Lymphangioleiomyomatosis (LAM)


Features Which Distinguish Tuberous Sclerosis (see Tuberous Sclerosis, [[Tuberous Sclerosis]]) from Lymphangioleiomyomatosis

  • Tuberous Sclerosis Manifests Mendelian Inheritance
  • In Contrast to Lymphangioleiomyomatosis, Tuberous Sclerosis Manifests Dermatologic, Central Nervous System, and Ocular Involvement
  • Tuberous Sclerosis-Associated Lung Disease Cases are Generally Younger and Have Less Impaired Lung Function Than Sporadic Lymphangioleiomyomatosis Cases [MEDLINE]


Normal Function

TSC Genes

  • TSC1 Gene: encodes for the hamartin protein (which is widely expressed in normal tissues)
    • Dysfunctional/absent hamartin results in a loss of functional tuberin-hamartin complex -> loss of inhibition on the cell cycle
  • TSC2 Gene: encodes for the tuberin protein
    • Dysfunctional/absent tuberin results in a loss of functional tuberin-hamartin complex -> loss of inhibition on the cell cycle

Mechanistic Target of Rapamycin (mTOR)

  • mTOR Pathway Regulates Protein Expression (in Response to Nutrition), Cell Cycle Progression, and the Response to Hypoxia: hamartin-tuberin complex plays a role in mTOR signaling

Majority of Lymphangioleiomyomatosis Cases Have Bi-Allelic Mutations in the TSC1 and TSC2 Tumor Supressor Genes in Somatic Cells

  • Pulmonary Lymphangioleiomyomatosis is Considered a Benign Mesenchymal Neoplasm with Perivascular Epithelioid Cell Differentiation (PEComa)
  • In Contrast, Tuberous Sclerosis Patients Have Germ Line Mutations in the TSC1 and TSC2 Genes (see Tuberous Sclerosis, [[Tuberous Sclerosis]])
    • Both Sporadic Lymphangioleiomyomatosis and Tuberous Sclerosis-Associated Lung Disease Have Abnormal Pulmonary Interstitial Accumulation of Smooth Muscle Cells and Cyst Formation

Role of VEGF-D in the Pathogenesis of Lymphangioleiomyomatosis

  • VEGF-D is a Lymphangiogenic Factor

Role of Estrogen in Pathogenesis of Lymphangioleiomyomatosis

  • Estrogen Likely Plays a Role in Disease Pathogenesis
    • LAM does not occur prior to menarche and rarely occurs after menopause
    • LAM may accelerate during pregnancy and resolve after oophorectomy
  • Estrogen and Progesterone Receptors are Found in a Subpopulation of LAM Cells: receptors are downregulated by hormonal therapy
  • In Animal Models, Estrogen Enhances the Survival and Lung Metastasis of Tuberin-Null Cells

Pulmonary Cyst Formation (with Emphysema-Like Disease) in Lymphangioleiomyomatosis

  • Airway Smooth Muscle Proliferation: creates a “ball-valve” obstruction which leads to distention of terminal airspaces
  • Elastic Fiber Degradation Due to Imbalance Between Elastase and Alpha-1 Antitrypsin: may be the predominant mechanism
  • Compression of Conducting Airways by Interstitial Proliferation of Smooth Muscle Cells: unclear if this mechanism plays a role

Pathologic Changes Leading to Specific Organ Involvement in Lymphangioleiomyomatosis

  • Proliferation of Smooth Muscle in Walls of Pulmonary Lymphatics
  • Proliferation of Smooth Muscle in Pulmonary Interstitial, Bronchial, and Vascular Structures
  • Obstructed Pulmonary Lymphatics: results in chylothorax
  • Involvement of Alveolar Septa: results in interstitial lung disease
  • Involvement of Distal Airways: results in airway narrowing, airflow limitation, and hyperinflation
  • Occlusion of Venules and Small Veins (with Absence of Pulmonary Capillaritis): results in diffuse alveolar hemorrhage
  • Rupture of Parenchymal Cysts: results in pneumothorax


Complete Blood Count (CBC) (see Complete Blood Count, [[Complete Blood Count]])

Abdominal-Pelvic CT (see Abdominal-Pelvic Computed Tomography, [[Abdominal-Pelvic Computed Tomography]])

Serum Vascular Endothelial Growth Factor-D (VEGF-D) (see Serum Vascular Endothelial Growth Factor-D, [[Serum Vascular Endothelial Growth Factor-D]])

VEGF-D Assay

Clinical Manifestations

Cardiovascular Manifestations

Chylopericardium (see Chylopericardium, [[Chylopericardium]])

Gastrointestinal Manifestations

Chylous Ascites (Chyloperitoneum) (see Chylous Ascites, [[Chylous Ascites]])

Hematologic Manifestations

Retroperitoneal Lymphadenopathy (see Lymphadenopathy, [[Lymphadenopathy]])

Lymphangioleiomyomas (Lymphangiomyomas)

Neurologic Manifestations

Pulmonary Manifestations

Chyloptysis (see Chyloptysis, [[Chyloptysis]])

Chylothorax (Chylous Pleural Effusion) (see Pleural Effusion-Chylothorax, [[Pleural Effusion-Chylothorax]])

Diffuse Alveolar Hemorrhage (DAH) (see Diffuse Alveolar Hemorrhage, [[Diffuse Alveolar Hemorrhage]])

Interstitial Lung Disease (see Interstitial Lung Disease, [[Interstitial Lung Disease]])

Pneumothorax (see Pneumothorax, [[Pneumothorax]])

Pulmonary Hypertension (see Pulmonary Hypertension, [[Pulmonary Hypertension]])

Rounded Atelectasis (see Rounded Atelectasis, [[Rounded Atelectasis]])

Small Airways Disease (see Obstructive Lung Disease, [[Obstructive Lung Disease]])

Renal Manifestations

Renal Angiomyolipoma (Hamartoma)

Chyluria (see Chyluria, [[Chyluria]])

Rheumatologic Manifestations


General Measures

Treatment of Pneumothorax (see Pneumothorax)


Mechanistic Target of Rapamycin (mTOR) Inhibitors (see Mechanistic Target of Rapamycin Inhibitors)

Hormonal Therapy

Therapies with No Demonstrated Clinical Benefit

Lung Transplant (see Lung Transplant)