Limb lymphedema: clinical guidelines

List of Abbreviations

AGREE – Appraisal of Guidelines for Research & Evaluation;

AMSTAR – Assessor of Multiple Systematic Reviews;

CEAP – international classification of chronic lower limb venous disorders;

ICG – indocyanine green lymphography (ICG lymphography). Synonym – NIR lymphography;

ISL – International Society of Lymphology;

LPG – a type of mechanized roller massage, the acronym is formed from the three initials of the method's creator;

NIR – near-infrared (NIR) lymphography (NIR lymphography). Synonym – ICG lymphography; by NMC: Fluorescent spectroscopic examination for diseases of the skin, subcutaneous adipose tissue, and skin appendages;

NPWT – negative pressure wound therapy;

PRISMA – Preferred Reporting Items for Systematic Reviews and Meta-Analyses;

RLCS – recurrent lymphangitic cellulitis syndrome;

SD – standard deviation;

ALR – Association of Lymphologists of Russia;

ALT – alanine aminotransferase;

AST – aspartate aminotransferase;

AFR – Association of Phlebologists of Russia;

CI – confidence interval;

DNA – deoxyribonucleic acid;

BMI – body mass index;

MCB – multi-layer compression bandage (medical compression bandages), multi-layer compression bandaging (elastic compression of the lower extremities);

CT – computed tomography;

CDT – Complete Decongestive Therapy (Complete Decongestive Therapy (CDT), Complete Decongestive Physiotherapy (CDP));

LVA – lymphovenous anastomosis;

LNVA – lymphonodovenous anastomosis;

ABI – ankle-brachial index;

ET – exercise therapy (exercise therapy for peripheral vascular disease);

MLD – manual lymphatic drainage;

MR lymphography – magnetic resonance lymphography (non-contrast);

MRI – magnetic resonance imaging (Magnetic resonance imaging of the upper extremity; Magnetic resonance imaging of the lower extremity);

LLLT – low-level laser therapy, also known as photobiomodulation therapy (PBMT);

NMC – nomenclature of medical services;

IVC – inferior vena cava;

RR – relative risk;

OR – odds ratio;

SCAT – subcutaneous adipose tissue;

IPC – intermittent pneumatic compression (apparatus pneumatic compression) (according to the Nomenclature of Medical Services: Electronic lymph drainage for skin and subcutaneous tissue diseases; Intermittent pneumatic compression of the lower extremities);

PTS – post-thrombotic syndrome;

RCT – randomized controlled trial;

ACD – adjustable compression wrap devices;

BC – breast cancer;

RP – radiopharmaceutical (diagnostic radiopharmaceuticals);

GFR – glomerular filtration rate;

SLD – simple lymphatic drainage (self-massage);

SMD – standardized mean difference;

STS – Stewart–Treves syndrome;

LoE – level of evidence;

DUS – duplex ultrasonography (Duplex scanning of upper extremity vessels [arteries and veins]; Duplex scanning of upper extremity veins; Duplex scanning of lower extremity vessels [arteries and veins]; Duplex scanning of lower extremity veins);

LeRM – level of recommendation credibility;

CVI – chronic venous insufficiency;

CHF – chronic heart failure.

Terms and Definitions

Lymphedema or lymphatic edema is a pathological condition in which lymph escapes from lymphatic capillaries as a result of dermal backflow and accumulates in the connective tissue septa between the fat lobules of the subcutaneous adipose tissue in the form of lymphatic cavities of various sizes and shapes. Consequently, such edema is called lymphatic because the edematous fluid is lymph.

Primary lymphedema is congenital, associated with a developmental defect of the lymphatic system.

Secondary lymphedema is acquired, associated with exposure to factors leading to damage to the lymphatic system and impaired lymphatic drainage.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Lymphedema is a congenital or acquired chronic progressive disease characterized by impairment of the transport function of the lymphatic bed, the main manifestation of which is an increase in the volume of the affected body part due to lymphatic edema, and subsequently, the development of soft tissue fibrosis and adipose tissue overgrowth.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

According to its etiology, extremity lymphedema can be primary or secondary [1]. The etiology of lymphedema is schematically presented in Figure 1 [2]:

Figure 1. Etiology of lymphedema (based on Kerchner K. et al.)

1.2.1 Physiology of lymph formation and lymphatic drainage.

Lymph is an intravascular fluid normally located within the lumen of lymphatic vessels (Foldi, M 1952) [3]. Interstitial fluid becomes lymph only upon entering the lymphatic capillaries [4]. From the lymphatic capillaries, part of the water returns to the interstitial space via ultrafiltration, resulting in an approximately threefold increase in lymph protein concentration [5]. The processes of water ultrafiltration through the lymphatic vessel wall continue as lymph moves along the collecting lymphatic vessels, leading to its further concentration [6].

Endothelial cells of lymphatic capillaries partially overlap each other, forming entry valves. There are no tight junctions between them, and the basement membrane is fragmented [4]. The endothelium of lymphatic capillaries is supported by connective tissue fibers or anchoring filaments, which on one hand intertwine into the entry valves, and on the other into the elastic fibers of the surrounding connective tissue. When interstitial fluid accumulates in the intercellular space, the anchoring filaments act as cables and open the entry valves [7]. Since the interstitial fluid pressure turns out to be higher than the pressure in the lymphatic capillary, the interstitial fluid, together with blood cells that have escaped from the microvasculature and Langerhans cells, is directed via pre-lymphatic channels into the lymphatic capillaries. This movement continues until the lymphatic capillary is filled [8]. In this process, the pressure within it increases, and the moment it exceeds the interstitial fluid pressure, the entry valves close.

1.2.2 Pathogenesis of lymphedema.

In the pathogenesis of lymphedema, the triggering factor for the cascade of pathological processes and reactions is elevated endolymphatic pressure resulting from a prolonged lag of active lymph transport behind the volume of lymph formed [9-11]. A number of studies using the direct pressure measurement method have proven that in primary and secondary lymphedema, the main factor leading to edema development is an increase in endolymphatic pressure in the initial segments of the capillary lymphatic networks of the skin [12,13]. Thus, lymphedema is characterized by peripheral capillary lymphohypertension [12]. Subsequently, depolarization of the myocyte membrane occurs, leading to a change in the balance of excitatory and inhibitory influences of other regulatory factors [14]. As a result, the autoregulation of the lymphangion pumping function level is impaired, leading to a further increase in endolymphatic pressure. All of this formed the basis of the etiopathogenesis of lymphedema [15].

Thus, the main mechanism of lymphedema development is primary or secondary damage to the lymphatic drainage pathways, which leads to a whole cascade of pathological processes with the development of peripheral lymphohypertension and impaired exchange and metabolic processes in the interstitial space.

The main factor ensuring lymph drainage is the preservation of the contractile capacity of the lymphangions of lymphatic vessels. The degree and level of damage to the transport pathways of the lymphatic system, the primary or secondary etiology of lymphedema, and the state of functional activity of the lymphangions determine the choice of surgical or conservative treatment tactics.

The accumulation of lymph in the subcutaneous tissue causes the development of complex pathohistological reactions with impaired intercellular interaction, the release of pro-inflammatory cytokines by cells, which causes chronic inflammation, entails remodeling of the extracellular matrix, and an increase in the volume of the connective tissue matrix. This leads to dystrophic tissue changes with connective tissue proliferation and fibrosis development; to an increase in the volume of body parts in the affected area, and subsequently, to secondary impairment of lymphatic transport and drainage [16-23].

1.3 Epidemiology of the Disease or Condition

Epidemiological studies on lymphedema have not been conducted in Russia. There are many different foreign studies on the incidence rate of primary and secondary forms of lymphedema.

Lymphedema is a disease that patients often ignore, and other causes of edema with a similar external appearance are misdiagnosed. As a result, the exact number of people suffering from lymphedema is unknown. However, according to Brix et al., 2021, it ranges worldwide from 140 to 300 million people [34].

According to foreign studies conducted in various countries (France, Turkey, Great Britain, Canada, and others), approximately 70–79% of patients are women [35].

Compared to men, the incidence of lymphedema is higher in women (women: men ratio 4.6:1) [36]. However, the actual prevalence of lymphedema varies depending on etiology. Accordingly, primary lymphedema associated with a developmental defect of the extremity lymphatic system can manifest at any age, but most often the edema appears during puberty [37], being observed in 1 out of 100,000 individuals [38]. In primary lymphedema, edema develops in adults in 19% of cases and usually without apparent cause [39].

Secondary lymphedema, which occurs as a result of various impacts on the normal lymphatic system, is observed in a total of 1:1,000 individuals [38].

Data from Jemal A., 2011, show that 1.38 million women are diagnosed with breast cancer worldwide each year. Of these, 295,320 (21%) develop upper extremity lymphedema after mastectomy with lymph node dissection [40].

The urgency of the problem of lymphedema treatment is determined by the fact that it is observed in every fifth woman who has undergone mastectomy [41]. According to a systematic review by DiSipio T. (2013), the incidence of secondary lymphedema after mastectomy averages 21.4%, ranging depending on the time elapsed after surgery. With extended lymph node dissection, it is 19.9%, and with sentinel lymph node biopsy, 5.6%.

In a systematic review by Hahn, B. A., 2024, it was established that the average prevalence rate of secondary lymphedema after inguinal lymphadenectomy was 24%. For melanoma 25.75%, penile cancer 12.22%, vulvar cancer 30.96%, and for other localizations 13.62% [42].

According to another systematic review [43], the prevalence of lower extremity lymphedema after genital cancer treatment was 0–14%, and 0–1% after radical prostatectomy with pelvic lymph node dissection (pelvic lymphadenectomy). After pelvic lymph node irradiation, it was 0–9%, and 0–8% for genital irradiation. However, in patients who underwent both pelvic lymph node dissection and irradiation, the prevalence of lower extremity lymphedema was 18–29%, and genital lymphedema 2–22% [43].

Thus, prostate cancer patients who have undergone surgery or pelvic lymph node irradiation are at risk of developing secondary lymphedema in the lower extremities and genital area. Patients who undergo pelvic irradiation following pelvic lymph node dissection have the highest prevalence of lymphedema. The lack of a unified definition and standardized diagnostic criteria for lower extremity and genital lymphedema makes accurate estimation of their true prevalence difficult.

Further clinical studies are needed to specifically assess secondary lymphedema in patients undergoing treatment for various cancer localizations, identify potential risk factors, and determine the impact on quality of life.

1.4 Features of Coding the Disease or Condition

Q82.0 Hereditary lymphedema

I89 Other noninfective disorders of lymphatic vessels and lymph nodes

I97.2 Postmastectomy lymphedema syndrome

1.5 Classification of the disease or condition

According to the classification, lymphedema is divided into primary and secondary, which differ in the causes of edema development [24].

Primary lymphedema is a developmental malformation of the lymphatic system of the limbs, lymphatic vessels, and lymph nodes, which is subdivided into hypo- and aplasia with predominant involvement of the proximal or distal parts of the extremities [25]. Another type of involvement, conversely, is associated with primary lymphangiectasia or hyperplasia of the lymphatic vessels in various parts of the lymphatic system.

Depending on the time of onset of edema, primary forms of lymphedema are subdivided into congenital, early, and late [25].

At the same time, specific timeframes for the appearance of persistent edema have been defined for each form of primary lymphedema, categorized as follows:

- congenital lymphedema: in individuals under 1 year of age,

- lymphedema praecox (early): in the age group from 1 to 35 years,

- lymphedema tarda (late): in individuals over 35 years of age [26].

Mortimer P.S. proposed a more detailed differentiation of the etiological division of lymphedema. He subdivided the primary form of lymphedema into congenital and familial, noting the presence of a genetic predisposition, and also retained the division of lymphedema into early and late [27].

Mortimer P.S. classified congenital vascular malformations with lymphangioma and chylous lymphedema, as well as Milroy disease, Meige syndrome, and lymphedema-distichiasis, among the congenital forms [28].

Late-onset lymphedema was divided into:

1. distal hypoplasia (bilateral edema);

2. proximal obstructive node involvement (unilateral edema of the entire limb);

3. megalymphatics (bilateral edema of the entire limb).

In most cases, primary or congenital lymphedema is inherited in an autosomal dominant manner [29]. Currently, 28 genes have been identified that may contain mutations to varying degrees, along with many other factors causing the development of primary lymphedema [30]. Genetic mutations in the vascular endothelial growth factor-C (VEGF-C) and vascular endothelial growth factor receptor-3 (VEGFR-3) signaling pathways are responsible for primary lymphedema in 30–50% of patients [29,31].

Secondary lymphedema

Secondary or acquired lymphedema is limb edema resulting from obstruction of lymphatic drainage caused by trauma, surgical interventions with lymph node dissection, inflammation, irradiation, parasitic diseases, and metastatic processes in the lymph nodes [32].

Prognostically, the most favorable cases for surgical treatment are edema resulting from trauma and surgery, because these cases feature a localized block of lymphatic drainage while preserving the contractile function of lymphangions [15,33].

Secondary lymphedema develops as a complication of another disease or intervention as a result of damage to the lymphatic bed with impaired lymph flow, lymph stasis in the lymphatic vessels, and increased endolymphatic pressure [18].

The most common causes of secondary lymphedema [2]:

- Cancer/tumor-associated — edema occurring due to involvement of lymphatic drainage pathways (lymph nodes, lymphatic vessels) as a result of tumor compression or spread along them;

- Cancer treatment-related lymphedema — damage to lymphatic drainage pathways during therapeutic measures associated with cancer treatment (lymph node puncture or biopsy, lymph node dissection, radiation therapy, transection of lymphatic collectors, etc.);

- Infection (including erysipelas);

- Trauma;

- Lymphedema associated with medical manipulations and non-cancer-related surgeries (lymph node puncture or biopsy, surgical operations involving areas where lymphatic vessels and collectors are located, etc.);

- CVI (chronic venous insufficiency);

- Filariasis.

Regarding lymphedema associated with cancer diagnosis and treatment, the term "cancer-related lymphedema" is acceptable; for breast cancer diagnosis and treatment-related lymphedema, "breast cancer-related lymphedema" (BCRL) is used. The variant of lymphedema associated with breast cancer surgery may be called "postmastectomy edema".

There are clinical-symptomatic classifications based on a visual description of the edema, as well as palpation characteristics of tissues, and concomitant inflammatory and degenerative processes in the skin.

C. Campisi classification of lymphedema [44] is divided into 5 stages (Figure 2):

Stage 1a — No edema with the presence of lymphatic dysfunctions (e.g., after mastectomy and axillary lymphadenectomy, with no difference in volume and consistency between the arms);

Stage 1b — Mild edema, reversible with elevation and night rest;

Stage 2 — Persistent edema that regresses only partially with elevation and night rest;

Stage 3 — Persistent and progressively worsening edema (acute erysipelas lymphangitis);

Stage 4 — Fibrotic lymphedema (with initial lymphostatic verrucosis) and column-like limb;

Stage 5 — Elephantiasis with severe limb deformity, scleroindurative pachydermia, and pronounced, widespread lymphostatic verrucosis.

Figure 2. C. Campisi classification of lymphedema (2001).

The most common is the clinical-symptomatic classification of lymphedema by the International Society of Lymphology (ISL) [45].

The ISL classification of lymphedema has III stages (ISL 2013).

Stage I — There is an accumulation of protein-rich fluid in the soft tissues that subsides upon limb elevation. Pitting may occur upon finger pressure.

Stage IIa — There is limb edema that decreases slightly upon elevation. Pitting upon finger pressure becomes pronounced.

Stage IIb — Pitting upon finger pressure does not always persist, as fibrotic changes occur in the subcutaneous adipose tissue.

Stage III — Characterized by lymphostatic elephantiasis, in which pitting may be absent as fibrotic skin changes develop. Skin thickening, hyperpigmentation, skin fold enlargement, further subcutaneous fibrosis, as well as wart-like growths and acanthosis.

Currently, the ISL classification has begun to distinguish Stage Ia, which refers to a latent or subclinical state when there is no overt clinical manifestation of edema, despite impaired lymph transport, minor changes in tissue fluid composition, and changes in subjective symptoms. The duration of Stage Ia can be indefinitely long. Patients can remain in this state for months or years before overt edema (Stages I–III) develops.

Classification for postmastectomy lymphedema syndrome (PMLS).

The most comprehensive and optimal classification is the one adopted by the International Society of Lymphology, which distinguishes the following stages of PMLS:

Stage 0 (stage of preclinical manifestations of PMLS) — the volume of the arm on the affected side increases by up to 150 ml compared to the contralateral upper extremity. This stage is fundamentally important for PMLS, as examining patients before clinical manifestations appear allows for predicting their further treatment in many cases.

Stage I (transient edema, onset of clinical manifestations of PMLS) — arm volume exceeds the contralateral extremity by 150–300 ml. Characterized by inconstant volume increase of the entire upper extremity or its individual segments, with periodic return of its dimensions to baseline. Skin mobility is fully preserved, and it is easily gathered into a fold.

Stage IIa ("soft" edema) – increase in arm volume by 300–500 ml. Limb edema is constant. The skin can be pinched into a fold but does not slide relative to the underlying tissues. When pressed, a clearly visible deep pit remains (positive pitting test).

Stage IIb ("firm" edema) – arm volume exceeding by 500–700 ml. Permanent upper limb edema develops, transitioning into fibredema. The skin cannot be pinched into a fold and does not slide relative to the underlying tissues. Pressing the skin produces a visible pit, or no pit remains (the pitting test can be either positive or negative). Areas of hyperpigmented skin are often present. The limb partially loses its function.

Stage III ("deforming" edema) – increase in arm volume by 700 ml or more. Characterized by limb disfigurement due to excessive soft tissue overgrowth. The limb completely loses its function. Pronounced trophic disorders appear. The pitting test is negative. Hyperkeratosis is common. Joint movements in the limb are restricted due to the weight of the soft tissues. Patients are forced to keep the arm in a suspended state. It is necessary to consider the presence or absence of axillary or subclavian vein stenosis (venous hypertension) on the affected side.

To date, there is no unified classification of post-mastectomy lymphedema (PMLE). Most classifications are based on symmetrical measurement of the healthy and affected upper extremities [46–49].

Formulation of the diagnosis.

When describing lymphedema and formulating the diagnosis, it is advisable to:

1. Indicate the etiology of lymphedema: primary or secondary;

2. Clarify the etiology of lymphedema;

2.1. For primary lymphedema:

- indicate the approximate age of the patient at the onset of lymphedema; for congenital lymphedema, indicating "congenital" is sufficient;

- note the presence of inheritance signs, if identified (the term "familial" is applicable);

2.2. For secondary lymphedema:

- indicate the association with the main triggering factor;

- indicate the approximate date (year) of lymphedema onset.

3. Indicate the stage of lymphedema. For lymphedema staging, it is recommended to use the International Society of Lymphology (ISL) 2013 grading or C. Campisi's classification (2001).

Examples of diagnosis formulation:

- Congenital malformation of the lymphatic system of the upper (lower) extremity, stage 2 lymphedema. Distal (proximal) hypoplasia (aplasia).

- Primary lymphedema of the right lower extremity, stage 3, onset at 18 years of age or indicating the duration of the edema.

- Congenital familial lymphedema of both lower extremities; right side stage 2, left side stage 1.

- Post-mastectomy lymphedema syndrome. Secondary lymphedema of the left upper extremity, stage 2: Duration of edema 2 years. History of radiation therapy and/or regional lymph node lymphadenectomy.

- Secondary lymphedema of the right lower extremity, stage 3. Chronic erysipelas.

Applicability of lymphedema classification by age at onset.

For a long time, it was customary to classify primary lymphedema according to the age at which its symptoms first appear [2,50,51]:

- Congenital lymphedema is defined as lymphedema present at birth or manifesting under 1–2 years of age.

- Early lymphedema (Lat., praecox) manifests between 1 and 35 years of age, most commonly during puberty, and is the most common type of primary lymphedema.

- Late lymphedema (Lat., tarda) manifests at age > 35 years. It is the least common type of primary lymphedema.

1.6 Clinical presentation of the disease or condition

1.6.1. Clinical features of lymphedema depending on etiology and pathogenesis

Clinical manifestations of lymphedema of the same stage but different etiology do not have significant clinical differences.

1.6.2. Clinical features of lymphedema depending on the stage

Clinical manifestations of limb lymphedema vary depending on the stage of the disease [52]:

Stage 0. Latent or subclinical stage. Edema is not detected. Subjective symptoms may occur. Distinguishing the latent stage in the lymphedema severity classification is important for early detection of lymphedema in high-risk patients. Early detection and treatment of lymphedema can prevent its progression and reduce negative psychosocial and functional consequences for patients. Detecting the latent stage of lymphedema can be difficult because clinical manifestations of lymphedema are absent at this stage, subjective symptoms are non-specific, and instrumental diagnostic methods are not standardized in terms of performance and interpretation.

Stage I. Edema is minimal or slightly pronounced. Edema may completely or almost completely regress when the limb is elevated or during night rest. "Pitting edema" is characteristic. Stemmer's sign may not be detected or may be doubtful, especially at the onset of the disease or when lymphedema begins proximally [67]. Edema may appear only upon loading the lymphatic system and completely disappear at rest.

Stage II. Clinical manifestations can vary significantly as the disease progresses within stage 2. In general, pitting edema is characteristic, but in the late phase of this stage, due to fibrosis formation, non-pitting edema may be detected. Edema is pronounced, and does not completely resolve with limb elevation. A positive Stemmer's sign is characteristic. Due to edema, excess subcutaneous adipose tissue, and fibrosis formation, limb mobility may be restricted.

Stage III. Hypertrophy of subcutaneous tissue, signs of subcutaneous tissue fibrosis, and trophic skin changes and/or the presence of skin complications of lymphedema are hallmark features of stage 3 lymphedema. Elephantiasis of the limb is possible – an extreme degree of proliferation and hypertrophy of subcutaneous adipose tissue. Due to the presence of subcutaneous fibrosis, non-pitting edema may be detected in certain areas of the limb.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of "lymphedema" is primarily a clinical diagnosis based on medical history, objective signs and symptoms, including a physical examination that includes limb volume measurement [38,61-66,75]. Careful history-taking and clinical examination are sufficient to establish the diagnosis of limb lymphedema in the majority of cases [29,75]. According to the international consensus document on the diagnosis and treatment of lymphedema, clinical recognition of lymphedema is preferred over instrumental imaging [59]. The use of instrumental imaging methods is necessary for the differential diagnosis of lymphedema in cases of unclear diagnosis and when planning surgical treatment [59,76-77].

Decoding of medical service codes (NMU) is presented in Appendix A3.

2.1 Complaints and Anamnesis

• At the diagnostic stage, all patients with lymphedema are recommended to undergo symptom assessment and history-taking to verify the diagnosis [49,53-58].

LNC 4 LeC C

Comment: when collecting complaints and disease history, it is necessary to find out information from patients about the presence of edema, age of edema onset, time of edema appearance, paresthesias, and skin color. Information about the reversibility of edema, the initial location of peripheral edema (distal or proximal), and its further spread is of great importance for determining the stage of the disease. In the case of surgical intervention, it is necessary to find out the date and nature of previous treatment, as well as inquire about past inflammatory diseases and venous diseases on the affected side.

Currently, criteria for diagnosing limb lymphedema have not been defined [59,60,61,62].

• When taking the medical history, it is recommended to pay attention to the age at which lymphedema manifested, the areas of onset and spread of edema, the chronology of lymphedema progression, associated symptoms (discomfort, pain, feeling of swelling, heaviness, tightness, etc.), medical history (previous skin infections, anti-tumor therapy, surgical interventions), episodes of significant mobility reduction (travel, immobilization), and family history of lymphedema, as well as the dynamics of edema throughout the day [69].

LNC 5 LeC C

2.2 Physical Examination

• When establishing the diagnosis of limb lymphedema, it is recommended to evaluate the consistency of the patient's complaints, disease history data, clinical examination, and take into account the presence of characteristic objective signs of lymphedema [38,61-65].

Level of Evidence (LE) 3, Grade of Recommendation (GR) C

Comment: in the literature analyzed by the working group, the proposition that a physician must base the diagnosis of "lymphedema" on a combination of medical history data and characteristic clinical signs is formulated in various forms.

Leveled Research Evidence (LE) 2 Grade of Recommendation (GR) B

Comment: when assessing the presence of limb edema at an early stage of lymphedema, it should be borne in mind that initially the edema may affect only the proximal or only the distal parts of the limbs, and in breast cancer-associated lymphedema, it may begin on the chest wall.

LNC 5 LeC C

Comment 1: the necessity of quantitative assessment of limb edema in lymphedema was supported by 94% of experts in the international consensus document on the diagnosis and treatment of lymphedema [59]. Quantitative assessment of edema can be performed by measuring limb circumference at specific positions or using various volumetry methods.

Comment 2: limb circumference measurement (determining the circumference of the lower leg, thigh, neck, forearm, upper arm) is a simple and objective method for quantitative assessment of the degree of edema, while demonstrating a good correlation with volumetry results [80,81]. Measurements can be made at any level of the upper or lower extremity if the clinician uses anatomical landmarks to reproduce the measurements. To correlate the difference in limb circumference with the stage of lymphedema, the American Physical Therapy Association (APTA) grading system can be used [79]:

− Mild lymphedema (Stage 1) – circumference difference < 3 cm;

− Moderate lymphedema (Stage 2) – circumference difference 3–5 cm;

− Severe lymphedema (Stage 3) – circumference difference > 5 cm.

This grading system can only be used for unilateral involvement. The grading of lymphedema severity in this system is conventional; the final stage and severity of lymphedema are determined by the physician diagnosing the disease, taking into account the specifics of the particular clinical case.

Comment 3: for a simplified system of measuring the circumference of the affected and healthy limb, the proposals of the 2006 International Consensus on Lymphedema Treatment regarding measurements at 4 points can be used [82].

Upper extremities:

− Level of metacarpophalangeal joints;

− Wrist;

− 10 cm distal to the olecranon process of the ulna;

− 10 cm proximal to the olecranon process of the ulna;

Lower extremities:

− Level of metacarpophalangeal joints;

− 2 cm above the medial malleolus;

− 10 cm distal to the lower pole of the patella;

− 10 cm proximal to the upper pole of the patella.

2.3 Laboratory Diagnostics

LNC 5 LeC C

Comment: currently, there are no laboratory parameters used in establishing the diagnosis of lymphedema or influencing its treatment tactics and methods. Laboratory diagnostics are not mentioned in existing guidelines for the diagnosis and treatment of lymphedema. If signs of a decompensated comorbid disease are detected, it is advisable to refer the patient to a subspecialist to determine the scope and nature of the required additional examination and to treat the concomitant pathology.

2.3.1. Genetic diagnostics

• Genetic testing to determine treatment tactics is not recommended [59,61,78,83].

LNC 5 LeC C

Comment 1: to date, genetic testing for limb lymphedema does not affect prevention and treatment practices and is important for scientific research and the development of promising areas for disease prevention and treatment. Genetic testing is not proposed as part of the limb lymphedema diagnostic algorithm in professional society guidelines, is not discussed in the 2002/2022 International Consensus Document on the Prevention and Treatment of Lymphedema, and is considered in guidelines and recommendations as a promising diagnostic direction requiring further development [59,61,78,83].

Comment 2: genetic testing can be used in developing promising areas for the prevention and treatment of patients with limb lymphedema. Panels for molecular genetic diagnostics of primary lymphedema can include more than 40 genes. For patients with lymphedema without signs of hereditary syndromes, testing is performed for mutations in individual genes associated with the most common subtypes of primary lymphedema (ANGPT2, CALCRL, CELSR1, EPHB4, FLT4, GJC2, MDFIC, PIEZO1, TIE1, VEGFC) [84,85]. Testing for chromosomal abnormalities and mutations in individual genes associated with monogenic syndromes is performed in patients with characteristic dysmorphisms, congenital malformations, developmental delays, and other clinical and phenotypic manifestations [86,87].

Comment 3: gene therapy is promising in determining the treatment tactics for patients with limb lymphedema. For example, the FOXC2 mutation leads to lymphatic valve dysfunction with lymph reflux as the main mechanism of lower extremity lymphedema formation. This may account for a good clinical response in patients with this type of disorder to complete decongestive therapy [85].

Comment 4: genetic diagnostics is primarily focused on primary lymphedema, but recent studies have shown prospects for identifying genetic predisposition to the development of secondary lymphedema after breast cancer treatment [88].

Comment 5: genetic testing may find practical application in the development of effective targeted therapy for certain syndromes associated with the development of lymphedema, such as Noonan syndrome [89].

2.4 Instrumental Diagnostics

• Instrumental diagnostics of lymphedema is recommended as an objective and documented method for establishing the diagnosis, as well as for evaluating the effectiveness of various treatment methods [59].

LNC 5 LeC C

Comment: currently, there are no direct comparative trials confirming the superiority of one instrumental diagnostic method over another, although research is ongoing [83].

• Lymphoscintigraphy is recommended for differential diagnosis of the etiology of edema and allows for the detection of the presence or absence of lymphatic system involvement, as well as the presence and severity of pathological processes in the lymphatic system [59,61,65].

LNC 5 LeC C

Comment 1: lymphoscintigraphy has high specificity (1.0), while estimates of the method's sensitivity are heterogeneous: ranging from moderate (0.62) to high (0.96) [92,93,94].

Comment 2: lymphoscintigraphy (LSG) allows for establishing the clinical diagnosis of lymphedema and determining the degree of morphological and functional impairment. LSG is a minimally invasive method of indirect lymphography based on the resorption of a radiopharmaceutical (diagnostic radiopharmaceutical agents) into the lymphatic bed. A multicenter analysis [90] showed that lymphoscintigraphy remains the "gold standard" for the diagnosis of lymphedema and the only documented instrumental diagnostic method with morphological and functional interpretation of results that allows for a clinical diagnosis based on the analysis of quantitative and qualitative study results.

Comment 3: lymphoscintigraphy is used to evaluate [95]:

- assessment of the radiopharmaceutical injection site (depot), filling time and number of lymphatic vessels, and diagnosis of lymphatic block;

- assessment of the symmetry and timeliness of nanocolloid (radiopharmaceutical) fixation in lymph nodes and their relative number;

- detection of collateral lymph flow and dermal backflow, collateral filling of lymph nodes;

- assessment of the effect of treatment on lymph transport;

- quantitative assessment of the resorption function of lymphatic capillaries by clearance, which is determined by the half-life of the radiopharmaceutical from the depot or its injection site [96].

LSG allows for determining [97]:

- accumulation of nanocolloid (radiopharmaceutical) at the injection sites (depot) and visualization of the distal collector segment;

- number of functioning collector lymphatic vessels, timeliness and intensity of contrast enhancement of lymph transport pathways to the inguinal (axillary) lymph nodes;

- presence of lymph flow impairment: by the degree of lymph flow impairment (complete/incomplete block), by the level of the block (proximal/distal); collateral lymph flow into the deep lymphatic system or contralaterally; dermal backflow by prevalence (local/diffuse);

- symmetry and timeliness of nanocolloid (radiopharmaceutical) accumulation in the inguinal (axillary) lymph nodes, as well as assessment of the intensity of their enhancement;

- patency of the thoracic duct.

Comment 4: currently, for lymphoscintigraphy in the Russian Federation, a radiopharmaceutical is registered and used, represented by colloidal particles of human albumin with a neutral pH and a size of 4–100 nm, of which at least 95% have a diameter of ≤ 80 nm. This nanocolloid (radiopharmaceutical) is used for scintigraphy of the lymphatic system of the extremities to detect pathology. The drug is intended for use solely as a diagnostic agent. The contents of the kit prior to its preparation for the study are not radioactive. The preparation becomes radioactive after radiolabeling with sodium pertechnetate-⁹⁹Tc solution, and the resulting labeled albumin colloidal nanoparticles are used for subcutaneous administration. Thus, after adding the radioactive drug solution - sodium pertechnetate-⁹⁴Tc [sic], the particles become radioactive or radioisotope-labeled (radioactive label). The radiopharmaceutical is used to study the lymphatic system.

Comment 5: pharmacokinetic properties of the radiopharmaceutical. After subcutaneous injection into connective tissue, 30-40% of the administered ⁹⁹Tc-labeled colloidal albumin particles (less than 100 nm) are filtered into lymphatic capillaries, whose main function is to drain proteins from the interstitial fluid back into the blood. The ⁹⁹Tc-labeled colloidal albumin particles are then transported via lymphatic vessels to regional lymph nodes and collecting lymphatic vessels, and subsequently enter the lymph nodes. Part of the administered dose of the radiopharmaceutical is phagocytosed by histiocytes at the injection site. The bulk of the radiopharmaceutical passes from the lymphatic system into the blood and accumulates predominantly in the reticuloendothelial system of the liver, spleen, and bone marrow; trace amounts of the drug are excreted in the urine.

Comment 6: the use of a contrast injection method using a radiopharmaceutical is accompanied by a minor radiation exposure (less than 1 mSv) and has minimal risks of side effects, among which, according to the radiopharmaceutical instructions, allergic reactions, both systemic and local (erythema, urticaria, edema), are very rare (<1/10,000) [98].

Comment 7: high efficacy and diagnostic capabilities of lymphoscintigraphy are presented in systematic reviews and single-center studies [99, 100, 101].

• Lymphoscintigraphy is recommended for the qualitative and quantitative assessment of treatment outcomes using lymph-draining surgeries and conservative therapy [100].

Level of Evidence (LE) 3, Grade of Recommendation (GR) C

Comment 1: "classic" lymphoscintigraphy provides 2D images; for the precise anatomical localization of lymphatic anomalies, single-photon emission computed tomography of lymph nodes (SPECT/CT) technology is used, in which the scintigraphic image using technetium-based agents (diagnostic radiopharmaceuticals) is combined with 3D CT images that fairly accurately display the localization of the radioactive signal in relation to other tissues [97, 102].

Comment 2: studies of the lymphodynamic state and clinical efficacy of lymphovenous anastomosis (LVA) in patients with lower extremity lymphedema using 2-phase lymphoscintigraphy with a radiopharmaceutical combined with single-photon emission computed tomography of lymph nodes showed a high degree of informativeness [102]. The relationship between functional and morphological information was determined. Early and delayed scans were used to evaluate accumulation in inguinal lymph nodes, dermal backflow, and their sequential alternations; furthermore, the liver-to-blood and inguinal lymph node-to-blood radiopharmaceutical uptake ratios were calculated. All participants were classified into 6 types of lymphodynamic states based on the imaging results. Patients with both dermal backflow and concomitant normal lymphatic vessel accumulation proceeded to LVA and underwent a second lymphoscintigraphy postoperatively. The largest population was assigned to type 4 with a persistent defect of accumulation in the inguinal lymph nodes, and a decrease in dermal lymphatic backflow was observed as a result of LVA functioning. The liver-to-blood ratio on both early and delayed scans, and the inguinal lymph node-to-blood ratio on the delayed image, significantly increased after LVA.

Comment 3: SPECT/CT lymphoscintigraphy allows for the simultaneous assessment of both the functional and morphological state of the lymphatic system in patients with lower extremity lymphedema. Using these procedures, a categorization of types was developed for patients that reflects their lymphodynamic state. The clinical efficacy of LVA can also be quantitatively assessed based on the obtained results.

LNC 5 LeC C

Comments: duplex scanning of the veins of the upper extremities and duplex scanning of the veins of the lower extremities in lymphedema may be performed to detect or rule out thrombosis and post-thrombotic lesions of the extremity veins, to detect other pathology accompanied by edema or increased extremity volume, as well as during soft tissue ultrasound to assess the condition of soft tissues before and during the treatment of lymphedema (echogenicity of the skin and subcutaneous tissue, presence of free fluid cavities, blurring of the skin layer differentiation [blurring of the border between the skin and subcutaneous tissue], thickness of the skin layer, subcutaneous tissue, deep fascia, and muscle layer).

LNC 5 LeC C

Comment: fluorescence lymphography (A22.01.008) is a modern type of indirect lymphography using green #indocyanine (indocyanine green, ICG, ICG lymphography), which is administered subcutaneously in a volume of 0.2 ml [107]. Indocyanine green has a well-defined absorption maximum in the infrared region at 800 nm in blood plasma or blood, which makes it possible to perform lymphography in the near-infrared (NIR) range (near-infrared (NIR) lymphography, NIR lymphography) [106]. Using this method, the feasibility of visualizing abnormal lymphatic architecture and lymphatic flow velocity in patients with secondary lymphedema has been demonstrated [107]. Due to high light penetration and low light scattering in the near-infrared range, fluorescence lymphography allows accurate visualization of lymphatic structures up to 2 cm beneath the skin and quantitative assessment of collecting vessel contractility using fluorescence lymphography [108]. Fluorescence lymphography allows observation of various patterns of dermal backflow (splash, stardust, and diffuse), which correlate with the severity of lymphatic dysfunction and clinical symptoms [109]. Fluorescence lymphography is a rapid, highly sensitive, reproducible method providing precise details of lymphatic vessel anatomy and lymphangion function, as well as response to therapy [110]. Disadvantages include limited imaging depth (~2 cm from the skin surface), undesirable physicochemical properties of indocyanine green — poor stability, self-quenching, and low quantum yield, which can only be overcome by developing clinically approved contrast agents optimized for the lymphatic system [111]. Given the imaging depth limitation, to obtain the most objective study results, the fluid component of lymphedema must be eliminated prior to the procedure [111]. Fluorescence lymphography in patients with known lymphedema demonstrated a sensitivity of 1.0 and specificity of 1.0 compared to CT (computed tomography of soft tissues) and MRI (magnetic resonance imaging of soft tissues) (sensitivity 0.97, specificity 0.55, and accuracy 0.82 when compared with lymphoscintigraphy) [112,113]. Fluorescence lymphography can be performed by injecting a fluorescent agent (diagnostic agent) directly into a lymphatic vessel visualized after preliminary indirect color lymphography, or by intradermal injection near the area of interest, where the area of interest is visualized using a charge-coupled device (CCD) camera.

Near-infrared fluorescence lymphography is highly sensitive and rapidly reproducible, and provides minute details of lymphatic vessel anatomy and lymphangion function, as well as the response to therapy.

Table I presents the stages of lymphedema according to fluorescence lymphography. Observed near-infrared fluorescence phenotypes and disease stage [110].

• Lymphoscintigraphy is recommended to visualize the location of lymphatic vessels and lymph nodes when objective information is required for surgical interventions on the lymphatic system [59,61,65].

LNC 5 LeC C

Comment 1: lymphoscintigraphy is a method involving direct (indirect) administration of contrast agents and radiographic visualization of the lymphatic system. During lymphoscintigraphy, it is possible to assess the state of the contractile apparatus of lymphatic vessels by determining the shape of the lymphatic vessel and its segmentation into lymphangions. At the same time, spindle- or bead-like segmentation indicates that the contractile apparatus has retained its functional properties. If the vessel is unsegmented and tube-like, this is evidence of the loss of contractile capacity. To assess the severity of the pathological process, the ratio of segmented to unsegmented vessels should be determined [95]. The method allows for identifying the level of lymph flow blockade (distal, middle, proximal), its character (complete, incomplete), the degree of lymphatic vessel damage (hyperplasia, hypoplasia, aplasia), and other symptoms (tortuosity of lymphatic vessels, retrograde lymph flow, extravasation).

• Computed lymphography is recommended for spatial visualization of the lymphatic system, determination of its anatomical structure, and qualitative and quantitative state when performing surgeries on the lymphatic system [59,61,65].

LNC 5 LeC C

• MR lymphography is recommended in case of lymphatic vessel hyperplasia to identify and determine the characteristics of lymphatic system lesions and to perform surgeries on the lymphatic system [61,65,114].

LE 3 GSR C

Comment 1: non-contrast magnetic resonance lymphography (contrast-enhanced MR lymphography) is a non-invasive diagnostic method.

Comment 2: contrast enhancement allows for visualizing a larger number of lymphatic vessels [115]. This is due to the isolation of lymphatic vessel origins, as a result of which the administered contrast agent can reach only a portion of the limb's lymphatic vessels [116]. Anatomical information is useful in the preoperative period to determine the area of formation [117,118].

Comment 3: contrast-enhanced MR lymphography of the limbs belongs to indirect lymphography methods. Gadobutrol** is used for the resorption of the contrast agent [119].

2.5 Other Procedures

No.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1. Conservative and surgical treatment of limb lymphedema.

Lymphedema therapy aims to achieve social, functional, and psychological adaptation of patients.

Goals of lymphedema treatment [61]:

- Restoration (if possible) of lymphatic drainage;

- Elimination or reduction of lymphatic edema (reduction or normalization of the volume of the affected limb);

- Improvement of limb function;

- Elimination or reduction of subjective symptoms of lymphedema, reduction of pain associated with lymphedema;

- Reduction of the risk of disability;

- Improvement of quality of life;

- Prevention of infectious and skin complications of lymphedema;

- Prevention of lymphedema progression;

- Reduction of lymphedema manifestations (an integral goal including volume reduction, improvement/restoration of limb function, reduction of pain associated with lymphedema);

- Maintenance of achieved treatment results for as long as possible.

To achieve these goals, complex lymphedema treatment programs are used, based on the principles of physical impact on tissues and physiotherapeutic methods that improve the drainage of stagnant lymph, local immune and anti-inflammatory processes.

3.1.1. General provisions, principles, and tactics of lymphedema treatment.

The patient must be informed in an accessible form about all aspects of their disease, provided with educational materials, and helped to form realistic expectations of treatment results and a sense of responsibility for maintaining the results, making them an active participant in the treatment process and teaching them self-care methods (self-management).

Basic principles of conservative treatment of lymphedema.

In domestic literature, a program for the conservative treatment of lymphedema has been developed, based on the concept of complex lymphatic therapy (CLT). Treatment involves two main options in the form of CLT—as an independent method of conservative treatment of lymphedema and CLT as a program combined with surgical operations [143,144]. In foreign literature, the concept of complete decongestant therapy (CDT) is used, which is based on the principles of lymphedema treatment using physical methods of tissue impact [145,148]. Both concepts are similar in terms of main treatment methods. However, the CLT program includes a broader use of physiotherapy methods, including intermittent pneumatic compression, electromagnetic, and laser therapy. Complex conservative therapy is indicated in all cases of lymphedema treatment in the absence of contraindications and is the method of choice for treatment.

To achieve the previously stated goals, complex lymphedema treatment programs are used, based on the principles of physical impact on tissues and physiotherapeutic methods that improve the drainage of stagnant lymph, local immune and anti-inflammatory processes.

Methods of complex conservative therapy.

1. physical direction methods:

   - active impact (MLD, IPC);

   - passive impact (MCEB and medical compression-elastic knitwear (MCEK));

2. physiotherapeutic methods (low-level laser therapy, electromagnetic therapy (A17.30.036), electrical stimulation);

3. exercise therapy;

4. hygienic methods.

3.1.2. Complex therapy of lymphatic edema

Level of Evidence (LE) 3, Grade of Recommendation (GR) C

Comments: the complex lymphedema treatment program is built on the continuity of two main stages of treatment [143,144]:

- Inpatient CLT;

- Prophylactic conservative therapy (CT).

Inpatient complex lymphatic therapy (CLT) involves multicomponent conservative treatment in a hospital setting. The duration of one course of such therapy usually does not exceed one month and depends on the stage of lymphedema and the effectiveness of the treatment.

Prophylactic conservative therapy includes individual elements of CLT and aims to prevent edema recurrence and infectious complications, patient rehabilitation, and adaptation to work and daily life. The duration of the prophylactic stage continues throughout the patient's life.

The complex treatment program is used in two options:

1. CLT as an independent method of conservative treatment of lymphedema.

2. CLT in combination with surgical operations.

The first option includes courses of inpatient and prophylactic treatment. Repeated courses of inpatient CLT are carried out 1–4 times a year, depending on the degree of lymphedema and the effectiveness of the treatment.

The second option includes combined treatment, in which CLT is intended to potentiate the effectiveness of surgical operations and is carried out according to a regimen of preoperative preparation, postoperative recovery, and long-term prophylactic treatment.

I. Inpatient (CLT)

1. Compression therapy.

2. Manual or hand lymphatic drainage [Foldi M. 1991].

3. Intermittent pneumatic compression (IPC, A15.12.002.001).

4. Electromagnetic therapy (A17.30.036).

5. Infrared laser therapy.

6. Electrical stimulation.

7. Drug therapy for complications.

8. Therapeutic exercises.

9. Patient education on the basic principles of edema recurrence prevention.

Almost all these methods are universal and can be successfully used for any type of lymphatic edema, both primary and secondary in origin.

The compression class of MCEK (medical elastic compression products) is prescribed by a physician based on the stage and "aggressive" course of lymphedema. Throughout life, depending on the effectiveness of compression therapy, the compression class of MCEK is decreased or conversely increased.

An additional therapeutic effect is provided by external electromagnetic therapy, which affects the rheological properties of lymph located in the subcutaneous adipose tissue, lymphatic vessels, and cutaneous capillary networks. The alternating electromagnetic field reduces viscosity and increases the fluidity of stagnant lymph, converting it from a colloidal to a liquid state. This significantly increases the efficacy of intermittent pneumatic compression systems.

Infrared laser therapy makes it possible to enhance local immunity and increase the throughput capacity of lymph nodes, serving as an adjunctive modality for intermittent pneumatic compression and manual lymphatic drainage in the complex treatment of lymphedema.

An exception is electrical stimulation, which produces a positive effect and is indicated only when it is possible to restore the contractile capacity of the lymphangions of the lymphatic vessels.

Pharmacotherapy is not mandatory in all cases of lymphedema treatment. Considering frequent inflammatory processes, one of the components of drug therapy is anti-inflammatory treatment (traditional, endolymphatic, and lymphotropic antibacterial therapy). Another purpose of pharmacotherapy is to exert a direct effect on various functions of the lymphatic system: improving lymphatic drainage, increasing the number of functioning lymphatic capillaries and lymphangion contractility, stimulating lymphangiogenesis, etc.

The final point of inpatient Complete Decongestive Lymphedema Therapy (CDLT)—training patients in the basic principles of edema recurrence prevention—is given the greatest importance because long-term treatment outcomes ultimately depend on its implementation.

The second component of complex conservative therapy is preventive (individualized) conservative therapy, which is carried out between courses of the main inpatient CDLT on a continuous basis and is an integral part of the patient's life.

II. Preventive conservative therapy (individualized, administered continuously)

1. Hygienic measures.

2. Therapeutic exercises.

3. Lifestyle management.

4. Elastic bandaging.

5. Compression and elastic garments.

6. Intermittent pneumatic compression (A15.12.002.001).

7. Pharmacotherapy (in courses).

The main principle of preventive conservative therapy is the correct and consistent use of all its components, each of which is of great physiological importance.

Hygiene of the limb skin helps prevent infectious diseases.

Lifestyle management implies working without prolonged standing, heavy lifting, and other harmful factors. The patient must organize their daily routine to allocate time for anti-recurrence treatment. The main factors in preventing edema recurrence are elastic bandaging (or wearing elastic stockings) and individualized home-based pneumatic compression.

Among all presented treatment methods, intermittent pneumatic compression (A15.12.002.001), manual lymphatic drainage, and compression-elastic bandages (adjustable non-stretch medical compression wraps for the upper or lower extremity) possess a direct lymph-draining effect for removing stagnant lymph from tissues. Pharmacotherapy is important as an anti-inflammatory agent and for stimulating lymphangiogenesis in certain forms of lymphedema.

3.1.3. Complete Decongestive Physiotherapy (CDPT).

CDPT includes:

1. Manual Lymphatic Drainage (MLD).

2. Compression therapy.

3. Therapeutic exercise (exercise therapy).

4. Hygienic measures.

CDPT consists of two treatment phases:

1 – Phase of active limb edema reduction. (MLD, multilayer compression-elastic bandaging, exercise therapy, hygienic measures).

2 – Maintenance therapy phase. (Medical elastic compression garments [MECG], self-massage, therapeutic exercise, hygienic measures).

The main active treatment method in CDPT is manual lymphatic drainage (MLD), which belongs to physical methods of edema reduction and is part of the comprehensive conservative treatment program for lymphedema [149].

LRE 1, GR A

Comment 1: the principle of MLD is based on the mechanical removal of lymph pooled in the extremity. As a result of manual movements, stagnant fluid is renewed, the function of the capillary lymphatic pump is enhanced, the phagocytic activity of tissue macrophages and extralymphatic destruction of macromolecular substances are stimulated, which is of exceptional importance for the treatment of lymphedema. Unlike conventional massage, lymphatic drainage is a more labor-intensive procedure. It is determined not by the force of physical exertion, but by the need for continuous control of the rhythm of movements (one movement per second), the pressure force on tissues, and the precision of movement across zones in a centripetal direction. Manual lymphatic drainage is based on the principle of grips which, unlike conventional massage, involve moving tissues in a centripetal direction. The grips are characterized by a wide scope of impact in which the tissue never loses its elasticity. All grips have a compression-advancement phase and a relaxation phase, when only contact with the skin is maintained.

Circular spot movements are performed in such a way that when the palm moves in the proximal direction, the pressure on the tissues is stronger than when the palm returns in the distal direction, when only contact with the skin is maintained. During a circular movement, the main task is to create a directed flow of lymph in the cutaneous capillary networks. Its essence is that when the palm moves in the direction of movement, lymph is squeezed out of the superficial cutaneous capillary networks in a centripetal direction.

The second movement is the pumping grip, in which "pumping" movements of the palm are performed with a phase of lymph advancement from the deep lymphatic networks.

The third stage involves "scooping" movements, stimulating lymphatic drainage from deeper tissues.

The fourth movement creates a directed centripetal flow of lymph by advancing the palm forward with the participation of the thumb, which directs the lymph flow into the area beneath the palm.

Comment 2: MLD belongs to methods that do not cure the disease, but only help alleviate the patient's condition. MLD is used in the complex treatment of lymphedema as a method that, according to the authors, improves lymph drainage. According to randomized controlled trials, manual lymphatic drainage is not recommended for the rehabilitation of patients after total knee replacement, as no differences in lower extremity circumference (edema) were observed after knee arthroplasty [150]. Kasseroller, R. G. (2024) notes that although MLD has been used in many countries for decades, recent systematic reviews, including a Cochrane systematic review with six randomized trials, failed to demonstrate any additional benefit of MLD in the context of CDT [151, 152, 153].

Recent studies have also failed to demonstrate additional benefit [152-155, 156, 157]. Furthermore, an implicit goal is to reduce the cost of therapy, which can be achieved by eliminating MLD when necessary therapists are available.

Manual lymphatic drainage with or without fluoroscopic guidance did not significantly improve the effect of decongestive lymphatic therapy in people with breast cancer-related lymphedema: a multicenter randomized trial. De Vrieze T. (2022) found that in patients with post-mastectomy lymphedema, MLD provided no clinically important additional benefits when added to other components of decongestive lymphatic therapy (DLT) [152].

Regular MLD can only be performed during inpatient treatment. At the same time, massage must be performed daily. After receiving appropriate instructions, patients should perform self-massage twice a day (morning and evening) continuously for 15 minutes [7].

• Self-lymphatic drainage is recommended in the maintenance phase of treatment in combination with compression therapy [66, 158, 159].

LNC 4 LeC C

Comments: self-lymphatic drainage (SLD) or self-massage, "simple" manual lymphatic drainage, is a simplified version of MLD that patients and/or their relatives can apply independently to maintain treatment results in phase 2 – maintenance therapy [66, 158, 159].

Absolute contraindications to manual lymphatic drainage massage are generally considered to be:

• Chronic heart failure;

  • Acute infectious diseases (erysipelas);

  • Metastases to organs and skin.

• It is recommended to use compression therapy as the primary treatment and prevention method for primary and secondary lymphedema, either as part of complex therapy or as a standalone modality [59,160-162].

Level of Evidence (LoE) 1, Grade of Recommendation (GoR) A

Comment 1: elastic bandages and medical compression knitwear are used to provide constant compression.

Types of compression-elastic products used in the treatment of lymphedema:

- Mixed band compression elastic bandages;

- Medical compression knitwear for the lower and upper extremities (circular or flat knit);

- Adjustable non-stretch medical compression garments for the upper or lower extremity with accessories.

Various types of compression therapy may be more or less preferable depending on the specifics of a particular clinical case. The selection of the optimal type of compression therapy and the determination of its application regimen is the prerogative of the specialist treating the patient's lymphedema.

Methods of compression therapy:

1. Multi-layer compression-elastic bandaging (using short- and medium-stretch elastic bandages);

2. Compression using medical compression knitwear (compression stockings, socks, gloves, etc.).

Comments 2: compression therapy is the simplest, most accessible, and effective means of eliminating limb edema and preventing its recurrence. Compression therapy can be used as an independent treatment method when intermittent pneumatic compression and/or MLD cannot be used due to contraindications, unavailability of specialists, or lack of equipment.

Comment 3: the effectiveness of compression therapy in treating patients with extremity lymphedema has been proven in numerous randomized controlled trials [161,163,164]. At the same time, the level of evidence for effectiveness varies for primary and secondary lymphedema, for different clinical outcomes, and for different compression products or methods.

Comment 4: the clinical goals of compression therapy for lymphedema include [23,59,61,65,78,165]:

− Reduction or elimination of subjective symptoms of lymphedema;

− Reduction of lymphatic edema;

− Prevention of lymphatic edema progression;

− Prevention of the development of lymphatic edema after surgical interventions on the lymphatic system;

− Prevention and treatment of trophic ulcers in lymphedema;

− Improvement of quality of life through the elimination or reduction of subjective and objective manifestations of lymphedema;

− Reduction of the risk of developing erysipelas.

Level of Evidence (LE) 2, Grade of Recommendation (GR) A

Comment: multi-layer compression-elastic bandaging has shown the highest efficacy as part of complex therapy, but its use as monotherapy also yields results in the form of a significant reduction in edema. The feasibility, appropriateness, and safety of using multi-layer compression-elastic bandaging as an independent treatment method are determined by the specialist treating the lymphedema patient, based on the specifics of the clinical case.

• To form a multi-layer compression-elastic bandage, it is recommended to use short- and/or medium-stretch bandages and materials to create a cylindrical limb profile [169-172].

Level of Evidence (LE) 2, Grade of Recommendation (GR) A

Comment 1: the main principle lies in the correct distribution of external elastic pressure on the limb tissues, which normally should decrease from the distal parts of the limb to the proximal ones. Thus, a gradient of external compression pressure or the so-called pushing force is created at rest and during activity (walking).

• When performing multi-layer compression-elastic bandaging (MCEB) in patients at the first stage, medical compression bandages are recommended daily throughout the day with rest breaks, or around the clock depending on the stage of edema [173,175].

Level of Evidence (LE) 3, Grade of Recommendation (GR) B

Comment: MCEB is removed only during active lymphatic drainage and hygienic procedures. It is necessary to use medium- and short-stretch bandages that provide sufficient external compression pressure.

The dynamics of limb size changes must be assessed by daily measurement of its circumference when replacing multi-layer compression-elastic bandages to determine the end of the first phase of treatment.

Leveled Research Evidence (LE) 2 Grade of Recommendation (GR) B

LNC 5 LeC C

Comment 1: it is used at the prophylactic or maintenance stage of treatment once the maximum decongestive effect has been achieved. Medical compression knitwear is selected according to the measurements of the "non-edematous" limb achieved at the first stage of decongestive therapy.

Comment 2: medical compression knitwear is used continuously from morning until evening to maintain the limb in the most non-edematous state possible. If the limb size increases, the patient must switch to using a multi-layer compression-elastic bandage (medical elastic compression bandages) until the target limb size indicators are reached.

In reducing edema, medical compression knitwear has limited capabilities and can be used for this purpose only in the early stages of lymphedema with minimal edema up to 3 cm. In cases of pronounced edema, it is impractical to select and use medical compression knitwear until the active phase of CDTL/CDT is completed. According to a 2016 systematic review, regular use of medical compression knitwear in secondary lymphedema does not reduce edema, but prevents its progression [182]. Regular use of medical compression knitwear slows down or stops the progression of lymphedema. RCTs have established a lower rate of lymphedema progression in the compression sleeve group compared to the group without compression at 6 months of follow-up: 16% and 57%, respectively, p = 0.001 [164].

Comment 3: there are recommendations for selecting the compression class of knitwear: for upper extremities with lymphedema, medical compression knitwear with a pressure of 22-32 mm Hg is most often chosen; for poorly controlled lymphatic edema, the compression class for upper extremities can be increased to 34-46 mm Hg. For lower extremities with lymphedema, knitwear with a pressure of 34-46 mm Hg or higher than 49 mm Hg is usually used [293].

Comment 4: in the treatment of stage 0-1 lymphedema, both circular-knit and flat-knit medical compression knitwear can be used. Circular-knit products are generally more stretchable than flat-knit products. However, such knitwear may be sufficient for small or moderate lymphedema and is a "first-line" compression product.

Comment 5: individual selection of compression knitwear is carried out at points of sale by specialist consultants trained by the manufacturers. The physician recommending medical compression knitwear is obliged to indicate the compression class, type, and area of application of the product. The physician may also offer the patient an individual type of compression product, which is selected at their discretion, depending on the localization and severity of the pathological process.

• Adjustable non-stretch medical compression garments (ANCG) are recommended for deforming forms and stage 3 lymphedema at the prophylactic stage of treatment [185-188].

Level of Evidence 1, Grade of Recommendation B

Comments: ADCs are devices consisting of multiple circular compression bands integrated into a single system. The required pressure profile is provided by tightening or loosening individual bands. ADCs are classified as inelastic or low-stretch compression devices. Since the introduction of ADCs in the early 2000s, these systems have been evaluated in a number of studies, though most of them are observational or case series designs [183,184]. Due to the specific features of donning and adjusting the compression level, in some cases ADCs facilitate independent compression therapy, skin care for patients, and improve their adherence to the physician-prescribed compression therapy regimen in the second phase of CDT [185–188].

Level of Evidence 2, Grade of Recommendation B

Level of Evidence (LoE) 2, Grade of Recommendation (GoR) B

Comments: the exercise program is performed only in the presence of a medical compression bandage or medical compression hosiery. It includes special exercises that promote lymph drainage and reduce limb volume.

• During daily hygienic care of the lymphedematous limb, it is recommended to follow the protocol for daily skin care of the affected limb (see Appendix A3.3) [60,196].

LNC 5 LeC C

Comment 1: the daily skin care protocol (see Appendix A3.3) was developed based on the All-Ireland Lymphoedema Guidelines 2022, which utilize materials from 2 systematic literature reviews, as well as additions from Hobday A [60,196,197,198].

Comment 2: use warm water for skin cleansing. Soap should preferably be replaced by water- or oil-based substitutes (e.g., Aqueous cream). Such substitutes do not have drying and irritating effects. If soap is used, it should be pH-neutral and thoroughly rinsed off.

Comment 3: when choosing a skin moisturizer, the base of the skin product should be considered. Predominantly dry skin is best moisturized with high-fat creams. Although skin lotions have a pleasant cooling effect and are quickly absorbed by the skin, in the long term they dry out the skin. Oil-based cream bases can be used on cooler days when less sweat evaporates from the skin. Fast-absorbing hand creams can be used during the day, and richer creams at night [197,199-201].

3.1.4. Skin complications of lymphedema

The most frequent cutaneous complications of lymphedema include:

- Papillomatosis;

- Plantar dermatitis;

- Atopic eczema;

- Hyperkeratosis;

- Maceration of skin folds;

- Lymphorrhea;

- Folliculitis;

- Fungal infections; onychomycosis;

- Trophic defects (erosions, ulcers);

- Erysipelas.

Treatment of skin complications should be carried out in cooperation with a dermatovenerologist and an infectious disease physician.

• In case of limb papillomatosis in lymphedema, it is recommended to perform laser ablation or surgical removal (excising) of papillomas (removal of benign skin neoplasms) to slow down its progression [74,202,204].

LNC 5 LeC C

Comment 1: lymphostatic cutaneous papillomatosis is a severe complication of chronic lymphedema, characterized by wart-like papillomatous growths. Papillomatosis develops against the background of skin fibrosis and hyperkeratosis [202,203].

Comment 2: active treatment of skin lesions is essential to slow down disease progression. Papillomatous skin growths serve as a substrate for bacterial and fungal colonization. To consider and prescribe pharmacotherapy, a patient with papillomatosis must be referred for a consultation with a dermatovenerologist. In early stages, papillomatosis may be reversible with active CDT. One of the main methods for eliminating papillomatous growths is their laser ablation. In severe cases, surgical excision is advisable to slow down disease progression. Surgical excision or laser ablation should be performed down to the papillary dermis [202].

• If lymphorrhea develops, it is recommended to initiate active compression therapy with multi-layer compression bandaging as early as possible to stop lymphorrhea and prevent skin maceration [60].

Level of Evidence 5, Grade of Recommendation C

Comment 1: lymph is a chemically active alkaline fluid that rapidly causes skin maceration and can lead to the formation of extensive erosions. The onset of lymphorrhea requires treatment adjustment due to the risk of infectious complications and secondary skin damage.

Comments 2: lymphorrhea is a common complication of lymphedema. Despite the lack of high-quality clinical studies, professional societies have formulated recommendations for the treatment of lymphorrhea based on expert consensus. Active compression therapy using multi-layer compression bandaging is recognized as the main method to manage lymphorrhea. Features of lymphorrhea management:

• Initiate (adjust) limb bandaging as early as possible upon the development of lymphorrhea;

• After cleaning the skin of the affected limb and before applying the bandage, a barrier cream must be applied around the lymphorrhea area to protect the skin from maceration;

• Use absorbent materials in the first layer of the bandage; in case of pronounced lymphorrhea, superabsorbents must be used;

• In case of significant lymph leakage, bandage changes may be required more frequently than once a day.

A promising method for treating lymphorrhea is negative pressure wound therapy (NPWT) [205,206].

• Treatment of trophic ulcers in limb lymphedema is recommended to be carried out in accordance with the principles of venous leg ulcer management [208].

LNC 5 LeC C

Comments 1: a trophic ulcer is a defect of the skin and soft tissues that has not healed within 6 weeks. If an ulcer defect is present or appears in a patient with limb lymphedema, concomitant arterial and venous pathology as a potential cause of ulceration must be excluded [207].

Comments 2: the mainstay of treatment is edema reduction; surgical debridement is used as the preferred local treatment method at the initial stage of trophic ulcer cleaning (surgical debridement is the removal of pathological tissues (necrectomy) and fibrin deposits using a scalpel, curette, scissors, Volkmann spoon, or laser); it is advisable to use modern wound dressings adapted to the stage of the wound healing process, creating a balanced moist environment optimal for regenerative processes. The choice of specific therapeutic agents depends on the characteristics of the wound healing process and the condition of the tissues surrounding the trophic ulcer. The choice of dressing requires mandatory consideration of the wound healing phase and the degree of exudation. In case of pronounced exudation from a trophic ulcer or erosion, superabsorbents must be used.

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Comments: antibacterial therapy is the method of choice for treating infectious complications in lymphedema. Modern antibacterial therapy regimens utilize semi-synthetic penicillins (beta-lactam antibiotics, penicillins), fluoroquinolones, macrolides, and tetracyclines in courses of 5-7 days.

One of the latest developments in the treatment of acute skin and soft tissue infections are antibiotics combining the properties of glycopeptides and cephalosporins: tedizolid**.

Tedizolid** is prescribed at 200 mg once daily for 6 days.

Prevention of erysipelas recurrence involves the administration of long-acting antibiotics: Benzathine benzylpenicillin + Benzylpenicillin procaine at 1.5 million IU or Benzathine benzylpenicillin** at 2.4 million IU, 3–4 injections at 1-month intervals. In case of frequent recurrences of erysipelas (at least 3 in the past year), continuous (year-round) antibiotic prophylaxis is advisable for 2–3 years with a drug administration interval of 3–4 weeks (in the first months, the interval can be shortened to 2 weeks). For seasonal recurrences, administration of the drug is started one month before the onset of the morbidity season for the given patient, with an interval of 4 weeks for 3–4 months annually.

Types of dressings are presented in Appendix A3.5. "Types of dressings for the treatment of ulcers in patients with limb lymphedema".

3.1.5. Additional methods of complex lymphedema therapy

LRE 1, GR A

Comment 1: intermittent pneumatic compression (IPC, intermittent pneumatic compression therapy, A15.12.002.001) is one of the methods used in the treatment of lymphedema.

The system consists of an air pump equipped with an intermittent air delivery mechanism with adjustable pressure, and various designs of pneumatic cuffs divided into sections. The therapeutic principle is based on applying external pressure to tissues in an intermittent inflation and deflation mode of the pneumatic cuff, and sequential inflation of the pneumatic cuff sections from the periphery to the center in two modes: the first mode is a rising wave, and the second is a "dual running wave". Depending on the severity and stage of the disease, the intermittent pneumatic compression system provides a mode of adjustable pressure generated in the pneumatic cuffs, and it is also possible to adjust the exposure time separately for the inflation and deflation periods.

Comment 2: a systematic review and meta-analysis (Hou S. 2024) of articles on the use of IPC in the treatment of lymphedema from 1995 to 2024 showed that the use of IPC + CDT provides additional improvement in the intensive phase of lymphedema treatment, which persists for 4 weeks. However, this additional benefit of IPC decreased during 9.4 ± 2.6 weeks of follow-up after treatment cessation. As a result, the IPC method is proposed as a periodic continuous treatment to maintain the decongestive effect of CDT + IPC to enhance lymphatic drainage and prevent lymphedema recurrence. The IPC method can be used in both the intensive and maintenance (preventive) phases of CDT.

A meta-analysis (Shao Y. 2014) showed that to prolong the effect of IPC after its use in the intensive phase of CDT, it is recommended to periodically conduct courses of IPC treatment in a clinic and continuous independent use at home during the maintenance (preventive) phase (Rogan S. 2016, Shao Y. 2014).

Comment 3: a prospective RCT (Szuba A. 2002) established that the use of IPC in addition to CDT enhances the therapeutic effect. The IPC method is well tolerated and causes no complications (Szuba A. 2002).

Mechanical compression pressure on edematous tissues is an important external factor of the decongestive effect (Zaleska MT 2019).

Szuba A. 2002 revealed that the combined use of complete decongestive therapy (CDT) or decongestive lymphatic therapy (DLT) and IPC during the intensive phase of treatment yielded an additional reduction in limb volume by an average of 45.3%, whereas isolated use of CDT yielded only 26% (P < 0.05). During the maintenance phase, isolated use of CDT, conversely, led to an increase in limb volume accordingly (32.7 ± 115.2 ml) (Szuba A. 2002), while the combination of CDT and IPC showed a decrease in limb volume on average (89.5 ± 195.5 ml; P < 0.05). As an independent treatment method, IPC does not have long-term efficacy and therefore must be combined with compression therapy.

Thus, the use of IPC in addition to the main methods of combination therapy leads to an enhancement of the decongestive effect in the intensive phase of treatment and in the maintenance or preventive phase, provided that IPC is used continuously in clinical and home settings.

• Kinesio taping for the treatment of lymphedema is recommended as an adjunct method in combination therapy [215,218].

Level of Evidence (LE) 2, Grade of Recommendation (GR) A

Comment 1: taping involves fixing narrow strips of physical tape to the skin in the affected area. Kinesio taping in the treatment of patients with lymphedema has an extremely limited evidence base and is not always mentioned as a possible treatment option in professional society guidelines. The 2020 guidelines of the International Society of Lymphology note the existence of studies on the use of kinesio taping in patients with breast cancer-related lymphedema with positive effects [61]. Despite extremely limited data on the efficacy of kinesio taping in certain clinical situations, this method has become quite widespread in practice [214].

Comment 2: the efficacy of kinesio taping in reducing limb volume in lymphedema has been proven in a systematic review with a meta-analysis of RCT data from 2023 [215]. Of the 123 studies initially screened, only 7 RCTs met the inclusion criteria for this systematic review. The authors note that evidence of a positive effect of kinesio taping on limb volume was obtained, but they rate the quality of the evidence as low. Individual studies describe various positive clinical effects of kinesio taping: reduction of limb volume, reduction of pain and other subjective symptoms, and improvement of limb function. In an RCT from 2023, the authors compared the efficacy of kinesio taping, MLD, and low-level laser skin irradiation prior to mandatory limb banding and exercise in female patients with lymphedema. Procedures were performed 5 days a week for 3 weeks, with follow-up at the end of treatment and at 4 and 12 weeks post-treatment. The kinesio taping group recorded the greatest regression of limb edema (differences with the MLD group were statistically significant, p = 0.009, p = 0.039, and p = 0.042 relative to the control visits, respectively) [216]. Similar results were obtained in female patients with breast cancer-related lymphedema in an RCT comparing kinesio taping and the use of a compression sleeve. Kinesio taping showed a greater regression of edema (-5.7%, SD = 2.0 vs. -3.4%, SD = 2.9, p < 0.001) [217]. It is advisable to consider the use of kinesio taping in areas where edema is difficult to manage with compression therapy, such as the breast, face, and pubic region.

Level of Evidence (LE) 3, Grade of Recommendation (GR) C

• Electromagnetic therapy (A17.30.036) is recommended as an adjunct method in the complex treatment of patients with lymphedema in order to improve the efficacy of comprehensive conservative therapy [219,220,221].

Level of Evidence (LE) 3, Grade of Recommendation (GR) C

Comment: electromagnetic oscillations act on stagnant lymph in tissues, leading to an increase in its fluidity, which increases the efficacy of physical treatment methods. According to some studies, a reduction in the severity of pain and edema syndrome was found in patients with lymphedema who received electromagnetic therapy compared to the placebo-controlled group [219,220,221]. Electromagnetic therapy affects the rheological properties of lymph, reduces viscosity, increases fluidity, and converts it from a colloidal to a liquid state. Electrical stimulation helps increase the intrinsic contractility of lymphatic vessels.

Level of Evidence (LE) 2, Grade of Recommendation (GR) C

Comment 1: LLT (low-level laser therapy, LLLT), also known as photobiomodulation therapy (PBMT), is a non-invasive therapy that uses red or near-infrared light wavelengths from 650 to 1000 nm to deliver low-intensity radiation to the target tissue. Infrared laser therapy makes it possible to enhance local immunity and increase the throughput capacity of lymph nodes, and serves as an adjunct to intermittent pneumatic compression and manual lymphatic drainage in the complex treatment of lymphedema. As a result, all these methods potentiate the efficacy of compression treatments.

Comment 2: there is evidence of positive results from the use of low-level laser therapy or photobiomodulation (PBM) [225] in the treatment of cancer-related lymphedema. Over the past two decades, the efficacy of photobiomodulation (PBM) for the treatment of lymphedema has been actively studied. PBM is used to reduce inflammation, stimulate lymphatic vessel regeneration, improve lymph mobility, and treat and prevent tissue fibrosis [226].

Systematic reviews [227, 228, 229] provide compelling evidence in favor of photobiomodulation (PBM) compared to placebo in terms of reducing limb edema during short-term follow-up. To date, infrared wavelengths (808–905 nm) have been used most frequently, and the reported energy densities that yielded positive results ranged from 1.5 J/cm² to 2.4 J/cm².

A systematic review and RCTs evaluating a range of conservative treatments showed that PBM provides a similar percentage of volume reduction (approximately 11%) compared to compression garments or bandages [230, 231, 232].

• Pharmacotherapy (including lymphotropic therapy) in the treatment of extremity lymphedema is not recommended due to a lack of proven efficacy [60, 61, 64].

LNC 5 LeC C

Comments: in clinical guidelines and professional society recommendations, pharmacotherapy is not a treatment method for lymphedema [60, 61, 64].

3.2 Surgical treatment of lymphedema

Main principles of surgical treatment for lymphedema.

Conservative treatment is the primary (basic) and mandatory type of care for a patient with lymphedema. Surgical interventions are independent treatment methods and, depending on their type (resectional or drainage), have indications based on the etiology and stage of lymphedema. The concept of a comprehensive approach to lymphedema management implies the advisability of combining conservative and surgical approaches [144].

Systematic reviews indicate that as microsurgical techniques for lymphedema treatment improve, their efficacy increases [69, 70, 146, 147]. Indications for reconstructive surgery include the formation of direct lymphovenous drainage and, thereby, the creation of a sustained anti-edema effect, which helps reduce dependence on compression therapy, decrease the frequency of erysipelas episodes, lower tissue tension, and improve the patient's quality of life (Appendix G1. Lymphedema Surgical Treatment Assessment Scale).

3.2.1 Types of surgical interventions for lymphedema.

Surgical interventions for lymphedema are divided into 3 categories:

1. Resectional (reduction) category – methods of surgical reduction of the volume of lymphedematous limb tissues.

2. Drainage category – methods of surgically creating pathways for lymph outflow into the venous bed.

3. Combined category – simultaneous use of lymphatic drainage methods and resectional surgeries.

Resection surgeries are performed to reduce limb size. Main goals:

- reduction of limb volume and deformity;

- improvement of cosmetic outcomes;

- improvement of limb function;

- improvement of quality of life.

Resection surgeries for limb lymphedema include direct excision of the skin and subcutaneous adipose tissue, as well as liposuction [233]. The staged resection-plastic surgery method using local tissue flaps allows for the removal of the maximum volume of excessive lymphedematous tissues, achieving a good cosmetic effect and molding the correct limb configuration [234, 235, 236, 237].

• Resection surgeries are recommended for patients with deforming forms of lymphedema after the active phase of edema reduction to remove excess skin and lymphedematous tissues [66, 237, 238].

LNC 5 LeC C

• Liposuction is recommended for the removal of excess subcutaneous adipose tissue to normalize limb volume [66, 239].

LNC 5 LeC C

Comment: liposuction is an effective method for reducing limb volume by suctioning out excess subcutaneous adipose tissue. Liposuction is performed after the active phase of decongestive therapy. Following liposuction, a significant (>90%) and long-term reduction in limb volume and improvement in quality of life can be achieved, provided that lifelong maintenance compression therapy is carried out [123]. In a systematic review, the use of liposuction in lymphedema treatment showed a substantial reduction in volume, improved limb function, and better quality of life with a reduced risk of infectious complications of lymphedema [240]. The authors recommend liposuction for stage II-III lymphedema followed by maintenance compression therapy. In a systematic review on upper extremity lymphedema, liposuction achieved complete elimination of excess limb volume when prior conservative therapy failed to resolve the volume difference (conservative therapy resolves the fluid component but not the tissue component of lymphedema) [240].

Contraindications to liposuction [233, 241, 242]:

- Lymphangiosarcoma;

- Skin lesions (wounds, ulcers, maceration, etc.);

- Neoplasms and metastases in the surgical area;

- Blood clotting disorders and anticoagulant therapy.

According to H. Brorson, liposuction should not be used to treat lymphedema in patients with a BMI >30–32, in cases of refusal to wear lifelong compression garments, or when the volume difference is less than 600 cm³ for upper extremities.

Features of preoperative preparation, liposuction procedures, and postoperative patient management are detailed in Appendix A3.6. "Liposuction: features of preparation, performance, and postoperative management".

Level of Evidence 2, Grade of Recommendation B

Comment 1: reconstructive microsurgeries for limb lymphedema include lymphovenous shunting, the formation of lymphovenous or lymphovenular anastomoses (LVAs), lymphonodovenous anastomoses, and vascularized lymph node transfer (VLNT).

Comment 2: data on the efficacy of microsurgeries, including lymphovenous anastomoses and vascularized lymph node transfer, remained contradictory for a long time [243, 244].

Furthermore, early systematic reviews of these studies failed to pool the data [245]. Results of recent systematic reviews with meta-analysis consistently demonstrate the benefits of LVA and VLNT in a number of clinical situations [246]. Following microsurgery, 63% of patients did not require the active phase of complete decongestive therapy, and 96% experienced no recurrence of skin infections. Only 12% of patients reported that limb edema recurred in the long term.

Comment 3: in recent systematic reviews [247], clinical results of microvascular autotransplantation of the greater omentum containing lymph nodes and vessels showed a significant reduction in limb volume and improvement in lymphatic drainage, overall patient satisfaction, and improved quality of life. The systematic review [247] highlights promising results of using a greater omentum flap in lymphedema treatment with low complication rates and significant improvements in both clinical and patient-reported outcomes.

Comment 4: several systematic reviews of studies have established a significant improvement in quality of life after LVA and VLNT, regardless of lymphedema etiology, stage, or time since diagnosis [248, 249]. There is considerable disagreement within the professional community regarding the appropriate waiting period before considering reconstructive surgery. The best results are obtained when reconstructive surgeries are performed at early stages of lymphedema [250]. At the same time, delaying surgery by more than one year significantly increases the risk of surgical failure due to chronic damage to the lymphatic system [253]. Some specialized centers use lymphovenous anastomoses as a prophylactic measure in patients at high risk for developing lymphedema. Meanwhile, the international consensus document on the diagnosis and treatment of lymphedema states that surgical lymphatic drainage methods are an acceptable strategy for preventing the development and treating lymphedema in high-risk patients at an early stage (stages 0–I) [252]. Reconstructive surgeries are most effective before irreversible changes occur in the soft tissues and lymphatic vessels of the limb.

Features of preoperative preparation and postoperative patient management during reconstructive lymphatic surgery are detailed in Appendix A3.7. "Reconstructive surgeries: features of preparation and postoperative management".

• Lymphovenous anastomosis procedures are recommended to establish direct lymphatic drainage into the venous system and decompress lymphangipertension, showing high efficacy with a minimal complication rate [102,236,254,255,256,257,258,259,260,261,262,263,264,265,266,267,268,269].

Level of Evidence (LE) 1, Grade of Recommendation (GR) A

Comment 1: lymphovenous and lymphovenular anastomoses (LVA) are types of microsurgical reconstructive operations on the lymphatic system aimed at improving lymph outflow by draining lymphatic fluid into the venous system. There is no fundamental difference in technique, indications, and contraindications between these two procedures. The only difference lies in the diameters of the anastomosed vessels (for lymphovenous anastomoses, vessels with a diameter of more than 0.5 mm are sutured, while for lymphovenular anastomoses, the diameter ranges from 0.2 mm to 0.5 mm).

Comment 2: currently, LVA operations are the most frequently used surgical method for treating lymphedema. The technical methods of LVA formation are constantly being improved, which helps to enhance clinical treatment outcomes [259,265]. LVA operations result in an objective reduction in limb circumference and a subjective improvement in the quality of life in both upper and lower limb lymphedema. In addition, there is a notable decrease in the frequency of erysipelas episodes. Another significant factor of efficacy is the possibility of discontinuing compression therapy [269].

A systematic review [264] included 18 studies and 939 patients who underwent the creation of various types and numbers of LVAs for lymphedema treatment. All studies noted an objective decrease in the circumference of the edematous limb. Additionally, 50–100% of patients experienced subjective relief of symptoms characterized by a reduction in tension, pain, and heaviness, as well as a decrease in the number of erysipelas episodes in all studied cases.

A systematic review and meta-analysis [257] revealed that prophylactic lymphovenous anastomosis reduces the risk of developing lymphedema in 1/3 of patients.

A systematic review and meta-analysis [260] included only original studies in which LVAs were performed for primary and/or secondary lymphedema.

A meta-analysis of articles with a clearly defined endpoint [260] confirmed the high efficacy of LVA in the treatment of lymphedema, when analyzing subgroups of different clinical stages, lymphedema duration, localization, and duration of lymphedema, as well as the type of microsurgical LVA.

Forty-eight studies, including 6 clinical trials and 42 observational studies with a low risk of bias, were included in the meta-analysis [260], which demonstrated that lymphovenous drainage operations lead to a persistent and long-term reduction in edema of the affected limb.

The clinical efficacy of LVA surgery primarily depends on the functional activity of the lymphangions of the lymphatic vessels, as well as the location and competence of the recipient vein valves [259,261,263].

The use of the ICG-L intraoperative navigation system allows for the rapid identification of lymphatic vessels and the creation of LVA [268].

Various options for LVA creation have shown that both side-to-end and end-to-end anastomoses effectively reduce limb edema. Side-to-end LVA showed greater clinical efficacy when forming only a single anastomosis. The advantage of lymphatic drainage operations compared to conservative treatment methods is the ability to achieve a sustained, long-term anti-edema effect without the use of compression garments [254,267,269].

A study [258] showed that both end-to-end and side-to-end LVAs resulted in an effective reduction of limb volume. However, side-to-end LVA showed significantly better results in patients with stage I lymphedema, whereas no significant difference was observed in stages II-III [258]. Side-to-side LVA of the lymphatic and venous vessels provides both antegrade and retrograde lymph flow depending on the patient's position.

Various methods of indirect and direct lymphography, including fluorescence methods, contrast lymphography, and Doppler ultrasound lymphangiography, were used to assess LVA patency [102].

A review [262] found that increasing the number of LVAs does not lead to an increase in clinical efficacy.

High-frequency ultrasonography, including intraoperative ultrasonography, makes it possible to identify a recipient vein without reflux, which is crucial for the efficacy and duration of LVA functioning [255,256].

Comment 3: the essence of the method lies in the intradermal administration of a blue dye (or other diagnostic agent) prior to the removal of axillary lymph nodes (A16.06.006.001; A16.06.014; A16.06.014.001; A16.06.014.002; A16.06.014.003; A16.06.015; A16.06.016; A16.06.016.001; A16.06.016.002). The method of lymphatic vessel mapping during mastectomy has been known since 2007.

Gaber A. et al. [103] performed color mapping of lymphatic vessels prior to axillary lymph node dissection by intradermal administration of a diagnostic agent. The technique consisted of injecting a blue dye (another diagnostic agent) intradermally in the shoulder area after mastectomy and 5–10 minutes before the removal of axillary lymph nodes. Intraoperatively, undamaged blue lymphatic vessels were identified and preserved, and damaged lymphatic vessels with lymphorrhea were ligated. The color mapping group showed a significant reduction in the incidence of seroma (p = 0.040) and secondary lymphedema (p = 0.031), as well as a reduction in the time to drain removal (p < 0.001). The authors recommend color lymphography as a simple and effective method for preventing lymphatic complications and the risk of secondary lymphedema development.

The incidence of lymphocele formation after breast surgery varies widely, from 2.5% to 51% up to 3% - 85% [104,105].

Blue dyes (other diagnostic agents) are used for intraoperative visualization of lymphatic vessels during the creation of lymphovenous anastomoses [306].

Blue dyes are non-toxic to lymphatic vessels and nodes [307]. Mild allergic reactions in the form of local urticaria are observed rarely, and more severe allergies without fatal outcomes are very rare [308,309].

Comment 4: color lymphography is performed to visualize lymphatic vessels by injecting a blue dye solution (other diagnostic agents). Currently, color lymphography is used as a preparatory stage when performing X-ray contrast lymphography (lymphorentgenography) to identify a lymphatic vessel [92]. In clinical practice, the indirect color lymphography method is most frequently used. When performing it, the contrast agent is injected in a volume of 0.2–0.5 ml subcutaneously or intradermally, followed by observation of its spread through the superficial lymphatic vessels. In direct color lymphography, lymphatic vessels can be injected by introducing the solution into the lymph node using a percutaneous puncture method or an open method with isolation of the lymphatic vessel or lymph node in the surgical wound.

• Lymph node autotransplantation procedures are recommended for stage I–II lymphedema [270,271,272].

Level of Evidence (LoE) 1, Grade of Recommendation (GoR) A

Comments: for autotransplantation (drainage-type procedures), lymph nodes from the lateral inguinal region (above the inguinal ligament level) are used, which are not involved in the lymphatic drainage of the lower extremity. This treatment method has a long-lasting positive effect in relieving lymphedema, preventing infectious complications, and improving skin elasticity.

A systematic review with meta-analysis [270] concluded that lymph node autotransplantation procedures significantly reduced the number of erysipelas episodes, in 45% of cases patients stopped using compression knitwear, while the procedures had a minimal number of complications [270]. The meta-analysis [271] demonstrated efficacy in reducing excessive limb volume and also in decreasing the number of erysipelas episodes.

A 2016 RCT on VLNT achieved an average limb volume reduction of 57%, a decrease in the frequency of infection recurrence, and an improvement in limb function [272].

• Combined interventions are recommended to maximize treatment efficacy for lymphedema [273].

LE 3 GSR C

Comment: a 2019 systematic review demonstrated the benefits of combining lymph node transfer and liposuction for lymphedema [273]. The results of this systematic review suggest that combining lymph node transfer and lipoaspiration is a method that can improve outcomes achievable by either surgery alone in patients with stage 2–3 lymphedema.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

4.1 Medical rehabilitation for limb lymphedema: general information

Lymphedema of the upper and lower extremities impairs patients' quality of life and working capacity, as demonstrated in a number of systematic reviews [274, 275]. Surgical and conservative treatment of lymphedema improves quality of life and limb function; however, it is not always possible to achieve the maximum possible therapeutic effect and maintain its results over a long period [274, 276]. Therefore, it is advisable to use rehabilitation methods during the monitoring and treatment of a patient with limb lymphedema. The goal of rehabilitation methods is to compensate for lost/impaired limb functions and improve the patients' quality of life. Although secondary lymphedema is often associated with oncological pathology, cancer rehabilitation methods and programs are not discussed in this paper. Rehabilitation of patients with lymphedema may include elements of physical and psychological rehabilitation.

Sanatorium-resort treatment is worth considering for the rehabilitation of patients with limb lymphedema. When choosing sanatorium-resort treatment, one should focus on the availability of therapeutic exercise, walking techniques (terrain cure), and water exercises (in a swimming pool). Water exercises and walking as methods of therapeutic physical training are described in detail in the subsections "Water Exercises" and "Nordic Walking" under "Conservative Treatment of Lymphedema" / "CDT: Therapeutic Physical Training, Physical Exercises" / "Specific Types of Physical Activity".

4.2 Psychological correction

• Psychological counseling is recommended for patients with limb lymphedema to reduce symptoms of anxiety, depression, and asthenic syndrome (Appendix G2. Quality of Life Assessment in Lymphedema (LYMQOL)) [277, 278, 279, 280, 281].

Level of Evidence (LE) 3, Grade of Recommendation (GR) B

Comment 1: it has been established that patients with breast cancer-related lymphedema exhibit a high degree of anxiety and depression. The study investigated the effect of relaxation techniques on the level of edema, anxiety, and women undergoing CDT compared to CDT alone. Edema volume, anxiety, and depression scores were compared at the first and last sessions of the first phase of treatment and six weeks thereafter. The reduction rates for edema, anxiety, and depression were 63.6%, 54.1%, and 65.5% in the relaxation plus CDT group, and 60.7%, 31.4%, and 35.2% in the CDT-only group. There were significant differences between the two groups in terms of reduced depression scores (p = 0.024) and anxiety scores (p = 0.011) throughout the study. This significant correlation was due to differences in depression scores at weeks 3 and 9 of the study between the two groups. Similarly, anxiety levels differed significantly between the two groups at week 9 of the study (P = 0.013). Thus, it was established that relaxation techniques reduced anxiety and depression scores, as well as edema volume in lymphedema patients [277].

Comment 2: at the initial stage, the severity of psycho-emotional disorders requires psychotherapeutic intervention using individual counseling and cognitive behavioral therapy to desensitize psychological trauma [278, 279, 280, 281].

4.3 Balneotherapy, hydrotherapy, and aquatherapy in patients with limb lymphedema.

A published systematic review of RCTs on the effectiveness of physical exercises in water in patients with primary or secondary upper or lower extremity lymphedema analyzed the results of 88 included English-language RCTs (from 2000 to 2021), of which 8 RCTs were selected.

It was shown that the range of shoulder flexion, external rotation, and abduction improves following a water exercise protocol. Some data also demonstrated that the strength of edematous limbs improves after treatment. Moreover, water exercises appeared to improve pain perception and quality of life in patients with upper or lower extremity lymphedema. Conversely, quality of life in control groups tended to worsen over time [282]. Numerous studies indicate various mechanisms of the positive effects of balneo-hydrotherapy in the complex treatment of lymphedema [283–289].

• Balneotherapy and hydrotherapy are recommended as adjunctive treatments for lymphedema during the maintenance phase of treatment [282–289].

Level of Evidence (LE) 3, Grade of Recommendation (GR) B

Comments: skin lesions or skin diseases are a contraindication to hydrotherapy in a public pool. Therefore, balneotherapy, hydrotherapy, and aquatherapy are used in comprehensive rehabilitation programs and when planning sanatorium-resort treatment, taking into account patient preferences and the absence of contraindications, as well as a treatment method in the maintenance phase of complex therapy [282, 285].

5. Prevention and Dispensary Observation

LE 4 GSR C

Comment: lymphedema is a chronic disease requiring lifelong palliative treatment. During the inpatient stage of lymphedema treatment within the complex lymphatic therapy (CLT) program [37, 144], patient education on basic self-management methods of lymphedema is provided. During the prophylactic stage, the patient performs self-management to prevent edema progression. As an active lymphatic drainage intervention, patients perform self-lymphatic drainage massage [7]. There are various special programs for self-management and prevention of lymphedema in breast cancer patients (SMLEP and SMLP) [291–292]. Given the similar pathogenesis of lymphedema regardless of the etiology, these programs can be applied to any category of lymphedema patients. Whenever possible, it is advisable to provide the patient with an educational booklet containing information about the disease, an exercise program, and a self-monitoring diary. The disease information section should preferably cover the following topics:

− symptoms and signs of lymphedema;

− risk factors for the development and progression of lymphedema;

− assessment of lymphedema severity;

− prevention of infectious complications;

− skin care;

− protection against injuries;

− weight control;

− physical exercises.

6. Organization of Medical Care

The organization of medical care for the adult population in the profile of "surgery" is regulated by the current Order of the Ministry of Health of the Russian Federation (dated November 15, 2012, No. 922n), and the organization of medical care for patients with cardiovascular diseases (dated November 15, 2012, No. 918n), and is provided in accordance with the established procedure. Medical care for individuals with limb lymphedema or its complications, as well as in suspected cases of these conditions, can be provided as primary health care, emergency (including specialized emergency) medical care, and specialized (including high-tech) medical care. Medical care can be provided on an outpatient basis (i.e., in settings that do not require round-the-clock medical observation and treatment); inpatient basis (if there are indications for round-the-clock medical observation and treatment); or in a day hospital setting (providing medical observation and treatment during the daytime without requiring round-the-clock medical observation and treatment).

For most patients with an established diagnosis of limb lymphedema, outpatient treatment is possible. The decision on the need for hospitalization should be made by the attending physician individually, based on the stage of lymphedema, the patient's ability to receive treatment on an outpatient basis or in a day hospital, the severity of lymphedema complications, comorbid conditions, and the availability of surgical treatments.

7. Additional Information

7.1 Differential diagnosis of lymphedema and edema of other origins

The goal of differential diagnosis is to rule out phlebohypertension of various etiologies.

Upper extremity edema.

For the differential diagnosis of upper extremity edema (rather than hypertrophy), it is sufficient to exclude venous thrombosis and involvement of major vessels in the cicatricial process [69].

Unilateral lower extremity edema.

Unilateral lower extremity edema in an adult primarily requires the exclusion of acute occlusive venous thrombosis as a condition requiring immediate therapeutic management. Other causes of generalized unilateral lower extremity edema include:

- Post-thrombotic syndrome;

- Chronic non-thrombotic proximal venous outflow obstruction (May-Thurner syndrome);

- Ruptured Baker's cyst;

- Tear of the medial head of the gastrocnemius muscle.

Bilateral lower extremity edema.

The most common causes of bilateral lower extremity edema [69,120-122]:

- Heart failure;

- Chronic venous insufficiency (CVI);

- Renal or hepatic failure;

- Hypoproteinemia;

- Hypothyroidism;

- Nephrotic syndrome;

- Idiopathic cyclic edema;

- Drug-induced edema;

- Physical inactivity, prolonged immobilization, paralysis (including cerebral palsy), paresis;

- Obesity.

Idiopathic cyclic edema. Moderate bilateral lower extremity edema may be caused by idiopathic cyclic edema syndrome associated with the menstrual cycle [123]. This syndrome manifests as edema not only of the lower extremities, but also of the face and upper extremities. Idiopathic cyclic edema is accompanied by temporary weight gain due to pathological fluid retention. Notably, idiopathic cyclic edema can accompany lymphedema. In a study by Pereira de Godoy et al., this syndrome was identified in 9% of women with stage 2 lower extremity lymphedema [124]. It is possible that the condition known as "premenstrual syndrome," which includes potential edema of the extremities, face, and various body areas, and cyclic idiopathic edema belong to the same pathological cyclic condition. In a study by Tacani P. et al., edema of the extremities, face, or trunk occurred in 65% of women diagnosed with "premenstrual syndrome" [122]. For differential diagnosis, such patients require a careful medical history, observation, frequent weight monitoring during the diagnostic period to record rapid fluctuations due to fluid retention variations, and additional diagnostic methods. Diagnosis and management are carried out by an obstetrician-gynecologist or general practitioner (family physician), while the lymphedema specialist's task is to suspect this syndrome and confirm or exclude the presence of lymphedema.

Drug-induced peripheral edema. Drug-induced peripheral edema is poorly understood, frequently underestimated, and misdiagnosed [125]. The most commonly used drugs whose side effect is peripheral edema include calcium channel blockers, particularly nifedipine** [126]. The onset of edema can be triggered by non-steroidal anti-inflammatory and antirheumatic drugs and non-selective endothelin receptor antagonists (antihypertensive agents for the treatment of pulmonary arterial hypertension) [127,128]. It should be noted that in cases of adverse drug reactions, there is a fairly clear causal relationship.

Lymphedema and syndromes accompanied by limb hypertrophy.

Some syndromes are characterized by limb volume discrepancy, which may be due to soft tissue hypertrophy (e.g., Klippel-Trenaunay syndrome) or disproportionate growth of a body part (e.g., Proteus syndrome), including idiopathic hemihypertrophy and partial gigantism [129]. In most cases, such syndromes present with other clinical manifestations (specifically, vascular or pigmented birthmarks or enlargement not only of the subcutaneous adipose tissue, but of all limb tissues, including bone) that allow for a correct assessment of the etiology of the limb alterations.

Lymphedema and myxedema.

Myxedema (a complication and extreme form of hypothyroidism) manifests as edema due to fluid retention resulting from soft tissue infiltration (primarily the skin) by glycosaminoglycans. This results in the formation of non-pitting edema. Bilateral involvement is characteristic, with edema affecting the lower extremities, face, and upper extremities. Concomitant endocrine ophthalmopathy is present in 13% of patients. In typical cases of pretibial myxedema, purple, yellow, and brown skin lesions appear on both shins.

The key differences from lymphedema are the simultaneous edema of the lower and upper extremities and face, and the development of the characteristic skin pigmentation of the shins seen in myxedema.

Lipedema.

Lipedema is an adipose tissue disorder characterized by abnormal deposition of subcutaneous fat, manifesting as edema and enlargement of the lower extremities. Inheritance via an X-linked dominant or autosomal dominant pattern with sex limitation is possible [130].

Lipedema is an underdiagnosed condition and is frequently misdiagnosed as lymphedema. The treatment for these two conditions differs. Awareness of the manifestations of lipedema enables physicians to properly diagnose and treat these patients [131].

The diagnosis of lipedema is frequently missed due to clinicians' unfamiliarity with this condition. Physicians must be aware of this disease to be able to provide the correct approach. Advanced cases of lipedema have led to venous disease (venolipedema), lymphatic impairment (lympholipedema), and subsequently ulceration and recurrent infection.

In lipedema, there is increased capillary permeability due to microangiopathy and a diminished venoarterial reflex [132,133]. The venoarterial reflex protects the capillary bed from localized elevated hydrostatic pressure through arteriolar constriction [134]. Fluid extravasation can be exacerbated when this reflex is impaired.

Tissue edema may initially be compensated by enhanced lymphatic drainage [135,136,137]. As the disease progresses, the amount of fluid produced exceeds the transport capacity of the lymphatic system, and the pressure exerted by the adipose tissue itself causes obstruction of lymphatic vessels and secondary lymphedema with reduced lymphatic flow, as observed in lower extremity lymphoscintigraphy [138,139,140,141]. Stasis of protein extravasation causes initial inflammation followed by fibrosis, leading to pathological changes in lymphatic capillaries typical of lipedema (Appendix A 3.1. Differential diagnosis of lymphedema, lipedema, and obesity) [142].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Apkhanova T.V., Candidate of Medical Sciences, Member of the National Association of Experts in Sanatorium-Resort Treatment, Member of the Russian Society of Cardiology (RSC), Member of the American Vein and Lymphatic Society (AVLS), Member of the European Society of Cardiology (ESC);

2. Baytinger V.F., Doctor of Medical Sciences, Professor, Member of the Association of Lymphologists of Russia (ALR), Member of the Russian Society of Plastic, Reconstructive and Aesthetic Surgeons, Member of the Russian Society for Surgery of the Hand, Member of the German Society of Plastic and Reconstructive Surgery (Deutsche Gesellschaft fuer Plastische und Wiederherstellungschirurgie);

3. Belyanina E.O., Member of the Association of Phlebologists of Russia (APR);

4. Bukina O.V., Candidate of Medical Sciences, Member of the Association of Phlebologists of Russia (APR);

5. Demekhova M.Yu., Member of the Association of Phlebologists of Russia (APR), Association of Lymphologists of Russia (ALR), International Lipoedema Association;

6. Dzhabaeva M.S., Member of the Association of Cardiovascular Surgeons of Russia (ACVS);

7. Zolotukhin I.A., Dr. of Sci. (Med.), Professor, Professor of the RAS, Executive Secretary of the Association of Phlebologists of Russia (APR);

8. Ilyukhin E.A., Cand. of Sci. (Med.), Vice-President of the Association of Phlebologists of Russia (APR), member of the Russian Society of Surgeons (RSS);

9. Kalinin R.E., Dr. of Sci. (Med.), Professor, member of the Executive Council of the Association of Phlebologists of Russia (APR), member of the Russian Society of Surgeons (RSS), member of the Board of the Russian Society of Angiologists and Vascular Surgeons (RSAVS), member of the Association of Cardiovascular Surgeons of Russia (ACSR), member of European Society for Vascular Surgery (ESVS);

10. Katorkin S.E., Doctor of Medical Sciences, Associate Professor, Member of the Association of Phlebologists of Russia (APR), Member of the Russian Society of Surgeons (RSS), Member of the Association of Coloproctologists of Russia (ACR);

11. Konchugova T.V., Doctor of Medical Sciences, Professor, Member of the National Association of Experts in Sanatorium-Resort Treatment;

12. Kulchitskaya D.B., Doctor of Medical Sciences, Professor, Member of the National Association of Experts in Sanatorium-Resort Treatment;

13. Kurochkina O.S., Candidate of Medical Sciences, Member of the Association of Lymphologists of Russia (ALR), Member of the Russian Society of Plastic, Reconstructive and Aesthetic Surgeons, Member of the Russian Society for Surgery of the Hand;

14. Kushnarchuk M.Yu., Member of the Association of Phlebologists of Russia (APR);

15. Letyagin A.Yu., Doctor of Medical Sciences, Professor, Member of the Association of Radiologists, Radiotherapists, Ultrasound Diagnostics Physicians and Endovascular Diagnostics and Treatment Physicians of the Siberian Federal District, Member of the Scientific Medical Society of Anatomists, Histologists and Embryologists of Russia;

16. Makarov I.G., Executive Director of the Association of Lymphologists of Russia (ALR), Member of the International Society of Lymphology (ISL) and European Society of Lymphology (ESL);

17. Makarova N.V., Member of the Association of Lymphologists of Russia (ALR);

18. Malinin A.A., Doctor of Medical Sciences, Member of the Association of Cardiovascular Surgeons of Russia (ACVS);

19. Melnikov M.A., Candidate of Medical Sciences, Associate Professor, Member of the Association of Phlebologists of Russia (APR), Russian Society of Surgeons (RSS);

20. Myshentsev P.N., Candidate of Medical Sciences, Associate Professor, Member of the Association of Phlebologists of Russia (APR), Russian Society of Surgeons (RSS);

21. Nimaev V.V., Doctor of Medical Sciences, Member of the Association of Lymphologists of Russia (ALR);

22. Pryadko S.I., Candidate of Medical Sciences, Member of the Association of Phlebologists of Russia (APR), Member of the Association of Cardiovascular Surgeons of Russia (ACVS);

23. Sapelkin S.V., Doctor of Medical Sciences, Professor, Member of the Association of Phlebologists of Russia (APR), Russian Society of Angiologists and Vascular Surgeons, European Society of Angiology, American Venous Forum (AVF);

24. Svetlikov A.V., Doctor of Medical Sciences, Associate Professor, Member of the Russian Society of Angiologists and Vascular Surgeons, European Society for Vascular Surgery (ESVS);

25. Silchuk E.S., Candidate of Medical Sciences, Member of the Association of Lymphologists of Russia (ALR);

26. Sinitsyn A.A., Member of the Association of Phlebologists of Russia (APR);

27. Stoyko Yu.M., Doctor of Medical Sciences, Professor, Honorary President of the Association of Phlebologists of Russia (APR), Member of the Russian Society of Surgeons (RSS), Russian Society of Angiologists and Vascular Surgeons;

28. Suchkov I.A., Doctor of Medical Sciences, Professor, President of the Association of Phlebologists of Russia (APR), Member of the Russian Society of Surgeons (RSS), Russian Society of Angiologists and Vascular Surgeons, Member of the Association of Cardiovascular Surgeons of Russia (ACVS), European Society for Vascular Surgery (ESVS);

29. Urtaev B.M., Doctor of Medical Sciences, Professor, President of the Association of Lymphologists of Russia (ALR);

30. Feyskhanov A.K., Candidate of Medical Sciences, Member of the Association of Lymphologists of Russia (ALR);

31. Filina Yu.V., Candidate of Biological Sciences;

32. Fionik O.V., Doctor of Medical Sciences, Associate Professor, Member of the Association of Lymphologists of Russia (ALR), Russian Society of Angiologists and Vascular Surgeons;

33. Chernyago T.Yu., Candidate of Medical Sciences, Member of the Association of Phlebologists of Russia (APR);

34. Shevela A.I., Dr. of Sci. (Med.), Professor, Member of the Association of Phlebologists of Russia (APR), Russian Society of Surgeons (RSS), Russian Society of Endoscopic Surgeons (RSES);

35. Yarovenko G.V., Doctor of Medical Sciences, Associate Professor, Member of the Association of Phlebologists of Russia (APR).

All members of the Working Group confirmed the absence of financial support or other conflicts of interest in the preparation of these guidelines.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

- Cardiovascular surgeon;

- Endovascular diagnostics and treatment physician;

- Surgeon;

- Ultrasound diagnostics physician;

- General practitioner / internist;

- Cardiologist;

- Exercise therapy physician;

- Medical rehabilitation physician;

- Physical and rehabilitation medicine physician;

- Exercise therapy physician;

- Physiotherapist;

- Trauma and orthopedic surgeon;

- Oncologist;

- Medical students, residents, postgraduate students.

The recommendations are based on a cumulative analysis of evidence presented in global literature and obtained through the clinical application of modern principles and methods for the diagnosis and treatment of limb lymphedema. The main provisions of the recommendations are ranked in accordance with Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, "On Approval of the Procedure and Timelines for the Development of Clinical Practice Guidelines, Their Revision, Standard Form of Clinical Practice Guidelines, and Requirements for Their Structure, Composition, and Scientific Validity of Information Included in Clinical Practice Guidelines." The recommendations were prepared in accordance with the Methodological Recommendations for Assessing the Scientific Validity of Information Included in Clinical Practice Guidelines by the Center for Expertise and Quality Control of Medical Care of the Ministry of Health of the Russian Federation, 2019.

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing levels of evidence (LE) for methods of prevention, treatment, and medical rehabilitation, including those based on the use of natural therapeutic factors (preventive, therapeutic, rehabilitative interventions)

Table 3. Scale for assessing grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Appendix A3.1. Differential diagnosis of lymphedema, lipedema, and obesity

The table was compiled using materials from the Best Practice Guidelines: The Management of Lipoedema [72]

Appendix A3.2. Main components of the multi-layer compression bandage (MCB) [66]

Appendix A3.3. Daily skin care protocol for a lymphedematous limb

The daily skin care protocol is based on the All-Ireland Lymphoedema Guidelines 2022, which incorporate materials from 2 systematic literature reviews and additions from Hobday A [60,186,197,198].

Appendix A3.4. Exercise therapy (Physical Therapy) guidelines for patients undergoing surgery in the lymphatic pathway area of the limb

Exercise therapy guidelines for patients who have undergone surgery in the lymphatic pathway area of the limb, based on an umbrella systematic review by Wang L. et al., 2023 [294].

1RM* - one-repetition maximum: the maximum weight of a sports implement (or weight on exercise equipment) that a subject can lift in a single repetition through a full range of motion for a given exercise in one set. 1RM is used as the upper limit to determine the required load when performing exercises (as a percentage of 1RM).

Appendix A3.5. Types of dressings for ulcer treatment in patients with limb lymphedema

Types of dressings for ulcer treatment in patients with limb lymphedema (based on the section on the treatment of venous trophic ulcers in the Russian Ministry of Health guidelines "Varicose Veins of the Lower Extremities", ID:680_2) [208,295].

Appendix A3.6. Liposuction: features of preparation, performance, and postoperative management.

Features of preoperative preparation, liposuction performance, and postoperative management of a patient with limb lymphedema [61,233,241,242,296].

Preoperative preparation for liposuction. To minimize potential postoperative complications and achieve the maximum effect, liposuction should be performed only after maximum reduction or complete elimination of limb edema using complete decongestive therapy (CDT). The preoperative course of CDT should preferably be carried out no later than 6 months before surgery. Upon completion of the preoperative course of CDT, the patient is required to wear compression knitwear to maintain the achieved result. Measurements for custom flat-knit compression garments based on the healthy limb's measurements must be taken well in advance of the surgery. The first set must be sterilized on the eve of the surgery. If pitting edema is detected in the operated limb before the intervention, CDT is repeated to maximally reduce or completely eliminate the edema.

Technical features of liposuction:

- It is preferable to use power-assisted liposuction, as the density of subcutaneous adipose tissue is increased;

- Prior to surgery, the first set of custom flat-knit garments tailored to the measurements of the healthy limb must already be ready and sterilized;

- On the operating table, limb elevation and short-term application of a rubber bandage are performed to maximally exsanguinate the limb;

- A cuff is applied to the proximal part of the limb and inflated with air to a pressure level that will obstruct blood flow;

- Liposuction is performed on the distal parts of the limb, followed by the proximal parts;

- After performing liposuction on the distal part of the limb (forearm, lower leg), compression knitwear is donned up to this level;

- The pressure cuff is removed; liposuction is performed using the tumescent technique with the administration of saline and adrenaline;

- During the surgery, to achieve maximum limb symmetry and ensure the effectiveness of compression knitwear, limb volumes are assessed and compared, and the volume of removed tissues is estimated;

- After liposuction is completed, compression knitwear is donned on the proximal parts of the limb.

Postoperative patient management. Compression knitwear is donned on the operated limb directly on the operating table after the completion of each stage of liposuction. It is most effective to use custom-made flat-knit compression garments; this type of compression immediately after surgery helps reduce the risk of hematomas and, due to low resting pressure, reduces the risks of trophic complications. If the use of compression knitwear is impossible immediately after surgery, it is permissible to use compression bandages for several days, followed by a transition to flat-knit garments. Knitwear/bandages must cover all areas of the limb, including the toes. For the upper limb, it is recommended to use a combination of a flat-knit sleeve and glove (for the first 24 hours after surgery, this may be a fingerless glove) with a pressure of 20-30 mmHg; for the lower limb, a single-leg pantyhose + thigh-high stocking + foot glove (it is advisable to use the glove starting from the 2nd day after surgery) made of flat-knit fabric with a pressure of 20-45 mmHg. The knitwear must be ordered in two sets and changed every 2 days for the first 1-2 weeks, and then daily. During the daytime, the compression knitwear on the lower limb is worn in two layers (stocking over pantyhose), and at night the top layer is removed. During the first year, replacing the knitwear with necessary measurement adjustments is required at 3, 6, 9, and 12 months. If stabilization of results is achieved after the 6th month, the replacement at the 9th month is omitted, and it is done only at the 12th month. Thereafter, the replacement of the knitwear (2 sets) is carried out every 6 months. Wearing regimen: 24/7 for the first year; after 12 months, under the supervision of a physician and a measurement diary, some patients may wear compression knitwear only during the daytime. Circular-knit compression garments do not maintain liposuction results. Performing liposuction without correct compression therapy subsequently will not only lead to a lack of the desired efficacy but also significantly increase the risk of complications (hematomas, extensive seromas, infection).

Appendix A3.7. Reconstructive surgery: features of preparation and postoperative management.

Features of preoperative preparation and postoperative management of patients undergoing reconstructive surgery on the lymphatic system [297,298–303].

Preoperative preparation for reconstructive surgery. To minimize potential postoperative complications and achieve maximum effect, reconstructive surgeries should be performed only after maximum reduction or complete elimination of limb edema using complex decongestive therapy (CDT). The preoperative CDT course should preferably be carried out no later than 6 months before surgery. Upon completion of the preoperative course of complex therapy, it is mandatory for the patient to wear compression garments that maintain the achieved result. Measurements for custom flat-knit compression garments must be taken well in advance. Before surgery, it is necessary to ensure that the garments are made correctly, perform their functions, and do not cause complications or fluid shift, as an improper gradient and ineffectiveness of the garments in the postoperative period can significantly reduce the effectiveness of the surgical intervention.

Postoperative patient management. In the early postoperative period, either limb elevation (bed rest + passive movements) or compression bandaging with short-stretch bandages is recommended for the first 2–7 days, followed by a transition to flat-knit compression garments. Some surgeons recommend limb elevation for up to 5 days, as this is the time required for the completion of reparative processes in the intima of the anastomosed vessels, during which hydrostatic pressure in them—which increases when the limb is lowered—should not be elevated. Other specialists recommend immediate compression on the operating table with short-stretch bandages to reduce ultrafiltration and lymphatic load, ensure the competence of the valve apparatus, and accelerate lymph flow by maintaining a constricted state of the lymphatic vessels. The efficacy and safety of immediate compression therapy have been demonstrated in a number of studies, including those by T. Yamamoto and A. Nistor. In his postoperative protocol, A. Nistor recommends applying bandages on the operating table with a change after 18 hours, followed by round-the-clock wear with changes once a day for the first 7 days.

After surgery, it is recommended to continue supportive compression therapy using compression garments, preferably flat-knit, for at least 6 months postoperatively (for the first 3 months, round-the-clock wear of compression garments is advisable, transitioning to daytime wear for the subsequent 3 months). After the first 6 months, the number of hours wearing compression garments can be reduced under measurement control, provided there is no recurrence of edema. The regimen and duration of compression use are determined by the physician monitoring and treating the patient after surgery. In the absence of lymphedema manifestations after surgery, prophylactic use of compression garments during physical exertion and flights is advisable.

For 4 weeks after surgery, the use of active conservative treatment methods (manual lymphatic drainage, pneumatic compression therapy, etc.) on the operated limb is discouraged.

Appendix A3.8. Nomenclature of medical services

Nomenclature of medical services. Approved by the Order of the Ministry of Health and Social Development of the Russian Federation dated October 13, 2017, No. 804n. In effect since January 1, 2018; as amended by Orders of the Russian Ministry of Health dated April 16, 2019, No. 217n; March 5, 2020, No. 148n; September 24, 2020, No. 1010n; (including amendments dated October 26, 2022); current edition for 2025.

A-Medical services representing specific types of medical interventions aimed at the prevention, diagnosis, and treatment of diseases, medical rehabilitation, and having independent completed significance

Appendix B. Physician Action Algorithms

Algorithm for the management of a patient with limb lymphedema or at risk of its development (based on the International Consensus Document "Lymphoedema Framework. Best Practice for the Management of Lymphoedema. International Consensus") [66]

Appendix C. Patient Information

Lymph. This is a clear fluid containing primarily protein and leukocytes (white blood cells that fight infection). Lymphatic vessels drain lymphatic fluid from the body's tissues and organs. The fluid is filtered through lymph nodes and ultimately enters the bloodstream.

Lymphedema. This is swelling caused by the accumulation of fluid, connective tissue, and fat, which most commonly occurs in the arms, legs, or other parts of the body as a result of impaired transport function of the lymphatic system.

The body has a network of vessels called the lymphatic system. Lymph nodes are part of this system. The lymphatic system is similar to the blood vessel system, but instead of blood, it carries lymph. Lymphedema occurs when lymph flow in the lymphatic system is disrupted.

Who develops lymphedema? The development of lymphedema can be caused by either congenital (primary lymphedema) or acquired (secondary lymphedema) impairments in lymph transport. The causes of the disease should be investigated together with a physician.

What are the symptoms of lymphedema? The most common are:

- limb swelling;

- sensation of tightness or heaviness in the affected limb;

- mobility issues in the affected limb.

In some cases, these symptoms develop before noticeable swelling appears. Consult a doctor as soon as possible if you experience any of these symptoms: early recognition and treatment of lymphedema can help prevent progression over time and reduce severity. Keep in mind that symptoms may develop very gradually.

How is lymphedema diagnosed? The diagnosis is made by a physician based on physical examination and medical history. An important part of the examination includes measuring the volume of the affected limb. A doctor or nurse measures the limb circumference at multiple points. The limbs should be monitored according to your doctor's instructions.

How is lymphedema treated? Treatment should be started as early as possible. Before starting lymphedema therapy, other causes of limb swelling, such as deep vein thrombosis or cancer recurrence (in secondary lymphedema), must be ruled out. There is no cure for lymphedema, but there are treatments that can help reduce swelling and improve quality of life. These methods work best when started at the earliest stage of the disease, so contact your doctor as soon as you notice any swelling. It is best to seek care at clinics with specialists experienced in treating lymphedema.

Treatment may include:

- Physical exercise. This can help prevent the progression of lymphedema. Individuals with lymphedema should always wear compression garments during physical activity.

- Compression bandaging. This is a specialized method of multilayer bandaging using various materials to apply gentle, constant pressure to the swollen area.

- Compression garments (sleeves or hosiery). Very similar to compression bandages, they apply gentle, constant pressure to the affected limb to reduce swelling.

- Manual lymphatic drainage. During this procedure, a specialist massages the limb in a specific manner to help clear accumulated fluid.

- Surgical intervention. In severe cases of lymphedema, a physician may recommend surgery. It is important to understand that surgery does not replace or eliminate compression therapy!

Several surgical procedures can help manage lymphedema in specific situations:

- Vascularized lymph node transfer (VLNT) is a procedure where healthy lymph nodes are harvested from one area of the body and transplanted into the lymphedematous limb. These lymph nodes can compensate for the limb's lymphatic circulation and improve its condition.

- Lymphovenous anastomosis (LVA) is a procedure in which lymphatic vessels are connected to adjacent small veins, bypassing the area where the lymphatic vessels were damaged.

These two types of procedures are most beneficial in the early stages of lymphedema and require consultation with a qualified and experienced lymphatic surgeon.

- Liposuction is a procedure in which excess adipose tissue is removed from the lymphedematous limb using a cannula (a thin tube). This procedure is most beneficial for patients with advanced disease who have significant accumulation of fibrotic tissue and excess fat in their limbs.

Your doctor can discuss potential treatment options with you based on your individual situation.

Prevention of complications if you have lymphedema. To avoid trauma and/or injury to the affected limb:

- Keep the skin clean. Perform daily hygiene routines using a mild soap.

- Be careful with your nails. Do not damage the skin around the nails and avoid cutting the cuticles.

- Use nourishing ointments to prevent skin from drying and cracking.

- Use an electric razor instead of a blade for shaving.

- Always wear sunscreen when going outside.

- If the arm is affected, wear gloves when gardening, cooking, or doing activities that could damage the skin.

- If the leg is affected, wear hard-soled shoes outdoors.

- If you have a small cut, scratch, or insect bite on your arm or leg, wash it thoroughly with soap and water. Then apply an antibiotic and antimicrobial cream used in dermatology (e.g., betamethasone/gentamicin). Contact your doctor if the wound does not heal quickly or if you notice signs of infection.

- When possible, avoid injections, blood draws, or IV catheter insertions in the lymphedematous limb. Avoid other skin-puncturing procedures (acupuncture, tattooing).

- Avoid saunas, steam rooms, and hot tubs.

Additional rules:

- Do not wear clothing that restricts lymph flow to and from the limb, and avoid activities that may impede lymphatic drainage (e.g., using a pelvic harness during rock climbing can hinder lymph drainage from the lower extremity).

- Wear compression garments (specialized sleeves or stockings) to reduce swelling. Custom-fitted medical compression knitwear is the most effective.

- Maintain a healthy weight. Excessive weight gain can worsen lymphedema and reduce the effectiveness of compression garments.

- Consult a lymphedema specialist. They are trained in specialized treatments that can help improve your condition.

- Try to perform aerobic exercises. These activities have been proven to reduce lymphedema severity, improve overall fitness, and help with weight control. Even light physical activity (such as walking) is beneficial for your health.

- Avoid blood pressure measurements on the affected arm. Blood pressure can be measured on the opposite arm or, if both arms are affected, on the leg.

You should additionally consult a doctor if:

- The swelling increases.

- Redness (red spots or streaks) appears.

- Blisters or a rash develop on the affected limb.

- The affected limb is painful or warm to the touch.

- Body temperature exceeds 38°C and is not related to a cold or other illness.

These symptoms may indicate a potential infection that can worsen the course of lymphedema.

Impact of lymphedema on daily life. Although lymphedema is usually not a life-threatening condition, it can severely impact quality of life. Alterations in limb appearance can be both distressing and painful.

- Lymphedema can slow tissue healing and sometimes causes chronic pain.

- Cellulite, a skin infection requiring antibiotic treatment (systemic antimicrobial agents) and potential hospitalization, can develop in the lymphedematous limb.

- Following breast cancer surgery, a swollen or deformed arm can cause anxiety and depression.

- If lymphedema impairs normal arm or leg function, it can reduce the patient's quality of life and mobility.

If you develop lymphedema or suspect you have it, consult a doctor immediately.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Russian title: Lymphedema Surgical Treatment Rating Scale

Original title: Grading Scale for the Surgical Treatment of Lymphedema

Source (official developer website, validated publication): [304]

Type (underline): rating scale

Purpose: limb measurements are taken at two or three sites of both the upper and lower extremity, respectively. On the upper extremity, circumference measurements are taken 10 cm above and below the elbow joint. On the lower extremity, they are taken on the thigh and upper calf 15 cm proximal and distal to the lower edge of the patella, and 10 cm proximal to the ankle.

Key (interpretation):

TABLE 1 Grading Scale for the Surgical Treatment of Lymphedema

Appendix G2. Russian title: Quality of life assessment in lymphedema (LYMQOL)

LYMQOL is a questionnaire used to evaluate the effectiveness of treatment plans related to lymphedema [305].

Original title: Lymphoedema Quality of Life Study (LYMQOL)

Source (official website of the developers, validation publication):

https://lymphoedemaeducation.com.au/wpcontent/uploads/2019/03/JoL_Quality_of_Life_Measures1.pdf.

Type (underline):

-rating scale

-index

-into the questionnaire

-other (specify)

Purpose: assessment of the quality of life in patients with limb lymphedema, both for the clinical evaluation of lymphedema and for assessing treatment outcomes. LYMQOL covers 4 domains: functional activity, appearance, symptoms and mood, and overall quality of life.

Each item is scored as: not at all = 1; a little = 2; a lot = 3; a great deal = 4.

Content (template):

Appendix Ia. Lymphoedema Quality of Life Study (LYMQOL) Upper Limb.

Key (interpretation): if an item is not scored or left blank, it is scored as 0.

Each domain is summed, and the total score is divided by the total number of answered questions (if more than 50% of the questions in a domain are unanswered, the domain cannot be scored and =0).

The 4 domains and their questions reflect:

- functional activity I(a-f)2,3;

- appearance 4,5,6,7,8;

-symptoms 9,10,11,12,13,14;

-mood 15,16,17,18,19,20.

Overall quality of life Q21 is assessed as the value indicated by the patient on a scale from 0 to 10.

Appendix Ib.Lower extremity.

Key (interpretation): if an item is not rated or left blank, it is scored as 0.

Each section is summed up, and the total score is divided by the total number of answered questions (if more than 50% of the questions in a section are unanswered, the section cannot be summed and = 0).

The 4 domains and their questions reflect:

- functional activity I(a-f)2,3;

- appearance 4,5,6,7,8,9,10;

- symptoms 11,12,13,14.15;

- mood 16,17,18,19,20,21.

Overall quality of life Q22 is assessed as the value indicated by the patient on a scale from 0 to 10.