A Evolução do Manejo da Linfangioleiomiomatose (LAM): Da Manipulação Hormonal à Inibição Direcionada da Via mammalian target of rapamycin (mTOR)
DOI:
https://doi.org/10.33448/rsd-v14i4.48656Palavras-chave:
Linfangioleiomiomatose, Inibidores de mTOR, Doenças Raras, Sirolimo, Everolimo.Resumo
A Linfangioleiomiomatose (LAM), doença pulmonar rara e progressiva que afeta predominantemente mulheres, passou por uma significativa transformação em seu manejo terapêutico nas últimas décadas. Esta revisão objetiva analisar criticamente essa evolução, contrastando as estratégias históricas de manipulação hormonal com a terapia moderna direcionada à inibição da via mammalian target of rapamycin (mTOR), elucidando a transição para o padrão de tratamento atual. Conduzida como uma revisão narrativa da literatura científica, a análise demonstra que as abordagens hormonais, apesar de um racional biológico inicial envolvendo receptores e interações estrogênicas, não apresentaram eficácia robusta para modificar a progressão da doença pulmonar. O ponto de inflexão ocorreu com a identificação da via mTOR como central na patogênese da LAM, impulsionada por mutações nos genes TSC. Esta descoberta levou ao desenvolvimento e validação clínica de inibidores de mTOR, como sirolimo e everolimo, que demonstraram estabilizar a função pulmonar e melhorar os desfechos das pacientes. Atualmente, os inibidores de mTOR constituem o padrão-ouro terapêutico, representando um marco da medicina de precisão no tratamento da LAM. Ao consolidar a evidência que sustenta essa mudança de paradigma, esta revisão também destaca os desafios persistentes e as direções para pesquisas futuras, incluindo a otimização da terapia, a identificação de novos biomarcadores e a busca por tratamentos complementares.
Referências
Argula, R. G., Kokosi, M., Lo, P., Kim, H. J., Ravenel, J. G., Meyer, C., Goldin, J., Lee, H.-S., Strange, C., & McCormack, F. X. (2016). A novel quantitative computed tomographic analysis suggests how sirolimus stabilizes progressive air trapping in lymphangioleiomyomatosis. Annals of the American Thoracic Society, 13(3), 342–349. https://doi.org/10.1513/AnnalsATS.201509-631OC
Baldi, B. G., Feitosa, P. H. R., Rubin, A. S., Amaral, A. F., Freitas, C. S. G., Costa, C. H. da, Mancuzo, E. V., Nascimento, E. C. T. do, Araujo, M. S., Rocha, M. J. J., Oliveira, M. R. de, Galvão, T. S., Torres, P. P. T. e S., Carvalho, C. R. R., ... [verificar regra APA 7ª para lista completa >20 autores]. (2025). Brazilian Thoracic Association recommendations for the management of lymphangioleiomyomatosis. Jornal Brasileiro de Pneumologia, 51(1), e20240378. https://doi.org/10.36416/1806-3756/e20240378
Baldi, B. G., Freitas, C. S., Araujo, M. S., Dias, O. M., Pereira, D. A., Pimenta, S. P., Kairalla, R. A., & Carvalho, C. R. R. (2014). Clinical course and characterisation of lymphangioleiomyomatosis in a Brazilian reference centre. Sarcoidosis, Vasculitis, and Diffuse Lung Diseases, 31(2), 129–135.
Bissler, J. J., Kingswood, J. C., Radzikowska, E., Zonnenberg, B. A., Frost, M., Belousova, E., Sauter, M., Nonomura, N., Brakemeier, S., de Vries, P. J., Berkowitz, N., Miao, S., Segal, S., Peyrard, S., & Budde, K. (2016). Everolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: Extension of a randomized controlled trial. Nephrology Dialysis Transplantation, 31(1), 111–119. https://doi.org/10.1093/ndt/gfv249
Bissler, J. J., Kingswood, J. C., Radzikowska, E., Zonnenberg, B. A., Frost, M., Belousova, E., Sauter, M., Nonomura, N., Brakemeier, S., de Vries, P. J., Whittemore, V. H., Chen, D., Sahmoud, T., Shah, G., Lms, G., & Budde, K. (2013). Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): A multicentre, randomised, double-blind, placebo-controlled trial. The Lancet, 381(9869), 817–824. https://doi.org/10.1016/S0140-6736(12)61767-X
Bissler, J. J., McCormack, F. X., Young, L. R., Elwing, J. M., Chuck, G., Leonard, J. M., Schmithorst, V. J., Laor, T., Brody, A. S., Bean, J., Salisbury, S., & Franz, D. N. (2008). Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. New England Journal of Medicine, 358(2), 140–151. https://doi.org/10.1056/NEJMoa063564
Bissler, J. J., Nonomura, N., Budde, K., Zonnenberg, B. A., Fischereder, M., Voi, M., Louveau, A.-L., Herbst, F., Bebin, E. M., Curatolo, P., Zonta, A., & Belousova, E. (2018). Angiomyolipoma rebound tumor growth after discontinuation of everolimus in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. PLoS ONE, 13(9), e0201005. https://doi.org/10.1371/journal.pone.0201005
Cai, X., Zhang, L., Xu, W., Zhang, J., Tian, X., Gu, S., ... & Xu, K. F. (2021). Long-term efficacy and safety of sirolimus for the treatment of lymphangioleiomyomatosis: A pooled analysis of 638 patients in China. Orphanet Journal of Rare Diseases, 16(1), 158. https://doi.org/10.1186/s13023-021-01776-7
Carsillo, T., Astrinidis, A., & Henske, E. P. (2000). Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proceedings of the National Academy of Sciences of the United States of America, 97(11), 6085–6090. https://doi.org/10.1073/pnas.97.11.6085
Cottin, V., Cases, A., Bourdin, V., Reynaud-Gaubert, M., Hirschi, S., Kerjouan, M., Diesler, R., Chardès, B., Fiévez, S., Assi, N., Schmidt, A., Denis, H., Wémeau-Stervinou, L., & Uzunhan, Y. (2025). Characteristics and outcomes of patients with LAM receiving sirolimus in France based on real-life data. Frontiers in Medicine, 11, 1494713. https://doi.org/10.3389/fmed.2024.1494713
Courtwright, A. M., Goldberg, H. J., Henske, E. P., & El-Chemaly, S. (2017). The effect of mTOR inhibitors on respiratory infections in lymphangioleiomyomatosis. European Respiratory Review, 26(143), 160004. https://doi.org/10.1183/16000617.0004-2016
Crino, P. B., Nathanson, K. L., & Henske, E. P. (2006). The tuberous sclerosis complex. New England Journal of Medicine, 355(13), 1345–1356. https://doi.org/10.1056/NEJMra055323
El-Hashemite, N., Walker, V., & Kwiatkowski, D. J. (2005). Estrogen enhances whereas tamoxifen retards development of Tsc mouse liver hemangioma: A tumor related to renal angiomyolipoma and pulmonary lymphangioleiomyomatosis. Cancer Research, 65(6), 2474–2481. https://doi.org/10.1158/0008-5472.CAN-04-3840
Eliasson, A. H., Phillips, Y. Y., & Tenholder, M. F. (1989). Treatment of lymphangioleiomyomatosis. A meta-analysis. Chest, 96(6), 1352–1355. https://doi.org/10.1378/chest.96.6.1352
Franciosi, A. N., Gupta, N., Murphy, D. J., Wikenheiser-Brokamp, K. A., & McCarthy, C. (2025). Diffuse cystic lung disease: A clinical guide to recognition and management. Chest, 167(2), 529–547. https://doi.org/10.1016/j.chest.2024.08.008
Gibbons, E., Minor, B. M. N., & Hammes, S. R. (2023). Lymphangioleiomyomatosis: Where endocrinology, immunology and tumor biology meet. Endocrine-Related Cancer, 30(9), e230102. https://doi.org/10.1530/ERC-23-0102
Goldberg, H. J., Harari, S., Cottin, V., Rosas, I. O., Peters, E., Biswal, S., Cheng, Y., Khindri, S., Kovarik, J. M., Ma, S., McCormack, F. X., & Henske, E. P. (2015). Everolimus for the treatment of lymphangioleiomyomatosis: A phase II study. European Respiratory Journal, 46(3), 783–794. https://doi.org/10.1183/09031936.00210714
Guertin, D. A., & Sabatini, D. M. (2007). Defining the role of mTOR in cancer. Cancer Cell, 12(1), 9–22. https://doi.org/10.1016/j.ccr.2007.05.008
Gupta, N., Finlay, G. A., Kotloff, R. M., Strange, C., Wilson, K. C., Young, L. R., Taveira-DaSilva, A. M., Johnson, S. R., Cottin, V., Sahn, S. A., Ryu, J. H., Seyama, K., Inoue, Y., Downey, G. P., Han, M. K., Colby, T. V., Wikenheiser-Brokamp, K. A., Meyer, C. A., Smith, K., Moss, J., & ATS Assembly on Clinical Problems. (2017). Lymphangioleiomyomatosis diagnosis and management: High-resolution chest computed tomography, transbronchial lung biopsy, and pleural disease management. An Official American Thoracic Society/Japanese Respiratory Society clinical practice guideline. American Journal of Respiratory and Critical Care Medicine, 196(10), 1337–1348. https://doi.org/10.1164/rccm.201709-1965ST
Hammes, S. R., & Krymskaya, V. P. (2013). Targeted approaches toward understanding and treating pulmonary lymphangioleiomyomatosis (LAM). Hormones and Cancer, 4(2), 70–77. https://doi.org/10.1007/s12672-012-0128-4
Harari, S., Elia, D., Caminati, A., Geginat, J., Luisi, F., Pelosi, G., Specchia, C., Torre, O., Trevisan, R., Vasco, C., Zompatori, M., & Cassandro, R. (2024). Nintedanib for patients with lymphangioleiomyomatosis: A phase 2, open-label, single-arm study. The Lancet. Respiratory Medicine, 12(12), 967–974. https://doi.org/10.1016/S2213-2600(24)00217-0
Harari, S., Spagnolo, P., Cocconcelli, E., Luisi, F., & Cottin, V. (2018). Recent advances in the pathobiology and clinical management of lymphangioleiomyomatosis. Current Opinion in Pulmonary Medicine, 24(5), 469–476. https://doi.org/10.1097/MCP.0000000000000502
Henske, E. P., & McCormack, F. X. (2012). Lymphangioleiomyomatosis - a wolf in sheep's clothing. Journal of Clinical Investigation, 122(11), 3807–3816. https://doi.org/10.1172/JCI58709
Huang, L., Xiao, Y., Yang, L., & Ren, S. (2024). The development for emerging biomarkers of lymphangioleiomyomatosis. Orphanet Journal of Rare Diseases, 19(1), 445. https://doi.org/10.1186/s13023-024-03455-9
Johnson, S. R., Cordier, J. F., Lazor, R., Cottin, V., Costabel, U., Harari, S., Reynaud-Gaubert, M., Boehler, A., Brauner, M., Popper, H., Bonetti, F., Kingswood, C., & Review Panel of the ERS LAM Task Force. (2010). European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. European Respiratory Journal, 35(1), 14–26. https://doi.org/10.1183/09031936.00076209
Krymskaya, V. P., & McCormack, F. X. (2017). Lymphangioleiomyomatosis: A monogenic model of malignancy. Annual Review of Medicine, 68, 69–83. https://doi.org/10.1146/annurev-med-050715-104245
Kundu, N., & Holz, M. K. (2023). Lymphangioleiomyomatosis: A metastatic lung disease. American Journal of Physiology - Cell Physiology, 324(2), C320–C326. https://doi.org/10.1152/ajpcell.00202.2022
Laplante, M., & Sabatini, D. M. (2012). mTOR signaling in growth control and disease. Cell, 149(2), 274–293. https://doi.org/10.1016/j.cell.2012.03.017
Lu, C., Lee, H.-S., Pappas, G. P., Dilling, D. F., Burger, C. D., Shifren, A., Veeraraghavan, S., Chapman, J. T., Parambil, J., Ruoss, S. J., Young, L. R., Hammes, S. R., Kopras, E. J., Roads, T., Krischer, J. P., & McCormack, F. X. (2017). A phase II clinical trial of an aromatase inhibitor for postmenopausal women with lymphangioleiomyomatosis. Annals of the American Thoracic Society, 14(6), 919–928. https://doi.org/10.1513/AnnalsATS.201610-824OC
McCarthy, C., Gupta, N., Johnson, S. R., Yu, J. J., & McCormack, F. X. (2021). Lymphangioleiomyomatosis: Pathogenesis, clinical features, diagnosis, and management. The Lancet. Respiratory Medicine, 9(11), 1313–1327. https://doi.org/10.1016/S2213-2600(21)00228-9
McCormack, F. X. (2008). Lymphangioleiomyomatosis: A clinical update. Chest, 133(2), 507–516. https://doi.org/10.1378/chest.07-0898
McCormack, F. X., Inoue, Y., Moss, J., Singer, L. G., Strange, C., Nakata, K., Barker, A. F., Chapman, J. T., Brantly, M. L., Stocks, J. M., Brown, K. K., Lynch, J. P., III, Goldberg, H. J., Young, L. R., Kinder, B. W., Downey, G. P., Sullivan, E. J., Colby, T. V., McKay, R. T., Cohen, M. M., ... MILES Trial Group. (2011). Efficacy and safety of sirolimus in lymphangioleiomyomatosis. New England Journal of Medicine, 364(17), 1595–1606. https://doi.org/10.1056/NEJMoa1100391
Minor, B. M. N., LeMoine, D., Seger, C., Gibbons, E., Koudouovoh, J., Taya, M., Kurtz, D., Xu, Y., & Hammes, S. R. (2023). Estradiol augments tumor-induced neutrophil production to promote tumor cell actions in lymphangioleiomyomatosis models. Endocrinology, 164(6), bqad061. https://doi.org/10.1210/endocr/bqad061
Moir, L. M. (2016). Lymphangioleiomyomatosis: Current understanding and potential treatments. Pharmacology & Therapeutics, 158, 114–124. https://doi.org/10.1016/j.pharmthera.2015.12.008
Northrup, H., Koenig, M. K., Pearson, D. A., & Au, K. S. (2024). Tuberous sclerosis complex. In M. P. Adam, G. M. Mirzaa, R. A. Pagon, S. E. Wallace, L. J. H. Bean, K. W. Gripp, & A. Amemiya (Eds.), GeneReviews®. University of Washington, Seattle. https://www.ncbi.nlm.nih.gov/books/NBK1220/
Ohori, N. P., Yousem, S. A., Sonmez-Alpan, E., & Colby, T. V. (1991). Estrogen and progesterone receptors in lymphangioleiomyomatosis, epithelioid hemangioendothelioma, and sclerosing hemangioma of the lung. American Journal of Clinical Pathology, 96(4), 529–535.
Pereira A. S. et al. (2018). Metodologia da pesquisa científica. [free e-book]. Santa Maria/RS. Ed. UAB/NTE/UFSM. (Referência adicionada)
Prizant, H., & Hammes, S. R. (2016). Minireview: Lymphangioleiomyomatosis (LAM): The "other" steroid-sensitive cancer. Endocrinology, 157(9), 3374–3383. https://doi.org/10.1210/en.2016-1395
Rother, E. T. (2007). Revisão sistemática X revisão narrativa [Systematic review X narrative review]. Acta Paulista de Enfermagem, 20(2), v–vi. https://doi.org/10.1590/S0103-21002007000200001
Shen, A., Iseman, M. D., Waldron, J. A., & King, T. E. (1987). Exacerbation of pulmonary lymphangioleiomyomatosis by exogenous estrogens. Chest, 91(5), 782–785.
Tai, J., Liu, S., Yan, X., Huang, L., Pan, Y., Huang, H., Zhao, Z., Xu, B., & Liu, J. (2024). Novel developments in the study of estrogen in the pathogenesis and therapeutic intervention of lymphangioleiomyomatosis. Orphanet Journal of Rare Diseases, 19(1), 236. https://doi.org/10.1186/s13023-024-03239-1
Takada, T., Mikami, A., Kitamura, N., Seyama, K., Inoue, Y., Nagai, K., Suzuki, M., Moriyama, H., Akasaka, K., Tazawa, R., Hirai, T., Mishima, M., Hayashida, M., Hirose, M., Sugimoto, C., Arai, T., Hattori, N., Watanabe, K., Tamada, T., ... Nakata, K. (2016). Efficacy and safety of long-term sirolimus therapy for Asian patients with lymphangioleiomyomatosis. Annals of the American Thoracic Society, 13(11), 1912–1922. https://doi.org/10.1513/AnnalsATS.201605-335OC
Taveira-DaSilva, A. M., Hathaway, O., Stylianou, M., & Moss, J. (2011). Changes in lung function and chylous effusions in patients with lymphangioleiomyomatosis treated with sirolimus. Annals of Internal Medicine, 154(12), 797–805, W-292–W-293.
Taveira-DaSilva, A. M., & Moss, J. (2014). Management of lymphangioleiomyomatosis. F1000Prime Reports, 6, 116. https://doi.org/10.12703/P6-116
Taveira-DaSilva, A. M., & Moss, J. (2016). Epidemiology, pathogenesis and diagnosis of lymphangioleiomyomatosis. Expert Opinion on Orphan Drugs, 4(4), 369–378. https://doi.org/10.1517/21678707.2016.1148597
Torres, V. E., Björnsson, J., King, B. F., Kumar, R., Zincke, H., Edell, E. S., Wilson, T. O., Hattery, R. R., & Gomez, M. R. (1995). Extrapulmonary lymphangioleiomyomatosis and lymphangiomatous cysts in tuberous sclerosis complex. Mayo Clinic Proceedings, 70(7), 641–648. https://doi.org/10.4065/70.7.641
Vaggers, S., Rice, P., Somani, B. K., Veeratterapillay, R., & Rai, B. P. (2020). Evidence-based protocol-led management of renal angiomyolipoma: A review of literature. Turkish Journal of Urology, 47(Supp. 1), S9–S18. https://doi.org/10.5152/tud.2020.20343
Wahedna, I., Cooper, S., Williams, J., Paterson, I. C., Britton, J. R., & Tattersfield, A. E. (1994). Relation of pulmonary lymphangioleiomyomatosis to use of the oral contraceptive pill and fertility in the UK: A national case control study. Thorax, 49(9), 910–914. https://doi.org/10.1136/thx.49.9.910
Wang, Q., Luo, M., Xiang, B., Chen, S., & Ji, Y. (2020). The efficacy and safety of pharmacological treatments for lymphangioleiomyomatosis. Respiratory Research, 21(1), 55. https://doi.org/10.1186/s12931-020-1316-3
Yao, J., Taveira-DaSilva, A. M., Jones, A. M., Julien-Williams, P., Stylianou, M., & Moss, J. (2014). Sustained effects of sirolimus on lung function and cystic lung lesions in lymphangioleiomyomatosis. American Journal of Respiratory and Critical Care Medicine, 190(11), 1273–1282.
Young, L. R., Lee, H.-S., Inoue, Y., Moss, J., Singer, L. G., Strange, C., Nakata, K., Barker, A. F., Chapman, J. T., Brantly, M. L., ... MILES Trial Group. (2013). Serum VEGF-D concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: A prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial. The Lancet Respiratory Medicine, 1(6), 445–452. https://doi.org/10.1016/S2213-2600(13)70090-0
Yu, J., Astrinidis, A., Howard, S., & Henske, E. P. (2004). Estradiol and tamoxifen stimulate LAM-associated angiomyolipoma cell growth and activate both genomic and nongenomic signaling pathways. American Journal of Physiology. Lung Cellular and Molecular Physiology, 286(4), L694–L700. https://doi.org/10.1152/ajplung.00204.2003
Yu, J. J., Robb, V. A., Morrison, T. A., Ariazi, E. A., Karbowniczek, M., Astrinidis, A., Wang, C., Hernandez-Cuebas, L., Seeholzer, L. F., Nicolas, E., ... Henske, E. P. (2009). Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells. Proceedings of the National Academy of Sciences of the United States of America, 106(8), 2635–2640. https://doi.org/10.1073/pnas.0810790106
Zhang, X., Liu, S., Yang, L., Cheng, C., Wang, H., Hu, D., Zhang, X., Zhang, M., Liu, Y., Tian, X., Zhang, H., & Xu, K. F. (2024). Omics research in lymphangioleiomyomatosis: Status and challenges. Expert Review of Respiratory Medicine, 18(10), 805–814. https://doi.org/10.1080/17476348.2024.2403498
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