Lymphangioleiomyomatosis (LAM)

Epidemiology

  • Occurs Almost Exclusively in Premenopausal Females/Women of Childbearing Age: symptoms generally first appear between 17-47 y/o
    • Mean Age of Onset: 44 y/o (with range 18-76 y/o) [MEDLINE]
    • 60% of Cases are Premenopausal
    • Rare Cases of LAM Have Been Reported in Males: usually in association with definite or probable tuberous sclerosis (see Tuberous Sclerosis, [[Tuberous Sclerosis]])
      • However, one case of LAM has been reported in a male with no clinical/genotypic evidence of tuberous sclerosis [MEDLINE]
  • Prevalence (From LAM Registry): there are approximately 1300 LAM patients in North America
  • Race: LAM is more common in Caucasians, as compared to patients of African/Asian descent
  • Relationship to Tobacco: 60% of LAM patients are non-smokers [MEDLINE]
  • Estrogen Replacement Therapy May Precipitate Lymphangioleiomyomatosis (see Estrogen, [[Estrogen]]): some cases

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]

Physiology

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

Diagnosis

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

  • Leukocytosis (see Leukocytosis, [[Leukocytosis]])
  • Anemia (see Anemia, [[Anemia]]): iron deficiency if DAH is severe/recurrent

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

  • Recommended in the Evaluation of Suspected Lymphangioleiomyomatosis: due to the high prevalence of renal angiomyolipomas, retroperitoneal/pelvic lymphadenopathy, and lymphangioleiomyomas

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

VEGF-D Assay

  • Assay Availability is Limited: available through the translational trials laboratory at the Cincinnati Children’s Hospital
  • Threshold VEGF-D Level (Chest, 2010) [MEDLINE]: VEGF-D >800 pg/mL has a 100% specificity for the diagnosis of LAM in the setting of unexplained cystic lung disease
    • However, a Negative VEGF-D Level Does Not Exclude the Diagnosis of LAM
  • Clinical Efficacy/Utility of VEGF-D Level
    • Review of Lymphatic Involvement in LAM (Lymphat Res Biol, 2009) [MEDLINE]
      • Serum VEGF-D is Correlated with Lymphatic Disease
      • Serum VEGF-D Levels are Higher in Patients with LAM and Lymphatic Involvement, as Compared to Healthy Normals and LAM Patients with Cystic Disease Limited to the Lung
    • Study of the Diagnostic Utility of Clinical Features in VEGF-D in LAM (Respir Res, 2012) [MEDLINE]
      • Using a Combination of the European Respiratory Society Criteria for LAM and Serum VEGF-D Decreases the Need for Diagnostic Lung Biopsy in LAM
    • Chinese Study of Diagnostic Value of Serum VEGF-D (Respir Med, 2013) [MEDLINE]
      • Serum VEGF-D Levels in Patients with Isolated Cystic Lung Disease were Higher than in Normals, But Not as High as Levels in Renal Angiomyolipoma, Chylous Pleural Effusion, Lymphadenopathy, Lymphangioleiomyomas, or Tuberous Sclerosis
      • In Probable LAM, 92.9% of Patients had Serum VEGF-D Level >850.7 pg/mL
      • VEGF-D Levels Correlated with LAM Disease Severity (As Measured by LAM CT Grade) and Presentations of Chylous Pleural Effusion and/or Lymphatic Involvement
    • Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) Trial Data Examining the Value of VEGF-D Levels (Lancet Respir Med, 2013) [MEDLINE]
      • Serum VEGF-D Levels are Correlated with Disease Severity and Treatment Response in LAM

Clinical Manifestations

Cardiovascular Manifestations

Chylopericardium (see Chylopericardium, [[Chylopericardium]])

  • Epidemiology: rare

Gastrointestinal Manifestations

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

  • Epidemiology: occurs in 10% of cases
  • Diagnosis
    • Pleural Fluid Immunohistochemistry for HMB-45 or Smooth Muscle Action: may be diagnostic
  • Clinical
    • Ascites

Hematologic Manifestations

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

  • Epidemiology: common

Lymphangioleiomyomas (Lymphangiomyomas)

  • Epidemiology: occur in 16-20% of cases
  • Physiology: benign neoplasms of lymphatic vessels (PEComas)
    • May Vary In Size Diurnally (and Decrease in Size with Fasting): due to diet/exercise-related changes in chyle flow
  • Clinical: cystic masses (may mimic lymphoma)
    • Mediastinal
    • Pelvic
    • Retroperitoneal

Neurologic Manifestations

  • Absence of Central Nervous System Involvement: aids in differentiation of LAM from tuberous sclerosis (see Tuberous Sclerosis, [[Tuberous Sclerosis]])
  • Increased Risk of Meningioma (see Meningioma, [[Meningioma]]): risk appears to be independent of associated tuberous sclerosis [MEDLINE]

Pulmonary Manifestations

Chyloptysis (see Chyloptysis, [[Chyloptysis]])

  • Epidemiology: rarely occurs

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

  • Epidemiology: characteristic of LAM (but only present in a minority of patients at the time of diagnosis)
  • Physiology: due to proliferation of smooth muscle cells, leading to thoracic duct obstruction or rupture of the lymphatics in the pleura or mediastinum
  • Diagnosis
    • Pleural Fluid Immunohistochemistry for HMB-45 or Smooth Muscle Action: may be diagnostic
  • Clinical
    • Dyspnea
    • Nutritional Wasting
    • Imunocompromised State

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

  • Epidemiology
  • Clinical
    • Chest Pain: may occur
    • Cough
    • Dyspnea
    • Hemoptysis: occurs in 40% of cases
      • Hemoptysis may be absent on initial presentation in some cases, even after significant bleed

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

  • General Comments: sporadic LAM more resembles pulmonary emphysema (with significant airway obstruction) than it does classic interstitial lung diseases (such as idiopathic pulmonary fibrosis)
    • Consequently, it may be misdiagnosed as asthma or chronic obstructive pulmonary disease
  • Diagnosis
    • Arterial Blood Gas (ABG) (see Arterial Blood Gas, [[Arterial Blood Gas]])
      • Hypoxemia: may occur
    • Exercise Test (see Exercise Testing, [[Exercise Testing]]): decreased exercise tolerance due predominantly to airflow limitation, mechanical factors (decreased respiratory reserve, increased work of breathing), and pulmonary vascular destruction (which may be seen in advanced disease)
      • Decreased oxygen consumption
      • Low anaerobic threshold
      • Abnormal/excessive ventilatory response: high respiratory rate, high minute ventilation, and decreased respiratory reserve
      • Abnormal baseline and exercise VD/VT ratio
      • Dynamic hyperinflation
    • 6-Minute Walk Test (see 6-Minute Walk Test, [[6-Minute Walk Test]]): useful to evaluate exercise-related oxygenation and tolerance over time
    • Sleep Study: nocturnal hypoxemia is common (even in patients with normal SaO2 while awake), especially in patients with hyperinflation on PFT’s [MEDLINE]
    • Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests, [[Pulmonary Function Tests]])
      • Normal: 57% of cases
      • Obstructive Pattern (see Obstructive Lung Disease, [[Obstructive Lung Disease]]): 34% of cases
      • Mixed Pattern: 9% of cases
      • Bronchodilator Responsiveness (β2 Agonists or Muscarinic Antagonists): 30% of cases (those with bronchodilator responsiveness have a lower baseline FEV1)
      • Hyperinflation with Increased TLC: common
      • Gas Trapping with Increased RV and RV/TLC Ratio: common
      • Decreased DLCO (although may be increased during episodes of diffuse alveolar hemorrhage)
    • Chest X-Ray (CXR) (see Chest X-Ray, [[Chest X-Ray]])
      • Normal: early in the course
      • Reticulonodular Infiltrates: due to compression of interstitial spaces by more Dilated cystic airspaces
      • Hyperinflation (33-62% of cases)
      • Emphysematous Changes: may be severe in advanced disease
    • High-Resolution Chest CT (HRCT) (see High-Resolution Chest Computed Tomography, [[High-Resolution Chest Computed Tomography]]): extent of parenchymal changes on HRCT correlates with disease severity (as assessed by spirometry, DLCO, lung volumes, and exercise performance) [MEDLINE]
      • Diffuse, thin-walled cysts (2-40 mm in diameter with walls 0.1-2 mm in thickness): usually, >10 cysts are present
      • Hilar/mediastinal, and retroperitoneal lymphadenopathy: common
      • Thickened, dilated thoracic duct
      • Complex pleural masses (see Lung Nodule or Mass, [[Lung Nodule or Mass]]) [MEDLINE]: may occur in patients with have been treated with pleurodesis for recurrent pneumothorax
    • Bronchoscopy with Bronchoalveolar Lavage (BAL) (see Bronchoscopy, [[Bronchoscopy]]): generally not diagnostic
    • Bronchoscopy with Transbronchial Lung Biopsy (TBB) with Immunohistochemistry Stains for HMB-45 or Smooth Muscle Actin (see Bronchoscopy, [[Bronchoscopy]]): positive in 50-60% of cases
      • Risk of pneumothorax is generally low (despite presence of cysts)
    • Open Lung Biopsy
      • Proliferation of atypical smooth muscle cells (LAM cells, which resemble vascular smooth muscle cells) and perivascular epithelioid cells (PECs) around bronchovascular structures and in interstitium
        • Positive immunohistochemistry for VEGF-D
        • Positive immunohistochemistry for melanocytic markers (HMB-45, Melan-A, tyrosinase, microphthalmia transcription factor, NKI/C3) and muscle markers (smooth muscle actin, pan-muscle actin, muscle myosin, calponin)
      • Tortuous and dilated lymphatics and veins
      • Hemosiderosis: common (due to clinically insignificant hemorrhage due to the rupture of dilated and tortuous venules)
  • Clinical
    • Clubbing (see Clubbing, [[Clubbing]]): uncommon (occurs in <5% of cases)
    • Cough with Sputum (see Cough, [[Cough]]): common
    • Crackles (End-Expiratory): occur in 22% of cases
    • Decreased/Absent Breath Sounds: common
    • Dyspnea (see Dyspnea, [[Dyspnea]]): common presentation (occurs in 70% of cases)
    • Hyperinflation: common
    • Wheezing

Pneumothorax (see Pneumothorax, [[Pneumothorax]])

  • Epidemiology
    • Occurs in 40-50% of LAM cases (recurrent in 66% of cases)
    • Common presenting symptom
  • Clinical: may occur at any time in the course of the disease (and may be bilateral)

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

  • Epidemiology: although resting pulmonary hypertension is uncommon in LAM, exercise-associated pulmonary hypertension may occur more commonly
  • Physiology: probably caused by chronic hypoxemia, pulmonary capillary destruction caused by cystic lung lesions, and intrapulmonary arteriovenous shunting [MEDLINE]
  • Clinical: exercise-associated oxygen desaturation may be associated

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

  • Epidemiology: case reports describe rounded atelectasis occurring in the setting of LAM-associated pneumothorax and chylothorax

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

  • Epidemiology: reported in some cases
  • Clinical
    • Dyspnea
    • Wheezing

Renal Manifestations

Renal Angiomyolipoma (Hamartoma)

  • Epidemiology: occurs in up to 50% of cases
  • Physiology: benign tumor which contains blood vessels, muscle tissue, and fat
  • Clinical
    • Chronic Kidney Disease (CKD) (see Chronic Kidney Disease, [[Chronic Kidney Disease]]): due to replacement and/or compression of the renal parenchyma
    • Flank Pain (see Flank Pain, [[Flank Pain]])
    • Hematuria (see Hematuria, [[Hematuria]]): risk of hemorrhage increases with size
    • Renin-Dependent Hypertension (see Hypertension, [[Hypertension]]): may occur
    • Renal Mass (see Renal Mass, [[Renal Mass]]): often with areas of fat attenuation on CT

Chyluria (see Chyluria, [[Chyluria]])

  • Epidemiology: occurs in 2% of cases
  • Physiology: due to abnormal connections between dilated retroperitoneal lymphatics and the renal collecting system

Rheumatologic Manifestations


Treatment

General Measures

Treatment of Pneumothorax (see Pneumothorax)

  • Pleurodesis: usually recommended after the first episode of pneumothorax (due to high recurrence rate)
  • Considerations for Air Travel: risk of pneumothorax is probably low [MEDLINE] [MEDLINE], but patients should be counseled as the risk regardless

Bronchodilators

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

  • General Comments: mTOR inhibitors act similarly to the normally functioning hamartin-tuberin complex -> inhibition of mTOR complex may have a beneficial effect in LAM and other PEComas
  • Sirolimus (Rapamune, Rapamycin) (see Sirolimus)
    • Indications
      • Pulmonary LAM: sirolimus decreases the decline in FEV1, improved FVC, improved FRC, improved the quality of life and functional performance in moderate-severe LAM [MEDLINE]
        • However, sirolimus did not improve 6-minute walk distance or DLCO
        • Adverse Effects: mucositis, diarrhea, nausea, hypercholesterolemia, acneiform rash, and peripheral edema
        • Importantly, the pulmonary function resumed the normal rate of decline in the 12 month follow-up period (off of sirolimus)
      • Chylothorax: sirolimus may be useful
      • Lymphangioleiomyomas: sirolimus has been shown to have benefit, with resolution of tumors
    • Administration
      • Generally, max of 2 mg/day (does above this may have more toxicity without additional clinical benefit)
      • Monitor sirolimus levels (aim for trough level: 5-15 ng/mL)
      • Monitor fasting lipids, glucose, blood counts, liver function, renal function, and urine protein after the first month of therapy and then, q3-6 mo
  • Everolimus (Afinitor) (see Everolimus)
    • Indications
      • Pulmonary LAM: although everolimus is not FDA-approved for the treatment of LAM, it has been used off-label in patients who do not tolerate sirolimus -> it has been demonstrated to improve FEV1 and 6-minute walk distance [MEDLINE]
      • Lymphangioleiomyomas: everolimus has been shown to have benefit, with resolution of tumors [MEDLINE] -> however, recurrence may be seen with everolimus cessation
    • Adverse Effects [MEDLINE]: peripheral edema, pneumonia, cardiac failure, and Pneumocystis Jirovecii infection

Hormonal Therapy

  • General Comments: hormonal therapy has been used historically to treat LAM, but efficacy data are conflicting [MEDLINE]
  • Medroxyprogesterone Acetate (Provera, Depo-Provera)(see Medroxyprogesterone Acetate): can be considered for patients who are not candidates for mTOR inhibitors
    • Pharmacology: progestin
    • Administration: IM or PO
    • Adverse Effects (with Long-Term Progesterone Administration)
      • Increased Risk of Meningioma (see Meningioma)
      • Increased Risk of Thromboembolic Disease (see Deep Venous Thrombosis, [[Deep Venous Thrombosis]])
      • Menstrual Abnormalities
  • Tamoxifen (see Tamoxifen)
    • Pharmacology: anti-estrogen
  • Gonadotropin Releasing Hormone (GnRH) Agonists

Therapies with No Demonstrated Clinical Benefit

  • Inhaled/Systemic Corticosteroids (see Corticosteroids)
  • Doxycycline (see Doxycycline)
    • Pharmacology matrix metalloproteinase (MMP) inhibitor
  • Interferon Alfa-2b (see Interferon Alfa-2b)
  • Oophorectomy
  • Simvastatin (Zocor) (see Simvastatin): LAM treatment trials of simvastatin combined with either sirolimus or everolimus are in progress
    • Pharmacology: RhoA GTPase inhibitor

Lung Transplant (see Lung Transplant)

  • Clinical Efficacy in a Series of Lung Transplants in LAM Patients (45 Bilateral Lung + 34 Single Lung) [MEDLINE]: lung transplant improves lung function and quality of life
    • Survival Rates: overall, similar to that of lung transplants performed for idiopathic pulmonary fibrosis and emphysema
      • 30-Day Survival: 95%
      • 1-Year Survival: 86%
      • 3-Year Survival: 76%
      • 5-Year Survival: 65%
    • Main Causes of Death: primary graft dysfunction, infection, and bronchiolitis obliterans
    • High Frequency of Disease-Related, Peri-Operative Complications
      • Pneumothorax in Native Lung: in cases with single lung transplant
      • Postoperative Chylothorax
      • Extensive Pleural Adhesions: resulting in intraoperative bleeding
      • Recurrent LAM in Allograft Lung: likely due to hematogenous migration of LAM cells into the transplanted lung
  • Sirolimus: stopped 3 mo prior to lung transplant (due to adverse effects on wound/anastomotic healing), but may be resumed later

Prognosis

  • LAM Foundation Population-Based Registry Data [MEDLINE]
    • Median Transplant-Free Survival Time
      • 29 yrs from symptom onset
      • 23 yrs from diagnosis
  • Poor Prognostic Factors [MEDLINE]
    • Elevated Total Lung Capacity (TLC) at Presentation
    • Decreased FEV1/FVC Ratio at Presentation
    • Predominantly Cystic Histology: as opposed to predominantly muscular histology

References

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