Diffuse cystic lung diseases

Abstract

Diffuse cystic lung diseases are uncommon but can present a diagnostic challenge because increasing number of diseases have been associated with this presentation. Cyst in the lung is defined as a round parenchymal lucency with a well-defined thin wall (<2 mm thickness). Focal or multifocal cystic lesions include blebs, bullae, pneumatoceles, congenital cystic lesions, traumatic lesions, and several infectious processes such as coccidioidomycosis, Pneumocystis jiroveci pneumonia, and hydatid disease. “Diffuse” distribution in the lung implies involvement of all lobes. Diffuse lung involvement with cystic lesions can be seen in pulmonary lymphangioleiomyomatosis, pulmonary Langerhans’ cell histiocytosis, lymphoid interstitial pneumonia, Birt-Hogg-Dubé syndrome, amyloidosis, light chain deposition disease, honeycomb lung associated with advanced fibrosis, and several other rare causes including metastatic disease. High-resolution computed tomography of the chest helps define morphologic features of the lung lesions as well as their distribution and associated features such as intrathoracic lymphadenopathy. Correlating the tempo of the disease process and clinical context with chest imaging findings serve as important clues to defining the underlying nature of the cystic lung disease and guide diagnostic evaluation as well as management.

Keywords

cyst / lung disease / interstitial lung disease / lymphangioleiomyomatosis / Langerhans’ cell histiocytosis / Birt-Hogg-Dubé syndrome

Introduction

Cysts and cavities are commonly encountered lesions on chest imaging. Both types of lesions are seen as foci of lucency surrounded by wall of tissue. Cysts are characterized by the presence of a thin wall, usually<2 mm thick [1–3]. Cavities have thicker walls and usually represent necrosis within a mass or a consolidative process [1,2]. Emphysematous airspaces usually lack such perceptible walls [1,2]. Distinguishing cysts from cavities and assessing the distribution of these lung lesions, i.e., focal or multifocal versus diffuse, are helpful in the differential diagnosis [2,4,5]. “Diffuse” distribution implies involvement of all lobes of both lungs. These parameters are efficiently depicted by high-resolution computed tomography (HRCT) which produces thin collimation (typically 1 mm) slices of images with high-spatial frequency algorithm, particularly since cystic lesions can sometimes be difficult to appreciate by chest radiography.

Although focal cystic lesions, e.g., bullae associated with emphysema, are frequently seen on chest imaging, diffuse cystic lung diseases are uncommon and usually offer a limited number of diagnostic possibilities that include pulmonary lymphangioleiomyomatosis (LAM), pulmonary Langerhans’ cell histiocytosis (PLCH), lymphoid interstitial pneumonia (LIP), and Birt-Hogg-Dubé syndrome (BHD). However, in recent years increasing number of other disorders has been associated with diffuse cystic lung disease (Table 1). Thus the differential diagnosis of diffuse cystic lung disease has become more complex.

Diagnostic approach

Understanding the clinical significance of diffuse cystic lung disease requires that its underlying nature be identified, i.e., correct diagnosis. Active infectious or inflammatory processes and malignancies obviously need to be diagnosed promptly to treat effectively and optimize clinical outcomes. In addition, the presence of cysts in the lung predisposes to the occurrence of pneumothorax. Most of the diffuse cystic lung diseases are chronic and present with slowly progressive respiratory symptoms.

Two clinical parameters are of importance in evaluating patients with diffuse cystic lung diseases. These are tempo of the disease process and the clinical context. First, the differential diagnosis is influenced by knowing whether a disease process is acute or subacute (days to weeks) versus chronic (more than one month in duration). The tempo of the disease process can be assessed based on the duration and symptoms as well as comparison to previous imaging studies, when available. Acute and subacute courses generally suggest infectious or inflammatory disorders while a chronic course is more likely to be due to noninfectious infiltrative processes. Secondly, the clinical context needs to be correlated with the radiologic findings. Relevant components of the clinical context include age, sex, smoking history, immunocompetency, underlying diseases, drug or other treatments, associated extrapulmonary symptoms and signs, environmental and occupational exposure, recent illnesses, travel history, and relevant laboratory results.

With these general concepts in mind we will discuss several disease entities that can manifest diffuse cystic lung disease (Table 2) and update the reader regarding recent progress in our understanding of these disorders.

Pulmonary lymphangioleiomyomatosis (LAM)

LAM is a slowly progressive lung disease that mostly affects women [6–9]. It can be encountered in patients with tuberous sclerosis complex (TSC) or occur in a sporadic form (without underlying TSC) [6,9]. Histologically, LAM is characterized by proliferation of neoplastic smooth muscle cells (LAM cells) in the lung parenchyma that is intimately associated with diffuse cystic lesions [7]. LAM cells found in the lung are thought to represent a metastatic process with an origin outside the lung [10]. Lymphangiogenesis has been shown to play a central pathogenetic role whereby LAM cells invade and spread through the lymphatics, a process that is associated with an elevated vascular endothelial growth factor-D (VEGF-D) level [11–15]. Clinical manifestations of LAM include slowly progressive dyspnea, chest pain, cough, recurrent pneumothoraces, and chylous complications including chylothorax, chyloptysis, and chylous ascites [6,9].

The cystic changes in the lung may be difficult to detect by chest radiography particularly in earlier stages of the disease. High-resolution CT demonstrates numerous cystic lesions that are uniformly scattered throughout the lung with normal intervening lung parenchyma (Fig. 1) [2,3,16,17]. Cysts are round, mostly 2 mm to 2 cm in size, and thin-walled. As the disease progresses into advanced stages, some of the cysts may coalesce into larger, more bizarre-shaped lesions. In contrast to PLCH, there is no relative sparing of basilar lung zones [2,3,16,17]. LAM can be associated with renal angiomyolipomas and extrapulmonary lymphangiomyomas in patients with and without underlying TSC.

Pulmonary function testing typically reveals an obstructive pattern of impairment, the severity of which depends on the stage of the disease. Approximately 25% of patients will show a bronchodilator response [9]. A superimposed restrictive pattern may be seen in the presence of pleural complications or prior thoracic surgical procedures.

A confident diagnosis of LAM can be made in the presence of typical HRCT findings in combination with renal angiomyolipoma, chylothorax, or features of TSC. In addition, an elevated serum level of VEGF-D can help confirm the diagnosis [14,15]. In patients with suspected LAM who have atypical CT features or lack associated findings, lung biopsy, bronchoscopic or surgical, may be needed to confirm the diagnosis [6,8,18].

It has been noted that 25% to 40% of women with tuberous sclerosis complex (TSC) have LAM [19–21]. Exploration of the relationship between LAM and TSC has led to important insights into the pathogenesis of LAM and a new targeted therapy in recent years. As in TSC, sporadic form of LAM involves mutations in the TSC genes, resulting in constitutive activation of the mTOR complex 1 signaling pathway. Sirolimus therapy, an mTOR inhibitor, has been shown to stabilize lung function and improve the quality of life in patients with LAM [22]. Potential therapeutic role of other agents such as estrogen suppressors, matrix metalloproteinase inhibitors, statins, and VEGF inhibitors is being explored [6]. Lung transplantation is an option for those patients with severe impairment from progressive LAM [23,24]. Recurrence of LAM in the transplanted lung has been observed and suggests LAM is a metastatic disease of extrapulmonary origin [24–26].

Pulmonary Langerhans’ cell histiocytosis (PLCH)

Pulmonary Langerhans’ cell histiocytosis (PLCH) encountered in adults is generally considered a smoking-related interstitial lung disease [27,28]. This disease has previously been referred to as histiocytosis X, pulmonary Langerhans granulomatosis, and pulmonary eosinophilic granuloma. It is diagnosed predominantly in younger adults, 3rd and 4th decades [29,30]. Langerhans cells are derived from dendritic cells and are potent antigen-presenting accessory cells.

Vast majority of patients with PLCH are active or prior smokers [27,30]. Constituents of cigarette smoke are thought to recruit and activate Langerhans cells in the lung [31]. Activated Langerhans cells and macrophages promote secondary recruitment of other immune and inflammatory cells resulting in a bronchiolocentric pattern of disease [27,28,32].

Patients with PLCH commonly present with dyspnea and cough but some patients present with abnormal chest imaging in the absence of respiratory symptoms [27,30]. Pneumothorax occurs in 10% to 20% of patients and may occasionally be the presenting manifestation [33,34]. Extrapulmonary manifestations such as bone involvement or diabetes insipidus may be associated in approximately 15% of patients [27,29].

Chest radiography usually demonstrates reticulonodular infiltrates with cystic changes that are predominant in the upper and middle lung zones with relative sparing of the costophrenic angles [29,34]. High-resolution CT reveals cystic changes with intervening architectural distortion that includes nodules and reticular densities more severely affecting upper and middle lung zones compared to lung bases (Fig. 2 A, B) [2,16,29]. Cysts are more irregular and complex than in LAM and some lesions appear as cavitated nodules with thicker walls. Most cysts are less than 10 mm in diameter but larger irregular cysts may also be seen in advanced stages.

Pulmonary function testing typically reveals an obstructive or mixed obstructive-restrictive pattern of impairment. Diffusing capacity is usually reduced.

In the proper clinical context, typical HRCT findings may be sufficient to make the diagnosis of PLCH. If a lung biopsy is needed to confirm the diagnosis, bronchoscopy with bronchoalveolar lavage and biopsy may yield diagnostic results. The presence of≥5% CD1a-positive cells in the BAL fluid is highly specific for PLCH [35]. Bronchoscopic biopsy may be diagnostic if adequate tissue is secured. S-100, CD1a and langerin immunostains identify Langerhans cells and can be helpful in diagnosing PLCH [28,36]. Langerhans cells can also be identified on electron microscopy by the presence of intracellular Birbeck granules (pentalaminar rod-shaped structures) [28,36]. If neither bronchoalveolar lavage nor bronchoscopic biopsy results are diagnostic, surgical lung biopsy is needed to confirm the diagnosis.

Smoking cessation is imperative for patients with PLCH who are actively smoking [27,29]. Radiologic improvement and even complete resolution of PLCH has been observed with smoking cessation [37,38]. Cladribine (2-chlorodeoxyadenosine), a synthetic purine analog chemotherapeutic agent, has been reported to be effective in several cases of progressive PLCH [39–41]. Lung transplantation has yielded good results in patients with severe PLCH, but as in LAM, recurrence of disease in the transplanted lung has been observed in some cases [42].

Lymphoid interstitial pneumonia (LIP)

Lymphoid interstitial pneumonia (LIP), also called lymphocytic interstitial pneumonia, is characterized by diffuse interstitial infiltration of the lung with lymphocytic and plasma cell components and belongs in the spectrum of benign pulmonary lymphoproliferative disorders [43–47]. Lymphoid interstitial pneumonia is usually encountered in association with various underlying disorders including human immunodeficiency virus (HIV) infection, connective tissue diseases such as Sjögren’s syndrome, Hashimoto’s thyroiditis, primary biliary cirrhosis, myasthenia gravis, and several other disorders [45–47]. It can also occur on its own as a form of idiopathic interstitial pneumonia [48].

Clinical presentation of LIP is nonspecific and includes dyspnea, cough, fever, and weight loss in the majority of patients [45–47]. Additional clinical features may be noted that reflect the underlying systemic disease, if present. Laboratory testing is notable for dysproteinemia, most commonly polyclonal hypergammaglobulinemia, detected in the majority of patients [45–47]. A restrictive dysfunction is usually seen on pulmonary function testing [45–47].

Chest radiography tends to reveal nonspecific abnormalities consisting of patchy reticular or reticulonodular opacities bilaterally, sometimes with superimposed alveolar infiltrates. High-resolution CT usually demonstrates areas of ground-glass opacities and centrilobular nodules along with thin-walled cystic spaces which can sometimes be extensive (Fig. 3) [44,49–51]. Interlobular thickening and intrathoracic lymphadenopathy are also common CT findings.

Cyst formation in LIP appears to arise from peribronchiolar lymphoid infiltration resulting in bronchiolar stenosis or occlusion with distal cyst formation from small airway obstruction [49,51]. In some patients these cystic changes may predispose to recurrent pneumothorax [52].

Treatment of LIP partly depends on the nature of the underlying disorder, e.g., Sjögren’s syndrome, when present. Corticosteroid therapy is commonly employed, especially for patients with idiopathic LIP who experience progression of their lung disease [45–47]. There are relatively few data on the use of other immunomodulating agents. Prognosis of these patients is variable and is influenced by the course of the underlying systemic disease that may be present [45–47].

Birt-Hogg-Dubé syndrome (BHD)

Birt-Hogg-Dubé syndrome (BHD) has gained increasing interest over the past several years in regard to its pulmonary manifestations. This autosomal dominant genodermatosis was originally described in 1977 and characterized by multiple benign cutaneous neoplasms, including fibrofolliculomas, trichodiscomas, and acrochordons, manifesting as papules on the head, neck, and upper trunk [53,54]. These skin lesions become apparent during the 3rd to 4th decades of life. A number of non-cutaneous features of BHD have become recognized, including a markedly increased risk of renal neoplasia, lung cysts, and spontaneous and often recurrent pneumothoraces [55–59].

BHD is a tumor suppressor syndrome resulting from germline mutations in the FLCN gene, whose product is folliculin [53,54,60]. Folliculin appears to have a role in the mTOR pathway but its range of functions remains to be clarified [54,59,61–63]. It has been suggested that pulmonary cysts may represent cystic alveolar formation associated with abnormal signaling in the mTOR pathway [64].

Approximately 90% of patients with BHD have cystic lesions in the lung demonstrable by chest HRCT [57]. Patients with the presence of cysts in the lung are predisposed to the occurrence of pneumothorax [55,57,59]. In patient surveys, approximately 15% to 25% of those with BHD report having experienced one or more episodes of pneumothorax [57,59]. Pneumothorax occurs during adulthood, usually before the age of 50 years [57].

Thin-walled cysts seen in patients with BHD may be difficult to detect by chest radiography but HRCT will demonstrate multiple cystic lesions bilaterally (Fig. 4). These cysts vary in size and shape and tend to be more numerous in the lower lobes [58,65].

There are relatively few data regarding pulmonary function testing on patients with BHD. Pulmonary function impairment tends to be relatively modest or absent in these patients with a slow rate progression over a number of years [55,66,67].

At present, management of cystic lung disease associated with BHD focuses on management of pneumothorax, typically with tube thoracostomy followed by pleurodesis to prevent recurrence [55,57]. There is no specific therapy for the cystic lung disease currently available. It remains to be seen whether mTOR inhibition has a role in BHD patients with progressive cystic lung disease.

Amyloidosis

Amyloidosis refers to systemic or organ-limited disease resulting from extracellular deposition of insoluble fibrillar protein in tissue [68]. There are several types of amyloidosis which are classified by precursor protein of amyloid and organ involvement. The diagnosis of amyloidosis is confirmed by tissue biopsy demonstrating amorphous material that stains positively with Congo red.

Pulmonary involvement in amyloidosis is usually associated with AL amyloidosis with deposition of protein derived from immunoglobulin light chain fragments [69,70]. Pulmonary amyloidosis consists of a broad spectrum of manifestations including tracheobronchial disease, parenchymal nodules and infiltrates, pleural disease and lymphadenopathy. Although not widely appreciated, pulmonary amyloidosis can also present with cystic lung disease [71,72]. In these cases, scattered cysts of varying sizes are seen, sometimes in association with Sjögren’s syndrome or mucosa-associated lymphoid tissue lymphoma (MALT lymphoma) (Fig. 5) [73,74]. Pulmonary cyst formation in amyloidosis is thought to involve multiple mechanisms including airway obstruction with check-valve effect, increased fragility caused by amyloid deposition with disruption of the alveolar structures, and ischemia related to vascular amyloid deposits and reduced blood flow [75,76].

Light chain deposition disease

Light chain deposition disease (LCDD) has a similar pathogenesis and shares some clinical features with AL amyloidosis. Light chain deposition disease is also a monoclonal plasma cell proliferative disorder and results from tissue deposition of light chain fragments that do not form amyloid fibrils and therefore do not stain positively with Congo red. Kidney is the most common organ involved in LCDD.

Recently, a peculiar form of diffuse cystic lung disease has been reported as a manifestation of pulmonary LCDD [77,78]. Numerous cysts can be seen in the lung diffusely and can progress in number and size with some cysts coalescing to form irregular shapes (Fig. 6) [77]. In most cases, linear opacities and small nodules are also present [77,78]. Cyst formation seen in pulmonary LCDD is likely mediated by macrophages that release metalloproteinases in reaction to light chain deposition, resulting in elastolysis and tissue destruction [79].

Other cystic lung diseases

Depending on the clinical context, there are several other disorders that need to be considered in the differential diagnosis of diffuse cystic lung disease. Cystic air spaces can form with progressive parenchymal fibrosis (honeycombing) as seen in idiopathic pulmonary fibrosis, asbestosis, pulmonary fibrosis associated with connective tissue disorders, chronic hypersensitivity pneumonitis, and sarcoidosis. In such cases of advanced fibrosis, the cysts are usually 3 mm to 10 mm in diameter and have thicker fibrous walls (2 mm to 3 mm) compared to those seen in LAM [2,80]. In addition, cystic changes are usually accompanied by other signs of the underlying disease process including nodules, ground-glass opacities, reticulation, traction bronchiectasis and architectural distortion [2,80]. The distribution of these cysts seen in these other interstitial lung diseases can also be helpful in identifying the underlying cause of the lung disease. For example, honeycombing seen in IPF involves mainly the subpleural lung regions of the lower lung zones (Fig. 7 A, B). In advanced sarcoidosis, cystic changes are located predominantly in perihilar regions with relative sparing of the lung bases.

Scattered cysts in the lung can be seen in disorders other than those already discussed. Desquamative interstitial pneumonia is included under the rubric of idiopathic interstitial pneumonias but is likely a form of smoking-related interstitial lung disease [27,81,82]. The predominant HRCT findings in patients with desquamative interstitial pneumonia are ground-glass opacities but some patients will also exhibit small cystic lesions. These cystic lesions appear to represent dilated alveolar ducts and bronchioles as well as parenchymal cysts [83]. Similarly, a minority of patients with hypersensitivity pneumonitis may exhibit a limited number of cysts (usually<15) that range in size from 3 mm to 25 mm in diameter and have a random distribution [84]. In patients with hypersensitivity pneumonitis, HRCT will also demonstrate other parenchymal findings including diffuse ground-glass opacities, ill-defined centrilobular nodules, and areas of air trapping (mosaic pattern) [84].

The term “bronchiolitis” refers to a spectrum of disorders that affect small airways that are 2 mm or less in internal diameter, i.e., bronchioles [85–87]. Bronchiolar involvement is relatively common in lung diseases and a broad spectrum of bronchiolar pathology can be seen. Radiologically, bronchiolitis is usually characterized by small centrilobular nodules, “tree-in-bud” pattern, bronchiolar wall thickening, and bronchiolectasis [86,88]. Mosaic attenuation pattern (alternating geographic regions of increased and decreased attenuation) can be seen due to patchy air trapping [86,88]. Cysts are uncommonly associated with bronchiolar disorders but can occur in two forms of bronchiolitis, follicular bronchiolitis and, rarely, constrictive bronchiolitis.

Follicular bronchiolitis is histologically characterized by the presence of hyperplastic lymphoid follicles in the peribronchiolar regions [85,86]. It is encountered in several clinical settings including connective tissue diseases (especially rheumatoid arthritis), immunodeficiency disorders, and bronchiectasis. High-resolution CT scanning typically reveals bilateral centrilobular nodules measuring 12 mm or less and patchy ground-glass opacities [89,90]. In some of these patients, however, scattered pulmonary cysts may also be seen [16]. In constrictive bronchiolitis the dominant HRCT findings are areas of decreased attenuation due to air trapping. Scattered pulmonary cysts have been recently described as the main radiologic findings in some patients with constrictive bronchiolitis [91]. In both of these instances, cystic changes are thought to occur due to bronchiolar obstruction involving a check-valve mechanism causing distention and rupturing of alveoli [91,92].

Aside from TSC, several other hereditary syndromes have been associated with cystic lung disease. These have included Marfan syndrome, neurofibromatosis 1, Ehlers-Danlos syndrome, and Proteus syndrome [93–99]. In all of these conditions the number of pulmonary cysts are limited and the consideration of the clinical context will make confusion with previously discussed diffuse cystic lung diseases unlikely.

Pulmonary infections can cause parenchymal necrosis and cavitation, sometimes resulting in cysts. Coccidioidomycosis is an endemic fungal disease found mainly in semiarid regions of the south-western United States and northern Mexico as well as Central and South America [100,101]. Although cavitation is a major characteristic of chronic pulmonary coccidioidomycosis, multiple thin-walled cysts may form as the primary infection resolves. Pneumocystis jiroveci pneumonia is seen mainly in patients with acquired immunodeficiency syndrome (AIDS) [102,103]. Although the dominant CT finding in Pneumocystis jiroveci pneumonia is diffuse grounds-glass opacities, pulmonary cysts of varying size and shape may be seen in some patients and are associated with an increased risk of pneumothorax [104].

Rarely, neoplastic processes may cause diffuse cystic lung lesions (Fig. 8). This has been described with several types of cancers including metastatic sarcomas and MALT lymphoma [105,106].

Lastly, it should be added that some cases of bronchiectasis can be confused for cystic lung disease. This can occur with cystic or varicose type of bronchiectasis in which dilated airways may appear cystic on cross-sectional views. In particular, allergic bronchopulmonary aspergillosis causes proximal bronchiectasis that is cystic or varicose in appearance [107,108]. Assessment of adjacent sections on CT should distinguish cystic bronchiectasis from parenchymal cystic disease.

Conclusions

Diffuse cystic lung diseases are uncommon but consist of a fascinating array of disease entities associated with diverse pathologic processes. In recent years, significant advances have been achieved in our understanding of these diseases and additional causes of diffuse cystic lung diseases have been described. Several mechanisms for cyst formation have been characterized including the role of metalloproteinases in LAM [109] and LCDD [79] while airway narrowing and check valve mechanism appear to be more important in pulmonary amyloidosis [73]. In PLCH, cysts appear to result from destruction of the bronchial wall and progressive luminal dilatation [32]. Diagnostic evaluation of patients with diffuse cystic lung diseases requires correlation of imaging features seen on HRCT with the clinical context and tempo of the disease process. Optimal management of these patients requires a correct diagnosis that can be reached by a thoughtful analysis of these presenting features along with judicious use of laboratory tests and biopsy procedures when needed. In addition, advances in our understanding of the pathogenesis of these diseases and mechanisms underlying cyst formation will lead to improved outlook for these patients.

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