American Journal of Respiratory and Critical Care Medicine

The diffuse cystic lung diseases (DCLDs) are a group of pathophysiologically heterogenous processes that are characterized by the presence of multiple spherical or irregularly shaped, thin-walled, air-filled spaces within the pulmonary parenchyma. Although the mechanisms of cyst formation remain incompletely defined for all DCLDs, in most cases lung remodeling associated with inflammatory or infiltrative processes results in displacement, destruction, or replacement of alveolar septa, distal airways, and small vessels within the secondary lobules of the lung. The DCLDs can be broadly classified according to underlying etiology as those caused by low-grade or high-grade metastasizing neoplasms, polyclonal or monoclonal lymphoproliferative disorders, infections, interstitial lung diseases, smoking, and congenital or developmental defects. In the first of a two-part series, we present an overview of the cystic lung diseases caused by neoplasms, infections, smoking-related diseases, and interstitial lung diseases, with a focus on lymphangioleiomyomatosis and pulmonary Langerhans cell histiocytosis.

The diffuse cystic lung diseases (DCLDs) are a diverse group of lung disorders characterized by the presence of multiple regular or irregular spherical parenchymal lucencies bordered by a thin wall and having a well defined interface with normal lung (1). The advent of high-resolution computed tomography (HRCT) scanning has transformed our approach to the DCLDs, revealing patterns that substantially narrow the differential, and, in some cases, providing a definitive diagnosis. The differential diagnosis of DCLDs encompasses a broad set of diseases that can be classified based on underlying pathophysiologic mechanisms, including neoplastic, congenital, genetic, developmental, lymphoproliferative, infectious, inflammatory, or smoking related (Table 1).

Table 1. Classification of Diffuse Cystic Lung Diseases

1. NeoplasticLymphangioleiomyomatosis—sporadic as well as associated with tuberous sclerosis
Pulmonary Langerhans cell histiocytosis, and non–Langerhans cell histiocytoses, including Erdheim Chester disease
Other primary and metastatic neoplasms, such as sarcomas, adenocarcinomas, pleuropulmonary blastoma, etc.
2. Genetic/developmental/congenitalBirt-Hogg-Dubé syndrome
Proteus syndrome, neurofibromatosis, Ehlers-Danlos syndrome
Congenital pulmonary airway malformation, bronchopulmonary dysplasia, etc.
3. Associated with lymphoproliferative disordersLymphocytic interstitial pneumonia
Follicular bronchiolitis
Sjögren syndrome
Light-chain deposition disease
4. InfectiousPneumocystis jiroveci
Staphylococcal pneumonia
Recurrent respiratory papillomatosis
Endemic fungal diseases, especially coccidioidomycosis
5. Associated with interstitial lung diseasesHypersensitivity pneumonitis 
Desquamative interstitial pneumonia 
6. Smoking relatedPulmonary Langerhans cell histiocytosis 
Desquamative interstitial pneumonia 
Respiratory bronchiolitis 
7. Other/miscellaneousPost-traumatic pseudocysts 
Fire-eater’s lung 
Hyper-IgE syndrome 
8. DCLD mimicsEmphysema 
α1-antitrypsin deficiency 
Honeycombing seen in late-stage scarring interstitial lung diseases 

Definition of abbreviation: DCLD = diffuse cystic lung disease.

A proposed classification for the DCLDs discussed in parts I and II of this review is presented. Many DCLDs have overlapping features and can be classified in more than one category. Pulmonary Langerhans cell histiocytosis is classified as both a neoplasm and a smoking-related cystic lung disease. Similarly, desquamative interstitial pneumonia is an interstitial lung disease as well as a smoking-related cystic lung disease. Although classified as a lymphoproliferative disorder, light-chain deposition disease could also be considered under the neoplastic category. Similarly, hyper-IgE syndrome, although classified as other/miscellaneous, could also be classified under the category of infections causing cystic lung disease.

In part 1 of this review, we provide an overview of the neoplastic etiologies of DCLDs with a focus on lymphangioleiomyomatosis (LAM) and pulmonary Langerhans cell histiocytosis (PLCH). In addition, we discuss DCLDs secondary to infectious etiologies, smoking-related diseases, and interstitial lung diseases (ILDs). In part II, we will describe the DCLDs arising from lymphoproliferative, congenital, developmental, and genetic etiologies. We will conclude by discussing the mechanisms of pulmonary cyst formation, the radiological and pathological evaluation of cystic lung disease, and an approach to the diagnosis and management of the DCLDs.

LAM is an uncommon cystic lung disease caused by infiltration of the lung with smooth muscle cells that arise from an unknown source, spread via blood and lymphatics, and contain growth-activating mutations in tuberous sclerosis genes (2, 3). LAM occurs in patients with tuberous sclerosis complex (TSC-LAM) and in a “sporadic” form in patients who do not have tuberous sclerosis (S-LAM) (4). In TSC-LAM, tuberous sclerosis mutations are found in all cells, whereas, in S-LAM, tuberous sclerosis mutations are found only in neoplastic lesions (5, 6). TSC-LAM occurs in over 30% of women with TSC (79), and as many as 10–15% of men with TSC (10, 11), but S-LAM appears to be almost entirely restricted to women, with only one published exception to date (12).

The average age at diagnosis of LAM is about 35 years, but rare cases have been reported in prepubertal females (13) and octogenarians (14). The diagnosis of LAM is recorded in about 3.4–7.8 per million women in the United States and Europe (15), which, if extrapolated across the globe, would predict a prevalence of 35,000 patients with LAM on earth. This is certainly an underestimate, however. Given the global prevalence of TSC of about 1 million persons (16) and a conservative estimate of 30–40% penetrance of LAM in female patients with TSC (79, 17), the predicted worldwide prevalence of patients with TSC-LAM alone is 150,000–200,000. Yet most patients who seek medical attention for LAM have S-LAM rather than TSC-LAM. Partial explanations for this paradox may include that TSC-LAM and S-LAM appear to have different natural histories, that only a fraction (5–10%) of patients with TSC-LAM become symptomatic, and that other health priorities may impede patients with TSC from seeking medical attention for pulmonary issues.


TSC and TSC-LAM are caused by mutations in either of the two known TSC genes, TSC1 or TSC2, whereas only TSC2 mutations have been reported in S-LAM. In patients with TSC or TSC-LAM, mutations in TSC genes are present in all cells, including the germ line (“first hit”), and neoplasms and dysplasias arise in various organs when somatic “second hit” TSC mutations occur. In patients with S-LAM, both first- and second-hit TSC mutations appear to occur after conception in somatic tissues, and to be confined to lesions in the lung, kidney, and lymph nodes (5, 18). These genetic patterns are consistent with the occasional occurrence of vertical transmission of TSC-LAM, but never S-LAM (19).

Genetic analysis of blood (19), lymphatic fluid, and recurrent LAM lesions in the donor allografts of patients with LAM who have undergone lung transplantation (35) have revealed that LAM cells circulate and metastasize (20). TSC1 and TSC2 encode large proteins, called hamartin and tuberin, respectively, that form a heterodimer that regulates cell growth, survival, and motility downstream of protein kinase B in the phosphoinositide 3-kinase signaling pathway (21, 22). Hamartin or tuberin deficiency or dysfunction results in up-regulated activity of mechanistic target of rapamycin (mTOR), which leads to increased protein translation and ultimately inappropriate cellular proliferation, migration, and invasion. Additional “cancer-like” programs that are activated by mTOR in LAM cells include suppression of autophagy, shift from oxidative phosphorylation to glycolytic (Warburg) metabolism (23), and expression of the metastasis-promoting lymphangiogenic vascular endothelial growth factors (VEGFs), VEGF-C and VEGF-D (2). Serum levels of VEGF-D are elevated in about 50–70% of patients with LAM, and are useful both diagnostically and prognostically (2426). At autopsy, the conducting lymphatics are often extensively infiltrated with LAM cells and contain luminal clusters of LAM cells enveloped by a single layer of lymphatic endothelial cells (27, 28). These “tumor emboli” presumably reach the pulmonary microvasculature via the anastomosis between the thoracic duct and left subclavian vein in the neck (29), and once wedged in the lung capillary bed, likely promote a program of “frustrated lymphangiogenesis” driving chaotic lymphatic channel development and cystic remodeling (2). Matrix metalloproteinase (MMP) imbalances involving MMP-2, MMP-9, and tissue inhibitor of metalloproteinase-3 have been described in LAM lesions and may play a role in matrix degradation (3032). The role of estrogen in disease initiation and/or progression is incompletely understood, but recent evidence suggests that estrogen can activate protein kinase B, facilitate metastasis (33, 34), and promote dysregulated protein translation through up-regulation of Fra1 (Fos-related antigen 1) (35). LAM cells have perivascular epithelioid cell morphology and staining characteristics, but the cell and organ of origin are unclear (36). Candidate primary organ sources for LAM cells include the uterus (37), kidney, genitourinary tract, and the lymphatic system.


Microscopic examination of the lung reveals foci of smooth muscle cell infiltration of the lung parenchyma, airways, lymphatics, and blood vessels, associated with areas of thin-walled cystic change (Figure 1A) (38). There are two major cell morphologies in the LAM lesions: small, spindle-shaped cells and cuboidal epithelioid cells (39). LAM cells stain positively for smooth muscle actin, vimentin, desmin, and estrogen and progesterone receptors (40). The cuboidal cells within LAM lesions also react with a monoclonal antibody called HMB-45 (human melanoma black-45) developed against the premelanosomal protein, glycoprotein-100, an enzyme in the melanogenesis pathway (Figure 1C) (39). LAM lesions express VEGF-C and VEGF-D, and often contain an abundance of lymphatic channels lined by VEGFR-3–expressing endothelial cells (28, 29). LAM cells generally expand the interstitium without violating tissue planes, but have occasionally been observed to invade the airways, pulmonary artery, diaphragm, aorta, and retroperitoneal fat, as well as to destroy bronchial cartilage and arteriolar walls and occlude pulmonary arteriolar lumens (27, 41).

Diagnostic Approach

The following presentations warrant consideration of HRCT screening for LAM: (1) young-to-middle-aged nonsmoking women with pneumothorax (42); (2) asymptomatic females with TSC after age 18 years and every 5–10 years thereafter, per Tuberous Sclerosis Association guidelines (43, 44); (3) incidental discovery of an angiomyolipoma (45), lymphangiomyoma, cysts in the lung bases on abdominal CT, and unexplained chylous ascites or chylous effusions; and (4) unexplained progressive dyspnea on exertion in women with presentations that are atypical for chronic obstructive pulmonary disease or asthma.

The European Respiratory Society Guidelines indicate that the diagnosis of LAM can be made with reasonable certainty on the basis of characteristic cystic change on CT in a patient with tuberous sclerosis, angiomyolipoma, lymphadenopathy, or chylothorax (46). A serum VEGF-D level greater than 800 pg/ml in a patient with typical HRCT findings is also diagnostic for LAM (25).

Efforts should be made to establish the diagnosis with certainty before considering chronic treatment with agents that have potential toxic adverse effects. We recommend the following “least-invasive” stepwise approach to diagnosis when a patient with thin-walled cysts on HRCT is evaluated for LAM: (1) thorough personal history and family history for TSC, LAM, or pneumothorax; (2) serum VEGF-D testing; (3) CT or magnetic resonance imaging of the abdomen to screen for the presence of lymphangiomyomas and angiomyolipomas; (4) transbronchial biopsy (which has a yield of >60% and appears to be safe based upon small series) (47, 48) or cytological examination of pleural fluid, lymph nodes, or masses (49); and, if necessary, (5) video-assisted thoracoscopic surgery lung biopsy. When tissues are obtained, consultation with an expert pathologist who is familiar with LAM is essential. LAM is typically negative on fluorodeoxyglucose–positron emission tomography (PET), which can be useful in distinguishing LAM from other neoplastic mimics, such as lymphoma, malignant perivascular epithelioid cell tumor, or ovarian cancer (50).


Angiomyolipomas that exceed 4 cm in size are more likely to bleed (51) and should be evaluated for embolization or treatment with mTOR inhibitors (52). Air travel is safe in most patients with LAM (53, 54). Bronchodilators are warranted in patients with reversible airflow obstruction on pulmonary function testing and in patients who report symptomatic benefit from a bronchodilator trial (55). Pleurodesis should be performed with the initial pneumothorax in each hemithorax, because the rate of ipsilateral recurrence is greater than 70% (56). Lung transplantation is an important option for patients with LAM, and can be safely performed by experienced surgeons in most patients, despite prior unilateral or bilateral pleurodesis (5759).

The clinical course of LAM is characterized by progressive dyspnea on exertion, recurrent pneumothorax, and chylous fluid accumulations in the chest and abdomen (60). By 10 years after diagnosis, approximately 55% of patients with LAM experience shortness of breath with daily activities, 20% require supplemental oxygen, and 10% have died (61, 62). Airflow obstruction and hyperinflation are the most common physiologic manifestations, and FEV1 declines at rates that vary from 50 to 250 ml/yr (6367). Lung function decline is more rapid in patients with S-LAM, premenopausal patients, and patients with an elevated serum VEGF-D (24), and is likely accelerated by pregnancy and use of estrogen-containing medications.

The Multicenter International LAM Efficacy of Sirolimus (MILES) Trial was a double-blind, randomized, parallel-group trial of 1 year of treatment with sirolimus versus placebo, followed by 1 year of observation (68). Inclusion criteria included a definite diagnosis of LAM and an FEV1 less than 70% predicted. Patients who were treated with placebo lost approximately 10% of their lung function over the course of the treatment year. In contrast, patients who received sirolimus had stable lung function, improved quality of life, and improved functional performance. Side effects typical of mTOR inhibitors were common, but serious adverse events were balanced in the two groups. Patients with elevated VEGF-D tended to decline faster without treatment and to respond better to sirolimus (24). During the observation year, lung function decline resumed in the sirolimus group and paralleled that of the placebo group. Based on the MILES trial, we recommend sirolimus treatment for patients with LAM who have FEV1 less than or equal to 70% predicted. The optimal duration of treatment is unclear, but because the effect of the drug is suppressive rather than remission inducing, most patients have been maintained on treatment indefinitely. Recent studies from Japan suggest that low-dose sirolimus (trough serum level < 5 ng/ml compared with the trough level of 5–15 ng/ml in the MILES trial) is effective, which, if borne out by other studies, may enhance the safety of long-term treatment (69). Sirolimus treatment of patients with other presentations of LAM has also been shown to be effective in small series, including chylous effusions, lymphangiomyomas, and patients with rapidly declining lung function while awaiting transplant (63, 70). Trials are needed to determine the risks and benefits of treating patients with early disease, and to define optimal dose and duration of therapy. Lung transplantation remains an important option for patients with end-stage LAM, despite reports of recurrence in the graft (57, 58, 7173), because survival rates are comparable to those of other diseases, and graft failure due to recurrence has not been reported.

PLCH is a DCLD most commonly encountered in young adult smokers (74). Approximately 90% of adult patients with PLCH smoke cigarettes or have a history of exposure to substantial second-hand smoke (74, 75). About two-thirds of patients with PLCH present with nonspecific symptoms of shortness of breath or cough, but many are asymptomatic or minimally symptomatic (smoker’s cough) and identified incidentally by chest radiography (74). Constitutional symptoms, such as weight loss and fever, may occur in approximately 20% of patients (74). Sudden-onset chest pain and dyspnea often herald the occurrence of pneumothorax, which develops in approximately 15% of patients (76). A small proportion of patients with PLCH may have symptoms due to disease outside of the thorax.


The earliest lesion in PLCH is the peribronchiolar accumulation of Langerhans and other immune cells (7779) (Figures 2A–2C). Langerhans cells are specialized epithelial-associated dendritic cells that regulate mucosal airway immunity. Cigarette smoke may be a key factor mediating the accumulation and activation of Langerhans cells (80) through induction of cytokines, such as granulocyte/macrophage colony–stimulating factor and transforming growth factor-β (77, 81). Osteopontin, a glycoprotein with chemotactic activity for monocytes, Langerhans cells, and dendritic cells, has recently been shown to be spontaneously released by bronchioalveolar macrophages obtained by lavage from patients with PLCH (82). This finding is especially intriguing, since osteopontin overexpression in murine lungs is associated with interstitial accumulation of Langerhans cells (82). The Langerhans cells in PLCH lesions have an activated phenotype with abundant expression of costimulatory molecules (79). Whether infection or other activating signals play a role in the abnormal activation and persistence of Langerhans cells is not known. The persistence of activated Langerhans cells and secondary recruitment of other immune cells results in the formation of cellular nodules that precede the development of airway remodeling and cystic change (Figures 2A–2C). MMPs produced by immune cells in the PLCH nodules likely play an important role in the airway remodeling and bronchiolar destruction and eventual formation of lung cysts (83). Whether PLCH represents a clonal proliferative process (akin to a neoplasm) or a polyclonal reactive process induced by cigarette smoke has been debated for a long time. Recent studies revealed the presence of mutations in BRAF (v-Raf murine sarcoma viral oncogene homolog B), ARAF (v-Raf murine sarcoma 3611 viral oncogene homolog), and MAP2K1 (mitogen-activated protein kinase kinase 1) (cell cycle–regulating pathways that are mutated in a number of malignancies and other disease states) in lesional Langerhans cells of both PLCH and systemic forms of LCH (8486). The most commonly identified BRAF mutation in PLCH is V600E, which is also a prevalent mutation in melanoma. The identification of BRAF and MAP2K1 mutations in up to 50% of PLCH cases suggests that at least a proportion of PLCH is a cigarette smoke–induced or –promoted dendritic cell neoplasm that is associated with a prominent immune-inflammatory component.


Accumulation of Langerhans and other immune cells around terminal and respiratory bronchioles is one of the earliest histopathologic findings in PLCH (Figures 2A–2C) (78). Morphologically, these bronchiolocentric lesions evolve from highly cellular micro- and macronodules to a paucicellular, and often stellate-shaped, fibrotic scars later in the disease process (Figures 2D and 2E) (78, 87). Langerhans cells in tissue specimens can be identified by their unique morphological features (pale, eosinophilic cytoplasm with indistinct cell borders, and grooved nuclei with small or inconspicuous nucleoli) and immunohistochemical staining for S-100 and CD1a (Figure 2C). In later stages, pericicatricial airspace enlargement and cavitation of nodules can occur (Figure 2) (78, 87). Smoking-induced changes, such as respiratory bronchiolitis (RB) and distal airspace macrophage accumulation resembling desquamative interstitial pneumonia (DIP), are commonly seen on lung biopsy (Figure 2F) (100). Venous and arterial structures are frequently abnormal. In some patients, a prominent vasculopathy that mimics idiopathic pulmonary arterial hypertension may occur (87).

Diagnostic Approach

The diagnosis of PLCH should be considered not only in individuals with cystic or nodular infiltrates on chest imaging, but also in cigarette smokers or former smokers with indeterminate upper lobe infiltrates, patients with a history of spontaneous or recurrent pneumothorax, and any patient with lung infiltrates and a history of skin rash or diabetes insipidus. Pulmonary function testing may be normal, or demonstrate obstructive, restrictive, or mixed abnormalities (74). Normal lung function or mild restrictive impairment is more common in earlier phases of disease, whereas obstructive defects predominate in more advanced disease (74, 88). A proportion of patients with PLCH have abnormal pulmonary vascular function measurements, such as reduced diffusing capacity for carbon monoxide and oxygen desaturation during exercise. In patients with advanced PLCH, which is usually accompanied by extensive cystic lung disease, lung function testing often reveals obstruction and air trapping together with reduction in diffusing capacity and hypoxemia.

Whenever PLCH is suspected, a chest HRCT should be performed. Characteristic imaging findings include nodular and cystic abnormalities that occur predominantly in upper and middle lung zones (Figures 2A and 2D) (89). PLCH cysts are often bizarrely shaped, in contrast to the more uniform and bland-appearing cysts typical of other DCLDs. When clinical and radiographic features suggest PLCH, further evaluation may be indicated to establish a definitive diagnosis. Bronchoscopy with transbronchial lung biopsy is diagnostic in about 30% of cases, and is valuable in excluding other diagnoses that mimic PLCH (47, 90). In some instances, surgical lung biopsy is required for definitive diagnosis. Occasionally, the diagnosis may be established by biopsy of an involved site outside the thorax (skin or bone lesions, for example). PLCH lesions are often fluorodeoxyglucose avid, and PET scanning may be helpful to assess the extent of disease activity outside the thorax or detect occult extrapulmonary disease (91).


The three key components of PLCH management include: (1) smoking cessation and avoidance of second-hand smoke exposure when applicable; (2) consideration for pharmacotherapy (including chemotherapy); and (3) assessment and treatment of any disease-specific complications, including pneumothorax, hypoxemic respiratory failure, diabetes insipidus, and secondary pulmonary hypertension. Although the natural history of disease after smoking cessation has not been fully characterized, smoking cessation may promote disease stabilization/regression, and sometimes complete resolution, of PLCH (75, 92). Some patients have an excellent prognosis and experience very little decline in lung function, whereas others develop progressive lung disease, even after smoking cessation (88). Serial pulmonary function measurements at 3–6 monthly intervals is a reasonable approach for longitudinal disease follow up, especially for patients with impaired lung function at presentation (88). Pharmacotherapy should be considered for patients with impaired lung function, and especially when serial lung function testing demonstrates a progressive decline in FEV1 (88) despite successful smoking cessation. Anecdotal experience suggests that oral corticosteroids have limited efficacy, and, although combinations of corticosteroids with vinblastine (standard therapy in childhood LCH) appear to have been effective in some patients, this combined therapy is often poorly tolerated by adult patients with PLCH. Case reports and small series suggest that chlorodeoxyadenosine (also known as cladribine or 2-CDA) may induce remission or improvement of nodular and possibly even cystic lesions (9395). In a recent report, cladribine as a single agent led to improvement in lung function, CT findings, and pulmonary hemodynamics in cases of PLCH that were progressive despite smoking cessation. Greater response was seen in patients with nodular/thick-walled lesions with increased uptake on PET scan (95). Azathioprine, methotrexate, and other drugs may show efficacy in selected cases (96). With identification of causative mutations, targeted therapies, such as BRAF inhibitors, may become promising future therapeutic options for a subset of patients with PLCH (97). Caution must be exercised, however, as these agents have been linked to development of resistance and other neoplasms (98). Patients should be screened for pulmonary hypertension by echocardiography, and, when appropriate, serial echocardiographic assessment may be necessary to identify patient subgroups that develop significant pulmonary hypertension. The identification of pulmonary hypertension should prompt consideration of a vasodilator therapy trial, as some patients may respond symptomatically and physiologically (99). Pneumothoraces should be managed in a standard fashion, and early pleurodesis considered, as the rate of recurrence is high (76). Lung transplantation is an option for patients with severe lung function impairment and/or moderate to severe pulmonary hypertension.


Other non-Langerhans cell forms of histiocytosis, especially Erdheim-Chester disease (ECD), can rarely produce pulmonary cysts (100). ECD is characterized by xanthomatous infiltration of involved tissues by foamy histiocytes (101), which stain positively for CD68 and are negative for CD1a staining (100). Almost all patients with ECD have involvement of the osseous structures, most commonly in the form of osteosclerosis of the long bones (101). Pulmonary involvement can be detected in 50% of cases by HRCT (100). Although the predominant HRCT findings include interlobular septal thickening and centrilobular micronodules, small microcysts associated with bronchial distortion are present in 12% of patients (100). Similar to PLCH, mutations in the BRAF pathway have been identified in over 50% of ECD cases (102), and treatment with the BRAF inhibitor, vemurafenib, has resulted in clinical improvement in a few cases (103, 104).

Cystic lung disease develops rarely as a result of a frank malignant process, typically secondary to metastases from peripheral sarcomas and mesenchymal tumors. Cystic metastases due to sarcomas are often complicated by pneumothoraces and portend a poor prognosis (105). Hoag and colleagues (105) studied 153 patients with sarcomas of various cell types who suffered a pneumothorax, and found cystic or cavitary changes in 25% of patients by chest radiography. Tateishi and colleagues (106) evaluated CT findings in 24 patients with metastatic pulmonary angiosarcoma and found that 21% (5/24) of patients had multiple thin-walled pulmonary cysts with a mean diameter of 46 mm (range = 8–71 mm). All five patients with cystic lung disease developed pneumothoraces, and follow-up studies showed an increase in cyst size and wall thickness. Endometrial stromal sarcomas can result in cystic pulmonary metastases that closely mimic LAM (107, 108). Synovial sarcomas have also been reported to cause metastatic cystic pulmonary lesions (109).

Pleuropulmonary blastoma (PPB), the most common primary pediatric lung neoplasm, typically presents in children under 6 years of age, and can manifest as a multilocular cystic neoplasm designated type I PPB (110) (Figure 3). PPB can also present as a mixed solid and cystic tumor (type II) or a purely solid, high-grade sarcoma (type III) (111, 112). Low-grade mucosa-associated lymphoid tissue lymphomas rarely present as cystic lesions (113). Pulmonary cysts have also been reported in a variety of other metastatic and primary lung malignancies (105109) (Table 2).

Table 2. List of Malignancies Reported to Be Associated with Cystic Pulmonary Lesions

Primary pulmonary neoplasms
 Bronchioalveolar cell carcinoma
 Mesenchymal cystic hamartoma
 Pleuropulmonary blastoma
Sarcomas of various cell types
 Synovial cell sarcoma
 Ewing’s sarcoma
 Endometrial stromal sarcoma
 Wilm’s tumor
 Pineal teratoma
 Other sarcomas
Metastatic epithelial tumors
 Adenocarcinomas of the gastrointestinal and genitourinary tract
Systemic malignancies

Data from References 105109.

Smoking-related DCLDs

Exposure to cigarette smoke can cause a variety of diffuse lung diseases, many with a diffuse cystic pattern, including PLCH, DIP, and RB-associated ILD (RB-ILD) (114). RB is a nearly ubiquitous pulmonary process in smokers (114) that is characterized by bronchial metaplasia and the accumulation of pigmented macrophages in distal airways. The pathology of DIP is similar, though the intra-alveolar accumulation of pigmented macrophages is more profuse (115). The radiologic features of RB-ILD and DIP overlap significantly, with common abnormalities including bronchial wall thickening, centrilobular nodules, and ground-glass attenuation (116). Although ground-glass attenuation is the most common radiographic abnormality in DIP, cystic changes have been reported in 32–75% of patients (117, 118). The cysts in DIP are typically lower lung zone predominant, involve less than 10% of the parenchyma (118), and often appear within areas of ground-glass attenuation (Figure 4A). Smoking can also lead to small airway destruction, producing a diffuse cystic pattern on chest imaging that can mimic LAM and other DCLDs (Figure 4B) (119).

Infectious Etiologies of Cystic Lung Disease

Infectious diseases can occasionally present with diffuse cystic changes. The parenchymal lucencies in these cases are often referred to as pneumatoceles. Pneumocystis jiroveci–associated pneumatoceles are the most characteristic of this group of diseases. Pneumocystis pneumonia usually manifests as bilateral ground-glass attenuation and reticulation; however, a minority of cases (10–34%) can present with a predominant DCLD pattern associated with pneumothoraces (120). Cysts associated with Pneumocystis are usually numerous, bilateral, diffusely distributed or upper lobe predominant, and of variable size and wall thickness (Figure 5A). Diagnosis is confirmed by identification of microorganisms with appropriate staining (Figures 5B and 5C). The cysts can shrink or completely resolve with treatment of Pneumocystis pneumonia (121). Formation of pulmonary cysts is more commonly seen in Pneumocystis infections associated with acquired immune deficiency syndrome (∼56%) compared with other immune-suppressed states (∼3%) (122).

Diseases caused by Staphylococcus species can present with multiple pneumatoceles, most often in pediatric populations (123). Effective antibiotic therapy has dramatically reduced this disease presentation, but it is still occasionally reported in cases of septic emboli, especially in immunosuppressed patients (124). Coccidioidomycosis and other endemic fungal microorganisms are infrequently associated with cystic lung disease (125).

Recurrent respiratory papillomatosis (RRP) can rarely present with a DCLD pattern on chest radiography. This predominantly pediatric disorder is caused by the human papilloma virus, and mainly affects the upper airways (126). Respiratory papillomas most commonly occur in the larynx, but can spread to involve the trachea and upper airways, causing mural irregularities, nodule formation, and airway obstruction in severe cases (127, 128). Bronchopulmonary spread of RRP is rare (2–5% of cases) (128, 129), but is typically present in cases associated with cystic lung disease. The pulmonary lesions of RRP are characterized by multiple cavities, thin-walled cysts, and lower-zone-predominant nodules (Figure 5D). Cysts vary from round to irregular in shape, are usually less than 5 cm in diameter, and can contain air–fluid levels. Cysts can increase in size and number with disease progression. The disease can be fatal, but improvement in cysts and nodules has been reported in a few cases after treatment with cidofovir (127, 130).

Paragonimiasis is a parasitic zoonosis caused by the oriental lung fluke, Paragonimus westermani. The infection is acquired after ingestion of freshwater crabs, and is endemic in Southeast Asia. After ingestion, the larvae of P. westermani migrate through the abdominal cavity to the pleural space and lungs, causing a variety of pleuropulmonary complications (131, 132). The radiographic findings of pulmonary paragonimiasis include formation of nodules, areas of consolidation, and cysts. Cysts are thought to form as a result of ischemic infarction caused by obstruction of an arteriole or a vein by the worm, and have been reported in 15–100% of pulmonary paragonimiasis cases (131, 133, 134). Cysts vary in size from 5 to 15 mm in diameter, and can have variable wall thickness. They are frequently present within areas of consolidation but can also be seen in isolation (133). Migration tracks can sometimes be visualized on chest radiography, and are considered a specific finding of paragonimiasis (131). Diagnosis can be established by serology and detection of eggs in sputum or bronchoalveolar lavage. Praziquantel is the drug of choice and is effective in over 90% of patients (131).

ILDs with a Cystic Component

ILDs, such as idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (HP), and sarcoidosis, can present with cystic changes in the lung parenchyma, although cystic change is rarely the dominant feature. Subacute HP (135), as well as chronic HP (136), can present with a cystic lung disease pattern. In fact, the presence and nature of cysts can help distinguish chronic HP from IPF. Cysts in chronic HP are usually seen within areas of ground-glass attenuation (Figure 6A) (136). Centrilobular nodules and areas of decreased lobular attenuation are almost always seen in conjunction with cysts in patients with chronic HP (136).

Cysts in IPF vary from 3 to 10 mm in size, often have thick, fibrous walls, and are invariably associated with other fibrotic features, such as reticulation, traction bronchiectasis, architectural distortion, and honeycombing (Figure 6B) (125). The distribution of lucencies can suggest the underlying diagnosis. Cysts in IPF and other ILDs have a peripheral, subpleural, and basilar predominance, whereas cysts in sarcoidosis tend to have a perihilar distribution (125).

DCLD is an uncommon clinical and radiographic presentation with a broad differential diagnosis. Neoplastic etiologies, especially LAM and PLCH, are the most common DCLDs seen in clinical practice. Chest HRCT remains the diagnostic modality of choice, and can be sufficient to establish the diagnosis in some cases. The use of serum biomarkers, such as VEGF-D, has further reduced the need for a tissue biopsy. Bronchoscopy with transbronchial biopsy can be helpful in establishing the diagnosis in cases of LAM and PLCH, but surgical lung biopsy may be required when the diagnosis is not obtained by less-invasive means. Numerous other diseases, such as metastatic malignancies, smoking-related lung diseases, infectious etiologies, and ILDs, can have a predominantly cystic presentation. Clinicians should consider a broad differential diagnosis when evaluating patients with DCLD.

1. Hansell DM, Bankier AA, MacMahon H, McLoud TC, Müller NL, Remy J. Fleischner Society: glossary of terms for thoracic imaging. Radiology 2008;246:697722.
2. Henske EP, McCormack FX. Lymphangioleiomyomatosis - a wolf in sheep’s clothing. J Clin Invest 2012;122:38073816.
3. McCormack FX, Travis WD, Colby TV, Henske EP, Moss J. Lymphangioleiomyomatosis: calling it what it is: a low-grade, destructive, metastasizing neoplasm. Am J Respir Crit Care Med 2012;186:12101212.
4. Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med 2006;355:13451356.
5. Carsillo T, Astrinidis A, Henske EP. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci USA 2000;97:60856090.
6. Strizheva GD, Carsillo T, Kruger WD, Sullivan EJ, Ryu JH, Henske EP. The spectrum of mutations in TSC1 and TSC2 in women with tuberous sclerosis and lymphangiomyomatosis. Am J Respir Crit Care Med 2001;163:253258.
7. Costello LC, Hartman TE, Ryu JH. High frequency of pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex. Mayo Clin Proc 2000;75:591594.
8. Moss J, Avila NA, Barnes PM, Litzenberger RA, Bechtle J, Brooks PG, Hedin CJ, Hunsberger S, Kristof AS. Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex. Am J Respir Crit Care Med 2001;164:669671.
9. Franz DN, Brody A, Meyer C, Leonard J, Chuck G, Dabora S, Sethuraman G, Colby TV, Kwiatkowski DJ, McCormack FX. Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis. Am J Respir Crit Care Med 2001;164:661668.
10. Muzykewicz DA, Sharma A, Muse V, Numis AL, Rajagopal J, Thiele EA. TSC1 and TSC2 mutations in patients with lymphangioleiomyomatosis and tuberous sclerosis complex. J Med Genet 2009;46:465468.
11. Adriaensen ME, Schaefer-Prokop CM, Duyndam DA, Zonnenberg BA, Prokop M. Radiological evidence of lymphangioleiomyomatosis in female and male patients with tuberous sclerosis complex. Clin Radiol 2011;66:625628.
12. Schiavina M, Di Scioscio V, Contini P, Cavazza A, Fabiani A, Barberis M, Bini A, Altimari A, Cooke RM, Grigioni WF, et al. Pulmonary lymphangioleiomyomatosis in a karyotypically normal man without tuberous sclerosis complex. Am J Respir Crit Care Med 2007;176:9698.
13. Ciftci AO, Sanlialp I, Tanyel FC, Buyukpamukçu N. The association of pulmonary lymphangioleiomyomatosis with renal and hepatic angiomyolipomas in a prepubertal girl: a previously unreported entity. Respiration 2007;74:335337.
14. Ho TB, Hull JH, Hughes NC. An 86-year-old female with lymphangioleiomyomatosis. Eur Respir J 2006;28:1065.
15. Harknett EC, Chang WY, Byrnes S, Johnson J, Lazor R, Cohen MM, Gray B, Geiling S, Telford H, Tattersfield AE, et al. Use of variability in national and regional data to estimate the prevalence of lymphangioleiomyomatosis. QJM 2011;104:971979.
16. O’Callaghan FJ, Shiell AW, Osborne JP, Martyn CN. Prevalence of tuberous sclerosis estimated by capture-recapture analysis. Lancet 1998;351:1490.
17. Cudzilo CJ, Szczesniak RD, Brody AS, Rattan MS, Krueger DA, Bissler JJ, Franz DN, McCormack FX, Young LR. Lymphangioleiomyomatosis screening in women with tuberous sclerosis. Chest 2013;144:578585.
18. Smolarek TA, Wessner LL, McCormack FX, Mylet JC, Menon AG, Henske EP. Evidence that lymphangiomyomatosis is caused by TSC2 mutations: chromosome 16p13 loss of heterozygosity in angiomyolipomas and lymph nodes from women with lymphangiomyomatosis. Am J Hum Genet 1998;62:810815.
19. Slingerland JM, Grossman RF, Chamberlain D, Tremblay CE. Pulmonary manifestations of tuberous sclerosis in first degree relatives. Thorax 1989;44:212214.
20. Henske EP. Metastasis of benign tumor cells in tuberous sclerosis complex. Genes Chromosomes Cancer 2003;38:376381.
21. Ito N, Rubin GM. gigas, a Drosophila homolog of tuberous sclerosis gene product-2, regulates the cell cycle. Cell 1999;96:529539.
22. Tapon N, Ito N, Dickson BJ, Treisman JE, Hariharan IK. The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 2001;105:345355.
23. Sun Q, Chen X, Ma J, Peng H, Wang F, Zha X, Wang Y, Jing Y, Yang H, Chen R, et al. Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. Proc Natl Acad Sci USA 2011;108:41294134.
24. Young L, Lee HS, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, et al.; MILES Trial Group. Serum VEGF-D a concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial. Lancet Respir Med 2013;1:445452.
25. Young LR, Vandyke R, Gulleman PM, Inoue Y, Brown KK, Schmidt LS, Linehan WM, Hajjar F, Kinder BW, Trapnell BC, et al. Serum vascular endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other diseases. Chest 2010;138:674681.
26. Young LR, Inoue Y, McCormack FX. Diagnostic potential of serum VEGF-D for lymphangioleiomyomatosis. N Engl J Med 2008;358:199200.
27. Corrin B, Liebow AA, Friedman PJ. Pulmonary lymphangiomyomatosis: a review. Am J Pathol 1975;79:348382.
28. Kumasaka T, Seyama K, Mitani K, Sato T, Souma S, Kondo T, Hayashi S, Minami M, Uekusa T, Fukuchi Y, et al. Lymphangiogenesis in lymphangioleiomyomatosis: its implication in the progression of lymphangioleiomyomatosis. Am J Surg Pathol 2004;28:10071016.
29. Kumasaka T, Seyama K, Mitani K, Souma S, Kashiwagi S, Hebisawa A, Sato T, Kubo H, Gomi K, Shibuya K, et al. Lymphangiogenesis-mediated shedding of LAM cell clusters as a mechanism for dissemination in lymphangioleiomyomatosis. Am J Surg Pathol 2005;29:13561366.
30. Zhe X, Yang Y, Jakkaraju S, Schuger L. Tissue inhibitor of metalloproteinase-3 downregulation in lymphangioleiomyomatosis: potential consequence of abnormal serum response factor expression. Am J Respir Cell Mol Biol 2003;28:504511.
31. Hayashi T, Stetler-Stevenson WG, Fleming MV, Fishback N, Koss MN, Liotta LA, Ferrans VJ, Travis WD. Immunohistochemical study of metalloproteinases and their tissue inhibitors in the lungs of patients with diffuse alveolar damage and idiopathic pulmonary fibrosis. Am J Pathol 1996;149:12411256.
32. Hayashi T, Rush WL, Travis WD, Liotta LA, Stetler-Stevenson WG, Ferrans VJ. Immunohistochemical study of matrix metalloproteinases and their tissue inhibitors in pulmonary Langerhans’ cell granulomatosis. Arch Pathol Lab Med 1997;121:930937.
33. Li C, Lee PS, Sun Y, Gu X, Zhang E, Guo Y, Wu CL, Auricchio N, Priolo C, Li J, et al. Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells. J Exp Med 2014;211:1528.
34. Yu JJ, Robb VA, Morrison TA, Ariazi EA, Karbowniczek M, Astrinidis A, Wang C, Hernandez-Cuebas L, Seeholzer LF, Nicolas E, et al. Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells. Proc Natl Acad Sci USA 2009;106:26352640.
35. Gu X, Yu JJ, Ilter D, Blenis N, Henske EP, Blenis J. Integration of mTOR and estrogen-ERK2 signaling in lymphangioleiomyomatosis pathogenesis. Proc Natl Acad Sci USA 2013;110:1496014965.
36. Hornick JL, Fletcher CD. PEComa: what do we know so far? Histopathology 2006;48:7582.
37. Hayashi T, Kumasaka T, Mitani K, Terao Y, Watanabe M, Oide T, Nakatani Y, Hebisawa A, Konno R, Takahashi K, et al. Prevalence of uterine and adnexal involvement in pulmonary lymphangioleiomyomatosis: a clinicopathologic study of 10 patients. Am J Surg Pathol 2011;35:17761785.
38. Ferrans VJ, Yu ZX, Nelson WK, Valencia JC, Tatsuguchi A, Avila NA, Riemenschn W, Matsui K, Travis WD, Moss J. Lymphangioleiomyomatosis (LAM): a review of clinical and morphological features. J Nippon Med Sch 2000;67:311329.
39. Matsumoto Y, Horiba K, Usuki J, Chu SC, Ferrans VJ, Moss J. Markers of cell proliferation and expression of melanosomal antigen in lymphangioleiomyomatosis. Am J Respir Cell Mol Biol 1999;21:327336.
40. Gao L, Yue MM, Davis J, Hyjek E, Schuger L. In pulmonary lymphangioleiomyomatosis expression of progesterone receptor is frequently higher than that of estrogen receptor. Virchows Arch 2014;464:495503.
41. Cottin V, Harari S, Humbert M, Mal H, Dorfmüller P, Jaïs X, Reynaud-Gaubert M, Prevot G, Lazor R, Taillé C, et al.; Groupe d’Etudes et de Recherche sur les Maladies “Orphelines” Pulmonaires (GERM”O”P). Pulmonary hypertension in lymphangioleiomyomatosis: characteristics in 20 patients. Eur Respir J 2012;40:630640.
42. Hagaman JT, Schauer DP, McCormack FX, Kinder BW. Screening for lymphangioleiomyomatosis by high-resolution computed tomography in young, nonsmoking women presenting with spontaneous pneumothorax is cost-effective. Am J Respir Crit Care Med 2010;181:13761382.
43. Northrup H, Krueger DA; International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013;49:243254.
44. Krueger DA, Northrup H; International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013;49:255265.
45. Ryu JH, Hartman TE, Torres VE, Decker PA. Frequency of undiagnosed cystic lung disease in patients with sporadic renal angiomyolipomas. Chest 2012;141:163168.
46. Johnson SR, Cordier JF, Lazor R, Cottin V, Costabel U, Harari S, Reynaud-Gaubert M, Boehler A, Brauner M, Popper H, et al.; Review Panel of the ERS LAM Task Force. European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur Respir J 2010;35:1426.
47. Harari S, Torre O, Cassandro R, Taveira-DaSilva AM, Moss J. Bronchoscopic diagnosis of Langerhans cell histiocytosis and lymphangioleiomyomatosis. Respir Med 2012;106:12861292.
48. Meraj R, Wikenheiser-Brokamp KA, Young LR, Byrnes S, McCormack FX. Utility of transbronchial biopsy in the diagnosis of lymphangioleiomyomatosis. Front Med 2012;6:395405.
49. Mitani K, Kumasaka T, Takemura H, Hayashi T, Gunji Y, Kunogi M, Akiyoshi T, Takahashi K, Suda K, Seyama K. Cytologic, immunocytochemical and ultrastructural characterization of lymphangioleiomyomatosis cell clusters in chylous effusions of patients with lymphangioleiomyomatosis. Acta Cytol 2009;53:402409.
50. Young LR, Franz DN, Nagarkatte P, Fletcher CD, Wikenheiser-Brokamp KA, Galsky MD, Corbridge TC, Lam AP, Gelfand MJ, McCormack FX. Utility of [18F]2-fluoro-2-deoxyglucose-PET in sporadic and tuberous sclerosis-associated lymphangioleiomyomatosis. Chest 2009;136:926933.
51. Bissler JJ, Kingswood JC. Renal angiomyolipomata. Kidney Int 2004;66:924934.
52. Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, Sauter M, Nonomura N, Brakemeier S, de Vries PJ, et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2013;381:817824.
53. Taveira-DaSilva AM, Burstein D, Hathaway OM, Fontana JR, Gochuico BR, Avila NA, Moss J. Pneumothorax after air travel in lymphangioleiomyomatosis, idiopathic pulmonary fibrosis, and sarcoidosis. Chest 2009;136:665670.
54. Pollock-BarZiv S, Cohen MM, Downey GP, Johnson SR, Sullivan E, McCormack FX. Air travel in women with lymphangioleiomyomatosis. Thorax 2007;62:176180.
55. Taveira-DaSilva AM, Steagall WK, Rabel A, Hathaway O, Harari S, Cassandro R, Stylianou M, Moss J. Reversible airflow obstruction in lymphangioleiomyomatosis. Chest 2009;136:15961603.
56. Almoosa KF, Ryu JH, Mendez J, Huggins JT, Young LR, Sullivan EJ, Maurer J, McCormack FX, Sahn SA. Management of pneumothorax in lymphangioleiomyomatosis: effects on recurrence and lung transplantation complications. Chest 2006;129:12741281.
57. Boehler A, Speich R, Russi EW, Weder W. Lung transplantation for lymphangioleiomyomatosis. N Engl J Med 1996;335:12751280.
58. Kpodonu J, Massad MG, Chaer RA, Caines A, Evans A, Snow NJ, Geha AS. The US experience with lung transplantation for pulmonary lymphangioleiomyomatosis. J Heart Lung Transplant 2005;24:12471253.
59. Benden C, Rea F, Behr J, Corris PA, Reynaud-Gaubert M, Stern M, Speich R, Boehler A. Lung transplantation for lymphangioleiomyomatosis: the European experience. J Heart Lung Transplant 2009;28:17.
60. McCormack FX. Lymphangioleiomyomatosis: a clinical update. Chest 2008;133:507516.
61. Johnson SR, Tattersfield AE. Clinical experience of lymphangioleiomyomatosis in the UK. Thorax 2000;55:10521057.
62. Johnson SR, Whale CI, Hubbard RB, Lewis SA, Tattersfield AE. Survival and disease progression in UK patients with lymphangioleiomyomatosis. Thorax 2004;59:800803.
63. Neurohr C, Hoffmann AL, Huppmann P, Herrera VA, Ihle F, Leuschner S, von Wulffen W, Meis T, Baezner C, Leuchte H, et al. Is sirolimus a therapeutic option for patients with progressive pulmonary lymphangioleiomyomatosis? Respir Res 2011;12:66.
64. Urban T, Lazor R, Lacronique J, Murris M, Labrune S, Valeyre D, Cordier JF. Pulmonary lymphangioleiomyomatosis. A study of 69 patients. Groupe d’Etudes et de Recherche sur les Maladies “Orphelines” Pulmonaires (GERM”O”P). Medicine (Baltimore) 1999;78:321337.
65. Taveira-DaSilva AM, Steagall WK, Moss J. Lymphangioleiomyomatosis. Cancer Contr 2006;13:276285.
66. Johnson SR, Tattersfield AE. Decline in lung function in lymphangioleiomyomatosis: relation to menopause and progesterone treatment. Am J Respir Crit Care Med 1999;160:628633.
67. Taveira-DaSilva AM, Stylianou MP, Hedin CJ, Hathaway O, Moss J. Decline in lung function in patients with lymphangioleiomyomatosis treated with or without progesterone. Chest 2004;126:18671874.
68. McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, et al.; National Institutes of Health Rare Lung Diseases Consortium; MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 2011;364:15951606.
69. Ando K, Kurihara M, Kataoka H, Ueyama M, Togo S, Sato T, Doi T, Iwakami S, Takahashi K, Seyama K, et al. Efficacy and safety of low-dose sirolimus for treatment of lymphangioleiomyomatosis. Respir Investig 2013;51:175183.
70. Taveira-DaSilva AM, Hathaway O, Stylianou M, Moss J. Changes in lung function and chylous effusions in patients with lymphangioleiomyomatosis treated with sirolimus. Ann Intern Med 2011;154:797805, W-292–W-293.
71. Nine JS, Yousem SA, Paradis IL, Keenan R, Griffith BP. Lymphangioleiomyomatosis: recurrence after lung transplantation. J Heart Lung Transplant 1994;13:714719.
72. O’Brien JD, Lium JH, Parosa JF, Deyoung BR, Wick MR, Trulock EP. Lymphangiomyomatosis recurrence in the allograft after single-lung transplantation. Am J Respir Crit Care Med 1995;151:20332036.
73. Bittmann I, Rolf B, Amann G, Löhrs U. Recurrence of lymphangioleiomyomatosis after single lung transplantation: new insights into pathogenesis. Hum Pathol 2003;34:9598.
74. Vassallo R, Ryu JH, Schroeder DR, Decker PA, Limper AH. Clinical outcomes of pulmonary Langerhans’-cell histiocytosis in adults. N Engl J Med 2002;346:484490.
75. Schönfeld N, Dirks K, Costabel U, Loddenkemper R; Wissenschaftliche Arbeitsgemeinschaft für die Therapie von Lungenkrankheiten. A prospective clinical multicentre study on adult pulmonary Langerhans’ cell histiocytosis. Sarcoidosis Vasc Diffuse Lung Dis 2012;29:132138.
76. Mendez JL, Nadrous HF, Vassallo R, Decker PA, Ryu JH. Pneumothorax in pulmonary Langerhans cell histiocytosis. Chest 2004;125:10281032.
77. Tazi A, Bonay M, Bergeron A, Grandsaigne M, Hance AJ, Soler P. Role of granulocyte-macrophage colony stimulating factor (GM-CSF) in the pathogenesis of adult pulmonary histiocytosis X. Thorax 1996;51:611614.
78. Colby TV, Lombard C. Histiocytosis X in the lung. Hum Pathol 1983;14:847856.
79. Tazi A, Moreau J, Bergeron A, Dominique S, Hance AJ, Soler P. Evidence that Langerhans cells in adult pulmonary Langerhans cell histiocytosis are mature dendritic cells: importance of the cytokine microenvironment. J Immunol 1999;163:35113515.
80. Xaubet A, Agustí C, Picado C, Gueréquiz S, Martos JA, Carrión M, Agustí-Vidal A. Bronchoalveolar lavage analysis with anti-T6 monoclonal antibody in the evaluation of diffuse lung diseases. Respiration 1989;56:161166.
81. Asakura S, Colby TV, Limper AH. Tissue localization of transforming growth factor-beta1 in pulmonary eosinophilic granuloma. Am J Respir Crit Care Med 1996;154:15251530.
82. Prasse A, Stahl M, Schulz G, Kayser G, Wang L, Ask K, Yalcintepe J, Kirschbaum A, Bargagli E, Zissel G, et al. Essential role of osteopontin in smoking-related interstitial lung diseases. Am J Pathol 2009;174:16831691.
83. Colombat M, Caudroy S, Lagonotte E, Mal H, Danel C, Stern M, Fournier M, Birembaut P. Pathomechanisms of cyst formation in pulmonary light chain deposition disease. Eur Respir J 2008;32:13991403.
84. Sahm F, Capper D, Preusser M, Meyer J, Stenzinger A, Lasitschka F, Berghoff AS, Habel A, Schneider M, Kulozik A, et al. BRAFV600E mutant protein is expressed in cells of variable maturation in Langerhans cell histiocytosis. Blood 2012;120:e28e34.
85. Brown NA, Furtado LV, Betz BL, Kiel MJ, Weigelin HC, Lim MS, Elenitoba-Johnson KS. High prevalence of somatic MAP2K1 mutations in BRAF V600E-negative Langerhans cell histiocytosis. Blood 2014;124:16551658.
86. Nelson DS, Quispel W, Badalian-Very G, van Halteren AG, van den Bos C, Bovée JV, Tian SY, Van Hummelen P, Ducar M, MacConaill LE, et al. Somatic activating ARAF mutations in Langerhans cell histiocytosis. Blood 2014;123:31523155.
87. Travis WD, Borok Z, Roum JH, Zhang J, Feuerstein I, Ferrans VJ, Crystal RG. Pulmonary Langerhans cell granulomatosis (histiocytosis X): a clinicopathologic study of 48 cases. Am J Surg Pathol 1993;17:971986.
88. Tazi A, Marc K, Dominique S, de Bazelaire C, Crestani B, Chinet T, Israel-Biet D, Cadranel J, Frija J, Lorillon G, et al. Serial computed tomography and lung function testing in pulmonary Langerhans’ cell histiocytosis. Eur Respir J 2012;40:905912.
89. Brauner MW, Grenier P, Mouelhi MM, Mompoint D, Lenoir S. Pulmonary histiocytosis X: evaluation with high-resolution CT. Radiology 1989;172:255258.
90. Baqir M, Vassallo R, Maldonado F, Yi ES, Ryu JH. Utility of bronchoscopy in pulmonary Langerhans cell histiocytosis. J Bronchology Interv Pulmonol 2013;20:309312.
91. Krajicek BJ, Ryu JH, Hartman TE, Lowe VJ, Vassallo R. Abnormal fluorodeoxyglucose PET in pulmonary Langerhans cell histiocytosis. Chest 2009;135:15421549.
92. Mogulkoc N, Veral A, Bishop PW, Bayindir U, Pickering CA, Egan JJ. Pulmonary Langerhans’ cell histiocytosis: radiologic resolution following smoking cessation. Chest 1999;115:14521455.
93. Lazor R, Etienne-Mastroianni B, Khouatra C, Tazi A, Cottin V, Cordier JF. Progressive diffuse pulmonary Langerhans cell histiocytosis improved by cladribine chemotherapy. Thorax 2009;64:274275.
94. Lorillon G, Bergeron A, Detourmignies L, Jouneau S, Wallaert B, Frija J, Tazi A. Cladribine is effective against cystic pulmonary Langerhans cell histiocytosis. Am J Respir Crit Care Med 2012;186:930932.
95. Grobost V, Khouatra C, Lazor R, Cordier JF, Cottin V. Effectiveness of cladribine therapy in patients with pulmonary Langerhans cell histiocytosis. Orphanet J Rare Dis 2014;9:191.
96. Girschikofsky M, Arico M, Castillo D, Chu A, Doberauer C, Fichter J, Haroche J, Kaltsas GA, Makras P, Marzano AV, et al. Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net. Orphanet J Rare Dis 2013;8:72.
97. Arceci RJ. Biological and therapeutic implications of the BRAF pathway in histiocytic disorders. Am Soc Clin Oncol Educ Book 2014:e441e445.
98. Callahan MK, Rampal R, Harding JJ, Klimek VM, Chung YR, Merghoub T, Wolchok JD, Solit DB, Rosen N, Abdel-Wahab O, et al. Progression of RAS-mutant leukemia during RAF inhibitor treatment. N Engl J Med 2012;367:23162321.
99. Le Pavec J, Lorillon G, Jaïs X, Tcherakian C, Feuillet S, Dorfmüller P, Simonneau G, Humbert M, Tazi A. Pulmonary Langerhans cell histiocytosis-associated pulmonary hypertension: clinical characteristics and impact of pulmonary arterial hypertension therapies. Chest 2012;142:11501157.
100. Arnaud L, Pierre I, Beigelman-Aubry C, Capron F, Brun AL, Rigolet A, Girerd X, Weber N, Piette JC, Grenier PA, et al. Pulmonary involvement in Erdheim-Chester disease: a single-center study of thirty-four patients and a review of the literature. Arthritis Rheum 2010;62:35043512.
101. Veyssier-Belot C, Cacoub P, Caparros-Lefebvre D, Wechsler J, Brun B, Remy M, Wallaert B, Petit H, Grimaldi A, Wechsler B, et al. Erdheim-Chester disease. Clinical and radiologic characteristics of 59 cases. Medicine (Baltimore) 1996;75:157169.
102. Haroche J, Charlotte F, Arnaud L, von Deimling A, Hélias-Rodzewicz Z, Hervier B, Cohen-Aubart F, Launay D, Lesot A, Mokhtari K, et al. High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses. Blood 2012;120:27002703.
103. Haroche J, Cohen-Aubart F, Emile JF, Arnaud L, Maksud P, Charlotte F, Cluzel P, Drier A, Hervier B, Benameur N, et al. Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood 2013;121:14951500.
104. Haroche J, Cohen-Aubart F, Emile JF, Maksud P, Drier A, Tolédano D, Barete S, Charlotte F, Cluzel P, Donadieu J, et al. Reproducible and sustained efficacy of targeted therapy with vemurafenib in patients with BRAF(V600E)-mutated Erdheim-Chester disease. J Clin Oncol 2015;33:411418.
105. Hoag JB, Sherman M, Fasihuddin Q, Lund ME. A comprehensive review of spontaneous pneumothorax complicating sarcoma. Chest 2010;138:510518.
106. Tateishi U, Hasegawa T, Kusumoto M, Yamazaki N, Iinuma G, Muramatsu Y, Moriyama N. Metastatic angiosarcoma of the lung: spectrum of CT findings. AJR Am J Roentgenol 2003;180:16711674.
107. Aubry MC, Myers JL, Colby TV, Leslie KO, Tazelaar HD. Endometrial stromal sarcoma metastatic to the lung: a detailed analysis of 16 patients. Am J Surg Pathol 2002;26:440449.
108. Abrams J, Talcott J, Corson JM. Pulmonary metastases in patients with low-grade endometrial stromal sarcoma. Clinicopathologic findings with immunohistochemical characterization. Am J Surg Pathol 1989;13:133140.
109. Traweek T, Rotter AJ, Swartz W, Azumi N. Cystic pulmonary metastatic sarcoma. Cancer 1990;65:18051811.
110. Hill DA, Jarzembowski JA, Priest JR, Williams G, Schoettler P, Dehner LP. Type I pleuropulmonary blastoma: pathology and biology study of 51 cases from the international pleuropulmonary blastoma registry. Am J Surg Pathol 2008;32:282295.
111. Odev K, Guler I, Altinok T, Pekcan S, Batur A, Ozbiner H. Cystic and cavitary lung lesions in children: radiologic findings with pathologic correlation. J Clin Imaging Sci 2013;3:60.
112. Priest JR, McDermott MB, Bhatia S, Watterson J, Manivel JC, Dehner LP. Pleuropulmonary blastoma: a clinicopathologic study of 50 cases. Cancer 1997;80:147161.
113. Ioachimescu OC, Sieber S, Walker MJ, Rella V, Kotch A. A 35-year-old woman with asthma and polycystic lung disease. Chest 2002;121:256260.
114. Vassallo R. Diffuse lung diseases in cigarette smokers. Semin Respir Crit Care Med 2012;33:533542.
115. Ryu JH, Colby TV, Hartman TE, Vassallo R. Smoking-related interstitial lung diseases: a concise review. Eur Respir J 2001;17:122132.
116. Vassallo R, Ryu JH. Smoking-related interstitial lung diseases. Clin Chest Med 2012;33:165178.
117. Akira M, Yamamoto S, Hara H, Sakatani M, Ueda E. Serial computed tomographic evaluation in desquamative interstitial pneumonia. Thorax 1997;52:333337.
118. Hartman TE, Primack SL, Swensen SJ, Hansell D, McGuinness G, Müller NL. Desquamative interstitial pneumonia: thin-section CT findings in 22 patients. Radiology 1993;187:787790.
119. Gupta N, McCormack F, Wikenheiser-Brokamp K. Smoking related small airway involvement presenting as diffuse multicystic lung disease: a new lymphangioleiomyomatosis mimic [abstract]. Am J Respir Crit Care Med 2015;191:A1396.
120. Boiselle PM, Crans CA Jr, Kaplan MA. The changing face of Pneumocystis carinii pneumonia in AIDS patients. AJR Am J Roentgenol 1999;172:13011309.
121. Chow C, Templeton PA, White CS. Lung cysts associated with Pneumocystis carinii pneumonia: radiographic characteristics, natural history, and complications. AJR Am J Roentgenol 1993;161:527531.
122. Hardak E, Brook O, Yigla M. Radiological features of Pneumocystis jirovecii Pneumonia in immunocompromised patients with and without AIDS. Lung 2010;188:159163.
123. Erdem G, Bergert L, Len K, Melish M, Kon K, DiMauro R. Radiological findings of community-acquired methicillin-resistant and methicillin-susceptible Staphylococcus aureus pediatric pneumonia in Hawaii. Pediatr Radiol 2010;40:17681773.
124. Godwin JD, Webb WR, Savoca CJ, Gamsu G, Goodman PC. Multiple, thin-walled cystic lesions of the lung. AJR Am J Roentgenol 1980;135:593604.
125. Ryu JH, Swensen SJ. Cystic and cavitary lung diseases: focal and diffuse. Mayo Clin Proc 2003;78:744752.
126. Cordier JF, Johnson SR. Multiple cystic lung diseases. Eur Respir Mon 2011;54:4683.
127. Ruan SY, Chen KY, Yang PC. Recurrent respiratory papillomatosis with pulmonary involvement: a case report and review of the literature. Respirology 2009;14:137140.
128. Soldatski IL, Onufrieva EK, Steklov AM, Schepin NV. Tracheal, bronchial, and pulmonary papillomatosis in children. Laryngoscope 2005;115:18481854.
129. Zawadzka-Głos L, Jakubowska A, Chmielik M, Bielicka A, Brzewski M. Lower airway papillomatosis in children. Int J Pediatr Otorhinolaryngol 2003;67:11171121.
130. Schraff S, Derkay CS, Burke B, Lawson L. American Society of Pediatric Otolaryngology members’ experience with recurrent respiratory papillomatosis and the use of adjuvant therapy. Arch Otolaryngol Head Neck Surg 2004;130:10391042.
131. Kuroki M, Hatabu H, Nakata H, Hashiguchi N, Shimizu T, Uchino N, Tamura S. High-resolution computed tomography findings of P. westermani. J Thorac Imaging 2005;20:210213.
132. Kim TS, Han J, Shim SS, Jeon K, Koh WJ, Lee I, Lee KS, Kwon OJ. Pleuropulmonary paragonimiasis: CT findings in 31 patients. AJR Am J Roentgenol 2005;185:616621.
133. Im JG, Whang HY, Kim WS, Han MC, Shim YS, Cho SY. Pleuropulmonary paragonimiasis: radiologic findings in 71 patients. AJR Am J Roentgenol 1992;159:3943.
134. Mukae H, Taniguchi H, Matsumoto N, Iiboshi H, Ashitani J, Matsukura S, Nawa Y. Clinicoradiologic features of pleuropulmonary Paragonimus westermani on Kyusyu Island, Japan. Chest 2001;120:514520.
135. Franquet T, Hansell DM, Senbanjo T, Remy-Jardin M, Müller NL. Lung cysts in subacute hypersensitivity pneumonitis. J Comput Assist Tomogr 2003;27:475478.
136. Silva CI, Müller NL, Lynch DA, Curran-Everett D, Brown KK, Lee KS, Chung MP, Churg A. Chronic hypersensitivity pneumonitis: differentiation from idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia by using thin-section CT. Radiology 2008;246:288297.
Correspondence and requests for reprints should be addressed to Nishant Gupta, M.D., 231 Albert Sabin Way, MSB Room 6053, ML 0564, Cincinnati, OH 45267. E-mail:

Author Contributions: N.G. led the writing group; N.G., R.V., K.A.W.-B., and F.X.M. wrote the manuscript; and K.A.W.-B. provided the pathology cases and pathological descriptions.

CME will be available for this article at

Originally Published in Press as DOI: 10.1164/rccm.201411-2094CI on April 23, 2015

Author disclosures are available with the text of this article at


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