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A 28-year-old nonsmoking woman was referred to the pulmonary clinic for further evaluation of shortness of breath with exertion. She had slowly progressing dyspnea over the past year and general fatigue. She did not report a history of xerostomia, keratoconjunctivitis sicca, pleural effusions, pneumothoraces, seizure, cognitive impairment, recurrent sinopulmonary infections, or previous autoimmune disease diagnosis and had no relevant family history of lung disease. Her physical examination findings were unremarkable and there was no evidence of cutaneous lesions. A high-resolution computed tomographic (CT) scan of her chest revealed diffuse thin-walled pulmonary cysts without nodules, parenchymal changes, or lymphadenopathy (Figure). Imaging of her abdomen did not show kidney lesions or abdominal masses. The patient’s serum vascular endothelial growth factor D (VEGF-D) level was elevated at 1300 pg/mL (reference range, <600 pg/mL).
High-resolution computed tomography scan of the chest showing numerous, diffuse, thin-walled lung cysts surrounded by normal-appearing lung parenchyma. There is no mediastinal or hilar adenopathy.
The VEGF-D level is nonspecific and the patient should undergo further evaluation with a lung biopsy.
The VEGF-D level is supportive of a diagnosis of pulmonary Langerhans cell histiocytosis.
The VEGF-D level is supportive of a diagnosis of lymphangioleiomyomatosis.
The VEGF-D level indicates that the patient should undergo folliculin gene test for Birt-Hogg-Dubé syndrome.
C. The VEGF-D level is supportive of a diagnosis of lymphangioleiomyomatosis
Pulmonary cysts are characteristic of different diseases that include, but are not limited to, Langerhans cell histiocytosis, lymphangioleiomyomatosis (LAM), and Birt-Hogg-Dubé syndrome. Pulmonary Langerhans cell histiocytosis is a rare lung disease characterized by accumulation of Langerhans cells in small airways and is usually seen in young adult smokers.1 High-resolution CT images commonly demonstrate nodules and upper and middle lobe cysts that may progress to a thick, irregular-walled, bizarre-shaped appearance.1 Birt-Hogg-Dubé is an autosomal dominant syndrome characterized by multiple irregular lung cysts commonly found in the peripheral lung zones at the lung bases and along the mediastinum, and it is associated with cutaneous fibrofolliculomas, spontaneous pneumothorax, and kidney cancer.1 LAM is a rare disease that predominantly affects women of childbearing age, with a prevalence of approximately 3 to 8 cases per million women.2 LAM may occur sporadically or in association with tuberous sclerosis complex.2 A diagnosis of LAM can be confidently made with characteristic high-resolution CT image findings of diffuse thin-walled pulmonary cysts surrounded by normal lung parenchyma and 1 of the following: renal angiomyolipomas, chylous effusions, lymphangioleiomyomas, or a diagnosis of tuberous sclerosis complex.3 In the absence of these other findings, a lung biopsy may be required to differentiate the symptoms from other cystic lung diseases. More recently, serum VEGF-D testing has emerged as a noninvasive means of confirming the diagnosis in a subset of patients with cystic lung disease in whom the level is documented to be elevated.4
VEGF is an angiogenic growth factor that is usually produced by malignant cells. A member of the VEGF family is VEGF-D, a ligand for lymphatic growth factor VEGF receptors (VEGFR), specifically VEGFR-2 (fetal liver kinase 1) and VEGFR-3 (fms-like tyrosine kinase 4).5 Activation of VEGFR-3 can promote lymphatic formation and spread of malignant tumor cells through the lymphatic system to the lymph nodes.6
The serum level of VEGF-D has been found to be elevated in patients with LAM compared with healthy controls as well as patients with other forms of cystic lung disease and emphysema.7 The VEGF-D levels also seem to inversely correlate with pulmonary function testing, which was demonstrated in the Multicenter International Lymphangioleiomyomatosis Efficacy and Safety of Sirolimus (MILES) trial that showed that patients with elevated VEGF-D levels treated with US Food and Drug Administration–approved sirolimus had improvement in forced expiratory volume in the first second (FEV1) and decreased VEGF-D levels compared with the placebo group.8 In patients with high-resolution CT image findings indicative of cystic lung disease, a serum VEGF-D cutoff of greater than 800 pg/mL has a sensitivity of 73% and a specificity of 100% and a definite diagnosis of LAM can be made in the right clinical context without the need for a lung biopsy.7 However, a VEGF-D level less than or equal to 800 pg/mL does not rule out a diagnosis of LAM. Recent guidelines by the American Thoracic Society/Japanese Respiratory Society recommend that in patients with cystic lung disease suggestive of LAM but no other clinical or radiological confirmatory features besides lung cysts, a VEGF-D level should be obtained before proceeding with lung biopsy, with a threshold of greater than 800 pg/mL to be used to diagnose LAM.4 Among patients with LAM who are treated with sirolimus, there is sustained reduction in VEGF-D levels while undergoing therapy compared with before therapy.9
In the United States, the only serum VEGF-D testing certified by the College of American Pathologists and Clinical Laboratory Improvement Amendments is conducted at the translational trial development and support laboratory at the Cincinnati Children’s Hospital Medical Center.
The patient’s clinical presentation and high-resolution CT image findings of cystic lung disease are suggestive of LAM. However, in the absence of other clinical or radiographic features, the diagnosis cannot be definitively established. The elevated VEGF-D level in this setting can confidently confirm the diagnosis of LAM without the need for lung biopsy.
LAM was diagnosed based on the patient’s serum VEGF-D level and pulmonary function testing results that showed a restrictive lung pattern with a reduced FEV1 at 65%; there was no bronchodilator response. The patient was prescribed sirolimus with improvement in her symptoms. Two years after her initial presentation, she continues to follow up in pulmonary clinic with serial pulmonary function testing that has shown stabilization of her lung function over time.
Serum VEGF-D is a useful noninvasive, diagnostic test for patients presenting with cystic lung disease.
Serum VEGF-D levels greater than 800 pg/mL are almost 100% specific for the diagnosis of LAM and can help avoid invasive diagnostic procedures, such as lung biopsy.
Approximately 30% of patients with LAM can have normal serum VEGF-D levels, and a normal level does not exclude the diagnosis of LAM.
Sirolimus is an effective, FDA-approved treatment for LAM that also leads to consistent reductions in serum VEGF-D levels.
Corresponding Author: Ali Ataya, MD, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, 1600 SW Archer Rd, M452, PO Box 100225, Gainesville, FL 32610 (email@example.com).
Published Online: January 3, 2019. doi:10.1001/jama.2018.20926
Conflict of Interest Disclosures: None reported.
Additional Contributions: We thank the patient for providing permission to share her information.
Ataya A, Riley L, Brantly ML. Serum Vascular Endothelial Growth Factor D in Cystic Lung Disease. JAMA. Published online January 03, 2019. doi:10.1001/jama.2018.20926
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