Nonmalignant Adult Thoracic Lymphatic Disorders

Nonmalignant Adult

Thoracic Lymphatic

Disorders

Maxim Itkin, MD, FSIR

, Francis X. McCormack,

INTRODUCTION

Primary lymphatic anomalies comprise a bewil-

dering array of congenital and acquired conditions

that can affect every organ system containing

lymphatic channels, generally considered to be

all tissues except brain and bone marrow.

Lymphatic anomalies usually come to medical

attention during childhood or early adulthood,

but can also present later in life. For the purpose

of this article, the discussion focuses on the

lymphatic disorders that involve thoracic struc-

tures, either primarily or as part of a more global

lymphatic disease process, and which preferen-

tially affect older children and adults.

The pulmonary lymphatics are a network of ves-

sels that function to transport cells and fluids from

the periphery of the lung to the central lymphatic

conduits, in order to regulate tissue pressure and

facilitate regional immune responses. The periph-

eral lymphatic vessels converge on the larger

conduits coursing on the surface of major airways

in the hila and mediastinum and ultimately drain

into the right lymphatic duct and thoracic duct

(TD). The right lymphatic duct inserts into the sub-

clavian vein in the neck and drains the right upper

lobe. The TD inserts into the left innominate vein at

the junction with the internal jugular vein and

drains the left lung, right middle and lower lobes

of the right lung, as well as all structures below

the diaphragm (

Fig. 1). A broad discussion of

lymphatic anatomy is beyond the scope of this

article, but it is important to note that intestinal

lymph (chyle) that contains chylomicrons (dietary

fats) enters the TD at the level of cisterna chyli in

the upper abdomen and is transported to the

venous system in the neck. The primary route thor-

ough which chylous fluid reaches the pleural space

or other thoracic structures in subjects with

chylous effusions, therefore, is either through (1)

reflux from an obstructed or pressure-overloaded

Disclosures: None.

Interventional Radiology, Hospital of the University of Pennsylvania, Penn Medicine, 1 Silverstein, 3400

Spruce Street, Philadelphia, PA 19104, USA;

Division of Pulmonary, Critical Care and Sleep Medicine, Univer-

sity of Cincinnati, MSB 6165, 231 Albert Sabin Way, Cincinnati, OH 45267-0564, USA

* Corresponding author.

E-mail address:

[email protected]

KEYWORDS



Lymphangioma



Lymphangiomatosis



Lymphangiectasia



Generalize lymphatic anomaly (GLA)



Gorham-Stout disease (GSD)



Kaposiform lymphangiomatosis (KL)



Pulmonary lymphangiectasia



Yellow nail syndrome

KEY POINTS

 The thoracic lymphatic disorders typically present with symptoms of cough, shortness of breath,

chyloptysis, or expectoration of branching casts.

 Typical pulmonary manifestations of the thoracic lymphatic disorders include chylous effusions,

peribronchiolar interstitial infiltrates, and mediastinal masses.

 The emergence of sophisticated imaging techniques that characterize abnormal lymphatic flow

promises to improve the classification and therapeutic approaches to the thoracic lymphatic

disorders.

Clin Chest Med 37 (2016) 409–420

http://dx.doi.org/10.1016/j.ccm.2016.04.004

chestmed.theclinics.com

TD into the pulmonary lymphatic stream, or (2)

through a pathologic connection between chylous

lymphatics and the pleural space, airways, or lung

parenchyma, as can occur following surgery or

trauma or as part of a pathologic process. Other

thoracic chylous complications that can result

from these 2 processes include chylous conges-

tion in the lung parenchyma,

plastic bronchitis

(PB; expectoration of branching casts),

chyloper-

icardium, and chyloptysis.

The thoracic lymphatic disorders (TLD)

comprise a group of diseases that are variably

associated with mediastinal or pulmonary masses,

interstitial infiltrates, airway disorders including

chyloptysis, PB, pleural effusions that are often

chylous, and repeated pulmonary infections and

bronchiectasis (eg, yellow nail syndrome, YNS).

Extrapulmonary manifestations of the TLDs can

include lymphatic leaks in various distributions

(eg, chylous ascites), protein-losing enteropathy,

recurrent fevers and prostration, lymphatic

obstruction resulting in lymphedema of extrem-

ities, coagulopathy, and bony lesions. The TLDs

often present in protean manner and can be

congenital or acquired, localized or systemic.

Attempts to classify these disorders have gener-

ally been based on defining commonalities of a

limited number of cases or the consensus of

experts.

3–6

Most of the published classification

systems use inconsistent terminology and lack

clear diagnostic, clinical, laboratory, or imaging

standards. The TLDs are often grouped based on

symptoms, age of presentation, histologic appear-

ance, associated illnesses, or secondary imaging

Visceral pleura

lymphatics

Contralateral

course

Ipsilateral

course

Visceral

pleura

lymphatics

Peribroncho-

vascular

lymphatic

collectors

Inferior

pulmonary

ligament

Intra-

abdominal

collectors

Visceral

pleura

lymphatics

Arch of

thoracic duct

Right

tracheobronchial

node

Subcarinal

node

Aortopulmonary

node

Left

tracheobronchial

node

Peribronchovascular

lymphatic collectors

Ipsilateral

course

Contralateral

course

Inferior

pulmonary

ligament

Intra-abdominal

collector

Visceral

pleura

lymphatics

Right lymphatic

collector arches

Arch of

thoracic

duct

Left

paratracheal

collectors

Superior

vena cava

Right

paratracheal

collectors

Fig. 1. Schematic representation of pulmonary lymphatic anatomy. (Adapted from Riquet M. Bronchial arteries

and lymphatics of the lung. Thorac Surg Clin 2007;17:619–38; with permission.)

Itkin & McCormack

410

findings rather than on unifying pathologic

processes.

Common terms that have been used to describe

primary lymphatic disorders include lymphan-

gioma, lymphangiectasia, lymphangiomatosis,

primary lymphedema,

pulmonary lymphangiecta-

sia (PL),

8–10

intrathoracic lymphangiomatosis,

thoracic lymphangiomatosis,

diffuse pulmonary

lymphangiomatosis,

and mediastinal lymphan-

giomatosis.

The mode of clinical presentation is

often added to modify these disease classifica-

tions, using terms idiopathic, congenital, neonatal,

or acquired to describe chylothorax, chylous asci-

tes, or chylopericardium.

15–18

In particular, the terms lymphangioma and lym-

phangiectasia have been used interchangeably to

describe a heterogeneous group of disorders

associated with excess lymphatic tissue. Although

both conditions are very similar histologically,

6,19

by definition lymphangiomas are sequestered

from the main lymphatic system, and lymphan-

giectasias are connected to it. The primary means

to differentiate between these 2 disorders clinically

is with imaging capable of revealing lymphatic

flow. Revealing lymphatic flow was formerly

accomplished with pedal lymphangiogram and

lymphoscintigraphy,

20,21

which have been re-

ported to demonstrate pathologic lymphatic flow

(“lymphatic reflux”) in lymphangiectasia despite

its limitations in anatomic definition.

22–24

Over the

last few decades, however, these procedures

have been less frequently performed and the

expertise required to execute them has been lost

to many radiology departments. Intranodal

lymphangiogram (IL)

and dynamic contrast-

enhanced magnetic resonance lymphangiogram

(DCMRL)

26,27

are new imaging techniques

that can better define lymphatic anatomy and

lymphatic flow. These approaches have

opened new vistas in the understanding the impor-

tance of lymphatic flow in primary lymphatic

disorders

26,27

and will likely lead to more rational

approaches to classification.

The International Society for the Study of

Vascular Anomalies (ISSVA) approved new guide-

lines for classification of the lymphatic disorders at

the 20th ISSVA Workshop in Melbourne, Australia

in 2014. Disorders of the pulmonary lymphatic

system include macrocystic, microcystic, and

mixed lymphatic malformations, generalized

lymphatic anomalies (GLA, also previously known

as diffuse lymphangiomatosis), lymphatic malfor-

mations in Gorham-Stout disease (GSD),

channel-type lymphatic malformations, and pri-

mary lymphedema. Not mentioned in the ISSVA

classification are disorders associated with com-

binations of lymphatic and other tissue anomalies,

including lymphangioleiomyomatosis (LAM), or

YNS. The disorders we have chosen to discuss

below are a subset of TLDs that might conceivably

present with pulmonary infiltrates, thoracic

masses, or chylous leaks in an adult pulmonary

clinic, including lymphangioma (a term that has

now been replaced with microcystic or macrocys-

tic lymphatic malformation), diffuse pulmonary

lymphangiomatosis (DPL; a term that is obsolete

but without an accepted replacement, here called

primary pulmonary lymphatic anomaly [PPLA]),

GLA with pulmonary involvement, a new subtype

of GLA called Kaposiform lymphangiomatosis

(KLA), lymphatic malformation in GSD, PB, and

YNS. Disorders that are exclusively found in neo-

nates primarily, are malignant, or which do not

typically involve thorax, such as congenital chylo-

thorax, primary lymphedema, Kaposi sarcoma, or

lymphangiosarcoma, are not discussed in this

article. An overriding theme in this review is the

importance of lymphatic imaging in classifying

and treating these disorders.

THORACIC LYMPHANGIOMAS (MICROCYSTIC

AND MACROCYSTIC LYMPHATIC

MALFORMATIONS)

Lymphangiomas are focal proliferations of well-

differentiated lymphatic tissue that present as

multicystic or sponge-like accumulations.

19,28

many cases, they represent embryologic rem-

nants of lymphatic tissues. Acquired or seco nd-

ary lymphangiomas can occ ur at the site of

radiation, trauma, or infection. Cystic lymphan-

giomas (also known as cystic hygromas or cystic

hydromas) can occur anywhere but are most

common in the armpit and the neck. In the

thorax,theymanifestasmassesinthemedias-

tinum,

29,30

pleura,

31,32

or intrapulmonary

distri-

butions (

Fig. 2). Mediastinal lymphangiomas are

equally distributed between the anterior, poste-

rior, and medial media stinal compartments and

often envelop and di splace mediastinal vessels.

Thoracic l ymphangiomas are usually detected

asnodulesorcysticmassesonchestradio-

graphs. MRI is the most useful diagnostic m odal-

ity, bec ause it accurately predicts i ntraoperative

findings, and heavy T2 weighting brightly eluci-

dates tumor boundaries. Histologically, l ym-

phangiomas are composed of an increased

number d ilated lymphatic channels and are filled

with proteinaceous fluid. Although most lym-

phangiomas occur in the first 2 years of life,

40% of 151 lymphangio mas reviewed in consul-

tation by the Air For ce Institute of Pathol ogy

were from patients who were older than 16 years

of age.

Clinically, intrathoracic lymphangiomas

Nonmalignant Adult Thoracic Lymphatic Disorders

411

can present as inci dental findings or associate d

with symptoms of organ compression, such a s

cough, dyspne a, stridor, or Horner syndrome.

Because they are often isolated from the main

lymphatic system, intrathoracic lymphangiomas

are typically not associated with c hylous pleural

effusions. Surgical resection o f mediastinal lym-

phangiomas has been successfully performed

to relieve compression on a djacent organs.

35,36

Recently, a high prevalence of PIK3CA mutations

have been repo rted in patients with lymphatic

malformations and malformative syndromes.

LYMPHANGIOLEIOMYOMATOSIS

LAM, also known as lymphangio myomatosis, is a

rare cystic lung disease that occurs most

commonly in women.

Recent research from

multiple laboratories has revealed that LAM is a

progressive, low-grade metastasizing neoplasm

associated with smooth muscle-like cell infiltra-

tion of the lung interstitium and cystic remodel-

ing of the pulmonary pare nchyma.

39,40

Cystic

changes consistent with LAM occur in both

men and women with tuberous sclerosis com-

plex,

associated with germ-line mutations in

either TSC1 or T SC2.

Sporadic LAM occurs

in patients who do not have TSC, has been re-

ported only in women, and is driven by somatic

mutations in TSC2.

43,44

Although the s ource of

LAM cells that infiltrate the lung is unknown,

available evidence suggests that the disease

spreads primarily through lymphatic chan-

nels.

45,46

Lymph node involvement is grea test

in low abdominal and pelvic locations and d e-

creases in a gradient-like fashion to the thor acic

mediastinum, suggestive o f an orig in in the

pelvis.

The ute rus is a prime candidate for the

source of LAM c ells, a notion that is supported

by the estrogen and progesterone receptor pos-

itivity of the neoplastic cells and multiple case

reports of uterine involvement in LAM.

48–51

Lymphatic manifestations of LAM include TD

wall invasion, mediastinal lymphangioleiomyoma

formation, and c hylous fluid collections in the

peritoneal, pleural, and pericardial spaces.

Abnormal communications between lymphatic

channels and hollow viscera can result in

protein-losing enteropathy, chyluria, chyloptysis,

chylocolporrhea ( chylometrorrhea), chyle leak

from the umbilicus, chylous pulmonary conges-

tion, and lower extremity lymphedema. LAM

lesions express lymphangiogenic growth factors,

vascular endothelial growth factor (VEGF)-C and

VEGF-D,

growth factor r eceptors, VEGFR-2

and VEGF R-3 (Flt-4), and m arkers LYVE-1 and

podoplanin, and are laced with chaotic lymphatic

channels.

Serum VEGF-D is elevated in 70% of

patients with LAM and is a clinically useful diag-

nostic and pro gnostic biomarker.

53–56

Molecular

targeted therapy with sirolimus is antilymphan-

giogenic and is effective at stabilizing lung func-

tion and for the lymphatic and chylous

complications of LAM,

51,57

although little is

known about the optimal dose and d uration of

the drug. Other approaches to control chylous

pleural effusions include pleurodesis, TD emboli-

zation, and TD ligation. Patients with problematic

or refractory chylous fluid collections and leaks

should undergo imag ing with IL

or DCMRL

26,27

to identify the source of the leak (Fig. 3). As an

example of the importance of understanding un-

derlying pathologic lymphatic anatomy and flow

before intervening, chylous pleural effusions

requiring repeated taps may be revealed by IL

or DCMRL to arise from lymphatic leakage into

the a bdomen rather than into the chest. Because

in those cases the thoracic effusion arises from

chylous ascites that is dr awn into the chest by

negative pleural pressures generated during

respiration, TD ligation would be contraindi-

cated. In this situation, embolization, pleurode -

sis, or sirolimus treatment would be preferred

approaches.

Fig. 2. MRI features of patient with mediastinal lymphangioma (arrows). (A) Axial T2-weighted MRI shows high

signal pretracheal and paratracheal masses. The high signal is due to high water content in lymphangiomas. (B)

The signal on T1-weighted image is similar to smooth muscle.

Itkin & McCormack

412

PRIMARY PULMONARY LYMPHATIC

ANOMALY

In rare cases, especially in children, primary

lymphatic anomalies may be entirely restricted to

the thoracic cavity. These disorders have been

reported in the literature as DPL,

13,19

pulmonary

lymphangiectasis,

intrathoracic lymphangioma-

tosis,

thoracic lymphangiomatosis,

and diffuse

pulmonary angiomatosis.

Tazelaar and col-

leagues

originally proposed the term “diffuse pul-

monary lymphangiomatosis,” but the most recent

ISSVA guidelines support the use of the suffix

“-oma” only in cases where the lymphatic abnor-

mality is known to be neoplastic. Indeed, most

lymphatic disorders discussed here are likely due

to persistence or duplication of well-differentiated

lymphatics rather than clonal tumor growth. Taze-

laar also proposed that DPL be distinguished

from PL, which he thought should be restricted to

the very rare congenital or secondary cause cases

where pulmonary lymphatics are dilated but not

increased in number. In the new classification of

vascular malformations, the ISSVA avoids using

the term lymphangiomatosis and describes 2

distinct lymphatic malformation conditions

:GLA,

and GSD. Because the ISSVA group does not

appear to have directly addressed the nomencla-

ture for the organ-restricted disorder formerly

known as DPL, the term PPLA is used here. On

gross examination, the lung parenchyma in cases

of PPLA does not reveal any discrete nodules or

masses. At low power, the lung may reveal spongi-

form expansion of interlobular septa, but no true

cysts. Histologically, PPLA is associated with

extensively anastomosing, variably sized, endothe-

lial cell-lined spaces distributed along lymphatic

routes throughout the lung. According to Tazelaar

and colleagues,

compared with PL, there is a

prominence of collagen and spindle-shaped cells

surrounding endothelial lined channels. Compared

with LAM, although hemosiderin-laden macro-

phages can be prominent in either, the surrounding

lung parenchyma is usually normal in PPLA. Chest

radiographs and computed tomography (CT)

scans reveal alveolar and interstitial infiltrates,

and pulmonary function tests often reveal a restric-

tive abnormality.

PPLA can be confused with

LAM because of the presence of vimentin and des-

min–positive spindle cell smooth muscle infiltrates

and chylous accumulations, but PPLA is generally

not associated with cystic change in the pulmonary

parenchyma or with positivity for HMB-45. There

are no known treatments for PPLA, but if proven

to be a true lymphangiectasia, it is possible that

the disorder could be treated by interruption of

caudal lymphatic flow, such as TD ligation or TD

embolization.

GENERALIZED LYMPHATIC ANOMALY WITH

PULMONARY INVOLVEMENT

GLA may affect the skin, superficial soft tissue,

abdominal and thoracic viscera, and bone.

GLA

Fig. 3. (A) DCMRL imaging of a patient with LAM, demonstrating large retroperitoneal masses (black arrow),

prominent TD (white arrow), and abnormal branching of the lymphatic vessels from TD, resulting in development

of chylothorax (arrowhead). (B) Corresponding fluoroscopy image of the TD of the same patient, following injec-

tion of contrast material through the microcatheter positioned in the proximal part of TD. Injection confirms mild

dilation of the TD (white arrow) and abnormal branching of the lymphatic vessels from the TD, resulting in devel-

opment of chylothorax (arrowhead).

Nonmalignant Adult Thoracic Lymphatic Disorders

413

has been described in all ages, from birth to age 80.

Thoracic involvement is common and often in-

cludes mediastinal lymphangioma, chylothorax,

chylopericardium, chyloptysis, or PB, and intersti-

tial changes that are often most prominent along

bronchovascular bundles. Extrapulmonary fea-

tures can include chylous ascites, protein-losing

enteropathy, peripheral lymphedema, lymphope-

nia, hemihypertrophy, and disseminated intravas-

cular coagulopathy. Bony involvement is common

in GLA. When present, GLA tends to spare the cor-

tex and to follow a more stable course than GSD.

Single or multiple lymphangiomyomas can be

found within the mediastinum, diffusely infiltrating

mediastinal fat, or adherent to the pleura or chest

wall. Lymphangiography reveals multiple lesions

of the TD, dilated lymphatic channels, and lym-

phangiomas throughout the bones and lungs.

Bilateral interstitial infiltrates or pericardial and

pleural effusions are often present on the chest

radiograph. Pulmonary function tests may reveal

a restrictive pattern, but mixed patterns are also

found. CT scans of the thorax reveal diffuse thick-

ening of intralobular septa and bronchovascular

bundles with extensive involvement of mediastinal

fat and perihilar regions. Histopathology demon-

strates anastomosing endothelial-lined spaces

along pulmonary lymphatic routes. Heavy T2-

weighted MRI may reveal lymphatic anomalies in

the thorax and abdomen, and IL

or DCMRL

26,27

can be used to define abnormal lymphatic low. A

recent phase II trial demonstrated that sirolimus

resulted in at least partial responses in 100% of pa-

tients with GLA.

GORHAM-STOUT DISEASE

GSD, also called vanishing bone disease, is asso-

ciated with abdominal and thoracic visceral

lymphatic involvement, effusions, and destructive

bony disease (

Fig. 4).

In contrast to GLA, GSD

involves the bone cortex and can result in progres-

sive osteolysis.

Tissue samples are positive for

lymphatic endothelial cell markers, suggesting

that GSD is primarily a disease of disordered lym-

phangiogenesis.

Current treatments for GSD are

primarily symptomatic and supportive and include

control of mass effect using sclerotherapy,

and

conservative and surgical treatment of chylous

leaks. In a recent phase II trial of sirolimus treat-

ment, 3 of 3 patients with GSD had partial

responses.

KAPOSIFORM LYMPHANGIOMATOSIS

KLA is a newly characterized entity that was

initially described as a subtype of GLA but is now

pathologically differentiated from that disorder by

the presence of clusters or sheets of spindle-

shaped lymphatic endothelial cells infiltrating mal-

formed lymphatic channels.

It is important to

distinguish KLA from PPLA or GLA because it

tends to follow a more aggressive course, at least

in children. Characteristic hematological abnor-

malities that occur in KLA can be helpful in that

regard, including elevated fibrin split products

and

D-dimer, low fibrinogen and platelet count.

Hemorrhagic complications also occur, including

bloody effusions and expectorations. As with

GLA, dilated, malformed lymphatic channels are

lined by a single layer of endothelial cells in KLA.

However, in KLA, foci of pattern-less clusters of

intralymphatic or perilymphatic podoplanin,

PROX1, and LYVE-1-positive spindled cells are

found associated with platelet microthrombi,

extravasated red blood cells, hemosiderin, and

fibrosis without significant atypia or mitoses. It is

not known whether spindled cells are clonal/

neoplastic or reactive. Although the disease typi-

cally presents in early childhood, later onset has

also been reported.

The most common manifes-

tations of KLA are respiratory symptoms, including

cough, shortness of breath and hemoptysis (50%),

hemostatic abnormalities (50%), enlarging,

palpable masses (35%),

mediastinal masses,

interstitial infiltrates (

Fig. 5), and effusions, which

can be chylous or hemorrhagic. Dilated, blood-

filled lymphatic channels may be visualized on

the pleural surface during video-assisted thoraco-

scopic surgery. Hemorrhagic lesions have also

been seen on peritoneal and pericardial surfaces.

Progressive interstitial lung disease and chylous

Fig. 4. Chest radiograph of an 11-year-old patient

with GSD. Note the absence of the left clavicle (black

star) due to osteolysis.

Itkin & McCormack

414

pleural effusions can lead to respiratory failure.

Vincristine and sirolimus treatment have been re-

ported in KLA.

70,71

In a recent phase II sirolimus

trial, 5 of 7 patients with KLA had a partial

response and 1 had stable disease.

CHYLOPTYSIS AND PLASTIC BRONCHITIS

PB describes a heterogenous group of allergic,

immunologic, infectious, cardiac, neoplastic, and

lymphatic disorders that are associated with

expectoration of bronchial casts.

PB as it has

been defined is not a single disease with a unifying

mechanism that explains cast formation in all con-

ditions. Indeed, it is not clear that PB is always

associated with bronchitis, defined as disruption,

dysfunction, or inflammation of bronchial mucosa.

In most cases of true PB, the bronchial system

may be serving as no more than a mold for con-

gealing bronchial contents. This finding is certainly

true in the most common form of PB, which follows

cardiac surgery for congenital heart disease,

especially the Fontan procedure. In these cases,

abnormal pulmonary lymphatic flow (

Fig. 6) results

in leakage of proteinaceous and lipid-rich fluids

into the bronchial tree.

Recently, heavy T2-

weighted MRI has revealed that occult lymphatic

anomalies that represent developmental remnants

or subclinical GLA are present in adults who pre-

sent with expectoration of large multiantennary,

branching casts.

and DCMRL

26,27

have

been used to more precisely image the leaks,

and in the small number of patients who have

been treated to date, embolization of the TD has

Fig. 5. Chest radiograph and chest CT of a patient with KLA shows increased interstitial markings.

Fig. 6. (A) DCMRL in patient with idiopathic PB demonstrating small TD (white arrow) and abnormal pulmonary

lymphatic perfusion in the mediastinum and lung hila (white arrowheads). (B) Corresponding fluoroscopy image

of the TD of the same patient, following injection of contrast material through the microcatheter positioned in

the proximal part of TD, demonstrating occlusion of the distal part of the TD (white arrow) and retrograde flow

of the contrast in the mediastinal lymphatic ducts (black arrowheads).

Nonmalignant Adult Thoracic Lymphatic Disorders

415

been highly successful in controlling cast forma-

tion (Maxim Itkin, Francis X. McCormack, Yoav

Dori, unpublished data, 2016). The authors submit

that lymphatic causes should be considered in all

patients who present with expectoration of

complex, multiantennary branching casts. Heavy

T2-weighted MRI, and, as appropriate, IL and/or

DCMRL may be useful for identifying pathogenic

lymphatic tissue and lymphatic flow. Cannulation

of the TD followed by embolization should be

considered in those patients who are shown to

have leakage of lymphatic fluid into the airway.

Therapeutic interventions with medium-chain tri-

glyceride-enriched low-fat diets, intratracheal

heparin, inhaled tissue plasminogen activator,

and steroids have also been reported and have

met with variable success.

74–77

PULMONARY LYMPHANGIECTASIA

PL describes pathologic dilation of lymphatic ves-

sels in the lungs. Both primary and secondary

forms have been described. The former primarily

occurs in neonates due to failure of pulmonary

interstitial tissues to regress and is typically fatal,

and the secondary forms are usually due to pro-

cesses that impair lymphatic flow or increase

lymph production. The ISSVA defined isolated

lymphangiectasia as a lymphatic conductive dis-

order,

highlighting that the ectatic lymphatic ves-

sels are connected to the main lymphatic system.

As a result, a common presentation of thoracic

lymphangiectasia is chylous effusion. The cause

of lymphangiectasia is unknown, but may be due

to congenital occlusion of parts of the central

lymphatic system, such as the TD, absence of

the lymphatic valves, or lymphatic fluid overpro-

duction that results in overdistention and over-

growth of the lymphatic vessels.

The clinical presentation of PL includes respira-

tory symptoms of wheezing, chronic cough or

chest pain, bilateral interstitial infiltrates, restrictive

pulmonary physiology, and pericardial and pleural

effusions.

The diagnosis of PL is based on dilated

lymphatic vessels in perivascular and peribron-

chial distributions on pathologic analysis,

patchy ground glass opacification and thick-

ening of the interlobular septa on CT,

or reflux

of contrast into the lung parenchyma on

lymphangiogram.

Occlusion and narrowing of the upper part of the

TD with retrograde pulmonary lymphatic flow oc-

curs in patients with idiopathic chylopericardium

and chylothorax on DCMRL and IL (

Fig. 7). For

that reason, the authors recommend DCMRL

and IL as the first imaging modalities for a patient

presenting with idiopathic chylothorax/chyloperi-

cardium with and without lung disease.

Treatments that have been attempted for PL

include thoracentesis, dietary modification, pleu-

rodesis, octreotide, and interruption of cranial

thoracic lymphatic flow (TD embolization, TD

ligation).

Prognosis is usually good in cases

where chylothorax and chylopericardium can be

controlled.

THE YELLOW NAIL SYNDROME

Of all the TLDs, the YNS is one of the most likely to

present in adulthood, at a median age of 40 to

50 years.

81,82

The YNS was first described by

Fig. 7. (A) DCMRL in a patient with pulmonary lymphangiectasia demonstrating dilated TD (white arrow) and

abnormal pulmonary lymphatic perfusion in the lung hilum (white arrowheads). (B) Corresponding fluoroscopy

image of the TD of the same patient, following injection of contrast material through the microcatheter posi-

tioned in proximal part of TD, confirms the dilation of the TD (white arrow) and retrograde flow of the contrast

in the mediastinal lymphatic ducts (white arrowhead).

Itkin & McCormack

416

White and Samman in 1964,

now defined as the

triad of yellow dystrophic fingernails (86%), pleural

effusion (36%), and idiopathic lymphedema (80%).

Only 20% to 30% of cases have all 3 manifesta-

tions, and the presence of any 2 is generally

considered to be diagnostic. More than 60% of

patients develop sinopulmonary manifestations

other than pleural effusion, which can include

chronic cough, repeated infection, rhinosinusitis,

recurrent pneumonia, bronchiectasis, and sinus-

itis. Whether YNS represents a genetic or acquired

disorder remains controversial.

84,85

Wells

described an extended family with 8 affected

members.

The proband developed lower ex-

tremity lymphedema as well as edema in the vocal

cords, genitalia, hands, and face. Although cases

of YNS have occurred in patients with connective

tissue disease, neoplasms, immunodeficiencies,

and endocrine disorders, it is unclear if these

disorders play a direct role in disease pathogen-

esis or simply represent chance associations. In

the largest retrospective study of YNS to date, 9

of 150 patients were found to have a family history

of lymphedema or YNS.

Two reports of infants

born with hydrops and chylothorax to

mothers with YNS suggest a heritable cause in

some cases.

87,88

Mutations in the FOXC2 gene

have been described in patients with the

lymphedema-distichiasis (LD) syndrome, some of

whom also have yellow nails, leading Finegold

and colleagues

to conclude that there is pheno-

typic overlap between LD and YNS. A subsequent

analysis of 4 families with YNS revealed no evi-

dence of FOXC2 mutations, however.

It is impor-

tant to note that although nail changes and

yellowing occur in other forms of lymphedema,

the nail manifestations of YNS are quite distinctive

and include marked thickening, very slow growth,

excessive side-to-side curvature, loss of lunulae

and cuticles, and detachment from the nail bed

(onycholysis).

It is interesting that the nail

changes in YNS can spontaneously regress. The

male:female ratio of affected patients is 1.2/1.

Pulmonary effusions are bilateral in 68% of cases

and are most commonly lymphocytic exudates.

Chylothorax is documented in a minority of cases

in retrospective series (w20%), but it is unclear if

the diagnosis was rigorously pursued in all cases.

Pleural effusions routinely reoccur despite

repeated taps, but pleurodesis is effective in

more than 80% of cases. Pericardial effusions

have also been described, and in some cases,

have required pericardiectomy. Nail matrix bi-

opsies reveal ectatic endothelial lined channels

and dense stromal fibrosis, and pleural biopsies

demonstrate dilated lymphatics associated with

lymphocytic pleuritis and moderate fibrosis.

Lymphangiograms and lymphoscintigraphy often

reveal hypoplasia of lymphatics. There is no effec-

tive treatment for YNS, but octreotide therapy has

been attempted in some cases.

92,93

SUMMARY AND FUTURE DIRECTIONS

There has been an explosion in molecular under-

standing of lymphatic development in the last 2

decades, yielding powerful new markers to probe

disease pathogenesis in the TLD.

More detailed

histopathologic and immunohistochemical char-

acterization using these tools is defining subsets

of GLA that exhibit more aggressive behavior.

Improved imaging of the lymphatic system (eg,

DCMRL) promises to rapidly enhance the under-

standing of the pathogenesis of TLD. Genetic ana-

lyses are revealing the genetic basis of lymphatic

malformation and primary lymphedema disorders.

Recent trials of the antilymphangiogenic drug

sirolimus have revealed stabilizing effects on lung

function, reversal of chylous effusions, shrinkage

of lymphatic masses, and promising benefits in

many of the complex vascular anomalies

described here. Lymphatic biomarkers that are

useful diagnostically and correlate with disease

progression have been reported. Recent technical

advances have resulted in novel approaches

to controlling lymphatic leaks. Powerful new ap-

proaches to molecular and genetic characteriza-

tion promise to shed new light on disease

pathogenesis and uncover novel therapeutic

targets.

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