Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation

INTRODUCTION — Lymphangioleiomyomatosis (LAM) is a rare multisystem disease that mostly afflicts young females [1-4]. While, in the past, surgical biopsy was a commonplace approach for the diagnosis of LAM, there is now a paradigm shift in practice towards less invasive methods that obviate the need for surgery in most patients.

The clinical features and diagnostic evaluation of LAM will be reviewed here. The epidemiology, pathogenesis, treatment, and prognosis of sporadic and tuberous sclerosis complex-associated LAM are discussed separately. (See "Sporadic lymphangioleiomyomatosis: Epidemiology and pathogenesis" and "Sporadic lymphangioleiomyomatosis: Treatment and prognosis" and "Tuberous sclerosis complex: Clinical features" and "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults".)

DEFINITION — The term sporadic LAM is used for patients with LAM not associated with tuberous sclerosis complex (TSC), while TSC-LAM refers to LAM that is associated with TSC. (See "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults".)

CLINICAL MANIFESTATIONS — LAM commonly afflicts young females (see 'General' below). The presenting symptoms and signs of LAM vary depending upon the organs affected by the disease. Most commonly, patients have the signs and symptoms of lung disease (see 'Pulmonary' below) but can also present with manifestations and symptomatology arising from disease in extrapulmonary sites, especially renal angiomyolipomas (AMLs) and the lymphatic vasculature [5,6] (see 'Nonpulmonary' below). Neurocutaneous findings and disease manifestations that are typical of tuberous sclerosis complex (TSC; eg, angiofibromas, Shagreen patches, cortical tubers, seizures, cognitive impairment, etc) are absent in sporadic LAM.

General — Patients with LAM are mostly premenopausal (approximately two-thirds in most trials and registries) females [7]. While the average age at presentation is typically between the mid-thirties and mid-forties, the range extends from preadolescence to elderly (>80 years) [4,7-15]. Prepubertal LAM is rare [16]. Cystic changes consistent with LAM occur in up to 10 percent of males with TSC, based on screens of males in large TSC clinics, but symptomatic LAM in males is exceedingly rare. (See "Sporadic lymphangioleiomyomatosis: Epidemiology and pathogenesis", section on 'Epidemiology'.)

In some patients, symptom onset and diagnosis occur while the patient is receiving estrogen replacement therapy (eg, oral contraception, fertility treatment) or is pregnant. [17-28].

Although in our experience, LAM can affect all races, one study suggested that LAM is more common in White females with a higher socioeconomic status, an observation that likely reflects differential access to information [7].

Pulmonary — The presenting characteristics of patients with LAM were best illustrated in a United States registry that enrolled 230 patients [7]. The most common manifestations in this study are supported by smaller studies performed before and after that publication [1,8,9,17,29-35]:

Common presentations include:

●Fatigue (approximately two-thirds)

●Progressive dyspnea (approximately two-thirds)

●Spontaneous pneumothorax (approximately one-third)

●Pleural effusion (approximately one-quarter)

Less common manifestations include:

●Chest pain (<15 percent)

●Cough or phlegm (<15 percent)

●Pulmonary hypertension (<7 percent)

●Chyloptysis (<10 percent)

●Chyle in urine, vaginal discharge, stool (<5 percent)

●Hemoptysis (~10 percent)

Dyspnea during exercise is the most common presenting symptom in LAM. As dyspnea is nonspecific and LAM is rare, females are often labeled with a diagnosis of asthma, emphysema, or chronic obstructive pulmonary disease (COPD) before LAM is suspected. Furthermore, up to one-third of females with LAM also have reversible airflow obstruction, which can lead to confusion with other obstructive lung diseases [31,36-38].

Cyclical worsening of respiratory symptoms coinciding with the menstrual cycle is reported by up to one-third of patients with LAM. These patients are more likely to be diagnosed at a younger age and tend to be more symptomatic compared with LAM patients without menstrual cycle-related respiratory symptom variability [39].

Pneumothorax is the presenting complaint in one-third of patients and occurs during the course of the disease in up to two-thirds of patients [7,17,40,41]. Recurrences are frequent. In one observational study, in those with recurrent pneumothorax, the mean number of cumulative pneumothoraces was four (ipsilateral, contralateral, or bilateral) [7]. Patients with larger cysts may be more likely to present with a pneumothorax [42]. Spontaneous pneumothoraces in females with LAM tend to occur more frequently in reproductive age ranges and are less common after menopause [43]. It has been suggested that females who present with pneumothorax have a more benign course than those who present with dyspnea [44], although ascertainment earlier in the course of disease likely confounds interpretation of this observation. (See "Treatment of secondary spontaneous pneumothorax in adults".)

Pleural effusions are most commonly due to chylothorax, occurring in 10 to 30 percent of females with LAM [17,45]. One systematic review of 94 studies consisting of a total of 199 LAM patients reported that chylous effusions were typically unilateral (76 percent) and right-sided, although bilateral effusions can also occur [34]. Biochemical parameters may reveal an exudative effusion with the typical features of chyle (eg, high triglyceride, cholesterol, chylomicrons). Chylothorax volume varies and can be quite stable over time. Pleural chyle may arise from sources leaking into the peritoneum, pumped into the thorax by the bellows action of the chest, but more often occurs in the absence of chylous accumulation in the peritoneal space (<5 percent) or elsewhere. (See "Etiology, clinical presentation, and diagnosis of chylothorax", section on 'Pleural fluid analysis'.)

Lymphatic pulmonary congestion due to reflux of chyle from the axial lymphatics into the pulmonary lymphatic circuit can result in worsening shortness of breath associated with chyloptysis or chylous pleural effusion. Chest radiographs and computed tomographic (CT) studies may reveal ground glass or an interstitial pulmonary edema pattern with septal thickening [46-48]. Further details regarding the lymphatic manifestations of LAM are provided separately. (See 'Lymphatic manifestations' below.)

Resting pulmonary hypertension (PH) is uncommon (<7 percent) in LAM, but exercise-induced increases in pulmonary pressures occur, likely due to hypoxic vasoconstriction but other mechanisms may also be involved [49-52]. In a series of 120 patients with LAM, 7 percent had resting PH on echocardiography, and approximately 50 percent experienced a decline in oxygen saturation with exertion, which correlated with a rise in pulmonary artery pressure (PAP) [49]. In a separate report, intrapulmonary arteriovenous shunts were demonstrated by contrast echocardiography in a small number of patients with LAM who developed hypoxemia and increased pulmonary artery systolic pressure during exercise [50]. Another retrospective study of 20 females with LAM who had PH by right heart catheterization found that when present, PH was typically mild (mean PAP 32 mmHg) [51]. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults".)

The physical examination in patients with LAM is often unrevealing but may demonstrate wheezes, hyperinflation, decreased or absent breath sounds (especially when chylous effusion or pneumothorax is present), crackles (when lymphatic pulmonary congestion is present), ascites, and intra-abdominal or adnexal masses. Clubbing is rare [35,53,54]. Characteristic features of TSC (eg, subungual fibromas, facial angiomas, hypomelanotic macules) are absent in sporadic LAM. (See "Tuberous sclerosis complex: Clinical features".)

Nonpulmonary

Renal angiomyolipomas — Renal angiomyolipomas (AMLs) are benign masses that contain blood vessels, muscle tissue, and fat. They occur in approximately 30 percent of patients with sporadic LAM (compared with >80 percent in patients with TSC-LAM) (image 1A-B) [7,55-57]. While renal AMLs may be asymptomatic (especially small lesions), patients with lesions larger than 4 cm, especially those that contain aneurysms, may present with the features of hemorrhage (abdominal pain and a mass). Rarely, AMLs may grow to enormous size prior to clinical detection in patients with TSC-LAM or sporadic LAM, but do not typically affect renal function in the absence of TSC. If AMLs are large, bilateral, or multiple, then TSC should be suspected (>80 percent of patients with TSC have AMLs). (See 'Abdominal imaging' below and "Renal manifestations of tuberous sclerosis complex", section on 'Angiomyolipomas' and "Renal angiomyolipomas (AMLs): Management".)

Small sporadic AMLs are frequently encountered incidentally on abdominal CT imaging done for another reason in the general population. When large, multiple, or bilateral, a low threshold for performing a chest CT is prudent given that approximately 11 percent of patients with sporadic AMLs have cystic changes in the lung consistent with LAM [58].

Lymphatic manifestations — Lymphatic manifestations are much more common in sporadic LAM than TSC-LAM [59] for reasons that are not well understood.

Chylothorax and chyloperitoneum — Chylothorax is the most common lymphatic manifestation of LAM (10 to 30 percent) (image 2) [5-7,17,45,60]. Patients may present with a pleural effusion or chyloptysis. (See 'Pulmonary' above.)

Less commonly, chylous accumulation can result in the following:

●Chyloperitoneum (also known as chylous ascites), which occurs in approximately 4 percent of LAM patients, may present with abdominal swelling or chyle leak from the umbilicus

●Chyluria, which is thought to be due to connections between dilated retroperitoneal lymphatics and the renal collecting system, is seen in 2 percent of reported cases

●Lymphatic pulmonary congestion due to reflux of chylous fluids from axial lymphatics into pulmonary lymphatic circuit (<1 percent)

●Chylopericardium (<1 percent)

●Vaginal chylous discharge (chylometrorrhea; <1 percent)

●Chyle in stool (chylocolporrhea) with or without protein losing enteropathy (<1 percent)

Lymphangioleiomyomas — Lymphangioleiomyomas (also known as lymphangiomyomas) of the retroperitoneum and pelvis, and less commonly, the mediastinum, are lymphatic fluid-filled, benign tumors that occur in 16 to 38 percent of patients with LAM [61-64]. They may be asymptomatic or present with nausea, bloating, abdominal pain, edema of the lower extremities, or urinary symptoms (eg, frequency due to bladder displacement or chyluria due to lymphangioleiomyomatous connections with the renal collecting system). Worsening of symptoms as the day progresses may be explained by diurnal variation in size of the tumors due to gravity, dietary intake, or exercise [63]. Lymphedema of the lower extremities and buttocks was described in 8 of 228 patients with sporadic LAM in Japan [65]; all eight patients had enlarged retroperitoneal or pelvic lymph nodes, thought to be lymphangioleiomyomas. (See 'Abdominal imaging' below.)

Lymphadenopathy — Enlarged axial lymph nodes are not uncommon, with reports ranging from 25 to 77 percent of patients with pulmonary LAM [5,17,35,55,66]. Lymphadenopathy is more common in sporadic LAM than TSC-LAM. Retroperitoneal and pelvic lymphadenopathy is more common than mediastinal and hilar node involvement, consistent with an origin in the pelvis or low abdomen [67]. There are sparse case reports of LAM in supraclavicular and groin nodes [68-70]. LAM has been reported in lymph nodes biopsied during evaluation for suspected lymphoma or pelvic mass, or during staging of a known uterine or ovarian cancer [71,72].

Although the yield is uncertain, in our practice, incidental discovery of LAM in an axial lymph node prompts an evaluation for cystic lung disease with a chest CT.

Uterine lymphangioleiomyomatosis lesions — Several reports of LAM lesions in the uterus, ovaries, and adnexa have been published [73-75]. As an example, LAM lesions were discovered in uterine specimens from 9 of 10 patients with pulmonary LAM [76]. The lesions were more profuse and diffusely distributed in the myometrium of uterine specimens from patients with TSC-LAM and more sparse and subadventitial in the specimens from sporadic LAM patients. An analysis utilizing single cell RNA transcriptomics performed on lung and uterus specimens obtained from LAM patients has suggested the uterus as the source for LAM cells that infiltrate the lung [77].

Uterine leiomyomas (fibroids) are common in LAM but do not appear to be more common in females with LAM than in the general population.

Other — An increased incidence of cerebral meningiomas has been reported in LAM [78], although the validity of the association has been challenged [79].

AMLs of the liver and spleen, and sclerotic bone lesions also occur in patients with sporadic LAM but are more common in TSC-LAM [6,59,76,78,80,81]. (See "Sporadic lymphangioleiomyomatosis: Epidemiology and pathogenesis", section on 'Lam cell origin'.)

EVALUATION — LAM should be suspected in females with a spontaneous pneumothorax or unexplained dyspnea, especially nonsmoking females of reproductive age. LAM should also be suspected in females (and less commonly in males) with tuberous sclerosis complex (TSC) as well as in those who present with pleural or peritoneal chylous accumulations or a renal angiomyolipoma (AML). The following sections outline the evaluation of suspected LAM, which includes pulmonary function testing, chest imaging, and selected laboratory testing (algorithm 1). For patients who have previously undergone such testing, careful review of the existing data looking for clues to the presence of LAM is prudent. As an example, with the growing use of CT of the chest and abdomen, thin-walled cysts characteristic of LAM are increasingly discovered incidentally.

In general, these recommendations are consistent with guidelines provided by international societies and modified as new data arise [61,82-85].

Pulmonary function tests — Pulmonary function tests (PFTs), including spirometry with and without bronchodilator testing, lung volumes, and diffusing capacity for carbon monoxide (DLCO), are an essential component of the evaluation of dyspnea and should be performed in females suspected to have LAM. However, PFTs are diagnostically nonspecific and a normal study does not preclude the diagnosis of LAM. In patients with severe symptoms or severe lung dysfunction or in patients with reduced resting pulse oxygen saturation <95 percent, a six-minute walk test and/or arterial blood gas analysis can be used to assess the need for supplemental oxygen at rest or with exertion [86]. Nocturnal oximetry can be obtained to assess the need for oxygen with sleep. (See "Overview of pulmonary function testing in adults" and "Office spirometry" and 'Imaging' below.)

The proportions of females who present with mild, moderate, or severe lung disease varies widely based on mode of ascertainment in different populations, and with increased use of CT scanning, "incidental" detection of lung cysts is expanding the proportion of females who are discovered to have asymptomatic diseases [32]. However, observational studies consistently report the following findings on PFTs in females with LAM [7,9,30,32,33,35,53,87,88]:

●Normal spirometry (30 to 60 percent)

●Obstructive pattern on spirometry (25 to 66 percent)

●Restrictive or mixed obstructive and restrictive pattern on spirometry (less than one-quarter)

●Reduced DLCO (60 to 90 percent)

Approximately 25 to 30 percent of patients demonstrate reversible airflow obstruction following an inhaled bronchodilator [17,36,89]. In a study of 130 patients with baseline airflow limitation who underwent testing on multiple occasions, 39 patients demonstrated reversibility in airflow obstruction after administration of an inhaled bronchodilator, including 9 to albuterol, 12 to ipratropium, and 18 to both [36]. The patients with a positive bronchodilator response had a lower baseline forced expiratory volume in one second (FEV₁). In another study, bronchodilator reversibility was seen in approximately one-quarter of the patients who underwent reversibility testing (25 out of 95) [38]. The mechanism of airflow obstruction is unclear, but possible explanations include loss of elastic recoil, LAM cell involvement of bronchial airways, or reduction in the number of small airways [31,90-93].

Lung volumes may be elevated in LAM (due to hyperinflation), resulting in an increased total lung capacity (TLC), residual volume (RV), and RV:TLC ratio. However, lung volumes may also be normal or reduced.

Diffusing capacity is reduced in many patients with LAM, even in those with normal spirometry [7,30,53,87,88]. Thus, an isolated reduction in DLCO in a young female with dyspnea should prompt consideration of a chest CT to look for pulmonary parenchymal disorders, such as LAM, once other common causes of reduced DLCO, such as anemia, have been excluded. Several reports indicate that DLCO correlates with disease severity as assessed by CT, histology, and exercise testing, and may also correlate with the number of small cysts [94-98]. Thus, when following patients before and during therapy, we follow both spirometry and diffusion. (See "Sporadic lymphangioleiomyomatosis: Treatment and prognosis".)

Resting, nocturnal, or exercise-induced hypoxemia and (rarely) hypercapnia may be present in those with more advanced disease, and a six-minute walk test with oximetry and/or arterial blood gas analysis may be warranted to determine if supplemental oxygen is needed [55,86,99]. (See "Overview of pulmonary function testing in adults", section on 'Six-minute walk test'.)

Although useful as a research tool, cardiopulmonary exercise testing (CPET) is generally not indicated for the routine diagnosis and management of females with suspected LAM. However, it is often performed as part of the evaluation of unexplained dyspnea. Characteristic findings are those of decreased pulmonary reserve with or without pulmonary vascular dysfunction, although obstruction only partially explains reduced physical activity in this population [31,91,100,101]. Other findings that might be observed during CPET in patients with LAM include reduced oxygen consumption, low anaerobic threshold, abnormal and excessive ventilatory response with a high respiratory rate, excessive minute ventilation, reduced breathing reserve, abnormal baseline or exercise dead space to tidal volume (VD:VT) ratio, and dynamic hyperinflation. Incremental shuttle walk testing may be used as a simpler alternative to assess maximal exercise capacity in LAM [102]. (See "Cardiopulmonary exercise testing in cardiovascular disease".)

PFTs are important in assessing baseline disease severity as well as following lung function over time [103]. There is a very low risk of pneumothorax during lung function or exercise testing in this setting [104]. (See 'Assessment of disease extent' below.)

Imaging — Noncontrast high-resolution CT (HRCT) of the chest should be performed in females with suspected LAM to look for pulmonary cysts characteristic of the disease. In most cases, the decision to pursue HRCT is triggered by recurrent pneumothorax, chylothorax, or relentlessly progressive dyspnea on exertion, although an increasing proportion of females are presenting with evidence of characteristic thin-walled, diffusely distributed pulmonary cysts on chest or abdominal CT performed for a different indication. Noncontrast abdominopelvic CT is indicated to look for the presence of AMLs if cysts are found on chest CT or the patient has abdominal or pelvic symptoms or signs that warrant dedicated abdominal imaging (eg, sudden flank pain). The spectrum of radiographic findings in females with LAM are discussed in the sections below. LAM guidelines recommend against the use of HRCT as the sole basis for the diagnosis of LAM [84].

Chest radiograph — A chest radiograph is typically obtained in patients with unexplained dyspnea, particularly when dyspnea is acute in onset. In patients with LAM, the chest radiographic findings are variable (image 3A-B) [1,7,53,105,106]. These include a normal radiograph (early in the course of the disease), reticular or nodular opacities (from the compression of lung tissue by dilated cystic airspaces), hyperinflation (33 to 62 percent of patients), emphysematous-like changes, pleural effusion (often due to a chylothorax), pneumothorax, or lymphadenopathy. The findings on plain chest radiograph are often uninformative or nonspecific, and are never sufficient to diagnose LAM.

Chest CT — The rationale for performing noncontrast HRCT of the chest in patients suspected of having LAM is based upon the principles that thin-walled cysts, the hallmark lesion in LAM, are seen in almost every patient with LAM and that cysts are often undetectable on routine chest radiography (image 4A-C) [55,107-109].

The following features may be found on HRCT chest:

●Cysts – Pulmonary cysts are the hallmark feature of LAM on HRCT chest. Cysts characteristic of LAM are thin-walled, diffuse, round, well-defined, bilateral, and without lobar predominance (image 5) [59,61,66,67,105,108,110,111], although one study suggested cyst predominance in the middle one-half of the lungs compared with the upper and lower quarters [112]. They vary in size ranging from 2 to 40 mm in diameter and typically have walls ranging from 0.1 to 2 mm in thickness. The cysts are typically devoid of internal structures (eg, centrilobular vessels or septae) or consistent relationships with adjacent vessels, airways, or interlobular septae.

Although cystic change in the lung parenchyma progresses over time, no natural history studies have clearly delineated when cysts begin to develop or their rate of progression. Similarly, because isolated cysts are occasionally found in healthy nonsmoking subjects, it is important to set a threshold for the number of cysts in any one individual that is considered to be abnormal. While some experts have suggested a cutoff of >3 [58], we and other experts usually select a higher cutoff of >10 cysts, such that LAM should be highly suspected in females with more than 10 typical cysts [61]. The likelihood of LAM may be lower in those with fewer cysts (eg, >2 and ≤10), but LAM is still theoretically possible in such cases. While the 10-cyst cutoff is arbitrary and needs to be validated in formal studies, it was chosen in part to discourage lung biopsy in asymptomatic patients with very few cysts and normal lung physiology. The approach to biopsy in those with atypical cysts is discussed below. (See 'Other presentations' below.)

●Pneumothorax – Pneumothorax is the presenting manifestation in approximately one-third of patients with sporadic LAM (image 6) (see 'Pulmonary' above), and ultimately occurs in over two-thirds of LAM patients. Asymptomatic pneumothorax may be identified in approximately 5 percent of LAM patients undergoing chest CT in the absence of acute symptoms [67]. Chronic loculated pneumothoraces may also be noted (image 3A-B) [7]. (See "Treatment of secondary spontaneous pneumothorax in adults".)

●Pleural masses or thickening – Macroscopic pleural masses and thickening are not a natural feature of LAM, although microscopic pleural involvement is common. Among patients who have undergone pleurodesis for recurrent pneumothorax prior to diagnosis, pleural thickening and complex pleural masses may be apparent [113-115]. The masses in patients who have received talc for pleurodesis may be solid and hyperdense, contain areas of calcification, and are often positron emission tomography (PET)-positive for many years after pleurodesis suggesting ongoing inflammation [116].

●Thoracic lymphatic involvement and pleural effusion – Lymphatic involvement by LAM can cause chylous parenchymal congestion with septal thickening, unilateral or bilateral chylothorax (10 to 20 percent), mediastinal lymphadenopathy (26 percent; hilar adenopathy is unusual), dilated thoracic duct (11 percent), pericardial effusion (6 percent), or, rarely, cystic lymph nodal lesions typical of lymphangioleiomyomas [17,46,49,66].

●Other – Additional features on HRCT include:

•Ground glass opacities (GGOs) and septal thickening – GGOs are rare but may represent compression from air trapping and hyperinflation in adjacent cystic lung parenchyma, pneumonia, pulmonary edema, or alveolar filling with blood or lymphatic fluid [117]. Septal thickening due to lymphatic obstruction may also present as GGOs [66].

•Multifocal micronodular pneumocyte hyperplasia – Features of multifocal micronodular pneumocyte hyperplasia, due to focal proliferation of alveolar type II cells, may be encountered in LAM patients with TSC. Although rarely reported in subjects with sporadic LAM, we suspect these cases may represent clinically occult TSC [118]. (See "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults", section on 'Clinical manifestations'.)

•Renal angiomyolipomas – Renal AMLs may be incidentally found in females with LAM on HRCT. (See 'Abdominal imaging' below.)

Abdominal imaging — In patients with suspected LAM who have characteristic cysts on chest CT, the abdominal sections of the chest CT should be reviewed for renal AMLs. Whether present or not on chest CT, most experts obtain additional abdominal-pelvic imaging to determine the presence and extent of AML involvement [61], most commonly by CT scan or magnetic resonance imaging (MRI). Ultrasound (USG) may be a reasonable alternative but is less sensitive and less accurate, especially for small lesions. The rationale for this approach is that the prevalence of renal AMLs is high (approximately 30 percent) in sporadic LAM [6] and, when present, AMLs can provide the basis for a clinical nonpathologic diagnosis of LAM, thereby obviating the need for lung biopsy. Less commonly, evidence of lymphatic involvement may be found on CT, which may support a diagnosis of LAM (eg, lymphangioleiomyomas) or provide the clinician with a less invasive alternative to lung biopsy (eg, cytologic evaluation of a lymph node aspirate or chylous fluid).

●Renal AMLs – Renal AMLs occur in approximately one-third of females with sporadic LAM, which is much less frequent than in those with TSC-LAM (>80 percent) [7,57,119,120]. Most renal AMLs can be readily identified and diagnosed radiographically, typically by the presence of fat within a renal tumor on noncontrast-enhanced CT (image 7 and image 8). Fat-free or fat-poor AMLs can also occur and must be distinguished from renal cell carcinomas, oncocytomas, or other more aggressive neoplasms, which can rarely complicate TSC and sporadic LAM. MRI can be helpful in some of these cases because it is more sensitive than CT for detecting fat density [55]. Imaging findings must be carefully interpreted because hemorrhage into an AML can complicate renal imaging in a manner that may be confused with renal cell carcinoma (RCC) and small amounts of fat can be rarely found in RCCs. Knowledge of a pre-existing AML and the presence of fat attenuation may help in the differentiation of these entities [113]. Ultrasound is typically less sensitive than CT for detection of small lesions. When the diagnosis remains in question, needle aspiration may be an alternative to surgical biopsy for diagnosis. Further details regarding the diagnosis of AMLs are provided separately. (See "Renal manifestations of tuberous sclerosis complex", section on 'Angiomyolipomas' and "Renal angiomyolipomas (AMLs): Management".)

●Lymphadenopathy – Axial lymphadenopathy is common, particularly in sporadic LAM as opposed to TSC-LAM and peripheral lymphadenopathy is very rare in LAM. Retroperitoneal lymphadenopathy is reported in up to 77 percent of patients [35,55]. Lymph node involvement is rare in the supraclavicular and inguinal regions and common in the pelvis and abdomen. Low density within enlarged axial lymph nodes can lead to confusion with lymphoma or necrotizing neoplasms. (See 'Lymphatic manifestations' above.)

●Lymphangioleiomyomas – Lymphangioleiomyomas are benign neoplasms of lymphatic vessels that are found in up to 20 percent of patients with LAM [63]. Proliferation of smooth muscle cells in the lymph vessels results in mural thickening, obstruction, dilation, and pooling of chyle. Radiologically, they have distinct outer walls and appear as dilated fluid-filled spaces. They are found more commonly in the retroperitoneum or pelvis compared with the mediastinum. Lymphangioleiomyomas can exhibit substantial diurnal variation in size, sometimes increasing with eating and exercise and decreasing with fasting [63,64,113].

●Other – Other features that can be found on abdominal CT include liver and spleen AMLs as well as abdominal fluid that may represent chylous ascites [67].

Other imaging

●Ventilation perfusion scan – Ventilation-perfusion scans are frequently abnormal in LAM, revealing a distinctive speckled pattern on the ventilation images, but they are not routinely performed for diagnostic purposes [55].

●PET – 18-fluorodeoxyglucose (FDG)-PET is not typically performed, since LAM is a slow-growing, low-grade neoplasm that does not take up FDG efficiently. However, should PET be positive, an alternate diagnosis (eg, lymphoma, cancer, PEComa) or reason (inflammatory lesion) should be sought [116].

●Advanced lymphatic imaging – Lymphatic imaging is not typically performed for diagnostic purposes but can be helpful to guide therapeutic decisions in patients with problematic pleural effusions, chylous ascites, or other chylous complications [121]. (See "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'Chylothorax and chylous ascites'.)

Laboratory — In females who have suspected LAM with typical cystic changes on chest CT, serum vascular endothelial growth factor-D (VEGF-D) quantification is diagnostic for LAM if the level is greater than or equal to 800 pg/mL. Other laboratory tests that are commonly ordered as part of the investigation for cystic lung disease include testing for alpha-1 antitrypsin deficiency, serum protein electrophoresis and free light chain quantification for light chain deposition disease, and autoantibody testing for rheumatic diseases that can mimic LAM, such as rheumatoid factor (RF), antinuclear antibody (ANA), and Sjögren's-related antibodies (SSA/Ro and SSB/La antibodies). (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency", section on 'Evaluation and diagnosis' and "Diagnosis and classification of Sjögren’s disease".)

Vascular endothelial growth factor-D — We suggest that serum VEGF-D levels be measured in patients with suspected LAM, in whom typical thin-walled cysts are found on chest CT. The rationale for this approach is that several studies have shown that serum levels of VEGF-D are elevated in up to two-thirds of females with LAM [122-130] and that a level ≥800 pg/mL reliably distinguishes LAM from other cystic lung diseases [123,126,127,130]. VEGF-D analysis is currently available in the United States as a College of American Pathologists/Clinical Laboratory Improvement Act (CAP/CLIA)-certified test only through the Translational Trials Laboratory at Cincinnati Children's Hospital Medical Center. The LAM Foundation website includes useful resources including a link that describes the proper collection, handling, and shipping of VEGF-D specimens.

The ability of VEGF-D to distinguish LAM from other etiologies of cystic lung disease was best illustrated in a study of 195 females with cystic lung diseases due to several etiologies including LAM [123]. Serum VEGF-D levels were significantly greater in sporadic LAM (median 1175 pg/mL versus 281 pg/mL) than in other cystic lung diseases. When a cutoff of VEGF-D ≥800 pg/mL was used, the sensitivity and specificity of serum VEGF-D to diagnose LAM were 71 and 100 percent, respectively. Similar results were obtained in other VEGF-D studies, although differences between laboratories in the normative ranges [125] and the use of normal volunteers instead of cystic lung disease controls limits direct comparisons [127-129]. A VEGF-D level <800 pg/mL is uninformative and should not be used to exclude the diagnosis of LAM [123]. VEGF-D would not likely be useful for population screening in the absence of documented cystic change on CT as this test has only been validated in females with cystic lung disease and even a near perfect specificity of 99.9 percent would lead to too many false positives.

The optimal approach in those with a VEGF-D between 600 and 799 pg/mL is less certain. Although a cutoff ≥600 pg/mL has a diagnostic sensitivity and specificity of 84 and 98 percent, respectively, false positives are highly undesirable, especially when considering initiating long-term or lifetime exposure to therapies such as mechanistic target of rapamycin inhibitors. Thus, we and other experts use a cutoff of ≥800 pg/mL to be diagnostic, and consider VEGF-D ≥600 pg/mL to be suggestive but not diagnostic of LAM. Establishing a probable diagnosis of LAM based on VEGF-D >600 pg/mL may have value in some lower risk situations, such as for patients who have a low burden of disease that would not justify treatment or those who are not interested in therapies or interventions. (See 'Other presentations' below.)

This approach is supported by the American Thoracic Society/Japanese Respiratory Society Guidelines on the evaluation and management of LAM [82].

The value of VEGF-D testing as a biomarker for disease progression and response to treatment and as a screening tool for young females with TSC is discussed separately. (See "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults" and "Sporadic lymphangioleiomyomatosis: Treatment and prognosis" and "Sporadic lymphangioleiomyomatosis: Epidemiology and pathogenesis", section on 'Abnormal lymphangiogenesis' and "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'Monitored observation'.)

Future directions — Cancer antigen-125, an ovarian antigen, in one retrospective study, was elevated in 25 percent of patients with LAM and correlated with a lower FEV₁, premenopausal status, and pleural effusion [131]. Another retrospective study reported that vitamin D-binding protein (VDBP) was lower in patients with LAM compared with healthy controls; lower VDBP levels correlated with the DLCO and disease progression [132]. Although serum VEGF-C demonstrated reversible suppression with the administration of sirolimus in a manner similar to VEGF-D, it had little utility as a diagnostic biomarker in LAM [133]. A single cell transcriptomics-based analysis conducted on human LAM lung and uterus has suggested other potential novel biomarkers, such as IGFBP-4 and endostatin [77]. While cells with loss of heterozygosity for the tuberous sclerosis 2 gene have been found in the blood and urine of patients with LAM, they have also been found in patients with other forms of cystic lung disease [134]. In a small single-center study, serum FGF23 levels were found to be elevated in females with LAM compared with healthy controls [135]. Serum metalloproteinase (MMP)-2 quantification combined with VEGF-D was shown to be superior than VEGF-D alone in distinguishing LAM from other cystic lung diseases [136]. Further work is needed to determine the diagnostic and prognostic value of these tests before they can be broadly recommended.

SECURING A DIAGNOSIS

General principles — Surgical lung biopsy was the original gold standard for definitive diagnosis of LAM. However, surgical lung biopsy is not always necessary and a confident diagnosis can often be achieved less invasively (algorithm 1). Thus, there has been a paradigm shift in practice that involves the following:

●Obtaining a clinically confident diagnosis through the least invasive means possible using an approach that integrates clinical, radiologic, and laboratory data. Observational data suggest that utilizing such strategies reduces the need for biopsy by as much as 60 to 80 percent [127]. (See 'Clinical nonpathologic diagnosis' below.)

●Limiting the patients who are referred for lung biopsy to those in whom a confident diagnosis cannot be achieved using less invasive methods. (See 'Definitive pathologic diagnosis' below.)

Referral to a specialized center, particularly when deciding whether to pursue a lung biopsy or to initiate chronic treatment with a mechanistic target of rapamycin (mTOR) inhibitor, is recommended for centers and clinicians with limited experience with LAM. (See 'Additional resources' below.)

We base our approach to the diagnosis of LAM on the following factors:

●Mode of presentation – The approach to a pathologic diagnosis of LAM varies based on presentation.

•Typical presentations – Most experts agree on the typical presentations that meet the criteria for a clinically confident diagnosis (eg, typical cysts plus tuberous sclerosis complex [TSC] or angiomyolipoma [AML]). For patients with typical lung cysts who do not meet criteria for a clinically confident diagnosis, measurement of serum vascular endothelial growth factor-D (VEGF-D) or the pathologic analysis of tissue or fluid that is more readily accessible (eg, effusion that can be tapped or lymph node accessible by endobronchial ultrasonography) present diagnostic opportunities that are less invasive than lung biopsy. Similarly, a lung biopsy performed at the time of therapeutic pleurodesis for recurrent pneumothorax carries limited additional risk compared with a separate biopsy procedure, although air leaks can occur as a complication. (See 'Characteristic cysts with supportive features' below and 'Characteristic cysts alone on CT' below.)

•Atypical presentations – For those with atypical presentations, there are no clear guidelines and the approach should be individualized. (See 'Other presentations' below.)

●Therapeutic impact of definitive diagnosis – The decision to pursue lung biopsy in patients with cystic lung disease of unknown etiology should take into consideration the availability of therapies or interventions that can affect the outcome of the diseases in the differential (eg, mTOR inhibitors if LAM is suspected or cessation of smoking if pulmonary Langerhans cell histiocytosis is suspected). (See "Sporadic lymphangioleiomyomatosis: Treatment and prognosis".)

●Assessment of risk and benefit – Decisions regarding the importance of obtaining a pathologic diagnosis are based upon assessments of risks and benefits. As examples, observation may be appropriate in patients with only a few cysts and normal lung function, as well as in postmenopausal patients with mild disease (ie, when disease progression is known to be slower). In addition, the value of establishing a definitive diagnosis by biopsy in patients with severe end-stage lung disease approaching lung transplantation is questionable. (See 'Choosing transbronchial or surgical lung biopsy' below.)

●The values and preferences of the patient – Some patients place a high value on diagnostic certainty and are willing to accept the risks associated with an invasive procedure, while others prefer to avoid them. Thus, a risk-benefit discussion is critical so that the decision to pursue biopsy can be shared between the patient and the clinician. (See "Discussing goals of care" and "Informed procedural consent".)

We propose the algorithmic diagnostic strategy outlined in the sections below acknowledging that it should be tailored for each individual. This strategy is consistent with the American Thoracic Society/Japanese Respiratory Society LAM Guidelines as well as the French recommendations [85] but differs slightly from the European Respiratory Society Guidelines, which were published prior to the availability of data on the diagnostic value of VEGF-D [61,82,84].

Characteristic cysts with supportive features — During the diagnostic evaluation of patients with suspected LAM, a surgical biopsy may be avoided in select populations who have characteristic cysts on CT of the chest (see 'Chest CT' above) and one or more of the features listed in the sections below. A nonpathologic diagnosis may be reached with high certainty (ie, clinically confident diagnosis) in most of these populations. However, in a small proportion, a more definitive diagnosis may be needed and can be obtained cytologically using needle aspiration (ie, less invasive) techniques or pathologically on tissue biopsy of lung or lymph nodes. Reasons that may mandate a more aggressive invasive approach include atypical presentations (especially when considering interventions entailing risk, such as institution of mTOR inhibitor therapy), suspicion of an alternate diagnosis, and patient preferences for certainty. The American Thoracic Society/Japanese Respiratory Society LAM Guidelines advise against the use of chest CT alone to establish a confirmed diagnosis of LAM [84].

Tuberous sclerosis complex — Patients with TSC and lung cysts characteristic of LAM on chest CT do not typically need to undergo diagnostic lung biopsy due to the high prevalence of LAM and the low likelihood that lung cysts in TSC are due to a non-LAM-related condition. Patients with sporadic LAM do not have stigmata of TSC (other than AMLs). However, the features of TSC can be subtle leading to a missed diagnosis. Thus, a thorough history and examination should be performed in patients with suspected sporadic LAM to look for manifestations of TSC (eg, subungual fibromas, facial angiofibromas, hypomelanotic macules, confetti lesions, retinal hamartomas, Shagreen patches, seizures, autism, cognitive impairment). (See "Tuberous sclerosis complex: Clinical features".)

Genetic testing for mutations in the TSC genes, TSC1 and TSC2, is generally not indicated for ruling out TSC in patients who present with apparent sporadic LAM. Screening for TSC manifestations in the brain in LAM patients who do not have any other discernable neurocutaneous TSC features is controversial and probably has a low yield but is sometimes performed in patients who have multiple bilateral AMLs. When TSC is suspected, patients should be referred to a specialized center for a formal diagnosis. Details regarding criteria for the clinical and genetic diagnosis of TSC are provided separately. (See "Tuberous sclerosis complex: Clinical features" and 'Excluding tuberous sclerosis complex' below.)

Renal angiomyolipoma — Patients with characteristic cysts on CT and one or more renal AMLs do not typically require diagnostic lung biopsy. Most experts believe that these criteria establish a clinical diagnosis of LAM that is sufficiently certain to support the initiation of long-term treatment with mTOR inhibitors. The rationale for avoiding biopsy in this group is based upon the high prevalence of AMLs in females with sporadic LAM, the rarity of AMLs in other cystic lung diseases that mimic LAM, and the risks of biopsy.

However, the clinician should be aware that sporadic AMLs may rarely occur in patients who have cystic lung disease due to other etiologies (eg, Birt-Hogg-Dubé syndrome [BHD]) [137-139].

Vascular endothelial growth factor-D positive — Females with cystic change on chest CT that is characteristic for LAM who also have an elevated VEGF-D level ≥800 pg/mL do not require lung biopsy. A clinically confident diagnosis of LAM can be made in this population, which is sufficient to justify proceeding with mTOR inhibitor therapy, when indicated. The rationale for this approach is based upon observational studies that demonstrated that elevated serum VEGF-D distinguishes LAM from other cystic lung diseases [123,130], the details of which are discussed above. (See 'Vascular endothelial growth factor-D' above.)

Although false positive results associated with an elevated VEGF-D level ≥800 pg/mL are rarely reported [140], the decision to pursue lung biopsy for diagnostic purposes in this population is best made in consultation with a LAM expert or a specialized LAM center.

Chylous accumulation — Patients may present with a known chylous accumulation (pleural, peritoneal, pericardial) or alternatively, have a fluid collection(s) suspicious for chyle.

●Patients with characteristic cystic change on CT and known chylothorax or chyloperitoneum have a high likelihood of having LAM and, therefore, typically do not require biopsy; however, the strength of this association is considered by some experts to be weaker when compared with the combination of typical cysts on chest CT with either TSC or AML. Since serum VEGF-D levels may be reflective of the extent of lymphatic involvement in LAM [125] and LAM cell clusters (LCCs) may be found on cytology, we also generally measure VEGF-D levels and/or resample chylous fluid for cytologic analysis, especially when considering mTOR therapy. (See 'Vascular endothelial growth factor-D' above and 'Cytology' below.)

●In patients with characteristic cysts and pleural effusion that is suspected to be chylous, a sample should be obtained to look for the characteristic biochemical findings of chyle (ie, elevated triglycerides and cholesterol, chylomicrons) and cytologic LCCs, provided sample acquisition is safe and feasible (eg, tiny accumulations, particularly in the pericardial space, may not be safely sampled).

Although the diagnostic yield of cytologic analysis of chylous fluids tends to be low in our experience, when LAM cells are identified pathologically, the diagnosis is certain. Thus, thoracentesis and cytology can be useful in distinguishing the etiology of chylous effusion in the rare cases where cystic lung diseases that mimic LAM and chylothorax can coexist (eg, lymphoma). Elevated levels of serum VEGF-D can also support the diagnosis of LAM. (See "Etiology, clinical presentation, and diagnosis of chylothorax", section on 'Evaluation'.)

The rationale for avoiding biopsy in this population is the same as that for patients with a combination of cysts and either TSC or AMLs in that the likelihood of LAM is high and does not warrant the risk of lung biopsy.

Lymphangioleiomyoma or lymph node disease — Patients may present with a known or suspected lymphangioleiomyoma or lymph node involvement with LAM:

●Patients with characteristic pulmonary cysts on CT and pathologically or cytologically identified LAM lymph node involvement do not need to undergo lung biopsy. Most experts consider these features to be definitively diagnostic and sufficient for eligibility for mTOR inhibitors, when indicated. In our opinion, the diagnosis of a lymphangioleiomyoma can usually be made based on radiographic appearance alone and biopsy or surgical manipulation of chyle-filled lesions is discouraged because of the potential for causing long-term leakage.

●The optimal approach in patients with cystic change on chest CT who do not already have a pathologic diagnosis of lymph nodal LAM or have an atypical CT appearance of lymphangioleiomyoma is unknown. Elevated levels of serum VEGF-D (≥800 pg/mL) can obviate the need for lung or lymph node biopsy in this population [82]. The choice between lung or lymph node biopsy in those with a negative VEGF-D level should be individualized and depends upon number, location/accessibility, and size of lymph nodes, the severity of underlying lung disease, and patient preferences. When lymph node biopsy is chosen, we typically attempt to perform needle aspiration and avoid excisional biopsy since in our anecdotal experience, and that of others, the postoperative course of surgical resection can be complicated by significant and prolonged chyle leak.

Characteristic cysts alone on CT — We suggest that patients with characteristic cysts on chest CT and absence of any other confirmatory features, including pathologic or cytologic confirmation, TSC, AML, lymphatic manifestations (lymphadenopathy, lymphangioleiomyoma, chylous accumulation) or elevated serum VEGF-D level (≥800 pg/mL), sometimes referred to as "lone LAM," should undergo lung biopsy when a definitive diagnosis is desired by the patient and/or necessary for optimal management [84]. This approach is based upon data that suggest that the classic appearance of cysts on chest CT is not sufficiently diagnostic to support interventions that entail risk, such as long-term exposure to mTOR inhibitors [84,141-143]. While an expert thoracic radiologist can diagnose LAM based upon chest CT findings alone with a sensitivity of 87 percent and a specificity of 97 percent, the performance of pulmonary clinicians was inferior to the radiologists [143] and not every facility has access to an expert thoracic radiologist familiar with the imaging characteristics of LAM and other rare cystic lung diseases. Based on this rationale, and the potential for adverse effects associated with long-term exposure to mTOR inhibitors, we perform lung biopsy in patients with apparent lone LAM who may require pharmacologic treatment. Choosing between transbronchial and surgical lung biopsy is discussed below. (See 'Choosing transbronchial or surgical lung biopsy' below.)

Other presentations — The optimal approach to diagnosis in patients who have atypical features of LAM remains unclear. This includes patients with noncharacteristic cyst distribution, size, or morphology; asymptomatic patients with few cysts and normal lung function; patients with concurrent interstitial abnormalities; males with cystic lung disease; asymptomatic patients with incidentally detected mild disease; and patients with borderline serum VEGF-D levels (eg, 600 to 799 pg/mL). We suggest an individualized approach using the principles outlined above, close monitoring of the disease with frequent clinical and lung function follow-up, and a low threshold to obtain tissue for cytologic or pathologic examination when candidacy for therapy is dependent on a definitive diagnosis and disease is progressive over time. As an example, in patients with a borderline VEGF-D (eg, 600 to 799 pg/mL) and a very low cyst burden (perhaps a few dozen cysts on chest CT), we typically follow conservatively by monitoring lung function at least annually and repeating the serum VEGF-D level and high-resolution CT (HRCT) at one year. If stability or slow progression is documented, we extend the interval for the next HCRT to three to five years, whereas if progression is more rapid, we follow lung function more frequently (perhaps every three to six months), and consider tissue confirmation.

Similarly, atypical presentations of other diseases that mimic LAM should be considered in the differential and an individualized approach used for diagnosis (eg, cyst and AML in Birt Hogg Dubé syndrome, cysts and chylous effusion in lymphoma). Details are discussed below. (See 'Differential diagnosis' below.)

Choosing transbronchial or surgical lung biopsy — The optimal approach for obtaining lung tissue in patients with suspected LAM is unknown. Options include transbronchial biopsy (TBBx), which has a yield of approximately 60 percent, and surgical lung biopsy, which has a yield approaching 100 percent. Choosing between these options is influenced by several additional factors including clinician experience, disease severity, morbidity of the procedures, and values of the patient [84]. As an example, TBBx may be preferred in those who wish to avoid surgery and who accept the lower diagnostic yield and uncertainty regarding pneumothorax risk. In contrast, surgical biopsy may be preferred in those who desire a definitive and expeditious approach, those with a history of an uninformative TBBx, or those who are undergoing a therapeutic thoracoscopic pleurodesis for pneumothorax. (See "Treatment of secondary spontaneous pneumothorax in adults", section on 'Preventing recurrence and follow-up'.)

●Transbronchial lung biopsy – The value of TBBx for patients with suspected LAM is supported by the American Thoracic Society/Japanese Respiratory Society LAM Guidelines [84]. Several small observational studies report successful diagnosis using TBBx, with yields ranging from 33 to 87 percent of patients with LAM when an experienced pathologist examines the tissue with appropriate immunohistochemical staining (eg, human melanoma black [HMB]-45, smooth muscle actin) [30,144-151]. The likelihood of making a diagnosis is likely dependent on cyst burden, with lower yields in patients with few cysts. The risk of iatrogenic pneumothorax is a concern in the presence of diffuse cystic changes. Although rates of this complication are not reported to be higher than that in other patient populations (approximately 1 to 5 percent), the true rate in patients with cystic lung disease who undergo TBBx is unknown since it has not been prospectively studied [152]. The value of transbronchial cryobiopsy in patients with cystic lung diseases remains investigational but may hold promise for the diagnosis of LAM [153,154]. (See "Flexible bronchoscopy in adults: Preparation, procedural technique, and complications" and "Flexible bronchoscopy in adults: Associated diagnostic and therapeutic procedures", section on 'Transbronchial biopsy' and "Bronchoscopic cryotechniques in adults", section on 'Cryobiopsy' and "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'When is cryo-TBB most helpful?'.)

●Surgical lung biopsy – Surgical lung biopsy via video-assisted thoracoscopy, or the more invasive and uncommonly employed thoracotomy approach, has a high diagnostic yield that approaches 100 percent and is the gold standard for the diagnosis of pulmonary LAM. However, surgical biopsy is associated with added risk, including potential adverse effects from anesthesia, prolonged air leak, persistent thoracic pain, and, rarely, death. (See "Overview of minimally invasive thoracic surgery".)

Bronchoalveolar lavage with cytological evaluation is generally not helpful for confirming a diagnosis of LAM, although it can yield useful information for other cystic lung diseases, such as pulmonary Langerhans cell histiocytosis (PLCH) [150].

DIAGNOSIS — The definitive diagnosis of LAM is made by the identification of LAM cells pathologically or cytologically in lung, lymph node, or body fluid (algorithm 1) [61,82]. While the definitive diagnosis of pulmonary LAM is also dependent upon the identification of typical cystic change in the lung, the diagnosis of extrapulmonary LAM restricted to abdominal or pelvic organs (ie, with no evidence of pulmonary cysts) requires pathologic or cytologic analysis (see 'Definitive pathologic diagnosis' below). A clinical diagnosis of LAM can also be made using a combination of clinical, radiologic, and laboratory data, the details of which are discussed below. (See 'Clinical nonpathologic diagnosis' below.)

The diagnosis of LAM is usually delayed because of the nonspecific nature of the presenting symptoms and rarity of the disease; in one study, patients had symptoms for approximately two years prior to diagnosis [7]. This may improve with the advent of better patient education, improved access to experts knowledgeable in LAM, and the widespread use of chest CT.

Clinical nonpathologic diagnosis — The diagnosis of LAM can be established by HRCT of the chest when characteristic cysts are noted in patients who have tuberous sclerosis complex (TSC), renal angiomyolipomas (AMLs), elevated levels of vascular endothelial growth factor-D (VEGF-D; ≥800 pg/mL), chylous accumulations, and/or typical appearance on CT of lymphangioleiomyomas. (See 'Characteristic cysts with supportive features' above and 'Vascular endothelial growth factor-D positive' above.)

For those with a clinical diagnosis of LAM, an opportunity may arise to make a definitive diagnosis from lung tissue obtained during thoracoscopic pleurodesis or from chyle that may develop the course of disease.

Definitive pathologic diagnosis — A definitive diagnosis of LAM is made by the identification of LAM cells in lung (together with cysts), lymph node, or body fluid. Pathologic and cytologic findings are described in the sections below.

Tissue pathology — The two hallmark histopathologic features of pulmonary LAM are lung cysts and smooth muscle-like LAM cells (picture 1). Histopathologic findings similar to those described in the lung are found in biopsy tissue from lymph nodes but without the cystic change:

●Cysts – In pulmonary LAM, the normal architecture of the lung is distorted by multiple small cysts, ranging from 0.1 cm to several centimeters in diameter (picture 2A-C) [1,53].

●LAM cells – The primary histopathologic abnormality is the proliferation of atypical smooth muscle-like cells (LAM cells) (picture 3A-B and picture 4). The proliferating cells are composed of two types, those that resemble vascular smooth muscle cells, spindle shaped but somewhat shortened and pleomorphic, and more cuboidal cells that have other features of perivascular epithelioid cells [155], including clear to granular, lightly eosinophilic cytoplasm located in a perivascular location. The interstitium is thickened, with evidence of LAM cells (or "LAM nodules") around and within the pulmonary lymphatics, venules, and airways [1,29,92]. The lymphatic and venous vessels are often tortuous and dilated. Hemosiderosis is common and is a consequence of usually clinically insignificant hemorrhage due to the rupture of dilated and tortuous venules [53].

Immunohistochemical stains for melanocytic markers (eg, human melanoma black [HMB]-45, Melan-A, tyrosinase, microphthalmia transcription factor, NKI/C3) (picture 5) and muscle markers (eg, smooth muscle actin, pan-muscle actin, muscle myosin, calponin) are often positive (picture 6) [156,157]. While HMB-45 positivity is classically associated with the diagnosis of LAM, staining is sometimes sparse or absent, and while helpful, is not absolutely necessary for the diagnosis.

Immunohistochemical evaluation of lung tissue from LAM patients demonstrates immunoreactivity of LAM cells for estrogen receptor and progesterone receptor [158]. Although LAM nodules may demonstrate positivity for VEGF-C and VEGF-D, these stains are not routinely performed by most pathology departments [124].

Cytology — Cytology of pleural or peritoneal fluid or of needle aspirates of enlarged lymph nodes can occasionally provide a minimally invasive diagnosis. Case reports of patients with chylothorax or chyloperitoneum have identified LAM cell clusters (LCCs) with an immunoreactivity profile for HMB-45, hormone receptors, and/or smooth muscle actin that provides a definitive diagnosis [68,159-164]. Similarly, LAM cells may be identified by needle aspiration (laparoscopic or percutaneous) of an enlarged retroperitoneal, axial, or pelvic lymph node. While the true sensitivity of cytology is unknown, in our experience, the diagnostic yield is modest at best.

Excluding tuberous sclerosis complex — TSC gene testing is not routinely indicated for diagnostic purposes in patients with LAM. Patients with sporadic LAM do not have germ line mutations in TSC genes, and DNA mutations are not present in cells isolated from peripheral blood. A negative result in a patient with suspected TSC-LAM does not exclude the disease, since the test is not 100 percent sensitive. Although a positive result for a pathogenic (ie, functionally inactivating) mutation establishes the diagnosis of TSC [165], that result is not required for the diagnosis, it is unlikely to be positive in patients who do not have other disease manifestations of TSC, a positive result has limited clinical utility beyond its diagnostic use, and the test is quite expensive. In cases where TSC is suspected, the patient should be referred to a specialized center for a formal evaluation. (See 'Tuberous sclerosis complex' above and "Tuberous sclerosis complex: Clinical features".)

DIFFERENTIAL DIAGNOSIS — LAM can be confused with other diseases, such as asthma, emphysema, or pulmonary hypertension (PH), based on symptomatic presentation alone. Asthma may be suggested by the presence of allergies, wheezing, and intermittent exacerbations, emphysema by its association with cigarette smoking in an older population, and PH by syncope or increased jugular venous pressure; however, these features are nonspecific and their presence does not rule out LAM. Once a chest CT is obtained and thin-walled cysts are demonstrated, the differential diagnosis narrows considerably.

●Differential diagnosis of cystic lung disease – The differential diagnosis of cystic lung disease is broad (table 1) [166-170]. The most common conditions that mimic sporadic LAM are emphysema, pulmonary Langerhans cell histiocytosis (PLCH), lymphocytic interstitial pneumonia (LIP)/follicular bronchiolitis (FB), and Birt-Hogg-Dubé syndrome (BHD). Although some of these conditions can be distinguished from LAM clinically, radiologically, or serologically, atypical presentations exist and sometimes tissue biopsy is required for diagnostic certainty. (See 'Securing a diagnosis' above.)

•Emphysema – Emphysema, with or without alpha-1 antitrypsin deficiency, is associated with obstructive physiology on pulmonary function tests (PFTs) and hyperlucent cyst-like changes on high-resolution CT (HRCT) of the chest. In contrast to cysts in LAM, the dilated airspaces found in emphysema may contain septae or centrilobular vessels, and are often upper lobe predominant with indiscernible borders. Although a definitive diagnosis of emphysema can be made histopathologically, the history of smoking and CT appearance is sufficiently diagnostic that biopsy is rarely performed to confirm the diagnosis. (See "Chronic obstructive pulmonary disease: Diagnosis and staging", section on 'Diagnosis' and "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency", section on 'Evaluation and diagnosis' and "Overview of pulmonary disease in people who inject drugs", section on 'Bullous lung disease and emphysema'.)

•Birt-Hogg-Dubé Syndrome – BHD is an autosomal dominant disease caused by mutations in the folliculin (FLCN) gene, a tumor suppressor gene. It is a multisystem disorder that is associated with renal cysts and neoplasms (including chromophobe adenomas, oncocytomas, renal cell carcinomas or rarely angiomyolipomas [AMLs]), cutaneous fibrofolliculomas and trichodiscomas, and cystic lung disease that frequently presents with recurrent spontaneous pneumothoraces. Lung cysts are found in over 80 percent of BHD patients, and are usually basilar or perivascular, subpleural, and crescent-shaped or elliptical [171,172]. While a family history may be present, many patients present without a positive family history, renal or skin manifestations. The diagnosis can be made by biopsy confirmation of fibrofolliculomas or by identifying the pathogenic FLCN gene mutation, but there are no specific lung findings on biopsy that can distinguish BHD from other causes of airspace dilation such as emphysema. (See "Hereditary kidney cancer syndromes", section on 'Birt-Hogg-Dubé syndrome'.)

•Pulmonary Langerhans cell histiocytosis – PLCH (also known as eosinophilic granuloma) is associated with cystic changes on HRCT that are typically upper lobe predominant, more bizarrely shaped, peribronchiolar, and thicker-walled than LAM cysts (image 9). In addition, PLCH is strongly associated with cigarette smoking (90 to 100 percent are smokers), has no female predilection, and is associated with nodular findings on CT (which are typically early manifestations of the disease). Thus, thick-walled cystic changes in a young male smoker that spares the costophrenic angles are more likely due to PLCH while thin-walled cysts in a nonsmoking female would be more consistent with LAM. The finding of more than 5 percent of Langerhans cells (CD-1a positive) on bronchoalveolar lavage is diagnostic of PLCH, although this find is not very sensitive, limiting its clinical utility. While the clinical and radiographic presentation of PLCH is often sufficiently distinctive that a presumptive diagnosis can be made, a definitive diagnosis of PLCH may require pathologic confirmation, via either a transbronchial biopsy (yield of approximately 30 percent) or a video assisted thoracoscopic-guided surgical lung biopsy. (See "Pulmonary Langerhans cell histiocytosis", section on 'Evaluation'.)

•Lymphocytic interstitial pneumonia/follicular bronchiolitis (LIP/FB) – Cystic changes can be seen in up to two-thirds of patients with LIP/FB. LIP/FB is usually seen in middle-aged females and in association with an autoimmune disorder (eg, Sjögren's disease [SjD], systemic lupus erythematosus), or immunodeficiency state (eg, human immunodeficiency virus, common variable immune deficiency). Diffuse thin-walled cystic change without other interstitial infiltrates can be the presenting manifestation of lupus or Sjögren's-related LIP/FB and can closely mimic LAM.

Characteristic features of cysts associated with LIP/FB include wide variation in size, a predilection for lower-lung zone involvement, and perivascular distribution, internal structures and septations, often together with centrilobular nodules and ground-glass attenuations (image 10). The cysts in FB are often sufficiently distinctive that a presumptive diagnosis can be made in patients with other corroborative features, such as a known diagnosis of SjD or lupus, sicca symptoms (eg, xerostomia and xerophthalmia may suggest SjD), or appropriate serologies (eg, Sjögren’s-related antibodies [SSA/Ro and SSB/La antibodies], etc). A definitive diagnosis of LIP/FB or SjD may require a biopsy (eg, lung, lip) in the absence of these features. (See "Lymphoid interstitial pneumonia", section on 'Diagnosis' and "Diagnosis and classification of Sjögren’s disease".)

•Light chain deposition disease (LCDD) – LCDD is a progressive cystic lung disease that can lead to respiratory failure. HRCT findings of LCDD can vary from multiple small round cysts in a diffuse distribution that mimics LAM to large cystic spaces associated with reticulonodular opacities mimicking PLCH [173]. Histologically, LCDD is characterized by kappa light chain deposition in the alveolar walls, small airways, and vessels accompanied by emphysematous changes and dilation of small airways. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Light chain deposition disease'.)

•Sarcoidosis and advanced interstitial lung disease – Advanced sarcoidosis can be associated with development of lung cysts, which tend to exhibit a perihilar or upper lobe distribution and are associated with fibrosis (image 11). Bilateral hilar adenopathy, which is rare in LAM, is common in sarcoidosis. Similarly, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis can be associated with lung cysts due to scarring in advanced disease. These diseases are easily differentiated from LAM in the presence of other radiographic findings (eg, reticulations, scarring, nodules), or by histopathologic analysis in those cases that are biopsied. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis", section on 'High resolution computed tomography' and "Clinical manifestations and diagnosis of sarcoidosis", section on 'Chest radiograph'.)

•Others – Less common causes of lung cysts include pneumatoceles from previous infection, barotrauma or physical trauma, or tumors (metastatic sarcomas, epithelial tumors or lymphomas). Infectious causes of lung cysts include Pneumocystis jirovecii pneumonia, chronic paracoccidioidomycosis or coccidiomycosis, and recurrent human papilloma virus infection. In addition, hyper-immunoglobulin E syndrome, amyloidosis, neurofibromatosis, Marfan syndrome, and Ehlers-Danlos syndrome have been associated with lung cysts.

●Differential diagnosis of pneumothorax – Although a CT of the chest is not recommended in every patient with pneumothorax [174], our practice is to have a low threshold for obtaining a HRCT in patients with spontaneous pneumothorax of unknown etiology, particularly in young, nonsmoking females. Data from countries that routinely perform CT for primary spontaneous pneumothorax (PSP) may diagnose LAM at an earlier age, and performing a chest CT in patients with apparent PSP to screen for cystic lung diseases (LAM, BHD, and PLCH) has been shown to be cost-effective in some studies [33,109,175] while another analysis has questioned this conclusion [176]. (See "Pneumothorax in adults: Epidemiology and etiology" and "Treatment of secondary spontaneous pneumothorax in adults".)

●Differential diagnosis of chylothorax – The various etiologies of chylous accumulations, including trauma, lymphoma, and congenital lymphatic anomalies, are listed in the table (table 2). LAM may be suggested from other causes of chylothorax if classic cysts typical of LAM are identified or rarely by identifying LAM cell clusters in chylous fluid. Determination of the cause of chylothorax is discussed separately. (See "Etiology, clinical presentation, and diagnosis of chylothorax", section on 'Differential diagnosis'.)

ASSESSMENT OF DISEASE EXTENT — Sporadic LAM is a multisystem, progressive disease that requires an initial assessment of extent of disease followed by longitudinal monitoring for disease progression and complications. For those with a clinical diagnosis of LAM, an opportunity may arise during this period to make a definitive diagnosis from lung tissue obtained during thoracoscopic pleurodesis or from analysis of chyle that may develop during the course of disease.

Much of the information that is needed to assess the extent of the disease is available from tests obtained during the diagnostic investigation. If not already performed, we suggest the following:

●Abdominal-pelvic imaging – Most experts obtain additional abdominal-pelvic imaging to fully assess for renal and extrarenal angiomyolipomas (AMLs), lymphadenopathy and lymphangioleiomyomas by CT and/or MRI [61]. For patients with a chylothorax or peripheral lymphedema, such imaging can also detect intra-abdominal fluid collections and lymphatic manifestations including lymphangioleiomyomas and lymphadenopathy.

●Exercise capacity – For patients with dyspnea on exertion or reduced diffusing capacity for carbon monoxide (DLCO), we obtain six-minute walk testing and repeat the test based upon clinical symptoms. Rarely, arterial blood gases may be needed for those in whom hypercapnia is suspected. (See 'Pulmonary function tests' above.)

●Others – While some experts routinely perform testing, we use a symptom-directed approach to detect the following:

•Pulmonary hypertension (eg, echocardiography)

•Osteoporosis (bone density scan)

•Tuberous sclerosis complex manifestations (retinal exam, central nervous system imaging)

•Cerebral meningioma (eg, brain imaging)

The value of serial vascular endothelial growth factor-D (VEGF-D) levels as a prognostic biomarker in untreated patients with LAM is evolving. Its potential role in assisting treatment decisions is discussed separately. (See "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'Monitoring clinical response'.)

We do not routinely perform lymphatic imaging, 18-fluorodeoxyglucose (FDG)-positron emission tomographic imaging, sleep studies, or bone density scans unless an indication to do so is present.

Age-appropriate screening for breast and gynecological cancer, as well as for osteoporosis (found in up to 70 percent of patients with LAM) [177], is also prudent. (See "Screening for osteoporosis in postmenopausal women and men".)

We recommend frequent pulmonary function testing (such as postbronchodilator spirometry every three months) during follow-up since multiple measurements of the forced expiratory volume in one second are required to establish the true trajectory of lung function change [88].

ADDITIONAL RESOURCES — The LAM Foundation offers information and patient support, and has identified LAM specialty clinics across the United States and the world; a list of these and other useful information can be found at The LAM Foundation, the TSC Alliance, LAM Action, and the University of Cincinnati.

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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

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 topic (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

●Definition – Lymphangioleiomyomatosis (LAM) is a rare multisystem disease that mostly afflicts young females. The term sporadic LAM is used for patients who do not have tuberous sclerosis complex (TSC). (See 'Introduction' above and 'Definition' above.)

●Clinical features – LAM should be suspected in a young female who presents with a spontaneous pneumothorax, unexplained dyspnea, pleural or peritoneal chylous fluid collections, TSC, or a renal angiomyolipoma (AML). With increasing use of CT, lung cysts characteristic of LAM are often discovered incidentally in asymptomatic patients. Other manifestations of LAM include pulmonary hypertension, lymphadenopathy, or lymphangioleiomyomas. (See 'Clinical manifestations' above.)

●Diagnostic evaluation – When LAM is suspected, the following should be performed:

•Pulmonary function tests (PFTs), including spirometry with bronchodilator testing, lung volumes, and diffusing capacity for carbon monoxide (DLCO). While airflow obstruction and/or a reduced DLCO are typical, normal PFTS do not preclude the diagnosis. (See 'Pulmonary function tests' above.)

•Noncontrast high-resolution CT should be obtained to demonstrate pulmonary cysts characteristic of the disease. Cysts are classically multiple (>10), diffuse, round, well-defined, bilateral, without lobar predominance, and thin-walled. (See 'Chest CT' above.)

•If characteristic cysts are found, we suggest that the following be performed (algorithm 1):

-A thorough history and examination for the symptoms and signs of TSC. (See "Tuberous sclerosis complex: Clinical features".)

-Abdominopelvic imaging to primarily look for the presence of AMLs but also for chylous effusions, lymphadenopathy, and/or lymphangioleiomyomas. (See 'Abdominal imaging' above.)

-Measurement of serum vascular endothelial growth factor-D (VEGF-D); level ≥800 pg/mL distinguishes LAM from other cystic lung diseases. This can be obtained as a send-out test through the Translational Trials Laboratory at Cincinnati Children's. Other serologic tests, including alpha-1 antitrypsin levels, rheumatoid factor, antinuclear antibody, and Sjögren's-related antibodies (SSA/Ro and SSB/La antibodies), serum-free light chain measurement, serum and urine protein electrophoresis may be performed to exclude disorders that can mimic LAM. (See 'Laboratory' above.)

●Who to biopsy – When considering a diagnosis of LAM, the ideal goal is to obtain the most definitive possible diagnosis using the least invasive strategy as is feasible (algorithm 1). Utilizing such strategies reduces the need for biopsy and is sufficient to support the use of mechanistic target of rapamycin (mTOR) inhibitors for treatment. Our approach is the following:

•In patients who have characteristic cysts on chest CT and known TSC, AML, chylous effusions, classic CT appearance of lymphangioleiomyoma, and/or a VEGF-D level ≥800 pg/mL, a lung biopsy is not required and a clinically confident nonpathologic diagnosis may be made. Pursuit of a definitive pathologic diagnosis may occasionally be indicated in this population in patients who have atypical presentations (especially when considering interventions entailing risk, such as mTOR inhibitor therapy) when there is suspicion of an alternate diagnosis and to honor patient preferences for certainty. (See 'Characteristic cysts with supportive features' above and 'Vascular endothelial growth factor-D positive' above and 'Other presentations' above and 'Clinical nonpathologic diagnosis' above.)

•In most patients who have characteristic cysts on chest CT without any of the listed supporting features, we suggest a tissue biopsy be performed, if feasible. Options include lung biopsy (eg, transbronchial and surgical) or lymph node biopsy (needle aspiration or resectional). The decision to proceed with biopsy and choosing among the options should be individualized and is influenced by factors including the presenting manifestations, clinician experience, availability of expert pathologists, disease severity, and values of the patient. The definitive diagnosis of LAM is made by the histopathologic or cytologic identification of LAM cells in lung, lymph node, or body fluid. (See 'Characteristic cysts alone on CT' above and 'Choosing transbronchial or surgical lung biopsy' above and 'Definitive pathologic diagnosis' above.)

•In patients with atypical presentations, the approach should be individualized using the minimally invasive approach, when appropriate. (See 'Other presentations' above.)

●Differential diagnosis – Conditions that are in the differential diagnosis of LAM include other causes of cystic lung disease, pneumothorax, and chylothorax. (See 'Differential diagnosis' above.)

●Assessment of disease extent – Sporadic LAM is a multisystem, progressive disease that requires assessment of disease extent. For those with a clinical diagnosis of LAM, an opportunity may arise during follow-up to make a definitive diagnosis from lung tissue obtained during thoracoscopic pleurodesis or from analysis of chylous fluid accumulations that may develop the course of disease. (See 'Assessment of disease extent' above.)