Date Published: February 28, 2019
Publisher: Public Library of Science
Author(s): Masaki Hirose, Akiko Matsumuro, Toru Arai, Chikatoshi Sugimoto, Masanori Akira, Masanori Kitaichi, Lisa R. Young, Francis X. McCormack, Yoshikazu Inoue, Wei Shi.
In lymphangioleiomyomatosis (LAM), tuberous sclerosis gene mutations activate the mechanistic target of the rapamycin pathway, resulting in vascular endothelial growth factor-D (VEGF-D) overproduction. While the utility of serum VEGF-D testing for the diagnosis of LAM is outlined in ATS/JRS LAM Guidelines, the assay has not been fully validated for Asian populations. Our aims were to validate serum VEGF-D testing in Japan, by directly comparing measurements in Japan and the U.S., determining the diagnostic cut-off for serum VEGF-D levels among the Japanese women with typical thin walled cystic change on CT, and determining the performance of VEGF-D as a prognostic biomarker.
We determined serum VEGF-D levels from 108 LAM patients, 14 disease controls, and 51 healthy volunteers from the Japanese population. Measurements of 61 LAM patients were compared to those from the principal VEGF-D laboratory in the U.S at Cincinnati Children’s Hospital Medical Center. We correlated baseline serum VEGF-D levels with baseline and longitudinal clinical data to determine how pregnancy, sirolimus or gonadotrophin-releasing hormone (GnRH) agonists influence serum VEGF-D levels.
Serum VEGF-D measurements in Japan and the U.S. were very similar. Baseline serum VEGF-D levels effectively distinguished LAM from other diseases and healthy volunteers at a cut-off level of 645 pg/ml and were diagnostically specific at 800 pg/ml, consistent with the recommendations of the ATS/JRS LAM Guidelines. Baseline serum VEGF-D correlated negatively with the DLco baseline % predicted and with the annual decrease in DLco % predicted. There was no significant association between baseline serum VEGF-D level and the outcomes of death or transplant. Serum VEGF-D levels markedly decreased during treatment with sirolimus, but not with GnRH analogues. Serum VEGF-D levels of most LAM patients did not increase over time, and neither pregnancy nor menopause significantly modulated serum VEGF-D levels.
Serum VEGF-D is a useful diagnostic and therapeutic biomarker for LAM. Satisfactory precision and international inter-laboratory agreement of the clinical assay support VEGF-D recommendations in the ATS/JRS LAM Guidelines for the Japanese population.
Lymphangioleiomyomatosis (LAM) is a rare and progressive cystic lung disease that primarily affects premenopausal women. It can occur sporadically (S-LAM) or in association with tuberous sclerosis complex (TSC-LAM), a heritable tumor suppressor syndrome caused by TSC1 or TSC2 germ line mutations. TSC-LAM typically presents with seizures, cognitive impairment, and neoplastic growths in multiple organs, including renal angiomyolipomas (AML) [1, 2]. S-LAM is also associated with TSC1 and TSC2 somatic mutations of LAM cells. Hamartin and tuberin, the gene products of TSC1 and TSC2, respectively, form a complex that suppresses the signaling effector, mechanistic target of rapamycin (mTOR). LAM cells harboring TSC mutations exhibit constitutive mTOR activation and metastasize to the lung from an unknown source, resulting in tissue remodeling that leads to cystic changes . LAM cells also express elevated levels of serum vascular endothelial growth factor (VEGF)-D, a growth factor this in known to promote active tumor lymphangiogenesis and spread to regional lymph nodes for other neoplasms .
In this study, we assessed the utility of serum VEGF-D as a diagnostic and therapeutic biomarker in Japanese patients. We found baseline serum VEGF-D levels effectively distinguished LAM from healthy volunteers and patients with other lymphatic and cystic lung diseases, with a sensitivity and specificity of 0.83 and 0.97, respectively, at a cut-off level of 645 pg/ml. At 800 pg/ml serum VEGF-D was slightly less sensitive (0.70) but was diagnostically specific (0.90) . Therefore, as in the U.S., serum VEGF-D levels of 800 pg/ml can establish the diagnosis of LAM in Japanese women with typical cystic changes on HRCT with nearly 100% specificity .
In summary, we confirmed that serum VEGF-D is a useful diagnostic and prognostic biomarker in the Japanese patient population. We also found that serum VEGF-D levels tend to be remarkably consistent over time, and that neither menopausal status nor hormonal fluxes during pregnancy significantly modulate VEGF-D levels, although further studies are needed to confirm these relationships testing. We concluded that serum VEGF-D levels are a globally useful diagnostic and therapeutic biomarker for LAM. Satisfactory precision and international inter-laboratory agreement of the clinical assay support the application of ATS/JRS LAM Guidelines in the Japanese population.