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Annual Review of Medicine

Volume 69, 2018

Lymphedema: Pathogenesis and Novel Therapies

Abstract

Lymphedema affects up to 1 in 6 patients who undergo treatment for a solid tumor in the United States. Its prevalence has increased as more effective oncologic therapies have improved patient survival, but there remains no definitive cure. Recent research has elucidated new details in the pathogenesis of the disease and has demonstrated that it is fundamentally an immunologic process that ultimately results in inflammation, fibroadipose deposition, impaired lymphangiogenesis, and dysfunctional lymphatic pumping. These findings have allowed for the development of novel medical and surgical therapies that may potentially alter the standard of care for a disease that has largely been treated by compression. This review seeks to provide an overview of the emerging therapies and how they can be utilized for effective management of lymphedema.

Keyword(s): CD4+ cells, complete decongestive therapy, lymph node transfer, lymphovenous bypass
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2018-01-29
2024-04-18
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Literature Cited

  1. Petrek JA, Heelan MC. 1.  1998. Incidence of breast carcinoma-related lymphedema. Cancer 83:2776–81 [Google Scholar]
  2. Cormier JN, Askew RL, Mungovan KS. 2.  et al. 2010. Lymphedema beyond breast cancer: a systematic review and meta-analysis of cancer-related secondary lymphedema. Cancer 116:5138–49 [Google Scholar]
  3. Olszewski WL, Jamal S, Manokaran G. 3.  et al. 1993. Skin changes in filarial and non-filarial lymphoedema of the lower extremities. Trop. Med. Parasitol 44:40–44 [Google Scholar]
  4. Brorson H, Hoijer P. 4.  2012. Standardised measurements used to order compression garments can be used to calculate arm volumes to evaluate lymphoedema treatment. J. Plast. Surg. Hand Surg. 46:410–15 [Google Scholar]
  5. Armer JM, Stewart BR. 5.  2005. A comparison of four diagnostic criteria for lymphedema in a post-breast cancer population. Lymphat. Res. Biol. 3:208–17 [Google Scholar]
  6. Ward LC. 6.  2006. Bioelectrical impedance analysis: proven utility in lymphedema risk assessment and therapeutic monitoring. Lymphat. Res. Biol. 4:51–56 [Google Scholar]
  7. Karacavus S, Yilmaz YK, Ekim H. 7.  2015. Clinical significance of lymphoscintigraphy findings in the evaluation of lower extremity lymphedema. Mol. Imag. Radionucl. Ther. 24:80–84 [Google Scholar]
  8. Mihara M, Hara H, Hayashi Y. 8.  et al. 2012. Pathological steps of cancer-related lymphedema: histological changes in the collecting lymphatic vessels after lymphadenectomy. PLOS ONE 7:e41126 [Google Scholar]
  9. Liu N, Wang C, Sun M. 9.  2005. Noncontrast three-dimensional magnetic resonance imaging vs lymphoscintigraphy in the evaluation of lymph circulation disorders: a comparative study. J. Vasc. Surgery 41:69–75 [Google Scholar]
  10. Sevick-Muraca EM, Kwon S, Rasmussen JC. 10.  2014. Emerging lymphatic imaging technologies for mouse and man. J. Clin. Investig. 124:905–14 [Google Scholar]
  11. Bernas MJ, Witte CL, Witte MH. 11.  2001. The diagnosis and treatment of peripheral lymphedema: draft revision of the 1995 Consensus Document of the International Society of Lymphology Executive Committee for discussion at the September 3–7, 2001, XVIII International Congress of Lymphology in Genoa, Italy. Lymphology 34:84–91 [Google Scholar]
  12. Kwan ML, Darbinian J, Schmitz KH. 12.  et al. 2010. Risk factors for lymphedema in a prospective breast cancer survivorship study: the Pathways Study. Arch. Surg. 145:1055–63 [Google Scholar]
  13. Abu-Rustum NR, Alektiar K, Iasonos A. 13.  et al. 2006. The incidence of symptomatic lower-extremity lymphedema following treatment of uterine corpus malignancies: a 12-year experience at Memorial Sloan-Kettering Cancer Center. Gynecol. Oncol. 103:714–18 [Google Scholar]
  14. Ryan M, Stainton MC, Slaytor EK. 14.  et al. 2003. Aetiology and prevalence of lower limb lymphoedema following treatment for gynaecological cancer. Aust. NZ J. Obstet. Gynaecol. 43:148–51 [Google Scholar]
  15. Zampell JC, Yan A, Elhadad S. 15.  et al. 2012. CD4+ cells regulate fibrosis and lymphangiogenesis in response to lymphatic fluid stasis. PLOS ONE 7:e49940 [Google Scholar]
  16. Gardenier JC, Kataru RP, Hespe GE. 16.  et al. 2017. Topical tacrolimus for the treatment of secondary lymphedema. Nat. Commun. 8:14345 [Google Scholar]
  17. Avraham T, Zampell JC, Yan A. 17.  et al. 2013. Th2 differentiation is necessary for soft tissue fibrosis and lymphatic dysfunction resulting from lymphedema. FASEB J 27:1114–26 [Google Scholar]
  18. Wynn TA. 18.  2008. Cellular and molecular mechanisms of fibrosis. J. Pathol. 214:199–210 [Google Scholar]
  19. Shiao SL, Ganesan AP, Rugo HS, Coussens LM. 19.  2011. Immune microenvironments in solid tumors: new targets for therapy. Genes Dev 25:2559–72 [Google Scholar]
  20. Skobe M, Hawighorst T, Jackson DG. 20.  et al. 2001. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat. Med. 7:192–98 [Google Scholar]
  21. Savetsky IL, Ghanta S, Gardenier JC. 21.  et al. 2015. Th2 cytokines inhibit lymphangiogenesis. PLOS ONE 10:e0126908 [Google Scholar]
  22. Rutkowski JM, Moya M, Johannes J. 22.  et al. 2006. Secondary lymphedema in the mouse tail: lymphatic hyperplasia, VEGF-C upregulation, and the protective role of MMP-9. Microvasc. Res. 72:161–71 [Google Scholar]
  23. McLaughlin SA, Wright MJ, Morris KT. 23.  et al. 2008. Prevalence of lymphedema in women with breast cancer 5 years after sentinel lymph node biopsy or axillary dissection: objective measurements. J. Clin. Oncol. 26:5213–19 [Google Scholar]
  24. Werner RS, McCormick B, Petrek J. 24.  et al. 1991. Arm edema in conservatively managed breast cancer: obesity is a major predictive factor. Radiology 180:177–84 [Google Scholar]
  25. Escobedo N, Proulx ST, Karaman S. 25.  et al. 2016. Restoration of lymphatic function rescues obesity in Prox1-haploinsufficient mice. JCI Insight 1:e85096 [Google Scholar]
  26. Garcia Nores GD, Cuzzone DA, Albano NJ. 26.  et al. 2016. Obesity but not high-fat diet impairs lymphatic function. Int. J. Obes. 40:1582–90 [Google Scholar]
  27. Shaw C, Mortimer P, Judd PA. 27.  2007. A randomized controlled trial of weight reduction as a treatment for breast cancer-related lymphedema. Cancer 110:1868–74 [Google Scholar]
  28. Kwan ML, Cohn JC, Armer JM. 28.  et al. 2011. Exercise in patients with lymphedema: a systematic review of the contemporary literature. J. Cancer Surviv. 5:320–36 [Google Scholar]
  29. Lasinski BB. 29.  2013. Complete decongestive therapy for treatment of lymphedema. Semin. Oncol. Nurs. 29:20–27 [Google Scholar]
  30. Feldman JL, Stout NL, Wanchai A. 30.  et al. 2012. Intermittent pneumatic compression therapy: a systematic review. Lymphology 45:13–25 [Google Scholar]
  31. Shao Y, Qi K, Zhou QH, Zhong DS. 31.  2014. Intermittent pneumatic compression pump for breast cancer-related lymphedema: a systematic review and meta-analysis of randomized controlled trials. Oncol. Res. Treat. 37:170–74 [Google Scholar]
  32. Smoot B, Chiavola-Larson L, Lee J. 32.  et al. 2015. Effect of low-level laser therapy on pain and swelling in women with breast cancer-related lymphedema: a systematic review and meta-analysis. J. Cancer Surviv. 9:287–304 [Google Scholar]
  33. Assis L, Moretti AI, Abrahao TB. 33.  et al. 2013. Low-level laser therapy (808 nm) contributes to muscle regeneration and prevents fibrosis in rat tibialis anterior muscle after cryolesion. Lasers Med. Sci 28:947–55 [Google Scholar]
  34. Hou C, Wu X, Jin X. 34.  2008. Autologous bone marrow stromal cells transplantation for the treatment of secondary arm lymphedema: a prospective controlled study in patients with breast cancer related lymphedema. Jpn. J. Clin. Oncol. 38:670–74 [Google Scholar]
  35. Maldonado GE, Perez CA, Covarrubias EE. 35.  et al. 2011. Autologous stem cells for the treatment of post-mastectomy lymphedema: a pilot study. Cytotherapy 13:1249–55 [Google Scholar]
  36. Toyserkani NM, Jensen CH, Sheikh SP, Sorensen JA. 36.  2016. Cell-assisted lipotransfer using autologous adipose-derived stromal cells for alleviation of breast cancer-related lymphedema. Stem Cells Transl. Med. 5:857–59 [Google Scholar]
  37. Conrad C, Niess H, Huss R. 37.  et al. 2009. Multipotent mesenchymal stem cells acquire a lymphendothelial phenotype and enhance lymphatic regeneration in vivo. Circulation 119:281–89 [Google Scholar]
  38. Baker A, Kim H, Semple JL. 38.  et al. 2010. Experimental assessment of pro-lymphangiogenic growth factors in the treatment of post-surgical lymphedema following lymphadenectomy. Breast Cancer Res 12:R70 [Google Scholar]
  39. Hartiala P, Saarikko AM. 39.  2016. Lymphangiogenesis and lymphangiogenic growth factors. J. Reconstr. Microsurg. 32:10–15 [Google Scholar]
  40. Brorson H, Svensson H. 40.  1998. Liposuction combined with controlled compression therapy reduces arm lymphedema more effectively than controlled compression therapy alone. Plast. Reconstr. Surg. 102:1058–67 [Google Scholar]
  41. Carl HM, Walia G, Bello R. 41.  et al. 2017. Systematic review of the surgical treatment of extremity lymphedema. J. Reconstr. Microsurg. 33:412–25 [Google Scholar]
  42. Chang DW, Suami H, Skoracki R. 42.  2013. A prospective analysis of 100 consecutive lymphovenous bypass cases for treatment of extremity lymphedema. Plast. Reconstr. Surg. 132:1305–14 [Google Scholar]
  43. Campisi CC, Ryan M, Boccardo F, Campisi C. 43.  2016. A single-site technique of multiple lymphatic-venous anastomoses for the treatment of peripheral lymphedema: long-term clinical outcome. J. Reconstr. Microsurg. 32:42–49 [Google Scholar]
  44. Campisi C, Davini D, Bellini C. 44.  et al. 2006. Lymphatic microsurgery for the treatment of lymphedema. Microsurgery 26:65–69 [Google Scholar]
  45. Chang DW. 45.  2010. Lymphaticovenular bypass for lymphedema management in breast cancer patients: a prospective study. Plast. Reconstr. Surg. 126:752–58 [Google Scholar]
  46. Boccardo F, Casabona F, De Cian F. 46.  et al. 2014. Lymphatic microsurgical preventing healing approach (LYMPHA) for primary surgical prevention of breast cancer-related lymphedema: over 4 years follow-up. Microsurgery 34:421–24 [Google Scholar]
  47. Feldman S, Bansil H, Ascherman J. 47.  et al. 2015. Single institution experience with lymphatic microsurgical preventive healing approach (LYMPHA) for the primary prevention of lymphedema. Ann. Surg. Oncol. 22:3296–301 [Google Scholar]
  48. Boccardo F, Valenzano M, Costantini S. 48.  et al. 2016. LYMPHA technique to prevent secondary lower limb lymphedema. Ann. Surg. Oncol. 23:3558–63 [Google Scholar]
  49. Aschen SZ, Farias-Eisner G, Cuzzone DA. 49.  et al. 2014. Lymph node transplantation results in spontaneous lymphatic reconnection and restoration of lymphatic flow. Plast. Reconstr. Surg. 133:301–10 [Google Scholar]
  50. Raju A, Chang DW. 50.  2015. Vascularized lymph node transfer for treatment of lymphedema: a comprehensive literature review. Ann. Surg. 261:1013–23 [Google Scholar]
  51. Scaglioni MF, Arvanitakis M, Chen YC. 51.  et al. 2016. Comprehensive review of vascularized lymph node transfers for lymphedema: outcomes and complications. Microsurgery In press. https://doi.org/10.1002/micr.30079 [Crossref]
  52. Dayan JH, Dayan E, Smith ML. 52.  2015. Reverse lymphatic mapping: a new technique for maximizing safety in vascularized lymph node transfer. Plast. Reconstr. Surg. 135:277–85 [Google Scholar]
  53. Nguyen AT, Suami H, Hanasono MM. 53.  et al. 2017. Long-term outcomes of the minimally invasive free vascularized omental lymphatic flap for the treatment of lymphedema. J. Surg. Oncol. 115:84–89 [Google Scholar]
  54. Cuzzone DA, Albano NJ, Aschen SZ. 54.  et al. 2015. Decellularized lymph nodes as scaffolds for tissue engineered lymph nodes. Lymphat. Res. Biol. 13:186–94 [Google Scholar]
  55. Ozturk CN, Ozturk C, Glasgow M. 55.  et al. 2016. Free vascularized lymph node transfer for treatment of lymphedema: a systematic evidence based review. J. Plast. Reconstr. Aesthet. Surg. 69:1234–47 [Google Scholar]
/content/journals/10.1146/annurev-med-060116-022900
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Lymphedema: Pathogenesis and Novel Therapies
Annual Review of Medicine 69, 263 (2018); https://doi.org/10.1146/annurev-med-060116-022900
/content/journals/10.1146/annurev-med-060116-022900
/content/journals/10.1146/annurev-med-060116-022900
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  • Article Type: Review Article

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