CONTENTS

• Definitions of cystic & cavitary lung lesions
• Approach to diffuse/multiple lung cysts
  • Clinical features
  • Radiologic features
• List of causes of pulmonary cysts
• Specific cystic lung diseases:
  • PLCH (Pulmonary Langerhans Cell Histiocytosis)
  • LAM (Lymphangioleimyomatosis)
    • Tuberous sclerosis
  • BHD (Birt-Hogg-Dube syndrome)
  • LCDD (Light chain deposition disease)
  • CPAM (Congenital pulmonary airway malformation)
  • Pneumatocele
  • Incidental cyst(s)
• Questions & discussion

abbreviations used in the pulmonary section:

• AE-ILD: Acute exacerbation of ILD 📖
• AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
• ANA: Antinuclear antibody 📖
• ANCA: Antineutrophil cytoplasmic antibodies 📖
• ARDS: Acute respiratory distress syndrome 📖
• ASS: Antisynthetase Syndrome 📖
• BAL: Bronchoalveolar lavage 📖
• BiPAP: Bilevel positive airway pressure 📖
• COP: Cryptogenic organizing pneumonia 📖
• CPAP: Continuous positive airway pressure 📖
• CPFE: Combined pulmonary fibrosis and emphysema 📖
• CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
• CTEPH: Chronic thromboembolic pulmonary hypertension 📖
• DAD: Diffuse alveolar damage 📖
• DAH: Diffuse alveolar hemorrhage 📖
• DIP: Desquamative interstitial pneumonia 📖
• DLCO: Diffusing capacity for carbon monoxide 📖
• FEV1: Forced expiratory volume in 1 second 📖
• FVC: Forced vital capacity 📖
• GGO: Ground glass opacity 📖
• GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
• HFNC: High flow nasal cannula 📖
• HP: Hypersensitivity pneumonitis 📖
• IPAF: Interstitial pneumonia with autoimmune features 📖
• IPF: Idiopathic pulmonary fibrosis 📖
• IVIG: Intravenous immunoglobulin 📖
• LAM: Lymphangioleiomyomatosis 📖
• LIP: Lymphocytic interstitial pneumonia 📖
• MCTD: Mixed connective tissue disease 📖
• NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
• NSIP: Nonspecific interstitial pneumonia 📖
• NTM: Non-tuberculous mycobacteria 📖
• OP: Organizing pneumonia 📖
• PAP: Pulmonary alveolar proteinosis 📖
• PE: Pulmonary embolism 📖
• PFT: Pulmonary function test 📖
• PLCH: Pulmonary Langerhans Cell Histiocytosis 📖
• PPFE: Pleuroparenchymal fibroelastosis 📖
• PPF: Progressive pulmonary fibrosis 📖
• PVOD/PCH Pulmonary venoocclusive disease/pulmonary capillary hemangiomatosis 📖
• RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
• RP-ILD: Rapidly progressive interstitial lung disease 📖
• TNF: tumor necrosis factor
• UIP: Usual Interstitial Pneumonia 📖

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definitions of various cyst-like radiologic findings

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three main classes of abnormalities

[#1/3] centrilobular emphysema (no wall)

• There is usually no visible wall.
• Luciencies measure up to 1 cm in diameter.(27180915)
• Centrilobular core structures may be seen (e.g., central vessel produces a central dot).
• Lesions typically are most prominent in the upper lung zones.

[#2/3] cyst (<2 mm wall)

• Radiological definition of a cyst:
  • Thin, well-defined wall (<2 mm).
  • Forms a smooth interface within lung tissue.
  • Cysts usually contain gas, but can contain fluid as well (e.g., during a superinfection).
• (Pathologically, cysts are defined by the presence of an epithelial lining. In clinical practice this distinction is irrelevant, because surgical lung biopsy is only rarely performed on these patients.)

[#3/3] cavity (>4 mm wall)

• A cavity is defined as a gas-filled space within a nodule, mass, or area of parenchymal consolidation. This usually implies a necrotic process.
• Radiologically:
  • Cavities are usually defined as being thick-walled (>~4 mm).(29518379)
  • Cavitation often occurs within areas of diseased lung tissue, so there are often surrounding parenchymal infiltrates.
• ⚠️ Consolidation of lung that contains pre-existing bullae may mimic cavitary lung disease. If available, archival scans may help clarify this.

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three cyst-like lesions that aren't real cysts

blebs

• Focal lucency, usually <1 cm in size.
• Bounded by a thin wall (<1 mm).
• Located within the visceral pleura, or in the subpleural space.(25897602)
• Generally occurs as a component of paraseptal emphysema (the Fleischner Society recommends that blebs be considered as focal paraseptal emphysema).(27180915) 
• Blebs are often associated with centrilobular emphysema (but not necessarily).

bulla

• Spherical focal lucency >1 cm in size (usually several centimeters).
• Bounded by a thin wall (<1 mm).
• Usually within an area of emphysematous lung.
• Usually located within the subpleural lung, rather than within the lung parenchyma. (31464115)

honeycombing

• Cystic air spaces arranged in a stacked fashion, similar to a honeycomb.
• Airspaces are 3-10 mm in size, with 1-3 mm wall thickness.
• Usually arranged in a subpleural distribution.
• Generally associated with other features of fibrosis (e.g., traction bronchiectasis, reticulation, architectural distortion).

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approach to diffuse/multiple lung cysts

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Cystic lung diseases are associated with various clinical and radiological features. Such associations often help suggest a limited number of differential diagnostic possibilities. Please note that many of these associations are not mutually exclusive – so consideration should be given to all associations that are identified.

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associations of cystic lung diseases with various clinical manifestations

gradual-onset dyspnea suggests:

• LAM (Lymphangiomyomatosis). 📖
• PLCH (Pulmonary Langerhans cell histiocytosis). 📖
• DIP (Desquamative interstitial pneumonia). 📖
• LIP (Lymphocytic interstitial pneumonia). 📖
• LCDD (Light chain deposition disease). 📖

pneumothorax suggests:

• LAM (Lymphangiomyomatosis). 📖
• BHD (Birt-Hogg-Dube syndrome). 📖
• PLCH (Pulmonary Langerhans cell histiocytosis). 📖
• Pneumocystis. 📖
• (More on the causes of pneumothorax: 📖)

recurrent pneumonia suggests:

• CPAM (cystic pulmonary adenomatoid malformation). 📖
• Pulmonary sequestration.
• Bronchogenic cyst.
• HIV plus pneumocystis pneumonia. 📖

skin manifestations suggest: 

• PLCH (Pulmonary Langerhans cell histiocytosis). 📖
  • May include erythematous, nodular, ulcerative, or a generalized maculopapular rash.
  • Nail involvement may include onycholysis (nail separation from the nailbed), onychoschizia (nail splitting).(32194766)
• BHD (Birt-Hogg-Dube syndrome). 📖
  • Fibrofolliculomas are benign tumors of hair follicles that are seen in >85% of patients, usually appearing in the patient's 30s. These appear as numerous, dome-shaped papules on the scalp, neck, face, and/or upper chest.(Fishman 2023)
  • Other skin lesions that may occur include trichodiscomas, perifollicular fibromas, and acrochordons (skin tags).
• LAM (Lymphangiomyomatosis). 📖
  • LAM itself can cause lymphedema.
  • LAM in the context of tuberous sclerosis may be associated with:
    • Pale hypomelanotic macules (“ash leaf spots”)
    • Facial angiofibromas (may resemble acne).
    • Fibromas near fingernails or teeth.
    • Shagreen patches (flesh-colored, orange-peel textured area of skin often located on the back or neck). (Fishman 2023)

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associations with various radiological findings: 

cysts + GGO (ground glass opacities):

• DIP (Desquamative interstitial pneumonia). 📖
• PLCH (Pulmonary Langerhans Cell Histiocytosis) plus another smoking-related lung disorder (e.g., DIP). 📖
• LIP (Lymphocytic interstitial pneumonia). 📖
• Pneumatoceles (e.g., 2/2 pneumocystis or other infection): 📖

cysts + nodules:

• Amyloidosis. 📖
• LCDD (Light chain deposition disease). 📖
• LIP (Lymphocytic interstitial pneumonia). 📖
• PLCH (Pulmonary Langerhans cell histiocytosis). 📖
• Cystic metastatic disease.
• LAM in patients with tuberous sclerosis (multifocal micronodular pneumocyte hyperplasia). 📖

cysts + pleural effusion

• LAM (Lymphangiomyomatosis) causes chylous effusions. 📖
• LIP (Lymphocytic interstitial pneumonia) in a patient with connective tissue disease (e.g., rheumatoid arthritis) that is causing pleural effusion. 📖

cysts + otherwise normal lung

• LAM (Lymphangiomyomatosis). 📖
• BHD (Birt-Hogg-Dube syndrome). 📖
• LIP (Lymphocytic interstitial pneumonia) 📖 may occasionally present with isolated cysts.

cysts + renal/intra-abdominal pathology

• LAM (Lymphangiomyomatosis). 📖
  • Renal angiomyolipomas.
  • Lymphangioleiomyomatosis (fluid-filled cystic masses).
  • Chylous ascites.
• BHD (Birt-Hogg-Dube syndrome). 📖
  • Various renal neoplasms.
• Cystic metastatic disease (depending on the location of the primary tumor & disease stage).

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causes of lung cysts

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infectious

• Pneumatoceles are especially associated with: 📖
  • Pneumocystis.
  • Staphylococcal pneumonia.
  • COVID-19.
  • (Other infectious causes of pneumatocele discussed above 📖).
• Quiescent, chronic cysts due to maturation of a prior cavity:
  • Endemic fungal diseases, especially coccidiomycosis.
  • Tuberculosis or non-tuberculous mycobacteria.
• Recurrent respiratory papillomatosis.

neoplasia

• Neoplastic-like processes:
  • LAM (Lymphangiomyomatosis). 📖
  • PLCH (Pulmonary Langerhans cell histiocytosis). 📖
• Associated with lymphoproliferative disorder:
  • LIP/FB (Lymphocytic interstitial pneumonia/follicular bronchiolitis). 📖
  • LCDD (Light chain deposition disease). 📖
  • Amyloidosis. 📖
• Primary pulmonary neoplasms:
  • Non-small-cell carcinoma.
  • Lymphoma.
• Metastatic malignancy (especially s/p chemotherapy):
  • Sarcomas (e.g., metastatic endometrial synovial sarcoma or synovial sarcomas can mimic benign diffuse cystic lung diseases).(Fishman 2023)
  • Metastatic adenocarcinomas (e.g., gastrointestinal and genitourinary).
  • Systemic lymphoma.

associated with interstitial lung diseases

• Smoking-related ILD:
  • PLCH (Pulmonary Langerhans cell histiocytosis). 📖
  • DIP (Desquamative interstitial pneumonia). 📖
  • Respiratory bronchiolitis/smoking-related cystic lung disease.
• Occasionally may be seen as a secondary finding in:
  • Hypersensitivity pneumonitis.
  • Sarcoidosis

genetic/developmental/congenital

• BHD (Birt-Hogg-Dube syndrome). 📖
• Phakomatoses, e.g.:
  • Cowden syndrome.
  • Neurofibromatosis.
• Marfan syndrome.
• Ehlers-Danlos syndrome type IV.
• Down syndrome.
• Congenital pulmonary airway malformation (CPAM).

other/miscellaneous

• Pneumatoceles due to other etiology (e.g., posttraumatic). 📖
• Bronchogenic cyst:
  • Usually solitary, asymptomatic.
  • Often in lower lobes.
  • Generally fluid-filled.
• Incidental cyst(s). 📖

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pulmonary langerhans cell histiocytosis (PLCH)

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basics

• PLCH involves infiltration of Langerhans cells into the lung parenchyma. The disease centers on the bronchioles, initially creating a pattern of centrilobular nodules on CT scan. Obstruction of bronchioles eventually leads to the formation of lung cysts (due to hyperinflation of downstream alveoli).
• Clues to the diagnosis of PLCH may include:
  • 🚩 Smoking history.
  • 🚩 Recurrent pneumothorax.
  • 🚩 Diabetes insipidus.
  • 🚩 Bone pain.

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epidemiology

• PLCH is rare (constituting ~3% of all patients referred for evaluation of interstitial lung disease).
• PLCH typically affects patients ~20-40 years old (incidence decreases with increasing age). There is no difference between the sexes.
• Nearly all patients have active or prior smoking or cannabis exposure. (ERS handbook 3rd ed.)
  • PLCH may be associated with other smoking-related interstitial lung diseases, for example, DIP/RBILD (desquamative interstitial pneumonia / respiratory bronchiolitis interstitial lung disease)
  • Langerhans cell histiocytosis can occur in the absence of tobacco exposure, with pulmonary involvement. In this situation, the disease may resemble a malignant, clonal process involving multiple organ systems (Langerhans cell histiocytosis). (32194766)

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symptoms

presentations

• Nonproductive cough and/or dyspnea develop insidiously over several months to years.
  • Hemoptysis may rarely occur, but this should still raise concern for a superimposed infection or tumor.
• Pleuritic chest pain may occur in ~15% of patients.(33280769)
• Spontaneous pneumothorax (may be recurrent and bilateral, potentially requiring surgical pleurodesis). (33280769)
• Constitutional symptoms in ~20% of patients (e.g., fever, anorexia, weight loss, sweats). (ERS handbook 3rd ed.)
• PLCH may be discovered as an asymptomatic radiological abnormality (in up to 25%, depending on the intensity of imaging). (Walker 2019) 

extra-pulmonary features are seen in ~15% of patients

• Cystic bone lesions may cause pain or pathological fracture (tending to involve the skull, ribs, pelvis, jaw, and vertebra).
• CNS involvement:
  • Diabetes insipidus, headaches, or seizures.
  • Neurodegeneration may occur, possibly due to a paraneoplastic mechanism that might be treatable with therapies such as IV immunoglobulin. (36088096)
• Skin & nail involvement:
  • It may include erythematous, nodular, ulcerative, or generalized maculopapular rash.
  • Nail involvement may include onycholysis (nail separation from the nailbed), onychoschizia (nail splitting). (32194766)
• Rarely may involve the heart, thyroid, liver, spleen, bone marrow, and/or lymph nodes.

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thoracic imaging

general pattern

• The disease evolves from nodules that cavitate to generate thick-walled cysts, which subsequently mature into thin-walled cysts. Depending on when the patient is imaged, the predominant finding may be nodules or cysts.
• Involvement tends to predominate in the upper lung and central lung.
  • Chest X-ray: costophrenic angles are spared.
  • CT scan: tips of the middle lobes are spared, and lung bases are often spared.

cysts (>85%)

• Cyst characteristics:
  • Wall thickness varies.
  • Cyst size varies widely (~1 mm – 30 mm).
  • Cysts may coalesce, creating bizarre shapes (more irregular and complex than in lymphangioleiomyomatosis).
• Cystic lesions correlate with worsening pulmonary function tests, including airflow obstruction. (Fishman 2023)

centrilobular nodules (~70%)

• Nodules may be stellate or ill-defined, with adjacent radiating reticular markings.
• Nodules range in size from 2-20 mm.
• Nodules are often innumerable, but sometimes only a few.
• Large nodules can undergo cavitation, potentially mimicking metastases.
• Nodules usually cause minimal impairment in lung function, so patients who only have nodules may be asymptomatic. (Fishman 2023)

other findings

• Spontaneous pneumothorax is common.
• Expansile lytic bone lesions may occur in up to 20% of patients.
• Hyperinflation of the entire lung occurs in more advanced disease.
• Pulmonary hypertension can occur in advanced disease.
• Ground glass opacities are rarely reported due to PLCH. However, these might reflect coexisting RB-ILD and/or DIP 📖 in the context of tobacco use.

differential diagnosis of cystic disease in a patient with a history of smoking: 

• PLCH (discussed above).
• Emphysema.
• CPFE 📖 (combined pulmonary fibrosis with emphysema) may cause honeycombing.
• DIP 📖 (desquamative interstitial pneumonitis).

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additional diagnostic tests

overall approach for PLCH

• For patients with mild disease and typical radiographic findings, invasive diagnostic testing isn't necessary. Treatment focuses on tobacco cessation with appropriate follow-up (more on this below).
• In patients with multiple organ system involvement, a biopsy of other organs (e.g., skin or bone) may be utilized to support the diagnosis. PET scanning may be helpful to identify sites of occult extrapulmonary disease (present in 10-15% of patients). (Murray 2022)

BAL (bronchoalveolar lavage)

• >5% CD1a+ cells (Langerhans cells) is nearly diagnostic in the appropriate clinical context.
  • Sensitivity is variable (perhaps ~40%) but may decrease in later stages of the disease. (33280769)
  • Lower levels of Langerhans cells (2-4%) may be seen in patients who smoke and in those with RBILD (respiratory bronchiolitis interstitial lung disease), bronchoalveolar carcinoma, or other interstitial lung diseases.
• Increased pigmented macrophages may be seen (a nonspecific finding among patients who smoke).
• Other findings may include moderate increases in neutrophils and eosinophils. Lymphocytosis should not be seen; it suggests an alternative diagnosis if this occurs. (Fishman 2023)

lung biopsy

• Tissue may be obtained via transbronchial biopsy (10-40% yield) or surgical biopsy. The patchy nature of the disease may render tissue diagnosis challenging.
• Loosely formed bronchiolocentric granulomas may be seen. Eventually, these destroy the bronchiolar wall, leading to the dilation of the bronchiolar lumen with the formation of cystic cavities. (ERS handbook 3rd ed.)
• Langerhans cells may be seen:
  • Proliferation of atypical histiocytes.
  • Stains are positive for CD1a, Langerin (CD207), and S100 (a less specific stain).
  • Specific genetic variants should be evaluated by testing for the BRAF V600E gene and other MAPK variants. (33280769) 
  • Detection of BRAF V600E or MEK pathway mutations may affect the use of targeted therapy (discussed further below).

evaluation for systemic involvement with Langerhans cell histiocytosis

• Skin biopsy may provide tissue diagnosis for patients with skin involvement.
• Skeletal survey may be considered for patients with bony pain suggestive of skeletal involvement (with radiographs of the skull, spine pelvis, and upper and lower limbs). If lesions are found, bone biopsy may yield a tissue diagnosis. PET scans may also be utilized to survey for systemic involvement. (32194766)

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treatment

(#1) Smoking cessation

• This is the most important intervention.
• Smoking cessation alone usually causes disease stabilization and possibly regression.
• Ongoing smoking will generally cause disease progression.
• Further discussion of smoking cessation therapies: 📖

(#2) Supportive care

• Steroids don't seem to be effective.
• Supplemental oxygen may be needed.
• Pneumothorax management:
  • The recurrence rate is high (~50%).
  • Early pleurodesis should be considered.
• COPD management: Patients may have intercurrent COPD, which may be managed with the usual therapies. 📖
• Lung transplantation: Referral may be considered for progressive or severe disease (e.g., severely impaired pulmonary function tests, chronic hypoxemia, or significant pulmonary artery hypertension). However, recurrence may occur in allograft, especially if tobacco smoking is resumed. (ERS handbook 3rd ed.)

(#3) Targeted therapy directed at Langerhans cells

• Potential indications for therapy targeted to Langerhans cells may include:
  • The primary indication is multi-system disease (especially CNS involvement).
  • Pulmonary disease progresses despite tobacco cessation.
• B-RAF proto-oncogene (BRAF) V600E mutation is found in 35-50% of patients with PLCH; the MAPK2K1 mutation is found in ~25% of patients. These lead to constitutive activation of the MAP-kinase pathway (figure above). Even patients who lack the BRAF-V600E mutation seem to demonstrate evidence of excess activation of the MAP-kinase pathway. (Murray 2022)
  • Vemurafenib, dabrafenib, and trametinib are targeted inhibitors of the BRAF/MAPK/MEK pathways. These agents may have a role for patients who have progressive disease despite smoking cessation. (Murray 2022, 36088096)
• Other treatments: chemotherapy
  • Hematology consultation may be obtained to consider whether various systemic therapies may be beneficial.
  • Cladribine is a chemotherapeutic agent that is cytotoxic for lymphocytes and monocytes. It has not been formally studied in PLCH. (25433492) Other regimens that might be utilized for multi-system Langerhans cell disease may include prednisone and vinblastine, or cytarabine. (36001715)

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lymphangioleiomyomatosis (LAM)

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basics

• LAM involves a low-grade metastatic proliferation of atypical smooth muscle cells that spread along lymphatics in the lung, thorax, abdomen, and pelvis. Bronchiolar obstruction with air trapping eventually leads to the formation of lung cysts.
• Consider LAM in women of childbearing age with any of the following red flags:
  • 🚩 Spontaneous pneumothorax.
  • 🚩 Cystic lung disease.
  • 🚩 Chylothorax.
  • 🚩 Tuberous sclerosis.
  • 🚩 Angiomyolipoma.

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epidemiology

• LAM is a rare disease usually affecting premenopausal women. The average age of onset is in the 30s-40s, but there is a broad age range.
• LAM may be aggravated by pregnancy or exogenous estrogen.
  • One quarter of patients are initially diagnosed during pregnancy.(32505325)
• Tuberous sclerosis is associated with LAM:
  • A third of women with tuberous sclerosis will develop LAM. This makes tuberous sclerosis-associated LAM more common than sporadic LAM.(Shepard 2019)
  • LAM associated with tuberous sclerosis is often milder than spontaneous LAM. Consequently, ~80-90% of patients with LAM who reach the attention of pulmonologists have spontaneous LAM.(Murray 2022)
  • Men with tuberous sclerosis may occasionally develop lung cysts, but this is rarely symptomatic.

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clinical manifestations

dyspnea

• Chronically progressive dyspnea on exertion is the most common symptom.
• Chronic dyspnea is usually due to progressive airflow obstruction and replacement of lung tissue by cysts. Unfortunately, this will frequently be misdiagnosed as asthma or COPD.
• Acute dyspnea may be caused by pneumothorax.

pneumothorax

• Pneumothorax is the presenting feature in about a third of patients. (Shah 2019)
• The recurrence rate is high (including either ipsilateral or contralateral pneumothorax).
• Patients often develop ~2-3 pneumothoraces prior to the diagnosis of LAM.

lymphatic dysregulation

• Chylothorax occurs in ~25% of patients, often requiring intervention. Fluid should be sent for cytological evaluation, as this may occasionally reveal LAM cell clusters (thereby helping establish the diagnosis).
• Chylous ascites.
• Lymphedema.
• Rare manifestations:
  • Chyloptysis (expectoration of sticky, white sputum).
  • Chylopericardium.
  • Chyle in the stool, causing protein-losing enteropathy. (Murray 2022)
  • Genitourinary involvement (chyluria, chylous metorrhea).

hemoptysis

• Hemoptysis rarely can be caused by smooth muscle proliferation in the pulmonary veins or venules.
• Hemoptysis may be life-threatening.

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radiology

cysts are the hallmark

• Cysts are usually thin-walled.
• Size ranges from a few mm to several cm.
• Cysts are usually rounded (although when large, cysts may become polygonal or bizarrely shaped).
• Cysts are distributed homogeneously throughout the lungs.
• There are nearly always ≧10 cysts. Some patients may have innumerable cysts nearly replacing the lung.

pleural disease:

• Pneumothorax is common.
• Chylothorax may be seen in ~10-20% of patients.(25897602) This tends to be large.

other features that may be seen:

• Hyperinflation is usually seen in severe disease.
• Lung parenchyma is usually normal. However:
  • GGO (ground-glass opacities) are reported in ~25% of cases, possibly due to foci of pulmonary hemorrhage.(Walker 2019)
  • Septal thickening is sporadically seen, possibly due to chylous pulmonary congestion.(Walker 2019)
• Pericardial effusion.
• Lymphadenopathy is uncommon (0-6% of larger series). Nodes may have low-density areas, possibly due to lymph accumulation.(Walker 2019)

associated hamartomas:

• Angiomyolipomas:
  • These are hamartomas containing fat, smooth muscle, and abnormal blood vessels.
  • Most often located in the kidneys (renal angiomyolipomas). Other locations may include the liver or adrenals.
  • Renal angiomyolipomas are seen in ~33% of patients with spontaneous LAM, and about 90% of patients with LAM and tuberous sclerosis.
  • Fat density within a renal mass is pathognomonic for an angiomyolipoma.
  • Hemorrhage may occur, leading to symptoms including flank pain, hematuria, and rarely hemorrhagic shock.(Walker 2021)
  • Detecting angiomyolipoma(s) is strongly supportive of a LAM diagnosis, but this may occasionally occur among patients who do not have LAM.
• Lymphangioleiomyomas:
  • These are benign tumors of the lymphatic vessels that contain lymphatic fluid. They usually occur within the abdomen/pelvis, but may also occur within lymphatic vessels and lymph nodes in the mediastinum or lung. (Murray 2022)
  • They are more common in spontaneous LAM.
  • Lymphangioleiomyomas may cause symptoms due to local mass effect or lymphatic obstruction (e.g., lymphedema involving the legs).
  • Lesions tend to enlarge as the day progresses. Diurnal variation in size on serial imaging studies may help exclude malignancy and avoid the need for biopsy.(Walker 2019)

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diagnosis

serum level of VEGF-D (vascular endothelial growth factor-D)

• LAM is fundamentally caused by mutations that cause constitutive activation of the mTOR molecular pathway. This pathway also results in overproduction of VEGF-D (an angiogenic growth factor).(32505325) 
• Serum VEGF-D levels >800 pg/ml are ~65% sensitive and nearly 100% specific for LAM. (Murray 2022) Within the appropriate clinical context, this is sufficient to diagnose LAM.
• Serum VEGF-D levels >600 pg/mL are ~85% sensitive and ~98% specific for LAM.
  • 98% specificity isn't adequate to reach a definite diagnosis (given the risks of chronic sirolimus therapy).
  • LAM patients with VEGF-D >600 pg/ml may have faster disease progression compared to patients with lower VEGF-D levels. This implies a greater role for sirolimus therapy.(Murray 2022) 
• Normal levels of VEGF-D doesn't exclude LAM.(ERS handbook 3rd ed.)

tissue diagnosis

• Staining pattern of LAM cells:
  • LAM cells stain positive with antibodies against smooth muscle actin, desmin, and HMB-45.(ERS handbook 3rd ed.)
  • Staining for human melanoma black-45 (HMB-45) is strongly supportive of the diagnosis, if present. HMB-45 is highly specific for either LAM, angiomyolipoma, or clear cell tumor of the lung. It should not be detected in normal smooth muscle.
• Source of tissue:
  • Pleural or peritoneal fluid may occasionally yield clusters of LAM cells on cytological examination.
  • Retroperitoneal/pelvic masses or lymphadenopathy may provide a source of tissue, allowing avoidance of a lung biopsy. However, cytic lymphatic lesions should probably not be biopsied due to risk of causing a chyle leak.
  • If mediastinal lymphadenopathy is present, this may be sampled via endobronchial ultrasonography (EBUS).
  • Transbronchial biopsies have a yield of ~50% (which will vary, depending on the experience of the proceduralist and the pathologist).
  • Surgical biopsy has a yield of ~100%.

differential diagnosis includes:

• Birt-Hogg-Dube syndrome.
• Emphysema.
• PLCH (pulmonary Langerhans cell histiocytosis)
• LIP/FB (lymphoid interstitial pneumonia/follicular bronchiolitis).
• Lymphoma (may cause cystic lung disease plus chylous effusion).

criteria for diagnosing LAM:

• (1) Typical cystic change on lung CT.
• (2) Clinical presentation is consistent with LAM.
• (3) Any one of the following features: (Murray 2022)
  • Tuberous sclerosis (thorough review for subtle symptoms should be performed; more on tuberous sclerosis below: 📖).
  • Renal angiomyolipoma(s), diagnosed based on typical CT features and/or pathology. (ERS handbook 3rd ed.)
  • Lymphangiolieomyomas (e.g., based on typical appearance on CT scan).
  • Chylous fluid collection (e.g., chylothorax or chylous ascites).
  • Serum VEGF-D (vascular endothelial growth factor-D) >800 pg/ml.
  • Identification of LAM cells on cytologic examination from:
    • Effusion.
    • Lymph node biopsy (e.g., via endobronchial ultrasonography).
    • Lung biopsy.

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management of LAM

sirolimus 💊

• Sirolimus suppresses smooth muscle proliferation, thereby stabilizing the disease. Unfortunately, as soon as sirolimus is discontinued, disease progression will resume.
• Sirolimus is indicated for patients with LAM and indicators of significant disease burden, e.g.:
  • FEV1 <70% predicted.
  • FEV1 declining >90 ml/yr.
  • Hypoxemia (either at rest, or exercise-induced). (Murray 2022)
  • Symptomatic chylous effusions.
• Other considerations:
  • Disease trajectory is an important consideration in borderline cases (e.g., stable disease discovered in a postmenopausal woman may require less aggressive treatment).
  • Moderately to markedly elevated levels of VEGF-D suggest more aggressive disease and favorable response to sirolimus, so this might be an indication to consider therapy.
• Everolimus appears to have similar efficacy. Everolimus is an alternative therapy for patients who cannot tolerate sirolimus.

pneumothorax

• ATS guidelines recommend ipsilateral pleurodesis following the first pneumothorax, given >70% likelihood of recurrence.(29140122) 
• The optimal technique for pleurodesis is controversial. For unclear reasons, the success rate of pleurodesis in patients with lymphangioleiomyomatosis is unusually low.
• Sirolimus should ideally be held around the time of pleurodesis to optimize wound healing (e.g., for one week before and 2-4 weeks after pleurodesis).

chylous pleural effusion

• Sirolimus is the treatment of choice for chylous pleural effusions (discussed above). Improvement is often dramatic, although this may be delayed for months.
• Other treatments for chylothorax are discussed further here: 📖

hormonal manipulation

• Systemic exogenous estrogens may worsen disease progression and should be avoided if possible (e.g., contraceptive pill, hormone replacement, or ovulation induction).(ERS handbook 3rd ed.) 
• Intentional suppression of estrogens with a goal of treating LAM is not generally recommended (e.g., aromatase inhibitors, gonadotropin-releasing hormone agonists).(32505325) However, this could be considered for patients who are unable to tolerate an mTOR inhibitor, or patients with treatment-refractory disease.

other treatments

• Bronchodilators might be useful among the ~20% of LAM patients who have bronchodilator-responsive airflow obstruction.

lung transplantation

• It may be challenging to determine optimal transplantation window, because the prognosis of the disease varies widely.
• Potential indications for transplantation evaluation might include:
  • FEV1 <30%.
  • Dyspnea with minimal exertion.
  • Rapidly deteriorating pulmonary function.
  • Hypoxemia at rest.
• LAM may recur within the allograft, but this doesn't affect survival.(ERS handbook 3rd ed.) Indeed, 10-year survival seems to be favorable as compared to other lung diseases (e.g., 56%).(Elia 2021)

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tuberous sclerosis (TSC)

basics

• Tuberous sclerosis (TSC) is a genetic disorder due to constitutive activation of the mammalian target of rapamycin (mTOR) signaling. This is the same genetic pathway which is altered in patients with isolated lymphangioleiomyomatosis.

epidemiology

• Most cases of TSC are sporadic. However, some may be inherited as an autosomal dominant trait.
• Lymphangioleiomyomatosis is reported in 42% of women and 13% of men with TSC.(28459628)

most common clinical manifestations of tuberous sclerosis

• Neurologic:
  • Epilepsy.
  • Mental retardation.
  • Brain and retinal hamartomas (e.g., subependymal nodules).
• Skin lesions may include:
  • Pale hypomelanotic macules (“ash leaf spots”)
  • Facial angiofibromas (may resemble acne).
  • Fibromas near fingernails or teeth.
  • Shagreen patches (flesh-colored, orange-peel textured area of skin often located on the back or neck).
• Renal tumors:
  • Renal angiomyolipomas (often more numerous than in patients with sporadic LAM).
  • Renal cysts which are usually mild (although rare patients may have an extensive deletion that simultaneously causes TSC and polycystic kidney disease). (28459628)
  • Renal cell carcinoma.
• Tuberous sclerosis – lymphangioleiomyomatosis (TSC-LAM)
  • About 25% of women with TSC have lymphangioleiomyomatosis.
  • TSC-LAM is usually less severe than sporadic, isolated LAM.
• Multifocal micronodular pneumocyte hyperplasia (MMPH)
  • Affects about half of patients with tuberous sclerosis.
  • Hamartomatous proliferation of pneumocytes causes nodular lesions. Radiographically these may appear as scattered 3-10 mm ground-glass nodules, or miliary 1-3 mm nodules (figure below).(33036119, Walker 2019)
  • This usually doesn't cause respiratory symptoms or dysfunction.(33036119)

diagnosis

• Genetic analysis of TSC genes TSC1 & TSC2 may help secure a diagnosis.

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Birt-Hogg-Dube syndrome

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basics

• Birt-Hogg-Dube syndrome may mimic LAM (since both involve cystic lung disease, pneumothorax, and renal tumors).

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epidemiology

• Pulmonary cysts often manifest in the patient's 30s-40s.(Fishman 2023)
• Birt-Hogg-Dube syndrome accounts for ~7.5% of primary spontaneous pneumothorax.(Fishman 2023)
• Autosomal dominant transmission:
  • Patients may have a family history of pneumothorax and/or kidney tumors.
  • The disease has variable penetrance, so lack of a family history doesn't exclude Birt-Hogg-Dube syndrome.

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clinical features

Patients can present with any combination of pulmonary, renal, or skin manifestations.(Fishman 2023) Different mutations present in different families may tend to present differently. 

pulmonary

• Multiple pulmonary cysts are seen in ~75% of patients.
• Pneumothorax is the primary clinical manifestation.
  • ~40% of patients will develop spontaneous pneumothorax.
  • Without pleurodesis, pneumothorax is often recurrent.
• (Otherwise, lung function is generally preserved. Neither cough nor dyspnea tend to occur.)

fibrofolliculomas

• Fibrofolliculomas are benign tumors of hair follicles that are seen in >85% of patients, usually appearing in the patient's 30s.(Fishman 2023)
• Fibrofolliculomas appear as numerous, dome-shaped papules on the scalp, neck, face, and/or upper chest.
• Other skin lesions that may occur include trichodiscomas, angiofibromas, and acrochordons (skin tags).(34099154)

malignancies

• About a third of patients develop renal cancers, at a mean age of ~50 years old.(24297131)
• Several types of tumor may occur:(34099154) 
  • Hybrid chromophobe/oncocytic tumors.
  • Chromophobe renal cell carcinoma.
  • Clear cell carcinoma.
  • Papillary carcinoma.
  • Nonmalignant renal oncocytoma.
• Thyroid tumors or parathyroid adenomas may also occur.

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radiographic features

cyst attributes

• Cysts may be multi-septated, unlike most other cystic lung diseases.(Shepard 2019) 
• Shape is often irregular, frequently with a lentiform configuration.
• Size varies (ranging from 0.2 – 8 cm).(Shepard 2019)

cyst distribution

• Distribution is often:
  • Lower lung.
  • Peripheral.
  • A paramediastinal distribution is relatively specific for Birt-Hogg-Dube disease, if this is encountered.(Shepard 2019)
• Cysts may encircle the bronchovascular structures (“air-cuff” sign).(Fishman 2023)

other imaging features:

• Remaining lung parenchyma should be normal. Cysts usually occupy <10% of the lung parenchyma and don't affect pulmonary function tests.(Fishman 2023)

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diagnosis

• The clinical and radiologic picture is often sufficient to have a strong suspicion for Birt-Hogg-Dube syndrome.
• Confirmation may involve:
  • Skin biopsy confirming fibrofolliculomas.
  • Family history of pulmonary cysts, pneumothorax, and/or renal tumors.
  • Genetic testing to detect pathogenic mutations in folliculin interacting protein-1 (FLCN). This testing has a sensitivity of ~90%.(Fishman 2023)
• Various diagnostic criteria exist, but there is no consensus regarding the optimal criterion. 🌊
• ⚠️ Lung biopsy generally has no role in the diagnosis of Birt-Hogg-Dube syndrome; if performed, it will be uninformative.(Elia 2023)

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management

pneumothorax

• Pneumothorax has a very high recurrence rate (~75%). Consequently, pleurodesis is recommended following the initial episode of spontaneous pneumothorax.(Fishman 2023)
• Air travel or deep sea diving carries a ~1% risk of pneumothorax. Diving should be avoided given the potential consequences. Risks of air travel should be discussed with the patient.

renal tumors

• Screening for renal tumors should begin at 20 years old and continue roughly every 2-3 years. Contrasted MRI may be ideal, since this provides high sensitivity and avoids ionizing radiation.(Fishman 2023)
• If tumors do occur, they may require special nephron-sparing resection (because additional tumors are likely to develop).

genetic testing of relatives

• Genetic counseling should be offered to family members.
• Early identification and screening for renal tumors may improve outcome.

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light chain deposition disease

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basics

• This involves systemic deposition of light chains secreted by a clone of plasma cells.
• This is usually a systemic process, which often involves predominantly the kidneys, heart, and liver.

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epidemiology

overall epidemiology

• Systemic light chain deposition disease usually affects middle-aged men.
• Cystic lung disease tends to be seen in younger women. (34366044)

underlying disorder that generates light chains: 

• Usually light chain deposition disorder is due to a plasma cell dyscrasia:
  • Multiple myeloma is most often the cause (~75%).
  • Monoclonal gammopathy of unknown significance (MGUS).
• Autoimmune diseases (especially Sjogren syndrome).
• Idiopathic.

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clinical manifestations

• The clinical course is often dominated by non-pulmonary manifestations, e.g.: (34366044)
  • Renal involvement usually causes nephrotic syndrome and renal failure.
  • Cardiac failure and/or hepatic dysfunction may occur.
• Pulmonary symptoms:
  • Exertional dyspnea or nonproductive cough are common.
  • Cysts may be found as an incidental radiological abnormality.

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radiology

cysts are the most common finding:

• Cysts may be diffuse, or preferentially distributed in lower lung zones.(Fishman 2023)
• Cysts are thin-walled, with variable size.
• Cysts are often perivascular, with vessels in the cyst wall or even traversing the cyst.
• Over time, cysts may coalesce into irregular shapes.

other findings may include:

• Pulmonary nodules (some of which may be calcified).(34366044)
• Small airway dilation.
• Lymphadenopathy.

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diagnosis

• An elevated serum free kappa light chain level, and elevated kappa/lambda ratio, are seen in more than two thirds of patients.(Fishman 2023)
• Amyloidosis should be considered in the differential diagnosis, since it may also be associated with plasma cell abnormalities. (31573343) 
• Definitive diagnosis requires tissue histopathology: Eosinophilic granular amorphous deposits are seen that stain positive for light chains. This may appear similar to amyloid, but it doesn't display birefringence.

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management

• Treatment of the underlying disorder:
  • Any underlying lymphoproliferative disorder should be treated.
  • Underlying connective tissue disorder (e.g., Sjogren syndrome) may warrant treatment.
• Patients should be evaluated for renal involvement (proteinuria, microscopic hematuria) and/or cardiac involvement (arrhythmia, diastolic dysfunction, heart failure).

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congenital pulmonary airway malformation (CPAM)

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basics

• CPAM is a hamartomatous abnormality of lung maturation that results in proliferation and cystic dilation of the terminal bronchioles. It was previously known as congenital cystic adenomatoid malformation (CCAM).
• CPAM is a rare disorder which is mostly diagnosed shortly after birth. However, it may occasionally be diagnosed in adulthood.

two types most frequently present in adulthood

• Type 1 (~60% of adult cases):
  • One or more large dominant cysts are seen (3-10 cm).
  • May be surrounded by smaller cysts.
  • There is a risk of malignant transformation into mucinous adenocarcinoma.
• Type 2 (~20% of adult cases):
  • Multiple evenly spaced small cysts (<2 cm), often with solid components.(Fishman 2023) 
  • Often associated with other congenital abnormalities (pulmonary sequestration, congenital cardiac anomalies, renal dysgenesis).
  • There is a risk of malignant transformation into rhabdomyosarcoma.

clinical presentation

• More common presentations:
  • (1) Asymptomatic radiologic finding.
  • (2) Persistent/recurrent pneumonia. This may be mistaken for lung abscess, tuberculosis, or focal bronchiectasis.(25897602)
• Less common manifestations:
  • Hemoptysis.
  • Pneumothorax.

radiology

• Usually causes a mass of numerous air-containing cysts that expand the ipsilateral hemithorax.
• Most often in the lower lobe.
• Superinfection may produce an air-fluid level, which will mimic a lung abscess.

differential diagnosis of a single large lung cyst

• CPAM.
• Intralobar pulmonary sequestration.
• Intrapulmonary bronchogenic cyst.
• LIP (Lymphocytic interstitial pneumonia).
• Cystic thoracic malignancy.
• Large emphysematous bullae.
• Prior infection with pneumatocele. (33522868)

management

• Surgical removal may be indicated for symptomatic patients (e.g., recurrent infections).
• Type I lesions carry a risk of malignant transformation, so either resection or longitudinal follow-up may be appropriate.

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pneumatocele

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basics

• Pneumatoceles are one type of cyst that form due to a check-valve opening between a bronchus and an area of diseased or necrotic lung (although precisely how these form is subject to some debate).
• Pneumatoceles shouldn't be mistaken for cavitation. (Cavitation would imply a greater amount of tissue necrosis.)
• Pneumatoceles may also be known as “pulmonary pseudocysts.” Technically, since there is no epithelial lining, these lesions might not meet a pathological definition of cystic lung disease.

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causes of pneumatocele

• Infection:
  • Staphylococcus aureus (most common).
  • Pneumocystis.
  • Klebsiella pneumoniae.
  • Streptococcus pneumoniae.
  • Haemophilus influenzae.
  • Escherichia coli.
  • Group A streptococci.
  • Adenovirus.
  • COVID.
  • Primary pulmonary tuberculosis.
• Traumatic pneumatocele:
  • Often caused by blunt trauma (e.g., motor vehicle collision).
  • This may initially appear as cystic lesion(s) surrounded by consolidated lung parenchyma (pulmonary contusion) within hours after severe chest trauma.
  • Symptoms may include cough, fever, dyspnea, hemoptysis, and chest pain. Hemoptysis can persist for up to two weeks.(24936697)
• Positive pressure ventilation.
• Hydrocarbon aspiration.

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symptoms & clinical behavior of a pneumatocele

evolution over time

• Pneumatoceles can expand rapidly, with compression of surrounding lung tissue.
• When lung injury improves, pneumatoceles resolve.

clinical manifestations

• Pneumatoceles are generally asymptomatic.
• Pneumothorax:
  • Pneumatoceles can rupture into the pleura, leading to a pneumothorax (the classic example of this being in the context of pneumocystis).
• Occasionally pneumatoceles may grow large enough to compress adjacent structures (occasionally with tension physiology).(33422238)
• Pneumatoceles can become secondarily infected.

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radiology of a pneumatocele

general features of pneumatoceles

• Usually thin-walled, cystic structures.
• Size may vary considerably (e.g., ~1-14 cm).
• Lesions may be single or multiple.
• Lesions may contain hyperattenuating fluid (due to bleeding into the lesion).
• Common causes of confusion:
  • If a pneumatocele occurs within the context of consolidated lung, the wall may be difficult to discern.
  • The pneumatocele may compress adjacent lung tissue, thereby causing it to have a thicker wall.

features that favor a pneumatocele (rather than an abscess or cavitation):

• The wall is thin and regular (if discernable).
• Smooth inner margins.
• Little, if any, fluid content.
• A pneumatocele may persist in a patient who is clinically well (whereas a lung abscess would cause clinical illness).

radiographic differential diagnosis

• Cavitary lesions (e.g., malignancy or lung abscess).
• Emphysematous bullae (may be indistinguishable at a single point in time, but pneumatoceles tend to resolve whereas bullae are stable).(Rosado-de-Christenson 2022)
• Other types of cystic lung disease.

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diagnosis of a pneumatocele

• A pneumatocele is a diagnosis of exclusion.
• Definitive diagnosis with 100% certainty may be impossible to obtain initially.
• Serial imaging may help secure the diagnosis. Pneumatoceles should generally resolve over time.

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management of a pneumatocele

• Generally, management will focus on the underlying disease process (e.g., antibiotic therapy for pneumonia). The natural history of pneumatoceles is usually to resolve, but occasionally persistence can occur.(27180915)
• For patients on mechanical ventilation, reduction in airway pressures could theoretically reduce ongoing growth of pneumatocele(s). However, this is speculative.
• If the pneumatocele is exerting significant mass effect on nearby structures, surgery may be needed.
• Complications can occur that require specific intervention (e.g., superinfection, abscess formation, hemothorax, or secondary pneumothorax).(24936697)

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incidental cyst(s)

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• Basics:
  • Normal finding which is increasingly common at older ages (>~40-55 years old).(Shepard 2019; 31464115)
  • Do not cause symptoms.
• Radiologic features:
  • Mostly solitary, but ~1-5 cysts may occur.
  • Cysts are thin-walled.
  • Average size is ~1 cm.
  • Size is stable or slightly increasing over time. (31464115)

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questions & discussion

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