only a few microRNAs displayed upregulated expression, while most of them were downregulated in tumor samples, suggesting a tumor growth-inhibitory function. This property has been addressed for miR-9 and miR-125a, whose rescued expression promoted medulloblastoma cell growth arrest and apoptosis while targeting the proproliferative truncated TrkC isoform. In conclusion, misregulated microRNA expression profiles characterize human medulloblastomas, and may provide potential targets for novel therapeutic strategies.     

Medulloblastomas overexpress the p53-inactivating oncogene <Emphasis Type="Italic">WIP1/PPM1D</Emphasis>

Medulloblastoma is the most common malignant brain tumor of childhood. Despite numerous advances, clinical challenges range from recurrent and progressive disease to long-term toxicities in survivors. The lack of more effective, less toxic therapies results from our limited understanding of medulloblastoma growth. Although TP53 is the most commonly altered gene in cancers, it is rarely mutated in medulloblastoma. Accumulating evidence, however, indicates that TP53 pathways are disrupted in medulloblastoma. Wild-type p53-induced phosphatase 1 (WIP1 or PPM1D) encodes a negative regulator of p53. WIP1 amplification (17q22-q23) and its overexpression have been reported in diverse cancer types. We examined primary medulloblastoma specimens and cell lines, and detected WIP1 copy gain and amplification prevalent among but not exclusively in the tumors with 17q gain and isochromosome 17q (i17q), which are among the most common cytogenetic lesions in medulloblastoma. WIP1 RNA levels were significantly higher in the tumors with 17q gain or i17q. Immunoblots confirmed significant WIP1 protein in primary tumors, generally higher in those with 17q gain or i17q. Under basal growth conditions and in response to the chemotherapeutic agent, etoposide, WIP1 antagonized p53-mediated apoptosis in medulloblastoma cell lines. These results indicate that medulloblastoma express significant levels of WIP1 that modulate genotoxic responsiveness by negatively regulating p53.     

Non Malignant Maxillary Lesions: Our Experience

A wide variety of lesions occur in maxilla. Non specificity of clinical and radiological features makes diagnosis of these lesions a difficult task. We report six interesting cases of maxillary swelling among a total number of 37 such lesions of maxilla. These six cases are as follows two cases of central giant cell granuloma, two cases of fibrous dysplasia, one case of pigmented melanotic neuroectodermal tumor and one case of solitary myofibroma.     

210例髓母细胞瘤临床病理研究及预后因素分析

目的 :分析髓母细胞瘤 (MB)的临床病理特点及影响预后的因素。方法 :对 33年间病理证实的 2 10例 MB进行组织学及免疫组织化学观察。采用 L og- rank检验进行预后分析。结果 :MB病人术后 1年、3年及 5年生存率分别为 34.6 5 %、13.77%和 10 .71% ,平均生存 2 2个月。与病人生存期延长的有关因素为病人年龄≥ 18岁 (P=0 .0 44 4)、促纤维增生型 MB(P=0 .0 317) PCNA标记指数低 (P=0 .0 2 2 7)、肿瘤无灶状坏死 (P=0 .0 0 0 2 )及术后接受放射治疗 (P=0 .0 0 0 1)。性别、术前病程长短、肿瘤大小、部位及分化程度与病人预后无明显关系。结论 :年龄、组织类型、细胞增殖活性、肿瘤灶状坏死及术后放疗是与 MB病人预后有关的重要因素。