Cystic Disorders of the Lung

Structured Answer for MD Examination (15 Marks)

I. DEFINITION AND CONCEPT

II. DISTINCTION FROM CYST MIMICS

III. CLASSIFICATION OF DCLDs (Fishman's Table 61-2)

┌─────────────────────────────────────────────────────────────┐
│ 1. GENETIC/DEVELOPMENTAL/CONGENITAL                         │
│    • Birt-Hogg-Dubé syndrome (BHD)                          │
│    • Tuberous Sclerosis Complex (TSC)                        │
│    • Congenital Pulmonary Airway Malformation (CPAM)        │
│    • Bronchopulmonary Sequestration                         │
│    • Down syndrome (trisomy 21) lung growth abnormality     │
│    • Filamin A mutation                                     │
│                                                             │
│ 2. SMOKING-RELATED                                          │
│    • Pulmonary Langerhans Cell Histiocytosis (PLCH)         │
│    • Desquamative Interstitial Pneumonia (DIP)              │
│    • Respiratory Bronchiolitis-associated ILD (RB-ILD)      │
│                                                             │
│ 3. ASSOCIATED WITH ILD                                      │
│    • Lymphangioleiomyomatosis (LAM)                         │
│    • Hypersensitivity Pneumonitis (HP)                      │
│    • Sarcoidosis                                            │
│                                                             │
│ 4. LYMPHOPROLIFERATIVE / IMMUNE-DYSREGULATORY              │
│    • Follicular Bronchiolitis (FB)                          │
│    • Lymphoid Interstitial Pneumonia (LIP)                  │
│    • Amyloidosis                                            │
│    • Light Chain Deposition Disease (LCDD)                  │
│                                                             │
│ 5. INFECTIOUS                                               │
│    • Pneumocystis jirovecii pneumonia (PJP)                 │
│                                                             │
│ 6. NEOPLASTIC                                               │
│    • Primary pulmonary mucinous cystic tumor                │
│                                                             │
│ 7. MISCELLANEOUS                                            │
│    • Hyper-IgE syndrome, Fire-eaters lung, ARDS             │
└─────────────────────────────────────────────────────────────┘

IV. KEY INDIVIDUAL DISEASES IN DETAIL

A. LYMPHANGIOLEIOMYOMATOSIS (LAM)

• Almost exclusively women of childbearing age (mean age ~35 years)
• Two forms: Sporadic LAM and TSC-associated LAM (TSC-LAM)
• TSC-LAM occurs in ~40% of women with TSC

• Loss-of-function mutations in TSC1 (hamartin) or TSC2 (tuberin) → constitutive activation of mTORC1 → uncontrolled proliferation of LAM cells (smooth muscle-like spindle cells)
• LAM cells spread via a metastatic mechanism (bloodborne dissemination from a clonal primary tumor)
• mTORC1 activation drives VEGF-D production → lymphangiogenesis → chylous effusions

• Multiple bilateral thin-walled cysts throughout both lung fields (diffuse, no zonal predominance)
• Smooth muscle-like LAM cell nests around cyst walls; cysts formed by air-trapping via check-valve mechanism
• Extrapulmonary: renal angiomyolipomas (80%), lymphangioleiomyomas, chylous ascites

• Progressive exertional dyspnea (most common)
• Spontaneous pneumothorax (50% of patients; recurrence rate ~70%)
• Chylothorax (lymphatic obstruction by LAM cells)
• Hemoptysis, chylous ascites, chyluria

• Multiple, bilateral, diffusely distributed thin-walled round cysts (2–5 mm to >2 cm)
• No zonal predominance; background lung parenchyma initially normal

• Obstructive pattern with reduced DLCO; air trapping on expiratory CT
• FEV₁ decline ~100 mL/year in untreated patients

• Definitive (no biopsy needed): HRCT pattern of LAM cysts + any one of: renal AML, TSC, chylous effusion, chylous ascites, lymphangioleiomyoma, or serum VEGF-D ≥800 pg/mL
• Serum VEGF-D: sensitivity ~70%, specificity ~96% for LAM

• Sirolimus (mTOR inhibitor): First-line disease-modifying therapy — stabilizes FEV₁, reduces VEGF-D, resolves chylous effusions (87% complete/partial resolution in chylothorax; Murray & Nadel)
• Everolimus: alternative mTOR inhibitor
• Bronchodilators for obstructive component
• Pleurodesis for recurrent pneumothorax (with caution — complicates future transplant)
• Lung transplantation for end-stage disease

• 10-year transplant-free survival ~85% (with sirolimus era); disease can recur in transplanted lungs

B. PULMONARY LANGERHANS CELL HISTIOCYTOSIS (PLCH)

• Adults 20–40 years; M = F ratio
• >90% are smokers (cigarette smoking is the principal risk factor)
• Accounts for ~3% of ILD referrals

• Tobacco smoke → bronchiolar epithelial activation → recruitment of Langerhans cells
• BRAF V600E mutation present in ~50% (clonal neoplastic process vs. reactive?)
• MAP2K1 mutations also reported
• Stellate nodules → central cavitation → cyst formation as Langerhans cells disappear and fibrosis replaces them (Murray & Nadel, Ch. 78)

• Loose cellular nodules adjacent to small airways (bronchiolocentric)
• Mixed population: Langerhans cells (CD1a+, S100+, Birbeck granules on EM), T lymphocytes, eosinophils
• Progresses: nodule → cavitation → thin-walled cyst
• Advanced disease: bullous/cystic destruction of middle and upper lung zones

• Cough, dyspnea, constitutional symptoms; may be asymptomatic (incidental)
• Spontaneous pneumothorax (25% of cases)
• Diabetes insipidus (if multisystem LCH)

• Upper and mid-zone predominance, sparing costophrenic angles and lung bases
• Mixed nodules and cysts (pathognomonic early pattern)
• Late: predominantly cysts ± emphysema; bizarre/irregular cyst shapes

• Normal to obstructive/mixed; reduced DLCO; may show pulmonary hypertension in advanced disease

• HRCT pattern in a smoker is strongly suggestive
• BAL: CD1a+ cells >5% is supportive
• Transbronchial or cryobiopsy; surgical lung biopsy if unclear
• BRAF V600E testing on biopsy

• Smoking cessation — mandatory; may lead to spontaneous stabilization or regression
• Cladribine or cytarabine for progressive or multisystem disease
• BRAF inhibitors (vemurafenib): for BRAF V600E-positive progressive PLCH
• Lung transplantation for end-stage; disease can recur in transplanted lungs

• Good if smoking ceases early; worse prognosis with extensive cysts, low DLCO, low FEV₁/FVC, high RV/TLC ratio, multisystem involvement (Murray & Nadel)
• Increased risk of secondary malignancies (lymphoma, myeloma, MDS)

C. BIRT-HOGG-DUBÉ SYNDROME (BHD)

• Skin: Multiple dome-shaped whitish papules — fibrofolliculomas on face/neck
• Renal tumors: Hybrid oncocytic/chromophobe renal tumors (most common); clear cell RCC (aggressive)
• Pulmonary cysts: Present in >80% of patients; typically involve <10% of parenchyma; bilateral, basilar, subpleural, perihilar/paravascular in distribution; lentiform or oval shape

• Occurs in 25–75% of patients with BHD
• 50-fold higher risk compared to age-matched controls
• Mean age at first pneumothorax: mid-to-late 30s
• No gender predilection

• Germline FLCN gene sequencing
• Clinical: fibrofolliculomas + family history + pulmonary cysts/renal tumors

• Surveillance renal imaging (annual/biennial MRI or CT)
• Pleurodesis after first pneumothorax (given very high recurrence risk)
• Dermatologic management of fibrofolliculomas (CO₂ laser)

D. LYMPHOID INTERSTITIAL PNEUMONIA (LIP) / FOLLICULAR BRONCHIOLITIS (FB)

• FB: Reactive lymphoid hyperplasia centered around conducting airways
• LIP: Diffuse polyclonal lymphocytic expansion of pulmonary interstitium including alveolar septa
• Associated with: Sjögren syndrome, SLE, rheumatoid arthritis, CVID, HIV (especially pediatric)
• Cysts form via a check-valve mechanism (bronchiolar compression by lymphoid tissue) or ischemic parenchymal destruction

• Bilateral ground-glass opacities with scattered thin-walled cysts (LIP)
• Lower lobe predominance
• Cysts typically fewer and smaller than in LAM

• Treat underlying immune-dysregulatory condition
• Corticosteroids; rituximab for Sjögren-associated LIP

E. INFECTIOUS — PNEUMOCYSTIS JIROVECII PNEUMONIA (PJP)

• Prototypic infection producing cystic lung disease
• Cysts (pneumatoceles) develop due to ball-valve air trapping and ischemic necrosis
• Occur in 10–35% of PJP cases, especially in HIV-positive patients with CD4 <200
• Bilateral ground-glass opacities on CT + perihilar/upper lobe cysts
• Risk of pneumothorax is high when cysts are present
• Treatment: TMP-SMX (co-trimoxazole) ± adjuvant corticosteroids; cyst management conservative

F. CONGENITAL PULMONARY AIRWAY MALFORMATION (CPAM)

• Abnormally opposed bronchiole-like structures without accompanying arteries
• Spectrum from macrocystic (type I/II) to microcystic/solid (type III/IV)
• Detected prenatally or in neonates/children; some discovered incidentally in adults
• Type I (most common): Single or multiple large cysts (>2 cm); good prognosis
• Surgical resection recommended due to risk of recurrent infection and rare malignant transformation

V. DIAGNOSTIC APPROACH

Step 1 — HRCT Characterization

• Number/distribution: Diffuse vs. focal; upper/mid vs. lower zone predominance; subpleural vs. perihilar
• Cyst morphology: Round, oval, lenticular; wall thickness; internal septations
• Background parenchyma: GGO, nodules, fibrosis

Step 2 — Demographic/Clinical Clues

Step 3 — Confirmatory Testing

• Serum VEGF-D ≥800 pg/mL → LAM (high specificity)
• FLCN genetic sequencing → BHD
• TSC1/TSC2 mutation → TSC-LAM
• BAL CD1a+ >5% → PLCH; BRAF V600E on biopsy
• ANA, anti-SSA/SSB, serum immunoglobulins → CTD-associated LIP
• Serum/urine protein electrophoresis, serum free light chains → amyloidosis, LCDD
• Lung biopsy (cryo/VATS): When non-invasive workup is inconclusive

VI. GENERAL MANAGEMENT PRINCIPLES FOR ALL DCLDs

1. Smoking cessation: Mandatory — reduces PLCH progression; reduces cyst progression in smoking-related DCLDs
2. Vaccinations: Influenza + pneumococcal — all patients
3. Bronchodilators: Trial in patients with obstructive spirometry; continue if symptomatic benefit
4. Spontaneous pneumothorax:
   • High recurrence rate in DCLDs (especially LAM, BHD, PLCH)
   • Early pleurodesis recommended after first episode (unlike general population where second episode is the threshold)
   • Risk of air travel ~1 episode per 100 flights — generally safe to fly
5. Specific therapies: Sirolimus/everolimus for LAM; smoking cessation/cladribine/BRAF inhibitors for PLCH; treat underlying disease for LIP/PJP
6. Lung transplantation: For end-stage disease; LAM and PLCH can recur in the allograft

VII. SUMMARY TABLE

• Fishman's Pulmonary Diseases and Disorders, 5e — Chapter 61: Diffuse Cystic Lung Diseases (Gupta, Bang, Wikenheiser-Brokamp)
• Murray & Nadel's Textbook of Respiratory Medicine, 7e — Chapter 95: Pulmonary Langerhans Cell Histiocytosis; Chapter 97: LAM; Chapter 78: Rare Pulmonary Tumors/Neoplastic DCLDs