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Subclavian Artery Occlusion Following Radiotherapy for Carcinoma of the Breast 1
Therapeutic Radiology
Joel A. Budin, M.D., William J. Casarella, M.D., and Leonidas Harlsiadls, M.D. Four cases of subclavian artery occlusion occurring 5-17 years after irradiation for breast carcinoma are presented. Although arterial insufficiency is a rarely reported sequel of radiotherapy, it may be the cause of pain and disability in the upper extremity in a postmastectomy patient. Particular attention should be paid to the presence of a bruit over the subclavian and axillary arteries. Arteriography will often reveal a short, segmental lesion of the subclavian artery that frequently can be repaired surgically. INDEX TERMS: Arteries, subclavian· Breast Neoplasms, therapeutic radiology· Radiations, injurious effects, cardiovascular Radiology 118: 169-173, January 1976
• HE
ADVERSE
effect of radical mastectomy and
Tradiotherapy upon the upper extremity in patients
with carcinoma of the breast is a common and often frustrating clinical problem. Pain, limitation of motion, and lymphedema are well recognized complications of treatment. Arterial insufficiency in the upper extremity is a much rarer sequel of therapy which may in fact be concealed by the frequent presence of lymphedema in these patients. Although scattered reports of radiation damage to large arteries have appeared in the literature, only 3 cases of subclavian artery occlusion following treatment for breast carcinoma have been reported previously to our knowledge (1, 13). We wish to present 4 additional cases of focal subclavian artery occlusive disease occurring in the field of irradiation 5 to 17 years after postoperative radiotherapy for breast carcinoma. CASE REPORTS Fig. 1. CASE I: A 61-year-old woman presented in 1972 with pain and swelling of the right upper extremity. Five years previously she had undergone a right radical mastectomy for carcinoma of the breast. She received postoperative radiotherapy on a 60CO unit. A tumor dose of 4,500 rads in 25 equal fractions over 36 days was delivered to the right supraclavicular fossa-right axilla through an anterior port measuring 8.5 X 13 cm at 60 cm SSD. It is estimated that 5,775 rads was delivered to the subclavian artery. This dose-fractionation scheme is associated with a nominal standard dose (NSD) value of 1,798 rets. In addition, the right internal mammary chain was irradiated to a tumor dose of 4,500 rads in 25 fractions over 35 days using a 7.5 X 16-cm port. Medial and lateral tangential chest wall ports measuring 6 X 15 cm were also employed for a dose of 5,500 rads in 20 fractions over 31 days. The following year a left axillary node biopsy showed metastatic disease, which was treated with 4,600 rads to the left axilla. Progressive lymphedema and pain in the right arm ensued with compromised range of motion. Physical examination revealed induration of
CASE I. Selective innominate arteriogram demonstrates high-grade stenosis of the right subclavian artery.
the skin over the right axilla and supraclavicular area compatible with radiation change, a harsh bruit over the right subclavian artery, and a weak right radial pulse. Evidence of ulnar nerve neuropathy was found. An aortic arch study and a selective innominate arteriogram (Fig. 1) revealed a high-grade 2-cm stenosis of the right subclavian artery with poor collateral circulation. It was elected to treat the patient conservatively. CASE II: A 56-year-old woman was hospitalized in 1968 because of pain in the right arm and shoulder. Seven years previously she had undergone a right radical mastectomy for carcinoma. Postoperatively she received radiation therapy on a 240 kV constant-potential x-ray unit (filtration 0.5 mm Cu 1 mm AI) operating at 50 cm FSD. A dose of 2,400 R in air in 8 equal fractions was delivered over 24 days to each of two fields: opposed right supraclavicular and right suprascapular, each measuring 10 X 15 cm. An estimated dose of
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1 From the Department of Radiology, College of Physicians and Surgeons, Columbia-Presbyterian Medical Center, New York, N. Y. Presented at the Sixty-first Scientific Assembly and Annual Meeting of the Radiological Society of North America, Chicago, III., Nov. 30-Dec. 5, 1975. elk
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Fig. 2. CASE II. Complete occlusion of the right subclavian artery is seen with reconstitution of the axillary artery through collaterals (composite of two films). 3,900 rads in 8 fractions was delivered to the subclavian artery by these fields. The NSD associated with such a treatment scheme has a value of 1,669 rets; however, the dose to the subclavian artery, especially the distal portion, is likely to be significantly higher because a supplementary direct axillary port 10 cm in diameter was employed to a dose of 2,400 R in air in 8 fractions in 24 days. In addition, the right internal mammary chain was irradiated through an 8 X 15-cm anterior port to a dose of 3,000 R in air in 10 fractions over 24 days. Physical examination revealed telangiectasia of the skin over the right shoulder and absent right axillary, brachial, and radial pulses. Arch aortography and a selective innominate arteriogram (Fig. 2) demonstrated complete occlusion of the right subclavian artery just distal to the costovertebral artery with reconstitution of the axillary artery via collateral flow. Resection of the occluded segment of the right subclavian artery was performed, and an autogenous vein graft was inserted. Microscopic examination of the occluded arterial segment demonstrated marked intimal proliferation, slight fraying of the internal elastic membrane, adventitial fibrosis, and an organizing thrombus filling the narrowed lumen (Fig. 3, A and B). Postoperatively, clinical improvement was noted with restoration of the right radial pulse.
January 1976
CASE III: A 57-year-old woman was referred in 1974 for evaluation of a dusky, painful left index finger noted.after falling on her outstretched hand. Seven years previously she had undergone a left radical mastectomy for carcinoma, with 3 out of 25 axillary nodes positive for metastases. Postoperative radiotherapy was given using a 200 kV, h.v.1. 1-mm Cu x-ray unit operating at 50 em FSD. A dose of 2,200 rads in air in 11 equal fractions was delivered over 32 days to each of the following ports: anterior supraclavicular-axillary port measuring 10 X 15 cm, posterior suprascapular port, also measuring 10 X 15 cm, and medial and lateral tangential chest wall ports, each measuring 7 X 16 cm. An estimated dose of 3,815 rads was delivered to the subclavian artery, producing an NSD value of 1,466 rets for the fractionation scheme employed. Physical examination revealed a harsh systolic murmur over the left subclavian artery with a slightly diminished left radial pulse. The left index finger was mildly cyanotic and cold. An aortic arch study (Fig. 4, A and B) demonstrated complete occlusion of the left subclavian artery 1 cm distal to its origin. Reconstitution of the distal subclavian via retrograde flow in the left vertebral artery was noted. The patient's index finger improved with conservative management. It was theorized that the trauma of the patient's fall had dislodged a fragment of an atherosclerotic plaque or thrombus in the left subclavian artery, with embolization to the index finger. CASE IV: An 87-year-old woman was hospitalized in 1974 for evaluation of pain in her left arm. Thirteen years earlier she had undergone a left radical mastectomy for an infiltrating ductal carcinoma with metastatic involvement of six axillary nodes. Postoperatively she was treated with 200 kV x rays, h.v.1. 1.3 mm Cu, 50 cm FSD. A daily dose of 250 R in air was delivered to each of three ports: anterior left supraclavicular-axillary port measuring 10 X 20 cm, posterior suprascapular port, also measuring 10 X 20 cm, and left internal mammary chain port measuring 4 X 10 cm. The total dose of lrradiation is unavailable. Over the ensuing years progressive lymphedema and pain in her left arm developed, with limitation of motion. Her symptoms were aggravated by exposure to cold. Physical examination revealed marked lymphedema of the left upper extremity with radiation changes in the skin Over the left supraclavicular area and axilla. No pulses were palpable below the subclavian in the left arm. An aortic arch study (Fig. 5) demonstrated complete occlusion of the left subclavian artery just distal to the origin of the internal mammary artery. Reconstitution of the left axillary artery through collateral channels was noted. A venogram obtained via a left antecubital vein revealed a normally patent left subclavian vein in the region of the arterial occlusion. The patient was treated conservatively.
Fig. 3. CASE II. A. Section of occluded right subclavian artery shows intimal proliferation. The narrowed lumen is filled with organizing thrombus. Adventitial fibrosis is seen. (Masson's Trichrome, 38X). B. Elastic stain shows minimal fraying and duplication of internal elastic membrane (arrows), but the media is otherwise intact (Verhoeff, 63X).
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DISCUSSION
In view of the prevalence of carcinoma of the breast in the general population, it is surprising that this manifestation of radiotherapy has not been observed more frequently _ Obviously, the majority of patients selected for radiotherapy already have evidence of lymph node or more distant metastases, and a large proportion of these patients do not survive long enough for significant arterial changes to develop, Moreover, it seems likely that the clinician may fail to consider the possibility of arterial occlusion as a contributing cause of arm pain in the postmastectomy patient. Lymphedema, contracture, and nerve-root symptoms all tend to conceal the presence of arterial insufficiency. Note that 3 of our 4 patients had significant lymphedema of the upper extremity. Several factors strongly implicate irradiation as the cause of the arterial occlusions in our series. First, the obstructing lesions in all cases were within the supraclavicular portal employed. Second, in all 4 patients the occluded segment was located distal to the origin of the subclavian artery; spontaneous atherosclerotic plaques, in contrast, typically occur at the origin of the vessel. Third, aortic arch studies in all of our patients showed relative sparing of the other aortic branches outside the field of irradiation. In the case of subclavian-axillary occlusion reported by Benson (1), and the 2 cases reported by Mavor et al. (13), the arterial lesions were similarly located distal to the origin of the subclavian artery. These patients were studied 3, 11, and 26 years after their courses of radiotherapy, respectively. Conceivably, tumor recurrence with vascular encasement might account for subclavian artery occlusion in the postmastectomy patient. Clearly, in CASE II in our series, the resected specimen was free of tumor. Although no patholoqical proof is available in the remainder of our patients, 5-17 years elapsed from the time of their mastectomies until their arteriographic studies and, moreover, 14 months-3 years have elapsed frorri the time of their radiographic evaluation until now. There has been no progression of the lesions clinically, land all patients presently are free of tumor recurrence or metastatic disease. The estimated radiation doses given the patients in this series do not seem excessive. The calculated NSD values to the subclavian artery available in 3 of our patients ranged from 1,466 to 1,798 rets. This range is somewhat higher than the NSD of 1,200 rets reported by Hayward in his patient with carotid artery occlusions (5). Since all of our patients were irradiated through multiple ports, it is conceivable that overlap of adjacent fields occurred, causing segmental stenosis to the portion of the artery underlying the area of overlap. This is a particularly interestinq consideration with reference to the patient in CASE I, in whom the stenotic segment in the subclavian artery is quite short. Unfortunately, no
Fig. 4. CASE III. A. Complete occlusion of the left subclavian artery is seen shortly beyond its origin. B. Reconstitution of the left subclavian artery is demonstrated via retrograde flow in the left vertebral artery.
Fig. 5. CASE IV. Selective left subclavian arteriogram shows complete occlusion of the left subclavian artery with reconstitution of the distal artery via scapular collaterals.
verification port films are available to substantiate this hypothesis. Whether or not overlap of adjacent fields is a factor in an individual patient, the subclavian artery receives the largest dose of all the brachiocephalic vessels when it is directly irradiated with a supraclavicular port in the usual treatment of breast carcinoma. The slowly evolving occlusion that ensues stimulates the development of collateral channels which are at a different depth from the subclavian artery and course around the periphery of the radiation field. These collateral vessels are well illustrated by the periscapular arteries in CASES II and IV (Figs. 2 and 5) and by the subclavian steal in CASE III (Fig. 4, A and B). It is well known that there is considerable individual variation in sensitivity to the effects of irradiation. The calculated arterial NSD range utilized in our patients may be tolerated well in many other subjects. There is little data available at present to explain a particular patient's radiation sensitivity. It is probable that factors such as hypertension and hyperlipidemia act synergisti-
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cally with radiation to produce arteriosclerotic change. That this is true in respect to hypercholesterolemia seems to be substantiated by Gold (3) and Lamberts and De Boer (9) (see below). Two of the patients in our series (CASES I and III) had mild essential hypertension. CASES II and IV had elevated serum cholesterol values of 306 and 359 mg/100 ml, respectively. Clinical reports of radiation damage involving the aorta (12, 20), carotid (2, 5, 7, 10, 12, 14), iliac (1, 8), femoral (1, 4, 15, 16), and more recently the coronary arteries (21) have appeared. An interesting case of "pulseless disease" was described by Heidenberg et al. in a patient who was treated with radiotherapy for Hodgkin's disease (6). Stenoses of the innominate, both common carotids, and complete occlusions of both subclavian arteries were found. Injury to large arteries in these reports ranged from rupture during the acute phase following irradiation to aneurysm formation and typical atherosclerotic lesions in the late stages. Early experimental work with radiation-induced vas~ cular injury stressed the sensitivity of the endothelium (22). Damage was most extensive in small vessels, having a proportionally larger endothelial component. Damage to major vessels was rarely seen with doses below 500 R. In 1950, Smith and Lowenthal (19) demonstrated changes in the media of elastic arteries in irradiated mice comparable to physiological aging: fraying of the elastic membrane and an increase in ground substance and in the numbers of interlamellar fibers. This work was confirmed in 1961 by Gold (3), who produced severe atherosclerotic lesions in the aorta, coronary arteries, pulmonary arteries, and endocardium by irradiating hypercholesterolemic rats. The arteriosclerotic changes were much more extensive but otherwise identical to those in a control group of rats fed a high-cholesterol diet. Lindsay et al. studied the effects of localized aortic irradiation in the dog (11). After administering doses of 1,500-5,500 R to localized aortic segments, he found typical arteriosclerotic changes in dogs sacrificed 3-48 weeks later. These changes were more pronounced with increasing time interval after irradiation, and consisted of degeneration and fragmentation of the internal elastic membrane, accumulation of mucopolysaccharide ground substance in the intima, and fibroblastic proliferation leading to diffuse intimal fibrosis or localized fibrous plaques. Similar arteriosclerotic lesions with the additional features of fatty infiltration of the arterial wall and atheroma formation were produced by Lamberts and De Boer in hypoercholesterolemic rabbits after localized irradiation of the carotid artery (9). Other investigators have related large artery injury to radiation damage in surrounding tissue rather than to the direct effect of irradiation on the vessel itself. Sams produced pathological changes similar to those described above in irradiated mice and related them to fibrosis in adjacent tissues, causing both direct pressure on the blood vessels and decreased muscular contraction leading to reduction in blood flow in the involved ex-
January 1976
tremity (18). Rubin and Casarett emphasized x-ray damage to small vessels, particularly occlusions of the vasa vasorum, which in turn cause ischemic injury to the walls of large arteries (17). Pathological examination of the occluded arterial segment was available only in CASE II in our series. Microscopically this segment showed many of the characteristic changes described above, with striking intimal thickening and superimposed thrombosis. No significant atheroma formation or fatty infiltration was noted. Some adventitial fibrosis was evident, but the few vasa vasorum included in the specimen appeared patent. Supportive evidence for a direct effect of irradiation on the subclavian artery was the finding of a subclavian vein of normal caliber in CASE IV. It is unlikely that perivascular fibrosis could cause high-grade stenosis of a major artery without leaving a similar effect on the immediately adjacent vein. The cost of arterial injury following radiotherapy appears relatively slight in view of the fact that all 4 of our patients were tumor-free at the time of their evaluation. Significant alteration in the mode of radiation treatment in order to avoid this complication seems unwarranted, since the subclavian artery is contiguous with the axillary lymph nodes draining the breast. However, it is important for the clinician to recognize that arterial insufficiency may be the source of pain and disability in the upper extremity of the postmastectomy patient. Evidence of diminished arterial pulsation must be carefully looked for, and particular attention should be paid to the presence of a bruit over the subclavian and axillary arteries. As demonstrated in our 4 patients, when the clinical findings point to arterial occlusion, arteriography will often reveal a short, segmental lesion of the subclavian artery that can frequently be treated surgically. , SUMMARY Four patients presented with subclavian artery occlusion 5-17 years after irradiation for breast carcinoma. Although arteriaL insufficiency is a rarely reported sequel of radiotherapy, it may be the cause of pain and disability in the upper extremity in the postmastectomy patient. When a careful physical examination points to arterial occlusion, arteriography will often demonstrate a short, segmental lesion that may be corrected by surgery. Department of Radiology Columbia-Presbyterian Medical Center 622 W. 168 St. New York, N. Y. 10032
REFERENCES 1. Benson EP: Radiation injury to large arteries. Radiology 106:195-197, Jan 1973 2. Glick B: Bilateral carotid occlusive disease following irradiation for carcinoma of the vocal cords. Arch Pathol 93:352-355, Apr 1972 3. Gold H: Production of arteriosclerosis in the rat. Effect of x-ray and a high-fat diet. Arch Pathol 71:268-273, Mar 1961
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4. Gross l, Manfredi Ol, Frederick we: Radiation-induced major vascular occlusion in a patient cured of widespread metastases of nasopharyngeal origin. Radiology 93:664-666, Sep 1969 5. Hayward RH: Arteriosclerosis induced by radiation. Surg Clin North Am 52:359-366, Apr 1972 6. Heidenberg WJ, Lupovitch A, Tarr H: "Pulseless disease" complicating Hodgkin's disease; a case apparently caused by radiotherapy. JAMA 195:488-491, Feb 1966 7. Huvos AG, Leaming RH, Moore as: Clinicopathologic study of the resected carotid artery. Analysis of sixty-four cases. Am J Surg 126:570-574, Oct 1973 8. Johnson AG, Lane B, Harding Rains AJ, et al: Large artery damage after x radiation. Br J Radiol 42:937-939, Dec 1969 9. Lamberts HB, De Boer WGRM: Contributions to the study of immediate and early x-ray reactions with regard to chemoprotection. VII. X-ray induced atheromatous lesions in the arterial wall of hypercholesterolaemic rabbits. Int J Hadiat Bioi 6:343-350, Apr 1963 10. Levinson SA, Close MB, Ehrenfeld WK, et al: Carotid artery occlusive disease following external cervical irradiation. Arch Surg 107:395-397, Sep 1973 11. Lindsay S, Kohn HI, Dakin RL, et al: Aortic arteriosclerosis in the dog after localized aortic x-irradiation. Circ Res 10:51-60, Jan 1962 12. Marcial-Rojas RA, Castro JR: Irradiation injury to elastic arteries in the course of treatment of neoplastic disease. Ann Otol Rhinol LaryngoI71:945-958, Dec 1962
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13. Mavor GE, Kasenally AT, Harper DR, et al: Thrombosis of the subclavian-axillary artery following radiotherapy for carcinoma of the breast. Br J Surg 60:983-985, Dec 1973 14. Momose KJ, New PF: Non-atheromatous stenosis and occlusion of the internal carotid artery and its main branches. Am J Roentgenol 118:550-566, Jul 1973 15. Pauliaf GE, Giannopoulos GO, Frangagis E: Selective constriction of the profunda femoris as a postradiotherapy sequel. Radiology 89:127-128, Jul1967 16. Ross HB, Sales JE: Post-irradiation femoral aneurysm treated by iIiopopliteal by-pass via the obturator foramen. Br J Surg 59:400-405, May 1972 17. Rubin P, Casarett GW: Clinical Radiation Pathology. Philadelphia, Saunders, 1968, pp 43-51,501-515 18. Sams A: Histological changes in the larger blood vessels of the hind limb of the mouse after x-irradiation. Int J Radiat Bioi 9: 165-174, Jul 1965 19. Smith C, Lowenthal LA: Study of elastic arteries in irradiated mice of different ages. Proc Soc Exp Bioi Med 75:859-861, Dec 1950 20. Thomas E, Forbus WD: Irradiation injury to the aorta and the lung. Arch PathoI67:256-263, Mar 1959 21. Tracy GP, Brown DE, Johnson LW, et al: Radiation-induced coronary artery disease. JAMA 228: 1160-1662, 24 Jun 1974 22. Warren S: Effects of radiation on normal tissues. VI. Effects of radiation on the cardiovascular system. Arch Pathol 34: 1070-1079, Dec 1942
•
Subclavian Artery Occlusion Following Radiotherapy for Carcinoma of the Breast 1
Therapeutic Radiology
Joel A. Budin, M.D., William J. Casarella, M.D., and Leonidas Harlsiadls, M.D. Four cases of subclavian artery occlusion occurring 5-17 years after irradiation for breast carcinoma are presented. Although arterial insufficiency is a rarely reported sequel of radiotherapy, it may be the cause of pain and disability in the upper extremity in a postmastectomy patient. Particular attention should be paid to the presence of a bruit over the subclavian and axillary arteries. Arteriography will often reveal a short, segmental lesion of the subclavian artery that frequently can be repaired surgically. INDEX TERMS: Arteries, subclavian· Breast Neoplasms, therapeutic radiology· Radiations, injurious effects, cardiovascular Radiology 118: 169-173, January 1976
• HE
ADVERSE
effect of radical mastectomy and
Tradiotherapy upon the upper extremity in patients
with carcinoma of the breast is a common and often frustrating clinical problem. Pain, limitation of motion, and lymphedema are well recognized complications of treatment. Arterial insufficiency in the upper extremity is a much rarer sequel of therapy which may in fact be concealed by the frequent presence of lymphedema in these patients. Although scattered reports of radiation damage to large arteries have appeared in the literature, only 3 cases of subclavian artery occlusion following treatment for breast carcinoma have been reported previously to our knowledge (1, 13). We wish to present 4 additional cases of focal subclavian artery occlusive disease occurring in the field of irradiation 5 to 17 years after postoperative radiotherapy for breast carcinoma. CASE REPORTS Fig. 1. CASE I: A 61-year-old woman presented in 1972 with pain and swelling of the right upper extremity. Five years previously she had undergone a right radical mastectomy for carcinoma of the breast. She received postoperative radiotherapy on a 60CO unit. A tumor dose of 4,500 rads in 25 equal fractions over 36 days was delivered to the right supraclavicular fossa-right axilla through an anterior port measuring 8.5 X 13 cm at 60 cm SSD. It is estimated that 5,775 rads was delivered to the subclavian artery. This dose-fractionation scheme is associated with a nominal standard dose (NSD) value of 1,798 rets. In addition, the right internal mammary chain was irradiated to a tumor dose of 4,500 rads in 25 fractions over 35 days using a 7.5 X 16-cm port. Medial and lateral tangential chest wall ports measuring 6 X 15 cm were also employed for a dose of 5,500 rads in 20 fractions over 31 days. The following year a left axillary node biopsy showed metastatic disease, which was treated with 4,600 rads to the left axilla. Progressive lymphedema and pain in the right arm ensued with compromised range of motion. Physical examination revealed induration of
CASE I. Selective innominate arteriogram demonstrates high-grade stenosis of the right subclavian artery.
the skin over the right axilla and supraclavicular area compatible with radiation change, a harsh bruit over the right subclavian artery, and a weak right radial pulse. Evidence of ulnar nerve neuropathy was found. An aortic arch study and a selective innominate arteriogram (Fig. 1) revealed a high-grade 2-cm stenosis of the right subclavian artery with poor collateral circulation. It was elected to treat the patient conservatively. CASE II: A 56-year-old woman was hospitalized in 1968 because of pain in the right arm and shoulder. Seven years previously she had undergone a right radical mastectomy for carcinoma. Postoperatively she received radiation therapy on a 240 kV constant-potential x-ray unit (filtration 0.5 mm Cu 1 mm AI) operating at 50 cm FSD. A dose of 2,400 R in air in 8 equal fractions was delivered over 24 days to each of two fields: opposed right supraclavicular and right suprascapular, each measuring 10 X 15 cm. An estimated dose of
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1 From the Department of Radiology, College of Physicians and Surgeons, Columbia-Presbyterian Medical Center, New York, N. Y. Presented at the Sixty-first Scientific Assembly and Annual Meeting of the Radiological Society of North America, Chicago, III., Nov. 30-Dec. 5, 1975. elk
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Fig. 2. CASE II. Complete occlusion of the right subclavian artery is seen with reconstitution of the axillary artery through collaterals (composite of two films). 3,900 rads in 8 fractions was delivered to the subclavian artery by these fields. The NSD associated with such a treatment scheme has a value of 1,669 rets; however, the dose to the subclavian artery, especially the distal portion, is likely to be significantly higher because a supplementary direct axillary port 10 cm in diameter was employed to a dose of 2,400 R in air in 8 fractions in 24 days. In addition, the right internal mammary chain was irradiated through an 8 X 15-cm anterior port to a dose of 3,000 R in air in 10 fractions over 24 days. Physical examination revealed telangiectasia of the skin over the right shoulder and absent right axillary, brachial, and radial pulses. Arch aortography and a selective innominate arteriogram (Fig. 2) demonstrated complete occlusion of the right subclavian artery just distal to the costovertebral artery with reconstitution of the axillary artery via collateral flow. Resection of the occluded segment of the right subclavian artery was performed, and an autogenous vein graft was inserted. Microscopic examination of the occluded arterial segment demonstrated marked intimal proliferation, slight fraying of the internal elastic membrane, adventitial fibrosis, and an organizing thrombus filling the narrowed lumen (Fig. 3, A and B). Postoperatively, clinical improvement was noted with restoration of the right radial pulse.
January 1976
CASE III: A 57-year-old woman was referred in 1974 for evaluation of a dusky, painful left index finger noted.after falling on her outstretched hand. Seven years previously she had undergone a left radical mastectomy for carcinoma, with 3 out of 25 axillary nodes positive for metastases. Postoperative radiotherapy was given using a 200 kV, h.v.1. 1-mm Cu x-ray unit operating at 50 em FSD. A dose of 2,200 rads in air in 11 equal fractions was delivered over 32 days to each of the following ports: anterior supraclavicular-axillary port measuring 10 X 15 cm, posterior suprascapular port, also measuring 10 X 15 cm, and medial and lateral tangential chest wall ports, each measuring 7 X 16 cm. An estimated dose of 3,815 rads was delivered to the subclavian artery, producing an NSD value of 1,466 rets for the fractionation scheme employed. Physical examination revealed a harsh systolic murmur over the left subclavian artery with a slightly diminished left radial pulse. The left index finger was mildly cyanotic and cold. An aortic arch study (Fig. 4, A and B) demonstrated complete occlusion of the left subclavian artery 1 cm distal to its origin. Reconstitution of the distal subclavian via retrograde flow in the left vertebral artery was noted. The patient's index finger improved with conservative management. It was theorized that the trauma of the patient's fall had dislodged a fragment of an atherosclerotic plaque or thrombus in the left subclavian artery, with embolization to the index finger. CASE IV: An 87-year-old woman was hospitalized in 1974 for evaluation of pain in her left arm. Thirteen years earlier she had undergone a left radical mastectomy for an infiltrating ductal carcinoma with metastatic involvement of six axillary nodes. Postoperatively she was treated with 200 kV x rays, h.v.1. 1.3 mm Cu, 50 cm FSD. A daily dose of 250 R in air was delivered to each of three ports: anterior left supraclavicular-axillary port measuring 10 X 20 cm, posterior suprascapular port, also measuring 10 X 20 cm, and left internal mammary chain port measuring 4 X 10 cm. The total dose of lrradiation is unavailable. Over the ensuing years progressive lymphedema and pain in her left arm developed, with limitation of motion. Her symptoms were aggravated by exposure to cold. Physical examination revealed marked lymphedema of the left upper extremity with radiation changes in the skin Over the left supraclavicular area and axilla. No pulses were palpable below the subclavian in the left arm. An aortic arch study (Fig. 5) demonstrated complete occlusion of the left subclavian artery just distal to the origin of the internal mammary artery. Reconstitution of the left axillary artery through collateral channels was noted. A venogram obtained via a left antecubital vein revealed a normally patent left subclavian vein in the region of the arterial occlusion. The patient was treated conservatively.
Fig. 3. CASE II. A. Section of occluded right subclavian artery shows intimal proliferation. The narrowed lumen is filled with organizing thrombus. Adventitial fibrosis is seen. (Masson's Trichrome, 38X). B. Elastic stain shows minimal fraying and duplication of internal elastic membrane (arrows), but the media is otherwise intact (Verhoeff, 63X).
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DISCUSSION
In view of the prevalence of carcinoma of the breast in the general population, it is surprising that this manifestation of radiotherapy has not been observed more frequently _ Obviously, the majority of patients selected for radiotherapy already have evidence of lymph node or more distant metastases, and a large proportion of these patients do not survive long enough for significant arterial changes to develop, Moreover, it seems likely that the clinician may fail to consider the possibility of arterial occlusion as a contributing cause of arm pain in the postmastectomy patient. Lymphedema, contracture, and nerve-root symptoms all tend to conceal the presence of arterial insufficiency. Note that 3 of our 4 patients had significant lymphedema of the upper extremity. Several factors strongly implicate irradiation as the cause of the arterial occlusions in our series. First, the obstructing lesions in all cases were within the supraclavicular portal employed. Second, in all 4 patients the occluded segment was located distal to the origin of the subclavian artery; spontaneous atherosclerotic plaques, in contrast, typically occur at the origin of the vessel. Third, aortic arch studies in all of our patients showed relative sparing of the other aortic branches outside the field of irradiation. In the case of subclavian-axillary occlusion reported by Benson (1), and the 2 cases reported by Mavor et al. (13), the arterial lesions were similarly located distal to the origin of the subclavian artery. These patients were studied 3, 11, and 26 years after their courses of radiotherapy, respectively. Conceivably, tumor recurrence with vascular encasement might account for subclavian artery occlusion in the postmastectomy patient. Clearly, in CASE II in our series, the resected specimen was free of tumor. Although no patholoqical proof is available in the remainder of our patients, 5-17 years elapsed from the time of their mastectomies until their arteriographic studies and, moreover, 14 months-3 years have elapsed frorri the time of their radiographic evaluation until now. There has been no progression of the lesions clinically, land all patients presently are free of tumor recurrence or metastatic disease. The estimated radiation doses given the patients in this series do not seem excessive. The calculated NSD values to the subclavian artery available in 3 of our patients ranged from 1,466 to 1,798 rets. This range is somewhat higher than the NSD of 1,200 rets reported by Hayward in his patient with carotid artery occlusions (5). Since all of our patients were irradiated through multiple ports, it is conceivable that overlap of adjacent fields occurred, causing segmental stenosis to the portion of the artery underlying the area of overlap. This is a particularly interestinq consideration with reference to the patient in CASE I, in whom the stenotic segment in the subclavian artery is quite short. Unfortunately, no
Fig. 4. CASE III. A. Complete occlusion of the left subclavian artery is seen shortly beyond its origin. B. Reconstitution of the left subclavian artery is demonstrated via retrograde flow in the left vertebral artery.
Fig. 5. CASE IV. Selective left subclavian arteriogram shows complete occlusion of the left subclavian artery with reconstitution of the distal artery via scapular collaterals.
verification port films are available to substantiate this hypothesis. Whether or not overlap of adjacent fields is a factor in an individual patient, the subclavian artery receives the largest dose of all the brachiocephalic vessels when it is directly irradiated with a supraclavicular port in the usual treatment of breast carcinoma. The slowly evolving occlusion that ensues stimulates the development of collateral channels which are at a different depth from the subclavian artery and course around the periphery of the radiation field. These collateral vessels are well illustrated by the periscapular arteries in CASES II and IV (Figs. 2 and 5) and by the subclavian steal in CASE III (Fig. 4, A and B). It is well known that there is considerable individual variation in sensitivity to the effects of irradiation. The calculated arterial NSD range utilized in our patients may be tolerated well in many other subjects. There is little data available at present to explain a particular patient's radiation sensitivity. It is probable that factors such as hypertension and hyperlipidemia act synergisti-
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cally with radiation to produce arteriosclerotic change. That this is true in respect to hypercholesterolemia seems to be substantiated by Gold (3) and Lamberts and De Boer (9) (see below). Two of the patients in our series (CASES I and III) had mild essential hypertension. CASES II and IV had elevated serum cholesterol values of 306 and 359 mg/100 ml, respectively. Clinical reports of radiation damage involving the aorta (12, 20), carotid (2, 5, 7, 10, 12, 14), iliac (1, 8), femoral (1, 4, 15, 16), and more recently the coronary arteries (21) have appeared. An interesting case of "pulseless disease" was described by Heidenberg et al. in a patient who was treated with radiotherapy for Hodgkin's disease (6). Stenoses of the innominate, both common carotids, and complete occlusions of both subclavian arteries were found. Injury to large arteries in these reports ranged from rupture during the acute phase following irradiation to aneurysm formation and typical atherosclerotic lesions in the late stages. Early experimental work with radiation-induced vas~ cular injury stressed the sensitivity of the endothelium (22). Damage was most extensive in small vessels, having a proportionally larger endothelial component. Damage to major vessels was rarely seen with doses below 500 R. In 1950, Smith and Lowenthal (19) demonstrated changes in the media of elastic arteries in irradiated mice comparable to physiological aging: fraying of the elastic membrane and an increase in ground substance and in the numbers of interlamellar fibers. This work was confirmed in 1961 by Gold (3), who produced severe atherosclerotic lesions in the aorta, coronary arteries, pulmonary arteries, and endocardium by irradiating hypercholesterolemic rats. The arteriosclerotic changes were much more extensive but otherwise identical to those in a control group of rats fed a high-cholesterol diet. Lindsay et al. studied the effects of localized aortic irradiation in the dog (11). After administering doses of 1,500-5,500 R to localized aortic segments, he found typical arteriosclerotic changes in dogs sacrificed 3-48 weeks later. These changes were more pronounced with increasing time interval after irradiation, and consisted of degeneration and fragmentation of the internal elastic membrane, accumulation of mucopolysaccharide ground substance in the intima, and fibroblastic proliferation leading to diffuse intimal fibrosis or localized fibrous plaques. Similar arteriosclerotic lesions with the additional features of fatty infiltration of the arterial wall and atheroma formation were produced by Lamberts and De Boer in hypoercholesterolemic rabbits after localized irradiation of the carotid artery (9). Other investigators have related large artery injury to radiation damage in surrounding tissue rather than to the direct effect of irradiation on the vessel itself. Sams produced pathological changes similar to those described above in irradiated mice and related them to fibrosis in adjacent tissues, causing both direct pressure on the blood vessels and decreased muscular contraction leading to reduction in blood flow in the involved ex-
January 1976
tremity (18). Rubin and Casarett emphasized x-ray damage to small vessels, particularly occlusions of the vasa vasorum, which in turn cause ischemic injury to the walls of large arteries (17). Pathological examination of the occluded arterial segment was available only in CASE II in our series. Microscopically this segment showed many of the characteristic changes described above, with striking intimal thickening and superimposed thrombosis. No significant atheroma formation or fatty infiltration was noted. Some adventitial fibrosis was evident, but the few vasa vasorum included in the specimen appeared patent. Supportive evidence for a direct effect of irradiation on the subclavian artery was the finding of a subclavian vein of normal caliber in CASE IV. It is unlikely that perivascular fibrosis could cause high-grade stenosis of a major artery without leaving a similar effect on the immediately adjacent vein. The cost of arterial injury following radiotherapy appears relatively slight in view of the fact that all 4 of our patients were tumor-free at the time of their evaluation. Significant alteration in the mode of radiation treatment in order to avoid this complication seems unwarranted, since the subclavian artery is contiguous with the axillary lymph nodes draining the breast. However, it is important for the clinician to recognize that arterial insufficiency may be the source of pain and disability in the upper extremity of the postmastectomy patient. Evidence of diminished arterial pulsation must be carefully looked for, and particular attention should be paid to the presence of a bruit over the subclavian and axillary arteries. As demonstrated in our 4 patients, when the clinical findings point to arterial occlusion, arteriography will often reveal a short, segmental lesion of the subclavian artery that can frequently be treated surgically. , SUMMARY Four patients presented with subclavian artery occlusion 5-17 years after irradiation for breast carcinoma. Although arteriaL insufficiency is a rarely reported sequel of radiotherapy, it may be the cause of pain and disability in the upper extremity in the postmastectomy patient. When a careful physical examination points to arterial occlusion, arteriography will often demonstrate a short, segmental lesion that may be corrected by surgery. Department of Radiology Columbia-Presbyterian Medical Center 622 W. 168 St. New York, N. Y. 10032
REFERENCES 1. Benson EP: Radiation injury to large arteries. Radiology 106:195-197, Jan 1973 2. Glick B: Bilateral carotid occlusive disease following irradiation for carcinoma of the vocal cords. Arch Pathol 93:352-355, Apr 1972 3. Gold H: Production of arteriosclerosis in the rat. Effect of x-ray and a high-fat diet. Arch Pathol 71:268-273, Mar 1961
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4. Gross l, Manfredi Ol, Frederick we: Radiation-induced major vascular occlusion in a patient cured of widespread metastases of nasopharyngeal origin. Radiology 93:664-666, Sep 1969 5. Hayward RH: Arteriosclerosis induced by radiation. Surg Clin North Am 52:359-366, Apr 1972 6. Heidenberg WJ, Lupovitch A, Tarr H: "Pulseless disease" complicating Hodgkin's disease; a case apparently caused by radiotherapy. JAMA 195:488-491, Feb 1966 7. Huvos AG, Leaming RH, Moore as: Clinicopathologic study of the resected carotid artery. Analysis of sixty-four cases. Am J Surg 126:570-574, Oct 1973 8. Johnson AG, Lane B, Harding Rains AJ, et al: Large artery damage after x radiation. Br J Radiol 42:937-939, Dec 1969 9. Lamberts HB, De Boer WGRM: Contributions to the study of immediate and early x-ray reactions with regard to chemoprotection. VII. X-ray induced atheromatous lesions in the arterial wall of hypercholesterolaemic rabbits. Int J Hadiat Bioi 6:343-350, Apr 1963 10. Levinson SA, Close MB, Ehrenfeld WK, et al: Carotid artery occlusive disease following external cervical irradiation. Arch Surg 107:395-397, Sep 1973 11. Lindsay S, Kohn HI, Dakin RL, et al: Aortic arteriosclerosis in the dog after localized aortic x-irradiation. Circ Res 10:51-60, Jan 1962 12. Marcial-Rojas RA, Castro JR: Irradiation injury to elastic arteries in the course of treatment of neoplastic disease. Ann Otol Rhinol LaryngoI71:945-958, Dec 1962
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13. Mavor GE, Kasenally AT, Harper DR, et al: Thrombosis of the subclavian-axillary artery following radiotherapy for carcinoma of the breast. Br J Surg 60:983-985, Dec 1973 14. Momose KJ, New PF: Non-atheromatous stenosis and occlusion of the internal carotid artery and its main branches. Am J Roentgenol 118:550-566, Jul 1973 15. Pauliaf GE, Giannopoulos GO, Frangagis E: Selective constriction of the profunda femoris as a postradiotherapy sequel. Radiology 89:127-128, Jul1967 16. Ross HB, Sales JE: Post-irradiation femoral aneurysm treated by iIiopopliteal by-pass via the obturator foramen. Br J Surg 59:400-405, May 1972 17. Rubin P, Casarett GW: Clinical Radiation Pathology. Philadelphia, Saunders, 1968, pp 43-51,501-515 18. Sams A: Histological changes in the larger blood vessels of the hind limb of the mouse after x-irradiation. Int J Radiat Bioi 9: 165-174, Jul 1965 19. Smith C, Lowenthal LA: Study of elastic arteries in irradiated mice of different ages. Proc Soc Exp Bioi Med 75:859-861, Dec 1950 20. Thomas E, Forbus WD: Irradiation injury to the aorta and the lung. Arch PathoI67:256-263, Mar 1959 21. Tracy GP, Brown DE, Johnson LW, et al: Radiation-induced coronary artery disease. JAMA 228: 1160-1662, 24 Jun 1974 22. Warren S: Effects of radiation on normal tissues. VI. Effects of radiation on the cardiovascular system. Arch Pathol 34: 1070-1079, Dec 1942
