Cystic lung disease: Clinical, laboratory, and radiographic features

Cystic lung disease	Distinctive clinical features	Typical CT features*	Confirmation of diagnosis (in association with compatible chest CT)
LAM	Occurs almost exclusively in females (occasionally in males with TSC) Renal angiomyolipomas in up to 50% of cases Retroperitoneal or pelvic lymphangioleiomyomas Chylous effusion, chylous ascites May be accompanied by clinical features of TSC	Small, thin-walled, round cysts varying little in size or shape, uniformly distributed throughout the lungs	One of the following: Noncontrast abdomen/pelvis CT or MRI demonstrating renal angiomyolipoma or cystic lymphangioleiomyoma Presence of chylous pleural effusion or ascites^¶ Serum VEGF-D >800 pg/mL Presence of TSC Transbronchial or surgical lung biopsy demonstrating diagnostic histological features^Δ (if all of the above are absent)
PLCH	Nearly all affected individuals are current or former cigarette smokers^◊ Diabetes insipidus Bone lesions	Mix of nodules and thick-walled cysts (early stages) or bizarrely shaped cysts varying in size and shape (advanced stages) Upper and mid-lung zone distribution with sparing of costophrenic angles	One of the following: BAL with ≥5% CD1a-positive cells Transbronchial or surgical lung biopsy demonstrating diagnostic histological features
BHD	Fibrofolliculomas Renal neoplasms, typically multifocal hybrid oncocytic tumors or chromophobe renal cell carcinomas Family history of pneumothorax or renal neoplasms	Bilateral thin-walled round or lentiform cysts of variable sizes, often subpleural and/or abutting the mediastinum, with a lower lung zone predominance	One of the following: Biopsy-proven skin fibrofolliculoma Bilateral, multifocal hybrid oncocytic renal tumors or chromophobe renal cell carcinomas Genetic testing positive for FLCN mutation NOTE: Lung biopsy NOT helpful
LIP	Underlying autoimmune or immunodeficiency state in 80% of cases Sjögren syndrome is most common underlying disorder	Thin-walled cysts, typically few in number, associated with ground glass opacities and centrilobular nodules	Serologic testing for HIV and systemic rheumatic disease (eg, antinuclear antibody, anti-Ro/SSA, anti-La/SSB, rheumatoid factor) adds support to clinical diagnosis Lacrimal gland or lip biopsy Surgical lung biopsy, when a definitive diagnosis is needed to guide therapy NOTE: Transbronchial biopsy size too small to be definitive for LIP, so TBLB only helpful if an alternate diagnosis suspected (eg, LAM)

CT: computed tomography; LAM: lymphangioleiomyomatosis; TSC: tuberous sclerosis complex; MRI: magnetic resonance imaging; VEGF-D: vascular endothelial growth factor-D; PLCH: pulmonary Langerhans cell histiocytosis; BAL: bronchoalveolar lavage; CD1-a: CD1 antigen; BHD: Birt-Hogg-Dubé syndrome; FLCN: folliculin; LIP: lymphoid interstitial pneumonia; TBLB: transbronchial lung biopsy; HRCT: high resolution computed tomography.
* While these features are characteristic, they are not pathognomonic.
¶ Pleural fluid should be assessed for chyle and LAM cells (atypical smooth muscle-like cells that display positive immunohistochemical staining for melanocytic markers, such as human melanoma black [HMB]-45). If no evidence of chylous pleural fluid and abdominal-pelvic HRCT shows ascites, perform paracentesis with assessment for chyle and LAM cells.
Δ The two hallmark histopathologic features of pulmonary LAM are lung cysts and smooth muscle-like LAM cells.
◊ Other cystic lung diseases can occur in smokers, but PLCH is almost unheard of in those without cigarette smoke exposure.

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