Clinical Representation and Course of Lymphangioleiomyomatosis (LAM)

General Facts about the Clinical Representation and Course of LAMplus

  • Average age at diagnosis: 35 years old
  • Average symptomatic period prior to diagnosis: 3 to 5 years
  • Patient age range: 12 to 75 years old
  • Most common complaints: Dyspnea on exertion (51%), symptoms of cough (6%), chest pain (5%), hemoptysis (5%), chyloptysis and wheezing (less than 5%)
  • Pneumothorax occurs in 66% of patients at some point in the course of their illness with slightly more episodes on the right side. First recurrences after an initial pneumothorax occur in more than 70% of patients, and contralateral pneumothoraces are almost as common.
  • Chylothorax occurs in about 33% of LAM patients at some point in the illness.
  • Angiomyolipomas are present in most patients with LAM, including 70 to 80% of patients with TSC-LAM and 40 to 50% of patients with sporadic LAM (S-LAM).
  • Rarely, LAM presents as retroperitoneal masses or adenopathy which mimic lymphoma, ovarian or renal cancer, or other malignancy.
  • Large lymph-filled abdominal lymphangiomyomas have also been described, and may vary in size with gravitational influences in supine and erect patients.

Pulmonary Physiology of LAMplus

  • Lung function may be normal in LAM, especially in TSC patients whose LAM is identified through screening and have no pulmonary symptoms.
  • LAM commonly presents with reductions in FEV1 out of proportion to reduction in FVC, consistent with obstructive physiology.
  • Reversible airflow obstruction is present in up to 20 to 25% of patients.
  • Elevations in RV and the ratio of RV/TLC consistent with air trapping are frequently noted.
  • Hyperinflation may also occur, which is unusual among the interstitial lung diseases.
  • Mixed physiologic defects with superimposed restrictive changes are not uncommon, but it is unclear to what extent prior surgeries and pleural symphysis procedures may contribute to restrictive physiology.
  • Impaired gas exchange and hypoxemia occur, but hypercapnea is rare even in end-stage disease.
  • Diffusion capacity for carbon monoxide (DLCO) is frequently reduced, and in some cases may be reduced out of proportion to the obstructive defect.

National Heart, Lung and Blood Institute (NHLBI) LAM Registry Summaryplus

The National Heart, Lung and Blood Institute (NHLBI) has a registry of LAM patients. Among them:

  • 57% exhibited an obstructive pattern and the average FEV1 was about 70% of predicted.
  • 34% had normal spirometry.
  • The NHLBI has reported that the average rate of decline in FEV1 and DLCO in their cohort of over 300 patients was 75 ± 9 mls/year and 0.69 mL/min/mmHg/year, respectively.
  • Investigators in Europe have reported somewhat higher rates of decline in FEV1 of 118 ± 142 mL/year and 106 ± 143 ml/yr.
  • Roughly half of patients with LAM develop dyspnea with walking on flat ground by ten years following the onset of symptoms.
  • In the setting of relatively mild disease (<30% abnormal lung), patients with pneumothorax have lower FEV1 and exhibit a more rapid decline in FEV1 than those without pneumothorax. These correlations are not present in patients with more profuse cystic change. Cyst size is significantly associated with pneumothorax; patients with cyst sizes of >0.5 cm are more likely to have pneumothorax than patients with cyst sizes of <.5 cm.
  • Certain polymorphisms in collagen genes COL1A2 and COl3A1, and in metalloproteinase gene MMP-1 were, also associated with pneumothorax.
  • Compared to patients with TSC-LAM, patients with S-LAM in the NHLBI program had a higher frequency of abdominal lymphangioleiomyomas (29% vs. 9%), thoracic duct dilation (4% vs. 0%), pleural effusion (12% vs. 6%) and ascites (10% vs. 6%).
  • Patients with TSC-LAM had a higher frequency of noncalcified pulmonary nodules, hepatic and renal angiomyolipomas and prior nephrectomy.
  • Mortality at ten years is approximately 10 to 20% from the onset of symptoms and 30% at ten years from the time of lung biopsy but varies widely; cases of LAM in octogenarians and of over 30 years in duration have been documented.
  • A recent report from Japan suggests that presentation with pneumothorax is associated with younger age and a much more favorable prognosis (10-year survival 89%) than presentation with dyspnea (10-year survival, 47%).
  • Steagall et al. reported 10-year survivals of 91.3% and 92% respectively for patients with and without a history of ever having had pneumothorax; the distinction in the definition of the pneumothorax groups is important to note.

Renal Angiomyolipomas in Lymphangioleiomyomatosis (LAM)plus

  • Kidney tumors called angiomyolipomas, unusual hamartomas containing fat, smooth muscle and blood vessels, are present in about 90% of patients with TSC and 30% to 50% of sporadic LAM.
  • Hemorrhage into an angiomyolipoma can produce symptoms from chronic intermittent flank pain to acute abdomen with hypovolemic shock.
  • Embolization or cauterization may be required to prevent bleeding, which may be more common in tumors that exceed 4 cm in diameter.
  • Nephron-sparing partial resections may be required for very large tumors.
  • In most patients, angiomyolipomas are clinically silent, however, flank pain, hydronephrosis, hematuria and loss of renal function can all occur.
  • In S-LAM, angiomyolipomas are usually unilateral, small, solitary, and restricted to the kidney.
  • In TSC-LAM they are more often larger, bilateral, multiple, multiorgan involving the spleen or liver, and prone to hemorrhage.
  • The risk of renal hemorrhage from angiomyolipomas is associated with large size and with profusion of aneurysms.
  • Treatment with mTOR inhibitors such as everolimus and sirolimus can shrink the angiomyolipomas and may be effective in preventing bleeding.

Tuberous Sclerosis Complex-LAM (TSC-LAM) vs. Sporadic LAM (S-LAM)plus


Tuberous Sclerosis Complex-LAM
(TSC-LAM)

Sporadic LAM (S-LAM)

Estimated patients globally

250,000

30,000-50,000

Cases reported in males

+

-

Cases reported in children

+

+

Ascertainment

mostly by screening

dyspnea and pneumothorax

Germ line TSC mutations

+

-

Both hits = somatic mutations

-

+

Heritable

+

-

TSC1/TSC2 mutations reported

33%/66%

0%/100%

Angiomyolipomas

70-80%
multiple/bilateral

40-50%
single/unilateral

Multifocal micronodular pneumocyte hyperplasia (MMPH)

+

very rare

Central nervous system (CNS)/skin/eye/cardiac lesions

+

-

Retroperitoneal, thoracic adenopathy

+

+

Dyspnea

less common

more common

Chylothorax

less common

33%

Pneumothorax

less common

66%

Respiratory failure

less common

more common

Recommended Interventions, Studies and Immunizations for Patients with LAMplus

General Recommendations for All

Tuberous Sclerosis Complex-LAM (TSC-LAM)

Sporadic LAM (S-LAM)

Stop smoking
No estrogen containing meds

Pulmonary function testing

Head CT to r/o TSC

Yearly flu shot and pneumovax

Rest, sleep, exercise, oximetry

Wood's lamp
Skin exam

Counsel re: pneumothorax and pregnancy

HRCT chest

Transplant eval for FEV1 < 30%

Pleurodesis on first pneumothorax

α1-antitrypsin level

Refer for embolization in AML > 4cm and consider use of mTOR inhibitor

Baseline bone densitometry

Abdominal CT/USG

Oophorectomy rarely recommended