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Imaging and Differential Diagnosis of Cystic Lung Disease

PCCSU Volume 25, Lesson 23

PCCSU

The American College of Chest Physicians offers this lesson as a review of a previously offered self-study program. The program provides information on pulmonary, critical care, and sleep medicine issues. CME is no longer available for the PCCSU program.

Objectives

  • Update your knowledge and understanding of pulmonary medicine topics.
  • Update your knowledge and understanding of critical care medicine topics.
  • Update your knowledge and understanding of sleep medicine topics.
  • Learn clinically useful practice procedures.

CME Availability

Effective July 1, 2013, PCCSU Volume 25 is available for review purposes only.

Effective December 31, 2012, PCCSU Volume 24 is available for review purposes only.

Effective December 31, 2011, PCCU Volume 23 is available for review purposes only. CME credit for this volume is no longer being offered

Effective December 31, 2010, PCCU Volume 22 is available for review purposes only. CME credit for this volume is no longer being offered.

Accreditation Statement

The American College of Chest Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

CME Statement

Credit no longer available as of July 1, 2013.

Disclosure Statement

The American College of Chest Physicians (CHEST) remains strongly committed to providing the best available evidence-based clinical information to participants of this educational activity and requires an open disclosure of any potential conflict of interest identified by our faculty members. It is not the intent of CHEST to eliminate all situations of potential conflict of interest, but rather to enable those who are working with CHEST to recognize situations that may be subject to question by others. All disclosed conflicts of interest are reviewed by the educational activity course director/chair, the Education Committee, or the Conflict of Interest Review Committee to ensure that such situations are properly evaluated and, if necessary, resolved. The CHEST educational standards pertaining to conflict of interest are intended to maintain the professional autonomy of the clinical experts inherent in promoting a balanced presentation of science. Through our review process, all CHEST CME activities are ensured of independent, objective, scientifically balanced presentations of information. Disclosure of any or no relationships will be made available for all educational activities.

CME Availability

Volume 25 Through June 30, 2013
Volume 24 Through December 31, 2012
Volume 23 Through December 31, 2011
Volume 22 Through December 31, 2010

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PCCSU Volume 25 Editorial Board

Editor-in-Chief
Steven A. Sahn, MD, FCCP

Director, Division of Pulmonary and Critical Care Medicine, Allergy, and Clinical Immunology
Medical University of South Carolina
Charleston, SC

Dr. Sahn has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Deputy Editor
Richard A. Matthay, MD, FCCP

Professor of Medicine
Section of Pulmonary and Critical Care Medicine
Yale University School of Medicine
New Haven, CT

Dr. Matthay has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Alejandro C. Arroliga, MD, FCCP
Professor of Medicine
Texas A&M Health Science Center
College of Medicine
Temple, TX

Dr. Arroliga has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Paul D. Blanc, MD, FCCP
Professor of Medicine
University of California, San Francisco
San Francisco, CA

Dr. Blanc has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health, Flight Attendants Medical Research Institute – university grant monies
University of California San Francisco, US Environmental Protection Agency, California Environmental Protection Agency Air Resources Board – consultant fee
Habonim-Dror Foundation Board of Trustees – fiduciary position

Guillermo A. do Pico, MD, FCCP
Professor of Medicine
University of Wisconsin Medical School
Madison, WI

Dr. do Pico has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Ware G. Kuschner, MD, FCCP
Associate Professor of Medicine
Stanford University School of Medicine
Palo Alto, CA

Dr. Kuschner has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Teofilo Lee-Chiong, MD, FCCP
Associate Professor of Medicine
National Jewish Medical Center
Denver, CO

Dr. Lee-Chiong has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health – grant monies (from sources other than industry)
Covidien, Respironics, Inc. – grant monies (from industry-related sources)
Elsevier – consultant fee

Margaret Pisani, MD, MPH, FCCP
Assistant Professor of Medicine
Yale University School of Medicine
New Haven, CT

Dr. Pisani has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Stephen I. Rennard, MD, FCCP
Professor of Medicine
University of Nebraska Medical Center
Omaha, NE

Dr. Rennard has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

AstraZeneca, Biomark, Centocor, Novartis – grant monies (from industry-related sources)

Almirall, Aradigm, AstraZeneca, Boehringer Ingelheim, Defined Health, Dey Pharma, Eaton Associates, GlaxoSmithKline, Medacrop, Mpex, Novartis, Nycomed, Otsuka, Pfizer, Pulmatrix, Theravance, United Biosource, Uptake Medical, VantagePoint – consultant fee/advisory committee

AstraZeneca, Network for Continuing Medical Education, Novartis, Pfizer, SOMA – speaker bureau

Ex Officio
Gary R. Epler, MD, FCCP

Clinical Associate Professor of Medicine
Harvard Medical School
Brigham & Women's Hospital
Boston, MA

Dr. Epler has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Lilly Rodriguez
ACCP Staff Liaison

By Isabel B. Oliva, MD; Danielle E. Antin-Ozerkis, MD; and Ami N. Rubinowitz, MD

Dr. Oliva is Assistant Professor, Dr. Antin-Ozerkis is Assistant Professor, and Dr. Rubinowitz is Associate Professor, Yale School of Medicine, New Haven, Connecticut.

Drs. Oliva, Antin-Ozerkis, and Rubinowitz have disclosed no significant relationships with the companies/organizations whose products or services may be discussed within this chapter.

Objectives

  1. Recognize the radiographic appearance of lung cysts on chest CT scan.
  2. Differentiate lung cysts from their radiographic mimics.
  3. Formulate a differential diagnosis for cystic lung disease.
  4. Recognize specific imaging patterns among the various causes of cystic lung disease.
  5. Recognize clinical characteristics associated with specific cystic lung diseases.

Key words: cystic lung disease; Langerhans cell histiocytosis; lung cyst; lymphangiomyomatosis

Abbreviations: BHDS = Birt-Hogg-Dubé syndrome; Dlco = diffusing capacity of the lung for carbon monoxide; LAM = lymphangioleiomyomatosis; LCH = Langerhans cell histiocytosis; LIP = lymphocytic interstitial pneumonia; PLCH = pulmonary Langerhans cell histiocytosis; TSC = tuberous sclerosis complex; VEGF-D = vascular endothelial growth factor D

A lung cyst is defined as a well-circumscribed, air-filled structure that is localized within the lung parenchyma, is >1 cm in diameter, and has a definable epithelial or fibrous wall that is usually <1 mm thick but that may be up to 2 or 3 mm thick1 (Fig 1). Pulmonary cysts may occur as an isolated abnormality but may also be present in a multifocal distribution or even involve the lung parenchyma diffusely.


Figure 1. Chest CT scan of a 54-year-old woman with lymphoma showing a few bilateral intraparenchymal cysts. Note that the centrilobular artery is displaced by the lung cyst and is seen eccentric to the lucent area (arrows).


Cystic lung diseases are rare entities characterized by multiple intrapulmonary cysts. The more common of these rare disorders are Langerhans cell histiocytosis (LCH) and lymphangioleiomyomatosis (LAM). Less common ones include Pneumocystis jiroveci pneumonia, Birt-Hogg-Dubé syndrome (BHDS), lymphocytic interstitial pneumonia (LIP), and amyloidosis.2,3

Air-filled lucencies within the lung parenchyma are frequently detected on routine chest CT. These lucent areas may represent pulmonary cysts, but other causes include cavities, emphysema, bronchiectasis, and honeycombing (Table 1).4 These entities can mimic a lung cyst on both chest radiograph and chest CT, and should be excluded before labeling a patient as having cystic lung disease. Additional imaging findings, clinical data, and laboratory data help narrow the differential diagnosis.


Table 1Imaging Clues to Help Differentiate Pulmonary Cysts and Their Mimics

Entity Imaging Characteristics
Lung cyst Well-circumscribed, rounded, thin-walled air-filled structure within the lung parenchyma. Wall thickness of ≤3mm.
Cavity Air-filled space within the pulmonary parenchyma with thicker walls (>4 mm).
Emphysema Polygonal-shaped lucent area without definable walls.
Bronchiectasis Air-filled space within the lung parenchyma that branches and connects with the airway. Associated airway abnormalities including air trapping, bronchial wall thickening, and bronchiolar impactions.
Honeycombing Clustered subpleural airspaces with variable size and wall thickness. Other signs of pulmonary fibrosis: architectural distortion, traction bronchiectasis, and reticular opacities.

 


In this review, we discuss disorders that mimic the appearance of lung cysts and describe the clinical and radiographic features that help distinguish the different causes of cystic lung disease.

Air-Filled Lucencies That Mimic Pulmonary Cysts

Cavitary Lesions
Cavities are air-filled spaces within the pulmonary parenchyma with definable walls that are thicker than the ones seen in lung cysts (usually >4 mm; Fig 2).1 The distinction between lung cysts and cavities is mainly based on this difference in wall thickness. Cavitary lesions in the lung parenchyma can be caused by primary bronchogenic carcinoma, lung metastases, vasculitides (Wegener granulomatosis, rheumatoid arthritis), and different infectious etiologies, including bacterial abscess, septic emboli, TB, or fungal pneumonia (including invasive aspergillosis).4


L23Fig2A

L23Fig2B

Figure 2. Thick-walled cavities in A, a 66-year-old man with squamous cell carcinoma of the lung and B, a 40-year-old man with Staphylococcus pneumonia. Note that the walls of these cavities are more than 4 mm thick, allowing differentiation from a pulmonary cyst.


Emphysema
Pulmonary emphysema is defined by the American Thoracic Society as permanent abnormal enlargement of the airspaces distal to the terminal bronchiole, accompanied by destruction of their walls and absence of obvious pulmonary fibrosis (Fig 3).5 Lung volumes are usually increased in affected patients because of hyperinflation. Emphysematous destruction of the lungs is classified as centrilobular, paraseptal, or panlobar depending on which anatomic location of the secondary pulmonary lobule is involved.6


L23Fig3

Figure 3. Axial CT image through the lung apices of a 47-year-old woman with a smoking history showing presence of centrilobular and paraseptal types of emphysema.


A bulla is defined as a sharply demarcated area of emphysema that is ≥1 cm in diameter and that has a wall that is ≤1 mm thick.1 Bullae are located in the subpleural region rather than within the lung parenchyma and are a manifestation of paraseptal emphysema, although they can also occur in centrilobular emphysema.3

On chest CT, centrilobular emphysema appears as a lucent area without definable walls. This type of emphysema, which is most common in patients with a history of cigarette smoking, is distributed predominantly in the upper lobes.5 The pulmonary destruction begins in the center of the secondary pulmonary lobule, but as the disease progresses, the entire secondary pulmonary lobule becomes involved so that the interlobular septa between the destroyed lobules may appear to be the walls of a cyst. Because the destruction occurs centrally in the secondary pulmonary lobule, the centrilobular artery is typically visible in the center of the lucent area rather than eccentrically. Whereas in a lung cyst, the centrilobular artery is either not visible or is displaced and therefore seen eccentric to the lucent area. In emphysema, the lucent area preserves the polygonal shape of the secondary pulmonary lobule, whereas cysts are typically perfectly rounded or sometimes irregularly shaped.5

The paraseptal type of emphysema involves the most distal aspect of the secondary pulmonary lobule and is most commonly seen as a single row of elongated, thin-walled, air-filled structures distributed along the subpleural region.5 Unlike centrilobular emphysema, paraseptal emphysema may occur in nonsmokers. Paraseptal emphysema has a predominant subpleural distribution, in contrast to the intraparenchymal location of cysts.

In panlobar emphysema, the pulmonary parenchymal destruction is distributed evenly throughout the secondary pulmonary lobule.1 Panlobar emphysema is classically associated with α1-antitrypsin deficiency, but it may also occur in smokers or elderly patients or in association with illicit drug use.7 Unlike centrilobular and paraseptal emphysema, which predominantly involve the upper lung zones, panlobar emphysema involves the lung parenchyma diffusely or is most severe in the lower lobes.7 On chest CT, panlobar and centrilobular emphysema appear as a lucent area without definable walls, thereby differentiating them from lung cysts.

Bronchiectasis
Bronchiectasis is defined as localized dilatation of the bronchial tree and is classified on the basis of the severity of bronchial dilatation as cylindrical or tubular, a mild form; varicoid, a moderate form; and cystic or saccular, a severe form.1 Bronchiectasis most commonly occurs secondary to recurrent pulmonary infections, but it may also occur in association with hereditary syndromes, such as cystic fibrosis, dysmotile cilia syndrome, and Williams-Campbell syndrome, as well as in immunodeficiency disorders, connective tissue diseases, and pulmonary fibrosis (traction bronchiectasis).8

In bronchiectasis, the lung volumes vary and may be reduced when there is advanced scarring or increased if air trapping is present. Bronchiectasis can be distinguished from pulmonary cysts by following the dilated airways on multiple sequential chest CT scan images, which will show a branching pattern that is usually better visualized on the coronal and sagittal reformatted images (Fig 4). Bronchiectasis is usually associated with other tracheobronchial tree abnormalities, such as bronchial wall thickening, clustered centrilobular nodules, and air trapping, whereas pulmonary cysts usually appear isolated without associated airway abnormalities.9


L23Fig4A

L23Fig4B

L23Fig4C

Figure 4. A 34-year-old woman with history of dysmotile cilia syndrome has increased cough and leukocytosis. A, Axial CT images show multiple air-filled structures within the lung parenchyma. B, C, Sagittal and coronal reformatted images depict well the branching configuration of these structures and their connection with the airway.


Honeycombing
On chest CT, patients with end-stage pulmonary fibrosis and honeycombing have multiple rows of air-filled spaces clustered in the subpleural region, predominantly in the lower lobes (Fig 5).1 These spaces vary in size, shape, and wall thickness but are typically <1 cm in diameter. Other signs of pulmonary fibrosis may be seen, such as decreased lung volumes, reticular opacities, architectural distortion, and traction bronchiectasis.3 Honeycombing is not classified as cystic lung disease because the air-filled spaces are distributed along the subpleural space and not within the lung parenchyma.


L23Fig5

Figure 5. A 57-year-old woman with diagnosis of idiopathic pulmonary fibrosis has increasing shortness of breath and chest pain. Axial CT image shows at least three rows of small clustered cystic airspaces along the subpleural region of both lung bases, consistent with honeycombing secondary to pulmonary fibrosis.


Cystic Lung Diseases

After recognizing that multiple lung cysts are indeed present and have been differentiated from cavitary lesions, emphysema, bronchiectasis, and honeycombing, the clinician’s next effort should be to diagnose the underlying pulmonary disease. This differentiation is important because different entities require different treatments and imply distinct prognoses.

To make the correct diagnosis, we suggest using a multidisciplinary approach that takes into consideration the patient’s clinical history, physical examination, and the radiologic appearance; certain clinical and radiographic features may eliminate the need for surgical lung biopsy.

Helpful clinical data include the patient’s sex, age, smoking history, and findings on physical examination. However, patients with different types of cystic lung disease often have similar nonspecific symptoms, such as chronic cough and shortness of breath. Therefore, imaging is particularly important in narrowing down the differential diagnosis. Important chest imaging factors that should be taken into consideration when evaluating patients with diffuse cystic lung disease include the following: lung volume; size, wall thickness, shape, and distribution of the pulmonary cysts; and associated findings, such as pulmonary nodules, septal thickening, pleural effusions, lymphadenopathy, and extrathoracic abnormalities.

The chest radiograph is not a sensitive imaging modality for patients with pulmonary cysts, as the discrete cysts are usually not visible via radiography. In patients with cystic lung disease, the chest radiograph can either appear normal or show large lung volumes and nonspecific increased interstitial markings caused by summation and superimposition of the cyst walls.3 Chest CT scan is the imaging modality of choice to detect and differentiate among the various causes of cystic lung disease. The following sections include clinical and radiologic characteristics of the most common cystic lung diseases that help the radiologist and clinician formulate a differential diagnosis. These characteristics are summarized in Table 2.


Table 2Clinical and Imaging Findings That Help Differentiate Among Cystic Lung Diseases

Disease Clinical Features Imaging Characteristics
PLCH Smoking-related; male predominance Upper lobe predominant, sparing costophrenic sulci, bizarre-shaped cysts; associated emphysema and peribronchiolar nodules
LAM Women of childbearing age; sporadic or associated with TSC Diffuse involvement, uniform cyst size, normal intervening lung; associated chylous effusion and dilated thoracic duct; elevated serum VEGF-D
Pneumocystis pneumonia Immunodeficiency and AIDS Symmetric involvement of upper and mid lung zones; cysts within areas of consolidation and ground-glass opacities
LIP HIV, connective tissue disorders, Castleman disease, and lymphoproliferative disorders Few cysts distributed along the peribronchovascular interstitium
BHDS Autosomal dominant; involves skin, lungs, and kidneys Basilar and peripherally predominant lentiform cysts abutting the pulmonary arteries and veins

 


Langerhans Cell Histiocytosis
LCH, formerly known as eosinophilic granuloma, is characterized histopathologically by the accumulation of Langerhans cells in one or more systems, including lungs, bones, pituitary gland, skin, mucous membranes, lymph nodes, and liver. About 40% of patients with LCH will have involvement of the lungs and 28% will exhibit isolated pulmonary involvement.10

Pulmonary LCH (PLCH) is a smoking-related disease that is more prevalent between the second and fourth decades of life and has a slight male and Caucasian predominance.11 Smoking is the main risk factor for PLCH and it is has been proven to be associated with a higher incidence of pulmonary findings and precipitation of disease recurrence. Smoking cessation may alleviate symptoms and improve radiographic findings.11 Affected patients have nonspecific symptoms, such as dry cough and dyspnea, but approximately 15% present with spontaneous pneumothorax as the initial manifestation.12 About 25% of patients are asymptomatic, with the lung cysts detected incidentally on routine chest CT scan performed for other reasons.12

Patients with isolated PLCH have a better prognosis than those with multisystem involvement. Most of the patients with isolated pulmonary involvement have a favorable clinical course, with remission occurring either spontaneously or after corticosteroid therapy, and with partial or complete resolution of the radiographic abnormalities. Only about 10% to 20% of patients with PLCH have a rapidly progressive course of disease, with recurrent pneumothoraces or progressive respiratory failure.11

Pulmonary function tests in patients with PLCH commonly show a restrictive ventilatory defect, but obstructive and mixed patterns have also been reported. Approximately 60% to 90% of these patients also have a reduction in diffusing capacity of lung for carbon monoxide (Dlco).12

There is a well-recognized sequence of radiographic events in patients with PLCH.11 Early in the course of disease, centrilobular nodules are seen and may undergo cavitation. As the disease progresses, thick-walled and then thin-walled cysts usually develop. It has been postulated that the nodules cavitate and turn into lung cysts (Fig 6). The cystic lesions may eventually become the predominant finding; as they progress, the lesions may eventually become indistinguishable from underlying emphysema.10


L23Fig6A

L23Fig6B

Figure 6. A 33-year-old man with a smoking history presented with a dry cough and restrictive ventilatory defect on pulmonary function testing. A, Chest CT scan demonstrates multiple centrilobular ground-glass nodules. B, Follow-up chest CT scan 10 years later shows replacement of these nodules by round, well-circumscribed, thin-walled cysts (arrows), which were pathologically proven to represent PLCH. The patient also developed centrilobular emphysema, seen as intrapulmonary polyhedral lucent areas without definable walls.


Lung volumes are normal or increased, and the superimposed walls of the cysts may mimic honeycombing or reticular markings on chest radiography.10 There is an apical to basal gradient of severity with the cysts being larger and more numerable in the upper lobes than the lower lung zones.12 This differential severity occurs because PLCH is a smoking-related disease, and there is more ventilation (increased cigarette smoke) in the upper lobes than in the lower lobes. There is also relative sparing of the costophrenic angles, lung bases, and anterior tip of the right middle lobe and lingula.

These findings are much better appreciated on chest CT scan compared with chest radiography. Centrilobular emphysema and ill-defined peribronchiolar ground-glass nodules, which represent peribronchiolar granulomas containing Langerhans cells and eosinophils, can also be seen predominately in the upper lobes.2,11

Late in the course of PLCH, patients may develop secondary pulmonary artery hypertension, which is seen radiographically as enlargement of the central pulmonary arteries. The cysts can coalesce and become more irregularly shaped (for example, bilobed or cloverleaf) with progression of disease. Areas of air trapping can also be seen owing to the peribronchiolocentric inflammation. There is no honeycombing or fibrosis. Mediastinal lymphadenopathy and pleural effusions are rare.

Lymphangioleiomyomatosis
Lymphangioleiomyomatosis (LAM) is a rare idiopathic multisystem disorder characterized by progressive proliferation of immature smooth muscle and spindle cells along the axial lymphatics. Pathologically, the peribronchiolar infiltration may lead to bronchiolar obstruction, destruction of lung parenchyma, and formation of lung cysts. Tiny, subcentimeter pulmonary nodules may form as a result of focal proliferation within type II pneumocytes.13

LAM can occur sporadically or in association with tuberous sclerosis complex (TSC). Pulmonary involvement in patients with TSC demonstrates pathologic and radiologic findings similar to the ones seen in patients with sporadic LAM. Tuberous sclerosis affects both sexes equally but, similar to sporadic LAM, pulmonary involvement occurs exclusively in women of childbearing age. TSC-associated LAM is five to 10 times more common than sporadic LAM, and about 30% of women with TSC will have pulmonary involvement.14

The classic clinical triad seen in patients with TSC includes adenoma sebaceum, mental retardation, and seizures. Other findings that may help in the diagnosis include multiple renal angiomyolipomas, cardiac rhabdomyoma, splenic cysts, chylous pleural effusions, skin lesions (ash-leaf spot, shagreen patch), subungual fibroma, cystic hygroma, and uterine fibroids. On ophthalmologic exam, Lisch nodules may be present. CNS findings include calcified subependymal nodules, cortical tubers, and giant cell astrocytoma. Renal angiomyolipoma is the most common abdominal finding, and its prevalence has been reported to range between 15% and 57% of patients with TSC-associated LAM.

Most patients with TSC-associated LAM are asymptomatic; retrospective series have estimated that only 2% to 5% of these patients have symptoms.11 Patients with LAM, either sporadic or associated with TSC, complain of nonspecific symptoms, such as dyspnea and chronic cough. Progressive dyspnea is the most commonly reported presenting symptom and cough occurs in approximately 39% of patients. Approximately 40% to 80% of patients present with spontaneous pneumothorax and 15% develop hemoptysis. The mean time from onset of symptoms to diagnosis is typically between 3 and 5 years.14,15

At presentation, most patients with LAM have abnormal findings on pulmonary function tests. Airway obstruction is the most common finding, occurring in approximately 57% of patients. Approximately 25% of patients have reversible obstructive airway disease. About one-third of patients have normal spirometric values on presentation. The extent of cystic disease on chest CT scan correlates with reduction in Dlco.14,15

Patients with LAM demonstrate higher serum concentrations of vascular endothelial growth factor D (VEGF-D) when compared with the healthy normal population. The combination of VEGF-D levels >800 pg/mL and the presence of pulmonary cysts on imaging is specific for LAM. This biomarker is particularly helpful in patients who present with isolated pulmonary cystic lung disease, for whom an open-lung biopsy is often recommended to confirm diagnosis of LAM.16

LAM is a progressive lung disease with a poor long-term prognosis.14 Several therapeutic options have been studied based on the relationship between hormonal stimulation and worsening/recurrence of symptoms. Oophorectomy and progesterone therapy appear to improve or stabilize the disease, but a favorable response to hormonal manipulation is not universal.17 A few studies have also proven that treatment with rapamycin (sirolimus) stops decline of lung function and improves quality of life, but there are tolerance and safety issues with this agent that should be considered after individual evaluation. Lung transplantation is the only current curative therapy for patients with LAM, but the disease has been reported to recur in the transplanted lung.17

Approximately 10% to 25% of patients with LAM have normal chest radiograph findings despite the presence of lung cysts.13 A fine reticular pattern is noted in approximately 80% of patients, likely the result of superimposition of the walls of the lung cysts.13 This appearance can also mimic honeycombing when seen at the lung bases. The lung volumes are commonly increased. The lung cysts are typically uniform in size and shape and are distributed diffusely; the apices and lung bases are involved to the same extent.13

Chest CT scan can accurately depict the diffuse involvement of the lung parenchyma with multiple round pulmonary cysts that have uniform size and faint walls (Fig 7). These cysts increase in size with progression of the disease. The intervening lung parenchyma is usually normal, but patchy ground-glass opacities can occur, presumably from recurrent hemorrhage. Small pulmonary nodules can sometimes be seen in the intervening lung parenchyma but they are not the predominant feature. Areas of air trapping are usually found on the expiratory portion of the CT scan.


L23Fig7B

L23Fig7C

Figure 7. A 51-year-old woman with TSC complained of chronic dry cough. A, B, Axial CT images through the chest demonstrate innumerable lung cysts distributed diffusely throughout the lung parenchyma. C, Axial image of an abdominal CT shows bilateral angiomyolipomas, frequently encountered in patients with TSC.


Approximately 10% to 20% of patients develop chylous pleural effusion as a result of lymph node and lymphatic involvement.11

Pneumocystis Pneumonia
P jiroveci (formerly known as Pneumocystis carinii) pneumonia is an opportunistic fungal infection affecting individuals with T-cell immunodeficiency. It is the most prevalent opportunistic infection in patients with AIDS, affecting approximately 60% to 80% of these patients.18 Because P jiroveci organisms can be found in normal lungs, prophylaxis with aerosolized pentamidine is recommended for patients with AIDS who demonstrate a CD4 cell count of <200/mm3.19 The incidence of Pneumocystis pneumonia has decreased dramatically with the advent of antiretroviral therapy.20

Patients with Pneumocystis pneumonia have nonspecific symptoms, such as nonproductive cough, low-grade fever, and dyspnea. Patients can also have spontaneous pneumothorax, with reported prevalence ranging from 0% to 6% in the absence of lung cysts.18

Serum lactate dehydrogenase levels are elevated (>220 U/L) in 90% of patients who are infected with HIV and P jiroveci. Pulmonary function tests demonstrate a decreased Dlco (<75% of predicted) and although this finding has a high sensitivity (90% to 100%), it is not specific (53% specificity). BAL has a diagnostic yield exceeding 90%, but it is less sensitive in patients receiving aerosolized pentamidine. In such patients, transbronchial biopsy is recommended.18

The cystic form of Pneumocystis pneumonia is more common in AIDS patients and has a more chronic clinical course.4 Cyst formation is also more prevalent in patients who are receiving prophylaxis with aerosolized pentamidine.4 From a pathology standpoint, there are two types of pulmonary cysts related to Pneumocystis pneumonia: the intraparenchymal form with thin-walled cysts demonstrating a necrotic component and internal organisms, and the subpleural form characterized by sterile cysts lined by granulomatous and fibrous tissues and predominating at the lung apices.4

In patients with Pneumocystis pneumonia, the chest radiograph demonstrates bilateral ground-glass opacities and consolidations predominating in the perihilar regions and upper lobes.21 On chest CT, the ground-glass opacities are the dominant feature and are thought to represent acute pneumonitis. These opacities are distributed symmetrically in the central portion of the lungs and predominate in the upper lung zones.21

Patients with Pneumocystis pneumonia will develop small thin- or thick-walled intrapulmonary cysts within the ground-glass opacities (Fig 8).21 Occasionally, larger subpleural cysts are present, presumably arising from intrapleural rupture of intraparenchymal necrotizing lesions. Approximately 10% to 34% of HIV-positive patients with Pneumocystis pneumonia develop postinfectious pulmonary fibrosis.22 A recent study in HIV-negative patients with Pneumocystis pneumonia reported resolution of the radiologic abnormality in approximately 72% of patients.21


L23Fig8

Figure 8. A 22-year-old HIV-positive man receiving prophylactic aerosolized pentamidine presented with nonproductive cough and low-grade fever. Chest CT scan image shows thin-walled pulmonary cysts within bilateral areas of ground-glass opacities. A few of these cysts demonstrate air-fluid levels likely secondary to superimposed infection. Subsequent laboratory study detected elevated serum levels of lactate dehydrogenase and BAL fluid was positive for P jirovecii pneumonia.


Lymphocytic Interstitial Pneumonia
LIP is a rare benign lymphoproliferative disease characterized by infiltration of lymphocytes, plasma cells, and histiocytes along the airways and pulmonary interstitium.23 Imaging findings in pediatric patients with HIV infection who have LIP in the lungs are different from those in HIV-infected adults. Children with LIP typically have diffuse miliary nodules on imaging, mimicking the radiographic picture of miliary tuberculosis. In HIV-infected adults with LIP, chest CT scan shows small lung cysts, reticular markings, and ground-glass opacities. LIP in adults that is not associated with HIV infection usually occurs in women in their fourth or fifth decade of life.23

LIP is commonly seen in patients with connective tissue disorders (particularly Sjögren syndrome), autoimmune thyroid disease, and AIDS; other less common associations include Castleman disease and lymphoproliferative disorders.4 HIV patients with LIP have a slightly increased incidence of lymphoma.23

Patients usually present with progressive cough and dyspnea. Pulmonary function test results show restrictive physiology and impaired gas exchange. Although most patients with LIP initially respond to corticosteroid therapy, almost half of affected patients die within 5 years of diagnosis.23 Treatment is directed at the underlying systemic disease.

Radiographic findings in LIP include multiple thin-walled cysts (but with fewer cysts than are seen in patients with LCH and LAM) distributed along the peribronchovascular interstitium (Fig 9). Cystic airspaces range in size and are randomly distributed. Additional abnormalities may be noted on chest CT scan depending on the underlying systemic disorder. In a series of 22 patients with Sjögren syndrome, Castleman disease, or AIDS, CT scan revealed ground-glass opacities and poorly defined centrilobular nodules in all of the patients.24 Most of these patients also had thickening of the bronchovascular bundles and interlobular septa, as well as lymph node enlargement. Discrete nodules, consolidations, and fibrosis are rare in patients with LIP.24


L23Fig9

Figure 9. A 70-year-old woman with history of Sjögren syndrome presented with complaints of progressive cough and dyspnea. Chest CT image demonstrates diffuse ground-glass opacities and multiple intrapulmonary cysts. The patient has biopsy-proven LIP.


The main differential diagnosis of bilateral ground-glass opacities and lung cysts on CT imaging in an HIV-positive patient is LIP and Pneumocystis jirovecii pneumonia.

Birt-Hogg-Dubé Syndrome
BHDS is a rare autosomal dominant disorder characterized by mutation of the gene that encodes folliculin, leading to abnormal mesodermal development. Folliculin is a tumor-suppressor protein highly expressed in the stromal cells and type I pneumocytes of the lungs as well as in the skin and kidneys.25

Affected patients may be asymptomatic, but the most common presentation is skin papules, which histologically reflect fibrofolliculomas.26 The disease initially manifests itself in the patient’s third or fourth decade of life, and progresses with advancing age. Approximately 80% of patients with BHDS present with multiple lung cysts, but they may also have renal tumors, ranging from oncocytoma to renal cell carcinoma, as well as chorioretinal disease.27 The prognosis is based on the comorbidities, such as renal cell carcinoma or pneumothorax, rather than the lung cysts themselves. It is thought that the pulmonary involvement is more severe in patients with a smoking history.26

TSC-associated LAM and BHDS can both involve the lungs, skin, and kidneys; therefore, distinguishing the two disorders may be difficult. Findings that favor TSC-associated LAM include diffuse involvement of the lung parenchyma and associated central nervous system abnormalities.

Chest radiography in patients with BHDS may be normal. Chest CT scan most commonly demonstrates lentiform-shaped cysts that predominate in the lung bases and periphery.27 The intervening lung parenchyma is usually normal. The lung cysts usually abut or include the proximal portions of the lower lobe pulmonary arteries and veins (Fig 10). Like patients with other forms of cystic lung disease, patients with BHDS may have spontaneous pneumothorax.


L23Fig10

Figure 10. A 48-year-old woman with a diagnosis of Birt-Hogg-Dubé syndrome has shortness of breath. Chest CT scan shows multiple variably sized thin-walled lung cysts.


Amyloidosis
Amyloidosis is the result of extracellular deposition of insoluble fibrillar proteins (amyloid) in different tissues and organs. Amyloidosis most commonly has a systemic involvement, but a small percentage of patients can present with localized disease. There are two types of systemic amyloidosis: primary amyloidosis, which results from deposition of proteins secreted by lymphocytes and plasma cells; and secondary amyloidosis, which is associated with chronic inflammatory diseases, such as rheumatoid arthritis, Crohn disease, and cystic fibrosis.4

Amyloid deposition in the respiratory tract is common in both primary and secondary forms of systemic amyloidosis. Primary pulmonary amyloidosis, which can occur as a localized process or as part of a systemic disease, has four distinct forms: tracheobronchial form, pulmonary nodular form, diffuse parenchymal form, and senile form.28

Pulmonary amyloidosis associated with systemic disease has a poor long-term outcome after diagnosis.29 Patients with isolated pulmonary amyloidosis have a benign clinical course with a good prognosis. However, patients with the tracheobronchial form have worse morbidity owing to potential obstruction of the airways.29

Pulmonary cysts are a rare finding that has been reported on CT imaging in patients with amyloidosis. The cysts demonstrate thin walls and are usually located along the periphery of the lung parenchyma without an apicobasal gradient. Proposed pathophysiologic mechanisms of cyst formation include narrowing of the airway, disruption of the alveolar walls as a result of amyloid deposition, and ischemia from amyloid deposition around the capillaries.30

Multiple small lung nodules (with or without calcification) may also be present and rarely circumferential thickening of the tracheal wall is seen. Other CT findings of patients with pulmonary amyloidosis include interlobular septal thickening, honeycombing, ground-glass opacities, and lymphadenopathy.30

Pulmonary nodular amyloidosis has been reported to be associated with Sjögren syndrome. Affected patients may develop thin-walled pulmonary cysts associated with nodular calcifications. Half of these nodules abut the walls of the parenchymal cysts (Fig 11).30 Although the concomitant presence of pulmonary nodules and cysts suggests the diagnosis of LCH, when the cysts and nodules are randomly distributed and there are associated bronchiectasis and parenchymal opacities in a patient with Sjögren syndrome, pulmonary amyloidosis is the more likely diagnosis.


L23Fig11A

L23Fig11B

Figure 11. An 84-year-old man with a history of amyloidosis. Routine chest CT scan demonstrates a few thin-walled pulmonary cysts. Note the presence of A, associated nodules and B, nodular calcification of the walls.


Conclusions

Cystic lung diseases are rare entities characterized by multiple intraparenchymal pulmonary cysts. However, there are other more common causes of focal parenchymal lucencies that can mimic a lung cyst on both chest radiograph and chest CT. These entities include cavitary lesions, emphysema, bronchiectasis, and honeycombing. Clinical and radiographic features help distinguish the different causes of cystic lung disease and can also help exclude other processes before labeling a patient as having diffuse cystic lung disease. We recommend a multidisciplinary approach that takes into consideration the patient’s clinical history, physical examination, and radiologic findings. In some cases, certain clinical and radiographic features may eliminate the need for surgical lung biopsy. Imaging plays a vital role in making the correct diagnosis or at least in narrowing down the differential diagnosis. Chest radiography is both insensitive and nonspecific in detecting lung cysts, whereas chest CT scan remains the imaging modality of choice when evaluating these patients.


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