Both groups of patients treated with RT (IORT±EBRT and EBRT) had significantly smaller measured aortic diameters than the predicted age-adjusted normal aortic diameters before RT. Patients with neuroblastoma who received abdominal RT had a significant decrease in aortic growth. Several patients treated with IORT±EBRT developed serious complications, including MAS. MAS is a rare entity most prevalent among adolescents and young adults [22
]. Sen et al. [23
] were the first to describe it in 1963 as a severe narrowing of the proximal abdominal aorta. Clinically the main presenting symptom is hypertension and symptoms may variably include severe headache, nosebleeds, chest pain, cardiac failure and kidney failure [26
]. The etiology remains unknown [22
]. The histology of MAS is described as nonspecific dysplastic, fibrotic changes lacking signs of inflammation, or necrosis [27
The biological effect of radiation on the vasculature is well documented for the coronary arteries and microvasculature, but otherwise is not well documented [29
]. Gillette et al. [20
] described the response of canine aorta and branch arteries to experimental IORT and reported a narrowing of the aorta on aortography and a thickening of the intima on histopathology, occurring more than 5 years after IORT [30
]. From these studies, it is evident that follow-up time is an important factor when fully assessing toxicities of IORT and EBRT.
As a result of continuing therapeutic advances, children with cancer are surviving longer than in previous decades, rendering long-term follow-up studies essential for optimal treatment and continued care. Pediatric studies reviewing the effects of IORT in children involve follow-up ranges of 6 to 101 months after RT. These reports suggest that IORT improves local control of disease with high doses of radiation and that complications at doses used were trivial.
It should be noted that the populations studied were small and follow-up periods relatively short [7
]. Of note, there was no radiological documentation in the aforementioned studies of MAS. Our findings are in accordance with reports of a patient with renal artery stenosis, a patient with mesenteric artery ischemia, and a patient with hypertension after IORT for neuroblastoma [7
]. In the adult population, analyses of side effects in patients surviving more than 5 years after IORT have identified significant vascular occlusion resulting in irreversible functional damage requiring aggressive management [15
]. CT imaging studies were used because all patients underwent CT at diagnosis and subsequently to monitor disease progression and/or therapeutic response, thus allowing this retrospective review. A gold-standard modality to measure the abdominal aorta does not exist. CT and US are commonly used; however, they are both subject to significant interobserver variability. Research evaluating the size of the pediatric aorta is extremely limited and there are no recognized age-adjusted reference values for either CT or US. Fitzgerald et al. [24
] have conducted the only study that has evaluated the pediatric aortic diameter on CT. Several US studies have shown independent pediatric abdominal aortic diameter nomograms in relation to various factors such as age, gender, weight, height, body mass index and body surface area without consensus on variations in relation to sex.
Several limitations of this retrospective study have to be recognized. First, the exact etiology of the decreased aortic size and growth was uncertain, although RT is certainly plausible; yet other confounding variables must be considered. The aggressive nature of the tumor itself may have contributed to the observed decrease in pre-RT aortic diameter, and residual tumor after gross surgical resection may have caused the subsequent decreased rate of aortic growth. However, MAS was documented in four patients in remission. In addition, a specific biochemical profile/growth factor, chemotherapy, surgery, hematopoietic stem cell transplantation and/or unknown pathologic contributing factor could have contributed to the impaired aortic size and growth, and development of MAS. Evaluation of aortic size and growth in a matched cohort of neuroblastoma patients not treated with RT would provide additional information. Second, we could not determine a direct correlation between the degree of decrease in aortic caliber and vascular complications. This may have been due to potential additional contributing factors such as impairments at the level of major abdominal arteries or microvessels and the small size of the study cohort. Conversely, some of our results may describe complications not related to radiation or may be confounded by additional therapeutic procedures such as surgery. All patients who received IORT did so for gross residual disease or for tumors deemed unresectable, and so many had worse tumors, explaining the higher rate of complications, i.e. these patients may have developed the problems from the tumor and/or surgery itself. Finally, the CT imaging protocol used was not defined and institutional access to CT scans limited the cohort size and median follow-up for aortic growth. A prospective large study of comparable cohorts of patients as to the extent of disease treated with designated radiation modalities and careful uniform imaging at defined time points would be necessary to answer some of these questions.
Medical management for MAS in the pediatric population is preferred until the child has ceased growing so as to prevent a second surgery to accommodate the growth. The treatment of choice for MAS is now either a one-stage reconstructive prosthetic or autologous venous surgical arterial bypass graft.
In conclusion, limited aortic growth after RT in patients with neuroblastoma diagnosed on CT scans may be the first sign of MAS. Radiologists and clinicians should be aware of the possibility of such a diagnosis and the important consequences that arise in regard to patient management. Long-term CT follow-up studies including coronal reconstruction images are required in pediatric patients who receive IORT and EBRT to assess potential toxicities and to determine the exact complication rate.