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Lymphology 49 (2016) 170-184

THE DIAGNOSIS AND TREATMENT OF PERIPHERAL : 2016 CONSENSUS DOCUMENT OF THE INTERNATIONAL SOCIETY OF LYMPHOLOGY

This International Society of Lymphology “Consensus” of the international community (ISL) Consensus Document is the latest based on various levels of evidence. The revision of the 1995 Document for the document is not meant to override individual evaluation and management of peripheral clinical considerations for complex patients lymphedema (1). It is based upon modifica- nor to stifle progress. It is also not meant to tions: [A] suggested and published following be a legal formulation from which variations the 1997 XVI International Congress of define medical malpractice. The Society Lymphology (ICL) in Madrid, Spain (2), understands that in some clinics the method discussed at the 1999 XVII ICL in Chennai, of treatment derives from national standards India (3), and considered/ confirmed at the while in others access to medical equipment 2000 (ISL) Executive Committee meeting in and supplies is limited; therefore the suggested Hinterzarten, Germany (4); [B] derived from treatments might be impractical. Adaptability integration of discussions and written and inclusiveness does come at the price that comments obtained during and following the members can rightly be critical of what they 2001 XVIII ICL in Genoa, Italy as modified see as vagueness or imprecision in definitions, at the 2003 ISL Executive Committee meeting qualifiers in the choice of words (e.g., the use in Cordoba, Argentina (5); [C] suggested of “may... perhaps... unclear”, etc.) and from comments, criticisms, and rebuttals as mentions (albeit without endorsement) of published in the December 2004 issue of treatment options supported by limited hard Lymphology (6); [D] discussed in both the data. Most members are frustrated by the 2005 XX ICL in Salvador, Brazil and the reality that NO treatment method has really 2007 XXI ICL in Shanghai, China and undergone a satisfactory meta-analysis modified at the 2008 Executive Committee (let alone rigorous, randomized, stratified, meeting in Naples, Italy (7,8);[E] modified long-term, controlled study). With this under- from discussions and written comments from standing, the absence of definitive answers the 2009 XXII ICL in Sydney, Australia, the and optimally conducted clinical trials, 2011 XXIII ICL in Malmö, Sweden, the 2012 and with emerging technologies and new Executive Committee Meetings (9),and [F] approaches and discoveries on the horizon, from discussions at the 2013 XXIV ICL in some degree of uncertainty, ambiguity, and Rome, Italy, and the 2015 XXV ICL in San flexibility along with dissatisfaction with Francisco, USA, as well as multiple written current lymphedema evaluation and manage- comments and feedback from Executive ment is appropriate and to be expected. Committee and other ISL members during We continue to struggle to keep the document the 2016 drafting. concise while balancing the need for depth The document attempts to amalgamate and details. With these considerations in the broad spectrum of protocols and practices mind, we believe that this 2016 version advocated worldwide for the diagnosis and presents a Consensus that embraces the entire treatment of peripheral lymphedema into a ISL membership, rises above national coordinated proclamation representing a standards, identifies and stimulates promising

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 171 areas for future research, and represents the giosclerosis (secondary lymphedema) or as best judgment of the ISL membership on how a consequence of functional deficiency to approach patients with peripheral lymph- (e.g., lymphangiospasm, stasis, and valvular edema in the light of currently available insufficiency in primary or secondary evidence. Therefore, the document has been, lymphedema. Nonetheless, the common and should continue to be, challenged and denominator is that the debated in the pages of Lymphology (e.g., as (whether vessels, nodes, interstitium, etc, Letters to the Editor) and ideally will remain a or combinations) transport has fallen below continued focal point for robust discussion at the capacity needed to handle the presented local, national and international conferences load of microvascular filtrate including in lymphology and related disciplines. We plasma protein and cells that normally leak further anticipate as experience evolves and from the bloodstream into the interstitium. new ideas and technologies emerge that Swelling is produced by accumulation in the this “living document” will undergo further extracellular space of excess water, filtered/ periodic revision and refinement as the diffused plasma proteins, extravascular blood practice and conceptual foundations of cells and parenchymal/stromal cell products. medicine and specifically lymphology change This process culminates in proliferation of and advance. parenchymal and stromal elements with excessive deposition of extracellular matrix Keywords: Consensus, lymphedema, substances and adipose tissue. High output diagnosis, treatment, ISL, International failure (dynamic insufficiency) of the lymph Society of Lymphology circulation, on the other hand, occurs when a normal or increased transport capacity of I. GENERAL CONSIDERATIONS intact lymphatics is overwhelmed by an excessive burden of blood capillary filtrate. As a fundamental starting point, Examples include hepatic cirrhosis (ascites), lymphedema is an external (and/or internal) hypoalbuminemia associated with nephrotic manifestation of lymphatic system syndrome (anasarca), right heart failure, insufficiency and deranged lymph transport and deep venous insufficiency of the leg Some members prefer to define peripheral (peripheral edema). Although the final lymphedema as a symptom or sign resulting pathway is the manifestation of tissue edema from underlying lymphatic disease. It is whenever lymph formation exceeds lymph defined as an illness by the International absorption, the latter entities should properly Classification of Diseases from the World be distinguished from lymphedema, which is Health Organization. Lymphedema may be characterized by decreased lymphatic trans- an isolated phenomenon or associated with a port. In some syndromes where high output multitude of other disabling local sequelae or lymphatic transport failure is longstanding, even life-threatening systemic syndromes. Its a gradual functional deterioration of the nature may be acute, transitory, or chronic. draining lymphatics may supervene and In its purest form, the central disturbance is a thereby reduce overall transport capacity. low output failure (mechanical insufficiency) A reduced lymphatic circulatory capacity of the lymphvascular system; that is, overall then develops in the face of increased blood lymphatic transport is reduced. This capillary filtration. Examples include derangement arises either from congenital recurring infection, thermal burns, and lymphatic dysplasia () repeated allergic reactions. These latter or anatomical obliteration, such as after conditions are associated with “safety valve radical operative dissection (e g., axillary or insufficiency” of the lymphatic system where retroperitoneal nodal sampling), irradiation, the lymph load increases over “normal” flow or from repeated with lymphan- to eventually become overwhelmed and this

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 172 can be considered a mixed form of edema/ patient condition (ambulation, portability, lymphedema and as such are particularly fragility, etc.) can all impact individualized troublesome to treat. patient care and treatment. Peripheral lymphedema associated with chylous and non-chylous reflux syndromes Prevention/Early Identification and Treatment is an infrequent but complex condition that requires specific diagnostic measures and The recent promulgation of lists of risk treatment methods. There are other factors for secondary lymphedema has complicating diagnoses (e.g., genetic with become a highlighted issue due to publica- Turner or Noonan syndromes or arterial/ tions of “do’s and don’ts”. These are largely venous malformations) which require anecdotal and not sufficiently investigated. additional considerations. While some precautions rest on solid In the treatment of “classical” lymph- physiological principles (e.g., avoiding edema of the limbs (that is, peripheral excessive heat on an “at risk” limb, not lymphedema), improvement in swelling can having chemotherapy administered into the usually be achieved by non-operative therapy. limb unless medically necessary, or trying to Because lymphedema most often becomes a avoid infections), others are less supported. chronic, generally incurable condition, it Consistently, a BMI >25, axillary node generally requires, as do other chronic dissection, radiation to the axilla, and disorders, lifelong care and attention along appearance of cellulitis following operation with psychosocial support. The continued are more firmly supported as true risks. It need for therapy does not mean a priori that must be noted that most published studies on treatment is unsatisfactory, although often it incidence of secondary lymphedema of the is less than optimal. For example, patients extremities report less than 50% chance of with diabetes mellitus continue to need developing lymphedema with nodal basin drugs (insulin) or special diet (low calorie, operations, irradiation, and taxane-based low sugar) in order to maintain metabolic chemotherapy (substantially less with more homeostasis. Similarly, patients with chronic conservative treatments, e.g., lumpectomy venous insufficiency require lifelong external with sentinel biopsy). Therefore, compression therapy to minimize edema, standard use of some of these “don’ts” for lipodermatosclerosis and skin ulceration risk reduction of lymphedema may not be (treatments may be preventative if initiated appropriate and possibly subjects patients to early). Compliance and adherence of the therapies which are unsupported until a point patient is also essential to an improved in the future when evaluation and prognosti- outcome. With chronic venous insufficiency, cation evidence has demonstrated more poor patient compliance may be causally clearly specific risks and the corresponding associated with progressive skin ulceration, preventative measures. hyperpigmentation, and other trophic The concepts of “primary” and changes in the lower leg. Similarly, failure to “secondary” prevention (including risk control lymphedema may lead to repeated reduction) are receiving increased attention. infections (cellulitis/lymphangitis), Operative imaging techniques to lessen progressive elephantine trophic changes in lymphatic system impact by identifying the skin, sometimes crippling invalidism and lymphatic vessels to avoid during procedures on rare occasions, the development of a as well as performing prophylactic lymphatic- highly lethal lymphangiosarcoma (widely venous shunts in high-risk patients are being known as Stewart-Treves syndrome). explored. Exercise, self-MLD, and education The particular setting of examination, for prevention of secondary lymphedema are diagnosis, and treatment (clinic, hospital, also undergoing investigation. Radiation properly designed teams, etc.) as well as treatment techniques are continually evolving

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 173 to reduce and isolate secondary damage. II. STAGING OF LYMPHEDEMA Further research is needed, and all such techniques will have to be tempered by the Most ISL members rely on a three stage actual risk of developing lymphedema in scale for classification of a lymphedematous specific populations based on emerging limb with an increasing number recognizing incidence evidence. Stage 0 (or Ia) which refers to a latent or sub- Recently, the question of when to monitor clinical condition where swelling is not yet a patient has emerged for patients undergoing evident despite impaired lymph transport, cancer treatment. Prospective surveillance subtle alterations in tissue fluid/composition, models (PSM) have been developed to address and changes in subjective symptoms. It may early detection of lymphedema leading to exist months or years before overt edema earlier and more efficacious treatment. The occurs (Stages I-III). Assessment of early prospective surveillance model involves a pre- fluid changes can be accomplished using operative cancer treatment assessment where bioimpedance spectroscopy or tissue dielectric baseline limb volume and functional mobility constant analysis. Stage I represents an early measurements are established (some clinics accumulation of fluid relatively high in with the availability of bioimpedance protein content (e.g., in comparison with spectroscopy may utilize that to detect early “venous” edema) which subsides with limb changes in tissue fluid accumulation). elevation. Pitting may occur. An increase in Patients are then followed in a prospective various types of proliferating cells may also manner (e.g., 3 month intervals for the first be seen. Stage II signifies that limb elevation year during and post- cancer treatment and alone rarely reduces the tissue swelling and then less frequently). Followup visits include pitting is manifest. Later in Stage II, the limb psychosocial support and reassessment of may not pit as excess subcutaneous fat and limb volume and functional mobility to offer fibrosis develop. Stage III encompasses a comparison to baseline measures to enable lymphostatic elephantiasis where pitting can identification of meaningful change associ- be absent and trophic skin changes such as ated with sub-clinical onset of lymphedema. acanthosis, alterations in skin character Sub-clinical lymphedema is measurable at and thickness, further deposition of fat and low diagnostic thresholds (3-5% volume fibrosis, and warty overgrowths have change from baseline in swelling not due to developed. It should be noted that a limb weight change –i.e. determined by measuring may exhibit more than one stage, which may both limbs) and may initially present in only reflect alterations in different lymphatic one segment of the limb. Identifying sub- territories. clinical lymphedema facilitates early, These Stages only refer to the physical conservative intervention and may reduce the condition of the extremities. A more detailed likelihood that the condition will progress to and inclusive classification needs to be a chronic advanced stage. Identifying and formulated in accordance with improved treating lymphedema at an early stage offers understanding of the pathogenic mechanisms greater treatment success and potential cost of lymphedema (e.g., nature and degree of savings with conservative management lymphangiodysplasia, lymph flow perturba- programs including compression garments, tions, and nodal dysfunction as defined by education for self-care, self-MLD (and/or anatomic features and physiologic imaging partner/care giver-MLD), psychosocial and testing) and underlying genetic support and exercise. Early identification disturbances, which are gradually being may also offer the opportunity for lymphatic- elucidated. Recent publications combining venous shunts in appropriate situations to both physical (phenotypic) findings with offer a potential life-long avoidance of further functional lymphatic imaging as well as treatment. those classifications which propose inclusion

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 174 of disability grading, assessment of inflamma- An accurate diagnosis of lymphedema is tion, and even immunohistochemical changes essential for appropriate therapy. In most determined by biopsy of nodes/vessels may patients, the diagnosis of lymphedema can be be forecasting the future evolution of staging. readily determined from the clinical history In addition, incorporation of genotypic and physical examination. In other patients, information, expanded from what is available confounding conditions such as morbid even in current screening, would further obesity, lipohyperdystrophy, endocrine advance staging and classification of patients dysfunction, venous insufficiency, unrecog- with peripheral (and other) lymphedema. nized trauma, and repeated infection may Within each Stage, a limited but complicate the clinical picture. Moreover, in nonetheless functional severity assessment considering the basis of unilateral extremity has utilized simple volume differences lymphedema, especially in adults, solid assessed as minimal (>5-<20% increase in organ tumors (primary and/or metastatic), limb volume), moderate (20-40% increase), lymphomas, and soft tissue sarcomas which or severe (>40% increase). Some clinics prefer may obstruct or invade more proximal to use >5-10% as minimal and >10-<20% lymphatics need to be considered. For these as mild. Volume differentials are most reasons, a thorough medical evaluation is commonly determined using circumferential indispensable before embarking on lymph- measurement due to wide availability and low edema treatment. Co-morbid conditions such cost. A flexible nonstretch tape is preferred as congestive heart failure, hypertension, and the truncated cone formula is utilized thyroid abnormalities, cerebrovascular disease for calculating volume. Water displacement including stroke, and vascular malformations volumetry is used in some clinics for arm or may also influence the diagnosis and thera- lower leg volumes although there are some peutic approach undertaken. practical limits (e.g., size of limb, measuring areas near the root of the limb, and hygiene A. Imaging issues). Perometry provides high accuracy by using infrared light beams to estimate limb If the diagnosis of lymphedema is volume but the equipment cost is significant unclear or in need of better definition for for smaller clinics and the hand and foot are prognostic or therapeutic considerations, not included. consultation with a clinical lymphologist or Clinicians also incorporate factors such referral to a lymphologic center if accessible as extensiveness, occurrence of erysipelas is recommended. Commonly, ultrasound attacks, inflammation, and other descriptors techniques are first used to assess and rule or complications into their own individual out venous disease in many centers (although severity determinations. this is also used in some centers to assess Some healthcare professionals focus on lymphedema). The diagnostic tool of isotope disability rating utilizing the World Health lymphography (also termed lymphoscin- Organization’s guidelines for the International tigraphy – for both vessels and nodes – or Classification of Functioning, Disability, and more commonly lymphangioscintigraphy Health (ICF). Quality of Life issues (psycho- despite its reference only to the vessels) has social, social, emotional, physical disabilities, proved extremely useful for depicting the etc.) may also be addressed by individual specific lymphatic abnormality. Where clinicians and groups, and note that these can specialists in nuclear medicine are available, positively or negatively impact therapy and lymphangioscintigraphy (LAS) has largely compliance (maintenance). replaced conventional oil contrast lymphography for visualizing the lymphatic III. DIAGNOSIS network. Although LAS has not been strictly standardized (various radiotracers and

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 175 radioactivity doses, different injection giography (FM). NIRF has been increasingly volumes, intracutaneous versus subcutaneous used in some centers for examining the or subfascial injections, one or more superficial lymphatic system and in the injections, different protocols of passive and operative setting. Both peripheral MRL and active physical activity, varying imaging NIRF are becoming more widespread in use times, static and/or dynamic techniques), the around the world despite limitations for images, which can be easily repeated, offer imaging the deeper lymphatic system. DEXA remarkable insight into lymphatic structural (dual-energy X-ray absorptiometry or bi- abnormalities and (dys)function. The etiology photonic absorptiometry) may help classify is not necessarily determined from the image and define a lymphedematous limb but its alone. LAS has been used frequently in greatest potential use may be to assess the newborns and children obtaining reprodu- chemical composition of limb swelling cible, pre-clinical diagnostic images. (especially increased fat deposition, which by LAS provides dynamic images of both its added weight can lead to muscle lymphatics and lymph nodes in the peripheral hypertrophy). IL and FM are best suited to and central system as well as semi-quantitative depict initial lymphatics and more superficial data on radiotracer (lymph) transport, and it collectors and accordingly have limited does not require dermal injections of blue-dye clinical usefulness albeit valuable in research (as often used for example in axillary or groin investigations. US has found practical value sentinel node visualize(correctly termed in depicting the “dance” of the living adult lymphadenoscintigraphy). Blue dye injection worms in scrotal lymphatic filariasis, and it is occasionally complicated by an allergic skin is also increasingly used to highlight tissue reaction or serious anaphylaxis. Moreover, alterations. clinical interpretation of lymphatic function after vital dye injection alone (“the blue test”) B. Genetics can be misleading. Direct oil contrast lymphography, which is cumbersome and Genetic testing has become practical and occasionally associated with minor and even commercially available to screen for a number major complications, is usually reserved for of specific hereditary syndromes with discrete complex conditions such as chylous reflux gene mutations such as lymphedema- syndrome and thoracic duct injury, where distichiasis (FOXC2), some forms of Milroy LAS can provide at least preliminary disease (FLT-4), and hypotrichosis- diagnostic images for screening. Non-invasive lymphedema-telangiectasia (SOX18), as well duplex-Doppler studies and occasionally as a variety of chromosomal abnormalities. phlebography are useful for examining the Other genes identified include: Generalized deep venous system and supplement or Lymphatic Dysplasia (Hennekam syndrome) complement the evaluation of extremity (CCBE1, FAT4), Inherited Lymphedema edema. Other diagnostic and investigational Types 1C (GJC2) and 1D (VEGFC), tools used to elucidate lymphangiodysplasia/ Lymphedema-Choanal Atresia (PTPN14), lymphedema syndromes (including newborns Emberger (GATA2), oculodento-digital and children) include magnetic resonance syndrome (GJA1), lymphedema-lymphangi- imaging (MRI) – including MR lymphography ectasia (HGF), and hereditary lymphedema (MRL) and MR angiography techniques, III (PIEZO1). The future holds promise that computed tomography (CT), CT lymphograms, such testing for other known mutations and 3-D oil contrast lymphography, CT-SPECT, chromosomal defects, as well as newly ultrasonography (US), indirect (water soluble) discovered ones, combined with careful lymphography (IL), near infrared fluorescent phenotypic descriptions, will become routine imaging (NIRF) (also known as ICG to classify familial lymphangiodysplastic lymphography) and fluorescent microlymphan- (correctly lymphdysplastic since nodes can

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 176 also be involved) syndromes and other C. Biopsy/Lymph Node Exam congenital/genetic- dysmorphogenic disorders characterized by lymphedema, lymphangi- Caution should be exercised before ectasia, and lymphangiomatosis. Algorithms removing enlarged regional lymph nodes in have been developed to assist clinicians in the setting of longstanding peripheral phenotyping and directing genetic analysis. lymphedema as the histologic information is There are many other clinical syndromes seldom helpful, and such excision may with lymphedema as a component. Some of aggravate distal swelling. Fine needle these have genes identified [Noonan (PTPN11, aspiration with cytological examination by a KRAS, SOS1, and others); microcephaly- skilled pathologist is a useful alternative if chorioretinopathy-lymphedema-mental retar- malignancy is suspected. Use of sentinel node dation (MCLMR) (KIF11); Proteus syndrome biopsy in the axilla or groin for staging (AKT1); Clove (fibroadipose hyperplasia malignancy such as breast and melanoma (PIK3CA); Park-Weber syndrome (capillary appears to have substantially lessened the malformation-arteriovenous malformation) incidence of peripheral lymphedema by (RASA1); and lymphatic related hydrops discouraging removal of normal lymph nodes; fetalis (LRHG) (EPHB4)] while others still however, an increased number of sentinel have no known associated genes. It is impor- nodes taken may reduce this protective effect. tant to consider that the number of de novo germinal variations in these genes is increasing. IV. TREATMENT In addition, recent and ongoing research is exploring a possible genetic (and epigenetic) Therapy of peripheral lymphedema is basis underlying increased risk of developing divided into conservative (non-operative) secondary lymphedema after treatment and operative methods. Applicable to both involving injury to the lymphatic system. methods is an understanding that meticulous Newer genetic techniques such as skin hygiene and care (cleansing, low pH genome-wide association studies (GWA lotions, emollients) is of the utmost impor- study, or GWAS), whole genome sequencing tance to the success of virtually all treatment (WGS), and whole exome sequencing (WES) approaches, as is patient education and are rapidly advancing genetic analysis. A training. Basic motion exercises of the targeted Next Generation Sequencing panel extremities (muscle pumping exercises), examining all known genes associated with especially combined with external limb lymphedema is currently the most common compression and preferably performed as choice for analyzing hereditary forms of daily life activities (walking, yoga, bicycling, lymphedema. As costs decrease, more and climbing stairs) are useful. Limb patients will undergo such analysis and more elevation (specifically bed rest if indicated) single, multiple, and interacting variants will is also helpful to the appropriate patient be identified to help classify individuals with undergoing treatment. Newer studies have genetic defects related to the lymphatic indicated that more vigorous exercise can be system. These more refined classifications undertaken under the proper conditions, and may impact diagnosis (perhaps allowing strong evidence is now available on the safety proactive rather than reactive care), future of resistance exercise in controlled trials for treatments (targeted therapy), and quality breast cancer-related lymphedema. Evidence of life as precision medicine is applied to has not been published on how soon after the lymphatic diseases. These newer techniques operation exercises (and what type) should be will also contribute to prenatal diagnosis and, initiated, and this area needs further study. combined with multimodal imaging, to the As previously stated, even widely used treat- early diagnosis and potential treatment of ment methods have yet to undergo sufficient congenital lymphatic conditions. meta-analysis of multiple studies which

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 177 have been rigorous, well-controlled, and with insurers to underwrite the cost of treatment, sufficient followup. Satisfactory studies willingness of biomaterials industry to comparing different methods of treatment do produce and provide high quality affordable not exist, and advocates of all methods report products, and an understanding of the that earlier treatment is optimal for the best holistic needs of each patient impact success. results. It is also worth considering that a Compressive bandages, when applied combination of therapies may be best for incorrectly, can be harmful and/or useless. some patients, but these combinations are Accordingly, such multilayer wrapping even less frequently studied in comparison should be carried out only by professionally trials. Use of various treatment options is trained personnel. Multiple manufactured appropriate for neonates and children with devices/garments to assist in compression careful consideration from the treatment (i.e., pull on, velcro-assisted, quilted, etc.) team. Treatments can take place in the may relieve some patients of the bandaging outpatient setting, a day hospital, or during burden and perhaps facilitate compliance hospitalization as judged appropriate by the with the full treatment program, and some medical team for each patient. clinics find that patient self-care and risk reduction strategies help maintain edema A. Non-operative Treatment reduction (although neither of these has undergone rigorous study). 1. Physical therapy and adjuvants CDT may also be of use for pallia- tion as, for example, to control secondary a. Complex Decongestive Therapy lymphedema from tumor-blocked lymphatics. (CDT) also known as Combined Physical Treatment is typically performed in Therapy (CPT) or Complex Decongestive conjunction with chemo- or radiotherapy Physiotherapy (CDP) (among others) is directed specifically at producing tumor backed by longstanding experience and regression. Only theoretically, massage and generally involves a two-stage treatment mechanical compression could mobilize program that can be applied to both children dormant tumor cells; however lymph flow and adults for most areas of the body. The does not stop after a cancer diagnosis and first phase consists of skin care, a specific only diffuse carcinomatous infiltrates which light manual massage (manual lymphatic have already spread to lymph collectors as drainage-MLD) and sometimes deeper tumor thrombi might be mobilized by such techniques with patients classified above treatment. Because the long- term prognosis Stage I, using muscle pumping exercises, and for such an advanced patient is usually compression typically applied with multi- dismal, any reduction in morbid swelling is layered bandage wrapping. Phase 2 (initiated decidedly palliative. promptly after Phase 1) aims to conserve A prescription for elastic garments and optimize the results obtained in Phase 1. (custom made with correctly-obtained It consists of compression by a low-stretch specific measurement if needed) to maintain elastic stocking or sleeve, skin care, continued lymphedema reduction after CDT is essential “remedial” exercise, and repeated MLD for long-term care. Preferably, a physician as needed. (sometimes with assistance of highly-skilled Prerequisites of successful combined specialists) should prescribe the compression physiotherapy are the availability of physi- garment to avoid inappropriate usage in a cians (i.e., clinical lymphologists), nurses, patient with medical contraindications such physiotherapists, occupational and other as arterial disease, painful postphlebitic syn- therapists specifically trained, educated, and drome or occult visceral neoplasia. Generally experienced in this method. In addition, the highest compression level tolerated factors such as the acceptance of health (~20-60 mmHg) by the patient is likely to be

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 178 the most beneficial. Some clinics prefer to stockings or sleeves are used to maintain use only flat-knit garments while others use edema reduction. Newer devices that simulate both flat and round-knit garments (or combi- manual massage and design improvements nation). Sometimes patient selection, choice, for area of coverage, ease of use, and physical ability as well as cost need to be sequence/actions may increase patient taken into consideration particularly when compliance particularly for those who cannot assessing mobility and future compliance. complete both phases of CDT (e.g., exercise Failure of CDT is confirmed only with compression). Displacement of edema when intensive non- operative treatment in more proximally in the limb and genitalia a clinic specializing in management of and the development of a fibrosclerotic ring peripheral lymphedema and directed by an at the root of the extremity with exacerbated experienced clinical lymphologist has been obstruction of lymph flow need to be unsuccessful. assiduously avoided by careful observation. b. Compression garments alone have Combining pneumatic compression with been successfully used for treatment particu- manual lymph drainage has been suggested larly in breast cancer-related lymphedema but not sufficiently evaluated. at first indication of fluid build-up and e. Thermal therapy. Although minimal volume change as well as in early combinations of heat, skin care, and external Stage I. Data on the use for later stages are compression have been advocated for and very limited. successfully used by practitioners in Europe c. Massage alone. Performed as an and Asia for thousands of patients, the role isolated technique, classical massage or and value of thermotherapy alone without effleurage generally does not appear to be of compression in the management of lymph- benefit. Moreover, if performed overly edema remains unclear and further rigorous vigorously, massage (classical or others, not studies are needed. Studies have shown that MLD) may damage lymphatic vessels or their under bandaging the skin temperature slowly attachment to surrounding tissues. rises, and it is proposed that this lower level There are several published studies thermal therapy is helpful. Some centers use demonstrating the utility of MLD mono- far infrared light as an adjunct to bandaging therapy in specific populations (i.e., early and report improved outcomes. breast cancer-related lymphedema and newly f. Elevation. Simple elevation (particu- established and/or mild lymphedema without larly by bed rest) of a lymphedematous limb adipose or fibrosis tissue deposition) but there often reduces swelling, particularly in Stage I is a need for more robust studies to generate of lymphedema. If swelling is reduced by convincing evidence. This is counterbalanced antigravimetric means, the effect should be against several systematic reviews with meta- maintained by wearing of a low-stretch, analysis concluding that MLD (in breast elastic stocking/sleeve during daytime. cancer-related arm lymphedema) has no or g. Low level laser. Reports with small very little additional effect on compression numbers of patients and small meta-analysis therapy. have demonstrated efficacy of low level laser There are some published reports use for patients with lymphedema. More supporting the use of manual lymph drainage robust changes are noted with reduction of as a monotherapy for lymphedema prevention pain and mobility of tissue than just pure after cancer surgery. lymphedema volume reduction. More studies d. Intermittent pneumatic compression. with larger numbers of patients in diverse Pneumomassage is usually a two-phase settings are needed to confirm these findings. program. After external compression therapy h. Aquatic therapy/ water-based is applied, preferably by a sequential gradient exercise programs have gained some success “pump,” form-fitting low-stretch elastic due to the natural compression of water

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 179 when exercising and improvements to skin (cellulitis/lymphangitis or erysipelas). condition. Not all patients (particularly those Typically, these episodes are characterized with wounds or skin issues) are candidates by erythema, pain, high fever and, less for aquatic therapy. commonly, even septic shock. Mild skin i. For appropriate patients, adjuvant erythema without systemic signs and symp- devices such as ultrasound or shockwaves toms does not necessarily signify bacterial may be useful to help break up fibrous tissue, infection. If repeated limb “sepsis” recurs although no large patient series have been despite optimal CDT, the administration of published. a prophylactic penicillin or broad spectrum j. Wringing out. “Tuyautage” or antibiotic is recommended (continuance wringing out performed with bandages or depends on medical risk/benefit assessment). rubber tubes is probably injurious to lymph Fungal infection, a common complication of vessels and should seldom if ever be extremity lymphedema, can be treated with performed. antimycotic drugs. In most instances, washing the skin using a mild disinfectant 2. Drug therapy followed by antibiotic-antifungal cream is helpful. Short- term use of anti-histamines a. Diuretics. Diuretic agents are of and steroids in selected patients with limited use during the initial treatment phase inflammation has also been utilized by some of CDT and should be reserved for patients practitioners. with specific co-morbid conditions or d. Filariasis. To eliminate microfilariae complications. Long-term administration of from the bloodstream in patients with diuretics, however, is discouraged for it is of lymphatic filariasis, the drugs diethylcarba- marginal benefit in treatment of peripheral mazine, albendazole, or ivermectin are lymphedema and potentially may induce recommended. Killing of the adult nematodes fluid and electrolyte imbalance. Diuretic by these drugs (macrofilaricidal effect) is drugs may be helpful to treat effusions in variable and may be associated with an body cavities (e.g., ascites, hydrothorax) and inflammatory-immune response by the host with protein-losing enteropathy as well as in with aggravation of lymphatic blockage. those patients in palliative care. Patients with Short and long-term efficacy of antibiotics peripheral lymphedema from malignant (e.g., penicillin or doxycyclin) separate from lymphatic blockage may also derive benefit general skin hygiene in patients with from a short course of diuretic drug treatment. lymphatic filariasis to prevent elephantine b. Benzopyrones. Oral benzopyrones, trophic changes remains to be determined to which have been reported to hydrolyze tissue gain wider acceptance. proteins and facilitate their absorption while e. Mesotherapy. The injection of stimulating lymphatic collectors, are neither hyaluronidase or similar agents to loosen the an alternative nor substitute for CDT. The extracellular matrix is of unclear benefit and exact role for benzopyrones (which include may actually be harmful. those termed rutosides and bioflavonoids) as f. Immunological therapy. Efficacy of an adjunct is still not definitively determined boosting immunity by intraarterial injection including appropriate formulations and dose of autologous lymphocytes is unclear and regimens. Coumarin, one such benzopyrone, needs independent, reproducible evidence. in higher doses has been linked to liver Recent proposals for the use of toxicity particularly in some patients with anti-inflammatory pharmaceuticals have specific liver enzyme defects. not yet demonstrated efficacy and may face c. Antimicrobials. Antibiotics should drawbacks if administered long-term. be administered for bona fide superimposed g. Diet. No special diet has proved to be acute lymph stasis-related inflammations of therapeutic value for most uncomplicated

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 180 peripheral lymphedema. In breast cancer- procedures currently provide the closest related lymphedema and in obese patients, chance for a cure of lymph flow disorders. weight reduction has been shown to help. In carefully selected patients following full Restricted fluid intake is not of demonstrated evaluations, these procedures act as an benefit for peripheral lymphedema. In chylous adjunct to CDT or are undertaken when reflux syndromes (e.g., intestinal lymphangi- CDT has clearly been unsuccessful (or has ectasia), a diet as low as possible or even removed the fluid component). Recent free of long-chain triglycerides (absorbed via research has also focused on a preventive intestinal lacteals) and high in short and aspect in high risk patients (in limited medium chain triglycerides (e.g., MCT reports). Imaging is indispensable to identify absorbed via the portal vein) is of benefit functional vessels or nodes to manipulate. especially in children. Specific vitamin As with physical methods above, proponents supplements may be needed in very low or report that greater success is found in those no fat diets. Some clinics suggest diets (e.g., patients with early (Stage I) lymphedema enriched with omega 3’s) that may lower (with the notable exception to liposuction, inflammation, but evidence is not currently which is usually performed in later stages). robust. Worldwide, surgical resection (in several h. In complicated patients with forms) is the most widely used operative lymphatic system overgrowth (lymphangio- technique to reduce the bulk of lymphedema dysplasia) associated with lymphedema, (especially in genitalia cases). Liposuction to specialized centers may utilize pharmaco- reduce excess fat deposition is becoming more therapeutic options such as octreotide, OK- widespread with surgeons in multiple 432, rapamycin, or other anti-proliferative countries now performing the procedure. agents (these treatments are particularly used In some specialized centers, operative in newborns and children). treatment within specific guidelines may now be a preferred approach depending on the 3. Psychosocial rehabilitation treatment team training and availability of various treatments. The magnitude of the relationships It is noted that there is no clear clinical between negative psychological and differential for choosing which of these psychosocial factors and lymphedema has different techniques to use for treating been documented as a cause of non- individual patients and no head-to-head adherence to self-management as well as comparisons or randomized studies of the diminution in quality of life. Psychosocial techniques. In addition, many centers also support, quality of life assessment- use combinations of operative procedures improvement program, and a patient self- (along with added non-operative methods) in efficacy assessment are integral components their approach to treating patients making of any lymphedema treatment. determination of individual treatment effects more difficult to evaluate. B. Operative Treatment 1. Microsurgical procedures Operations designed to alleviate peripheral lymphedema by enhancing lymph This operative approach is designed to return have gained increased acceptance augment the rate of return of lymph to the worldwide but in advanced stages usually blood circulation. The surgeon should be require long-term combined physiotherapy well-schooled in both microsurgery and and/or other compression after the procedure lymphology and utilize appropriate imaging to maintain edema reduction and ensure tools to document efficacy. In general, vascular/shunt patency. These microsurgical microsurgical procedures must be performed

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 181 with special caution in children. Experience approach to limb lymphedema. with these procedures suggests that improved Long-term followup data on risk and and a longer lasting benefit is forthcoming efficacy is scant along with the influence of if performed early in the course of lymph- adjunctive physical methods. There have edema before damage to the lymphatic wall been several reports of lymphedema and impaired lymphatic contractility have developing in the donor area. While imaging occurred. has demonstrated blood flow to the a. Derivative methods. Lymphatic- transplanted nodes, sparse data have been venous (or lymphovenous) anastomoses published on lymph flow through the (LVA) are currently in use at multiple centers transplanted nodes. Further research showing around the world. These procedures have long-term efficacy and improvement in undergone confirmation of long-term patency techniques to avoid donor site lymphedema (in some cases more than 20 years) and some are needed. Some surgeons combine this demonstration of improved lymphatic trans- procedure with liposuction and postoperative port (by objective physiologic measurements compression claiming favorable outcome, of long-term efficacy). Multiple lymphatic- which makes it difficult to evaluate the venous anastomoses in a single surgical site surgical procedure per se. with both the superficial and deep lymphatics, allow the creation of a positive pressure 3. Liposuction gradient (lymphatic-venous) and evade the phenomenon of gravitational reflux without Liposuction (or suction-assisted interrupting the distal peripheral superficial lipectomy) using a variety of methods has lymphatic pathways. Some centers also been shown to completely reduce non-pitting, practice lymph nodal-venous shunts as a primarily non- fibrotic, extremity lymph- derivative method. edema due to excess fat deposition (which b. Reconstructive methods. These has not responded to non-operative therapy) sophisticated techniques involve the use of a in both primary and secondary lymphedema lymphatic collector (LLA) or an interposition (and more limited studies in lipedema). vein segment (LVLA) to restore lymphatic Even patients with signs of fibrosis can continuity in lymphedema conditions due to benefit from the procedure when using a locally interrupted lymphatic system. power- assisted liposuction, which facilitates Autologous lymph vessel transplantation breaking down fibrosis especially in leg mimics the normal physiology and has shown lymphedema. Similar to conservative long-term patencies of more than 10 years. treatment, long- term management requires This procedure generally has been restricted strict patient adherence with dedicated to unilateral peripheral lymphedema of the continuous wearing of low-stretch elastic leg due to the need for one healthy leg to compression garments, which may be harvest the graft but it has also been utilized challenging in warmer climates and pose for bilateral upper extremity lymphedema financial considerations. This operation and where two healthy legs are available for followup are very different from cosmetic lymphatic harvesting. liposuction and should be performed by an experienced team of surgeons, nurses and 2. Vascularized Lymph Node Transplantation physiotherapists to obtain and sustain optimal outcomes. Transplantation of superficial lymph Newer investigations have focused on nodes from an uninvolved area together with combining microsurgery with lymph vessel the vascular supply (VLNT) to the site of sparing liposuction in an effort to alleviate lymphadenectomy for cancer has been pro- the need for continual compression. posed both as a preventive and therapeutic

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4. Surgical Resection ment in children and even pre-natal care is expanding. The simplest operation is “debulking,” There has been recent work with that is, removal of excess skin and subcu- implantation of silicone tubes as artificial taneous tissue of the lymphedematous limb. lymphatics, and new developments in The major disadvantage is that superficial coatings and techniques may produce added skin lymphatic collaterals are removed or improvements. further obliterated. It can also be associated Extratruncal disease (i.e., lymphatic with significant scarring, risk of infection, malformations outside of the main trunks and difficult wound healing. After intensive which may or may not be associated with CDT, redundant skin folds may require arterial/venous malformations) are often excision. Debulking has been reported to be treated with a variety of these surgical pro- useful mainly in treatment of the most cedures (as well as with pharmacotherapy) severe forms of fibrosclerotic lymphedema in highly specialized centers. (elephantiasis) and in cases of advanced Rehabilitation and even habilitation is a genital lymphedema. Caution should be particularly necessary component of care. exercised in removing enlarged lymph nodes or soft-tissue masses (e.g., lymphangiomas) in C. Treatment Assessment/Followup the affected extremity as lymphedema may worsen thereafter. Operations including the In each patient undergoing therapy, an Charles and Thompson procedures are assessment of limb volumes should be made seldom used when other options are available. before, during and after treatment. This volume can be measured by water displace- 5. Tissue Engineering/Lymphatic ment, derived from circumferential (Re)Vascularization measurements using the truncated cone formula, or by perometry. The excess volume The implantation of tubes to transport (affected limb – unaffected limb) should be lymph or engineered tubes/devices to promote measured since limb volumes vary with new substitute lymphatic growth have not yet weight increase/decrease of the patient as documented long-term value in large studies, well as whether measurements are made in and these techniques are continuing to the morning or afternoon. Only measuring undergo investigation. the affected extremity can lead to unreliable Omental transposition, enteromesenteric values. It is desirable, however, that treat- bridge operations, and implantation of ment outcomes be reported in a standardized threads to promote perilymphatic spaces manner in order to compare and contrast the (substitute lymphatics) have not shown long- effectiveness of various treatment protocols. term value and should be avoided without Additional assessments by imaging further published evidence. modalities such as LAS and NIRF to document functional changes in lymphatic 6. Specialized Considerations drainage, DEXA, US, or MR imaging to determine volume and tissue compositional Chylous and other reflux syndromes are changes, tonometry/indurometry, bioelectrical special disorders which may benefit from impedance BIS or BIA), and tissue dielectric CT- or MR-guided sclerosis, interventional constant (TDC) to examine tissue alterations radiology techniques, or operative ligation and fluid changes add scientific rigor to of visceral dysplastic lymphatics, and/or analysis of the outcomes of different lymphatic to venous diversion to close and treatment approaches. decompress leaking lymphatic vessels after Health Related Quality of Life (HRQOL) delineation by multimodal imaging. Assess- and patient perceptions of self-efficacy

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 183 assessed by a variety of validated disease confirmation and improvements with a specific instruments and visual analog scales particular focus on personalization, and of patients with lymphedema should be used better delineation of prognosis is necessary. in conjunction with physiological measures Multinational collaborative studies and to evaluate effects of treatment. innovative clinical research designs in Timing and longevity of assessments is addition to randomized control trials need an area that is recognized as a need but there to be done and are encouraged with the aim are no good guidelines or model systems in of translating new discoveries and potentially place. Pre-treatment and pre-operative improved approaches more rapidly into assessment (in the Prospective Surveillance the clinical arena. Ongoing epidemiologic model- Section I) should continue after studies on the incidence and prevalence of treatment and likely should be life-long to lymphedema regionally and worldwide will include HRQOL, self-efficacy, and self- benefit from the further development and regulation measures. Data on long-term establishment of standardized, secure, results will be useful in comparing treatment intercommunicating database-registries. options and success, as well as enable patients Assessment of lymphedema risk and steps for to have the opportunity to participate in lymphedema prevention in different groups best-practice decisions. of at risk patients need to be determined. Studies might include research on minimi- D. Molecular Therapy zing or preventing secondary lymphedema through altered operative/nodal sampling Despite ongoing basic research and techniques (e.g., sentinel node biopsy or clinical trials, molecular treatments (e.g., precise anatomical knowledge of derivative administration of VEGF-C or other pathways), vector control (as demonstrated lymphatic-targeting molecules by various in China) and prophylactic drugs for methods) have not yet been significantly filariasis, identification of patients with translated to the clinic. While the addition heritable genetic defects for lymphangio- of lymphatic growth (or inhibitory) factors dysplasia (lymphedema), and use of massage is attractive, the applicability of these or compression where lymphatic drainage is treatments is uncertain at this time and subclinically impaired as documented by should be examined carefully in the context imaging techniques (e.g., LAS and NIRF). of co-morbid conditions (e.g., presence of Research in molecular lymphology including cancer, cancer treatments, drug regimens). It lymphatic system genomics, proteomics, and is also apparent when examining the growth “systemomics” should be greatly expanded. of new lymphatics in the laboratory that for With the cellular and molecular basis of all but the smallest microlymphatics a milieu lymphedema-associated syndromes better of growth (and other) factors may be needed defined, an array of specific biologically- for initiation and development of functional based treatments including modulators of macrolymphatics (and even more for the lymphatic growth and function should de novo development of a lymph node). become available. Improved imaging techniques and physiological tests need to be V. RESEARCH AGENDA devised to allow more precise non-invasive methods to measure lymph flow dynamics While recognizing and encouraging and lymphangion activity. Advances in individual investigators to pursue many imaging including molecular imaging different avenues of research, some general techniques as well as development of new directions can be formulated. Diagnostic and improved technologies (e.g., NIRF and techniques need to be continually explored photoacoustics) to visualize the superficial and developed, treatment options need and deep lymphatic system and soft tissues

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

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