Advertisement

The Diagnostic Approach to Lymphedema: a Review of Current Modalities and Future Developments

  • Anjali C. Raghuram
  • Roy P. Yu
  • Cynthia Sung
  • Sherry Huang
  • Alex K. WongEmail author
Hot Topics in Breast Cancer (K Hunt, Section Editor)
  • 19 Downloads
Part of the following topical collections:
  1. Topical Collection on Hot Topics in Breast Cancer

Abstract

Purpose of Review

Breast cancer–related lymphedema (BCRL) is a chronic disease that results from a disruption or obstruction in the lymphatic system and affects 15 in 100 individuals in the USA with newly diagnosed breast cancer. As no curative therapy exists for lymphedema, early detection is crucial in order to reduce the risk of developing late stage symptoms, such as swelling, decreased limb flexibility, disfigurement, and impaired function of the extremity. The objective of this review is to discuss current modalities and devices as well as highlight promising advancements intended to aid in diagnosing secondary lymphedema in breast cancer patients.

Recent Findings

Imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) can offer high resolution of the lymphatics but are expensive and time-consuming. Single photon emission computed tomography (SPECT) is an alternative that reveals organ function as opposed to organ structure. Other imaging methods, such as color duplex ultrasound (CDU), laser scanner 3D (LS3D), and dual-energy X-ray absorptiometry (DXA), are relatively easy to use, reproducible, and fast to perform. However, the disadvantages of these techniques include lower sensitivity and specificity compared with CT and MRI. Of note, direct imaging techniques are highly effective for the diagnosis of lymphedema because they utilize dyes or radiotracers in order to directly visualize lymphatic vessels. Fluorescent microlymphography (FMLG) and near-infrared imaging (NIR) involve injection of fluorescent dyes that can be excited with light. Lymphoscintigraphy has effectively replaced lymphangiography as the method of choice for the diagnosis of lymphedema because it is safer, less invasive, and has no risk of causing an allergic reaction in patients. Novel approaches that are currently in development include bioimpedance spectroscopy, ultra-high-frequency ultrasound systems (UHFUS), and magnetic resonance lymphography (MRL).

Summary

The wide range of diagnostic methods for BCRL exhibit the tradeoff between simplicity and sensitivity; some techniques provide high resolution but are expensive and time consuming. On the other hand, other modalities are easy to use, reliable, and relatively fast in execution yet lack the ability to precisely visualize the lymphatic system. In review of these various techniques, lymphoscintigraphy serves as a clear gold standard for diagnosing secondary lymphedema while more advanced and promising techniques continue to emerge as newer alternatives in clinical practice.

Keywords

Lymphedema Diagnostics Devices 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Group USCSW. U.S. Cancer Statistics Data Visualizations Tool, based on November 2018 submission data (1999-2016). U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute. https://gis.cdc.gov/Cancer/USCS/DataViz.html. Accessed 6 Aug 2019.
  2. 2.
    Lawenda B, Mondry T, Johnstone P. Lymphedema: a primer on the identification and management of a chronic condition in oncologic treatment. CA Cancer J Clin. 2009;59:8–24.  https://doi.org/10.3322/caac.20001.CrossRefPubMedGoogle Scholar
  3. 3.
    Mak S, Yeo W, Lee Y, Mo K, Tse K, Tse S, et al. Predictors of lymphedema in patients with breast cancer undergoing axillary lymph node dissection in Hong Kong. Nurs Res. 2008;57:416–25.  https://doi.org/10.1097/NNR.0b013e31818c3de2.CrossRefPubMedGoogle Scholar
  4. 4.
    McLaughlin S, Bagaria S, Gibson T, Arnold M, Diehl N, Crook J, et al. Trends in risk reduction practices for the prevention of lymphedema in the first 12 months after breast cancer surgery. J Am Coll Surg. 2013;216:380–9.  https://doi.org/10.1016/j.jamcollsurg.2012.11.004.CrossRefPubMedGoogle Scholar
  5. 5.
    Morrell R, Halyard M, Schild S, Ali M, Gunderson L, Pockaj B. Breast cancer-related lymphedema. Mayo Clin Proc. 2005;80:1480–4.  https://doi.org/10.4065/80.11.1480.CrossRefPubMedGoogle Scholar
  6. 6.
    • Pamarthi V, Pabon-Ramos W, Marnell V, Hurwitz L. MRI of the central lymphatic system: indications, imaging, technique, and pre-procedural planning. Top Magn Reson Imaging. 2017;26:175–80.  https://doi.org/10.1097/RMR.0000000000000130This review describes advances in magnetic resonance (MR) software that allow improved visualization of the lymphatics. In providing helpful visualization of central lymphatic system anatomy and pathology, this technology can be utilized for both lymphedema diagnosis and pre-procedural planning. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Scallan J, Zawieja S, Castorena-Gonzalez J, Davis M. Lymphatic pumping: mechanics, mechanisms and malfunction. J Physiol. 2016;594:5749–68.  https://doi.org/10.1113/JP272088.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Hancock D, Potezny T, White P. The peripheral lymphatics as an active player in the immune response. J Clin Cell Immunol. 2014;5:268.  https://doi.org/10.4172/2155-9899.1000268.CrossRefGoogle Scholar
  9. 9.
    Padera T, Meijer E, Munn L. The lymphatic system in disease processes and cancer progression. Annu Rev Biomed Eng. 2016;18:125–58.  https://doi.org/10.1146/annurev-bioeng-112315-031200.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Greene A. History and physical examination. In: Greene A, Slavin S, Brorson H, editors. Lymphedema. Cham: Springer; 2015.Google Scholar
  11. 11.
    Gerber L. A review of measures of lymphedema. Cancer. 1998;83:2803–4.  https://doi.org/10.1002/(sici)1097-0142(19981215)83:12b+<2803::aid-cncr29>3.3.co;2-n.CrossRefPubMedGoogle Scholar
  12. 12.
    Lymphology ISo. The diagnosis and treatment of peripheral lymphedema: 2013 Consensus Document of the International Society of Lymphology. Lymphology. 2013;46:1–11.Google Scholar
  13. 13.
    Schook C, Mulliken J, Fishman S, Grant F, Zurakowski D, Greene A. Primary lymphedema: clinical features and management in 138 pediatric patients. Plast Reconstr Surg. 2011;127:2419–31.  https://doi.org/10.1097/PRS.0b013e318213a218.CrossRefPubMedGoogle Scholar
  14. 14.
    Shin S, Lee W, Park E, Shin C, Chung J, Park J. Comparison of characteristic CT findings of lymphedema, cellulitis, and generalized edema in lower leg swelling. Int J Card Imaging. 2013;29:135–43.  https://doi.org/10.1007/s10554-013-0332-5.CrossRefGoogle Scholar
  15. 15.
    Liu N, Wang C, Sun M. Noncontrast three-dimensional magnetic resonance imaging vs lymphoscintigraphy in the evaluation of lymph circulation disorders: a comparative study. J Vasc Surg. 2005;41:69–75.  https://doi.org/10.1016/j.jvs.2004.11.013.CrossRefPubMedGoogle Scholar
  16. 16.
    Bourgeois P. Combined role of lymphoscintigraphy, x-ray computed tomography, magnetic resonance imaging, and positron emission tomography in the management of lymphedematous disease. In: Lee B, Bergan J, Rockson S, editors. Lymphedema. London: Springer; 2011.Google Scholar
  17. 17.
    Nishiyama Y, Yamamoto Y, Mori Y, Satoh K, Takashamia H, Ohkawa M, et al. Usefulness of Technetium-99m human serum albumin lymphoscintigraphy in chyluria. Clin Nucl Med. 1998;23:429–31.  https://doi.org/10.1097/00003072-199807000-00006.CrossRefPubMedGoogle Scholar
  18. 18.
    Cavezzi A. Duplex ultrasonography. In: Lee B, Bergan J, Rockson S, editors. Lymphedema. London: Springer; 2011.Google Scholar
  19. 19.
    Cammarota T, Pinto F, Magliaro A, Sarno A. Current uses of diagnostic high-frequency US in dermatology. Eur J Radiol. 1998;27:S215–S23.  https://doi.org/10.1016/S0720-048X(98)00065-5.CrossRefPubMedGoogle Scholar
  20. 20.
    Matter D, Grosshans E, Muller J, Furderer C, Mathelin C, Warter S, et al. Sonographic imaging of lymphatic vessels compared to other methods. J Radiol. 2002;83:599–609.PubMedGoogle Scholar
  21. 21.
    Suehiro K, Morikage N, Murakami M, Yamashita O, Samura M, Hamano K. Significance of ultrasound examination of skin and subcutaneous tissue in secondary lower extremity lymphedema. Ann Vasc Dis. 2013;6:180–8.  https://doi.org/10.3400/avd.oa.12.00102.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Krasnow A, Elgazzar A, Kazem N. Lymphoscintigraphy. In: Elgazzar A, editor. The pathophysiologic basis of nuclear medicine. Berlin, Heidelberg: Springer; 2006.Google Scholar
  23. 23.
    Ohtake E, Matsui K. Lymphoscintigraphy in patients with lymphedema: a new approach using intradermal injections of technetium-99m human serum albumin. Clin Nucl Med. 1986;11:474–8.CrossRefGoogle Scholar
  24. 24.
    •• O’Donnell T, Rasmussen J, Sevick-Muraca E. New diagnostic modalities in the evaluation of lymphedema. J Vasc Surg Venous Lymphat Disord. 2017;5:261–73.  https://doi.org/10.1016/j.jvsv.2016.10.083This review examines new diagnostic modalities for evaluating lymphedema and evaluates the utility of each modality. The strength of the literature in support of each modality offers helpful context for physicians to decide which modality to apply in individual patient cases. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Allegra C, Bartolo M, Carlizza A. Fluorescent microlymphaniography. In: Lee B, Bergan J, Rockson S, editors. Lymphedema. London: Springer; 2011.Google Scholar
  26. 26.
    Mulasi U, Kuchnia A, Cole A, Earthman C. Bioimpedance at the bedside: current applications, limitations, and opportunitie. Nutr Clin Pract. 2015;30:180–93.  https://doi.org/10.1177/0884533614568155.CrossRefPubMedGoogle Scholar
  27. 27.
    Cornish B, Chapman M, Hirst C, Mirolo B, Bunce I, Ward L, et al. Early diagnosis of lymphedema using multiple frequency bioimpedance. Lymphology. 2001;34:2–11.PubMedGoogle Scholar
  28. 28.
    Czerniec S, Ward L, Lee M, Refshauge K, Beith J, Kilbreath S. Segmental measurement of breast cancer-related arm lymphoedema using perometry and bioimpedance spectroscopy. Support Care Cancer. 2011;19:703–10.  https://doi.org/10.1007/s00520-010-0896-8.CrossRefPubMedGoogle Scholar
  29. 29.
    Ward L. Bioelectrical impedance analysis: proven utility in lymphedema risk assessment and therapeutic monitoring. Lymphat Res Biol. 2006;4:51–6.  https://doi.org/10.1089/lrb.2006.4.51.CrossRefPubMedGoogle Scholar
  30. 30.
    Cornish B, Thomas B, Ward L. Improved prediction of extracellular and total body water using impedance loci generated by multiple frequency bioelectrical impedance analysis. Phys Med Biol. 1993;38:337–46.  https://doi.org/10.1088/0031-9155/38/3/001.CrossRefPubMedGoogle Scholar
  31. 31.
    Cornish B, Bunce I, Ward L, Jones L, Thomas B. Bioelectrical impedance for monitoring the efficacy of lymphoedema treatment programmes. Breast Cancer Res Treat. 1996;38:169–76.  https://doi.org/10.1007/BF01806671.CrossRefPubMedGoogle Scholar
  32. 32.
    Ward L, Dylke E, Czerniec S, Isenring E, Kilbreath S. Confirmation of the reference impedance ratios used for assessment of breast cancer-related lymphedema by bioelectrical impedance spectroscopy. Lymphat Res Biol. 2011;9:47–51.  https://doi.org/10.1089/lrb.2010.0014.CrossRefPubMedGoogle Scholar
  33. 33.
    • Qin E, Bowen M, James S, Chen W. Multi-segment bioimpedance can assess patients with bilateral lymphedema. J Plast Reconstr Aesthet Surg. 2019.  https://doi.org/10.1016/j.bjps.2019.06.041This single institution study examined the role of bioimpedance spectroscopy as a lymphedema diagnostic modality. Single-segment bioimpedance (SSB) was more sensitive than multi-segment impedance (MSB) for diagnosing unilateral lymphedema, while MSB had greater sensitivity and specificity for diagnosing bilateral lymphedema. Moreover, MSB was found to be easier to perform and therefore adapted in the authors’ department practice.
  34. 34.
    Maus E, Tan I, Rasmussen J, Marshall M, Fife C, Smith L, et al. Near-infrared fluorescence imaging of lymphatics in head and neck lymphedema. Head Neck. 2012;34:448–53.  https://doi.org/10.1002/hed.21538.CrossRefPubMedGoogle Scholar
  35. 35.
    Rasmussen J, Aldrich M, Tan I, Darne C, Zhu B, O’Donnell TJ, et al. Lymphatic transport in patients with chronic venous insufficiency and venous leg ulcers following sequential pneumatic compression. J Vasc Surg Venous Lymphat Disord. 2016;4:9–17.  https://doi.org/10.1016/j.jvsv.2015.06.001.CrossRefPubMedGoogle Scholar
  36. 36.
    Zhu B, Rasmussen J, Litorja M, Sevick-Muraca E. Determining the performance of fluorescence molecular imaging devices using traceable working standards with SI units of radiance. IEEE Trans Med Imaging. 2016;35:802–11.  https://doi.org/10.1109/TMI.2015.2496898.CrossRefPubMedGoogle Scholar
  37. 37.
    Deltombe T, Jamart J, Recloux S, Legrand C, Vandenbroeck N, Theys S, et al. Reliability and limits of agreement of circumferential, water displacement, and optoelectronic volumetry in the measurement of upper limb lymphedema. Lymphology. 2007;40:26–34.PubMedGoogle Scholar
  38. 38.
    Stout Gergich N, Pfalzer L, McGarvey C, Springer B, Gerber L, Soballe P. Preoperative assessment enables the early diagnosis and successful treatment of lymphedema. Cancer. 2008;112:2809–19.  https://doi.org/10.1002/cncr.23494.CrossRefPubMedGoogle Scholar
  39. 39.
    Cau N, Galli M, Cimolin V, Grossi A, Battarin I, Puleo G, et al. Quantitative comparison between the laser scanner three-dimensional method and the circumferential method for evaluation of arm volume in patients with lymphedema. J Vasc Surg Venous Lymphat Disord. 2017;6:96–103.  https://doi.org/10.1016/j.jvsv.2017.08.014.CrossRefGoogle Scholar
  40. 40.
    Cau N, Galli M, Cimolin V, Aranci M, Caraceni A, Balzarini A. Comparative study between circumferential method and laser scanner 3D method for the evaluation of arm volume in healthy subjects. J Vasc Surg: Venous and Lymphat Disord. 2016;4:64–72.  https://doi.org/10.1016/j.jvsv.2015.05.005.CrossRefGoogle Scholar
  41. 41.
    Gjorup C, Zerahn B, Juul S, Hendel H, Christensen K, Holmich L. Repeatability of volume and regional body composition measurements of the lower limb using dual-energy x-ray absorptiometry. J Clin Densitom. 2017;20:82–96.  https://doi.org/10.1016/j.jocd.2016.08.009.CrossRefPubMedGoogle Scholar
  42. 42.
    Gjorup C, Zerahn B, Hendel H. Assessment of volume measurement of breast cancer-related lymphedema by three methods: circumference measurement, water displacement, and dual energy X-ray absorptiometry. Lymphat Res Biol. 2010;8:111–9.  https://doi.org/10.1089/lrb.2009.0016.CrossRefPubMedGoogle Scholar
  43. 43.
    Hayashi A, Yamamoto T, Yoshimatsu H, Hayashi N, Furuya M, Harima M, et al. Ultrasound visualization of the lymphatic vessels in the lower leg. Microsurgery. 2016;36:397–401.  https://doi.org/10.1002/micr.22414.CrossRefPubMedGoogle Scholar
  44. 44.
    Hayashi A, Hayashi N, Yoshimatsu H, Yamamoto T. Effective and efficient lymphaticovenular anastomosis using preoperative ultrasound detection technique of lymphatic vessels in lower extremity lymphedema. J Surg Oncol. 2018;117:290–8.  https://doi.org/10.1002/jso.24812.CrossRefPubMedGoogle Scholar
  45. 45.
    Hayashi A, Giacalone G, Yamamoto T, Belva F, Visconti G, Hayashi N, et al. Ultra high-frequency ultrasonographic imaging with 70 MHz scanner for visualization of the lymphatic vessels. Plast Reconstr Surg Glob Open. 2019;7:e2086.  https://doi.org/10.1097/GOX.0000000000002086.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Grassi R, Lagalla R, Rotondo A. Genomics, proteomics, MEMS and SAIF: which role for diagnostic imaging? Radiol Med. 2008;113:775–8.  https://doi.org/10.1007/s11547-008-0309-y.CrossRefPubMedGoogle Scholar
  47. 47.
    Grassi R, Cavaliere C, Cozzolino S, Mansi L, Cirillo S, Tedeschi G, et al. Small animal imaging facility: new perspectives for the radiologist. Radiol Med. 2009;114:152–67.  https://doi.org/10.1007/s11547-008-0352-8.CrossRefPubMedGoogle Scholar
  48. 48.
    Lux F, Mignot A, Mowat P, Louis C, Dufort S, Bernhard C, et al. Ultrasmall rigid particles as multimodal probes for medical applications. Angew Chem Int Ed Eng. 2011;50:12299–303.  https://doi.org/10.1002/anie.201104104.CrossRefGoogle Scholar
  49. 49.
    Muller A, Fries P, Jelvani B, Lux F, Rube C, Kremp S, et al. Magnetic resonance lymphography at 9.4T using a gadolinium-based nanoparticle in rats: investigations in healthy animals and in a hindlimb lymphedema model. Investig Radiol. 2017;52:725–33.  https://doi.org/10.1097/RLI.0000000000000398.CrossRefGoogle Scholar
  50. 50.
    Taradaj J, Rosinczuk J, Dymarek R, Halski T, Schneider W. Comparison of efficacy of the intermittent pneumatic compression with a high- and low-pressure application in reducing the lower limbs phlebolymphedema. Ther Clin Risk Manag. 2015;11:1545–54.  https://doi.org/10.2147/TCRM.S92121.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Adams K, Rasmussen J, Darne C, Tan I, Aldrich M, Marshall M, et al. Direct evidence of lymphatic function improvement after advanced pneumatic compression device treatment of lymphedema. Biomed Opt Express. 2010;1:114–25.  https://doi.org/10.1364/BOE.1.000114.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Brayton K, Hirsch A, O Brien P, Cheville A, Karaca-Mandic P, Rockson S. Lymphedema prevalence and treatment benefits in cancer: impact of a therapeutic intervention on health outcomes and costs. PLoS One. 2014;9:e114597.  https://doi.org/10.1371/journal.pone.0114597.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Mayrovitz H, Ryan S, Hartman J. Usability of advanced pneumatic compression to treat cancer-related head and neck lymphedema: a feasibility study. Head Neck. 2018;40:137–43.  https://doi.org/10.1002/hed.24995.CrossRefPubMedGoogle Scholar
  54. 54.
    Chang C, Cormier J. Lymphedema interventions: exercise, surgery, and compression devices. Semin Oncol Nurs. 2013;29:28–40.  https://doi.org/10.1016/j.soncn.2012.11.005.CrossRefPubMedGoogle Scholar
  55. 55.
    Melam G, Buragadda S, Alhusaini A, Arora N. Effect of complete decongestive therapy and home program on health- related quality of life in post mastectomy lymphedema patients. BMC Womens Health. 2016;16:23.  https://doi.org/10.1186/s12905-016-0303-9.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Szuba A, Achalu R, Rockson S. Decongestive lymphatic therapy for patients with breast carcinoma-associated lymphedema: a randomized, prospective study of a role for adjunctive intermittent pneumatic compression. Cancer. 2002;95:2260–7.  https://doi.org/10.1002/cncr.10976.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Anjali C. Raghuram
    • 1
  • Roy P. Yu
    • 1
  • Cynthia Sung
    • 1
  • Sherry Huang
    • 1
  • Alex K. Wong
    • 1
    Email author
  1. 1.Division of Plastic and Reconstructive Surgery, Department of Surgery, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA

Personalised recommendations