LAM can manifest itself in a number of ways. Most commonly respiratory symptoms are the presenting problem, but abdominal disease, LAM detected as a consequence of TSC and identification in asymptomatic individuals undergoing CT scanning for other problems also occur.

Cysts replace the lung parenchyma to cause breathlessness and symptoms of airway narrowing including cough and wheezing. This collection of symptoms is the presenting feature in over 40 % of patients and frequently leads to treatment for asthma: a poor response to treatment or other features not typical of asthma may then prompt further investigation. Lung cysts also cause pneumothorax which may be recurrent and difficult to treat. Dyspnoea or pneumothorax are the presenting problem in approximately 80 % of patients. Around 5 % of patients present with chylous pleural effusions due to obstruction of the thoracic duct by LAM cells [1]. Chylous effusion and lung cysts in women being pathognomonic of LAM. Some patients cough chylous secretions due to blockage of the intrapulmonary lymphatics whilst others may develop haemoptysis. Onset of respiratory symptoms may occur during pregnancy particularly with refractory pneumothorax including bilateral pneumothorax or chylopneumothorax. Symptoms may persist until surgical correction can be performed, often after delivery [21].

Occasionally abdominal disease may present before lung symptoms. Most commonly this is with symptomatic renal angiomyolipoma. Sometimes large tumours present with abdominal fullness but more commonly haemorrhage causes acute flank pain with or without haematuria. The use of CT scanning to evaluate renal tumours in these situations may coincidentally reveal lung cysts. In some patients, symptomatic angiomyolipoma has preceded lung symptoms by many years. Up to 20 % of patients have cystic lymphatic masses caused by occlusion of abdominal, retroperitoneal or pelvic lymphatics by LAM cells. Termed lymphangioleiomyomas, these can give rise to abdominal bloating, swelling or peripheral oedema [22]. In a small number of cases, discovery of these masses may lead to a biopsy for suspected malignant disease often resulting in chylous leakage with characteristic histology usually leading to the correct diagnosis. In rare cases, symptoms from chylous ascites can be the presenting problem although chylous ascites is generally associated with advanced disease.

Up to 40 % of adult women with TSC have LAM when examined by CT scanning although only a minority of these develop symptomatic respiratory disease [23–25]. The presenting symptoms in TSC-LAM are similar to sporadic LAM with dyspnoea and pneumothorax. Treatment guidelines for TSC recommend screening adult women for TSC at 18 years [26]. This, as well as CT performed for non-respiratory problems in both TSC and sporadic LAM inevitably results in the detection of patients with early and asymptomatic disease. Occasionally, patients with severe learning difficulties may present with advanced disease and even cyanosis or behavioural change due to pneumothorax. The majority of patients with TSC-LAM have renal angiomyolipomas which may be very large, multiple and bilateral and may be the presenting feature [27]. Lymphatic disease appears less common in TSC-LAM than sporadic disease [28]. Clinical presentations suggestive of LAM are listed in Table 17.1.

Interstitial changes and preserved lung volumes may be present on chest radiograph (Fig. 17.3) although plain X-rays are often normal at diagnosis. In patients with suspected LAM, high resolution CT scanning is the investigation of choice. The characteristic features are of thin walled cysts. Cysts are evenly distributed throughout the lung fields, are generally round, and vary in diameter between 0.5 and 5 cm. The intervening lung parenchyma is normal although occasionally small areas of airspace shadowing representing haemorrhage or chyle may be present [29] (Fig. 17.4). Widespread alveolar shadowing however is not typical of LAM. Chylous pleural effusions and pneumothorax may also be present (Fig. 17.5). In patients with TSC, nodules of proliferating type 2 pneumocytes, termed multifocal micronodular pneumocyte hyperplasia, may coexist with LAM or occur without LAM [30]. The presence of interstitial abnormalities, thick walled cysts or unevenly distributed cysts is not typical of LAM. CT alone is not diagnostic of LAM and once LAM is suspected, confirmatory features are required to make a definite diagnosis. Either, the presence of renal angiomyolipomas, chylous pleural or abdominal effusions, lymphatics involved by LAM or the presence of TSC. The European Respiratory Society has recently developed clinical guidelines for LAM and their diagnostic criteria are summarised in Table 17.2 [31]. A previous history of renal tumours and symptoms of TSC, should be sought. A careful clinical examination should be made for signs of TSC including the key skin manifestations, facial angiofibromas, periungual fibromas, hypomelanotic macules and shagreen patches. In some patients, these abnormalities are mild and where there is no history of epilepsy or learning difficulties the diagnosis can be difficult to make and evaluation by a TSC specialist or dermatologist may be helpful. Diagnostic criteria for TSC have been clearly defined [32] but where doubt exists referral to a clinical geneticist is advised. To detect the abdomino-pelvic manifestations to aid diagnosis and management, once LAM is suspected contrast CT scanning of the abdomen and pelvis is recommended to detect angiomyolipoma, lymphangioleiomyoma, lymphadenopathy or ascites which are collectively present in over half of patients [31].

Pulmonary function testing may be normal in early disease but a fall in DLCO is generally the first abnormality that develops [33]. As the disease progresses airflow obstruction develops. Lung volumes are generally preserved [34]. Cardiopulmonary exercise testing provides more information on physiological derangement in early disease although is seldom performed [35]. The 6 min walk test probably provides more information about disability and exertional hypoxaemia.

Women with both sporadic and TSC-LAM are at increased risk of meningioma; being present in 8 of 250 patients screened by MRI scanning in one series [36]. Some meningiomas can cause symptoms and require surgery. MRI of the brain may be performed at baseline especially in the presence of headache, seizures or other neurological symptoms. In patients with TSC-LAM and those presenting with LAM who are suspected of having TSC, brain MRI scanning should also be performed [31].

A definite diagnosis of LAM according to ERS criteria can be made without lung biopsy in around 2/3 of patients [37]. In the remainder, a lung biopsy is required to make a firm diagnosis. Whether to perform a lung biopsy or not should be discussed with the patient. In general terms, it is important to obtain a definite diagnosis in patients with progressive disease who require (or may require in the future) specific treatment for LAM. Those with few symptoms and stable lung function may be observed with biopsy being performed if the disease progresses [31]. Lung biopsy may be hazardous for patients with advanced disease and should only be considered if essential to management. Lung tissue may be obtained by transbronchial biopsy and when combined with immunostaining with the monoclonal antibody HMB45 can be diagnostic in some cases and avoid the need for a surgical biopsy [38, 39]. Video assisted thoracoscopic biopsy is performed more often, gives a better indication of the tissue architecture which provides some prognostic information and has better sensitivity and specificity. In most cases the appearance of cysts surrounded by nodular proliferations of mesenchymal cells is sufficient to make the diagnosis in the correct clinical context. In early disease LAM cells may be sparse and their detection can be improved by immunostaining for the smooth muscle markers α-smooth muscle actin and desmin, oestrogen and progesterone receptors [40, 41] (Fig. 17.6). HMB45 stains 30–70 % of LAM cells in biopsy tissue. HMB45 is particularly useful diagnostically, not being expressed in normal lung. Only isolated reports have described cases with the morphological characteristics of LAM in tissues biopsy that do not stain with HMB45.

Recently it has been observed that the lymphatic growth factor, vascular endothelial growth factor-D (VEGF-D) is elevated in around 2/3 of patients with LAM, particularly those with lymphatic involvement [42]. A serum VEGF-D level of greater than 800 pg/ml has been shown to differentiate LAM from other cystic lung diseases and when used in combination with the ERS diagnostic criteria, can further reduce the need for lung biopsy for diagnosis [37, 43]. At the time of writing, the test is not routinely available in all centres.

It is currently difficult to predict prognosis accurately at diagnosis in individual patients. Various studies have associated clinical and pathologic features with outcome and it is likely that presentation with breathlessness rather than pneumothorax, a response to bronchodilators, low K_CO at presentation and extensive involvement of the lung biopsy with either cystic change or muscular proliferation are associated with more rapid disease progression [44–47]. In practice, calculation of the disease trajectory by estimating the change in lung function from the onset of symptoms or over a period of observation is probably the most reliable approach. Estimating survival for women with LAM is difficult as older studies have tended to over-represent patients with severe disease and worse outcome and it is important to put these studies into context for patients. Recent studies based on larger patient cohorts have estimated median to be between 20 and 30 years. Improvements in lung transplant outcome and the impact of mTOR inhibitors mean that the prognosis for many patients with a recent diagnosis of LAM should continue to improve.