Lymphangioleiomyomatosis: a clinical review

Abstract

Lymphangioleiomyomatosis (LAM) is a diffuse cystic lung disease. There are two main types of LAM: sporadic, and LAM associated with the tuberous sclerosis complex (TSC), which is caused by mutations in the TSC1 and TSC2 genes. LAM is characterised by cystic lung disease resulting in progressive dyspnoea, renal angiomyolipomas and lymphatic complications. Pneumothorax occurs frequently (70%) and definitive management with pleurodesis is recommended as the risk of recurrence is high. Characteristic thin-walled cysts are seen on computed tomography and the presence of elevated serum levels of a vascular endothelial growth factor-D has good diagnostic specificity. Currently, no single clinical or serological factor has been shown to predict prognosis. However, over the past decade, significant advances in our understanding of the pathophysiology of LAM has led to improved recognition of this rare disease and identification of treatment options. Mechanistic target of rapamycin inhibitors slow the rate of lung function decline and can resolve chylous effusion and regress angiomyolipomas. Life expectancy in patients with LAM is favourable, with a mean transplant-free survival >20 years from the time of diagnosis. Continued advances in understanding the molecular basis of LAM will lead to improved therapeutic targets and the development of more robust prognostic indicators.

Educational aims: To illustrate the clinical features, common presentations and radiological features of LAMTo outline the diagnostic approach to LAM, including the role of VEGF-DTo review the current prognostic indicators in LAM, and outline the impact of lung function, hormonal status, VEGF-D and clinical presentation on outcomeTo inform clinicians on the management options for LAM both pharmacological and nonpharmacological.

Figure 1

mTOR signalling pathways and sites of action of mTOR inhibitors. Two different complexes contain mTOR: mTORC1 (acutely sensitive to rapamycin) and mTORC2 (inhibited by rapamycin after prolonged exposure). The tuberin–hamartin complex acts as a regulator of protein synthesis and cell growth. Upstream signals such as growth factors, energy state and amino acids (AA) serve to regulate mTOR. The complex maintains Rheb (Ras homologue enriched in brain) in the guanosine diphosphate (GDP)-loaded state, thereby inhibiting mTORC1 function. Activation of mTORC1 leads to phosphorylation of S6 kinase 1 (S6K1), which is required for ribosome assembly and protein synthesis. Activation of mTORC2 results in phosphorylation of Akt, further promoting mTOR activity by inhibition of tuberin–hamartin. When activated, mTORC1 blocks further phosphorylation of Akt via a negative feedback loop. AMPK: AMP-dependent protein kinase; Raptor: regulatory associated protein of TOR; mLST8: mammalian lethal with SEC13 protein 8; PRR5: proline-rich protein 5; Rictor: rapamycin-insensitive companion of TOR; mSIN1: mammalian stress-activated protein kinase-interacting protein 1; 4E-BP1: factor 4E-binding protein 1.

Figure 2

Computed tomography (CT) Findings in LAM. a) Axial CT thorax in a 48-year-old woman demonstrates a small number of uniform thin-walled pulmonary cysts (arrows) with intervening normal lung parenchyma consistent with mild LAM. b) Axial CT of the lower thorax in a 41-year-old woman with LAM demonstrates a moderate number of relatively uniform pulmonary cysts. c) Axial CT thorax in a 36-year-old woman with severe LAM shows innumerable cysts throughout both lungs, with little intervening normal lung parenchyma visible.

Figure 3

CT image of angiomyolipoma (AML). Coronal CT abdomen in a 48-year-old woman (figure 1a) demonstrates a 22-cm AML arising from the lower pole of the right kidney. Note the internal large vessels within the AML (arrows).

Figure 4

Lung biopsy in LAM. a) Lung parenchyma showing multiple cysts (arrows) with proliferation of b) spindle cells that are c) Human Melanoma Black 45 positive. Scale bars: a) 1000 μm; b and c) 100 μm.

Figure 5

Diagnostic algorithm. ^#: features may include middle-aged female patients presenting with a pneumothorax, progressive dyspnoea or isolated low D_LCO, patents with features of TSC (subungual fibromas and facial angiofibromas) or patients with chylous complications such as chylothorax, chylous ascites or lymphatic complications (lymphangioleiomyomas). ^¶: characteristic features on CT include multiple, diffuse, round, thin-walled cysts in a uniform distribution, often devoid of internal structures. ⁺: features such as subungual fibromas, facial angiofibromas, history of cognitive impairment or seizures; patients should be considered for referral to a centre that specialises in TSC. ^§: serum VEGF-D levels >800 pg·mL⁻¹ in the presence of characteristic lung cysts on HRCT is associated with a specificity that approaches 100% for the diagnosis of LAM. ^ƒ: decision to undergo biopsy should be individualised; certain patients who are asymptomatic with only mild disease can undergo surveillance with serial PFTs every 3–6 months; however, all efforts to establish a diagnosis should be made if treatment with a mTOR inhibitor is planned. LN: lymphadenopathy. Reproduced and modified from [36] with permission from the publisher.