New and Emerging Treatments for Lymphedema

Abstract

Although nonoperative and operative treatments for lymphedema (LE) are well established, these procedures typically provide only partial relief from limb swelling, functional impairment, and the risk of cellulitis. The lack of a cure for LE, however, is due to an incomplete understanding of the underlying pathophysiological mechanisms, and current research efforts are focusing on elucidating these processes to provide new, targeted therapies for this prevalent disease for which there is no cure. This article reviews the current literature regarding the pathophysiological mechanisms that underlie LE, as well as new and emerging therapies for the condition.

Keywords

lymphedema - treatment - therapies - inflammation

• References

• 1 Shaitelman SF, Chiang YJ, Griffin KD. , et al. Radiation therapy targets and the risk of breast cancer-related lymphedema: a systematic review and network meta-analysis. Breast Cancer Res Treat 2017; 162 (02) 201-215
• 2 Rutkowski JM, Swartz MA. A driving force for change: interstitial flow as a morphoregulator. Trends Cell Biol 2007; 17 (01) 44-50
• 3 Mihara M, Hara H, Hayashi Y. , et al. Pathological steps of cancer-related lymphedema: histological changes in the collecting lymphatic vessels after lymphadenectomy. PLoS One 2012; 7 (07) e41126
• 4 Olszewski WL, Jamal S, Manokaran G, Lukomska B, Kubicka U. Skin changes in filarial and non-filarial lymphoedema of the lower extremities. Trop Med Parasitol 1993; 44 (01) 40-44
• 5 Zampell JC, Yan A, Elhadad S, Avraham T, Weitman E, Mehrara BJ. CD4(+) cells regulate fibrosis and lymphangiogenesis in response to lymphatic fluid stasis. PLoS One 2012; 7 (11) e49940
• 6 Suami H, Pan WR, Taylor GI. Changes in the lymph structure of the upper limb after axillary dissection: radiographic and anatomical study in a human cadaver. Plast Reconstr Surg 2007; 120 (04) 982-991
• 7 Avraham T, Daluvoy S, Zampell J. , et al. Blockade of transforming growth factor-beta1 accelerates lymphatic regeneration during wound repair. Am J Pathol 2010; 177 (06) 3202-3214
• 8 Ly CL, Kataru RP, Mehrara BJ. Inflammatory Manifestations of lymphedema. Int J Mol Sci 2017; 18 (01) E171
• 9 Kataru RP, Kim H, Jang C. , et al. T lymphocytes negatively regulate lymph node lymphatic vessel formation. Immunity 2011; 34 (01) 96-107
• 10 Zampell JC, Avraham T, Yoder N. , et al. Lymphatic function is regulated by a coordinated expression of lymphangiogenic and anti-lymphangiogenic cytokines. Am J Physiol Cell Physiol 2012; 302 (02) C392-C404
• 11 Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol 2008; 214 (02) 199-210
• 12 Gousopoulos E, Proulx ST, Scholl J, Uecker M, Detmar M. Prominent lymphatic vessel hyperplasia with progressive dysfunction and distinct immune cell infiltration in lymphedema. Am J Pathol 2016; 186 (08) 2193-2203
• 13 Gardenier JC, Kataru RP, Hespe GE. , et al. Topical tacrolimus for the treatment of secondary lymphedema. Nat Commun 2017; 8: 14345
• 14 Avraham T, Zampell JC, Yan A. , et al. Th2 differentiation is necessary for soft tissue fibrosis and lymphatic dysfunction resulting from lymphedema. FASEB J 2013; 27 (03) 1114-1126
• 15 Savetsky IL, Ghanta S, Gardenier JC. , et al. Th2 cytokines inhibit lymphangiogenesis. PLoS One 2015; 10 (06) e0126908
• 16 Shin K, Kataru RP, Park HJ. , et al. TH2 cells and their cytokines regulate formation and function of lymphatic vessels. Nat Commun 2015; 6: 6196
• 17 Gousopoulos E, Proulx ST, Bachmann SB. , et al. Regulatory T cell transfer ameliorates lymphedema and promotes lymphatic vessel function. JCI Insight 2016; 1 (16) e89081
• 18 García Nores GD, Ly CL, Savetsky IL. , et al. T-regulatory cells mediate local immunosuppression in lymphedema. J Invest Dermatol 2017; S0022-202X(17)32961-5
• 19 Clavin NW, Avraham T, Fernandez J. , et al. TGF-beta1 is a negative regulator of lymphatic regeneration during wound repair. Am J Physiol Heart Circ Physiol 2008; 295 (05) H2113-H2127
• 20 Gardenier JC, Hespe GE, Kataru RP. , et al. Diphtheria toxin-mediated ablation of lymphatic endothelial cells results in progressive lymphedema. JCI Insight 2016; 1 (15) e84095
• 21 Harvey NL, Srinivasan RS, Dillard ME. , et al. Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity. Nat Genet 2005; 37 (10) 1072-1081
• 22 Cuzzone DA, Weitman ES, Albano NJ. , et al. IL-6 regulates adipose deposition and homeostasis in lymphedema. Am J Physiol Heart Circ Physiol 2014; 306 (10) H1426-H1434
• 23 Scallan JP, Zawieja SD, Castorena-Gonzalez JA, Davis MJ. Lymphatic pumping: mechanics, mechanisms and malfunction. J Physiol 2016; 594 (20) 5749-5768
• 24 Torrisi JS, Hespe GE, Cuzzone DA. , et al. Inhibition of inflammation and iNOS improves lymphatic function in obesity. Sci Rep 2016; 6: 19817
• 25 Cintolesi V, Stanton AW, Bains SK. , et al. Constitutively enhanced lymphatic pumping in the upper limbs of women who later develop breast cancer-related lymphedema. Lymphat Res Biol 2016; 14 (02) 50-61
• 26 Liao S, Cheng G, Conner DA. , et al. Impaired lymphatic contraction associated with immunosuppression. Proc Natl Acad Sci U S A 2011; 108 (46) 18784-18789
• 27 Rutkowski JM, Moya M, Johannes J, Goldman J, Swartz MA. Secondary lymphedema in the mouse tail: Lymphatic hyperplasia, VEGF-C upregulation, and the protective role of MMP-9. Microvasc Res 2006; 72 (03) 161-171
• 28 Ghanta S, Cuzzone DA, Torrisi JS. , et al. Regulation of inflammation and fibrosis by macrophages in lymphedema. Am J Physiol Heart Circ Physiol 2015; 308 (09) H1065-H1077
• 29 Ogata F, Fujiu K, Matsumoto S. , et al. Excess lymphangiogenesis cooperatively induced by macrophages and CD4(+) T cells drives the pathogenesis of lymphedema. J Invest Dermatol 2016; 136 (03) 706-714
• 30 Zampell JC, Elhadad S, Avraham T. , et al. Toll-like receptor deficiency worsens inflammation and lymphedema after lymphatic injury. Am J Physiol Cell Physiol 2012; 302 (04) C709-C719
• 31 Tian W, Rockson SG, Jiang X. , et al. Leukotriene B4 antagonism ameliorates experimental lymphedema. Sci Transl Med 2017; 9 (389) 3920
• 32 Peters-Golden M, Henderson Jr WR. Leukotrienes. N Engl J Med 2007; 357 (18) 1841-1854
• 33 Nakamura K, Radhakrishnan K, Wong YM, Rockson SG. Anti-inflammatory pharmacotherapy with ketoprofen ameliorates experimental lymphatic vascular insufficiency in mice. PLoS One 2009; 4 (12) e8380
• 34 Jiang X, Nicolls MR, Tian W, Rockson SG. Lymphatic dysfunction, leukotrienes, and lymphedema. Annu Rev Physiol 2017
• 35 Aldrich MB, Guilliod R, Fife CE. , et al. Lymphatic abnormalities in the normal contralateral arms of subjects with breast cancer-related lymphedema as assessed by near-infrared fluorescent imaging. Biomed Opt Express 2012; 3 (06) 1256-1265
• 36 Bains SK, Peters AM, Zammit C. , et al. Global abnormalities in lymphatic function following systemic therapy in patients with breast cancer. Br J Surg 2015; 102 (05) 534-540
• 37 Burnand KM, Glass DM, Mortimer PS, Peters AM. Lymphatic dysfunction in the apparently clinically normal contralateral limbs of patients with unilateral lower limb swelling. Clin Nucl Med 2012; 37 (01) 9-13
• 38 Pain SJ, Barber RW, Ballinger JR. , et al. Local vascular access of radioprotein injected subcutaneously in healthy subjects and patients with breast cancer-related lymphedema. J Nucl Med 2004; 45 (05) 789-796
• 39 Pain SJ, Purushotham AD, Barber RW. , et al. Variation in lymphatic function may predispose to development of breast cancer-related lymphoedema. Eur J Surg Oncol 2004; 30 (05) 508-514
• 40 Hanley CA, Elias RM, Movat HZ, Johnston MG. Suppression of fluid pumping in isolated bovine mesenteric lymphatics by interleukin-1: interaction with prostaglandin E2. Microvasc Res 1989; 37 (02) 218-229
• 41 Wee JL, Greenwood DL, Han X, Scheerlinck JP. Inflammatory cytokines IL-6 and TNF-α regulate lymphocyte trafficking through the local lymph node. Vet Immunol Immunopathol 2011; 144 (1-2): 95-103
• 42 Baluk P, Yao LC, Feng J. , et al. TNF-alpha drives remodeling of blood vessels and lymphatics in sustained airway inflammation in mice. J Clin Invest 2009; 119 (10) 2954-2964
• 43 Aldrich MB, Sevick-Muraca EM. Cytokines are systemic effectors of lymphatic function in acute inflammation. Cytokine 2013; 64 (01) 362-369
• 44 Chen Y, Rehal S, Roizes S, Zhu HL, Cole WC, von der Weid PY. The pro-inflammatory cytokine TNF-alpha inhibits lymphatic pumping via activation of the NF-kB-iNOS signaling pathway. Microcirculation 2017;
• 45 Conrad C, Niess H, Huss R. , et al. Multipotent mesenchymal stem cells acquire a lymphendothelial phenotype and enhance lymphatic regeneration in vivo. Circulation 2009; 119 (02) 281-289
• 46 Hou C, Wu X, Jin X. 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 2008; 38 (10) 670-674
• 47 Maldonado GE, Pérez CA, Covarrubias EE. , et al. Autologous stem cells for the treatment of post-mastectomy lymphedema: a pilot study. Cytotherapy 2011; 13 (10) 1249-1255
• 48 Toyserkani NM, Jensen CH, Andersen DC, Sheikh SP, Sørensen JA. Treatment of breast cancer-related lymphedema with adipose-derived regenerative cells and fat grafts: a feasibility and safety study. Stem Cells Transl Med 2017; 6 (08) 1666-1672
• 49 Vandermeeren L, Belgrado JP, Vankerckhove S. , et al. Lipofilling of the axilla to reduce secondary lymphedema after axillary lymph node dissection. Eur J Cancer 2016; 57 (Suppl. 02) 72
• 50 Hayashida K, Yoshida S, Yoshimoto H. , et al. Adipose-derived stem cells and vascularized lymph node transfers successfully treat mouse hindlimb secondary lymphedema by early reconnection of the lymphatic system and lymphangiogenesis. Plast Reconstr Surg 2017; 139 (03) 639-651
• 51 Baker A, Kim H, Semple JL. , et al. Experimental assessment of pro-lymphangiogenic growth factors in the treatment of post-surgical lymphedema following lymphadenectomy. Breast Cancer Res 2010; 12 (05) R70
• 52 Hartiala P, Saarikko AM. Lymphangiogenesis and lymphangiogenic growth factors. J Reconstr Microsurg 2016; 32 (01) 10-15
• 53 Tervala TV, Hartiala P, Tammela T. , et al. Growth factor therapy and lymph node graft for lymphedema. J Surg Res 2015; 196 (01) 200-207
• 54 Viitanen TP, Visuri MT, Sulo E, Saarikko AM, Hartiala P. Anti-inflammatory effects of flap and lymph node transfer. J Surg Res 2015; 199 (02) 718-725
• 55 Skobe M, Hawighorst T, Jackson DG. , et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 2001; 7 (02) 192-198
• 56 Shiao SL, Ganesan AP, Rugo HS, Coussens LM. Immune microenvironments in solid tumors: new targets for therapy. Genes Dev 2011; 25 (24) 2559-2572
• 57 Miller KD, Brown C, Perkins SM, Schneider BP, Storniolo A, Sledge GW. A pilot study of vascular endothelial growth factor inhibition with pazopanib in patients (pts) with lymphedema following breast cancer treatment. Cancer Res 2010; 70 (Suppl. 24) P2-14-02
• 58 Handley WS. Two Cases of Lymphangioplasty for the brawny arm of breast cancer. Proc R Soc Med 1908; 1 (Clin Sect): 186-190
• 59 Silver D, Puckett CL. Lymphangioplasty: a ten year evaluation. Surgery 1976; 80 (06) 748-755
• 60 Olszewski WL, Zaleska M. Treatment of postmastectomy lymphedema by bypassing the armpit with implanted silicone tubings. Int Angiol 2017; 36 (01) 50-58
• 61 Hadamitzky C, Zaitseva TS, Bazalova-Carter M. , et al. Aligned nanofibrillar collagen scaffolds – guiding lymphangiogenesis for treatment of acquired lymphedema. Biomaterials 2016; 102: 259-267
• 62 Kanapathy M, Patel NM, Kalaskar DM, Mosahebi A, Mehrara BJ, Seifalian AM. Tissue-engineered lymphatic graft for the treatment of lymphedema. J Surg Res 2014; 192 (02) 544-554
• 63 Kanapathy M, Kalaskar D, Mosahebi A, Seifalian AM. Development of a tissue-engineered lymphatic graft using nanocomposite polymer for the treatment of secondary lymphedema. Artif Organs 2016; 40 (03) E1-E11
• 64 Huang NF, Okogbaa J, Lee JC. , et al. The modulation of endothelial cell morphology, function, and survival using anisotropic nanofibrillar collagen scaffolds. Biomaterials 2013; 34 (16) 4038-4047
• 65 Nakayama KH, Hong G, Lee JC. , et al. Aligned-braided nanofibrillar scaffold with endothelial cells enhances arteriogenesis. ACS Nano 2015; 9 (07) 6900-6908