Differentiation in medulloblastomas and other primitive neuroectodermal tumours

Fifty-four cases of primitive neuroectodermal tumour (PNET) including 47 medulloblastomas, were examined for evidence of neuronal and glial differentiation, using antibodies to neuron-specific enolase (NSE), neurofilament protein (NF), and glial fibrillary acidic protein (GFAP). In 30 of the cases, antibodies to vimentin, alphafetoprotein, cytokeratin, epithelial membrane antigen and lymphoid markers were also used. Most of the 47 medulloblastomas in the group were NSE positive but NF negative; about half were GFAP positive and three of them were positive for both neuronal markers and for GFAP. Vimentin was demonstrated in four cases and was not always co-expressed with GFAP. Medulloblastomas were negative for all the other markers. Supratentorial PNETs were sometimes positive with neuronal markers but were GFAP negative. The cell specificity of these markers and the interpretation of immunocytochemical findings are discussed in relation to differentiation potential in primitive neuroectodermal tumours.     

Cerebellar medulloblastomas: A study of 35 cases with particular reference to cellular differentiation

A series of 35 cerebellar medulloblastomas was studied using light microscopy and immunohistochemistry for localization of glial fibrillary acidic protein, an antigen specific for neuroglia. Most medulloblastomas occurred in children less than 15 years of age (77.1%), especially in the first decade of life (65.7%), with the peak incidence (40.0%) between 6 and 10 years. The rest were found in adults beyond 15 years of age (22.9%). The male to female ratio was 4:3. Ependymal differentiation was observed in 100% of medulloblastomas, astrocytic differentiation in 88.6%, oligodendroglial differentiation in 34.3%, glioblastomatous differentiation in 8.9%, and neuronal differentiation in 8.9%. These data suggest that medulloblastoma is a primitive (stem cell) neuroepithelial neoplasm with the capacity of differentiating along both neuroglial and neuronal directions. Excessive mucin production was encountered in one medulloblastoma. Leptomeningeal invasion occurred in 34.3% of medulloblastomas and endothelial hyperplasia in 28.6%. One medulloblastoma (2.9%) spread postoperatively to several bones.     

Prognostic importance of DNA ploidy in medulloblastoma of childhood

The deoxyribonucleic acid (DNA) content of 53 medulloblastomas was analyzed by means of flow cytometry and compared with the clinical and histological findings in the host patients. Analysis of DNA showed that about half of the tumors were diploid and the other half were aneuploid. More diploid tumors were found among patients of a young age, but the difference was without statistical significance. Cellular differentiation of the tumor did not correlate with DNA ploidy. No correlation was found between Chang's T staging system and the DNA ploidy, whereas the M staging correlated with the ploidy; diploid medulloblastomas had a greater tendency to metastasize than aneuploid medulloblastomas (p = 0.0003). Four-year survival was compared with the extent of resection and DNA ploidy. The patients with total resection and aneuploid medulloblastoma had a better prognosis than those with subtotal resection and diploid tumor (p = 0.001). There was only one survivor among eight patients with subtotally resected diploid medulloblastomas, while all of the seven patients with totally resected aneuploid medulloblastomas survived. Comparison of the G0/G1 phase fraction and S phase fraction in the surviving group and the deceased group offered no significant information.     

Analysis of various factors related to the prognosis of medulloblastoma

Thirty-three patients with medulloblastoma were treated in our department by surgical resection of tumor and radio-chemotherapy, and obtained 40.1% of 5 year survival. The present study analyzed the various factors related to the prognosis from clinical and pathological points of view in our series. Good factors were extensive resection of tumor and completement of whole CNS radiationtherapy. In contrast, poor factors were the presence of subarachnoid dissemination of tumor and identification of differentiated cells in tumor tissue histologically. The protection and treatment of subarachnoid dissemination was difficult with any kind of therapy. With surgical specimens obtained from 26 patients, glial fibrillary acidic protein (GFAP) and neuron specific enolase (NSE) were stained immunohistochemically. Two cases out of 12 with GFAP and/or NSE positive cells are alive and their mean survival time is 27 months. On the other hand, eight cases out of 14 without GFAP nor NSE positive cells are alive and their mean survival time is 44 months.     

Large cell/anaplastic medulloblastomas and medullomyoblastomas: clinicopathological and genetic features.

OBJECT: Medulloblastoma is the most common malignant central nervous system neoplasm found in children. A distinct variant designated large cell/anaplastic (LC/A) medulloblastoma is characterized by frequent dissemination of cerebrospinal fluid (CSF) at presentation and a more aggressive clinical course. The authors report on their examination of the clinicopathological and genetic features of seven such cases encountered at their institution. METHODS: Eighty cases of medulloblastomas were reviewed and seven (8.8%) of these were believed to fit the histological and immunohistochemical criteria for LC/A medulloblastoma. In three cases (43%) either desmoplastic or classic medulloblastoma was the underlying subtype, and in two cases (28%) the LC/A tumor was found within the setting of medullomyoblastoma. Fluorescence in situ hybridization was used in six of the seven cases to characterize the presence of isochromosome 17q, deletion of chromosome 22q (a deletion characteristically found in atypical teratoid/rhabdoid tumors), and c-myc amplification. The patients' clinical histories revealed CSF dissemination in all cases and lymph node metastasis in one case. Isochromosome 17q was found in five (83%) of six cases. Evidence of chromosomal gains indicated aneuploidy in three tumors (50%), and amplification of c-myc was found in three tumors (50%). No 22q deletions were encountered. CONCLUSIONS: A high percentage of LC/A medulloblastomas arise within a background of typical medulloblastomas or medullomyoblastomas. As is the case in conventional medulloblastomas, the presence of 17q is a common early tumorigenic event; however, in a significant percentage of specimens there is also evidence of aneuploidy and/or amplification of c-myc. These findings indicate that LC/A morphological characteristics reflect a more advanced tumor stage than that found in pure medulloblastomas or in typical medullomyoblastomas.     

Neuron-specific enolase and neurofilament protein as markers of differentiation in medulloblastoma

Immunocytochemical localization of neuron-specific enolase was performed attempting evaluation for neuronal cell differentiation in medulloblastoma. Twenty-seven cases of human medulloblastomas were stained with anti-neuron-specific enolase and antineurofilament protein serum using the peroxidase-antiperoxidase technique. All medulloblastomas showed neuron-specific enolase immunoreaction but only few had neurofilament protein-positive cells. These results suggest that a practically universal tendency towards neuronal cell differentiation occurs in medulloblastomas and that synthesis of neuron-specific enolase takes place before sufficient amounts of neurofilament protein are produced to become immunocytochemically detectable.     

Medulloblastoma: clinical presentation and management. Experience at the hospital for sick children, toronto, 1950-1980

The authors review the cases of 144 children with medulloblastoma treated between 1950 and 1980. Duration of time between onset of symptoms and initial treatment was less than 1 1/2 months in 51% of cases, and less than 3 months in 76%. The tumor was located in the cerebellar vermis in 93% of patients. Brainstem infiltration was noted in 32%. Classical medulloblastomas comprised 82% of the total number reviewed, and desmoplastic medulloblastomas 15%. The majority of desmoplastic medulloblastomas were found in the midline of the cerebellum and in patients under 10 years of age. The prognosis for patients with desmoplastic medulloblastomas was worse than that for children with classical medulloblastomas. Spontaneous hemorrhage associated with primary or recurrent medulloblastoma occurred in 5.6% of the patients. Supratentorial metastases were found in 14.6% of cases, spinal cord metastases in 12.5%, and systemic metastases in 9%. The overall 5-year survival rate was 47%, and the 10-year survival rate 42%. Extent of surgical excision proved to be a statistically significant prognostic factor. Two patients developed recurrence after the "period of risk" as defined by Collins' rule. Delayed complications of radiotherapy were found to be substantial. Intelligence quotient (IQ) testing on 16 survivors revealed verbal IQ, performance IQ, and full-scale IQ to be within the normal range in 11, seven, and nine cases, respectively. Two were retarded on all scores.     

Cerebellar medulloblastoma in a 73-year-old woman

A case of a 73-year-old woman with cerebellar medulloblastoma is described. The patient presented with the classical symptoms and signs of a medulloblastoma, and radiological findings were also consistent with this entity. Nevertheless, because of the patient's advanced age, the possibilities of metastatic tumor involving the cerebellum or a primary cerebellar lymphoma were considered before operation. Pathological examination of the operative specimen showed a classical medulloblastoma with occasional areas of early neuroblastic differentiation. Immunoperoxidase strains for neurofilaments were of help in confirming the neurogenic origin of the neoplastic cells. Although medulloblastomas in adults are not rare, onset after the age of 50 is exceptional, with only two cases on record in patients 65 or older. The present patient seems to be the oldest individual with a cerebellar medulloblastoma thus far reported.     

Medulloblastoma during pregnancy: Hormone-mediated association? Report of 2 cases

ObjectiveTo report two rare cases of medulloblastoma in pregnant patients and a review of the literature.Material and methodsReport of patients diagnosed with medulloblastoma during their pregnancies, who were treated with surgery and adjuvant therapy. We also reviewed other cases reported in the literature and the association made with hormonal receptors.ResultsBrain tumors in coincidence with pregnancy are unusual, and the incidence of medulloblastoma in pregnancy is still rarer. We found 8 cases of medulloblastomas diagnosed during pregnancy. Reports suggest that hormonal changes and increases in the levels of growth factors and angiogenic factors during pregnancy influence the rate of growth of brain tumors (not only medulloblastomas but also meningiomas or glial tumors).ConclusionsThe uniqueness of these cases is their rarity. The symptoms are usually masked by the symptoms of pregnancy. At present, there is still little evidence regarding the pathogenesis and treatment of medulloblastoma in pregnancy.     

Cerebellar liponeurocytoma. Case report and review of the literature

Cerebellar liponeurocytoma is a rare tumor of the posterior fossa that has many morphological similarities to medulloblastoma and neurocytoma. Recently the World Health Organization working group for classification of central nervous system neoplasms adopted the term "cerebellar liponeurocytoma" to provide a unified nomenclature for a tumor variously labeled in the literature as lipomatous medulloblastoma, lipidized medulloblastoma, medullocytoma. neurolipocytoma, lipomatous glioneurocytoma, and lipidized mature neuroectodermal tumor of the cerebellum. The rarity of this tumor and paucity of pertinent information regarding its biological potential and natural history have resulted in the application of various treatment modalities. It is suggested in the available literature that these lesions have a much more favorable prognosis than typical medulloblastomas, and that adjuvant therapy for liponeurocytoma need not be as extensive as that administered for medulloblastomas.     

大肠癌中DCC基因与蛋白激酶C的表达与预后

目的 探讨大肠癌组织中 DCC（Deleted in Colorectal Carcinoma）基因和蛋白激酶 C（Protein Ki-nase C）的表达与预后的关系。方法 采用免疫组化 En VisionTM法,对91例大肠癌组织中的DCC蛋白及PKC表达状态进行检测,并对其结果与各临床病理因素和生存期的关系进行相关的统计分析。结果 91例大肠癌中DCC阴性率为43.9％,PKC阴性率为51.6％,两者的表达水平呈正相关（相关系数r=0.041,P=0.005）。其中DCC的表达与肿瘤分化程度、术后有无脏器的转移、5年生存率有统计学相关性（P<0.05）;而PKC的表达仅与肿瘤组织分化程度有统计学相关性（P=0.019）。利用Cox回归模型进行单因素和多因素分析,发现只有分期与DCC表达水平可做为大肠癌独立的预后因素。结论　DCC基因的表达缺失可以作为判断大肠癌转移潜能及预后的独立指标。     

E, N-cadherins and beta-catenin expression in medulloblastoma and atypical teratoid/rhabdoid tumor

Cadherins are cell-surface glycoproteins that mediate Ca2+-dependent, homophilic cell-cell adhesion. The classical cadherins, E- and N-cadherins, bind to beta-catenin, the lining protein. Dysfunctional expression of these factors seems to be related to tumor invasion and metastasis. This study examined the relationship between changes in E- and N-cadherins, and catenin expression, and biological behavior in medulloblastomas and atypical teratoid/rhabdoid tumors. Specimens of 13 medulloblastomas and two atypical teratoma/rhabdoid tumors were collected and stained immunohistochemically to detect E- and N-cadherins, and beta-catenin. None of the medulloblastomas were immunoreactive for E-cadherin, but both atypical teratoma/rhabdoid tumors were immunoreactive for E-cadherin at the cell-cell borders where epithelial differentiation occurred. In contrast, N-cadherin and beta-catenin were present at the cell-cell borders in 12 of the 13 medulloblastomas and both atypical teratoma/rhabdoid tumors. Nuclear beta-catenin staining was not present in the medulloblastomas or atypical teratoma/rhabdoid tumors. There was no significant difference in the Ki-67 staining index between patients with medulloblastomas showing high and low immunoreactivity for N-cadherin and beta-catenin. Moreover, immunoreactivity for N-cadherin and beta-catenin increased with dissemination in the medulloblastomas. Low immunoreactivity in medulloblastomas tended to be associated with a better prognosis. These results suggest that expression of E-cadherin is useful for the differential diagnosis of atypical teratoma/rhabdoid tumor and medulloblastoma, and the expression of N-cadherin or beta-catenin may be related to the biological behavior of medulloblastomas.     

Cerebellar medulloblastomas in adults

Between 1981 and 1991, 11 adults over 16 years of age were treated for medulloblastoma at the authors' institutions. These patients were studied retrospectively. The patients were managed uniformly, and the treatment included extensive surgical resections and radiation therapy. Chemotherapy was used on only three patients with recurrence. Probable prognostic factors, including tumor location, extent of surgical resection, dose and extent of radiation therapy, and histological characteristies of the tumor such as neuronal or glial differentiation and desmoplasia were investigated. The classical form of medulloblastoma was present in seven cases while the desmoblastic subtype was found in four cases. All patients with the desmoplastic form had the tumor in cerebellar hemisphere. Gross total removal of the tumor was achieved in seven patients and subtotal excision in four patients. There was no surgical mortality in our series. The extent of surgical resection and location of the tumor had an important effect on longterm survival. The extent and dose of radiation therapy had a major effect on recurrence-free survival. Survival rates were best for patients receiving high-dose irradiation to the entire neuroaxis. Other factors such as age and sex had no major effect on prognosis.     

Molecular cytogenetic analysis of medulloblastomas and supratentorial primitive neuroectodermal tumors by using conventional banding, comparative genomic hybridization, and spectral karyotyping

OBJECT: Medulloblastomas and related primitive neuroectodermal tumors (PNETs) of the central nervous system are malignant, invasive embryonal tumors with predominantly neuronal differentiation that comprise 20% of pediatric brain tumors. Cytogenetic analysis has shown that alterations in chromosome 17, particularly the loss of 17p and the formation of isochromosome 17q, as well as the gain of chromosome 7 are the most common changes among this group of tumors. Comparative genomic hybridization (CGH) studies have largely confirmed these cytogenetic findings and have also identified novel regions of gain, loss, and amplification. The advent of more sophisticated multicolored fluorescence in situ hybridization (FISH) procedures such as spectral karyotyping (SKY) now permits complete recognition of all aberrations including extremely complex rearrangements. The authors report a retrospective analysis of 19 medulloblastoma and five PNET cases studied using combinations of classic banding analysis, FISH, CGH, and SKY to examine comprehensively the chromosomal aberrations present in this tumor group and to attempt to identify common structural rearrangement(s). METHODS: The CGH data demonstrate gains of chromosomes 17q and 7 in 60% of the tumors studied, which confirms data reported in the current literature. However, the authors have also combined the results of all three molecular cytogenetic assays (Giemsa banding, CGH, and SKY) to reveal the frequency of chromosomal rearrangement (gained, lost, or involved in structural rearrangement). CONCLUSIONS: The combined results indicate that chromosomes 7 and 17 are the most frequently rearranged chromosomes (10.1% and 8.9%, respectively, in all rearrangements detected). Furthermore, chromosomes 3 (7.8%), 14 (7%), 10 (6.7%), and 22 (6.5%) were also found to be frequently rearranged, followed by chromosomes 6 (6.5%), 13 (6.2%), and 18 (6.2%). Eight (33%) of 24 tumors exhibited high-level gains or gene amplification. Amplification of MYCN was identified in four tumors, whereas amplification of MYCC was identified in one tumor. One tumor exhibited a high-level gain of chromosome 9p. Additionally, desmoplastic medulloblastomas and large-cell medulloblastomas exhibited higher karyotype heterogeneity, amplification, and aneusomy than classic medulloblastomas.     

Familial medulloblastoma: case report of one family and review of the literature

OBJECTIVE AND IMPORTANCE: Medulloblastoma is the most common malignant brain tumor and the most common malignant solid tumor in children. Most medulloblastomas are sporadic, but rare familial forms have been described. To the best of our knowledge, only 10 case reports of familial medulloblastoma have been published. A variety of candidate genes have been suggested to be involved in familial medulloblastomas. However, the exact pathogenesis and genetics involved in familial medulloblastoma remain unknown. CLINICAL PRESENTATION: We describe the presentation of medulloblastoma in two siblings (one of each sex) and their great-uncle. The three cases differ with regard to age at onset and pathological subtype of medulloblastoma. INTERVENTION OR TECHNIQUE: Immunostaining of tissue blocks for gene products involved in medulloblastoma differed in the two siblings for beta-catenin and was similar with staining for gli. CONCLUSION: This article is only the second report in the literature to address the genetics of familial medulloblastoma in the absence of characterized conditions such as Li-Fraumeni's cancer syndrome and basal cell nevus, Rubinstein-Taybi's, and Turcot's syndromes. The discrepancy in beta-catenin staining in the two siblings suggests that the two tumors differentiated through divergent pathways. We briefly summarize all published cases of familial medulloblastoma and review the literature on the genes involved in medulloblastoma formation.     

Ultrastructure of capillary permeability in human brain tumor: disseminated and metastatic medulloblastoma

The ultrastructure of the tumor vessels of primary cerebellar, subarachnoidal disseminated and extraneural metastatic medulloblastomas was studied. They were compared with those in glial, nonglial and metastatic brain tumors which have been previously reported. Twelve surgical specimens were examined. Seven tumors were limited to the vermis, the floor of the fourth ventricle and the cerebellar hemispheres. Four gross nodule seedings were demonstrated in the cerebral and spinal subarachnoid space. One metastasis was demonstrated in the subclavicular lymph node. Ultrathin section of those tumors and replica specimens were studied under the transmission electron microscope. The tumor vessels of primary medulloblastoma and glial tumors had nonfenestrated capillaries and were morphologically similar to normal brain capillaries. On the other hand, the tumor vessels of disseminated and metastatic medulloblastoma, nonglial tumors, and metastatic brain tumors had fenestrated capillaries. These findings were anticipated because the arachnoid membrane and lymph nodes have fenestrated capillaries. The presence of fenestration suggests that the tumor vessels of disseminated and metastatic brain tumors resemble the blood vessels found in normal arachnoid membrane and lymph nodes.     

经典型与促纤维增生型髓母细胞瘤MRI表现

目的比较经典型和促纤维增生型髓母细胞瘤MRI表现及ADC值的差异。方法回顾性分析49例经手术病理证实为髓母细胞瘤患儿的影像学资料,观察其MRI表现,测量ADC值;根据2007年WHO标准对髓母细胞瘤进行病理分型,比较经典型和促纤维增生型髓母细胞瘤MRI表现和ADC值的差异。结果 49例中,经典型髓母细胞瘤41例,促纤维增生型髓母细胞瘤8例,常规MRI征象如肿瘤位置、T2信号、囊变、瘤周水肿及强化等差异无统计学意义(P均0.05);促纤维增生型髓母细胞瘤ADC值[(0.78±0.12)×10-3 mm2/s]低于经典型髓母细胞瘤[(0.88±0.10)×10-3 mm2/s;P0.05)。结论经典型和促纤维增生型髓母细胞瘤常规MRI表现无明显差异;促纤维增生型髓母细胞瘤的ADC值低于经典型。     

Congenital cerebellar medulloblastoma

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.     

Immunohistochemical study of p53 and Ki-67 overexpression in grade 3 superficial bladder tumor in relationship to tumor recurrence and prognosis]

PURPOSE: The major drawback of the current treatment for superficial bladder tumor is the high rate of recurrence. Especially, the tumor with grade 3 component has a tendency to recur and progress in stage. However, we have difficulty in predicting tumor recurrence and stage progression accurately by conventional clinicopathological factors. We evaluated the efficacy of p53 and Ki-67 overexpression as a predictor of recurrence or prognosis in patients with superficial bladder tumor of grade 3. MATERIALS AND METHODS: Samples were obtained from 41 patients with superficial transitional cell carcinoma of the bladder of grade 3 who were treated by transurethral resection (TUR). The immunohistochemical study was performed using the antibodies against the p53 protein and Ki-67 antigen on formalin-fixed, paraffinembedded tissue specimens from initial tumors. We evaluated the correlation between these results and several clinicopathological factors. RESULTS: The p53 index and the Ki-67 index in pTa, pT1a and pT1b tumors were 26.4 +/- 30.1%, 28.6 +/- 30.0%, and 34.6 +/- 32.6% (p53) and 20.5 +/- 22.5%, 20.0 +/- 29.3%, and 29.2 +/- 28.4% (Ki-67). There was no significant difference between the each index and tumor stage. Eighteen cases (43.9%) had intravesical recurrence. The p53 index of the initial tumor from the tumor free cases (n = 23), recurrent cases without stage progression (n = 12), and stage progression cases (n = 6) were 19.7 +/- 28.2%, 42.0 +/- 28.7%, and 42.5 +/- 32.0%. Between the recurrence-free cases and the recurrent cases without progression, the p53 index of the initial tumor had statistical significance (p < 0.05). The Ki-67 index was shown to be the same pattern as the p53 index, but there was not statistical significance. Four of patients with stage progression had tumor progression within six months. Three of the patients with tumors with stage progression died of the cancer. In multivariate analysis, tumor multiplicity (p = 0.01), BCG intravesical instillation (p = 0.04), p53 index (p = 0.01) and Ki-67 index (p = 0.02) were the positive risk factors for tumor recurrence, but only the p53 index was the positive risk factor for prognosis fo the patients (p = 0.03). CONCLUSION: These results suggest that the immunohistochemical study of p53 overexpression is a useful predictor for tumor recurrence and prognosis in patients with superficial bladder tumor with grade 3.     

Patterns of allelic loss of synchronous adenocarcinomas of the lung

Distinction of multiple primary lung carcinomas from intrapulmonary metastases using empiric clinical and histopathologic criteria can be difficult. Recent advances have provided several molecular markers that can be used for clonal analysis of separate tumor nodules and enhance tumor staging and subsequent treatment and prognosis. To address this issue, we performed a microdissection-based allelotyping of 20 cases of histologically similar, pathologic stage T4 adenocarcinomas (ADCs). Loss of heterozygosity (LOH) analysis included a panel of 15 polymorphic microsatellite markers located on 1p, 3p, 5q, 9p, 9q, 10q, 17p, and 22q. The tumor size, visceral pleural and angiolymphatic invasion, lymph node status, outcome, and survival were assessed. Allelotypes of 60 cases of solitary primary non-small cell lung carcinomas (NSCLC) (stages I-II) were used to define the percentage of discordant LOH patterns within solitary primary lung carcinoma that would discriminate between survivors and nonsurvivors. These criteria were used in the analysis of pathologic stage T4 ADC. Two groups of stage T4 cases were created: molecularly homogenous (< or = 40% discordances) (14 cases, 70%), and molecularly heterogenous (>40% discordances) (6 cases, 30%). Molecularly homogenous tumors were more frequently associated with visceral pleural invasion (92% vs. 8%) (P = 0.018). Allelotype did not correlate with age, gender, tumor size, tumor differentiation, lymph node status, angiolymphatic invasion, survival, or outcome. Our study showed that discordant and concordant genotypic profiles exist in morphologically similar synchronous ADC of the lung.