Ruchi Yadav, MD

Primary care physicians are playing a bigger role in evaluating the incidental finding of interstitial lung diseases since the recent publication of guidelines recommending computed tomography (CT) to screen for lung cancer.

In August 2011, the National Cancer Institute published its findings from the National Lung Screening Trial, which demonstrated a 20% reduction in mortality from lung cancer in patients at high risk screened with low-dose CT.¹ Based on these results, the American Cancer Society, the American College of Chest Physicians, the American Society of Clinical Oncology, and the National Comprehensive Cancer Network recommended annual screening for lung cancer with low-dose CT in adults ages 55 to 74 who have a 30-pack-year smoking history and who currently smoke or have quit within the past 15 years.² In December 2013, the US Preventive Services Task Force published similar guidelines but increased the age range to include high-risk patients ages 55 to 80.³

Bach et al⁴ estimated that, in 2010 in the United States, 8.6 million people met the criteria used in the National Lung Screening Trial for low-dose CT screening. These are the same criteria as in the multisociety recommendations cited above.² With such large numbers of patients eligible for CT screening, internists and other primary care physicians are undoubtedly encountering the incidental discovery of nonmalignant pulmonary diseases such as interstitial lung disease.

This article reviews the radiographic characteristics of the most common interstitial lung diseases the internist may encounter on screening CT in long-term smokers.

Referral to a specialist has been associated with lower rates of morbidity and death,⁵ and a diagnosis of interstitial lung disease should be confirmed by a pulmonologist and a radiologist specializing in differentiating the subtypes. But the primary care physician now plays a critical role in recognizing the need for further evaluation.

HOW COMMON IS INTERSTITIAL LUNG DISEASE IN SMOKERS?

Several studies have published data on the prevalence of interstitial lung disease in patients undergoing low-dose CT for lung cancer screening.

A trial at Mayo Clinic in current and former smokers identified “diffuse lung disease” in 9 (0.9%) of 1,049 participants.⁶

A trial in Ireland identified idiopathic pulmonary fibrosis in 6 (1.3%) of 449 current smokers who underwent low-dose CT screening for lung cancer.⁷

Sverzellati et al⁸ evaluated 692 participants in the Multicentric Italian Lung Detection CT screening study and reported a respiratory bronchiolitis pattern in 109 (15.7%), a usual interstitial pneumonia pattern in 2 (0.3%), and other patterns of chronic interstitial pneumonia in 26 (3.8%).

The National Lung Screening Trial reported that the frequency of “clinically significant” incidental findings (including pulmonary fibrosis) in all participants was 7.5%.¹ A retrospective analysis of 884 participants at a single site in this trial identified interstitial lung abnormalities in 86 participants (9.7%).⁹ These abnormalities were further categorized as nonfibrotic in 52 (5.9%) of 884, fibrotic in 19 (2.1%) of 884, and mixed fibrotic and nonfibrotic in 15 (1.7%) of 884.

Follow-up CT at 2 years in this trial demonstrated improvement in 50% and progression in 11% of patients who had nonfibrotic abnormalities, while fibrotic abnormalities improved in no cases and progressed in 37%. Interstitial lung abnormalities were more common in those who currently smoked and in those with more pack-years of cigarette smoking.⁹

In sum, these trials suggest that low-dose CT screening for lung cancer can detect the most common forms of interstitial lung disease in this at-risk population and can characterize them as fibrotic or nonfibrotic, a distinction important for prognosis and subsequent management.

NONFIBROTIC VS FIBROTIC DISEASE

It is important to distinguish between nonfibrotic and fibrotic interstitial lung disease, as fibrotic disease carries a worse prognosis and is treated differently.

Features of nonfibrotic interstitial lung disease:

• Ground-glass opacities
• Nodules
• Mosaic attenuation or consolidation.

Features of fibrotic interstitial lung disease:

• Combination of ground-glass opacities and reticulation
• Reticulation by itself
• Traction bronchiectasis
• Honeycombing
• Loss of lung volume.

NONFIBROTIC INTERSTITIAL LUNG DISEASES

Given the strong likelihood that a patient undergoing screening CT is either a current or former smoker, physicians may encounter, in addition to emphysema and lung cancer, the following smoking-related interstitial lung diseases, which are primarily nonfibrotic and which frequently coexist (Table 1):

• Respiratory bronchiolitis
• Respiratory bronchiolitis-interstitial lung disease
• Desquamative interstitial pneumonia
• Pulmonary Langerhans cell histiocytosis.

Respiratory bronchiolitis

Respiratory bronchiolitis occurs mostly in smokers and does not necessarily lead to respiratory symptoms in all patients.¹⁰ It cannot always be identified radiographically but occasionally appears as predominantly upper-lobe, patchy ground-glass opacities or ill-defined centrilobular nodules without evidence of fibrosis (Figure 1).

Respiratory bronchiolitis-interstitial lung disease

In rare cases, respiratory bronchiolitis leads to peribronchial fibrosis invading the alveolar walls, which is then classified as respiratory bronchiolitis-interstitial lung disease.¹¹ The CT findings in respiratory bronchiolitis-interstitial lung disease are upper-lobe-predominant centrilobular ground-glass nodules, patchy ground-glass opacities, and bronchial wall thickening (Figure 2).¹⁰ Occasionally, mild reticulation is noted without honeycombing. Mild air trapping can be seen in the lower lobes, with centrilobular emphysema in the upper lobes.¹²

The only successful therapy for respiratory bronchiolitis and respiratory bronchiolitis-interstitial lung disease is smoking cessation. Finding either of these diseases should prompt aggressive counseling by the internist and consideration of referral to a specialist in interstitial lung disease.

Desquamative interstitial pneumonia

Although pathologically different from respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneumonia has a similar clinical and radiographic presentation. Because their features significantly overlap, they are considered a pathomorphologic continuum, representing degrees of severity of the same disease process caused by prolonged tobacco inhalation.^10,13

Widespread ground-glass opacities are the predominant CT finding. These are bilateral and symmetric in distribution in 86%, basal and peripheral in 60%, patchy in 20%, and diffuse in 20% (Figure 3).¹⁴ Other frequent findings are mild reticulation with traction bronchiectasis and coexistent emphysema (Figure 4).¹⁵ The small peripheral cystic spaces noted in this disease most likely represent dilated bronchioles and alveolar ducts rather than honeycombing.¹⁶

No additional treatment beyond elimination of smoking has been proven effective for desquamative interstitial pneumonia, and patients who manage to quit smoking generally have a favorable prognosis.^17,18

Pulmonary Langerhans cell histiocytosis

The combination of upper-lobe-predominant cysts and nodules in a young heavy smoker are diagnostic of pulmonary Langerhans cell histiocytosis. The cysts are bizarrely shaped, thin- or thick-walled, and nonuniform in size (Figure 5). The irregular cavitary nodules are centrilobular. The disease characteristically spares the costophrenic angles.

Spontaneous pneumothorax is the initial clinical presentation in 15% of patients.¹⁶ In the early stages of the disease (nodule-predominant disease without cysts), infection and metastatic disease need to be excluded (Figure 6). In the later stages, the cysts become coalescent, making the distinction between this disease and “burned-out” lymphangioleiomyomatosis or severe emphysema extremely difficult (Figure 7).¹⁷ Smoking cessation and corticosteroids are the mainstay of medical therapy for pulmonary Langerhans cell histiocytosis, and about 50% of patients who quit smoking and receive corticosteroids demonstrate partial or complete clearing of the radiographic abnormalities and symptoms (Figure 8).

FIBROTIC INTERSTITIAL LUNG DISEASES

If CT identifies a diffuse fibrotic pattern, the two most common possibilities (Table 2) are:

• Nonspecific interstitial pneumonia
• Usual interstitial pneumonia.

As noted above, these carry a worse prognosis than the nonfibrotic interstitial lung diseases.

Nonspecific interstitial pneumonia

While most frequently idiopathic, the nonspecific interstitial pneumonia pattern can often be seen in connective tissue diseases. It has also been associated with chronic hypersensitivity pneumonitis, drug toxicity, and slowly resolving diffuse alveolar damage.¹⁹ Although it is not the only pathologic pattern in interstitial lung disease associated with connective tissue disease, it is the most common pattern in systemic sclerosis, systemic lupus erythematosus, dermatomyositis-polymyositis, and mixed connective tissue disease.²⁰

The parenchymal changes are typically subpleural and symmetric in distribution (Figure 9). In about one-third of cases, there is a peribronchovascular distribution of the abnormalities (Figure 10).

Ground-glass opacities are the dominant imaging findings, seen in 80% of cases.¹⁸ In advanced disease (also referred to as fibrotic nonspecific interstitial pneumonia), patients have accompanying fine or coarse reticular opacities, traction bronchiectasis, and consolidation (Figure 11). Honeycombing is seen in 1% to 5% of patients.²¹

The most specific sign of nonspecific interstitial pneumonia is sparing of the immediate subpleural lung, apparent in 30% to 50% of patients (Figure 12).²² Subpleural sparing with a peribronchovascular distribution of abnormalities, absence of lobular areas with decreased attenuation, and lack of honeycombing are imaging features that increase the diagnostic confidence of nonspecific interstitial pneumonia (Table 3).²³ Clinically, compared with those who have usual interstitial pneumonia (see below), patients are younger and more of them are female. These patients also present with extrapulmonary manifestations such as joint involvement, rash, and Raynaud phenomenon. Therefore, these associated symptoms on presentation can help distinguish nonspecific interstitial pneumonia or usual interstitial pneumonia related to connective tissue disease from the idiopathic forms.

The first step in managing nonspecific interstitial pneumonia is to remove all potential exposure to inhaled substances or to drugs. Although immunosuppressive therapy has never been studied in a randomized controlled trial in this disease, numerous reports suggest that patients may respond to prednisone and to steroid-sparing immunosuppressants.²⁴

In several studies, survival rates in nonspecific interstitial pneumonia were significantly greater than in usual interstitial pneumonia independent of the treatment strategy. In long-term follow-up of patients with idiopathic nonspecific interstitial pneumonia treated with immunosuppressive therapy, two-thirds remained stable or improved.^25–27

Although most connective tissue diseases cause a lung pattern of nonspecific interstitial pneumonia, some (eg, rheumatoid arthritis) may present with a pattern of usual interstitial pneumonia. In these cases and in those of advanced fibrotic nonspecific interstitial pneumonia, the prognosis is worse, as the disease is less responsive to immunosuppressive therapy.²⁰

Usual interstitial pneumonia

Usual interstitial pneumonia is the most severe form of lung fibrosis. Most cases are idio­pathic and are termed idiopathic pulmonary fibrosis. Other causes of the usual interstitial pneumonia pattern include domestic and occupational environmental exposures, connective tissue disease, and drug toxicity.²⁸ An epidemiologic association between smoking and usual interstitial pneumonia is well documented.²⁸

Idiopathic pulmonary fibrosis typically affects men ages 50 to 70. Because its risk factors coincide with those of lung cancer, there is a high likelihood of detecting idiopathic pulmonary fibrosis early in this screening population. It has an especially poor prognosis, with a mean survival of 2 to 5 years from the time of diagnosis.¹⁸

The distribution of disease in usual interstitial pneumonia is characteristically subpleural and basal. CT features include coarse subpleural reticulation and honeycombing combined with traction bronchiectasis or bronchiolectasis and architectural distortion (Figure 13).¹⁸ Honeycombing is the most specific and key diagnostic CT finding for establishing a definitive diagnosis of usual interstitial pneumonia.²⁹ However, ground-glass opacities are present in most patients, typically in the region of interstitial fibrosis, and are always less extensive than the reticulation.³⁰ The findings demonstrate morphologic heterogeneity, with areas of fibrosis adjacent to areas of normal lung (Figure 14).

In addition to the aforementioned imaging features, the 2011 American Thoracic Society and European Respiratory Society joint guidelines for the CT diagnosis of usual interstitial pneumonia patterns require the absence of atypical features that suggest an alternative diagnosis, including those seen in nonspecific interstitial pneumonia, such as an upper, midlung, or peribronchovascular distribution and extensive ground-glass attenuation.²⁸ Mild mediastinal lymphadenopathy (usually < 1.5 cm in the short axis) is common in usual interstitial pneumonia.³¹

Because other chronic interstitial pneumonias that may resemble usual interstitial pneumonia have a more favorable course and may respond to immunosuppressive therapy, establishing an early and accurate diagnosis is of the utmost importance.⁵ Additionally, the emergence of possible new therapies for idiopathic pulmonary fibrosis makes early referral to a specialist paramount in these cases. Recent studies have demonstrated significant slowing of the progression of disease in idiopathic pulmonary fibrosis with both pirfenidone and nintedanib.^32,33

DIAGNOSIS AND MANAGEMENT

The diagnosis of these nonfibrotic and fibrotic lung diseases is complex. In all cases in which interstitial lung disease is detected on screening CT for lung cancer, the internist should strongly consider further evaluation with dedicated high-resolution CT and early referral to a specialist (Figure 15).

Because smoking cessation is the only recommended treatment for nonfibrotic smoking-related interstitial lung diseases, particular emphasis on smoking cessation counseling is essential.

Referral for bronchoscopy with transbronchial lung biopsy is generally not helpful in the diagnosis of the interstitial lung diseases discussed in this article unless there is a need to rule out infection or neoplasm.³⁴ Referral for surgical lung biopsy may be indicated in some cases of suspected pulmonary Langerhans cell histiocytosis, desquamative interstitial pneumonia, nonspecific interstitial pneumonia, or usual interstitial pneumonia if the diagnosis is uncertain (Tables 1 and 2).³⁵

The American Thoracic Society/European Respiratory Society guidelines suggest a multidisciplinary team approach that includes a pathologist, radiologist, and clinician.³⁵ This approach more readily determines the correct diagnosis and relies less on invasive methods such as surgical biopsy and more on noninvasive methods such as radiology and clinical history. Overall, this will promote earlier access to appropriate therapies, clinical trial enrollment, and in more severe cases, lung transplant.

Currently, 23% of all lung transplants worldwide are performed in patients with idiopathic pulmonary fibrosis. Other forms of pulmonary fibrosis account for 3% to 4% of lung transplants performed.³⁶

Evidence suggests that early referral reduces rates of morbidity and death in these patients. The results of a single-center study³⁷ of patients with idiopathic pulmonary fibrosis demonstrated that a longer delay from the onset of symptoms to evaluation by a specialist at a tertiary care referral center was associated with a higher rate of death from this disease independent of disease severity. Those with the longest delay in referral had a multivariable-adjusted death rate 3.4 times higher than those with the shortest delay.^5,37

In summary, with implementation of the new lung cancer screening guidelines, primary care physicians are more often encountering the incidental finding of interstitial lung disease in their patients. Prompt diagnosis of interstitial lung disease helps ensure that patients receive appropriate care and early consideration for clinical trials and lung transplant.

Primary care physicians play a critical role in the initial identification of key characteristics of the interstitial abnormality—namely, whether the pattern is nonfibrotic or fibrotic—and in the correlation of the history and physical findings to expedite the diagnosis. Subsequently, ordering high-resolution CT for more detailed characterization and prompt referral to a specialist in interstitial lung disease allow for a more rapid and accurate diagnosis, specialized therapy, and supportive care.

Primary care physicians are playing a bigger role in evaluating the incidental finding of interstitial lung diseases since the recent publication of guidelines recommending computed tomography (CT) to screen for lung cancer.

In August 2011, the National Cancer Institute published its findings from the National Lung Screening Trial, which demonstrated a 20% reduction in mortality from lung cancer in patients at high risk screened with low-dose CT.¹ Based on these results, the American Cancer Society, the American College of Chest Physicians, the American Society of Clinical Oncology, and the National Comprehensive Cancer Network recommended annual screening for lung cancer with low-dose CT in adults ages 55 to 74 who have a 30-pack-year smoking history and who currently smoke or have quit within the past 15 years.² In December 2013, the US Preventive Services Task Force published similar guidelines but increased the age range to include high-risk patients ages 55 to 80.³

Bach et al⁴ estimated that, in 2010 in the United States, 8.6 million people met the criteria used in the National Lung Screening Trial for low-dose CT screening. These are the same criteria as in the multisociety recommendations cited above.² With such large numbers of patients eligible for CT screening, internists and other primary care physicians are undoubtedly encountering the incidental discovery of nonmalignant pulmonary diseases such as interstitial lung disease.

This article reviews the radiographic characteristics of the most common interstitial lung diseases the internist may encounter on screening CT in long-term smokers.

Referral to a specialist has been associated with lower rates of morbidity and death,⁵ and a diagnosis of interstitial lung disease should be confirmed by a pulmonologist and a radiologist specializing in differentiating the subtypes. But the primary care physician now plays a critical role in recognizing the need for further evaluation.

HOW COMMON IS INTERSTITIAL LUNG DISEASE IN SMOKERS?

Several studies have published data on the prevalence of interstitial lung disease in patients undergoing low-dose CT for lung cancer screening.

A trial at Mayo Clinic in current and former smokers identified “diffuse lung disease” in 9 (0.9%) of 1,049 participants.⁶

A trial in Ireland identified idiopathic pulmonary fibrosis in 6 (1.3%) of 449 current smokers who underwent low-dose CT screening for lung cancer.⁷

Sverzellati et al⁸ evaluated 692 participants in the Multicentric Italian Lung Detection CT screening study and reported a respiratory bronchiolitis pattern in 109 (15.7%), a usual interstitial pneumonia pattern in 2 (0.3%), and other patterns of chronic interstitial pneumonia in 26 (3.8%).

The National Lung Screening Trial reported that the frequency of “clinically significant” incidental findings (including pulmonary fibrosis) in all participants was 7.5%.¹ A retrospective analysis of 884 participants at a single site in this trial identified interstitial lung abnormalities in 86 participants (9.7%).⁹ These abnormalities were further categorized as nonfibrotic in 52 (5.9%) of 884, fibrotic in 19 (2.1%) of 884, and mixed fibrotic and nonfibrotic in 15 (1.7%) of 884.

Follow-up CT at 2 years in this trial demonstrated improvement in 50% and progression in 11% of patients who had nonfibrotic abnormalities, while fibrotic abnormalities improved in no cases and progressed in 37%. Interstitial lung abnormalities were more common in those who currently smoked and in those with more pack-years of cigarette smoking.⁹

In sum, these trials suggest that low-dose CT screening for lung cancer can detect the most common forms of interstitial lung disease in this at-risk population and can characterize them as fibrotic or nonfibrotic, a distinction important for prognosis and subsequent management.

NONFIBROTIC VS FIBROTIC DISEASE

It is important to distinguish between nonfibrotic and fibrotic interstitial lung disease, as fibrotic disease carries a worse prognosis and is treated differently.

Features of nonfibrotic interstitial lung disease:

• Ground-glass opacities
• Nodules
• Mosaic attenuation or consolidation.

Features of fibrotic interstitial lung disease:

• Combination of ground-glass opacities and reticulation
• Reticulation by itself
• Traction bronchiectasis
• Honeycombing
• Loss of lung volume.

NONFIBROTIC INTERSTITIAL LUNG DISEASES

Given the strong likelihood that a patient undergoing screening CT is either a current or former smoker, physicians may encounter, in addition to emphysema and lung cancer, the following smoking-related interstitial lung diseases, which are primarily nonfibrotic and which frequently coexist (Table 1):

• Respiratory bronchiolitis
• Respiratory bronchiolitis-interstitial lung disease
• Desquamative interstitial pneumonia
• Pulmonary Langerhans cell histiocytosis.

Respiratory bronchiolitis

Respiratory bronchiolitis occurs mostly in smokers and does not necessarily lead to respiratory symptoms in all patients.¹⁰ It cannot always be identified radiographically but occasionally appears as predominantly upper-lobe, patchy ground-glass opacities or ill-defined centrilobular nodules without evidence of fibrosis (Figure 1).

Respiratory bronchiolitis-interstitial lung disease

In rare cases, respiratory bronchiolitis leads to peribronchial fibrosis invading the alveolar walls, which is then classified as respiratory bronchiolitis-interstitial lung disease.¹¹ The CT findings in respiratory bronchiolitis-interstitial lung disease are upper-lobe-predominant centrilobular ground-glass nodules, patchy ground-glass opacities, and bronchial wall thickening (Figure 2).¹⁰ Occasionally, mild reticulation is noted without honeycombing. Mild air trapping can be seen in the lower lobes, with centrilobular emphysema in the upper lobes.¹²

The only successful therapy for respiratory bronchiolitis and respiratory bronchiolitis-interstitial lung disease is smoking cessation. Finding either of these diseases should prompt aggressive counseling by the internist and consideration of referral to a specialist in interstitial lung disease.

Desquamative interstitial pneumonia

Although pathologically different from respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneumonia has a similar clinical and radiographic presentation. Because their features significantly overlap, they are considered a pathomorphologic continuum, representing degrees of severity of the same disease process caused by prolonged tobacco inhalation.^10,13

Widespread ground-glass opacities are the predominant CT finding. These are bilateral and symmetric in distribution in 86%, basal and peripheral in 60%, patchy in 20%, and diffuse in 20% (Figure 3).¹⁴ Other frequent findings are mild reticulation with traction bronchiectasis and coexistent emphysema (Figure 4).¹⁵ The small peripheral cystic spaces noted in this disease most likely represent dilated bronchioles and alveolar ducts rather than honeycombing.¹⁶

No additional treatment beyond elimination of smoking has been proven effective for desquamative interstitial pneumonia, and patients who manage to quit smoking generally have a favorable prognosis.^17,18

Pulmonary Langerhans cell histiocytosis

The combination of upper-lobe-predominant cysts and nodules in a young heavy smoker are diagnostic of pulmonary Langerhans cell histiocytosis. The cysts are bizarrely shaped, thin- or thick-walled, and nonuniform in size (Figure 5). The irregular cavitary nodules are centrilobular. The disease characteristically spares the costophrenic angles.

Spontaneous pneumothorax is the initial clinical presentation in 15% of patients.¹⁶ In the early stages of the disease (nodule-predominant disease without cysts), infection and metastatic disease need to be excluded (Figure 6). In the later stages, the cysts become coalescent, making the distinction between this disease and “burned-out” lymphangioleiomyomatosis or severe emphysema extremely difficult (Figure 7).¹⁷ Smoking cessation and corticosteroids are the mainstay of medical therapy for pulmonary Langerhans cell histiocytosis, and about 50% of patients who quit smoking and receive corticosteroids demonstrate partial or complete clearing of the radiographic abnormalities and symptoms (Figure 8).

FIBROTIC INTERSTITIAL LUNG DISEASES

If CT identifies a diffuse fibrotic pattern, the two most common possibilities (Table 2) are:

• Nonspecific interstitial pneumonia
• Usual interstitial pneumonia.

As noted above, these carry a worse prognosis than the nonfibrotic interstitial lung diseases.

Nonspecific interstitial pneumonia

While most frequently idiopathic, the nonspecific interstitial pneumonia pattern can often be seen in connective tissue diseases. It has also been associated with chronic hypersensitivity pneumonitis, drug toxicity, and slowly resolving diffuse alveolar damage.¹⁹ Although it is not the only pathologic pattern in interstitial lung disease associated with connective tissue disease, it is the most common pattern in systemic sclerosis, systemic lupus erythematosus, dermatomyositis-polymyositis, and mixed connective tissue disease.²⁰

The parenchymal changes are typically subpleural and symmetric in distribution (Figure 9). In about one-third of cases, there is a peribronchovascular distribution of the abnormalities (Figure 10).

Ground-glass opacities are the dominant imaging findings, seen in 80% of cases.¹⁸ In advanced disease (also referred to as fibrotic nonspecific interstitial pneumonia), patients have accompanying fine or coarse reticular opacities, traction bronchiectasis, and consolidation (Figure 11). Honeycombing is seen in 1% to 5% of patients.²¹

The most specific sign of nonspecific interstitial pneumonia is sparing of the immediate subpleural lung, apparent in 30% to 50% of patients (Figure 12).²² Subpleural sparing with a peribronchovascular distribution of abnormalities, absence of lobular areas with decreased attenuation, and lack of honeycombing are imaging features that increase the diagnostic confidence of nonspecific interstitial pneumonia (Table 3).²³ Clinically, compared with those who have usual interstitial pneumonia (see below), patients are younger and more of them are female. These patients also present with extrapulmonary manifestations such as joint involvement, rash, and Raynaud phenomenon. Therefore, these associated symptoms on presentation can help distinguish nonspecific interstitial pneumonia or usual interstitial pneumonia related to connective tissue disease from the idiopathic forms.

The first step in managing nonspecific interstitial pneumonia is to remove all potential exposure to inhaled substances or to drugs. Although immunosuppressive therapy has never been studied in a randomized controlled trial in this disease, numerous reports suggest that patients may respond to prednisone and to steroid-sparing immunosuppressants.²⁴

In several studies, survival rates in nonspecific interstitial pneumonia were significantly greater than in usual interstitial pneumonia independent of the treatment strategy. In long-term follow-up of patients with idiopathic nonspecific interstitial pneumonia treated with immunosuppressive therapy, two-thirds remained stable or improved.^25–27

Although most connective tissue diseases cause a lung pattern of nonspecific interstitial pneumonia, some (eg, rheumatoid arthritis) may present with a pattern of usual interstitial pneumonia. In these cases and in those of advanced fibrotic nonspecific interstitial pneumonia, the prognosis is worse, as the disease is less responsive to immunosuppressive therapy.²⁰

Usual interstitial pneumonia

Usual interstitial pneumonia is the most severe form of lung fibrosis. Most cases are idio­pathic and are termed idiopathic pulmonary fibrosis. Other causes of the usual interstitial pneumonia pattern include domestic and occupational environmental exposures, connective tissue disease, and drug toxicity.²⁸ An epidemiologic association between smoking and usual interstitial pneumonia is well documented.²⁸

Idiopathic pulmonary fibrosis typically affects men ages 50 to 70. Because its risk factors coincide with those of lung cancer, there is a high likelihood of detecting idiopathic pulmonary fibrosis early in this screening population. It has an especially poor prognosis, with a mean survival of 2 to 5 years from the time of diagnosis.¹⁸

The distribution of disease in usual interstitial pneumonia is characteristically subpleural and basal. CT features include coarse subpleural reticulation and honeycombing combined with traction bronchiectasis or bronchiolectasis and architectural distortion (Figure 13).¹⁸ Honeycombing is the most specific and key diagnostic CT finding for establishing a definitive diagnosis of usual interstitial pneumonia.²⁹ However, ground-glass opacities are present in most patients, typically in the region of interstitial fibrosis, and are always less extensive than the reticulation.³⁰ The findings demonstrate morphologic heterogeneity, with areas of fibrosis adjacent to areas of normal lung (Figure 14).

In addition to the aforementioned imaging features, the 2011 American Thoracic Society and European Respiratory Society joint guidelines for the CT diagnosis of usual interstitial pneumonia patterns require the absence of atypical features that suggest an alternative diagnosis, including those seen in nonspecific interstitial pneumonia, such as an upper, midlung, or peribronchovascular distribution and extensive ground-glass attenuation.²⁸ Mild mediastinal lymphadenopathy (usually < 1.5 cm in the short axis) is common in usual interstitial pneumonia.³¹

Because other chronic interstitial pneumonias that may resemble usual interstitial pneumonia have a more favorable course and may respond to immunosuppressive therapy, establishing an early and accurate diagnosis is of the utmost importance.⁵ Additionally, the emergence of possible new therapies for idiopathic pulmonary fibrosis makes early referral to a specialist paramount in these cases. Recent studies have demonstrated significant slowing of the progression of disease in idiopathic pulmonary fibrosis with both pirfenidone and nintedanib.^32,33

DIAGNOSIS AND MANAGEMENT

The diagnosis of these nonfibrotic and fibrotic lung diseases is complex. In all cases in which interstitial lung disease is detected on screening CT for lung cancer, the internist should strongly consider further evaluation with dedicated high-resolution CT and early referral to a specialist (Figure 15).

Because smoking cessation is the only recommended treatment for nonfibrotic smoking-related interstitial lung diseases, particular emphasis on smoking cessation counseling is essential.

Referral for bronchoscopy with transbronchial lung biopsy is generally not helpful in the diagnosis of the interstitial lung diseases discussed in this article unless there is a need to rule out infection or neoplasm.³⁴ Referral for surgical lung biopsy may be indicated in some cases of suspected pulmonary Langerhans cell histiocytosis, desquamative interstitial pneumonia, nonspecific interstitial pneumonia, or usual interstitial pneumonia if the diagnosis is uncertain (Tables 1 and 2).³⁵

The American Thoracic Society/European Respiratory Society guidelines suggest a multidisciplinary team approach that includes a pathologist, radiologist, and clinician.³⁵ This approach more readily determines the correct diagnosis and relies less on invasive methods such as surgical biopsy and more on noninvasive methods such as radiology and clinical history. Overall, this will promote earlier access to appropriate therapies, clinical trial enrollment, and in more severe cases, lung transplant.

Currently, 23% of all lung transplants worldwide are performed in patients with idiopathic pulmonary fibrosis. Other forms of pulmonary fibrosis account for 3% to 4% of lung transplants performed.³⁶

Evidence suggests that early referral reduces rates of morbidity and death in these patients. The results of a single-center study³⁷ of patients with idiopathic pulmonary fibrosis demonstrated that a longer delay from the onset of symptoms to evaluation by a specialist at a tertiary care referral center was associated with a higher rate of death from this disease independent of disease severity. Those with the longest delay in referral had a multivariable-adjusted death rate 3.4 times higher than those with the shortest delay.^5,37

In summary, with implementation of the new lung cancer screening guidelines, primary care physicians are more often encountering the incidental finding of interstitial lung disease in their patients. Prompt diagnosis of interstitial lung disease helps ensure that patients receive appropriate care and early consideration for clinical trials and lung transplant.

Primary care physicians play a critical role in the initial identification of key characteristics of the interstitial abnormality—namely, whether the pattern is nonfibrotic or fibrotic—and in the correlation of the history and physical findings to expedite the diagnosis. Subsequently, ordering high-resolution CT for more detailed characterization and prompt referral to a specialist in interstitial lung disease allow for a more rapid and accurate diagnosis, specialized therapy, and supportive care.

Primary care physicians are playing a bigger role in evaluating the incidental finding of interstitial lung diseases since the recent publication of guidelines recommending computed tomography (CT) to screen for lung cancer.

In August 2011, the National Cancer Institute published its findings from the National Lung Screening Trial, which demonstrated a 20% reduction in mortality from lung cancer in patients at high risk screened with low-dose CT.¹ Based on these results, the American Cancer Society, the American College of Chest Physicians, the American Society of Clinical Oncology, and the National Comprehensive Cancer Network recommended annual screening for lung cancer with low-dose CT in adults ages 55 to 74 who have a 30-pack-year smoking history and who currently smoke or have quit within the past 15 years.² In December 2013, the US Preventive Services Task Force published similar guidelines but increased the age range to include high-risk patients ages 55 to 80.³

Bach et al⁴ estimated that, in 2010 in the United States, 8.6 million people met the criteria used in the National Lung Screening Trial for low-dose CT screening. These are the same criteria as in the multisociety recommendations cited above.² With such large numbers of patients eligible for CT screening, internists and other primary care physicians are undoubtedly encountering the incidental discovery of nonmalignant pulmonary diseases such as interstitial lung disease.

This article reviews the radiographic characteristics of the most common interstitial lung diseases the internist may encounter on screening CT in long-term smokers.

Referral to a specialist has been associated with lower rates of morbidity and death,⁵ and a diagnosis of interstitial lung disease should be confirmed by a pulmonologist and a radiologist specializing in differentiating the subtypes. But the primary care physician now plays a critical role in recognizing the need for further evaluation.

HOW COMMON IS INTERSTITIAL LUNG DISEASE IN SMOKERS?

Several studies have published data on the prevalence of interstitial lung disease in patients undergoing low-dose CT for lung cancer screening.

A trial at Mayo Clinic in current and former smokers identified “diffuse lung disease” in 9 (0.9%) of 1,049 participants.⁶

A trial in Ireland identified idiopathic pulmonary fibrosis in 6 (1.3%) of 449 current smokers who underwent low-dose CT screening for lung cancer.⁷

Sverzellati et al⁸ evaluated 692 participants in the Multicentric Italian Lung Detection CT screening study and reported a respiratory bronchiolitis pattern in 109 (15.7%), a usual interstitial pneumonia pattern in 2 (0.3%), and other patterns of chronic interstitial pneumonia in 26 (3.8%).

The National Lung Screening Trial reported that the frequency of “clinically significant” incidental findings (including pulmonary fibrosis) in all participants was 7.5%.¹ A retrospective analysis of 884 participants at a single site in this trial identified interstitial lung abnormalities in 86 participants (9.7%).⁹ These abnormalities were further categorized as nonfibrotic in 52 (5.9%) of 884, fibrotic in 19 (2.1%) of 884, and mixed fibrotic and nonfibrotic in 15 (1.7%) of 884.

Follow-up CT at 2 years in this trial demonstrated improvement in 50% and progression in 11% of patients who had nonfibrotic abnormalities, while fibrotic abnormalities improved in no cases and progressed in 37%. Interstitial lung abnormalities were more common in those who currently smoked and in those with more pack-years of cigarette smoking.⁹

In sum, these trials suggest that low-dose CT screening for lung cancer can detect the most common forms of interstitial lung disease in this at-risk population and can characterize them as fibrotic or nonfibrotic, a distinction important for prognosis and subsequent management.

NONFIBROTIC VS FIBROTIC DISEASE

It is important to distinguish between nonfibrotic and fibrotic interstitial lung disease, as fibrotic disease carries a worse prognosis and is treated differently.

Features of nonfibrotic interstitial lung disease:

• Ground-glass opacities
• Nodules
• Mosaic attenuation or consolidation.

Features of fibrotic interstitial lung disease:

• Combination of ground-glass opacities and reticulation
• Reticulation by itself
• Traction bronchiectasis
• Honeycombing
• Loss of lung volume.

NONFIBROTIC INTERSTITIAL LUNG DISEASES

Given the strong likelihood that a patient undergoing screening CT is either a current or former smoker, physicians may encounter, in addition to emphysema and lung cancer, the following smoking-related interstitial lung diseases, which are primarily nonfibrotic and which frequently coexist (Table 1):

• Respiratory bronchiolitis
• Respiratory bronchiolitis-interstitial lung disease
• Desquamative interstitial pneumonia
• Pulmonary Langerhans cell histiocytosis.

Respiratory bronchiolitis

Respiratory bronchiolitis occurs mostly in smokers and does not necessarily lead to respiratory symptoms in all patients.¹⁰ It cannot always be identified radiographically but occasionally appears as predominantly upper-lobe, patchy ground-glass opacities or ill-defined centrilobular nodules without evidence of fibrosis (Figure 1).

Respiratory bronchiolitis-interstitial lung disease

In rare cases, respiratory bronchiolitis leads to peribronchial fibrosis invading the alveolar walls, which is then classified as respiratory bronchiolitis-interstitial lung disease.¹¹ The CT findings in respiratory bronchiolitis-interstitial lung disease are upper-lobe-predominant centrilobular ground-glass nodules, patchy ground-glass opacities, and bronchial wall thickening (Figure 2).¹⁰ Occasionally, mild reticulation is noted without honeycombing. Mild air trapping can be seen in the lower lobes, with centrilobular emphysema in the upper lobes.¹²

The only successful therapy for respiratory bronchiolitis and respiratory bronchiolitis-interstitial lung disease is smoking cessation. Finding either of these diseases should prompt aggressive counseling by the internist and consideration of referral to a specialist in interstitial lung disease.

Desquamative interstitial pneumonia

Although pathologically different from respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneumonia has a similar clinical and radiographic presentation. Because their features significantly overlap, they are considered a pathomorphologic continuum, representing degrees of severity of the same disease process caused by prolonged tobacco inhalation.^10,13

Widespread ground-glass opacities are the predominant CT finding. These are bilateral and symmetric in distribution in 86%, basal and peripheral in 60%, patchy in 20%, and diffuse in 20% (Figure 3).¹⁴ Other frequent findings are mild reticulation with traction bronchiectasis and coexistent emphysema (Figure 4).¹⁵ The small peripheral cystic spaces noted in this disease most likely represent dilated bronchioles and alveolar ducts rather than honeycombing.¹⁶

No additional treatment beyond elimination of smoking has been proven effective for desquamative interstitial pneumonia, and patients who manage to quit smoking generally have a favorable prognosis.^17,18

Pulmonary Langerhans cell histiocytosis

The combination of upper-lobe-predominant cysts and nodules in a young heavy smoker are diagnostic of pulmonary Langerhans cell histiocytosis. The cysts are bizarrely shaped, thin- or thick-walled, and nonuniform in size (Figure 5). The irregular cavitary nodules are centrilobular. The disease characteristically spares the costophrenic angles.

Spontaneous pneumothorax is the initial clinical presentation in 15% of patients.¹⁶ In the early stages of the disease (nodule-predominant disease without cysts), infection and metastatic disease need to be excluded (Figure 6). In the later stages, the cysts become coalescent, making the distinction between this disease and “burned-out” lymphangioleiomyomatosis or severe emphysema extremely difficult (Figure 7).¹⁷ Smoking cessation and corticosteroids are the mainstay of medical therapy for pulmonary Langerhans cell histiocytosis, and about 50% of patients who quit smoking and receive corticosteroids demonstrate partial or complete clearing of the radiographic abnormalities and symptoms (Figure 8).

FIBROTIC INTERSTITIAL LUNG DISEASES

If CT identifies a diffuse fibrotic pattern, the two most common possibilities (Table 2) are:

• Nonspecific interstitial pneumonia
• Usual interstitial pneumonia.

As noted above, these carry a worse prognosis than the nonfibrotic interstitial lung diseases.

Nonspecific interstitial pneumonia

While most frequently idiopathic, the nonspecific interstitial pneumonia pattern can often be seen in connective tissue diseases. It has also been associated with chronic hypersensitivity pneumonitis, drug toxicity, and slowly resolving diffuse alveolar damage.¹⁹ Although it is not the only pathologic pattern in interstitial lung disease associated with connective tissue disease, it is the most common pattern in systemic sclerosis, systemic lupus erythematosus, dermatomyositis-polymyositis, and mixed connective tissue disease.²⁰

The parenchymal changes are typically subpleural and symmetric in distribution (Figure 9). In about one-third of cases, there is a peribronchovascular distribution of the abnormalities (Figure 10).

Ground-glass opacities are the dominant imaging findings, seen in 80% of cases.¹⁸ In advanced disease (also referred to as fibrotic nonspecific interstitial pneumonia), patients have accompanying fine or coarse reticular opacities, traction bronchiectasis, and consolidation (Figure 11). Honeycombing is seen in 1% to 5% of patients.²¹

The most specific sign of nonspecific interstitial pneumonia is sparing of the immediate subpleural lung, apparent in 30% to 50% of patients (Figure 12).²² Subpleural sparing with a peribronchovascular distribution of abnormalities, absence of lobular areas with decreased attenuation, and lack of honeycombing are imaging features that increase the diagnostic confidence of nonspecific interstitial pneumonia (Table 3).²³ Clinically, compared with those who have usual interstitial pneumonia (see below), patients are younger and more of them are female. These patients also present with extrapulmonary manifestations such as joint involvement, rash, and Raynaud phenomenon. Therefore, these associated symptoms on presentation can help distinguish nonspecific interstitial pneumonia or usual interstitial pneumonia related to connective tissue disease from the idiopathic forms.

The first step in managing nonspecific interstitial pneumonia is to remove all potential exposure to inhaled substances or to drugs. Although immunosuppressive therapy has never been studied in a randomized controlled trial in this disease, numerous reports suggest that patients may respond to prednisone and to steroid-sparing immunosuppressants.²⁴

In several studies, survival rates in nonspecific interstitial pneumonia were significantly greater than in usual interstitial pneumonia independent of the treatment strategy. In long-term follow-up of patients with idiopathic nonspecific interstitial pneumonia treated with immunosuppressive therapy, two-thirds remained stable or improved.^25–27

Although most connective tissue diseases cause a lung pattern of nonspecific interstitial pneumonia, some (eg, rheumatoid arthritis) may present with a pattern of usual interstitial pneumonia. In these cases and in those of advanced fibrotic nonspecific interstitial pneumonia, the prognosis is worse, as the disease is less responsive to immunosuppressive therapy.²⁰

Usual interstitial pneumonia

Usual interstitial pneumonia is the most severe form of lung fibrosis. Most cases are idio­pathic and are termed idiopathic pulmonary fibrosis. Other causes of the usual interstitial pneumonia pattern include domestic and occupational environmental exposures, connective tissue disease, and drug toxicity.²⁸ An epidemiologic association between smoking and usual interstitial pneumonia is well documented.²⁸

Idiopathic pulmonary fibrosis typically affects men ages 50 to 70. Because its risk factors coincide with those of lung cancer, there is a high likelihood of detecting idiopathic pulmonary fibrosis early in this screening population. It has an especially poor prognosis, with a mean survival of 2 to 5 years from the time of diagnosis.¹⁸

The distribution of disease in usual interstitial pneumonia is characteristically subpleural and basal. CT features include coarse subpleural reticulation and honeycombing combined with traction bronchiectasis or bronchiolectasis and architectural distortion (Figure 13).¹⁸ Honeycombing is the most specific and key diagnostic CT finding for establishing a definitive diagnosis of usual interstitial pneumonia.²⁹ However, ground-glass opacities are present in most patients, typically in the region of interstitial fibrosis, and are always less extensive than the reticulation.³⁰ The findings demonstrate morphologic heterogeneity, with areas of fibrosis adjacent to areas of normal lung (Figure 14).

In addition to the aforementioned imaging features, the 2011 American Thoracic Society and European Respiratory Society joint guidelines for the CT diagnosis of usual interstitial pneumonia patterns require the absence of atypical features that suggest an alternative diagnosis, including those seen in nonspecific interstitial pneumonia, such as an upper, midlung, or peribronchovascular distribution and extensive ground-glass attenuation.²⁸ Mild mediastinal lymphadenopathy (usually < 1.5 cm in the short axis) is common in usual interstitial pneumonia.³¹

Because other chronic interstitial pneumonias that may resemble usual interstitial pneumonia have a more favorable course and may respond to immunosuppressive therapy, establishing an early and accurate diagnosis is of the utmost importance.⁵ Additionally, the emergence of possible new therapies for idiopathic pulmonary fibrosis makes early referral to a specialist paramount in these cases. Recent studies have demonstrated significant slowing of the progression of disease in idiopathic pulmonary fibrosis with both pirfenidone and nintedanib.^32,33

DIAGNOSIS AND MANAGEMENT

The diagnosis of these nonfibrotic and fibrotic lung diseases is complex. In all cases in which interstitial lung disease is detected on screening CT for lung cancer, the internist should strongly consider further evaluation with dedicated high-resolution CT and early referral to a specialist (Figure 15).

Because smoking cessation is the only recommended treatment for nonfibrotic smoking-related interstitial lung diseases, particular emphasis on smoking cessation counseling is essential.

Referral for bronchoscopy with transbronchial lung biopsy is generally not helpful in the diagnosis of the interstitial lung diseases discussed in this article unless there is a need to rule out infection or neoplasm.³⁴ Referral for surgical lung biopsy may be indicated in some cases of suspected pulmonary Langerhans cell histiocytosis, desquamative interstitial pneumonia, nonspecific interstitial pneumonia, or usual interstitial pneumonia if the diagnosis is uncertain (Tables 1 and 2).³⁵

The American Thoracic Society/European Respiratory Society guidelines suggest a multidisciplinary team approach that includes a pathologist, radiologist, and clinician.³⁵ This approach more readily determines the correct diagnosis and relies less on invasive methods such as surgical biopsy and more on noninvasive methods such as radiology and clinical history. Overall, this will promote earlier access to appropriate therapies, clinical trial enrollment, and in more severe cases, lung transplant.

Currently, 23% of all lung transplants worldwide are performed in patients with idiopathic pulmonary fibrosis. Other forms of pulmonary fibrosis account for 3% to 4% of lung transplants performed.³⁶

Evidence suggests that early referral reduces rates of morbidity and death in these patients. The results of a single-center study³⁷ of patients with idiopathic pulmonary fibrosis demonstrated that a longer delay from the onset of symptoms to evaluation by a specialist at a tertiary care referral center was associated with a higher rate of death from this disease independent of disease severity. Those with the longest delay in referral had a multivariable-adjusted death rate 3.4 times higher than those with the shortest delay.^5,37

In summary, with implementation of the new lung cancer screening guidelines, primary care physicians are more often encountering the incidental finding of interstitial lung disease in their patients. Prompt diagnosis of interstitial lung disease helps ensure that patients receive appropriate care and early consideration for clinical trials and lung transplant.

Primary care physicians play a critical role in the initial identification of key characteristics of the interstitial abnormality—namely, whether the pattern is nonfibrotic or fibrotic—and in the correlation of the history and physical findings to expedite the diagnosis. Subsequently, ordering high-resolution CT for more detailed characterization and prompt referral to a specialist in interstitial lung disease allow for a more rapid and accurate diagnosis, specialized therapy, and supportive care.

Air-filled pulmonary lesions commonly detected on chest computed tomography. Cystic lung lesions should be distinguished from other air-filled lesions to facilitate diagnosis. Primary care physicians play an integral role in the recognition of cystic lung disease.

The differential diagnosis of cystic lung disease is broad and includes isolated pulmonary, systemic, infectious, and congenital etiologies.

Here, we aim to provide a systematic, stepwise approach to help differentiate among the various cystic lung diseases and devise an algorithm for diagnosis. In doing so, we will discuss the clinical and radiographic features of many of these diseases:

• Lymphangioleiomyomatosis
• Birt-Hogg-Dubé syndrome
• Pulmonary Langerhans cell histiocytosis
• Interstitial pneumonia (desquamative interstitial pneumonia, lymphocytic interstitial pneumonia)
• Congenital cystic lung disease (congenital pulmonary airway malformation, pulmonary sequestration, bronchogenic cyst) Pulmonary infection
• Systemic disease (amyloidosis, light chain deposition disease, neurofibromatosis type 1).

STEP 1: RULE OUT CYST-MIMICS

A pulmonary cyst is a round, circumscribed space surrounded by an epithelial or fibrous wall of variable thickness.¹ On chest radiography and computed tomography, a cyst appears as a round parenchymal lucency or low-attenuating area with a well-defined interface with normal lung.¹ Cysts vary in wall thickness but  usually have a thin wall (< 2 mm) and occur without associated pulmonary emphysema.¹ They typically contain air but occasionally contain fluid or solid material.

A pulmonary cyst can be categorized as a bulla, bleb, or pneumatocele.

Pulmonary cysts can be categorized as bullae, blebs, or pneumatoceles

Bullae are larger than 1 cm in diameter, sharply demarcated by a thin wall, and usually accompanied by emphysematous changes in the adjacent lung.¹

Blebs are no larger than 1 cm in diameter, are located within the visceral pleura or the subpleural space, and appear on computed tomography as thin-walled air spaces that are contiguous with the pleura.¹ The distinction between a bleb and a bulla is of little clinical importance, and is often unnecessary.

Pneumatoceles are cysts that are frequently caused by acute pneumonia, trauma, or aspiration of hydrocarbon fluid, and are usually transient.¹

Mimics of pulmonary cysts include pulmonary cavities, emphysema, loculated pneumothoraces, honeycomb lung, and bronchiectasis (Figure 1).²

Pulmonary cavities differ from cysts in that their walls are typically thicker (usually > 4 mm).³

Emphysema differs from cystic lung disease as it typically leads to focal areas or regions of decreased lung attenuation that do not have defined walls.¹

Honeycombing refers to a cluster or row of cysts, 1 to 3 mm in wall thickness and typically 3 to 10 mm in diameter, that are associated with end-stage lung fibrosis.¹ They are typically subpleural in distribution and are accompanied by fibrotic features such as reticulation and traction bronchiectasis.¹

Bronchiectasis is dilation and distortion of bronchi and bronchioles and can be mistaken for cysts when viewed en face.¹

Loculated pneumothoraces can also mimic pulmonary cysts, but they typically fail to adhere to a defined anatomic unit and are subpleural in distribution.

STEP 2: CHARACTERIZE THE CLINICAL PRESENTATION

Clinical signs and symptoms of cystic lung disease play a key role in diagnosis (Table 1). For instance, spontaneous pneumothorax is commonly associated with diffuse cystic lung disease (lymphangioleiomyomatosis and Birt-Hogg-Dubé syndrome), while insidious dyspnea, with or without associated pneumothorax, is usually associated with the interstitial pneumonias (lymphocytic interstitial pneumonia and desquamative interstitial pneumonia).

In addition, congenital abnormalities of the lung can lead to cyst formation. These abnormalities, especially when associated with other congenital abnormalities, are often diagnosed in the prenatal and perinatal periods. However, some remain undetected until incidentally found later in adulthood or if superimposing infection develops.

Primary pulmonary infections can also cause parenchymal necrosis, which in turn cavitates or forms cysts.⁴

Lastly, cystic lung diseases can occur as part of a multiorgan or systemic illness in which the lung is one of the organs involved. Although usually diagnosed before the discovery of cysts or manifestations of pulmonary symptoms, they can present as a diagnostic challenge, especially when lung cysts are the initial presentation.bsence of amyloid fibrils.

In view of the features of the different types of cystic lung disease, adults with cystic lung disease can be grouped according to their typical clinical presentations (Table 2):

• Insidious dyspnea or spontaneous pneumothorax
• Incidentally found cysts or recurrent pneumonia
• Signs and symptoms of primary pulmonary infection
• Signs and symptoms that are primarily nonpulmonary.

Insidious dyspnea or spontaneous pneumothorax

Insidious dyspnea or spontaneous pneumothorax can be manifestations of lymphangioleiomyomatosis, Birt-Hogg-Dubé syndrome, pulmonary Langerhans cell histiocytosis, desquamative interstitial pneumonia, or lymphocytic interstitial pneumonia.

Lymphangioleiomyomatosis is characterized by abnormal cellular proliferation within the lung, kidney, lymphatic system, or any combination.⁵ The peak prevalence is in the third to fourth decades of life, and most patients are women of childbearing age.⁶ In addition to progressive dyspnea on exertion and pneumothorax, other signs and symptoms include hemoptysis, nonproductive cough, chylous pleural effusion, and ascites.^7,8

Birt-Hogg-Dubé syndrome is caused by germline mutations in the folliculin (FLCN) gene.⁹ It is characterized by skin fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax, and renal cancer.¹⁰

Pulmonary Langerhans cell histiocytosis is part of the spectrum of Langerhans cell histiocytosis that, in addition to the lungs, can also involve the bone, pituitary gland, thyroid, skin, lymph nodes, and liver.¹¹ It occurs almost exclusively in smokers, affecting individuals in their 20s and 30s, with no gender predilection.^12,13 In addition to nonproductive cough and dyspnea, patients can also present with fever, anorexia, and weight loss,¹³ but approximately 25% of patients are asymptomatic.¹⁴

Desquamative interstitial pneumonia is an idiopathic interstitial pneumonia that, like pulmonary Langerhans cell histiocytosis, is seen almost exclusively in current or former smokers, who account for about 90% of patients with this disease. It affects almost twice as many men as women.^15,16 The mean age at onset is 42 to 46.^15,16 In addition to insidious cough and dyspnea, digital clubbing develops in 26% to 40% of patients.^16,17

Lymphocytic interstitial pneumonia is another rare idiopathic pneumonia, usually associated with connective tissue disease, Sjögren syndrome, immunodeficiencies, and viral infections.^18­–21 It is more common in women, presenting between the 4th and 7th decades of life, with a mean age at diagnosis of 50 to 56.^18,22 In addition to progressive dyspnea and cough, other symptoms include weight loss, pleuritic pain, arthralgias, fatigue, night sweats, and fever.²³

In summary, in this clinical group, lymphangioleiomyomatosis and Birt-Hogg-Dubé syndrome should be considered when patients present with spontaneous pneumothorax; those with Birt-Hogg-Dubé syndrome also present with skin lesions or renal cancer. In patients with progressive dyspnea and cough, lymphocytic interstitial pneumonia should be considered in those with a known history of connective tissue disease or immunodeficiency. Pulmonary Langerhans cell histiocytosis typically presents at a younger age (20 to 30 years old) than desquamative interstitial pneumonia (smokers in their 40s). Making the distinction, however, will likely require imaging with computed tomography.

Incidentally found cysts or recurrent pneumonia

Incidentally found cysts or recurrent pneumonia can be manifestations of congenital pulmonary airway malformation, pulmonary sequestration, or bronchogenic cyst.

Congenital pulmonary airway malformation, of which there are five types, is the most common pulmonary congenital abnormality. It accounts for up to 95% of cases of congenital cystic lung disease.^24,25 About 85% of cases are detected in the prenatal or perinatal periods.²⁶ Late-onset congenital pulmonary airway malformation (arising in childhood to adulthood) presents with recurrent pneumonia in about 75% of cases and can be misdiagnosed as lung abscess, pulmonary tuberculosis, or bronchiectasis.²⁷

Pulmonary sequestration, the second most common pulmonary congenital abnormality, is characterized by a portion of lung that does not connect to the tracheobronchial tree and has its own systemic arterial supply.²⁴ Intralobar sequestration, which shares the pleural investment with normal lung, accounts for about 80% of cases of pulmonary sequestration.^28–30 In addition to signs or symptoms of pulmonary infection, patients with pulmonary sequestration can remain asymp-
tomatic (about 25% of cases), or can present with hemoptysis or hemothorax.^28–30 In adults, the typical age at presentation is between 20 and 25.^29,30

Bronchogenic cyst is usually life-threatening in children. In adults, it commonly causes cough and chest pain.³¹ Hemoptysis, dysphagia, hoarseness, and diaphragmatic paralysis can also occur.^32,33 The mean age at diagnosis in adults is 35 to 40.^31,32

In summary, most cases of recurrent pneumonia with cysts are due to congenital pulmonary airway malformation. Pulmonary sequestration is the second most common cause of cystic lung disease in this group. Bronchogenic cyst is usually fatal in fetal development; smaller cysts can go unnoticed during the earlier years and are later found incidentally as imaging abnormalities in adults.

Signs and symptoms of primary pulmonary infections

Signs and symptoms of primary pulmonary infections can be due to Pneumocystis jirovecii pneumonia or echinococcal infections.

P jirovecii pneumonia commonly develops in patients with human immunodeficiency virus infection and low CD4 counts, recipients of hematologic or solid-organ transplants, and those receiving immunosuppressive therapy (eg, glucocorticoids or chemotherapy).

Echinococcal infections (with Echinococcus granulosus or multilocularis species) are more common in less-developed countries such as those in South America or the Middle East, in China, or in patients who have traveled to endemic areas.³⁴

In summary, cystic lung disease in patients with primary pulmonary infections can be diagnosed by the patient’s clinical history and risk factors for infections. Those with human immunodeficiency virus infection and other causes of immunodeficiency are predisposed to P jirovecii pneumonia. Echinococcal infections occur in those with a history of travel to an endemic area.

Primarily nonpulmonary signs and symptoms

If the patient has primarily nonpulmonary signs and symptoms, think about pulmonary amyloidosis, light chain deposition disease, and neurofibromatosis type 1.

Pulmonary amyloidosis has a variety of manifestations, including tracheobronchial disease, nodular parenchymal disease, diffuse or alveolar septal pattern, pleural disease, lymphadenopathy, and pulmonary cysts.⁴

Light chain deposition disease shares some clinical features with amyloidosis. However, the light chain fragments in this disease do not form amyloid fibrils and therefore do not stain positively with Congo red. The kidney is the most commonly involved organ.⁴

Neurofibromatosis type 1 is characterized by collections of neurofibromas, café-au-lait spots, and pigmented hamartomas in the iris (Lisch nodules).³⁵

In summary, patients in this group typically present with complications related to systemic involvement. Those with neurofibromatosis type 1 present with ophthalmologic, dermatologic, and neurologic manifestations. Amyloidosis and light chain deposition disease most commonly involve the renal system; their distinction will likely require tissue biopsy and Congo-red staining.

STEP 3: CHARACTERIZE THE RADIOGRAPHIC FEATURES

Characterization of pulmonary cysts and their distribution plays a key role in the diagnosis. Radiographically, cystic lung diseases can be subclassified into two major categories according to their cystic distribution:

• Discrete (focal or multifocal)
• Diffuse (unilobular or panlobular).^2,3

Discrete cystic lung diseases include congenital abnormalities, infectious diseases, and interstitial pneumonias.^2,3

Diffuse, panlobular cystic lung diseases include lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, Birt-Hogg-Dubé syndrome, amyloidosis, light chain deposition disease, and neurofibromatosis type 1.^7,13,36–39

In addition, other associated radiographic findings play a major role in diagnosis.

Cysts in patients presenting with insidious dyspnea or spontaneous pneumothorax

Lymphangioleiomyomatosis. Cysts are seen in nearly all cases of advanced lymphangioleiomyomatosis, typically in a diffuse pattern, varying from 2 mm to 40 mm in diameter, and uniform in shape (Figure  2A).^7,8,40–42

Other radiographic features include vessels located at the periphery of the cysts (in contrast to the centrilobular pattern seen with emphysema), and chylous pleural effusions (in about 22% of patients).⁴⁰ Nodules are typically not seen with lymphangioleiomyomatosis, and if found represent type 2 pneumocyte hyperplasia.

Pulmonary Langerhans cell histiocytosis. Nodules measuring 1 to 10 mm in diameter and favoring a centrilobular location are often seen on computed tomography. Pulmonary cysts occur in about 61% of patients.^13,43 Cysts are variable in size and shape (Figure 2B), in contrast to their uniform appearance in lymphangioleiomyomatosis. Most cysts are less than 10 mm in diameter; however, they can be up to 80 mm.^13,43 Early in its course, nodules may predominate in the upper and middle lobes. Over time, diffuse cysts become more common and can be difficult to differentiate from advanced smoking-induced emphysema.⁴⁴

Birt-Hogg-Dubé syndrome. Approximately 70% to 100% of patients with Birt-Hogg-Dubé syndrome will have multiple pulmonary cysts detected on computed tomography. These cysts are characteristically basal and subpleural in location, with varying sizes and irregular shapes in otherwise normal lung parenchyma (Figure 2C).^36,45,46

Desquamative interstitial pneumonia. Pulmonary cysts are present on computed tomography in about 32% of patients.⁴⁷ They are usually round and less than 20 mm in diameter.⁴⁸ Ground-glass opacity is present in almost all cases of desquamative interstitial pneumonia, with a diffuse pattern in 25% to 44% of patients.^16,17,47

Pulmonary cysts occur in up to two-thirds of those with lymphocytic interstitial pneumonia. Cysts are usually multifocal and perivascular in distribution and have varying sizes and shapes (Figure 2D).²² Ground-glass opacity and poorly defined centrilobular nodules are also frequently seen. Other computed tomographic findings include thickening of the bronchovascular bundles, focal consolidation, interseptal lobular thickening, pleural thickening, and lymph node enlargement.²²

In summary, in this group of patients, diffuse panlobular cysts are due to lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, or Birt-Hogg-Dubé syndrome. Cysts due to lymphangioleiomyomatosis have a diffuse distribution, while those due to pulmonary Langerhans cell histiocytosis tend to be upper-lobe-predominant and in the early stages are associated with stellate centrilobular nodules. Cysts in Birt-Hogg-Dubé syndrome tend to be subpleural and those due to lymphocytic interstitial pneumonia are perivascular in distribution.

Cysts that are incidentally found or occur in patients with recurrent pneumonia

Congenital pulmonary airway malformation types 1, 2, and 4 (Figure 3A, 3B). Cysts are typically discrete and focal or multifocal in distribution, but cases of multilobar and bilateral distribution have also been reported.^27,49 The lower lobes are more often involved.⁴⁹ Cysts vary in size and shape and can contain air, fluid, or both.^27,49 Up to 50% of cases can occur in conjunction with pulmonary sequestration.⁵⁰

Pulmonary sequestration displays an anomalous arterial supply on computed tomography (Figure 3C). Other imaging findings include mass lesions (49%), cystic lesions (29%), cavitary lesions (12%), and bronchiectasis.³⁰ Air trapping can be seen in the adjacent lung. Lower lobe involvement accounts for more than 95% of total cases of sequestration.³⁰ The cysts are usually discrete or focal in distribution. Misdiagnosis of pulmonary sequestration is common, and can include pulmonary abscess, pneumonia, bronchiectasis, and lung cancer.³⁰

Bronchogenic cyst. Cyst contents generally demonstrate water attenuation, or higher attenuation if filled with proteinaceous/mucoid material or calcium deposits; air-fluid levels are seen in infected cysts.³² Intrapulmonary cysts have a predilection for the lower lobes and are usually discrete or focal in distribution.^31,32 Mediastinal cysts are usually homogeneous, solitary, and located in the middle mediastinum.³² Cysts vary in size from 20 to 90 mm, with  a mean diameter of 40 mm.³¹

In summary, in this group of cystic lung diseases, characteristic computed tomographic findings will suggest the diagnosis—air-filled cysts of varying sizes for congenital pulmonary airway malformation and anomalous vascular supply for pulmonary sequestration. Bronchogenic cysts will tend to have water or higher-than-water attenuation due to proteinaceous-mucoid material or calcium deposits.

Cysts in patients with signs and symptoms of primary pulmonary infections

P jirovecii pneumonia. Between 10% and 15% of patients have cysts, and about 18% present with spontaneous pneumothorax.⁵¹ Cysts in P jirovecii pneumonia vary in size from 15 to 85 mm in diameter and tend to occur in the upper lobes (Figure 4A).^51,52

Echinococcal infection. Echinococcal pulmonary cysts typically are single and located more often in the lower lobes (Figure 4B).^53,54 Cysts can be complicated by air-fluid levels, hydropneumothorax, or pneumothorax, or they can turn into cavitary lesions.

The diagnoses of these pulmonary infections are usually made by clinical and computed tomographic findings and depend less on detecting and characterizing lung cysts. Patients with P jirovecii pneumonia tend to have bilateral perihilar ground-glass opacities, while air-fluid levels suggest echinococcal infections. Cysts in this group of patients tend to be discrete or focal or multifocal in distribution, and vary in size.

Cysts in patients with primarily nonpulmonary signs and symptoms

Amyloidosis. Cyst formation is rare in amyloidosis.⁴ When present, cysts can be diffuse and scattered in distribution, in varying sizes (usually < 30 mm in diameter) and irregular shapes (Figure 5).^55,56

Pulmonary light chain deposition disease usually presents as linear opacities and small nodules on chest computed tomography. Numerous cysts that are diffuse in distribution and have no topographic predominance can also be present. They can progress in number and size and coalesce to form irregular shapes.⁵⁷

Neurofibromatosis type 1. In neurofibromatosis type 1, the most common radiographic presentations are bibasilar reticular opacities (50%), bullae (50%), and ground glass opacities (37%).⁵⁸ Well-formed cysts occur in up to 25% of patients and tend to be diffuse and smaller (2 to 18 mm in diameter), with upper lobe predominance.^58,59

In summary, in this group of patients, bibasilar reticular and ground-glass opacities suggest neurofibromatosis type 1, while nodules and linear opacities suggest amyloidosis or light chain deposition disease. Cysts tend to be diffuse with varying sizes.

STEP 4: PUT IT ALL TOGETHER

Diagnosis in insidious dyspnea or spontaneous pneumothorax

For patients who present with insidious dyspnea or spontaneous pneumothorax, the diagnosis of cystic lung disease can be made by characterizing the distribution, size, and shape of the cysts (Table 3).

Diffuse, panlobular distribution. Cystic lung diseases with this pattern include lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, and Birt-Hogg-Dubé syndrome. In this group, cysts that are uniform in size and regular in shape are invariably due to lymphangioleiomyomatosis. Those with variable size and irregular shapes can be due to pulmonary Langerhans cell histiocytosis or Birt-Hogg-Dubé syndrome. Patients with pulmonary Langerhans cell histiocytosis tend to be smokers and their cysts tend to be upper- lobe-predominant. Those with Birt-Hogg-Dubé syndrome will likely have renal cancer or skin lesions; their cysts tend to be basilar and subpleural in distribution.

Cysts that are focal or multifocal and unilobular are due to lymphocytic interstitial pneumonia or desquamative interstitial pneumonia. Patients with lymphocytic interstitial pneumonia tend to have underlying connective tissue disease; those with desquamative interstitial pneumonia are almost always smokers. The definitive diagnosis for lymphocytic interstitial pneumonia or desquamative interstitial pneumonia can require a tissue biopsy.

Diagnosis in patients with incidentally found cysts or recurrent pneumonia

In those who present with incidentally found cysts or recurrent pneumonia, suspicion for a congenital lung malformation should be raised. Patients with a type 1, 2, or 4 congenital pulmonary airway malformation typically have air-filled cysts in varying sizes; those with pulmonary sequestration have an anomalous arterial supply in addition to cysts that are usually located in the lower lobes. Bronchogenic cysts tend to be larger, with attenuation equal to or greater than that of water, and distinguishing them from congenital pulmonary airway malformation will likely require surgical examination.

Diagnosis in patients with signs and symptoms of pulmonary infections

Patients with signs and symptoms of pulmonary infections should be investigated according to clinical risk factors for P jirovecii pneumonia or echinococcal infections.

Diagnosis in patients with primarily nonpulmonary presentations

The distinction between amyloidosis and neurofibromatosis type 1 can be made by the history and the clinical examination. However, a  definitive diagnosis of amyloidosis or light chain deposition disease requires tissue examination for the presence or absence of amyloid fibrils.

Air-filled pulmonary lesions commonly detected on chest computed tomography. Cystic lung lesions should be distinguished from other air-filled lesions to facilitate diagnosis. Primary care physicians play an integral role in the recognition of cystic lung disease.

The differential diagnosis of cystic lung disease is broad and includes isolated pulmonary, systemic, infectious, and congenital etiologies.

Here, we aim to provide a systematic, stepwise approach to help differentiate among the various cystic lung diseases and devise an algorithm for diagnosis. In doing so, we will discuss the clinical and radiographic features of many of these diseases:

• Lymphangioleiomyomatosis
• Birt-Hogg-Dubé syndrome
• Pulmonary Langerhans cell histiocytosis
• Interstitial pneumonia (desquamative interstitial pneumonia, lymphocytic interstitial pneumonia)
• Congenital cystic lung disease (congenital pulmonary airway malformation, pulmonary sequestration, bronchogenic cyst) Pulmonary infection
• Systemic disease (amyloidosis, light chain deposition disease, neurofibromatosis type 1).

STEP 1: RULE OUT CYST-MIMICS

A pulmonary cyst is a round, circumscribed space surrounded by an epithelial or fibrous wall of variable thickness.¹ On chest radiography and computed tomography, a cyst appears as a round parenchymal lucency or low-attenuating area with a well-defined interface with normal lung.¹ Cysts vary in wall thickness but  usually have a thin wall (< 2 mm) and occur without associated pulmonary emphysema.¹ They typically contain air but occasionally contain fluid or solid material.

A pulmonary cyst can be categorized as a bulla, bleb, or pneumatocele.

Pulmonary cysts can be categorized as bullae, blebs, or pneumatoceles

Bullae are larger than 1 cm in diameter, sharply demarcated by a thin wall, and usually accompanied by emphysematous changes in the adjacent lung.¹

Blebs are no larger than 1 cm in diameter, are located within the visceral pleura or the subpleural space, and appear on computed tomography as thin-walled air spaces that are contiguous with the pleura.¹ The distinction between a bleb and a bulla is of little clinical importance, and is often unnecessary.

Pneumatoceles are cysts that are frequently caused by acute pneumonia, trauma, or aspiration of hydrocarbon fluid, and are usually transient.¹

Mimics of pulmonary cysts include pulmonary cavities, emphysema, loculated pneumothoraces, honeycomb lung, and bronchiectasis (Figure 1).²

Pulmonary cavities differ from cysts in that their walls are typically thicker (usually > 4 mm).³

Emphysema differs from cystic lung disease as it typically leads to focal areas or regions of decreased lung attenuation that do not have defined walls.¹

Honeycombing refers to a cluster or row of cysts, 1 to 3 mm in wall thickness and typically 3 to 10 mm in diameter, that are associated with end-stage lung fibrosis.¹ They are typically subpleural in distribution and are accompanied by fibrotic features such as reticulation and traction bronchiectasis.¹

Bronchiectasis is dilation and distortion of bronchi and bronchioles and can be mistaken for cysts when viewed en face.¹

Loculated pneumothoraces can also mimic pulmonary cysts, but they typically fail to adhere to a defined anatomic unit and are subpleural in distribution.

STEP 2: CHARACTERIZE THE CLINICAL PRESENTATION

Clinical signs and symptoms of cystic lung disease play a key role in diagnosis (Table 1). For instance, spontaneous pneumothorax is commonly associated with diffuse cystic lung disease (lymphangioleiomyomatosis and Birt-Hogg-Dubé syndrome), while insidious dyspnea, with or without associated pneumothorax, is usually associated with the interstitial pneumonias (lymphocytic interstitial pneumonia and desquamative interstitial pneumonia).

In addition, congenital abnormalities of the lung can lead to cyst formation. These abnormalities, especially when associated with other congenital abnormalities, are often diagnosed in the prenatal and perinatal periods. However, some remain undetected until incidentally found later in adulthood or if superimposing infection develops.

Primary pulmonary infections can also cause parenchymal necrosis, which in turn cavitates or forms cysts.⁴

Lastly, cystic lung diseases can occur as part of a multiorgan or systemic illness in which the lung is one of the organs involved. Although usually diagnosed before the discovery of cysts or manifestations of pulmonary symptoms, they can present as a diagnostic challenge, especially when lung cysts are the initial presentation.bsence of amyloid fibrils.

In view of the features of the different types of cystic lung disease, adults with cystic lung disease can be grouped according to their typical clinical presentations (Table 2):

• Insidious dyspnea or spontaneous pneumothorax
• Incidentally found cysts or recurrent pneumonia
• Signs and symptoms of primary pulmonary infection
• Signs and symptoms that are primarily nonpulmonary.

Insidious dyspnea or spontaneous pneumothorax

Insidious dyspnea or spontaneous pneumothorax can be manifestations of lymphangioleiomyomatosis, Birt-Hogg-Dubé syndrome, pulmonary Langerhans cell histiocytosis, desquamative interstitial pneumonia, or lymphocytic interstitial pneumonia.

Lymphangioleiomyomatosis is characterized by abnormal cellular proliferation within the lung, kidney, lymphatic system, or any combination.⁵ The peak prevalence is in the third to fourth decades of life, and most patients are women of childbearing age.⁶ In addition to progressive dyspnea on exertion and pneumothorax, other signs and symptoms include hemoptysis, nonproductive cough, chylous pleural effusion, and ascites.^7,8

Birt-Hogg-Dubé syndrome is caused by germline mutations in the folliculin (FLCN) gene.⁹ It is characterized by skin fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax, and renal cancer.¹⁰

Pulmonary Langerhans cell histiocytosis is part of the spectrum of Langerhans cell histiocytosis that, in addition to the lungs, can also involve the bone, pituitary gland, thyroid, skin, lymph nodes, and liver.¹¹ It occurs almost exclusively in smokers, affecting individuals in their 20s and 30s, with no gender predilection.^12,13 In addition to nonproductive cough and dyspnea, patients can also present with fever, anorexia, and weight loss,¹³ but approximately 25% of patients are asymptomatic.¹⁴

Desquamative interstitial pneumonia is an idiopathic interstitial pneumonia that, like pulmonary Langerhans cell histiocytosis, is seen almost exclusively in current or former smokers, who account for about 90% of patients with this disease. It affects almost twice as many men as women.^15,16 The mean age at onset is 42 to 46.^15,16 In addition to insidious cough and dyspnea, digital clubbing develops in 26% to 40% of patients.^16,17

Lymphocytic interstitial pneumonia is another rare idiopathic pneumonia, usually associated with connective tissue disease, Sjögren syndrome, immunodeficiencies, and viral infections.^18­–21 It is more common in women, presenting between the 4th and 7th decades of life, with a mean age at diagnosis of 50 to 56.^18,22 In addition to progressive dyspnea and cough, other symptoms include weight loss, pleuritic pain, arthralgias, fatigue, night sweats, and fever.²³

In summary, in this clinical group, lymphangioleiomyomatosis and Birt-Hogg-Dubé syndrome should be considered when patients present with spontaneous pneumothorax; those with Birt-Hogg-Dubé syndrome also present with skin lesions or renal cancer. In patients with progressive dyspnea and cough, lymphocytic interstitial pneumonia should be considered in those with a known history of connective tissue disease or immunodeficiency. Pulmonary Langerhans cell histiocytosis typically presents at a younger age (20 to 30 years old) than desquamative interstitial pneumonia (smokers in their 40s). Making the distinction, however, will likely require imaging with computed tomography.

Incidentally found cysts or recurrent pneumonia

Incidentally found cysts or recurrent pneumonia can be manifestations of congenital pulmonary airway malformation, pulmonary sequestration, or bronchogenic cyst.

Congenital pulmonary airway malformation, of which there are five types, is the most common pulmonary congenital abnormality. It accounts for up to 95% of cases of congenital cystic lung disease.^24,25 About 85% of cases are detected in the prenatal or perinatal periods.²⁶ Late-onset congenital pulmonary airway malformation (arising in childhood to adulthood) presents with recurrent pneumonia in about 75% of cases and can be misdiagnosed as lung abscess, pulmonary tuberculosis, or bronchiectasis.²⁷

Pulmonary sequestration, the second most common pulmonary congenital abnormality, is characterized by a portion of lung that does not connect to the tracheobronchial tree and has its own systemic arterial supply.²⁴ Intralobar sequestration, which shares the pleural investment with normal lung, accounts for about 80% of cases of pulmonary sequestration.^28–30 In addition to signs or symptoms of pulmonary infection, patients with pulmonary sequestration can remain asymp-
tomatic (about 25% of cases), or can present with hemoptysis or hemothorax.^28–30 In adults, the typical age at presentation is between 20 and 25.^29,30

Bronchogenic cyst is usually life-threatening in children. In adults, it commonly causes cough and chest pain.³¹ Hemoptysis, dysphagia, hoarseness, and diaphragmatic paralysis can also occur.^32,33 The mean age at diagnosis in adults is 35 to 40.^31,32

In summary, most cases of recurrent pneumonia with cysts are due to congenital pulmonary airway malformation. Pulmonary sequestration is the second most common cause of cystic lung disease in this group. Bronchogenic cyst is usually fatal in fetal development; smaller cysts can go unnoticed during the earlier years and are later found incidentally as imaging abnormalities in adults.

Signs and symptoms of primary pulmonary infections

Signs and symptoms of primary pulmonary infections can be due to Pneumocystis jirovecii pneumonia or echinococcal infections.

P jirovecii pneumonia commonly develops in patients with human immunodeficiency virus infection and low CD4 counts, recipients of hematologic or solid-organ transplants, and those receiving immunosuppressive therapy (eg, glucocorticoids or chemotherapy).

Echinococcal infections (with Echinococcus granulosus or multilocularis species) are more common in less-developed countries such as those in South America or the Middle East, in China, or in patients who have traveled to endemic areas.³⁴

In summary, cystic lung disease in patients with primary pulmonary infections can be diagnosed by the patient’s clinical history and risk factors for infections. Those with human immunodeficiency virus infection and other causes of immunodeficiency are predisposed to P jirovecii pneumonia. Echinococcal infections occur in those with a history of travel to an endemic area.

Primarily nonpulmonary signs and symptoms

If the patient has primarily nonpulmonary signs and symptoms, think about pulmonary amyloidosis, light chain deposition disease, and neurofibromatosis type 1.

Pulmonary amyloidosis has a variety of manifestations, including tracheobronchial disease, nodular parenchymal disease, diffuse or alveolar septal pattern, pleural disease, lymphadenopathy, and pulmonary cysts.⁴

Light chain deposition disease shares some clinical features with amyloidosis. However, the light chain fragments in this disease do not form amyloid fibrils and therefore do not stain positively with Congo red. The kidney is the most commonly involved organ.⁴

Neurofibromatosis type 1 is characterized by collections of neurofibromas, café-au-lait spots, and pigmented hamartomas in the iris (Lisch nodules).³⁵

In summary, patients in this group typically present with complications related to systemic involvement. Those with neurofibromatosis type 1 present with ophthalmologic, dermatologic, and neurologic manifestations. Amyloidosis and light chain deposition disease most commonly involve the renal system; their distinction will likely require tissue biopsy and Congo-red staining.

STEP 3: CHARACTERIZE THE RADIOGRAPHIC FEATURES

Characterization of pulmonary cysts and their distribution plays a key role in the diagnosis. Radiographically, cystic lung diseases can be subclassified into two major categories according to their cystic distribution:

• Discrete (focal or multifocal)
• Diffuse (unilobular or panlobular).^2,3

Discrete cystic lung diseases include congenital abnormalities, infectious diseases, and interstitial pneumonias.^2,3

Diffuse, panlobular cystic lung diseases include lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, Birt-Hogg-Dubé syndrome, amyloidosis, light chain deposition disease, and neurofibromatosis type 1.^7,13,36–39

In addition, other associated radiographic findings play a major role in diagnosis.

Cysts in patients presenting with insidious dyspnea or spontaneous pneumothorax

Lymphangioleiomyomatosis. Cysts are seen in nearly all cases of advanced lymphangioleiomyomatosis, typically in a diffuse pattern, varying from 2 mm to 40 mm in diameter, and uniform in shape (Figure  2A).^7,8,40–42

Other radiographic features include vessels located at the periphery of the cysts (in contrast to the centrilobular pattern seen with emphysema), and chylous pleural effusions (in about 22% of patients).⁴⁰ Nodules are typically not seen with lymphangioleiomyomatosis, and if found represent type 2 pneumocyte hyperplasia.

Pulmonary Langerhans cell histiocytosis. Nodules measuring 1 to 10 mm in diameter and favoring a centrilobular location are often seen on computed tomography. Pulmonary cysts occur in about 61% of patients.^13,43 Cysts are variable in size and shape (Figure 2B), in contrast to their uniform appearance in lymphangioleiomyomatosis. Most cysts are less than 10 mm in diameter; however, they can be up to 80 mm.^13,43 Early in its course, nodules may predominate in the upper and middle lobes. Over time, diffuse cysts become more common and can be difficult to differentiate from advanced smoking-induced emphysema.⁴⁴

Birt-Hogg-Dubé syndrome. Approximately 70% to 100% of patients with Birt-Hogg-Dubé syndrome will have multiple pulmonary cysts detected on computed tomography. These cysts are characteristically basal and subpleural in location, with varying sizes and irregular shapes in otherwise normal lung parenchyma (Figure 2C).^36,45,46

Desquamative interstitial pneumonia. Pulmonary cysts are present on computed tomography in about 32% of patients.⁴⁷ They are usually round and less than 20 mm in diameter.⁴⁸ Ground-glass opacity is present in almost all cases of desquamative interstitial pneumonia, with a diffuse pattern in 25% to 44% of patients.^16,17,47

Pulmonary cysts occur in up to two-thirds of those with lymphocytic interstitial pneumonia. Cysts are usually multifocal and perivascular in distribution and have varying sizes and shapes (Figure 2D).²² Ground-glass opacity and poorly defined centrilobular nodules are also frequently seen. Other computed tomographic findings include thickening of the bronchovascular bundles, focal consolidation, interseptal lobular thickening, pleural thickening, and lymph node enlargement.²²

In summary, in this group of patients, diffuse panlobular cysts are due to lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, or Birt-Hogg-Dubé syndrome. Cysts due to lymphangioleiomyomatosis have a diffuse distribution, while those due to pulmonary Langerhans cell histiocytosis tend to be upper-lobe-predominant and in the early stages are associated with stellate centrilobular nodules. Cysts in Birt-Hogg-Dubé syndrome tend to be subpleural and those due to lymphocytic interstitial pneumonia are perivascular in distribution.

Cysts that are incidentally found or occur in patients with recurrent pneumonia

Congenital pulmonary airway malformation types 1, 2, and 4 (Figure 3A, 3B). Cysts are typically discrete and focal or multifocal in distribution, but cases of multilobar and bilateral distribution have also been reported.^27,49 The lower lobes are more often involved.⁴⁹ Cysts vary in size and shape and can contain air, fluid, or both.^27,49 Up to 50% of cases can occur in conjunction with pulmonary sequestration.⁵⁰

Pulmonary sequestration displays an anomalous arterial supply on computed tomography (Figure 3C). Other imaging findings include mass lesions (49%), cystic lesions (29%), cavitary lesions (12%), and bronchiectasis.³⁰ Air trapping can be seen in the adjacent lung. Lower lobe involvement accounts for more than 95% of total cases of sequestration.³⁰ The cysts are usually discrete or focal in distribution. Misdiagnosis of pulmonary sequestration is common, and can include pulmonary abscess, pneumonia, bronchiectasis, and lung cancer.³⁰

Bronchogenic cyst. Cyst contents generally demonstrate water attenuation, or higher attenuation if filled with proteinaceous/mucoid material or calcium deposits; air-fluid levels are seen in infected cysts.³² Intrapulmonary cysts have a predilection for the lower lobes and are usually discrete or focal in distribution.^31,32 Mediastinal cysts are usually homogeneous, solitary, and located in the middle mediastinum.³² Cysts vary in size from 20 to 90 mm, with  a mean diameter of 40 mm.³¹

In summary, in this group of cystic lung diseases, characteristic computed tomographic findings will suggest the diagnosis—air-filled cysts of varying sizes for congenital pulmonary airway malformation and anomalous vascular supply for pulmonary sequestration. Bronchogenic cysts will tend to have water or higher-than-water attenuation due to proteinaceous-mucoid material or calcium deposits.

Cysts in patients with signs and symptoms of primary pulmonary infections

P jirovecii pneumonia. Between 10% and 15% of patients have cysts, and about 18% present with spontaneous pneumothorax.⁵¹ Cysts in P jirovecii pneumonia vary in size from 15 to 85 mm in diameter and tend to occur in the upper lobes (Figure 4A).^51,52

Echinococcal infection. Echinococcal pulmonary cysts typically are single and located more often in the lower lobes (Figure 4B).^53,54 Cysts can be complicated by air-fluid levels, hydropneumothorax, or pneumothorax, or they can turn into cavitary lesions.

The diagnoses of these pulmonary infections are usually made by clinical and computed tomographic findings and depend less on detecting and characterizing lung cysts. Patients with P jirovecii pneumonia tend to have bilateral perihilar ground-glass opacities, while air-fluid levels suggest echinococcal infections. Cysts in this group of patients tend to be discrete or focal or multifocal in distribution, and vary in size.

Cysts in patients with primarily nonpulmonary signs and symptoms

Amyloidosis. Cyst formation is rare in amyloidosis.⁴ When present, cysts can be diffuse and scattered in distribution, in varying sizes (usually < 30 mm in diameter) and irregular shapes (Figure 5).^55,56

Pulmonary light chain deposition disease usually presents as linear opacities and small nodules on chest computed tomography. Numerous cysts that are diffuse in distribution and have no topographic predominance can also be present. They can progress in number and size and coalesce to form irregular shapes.⁵⁷

Neurofibromatosis type 1. In neurofibromatosis type 1, the most common radiographic presentations are bibasilar reticular opacities (50%), bullae (50%), and ground glass opacities (37%).⁵⁸ Well-formed cysts occur in up to 25% of patients and tend to be diffuse and smaller (2 to 18 mm in diameter), with upper lobe predominance.^58,59

In summary, in this group of patients, bibasilar reticular and ground-glass opacities suggest neurofibromatosis type 1, while nodules and linear opacities suggest amyloidosis or light chain deposition disease. Cysts tend to be diffuse with varying sizes.

STEP 4: PUT IT ALL TOGETHER

Diagnosis in insidious dyspnea or spontaneous pneumothorax

For patients who present with insidious dyspnea or spontaneous pneumothorax, the diagnosis of cystic lung disease can be made by characterizing the distribution, size, and shape of the cysts (Table 3).

Diffuse, panlobular distribution. Cystic lung diseases with this pattern include lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, and Birt-Hogg-Dubé syndrome. In this group, cysts that are uniform in size and regular in shape are invariably due to lymphangioleiomyomatosis. Those with variable size and irregular shapes can be due to pulmonary Langerhans cell histiocytosis or Birt-Hogg-Dubé syndrome. Patients with pulmonary Langerhans cell histiocytosis tend to be smokers and their cysts tend to be upper- lobe-predominant. Those with Birt-Hogg-Dubé syndrome will likely have renal cancer or skin lesions; their cysts tend to be basilar and subpleural in distribution.

Cysts that are focal or multifocal and unilobular are due to lymphocytic interstitial pneumonia or desquamative interstitial pneumonia. Patients with lymphocytic interstitial pneumonia tend to have underlying connective tissue disease; those with desquamative interstitial pneumonia are almost always smokers. The definitive diagnosis for lymphocytic interstitial pneumonia or desquamative interstitial pneumonia can require a tissue biopsy.

Diagnosis in patients with incidentally found cysts or recurrent pneumonia

In those who present with incidentally found cysts or recurrent pneumonia, suspicion for a congenital lung malformation should be raised. Patients with a type 1, 2, or 4 congenital pulmonary airway malformation typically have air-filled cysts in varying sizes; those with pulmonary sequestration have an anomalous arterial supply in addition to cysts that are usually located in the lower lobes. Bronchogenic cysts tend to be larger, with attenuation equal to or greater than that of water, and distinguishing them from congenital pulmonary airway malformation will likely require surgical examination.

Diagnosis in patients with signs and symptoms of pulmonary infections

Patients with signs and symptoms of pulmonary infections should be investigated according to clinical risk factors for P jirovecii pneumonia or echinococcal infections.

Diagnosis in patients with primarily nonpulmonary presentations

The distinction between amyloidosis and neurofibromatosis type 1 can be made by the history and the clinical examination. However, a  definitive diagnosis of amyloidosis or light chain deposition disease requires tissue examination for the presence or absence of amyloid fibrils.

Air-filled pulmonary lesions commonly detected on chest computed tomography. Cystic lung lesions should be distinguished from other air-filled lesions to facilitate diagnosis. Primary care physicians play an integral role in the recognition of cystic lung disease.

The differential diagnosis of cystic lung disease is broad and includes isolated pulmonary, systemic, infectious, and congenital etiologies.

Here, we aim to provide a systematic, stepwise approach to help differentiate among the various cystic lung diseases and devise an algorithm for diagnosis. In doing so, we will discuss the clinical and radiographic features of many of these diseases:

• Lymphangioleiomyomatosis
• Birt-Hogg-Dubé syndrome
• Pulmonary Langerhans cell histiocytosis
• Interstitial pneumonia (desquamative interstitial pneumonia, lymphocytic interstitial pneumonia)
• Congenital cystic lung disease (congenital pulmonary airway malformation, pulmonary sequestration, bronchogenic cyst) Pulmonary infection
• Systemic disease (amyloidosis, light chain deposition disease, neurofibromatosis type 1).

STEP 1: RULE OUT CYST-MIMICS

A pulmonary cyst is a round, circumscribed space surrounded by an epithelial or fibrous wall of variable thickness.¹ On chest radiography and computed tomography, a cyst appears as a round parenchymal lucency or low-attenuating area with a well-defined interface with normal lung.¹ Cysts vary in wall thickness but  usually have a thin wall (< 2 mm) and occur without associated pulmonary emphysema.¹ They typically contain air but occasionally contain fluid or solid material.

A pulmonary cyst can be categorized as a bulla, bleb, or pneumatocele.

Pulmonary cysts can be categorized as bullae, blebs, or pneumatoceles

Bullae are larger than 1 cm in diameter, sharply demarcated by a thin wall, and usually accompanied by emphysematous changes in the adjacent lung.¹

Blebs are no larger than 1 cm in diameter, are located within the visceral pleura or the subpleural space, and appear on computed tomography as thin-walled air spaces that are contiguous with the pleura.¹ The distinction between a bleb and a bulla is of little clinical importance, and is often unnecessary.

Pneumatoceles are cysts that are frequently caused by acute pneumonia, trauma, or aspiration of hydrocarbon fluid, and are usually transient.¹

Mimics of pulmonary cysts include pulmonary cavities, emphysema, loculated pneumothoraces, honeycomb lung, and bronchiectasis (Figure 1).²

Pulmonary cavities differ from cysts in that their walls are typically thicker (usually > 4 mm).³

Emphysema differs from cystic lung disease as it typically leads to focal areas or regions of decreased lung attenuation that do not have defined walls.¹

Honeycombing refers to a cluster or row of cysts, 1 to 3 mm in wall thickness and typically 3 to 10 mm in diameter, that are associated with end-stage lung fibrosis.¹ They are typically subpleural in distribution and are accompanied by fibrotic features such as reticulation and traction bronchiectasis.¹

Bronchiectasis is dilation and distortion of bronchi and bronchioles and can be mistaken for cysts when viewed en face.¹

Loculated pneumothoraces can also mimic pulmonary cysts, but they typically fail to adhere to a defined anatomic unit and are subpleural in distribution.

STEP 2: CHARACTERIZE THE CLINICAL PRESENTATION

Clinical signs and symptoms of cystic lung disease play a key role in diagnosis (Table 1). For instance, spontaneous pneumothorax is commonly associated with diffuse cystic lung disease (lymphangioleiomyomatosis and Birt-Hogg-Dubé syndrome), while insidious dyspnea, with or without associated pneumothorax, is usually associated with the interstitial pneumonias (lymphocytic interstitial pneumonia and desquamative interstitial pneumonia).

In addition, congenital abnormalities of the lung can lead to cyst formation. These abnormalities, especially when associated with other congenital abnormalities, are often diagnosed in the prenatal and perinatal periods. However, some remain undetected until incidentally found later in adulthood or if superimposing infection develops.

Primary pulmonary infections can also cause parenchymal necrosis, which in turn cavitates or forms cysts.⁴

Lastly, cystic lung diseases can occur as part of a multiorgan or systemic illness in which the lung is one of the organs involved. Although usually diagnosed before the discovery of cysts or manifestations of pulmonary symptoms, they can present as a diagnostic challenge, especially when lung cysts are the initial presentation.bsence of amyloid fibrils.

In view of the features of the different types of cystic lung disease, adults with cystic lung disease can be grouped according to their typical clinical presentations (Table 2):

• Insidious dyspnea or spontaneous pneumothorax
• Incidentally found cysts or recurrent pneumonia
• Signs and symptoms of primary pulmonary infection
• Signs and symptoms that are primarily nonpulmonary.

Insidious dyspnea or spontaneous pneumothorax

Insidious dyspnea or spontaneous pneumothorax can be manifestations of lymphangioleiomyomatosis, Birt-Hogg-Dubé syndrome, pulmonary Langerhans cell histiocytosis, desquamative interstitial pneumonia, or lymphocytic interstitial pneumonia.

Lymphangioleiomyomatosis is characterized by abnormal cellular proliferation within the lung, kidney, lymphatic system, or any combination.⁵ The peak prevalence is in the third to fourth decades of life, and most patients are women of childbearing age.⁶ In addition to progressive dyspnea on exertion and pneumothorax, other signs and symptoms include hemoptysis, nonproductive cough, chylous pleural effusion, and ascites.^7,8

Birt-Hogg-Dubé syndrome is caused by germline mutations in the folliculin (FLCN) gene.⁹ It is characterized by skin fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax, and renal cancer.¹⁰

Pulmonary Langerhans cell histiocytosis is part of the spectrum of Langerhans cell histiocytosis that, in addition to the lungs, can also involve the bone, pituitary gland, thyroid, skin, lymph nodes, and liver.¹¹ It occurs almost exclusively in smokers, affecting individuals in their 20s and 30s, with no gender predilection.^12,13 In addition to nonproductive cough and dyspnea, patients can also present with fever, anorexia, and weight loss,¹³ but approximately 25% of patients are asymptomatic.¹⁴

Desquamative interstitial pneumonia is an idiopathic interstitial pneumonia that, like pulmonary Langerhans cell histiocytosis, is seen almost exclusively in current or former smokers, who account for about 90% of patients with this disease. It affects almost twice as many men as women.^15,16 The mean age at onset is 42 to 46.^15,16 In addition to insidious cough and dyspnea, digital clubbing develops in 26% to 40% of patients.^16,17

Lymphocytic interstitial pneumonia is another rare idiopathic pneumonia, usually associated with connective tissue disease, Sjögren syndrome, immunodeficiencies, and viral infections.^18­–21 It is more common in women, presenting between the 4th and 7th decades of life, with a mean age at diagnosis of 50 to 56.^18,22 In addition to progressive dyspnea and cough, other symptoms include weight loss, pleuritic pain, arthralgias, fatigue, night sweats, and fever.²³

In summary, in this clinical group, lymphangioleiomyomatosis and Birt-Hogg-Dubé syndrome should be considered when patients present with spontaneous pneumothorax; those with Birt-Hogg-Dubé syndrome also present with skin lesions or renal cancer. In patients with progressive dyspnea and cough, lymphocytic interstitial pneumonia should be considered in those with a known history of connective tissue disease or immunodeficiency. Pulmonary Langerhans cell histiocytosis typically presents at a younger age (20 to 30 years old) than desquamative interstitial pneumonia (smokers in their 40s). Making the distinction, however, will likely require imaging with computed tomography.

Incidentally found cysts or recurrent pneumonia

Incidentally found cysts or recurrent pneumonia can be manifestations of congenital pulmonary airway malformation, pulmonary sequestration, or bronchogenic cyst.

Congenital pulmonary airway malformation, of which there are five types, is the most common pulmonary congenital abnormality. It accounts for up to 95% of cases of congenital cystic lung disease.^24,25 About 85% of cases are detected in the prenatal or perinatal periods.²⁶ Late-onset congenital pulmonary airway malformation (arising in childhood to adulthood) presents with recurrent pneumonia in about 75% of cases and can be misdiagnosed as lung abscess, pulmonary tuberculosis, or bronchiectasis.²⁷

Pulmonary sequestration, the second most common pulmonary congenital abnormality, is characterized by a portion of lung that does not connect to the tracheobronchial tree and has its own systemic arterial supply.²⁴ Intralobar sequestration, which shares the pleural investment with normal lung, accounts for about 80% of cases of pulmonary sequestration.^28–30 In addition to signs or symptoms of pulmonary infection, patients with pulmonary sequestration can remain asymp-
tomatic (about 25% of cases), or can present with hemoptysis or hemothorax.^28–30 In adults, the typical age at presentation is between 20 and 25.^29,30

Bronchogenic cyst is usually life-threatening in children. In adults, it commonly causes cough and chest pain.³¹ Hemoptysis, dysphagia, hoarseness, and diaphragmatic paralysis can also occur.^32,33 The mean age at diagnosis in adults is 35 to 40.^31,32

In summary, most cases of recurrent pneumonia with cysts are due to congenital pulmonary airway malformation. Pulmonary sequestration is the second most common cause of cystic lung disease in this group. Bronchogenic cyst is usually fatal in fetal development; smaller cysts can go unnoticed during the earlier years and are later found incidentally as imaging abnormalities in adults.

Signs and symptoms of primary pulmonary infections

Signs and symptoms of primary pulmonary infections can be due to Pneumocystis jirovecii pneumonia or echinococcal infections.

P jirovecii pneumonia commonly develops in patients with human immunodeficiency virus infection and low CD4 counts, recipients of hematologic or solid-organ transplants, and those receiving immunosuppressive therapy (eg, glucocorticoids or chemotherapy).

Echinococcal infections (with Echinococcus granulosus or multilocularis species) are more common in less-developed countries such as those in South America or the Middle East, in China, or in patients who have traveled to endemic areas.³⁴

In summary, cystic lung disease in patients with primary pulmonary infections can be diagnosed by the patient’s clinical history and risk factors for infections. Those with human immunodeficiency virus infection and other causes of immunodeficiency are predisposed to P jirovecii pneumonia. Echinococcal infections occur in those with a history of travel to an endemic area.

Primarily nonpulmonary signs and symptoms

If the patient has primarily nonpulmonary signs and symptoms, think about pulmonary amyloidosis, light chain deposition disease, and neurofibromatosis type 1.

Pulmonary amyloidosis has a variety of manifestations, including tracheobronchial disease, nodular parenchymal disease, diffuse or alveolar septal pattern, pleural disease, lymphadenopathy, and pulmonary cysts.⁴

Light chain deposition disease shares some clinical features with amyloidosis. However, the light chain fragments in this disease do not form amyloid fibrils and therefore do not stain positively with Congo red. The kidney is the most commonly involved organ.⁴

Neurofibromatosis type 1 is characterized by collections of neurofibromas, café-au-lait spots, and pigmented hamartomas in the iris (Lisch nodules).³⁵

In summary, patients in this group typically present with complications related to systemic involvement. Those with neurofibromatosis type 1 present with ophthalmologic, dermatologic, and neurologic manifestations. Amyloidosis and light chain deposition disease most commonly involve the renal system; their distinction will likely require tissue biopsy and Congo-red staining.

STEP 3: CHARACTERIZE THE RADIOGRAPHIC FEATURES

Characterization of pulmonary cysts and their distribution plays a key role in the diagnosis. Radiographically, cystic lung diseases can be subclassified into two major categories according to their cystic distribution:

• Discrete (focal or multifocal)
• Diffuse (unilobular or panlobular).^2,3

Discrete cystic lung diseases include congenital abnormalities, infectious diseases, and interstitial pneumonias.^2,3

Diffuse, panlobular cystic lung diseases include lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, Birt-Hogg-Dubé syndrome, amyloidosis, light chain deposition disease, and neurofibromatosis type 1.^7,13,36–39

In addition, other associated radiographic findings play a major role in diagnosis.

Cysts in patients presenting with insidious dyspnea or spontaneous pneumothorax

Lymphangioleiomyomatosis. Cysts are seen in nearly all cases of advanced lymphangioleiomyomatosis, typically in a diffuse pattern, varying from 2 mm to 40 mm in diameter, and uniform in shape (Figure  2A).^7,8,40–42

Other radiographic features include vessels located at the periphery of the cysts (in contrast to the centrilobular pattern seen with emphysema), and chylous pleural effusions (in about 22% of patients).⁴⁰ Nodules are typically not seen with lymphangioleiomyomatosis, and if found represent type 2 pneumocyte hyperplasia.

Pulmonary Langerhans cell histiocytosis. Nodules measuring 1 to 10 mm in diameter and favoring a centrilobular location are often seen on computed tomography. Pulmonary cysts occur in about 61% of patients.^13,43 Cysts are variable in size and shape (Figure 2B), in contrast to their uniform appearance in lymphangioleiomyomatosis. Most cysts are less than 10 mm in diameter; however, they can be up to 80 mm.^13,43 Early in its course, nodules may predominate in the upper and middle lobes. Over time, diffuse cysts become more common and can be difficult to differentiate from advanced smoking-induced emphysema.⁴⁴

Birt-Hogg-Dubé syndrome. Approximately 70% to 100% of patients with Birt-Hogg-Dubé syndrome will have multiple pulmonary cysts detected on computed tomography. These cysts are characteristically basal and subpleural in location, with varying sizes and irregular shapes in otherwise normal lung parenchyma (Figure 2C).^36,45,46

Desquamative interstitial pneumonia. Pulmonary cysts are present on computed tomography in about 32% of patients.⁴⁷ They are usually round and less than 20 mm in diameter.⁴⁸ Ground-glass opacity is present in almost all cases of desquamative interstitial pneumonia, with a diffuse pattern in 25% to 44% of patients.^16,17,47

Pulmonary cysts occur in up to two-thirds of those with lymphocytic interstitial pneumonia. Cysts are usually multifocal and perivascular in distribution and have varying sizes and shapes (Figure 2D).²² Ground-glass opacity and poorly defined centrilobular nodules are also frequently seen. Other computed tomographic findings include thickening of the bronchovascular bundles, focal consolidation, interseptal lobular thickening, pleural thickening, and lymph node enlargement.²²

In summary, in this group of patients, diffuse panlobular cysts are due to lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, or Birt-Hogg-Dubé syndrome. Cysts due to lymphangioleiomyomatosis have a diffuse distribution, while those due to pulmonary Langerhans cell histiocytosis tend to be upper-lobe-predominant and in the early stages are associated with stellate centrilobular nodules. Cysts in Birt-Hogg-Dubé syndrome tend to be subpleural and those due to lymphocytic interstitial pneumonia are perivascular in distribution.

Cysts that are incidentally found or occur in patients with recurrent pneumonia

Congenital pulmonary airway malformation types 1, 2, and 4 (Figure 3A, 3B). Cysts are typically discrete and focal or multifocal in distribution, but cases of multilobar and bilateral distribution have also been reported.^27,49 The lower lobes are more often involved.⁴⁹ Cysts vary in size and shape and can contain air, fluid, or both.^27,49 Up to 50% of cases can occur in conjunction with pulmonary sequestration.⁵⁰

Pulmonary sequestration displays an anomalous arterial supply on computed tomography (Figure 3C). Other imaging findings include mass lesions (49%), cystic lesions (29%), cavitary lesions (12%), and bronchiectasis.³⁰ Air trapping can be seen in the adjacent lung. Lower lobe involvement accounts for more than 95% of total cases of sequestration.³⁰ The cysts are usually discrete or focal in distribution. Misdiagnosis of pulmonary sequestration is common, and can include pulmonary abscess, pneumonia, bronchiectasis, and lung cancer.³⁰

Bronchogenic cyst. Cyst contents generally demonstrate water attenuation, or higher attenuation if filled with proteinaceous/mucoid material or calcium deposits; air-fluid levels are seen in infected cysts.³² Intrapulmonary cysts have a predilection for the lower lobes and are usually discrete or focal in distribution.^31,32 Mediastinal cysts are usually homogeneous, solitary, and located in the middle mediastinum.³² Cysts vary in size from 20 to 90 mm, with  a mean diameter of 40 mm.³¹

In summary, in this group of cystic lung diseases, characteristic computed tomographic findings will suggest the diagnosis—air-filled cysts of varying sizes for congenital pulmonary airway malformation and anomalous vascular supply for pulmonary sequestration. Bronchogenic cysts will tend to have water or higher-than-water attenuation due to proteinaceous-mucoid material or calcium deposits.

Cysts in patients with signs and symptoms of primary pulmonary infections

P jirovecii pneumonia. Between 10% and 15% of patients have cysts, and about 18% present with spontaneous pneumothorax.⁵¹ Cysts in P jirovecii pneumonia vary in size from 15 to 85 mm in diameter and tend to occur in the upper lobes (Figure 4A).^51,52

Echinococcal infection. Echinococcal pulmonary cysts typically are single and located more often in the lower lobes (Figure 4B).^53,54 Cysts can be complicated by air-fluid levels, hydropneumothorax, or pneumothorax, or they can turn into cavitary lesions.

The diagnoses of these pulmonary infections are usually made by clinical and computed tomographic findings and depend less on detecting and characterizing lung cysts. Patients with P jirovecii pneumonia tend to have bilateral perihilar ground-glass opacities, while air-fluid levels suggest echinococcal infections. Cysts in this group of patients tend to be discrete or focal or multifocal in distribution, and vary in size.

Cysts in patients with primarily nonpulmonary signs and symptoms

Amyloidosis. Cyst formation is rare in amyloidosis.⁴ When present, cysts can be diffuse and scattered in distribution, in varying sizes (usually < 30 mm in diameter) and irregular shapes (Figure 5).^55,56

Pulmonary light chain deposition disease usually presents as linear opacities and small nodules on chest computed tomography. Numerous cysts that are diffuse in distribution and have no topographic predominance can also be present. They can progress in number and size and coalesce to form irregular shapes.⁵⁷

Neurofibromatosis type 1. In neurofibromatosis type 1, the most common radiographic presentations are bibasilar reticular opacities (50%), bullae (50%), and ground glass opacities (37%).⁵⁸ Well-formed cysts occur in up to 25% of patients and tend to be diffuse and smaller (2 to 18 mm in diameter), with upper lobe predominance.^58,59

In summary, in this group of patients, bibasilar reticular and ground-glass opacities suggest neurofibromatosis type 1, while nodules and linear opacities suggest amyloidosis or light chain deposition disease. Cysts tend to be diffuse with varying sizes.

STEP 4: PUT IT ALL TOGETHER

Diagnosis in insidious dyspnea or spontaneous pneumothorax

For patients who present with insidious dyspnea or spontaneous pneumothorax, the diagnosis of cystic lung disease can be made by characterizing the distribution, size, and shape of the cysts (Table 3).

Diffuse, panlobular distribution. Cystic lung diseases with this pattern include lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, and Birt-Hogg-Dubé syndrome. In this group, cysts that are uniform in size and regular in shape are invariably due to lymphangioleiomyomatosis. Those with variable size and irregular shapes can be due to pulmonary Langerhans cell histiocytosis or Birt-Hogg-Dubé syndrome. Patients with pulmonary Langerhans cell histiocytosis tend to be smokers and their cysts tend to be upper- lobe-predominant. Those with Birt-Hogg-Dubé syndrome will likely have renal cancer or skin lesions; their cysts tend to be basilar and subpleural in distribution.

Cysts that are focal or multifocal and unilobular are due to lymphocytic interstitial pneumonia or desquamative interstitial pneumonia. Patients with lymphocytic interstitial pneumonia tend to have underlying connective tissue disease; those with desquamative interstitial pneumonia are almost always smokers. The definitive diagnosis for lymphocytic interstitial pneumonia or desquamative interstitial pneumonia can require a tissue biopsy.

Diagnosis in patients with incidentally found cysts or recurrent pneumonia

In those who present with incidentally found cysts or recurrent pneumonia, suspicion for a congenital lung malformation should be raised. Patients with a type 1, 2, or 4 congenital pulmonary airway malformation typically have air-filled cysts in varying sizes; those with pulmonary sequestration have an anomalous arterial supply in addition to cysts that are usually located in the lower lobes. Bronchogenic cysts tend to be larger, with attenuation equal to or greater than that of water, and distinguishing them from congenital pulmonary airway malformation will likely require surgical examination.

Diagnosis in patients with signs and symptoms of pulmonary infections

Patients with signs and symptoms of pulmonary infections should be investigated according to clinical risk factors for P jirovecii pneumonia or echinococcal infections.

Diagnosis in patients with primarily nonpulmonary presentations

The distinction between amyloidosis and neurofibromatosis type 1 can be made by the history and the clinical examination. However, a  definitive diagnosis of amyloidosis or light chain deposition disease requires tissue examination for the presence or absence of amyloid fibrils.