Radiation-Induced Arteritis

Comparison with Arteriosclerosis

Radiation-associated arterial lesions and arteriosclerosis are both segmental in nature, although the latter can be diffuse. It is axiomatic that the vessels affected by radiation lie within the field of treatment. Similarly, vessels outside the irradiated field are essentially disease-free. Associated injuries to adjacent tissue such as skin, muscle, lung, rectum, bladder, and other tissues can occur. However, venous injury is rare, and we have not observed clinically relevant damage to nerves adjacent to radiation-injured arteries.

The sites of radiation arteritis are atypical compared with the segmental distribution of arteriosclerotic lesions. In the cerebrovascular circulation, one or both common carotid arteries may be affected while the bifurcation is spared. Subjacent vertebral arteries often are narrowed not at their origins but distally, corresponding to the radiation portal. When carotid bifurcation disease is identified by a bruit, there may be an external carotid stenosis rather than the more prevalent bifurcation and internal carotid involvement.

Clinically important upper extremity ischemia following radiation therapy for breast carcinoma usually results from poorly collateralized, often ulcerated occlusive lesions near the subclavian–axillary junction. In contrast, arteriosclerosis usually arises proximally at the subclavian artery origin, not infrequently with an associated steal syndrome. Additional sites of atypical arterial stenosis include isolated renal artery lesions after abdominal irradiation for Hodgkin’s disease, external iliac artery lesions after uterine or prostate cancer treatment, superficial femoral artery occlusion many years after successful radiation of lower extremity sarcoma, and midaortic and visceral artery stenosis decades after external irradiation to the midabdomen for a variety of neoplasms.

The clinical syndromes of radiation arteritis tend to present 10 to 15 years earlier than those of arteriosclerosis. This relative prematurity has been observed for both carotid and subclavian–axillary occlusions. The coexistence of risk factors for arteriosclerosis, such as hyperlipidemia, male gender, smoking, and hypertension, also predisposes to radiation arteritis. For example, 26 of the 28 patients in our study were smokers. The microscopic similarity of arteriosclerosis and radiation-induced lesions suggests possible shared pathogenic mechanisms. It is believed that superimposed arteriosclerosis can accelerate the development of stenosing or aneurysmal lesions initiated by irradiation.

Pathophysiology

Early and late sequelae of arterial irradiation have been characterized clinically and histopathologically. The severity of the arterial injury is related to radiation dose. Smaller doses cause lesser degrees of cellular damage, whereas larger doses may be acutely or subacutely necrotizing. Macroscopic radiation effects include arterial spasm and epithelial denudation. Within 24 hours, intimal disruption, subintimal edema, and internal elastic membrane fragmentation are widespread. This is followed by degeneration of collagen and smooth muscle. Subsequently, adventitial fibrosis, hemorrhage, and lymphocytic infiltration occur. The sensitivity of elastic tissue to irradiation damage, in particular, might partially account for the preferential occurrence of rupture in affected elastic arteries.

Signs of healing tend to occur along with myointimal fibrous proliferation and luminal resurfacing with nonendothelial cells. The resultant artery, with its altered architecture, can undergo subsequent arteriosclerotic degeneration with foam cell deposition and plaque formation. Diminished fibrinolytic activity, endothelium-derived plasminogen activator activity, and prostacylin synthesis have been reported.

Among early lesions (<5 years), mural thrombosis predominates. Findings in intermediate lesions (5–10 years) include panmural fibrosis, occlusions, and a relative lack of collaterals. Late lesions (mean, 26 years) exhibit periarterial fibrosis incorporating a pronounced arteriosclerosis.

Clinical Manifestations

The lengthy interval between irradiation and the appearance of the arterial lesion requires either cure of the underlying malignancy or a very long disease-free interval. None of our 28 patients with symptomatic arterial lesions had recurrent or residual cancer. Because of this latency and the mortality from cancer, the true incidence of arterial lesions is unknown. Not to be overlooked are important lesions of the aorta in children and symptomatic coronary artery stenoses.