FormalPara Summary of Basic Concepts

Beyond lymphedema, in its diverse manifestations, there is a spectrum of human disease that directly or indirectly alters lymphatic structure and function. Diagnosis and differential diagnosis pose distinct challenges. In this overview, various categories of lymphatic disease are enumerated and viewed through the prism of lymphatic embryological development.

  • Defects in the growth and development of lymphatic vessels underlie the lymphatic clinical disorders, including lymphedema, vascular malformations, and lymphangiectasia.

  • Lymphedema represents the most commonly encountered disease state of the lymphatics. It can present in both acquired and heritable forms.

  • Clinical manifestations of primary lymphedema can be mistaken for secondary lymphedema if edema first appears after an apparent provoking secondary inciting event.

  • A genetic predisposition for the development of lymphedema, even when the inciting secondary events are easy to identify.

  • There are at least nine causal mutations known for inherited human lymphedema.

  • Beyond peripheral lymphedema, the spectrum of lymphatic vascular disease is remarkably diverse. The pathological alterations can be isolated, regionalized, or diffuse and can occur in isolation or in concert with other complex vascular lesions.

  • Lymphatic malformations are microcystic, macrocystic, or mixed; generalized lymphatic anomaly is a multifocal lymphatic malformation that can involve the skin, superficial soft tissues, bone, and abdominal and thoracic viscera.

  • In protein-losing enteropathy, loss of lymphatic fluid and plasma protein within the lumen of the gastrointestinal tract can lead to edema and hypoproteinemia.

Beyond lymphedema, in its diverse manifestations, there is a spectrum of human disease that directly or indirectly alters lymphatic structure and function. Not surprisingly, the symptomatic and objective presentation of these patients is quite heterogeneous. Diagnosis and differential diagnosis pose distinct challenges. In this overview, various categories of lymphatic disease are enumerated and viewed through the prism of lymphatic embryological development (► Chap. 4).

1 Development of the Lymphatic System

It is vital that we understand the processes of normal lymphatic development, since defects in the growth and development of lymphatic vessels (lymphangiogenesis) underlie the clinical disorders of this vascular system, including lymphedema, vascular malformations, and lymphangiectasia [5].

It is now reasonably well established that the lymphatic progenitors arise from the endothelial cell population within embryonic venous structures. Lymphatic endothelial cell specification entails the expression of the unique molecular markers that impose the characteristic phenotype of this cell. As the lymphatic endothelial cells attain higher levels of differentiation, additional lymphatic-specific markers are expressed, along with concomitant suppression of the markers of blood vascular expression [6]. The committed lymphatic cell population achieves complete autonomy from the local venous microenvironment and migrates peripherally. Thereafter, the formation of primary lymph sacs occurs throughout the embryo. Secondary budding and migration distinguish the final stages of lymphatic development. However, despite this generally described phenomenon, recent studies provide evidence that, in humans and other complex organisms, there are distinct and tissue-specific differences in the mechanisms by which the lymphatic vasculature arises and develops; accordingly, dermal, intestinal, brain, visceral, and cardiac lymphatics each possess a unique and diverse developmental program [7]. Specifically, in embryonic skin, heart, and mesentery, sources of progenitor cells beyond the venous pool have now been identified [7].

2 Lymphatic Vascular Disease Classification

Evolving insights into molecular embryology continue to inform our comprehension of lymphatic vascular development. The spectrum of lymphatic vascular disease is broad: an informed classification schema, with therapeutic implications, should ultimately be derived from the insights drawn from developmental biology. In fact, until quite recently, disease classification and risk stratification have been very imprecise, and comprehension of disease natural history and epidemiology has been disappointingly primitive [8, 9]. The recognized categories and representative subsidiary diseases are summarized in ◘ Table 2.1.

Table 2.1 Lymphatic disease classification
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2.1 Lymphedema

Lymphedema represents the most commonly encountered disease state of the lymphatics. It can present in both acquired and heritable forms [8]. Conventionally, a distinction has been established among primary and secondary causes of lymphedema [10]. In approach, primary lymphedemas encompass both the sporadic and hereditary forms, as well as those that are syndrome associated [1]; secondary lymphedema is either malignant (i.e., associated with direct neoplastic invasion and/or obstruction of the vascular channels and nodes) or benign (acquired as a consequence of infection, trauma, obesity ([11, 12], or iatrogenic causes, including the surgical and radiotherapeutic treatment of malignancies). More recent approaches to the mechanistic classification of lymphedemas suggest that the boundaries that separate the seemingly distinct categories of primary and secondary lymphedema may, in fact, be indistinct: primary cases often declare themselves after a «secondary» provocation, and evolving clinical data suggests that there might be a genetic predisposition for the development of lymphedema, even when the inciting secondary events are easy to identify [13, 14].

At the present time, there are at least nine causal mutations known for inherited human lymphedema [1]. Heritable congenital lymphedema of the lower extremities was first described in 1891 [15]; in 1892, Milroy [16] described the familial distribution of congenital lymphedema, noting the involvement of 26 persons in a single family, spanning six generations. Nonne–Milroy’s lymphedema is characterized by unilateral or bilateral swelling of the legs, arms, and/or face with gradual and irreversible fibrotic changes. Additional, distinct variants of heritable lymphedema have subsequently been described. In 1898, Meige reported cases of lymphedema in which the age of onset was after puberty and that often appeared alongside acute cellulitis [17]. In 1964, another variety of pubertal-onset lymphedema was reported, in which the affected individuals had distichiasis (i.e., an auxiliary set of eyelashes) [18].

In addition to the isolated gene mutations responsible for Milroy’s disease and lymphedema distichiasis, there is an array of syndromic heritable disorders that are associated with dysfunction of the lymphatic vasculature (◘ Fig. 2.1) [2]. Often, these syndromes are associated with abnormal facial and mental development.

Fig. 2.1
figure 1

An algorithm for the classification of the primary lymphedemas (Reprinted with permission from Connell et al. [2])

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An additional useful organizational schema is to classify the disorders by their autosomal dominant (Noonan syndrome, Adams–Oliver syndrome, and neurofibromatosis) or autosomal recessive (Hennekam syndrome, the Prader–Willi syndrome, and Aagenaes’ syndrome) modes of genetic transmission.

Chromosomal disorders can also result in multiple organ defects, in addition to lymphedema when present. These disorders are uncommon; hence, the chromosomal basis can be readily overlooked or misdiagnosed. Confirmatory identification can be achieved only through detailed cytogenetic studies. Many of these disorders severely distort lymphatic function. Turner’s syndrome and Klinefelter syndrome are linked to the sex chromosomes, whereas Edwards syndrome and Patau syndrome are linked to autosomal chromosomes. Triploidy syndrome denotes the presence of an extra copy of all of the chromosomes.

Beyond peripheral lymphedema, the spectrum of lymphatic vascular disease is remarkably diverse. Histologically, the vasculature can display any combination of pathological dilation of structures that are normal in number and distribution or abnormal patterns of vascular growth. The pathological alterations can be isolated, regionalized, or diffuse and can occur in isolation or in concert with other complex vascular lesions.

3 Lymphatic Vascular Malformation

Lymphatic vascular malformations, formerly known as lymphangiomas [3], arise during embryological development. These lesions may arise from segments of lymphatic vascular tissue that fail to undergo proper anastomosis, or they may represent portions of lymph sacs that become grouped together during development [19]. The presence of multiple or widespread lymphatic vascular malformations, previously designated as lymphangiomatosis [4], now more properly implies the diagnosis of generalized lymphatic anomaly (GLA) [3]. GLA is characterized as a multifocal lymphatic malformation that can involve the skin, superficial soft tissues, and abdominal and thoracic viscera; they often involve bone, with osseous involvement that is typically nonprogressive and that spares the bone cortical boundaries [3]. Chylous pleural, pericardial, or peritoneal effusions may be present [3]. At least two distinct genetic mutations have recently been linked to heritable forms of GLA [20, 21]. Lymphatic malformations were previously classified by size and depth of formation, with the smaller, superficial form previously designated as lymphangioma circumscriptum and the deeper lesions as cavernous lymphangiomas and cystic hygromas. This terminology has been replaced with the simple designation of the lesions as microcystic, macrocystic, or mixed [3]. Lymphatic malformations can also occur in association with other vascular and structural anomalies.

4 Protein-Losing Enteropathy and Intestinal Lymphangiectasia

Loss of lymphatic fluid and plasma protein within the lumen of the gastrointestinal tract can lead to edema and hypoproteinemia [4]. Patients with protein-losing enteropathy typically have local lymphatic obstruction and stasis [22], while those with lymphangiectasia have dilated lymphatic vessels in the intestinal villi [23].

In general, lymphatic obstruction leads to increased hydrostatic pressure throughout the lymphatic system of the gastrointestinal tract, resulting in lymph stasis. Protein-rich lymphatic fluid is consequently lost into the gastrointestinal lumen through the lacteals in the intestinal microvilli.

Intestinal lymphangiectasia is a rare condition characterized by severe edema, thickening of the small bowel wall, protein-losing enteropathy, ascites, and pleural effusion [24]. The condition may be primary, resulting from a congenital lymphatic vascular disorder, or secondary, as a consequence of inflammatory or neoplastic involvement of the lymphatic system [25]. Although intestinal lymphangiectasia can occur in the context of generalized lymphatic dysplasia, the pathogenesis of this disorder is unknown.

4.1 Complex Vascular Malformations

Various disorders result from abnormal development of, or insult to, the blood vascular and lymphatic vascular systems [4].

Cystic angiomatosis is a congenital condition of unknown etiology, defined by the presence of numerous cystic skeletal lesions. The lesions are generally round or oval, and they vary widely in size. The cystic lesions may be due to dilated blood vessels or lymphatic channels or both. The cysts are encircled by a single, flat layer of endothelial cells.

Maffucci’s syndrome is characterized by the presence of hard subcutaneous enchondromas and hemangiomas due to mesodermal dysplasia [26]. Patients with Maffucci’s syndrome are also at risk for the development of a variety of malignant tumors [27]. Maffucci’s syndrome is often associated with lymphatic system dysfunction, with consequent edema and secondary infection. Lesions appear during childhood and may progressively worsen.

Gorham’s disease results from the uncontrolled growth of nonmalignant vascular channels that lead to lysis of the affected bone [28]. Osteolytic lesions are consecutive and progressive [29], and pathologic fractures can occur [3]. The condition is associated with angiomatosis of blood and lymphatic vessels. Chylous pericardial and pleural effusions are associated with this condition, and chylothorax can sometimes result from dilation of the lymphatic vessels, with reflux into pleural cavity.

Klippel–Trenaunay syndrome consists of a combination of vascular malformations, including capillary anomalies (port-wine stain), varicose veins, and hypertrophy of bone and soft tissue [30]. While Klippel–Trenaunay syndrome generally manifests in a single extremity, it can also affect multiple limbs or the entire body. Histologically, the condition is associated with dilated telangiectatic vessels in the upper dermis that do not spontaneously regress. The etiology of this condition is unknown; it is hypothesized that it might reflect a mutation in a mosaic state, in a gene that would be lethal when mutated in a non-mosaic state [31]. The putative gene(s) have not been identified.

Beyond lymphedema and the primary defects of lymphatic vasculature, there are numerous additional categories of disease that can be considered to be part of the spectrum of lymphatic vascular disease.

5 Infectious Diseases

Lymphatic dysfunction can arise as a consequence of invading pathogens.

Globally, more than 129 million patients are afflicted by lymphatic filariasis (► Chap. 63). This condition is characterized by markedly impaired lymphatic function and lymphangiectasia. Patients are infected by filariae, or parasitic worms, which take up residence in the lymphatic structures. As a result, the lymphatics become compromised; the formation of new lymph channels is impaired by the adenolymphangitis, fibrosis, and stenosis of the lymph nodes.

Lymphangitis is, in general, a consequence of the inflammation of lymphatic channels through tissue infection. Pathogenic organisms can include bacteria, fungi, viruses, and protozoa.

5.1 Lipedema

Lipedema [32] was first described in 1940 as a bilateral, gradual accumulation of fatty deposition in the lower extremities and buttocks. The body habitus superficially resembles that of bilateral lower extremity lymphedema, although the involvement of the two limbs is substantially more symmetrical than in lymphedema, and there is almost always sparing of the feet. The condition is found almost exclusively in female subjects. A family history of large legs is commonly encountered [33]. Earlier stages of lipedema are characterized further by the presence of normal cutaneous architecture, lacking the fibrotic changes often seen in lymphedema. The histopathology describes edematous adipose cells that are sometimes hyperplastic. The microlymphatic function can become distorted in lipedema, and a component of secondary lymphedema often supervenes.

5.2 Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a hybrid disorder that has a distinct lymphatic component to the clinical presentation [34]. Among the complex components to the disease are mutational inactivation of the tuberous sclerosis complex genes, TSC1 and TSC2, activation of the mammalian target of rapamycin (mTOR) pathway, enhanced cell proliferation and migration, lymphangiogenesis, metastatic spread through the blood and lymphatic circulations, sex steroid sensitivity, and dysregulated autophagy [35]. The disease is characterized by the spread of abnormal smooth muscle cells (LAM cells) through both the pulmonary interstitium and the axial lymphatics, leading to the cystic destruction of the lung, along with lymphatic wall thickening. LAM is also characterized by the presence of pulmonary cysts and angiomyolipomas, tumors consisting of LAM cells, adipose tissue, and underdeveloped blood vessels. LAM chiefly affects women of childbearing age. It is an extremely rare disease, found in fewer than one in a million individuals. The primary clinical presentation associated with LAM is pulmonary, including pneumothorax, progressive dyspnea, chylous pleural effusions, cough, hemoptysis, and chyloptysis. Non-pulmonary findings include lymphangioleiomyomas, the large cystic masses commonly found in the abdominal and retroperitoneal regions, and chylous ascites [4].