, George B. Kuzycz3, Marcelo C. DaSilva4, Raymond A. DieterIII5, Anthony M. Joudi6 and Morgan M. Meyer7
(1)
Northwestern Medicine, At Central DuPage Hospital, Winfield, IL 60190, USA
(2)
International College of Surgeons, Cardiothoracic and Vascular Surgery, Glen Ellyn, IL, USA
(3)
Thoracic and Cardiovascular Surgery, Cadence Hospital of Northwestern System, Winfield, IL 60190, USA
(4)
Thoracic Surgery, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA 02115, USA
(5)
Division of Cardiothoracic Surgery, The University of Tennessee Medical Center, Knoxville, TN 37920, USA
(6)
Loyola University Medical Center, Stritch School of Medicine, Maywood, IL 60153, USA
(7)
Internal Medicine, Past President of the Illinois State Medical Society, Lombard, IL 60148, USA
Keywords
IschemiaLimb ischemiaMalignancy-induced ischemiaEmbolic ischemiaPrimary tumor ischemiaGangrene due to malignancyBenign tumor limb ischemiaMedication-induced ischemiaParaneoplastic syndromesExtremity ischemia represents one of the most devastating disabilities an individual may develop. The usual cause for critical circulatory ischemia is related to disease developing in an elderly individual. These diseases include the arteriosclerotic and diabetic conditions in a large proportion of the older patients. However, other causes of circulatory concerns may also develop on occasion. The less commonly occurring etiologies for critical limb ischemia involve both large and small vessel maladies. These include such lesions as the nonatherosclerotic arteriopathies, including Buerger’s disease, vasculitis (large, medium, and small vessel), congenital abnormalities, and peripheral aneurysms [1].
The diagnoses of malignancy may also be a harbinger of serious and life-threatening events to come. Seldom does one consider malignancy as the cause of or to be associated with critical ischemia, gangrene, or loss of an extremity due to circulatory concerns. However, this situation does occur on occasion and may lead to loss of digits, an extremity, or even vascular-associated death. When one combines the two—ischemia of the extremity and a life-threatening malignancy—this may be an overwhelming situation for the individual both mentally and physically.
Case Reports
Patient #1
A middle-aged university professor was seen complaining of multiple physical changes during the previous 6 months. Initially, his dark brown to black hair had turned totally white during a 4-month period of time. He also noted a lack of energy and saw several physicians while developing gangrenous ulceration of his fingertips on both hands. Multiple laboratory tests and X-rays were not diagnostic. After several months of symptomatology progression and lack of diagnosis, he sought vascular consultation from us. On physical examination, he had pure white hair, ischemic changes and necrotic ulceration of his digits, and a suspicious mass or adenopathy deep in the right scalene area. Chest X-ray and CT (computerized tomography) examination failed to demonstrate any mass in the chest. During surgery, a right scalene “egg-sized” 4 × 6 cm mass was removed. Pathologic diagnosis was that of amelanotic melanoma. Extensive examination of his body surfaces failed to demonstrate any other lesion. Oncologic consultation, extensive ear, nose and throat examination, and radiologic gastrointestinal exam did not delineate a primary tumor. The entire visible mass had been removed. Additional oncologic consultation failed to demonstrate a beneficial course—including an antigen-antibody-induced program. A few months later, he developed a recurrence of the mass in the right scalene area. On resection the same pathologic diagnosis of amelanotic melanoma was established. Again no beneficial treatment program was found for this individual. His findings and photographs were presented at a world congress exemplifying an ischemic paraneoplastic syndrome due to melanoma with secondary gangrene of the fingers [2].
Patient #2
An elderly male with a long history of smoking developed a cough and weight loss. On X-ray evaluation, he was found to have a carcinoma of the lung . At surgery, the tumor was found to be more central and required extensive dissection and lobectomy. Upon completion of surgery and closure of the chest, the patient was placed in the supine position and extubated. At this time, he was noted to have a morbid left lower extremity. No pulses were palpable in the left foot or in the left groin. Immediate exploration of the left common femoral artery with balloon catheter thromboendarterectomy was performed. Pathologic examination of the specimen was compatible with a squamous cell carcinoma tumor embolism. Postembolectomy, the patient’s leg developed a pink color with palpable pulsations. The tumor embolus was felt to have originated in the left atrium and to have dislodged during surgical manipulation.
Patient #3
A previously healthy 26-year-old male with a 20-pack-year smoking history presented with acute left lower extremity ischemia , which began as he was exercising. He suddenly felt a “pop” in his left hip, followed by numbness, coldness, and pain from the calf to the left foot. On physical exam, the patient was in sinus rhythm, had no murmurs and no pulses in the left foot. An emergency CT angiogram revealed occlusion of the distal left common femoral artery, profunda femoral artery, superficial femoral artery, and distal vessels. A hypercoagulable lab work-up was negative. In surgery, he had a left femoral thromboembolectomy and four compartment fasciotomies. The transverse arteriotomy on the distal common femoral artery revealed a yellow, firm mass within the artery. A Fogarty embolectomy catheter was passed to the popliteal level and an additional embolus was retrieved (Fig. 29.1). An operative arteriogram demonstrated a patent femoral tibial system. The patient had an uneventful recovery.
Fig. 29.1
Embolic angiosarcoma to the femoral artery causing acute ischemic symptoms
Pathology examination of the specimens described a large clot with a thin rim of viable tumor cells at the periphery. The remainder of the clot appeared amorphous and eosinophilic with focal areas of calcification. The tumor cells were small and contained a small amount of ill-defined cytoplasm , ovoid nuclei, and formed focal rosette-like structures. The specimens stained positively for CD56, CK8/18, AE1/AE3, CD117, vimentin, synaptophysin (focally), and CD34 (focally). Initially, the tumor diagnosis was a small cell carcinoma. After the review, it was felt to be an undifferentiated cancer with spindle cell and neuroendocrine features. Three-month follow-up CT scan of the chest demonstrated an increased cavitary ground-glass opacity in the right lower lobe and continued left pulmonary vein thrombosis. Repeat PET scan demonstrated interval development of the ground-glass opacity with mild FDG uptake (maximum SUV of 1.8) in the right lower lobe. A core needle biopsy demonstrated poorly differentiated carcinoma with neuroendocrine differentiation and appeared morphologically similar to the embolic lesion.
The patient underwent video-assisted thoracoscopic (VAT) right lower lobectomy. The surgical specimens stained positive for CD56 and CD117, as well as focally positive for MCK and CK7. Stains for CK20, p63, TTF-1, MOC-31, AFP, synaptophysin, and chromogranin were negative. Up to 30 % of the tumor cells showed reactivity for Ki67. Morphologically, the specimen demonstrated formation of primitive vascular channels with protrusion of neoplastic cells into the vascular spaces and abundant basement membrane production. The final pathologic diagnosis was angiosarcoma showing aberrant neuroendocrine differentiation. Lymph node biopsies and CT of the abdomen were negative for metastatic disease. The postoperative course was uneventful and he was discharged on postoperative day 3.
Patient #4
A 70-year-old Caucasian male was admitted to a small downstate community hospital in a wheelchair because of low back pain. He was short of breath and on evaluation was felt to have a carcinoma of the right lower lobe of the lung with probable bone metastases—including the spine. He came to see ourselves for a second opinion. Magnetic resonance (MR) study of the lumbar spine demonstrated a ruptured lumbar disc. Following lumbar discectomy, he was discharged home on continuous oxygen with the plan for future evaluation of his lung. Following repeat back surgery for another acutely ruptured disc, he had bronchoscopy and a right thoracotomy. A radical pneumonectomy with partial resection of the left atrium demonstrated the squamous cell tumor invasion of the cardiac muscle with a negative atrial myocardial resection margin for any remaining tumor, and he had no evidence of a dislodged embolic phenomenon (Fig. 29.2). Following the preoperatively anticipated prolonged postoperative period, the patient recovered and enjoyed a 6.5 year oxygen-free survival until developing high altitude pneumonia.
Fig. 29.2
Squamous cell carcinoma of the atrium showing tumor cells with normal muscle beyond
Patient #5
This middle-aged individual was admitted to the hospital with acute lower extremity ischemia. Open surgical balloon embolectomy of tumor bearing clot from the lower extremities relieved his symptoms. CT examination of the chest and cardiac catheterization demonstrated that this individual had a primary endocardial tumor (Fig. 29.3). Utilizing cardiopulmonary bypass and open cardiac surgery, the primary benign myxomatous endocardial tumor was resected. The patient made a full recovery without residual sequela.
Fig. 29.3
Benign endocardial tumor demonstrated on CT scan
Patient #6
A middle-aged female with multiple complaints was admitted to the hospital. A previous gynecologic malignancy of the pelvis had been treated with extensive pelvic radiation and apparent control of the malignancy . Several years later, we were asked to see the patient with complaints of gastrointestinal and peripheral limb ischemic symptoms. Eventually, she required a colostomy and vascular surgical intervention. However, a few years later, she had progressive lower extremity difficulty with severe ischemic changes, marked lower abdominal and pelvic fibrosis, and extensive radiation-induced skin and soft tissue findings. Following repeated attempts to salvage her extremities, amputation and probable hemicorporectomy were offered—which she declined.
Patient #7
This patient had a long history of chronic lymphatic leukemia . However, chronic changes had developed in her right leg over time. Despite a mild anemia, the patient was able to live a moderately healthy life until she injured her foot. With the injury, a splinter was embedded in the right foot producing gangrenous changes, as a result of her leukemia and diminished circulation (Fig. 29.4).
Fig. 29.4
Gangrene of the foot due to splinter in patient with chronic lymphatic leukemia
Discussion
As one begins to see from these case illustrations, the complexity of the situation for the dually afflicted individual is great—malignancy and ischemia. Two patients (#1, 2) of the above seven illustrative patients had markedly shortened survival after diagnosis of their tumor and associated ischemic process (1 year or less). Three patients (#4, 5, 7) were prolonged survivors of their malignant processes. Patient 1 had rapid progression of his primary malignant disease but eventual healing of his digits. Patient 6 had severe therapeutic complications of her malignancy. Patient 3 is a more recently treated and confusing patient. We await the longer-term progress of his primary malignant lung disease and treatment. Four patients are examples of a potential cardiovascular source for an embolus as demonstrated by the microscopic examinations of the pulmonary and cardiac tissues after resection. Patient 5 had a benign cardiac myxoma which embolized and did well postoperatively. The above cases demonstrate a diversity of etiologies as well as the complexity of therapy. As demonstrated, the diagnostic and therapeutic concerns for these patients present major challenges for both the patient and their treating physicians, as illustrated in Table 29.1. Further, these patients demonstrate the need for thromboembolectomy specimens to be examined microscopically in order to avoid missing the diagnosis of a tumor embolus.
Table 29.1
Some examples of tumor-related extremity ischemia
Patient | Disease | Type of ischemia |
|---|---|---|
1 | Amelanotic melanoma | Paraneoplastic |
2 | Carcinoma lung | Embolic |
3 | Angiosarcoma | Embolic |
4 | Carcinoma lung | Embolic |
5 | Cardiac myxoma | Embolic |
6 | Gynecologic carcinoma | Radiation-induced fibrosis |
7 | Chronic leukemia | Foreign body gangrene |
Critical ischemia of the upper and lower extremities is not a rare occurrence. A number of these critical limb situations may end in amputation of a portion or all of an extremity. The pathophysiology of these lesions has been discussed extensively by Varu et al. They have classified the ischemic disease processes according to the patient’s symptoms beginning with the asymptomatic individual and progressing to those with severe pain and loss of tissue or gangrene [3]. They further mention that individuals with critical limb ischemia have poor survival statistics and thus discussed the appropriateness of therapy, including gene, cell, and emergency therapy for individuals with tumors and critical limb ischemia. However, a number of their patients did show improvement in walking distance and the ankle—brachial index. Because of the high risk of leg amputation in the United Kingdom area (12,000 lower limb amputations in England during 2012 and 2013), a major review of the treatment of these individuals included the proposal of additional recommendations including a multidisciplinary team and rapid treatment initiation within the first 24 h of patient presentation [4]. In these critical acute, subacute, and chronic limb ischemia situations, a review of the management and options for these individual patients is well presented in an online outline of the nonoperative and operative interventions available, as well as various research-oriented studies [5]. Cell therapy, omental transplants, and wound V. A. C. are all discussed for the patient’s benefit [6]. Despite the limitations of these concepts and therapeutic programs, treatments may be successful in a significant percentage of these patients.
Few authors discuss the occurrence of critical limb ischemia due to malignancy and its therapy except as case reports. We have illustrated a number of patients who had critical limb ischemia or the potential to develop critical ischemic changes of either the upper or lower extremity as a result of a malignant neoplasm or its therapy. In our experience, the incidence of such a relationship is very low, but the morbidity and potential effects are devastating. We have seen additional patients with other concerns related to tumors and have noted many of the signs or findings that may alert a physician to potential upcoming disasters. The multiple and various etiologies delineated above demonstrate the potential for tumor-induced peripheral ischemia and further demonstrate the need for critical examination of the diagnostic X-rays (especially thoracic CTs) and the patient’s history and physical.
Various etiologies of tumor-induced peripheral ischemia are presented below (Table 29.2). The most common cause for such an acute tumor-induced ischemic calamity revolves around embolic phenomena from more central structures to the periphery. In our experience, most of these central lesions are located in the heart as a result of primary malignant or benign cardiac lesions or direct extension from pulmonary or mediastinal malignancies. Certainly, when one is considering major pulmonary surgery for a malignancy that is central in origin, one should closely review the CT (computerized tomography studies) of the chest to be certain that there is no intracardiac or major pulmonary vessel involvement by the tumor that might embolize. A non-cardiopulmonary origin of an embolic tumor may also include the aorta [7].
Table 29.2
Tumor-induced causes of extremity ischemia
Embolic sources |
Benign tumors |
Cardiac myxoma |
Malignant tumors |
Heart |
Aorta |
Lung |
Mediastinum |
Nuclear protein in testis (NUT) in childhood |
Paraneoplastic syndromes |
Pulmonary tumors |
Gastric tumors |
Melanomas |
Ovarian tumors |
Lymphoma/leukemias |
Sarcoma |
Vascular |
Aortic intima
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