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 reasonable certainty and lung biopsy may not be necessary. Lung biopsy should be considered when pulmonary cystic change is present without other clinical indicators and/or pulmonary cystic change on HRCT does not show the typical LAM pattern. If lung transplantation is imminent knowing the precise cause of the end stage lung disease is not usually critical and therefore a biopsy may not be helpful. 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 diagnoses include 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 also be confused with micronodularpneumocyte 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. Like TSC-LAM, BHD is a rare tumor suppressor syndrome associated with spontaneous pneumothorax, skin lesions, pulmonary cysts, and predisposition to developing renal cell cancer. Mutations in the folliculin gene cause familial BHD that can present with spontaneous pneumothorax. It appears that BHD is also associated with aberrant signaling through the Akt pathway, but the loss of regulation occurs upstream of mTOR. Rare syndromes of benign or malignant smooth muscle metastasis may also produce cystic change and closely mimic LAM, including benign metastasizing leiomyoma, metastatic endometrial stromal sarcomas, and low-grade leiomyosarcomas. Less common diseases that can mimic LAM and should also be considered include follicular bronchiolitis, hypersensitivity pneumonitis, amyloidosis, light chain deposition disease (LCDD) and bronchopulmonary dysplasia. 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 extrarenalangiomyolipomas 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 alpha-1 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 the 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.
Ways to Diagnose LAM
Because many of the early signs and symptoms of LAM are similar to those of other lung diseases, including asthma, emphysema and bronchitis, LAM can be difficult to diagnose.
Often a woman with LAM first goes to her physician complaining of chest pain and/or shortness of breath. Some women first consult their physician because of shortness of breath with physical activity. There are a number of tests the physician can run to confirm or rule out the existence of LAM, evaluate the spread of the disease or determine the extent of lung damage:
High-resolution CT scan - provides a more detailed (two-dimensional) image of the inside of the lungs and chest. It is the most accurate imaging test for diagnosing LAM. A computed tomography, or CT scan, can reveal cysts or abnormal clusters of cells in the lungs, a collapsed lung or enlarged lymph nodes. It can also show the extent to which the cysts have spread. An abdominal CT scan is also recommended, as benign kidney tumors, known as angiomyolipomas, are found in about 40 percent of women with LAM.
HRCT Screening Recommendations
The LAM Foundation recommends that a high resolution CT scan of the chest be obtained in the following situations and patient subgroups;
For patients with known Tuberous Sclerosis Complex:
1. All females, at least once after the age of 18*
2. All patients who present with pneumothorax or chylothorax
* The Tuberous Sclerosis Alliance has previously published this recommendation in the J. Child Neurology
For patients who do not have known Tuberous Sclerosis Complex:
1. All nonsmoking women who present with spontaneous pneumothorax.
2. All women who present with recurrent spontaneous pneumothorax regardless of smoking status.
3. All women found to have an angiomyolipoma, abdominal lymphangiomyoma, or chylous effusion.
VEGF-D blood test – offers the first blood-based diagnostic test for LAM in women. VEGF-D levels can be used to distinguish LAM from other cystic lung diseases that present with similar high resolution CT scan appearances. When VEGF-D levels are elevated above a certain threshold, surgical biopsy may not be required for diagnosis in some cases. VEGF-D may also be useful as a screening test for LAM in women with TSC.
The testing is done in a clinical lab at Cincinnati Children’s Hospital Medical Center.
The lab website link is: https://research.cchmc.org/translationalcores/ttdsl
The lab email is firstname.lastname@example.org and phone is 513-636-5998. Dr. Elke Grassman and her team can answer logistical questions about sending the sample, etc.
For samples sent in from outside the US there is a special customs from that will need to be filled out with the FEDEX shipping form.
Lung biopsy - involves removing samples of lung tissue, which are examined under a microscope to look for abnormalities that may indicate LAM. There are several ways physicians can remove lung tissue.
- Thoracoscopy, also called video-assisted thorascopic surgery (VATS), involves inserting a small lighted tube (endoscope) into tiny incisions in the chest wall so that the lung can be viewed, and small wedges of lung tissue can be removed for examination under a microscope to look for changes associated with LAM. This procedure must be done in the hospital under general anesthesia.
- Transbronchial biopsy may also be used to obtain a small amount of lung tissue. A long, narrow, flexible, lighted tube (bronchoscope) is inserted down the windpipe (trachea) and into the lungs. Pieces of lung tissue are sampled using a tiny forceps. This procedure is usually done in a hospital on an outpatient basis under local anesthesia. However, the amount of tissue that can be sampled is less than in a VATS procedure and is usually not adequate to definitively diagnose LAM.
- Open biopsy should only be performed as a last resort to diagnose LAM; recovery is longer than other, less invasive biopsy methods. In this procedure, small wedges of lung tissue are removed through an incision made in the chest wall between the ribs. This procedure also takes place in the hospital under general anesthesia.
Chest X-ray - takes a picture of the heart, lungs and surrounding tissue. It can show whether there is a collapsed lung or a build-up of fluid around the lungs. The X-ray may show cysts or clusters of cells on the lungs, which are suggestive of LAM; however, this is not the optimal way to diagnose the disease.
Pulmonary function test (PFT) - evaluates how well the lungs are working by measuring the amount (volume) of air inhaled or exhaled, and how much time each breath takes (rate). The patient breathes through a mouthpiece into a machine called a spirometer. The spirometer records the movement of air into and out of the lungs. Although these tests are used to determine the effect LAM has on lung function, they are not typically used for diagnosis.