CHAPTER 12 Pathophysiology of Primary Lymphedema
KEY POINTS
Primary lymphedema usually manifests as a truncular lymphatic malformation, the origin of which is a structural birth defect.
Although most primary lymphedemas are independent truncular lymphatic malformations, they can coexist with extratruncular lesions.
Occasionally, primary lymphedema and truncular lymphatic malformations develop along with congenital vascular malformations to form a hemolymphatic malformation.
The defective development of the lymphatic system can occur at any stage of lymphangiogenesis, even as early as the eighth week of gestation.
In primary lymphedema the cause of reduced lymph transport is either an intrinsic defect or malfunction of the lymph conducting elements that result from a genetic abnormality in lymphatic function or anatomy.
Primary lymphedema mostly presents as the clinical manifestation of a truncular lymphatic malformation, with defective structural development of the lymphatic system observed as a birth defect. 1 – 4 Most primary lymphedemas exist alone as an independent truncular lymphatic malformation lesion.
However, because of the pathogenesis of congenital vascular malformations (CVMs), some of the primary lymphedemas and truncular lymphatic malformations exist with another form of lymphatic malformation, the extratruncular lesions, also known as cystic, cavernous, or capillary lymphangiomas. 5 – 8 In addition, lymphatic malformations exist with other types of CVMs as part of complex birth defects affecting the entire circulation, including the arteries, veins, lymphatics, and capillary system. 9 – 12 Therefore primary lymphedemas and truncular lymphatic malformations infrequently develop together with other CVMs to form a hemolymphatic malformation, 13 – 16 consisting of a venous malformation, 17 – 20 an arteriovenous malformation, 21 – 24 and/or a capillary malformation. 25 , 26
For example, the lymphatic malformation coexists with venous and lymphatic malformations as the vascular malformation component of Klippel-Trenaunay syndrome. 27 , 28 When they are further combined with an arteriovenous malformation, it is Parkes Weber syndrome. 29 , 30
The defective development of the lymphatic system can occur throughout any stage of lymphangiogenesis, resulting in various malformations of the lymphatic system, all of which have a basic outcome—lymphatic dysfunction. 31 – 34
As early as the eighth week of gestation, the developing lymphatic sacs, which consist of two jugular and two iliac sacs, one of which is positioned at the base of the root of the mesentery and the other dorsal to the abdominal aorta/cisterna chyli, can show defective maturation. This results in sequestration of primitive lymphatic tissue; it remains as isolated clusters of amorphous lymphatic tissues (for example, lymphangioma). 35 , 36
When these primitive lymphatic tissues do not develop normally and communicate with the remainder of the lymphatic networks and are consequently sequestered in various regions, they continue to dilate and become macrocystic and microcystic lesions, such as a cystic hygroma. 37 – 40
This malformed lymphatic tissue has the unique characteristic of the mesenchymal cell when stimulated and appears as a residual embryonic tissue remnant originating from its early stage of lymphangiogenesis. These premature lymphatic tissues are classified as extratruncular lesions of the lymphatic malformation and are the outcome of defective development after the developmental arrest in the early stage of lymphangiogenesis. 41 – 44
Extratruncular lymphatic malformation lesions, often called lymphangioma, continue to grow after birth through the unique characteristics of mesenchymal cells and lymphangioblasts (by way of comparison, truncular lymphatic malformation) whenever conditions are suitable. Some examples include menarche, pregnancy, female hormones, trauma, and surgery.
After the ninth week of gestation, when disturbances in the lymph nodes and vessel formation processes associated with the main lymphatic trunk formation occur, various and often more significant structural variants of the lymph transporting system take place, including those of the thoracic duct. 45 , 46
Such defective development during the later stage of lymphangiogenesis before the completion of fully mature normal lymphatic trunk formation is also grouped separately as truncular lymphatic malformations. These truncular lesions no longer have the ability to grow like extratruncular lesions (as previously described), but they can have a much more serious impact overall with respect to lymph transport function because of their direct structural impact on the lymph vessels. 47 , 48
Therefore primary lymphedema mainly presents as a clinical manifestation of these defective formations of the lymphatic trunk, vessels, and nodes from the late stage of lymphangiogenesis. We see a range of defects, including lymphatic trunk hypoplasia, aplasia, numeric hyperplasia, or dilation (lymphangiectasia) with valvular incompetence. Regarding the lymph nodes, we often see selective lymph node dysplasia alone, which is also indicative of primary lymphedema, and is best known as lymphnododysplasia, although it is generally involved with lymphangiodysplasia as indicated previously. 49 , 50
To add complexity, not all primary lymphedemas are associated with such anatomic defects, or if present, they seemingly have little effect. Instead, some show only defective function, such as Milroy disease. 51 – 54 Indeed, some primary lymphedemas have very little structural derangement and are limited to a functional defect that appears molecular in origin.
For these reasons, some investigators believe that all lymphedemas caused by lymphatic malformations are genetically derived, and they define lymphedema as an abnormality of lymph drainage in which the predominant effect is on the tissue territory(ies) drained. Therefore a malformation may not necessarily have attributes that can be imaged, but may ultimately require detection or definition in molecular or other functional terms. 3 , 4 , 55 , 56
Thus the cause of decreased lymphatic transport in primary lymphedema is either an intrinsic defect 5 , 8 , 57 – 60 or a malfunction of the lymph-conducting elements 61 – 64 resulting from a genetically determined abnormality of lymphatic anatomy or function. When primary chronic lymphedema represents the clinical expression of heritable abnormal structural development, it clinically manifests as a macroscopic structural abnormality, which is defined as a truncular lymphatic malformation. 8 , 65
Furthermore, primary lymphedema includes all the lymphedemas caused by the mutation of any of the genes involved in the development of the lymphatic system. Currently, representative genetic mutations identified in a familial distribution of primary lymphedema are FLT4, 52 , 57 , 66 FoxC, 54 , 57 and GJC2. 67 , 68
The major clinical sign of all these forms of genetically determined lymphedema is lymphedema as the primary phenotype. For these families, an autosomal dominant pattern of inheritance has been reported. Various genes strongly associated with this pattern of inheritance have been demonstrated, with variable expression and variable age at onset. 56 , 63 , 66
Milroy disease is one example of a familial lymphedema caused by an autosomal dominant, single gene disorder inherited as a germ line mutation at the locus 5q35.3. The gene mutated is FLT4, which encodes for the vascular endothelial growth factor receptor 3 (VEGFR-3). 56 , 66 , 69 However, because of a somatic mutation, regionally limited genetic disorders will allow some tissue (for example, skin) to be unaffected, whereas the adjacent tissue (skin) carries the mutation (for example, mosaicism).
Nevertheless, the hereditary type of primary lymphedema is quite rare, whereas the sporadic type represents the majority, although both have a genetic basis. What is important, however, is to acknowledge that all the malformations by definition are present at birth, although there is some concern regarding the current definition of primary lymphedema, because postnatal obliterations of lymph collectors and lymph nodes can mimic congenital and prenatal pathologies.
Overcoming the Problem
Various cytokines 70 , 71 are involved in the stimulation of lymphangiogenesis. For instance, vascular endothelial growth factor (VEGF)-C and -D are known to activate VEGFR-3 expressed on lymphatic endothelial cells. 72 VEGF-C–deficient mice fail to develop a functional lymphatic system, 73 attesting to its importance.
Angiopoietin 1 also promotes lymphatic vessel formation through Tie2. 74 Also, gene transfer of VEGF-C through its promotion of lymphangiogenesis reduces lymphedema, at least in an animal model. 75
For these reasons, patients with lymphatic malformations with such risks for several congenital lymphatic disorders, including Down syndrome, Turner syndrome, and Noonan syndrome in particular, should receive genetic counseling for cytogenetic analysis for chromosomal aneuploidy before they consider becoming parents, because aneuploidic conditions can recur in subsequent pregnancies. 76 – 79
As the previously mentioned case demonstrates, an accurate definition of the normal anatomophysiology of the lymphatic system is essential for a proper understanding of the pathophysiology of primary lymphedema and perhaps for better management of the condition.
Normal Role of the Lymphatics and Impact of Defects on the Cells, Tissue, and Body
The circulatory function is the principal role of the lymphatic system, which maintains the drainage and transport of interstitial fluid to the main blood circulation. However, in addition to such an essential role for interstitial fluid homeostasis, the lymphatic system has multiple roles. It plays a crucial role for the immune systems, providing the immune traffic route to transport white blood cells and antigen-presenting cells to the lymphoid organs. 80 It also has another unique function for the lipid absorption from the gastrointestinal tract. Absorption of fat from the intestine occurs through the lymphatic system, and subsequent transportation of the chyle to the liver depends on this system. 81 – 83 Such crucial functions are directly affected by a defective development no matter what the reason. Many if not most of the structural malformations previously described lead to functional issues.
The lymphatics are found throughout the body except in the central nervous system, and lymphatic vasculature and lymphoid tissue are more prevalent in tissues that are in close contact with the external environment (for example, the gastrointestinal tract and lungs). 84 Such distribution seems to reflect the unique role of the lymphatics against infectious agents and foreign materials. Thus the location of the malformations may have an impact on any or all tissues.
In the extremities the lymphatic system consists of superficial and deeper systems. A superficial system collects lymph from the epifascial tissue, such as skin and subcutaneous tissue, whereas a deeper system drains subfascial tissue, such as muscle, bone, and other deep structures like blood vessels. The two systems are mutually interdependent to provide the compensatory function, especially when one system fails because of a structural malformation or functional failure associated with it to maintain normal function and drainage. For example, the deep lymphatic system participates in lymph transport from the skin during lymphatic obstruction. 85
The failure of adequate lymph transport promotes lymphedema and likely contributes to the pathologic presentation of a wide variety of lymphatic vascular diseases. In a normal state, the extravasation of fluids and proteins from blood vessels is adequately handled by lymphatic drainage and return into the bloodstream. However, if microvascular filtration in blood capillaries and venules exceeds the capacity of lymphatic drainage for long periods, an edema develops because of the accumulation of interstitial fluid in the interstitium (for example, advanced chronic venous disease). 3
Lymph flow is established by the autonomous rhythmic contractions of the lymphangions, which propel the lymph. 86 – 88 When interstitial fluid enters the initial lymphatics to flow into the lymphangions, the lymphatic wall is stretched by inflowing interstitial fluid. It stimulates the lymphatic wall muscles to evoke the contractions to generate the flow in a peristaltic fashion. The frequency of rhythmic contraction of the lymphatics depends on the volume of the interstitial fluid entering. 88 , 89
Fluid transport into the initial lymphatics occurs against a pressure gradient. Such a phenomenon is explained based on the condition when episodic increases in interstitial fluid pressure by tissue movement combine with suction forces generated through the contraction of the collecting lymphatics. 90
Under normal conditions, muscular activity, respiratory movements, passive movements, and arterial pulsation have little if no effect on lymph flow when the lymphangion-based peristaltic movement is sufficient for lymph transport and flow. 87 – 89 Therefore the lymphatics of the limb are generally empty, with only a few microliters of lymph in some lymphangions. There is no hydrostatic pressure in the lymphatics of a normal leg in the upright position. 88 , 89
The normal lymph transport mechanism is based on the autoregulated peristaltic flow led by the lymphangions; however, in lymphedema this mechanism fails. In addition, the unique lymphodynamics that would be applicable to normal conditions are no longer valid, and new fluid dynamics to compensate for the lymphedematous condition become identical to the venodynamics. Thus muscular contraction of the foot and calf may increase lymph pressure, and patent lymphatics are filled with lymph. Compression of the muscles could create a pressure gradient between the distal and proximal lymphatics. 88 , 89
In normal limbs, the lymph flow occurs only during spontaneous contractions of lymphangions. 89 However, in lymphedematous limbs, most of the lymph collectors are partially or totally obliterated as a consequence of the destruction of lymph vessel musculature and valves, and only some spontaneous flow may remain in patent vessel segments at different levels of the limb. 91 – 93
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