Cystic lung disease (CLD) is a group of lung disorders characterized by the presence of multiple cysts, defined as air-filled lucencies or low-attenuating areas, bordered by a thin wall (usually < 2 mm). The recognition of CLDs has increased with the widespread use of computed tomography. This article addresses the mechanisms of cyst formation and the diagnostic approaches to CLDs. A number of assessment methods that can be used to confirm CLDs are discussed, including high-resolution computed tomography, pathologic approaches, and genetic/ serologic markers, together with treatment modalities, including new therapeutic drugs currently being evaluated. The CLDs covered by this review are lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, Birt-Hogg-Dube syndrome, lymphocytic interstitial pneumonia/follicular bronchiolitis, and amyloidosis. Cysts and parenchymal lucencies that mimic cystic disease are typically defined by their appearance on high-resolution computed tomography. Cysts — A pulmonary cyst is defined as a “round parenchymal lucency or low-attenuating area with a well-defined interface with normal lung”
Parenchymal lucencies that may mimic cysts — Causes of lung parenchymal lucencies that may mimic cysts but do not fit the definition of true cystic lung disease include bullae, blebs, bronchiectasis, cavities, and pneumatoceles
● emphysema – Areas of emphysema appear as polygonal or rounded low-attenuation areas. A central dot representing the pulmonary artery contained within the secondary pulmonary lobule can sometimes be seen.
Emphysematous areas, by definition, lack walls. However, this distinction may be difficult to discern, as interlobular septa surrounding emphysematous areas of the lung may be misinterpreted as walls (image 1A-B). Some forms of atypical emphysema present as lucencies that are indistinguishable from cysts. Conversely, in advanced stages, cystic lung disease may coalesce into larger areas of low attenuation that mimic emphysema.
● Bulla – The term bulla refers to a region of focal lucency that is >1 cm in diameter, bounded by a thin wall (<1 mm), and usually accompanied by adjacent emphysema. Bullae can be isolated and vary in size, sometimes filling the hemithorax . A bleb is a type of subpleural bulla; the term bleb is now discouraged.
● Honeycombing – Honeycombing represents the advanced, destructive phase of a variety of fibrotic lung disorders that lead to enlarged airspaces with thick fibrous walls. On high resolution computed tomography (HRCT), honeycombing appears as clustered hypolucent areas ranging in diameter from 0.3 to 1.0 cm (but occasionally as large as 2.5 cm), with well-defined, often thick walls. Honeycombing areas tend to be subpleural, stacked together in contiguous rows, and sharing common walls. Associated radiologic features such as architectural distortion, subpleural reticular changes, and traction bronchiectasis further aid in distinguishing honeycombing due to pulmonary fibrosis from cystic lung disease.
● Bronchiectasis – Bronchiectatic cysts (also known as “cystic bronchiectasis”) can be differentiated from cystic lung disease based on their continuity with an airway, tendency to form clusters, and associated findings of tram lines and signet or Cabochon ring sign.
● Cavitary lung disease – Pulmonary cavities are typically thick-walled (>4 mm) gas-filled spaces often within an area of consolidation, mass, or nodule and may be filled with other contents in addition to air (eg, fluid, debris, mycetoma)
● Pneumatoceles – Pneumatoceles are a type of thin-walled parenchymal cyst. They most commonly arise in the setting of acute bacterial pneumonia, typically in children, but can also result from Pneumocystis jirovecii pneumonia, chest trauma, or barotrauma from mechanical ventilation. While usually few in number, pneumatoceles can occasionally be numerous and in such cases, can be confused with the more diffuse cystic lung diseases. Notably, pneumatoceles are typically asymptomatic and often disappear following the resolution of the inciting event.
CAUSES OF CYSTIC LUNG DISEASE
The majority of adults with cystic lung disease have one of four underlying diseases: lymphangioleiomyomatosis (LAM), pulmonary Langerhans cell histiocytosis (PLCH), Birt-Hogg-Dubé syndrome (BHD), or lymphoid interstitial pneumonia (LIP).
A separate category of cystic lung disease is associated with infectious etiologies; these patients typically present with acute onset of symptoms with fever and/or chills. Often the lung cysts are pneumatoceles that are caused by the infection (eg, coccidioidomycosis, hyperimmunoglobulinemia E syndrome, Pneumocystis jirovecii, recurrent respiratory papillomatosis, staphylococcal pneumonia)
Some common symptoms include:
• breathing difficulty
• pain with breathing
• shortness of breath
• recurrent pneumonia
Symptoms of cystic lung diseases may resemble other conditions or medical problems.
In the treatment of these pathologies, in addition to the specific treatment of each of them, complications must always be treated (pleurodesis in recurrent pneumothorax, specific treatment of pulmonary hypertension). Pulmonary transplantation is an option in the advanced stages of the disease.
Ignorance of the pathogenesis of many of these diseases makes specific treatment difficult . For example, in pulmonary Langerhans cell histiocytosis, since BRAF mutations have been described, vemurafenib treatment has been tested with promising results.
In the lymphangioleiomyomatosis, it is known that both sporadic and genetically modified mutations occur in tumor suppressor genes: TSC1 (encoding hamartin) and TSC2 (encoding tuberin), leading to abnormal activation of the signaling pathway of mammalian target of the rapamycin (mTOR), responsible for regulating cell growth, proliferation, migration and cell survival. That is why mTOR inhibitors (sirolimus, everolimus) are used in the treatment of this disease, demonstrating improving lung function and improving the quality of life, but further studies are needed to know the dose, duration and side effects of this treatment.
In the Brit-Hogg-Dube syndrome, numerous mutations have been described (in the FLCN gene) that also produce an alteration in TOR signaling, although it is not known whether the active or inactivated signaling, nor what is the role of mRT in the pathogenesis of the illness.
What do we not know about cystic lung disease?
In summary, we have to know how to differentiate true cystic lung diseases from other pathologies and the spectrum of diseases to be considered. It is important to know that the localization, size, and cyst morphology as well as the clinic characteristics can help us to guide the diagnosis. We also have to know when we have to perform invasive tests to confirm the diagnosis and how to treat these diseases. Finally, it is essential what we do know about cystic lung diseases in order to better management of the patients suffering these diseases.