- Email: [email protected]
Epithelioid hemangioendotheliomia as a rare cause of blue toe syndrome
Epithelioid hemangioendotheliomia as a rare cause of blue toe syndrome Eitan Heldenberg, MD,a Igor Rabin, MD,a David Cheyn, MD,a Jonathan Lorber, MD,a Erez Elkabetz, MD,a Judith Sandbank, MD,b and Arie Bass,a Zerifin, Israel Blue toe syndrome (BTS), is a well-known entity of toe gangrene and rest pain secondary to micro emboli lodged within the digital arteries. BTS among young patients should alert physicians to look for causes such as trauma, connective tissue disease, hypercoagulability state, and others. We hereby describe a 32-year-old female with right BTS. A mass obstructing 80% of the right popliteal artery lumen was the source of emboli. The histologic results of the replaced arterial segment revealed a thrombus on top of epithelioid hemangioendothelioma. This is the first description of the association between primary vascular tumor and BTS. ( J Vasc Surg 2011;54:854-6.)
Blue toe syndrome (BTS) is a well-known entity of toe gangrene and rest pain secondary to micro emboli, originating from an atherosclerotic plaque, which breaks down and lodges within the digital arteries. The presentation of BTS among young patients should alert the treating physician to look for other causes such as trauma, connective tissue disease, hypercoagulability state, and others. We hereby report on a young patient with blue toes that was caused by microemboli from an isolated tumor, epithelioid hemangioendothelioma (EHE), in her popliteal artery. The association between primary vascular tumor and BTS has not been previously described, to our knowledge. CASE REPORT A 32-year-old female presented to the emergency room with a blue right great toe. There were no similar episodes in the past, no history of heart rate irregularities or walking problems, and no history of any trauma to the foot or the knee region. On physical examination, normal pedal pulses were palpated at all locations. Her first toe on the right was bluish and painful. Her medical history revealed a few risk factors for atherosclerosis (diabetes mellitus, well controlled on oral hypoglycemic agents, and heavy smoking, up to two packs a day). A duplex scan (LOGIQ P6; GE Healthcare, Waukesha, Wisc) revealed a cauliflower lesion at the right middle popliteal artery; the rest of the examination was normal. Computed tomography angiography demonstrated a single lesion in the right middle popliteal artery, obstructing 70% of the arterial lumen (Fig 1). No other pathology was found in her entire arterial tree. Hypercoagulability scan was normal. Cardiac echography revealed no source of emFrom the Department of Vascular Surgery, Assaf Harofeh Medical Center,a and the Institute of Pathology, Assaf Harofeh Medical Center,b The Sackler School of Medicine, Tel Aviv University. Competition of interest: none. Reprint requests: Dr Eitan Heldenberg, Sackler School of Medicine, Tel Aviv University, Department of Vascular Surgery, Assaf Harofeh Medical Center, Zerifin, 60930 Zriffin, Israel (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a competition of interest. 0741-5214/$36.00 Copyright © 2011 by the Society for Vascular Surgery. doi:10.1016/j.jvs.2011.02.034
854
boli. A tentative diagnosis of a primary vascular tumor was made, and the patient was scheduled for elective surgical resection of the lesion and a segment of the artery. The popliteal artery was exposed via a posterior approach, and an oval lesion, occupying about 75% of the popliteal artery lumen, was found (Fig 2). This lesion was easily dislodged from the endothelium. A short segment of the artery (3 cm) was resected and replaced by an interposition reversed saphenous vein graft (RSVG). Frozen section done during the operation did not show clear signs of malignancy. The vein graft occluded after several hours, and the patient was taken to the operating room for revision. No technical problems were found, either in the anastomosis sites, the conduit, or the trajectory of the graft, and thrombectomy was done. Intravenous heparin treatment was started, and adequate therapeutic levels were reached. The graft occluded again on the following day, and the patient was retaken to the operating room for a formal distal superficial femoral artery to below knee popliteal artery bypass, using, once again, RSVG. Several hours following that operation, the bypass reoccluded. Heparin-induced thrombocytopenia assay, which was considered as a probable cause for those reocclusions, was negative. The patient was taken once again to the operating room, and a common femoral artery to the below knee popliteal artery (Distaflo; Bard, Tempe, Ariz) bypass was done. The postoperative course following the last operation was uneventful, and the patient was discharged with warfarin treatment for the rest of her life. On histologic examination, the mass showed features consistent with an epitheloid hemangioendothelioma, with a low level of cellular atypia but with a high proliferative rate (70%) overlaid by thrombus (Fig 3). Taking into account the nature of the tumor (ie, resistant to chemotherapy and radiation), and given the possibility that the micro emboli were of tumor cells as well, the oncologist opted for follow-up only.
DISCUSSION The EHE has been defined as a borderline or a lowgrade malignant tumor in 1982.1 This tumor is a rare vascular tumor, which originates from endothelial cells, usually venous in origin. EHE is believed to be in the middle of the spectrum of endothelial tumors, between the benign hemangioendothelioma and the malignant epithelioid angiosarcoma.2-4 Lung and liver involvement were described.1,2 EHE usually develops as a solitary, slightly
JOURNAL OF VASCULAR SURGERY Volume 54, Number 3
Heldenberg et al 855
Fig 1. A lesion occupying 80% of the right popliteal artery.
Fig 3. Significant proliferative cellular activity: 60% to 70%; Ki staining (⫻10 original magnification).
Fig 2. Mass within the right popliteal artery.
painful mass in either superficial or deep soft tissue. Both genders are affected about equally, and the age of onset varies greatly. Symptoms such as edema or thrombophlebitis might be seen, but ischemic symptoms are very rare. Although EHE is considered a tumor of intermediate malignancy, it is reported that it has a potential to recur in 12% to 13% and metastasize in 21% to 61% of the cases.2 The most common sites of metastasis are the lung and the liver, and it might occur after quite a period of time. Death rates from lung and liver disease vary from 40% to 65%, respectively, compared with a 13% death rate in soft tissue involvement.1,2 The clinical course of the EHE is unpredictable according to the 30 cases involving the arterial tree of the limbs that were published in the literature.3,5,6 BTS is a well-known entity, mostly affecting the older age group, secondary to plaque breakdown that embolizes to the digital arteries, causing bluish discoloration and sometimes even gangrene of a toe in patients with palpable pedal pulses.7 Among the younger age groups, hypercoagulability states is the most common cause of this syndrome in healthy individuals, while other causes are related
to the primary disease of the affected patient, such as Raynaud’s disease, polycystemia vera, or thrombocytosis. “Embolic material” that is not located in bifurcation areas should alert the treating physician to look for an unordinary cause of the embolic phenomena. Previous report of primary metastasizing aortic endothelioma, originating from the thoracic aorta, described metastases to the femoral arteries, liver, intestine, and pelvis, as well as to the leg bones.8 A collection of all cases of aortic sarcomas, published in the literature, revealed 50 cases.9 It seems peculiar that the vein grafts in this case occluded so many times when no technical problem was found. There is no clear answer to this question. It might be related to some kind of abnormality of her veins, which we cannot specify further since no vein sample was sent to histologic examination, or it might be a consequence of hypercoagulability states either secondary to her malignancy, or primary one. The medical history and an unordinary location of the lesion, combined with the duplex findings as well as the normal architecture of the rest of the arterial tree on computed tomography angiography, should raise the suspicion that the cause might be a primary arterial tumor, although this diagnosis is extremely rare. Considering a primary arterial tumor as the cause of the BTS will dictate a proper surgical management; mainly, planning the operation for an excision of the tumor with wide surgical margins. An extremely important question regarding the malignant potential of the tumor throughout its course, to the digital arteries where it lodges, cannot be answered. Soft tissue tumors are being treated by surgical excision (ie, in this context, limb amputation), if the course is considered
856 Heldenberg et al
to be involved. It seems that for a tumor without any proven malignancy potential, it would be overtreatment. It seems that the best recommendation in such cases should be a close follow-up. REFERENCES 1. Mentzel T, Beham A, Calonje E, Katenkamp D, Fletcher CD. Epithelioid hemangioendothelioma of skin and soft tissues: clinicopathologic and immunohistochemical study of 30 cases. Am J Surg Pathol 1997;21: 363-74. 2. Enzinger FM, Weiss SW. Hemangioendothelioma: vascular tumors of intermediate malignancy. In: Enzinger FM, editor. Soft tissue tumors. 5th ed. St. Louis: Mosby; 2008. p. 681-7. 3. Ignacio EA, Palmer KM, Mathur SC, Schwartz AM, Olan WJ. Epithelioid hemangioendothelioma of the lower extremity. RadioGraphics 1999; 19:531-7.
JOURNAL OF VASCULAR SURGERY September 2011
4. Castelli P, Caronno R, Piffaretti G, Tozzi M. Epithelioid hemangioendothelioma of the radial artery. J Vasc Surg 2005;41:151-4. 5. Charette S, Nehler MR, Whitehill TA, Gibbs P, Foulk D, Krupski WC, et al. Epithelioid hemangioendothelioma of the common femoral vein: case report and review of the literature. J Vasc Surg 2001;33:1100-3. 6. Delin A, Johansson G, Silfverswärd C. Vascular tumours in occlusive disease of the iliac-femoral vessels. Eur J Vasc Surg 1990;4:539-42. 7. Brewer ML, Kinnison ML, Perler BA, White RI. Blue toe syndrome: treatment with anticoagulants and delayed percutaneous transluminal angioplasty. Radiology 1988;166:31-6. 8. Schmid E, Port J, Carrol RM, Friedman NB. Primary metastasizing aortic endothelioma. Cancer 1984;54:1407-11. 9. Shijubo N, Nakata H, Sugaya F, Imada A, Suzuki A, Kudoh K, et al. Malignant hemangioendothelioma of the aorta. Intern Med 1995;34: 1126-9.
Submitted Nov 16, 2010; accepted Feb 15, 2011.
Blue toe syndrome (BTS) is a well-known entity of toe gangrene and rest pain secondary to micro emboli, originating from an atherosclerotic plaque, which breaks down and lodges within the digital arteries. The presentation of BTS among young patients should alert the treating physician to look for other causes such as trauma, connective tissue disease, hypercoagulability state, and others. We hereby report on a young patient with blue toes that was caused by microemboli from an isolated tumor, epithelioid hemangioendothelioma (EHE), in her popliteal artery. The association between primary vascular tumor and BTS has not been previously described, to our knowledge. CASE REPORT A 32-year-old female presented to the emergency room with a blue right great toe. There were no similar episodes in the past, no history of heart rate irregularities or walking problems, and no history of any trauma to the foot or the knee region. On physical examination, normal pedal pulses were palpated at all locations. Her first toe on the right was bluish and painful. Her medical history revealed a few risk factors for atherosclerosis (diabetes mellitus, well controlled on oral hypoglycemic agents, and heavy smoking, up to two packs a day). A duplex scan (LOGIQ P6; GE Healthcare, Waukesha, Wisc) revealed a cauliflower lesion at the right middle popliteal artery; the rest of the examination was normal. Computed tomography angiography demonstrated a single lesion in the right middle popliteal artery, obstructing 70% of the arterial lumen (Fig 1). No other pathology was found in her entire arterial tree. Hypercoagulability scan was normal. Cardiac echography revealed no source of emFrom the Department of Vascular Surgery, Assaf Harofeh Medical Center,a and the Institute of Pathology, Assaf Harofeh Medical Center,b The Sackler School of Medicine, Tel Aviv University. Competition of interest: none. Reprint requests: Dr Eitan Heldenberg, Sackler School of Medicine, Tel Aviv University, Department of Vascular Surgery, Assaf Harofeh Medical Center, Zerifin, 60930 Zriffin, Israel (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a competition of interest. 0741-5214/$36.00 Copyright © 2011 by the Society for Vascular Surgery. doi:10.1016/j.jvs.2011.02.034
854
boli. A tentative diagnosis of a primary vascular tumor was made, and the patient was scheduled for elective surgical resection of the lesion and a segment of the artery. The popliteal artery was exposed via a posterior approach, and an oval lesion, occupying about 75% of the popliteal artery lumen, was found (Fig 2). This lesion was easily dislodged from the endothelium. A short segment of the artery (3 cm) was resected and replaced by an interposition reversed saphenous vein graft (RSVG). Frozen section done during the operation did not show clear signs of malignancy. The vein graft occluded after several hours, and the patient was taken to the operating room for revision. No technical problems were found, either in the anastomosis sites, the conduit, or the trajectory of the graft, and thrombectomy was done. Intravenous heparin treatment was started, and adequate therapeutic levels were reached. The graft occluded again on the following day, and the patient was retaken to the operating room for a formal distal superficial femoral artery to below knee popliteal artery bypass, using, once again, RSVG. Several hours following that operation, the bypass reoccluded. Heparin-induced thrombocytopenia assay, which was considered as a probable cause for those reocclusions, was negative. The patient was taken once again to the operating room, and a common femoral artery to the below knee popliteal artery (Distaflo; Bard, Tempe, Ariz) bypass was done. The postoperative course following the last operation was uneventful, and the patient was discharged with warfarin treatment for the rest of her life. On histologic examination, the mass showed features consistent with an epitheloid hemangioendothelioma, with a low level of cellular atypia but with a high proliferative rate (70%) overlaid by thrombus (Fig 3). Taking into account the nature of the tumor (ie, resistant to chemotherapy and radiation), and given the possibility that the micro emboli were of tumor cells as well, the oncologist opted for follow-up only.
DISCUSSION The EHE has been defined as a borderline or a lowgrade malignant tumor in 1982.1 This tumor is a rare vascular tumor, which originates from endothelial cells, usually venous in origin. EHE is believed to be in the middle of the spectrum of endothelial tumors, between the benign hemangioendothelioma and the malignant epithelioid angiosarcoma.2-4 Lung and liver involvement were described.1,2 EHE usually develops as a solitary, slightly
JOURNAL OF VASCULAR SURGERY Volume 54, Number 3
Heldenberg et al 855
Fig 1. A lesion occupying 80% of the right popliteal artery.
Fig 3. Significant proliferative cellular activity: 60% to 70%; Ki staining (⫻10 original magnification).
Fig 2. Mass within the right popliteal artery.
painful mass in either superficial or deep soft tissue. Both genders are affected about equally, and the age of onset varies greatly. Symptoms such as edema or thrombophlebitis might be seen, but ischemic symptoms are very rare. Although EHE is considered a tumor of intermediate malignancy, it is reported that it has a potential to recur in 12% to 13% and metastasize in 21% to 61% of the cases.2 The most common sites of metastasis are the lung and the liver, and it might occur after quite a period of time. Death rates from lung and liver disease vary from 40% to 65%, respectively, compared with a 13% death rate in soft tissue involvement.1,2 The clinical course of the EHE is unpredictable according to the 30 cases involving the arterial tree of the limbs that were published in the literature.3,5,6 BTS is a well-known entity, mostly affecting the older age group, secondary to plaque breakdown that embolizes to the digital arteries, causing bluish discoloration and sometimes even gangrene of a toe in patients with palpable pedal pulses.7 Among the younger age groups, hypercoagulability states is the most common cause of this syndrome in healthy individuals, while other causes are related
to the primary disease of the affected patient, such as Raynaud’s disease, polycystemia vera, or thrombocytosis. “Embolic material” that is not located in bifurcation areas should alert the treating physician to look for an unordinary cause of the embolic phenomena. Previous report of primary metastasizing aortic endothelioma, originating from the thoracic aorta, described metastases to the femoral arteries, liver, intestine, and pelvis, as well as to the leg bones.8 A collection of all cases of aortic sarcomas, published in the literature, revealed 50 cases.9 It seems peculiar that the vein grafts in this case occluded so many times when no technical problem was found. There is no clear answer to this question. It might be related to some kind of abnormality of her veins, which we cannot specify further since no vein sample was sent to histologic examination, or it might be a consequence of hypercoagulability states either secondary to her malignancy, or primary one. The medical history and an unordinary location of the lesion, combined with the duplex findings as well as the normal architecture of the rest of the arterial tree on computed tomography angiography, should raise the suspicion that the cause might be a primary arterial tumor, although this diagnosis is extremely rare. Considering a primary arterial tumor as the cause of the BTS will dictate a proper surgical management; mainly, planning the operation for an excision of the tumor with wide surgical margins. An extremely important question regarding the malignant potential of the tumor throughout its course, to the digital arteries where it lodges, cannot be answered. Soft tissue tumors are being treated by surgical excision (ie, in this context, limb amputation), if the course is considered
856 Heldenberg et al
to be involved. It seems that for a tumor without any proven malignancy potential, it would be overtreatment. It seems that the best recommendation in such cases should be a close follow-up. REFERENCES 1. Mentzel T, Beham A, Calonje E, Katenkamp D, Fletcher CD. Epithelioid hemangioendothelioma of skin and soft tissues: clinicopathologic and immunohistochemical study of 30 cases. Am J Surg Pathol 1997;21: 363-74. 2. Enzinger FM, Weiss SW. Hemangioendothelioma: vascular tumors of intermediate malignancy. In: Enzinger FM, editor. Soft tissue tumors. 5th ed. St. Louis: Mosby; 2008. p. 681-7. 3. Ignacio EA, Palmer KM, Mathur SC, Schwartz AM, Olan WJ. Epithelioid hemangioendothelioma of the lower extremity. RadioGraphics 1999; 19:531-7.
JOURNAL OF VASCULAR SURGERY September 2011
4. Castelli P, Caronno R, Piffaretti G, Tozzi M. Epithelioid hemangioendothelioma of the radial artery. J Vasc Surg 2005;41:151-4. 5. Charette S, Nehler MR, Whitehill TA, Gibbs P, Foulk D, Krupski WC, et al. Epithelioid hemangioendothelioma of the common femoral vein: case report and review of the literature. J Vasc Surg 2001;33:1100-3. 6. Delin A, Johansson G, Silfverswärd C. Vascular tumours in occlusive disease of the iliac-femoral vessels. Eur J Vasc Surg 1990;4:539-42. 7. Brewer ML, Kinnison ML, Perler BA, White RI. Blue toe syndrome: treatment with anticoagulants and delayed percutaneous transluminal angioplasty. Radiology 1988;166:31-6. 8. Schmid E, Port J, Carrol RM, Friedman NB. Primary metastasizing aortic endothelioma. Cancer 1984;54:1407-11. 9. Shijubo N, Nakata H, Sugaya F, Imada A, Suzuki A, Kudoh K, et al. Malignant hemangioendothelioma of the aorta. Intern Med 1995;34: 1126-9.
Submitted Nov 16, 2010; accepted Feb 15, 2011.