Abeloff's Clinical Oncology, 4th Edition

Part II – Problems Common to Cancer and its Therapy

Section A – Symptom Management and Palliative Care

Chapter 42 – Lymphedema

Lance Wyatt,Julian Pribaz

SUMMARY OF KEY POINTS

Definition

  

   

Lymphedema is the accumulation of protein-rich interstitial fluid within the skin and subcutaneous tissue.

Etiology and Classification

  

   

Primary lymphedema is thought to be a genetically determined disease with expression at or shortly after birth (Milroy disease), puberty (lymphedema praecox), or after 35 years of age (lymphedema tarda).

  

   

Secondary lymphedema occurs as a result of a precipitating cause.

Incidence

  

   

The incidence of lymphedema is not known.

  

   

The most common cause of secondary lymphedema worldwide is lymphatic filariasis.

  

   

In Western countries the most common cause is damage to or removal of lymph nodes by surgery, radiotherapy, tumor invasion, or as the result of infection or inflammation.

Diagnosis

  

   

Diagnosis is made in the majority of cases by history and physical examination; lymphoscintigraphy, computed tomography and magnetic resonance imaging may be needed.

  

   

Soft, pitting edema generally begins distally and progresses proximally over months to years.

Goals of Treatment

  

   

There is no cure for lymphedema.

  

   

Goals of therapy are to (1) reduce fluid production and accumulation, (2) reduce associated complications, and (3) improve limb function and appearance.

Medical Treatment

  

   

Skin care, extremity elevation, compressive garments, pneumatic compression pumps, noninvasive complex lymphedema therapy, and treatment of infection are the mainstays of medical therapy.

Surgical Treatment

  

   

Surgery is a continuum of medical management and is performed for failure of medical management, gross extremity size and weight with impaired extremity function, severe skin changes, and/or recurrent lymphangitis (more than three episodes per year).

  

   

Physiologic procedures attempt to restore lymphatic drainage.

  

   

Excisional procedures remove lymph-producing as well as fibrosclerotic tissue and fat.

INTRODUCTION

Lymphedema is the accumulation of protein-rich interstitial fluid within the skin and subcutaneous tissue. Cases in which the etiology is unknown or that develop as a result of congenital lymphatic dysfunction are referred to as primary lymphedema. All forms of lymphedema that occur as a result of a precipitating cause are termed secondary lymphedema. No cure exists for lymphedema. The aims of therapy are to reduce fluid production and accumulation, to reduce associated complications, and to improve limb function and appearance.

ETIOLOGY AND CLASSIFICATION

The most commonly used classification categorizes the etiology of lymphedema as primary or secondary to some inciting event. Primary lymphedema, which is thought to be due to aplasia or hypoplasia of the lymphatics, has long been thought to be a genetically determined disease with expression at or shortly after birth (Milroy disease), puberty (lymphedema praecox), or after 35 years of age (lymphedema tarda). The time of onset may be related to the relative number of functioning lymphatics. It is generally thought that the fewer lymphatics the earlier the onset. The molecular basis for congenital primary lymphedema (Milroy disease) has been established as autosomal dominant with incomplete penetrance due to a mutation in the gene locus encoding VEGFR3. [1] [2] This condition may be diagnosed prenatally.[3]

Lymphedema praecox, the most common form of primary lymphedema, is responsible for as many as 94% of cases in large reported series. The uncertainties of this condition derive from its unusual, unexplained features: female predominance (ratio of females to males is estimated to be 10 : 1), development around the time of menarche, more common involvement of the left leg, and rare upper extremity involvement. Estrogenic hormones have been implicated.[4] The edema typically is limited to the foot and calf. Lymphedema tarda, which develops later in life, accounts for fewer than 10% of cases of primary lymphedema. The precipitating cause often follows minor trauma or an inflammatory process (e.g., cellulitis) that can damage and possibly obstruct an already reduced number of lymphatics, tipping the balance in favor of lymphedema.

The most common cause of secondary lymphedema worldwide is lymphatic filariasis. In its most obvious manifestations, lymphatic filariasis, also known as elephantiasis, causes edema of the entire arm or leg; the genital regions (vulva, scrotum, breasts) also may be involved. Lymphatic filariasis is a significant cause of poverty in more than 80 countries in which it is endemic, primarily in Asia, Africa, the Western Pacific, and the Americas. Approximately 90% of these infections are caused by Wuchereria bancrofti, with most of the remainder by Brugia malayi and B. timori. The major vectors for W. bancrofti are CulexAedes species, and Anopheles mosquitoes. The World Health Organization estimates that at least 120 million people are infected, with approximately 40 million disabled as a result of this condition.

In Western countries, damage or removal of lymph nodes by surgery, radiation therapy, tumor invasion, or as the result of infection or inflammation are the most common causes of secondary lymphedema. The onset of upper extremity edema following axillary lymph node dissection is probably the most common cause of lymphedema in the United States.[5] The incidence of lymphedema following breast cancer therapy ranges broadly depending on the definition of lymphedema, on type of therapy, and on time elapsed since therapy; however, an overall incidence rate of 25% has been reported. The incidence rate climbs to 38% among patients with axillary node dissection and radiation.[6] Changes in clinical practice, such as the use of sentinel lymph node biopsy rather than full axillary dissection in breast cancer treatment, may lead to a reduction of this rate. Studies have shown that, at least in the short term, the incidence of lymphedema is reduced in patients undergoing sentinel lymph node biopsy as compared with standard axillary dissection. [7] [8] In the ALMANAC trial,[8] self-assessment among 954 patients randomized to each of these treatment groups, the relative risk self-reported of moderate to severe lymphedema within 12 months of surgery in the sentinal node biopsy group was 0.37 in comparison to the axillary dissection group. Furthermore, objective measurements of arm circumference were shown to be greater in the axillary dissection group at all sampling time points. The difference was statistically significant at 1, 3, and 6 months, but failed to meet that threshold at the 12-month measurement. No long-term results have yet been reported on the effect of sentinal node biopsy on the incidence of lymphedema, but studies are under way. Lymphedema of the lower extremity may occur after inguinal and pelvic lymph node dissection or irradiation, with a published frequency of 1% to 47%. [9] [10]

Why do the vast majority of individuals not develop lymphedema after surgery, regional node dissection, malignancy, radiotherapy, trauma, inflammation, and infection? The capacity for compensation by collateral flow and regeneration of damaged lymphatics may explain whether lymphedema develops. Disrupted lymphatics are not reconnected during replantation or microsurgical free-tissue transfer. Temporary swelling of a re-implanted or transplanted part resolves without intervention. Radiocolloid lymphoscintigraphy with technetium-99m–antimony trisulfide colloid (Sb2S3) studies in individuals without lymphedema have demonstrated spontaneous regeneration or reconnection of lymphatics after free-tissue transfer.[11] These findings suggest that persons with lymphedema lack compensatory mechanisms necessary to prevent the development of lymphedema.

Lymphedema may be either genetic or syndromic. Turner's syndrome, Noonan's syndrome, and Hennekam syndrome are examples of syndromic lymphedema. Lymphedema-distichiasis syndrome, cholestasis-lymphedema syndrome, all forms of primary, and most forms of secondary lymphedema may be classified as genetic lymphedema. Individuals who manifest the disease at or shortly after birth may have a more severe form of lymphedema without sufficient compensatory mechanisms. The mildest forms of the condition may exist as a subclinical process, with expression only after an inciting event.

PATHOPHYSIOLOGY

Lymphedema is confined to the subcutaneous compartment; the deep muscle regions appear to be clinically uninvolved. Extravasation of protein-rich fluid occurs when lymphatic transport capacity is reduced because of reduced numbers of functioning lymphatics or increased lymphatic load. This high-protein edema causes a shift in Starling's equilibrium, resulting in the accumulation of more fluid. In time, low oxygen tension, decreased macrophage function, and the presence of increasing amounts of protein-rich fluid give rise to a chronic inflammatory state and gradual tissue fibrosis. In chronic lymphedema, a hypertrophy of adipose tissue also occurs, but the mechanism for this has not been elucidated. The high-protein edema serves as a medium for bacteria, and episodes of infection so characteristic of the condition lead to additional lymphatic sclerosis and further lymphatic transport dysfunction ( Table 42-1 ).


Table 42-1   -- Pathophysiology of Lymphedema

REDUCED NUMBER OF LYMPHATICS BELOW CRITICAL LEVEL

Congenital lymphedema

Surgical ablation

Scar, radiation, infection

INCREASED LYMPHATIC LOAD

High-protein edema

Increased osmotic pressure

Inflammation

Perilymphatic scarring

Increased fatty deposition

PROGRESSIVE DETERIORATION

Increased volume

Induration

Fibrosis

 

 

DIAGNOSIS

In the vast majority of patients, diagnosis can be made by history and physical examination. The National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE, version 3) outlines the diagnostic and staging criteria for lymphedema related to malignancy ( Table 42-2 ).[12] Edema generally begins distally and progresses proximally over months to years. Early in the course of lymphedema the accumulation of protein-rich interstitial fluid results in a soft, pitting edema. With time the chronic inflammatory state and accumulation of fat and gradual tissue fibrosis give rise to a nonpitting edema. Skin changes may occur, but ulceration is infrequent. Individuals with lymphedema may complain of fatigue or pressure in the extremity, but the complaint of pain should prompt the physician to search for an alternative cause. Lymphoscintigraphy with radiocolloids has been successful in delineating the anatomy of lymph vessels and in evaluating the dynamics of lymph flow. This technique has replaced lymphangiography, which may damage lymphatics and worsen lymphedema.[13] Lymphangiography is not recommended. Computed tomography and magnetic resonance imaging may be useful to rule out malignancy.


Table 42-2   -- National Cancer Institute's Common Terminology Criteria for Adverse Events Staging and Diagnosis for Lymphedema

 

GRADE

Adverse Event

1

2

3

4

5

Edema: head and neck

Localized to dependent areas, no disability or functional impairment

Localized facial or neck edema with functional impairment

Generalized facial or neck edema with functional impairment (e.g., difficulty in turning neck or opening mouth compared with baseline)

Severe with ulceration or cerebral edema; tracheotomy or feeding tube indicated

Death

Edema: limb

5% to 10% interlimb discrepancy in volume or circumference at point of greatest visible difference; swelling or obscuration of anatomic architecture on close inspection; pitting edema

>10% to 30% interlimb discrepancy in volume or circumference at point of greatest visible difference; readily apparent obscuration of anatomic architecture; obliteration of skin folds; readily apparent deviation from normal anatomic contour

>30% interlimb discrepancy in volume; lymphorrhea; gross deviation from normal anatomic contour; interfering with ADL

Progression to malignancy (i.e., lymphangiosarcoma); amputation indicated; disabling

Death

Edema: trunk/genital

Swelling or obscuration of anatomic architecture on close inspection; pitting edema

Readily apparent obscuration of anatomic architecture; obliteration of skin folds; readily apparent deviation from normal anatomic contour

Lymphorrhea; interfering with ADL; gross deviation from normal anatomic contour

Progression to malignancy (i.e., lymphangiosarcoma); disabling

Death

ADL, activities of daily living.

National Cancer Institute: NCI common terminology criteria for adverse events v3.0 (CTCAE). Available at: http://ctep.cancer.gov/forms/CTCAEv3.pdf. Accessed 8 December 2006.

 

 

 

Edema from cardiac, renal, or hepatic insufficiency is distinguished from lymphedema by history and examination. Chronic venous insufficiency and postphlebitic syndrome are associated with aching discomfort and chronic pruritus.[14] Physical examination reveals hemosiderin deposits in the skin, dusky discoloration and venous engorgement with dependence, varicosities, and ulceration in advanced cases.

Myxedema of thyroid disease may be confused with lymphedema and develops when abnormal mucinous substances accumulate in the skin. Individuals with myxedema develop roughening of the skin of the palms, soles, elbows, and knees. These individuals also may have diminished sweat production, yellow-orange discoloration of the skin, thinning hair, and uneven nails. The process may be localized to the pretibial region in thyrotoxicosis[15] but is more generalized in hypothyroidism.

Lipedema is caused by the abnormal accumulation of fatty substances in the subcutaneous regions, typically between the pelvis and the ankle. The feet are spared, and the swelling is symmetric, bilateral, and often painful. The condition affects women or men with a feminizing disorder and arises within 1 to 2 years after the onset of puberty. Patients often have a propensity to bruising, possibly as a result of increased fragility of capillaries within the adipose tissue. Skin changes characteristic of lymphedema are not present, and consistent fat pads anterior to the lateral malleoli are found in individuals with lipedema.[16]

In the United States a frequent cause of lymphedema of both the upper and lower extremities is neoplastic disease. Individuals previously treated for neoplastic disease who develop new or worsening lymphedema must be evaluated for the recurrence of cancer. Malignant lymphedema often develops rapidly and results in intrinsic or extrinsic obstruction of lymph flow. Pain, generally absent in lymphedema, may be present ( Fig. 42-1 ).[17]

 
 

Figure 42-1  A 59-year-old man with gross end-stage obstructive lymphedema after recurrent squamous cell cancer excision and irradiation. The limb was nonfunctional and was treated with amputation.

 

 

Lymphangiosarcoma is an extremely rare tumor that initially appears as multiple blue-red subcutaneous nodules. In the upper extremity, it most frequently occurs in cases of chronic lymphedema after mastectomy (described by Stewart and Treves in 1948 and known as Stewart-Treves syndrome[18]). Lymphangiosarcoma seldom occurs in the lower extremity but may develop in the presence of lymphatic filariasis. The usual interval between mastectomy and the appearance of lymphedema is approximately 1 year; lymphangiosarcoma develops approximately 5 to 9 years after mastectomy. The reported incidence varies from between 0.07% and 0.45%.[19] Immunologic and electron microscopic studies suggest that these tumors arise from vascular endotheliocytes, despite the clinical appearance of arising from lymphatic vessels.

Why lymphangiosarcoma has a predilection for lymphedematous tissue is unknown. It has been shown that these tumors grow more consistently in lymphedematous as opposed to non-lymph-rich tissue. Some have speculated that the presence of a local immune deficiency creates a climate for malignant degeneration. Lymphangiosarcomas develop multicentrically and spread rapidly. These are extremely aggressive, highly malignant tumors; limb-sparing procedures are not recommended. Amputation may be the only hope for survival. Prognosis for patients with lymphangiosarcoma is extremely poor, with 5-year survival reported in between 8.5% and 13.6% despite aggressive treatment.[19]

MEDICAL MANAGEMENT

The aim of all forms of management is to restore the balance between lymphatic load and transport capacity. No treatment option is completely and permanently curative. The patient must understand the chronicity of the condition as well as the patient's important role in controlling the edema and preventing complications.

Limb girth should be assessed at the initial visit and at regular intervals thereafter to provide an accurate determination of the effect of therapy. Various methods allow assessment of limb volume, and all are prone to error in reproducibility. Measuring tapes may be used, and circumferential measurements should be obtained from standard, regional landmarks (antecubital fossa, etc.; Table 42-3 ). The physician should recognize that measurements taken at various times of the day may yield different results; the girth of an extremity may increase throughout the day, because it is in a dependent position and subjected to the effects of gravity. Measurements of water volume displacement are more precise, but do not identify changes in a specific area of the limb ( Fig. 42-2 ). Another useful modality to measure is the degree of limb tissue turgor; the degree of hardness or softness can be measured by a specially designed tonometer ( Fig. 42-3 ).[20] Patients should be serially followed up by physical examination, with any combination of the following: circumferential measurements, volume displacement, tonometry, serial photography, lymphoscintigraphy, and patient survey.


Table 42-3   -- Measurement of Lymphedema

  

 

Linear: girth

  

 

Hand (foot)

  

 

Wrist (ankle)

  

 

15 cm below elbow (knee)

  

 

Elbow (knee)

  

 

15 cm above elbow (knee)

  

 

Volume

  

 

Water tank: volume displacement

  

 

Tonometry

 

 

 
 

Figure 42-2  Volume measurement of the upper limb.

 

 

 
 

Figure 42-3  Tonometry measurement of the upper limb.

 

 

Weight reduction and extremity elevation are important measures that decrease edema. The individual must elevate the affected extremity at night. A sling may be used for the upper extremity, and elevating the foot of the bed on 4- to 6-inch blocks is recommended for edema of the lower extremity.

Custom-fitted elastic compressive garments (sleeves or stockings) are often worn during the day to maintain limb volume. The length of the garment should match the extent of disease. A comfortable fit is essential to ensure compliance.

Intermittent pneumatic compression with multichamber pumps removes excess fluid from the involved limb and may be helpful if used early in the course of disease, before the development of fibrosclerotic tissue changes. These devices apply a sequential pattern of compression to the extremity, permitting a physiologic distal-to-proximal milking action of the lymphedematous limb.[21] Therapy is most effective if continued at regular intervals, and compressive garments should be worn between treatments. Cardiac failure, active infection, and deep venous thrombosis are contraindications to pump therapy.

Noninvasive complex lymphedema therapy, which consists of manual lymph drainage, compressive bandaging, and physical therapy exercises, may be used with promising results.[22] Complex lymphedema therapy facilitates lymph drainage by recruiting collateral vessels so that the lymphedematous area can be drained into normally functioning lymphatic systems. Recent series have demonstrated therapeutic responses in compliant patients. [23] [24]

Basic skin care is essential in the prevention of infection and may assist in preventing associated skin changes, including dermatitis, hyperkeratosis, warty verrucosis, as well as breakdown of the epidermis and leakage of lymph fluid (lymphorrhea). Meticulous foot care for individuals with lower extremity lymphedema with daily use of a low-pH, water-based lotion will help to prevent fungal infections of the web spaces. Topical antifungal therapy is recommended for localized fungal infections, but invasive infection may require systemic antifungal therapy.

Aggressive and prompt treatment of lymphangitis and cellulitis is recommended to prevent the development of sepsis. It is thought that each bout of sepsis causes further sclerosis of existing lymphatics. Systemic antibiotic therapy targeted toward staphylococcal and streptococcal species for 5 to 7 days, combined with bedrest and extremity elevation, is suggested. Approximately 15% to 25% of patients will have recurrent lymphangitis and cellulitis, and these individuals may require long-term prophylactic antibiotic therapy.

Benzopyrones have been advocated in the treatment of lymphedema.[25] Benzo-a-pyrone (coumarin) is thought to have a stimulatory effect on macrophages and other elements of the immune system, enhancing proteolysis in breaking down large complex tissue proteins into peptides, which can be absorbed by the venous system. Although coumarin is used in mild cases of lymphedema outside of North America, its hepatotoxicity and studies showing a lack of efficacy in lymphedema have led North American experts to conclude that the risk-to-benefit ratio does not justify its use.[26] Parasitic infections involving W. bancroftiB. malayi, and B. timori are initially treated with albendazole and ivermectin or albendazole with diethylcarbamazine. Antihistamine and/or anti-inflammatory agents are used to control the allergic reactions to the dying parasite.

Laser therapy,[27] hyperthermia,[28] and intra-arterial injection of lymphocytes[29] are investigational treatments purported to play a role in the management of lymphedema. Further evidence is needed to better clarify the role of these modalities in the management of lymphedema ( Box 42-1 ).

Box 42-1 

LYMPHEDEMA: MEDICAL THERAPY

  

 

Meticulous skin care

  

 

Weight reduction

  

 

Limb elevation

  

 

Exercise

  

 

Custom—fitted elastic compressive garments

  

 

Pneumatic compressive pump

  

 

Noninvasive complex lymphedema therapy

  

 

Treatment of infection

  

 

Diuretics (optional)

  

 

Heat (investigational)

  

 

Benzopyrones (investigational)

  

 

Dietary flavonoids (investigational)

  

 

Intra-arterial injection of lymphocytes (investigational)

SURGICAL MANAGEMENT

Numerous surgical procedures have been described for the treatment of lymphedema. None is curative, and quantitative, long-term data on outcome are sparse. Individuals must view surgery as a continuum of management; the physician must emphasize that surgery does not obviate the need for continued medical therapy.

It is estimated that approximately 10% of patients with lymphedema will need surgery.[30] Operative intervention has traditionally been recommended if medical therapy is ineffective in controlling lymphedema or preventing complications. Surgery also is recommended for impaired extremity function secondary to gross extremity size and weight, severe skin changes, and recurrent lymphangitis (more than three episodes per year; Box 42-2 ).

Box 42-2 

LYMPHEDEMA: SURGICAL INDICATIONS

  

 

Failure of medical management

  

 

Excessive extremity size and weight, with functional impairment

  

 

Severe skin changes

  

 

Recurrent infection (more than three episodes of cellulitis or lymphangitis per year)

All procedures aim to reduce lymph fluid accumulation, halt the progression of disease, improve limb function, reduce bulk, improve appearance, and facilitate conservative therapy. Physiologic procedures attempt to reestablish lymphatic drainage, whereas excisional procedures debulk the limb, removing both fibrosclerotic and normal, lymph-producing tissue and fat. This distinction is blurred, in that many physiologically designed operations have excisional components; moreover, excisional procedures have an apparent physiologic effect.[31] Combinations of excisional and physiologic procedures also are commonly used to maximize the improvement in lymphedema ( Box 42-3 ).

Box 42-3 

SURGICAL THERAPY

Physiologic

  

 

Lymphangioplasty

  

 

Omental transposition

  

 

Enteromesenteric bridge

  

 

Lymphaticovenous anastomoses

  

 

Lympholymphatic anastomoses

Excisional

  

 

Total skin and subcutaenous excision (“Charles procedure”)

  

 

Buried dermal flap (“Thompson procedure”)

  

 

Staged subcutaneous excision beneath flaps (“modified Homans’ procedure”)

  

 

Suction-assisted lipectomy

Physiologic Procedures

Physiologic procedures include lymphangioplasty, [30] [31] [32] [33] [34] [35] [36] [37] pedicle flap procedures (omental transposition, enteromesenteric bridge), [38] [39] [40] [41] and microsurgical anastomosis (lymph nodal-venous, lymphaticovenous, lympholymphatic shunts). [42] [43] [44] [45] [46] [47] [48] [49]

Lymphatic Bridging

One of the earliest procedures for lymphedema was the subcutaneous implantation of silk threads (lymphangioplasty) advocated by Handley in 1908.[32] Many materials (rubber,[33] polythene,[34]polyvinylchloride[35]) have subsequently been used in the attempt to create drainage channels. This technique was abandoned because of the consistently high incidence of infection and extrusion of material.

Pedicle flap procedures juxtapose lymphatic-rich flaps and lymphedematous tissue to induce lymphatic communication and provide drainage. Initially, tube pedicles with a random blood supply were fashioned in multiple stages by Gillies and Fraser[50] and Mowlem.[51] These resulted in considerable scarring and poor function. Clodius and colleagues[52] found that skin flaps with an axial blood supply also contained axial lymphatics and allowed spontaneous lymphatic connections. He reported using these flaps to improve brachial neuritis and upper extremity lymphedema simultaneously ( Fig. 42-4 ). Omentum and small bowel have also been used as pedicle flaps. These operations require celiotomy; hernia, adhesion formation, and bowel obstruction have been reported with these procedures (see Fig. 42-4 ).

 
 

Figure 42-4  Patient with lymphedema and brachial plexus neuropathy after right radical mastectomy and irradiation for breast cancer. She was treated with excision of dense axillary contracture, brachial plexus neurolysis, and latissimus dorsi myocutaneous flap to provide better coverage with well-vascularized tissue to the brachial plexus and also to help bridge obstructed upper limb lymphatics. Upper extremity volume decreased, and the arm felt subjectively softer and less heavy for this woman.

 

 

The omental transposition operation depends on lymphatic connections developing between the omentum and lymphadematous tissue ( Fig. 42-5 ). This was first used by Dick[53] in 1935 in two cases of scrotal lymphedema. The omentum is rich in lymphatics and can easily reach the chest and axilla, but when it has to be lengthened to reach farther into the upper or lower limb, many of the lymphatics may be divided. Goldsmith[39] reported long-term results but provided no objective data on the extent of extremity size reduction. The complication rate was high, and there was no clarification as to how many patients were followed up beyond 3 years (see Fig. 42-5 ).

 
 

Figure 42-5  A, A 79-year-old woman with radiation necrosis of the left chest wall and axilla after radical mastectomy and irradiation with upper limb lymphedema. B, Omental flap was raised and pedicled on right gastroepiploic vessels. The chest wall and axilla were debrided; the omentum was transferred to cover both the chest wall and axilla and to serve as a bridge for lymphatic drainage. C, Nine months after radical debridement, omental flap, and skin graft to chest wall and axilla, with some improvement in upper limb lymphedema.

 

 

Hurst and associates[41] followed up for 2.5 to 7 years eight patients who underwent the enteromesenteric bridge procedure. This operation, physically limited to individuals with proximal lymphatic obstruction at the level of the iliac or lower aortic nodes, also requires a celiotomy. Of patients in this series, 25% failed to improve and underwent a subsequent excisional procedure. Five patients were noted to improve clinically, but the authors provide no objective data.

Drainage into Deep Lymphatics

Thompson[54] proposed that a dermal wick of a lymphedematous tissue could be transposed deep to the muscle fascia, to allow bypass of lymph from superficial to deep lymphatics. The reported results may have been due to the excisional aspect of this procedure that accompanies the dermal wick. Sawhney[55] studied this procedure with radioactive serum albumin but was unable to demonstrate an increased uptake after dermal-wick procedures.

Microsurgical Procedures

Microsurgical procedures designed to reestablish lymphatic drainage to an affected extremity may be divided into three categories: (1) lymph nodal–venous shunts, (2) lymphaticovenous anastomoses (LVAs), and (3) lympholymphatic anastomoses.

Lymph Nodal–Venous Shunts

Lymph nodal–venous shunts involve anastomosis of a transected lymph node to a neighboring vein. This was first described by Neilubowicz and Olszewski.[56] These procedures have been used for lymphedema involving the male and female genitalia, and these authors have reported good results in 50% of the patients. However, Calnan and coworkers[57] found that these lymph node–venous anastomoses remained patent for only a limited time in individuals with lower extremity lymphedema, and by 3 months they were all obstructed. Unfortunately, obstructive lymphedema usually results after lymphadenectomy, and thus lymph nodes are typically not available for use in this type of anastomosis.

Lymphaticovenous Anastomoses

Because lymph eventually drains into the venous system via the thoracic duct, in cases in which obstruction to flow occurs, it makes intuitive sense that it should be possible to bypass a lymphatic obstruction by allowing the lymph to enter the venous system more peripherally. In obstructive lymphedema lymphatic pressure is higher than venous pressure,[58] which should theoretically keep the LVA patent.

One of the pioneers of microlymphatic research for treatment of obstructive lymphedema was O'Brien, working at St. Vincent's Hospital in Melbourne, with whom the senior author trained and subsequently worked. In the first results, reported in 1976, an 83% patency of LVA was achieved in nonlymphedematous dogs. Considerable work was involved in creating a canine chronic lymphedema model, and once this was achieved, extensive research in LVA, free microvascular nodal transfers, and free microvascular omental transfers followed. [59] [60] [61]

Concurrent with this basic research, clinical studies on individuals with obstructive lymphedema ensued. A 15-year study of 134 persons (116 females and 18 males) with established obstructive lymphedema from various causes and treated with LVA was reported in 1990.[45] Most patients (102) had lymphedema of the upper extremity, and 32, of the lower extremity. These individuals were all treated with LVA with or without additional reduction procedures. Of these patients, 90 were available for long-term follow-up (Tables 42-4 and 42-5 [4] [5]): 52 patients had LVA only (mean, five anastomoses), and 38 patients had LVA plus segmental reduction (mean, 4.1 anastomoses). The results were graded both subjectively (“limb smaller and softer,” “less weight,” “more comfortable,” “clothes fit better,” etc.) and objectively with linear, volume, and tonometry measurements (see Tables 42-4 and 42-5 [4] [5])


Table 42-4   -- St. Vincent's Lymphedema Experience[*]

  

 

LVA (134 patients)

  

 

116 females, 18 males

  

 

Average age 52 yr

  

 

102 upper limb, 32 lower limb

  

 

No suitable lymphatics (20 patients)

Adapted from O'Brien et al: Long term results after microlympyhaticovenous anastomoses for treatment of obstructive lymphedema. Plast Reconstr Surg 1990;85:562.

LVA, lymphaticovenous anastomosis.

 

*

Surgery for obstructive lymphedema in 154 patients (1974–1988)

 

 


Table 42-5   -- St. Vincent's Lymphedema Experience[*]

 

LVA Only

LVA and Reduction

Patients

52

38

No. of LVAs (mean)

5

4.1

Mean volume reduction (%)

44 (10–84)

44 (10–84)

Subjective improvement (%)

73

78

Objective improvement (%)

42

60

Objective no change (%)

12

16

Objective worse (%)

46

24

58% Reduction cellulitis upper limb

  

   

Better results than lower limb

  

   

Hand better than forearm

  

   

All patients who improved initially continued to do so

Adapted from O'Brien et al: Long term results after microlympyhaticovenous anastomoses for treatment of obstructive lymphedema. Plast Reconstr Surg 1990;85:562.

LVA, lymphaticovenous anastomosis.

 

*

Long-term follow-up in 90 of 134 patients (1974–1988).

 

 

Subjectively, 73% and 78% of these individuals reported improvement after LVA alone and LVA plus segmental reduction, respectively. Objectively, 42% had improvement after LVA alone, and 60% had improvement after LVA and reduction. Of the entire group, 58% reported fewer episodes of cellulitis. The results were generally better in the upper extremity compared with the lower extremity, a finding that other authors also reported.[49] Furthermore, of the persons who obtained postoperative improvement, none subsequently became worse. Of the remaining individuals whose condition did not improve, 12% reported no change in lymphedema, and in 46%, the lymphedema became gradually worse, as is the natural history of untreated lymphedema.[45]

The technique used in this series of patients involved perform-ing multiple LVAs at multiple levels (wrist, medial forearm [upper calf], medial arm [leg]). In individuals who would benefit from a segmental reduction, this was done laterally (upper lateral arm, lateral thigh). Patent blue dye was injected subdermally into the web spaces. A tourniquet was used, but the limb was not exsanguinated. With 4 × loupe magnification, the subcutaneous tissues were carefully dissected to isolate the lymphatics, which appeared as beaded, blue, thin, fragile vessels measuring 0.3 to 0.5 mm in diameter. Adjacent veins also were located or transposed from adjacent areas to lie near the dissected lymphatics. The lymphatics and veins were tagged with loose silk loops. The anastomosis of the lymphatic to the vein was performed in end-to-end fashion with the operating microscope and 11-0 nylon suture on a 75-mm needle. Approximately four to six sutures were used per anastomosis. As many anastomoses as possible were performed at multiple levels (Figs. 42-6 and 42-7 [6] [7]).

 
 

Figure 42-6  A, Patient with lymphedema of upper extremity affecting hand and forearm. B, Patent blue dye has been injected into web spaces and lymphatics, and veins dissected out at wrist, proximal forearm, and arm levels. C, Magnified view. Typical lymphaticovenous anastomoses completed. This patient had a total of six anastomoses at three levels. D, Three months after surgery, with complete resolution of the lymphedema; this woman was able to wear her rings.

 

 

 
 

Figure 42-7  A, Woman with lymphedema of right upper limb after mastectomy and irradiation. B, Six months after multiple-level lymphaticovenous anastomosis with smaller, softer limb.

 

 

This type of surgery is very demanding, but a significant number of patients obtain subjective improvement, and approximately half obtain measurable objective improvement. Critics of this type of surgery argue that no easy way exists of knowing how many LVAs stay patent in the long term. [47] [49]

Similar results have been reported by Huang and colleagues,[58] who reported excellent and good results in 79% of patients, most of whom had obstructive lymphedema of the lower limb resulting from filariasis.[58] Both Huang and O'Brien have found that the results are better when the duration of the edema is shorter, and Huang, but not O'Brien, found that the number of anastomoses performed was significant, whereas O'Brien's group did not find the same correlation.

Lymphaticolymphatic Anastomosis

Lymphaticolymphatic shunts bypass regional areas of lymphatic obstruction. Baumeister and associates[62] first reported this technique in 1981 and later reported his results in 55 patients in 1990. He believes that lymphaticolymphatic anastomoses are better than LVAs, because no increased back pressure is found, as can sometimes occur in higher venous pressure. He described the harvest of two to three lymphatic tracts from the anteromedial aspect of the thigh (adjacent to the saphenous vein).[62] In the lower extremity, these are pedicled from the normal limb to the lymphedematous limb, across the pubic area, and the lymphatics anastomosed to the dilated obstructed lymphatics on the involved side. For the upper extremity the lymphatic grafts are harvested and transferred as free grafts to bridge the obstruction across the axilla with the proximal anastomoses into a lymphatic trunk in the neck. In his series of patients Baumeister was able to show an 80% reduction in limb volume over a 3-year follow-up and also was able to demonstrate graft patency and improved transport index with lymphoscintigraphy. Better results were obtained in the upper limb ( Fig. 42-8 ).[63]

 
 

Figure 42-8  A, Male with obstructive lymphedema of left leg and increased venous pressures on manometry in saphenous vein. B, Dissection of right saphenous vein and surrounding lymphatics and pedicled across the pubic area to the left thigh (groin superior). C,Venous and lymphatic anastomoses performed. (groin superior). D, Two months after surgery: improvement in lymphedema in left leg.

 

 

Excisional Procedures

Excisional procedures include total skin and subcutaneous skin excision (erroneously referred to as the Charles procedure), [64] [65] [66] staged subcutaneous tissue excision (erroneously referred to as the Kondoleon operation), [67] [68] [69] [70] [71] [72] and suction-assisted lipoplasty. [73] [74] [75] The buried dermal flap described by Thompson is an excisional procedure proposed to have a physiologic component. [76] [77] [78] [79] Excisional procedures are suitable for both primary and secondary lymphedema.

Charles [64] [65] [66] described a surgical technique for the treatment of scrotal edema. The Charles procedure, however, has become an eponym for an operation in which the skin and subcutaneous compartment is completely excised and resurfaced with skin grafts. [64] [65] [66] Chronic ulceration, skin graft breakdown, and hypertrophic, unstable scarring have been consistently seen when split-thickness grafts are used.[65] Coverage with full-thickness grafts provides a more durable graft site, but graft breakdown and substantial scar formation also may occur.

Staged subcutaneous tissue excision was initially described by Sistrunk,[68] and modifications of the procedure have been reported by others, notably Homans. [69] [70] This excisional approach removes significant amounts of skin and subcutaneous tissue, recognizing that the pathology of lymphedema is essentially limited to the superficial tissue compartment. The operation reduces the amount of subcutaneous tissue that produces lymph, and excisions of redundant skin also result in circumferential compression, which probably works in concert with muscular activity to facilitate the subdermal lymph drainage preserved within the flap. A recent study demonstrated long-lasting results for improvement in lower extremity lymphedema, regardless of cause, in a majority of patients treated.[71] This procedure has not been as effective for upper extremity lymphedema (Figs. 42-9 and 42-10 [9] [10]). [64]

 
 

Figure 42-9  A, A 45-year-old patient with lymphedema tarda of left leg, with lymphedema worse laterally. B, At 17 months after first excision on lateral aspect of left leg before medical excision. C, Intraoperative view after medial wedge excisions. D, Four years after surgery with stable leg.

 

 

 
 

Figure 42-10  A, A 22-year-old man with gross primary lymphedema commencing in early puberty (lymphedema praecox). He was unable to wear normal clothes. B, Extended medial wedge excision of the thigh, knee, calf, and ankle. C, Intraoperative view of filled leg after excision of lymphedematous tissue. D, Immediate intraoperative result. E and F, Three months after second-stage lateral wedge excision: lateral (E) and anterior view (F). G, He was now able to wear normal clothes.

 

 

Although presented as a physiologically designed procedure, the buried dermal flap procedure described by Thompson[76] incorporates the excision of considerable amounts of tissue. In this procedure the subcutaneous compartment is buried in the deep subfascial area in an attempt to drain lymph. Radioactive iodinated human albumin clearance studies have been reported to support a physiologic improvement.[78] However, identical improvement in postoperative clearance was demonstrated in patients after skin and subcutaneous excision.[79] These findings could indicate that the reduction of the subcutaneous tissue improves overall function.

Suction-Assisted Lipectomy

Many authors have advocated the use of liposuction in both primary and secondary lymphedema to reduce the size of lymphatic extremities, as an alternative to segmental wedge excision, removing excess fluid and fat. [73] [74] [75] Most authors agree that individuals who will benefit most from this procedure are those who have lymphedema of short duration and have yet to develop the fibrosclerotic changes associated with long-standing disease. However, Brorson and colleagues [73] [80] [81] in Sweden have advocated a new concept in the management of upper extremity lymphedema in women after mastectomy. Brorson has made a distinction between the presence of edema fluid and the increased fatty deposition that is seen in individuals with chronic lymphedema. His hypothesis is that liposuction should address only the increased fatty deposit, and conservative methods should be used to treat the increased lymphatic fluid. He has rightly observed that individuals with chronic lymphedema have an increase in subcutaneous fatty deposition, a finding that has been greatly underappreciated by advocates of physiologic-type approaches to the management of lymphedema. Brorson's strategy has been to reduce the edema first, using compression therapy until all the pitting edema has subsided, and then proceed to extensive circumferential liposuction with a specially designed cannula. His experience thus far has been in lymphedematous upper extremities in women after mastectomy, and he has been able to achieve excellent long-term results with minimal complications. However, a mainstay of therapy after the surgery is ongoing controlled compression therapy, day and night, indefinitely. His studies have shown that the excess fat is permanently removed, and that there is no worsening of an already impaired lymph transport system. [73] [80] [81]

Heat Treatment

The Chinese have been able to demonstrate that the use of local limb hyperthermia also is a useful adjunct for the treatment of lymphedema. In 1984 Zhang[82] reported a regimen of heating the involved limb to 6°C to 7°C above normal for 1 hour per day for 20 days. He used three to four courses that were 7 to 10 days apart. Between treatments, bandaging was used to compress the limb. He reported a reduction in limb volume in two thirds of patients and a sixfold decrease in incidence of cellulitis.

The continuing debate on the most efficacious medical and surgical approach underscores the need for intensified research. Management of individuals with lymphedema suffers because of a lack of randomized, controlled prospective studies. Furthermore, no well-defined standards exist with respect to the definition of edema, documentation of results, and outcomes of therapy.

OUTCOMES

Little information exists on the economic outcome after surgery for lymphedema. This condition may manifest as recurrent infections, discomfort, functional impairment from increased extremity size and weight, musculoskeletal problems, psychosocial distress caused by cosmetic issues, and difficulty in carrying out activities of daily living.[83] However, patients should be informed that regional and Internet-based support groups exist, and individuals with lymphedema who are compliant with management regimens can decrease in-hospital stays; many will enjoy a normal or near-normal quality of life.

THE FUTURE

Those in whom lymphedema develops seem to be incapable of lymphatic generation or regeneration. Evidence suggests the presence of growth factors specific for the lymphatic system [84] [85] and a capacity for lymphatic regeneration in individuals who do not have lymphedema.[11] Do those in whom lymphedema develops after some inciting event lack the mechanisms needed for lymphatic vessel repair? Or is there a deficit in the response to a growth factor(s), or is there a lack of growth factor(s)? We submit that a genetic etiology explains why, in a fraction of individuals who undergo similar procedures, this condition develops.

SUMMARY

The large number of medical therapies and surgical procedures that have been described in the treatment of lymphedema emphasize the discouraging fact that this condition remains incurable by any means. The severity of symptoms may vary from mild extremity swelling to serious disabling or life-threatening complications such as recurrent infections and rarely, lymphangiosarcoma. Most patients are diagnosed by history and physical examination alone and may be managed conservatively. If this is unsuccessful, and the individual has primary lymphedema, then a reduction procedure is all that is available. Traditionally, this has involved staged resection of skin and subcutaneous tissue. However, liposuction is gaining popularity, especially in relatively early cases in which the quality of skin is good and little fibrosis is found. In individuals with secondary or obstructive lymphedema that is not well controlled with conservative management, a physiologic procedure, often using multiple modalities (e.g., pedicle flaps plus LVAs or LVAs with or without segmental reduction or liposuction) has been the authors’ preferred method of treatment ( Fig. 42-11 ). Regardless of treatment modality, patient cooperation is critical for successful outcome. Future efforts should focus on clarifying the genetic etiology of lymphedema, with hope that a better understanding of the basis of disease will lead to more effective treatment strategies.

 

 

Figure 42-11  A, A 74-year-old patient with chronic wound draining lymphatic fluid in right hip area, after radical excision of chondrosarcoma and irradiation. The right leg is lymphedematous. B, Design of contralateral vertical rectus abdominis musculocutaneous (VRAM) flap (based on superficial and deep inferior epigastric vascular pedicle). The lymphatic drainage into left groin is intact. Plan to dissect out multiple small venous channels at upper aspect of flap for lymphaticovenous anastomoses (LVAs). C, Methyl blue dye injected intradermally into web spaces for foot. D, Multiple dilated lymphatics dissected out in upper right thigh, marked with silk loops. E, The VRAM flap was transposed across the lower abdomen to the deficit in the right groin. Magnified view of two LVAs is shown. Four LVAs were performed from thigh lymphatics into small veins of distal (top) end of VRAM flap using 10-0 nylon suture. F, Immediate result after wound closure. G, Result at 11 months showing healed wound and reduced lymphedma.

 

 

REFERENCES

  1. Karkkainen MJ, Ferrell RE, Lawrence EC, et al: Missense mutations interfere with VEGFR-3 signalling in primary lymphedema.  Nat Genet2000; 25:153-159.
  2. Irrthum A, Karkkainen MJ, Devriendt K, et al: Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase.  Am J Hum Genet2000; 67:295-301.
  3. Makhoul IR, Sujov P, Ghanem N, Bronshtein M: Prenatal diagnosis of Milroy's primary congenital lymphedema.  Prenat Diagn2002; 22:823-826.
  4. Wolfe JHN, Kinmonth JB: The prognosis of primary lymphedema of the lower limbs.  Arch Surg1981; 116:1157-1160.
  5. Segerstrom K, Bjerle P, Graffman S, Nystrom A: Factors that influence the incidence of brachial oedema after treatment of breast cancer.  Scand J Plast Reconstr Surg Hand Surg1992; 26:223-227.
  6. Erickson VS, Pearson ML, Ganz PA, et al: Arm edema in breast cancer patients.  J Natl Cancer Inst2001; 93:96-111.
  7. Purushotham AD, Upponi S, Klevesath MB, et al: Morbidity after sentinel lymph node biopsy in primary breast cancer: results from a randomized controlled trial.  J Clin Oncol2005; 23:4312-4321.
  8. Mansel RE, Fallowfield L, Kissin M, et al: Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC trial.  J Natl Cancer Inst2006; 98:599-609.
  9. Fiorica JV, Roberts WS, Greenberg H, et al: Morbidity and survival patterns in patients after radical hysterectomy and postoperative adjuvant pelvic radiotherapy.  Gynecol Oncol1990; 36:343-347.
  10. Werngren-Elgstrom M, Lidman D: Lymphoedema of the lower extremities after surgery and radiotherapy for cancer of the cervix.  Scand J Plast Reconstr Surg Hand Surg1994; 28:289-293.
  11. Slavin SA, Upton J, Kaplan WD, Van den Abbeele AD: An investigation of lymphatic function following free-tissue transfer.  Plast Reconstr Surg1997; 99:730-741.
  12. National Cancer Institute : NCI common terminology criteria for adverse events v3.0 (CTCAE).  Accessed 8 December 2006 Available at: http://ctep.cancer.gov/forms/CTCAEv3.pdf
  13. O'Brien BM, Das SK, Franklin JD, Morrison WA: Effect of lymphangiography on lymphedema.  Plast Reconstr Surg1981; 68:922-926.
  14. Bergan J, Yao J, Flinn W, McCarthy W: Surgical treatment of venous obstruction and insufficiency.  J Vasc Surg1986; 3:174-181.
  15. Bull RH, Coburn PR, Mortimer PS: Pretibial myxoedema: a manifestation of lymphoedema?.  Lancet1993; 341:403-404.
  16. Rudkin GH, Miller TA: Lipedema: a clinical entity distinct from lymphedema.  Plast Reconstr Surg1994; 94:841-847.
  17. Scanlon E: James Ewing Lecture: the process of metastasis.  Cancer1985; 55:1163-1166.
  18. Stewart FW, Treves N: Lymphangiosarcoma in postmastectomy lymphedema.  Cancer1948; 1:64-81.
  19. Janse AJ, van Coevorden F, Peterse H, et al: Lymphedema-induced lymphangiosarcoma.  Eur J Surg Oncol1995; 21:155-158.
  20. Chen HC, O'Brien B, Pribaz JJ, Roberts AH: The use of tonometry in the assessment of lymphedema.  Br J Plast Surg1988; 41:399-402.
  21. Pappas CJ, O'Donnell Jr TF: Long-term results of compression treatment for lymphedema.  J Vasc Surg1992; 16:555-562.
  22. Boris M, Weindorf S, Lasinski B, Boris G: Lymphedema reduction by noninvasive complex lymphedema therapy.  Oncology1994; 8:95-106.
  23. Ko DS, Lerner R, Klose G, Cosimi AB: Effective treatment of lymphedema of the extremities.  Arch Surg1998; 133:452-458.
  24. Szuba A, Cooke JP, Yousuf S, Rockson SG: Decongestive lymphatic therapy for patients with cancer-related or primary lymphedema.  Am J Med2000; 109:296-300.
  25. Casley-Smith JR, Morgan RG, Piller NB: Treatment of lymphedema of the arms and legs with 5,6-benzo-a-pyrone.  N Engl J Med1993; 329:1158-1163.
  26. Loprinzi CL, Kugler JW, Sloan JA, et al: Lack of effect of coumarin in women with lymphedema after treatment for breast cancer.  N Engl J Med1999; 340:346-350.
  27. Piller NB, Thelander A: Treatment of chronic postmastectomy lymphedema with low level laser therapy: a 2.5-year follow-up.  Lymphology1998; 31:74-86.
  28. Casley-Smith J, Casley-Smith J: Other physical therapy for lymphedema: pumps, heating, etc.   In: Casley-Smith J, Casley-Smith J, ed. Lymphedema,  Adelaide: Lymphedema Association of Australia; 1991:155.
  29. Ogawa Y, Yoshizumi M, Kitagawa T, et al: Investigation of the mechanism of lymphocyte injection therapy in treatment of lymphedema with special emphasis on cell adhesion molecule (L-selectin).  Lymphology1999; 32:151-156.
  30. Hafez HM, Wolfe JHN: Basic data underlying clinical decision making: lymphedema.  Ann Vasc Surg1996; 10:88-95.
  31. Miller TA: Surgical management of lymphedema of the extremity.  Ann Plast Surg1978; 1:184-187.
  32. Handley WS: Lymphangioplasty: a new method for the relief of the brawny arm of breast cancer and for similar conditions of the lymphatic oedema: preliminary note.  Lancet1908; 1:783-785.
  33. Walther C: Note sur une nouvelle methode de traitment de l'elephantiasis des membres!.  Bull Acad Natl Med1918; 3(Ser. 79):195-198.
  34. Hogeman KE: Artificial subcutaneous channels in draining lymphoedema.  Acta Chir Scand1955; 100:154-156.
  35. Jantet GA, Taylor GW, Kinmoth JB: Operations for primary lymphedema of the lower limb: results after 1 to 9 years.  J Cardiovasc Surg1961; 2:27-36.
  36. Zeiman SA: Re-establishing lymph drainage for lymphedema of the extremities.  J Int Coll Surg1951; 15:328-331.
  37. Silver D, Puckett CL: Lymphangioplasty: a ten year evaluation.  Surgery1976; 80:748-755.
  38. Goldsmith HS, de los Santos R, Beattie EJ: Relief of chronic lymphedema by omental transposition.  Ann Surg1967; 166:572-585.
  39. Goldsmith HS: Long-term evaluation of omental transposition for chronic lymphedema.  Ann Surg1974; 180:847-849.
  40. Harii K: Clinical application of free omental flap transfer.  Clin Plast Surg1978; 5:273-281.
  41. Hurst PA, Stewart G, Kinmonth JB, Browse NL: Long-term results of the enteromesenteric bridge operation in the treatment of primary lymphedema.  Br J Surg1985; 72:272-274.
  42. Olszewski WL: The treatment of lymphedemas of the extremities with microsurgical lymphovenous anastomoses.  Intl Angiol1988; 7:312-321.
  43. Baumeister RG, Siuda S: Treatment of lymphedema by microsurgical lymphatic grafting: what is proved?.  Plast Reconstr Surg1990; 85:64-74.
  44. Rivero OR, Calnan JS, Reis ND, Taylor LM: Experimental peripheral lymphovenous communications.  Br Plast Surg1967; 20:124-133.
  45. O'Brien BMcC, Mellow CG, Khazanchi RK, et al: Long-term results after microlymphaticovenous anastomoses for the treatment of obstructive lymphedema.  Plast Reconstr Surg1990; 85:562-572.
  46. Olszewski WL: Lymphostasis: Pathophysiology, Diagnosis, and Treatment,  Boca Raton, FL, CRC Press, 1991.
  47. Puckett CL, Jacobs GR, Hurvitz JS, Silver D: Evaluation of lymphovenous anastomoses in obstructive lymphedema.  Plast Reconstr Surg1980; 66:116-120.
  48. Weiss M, Baumeister RG, Tatsch K, Hahn K: Lymphoscintigraphy for noninvasive long-term follow-up of functional outcome in patients with autologous lymph vessel transplantation.  Nuklearmedizin1996; 35:236-242.
  49. Campisi C, Boccardo F, Alitta P, Tacchella M: Derivative lymphatic microsurgery: indications, techniques, and results.  Microsurgery1995; 16:463-468.
  50. Gillies HD, Fraser FR: The lymphatic wick.  Proc R Soc Med1950; 43:1054-1059.
  51. Mowlem R: The treatment of lymphedema.  Br J Plast Surg1948; 1:48-55.
  52. Clodius L, Uhlschmid G, Hess K: Irradiation plexitis of the brachial plexus.  Clin Plast Surg1984; 11:161-165.
  53. Dick W: Über die Lymphgefdsse des menschlichten Netzez, zugleich ein Beitrag zur Behandlung der Elephantiasis.  Beitr Klin Chir1935; 162:296-314.
  54. Thompson N: The surgical treatment of advanced post mastectomy lymphedema of the upper limb with later results of treatment by the buried dermal flap operation.  Scand J Plast Surg1969; 3:54-60.
  55. Sawhney CP: Evaluation of Thompson's buried dermal flap operation for lymphedema of the limbs: a clinical radioisotope study.  Br J Plast Surg1974; 27:278-283.
  56. Neilubowicz J, Olszewski W: Surgical lymphaticovenous shunts in patients with secondary lymphedema.  Br J Surg1968; 55:440-442.
  57. Calnan JS, Reis ND, Rivero OR, et al: Natural history of lymph node to vein anastomosis.  Br J Plast Surg1967; 20:134-145.
  58. Huang GK, Hu R, Liu ZZ, et al: Microlymphaticovenous anastomosis in the treatment of lower limb obstructive lymphedema: analysis of 91 cases.  Plast Reconstr Surg1985; 76:671-685.
  59. Chen HC, Pribaz JJ, O'Brien B, et al: Creation of distal canine limb lymphedema.  Plast Reconstr Surg1989; 83:1022-1026.
  60. Chen HC, O'Brien B, Rogers IW, et al: Lymph node transfer for the treatment of obstructive lymphedema in canine model.  Br J Plast Surg1990; 43:578-586.
  61. O'Brien B, Hickey MJ, Hurley JU, et al: Microsurgical transfer of the greater omentum in treatment of canine obstructive lymphedema. Br. J Plast Surg 190;43:440–446.
  62. Baumeister RG, Siefert J, Wiebecke B, Hahn D: Experimental basis and first application of clinical lymph vessel transplantation of secondary lymphedema.  World J Surg1981; 5:401-407.
  63. Baumeister RG, Siuda S: Treatment of lymphedema by microsurgical lymphatic grafts: what is proved.  Plast Reconstr Surg1990; 85:64-74.
  64. Mavili ME, Naldoken S, Safak T: Modified Charles operation for primary fibrosclerotic lymphedema.  Lymphology1994; 27:14-20.
  65. Miller TA: Charles procedure for lymphedema: a warning.  Am J Surg1980; 139:290-292.
  66. Dellon AL, Hoopes JE: The Charles procedure for primary lymphedema: long-term clinical results.  Plast Reconstr Surg1977; 60:589-595.
  67. Kondoleon E: Die operative Behandlung der elephantiastichen Oedema.  Zentralbl Chir1912; 39:1022-1025.
  68. Sistrunk WE: Further experiences with the Kondoleon operation for elephantiasis.  JAMA1918; 71:800-806.
  69. Homans J: The treatment of elephantiasis of the legs: a preliminary report.  N Engl J Med1936; 215:1099-1104.
  70. Auchincloss H: New operation for elephantiasis.  Puerto Rico J Publ Health Trop Med1930; 6:149.
  71. Miller TA, Wyatt LE, Rudkin GH: Staged skin and subcutaneous excision for lymphedema: a favorable report of long-term results.  Plast Reconstr Surg1998; 102:1486-1498.
  72. Miller TA: Surgical approach to lymphedema of the arm after mastectomy.  Am J Surg1984; 148:152-156.
  73. Brorson H, Svensson H: Liposuction combined with controlled compression therapy reduces arm lymphedema more effectively than controlled compression therapy alone.  Plast Reconstr Surg1998; 102:1058-1067.
  74. Apesos J, Chami R: Functional applications of suction-assisted lipectomy: new treatment for old disorders.  Aesthetic Plast Surg1991; 15:73-79.
  75. O'Brien BMcC, Khazanchi RK, Kumar PAV, et al: Liposuction in the treatment of lymphedema: a preliminary report.  Br J Plast Surg1989; 42:530-533.
  76. Thompson N: Surgical treatment of chronic lymphoedema of the lower limb: with preliminary report of a new operation.  Br Med J1962; 2:1567-1573.
  77. Thompson N: Buried dermal flap operation for chronic lymphedema of the extremities: ten-year survey of results of 79 cases.  Plast Reconstr Surg1970; 45:541-548.
  78. Thompson N, Wee JTK: Twenty years experience of the buried dermis flap operation in the treatment of chronic lymphedema of the extremities.  Chir Plast1980; 5:147-161.
  79. Serville M: Surgical treatment of lymphedema: a report on 652 cases.  Surgery1987; 101:485-495.
  80. Brorson H: Liposuction gives complete reduction of chronic large arm lymphedema after breast cancer.  Acta Oncol2000; 39:407-420.
  81. Brorson H, Svensson H, Norrgren K, Thorsson O: Liposuction reduces arm lymphedema without significantly altering the already impaired lymph transport.  Lymphology1998; 31:156-172.
  82. Zhang TS, Huang WY, Han LY, Liu WY: Heat and bandage treatment of chronic lymphedema of the extremities.  Chin Med J1984; 97:567-577.
  83. Brennan MJ, DePompolo RW, Garden F: Focused review: postmastectomy lymphedema.  Arch Phys Med Rehabil1996; 77:S74-S80.
  84. Jeltsch M, Kaipainen A, Joukov V, et al: Hyperplasia of lymphatic in VEGF-C transgenic mice.  Science1997; 276:1423-1425.
  85. Kukk E, Lymboussaki A, Taira S, et al: VEGF-C receptor binding and pattern of expression with VEGF-3 suggests a role in lymphatic vascular development.  Development1996; 122:3829-3837.