Introduction

Complex lymphatic anomalies (CLAs) not only comprise a diverse set of congenital disorders that usually come to medical attention early in life, either in utero or during early childhood, but can also manifest in adulthood [1]. The major members of this family include generalized lymphatic anomaly (GLA), Gorham-Stout disease (GSD), kaposiform lymphangiomatosis (KLA), and central collecting lymphatic anomaly (CCLA). Depending on the anomaly, these manifestations can be systemic or isolated to a single site or organ system. Lung involvement with

CLAs is not uncommon, and can be the primary manifestation [2]. Lymphangioleiomyomatosis, which can present with lymphatic masses, cystic lung disease, and chylous effusions, is the subject of another chapter and will not be addressed here. Although not considered a CLA, Yellow Nail Syndrome is an acquired lymphatic disorder that typically presents in adulthood with some combination of discolored nails, lymphedema, sinusitis, bronchiectasis, and pleural effusion that is occasionally chylous [3]. This chapter will focus on these ve lymphatic disorders that may present to an adult pulmonologist (Table 21.1).

The Pulmonary Lymphatic System: Structure

and Function

Lymphatics are a blind-ended organ system of interconnected vessels, lymph nodes and lymphatic tissues that transport 2–4 L per day of a clear fuid called lymph from peripheral tissues toward the heart [4] (Fig. 21.1). They play an essential role in the circulatory system by returning extravasated cells, plasma, macromolecules, and interstitial components to the bloodstream. Chylomicrons are triglyceride rich lipoprotein particles that are generated in the endoplasmic reticulum of enterocytes and secreted into gut lacteals where they enter the lymphatic stream to become chyle. They ultimately fow into the venous circulation to transport lipid to adipose tissue and skeletal and cardiac muscle. As an integral component of the immune system, the lymphatics are responsible for transporting antigen-

loaded dendritic cells and memory/effector T cells to draining lymph nodes, providing a platform for initiation of adaptive immune responses. Lymphatic capillaries are present in all tissues, with the exception of the bone marrow and cartilage. Lymphatic networks were recently discovered in the brain [5], an organ that was thought to be devoid of these structures.

Below the diaphragm, the lymphatic system consists of three major components: the soft tissue lymphatic system, the intestinal lymphatic system, and the hepatic lymphatic system (Fig. 21.1) [4]. These organ systems drain into cisterna chyli and ultimately into the thoracic duct (TD) which courses through the thorax and inserts into the left innominate vein at the junction with the internal jugular vein. The pulmonary lymphatic system primarily drains into the thoracic duct. A smaller lymphatic network comprises the right upper lobe, right head and neck, and right

Thoracic duct flow 2-4 liters per day

1.4L

1.4L

.7L

Fig. 21.1  Lymphatic fuid courses through the soft tissue, hepatic and intestinal lymphatic networks, and converges on the cisterna chyli in the abdomen. The approximately daily volume of fuid generated from each source is shown. Chylomicrons generated in the lacteals of the gut impart a milky white appearance to the lymphatic fuid as it fows cephalad via the thoracic duct to the junction between the left innominate and left internal jugular vein [113]

arm drains into right thoracic duct, which inserts into the right subclavian vein [2, 4]. It is important to note that chyle is generated in the abdomen and can only enter the lung or pleural space through abnormal abdominal pulmonary lymphatic communications with the airways or pleural space, or via refux from the thoracic duct into the pulmonary lymphatic network when the pressure gradient for fow is reversed [6].

On microscopy, lymphatics capillaries are characterized by thin walled vessels with a mostly round/irregular lumen lined by a single layer of endothelium resting on a discontinuous basement membrane [7]. Smooth muscle cells or pericytes may be absent or only partially surround the vessel [4, 8] (Fig. 21.2). These lymphatics drain into pre-collecting vessels and then into contractile collecting vessels with a continuous muscular layer made up of intima, media, and adventitia layers that propel lymph forward, augmented by skeletal muscle contraction and arterial pulsations, with one-­way valves to prevent backfow. Afferent collecting vessels deliver soluble and antigen presenting cell-associated antigens to lymph nodes, and efferent vessels directly processed lymph to the venous system via the thoracic duct or the right lymphatic duct.

The pulmonary lymphatics transport cells and fluids from the peripheral lung to the venous system via central lymphatic conduits, to regulate tissue pressure, keep the alveolus dry for optimal gas exchange, and to facilitate regional immune responses (Fig. 21.3a) [8, 9]. There are two major lymphatic networks in the lung; the subpleural superficial plexus located within the connective tissues of the visceral pleura and the deep peribronchovascular

Fig. 21.2  (a) Lymphatic capillary showing single layer of lymphatic endothelial cells allowing access for cells (blue dumbbell-shaped structure and small molecules (green dots)). (b) Central lymphatic vessel

composed of lymphatic endothelial cells surrounded by smooth muscle cells (orange cells)

plexus comprised of interand of intra-lobular lymphatics located in the connective tissues lining vascular structures and airways. The subpleural lymphatics are most abundant in the lower lobes and join with the lymphatics of the deep plexus near the hilum, or more rarely drain directly into the mediastinum. The more distal, smaller lymphatics associated with arterioles are involved in absorption and propulsion of lymph with the help of arterial, respiratory, and cardiac movements, with the peribronchovascular plexus providing most of the drainage (Fig. 21.3b).

Lymphatic Development

A comprehensive discussion of lymphatic development is beyond the scope of this review, but a basic awareness of the process of lymphangiogenesis provides a platform for understanding adult lymphatic disorders, including biomarkers and molecular targets. Florence Sabin is credited with recognizing that the lymphatic system arises from the cardinal vein [10]. Endothelial cells differentiate from angioblasts, and undergo arterial or venous speci cation [11–13]. Embryonic venous endothelial cells express high levels of VEGFR3, LYVE-1 (in a lateralizing subpopula-

tion), and SOX18, which in turn upregulates PROX-1, therst step in lymphatic endothelial cell speci cation. As VEGFR3 expression is diminishing in blood vessels, neuropilin 1 expression is induced in LECs making them more responsive to VEGF-C signals arising from the lateral mesenchyme, which promotes sprouting of lymphatic sacs from central veins. LECs express podoplanin (D2–40), which through Clec-2 promotes platelet aggregation to form a barrier between the vein and the budding lymphatic sac, separating the blood and lymphatic vascular systems. Further maturation of the differentiating lymphatic collecting vessels follows, including the formation of intraluminal valves, recruitment of smooth muscle, and assembly of a basement membrane.

Clinical Presentation of Lymphatic Disorders

Patients with pulmonary lymphatic disorders may develop chylous complications, including chyloptysis, chylous pulmonary congestion or lymph collections in the pleural space or pericardium [2, 6]. Chyloptysis presents with expectoration of milky white material and can occur when chylous lymphatic fuid gains access to airways by direct communication through abnormal or stulous tracks, rup-

Fig. 21.3  The pulmonary lymphatics transport cells and fuids from the periphery of the lung via central lymphatic conduits to the venous system, to regulate tissue pressure, facilitate regional immune responses, and to provide a mechanism for antigens and infectious pathogens to

interact with immune cells within lymph nodes. Flow is propelled forward by arterial pulsations and respiratory motion, and backfow is prevented by one way valves. (Used with permission from [112])

ture of airway lymphatics, or fooding of alveoli with lymphatic fuid due to refux of chyle via retrograde fow through pulmonary lymphatics in a condition known as chylous pulmonary congestion (CPC) or lymphatic pulmonary edema [14]. CPC not only was originally described in lymphangioleiomyomatosis (LAM) but also occurs in other lymphatic disorders (Fig. 21.4). In the case of LAM, CPC is usually accompanied by thickened alveolar septa and often by chylous pleural effusion and tends to respond to sirolimus treatment [15]. Occasionally, chylous material that lls the airway can solidify and be expectorated as branching multi-antennary structures that represent molds of the bronchial tree (Fig. 21.5) [6, 16]. This condition, known as plastic bronchitis, has also been described in nonlymphatic disorders, including Mycobacteria infections, allergic bronchopulmonary disorders, and post-Fontan repair [17]. Chylopericardium is a rare manifestation of thoracic lymphatic disorders [18]. In addition to the CLAs, chylous pleural effusions can occur in patients with LAM, lymphoma, other neoplasms, or infectious diseases that obstruct or violate the thoracic duct [19]. The hallmarks of chylous pleural effusions are a milky white appearance with lymphocyte predominance and excess triglycerides on laboratory evaluation.

Pulmonary lymphatic disorders, such as GLA, may present with malformed lymphatic channels within the pleura, bronchovascular bundles, and interstitium (Fig. 21.6). Similarly, the bronchiectasis that occurs in patients with Yellow Nail Syndrome may be a consequence of lymphatic dysregulation (Fig. 21.7). Finally, in the CLAs, solid or cystic lymphangiomas can occur in the chest or abdomen (Fig. 21.8), as well as hepatic, splenic, or bony involvement.

Fig. 21.4  (a) chylous pulmonary congestion associated with interlobular septa thickening, patchy consolidation, and pleural effusion on a background of cystic parenchymal lung disease due to LAM. (b) Near complete resolution after treatment with sirolimus. (Used with permission from [15])