The authors address the major features of lymphangioleiomyomatosis (LAM), a rare, idiopathic disease that affects women that is characterized by progressive smooth muscle proliferation in the lymphatics, blood vessels, and airways. LAM has many associated thoracic and abdominal findings that should be recognized by radiologists in order to help expedite the diagnosis and prevent misdiagnosis that could lead to unnecessary biopsies or surgeries.
Dr. Avila and Dr. Dwyer are Clinical Staff Radiologists in
the Diagnostic Radiology Department, Warren Grant Magnuson
Clinical Center, National Institutes of Health, Bethesda,
Lymphangioleiomyomatosis(LAM) is a rare, idiopathic disease that
affects women and is characterized by progressive smooth muscle
proliferation in the lymphatics, blood vessels, and airways.
Parenchymal cysts are the principal pulmonary finding in patients
with LAM. These may vary in size from a few millimeters to many
centimeters, and may vary in extent from a few scattered cysts to
diffuse replacement of the lung.
Some observers think that the cysts develop as a result of air
trapping distal to small airways narrowed by smooth muscle
Others have shown LAM cells to produce matrix metalloproteinases
that destroy both collagen and elastin in the pulmonary
interstitium. This suggests enzymatic breakdown of lung parenchyma
in the pathogenesis of the cysts.
In addition to these findings, patients with LAM have other
interesting pulmonary and abdominal imaging findings. Radiologists
should be aware of these to properly diagnose the disease. This
article will address the major imaging features of LAM and indicate
their prevalence in our NIH experience.
Chest radiography--The classic chest radiographic manifestations
of LAM include: interstitial lung disease, recurrent
pneumothoraces, and chylous pleural effusions.
The interstitial changes on radiographs actually result from
superimposition of parenchymal cysts, which are the hallmark of
this disease (figure 1A).
Evaluation of the pulmonary cysts in LAM is best done with CT;
chest radiographs often fail to demonstrate or may underestimate
the extent of disease.
More than 90% of patients may have lung cysts on CT scans that are
not apparent on radiographs. Only when the cysts are >1 cm in
diameter are they recognized clearly on chest radio-graphs.
CT and high-resolution CT (HRCT)--HRCT demonstrates that all
patients with LAM have pulmonary cysts. The cysts are better seen
on HRCT than on conventional CT scanning. HRCT shows no evidence of
interstitial lung disease, such as thickening of the interlobular
septae or reticulation in patients with LAM. Usually, the cysts are
distributed evenly throughout the lungs and vary in size from
millimeters to many centimeters (figure 1B). Cyst size on CT does
not correlate significantly with disease severity; patients with
the greatest extent of disease do not necessarily have the largest
Less common findings on chest CT include: pneumothorax,
pericardial effusion, dilated thoracic duct, pleural effusions, and
precarinal and retrocrural lymph nodes.
Ventilation/perfusion scans--On ventilation scans, patients with
LAM may have a pattern of "well-defined hot spots," which are
postulated to represent accumulation of radionuclide in peripheral
Presumably, aerosol DTPA droplets that adhere to the cyst walls
coalesce and result in focal collections of activity superimposed
on a background of activity within normal alveoli. This pattern of
uptake has been termed "speckling" and has been noted in
approximately two-thirds of patients with LAM. The degree of
speckling correlates with the extent of disease on CT scans and
chest radiographs and with pulmonary dysfunction. While the pattern
is nonspecific in its milder forms, it has a very distinctive
appearance in its severe form (figure 1C).
Pulmonary function studies--The results of pulmonary function
studies are abnormal in most patients with LAM. Commonly, FEV1%,
FEV1/ FVC%, and DLCO% LAM are significantly lower than the
predicted values. In contrast, the FVC and TLC (total lung
capacity) are similar to the predicted values. All major imaging
parameters of lung structure and function (overall ventilation,
perfusion, speckling, extent of disease on CT, average pulmonary
cyst size on CT, and extent of disease on chest radio-graphs)
correlate significantly with degree of impairment of FEV1%, DLCO%,
and FEV1/FVC%, but not with FVC% or TLC%. Cyst size correlates
significantly with worsening scintigraphic abnormalities, including
More than three-quarters of patients with LAM have positive
abdominal CT or sonography examinations, or both. Common abdominal
findings include: renal angiomyolipomas (in more than half of
patients); enlarged abdominal lymph nodes (in more than a third);
and lymphangioleiomyomas (in more than 20%).
Renal masses--The renal angiomyolipoma (AML), also called renal
hamartoma, is the most common tumor associated with LAM.
Renal AML is a benign tumor that contains vascular, muscle, and
fatty elements. A presumptive diagnosis can be made by the
demonstration of fat within the mass. Fat is usually diagnosed on
CT scans by very low attenuation numbers (less than -10 Hounsfield
units [HU]) and on ultrasound by a hyperechogenic appearance.
Neither CT nor ultrasound provides a definitive diagnosis, since
other benign tumors and even renal cell cancer can contain fat.
Given the high incidence of AML, a renal mass that contains fat in
a patient with LAM is most likely an AML. A major complication of
renal AMLs is hemorrhage, which may present as flank pain or shock
and may lead to nephrectomies if the correct diagnosis is not made.
The recommended management of renal angiomyolipomas is based on
tumor size and symptoms.
Patients with asymptomatic lesions <4 cm may be followed with
yearly sonography or CT. Lesions >=4 cm should be followed by
semiannual sonography or CT. Knowledge of the increased incidence
of AMLs in patients with LAM may be helpful in guiding therapy. If
a patient with renal pain or hematuria is known to have a renal
AML, partial nephrectomy or embolization should be considered
rather than a more radical procedure.
Thin-section nonenhanced CT is essential for visualization of the
fat content of angiomyolipomas (figure 2).
CT or sonography alone may not be sufficient to detect renal
angiomyolipomas. Sonography may miss the AMLs if they are isoechoic
to normal renal parenchyma and do not deform the renal contour or
if they are adjacent to normal renal sinus fat. CT may fail to find
small AMLs because of partial volume artifact.
Hence, in difficult cases, both studies should be performed to
ascertain the correct diagnosis. A minority of renal AMLs may have
an atypical appearance with no evidence of fat within the lesion;
some may have a solid or even complex appearance. Given an atypical
renal mass, biopsy should be recommended to exclude a malignant
Enlarged abdominal lymph nodes--More than a third of patients
with LAM have enlarged abdominal lymph nodes. The adenopathy may be
quite extensive; some of the lymph nodes may measure up to 4 cm in
diameter. Biopsy material obtained from lymph nodes demonstrates
replacement of the lymph nodes with smooth muscle. Some of the
abdominal lymph nodes may contain central areas of low attenuation,
ranging in attenuation from -72 HU to +50 HU (figure 3). Such low
Hounsfield numbers may indicate chylous lymph collections or fat
within the lymph nodes. Patients with LAM do not characteristically
have enlarged axillary or inguinal lymph nodes; this may help in
differentiating LAM from lymphoma.
Lymphangioleiomyoma--More than one-fifth of patients with LAM
have lymphangioleiomyomas (figure 4). These are complex lymphatic
masses resulting from dilatation and mural thickening of lymphatics
due to proliferation of smooth muscle cells in their walls.
The lymphangioleiomyomas are located most commonly in the
retroperitoneum, but may involve the pelvis or chest and rarely
involve the neck region. These masses may be large and have volumes
ranging from 10 to 1500 cc. Although most are lobulated and
well-defined, they may infiltrate the retroperitoneum and have
ill-defined borders. The majority have thin walls and contain low
attenuation material consistent with chyle. The areas of low
attenuation within the lymphangio-leiomyomas range in density from
3 to 25 HU.
Sonography may show cystic components, or thick, echogenic rinds
surrounding a central hypoechoic area.
The abdominal adenopathy and lymphangioleiomyomas may be
misdiagnosed as a neoplastic process, such as lymphoma. Indeed,
some patients who were asymptomatic from their lung disease were
diagnosed to have LAM from lymph node biopsies performed to exclude
Abdominopelvic ascitesApproximately 10% of patients with LAM
have abdominopelvic ascites, this ranges in attenuation from -10 to
+21 HU, the variation is thought to be related the amount of chyle
contained in the fluid.
Overdistension of lymph cysts may result in rupture and chylous
ascites, the onset of ascites sometimes accompanied by a marked
decrease in the size of the cystic retroperitoneal masses.
Dilatation of thoracic ductLess than one-tenth of patients
have dilated thoracic ducts. Dilatation of the thoracic duct may be
seen either as the result of lymphatic obstruction and smooth
muscle proliferation or as a result of thoracic duct ligation to
prevent recurrent pleural effusions in some patients.
Fatty liver massesApproximately 5% of patients have fatty
liver lesions consistent with AMLs or lipomas. These may be single
or multiple. The CT attenuation measurements of the hepatic lesions
range from -21 to -94 HU; all are echogenic on sonography.
Symptoms related to abdominal involvement with
Patients with LAM may have abdominal symptoms related to their
disease, including flank pain and hematuria, due to intratumoral
hemorrhage. They may resolve spontaneously or lead to partial
nephrectomy because of persistent or worsening symptoms.
Patients with lymphangioleiomyo-mas may report the following
symptoms: bloating and increased abdominal girth; abdominal pain;
nocturia; perineal swelling; and chylous vaginal discharge. Edema
of the lower extremities and paresthesias are reported by patients
with masses extending into the pelvis. Two patients have had
thoracic masses posterior and adjacent to the heart, one reported
Horner's syndrome and the other recurrent palpitations.
Patients with ascites may experience bloating.
Correlation of abdominopelvic imaging findings with
severity of lung disease
Patients with more severe lung disease are more frequently found
to have enlarged abdominal lymph nodes, renal AMLs, and
lymphangio-leiomyomas than those patients with less severe lung
Despite the suggestive appearance of LAM on CT scans, the
differential diagnosis, includes tuberous sclerosis (TSC),
Langerhans cell histiocytosis, and emphysema.
LAM can occur alone (referred to as "sporadic LAM") or in
association with TSC.
TSC is an autosomal dominant genetic disorder with pulmonary,
renal, and lymph node findings similar to LAM. It is thought that
LAM may be a "forme-fruste" of TSC.
A hallmark of TSC is the presence of multiple renal AMLs, which
occur in 40% to 80% of patients (mostly female) usually
bilaterally. In LAM, more than 50% of patients have solid renal
masses; but in contrast, these are multiple in less than one-fifth.
Although in TSC the AMLs occur in both genders, the cystic lung
disease is only found in women.
Patients with TSC have brain and skin findings (cortical tubers,
subependymal nodules, retinal hamartomas, facial angiofibromas,
periungual fibromas) not found in patients with LAM.
Patients with TSC have increased risk of renal cell carcinoma (1%
to 2%) and clear cell carcinoma; however, to date, there has been
no increased incidence of renal cancer reported in patients with
Specific genetic abnormalities in chromosomes 9q34 (TSC1) and 16p13
(TSC2) have been discovered in TSC.
Although no genetic defect has been discovered in LAM, some AMLs
and abdominal lymph nodes from women with LAM have been found to
have loss of heterozygosity in chromosome 16p13, this finding is
similar to that seen in TSC and suggests that LAM may be caused by
mutations of the TSC2 gene.
As in LAM, pulmonary cysts are a primary morphologic feature in
histiocytosis X. However, the cyst walls in Langerhans cell
histiocytosis are often more variable in thickness than those seen
in LAM. In addition, pulmonary nodules and cavitary nodules are a
common feature of histiocytosis X.
Furthermore, histiocytosis X characteristically involves the upper
two-thirds of the lungs and spares the costophrenic angles, whereas
LAM involves the lungs diffusely.
In emphysema, the lung cysts have almost imperceptible walls
compared with the cysts in LAM that have well-defined walls.
Although emphysema may be seen diffusely in the lungs, it may also
be distributed segmentally. In patients with LAM, the cysts are
distributed diffusely bilaterally.
Pulmonary LAM has a characteristic appearance of cysts
surrounded by normal lung on CT scans, and an abnormal speckling
pattern on ventilation/perfusion scintigrams. LAM has many
associated thoracic and abdominal findings that should be
recognized by radiologists in order to help expedite the diagnosis
and prevent misdiagnosis that could lead to unnecessary biopsies or
surgeries. Renal AML should be followed in order to plan embolic
therapy or partial nephrectomy in patients with developing or
worsening symptoms. Atypical renal AML should be followed and
biopsy performed if there is rapid growth of the mass. AR
The authors would like to thank Dr. Clara Chen from the Nuclear
Medicine Department at the Warren G. Magnuson Clinical Center for
the use of the ventilation/perfusion scintigram.