Lymphedema is a chronic and progressive condition characterized by localized swelling caused by a compromised lymphatic system. The most common symptom is upper- or lower-extremity swelling. In the early stage of the disease, patients experience heaviness or tightness of the affected extremity without swelling. Significant swelling, inflammation, and fibrosis develop as the disease progresses. Patients with lymphedema experience pain, discomfort, recurrent bouts of cellulitis, and an overall decreased quality of life.

Lymphedema is classified as primary or secondary. Pri-mary lymphedema is caused by intrinsic problems with or inborn defects of the lymphatic system, such as lymph node or vessel dysplasia or agenesis. The central role of genetics in the normal development of the lymphatic system has been established. Several of the identified mutations reside within genes that encode proteins that are active in this pathway, including VEGFR3, VEGFC, CCBE1 (collagen and calcium-binding epidermal growth factor domain 1), and ADAMTS3 (ADAM metallopeptidase with thrombospondin type 1 motif 3) (1).

Oncologic surgery, which includes lymph node dissection, radiation, and chemotherapy, is among the leading causes of secondary lymphedema. Approximately 20% of breast cancer survivors and up to 50% of gynecological cancer patients experience lymphedema after oncologic surgery. Approximately 250 million people worldwide suffer from lymphedema.

The initial diagnosis of lymphedema can be determined through clinical examination. Lymphedema usually starts in a unilateral extremity following breast or gynecologic cancer surgery. It deteriorates in the evening after an activity and improves in the morning. The most representative symptom is that when the dorsal side of the second toe or second finger is pinched, the stemmer sign is positive and the tissue cannot be lifted normally.

To characterize lymphedema severity, the International Society of Lymphology (ISL) and Campisi staging systems are most widely used in clinical practice (Table 1). In particular, since an evaluation of peripheral lymphedema was first published in 1995, the latest version of the ISL consensus in 2020 was recently used as a standard grading system to describe lymphedema progression or severity.

Table 1

The stages of lymphedema

	ISL stage and description		Campisi stage and description		Recommended treatment
Subclinical	0	No swelling, change only on imaging
Mild	I	Accumulation of fluid which subsides with limb elevation, usually lasts <24 h, Pitting may occur	Ia	No overt swelling despite impaired lymph drainage	LVA
			Ib	Reversible swelling with limb elevation
Moderate	IIa	Rarely resolves with limb elevation alone	II	Mild persistence of swellingwith elevation	LVA, VLNT
	IIb	Loss of pitting to progression of dermal fibrosis	III	Persistent swelling with recurrent lymphangitis	VLNT, liposuction
Severe	III	Lymphostatic elephantitiasis	IV	Fibrotic changes with column-like limb	VLNT, liposuction, excision
		No pitting, development trophic skin change	V	Elephantiasis with limb deformation incdluding lymphostatic warts

ISL: immediate lymphatic reconstruction, LVA: lymphaticovenular anastomosis, VLNT: vascularized lymph node transfer.

The diagnosis is classically made using lymphoscintigraphy, which has long been considered the gold standard for the diagnosis and evaluation of lymphedema (Fig. 1). Radiolabeled tracer is injected subdermally into the distal extremity. The tracer is then taken up by the lymphatic vessels and travels proximally along the lymphatic vessels to reach the lymph nodes. Its transport is degraded or impaired in patients with lymphedema. Although lymphoscintigraphy is helpful for making the diagnosis of lymphedema, it has several drawbacks including injection pain and poor resolution.

Fig. 1. Preoperative lymphoscinti-graphy scan of the upper extremity. Serial images of the bilateral upper extremities were taken at 3, 15, 30, and 60 min after the injection of the Tc-99m phytate colloid into the web spaces of both hands. Dermal backflow was observed in the right upper extremity.

Indocyanine green lymphography (ICG) recently became a popular imaging technique for making the lymphedema diagnosis (Fig. 2). ICG is injected subdermally into the distal extremity. ICG binds to albumin and is taken up by lymphatic vessels; lymphatic flow can be visualized in real time. The examination can be performed in an outpatient clinic. ICG lymphography is useful for evaluating the stages of lymphedema and determining the possibility of physio-logical lymphatic surgery.

Fig. 2. Preoperative indocyanine green lymphography. After a subdermal injection of indocyanine green in the distal extre-mity, the lymphatic flow can be visualized in real time.

New imaging techniques, including magnetic resonance angiography and ultrasound, are also being actively used. In recent years, many plastic surgeons have used high-frequency ultrasonography to identify functional lymphatic vessels, even in patients at an advanced disease stage, and perform lympha-ticovenular anastomosis (LVA) more efficiently (2).

1) Lymphaticovenular anastomosis

Because of recent advances in microsurgical techniques and instruments, lymphatic vessels with a diameter of 0.3∼0.8 mm can be anastomosed to venules or veins to create lymphovenous bypass (Fig. 3) (3). This surgery can restore physiologic lymphatic flow from lymphatic vessels to veins when the proximal part of the lymphatic flow is obstructed. Proximal obstruction of the lymphatic flow is commonly observed in lymphedema following oncological surgery.

Fig. 3. Intraoperative photographs of lymphaticovenular anastomosis. (A) The lymphatic vessel was anastomosed to the distal end of the venule. (B) Indocyanine green lymphography showed flow from the lymphatic vessel to the vein after lymphaticovenular anastomosis.

Because LVA targets superficial lymphatic vessels, which are located in the superficial fat layer, surgery is minimally invasive and postoperative pain minimal. Surgery can be performed with skin incisions less than 2∼3 cm long using local or general anesthesia. However, not all patients are candidates for this surgery because the lymphatic vessels undergo degenerative changes as the lymphedema progresses. ICG lymphographic examination is a useful tool for eva-luating the suitability of lymphatic vessels for LVA surgery.

In most studies published to date, LVA showed signifi-cant improvement in subjective symptoms and a lower rate of infection in patients with lymphedema (4,5). In particular, this improvement was noticed within the first postoperative week in several studies. However, the procedure’s long-term efficacy remains controversial. In patients with upper- extremity lymphedema, long-term patency was relatively well maintained even after 1 year (5). In patients with lower- extremity lymphedema, the therapeutic effect was maintained in 20∼76.7% of cases (6). Therefore, it is generally accepted that LVA is more effective for upper- than lower-extremity lymphedema and more beneficial in patients with ISL stage 2a or lower (7).

2) Vascularized lymph node transfer

Free tissue transfer of the lymph nodes is the most recent development in lymphedema treatment (8,9). Two current hypotheses are commonly accepted as the principle of vascular lymph node transfer (VLNT). First, the “pump theory” suggests that the VLN flap absorbs the lymph fluid like a pump and drains it into the vein through natural lymphati-covenular connections inside it (10,11). The other hypothesis, known as the “lymphangiogenesis theory,” suggests that the transferred lymph nodes have a high capacity for sponta-neous regeneration and improve the drainage by forming a bridge to the lymphatic pathway (12,13). VLNT has recently gained consensus as a promising operative technique for lymphedema based on its excellent outcomes, especially in patients with advanced disease (Fig. 4).

Fig. 4. Schematic illustration of vascularized lymph node transfer. A lymph node flap is transplanted into the arms of legs with lymphedema in the form of a free flap.

There are various donor sites for VLNT, including the groin, submental, and supraclavicular areas. Similar to the donor sites, the recipient sites vary widely. In treating upper- extremity lymphedema, the recipient sites include the wrist, elbow, and axillary regions. In lower-extremity lymphedema, the ankle and groin are the most common recipient sites.

Although the literature on VLNT remains in its infancy, the results reported to date are favorable (14). A recent meta-analysis showed that VLNT combined with rehabilitative treatment significantly reduced limb circumference by a mean 1.64 cm (15). Also, in many cases, it can be performed with simultaneous multiple LVA to achieve better outcomes.

3) Debulking procedure

(1) Liposuction

In late-stage cases, adipose tissue deposition and fibrosis are prominent manifestations of the disease. In such cases, liposuction can be used to remove hypertrophic tissues and reduce edematous symptoms. This is a useful treatment option in conjunction with controlled compression therapy.

(2) Excisional procedures

Invasive reductive procedures, such as the Charles ope-ration, can be used as the sole treatment option for patients with terminal refractory lymphedema (16). However, it has not been used in a while because of extensive scarring and substantial morbidity, including significant blood loss or infection. Recently, however, radical reduction of lymphedema with preservation of the perforators and a modified Charles procedure, composed of a negative dressing and delayed skin graft, have provided optimal outcomes for patients with advanced stage lymphedema.

4) Preventive procedure: Immediate lymphatic reconstruction

Lymphedema is a refractory disease that is challenging to treat. Immediate lymphatic reconstruction has drawn attention as a novel preventive technique (17,18). After re-verse mapping with ICG lymphography, surgeons connect lymphatic vessels of the upper and lower extremities to the surrounding vein (Fig. 5). This can improve lymphatic fluid drainage and reduce the lymphedema rate.

Fig. 5. Intraoperative photo of lymphatic reconstruction.

Unfortunately, a cure for lymphedema is lacking, as is consensus regarding treatment approach. However, with the advent of supermicrosurgery, physiologic surgeries such as LVA or VLNT are now considered promising treatment options for refractory lymphedema. Furthermore, as preventive surgery and regenerative treatment technologies are gradually emer-ging, better treatment results are expected in the future.

This content was presented at the 43rd Conference of the Korean Society for Phlebology on November 6th, 2022.

We have no potential conflicts of interest relevant to this article to report.