Lymphangiosarcoma

WikiDoc Resources for Lymphangiosarcoma
Articles
Most recent articles on Lymphangiosarcoma Most cited articles on Lymphangiosarcoma Review articles on Lymphangiosarcoma Articles on Lymphangiosarcoma in N Eng J Med, Lancet, BMJ
Media
Powerpoint slides on Lymphangiosarcoma Images of Lymphangiosarcoma Photos of Lymphangiosarcoma Podcasts & MP3s on Lymphangiosarcoma Videos on Lymphangiosarcoma
Evidence Based Medicine
Cochrane Collaboration on Lymphangiosarcoma Bandolier on Lymphangiosarcoma TRIP on Lymphangiosarcoma
Clinical Trials
Ongoing Trials on Lymphangiosarcoma at Clinical Trials.gov Trial results on Lymphangiosarcoma Clinical Trials on Lymphangiosarcoma at Google
Guidelines / Policies / Govt
US National Guidelines Clearinghouse on Lymphangiosarcoma NICE Guidance on Lymphangiosarcoma NHS PRODIGY Guidance FDA on Lymphangiosarcoma CDC on Lymphangiosarcoma
Books
Books on Lymphangiosarcoma
News
Lymphangiosarcoma in the news Be alerted to news on Lymphangiosarcoma News trends on Lymphangiosarcoma
Commentary
Blogs on Lymphangiosarcoma
Definitions
Definitions of Lymphangiosarcoma
Patient Resources / Community
Patient resources on Lymphangiosarcoma Discussion groups on Lymphangiosarcoma Patient Handouts on Lymphangiosarcoma Directions to Hospitals Treating Lymphangiosarcoma Risk calculators and risk factors for Lymphangiosarcoma
Healthcare Provider Resources
Symptoms of Lymphangiosarcoma Causes & Risk Factors for Lymphangiosarcoma Diagnostic studies for Lymphangiosarcoma Treatment of Lymphangiosarcoma
Continuing Medical Education (CME)
CME Programs on Lymphangiosarcoma
International
Lymphangiosarcoma en Espanol Lymphangiosarcoma en Francais
Business
Lymphangiosarcoma in the Marketplace Patents on Lymphangiosarcoma
Experimental / Informatics
List of terms related to Lymphangiosarcoma

For patient information, click here

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

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.

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)

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:

Diseases	Etiology	Congenital	Acquired	Demography	Clinical manifestations							Lab findings						Gold standard diagnosis	Associated findings
					Symptoms			Signs				CBC			LFT	ESR/CRP	Histopathology
					Appearance	Fever	Bleeding	BP	Hepatosplenomegaly	Lymphadenopathy	Other	WBC	Hb	Plt
Bacillary angiomatosis	HIV Chronic lymphocytic leukemia Cytotoxic chemotherapy Organ transplantation	–	+	Any age, usually between 20 -50 years	Solitary or multiple red, purple, flesh-colored, or colorless papules	±	±	Nl	–	–	Anorexia Weight loss Abdominal pain Nausea and vomiting Headache	Nl	Nl	Nl	Nl	Nl	Lobular vascular proliferations of vessels lined by plump endothelial cells	Clinical manifestation	Psychiatric disorders Personality changes Seizure
Arteriovenous malformation	Idiopathic	+	–	Any age	Nl	–	+	Nl	–	–	Headache Neurologic deficits Heart failure Macrocephaly	Nl	Nl	Nl	Nl	Nl	NA	Imaging	Hereditary hemorrhagic telangiectasia
Acroangiodermatitis	Idiopathic Hyperplasia of pre-existing vasculature HTN	–	–	Any age, more in males	Purplish-blue to brown papules and plaques	–	–	Nl	–	–	Paralysed legs	Nl	Nl	Nl	Nl	Nl	Hyperkeratosis Parakeratosis Acanthosis Mild spongiosis	Clinical manifesttations	Amputation Haemodialysis patients with arteriovenous shunts Hepatitis C Chronic venous insufficiency AV malformations
Angiosarcoma	Idiopathic	–	–	Adults, more in males	Enlarging bruise, a blue-black nodule, or an unhealed ulceration	–	–	Nl	–	–	–	Nl	↓	↓	Nl	Nl	Intercellular and intracellular lumina with or without red cells Intermediate filaments and pinocytotic vesicles in cytoplasm Weibel-Palade bodies	Biopsy	NA
Diseases	Etiology	Congenital	Acquired	Demography	Appearance	Fever	Bleeding	BP	Hepatosplenomegaly	Lymphadenopathy	Other	WBC	Hb	Plt	LFT	ESR/CRP	Histopathology	Gold standard diagnosis	Associated findings
Masson's hemangioma	Idiopathic	–	–	Rare	Normal	–	–	Nl	–	–	–	Nl	Nl	Nl	Nl	Nl	Papillary fronds lined by proliferating endothelium	Biopsy	Hemangioma Pyogenic granulomas Lymphangiomas
Seborrheic keratosis	Clonal expansion of a mutated epidermal keratinocyte	+	–	Any age	Usually asymptomatic Being stuck on the skin surface	–	–	Nl	–	–	–	Nl	Nl	Nl	Nl	Nl	Papillomatous epithelial proliferation containing horn cysts	Clinical manifestations	Dermatosis papulosa nigra Stucco keratosis Melanoacanthoma Polypoid lesions
Systemic lupus erythematosus (SLE)	Idiopathic	–	–	More common in female, typically in the 20 to 30 years	Erythema on the nasolabial folds Macular or diffusely erythematous in sun-exposed areas Discoid rash	±	–	↑	±	±	Weight loss Headache Arthralgia Myalgia Nausea Dyspepsia Pleuritic chest pain Dyspnea Hematuria	↑	↓	↓	Nl	Nl	Hyperkeratosis, epidermal atrophy, vacuolar interface dermatitis Thickening of the basement membrane Superficial, perivascular, and perifollicular mononuclear cell inflammatory infiltrate	Clinical manifestations	Raynaud phenomenon Neuropsychiatric symptoms Pleural effusion Peptic ulcer disease Pericarditis Myocarditis
Pyogenic granuloma	Trauma Hormonal influences Viruses Cytogenetic clonal deletion abnormalities	+	+	Any age, usually in 20-30 years	Painless red lesion Lobular capillary hemangioma	–	+	Nl	–	–	–	Nl	Nl	Nl	Nl	Nl	Neutrophilic infiltration Hemorrhage Necrosis of the overlying epidermis	Clinical manifestation	NA
Benign lymphangioendothelioma	Idiopathic	–	+	Any ages, median age is 50 years	single, slowly expanding patch, plaque, or nodule	–	–	Nl	–	–	–	Nl	Nl	Nl	Nl	Nl	Thin-walled endothelial-lined spaces that are interspersed between strands of collagen	Biopsy	NA
Cavernous hemangioma	Idiopathic	–	–	Usually in third to fifth decades of life.	Painless, slowly progressive protrusion or bulging of their globe	–	–	Nl	–	–	–	Nl	Nl	Nl	Nl	Nl	Engorged vascular channels, which are tightly knit and separated by fibrous septae	Clinical manidestation	Diplopia Decreased color vision Visual field deficits
Diseases	Etiology	Congenital	Acquired	Demography	Appearance	Fever	Bleeding	BP	Hepatosplenomegaly	Lymphadenopathy	Other	WBC	Hb	Plt	LFT	ESR/CRP	Histopathology	Gold standard diagnosis	Associated findings

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
• Milroy’s 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

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.

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 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.
• 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.