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Background

This is a rare and aggressive tumor of the brain that usually occurs in children or young adults. These tumors typicall occur in an infratentorial location, below the tentorium cerebelli in the brain. It can spread from the brain to the spine or to other parts of the body.

OUTLINE

Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/Other Diagnostic Testing  
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/Immunohistochemistry/Electron Microscopy  
Differential Diagnosis  
Prognosis and Treatment  
Commonly Used Terms  
Internet Links  


EPIDEMIOLOGY CHARACTERIZATION
INCIDENCE Rare
AGE RANGE-MEDIAN Childhood

 

DISEASE ASSOCIATIONS CHARACTERIZATION
MALIGNANT RHABDOID TUMOR  


Medulloblastoma associated with malignant rhabdoid tumor of the kidney: case report.

Watanabe K, Wakai S, Kumakura N, Kurosu A, Nagai M, Tsuchioka T, Fujiwara T.

Department of Neurosurgery, Dokkyo University School of Medicine.

Noshuyo Byori 1993;10(1):75-9 Abstract quote

The authors report a case of 6-month-old boy with cerebellar medulloblastoma associated with malignant rhabdoid tumor of the kidney, presenting with an abdominal mass, large head and projectile vomiting.

Following removal of the renal tumor, the mass arising from the superior vermis about 6 cm in diameter was removed by a combined right occipital transtentorial and suboccipital approach. The patient had been well for 3 months after surgery followed by chemotherapy but died eventually of tumor recurrence in the abdomen.

Reported cases of malignant rhabdoid tumor of the kidney associated with brain tumor are reviewed and its characteristics are discussed.

RUBINSTEIN-TAYBI SYNDROME  


Medulloblastoma in a child with Rubenstein-Taybi Syndrome: case report and review of the literature.

Taylor MD, Mainprize TG, Rutka JT, Becker L, Bayani J, Drake JM.

The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8 Canada.

Pediatr Neurosurg 2001 Nov;35(5):235-8 Abstract quote

Although medulloblastoma is usually sporadic, there are a number of uncommon predisposing germline mutation syndromes, including: Gorlin's Syndrome, Turcot's Syndrome and Li-Fraumeni Syndrome. Patients with Rubenstein-Taybi Syndrome secondary to mutation/deletion of the CBP gene on chromosome 16 are predisposed to a variety of developmental anomalies as well as cancer.

We report a child with Rubenstein-Taybi syndrome who developed a cerebellar medulloblastoma and review the literature on Rubenstein-Taybi Syndrome and pediatric medulloblastoma. As the product of the CBP gene functions in a variety of signaling pathways, we discuss the molecular implications of findings a medulloblastoma in a child with Rubenstein-Taybi Syndrome.

 

PATHOGENESIS CHARACTERIZATION
ANGIOGENESIS  


Angiogenic profile of childhood primitive neuroectodermal brain tumours/medulloblastomas.

Huber H, Eggert A, Janss AJ, Wiewrodt R, Zhao H, Sutton LN, Rorke LB, Phillips PC, Grotzer MA.

Division of Oncology, The Children's Hospital of Philadelphia, PA 19104, USA.

 

Eur J Cancer 2001 Nov;37(16):2064-72 Abstract quote

Primitive neuroectodermal brain tumours (PNET) including medulloblastomas (PNET/MB) are the most common malignant brain tumours of childhood. Similar to many other brain tumours, PNET/MB often show marked neovascularisation.

To determine which angiogenic factors contribute to PNET/MB angiogenesis, we examined the expression of eight angiogenic factors (vascular endothelial growth factors (VEGF, VEGF-B, VEGF-C), basic fibroblast growth factor (bFGF), angiopoetins (Ang-1, Ang-2), transforming growth factor (TGF-alpha), and platelet-derived endothelial growth factor (PDGF-A)) by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) in six PNET cell lines and 28 primary PNET/MB. Expression levels of angiogenic factors were compared with microvessel density, TrkC mRNA expression, clinical variables and survival outcomes.

Our results indicate that all PNET/MB tested produce a wide range of angiogenic factors that are, individually or together, likely to play a direct role in PNET/MB tumour growth. This suggests that anti-angiogenesis approaches targeting VEGF alone may be insufficient in PNET/MB.

CHROMOSOMAL ABNORMALITIES  


Comparative genomic hybridization detects an increased number of chromosomal alterations in large cell/anaplastic medulloblastomas.

Eberhart CG, Kratz JE, Schuster A, Goldthwaite P, Cohen KJ, Perlman EJ, Burger PC.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Brain Pathol 2002 Jan;12(1):36-44 Abstract quote

We correlate chromosomal changes in medulloblastomas with histologic subtype, reporting the analysis of 33 medulloblastoma specimens by comparative genomic hybridization, and a subset by fluorescence in situ hybridization.

Of the 33 tumors, 5 were desmoplastic/nodular, 10 were histologically classic, and 18 were large cell/anaplastic. Chromosomal gains and losses were more common in anaplastic medulloblastomas than in non-anaplastic ones.

We identified 4 medulloblastomas with c-myc amplification and 5 medulloblastomas with N-myc amplification; all 9 were of the large cell/anaplastic subtype. Additional regions with high level gains included 2q14-22, 3p23, 5p14-pter, 8q24, 9p22-23, 10p12-pter, 12q24, 12p11-12, 17p11-12, and Xp11. The majority of these high level gains occurred in anaplastic cases. We also found loss of chromosome 17p in 7 large cell/anaplastic cases but no nonanaplastic medulloblastomas. Finally, we detected a significantly increased overall number of chromosomal alterations in large cell/anaplastic medulloblastomas (6.8/case) compared to non-anaplastic ones (3.3/case).

These findings support an association between myc oncogene amplification, 17p loss, and large cell/anaplastic histology.


Genetic alterations in childhood medulloblastoma analyzed by comparative genomic hybridization.

Michiels EM, Weiss MM, Hoovers JM, Baak JP, Voute PA, Baas F, Hermsen MA.

Department of Pediatric Oncology, Emma Kinderziekenhuis/Academic Medical Center, Amsterdam, The Netherlands.


J Pediatr Hematol Oncol 2002 Mar-Apr;24(3):205-10 Abstract quote

Despite intensive therapy, the survival of children with medulloblastoma remains disappointing. Moreover, children who survive are affected by serious long-term sequelae of treatment that impair their quality of life.

In search of chromosomal aberrations indicative of sites involved in oncogenic transformation and in an attempt to find reliable prognostic markers, the authors analyzed 15 medulloblastomas by comparative genomic hybridization. All neoplasms showed chromosomal abnormalities. The most frequent losses were 17p (7/15 tumors), 8p and 11p (6/15), 10p, 1lq, 16q, and 20q (5/15), and 20p (4/15). Gains were recurrently found at 7q (10/15 tumors), 17q and 18q (9/15 tumors), 7p and 13q (7/15), 18p (6/15), and 1q, 4q, 6q. and 9p (5/15 tumors). Four tumors showed loss of 17p together with gain of 17q, suggesting an isochromosome 17q. High-level amplifications were seen at 1p34, 5p15, 13q34, and 18p11 (one tumor each), and at 2p15 in two tumors, one of which was proven to be N-Myc amplification.

The overall pattern of alterations found in this study confirms the findings of other studies and adds two novel regions with chromosomal gains, at 13q and 18q. Previous reports on the relation between 17q gain and survival could not be confirmed, whereas amplification of N-myc or L-myc seems to indicate poor clinical outcome.


Comprehensive molecular cytogenetic investigation of chromosomal abnormalities in human medulloblastoma cell lines and xenograft.

Aldosari N, Wiltshire RN, Dutra A, Schrock E, McLendon RE, Friedman HS, Bigner DD, Bigner SH.

Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.

Neuro-oncol 2002 Apr;4(2):75-85 Abstract quote

Cell lines and xenografts derived from medulloblastomas are useful tools to investigate the chromosomal changes in these tumors.

Here we used G-banding, fluorescence in situ hybridization (FISH), spectral karyotyping (SKY), and comparative genomic hybridization to study 4 medulloblastoma cell lines and 1 xenograft. Cell line D-425 Med had a relatively simple karyotype, with a terminal deletion of 10q and amplification of MYC in double-minutes (dmins). FISH demonstrated that an apparent isochromosome (17q) by routine karyotyping was actually an unbalanced translocation between 2 copies of chromosome 17. Cell line D-556 Med also had a simple near-diploid stemline with an unbalanced 1;13 translocation resulting in a gain of 1q, an isochromosome (17q), and dmins.

These findings were initially described using routine G-banded preparations, and FISH showed that the dmins were an amplification of MYC and the i(17q) was an isodicentric 17q chromosome. The other finding was confirmed by FISH, SKY, and comparative genomic hybridization. Cell lines D-721 Med and D-581 Med had complex karyotypic patterns that could be completely characterized only when FISH and SKY were used. Xenograft D-690 Med also had a complex pattern that FISH and SKY were helpful in completely elucidating. Interestingly, balanced reciprocal translocations were seen as well as complicated unbalanced translocations and marker chromosomes. Comparative genomic hybridization demonstrated only a deletion of 10q22-10q24, supporting the idea that despite the complexity of the chromosomal rearrangements, minimal alterations in the overall chromosomal content had occurred.

This study demonstrates that routine cytogenetic preparations are adequate to describe chromosomal abnormalities in occasional medulloblastoma samples, but a broader spectrum of molecular cytogenetic methods is required to completely analyze most of these tumor samples.

ONCOGENE  


Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease.

MacDonald TJ, Brown KM, LaFleur B, Peterson K, Lawlor C, Chen Y, Packer RJ, Cogen P, Stephan DA.

Center for Cancer and Transplantation Biology, Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC, USA.

Nat Genet 2001 Oct;29(2):143-52 Abstract quote

Little is known about the genetic regulation of medulloblastoma dissemination, but metastatic medulloblastoma is highly associated with poor outcome.

We obtained expression profiles of 23 primary medulloblastomas clinically designated as either metastatic (M+) or non-metastatic (M0) and identified 85 genes whose expression differed significantly between classes. Using a class prediction algorithm based on these genes and a leave-one-out approach, we assigned sample class to these tumors (M+ or M0) with 72% accuracy and to four additional independent tumors with 100% accuracy. We also assigned the metastatic medulloblastoma cell line Daoy to the metastatic class. Notably, platelet-derived growth factor receptor alpha (PDGFRA) and members of the downstream RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway are upregulated in M+ tumors. Immunohistochemical validation on an independent set of tumors shows significant overexpression of PDGFRA in M+ tumors compared to M0 tumors. Using in vitro assays, we show that platelet-derived growth factor alpha (PDGFA) enhances medulloblastoma migration and increases downstream MAP2K1 (MEK1), MAP2K2 (MEK2), MAPK1 (p42 MAPK) and MAPK3 (p44 MAPK) phosphorylation in a dose-dependent manner. Neutralizing antibodies to PDGFRA blocks MAP2K1, MAP2K2 and MAPK1/3 phosphorylation, whereas U0126, a highly specific inhibitor of MAP2K1 and MAP2K2, also blocks MAPK1/3. Both inhibit migration and prevent PDGFA-stimulated migration.

These results provide the first insight into the genetic regulation of medulloblastoma metastasis and are the first to suggest a role for PDGFRA and the RAS/MAPK signaling pathway in medulloblastoma metastasis. Inhibitors of PDGFRA and RAS proteins should therefore be considered for investigation as possible novel therapeutic strategies against medulloblastoma.


MYCC and MYCN oncogene amplification in medulloblastoma. A fluorescence in situ hybridization study on paraffin sections from the Children's Oncology Group.

Aldosari N, Bigner SH, Burger PC, Becker L, Kepner JL, Friedman HS, McLendon RE.

Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.

Arch Pathol Lab Med 2002 May;126(5):540-4 Abstract quote

CONTEXT: Brain tumors are the most common solid tumor in childhood, and medulloblastoma is the most common malignant brain tumor in this age group. Cytogenetic abnormalities that have been described in childhood medulloblastoma include loss of 17p, amplification of MYCC (c-myc), amplification of MYCN (N-myc), and isochromosome 17q. Data on these tumors indicate that the frequency of MYCC amplification is 5% to 10%. Fluorescence in situ hybridization is a powerful tool for investigating these features on archival material.

OBJECTIVES: To determine if intratumoral heterogeneity exists for MYCC and MYCN in medulloblastomas and if tumors with amplified MYCC or MYCN exhibit consistent histologic patterns.

DESIGN: In this fluorescence in situ hybridization study, we investigated the frequency and prognostic significance of MYCC and MYCN amplification in 77 medulloblastomas derived from the Children's Oncology Group.

RESULTS: MYCC amplification occurred in only 4 (5.2%) of 77 tumors. The 4 patients died of clinically aggressive neoplasms within 7 months of diagnosis. Similarly, 4 of 77 patients' tumors were found to exhibit MYCN amplification, but survival data are incomplete at present, therefore prognostic significance cannot be characterized.

CONCLUSIONS: These data establish the frequency of MYCC amplification in a large cohort of children with medulloblastoma and further suggest that MYCC amplification may be a marker of poor prognosis. Intratumoral heterogeneity was identified for these oncogenes in that 1 patient's tumor exhibited evidence of both MYCN and MYCC amplification, and this patient experienced a shortened survival time.

 

LABORATORY/RADIOLOGIC/
OTHER TESTS

CHARACTERIZATION
RADIOLOGIC  

Medulloblastoma with extensive calcification.

Prasad A, Madan VS, Buxi TB, Prasad ML.

Department of Neurosurgery, Sir Ganga Ram Hospital, New Delhi.

Neuroradiology 1991;33(5):447-8 Abstract quote

Calcification in cases of medulloblastoma has been described with varying frequency (10%-15.4%) on computed tomographic (CT) scan. Usually these calcifications are small in size and speckled.

The authors report a case of medulloblastoma with extensive calcification in the lateral hemisphere of the cerebellum in an 18-year-old boy.

 

GROSS APPEARANCE/
CLINICAL VARIANTS
CHARACTERIZATION
GENERAL  
VARIANTS  
ADULT  


Adult cerebellar medulloblastomas: the pathological, radiographic, and clinical disease spectrum.

Hubbard JL, Scheithauer BW, Kispert DB, Carpenter SM, Wick MR, Laws ER Jr.

Department of Neurosurgery, Mayo Clinic, Mayo Medical School, Rochester, Minnesota.


J Neurosurg 1989 Apr;70(4):536-44 Abstract quote

The records of 34 patients over 16 years of age with cerebellar medulloblastoma were retrospectively reviewed. All patients were treated by surgery, and all surviving patients were given radiation therapy.

The imaging characteristics of this rare entity were evaluated with regard to the tumor location in the cerebellum, and the prognostic effects of histological characteristics such as neuronal or glial differentiation and the presence of desmoplasia were investigated. Neither histological parameters nor tumor location (median, paramedian, or lateral cerebellar) affected patient survival. The desmoplastic variant was encountered in 38% of these adult medulloblastomas and occurred in all three cerebellar locations. The degree of surgical resection did not have a major effect on long-term survival; long-term survival was possible even in patients who had received only a biopsy.

The extent of initial radiation therapy was positively correlated with recurrence-free survival; full neuraxis irradiation was associated with a 13% incidence of delayed spinal metastases, whereas 75% of patients treated with irradiation of only the posterior fossa and/or the whole brain developed spinal deposits. A similar local recurrence rate (12.5%) was noted in both irradiation groups. Chemotherapy resulted in palliation in some patients with metastatic disease.


Cerebellar medulloblastomas in adults.

Tekkok IH, Suzer T, Ozgen T, Erbengi A.

Department of Neurosurgery, Hacettepe University School of Medicine, Ankara, Turkey.

Neurosurg Rev 1991;14(2):135-40 Abstract quote

A retrospective analysis of 32 patients older than 16 years of age treated at Neurosurgical Department of Hacettepe University within the last 30 years (1959-1988) for cerebellar medulloblastoma was considered. The clinical features, treatment modalities and outcome are discussed.

The survival rates for 5 and 10 years were 14% and 7% respectively. The results are compared with that of literature.


Medulloblastoma in late adults. Case report and critical review of the literature.

Salvati M, Cervoni L.

Department of Neurosurgery, Mediterranean Neurological Neuromed Institute IRCCS, Pozzilli, Isernia, Italy.

J Neurosurg Sci 2000 Dec;44(4):230-2; discussion 232-3 Abstract quote

BACKGROUND: Medulloblastoma in late adults (older than 65 years) is an exceptional occurrence; in fact only 8 cases are reported with complete clinical notes in the literature.

METHODS: The authors describe a case of medulloblastoma occurring in a 68-year-old man and analyzed cases reported in the literature.

RESULTS: The overall average age of the patients was 72.8 years (range 67-88 years), and the male prevalence of this tumour (70% of cases) seems to be unrelated to age. There is a lateral predominance in late adults (77.7% of cases). Seven patients underwent operation and subsequently these patients underwent a course of radiation therapy. Only two patient was treated with postoperative chemotherapy. Median survival for seven patients treated was 43.2 months (range 23-96 months).

CONCLUSIONS: It is interesting to note that: 1) histological analysis revealed a classic type medulloblastoma (88.8% of cases) similar to the children: 2) site of the tumor is lateral similar to the adults (77.7% of cases).

CONGENITAL  


Congenital cerebellar medulloblastoma.

Kim JH, Duncan C, Manuelidis EE.

Surg Neurol 1985 Jan;23(1):75-81 Abstract quote

Congenital cerebellar medulloblastoma is extremely rare. Reported here is a female infant who presented her first abnormal clinical manifestations on the sixth day of life and who was subsequently found to have medulloblastoma at operation.

Electron microscopy revealed glial filaments and short cytoplasmic projections in some neoplastic cells and the presence of junctional complexes between neoplastic cells with and without glial filaments, which suggests the astrocytic differentiation of the tumor.

Including our own case, there have been only 21 reported cases of congenital cerebellar medulloblastoma. A strong female preponderance and some familial occurrence are noted in congenital cerebellar medulloblastoma.

DIRECT INVASION  


Direct spread of medulloblastoma in adjacent extrameningeal tissues.

Jamjoom ZB, el Saghir NS, Sadiq S, Malabarey T, al-Khudairy NN.

Division of Neurosurgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia.

Acta Neurochir (Wien) 1989;97(3-4):171-6 Abstract quote

A case of a medulloblastoma with extensive intradural dissemination and direct tumour spread from a lumbosacral deposit in the pelvis is presented. A review of the literature revealed six similar cases. In all of them direct invasion of contiguous structures occurred at sites of secondary deposits.

Two predilection site were identified: 1. The anterior fossa with tumour invasion of the paranasal air sinuses. 2. The lumbosacral spine with tumour extension into the retroperitoneum and pelvis. Generally, this unusual mode of tumour spread indicates a final stage in the course of the disease. The possible pathogenesis is discussed.

 

HISTOLOGICAL TYPES CHARACTERIZATION
GENERAL  


Cytologic findings of medulloblastoma in crush smears.

Kumar PV, Hosseinzadeh M, Bedayat GR.

Department of Pathology, Shiraz Medical School, Shiraz University of Medical Sciences, Iran.

Acta Cytol 2001 Jul-Aug;45(4):542-6 Abstract quote

OBJECTIVE: To describe the cytologic findings of medulloblastomas on intraoperative crush preparation smears and compare them with the findings of other central nervous system tumors.

STUDY DESIGN: The intraoperative crush preparation smears of 19 cases of medulloblastoma were studied (6 undifferentiated type and 13 well-differentiated type). The findings were compared with those of a control group consisting of 31 astrocytomas, 22 ependymomas, 18 oligodendrogliomas, 27 meningiomas, 17 schwannomas, 17 pituitary adenomas, 3 lymphomas, 5 hemangioblastomas, 5 chordomas and 11 metastatic tumors.

RESULTS: Medulloblastomas revealed clusters and isolated small, round malignant cells with hyperchromatic nuclei and indistinct cytoplasm. Typical Homer-Wright rosettes were seen in the well-differentiated type, but they were poorly formed in the undifferentiated type. Tumor cannibalism, target inclusions, cytoplasmic vacuoles and prominent multiple nucleoli were noticed frequently in the undifferentiated type. The control group (metastatic tumors and high grade astrocytomas) rarely showed tumor cannibalism or multiple nucleoli.

CONCLUSION: Smears of the undifferentiated type of medulloblastomas frequently revealed tumor cannibalism, cytoplasmic vacuoles, target inclusions and prominent multiple nucleoli. These findings have been rarely reported. The prognosis of the undifferentiated type of medulloblastoma was poor.


Histopathologic grading of medulloblastomas: a Pediatric Oncology Group study.

Eberhart CG, Kepner JL, Goldthwaite PT, Kun LE, Duffner PK, Friedman HS, Strother DR, Burger PC.

Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.

Cancer 2002 Jan 15;94(2):552-60 Abstract quote

BACKGROUND: Medulloblastomas are small cell embryonal tumors of the cerebellum found predominantly in children, only slightly more than half of whom survive. Predicting favorable outcome has been difficult, and improved stratification clearly is required to avoid both undertreatment and overtreatment. Patients currently are staged clinically, but no pathologic staging system is in use. Two rare subtypes at extreme ends of the histologic spectrum, i.e., medulloblastomas with extensive nodularity and large cell/anaplastic medulloblastomas, are associated with better and worse clinical outcomes, respectively. However, there is little data about correlations between histologic features and clinical outcome for most patients with medulloblastomas that fall between these histologic extremes of nodularity and anaplasia. Therefore, the authors evaluated the clinical effects of increasing anaplasia and nodularity in a large group of children with medulloblastomas, hypothesizing that increasing nodularity would predict better clinical outcomes and that increasing anaplasia would presage less favorable results.

METHODS: Medulloblastomas from 330 Pediatric Oncology Group patients were evaluated histologically with respect to extent of nodularity, presence of desmoplasia, grade of anaplasia, and extent of anaplasia. Pathologic and clinical data were then compared using Kaplan-Meier and log-rank analyses.

RESULTS: Increasing grade of anaplasia and extent of anaplasia were associated strongly with progressively worse clinical outcomes (P < 0.0001 for both). Significant anaplasia (moderate or severe) was identified in 24% of medulloblastoma specimens. Neither increasing degrees of nodularity nor desmoplasia were associated significantly with longer survival.

CONCLUSIONS: Moderate anaplasia and severe anaplasia were associated with aggressive clinical behavior in patients with medulloblastomas and were detected in a significant number of specimens (24%). Pathologic grading of medulloblastomas with respect to anaplasia may be of clinical utility.

VARIANTS  
LIPOMEDULLOBLASTOMA  


Lipomatous medulloblastoma in adults. A distinct clinicopathological entity.

Soylemezoglu F, Soffer D, Onol B, Schwechheimer K, Kleihues P.

Institute of Neuropathology, Department of Pathology, University Hospital, Zurich, Switzerland.

Am J Surg Pathol 1996 Apr;20(4):413-8 Abstract quote

We report on three patients who presented with a cerebellar medulloblastoma at age 48, 53, and 59 years.

Histopathology showed typical features of medulloblastoma, in one case with marked neuronal differentiation. In addition, all neoplasms contained focal accumulations of mature fat cells. Immunoreactivity of adipocytes for S-100 protein, neuron-specific enolase, synaptophysin, microtubule-associated protein-2, and glial fibrillary acidic protein and the lack of immunoreactivity to type IV collagen suggest lipomatous differentiation of neoplastic primitive neuroectodermal cells rather than an admixture of mesenchymal elements. Mitotic activity was low and the growth faction, as determined by the MIB-1 labeling index, was less than 5%. All patients are alive with a recurrence-free interval ranging from 3.5 to 12 years.

These three patients and five similar previously reported cases all fit into the concept of the lipomatous medulloblastoma as a new clinicopathological entity characterized by (a) typical features of a cerebellar medulloblastoma with advanced neuronal differentiation, (b) areas of lipomatous differentiation, (c) low proliferative potential, (d) manifestation in adults (mean age, 50 years), and (e) apparent favorable clinical prognosis.

Lipomedulloblastoma in a child: a controversial entity.

Sharma MC, Agarwal M, Suri A, Gaikwad S, Mukhopadhyay P, Sarkar C.

Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.

Hum Pathol 2002 May;33(5):564-9 Abstract quote

Lipomedulloblastoma is regarded as a distinct entity that occurs exclusively in adults and has a low proliferative potential and a favorable outcome.

We describe a rare case of lipomedulloblastoma in a 6-year-old female child showing a high labeling index that needs documentation. The various hypotheses of adiposal change are discussed.

MEDULLOMYOBLASTOMA  


Medullomyoblastoma. A case report.

Lata M, Mahapatra AK, Sarkar C, Roy S.

Indian J Cancer 1989 Dec;26(4):240-6 Abstract quote

A case of medullomyoblastoma was studied by light and electron microscopy and by immunohistochemistry. It showed glial and neuronal differentiation in the medulloblastoma areas and rhabdomyoblastic differentiation in the intervening areas


Medullomyoblastoma: case report.

Cheema ZF, Cannon TC, Leech R, Brennan J, Adesina A, Brumback RA.

Department of Neurology, University of Oklahoma, Oklahoma City, Oklahoma, USA

J Child Neurol 2001 Aug;16(8):598-9 Abstract quote

This 7-year-old boy presented with a 2-week history of headache, nausea, vomiting, anorexia, lethargy, and unsteadiness of gait. Brain magnetic resonance imaging (MRI) revealed a cystic mass within the vermis of the cerebellum.

A suboccipital craniectomy was performed to remove a tumor that contained primitive neuroectodermal cells with florid skeletal muscle differentiation. Immunohistochemical studies and electron microscopy confirmed the presence of both a primitive neuroectodermal component and rhabdomyoblastic differentiation, consistent with the diagnosis of medullomyoblastoma.

This exceedingly rare tumor of the cerebellar vermis of children is characterized by two components: primitive neuroectodermal tumor cells and skeletal muscle. Although the histogenesis remains uncertain, advances in immunohistochemistry and electron microscopy suggest the origin of this tumor from a multipotential stem cell precursor.

 

SPECIAL STAINS/IMMUNOPEROXIDASE/
OTHER
CHARACTERIZATION
SPECIAL STAINS  
IMMUNOPEROXIDASE  


Apoptosis, neuronal maturation, and neurotrophin expression within medulloblastoma nodules.

Eberhart CG, Kaufman WE, Tihan T, Burger PC.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

J Neuropathol Exp Neurol 2001 May;60(5):462-9 Abstract quote

Nodular/desmoplastic medulloblastomas are a well-established histopathological subtype containing reticulin-free nodules or "pale islands' that are comprised of cells with round "neurocytic" nuclei and abundant cytoplasm. Significant neuronal maturation occurs within nodules.

We used immunohistochemistry to evaluate neuronal differentiation in the nodules of 6 of these tumors. The neuronal markers NeuN, synaptophysin, and MAP-2 were identified in the "pale islands" of all 6 nodular medulloblastomas examined, and high and medium molecular weight nonphosphorylated neurofilaments were detected in 2 of the 6 cases. We also observed collections of apoptotic cells within nodules. Given the known role of neurotrophin signaling in neuronal maturation and apoptosis, we analyzed immunohistochemically the distribution of neurotrophin receptors TrkA and TrkC and their primary ligands NGF and NT3 in 14 nodular medulloblastomas. TrkA and TrkC were detected in 13 and 10 cases, respectively, and were predominantly localized within nodules. NGF and NT3 were distributed diffusely with some nodular accentuation. The localized expression of Trk receptors within nodules of desmoplastic medulloblastomas suggests neurotrophin signaling is involved in the apoptosis and neuronal differentiation in medulloblastomas. We also examined expression of p53 and BCL-2 in these tumors; both were prominent in internodular regions but only weakly expressed within nodules. Trk receptors, p53, and BCL-2 are all expressed during development of the normal cerebellum. Interestingly, the immunohistochemical expression profile of these proteins in the differentiating nodules of medulloblastomas is in many ways similar to their expression in the developing cerebellum.

Thus similar signaling pathways may be operational in cerebellar development and medulloblastoma tumor differentiation.

 

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
MALIGNANT RHABDOID TUMOR  


Congenital disseminated malignant rhabdoid tumor and cerebellar tumor mimicking medulloblastoma in monozygotic twins: pathologic and molecular diagnosis.

Fernandez C, Bouvier C, Sevenet N, Liprandi A, Coze C, Lena G, Figarella-Branger D.

Service d'Anatomie Pathologique et de Neuropathologie, CHU Timone, 264 rue Saint-Pierre, 13385 Marseille cedex 05, France.

Am J Surg Pathol 2002 Feb;26(2):266-70 Abstract quote

Malignant rhabdoid tumors are highly aggressive childhood tumors. Recently, all of the malignant rhabdoid tumors, whatever their location, have been related to the inactivation of the hSNF5/INI1 gene. A subset of cerebral tumors, associated with malignant rhabdoid tumors or isolated ones arising in siblings, showed similar molecular alterations.

We report for the first time in monozygotic twins a congenital disseminated malignant rhabdoid tumor in one twin and a cerebellar tumor mimicking a medulloblastoma in the other. Molecular analysis revealed similar alterations for both tumors: a deletion of exon 7 of the hSNF5/INI1 gene in one allele, and a point mutation in the same exon in the other, suggesting a common genetic pathway. Analysis of constitutional DNA revealed a germline mutation.

These findings are in favor of a common etiology for rhabdoid tumor and a subset of brain tumors developing in infancy.

 

PROGNOSIS AND TREATMENT CHARACTERIZATION
PROGNOSTIC FACTORS  
GENERAL  


Medulloblastoma: a clinicopathological study of 42 cases.

Ojeda VJ, Armstrong BK, Cullity GJ, Jacobsen PF, Lee MA, Papadimitriou JM, Shepherd JM, Stokes BA, Thomas GW, Kakulas BA.

Med J Aust 1985 Jul 22;143(2):60-2 Abstract quote

Clinicopathological data have been collected for 42 patients with cerebellar medulloblastoma diagnosed and treated in Western Australia between the years 1961 and 1984.

Thirty-one patients were male and 12 were over 14 years of age. In 31 patients the neoplasms were localized to the midline, while in 10 they were placed laterally in the cerebellar hemispheres. The remaining patient had a diffusely spreading neoplasm in the meninges of the posterior fossa. Thirty-nine underwent surgical treatment followed by postoperative radiotherapy. Three patients died in the early postoperative period.

Twenty-four patients survived for one year or longer, 15 for two or more years, 10 for five years, and five survived longer than 10 years. The survival proportions estimated by the life-table method were 66% at one year, 48% at two years and 32% at 5 and 10 years. In one patient who survived for 23 years a meningioma developed, possibly due to radiotherapy.


Duration of symptoms prior to diagnosis is related inversely to presenting disease stage in children with medulloblastoma.

Halperin EC, Watson DM, George SL.

Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.

Cancer 2001 Apr 15;91(8):1444-50 Abstract quote

BACKGROUND: The authors tested the hypothesis that children with a longer duration of symptoms prior to diagnosis of medulloblastoma have more advanced disease. In addition, they evaluated whether there are correlations between gender, duration of presenting symptoms, and disease stage.

METHODS: The study population consisted of 122 patients with medulloblastoma who were evaluated between 1974 and 1999. The data abstracted from each chart included the date of diagnosis, date of birth, gender, race, presenting symptoms, duration of symptoms in weeks, and disease stage.

RESULTS: There were 70 males (57%) and 52 females (43%); 105 Caucasians (86%), 16 non-Caucasians (13%), and 1 patient of unknown race. Eighteen percent of the patients were age < or = 3 years, 59% were ages 4-16 years, and 23% were age > or = 17 years. The presenting stage was determined in 108 patients. Thirty-eight patients (35%) had high stage disease (T1-T4 M1-M4), and 70 patients (65%) had low stage disease (T1-T4 M0). The most common presenting symptoms were emesis (68%), headache (66%), nausea (40%), and ataxia (40%). The median symptom durations for patients ages 0-3 years were 4 weeks and 8 weeks for both those ages 4-16 years and those age > or = 17 years, respectively (P > 0.11). The median symptom duration for males (8 weeks) was longer than for females (5 weeks; P = 0.08). Patients with low stage disease had a median duration of symptoms (8 weeks) that was significantly greater compared with patients with high stage disease (4 weeks; P = 0.01). Relating patient age to disease stage, 47% of patients ages 0-3 years had high stage disease; 36% of patients ages 4-16 years had high stage disease; and 24% of patients age > or = 17 years had high stage disease (P = 0.20). Relating disease stage to gender, 40% of males had high stage disease compared with 28% of females (P = 0.20). Of the factors age, gender, race, and duration of symptoms, only the later was correlated significantly with disease stage at the time of presentation in both univariate and multivariate analyses.

CONCLUSIONS: Contrary to expectations, the duration of presenting symptoms was correlated inversely with disease state at the time of presentation. This finding has implications for lawsuits alleging that a "delay in diagnosis" leads to more advanced disease. There is weak evidence (P = 0.08) that males have a longer duration of symptoms than females. This may be related to gender-associated behavior expectations.


Survival and recurrence factors in adult medulloblastoma: the M.D. Anderson Cancer Center experience from 1978 to 1998.

Kunschner LJ, Kuttesch J, Hess K, Yung WK.

Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.

Neuro-oncol 2001 Jul;3(3):167-73 Abstract quote

Medulloblastoma is a rare adult primary brain tumor for which limited retrospective studies are available to elucidate natural history or to guide therapy. A retrospective chart and imaging review of adult patients (aged >18 years) with medulloblastoma was performed to identify survival and prognostic factors.

Fifty-seven patients were evaluated at the University of Texas M.D. Anderson Cancer Center from 1978-1998. Statistical analysis of prognostic factors and overall survival was performed for a subgroup of 28 patients who were followed exclusively at our institution from the time of diagnosis until death or last follow-up. These 28 patients had an overall survival of 91% at 3 years and 84% at 5 years, whereas median survival was not reached after a median follow-up of 168 weeks (range, 9-602 weeks). Progression-free survival for all patients was 68% at 3 years and 62% at 5 years, and was not statistically different between poor- and standard-risk patients. Univariate analysis of clinical features, such as age, sex, extent of local disease, extent of resection, and use of adjuvant chemotherapy, did not identify any prognostic variables for survival among the 28 patients. Patterns of recurrence revealed that the posterior fossa was the most common site (56%), followed by bone marrow (25%). Adult medulloblastoma appears to have a favorable prognosis after treatment with maximally surgically feasible resection followed by craniospinal irradiation.

Optimal treatment remains to be clarified, as both standard-risk and poor-risk patients have prolonged disease-free survival. The marked difference between survival and progression-free survival suggests that salvage therapy, usually with combination chemotherapy in this cohort of patients, is of benefit. More formal analysis of the survival benefit was not possible, however, because of the small number of patients treated at recurrence with any one therapeutic regimen.


Clinical and molecular stratification of disease risk in medulloblastoma.

Gilbertson R, Wickramasinghe C, Hernan R, Balaji V, Hunt D, Jones-Wallace D, Crolla J, Perry R, Lunec J, Pearson A, Ellison D.

Dept. Developmental Neurobiology, St Jude Children's Research Hospital, Room 2006G, 332 North Lauderdale St, Memphis, TN 38105, USA.

Br J Cancer 2001 Sep 1;85(5):705-12 Abstract quote

The accurate assessment of disease risk among children with medulloblastoma remains a major challenge to the field of paediatric neuro-oncology. In the current study we investigated the capacity of molecular abnormalities to increase the accuracy of disease risk stratification above that afforded by clinical staging alone. 41 primary medulloblastoma tumour samples were analysed for ErbB2 receptor expression using immunohistochemistry, and for aberrations of chromosome 17 and amplification of the MYC oncogene using fluorescence in situ hybridisation.

The ErbB2 receptor and deletion of 17p were detected in 80% and 49% of tumours, respectively. 17p loss occurred either in isolation (20%), or in association with gain of 17q (29%), compatible with an isochromosome of 17q. Amplification of MYC was detected in only 2 tumours. Significant prognostic factors included, 'metastatic disease' (P = 0.0006), 'sub-total tumour resection' (P = 0.007), 'high ErbB2 receptor expression' (P = 0.003) and 'isolated 17p loss' (P = 0.003). Combined analysis of clinical and molecular factors enabled greater resolution of disease risk than clinical factors alone, identifying a sub-population of patients with particularly favourable disease outcome.

These data support the hypothesis that a combination of clinical and molecular factors may afford a more reliable means of assigning disease risk in patients with medulloblastoma, thereby providing a more accurate basis for targeting therapy in children with this disease.


Prediction of central nervous system embryonal tumour outcome based on gene expression.

Pomeroy SL, Tamayo P, Gaasenbeek M, Sturla LM, Angelo M, McLaughlin ME, Kim JY, Goumnerova LC, Black PM, Lau C, Allen JC, Zagzag D, Olson JM, Curran T, Wetmore C, Biegel JA, Poggio T, Mukherjee S, Rifkin R, Califano A, Stolovitzky G, Louis DN, Mesirov JP, Lander ES, Golub TR.

Division of Neuroscience, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

Nature 2002 Jan 24;415(6870):436-42 Abstract quote

Embryonal tumours of the central nervous system (CNS) represent a heterogeneous group of tumours about which little is known biologically, and whose diagnosis, on the basis of morphologic appearance alone, is controversial. Medulloblastomas, for example, are the most common malignant brain tumour of childhood, but their pathogenesis is unknown, their relationship to other embryonal CNS tumours is debated, and patients' response to therapy is difficult to predict.

We approached these problems by developing a classification system based on DNA microarray gene expression data derived from 99 patient samples. Here we demonstrate that medulloblastomas are molecularly distinct from other brain tumours including primitive neuroectodermal tumours (PNETs), atypical teratoid/rhabdoid tumours (AT/RTs) and malignant gliomas. Previously unrecognized evidence supporting the derivation of medulloblastomas from cerebellar granule cells through activation of the Sonic Hedgehog (SHH) pathway was also revealed.

We show further that the clinical outcome of children with medulloblastomas is highly predictable on the basis of the gene expression profiles of their tumours at diagnosis.


Survival of children under 3 years old with medulloblastoma: a study from the Mexican Cooperative Group for Childhood Malignancies (AMOHP).

Rivera-Luna R, Lopez E, Rivera-Marquez H, Rivera-Ortegon F, Altamirano-Alvarez E, Mercado G, Covarrubias G, Rueda-Franco F, Marhx-Bracho A, Gutierrez P.

Department of Oncology, Instituto Nacional de Pediatria (INP), Insurgentes Sur 3700-C, Mexico, D.F. Mexico 04530,

Childs Nerv Syst 2002 Feb;18(1):38-42 Abstract quote

BACKGROUND: The prognosis of medulloblastoma in children under 3 years of age is poor.

METHODS: A retrospective analysis was performed to evaluate children under 3 years of age with medulloblastoma. Overall survival (OS) and progression-free survival (PFS) were assessed in children with and without metastasis.

RESULTS: A total of 534 children were diagnosed with medulloblastoma during the study period, 49 (9.1%) of whom were under 3 years of age and were evaluated. Their ages ranged from 5 to 35 months with a mean of 18.5 months. In 39 (79.6%) of these patients the tumors were staged as T3M0 or under, while 10 (20.4%) had metastasis at diagnosis. The OS was 38% and PFS 37% in the whole series, while PFS was 32% in those with metastasis and 40% in those without ( P=0.78). For those who received radiotherapy the PFS was 62%, and in those not treated with radiotherapy PFS was nil ( P=0.0001). When the children were divided into those who received surgical treatment plus chemotherapy and those who received surgery plus radiotherapy plus chemotherapy, the PFS was nil and 66%, respectively ( P=0.00001).

CONCLUSION: Because of the high morbidity of radiotherapy in children under 3 years old, surgery continues to be the basis of improved prognosis, followed by chemotherapy.


Value of surveillance imaging in the management of medulloblastoma.

Yalcin B, Buyukpamukcu M, Akalan N, Cila A, Kutluk MT, Akyuz C.

Department of Pediatric Oncology, Hacettepe University Institute of Oncology, Ankara, Turkey.

 

Med Pediatr Oncol 2002 Feb;38(2):91-7 Abstract quote

BACKGROUND: To investigate the value of surveillance scanning for the detection of recurrences in medulloblastoma.

PROCEDURE: The charts of 95 patients with medulloblastoma were retrospectively reviewed. Information regarding the patient characteristics, treatment modalities, dates, types and results of CT and MRI studies, the frequency with which recurrences were identified on surveillance images, changes in patient management, outcome of the patients following recurrences, and survival data were analyzed.

RESULTS: Thirty-one patients had a recurrence of tumor in the central nervous system; none experienced extraneural relapses. Of all recurrences, 21 were symptomatic and 10 were discovered by surveillance scans asymptomatically. None of the patients with a recurrence survived. For all 95 patients, 5-year overall and event-free survival rates were 47.1 and 49.8%, respectively. In patients with symptomatic and asymptomatic recurrences, the mean time to recurrence since initial diagnosis, the mean duration of survival post-recurrence, and the mean duration of overall follow-up were 19.2 and 26.1 months, 3.6 and 8.0 months, and 22.8 and 34.1 months, respectively. For 95 patients, 468 surveillance and 38 symptomatic images were reviewed as 313 CTs and 193 MRIs. Rate of diagnosis of recurrence per surveillance image was 2.1% (10/468).

CONCLUSIONS: In our study, surveillance scanning brought no survival advantage since it detected a minority of recurrences. Longer survival achieved by early detection of recurrences might be a reflection of lead-time and length biases. Surveillance procedures will gain more importance as new effective therapeutic options are developed for recurrent medulloblastoma.

DNA CONTENT  


DNA content and other prognostic features in childhood medulloblastoma. Proposal of a scoring system.

Schofield DE, Yunis EJ, Geyer JR, Albright AL, Berger MS, Taylor SR.

Department of Pathology, Children's Hospital, Boston, MA 02115.

Cancer 1992 Mar 1;69(5):1307-14 Abstract quote

The authors reviewed clinical features, surgical extent of resection, histologic parameters, and DNA content in 55 children with medulloblastomas and found that complete or near total resection, absence of tumor dissemination, tumor DNA aneuploidy, and low proliferative index correlated with a favorable clinical outcome.

A scoring system was developed based upon these features to identify patients who, in the future, may benefit from more aggressive or novel therapeutic regimens. Patient age and sex and adjuvant chemotherapy did not significantly correlate with long-term survival.

The data also suggest that tumors that have been designated as cerebellar neuroblastomas may be a distinct group of posterior fossa tumors, which may have a better prognosis.

GRADING  


Histopathologic grading of medulloblastomas: a Pediatric Oncology Group study.

Eberhart CG, Kepner JL, Goldthwaite PT, Kun LE, Duffner PK, Friedman HS, Strother DR, Burger PC.

Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.

Cancer 2002 Jan 15;94(2):552-60 Abstract quote

BACKGROUND: Medulloblastomas are small cell embryonal tumors of the cerebellum found predominantly in children, only slightly more than half of whom survive. Predicting favorable outcome has been difficult, and improved stratification clearly is required to avoid both undertreatment and overtreatment. Patients currently are staged clinically, but no pathologic staging system is in use. Two rare subtypes at extreme ends of the histologic spectrum, i.e., medulloblastomas with extensive nodularity and large cell/anaplastic medulloblastomas, are associated with better and worse clinical outcomes, respectively. However, there is little data about correlations between histologic features and clinical outcome for most patients with medulloblastomas that fall between these histologic extremes of nodularity and anaplasia. Therefore, the authors evaluated the clinical effects of increasing anaplasia and nodularity in a large group of children with medulloblastomas, hypothesizing that increasing nodularity would predict better clinical outcomes and that increasing anaplasia would presage less favorable results.

METHODS: Medulloblastomas from 330 Pediatric Oncology Group patients were evaluated histologically with respect to extent of nodularity, presence of desmoplasia, grade of anaplasia, and extent of anaplasia. Pathologic and clinical data were then compared using Kaplan-Meier and log-rank analyses.

RESULTS: Increasing grade of anaplasia and extent of anaplasia were associated strongly with progressively worse clinical outcomes (P < 0.0001 for both). Significant anaplasia (moderate or severe) was identified in 24% of medulloblastoma specimens. Neither increasing degrees of nodularity nor desmoplasia were associated significantly with longer survival.

CONCLUSIONS: Moderate anaplasia and severe anaplasia were associated with aggressive clinical behavior in patients with medulloblastomas and were detected in a significant number of specimens (24%). Pathologic grading of medulloblastomas with respect to anaplasia may be of clinical utility.

MDM2  


MDM2 overexpression is associated with short survival in adults with medulloblastoma.

Giordana MT, Duo D, Gasverde S, Trevisan E, Boghi A, Morra I, Pradotto L, Mauro A, Chio A.

Department of Neuroscience, University of Turin, 10126 Turin, Italy.

Neuro-oncol 2002 Apr;4(2):115-22 Abstract quote

In adult medulloblastoma, postoperative radiotherapy is significantly effective in prolonging time to recurrence and survival time; however, the response of individual cases to radiotherapy, that is the total survival, is different. Apoptosis is an important cellular response to radiation. It can be hypothesized that the individual radiosensitivity of medulloblastomas depends on the individual capability to undergo apoptosis. p53 protein is involved in the apoptotic response to ionizing radiation; loss of function of p53 can be the consequence not only of TP53 mutations, but also of amplification and/or overexpression of the MDM2 gene.

We have analyzed cerebellar medulloblastomas from 51 adults (>16 years of age) for MDM2 gene amplification (by differential polymerase chain reaction assay), TP53 gene mutation (by polymerase chain reaction single-strand conformation polymorphism analysis of exons 5-8), and immunohistochemical expression of p53 (clone DO1) and MDM2 (clone IF2). The results have been evaluated in relation to age, tumor location, classic or desmoplastic type, MIB-1 labeling index, and total survival. No tumor had MDM2 amplification. Ten tumors had MDM2 positive tumor cells. One case had a mutated TP53 gene; 16/51 cases had intense p53 immunostaining. Only 2 MDM2 protein-positive tumors were also p53-positive.

Both subgroups of MDM2 - and p53-positive tumors had a significantly shorter postoperative survival. In conclusion, the overexpression of MDM2 protein and the accumulation of wild-type p53 are unrelated in adult medulloblastoma; they may result in a reduced apoptotic response after radiotherapy and contribute to a shortened survival. Also, MDM2 amplification and TP53 gene mutation are rare events in medulloblastomas of adults.

MYC AMPLIFICATION  


MYCC and MYCN oncogene amplification in medulloblastoma. A fluorescence in situ hybridization study on paraffin sections from the Children's Oncology Group.

Aldosari N, Bigner SH, Burger PC, Becker L, Kepner JL, Friedman HS, McLendon RE.

Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA

Arch Pathol Lab Med 2002 May;126(5):540-4 Abstract quote

CONTEXT: Brain tumors are the most common solid tumor in childhood, and medulloblastoma is the most common malignant brain tumor in this age group. Cytogenetic abnormalities that have been described in childhood medulloblastoma include loss of 17p, amplification of MYCC (c-myc), amplification of MYCN (N-myc), and isochromosome 17q. Data on these tumors indicate that the frequency of MYCC amplification is 5% to 10%. Fluorescence in situ hybridization is a powerful tool for investigating these features on archival material.

OBJECTIVES: To determine if intratumoral heterogeneity exists for MYCC and MYCN in medulloblastomas and if tumors with amplified MYCC or MYCN exhibit consistent histologic patterns.

DESIGN: In this fluorescence in situ hybridization study, we investigated the frequency and prognostic significance of MYCC and MYCN amplification in 77 medulloblastomas derived from the Children's Oncology Group.

RESULTS: MYCC amplification occurred in only 4 (5.2%) of 77 tumors. The 4 patients died of clinically aggressive neoplasms within 7 months of diagnosis. Similarly, 4 of 77 patients' tumors were found to exhibit MYCN amplification, but survival data are incomplete at present, therefore prognostic significance cannot be characterized.

CONCLUSIONS: These data establish the frequency of MYCC amplification in a large cohort of children with medulloblastoma and further suggest that MYCC amplification may be a marker of poor prognosis. Intratumoral heterogeneity was identified for these oncogenes in that 1 patient's tumor exhibited evidence of both MYCN and MYCC amplification, and this patient experienced a shortened survival time.

SECOND MALIGNANCIES  


Prognostic factors and secondary malignancies in childhood medulloblastoma.

Stavrou T, Bromley C M, Nicholson H S, Byrne J, Packer R J, Goldstein A M, Reaman G H.

Department of Hematology-Oncology, Children's National Medical Center, Washington, DC, USA.

J Pediatr Hematol Oncol 2001 Oct;23(7):431-6 Abstract quote

PURPOSE: Little is known of the outcome of long-term survivors of childhood medulloblastoma, one of the most common pediatric malignancies. To determine the potential for secondary malignancies, a retrospective outcome evaluation in 88 consecutive cases of childhood medulloblastoma was performed.

PATIENTS AND METHODS: The records of all patients with childhood medulloblastoma diagnosed at Children's National Medical Center in Washington, DC from 1969 through 1997 were reviewed.

RESULTS: The median follow-up time was 92 months (range 6-257 months). Overall survival was 59% at 5 years and 52% at 10 years. Univariate analysis showed that age at diagnosis, extent of surgical resection, presence of metastatic disease (M stage), ventriculoperitoneal shunt placement within 30 days from diagnosis, posterior fossa radiation therapy dose, and adjuvant chemotherapy significantly affected survival. Although based on small numbers, the risk of second neoplasms was significantly increased in this cohort. Multiple basal cell carcinomas developed in the areas of radiation therapy in two patients; these patients also had nevoid basal cell carcinoma syndrome (NBCCS) diagnosed. One other patient died of glioblastoma multiforme 8 years after treatment of medulloblastoma. A meningioma developed in another patient 10 years after radiation therapy.

CONCLUSION: As survival of medulloblastoma patients improves, increased surveillance regarding secondary malignancies is required, especially because radiation-induced tumors may occur many years after treatment. These two cases of NBCCS also illustrate the importance of considering the concomitant diagnosis of NBCCS in young patients with medulloblastoma. In those patients, alternative therapy should be considered to minimize radiation therapy-related sequelae.

TREATMENT  
CHEMOTHERAPY  


Adult medulloblastoma: multiagent chemotherapy.

Greenberg HS, Chamberlain MC, Glantz MJ, Wang S.

Department of Neurology, University of Michigan, Ann Arbor 48109, USA.

 

Neuro-oncol 2001 Jan;3(1):29-34 Abstract quote

In this study, the records of 17 adult patients with medulloblastoma treated with craniospinal radiation and 1 of 2 multiagent chemotherapy protocols were reviewed for progression-free survival, overall survival, and toxicity, and the patients were compared with each other and with similarly treated children and adults.

Records of patients treated at 3 institutions were reviewed. Seventeen medulloblastoma patients (11 female, 6 male) with a median age of 23 years (range, 18-47 years) were treated with surgery, craniospinal radiation (CSRT) plus local boost, and 1 of 2 adjuvant chemotherapy regimens. All tumors were infratentorial (10 in 4th ventricle and 7 in left or right hemisphere). Ten patients presented with hydrocephalus, and 7 of them were shunted. Eight patients had gross total resection, 7 had subtotal resection (>50% removed), and 2 had partial resection (<50% removed). Postoperatively, 3 patients had positive cytology and 3 had positive spinal MRI. Five patients were classified as good risk and 12 were classified as poor risk (Chang staging system). Ten patients were treated with the "Packer protocol," consisting of CSRT plus weekly vincristine followed by 8 cycles of cisplatin, lomustine, and vincristine.

Seven patients were treated with the Pediatric Oncology Group (POG) protocol, consisting of alternating courses of cisplatin/etoposide and cyclophosphamide/vincristine, followed by CSRT. Eight of 17 patients relapsed, with all 8 relapsing at the primary site. Other relapse sites included the leptomeninges (5), bone (1), and brain (1). The estimated median relapse-free survival (Kaplan-Meier) for all patients was 48 months (95% confidence interval, >26 months to infinity). Median relapse-free survival for patients on the Packer protocol was 26 months, and for those on the POG regimen was 48 months (P = 0.410). Five of 10 on the Packer protocol were relapse-free, while 4 of 7 were relapse-free on the POG regimen. Two patients relapsed during chemotherapy and 6 relapsed after completing all therapy at 18, 18, 26, 30, 40, and 48 months.

The estimated median survival of all patients was 56 months (95% confidence interval, 27 to infinity) with 11 patients alive; for the Packer protocol, median survival was 36 months, and for the POG protocol, it was 57 months (P = 0.058). The hazard ratio was 0 (95% confidence interval, 0 to infinity). Toxicity during the Packer protocol was moderately severe, with only 1 of 10 patients able to complete all therapy. Two patients had severe abdominal pain during CSRT + vincristine, and 5 had peripheral neuropathy during vincristine therapy. Hearing loss (>20 dB) occurred in 7, neutropenia (<500 microl) in 6, thrombocytopenia (<50,000 microl) in 6, nephrotoxicity (>25% decrease by creatinine clearance) in 2, and decreased pulmonary function (diffusing capacity for carbon monoxide decrease >40%) in 1. On the POG protocol, only 1 patient had persistent nausea and vomiting, 2 had peripheral neuropathy, and 3 had hearing deficit (>20 dB) or tinnitus. The POG and Packer protocols did not have a statistically significant difference in relapse-free or overall survival because of the small sample size. The POG protocol seemed to have less nonhematologic toxicity.

Adults on the Packer protocol appeared to have shorter median survival and greater toxicity than did children. To know whether adding adjuvant chemotherapy to craniospinal radiation in adult therapy increases relapse-free and overall survival, we must await the results of a larger randomized controlled clinical trial.

RADIATION  


Intensity-modulated radiation therapy for pediatric medulloblastoma: early report on the reduction of ototoxicity.

Huang E, Teh BS, Strother DR, Davis QG, Chiu JK, Lu HH, Carpenter LS, Mai WY, Chintagumpala MM, South M, Grant WH 3rd, Butler EB, Woo SY.

Department of Radiology/Section of Radiation Oncology, Baylor College of Medicine, Houston, TX, USA.

Int J Radiat Oncol Biol Phys 2002 Mar 1;52(3):599-605 Abstract quote

PURPOSE: The combination of cisplatin chemotherapy and radiation therapy for the treatment of medulloblastoma has been shown to cause significant ototoxicity, impairing a child's cognitive function and quality of life. Our purpose is to determine whether the new conformal technique of intensity-modulated radiation therapy (IMRT) can achieve lower rates of hearing loss by decreasing the radiation dose delivered to the cochlea and eighth cranial nerve (auditory apparatus).

PATIENTS AND METHODS: Twenty-six pediatric patients treated for medulloblastoma were retrospectively divided into two groups that received either conventional radiotherapy (Conventional-RT Group) or IMRT (IMRT Group). One hundred thirteen pure-tone audiograms were evaluated retrospectively, and hearing function was graded on a scale of 0 to 4 according to the Pediatric Oncology Group's toxicity criteria. Statistical analysis comparing the rates of ototoxicity was performed using Fisher's exact test with two-tailed analysis.

RESULTS: When compared to conventional radiotherapy, IMRT delivered 68% of the radiation dose to the auditory apparatus (mean dose: 36.7 vs. 54.2 Gy). Audiometric evaluation showed that mean decibel hearing thresholds of the IMRT Group were lower at every frequency compared to those of the Conventional-RT Group, despite having higher cumulative doses of cisplatin. The overall incidence of ototoxicity was lower in the IMRT Group. Thirteen percent of the IMRT Group had Grade 3 or 4 hearing loss, compared to 64% of the Conventional-RT Group (p < 0.014).

CONCLUSION: The conformal technique of IMRT delivered much lower doses of radiation to the auditory apparatus, while still delivering full doses to the desired target volume. Our findings suggest that, despite higher doses of cisplatin, and despite radiotherapy before cisplatin therapy, treatment with IMRT can achieve a lower rate of hearing loss.

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Commonly Used Terms

Primitive Neuroectodermal Tumor


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