Review

Lymphangioleiomyomatosis: pathogenesis, clinical features,

diagnosis, and management
Cormac McCarthy, Nishant Gupta, Simon R Johnson, Jane J Yu, Francis X McCormack

Lymphangioleiomyomatosis (LAM) is a slowly progressive, low-grade, metastasising neoplasm of women, Lancet Respir Med 2021
characterised by infiltration of the lung parenchyma with abnormal smooth muscle-like cells, resulting in cystic lung Published Online
destruction. The invading cell in LAM arises from an unknown source and harbours mutations in tuberous sclerosis August 27, 2021
https://doi.org/10.1016/
complex (TSC) genes that result in constitutive activation of the mechanistic target of rapamycin (mTOR) pathway,
S2213-2600(21)00228-9
dysregulated cellular proliferation, and a programme of frustrated lymphangiogenesis, culminating in disordered
Department of Respiratory
lung remodelling and respiratory failure. Over the past two decades, all facets of LAM basic and clinical science have Medicine, St Vincent’s
seen important advances, including improved understanding of molecular mechanisms, novel diagnostic and University Hospital, University
prognostic biomarkers, effective treatment strategies, and comprehensive clinical practice guidelines. Further College Dublin, Dublin, Ireland
(C McCarthy PhD); Division of
research is needed to better understand the natural history of LAM; develop more powerful diagnostic, prognostic,
Pulmonary, Critical Care,
and predictive biomarkers; optimise the use of inhibitors of mTOR complex 1 in the treatment of LAM; and explore and Sleep Medicine, University
novel approaches to the development of remission-inducing therapies. of Cincinnati, Cincinnati,
OH, USA (N Gupta MD,
Introduction natural history of LAM, the optimisation of mTOR Prof J J Yu PhD,
Prof F X McCormack MD);
Lymphangioleiomyomatosis (LAM) is a rare, slowly inhibitor use, and the discovery of remission-inducing Division of Respiratory
progressive, systemic disease associated with cystic lung therapies. Medicine, University of
destruction, abdominal tumours, and chylous fluid In this Review, we highlight advances in under­standing Nottingham, NIHR Respiratory
Biomedical Research Centre,
accumulations due to infiltration of neoplastic LAM cells.1–3 of disease pathogenesis, including molecular mechanisms
Nottingham, UK
These cells arise from an unknown source and probably of disease and targets for treatment. We describe the (Prof S R Johnson DM)
reach the lung via the lymphatic system or bloodstream. clinical features of LAM, discuss current approaches to Correspondence to:
Radiological evidence of LAM develops in most women evaluation and diagnosis, and provide an update on Dr Cormac McCarthy,
(30–60%)4–6 and up to 10% of men with tuberous sclerosis pharmacological treatment options and considerations for Department of Respiratory
Medicine, St Vincent’s University
complex (TSC), a multisystem genetic disease caused by
Hospital, University College
germline mutations in TSC genes, TSC1 or TSC2. LAM Dublin, Dublin 4, Ireland
occurring in patients with underlying TSC is termed Key messages cormac.mccarthy@ucd.ie
TSC-LAM. This disease can also occur sporadically in • In women with compatible cystic lung disease on a chest
women who do not have TSC, due to somatic mutations in CT scan, the additional presence of any one of the
the TSC2 gene, in a form known as sporadic LAM. following is sufficient to establish a definitive diagnosis of
Progressive dyspnoea on exertion and spontaneous lymphangioleiomyomatosis (LAM) without requiring a
pneumothorax are the most common presenting lung biopsy: tuberous sclerosis complex (TSC), elevated
manifestations of LAM. Pneumothorax tends to be serum vascular endothelial growth factor D (VEGF-D;
recurrent (lifetime average of 3–4 per patient) and a major ≥800 pg/mL), renal angiomyolipoma,
source of morbidity, often requiring multiple interventions. lymphangioleiomyoma, or chylous effusions
Angiomyolipomas occur in most patients with TSC-LAM • High-resolution CT screening of women of childbearing
and around 30–40% of those with sporadic LAM,7,8 age who present with spontaneous pneumothorax can
although lymphatic manifestations—including axial facilitate timely recognition of LAM
lymphadenopathy in the pelvis, abdomen, and chest, • Initial assessment in women with suspected LAM should
abdominal lymphangioleiomyomas, and chylous fluid include screening for angiomyolipoma, lymphatic
collections in the chest and abdomen—occur more involvement, and the presence of unrecognised TSC
frequently in patients with sporadic LAM (approximately • Disease manifestations and rate of progression in LAM
30–40%) than in those with TSC-LAM (10%).8 are highly variable and best managed with a personalised
Discovery of the genetic basis of LAM rapidly led to treatment and monitoring plan
trials of mechanistic target of rapamycin (mTOR) • mTORC1 inhibitors reduce loss of lung function, chylous
inhibitors, which showed efficacy in stabilising lung accumulation, and angiomyolipoma growth, and are the
function for most patients with LAM.9–11 Additional first-line treatment for patients with LAM
advances have included the development of a useful • Early definitive treatment for pneumothorax reduces
diagnostic and prognostic biomarker in the form of morbidity associated with recurrent spontaneous
vascular endothelial growth factor D (VEGF-D),12–14 pneumothoraces and should be considered after the
evidence for a uterine source of LAM cells,15 and the initial episode rather than after a recurrent event;
development of clinical practice guidelines.16–18 However, previous pleurodesis is not a contraindication for future
challenges that remain in meeting the needs of people lung transplantation
with LAM include progress in understanding of the

www.thelancet.com/respiratory Published online August 27, 2021 https://doi.org/10.1016/S2213-2600(21)00228-9 1

 Review
the management of LAM. Finally, we consider the natural
history and prognosis of TSC-LAM and sporadic LAM.
Epidemiology
Data suggest that sporadic LAM is restricted to
women.1,7,19 Although cystic change on CT consistent
with LAM is seen in 10–38% of men with TSC,4,20,21
including some cases with histological confirmation,
symptomatic disease is rare in men.22,23 There is one
report24 of suspected sporadic LAM in a man that was
shown to be caused by TSC mosaicism. Another report23
requires further confirmation because of limitations in
the sensitivity of genetic analysis to identify TSC
mutations and mosaicism at the time. LAM is estimated
to affect approxi­mately 3·4–7·8 per million women,
although the true prevalence is probably much higher.19
TSC has an incidence of around 1 in 6000 births, a
prevalence of 7–12 per 100 000 people, and no sex bias.
Neither TSC nor LAM is known to have a geographical
or racial predilection.7 Conservative estimates suggest
that there are approximately 8000–21 000 patients with
sporadic LAM and 80 000–160 000 patients with TSC-
LAM worldwide. Therefore, although TSC-LAM appears
to be more common, more than 80% of patients with
LAM in pulmonary clinics, registries, and trials have
sporadic LAM. This paradox remains unexplained, but
could be attributable to differences in the severity of
sporadic LAM compared with TSC-LAM, or because
other TSC health priorities divert the focus of patients
with TSC and their health-care providers away from
lung manifestations.
Pathogenesis
Signalling pathways in LAM pathogenesis
TSC1 encodes hamartin and TSC2 encodes tuberin,
which associate with TBC1D7 in a complex that functions
as a key regulator of the kinase mTOR through an
intermediate G protein called Rheb.25–27 The intact
tuberin–hamartin complex maintains Rheb in an inactive,
GDP-bound form (figure 1). Phosphorylation of tuberin
by Akt (protein kinase B) inactivates the tuberin–hamartin
complex, increases the abundance of Rheb-GTP, drives
association of mTOR with Raptor (and mLST8 and
PRAS40) to form the mTORC1 complex, and results in
phosphorylation and activation of downstream proteins
mTOR, p70S6K, and 4E-BP1. These events lead to
increased expression of proteases, HIF-1α, VEGF-A,28
VEGF-C, VEGF-D, and IMPDH;29 and inhibition of
FKBP38–BCL2,30 transcription factor EB,31 and ULK1.
The association of mTOR with Rictor (and mSIN1
and mLST8) to form mTORC2 results in activation of
Akt (Ser473), ROCK, and RhoA kinase, and expression
of cyclo­oxygenase 2, thereby supporting glucose met­
abol­
­ ism, cell survival, cytoskeletal rearrangement, cell
movement, and prostaglandin metabolism.32–35 mTORC1
hyper­activity in TSC mutant cells promotes anabolic
metabolism by increasing protein, lipid, and nucleotide
2 www.thelancet.com/respiratory Published online August 27, 2021 https://doi.org/10.1016/S2213-2600(21)00228-9
synthesis in a balanced and coordinated manner, and
ultimately leads to cell growth and proliferation.29,36–39
Increased expression of the angiogenic factor VEGF-A,28
and lymphangiogenic growth factors VEGF-C and
VEGF-D, stimulates angiogenesis and the formation of
lymphatic channels within and around LAM lesions that
might facilitate access of LAM cells to the circulation.
There is increasing evidence that LAM cells are capable of
immune evasion though mTOR-dependent expression
of checkpoint ligands and modulation of natural killer
cell function.40–42 Improved understanding of disease
pathogenesis has identified a multitude of potential
treatment targets for patients with LAM (figure 1).
The metastatic origin of LAM
LAM has been reported to recur in donor allografts
of patients who have undergone lung transplantation.
The lesions are composed of LAM cells that have
been genetically proven to arise from the recipient.43,44
Although these findings first supported a metastatic
mechanism for the disease almost 20 years ago,
the source of the invading cell has remained elusive.
Because angiomyolipomas contain cells with genetic,
morphological, and immunohistochemical profiles that
are similar to those of LAM cells,45 these tumours have
been proposed as the potential primary origin; however,
not all patients with LAM have angiomyolipomas.
LAM lesions have also been reported in the uterus,46–48
but whether the uterus is the source or another target of
metastases has been the subject of debate. Single-cell
RNA sequencing of lungs from patients with LAM
reveals an ectopic population of mesenchymal cells that
express a uterine transcriptional programme, consistent
with a uterine source.15 The same cellular transcriptional
profile was discovered in a mesenchymal subpopulation
by single-nuclear RNA sequencing of the uterus from a
patient with sporadic LAM, and identical TSC2 mutations
were present in the uterus and lungs, also consistent
with a mechanism involving uterine metastasis. Other
potential sources must exist given the occurrence of
LAM in males, and presumably would overlap with
locations where perivascular epithelioid cell tumours
have been found, including the kidney, bladder, prostate,
gastrointestinal tract, soft tissue, and bone.
Sex hormone dependence
LAM has the strongest sex predilection of any non-
genitourinary neoplasm. The almost exclusive restriction
of symptomatic LAM to women strongly suggests
that female hormones play an important part in the
development and progression of the disease. LAM
cells uniformly express oestrogen and progesterone
receptors.49,50 Pulmonary symptoms worsen immediately
before and during menses in around 30% of women
with LAM, and exogenous oestrogen use and pregnancy
have been associated with accelerated decline in lung
function.51–55 Oestrogen promotes anoikis resistance,
 Review

Ligand Oestrogen

RTK RTK inhibitors Oestrogen receptor antagonist

Oestrogen receptor

TSC1
TSC2

TBC1D7
(Inactive) Rheb-GDP
GAP

(Active) Rheb-GTP TSC Complex

resistance

metabolism
Glucose
Anoikis

MEK–MAPK B-Raf Raptor Rictor Akt

mTOR mTOR
MEK inhibitors
Sirolimus mTORC2
mTORC1
Lung remodelling and LAM cell metastasis

Angiogenesis

Everolimus

Cell survival and metastasis

HIF1α
Simvastatin

movement
Cell
VEGF-A

ROCK–RhoA
Lymphangio-

VEGF-C and VEGF-D

genesis

VEGFR3
inhibitors metabolism
Prostaglandin

Celecoxib
Extracellular matrix

MMP or CatK
inhibitors
P38

Resveratrol COX2
dynamics

FKB

TFEB

Hydroxychloroquine Mizoribine
MMP
ULK1

CatK
BCL2 4E-BP1 p70S6K IMPDH SREBP

Mitochondrial Lysosome Protein Nucleotide Lipid

Autophagy
degradation biogenesis translation synthesis synthesis

Apoptosis Cell survival Cell proliferation and growth

Figure 1: Dysregulation of signalling pathways in LAM pathogenesis reveals targets for LAM clinical trials
The TBC1D7, TSC1, and TSC2 protein complex inactivates GTPase Rheb via a GAP moiety on TSC2. Rheb suppression of B-Raf leads to inactivation of MEK–MAPK
signalling. Mutations in TSC1 or TSC2 result in an activation cascade that includes GTP-loaded Rheb, Raptor-containing mTORC1, and p70S6K, and pathways that
upregulate IMPDH, SREBP, HIF-1α, VEGF-A, VEGF-C, VEGF-D, MMPs, and CatK; and inhibit 4E-BP1, ULK1, TFEB, and BCL2. Rictor-containing mTORC2 activates Akt,
ROCK–RhoA, and COX2. Oestrogen stimulates activation of MEK–MAPK and Akt. RTKs mediate activation of STAT and MEK–MAPK signalling. Dysregulated mTOR
signalling in LAM cells alters the processes shown in blue boxes and cell behaviours shown in red boxes. Agents studied in clinical trials are shown in bold.
4E-BP1=eukaryotic translation initiation factor 4E-binding protein 1. Akt=AKT serine–threonine protein kinase. BCL2=B-cell lymphoma 2. B-Raf=V-Raf murine sarcoma
viral oncogene homologue B1. CatK=cathepsin K. COX2=cyclooxygenase 2. FKBP38=FK506-binding protein 38. GAP=GTPase-activating protein. HIF-1α=hypoxia-
inducible factor 1α. IMPDH=inosine 5’-monophosphate dehydrogenase. LAM=lymphangioleiomyomatosis. MAPK=mitogen-activated protein kinase. MEK=MAPK
kinase. MMP=matrix metalloproteinase. mTOR=mechanistic target of rapamycin. mTORC1=mTOR complex 1. p70S6K=70 kDa ribosomal protein S6 kinase. Rheb=Ras
homologue enriched in brain. RhoA=Ras homologue family member A. ROCK=Rho-associated protein kinase. RTK=receptor tyrosine kinase. SREBP=sterol regulatory
element-binding protein. STAT=signal transducer and activator of transcription. TBC1D7=TBC1 domain family member 7. TFEB=transcription factor EB. TSC=tuberous
sclerosis complex. ULK1=Unc-51-like autophagy-activating kinase 1. VEGF=vascular endothelial growth factor.

survival and pulmonary metastasis of tuberin-null function decline in LAM is more rapid in premenopausal
cells in preclinical models,48,56–59 and phosphorylation of women and slows down after menopause,64 retrospective
pro-survival kinases MAPK and Akt in uterine leiomyoma- case series of anti-hormonal interventions have yielded
derived ELT3 cells from Eker rats60,61 and in cells derived conflicting results. The only randomised trial of an anti-
from patients with LAM (figure 1).35,58,62,63 Although lung oestrogen strategy in LAM showed that the aromatase

www.thelancet.com/respiratory Published online August 27, 2021 https://doi.org/10.1016/S2213-2600(21)00228-9 3

 Review
inhibitor letrozole was safe in postmenopausal women,
but the study underenrolled women and was not
adequately powered to address questions of efficacy.65
Presentation and clinical features
Spontaneous pneumothorax in a woman in her fourth or
fifth decade of life, especially when recurrent, is a classic
presentation of LAM.66 The number of patients with
LAM who first seek medical attention for progressive
dyspnoea is almost equal to that of patients presenting
with pneumothorax, with the initial evaluation often
revealing an unremarkable chest radiograph and an
obstructive defect on spirometry. Presentation with
dyspnoea is almost invariably initially interpreted as
asthma or chronic obstructive pulmonary disease, and
the diagnosis of LAM is often delayed for another
3–5 years until suspicions are raised by the absence of a
pattern of exacerbations and remissions, or lack of
response to conventional therapy. Chylothorax is the
presenting manifestation in approxi­ mately 20% of
patients, and chylous ascites occurs in around 5% of
patients.7 Additional atypical presentations include
haemoptysis, abdominal pain due to angio­myolipoma
rupture or lymphangioleiomyoma distension, or appear­
ance of chyle in sputum, urine, stool, or vaginal
discharge. Increasingly, LAM and angiomyolipoma are
discovered as incidental findings on imaging done for
other purposes.
Regardless of the mode of presentation, a CT scan of
the chest that reveals diffuse, thin-walled cystic change is
the key to correct diagnosis. For a definitive diagnosis,
tissue or cytological confirmation is required, but a
clinical diagnosis can be achieved with a compatible CT
and at least one other accompanying feature, such as a
diagnosis of TSC, an angiomyolipoma, elevated VEGF-D
(≥800 pg/mL), a chylous effusion, or a lymphangio­
leiomyoma.16,18 Doing a chest CT for patients presenting
with spontaneous pneumothorax to screen for the
presence of underlying cystic lung diseases such as LAM,
Birt-Hogg-Dubé syndrome, and pulmonary Langerhans
cell histiocytosis has been shown to be cost-effective.67,68
We recommend CT screening for the first event of
pneumothorax in women of childbearing age, for all
women with recurrent pneumothorax or spontaneous
bilateral pneumothorax, and for those aged 18 years or
older with TSC.67,69,70
Angiomyolipomas are benign mixed mesenchymal
tumours that are most often found in the kidneys but can
occur in the liver, lung, bowel, bladder wall, and at other
sites. Angiomyolipomas occur in around 30–40% of
women with sporadic LAM and almost 90% of women
with TSC-LAM.7,8 Sporadic angiomyolipomas are
common in the general population, occurring as an
incidental finding in almost 1 in 100 abdominal CTs, and
have been associated with cystic pulmonary changes
consistent with LAM in around 12% of patients in a
referral population.71 Most of these tumours are small
4 www.thelancet.com/respiratory Published online August 27, 2021 https://doi.org/10.1016/S2213-2600(21)00228-9
and asymptomatic, but those greater than 4 cm or
containing aneurysmal blood vessels are prone to
haemorrhage.72 Large, multiple, and bilateral tumours
are more typical of TSC-LAM than sporadic LAM, and
more rapid growth has been reported in patients with
large tumours and during pregnancy.73–75 Chronic
abdominal pain can occur, and a haemorrhage turning
into an angiomyolipoma can result in acute abdomen,
life-threatening blood loss, and death.76
Dyspnoea in LAM results from the replacement of
lung parenchyma with cysts, airway narrowing due to
reduced elastic recoil or direct involvement of airways,
reactive airway disease, chylous congestion of the
parenchyma, chylous effusions, or pneumothorax.
Pneumothoraces and chylothoraces in LAM are often
refractory to conservative treatment and can recur even
after well executed pleurodesis.77,78 The causes of
pleurodesis failure are unknown, but infiltration of
pleura with LAM cells or prevention of close apposition
of the visceral and parietal pleural surfaces by blebs
might play a part. Infiltration of axial and mesenteric
lymphatic tissues by LAM cells can lead to lymph­
adenopathy, thoracic duct enlargement and occlusion,
lymphangioleiomyomas, or weeping masses of dys­
plastic tissue (most often in the omentum), resulting
in chylous pleural effusions and ascites.79,80 Chylous
pericardial effusions, chyloptysis, and chyluria are also
occasionally seen, often due to atypical communications
between hollow viscera, airways, or potential spaces.
Abdominopelvic lymphatic disease can cause protein-
losing enteropathy, abdominal bloating, and distention
that sometimes worsens throughout the day due to
gravitational engorgement and increase in size of the
lymphangioleiomyomas.81
Evaluation and diagnosis
Diagnostic approach
When cystic change compatible with LAM is found on
chest CT—whether identified by the screening of
women with TSC or pneumothorax, revealed incidentally
on scans done for another purpose, or discovered during
evaluation for recurrent pneumothorax, progressive
dyspnoea, or chylous complications—the objective is to
exclude other diffuse cystic lung diseases in the differ­
ential and establish a diagnosis of LAM using the least
invasive means possible. The diseases that can mimic
LAM radiologically include emphysema, Birt-Hogg-Dubé
syndrome, follicular bronchiolitis or lymphoid inter­
stitial pneumonia, amyloidosis, light-chain deposition
disease, and pulmonary Langerhans cell histiocytosis.
Although a chest CT is not typically sufficient to defini­
tively distinguish between these entities,82 the radio­
logical characteristics of cysts—including distribution,
wall thickness, internal structure, and relationship to
other structures—can provide helpful clues.
Laboratory evaluation should include testing to rule out
the following conditions: α1-antitrypsin deficiency, which

can predispose patients to emphysema; connective
tissue diseases, which can be associated with follicular
bronchiolitis or lymphoid interstitial pneumonia (such
as rheumatoid factor, antinuclear antibodies, anti-Ro,
and anti-La); and lymphoproliferative disorders such as
multiple myeloma (including serum and urine protein
electrophoresis and serum free light chains). A serum
VEGF-D value greater than 800 pg/mL is reasonably
sensitive and highly specific for the diagnosis of LAM.
A dedicated abdominopelvic CT to screen for lymph­
angioleiomyomas and renal and extrarenal angio­myo­
lipomas should be considered, because ident­ification of
these entities can obviate the need for biopsy. However,
in some situations in which a firm diagnosis cannot be
established in a non-invasive way, a lung biopsy might be
needed to guide treatment, especially in symptomatic
patients with substantial disease burden and those with
atypical features suggestive of other causes.
Pulmonary function testing
Pulmonary function tests are useful for determining
the severity of pulmonary dysfunction and for guiding
therapy. LAM causes diffuse infiltration of the pulmonary
interstitium with smooth muscle cells and cystic
remodelling of the lung parenchyma, which have
opposing effects on elastic recoil. Additionally, extensive
infiltration of the airways with LAM cells results in chronic
inflammation, goblet cell hyperplasia, and squamous cell
metaplasia of the epithelium, all of which contribute to
increased airflow resistance and reversible airflow
obstruction.83 These unique pathological features result in
physiological patterns that are unusual among interstitial
lung diseases. Airflow obstruction is the most common
physiological manifestation of LAM, but restrictive or
mixed patterns might also occur. Air trapping in the form
of elevated residual volume is often evident when
measured by plethysmography but not always by gas
dilution, suggesting poor communication between air­
ways and cystic spaces,7 as confirmed by a hyperpolarised
¹²⁹Xe MRI study.84 Reversible airflow obstruction is
present in approximately 20–30% of patients and has been
reported to correlate inversely with prognosis.64,85 Diffusion
capacity is reduced in up to 90% of patients7 and, along
with elevated residual volume, is often the first pulmonary
function abnormality that develops.
Radiological evaluation
Early in the disease course, the chest radiograph is often
normal or might show features of a subtle increase
in interstitial markings or a pleural effusion. As LAM
progresses, reticular or nodular opacities, pleural thick­
ening, lymphadenopathy, or hyperinflation can appear.7,86
A chronic or acute pneumothorax is occasionally
discovered as an incidental finding in asymptomatic
patients (figure 2).87
Thin-walled cysts on chest CT are essential for the
diagnosis of pulmonary LAM (figure 2). Radiologically,
www.thelancet.com/respiratory Published online August 27, 2021 https://doi.org/10.1016/S2213-2600(21)00228-9
Review
pulmonary cysts are defined as spherical parenchymal
lucencies or low-attenuating areas with a well defined
boundary with normal appearing lung.88 LAM cysts
are thin-walled, bilateral, diffusely distributed, round,
2–30 mm in size, and typically devoid of internal
structure.16,18,74,87,89,90 Over time, cysts might coalesce and
become polygonal or atypically shaped.87,89 Pulmonary
cysts can occur as a normal consequence of ageing;91
therefore, a minimum number of four cysts has been
suggested as the threshold for considering a pathological
origin of cysts,69 and four71,92 or ten16 cysts as the threshold
for establishing a diagnosis of LAM in patients with
TSC.93
Other radiological features that might be identified on
CT chest include focal ground-glass opacities, which
occur secondary to proliferation of smooth muscle cells,
pulmonary haemorrhage, lymphatic congestion (a form
of interstitial pulmonary oedema), or alveolar filling
with lymphatic fluid (figure 2).89,94 Other thoracic
lymphatic manifestations of LAM include septal
thickening, chylothorax, pericardial effusion, thoracic
duct dilatation, mediastinal lymph node enlargement,
and rarely, cystic lymphangioleiomyomas.77,89,95 Centri­
lobular nodules have also been reported, suspected to be
a manifestation of smooth muscle infiltration and
macroscopic nodule formation.89 Features of multifocal
micronodular pneumocyte hyperplasia, resulting from
benign pro­liferation of type 2 alveolar epithelial cells,
might occur in patients with TSC-LAM.96
Several radiological features can help to distinguish
LAM from other diffuse cystic lung diseases.18,89 The
A B C
D E F
Figure 2: Radiological features of LAM
(A) Chest radiograph showing a small-to-moderate right pneumothorax (arrow). (B) Axial CT of the thorax
showing scattered thin-walled pulmonary cysts with uniform shape. (C) Axial CT thorax showing diffuse cysts,
a large loculated left chylous pleural effusion, and smooth interlobular septal thickening secondary to lymphatic
congestion (arrow). Images A–C courtesy of David Murphy (St Vincent’s University Hospital, Dublin, Ireland).
(D) MRI coronal maximum-intensity projection image of the abdomen and pelvis acquired with a heavily
T2-weighted sequence with fat suppression, showing a grossly dilated left pelvic sidewall and retroperitoneal
lymphatics (arrows). (E) Axial CT image of the upper abdomen showing a large vascular fatty mass (arrow) arising
from the interpolar region of the right kidney and displacing abdominal and retroperitoneal structures compatible
with a large angiomyolipoma. (F) Hyperpolarised ¹²⁹Xe ventilation MRI image showing ventilation heterogeneity
within pulmonary cysts. Image F courtesy of Laura Walkup (Cincinnati Children’s Hospital Medical Center,
OH, USA). LAM=lymphangioleiomyomatosis.
5
 Review
A B
0 1 2 3 4 5 mm 0 0·2 0·4 0·6 0·8 1 mm
C D
0 20 40 60 80 100 μm
Figure 3: Histopathological appearance of LAM
(A) Low-power lung biopsy stained with haematoxylin and eosin showing cystic spaces and LAM nodules
interspersed with normal lung parenchyma. (B) Lung biopsy stained with α smooth muscle actin to highlight LAM
nodules, which stain brown. Nodules appear within lung parenchyma (green arrow), surrounding cystic spaces
(red arrow), and within small lymphatics (blue arrow). (C) High-power view of a LAM nodule stained with PNL2
monoclonal antibody, showing LAM cells marked with granular cytoplasmic brown staining representing
pre-melanosomes (green arrow). (D) Dual immunostaining of a LAM nodule for the LAM cell marker
glycoprotein 100 (brown) and the lymphatic endothelial marker podoplanin (blue), showing clefts lined by
lymphatic endothelial cells within LAM nodules (green arrow). Immunostaining done by Suzanne Miller and
Debbie Clements (University of Nottingham, Nottingham, UK). Reproduced from Miller and colleagues,108
by permission of John Wiley and Sons. LAM=lymphangioleiomyomatosis.
presence of nodules, upper lobe predominance, thicker
cyst walls, atypical cyst shapes, and relative sparing of the
bases could indicate pulmonary Langerhans cell histio­
cytosis. Cysts in Birt-Hogg-Dubé syndrome are thin
walled, round or elliptical, predominant in the lower
zone, often paramediastinal, and closely associated with
pleura and blood vessels, whereas those in follicular
bronchiolitis or lymphoid interstitial pneumonia tend to
contain internal septae, are bordered by eccentric vessels,
and are more variable in size.97,98 Despite sensitivity
and specificity for a LAM diagnosis of around 90%,
characteristic cystic disease on CT alone is not considered
sufficiently diagnostic of LAM to support long-term
therapy with sirolimus.17,18,82
Serum VEGF-D
The 2016–17 American Thoracic Society and Japanese
Respiratory Society clinical practice guidelines17,18 support
the use of serum VEGF-D as a diagnostic test when LAM
is suspected in women with a compatible CT, even if other
confirmatory features such as TSC, angiomyolipoma,
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lymphangioleiomyoma, or chylous effusion are not
present. A serum VEGF-D concentration of more than
800 pg/mL in the presence of characteristic cysts on CT is
associated with a sensitivity of approximately 60–70% and
specificity of nearly 100% for distinguishing LAM from
other cystic lung diseases, whereas concentrations greater
than 600 pg/mL have a sensitivity of 84% and specificity
of 98%.12,18,99 In a woman with a compatible chest CT, a
serum VEGF-D concentration of more than 800 pg/mL
obviates the need for lung biopsy, concentrations between
600–800 pg/mL are highly suspicious for LAM, and values
of less than 600 pg/mL are considered uninformative and
do not exclude LAM. Commercially available VEGF-D
testing is offered in the USA, but ready access to
standardised, quality-controlled, and third-party payer
reimbursable VEGF-D testing remains a global need.
Pathological evaluation
The decision to proceed to biopsy should be made jointly
by the physician and patient, and considered only when
minimally invasive measures have been unsuccessful
and the benefit of a diagnosis exceeds the risk.18 In
patients with mild disease, a clinical diagnosis of
probable LAM with regular monitoring might suffice,
especially if the care plan would not be altered by a
definite diagnosis and the patient is comfortable with a
degree of diagnostic uncertainty.16,18
Although surgical lung biopsy was previously considered
the gold standard, transbronchial lung biopsy has been
reported in a small series100 to have an estimated diagnostic
yield of more than 50%, and might be useful in some
cases. The yield and safety of transbronchial lung biopsy
and the newer technique of transbronchial cryobiopsy
require further study. The diagnostic yield of surgical
lung biopsy is almost 100% and might be required to
distinguish between LAM, follicular bronchiolitis or
lymphoid interstitial pneumonia, pulmonary Langerhans
cell histiocytosis, and amyloidosis or light-chain deposition
disease when less invasive methods are inadequate.
However, surgical lung biopsy is associated with risks of
general anaesthesia, the potential for intraoperative
pneumothorax, persistent air leak, and chronic chest pain
due to intercostal nerve compression.18
Expert pathological consultation is a key component of
diagnosing LAM. LAM cells are spindle shaped or
epithelioid with few mitoses and a bland appearance.
These cells have features of smooth muscle that can be
identified by antibodies, including smooth muscle actin,
and pre-melanocytic lineages identified by human
melanoma black (HMB-45) antibody.101 LAM cells also
express oestrogen receptors α and β and progesterone
receptor.102,103 This unusual immunohistochemical profile
is seen in all perivascular epithelioid tumours, often
termed PEComas, which in addition to LAM also
include angiomyolipoma and clear cell tumours.104
Immunostaining for HMB-45 is useful diagnostically
especially when examining small samples such as
 Review

transbronchial biopsies, although in rare cases, LAM

lesions do not express this marker.105 As the disease Clinical presentation and CT
features suggestive of LAM
progresses, lung cysts increase in number and LAM cells
form characteristic nodules and line the walls of cysts
and small airways.79 Hyperplastic alveolar type 2 cells are Detailed clinical review* confirms
Yes
Confirmed diagnosis
the presence of TSC of TSC-LAM
found lining cysts in a discontinuous manner and
surrounding LAM nodules.106 The stroma of LAM
nodules evolves to become more abundant and complex, No
comprising fibroblasts, T cells, and mast cells, such that
only a proportion (4–60%) of cells in the mature LAM
Abdominopelvic imaging Confirmed diagnosis
lesion contains TSC mutations.107,108 Lymphatic clefts (non-contrast CT or MRI) reveals of LAM
lined by LYVE1, podoplanin, and VEGFR3-positive angiomyolipomas or Yes
lymphangioleiomyomas
lymphatic endothelial cells are found in and around LAM
nodules (figure 3).109 Interactions between multiple cell
types within nodules are thought to facilitate LAM cell No
growth and survival, and the production of tissue-
damaging proteases.110–113 A stepwise algorithm to guide
the diagnosis of LAM in patients with compatible clinical Serum VEGF-D concentration Confirmed diagnosis
Yes
≥800 pg/mL of LAM
presentation and chest CT findings is shown in figure 4.
The management of LAM is shown in the table.
No
Pharmacological treatment
mTORC1 inhibitors Confirmation of chyle by chemical Confirmed diagnosis
Discovery of the central role of activated mTORC1 analysis in patients with pleural of LAM
signalling in LAM pathogenesis formed the basis for effusions or ascites, or both, or
Yes
the presence of LAM cells by
trials of the mTORC1 inhibitor sirolimus (rapamycin) as cytological examination of
a potential treatment for LAM. In an open-label pilot effusions or lymph node aspirates
study9 in patients with TSC or LAM, the use of sirolimus
for 12 months led to an almost 50% reduction in No
angiomyolipoma size (n=20) and an improvement in
FEV1 and forced vital capacity (FVC), along with a
reduction in residual volume in patients with LAM (n=11). Is there a need to obtain Probable diagnosis
histopathological confirmation of LAM; serial PFT
These results led to the pivotal MILES trial (NCT00414648), on the basis of symptom severity, No monitoring done to
a randomised, double-blind, placebo-controlled, phase 3 disease extent on CT or PFTs, or assess disease
both, and patient preferences? progression
trial in which 89 women with LAM and abnormal lung
function (percentage of predicted FEV1 ≤70%) were
assigned (1:1) to receive sirolimus or placebo for Yes
12 months followed by 12 months of off-treatment
observation. During the 12-month treatment period, FEV1
Lung biopsy done; we suggest a Confirmed diagnosis
declined at a rate of –12 mL (SD 2 mL) per month in the stepwise approach, with of LAM
placebo group and increased by 1 mL (SD 2 mL) transbronchial biopsy considered
before a VATS-guided lung biopsy
per month in the treatment group (p<0·001). Treatment
with sirolimus also led to an improvement in the FVC
slope and in overall quality of life, and a reduction in Figure 4: Methods for the diagnosis of LAM
Methods presented from least (top) to most (bottom) invasive. *Includes
serum VEGF-D concentrations compared with placebo. detailed family history for TSC and seizures or cognitive impairment, physical
During off-treatment observation, the FEV1 decline examination focused on facial angiofibromas, subungual fibromas, shagreen
resumed in the sirolimus group at a similar rate to that of patches, dental pitting, hypomelanotic macules, confetti lesions, and imaging
the placebo group. These results indicate that sirolimus is review for the presence of cortical dysplasias, subependymal nodules,
and subependymal giant cell astrocytomas. LAM=lymphangioleiomyomatosis.
an effective suppressive treatment for LAM that stabilises PFT=pulmonary function test. TSC=tuberous sclerosis complex.
lung function decline while the therapy continues, but VATS=video-assisted thoracoscopic surgery. VEGF-D=vascular endothelial
that disease progression resumes upon cessation of growth factor D.
treatment.11
The beneficial effect of sirolimus and another mTORC1 Sirolimus was also shown to be helpful in managing
inhibitor, everolimus, in patients with LAM has been lymphatic manifestations of LAM, such as chylous
reported in multiple other studies.118,119,135–142 Although not effusions and lymphangioleiomyomas.18,118,119 Questions
studied as rigorously, everolimus appears to have similar about the long-term safety and efficacy of sirolimus for
efficacy to sirolimus in the management of LAM.135 LAM await results from the MIDAS Registry

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 Review
Pneumothorax18,77,78,114,115
Angiomyolipoma9,69,72,116,117
Lymphatic
complications17,118–120
End-stage respiratory
failure121–126
Vaccinations127–129
Pulmonary rehabilitation130 Shown to improve exercise capacity, 6-min walk distance, and quality of life Pulmonary rehabilitation programme an option in patients with reduced physical
Supplemental oxygen
Pregnancy52,55,131,132
Bone density16,133,134
LAM=lymphangioleiomyomatosis. mTORC1= mechanistic target of rapamycin complex 1. PaO2=partial pressure of arterial oxygen. SpO2=blood oxygen saturation. TSC=tuberous sclerosis complex.
Table: Management considerations in patients with LAM
8 www.thelancet.com/respiratory Published online August 27, 2021 https://doi.org/10.1016/S2213-2600(21)00228-9
Considerations
High rate of recurrent pneumothorax
Risk of haemorrhage in large angiomyolipomas
Pleural drainage might be needed to relieve dyspnoea or abdominal
distension from large effusions; mTORC1 inhibitors might take several
months for full effect
Discuss with transplant team, consider continued mTORC1 inhibitor use or
switching to mTORC1 inhibitor with shorter half-life such as everolimus
while on transplant waiting list; stop treatment immediately before
transplantation; previous pleurodesis should not be considered a
contraindication for lung transplantation
Avoid live vaccines in patients taking mTORC1 inhibitors
activity
Required in patients with hypoxia
Often associated with accelerated disease progression and increased risk of
spontaneous pneumothorax
Low bone mineral density is prevalent in patients with LAM
(NCT02432560), but a 2014 US National Institutes of
Health report of 12 patients who received long-term
sirolimus therapy indicated that the drug has durable
efficacy and an acceptable safety prolife during 5-year
follow-up.139 The American Thoracic Society and Japanese
Respiratory Society clinical practice guidelines recom­
mend using sirolimus as first-line treatment for patients
with LAM who meet at least one of the following criteria:
percentage of predicted FEV1 of 70% or less, chylous
complications, rapidly declining lung function (FEV1
decline ≥90 mL per year), or other measures suggesting
substantial disease burden such as abnormal diffusion
capacity, air trapping, hyperinflation, or the need for
supplemental oxygen.17 Sirolimus is approved for the
treatment of LAM by the US Food and Drug Adminis­
tration, the European Medicines Agency, and regulatory
agencies in multiple other countries such as Japan,
South Korea, Brazil, Russia, and Uruguay.
In general, sirolimus is a well tolerated drug with a
favourable side-effect profile. The most common adverse
events related to sirolimus in the MILES trial were
nausea, diarrhoea, mucositis, acne, lower-extremity
swelling, and hyperlipidaemia.11 Adverse events are most
Management options and indication
Video-assisted thoracoscopic surgery-guided mechanical pleurodesis after first
pneumothorax; chemical pleurodesis, talc pleurodesis, or pleurectomy for recurrent or
refractory pneumothorax
Surveillance imaging every 12–24 months (angiomyolipomas <3 cm); mTORC1
inhibitors (angiomyolipomas >3 cm), especially in patients with significant
concomitant pulmonary disease or with multiple, bilateral or symptomatic, growing
angiomyolipomas; embolisation, especially for single lesion with high burden of
aneurysmal vessels, if refractory to mTORC1 inhibitors, or if sole indication for
mTORC1 inhibitors; surgical resection for large, complex lesions refractory to mTORC1
inhibitors or if concern for malignant transformation (nephron-sparing surgeries
preferred, total nephrectomy as a last resort)
mTORC1 inhibitors as preferred first-line treatment; lymphatic imaging and thoracic
duct embolisation for recurrent or refractory cases
Lung transplantation for end-stage respiratory failure, as defined by one of the
following: FEV1% predicted of 30% or less, resting hypoxaemia, progressive lung
function decline, New York Heart Association functional class 4
Annual influenza vaccination with inactivated vaccine, pneumococcal vaccination
with PCV13 and PPSV23 for all patients with LAM; herpes zoster vaccination with
recombinant zoster vaccine for patients >50 years or those on mTORC1 inhibitors
(regardless of age)
Ambulatory oxygen or long-term oxygen therapy (resting room air PaO2 <7·3 kPa and
SpO2 desaturation with exercise or sleep)
Counselling for all patients with LAM about potential risks; genetic counselling for
prospective mothers with TSC-LAM; mTORC1 inhibitors withheld before conception
and throughout pregnancy; close monitoring of patients with LAM during pregnancy
Dual-energy x-ray absorptiometry scan done periodically; treatment for low bone
mineral density as per guidelines in all postmenopausal patients, those with
substantial impairment in mobility, and those receiving anti-oestrogen agents
common in the first 6 months of therapy and decrease
over time.14,136,137,140 In the MILES trial, sirolimus was
started at 2 mg per day and the dose was titrated to
maintain a blood trough of 5–15 ng/mL, with a
mean sirolimus trough concentration of 7·2 ng/mL.11,14
Subsequent studies136,119 have suggested that lower doses
of sirolimus might have similar treatment efficacy and a
reduced incidence of adverse events, but one study143
found better treat­ment response with higher sirolimus
doses. Further investigation is required to define the
optimal sirolimus dosing strategy for patients with LAM
that maximises efficacy and balances the risk of adverse
events.
Other pharmacological agents
Reversible airflow obstruction can be seen in approximately
20% of patients with LAM,7,144 and a therapeutic trial of
bronchodilators should be considered for symptomatic
patients, especially those with an obstructive defect on
spirometry.16 Doxycycline is active against several matrix
metalloproteinases,145 and was believed to be a promising
drug for LAM on the basis of a 2006 case report.146 However,
subsequent investigations did not show a beneficial

effect,147–150 and routine use of doxycycline in LAM is not
recommended.18 Owing to the female predominance of
LAM, the slowing of lung function decline after
menopause, and reports of disease worsening with
exogenous oestrogen supplemen­ tation,53 several hor­-
monal agents such as selective oestrogen receptor
modulators,66,151 proges­terone,51,66,131,152,153 aromatase inhib­
itors,65 gonadotropin-releasing hormone agonists,154–156 and
surgical procedures such as oophorectomy66,131,157–159 have
been attempted as potential treatments for LAM with
inconsistent and often inconclusive results. Currently,
anti-oestrogen treatments are not recommended outside
of clinical trials, although further studies including
combination therapies with mTORC1 inhibitors and anti-
oestrogen agents are warranted.16,18 Early-stage investi­
gations of statins,160 hydroxychloroquine,161 and celecoxib162
in LAM have been published, but larger studies are needed
to determine their clinical effects. Exciting new data from
cell and animal models suggest that immune checkpoint
inhibitors and purine and pyrimidine nucleotide ana­
logues might have the potential to induce LAM cell death.41
Spontaneous pneumothorax
Patients with LAM should be informed about the signs
and symptoms of pneumothorax and counselled to seek
medical attention promptly if symptoms develop. Given
the high rate of pneumothorax recurrence after con­
servative treatment,77,78,114,115 pleurodesis is recommen­ded
with the first episode of spontaneous pneumothorax
rather than during recurrent events.18 Pleurodesis can
reduce the 70% risk of recurrence with conservative
treatment to around 30%.78 Video-assisted thoracoscopic
surgery-guided mechanical abrasion is generally the
preferred method for initial pleurodesis, with chemical
pleurodesis using agents such as talc reserved for
recurrent or refractory episodes.18 Another technique
that has been used successfully to prevent recurrent
pneumothoraces is total pleural covering, in which the
visceral pleural surface is reinforced with a bioabsorbable
mesh.163 However, this technique is currently available
only at select centres in Japan and requires specialised
technical expertise, limiting its generalised application.
Although not yet studied rigorously, treatment with
sirolimus might help to reduce the risk of recurrent
pneumothoraces.164 Notably, because of the delayed
wound healing associated with sirolimus, stopping the
drug for 2–4 weeks after the resolution of a pneumo­
thorax before reinitiating might be prudent. The
atmospheric pressure changes associated with air travel
might cause expansion of pulmonary cysts and lead to
spontaneous pneumothorax in patients with LAM, with
a risk that has been estimated to range from one to
two episodes per 100 flights.115,165,166 Although patients
should be counselled regarding this risk and the
potential need for supplemental oxygen in flight, most
LAM clinicians do not recommend restricting air
travel.167
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Review
Lymphatic involvement
The most common lymphatic complications encountered
in patients with LAM include the following: lymphaden­
opathy; lymphangioleiomyomas of the pelvis, abdomen,
or mediastinum; and chylous fluid collections in pleural
or peritoneal cavities. Drainage procedures might be
needed to confirm the chylous nature of the fluid at initial
presentation or to relieve dyspnoea from large effusions;
however, cystic lymphangioleiomyomas generally should
not be biopsied, drained, or resected given the risk of
inducing a chronic leak. Sirolimus was shown to be
effective at reducing chylous accumulation,118–120 and is
the preferred first-line treatment option for chylous
complications in LAM rather than invasive procedures.17
Notably, in some patients sirolimus might take several
months to be effective for chylous indications. Invasive
options such as thoracic duct embolisation should be
reserved for recurrent or refractory cases and considered
only if the source of the leak is identified through
specialised lymphatic imaging techniques.168
Pregnancy and LAM
Pregnancy in patients with LAM has been associated with
accelerated disease progression and increased incidence
of spontaneous pneumothorax.52,55,131,132 Uneventful preg­
nancies have also been reported.77 In an analysis
involving 16 pregnant patients with LAM who had lung
function data available for the pre-pregnancy and
post-pregnancy periods, accelerated rate of decline in
FEV1 and diffusing capacity of the lungs for carbon
monoxide (DLCO) was noted during and after pregnancy
in most patients. A third of patients (five of 16) had
spontaneous pneumothorax during pregnancy.52 Patients
with LAM who are considering becoming pregnant
should be counselled about the potential risks, which
depend partly on the pulmonary reserves of the mother.169
Although not known to be teratogenic, in animal models,
sirolimus has been associated with intrauterine fetal
demise and is excreted in breastmilk. Safe use of
sirolimus throughout pregnancy has been reported in
patients who had a renal transplant and in at least one
patient with LAM;170,171 however, the long-term safety and
efficacy of sirolimus for mother and child requires
further investigation.
Lung transplantation
Lung transplantation is a viable management option for
patients with LAM and end-stage disease. Outcomes after
lung transplantation are similar to121–123 or better than124–126
post-transplant outcomes in other chronic pulmonary
conditions. In a 2019 analysis, Khawar and colleagues126
evaluated outcomes in 134 patients with LAM who had a
lung transplant in the USA between 2003 and 2017, and
reported a remarkable median post-transplant survival of
12 years, with a survival rate of 94% at 1 year, 73% at
5 years, and 55% at 10 years. Previous pleurodesis is
not a contraindication for lung trans­plantation.18,172 Use
9
 Review
of sirolimus in the immediate post-operative period
following lung transplantation has been associated
with increased risk of dehiscence of the bronchial
anastomosis.173 However, premature discontinuation of
sirolimus before transplantation can put patients at
risk of precipitous lung function decline. Given that
most cases of bronchial dehiscence occur 4–6 weeks
post-transplantation, after the sirolimus wash-out period
(<1 week), some centres have adopted a policy of
continuing sirolimus until the day of surgery, or a change
to an mTORC1 inhibitor with a shorter half-life, such as
everolimus, upon placement on the waiting list.174,175
Natural history and prognosis
LAM is a gradually progressive disease with over half of
patients estimated to have MRC grade 3 dyspnoea (when
walking on a level surface) 10 years after symptom
onset,176 although these data were collected before the
routine use of mTORC1 inhibitors as therapy. The rate of
decline in FEV1 in patients with LAM is variable (range
47–134 mL per year).11,51,64,152,131,177,178 In a prospective,
longitudinal analysis of 230 patients with LAM enrolled
in the US National Heart, Lung, and Blood Institute
(NHLBI) LAM Registry, the mean rate of decline in FEV1
was 89 mL (SD 53 mL) per year.64
Premenopausal women with LAM have a faster rate of
decline in FEV1 than do postmenopausal women.14,51,64,152,177
In a post-hoc analysis of the placebo cohort from the
MILES trial, FEV1 in premenopausal women declined
approximately five-times faster than in postmenopausal
women (approximately 200 mL per year vs 40 mL
per year; p=0·003).14 Similarly, the rate of decline in
FEV1 in the NHLBI cohort was 44 mL per year lower in
post­
menopausal women than in premenopausal
women (74 mL per year vs 118 mL per year; p=0·003).64
Search strategy and selection criteria
We searched MEDLINE and PubMed from database inception
to April 28, 2021, for reviews and original research papers
about lymphangioleiomyomatosis, published in English.
We used the terms “lymphangioleiomyomatosis”, “LAM”,
and “lymphangiomyomatosis” in combination with
“pathogenesis”, “diagnosis”, and “treatment”. We also
searched individual terms such as “mTOR inhibitors”,
“tuberous sclerosis complex”, “sirolimus”, “rapamycin”,
“angiomyolipoma”, “lymphangioleiomyoma”, “chylothorax”,
and “lung transplantation”. We focused on studies published
in the past 20 years, although we did not exclude earlier
reports, especially if they were unique or high-quality clinical
trials. We also searched the reference lists of articles identified
using this search and our own personal files. We used original
reports where available, with the aim of highlighting the
most important advances in the field and providing a
comprehensive overview of pathogenesis, diagnosis,
and management.
10 www.thelancet.com/respiratory Published online August 27, 2021 https://doi.org/10.1016/S2213-2600(21)00228-9
Elevated baseline serum VEGF-D concentrations are
linked to faster disease progression in some studies13,14,179
but not others.64,180–182 Similarly, a positive response to
bronchodilators has been linked to faster disease
progression,64,85 although this association was not seen
in the MILES trial.14 Neither baseline FEV114,51,64 nor the
presence or number of spontaneous pneumothoraces64
seems to have a significant effect on future rate of
decline in FEV1.
The median survival of patients with LAM is estimated
at more than 20 years after diagnosis,64,183 with a transplant-
free survival probability of 94% at 5 years, 85% at 10 years,
75% at 15 years, and 64% at 20 years.64 In general, these
estimates represent an overall improvement in prognosis
compared with earlier reports,66,184 probably because of
increased awareness of LAM and identification earlier in
the disease course. Premenopausal status,64 abnormal
baseline lung function (FEV1 and DLCO),64 lower
FEV1:FVC ratio,184 presentation with dyspnoea (as opposed
to pneumothorax),185 a worse histology score,186 and the
need for supplemental oxygen183 have all been linked to
lower survival in LAM.
Although TSC-LAM is believed to represent a milder
lung disease than sporadic LAM, guideline-directed
screening of young adult females with TSC identifies
early disease, which probably leads to ascertainment
bias.69 In a NHLBI cohort study8 in which patients with
TSC-LAM and sporadic LAM were matched for disease
severity, the rates of decline in FEV1 were similar in
both groups. Similar conclusions were reached by a
post-hoc analysis of participants in the MILES trial14
and in a Brazilian cohort of patients with an incidental
diagnosis of LAM, an approach that was not confounded
by the selection bias posed by screening.187 LAM can be
a substantial cause of mortality in patients with TSC; in
a retrospective analysis of a large tertiary care referral
centre for TSC, LAM was reported as the second most
common cause of death in adults overall and the
leading cause of death among adult women with TSC.188
The effect of sirolimus on overall survival and the
likelihood of progression to lung transplantation is not
yet known.
Conclusions
Rapid advances in understanding and management, and
improved outcomes in LAM can be attributed in part to
the foresight of patients who have collaborated in a
manner that has facilitated research and clinical trials.
Close interactions between investigators and patients in
scientific meetings, grassroots fundraising to support
pilot studies, and distribution of expertise across multiple
centres have been key to progress. Lessons learned from
the study of the mTOR pathway in TSC and LAM have
led to fundamental advances in our understanding of
cellular metabolism and contributed to interest in the
use of mTOR inhibitors in other lung diseases, such
as sarcoidosis, diffuse idiopathic neuroendocrine cell

hyperplasia, Castleman disease, and COVID-19. Future
research goals include generating cell and animal models
of LAM that more accurately recapitulate the human
disease, understanding the role of the immune system in
LAM pathogenesis and therapy, and further defining how
mTORC1 activation promotes cell growth and metastasis.
The next steps in LAM therapeutic development are to
refine the approach to mTORC1 inhibitor use, including
optimal dosing and cytolytic combination therapies;
to harness understanding of disease mechanisms to
develop more powerful diagnostic, prognostic, and pre­
dictive biomarkers; and to explore novel approaches to
trial design for the development of remission-inducing
therapies.
Contributors
All authors conceptualised and planned the Review, and prepared the
figures and table. All authors contributed equally to the writing and
revision of this Review.
Declaration of interests
CM, NG, SRJ, and FXM are scientific advisory board members of the LAM
Foundation. CM reports grants (LAM0144SG01-20) from the LAM
Foundation, which did not influence the content of this Review.
SRJ reports grants from the UK Medical Research Council, LAM Action,
the LAM Foundation, and the Tuberous Sclerosis Association; and a grant
from Pfizer for post-marketing surveillance on rapamycin, outside the
submitted work. FXM reports grants from National Institutes of Health
(NIH; U01HL131755, U01HL131022). JJY reports grants from NIH
National Heart, Lung, and Blood Institute (RO1HL153045, R01HL138481),
the US Department of Defense (W81XWH1910474, 81XWH2010736),
and The LAM Foundation (LAM0141E01-20). NG reports grants from NIH
(U01HL131755, R34HL138235) and the LAM Foundation.
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