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

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Physiology

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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

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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

• Peripheral Edema (see Peripheral Edema, [[Peripheral Edema]])

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Treatment

General Measures

• Avoidance of Tobacco (see Tobacco)
• Avoidance of Estrogen Exposure
  • Estrogen Replacement Therapy (see Estrogen)
  • Oral Contraceptives (see Oral Contraceptives)
• Avoidance of Pregnancy (see Pregnancy): due to the potential for exacerbation of LAM
• Pulmonary Rehabilitation (see Pulmonary Rehabilitation): may be useful
• Supplemental Oxygen (see Oxygen): per standard criteria
• Vaccination
  • Influenza (see Influenza Virus)
  • Pneumococcus (see Streptococcus Pneumoniae)

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

• β2 Agonists (see β2-Adrenergic Receptor Agonists): may be useful in patients with airflow obstruction (particularly those with bronchodilator responsiveness)
• Muscarinic Antagonists (see Muscarinic Antagonists): may be useful in patients with airflow obstruction

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
  • Leuprolide (Lupron) (see Leuprolide)

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

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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

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References

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