Thoracic Lymphangiomas, Lymphangiectasis, Lymphangiomatosis, and Lymphatic Dysplasia Syndrome
American Journal of Respiratory and Critical Care Medicine
Introduction
Classification
Lymphangiomas
Pulmonary Lymphangiectasis
Lymphangiomatosis
Lymphatic Dysplasia Syndrome
Other Thoracic Lymphatic Disorders
Lymphatic Embryogenesis
Lymphangiomas
Pulmonary Lymphangiectasis
Lymphangiomatosis
Lymphatic Dysplasia Syndrome
Pathology
Clinical Features
Lymphangiomas
Pulmonary Lymphangiectasis
Lymphangiomatosis
Lymphatic Dysplasia Syndrome
Diagnosis
Lymphangiomas
Pulmonary Lymphangiectasis
Lymphangiomatosis
Lymphatic Dysplasia Syndrome
Treatment
Lymphangiomas
Pulmonary Lymphangiectasis
Lymphangiomatosis
Lymphatic Dysplasia Syndrome
Conclusion
Introduction
The lymphatic system plays an important role in human circulation and organ perfusion homeostasis (1). Disorders of the pulmonary lymphatic system occur in a variety of clinical settings (ranging from trauma to cancer) and may lead to serious pulmonary disease (Figure 1A). In addition, congenital errors of lymphatic development can lead to primary pulmonary lymphatic disorders (lymphangiomas, lymphangiectasis, lymphangiomatosis, and lymphatic dysplasia syndrome) (2). Because of their scarcity, these latter conditions are often misdiagnosed (Figure 1B) and their management is difficult. Research on thoracic lymphatic disorders has been hampered by a confusing and inconsistent use of terminology. Their origins and pathogenesis are currently unknown. Future advances in our understanding of vasculogenesis may provide clues about the relation between abnormal embryogenesis and the development of lymphatic disease.
Classification
The classification of pulmonary lymphatic disorders is challenging (6). The literature uses inconsistent terminology and describes only case reports and a handful of small case series (6). Several investigators have proposed classification systems for lymphatic disorders based on pathology or presumed pathophysiologic mechanisms (2). We believe that the classification of thoracic lymphatic disorders should be based on clinical presentation and pathologic features, rather than on their assumed pathophysiology (Table 1). In this report, we employ a modification of Hilliard's classification (6). The identification of characteristic features should allow patients to be placed into one of the categories listed in Table 1.
Lymphangiomas
Lymphangiomas are focal proliferations of well differentiated lymphatic tissue that present as multicystic or spongelike accumulations (Figure 1C) (11, 12). They are subdivided into three pathologic categories (11, 12): lymphangioma simplex (capillary lymphangioma) describes thin-walled lymphatic channels that occur as small, well circumscribed cutaneous lesions; cavernous lymphangiomas are microscopic thin-walled lymphatic channels with associated stroma; and cystic lymphangiomas (cystic hygromas) are large, well-circumscribed, multiloculated cystic spaces lined by endothelium that contain a significant connective tissue component. Cavernous and cystic lymphangiomas can coexist within the same lesion (12).
Pulmonary Lymphangiectasis
Lymphangiectasis describes pathologic dilation of lymphatics (Figures 1E, 1F, 1G, and 1H) (13, 14). Primary (congenital) and secondary forms have been described. The primary form presents in neonates and is usually fatal. Secondary forms of lymphangiectasis result from a variety of processes that impair lymph drainage and increase lymph production. We propose that primary and secondary lymphangiectasis are distinguishable by their age of presentation and their clinical courses.
Lymphangiomatosis
Lymphangiomatosis describes the presence of multiple lymphangiomas (15). It is frequently associated with other lymphatic related abnormalities and usually (in 75% of cases) involves multiple organs. Diffuse pulmonary lymphangiomatosis (Figures 1A and 1B) (10) has been reported in the literature as pulmonary lymphangiectasis (2, 3, 13), generalized lymphangiectasis (14), intrathoracic lymphangiomatosis (15), thoracic lymphangiomatosis (16), and diffuse pulmonary angiomatosis (17).
Lymphatic Dysplasia Syndrome
The term "lymphatic dysplasia syndrome" includes primary (idiopathic) lymphedema syndromes, congenital chylothorax (18), idiopathic effusions (often chylous), and the yellow nail syndrome (19). The yellow nail syndrome describes a triad of idiopathic pleural effusions, lymphedema, and dystrophic nails. The lymphatic dysplasia syndrome encompasses effusions of the pericardium, pleura, peritoneum, and lymphedema (19), without an identifiable cause, such as cancer or injury (20), and in the absence of lymphangiomas, lymphangiectasis, or lymphangiomatosis. Primary lymphedema has been subdivided into categories based upon the age of presentation (19): lymphedema congenita (neonates), lymphedema precox (<> 35 yr) (19).
Other Thoracic Lymphatic Disorders
Lymphedema can arise due to disruption of the normal lymphatic circulation by trauma, infection, surgery, radiation, or cancer (e.g., lymphoma, lymphangitis carcinomatosis) (19). Acquired progressive lymphangiomas, sometimes referred to as angioendothelioma (lymphatic type), are localized cutaneous macular or papular lesions that appear brown or violaceous. They can occur on the chest after local trauma and have a benign natural history (33, 34).
Lymphangioleiomyomatosis (LAM) is a disease of premenopausal women characterized by proliferation of abnormal smooth muscle cells and cyst formation in lung parenchyma. LAM can involve mediastinal and retroperitoneal lymphatics and lymph nodes (35). Pneumothoraces and chylous effusions are common and patients typically develop end-stage restrictive ventilatory defects. Lymphangiosarcoma is a vascular malignancy that develops in areas of chronic lymphedema (12, 38). It most commonly presents as a large arm mass in a woman many years after a radical mastectomy (Stewart-Treves syndrome) (12, 38). The histology is indistinguishable from angiosarcoma and poorly differentiated lesions that share the features of both lymphatics and blood vessels have been termed hemangiolymphangiomas or hamartomatous heme-lymphangiomatosis (42).
Lymphatic Embryogensis
Lymphangiomas, lymphangiectasis, lymphangiomatosis, and lymphatic dysplasia syndrome are thought to result from congenital errors of lymphatic development (4, 18). The lymphatic vascular system develops during the sixth week of life as an outgrowth of the venous system or as a de novo differentiation within mesenchymal tissues (1, 49). Primordial lymphatic tissues join one another to form lymphatic channels and six lymph sacs. Paired juguloaxillary lymph sacs, paired inguinal lymph sacs, a retroperitoneal lymph sac, and a single cisterna chyli sprout endothelial buds that grow with the venous system to form the peripheral lymphatic plexus. Before the twentieth week of fetal development, the pulmonary lymphatic channels and surrounding mesenchymal tissues are prominent and individual pulmonary lobules can be delineated. After the twentieth week, the alveolar tissues grow and the lymphatic and connective tissue elements start to regress (50, 51).
Lymphangiomas
Lymphangiomas probably represent embryologic remnants of lymphatic tissues that either failed to connect to efferent channels or arose from portions of lymph sacs that were sequestered during development (50, 51). Most lymphangiomas are discovered in fetuses, neonates, or young children, at the sites of the primordial lymph sacs. Acquired or secondary lymphangiomas develop in areas of chronic lymphatic obstruction related to surgery, chronic infection, or radiation (52). There is a propensity for lymphangiomas to recur at sites of surgical resection, because of their autonomous growth (55, 56) and also by their reaccumulation of lymph fluid (12).
Lymphangiectasis
Congenital lymphangiectasis probably results from a failure of pulmonary interstitial connective tissues to regress (this normally occurs in the fifth month of fetal life) leading to dilation of pulmonary lymphatic capillaries (Figures 1F, 1G, and 1H) (51). Secondary lymphangiectasis can occur if surgery, radiation, infection, tumor, or trauma disturbs effective lymphatic drainage. Children with congenital heart diseases (for example, total anomalous pulmonary venous return or hypoplastic left heart syndromes) and adults with severe mitral valve disease have increased lymphatic circulation that contributes to the lymphatic dilatation (2, 3, 57) and the severity of lymphangiectasis.
Lymphangiomatosis
Lymphangiomatosis also appears to be due to a lymphatic developmental abnormality (4), but presents at a later age than solitary lymphangiomas either because of an influence of hormonal factors or because a more subtle, albeit more widespread, defect requires a longer period for growth.
Lymphatic Dysplasia Syndrome
The lymphatic dysplasia syndrome includes a diverse group of disorders with variable prognosis (58). In primary lymphedema, for example, at least four separate distinct patterns are found on lymphangiography. The majority of patients have hypoplastic or aplastic peripheral lymphatics; one-third have obstructed proximal lymphatics; a few have hyperplastic peripheral lymphatics; and some have incompetent lymphatic valves that develop into megalolymphatics (19, 58, 59).
Abnormalities of lymphatic development are associated with a variety of inheritance patterns (18), including congenital anomaly syndromes (achondrogenesis Type 1), and aneuploidy syndromes (Turner syndrome). Familial Milroy lymphedema is inherited in an autosomal dominant pattern, with variable penetrance, whereas congenital chylothorax appears to be inherited in an autosomal recessive pattern (18). Therefore, several factors, some of them genetic, probably lead to the development of a broad range of diseases of the lymphatic system (9).
In neonates, most chylous effusions are congenital. In older children and adults they result from malignancy, infection, or trauma (8). Primary chylous effusion formation is attributable to reflux of chyle from the thoracic duct, or cisterna chyli, through incompetent lymphatic channels (7, 8, 23, 60). The yellow nail syndrome is thought to be due to impaired lymphatic drainage, based on abnormal lymphangiography studies and delayed albumin turnover in the pleural space (63). Moreover, the nail changes, lymphedema, and pleural effusions can be reversible (69).
Pathology
Lymphangiomas
The first detailed description of a lymphangioma is attributed to Redenbacker in 1828 (70). Wernher first used the term cystic hygroma in 1843 (71). Capillary lymphangiomas appear as wartlike or vesicular lesions that are unrelated to internal lymphangiomas (53, 54). Cavernous lymphangiomas have indiscrete margins and insinuate themselves into the surrounding structures. Cystic lymphangiomas, in contrast, are multiloculated fluctuant growths often enveloped in a fibrous capsule (72, 73). Individual cysts contain serous fluid and vary in size from 2-3 millimeters to several centimeters.
Histologically, (Figure 1D) lymphangiomas are composed of an increased number of dilated lymphatic channels, lined by endothelium (12, 74). The cystic spaces are filled with proteinaceous lymph fluid (without erythrocytes). Surgical trauma or damage caused by tissue handling during processing can result in hemorrhage that can make the diagnosis of lymphangioma difficult to differentiate from hemangioma or Kaposi's sarcoma. Cavernous lymphangiomas have inconspicuous amounts of loose connective tissue compared with cystic lesions, which can have thick adventitial coats. The connective tissue stroma consists of varying amounts of spindle-shaped smooth muscle cells, collagen bundles, fibroblasts, and lymphocytes (12, 75, 76). The presence of benign lymphoid aggregates is helpful in the identification of lymphangiomas. The cellular components are generally well-differentiated and lack cytologic atypia.
Lymphangiectasis
Virchow first reported the primary (congenital) form of lymphangiectasis (a rare disease of neonates) in 1856 (77). In pulmonary lymphangiectasis, the lungs appear heavy and noncompliant (Figure 1F). The visceral pleura has a network of dilated lymphatics that weep lymph fluid when sectioned. In some cases, simple cystic spaces can be macroscopically identified along the anatomic lymphatic routes. The interlobular septa are widened and prominent. The lymphatic spaces are dilated and, in some instances, cystic. A small amount of collagen and smooth muscle may be found in the walls of the vessels, particularly in the secondary form of pulmonary lymphangiectasis (10). Lymphangiectasis should be morphologically distinguished from interstitial emphysema (78, 79).
Lymphangiomatosis
The histology of lymphangiomatosis can pathologically resemble a lymphangioma (12, 74, 80). Lymphangiomatosis can appear to infiltrate tissues, raising concern for a more aggressive lesion, but histopathology demonstrates that they are always comprised of mature cells (Figure 1D) (80).
Diffuse pulmonary lymphangiomatosis involves both lungs and, by definition, is without extrathoracic lymphatic abnormalities. Pathologic features (10) include a proliferation of complex anastamosing lymphatic channels that markedly expand the typical lymphatic routes within the lungs and mediastinum. Compared with primary pulmonary lymphangiectasis, there is a prominence of collagen and spindle-shaped cells surrounding the endothelial-lined channels. The adjacent lung parenchyma may contain collections of hemosiderin-laden macrophages but in contrast to lymphangioleiomyomatosis, the lung parenchyma is preserved (35, 36). Pleural effusions are common. The containment of diffuse pulmonary lymphangiomatosis to normal lymphatic pathways within the lung, and the small proportion and more mature appearance and alignment of smooth muscle cells, help to distinguish this from lymphangioleiomyomatosis (10).
Lymphatic Dysplasia Syndrome
In primary lymphedema, prominent fibrous septations may develop in subcutaneous adipose tissue. Histology reveals epidermal atrophy, dermal fibrosis, perivascular inflammation, and dilated lymphatics. Enlarged regional lymph nodes and sinusoidal fibrosis are found in some cases of primary lymphedema (76). In 1964 Samman and White coined the term "yellow nail syndrome" to describe 13 patients with idiopathic lymphedema and yellow, dystrophic, fingernails (63). Later, Emerson added the presence of idiopathic pleural effusions to complete the triad of clinical features by which the syndrome is recognized today (81, 82). In the yellow nail syndrome, nail matrix biopsies may reveal dense stromal fibrosis with numerous ectatic endothelial-lined vessels (83). Pleural biopsies have demonstrated features of lymphocytic pleuritis associated with moderate fibrosis and dilated lymphatics (84, 85).
Clinical Features
Lymphangiomas
Although the majority of lymphangiomas present in the first 2 yr of life (4), there has recently been an increased recognition of lymphangiomas in adults (86, 87). Over 40% of 151 lymphangiomas seen in consultation by the Armed Forces Institute of Pathology between 1980 and 1989 were from patients older than 16 yr of age (mean 19 yr) (86). The manifestations of thoracic lymphangiomas are believed to present after a period of latency because of their slow growth. Most appear as a swelling in the head, neck, or axilla and approximately 10% extend into the mediastinum (12, 73, 88, 89). Approximately 1% of all lymphangiomas are confined to the chest (73). Mediastinal lymphangiomas are equally distributed between the anterior, middle, and posterior compartments (73). Intrapulmonary lymphangiomas are rare: approximately a dozen cases, with patient ages ranging from 6 mo to 54 yr, are described in the literature (88, 90).
Thoracic lymphangiomas may remain asymptomatic for many years and only become apparent when patients develop problems related to compression of vital structures. Alternatively, they present as incidental findings on roentgenograms (73, 89, 92, 93, 98, 99). A thoracic lymphangioma can appear as a multicystic mass, or as a more amorphous configuration that insinuates itself into mediastinal structures. Patients can complain of cough and dyspnea (from extrinsic compression of airways), stridor, hemoptysis, Horner's syndrome, dysphagia, superior vena cava syndrome, constrictive pericarditis, phrenic nerve palsy, or of symptoms related to a secondarily infected lymphangioma (91, 100).
Lymphangiectasis
Primary pulmonary lymphangiectasis is often fatal in early life, and cases are frequently stillborn (103). Secondary pulmonary lymphangiectasis can present with respiratory distress at any age (57, 90, 104, 105). Cases associated with pulmonary venous obstruction or other congenital heart defects, usually present in early childhood. In addition, a number of congenital and genetic diseases have been associated with pulmonary lymphangiectasis, including Noonan, Ullrich-Turner, Ehlers-Danlos, and Down syndromes (2, 57, 106).
Lymphangiomatosis
Lymphangiomatosis has been described in patients ranging from birth up to 80 yr (86, 109). It most frequently presents in late childhood. There is no clear sex predilection (72, 86). The lesions of lymphangiomatosis can occur in any tissue in which lymphatics are normally found, but there appears to be a predilection for thoracic and neck involvement (76). Up to 75% of patients with lymphangiomatosis have bony involvement (17, 55, 74, 80, 110). Single or multiple lymphangiomas may be found within the mediastinum, adherent to the pleura, or within the chest wall (10, 17, 72, 74, 80, 113, 125). Mediastinal fat may be diffusely infiltrated with anastamosing, dilated lymphatics (14, 128). Chylous effusions are common. Associated chyloptysis (108), hemoptysis (18, 126, 129), chylopericardium (8, 10, 13, 17, 112, 130), chylous ascites (8, 132), protein wasting enteropathy (134, 136), peripheral lymphedema (9, 129, 134), hemihypertrophy (105), lymphopenia (140), and disseminated intravascular coagulopathy (141) have been described. Interestingly, many patients with lymphangiomatosis experience wheeze and may be misdiagnosed with asthma prior to the recognition of the lymphatic disorder (10, 57).
Lymphatic Dysplasia Syndrome
The incidence of primary lymphedema is estimated at 0.1 per 100,000 persons under the age of 20 yr (females more than males). When the cause is related to agenesis or hypoplasia of distal lymphatics, the extremity swelling is usually bilateral. The swelling is unilateral and more severe if proximal lymphatics or nodes are obstructed (19, 58). Early in lymphedema, soft "pitting" edema is indistinguishable from vascular forms of edema. Later, chronic lymphedema can cause the skin to become thickened and brawny, with accentuated pitting of hair follicles ("peau d'orange"). Primary lymphedema has been associated with several congenital disorders including Noonan's and Turner's syndromes.
Primary chylothorax constitutes approximately one-sixth of all chylothoraces (23). Among newborns, chylothorax is the most common type of pleural effusion and in this age group males outnumber females (8). Patients with chylothorax usually present with a history of the insidious onset of dyspnea (a result of the space occupying effect of the pleural fluid). Fever, pleuritic chest pain, and chyloptysis are rare (142). Congenital chylothorax has a variable prognosis, dependent on gestational age at birth, the presence of other congenital abnormalities, and the severity of pulmonary hypoplasia.
Primary pericardial lymphedema has been reported in approximately 80 patients (ranging in age from 1 d to 77 yr) (60, 61, 143). Many cases are asymptomatic and present with an abnormal chest roentgenogram. One-third have dyspnea, approximately 10% have cough, and, rarely, cases may present with palpitations and chest pain (60). Of all the primary lymphatic disorders discussed in this review, the yellow nail syndrome is the most likely to present in adulthood. The male to female ratio is 1:1.5, the median age at presentation is 40 to 50 yr [range, birth to 80 yr (64, 69, 84)]. The complete triad of yellow nails (89%), lymphedema (80%), and idiopathic pleural effusions (36%) is seen in a minority of patients (20%) (64, 150). Any case with two of the three findings (yellow nails, pleural effusion, lymphedema) is accepted as having clinical evidence of yellow nail syndrome (64, 84, 151, 152). The nail abnormalities include shades of yellow-green-brown discoloration, longitudinal ridges, onycholysis, slow growth.
Diagnosis
Lymphangiomas
Thoracic lymphangiomas are usually detected as nodules or cystic masses on chest radiographs. Mediastinal lymphangiomas commonly envelop great vessels and displace mediastinal organs (89, 93). Plain radiographs, barium meal, ultrasound, computer tomographic (CT) scanning, and magnetic resonance imaging (MRI) have proven useful in determining the number and extent of lesions (155). Accurate anatomic localization plays an important role in the management of lymphangioma, because the diagnosis is ultimately made postoperatively (after the histopathologic examination of resected tissue). Three-dimensional ultrasonography may reveal cystic masses with thin septations, consistent with lymphangioma (158). MRI is probably the diagnostic modality of choice for lymphangiomas, because it accurately predicts subsequent intraoperative findings, and it helps to demonstrate lymphatic architecture at different tissue levels (159).
Lymphangiectasis
Primary pulmonary lymphangiectasis presents soon after birth and is commonly fatal in early life (Figure 1E). The dilated lymphatics, in association with chylothoraces, lead to life-threatening pulmonary hypoplasia and respiratory failure. Secondary lymphangiectasis presents as localized or diffuse pulmonary interstitial infiltrates, or cystic lesions, on chest radiography and MRI (see Figure 1E) (162). Lymphangiography demonstrates abnormally dilated lymphatics with obstructive changes and collateral channels in the retroperitoneal, mediastinal, and cervical lymphatic systems (156). The presence of pulmonary lymphangiectasis may be confirmed by lung biopsy (10).
Lymphangiomatosis
Congenital lymphangiomatosis is a rare disorder that is often fatal. In lymphangiomatosis, multiple lymphangiomas occur most commonly in lung and bone. The coexistence of lytic bone lesions and chylothorax serves as an important diagnostic clue. The diagnosis is sometimes made by bone biopsy that shows that these lytic lesions are lymphangiomas containing lymph fluid (10, 165). Lymphangiography reveals multiple lesions of the thoracic duct, dilated lymphatic channels, and lymphangiomas throughout the bones and lungs (156).
Bilateral interstitial infiltrates and pericardial or pleural effusions are evident on chest radiograph (14, 18). Pulmonary function testing may reveal a mixed obstructive and restrictive pattern (10). CT scans of the thorax reveal diffuse smooth thickening of interlobular septa and bronchovascular bundles with extensive involvement of mediastinal fat and perihilar regions. Lymphangiography is useful to exclude the presence of a mediastinal tumor, but is rarely required for the diagnosis of chylothorax or lymphangioma in infants and children. Obstruction of the thoracic duct is a rare cause of chylothorax in children (23). The radiologic findings and the clinical course of lymphangiomatosis may mimic that of lymphangioleiomyomatosis (35, 36, 166). Histopathology demonstrates anastomosing endothelial lined spaces along pulmonary lymphatic routes accompanied by asymmetrically spaced bundles of spindle cells. Factor VIII related antigen and CD31 are endothelial markers that are useful in immunohistochemical staining of these channels (167).
Lymphatic Dysplasia Syndrome
The clinical diagnosis of the yellow nail syndrome is based on the presence of two of the following features: yellow or dystrophic nails, chylous effusions, and lymphedema (66, 82). Chylous effusions have a protein content greater than 30 g/L; fat content greater than 10 g/L (with elevated concentrations of chylomicrons and triglycerides), and a specific gravity greater than 1.012, in the absence of microorganisms (23). Lymphangiography and lymphoscintigraphy allow an anatomic and functional assessment of lymphatic transport, and a depiction of regional lymph nodes (67, 161, 162, 168
Treatment
Lymphangiomas
In contrast to hemangiomas, which usually resolve spontaneously, congenital lymphangiomas typically require excision (165). Hemangiomas and lymphangiomas may coexist in the same patient. Important differential diagnoses of lymphangioma include acute suppurative lymphadenitis, which is common and easily diagnosed; and chronic lymphadenitis, which should be biopsied to exclude malignancy (163). Surgical resection, or sclerotherapy, of lymphangiomas are the therapies of choice (161, 165). Surgery is frequently mandated both to confirm the diagnosis, and to prevent complications that arise from compressive effects on vital structures (101, 102). Complete surgical resection may prove technically difficult, because lymphangiomas may surround large blood vessels, airways, and mediastinal organs (73, 89, 93). Incomplete resection, or sclerosis, can result in recurrence of the lymphangioma and a return of symptoms. Before surgical exploration and excision, it is prudent to investigate for other lymphangiomatous lesions and associated congenital anomalies (50, 105).
Lymphangiectasis
Thoracic lymphangiectasis usually leads to respiratory failure (106, 107, 109). Conservative treatment includes a low-fat, high-protein diet, with medium chain triglyceride (MCTG) and vitamin supplementation, in addition to repeated aspirations of the lymph accumulations (108). A low fat intake is thought to reduce the flow of lymph and the size of the lymphatic channels. Heart and lung transplantation has been attempted with poor results (169) (J. Theodore, personal communication).
Lymphangiomatosis
The natural history of pulmonary lymphangiomatosis is characterized by progressive growth and compression of adjacent structures (10, 161). Therapy should aim to decrease the symptoms that arise from compressive effects, to control chylous fluid accumulations, and to maintain optimal cosmesis (161). The success of surgical resection is impaired by an inability to separate lymph collections from normal structures, leading to high rates of recurrence (118, 124). Anatomically complicated lesions may be impossible to completely excise without damage to adjacent structures. In patients with widespread disease, therefore, therapeutic options are palliative. Percutaneous sclerotherapy with doxycycline has been employed with good results (161). CT and magnetic resonance (MR) not only help to define the size and location of lesions, but may also serve to guide sclerosis and monitor follow-up. Lymphoscintigraphy helps to guide therapy, by helping to delineate the direction of lymphatic flow and the relation between normal and abnormal lymphatics (168).
Lymphatic Dysplasia Syndrome
The treatment of chylothorax in infancy and childhood has become standardized (23). After the initial thoracentesis, one or two more therapeutic taps should be performed to eliminate the effusion. In addition, a high-protein, MCTG diet with fat-soluble vitamin supplements should lessen the flow of chyle from the intestinal tract (133). If the chylothorax remains after 2 wk, a chest drain with slight negative pressure should be inserted, and total parenteral nutrition instituted. Antenatal drainage of large congenital chylothoraces helps neonatal survival and perinatal resuscitation.
In addition to the management of chylothorax (as discussed previously), some patients with lymphatic dysplasia syndrome are treated with antibiotics for recurring pulmonary infections (150). Impaired lymphatic drainage is associated with immunoglobulin deficiencies. Patients with lymphatic dysplasia syndrome suffer recurrent infections, in part because of an IgG2 deficiency, but also because of the associated bronchiectasis and rhinosinusitis. Intravenous immunoglobulin and albumin therapies have been used in selected patients with marked IgG deficiency (151). Conservative management of lymphatic dysplasia syndrome includes high-protein, MCTG diet and vitamin supplementation, reduced oral nutrition, and repeated aspirations of fluid collections or pleurodesis (167).
Most patients with primary lymphedema are managed conservatively, by means of various forms of compression therapy, including massage, physical therapy, intermittent pneumatic compression pumps, and compressive garments (25, 26, 29, 170). Volume-reducing surgery and lymphatic microsurgery have been reported to provide favorable outcomes. The mainstay of treatment, however, is the reduction of edema by regular elevation, massage, and external compression with elastic stockings (25, 30, 170). Gross edema may be reduced surgically by simple excision (Homans' operation) or complete excision and skin grafting (Charles' operation) (170). Combined medical, surgical, and physiotherapeutic approaches benefit patients with marked lymphedema (25, 170).
Conclusion
Diseases of the thoracic lymphatic circulation should be differentiated on the basis of their pathologic and clinical features (6, 9, 10). The characteristic features of lymphangiomas, pulmonary lymphangiectasis, lymphangiomatosis, and lymphatic dysplasia syndrome are summarized in Table 2. Characteristic clinical features and radiographic appearances, the analysis of chylothorax fluid, and the presence of features of extrathoracic lymphatic dysfunction should prompt a differential diagnosis of disordered thoracic lymphatic function (6). Many of these disorders are diagnosed in childhood. In adulthood they are probably under-recognized (14, 86, 87). Their pathogenesis is unknown, but appears to be related, in part, to congenital malformations of the thoracic lymphatic system (10, 17, 50). Surgical excision of localized lesions (100, 165) and CT-guided sclerotherapy of large and numerous lymphangiomas are useful management strategies (161). Sclerotherapy provides relief of lymphedema, lymphorrhea, and a decrease in size of lymph accumulations. Sclerotherapy is acutely painful, and requires careful analgesic management with intravenous narcotics, benzodiazepines, and/or intracavitary lidocaine (161). Dietary modifications reduce the flow of lymph in subjects with widespread lymphatic dysfunction (133). Standardized therapy for chylothorax and lymphedema can lead to improved patient functionality (23, 25, 170). There is a need for a greater awareness of disorders of the thoracic lymphatic circulation, because accurate and early diagnosis may prompt more effective management strategies.
Article with Tables, Footnotes and References
JOHN L. FAUL, GERALD J. BERRY, THOMAS V. COLBY, STEPHEN J. RUOSS, MATTHEW B. WALTER, GLENN D. ROSEN, and THOMAS A. RAFFIN
Division of Pulmonary and Critical Care Medicine and the Department of Pathology, Stanford University School of Medicine, Stanford, California; and the Department of Pathology, Mayo Clinic, Scottsdale, Arizona
Contents:Introduction
Classification
Lymphangiomas
Pulmonary Lymphangiectasis
Lymphangiomatosis
Lymphatic Dysplasia Syndrome
Other Thoracic Lymphatic Disorders
Lymphatic Embryogenesis
Lymphangiomas
Pulmonary Lymphangiectasis
Lymphangiomatosis
Lymphatic Dysplasia Syndrome
Pathology
Clinical Features
Lymphangiomas
Pulmonary Lymphangiectasis
Lymphangiomatosis
Lymphatic Dysplasia Syndrome
Diagnosis
Lymphangiomas
Pulmonary Lymphangiectasis
Lymphangiomatosis
Lymphatic Dysplasia Syndrome
Treatment
Lymphangiomas
Pulmonary Lymphangiectasis
Lymphangiomatosis
Lymphatic Dysplasia Syndrome
Conclusion
Introduction
The lymphatic system plays an important role in human circulation and organ perfusion homeostasis (1). Disorders of the pulmonary lymphatic system occur in a variety of clinical settings (ranging from trauma to cancer) and may lead to serious pulmonary disease (Figure 1A). In addition, congenital errors of lymphatic development can lead to primary pulmonary lymphatic disorders (lymphangiomas, lymphangiectasis, lymphangiomatosis, and lymphatic dysplasia syndrome) (2). Because of their scarcity, these latter conditions are often misdiagnosed (Figure 1B) and their management is difficult. Research on thoracic lymphatic disorders has been hampered by a confusing and inconsistent use of terminology. Their origins and pathogenesis are currently unknown. Future advances in our understanding of vasculogenesis may provide clues about the relation between abnormal embryogenesis and the development of lymphatic disease.
Classification
The classification of pulmonary lymphatic disorders is challenging (6). The literature uses inconsistent terminology and describes only case reports and a handful of small case series (6). Several investigators have proposed classification systems for lymphatic disorders based on pathology or presumed pathophysiologic mechanisms (2). We believe that the classification of thoracic lymphatic disorders should be based on clinical presentation and pathologic features, rather than on their assumed pathophysiology (Table 1). In this report, we employ a modification of Hilliard's classification (6). The identification of characteristic features should allow patients to be placed into one of the categories listed in Table 1.
Lymphangiomas
Lymphangiomas are focal proliferations of well differentiated lymphatic tissue that present as multicystic or spongelike accumulations (Figure 1C) (11, 12). They are subdivided into three pathologic categories (11, 12): lymphangioma simplex (capillary lymphangioma) describes thin-walled lymphatic channels that occur as small, well circumscribed cutaneous lesions; cavernous lymphangiomas are microscopic thin-walled lymphatic channels with associated stroma; and cystic lymphangiomas (cystic hygromas) are large, well-circumscribed, multiloculated cystic spaces lined by endothelium that contain a significant connective tissue component. Cavernous and cystic lymphangiomas can coexist within the same lesion (12).
Pulmonary Lymphangiectasis
Lymphangiectasis describes pathologic dilation of lymphatics (Figures 1E, 1F, 1G, and 1H) (13, 14). Primary (congenital) and secondary forms have been described. The primary form presents in neonates and is usually fatal. Secondary forms of lymphangiectasis result from a variety of processes that impair lymph drainage and increase lymph production. We propose that primary and secondary lymphangiectasis are distinguishable by their age of presentation and their clinical courses.
Lymphangiomatosis
Lymphangiomatosis describes the presence of multiple lymphangiomas (15). It is frequently associated with other lymphatic related abnormalities and usually (in 75% of cases) involves multiple organs. Diffuse pulmonary lymphangiomatosis (Figures 1A and 1B) (10) has been reported in the literature as pulmonary lymphangiectasis (2, 3, 13), generalized lymphangiectasis (14), intrathoracic lymphangiomatosis (15), thoracic lymphangiomatosis (16), and diffuse pulmonary angiomatosis (17).
Lymphatic Dysplasia Syndrome
The term "lymphatic dysplasia syndrome" includes primary (idiopathic) lymphedema syndromes, congenital chylothorax (18), idiopathic effusions (often chylous), and the yellow nail syndrome (19). The yellow nail syndrome describes a triad of idiopathic pleural effusions, lymphedema, and dystrophic nails. The lymphatic dysplasia syndrome encompasses effusions of the pericardium, pleura, peritoneum, and lymphedema (19), without an identifiable cause, such as cancer or injury (20), and in the absence of lymphangiomas, lymphangiectasis, or lymphangiomatosis. Primary lymphedema has been subdivided into categories based upon the age of presentation (19): lymphedema congenita (neonates), lymphedema precox (<> 35 yr) (19).
Other Thoracic Lymphatic Disorders
Lymphedema can arise due to disruption of the normal lymphatic circulation by trauma, infection, surgery, radiation, or cancer (e.g., lymphoma, lymphangitis carcinomatosis) (19). Acquired progressive lymphangiomas, sometimes referred to as angioendothelioma (lymphatic type), are localized cutaneous macular or papular lesions that appear brown or violaceous. They can occur on the chest after local trauma and have a benign natural history (33, 34).
Lymphangioleiomyomatosis (LAM) is a disease of premenopausal women characterized by proliferation of abnormal smooth muscle cells and cyst formation in lung parenchyma. LAM can involve mediastinal and retroperitoneal lymphatics and lymph nodes (35). Pneumothoraces and chylous effusions are common and patients typically develop end-stage restrictive ventilatory defects. Lymphangiosarcoma is a vascular malignancy that develops in areas of chronic lymphedema (12, 38). It most commonly presents as a large arm mass in a woman many years after a radical mastectomy (Stewart-Treves syndrome) (12, 38). The histology is indistinguishable from angiosarcoma and poorly differentiated lesions that share the features of both lymphatics and blood vessels have been termed hemangiolymphangiomas or hamartomatous heme-lymphangiomatosis (42).
Lymphatic Embryogensis
Lymphangiomas, lymphangiectasis, lymphangiomatosis, and lymphatic dysplasia syndrome are thought to result from congenital errors of lymphatic development (4, 18). The lymphatic vascular system develops during the sixth week of life as an outgrowth of the venous system or as a de novo differentiation within mesenchymal tissues (1, 49). Primordial lymphatic tissues join one another to form lymphatic channels and six lymph sacs. Paired juguloaxillary lymph sacs, paired inguinal lymph sacs, a retroperitoneal lymph sac, and a single cisterna chyli sprout endothelial buds that grow with the venous system to form the peripheral lymphatic plexus. Before the twentieth week of fetal development, the pulmonary lymphatic channels and surrounding mesenchymal tissues are prominent and individual pulmonary lobules can be delineated. After the twentieth week, the alveolar tissues grow and the lymphatic and connective tissue elements start to regress (50, 51).
Lymphangiomas
Lymphangiomas probably represent embryologic remnants of lymphatic tissues that either failed to connect to efferent channels or arose from portions of lymph sacs that were sequestered during development (50, 51). Most lymphangiomas are discovered in fetuses, neonates, or young children, at the sites of the primordial lymph sacs. Acquired or secondary lymphangiomas develop in areas of chronic lymphatic obstruction related to surgery, chronic infection, or radiation (52). There is a propensity for lymphangiomas to recur at sites of surgical resection, because of their autonomous growth (55, 56) and also by their reaccumulation of lymph fluid (12).
Lymphangiectasis
Congenital lymphangiectasis probably results from a failure of pulmonary interstitial connective tissues to regress (this normally occurs in the fifth month of fetal life) leading to dilation of pulmonary lymphatic capillaries (Figures 1F, 1G, and 1H) (51). Secondary lymphangiectasis can occur if surgery, radiation, infection, tumor, or trauma disturbs effective lymphatic drainage. Children with congenital heart diseases (for example, total anomalous pulmonary venous return or hypoplastic left heart syndromes) and adults with severe mitral valve disease have increased lymphatic circulation that contributes to the lymphatic dilatation (2, 3, 57) and the severity of lymphangiectasis.
Lymphangiomatosis
Lymphangiomatosis also appears to be due to a lymphatic developmental abnormality (4), but presents at a later age than solitary lymphangiomas either because of an influence of hormonal factors or because a more subtle, albeit more widespread, defect requires a longer period for growth.
Lymphatic Dysplasia Syndrome
The lymphatic dysplasia syndrome includes a diverse group of disorders with variable prognosis (58). In primary lymphedema, for example, at least four separate distinct patterns are found on lymphangiography. The majority of patients have hypoplastic or aplastic peripheral lymphatics; one-third have obstructed proximal lymphatics; a few have hyperplastic peripheral lymphatics; and some have incompetent lymphatic valves that develop into megalolymphatics (19, 58, 59).
Abnormalities of lymphatic development are associated with a variety of inheritance patterns (18), including congenital anomaly syndromes (achondrogenesis Type 1), and aneuploidy syndromes (Turner syndrome). Familial Milroy lymphedema is inherited in an autosomal dominant pattern, with variable penetrance, whereas congenital chylothorax appears to be inherited in an autosomal recessive pattern (18). Therefore, several factors, some of them genetic, probably lead to the development of a broad range of diseases of the lymphatic system (9).
In neonates, most chylous effusions are congenital. In older children and adults they result from malignancy, infection, or trauma (8). Primary chylous effusion formation is attributable to reflux of chyle from the thoracic duct, or cisterna chyli, through incompetent lymphatic channels (7, 8, 23, 60). The yellow nail syndrome is thought to be due to impaired lymphatic drainage, based on abnormal lymphangiography studies and delayed albumin turnover in the pleural space (63). Moreover, the nail changes, lymphedema, and pleural effusions can be reversible (69).
Pathology
Lymphangiomas
The first detailed description of a lymphangioma is attributed to Redenbacker in 1828 (70). Wernher first used the term cystic hygroma in 1843 (71). Capillary lymphangiomas appear as wartlike or vesicular lesions that are unrelated to internal lymphangiomas (53, 54). Cavernous lymphangiomas have indiscrete margins and insinuate themselves into the surrounding structures. Cystic lymphangiomas, in contrast, are multiloculated fluctuant growths often enveloped in a fibrous capsule (72, 73). Individual cysts contain serous fluid and vary in size from 2-3 millimeters to several centimeters.
Histologically, (Figure 1D) lymphangiomas are composed of an increased number of dilated lymphatic channels, lined by endothelium (12, 74). The cystic spaces are filled with proteinaceous lymph fluid (without erythrocytes). Surgical trauma or damage caused by tissue handling during processing can result in hemorrhage that can make the diagnosis of lymphangioma difficult to differentiate from hemangioma or Kaposi's sarcoma. Cavernous lymphangiomas have inconspicuous amounts of loose connective tissue compared with cystic lesions, which can have thick adventitial coats. The connective tissue stroma consists of varying amounts of spindle-shaped smooth muscle cells, collagen bundles, fibroblasts, and lymphocytes (12, 75, 76). The presence of benign lymphoid aggregates is helpful in the identification of lymphangiomas. The cellular components are generally well-differentiated and lack cytologic atypia.
Lymphangiectasis
Virchow first reported the primary (congenital) form of lymphangiectasis (a rare disease of neonates) in 1856 (77). In pulmonary lymphangiectasis, the lungs appear heavy and noncompliant (Figure 1F). The visceral pleura has a network of dilated lymphatics that weep lymph fluid when sectioned. In some cases, simple cystic spaces can be macroscopically identified along the anatomic lymphatic routes. The interlobular septa are widened and prominent. The lymphatic spaces are dilated and, in some instances, cystic. A small amount of collagen and smooth muscle may be found in the walls of the vessels, particularly in the secondary form of pulmonary lymphangiectasis (10). Lymphangiectasis should be morphologically distinguished from interstitial emphysema (78, 79).
Lymphangiomatosis
The histology of lymphangiomatosis can pathologically resemble a lymphangioma (12, 74, 80). Lymphangiomatosis can appear to infiltrate tissues, raising concern for a more aggressive lesion, but histopathology demonstrates that they are always comprised of mature cells (Figure 1D) (80).
Diffuse pulmonary lymphangiomatosis involves both lungs and, by definition, is without extrathoracic lymphatic abnormalities. Pathologic features (10) include a proliferation of complex anastamosing lymphatic channels that markedly expand the typical lymphatic routes within the lungs and mediastinum. Compared with primary pulmonary lymphangiectasis, there is a prominence of collagen and spindle-shaped cells surrounding the endothelial-lined channels. The adjacent lung parenchyma may contain collections of hemosiderin-laden macrophages but in contrast to lymphangioleiomyomatosis, the lung parenchyma is preserved (35, 36). Pleural effusions are common. The containment of diffuse pulmonary lymphangiomatosis to normal lymphatic pathways within the lung, and the small proportion and more mature appearance and alignment of smooth muscle cells, help to distinguish this from lymphangioleiomyomatosis (10).
Lymphatic Dysplasia Syndrome
In primary lymphedema, prominent fibrous septations may develop in subcutaneous adipose tissue. Histology reveals epidermal atrophy, dermal fibrosis, perivascular inflammation, and dilated lymphatics. Enlarged regional lymph nodes and sinusoidal fibrosis are found in some cases of primary lymphedema (76). In 1964 Samman and White coined the term "yellow nail syndrome" to describe 13 patients with idiopathic lymphedema and yellow, dystrophic, fingernails (63). Later, Emerson added the presence of idiopathic pleural effusions to complete the triad of clinical features by which the syndrome is recognized today (81, 82). In the yellow nail syndrome, nail matrix biopsies may reveal dense stromal fibrosis with numerous ectatic endothelial-lined vessels (83). Pleural biopsies have demonstrated features of lymphocytic pleuritis associated with moderate fibrosis and dilated lymphatics (84, 85).
Clinical Features
Lymphangiomas
Although the majority of lymphangiomas present in the first 2 yr of life (4), there has recently been an increased recognition of lymphangiomas in adults (86, 87). Over 40% of 151 lymphangiomas seen in consultation by the Armed Forces Institute of Pathology between 1980 and 1989 were from patients older than 16 yr of age (mean 19 yr) (86). The manifestations of thoracic lymphangiomas are believed to present after a period of latency because of their slow growth. Most appear as a swelling in the head, neck, or axilla and approximately 10% extend into the mediastinum (12, 73, 88, 89). Approximately 1% of all lymphangiomas are confined to the chest (73). Mediastinal lymphangiomas are equally distributed between the anterior, middle, and posterior compartments (73). Intrapulmonary lymphangiomas are rare: approximately a dozen cases, with patient ages ranging from 6 mo to 54 yr, are described in the literature (88, 90).
Thoracic lymphangiomas may remain asymptomatic for many years and only become apparent when patients develop problems related to compression of vital structures. Alternatively, they present as incidental findings on roentgenograms (73, 89, 92, 93, 98, 99). A thoracic lymphangioma can appear as a multicystic mass, or as a more amorphous configuration that insinuates itself into mediastinal structures. Patients can complain of cough and dyspnea (from extrinsic compression of airways), stridor, hemoptysis, Horner's syndrome, dysphagia, superior vena cava syndrome, constrictive pericarditis, phrenic nerve palsy, or of symptoms related to a secondarily infected lymphangioma (91, 100).
Lymphangiectasis
Primary pulmonary lymphangiectasis is often fatal in early life, and cases are frequently stillborn (103). Secondary pulmonary lymphangiectasis can present with respiratory distress at any age (57, 90, 104, 105). Cases associated with pulmonary venous obstruction or other congenital heart defects, usually present in early childhood. In addition, a number of congenital and genetic diseases have been associated with pulmonary lymphangiectasis, including Noonan, Ullrich-Turner, Ehlers-Danlos, and Down syndromes (2, 57, 106).
Lymphangiomatosis
Lymphangiomatosis has been described in patients ranging from birth up to 80 yr (86, 109). It most frequently presents in late childhood. There is no clear sex predilection (72, 86). The lesions of lymphangiomatosis can occur in any tissue in which lymphatics are normally found, but there appears to be a predilection for thoracic and neck involvement (76). Up to 75% of patients with lymphangiomatosis have bony involvement (17, 55, 74, 80, 110). Single or multiple lymphangiomas may be found within the mediastinum, adherent to the pleura, or within the chest wall (10, 17, 72, 74, 80, 113, 125). Mediastinal fat may be diffusely infiltrated with anastamosing, dilated lymphatics (14, 128). Chylous effusions are common. Associated chyloptysis (108), hemoptysis (18, 126, 129), chylopericardium (8, 10, 13, 17, 112, 130), chylous ascites (8, 132), protein wasting enteropathy (134, 136), peripheral lymphedema (9, 129, 134), hemihypertrophy (105), lymphopenia (140), and disseminated intravascular coagulopathy (141) have been described. Interestingly, many patients with lymphangiomatosis experience wheeze and may be misdiagnosed with asthma prior to the recognition of the lymphatic disorder (10, 57).
Lymphatic Dysplasia Syndrome
The incidence of primary lymphedema is estimated at 0.1 per 100,000 persons under the age of 20 yr (females more than males). When the cause is related to agenesis or hypoplasia of distal lymphatics, the extremity swelling is usually bilateral. The swelling is unilateral and more severe if proximal lymphatics or nodes are obstructed (19, 58). Early in lymphedema, soft "pitting" edema is indistinguishable from vascular forms of edema. Later, chronic lymphedema can cause the skin to become thickened and brawny, with accentuated pitting of hair follicles ("peau d'orange"). Primary lymphedema has been associated with several congenital disorders including Noonan's and Turner's syndromes.
Primary chylothorax constitutes approximately one-sixth of all chylothoraces (23). Among newborns, chylothorax is the most common type of pleural effusion and in this age group males outnumber females (8). Patients with chylothorax usually present with a history of the insidious onset of dyspnea (a result of the space occupying effect of the pleural fluid). Fever, pleuritic chest pain, and chyloptysis are rare (142). Congenital chylothorax has a variable prognosis, dependent on gestational age at birth, the presence of other congenital abnormalities, and the severity of pulmonary hypoplasia.
Primary pericardial lymphedema has been reported in approximately 80 patients (ranging in age from 1 d to 77 yr) (60, 61, 143). Many cases are asymptomatic and present with an abnormal chest roentgenogram. One-third have dyspnea, approximately 10% have cough, and, rarely, cases may present with palpitations and chest pain (60). Of all the primary lymphatic disorders discussed in this review, the yellow nail syndrome is the most likely to present in adulthood. The male to female ratio is 1:1.5, the median age at presentation is 40 to 50 yr [range, birth to 80 yr (64, 69, 84)]. The complete triad of yellow nails (89%), lymphedema (80%), and idiopathic pleural effusions (36%) is seen in a minority of patients (20%) (64, 150). Any case with two of the three findings (yellow nails, pleural effusion, lymphedema) is accepted as having clinical evidence of yellow nail syndrome (64, 84, 151, 152). The nail abnormalities include shades of yellow-green-brown discoloration, longitudinal ridges, onycholysis, slow growth.
Diagnosis
Lymphangiomas
Thoracic lymphangiomas are usually detected as nodules or cystic masses on chest radiographs. Mediastinal lymphangiomas commonly envelop great vessels and displace mediastinal organs (89, 93). Plain radiographs, barium meal, ultrasound, computer tomographic (CT) scanning, and magnetic resonance imaging (MRI) have proven useful in determining the number and extent of lesions (155). Accurate anatomic localization plays an important role in the management of lymphangioma, because the diagnosis is ultimately made postoperatively (after the histopathologic examination of resected tissue). Three-dimensional ultrasonography may reveal cystic masses with thin septations, consistent with lymphangioma (158). MRI is probably the diagnostic modality of choice for lymphangiomas, because it accurately predicts subsequent intraoperative findings, and it helps to demonstrate lymphatic architecture at different tissue levels (159).
Lymphangiectasis
Primary pulmonary lymphangiectasis presents soon after birth and is commonly fatal in early life (Figure 1E). The dilated lymphatics, in association with chylothoraces, lead to life-threatening pulmonary hypoplasia and respiratory failure. Secondary lymphangiectasis presents as localized or diffuse pulmonary interstitial infiltrates, or cystic lesions, on chest radiography and MRI (see Figure 1E) (162). Lymphangiography demonstrates abnormally dilated lymphatics with obstructive changes and collateral channels in the retroperitoneal, mediastinal, and cervical lymphatic systems (156). The presence of pulmonary lymphangiectasis may be confirmed by lung biopsy (10).
Lymphangiomatosis
Congenital lymphangiomatosis is a rare disorder that is often fatal. In lymphangiomatosis, multiple lymphangiomas occur most commonly in lung and bone. The coexistence of lytic bone lesions and chylothorax serves as an important diagnostic clue. The diagnosis is sometimes made by bone biopsy that shows that these lytic lesions are lymphangiomas containing lymph fluid (10, 165). Lymphangiography reveals multiple lesions of the thoracic duct, dilated lymphatic channels, and lymphangiomas throughout the bones and lungs (156).
Bilateral interstitial infiltrates and pericardial or pleural effusions are evident on chest radiograph (14, 18). Pulmonary function testing may reveal a mixed obstructive and restrictive pattern (10). CT scans of the thorax reveal diffuse smooth thickening of interlobular septa and bronchovascular bundles with extensive involvement of mediastinal fat and perihilar regions. Lymphangiography is useful to exclude the presence of a mediastinal tumor, but is rarely required for the diagnosis of chylothorax or lymphangioma in infants and children. Obstruction of the thoracic duct is a rare cause of chylothorax in children (23). The radiologic findings and the clinical course of lymphangiomatosis may mimic that of lymphangioleiomyomatosis (35, 36, 166). Histopathology demonstrates anastomosing endothelial lined spaces along pulmonary lymphatic routes accompanied by asymmetrically spaced bundles of spindle cells. Factor VIII related antigen and CD31 are endothelial markers that are useful in immunohistochemical staining of these channels (167).
Lymphatic Dysplasia Syndrome
The clinical diagnosis of the yellow nail syndrome is based on the presence of two of the following features: yellow or dystrophic nails, chylous effusions, and lymphedema (66, 82). Chylous effusions have a protein content greater than 30 g/L; fat content greater than 10 g/L (with elevated concentrations of chylomicrons and triglycerides), and a specific gravity greater than 1.012, in the absence of microorganisms (23). Lymphangiography and lymphoscintigraphy allow an anatomic and functional assessment of lymphatic transport, and a depiction of regional lymph nodes (67, 161, 162, 168
Treatment
Lymphangiomas
In contrast to hemangiomas, which usually resolve spontaneously, congenital lymphangiomas typically require excision (165). Hemangiomas and lymphangiomas may coexist in the same patient. Important differential diagnoses of lymphangioma include acute suppurative lymphadenitis, which is common and easily diagnosed; and chronic lymphadenitis, which should be biopsied to exclude malignancy (163). Surgical resection, or sclerotherapy, of lymphangiomas are the therapies of choice (161, 165). Surgery is frequently mandated both to confirm the diagnosis, and to prevent complications that arise from compressive effects on vital structures (101, 102). Complete surgical resection may prove technically difficult, because lymphangiomas may surround large blood vessels, airways, and mediastinal organs (73, 89, 93). Incomplete resection, or sclerosis, can result in recurrence of the lymphangioma and a return of symptoms. Before surgical exploration and excision, it is prudent to investigate for other lymphangiomatous lesions and associated congenital anomalies (50, 105).
Lymphangiectasis
Thoracic lymphangiectasis usually leads to respiratory failure (106, 107, 109). Conservative treatment includes a low-fat, high-protein diet, with medium chain triglyceride (MCTG) and vitamin supplementation, in addition to repeated aspirations of the lymph accumulations (108). A low fat intake is thought to reduce the flow of lymph and the size of the lymphatic channels. Heart and lung transplantation has been attempted with poor results (169) (J. Theodore, personal communication).
Lymphangiomatosis
The natural history of pulmonary lymphangiomatosis is characterized by progressive growth and compression of adjacent structures (10, 161). Therapy should aim to decrease the symptoms that arise from compressive effects, to control chylous fluid accumulations, and to maintain optimal cosmesis (161). The success of surgical resection is impaired by an inability to separate lymph collections from normal structures, leading to high rates of recurrence (118, 124). Anatomically complicated lesions may be impossible to completely excise without damage to adjacent structures. In patients with widespread disease, therefore, therapeutic options are palliative. Percutaneous sclerotherapy with doxycycline has been employed with good results (161). CT and magnetic resonance (MR) not only help to define the size and location of lesions, but may also serve to guide sclerosis and monitor follow-up. Lymphoscintigraphy helps to guide therapy, by helping to delineate the direction of lymphatic flow and the relation between normal and abnormal lymphatics (168).
Lymphatic Dysplasia Syndrome
The treatment of chylothorax in infancy and childhood has become standardized (23). After the initial thoracentesis, one or two more therapeutic taps should be performed to eliminate the effusion. In addition, a high-protein, MCTG diet with fat-soluble vitamin supplements should lessen the flow of chyle from the intestinal tract (133). If the chylothorax remains after 2 wk, a chest drain with slight negative pressure should be inserted, and total parenteral nutrition instituted. Antenatal drainage of large congenital chylothoraces helps neonatal survival and perinatal resuscitation.
In addition to the management of chylothorax (as discussed previously), some patients with lymphatic dysplasia syndrome are treated with antibiotics for recurring pulmonary infections (150). Impaired lymphatic drainage is associated with immunoglobulin deficiencies. Patients with lymphatic dysplasia syndrome suffer recurrent infections, in part because of an IgG2 deficiency, but also because of the associated bronchiectasis and rhinosinusitis. Intravenous immunoglobulin and albumin therapies have been used in selected patients with marked IgG deficiency (151). Conservative management of lymphatic dysplasia syndrome includes high-protein, MCTG diet and vitamin supplementation, reduced oral nutrition, and repeated aspirations of fluid collections or pleurodesis (167).
Most patients with primary lymphedema are managed conservatively, by means of various forms of compression therapy, including massage, physical therapy, intermittent pneumatic compression pumps, and compressive garments (25, 26, 29, 170). Volume-reducing surgery and lymphatic microsurgery have been reported to provide favorable outcomes. The mainstay of treatment, however, is the reduction of edema by regular elevation, massage, and external compression with elastic stockings (25, 30, 170). Gross edema may be reduced surgically by simple excision (Homans' operation) or complete excision and skin grafting (Charles' operation) (170). Combined medical, surgical, and physiotherapeutic approaches benefit patients with marked lymphedema (25, 170).
Conclusion
Diseases of the thoracic lymphatic circulation should be differentiated on the basis of their pathologic and clinical features (6, 9, 10). The characteristic features of lymphangiomas, pulmonary lymphangiectasis, lymphangiomatosis, and lymphatic dysplasia syndrome are summarized in Table 2. Characteristic clinical features and radiographic appearances, the analysis of chylothorax fluid, and the presence of features of extrathoracic lymphatic dysfunction should prompt a differential diagnosis of disordered thoracic lymphatic function (6). Many of these disorders are diagnosed in childhood. In adulthood they are probably under-recognized (14, 86, 87). Their pathogenesis is unknown, but appears to be related, in part, to congenital malformations of the thoracic lymphatic system (10, 17, 50). Surgical excision of localized lesions (100, 165) and CT-guided sclerotherapy of large and numerous lymphangiomas are useful management strategies (161). Sclerotherapy provides relief of lymphedema, lymphorrhea, and a decrease in size of lymph accumulations. Sclerotherapy is acutely painful, and requires careful analgesic management with intravenous narcotics, benzodiazepines, and/or intracavitary lidocaine (161). Dietary modifications reduce the flow of lymph in subjects with widespread lymphatic dysfunction (133). Standardized therapy for chylothorax and lymphedema can lead to improved patient functionality (23, 25, 170). There is a need for a greater awareness of disorders of the thoracic lymphatic circulation, because accurate and early diagnosis may prompt more effective management strategies.
Article with Tables, Footnotes and References
posted by Pat O'Connor @ 5:30 AM
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