Lymphangiosarcoma
Synonyms and keywords:  Stewart-Treves syndrome

# Overview
Lymphangiosarcoma was first discovered by Lowenstein, in 1906. The index case of lymphangiosarcoma was found in a patient suffering from severe post-traumatic lymphedema of arm. 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 must be differentiated from other diseases that cause swelling of limb. Lymphangiosarcoma is a rare entity and 300 cases of lymphangiosarcoma after breast cancer have been reported worldwide. Common risk factors that may lead to the development of lymphangiosarcoma include lymphatic blockage, radiotherapy, mastectomy, cardiovascular diseases, and hypertension. The sarcoma first appears as a bruise mark, a purplish discoloration or a tender skin nodule in the extremity, typically on the anterior surface. Findings on biopsy and ultrastructural histologic studies suggestive of lymphangiosarcoma include proliferating vascular channels, 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. The index case of lymphangiosarcoma was found in a patient suffering from severe post-traumatic lymphedema of arm.
- In 1948, Fred Stewart and Norman Treves first identified postmastectomy lymphedema as a precursor condition leading to lymphangiosarcoma.
- In 1960, the first homograft skin transplantation was developed to treat lymphangiosarcoma.
- In 1979, the concept of local immunodeficiency was first identified as a possible mechanism leading to the development 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 non-pitting edema 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.
- The idea of "an immunologically privileged site" was proposed by Schreiber. He explained the concept of chronic lymphedema leading to local immunodeficiency which in turn leads to development of sarcoma.
- On gross pathology, pachydermatous skin, edema, and reddish blue macules or nodules are characteristic findings of lymphangiosarcoma.
- The development of lymphangiosarcoma gradually progresses through 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 haemorrhage.
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 may be found.
- 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.
- 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 haemorrhage.
- 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 haemorrhage.
- 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 may be found.
- 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 may be found.

# Causes
- Lymphangiosarcoma is caused by chronic lymphedema.
- Causes of lymphedema include:
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)
- Primary lymphedema
Congenital
Precox (adolescence)
Tarda (adulthood)
- Congenital
- Precox (adolescence)
- Tarda (adulthood)
- Secondary lymphedema
Malignancy
Recurrent cellulitis
Connective tissue disease
Infection (filariasis)
Contact dermatitis
Lymphatic damage (surgery, radiation therapy, burns, etc)
- 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 swelling of limb such as:
- 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
The following table differentiates various conditions that may lead to limb swelling:

# Epidemiology and Demographics

## Prevalence
- Lymphangiosarcoma is a rare entity and 300 cases of lymphangiosarcoma after breast cancer have been reported worldwide.

## Incidence
- Incidence of lymphangiosarcoma in white American women is estimated to be 1.6 per 100,000.

## Age
- Lymphangiosarcoma is more commonly observed among middle-aged or elderly (mostly between sixth and seventh decade of life which correlates with a higher incidence of breast cancer.

## Gender
- Female are more commonly affected with lymphangiosarcoma compared to males.

## Race
- There is no racial predilection for lymphangiosarcoma.

# Risk Factors
Common risk factors in the development of lymphangiosarcoma include:
- Lymphatic blockage
- Radiotherapy
- Mastectomy
- Cardiovascular diseases
- Hypertension
- Milroys disease
- Filarial lymphedema

# Natural History, Complications and Prognosis

## Natural History
- Lymphangiosarcoma usually develops in patients with a history of chronic lymphedema, after mastectomy for breast cancer.
- If left untreated, chronic lymphedema leads to severe chronic edema of the affected extremity.
- The skin becomes atrophic and pachydermatous with telangiectasias.
- In the area of edema, a purple patch appears that becomes a subcutaneous nodule, sometimes associated with bleeding and oozing.
- With time multiple bluish-red nodules appear with ulcer formation, surrounded by areas of necrosis.
- Metastasis appears quickly after nodules are formed, the most common site for metastasis being the lungs.

## Complications
- Complications of lymphangiosarcoma include:
Erysipelas
Deep venous thrombosis in areas of chronic lymphedema
Recurrent infections
Bacteremia
Malignancy
- Erysipelas
- Deep venous thrombosis in areas of chronic lymphedema
- Recurrent infections
- Bacteremia
- Malignancy

## Prognosis
- Prognosis is generally poor, and the 5 year survival rate of patients with lymphangiosarcoma is 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: Non-tender 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.
- 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 extent 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 VIIIrelated 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.
- Treatment of lymphedema will prevent the development of lymphangiosarcoma.

## Surgery
- Amputation of the affected limb is the most common approach to the treatment of lymphangiosarcoma.

## Prevention
- Treatment of lymphedema is the primary preventive measure available for lymphangiosarcoma.