Diagnostic and prognostic value of glycosyltransferase mRNA in glioblastoma multiforme patients.

Glioblastoma multiforme (GBM) is the most common and aggressive primary human brain tumour in adults with an average survival of 11 months. The 2-year survival is less than 10%, and only a small proportion of patients are alive at 3 years. Despite improved treatment strategies and aggressive therapy, the prognosis of GBM has changed little in past decades. Thus, any test that can reliably and rapidly diagnose the tumour and predict patient survival could be a valuable tool. Herein we report the use of quantitative real-time polymerase chain reaction (PCR) to quantify five glycosyltransferase transcripts in gliomas. Our results indicate that measuring GM1 synthase (beta-1,3 galactosyltransferase) mRNA may provide a useful method for segregating GBMs from other types of gliomas. In these studies, 97% of gliomas (36/37 tumours) below a threshold value had a diagnosis of GBM compared with 49% (52/106 tumours) above the threshold. More importantly, the increased expression of GD3 synthase mRNA in combination with decreased GalNAcT message correlated with increased survival in 79 GBM patients (proportional hazards model controlling for age, P = 0.02). These data were further corroborated by a data analysis from one of our previous studies on gangliosides of 80 GBMs, in which increased amounts of GM3 and GD3 (which accumulate in the absence of GalNAcT) correlated with a longer survival (P < 0.01). Thus, measuring GalNAcT and GD3 transcripts may provide a rapid method to assess prognosis in GBM patients. In summary, the data indicate that measuring glycosyltransferase mRNA levels by real-time PCR may be clinically useful for determining both diagnosis and prognosis in GBM patients.

Pilomyxoid astrocytoma in a patient with neurofibromatosis.

Pilomyxoid astrocytoma (PMA), a recently described variant of low-grade astrocytoma is associated with a high rate of recurrence and a propensity for CSF seeding. While cases of PMA have been reported in infants and young children, there has been no report of PMA in patients with neurofibromatosis. The first reportable case of PMA occurring in a child with neurofibromatosis type 1 (NF1) is described. Following presentation with obstructive hydrocephalus, the patient underwent a partial resection of a third ventricular tumor. Histology confirmed the typical features of PMA. The patient demonstrated a partial response to chemotherapy. The authors review the literature on PMA and discuss the specific issues associated with this diagnosis in the context of a child with neurofibromatosis.

[Extraordinary findings after radiofrequency ablation]. / Aussergewöhnliche Befunde nach Radiofrequenzablation.

We report the successful treatment with Heparin and Phenprocoumon of a large, free-floating, right atrial thrombus that developed after radiofrequency ablation (RFA) of an accessory pathway in a 24 year old patient with Wolff-Parkinson-White (WPW) Syndrome. In addition, "T-wave memory", a relatively common phenomenon after RFA in WPW-Syndrome, is demonstrated.

Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease.

Somatic inactivation of PTEN occurs in different human tumors including glioblastoma, endometrial carcinoma and prostate carcinoma. Germline mutations in PTEN result in a range of phenotypic abnormalities that occur with variable penetrance, including neurological features such as macrocephaly, seizures, ataxia and Lhermitte-Duclos disease (also described as dysplastic gangliocytoma of the cerebellum). Homozygous deletion of Pten causes embryonic lethality in mice. To investigate function in the brain, we used Cre-loxP technology to selectively inactivate Pten in specific mouse neuronal populations. Loss of Pten resulted in progressive macrocephaly and seizures. Neurons lacking Pten expressed high levels of phosphorylated Akt and showed a progressive increase in soma size without evidence of abnormal proliferation. Cerebellar abnormalities closely resembled the histopathology of human Lhermitte-Duclos disease. These results indicate that Pten regulates neuronal size in vivo in a cell-autonomous manner and provide new insights into the etiology of Lhermitte-Duclos disease.

Extraventricular neurocytomas: pathologic features and clinical outcome.

Neurocytic neoplasms usually arise within the lateral ventricles, generally as circumscribed, slowly growing masses curable by total resection. Both subtotal resection and histologic atypia are associated with an increased risk of recurrence. In contrast, neurocytic neoplasms situated within brain parenchyma, so-called "extraventricular neurocytomas" (EVNs), are not as well characterized. The relationships between histologic features and extent of resection versus clinical behavior have not been defined. We evaluated pathologic features, clinical data, and neuroimaging of 35 examples. The tumors occurred in 18 males and 17 females, age 5-76 years (median 34 years). All tumors involved the cerebrum. On imaging, EVNs were solitary, variably contrast-enhancing, and often (57%) cystic. Tumor cells were arranged in sheets, clusters, ribbons, or rosettes, in association with fine neuropil dispersed in broad zones that separated cell aggregates. Ganglion cell differentiation was seen in 66%. All tumors showed strong synaptophysin immunoreactivity. Despite the lack of apparent astrocytes in hematoxylin and eosin-stained sections, focal glial fibrillary acidic protein reactivity was seen in 46%. Eleven EVNs were designated "atypical" based on the presence of necrosis, vascular proliferation, or elevated mitotic activity (> or = 3 mitoses/10 high power fields). Nineteen tumors were subtotally resected or biopsied, whereas 14 were totally resected grossly. Seventeen patients underwent radiotherapy (mean 55 Gy). In 30 cases with follow-up, 10 tumors recurred, 3 causing death at 6, 14, and 43 months. All 10 recurrences followed subtotal resection. No totally resected tumors recurred. Thus, the majority of EVNs are well differentiated and appear unlikely to recur after gross total resection. Subtotal resection, atypical histologic features, and high cell proliferation rates correlate with recurrence.

Small cell architecture--a histological equivalent of EGFR amplification in glioblastoma multiforme?

Although there is much written about the molecular definitions of "primary" glioblastomas (GBM), there is little known about the histological features of this predominant subtype. We hypothesized that the "small cell architecture" would represent a histological feature of most primary GBMs. This was tested by comparing the presence of the small cell phenotype with the presence or absence of amplification of the epidermal growth factor receptor (EGFR), a common event in primary GBMs. After a pilot study that found a correlation between this small cell phenotype and EGFR amplification, we selected 9 pure small cell GBMs (SCGBM) and 12 non-SCGBMs to be studied for EGFR amplification by fluorescence in situ hybridization (FISH). In this set of 21 cases, 8 of 9 SCGBMs and 5 of 12 non-SCGBMs were amplified for EGFR. We then correlated the EGFR status of 79 GBMs unselected for their histological features from a set that had been previously characterized in regard to EGFR amplification. Fourteen of 21 (67%) exclusively small cell neoplasms, 8 of 25 (32%) GBMs with both small cell and non-small cell areas, and 3 of 33 (9%) non-small cell GBMs were amplified for EGFR (p = 0.0004 with an exact test). We conclude that EGFR amplification is associated with a small cell phenotype in GBMs and that SCGBMs are an important component of "primary" GBMs.

Subacute diencephalic angioencephalopathy: biopsy diagnosis and radiological features of a rare entity.

Subacute diencephalic angioencephalopathy (SDAE) is a rare and fatal disease of unknown etiology that involves the thalami bilaterally. To date, there have been four cases reported, in which the diagnosis was established only after post mortem examination of the brain. We report two male patients, ages 69 and 41 years, who presented with progressive dementia and somnolence. Radiological evaluation revealed enhancing lesions involving both thalami. The differential diagnosis included a number of neoplastic, inflammatory and vascular processes. In both cases, pathological evaluation of biopsy specimens suggested the diagnosis of SDAE. Despite supportive care, the disease progressed rapidly and both patients died within weeks after initial presentation. The diagnosis was confirmed at autopsy in both cases. SDAE is a rare cause of bithalamic disease that can be mistaken for a neoplasm as well as a number of conditions that necessitate different treatment choices. The histopathological findings can establish the diagnosis when combined with radiological and clinical information. This report emphasizes the utility of stereotactic biopsy in early diagnosis of SDAE.

Losses of chromosomal arms 1p and 19q in the diagnosis of oligodendroglioma. A study of paraffin-embedded sections.

Comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), polymerase chain reaction-based microsatellite analysis, and p53 sequencing were performed in paraffin-embedded material from 18 oligodendrogliomas and histologically similar astrocytomas. The study was undertaken because of evidence that concurrent loss of both the 1p and 19q chromosome arms is a specific marker for oligodendrogliomas. Of the six lesions with a review diagnosis of oligodendroglioma, all had the predicted loss of 1p and 19q seen by CGH, FISH, and polymerase chain reaction. Other lesions, including some considered oligodendroglioma or mixed glioma by the submitting institution, did not. There were no p53 mutations in any of the six oligodendrogliomas, whereas 5 of the 10 remaining, successfully studied cases did have p53 mutations. The results suggest that CGH and FISH performed on current or archival tissue can aid in classification of infiltrating gliomas such as oligodendrogliomas and astrocytomas. The results of the p53 studies are consistent with findings of previous investigations that such mutations are less common in oligodendrogliomas than they are in astrocytomas.

Tau-associated neuropathology in ganglion cell tumours increases with patient age but appears unrelated to ApoE genotype.

Ganglion cell tumours, including gangliogliomas and gangliocytomas, are low grade neoplasms with a mature neuronal component. Ganglion cells within these lesions occasionally exhibit neurodegenerative changes including neurofibrillary tangles (NFT) similar to those in Alzheimer's disease. The frequency and spectrum of degenerative pathology in these lesions have not been defined, nor has their relation to patient age or factors such as apolipoprotein E (ApoE) genotype that predispose to Alzheimer's disease. We studied 72 ganglion cell tumours (61 gangliogliomas, 11 gangliocytomas) from patients 7 months to 72-years-old. Haematoxylin and eosin (H&E), silver stains (Hirano method) and immunohistochemistry for tau, alpha-synuclein and beta-amyloid were performed on formalin-fixed, paraffin-embedded tissue from surgical specimens. Tau-and silver-positive NFT and neuropil threads (NPT) were present in four of 26 ganglion cell tumours from patients over 30-years-old (ages 31, 38, 50, and 58 years). Neuronal granulovacuolar degeneration (GVD) was noted in five of 26 tumours from patients over 30-years-old (mean, 48 years). NFT, NPT, and GVD were not seen in ganglion cell tumours from patients under 30-years-old[0/46]. Cytoplasmic argentophilic bodies distinct from NFT were present in five of 26 tumours from patients over 30-years-old and in two of 46 under 30 years. Neither alpha-synuclein positive neuronal inclusions nor beta-amyloid immunoreactivity was noted in ganglion cell tumours from any age group. The distribution of ApoE genotypes was similar among those tumours that contained tau-associated neuropathology and those that did not. Neurodegenerative changes are uncommon in ganglion cell tumours, but increase in frequency with patient age. GVD, tau-positive NFT and NPT, and argentophilic bodies occur more often in ganglion cell tumours from patients over 30-yrs-old, but do not appear to be associated with a specific ApoE genotype.

Expression of multiple larger-sized transcripts for several genes in oligodendrogliomas: potential markers for glioma subtype.

Astrocytomas and oligodendrogliomas are two brain tumors that follow different clinical courses. Although many of these tumors can be identified based on standard histopathological criteria, a significant percentage present notable problems in diagnosis. To identify markers that might prove useful in distinguishing glioma subtypes, we prepared and analyzed cDNA libraries for differential expression of genes in an astrocytoma (grade II), an oligodendroglioma (grade II), and a meningioma (benign). The tumor libraries were compared by sequencing randomly selected clones and tabulating the expression frequency of each gene. In addition to identifying several genes previously reported or expected to be differentially expressed among these tumors, several potential new brain tumor markers were identified and confirmed by Northern blot analysis of a panel of brain tumors. A surprising result of this analysis was the observation that several larger-sized transcripts for various genes were predominantly expressed in the oligodendroglioma tumors, when compared to the other brain tumors or in non-tumor gray matter. These findings are consistent with different pre-mRNA splicing patterns observed between oligodendrogliomas and astrocytomas. In support of this hypothesis, our screen revealed significantly higher levels of two hnRNP A1 transcripts in oligodendrogliomas. hnRNP A1 is a component of the spliceosome whose expression levels affect splice site selection in vivo. The preferential expression of larger-sized transcripts for several genes in oligodendrogliomas may be useful for distinguishing astrocytic and oligodendroglial gliomas.

Tumoral calcinosis of the spine: a study of 21 cases.

STUDY DESIGN: A retrospective study was conducted to investigate 21 patients found during spinal surgery to have paraspinal masses of dystrophic calcification (tumoral calcinosis). OBJECTIVES: To determine the magnetic resonance imaging characteristics of this disorder, and to document the associated spinal pathology. SUMMARY OF BACKGROUND DATA: Tumoral calcinosis usually is associated with hereditary disorders of calcium metabolism or renal dialysis. It also occurs in degenerated tissues in the absence of systemic disorders. Characteristically, calcific masses in the appendicular skeleton are visible on plain radiographs. Tumoral calcinosis has only rarely been reported in the spine. Documented patients have had an obvious calcific mass, and almost always the disorder has existed in other locations as well. Careful histologic study of specimens removed during spinal surgery suggests that tumoral calcinosis is common in the spine and usually is secondary to preexisting pathology. METHODS: This study involved 21 patients with lesions of tumoral calcinosis identified by histopathologic analysis of specimens removed during spinal surgery. The magnetic resonance images and the plain radiographs of the patients were reviewed and correlated with their clinical histories. RESULTS: In all the patients, the lesion of tumoral calcinosis was associated with a mass lesion seen on magnetic resonance imaging. Calcific masses were not apparent on plain films. In no case was the mass diagnosed before surgery as tumoral calcinosis. The magnetic resonance imaging changes were variously misinterpreted as neoplasms, infections, extruded disc material, or cysts. The observed features of tumoral calcinosis were those of an extradural mass showing a heterogeneous mixed-signal lesion that was identical on T1- and T2-weighted images. Characteristically, gadolinium did not enhance the lesions. CONCLUSIONS: Awareness of tumoral calcinosis of the spine may prevent unwarranted diagnoses of a more serious lesion in patients with characteristic magnetic resonance imaging changes. Also, this awareness may prevent pathologists from interpreting lesional tissue as nondiagnostic when other diagnoses are suspected clinically. This process may be a manifestation of degenerative spinal disease that has become so dominant that the underlying processes are obscured.

Proton magnetic resonance spectroscopy of choroid plexus tumors in children.

A variety of lesions may present as intraventricular masses in children. We report quantitative proton magnetic resonance spectroscopy (MRS) of two intraventricular tumors of the choroid plexus: choroid plexus carcinoma (CPC) and choroid plexus papilloma (CPP). Both lesions were characterized by high levels of choline-containing compounds and a complete absence of creatine and the neuronal/axonal marker N-acetyl aspartate. The CPC showed higher levels of choline compared to the CPP, and it also had elevated lactate. These preliminary results, if confirmed in a larger cohort of patients, indicate that proton MRS may have a role in the presurgical diagnosis of choroid plexus tumors in children, which may also have important implications for therapy and prognosis.

Second surgery for recurrent pilocytic astrocytoma in children.

Pilocytic astrocytoma (PA) is the most common childhood brain tumor. In cases where the tumor progresses or recurs following primary surgical resection, the appropriate treatment is unclear. Options include chemotherapy, radiation therapy, surgical resection or a combination thereof. To analyze the utility of further surgery, we performed a retrospective, single-institution review of pediatric patients with recurrent PAs from 1990 to 1999 who were treated with a second surgical resection. Patients were excluded if they received adjuvant chemotherapy or radiation therapy. Twenty cases were identified. Tumor locations included: cerebral hemisphere (3), cerebellum (7), optic pathway/hypothalamus (5), thalamus (1) and brainstem (4). The indication for 4 surgeries included an enlarging tumor-associated cyst. At second surgery, 10 of 20 patients had a gross total resection (GTR), 2 a near total resection (NTR), and the remaining 8 patients had a subtotal resection (STR). No patients have died. Two of 10 tumors after GTR, 0 of 2 tumors after NTR, and 7 of 8 tumors after STR had second recurrence/progression at a mean of 15 months (range 4-33 months) following second surgery. The remaining 11 patients are recurrence/progression-free at a mean of 40.7 months (range 19-119 months). Surgery for tumors or midline structures rarely resulted in a GTR (1 of 10 cases). Surgery for tumors located in the cerebral hemispheres or cerebellum resulted in GTR or NTR in all cases and can result in long periods of progression-free survival without further adjuvant treatment.

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

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.

The frozen section yesterday and today: pediatric solid tumors--crucial issues.

This article is the offshoot of a Pediatric Oncology Group (POG) seminar presented at the Adams Mark Hotel, Denver, Colorado, Friday, May 21, 1999, titled "The Frozen Section in Pediatric Solid Tumors--Crucial Issues." There were eight presenters who spoke on a wide range of topics that included historical perspectives of the frozen section and discussion of the following systems: brain, renal, germ cell, bone, soft tissue, and lymph nodes. To complement these presentations, a pediatric surgeon explained his concern and philosophy regarding the use of frozen sections, and a lawyer tackled the issues and risks in rendering a frozen section diagnosis. We think that this review covers all the important aspects of the frozen section in our current practice of pediatric pathology.

Prognostic implications for gadolinium enhancement of the meninges in low-grade astrocytomas of childhood.

BACKGROUND: Persistent gadolinium enhancement on MRI of the meninges in some children with low-grade astrocytomas (LGA) is a widely recognized phenomenon. The relationship of this finding with the clinical course is unclear. METHODS: From a consecutive cohort of 282 children with pathologically confirmed LGA we identified all patients with asymptomatic gadolinium enhancement of the meninges found on surveillance MRI. A nested case-control study was performed, comparing patients with meningeal enhancement to controls without enhancement. RESULTS: Twenty-one children were identified with meningeal enhancement. The median follow-up was 5.2 years with enhancement noted for a median of 2.2 years. The 5-year overall survival for this cohort was 91.2% (Greenwood SE 8.0%), and the 5-year progression-free survival was 20.9% (SE 11.9%). Five patients are now free of disease, while 15 continue to have stable disease. The overall and progression-free survival was not significantly different compared to controls. CONCLUSIONS: Gadolinium enhancement of the meninges on MRI may occur in a significant number of children with LGA, particularly juvenile pilocytic astrocytoma, but does not appear to affect progression-free or overall survival. Change in management based on this finding alone is unwarranted.

Dysembryoplastic neuroepithelial tumor-like neoplasm of the septum pellucidum: a lesion often misdiagnosed as glioma: report of 10 cases.

The authors report a series of 10 low-grade neoplasms arising in the midline anteriorly in the region of the septum pellucidum with many of the histologic features of dysembryoplastic neuroepithelial tumor (DNT). The patients (five female, five male) ranged in age from 6 to 35 years (mean age, 21.5 years). The most common presenting symptoms were headache, nausea and vomiting, and visual disturbances. Radiographically, the tumors extended into the lateral ventricles from the septal region and obstructed the foramen of Monro. Varying degrees of hydrocephalus were present. The lesions were lobular, well-delineated, hypointense to brain on T1-weighted magnetic resonance imaging, and hyperintense on T2-weighted images. They were uniformly nonenhancing or showed only minimal peripheral enhancement. The tumors, in aggregate, had the histologic features of DNT. These included a mucin-rich background, oligodendrocyte-like cells, "floating neurons," and a "specific glioneuronal element." Seven patients underwent gross total resection and two underwent subtotal resection. No patients received adjuvant chemotherapy or radiotherapy. On follow-up (n = 6; median, 14 months), all tumors had either not recurred or were radiologically stable. On the basis of both neuroimaging and histopathology, DNT-like lesions should be considered in the differential diagnosis of midline intraventricular tumors in children and young adults. Distinction from more aggressive neoplasms is essential because these tumors appear to behave in a benign fashion.

Oligodendrogliomas: reproducibility and prognostic value of histologic diagnosis and grading.

Prognostic value of histological grading of oligodendroglial tumors is controversial and interobserver reproducibility in grading of these tumors is unknown. Seven neuropathologists and 6 surgical pathologists experienced in brain tumor-diagnosis assessed 124 oligodendroglial tumors operated at the Mayo Clinic (1960-1990). Among histologic parameters upon which current oligodendroglioma grading systems are based, only high cellularity, presence of mitoses, microcalcifications, endothelial hypertrophy, endothelial proliferation, and necrosis appeared to be reproducible. Reproducible histologic features, based on consensus ratings among neuropathologists (defined as > 60%), were evaluated for the association with cause-specific survival by fitting Cox regression models. By univariate analysis, a significant association with survival was found for age, high cellularity, presence of mitoses, endothelial hypertrophy and proliferation and necrosis. On multivariable analysis with a stepwise variable selection method, only age and presence of endothelial proliferation were found to be independently associated with survival with a discriminatory index of the model of 0.68. Mitotic index was significantly associated with survival based on the grading from each separate neuropathologist, but it was not based on consensus, most likely because this was classified as indeterminate in 54% of cases. Alternatively, "models fit" considering the assessment of single neuropathologists, identified a model based on age and on mitotic index with similar discriminatory indices of 0.69-0.7. Our study found few factors independently associated with cause specific-survival among morphological parameters. These findings are consistent with the present WHO stratification of oligodendrogliomas into low- and high-grade variants.

Chordoid glioma: a neoplasm unique to the hypothalamus and anterior third ventricle.

BACKGROUND AND PURPOSE: Chordoid glioma is a new clinicopathologic entity that occurs in the region of the hypothalamus/anterior third ventricle. The aims of this study were to describe the characteristic radiographic features of chordoid glioma, identify specific imaging features that may enable differentiation of chordoid glioma from other suprasellar tumors, and increase neuroradiologists' awareness of this newly described tumor, facilitating prospective diagnosis. METHODS: CT scans and/or MR images of six patients with chordoid glioma were reviewed retrospectively to determine whether any characteristic radiographic features would emerge. Reports of the clinical presentation, pathologic findings, and radiographic findings of another six patients were reviewed and included, for a total patient population of 12 (mean age +/- SD, 46 +/- 13 years). RESULTS: Imaging features were strikingly similar for all tumors. In each case, the mass was ovoid, was well circumscribed, was located in the region of the hypothalamus/anterior third ventricle, and enhanced uniformly and intensely. Tumors were hyperdense to gray matter on CT scans and were isointense on T1-weighted MR images and slightly hyperintense on long-TR MR images. In two patients, vasogenic edema extended into the optic tracts, and in three, there was hydrocephalus. CONCLUSION: Chordoid glioma is a recently described unique histopathologic entity that has been added to the World Health Organization glioma classification scheme and must be included in the differential diagnosis of a suprasellar mass. Distinctive imaging features are its location, ovoid shape, hyperdensity on CT scans, and uniform intense contrast enhancement.