Masterclass Guides: Lymphedema in Clinical Practice

March - April 2023

Masterclass GUIDES

Introduction

Lower extremity lymphedema is an under recognized and under managed clinical condition. Too often unrecognized, the correct diagnosis of lymphedema is essential for appropriate clinical management.1,2 Often undermanaged, or potentially mismanaged through the liberal use of diuretics, the result can lead to secondary unintended consequences and result in progressive adipose deposition, tissue fibrosis, increasing limb volume, heaviness, functional difficulties,increased susceptibility to recurrent episodes of cellulitis, and overall higher healthcare utilization.

This Masterclass Guide provides an overview of this condition in clinical practice.

What is Lymphedema?

Assessment of Lymphedema

■ Lymphedema is the result of a loss of the finely tuned balance of microvascular tissue fluid production and recovery through the lymphatic vasculature, chronic inflammation, and loss of integrity of the lymphatic endothelial cell GCX 3-7

■ Primary lymphedema is due to a genetic mutation resulting in abnormal lymphatic vascular development causing either a structural or functional abnormality that impairs proper drainage of lymphatic fluid, and is further categorized as congenital (identification based upon abnormalities identified shortly after birth), praecox (abnormalities identified most often during teenage years or early adulthood), or tarda (typically occurring after age 35) 3

■ Due to the challenges associated with accurately diagnosing lymphedema, clinicians should carefully consider the differential diagnosis. Patients can be broadly segregated by those with unilateral asymmetric or bilateral leg edema, and by acuity of onset

Acute onset unilateral leg edema

■ Consider DVT and evaluate using duplex ultrasonography. If DVT has been excluded, patients should be evaluated for musculoskeletal injury or cellulitis, which should be evident based on history and physical exam findings

Bilateral leg edema

■ The differential diagnosis includes medication-induced edema, acute heart failure, end-stage renal disease, and bilateral DVT. Common medicationinduced edema is often forgotten within the differential, yet is well described in the literature. Clinicians should closely examine medication lists as a significant proportion of patients now take antihypertensive medications commonly associated with edema (Table 1) 8

Unilateral leg edema

■ The differential diagnosis includes chronic venous insufficiency, chronic lymphedema, Baker’s cyst, May-Thurner syndrome, pelvic tumor, complex regional pain syndrome, syndromic limb hypertrophy (Klippel-Trenaunay syndrome and Proteus syndrome), and poor calf contractility (radiculopathy, stroke). Duplex ultrasonography can be helpful to identify chronic venous insufficiency and Baker’s cyst

Lymphedema in Clinical Practice

Keywords

■ Lymphedema

■ Chronic edema

■ Phlebolymphedema

■ Chronic venous insufficiency

■ Lymphedema

■ Glycocalyx

Table 1: Medications commonly associated with edema.

Class

Antidepressants

Antihypertensives

Antivirals

Chemotherapeutics

Cytokines

Hormones

Nonsteroidal anti-inflammatory drugs

Specific medications

Monoamine oxidase inhibitors, trazodone

Beta-adrenergic blockers, calcium channel blockers, clonidine (Catapres), hydralazine, methyldopa, minoxidil

Acyclovir (Zovirax)

Cyclophosphamide, cyclosporine (Sandimmune), cytosine arabinoside, mithramycin

Granulocyte colony-stimulating factor, granulocyte-macrophase colony-stimulating factor, interferon alfa, interleukin-2, interleukin-4

Androgen, corticosteroids, estrogen, progesterone, testosterone

Celecoxib (Celebrex), ibuprofen

What Are the Stages of Lymphedema?

Stage 0

■ Latent or subclinical; no evidence of swelling; subjective symptoms

Stage I

■ Early accumulation of fluid; usually pitting; subsides with elevation

Stage II

■ Swelling rarely reduced with elevation; pitting still present in early stage II, whereas pitting is absent in later stages as fibrosis and fat deposition begin

Stage III

■ Lymphostatic elephantiasis; non pitting with trophic skin changes, further deposition of fat and fibrosis, and warty overgrowths 9

Figure 1: Lymphosomes of the body.30

Lymphedema in Clinical Practice Masterclass GUIDES

Assessment of Lymphedema

Cutaneous changes

■ The benign, reactive cutaneous changes associated with chronic lymphedema include erythema, skin thickening and fibrotic, scar-like changes with hyperkeratosis and a distinctive ‘cobblestone’ pattern referred to as ‘lymphostasis verrucosa cutis’ or ‘elephantiasis nostras verrucosa’ (ENV) 10

■ ENV presents as a diffusely infiltrated, typically hyperpigmented, firm plaque of the distal lower extremities, with a verruous, ‘pebbly’ surface and hyperkeratosis which is sometimes described as ‘mossy’ in appearance 10

Lymphatic imaging

■ Imaging modalities for chronic lymphedema include lymphoscintigraphy and indocyanine green lymphangiography, but are not usually necessary and are generally reserved for diagnostic dilemmas

■ Duplex ultrasound has become a practical first-line modality for the evaluation of lymphedema due to its availability and low cost. DUS not only provides diagnostic value, but has also been shown to allow for classifying edema severity and monitoring response to treatment 11

■ DUS can be used to differentiate dependent edema from secondary lower extremity edema by visualization of subcutaneous echogenicity and echo-free space, and can also aid in differentiating lipidema from lymphedema, as lipidema characteristically demonstrates normal dermal thickness and echogenicity whereas lymphedema often demonstrates increased dermal thickness and reduced echogenicity 12

■ A newer modality, although not available currently in the United States, is the use of magnetic resonance lymphography (MRL). MRL has been shown to identify superficial lymphatic vessels down to the 0.5 mm level with a high sensitivity and specificity for illustrating abnormal lymphatics and drainage patterns 13

■ Similarly, the use of multi-frequency bioimpedance analysis has been shown to be reliable and reproducible for accurately documenting the presence of lymphedema in a quick, costeffective manner 14,15

Figure 2:

2a: True-negative Stemmer sign (examiner is able to pinch the skin in a patient without lymphedema).

2b: True-positive Stemmer sign (skin is unable to be pinched in an individual with lymphedema).

2c: False-negative Stemmer sign (the skin is able to be pinched in a subject with lymphedema).16

■ After other etiologies for generalized edema have been excluded, the diagnosis of chronic lymphedema is usually established based on typical clinical features found on thorough history and physical examination:

■ Slowly progressive edema affecting one or both lower extremities

■ History of surgery, lymph node dissection, or radiation therapy

■ Non-pitting edema is suggestive, although pitting edema may be present in early-stage lymphedema until further deposition of fat and fibrosis causes the characteristic nonpitting presentation

■ Positive Stemmer sign: inability to pinch the skin fold at the base of the second toe (Figure 2) 16

■ Positive Bjork Bow Tie Test: gently pinched skin when lifted and rolled is thickened, less pliable, less able to be pinched and lifted off, and produce limited ‘Bow Tie’ of wrinkles (Figure 3) 17

■ Bier spots are the presence of multiple irregular white macules along extensor surfaces and have been associated with lower extremity lymphedema 18

■ Characteristic skin changes: hypertrophic nodules, hyperkeratotic, verrucous and vesicular skin lesions

■ Dorsal hump and squaring of toes; this distinguishes lymphedema from lipedema which often spares the foot and toes. Lipedema can be further distinguished from lymphedema due to its characteristic adiposity distribution from hips to ankles while sparing the feet in a distinct ‘step off’ appearance 19

3a: Negative Bjork ‘bow tie’ test.

3b: Positive Bjork ‘bow tie’ test.

3c: ‘Bow tie’ of wrinkles in negative test.31

Lymphatic examination

Figure 3:

Management of Lymphedema

■ Although there is currently no cure for lymphedema, it is a manageable disease by implementing the components of Complete Decongestive Physiotherapy (CDPT)

■ The objective of CDPT is to achieve a reduction in limb volume and improve the integrity and quality of the skin. This is attained through a two-phase approach:

■ Phase I is the intensive or decongestion phase that is clinician-driven, and Phase II is the maintenance phase that is patient-driven

■ The intensive phase is best performed daily (or as frequently as possible) until maximal volume reduction is achieved. Once the lymphedematous limb has plateaued and is no longer achieving a reduction in volume, the patient is transitioned into the maintenance phase, which is continued for life

■ The components of CDPT are implemented and facilitated by a trained lymphedema specialist during the intensive phase and include:

■ Meticulous skin and nail care to the affected areas

■ Manual lymphatic drainage (MLD) which is a gentle manual technique that redirects lymph flow

■ Multilayer, short-stretch compression bandaging during active decongestion and over-the-counter or custom garments once the limb has decongested

■ Therapeutic exercise to enhance and promote lymphatic pumping

■ During the intensive phase, patient education is paramount as all aspects of CDPT continue as part of the maintenance phase directed by the patient or a caregiver for lifelong lymphedema management. The major difference between the two phases of CDPT is the form of compression utilized

■ Once the limb volume is stable, compression garments are worn during the day followed by short-stretch bandaging or an alternative compression system at night

■ Alternative systems utilize Velcro closure mechanisms that assist the patient with donning and doffing often improving adherence with use. Compression systems are available in both elastic or inelastic material

■ Multiple over the counter medications tout a venotonic or lymphotonic effect. Quality peer reviewed publications are limited regarding many components present in over the counter medications

■ Flavonoids are a phenolic plant derived compound found in over 8000 different forms with multiple biological properties and among the most studied medications for management of lymphedema associated with chronic venous insufficiency 20

■ The specific flavonoids, hesperidin and diosmin, were evaluated in a 2017 meta-analysis, identifying moderate quality evidence demonstrating benefit for management of venous ulcerations and edema (phlebolymphedema) 21

■ Diosmin, as a component of a hybrid medication, was found to improve outcomes when used in conjunction with CDPT as compared to CDPT alone 22

■ Micronized purified flavonoid fraction (MPFF) has been shown to decrease the inflammatory cascade and leukocyteendothelial activation thereby discouraging edema formation 23

■ MPFF consists of 90% diosmin and 10% hesperidin and supplementary flavonoids and comes from extracts of rutaceaeaurantiae, a type of small orange that is micronized for improved bioavailability 23,24

■ MPFF has not been associated with known major side effects while simultaneously showing significant improvement in quality of life in patients with chronic venous insufficiency and accelerated healing of leg ulcers 23,25,26,27

■ Similarly, selenium has been noted to have a positive impact on lymphedema symptoms in a recent literature review 28

■ Often considered for patients with lymphedema undergoing long-distance travel or flight is the use of pinus pinaster bark extract (PBE) which goes by the trade name, Pycnogenol. PBE possesses vasorelaxant activity and enhances microcirculation through increasing capillary permeability

■ PBE has been shown to be effective in improving leg heaviness, subcutaneous edema, and venous pressure in patients with chronic venous insufficiency 29

Complete Decongestive Physiotherapy (CDPT) Pharmacotherapy

Lymphedema in Clinical Practice Masterclass GUIDES

Key Points

■ Current medical and clinical education regarding the anatomical and pathophysiological state of lymphedema have far lagged behind the rapidly advancing field of lymphatic medicine. Consequently, the accurate and evidenced-based approach to lymphedema assessment and management are not unanimously and universally employed

■ As patients with lymphedema often present in a myriad of different clinical settings, it is important to deploy accurate clinical assessment and readily offer best practice management options

■ These management options should include meticulous skin and nail care, manual lymphatic drainage, compression, therapeutic exercise, and review of pharmacologic options

■ The use of IPC devices as adjuncts to traditional therapy can be used to decrease lymphedema related complications and improve patient quality of life. In addition, IPC devices have the ability to be used in regions where limited lymphedema therapists or specialists exist thereby continuing to provide patients with lymphatic stimulation

■ The goal of MLD or IPC devices is to stimulate the underlying lymphatic system to redistribute stagnant lymph as outlined by the revised starling curve

■ By redistributing stagnant lymph back into circulation, the not uncommon lymphedema sequelae of recurrent infection, ulceration, deformity, and dermal/ epidermal skin changes can be minimized

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4. Ghanta, Swapna, Daniel A. Cuzzone, Jeremy S. Torrisi, Nicholas J. Albano, Walter J. Joseph, Ira L. Savetsky, Jason C. Gardenier, David Chang, Jamie C. Zampell, and Babak J. Mehrara. 2015. “Regulation of Inflammation and Fibrosis by Macrophages in Lymphedema.” American Journal of Physiology. Heart and Circulatory Physiology 308 (9): H1065-1077. https://doi.org/10.1152/ajpheart.00598.2014.

5. Reitsma, Sietze, Dick W. Slaaf, Hans Vink, Marc A. M. J. van Zandvoort, and Mirjam G. A. oudeEgbrink. 2007. “The Endothelial Glycocalyx: Composition, Functions, and Visualization.” PflugersArchiv: European Journal of Physiology 454 (3): 345–59. https://doi.org/10.1007/s00424-007-0212-8.

6. Zolla V, Nizamutdinova IT, Scharf B, Clement CC, Maejima D, Akl T, Nagai T, Luciani P, Leroux JC, Halin C, Stukes S, Tiwari S, Casadevall A, Jacobs WR Jr, Entenberg D, Zawieja DC, Condeelis J, Fooksman DR, Gashev AA, Santambrogio L. Aging-related anatomical and biochemical changes in lymphatic collectors impair lymph transport, fluid homeostasis, and pathogen clearance. Aging Cell. 2015 Aug;14(4):582-94. doi: 10.1111/acel.12330. Epub 2015 May 15. PMID: 25982749; PMCID: PMC4531072.

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Bush, Ronald, Anthony Comerota, Mark Meissner, Joseph D. Raffetto, Steven R. Hahn, and Katherine Freeman. 2017. “Recommendations for the Medical Management of Chronic Venous Disease: The Role of Micronized Purified Flavanoid Fraction (MPFF).” Phlebology 32 (1_suppl): 3–19. https://doi.org/10.1177/0268355517692221.

22. Cacchio, Angelo, Rosa Prencipe, Marina Bertone, Luciana De Benedictis, Luciano Taglieri, Erika D’Elia, CesidiaCentoletti, and Giancarlo Di Carlo. 2019. “Effectiveness and Safety of a Product Containing Diosmin, Coumarin, and Arbutin (Linfadren®) in Addition to Complex Decongestive Therapy on Management of Breast Cancer-Related Lymphedema.” Supportive Care in Cancer 27 (4): 1471–80. https://doi.org/10.1007/s00520-018-4514-5.

23. Katsenis K. Micronized purified flavonoid fraction (MPFF): a review of its pharmacological effects, therapeutic efficacy and benefits in the management of chronic venous insufficiency. CurrVascPharmacol. 2005;3(1):1–9. doi:10.2174/1570161052773870

24. Nair B. Venous leg ulcer: systemic therapy. Indian Dermatol Online J. 2014;5(3):374–377. doi:10.4103/2229-5178.137821

25. Coleridge-Smith P, Lok C, Ramelet AA. Venous leg ulcer: a meta-analysis of adjunctive therapy with micronized purified flavonoid fraction. Eur VascEndovascSurg. 2005;30(2):198–208. doi:10.1016/j.ejvs.2005.04.017

26. Danielsson G, Jungbeck C, Peterson K, Norgren L. A randomized controlled trial of micronized purified flavonoid fraction vs placebo in patients with chronic venous disease. Eur J VascEndovasc Surg. 2002;23(1):73–76.