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Neuroblastoma With Symptomatic Spinal Cord Compression at Diagnosis: Treatment and Results With 76 Cases

From the Departments of Hematology-Oncology and Neurology, Giannina Gaslini Children’s Hospital, and Clinical Epidemiology Unit, National Institute for Cancer Research, Genova; Division of Oncology, Bambino Gesù Children’s Hospital, Roma; and Department of Pediatrics, Universities of Bari, Bologna, Brescia, Catania, Firenze, Napoli, Padova, Palermo, and Torino, Italy.

Address reprint requests to Bruno De Bernardi, MD, Giannina Gaslini Children’s Hospital, Largo Gerolamo Gaslini 5, 16147 Genova, Italy; email brunodebernardi{at}ospedale-gaslini.ge.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: To report on the treatment of patients with newly diagnosed neuroblastoma presenting with spinal cord compression (SCC).

PATIENTS AND METHODS: Of 1,462 children with neuroblastoma registered between 1979 and 1998, 76 (5.2%) presented with signs/symptoms of SCC, including motor deficit in 75 patients (mild in 43, moderate in 22, severe [ie, paraplegia] in 10), pain in 47, sphincteric deficit in 30, and sensory loss in 11. Treatment of SCC consisted of radiotherapy in 11 patients, laminectomy in 32, and chemotherapy in 33. Laminectomy was more frequently performed in cases with favorable disease stages and in those with severe motor deficit, whereas chemotherapy was preferred in patients with advanced disease.

RESULTS: Thirty-three patients achieved full neurologic recovery, 14 improved, 22 remained stable, and eight worsened, including three who become paraplegic. None of the 10 patients with grade 3 motor deficit, eight of whom were treated by laminectomy, recovered or improved. In the other 66 patients, the neurologic response to treatment was comparable for the three therapeutic modalities. All 11 patients treated by radiotherapy and 26 of 32 patients treated by laminectomy, but only two of 33 treated by chemotherapy, received additional therapy for SCC. Fifty-four of 76 patients are alive at time of the analysis, with follow-up of 4 to 209 months (median, 139 months). Twenty-six (44%) of 54 survivors have late sequelae, mainly scoliosis and sphincteric deficit.

CONCLUSION: Radiotherapy, laminectomy, and chemotherapy showed comparable ability to relieve or improve SCC. However, patients treated with chemotherapy usually did not require additional therapy, whereas patients treated either with radiotherapy or laminectomy commonly did. No patient presenting with (or developing) severe motor deficit recovered or improved. Sequelae were documented in 44% of surviving patients.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
NEUROBLASTOMA IS a tumor of early childhood that originates from embryonal residues of the sympathetic nervous system.¹ In approximately one half of the cases, the primary tumor arises at the level of paravertebral ganglia. Following the connections that link these ganglia with the spinal cord, the tumor may infiltrate the adjacent intervertebral foramina and eventually compress the spinal cord and the intraspinal part of the spinal nerves.² In these instances, a variety of neurologic deficits may occur that tend to progressively aggravate, ending sometimes in the usually irreversible pattern of transverse myelopathy (quadriplegia or paraplegia, depending on level of compression).³ Clearly, the timely detection of spinal cord compression is of crucial importance to avoid late sequelae capable of greatly altering the quality of life. Unfortunately, the signs/symptoms by which spinal cord compression manifests are difficult to diagnose at an early phase, especially in the youngest patients.^4,5

Treatment of symptomatic spinal cord compression in neuroblastoma at diagnosis remains a controversial issue. Radiation therapy, decompressive laminectomy, and chemotherapy may all be effective. There are, however, remarkably different opinions on which therapeutic modality should be preferred in a given situation.^4,6-10 Because any of these treatments may cause potentially severe toxicity, the information derived by large series of patients could help determine the optimal therapy for individual patients.

Because the literature concerning this issue is scarce and the majority of published reports focus on small numbers of patients, the Italian Cooperative Group for Neuroblastoma (ICGNB), an affiliation of the Italian Association for Pediatric Hematology and Oncology, undertook a retrospective review of the data concerning children with neuroblastoma diagnosed in the participating institutions who at the time of presentation had clinical evidence of spinal cord compression.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
To the purpose of this study, the authors reviewed the records of 1,462 children with previously untreated neuroblastoma (ranging in age between 0 and 15 years at the time of diagnosis) who were enrolled in the ICGNB Registry in the period from January 1979 to December 1998 from 22 Italian institutions (see Appendix).

Patient Staging and Treatment Modalities
Disease extension was graded according to the ICGNB criteria ¹¹ until mid-1988 and according to the criteria of the International Neuroblastoma Staging System¹² thereafter. However, to obtain a uniform classification of disease extension, patients of the former period were reclassified according to the International Neuroblastoma Staging System and are herewith reported accordingly.

In the 20-year study period, five consecutive protocols were applied (ICGNB79, ICGNB82, ICGNB85, ICGNB89, and ICGNB92). Treatment of the tumor depended on the current protocols for the specific disease stage. In brief, stage 1 and 2 patients received little or no chemotherapy,¹² stage 3 patients received chemotherapy after biopsy in preparation for surgery,¹³ and stage 4 patients received chemotherapy of different intensity in relation to the period of diagnosis and age at onset.¹⁴ Stage 4s patients were usually treated only if life-threatening disease progression had developed.

Inclusion Criteria and Identification of Patients With Spinal Cord Compression
Requirements for patients with neuroblastoma to be eligible for this study included the following: (1) presentation with the clinical pattern of spinal cord compression, which included motor deficit, sphincteric dysfunction (see Definition of Sphincteric Dysfunction for definition), back and/or radicular pain, and sensory deficit in any combination, and (2) documentation of spinal cord compression by imaging studies. The serendipitous detection by imaging studies of intravertebral foramina infiltration by tumor or even of spinal cord compression in patients free of any neurologic complaints was considered inadequate to make a patient eligible for this analysis.

On this basis, the case report forms of the 1,462 neuroblastoma patients were reviewed to detect information relative to the existence of symptoms and/or signs of spinal cord compression. Seventy-six patients meeting the above eligibility criteria were encountered. The institutions where patients had been diagnosed and treated were requested to provide additional information concerning the interval between the appearance of neurologic symptoms and the definitive tumor diagnosis, the level and extension of spinal cord compression, details on neurologic abnormalities and their evolution before therapy, timing of therapeutic modalities, the response of neurologic deficits to specific therapy, and the long-term results in term of survival and sequelae, if any.

Imaging Studies
The imaging techniques suitable to document the extension of the tumor into the spinal canal varied considerably during the time of the study. Myelography was the only method used for patients diagnosed before 1982. Subsequently, computed tomography was used with increasing frequency for reason of its obvious advantages. Magnetic resonance imaging has been used in most cases since 1988 and is presently considered the technique of choice to accurately document the presence and the extension of spinal cord compression.¹⁵

Grading of Motor Deficit
The entity of motor deficit was evaluated retrospectively using a modification of the American Spinal Injury Association Impairment Scale ¹⁶ and was graded as follows: grade 1, mild hyposthenia with walking disability for legs, or difficulty in raising hands above head for arms; grade 2, moderate hyposthenia with inability to walk and make movements against gravity or raise hands above head; grade 3, severe hyposthenia with paraplegia, no elicitable tendon reflexes or muscular movements.

Definition of Sphincteric Deficit
The minimal clinical findings required to define a sphincteric deficit included distended bladder, patulous anus, constant urine dripping (causing increased frequency of diaper changes), stress incontinence, and any significant variation of precedent bladder function and bowel habits.

Evaluation of Response of Spinal Cord Compression to Treatment
The definition of response of neurologic deficits to treatment was obtained by reviewing patients’ forms. Only for a minority of cases were copies of the original medical records retrieved. The judgment of the clinicians completing the forms was usually based on patient’s clinical improvement and was documented by imaging studies in a minority of patients.

Statistical Methods
Data are expressed as proportions and means as appropriate. Comparison of proportions was based on the ² test for heterogeneity, or the Fisher’s exact test when appropriate.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The overall study population consisted of 1,462 children with previously untreated neuroblastoma who were younger than 15 years of age at onset and were diagnosed in a 20-year period (1979 through 1998) in 22 institutions participating in the ICGNB. Of these 1,462 patients, seventy-six (5.2%) presented with clinical evidence of spinal cord compression, which was confirmed in all either by myelography, computed tomography, and/or magnetic resonance imaging. Three more patients (two of stage 2, one of stage 3) with evidence of spinal cord compression on magnetic resonance imaging but no neurologic abnormality and two others (both of stage 3) with unilateral leg hypotonia but no radiologic sign of spinal compression were not included in this analysis (these patients did not receive specific treatment for cord compression and all survive without neurologic abnormality).

The proportion of patients with this presentation in the overall neuroblastoma population was 9.7% in the first 5-year period and decreased to 5.2%, 4.8%, and 2.7%, respectively, in the three subsequent quinquennia. There was a greater incidence of spinal cord compression in patients with localized compared with disseminated disease, both as a whole (7.7% v 2.8%) and in all four 5-year periods.

The main clinical characteristics at the time of diagnosis of these 76 patients are listed in Table 1. There were an equal number of male and female patients. Median age at diagnosis was 16 months (range, 0 to 167 months). Forty percent of the patients were infants (age between 0 and 11 months) with seven of 30 diagnosed in the first month of life. The most common site of the primary tumor was the abdomen (42 cases), followed by thorax (28 cases) and pelvis (five cases). The thoracic spine was the most frequent level of spinal cord compression (34 cases), followed by the lumbar (17) and thoracolumbar spinal regions (14). There was a majority of patients with localized versus disseminated disease (54 v 22). Among the 54 patients with localized disease, 22 were classified as stage 2 and 32 as stage 3. Among the 22 patients with widespread disease, 19 had stage 4 and the remaining three had stage 4s disease. Compared with patients without evidence of spinal cord compression, the 76 children of this series had a slightly lower median age (16 v 22 months), lower incidence of abdominal primary (55% v 79%; P < .001), and lower rate of disseminated disease (29% v 54%; P < .001).

The majority of patients (14 of 22; 64%) with resectable primary tumor (stage 2) underwent laminectomy first, whereas two were treated with radiotherapy and six with chemotherapy. In contrast, chemotherapy represented the preferred initial treatment for both patients with unresectable primary (stage 3; 17 of 32; 53%) and with disseminated disease (stage 4; nine of 19; 43%). Two of three infants with stage 4s disease (both paraplegic) were treated with laminectomy.

The only patient without motor deficit underwent laminectomy. Chemotherapy was preferred in patients with mild and moderate motor deficit (20 [46%] of 43 and 12 [55%] of 22, respectively), whereas laminectomy was applied in the large majority (eight of 10) of patients presenting with grade 3 motor deficit.

Results of Treatment of Spinal Cord Compression
As a result of treatment given to relieve spinal cord compression, 33 (43.4%) of 76 patients achieved full recovery of neurologic dysfunctions (Table 2). Recovery occurred in 31.2%, 36.4%, and 57.6% of patients treated with laminectomy, radiotherapy, or chemotherapy first, respectively.

An additional 14 patients (18.4%) achieved a significant improvement by treatment, and this occurred in six (18.8%) of 32 treated with laminectomy, three (27.3%) of 11 treated with radiotherapy, and five (15.2%) of 33 treated with chemotherapy first.

No change in neurologic conditions occurred in 22 other patients (29%), including 11 (34.4%) of 32 treated with laminectomy (including seven of the 10 patients presenting with paraplegia and one patient who become paraplegic after resection of the primary tumor), three (27.3%) of 11 treated with radiotherapy, and eight (24.2%) of 33 treated with chemotherapy.

Finally, seven patients (9.2%) did worse during treatment. Five of these seven patients had been treated with laminectomy (15.4% of patients treated by laminectomy); one with radiotherapy (9% of the patients treated by radiotherapy), during which the patient became paraplegic; and one (3%) with chemotherapy, who also developed paraplegia. None of these three patients with paraplegia occurring during treatment subsequently improved.

Results of Treatment in Relation to the Entity of Motor Deficit
The initial entity of motor dysfunction was strongly associated with the probability of patients to respond to treatment (Table 3). The large majority of patients with grade 1 motor deficit either recovered or improved (overall 74.4%) versus 63.7% of those with grade 2 deficit. None of the 10 patients presenting with paraplegia improved despite laminectomy (eight cases), radiotherapy, or chemotherapy (one case each). When the entity of motor deficit was taken into account, no clear-cut differences in the neurologic outcome could be observed, possibly because of the small numbers involved.

Long-Term Sequelae
At time of this analysis, 30 (44%) of the 54 surviving patients present significant sequelae attributable to the combined effects of tumor and treatment. Fifty-nine percent of patients treated with chemotherapy were free of sequelae, compared with 38% of those treated with laminectomy and 40% of those treated by radiotherapy. Scoliosis represents the most common late effect, affecting 17 (31%) of the surviving patients, and is more frequent in patients treated with laminectomy or radiotherapy compared with those treated with chemotherapy (33% and 60%, respectively, v 7%). However, the group of patients treated with laminectomy includes eight of 10 patients presenting with grade 3 motor deficit (paraplegia), a condition in which severe scoliotic changes almost always occur. Ten surviving patients, including six of 21 treated with laminectomy and four of 27 treated with chemotherapy, suffer sphincteric deficits, with five of them requiring multiple daily catheterizations.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
In this article, the clinical course of 76 children with neuroblastoma who presented with symptomatic spinal cord compression has been retrospectively reviewed. They represent 5.1% of all cases of neuroblastoma registered in a 20-year period into the ICGNB Registry by 22 Italian institutions. Of note, the incidence of this complication has lowered from 9.7% to 2.7% during the time of this study, suggesting a progressively earlier diagnosis that might have been associated with less time for the tumor to progress into the spinal canal and cause neurologic dysfunction. Another reason for this reduced incidence could be the fact that some patients may have received specific therapy before tumor diagnosis was made, rendering them ineligible for more recent trials requiring no previous antitumor treatment given.

The above overall percentage is comparable to the ones reported by others authors in small series,^{4,6,7-10,18-21} whereas it is far from the 13% reported in the relatively large series (42 cases) recently published by Plantaz et al.²² However, in this French study, the diagnosis of spinal cord compression was based on the evidence by imaging of the infiltration of the spinal canal by tumor and did not require the coexistence of neurologic abnormalities; thus 15 of these 42 patients underwent treatment for spinal cord compression despite being neurologically normal.

Compared with other patients of the ICGNB registry, the 76 children of this study had a younger median age at diagnosis and, more often, a thoracic location of the primary and localized rather then disseminated disease. Similar differences have been noticed in previous series and may partially account for the overall better outcome of children with spinal cord compression compared with others.⁴

The present analysis, like most previous studies related to this uncommon complication in a relatively rare tumor, suffers from two main limitations: (1) the small number of cases, and (2) the fact that the treatment modalities were not used in a systematic fashion, according to a predefined protocol (not to mention a randomized trial). Conversely, the decision of which treatment to apply in the individual patient was influenced by several factors, including the time of diagnosis, the treating institution, and the patient’s conditions. These limitations precluded any formal statistical comparison of the effectiveness of the individual treatment strategies. Nevertheless, the description of treatment outcomes in this series of patients, the largest reported so far, may provide useful information.

In our series, radiotherapy was used as primary treatment for 11 patients only, all diagnosed in the early phase of the study. Subsequently, it was abandoned because of its deleterious effect on bone growth in youngsters.

The discussion on the therapeutic strategy in the presence of spinal cord compression therefore pertains to the surgical versus the chemotherapeutic option. In fact, a comparable number of cases in our series (32 v 33) were treated with laminectomy and chemotherapy first, respectively. The decision to operate rather than give chemotherapy first was not affected by the time period in which the diagnosis of neuroblastoma was made, but rather depended on the disease extension, the severity of neurologic deficit, and, in some cases, the pressure of the local neurosurgeon. In general, spinal cord compression in patients with resectable primary tumor (stage 2 disease) was more often treated with surgery than by chemotherapy, whereas patients with unresectable primary or widespread disease (except for stage 4s) were more frequently treated with chemotherapy first. Furthermore, patients presenting with more severe neurologic deficit more often underwent laminectomy (eight of 10 with paraplegia did so), although none of them recovered or even improved.

As far as the neurologic response to treatment is concerned, our data indicate that full recovery was achieved in at least 30% of the cases with all three therapeutic modalities. The recovery rate obtained with surgery was apparently lower, but this is in part explained by the fact that laminectomy was the preferred therapeutic approach for patients presenting with paraplegia, a condition which is almost always irreversible. The percentages of patients whose neurologic conditions improved or remained stable were similar with each therapeutic modality. Of seven patients who did worse, five had been treated with laminectomy first. However, the three patients for whom the worsening translated into a condition of paraplegia were first treated by laminectomy, radiotherapy, and chemotherapy, respectively. It may be possible that laminectomy is overall endowed with greater risk or is perhaps less effective in less-experienced hands.

Our data suggest that chemotherapy is at least equally effective as other therapeutic modalities, even in low-stage patients. One advantage of using chemotherapy first is that most patients so treated do not need further specific therapies, and in particular may avoid laminectomy, whereas almost all patients undergoing laminectomy do receive additional specific therapy.

Forty percent of survivors developed significant late effects, with scoliosis and sphincteric deficit more frequently represented. A similar figure was recently reported by Hoover et al.²³ In particular, scoliosis affects approximately one third of patients (seven of 32) who underwent laminectomy, but it must be noted that most of these patients were paraplegic at presentation, and this condition favors per se the establishment of severe spine changes. Sphincteric deficits, another troublesome disturbance, affected 10 patients, who had been treated either with surgery (six patients) or chemotherapy (four patients).

In summary, although our data do not definitely demonstrate the superiority of chemotherapy to laminectomy in terms of capacity to relieve the effects of spinal cord compression in children with neuroblastoma, they indicate that a pure medical treatment can be applied to these patients without risk of undertreating them. Most of these patients do not require further therapy to consolidate the neurologic improvement, whereas this is considered necessary in almost all patients treated with laminectomy. Finally, the chance of developing late sequelae seems lower if laminectomy is not performed. We therefore suggest that chemotherapy is the preferable primary therapeutic approach for children with neuroblastoma presenting with this complication.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Participating institutions (with main investigators) are as follows: Giannina Gaslini Children’s Hospital, Genova (Bruno De Bernardi, Claudio Gambini, Alberto Garaventa, Elisabetta Viscardi, Claudio Granata, and Nora Marchese); Bambino Gesù Children’s Hospital, Roma (Alberto Donfrancesco, Aurora Castellano, and Camillo Boglino); Department of Pediatrics, University of Napoli, Napoli (Fiorina Casale and Maria Teresa Di Tullio); Department of Pediatrics, University of Torino, Torino (Luca Cordero di Montezemolo and Paola Pistamiglio); Department of Pediatrics, University of Padova, Padova (Modesto Carli, Gianni Bisogno, and Emanuele D’Amore); Department of Pediatrics, University of Bari, Bari (Serenella Bagnulo and Nicola Santoro); Department of Pediatrics, University of Bologna, Bologna (Antonia Mancini, Patrizia Alvisi, and Silvana Federici); Department of Pediatrics, University of Ancona, Ancona (Leonardo Felici); Department of Pediatrics, University of Palermo, Palermo (Margherita Lo Curto, Gabriella Fugardi, and Fortunato Siracusa); Department of Pediatrics, University of Brescia, Brescia (Alberto Arrighini); Burlo Garofalo Children’s Hospital, Trieste (Paolo Tamaro and Paolo Zanazzo); Department of Pediatrics, University of Modena, Modena (Monica Cellini); Department of Pediatrics, University of Parma, Parma (Giancarlo Izzi); Department of Pediatrics, Second University of Napoli, Napoli (Amedeo Fiorillo); Department of Pediatrics, University of Catania, Catania (Andrea Di Cataldo); Department of Pediatrics, University of Firenze, Firenze (Gabriella Bernini and Angela Tamburrini); Division of Pediatrics, Civic Hospital, Bergamo (Pier Emilio Cornelli); Division of Pediatric Surgery, Civic Hospital, Vicenza (Maria Angelica Fabbro); Department of Pediatrics, University of Perugia, Perugia (Augusto Amici); Department of Pediatrics, University of Siena, Siena (Antonio Acquaviva); and Department of Pediatrics, University of Cagliari, Cagliari, Italy (PierFranco Biddau and Roberto Targhetta).

	ACKNOWLEDGMENTS

 
Supported in part by Applicazione Cliniche per la Ricerca Oncologica-Consiglio Nazionale delle Ricerche grant no. 96.00691.PF39, Roma; and Associazione Italiana Neuroblastoma, Genova, Italy.

We acknowledge the secretarial assistance of Samantha Martini and the useful comments of Dr Maria Luisa Garré.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
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Submitted March 9, 2000; accepted July 18, 2000.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by De Bernardi, B. Articles by Bruzzi, P. Search for Related Content PubMed PubMed Citation Articles by De Bernardi, B. Articles by Bruzzi, P. Social Bookmarking                            What's this?