Neural Crest Tumors Research Articles

Imaging Findings of Retroperitoneal Ganglioneuroma

Purpose: To characterize the typical radiologic appearance of ganglioneuromas of the adrenal gland and extra-adrenal retroperitoneum. Materials and Methods: The findings of diagnostic imaging studies (CT, n=5; ultrasound, n=1) involving six patients aged 19-58 years with pathologically proven ganglioneuroma were retrospectively analyzed by three radiologist in terms of the lesions' size, shape, margin, location, CT attenuation (unenhanced/contrast-enhanced), necrosis, calcification, relationship with adjacent vessels, and US echogenicity. Results: The maximum diameter of the six tumors ranged from 10 to 14 (mean, 11.3) cm, and the margin was well-defined in all cases. The homogeneous or slightly heterogeneous attenuation demonstrated at unenhanced CT was less than that of muscle. Dense nodular calcification was present in one case. At contrast-enhanced CT, enhancement was poor (n=5), mild and septum-like, or delayed, heterogeneous and focal (n=3), or involved subtle foci (n=1). In no case was there evidence of necrosis or hemorrhage. Local invasion was absent, but adjacent vascular encasement (n=2) or displacement (n=2) occurred. Ultrasonic examination demonstrated low echogenicity and mild heterogeneity (n=1). Conclusion: A ganglioneuroma is an uncommon benign neural crest tumor which should be included in the differential diagnosis of a retroperitoneal mass which presents as a well-defined tumor, tend to encase or displace adjacent major blood vessels, and shows low attenuation at unenhanced CT and poor or septum-like focal enhancement at contrast-enhanced CT.

Gene expression in the Andes; relevance to neurology at sea level

Chronic mountain sickness (CMS), a maladaptation syndrome to chronic hypoxia, occurs in the Andes. Gene expression differences in Andeans could explain adaptation and maladaptation to hypoxia, both of which are relevant to neurology at sea level. Expression of genes responsive to cellular oxygen concentration, hypoxia-inducible factor-1α (HIF-1α), three splicing variants of vascular endothelial growth factor (VEGF) and von Hippel–Lindau protein (pVHL) was measured by reverse transcription polymerase chain reaction (RT-PCR) in 12 Cerro de Pasco (CP) (altitude 4338 m) natives and 15 CMS patients in CP. Thirteen high altitude natives living in Lima and five Lima natives were sea level controls. A CMS score (CMS-sc) was assigned clinically. Expression was related to the clinical assessment. High expression of HIF-1α and VEGF-121 was found in CMS ( P<0.001). Samples from CP had higher expression than those from Lima ( P<0.001). Expression of HIF-1α and VEGF-121 was related to age ( P<0.001); adjusting for age did not abolish the group effect. Higher CMS-sc was related to expression independent of age ( P<0.001). VEGF-165 and -189 were expressed only in CMS. Birth altitude had no effect on gene expression. pVHL was not quantifiable. HIF-1α and VEGF-121 participate in adaptation to hypoxia. The high levels may explain blood vessel proliferation in Andeans and hold lessons for patients at sea level. VEGF-165 expression suggests that it contributes to preservation of neuronal function in human chronic hypoxia. VHL mutations may mark those destined to develop neural crest tumors which are common in the Andes.

Decreased endothelin receptor B expression in large primary uveal melanomas is associated with early clinical metastasis and short survival.

The most devastating aspect of cancer is the metastasis of tumour cells to organs distant from the original tumour site. The major problem facing oncologists treating uveal melanoma, the most common cancer of the eye, is metastatic disease. To lower mortality, it is necessary to increase our understanding of the molecular genetic alterations involved in this process. Using suppression subtractive hybridisation, we have analysed differential gene expression between four primary tumours from patients who have developed clinical metastasis and four primary tumours from patients with no evidence of metastasis to date. We have identified endothelin receptor type B as differentially expressed between these tumours and confirmed this observation using comparative multiplex RT–PCR. In a further 33 tumours, reduced endothelin receptor type B expression correlated with death from metastatic disease. Reduced expression also correlated with other known prognostic indicators, including the presence of epithelioid cells, chromosome 3 allelic imbalance and chromosome 8q allelic imbalance. Endothelin receptor type B expression was also reduced in four out of four primary small cell lung carcinomas compared to normal bronchial epithelium. We also show that the observed down-regulation of endothelin receptor type B in uveal melanoma was not due to gene deletion. Our findings suggest a role for endothelin receptor type B in the metastasis of uveal melanoma and, potentially, in the metastasis of other neural crest tumours.British Journal of Cancer (2002) 87, 1308–1313. doi:10.1038/sj.bjc.6600620 www.bjcancer.com© 2002 Cancer Research UK

RASSF1A promoter region CpG island hypermethylation in phaeochromocytomas and neuroblastoma tumours.

Deletions of chromosome 3p are frequent in many types of neoplasia including neural crest tumours such as neuroblastoma (NB) and phaeochromocytoma. Recently we isolated several candidate tumour suppressor genes (TSGs) from a 120 kb critical interval at 3p21.3 defined by overlapping homozygous deletions in lung and breast tumour lines. Although mutation analysis of candidate TSGs in lung and breast cancers revealed only rare mutations, expression of one of the genes (RASSF1A) was absent in the majority of lung tumour cell lines analysed. Subsequently methylation of a CpG island in the promoter region of RASSF1A was demonstrated in a majority of small cell lung carcinomas and to a lesser extent in non-small cell lung carcinomas. To investigate the role of 3p TSGs in neural crest tumours, we (a) analysed phaeochromocytomas for 3p allele loss (n=41) and RASSF1A methylation (n=23) and (b) investigated 67 neuroblastomas for RASSF1A inactivation. 46% of phaeochromocytomas showed 3p allele loss (38.5% at 3p21.3). RASSF1A promoter region hypermethylation was found in 22% (5/23) of sporadic phaeochromocytomas and in 55% (37/67) of neuroblastomas analysed but RASSF1A mutations were not identified. In two neuroblastoma cell lines, methylation of RASSF1A correlated with loss of RASSF1A expression and RASSF1A expression was restored after treatment with the demethylating agent 5-azacytidine. As frequent methylation of the CASP8 gene has also been reported in neuroblastoma, we investigated whether RASSF1A and CASP8 methylation were independent or related events. CASP8 methylation was detected in 56% of neuroblastomas with RASSF1A methylation and 17% without RASSF1A methylation (P=0.0031). These results indicate that (a) RASSF1A inactivation by hypermethylation is a frequent event in neural crest tumorigenesis, particularly neuroblastoma, and that RASSF1A is a candidate 3p21.3 neuroblastoma TSG and (b) a subset of neuroblastomas may be characterized by a CpG island methylator phenotype.

Reversible Intestinal Pseudoobstruction Associated With Neural Crest Tumors

Reversible Intestinal Pseudoobstruction Associated With Neural Crest Tumors

Does simple estimation of 131I-metaiodobenzylguanidine uptake in patients with neural crest tumours correlate with clinical outcome?

A retrospective study was undertaken in six patients (three male and three female) with neural crest tumours who received therapeutic doses of 131I-meta-iodobenzylguanidine (131I-MIBG) (6.7-10.5 GBq). The age range of the patients was 13-65 years (mean 36 years). Quantification of tumour uptake was obtained from images acquired with a large-field-of-view gamma camera on a single occasion between 2 and 10 days post-treatment. Tumour uptake was calculated to be 0.1% and 3.2% of the administered dose, corresponding to uptakes of 6.7-142.8 MBq. Tumour volume was assessed from computed tomography (CT) or magnetic resonance (MR) images and estimates of tumour dose made from the Medical Internal Radiation Dosimetry scheme (MIRD) tables. Estimated doses were between 7 and 113 Gy. Most significantly, our findings indicate that high tumour uptake did not always correlate with good clinical response.

31. Comparison of 123I-MIBG, 111In-Octreotide and 18FDG PET imaging in neural crest tumours

31. Comparison of 123I-MIBG, 111In-Octreotide and 18FDG PET imaging in neural crest tumours

Discrepant flow cytometric expression and function of P‐glycoprotein in neuroblastic tumors

Background: Patients suffering from neuroblastic tumors are currently being classified into prognostic subsets based on different clinical and biologic features. In this study, a triple-color flow cytometric assay and a functional test were applied to neuroblastoma cell lines and patients with a neuroblastic tumor, and the value of P-glycoprotein expression and function as potential prognostic characteristics, was determined. Methods: Twenty-two single-cell suspensions prepared from tumors, and neuroblasts from four bone marrow samples were analyzed by triple-color flow cytometry. Neuroblasts were identified by NB84-positivity and absence of CD45. P-glycoprotein expression was evaluated using 4E3 and MRK16 antibodies. Eighteen samples were tested with a functional assay, based on accumulation and retention of rhodamine-123 with and without the inhibitor verapamil. Six neuroblastoma cell lines were also evaluated. Results: P-glycoprotein expression was seen in 18 of 26 patient samples and in three of six cell lines. The highest expression levels were found in low stage neuroblastoma and well-differentiated tumors; whereas the highest activities were found in stage 4 neuroblastoma and the lowest in ganglioneuroblastoma and ganglioneuroma patients. In 10 of 17 samples, concordant results were found between the flow cytometric immunological test and immunocytochemistry. Conclusions: The described flow cytometric technique is a new, alternative approach to detect P-glycoprotein expression and function in neural crest tumors. Based on the expression level and the activity value, patients can be segregated into different phenotypic groups. In particular, those patients with high P-glycoprotein activity might benefit from treatment regimens containing reversal agents. Cytometry 37:125–132, 1999. © 1999 Wiley-Liss, Inc.

Discrepant flow cytometric expression and function of P-glycoprotein in neuroblastic tumors

Patients suffering from neuroblastic tumors are currently being classified into prognostic subsets based on different clinical and biologic features. In this study, a triple-color flow cytometric assay and a functional test were applied to neuroblastoma cell lines and patients with a neuroblastic tumor, and the value of P-glycoprotein expression and function as potential prognostic characteristics, was determined. Twenty-two single-cell suspensions prepared from tumors, and neuroblasts from four bone marrow samples were analyzed by triple-color flow cytometry. Neuroblasts were identified by NB84-positivity and absence of CD45. P-glycoprotein expression was evaluated using 4E3 and MRK16 antibodies. Eighteen samples were tested with a functional assay, based on accumulation and retention of rhodamine-123 with and without the inhibitor verapamil. Six neuroblastoma cell lines were also evaluated. P-glycoprotein expression was seen in 18 of 26 patient samples and in three of six cell lines. The highest expression levels were found in low stage neuroblastoma and well-differentiated tumors; whereas the highest activities were found in stage 4 neuroblastoma and the lowest in ganglioneuroblastoma and ganglioneuroma patients. In 10 of 17 samples, concordant results were found between the flow cytometric immunological test and immunocytochemistry. The described flow cytometric technique is a new, alternative approach to detect P-glycoprotein expression and function in neural crest tumors. Based on the expression level and the activity value, patients can be segregated into different phenotypic groups. In particular, those patients with high P-glycoprotein activity might benefit from treatment regimens containing reversal agents.

Squamous carcinoma in situ of the skin containing premelanosomes, with melanocytic colonization of the tumor

Premelanosomes in nonmelanocytic epithelial neoplasms and “colonization” of nonmelanocytic tumors by melanocytes are two phenomena rarely documented in the literature. We report a squamous carcinoma-in-situ of skin displaying both phenomena. Light microscopy showed clusters of tumor cells in the epidermis, some of which contained melanin. Dendritic melanocytes were admixed with the tumor cells. No ulceration was present. Immunoperoxidase stains for keratin showed no staining of tumor cells. Some nondendritic cells stained for HMB-45, consistent with a melanocytic lesion. Electron microscopy showed two cell types, one with desmosomes, tonofilaments, and premelanosomes and a second dendritic type with only premelanosomes. Premelanosomes were also present free in the intercellular space. These findings suggest that premelanosomes may first be discharged by melanocytes into the intercellular space and are then phagocytosed by the neoplastic cells. Thus the presence of premelanosomes in a tumor cell is not pathognomonic for melanoma or other neural crest tumors.

Extrinsic tracheobronchial compression

Extrinsic compression of the airway is an uncommon cause of respiratory distress in children. The most significant lesions occur along the thoracic airway. The differential diagnosis includes vascular anomalies and mediastinal masses. Aberrant innominate artery, pulmonary vascular sling, and aortic vascular rings are the usual vascular lesions that cause extrinsic airway compression. Cardiac chamber and pulmonary vascular enlargement are less common causes. Mediastinal masses that compress the airway include inflammatory lymphadenopathy, lymphoma, germ cell tumors, thymus derivatives, neural crest tumors, and bronchogenic cysts. Recent refinements in tracheography, ultrasonography, spiral CT, and magnetic resonance imaging have increased our ability to identify specific causes with acceptable risk and morbidity.

Engraftment after myeloablative doses of 131I-metaiodobenzylguanidine followed by autologous bone marrow transplantation for treatment of refractory neuroblastoma.

Metaiodobenzylguanidine (MIBG) labeled with 131I has been used for targeted radiotherapy of neural crest tumors, with bone marrow suppression being the primary dose-limiting toxicity. The purpose of this study was to examine the engraftment and toxicity of higher myeloablative doses of 131I-MIBG with autologous bone marrow support. Twelve patients with refractory neuroblastoma were given infusions of their autologous, cryopreserved bone marrow following 1-4 doses of 131I-MIBG. The median cumulative administered activity per kilogram of 131I-MIBG was 18.0 mCi/kg (range 14.1-50.2 mCi/kg), the median total activity was 594 mCi (range 195-1,353 mCi), and the median cumulative whole body irradiation from 131I-MIBG was 426 cGy (range 256-800 cGy). A median of 2.5 x 10(8) viable cells/kg (range 0.9-4.7 x 10(8) cells/kg) was given in the bone marrow infusion. All 12 patients achieved an absolute neutrophil count > 500/microliter with a median of 19 days, but only 5/11 evaluable patients achieved red cell transfusion independence, in a median of 44 days; and 4/11 evaluable patients achieved platelet count > 20,000/microliter without transfusion, in a median of 27 days. Autologous bone marrow transplantation may allow complete hematopoietic reconstitution following ablative 131I-MIBG radiotherapy in patients with neuroblastoma. Risk factors for lack of red cell or platelet recovery include extensive prior chemotherapy, progressive disease at the time of transplant, especially in the bone marrow, and a history of prior myeloablative therapy with stem cell support.

Dancing Eye Syndrome and Hyperphosphatasemia

An 11-month-old boy with a relapsing dancing eye syndrome associated with elevation of serum alkaline phosphatase, lactate dehydrogenase, and aminotransferase activities is reported. During two clinical episodes the serum alkaline phosphatase activity increased up to four times the upper reference limit, remained elevated for a few weeks and normalized gradually in parallel with clinical improvement under steroid therapy. We found no evidence of liver or bone pathology nor of a neural crest tumor. The association between dancing eye syndrome and hyperphosphatasemia has not yet been described. The beneficial effect of the steroid therapy strengthens the hypothesis of an autoimmune origin.

Synthesis and radioiodination of 3-(E)-(2-iodovinyl)-N-acetyl-4-cysteaminylphenol, a putative tyrosinase substrate for imaging neural crest tumours

The synthesis of 3-(E)-(2-iodovinyl)-N-acetyl-4-cysteaminylphenol (3-IV-N-Ac-4-SCAP) started from 3-iodophenol, which on condensation with cysteamine hydrochloride gave 3-iodo-4-cysteaminylphenol (1). Acetylation of 1 followed by selective deacetylation yielded 3-iodo-N-acetyl 4-cysteaminylphenol (3-I-N-Ac-4-SCAP; 3). The stereospecific reaction of (E)-1-trimethylsilyl-2-tri-n-butyltinethylene with 3 afforded the vinyl-TMS precursor 3-(E)-(2-trimethylsilylvinyl)-N-acetyl-4-cysteaminylphenol (3-TMS-N-Ac-4-SCAP; 4) in high yield. This TMS vinyl precursor is a useful synthon for high specific radioiodination. Iodination of the synthon 3-(E)-(2-trimethylsilylvinyl)-N-acetyl-4-cysteaminylphenol with iodine monochloride gave 3-IV-N-Ac-4-SCAP (5). High specific activity (no carrier added) 3-(E)-(2-[125I]iodovinyl)-N-acetyl-4-cysteaminyl phenol was obtained in 85% radiochemical yield upon a 5 min exposure of a mixture of Na[125I]I and 3-TMS-N-Ac-4-SCAP to 2450 MHz radiation in a microwave oven. © 1998 John Wiley & Sons, Ltd.

4. A critical assessment of the effectiveness of MIBG treatment in neural crest tumours

4. A critical assessment of the effectiveness of MIBG treatment in neural crest tumours

The roles of mitotic arrest and protein synthesis in induction of apoptosis and differentiation in neuroblastoma cells in culture

Studies of the response of neural crest tumor cells to the DNA cleaving antimitotic agent, neocarzinostatin, have left unanswered the question of whether the DNA cleavage per se or the antimitotic effect is responsible for this response. Furthermore, they do not define the timeframe within which a cell commits to its fate. Using the reversible microtubule-active agent, vinblastine, we now demonstrate that mitotic arrest, even without DNA cleavage, results in the same cellular changes as those seen with neocarzinostatin treatment. The commitment of the cell to its fate occurs within a 15 min treatment with vinblastine, and requires new protein synthesis. The immediate early gene products, c-Fos and c-Jun, appear not to be determinants of this process.

111Indium pentetreotide scan detection of familial paragangliomas.

Approximately 10% of head and neck paragangliomas are familial. Magnetic resonance imaging (MRI) is reported to be the best method for screening these families. 111Indium pentetreotide (Octreoscan) scintigraphy has been shown to be a sensitive indicator of neural crest tumors such as paragangliomas. Early diagnosis and treatment of familial paragangliomas (FP) would decrease the morbidity of tumor excision. Patients from two kindred with FP were scanned 24 hours after intravenous injection with approximately 6 millicuries of 111Indium pentetreotide. The entire body was imaged. Areas of increased uptake were further imaged with MRI. Altogether, five patients had positive 111Indium pentetreotide scans. Two unsuspected glomus tympanicums and bilateral carotid body tumors were identified. Three people tested had no abnormal uptake. There were no untoward reactions to the nuclide. 111Indium pentetreotide scanning is a safe, noninvasive method for early diagnosis of FP and is useful in detecting multicentric lesions. Patients suspect for FP are undergoing 111Indium pentetreotide imaging and followed up with MRI of the involved site if positive.

Bilateral adrenal ganglioneuroblastomas in a teenage boy

Abdominal neural crest tumours are usually diagnosed using a combination of cross sectional imaging and urinary catecholamine assay. Although histological confirmation is required, in many cases the diagnosis is not in doubt preoperatively. Neural crest tumours in adolescents are rare, and in particular adrenal neuroblastoma needs to be differentiated from phaeochromocytoma. The role of imaging in making this distinction is highlighted in this case.

Elevated plasma concentrations of neuropeptide Y in children and adults with chronic and terminal renal failure

Neuropeptide Y (NPY) is a peptide hormone that is expressed, stored, and released in sympathetic neurones together with noradrenaline. Elevated plasma concentrations of NPY have been reported in patients with neural crest tumors (neuroblastoma, pheochromocytoma) and following exercise. We studied plasma concentrations of NPY in children and adults with chronic and terminal renal failure and compared them with those in healthy controls. Neuropeptide Y was significantly higher in children and adolescents receiving peritoneal dialysis (5.3 ± 2.8 pmol/L; n = 11 [mean ± sd]) or hemodialysis (5.4 ± 2.1 pmol/L; n = 14) than in healthy children (2.3 ± 0.9 pmol/L; n = 19) or pediatric patients with impaired renal function who are not receiving dialysis (2.7 ± 0.6 pmol/ L; n = 8; mean glomerular filtration rate, 41 mL/min × 1.73 m 2). There was a small but insignificant negative correlation between glomerular filtration rate and NPY concentrations in children with impaired renal function ( r = −0.49; P = 0.25). In healthy adults, NPY concentration was similar to that in healthy children (1.8 ± 1.0 pmol/ L; n = 13), and it was significantly elevated in adults receiving hemodialysis (5.9 ± 1.7 pmol/L; n = 16). No significant changes in NPY concentrations were found before and after hemodialysis in pediatric or adult patients. We conclude that plasma concentrations of NPY are elevated in patients with chronic renal failure who are receiving either peritoneal or hemodialysis, but not in patients with moderately impaired renal function. Whether elevated NPY concentration indicates increased sympathetic activity or is caused by reduced NPY clearance remains to be shown.

Bioanalysis of radioiodine labelled meta-iodobenzylguanidine, its metabolites and free radioiodide in body fluids

Radioiodinated meta-iodobenzylguanidine ([ 123I/ 131I]MIBG) is used for diagnostic scintigraphy of neural crest tumours (such as neuroblastoma and malignant phaeochromocytoma) and for scintigraphic assessment of cardiac neuronal integrity. Moreover, [ 131I]MIBG is also used for radionuclide therapy of neural crest tumours. Part I of this paper presents a simple solid phase extraction procedure for the separate quantification of [ 123I/ 131I]MIBG and its radiolysis product [ 123I/ 131I]iodide in biological matrices. The method has been validated for whole blood, plasma, urine and saliva. After intravenous administration of [ 123I]MIBG, containing only 2% free [ 123I]iodide, to a patient, the [ 123I]iodide level—expressed as percentage of total radioactivity in each matrix sample—amounted to: 3% (urine), 5% (blood cells), 20% (whole blood), 32% (plasma) and 100% (saliva). Part II describes a sensitive HPLC procedure, including sample pretreatment, for the determination of [ 131I]iodide, [ 131I]MIBG and three metabolites, including [ 131I] meta-iodohippuric acid ([ 131I]MIHA) and [ 131I] meta-iodobenzoic acid, in urine of patients treated with therapeutic amounts of [ 131I]MIBG. The parent drug and its metabolites could be detected in urine for at least 5 days after administration. The procedure was highly reproducible for the quantification of [ 131I]MIBG and [ 131I]MIHA, yielding relative standard deviations of <2% and <5%, respectively.