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 of lymphatic vessels or blood vessels.
• When it occurs following mastectomy it is known as Stewart-Treves Syndrome.
• 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.
• Lymphangiosarcoma can be classified into 3 stages.
  • Stage 1 (prolonged lymphedema):
    • This stage is characterized by extensive edema that causes the degeneration of fat and collagen mainly in the deep part of the dermis.
    • Lymphatic blockade causes persistent edema resulting in fibrosis in dermis and subdermis. Stage 2 (premalignant angiomatosis):
    • This stage involves multiple foci of small, proliferating channels in the dermis and subdermis.
    • These vessels are lined by hyperplastic endothelial cells.
    • Superficial areas can be seen as bruises or vesicles, whereas deeper areas are seen as areas of induration and hemorrhage. Stage 3 (malignant angiosarcoma):
    • These aggressive tumors develop from areas of premalignant angiomatosis.
    • On microscopic histopathological analysis, proliferating vascular channels, hyperchromatism, pleomorphism, mitoses, pinocytosis, intercellular junctions, cytoplasmic intermediate filaments, Weibel-Palade bodies, and erythrophagocytosis.

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
• Metastatic breast cancer
• Malignant melanoma
• Kaposi sarcoma
• Angiosarcoma

Epidemiology and Demographics

• There are 400 cases of lymphangiosarcoma reported worldwide.

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
• Hypertension.

Natural History, Complications and Prognosis

• History of chronic lymphedema, after mastectomy for breast cancer.
• Severe chronic edema of an upper extremity usually occurs in patients.
• The skin becomes atrophic and pachydermatous with telangactesias.
• In the area of edema, a puprle patch appears that becomes a subcutaneous nodule, sometimes associated with bleeding and oozing.
• With time multiple bluish-reddish nodules appear with ulcer formation, surrounded by areas of necrosis.
• Metastasis appears quickly after nodules are formed, the most common site being the lungs.
• Complications include erysipelas and deep venous thromboses in areas of chronic lymphedema.
• Other complications include recurrent infections and malignancies.
• Prognosis is generally poor, and the 5 year survival rate of patients with lymphangiosarcoma is approximately less than 5%.

Diagnosis

Symptoms

Symptoms of lymphangiosarcoma may include the following:

• Chronic swelling of the affected area.
• Painful nodules in the area of swelling.
• Non healing painful ulcers.
• Bleeding and oozing from the ulcers.

Physical Examination

Physical examination may be remarkable for:

• Lymphedema- Nontender and non pitting edema of the affected area.
• Lymphangiosarcoma-
  • 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

• Positive staining for laminin, CD31, collagen IV, and vimentin are specific for angiosarcoma.

Imaging Findings

• MRI with intravenous contrast is the imaging modality of choice to asses the local extend of lymphangiosarcoma.
• On MRI, lymphangiosarcoma is characterized by a soft tissue mass with extension through the sub cutaneous tissue and up to the muscle layer with enhancement.
• Chest radiography and chest CT scan 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, 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.