Composite Neuroblastoma Metastatic to a Lymph Node: The Novel Histopathologic Diagnosis of a Unique Multiclonal Neoplasm.

OBJECTIVE: Composite neuroblastoma is a tumor composed of multiple tumoral clones within the neuroblastoma family. To date, establishing this unique histopathologic diagnosis has required the evaluation of the primary tumor mass. We report a case of composite neuroblastoma diagnosed by evaluation of a metastatic lymph node. METHODS: One abdominal lymph node involved by tumor was evaluated in a 6-year-old boy. The primary abdominal mass was not examined. Following histopathologic examination, clonality studies using comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) were also performed. RESULTS: Two distinct tumor components were identified by histopathologic evaluation and classified as differentiating neuroblastoma (component A) and poorly differentiated neuroblastoma (component B). Based on the patient's age, each clone was further classified as Unfavorable Histology. The presence of these two different tumoral clones was confirmed by CGH and FISH. CONCLUSION: This case affirms the histopathologic approach to evaluating composite tumors, as established by the International Neuroblastoma Pathology Classification (INPC) model for ganglioneuroblastoma, nodular tumors. Also, when both components are metastatic, this case demonstrates that composite tumors can be diagnosed by the evaluation of metastatic lesions alone. Finally, it supports the addition of composite neuroblastoma to a future version of the INPC.

Transformation of Merkel cell carcinoma to ganglioneuroblastoma in intracranial metastasis.

Merkel cell carcinoma is an aggressive neuroendocrine tumor occasionally demonstrating aberrant differentiation to other epithelial and nonepithelial cell lines. We describe a case of Merkel cell carcinoma displaying unique patterns of differentiation in the primary focus and brain metastasis. The skin primary was almost uniformly small cell carcinoma positive for epithelial and neuroendocrine markers, with a few glial fibrillary acidic protein- and cytokeratin 20-positive cells. The neoplasm contained giant cells immunoreactive for neurofilament and negative for epithelial markers. The neck lymph node metastasis was a typical neuroendocrine Merkel cell carcinoma positive for cytokeratin 20. A solitary dural intracranial metastasis displayed features of aggressive ganglioneuroblastoma, expressing many neuronal antigens with no evidence of glial or epithelial differentiation. After total gross resection, the tumor recurred within 3 months, and the patient developed skeletal metastases and died 6 months after craniotomy.

Th-MYCN mice with caspase-8 deficiency develop advanced neuroblastoma with bone marrow metastasis.

Neuroblastoma, the most common extracranial pediatric solid tumor, is responsible for 15% of all childhood cancer deaths. Patients frequently present at diagnosis with metastatic disease, particularly to the bone marrow. Advances in therapy and understanding of the metastatic process have been limited due, in part, to the lack of animal models harboring bone marrow disease. The widely used transgenic model, the Th-MYCN mouse, exhibits limited metastasis to this site. Here, we establish the first genetic immunocompetent mouse model for metastatic neuroblastoma with enhanced secondary tumors in the bone marrow. This model recapitulates 2 frequent alterations in metastatic neuroblastoma, overexpression of MYCN and loss of caspase-8 expression. Mouse caspase-8 gene was deleted in neural crest lineage cells by crossing a Th-Cre transgenic mouse with a caspase-8 conditional knockout mouse. This mouse was then crossed with the neuroblastoma prone Th-MYCN mouse. Although overexpression of MYCN by itself rarely caused bone marrow metastasis, combining MYCN overexpression and caspase-8 deletion significantly enhanced bone marrow metastasis (37% incidence). Microarray expression studies of the primary tumors mRNAs and microRNAs revealed extracellular matrix structural changes, increased expression of genes involved in epithelial to mesenchymal transition, inflammation, and downregulation of miR-7a and miR-29b. These molecular changes have been shown to be associated with tumor progression and activation of the cytokine TGF-ß pathway in various tumor models. Cytokine TGF-ß can preferentially promote single cell motility and blood-borne metastasis and therefore activation of this pathway may explain the enhanced bone marrow metastasis observed in this animal model.

Metastatic ganglioneuroblastoma in head and neck diagnosed by fine needle aspiration: a case report.

BACKGROUND: To describe the cytologic findings of a case of ganglioneuroblastoma metastatic to the jaw and neck. CASE: A 15-year-old boy with a known case of ganglioneuroblastoma of the kidney for the previous 10 years manifested by right mandibular and neck masses on 2 occasions 1 year apart was diagnosed with metastatic ganglioneuroblastoma by fine needle aspiration (FNA). FNA showed neurofibrillary material, small malignant cells, Homer-Wright rosettes. mononucleated, binucleated and multinucleated ganglion cells and Reed Sternberg-like ganglion cells. Metastatic ganglioneuroblastoma was diagnosed on both occasions, and the patient received appropriate treatment, with resolution of the lesions. CONCLUSION: This case illustrates the FNA findings of metastatic ganglioneuroblastoma in the head and neck region.

Ganglioneuroblastoma metastatic to the orbit.

A 10-month-old girl presented with an extensive orbital and cranial metastatic lesion from an adrenal ganglioneuroblastoma. Treatment with chemotherapy alone resulted in complete regression of the tumors with over 7 years of follow-up. Good prognostic indicators included her young age at diagnosis, DNA index of tumor cells of 1.4, and the histologic subtype of neuroblastic tumor. This is the first reported case of ganglioneuroblastoma metastatic to the orbit.

[A case of ganglioneuroblastoma occurring in the superior mediastinum in an adult].

We report a case of ganglioneuroblastoma occurring in the superior mediastinum in adult. A 63-year-old man was admitted to our hospital for detailed investigation of an abnormal shadow on his chest radiograph. Chest radiography and CT imaging showed a left superior mediastinal tumor. Histopathologically, the tumor was identified as a ganglioneuroblastoma. Although ganglioneuroblastomas occur predominantly in children, 3 cases have been reported in adults in Japan. Incidentally, this is the first reported case of ganglioneuroblastoma occurring in the superior mediastinum in Japan.

Undifferentiated ganglioneuroblastoma in a sheep.

Ganglioneuroblastoma, presumably originating from the adrenal medulla, was found in an 18-month-old sheep. Histologically, the tumour was mainly composed of undifferentiated neuroblasts with neuropil and occasional ganglion cells. The morphological and immunohistochemical features with respect to intermediate filament proteins and the neuroendocrine nature of the tumour are described. The neoplastic cells were positive for neuron-specific enolase, synaptophysin and vimentin.

Extracranial neuroblastomas and neurological complications.

Between October 1989 and March 1997, 25 pediatric inpatients were treated for primary extracranial neuroblastoma (NB; n=20) or ganglioneuroblastoma (GNB; n=5) at the University of Istanbul, Institute of Pediatric Oncology, and these children were the subjects of this retrospective study. Seventeen (68%) of these patients experienced 19 neurological complications during the course of their disease. Fourteen had nervous system metastases or invasion. Nonmetastatic complications, including CNS infections (n=3) and new onset of seizures (n=2) secondary to metabolic encephalopathy were seen in 5 cases. By the time of the final analysis of the results, 8 of the 17 patients with neurological complications had died, 7 had either been lost to follow-up (n=4) or were in the terminal stage of their disease (n=3), and 2 were in remission. Both of the patients who were in remission had dumbbell neuroblastoma (DNB), and 1 of them, with congenital DNB, also had neurological sequelae, characterized by paraplegia and neurogenic bladder. Neurological complications occurred in 68% of NB and GNB cases. Metastatic complications were more common than nonmetastatic complications and had a poor prognosis. Neurological complications were the primary cause of mortality in this study, mortality being related to neurological complications in 63% of cases, and the final outcome was worse than expected. However, regardless of any differences in social, economic and geographic factors and different treatment protocols for NB in different pediatric oncology institutions, neurological complication rates in pediatric NB are similar in all.

In-111 pentetreotide scintigraphy in patients with neuroblastoma. Comparison with I-131 MIBG, N-Myc oncogene amplification, and patient outcome.

OBJECTIVE: 1. To evaluate the relative efficacy of In-111 pentetreotide and 1-131 radioiodinated meta-idobenzyl guanidine (MIBG) for detection of primary and metastatic neuroblastoma. 2. To assess the prognostic value of In-111 pentetreotide uptake. METHODS AND MATERIALS: Seven In-111 pentetreotide and seven I-131 MIBG scans were obtained in six patients with stage IV neuroblastoma and 1 with stage III ganglioneuroblastoma. Three scans were obtained at initial staging and four were obtained during therapy. Correlation was made with concomitant computed tomography scans, bone scans, N-myc oncogene amplification, and clinical outcome. RESULTS: Primary tumor was present in six patients and had been resected in 1. In-111 pentetreotide uptake was seen in two of six primary tumors, I-131 MIBG scan was positive in five of six. In-111 pentetreotide scan was positive in two of four patients with bone metastases, I-131 MIBG scan was positive in three of four. Both showed liver metastases in one patient and did not show bone marrow metastases in another. Overall sensitivity for primary or metastatic disease was 57% (four of seven) for In-111 pentetreotide and 86% (six of seven) for MIBG. Correlation between N-myc oncogene and In-111 pentetreotide uptake was seen in four of seven patients. In-111 pentetreotide uptake correlated with the clinical outcome in six patients with more than 1 year follow-up. Two patients with negative In-111 pentetreotide scans had unfavorable outcome. One patient died, and the other had local recurrence 15 months after diagnosis. Four patients with a positive scan are alive without disease on follow-up at 13-31 months after diagnosis. CONCLUSION: In-111 pentetreotide scintigraphy is less sensitive than I-131 MIBG for detecting active neuroblastoma. In-111 pentetreotide uptake on scintigraphy may correlate with the prognosis. However, a larger series of patients is needed for further evaluation.

Neurologic complications of the primary pediatric extracranial neuroblastomas.

Between January 1982 and June 1994, 32 children with primary extracranial neuroblastomas (n = 24) and ganglioneuroblastomas (n = 8) were admitted and treated at the UKMC. Twenty-two (68.7%) of these patients suffered with 29 neurological complications (up to 3 complications per case) during the course of their disease. Fourteen cases had nervous system metastases or invasion. Nonmetastatic complications, such as nervous system infections (n = 4) and new onset of seizures secondary to brain metastasis, hypertensive and metabolic encephalopathies (n = 3) were seen on 7 cases. Five cases had treatment related complications, one case first presented with opsoclonus-polymyoclonus syndrome. Eight of these 22 patients died, due to relapse or progression of the disease. The mean follow-up period of 14 surviving patients was 44.9 months (range, 12-110 months). Five of these 14 patients suffered with neurologic sequelae. The incidence of neurologic complications was 68.7%. Nervous system metastasis was the most common neurologic complication. Although 5 patients suffered with neurologic sequelae, outcome was not influenced by presence of neurologic complication.

Indium-111-pentetreotide scintigraphy in children with neuroblast-derived tumors.

UNLABELLED: The somatostatin analog 111In-pentetreotide was evaluated in 11 children with sympathetic embryonic cell-derived tumors. METHODS: Six neuroblastomas, four ganglioneuroblastomas and one ganglioneuroma (benign) were imaged 4 and 24 hr after injection of 111In-pentetreotide (5 MBq/kg) and 24 hr after administration of 123I-metaiodobenzylguanidine (MIBG) (3.7 MBq/kg). RESULTS: Primary tumor was detected with both tracers in four of the five patients studied before surgery (one Stage III neuroblastoma, one Stage IV neuroblastoma, one Stage IVs neuroblastoma, one ganglioneuroblastoma), but the ganglioneuroma was not localized. Detection of bone marrow metastases was clearly better with 111In-pentetreotide in two patients, similar or slightly better with MIBG in six and (true) negative with both procedures in three. The positivity rate of 111In-pentetreotide for imaging of metastases was higher in undifferentiated malignant tumors (six neuroblastomas: two very positive, three positive, one true-negative) than in histologically well-differentiated tumors (four ganglioneuroblastomas: three weakly positive, one true-negative). All patients with positive 111In-pentetreotide imaging results had elevated urinary catecholamine levels, and the two most 111In-pentetreotide-positive metastases were found in neuroblastomas from children with an aneuploid primary tumor. The 111In-pentetreotide and MIBG results were only partly correlated with bone marrow status, as assessed by immunocytological and histological studies at the time of scanning. CONCLUSION: Abnormalities detected in 111In-pentetreotide uptake were slightly different from those seen with MIBG as a first-line routine method in neuroblast-derived tumors. However, some MIBG as a first-line routine method in neuroblast-derived tumors. However, some MIBG-negative tumor sites were detected by 111In-pentetreotide in patients with neuroblastomas. Thus, 111In-pentetreotide could provide novel information on the biology and prognosis of tumors whose clinical significance remains to be defined.

Hypomelanosis of Ito associated with neuroblastoma.

We report a patient with hypomelanosis of Ito associated with neuroblastoma. Though not previously reported, the association is plausible since both conditions are forms of "neurocristopathy".

Diagnosis and follow-up of neuroblastoma by means of iodine-123 metaiodobenzylguanidine scintigraphy and bone scan, and the influence of histology.

The purpose of this work was to compare technetium-99m-diphosphono-propanedicarboxylate (DPD) and iodine-123-metaiodobenzylguanidine (MIBG) scans in the diagnosis and follow-up of neuroblastoma, and to study the role of histological differentiation in the uptake of MIBG. The uptake of MIBG and of DPD were studied retrospectively in 27 patients with neuroblastoma (primary, residual and recurrent tumours as well as bone and bone marrow metastases). The findings were related to the histological classification of the tumours as neuroblastoma (N1), differentiating neuroblastoma (N2) or ganglioneuroblastoma (N3). Uptake of MIBG by the primary tumour occurred in 17 of 19 patients, either at diagnosis or during follow-up. There were only two false-negatives with MIBG, both of which were N3. Ten patients were studied preoperatively with both MIBG and DPD. The primary tumour showed MIBG uptake in nine of the ten and DPD uptake in eight of them. Thirty-five sites of cortical bone metastasis were shown in eight patients by both MIBG and DPD, 12 sites in seven patients by MIBG only and seven sites in five patients by DPD only. In 14 patients both MIBG and bone scan were negative. Overall, MIBG demonstrated more lesions than DPD. Retrospectively several hot spots seen only with the bone scan are to be considered as false-positive. The highest incidence of false-negative MIBG and bone scans was observed in ganglioneuroblastoma with a predominance of the more mature component (ganglioneuroma).