Clinical Presentation and Course of Lymphangioleiomyomatosis (LAM)

The average age at diagnosis of S-LAM is about 35 years, after an average symptomatic period of 3-5 years. However, more recent reports include patients ranging from age 12-75 years. Most women registered with The LAM Foundation complained of dyspnea on exertion (51%). Symptoms of cough (6%), chest pain (5%), hemoptysis (5%), chyloptysis and wheezing were all considerably less common. Pneumothorax occurs in 66% of registered LAM patients at some point in the course of their illness, with slightly more episodes on the right side than on the left. First recurrences after an initial pneumothorax occurred in more than 70% of patients, and contralateral pneumothoraces were almost as common. Thus, once a LAM patient has had a pneumothorax, a second event is more likely than not. Chylothorax occurs in about 33% of LAM patients at some point in the illness. Angiomyolipomas are present in most patients with LAM, including 70-80% of patients with TSC-LAM and 40-50% of patients with 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.

For the two-thirds of women who have a pneumothorax at some point in the course of their illness, slightly more episodes occur on the right side.  Recurrences following an initial pneumothorax occur in more than 70 percent of patients, and pneumothoraces on the other side were almost as common.  Thus, once a LAM patient has had a pneumothorax, a second event is more likely to occur.  Chylothorax occurs in about 33 percent of LAM patients at some point in the illness.

Pulmonary Physiology in LAM

Lung function may be normal in LAM, especially in tuberous sclerosis 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 20-25% 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.

In the largest series of LAM patients published through the NHLBI LAM registry, 57% of patients exhibited an obstructive pattern and the average FEV1 was about 70% of predicted. Interestingly, 34% of subjects had normal spirometry. The longitudinal lung function data from the Registry is not yet available, but 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 10-20% 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 yr survival 89%) than presentation with dyspnea (10 yr 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)

Kidney tumors called angiomyolipomas, unusual hamartomas containing fat, smooth muscle and blood vessels, are present in about 90% of patients with TSC and 30%-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 while 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.

Table 1. Comparison of TSC-LAM and Sporadic LAM

TSC-LAM Sporadic LAM
Estimated # patients on earth 250,000 30,000-50,000
Reported in males + -
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
MMPH + very rare
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

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Abbreviations - CNS; central nervous system
MMPH; multifocal micronodular pneumocyte hyperplasia

Table 2. Recommended Interventions, Studies, and Immunizations in Patients with LAM

TSC-LAM Sporadic 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
Baseline bone densitometry Abdominal CT/USG Oophorectomy rarely recommended


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