Ann Thorac Surg 1997;64:1827-1829
© 1997 The Society of Thoracic Surgeons
Case Report
Intraoperative Discovery of Neuroblastoma in an Infant With Pulmonary Atresia
Doff B. McElhinney, MS,
V. Mohan Reddy, MD,
Burt G. Feuerstein, MD, PhD,
Gerald R. Marx, MD,
Frank L. Hanley, MD
Division of Cardiothoracic Surgery and Departments of Laboratory Medicine and Neurosurgery, University of California, San Francisco, San Francisco, California
Accepted for publication July 26, 1997.
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Abstract
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There have been 28 previously reported cases of neuroblastoma associated with congenital heart disease. Because many of these have been defects of the conotruncal region, it has been proposed that abnormal neural crest cell migration or maturation may be a factor that links these normally disparate pathologic conditions. Most neuroblastomas in these cases have been detected at autopsy or by radiologic studies conducted in the evaluation of the cardiac anomalies. Recently, we discovered an occult posterior mediastinal neuroblastoma in a patient undergoing a unifocalization procedure for tetralogy of Fallot with pulmonary atresia and major aortopulmonary collaterals. The tumor was resected, and the patient has demonstrated no evidence of residual or metastatic neuroblastoma.
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Introduction
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See also page 1829.
Neuroblastoma is the most common malignancy in infants, and can present as either clinically apparent disease or an occult tumor detected incidentally [1]. Neuroblastoma associated with congenital heart disease has been described in 28 patients (Table 1
) ranging in age from 2 days to 6 years when the tumor was detected [2–8]. Most cases (n = 18; 64%) were occult tumors detected at autopsy. Several investigators have reported an elevated incidence of congenital heart disease (especially conotruncal defects) in patients with neuroblastoma [2, 3, 6], and it has been proposed that abnormal neural crest cell migration may be responsible for this association [7]. Recently, we operated on a 6 month-old patient with tetralogy of Fallot, pulmonary atresia, and major aortopulmonary collateral arteries in whom an occult mediastinal neuroblastoma was discovered intraoperatively and removed during a unilateral unifocalization procedure.
The patient was noted on the first day of life to be cyanotic. Cardiac evaluation was performed and the patient was diagnosed with tetralogy of Fallot, pulmonary atresia, and major aortopulmonary collateral arteries. Cytogenetic analysis revealed a normal 46 XX karyotype. In addition, fluorescence in situ hybridization was performed to assess for chromosome 22q11 microdeletions. For the fluorescence in situ hybridization study, a cocktail of probes for the DiGeorge region (q11.2) on chromosome 22 (D22S75/D22S39) was used, and all cells showed two signals, suggesting that there was no deletion. Cardiac catheterization at 2 months of age showed a right aortic arch, pulmonary atresia, absence of true pulmonary arteries, and pulmonary blood supply via six collateral arteries that arose as three trunks from the descending aorta and divided to supply both lungs. The collaterals were severely hypoplastic, and multiple segmental level collateral stenoses were present. The patient was referred to the University of California, San Francisco, for surgical management.
Due to the multiple distal stenoses, we decided to unifocalize the right and left lung collaterals sequentially through thoracotomy incisions rather than in one stage through a midline approach. The right lung collaterals were unifocalized first, at 3 months of age, with the centralized neo-pulmonary artery supplied by a 4-mm systemic–pulmonary artery shunt. The postoperative course was complicated by respiratory distress due to tracheobronchial malacia. As a result, we decided to postpone unifocalization of the left lung, which we had intended to perform during the same hospitalization.
Three months later, when the patient was 6 months old, she was readmitted to the University of California, San Francisco, for unifocalization of the left lung collaterals. A standard left posterolateral thoracotomy was performed, the left pleural cavity was exposed, and a bulky mass of tissue measuring approximately 3 x 4 cm was discovered posterior to the lung, immediately to the left of the spinal column. The mass had the color and texture of lymph node tissue and did not appear to be invasive. However, it was in close proximity to the intervertebral foramina and gross extension into the spinal canal could not be ruled out. The mass was carefully resected to its full extent and sent for pathologic examination.
Histopathologically, the mass was interpreted as neuroblastoma. It was composed of small round cells, with no evidence of differentiation, rare pseudorosettes, and a very high index of mitosis with karrhyorhexis. Immunohistochemical stains for neuron-specific enolase, chromogranin, and S-100 were positive, and the stain for leukocyte common antigen was negative. Fluorescence in situ hybridization was performed to assess for NMYC gene amplification by dissociating the paraffin-embedded specimen into isolated nuclei, which were dropped onto glass slides and hybridized with a centromeric probe to chromosome 1 (PUC177, labeled with digoxigenin) and a cosmid probe to NMYC (obtained from A.T. Look, St. Jude's Hospital, Memphis, TN) labeled with digoxigenin. Nuclei had two, three, or four signals of both the centromeric probe and NMYC, which indicated no evidence of NMYC gene amplification, giving a more favorable prognosis than when NMYC is amplified. Magnetic resonance imaging, whole-body meta-iodobenzyl guanidine iodine-123, and technetium-99m bone scans did not show any evidence of metastasis.
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Comment
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Studies have yielded conflicting data regarding the relative frequency of congenital heart defects in patients with neuroblastoma, with some finding an increased incidence [2, 3, 6] and others concluding that the rate of coincidence does not differ from that in the general population [4, 5]. Regardless of whether congenital heart disease is more common in patients with neuroblastoma than in the general population, the high percentage of conotruncal defects among the 29 cases that have been reported is notable (45%, including transposition of the great arteries, tetralogy of Fallot, and arch anomalies). It has been proposed that neuroblastoma may be stimulated or potentiated by chronic hypoxia [6]. This hypothesis is based on the finding that extramedullary hematopoiesis was higher in patients with neuroblastoma than in those with primitive neuroectodermal tumors of the central nervous system, and that extramedullary hematopoiesis was significantly higher in patients with both neuroblastoma and congenital heart disease than in those with only one or the other or with central nervous system tumors of neuroectodermal origin [6]. However, patients with congenital heart disease have been diagnosed with neuroblastoma as early as 2 days of age [7, 8], which is difficult to explain solely on the basis of chronic hypoxia. Bellah and associates [7] have proposed that a more fundamental anomaly of aberrant neural crest cell development or migration may be responsible for the association of neuroblastoma with congenital conotruncal heart defects, which is based in part on evidence that neural crest cells are involved in conotruncal development [9]. This theory is supported by the recent discovery of an association between neuroblastoma and Hirschsprung's disease, which is also thought to result from disturbances in neuroendocrine cell migration [10]. Although chronic hypoxia is unlikely to be the primary etiologic factor in cases of neuroblastoma with congenital heart disease, it is possible that hypoxia potentiates the growth of neural crest derivative cells that may have developed abnormally due to a more fundamental neurocristopathy. It should be noted that conotruncal defects not characterized by hypoxemia, such as truncus arteriosus and interrupted aortic arch, have not been described in association with neuroblastoma, although these defects are also less common in general than tetralogy of Fallot and transposition. Moreover, tetralogy of Fallot and transposition of the great arteries are relatively common forms of severe lesions, and as such may be overrepresented in autopsy series. The issue is complicated by the fact that the incidence of clinically silent neuroblastoma may be higher than autopsy and clinical studies suggest [2], and that neuroblastoma in infants has a propensity to mature, making it especially difficult to estimate the true incidence. It may be significant that 80% (n = 23, including ours) of the reported cases of neuroblastoma associated with congenital heart defects have been localized tumors with no detectable metastasis and no clinical symptoms, discovered incidentally either at autopsy or during clinical evaluation of the cardiac anomalies. Among the 6 patients with clinically apparent neuroblastoma (see Table 1
), two of the most common forms of congenital heart disease in the general population (ventricular septal defect and isolated pulmonary stenosis) were present in 5, whereas the other patient had a probable acyanotic conotruncal defect (unspecified arch anomalies). Although it is difficult to generalize on the basis of 6 patients, it seems that the predominance of conotruncal defects (if true) is most dramatic among patients with occult neuroblastoma, and that those with clinically apparent neuroblastoma had a spectrum of heart defects more representative of the population at large.
Several genetic studies were performed on our patient in the course of evaluation. Metaphase analysis revealed a normal karyotype. There was no evidence of chromosome 22q11 microdeletions, which are commonly found in patients with conotruncal heart defects and which are thought to affect neural crest cell migration [9]. In addition, there was no amplification of the NMYC gene in the tumor, which ruled out this poor prognostic factor. Unfortunately, fluorescence in situ hybridization results or other specific genetic studies have not been reported in the previously described 28 patients, so the negative findings from our patient can only serve as a beginning in the study of this question. In the future, the task will be to sort out whether a common genetic perturbation is responsible for the coincidence of these two anomalies, or whether they occur together by chance. NMYC amplification and abnormalities of chromosome 1 are the most commonly investigated genetic aberrations associated with neuroblastoma because of their prognostic value, but many others have been identified. Recent work using comparative genomic hybridization identified chromosome 17 gain as the most frequent of the various genetic abnormalities in symptomatic neuroblastoma [11]. This technique and flow analysis might be used to help identify specific genetic anomalies that are associated with coincident neuroblastoma and conotruncal congenital heart defects.
Although a mere 29 cases of neuroblastoma associated with congenital heart disease have been described in the literature, it is important for surgeons to be aware not only of this association, but also that it is possible to find and definitively manage an unexpected tumor during an operation for congenital heart disease. Our patient is now 2 years of age and has no evidence of residual or recurrent neuroblastoma on follow-up chest roentgenograms, computed tomography scans, or subsequent operations for her congenital heart disease.
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Footnotes
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Address reprint requests to Dr Reddy, 505 Parnassus Ave, M593, San Francisco, CA 94143-0118.
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References
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Abstract
Introduction
