Ryan Becka

Background: Secondary lymphedema is a chronic, progressive disorder caused by lymphatic injury or obstruction and is most commonly associated with cancer surgery and radiation therapy in developed countries.^1,2,3,4 It is characterized by impaired lymphatic drainage, protein-rich interstitial fluid accumulation, chronic inflammation, adipose deposition, and fibrosis.^1,2,3,4 Current treatment consists largely of palliative measures such as compression, manual lymphatic drainage, exercise, and skin care; while surgical approaches such as lymphovenous bypass and vascularized lymph node transfer remain limited by incomplete long-term restoration of lymphatic function.^1,3,4 Research suggests that postsurgical secondary lymphedema is not simply a mechanical drainage disorder, but rather a biologically active disease of failed lymphatic regeneration marked by lymphatic stasis, immune-cell infiltration, fibrosis, and loss of functional lymphatic networks.^2,3,4 These findings have created interest in therapies that target the underlying regenerative defect rather than only symptom control.

Objective: In this narrative literature review, I explored the molecular and cellular mechanisms underlying postsurgical secondary lymphedema and examined the therapeutic rationale for dual targeting of lymphatic regeneration with 9-cis-retinoic acid (9-cis-RA) and vascular endothelial growth factor-C (VEGF-C).

Search Methods: An online search of the PubMed database was performed using combinations of the following keywords and MeSH terms: “secondary lymphedema,” “postsurgical lymphedema,” “lymphangiogenesis,” “9-cis-retinoic acid,” “RXR alpha,” “VEGF-C,” “VEGFR3,” “Prox1,” and “lymphatic regeneration.” Priority was given to review articles providing clinical and mechanistic background and to primary studies evaluating translational therapeutic strategies in experimental and human lymphedema. A customized search was used to extract publications from 2018 – 2026.

Results: Review studies demonstrated that lymphatic injury produces lymphatic stasis, which then drives chronic inflammation, CD4+ T-cell recruitment, Th2 cytokine signaling, fibrosis, adipocyte hypertrophy, and progressive loss of functional lymphatic vessels.^1,2,3,4 Mechanistic studies showed that 9-cis-RA promotes lymphangiogenesis at sites of lymphatic injury and that its therapeutic effect depends on retinoid X receptor alpha (RXRα) signaling in lymphatic endothelial cells.^5,6 Sustained local delivery of 9-cis-RA reduced swelling, improved lymphatic clearance, and preserved lymphatic architecture in murine postsurgical lymphedema models, supporting its role as an early perioperative conditioning therapy.^5,6,7 In contrast, VEGF-C functioned as a direct downstream lymphangiogenic signal. Nucleoside-modified VEGF-C mRNA induced organ-specific lymphatic growth, restored tracer transport, and reversed established experimental lymphedema.⁸ A phase 1 clinical study further demonstrated that adenoviral VEGF-C combined with vascularized lymph node transfer improved excess arm volume and quality of life in breast cancer-related lymphedema patients.¹⁰ Additional evidence from Prox1-based tissue nanotransfection suggested that upstream transcriptional programming may further improve the durability and organization of regenerative responses.⁹

Conclusion: Postsurgical secondary lymphedema is best understood as a disease of failed lymphatic regeneration after injury. The literature suggests that 9-cis-RA and VEGF-C target different but complementary levels of this process, with 9-cis-RA acting upstream to improve lymphatic endothelial regenerative competence and VEGF-C acting downstream to drive functional network rebuilding.^5,6,7,8,9,10 Together, these findings support a stage-specific or combination therapeutic model in which early pharmacologic conditioning is paired with later regenerative lymphangiogenesis to improve prevention and treatment of secondary lymphedema. Future studies should directly test combination therapy and determine whether coordinated expansion of both initial and collecting lymphatic vessels can produce more durable restoration of lymphatic function.

References

1. Bowman C, Rockson SG. The role of inflammation in lymphedema: a narrative review of pathogenesis and opportunities for therapeutic intervention. Int J Mol Sci. 2024;25(7):3907. doi:10.3390/ijms25073907
2. Hossain L, Gomes KP, Safarpour S, Gibson SB. The microenvironment of secondary lymphedema. The key to finding effective treatments? Biochim Biophys Acta Mol Basis Dis. 2025;1871(3):167677. doi:10.1016/j.bbadis.2025.167677
3. Lee SO, Kim IK. Molecular pathophysiology of secondary lymphedema. Front Cell Dev Biol. 2024;12:1363811. doi:10.3389/fcell.2024.1363811
4. Sung C, Wang S, Hsu J, Yu R, Wong AK. Current understanding of pathological mechanisms of lymphedema. Adv Wound Care (New Rochelle). 2022;11(7):361-373. doi:10.1089/wound.2021.0041
5. Lee GK, Perrault DP, Bouz A, et al. Prolymphangiogenic effects of 9-cis retinoic acid are enhanced at sites of lymphatic injury and dependent on treatment duration in experimental postsurgical lymphedema. Lymphat Res Biol. 2022;20(6):640-650. doi:10.1089/lrb.2021.0073
6. Sung C, Jiao W, Park SY, et al. Lymphatic endothelial cell RXRα is critical for 9-cis-retinoic acid-mediated lymphangiogenesis and prevention of secondary lymphedema. FASEB J. 2023;37(1):e22674. doi:10.1096/fj.202200146RR
7. Daneshgaran G, Paik CB, Cooper MN, et al. Prevention of postsurgical lymphedema via immediate delivery of sustained-release 9-cis retinoic acid to the lymphedenectomy site. J Surg Oncol. 2020;121(1):100-108. doi:10.1002/jso.25587
8. Szőke D, Kovács G, Kemecsei É, et al. Nucleoside-modified VEGFC mRNA induces organ-specific lymphatic growth and reverses experimental lymphedema. Nat Commun. 2021;12(1):3460. doi:10.1038/s41467-021-23546-6
9. Mohan G, Khan I, Neumann CR, et al. Topical tissue nanotransfection of Prox1 is effective in the prophylactic management of lymphedema. Mol Ther Nucleic Acids. 2024;35(1):102121. doi:10.1016/j.omtn.2024.102121
10. Leppäpuska IM, Hartiala P, Suominen S, et al. Phase 1 Lymfactin® study: 24-month efficacy and safety results of combined adenoviral VEGF-C and lymph node transfer treatment for upper extremity lymphedema. J Plast Reconstr Aesthet Surg. 2022;75(11):3938-3945. doi:10.1016/j.bjps.2022.08.011