‫‪CYSTIC LUNG DISEASES‬‬

‫المركز التخصصي لألمراض التنفسية في ذي فار‬

 Cystic lung diseases represent a heterogenous group of disorders
that share in common the radiographic feature of multiple air-filled
lucencies surrounded by discrete walls.

 Cysts — A pulmonary cyst is defined as a "round parenchymal

lucency or low-attenuating area with a well-defined interface with
normal lung“
 CAUSES
 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)
 Thin-wall cysts have been reported in 13 % of 182 patients with
nonfibrotic hypersensitivity pneumonitis (HP). The cysts measured 25
mm or less in diameter, ranged from 1 to 15 (average 4) in number,
and had a random distribution. They are more common in fibrotic HP
having been reported in 39 % of patients in one study
 Occasionally, multiple pulmonary cysts may be the initial
manifestation of metastatic cancer, such as squamous cell cancers
(eg, head and neck, cervical) [16], invasive mucinous adenocarcinoma
and angiosarcoma
 CLUES TO AN ETIOLOGY FOR CYSTIC
LUNG DISEASE
 Patients with cystic lung disease may be asymptomatic, with
radiographic abnormalities incidentally discovered on CT
obtained for other reasons, or may present with respiratory
symptoms, most commonly dyspnea or cough. Often,
spontaneous pneumothorax is the presenting manifestation.
However, none of these features is specific for a particular cystic
lung disease.
 Clinical history
 A detailed clinical history can help to narrow the differential diagnosis
of diffuse cystic lung disease. As examples, underlying systemic
disease, such as tuberous sclerosis complex or Sjögren syndrome, can
direct attention to possible lymphangioleiomyomatosis or lymphoid
interstitial pneumonia, respectively, while a family history of renal
cancer or pneumothorax, might raise suspicion for Birt-Hogg-Dubé
syndrome.
 Lymphangioleiomyomatosis – is a disorder that almost exclusively
affects females; reported cases of LAM in males have, with one
exception, occurred in association with tuberous sclerosis complex .
Symptoms typically develop in the third and fourth decades of life.
 Pulmonary Langerhans cell histiocytosis (PLCH) most commonly
affects young adults, typically between the ages of 20 to 40. Sex
distribution is equal to slightly female-predominant . Reliable
figures on racial distribution are lacking, though White individuals
comprise the overwhelming majority of cases documented in the
literature. PLCH is an exceedingly unlikely diagnosis in a never-
smoker with cystic lung disease.
 Birt-Hogg-Dubé syndrome – Lung cysts are seen in up to 84 percent of
patients with Birt-Hogg-Dubé syndrome (BHD) and appear at a median
age of 30 to 40 years [34-36]. Up to one-third of patients present with
a spontaneous pneumothorax, with a median age of occurrence of 38
years . However, the earliest and often overlooked manifestation of
the disease is the development of cutaneous fibrofolliculomas on the
face, neck, and chest that can be seen beginning in the third decade
of life. There does not appear to be a particular sex predilection, and
data on racial distribution are insufficient to allow comment.
 Family history
 A family history of lung disease or extrapulmonary findings is
often present in patients with BHD and TSC-LAM, but not PLCH or
LIP.
 BHD is inherited in an autosomal dominant pattern and often
affects multiple family members. As such, eliciting a careful
family history of spontaneous pneumothorax, lung cysts (often
misdiagnosed as bulla or emphysema), renal neoplasms, and
fibrofolliculomas
 Patients with TSC-LAM may have a family history of intellectual
disability, seizures, or cutaneous angiofibromas
 Pneumothorax and pleural effusion
 Pneumothorax is a frequent manifestation of cystic lung disease, and
may be the initial event calling attention to its presence. The
prevalence of spontaneous pneumothorax is highest in LAM patients,
in the range of 50 to 60 %. Reported frequencies of pneumothorax
among patients with BHD and PLCH are 24 to 38 % and 16 %,
respectively. Pneumothorax is an uncommon manifestation of LIP,
likely reflecting the paucity of cysts present in this disease.
 Chylous effusions develop in roughly 10 % of patients with LAM . The
combination of diffuse cystic lung disease and chylous effusion is
most often due to LAM, although lymphoma is a rare mimic of this
combination.
 Pleural effusion is unusual in other forms of cystic lung diseases.
 Extrapulmonary manifestations
 ●LAM –
 •Renal angiomyolipomas (30 %)
 •Chylous ascites (10 %)
 •Lymphangioleiomyomas (up to 40 %)
 •Cutaneous manifestations of TSC, such as malar angiofibromas,
hypopigmented macules (ash-leaf spots), Shagreen patches, and
periungual fibromas
 •Neurologic manifestations of TSC, including cognitive impairment,
seizures, subependymal giant cell astrocytomas, cortical
glioneuronal hamartomas, and subependymal nodules
 PLCH – Extrapulmonary involvement is seen in approximately 20 %
of patients with PLCH
 •Cystic bone lesions (7 %)
 •Arginine vasopressin disorder (formerly known as diabetes
insipidus) (8 %)
 •Rarely, skin lesions (brown papules and eczema) and generalized
lymphadenopathy
 BHD – In addition to pulmonary involvement, BHD is associated with
renal and cutaneous manifestations:
 •Renal neoplasms: most commonly hybrid oncocytic tumors (50 %),
followed by chromophobe renal cell carcinomas (35 %), clear cell
renal cell carcinomas (9 %), and renal oncocytomas (5 %).
 •Cutaneous lesions: 85 % of patients have fibrofolliculomas
 LIP – Although LIP is a disorder confined to the lungs, it is
associated with a wide variety of underlying systemic autoimmune
diseases and immunodeficiency in the majority of cases. Most
common among these is Sjögren syndrome, present in 25 to 50 % of
LIP cases. For this reason, patients presenting with cystic lung
disease should be queried about the presence of dry eyes and dry
mouth. Patients with immunodeficiency (eg, common variable
immunodeficiency, HIV) often have a history of infection.
 Associations of GGO and Nodules

The combination of cysts and GGO is a common radiographic presentation

of LIP and usually not a feature of the other diffuse cystic lung diseases
except in PLCH and a concurrent smoking-related disorder such as
RBILD/DIP.
Multiple nodules should alert the physician to PLCH, although nodules can
also be found in LIP and tuberous sclerosis complex (TSC)-LAM.
 ●PLCH – Radiographic abnormalities in PLCH typically begin as upper
lobe nodules. These nodules later cavitate ("cheerio sign") and
ultimately form cystic lesions. It is important to note that as the disease
evolves, nodules and cystic lesions can coexist, and this combination
may permit a radiographic diagnosis of PLCH with a high degree of
confidence.
 ●LIP – Ill-defined centrilobular nodules and subpleural nodules can
be seen in patients with LIP. In patients with Sjögren syndrome, the
presence of nodules along with cysts should raise suspicion for
concurrent lymphoma, light chain deposition disease, or
amyloidosis.
 ●TSC-LAM – In some patients with TSC-LAM, multiple lung nodules
accompany the cystic changes. These nodules usually represent
multifocal micronodular pneumocyte hyperplasia (MMPH).
b
 Laboratory testing
 On occasions when the clinical and HRCT findings do not allow
differentiation among the four main causes of cystic lung disease, some
experts test more broadly and obtain testing for antinuclear antibody,
anti-Ro/SSA and anti-La/SSB antibodies, rheumatoid factor, and vascular
endothelial growth factor-D (VEGF-D), as well as genetic testing for the
folliculin (FLCN) and tuberous sclerosis complex (TSC1 and TSC2)
genes, and rarely for inheritable causes of bronchiectasis (eg, primary
ciliary dyskinesia and cystic fibrosis). This approach is unproven and
costly.
 In LIP also send patient for Ig and CVID suspected and for HIV testing if
there is risk factors.
 Bronchoscopy
 Bronchoscopy with bronchoalveolar lavage (BAL) and/or
transbronchial lung biopsy (TBLB) may be helpful in selected
patients, such as those with suspected LAM or PLCH and
insufficient clinical or laboratory features to be confident in
the diagnosis
 Lymphangioleiomyomatosis – TBLB with immunohistochemical staining
for human melanoma black (HMB)-45 has been shown to identify LAM
smooth muscle cells in 60 to 86 % of cases. The yield from transbronchial
biopsy may correlate with cyst profusion, low DLCO, and low FEV1. BAL is
not helpful in the diagnosis of LAM, except to exclude other processes
 Pulmonary Langerhans cell histiocytosis – The presence of ≥5 % CD1a-
positive cells in BAL is considered strongly suggestive of PLCH but is
poorly sensitive. BAL and TBLB together may yield a diagnosis in
approximately 50 % of patients. Other patients will require video assisted
surgical lung biopsy to confirm the presence of Langerhans cells positive
for S-100 protein and CD1a
 Lymphoid interstitial pneumonia – BAL demonstrates lymphocytosis
in approximately 30 % of patients with LIP, but this is a nonspecific
finding also seen in diseases such as sarcoidosis and
hypersensitivity pneumonitis. Bronchoscopy is otherwise of limited
value as TBLB does not provide an adequate sample size for the
differentiation of interstitial pneumonias.
 ●Birt-Hogg-Dubé – There is no role for BAL or TBLB in suspected
cases of BHD since there are no distinctive histologic features
 Surgical biopsy
 VATS typically used for confirmation the diagnosis in
order to initiate therapy . Generally for LAM, PLCH and LIP
but not BHD due to no specific histopathology (also
neurofibromatosis). Lung biopsy may be the best option
for worrisome causes like metastatic cancer, amyloidosis,
light chain deposit disease and non Langerhans
histiocytosis.
 Skin biopsy for confirmation of BHD if HRCT is compatible
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