State of the Art

Thoracic Lymphangiomas, Lymphangiectasis,

Lymphangiomatosis, and Lymphatic
Dysplasia Syndrome
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 pulmonary disease (Figure 1A). In addition, congenital errors

of lymphatic development can lead to primary pulmonary
Introduction
lymphatic disorders (lymphangiomas, lymphangiectasis, lym-
Classification
phangiomatosis, and lymphatic dysplasia syndrome) (2–8).
Lymphangiomas
Because of their scarcity, these latter conditions are often mis-
Pulmonary Lymphangiectasis
diagnosed (Figure 1B) and their management is difficult. Re-
Lymphangiomatosis
search on thoracic lymphatic disorders has been hampered by
Lymphatic Dysplasia Syndrome
a confusing and inconsistent use of terminology. Their origins
Other Thoracic Lymphatic Disorders
and pathogenesis are currently unknown. Future advances in
Lymphatic Embryogenesis
our understanding of vasculogenesis may provide clues about
Lymphangiomas
the relation between abnormal embryogenesis and the devel-
Pulmonary Lymphangiectasis
opment of lymphatic disease.
Lymphangiomatosis
Lymphatic Dysplasia Syndrome
Pathology CLASSIFICATION
Clinical Features The classification of pulmonary lymphatic disorders is chal-
Lymphangiomas lenging (6). The literature uses inconsistent terminology and
Pulmonary Lymphangiectasis describes only case reports and a handful of small case series
Lymphangiomatosis (6–8). Several investigators have proposed classification sys-
Lymphatic Dysplasia Syndrome tems for lymphatic disorders based on pathology or presumed
Diagnosis pathophysiologic mechanisms (2–10). We believe that the
Lymphangiomas classification of thoracic lymphatic disorders should be based
Pulmonary Lymphangiectasis on clinical presentation and pathologic features, rather than
Lymphangiomatosis on their assumed pathophysiology (Table 1). In this report, we
Lymphatic Dysplasia Syndrome employ a modification of Hilliard’s classification (6). The iden-
Treatment tification of characteristic features should allow patients to be
Lymphangiomas placed into one of the categories listed in Table 1.
Pulmonary Lymphangiectasis
Lymphangiomatosis Lymphangiomas
Lymphatic Dysplasia Syndrome Lymphangiomas are focal proliferations of well differentiated
Conclusion lymphatic tissue that present as multicystic or spongelike ac-
cumulations (Figure 1C) (11, 12). They are subdivided into
three pathologic categories (11, 12): lymphangioma simplex (ca-
pillary lymphangioma) describes thin-walled lymphatic chan-
INTRODUCTION nels that occur as small, well circumscribed cutaneous lesions;
The lymphatic system plays an important role in human circu- cavernous lymphangiomas are microscopic thin-walled lym-
lation and organ perfusion homeostasis (1). Disorders of the phatic channels with associated stroma; and cystic lymphan-
pulmonary lymphatic system occur in a variety of clinical set- giomas (cystic hygromas) are large, well-circumscribed, mul-
tings (ranging from trauma to cancer) and may lead to serious tiloculated cystic spaces lined by endothelium that contain a
significant connective tissue component. Cavernous and cystic
lymphangiomas can coexist within the same lesion (12).
(Received in original form April 13, 1999 and in revised form September 15, 1999)
Supported by the Mr. and Mrs. C. F. Chan Family Fund and the Mr. and Mrs. Pulmonary Lymphangiectasis
Samuel Reeves and Family Fund.
Lymphangiectasis describes pathologic dilation of lymphatics
Correspondence and requests for reprints should be addressed to Professor Tho- (Figures 1E, 1F, 1G, and 1H) (13, 14). Primary (congenital)
mas A. Raffin, M.D., F.C.C.P., Chief of the Division of Pulmonary and Critical
Care Medicine, Stanford University School of Medicine, Stanford, CA 94305- and secondary forms have been described. The primary form
5236. presents in neonates and is usually fatal. Secondary forms of
Am J Respir Crit Care Med Vol 161. pp 1037–1046, 2000 lymphangiectasis result from a variety of processes that impair
Internet address: www.atsjournals.org lymph drainage and increase lymph production. We propose
1038 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 161 2000

Figure 1. (A) CT scan of the

thorax of a patient with dif-
fuse pulmonary lymphangi-
omatosis, demonstrating bi-
lateral chylous effusions (arrow)
and diffuse lymphatic prolif-
erations in the left lung (ar-
rowheads). (B) Pulmonary lym-
phangiomatosis in a 34-yr-old
woman with a long history
of suspected bronchiectasis.
Multifocal lymphatic prolifer-
ations along the lymphatic
routes of the interlobular septa
were found (hematoxylin–eosin;
original magnification: ⫻60).
Similar changes were also noted
along the bronchovascular
bundles (not shown). The right
panel shows bland endothe-
lial cells lining the lymphatic
spaces. (C) Pulmonary lym-
phangioma in a 25-yr-old
woman with a solitary pe-
ripheral lung lesion in the
subpleural and interlobular
septal tissues (hematoxylin–
eosin; original magnification:
⫻40). (D) High-power mag-
nification demonstrating the
anastomosing lymphatic chan-
nels. Occasional clusters of small
lymphocytes are found (hema-
toxylin–eosin; original magni-
fication: ⫻400). (E ) MRI of the
thorax of an infant boy who
underwent combined heart
and lung transplantation at 7
wk for congenital Pulmonary
lymphangiectasis, demonstrat-
ing widespread cyst formation
and abnormal lymphatic ves-
sel (coronal section, T2-weighted
image). (F) Pulmonary lym-
phangiectasis: numerous cys-
tic spaces, ranging from 5 to
20 mm are seen throughout
the lung fields. The right panel
shows the smooth walled spaces
distorting the parenchyma. (G)
Pulmonary lymphangiectasis,
demonstrating the character-
istic massive dilatation with-
out proliferation of lymphatics
(hematoxylin–eosin; original
magnification: ⫻50). (H) High-
power magnification of panel
G, demonstrating simple fluid-
filled lymphatic spaces (he-
matoxylin–eosin; original mag-
nification: ⫻400).

that primary and secondary lymphangiectasis are distinguish-
able by their age of presentation and their clinical courses.
Lymphangiomatosis
Lymphangiomatosis describes the presence of multiple lymphan-
giomas (15–17). It is frequently associated with other lymphatic
related abnormalities and usually (in 75% of cases) involves mul-
tiple organs. Diffuse pulmonary lymphangiomatosis (Figures 1A
and 1B) (10) has been reported in the literature as pulmonary
lymphangiectasis (2, 3, 13), generalized lymphangiectasis (14), in-
trathoracic lymphangiomatosis (15), thoracic lymphangiomato-
sis (16), and diffuse pulmonary angiomatosis (17).
State of the Art
TABLE 1
DISORDERS OF THE LYMPHATIC SYSTEM
Lymphangioma
Capillary
Cavernous
Cystic
Lymphangiectasis
Primary (congenital)
Secondary
Lymphangiomatosis
Single organ system involvement (e.g., diffuse pulmonary
lymphangiomatosis)
Multiple organ system involvement
Lymphatic dysplasia syndrome
Primary lymphedema
Lymphedema congenita
Lymphedema precox
Lymphedema tarda
Idiopathic effusion(s)
Pleural
Pericardial
Peritoneal
Yellow nail syndrome
Congenital chylothorax
Lymphatic injury (secondary chylous effusions and lymphedema) (19, 23–29)
Lymphangioma, acquired progressive (33, 34)
Lymphangiosarcoma (12, 38–41)
Lymphatic abnormalities combined with other tissue disorders
Lymphangioleiomyomatosis (35, 36)
Hemangiolymphangiomas (42, 43, 45–48)
Lymphangiolipoma (153, 154)
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 (20–22),
and in the absence of lymphangiomas, lymphangiectasis, or
lymphangiomatosis. Primary lymphedema has been subdi-
vided into categories based upon the age of presentation (19):
lymphedema congenita (neonates), lymphedema precox (⬍ 35
yr), and lymphedema tarda (⬎ 35 yr) (19).
Other Thoracic Lymphatic Disorders
Lymphedema can arise due to disruption of the normal lym-
phatic circulation by trauma, infection, surgery, radiation, or
cancer (e.g., lymphoma, lymphangitis carcinomatosis) (19–32).
Acquired progressive lymphangiomas, sometimes referred to
as angioendothelioma (lymphatic type), are localized cutane-
ous macular or papular lesions that appear brown or viola-
ceous. 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 for-
mation in lung parenchyma. LAM can involve mediastinal and
retroperitoneal lymphatics and lymph nodes (35–37). Pneu-
mothoraces and chylous effusions are common and patients
typically develop end-stage restrictive ventilatory defects. Lym-
phangiosarcoma is a vascular malignancy that develops in ar-
eas of chronic lymphedema (12, 38–41). 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 lymphat-
1039
ics and blood vessels have been termed hemangiolymphangio-
mas or hamartomatous heme-lymphangiomatosis (42–48).
LYMPHATIC EMBRYOGENESIS
Lymphangiomas, lymphangiectasis, lymphangiomatosis, and
lymphatic dysplasia syndrome are thought to result from con-
genital errors of lymphatic development (4–7, 18). The lym-
phatic vascular system develops during the sixth week of life
as an outgrowth of the venous system or as a de novo differen-
tiation within mesenchymal tissues (1, 49). Primordial lym-
phatic tissues join one another to form lymphatic channels and
six lymph sacs. Paired juguloaxillary lymph sacs, paired in-
guinal 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 twen-
tieth 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 chan-
nels or arose from portions of lymph sacs that were seques-
tered 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 lym-
phangiomas develop in areas of chronic lymphatic obstruction
related to surgery, chronic infection, or radiation (52–54).
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 nor-
mally 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, radia-
tion, infection, tumor, or trauma disturbs effective lymphatic
drainage. Children with congenital heart diseases (for exam-
ple, total anomalous pulmonary venous return or hypoplastic
left heart syndromes) and adults with severe mitral valve dis-
ease have increased lymphatic circulation that contributes to
the lymphatic dilatation (2, 3, 57) and the severity of lym-
phangiectasis.
Lymphangiomatosis
Lymphangiomatosis also appears to be due to a lymphatic de-
velopmental abnormality (4–7), but presents at a later age
than solitary lymphangiomas either because of an influence of
hormonal factors or because a more subtle, albeit more wide-
spread, defect requires a longer period for growth.
Lymphatic Dysplasia Syndrome
The lymphatic dysplasia syndrome includes a diverse group of
disorders with variable prognosis (58–61). In primary lymphe-
dema, 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 pe-
ripheral lymphatics; and some have incompetent lymphatic
valves that develop into megalolymphatics (19, 58, 59).
Abnormalities of lymphatic development are associated with
1040 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
a variety of inheritance patterns (18), including congenital anom-
aly syndromes (achondrogenesis Type 1), and aneuploidy syn-
dromes (Turner syndrome). Familial Milroy lymphedema is
inherited in an autosomal dominant pattern, with variable
penetrance, whereas congenital chylothorax appears to be in-
herited in an autosomal recessive pattern (18). Therefore, sev-
eral factors, some of them genetic, probably lead to the devel-
opment 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, 60–62). The
yellow nail syndrome is thought to be due to impaired lym-
phatic drainage, based on abnormal lymphangiography stud-
ies and delayed albumin turnover in the pleural space (63–68).
Moreover, the nail changes, lymphedema, and pleural effu-
sions 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 cys-
tic hygroma in 1843 (71). Capillary lymphangiomas appear as
wartlike or vesicular lesions that are unrelated to internal lym-
phangiomas (53, 54). Cavernous lymphangiomas have indis-
crete margins and insinuate themselves into the surrounding
structures. Cystic lymphangiomas, in contrast, are multilocu-
lated 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 protein-
aceous 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 sar-
coma. 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 lym-
phangiectasis (a rare disease of neonates) in 1856 (77). In pul-
monary lymphangiectasis, the lungs appear heavy and non-
compliant (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 identi-
fied 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 col-
lagen and smooth muscle may be found in the walls of the ves-
sels, particularly in the secondary form of pulmonary lym-
phangiectasis (10). Lymphangiectasis should be morphologically
distinguished from interstitial emphysema (78, 79).
Lymphangiomatosis
The histology of lymphangiomatosis can pathologically resem-
ble a lymphangioma (12, 74, 80). Lymphangiomatosis can ap-
VOL 161 2000
pear 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 abnor-
malities. Pathologic features (10) include a proliferation of
complex anastamosing lymphatic channels that markedly ex-
pand the typical lymphatic routes within the lungs and medi-
astinum. Compared with primary pulmonary lymphangiecta-
sis, 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 lymphan-
giomatosis to normal lymphatic pathways within the lung, and
the small proportion and more mature appearance and align-
ment of smooth muscle cells, help to distinguish this from lym-
phangioleiomyomatosis (10).
Lymphatic Dysplasia Syndrome
In primary lymphedema, prominent fibrous septations may
develop in subcutaneous adipose tissue. Histology reveals epi-
dermal atrophy, dermal fibrosis, perivascular inflammation,
and dilated lymphatics. Enlarged regional lymph nodes and si-
nusoidal fibrosis are found in some cases of primary lymphe-
dema (76). In 1964 Samman and White coined the term “yel-
low nail syndrome” to describe 13 patients with idiopathic
lymphedema and yellow, dystrophic, fingernails (63–65). 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 numer-
ous 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 lym-
phangiomas seen in consultation by the Armed Forces Insti-
tute 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 pe-
riod 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). Medi-
astinal lymphangiomas are equally distributed between the
anterior, middle, and posterior compartments (73). Intrapul-
monary lymphangiomas are rare: approximately a dozen cases,
with patient ages ranging from 6 mo to 54 yr, are described in
the literature (88, 90–97).
Thoracic lymphangiomas may remain asymptomatic for
many years and only become apparent when patients develop
problems related to compression of vital structures. Alterna-
tively, 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 com-
plain of cough and dyspnea (from extrinsic compression of air-
ways), stridor, hemoptysis, Horner’s syndrome, dysphagia, su-
perior vena cava syndrome, constrictive pericarditis, phrenic
State of the Art
nerve palsy, or of symptoms related to a secondarily infected
lymphangioma (91, 100–102).
Lymphangiectasis
Primary pulmonary lymphangiectasis is often fatal in early
life, and cases are frequently stillborn (103). Secondary pul-
monary 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, 106–108).
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 pre-
dilection for thoracic and neck involvement (76). Up to 75%
of patients with lymphangiomatosis have bony involvement
(17, 55, 74, 80, 110–124). 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, 125–127). Me-
diastinal fat may be diffusely infiltrated with anastamosing,
dilated lymphatics (14, 128). Chylous effusions are common.
Associated chyloptysis (108), hemoptysis (18, 126, 129), chylo-
pericardium (8, 10, 13, 17, 112, 130–132), chylous ascites (8,
132–135), protein wasting enteropathy (134, 136–139), periph-
eral lymphedema (9, 129, 134), hemihypertrophy (105), lym-
phopenia (140), and disseminated intravascular coagulopathy
(141) have been described. Interestingly, many patients with
lymphangiomatosis experience wheeze and may be misdiag-
nosed 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 lym-
phatics or nodes are obstructed (19, 58). Early in lymphe-
dema, soft “pitting” edema is indistinguishable from vascular
forms of edema. Later, chronic lymphedema can cause the
skin to become thickened and brawny, with accentuated pit-
ting of hair follicles (“peau d’orange”). Primary lymphedema
has been associated with several congenital disorders includ-
ing 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 usu-
ally 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 gesta-
tional age at birth, the presence of other congenital abnormal-
ities, and the severity of pulmonary hypoplasia.
Primary pericardial lymphedema has been reported in ap-
proximately 80 patients (ranging in age from 1 d to 77 yr) (60,
61, 143–149). Many cases are asymptomatic and present with
an abnormal chest roentgenogram. One-third have dyspnea,
approximately 10% have cough, and, rarely, cases may pres-
ent with palpitations and chest pain (60). Of all the primary
1041
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
(⬍ 0.25 mm/wk), and clubbing. The sino-respiratory tract is
frequently involved (63%). Pleural effusions (bilateral and ex-
udative), bronchiectasis, and rhinosinusitis lead to shortness
of breath and a productive cough. Symptoms often predate
the diagnosis of yellow nail syndrome by more than 10 yr.
DIAGNOSIS
Lymphangiomas
Thoracic lymphangiomas are usually detected as nodules or
cystic masses on chest radiographs. Mediastinal lymphangio-
mas commonly envelop great vessels and displace mediastinal
organs (89, 93). Plain radiographs, barium meal, ultrasound,
computer tomographic (CT) scanning, and magnetic reso-
nance imaging (MRI) have proven useful in determining the
number and extent of lesions (155–157). Accurate anatomic
localization plays an important role in the management of
lymphangioma, because the diagnosis is ultimately made post-
operatively (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 in-
traoperative findings, and it helps to demonstrate lymphatic
architecture at different tissue levels (159–161).
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) (162–164). Lymphan-
giography demonstrates abnormally dilated lymphatics with
obstructive changes and collateral channels in the retroperito-
neal, 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 diagnos-
tic 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 le-
sions of the thoracic duct, dilated lymphatic channels, and
lymphangiomas throughout the bones and lungs (156).
Bilateral interstitial infiltrates and pericardial or pleural ef-
fusions 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
1042 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 161 2000

with extensive involvement of mediastinal fat and perihilar re-
gions. 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. Ob-
struction 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 lymphangioleiomyoma-
tosis (35, 36, 166). Histopathology demonstrates anastomosing
endothelial lined spaces along pulmonary lymphatic routes ac-
companied by asymmetrically spaced bundles of spindle cells.
Factor VIII related antigen and CD31 are endothelial markers
that are useful in immunohistochemical staining of these chan-
nels (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 dystro-
phic nails, chylous effusions, and lymphedema (66, 82–84).
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). Lymphan-
giography and lymphoscintigraphy allow an anatomic and
functional assessment of lymphatic transport, and a depiction
of regional lymph nodes (67–69, 161, 162, 168).
TREATMENT
Lymphangiomas
In contrast to hemangiomas, which usually resolve spontane-
ously, congenital lymphangiomas typically require excision (165).
Hemangiomas and lymphangiomas may coexist in the same
patient. Important differential diagnoses of lymphangioma in-
clude 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 com-
pressive effects on vital structures (101, 102). Complete surgi-
cal resection may prove technically difficult, because lym-
phangiomas may surround large blood vessels, airways, and
mediastinal organs (73, 89, 93–95). 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 le-
sions 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 vita-
min supplementation, in addition to repeated aspirations of the
lymph accumulations (108). A low fat intake is thought to re-
duce 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 char-
acterized by progressive growth and compression of adjacent
structures (10, 161). Therapy should aim to decrease the
symptoms that arise from compressive effects, to control chy-
lous fluid accumulations, and to maintain optimal cosmesis
(161). The success of surgical resection is impaired by an in-
ability 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 wide-
spread disease, therefore, therapeutic options are palliative.
Percutaneous sclerotherapy with doxycycline has been em-
ployed 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 de-
lineate the direction of lymphatic flow and the relation be-
tween normal and abnormal lymphatics (168).

TABLE 2
DISEASES OF THE THORACIC LYMPHATIC SYSTEM: CLINICAL AND PATHOLOGIC FEATURES

Lymphangioma Lymphangiectasis Lymphangiomatosis Lymphatic Dysplasia Syndrome

Age at presentation Childhood (90% of cases present
at ⬍ 2 yr of age)
Sex predilection None
Natural history No spontaneous resolution.
Changes in the size of
lymphangiomas are often
related to secondary infections.
Thoracic manifestations Mediastinal mass, intrapulmonary
mass, chylous pleural effusion,
chylous pericardial effusion.
Pathologic features Benign proliferations of endothelial
lined channels and cysts with
varying amounts of intermixed
connective tissue.
Treatment Excision or sclerosis.
Primary: Neonate.
Secondary: Majority in childhood.
Males ⬎ females
Primary: Leads to severe
respiratory failure that is
commonly fatal.
Secondary: Disease severity is
dependent on inciting factors.
Primary: Diffuse dilation of
pulmonary lymph vessels.
Secondary: Dilation of pulmonary Chylous pericardial and/or
lymph vessels due to chronic
lymphatic obstruction.
Dilated pulmonary lymphatics
(not increased in number).
MCTG, high-protein diet.
Rare in neonate. Majority of
cases occur by 20 yr of age.
None
Poor prognosis with pulmonary or Recurrent chest infections,
intra-abdominal disease. Good
prognosis for bony or soft tissue bronchiectasis. Prognosis is
involvement.
Mediastinal, pulmonary and chest
wall lymphangiomas.
pleural effusions are
commonly seen.
Proliferation of lymphatics
arranged as complex
anastomosing spaces along
anatomic lymphatic routes.
MCTG, high-protein diet.
Drainage of large fluid
collections; sclerotherapy.
Adult (most present at ⬎ 20 yr)
Females ⬎ males
pleural effusions, and
related to the severity
of bronchiectasis.
Chylothorax, chylopericardium,
bronchiectasis.
Chronic pleuritis, fibrosis, and
dilated lymphatics.
MCTG, high-protein diet.
Drainage of chylothorax.
Pleurodesis, intravenous
immunoglobulin.

Definition of abbreviation: MCTG ⫽ medium chain triglyceride diet.

State of the Art
Lymphatic Dysplasia Syndrome
The treatment of chylothorax in infancy and childhood has be-
come 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 in-
serted, and total parenteral nutrition instituted. Antenatal drain-
age 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
(150–152). Impaired lymphatic drainage is associated with im-
munoglobulin deficiencies. Patients with lymphatic dysplasia
syndrome suffer recurrent infections, in part because of an
IgG2 deficiency, but also because of the associated bron-
chiectasis 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 con-
servatively, by means of various forms of compression ther-
apy, including massage, physical therapy, intermittent pneu-
matic compression pumps, and compressive garments (25, 26,
29, 170). Volume-reducing surgery and lymphatic microsur-
gery 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 com-
plete 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 dif-
ferentiated on the basis of their pathologic and clinical fea-
tures (6, 9, 10). The characteristic features of lymphangiomas,
pulmonary lymphangiectasis, lymphangiomatosis, and lym-
phatic dysplasia syndrome are summarized in Table 2. Charac-
teristic clinical features and radiographic appearances, the
analysis of chylothorax fluid, and the presence of features of
extrathoracic lymphatic dysfunction should prompt a differen-
tial diagnosis of disordered thoracic lymphatic function (6).
Many of these disorders are diagnosed in childhood. In adult-
hood 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 (100–102,
165) and CT-guided sclerotherapy of large and numerous lym-
phangiomas are useful management strategies (161). Sclero-
therapy 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 intracavi-
tary 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
1043
lymphatic circulation, because accurate and early diagnosis
may prompt more effective management strategies.
References
1. Miller, W. S. 1919. The lymphatics and lymph flow in the human lung.
Am. Rev. Tuberc. 3:193–209.
2. Felman, A. H., R. M. Rhatigan, and K. K. Pierson. 1972. Pulmonary
lymphangiectasia: observation in 17 patients and proposed classifica-
tion. Am. J. Roentgenol. Radium. Ther. Nucl. Med. 116:548–558.
3. Lloyd, E. S., and H. C. Press, Jr. 1979. Congenital pulmonary lym-
phangiectasis. South. Med. J. 72:1205–1206.
4. Bill, A. H., and D. S. Sumner. 1965. A unified concept of lymphangi-
oma and cystic hygroma. Surg. Gynecol. Obstet. 120:79–86.
5. Zadvinskis, D. P., M. T. Benson, H. H. Kerr, A. A. Mancuso, A. A.
Cacciarelli, B. L. Madrazo, M. F. Mafee, and K. Dalen. 1992. Con-
genital malformations of the cervicothoracic lymphatic system: em-
bryology and pathogenesis. Radiographics 12:1175–1189.
6. Hilliard, R. I., J. B. McKendry, and M. J. Phillips. 1990. Congenital ab-
normalities of the lymphatic system: a new clinical classification. Pe-
diatrics 86:988–994.
7. Levine, C. 1989. Primary disorders of the lymphatic vessels—a unified
concept. J. Pediatr. Surg. 24:233–240.
8. Smeltzer, D. M., G. B. Stickler, and R. E. Fleming. 1986. Primary lym-
phatic dysplasia in children: chylothorax, chylous ascites, and gener-
alized lymphatic dysplasia. Eur. J. Pediatr. 145:286–292.
9. Witte, M. H., and C. L. Witte. 1986. Lymphangiogenesis and lympho-
logic syndromes. Lymphology 19:21–28.
10. Tazelaar, H. D., D. Kerr, S. A. Yousem, M. J. Saldana, C. Langston,
and T. V. Colby. 1993. Diffuse pulmonary lymphangiomatosis. Hum.
Pathol. 24:1313–1322.
11. Wegner, G. 1877. Ueber Lymphangiome. Arch. Klin. Chir. 20:641.
12. Enzinger, F. M., and S. W. Weiss. 1995. Tumors of lymph vessels. In
S. M. Gay, editor. Soft Tissue Tumors. Mosby, St. Louis. 679–700.
13. Kirchner, J., V. Jacobi, M. Schneider, and R. Wagner. 1997. Primary
congenital pulmonary lymphangiectasia—a case report. Wien. Klin.
Wochenschr. 12:109:922–924.
14. White, J. E., D. Veale, D. Fishwick, L. Mitchell, and P. A. Corris. 1996.
Generalised lymphangiectasia: pulmonary presentation in an adult.
Thorax 51:767–768.
15. Swank, D. W., N. G. Hepper, K. E. Folkert, and T. V. Colby. 1989. In-
trathoracic lymphangiomatosis mimicking lymphangioleiomyomato-
sis in a young woman. Mayo Clin. Proc. 64:1264–1268.
16. Margraf, L. R. 1996. Thoracic lymphangiomatosis. Pediatr. Pathol. Lab.
Med. 16:155–160.
17. Canny, G. J., E. Cutz, I. B. MacLusky, and H. Levison. 1991. Diffuse
pulmonary angiomatosis. Thorax 46:851–853.
18. Fox, G. F., D. Challis, K. K. O’Brien, E. N. Kelly, and G. Ryan. 1998.
Acta Pediatr. 87:1010–1012.
19. Cooke, J. P., and T. W. Rooke. 1996. Lymphedema. In J. Loscalzo,
M. A. Creager, and V. J. Dzau, editors. Vascular Medicine: A Text-
book of Vascular Biology and Diseases. Little, Brown and Co., Bos-
ton. 1133–1146.
20. Promisloff, R. A., and D. J. Hogue. 1997. Chylothorax: the result of
previous radiation therapy? J. Am. Osteopath. Assoc. 97:164–166.
21. Van Renterghem, D. M., and R. A. Pauwels. 1995. Chylothorax and
pleural effusion as late complications of thoracic irradiation [Letter;
Comment]. Chest 108:886–887.
22. Berkman, N., R. Breuer, M. R. Kramer, and A. Polliack. 1996. Pulmo-
nary involvement in lymphoma. Leuk. Lymphoma 20:229–237.
23. Valentine, V. G., and T. A. Raffin. 1992. The management of chylotho-
rax. Chest 102:586–591.
24. Chan, B. B., M. C. Murphy, and B. M. Rodgers. 1990. Management of
chylopericardium. J. Pediatr. Surg. 25:1185–1189.
25. Consensus document of the International Society of Lymphology Exec-
utive Committee. 1995. The diagnosis and treatment of peripheral
lymphedema. Lymphology 28:113–117.
26. Harwood, C. A., and P. S. Mortimer. 1995. Causes and clinical manifes-
tations of lymphatic failure. Clin. Dermatol. 13:459–471.
27. Tanabe, N., M. Muya, M. Isonokami, T. Kozuka, T. Honda, and H.
Ohtani. 1996. Lymphedema due to chronic penile strangulation: a
case report. J. Dermatol. 23:648–651.
28. Marcks, P. 1997. Lymphedema: pathogenesis, prevention, and treat-
ment. Cancer Pract. 5:32–38.
29. Witte, C. L., and M. H. Witte. 1995. Disorders of lymph flow. Acad. Ra-
diol. 2:324–334.
1044 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
30. Szuba, A., and S. G. Rockson. 1997. Lymphedema: anatomy, physiol-
ogy and pathogenesis [In Process Citation]. Vasc. Med. 2:321–326.
31. Kostman, J. R., and M. J. DiNubile. 1993. Nodular lymphangitis: a dis-
tinctive but often unrecognized syndrome. Ann. Intern. Med. 118:
883–888.
32. Ikezoe, J., J. D. Godwin, K. J. Hunt, and S. I. Marglin. 1995. Pulmonary
lymphangitic carcinomatosis: chronicity of radiographic findings in
long-term survivors. Am. J. Roentgenol. 165:49–52.
33. Watanabe, M., K. Kishiyama, and A. Ohkawara. 1983. Acquired pro-
gressive lymphangioma. J. Am. Acad. Dermatol. 8:663–667.
34. Soohoo, L., M. G. Mercurio, R. Brody, and M. T. Zaim. 1995. An ac-
quired vascular lesion in a child: acquired progressive lymphangi-
oma. Arch. Dermatol. 131:341–345.
35. Kalassian, K. G., R. Doyle, P. Kao, S. Ruoss, and T. A. Raffin. 1997.
Lymphangioleiomyomatosis: new insights. Am. J. Respir. Crit. Care
Med. 55:1183–1186.
36. Taylor, J. R., J. Ryu, T. V. Colby, and T. A. Raffin. 1990. Lymphangi-
oleiomyomatosis: clinical course in 32 patients. N. Engl. J. Med. 323:
1254–1260.
37. Kitaichi, M., and T. Izumi. 1995. Lymphangioleiomyomatosis. Curr.
Opin. Pulm. Med. 5:417–424.
38. Stewart, N. J., D. J. Pritchard, A. G. Nascimento, and Y. K. Kang. 1995.
Lymphangiosarcoma following mastectomy. Clin. Orthop. 320:135–141.
39. Gebhart, M., E. Chasse, and M. Petein. 1995. Lymphangiosarcoma: re-
ports of 3 cases and review of the literature. Eur. J. Surg. Oncol. 21:
211–214.
40. Andersson, H. C., D. M. Parry, and J. J. Mulvihill. 1995. Lymphan-
giosarcoma in late-onset hereditary lymphedema: case report and
nosological implications. Am. J. Med. Genet. 56:72–75.
41. Tomita, K., A. Yokogawa, Y. Oda, and S. Terahata. 1988. Lymphan-
giosarcoma in postmastectomy lymphedema (Stewart-Treves syn-
drome): ultrastructural and immunohistologic characteristics. J. Surg.
Oncol. 38:275–282.
42. Sammis, A. F., Jr., S. Weitzman, and J. P. Arcomano. 1971. Hemangi-
olymphangioma of spleen and bone. N.Y. State J. Med. 71:1762–1764.
43. Koblenzer, P. J., and M. J. Bukowski. 1961. Angiomatosis (hamartoma-
tous hem-lymphangiomatosis): report of a case with diffuse involve-
ment. Pediatrics 28:65–76.
44. Gaillard de Collogny, L., and J. Delage. 1981. [Cervical hemolymphan-
gioma in a young patient]. J. Fr. Otorhinolaryngol. Audiophonol.
Chir. Maxillofac. 30:469–473.
45. Giacalone, P. L., P. Boulot, M. Marty, F. Deschamps, F. Laffargue, and
J. L. Viala. 1993. Fetal hemangiolymphangioma: a case report. Fetal
Diagn. Ther. 8:338–340.
46. Chandna, S., V. Bhatnagar, D. K. Mitra, and P. Upadhyaya. 1987. He-
mangiolymphangioma of the urinary bladder in a child. J. Pediatr.
Surg. 22:1051–1052.
47. Shah, K. D., F. A. Chervenak, A. M. Marchevsky, J. C. Rosenberg, and
R. L. Berkowitz. 1987. Fetal giant hemangiolymphangioma: report of
a case. Am. J. Perinatol. 4:212–214.
48. Vilalta, J., and J. M. Mascaro. 1985. Hemangiolymphangioma of the
tongue treated by transfixion technique. J. Dermatol. Surg. Oncol.
11:168–170.
49. Moore, K. L. 1988. The cardiovascular system. In M. Wonsiewicz, edi-
tor. The Developing Human. W. B. Saunders, Philadelphia. 325–333.
50. Spencer, H. 1977. Congenital abnormalities of the lung. In H. Spencer,
editor. Pathology of the Lung. Pergamon Press, New York.
51. Laurence, K. M. 1955. Congenital pulmonary cystic lymphangiectasis.
J. Path. Bact. 70:325–333.
52. Fisher, I., and M. Orkin. 1970. Acquired lymphangioma (lymphang-
iectasis): report of a case. Arch. Dermatol. 101:230–234.
53. Flanagan, B. P., and E. B. Helwig. 1977. Cutaneous lymphangioma.
Arch. Dermatol. 113:24–30.
54. Peachey, R., and I. Whimster. 1970. Lymphangioma of skin: a review of
65 cases. Br. J. Dermatol. 83:519–527.
55. Bowman, C. A., M. H. Witte, C. L. Witte, D. L. Way, R. B. Nagle, J. G.
Copeland, and C. C. Daschbach. 1984. Cystic hygroma reconsidered:
hamartoma or neoplasm? Primary culture of an endothelial cell line
from a massive cervicomediastinal hygroma with bony lymphangi-
omatosis. Lymphology 17:15–22.
56. Goetsch, E. 1938. Hygroma colli cysticum and hygroma axillare: patho-
logic and clinical study and report of 12 cases. Arch. Surg. 36:394.
57. Noonan, J. A., L. R. Walters, and J. T. Reeves. 1970. Congenital pul-
monary lymphangiectasis. Am. J. Dis. Child. 120:314–319.
58. Wolfe, J. H. N. 1984. The prognosis and possible cause of severe pri-
mary lymphoedema. Ann. R. Coll. Surg. Eng. 66:251.
59. Kinmonth, J. B., A. E. Young, J. M. Edwards, T. F. O’Donnell, and
VOL 161 2000
M. L. Thomas. 1976. Mixed vascular deformities of the lower limbs,
with particular reference to lymphography and surgical treatment.
Br. J. Surg. 63:899–906.
60. Akamatsu, H., J. Amano, T. Sakamoto, and A. Suzuki. 1994. Primary
chylopericardium. Ann. Thorac. Surg. 58:262–266.
61. Scholten, C., M. Staudacher, W. Girsch, G. Wolf, M. Grimm, T. Binder,
I. Lang, and T. Stefenelli. 1998. A novel therapeutic strategy for the
management of idiopathic chylopericardium and chylothorax. Sur-
gery 123:369–370.
62. Craven, C. E., A. S. Goldman, D. L. Larson, M. Patterson, and C. K.
Hendrick. 1967. Congenital chylous ascites: lymphangiography dem-
onstration of obstruction of the cisterna chyli and chylous reflux into
the peritoneal space and small intestine. J. Pediatr. 70:340–345.
63. Samman, P. D., and W. F. White. 1964. The “yellow nail” syndrome.
Br. J. Dermatol. 76:153–157.
64. Nordkild, P., H. Kromann-Andersen, and E. Struve-Christensen. 1986.
Yellow nail syndrome: the triad of yellow nails, lymphedema and
pleural effusions. Acta Med. Scand. 219:221–227.
65. d’Souza, M. F. 1970. Generalized lymphoedema and yellow nails, pleu-
ral effusions and macroglobulinaemia. Proc. R. Soc. Med. 63:24.
66. Muller, R. P., P. E. Peters, K. Echternacht-Happle, and R. Happle.
1979. Roentgenographic and clinical signs in yellow nail syndrome.
Lymphology 12:257–261.
67. Runyon, B. A., E. L. Forker, and J. A. Sopko. 1979. Pleural-fluid kinet-
ics in a patient with primary lymphedema, pleural effusions, and yel-
low nails. Am. Rev. Respir. Dis. 119:821–825.
68. Mambretti-Zumwalt, J., J. M. Seidman, and N. Higano. 1980. Yellow
nail syndrome: complete triad with pleural protein turnover studies.
South. Med. J. 73:995–997.
69. Bull, R. H., D. A. Fenton, and P. S. Mortimer. 1996. Lymphatic func-
tion in the yellow nail syndrome. Br. J. Dermatol. 134:307–312.
70. Redenbacker, E. A. H. 1828. De ranula sublingua, speciali, cum casa
congenita. Monachii, Lindhauer.
71. Wernher, A. 1843. Die angeborenen Kysten-Hygrome und die ihnen
verwandten Geschwültste in anatomischer, diagnostischer und thera-
peutischer Beziehung. Geissen: G. F. Heyer, Vater.
72. Kransdorf, M. J. 1997. Vascular and lymphatic tumors. In M. J. Krans-
dorf and M. D. Murphey, editors. Imaging of Soft Tissue Tumors.
W.B. Saunders, Philadelphia. 118–123.
73. Brown, L. R., H. M. Reiman, E. C. Rosenow, 3rd, P. M. Gloviczki, and
M. B. Divertie. 1986. Intrathoracic lymphangioma. Mayo Clin. Proc.
61:882–892.
74. Ramani, P., and A. Shah. 1993. Lymphangiomatosis: histologic and immu-
nohistochemical analysis of four cases. Am. J. Surg. Pathol. 17:329–335.
75. Landing, B. H., and S. Farber. 1956. Tumors of the lymphatic vessels.
In Atlas of Tumor Pathology: Section III, Fascicle 7: Tumors of the
Cardiovascular System. Armed Forces Institute of Pathology, Wash-
ington, DC. F7.124–F7.138.
76. Rosai, J. 1995. Lymph vessels. In J. Rosai, editor. Ackerman’s Surgical
Pathology. Mosby, St. Louis. 2221–2226.
77. Virchow, R. 1856. Gesammelte Abhandlungen zur Wissenschaftlichen
Medicin. Meidinger Sohn, Frankfurt. 982.
78. Stocker, J. T., and J. E. Madewell. 1977. Persistent interstitial pulmo-
nary emphysema: another complication of the respiratory distress
syndrome. Pediatrics 59:847.
79. Leonidas, J. C., I. Bhan, and R. G. McCauley. 1979. Persistent localized
pulmonary interstitial emphysema and lymphangiectasia: a causal re-
lationship? Pediatrics 64:165–171.
80. Carlson, K. C., W. N. Parnassus, and E. C. Klatt. 1987. Thoracic lym-
phangiomatosis. Arch. Pathol. Lab. Med. 111:475–477.
81. Emerson, P. 1970. Clinical manifestations of disorders of the pulmo-
nary and pleural lymphatics. Thorax 25:256.
82. Marks, R., and J. P. Ellis. 1990. Yellow nails: a report of six cases. Arch.
Derm. 102:619–623.
83. DeCoste, S. D., M. J. Imber, and H. P. Baden. 1990. Yellow nail syn-
drome. J. Am. Acad. Dermatol. 22:608–611.
84. Hiller, E., E. C. Rosenow, and A. M. Olsen. 1972. Pulmonary manifes-
tations of the yellow nail syndrome. Chest 61:452–458.
85. Solal-Celigny, P., Y. Cormier, and M. Fournier. 1983. The yellow nail
syndrome: light and electron microscopic aspects of the pleura. Arch.
Pathol. Lab. Med. 107:183–185.
86. Kransdorf, M. J. 1994. Benign soft tissue tumors in a large referral pop-
ulation: distribution of specific diagnoses by age, sex, and location.
A.J.R. 164:395–402.
87. Chou, Y. H., C. M. Tiu, H. J. Chiou, C. R. Lai, C. C. Hsu, and C. Yu.
1999. Echo-enhancing sonography of a large-vessel hemangioma of
the neck. J. Clin. Ultrasound 27:465–468.
State of the Art
88. Drut, R., and H. H. Mosca.1996. Intrapulmonary cystic lymphangioma.
Pediatr. Pulmonol. 22:204–206.
89. Miyake, H., M. Shiga, H. Takaki, H. Hata, R. Onishi, and H. Mori.
1996. Mediastinal lymphangiomas in adults: CT findings. J. Thorac.
Imaging 11:83–85.
90. Wagenaar, S. S., J. Swierenga, and C. A. Wagenvoort. 1978. Late pre-
sentation of primary pulmonary lymphangiectasis. Thorax 33:791–
795.
91. Holden, W. E., J. F. Morris, R. Antonovic, T. H. Gill, and S. Kessler.
1987. Adult intrapulmonary and mediastinal lymphangioma causing
haemoptysis. Thorax 42:635–636.
92. Wright, C. C., D. M. Cohen, R. K. Vegunta, J. T. Davis, and D. R. King.
1996. Intrathoracic cystic hygroma: a report of three cases. J. Pediatr.
Surg. 31:1430–1432.
93. Hamada, K., Y. Ishii, M. Nakaya, N. Sawabata, K. Fukuda, and H. Su-
zuki. 1995. Solitary lymphangioma of the lung. Histopathology
27:482–483.
94. Karmazin, N., H. B. Panitch, R. K. Balsara, E. N. Faerber, and J. P. de
Chadarevian. 1989. De novo circumscribed pulmonary lobar cystic
lymphatic anomaly in a young boy: a possible sequela of bronchopul-
monary dysplasia. Chest 95:1162–1163.
95. Kim, W. S., K. S. Lee, I. Kim, K. M. Yeon, C. J. Kim, J. G. Chi, and
M. C. Han. 1995. Cystic intrapulmonary lymphangioma: HRCT find-
ings. Pediatr. Radiol. 25:206–207.
96. Milovic, I., and D. Oluic. 1992. Lymphangioma of the lung associated
with respiratory distress in a neonate. Pediatr. Radiol. 22:156.
97. Wada, A., R. Tateishi, T. Terazawa, M. Matsuda, and S. Hattori. 1974.
Case report: lymphangioma of the lung. Arch. Pathol. 98:211–213.
98. Nakazato, Y., Y. Ohno, Y. Nakata, H. Yamaguchi, N. Hazato, S. Na-
gasawa, M. Yokoyama, and T. Yamada. 1995. Cystic lymphangioma
of the mediastinum. Am. Heart J. 129:406–409.
99. Swischuk, L. E., J. C. Hoeffel, and S. D. John. 1996. Primary intratho-
racic lymphangioma masquerading as teratoma. Pediatr. Radiol. 26:
827–829.
100. Grosfeld, J. L., T. R. Weber, and D. W. Vane. 1982. One-stage resec-
tion for massive cervicomediastinal hygroma. Surgery 92:693–699.
101. Papsin, B. C., and J. N. Evans. 1996. Isolated laryngeal lymphangioma:
a rare cause of airway obstruction in infants. J. Laryngol. Otol. 110:
969–972.
102. Williams, W. T., and R. R. Cole. 1993. Lymphangioma presenting as
congenital stridor. Int. J. Pediatr. Otorhinolaryngol. 26:185–191.
103. Stocker, J. T. 1988. Congenital and developmental diseases. In D. H.
Dail and S. P. Hammar, editors. Pulmonary Pathology. Springer-
Verlag, New York. 41–57.
104. Javett, S. N., I. Webster, and J. L. Braudo. 1963. Congenital dilatation
of the pulmonary lymphatics. Pediatrics 31:416–425.
105. Mann, T. P. 1955. Hemihypertrophy left side of body: congenital lym-
phatic edema of left arm: radiological enlargement of heart shadow.
Proc. Royal Soc. Med. 48:330.
106. Moerman, P., K. Vandenberghe, H. Devlieger, C. Van Hole, J. P.
Fryns, and J. M. Lauweryns. 1993. Congenital pulmonary lymphang-
iectasis with chylothorax: a heterogeneous lymphatic vessel abnor-
mality. Am. J. Med. Genet. 47:54–58.
107. Gilewski, M. K., C. C. Statler, G. Kohut, and H. V. Toriello. 1996. Con-
genital pulmonary lymphangiectasia and other anomalies in a child:
provisionally unique syndrome? Am. J. Med. Genet. 66:438–440.
108. Sanders, J. S., E. C. Rosenow, J. M. Piehler, P. Gloviczki, and L. R.
Brown. 1988. Chyloptysis (chylous sputum) due to thoracic lym-
phangiectasis with successful surgical correction. Arch. Intern. Med.
148:1465–1466.
109. Moerman, P., C. Van Geet, and H. Devlieger. 1997. Lymphangiomato-
sis of the body wall: a report of two cases associated with chylothorax
and fatal outcome. Pediatr. Pathol. Lab. Med. 17:617–624.
110. Asch, M. J., A. H. Cohen, and T. C. Moore. 1974. Hepatic and splenic
lymphangiomatosis with skeletal involvement: report of a case and
review of the literature. Surgery 76:334–339.
111. Bell, K. A., and B. K. Simon. 1978. Chylothorax and lymphangiomas of
bone: unusual manifestations of lymphatic disease. South. Med. J.
71:459–460.
112. Goldstein, M. R., A. Benchimol, W. Cornell, and D. R. Long. 1969.
Chylopericardium with multiple lymphangioma of bone. N. Engl. J.
Med. 280:1034–1037.
113. Case records of the Massachusetts General Hospital. Weekly clinico-
pathological exercises. Case 30-1980. N. Engl. J. Med. 303:270–276.
114. Ogita, S., E. Deguchi, K. Tokiwa, J. Iwata, Y. Kubota, and N. Iwai.
1998. Ongoing osteolysis in patients with lymphangioma. J. Pediatr.
Surg. 33:45–48.
1045
115. Canil, K., P. Fitzgerald, and G. Lau. 1994. Massive chylothorax associ-
ated with lymphangiomatosis of the bone. J. Pediatr. Surg. 29:1186–
1188.
116. Peh, W. C., and H. Ngan. 1993. Lymphography: still useful in the diag-
nosis of lymphangiomatosis. Br. J. Radiol. 66:28–31.
117. Shah, A. R., R. Dinwiddie, D. Woolf, R. Ramani, J. N. Higgins, and
D. J. Matthew. 1992. Generalized lymphangiomatosis and chylotho-
rax in the pediatric age group. Pediatr. Pulmonol. 14:126–130.
118. Dunkelman, H., N. Sharief, L. Berman, and T. Ninan. 1989. Generalised
lymphangiomatosis with chylothorax. Arch. Dis. Child. 64:1058–1060.
119. Bhatti, M. A., J. W. Ferrante, I. Gielchinsky, and J. C. Norman. 1985.
Pleuropulmonary and skeletal lymphangiomatosis with chylothorax
and chylopericardium. Ann. Thorac. Surg. 40:398–401.
120. Young, J. W., M. Galbraith, J. Cunningham, B. S. Roof, I. Vujic, R. P.
Gobien, L. Liebscher, W. M. Butler, and H. H. Fudenberg. 1983.
Progressive vertebral collapse in diffuse angiomatosis. Metab. Bone
Dis. Relat. Res. 5:53–60.
121. Reilly, B. J., J. W. Davidson, and H. Bain. 1972. Lymphangiectasis of
the skeleton: a case report. Radiology 103:385–386.
122. Morphis, L. G., E. L. Arcinue, and J. R. Krause. 1970. Generalized lym-
phangioma in infancy with chylothorax. Pediatrics 46:566–575.
123. Gutierrez, R. M., and H. J. Spjut. 1972. Skeletal angiomatosis: report of
three cases and a review of the literature. Clin. Orthop. 85:82–97.
124. Gilsanz, V., H. C. Yer, and M. G. Baron. 1976. Multiple lymphangio-
mas of the neck, axillae, mediastinum and bones in an adult. Radiol-
ogy 120:161–162.
125. White, M. A. 1987. Lymphangioma of the tongue: report of case.
A.S.D.C. J. Dent. Child. 54:280–282.
126. Nair, L. G., and C. P. Kurtz. 1996. Lymphangiomatosis presenting with
bronchial cast formation. Thorax 51:765–766.
127. Takahashi, K., H. Takahashi, K. Maeda, S. Homma, T. Uekusa, T.
Dambara, and S. Kira. 1995. An adult case of lymphangiomatosis of
the mediastinum, pulmonary interstitium and retroperitoneum com-
plicated by chronic disseminated intravascular coagulation. Eur.
Respir. J. 8:1799–1802.
128. Swensen, S. J., T. E. Hartman, J. R. Mayo, T. V. Colby, H. D. Tazelaar,
and N. L. Muller. 1995. Diffuse pulmonary lymphangiomatosis: CT
findings. J. Comput. Assist. Tomogr. 19:348–352.
129. Bresser, P., J. G. Kromhout, J. A. Reekers, and T. L. Verhage. 1993.
Chylous pleural effusion associated with primary lymphedema and
lymphangioma-like malformations. Chest 103:1916–1918.
130. de Haan, H. P., J. Kolff, and B. Buis. 1984. Isolated chylopericardium
due to lymphangiomatous dysplasia of the thymus. Eur. Heart. J.
5:846–849.
131. Joshi, M., S. Cole, D. Knibbs, and D. Diana. 1992. Pulmonary abnor-
malities in Klippel-Trenaunay syndrome: a histologic, ultrastruc-
tural, and immunocytochemical study. Chest 102:1274–1277.
132. Malek, N. P., K. Ocran, U. J. Tietge, H. Maschek, K. F. Gratz, C. Trau-
twein, S. Wagner, and M. P. Manns. 1996. A case of the yellow nail
syndrome associated with massive chylous ascites, pleural and peri-
cardial effusions. Z. Gastroenterol. 34:763–766.
133. Calabrese, P. R., H. Frank, and H. L. Taubin. 1977. Lymphangiomyo-
matosis with chylous ascites: treatment with dietary fat restriction
and medium chain triglycerides. Cancer 40:895–897.
134. Duhra, P. M., E. M. Quigley, and M. N. Marsh. 1985. Chylous ascites,
intestinal lymphangiectasia and the “yellow-nail” syndrome. Gut
26:1266–1269.
135. Joliat, G., H. Stalder, and Y. Kapanci. 1973. Lymphangiomyomatosis: a
clinico-anatomical entity. Cancer 31:455–461.
136. Case records of the Massachusetts General Hospital. Weekly clinico-
pathological exercises. Case 8-1984: an elderly woman with protein-
losing enteropathy and pleural effusions. N. Engl. J. Med. 310:512–520.
137. Ishida, O., K. Tamura, H. Uchida, and C. Kuroda. 1979. Lymphographic
studies on protein-losing enteropathy. Lymphology 12:26–28.
138. Nazer, H. M., H. Abutalib, C. Hugosson, M. al-Mahr, and M. A. Ali.
1991. Intestinal lymphangiectasia masquerading as coeliac disease.
Ann. Trop. Paediatr. 11:349–355.
139. Sorensen, R. U., T. C. Halpin, C. R. Abramowsky, D. L. Hornick,
K. M. Miller, P. Naylor, and G. S. Incefy. 1985. Intestinal lymphang-
iectasia and thymic hypoplasia. Clin. Exp. Immunol. 59:217–226.
140. Vardy, P. A., E. Lebenthal, and H. Shwachman. 1975. Intestinal lym-
phangiectasia: a reappraisal. Pediatrics 55:842–851.
141. Dietz, W. H., Jr., and M. J. Stuart. 1977. Splenic consumptive coagulo-
pathy in a patient with disseminated lymphangiomatosis. J. Pediatr.
90:421–423.
142. Buttiker, V., S. Fanconi, and R. Burger. 1999. Chylothorax in children:
guidelines for diagnosis and management. Chest 116:682–687.
1046 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
143. Groves, L. K., and D. B. Effler. 1954. Primary chylopericardium. N.
Engl. J. Med. 250:520–523.
144. Furrer, M., M. Hopf, and H. B. Ris. 1996. Isolated primary chyloperi-
cardium: treatment by thoracoscopic thoracic duct ligation and peri-
cardial fenestration [see comments]. J. Thorac. Cardiovasc. Surg. 112:
1120–1121.
145. Yuksel, M., B. Yildizeli, F. Zonuzi, and H. F. Batirel. 1997. Isolated pri-
mary chylopericardium. J. Thorac. Cardiovasc. Surg. 114:299–300.
146. Mewis, C., V. Kuhlkamp, R. Sokiranski, and K. R. Karsch. 1997. Pri-
mary chylopericardium due to partial aplasia of the thoracic duct.
Eur. Heart J. 18:880–881.
147. Svedjeholm, R., K. Jansson, and C. Olin. 1997. Primary idiopathic chy-
lopericardium—a case report and review of the literature. Eur. J.
Cardiothorac. Surg. 11:387–390.
148. Yuksel, M., B. Yildizeli, F. Zonuzi, and H. F. Batirel. 1997. Isolated pri-
mary chylopericardium. Eur. J. Cardiothorac. Surg. 12:319–321.
149. Kentsch, M., V. Doring, U. Rodemerk, M. Schumacher, I. Stabenow,
B. Flor, and G. Muller-Esch. 1997. [Primary chylopericardium: step-
wise diagnosis and therapy of a differential diagnostically important
illness]. Z. Kardiol. 86:417–422.
150. Cordasco, E. M., Jr., S. Beder, A. Coltro, S. Bavbek, H. Gurses, and
A. C. Mehta. 1990. Clinical features of the yellow nail syndrome.
Cleve. Clin. J. Med. 57:472–476.
151. Hershko, A., B. Hirshberg, M. Nahir, and G. Friedman. 1997. Yellow
nail syndrome. Postgrad. Med. J. 73:466–468.
152. Fields, C. L., T. M. Roy, M. A. Ossorio, and P. J. Mercer. 1991. Yellow
nail syndrome: a perspective. J. Ky. Med. Assoc. 89:563–565.
153. Radivoyevitch, M. A., and S. A. Mirmiran-Yazdy. 1989. Lymphangioli-
poma of the mesentery. Am. Surg. 55:435–437.
154. Whitley, J. M., and A. M. Flannery. 1996. Lymphangiolipoma of the
thoracic spine in a pediatric patient with Proteus syndrome. Childs.
Nerv. Syst. 12:224–227.
155. Ardenghy, M., Y. Miura, R. Kovach, and J. Hochberg. 1996. Cystic hy-
groma of the chest wall: a rare condition. Ann. Plast. Surg. 37:211–213.
156. Jang, H. J., K. S. Lee, and J. Han. 1998. Intravascular lymphomatosis of
the lung: radiologic findings. J. Comput. Assist. Tomogr. 22:427–429.
157. Pui, M. H., Z. P. Li, W. Chen, and J. H. Chen. 1997. Lymphangioma:
imaging diagnosis. Australas. Radiol. 41:324–328.
VOL 161 2000
158. Mentzel, H. J., D. Schramm, S. Vogt, A. Reuter, T. Mentzel, and W. A.
Kaiser. 1998. Intra-abdominal lymphangioma in a newborn. J. Clin.
Ultrasound 26:320–322.
159. Liu, N. F., and C. G. Wang. 1998. The role of magnetic resonance imag-
ing in diagnosis of peripheral lymphatic disorders. Lymphology
31:119–127.
160. Fung, K., D. Poenaru, D. A. Soboleski, and I. M. Kamal. 1998. Impact
of magnetic resonance imaging on the surgical management of cystic
hygromas. J. Pediatr. Surg. 33:839–841.
161. Molitch, H. I., E. C. Unger, C. L. Witte, and E. vanSonnenberg. 1995. Per-
cutaneous sclerotherapy of lymphangiomas. Radiology 194:343–347.
162. Bloomfield, F. H., W. Hadden, and T. R. Gunn. Lymphatic dysplasia in
a neonate with Noonan’s syndrome. Pediatr. Radiol. 27:321–323.
163. Brown, R. L., and R. G. Azizkhan. 1998. Pediatric head and neck le-
sions. Pediatr. Clin. North Am. 45:889–905.
164. Gardner, T. W., A. C. Domm, C. E. Brock, and A. W. Pruitt. 1983.
Congenital pulmonary lymphangiectasis: a case complicated by chy-
lothorax. Clin. Pediatr. (Phila) 22:75–78.
165. Vogt-Moykopf, I., B. Rau, and D. Branscheid. 1993. Surgery for con-
genital malformations of the lung. Ann. Radiol. (Paris) 36:145–160.
166. Adamson, D., W. L. Heinrichs, D. M. Raybin, and T. A. Raffin. 1985.
Successful treatment of pulmonary lymphangiomyomatosis with
oophorectomy and progesterone. Am. Rev. Respir. Dis. 132:916–921.
167. Hillerdal, G. 1997. Chylothorax and pseudochylothorax. Eur. Respir. J.
10:1157–1162.
168. Pui, M. H., and T. C. Yueh. 1998. Lymphoscintigraphy in chyluria, chy-
loperitoneum and chylothorax. J. Nucl. Med. 39:1292–1296.
169. Collins, M. H., R. K. Darragh, R. L. Caldwell, M. W. Turrentine, and
J. W. Brown. 1995. Short-term survivors of pediatric heart transplan-
tation: an autopsy study of their pulmonary vascular disease. J. Heart
Lung Transplant. 14:1116–1125.
170. Rockson, S. G., L. T. Miller, R. Senie, M. J. Brennan, J. R. Casley-Smith,
E. Foldi, M. Foldi, G. L. Gamble, R. G. Kasseroller, A. Leduc, R.
Lerner, P. S. Mortimer, S. A. Norman, C. L. Plotkin, M. E. Rinehart-
Ayres, and A. L. Walder. 1998. American Cancer Society Lymphe-
dema Workshop. Workgroup III: Diagnosis and management of
lymphedema. Cancer 15;83 (12 Suppl. American):2882–2885.