EPIDEMIOLOGY
The data obtained from the international literature, corresponding to that of the World Health Organization, report an incidence of lymphedema in the world of approximately 300 million cases (about one person in every 20). Almost half of lymphedema is of primary origin, characterized by a congenital Lymphangioadenodysplastic basis, that is due to a malformation and consequent malfunction of lymph nodes and / or lymphatic vessels. Another 70 million are of parasitic origin (the most frequent forms are represented by the infestation of Filaria Bancrofti), particularly present in tropical and subtropical areas (India, Brazil, South-Africa). Another 50 million are post-surgical and, especially, secondary to the treatment of breast cancer. The other 30 million are essentially caused by functional problems of overload of the lymphatic circulation (particularly, as a result of deep phlebothrombosis of the lower limb, liver failure, nephrotic syndrome, and arteriovenous fistulas).
In particular, with regards to secondary lymphedema, the incidence of secondary lymphedema of the upper limb in women undergoing mastectomy or quadrantectomy with axillary lymphadenectomy is best estimated to be equal to 20-25% of patients, up to 35-40% when associated to radiotherapy. With the sentinel lymph node technique, the incidence of secondary lymphedema varies from 3% to 22%. With regards to lymphedema of the lower secondary to the treatment of gynecological and urological tumors, the incidence varies from 5% to 30%. Given the high incidence of secondary lymphedema, it is worth emphasizing the importance of prevention of lymphatic pathology, both in terms of early diagnosis and timely treatment. The gender most often affected is the female sex and the most affected age corresponds to the third to fourth decade of life. The incidence of lymphangitis, clinically more or less manifest, as a complication of lymph stasis, is very high (practically in almost all cases), to the point of requiring a protracted antibiotic treatment, both for therapeutic and prophylactic purposes.
PATHOGENESIS
Lymphedema represents a not rare clinical picture characterized by the slowing or blockage of the lymphatic circulation of the affected limb or limbs, with a progressively worsening evolution and the appearance of recurrent acute lymphangitic complications, mostly of erysipeloid nature, responsible for a further and rapid increase in volume and consistency of edema. Although pathogenetic details are still an open question, the general principles of the pathophysiology of lymphedema are well known. On the one hand, the central disturbance may be represented by a low-output failure of the lymphatic system: in other words, there is a general reduction in lymphatic transport. An alteration of this type may be caused by congenital lymphatic dysplasia – primary lymphedema – or by anatomical obliteration, such as that resulting from a radical surgical resection (for example, in the case of axillary lymph node, iliac-inguinal, or retroperitoneal dissection), following repeated lymphangitis with lymphangiosclerosis or as a consequence of severe functional impairment (for example, lymphangiospasm, paralysis and valvular insufficiency) – secondary lymphedema.
However, the common denominator is the fact that lymphatic transport falls below the capacity needed to manage the daily microvascular filtrate load, comprising plasma proteins and cells, which normally enter the interstitium from the bloodstream.
On the other hand, a high output failure of the lymphatic circulation occurs when a normal or increased transport capacity is overwhelmed by an excessive load of capillary blood filtrate: for example, in cirrhosis of the liver (ascites), nephrotic syndrome (anasarca) and deep venous insufficiency of the lower limbs (post-thrombophlebitic syndrome).
Failure to control lymphedema can lead to repeated infections (dermatolymphangioadenitis – DLA), progressive pachydermic cutaneous trophic skin changes and, in rare cases, even to the development of a lymphangiosarcoma, which is a highly lethal pathology (Stewart-Treves syndrome).
ANATOMO-PATHOLOGICAL CLASSIFICATION AND STAGING
Lymphedema is generally divided into primary or congenital and acquired or secondary.
Primary lymphedemas are further categorized as congenital (connatal) that is, already present at birth, or as a praecox manifestation if they appear before 35 years of age, or tardive, if they occur after 35 years of age. Among the connatal forms, the sporadic forms are distinct from those heriditary-familial forms that, for the most part, can be framed in more or less complex malformation syndromes, related to specific genetic alterations. For the identification of the type of dysplasia that underlies the different forms of congenital lymphedema, the classification of C.Papendieck is followed: LAD I (lymphangiodysplasia – dysplasia of the lymphatic vessels), LAD II (lymphadenodysplasia – dysplasia of the lymph nodes), LAAD (lymphangio-adeno-dysplasia – dysplasia of lymphatics and lymph nodes). The term dysplasia includes: agenesis, hypoplasia, hyperplasia, fibrosis, lymphangiomatosis, hamartomatous, and valvular insufficiency. Secondary lymphedema can be calssified as post-surgical, post-actinic, post-traumatic, post-lymphagitic, and parasitic.
Classification of lymphedema:
Primary or Congenital
- Connatal (already present at birth)
- Sporadic
- Hereditary-familial
- Praecox (appears before 35 years)
- Tardive (appears after 35 years)
Secondary or acquired
- Post-surgical
- Post-actinic
- Post-traumatic
- Post-linfangitic
- Parasitic
This staging includes both primary and secondary lymphedema, already clinically manifest lymphedema, and also subclinical lymphedema (stage IA, in which lymphoscintigraphy allows early detection of an initial lymphatic circulatory alteration), and the clinical evolution of the disease, regardless of the nature of the lymphedema. The staging of lymphedema is based on clinical and diagnostic-instrumental criteria: extent of edema, clinical course of the disease during the day, and with the variation of the decubitus, number and extent of lymphangitic complications, consistency of edema, and skin changes related to the disease. Finally, it is possible to evaluate the severity of the clinical picture on the basis of the volumetric difference between the limbs, defining as minimal (<20% increase in volume), moderate (increase from 20 to 40%) and severe (> 40% increase). This staging in the above table was adapted by us starting from 2009, standardizing it with classification in three stages from the International Society of Lymphology
CLINICAL PRESENTATION AND PHYSIOPATHOLOGAL BACKGROUND
In most patients, on the basis of the medical history and objective physical examination, one can easily diagnose lymphedema: edema generally of thickened consistency (depending on the greater or lesser fibrosclerotic tissue component), absence of fovea sign, even in the precocious stages of the disease, presence of the Stemmer sign (inability to pinch the skin at the base of the 2nd toe), dystrophic cutaneous lesions (post-lymphangitic sequelae, hyperkeratosis, lymphatic verrucosis, lymphorrhea, chylorrhea), and frequent dermato-lympangioadenitic complications (DLA). Moreover, the evaluation of the lymph nodes is useful, to highlight the association of acute or chronic lymphadenopathy. In the more complex forms of angiodysplasia, characterized by a condition of arterio-venous hyperstomy (Mayall syndrome) or by congenital macro- and micro- arteriovenous fistulas (Klippel-Trénaunay or Klippel-Trénaunay-Servelle syndrome), the clinical picture can be characterized by: gigantism with elongation of the limb, more or less marked dysmorphism of the foot, “Port wine” or geographical map angiomas, hyperhidrosis of the sole of the foot. There are, however, spurious forms, even more difficult to diagnose for the prevalent lymphedematous component. Moreover, in some cases, there is the presence of overlapping conditions, such as pathological obesity, venous insufficiency, more or less evident trauma, and recurrent infections, which can complicate the clinical picture. Furthermore, when considering the origin of a uni- or bilateral lymphedema of the extremities, especially in adults, it is also necessary to consider the possibility of a tumor. For all these reasons, before embarking on the treatment of lymphedema, a complete and integrated diagnostic evaluation is absolutely essential. The association of other pathological conditions, such as congestive heart failure, arterial hypertension, and cerebrovascular diseases, including stroke, can in turn influence the therapeutic process. If the diagnosis of lymphedema is not clear or if there is a need, even for prognostic considerations, of a better diagnostic definition of the clinical picture, a specialized lymphological consultation is advisable, directing the patient to a specialized lymphology center.
DIAGNOSIS
Lymphoscintigraphy is the first choice exam for the diagnostic definition of edema, to confirm its lymphostatic nature, to identify the cause (from obstruction or reflux), to evaluate the extent of the disease (dermal back flow), the major or minor impairment of the deep lymphatic circulation with respect to the superficial one, and the drainage through the lymph node stations. The study of both the superficial and deep lymphatic circulation is very useful, through the appropriate injection of the tracer in the specific drainage sites of the two systems. The examination is not invasive, easily repeatable, can be performed even in neonatal age. It also allows the identification of stage IA lymph stasis, still not clinically manifest, thus playing a fundamental role in the prevention of secondary lymphedema. It is also useful, finally, for the study during the follow-up of the different therapeutic methods of lymphedema and, in particular, of lymphatic microsurgery techniques.
Lymphography is still an extremely useful investigation for the study of the complex congenital or acquired pathologies of chyliferous vessels, of the cisterna chyli, and of the thoracic duct. It is more modernly performed in the operating room, under local anesthesia, and with preparation of the lymphatic vessels by microsurgical technique. Ultrasound, CT, and MRI are useful diagnostic tools for the definition of complex syndromes in which angiodysplasia and lymphedema pathologies are associated, as well as for the study of the possible obstructive nature of lymphedema, secondary to oncological disease. The Lymphangio-MRI, in particular, performed with the digital fat-subtraction method, can provide important information in advanced obstructive pictures, in which the lymphatic pathways are dilated and filled with lymph. Indispensable is the study of venous circulation using Echo-Color-Doppler (an investigation constantly used in the evaluation of an edematous limb). Phleboscintigraphy and Phlebography may also be performed (if necessary on the basis of the Echo-Doppler exam). Even the study of the arterial circulation can be indispensable in panangiodysplasia clinical pictures with associated lymphedema. In these cases, in addition to the Echo-Color-Doppler exam, digital arteriographic study may be useful. Micro-lymphography with Indocyanine Green fluorescent dye (PDE Test) and the Houdack-Mc Master Lymphochromic Test (with Blue Patent Violet dye, BPV) are now available to provide very useful information for the most correct surgical approach for lymphedema.
Diagnosis s of lymphoedema-main investigations
- Lymphoscintigraphy
- Lymphangio-MRI
- Lymphography and lymphangio-CT (for the most complex cases of gravitational chylo-lymphatic reflux)
- Venous Echo-color-Doppler US (and, if indicated, arterial)
Complementary investigations (intra-operative)
- Houdack-Mc Master Lymphochromic Test
- Fluorescent microlymphography
Additional investigations (second line, for cases of lymphedema associated with venous and / or arterial pathology)
- Phleboscintigraphy
- Phlebography
- Digital arteriography
GALLERY
Clinically treated lymphedema cases surgically treated: long-term results.
Figure 1A
Figure 1B
Figure 2A
Figure 2B
BEFORE TREATMENT
AFTER TREATMENT
BEFORE TREATMENT
AFTER TREATMENT
BEFORE TREATMENT
AFTER TREATMENT
THERAPY
The treatment of peripheral lymphedema is divided into medical-physical-rehabilitative treatment and surgical methods.
Lymphedema therapy
Non-surgical treatment
- Physiotherapy
- Combined physical therapy (CPT)
- Mechanical lymphatic drainage (so-called Pressotherapy)
- Manual lymphatic drainage
Pharmacological therapy
- Benzopyrones
- Antibiotics
- Antifungals
- Diethylcarbamazine
- Diuretics
- Diet
Surgical treatment
- Microsurgery
- Derivative
- Reconstructive
- “Selective” and minimally invasive liposuction, with “Lymph Vessel Sparing” procedure (FLLA-LVSP)