Anaplasia is rare and does not influence prognosis in adult medulloblastoma

Histopathologic grading based on increasing anaplasia predicts clinical behavior of pediatric medulloblastomas. The present study was aimed at grading 86 medulloblastomas of adult patients (aged 18 and older) by anaplasia and analyzing the predictive power. Nodularity, desmoplasia, nuclear size, nuclear pleomorphism, necrosis, and endothelial proliferations have been evaluated. Morphometric analysis of nuclear size was performed using the Eclipse Net program. Patients treated with standard postoperative radiotherapy (35 Gy to craniospinal axis and 50 Gy to posterior fossa) were considered for correlation with survival. Pathologic data and total survival were compared by Kaplan-Meier and logrank analysis. No correlation was found between total survival duration and individual pathologic features. Cooccurrence of nuclear pleomorphism, large nuclear diameter, microvascular proliferations, and necroses did not predict outcome. Severe nuclear pleomorphism was found in 4 of 86 cases; the only large-cell medulloblastoma was from an 18-year-old patient. Histopathologic factors have no clinical use for stratification of patients in risk groups. The histologic spectrum of medulloblastoma in adults is different from that in children.     

Isochromosome 17q is a constant finding in medulloblastoma. An interphase cytogenetic study on tissue sections

Isochromosome 17q (i[17q]) is the most frequent chromosomal abnormality in medulloblastoma, occurring in 30–60% of cases by karyotype analysis. In the present study i[17q] was demonstrated in routinely processed tissue sections of 20 medulloblastomas by in situ hybridization (ISH), using a chromosome 17 centromeric alpha satellite DNA probe. All medulloblastomas showed the i[17q] specific signal, i.e. two hybridization spots slightly apart from each other. The specific hybridization signal was not observed in ependymomas, cerebellar astrocytomas, haemangioblastomas, supratentorial neuroblastomas and ependymoblastomas. The constant finding of i[17q] in medulloblastoma depends on the much higher number of nuclei which can be analysed by ISH compared with cytogenetic techniques. Molecular data on medulloblastoma are consistent with the present results. The number of cells with i[17q] in medulloblastoma cases ranged from 3% to 9%; these figures are underestimated because of nuclear truncation in tissue sections. The percentage was not linked to patients' age, location of tumour, MIB-1 labelling index and histological type (classical vs desmoplastic). The present results indicate that i[17q] is a key event in the pathogenesis of medulloblastoma, and suggest a genetic difference between medulloblastoma and other primitive neuroectodermal tumours     

Survivin is a negative prognostic marker in medulloblastoma

Survivin is a member of the inhibitor of apoptosis protein family, which is over-expressed in many human cancers. Our aim was to analyse survivin expression in medulloblastoma, its association with aberrant activation of the WNT (wingless) pathway and to test the prognostic significance of survivin expression. We immuno histochemically analysed survivin expression and localization of beta-catenin, a downstream mediator of the WNT pathway, in 56 cases of medulloblastoma. Survivin was detected in the nuclei of tumour cells in all cases, but the proportion of positive nuclei varied from 0.5 to 31.3%. Survivin expression tended to be higher in medulloblastomas with an aberrant activation of the WNT pathway (nuclear localization of beta-catenin), but did not correlate with histological type, age group or dissemination via cerebrospinal fluid pathways. Survivin expression and dissemination status were two independent negative prognostic variables for the overall survival of patients with medulloblastoma. In conclusion, survivin is up-regulated in medulloblastomas. It is a negative prognostic marker and a potential therapeutic target.     

Cerebellar medulloblastomas: a comparison between adults and children

A retrospective analysis of 19 medulloblastomas in patients aged 2 to 24 years was conducted employing 14 children (<15 years old) and 5 adults. All patients received gross total excision of the tumour with postoperative craniospinal irradiation. The patients were then followed up for more than 5 years. To determine which factors influenced the prognosis of these two age groups, we analysed the differences of the proliferating cell nuclear antigen (PCNA), the degree of tumour invasion and the outcome between adult and childhood medulloblastomas. In summary, medulloblastomas in adults and children had similar cell proliferative activity and long term survival rates but the tumours with brain stem invasion, which commonly occurred in children, had an early recurrence rate and a poor prognosis. The prognosis of medulloblastoma may depend upon the degree of tumour invasion of the brain stem.     

髓母细胞瘤中表皮生长因子受体的表达及基因扩增分析

目的：研究表皮生长因子受体在髓母细胞瘤中的蛋白表达及基因水平的扩增情况，从而分析二关系。方法：对48例髓母细胞瘤标本进行免疫组化染色，同时进行差异多聚酶链反应，放射自显影后根据其信号强弱来判断基因的扩增情况。结果：48例髓母细胞瘤中有7例表皮生长因子受体呈阳性表达（14．58％），其中成人6例，儿童1例；差异多聚酶链反应未显示表皮生长因子受体有基因水平的异常扩增。结论：表皮生长因子受体蛋白的过度表达存在于髓母细胞瘤，尤以成人为主，但其机制可能与基因的异常扩增无关。     

成人髓母细胞瘤的临床特点与治疗

目的研究成人髓母细胞瘤的临床特点及治疗措施。方法20例成人髓母细胞瘤，其中男性13例，女性7例，平均年龄26．6岁，平均病程5．5月。所有病人接受显微神经外科手术治疗，15例病人术后接受放疗，4例行术后化疗。结果肿瘤全切除15例，近全切除2例，部分切除3例，无手术死亡。术后复发6例，中枢神经系统种植转移2例，术后2年生存率90％，术后5年生存率75％。结论通过手术全切除肿瘤和术后全中枢轴放疗可使成人髓母细胞瘤患者得到较好的治疗效果。     

Medulloblastoma

Summary Fifty paraffin-embedded medulloblastomas (31 in children and 19 in adults) were reacted with a panel of ten antibodies to glial, neuronal, mesodermal and epithelial antigens. The tumours were divided according to their histological features into three groups: classic, desmoplastic and highly vascular. Reactivity for glial fibrillary acidic protein was observed in 20 cases. Forty tumours reacted with PGP9.5 (neuronal marker) in clusters of poorly differentiated cells, cell cords and some scattered cells. Cells forming rosettes were mostly negative except for slight central reactivity. Eight of the 40 tumours contained neurofilaments. In scattered cells somatic reactivity for vimentin was found in 14 tumours. Ten cases showed positivity for S-100 with a nuclear and perinuclear pattern. No difference in reactivity in relation with age was observed. Desmoplastic medulloblastomas showed less reactivity for glial and neural markers. It was concluded that medulloblastoma shows degrees of differentiation as evidenced by the expression of various proteins. Differentiation occurs along two lines: glial and/or neuronal. Most tumours also contain a component of poorly differentiated cells which may differentiate into one of these two lines or act as primarily stem cells.Supported in part by the Oxfordshire District Health Authority, the A. von Humboldt Foundation and the Bristol Brain Cancer Research Fund     

Medulloblastoma with lipidized cells versus lipomatous medulloblastoma

BACKGROUND: Lipomatous medulloblastoma is a recently identified clinicopathological entity, characterized by areas of lipomatous differentiation, manifestation in adults, and apparently by a favorable prognosis. MATERIAL AND METHODS: In our series of medulloblastomas of adults and children we have found lipidized cells within the tumor in 6 out of 78 cases of adults and in 8 out of 44 cases of children. In 3 adult cases and 3 children cases, lipidized cells were particularly numerous and clustered. RESULTS: Neuronal differentiation was found in 4/6 cases; no case showed GFAP-positive tumor cells. Lipidized cells were constantly immunopositive for vimentin and some of them also for KP-1 and CR3/43. The proliferation potential was evaluated by the immunohistochemical demonstration of MIB-1; MIB-1-labeling index (LI) ranged from 20.8% to 40.5%. No case survived longer than 7 years after diagnosis and postoperative radiotherapy. CONCLUSION: The present 6 cases of heavily lipidized medulloblastoma are not uniform as for age of occurrence, proliferation potential and survival. They do not share the clinical and pathologic features of "lipomatous medulloblastoma". Therefore, the finding of large numbers of lipidized cells in a medulloblastoma does not authorize to diagnose the tumor as "lipomatous medulloblastoma", for which a favorable clinical prognosis is foreseen.     

Diffusion-weighted imaging and pathological correlation in pediatric medulloblastomas����They are not always restricted!��

Introduction  

Some investigators have suggested that medulloblastomas can be distinguished from other cerebellar neoplasms by demonstrating “restricted diffusion” on the Apparent Diffusion Coefficient (ADC) map obtained from diffusion-weighted imaging (DWI) sequences on magnetic resonance imaging. Previous authors have postulated that this observed restricted diffusion is a reflection of very high cell density. There has been a tendency to assert that pediatric medulloblastoma uniformly demonstrates restricted diffusion on DWI. However, our clinical observation has been that there are pediatric medulloblastomas that exhibit normal or even increased diffusion on DWI. The current study was undertaken primarily to determine whether restricted diffusion is uniformly present in pediatric medulloblastoma and secondly to look for pathological features that might distinguish medulloblastomas with and without restricted diffusion.     

Genomic and transcriptomic analyses match medulloblastoma mouse models to their human counterparts

Medulloblastoma is a malignant embryonal brain tumor with highly variable outcome. In order to study the biology of this tumor and to perform preclinical treatment studies, a lot of effort has been put into the generation of appropriate mouse models. The usage of these models, however, has become debatable with the advances in human medulloblastoma subgrouping. This study brings together multiple relevant mouse models and matches genetic alterations and gene expression data of 140 murine tumors with 423 human medulloblastomas in a global way. Using AGDEX analysis and k-means clustering, we show that the Blbp-cre::Ctnnb1(ex3) ^Fl/+ Trp53 ^Fl/Fl mouse model fits well to human WNT medulloblastoma, and that, among various Myc- or Mycn-based mouse medulloblastomas, tumors in Glt1-tTA::TRE-MYCN/Luc mice proved to be most specific for human group 3 medulloblastoma. None of the analyzed models displayed a significant match to group 4 tumors. Intriguingly, mice with Ptch1 or Smo mutations selectively modeled SHH medulloblastomas of adulthood, although such mutations occur in all human age groups. We therefore suggest that the infantile or adult gene expression pattern of SHH MBs are not solely determined by specific mutations. This is supported by the observation that human medulloblastomas with PTCH1 mutations displayed more similarities to PTCH1 wild-type tumors of the same age group than to PTCH1-mutated tumors of the other age group. Together, we provide novel insights into previously unrecognized specificity of distinct models and suggest these findings as a solid basis to choose the appropriate model for preclinical studies on medulloblastoma.     

家族性髓母细胞瘤一例报告并文献复习

目的 报告家族性髓母细胞瘤1例并对文献进行回顾,探讨其可能病因.方法 该家族中共有4名患者,其中少年儿童3例,成人1例;男3例,女1例,有2名患者为同胞姐弟,表现为颅高压症状,均接受手术治疗.结果 4名患者病理证实髓母细胞瘤,其中1例于术后次日死亡,2例因肿瘤复发已死亡,1例现存活良好.结论 家族性髓母细胞瘤罕见,家族性髓母细胞瘤的发病可能与家族遗传易感性有关,但确切的发病机制及遗传学仍不明了,需进一步深入研究.     

Midline medulloblastoma versus astrocytoma: the position of the superior medullary velum as a sign for diagnosis

PURPOSE: We wish to describe the position of the superior medullary velum (SMV) in midline posterior fossa tumours as a sign in helping to distinguish between midline medulloblastoma and midline astrocytoma. MATERIAL AND METHODS: Sagittal T1-weighted MRI images of 21 consecutive patients with histologically documented posterior fossa midline astrocytomas (nine cases) and medulloblastomas (12 cases) were reviewed, with respect to the position of the velum medullare superius. RESULTS: In all medulloblastomas the SMV was superiorly dislocated; in eight astrocytomas it was anteriorly and/or inferiorly disclocated; only in one astrocytoma the SMV presented upward dislocation. CONCLUSION: In the differential diagnosis between medulloblastoma and astrocytoma the upward dislocation of the SMV is strongly suggestive of medulloblastoma.     

The use of the monoclonal antibody Ki-67 in determination of the growth fraction in pediatric brain tumors

Using the monoclonal antibody Ki-67, proliferating cells were demonstrated immunohistochemically in 16 tumors of the nervous system in children, and these findings compared with those in 44 adult tumors. The antibody, which reacts with a nuclear protein expressed during the G1, S, G2, and M phases of the cell cycle, was demonstrated in frozen (13 cases) or smear (3 cases) sections using the peroxidase-antiperoxidase method. The percentage of stained tumor cells in children was in general agreement with the histological grade, ranging from 0.2% in a schwannoma to 12.4% in a juvenile type of glioblastoma. In a medulloblastoma, the fraction of labeled nuclei was 10.2%. In malignant gliomas of children, the percentage of stained cells did not differ from that in adult tumors. However, some cases demonstrated an unusually higher number of positive cells associated with higher cellularity than did adult tumors; this is in agreement with the content of small immature tumor cells in many pediatric tumors. The use of Ki-67 staining could become an important additional criterion for predicting the biologic behavior of nervous system neoplasms in children.     

Neurotrophins and neuronal versus glial differentiation in medulloblastomas and other pediatric brain tumors

Medulloblastomas are highly malignant and poorly understood childhood neoplasms. To determine if neurotrophins might influence the phenotypic properties of medulloblastoma in a paracrine or autocrine manner, 51 pediatric brain tumors including 20 biopsy specimens of these primitive neuroectodermal tumors (PNETs) and 31 other pediatric brain tumors were studied. Immunohistochemistry was used with antibodies to nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and NT-3, their cognate high affinity receptors as well as to neuronal and glial markers. TrkA, TrkB, and TrkC were observed in 5 (25%), 8 (40%), and 17 (85%), respectively, of these medulloblastomas while NGF, BDNF, and NT-3 were observed in 6 (30%), 8 (40%), and 3 (15%), respectively, and antibodies to neurofilament (NF) and glial fibrillary acidic proteins (GFAP) stained 16 (80%) and 11 (55%), respectively. TrkA and NGF were not observed in the same biopsy samples, while TrkB and BDNF were co-distributed in 6 of the cases, all of which expressed NF proteins. TrkC and NT-3 were co-distributed in 3 of the medulloblastomas, and these areas overlapped with NF protein-positive tumor cells in all 3 cases. In contrast to medulloblastomas, TrkA and NGF co-distributed in other pediatric brain tumors, and both Trk receptors and their neurotrophins co-distributed with GFAP-positive tumor cells in 13 (42%) of the non-PNET pediatric brain tumors. The absence of medulloblastomas that contain NGF and TrkA is consistent with in vitro data demonstrating that NGF-mediated TrkA signaling induces apoptosis. Finally, this study also suggests that BDNF and NT-3 may act in a paracrine or autocrine manner through TrkB and TrkC receptors, respectively, to induce neuronal differentiation in medulloblastomas. Received: 2 October 1997 / Revised, accepted: 29 December 1997     

Primitive neuroectodermal tumors including the medulloblastoma: glial differentiation signaled by immunoreactivity for GFAP is restricted to the pure desmoplastic medulloblastoma ("arachnoidal sarcoma of the cerebellum")

Immunoreactivity of tumor cells for glial fibrillary acidic protein (GFAP) is usually regarded as sign of astrocytic histogenesis and/or differentiation. The present study aimed at a systematic evaluation of the significance of GFAP-containing cells in primitive neuroectodermal tumors (PNETs) with special reference to the controversial entity of desmoplastic medulloblastoma (so-called "circumscribed arachnoidal sarcoma of the cerebellum"). Fifty-three PNETs, including 17 pure desmoplastic medulloblastomas were investigated, using GFAP antisera and the peroxidase-antiperoxidase (PAP) technique. Seventy percent of the pure desmoplastic medulloblastomas showed GFAP immunoreactive cells, in 47% indistinguishable from adjacent nonreacting tumor cells. Most immunoreacting cells were found in the reticulin free islands, showing in 6 cases a gradual transition of immunoreacting cells from tumor cells to larger cells shaped like astrocytes. The classical medulloblastomas showed only larger immunoreacting cells which were interpreted as reactive astrocytes. Therefore, the so-called circumscribed arachnoidal cerebellar sarcoma or pure desmoplastic medulloblastoma merits a separate place in the group of PNETs as a tumor with frequent signs of astroglial differentiation; this interpretation appears to be clinically correlated by a difference in age incidence and prognosis of that special tumor-type in comparison with classical medulloblastoma.     

Sonic hedgehog-associated medulloblastoma arising from the cochlear nuclei of the brainstem

Medulloblastoma is a malignant brain tumor of childhood that comprises at least four molecularly distinct subgroups. We have previously described that cerebellar granule neuron precursors may give rise to the subgroup with a molecular fingerprint of Sonic hedgehog (Shh) signaling. Other recent data indicate that precursor cells within the dorsal brain stem may serve as cellular origins for Wnt-associated medulloblastomas. To see whether Shh-associated medulloblastomas are also able to develop in the dorsal brainstem, we analyzed two lines of transgenic mice with constitutive Shh signaling in hGFAP- and Math1-positive brainstem precursor populations, respectively. Our results show that in both of these lines, medulloblastomas arise from granule neuron precursors of the cochlear nuclei, a derivative of the auditory lower rhombic lip. This region is distinct from derivatives of precerebellar lower rhombic lip where medulloblastomas arise in mice with constitutive-active Wnt signaling. With respect to their histology and the expression of appropriate markers, Shh tumors from the murine cochlear nuclei perfectly resemble human Shh-associated medulloblastomas. Moreover, we find that in a series of 63 human desmoplastic medulloblastomas, 21 (33%) have a very close contact to the cochlear nuclei on MR imaging. In conclusion, we demonstrate that precursors of the murine rhombic lip, which either develop into cerebellar or into cochlear granule neurons, may give rise to Shh-associated medulloblastoma, and this has important implications for the cellular origin of human medulloblastomas.     

Contributions of immunohistochemistry to the problem of differentiation in medulloblastoma

The problem of differentiation of medulloblastoma is considered. In this regard 43 medulloblastomas, showing cells with glial or neuronal features by routine histologic methods, were studied. The investigation was carried out by means of the immunohistochemical demonstration of the glial fibrillary acidic protein (GFAP) and the neuron-specific enolase (NSE). In most cases, GFAP-positive cells are preexisting astrocytes; in two cases they correspond to the transitional cells of the subependymal layer. NSE was demonstrated in areas filled with cells with neuroblastic features. The relationship between medulloblastoma with neuron-differentiation and cerebellar neuroblastoma is discussed.