Yasuhito Sekimoto, Kazuhiro Suzuki, Makiko Okura, Takuo Hayashi, Hiroki Ebana, Toshio Kumasaka, Keiko Mitani, Koichi Nishino, Shouichi Okamoto, Etsuko Kobayashi, Kazuhisa Takahashi, Kuniaki Seyama
Uncommon radiologic computed tomography appearances of the chest in patients with lymphangioleiomyomatosis.
Sci Rep. 2021 Mar 30;11(1):7170. doi: 10.1038/s41598-021-85999-5. Epub 2021 Mar 30.
Abstract/Text
Lymphangioleiomyomatosis (LAM) is a rare destructive lung disease characterized by multiple thin-walled pulmonary cysts. The currently proposed diagnostic algorithm emphasizes the characteristic cystic appearance on high-resolution computed tomography (HRCT) so uncommon HRCT appearances present challenges to establishing the proper LAM diagnosis. The objective of this study is to accrue uncommon chest HRCT appearances, determine frequencies in both tuberous sclerosis complex (TSC)-associated LAM (TSC-LAM) and sporadic LAM (S-LAM) patients. 311 females referred to our hospital, including 272 S-LAM patients (mean age 39.2 years) and 39 TSC-LAM patients (mean age 38.3 years), were retrospectively evaluated. We found 2 types of radiologic findings likely to make HRCT cyst appearance atypical: characteristics of the cyst itself and uncommon findings in addition to cysts. We found that approximately 80% of LAM patients, whether TSC-associated or sporadic, showed typical HRCT appearance with mild to severe cystic destruction. The remaining 20% displayed unusual profiles in cyst appearance as well as additional findings aside from cyst: the former includes large cyst, thickened walls, and irregularly shaped whereas the latter includes ground glass attenuation and diffuse noncalcified nodules. It is important to be aware of various radiologic findings that make HRCT cystic appearance atypical of LAM.
Angelo M Taveira-DaSilva, Dara Burstein, Olanda M Hathaway, Joseph R Fontana, Bernardette R Gochuico, Nilo A Avila, Joel Moss
Pneumothorax after air travel in lymphangioleiomyomatosis, idiopathic pulmonary fibrosis, and sarcoidosis.
Chest. 2009 Sep;136(3):665-670. doi: 10.1378/chest.08-3034. Epub 2009 Mar 24.
Abstract/Text
BACKGROUND: The prevalence of pneumothorax associated with travel in patients with interstitial lung diseases is unknown. In patients with lymphangioleiomyomatosis (LAM), in whom pneumothorax is common, patients are often concerned about the occurrence of a life-threatening event during air travel. The aim of this study was to determine the prevalence of pneumothorax associated with air travel in patients with LAM, idiopathic pulmonary fibrosis (IPF), and sarcoidosis.
METHODS: Records and imaging studies of 449 patients traveling to the National Institutes of Health were reviewed.
RESULTS: A total of 449 patients traveled 1,232 times; 299 by airplane (816 trips) and 150 by land (416 trips). Sixteen of 281 LAM patients arrived at their destination with a pneumothorax. In 5 patients, the diagnosis was made by chest roentgenogram, and in 11 patients by CT scans only. Of the 16 patients, 14 traveled by airplane and 2 by land. Seven of the 16 patients, 1 of whom traveled by train, had a new pneumothorax; 9 patients had chronic pneumothoraces. A new pneumothorax was more likely in patients with large cysts and more severe disease. The frequency of a new pneumothorax for LAM patients who traveled by airplane was 2.9% (1.1 per 100 flights) and by ground transportation, 1.3% (0.5 per 100 trips). No IPF (n = 76) or sarcoidosis (n = 92) patients presented with a pneumothorax.
CONCLUSIONS: In interstitial lung diseases with a high prevalence of spontaneous pneumothorax, there is a relatively low risk of pneumothorax following air travel. In LAM, the presence of a pneumothorax associated with air travel may be related to the high incidence of pneumothorax and not to travel itself.
Mie Hayashida, Kuniaki Seyama, Yoshikazu Inoue, Keisaku Fujimoto, Keishi Kubo, Respiratory Failure Research Group of the Japanese Ministry of Health, Labor, and Welfare
The epidemiology of lymphangioleiomyomatosis in Japan: a nationwide cross-sectional study of presenting features and prognostic factors.
Respirology. 2007 Jul;12(4):523-30. doi: 10.1111/j.1440-1843.2007.01101.x.
Abstract/Text
BACKGROUND AND OBJECTIVE: To evaluate the characteristics and prognostic factors of Japanese patients with lymphangioleiomyomatosis (LAM).
METHODS: A nationwide survey to identify patients with LAM was conducted by questionnaire. Survival probability was estimated using the Kaplan-Meier method, and the prognostic factors were analysed by Cox regression.
RESULTS: Data were collected on 173 patients with pulmonary LAM. The major presenting features were pneumothorax (43%) and exertional dyspnoea (37%). The survival probabilities for patients presenting with exertional dyspnoea (Group A) were 85%, 60% and 47% after 5, 10 and 15 years, respectively, and for patients presenting with pneumothorax (Group B) were 95%, 89% and 89%, respectively. Although the age at symptom onset was higher among patients in Group A than in Group B, Cox regression revealed that the presenting feature was a prognostic factor independent of age at symptom onset (Group A/B hazard ratio = 5.732, P < 0.01). In the subgroup of patients whose initial FEV(1) was >1000 mL, or FEV(1)/FVC >40%, or %DL(CO) >40%, the rate of deterioration in these tests was greater in Group A than in Group B (P < 0.01 for FEV(1), P < 0.05 for FEV(1)/FVC and %DL(CO)).
CONCLUSIONS: There are two possible subgroups of LAM patients. One subgroup that presented with pneumothorax, had onset of symptoms at a younger age and a more favourable prognosis; the other presented with exertional dyspnoea, had onset of symptoms at an older age and a poorer prognosis.
リンパ脈管筋腫症（LAM）（指定難病89） – 難病情報センター [Internet]. [cited 2022 Nov 11]. Available from: https://www.nanbyou.or.jp/entry/339
結節性硬化症の診断基準及び治療ガイドライン -改訂版- 日皮会誌：128（1），1-16，2018.
Kuniaki Seyama, Toshio Kumasaka, Sanae Souma, Teruhiko Sato, Masatoshi Kurihara, Keiko Mitani, Sigeru Tominaga, Yoshinosuke Fukuchi
Vascular endothelial growth factor-D is increased in serum of patients with lymphangioleiomyomatosis.
Lymphat Res Biol. 2006;4(3):143-52. doi: 10.1089/lrb.2006.4.143.
Abstract/Text
BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare destructive lung disease characterized by an abnormal proliferation of smooth muscle-like cells (LAM cells) in the lung and along the axial lymphatics. LAM demonstrates a heterogeneous clinical course, but there is no serum surrogate marker available for assessing the disease severity or predicting the disease progression. Since the authors have recently demonstrated the extensive LAM-associated lymphangiogenesis and its potential role in progression and metastasis of LAM cells, they hypothesized that serum levels of lymphangiogenic growth factors might be increased in LAM and become a surrogate marker for disease severity.
METHODS AND RESULTS: VEGF-A, VEGF-C, and VEGF-D in serum of 44 patients with LAM were measured by enzyme-linked immunosorbant assay. Only VEGF-D was significantly increased in LAM patients as compared with age- and gender-matched healthy volunteers (n=24) (LAM vs. control, geometric mean 95% CI; 1069.3 pg/mL (809.4 approximately 1412.6) vs. 295.9 pg/mL (262.6 approximately 333.5), p<0.0001). Serum VEGF-D levels negatively correlated with variables of pulmonary function tests, FEV1/FVC (forced expiratory volume in one second/forced vital capacity) (r=-0.365, p<0.05) and %DLco/VA (the percentage of diffusing capacity for carbon monoxide/alveolar volume to the predicted value) (r=-0.560, p<0.001). As expected, the group who received hormone therapy showed more deteriorated pulmonary function with higher serum VEGF-D levels than the group who was just observed without hormone therapy. Immunohistochemical examination of lung specimens demonstrated the positive immunoreactivity of LAM cells for VEGF-D.
CONCLUSION: Serum VEGF-D levels may be a valuable surrogate marker for evaluating the disease severity in LAM.
Lisa R Young, Yoshikazu Inoue, Francis X McCormack
Diagnostic potential of serum VEGF-D for lymphangioleiomyomatosis.
N Engl J Med. 2008 Jan 10;358(2):199-200. doi: 10.1056/NEJMc0707517.
Abstract/Text
Connie G Glasgow, Nilo A Avila, Jing-Ping Lin, Mario P Stylianou, Joel Moss
Serum vascular endothelial growth factor-D levels in patients with lymphangioleiomyomatosis reflect lymphatic involvement.
Chest. 2009 May;135(5):1293-300. doi: 10.1378/chest.08-1160.
Abstract/Text
BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare multisystem disorder affecting primarily women of child-bearing age, and characterized by cystic lung destruction, tumors of the kidney (angiomyolipomas [AMLs]), and involvement of the axial lymphatics (lymphangioleiomyomas). Patients with LAM experience loss of pulmonary function attributed to the proliferation of abnormal-appearing smooth muscle-like cells (LAM cells). It is possible to group the LAM population by the presence or absence of extrapulmonary involvement (eg, AMLs, lymphangioleiomyomas, chylous effusions). Serum vascular endothelial growth factor (VEGF)-D, a lymphangiogenic factor, is higher in LAM patients than in healthy volunteers and has been proposed as a tool in the differential diagnosis of cystic lung disease. We assessed serum VEGF-D concentrations in relationship to clinical phenotype in LAM patients.
METHODS: Serum VEGF-D levels were quantified by enzyme immunosorbent assay for 111 patients with LAM and 40 healthy volunteers. VEGF-D levels in patients with pulmonary LAM, with or without extrapulmonary manifestations, were compared to those of healthy volunteers.
RESULTS: Serum VEGF-D levels were greater in patients with LAM compared to those of healthy volunteers (p < 0.001). However, when patient samples were grouped based on the extent of lymphatic extrapulmonary involvement (eg, lymphangioleiomyomas and adenopathy), the statistical difference was maintained only for patients with LAM with lymphatic involvement (p < 0.001), not for those patients whose disease was restricted to the lung. Serum VEGF-D levels are a good biomarker for lymphatic involvement (area under the curve [AUC], 0.845; p < 0.0001), and a fair predictor for LAM disease (AUC, 0.751; p < 0.0001). Serum levels correlated to CT scan grade (p = 0.033).
CONCLUSIONS: Serum VEGF-D concentration is a measure of lymphatic involvement in patients with LAM.
Lisa R Young, Rhonda Vandyke, Peter M Gulleman, Yoshikazu Inoue, Kevin K Brown, Laura S Schmidt, W Marston Linehan, Fuad Hajjar, Brent W Kinder, Bruce C Trapnell, John J Bissler, David N Franz, Francis X McCormack
Serum vascular endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other diseases.
Chest. 2010 Sep;138(3):674-81. doi: 10.1378/chest.10-0573. Epub 2010 Apr 9.
Abstract/Text
OBJECTIVES: The majority of women with lymphangioleiomyomatosis (LAM) present with cystic lung disease, and most require lung biopsy for definitive diagnosis. The purpose of this study was to determine the prospective diagnostic usefulness of a serologic test for vascular endothelial growth factor-D (VEGF-D), a lymphangiogenic growth factor.
METHODS: We prospectively measured serum VEGF-D levels by enzyme-linked immunoassay in 48 women presenting with cystic lung disease. Diagnostic test performance was determined from a cohort of 195 women, with tuberous sclerosis complex (TSC), TSC-LAM, sporadic LAM (S-LAM), and other cystic lung diseases in the differential diagnosis, including biopsy-proven or genetically proven pulmonary Langerhans cell histiocytosis, emphysema, Sjögren syndrome, or Birt-Hogg-Dubé syndrome.
RESULTS: Serum VEGF-D levels were significantly greater in S-LAM (median 1,175 [interquartile range (IQR): 780-2,013] pg/mL; n = 56) than in other cystic lung diseases (median 281 [IQR 203-351] pg/mL; n = 44, P < .001). In the cohort evaluated prospectively, 12 of the 15 individuals ultimately diagnosed with LAM by biopsy had VEGF-D levels of > 800 pg/mL, whereas levels were < 600 pg/mL in all 18 subjects later diagnosed with other causes of cystic lung disease. Receiver operating characteristic curves demonstrated that VEGF-D effectively identified LAM, with an area under the curve of 0.961(95% CI, 0.923-0.992). A VEGF-D level of > 600 pg/mL was highly associated with a diagnosis of LAM (specificity 97.6%, likelihood ratio 35.2) and values > 800 pg/mL were diagnostically specific. Serum VEGF-D levels were significantly elevated in women with TSC-LAM (median 3,465 [IQR 1,970-7,195] pg/mL) compared with women with TSC only (median 370 [IQR 291-520] pg/mL), P < .001).
CONCLUSIONS: A serum VEGF-D level of > 800 pg/mL in a woman with typical cystic changes on high-resolution CT (HRCT) scan is diagnostically specific for S-LAM and identifies LAM in women with TSC. A negative VEGF-D result does not exclude the diagnosis of LAM. The usefulness of serum VEGF-D testing in men or in women who do not have cystic lung disease on HRCT scan is unknown.
安藤克利、瀬山邦明、小林悦子、他. リンパ脈管筋腫症患者における血清・乳び液中VEGF-D値と臨床像の検討. 平成24年度総括・分担研究報告書. 2013; 249-253.
Kai-Feng Xu, Peng Zhang, Xinlun Tian, Aiping Ma, Xue Li, Jiong Zhou, Ni Zeng, Yao-Song Gui, Zijian Guo, Ruie Feng, Weihong Zhang, Wei Sun, Baiqiang Cai
The role of vascular endothelial growth factor-D in diagnosis of lymphangioleiomyomatosis (LAM).
Respir Med. 2013 Feb;107(2):263-8. doi: 10.1016/j.rmed.2012.10.006. Epub 2012 Nov 3.
Abstract/Text
BACKGROUND: Definite diagnosis of lymphangioleiomyomatosis (LAM) depends on either transbronchial lung biopsy or video-assisted thoracic surgery, unless there is a history of chylothorax, kidney angiomyolipoma (AML), or tuberous sclerosis complex (TSC). Vascular endothelial growth factor-D (VEGF-D) was recently considered as a novel diagnostic marker for LAM. Herein, we evaluated diagnostic value of serum VEGF-D in LAM patients.
METHODS: Serum samples were obtained from 78 cases of LAM (50 definite and 28 probable LAM based on European Respiratory Society guidelines), and 40 healthy female volunteers. VEGF-D was measured using enzyme-linked immunosorbant assay according to product instruction (R&D).
RESULTS: Serum VEGF-D was significantly increased in definite LAM group, compared with that of health control (median: 3841.9 pg/mL vs 405.5 pg/mL respectively, p < 0.001). The optimal cut-off point for definite LAM diagnosis was 850.7 pg/mL. In probable LAM group, the majority of patients (92.9%) had serum VEGF-D level over 850.7 pg/mL. The serum levels of VEGF-D in LAM patients with pulmonary cystic lesions only were lower than that in patients with any of evidences of AML, chylous effusions, adenopathy, lymphangioleiomyomas, or TSC, but higher than that in the health control. In addition, VEGF-D levels were correlated with disease severity measured as LAM CT grade, and presentations of chylous effusions and/or lymphatic involvement (p < 0.05).
CONCLUSION: Serum VEGF-D should be added to the current diagnosis algorithm to enhance definitive diagnosis for LAM.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Lisa Young, Hye-Seung Lee, Yoshikazu Inoue, Joel Moss, Lianne G Singer, Charlie Strange, Koh Nakata, Alan F Barker, Jeffrey T Chapman, Mark L Brantly, James M Stocks, Kevin K Brown, Joseph P Lynch, Hilary J Goldberg, Gregory P Downey, Jeffrey J Swigris, Angelo M Taveira-DaSilva, Jeffrey P Krischer, Bruce C Trapnell, Francis X McCormack, MILES Trial Group
Serum VEGF-D a concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial.
Lancet Respir Med. 2013 Aug;1(6):445-52. doi: 10.1016/S2213-2600(13)70090-0.
Abstract/Text
BACKGROUND: VEGF-D is a lymphangiogenic growth factor that has a key role in tumour metastasis. Serum VEGF-D concentrations are increased in most patients with lymphangioleiomyomatosis, a rare neoplasm associated with mTOR-activating tuberous sclerosis gene mutations, lymphadenopathy, metastatic spread, and pulmonary cyst formation. We used data from the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial to assess the usefulness of serum VEGF-D concentration as a marker of severity and therapeutic response to sirolimus in patients with lymphangioleiomyomatosis.
METHODS: In the MILES trial, patients with lymphangioleiomyomatosis who had forced expiratory volume in 1 second (FEV1) of 70% or less of predicted were randomly assigned (1:1) to 12 months masked treatment with sirolimus or placebo. Serum VEGF-D concentrations were measured at baseline, 6 months, and 12 months. We used a linear regression model to assess associations of baseline VEGF-D concentrations with markers of disease severity, and a linear mixed effects model to assess the associations of VEGF-D concentrations with between-group differences in clinical, physiological, and patient-reported outcomes.
FINDINGS: We included 42 patients from the placebo group and 45 from the sirolimus group in our analysis. Baseline VEGF-D concentrations in individual patients varied from 0·34 ng/mL to 16·7 ng/mL. Baseline VEGF-D concentrations were higher in patients who needed supplemental oxygen than in those who did not need supplemental oxygen (1·7 ng/mL [IQR 0·99–3·36] vs 0·84 ng/mL [0·52–1·39]; p<0·0001) and in those who had a bronchodilator response than in those who did not (2·01 ng/mL [0·99–2·86] vs 1·00 ng/mL [0·61–2·15]; 0·0273). Median serum VEGF-D concentrations were similar at baseline in the sirolimus and placebo groups, and fell from baseline at 6 and 12 months in the sirolimus group but remained roughly stable in the placebo group. Each one-unit increase in baseline log(VEGF-D) was associated with a between-group difference in baseline-to-12-month FEV1 change of 134 mL (p=0·0007). In the sirolimus group, improvement in baseline-to-12-month FEV1 occurred in 15 of 23 (65%) VEGF-D responders (ie, those in whom baseline-to-12-month VEGF-D concentrations decreased by more than they did in any patients in the placebo group) and four of 15 (27%) VEGF-D non-responders (p=0·0448).
INTERPRETATION: Serum VEGF-D is a biologically plausible and useful biomarker in lymphangioleiomyomatosis that correlates with disease severity and treatment response. Measurement of serum VEGF-D concentrations could inform the risk–benefit analysis of sirolimus therapy in patients with lymphangioleiomyomatosis and reduce the numbers of patients needed for clinical trials.
FUNDING: National Institutes of Health, US Department of Defense.
Lorriana E Leard, Are M Holm, Maryam Valapour, Allan R Glanville, Sandeep Attawar, Meghan Aversa, Silvia V Campos, Lillian M Christon, Marcelo Cypel, Göran Dellgren, Matthew G Hartwig, Siddhartha G Kapnadak, Nicholas A Kolaitis, Robert M Kotloff, Caroline M Patterson, Oksana A Shlobin, Patrick J Smith, Amparo Solé, Melinda Solomon, David Weill, Marlies S Wijsenbeek, Brigitte W M Willemse, Selim M Arcasoy, Kathleen J Ramos
Consensus document for the selection of lung transplant candidates: An update from the International Society for Heart and Lung Transplantation.
J Heart Lung Transplant. 2021 Nov;40(11):1349-1379. doi: 10.1016/j.healun.2021.07.005. Epub 2021 Jul 24.
Abstract/Text
Tens of thousands of patients with advanced lung diseases may be eligible to be considered as potential candidates for lung transplant around the world each year. The timing of referral, evaluation, determination of candidacy, and listing of candidates continues to pose challenges and even ethical dilemmas. To address these challenges, the International Society for Heart and Lung Transplantation appointed an international group of members to review the literature, to consider recent advances in the management of advanced lung diseases, and to update prior consensus documents on the selection of lung transplant candidates. The purpose of this updated consensus document is to assist providers throughout the world who are caring for patients with pulmonary disease to identify potential candidates for lung transplant, to optimize the timing of the referral of these patients to lung transplant centers, and to provide transplant centers with a framework for evaluating and selecting candidates. In addition to addressing general considerations and providing disease specific recommendations for referral and listing, this updated consensus document includes an ethical framework, a recognition of the variability in acceptance of risk between transplant centers, and establishes a system to account for how a combination of risk factors may be taken into consideration in candidate selection for lung transplantation.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
後藤直人、瀬山邦明、吉本啓助、他. リンパ脈管筋腫症の診断後に妊娠・出産を経験した症例の検討. 厚生労働省特定疾患呼吸不全に関する調査研究. 平成21年度研究報告書 2010; 292-7.
C C Yockey, R E Riepe, K Ryan
Pulmonary lymphangioleiomyomatosis complicated by pregnancy.
Kans Med. 1986 Oct;87(10):277-8, 293.
Abstract/Text
S R Johnson, J F Cordier, R Lazor, V Cottin, U Costabel, S Harari, M Reynaud-Gaubert, A Boehler, M Brauner, H Popper, F Bonetti, C Kingswood, Review Panel of the ERS LAM Task Force
European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis.
Eur Respir J. 2010 Jan;35(1):14-26. doi: 10.1183/09031936.00076209.
Abstract/Text
Hiroshi Toei, Xixi Zhang, Kuniaki Seyama, Daisuke Yashiro, Yoshiki Kuwatsuru, Ryohei Kuwatsuru
Prophylactic renal artery embolization before pregnancy in patients with lymphangioleiomyomatosis and renal angiomyolipoma.
J Int Med Res. 2022 Sep;50(9):3000605221123897. doi: 10.1177/03000605221123897.
Abstract/Text
OBJECTIVE: Pregnant patients with lymphangioleiomyomatosis (LAM) and renal angiomyolipomas (AMLs) require care for both renal AMLs and pulmonary dysfunction because AMLs can grow and rupture during pregnancy, potentially causing hemorrhagic shock and fetal death. This study examined whether prophylactic transcatheter arterial embolization (TAE) could prevent the pregnancy-associated growth and rupture of renal AMLs in patients with LAM.
METHODS: This retrospective study included five women with 14 renal AMLs (initial diameter, ≥2 cm) first encountered between September 2010 and August 2015 who subsequently became pregnant. Seven tumors in five patients were embolized, and seven tumors in two patients were not treated. Changes in the volume of each tumor were evaluated.
RESULTS: Untreated tumors were much more likely to grow than embolized tumors both during pregnancy (100% vs. 0%) and at the first follow-up visit after delivery (100% vs. 14%). One untreated hypervascular tumor grew rapidly during pregnancy to 409% of the pretreatment volume. No tumor ruptured.
CONCLUSIONS: Prophylactic pre-pregnancy TAE decreased the growth and bleeding of renal AMLs during pregnancy in patients with LAM. TAE can be recommended for hypervascular tumors before pregnancy regardless of the size of the aneurysm.
Jamielynn Sebaaly, Laura Bowers, Joe Mazur, Rob Kotloff, Blake R Olmsted, Allen Kaplan, Charlie Strange
Rapid oral desensitization to sirolimus in a patient with lymphangioleiomyomatosis.
J Allergy Clin Immunol Pract. 2016 Mar-Apr;4(2):352-3. doi: 10.1016/j.jaip.2015.11.007. Epub 2015 Dec 24.
Abstract/Text
