IMMUNODEFICIENCY IN CHRONIC LYMPHEDEMA
Lymphedema (Organic Lymphatic Vascular Disease) is a chronic medical condition characterized by tissue swelling (edema) caused by the accumulation of protein-rich interstitial fluid retention (lymphostasis) due to insufficient lymphatic drainage capacity.
Chronic lymphatic stasis has numerous consequences, including lipogenesis, inflammation, lymphangiogenesis, and immunosuppression. If not treated or undertreated, the disease progresses with skin thickening, subcutaneous fibrosis, increased adipose tissue volume, infections, disfigurement, and disability, very common in severe late Stage III lymphedema (elephantiasis). Untreated lymphedema has also higher possibility of developing Lymphangiosarcoma, a rare form of soft tissue cancer.
Causes of lymphatic dysfunction
Primary Lymphedema (Congenital or Idiopathic)
Secondary Lymphedema (Due to various causes that alter the lymphatic flow)
Chronic
lymphatic stasis impairs local immune surveillance, and the
lymphedematous region becomes an immunologically vulnerable area,
known to facilitate the onset of chronic inflammation, infection
(cellulitis), immune disorders, and tumors.
The local immunodeficiency caused by chronic lymphedema indirectly promotes oncogenesis and has a permissive effect on certain types of malignancies, particularly angiosarcomas, in what is known as lymphangiosarcoma. Most other cutaneous malignancies have also been described in lymphedematous areas, including basal cell carcinoma, squamous cell carcinoma, melanoma, Kaposi sarcoma, Merkel cell carcinoma, and several cutaneous lymphomas.
WHAT IS ANGIOSARCOMA?
Angiosarcoma is a rare subtype of soft-tissue sarcoma of vascular or lymphatic endothelial cell origin with a malignant potential. Even though tumors can appear throughout the body including uncommon locations, there is a predilection for the skin, where half of all tumors emerge. Angiosarcoma has a propensity for local recurrence and metastasis associated with a generally poor prognosis unless diagnosed early.
Although angiosarcoma can occur in any organ, it typically arises in the following clinical settings:
Face and scalp
Lymphedematous regions (Lymphedema)
Skin that has been previously irradiated (post-radiation angiosarcomas)
In all of these situations, angiosarcoma is associated with multifocality and an insidious growth pattern, making local control difficult.
WHAT IS LYMPHANGIOSARCOMA?
Lymphangiosarcoma is a quickly progressing rare cutaneous angiosarcoma, that arises from chronic lymphedema, which typically develops in the atrophic, pachydermatous, hyperkeratotic skin of limbs affected by long-standing chronic Lymphatic blockade.
Lymphangiosarcoma is associated with the possible occurrence of multiple local recurrences and pulmonary metastasis, however, early diagnosis and treatment are associated with increased survival.
Phases in the development of lymphangiosarcoma:
Prolonged lymphedema
Angiomatosis
Angiosarcoma
WHAT IS THE INCIDENCE AND PREVELANCE OF LYMPHANGIOSARCOMA?
Cutaneous angiosarcoma that develops in a long course chronic lymphedema after breast cancer are the cases that are most widely documented and is called Stewart-Treves syndrome.
Even though linfangiosarcoma is most frequently associated with post-mastectomy lymphedema, it can also arise in the following cases:
Primary Lymphedema - Congenital hereditary (Milroy's syndrome and Meige's Syndrome).
Primary Lymphedema - Non-hereditary spontaneous (Ideopathic, Praecox or Tarda).
Secondary Lymphedema acquired from the treatment of gynecologic and urologic malignancies,
Secondary Lymphedema acquired from trauma, infection, lipedema, venous insufficiency, parálisis, parasites (filariasis), podoconiosis, etc.
The incidence and prevalence of lymphangiosarcoma is highly underestimated. Due to the present situation in many countries, even in high-tech nations, of underdiagnosis, nontreatment, and undertreatment of Primary and Secondary lymphedema, there is a consequent lack of disease documentation and a subsequent lack of actual statistics.
In developing countries, given that lymphedema caused by filariasis and podoconiosis are the causes that are least being diagnosed and treated, it is not surprising that they are also the causes with the least documented lymphangiosarcoma development cases.
WHAT IS THE CLINICAL DIAGNOSIS?
Knowledge of clinical signs is important for diagnosis, and when evaluating patients with chronic lymphedema with new dermatological abnormalities, clinical suspicion must be raised, and a biopsy must be considered. Awareness of this association can lead to early diagnosis and appropriate treatment of this potentially fatal malignant tumor. There can be considerable treatment delay because of wrong diagnosis.
Some clinical signs are:
Painless skin lesions or apparent traumatic ecchymoses.
Palpable subcutaneous mass or a poorly healing eschar with recurrent bleeding.
In more advanced stages, multiple reddish blue macules or nodules develop and may become polypoid
There may also be small satellite areas surrounding the nodules that may become confluent.
As the lesions progress, the overlying atrophic skin can later progress to ulceration, infection, or necrosis.
WHAT IS THE TIME OF ONSET?
The
range of time for the progression of chronic lymphedema to the
development of angiosarcoma can range from 4 to even more than 50
years. Patients should be closely examined starting from the time of
lymphedema onset. To
avoid delays in the diagnosis and therapy of Lymphangiosarcoma,
physicians should actively look for signs or symptoms of malignancies
during the follow-up period and promptly manage patients developing
problems.
WHAT ARE THE RISK FACTORS AND PREVENTIVE MESURES?
Patients with chronic Primary and Secondary Lymphedema are susceptible to angiosarcoma although the overall risk is small. In practice, the prevention and treatment of lymphatic dysfunction, the regular monitoring of constituted lymphedemas, and the hygienic and preventive behaviors of infections are the best arrangements to avoid this tumoral occurrence.
Complete Decongestive Therapy (CDT) is the gold standard treatment for patients with Primary and Secondary Lymphedema. Effective intervention of lymphedema at an early stage helps control disease progression and improve patients' overall quality of life. Lymphedema treatment of the limbs should be optimized to help prevent the possible development of severe infections (cellulitis) and tumors.
Vigilance and regular follow-up clinical controls for patients with chronic lymphoedema are recommended. Yearly surveillance coupled with preventative measures in these patients may prove vital in the prevention or early treatment of malignant complications.
Patients with lymphedema need to be adequately informed about Lymphangiosarcoma, to be able to identify rapidly progressing skin lesions, and to promptly contact their health provider. Only early diagnosis and treatment confer a reasonable prognosis for this rare but aggressive disease
WHAT IS THE TREATMENT OF LYMPHANGIOSARCOMA?
Multidisciplinary care is critical for the management of localized disease, and an accurate diagnosis and knowledge of the underlying molecular landscape are essential to improve the prognosis. Treatment may include surgery, radiotherapy, systemic chemotherapy, or immunotherapy. Decisive for the prognosis of this fast-growing tumor of high malignancy is early detection and initiation of treatment.
In some countries adequate clinical and histopathologic diagnosis of angiosarcoma is difficult to access, often resulting in great delay that obviates against early and possibly successful treatment of these very aggressive neoplasms. Due to delay in diagnosis, inability to adequately define clinical and surgical margins, and its high local recurrence and metastatic rates, angiosarcomas generally have a poor prognosis.
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AWARENESS CAMPAIGNS AT THE PATIENT AND HEALTHCARE LEVEL
Despite the seemingly innocuous nature of chronic lymphedema, it does have the potential to evolve into a much more devastating entity. Lymphangiosarcoma is one of the most dangerous complications of chronic lymphedema, and an effort must be made in healthcare settings to highlight the possible development of lymphangiosarcoma in patients with lymphatic dysfunction.
The key to improving patient survival is the early diagnosis through a high alert of this disease by primary care physicians, comprehensive physical examinations of patients with pertinent history and suspicious clinical presentations, and prompt biopsy for definitive diagnosis.
Unfamiliarity with this disease and the innocuous appearance of the tumor often lead to delayed diagnosis and treatment. Vigilance must be urged, and regular follow-up appointments for patients with chronic lymphoedema to facilitate prevention or early treatment of this devastating syndrome.
Providers should include angiosarcoma in the differential diagnosis of ulcerative or vascular tumors arising in the context of lower extremity lymphedema. Despite the poor prognosis, early detection is important to facilitate a full range of available therapies, even an opportunity for curative treatment.
In developing countries with the filarial and podoconiosis load, it is of utmost importance that clinicians should keep lymphangiosarcoma developing in a setting of long-standing lymphedema in mind for early diagnosis and treatment.
REFERENCES:
Lymphangiosarcoma: Is Stewart-Treves Syndrome a Preventable Condition?
Lymph Leakage Promotes Immunosuppression by Enhancing Anti-Inflammatory Macrophage Polarization
Transformación maligna de linfedema crónico en miembro inferior en linfangiosarcoma
Incidence and Presenting Characteristics of Angiosarcoma in the US, 2001-2020
Chronic oedema/lymphoedema: under‐recognised and under‐treated
