INTRODUCTION — Tuberous sclerosis complex (TSC) is a disorder characterized by multiple benign tumors, and rarely malignant neoplasms of the skin, brain, eyes, heart, lung, liver, and kidney [1,2]. TSC is caused by mutations in the TSC1 or TSC2 gene and is transmitted as an autosomal dominant trait in one-third of cases while nonfamilial cases represent either spontaneous mutations or mosaicism. (See "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis", section on 'Genetics'.)
Lymphangioleiomyomatosis (LAM) is a multisystem disorder that primarily affects the lung. It can occur sporadically (sporadic-LAM) or in association with TSC (TSC-LAM). Many clinical, radiologic, and pathologic features are shared between TSC and sporadic variants. This review will focus on the elements of LAM that are specific to TSC. The epidemiology, diagnosis, and management of sporadic-LAM and TSC are discussed separately. (See "Sporadic lymphangioleiomyomatosis: Epidemiology and pathogenesis" and "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation" and "Sporadic lymphangioleiomyomatosis: Treatment and prognosis" and "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis".)
EPIDEMIOLOGY — Sporadic lymphangioleiomyomatosis (sporadic-LAM) is rare and almost exclusively affects females, with estimates of up to 8 cases per million females (see "Sporadic lymphangioleiomyomatosis: Epidemiology and pathogenesis", section on 'Epidemiology'). In contrast, TSC, an autosomal dominant genetic disorder, has an incidence of approximately 1 in 5000 to 10,000 live births with a high prevalence of LAM among adults [3]. Obtaining exact prevalence rates of TSC-LAM is challenging since data are derived from small retrospective observational studies that mostly utilize computed tomographic (CT) evidence of cystic lung disease for diagnosis:
●Several studies report prevalence rates in females with TSC (mostly TSC2 mutations) that range from 26 to 50 percent [4-9]. Rates increase with age after 15 years with the highest rates (up to 80 percent) reported in females over the age of 40 years and lowest rates (27 percent) in those <21 years [8,10]. Based upon the worldwide prevalence of over one million people and a conservative projection that 30 percent of females with TSC develop cystic changes consistent with LAM, it is estimated that the number of females with TSC-LAM and/or cystic changes consistent with LAM is over 100,000. However, the majority of females with TSC-LAM have normal lung function.
●Unlike sporadic-LAM, which is extremely rare in males, LAM can occur in males with TSC. The rates of cystic lung disease in males with TSC range from 10 to 38 percent, although the development of symptomatic disease or a decline in lung function is exceptionally rare in males [9,11,12].
Epidemiologic features of sporadic-LAM are discussed separately. (See "Sporadic lymphangioleiomyomatosis: Epidemiology and pathogenesis", section on 'Epidemiology'.)
PATHOGENESIS — The sporadic and tuberous sclerosis complex (TSC)-associated forms of lymphangioleiomyomatosis (LAM) are identical pathologically [4]. The high prevalence of LAM in TSC has led to the identification of a critical role for mutations in the TSC genes, particularly TSC2, in the smooth muscle cell proliferation which is characteristic of LAM lesions. In support of this hypothesis, LAM mostly occurs among patients with TSC2 mutations and is rare in patients with TSC1 mutations [7]. As an example, in a cohort study of 55 females with TSC, among the 23 females with cysts characteristic of LAM, 16 had TSC2 mutations while the remaining seven had no mutation identified [13]. In addition, the prevalence of LAM was higher in females with TSC2 mutations compared with females with TSC1 mutations (55 percent versus 0 percent). The pathogenesis of LAM discussed in detail separately. (See "Sporadic lymphangioleiomyomatosis: Epidemiology and pathogenesis", section on 'Pathogenesis'.)
CLINICAL MANIFESTATIONS — In most patients, the diagnosis of TSC is known. Data derived from small observational studies of TSC patients [4-12,14] and larger studies that included TSC-LAM and sporadic-LAM suggest that the respiratory manifestations of TSC-LAM and sporadic-LAM are similar. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Clinical manifestations'.)
Symptoms and signs — Features of LAM specific to TSC include the following [10,14-16]:
●The classic TSC features including cognitive disability and seizures can be absent in TSC-LAM (ie, "milder" version of TSC) [15], although this is not always the case [14]. (See "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis", section on 'Clinical features'.)
●TSC-LAM is more commonly encountered in those with TSC2 rather than TSC1 mutations.
●Relative to other complications of TSC, such as seizures that are often diagnosed in early childhood, LAM is a later manifestation during the course of TSC, typically from late adolescence through adulthood. Symptoms generally develop in the third decade of life and are uncommon before age 20.
●Renal angiomyolipomas (AMLs) are more frequent in TSC-LAM (>80 percent) and are often bilateral, when compared with sporadic-LAM (30 percent incidence of angiomyolipomas).
●Lymphatic complications such as chylothorax, chylous ascites, and lymphangioleiomyomas may be less common in patients with TSC-LAM than sporadic-LAM [17-19], although results vary [19].
●Patients with TSC-LAM may also have polycystic kidney disease since the PKD1 (polycystic kidney disease 1) and TSC2 genes are adjacent on chromosome 16p13, and a contiguous gene syndrome involving partial or complete deletion of both genes can occur.
Imaging characteristics — Several studies have reported pulmonary cysts in TSC-LAM identical to those seen in sporadic-LAM [5,6,9,17,20,21]. Cysts are thin-walled, multiple (≥10), diffuse, round, well-defined, and bilateral. They vary in size and are devoid of internal structures. Further details are provided separately. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Imaging'.)
Specific to TSC:
●Cysts may be larger and more numerous in females than males with TSC [9].
●Fewer cysts may occur in TSC-LAM (ie, milder disease) than the sporadic variant, although this may represent ascertainment bias [17].
●Renal AMLs, visualized on abdominal cuts of high resolution computed tomography (HRCT) chest or a dedicated abdominal CT scan, are more frequent in patients with TSC-LAM (often >80 percent) compared with sporadic-LAM (30 percent) (image 1) [5,11,14]. In addition, they are often large, multiple, and bilateral. In a series of males with TSC, renal AMLs were present in 14 of 25 patients with available imaging [11]. In a separate series among females with TSC-LAM, all had AMLS that were larger and required more interventions, when compared with females with TSC who did not have LAM [5]. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Renal angiomyolipomas' and "Renal manifestations of tuberous sclerosis complex", section on 'Clinical presentation'.)
●HRCT chest in patients with TSC-LAM may also identify multifocal micronodular pneumocyte hyperplasia (MMPH), a feature rarely seen with sporadic LAM. (See 'Multifocal micronodular pneumocyte hyperplasia' below.)
SCREENING FOR TSC-LAM — Although not definitively proven, based upon the reported high prevalence of LAM in this population, International Tuberous Sclerosis Complex Consensus Group recommendations suggest that screening of asymptomatic females 18 years and older should be with chest computed tomography (CT) using a low-dose noncontrast protocol [3]:
●One single-center retrospective review of initial chest CT scans performed in 133 female patients with TSC aged ≥15 years over a 12-year period, reported that 50 percent of patients had cysts consistent with LAM [8]. The risk of LAM was age dependent, rising by about 8 percent per year. Among asymptomatic patients, 84 had cysts identified on a single slice at the level of the carina. Most patients (two-thirds) with cysts eventually developed pulmonary symptoms and a smaller proportion (13 percent) died from LAM.
●Another study prospectively screened 23 asymptomatic females with TSC high-resolution computed tomography (HRCT) [5] and found cystic pulmonary parenchymal changes consistent with LAM in 39 percent. These patients were older than cyst-negative patients (32 versus 25 years). All cyst-positive patients had angiomyolipomas (AML), which were larger than those in cyst-negative patients.
If the CT chest reveals no cysts, we typically repeat a chest CT every 5 to 10 years or if symptoms emerge. If cystic lung disease consistent with LAM is identified, we proceed with baseline pulmonary function tests (PFTs; pre- and post-bronchodilator spirometry, lung volumes, and diffusing capacity for carbon monoxide) and a six-minute walk test to evaluate the degree of respiratory impairment.
Longitudinal serial measurement of serum vascular endothelial growth factor-D (VEGF-D) may be useful to detect the development of LAM in women with TSC [13]. However, VEGF-D has not been tested prospectively as a screening tool for TSC-LAM.
DIAGNOSTIC EVALUATION — LAM should be suspected in any TSC patient (males and females) with symptoms and signs consistent with LAM (eg, progressive dyspnea, cough, pneumothorax, chylothorax). The diagnostic evaluation of TSC-LAM should be done in conjunction with an expert in TSC and LAM.
Our approach to the diagnosis of TSC-LAM is described in the algorithm (algorithm 1).
High resolution computed tomography — In males and females of any age with a known diagnosis of TSC and respiratory symptoms, we suggest noncontrast high resolution computed tomography (HRCT) of the chest (algorithm 1) [12]. The rationale for performing noncontrast HRCT is based upon the principle that typical cysts, the hallmark lesion in LAM, are seen in almost every patient with LAM and that cysts are often undetectable on routine chest radiography. Upper abdominal images obtained at the same time may detect coexistent angiomyolipomas. (See 'Imaging characteristics' above.)
Depending on the HRCT chest findings, we next perform the following:
●Lung cysts consistent with LAM – The identification of multiple cysts consistent with LAM on HRCT in a patient with TSC provides a clinical diagnosis of LAM and, in most patients, avoids the need for definitive biopsy (see 'Imaging characteristics' above). Once cysts are identified, we typically obtain a vascular endothelial growth factor-D (VEGF-D level), which, if elevated (≥800 pg/mL), provides further support for the diagnosis. Imaging characteristics of sporadic-LAM on HRCT chest and details regarding the diagnostic value of VEGF-D are provided separately. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Tuberous sclerosis complex' and 'Vascular endothelial growth factor-D' below and 'Imaging characteristics' above.)
●No lung cysts – If the HRCT chest reveals no cysts, we evaluate for other potential causes of respiratory symptoms. Pulmonary function tests provide a starting point for this evaluation.
●Atypical cysts – If the HRCT reveals atypical cysts, a low number of cysts (eg, <10), or is suspicious for an alternate diagnosis, the approach should be individualized. Options include obtaining a VEGF-D level, investigating for an alternate diagnosis, follow up HRCT, and (rarely) lung biopsy. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Other presentations'.)
Occasionally, the diagnosis of TSC is not known, but is discovered during the evaluation of cystic lung disease because of a family history or characteristic cutaneous manifestations of TSC. In such cases, obtaining a definitive diagnosis of TSC (ie, clinical criteria and/or genetic testing) under the guidance of a TSC expert (table 1 and algorithm 1) is appropriate since a diagnosis of TSC will eliminate the need for tissue biopsy (see "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis", section on 'Evaluation and diagnosis'). The rationale for performing noncontrast HRCT of the chest is to identify typical cysts, the hallmark lesion in LAM. (See 'Imaging characteristics' above.)
Pulmonary function testing — While pulmonary function abnormalities can be nonspecific, patients with suspected TSC-LAM who are able should undergo pulmonary function tests (PFTs), including spirometry (pre- and post-bronchodilator), lung volumes, diffusing capacity for carbon monoxide (DLCO), and a six-minute walk test to evaluate the degree of respiratory impairment [3].
Although some experts use PFTs to screen asymptomatic females with TSC aged 18 years or older for development of LAM, it is often done in conjunction with HRCT. There is no validity to using PFTS alone as a screening tool since they are nonspecific, and a normal study does not preclude the diagnosis of LAM; HRCT is a more sensitive tool. Obtaining a baseline set of PFTs in females with TSC and cystic lung disease can be an important metric for future follow up evaluation.
PFT abnormalities, when present, are similar to those in patients with sporadic-LAM (eg, airflow limitation, restriction or mixed deficit, reduction in DLCO), the details of which are discussed separately. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Pulmonary function tests'.)
Although observational studies in females with TSC-LAM suggest milder impairment in lung function, when compared with females with sporadic-LAM, this may relate to ascertainment bias [22]. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Pulmonary function tests'.)
Vascular endothelial growth factor-D — Serum VEGF-D, a lymphangiogenic growth factor, can be elevated in TSC-LAM [23,24]. A VEGF-D level of ≥800 pg/mL is typically used as the diagnostic cut-off and may distinguish LAM (TSC or sporadic) from other causes of cystic lung disease but may not distinguish TSC-LAM from sporadic-LAM [24] and can be elevated in TSC patients who not have LAM Testing for serum VEGF-D is available through the Translational Trials Laboratory at Cincinnati Children's.
Data supporting the role of VEGF-D testing in females with TSC and suspected LAM include the following:
●In one prospective study of patients with cystic lung disease, 28 females with TSC-LAM had higher serum VEGF-D levels, when compared with females who had TSC but did not have LAM or females with cysts from other causes (3465 versus 370 versus 281 pg/mL, respectively) [23].
●In a retrospective study, higher VEGF-D levels were reported in females with TSC-LAM compared with sporadic-LAM (2682 versus 1281 pg/mL), although it could not distinguish TSC from the sporadic form of LAM [25].
●In another cohort study, higher levels of VEGF-D were seen in patients with TSC and LAM compared with patients who had TSC and did not have LAM (725 pg/mL versus 429 pg/mL) [13]; levels in those without LAM were consistently below 800 pg/mL suggesting that it may have diagnostic value similar to that seen in patients with sporadic LAM when discriminating between those that do an do not have LAM. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Vascular endothelial growth factor-D'.)
These and other data regarding VEGF-D are discussed separately. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Vascular endothelial growth factor-D' and "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Vascular endothelial growth factor-D positive'.)
DIFFERENTIAL DIAGNOSIS — LAM is the most common cause of lung cysts in patients with TSC, although mimics exist. The differential diagnosis of cystic lung disease in patients with TSC is similar to that in sporadic-LAM, the details of which are discussed separately. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Differential diagnosis'.)
DIAGNOSIS — A clinical diagnosis of TSC-LAM is typically made by identifying characteristic high resolution computed tomography (HRCT) findings in patients with an established diagnosis of TSC (table 1 and algorithm 1) [12,24,26]. The presence of an angiomyolipoma (AML) and/or elevated vascular endothelial growth factor-D (VEGF-D; ≥800 pg/mL) and/or other features of LAM such as a chylous effusion or lymphangioleiomyoma confirm the diagnosis of LAM, but their absence does not preclude it.
An opportunity may arise to make a definitive diagnosis from lung tissue obtained during thorascopic pleurodesis for pneumothorax or from cytological analysis of chylous pleural or ascitic fluid, but definitive histopathologic diagnosis is generally not necessary. The histopathology of TSC-LAM is identical to that described for sporadic-LAM (picture 1A-C and picture 2A-B and picture 3 and picture 4), the details of which are described separately. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Diagnosis'.)
Once the diagnosis of TSC-LAM is made, the assessment of disease extent is similar to that of sporadic LAM and is based on respiratory symptoms, HRCT findings, pulmonary function test results, and extrapulmonary complications. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Assessment of disease extent'.)
TREATMENT — The treatment of TSC-LAM is identical to that of sporadic-LAM. However, the data to support the same approach is based upon studies that include mostly patients with sporadic-LAM with only a minority of patients with TSC-LAM represented. None of the studies had sufficient power to compare the response between TSC and sporadic populations. TSC-LAM should be managed in conjunction with a TSC and LAM expert. Details are provided separately. (See "Sporadic lymphangioleiomyomatosis: Treatment and prognosis".)
General measures and treatment of complications — General measures used to treat TSC-LAM (separately from the use of sirolimus or everolimus, when appropriate) include avoidance of cigarette smoking, supplemental oxygen for hypoxemia, pulmonary rehabilitation, and bronchodilators, when indicated. Estrogen-containing medications and contraceptives should be avoided, and patients should be informed about the increased risks associated with pregnancy including pneumothorax, chylothorax, lung disease progression, and hemorrhage into angiomyolipomas. These measures as well as management recommendations for air travel, birth control, and management of complications (eg, pneumothorax, chylous accumulations) are discussed separately. (See "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'General measures' and "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'Treatment of complications'.)
Mild lung function impairment — Mild lung function impairment in TSC-LAM is considered to be a forced expiratory volume in one second (FEV1) 70 percent of predicted or greater, but less than 80 percent predicted. (See "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'Normal or mildly impaired lung function'.)
Monitored observation — Similar to patients with sporadic LAM, most patients with TSC-LAM who have normal or mildly impaired pulmonary function should undergo monitored observation with interval clinical assessment and pulmonary function testing, rather than initiating mechanistic target of rapamycin (mTOR) inhibitor therapy unless other indications for an mTOR inhibitor pertain (eg, refractory epilepsy, symptomatic subependymal giant cell tumors [SGCTs, also known as subependymal giant cell astrocytomas], lymphatic disease). For patients who are unable to perform pulmonary function tests, we use a combination of clinical judgment, serial levels of vascular endothelial growth factor-D (VEGF-D), and sometime repeat chest computed tomography in order to determine disease trajectory. The details of monitored observation are discussed separately. (See "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'Treatment of complications' and "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'Normal or mildly impaired lung function' and "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis", section on 'Subependymal giant cell tumors'.)
Moderate to severe lung function impairment — Moderate-to-severe lung function impairment in TSC-LAM is considered to be a FEV1 <70 percent predicted. (See "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'Moderate to severe lung function impairment'.)
mTOR inhibitors — The mTOR inhibitor, sirolimus, is first-line therapy for patients with moderate-to-severe TSC-LAM [3]. This approach is based upon data from a randomized trial in which sirolimus slowed the decline in lung function (relative to placebo) in patients with LAM, 9 percent of whom had TSC-LAM [27]. Patient selection, dosing, safety, efficacy, and follow up for those on sirolimus are discussed separately. (See "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'Sirolimus (first line)'.)
Everolimus, another mTOR inhibitor, is generally considered a second-line agent for LAM, although it is FDA-approved for other manifestations of TSC. One open-label trial that included five patients with TSC-LAM reported a similar efficacy and safety profile with everolimus compared to sirolimus [28]. Everolimus is approved for the treatment of TSC-related angiomyolipomas (AMLs) and central nervous system tumors (eg, SGCTs]) [29,30]. Thus, in some patients with TSC who have a clear indication for everolimus (eg, SGCTs), it would be appropriate to treat coexistent TSC-LAM on a trial basis with everolimus. Sirolimus and everolimus cannot be used simultaneously. More detailed discussion of mTOR inhibitor dosing, target levels and monitoring in TSC are provided separately. (See "Tuberous sclerosis complex: Management and prognosis", section on 'Everolimus' and "Renal angiomyolipomas (AMLs): Management".)
Refractory disease
Lung transplantation and clinical trials — For patients with advanced TSC-LAM or for those refractory to mTOR inhibitors, clinical trials (clinicaltrials.gov) or lung transplantation are the main therapeutic options. While patients with TSC-LAM have been successfully transplanted, antirejection medications may lower the seizure threshold and seizure medications may interfere with antirejection medications [31]. Other recommendations for this population are discussed separately. (See "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'Refractory disease'.)
Lymphatic disease and angiomyolipomas — Certain extrapulmonary manifestations of TSC-LAM may require treatment in concert with or independently from the lung disease:
●Chylous accumulations and lymphangioleiomyomas – mTOR inhibition with sirolimus is generally the treatment of choice for those with symptomatic chylous accumulations or lymphangioleiomyomas, the details of which are discussed separately. (See "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'Chylothorax and chylous ascites' and "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'Other lymphatic disease'.)
●Angiomyolipomas – Selected patients with larger or symptomatic AMLs may require treatment with mTOR inhibition or surgical intervention. The management of AMLs is discussed separately. (See "Renal manifestations of tuberous sclerosis complex", section on 'Treatment'.)
FOLLOWUP AND PROGNOSIS — Similar to sporadic lymphangioleiomyomatosis (sporadic-LAM), TSC-LAM is a progressive disorder with rates of progression that vary among individuals [32]. Patients with TSC-LAM should be monitored for progressive lung function decline with pulmonary function testing and for the development of complications. The optimal frequency of clinical and pulmonary function test (PFT) assessment is not well-defined. We typically schedule follow-up visits with spirometry pre and post bronchodilator at three to four month intervals and obtain additional studies such as a six-minute walk test (with oximetry) or chest imaging depending on the clinical assessment and PFT results. Further details on the follow up of LAM patients are provided separately. (See "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'Monitored observation' and "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'Monitoring clinical response' and "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'Treatment of complications'.)
In adult TSC patients, LAM is a major cause of death (figure 1) together with renal disease and sudden death from epilepsy (SUDEP) [15,33,34]. With the advent of mechanistic target of rapamycin (mTOR) inhibitor therapy and aggressive interventional approaches for renal disease, a single-center retrospective study suggests that fewer patients with TSC are dying from renal complications than in the past and that LAM is now the second most common cause of death after SUDEP [34]. It is widely believed among experts that TSC-associated LAM may have a more indolent course than sporadic LAM, although similar rates of decline in lung function have been reported in severity-matched patients [22,35]. One study reported an average life expectancy of TSC-LAM at 63 years [34,35]. Whether males with TSC-LAM live longer than females with TSC-LAM is unknown. The prognosis of TSC and of LAM are discussed separately. (See "Tuberous sclerosis complex: Management and prognosis", section on 'Prognosis' and "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'Prognosis'.)
OTHER TUBEROUS SCLEROSIS COMPLEX-RELATED LUNG DISORDERS
Multifocal micronodular pneumocyte hyperplasia — Unlike sporadic lymphangioleiomyomatosis (sporadic-LAM) where, multifocal micronodular pneumocyte hyperplasia (MMPH) is rare, MMPH can occur in up to two-thirds of patients with TSC, with or without LAM [6,20,21,36,37]. The etiology MMPH appears to be due to hyperphosphorylated mechanistic target of rapamycin (mTOR)-related proteins which may cause benign proliferation of type II pneumocytes along alveolar septa [38,39].
MMPH is generally asymptomatic and found incidentally in the lung on imaging or on pathology. Equal proportions of males and females with TSC are affected. On computed tomography, MMPH appears as multiple, centrilobular solid or ground glass nodular opacities ranging in size from 2 to 10 mm scattered throughout lungs in a random distribution.
MMPH can occur alone or with the cystic changes of LAM and can occur with either TSC1 or TSC2 mutations. In a retrospective study of 66 females with TSC, 28 percent had MMPH alone and a smaller proportion had MMPH in association with LAM. There were no specific clinical or genetic functional features [14]. Similarly, in a prospective study of 23 asymptomatic females with TSC, 43 percent had pulmonary parenchymal nodules which were more common in females with cysts consistent with LAM (78 percent) [5]. Unlike TSC-LAM, which is associated with TSC2 mutations, TSC-associated MMPH was associated with both TSC1 and TSC2 mutations.
In general, a biopsy is not required unless symptoms or imaging appearance suggests miliary metastases or progressive granulomatous disease. MMPH is generally indolent and nonprogressive [40], and as such no therapy is typically required (or available).
Clear cell tumor of the lung — Clear cell ("sugar") tumor of the lung (CCTL) is a rare, typically benign mesenchymal tumor with histologically and immunohistochemically distinctive perivascular epithelioid cells. Rare cases of CCTL have been reported in TSC-LAM [41]. LAM, angiomyolipoma, and CCTL are the major members of the neoplasms with perivascular epithelioid differentiation (ie, PEComa) family of lung tumors. CCTL affects males and females equally and usually presents as a nodule on chest imaging. Unlike pulmonary LAM, homatropine methylbromide (HMB)-45 staining is absent and S-100 staining is positive.
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: Tuberous sclerosis" and "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 AND RECOMMENDATIONS
●Lymphangioleiomyomatosis (LAM) is a multisystem disorder that primarily affects the lung, but is also associated with renal angiomyolipomas and retroperitoneal lymphangiomas. LAM can occur sporadically (sporadic-LAM) or can complicate tuberous sclerosis complex (TSC-LAM), an inheritable disorder caused by mutations in the TSC1 or TSC2 gene. TSC-LAM is identical clinically, radiologically, and pathologically, to the sporadic variant. Features specific to TSC are discussed in this review. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation" and "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis".)
●While sporadic-LAM is a rare disease that almost never affects males, LAM occurs commonly in those with TSC and can affect both males and females. Approximately, 26 to 50 percent of females and 10 to 38 percent of males with TSC develop cystic lung changes suggestive of or consistent with LAM, although only a minority will develop lung function decline. TSC-LAM typically occurs in those with TSC2 rather than TSC1 mutations, highlighting the role of TSC2 gene mutations in LAM pathogenesis. (See 'Epidemiology' above and "Sporadic lymphangioleiomyomatosis: Epidemiology and pathogenesis".)
●LAM is a later manifestation of TSC typically presenting with respiratory symptoms in the third to fourth decade and can occur in those with milder features of TSC (eg, without cognitive disability or seizures), although LAM can also present in early adolescence and coexist with severe TSC. The respiratory symptoms and signs are similar to sporadic-LAM (eg, progressive dyspnea, cough, pneumothorax, chylothorax). (See 'Clinical manifestations' above and "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Clinical manifestations'.)
●Pulmonary cysts are the hallmark feature of LAM on high resolution computed tomography (HRCT). Cysts characteristic of LAM are thin-walled, multiple (≥10), diffuse, bilateral, round, well-defined, varying in size, and devoid of internal structures. Typical findings on PFTs include airflow limitation, and/or a reduction in diffusing capacity, but normal PFTs do not preclude the diagnosis. (See 'Imaging characteristics' above and 'Pulmonary function testing' above.)
●For symptomatic females with TSC and symptoms of LAM, pulmonary function tests (PFTs) and noncontrast HRCT should be performed.
●For asymptomatic females with TSC who are ≥18 years of age, a screening low-dose noncontrast CT for the early identification of cysts consistent with LAM is advised. (See 'Diagnostic evaluation' above and 'Screening for TSC-LAM' above.)
●TSC-LAM should be evaluated and managed in conjunction with a TSC and LAM expert. Our proposed diagnostic approach is described in the algorithm (algorithm 1).
•In patients with TSC, the identification of typical cysts consistent with LAM on HRCT chest provides a clinical diagnosis of LAM and, in most patients, lung biopsy is not required. Once a clinical diagnosis is made, we also typically obtain a vascular endothelial growth factor-D (VEGF-D) level, which, if elevated (≥800 pg/mL), provides further support for the diagnosis. (See 'Imaging characteristics' above and 'Vascular endothelial growth factor-D' above and 'Diagnosis' above.)
•If the HRCT reveals no cysts, we typically repeat the HRCT every 5 to 10 years or when symptoms emerge.
•If the HRCT chest reveals atypical cysts, a low number of cysts (<10), or is suspicious for an alternate diagnosis, the approach should be individualized. Options include obtaining a VEGF-D level, lung biopsy, investigating for an alternate diagnosis, and follow up HRCT (eg, for appearance of additional cysts). (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Other presentations'.)
●The treatment of TSC-LAM is similar to that of sporadic-LAM. All patients should receive supportive measures and treatment of complications as they arise.
•Most patients with TSC-LAM who have normal or mildly impaired pulmonary function should undergo monitored observation clinical assessment and PFTs at regular intervals, rather than active mechanistic target of rapamycin (mTOR) inhibitor therapy. Exceptions would include patients with other indications for an mTOR inhibitor (eg, refractory epilepsy, symptomatic subependymal giant cell tumors [SGCTs], lymphatic disease). (See 'Mild lung function impairment' above.)
•For patients with moderate-to-severe progressive TSC-LAM, we recommend treatment with an mTOR inhibitor, preferably with sirolimus, rather than observation (Grade 1B). (See 'Moderate to severe lung function impairment' above.)
•For those with advanced lung disease refractory to mTOR inhibition, referral for lung transplantation or clinical trials is appropriate. (See 'Treatment' above and "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'Treatment of pulmonary LAM'.)
●TSC-LAM is a progressive disease, although the rate of progression varies among individuals and TSC-associated LAM may have a more indolent course than sporadic-LAM. Patients should be monitored for progressive lung function decline with pulmonary function testing and for the development of complications. (See 'Followup and prognosis' above and "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'Prognosis'.)
●Other pulmonary processes associated with TSC-LAM include multifocal micronodular pneumocyte hyperplasia (MMPH), which can occur in up to two-thirds of patients with TSC with or without LAM and clear cell tumors of the lung. (See 'Other tuberous sclerosis complex-related lung disorders' above.)
