Tuberous sclerosis complex for the pulmonologist

Abstract

Tuberous sclerosis complex (TSC) is a rare multisystem genetic disorder affecting almost all organs with no sex predominance. TSC has an autosomal-dominant inheritance and is caused by a heterozygous mutation in either the TSC1 or TSC2 gene leading to hyperactivation of the mammalian target of rapamycin (mTOR). TSC is associated with several pulmonary manifestations including lymphangioleiomyomatosis (LAM), multifocal micronodular pneumocyte hyperplasia (MMPH) and chylous effusions. LAM is a multisystem disorder characterised by cystic destruction of lung parenchyma, and may occur in either the setting of TSC (TSC-LAM) or sporadically (S-LAM). LAM occurs in 30-40% of adult females with TSC at childbearing age and is considered a nonmalignant metastatic neoplasm of unknown origin. TSC-LAM is generally milder and, unlike S-LAM, may occur in males. It manifests as multiple, bilateral, diffuse and thin-walled cysts with normal intervening lung parenchyma on chest computed tomography. LAM is complicated by spontaneous pneumothoraces in up to 70% of patients, with a high recurrence rate. mTOR inhibitors are the treatment of choice for LAM with moderately impaired lung function or chylous effusion. MMPH, manifesting as multiple solid and ground-glass nodules on high-resolution computed tomography, is usually harmless with no need for treatment.

FIGURE 1

From tuberous sclerosis complex (TSC) to lymphangioleiomyomatosis (LAM), proposed schema of pathophysiology. RHEB: Ras homologue enriched in brain; mTOR: mammalian target of rapamycin; mTORC1: mTOR complex-1; RAPTOR: regulatory-associated protein of mTOR; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor; AML: angiomyolipoma; MMP: matrix metalloproteinase.

FIGURE 2

Extrathoracic manifestations of tuberous sclerosis complex. a) Shagreen patch; b) angiofibromas; c) ungual fibroma (arrow); d) oral fibroma (arrow) and dental enamel pits (dotted arrow); e) bilateral renal angiomyolipoma (asterisks); f) retroperitoneal lymphangioma (arrow).

FIGURE 3

Pulmonary manifestations of tuberous sclerosis complex (TSC) and sporadic lymphangioleiomyomatosis (S-LAM). a) S-LAM; b) TSC-associated LAM with chylous lung congestion (right lower lobe); c) bilateral multifocal micronodular pneumocyte hyperplasia (asterisks); d) spontaneous pneumothorax secondary to LAM.

FIGURE 4

Proposed algorithm for the diagnosis of lymphangioleiomyomatosis (LAM) in a patient with compatible clinical history. HRCT: high-resolution computed tomography; TSC: tuberous sclerosis complex; VEGF: vascular endothelial growth factor; CT: computed tomography; MRI: magnetic resonance imaging; AML: angiomyolipoma; PFT: pulmonary function test. ^#: suspect LAM clinically in young to middle-aged female patients presenting with worsening dyspnoea 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. ^¶: characteristic 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). ⁺: referral to a TSC centre 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. ^§: serum VEGF-D is currently available in the USA as a College of American Pathologists/Clinical Laboratory Improvement Amendments-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/. ^ƒ: the diagnosis of AML can usually be made radiographically on the basis of the presence of fat in the tumours. 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 tumour, such as for evaluation of the potential for haemorrhage or planning for embolisation. Similarly, lymphangioleiomyomas can typically be diagnosed on the basis of characteristic radiographic appearance. ^##: the sensitivity of cytological analysis of pleural fluid for the diagnosis of LAM requires further investigation and may only be available at select centres. In a majority of patients with chylous effusions, the diagnosis of LAM can be established on the basis of elevated serum VEGF-D. ^¶¶: the decision to obtain tissue confirmation via invasive means should be individualised. 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 pharmacological therapy with mechanistic target of rapamycin inhibitors. ⁺⁺: transbronchial lung biopsy has an estimated yield of >50% for the diagnosis of LAM, and markers of parenchymal LAM burden such as abnormal diffusing capacity of the lung for carbon monoxide 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 centre is recommended in cases where transbronchial biopsy is being considered, and for interpretation of the biopsy. Reproduced and modified from [93] with permission.