Lymphangioleiomyomatosis Diagnosis and Management: High-Resolution Chest Computed Tomography, Transbronchial Lung Biopsy, and Pleural Disease Management. An Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guideline

Abstract

Background: Recommendations regarding key aspects related to the diagnosis and pharmacological treatment of lymphangioleiomyomatosis (LAM) were recently published. We now provide additional recommendations regarding four specific questions related to the diagnosis of LAM and management of pneumothoraces in patients with LAM.

Methods: Systematic reviews were performed and then discussed by a multidisciplinary panel. For each intervention, the panel considered its confidence in the estimated effects, the balance of desirable (i.e., benefits) and undesirable (i.e., harms and burdens) consequences, patient values and preferences, cost, and feasibility. Evidence-based recommendations were then formulated, written, and graded using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach.

Results: For women who have cystic changes on high-resolution computed tomography of the chest characteristic of LAM, but who have no additional confirmatory features of LAM (i.e., clinical, radiologic, or serologic), the guideline panel made conditional recommendations against making a clinical diagnosis of LAM on the basis of the high-resolution computed tomography findings alone and for considering transbronchial lung biopsy as a diagnostic tool. The guideline panel also made conditional recommendations for offering pleurodesis after an initial pneumothorax rather than postponing the procedure until the first recurrence and against pleurodesis being used as a reason to exclude patients from lung transplantation.

Conclusions: Evidence-based recommendations for the diagnosis and treatment of patients with LAM are provided. Frequent reassessment and updating will be needed.

Figure 1.

Proposed algorithm for the diagnosis of lymphangioleiomyomatosis (LAM) in a patient with compatible clinical history. The algorithm is designed as a step-wise, least-invasive approach to confirm the diagnosis of LAM. Modifications on the basis of clinical judgment are frequently required, and diagnostic decisions must be individualized. AML = angiomyolipoma; CT = computed tomography; Dl_CO = diffusion capacity of the lung for carbon monoxide; HRCT = high-resolution computed tomography; MRI = magnetic resonance imaging; mTOR = mechanistic target of rapamycin; PFTs = pulmonary function tests; TSC = tuberous sclerosis complex; VEGF-D = vascular endothelial growth factor-D. ¹Suspect LAM clinically in young to middle-aged female patients presenting with worsening dyspnea and/or pneumothorax/chylothorax. Most patients with LAM will have an obstructive defect on PFTs. Some patients, especially early in their disease course, may be asymptomatic and have normal PFTs. ²Characteristic HRCT features of LAM include the presence of multiple, bilateral, round, well-defined, relatively uniform, thin-walled cysts in a diffuse distribution. The intervening lung parenchyma often appears normal on HRCT. Other associated features that can be seen on HRCT in some patients with LAM include the presence of: chylous pleural effusion, pneumothorax, ground-glass opacity suggestive of chylous congestion, or multiple tiny nodules characteristic of multifocal micronodular pneumocyte hyperplasia (in patients with TSC-LAM). ³Referral to a TSC center should be considered if there is uncertainty regarding the diagnosis of TSC. Features suggestive of TSC include the presence of any of the following: subungual fibromas, facial angiofibromas, hypomelanotic macules, confetti lesions, Shagreen patches, positive family history of TSC, history of seizures or cognitive impairment, or presence of cortical dysplasias, subependymal nodules, and/or subependymal giant cell astrocytomas on brain imaging. Routine brain imaging is not indicated if clinical suspicion for TSC is low. Detailed diagnostic criteria for TSC to establish a definitive diagnosis have been published (65). ⁴Serum VEGF-D is currently available in the United States as a College of American Pathologists/Clinical Laboratory Improvement Act–certified test only through the Translational Trials Laboratory at Cincinnati Children’s Hospital Medical Center. Detailed instructions for proper collection, handling, and shipping of VEGF-D specimens are available at the laboratory website: www.cincinnatichildrens.org/ttdsl. ⁵The diagnosis of AML can usually be made radiographically on the basis of the presence of fat in the tumors. Routine use of contrast is not required or recommended for the diagnosis of AMLs. Contrast is useful to define the aneurysmal burden and other vascular characteristics of the tumor, such as for evaluation of the potential for hemorrhage or planning for embolization. Similarly, lymphangioleiomyomas can typically be diagnosed on the basis of characteristic radiographic appearance. ⁶The sensitivity of cytological analysis of pleural fluid for the diagnosis of LAM requires further investigation and may only be available at select centers. In a majority of patients with chylous effusions, the diagnosis of LAM can be established on the basis of elevated serum VEGF-D. ⁷The decision to obtain tissue confirmation via invasive means should be individualized. For some patients with mild disease and a paucity of symptoms, a probable clinical diagnosis of LAM with serial monitoring may be sufficient if a definitive diagnosis of LAM would not change management and some level of diagnostic uncertainty is acceptable to the patient and the clinician. Every attempt should be made to establish the diagnosis of LAM with certainty before initiation of pharmacologic therapy with mTOR inhibitors. ⁸Transbronchial lung biopsy has an estimated yield of greater than 50% for the diagnosis of LAM, and markers of parenchymal LAM burden such as abnormal Dl_CO are associated with an increased diagnostic yield. Transbronchial lung biopsy appears to be safe in LAM on the basis of case reports and small series, but additional studies are required. Consultation with an expert center is recommended in cases where transbronchial biopsy is being considered, and for interpretation of the biopsy.