Surgical Treatment of Primary Lymphedema

Abstract

Primary lymphedema is due to abnormal congenital development or dysfunction in the lymphatic system. Limited data exist on the prevalence of primary lymphedema and there are only few studies focusing on primary lymphedema. The purpose of this article is to review the current options for surgical treatment of primary lymphedema.

Introduction

Lymphedema is the swelling of the body part due to the accumulation of lymphatic fluid secondary to abnormal or damaged lymphatic system and is classified into primary and secondary. Primary lymphedema is due to abnormal congenital development (i.e., aplasia, hypoplasia, and hyperplasia) or dysfunction in the lymphatic system.¹ Secondary lymphedema is due to acquired damage to the lymphatic system (i.e., tumors, cancer treatment, trauma, infection, and so on).

The incidence of lymphedema is ∼1/1000 in the United States, and over 250 million people worldwide are thought to be affected.² However, despite its prevalence, its pathology and pathophysiology are poorly understood.³ Moreover, because most lymphedema is secondary, there are only a few studies focusing on primary lymphedema.^3–10 The purpose of this article is to review the current options for surgical treatment of primary lymphedema.

Incidence and Classification

Limited data exist on the prevalence of primary lymphedema. In 1985, Dale estimated its prevalence as 1/6000 population based on United Kingdom clinic,¹¹ and other study has indicated 1.2/100,000 in patients younger than 20 years.⁵

Traditionally, the primary lymphedema has been classified into three groups depending on the age of onset as follows: congenital (before age 2 years), praecox (between age 2 and 35 years), and tarda (after age 35 years) (Fig. 1). Although this classification is simple and easy to understand, classifying lymphedema based solely on the age of onset may be misleading in understanding the etiology of lymphedema.^12–14 For example, lymphedema distichiasis syndrome, which is caused by mutations in the FOXC₂ gene, can be classified into any of the subtypes because the onset may be at birth, at puberty, or at fifth decade.^7,15

FIG. 1.

A 35-year-old woman with right leg primary lymphedema.

To address these shortcomings, Connell et al. have recently proposed new classification system based on genetic causes and clinical phenotype.¹⁵ In this system, the primary lymphedema was classified according to age of onset, the sites affected, the presence of associated features, systemic lymphatic involvement, and family history. This classification system has the advantage of facilitating the identification of subgroups and providing better understanding of the natural history of each subgroup. In addition, it can be used for molecular studies to identify causal genes.

Clinical Presentation

The initial symptoms are usually painless swelling and feeling of heaviness in the limb, especially at the end of the day and in hot weather.¹⁶ However, acute onset or worsening of lymphedema can produce pain, caused by distension of the aponeurosis around deep lymphatic system.⁹ The lower extremity is most commonly affected, but upper extremity, abdomen, genital area, and trunk can be involved as well. Recent study showed that among 138 pediatric primary lymphedema patients, 95.7% of patients had lymphedema in the extremity and 18.1% of patients had genital swelling.¹⁴ It also showed that there was no difference in bilateral involvement between upper and lower extremity for male and female. However, bilateral disease was more likely in patients presenting in infancy or childhood compared with adolescence.

Generally, the foot swelling starts in the dorsal aspect of foot (buffalo hump) and has a squared-off appearance. The Kaposi-Stemmer sign is a clinical sign indicative of lymphedema, where the examiner is unable to pinch a fold of skin at the base of the second toe on the dorsal aspect of foot.^17,18 The edema is usually pitting in early stage; however, it becomes nonpitting with the progression of disease. If untreated, the involved skin becomes hyperkeratotic, hyperpigmented, and papillomatous or verrucous with increased skin turgor.¹⁷ In severe cases, the skin can breakdown with lymph exuding through it. This compromises healing and leads to increased risk of infection, which can cause further deterioration in lymphatic drainage, ending in a vicious cycle of infection and worsening edema.¹⁹

Furthermore, systemic lymphatic involvement such as pericardial or pleural effusion, chylous ascites, or gastrointestinal lymphangiectasia can be manifested.¹⁵ If the patients have additional physical finding (e.g., distichiasis and yellow nails), they should be consulted for genetic evaluation for a syndromic association.

Diagnosis

There is no specific diagnostic tool for primary lymphedema. Diagnosis is based on history and physical examination and by ruling out other edematous diseases. History should include age of onset, family history of limb or genital edema, episodes of infections, previous malignancy or trauma, and visit to tropical countries with endemic filariasis.^14,20 The exclusion of general medical causes for limb swelling should be a priority. These causes include, but are not limited to, renal failure, heart failure, pulmonary hypertension, obesity, drug-induced edema, and pregnancy.¹⁸

On physical examination, signs of lymphedema such as edema, skin change (peau d'orange, pinkish-red discolorization, hyperkeratosis, dermatitis, eczema, and ulceration), or yellow discoloration or other abnormalities of nails should be checked. The presence of Kaposi-Stemmer sign or puffiness of the forefoot should be also noted. In addition, any complications, such as cellulitis, lymphangitis, malnutrition, or, rarely, suspicion for malignancies (lymphangiosarcoma), must be documented.²⁰

If history and physical examination are equivocal for lymphedema, the diagnosis can be confirmed by lymphoscintigraphy, which is the gold standard. It is 92% sensitive and 100% specific for lymphedema. In addition, it can show the severity of functional derangement of lymphatic system even in obese patients.²¹ However, lymphoscintigraphy has not been standardized with regard to various radiotracers and radioactivity doses, different injection volumes, number of injections, different protocols of passive and active physical activity, varying imaging times, and static and/or dynamic techniques.²²

Currently, as the usage of indocyanine green (ICG) lymphography increases, there have been studies demonstrating the clinical usefulness of ICG lymphography in the diagnosis and treatment of lymphedema.^10,23–25 (Fig. 2) ICG images are classified into either a normal linear pattern or dermal backflow (DB) patterns: splash, stardust, and diffuse. The order of severity of these patterns increases from splash to diffuse.^26,27 In 2015, Yamamoto et al. have classified primary lymphedema according to extension of DB patterns and the visibility of enhanced lymphatics. In their classification, abnormal findings in primary lower leg lymphedema can be classified into four patterns as follows: proximal DB (PDB), distal DB (DDB), less enhancement, and no enhancement (NE).²⁸ In addition, they suggested that lymphatic bypass would be a useful treatment option for patients with PDB or DDB patterns, while vascularized lymph node transfer (VLNT) and/or debulking surgery would be more appropriate for patients with NE pattern.

FIG. 2.

Indocyanine green lymphography helps identify functioning lymphatic vessels.

The comparison of lymphoscintigraphy and ICG lymphography have shown that the diagnostic ability and the capability to evaluate the severity are similar in both examinations, while the invasiveness and examination of the cost are less in ICG lymphography. Moreover, for the diagnosis of the primary lymphedema, they advocated that ICG lymphography can be used as a primary diagnostic tool because its sensitivity and negative predictive value are high compared to lymphoscintigraphy. In addition, it can obviate the exposure of radiation and delineate the course of superficial lymphatics in real-time manner. The disadvantage of ICG lymphography is that its use is limited to lymphatic vessels less than 2 cm deep in the subcutaneous tissue.^29,30

Besides the above diagnostic tools, a venous duplex ultrasound is often used to differentiate deep vein thrombosis or venous edema from lymphedema. Computed tomographic scanning or magnetic resonance lymphangiography are also gaining popularity for evaluating the anatomical and functional status of lymphatic vessels and lymph nodes in lymphedematous limb.^20,31,32

Treatment

General consideration

The main aims are to prevent the progression of disease, restore cosmesis and functionality of the limb, and prevent potential complications associated with lymphedema.¹⁷ Due to the chronicity of the disease, patient participation is essential. Patients should be encouraged to be aware of the nature of disease and be properly guided on how to actively be involved in self-management.²⁰ Exercise is an important element in the management of lymphedema. Decreasing intrathoracic pressure through the act of inspiration increases lymph flow, and it is thought that increasing pulmonary work through exercise will assist in lymph clearance. Weight reduction is also important because therapy for lymphedema without concomitant weight reduction can ultimately hamper the rehabilitation effect.^33–36 In addition, good hygiene and prevention of infection are paramount in the management of lymphedema. The verrucous surface skin associated with lymphedema harbors microbes, which increase the risk of infection.¹⁷

Management of children with primary lymphedema begins with education and is mostly conservative. Cellulitis is treated promptly with oral antibiotics and prophylactic antibiotics should be prescribed for children with three or more episodes of cellulitis per year.¹⁴ In the neonate, initial observation alone may be sufficient, as delayed lymphatic development and maturation can result in spontaneous improvement.⁷

Nonsurgical treatment

Decongestive lymphatic therapy (DLT) has been established as the treatment of choice for lymphedema regardless of the underlying etiology (primary or secondary) or its clinical stage.²⁰ DLT consists of compression therapy, movement exercise, and manual lymphatic drainage (MLD), in addition to basic skin care.^36,37 In Phase I therapy, the main goals are reducing the size of the affected part and improving skin. Phase II therapy, consisting of an ongoing individualized self-management phase, should be followed to maintain the gains from Phase I.³⁸ The effectiveness of DLT is greater in the earlier (fluid) stages of lymphedema. There are a few theoretical contraindications of DLT as follows: risk of intravascular cancer metastases or thrombosis during MLD, high pressure bandaging to the patient with advanced cardiac failure, and in advanced peripheral arterial disease of the limb.²⁰

The role of pharmacotherapy in treating lymphedema has not been established. Anecdotally, diuretics have been reported to be beneficial in the early phases of the disease, but they are not effective for long-term management and may worsen the disease by increasing the concentration of high protein fluid in the interstitial space.^39,40 Although coumarin may induce immunomodulation and minor volume reduction, it can cause hepatotoxicity.^41,42 Targeted anti-inflammatory drugs and therapeutic augmentation of growth factor have shown promising results in animal models, but clinical application is still being studied.^43–46

Surgical treatment

If the symptoms are progressive and refractory to conservative therapies, surgical treatments may be considered.⁴⁷ There are two kinds of surgeries (physiologic and ablative) for the treatment of primary lymphedema. Generally, physiologic surgery is known to be effective for the earlier stages of lymphedema.⁴⁸ In extreme cases, ablative surgery may need to be considered.

Ablative surgery

Excision

The aim of ablative procedure is to decrease bulk and improve functional status by removing excess tissue. The “Charles Procedure” is a radical excision of skin and subcutaneous tissue together to the level of either deep fascia or epimysium with primary or staged skin grafting.⁴⁹ Although it carries a high degree of morbidity, including blood loss, poor skin graft take, and scarring, it is a practical option for patients with substantial functional deficits resulting from debilitating advanced-stage lymphedema. To minimize complications and to avoid the need for skin grafting, staged subcutaneous excision has been described.⁵⁰

Excision has also been reported for patients with severe psychosocial morbidity attributable to the appearance of the affected area, most commonly primary scrotal lymphedema in male patients.¹⁴

Liposuction

If lymphedema persists, it results in fat accumulation. Although the exact mechanism for adipose tissue hypertrophy is not fully understood, recent research has shown that local accumulation of adipogenic factors released from the lymphatic circulation may play a role.^51,52 When a patient has been treated conservatively and shows no or minimal pitting, liposuction can be performed. For patients with pitting edema, liposuction is not indicated because liposuction is a method to remove fat, not fluid.⁵³ Liposuction has been shown to be effective in secondary lymphedema patients, and some have used it as the first line intervention for pediatric extremity lymphedema because it is less morbid than direct excision.^14,53 It has been shown that excess limb volume can be reduced by 104% in the upper extremity and by 75% in the lower extremity.^54–56 To maintain the effects of liposuction, a patient must be committed to a lifelong, around the clock, use of compression garment.

However, for primary lymphedema, there is another study that doubted the efficacy of liposuction.²⁰ The clinical course of primary lymphedema is not necessarily same as that of secondary lymphedema, and there is no clear evidence of selective overgrowth of the adipose tissue in the primary lymphedema. Furthermore, when the condition of pitting edema progresses to nonpitting, the tissue becomes fibrosclerotic and the amount of fat tissue available for liposuction may be very limited.

Physiologic surgery

Physiologic surgery increases lymphatic drainage by creating a new path or inducing lymphangiogenesis. Currently, the most commonly performed physiologic procedures are lymphaticovenular anastomosis (LVA) or VLNT.

Lymphaticovenular anastomosis

In 1962, Jacobson first described the idea of lymphovenous shunt in a canine model.⁵⁷ Overtime, LVA using supermicrosurgical technique has become the preferred method of lymphatic bypass. By connecting multiple lymphatic vessels with venules, LVA allows excessive lymph to drain directly into the venous system. Using ICG lymphography, functioning superficial lymphatics deep to dermis are traced and anastomosed to nearby venules in an end-to-end or end-to-side manner (Fig. 3). A growing number of studies have demonstrated the efficacy of LVA in the treatment of lymphedema. Chang et al., on a prospective series of LVA for 100 extremities, have shown that 96% of patients reported subjective improvement in their symptoms, and the mean volume reduction at 12 months was 42%.⁵⁸ Mihara et al. have evaluated the efficacy of LVA for lower limb lymphedema and shown that 47.7% of patients reported improvement in limb circumference and 61.5% of them reported subjective improvement.⁵⁹ In addition, the postoperative mean occurrence of cellulitis was significantly decreased to 0.13 times per year compared with 0.89 preoperatively. In a recent meta-analysis study, which identified 22 studies of LVA efficacy, 89% of patients reported a subjective improvement, 88% experienced a quantitative improvement, and 56% of patients were able to discontinue compression therapy.⁶⁰

FIG. 3.

A lymphovenous bypass with green dye from lymphatic vessel (left) passing into venous system (right) after the bypass. A Color version of this figure is available in the online article at www.liebertpub.com/lrb.

For primary lymphedema patients, Demirtas et al. have shown the effect of microlymphatic surgery for 60 patients (80 extremities) and reported that 56.2% ± 22.8% of mean percent volume was reduced at the average follow-up of 13.3 months.⁸ Hara et al. have compared the effect of LVA in primary lymphedema according to the age of lymphedema onset. They found that 75% of patients whose lymphedema developed after the age of 11 years showed postoperative improvement in limb circumference, while patients with earlier onset showed less favorable results.¹⁰ This result is related to the previous study by O'Brien et al. where patients with early-onset disease might have severe lymphatic hypoplasia or aplasia.⁶¹

Despite some promising results, indications for LVA are still unclear and controversial because primary lymphedema patients have variation of defects in the lymph node and lymphatics. If there is evidence of functioning lymphatic system (hyperplastic lymphatics), LVA can be considered. However, if there is no evidence of active lymphatic channels (aplastic or hypoplastic lymphatics) with pitting edema, VLNT may be the only physiologic procedure possible (Fig. 4).

FIG. 4.

A supraclavicular lymph node transplant. A Color version of this figure is available in the online article at www.liebertpub.com/lrb.

Recently, there have been studies using lymphoscintigraphy or ICG lymphography in primary lymphedema for screening proper candidates for LVA.^10,24,28 Maegawa et al. suggested five types of primary lymphedema based on preoperative lymphoscintigraphy and they reported that the type III, where there is no detection of lymph nodes and DB is present in the thigh and/or leg, is the best indication for LVA.²⁴ In 2015, Hara et al. found that DDB pattern (stardust or diffuse DB pattern only in the distal lower limb) on preoperative ICG lymphography might be related to the presence of lymphatic hypoplasia and VLNT would be preferred in these cases rather than LVA.¹⁰ Tashiro et al. also showed similar results in secondary lymphedema patients, where DDB pattern on ICG lymphography might reflect “preexisting” hypoplasty of lymphatic vessels and LVA could be ineffective.⁶²

Vascularized lymph node transfer

When native lymph node basins are dysfunctional, vascularized lymph nodes from one area of the body can be transplanted to promote physiologic lymphatic drainage. Donor sites for VLNT include thoracic, submental, as well as omentum, but supraclavicular and groin are most commonly chosen.^48,63 Two main hypotheses have been proposed to explain the potential mechanism of VLNT in lymphedema.⁶⁴ First proposed mechanism is that the lymph node flap is naturally rich with lymphatic collectors and acts as a lymphatic wick to bridge the zone of obstruction. Second proposed mechanism is that the lymph node flap transferred to the distal extremity acts as a lymphatic pump by absorbing interstitial fluid and shifting it into the systemic circulation by means of the intrinsic lymphovenous shunt within nodes.

Cheng et al. prospectively found significantly greater reduction in upper extremity circumference in 10 patients who underwent VLNT (40%) compared with 10 control patients who elected nonsurgical therapy (8%) at a mean follow-up of 39 months.⁶⁵ Recent systematic review study looked at 18 studies to evaluate the efficacy of VLNT. The mean quality score of reviewed studies was 5.3 with levels of evidence ranging from II to IV. Among 182 patients, 91% showed postoperative improvement in limb circumference assessment. Reduction of limb volume was noted in 86% of patients. In addition, among 92 patients who underwent lymphoscintigraphy or lymphangiogram, 60% demonstrated moderate or significant improvement of flow.

For the efficacy of VLNT in primary lymphedema, Becker et al. have reported that the circumference of the limb was decreased in all cases with distal limb lymphedema and 46% of them were normalized. In generalized limb lymphedema patients, the circumference was decreased in 98% of patients, and 20% of the patients achieved complete normalization.⁹

Controversies

There are several challenges in performing lymphatic reconstructive surgery for primary lymphedema. Unlike in secondary lymphedema, there is no clear surgically correctable site.²⁰ In addition, the inherent anatomical defect in the lymphatic system may influence the efficacy of physiologic surgical treatment. O'Brien et al. claimed that distal superficial lymphatics are aplastic or hypoplastic in 80% of primary lymphedema cases, and lymphaticovenous shunt operations are confined to cases with proximal obliteration, which constitute only 10% of all primary lymphedema patients.⁶¹ In contrast, Demirtas et al. stated that morphologically normal lymphatics suitable for lymphaticovenous anastomosis could be found in 84% of primary lymphedema patients and advocated that microlymphatic surgery would be a valuable and relevant treatment of primary lymphedema.⁸

Another challenge is the age of the patient. What is the optimal time for surgical intervention in patients with primary lymphedema? Usually the ideal candidates for lymphatic surgery are the patients with early-stage lymphedema. For patients with “subclinical” secondary lymphedema, follow-up and monitoring of the progression can be done with LSG or ICG lymphography and early intervention is possible.²⁵ However, primary lymphedema patients usually visit the clinic after the swelling becomes evident or causes functional problem. In addition, for congenital lymphedema patients, waiting till the patient gets older may result in progression of lymphatic damage and hamper the efficacy of surgical treatment. In accordance with that, a consensus document produced by the International Union of Phlebology suggested that delay of surgery for more than 1 year increases the risk of surgical failure.²⁰ But there is another study that has shown that the duration of lymphedema did not negatively affect LVA outcomes, and LVA was effective even in patients who had lymphedema for more than 20 years.¹⁰

We think that these contradictory results are due to the different course of disease in pediatric primary lymphedema versus adult secondary lymphedema. Compared with the adult secondary lymphedema, pediatric primary lymphedema may cause less secondary complications and may not necessarily progress with time.^5,14 Schook et al. found that with average follow-up period of 7 years, only 18% of pediatric lymphedema patients had a history of cellulitis, while about one third of adult patients would have one episode of cellulitis per year.¹⁴ They also showed that one half of patients did not have increased swelling or symptoms during the follow-up period, while adult secondary lymphedema is thought to always progress. Similarly, Smeltzer et al. found that 57% of primary lymphedema patients had unchanged swelling for up to 27 years.⁵

Finally, although physiologic surgery seems to be attractive by means of offering a chance of “cure,” most studies to date are uncontrolled case series with heterogeneous patient population. Moreover, there are only a few articles showing the efficacy of physiologic surgery in primary lymphedema patients. To better understand the effects and potential benefit of it, well designed comparison studies should be done.

Conclusion

In contrast to secondary lymphedema, causes and natural course of primary lymphedema are heterogeneous and still remain elusive. The mainstay of its treatment is nonoperative, with DLT being the treatment of choice. However, physiologic and ablative surgeries are gaining popularity for treatment of lymphedema. In earlier stages of disease, physiologic surgery can provide promising results. With advances in diagnostic tools such as with ICG lymphography, functional lymphatic pathways can be visualized, making it easier to select the patients and perform the surgery. In later stages of disease, where lymphatic vessels are occluded and lymphedema becomes nonpitting, local resection or liposuction is needed to remove excess tissue. To further delineate the role of surgical options in treating primary lymphedema, high-quality controlled studies are needed.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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