The natural history of lymphangioleiomyomatosis: markers of severity, rate of progression and prognosis

Abstract

Lymphangioleiomyomatosis (LAM) is a multisystem disease of women, characterized by proliferation of abnormal smooth muscle-like cells (LAM cells) that can metastasize, leading to the formation of lung cysts, fluid-filled cystic structures in the axial lymphatics (e.g., lymphangioleiomyomas), and angiomyolipomas, benign tumors usually involving the kidneys, comprising LAM cells and adipocytes, intermixed with incompletely developed vascular structures. LAM occurs sporadically or in association with tuberous sclerosis complex, an autosomal dominant syndrome characterized by hamartoma-like tumor growths. LAM may present with progressive dyspnea, recurrent pneumothorax, chylothorax, or abdominal hemorrhage. Computed tomography scans show thin-walled cysts scattered throughout the lungs, abdominal angiomyolipomas, and lymphangioleiomyomas. Pulmonary function tests show reduced flow rates (FEV(1)) and diffusion capacity (DL(CO)). Exercise testing may reveal gas exchange abnormalities, ventilatory limitation, and hypoxemia, which can occur with near-normal lung function. Methods used to grade the severity of disease are the LAM histology score, semiquantitative and quantitative computer tomography, pulmonary function testing, and cardiopulmonary exercise testing. Currently, progression of disease is best assessed by serial measurements of FEV(1), DL(CO), and exercise performance. New quantitative radiographic techniques that may offer advantages over physiologic testing are now available. Several potential biomarkers, such as LAM cells in peripheral blood, urine, and chyle and chemokines, vascular endothelial growth factors, and matrix metalloproteinases, may be useful as diagnostic tools or markers of organ involvement, disease severity, and progression.

FIG. 1.

Left panel shows a close-up of LAM nodule (hematoxylin-eosin). The right panel shows that the same nodule reacts with the monoclonal antibody HMB 45 (original magnification ×200).

FIG. 2.

Pulmonary and extrapulmonary findings on computed tomography scans of patients with LAM. (A) Multiple thin-walled cysts scattered throughout the lungs, completely replacing the lung parenchyma. Arrow: cyst wall. (B) Bilateral chylous pleural effusions. (C) Complex pelvic cystic lymphangioleiomyomas. (D) Large lymphangioleiomyoma compressing the inferior vena cava. (E) Multiple bilateral angiomyolipomas.

FIG. 3.

Kaplan-Meier survival curves of LAM patients according to pulmonary lymphangioleiomyomatosis histologic score (LHS). Patients with LHS-1 have nearly 100% survival at 168 months. Patients with LHS-3 have a 52.3% survival at 156 months, and patients with LHS 2 have a 74.4% survival at 216 months (p < 0.002) (From Reference 54).

FIG. 4.

Relationship between VO2 max, FEV₁, and DL_CO and CT grade of disease severity. Grade I, white bars; grade II, black bars; grade III, cross-hatched bars. *p < 0.05, versus grade I and III. **p < 0.01, versus grade I and II. (From Reference 53).

FIG. 5.

Scores for predominantly cystic lesions (0–3), predominantly solid lesions (0–1), and LHS (1–3) in 19 patients who had a positive response to bronchodilators (white bars), 55 patients who did not respond to bronchodilators (black bars), and all patients combined (cross-hatched bars). The solid lesion score is significantly greater in patients who responded to bronchodilators than in patients who did not respond (From Reference 52).

FIG. 6.

Relationship between systolic pulmonary artery pressure (PAP) and pulse oxygen saturation (SaO2) at peak exercise in 95 patients with LAM (From Reference 63).

FIG. 7.

Correlation (n = 217, r = 0.674, p < 0.0001) between percent-predicted lung diffusion capacity (DL_CO) and change in percent arterial oxygen saturation at peak exercise (From Reference 53).

FIG. 8.

Relationship between LHS and lung function at the time of biopsy. DL_CO was lower for patients with LHS2 (blue) or LHS3 (red) than those with LHS1 (yellow). Patients with LHS2 (blue) or LHS3 (red) also have lower FEV₁ than patients with an LHS1. *p < 0.01, by ANOVA, **p < 0.05, by ANOVA (From Reference 52).