Cabot, Richard C; Scully, Robert E, MD; Mark, Eugene J, MD; McNeely, William F, MD; McNeely, Betty U; et al.The New England Journal of Medicine; Boston Vol. 329, Iss. 1, (Jul 1, 1993): 43-48. DOI:10.1056/NEJM199307013290109
A 73-year-old man was admitted to the hospital with a diagnosis of a contained, ruptured aneurysm of the left femoral artery.
The patient was a retired shipyard pipe fitter, with known exposure to asbestos. He had smoked one pack of cigarettes daily for 30 years and then switched to pipe-smoking 32 years before admission. He also had “chronic bronchitis,” which was managed with theophylline, and hypertension, which was treated with enalapril. Ten years before entry a stage B1 carcinoma of the prostate gland was found and was treated at another hospital by radiation therapy with a 4-MeV linear accelerator; the pelvis received a dose of 4500 cGy, and the prostate gland received 6900 cGy. In the same year a left hemicolectomy was performed at another hospital for a carcinoma of the colon. Seventeen months before admission a new prostatic nodule was palpated on a routine rectal examination. The prostate-specific antigen was 94.5 μg per liter (normal, 0.5 to 3.9); the acid phosphatase was normal. A transurethral resection of the prostate gland with bilateral orchiectomy was performed at that hospital.
On follow-up examination four months later a computed tomographic (CT) scan of the abdomen and pelvis showed a cyst, 10 cm, at the upper pole of the right kidney, with smaller cysts at the middle and inferior poles; no abdominal, pelvic, or retroperitoneal lymphadenopathy was seen; minimal periprostatic and perirectal stranding was observed; the diameter of the left femoral artery was 1.8 cm, and that of the right femoral artery was 1 cm. A radionuclide bone scan, obtained after the intravenous injection of [99m Tc]methylene diphosphonate, disclosed an isolated focus of increased activity in the proximal metaphysis of the right femur, which was believed to be post-traumatic.
At follow-up examination eight months before admission the prostate gland remained flat on rectal examination. The prostate-specific antigen and the acid phosphatase were normal.
Thereafter the patient was in stable health until two months before admission, when he began to have swelling of the left leg and pain in the left groin that radiated down the entire leg. Several days before admission his physician found a pulsatile swelling in the left groin and edema of the entire leg, with no calf tenderness. A CT scan of the abdomen and pelvis (Figure 1), obtained after the intravenous injection of contrast material, showed a poorly defined soft-tissue density surrounding the left external iliac artery from the bifurcation of the common iliac artery and extending into the left common femoral artery and superficial and profunda femoral arteries; scattered crescentic calcifications were present within the area of density, adjacent to the arterial lumen; the maximal diameter of the left common femoral artery was 2 cm; cysts were noted in the right kidney; the head and tail of the pancreas appeared normal, but the pancreatic body was not seen; no enlarged retroperitoneal lymph nodes were visible; degenerative changes were observed in the thoracic and lumbar spine, but no metastatic tumor was seen. The patient was admitted to the hospital.
The temperature was 37 °C, the pulse was 64, and the respirations were 18. The blood pressure was 150/80 mm Hg.
On physical examination the patient appeared well. The head, neck, lungs, and heart were normal. Abdominal examination was negative. There was +++ pitting edema of the left lower extremity; the right leg was normal. The left femoral pulse was prominent, with a diameter of 2.5 cm; the left popliteal and posterior tibial pulses were present; the dorsalis pedis pulse was absent; pulses in the right lower extremity were intact. Rectal examination showed that the prostatic bed was flat; a stool specimen gave a negative test for occult blood. Neurologic examination was negative.
The urine, a complete blood count, the prothrombin time, and the partial-thromboplastin time were normal. The urea nitrogen, creatinine, glucose, electrolytes, calcium, phosphorus, serum aspartate aminotransferase, amylase, and alkaline phosphatase were normal. An electrocardiogram showed a normal rhythm at a rate of 80, with complete right-bundle-branch block. Radiographs of the chest revealed bilateral calcific pleural plaques, which were unchanged from those seen on earlier examinations; the lung parenchyma appeared clear, and the cardiac and mediastinal shadows were normal; there was bridging ossification of the thoracic vertebral bodies, suggestive of diffuse idiopathic skeletal hyperostosis, but the remaining bones appeared normal. An aortographic study and angiographic examination of both lower extremities (Figure 2) disclosed a diffuse, irregular aneurysm that involved the distal left external iliac artery, common femoral artery, proximal superficial femoral artery, and proximal profunda femoris artery; there was a focal aneurysm in the left popliteal artery just above the level of the tibial plateau; right renal cysts were again observed; the celiac, superior, and inferior mesenteric arteries, a double right renal artery, and a single left renal artery were patent; the remainder of the study was negative.
A diagnostic procedure was performed.
Dr. Thomas F. O’Donnell, Jr.*: This 73-year-old man was seen for an enlarging left inguinal mass of two months’ duration associated with swelling and pain that radiated down the entire leg. Pertinent physical findings were the pulsatile left inguinal mass and marked edema of the leg with intact pulses. The results of a battery of blood tests performed on admission were normal.
May we review the radiologic studies in this man with a previous history of prostatic and colonic carcinoma?
Dr. John A. Kaufman: The bone scan was not available for review. One year before admission CT scanning of the pelvis without contrast enhancement demonstrated mild ectasia of the left common femoral artery; the surrounding soft tissues were normal. A CT scan of the abdomen and pelvis obtained at the time of admission with both intravenous and oral contrast material (Figure 1) demonstrates a poorly defined soft-tissue mass containing crescentic calcifications surrounding the left external iliac, common femoral, and proximal superficial femoral and profunda femoris arteries. The lumen of the common femoral artery had increased in diameter since the previous examination. Digital-subtraction and screen-film angiograms (Figure 2), obtained through the right common femoral artery, reveal slight dilatation of the left common femoral artery, with a strikingly irregular, shaggy lumen extending from the external iliac artery through the common femoral bifurcation.
Dr. O’Donnell: Is the increased activity in the right femur seen on the bone scan consistent with either sepsis or metastasis from the prostatic cancer rather than trauma?
Dr. Kaufman: In this clinical setting, increased activity shown on a bone scan is suggestive of metastatic tumor, although other causes cannot be excluded.
Dr. O’Donnell: Is it possible to determine from a CT scan whether the periarterial process represents lymph nodes or tumor superimposed on the wall of an aneurysm?
Dr. Kaufman: No.
Dr. O’Donnell: The arteriographic finding of a corrugated pattern along the lumen of the profunda femoris artery is not usually seen with either atherosclerosis or a thrombus lining an aneurysm.
In my analysis of this case I must decide whether an aneurysm could enlarge to the extent shown on the radiologic studies and account for the pain and swelling in the involved extremity. The CT scan and the arteriograms clearly demonstrate an aneurysm, but I doubt that the patient’s symptoms were related to it alone.
A femoral aneurysm is the second most common peripheral-artery aneurysm, accounting for nearly a third of all peripheral aneurysms. In the series reported from this institution1 nearly three quarters of the patients with femoral aneurysms had other aneurysms as well. This patient is no exception, in that he also had a popliteal-artery aneurysm. In the same series nearly half the patients presented with a major complication of a femoral aneurysm — namely, rupture, thrombosis, or embolism. Of interest in the case under discussion is the finding of unilateral aneurysmal disease, including the popliteal aneurysm, because about 70 percent of patients with a popliteal aneurysm have a contralateral aneurysm, and almost half the patients with a popliteal aneurysm have an abdominal aortic aneurysm as well. This frequency decreases, however, if the popliteal aneurysm is unilateral. Like abdominal aortic aneurysms, femoral aneurysms are principally atherosclerotic, although congenital defects such as fibromuscular dysplasia, infection, and sequelae of interventional procedures such as vascular anastomoses can also be causative factors. Femoral aneurysms may be classified anatomically as type I, in which the aneurysm ends before the bifurcation of the common femoral artery into the superficial femoral and profunda femoris arteries, and type II, in which the aneurysm involves the orifice of the profunda femoris artery. In the series from this institution the frequencies of type I and type II aneurysms were equal.
As in the patient under discussion, local pain, swelling, and tenderness are present in approximately 30 percent of the cases. These symptoms are forerunners of rupture in about 15 percent of the patients. Such patients have symptoms similar to those of the patient under discussion, with pain due to femoral-nerve compression and edema due to venous occlusion. In this case, however, the CT scan showed no evidence of iliofemoral venous thrombosis or areas consistent with acute leakage. Certainly, expansion of the femoral aneurysm rather than rupture could have caused the symptoms. The remaining patients in the reported series had thrombosis of the aneurysm or peripheral emboli. In contrast to this case, most of the patients have a clearly defined proximal neck of the femoral aneurysm, without involvement of the external iliac artery. Other features in the reported series differing from those in this case were a larger diameter, averaging 4.5 cm, and an inner lining that was usually smooth because of lamination of clot. When such an aneurysm ruptures, local tenderness and a hematoma within the groin are present, unlike the situation in this patient. The most striking aspect of this patient’s aneurysm is its extent. Since he had no known instrumentation or operation on his left femoral artery, a false aneurysm seems unlikely. Another study, reported by Pappas and his colleagues,2 emphasized that only 1 percent of femoral aneurysms involved the profunda femoris artery, although frequently there was dilatation at the origin of this vessel. Those authors explained that finding on the basis of muscular support around the profunda femoris artery. In summary, this patient’s CT scan and arteriographic findings are not typical of a femoral-artery aneurysm due to atherosclerosis alone.
Could this patient’s aneurysm have been related to arterial dysplasia, particularly in view of the history of radiotherapy? Fibromuscular dysplasia of the external iliac and femoral arteries was described more than 20 years ago3. It usually occurs in women in the fifth and sixth decades of life. The angiographic picture is not unlike that seen in this case. However, the thickened, fibrous material encasing the artery demonstrated on the CT scan in this case would be unusual for fibromuscular dysplasia. Moreover, the aneurysms associated with fibromuscular dysplasia are localized and saccular rather than fusiform3.
A third cause of an aneurysm that would be consistent with some of this patient’s symptoms is infection. Most patients with a mycotic aneurysm present with chronic sepsis of unknown cause associated with a potential for arterial rupture4. Jarrett et al.,5 from this hospital, emphasized the characteristic clinical presentation of a mycotic aneurysm — fever, pain over the aneurysm, a palpable tender mass, and positive blood cultures. Erosion of surrounding structures and absence of calcification in the aneurysm wall demonstrated on plain x-ray films are characteristic features. Since the aneurysm is frequently saccular or lobulated, arteriographic examination provides the most helpful information. The patient under discussion had none of the characteristic findings of a mycotic aneurysm.
I am thus left to conclude that another disease coexisted with the atherosclerotic aneurysm, with neoplasia the most likely culprit. The patient had a history of two neoplasms, a carcinoma of the prostate gland and a carcinoma of the colon. The prostatic cancer was treated with radiotherapy 10 years before admission. Approximately a year and a half before admission the level of prostate-specific antigen was elevated, and a prostatic nodule was found. Apparently, CT scanning was not performed at that time, but the marked elevation of the level of prostate-specific antigen suggested at least regional spread of the prostatic cancer. Prostatic cancer spreads not only by local invasion but also through vascular and lymphatic channels. The primary field of lymphatic drainage includes the hypogastric, obturator, presacral, and presciatic lymph nodes, with obturator-node involvement the most common. The secondary fields of involvement, which are relevant in this case, are the common iliac and inguinal lymph nodes6. Thirteen months before admission there was no evidence of lymphadenopathy on the CT scan, but the sensitivity of CT scanning in detecting lymph-node metastases from prostatic cancer averages only about 50 percent7. In view of the stage of the patient’s prostatic cancer 10 years ago the probability of lymph-node metastases at that time was between 25 and 35 percent6. The response of the prostatic tumor to orchiectomy shows that it was hormone-sensitive, since eight months before the recent admission the level of prostatic-specific antigen had dropped to normal and the acid phosphatase level was also normal. In addition, the CT scan of the spine was negative for metastatic tumor, although the bone-scan evidence of an abnormality in the right femur could indicate a metastatic tumor. On admission, no values were reported for prostate-specific antigen or acid phosphatase, and I assume that the levels were normal. The normal alkaline phosphatase level suggests an absence of bony involvement. Could this patient have had regional spread of his prostatic cancer without major bony involvement to account for the mass encircling the external iliac artery and profunda femoris artery? That is certainly possible, but it would not explain the arteriographic finding of a spiculated, irregular defect along the profunda femoris artery. Direct invasion of large arteries by a prostatic cancer has not been reported to my knowledge.
With neoplastic involvement of an artery, the vascular lumen may change in four ways: first, by smooth encasement, with the development of a stricture; second, by encasement and alteration in the vessel’s course; third, by abrupt change in the course; and fourth, by invasion of the arterial wall, which might produce the findings observed in the profunda femoris artery8. However, I do not think that the prostatic or colonic carcinoma produced these changes. Invasion of venous structures is more likely with regional spread of these tumors.
Did this patient have still another tumor? There was a history of exposure to asbestos and of radiotherapy, both of which can result in neoplasms such as a peritoneal mesothelioma. Patients with a peritoneal mesothelioma generally present with abdominal pain, a pelvic mass, and ascites and occasionally present with partial small-bowel obstruction9. The mass in this patient intimately involved the external iliac and more distal arteries, and he had no gastrointestinal symptoms. Therefore, mesothelioma appears unlikely despite the exposure to asbestos.
I believe that the findings in this case are consistent with a primary tumor of a blood vessel. In 1987 Kanno et al.10 reviewed 48 reported cases of primary tumors of the aorta and large arteries; 8 involved the femoral artery, 3 the iliac artery, and 1 the popliteal artery. Although leiomyosarcoma was the most common histologic type, angiosarcoma was next in frequency. It has been linked to exposure to both radiation and polyvinylchloride, an essential component of water pipes and wrapping materials. Although this patient was a pipe fitter, the workers who had angiosarcomas of the liver had been exposed to the gaseous form of polyvinylchloride11.
Tumors that involve major blood vessels are rare and usually appear unexpectedly on arteriographic examination or CT scanning. A convenient functional organization of these tumors is that proposed by Ratliff et al.12: tumors that arise in or involve a major vessel, those that present as a soft-tissue mass, and those that present as thrombi or emboli. I believe that the patient under discussion may have had a tumor in the first category. These tumors are generally sarcomas, of which leiomyosarcoma and the intimal sarcomas are the predominant types. The symptoms are nonspecific. Leiomyosarcomas generally involve veins and can invade surrounding structures earlier in their course than when they involve arteries, whose elastic laminas tend to keep the tumor confined to the artery. Vascular leiomyosarcomas have a preference for the inferior vena cava, with iliac, femoral, and superficial veins as distant second sites of origin. The pulmonary artery is the most common site of arterial involvement by leiomyosarcomas12.
Intimal sarcomas are pleomorphic13 and, unlike leiomyosarcomas, have a predilection for major arteries, but they spread by similar routes. An intimal sarcoma may be in the form of a leiomyosarcoma, a malignant fibrous histiocytoma, a rhabdomyosarcoma, or a chondrosarcoma. The distinctive feature of this tumor is growth both within the lumen and along the surface of the blood vessel, much as the CT scan suggests in this case14,15. Finally, a benign lesion, papillary endothelial hyperplasia, should be mentioned. Generally, it involves vessels smaller than the femoral artery and can be confused with a small-vessel angiosarcoma16. Although the arteriographic finding of an irregular lumen in the profunda femoris artery is suggestive of this lesion, the rest of the picture does not fit. Although angiosarcomas have been associated with radiation, which this patient had received, and exposure to polyvinylchloride, another carcinogen, to which as a pipe fitter he might have been exposed, these tumors usually present as soft-tissue masses and therefore involve the skin and the superficial fatty tissue rather than the deep tissue. Grossly, they appear as ill-defined, hemorrhagic masses with sponge-like cystic spaces. That appearance does not fit the clinical findings in this patient.
In summary, I believe that this patient had a primary tumor involving the iliac and femoral arteries. It probably was an intimal sarcoma with lateral spread, although a separate soft-tissue sarcoma cannot be ruled out. A CT-guided fine-needle biopsy might have provided the diagnosis, or the procedure may have been an open biopsy. However, at the end of this clinicopathological conference my diagnosis is influenced by the words of one of the most esteemed clinicians of all time, Sir William Osler, who commented on the protean manifestations of aneurysms, which can challenge the best of clinicians. He stated, “There is no disease more conducive to clinical humility than aneurysms of the aorta.” I am sure that this case will illustrate that appraisal .
Dr. Joon Lee: Do you think that the popliteal aneurysm was a separate process?
Dr. O’Donnell: Yes.
Ruptured iliac aneurysm.
? Soft-tissue sarcoma.
Dr. Thomas F. O’Donnell’s Diagnosis
Malignant vascular tumor of left external iliac, femoral, and profunda femoris arteries.
Dr. John X. O’Connell: The diagnostic procedure was a surgical exploration, which revealed an ill-defined fibrous mass that encased and partially replaced the common, superficial, and profunda femoris arteries. Segments of the vessel were markedly attenuated, and blood had extravasated focally into the adjacent soft tissue. An intraoperative frozen-section examination revealed a malignant spindle-cell tumor. A decision was made to resect the most severely involved part of the vessel, including the adjacent soft tissues, to the level of the femoral vein and nerve and to perform a more definitive surgical resection at a later date, after the final pathological diagnosis.
Microscopical examination disclosed pleomorphic spindle cells that had replaced the media of the arteries (Figure 3) and invaded through the intima to line the lumens and through the adventitia into adjacent soft tissues. Free tumor cells were aggregated with fibrin to form thrombi within the lumens. The tumor had a high mitotic count and was associated with the production of abundant extracellular collagen and focally tumor bone and osteoid (Figure 4), warranting the diagnosis of an extraskeletal osteosarcoma of the left femoral artery. The tumor arose within the field of the previous radiation therapy and was thus classified as a radiation-induced sarcoma. The second surgical procedure to remove the residual tumor and reconstruct the vessel was performed two months after the first operation (Figure 5).
The diagnostic criteria to establish radiation induction of a tumor were originally proposed in 1948 by Cahan et al.17 and have been modified only slightly since that time18. A radiation-induced tumor must develop within the field of radiation, differ from the neoplasm for which the radiation was administered, and occur after a latency period of at least two years. The frequency of radiation-induced sarcomas is hard to determine, but it is estimated that the cumulative risk of a radiation-induced cancer is between 0.2 and 2 percent 10 years after the radiation therapy19-22. This risk increases with time and with the total dose of radiation administered22. Tucker et al.22 have shown that certain patients are more predisposed to the development of cancers after radiation therapy and have estimated that patients treated for retinoblastoma have a cumulative risk of bone cancer of approximately 14 percent 20 years after treatment.
The oncogenic potential of radiation has been known since Frieben23 described the development of a squamous-cell carcinoma on the hand of an x-ray technician in 1902. The pathogenesis of this phenomenon has become clear only recently. Ionizing radiation produces oxygen-derived free radicals that are directly toxic to DNA, resulting in base substitutions and strand breaks throughout the genome24. Recently, investigators have focused on specific regions of the genome where these events may have greater importance, such as the sites of the tumor suppressor genes, p53 and Rb. Stratton et al.25 investigated 69 soft-tissue sarcomas for abnormalities of the Rb1 gene and identified heterozygous deletions in a third of the cases. A homozygous deletion was found in a radiation-induced leiomyosarcoma. Brachman et al.26 have reported preliminary data on a group of seven patients with radiation-induced sarcomas. Six of the seven tumors had abnormalities in the p53 gene or Rb protein.
Most radiation-induced sarcomas are osteosarcomas or fibrosarcomas18,20-22,27,28. Many of the fibrosarcomas reported earlier would probably now be classified as malignant fibrous histiocytomas. The latency period ranges from 2 to 47 years18,28 and has a mean of 13 years.18-21,27-29 The behavior of radiation-induced sarcomas is aggressive, with two-year to five-year survivals of 14 to 32 percent18,29.
In summary, this patient had a radiation-induced extraskeletal osteosarcoma of the left femoral artery.
Dr. Eugene J. Mark: Dr. Parsons, you have followed this patient subsequently. Will you give us follow-up findings on the patient?
Dr. W. Theodore Parsons: The patient was referred to us about a week after the original vascular procedure. While the wound was healing, we performed additional studies to clarify the picture. The radiation oncologists believed that he could not receive any additional external-beam therapy. We decided that the best course would be a wide local resection, which meant sacrificing the neurovascular bundle in the area, with reconstruction of the artery and adjuvant brachytherapy. After the second definitive procedure the patient was well for about a week but then began to have gastrointestinal problems. We finally determined that his abdominal contents were herniating into the left lower quadrant as a result of the surgical procedure, and he required an additional operation. Thereafter he received peripheral alimentation, recovered slowly, and was discharged to a rehabilitation center seven weeks postoperatively. He has now left the rehabilitation center and is home and relatively well, with persistent swelling of the limb as a result of the operation and radiation.
Radiation-induced osteogenic sarcoma of left femoral artery.
Chief, Division of Vascular Surgery, New England Medical Center Hospital; professor of surgery, Tufts University School of Medicine.
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CT Scan with Contrast Material, Obtained at the Level of the Inguinal Ligament.
There is an area of soft-tissue density surrounding the lumen of the left common femoral artery containing areas of mixed attenuation and calcification.
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Digital-Subtraction Angiograms of the Pelvis.
The lumen of the left external iliac artery is dilated and irregular in contour in the mid-pelvis (top). This abnormality extends below the inguinal ligament. The proximal vessels are slightly tortuous, and clips from the previous surgical procedure are visible. A detailed view of the abnormality (bottom) shows extension into the proximal left common femoral and profunda femoris arteries.
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Pleomorphic Spindle Cells Replacing the Media of the Femoral Artery (Right), with a Fibrous Atherosclerotic Plaque Occupying the Intima (Left)(x55).
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Neoplastic Bone (Short Arrow) and Osteoid (Long Arrow) (x22).
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Residual Sarcoma Surrounding the Prosthetic Vascular Graft Inserted at the Time of the Initial Resection.
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Copyright © 1993 Massachusetts Medical Society. All rights reserved.