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Great Saphenous Vein Leiomyosarcoma: A Rare Malignant Tumor of the Extremity—Two Case Reports
Case Reports Great Saphenous Vein Leiomyosarcoma: A Rare Malignant Tumor of the Extremity—Two Case Reports Thuc Le Minh, MD,1 Didier Cazaban, MD,2 Jean Michaud, MD,1 Marie Christine Ginestet-Auge, MD,1 Marie He´le`ne Laporte, MD,1 Annie Patelli, MD,3 and Alain Marre, MD,4 Figeac, Cahors, and Rodez, France
Peripheral vascular leiomyosarcomas are rare. Two cases of intramural leiomyosarcomas of the great saphenous vein are described. The first case is considered a high-grade sarcoma, based on the high mitotic index on histologic study. The second case presents only infrequent mitoses on light microscopy. Immunohistochemical analysis for factor VIII helped to establish the diagnosis. Characteristics of the tumor and differential diagnosis are discussed. Treatment consisted of wide local excision. Radiotherapy and chemotherapy were given to the patient with high-grade tumor.
INTRODUCTION
CASE REPORTS
Primary tumors arising from the smooth muscle cells of the vessel wall are rare. Vascular leiomyosarcomas represent only less than 2% of all leiomyosarcomas and involve veins five times more often than arteries.1 Because venous leiomyosarcomas are generally asymptomatic, diagnosis and treatment are frequently delayed, resulting in poor long-term survival. We report here a high-grade leiomyosarcoma of the great saphenous vein presenting as a thrombosed venous aneurysm, and a low-grade leiomyosarcoma of the anterior venous branch of the great saphenous vein.
Case 1
1 Department of Vascular Surgery, Clinique Font Redonde, Figeac, France. 2 Department of General Surgery, Centre Hospitalier, Cahors, France. 3
Cabinet d’Anatomie Pathologique, Cahors, France. Department of Oncology, Centre Hospitalier, Rodez, France. Correspondence to: Thuc Le Minh, MD, E-mail: thucleminh@ aol.com 4
Ann Vasc Surg 2004; 18: 234-236 DOI: 10.1007/s10016-003-0090-2 Annals of Vascular Surgery Inc. Published online: 15 March 2004
234
A 52-year-old woman noticed an asymptomatic swelling that had developed 2 months previously. It was localized in the anteromedial aspect of the right thigh in the region of the femoral triangle. No peripheral edema or tenderness was noted. Because the patient was thought to have a venous thrombosis of the great saphenous vein, she was treated with low-molecular-weight heparin (nadroprine 171 IU/kg once a day). Doppler ultrasound examination was performed and the diagnosis of a thrombosed great saphenous vein aneurysm was made. The saphenous femoral junction was competent. The patient was then referred to our institution for further treatment. On clinical examination, the tumor was not fixed to the skin or deep fascia structures, and it was mobile laterally. There was no inguinal adenopathy. At surgery, the tumor was found to be attached to the great saphenous vein and expanded into the surrounding tissue, from which it was not well separated, and measured 1.5 · 2 cm. The vein was occluded distally but not proximally. The entire lesion was excised subcutaneously. Histologic study revealed a leiomyosarcoma with intraluminal growth and an average mitotic rate of 27 per 10 high-power fields (Fig. 1). The tumor originated from the media musculature of the venous wall and stained positively for factor VIII–associated antigen (Von Willebrand factor), anti-desmin and anti-vimentin antigens,
Vol. 18, No. 2, 2004
Case reports 235
Fig. 1. High-grade leiomyosarcoma of the great saphenous vein. Dense, poorly differentiated spindle cell proliferation is apparent with large and irregular nuclei and frequent mitoses (original magnification, ·250).
Fig. 2. Low-grade leiomyosarcoma from the anterior branch of the great saphenous vein. There is regular spindle cell proliferation with symmetric, ‘‘cigar-shaped’’ nuclei, some atypical nuclei, and infrequent mitoses (original magnification, ·250).
and anti-human smooth muscle actin, and negatively for anti-CD 34 and anti–S-100 protein. Three weeks after the biopsy, the patient underwent surgery again. We performed a wide excision of the subcutaneous tissue of the tumor bed extending from just below the inguinal ligament to the junction of the middle and distal thirds of the thigh, leaving the deep fascia and including the proximal end of the great saphenous vein. The chest plain radiographs showed no evidence of pulmonary metastases, and the abdominal echography did not show any hepatic metastases. Adjuvant radiation therapy was given postoperatively for a total dose of 60 grays. The patient also received doxorubicin at 20 mg/m2, plus ifosfamide at 2500 mg/m2 in three doses, for a maximum of four cycles. The antimitotic agents were given before (cycle 1), during (cycles 2 and 3), and after (cycle 4) radiation therapy. After 1 year of follow-up, the patient is doing well, with no evident metastases and only moderate lymphoedema with local pigmentation of the skin of the thigh.
Because the lesion was considered a low-grade leiomyosarcoma, the patient was treated only with adjuvant radiation therapy for a total dose of 50 grays. Chest plain radiographs demonstrated no pulmonary metastases. At 6 months the patient is well with no evident metastases.
Case 2 A 66-year-old man with no significant past medical history noticed a nodular swelling in the anterior aspect of the right thigh, not in relation to any vascular structure, that had grown to the size of a small nut within a few months. Because the patient was totally asymptomatic, it was thought that the tumor was a subcutaneous lipoma, and the patient was referred for local excision. On examination, the mass was not fixed to the skin and was mobile laterally. There was no inguinal adenopathy and no swelling or edema of the limb. At surgery, the tumor was found to be well circumscribed and attached to the anterior venous branch of the great saphenous vein, and it measured 5 · 3 cm. The entire lesion was excised subcutaneously. Histologic study revealed a leiomyosarcoma developing from the venous wall with an average mitotic rate of 0 to 4 per 10 high-power fields (Fig. 2).
DISCUSSION Vascular leiomyosarcoma is extremely rare and represents only <2% of all leiomyosarcomas. The frequency of occurrence of leiomyosarcomas in veins is five times that in arteries with approximately half of them occurring in the inferior vena cava (IVC).2 Retroperitoneal veins near the IVC are affected in about 75% and include the renal, iliac, ovarian, and spermatic veins.3 Intravenous leiomyosarcomas of the extremities have been reported in short and long saphenous veins, the external jugular vein, and a superficial vein at the back of the hand.4 In the lower extremity, the great saphenous vein is the most frequent site of origin.2 The tumor most commonly develops proximal to the knee.5 Although female preponderance occurs among patients with leiomyosarcoma of the IVC, with a ratio of 4:1, primary venous leiomyosarcoma of the extremities affects women and men almost equally.5 The mean age varies between 55 and 61 years old,2,3 although leiomyosarcoma of the saphenous vein has been reported in a 2-year-old child.6 The most frequent clinical signs and symptoms of retroperitoneal primary venous leiomyosarcoma include a palpable mass, back pain, or abdominal pain. Obstruction of the hepatic veins can occur, and the right heart cavities may also be invaded.2 Because tumor growth in the lower extremity is slow, adequate venous collateral circulation frequently develops, and clinical presentation of acute
236 Case reports
deep-venous thrombosis is rare. Lower extremity swelling or chronic venous insufficiency is more frequent if the iliac or femoropopliteal veins are invaded. Primary leiomyosarcoma of the greater saphenous vein usually presents as a painless mobile mass, as in our reported cases, whereas those arising from deep veins can be fixed to the surrounding tissue.2 Histologically, leiomyosarcomas have a typical pattern of interlacing, sweeping bundles of spindle shaped–cells, with elongated, occasionally torquated, blunt-ended nuclei. The tumor may be more or less encapsulated but has an abundance of cellular and nuclear polymorphism.4 In the differential diagnosis, one must consider tumors originating from the endothelial layer (hemangioendothelioma, angiosarcoma) and fibrosarcomas. Tumors of endothelial origin may be detected by the presence of factor VIII within the tumor cells. The muscular origin of a tumor can be proved by the presence of desmin and/or smooth muscle actin antigens. Leiomyosarcoma contains desmin and vimentin, whereas fibrosarcoma contains vimentin only. Hemangioendotheliomas are characterized by the occurrence of factor VIII and the lack of both vimentin and desmin.4 Varela-Duran et al.7 attempted to make a correlation between their microscopic features and biologic behavior. According to these authors, the mitotic index of vascular leiomyosarcoma seemed to be closely related to the clinical outcome of these tumors. But the value of histologic prognostic indicators remains controversial.8 Tumors of the venous wall may grow intraluminally or expand from the media musculature into the surrounding perivascular tissue. Intraluminal growth finally causes a thrombotic occlusion of the vein.4 The natural history of primary venous leiomyosarcoma is that of slow but definite progression. Although some authors have found that leiomyosarcomas of the venous wall have a low potential to metastasize, at least until they reach a certain size,4,8 there is an overall 60% incidence of metastases in these tumors at the time of resection of the primary tumors.5 As is recommended for the treatment of sarcomas, complete surgical resections with 2- to 3-cm margins are mandatory. Local recurrence is rarely
Annals of Vascular Surgery
observed after complete resection.9 It is often impossible to differentiate benign from malignant tumors in the operating room. The sensitivity of venous leiomyosarcoma to radiotherapy or to antimitotic agents has never been proven in this infrequent and rare tumor. Although there has been little experience with the response of peripheral vascular leiomyosarcoma to radiation therapy, there are ample data to support the use of this method for local control of soft tissue sarcomas in general.5 In our first patient, because the lesion was found to be high-grade leiomyosarcoma, combined postoperative adjuvant treatment was used to prevent progression or recurrence of the disease.
CONCLUSIONS Primary vascular leiomyosarcoma of veins is a rare disease with a poor prognosis. Preoperative diagnosis of the great saphenous vein leiomyosarcoma is very difficult. Treatment should consist of wide local excision, associated with postoperative adjuvant therapy.
REFERENCES 1. Kevorkian J, Cento DP. Leiomyosarcoma of large arteries and veins. Surgery 1973;73:390-400. 2. Dzsinich C, Gloviczki P, Van Heerden JA, et al. Primary venous leiomyosarcoma: a rare but lethal disease. J. Vasc. Surg. 1992;15:595-603. 3. Kieffer E, Berrod JL, Chomette G. Primary tumors of the inferior vena cava In: Bergan, JJ, Yao, JST, editors Surgery of the Veins. New York: Grune and Stratton, 1985, pp 423-443. 4. Leu HJ, Makek M. Intramural venous leiomyosarcomas. Cancer 1986;57:1395-1400. 5. Humphrey M, Neff J, Lin F, et al. Leiomyosarcoma of the saphenous vein. J. Bone Joint Surg. 1987;69:282-286. 6. Byard RW, Bourne AJ, Phillips GE, et al. Leiomyosarcoma of the saphenous vein in a child with 12 years follow-up. J. Pediatr. Surg. 1993;28:271-274. 7. Varela-Duran J, Olivia H, Rosair J. Vascular leiomyosarcoma: the malignant counterpart of vascular leiomyoma. Cancer 1979;44:1684-1691. 8. Wile AG, Evans HL, Romsdahl MM. Leiomyosarcoma of soft tissue, a clinicopathologic study. Cancer 1981;48:1022-1032. 9. Reix T, Sevestre H, Sevestri-Pietri MA, et al. Primary malignant tumors of the venous system in the lower extremities. Ann. Vasc. Surg. 1998;12:589-596.
Peripheral vascular leiomyosarcomas are rare. Two cases of intramural leiomyosarcomas of the great saphenous vein are described. The first case is considered a high-grade sarcoma, based on the high mitotic index on histologic study. The second case presents only infrequent mitoses on light microscopy. Immunohistochemical analysis for factor VIII helped to establish the diagnosis. Characteristics of the tumor and differential diagnosis are discussed. Treatment consisted of wide local excision. Radiotherapy and chemotherapy were given to the patient with high-grade tumor.
INTRODUCTION
CASE REPORTS
Primary tumors arising from the smooth muscle cells of the vessel wall are rare. Vascular leiomyosarcomas represent only less than 2% of all leiomyosarcomas and involve veins five times more often than arteries.1 Because venous leiomyosarcomas are generally asymptomatic, diagnosis and treatment are frequently delayed, resulting in poor long-term survival. We report here a high-grade leiomyosarcoma of the great saphenous vein presenting as a thrombosed venous aneurysm, and a low-grade leiomyosarcoma of the anterior venous branch of the great saphenous vein.
Case 1
1 Department of Vascular Surgery, Clinique Font Redonde, Figeac, France. 2 Department of General Surgery, Centre Hospitalier, Cahors, France. 3
Cabinet d’Anatomie Pathologique, Cahors, France. Department of Oncology, Centre Hospitalier, Rodez, France. Correspondence to: Thuc Le Minh, MD, E-mail: thucleminh@ aol.com 4
Ann Vasc Surg 2004; 18: 234-236 DOI: 10.1007/s10016-003-0090-2 Annals of Vascular Surgery Inc. Published online: 15 March 2004
234
A 52-year-old woman noticed an asymptomatic swelling that had developed 2 months previously. It was localized in the anteromedial aspect of the right thigh in the region of the femoral triangle. No peripheral edema or tenderness was noted. Because the patient was thought to have a venous thrombosis of the great saphenous vein, she was treated with low-molecular-weight heparin (nadroprine 171 IU/kg once a day). Doppler ultrasound examination was performed and the diagnosis of a thrombosed great saphenous vein aneurysm was made. The saphenous femoral junction was competent. The patient was then referred to our institution for further treatment. On clinical examination, the tumor was not fixed to the skin or deep fascia structures, and it was mobile laterally. There was no inguinal adenopathy. At surgery, the tumor was found to be attached to the great saphenous vein and expanded into the surrounding tissue, from which it was not well separated, and measured 1.5 · 2 cm. The vein was occluded distally but not proximally. The entire lesion was excised subcutaneously. Histologic study revealed a leiomyosarcoma with intraluminal growth and an average mitotic rate of 27 per 10 high-power fields (Fig. 1). The tumor originated from the media musculature of the venous wall and stained positively for factor VIII–associated antigen (Von Willebrand factor), anti-desmin and anti-vimentin antigens,
Vol. 18, No. 2, 2004
Case reports 235
Fig. 1. High-grade leiomyosarcoma of the great saphenous vein. Dense, poorly differentiated spindle cell proliferation is apparent with large and irregular nuclei and frequent mitoses (original magnification, ·250).
Fig. 2. Low-grade leiomyosarcoma from the anterior branch of the great saphenous vein. There is regular spindle cell proliferation with symmetric, ‘‘cigar-shaped’’ nuclei, some atypical nuclei, and infrequent mitoses (original magnification, ·250).
and anti-human smooth muscle actin, and negatively for anti-CD 34 and anti–S-100 protein. Three weeks after the biopsy, the patient underwent surgery again. We performed a wide excision of the subcutaneous tissue of the tumor bed extending from just below the inguinal ligament to the junction of the middle and distal thirds of the thigh, leaving the deep fascia and including the proximal end of the great saphenous vein. The chest plain radiographs showed no evidence of pulmonary metastases, and the abdominal echography did not show any hepatic metastases. Adjuvant radiation therapy was given postoperatively for a total dose of 60 grays. The patient also received doxorubicin at 20 mg/m2, plus ifosfamide at 2500 mg/m2 in three doses, for a maximum of four cycles. The antimitotic agents were given before (cycle 1), during (cycles 2 and 3), and after (cycle 4) radiation therapy. After 1 year of follow-up, the patient is doing well, with no evident metastases and only moderate lymphoedema with local pigmentation of the skin of the thigh.
Because the lesion was considered a low-grade leiomyosarcoma, the patient was treated only with adjuvant radiation therapy for a total dose of 50 grays. Chest plain radiographs demonstrated no pulmonary metastases. At 6 months the patient is well with no evident metastases.
Case 2 A 66-year-old man with no significant past medical history noticed a nodular swelling in the anterior aspect of the right thigh, not in relation to any vascular structure, that had grown to the size of a small nut within a few months. Because the patient was totally asymptomatic, it was thought that the tumor was a subcutaneous lipoma, and the patient was referred for local excision. On examination, the mass was not fixed to the skin and was mobile laterally. There was no inguinal adenopathy and no swelling or edema of the limb. At surgery, the tumor was found to be well circumscribed and attached to the anterior venous branch of the great saphenous vein, and it measured 5 · 3 cm. The entire lesion was excised subcutaneously. Histologic study revealed a leiomyosarcoma developing from the venous wall with an average mitotic rate of 0 to 4 per 10 high-power fields (Fig. 2).
DISCUSSION Vascular leiomyosarcoma is extremely rare and represents only <2% of all leiomyosarcomas. The frequency of occurrence of leiomyosarcomas in veins is five times that in arteries with approximately half of them occurring in the inferior vena cava (IVC).2 Retroperitoneal veins near the IVC are affected in about 75% and include the renal, iliac, ovarian, and spermatic veins.3 Intravenous leiomyosarcomas of the extremities have been reported in short and long saphenous veins, the external jugular vein, and a superficial vein at the back of the hand.4 In the lower extremity, the great saphenous vein is the most frequent site of origin.2 The tumor most commonly develops proximal to the knee.5 Although female preponderance occurs among patients with leiomyosarcoma of the IVC, with a ratio of 4:1, primary venous leiomyosarcoma of the extremities affects women and men almost equally.5 The mean age varies between 55 and 61 years old,2,3 although leiomyosarcoma of the saphenous vein has been reported in a 2-year-old child.6 The most frequent clinical signs and symptoms of retroperitoneal primary venous leiomyosarcoma include a palpable mass, back pain, or abdominal pain. Obstruction of the hepatic veins can occur, and the right heart cavities may also be invaded.2 Because tumor growth in the lower extremity is slow, adequate venous collateral circulation frequently develops, and clinical presentation of acute
236 Case reports
deep-venous thrombosis is rare. Lower extremity swelling or chronic venous insufficiency is more frequent if the iliac or femoropopliteal veins are invaded. Primary leiomyosarcoma of the greater saphenous vein usually presents as a painless mobile mass, as in our reported cases, whereas those arising from deep veins can be fixed to the surrounding tissue.2 Histologically, leiomyosarcomas have a typical pattern of interlacing, sweeping bundles of spindle shaped–cells, with elongated, occasionally torquated, blunt-ended nuclei. The tumor may be more or less encapsulated but has an abundance of cellular and nuclear polymorphism.4 In the differential diagnosis, one must consider tumors originating from the endothelial layer (hemangioendothelioma, angiosarcoma) and fibrosarcomas. Tumors of endothelial origin may be detected by the presence of factor VIII within the tumor cells. The muscular origin of a tumor can be proved by the presence of desmin and/or smooth muscle actin antigens. Leiomyosarcoma contains desmin and vimentin, whereas fibrosarcoma contains vimentin only. Hemangioendotheliomas are characterized by the occurrence of factor VIII and the lack of both vimentin and desmin.4 Varela-Duran et al.7 attempted to make a correlation between their microscopic features and biologic behavior. According to these authors, the mitotic index of vascular leiomyosarcoma seemed to be closely related to the clinical outcome of these tumors. But the value of histologic prognostic indicators remains controversial.8 Tumors of the venous wall may grow intraluminally or expand from the media musculature into the surrounding perivascular tissue. Intraluminal growth finally causes a thrombotic occlusion of the vein.4 The natural history of primary venous leiomyosarcoma is that of slow but definite progression. Although some authors have found that leiomyosarcomas of the venous wall have a low potential to metastasize, at least until they reach a certain size,4,8 there is an overall 60% incidence of metastases in these tumors at the time of resection of the primary tumors.5 As is recommended for the treatment of sarcomas, complete surgical resections with 2- to 3-cm margins are mandatory. Local recurrence is rarely
Annals of Vascular Surgery
observed after complete resection.9 It is often impossible to differentiate benign from malignant tumors in the operating room. The sensitivity of venous leiomyosarcoma to radiotherapy or to antimitotic agents has never been proven in this infrequent and rare tumor. Although there has been little experience with the response of peripheral vascular leiomyosarcoma to radiation therapy, there are ample data to support the use of this method for local control of soft tissue sarcomas in general.5 In our first patient, because the lesion was found to be high-grade leiomyosarcoma, combined postoperative adjuvant treatment was used to prevent progression or recurrence of the disease.
CONCLUSIONS Primary vascular leiomyosarcoma of veins is a rare disease with a poor prognosis. Preoperative diagnosis of the great saphenous vein leiomyosarcoma is very difficult. Treatment should consist of wide local excision, associated with postoperative adjuvant therapy.
REFERENCES 1. Kevorkian J, Cento DP. Leiomyosarcoma of large arteries and veins. Surgery 1973;73:390-400. 2. Dzsinich C, Gloviczki P, Van Heerden JA, et al. Primary venous leiomyosarcoma: a rare but lethal disease. J. Vasc. Surg. 1992;15:595-603. 3. Kieffer E, Berrod JL, Chomette G. Primary tumors of the inferior vena cava In: Bergan, JJ, Yao, JST, editors Surgery of the Veins. New York: Grune and Stratton, 1985, pp 423-443. 4. Leu HJ, Makek M. Intramural venous leiomyosarcomas. Cancer 1986;57:1395-1400. 5. Humphrey M, Neff J, Lin F, et al. Leiomyosarcoma of the saphenous vein. J. Bone Joint Surg. 1987;69:282-286. 6. Byard RW, Bourne AJ, Phillips GE, et al. Leiomyosarcoma of the saphenous vein in a child with 12 years follow-up. J. Pediatr. Surg. 1993;28:271-274. 7. Varela-Duran J, Olivia H, Rosair J. Vascular leiomyosarcoma: the malignant counterpart of vascular leiomyoma. Cancer 1979;44:1684-1691. 8. Wile AG, Evans HL, Romsdahl MM. Leiomyosarcoma of soft tissue, a clinicopathologic study. Cancer 1981;48:1022-1032. 9. Reix T, Sevestre H, Sevestri-Pietri MA, et al. Primary malignant tumors of the venous system in the lower extremities. Ann. Vasc. Surg. 1998;12:589-596.