INTRODUCTION — Lymphangioleiomyomatosis (LAM) is a rare multisystem disorder, belonging to the family of neoplasms with perivascular epithelioid differentiation (ie, PEComa family) [1], that mostly afflicts females and primarily affects the lung [2-5]. The term sporadic LAM is used for patients with LAM who do not have tuberous sclerosis complex (TSC) while TSC-LAM refers to LAM that occurs in patients with TSC. Since the 2000s, studies exploring the pathogenesis of LAM have produced ground-breaking insights into the genetic and molecular basis of LAM and have led to the development of an effective treatment.
The epidemiology and pathophysiology of sporadic LAM will be reviewed here. The clinical evaluation and treatment of sporadic LAM and the clinical features and diagnosis of TSC and TSC-associated LAM are discussed separately. (See "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults" and "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation" and "Sporadic lymphangioleiomyomatosis: Treatment and prognosis" and "Tuberous sclerosis complex: Clinical features".)
EPIDEMIOLOGY — The true incidence and prevalence of sporadic LAM are unknown, as the available epidemiological data are observational and frequently include patients with tuberous sclerosis complex (TSC). Nonetheless, clinical experience and most studies confirm that the sporadic variant of LAM is rare and that it almost exclusively affects females.
Where previous estimates suggested a rate of 1 per million in the general population, regional and national registry data indicate higher rates, possibly reflecting advances in disease recognition and diagnosis [6-15]. As examples:
●One study that collected data from seven countries, including the United States, the United Kingdom, and Japan, reported that the prevalence of LAM was between 3 and 8 per million females [8].
●In a database study from Quebec, the prevalence of LAM was approximately 2 to 3 per million females [16].
●The LAM Foundation estimated a prevalence of 3 to 5 females per million females [17]. However, more than 2000 females from the United States have been diagnosed with LAM, consistent with a minimum prevalence of >18 cases per million females [15]. About 10 to 15 percent of patients registered with The LAM Foundation also report having TSC. Similarly, analysis of the UK National LAM Center suggests a minimum LAM prevalence of 17 cases per million adult females [15].
●An analysis of LAM referral centers from four countries in Europe found the pooled LAM prevalence of 23.5 cases per million adult females and the prevalence of sporadic LAM to be approximately 17 cases per million adult females [14,15].
●The highest rates of LAM occur in patients with TSC. Briefly, given the estimate of the worldwide prevalence of TSC of one million people (including 0.38 million females age 18 or older) and the conservative projection that 30 percent of females with TSC develop cystic changes consistent with LAM, the number of females with TSC-LAM on earth is predicted to be at least 100,000. The epidemiology of TSC is discussed separately. (See "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults", section on 'Epidemiology'.)
Although LAM can affect all races, one United States registry reported that White Americans may have a higher prevalence of LAM, especially when compared with individuals of African or Asian descent [13]. The same registry also reported that LAM was more commonly found in females of higher socioeconomic class; however, apparent racial and ethnic disparities in prevalence likely reflect differential access to healthcare and information rather than a true biological phenomenon.
LAM has rarely been reported in males, most often in association with definite or probable TSC [18-24]. Screening of large TSC clinics revealed cystic changes consistent with LAM in 10 to 13 percent of males [25,26]. There has been only one published case of a male with LAM with no clinical or genotypic evidence of TSC, although limitations in genetic analysis can result in "no mutation detected" in up to 15 percent of patients [21]. Cases of males who presented with apparent sporadic LAM and were found to be low level mosaics for TSC mutations have been reported [27,28].
Traditionally, LAM was thought to only affect young premenopausal females of childbearing age. The average age at diagnosis of LAM is around 35 years. However, studies report LAM in females ranging from teenagers to octogenarians [5,7,9,13,29-34]. Prepubertal LAM is rare [35].
There are no known risk factors, other than TSC, for the development of LAM. While smoking may potentially worsen disease progression it does not appear to be a risk factor for disease induction [13].
PATHOGENESIS — The primary histopathologic abnormality in LAM is the proliferation of atypical smooth muscle-like cells (LAM cells) (picture 1A-B and picture 2). Additionally, in the lung, LAM cell infiltration is associated with multiple cysts (picture 3A-C) (see "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Tissue pathology'). Significant advances in our understanding of the pathogenesis of LAM have occurred since the early 2000s [36-38]. Excessive proliferation of LAM cells is driven by mutations in tuberous sclerosis complex (TSC) genes, particularly TSC2. Additional factors that may contribute to cellular proliferation in sporadic LAM include aberrant stimulation of LAM cell growth by estrogen and other growth factors. Processes that promote differentiation (eg, expression of melanoma antigens), migration (estrogen), immune evasion (increased signaling through immune checkpoint inhibitors, such as programmed cell death protein 1 [PD-1], or their ligands, such as PD-L1), lymphangiogenesis (vascular endothelial growth factors [VEGF]-C and VEGF-D), and tissue destruction (eg, proteases) have also been implicated in the pathogenesis of LAM. It is likely that some combination of these mechanisms best explains the multisystemic nature and unique features that occur in LAM.
The pathogenesis of TSC is discussed separately. (See "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults".)
Cellular proliferation
Tuberous sclerosis gene mutations — Since the early 2000s, reports from several groups support a dominant role for loss of function of the tuberous sclerosis proteins, tuberin or hamartin, in the pathogenesis of LAM. Tuberin is the protein product of the TSC gene, TSC2, which is located on chromosome 16p13. Tuberin complexes with hamartin, a sister protein that is encoded by the TSC1 gene located on chromosome 9q34 [39,40]. The tuberin-hamartin hetero-oligomer functions as a tumor suppressor complex that inhibits mechanistic target of rapamycin (mTOR; previously called mammalian target of rapamycin), which in turn integrates and controls cellular signals that regulate cell growth, cell size, cell survival, and autophagy (figure 1) [41-43]. Thus, when tuberin or hamartin function is lost, mTOR activity is unrestrained and these processes become dysregulated. (See "Tuberous sclerosis complex: Genetics and pathogenesis", section on 'Mechanism of tumor formation'.)
The central role of the loss of functioning tuberin in the pathogenesis of sporadic LAM is supported clinically by the nearly identical pathological presentations of the sporadic and TSC subtypes of LAM, the high proportion of females with TSC who develop cysts consistent with LAM (up to 80 percent by age 40 years) [44], and consistent findings of mutations in TSC genes and activation of downstream signals (eg, phosphorylation of ribosomal protein S6) in LAM cells derived from patients with both sporadic LAM and TSC-LAM [45-53].
Unlike patients with TSC who have germline mutations (ie, genes that are either inherited in a Mendelian fashion or occur early in embryogenesis and are present in every cell of offspring) of TSC1 or TSC2, patients with sporadic LAM have only somatic mutations (ie, mutations limited to the abnormal lesions) in TSC genes; thus, sporadic LAM is not inheritable. One case of generalized mosaicism for TSC2 has been reported among 61 cases of sporadic LAM [54], and additional cases are emerging [27,28]. Interestingly, all cases of sporadic LAM that have genetic data available are due to mutations in TSC2 genes whereas both TSC1 and TSC2 mutations have been reported in patients with TSC-LAM [50,55]. Whereas lesions in TSC-LAM occur as a result of a germline (first hit) and a somatic (second hit) mutation in one of either TSC1 or TSC2, lesion development in sporadic LAM is thought to be due to somatic mutations in both parental TSC alleles [45-52]. Low-level somatic mosaicism as the genesis of the "first hit" cannot be excluded (ie, some, but not all, cells become mutated during embryogenesis). Regardless of the mechanism, the end result is deficient or defective tuberin or hamartin in affected cells and dysregulated signaling through the mTOR pathway.
Genetic studies of involved tissues have only been conducted in a limited number of patients with sporadic LAM. As examples, early studies revealed somatic TSC2 mutations and loss of heterozygosity (LOH) for TSC2 in approximately one-half of renal angiomyolipomas in patients with LAM. Within individuals who had tissue available from both lung and kidney, mutations were absent in normal tissue but were identical in AML and LAM lesions [45-47]. Subsequent studies have identified identical mutations and LOH for TSC2 in multiple sites, including the lung, angiomyolipomas, chyle, and urine, suggesting clonal origins [48,52,56-58]. For those in whom TSC2 mutations are not identified, LAM may be due to mutations in TSC1 genes or other unexplored pathogenetic mechanisms. (See "Tuberous sclerosis complex: Clinical features".)
Role of estrogen — Clinical and biologic data support a critical role for female hormones in LAM induction or progression. This role is supported by the predilection of LAM for females, reports of accelerated disease progression during pregnancy and in response to exogenous estrogens (eg, oral contraception, fertility treatments), cyclical worsening of LAM symptoms in relationship with the menstrual cycle in a subset of LAM patients, the presence of hormonal receptors on LAM cells (picture 4), and a slower decline in lung function after menopause [59-67].
Estrogen has been the primary focus in most LAM studies exploring hormonal influences on disease pathogenesis. Estrogen promotes the proliferation of tuberin null mouse leiomyoma cells as well as immortalized LAM-like cells derived from human kidney [68]. In addition, estrogen promotes the survival and lung metastasis of tuberin-null cells in rodent models [69]. In a model of progesterone receptor driven deletion of TSC2 in the uterus, growth of myometrial tumors and secretion of proteolytic enzymes were estrogen-dependent [70,71]. Estrogen has also been shown to promote tuberin null cell invasiveness via matrix metalloproteinases and through cooperative interactions between the extracellular signal regulated kinase (ERK) and mTOR pathways that result in epithelial mesenchymal transition [72,73]. (See 'Perivascular epithelioid cell (PEComa)' below.)
Prolactin is elevated in the serum of LAM patients and is expressed in LAM involved tissues. Higher levels of serum prolactin are associated with greater rates of lung function decline and pneumothorax [74]. Another study reported that loss of TSC2 enhances expression of prolactin receptors and promotes the growth and invasiveness of tuberin null cells [75].
Few studies have addressed the role of hormones other than estrogen and prolactin in LAM progression. While multiple investigators have described the presence of progesterone receptors in LAM lung, their role remains unclear [59,75,76]. Although there have been no controlled trials, the most widely quoted retrospective studies did not demonstrate a beneficial effect of progesterone on disease progression [62]. (See "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'Statins, doxycycline, hormone manipulation, hydroxychloroquine, celecoxib, resveratrol'.)
Growth factor stimulation — The increased expression of growth factors including insulin like growth factor, insulin like growth factor binding protein 4 and 5, platelet-derived growth factor, fibroblast growth factor, endothelin, and VEGF have all been identified in serum or immunohistochemically in LAM tissue [77-80]. Although their pathogenetic role is unknown, these growth factors presumably stimulate LAM cell growth. They may also play a role in differentiation and migration.
Abnormal lymphangiogenesis — Lymphatic clefts (ie, malformed vessels) are present in pulmonary LAM nodules, and LAM is known to involve lymph nodes and lymphatic channels [81-83]. The thoracic duct is often extensively infiltrated by LAM at autopsy [84], suggesting a model for spread based on cycles of implantation, proliferation, and budding that allows LAM cells to "leap frog" toward the venous system in the neck and ultimately reach the pulmonary microvasculature [83,85]. LAM cell clusters (LCCs), comprised of a spherical collection of LAM cells enveloped by a single layer of lymphatic endothelial cells, are found within the lymphatic lumen and in chylous accumulations in the chest and abdomen. Chylous effusions and other lymphatic manifestations can occur in approximately 20 percent of patients with sporadic LAM [86,87]. The lymphatic manifestations of LAM are discussed separately. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Cytology' and "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Lymphatic manifestations'.)
LAM involvement of these tissues is associated with the expression of lymphangiogenic proteins, including VEGF-C and VEGF–D, and their receptors, VEGFR-2 and VEGFR-3, as well as with other lymphatic markers, lymphatic vessel endothelial receptor-1 (LYVE-1), and podoplanin [82,86-92]. It has also been postulated that VEGF-D, which is elevated in the serum of females with LAM, may promote lymphangiogenesis and the shedding of LCCs from primary extrapulmonary lesions (eg, uterus) into the lumen of lymphatics [86,91]. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Vascular endothelial growth factor-D positive'.)
Tissue destruction-cyst formation — The mechanism of cyst formation in pulmonary LAM is incompletely understood. Some groups have postulated that cyst formation is due to smooth muscle cell proliferation within/around the airways, creating a "ball-valve" obstruction that leads to distention of the terminal airspaces, or that tissue degradation is related to an imbalance of proteases and anti-proteases [93-102]. Another theory for the destructive lung remodeling in LAM is that LAM cells that invade the lung and express lymphangiogenic growth factors, such as VEGF-D, drive a program of "frustrated lymphangiogenesis" that leads to cyst formation (figure 2) [85].
Pulmonary LAM nodules contain matrix metalloproteinase (MMP)-1, -2, -3, -9, -11, and -14, as well as MMP activators and MMP inhibitors, TIMP-1 and TIMP-2 [98,100-102]. MMP-2 [103] and MMP-9 [104] have also been reported to be elevated in serum. Cathepsin K, a serine protease, is abundantly expressed in LAM lung lesions [105]. It is unknown which of these and other proteases are directly involved in cyst formation, cell invasion, cell migration, differentiation, or remodeling [106].
Using quantitative micro computed tomography and histology of LAM lungs, one study demonstrated a reduced number of small airways (from generation 7 on), a phenomenon that may contribute to the airflow obstruction seen in LAM [107].
Other
Recruitment of stromal cells — Genetic studies indicate that only a fraction of cells (in some cases <10 percent) within the LAM lesions contain mutations in TSC genes, and the remaining cells are likely recruited into the LAM lesions [108]. Recruited cells include fibroblasts [109], mast cells [77], and neutrophils and lymphocytes [108]. As with all cancers, cooperative interactions between mutant cells and stromal cells play a major role in disease pathogenesis [110]. Their exact role in LAM remains undetermined.
Evasion of immune system — Tumor cells evade destruction by the innate immune system by expression of checkpoint inhibitor proteins (eg, PD-1) that suppress T lymphocyte mediated killing [111-113]. LAM and AML cells have been reported to exhibit [114-116] increased expression of natural killer (NK) cell ligands [114], PD-L1 [116], and B7-H3 (CD276) [117]. Staining of PD-1 on T cells within the LAM lesion has also been reported [118]. Anti-PD-1 antibody suppresses tumor growth of TSC deficient cells in mouse models of LAM [115]. A case report of effective treatment of a perivascular epithelioid differentiation tumor (PEComa) with checkpoint inhibitor therapy provides optimism that this approach could be applied to LAM [119].
Modulation of autophagy — As nutrients become limiting, cells regulate their metabolic state to sustain viability. A cellular program of bulk degradation of organelles and macromolecules called autophagy is deployed to generate substrate for generation of cellular biomass. Inappropriate activation of mTOR by TSC mutations simulates a fed state, and both stimulates proliferation and suppresses autophagy [120].
Altered cellular metabolism — mTOR is part of a complex (together with Raptor, Rictor, Sin) that forms the nexus of multiple cellular signaling networks and functions to balance metabolic supply with demand [121]. Mutations in mTOR mediate altered cellular metabolism that facilitate neoplastic growth, including a shift from oxidative phosphorylation to glycolysis as a mechanism to increase availability of metabolic substrate for generation of cellular biomass and for tolerance of anaerobic environments [122]. LAM cells take up glutamine as an alternative carbon source, which provides an adaptive mechanism to fuel mTOR activity when glucose pathways are insufficient to support it or are blocked [123]. In addition, activation of mTOR drives flux through purine and pyrimidine biosynthesis pathways and the pentose phosphate shunt pathway to provide substrate for the synthesis of polynucleotides, and activates super conserved receptor expressed in brain (SREB), which is required for the biosynthesis of fatty acids and cholesterol [124,125]. Activated mTOR stimulates ribonucleic acid (RNA) translation by regulating the assembly of the eukaryotic translation initiation factor (eIF4F) complex and phosphorylating downstream targets including eIF4F binding proteins (4E-BPs) and ribosomal protein S6 kinases [126]. Altered polyamine metabolism has also been reported in LAM cells, although several flaws in the study cast doubt on the validity of this effect [127]. Increased nuclear localization of transcription factor EB (TFEB) and increased lysosome biogenesis driving abnormal cellular proliferation has also been described as a pathogenic mechanism [128].
Miscellaneous — Other factors that have been found to be abnormally expressed in LAM include:
●High Mobility Group 2A [129]
●Adipocyte phospholipase A2 [130]
●Survivin [131]
●Osteopontin [132]
●HIF1 alpha targets
●Erythropoietin [133]
●Metastasis and invasion markers (eg, CD44V and CXCR4) [132,134]
●Src kinase [135]
●Plasminogen system [136]
●Urotensin [137]
●CA-125 [138]
●Nuclear receptor subfamily 2 group F member 2 (NR2F2) [139]
LAM CELL ORIGIN — The origin of the LAM cells, which are included in the family of neoplasms with perivascular epithelioid differentiation (PEComa), is unknown. Theories for the source of LAM cells that populate the lung include the uterus [71,140], angiomyolipomas [141], bone marrow [142], lymphatic system [45], or the neural crest [143]. Evidence to support potential sources is described in the sections below.
Perivascular epithelioid cell (PEComa) — LAM is classified by the World Health Organization (WHO) as a lung tumor, in the PEComa family [144-146], which also includes angiomyolipomas, clear cell "sugar" tumors, and other rare neoplasms of visceral organs. The classification of LAM as a low grade neoplasm is based upon the observations that LAM cells exhibit cellular and genetic fingerprints similar to neoplasms [145], have loss of heterozygosity (LOH) for the tumor suppressor gene TSC2, can recur in transplanted lung, exhibit invasive/immune evasive/migratory/metastatic behavior [40,46,56,86,105,147], and have the capacity to destroy remote organs.
Neural crest (melanoma antigen expression) — A monoclonal antibody to human melanoma black (HMB)-45 (also known as melanosome specific antigen), derived from melanoma hybridomas, is the classic marker for the diagnosis of LAM on lung biopsy (picture 5) [148,149] but can also be found in angiomyolipomas and some uterine PEComas [150-152].
The antigen to which HMB-45 binds is the premelanosome protein PMEL17, which is involved in the synthesis of melanin and catecholamines from the amino acid tyrosine.
Immunohistochemical staining of LAM lung or cells in culture have shown that pulmonary LAM cells aberrantly express the epitope for HMB-45 as well as other melanoma-derived antigens, further supporting the hypothesis that LAM cells may be of neural crest origin [143,153-156]. However, immunoreactivity for HMB-45 can be variable and even absent in LAM lesions. LAM cells also stain for other melanocytic proteins, including PNL2 [157], MART1 [153], and aPep13h [155].
Uterus — The uterus has been suggested as the source of origin of LAM cells by multiple observations. Rats with naturally occurring Tsc2 mutations develop uterine myometrial tumors with features similar to LAM. In addition, mice with inactivation of Tsc2 in the uterus develop smooth muscle tumors that metastasize to the lungs [70,71]. Although multiple case reports of LAM in the uterus have appeared in the literature, it remains possible that the uterus is another target for metastasis rather than the primary source [140,158]. Uterine-specific homeobox-pre-B-cell leukemia (HOX-PBX) transcriptional programs have been demonstrated to play a role as regulators of LAM [159]. A single cell transcriptomics analysis conducted on lungs and uteri obtained from LAM patients has shown that LAM cells in lung and uterus are morphologically indistinguishable and share similar gene expression profiles and biallelic Tsc2 mutations, supporting a uterine origin for LAM cells [160].
Other — Other purported origins for the LAM cell include the lymphatics [92] and the kidney (eg, from angiomyolipomas) [141]. Data to support these origins come from studies that report that LAM cells in the lung are morphologically or genetically similar to neoplastic cells in these organs and share identical TSC mutations [45-49,56,86,92,161].
RESEARCH MODELS — Experimental modeling is critical for effective LAM research. While multiple cellular and animal models of TSC and LAM have been developed, all have limitations. The most commonly used cell models for LAM are ELT3 cells, a uterine leiomyoma cell line from the Eker rat, which has a germ line mutation in Tsc2 [162], Tsc null murine embryonic fibroblast cell lines [163], 621-101 cells, a transformed cell line from a renal angiomyolipoma [164], and low passage mixed cultures isolated from LAM lung at the time of transplant [53]. Animal models for LAM that have been reported include uterus specific Tsc2 deletion [70], subcutaneous xenograft models [69,165], and intrapulmonary Tsc2 null cell administration through the endonasal route [166].
A LAM cell atlas has been created which facilitates collaborative research into the pathogenesis of LAM and can be found here [167].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lymphangioleiomyomatosis".)
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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Lymphangioleiomyomatosis (The Basics)")
PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Lymphangioleiomyomatosis (LAM)".)
SUMMARY
●Definition – Lymphangioleiomyomatosis (LAM) is a rare multisystem disease with a female predilection that is characterized by cyst formation in the lungs and the proliferation of immature smooth muscle with features of perivascular epithelioid cells (LAM cells) in affected organs. The term sporadic LAM is used for patients with LAM who do not have tuberous sclerosis complex (TSC), while TSC-LAM refers to LAM that is associated with TSC. (See 'Introduction' above.)
●Prevalence – Estimates of the prevalence of sporadic LAM vary, ranging from 1 to 20 per million females in the general population with the highest rates in females with TSC (more than 30 percent). (See 'Epidemiology' above and "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults", section on 'Clinical manifestations'.)
●Pathogenesis – The exact pathogenesis of LAM is unknown but appears to involve excessive proliferation of LAM cells due to loss of functioning TSC genes. Loss of heterozygosity and somatic mutations for the TSC2 gene are found in affected tissue in most sporadic LAM cases, but TSC mutations are not present in the germ line, so sporadic LAM cannot be inherited. The absence of tuberin prevents formation of the hamartin-tuberin complex, which regulates mechanistic (previously mammalian) target of rapamycin (mTOR), a molecule that controls cell growth and cell size. (See 'Tuberous sclerosis gene mutations' above and "Tuberous sclerosis complex: Clinical features".)
•Hormonal fluxes (eg, pregnancy, exogenous estrogen) play a key role in the pathogenesis of LAM. In particular, an important role for estrogen is suggested by the presence of estrogen receptors on LAM cells and a slower decline in lung function after menopause. Estrogen may also play a role in cell invasion and migration. (See 'Role of estrogen' above.)
•Abnormal lymphangiogenesis may play role in cell migration and disease progression as evidenced by lymphatic differentiation within LAM lesions and extensive involvement of lymphatic channels by LAM cells. (See 'Abnormal lymphangiogenesis' above.)
•The mechanism of cyst formation in LAM lung is unclear but may involve bronchial obstruction, tissue destruction by proteases, and/or dysregulated lymphangiogenesis. (See 'Tissue destruction-cyst formation' above.)
•LAM pathogenesis also involves recruitment of stromal cells, metabolic reprogramming of the LAM cells (eg, upregulation of glycolysis, increased synthesis of lipids, protein, and nucleotides), immune evasion by upregulation of immune checkpoint proteins, promotion of cell survival, and inhibition of autophagy. (See 'Other' above.)
●LAM cell origin – The exact origin of LAM cells that populate the lung is unknown. LAM is included in the family of neoplasms with perivascular epithelioid differentiation (ie, PEComa family). Accumulating evidence suggests that LAM may originate in the uterus. Expression of human melanoma black (HMB)-45 antigen suggests a possible neuroendocrine origin. (See 'LAM cell origin' above and 'Research models' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Talmadge E King, Jr, MD, who contributed to earlier versions of this topic review.
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