JADA Continuing Education
Detection of radiation-accelerated atherosclerosis of the carotid artery by panoramic radiography
A new opportunity for dentists
ARTHUR H. FRIEDLANDER, D.D.S. and
EARL G. FREYMILLER, D.M.D., M.D.
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ABSTRACT
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Background. The authors review the pathophysiology, epidemiology, course of disease, dental findings and dental treatment of patients who developed atherosclerosis of the carotid artery after having received therapeutic radiation to the neck for squamous-cell carcinoma of the oral cavity, pharynx or larynx; salivary gland tumors; and lymphomas involving the cervical lymph nodes.
Type of Studies Reviewed. The authors conducted a MEDLINE search for 1997 through 2002 using the key terms "radiation therapy," "carotid artery" "atherosclerosis," "cancer" and "dentistry." The articles selected for further review included those published in English in peer-reviewed journals, with preference given to articles reporting randomized, controlled trials.
Results. Recent advances in the delivery of radiation therapy to malignancies of the head and neck have resulted in the prolonged survival of increasing numbers of patients. However, the therapy has been implicated as causing atherosclerotic lesions in the cervical component of the carotid artery, which predisposes patients to an increased risk of developing stroke. Panoramic radiography can identify some of these lesions before they can cause a stroke. Radiation-induced atherosclerosis is common, with approximately 40 percent of patients developing hemodynamically significant carotid artery plaques within 10 years of having received irradiation.
Clinical Implications. Dentists treating patients who have received therapeutic radiation to the neck should examine the patients’ panoramic radiographs for evidence of atheromalike calcifications, which appear 1.5 to 2.5 centimeters posterior and inferior to the angle of the mandible. Patients with evidence of such lesions should be referred to their physician for an ultrasound examination of their carotid arteries.
Therapeutic radiation of the neck often is a necessary component of care for people with squamous-cell carcinoma of the oral cavity, pharynx and larynx; salivary gland tumors; and lymphomas involving the cervical lymph nodes. Dentists treating these patients traditionally have devoted their efforts to surveillance for signs of new or recurrent disease, managing xerostomia and preventing the development of radiation caries and osteoradionecrosis.1
Dentists treating patients who have received therapeutic radiation to the neck should examine the patients’ panoramic radiographs for evidence of atheromalike calcifications.
In the past four to five years, however, researchers have noted that radiation therapy is associated with an accelerated form of atherosclerosis (atheroma formation) in the cervical portion of the carotid artery, and a consequent increase in the risk of stroke.2–5 In some cases, these atheromas can be detected on panoramic radiographs, thus affording dentists an additional opportunity to assist these patients.6
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PATHOLOGY
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The atherosclerotic process is initiated by radiation injury to the endothelial cells lining the lumen of the carotid artery. This results in increased permeability, which permits circulating low-density lipoproteins to pass into the subendothelial space. In addition, platelets aggregate at the injury site and release growth factors that cause the smooth muscle cells of the vascular wall to hypertrophy. The resultant thickened and elevated lesion slowly calcifies and protrudes into the lumen, altering blood flow and becoming a nidus for embolus formation.
Radiation therapy also causes loss of smooth muscle cells in the carotid artery’s tunica media, as well as inflammation and hemorrhage in the tunica adventitia and fragmentation of the internal elastic membrane. In addition, radiation therapy injures the vasa vasorum, the nutrient supply to the outer two-thirds of the carotid artery wall. The vasa vasorum’s endothelial cells swell and detach, its walls thicken and its lumen occludes. These changes cause ischemia in the carotid artery wall and result in fibrotic (sclerotic) thickening of all of the wall’s components.7,8 Similar pathological changes have been demonstrated in other vascular territories (that is, the aorta and the coronary, iliac, renal and femoral arteries) where radiation therapy has been used to treat malignant disease.9–13
Identifying patients with occult carotid artery atheromas is of vital significance because it may be a sign of heightened risk of developing stroke.
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EPIDEMIOLOGY AND COURSE OF DISEASE
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Atherosclerosis associated with radiation therapy, while histologically similar to spontaneous atherosclerosis, is clinically distinct because it is limited to the irradiated area and is less likely to be associated with atherogenic risk factors (that is, aging, male sex, hypertension, cigarette smoking, diabetes and hypercholesterolemia) and concomitant illnesses (that is, coronary artery disease and peripheral vascular disease).14
Ultrasound studies of neurologically asymptomatic patients demonstrate that in the initial postradiation phase (months 1 through 8), the carotid artery lumen is unaffected.15,16 During the ensuing years (1 through 3), however, significant atherosclerotic luminal narrowing occurs, even though the patient may remain neurologically asymptomatic.17–21 In fact, these studies have shown that almost one-third of patients who received radiation therapy have hemodynamically significant carotid artery plaques (that is, blocking 50 percent or more of the vessel’s lumen), compared with approximately 4 percent of control patients.22–26 Estimations of the prevalence of radiation-induced extracranial carotid artery disease vary widely, with some scientists postulating that more than 50 percent of patients have severe stenosis or occlusion.27
Radiation dosages associated with the development of atherosclerosis range from 35 to 44 gray, which are used to treat patients with Hodgkin’s and non-Hodgkin’s lymphoma, to the significantly higher dosages of 50 to 80 Gy used to treat patients with squamous-cell carcinoma of the head and neck.28–30 The latency period (that is, the time from radiation therapy to neurological symptoms [historically reported as taking decades]) also varies significantly between patients.31,32 An acute ischemic stroke may be the first manifestation of radiation-induced atherosclerosis.33–36 Radical neck surgery and chemotherapy, however, do not appear to influence the prevalence of radiation-induced atherosclerosis.37
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DENTAL FINDINGS
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Identifying patients with occult carotid artery atheromas is of vital significance because it may be a sign of heightened risk of developing stroke.38,39 Historically, screening for cervical carotid artery atheromas was solely via auscultation of the neck in search of a bruit, and was only within the purview of physicians. At best, this was a crude screen, because the examination has less than 40 percent specificity when detecting disease.40 Confirmation often was wanting, but on occasion, the lesion could be visualized on a plain radiograph of the cervical spine or in the superior aspect of a standard chest radiograph. However, approximately 20 years ago, researchers prescribed a role for dentists by observing that panoramic radiographs were capable of demonstrating calcified carotid artery atheromas in neurologically asymptomatic patients who had not undergone radiation therapy.41
In recent years, researchers also have observed that the panoramic radiographs of neurologically asymptomatic men and women who had received therapeutic radiation to the neck demonstrated a statistically significant increase in the prevalence rates of atheromas. In one study, 21 percent of patients who received 50 Gy or more had atheromas on their panoramic radiographs 30 months after irradiation, while less than 5 percent of patients who did not receive irradiation exhibited such lesions.42
In a second study, 28 percent of patients who received 40 Gy or more and who developed osteo-radionecrosis of the mandible manifested atheromas on their panoramic radiographs (obtained 36 months after irradiation); by comparison, only 5 percent of patients who did not receive irradiation manifested atheromas on their radiographs.43
In the most recent study, Freymiller and colleagues44 followed for a number of years patients who had a negative panoramic radiograph at the time radiation therapy was initiated along with risk-matched control subjects to determine if and when atheromas could be detected on the panoramic radiographs. Patients who had received radiation therapy were significantly more likely (53 percent) to develop carotid artery atheromas within a three-year period than were patients who did not receive radiation therapy (5.9 percent).
The lesions harbored by the patients who received radiation therapy in all three studies had a radiographic appearance (Figures 1
and 2) that was similar to that seen in spontaneously arising calcified carotid atheromas. The lesions varied from single to multiple discrete radiopaque calcifications, and were located within the soft tissues of the neck, approximately 2.5 centimeters inferior and posterior to the angle of the mandible.45
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Figure 1. A standard panoramic radiograph that has been cropped, scanned and digitized to enhance visualization of the atherosclerotic process. The patient, a 66-year-old man with calcified carotid plaque visible in the neck (arrows), had received a radiation dose of 63 gray to the area as a component of treatment for squamous-cell carcinoma of the tongue and floor of the mouth.
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Figure 2. A standard panoramic radiograph that has been cropped, scanned and digitized to enhance visualization of the atherosclerotic process. The patient, a 62-year-old man with calcified carotid plaque visible in the neck (large arrow), had received a radiation dose of 38 gray to the area as a component of treatment for Hodgkin’s lymphoma. The small arrow delineates an area of plaque superimposed over the superior horn of the thyroid cartilage.
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DENTAL MANAGEMENT
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The ability to detect radiation-induced early-onset atherosclerosis via panoramic radiography augments dentistry’s responsibilities to this group of patients. The dentist should show the lesion to the patient, as well as its relationship to the course of the common and internal carotid arteries and the angle of the mandible. The dentist also should inform the patient that these lesions may be associated with a future cerebrovascular accident. Furthermore, the patient should be given a copy of a written consultation directed to his or her primary care physician that describes the radiographic findings and suggests that he or she undergo an ultrasound examination to confirm the presence and extent of disease. This protocol is consistent with a dentist’s professional responsibilities to diagnose oral manifestations of systemic disease and to counsel patients properly about the importance of arranging for, and following through with, the consultation.46
The physician likely will attempt to control hypertension, hyperlipidemia, cigarette smoking and hyperglycemia, if present, because irradiated vessels are uniquely susceptible to these atherogenic agents.47,48 The physician also may suggest carotid artery surgery (an arterial or venous graft, endarterectomy or percutaneous transluminal angioplasty and stenting) if the lesion is occluding more than 60 percent of the vessel’s lumen, because it has proven to be a safe and reliable method of reducing the morbidity associated with radiation-induced atherosclerosis.49 The long-term patency rates of surgery and the protection it affords against subsequent neurological events are similar to the results achieved in the absence of radiation therapy.50,51
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CONCLUSION
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Recent advances in radiation therapy have resulted in long-term survival of patients with malignancies of the head and neck; however, the treatment is associated with heightened risk of embolic or ischemic stroke because of the development of an accelerated form of atherosclerosis. Dentists caring for patients who have received irradiation should review their panoramic radiographs for evidence of atherosclerosis, and refer them for medical evaluation as indicated.
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Dr. Friedlander is associate chief of staff and director of Graduate Medical Education, VA Greater Los Angeles Healthcare System, director of Quality Assurance, Hospital Dental Service, University of California, Los Angeles Medical Center, and a professor of Oral and Maxillofacial Surgery, UCLA School of Dentistry. Address reprint requests to Dr. Fried-lander at VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd., Los Angeles, Calif. 90073, e-mail "arthur.friedlander{at}med.va.gov".
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Dr. Freymiller is chairman of Oral and Maxillofacial Surgery, School of Dentistry, University of California, Los Angeles, and chief of Dental Service, UCLA Medical Center.
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ABSTRACT
PATHOLOGY
