Lymphangiosarcoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Synonyms and keywords: Stewart-Treves syndrome

Overview

Lymphangiosarcoma was first discovered by Lowenstein, in 1906, following severe posttraumatic lymphedema of arm for 5 years. Lymphangiosarcoma is a rare malignant tumor which occurs in long-standing cases of primary or secondary lymphedema. It involves either the upper or lower lymphedemateous extremities but is most common in upper extremities. Lymphangiosarcoma may be caused by classical Halstedian radical mastectomy. Lymphangiosarcoma must be differentiated from other diseases that cause swelling of limb such as acquired angioedema due to C1 inhibitor deficiency, angioendotheliomatosis, angiolymphoid hyperplasia with eosinophilia, cutaneous melanoma, hereditary angioedema, lymphangiectasia, lymphangioma, and lymphocytoma cutis. On gross pathology, pachydermatous skin, edema, and reddish blue macules or nodules are characteristic findings of lymphangiosarcoma. On microscopic histopathological analysis, proliferating vascular channels, which dissect the dermal collagen, hyperchromatism, pleomorphism, mitoses, pinocytosis, intercellular junctions, cytoplasmic intermediate filaments, Weibel-Palade bodies, and erythrophagocytosis are charecteristic findings of lymphangiosarcoma. The prevalence of Stewart-Treves syndrome is approximately 400 worldwide. Common risk factors in the development of lymphangiosarcoma are lymphatic blockage, radiotherapy, mastectomy, cardiovascular diseases, and hypertension.The sarcoma first appears as a bruise mark, a purplish discolorization or a tender skin nodule in the extremity, typically on the anterior surface. Lymphangiosarcoma progresses to an ulcer with crusting, and finally to an extensive necrosis involving the skin and subcutaneous tissue. Lymphangiosarcoma metastasizes quickly. Findings on biopsy and ultrastructural histologic studies include proliferating vascular channels, which dissect the dermal collagen and, often, the obliterate appendages, hyperchromatism, pleomorphism, mitoses, pinocytosis, intercellular junctions, cytoplasmic intermediate filaments, Weibel-Palade bodies, and erythrophagocytosis. Amputation of the affected limb is the most common approach to the treatment of lymphangiosarcoma.

Historical Perspective

• Lymphangiosarcoma was first discovered by Lowenstein, in 1906, following severe posttraumatic lymphedema of arm for 5 years
• In 1948, postmastectomy lymphedema was first identified in the pathogenesis of lymphangiosarcoma by Fred Stewart and Norman Treves.
• In 1960, the first homograft skin transplantation was developed to treat lymphangiosarcoma.
• In 1979, the concept of local immunodeficiency was first identified in the pathogenesis of lymphangiosarcoma by Schreiber.

Pathophysiology

• Lymphangiosarcoma is a rare malignant tumor which occurs in cases of chronic lymphedema.
• Lymphedema is an abnormal collection of protein-rich fluid in the interstitium resulting from obstruction of lymphatic drainage.
• Lymphatic obstruction causes an increase in the protein content of the extravascular tissue, with subsequent retention of water and swelling of the soft tissue.
• The increase in the extravascular protein stimulates proliferation of fibroblasts, organization of the fluid, and the development of a nonpitting swelling of the affected extremity.
• Lymphangiosarcoma arises from the endothelial cells.
• When it occurs following mastectomy it is known as Stewart-Treves Syndrome.
• Stewart and Treves, proposed that a cancer causing agent is present in lymphedematous limbs.
• Schreiber et al. proposed that local immunodeficiency as a result of lymphedema results in a "immunologically privileged site" in which the sarcoma is able to develop.
• On gross pathology, pachydermatous skin, edema, and reddish blue macules or nodules are characteristic findings of lymphangiosarcoma
• On microscopic histopathological analysis, proliferating vascular channels, which dissect the dermal collagen and, often, the obliterate appendages, hyperchromatism, pleomorphism, mitoses, pinocytosis, intercellular junctions, cytoplasmic intermediate filaments, Weibel-Palade bodies, and erythrophagocytosis are charectoristic findings of lymphangiosarcoma.

Causes

• Lymphangiosarcoma is caused by chronic lymphedema.
• Causes of lymphedema
  • Primary lymphedema
    • Congenital
    • Precox (adolescence)
    • Tarda (adulthood)
  • Secondary lymphedema
    • Malignancy
    • Recurrent cellulitis
    • Connective tissue disease
    • Infection (filariasis)
    • Contact dermatitis
    • Lymphatic damage (surgery, radiation therapy, burns, etc)

Differentiating Lymphangiosarcoma from other Diseases

• Lymphangiosarcoma must be differentiated from other diseases that cause swellling of limb such as:

• Acquired angioedema due to C1 inhibitor deficiency
• Angioendotheliomatosis
• Angiolymphoid hyperplasia with eosinophilia
• Cutaneous melanoma
• Hereditary angioedema
• Lymphangiectasia
• Lymphangioma
• Lymphocytoma cutis

Epidemiology and Demographics

• The prevalence of Stewart-Treves syndrome is approximately 400 worldwide.
• In 1962, the incidence of Stewart-Treves syndrome was estimated to be 0.45% in patients who survive at least 5 years after radical mastectomy and 0.03% of patients surviving 10 or more years after radical mastectomy.

Age

• Lymphangiosarcoma is more commonly observed among middle-aged or elderly.

Gender

• Female are more commonly affected with lymphangiosarcoma than male.

Race

• There is no racial predilection for lymphangiosarcoma.

Risk Factors

• Common risk factors in the development of lymphangiosarcoma are lymphatic blockage, radiotherapy, mastectomy, cardiovascular diseases, and hypertension.
• Angiosarcoma commonly occurs in male patients older than 70 years of age. Caucasians are prone to the disease more than other racial groups. It might follow chronic lymphedema of any origin, whether congenital or acquired. It has also been observed following radiotherapy and exposure to vinyl chloride used in polymerization in the plastic industry. Carcinogens such as arsenic thorium dioxide factors might also play a role in the development of angiosarcoma. Certain surgical procedures might be followed by angiosarcoma, the most classic example being a radical mastectomy and lymph node dissection [Stewart-Treves syndrome]. Immunosuppressed patients are more likely to develop this type of cancer. Recent research suggests certain mutations in tumor suppressor genes like p53 might play a role especially in angiosarcoma of the liver.

Natural History, Complications and Prognosis

• The sarcoma first appears as a bruise mark, a purplish discolorization or a tender skin nodule in the extremity, typically on the anterior surface. It progresses to an ulcer with crusting, and finally to an extensive necrosis involving the skin and subcutaneous tissue. It metastasizes quickly.
• Prognosis is generally poor, and the 5 year survival rate of patients with lymphangiosarcomais approximately less than 5%.

Diagnosis

Symptoms

• Symptoms of lymphangiosarcoma may include the following:

• Bruise mark, a purplish discoloration
• Tender skin nodule in the extremity

Physical Examination

• Physical examination may be remarkable for:

• Bruise mark
• A purplish discolorization
• Tender skin nodule in the extremity, typically on the anterior surface
• Ulcer with crusting
• Extensive necrosis involving the skin and subcutaneous tissue

Laboratory Findings

• There are no specific laboratory findings associated with lymphangiosarcoma.

Imaging Findings

• MRI is the imaging modality of choice to asses the local extend of lymphangiosarcoma.
• On MRI, lymphangiosarcoma is characterized by low signal intensity on T2-weighting.
• Chest radiography may demonstrate pulmonary metastasis.

Other Diagnostic Studies

• Lymphangiosarcoma may also be diagnosed by measuring antibodies against factor VIII–related antigen, CD34 antigen, antikeratin antibodies, and positive staining for laminin, CD31, collagen IV, and vimentin.
• Findings on biopsy and ultrastructural histologic studies include proliferating vascular channels which dissect the dermal collagen, hyperchromatism, pleomorphism, mitoses, pinocytosis, intercellular junctions, cytoplasmic intermediate filaments, Weibel-Palade bodies, and erythrophagocytosis.

Treatment

Medical Therapy

• The medical therapy of lymphangiosarcoma is paclitaxel, doxorubicin, ifosfamide, and gemcitabine.

Surgery

• Amputation of the affected limb is the most common approach to the treatment of lymphangiosarcoma.

Prevention

• Monitoring patients with lymphedema is the primary preventive measure available for lymphangiosarcoma.