Figures
- 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 DLCO, 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.
Tables
- Table 1
Prognostic factors in LAM
Favourable prognosis Poor prognosis Older age at diagnosis [46]
Post-menopausal status [19]
FEV1 >70% pred at diagnosis [19]Progressive dyspnoea at presentation [47]
Pre-menopausal status [19, 37, 44, 45]
FEV1 <70% pred at diagnosis [20, 48]
Reversible airflow obstruction [19, 49]
Use of supplementary oxygen [19, 46]
VEGF-D: high levels (>800 ng·mL−1) [18]
