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Lymphology 53 (2020) 3-19

THE DIAGNOSIS AND TREATMENT OF PERIPHERAL : 2020 CONSENSUS DOCUMENT OF THE INTERNATIONAL SOCIETY OF LYMPHOLOGY

This International Society of Lymphology the XXVI ICL in Barcelona, Spain; and [G] (ISL) Consensus Document is the latest revi- discussions at a dedicated, focused Post-Con- sion of the 1995 Document for the evaluation gress session at the XXVII ICL in Iguazú, and management of peripheral lymphedema Argentina (2019) followed by additional written (1). It is based upon modifications: [A] sug- comments from the Executive Committee and gested and published following the 1997 XVI others. International Congress of Lymphology (ICL) The document attempts to amalgamate in Madrid, Spain (2), discussed at the 1999 the broad spectrum of protocols and practices XVII ICL in Chennai, India (3), and consid- advocated worldwide for the diagnosis and ered confirmed at the 2000 (ISL) Executive treatment of peripheral lymphedema into a Committee meeting in Hinterzarten, Germany coordinated proclamation representing a "Con- (4); [B] derived from integration of discussions sensus" of the international community based and written comments obtained during and on various levels of evidence. The document following the 2001 XVIII ICL in Genoa, Italy is not meant to override individual clinical as modified at the 2003 ISL Executive Commit- considerations for complex patients nor to tee meeting in Cordoba, Argentina (5); [C] sug- stifle progress. It is also not meant to be a legal gested from comments, criticisms, and rebuttals formulation from which variations define med- as published in the December 2004 issue of ical malpractice. The Society understands that Lymphology (6); [D] discussed in both the 2005 in some clinics the method of treatment derives XX ICL in Salvador, Brazil and the 2007 XXI from national standards while in others access ICL in Shanghai, China and modified at the to medical equipment, technical expertise, and 2008 Executive Committee meeting in Naples, supplies is limited; therefore, the suggested Italy (7,8); [E] modified from discussions and treatments might be impractical. Adaptability written comments from the 2009 XXII ICL and inclusiveness does come at the price that in Sydney, Australia, the 2011 XXIII ICL in members can rightly be critical of what they Malmö, Sweden, the 2012 Executive Commit- see as vagueness or imprecision in definitions, tee Meetings (9); [F] discussions at the 2013 qualifiers in the choice of words (e.g., the use of XXIV ICL in Rome, Italy, and the 2015 XXV "may... perhaps... unclear", etc.) and mentions ICL in San Francisco, USA, as well as multiple (albeit without endorsement) of treatment written comments and feedback from Execu- options supported by limited hard data. Most tive Committee and other ISL members during members are frustrated by the reality that the 2016 drafting (10); informal discussions at NO treatment method has really undergone a

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 4 satisfactory meta-analysis (let alone rigorous, Diseases from the World Health Organization. randomized, stratified, long-term, controlled Lymphedema may be an isolated phenomenon study). With this understanding, the absence or associated with a multitude of other dis- of definitive answers and optimally conducted abling local sequelae or even life-threatening clinical trials, and with emerging technologies systemic syndromes. Its nature may be acute, and new approaches and discoveries on the transitory, or chronic. In its purest form, the horizon, some degree of uncertainty, ambiguity, central disturbance is a low output failure and flexibility along with dissatisfaction with (mechanical insufficiency, low flow edema, low current lymphedema evaluation and manage- volume insufficiency) of the lymphvascular ment is appropriate and to be expected. We system; that is, overall lymphatic transport continue to struggle to keep the document is reduced. This derangement arises either concise while balancing the need for depth and from congenital lymphatic dysplasia (primary details. With these considerations in mind, we lymphedema) or acquired obliteration, such as believe that this 2020 version presents a Con- after radical operative dissection (e.g., exten- sensus that embraces the entire ISL member- sive axillary or retroperitoneal node removal). ship, rises above national standards, identifies These examples may be confusing for they and stimulates promising areas for future may not be radical (just node sampling), research, and represents the best judgment even though they may cause lymphedema, of the ISL membership on how to approach such as from irradiation, trauma, or repeated patients with peripheral lymphedema in the with lymphangiosclerosis (sec- light of currently available evidence. Therefore, ondary lymphedema) or as a consequence of the document has been and should continue functional deficiency (e.g., inadequate lym- to be challenged and debated in the pages of phatic growth or regrowth, lymphangiospasm, Lymphology (e.g., as Letters to the Editor) and stasis, and valvular insufficiency in primary or ideally will remain a continued focal point for secondary lymphedema. Nonetheless, the com- robust discussion at local, national and inter- mon denominator is that the national conferences in lymphology and related (whether vessels, nodes, interstitium, etc., or disciplines. We further anticipate as experience combinations) transport has fallen below the evolves and new ideas and technologies emerge capacity needed to handle the presented load that this "living document" will undergo further of microvascular filtrate including plasma periodic revision and refinement as the practice protein and cells that normally leak from the and conceptual foundations of medicine and bloodstream into the interstitium. Recent work specifically lymphology change and advance. has highlighted and reinforced that almost all interstitial fluid eventually becomes and is Keywords: 2020 consensus, lymphedema, transported as lymph. Swelling is produced diagnosis, treatment, research agenda, ISL, by accumulation in the extracellular space of International Society of Lymphology excess water, filtered/diffused plasma proteins, extravascular blood cells and parenchymal/ I. GENERAL CONSIDERATIONS stromal cell products. This process culmi- nates in proliferation of parenchymal and As a fundamental starting point, lymph- stromal elements with excessive deposition of edema is an external (and/or internal) man- extracellular matrix substances and adipose ifestation of lymphatic system insufficiency tissue (which starts early). High output failure and deranged lymph transport. Some mem- (dynamic insufficiency, high flow edema, high bers prefer to define peripheral lymphedema volume insufficiency) of the lymph circulation, as a symptom or sign resulting from under- on the other hand, occurs when a normal or lying . It is defined as an increased transport capacity of intact lym- illness by the International Classification of phatics is overwhelmed by an excessive burden

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of blood capillary filtrate. Examples include achieved by non-operative therapy. Because hepatic cirrhosis (ascites), hypoalbuminemia lymphedema most often becomes a chronic, associated with nephrotic syndrome (anasar- generally incurable condition, it typically ca), right heart failure, and venous insufficien- requires, as do other chronic disorders, lifelong cy of the leg (peripheral edema). Although the care and attention along with psychosocial final pathway is the manifestation of tissue support. The continued need for therapy does edema whenever lymph formation exceeds not mean a priori that treatment is unsatis- lymph absorption, the latter entities should factory, although often it is less than optimal. properly be distinguished from lymphedema, For example, patients with diabetes mellitus which is characterized by decreased lymphat- continue to need drugs (insulin) or special diet ic transport. In some syndromes where high (low calorie, low sugar) in order to maintain output lymphatic transport failure is long- metabolic homeostasis. Similarly, patients with standing, a gradual functional deterioration chronic venous insufficiency require lifelong of the draining lymphatics may supervene external compression therapy to minimize and thereby reduce overall transport capaci- edema, lipodermatosclerosis and skin ul- ty. A reduced lymphatic circulatory capacity ceration (treatments may be preventative if then develops in the face of increased blood initiated early). Compliance and adherence capillary filtration. Examples include recur- of the patient is also essential to an improved ring infection, thermal burns, and repeated outcome. With chronic venous insufficiency, allergic reactions. These latter conditions are poor patient compliance may be causally associated with "safety valve insufficiency" of associated with progressive skin ulceration, the lymphatic system where the lymph load hyperpigmentation, and other trophic changes increases beyond "normal" flow eventually to in the lower leg. Similarly, failure to control become overwhelmed and this can be consid- lymphedema may lead to repeated infections ered a mixed form of edema/ lymphedema and (cellulitis/lymphangitis), progressive elephan- as such is particularly troublesome to treat. tine trophic changes in the skin, sometimes Peripheral lymphedema associated with crippling invalidism and on rare occasions, chylous and non-chylous reflux syndromes is the development of a highly lethal lymphan- an infrequent but complex condition that re- giosarcoma (widely known as Stewart-Treves quires specific diagnostic measures and treat- syndrome). ment methods. There are other complicating The particular setting of examination, di- diagnoses (e.g., genetic with Turner or Noonan agnosis, and treatment (clinic, hospital, prop- syndromes and an expanding spectrum of erly designed teams, etc.) as well as patient hereditary lymphedemas due to specific patho- condition (ambulation, portability, fragility, genic genetic variants, or arterial/venous mal- etc.) can all impact individualized patient care formations) which require special attention. and treatment. Another consideration in differential diag- nosis is lipedema. This condition of abnormal Prevention/Early Identification and Treatment fat accumulation is not a lymphatic-related disease (at least in the early stages) and con- The promulgation of lists of risk factors ventional imaging results demonstrate normal for secondary lymphedema has become a lymphatic function. In later stages (and with highlighted issue due to publications of "do's morbid obesity), lymphedema can become a and don'ts." These are largely anecdotal and complicating comorbidity and lymphedema not sufficiently investigated. While some pre- treatments can be helpful. cautions rest on solid physiological principles In the treatment of "classical" lymphede- (e.g., avoiding excessive heat on an "at risk" ma of the limbs (that is, peripheral lymphede- limb, not having chemotherapy administered ma), improvement in swelling can usually be into the limb unless medically necessary, or

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 6 trying to avoid infections), others are less sup- secondary damage. Further research is need- ported. Consistently, higher BMI (particularly ed, and all such approaches and techniques >25), more extensive dissection, will have to be tempered by actual reductions more extensive surgical procedures, receipt of in risk of developing lymphedema in specif- adjuvant therapy (including radiotherapy or ic populations based on emerging incidence chemotherapy) and being insufficiently active evidence. are more firmly supported as risk factors for The question of when to monitor a patient the development of lymphedema. It must be has emerged for patients undergoing cancer noted that most published studies on incidence treatment. Prospective surveillance models of secondary lymphedema of the extremities (PSM) have been developed to address early report less than 50% chance of developing detection of lymphedema leading to earlier lymphedema with nodal basin operations, and more efficacious treatment. The prospec- irradiation, and taxane-based chemotherapy tive surveillance model involves a preoperative (substantially less with more conservative cancer treatment assessment where baseline treatments, e.g., lumpectomy with sentinel limb volume and functional mobility mea- lymph node biopsy). Therefore, standard use surements are established. Some clinics with of some of these "don'ts" for risk reduction of the availability of bioimpedance spectroscopy lymphedema may not be appropriate and pos- (BIS), bioimpedance analysis (BIA), tissue sibly subjects patients to therapies which are dielectric constant (TDC), or other measur- unsupported until a point in the future when ing devices may utilize these to detect early evaluation and prognostication evidence have changes in tissue fluid accumulation. Patients demonstrated more clearly specific risks and are then followed in a prospective manner the corresponding preventative measures. (e.g., 3-month intervals for the first year The concepts of "primary" and "second- during and post- cancer treatment and then ary" prevention (including risk reduction) are less frequently). Visits include psychosocial receiving increased attention with an emerging support and reassessment of limb volume and new concept of "tertiary" prevention: "prima- functional mobility to offer a comparison to ry" prevention to avoid lymphedema before baseline measures to enable identification of its onset; "secondary" prevention for lymph- meaningful change associated with subclinical edema treatment at early stage; and "tertiary" onset of lymphedema. Subclinical lymphede- prevention for lymphedema treatment at ma is measurable at low diagnostic thresholds late stage. Operative imaging techniques to (3-5% excess volume change from baseline lessen lymphatic system impact by identifying in swelling not due to weight change – i.e., lymphatic vessels to avoid during procedures determined by measuring both limbs) and may are being carefully applied (also known as initially present in only one segment of the lymph vessel sparing procedures). Operative limb (which may be identified using TDC). preventative prophylactic lymphatic-venous Identifying subclinical lymphedema facilitates shunts (LYMPHA) as preventative measures early, conservative intervention and will likely in high-risk patients have been shown to reduce the chances that the condition will reduce incidence of post-operative lymphede- progress to a chronic advanced stage. Identify- ma. Exercise, weight loss, self-manual lymph ing and treating lymphedema at an early stage drainage (MLD), and education for prevention offers greater treatment success and potential of secondary lymphedema continue to un- cost savings with conservative management dergo investigation and implementation with programs including compression garments, evidence from RCTs suggesting potential for education for self-care (brief anatomy, skin exercise to reduce risk of secondary lymph- care, weight control, etc.), self-MLD (and/ edema. Radiation treatment techniques are or partner/care giver-MLD), psychosocial continually improving to reduce and isolate support, and exercise. Early identification may

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 7 also offer the opportunity for lymphatic-ve- are gradually being elucidated. Publications nous shunts or other surgical approaches in combining both physical (phenotypic) findings appropriate situations to offer a potential life- with functional lymphatic imaging as well as long avoidance of further treatment. those classifications which propose inclusion of disability grading, assessment of inflamma- II. STAGING OF LYMPHEDEMA tion, and even immunohistochemical changes determined by biopsy of nodes/vessels are Most ISL members rely on a three stage forecasting the future evolution of staging. In scale for classification of a lymphedematous addition, incorporation of genotypic informa- limb with recognition of Stage 0, which refers tion, expanded from what is available in cur- to a latent or subclinical condition where rent screening, would further advance staging swelling is not yet evident despite impaired and classification of patients with peripheral lymph transport, subtle alterations in tissue (and other) lymphedemas. fluid/composition, and changes in subjective Within each Stage, a limited but nonethe- symptoms. It can be transitory and may exist less functional severity assessment has utilized months or years before overt edema occurs simple excess volume differences assessed as (Stages I-III). Assessment of early fluid minimal (>5<20% increase in limb volume), changes can be accomplished using BIS, BIA moderate (20-40% increase), or severe (>40% or TDC analysis. Stage I represents an early increase). Some clinics prefer to use >5-10% accumulation of fluid relatively high in protein as minimal and >10-<20% as mild. Volume content (e.g., in comparison with "venous" ede- differentials are most commonly determined ma) which subsides with limb elevation. Pit- using circumferential measurement due to ting may occur. An increase in various types wide availability and low cost. A flexible non- of proliferating cells may also be seen. Stage II stretch tape is preferred and the truncated involves more changes in solid structures, limb cone formula is utilized for calculating vol- elevation alone rarely reduces tissue swelling, ume. Water displacement volumetry is used in and pitting is manifest. Later in Stage II, the some clinics for arm or whole or lower leg vol- limb may not pit as excess subcutaneous fat umes although there are some practical limits and fibrosis develop. Stage III encompasses (e.g., size of limb, measuring areas near the lymphostatic elephantiasis where pitting can root of the limb, and hygiene issues). Perom- be absent and trophic skin changes such as etry provides high accuracy by using infrared acanthosis, alterations in skin character and light beams to estimate limb volume but the thickness, further deposition of fat and fibro- equipment cost is significant for smaller clinics sis, and warty overgrowths have developed. It and the hand and foot are not included. Prop- should be noted that a limb may exhibit more er use requires that the limb is perpendicular than one stage, which may reflect alterations when measuring since an oblique position will in different lymphatic territories. give incorrect volume. Finally, where bilateral These Stages only refer to the physical lymphedema is present, volume differences condition of the extremities. A more detailed between the limbs should be interpreted with and inclusive classification needs to be for- caution. mulated in accordance with improved un- Clinicians also incorporate factors such derstanding of the pathogenic mechanisms as extensiveness, occurrence of erysipelas of lymphedema (e.g., nature and degree of attacks, inflammation, and other descriptors lymphangiodysplasia, lymph flow perturba- or complications into their own individual tions, lymphatic valve maldevelopment, and severity determinations. Some clinics incor- nodal dysfunction as defined by anatomic porate physical measures using tonometry features and physiologic imaging and testing) or fibrometry to help stage tissue changes in and underlying genetic disturbances, which lymphedema.

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Some healthcare professionals focus on is also used in some centers to assess lymph- disability rating utilizing the World Health edema and associated tissue alterations). Organization's guidelines for the International The diagnostic tool of isotope lymphography Classification of Functioning, Disability, and (also termed lymphoscintigraphy) – for both Health (ICF). Quality of Life issues (psycho- superficial and deep lymphatic vessels and social, social, emotional, physical disabilities, lymph nodes – or more commonly lymphan- etc.) have demonstrated good reliability and gioscintigraphy (despite its reference only to reproducibility in studies and are also utilized the vessels) has proved extremely useful for by individual clinicians and groups, and note depicting the specific lymphatic abnormal- that these can positively or negatively impact ities. Where specialists in nuclear medicine therapy and compliance (maintenance). are available, lymphangioscintigraphy (LAS) has largely replaced conventional oil contrast III. DIAGNOSIS lymphography for visualizing the lymphatic network. Although LAS has not been strict- An accurate diagnosis of lymphedema ly standardized (various radiotracers and is essential for appropriate therapy. In most radioactivity doses, different injection vol- patients, the diagnosis of lymphedema can be umes, intracutaneous versus subcutaneous or readily determined from clinical history and subfascial injections, one or more injections, physical examination. In other patients, con- different protocols of passive and active physi- founding conditions such as morbid obesity, li- cal activity, varying imaging times, static and/ podystrophy, lipedema, endocrine dysfunction, or dynamic techniques, and the use of pro- venous insufficiency, unrecognized trauma, tocols for deep system imaging), the images, and repeated infection may complicate the which can be easily repeated, offer remarkable clinical picture. Moreover, in considering the insight into lymphatic structural abnormal- basis of unilateral extremity lymphedema, es- ities and (dys)function. The etiology is not pecially in adults, solid organ tumors (primary necessarily determined from the image alone and/or metastatic), lymphomas, and soft tissue but specific patterns are characteristic, e.g., sarcomas which may obstruct or invade more lymphatic aplasia/hypoplasia vs. hyperplasia proximal lymphatics need to be considered. in . LAS has been used For these reasons, a thorough medical eval- frequently in newborns and children obtaining uation is indispensable before embarking on reproducible, pre-clinical diagnostic images. lymphedema treatment. Co-morbid conditions When LAS is combined with single photon such as congestive heart failure, hypertension, emission computed tomography (LAS-SPECT- thyroid abnormalities, cerebrovascular disease CT), much higher resolution sequential 3-D including stroke, and vascular malformations images are displayed with greater sensitivity may also influence the diagnosis and thera- and improved spatial localization. peutic approach undertaken. LAS provides dynamic images of both lymphatics and lymph nodes in the peripheral A. Imaging and central system as well as semi-quantita- tive data on radiotracer (lymph) transport, If the diagnosis of lymphedema or its and it does not require dermal injections of cause is unclear or in need of better definition blue-dye (as often used for example in axillary for prognostic or therapeutic considerations, or groin sentinel node visualization- correctly consultation with a clinical lymphologist or termed lymphadenoscintigraphy). Blue dye referral to a lymphologic center if accessible injection is occasionally complicated by an is recommended. Commonly, ultrasound allergic skin reaction or serious anaphylaxis. techniques are first used to assess and rule out Moreover, clinical interpretation of lymphatic venous disease in many centers (although this function after vital dye injection alone ("the

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blue test") can be misleading. Direct oil con- precise evaluation of superficial lymphatic trast lymphography, which is cumbersome and flow in real-time without radiation exposure. occasionally associated with minor and even Prospective comparative studies demonstrate major albeit rare complications, is usually re- that early changes in ICG lymphography find- served for more precise delineation and local- ings predict lymphedema development and ization of complex conditions such as chylous progression risk in cancer survivors. reflux syndromes and thoracic duct injury, DXA (also known as DEXA- dual-energy where LAS can provide at least preliminary X-ray absorptiometry) may help classify and diagnostic images for screening and later for define a lymphedematous limb but its greatest monitoring treatment efficacy. Non-invasive potential use may be to assess the chemi- duplex-Doppler studies and occasionally phle- cal composition of limb swelling (especially bography are useful for examining the deep increased fat deposition, which by its added venous system and supplement or complement weight can lead to muscle hypertrophy). US the evaluation of extremity edema. has found practical value in depicting the Newer diagnostic, investigational, and po- "dance" of the living adult worms in scrotal tentially interventional tools used to elucidate lymphatic filariasis, and it is also increasingly lymphangiodysplasia/lymphedema syndromes used to highlight tissue alterations. (including in newborns and children) and structural alterations in the lymphatic system B. Genetics include magnetic resonance imaging (MRI). The MR repertoire encompasses MR lymphog- Genetic testing has become practical and raphy (MRL) and MR angiography (MRA) commercially available to screen for a number techniques both with (peripheral and intran- of specific hereditary syndromes with discrete odal injections) and non-invasively without gene mutations such as lymphedema-distichi- contrast, which are continually being refined asis (FOXC2), some forms of Milroy disease and utilized increasingly in specialized centers [FLT-4 (VEGFR-3) VEGF-C] and hypotricho- around the world. These techniques and sislymphedema-telangiectasia (SOX18) as well special protocols provide images with high as a variety of chromosomal abnormalities, spatial resolution including structures deep in notably Turner and Klinefelter syndromes and the body (i.e., thoracic duct). Other techniques Trisomy 21. Other genes identified include utilized include computed tomography (CT), (not exhaustive list): generalized lymphatic CT lymphograms, 3-D oil contrast lymphog- dysplasia (Hennekam syndrome) (CCBE1, raphy, ultrasonography (US), indirect (water FAT4), inherited lymphedema types 1C soluble) lymphography (IL), and fluorescent (GJC2) and 1D (VEGFC), lymphedema- cho- microlymphangiography (FM). anal atresia (PTPN14), Emberger (GATA2), Another technique gaining expanded use oculodento-digital syndrome (GJA1), lymph- around the world is near infrared fluorescent edema- (HGF), hereditary imaging (NIRF) (also known as ICG lym- lymphedema III (PIEZO1), microcephaly phography). NIRF has been increasingly used lymphoedema chorioretinal dysplasia syn- in multiple centers for examining the superfi- drome (KIF11), and mutations in CELSR1. cial peripheral lymphatic system and partic- The future holds promise that such testing ularly in assisting identification of functional for other known pathogenic mutations and lymphatic vessels for lymphatic bypass oper- chromosomal defects as well as newly discov- ations; visualizing lymph nodes for mapping ered ones, combined with careful phenotypic and reverse mapping in the operative setting descriptions including lymphatic imaging, will in cancer patients; and to minimize lymphat- become routine to classify familial lymph- ic injuries during suction-assisted lipectomy angiodysplastic (more correctly, lymphan- for lymphedema at late stage. NIRF allows gioadenodysplastic since nodes can also be

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 10 involved) syndromes and other congenital/ system. These more refined classifications may genetic-dysmorphogenic disorders character- impact diagnosis (perhaps allowing proactive ized by lymphedema, lymphangiectasia, and rather than reactive care), future treatments lymphangiomatosis. Algorithms have been (targeted therapy), and enhanced quality developed and published to assist clinicians in of life as precision personalized medicine is phenotyping and directing genetic analysis. applied to lymphatic diseases. These newer There are many other clinical syndromes techniques will also contribute to prenatal with lymphedema as a component. Some of diagnosis and, combined with multimodal these have genes identified [Noonan PTPN11( , imaging, to the early diagnosis and potential KRAS, SOS1, and others); Proteus syndrome treatment of congenital lymphatic disorders. (AKT1); CLOVES syndrome (congenital lipomatosis overgrowth, vascular malforma- C. Biopsy/Lymph Node Exam tion, epidermal nevi, scoliosis/skeletal/spinal abnormalities) (PIK3CA); Parkes-Weber syn- Caution should be exercised before remov- drome (capillary malformation-arteriovenous ing enlarged regional lymph nodes in the set- malformation) (RASA1); and lymphatic re- ting of longstanding peripheral lymphedema lated hydrops fetalis (LRHG) (EPHB4)] while as the histologic information is seldom helpful, others still have no known associated genes. and such excision may aggravate distal swell- It is important to consider that the number of ing. Fine needle aspiration with cytological de novo germinal variations in these genes is examination by a skilled pathologist is a useful increasing. alternative if malignancy is suspected. Use of Genetic testing is generally focused on pri- sentinel node biopsy in the axilla or groin for mary lymphedema. However, recent and ongo- staging malignancies such as breast and mela- ing limited investigations in secondary lymph- noma has substantially lessened the incidence edema have suggested genetic (and epigenetic) of peripheral lymphedema by discouraging predispositions underlying increased risk removal of normal lymph nodes; however, an of developing secondary lymphedema after increased number of sentinel nodes taken may treatments injuring or otherwise compromis- reduce this protective effect. ing the lymphatic system. Genetic information can be useful in counseling patients (modes of IV. TREATMENT inheritance and potential to pass on defect to future generations), for prognosis and other Therapy of peripheral lymphedema is potential complications (e.g. GATA2), and for divided into conservative (non-operative) and development of targeted therapies. operative methods. Applicable to both meth- Advances in genetic techniques such as ods is an understanding that meticulous skin genome-wide association studies (GWA study, hygiene and care (cleansing, low pH lotions, or GWAS), whole genome sequencing (WGS), emollients) is of the utmost importance to the and whole exome sequencing (WES) are success of virtually all treatment approaches, rapidly accelerating genetic analysis literally as is patient education and training. Basic on a daily basis. A targeted Next Generation motion exercises of the extremities (muscle Sequencing panel examining all known genes pumping exercises), preferably performed as associated with lymphedema is currently the daily life activities (such as, walking, using most common choice for analyzing heredi- stairs over escalators, hanging clothes on the tary forms of lymphedema. As costs decrease, line rather than using the dryer), are useful more patients will undergo such analysis and and could further support external limb com- more single, multiple, and interacting variants pression. However, for cancer patients with will be identified to help classify individuals lymphedema it may also be important that with genetic defects related to the lymphatic exercise at least on a moderate level (increas-

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 11 ing pulse frequency), is performed daily. Limb care, continued exercise, and MLD as needed. elevation (specifically bed rest if indicated Prerequisites of successful combined for patients needing intensive rehabilitation) physiotherapy are the availability of phy- may also be helpful to the appropriate patient sicians (i.e., clinical lymphologists), nurses, undergoing treatment. physiotherapists, occupational and other As previously stated, even widely used therapists specifically trained, educated, and treatment methods have yet to undergo experienced in this method. In addition, fac- sufficient meta-analysis of multiple studies tors such as the acceptance of health insurers which have been rigorous, well-controlled, and to underwrite the cost of treatment, willing- with sufficient followup. Satisfactory studies ness of biomaterials industry to produce and comparing different methods of treatment do provide high quality affordable products, and not exist, and advocates of all methods report an understanding of the holistic needs of each that earlier treatment is optimal for the best patient impact success. Compressive bandag- results. It is also worth considering that a es, when applied incorrectly, can be harmful combination of therapies may be best for some and/or useless. Accordingly, such multilayer patients but these combinations are even less wrapping should be carried out only by profes- frequently studied in comparison trials. Use of sionally trained personnel. Multiple manufac- various treatment options is appropriate for tured devices/garments to assist in compres- neonates and children with careful consider- sion (i.e., pull on, velcro-assisted, quilted, etc.) ation from the care team. Treatments can take may relieve some patients of the bandaging place in the outpatient setting, a day hospital, burden and facilitate compliance with the full or during hospitalization as judged appropri- treatment program by offering compression ate by the medical team for each patient. alternatives. Some clinics find that patient self-care and risk reduction strategies help A. Non-Operative Treatment maintain edema reduction (although neither of these has undergone rigorous study). These 1. Physical therapy and adjuvants strategies can be provided by patient educa- tion including brief anatomy and physiology, a. Complex Decongestive Therapy compression treatment (care and aids), meth- ods for self-check of status, skincare, self-mas- CDT also known as Complete sage, weight control, and exercise. Decongestive Therapy (CDT) or Combined CDT may also be of use for palliation Physical Therapy (CPT) or Complex Decon- as, for example, to control secondary lymphede- gestive Physiotherapy (CDP) (among others) ma from tumor-blocked lymphatics. Treatment is backed by longstanding experience and gen- is typically performed in conjunction with erally involves a two-stage treatment program chemo- or radiotherapy directed specifically at that can be applied to both children and adults producing tumor regression. Only theoretically, for most areas of the body. The first phase massage and mechanical compression could consists of skin care, a specific light manual mobilize dormant tumor cells; however lymph massage (manual lymphatic drainage-MLD) flow does not stop after a cancer diagnosis and and sometimes deeper techniques with pa- only diffuse carcinomatous infiltrates which tients classified above Stage I, using muscle have already spread to lymph collectors as pumping exercises, and compression typically tumor thrombi might be mobilized by such applied with multilayered bandage wrap- treatment. Because the long-term prognosis ping. Phase 2 (initiated promptly after Phase for such an advanced patient is usually dismal, 1) aims to conserve and optimize the results any reduction in morbid swelling is nonetheless obtained in Phase 1. It consists of compression decidedly palliative. by a low-stretch elastic stocking or sleeve, skin A prescription for elastic garments

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(custom made with correctly-obtained specific robust studies to generate convincing evidence measurement if needed) to maintain lymph- of benefit. This is disputed by several sys- edema reduction after CDT is essential for tematic reviews with meta-analysis conclud- long-term care. Preferably, a physician (some- ing that MLD (in breast cancer-related arm times with assistance of highly-skilled special- lymphedema) has no or very little additive ists) should prescribe the compression garment effect on compression therapy. to avoid inappropriate usage in a patient with There are some published reports medical contraindications such as arterial supporting the use of manual lymph drainage disease, painful postphlebitic syndrome, occult as a monotherapy for lymphedema preven- neoplasia, and acute infections and some skin tion after cancer surgery while others do not disorders. Generally the highest compression support its value. level tolerated (~20-60 mmHg) by the patient d. Intermittent pneumatic compres- is likely to be the most beneficial. More clinics sion. Pneumomassage is usually a two-phase prefer to use only flat-knit garments while oth- program. After external compression therapy ers use both flat and round-knit garments (and is applied, preferably by a sequential gradient combinations). Sometimes patient selection, "pump," form-fitting low-stretch elastic stock- choice, physical ability as well as cost need ings or sleeves are used to maintain edema to be taken into consideration particularly reduction. Newer devices that simulate manu- when assessing mobility and future compli- al massage and design improvements for area ance (including use of alternative compression of coverage, ease of use, and sequence/actions devices). may increase patient compliance particularly Failure of CDT should be confirmed for those who cannot complete both phases only when intensive non-operative treatment of CDT (e.g., exercise with compression). in a clinic specializing in management of Displacement of edema more proximally in peripheral lymphedema and directed by an the limb and genitalia and the development of experienced clinical lymphologist has been a fibrosclerotic ring at the root of the extremity unsuccessful. with exacerbated obstruction of lymph flow b. Compression garments alone have need to be assiduously avoided by careful been successfully used for treatment partic- observation. Some compression options now ularly in breast cancer-related lymphedema include treating the root of the limb as part of and for prevention at first indication of fluid the individual protocols/devices. Combining buildup and minimal volume change as well pneumatic compression with manual lymph as in early Stage I. Data on the garment alone drainage has been suggested but not sufficient- use for later stages are very limited. ly evaluated. c. Massage alone. Performed as an iso- e. Exercise programs. Exercise as a form lated technique, classical massage or effleu- of treatment for lymphedema has received rage generally does not appear to be of benefit. increasing attention over the past decade and Moreover, if performed overly vigorously, particularly for women with unilateral breast massage (classical or others, not MLD) may cancer-related lymphedema. Pre-post and damage lymphatic vessels or their attachment randomized, controlled trials have evaluated to surrounding tissues. the effect of a range of exercises [aerobic exer- There are several published studies cise including walking (normal, Nordic, pole), demonstrating the utility of MLD monother- aquatic exercise, exercise using ergometer; re- apy in specific populations (i.e., early breast sistance exercise using free, body and machine cancer-related lymphedema and newly estab- weights and therabands; other including yoga lished and/or mild lymphedema particularly and tai chi] and intensities (including moder- in younger children without adipose or fibrous ate and vigorous), conducted under supervised tissue deposition) but there is a need for more and unsupervised conditions on lymphedema

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status and lymphedema- associated outcomes. sion have been advocated for and successfully While the evidence base is unable to show used by practitioners in Europe and Asia for declines in lymphedema through exercise, the thousands of patients, the role and value of evidence consistently supports that participa- thermotherapy alone without compression in tion in physical activity including exercise is the management of lymphedema remains un- safe and will likely improve lymphedema-as- clear and further rigorous studies are needed. sociated symptoms as well as function, fitness Studies have shown that under bandaging the and quality of life. skin temperature slowly rises, and it is pro- f. Kinesiotaping: Kinesiotaping shows posed that this lower level thermal therapy is promise as a form of lymphedema treatment, helpful. Some centers use far infrared light as with studies involving women with breast can- an adjunct to bandaging and report improved cer-related lymphedema showing volume de- outcomes. clines following use. However, when compared l. Wringing out. "Tuyautage" or wring- with other forms of lymphedema treatment, ing out performed with bandages or rubber the benefit is less clear. tubes is probably injurious to lymph vessels g. Elevation. Simple elevation (partic- and should seldom if ever be performed. ularly by bed rest) of a lymphedematous limb often reduces swelling in specific patients, 2. Drug therapy particularly in Stage I of lymphedema. If swelling is reduced by antigravimetric means, a. Diuretics. Diuretic agents are of the effect should be maintained by wearing of limited use during the initial treatment phase a low-stretch, elastic compression garment. of CDT and should be reserved for patients Some centers use bed rest for intensive vas- with specific co-morbid conditions or compli- cular rehabilitation for: advanced stages with cations. Long-term administration of diuretics, comorbidity, those in need of 24 hour monitor- however, is discouraged for it is of marginal ing, patients lacking the ability for transport, benefit in treatment of peripheral lymph- and patients without a social support network. edema and potentially may induce fluid and h. Low level laser. Reports with small electrolyte imbalance. Diuretic drugs may be numbers and limited meta-analysis have helpful to treat effusions in body cavities (e.g., demonstrated efficacy of low level laser use ascites, hydrothorax) and in protein-losing for patients with lymphedema. More robust enteropathy as well as in those patients un- changes are noted with reduction of pain and dergoing palliative care. Patients with periph- mobility of tissue rather than just pure lymph- eral lymphedema from malignant lymphatic edema volume reduction. blockage may also derive benefit from a short i. Aquatic therapy/water-based exercise course of diuretic drug treatment. programs have shown some success due to the b. Benzopyrones. Oral benzopyrones, natural compression of water when exercising which have been reported to hydrolyze tissue and improvements to skin condition. Not all proteins and facilitate their absorption while patients (particularly those with wounds or stimulating lymphatic collectors, are neither skin conditions) are candidates for aquatic an alternative nor substitute for CDT. The therapy. exact role for benzopyrones (which include j. For appropriate patients, adjuvant those termed rutosides and bioflavonoids) as devices such as ultrasound or shockwaves an adjunct is still not definitively determined may be useful to help break up fibrous tissue including appropriate formulations and dose although no large patient series have been regimens. Coumarin, one such benzopyrone, published. in higher doses has been linked to liver toxicity k. Thermal therapy. Although combina- particularly in some patients with specific liver tions of heat, skin care, and external compres- enzyme defects.

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c. Antimicrobials. Antibiotics should be tered long-term. administered for bona fide superimposed acute g. Diet. No special diet has proved to be lymph stasis-related inflammations (cellulitis/ of therapeutic value for most uncomplicated lymphangitis or erysipelas). Typically, these peripheral lymphedema. While higher body episodes are characterized by erythema, pain, mass index has been consistently associated high fever and, less commonly, even septic with increased risk of developing lymphedema, shock. Mild skin erythema without systemic to date, there is only very limited evidence to signs and symptoms does not necessarily signi- support that weight loss may improve lymph- fy bacterial infection. If repeated limb "sepsis" edema. Nonetheless, weight loss is likely to recurs despite optimal CDT, the administra- contribute to improvements in lymphedema-as- tion of a prophylactic penicillin or broad spec- sociated symptoms as well as other benefits trum antibiotic is recommended (continuance (e.g., improved body image, insulin control) depends on medical risk/benefit assessment). which would be relevant to the majority of Fungal infection, a common complication of those with primary or secondary lymphedema. extremity lymphedema, can be treated with Restricted fluid intake is not of demonstrated antimycotic drugs. In most instances, washing benefit for peripheral lymphedema. In chylous the skin using a mild disinfectant followed by reflux syndromes (e.g., protein/lymph-losing antibiotic-antifungal cream is helpful. Short- enteropathy as in intestinal lymphangiectasia), term use of anti-histamines and steroids in a diet as low as possible or even free of long- selected patients with inflammation has also chain triglycerides (absorbed via intestinal been utilized by some practitioners. lacteals) and high in short and medium chain d. Filariasis. To eliminate microfilariae triglycerides (e.g., MCT absorbed via the portal from the bloodstream in patients with lym- vein) is of benefit especially in children. Specific phatic filariasis, the drugs diethylcarbamazine, vitamin supplements may be needed in very albendazole, or ivermectin are recommended. low or no fat diets. Killing of the adult nematodes by these drugs h. In complex patients with lymphat- (macrofilaricidal effect) is variable and may ic system and segmental body or specific be associated with an inflammatory-immune soft tissue overgrowth (e.g., Proteus, Klip- response by the host with aggravation of pel-Trenaunay, and other syndromes) asso- lymphatic blockage. Short- and long-term ciated with lymphedema, specialized centers efficacy of antibiotics (e.g., penicillin or doxy- may utilize an array of pharmacotherapeutic cycline) separate from vigorous skin hygiene options such as octreotide, sirolimus, OK432, in patients with lymphatic filariasis to prevent rapamycin and other anti-proliferative agents elephantine trophic changes is gaining wider (these treatments are particularly used in acceptance, and some work has demonstrated newborns and children). There have been that doxycycline can reduce the incidence of some reports of patients developing lymphede- lymphedema. ma after use of rapamycin and sirolimus, and e. Mesotherapy. The injection of hyal- serious side effects can be seen. uronidase or similar agents to loosen the extra- i. Curcumin. Some centers are exam- cellular matrix is of unclear benefit and may ining the use of curcumin. There are some actually be harmful. studies that report its inflammatory protective f. Immunological therapy. Efficacy of effect when sirolimus is administered. boosting immunity by intraarterial injection of autologous lymphocytes is unclear and needs 3. Psychosocial Rehabilitation independent, reproducible evidence. Recent trials of anti-inflammatory The magnitude of the relationships pharmaceuticals have not yet demonstrated between negative psychological and psy- efficacy and may face drawbacks if adminis- chosocial factors and lymphedema has been

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 15 documented as a cause of non-adherence to treatment within specific guidelines is now a self-management as well as diminution in preferred approach depending on the treat- quality of life. Psychosocial support, quality of ment team's training and the availability of life assessment- improvement programs, and various treatments. As is the case with any patient self-efficacy assessments are integral category of surgery, differences in surgical components of sound lymphedema treatment. treatment will exist among different centers and patients are strictly selected. B. Operative Treatment 1. Microsurgical Procedures Operations designed to alleviate pe- ripheral lymphedema by enhancing lymph This operative approach is designed to return have gained increasing acceptance and augment the rate of return of lymph to the application worldwide but in advanced stages blood circulation. The surgeon should be well- usually require long-term combined physio- schooled in both microsurgery and lymphol- therapy and/or other compression after the ogy and utilize appropriate imaging tools to procedure to maintain edema reduction and document efficacy short and longer term. In ensure vascular/shunt patency. These micro- general, microsurgical procedures must be surgical and supermicrosurgical procedures performed with special caution in children currently provide the closest chance for a cure and some forms of primary lymphedema. Ex- of lymph flow disorders. In carefully selected perience with these procedures suggests that patients following full evaluation, these pro- improved and longer lasting benefit is forth- cedures act as an adjunct to CDT (typically coming if performed early in the course of after the fluid component has been removed lymphedema before damage to the lymphatic and pitting is absent) or are undertaken wall and impaired lymphatic contractility when CDT has clearly been unsuccessful. have occurred. Liposuction, lymphaticovenous anastomosis a. Derivative methods. Lymphatic-ve- and lymph node transfer operations coupled nous (or lymphovenous) anastomoses (LVA) with appropriate lymphedema therapy and are currently in use at many centers around compression are effective when used to treat the world. These procedures have undergone properly selected lymphedema patients and confirmation of long-term patency (in some performed by an experienced lymphedema cases more than 25 years) and demonstration surgeon. Recent research has also focused on of improved lymphatic transport (by objective preventive use in high risk patients. Imaging is physiologic measurements of long-term effica- indispensable to identify functional lymphatic cy). Multiple lymphatic-venous anastomoses vessels or nodes to manipulate. As with the in a single surgical site, with both the super- physical methods described above, proponents ficial and deep lymphatics, allow the creation report that greater success is found in patients of a positive pressure gradient (lymphatic-ve- with early (Stage I) lymphedema (with the no- nous) and evade the phenomenon of gravita- table exception of liposuction, which is usually tional reflux without interrupting the distal performed in later stages). peripheral superficial lymphatic pathways. Worldwide, surgical resection (in sever- Some centers particularly in areas of endemic al forms) is the most widely used operative filariasis also practice lymph nodal-venous technique to reduce the bulk of lymphedema shunts as a derivative method. Multiple cen- (especially in genitalia cases). Liposuction to ters are using LVA (LYMPHA) as a preventa- reduce excess fat deposition is becoming more tive measure in high risk patients. widespread with surgeons in multiple coun- b. Reconstructive methods. These tries now performing the procedure. sophisticated techniques involve the use of a In some specialized centers, operative lymphatic collector (LLA) or an interposition

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vein segment (LVLA) to restore lymphatic liposuction, which facilitates breaking down continuity in lymphedema conditions due to a fibrosis especially in leg lymphedema. Similar locally interrupted lymphatic system. Autolo- to conservative treatment, long- term manage- gous lymph vessel transplantation mimics the ment requires strict patient adherence with normal physiology and has shown long-term dedicated continuous wearing of low-stretch, patencies of more than 20 years. This proce- flat-knitted elastic compression garments, dure generally has been restricted to unilateral which may be challenging in warmer cli- peripheral lymphedema of the leg due to the mates and pose financial considerations. This need for one healthy leg to harvest the graft surgical technique and followup are very but it has also been utilized for bilateral upper different from cosmetic liposuction and should extremity lymphedema where two healthy legs be performed by an experienced team of are available for lymphatic harvesting. The surgeons, nurses, occupational therapists and LVLA method is especially indicated in selected physiotherapists to obtain and sustain optimal patients with phlebolymphedema characterized outcomes. by stable and persistent venous hypertension, Liposuction for lymphedema does not contraindicating derivative methods. alter the need for compression therapy beyond appropriate garment after surgery. Rather, 2. Vascularized Lymph Node Transplan- continued patient compliance with conserva- tation tive treatment and compression both before and after lymphedema liposuction are essen- Transplantation of superficial lymph tial for successful results. Lymphedema sur- nodes from an uninvolved area together gery options may now include the possibility with the vascular supply (VLNT) to the site of combining microsurgery with lymph vessel of lymphadenectomy for cancer has been sparing liposuction in an effort to decrease the proposed both as a preventive and therapeutic need for continual compression. approach to limb lymphedema. As far as treatment of peripheral lymph- There have been several reports of lymph- edema at late stage is concerned, an effective edema developing in the donor area. Surgeon lymph vessel sparing procedure, by intraop- experience and the use of reverse lymphatic erative mapping of the superficial-subdermic mapping may decrease this risk. Vascularized lymphatic network through ICG lymphog- lymph node transfer procedures have been raphy, defined fibro-lipo-lymph-aspiration, shown to improve patient outcomes in several without tourniquet and previous tumescent studies but the effect may also depend on pro- infiltration of an appropriate solution to min- nounced scar release in the axilla increasing imize the bleeding, is showing some promise, the venous outflow. especially after microsurgical reconstruction.

3. Liposuction 4. Surgical Resection

Liposuction (or suction-assisted lipec- A much less used operation these days is tomy) using a variety of methods has been "debulking," that is, removal of excess skin and shown to completely reduce non-pitting, subcutaneous tissue of the lymphedematous primarily non- fibrotic, extremity lymphede- limb. The major disadvantage is that superfi- ma due to excess fat deposition (which has cial skin lymphatic collaterals are removed or not responded to non-operative therapy) in further obliterated. It can also be associated both primary and secondary lymphedema with significant scarring, risk of infection, and (and more limited studies in lipedema). Even difficult wound healing. After intensive CDT, patients with signs of fibrosis can benefit from redundant skin folds may require excision. the procedure when using power-assisted Debulking has been reported to be useful

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mainly in treatment of the most severe forms venous malformations) are often treated with a of fibrosclerotic lymphedema (elephantiasis) variety of surgical procedures (as well as with and in cases of advanced genital lymphede- pharmacotherapy) in highly specialized centers. ma. In the case of filariasis (Grade 3 and 4), Rehabilitation and even habilitation are reduction surgery in one or two stages (with- particularly necessary components of care. out skin grafting) may be performed after nod- al-venous shunts if needed. Caution should be C. Treatment Assessment/Followup exercised in removing enlarged lymph nodes or soft-tissue masses (e.g., lymphangiomas) In each patient undergoing therapy, an in the affected extremity as lymphedema may assessment of limb volumes should be made worsen thereafter. Operations including the before, during and after treatment. This vol- Charles and Thompson procedures are seldom ume can be measured by water displacement, used now that other options are available. derived from circumferential measurements using the truncated cone formula, or by per- 5. Tissue Engineering/Lymphatic (Re) ometry. The excess volume (affected limb - un- Vascularization affected limb) should be measured since limb volumes vary with weight increase/decrease of The implantation of silicone tubes as arti- the patient as well as whether measurements ficial lymphatics to transport lymph or engi- are made in the morning or afternoon. Only neered tubes/devices to promote new substitute measuring the affected extremity can lead lymphatic growth have not yet documented to unreliable values. However, in lower limb long-term value in large studies, and these tech- lymphedema following cancer treatment, niques are continuing to undergo investigation. both limbs may be affected and therefore each Omental transposition, enteromesenteric limb needs to be followed individually. It is bridge operations, and implantation of threads desirable, however, that treatment outcomes to promote perilymphatic spaces (substitute be reported in a standardized manner in order lymphatics) have not shown long-term value to compare and contrast the effectiveness of and should be avoided since convincing pub- various treatment protocols. lished evidence is lacking. Additional assessments by imaging modalities such as LAS and NIRF to docu- 6. Other Specialized Considerations ment functional changes in lymphatic drain- Including Interventional Therapy age, DXA, US, or MR imaging to determine volume and tissue compositional changes, Chylous and non-chylous reflux syn- tonometry/indurometry, BIS or BIA, and dromes are special disorders, which may tissue dielectric constant to examine tissue manifest as peripheral lymphedema. These alterations and fluid changes add scientific conditions may benefit from CT- or MR-guid- rigor to analysis of the outcomes of different ed sclerosis, other interventional radiology treatment approaches. techniques, or operative ligation of visceral Health Related Quality of Life (HRQOL) dysplastic lymphatics, and/or lymphatic to ve- and patient perceptions of self-efficacy nous diversion to close and decompress leak- assessed by a variety of validated disease ing lymphatic vessels including the thoracic specific instruments and visual analog scales duct after delineation by multimodal imaging. of patients with lymphedema should be used Assessment in children and even pre-natally is in conjunction with physiological measures to an expanding area of interest. evaluate effects of treatment. Extratruncal disease (i.e., lymphatic mal- Pinpointing timing and longevity of formations outside of the main trunks which assessments is an area that is recognized as a may or may not be associated with arterial/ need but there are no good guidelines or model

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 18 systems in place. Pre-treatment and pre-oper- translating new discoveries and potentially ative assessment (in the Prospective surveil- improved approaches more rapidly into the lance model- see Section I) should continue clinical arena. Ongoing epidemiologic studies after treatment and likely should be life-long on the incidence and prevalence of lymphede- to include HRQOL, self-efficacy, and self-reg- ma regionally and worldwide will benefit from ulation measures. Data on long-term results the further development and establishment will be useful in comparing treatment options of standardized, secure, intercommunicating and success as well as enable patients to have database-registries. Assessment of lymph- the opportunity to participate in best-practice edema risk and steps for lymphedema pre- decisions. vention in different groups of at risk patients need to be determined. Studies might include D. Molecular Therapy research on: minimizing or preventing second- ary lymphedema through revised operative/ Despite ongoing basic research and clin- nodal sampling protocols (e.g., advances in ical trials, molecular treatments (e.g., admin- sentinel node biopsy or precise anatomical istration of VEGF-C or other lymphatic-tar- delineation of derivative pathways); vec- geting molecules by various methods) have not tor control (as demonstrated in China) and yet been significantly translated to the clinic. prophylactic drugs for filariasis; identification While the addition of lymphatic growth (or of patients with heritable genetic defects for inhibitory) factors is attractive, the applica- lymphangiodysplasia (lymphedema); and use bility of these treatments is uncertain at this of massage or compression where lymphatic time and should be examined carefully in the drainage is subclinically impaired as clinically context of co-morbid conditions (e.g., presence documented by palpated increased skinfold of cancer, cancer treatments, drug regimens). thickness, small amounts of excess volume, It is also apparent when examining the growth and BIS and TDC values outside normal of new lymphatics in the laboratory that for range, as well as imaging techniques (e.g., all but the smallest microlymphatics, a milieu LAS-SPECT-CT, MR, and NIRF). Research of growth (and other) factors may be needed in molecular lymphology including lymphatic for initiation and development of functional system genomics, proteomics, metabolemics, macrolymphatics (and even more for the de and "systemomics" should be greatly expand- novo development of lymph nodes). ed. With the cellular and molecular basis of lymphedema-associated syndromes better V. RESEARCH AGENDA defined, an array of specific biologically-based treatments including modulators of lymphatic While recognizing and encouraging indi- growth and function should become available. vidual investigators to pursue many different Improved imaging techniques and physio- avenues of research including those specifical- logical tests need to be devised to allow more ly suggested in this document, some general precise non-invasive methods to measure directions can be formulated. Diagnostic lymph flow dynamics and lymphangion activ- techniques need to be continually explored, ity. Advances in imaging including molecular developed, and standardized. Treatment imaging techniques as well as development of options need confirmation and improvements new and improved technologies (e.g., pho- with a particular focus on personalization, and toacoustics) to visualize the superficial and better delineation of prognosis. Multinational deep lymphatic system and soft tissues need collaborative studies and innovative adaptive to continue. These may become point- of-care clinical research designs in addition to ran- devices available to all or even encompass domized controlled trials need to be carried wearable sensors for both early detection and out and further encouraged with the aim of treatment assessment sent digitally through

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 19 a mobile phone or over the internet. Telelym- REFERENCES phology consultations and followup linkage of specialized centers to remote areas should 1. International Society of Lymphology Executive enhance future care delivery. As knowledge Committee. The Diagnosis and Treatment of Peripheral Lymphedema. Lymphology 28 accrues, the current crude classification of (1995), 113-117. lymphedema should be revisited and modified 2. Witte MH, CL Witte, and M Bernas for the Ex- to include more encompassing clinical geno- ecutive Committee. ISL Consensus Document type-phenotype correlations based on anatom- Revisited: Suggested Modifications. Lympholo- ic and functional alterations in the lymphatic gy 31 (1998), 138-140. 3. International Congress of Lymphology, Chen- or associated affected systems. Accordingly, nai, India. General Assembly discussion. ISL treatment, whether by designer drugs, gene or Consensus Document Revisited. September 25, stem cell therapy, tissue engineering, physical 1999. methods or new operative approaches, should 4. ISL Executive Committee Meeting, Földi be directed at preventing, reversing or ame- Klinik, Hinterzarten, Germany. Discussions on modification of the ISL Consensus Document. liorating the specific lymphatic defects and August 30, 2000. restoring function and quality of life. 5. Discussions at the XVIII ICL in Genoa, Italy, September 2001 and over 50 written and verbal VI. CONCLUSION comments submitted to Executive Commit- tee members. Changes discussed, modified, deleted, and confirmed at 2002 ISL Executive Lymphedema may be uncomplicated or Committee meeting, May 2002, Cordoba, complex but should not be neglected. Accurate Argentina. early diagnosis and effective therapy is now 6. Consensus and dissent on the ISL Consensus available which should be able to shift the Document on the diagnosis and treatment of peripheral lymphedema (M. Bernas and focus to a more proactive rather than reactive M.H. Witte); Remarks (M Földi); Liposuction approach. Randomized trials need to take and the Consensus Document (H. Brorson); place. Lymphology itself is now recognized Adipose tissue in lymphedema (H. Brorson); as an important and distinct discipline in Liposuction in the Concensus Document (S. which clinicians from diverse specialties can Slavin); A search for consensus on staging and lymphedema (T.J. Ryan); and Guidelines be carefully trained and collaborate to unravel of the Societá Italiana Di Linfangiologia: the intricacies of the lymphatic system, lymph Excerpted sections (C. Campisi, S. Michelini, circulation, and related disorders. The emerg- F. Boccardo). Lymphology 37 (2004), 165- 184. ing era of molecular lymphology and precision 7. Changes discussed, modified, deleted, and medicine tailored to the individual patient confirmed at 2008 ISL Executive Committee meeting, June 2008, Naples, Italy. is likely to result in earlier recognition of a 8. The Diagnosis and Treatment of Peripheral potential problem, improved understanding, Lymphedema: 2009 Consensus Document of evaluation, and treatment in the lymphology the International Society of Lymphology. Lym- clinic, and in the larger context of clinical phology 42 (2009), 51-60. 9. The Diagnosis and Treatment of Peripheral medicine. Lymphedema: 2013 Consensus Document of the International Society of Lymphology. Lym- phology 46 (2013), 1-11. 10. The Diagnosis and Treatment of Peripheral Lymphedema: 2016 Consensus Document of the International Society of Lymphology. Lym- phology 49 (2016) 170-184.

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