Early lymphaticovenous anastomosis in lymphedema management: a pilot study

INTRODUCTION

Lymphedema is a progressive degenerative disease that can develop in severe cases with massive swelling, elephantiasis, and repeated infection. Conservative and surgical treatments can be offered to patients with lymphedema, with conservative treatment usually preceding surgery. CDT, a conservative treatment, comprises compression therapy, manual lymph drainage, remedial exercises, and skin care. Delay in the initiation of therapeutic intervention may cause resistance to treatment, which is one of the worst problems associated with lymphedema.

Over the past decade, LVA has evolved as a surgical treatment for lymphedema. LVA is indicated as an adjunct to CDT or when CDT fails to eliminate edema^[1]. In general, LVA is best suited for the treatment of early-stage lymphedema. Campisi et al. reported that lymphatic reconstruction in the early stages of disease, when tissue changes are minimal, can offer excellent outcomes with complete restoration of lymphatic flow^[2]. However, the dilemma of LVA becoming less effective arises when long-term CDT is not sufficient for improvement due to the progression of tissue fibrosis^[3,4]. Therefore, LVA should be performed prior to disease progression^[5].

However, the proper timing for LVA after CDT initiation remains unclear. Since the deterioration of lymphatic function due to tissue fibrosis would not cease even with CDT unless the edema disappeared completely, we hypothesized that earlier surgical indications should be considered and that early LVA would improve treatment outcomes.

This study aimed to test this hypothesis by evaluating whether the time from the start of CDT to LVA affects treatment outcomes, including conservative and surgical treatments.

METHODS

We retrospectively studied 50 consecutive patients with upper extremity lymphedema of the arm with clinical stage II (International Society of Lymphology^[1]) who underwent LVA between September 2015 and November 2022. All of them presented with secondary lymphedema after breast cancer treatment.

The patients were divided into two groups based on the duration of CDT before LVA: patients with CDT < 6 months (early group) and those with CDT > 6 months (non-early group). We compared the PEV between the two groups using the propensity score weighting method to adjust for confounding factors.

Surgical procedure

Prior to surgery, ICG lymphangiography was performed to visualize the lymphatic drainage pattern and plan the anastomotic sites, usually three sites [Figure 1]. Patent blue was additionally used in a subset of patients whose lymphatic vessels were anticipated to be challenging to identify under the surgical microscope with ICG alone. The collective lymphatic vessels and subcutaneous veins were located after skin incisions at each of the three surgical sites. The lymphatic and subcutaneous veins were anastomosed in a side-to-end fashion, where a side-wall incision was made on a lymphatic vessel to join it to a nearby subcutaneous vein using 11-0 nylon sutures under a surgical microscope.

Figure 1. Schematic drawing of the surgical planning of LVA for upper extremity lymphedema. LVA targets the linear-visualized lymphatic vessels or those with dermal backflow, if present. LVA: lymphaticovenous anastomosis.

RESULTS

All 50 patients were clinically classified as having stage II disease. Of these, 28 patients underwent LVA within 6 months of CDT initiation, whereas 22 patients underwent LVA > 6 months after CDT initiation [Table 1]. The stratified number of LVA cases per 2-year period over the study duration is shown in Figure 2.

Figure 2. Stratified histogram of the number of cases per 2-year period over the study duration.

All patients received CDT from the same trained therapist. Postoperative compression was individualized. Preoperatively, 10 Early Group patients (36%) wore Class 0 compression garments, 2 (7%) Class 1, and 16 (57%) Class 2. Among Non-early Group, 4 (18%) used Class 0, 1 (7.1%) Class 1, and 17 (77.3%) Class 2. Postoperatively, 6 Early Group patients (21.4%) wore Class 0, 4 (14.3%) Class 1, and 18 (64.3%) Class 2 compression. In the Non-early group postoperatively, 6 (27.3%) wore Class 0, 1 (4.5%) Class 1, and 15 (68.2%) Class 2. No significant differences were seen between the two groups both preoperatively and postoperatively [Table 2]. The primary outcomes were postoperative PEV and the reduction rate at 12 months. The results showed that, after applying overlap weighting, the baseline characteristics and demographics of the treatment and control groups were balanced [Table 2]. At the 12-month postoperative follow-up, the early treatment group had a significantly lower PEV of 4% compared with 10% in the delayed treatment group (P = 0.02) [Figure 3]. This difference corresponds to a medium effect size, with a standardized mean difference (SMD) of 0.42. Additionally, the early treatment group had a significantly greater reduction rate of 56% compared to 25% in the delayed treatment group (P = 0.03) [Figure 4]. The reduction rate difference also represented a medium effect size, with an SMD of 0.59 [Table 2].

Figure 3. PEV comparison at 1 year postoperatively.

Figure 4. Comparison of the volume reduction rate at 1 year postoperatively.

Representative cases

Case 1: A 52-year-old woman presented with lymphedema of the left upper extremity [Figure 5A]. CDT started 1 month after the onset of lymphedema, and LVA surgery was performed after four months of CDT management. The postoperative picture showed marked improvement of the edema in the affected limb [Figure 5B].

Figure 5. A patient in the early group before (A) and after (B) LVA. PEV for the affected limb reduced from 16.6 to 6.4 after LVA surgery. LVA: lymphaticovenous anastomosis; PEV: percent excess volume.

Case 2: A 60-year-old woman presented with lymphedema of the right upper extremity [Figure 6A]. CDT started 27 months after the onset of lymphedema, and LVA surgery was performed after eight months of CDT. Despite mild improvement, apparent edema remained [Figure 6B].

Figure 6. A patient in the non-early group before (A) and after (B) LVA. PEV of the affected limb decreased from 50.7 to 37.5 after LVA, showing a constant decrease, but still not less edema. LVA: lymphaticovenous anastomosis; PEV: percent excess volume.

DISCUSSION

This study compared the early and non-early groups in terms of the timing of LVA. The early group showed significantly better outcomes in PEV and volume reduction rate 1 year after LVA, adjusting for patient background as much as possible using the propensity score with an overlap weighting method. These results suggest the benefit of early indication of LVA after the initiation of CDT in patients with upper extremity lymphedema. This supports previous literature^[4], which argues that delaying reconstructive surgery beyond 1 year may compromise its efficacy because of irreversible damage to the lymphatic system. This is the first study to show how early LVA should be indicated for a better treatment prognosis of upper extremity lymphedema.

CDT is considered more beneficial when it begins as an early intervention^[8]. The mechanisms behind successful CDT are the remaining lymphatic drainage routes in the affected extremity and stimulation of smooth muscle contraction of lymphatic vessels, which is a major premise for the existence of functional lymphatic vessels^[9]. Namely, the efficacy of CDT depends on the residual lymphatic route. However, residual lymphatic pathways exhibit alterations in drainage patterns as early as stage 0/I^[10], which indicates most patients who are starting CDT already have a functional loss to some extent, potentially affecting the efficacy of CDT. Since microsurgical treatment such as LVA increases lymphatic return^[1] and relieves lymphatic hypertension^[4], it should work complementarily as an adjunct to CDT to improve treatment efficiency and outcomes.

The efficacy of LVA is influenced by residual lymphatic function. To obtain a sufficient LVA outcome, functional lymphatic vessels that suit the anastomosis must remain in the affected extremity^[11]. Lee et al. argued that it would be ideal to perform reconstructive surgery while the function of lymphatic transport is salvageable before damage to the lymphatic vessels becomes irreversible^[4]. In terms of residual lymphatic function, in future studies, it would be informative to directly compare ICG findings between earlier versus delayed LVA groups. This analysis could determine if preoperative lymphatic imaging characteristics correlate with surgical outcomes. Additionally, as the mechanisms of LVA are based on a pressure gradient through the bypass^[12], the benefit of LVA would be greater in the presence of lymphatic hypertension. Considering that lymphatic pressure rises at the beginning of lymphatic obstruction^[13], whereas it declines due to lymphatic pump failure from chronic excessive afterload to lymphatic smooth muscle cells^[14], LVA should be performed in the early phase of the disease.

For how long should preoperative CDT be performed? CDT has been effective in reducing edema and improving the patients’ quality of life; however, it does not address the cause of the disease and remains incomplete^[5]. Studies have demonstrated the long-term efficacy of CDT, with an edema reduction rate of approximately 60%^[15]. The remaining chronic edema continued to damage the lymphatic system, causing further tissue fibrosis and fat accumulation^[16]. Given the dilemma of LVA, the earliest evaluation of the efficacy of CDT and indications for reconstructive microsurgery is paramount. According to Hwang et al., the greatest decrease in percent excess volume was observed at 6 months after CDT, suggesting that evaluation for the indication of LVA can be performed at 6 months after the initiation of CDT^[17]. Moreover, another study stated that surgical intervention is considered after 3-6 months of the CDT protocol^[18]. Based on our results, it may be reasonable to consider LVA as early as 6 months or less to maximize treatment outcomes.

Our study has some limitations. First, our cohort had a limited sample size (n = 50), accrued over 7 years with an average of 7 cases annually, which may limit the generalizability of our findings. Additionally, upper extremity cases are less common than lower extremity cases in many Japanese institutions, further impacting external validity. However, we argue that our cohort of breast cancer-related lymphedema represents an appropriate population for evaluating this intervention’s efficacy. Still, caution is warranted when extrapolating these findings to other populations and settings. Further research is necessary to validate and expand on our observations. Second, even a propensity score analysis with overlap weighting or inverse probability weighting cannot be fully adjusted for potential biases. Randomized controlled trials are needed to determine the true effects of the early indications for LVA in the management of lymphedema. Third, the observed results include not only the LVA but also the CDT, which we should be aware of. The treatment effect should always be combined because these modalities are complementary.

CONCLUSION

LVA would be more beneficial if performed less than 6 months compared to if performed more than 6 months after CDT initiation for stage II upper extremity lymphedema. The present study suggests a potential improvement in the treatment prognosis of lymphedema by considering the early indication of LVA while impaired lymphatic function remains reversible and fibroadipose tissue accumulation is reduced.