Defining and Diagnosing LAM
Diagnosing Lymphangioleiomyomatosis (LAM)
LAM is typically discovered by HRCT scanning of patients with progressive dyspnea on exertion, pneumothorax or chylous effusion, or less commonly by biopsy of an abdominal or retroperitoneal mass suspected to be lymphoma or ovarian cancer. Routine screening of asymptomatic women with TSC identifies a subset of patients with early and often asymptomatic LAM. Biopsy-documented LAM has been reported in only four men; three with definite or probable TSC, and one without TSC. On the average, women with LAM have symptoms for 3-5 years and suffer an average of 2.2 pneumothoraces before the diagnosis of LAM is made. A definitive diagnosis of pulmonary LAM requires an HRCT demonstrating thin walled cystic change and either a positive tissue biopsy (including immunohistochemical reactivity with HMB-45) or a compatible clinical context such as clinically confirmed tuberous sclerosis, angiomyolipomata or chylothorax.
Chest HRCT screening of asymptomatic TSC patients identifies a population with fewer and less severe pulmonary manifestations, including lower incidence of associated manifestations of chylous pleural effusions, pneumothoraces, hemoptysis and chest x-ray and lung function abnormalities. Ascertainment bias almost certainly plays a dominant role in the differences in disease manifestations that have been described for TSC-LAM and S-LAM in the literature.
Interpretation of the HRCT screening by expert radiologists leads to the correct diagnosis of LAM about 80% of the time. Diagnostic accuracy of 80% is not adequate in the setting of a life-threatening lung disease, however. When deciding whether to perform a lung biopsy, the physician must determine if the clinical context is sufficiently compelling to make a clinical diagnosis without a biopsy. In the setting of a compatible HRCT and specific corroborating clinical features, such as chylothorax, known TSC, or the presence of an angiomyolipoma in the kidney, the diagnosis of LAM can be made with certainty and lung biopsy is often not necessary. Lung biopsy should be considered when pulmonary cystic change is present without other clues, unless lung transplantation is imminent, in which case knowing the precise cause of the end stage lung disease is not usually critical. Video assisted thoracoscopic lung biopsy is the preferred method if pathologic confirmation is indicated. Transbronchial biopsies have occasionally been reported to be diagnostic in LAM when HMB-45 staining is positive.
The primary differential includes pulmonary Langerhan's cell histiocytosis (LCH) and emphysema. The smoking history, and the morphology of the cysts, which are devoid of distinct walls in emphysema and thicker walled, mid and upper lung zone predominant, and more irregularly shaped in LCH, can be helpful in differentiating these disorders from LAM. Diffuse nodular changes are often present in LCH and can be a distinguishing feature, but can be confused with micronodular pneumocyte hyperplasia witch occurs in patients with TSC.
The differential diagnosis of the thin walled cystic change that is characteristic of LAM also includes lymphocytic interstitial pneumonitis, Birt Hogg Dube syndrome (BHD), and Sjogren's syndrome. Rare syndromes of benign or malignant smooth muscle metastasis may also produce cystic change and closely mimic LAM, including benign metastasizing leiomyoma, endometrial stromal sarcomas, and low-grade leiomyosarcomas. Less common diseases that can mimic LAM and should also be considered include follicular bronchiolitis and hypersensitivity pneumonitis, amyloidosis, light chain deposition disease (LCDD), bronchopulmonary dysplasia, metastatic endometrial stromal cell sarcoma and low grade leiomyosarcomas and Birt Hogg Dube (BHD) syndrome. Like TSC-LAM, BHD is a rare tumor suppressor syndrome associated with spontaneous pneumothorax, skin lesions, pulmonary cysts, and inherited renal cell cancer. Mutations in the folliculin gene cause BHD and familial spontaneous pneumothorax. It appears that BHD is also associated aberrant signaling through the Akt pathway, but the loss of regulation occurs upstream of mTOR. Lymphangiomatosis is a rare disease associated with abdominal and thoracic lymphatic smooth muscle infiltration, lymphadenopathy, lymphangiomas, chylous fluid collections, and variable bony involvement ("Gorham's disease"). Although lymphangiomatosis can involve the lung and is often confused with LAM, it affects males and females equally, does not produce lungs cysts and is immunophenotypically distinct (staining with HMB-45 is negative).
A full history including smoking, use of birth control pills, seizure history and family history of tuberous sclerosis (TSC) should be obtained. Physical evidence of TSC should be sought, including acne-like angiofibromas-like lesions on the face, subungual fibromas, Shagreen's patches, ash leaf lesions, and other hypomelanotic lesions that fluoresce under the Wood's lamp such as confetti lesions. An eye exam should be completed by an ophthalmologist. An abdominal CT or ultrasound to identify renal or extrarenal angiomyolipomas should be obtained if the abdominal cuts of a chest CT are inadequate. CT or MRI of the head should be considered for cortical tubers or other clinically occult manifestations of TSC. An α1 antitrypsin level should be sent to screen for hereditary forms of emphysema, and serologies for Sjogren's syndrome considered if xerostomia and xeroopthalmia are present. The most common presentation of LAM is progressive dyspnea on exertion, often in association with a history of pneumothorax or chylothorax. Pneumothorax can also be sentinel event that suggests the diagnosis of LAM in patients who do not have dyspnea on exertion. Other symptoms of LAM include chest pain and coughing.
Renal Angiomyolipomas in Lymphangioleiomyomatosis (LAM)
Kidney tumors called angiomyolipomas, unusual hamartomas containing fat, smooth muscle and blood vessels, are present in about 90% of patients with TSC and 30%-50% of sporadic LAM. Hemorrhage into an angiomyolipoma can produce symptoms from chronic intermittent flank pain to acute abdomen with hypovolemic shock
Interestingly, angiomyolipomas are the only known neoplastic lesions in which the intratumoral blood vessels are composed of the cells containing transforming mutations. In most patients, angiomyolipomas are clinically silent, however flank pain, hydronephrosis, hematuria and loss of renal function can all occur. In S-LAM, angiomyolipomas are usually unilateral, small, solitary, and restricted to the kidney while in TSC-LAM they are more often larger, bilateral, multiple, multiorgan involving the spleen or liver, and prone to hemorrhage. The risk of renal hemorrhage from angiomyolipomas is associated with large size and with profusion of aneurysms.
Click here to read article on Renal Angiomyolipomas by Drs. Bissler and Kingswood.
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