Accepted Manuscript

Cystic Lung Diseases: Algorithmic Approach

Suhail Raoof, MD, Praveen Bondalapati, MD, Ravikanth Vydyula, MD, Jay Ryu, MD,
Nishant Gupta, MD, Sabiha Raoof, MD, Jeff Galvin, MD, Mark J. Rosen, MD, David
Lynch, MD, William Travis, MD, Sanjeev Mehta, MD, Richard Lazzaro, MD, David
Naidich, MD

PII: S0012-3692(16)48812-4
DOI: 10.1016/j.chest.2016.04.026
Reference: CHEST 456

To appear in: CHEST

Received Date: 6 July 2015

Revised Date: 16 February 2016
Accepted Date: 6 April 2016

Please cite this article as: Raoof S, Bondalapati P, Vydyula R, Ryu J, Gupta N, Raoof S, Galvin J, Rosen
MJ, Lynch D, Travis W, Mehta S, Lazzaro R, Naidich D, Cystic Lung Diseases: Algorithmic Approach,
CHEST (2016), doi: 10.1016/j.chest.2016.04.026.

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 ACCEPTED MANUSCRIPT

Cystic Lung Diseases: Algorithmic Approach

Suhail Raoof, MD, Praveen Bondalapati, MD, Ravikanth Vydyula, MD, Jay Ryu, MD,
Nishant Gupta, MD, Sabiha Raoof, MD, Jeff Galvin, MD, Mark J. Rosen, MD, David Lynch,
MD, William Travis, MD, Sanjeev Mehta, MD, Richard Lazzaro, MD, David Naidich, MD

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Conflict of Interest: DL is a consultant to Parexel, Inc., Boehringer Ingelheim, Inc.,
Genentech, Inc., Gilead, Inc. and Veracyte, Inc. He has received support from Parexel, Inc.
Siemens, Inc. and NHLBI. DN is a consultant to Siemens Medical, Inc. for their development

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of a computer assisted detection (CAD) device. All others declare no conflicts of interest.

Abstract

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Cysts are commonly seen on CT scans of the lungs, and diagnosis may be challenging.
Clinical and radiographic features combined with a multidisciplinary approach may help

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differentiate among various disease entities, allowing correct diagnosis. It is important to
distinguish cysts from cavities as they each have distinct etiologies and associated clinical
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disorders. Conditions like emphysema, honeycomb lung and cystic bronchiectasis may also
mimic cystic disease. A simplified classification of cysts is proposed. Cysts may be present in
greater profusion in the sub-pleural areas, when they typically represent paraseptal
emphysema or bullae. Cysts present in the lung parenchyma but away from sub-pleural areas
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may be classified as simple, i.e. without any other abnormalities on high resolution CT scans
(HRCT). These are further categorized into solitary or multifocal/diffuse cysts. Multifocal
cysts may be seen with lymphocytic interstitial pneumonia, Birt-Hogg-Dub syndrome,
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tracheobronchial papillomatosis or primary and metastatic cancers. Multifocal cysts may be

associated with nodules (lymphocytic interstitial pneumonia, light chain deposition disease,
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amyloidosis, and Langerhans cell histiocytosis) or with ground glass opacities (Pneumocystis
jiroveci pneumonia and desquamative interstitial pneumonia). Using the results of the HRCT
as a starting point, and incorporating the clinical history, physical examination and laboratory
findings are likely to narrow the differential diagnosis of cystic lesions considerably.
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Introduction

A pulmonary cyst is a round air space defined pathologically by an epithelial or fibrous

outer wall, and radiographically as a round parenchymal lucency or low-attenuating
area with a well-defined interface with normal lung.1 Cysts are common in otherwise
normal individuals, but may occur in association with other lung diseases. (Figure1)

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Cysts must be differentiated from pulmonary cavities. A cavity is a discrete air and/or
fluid containing space identifiable as a focal lucency or low-attenuation area when air-
filled, frequently identified as an isolated lesion or lesions, (s) or in association with
pulmonary consolidation and/or mass (Figure.2). Most importantly, in distinction to

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cysts that by definition have thin walls (<2 mm), cavities characteristically present with
a wall thickness >4 mm.1

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Pulmonary parenchymal cysts are seen commonly on computed tomographic (CT) scans
and the differential diagnosis may be challenging. Regardless of the cause of cysts,
patients usually present with either no symptoms, the cysts discovered on chest imaging

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for another reason, or with nonspecific symptoms like cough and shortness of breath.
However, careful review and characterization of the radiographic abnormalities coupled
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with assessment of clinical and laboratory features that may point to an underlying
pulmonary or systemic disease is very helpful in distinguishing among numerous
possibilities to arrive at the correct diagnosis. This article presents a classification of
cysts allowing for a simplified algorithmic approach to diagnosis.
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Lung cysts can be conveniently divided into 4 specific categories based on their location,
number, distribution and associated CT findings. These include:
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1. Sub-pleural cysts - either solitary or multifocal

2. Parenchymal cysts without associated HRCT findings, either solitary or multiple
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3. Parenchymal cysts seen in association with nodules

4. Parenchymal cysts seen in association with ground-glass attenuation

Each of these categories carries a limited number of diagnostic possibilities, and

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differentiating them may be relatively straight forward.

Sub-pleural cysts are usually bullae or paraseptal emphysema. These need to be

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differentiated from honeycomb changes. Parenchymal cysts may be solitary - frequently

the sequelae of prior infections, rarely from metastatic disease to multifocal lesions
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including lympangioleiomyomatosis/tuberous sclerosis (LAM/TS). Cysts associated

with discrete lung nodules may be seen with lymphocytic interstitial pneumonits (LIP),
amyloidosis, or less frequently in light chain deposition disease (LCDD) and pulmonary
Langerhans cell histiocytosis (PLCH). Finally, cysts may be seen in association with
diffuse ground-glass attenuation, as occurs in patients with a variety of infections
including Pneumocystis jirovecii pneumonia, and less commonly in patients with diffuse
lung diseases like desquamative interstitial pneumonia (DIP).

Table.1 highlights the radiographic and clinical features of the cystic lung diseases.
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Sometimes a disorder can be included in more than one category. For example, PLCH may
present as diffuse cystic disease lung with nodules, or without any other radiographic
abnormalities. In some cases, cysts and cavities may both be present. Although overlap
may be anticipated employing this classification we emphasize a multimodality approach
to diagnosis. Central to this algorithmic approach is the role of high-resolution CT (HRCT)

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imaging as the starting point. HRCT produces images of great clarity and detail in
different orientations, and is critical in the diagnostic evaluation.2, 3 In this regard,
obtaining contiguous 1 or 1.5 mm sections using an edge-enhancing algorithm
throughout the thorax in a single breath-hold is essential. This will precisely define the

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walls, extent and distribution of lucent lung lesions, and also generate high quality-
coronal and sagittal image reconstructions. High resolution CT studies should be
performed with volumetric image acquisition during a single breath hold with contiguous

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1-2 mm images obtained through out the lungs using a high resolution/edge enhanced
reconstruction algorithm. Images obtained utilizing this technique are especially valuable
for showing the relationship between cysts and peripheral airways. Images in exhalation

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may also be valuable to identify focal or diffuse air trapping or morphological changes in
the central airways and parenchymal cysts. A critical review of HRCT features can reveal
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patterns that are diagnostic in a large proportion of patients with cystic lung disease. In a
recent analysis, expert radiologists were able to correctly assign the diagnosis of cystic
lung diseases in 80% of cases based on review of HRCT features alone.4,5
This article is not intended to be an exhaustive review of all cystic lung disease; however,
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it encompasses the majority of cysts encountered in clinical practice. For the sake of
completion, we have tabulated rare causes of cystic lung disease that are not covered in
this algorithm. (Table 2). We have included uncommon disorders where cystic
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abnormalities are common (e.g. Birt-Hogg-Dub syndrome), and excluded more

common diseases where cystic abnormalities are uncommon (e.g. hypersensitivity
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pneumonitis). For example, hypersensitivity pneumonitis may exhibit cysts in up to 10%

cases;13 we chose to exclude atypical manifestations in this algorithm. We have also
excluded congenital pulmonary airway malformation, a rare condition in which cysts
communicate with small airways or bronchioles in only one of its five classes. We do not
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include cystic bronchiectasis in this classification because the air spaces do not have true
walls. Regardless, some patients with otherwise typical radiographic and clinical
features may still require a biopsy to establish a diagnosis.
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Systematic Approach to Cystic Lung Disease

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A summary of the systematic approach to cystic lung disease is given in Figures. 6 and 7

Step 1 : Are there true cystic lesion(s)?

The first step is to determine that we are dealing with a true cystic lung disease by
distinguishing the radiographic abnormalities from cavities, centrilobular and
panlobular emphysema, cystic bronchiectasis and honeycombing. These conditions are
characterized as follows: (Figure.8)
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A cavity is a gas-filled space, seen as a lucency or low-attenuation area with a

wall thickness of >4 mm seen within pulmonary consolidation, a mass, or a
nodule. 14,15, (Figure.2)
Centrilobular emphysema is visualized on HRCT scans as centrilobular
lucencies that lack distinct walls, measure up to 1 cm in diameter and have a

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predilection for the upper lung zones (Figure.9). Many of these luciencies show a
central dot that is a branch of the pulmonary artery within the secondary lobule
14,16,17

Panlobular emphysema involves all portions of the acinus and secondary

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pulmonary lobule more or less uniformly14 (Figure.10). -1 antitrypsin deficiency
is suggested by panlobular emphysema in predominantly lower lung zone

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distribution.
Cystic bronchiectasis is typically associated with bronchial dilatation adjacent
to the accompanying pulmonary artery (signet-ring sign), absence of tapering of
bronchi, and identification of bronchi within 1 cm of the pleural surfaces. There

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may be accompanying bronchial wall thickening, tree-in-bud (TIB) opacities and
mosaic pattern (Figure.11). Coronal images or sequential axial images help
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distinguish cystic bronchiectasis from true cysts.14,18
Honeycombing results from advanced and irreversible fibrotic lung disease that
may lead to cysts that are typically 3-10 mm diameter, clustered (the walls of the
cyst abut each other), with thick walls (1-3 mm or larger), with architectural
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distortion and reticulation of intervening lung. ( Figure.5)14

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Step 2: Are the cysts located in the sub-pleural areas? (Figure. 12)
The next step is to see if the cysts are located primarily in the sub-pleural areas. If so,
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the differential diagnosis includes bullae and paraseptal emphysema

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1. Paraseptal emphysema (Figure. 3)

This subtype of emphysema involves distal alveoli, including alveolar ducts and sacs. The
cysts are discrete, thin-walled, and multiple. The cyst walls do not abut each other;
rather they are characteristically bound by pleural surfaces and interlobar septa. They
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are seen as radiolucent abnormalities ranging from a few mm to 1 cm in diameter in sub

pleural and peri-bronchovascular distribution with predominance in the dorsal surfaces
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of lung. 14,16,17 As opposed to honeycombing, the lung architecture is well preserved. The
coalescence of cysts in paraseptal emphysema leads to formation of bullae. A bleb is a
small gas-containing space within the visceral pleura or in the sub pleural lung, not
larger than 1 cm in diameter, usually not seen on chest radiographs14 The Fleischner
Society recommends blebs be considered as focal paraseptal emphysema.

Depending upon the extent of pulmonary involvement, patients with paraseptal

emphysema are usually asymptomatic, although exertional dyspnea may be present.
Infrequently it can present with spontaneous pneumothorax17 . Pulmonary function tests
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(PFTs) are generally normal, but airflow obstruction and reduced diffusing capacity can
be seen when other forms of emphysema are present.17

2. Bullae (Figure.4)
A bulla is a rounded focal lucency or area of decreased attenuation 1 cm or more in
diameter, bounded by thin, almost imperceptible wall; it may be formed by the

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coalescence of cysts of paraseptal emphysema. 14 They can enlarge over time and
compress normal lung causing vanishing lung syndrome. Bullae can present with
spontaneous pneumothorax, hemoptyis or infection Patients may present with dyspnea
on exertion, especially if the bullae are large or profuse. 19 PFTs usually reveal mild

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airflow flow obstruction and decreased diffusion capacity but large bullae may present
with restrictive spirometry caused by a large volume of non-communicating air
spaces.20,21 (This may be detected by increased lung volume measurents by body

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plethysmography.21 Primary bullous disease, seen in patients with Ehlers-Danlos or
Marfan syndrome, typically does not demonstrate an obstructive picture on PFTs. 20
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Step 3: Are cysts detected in LUNG PARENCHYMA without other radiographic
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abnormalities?(Figure.13)

If so, lung parenchymal cysts can be classified into:

solitary or incidental
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focal, multifocal or diffuse

Solitary (single) cysts are usually randomly distributed. In many instances, they are
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discovered in images obtained for other reasons. Focal disease is defined as more than
one cyst in one lobe of the lung, while multifocal disease involves more than one lobe of
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but does not involve all the lobes. Diffuse is defined as involving all five lobes of the lung.
Within the category of diffuse involvement, there may be a greater profusion of cysts in
one zone of the lung. For example, PLCH is considered a diffuse disease, even though it
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has a predilection for the upper and middle lobes.

Are the Lung Parenchymal Cysts Solitary? (Figure. 14)

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Examples of solitary cysts include:

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1. Incidental Cysts (Figure.15)

In a study of asymptomatic individuals evaluated by CT scan of chest 22, cysts were
discovered in about 25% of patients over 75 years of age, and almost never caused
symptoms. These cysts are equally prevalent among smokers and non-smokers,
distributed uniformly in all lobes of lungs and were on an average of 10 mm in size,
raising the possibility that they may represent part of the normal aging process. Of note,
none of the patients younger than 55 years demonstrated cysts on their HRCT scans22. A
single cyst may also be the remnant of a previous infection or trauma.
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2. Pneumatocele (Figure.16)
A pneumatocele is a transient, thin-walled, gas-filled space in the lung. It is most
frequently caused by acute pneumonia, trauma, or aspiration of hydrocarbon fluid and is
usually transient. The mechanism is believed to be a combination of parenchymal
necrosis and check-valve airway obstruction.14 It can be distinguished from other cysts
by its transient nature and relevant history such as pneumonia or trauma.

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3. Bronchogenic Cyst (Figure.17)
Bronchogenic cysts arise from abnormal budding of tracheobronchial tree during lung
development.23 While they commonly present as middle mediastinal masses,24 they

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can also present as lower lobe intra-parenchymal masses in about a third of cases. These
are most commonly filled with fluid. Air-filled intra-parenchymal cysts are rare.
On CT scan, it presents as a cyst with well-defined boundaries and attenuation of water

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or soft tissue.23

Are there more than one (or several, or many) lung parenchymal cysts?

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(Figure.18)
1. Birt-Hogg-Dub syndrome (BHD) (Figure. 19a,b)
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BHD is the term for an autosomal dominant syndrome characterized by cutaneous
fibro-folliculomas (Figure. 20), multiple lung cysts, spontaneous pneumothorax, and
renal cancer.25 HRCT findings of lung include multiple, thin-walled cysts in over 80%
patients, predominantly seen in peripheral lung zones at lung bases and along the
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mediastinum.4 These cysts are unique in that they either abut or encase the proximal
portion of the lower pulmonary veins. The cysts are less profuse compared with LAM,
and intervening lung parenchyma is normal. Spontaneous pneumothorax occurs in
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approximately 24% of persons with BHD.25 These lesions usually appear after the age
of 20 years. Renal cancer occurs in approximately 25% patients with this disorder25.
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2. Lymphocytic Interstitial Pneumonia (Figure.21)

This disease may present with randomly distributed, thin-walled cystic air spaces
(68%) some of which may be up to 30 mm, involving and usually affecting less than
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10% of the lung . Of note, this entity may also present with diffuse ground-glass
opacities, poorly-defined centrilobular nodules (100%), and perilymphatic nodules
mimicking lymphangitic spread of carcinoma (86%). A more detailed description is
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included under cysts with nodules.

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3. Tracheobronchial papillomatosis (Figure. 22)

HRCT findings show lesions in the larynx and trachea. Lung manifestations include
nodules which that are solid or cystic with thin or thick walls. The homogenous small
nodules progress to cystic lesions, which are distributed randomly in central,
peripheral, and occasionally in sub-pleural locations. 26 Juvenile papillomas
commonly occur in the larynx but can involve the lung by direct extension from
larynx. Lung involvement occurs after about 1012 years of diagnosis of laryngeal
papillomas. 26,27 The most common initial presenting symptoms are hoarseness of
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voice and cough. Most patients have a history of undergoing multiple endoscopies and
for resections of papillomas, and tracheostomies. Complications include respiratory
infection, sepsis and death.

4. Malignancy (Figure. 23)

Lung cancer

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Cavitation of primary lung cancer is common, detected in 7 -11% of patients by
chest radiographs and up to 22% by CT scan28 . If the wall is > 15 mm thick, there
is a 90% probability that a cavity is malignant.29 However, lung cancer presenting
with thin-walled cysts is described. 30,31

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Metastatic cancer

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In metastatic adenocarcinoma, cavities may rarely develop. The walls of cavities
in some cases become thin from inflation by a ball valve mechanism,
transforming them into true cystic lesions.15 Cysts iinn squamous carcinoma may

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result from cornification of squamous epithelium in the center of the lesion with
subsequent liquefaction and evacuation into small airways; these lesions appear
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most frequently in the upper lobes.32
Cystic metastasis may be considered when there is a history of squamous cell
cancer, and especially with head and neck primary tumors 32. Thin- walled cystic
lesions are seen occasionally within cavtary metastases from seminoma, Ewing
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sarcoma, myxosarcoma, Wilms tumor, osteogenic sarcoma, angiosarcoma,

transitional cell carcinoma, teratocarcinoma, and sarcoma of unknown type,32,33
If cystic lung lesions are seen in patients with a known malignancy, metastatic
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disease should be suspected, and tissue diagnosis may be needed to establish the
diagnosis.
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5. Infections (Figure. 24)

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Cystic lesions may be seen in many pulmonary infections. Chest CT scans in

patients with P. jiroveci pneumonia often disclose multiple pulmonary cysts,
predominantly in the upper lobes. Commonly the cysts are associated with
ground glass opacities. Occasionally these cysts rupture and lead to
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pneumothorax. While tuberculosis causes cavities that usually resolve with

treatment, they can persist as cystic lesions. Atypical mycobacterial infections can
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also cause thin-walled cystic lesions. Lung cysts can be seen in paragonimiasis,
echinococcosis and coccidioidomycosis. 27

6. Lymphangioleiomyomatosis (LAM) (Figure. 25)

HRCT shows numerous thin-walled (from imperceptible up to <4 mm) cysts

surrounded by normal-appearing lung parenchyma. Unlike PLCH, cysts caused by
LAM are distributed throughout the lung. Other findings include spontaneous
pneumothorax (69%) and chylothorax (23%).2
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LAM is seen almost exclusively in women of childbearing age. Occasionally it may be

seen in postmenopausal women. Most common symptoms are slowly progressive
dyspnea, spontaneous pneumothorax, hemoptysis, chylothorax or chylous ascites.
Uterine fibroids and renal angiomyolipomas are also seen. 34,35.

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LAM may occur sporadically, or is associated with with tuberous scerlosis (TSC-LAM).
In TSC-LAM, the HRCT may show diffuse nodular changes along with thin walled
cysts.36 TSC- LAM may involve the central nervous sytem (hamartomas,
developmental delays, seizures), and skin (hypomelanic macules, ash leaf spots,

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shagreen patches on the lower back or nape of neck, subungal fibromas, skin tags, and
caf-au-lait spots), and eye involvement (retinal phacomas). TSC-LAM occurs almost
in a third of patients with tuberous sclerosis, but is less severe than sporadic LAM.

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Tuberous sclerosis may also be associated with another pulmonary disorder called
multifocal micronodular pneumocyte hyperplasia (MMPH), a hamartomatous process
of the lung that is associated with multiple tiny pulmonary nodules. 36 Sporadic LAM is

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associated with renal angiomyolipomas (Figure. 26). It is almost exclusively seen in
women.36
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7. Pulmonary Langerhans Cell Histiocytosis (PLCH) (Figure. 27)
PLCH is a rare disease of lung and other organs characterized by accumulation of
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Langerhans cells and other inflammatory cells in small airways resulting in formation of
inflammatory nodules.37 . (Figure.28) HRCT findings vary according to the stage of
disease. Nodules are seen in early stages and cysts are seen in later stages. Cysts are
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usually thin walled ranging in size from 1 to 20 mm in early stages. These can progress
to form thick, irregular walled, bizzare-shaped cysts. There is relative sparing of the lung
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bases and costophrenic angles.37,38 PLCH is seen commonly in young adult smokers
between the ages of 20 and 40 years, with no gender predilection. 39 Most patients with
PLCH are asymptomatic, but cough and dyspnea are common, and pneumothorax may
occur in about 15% of patients. Systemic symptoms like weight loss, fatigue may be seen
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in a few patients.40 Diabetes insipidus (polydipsia and polyuria), pain due to skeletal
involvement and skin rashes are extra pulmonary manifestations of the disease. 37,38
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Step 4: Are the Lung Parenchymal Cysts Associated with Nodules? (Figure.29, 30)
If so, the differential diagnosis includes lymphocytic interstitial pneumonia (LIP), light
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chain deposition disease (LCDD), amyloidosis and PLCH . Some conditions may be
classified in more than one category. LIP and PLCH, are associated with cysts and
nodules in some cases and predominantly cysts in others. PLCH, depending upon the
stage of evolution of disease, may be concentrated in the upper and middle lobes and
may be associated with nodules without cysts.

1. Lymphoid Interstitial Pneumonia (LIP) (Figure.21)

LIP is a benign lymphoproliferative disorder limited to the lung, characterized
pathologically by lymphocytic and plasma cell infiltration of alveolar and interlobular
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septa. CT chest findings in LIP include alveolar opacities, ground glass attenuation
(mostly diffuse), poorly defined centrilobular nodules, small sub-pleural nodules,
thickening of bronchovascular bundles in a patchy distribution, interlobular septal
thickening and mediastinal and hilar lymphadenopathy.41,42, Cysts in LIP are
random in distribution, although they may have a basilar or perivascular
distribution. They involve less than 10% of lung parenchyma, are thin walled and

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range in size from 1 30 mm and are seen in approximately 50% cases.42

LIP is more common in women than in men (2.5-3: 1) and is most commonly seen in
fourth and sixth decade of life. 43 Idiopathic LIP is rare. Most commonly LIP is

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associated with connective tissue diseases (Sjgren syndrome, rheumatoid arthritis,
system lupus erythematosis, immune deficiency states such as HIV infection and
common variable immunodeficeiency, infections, drug exposure, and allogeneic

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hematopoietic stem cell transplants.41 Most common symptoms are cough, fatigue,
dyspnea and chest pain.44

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2. Light-chain deposition disease (LCDD) (Figure. 31)
Light-chain deposition disease (LCDD) is a rare disorder of middle-aged patients
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(mean age of 67 years) characterized by deposition of monoclonal immunoglobulin
light chain in various organs including kidneys, lungs, skin, joints, or blood vessels.33
(Figure.32)Seventy five percent of LCDD cases occur in association with multiple
myeloma or macroglobulinemia.45 HRCT manifestations commonly include nodules,
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lymphadenopathy, and cysts.46,33 Cyst formation is believed to correspond to dilation

of the small airways. The cysts are thin walled, round and measure up to 2 cm in size.
The associated nodules are irregular, multiple and can be bilateral or unilateral.
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Patchy areas of consolidation can also be seen.47 Although lung involvement is rare,
LCDD can result in respiratory failure and may require lung transplantation.48
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3. Amyloidosis (Figure. 33)

Amyloid deposition in the lungs can present with large thin walled cysts with
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internal septae abutting bronchiocentric nodules. The cysts may have a peripheral
predilection. The nodules in nodular pulmonary amyloidosis tend to be localized to
lower lobes and sub-pleural areas. The nodules have sharp, smooth lobulated
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contours, varying in size from 0.5 15 cm, with slow growth and often central
cavitation or calcification.49. Amyloidosis of the lung tends to occur in the 6th decade
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of life, commonly in association with Sjogrens syndrome (with or without LIP),

lymphoproliferative disease or mucosa-associated lymphoid tissue (MALT)
lymphoma.50 Depending on the type of amyloidosis, clinical manifestations may
include: a) tracheobronchial form causing diffuse or focal tracheal narrowing; b)
nodular form with lung parenchymal nodules that may be rather large; c) diffuse
form with resultant miliary nodules, reticulonodular opacities and honeycombing.
.When symptomatic, dyspnea on exertion is the most common symptom followed by
cough, wheezing, hemoptysis, and recurrent pneumonia. .
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4. Pulmonary Langerhans Cell Histiocytosis (Figure. 27)

Irregular, generally small nodules may be visible initially. With disease progression,
the nodules cavitate, giving rise to thick- and thin-walled, sometimes bizzare shaped
cysts and cavities. A more detailed description is included under the category of
diffuse disease

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Table 4: HRCT features of cystic lung diseases associated with nodules

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Step 5: Are Cysts associated with Ground Glass Opacities? (Figure.34)

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The differential diagnosis includes Pneumocystis jirovecii pneumonia (PJP) and
desquamative interstitial pneumonia (DIP)

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1. Pneumocystis jirovecii Pneumonia (PJP) (Figure. 35)
PJP is still the most common opportunistic pulmonary infection in patients with HIV
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infection. CT features of PJP include extensive ground glass opacities or dense air-
space disease in central and peri-hilar distribution along with septal wall thickening.
Cystic lesions of the lung are relatively common, occurring on HRCT in up to 34%
cases.51 Cysts are multiple with upper lobe predominance and vary in size, shape and
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wall thickness. Cysts may rupture and cause pneumothorax that is often difficult to
treat. Disease in secondary pulmonary lobules alternating with normal lobules
appear in , and presenting a striking contrast on HRCT, referred to as crazy paving.
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(Figure. 36)
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2. Desquamative Interstitial Pneumonia (DIP) (Figure. 37)

DIP usually occurs in patients 40-60 years of age, presenting with non-specific
symptoms like shortness of breath and cough. It occurs more in men than women
(2:1) and 90% of cases occur in smokers. However, it may be associated with other
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conditions, including inhalation of inorganic particles, connective tissue disease,

rheumatoid arthritis, Sirolimus and the heavy use of marijuana.52
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The characteristic CT findings are ground glass attenuation seen most prominently in
lower lung zones and subpleural regions. Unlike the honeycomb appearance of
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advanced fibrotic lung disease, cysts in DIP have imperceptible walls, mostly discrete
but occasionally can be clustered and are surrounded by ground glass opacities.4 The
lung architecture is well preserved and traction bronchiectasis is rare. 53,54 Cystic
lesions seen in DIP may represent dilatation of bronchioles, and can disappear
spontaneously or with treatment.

Presence of small cysts within areas of ground-glass opacity is a unique feature of DIP
and may be seen in approximately a third of patients with this disease. 18
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.
Summary

In this review, we provide a systemic approach to help clinicians in the diagnosis of

cystic lung disease. Rather than classify each diagnosis in a single category, we have
taken the most common presentations of each entity and placed them in one or

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more categories. Characteristics of cysts on HRCT imaging, taken together with
clinical features are helpful in guiding diagnostic and management strategies. First,
we differentiate cysts from cavities, panlobular and centrilobular emphysema,
honeycombing and cystic bronchiectasis. The next step is to classify true cystic

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lesions by location into subpleural and parenchymal cysts. Subpleural cysts are
commonly caused by paraseptal emphysema, bullae, and blebs. Parenchymal cysts
are further classified into three groups based upon whether they are the only HRCT

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abnormality or whether they are associated with nodules or ground glass opacities.

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Table 1:Definitions and radiographic features of conditions included under cystic lung disease
Condition Description Wall thickness (mm) Other features

Cyst (Figure 1a) A round parenchymal lucency or low- Thin-walled (<2 mm) Not associated with pulmonary

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attenuating area exhibiting a well- emphysema. May rarely contain
defined interface with normal lung and fluid or solid material.

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usually containing air

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Bulla (Figure 11 ) A rounded focal lucency or area of Thin walled, usually<1 Often accompanied by emphysema

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decreased attenuation measuring >1 mm in the adjacent lung
cm (usually several centimeters).

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Paraseptal Sub-pleural and peribronchovascular No walls Bounded by pleural surface and

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emphysema (Figure regions of low attenuation separated by interlobular septa. Rest of lung

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12) intact interlobular septa, sometimes architecture preserved.
associated with bullae. Centrilobular emphysema may be
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present

Honeycombing Closely approximated ring shadows 3- 1-3 mm Late stage of various lung diseases,
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(Figure 13 ) 10 mm in diameter, usually sub-pleural with complete loss of acinar

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with well-defined walls. architecture

The radiological definitions have been taken from the Fleischner Society (Glossary of terms for thoracic imaging. Radiology.
2008)
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Table. 2 :Description of HRCT features of rare cystic lung diseases R1

Condition HRCT features

HP Centrilobular ground glass nodules with mosaic attenuation and airways involvement.7
In<10% of cases of HP, cysts are seen. These are usually few in number and random in distribution.
Diffuse multiple thin-walled cysts and small ill-defined nodules exhibiting a perilymphatic pattern in bilateral lung fields. 7

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MALToma

Follicular Bronchiolitis Small centrilobular nodules with occasional peribronchial nodules and areas of ground glass opacity. It is included in the same

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category of lymphoproliferative diseases as lymphocytic interstitial pneumonia (LIP). IN FB, a major distinguishing feature from LIP
is that the findings are confined primarily to the interstitium and that ground glass opacities are uncommon. 8,9

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Lymphomatoid Small thin walled cysts, small lung nodules distributed in peribronchovascular (core) areas , coarse irregular opacities and mediastinal
nodal enlargement . 10
granulomatosis

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Ankylosing Spondylitis Upper lobe predominant with apical fibrosis, associated interstitial lung disease and bronchiectasis. Seen in 10% of patients with
ankylosing spondylitis . 11

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Neurofibromatosis Numerous upper lobe predominant cysts seen bilaterally. Cysts more commonly seen in smokers.

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Proteus Syndrome Rare syndrome characterized by vascular malformations and asymmetric post natal overgrowth of connective tissues. Thin and thick
walled cystic changes, as well as emphysematous enlargement of air spaces can be seen in approximately 10% of patients with Proteus

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Syndrome.
Ehlers-Danlos Syndrome Rare genetic disorder of connective tissues characterized by skin hyperextensibility, joint hypermobility, and tissue fragility. Multiple

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parenchymal cysts and cavities can rarely be seen in patients with Ehlers-Danlos syndrome.

Fire-Eaters lung Chemical pneumonitis resulting from accidental aspiration of petroleum products. Cystic changes in lung parenchyma represent
pneumatoceles, and typically follow a benign course leading to resolution in a few weeks.
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Hyper-IgE syndrome Primary immunodeficiency condition characterized by multiple skin and sino-pulmonary infections, and an elevated IgE level. Lung
cysts likely represent pneumatoceles secondary to staphylococcal infections.
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CPAM Presents as cystic or solid lung masses. The types of CPAM, based mainly on the size of the cysts, are 12
Type 1(70%): most common type, with large cysts (2-10mm).
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Type 2(20%): small uniform cysts, 0.5-2cm in diameter, associated with air-filled multicystic masses or focal areas of consolidation.
Type 3(10%): poor prognosis, lesions are visualized as multiple cysts less than 2 mm in size that usually involve entire lobe of the
lung.
Type 4: These are very large cysts, sometimes 10 cm in size or larger ,usually affecting one lobe.

These are either rare or uncommon manifestations of cystic lung diseases that are not discussed in this paper
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Slide 1

R1 I dont know if praveen went thru this references, I have changed the ref number on HP to 7 as indicated in the manuscript
Ravi, 28-12-2015

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HP : Hypersensitivity Pneumonitis

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MALToma: Mucoid Associated Lymphoid Tissue Lymphomas
CPAM: Congenital Pulmonary Airway Malformation

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Table 3: Radiographic, clinical and pathological characteristics of of tuberous sclerosis associated and sporadic
Lymphangioleiomyomatosis

TSC-LAM Sporadic LAM

Radiology HRCT may show diffuse nodular lesions

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Thin walled cysts surrounded by normal
along with thin walled cysts especially when parenchyma. 36
MMPH coexists. 36

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Severity (clinical s/s) Less severe More severe

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Genetic predisposition Familial Occurs Sporadically

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Associated Findings - CNS (hamartomas, developmental Renal angiomyolipomas . 34,35
delays, seizure disorder)

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- Skin (hypomelanic macules, ash leaf

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spots, Shagreen patches on the lower
back or nape of neck, subungal
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fibromas, skin tags, and caf-au-lait
spots)
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- Eye (retinal phacomas)

- Hepatic and renal angiomyolipomas
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MMPH: Multifocal Micronodular Pneumocyte Hyperplasia

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TSC-LAM: Tuberous sclerosis associated Lymphangioleiomyomatosis,
Sporadic LAM: Lymphangioleiomyomatosis,

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Table.4: Salient features of cystic lung diseases associated with nodules:

Characteristics of nodules seen in Cystic Diseases R2

LIP Centrilobular, ill-defined ground glass nodules, more profuse in sub-pleural

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regions, demonstrating a patchy distribution

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LCDD Nodules are irregular, multiple and can be bilateral or unilateral

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Amyloid The nodules tend to be localized to lower lobes and sub-pleural areas. They

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have sharp, smooth lobulated contours, varying in size from 0.5 15 cm, with
slow growth and often central cavitation or calcification

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PLCH Irregular mainly in upper and middle lobes, sparing the costophrenic angles
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LIP: Lymphocytic interstitial pneumonia, LCDD: Light chain deposition disease, PCLH:
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Pulmonary Langerhans cell histiocytosis

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R2 Do we need to have figure numbers here?

Ravi, 28-12-2015

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Figure 1a: True cysts: Round parenchymal lucencies surrounded by distinct wall < 2mm in
thickness , exhibiting a well-defined interface with normal lung tissue. Cysts are common in
otherwise normal individuals, but may occur in association with other lung diseases.

Figure 1b: Cavity. This is a gas-filled space, seen as a lucency or low-attenuation area, with a

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wall thickness of >4 mm. It is seen within pulmonary consolidation, a mass, or nodule.

Figure 2: Tracheobronchial papillomatosis: Please note that thin walled cysts may compress

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portions of the lung giving the spurious impression of asymmetric wall thickening

Figure 3: Traumatic Pneumatocele: Thin-walled, gas-filled space in the lungs, usually transient

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can be caused by acute pneumonia, trauma, or aspiration of hydrocarbon fluids. In this
illustration, there are adjacent areas of increased parenchymal density from lung contusion

Figure 4: Minimum Intensity Projection Imaging (MINiP) Imaging. A,B. Sequential coronal

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images through the posterior aspect of the lungs show extensive cystic bronchiectasis within the
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right apex and the entire left lower lobe. With MINiP projection image, only those voxels with
the lowest density in any row are projected in two dimensions, effectively eliminating all high
density structures, including most pulmonary vessels. Note that there is also evidence of mosaic
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lung attenuation identifiable as alternating geographical areas of low and higher lung density,
indicative of extensive air-trapping in this case due to associated obstructive small airway
disease. These changes are seen to especially good advantage using a MINiP technique
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Figure 5: A four step approach to managing cystic lung disease

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Figure 6: Detailed algorithmic approach to cystic lung disease. It is important to exclude mimics
of cystic lung disease before proceeding with the actual algorithm
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Figure 7: An algorithm showing the mimics of cystic lung disease along with their radiographic
and clinical features
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Figure 8: Centrilobular Emphysema: These luciencies demonstrate a predilection for the upper
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lung zones. Centrilobular lucencies are seen that lack distinct walls and measure up to 1 cm in
diameter. The luciencies may have a dot in the center, representing a branch of pulmonary artery.

Figure 9: Cystic bronchiectasis. Non-tapering tubular structures which course peripherally to

within 1 cm of pleural surface. The contiguity of these dilated bronchi can be appreciated on
adjacent transverse sections of airways and on coronal planes, distinguishing them from true
individual cysts
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Figure 10: Diagnostic algorithm showing the major etiologies of cysts that are present
predominantly in the sub-pleural areas. Of note, Birt Hogg Dube Syndrome may also give rise to
cysts in the sub-pleural area.

Figure 11: Bulla. Large (> 1 cm), air containing structures with very thin walls (< 1 mm). Walls
of bulla are formed by lung tissues, septa or pleura. They are usually associated with emphysema

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Figure 12: Paraseptal emphysema. Sub-pleural lucencies marginated by interlobular septa and
pleura. They demonstrate upper lobe predominance and are usually associated with centrilobular
emphysema

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Figure 13: Honeycombing. Lower lobe predominance, with cysts of similar diameter,
demonstrating thicker walls. Cysts are present in one or more layers. There is architectural

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distortion of the lung parenchyma with traction bronchiectasis, representing end stage lung
disease.

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Figure 14: Algorithm for intra-parenchymal cysts. These are either solitary or multiple
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Figure 15: Algorithm for solitary intra-parenchymal cysts

Figure 16: Incidental Cyst: These cysts may be present in any lobe of the lung. The average size
is 10 mm and may represent normal aging process or persist as a remnant of previous infection
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or trauma.

Figure 17: Bronchogenic cyst: Usually asymptomatic, these cysts arise from abnormal budding
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of tracheobronchial tree. Rarely they may communicate with the tracheobronchial tree and get
infected. An air-fluid level is seen in this large bronchogenic cyst
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Figure 18a: Algorithmic approach to intraparenchymal cysts-multiple

Figure 18b: Algorithmic approach to intraparenchymal cysts-multiple (Contd..)

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Figure 19a-d: Birt Hogg Dube Syndrome. Multiple, thin-walled cysts are seen in approximately
90% of patients. These cysts are distributed predominantly in the peripheral lung zones, at lung
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bases and along the mediastinum. These are less in number generally, as compared to those seen
in LAM
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Figure 20: Fibrofolliculomas of the face, neck and upper trunk are seen in Birt Hogg Dube
Syndrome

Figure 21: Lymphocytic Interstitial Pneumonia(LIP). Cysts are thin walled, random in
distribution and typically involve less than 10% of lung parenchyma. Note scattered foci of
increased lung density in close proximity to the medial aspect of a cyst in the right lower lobe
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Figure 22: Metastatic colon cancer with thin walled cysts. The images are from a 62 year old
male patient who was an ex-smoker with metastatic colon cancer. Colon cancer resected 10
months before this CT scan was obtained

Figure 23: Coccidioidomycosis cyst in a 24 year old man. Other HRCT findings include
multiple nodules that may cavitate, lymph node enlargement and pleural effusions.

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Figure 24a: Lymphangioleiomyomatosis(LAM): Thin walled round (2-5 mm) cysts, usually
involve juxtaphrenic recesses and spares extreme apices. The intervening lung is normal.

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Figure 24b: : Lymphangioleiomyomatosis (LAM) Pathology

a: Low power histology shows multiple cysts surrounded by bundles of smooth muscle.

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b: Surrounding cystic spaces are nodules of haphazardly arranged smooth muscle bundles

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c: HMB-45 immunohistochemistry shows positive cytoplasmic staining of the LAM cells.
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Figure 25a: Pulmonary Langerhan cell histiocytosis(PLCH). Generally seen in young smokers
(most common between 20-40yrs). Cysts are seen predominantly in upper and middle lobes, are
variable in size, thick or thin walled and have bizzare shapes. The costophrenic angles are
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spared. The intervening lung parenchyma shows architectural distortion.

Figure 25b : Langerhan cell Histiocytosis pathology

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a: Low power histology shows a stellate nodule composed of fibrosis with some cellular
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infiltrates. At the edges of the fibrotic scar there is pericicatricial emphysema giving some cystic
appearance.
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b: High power shows a cellular proliferation of Langerhans cells.

Figure 26: Algorithm for multiple intra-parenchymal cysts with associated findings on HRCT
scan
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Figure 27a: Algorithm for multiple intra-parenchymal cysts with associated nodules on HRCT
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scan

Figure 27b: Algorithm for multiple intra-parenchymal cysts with associated nodules on HRCT
scan (Contd..)
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Figure 28a: Light chain deposition disease (LCDD). Cysts are thin walled, round and may reach
up to 2 cm in diameter. Associated nodules are diffuse, irregular and small. Consolidation of
lung parenchyma may be present as well as associated mediastinal lymphadenopathy.

Figure 28b: Light chain deposition disease (LCDD) pathology

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a: Low power shows a sub-pleural cystic area.

b: Focally in the wall of one of the cysts is a nodular focus of amorphous eosinophilic material
characteristic of LCDD

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Figure 29: Amyloidosis. Cysts are thin walled with or without nodules. Interlobular septal

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thickening may be prominent. Ground glass opacities may be seen, along with associated
mediastinal lymphadenopathy.

Figure 30: Algorithm for multiple intra-parenchymal cysts with ground-glass opacities

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Figure 31a: Pneumocystis jirovecii: Diffuse ground glass opacities with septal thickening and
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occasional cysts (long standing)

Figure 31b: Pneumocystis jirovecii pathology

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a: Low power histology from a case of longstanding Pneumocystis jirovecii pneumonia shows
cystic spaces surrounded by thickened fibrotic walls containing some calcification.
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b. High power of GMS (Gomori methenamine silver) stain shows characteristic cysts of
Pneumocystis jirovecii with darkly stained foci.
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Figure 32: Desquamative Interstitial Pneumonia. 90% of cases of DIP are seen in smokers.
Small cysts are seen in the milieu of universal ground glass opacities and scanty ground glass
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