Radiological features of primitive neuroectodermal tumors in intra-abdominal and retroperitoneal regions: A series of 18 cases.

OBJECTIVES: To characterize the imaging and clinicopathological features of primitive neuroectodermal tumors (PNETs) arising in intra-abdominal and retroperitoneal regions. METHODS: Eighteen patients with histopathologically proven intra-abdominal and retroperitoneal PNET were enrolled; computed tomography was performed for all cases, and magnetic resonance imaging was performed for a single case. Typical computed tomography and magnetic resonance imaging findings, including morphology, texture and enhancement features, as well as clinicopathological characteristics and prognosis data were retrospectively analyzed. RESULTS: Of eighteen PNET patients, fifteen were male and three were female, with a median age of 36 years (range, 2-65 years). The onset of symptoms was most often nonspecific and insidious. The mean tumor diameter was 7.2 cm (range, 3.0-12.1 cm), with necrosis in fifteen cases, cystic changes in eight, partition structure in five, calcification in five, hemorrhage in two, and mural nodules in one. Contrast enhanced computed tomography showed multiple tiny feeding arteries within the masses in six cases, resulting in a crab-like appearance, and mild ring enhancement pattern in five cases. Eleven cases showed surrounding invasion and metastasis. Of the eighteen PNET cases, nine cases showed smooth, well-defined margins, and nine cases had irregular, ill-defined margins. A median survival was 10.0±1.6 months. However, chemotherapy had efficacy on patients even those with advanced disease. CONCLUSIONS: Primary intra-abdominal and retroperitoneal PNETs are rare, and imaging features documented here may help the diagnosis of this severe disease. Notably, two signs present in retroperitoneal PNET tumors, including a mild ring enhancement pattern and a crab-like appearance of the tiny feeding arteries, may have the potential to help us improve the ability to make a relatively reliable diagnosis.

Characteristics of human Ewing/PNET sarcoma models.

Ewing/PNET (peripheral neuroepithelioma) tumors are rare aggressive bone sarcomas occurring in young people. Rare-disease clinical trials can require global collaborations and many years. In vivo models that as accurately as possible reflect the clinical disease are helpful in selecting therapeutics with the most promise of positive clinical impact. Human Ewing/PNET sarcoma cell lines developed over the past 45 years are described. Several of these have undergone genetic analysis and have been confirmed to be those of Ewing/PNET sarcoma. The A673 Ewing sarcoma line has proven to be particularly useful in understanding the biology of this disease in the mouse. The chromosomal translocation producing the EWS/FLI1 fusion transcript characterizes clinical Ewing sarcoma. Cell lines that express this genetic profile are confirmed to be those of Ewing sarcoma. The A673 Ewing sarcoma line grows in culture and as a xenograft in immunodeficient mice. The A673 model has been used to study Ewing sarcoma angiogenesis and response to antiangiogenic agents. Many Ewing sarcoma clinical specimens express the cell surface protein endosialin. Several Ewing sarcoma cell lines, including the A673 line, also express cell surface endosialin when grown as subcutaneous tumor nodules and as disseminated disease; thus the A673 is a useful model for the study of endosialin biology and endosialin-directed therapies. With the advent of tools that allow characterization of clinical disease to facilitate optimal treatment, it becomes imperative, especially for rare tumors, to develop preclinical models reflecting disease subsets. Ewing PNET sarcomas are a rare disease where models are available.

The tumour-associated carbonic anhydrases CA II, CA IX and CA XII in a group of medulloblastomas and supratentorial primitive neuroectodermal tumours: an association of CA IX with poor prognosis.

BACKGROUND: Medulloblastomas (MBs) and supratentorial primitive neuroectodermal tumours (PNETs) are the most common highly aggressive paediatric brain tumours. In spite of extensive research on these tumours, there are only few known biomarkers or therapeutic target proteins, and the prognosis of patients with these tumours remains poor. Our aim was to investigate whether carbonic anhydrases (CAs), enzymes commonly overexpressed in various tumours including glioblastomas and oligodendrogliomas, are present in MBs and PNETs, and whether their expression can be correlated with patient prognosis. METHODS: We determined the expression of the tumour-associated carbonic anhydrases CA II, CA IX and CA XII in a series of MB/PNET specimens (n = 39) using immunohistochemistry. RESULTS: Endothelial CA II, cytoplasmic CA II, CA IX and CA XII were expressed in 49%, 73%, 23% and 11% of the tumours, respectively. CA II was detected in the neovessel endothelium and the tumour cell cytoplasm. CA IX was mainly expressed in the tumour cells located in perinecrotic areas. CA XII showed the most homogenous distribution within the tumours. Importantly, CA IX expression predicted poor prognosis in both univariate (p = 0.041) and multivariate analyses (p = 0.016). CONCLUSIONS: We suggest that CA IX should be considered a potential prognostic and therapeutic target in MBs and PNETs.

Dysembryoplastic neuroepithelial tumors: proton MR spectroscopy, diffusion and perfusion characteristics.

INTRODUCTION: We describe the magnetic resonance (MR) imaging characteristics of dysembryoplastic neuroepithelial tumors (DNT) and discuss their differential diagnosis. MATERIAL AND METHODS: Proton MR spectroscopy (TE 30 and 136 ms), diffusion-weighted and perfusion images were retrospectively evaluated in 22 patients with pathologically proven DNT (17 male and 5 female, mean age 18.7 years) and 14 control subjects (10 male and 4 female, mean age 16.9 years). The results from the DNT patients and from the control subjects were compared using an independent sample t-test and the degree of correlation was tested by Pearson's correlation. RESULTS: All DNTs were solitary and in a supratentorial cortical or subcortical location (ten temporal, eight frontal and four parietal). They had low-signal on T1-weighted images and high-signal on T2-weighted images without a prominent mass effect. Additionally a cystic appearance (six patients, 27.3%), cortical dysplasia (six patients, 27.3%) and contrast enhancement (four patients, 18.2%) were also noted. No significant differences were detected in NAA/Cho, NAA/Cr, NAA/Cho+Cr or Cho/Cr ratios between DNT and normal brain. DNTs had a significantly higher mI/Cr ratio and apparent diffusion coefficient (ADC) values and lower cerebral blood values than normal parenchyma (P < 0.001). ADC had the highest correlation with the diagnosis of DNT (r = 0.996) followed by relative cerebral blood volume (rCBV) (r = -0.883) and mI/Cr ratio (r = 0.663). CONCLUSION: Proton MR spectroscopy, diffusion-weighted and perfusion imaging characteristics of DNTs provide additional information to their MR imaging findings. The MR spectrum showing a slight increase in mI/Cr ratio, and higher ADC and lower rCBV values than normal parenchyma help to differentiate DNTs from other cortical tumors, which had higher rCBV and lower ADC values than DNTs.

Angiogenic profile of childhood primitive neuroectodermal brain tumours/medulloblastomas.

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.

High microvessel density in primitive neuroectodermal brain tumors of childhood.

Microvessel density (MVD), a measure of tumor angiogenesis, has been shown to correlate significantly with overall and progression-free survival outcomes in various cancers including astrocytic brain tumors. To assess if the MVD is an independent prognostic factor in primitive neuroectodermal tumors (PNET) of the central nervous system, formalin-fixed paraffin-embedded tumor sections of 78 children with PNET were studied by CD34 immunohistochemistry to highlight endothelial cells. Microvessel density was determined in the most active area of neovascularization according to well-established methods. While it was shown that MVD showed considerable inter-tumor variability (median 75; range 20-345 microvessels per 0.7 mm2 field), no significant associations were found between MVD and metastasis or survival outcomes. We conclude that many PNETs are highly vascular CNS tumors, indicating potent angiogenic activity. Therefore, these tumors would be good candidates for antiangiogenic strategies. However, MVD determined in the most active area of neovascularization is not a predictor of metastatic potential or survival outcomes in childhood PNET.

Upregulation of endoglin (CD105) expression during childhood brain tumor-related angiogenesis. Anti-angiogenic therapy.

During postnatal development, the formation of new blood vessels is possible only through angiogenesis. The initial growth of solid neoplasms, including childhood brain tumors, during the genetically determined stages of carcinogenesis, even at clinically undetectable sizes (a few mm3), depends upon the continuous formation of new blood capillaries [i.e. neovascularization (NV)/neoplasm-related angiogenesis (NRA)]. The generation of a malignant, invasive cellular immunophenotype (CIP) and distant metastases are also NRA-dependent processes. Endothelial cells undergo rapid proliferation during brain tumor related angiogenesis. Human endoglin (CD105/EDG), is a homodimeric cell surface component of the transforming growth factor-beta (TGF-beta) type I receptor complex and is also a proliferation-associated antigen (PAA) expressed at high density on endothelial cells. Formalin fixed, paraffin-wax embedded (3-5 microns thick), as well as frozen tissue sections (6 microns thick) of 62 childhood brain tumors [34 medulloblastomas (MEDs) and 28 astrocytomas (ASTRs)], were employed for the assessment of EDG expression. Both an indirect, four-step, alkaline phosphatase (AP) conjugated, biotin-streptavidin based (or a diamino-benzidine [DAB]) conjugated immunoperoxidase antigen detection technique were employed, utilizing the SN6h anti-EDG monoclonal antibody (DAKO Corp.). Another antigen detection method, based on the Histogold (Zymed) reaction was also employed using the same antibody on formalin fixed, paraffin-wax embedded tissues. Strong expression (A; +3 to +4) of EDG on endothelial cells and demonstrated in all 62 childhood brain tumor cases. The most striking feature of the newly formed tumor-related capillaries was the presence of a markedly enlarged perivascular space. Blood vessels in several normal human tissues (cortex, cerebellum, thymus, tonsil, spleen, lymph node, skin) used as control tissues contained significantly lower levels of EDG (B and mostly C; +/- to +), in accordance with the extremely slow turnover rate of normal endothelial cells. A close apposition between the capillaries and the adjacent parenchyma was also observed. Brain tumors, especially glioblastoma, are among the most vascularized human neoplasms, and thus are candidates for antiangiogenic therapy. VEGF/PF-R1 (flt-1) and VEGF/PF-R2 (flk-1) are formed de novo in a glioma progression-dependent manner. Further studies should substantiate the importance of EDG in the earliest possible detection, diagnosis and NRA inhibition-based treatment of mammalian solid neoplasms, especially childhood brain tumors.

Neoadjuvant chemotherapy for hypervascular malignant brain tumors of childhood.

Some large hypervascular brain tumors pose an exceptional challenge to surgical resection, particularly in young children with small blood volumes. To limit blood loss during resection of hypervascular tumors, the authors used upfront chemotherapy as the primary treatment modality in 2 young children. This produced a dramatic reduction in tumor size and vascularity and greatly facilitated definitive surgical removal.