Diagnostic approach to the adult with cystic

lung disease
Authors: Anupam Kumar, MD, FCCP, Robert M Kotloff, MD
Section Editors: Talmadge E King, Jr, MD, Nestor L Muller, MD, PhD
Deputy Editors: Geraldine Finlay, MD, Paul Dieffenbach, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.

Literature review current through: Feb 2023. | This topic last updated: Feb 16, 2023.

INTRODUCTION

Cystic lung diseases represent a heterogenous group of disorders that

share in common the radiographic feature of multiple air-filled lucencies
surrounded by discrete walls.

Conditions that are commonly referred to as diffuse cystic lung diseases

include lymphangioleiomyomatosis (LAM), pulmonary Langerhans cell
histiocytosis (PLCH), Birt-Hogg-Dubé syndrome (BHD), and lymphoid
interstitial pneumonia (LIP), although the differential diagnosis can at times
expand to encompass other extremely rare etiologies [1,2].

An approach to the diagnosis of diffuse cystic lung disease in adults will be

reviewed here. The clinical manifestations, evaluation, and management of
the individual causes of diffuse cystic lung disease are discussed in greater
detail separately. (See "Sporadic lymphangioleiomyomatosis: Clinical
presentation and diagnostic evaluation" and "Pulmonary Langerhans cell
histiocytosis" and "Birt-Hogg-Dubé syndrome" and "Lymphoid interstitial
pneumonia in adults".)

DEFINITION
Cysts and parenchymal lucencies that mimic cystic disease are typically
defined by their appearance on high resolution computed tomography (CT)
( table 1).

Cysts — A pulmonary cyst is defined as a "round parenchymal lucency or

low-attenuating area with a well-defined interface with normal lung" [3].
(See 'Parenchymal lucencies that may mimic cysts' below.)

Parenchymal lucencies that may mimic cysts — Causes of lung

parenchymal lucencies that may mimic cysts but do not fit the definition of
true cystic lung disease include bullae, blebs, bronchiectasis, cavities, and
pneumatoceles ( table 1).

● Emphysema – Areas of emphysema appear as polygonal or rounded

low-attenuation areas. A central dot representing the pulmonary artery
contained within the secondary pulmonary lobule can sometimes be
seen [3]. Emphysematous areas, by definition, lack walls. However, this
distinction may be difficult to discern, as interlobular septa
surrounding emphysematous areas of lung may be misinterpreted as
walls ( image 1A-B). Some forms of atypical emphysema present as
lucencies that are indistinguishable from cysts. Conversely, in
advanced stages, cystic lung disease may coalesce into larger areas of
low attenuation that mimic emphysema ( image 1A-B).

● Bulla – The term bulla refers to a region of focal lucency that is >1 cm
in diameter, bounded by a thin wall (<1 mm) and usually accompanied
by adjacent emphysema. Bullae can be isolated and vary in size,
sometimes filling the hemithorax ( image 2 and image 3). A bleb is
a type of subpleural bulla; the term bleb is now discouraged.

● Honeycombing – Honeycombing represents the advanced, destructive

phase of a variety of fibrotic lung disorders that lead to enlarged
airspaces with thick fibrous walls. On high resolution CT,
honeycombing appears as clustered hypolucent areas ranging in
 diameter from 0.3 to 1.0 cm (but occasionally as large as 2.5 cm), with
well-defined, often thick walls ( image 4 and image 5) [3].
Honeycombing areas tend to be subpleural, stacked together in
contiguous rows and sharing common walls. Associated radiologic
features such as architectural distortion, subpleural reticular changes,
and traction bronchiectasis further aid in distinguishing honeycombing
due to pulmonary fibrosis from cystic lung disease.

● Bronchiectasis – Bronchiectatic cysts (also known as "cystic

bronchiectasis") can be differentiated from cystic lung disease based
on their continuity with an airway, tendency to form clusters
( image 6), and associated findings of tram lines and signet or
Cabochon ring sign. (See "High resolution computed tomography of
the lungs", section on 'Bronchiectasis'.)

● Cavitary lung disease – Pulmonary cavities are typically thick-walled

(>4 mm) gas-filled spaces often within an area of consolidation, mass,
or nodule and may be filled with other contents in addition to air (eg,
fluid, debris, mycetoma ( image 7)) [4].

● Pneumatoceles – Pneumatoceles are a type of thin-walled

parenchymal cyst ( image 8). They most commonly arise in the
setting of acute bacterial pneumonia, typically in children, but can also
result from Pneumocystis jirovecii pneumonia ( image 9), chest
trauma, or barotrauma from mechanical ventilation. While usually few
in number, pneumatoceles can occasionally be numerous and in such
cases, can be confused with the more diffuse cystic lung diseases.
Notably, pneumatoceles are typically asymptomatic and often
disappear following resolution of the inciting event.

CAUSES OF CYSTIC LUNG DISEASE

The majority of adults with cystic lung disease have one of four underlying
diseases: lymphangioleiomyomatosis (LAM), pulmonary Langerhans cell
histiocytosis (PLCH), Birt-Hogg-Dubé syndrome (BHD), or lymphoid
interstitial pneumonia (LIP).

A separate category of cystic lung disease is associated with infectious

etiologies; these patients typically present with acute onset of symptoms
with fever and/or chills. Often the lung cysts are pneumatoceles that are
caused by the infection (eg, coccidioidomycosis,
hyperimmunoglobulinemia E syndrome, Pneumocystis jirovecii, recurrent
respiratory papillomatosis, staphylococcal pneumonia) [5-12]. (See
'Parenchymal lucencies that may mimic cysts' above.)

Thin-wall cysts have been reported in 13 percent of 182 patients with

nonfibrotic hypersensitivity pneumonitis (HP) [13,14]. The cysts measured
25 mm or less in diameter, ranged from 1 to 15 (average 4) in number, and
had a random distribution. They are more common in fibrotic HP having
been reported in 39 percent of patients in one study [15].

Occasionally, multiple pulmonary cysts may be the initial manifestation of

metastatic cancer, such as squamous cell cancers (eg, head and neck,
cervical) [16], invasive mucinous adenocarcinoma [17], and angiosarcoma
( image 10) [18].

Less common causes of diffuse cystic lung disease are listed in the table
( table 2). Examples include pulmonary amyloidosis [19,20], Sjögren
syndrome [21], light chain deposition disease [22], Ehlers Danlos syndrome
type IV [23], fire-eater's lung (pneumatoceles) [24,25], lymphomatoid
granulomatosis [26], neurofibromatosis [27], congenital pulmonary airway
(cystic adenomatoid) malformation, smoking related small airways injury
[28], and Proteus syndrome [29]. (See "Overview of amyloidosis" and
"Clinical manifestations and diagnosis of Ehlers-Danlos syndromes",
section on 'Vascular EDS' and "Pulmonary lymphomatoid granulomatosis"
and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and
diagnosis", section on 'Other manifestations' and "Congenital pulmonary
airway malformation" and "Common causes of hoarseness in children",
section on 'Papillomatosis' and "PTEN hamartoma tumor syndromes,
including Cowden syndrome", section on 'Proteus-like syndrome' and
"Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical
manifestations and diagnosis", section on 'Other processes caused by
inhalation of organic agents'.)

CLUES TO AN ETIOLOGY FOR CYSTIC LUNG DISEASE

Patients with cystic lung disease may be asymptomatic, with radiographic

abnormalities incidentally discovered on CT obtained for other reasons, or
may present with respiratory symptoms, most commonly dyspnea or
cough. Often, spontaneous pneumothorax is the presenting manifestation.
However, none of these features is specific for a particular cystic lung
disease. Importantly, the history, examination, and CT findings together
guide the diagnostic evaluation.

Clinical history — A detailed clinical history can help to narrow the

differential diagnosis of diffuse cystic lung disease. As examples,
underlying systemic disease, such as tuberous sclerosis complex or Sjögren
syndrome, can direct attention to possible lymphangioleiomyomatosis or
lymphoid interstitial pneumonia, respectively, while a family history of renal
cancer or pneumothorax, might raise suspicion for Birt-Hogg-Dubé
syndrome.

Age, sex, and ethnicity

● Lymphangioleiomyomatosis – Lymphangioleiomyomatosis (LAM) is a

disorder that almost exclusively affects females; reported cases of LAM
in males have, with one exception, occurred in association with
tuberous sclerosis complex (TSC) [30,31]. Symptoms typically develop
in the third and fourth decades of life [32]. In the United States, White
 people comprised 87 percent of patients enrolled in the National
Heart, Lung, and Blood Institute LAM Registry, with Black or African
Americans accounting for 6 percent, and Asian Americans accounting
for 4 percent [32]. (See "Sporadic lymphangioleiomyomatosis: Clinical
presentation and diagnostic evaluation".)

● Pulmonary Langerhans cell histiocytosis – Pulmonary Langerhans

cell histiocytosis (PLCH) most commonly affects young adults, typically
between the ages of 20 to 40. Sex distribution is equal to slightly
female-predominant [33]. Reliable figures on racial distribution are
lacking, though White individuals comprise the overwhelming majority
of cases documented in the literature. (See "Pulmonary Langerhans
cell histiocytosis".)

● Birt-Hogg-Dubé syndrome – Lung cysts are seen in up to 84 percent

of patients with Birt-Hogg-Dubé syndrome (BHD) and appear at a
median age of 30 to 40 years [34-36]. Up to one-third of patients
present with a spontaneous pneumothorax, with a median age of
occurrence of 38 years [37]. However, the earliest and often overlooked
manifestation of the disease is the development of cutaneous
fibrofolliculomas on the face, neck, and chest that can be seen
beginning in the third decade of life. There does not appear to be a
particular sex predilection, and data on racial distribution are
insufficient to allow comment. (See "Birt-Hogg-Dubé syndrome".)

● Lymphoid interstitial pneumonia – Demographic information is not

helpful in supporting a diagnosis of lymphoid interstitial pneumonia
(LIP).

Smoking — The nearly universal association of PLCH with current or

former cigarette smoking is well established [33]. Thus, PLCH is an
exceedingly unlikely diagnosis in a never-smoker with cystic lung disease.
Among five patients with BHD syndrome, cigarette smoking was associated
with more severe cystic changes and recurrent pneumothoraces [38], but in
a large single family cohort, cigarette smoking had no correlation with the
size or number of cysts [39].

Family history — A family history of lung disease or extrapulmonary

findings is often present in patients with BHD and TSC-LAM, but not PLCH
or LIP.

BHD is inherited in an autosomal dominant pattern and often affects

multiple family members [40]. As such, eliciting a careful family history of
spontaneous pneumothorax, lung cysts (often misdiagnosed as bulla or
emphysema), renal neoplasms, and fibrofolliculomas can provide
important clues to the diagnosis. In one study of 114 consecutive patients
presenting with spontaneous pneumothorax, seven patients had a family
history of pneumothorax and six of these were found to have BHD [41].
(See "Birt-Hogg-Dubé syndrome".)

Patients with TSC-LAM may have a family history of intellectual disability,

seizures, or cutaneous angiofibromas. (See "Tuberous sclerosis complex:
Genetics, clinical features, and diagnosis".)

Pulmonary manifestations — The most common respiratory symptoms

associated with these disorders are cough and dyspnea. Patients may also
present with a spontaneous pneumothorax or pleural effusion.

Pneumothorax — Pneumothorax is a frequent manifestation of cystic

lung disease, and may be the initial event calling attention to its presence.
The prevalence of spontaneous pneumothorax is highest in LAM patients,
in the range of 50 to 60 percent [32,42]. Reported frequencies of
pneumothorax among patients with BHD and PLCH are 24 to 38 percent
and 16 percent, respectively [43,44]. Pneumothorax is an uncommon
manifestation of LIP, likely reflecting the paucity of cysts present in this
disease.
Pleural effusion — Chylous effusions develop in roughly 10 percent of
patients with LAM [42]. The combination of diffuse cystic lung disease on
high resolution CT and chylous effusion is most often due to LAM, although
lymphoma is a rare mimic of this combination. Pleural effusion is unusual
in other forms of cystic lung diseases.

Extrapulmonary manifestations — Presence of extrapulmonary

manifestations can provide important clues to distinguish between the
various cystic lung diseases. Careful history (eg, abdominal swelling,
polyuria, polydipsia) and examination of the skin (manifestations of TSC
and BHD), together with imaging of the abdomen may identify
extrapulmonary manifestations to support an underlying etiology for a
specific cystic lung disorder.

● LAM – Manifestations associated with LAM include (see "Sporadic

lymphangioleiomyomatosis: Clinical presentation and diagnostic
evaluation", section on 'Nonpulmonary'):

• Renal angiomyolipomas (AMLs; approximately 30 percent)

( image 11)

• Chylous ascites (10 percent)

• Lymphangioleiomyomas (up to 40 percent)

• Cutaneous manifestations of TSC, such as malar angiofibromas,

hypopigmented macules (ash-leaf spots), Shagreen patches, and
periungual fibromas

• Neurologic manifestations of TSC, including cognitive impairment,

seizures, subependymal giant cell astrocytomas, cortical
glioneuronal hamartomas, and subependymal nodules

● PLCH – Extrapulmonary involvement is seen in approximately 20

percent of patients with PLCH [33] (see "Clinical manifestations,
 pathologic features, and diagnosis of Langerhans cell histiocytosis",
section on 'Clinical manifestations'):

• Cystic bone lesions (7 percent)

• Arginine vasopressin disorder (formerly known as diabetes

insipidus) (8 percent)

• Rarely, skin lesions (brown papules and eczema) and generalized

lymphadenopathy [33]

● BHD – In addition to pulmonary involvement, BHD is associated with

renal and cutaneous manifestations:

• Renal neoplasms: most commonly hybrid oncocytic tumors (50

percent), followed by chromophobe renal cell carcinomas (35
percent), clear cell renal cell carcinomas (9 percent), and renal
oncocytomas (5 percent). (See "Birt-Hogg-Dubé syndrome", section
on 'Kidney tumors'.)

• Cutaneous lesions: 85 percent of patients have fibrofolliculomas

( picture 1) [37]. (See "Birt-Hogg-Dubé syndrome", section on
'Cutaneous lesions'.)

● LIP – Although LIP is a disorder confined to the lungs, it is associated

with a wide variety of underlying systemic autoimmune diseases and
immunodeficiency in the majority of cases. Most common among
these is Sjögren syndrome, present in 25 to 50 percent of LIP cases
( image 12) [43,45]. For this reason, patients presenting with cystic
lung disease should be queried about the presence of dry eyes and dry
mouth. Patients with immunodeficiency (eg, common variable
immunodeficiency, HIV) often have a history of infection. (See "Clinical
manifestations of Sjögren's syndrome: Extraglandular disease".)

RADIOGRAPHIC FEATURES
High resolution CT (HRCT) of the chest is the cornerstone of the evaluation
of patients with cystic lung disease. HRCT permits detailed characterization
of the appearance and distribution of the cysts and identification of
accompanying features. It is often sufficiently characteristic to suggest a
presumptive diagnosis or, at the very least, to narrow the list of
possibilities. Importantly, HRCT features are not pathognomonic and need
to be interpreted in a clinical context so that further diagnostic testing can
be selective.

The value of HRCT was highlighted in one retrospective study of HRCT

performed in the evaluation of diffuse cystic lung disease [46]. A suspected
radiographic diagnosis was correct in 70 to 80 percent of cases when HRCT
was reviewed by radiologists or pulmonologists with expertise in cystic
lung disease.

Appearance and distribution of cysts — Typical HRCT features of cysts

are described for the following diseases:

● Lymphangioleiomyomatosis (LAM) – Parenchymal cysts associated

with LAM are typically profuse and evenly distributed throughout both
lungs ( image 13) [47]. They are thin-walled and round, display
limited variability in size and shape, and lack internal structures such
as vessels or septae.

● Pulmonary Langerhans cell histiocytosis (PLCH) – The cystic lesions

of PLCH are irregularly and bizarrely shaped, have prominent walls,
and tend to involve the upper lobes with relative sparing of the
costophrenic angles ( image 14) [48]. Intervening lung may be
normal or have multiple small nodules.

● Birt-Hogg-Dubé syndrome (BHD) – The cysts associated with BHD are

thin-walled, often lentiform in shape (lens-shaped), basilar
predominant, and distributed in subpleural regions and abutting the
mediastinum ( image 15). Intervening lung is normal. A study
 employing quantitative methods to compare the CT features of LAM
and BHD found significant differences in all parameters examined;
BHD cysts were quantitatively less numerous, larger, and less circular
in shape and demonstrated a lower-medial lung zone predominance
[47]. Another study comparing CT features of BHD, LAM, and LIP found
that patients with BHD were significantly more likely to have elliptical
paramediastinal cysts or a disproportionate number of
paramediastinal cysts [49].

● Lymphoid interstitial pneumonia (LIP) – Thin-walled cysts may be

seen in the majority of patients with LIP. These cysts are typically few in
number and are most often seen in areas of ground glass ( image 16)
but may occur as an isolated finding [50,51]. They are often
perivascular in distribution, vary in size ranging from 1 to 30 mm in
diameter, and may have internal septae.

Nodules — Multiple nodules should alert the physician to PLCH, although

nodules can also be found in LIP and tuberous sclerosis complex (TSC)-
LAM.

● PLCH – Radiographic abnormalities in PLCH typically begin as upper

lobe nodules [52]. These nodules later cavitate ("cheerio sign") and
ultimately form cystic lesions ( image 17) [48,53]. It is important to
note that as the disease evolves, nodules and cystic lesions can coexist,
and this combination may permit a radiographic diagnosis of PLCH
with a high degree of confidence [48,54].

● LIP – Ill-defined centrilobular nodules and subpleural nodules can be

seen in patients with LIP ( image 18) [50,55]. In patients with Sjögren
syndrome, the presence of nodules along with cysts should raise
suspicion for concurrent lymphoma, light chain deposition disease, or
amyloidosis [56].
 ● TSC-LAM – In some patients with TSC-LAM, multiple lung nodules
accompany the cystic changes. These nodules usually represent
multifocal micronodular pneumocyte hyperplasia (MMPH). The
nodules of MMPH range in size from 2 to 14 mm and can be either
solid or of ground glass attenuation. They tend to behave in an
indolent fashion; in one series of 32 cases, there was no change in
nodule number or size during a mean follow-up period of 2 +/- 1.1
years [57]. (See "Tuberous sclerosis complex associated
lymphangioleiomyomatosis in adults", section on 'Multifocal
micronodular pneumocyte hyperplasia'.)

Ground glass opacities — The combination of cysts and ground glass

opacities is a common radiographic presentation of LIP; septal thickening
and nodules may also be present. Ground glass opacities are usually not a
feature of the other diffuse cystic lung diseases, although ground glass
opacities have been described on CT scans of patients with PLCH and a
concurrent smoking-related disorder, such as respiratory
bronchiolitis/desquamative interstitial pneumonia [58]. (See "Respiratory
bronchiolitis-associated interstitial lung disease", section on 'Imaging'.)

Pleural effusion — Among the diffuse cystic lung diseases, pleural effusion
is most likely to be due to LAM. Chylous pleural effusions occur in
approximately 10 percent of patients with LAM and can be unilateral or
bilateral ( image 19). Pleuritis from a systemic rheumatic disease is an
uncommon cause of an effusion in LIP. Presence of pleural effusion in
patients with LIP should also prompt evaluation for lymphoma, particularly
when seen in association with large nodules and/or consolidative opacities
[59]. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and
diagnostic evaluation", section on 'Chest computed tomography'.)

Intra-abdominal features — A number of intra-abdominal features can

help determine the cause of diffuse cystic lung disease in patients with
LAM or BHD.
 ● Lymphangioleiomyomatosis – LAM is associated with a number of
intra-abdominal and pelvic features.

• In particular, renal angiomyolipomas ( image 11) are

demonstrated on abdominal imaging in 30 percent of individuals
with sporadic LAM and 80 percent of those with TSC-LAM [60]. The
imaging characteristics of renal AML and indications for
percutaneous needle or surgical biopsy are discussed separately.
(See "Renal manifestations of tuberous sclerosis complex", section
on 'Diagnosis'.)

Angiomyolipomas may also occasionally be seen within the liver

( image 20).

• Lymphangioleiomyomas (fluid filled cystic masses) are another

characteristic feature of LAM, occurring in approximately 16 percent.
They are most often located in the retroperitoneum but may extend
into, or arise in, the pelvis or mediastinum. (See "Sporadic
lymphangioleiomyomatosis: Clinical presentation and diagnostic
evaluation", section on 'Lymphangioleiomyomas'.)

• Other findings on abdominal imaging in patients with LAM include

ascites, thoracic duct dilatation, and lymphadenopathy [60].

● Birt-Hogg-Dubé – Renal neoplasms are found on abdominal imaging

performed for screening purposes in up to 27 percent of patients with
BHD [61]. These tumors are bilateral in approximately 50 percent of
cases and multifocal in 65 percent. CT or magnetic resonance imaging
(MRI) with contrast are the imaging procedures of choice. (See "Birt-
Hogg-Dubé syndrome", section on 'Kidney tumors'.)

DIAGNOSTIC APPROACH
The majority of patients with diffuse cystic lung disease have one of four
disorders: lymphangioleiomyomatosis (LAM), pulmonary Langerhans cell
histiocytosis (PLCH), Birt-Hogg-Dubé syndrome (BHD), or lymphoid
interstitial pneumonia (LIP). Other rare causes of diffuse cystic lung disease
are listed in the table ( table 2). Our diagnostic approach starts with
review of the clinical and radiographic features to narrow down the
diagnostic possibilities, followed by focused testing to confirm the
diagnosis ( algorithm 1). The typical clinical, laboratory, and radiographic
features and diagnostic criteria for each of the four main causes of diffuse
cystic lung disease are summarized in the table, along with commonly
employed confirmatory diagnostic studies ( table 3).

A characteristic constellation of clinical, laboratory, and radiographic

features is often sufficient to establish a diagnosis without need for a
surgical lung biopsy. In those cases where uncertainty remains and
confirmation is essential for management (eg, progressive disease,
anticipated initiation of sirolimus in LAM), histopathologic evaluation is
typically necessary. In some cases, particularly in asymptomatic patients
with normal lung function, a period of observation is also appropriate.

When pursuing a tissue biopsy, the least invasive method is selected. As an

example, a lacrimal gland or lip biopsy may confirm a diagnosis of Sjögren
syndrome, a skin biopsy can establish a diagnosis of BHD, while
bronchoalveolar lavage or transbronchial lung biopsy can provide a
diagnosis in PLCH or LAM, respectively.

Laboratory testing — Focused laboratory testing can be helpful in

suspected LIP, LAM, and BHD, as described in the following sections
( algorithm 1). As the differentiation between cystic lung disease and
emphysema can be difficult, we often obtain testing for alpha-1 antitrypsin
deficiency, although the yield of such testing is low. (See "Clinical
manifestations, diagnosis, and natural history of alpha-1 antitrypsin
deficiency", section on 'Laboratory testing'.)
On occasions when the clinical and high resolution CT findings do not allow
differentiation among the four main causes of cystic lung disease, some
experts test more broadly and obtain testing for antinuclear antibody, anti-
Ro/SSA and anti-La/SSB antibodies, rheumatoid factor, and vascular
endothelial growth factor-D (VEGF-D), as well as genetic testing for the
folliculin (FLCN) and tuberous sclerosis complex (TSC1 and TSC2) genes,
and rarely for inheritable causes of bronchiectasis (eg, primary ciliary
dyskinesia and cystic fibrosis). This approach is unproven and may be
associated with increased cost to the patient.

Serologic studies — For patients with a known or suspected systemic

rheumatic disease that might be associated with LIP, especially Sjögren
syndrome, we usually obtain or review serologic studies such as the
antinuclear antibody, anti-Ro/SSA and anti-La/SSB antibodies, and
rheumatoid factor. (See "Clinical manifestations of Sjögren's syndrome:
Extraglandular disease", section on 'Autoantibodies'.)

If common variable immunodeficiency is suspected as a cause of LIP,

serum immunoglobulin levels are measured or reviewed. Similarly, if a
patient has risk factors for HIV infection, we test for HIV. (See "Clinical
manifestations, epidemiology, and diagnosis of common variable
immunodeficiency in adults", section on 'Immunoglobulin levels' and
"Screening and diagnostic testing for HIV infection".)

Serum levels of vascular endothelial growth factor-D (VEGF-D) are elevated

above the upper limit of values in many patients with sporadic and TSC
LAM, compared with healthy volunteers or individuals with other cystic
lung disease [62,63]. A level of VEGF-D above 800 pg/mL is highly specific
for LAM and, in a patient with compatible radiographic features, is
considered diagnostic [63-65]. Notably, VEGF-D levels below this threshold
do not exclude the diagnosis. This test is only available at specialized
laboratories; its diagnostic value in LAM is described in greater detail
separately. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation
and diagnostic evaluation", section on 'Vascular endothelial growth factor-
D'.)

Genetic testing — For patients without characteristic skin

fibrofolliculomas or trichodiscomas, genetic testing may help with the
diagnosis of BHD, which is caused by germline mutations in the FLCN gene.
FLCN mutation analysis is available as a diagnostic test and detects
mutations in 81 to 88 percent of patients with BHD [37,40]. However,
deletion/duplication analysis (ie, copy number analysis) may be necessary,
if FLCN gene sequence analysis does not identify a pathogenic variant. (See
"Birt-Hogg-Dubé syndrome", section on 'Genetic testing'.)

Genetic testing for tuberous sclerosis complex (TSC1 and TSC2) genes, and
for heritable causes of bronchiectasis (eg, primary ciliary dyskinesia and
cystic fibrosis) is of unproven value but may be warranted in those in whom
TSC or inheritable bronchiectasis is suspected. While loss of heterozygosity
for the TSC2 gene has been found in the urine and blood of patients with
LAM, it may not be specific since it has also been found in patients with
pulmonary Langerhans cell histiocytosis [66]. (See "Genetic testing".)

Bronchoscopy — Bronchoscopy with bronchoalveolar lavage (BAL) and/or

transbronchial lung biopsy (TBLB) may be helpful in selected patients, such
as those with suspected LAM or PLCH and insufficient clinical or laboratory
features to be confident in the diagnosis ( algorithm 1). Bronchoscopic
cryobiopsy has been successfully utilized to diagnose LAM, PLCH, and LIP,
but there is insufficient experience with these disorders to comment on
yield [67-69].

● Lymphangioleiomyomatosis – TBLB with immunohistochemical

staining for human melanoma black (HMB)-45 has been shown to
identify LAM smooth muscle cells in 60 to 86 percent of cases,
particularly when reviewed by a pathologist with expertise in LAM
[65,70-73]. The yield from transbronchial biopsy may correlate with
cyst profusion, low DLCO, and low FEV1 [65]. BAL is not helpful in the
 diagnosis of LAM, except to exclude other processes. The role of biopsy
in patents with suspected LAM is discussed separately. (See "Sporadic
lymphangioleiomyomatosis: Clinical presentation and diagnostic
evaluation", section on 'Choosing transbronchial or surgical lung
biopsy'.)

● Pulmonary Langerhans cell histiocytosis – The presence of ≥5

percent CD1a-positive cells in BAL is considered strongly suggestive of
PLCH but is poorly sensitive. BAL and TBLB together may yield a
diagnosis in approximately 50 percent of patients [70]. Other patients
will require video assisted surgical lung biopsy to confirm the presence
of Langerhans cells positive for S-100 protein and CD1a. (See
"Pulmonary Langerhans cell histiocytosis", section on 'Flexible
bronchoscopy' and "Pulmonary Langerhans cell histiocytosis", section
on 'Lung biopsy'.)

● Lymphoid interstitial pneumonia – BAL demonstrates lymphocytosis

in approximately 30 percent of patients with LIP, but this is a
nonspecific finding also seen in diseases such as sarcoidosis and
hypersensitivity pneumonitis. Bronchoscopy is otherwise of limited
value as TBLB does not provide an adequate sample size for the
differentiation of interstitial pneumonias. (See "Lymphoid interstitial
pneumonia in adults", section on 'Bronchoalveolar lavage'.)

● Birt-Hogg-Dubé – There is no role for BAL or TBLB in suspected cases

of BHD since there are no distinctive histologic features.

Surgical lung biopsy — The decision to proceed with a surgical biopsy

(typically video-assisted thoracoscopic surgery [VATS]) is dependent on
multiple factors including a suspected diagnosis with pathognomonic
histopathology, the cystic burden, opportunity, need for therapy, and risk.

We typically proceed with surgical lung biopsy when the diagnosis remains
in question following clinical, radiographic, and laboratory evaluation;
when diagnostic confirmation is required in order to initiate therapy; and in
the absence of contraindicating factors such as marginal lung function or
significant pulmonary hypertension.

As the cystic changes in LIP tend to be nonprogressive, we are more likely

to observe patients with known systemic rheumatic disease without a
biopsy unless ground glass opacities or nodules are present, such that
systemic glucocorticoids would be warranted for LIP, or the nodular
opacities are concerning for lymphoma or infection.

Sometimes, surgical lung biopsy is obtained at the opportune time of

surgical treatment for a pneumothorax (eg, patients with mild or
nonprogressive disease).

VATS biopsy is generally definitive for diagnosis of LAM, PLCH, and LIP (or
follicular bronchiolitis). In contrast, surgical lung biopsy is not appropriate
in cases of confirmed BHD since there are no specific histologic features
associated with cysts in this disorder. Certain rare causes of cystic lung
disease may not be associated with specific histopathology (eg,
neurofibromatosis). However, biopsy may be indicated, if an alternate or
coexistent pathology is suspected (eg, LAM, lymphoma).

Less commonly, lung biopsy may be the best option to establish or exclude
worrisome etiologies, such as metastatic cancer (eg, invasive
adenocarcinoma, sarcoma, colorectal cancer), amyloidosis, light chain
deposit disease, and non-Langerhans histiocytosis ( table 2).

The characteristic histopathologic features of LAM, PLCH, and LIP are

described separately. (See "Sporadic lymphangioleiomyomatosis: Clinical
presentation and diagnostic evaluation", section on 'Definitive pathologic
diagnosis' and "Pulmonary Langerhans cell histiocytosis", section on 'Lung
biopsy' and "Interstitial lung disease associated with Sjögren syndrome:
Clinical manifestations, evaluation, and diagnosis", section on 'Lymphoid
interstitial pneumonia'.)
Skin biopsy — In a patient with compatible high resolution CT,
confirmation of BHD is achieved by skin biopsy showing fibrofolliculomas,
obviating the need for genetic testing for a folliculin gene mutation. (See
'Genetic testing' above.)

PATIENT PERSPECTIVE TOPIC

Patient perspectives are provided for selected disorders to help clinicians

better understand the patient experience and patient concerns. These
narratives may offer insights into patient values and preferences not
included in other UpToDate topics. (See "Patient perspective:
Lymphangioleiomyomatosis (LAM)".)

SUMMARY AND RECOMMENDATIONS

● Cystic lung diseases represent a diverse group of disorders that share
in common the radiologic feature of multiple air-filled lucencies
surrounded by discrete walls (≤2 mm thickness). Diffuse cystic lung
disease must be distinguished radiographically from emphysema,
honeycombing, cystic bronchiectasis, pulmonary cavities, and
pneumatoceles. (See 'Definition' above.)

● The four most common cystic lung diseases are

lymphangioleiomyomatosis (LAM), pulmonary Langerhans cell
histiocytosis (PLCH), Birt-Hogg-Dubé syndrome (BHD), and lymphoid
interstitial pneumonia (LIP). Other rare causes of cystic lung disease
are listed in the table ( table 2). (See 'Causes of cystic lung disease'
above.)

● The manifestations of cystic lung disease are typically not specific for a
particular disorder. Patients may present with cysts incidentally
discovered on CT obtained for other reasons. Alternatively, they may
present with nonspecific cough or dyspnea or with pneumothorax or a
 pleural effusion. (See 'Clues to an etiology for cystic lung disease'
above.)

● A detailed history with attention to demographics (age, sex, and

ethnicity), smoking history, and family history (eg, features of tuberous
sclerosis complex [TSC] or BHD) is important in the initial assessment.
A careful search for extrapulmonary features, including cutaneous,
pleural, and intra-abdominal manifestations, can provide insight into
the diagnosis ( table 3). (See 'Clues to an etiology for cystic lung
disease' above.)

● High resolution CT is an essential component of the evaluation process

and often can differentiate between the various cystic lung diseases,
especially when reviewed by an expert radiologist. (See 'Radiographic
features' above.)

● Our diagnostic approach starts with review of the clinical and

radiographic features to narrow down the diagnostic possibilities,
followed by focused testing to confirm the diagnosis ( algorithm 1).
(See 'Diagnostic approach' above.)

● Laboratory assessment can be used to establish a diagnosis of LAM

(serum levels of vascular endothelial growth factor-D level ≥800 pg/mL)
and can help identify patients with a systemic rheumatic disease that
would increase the likelihood of LIP. For patients without characteristic
skin fibrofolliculomas, genetic testing for folliculin (FLCN) gene variants
may be indicated for patients with suspected BHD. (See 'Laboratory
testing' above.)

● When tissue confirmation is required in patients with suspected LAM

or PLCH, bronchoscopy with transbronchial lung biopsy and
appropriate immunostaining (ie, human melanoma black [HMB]-45 for
LAM; CD1a antigen for PLCH) may be diagnostic in some cases.
Bronchoalveolar lavage (BAL) showing CD1a antigen staining of 5
 percent or more cells is considered supportive of PLCH. (See
'Bronchoscopy' above.)

● For patients without a clear diagnosis despite the above evaluation,

particularly in the setting of progressive disease, surgical lung biopsy
can be used to provide a definitive diagnosis of disorders associated
with specific histopathology (LAM, PLCH, LIP). A lung biopsy is not
indicated in disorders not associated with specific histopathology (eg,
BHD) unless an alternate or co-existent process is suspected. (See
'Surgical lung biopsy' above.)

● Skin biopsy of a folliculoma may be diagnostic in BHD or prompt

genetic testing for folliculin variants for confirmation. (See 'Skin biopsy'
above.)
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