Correspondence

Diagnostic Potential of Serum VEGF-D for Lymphangioleiomyomatosis

N Engl J Med 2008; 358:199-200January 10, 2008

Article

To the Editor:

Lymphangioleiomyomatosis is a rare, progressive, frequently fatal cystic lung disease that affects women almost exclusively.1,2 It occurs in up to 40% of women with the tuberous sclerosis complex, a tumor-suppressor syndrome associated with seizures, cognitive impairment, and hamartomas in multiple organs, and can also occur in a nonheritable sporadic form that involves only the lung, lymphatics, and kidney.3 The presence of the tuberous sclerosis complex or fat-containing renal hamartomas called angiomyolipomatas in a woman with characteristic cystic changes on a high-resolution computed tomographic (CT) scan of the chest is considered to be diagnostic of lymphangioleiomyomatosis. However, half of patients with sporadic lymphangioleiomyomatosis do not have angiomyolipomatas, and the accuracy of high-resolution CT is estimated at only 80%,4 so thoracoscopic biopsy is frequently required for definitive diagnosis. Lymphangiomatosis, pulmonary Langerhans'-cell histiocytosis, and emphysema are commonly considered in the differential diagnosis of lymphangioleiomyomatosis.

Vascular endothelial growth factor (VEGF) is a major angiogenic growth factor produced by malignant cells. VEGF-D, a ligand for the lymphatic growth-factor receptor VEGFR-3/Flt-4, induces formation of lymphatics and promotes the spread of tumor cells to lymph nodes. Seyama et al. reported that levels of VEGF-D, but not VEGF-A or VEGF-C, are elevated in patients with sporadic lymphangioleiomyomatosis as compared with healthy controls.5

We conducted a study to determine the diagnostic usefulness of VEGF-D levels in distinguishing lymphangioleiomyomatosis from other, clinically overlapping disorders. We found that serum VEGF-D levels were elevated by a factor of up to 30 in patients with lymphangioleiomyomatosis but were normal in patients with lymphangiomatosis, those with pulmonary Langerhans'-cell histiocytosis, and those with emphysema (Figure 1AFigure 1Serum VEGF-D Levels in Patients with Lymphangioleiomyomatosis (LAM) as Compared with Healthy Controls and Patients with Other Diseases, and VEGF-D Levels in Women with the Tuberous Sclerosis Complex (TSC) and LAM as Compared with Women and Men with TSC Only.). The area under the receiver-operating-characteristic curve was 0.951 for sporadic lymphangioleiomyomatosis. With a cutoff value for VEGF-D of 574 pg per milliliter, the test sensitivity for sporadic lymphangioleiomyomatosis was 86%, the specificity was 91%, and the positive likelihood ratio was 9.6; with a cutoff value of 750 pg per milliliter, the sensitivity, specificity, and positive likelihood ratio were 76%, 98%, and 41.7, respectively. Furthermore, VEGF-D levels were much higher in women with the tuberous sclerosis complex and lymphangioleiomyomatosis than in women with the tuberous sclerosis complex and normal high-resolution CT scans: mean value, 6804 pg per milliliter (95% confidence interval [CI], 3826 to 9781) versus 491 pg per milliliter (95% CI, 291 to 691; P<0.001). In contrast, some men with the tuberous sclerosis complex alone had elevated VEGF-D levels (Figure 1B).

Serum VEGF-D may be a clinically useful diagnostic test that can distinguish sporadic lymphangioleiomyomatosis from other cystic and chylous lung diseases, potentially decreasing the need for lung biopsy; but validation in a longitudinal study with a larger patient population is necessary.

Lisa R. Young, M.D.
Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229

Yoshikazu Inoue, M.D., Ph.D.
National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka 591-8555, Japan

Francis X. McCormack, M.D.
University of Cincinnati, Cincinnati, OH 45267
frank.mccormack@uc.edu

Supported by grants from the LAM Foundation, the National Institutes of Health (RR019498, to the Rare Lung Diseases Consortium), and the LYMF Foundation.

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