Peripheral neuroblastic tumors and congenital heart disease. Possible role of hypoxic states in tumor induction.

Peripheral neuroblastic tumors (PNT), including neuroblastomas, pheochromocytomas, ganglioneuromas, and paragangliomas, have been reported in association with congenital heart disease (CHD). If a significant correlation between PNT and CHD could be demonstrated, it would suggest that peripheral neuroblastic tumors might represent reactive, secondary phenomena rather than independent or incidental events. We examined this question by reviewing the autopsy files of The Johns Hopkins Hospital and found that the frequency of congenital cardiovascular problems among patients with PNT was significantly greater than the frequency of CHD in the general autopsy population (p less than 0.001). There was no correlation between CHD and central neuroblastic tumors (CNT), i.e., medulloblastomas, retinoblastomas, or pinealoblastomas, or between CHD and metastatic malignant melanoma. We examined the hypothesis that erythropoietic activity, as might be stimulated by hypoxia, was correlated with the presence of peripheral neuroblastic tumors. We found that most (87%) cardiac malformations associated with PNT produced cyanosis, and histologic assessment of hematopoiesis revealed greater activity in patients with PNT (with or without CHD) compared to those with CNT (p less than 0.05) or malignant melanoma (p less than 0.05). In addition, patients with PNT and CHD had higher frequencies of extramedullary hematopoiesis compared to age-matched controls with similar congenital heart defects (p less than 0.05), and compared to patients with CNT or metastatic malignant melanoma (p less than 0.01). These results suggest that peripheral neuroblastic tumors may arise in a setting of chronic hypoxia produced by congenital heart disease.