{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T04:30:46Z","timestamp":1786595446901,"version":"build-2736575974"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Secondary lower-extremity lymphedema has long been regarded primarily as a disorder of impaired lymphatic fluid return. However, growing evidence indicates that its core pathology is a lymph stasis-driven immune\u2013stromal remodeling process characterized by chronic inflammation, extracellular matrix remodeling, and progressive adipose deposition, which gradually reduces limb reversibility as the disease advances. Yet this mechanistic understanding remains disconnected from clinical therapeutic evaluation. Current endpoints still rely mainly on limb volume, circumference, and the degree of swelling reduction, which are insufficient to quantify fibrosis and adipose remodeling and cannot capture ongoing inflammatory and tissue progression when volume remains unchanged. This may create a misleading appearance of symptomatic improvement while the disease continues to progress toward a late fibroadipose stage, delaying timely referral for lymphaticovenular anastomosis (LVA) or vascularized lymph node transfer (VLNT) and increasing clinical risk. Therefore, we propose the introduction of Inflammation\u2013Fibrosis\u2013Anchored Endpoints (IFAE), which integrate four dimensions beyond volume-based assessment: immune\u2013inflammatory activity, tissue remodeling, lymphatic function, and clinical events. Within this framework, traditional volume-based measures should be downgraded to surrogate indicators of the fluid dimension rather than treated as definitive markers of disease modification. Meanwhile, complete decongestive therapy (CDT) and adjunctive physical therapies should be repositioned as strategies for fluid\u2013symptom management rather than disease-modifying interventions, to avoid equating symptomatic improvement with mechanistic disease control or cure.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1899048","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T04:23:58Z","timestamp":1786595038000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Do not mistake symptomatic improvement for disease modification: therapeutic endpoints in secondary lower-extremity lymphedema require inflammation\u2013fibrosis anchoring"],"prefix":"10.3389","volume":"17","author":[{"given":"Jia-wen","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Orthopedics, The Fourth Hospital of Hebei Medical University","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Na","family":"Jian","sequence":"additional","affiliation":[{"name":"Department of Pain Rehabilitation, The Fourth Hospital of Hebei Medical University","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1097\/PRS.0000000000009866","article-title":"The vicious circle of stasis, inflammation, and fibrosis in lymphedema","volume":"151","author":"Brown","year":"2023","journal-title":"Plast Reconstr Surg"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2025.1666522","article-title":"Advances in etiology, pathophysiology, diagnosis, and management of lymphedema: a comprehensive review","volume":"12","author":"Wu","year":"2025","journal-title":"Front Med (Lausanne)"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.2458\/lymph.6372","article-title":"The diagnosis and treatment of peripheral lymphedema: 2023 consensus document of The International Society of Lymphology","volume":"56","year":"2023","journal-title":"Lymphology"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-024-07298-7","article-title":"Development of a core set of outcome measures to be applied toward breast cancer-related lymphedema core outcome domains","volume":"205","author":"Doubblestein","year":"2024","journal-title":"Breast Cancer Res Treat"},{"key":"B5","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1007\/s12032-024-02472-9","article-title":"Current diagnostic and quantitative techniques in the field of lymphedema management: a critical review","volume":"41","author":"Vargo","year":"2024","journal-title":"Med Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1097\/PRS.0000000000008146","article-title":"Reply: Changing the paradigm: Lymphovenous anastomosis in advanced stage lower extremity lymphedema","volume":"148","author":"Hong","year":"2021","journal-title":"Plast Reconstr Surg"},{"key":"B7","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1089\/lrb.2020.0120","article-title":"Liposuction of breast cancer-related arm lymphedema reduces fat and muscle hypertrophy","volume":"20","author":"Karlsson","year":"2022","journal-title":"Lymphat Res Biol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1007\/s00520-023-07783-7","article-title":"Retrospective study on the trajectories of lower limb volume after outpatient-based complex decongestive therapy in post-operative gynecological cancer patients with lymphedema","volume":"31","author":"Masui","year":"2023","journal-title":"Support Care Cancer"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1080\/09593985.2022.2143252","article-title":"Effects of complex decongestive therapy and aquatic physiotherapy on markers of the inflammatory process in individuals with lymphedema","volume":"40","author":"Cristina de Sousa Pedrosa","year":"2024","journal-title":"Physiother Theory Pract"},{"key":"B10","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1089\/lrb.2021.0036","article-title":"Skin layer thickness and shear wave elastography changes induced by intensive decongestive treatment of lower limb lymphedema","volume":"20","author":"Zarrad","year":"2022","journal-title":"Lymphat Res Biol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1097\/SLA.0000000000006860","article-title":"Improvement of the natural progression of extremity lymphedema treated with lymphatic microsurgery","volume":"282","author":"Pappalardo","year":"2025","journal-title":"Ann Surg"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.00137","article-title":"The unresolved pathophysiology of lymphedema","volume":"11","author":"Azhar","year":"2020","journal-title":"Front Physiol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2024.1363811","article-title":"Molecular pathophysiology of secondary lymphedema","volume":"12","author":"Lee","year":"2024","journal-title":"Front Cell Dev Biol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1136\/ijgc-2019-001032","article-title":"Lower extremity lymphedema in patients with gynecologic malignancies","volume":"30","author":"Dessources","year":"2020","journal-title":"Int J Gynecol Cancer"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2025.1561836","article-title":"Risk factors for lower limb lymphedema after gynecological cancer treatment: a systematic review","volume":"15","author":"Decorte","year":"2025","journal-title":"Front Oncol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"5518","DOI":"10.1038\/s41598-025-90200-2","article-title":"The prognostic effect and mechanism of erysipelas in cancer-associated lymphedema","volume":"15","author":"Li","year":"2025","journal-title":"Sci Rep"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1970","DOI":"10.1038\/s41467-018-04418-y","article-title":"CD4+ T cells are activated in regional lymph nodes and migrate to skin to initiate lymphedema","volume":"9","author":"Garc\u00eda Nores","year":"2018","journal-title":"Nat Commun"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1096\/fj.12-222695","article-title":"Th2 differentiation is necessary for soft tissue fibrosis and lymphatic dysfunction resulting from lymphedema","volume":"27","author":"Avraham","year":"2013","journal-title":"FASEB J"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.758","article-title":"TGF-\u03b21 mediates pathologic changes of secondary lymphedema by promoting fibrosis and inflammation","volume":"12","author":"Baik","year":"2022","journal-title":"Clin Transl Med"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.192890","article-title":"TGF-\u03b2-mediated epithelial-mesenchymal transition of keratinocytes promotes fibrosis in secondary lymphedema","volume":"10","author":"Park","year":"2025","journal-title":"JCI Insight"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3390\/cimb45100507","article-title":"Tryptase-positive mast cells promote adipose fibrosis in secondary lymphedema through PDGF","volume":"45","author":"Nuri","year":"2023","journal-title":"Curr Issues Mol Biol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fsurg.2025.1578436","article-title":"High-frequency ultrasound combined with shear wave elastography to evaluate the efficacy of lymphaticovenular anastomosis in patients with secondary lymphedema","volume":"12","author":"Yu","year":"2025","journal-title":"Front Surg"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.21037\/gs.2020.02.08","article-title":"The basics of ultrasound elastography for diagnosis, assessment, and staging breast cancer-related lymphedema: a systematic review of the literature","volume":"9","author":"Forte","year":"2020","journal-title":"Gland Surg"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1089\/lrb.2021.0099","article-title":"Can tissue stiffness measured using shear-wave elastography represent lymphedema in breast cancer","volume":"20","author":"Lee","year":"2022","journal-title":"Lymphat Res Biol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics12081949","article-title":"Temporal changes in subcutaneous fibrosis in patients with lower extremity lymphedema following surgery for gynecologic cancer: a computed tomography-based quantitative analysis","volume":"12","author":"Lee","year":"2022","journal-title":"Diagnostics (Basel)"},{"key":"B26","doi-asserted-by":"publisher","first-page":"231","DOI":"10.3390\/medicina61020231","article-title":"Predictors of the efficacy of lymphedema decongestive therapy","volume":"61","author":"Dzupina","year":"2025","journal-title":"Medicina (Kaunas)"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2023.1173169","article-title":"Low-intensity pulsed ultrasound reduces lymphedema by regulating macrophage polarization and enhancing microcirculation","volume":"11","author":"Liu","year":"2023","journal-title":"Front Bioeng Biotechnol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.bjpt.2017.03.008","article-title":"Application of shortwave diathermy to lower limb increases arterial blood flow velocity and skin temperature in women: a randomized controlled trial","volume":"21","author":"Sousa","year":"2017","journal-title":"Braz J Phys Ther"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.841641","article-title":"Lymph leakage promotes immunosuppression by enhancing anti-inflammatory macrophage polarization","volume":"13","author":"Herrada","year":"2022","journal-title":"Front Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-025-18598-7","article-title":"Clinical features, microbial epidemiology, and recurrence risk of cellulitis in breast cancer-related lymphedema","volume":"33","author":"Wagner","year":"2026","journal-title":"Ann Surg Oncol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2023.1132097","article-title":"Imaging peripheral lymphatic dysfunction in chronic conditions","volume":"14","author":"Sevick-Muraca","year":"2023","journal-title":"Front Physiol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1097\/PRS.0b013e31820cf5df","article-title":"Characteristic indocyanine green lymphography findings in lower extremity lymphedema: the generation of a novel lymphedema severity staging system using dermal backflow patterns","volume":"127","author":"Yamamoto","year":"2011","journal-title":"Plast Reconstr Surg"},{"key":"B33","doi-asserted-by":"publisher","first-page":"676","DOI":"10.3390\/cancers15030676","article-title":"Plasma cytokines\/chemokines as predictive biomarkers for lymphedema in breast cancer patients","volume":"15","author":"Vang","year":"2023","journal-title":"Cancers (Basel)"},{"key":"B34","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1177\/1358863X231215329","article-title":"Advances in lymphedema: An under-recognized disease with a hopeful future for patients","volume":"29","author":"Carroll","year":"2024","journal-title":"Vasc Med"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1158\/2767-9764.CRC-25-0541","article-title":"Identification of a cytokine biomarker for prognostic modeling of breast cancer-related lymphedema","volume":"6","author":"Wu","year":"2026","journal-title":"Cancer Res Commun"},{"key":"B36","doi-asserted-by":"publisher","first-page":"6621","DOI":"10.3390\/ijms23126621","article-title":"Current mechanistic understandings of lymphedema and lipedema: Tales of fluid, fat, and fibrosis","volume":"23","author":"Duhon","year":"2022","journal-title":"Int J Mol Sci"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1899048\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T04:23:59Z","timestamp":1786595039000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1899048\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,13]]},"references-count":36,"alternative-id":["10.3389\/fimmu.2026.1899048"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1899048","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,13]]},"article-number":"1899048"}}