Diagnostic approach to the adult with cystic lung disease

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".)

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's disease [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's disease (SjD), 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: Clinical features".)

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 SjD, 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 disease: 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's disease, 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 CT'.)

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's disease (SjD), 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 SjD, 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 disease: 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", 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's disease: 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.)