Diseases of the Lymphatic Circulation

Diseases of the lymphatic circulation reflect either intrinsic, presumptively heritable (primary) defects or the aftermath of an acquired (secondary) disruption of lymphatic structure or function. Primary lymphatic disorders are thought to arise from faulty development of the lymphatic vasculature or from intrinsic functional derangements. Without regard to the mechanism, each of these disorders results in a disturbance in lymph transit. Secondary lymphatic dysfunction most often occurs following disruption of lymphatic channels, typically in the setting of trauma, infection, neoplasia, or surgical interventions.

In all forms of lymphatic vascular insufficiency, interstitial fluid accumulates and regional swelling ensues when regional lymphatic flow is insufficient to maintain tissue homeostasis. When lymph stasis is chronic, there is accompanying derangement of the soft tissue histological architecture that is nearly always characterized by adipose hypertrophy within the subcutis. The presence of hydrostatic edema and tissue hypertrophy is the defining characteristic of lymphedema, the end-organ failure state of the lymphatic vasculature. Because proliferative pathology of the lymphatic vessels often produces a functionally incompetent vasculature, these conditions are also often typified by the presence of a lymphedema component. When present in the viscera, lymphatic insufficiency can also lead to profound metabolic disturbances. In addition to its role in the preservation of tissue fluid homeostasis, the lymphatic circulation is responsible for immune traffic from the peripheral tissues to the lymphoid organs. Thus, in addition to the presence of edema, lymphatic vascular dysfunction is accompanied by functional compromise of regional and systemic immune responses.

Historically, the rather limited therapeutic options for lymphatic disease have reflected an incomplete understanding of the pathophysiology of lymphedema; nevertheless, recent advances in imaging and therapeutics, as well as insights gained from vascular biology, hold promise for the elaboration of more definitive therapies.

Anatomy of the lymphatic circulation

It was in the 17th century that Gasparo Aselli recognized the lymphatic vasculature as a distinct anatomic entity. On July 23, 1622, the anatomist undertook a demonstration of the action and innervation of the canine diaphragm.

While I was attempting this, and for that purpose had opened the abdomen and was pulling down with my hand the intestines and stomach…I suddenly beheld a great number of cords, as it were, exceedingly thin and beautifully white, scattered over the whole of the mesentery and the intestine, and starting from almost innumerable beginnings.... I noticed that the nerves belonging to the intestine were distinct from these cords, and wholly unlike them, and besides, were distributed quite separately from them. Wherefore struck by the novelty of the thing, I stood for some time silent.... When I gathered my wits together for the sake of the experiment, having laid hold of a very sharp scalpel, I pricked one of these cords and indeed one of the largest of them. I had hardly touched it, when I saw a white liquid like milk or cream forthwith gush out. Seeing this, I could hardly restrain my delight.

The chylous return from the intestine of the postprandial dog allowed Aselli to visualize the mesenteric lymphatics; when he repeated the demonstration several days later, no vessels were to be seen. Aselli eventually realized the relation between feedings and the visibility of the mesenteric lymphatics and duplicated the work in several species ( Fig. 57.1 ). Over the following half century, Aselli’s work was extended by Pecquet, Bartholinus, and Rudbeck, who defined the gross anatomy of the lymphatic system in toto. By the 18th century, smaller lymphatic channels were visualized by Anton Nuck, using mercury injections. With those techniques, Sappey observed and recorded the human lymphatic system in exquisite detail ( Fig. 57.2 ). Even greater resolution of the anatomy was provided by von Recklinghausen in 1862, with his discovery that the lymphatic endothelium stained darkly with silver nitrate. Using that technique, von Recklinghausen was able to differentiate lymphatic capillaries from the capillaries of the blood vascular system. Most recently, substantial advances in the techniques of immunohistochemistry and transmission electron microscopy have enabled the certain identification of the lymphatic microcirculation and its discrimination from the blood vasculature.

Fig. 57.1, The original anatomic illustration of the visceral lymphatics by Gasparo Aselli.

Fig. 57.2, (A and B) Nineteenth-century anatomic delineation of the cutaneous lymphatics.

It is now well established that the lymphatic capillaries are blind-ended tubular structures formed by a single layer of endothelial cells. These endothelial cells closely resemble those of blood vessels and have a common embryonic origin. Like blood vascular endothelium, cultured lymphatic endothelial cells form confluent “cobblestone” monolayers that “sprout” to form tubules. They elaborate many identical histologic markers (von Willebrand factor, F-actin, fibronectin, and Weibel-Palade bodies). Unlike systemic capillaries, the basement membrane of lymphatic capillaries is absent or widely fenestrated, allowing greater entry of interstitial proteins and particles.

The capillaries join to form larger vessels (100 to 200 μm) that are invested with smooth muscle and are capable of intrinsic vasomotion. These vessels, in turn, merge to form larger collecting conduits composed of three distinct layers: intima, media, and adventitia. The collectors possess intraluminal valves: these, separated by millimeters to centimeters, ensure that lymph flow will be directed centrally.

In the lower limbs, the lymphatic collectors aggregate into a system that is divided into superficial and deep components. The superficial component is composed of medial and lateral channels. The medial channel originates on the dorsum of the foot and runs along the course of the saphenous vein. The lateral channel begins on the lateral aspect of the foot and ascends to the midleg, where the tributaries cross anteriorly to the medial side to follow the course of the medial lymphatics up to the inguinal nodes. Deep lymphatics do not usually communicate with the superficial system except through the popliteal and inguinal lymph nodes. The latter originate in the subcutaneous compartment, follow the course of the deep blood vessels, and eventually pass through the inguinal nodes.

Small- and medium-sized lymphatic vessels empty into main channels, of which the thoracic duct is the largest. The duct, approximately 2 mm wide and 45 cm long, ascends from the abdomen through the lower chest just to the right of the vertebral column and anterior to it. At approximately the level of the fifth thoracic vertebra, it crosses to the left of the spine, where it continues to ascend through the superior mediastinum to the base of the neck and eventually empties into the left brachiocephalic vein. Other large right- and left-sided lymphatic ducts may exist, although their arrangement, size, and course are highly variable. Those vessels join with the main thoracic duct or empty directly into great veins; they provide important collateral conduits if the thoracic duct becomes obstructed.

Physiology of the lymphatic circulation

In 1786 William Hunter and two of his pupils, William Cruikshank and William Hewson, published the results of their work, laying the foundation for the physiology of the lymphatic system. They correctly inferred from clinical observations that the lymphatics are involved in the response to infection as well as in the absorption of interstitial fluid. A century later, their theories received experimental support from the physiologic studies of Karl Ludwig and Ernest Starling. Ludwig cannulated lymph vessels, collected and analyzed the lymph, and proposed that it was a filtrate of plasma. Starling elucidated the forces governing fluid transfer from the blood capillaries to the interstitial space and offered evidence that the same forces apply to the lymphatic capillaries. He proposed that an imbalance in those forces could give rise to edema formation:

In health, therefore, the two processes, lymph production and absorption, are exactly proportional. Dropsy depends on a loss of balance between these two processes—on an excess of lymph-production over lymph-absorption. A scientific investigation of the causation of dropsy will therefore involve, in the first place, an examination of the factors which determine the extent of these two processes and, so far as is possible, the manner in which these processes are carried out.

As first enunciated by Starling, interstitial fluid is largely an ultrafiltrate of blood. Its rate of production reflects the balance between factors that favor filtration out of capillaries (capillary hydrostatic pressure and tissue oncotic pressure) and those that favor reabsorption (interstitial hydrostatic pressure and capillary oncotic pressure). Under normal conditions, filtration exceeds reabsorption at a rate sufficient to create 2 to 4 L of interstitial fluid per day. There is a net filtration of protein (primarily albumin) from the vasculature into the interstitium; approximately 100 g of circulating protein may escape into the interstitial space daily. The interstitial fluid also receives the waste products of cellular metabolism as well as foreign matter or microbes that enter through breaks in the skin or by hematogenous routes.

A more recent revisiting of the Starling relationship suggests that the accumulation of capillary filtrate in the tissue spaces is avoided mainly through lymph drainage and not, as was previously thought, through reabsorption. Direct observations demonstrate that, in most vascular beds, there is net filtration along the entire length of well-perfused capillaries.

Entry of interstitial fluid into the lymphatic capillary is primarily governed by the prevailing interstitial fluid pressure; under steady-state conditions, this is typically subatmospheric. In situations where the pressure drops below the normal value of − 6 mm Hg, lymph flow becomes negligible. However, any physical force that increases interstitial fluid pressure will increase lymph flow. According to the Starling equation, increased capillary hydrostatic pressure , decreased plasma oncotic pressure , increased interstitial oncotic pressure , or increased capillary permeability can each result in an increase in tissue lymph production. Lymph flow becomes maximal when interstitial pressure is slightly higher than the atmospheric pressure. Paradoxically, the average prevailing pressure gradients do not seem to favor fluid entry into the terminal lymphatics, but it has been proposed that cyclical changes in the existing pressure gradients provide the dynamic force that favors fluid entry. Furthermore, active regulation of transendothelial transport of solutes, lipids, and even water across lymphatic capillaries can occur. These active mechanisms are thought to potentiate rapid control over rates of lymph formation without altering the integrity of the lymphatic vessels.

The volume and the composition of the interstitial fluid are kept in balance by the lymphatic system. The functions of that system include (1) transport of excess fluid, protein, and waste products from the interstitial space to the bloodstream; (2) distribution of immune cells and substances from the lymphoid tissues to the systemic circulation; (3) filtration and removal of foreign material from the interstitial fluid; and (4) in the viscera, to promote the absorption of lipids from the intestinal lumen.

Not surprisingly, the lymphatics require a complex interplay of specific anatomy and function to meet physiological requirements. Several forces drive fluid through the lymphatic system. Once interstitial fluid enters the lymphatic vasculature, its further transport relies on the effects of both intrinsic and extrinsic pumps. The extrinsic pump mechanism reflects the cyclical lymphatic compression and expansion produced by extrinsic tissue forces. These include the physical movement of parts of the body, skeletal muscle, arterial pulsation, and tissue compression by extrinsic forces. In other tissues, such as the splanchnic and cutaneous systems, it is primarily contractions of lymphatic smooth muscle that generate the driving force. Normal lymphatic pump function is determined by the intrinsic properties of lymphatic muscle and the regulation of pumping by lymphatic preload, afterload, spontaneous contraction rate, contractility and neural influences. These contractions are increased in frequency and amplitude by elevated filling pressure, sympathetic nerve activity, and shock; they may be modulated by circulating hormones and prostanoids. Considerable force can be generated by those contractions; experimentally induced obstruction of the popliteal lymphatic system augments the strength and frequency of contraction, generating pressures of up to 50 mm Hg. Other factors that may contribute to lymphatic flow include intermittent compression from arterial pulsations, and gastrointestinal peristalsis. In addition, it has recently been proposed that the initial lymphatics (the small lymphatic capillaries that begin blindly in the tissues) most likely possess a two-valve system. In addition to the classically described secondary intralymphatic valves, the initial lymphatics are thought to possess a primary valve system at the level of the endothelium to ensure unidirectional flow at this level. Once lymph enters the thorax, negative intrathoracic pressure generated during inspiration aspirates fluid into the thoracic duct (the “respiratory pump”).

Failure of adequate lymph transport promotes lymphedema and likely contributes to the pathological presentation of a wide variety of lymphatic vascular diseases.

Lymphatic insufficiency (Lymphedema)

Pathogenesis of Edema

Edema develops when the production of interstitial fluid (lymph) exceeds the transport capacity of the lymphatic vasculature. Thus either an overproduction of lymph (augmented lymphatic load) or a decreased ability to remove fluid (defective transport) from the interstitium, or both, can promote edema formation. Conditions associated with the overproduction of lymph include elevated venous pressures, increased capillary permeability, and hypoproteinemia. Elevated postcapillary hydrostatic pressure increases capillary filtration (as seen in right-sided congestive heart failure, tricuspid regurgitation, and deep venous thrombosis). Alternately, local inflammation increases capillary permeability, thus accelerating the egress of protein and fluid into the interstitium despite a normal capillary hydrostatic pressure. Lymph production may increase by 10- to 20-fold, exceeding lymphatic transport and resulting in marked edema. Hypoproteinemia may also lead to marked edema, in which case hydrostatic pressure and capillary permeability are normal but capillary oncotic pressure is reduced, favoring net fluid transit to the interstitium. The edema that ensues in these conditions can, strictly speaking, be called lymphedema only when there is objective evidence of impaired lymphatic clearance or physical evidence of consequences of impaired lymphatic function in the skin or subcutaneous tissues.

Pathogenesis of Lymphedema

Lymphedema occurs whenever lymphatic vessels are absent, underdeveloped, or obstructed. Impedance to lymphatic flow may be due to an inborn defect (primary lymphedema) or an acquired loss of lymphatic patency (secondary lymphedema).

Primary Lymphedema

Prevalence estimates for the heritable causes of lymphedema are difficult to ascertain and vary substantially. Primary lymphedema is thought to occur in approximately 1 of every 6 to 10,000 live births. Females are affected 2- to 10-fold more commonly than males. Primary lymphedema represents a heterogeneous group of disorders; therefore its classification schemes are numerous. Affected individuals can be classified by age of onset, functional anatomic attributes, or clinical setting.

Age of Onset

When distinguished by age of clinical onset, primary lymphedema can typically be divided into the following categories :

1.
Congenital lymphedema, clinically apparent at or near birth.
2.
Lymphedema praecox, with onset after birth and before age 35; lymphedema praecox , a term used by Allen in 1934, most typically appears in the peripubertal years.
3.
Lymphedema tarda appears after the age of 35.

Anatomic Patterns

An alternative classification scheme relies on an anatomic description of the lymphatic vasculature.

1.
Aplasia: no collecting vessels identified.
2.
Hypoplasia: a diminished number of vessels are seen.
3.
Numeric hyperplasia (as defined by Kinmonth): an increased number of vessels are seen.
4.
Hyperplasia: in addition to an increase in number, the vessels have valvular incompetence and display tortuosity and dilation (megalymphatics).

Approximately one-third of all cases are secondary to agenesis, hypoplasia, or obstruction of the distal lymphatic vessels, with relatively normal proximal vessels. In those cases the swelling is usually bilateral and mild and affects females much more frequently than males. The prognosis in such cases is good. Generally, after the first year of symptoms, there is little extension in the same limb or to uninvolved extremities. Although the extent of involvement is established early in the disease in about 40% of patients, the girth of the limb continues to increase.

In more than half of all cases, the defect primarily involves obstruction of the proximal lymphatics or nodes, with initial lack of involvement of distal lymphatic vessels. Pathologic studies reveal intranodal fibrosis. In those cases the swelling tends to be unilateral and severe; there may be a slight predominance of females in this group. In patients with proximal involvement, the extent and degree of the abnormality is more likely to progress and require surgical intervention. Initially uninvolved distal lymphatic vessels may become obliterated over time.

A minority of patients have a pattern of bilateral hyperplasia of the lymphatic channels or tortuous dilated megalymphatics. In these less common forms of primary lymphedema, there is a slight male predominance. Megalymphatics are associated with a greater extent of involvement and a worse prognosis.

Clinical Characteristics

As a third alternative, the primary lymphedemas can often be characterized by associated clinical anomalies or abnormal phenotype. Although sporadic instances of primary lymphedema are more common, the tendency for congenital lymphedema to cluster in families is significant. The syndrome of a familial predisposition to congenital lymphedema, ultimately described as an autosomal dominant form of inheritance with variable penetrance, was first delineated by Milroy in 1892. He reported “hereditary edema” affecting 22 individuals of one family over six generations. Although Milroy ultimately described praecox and tarda forms as variants of the syndrome, the praecox form of primary lymphedema more often carries the eponym of Meige disease.

In fact, a long list of disorders is associated with heritable forms of lymphedema. Increasingly these disorders have yielded to chromosomal mapping techniques. Lymphedema-cholestasis, or Aagenaes syndrome, has been mapped to chromosome 15q. In several family cohorts of Milroy disease, it has been determined that the disorder reflects missense inactivating mutations in the tyrosine kinase domain of vascular endothelial growth factor receptor 3 (VEGFR3), thus underscoring the likelihood that the pathogenesis of this condition likely reflects an inherited defect in lymphatic vasculogenesis. Several additional lymphedema syndromes have recently lent themselves to successful genetic mapping. Lymphedema-distichiasis, an autosomal dominant, dysmorphic syndrome in which the lymphedema presents in association with a supplementary row of eyelashes arising from the meibomian glands, has been linked to truncating mutations in the forkhead-related transcription factor FOXC2 ; mutations in FOXC2 have subsequently been associated with a broad variety of primary lymphedema presentations. Similarly, a more unusual form of congenital lymphedema, hypotrichosis-lymphedema-telangiectasia, has been ascribed to both recessive and dominant forms of inheritance of mutations in the transcription factor gene SOX18 . Most recently, linkage analysis of three affected family cohorts has associated the occurrence of autosomal recessive congenital lymphatic dysplasia (Hennekam syndrome) to the gene CCBE1 , also identified as critical to lymphangiogenesis in zebrafish. It is altogether plausible that further elucidation of the molecular pathogenesis of these diseases linked to FOXC2, SOX18 , and CCBE1 mutations will lead to enhanced insights into mechanisms of normal and abnormal lymphatic development. Furthermore, mutational analysis of families expressing inherited forms of lymphedema have disclosed specific mutations in HGF (which encodes hepatocyte growth factor) and MET (the HGF receptor). GJC2 , the gene that encodes connexin 47, has also been implicated in the familial occurrence of lymphedema.

At present, 12 distinct genes have been identified in association with syndromic and nonsyndromic primary lymphedema. In general, autosomal or sex-linked recessive forms of congenital lymphedema occur less commonly than the dominant forms of inheritance. The list of heritable lymphedema-associated syndromes is long and growing ( Box 57.1 ). Primary lymphedema has been described in association with various forms of chromosomal aneuploidy, such as Turner and Klinefelter syndromes, with various dysmorphogenic-genetic anomalies such as Noonan syndrome and neurofibromatosis, and with various as yet unrelated disorders such as yellow nail syndrome, intestinal lymphangiectasia, lymphangiomyomatosis, and arteriovenous malformation. The association of lymphedema with vascular anomalies likely derives from the shared embryological origin of the lymphatic and venous vasculature.

Box 57.1

Hereditary Conditions Associated With Lymphedema

Chromosomal Aneuploidy

Trisomy 13
Trisomy 18
Trisomy 21
Triploidy
Klinefelter syndrome
Turner syndrome

Dysmorphogenic-Genetic Disturbances

Cantu syndrome
Cardiovaciocutaneous syndrome
CHARGE syndrome
Cholestasis-lymphedema syndrome (Aagenaes syndrome)
CLOVE syndrome
Down syndrome
Emberger syndrome
Fibroadipose hyperplasia
Fabry disease
Frank-Ter Haar syndrome
Hennekam syndrome
Hereditary fibrosing poikiloderma
Hypotrichosis-lymphedema-telangiectasia syndrome
Irons Bianchi syndrome
Klippel-Trénaunay-Weber syndrome
Lymphedema-distichiasis
Lymphedema-hypoparathyroidism syndrome
Lymphedema-microcephaly-chorioretinopathy
Macrocephaly capillary malformation syndrome
Meige lymphedema (lymphedema praecox)
Mucke syndrome
Neurofibromatosis type I (von Recklinghausen)
Noonan syndrome
Noone-Milroy hereditary lymphedema
Oculo-dento-digital syndrome
OL-EDA-ID syndrome
Phelan-McDermid syndrome
Prader-Willi syndrome
Progressive encephalopathy with edema, hypsarrhythmia, optic atrophy
Proteus syndrome
Thrombocytopenia absent radius syndrome
Tuberous sclerosis
Velo-cardio-facial syndrome
Yellow nail syndrome

Secondary Lymphedema

Secondary lymphedema is an acquired condition that can arise after loss or obstruction of previously adequate lymphatic channels. A wide variety of pathologic processes may lead to such lymphatic obliteration.

Infection

Recurrent episodes of bacterial lymphangitis lead to thrombosis and fibrosis of the lymphatic channels and are among the most common causes of lymphedema. The responsible bacteria are almost always streptococci, which tend to enter through breaks in the skin or fissures induced by trichophytosis. Recurrent bacterial lymphangitis is also a frequent complicating factor of lymphedema from any cause.

Filariasis, a nematode infection endemic to regions of South America, Asia, and Africa, is the most common cause of secondary lymphedema in the world. The World Health Organization estimates that more than 130 million people may be affected by filarial infections; in India alone there are up to 14 million symptomatic cases. Common tropical filaria include Wuchereria bancrofti and Brugia malayi or timori . Other Brugia species are found in North America and occasionally cause lymphatic obstruction.

The microfilaria are transmitted by a mosquito vector and induce recurrent lymphangitis and eventual fibrosis of lymph nodes. It is unclear whether filaria themselves produce the lymphangitis or simply predispose those afflicted to recurrent episodes of bacterial lymphangitis. The filaria can also be identified in blood specimens of tissue obtained by fine-needle biopsy of the affected areas, and eosinophilia is a common local and systemic feature. Diethylcarbamazine remains the most popular drug for treating filariasis; although side effects are frequent, it is extremely efficacious. Ivermectin is a newer antifilarial agent that may replace diethylcarbamazine; it is less toxic, and a single oral dose (25 μg/kg) appears to be as efficacious as a 2-week course of diethylcarbamazine.

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