A systematic review of vascularised lymph node transfer in combination with autologous free flap breast reconstruction for breast cancer-related lymphedema

Introduction

Breast cancer remains one of the most prevalent malignancies affecting women globally, posing not only significant physical and emotional burdens during diagnosis and treatment but also contributing to long-term complications such as breast cancer-related lymphedema (BCRL) (1-6). BCRL commonly arises following axillary lymph node dissection or radiation therapy, leading to lymphatic fluid accumulation in the arm, chest wall, or breast. This condition manifests as swelling, discomfort, restricted mobility, and a marked decline in quality of life (QOL) (3,5). For many individuals, managing BCRL becomes a persistent challenge. Compression garments are a mainstay in conservative management, aiding in fluid control and promoting lymphatic return. However, these garments can be associated with several drawbacks, including discomfort, difficulty with application and removal, and aesthetic concerns. Consequently, they often become a focal point in both clinical management strategies and assessments of patient-reported outcomes. The reported incidence of BRCL in the current established literature can be as high as 42% within 10 years after breast cancer treatment with radiotherapy or axillary dissection (1-6). Moreover, axillary lymph node dissection seems to have higher lymphedema rates compared to women who only had sentinel lymph node biopsy as part of their breast cancer treatment (7). Proponents of lymphatic microsurgery sought to use either lymphovascular bypass anastomosis or vascularized lymph node transfer (VLNT) to help prevent patients from developing lymphedema or to reduce the disease burden of established chronic lymphedema successfully (8-12). VLNT is an emerging technique in reconstructive surgery, particularly in the management of lymphedema and as an adjunct in breast cancer surgery. The concept of VLNT is rooted in transferring healthy, functioning lymph nodes and their vascular supply to areas where lymphatic drainage is impaired, such as after breast cancer surgery, where axillary lymph node dissection (ALND) or radiation therapy often leads to lymphedema. More recently, Chang et al. showed that the integration of VLNT in autologous breast reconstruction procedures seems to not only restore aesthetic outcomes but also improve the patient’s functional outcomes by addressing issues related to lymphedema, a common complication after breast cancer axillary clearance (10). Abdomen-based free flaps have the added advantage of allowing access to groin lymph nodes and omental lymph nodes as potential donor sites for VLNT during breast reconstruction. Existing reviews have examined this topic by providing a general overview of the different modalities of surgical lymphedema treatments. However, this study presents a unique systematic review by focusing and exploring the efficacy as well as safety profile of VLNT when completed in combination with autologous breast reconstruction to manage BRCL. We present this article in accordance with the PRISMA reporting checklist (available at https://abs.amegroups.com/article/view/10.21037/abs-25-25/rc).

Methods

Two authors, J.C. and S.H., independently searched Embase, Medline, and Web of Science using a focused search strategy on the use of VLNT in deep inferior epigastric perforator (DIEP) or transverse rectus abdominis musculocutaneous (TRAM) flap breast reconstructions. In addition, manual hand searches were conducted in the references of the included studies to identify any other relevant data. Each phase of screening, from abstract to full-text, and finally data extraction and quality assessment, was conducted independently by the two authors. The discrepancies and conflicts were resolved by consensus agreement.

A comprehensive literature search listed below was conducted across PubMed, Embase, and Web of Science databases to identify studies evaluating VLNT in combination with autologous breast reconstruction: (“Breast Reconstruction”[MeSH Terms] OR “Breast Reconstruction”[Title/Abstract] OR “Deep Inferior Epigastric Perforator Flap”[MeSH Terms] OR “Deep Inferior Epigastric Perforator Flap”[Title/Abstract] OR “DIEP”[Title/Abstract] OR “Transverse Rectus Abdominis Myocutaneous Flap”[MeSH Terms] OR “Transverse Rectus Abdominis Myocutaneous Flap”[Title/Abstract] OR “TRAM”[Title/Abstract]) AND (“Vascularized Lymph Node Transfer”[MeSH Terms] OR “Vascularized Lymph Node Transfer”[Title/Abstract] OR “VLNT”[Title/Abstract] OR “Lymph Node Transfer”[Title/Abstract]).

Articles published within the last 30 years were included to capture evidence on VLNT, as early reports date back to the 1990s. Randomised controlled trials, observational or qualitative studies, and case series were included in search. Case reports with fewer than 10 cases were excluded to mitigate reporting bias in small case series. Our inclusion criteria included studies that assessed the use of VLNT in combination with autologous breast reconstruction.

Meta-analyses and isolated case reports were excluded from this review. However, their references were manually reviewed for appropriate articles. In addition, studies that only examined lymphovascular bypass anastomosis or did not include concurrent autologous breast reconstruction were also excluded, as they fall beyond the scope of this review. The review was registered under PROSPERO (ID: CRD20251017699).

The Newcastle-Ottawa Scale (NOS) was used to assess the risk of bias in this review for the included non-randomised studies (13). The total score was 9 points, with >7 points categorised as low-risk, 5–7 points categorised as medium risk, and <5 points categorised as high-risk.

To determine the efficacy of VLNT for BRCL, we evaluated the included studies based on primary outcomes, focusing on the number of patients who stopped or reduced their reliance on compression therapy, the upper extremity lymphoedema (UEL) index, arm circumference, and the arm volume difference. Our secondary outcomes included complication profiles, incidence and treatment of donor site lymphedema, as well as QOL scores. However, this review only provides narrative description of the included studies.

Results

Our literature search strategy resulted in a total of 880 studies. After duplicate articles were removed, the two reviewers independently screened 880 article abstracts, without being blinded. Only 43 articles met our inclusion criteria for full-text review, and out of those reviewed, 15 papers were ultimately included for this review, as illustrated in our PRISMA flow diagram in Figure 1. Any disagreements were resolved through consensus agreement. A meta-analysis of the data was not completed due to the heterogeneity of the studies.

Figure 1 PRISMA flow diagram.

Of the 15 articles included, 8 were retrospective cohort studies, 4 were prospective cohort studies, and 3 were prospective case series as summarised in Table 1. The total number of patients across all studies was 620, with 387 patients undergoing combined VLNT and abdominal-based breast reconstruction with either TRAM or DIEP free-flaps.

Patient characteristics

The included articles showed that the mean age for all patients was 44.5 years old, and the mean body mass index (BMI) was 25.5 kg/m². Out of 620 patients, 296 were reported to have had previous radiotherapy treatment and 352 had ALND. According to the International Society of Lymphology (ISL) lymphedema staging system, many of the included patients suffered from stage II to stage III lymphedema (8). The median follow-up was 25 months (range, 6–70 months) in the included studies. The average duration of lymphedema was 44.5 months.

Donor site characteristics for VLNT

Authors from 14 out of 15 included papers detailed the use of groin-based lymph nodes from the superficial circumflex iliac artery (SCIA) system or the superficial inferior epigastric artery (SIEA) system as their preferred donor sites to harvest lymph nodes from. The only exception was Ciudad et al., who used intra-abdominal omental lymph nodes for their VLNT procedure (14). The lymph nodes were anastomosed to the thoracodorsal vessels in most of the procedures.

Improvement in lymphoedema symptoms

While volume reduction may vary, some studies have demonstrated statistically significant reductions in the circumference measurements of the affected limb after VLNT and DIEP flap. For instance, Ciudad et al. reported a mean circumference reduction rate of 56.5%±3.9% after simultaneous DIEP flap and gastroepiploic VLNT, while Chen et al. demonstrated statistically significant reduction between pre- and post-operative arm circumference measurements by 2.12±2.3 cm (P<0.05) (14,15). Objectively, Saaristo et al. also found that the upper limb measurements decreased from 3.77±1.7 to 2.55±1.66 cm in 7 of the nine patients who underwent the combined VLNT and breast reconstruction procedure (22).

When examining changes in arm volume, Demiri et al. found a 15.5% drop in volume measurements in patients who underwent combined breast reconstruction and VLNT (11). Similarly, Nguyen et al. reported an 11% decrease from baseline measurements (19). Nevertheless, the findings are not exclusive to DIEP and VLNT in the study by Rannikko et al., who showed that pooled data from VLNT treatment demonstrated a statistically significant reduction in circumference and arm volume, regardless of any additional DIEP procedures (12). In contrast, two studies did not show an improvement in arm volumes (17,21).

Reduction in the need for compression therapy

A significant benefit reported across studies is the potential to reduce or eliminate the need for compression garments. Akita et al. found that the number of patients who could reduce compression therapy was significantly higher in the combined VLNT + DIEP flap group (24). In their study, 10 of 13 patients in the combined group saw a reduction compared to only 3 of 14 in the VLNT alone group. Winters et al. reported that 63% of their patients could decrease compression garment usage after VLNT with DIEP flap (23). Comparably, Di Taranto et al. also noted a reduction in the use of compression garments in patients undergoing simultaneous breast reconstruction and VLNT (16). However, Rannikko et al. observed that 42% of patients discontinued and 16% reduced compression garment use long-term regardless of whether they had VLNT with or without breast reconstruction (12).

Improved QOL

Multiple studies reported subjective improvements in lymphedema symptoms following VLNT with free flap reconstruction, including a reduction in heaviness, pain, and limitation in range of motion (9-12,15,22-24). Four studies completed an objective assessment of QOL improvements, and they showed significant improvements in scores after VLNT + DIEP procedures (9,16,21,23). For instance, Winters et al. found an increase in the total Upper Limb Lymphedema-27 (ULL-27) score, indicating improved lymphedema-specific QOL (23). Subdomain scores (physical, psychological, and social) also significantly increased in their study. Di Taranto et al. also reported an improvement in Lymphedema QOL (LYMQOL) from 6.7±1.7 to 8.6±1.4 (P=0.01) in patients who underwent simultaneous breast reconstruction and VLNT (16). Likewise, De Brucker et al. demonstrated a statistically significant improvement in QOL ULL-27 scores, from 44 to 26 (P<0.001) (9). Using the LYMPH-Q questionnaire, Myung et al. showed an improvement from 68 to 22 in their intervention group compared to the control group despite no objective improvements in arm volumes (P=0.01) (21).

Decreased incidence of infections

Patients with chronic lymphedema are particularly susceptible to recurrent skin infections. Some authors have reported improvements in infection rates after VLNT and DIEP procedures (9,16,23). For instance, Winters et al. and Di Taranto et al. noted a decrease in the incidence of skin infections in patients who had recurrent infections prior to VLNT with DIEP flap (16,23). Likewise, Montag et al. demonstrated a reduction in recurrent infection rates in their VLNT and DIEP cohorts compared to the DIEP-only cohort, suggesting that VLNT may have benefits in enhancing the innate immune response to combat infections (17).

Surgical complications

Post-operative seroma was reported to be the most common surgical complication in seven studies. In terms of flap-specific complications, Ciudad et al. reported one case of venous congestion in the lymph node flap requiring re-exploration (14). Moreover, Dionyssiou and Demiri documented one partial failure in a patient who had a combined DIEP + LNT flap procedure (20). More importantly, when looking at lymph node donor site morbidity, Nguyen et al. noted that one of their patients developed early lymphedema in the donor limb that required compressive therapy to resolve (19).

Reverse lymphatic mapping

Out of the 15 included papers, 6 authors reported the use of reverse lymphatic mapping either using blue dye or Indocyanine green lymphography to minimise morbidity and prevent iatrogenic lymphedema at the donor sites (9,10,17,18,20,24). Reverse lymphatic mapping was used to identify the drainage pattern to avoid injury to the main draining lymphatics during lymph node harvest.

Risk of bias assessment

Out of the 15 studies, 5 studies scored between 7 and 9 stars and were assessed to be of high quality with a low risk of bias (10,14,18,21,24). However, the remaining majority had scores between 5 and 6 stars with varying sources of bias, including reporting bias due to lack of adequate details of outcomes and potential confounding bias (9,11,12,15-17,19,20,22,23). A summary table of the assessment of bias is listed below in Table 2.

Discussion

This systematic review demonstrates that combining VLNT with abdominal-based flap reconstruction offers dual benefits for patients with breast cancer requiring delayed reconstruction, while simultaneously alleviating symptoms of BRCL, particularly in those with moderate to advanced disease.

Addressing two issues in one procedure and improving the QOL

In patients undergoing delayed breast reconstruction post-mastectomy, the combination of VLNT with DIEP flap reconstruction offers a dual therapeutic advantage: restoration of breast contour and simultaneous management of BCRL. This integrated surgical approach streamlines care by consolidating two procedures into a single operative session, thereby reducing the overall treatment burden. A cost-effectiveness analysis by Corkum and Bezuhly demonstrated an incremental cost-effectiveness ratio of $13,898.76 per quality-adjusted life year (QALY) gained for patients undergoing this combined approach, suggesting favourable economic and clinical outcomes (25).

The observed improvements in QOL following combined VLNT and DIEP flap reconstruction carry important clinical significance for patients with BCRL. Beyond the physical burden of swelling, pain, and reduced mobility, BCRL exerts a profound psychosocial impact, often limiting daily activities, social participation, and overall well-being. The consistent improvement across validated lymphedema-specific QOL instruments such as ULL-27, LYMQOL, and LYMPH-Q underscores that surgical intervention not only alleviates objective symptoms but also translates into meaningful functional recovery and enhanced psychosocial health (9,16,21,23). These findings suggest that addressing lymphedema at the time of breast reconstruction may provide a dual benefit—restoring breast contour while simultaneously improving patients’ independence, comfort, and emotional resilience. Such outcomes highlight the broader role of reconstructive surgery in improving survivorship and long-term QOL for individuals with breast cancer.

Surgical techniques

The optimal donor site for lymph node harvest remains an area of ongoing investigation, with the goal of minimising donor site morbidity while maximising therapeutic benefit. Anatomically, the superficial lymphatic system enables the reliable harvest of lymph nodes from the groin during the same operative session as DIEP flap elevation (26,27). Among the reviewed studies, the groin lymph nodes were most commonly harvested and used as vascular lymph nodes to be anastomosed to the thoracodorsal or internal mammary vessels for BCRL treatment. Nguyen et al. described their algorithm for selecting donor vessels based on the orientation of the lymph nodes within the flap (19). In their study, they recommended using the internal mammary vessels whenever possible, particularly when the lymph nodes are located on the contralateral side of the flap with the main DIEP pedicle on the ipsilateral side, or when the nodes are on the lateral side with the DIEP pedicle on the contralateral side. This will preserve the thoracodorsal axis as a lifeboat for future breast reconstruction with the latissimus dorsi.

Donor site morbidity

Groin harvest is not without risks. De Brucker et al. reported increased rates of seroma formation and wound complications in patients who underwent combined VLNT and DIEP/TRAM procedures, attributing these issues to the extensive dissection involved. Senior authors T.L. and Q.N. share similar experiences in their case report, where the patient developed a seroma after undergoing a combined TRAM and VLNT procedure, which was successfully managed through serial drainage (28).

Although less frequently reported in contemporary literature, donor-site lymphedema remains a potential complication. Demiri et al. found that the incidence in a prior study was up to 1.6% for lower limb lymphedema following groin node harvest (29). In the prospective case series by Nguyen et al., one patient developed transient donor-site lymphedema, which was successfully managed with compression therapy (19). Notably, reverse lymphatic mapping was not employed in that series. Ciudad et al. highlighted omental lymph nodes as a viable alternative, potentially mitigating the risk of donor-site morbidity (14). However, intra-abdominal node harvest necessitates specialised surgical expertise, often requiring the involvement of general or colorectal surgeons. Consequently, the choice of donor site should be tailored to patient-specific factors and the operating surgeon’s technical expertise.

Reverse lymphatic mapping is a critical technique for minimising the risk of donor-site lymphedema. By identifying and preserving lymph nodes responsible for limb drainage, this approach significantly reduces the likelihood of iatrogenic complications (30). Mapping can be performed preoperatively using dyes or lymphoscintigraphy to localise essential limb-draining nodes (6). This enables safe harvest of non-critical nodes, optimising both donor and recipient outcomes (31). In their case report, senior author T.L. and Q.N. indicated that, when possible, their preferred region to harvest groin nodes is usually above the inguinal ligament to minimise the risk of developing iatrogenic lymphedema (28).

Another alternative approach to avoid iatrogenic donor site lymphedema may be to adopt the lymphatic interpositional flap transfer (LIFT) procedure, as described by Yamamoto et al. (32). Free tissue transfer, without the intentional harvest of lymph nodes, can be used to augment lymphatic flow. The inherent axiality of lymphatic flow within the transferred tissue may provide a pathway to redirect disrupted lymphatics back into the circulatory system by approximating the lymphatic channels. However, this technique is yet to be used in breast reconstruction, and the orientation of the breast skin paddle might make it difficult to leverage this principle to augment lymphatic flow.

Potential for lymphatic regeneration and function restoration

Although some studies suggest that breast reconstruction alone may enhance lymphatic drainage by releasing tethered scar tissue and thereby improving lymphatic flow (32,33), we believe that BRCL patients have significant lymphatic destruction after axillary clearance. Hence, scar release may serve only as an adjunct to reduce the kinking of existing vessels rather than as a means of promoting true lymphatic regeneration, which is more likely to be achieved through VLNT. Nevertheless, in patients who undergo scar release and DIEP reconstruction only, the tissue from the DIEP may contain lymph nodes that can potentially augment lymphatic flow when tucked into the axilla during reconstruction (16,22).

Current evidence supports the use of VLNT in treating BRCL, especially in patients with ISL stage II or III lymphedema. The mechanism of action of VLNT is theorised to involve both a “lymphatic wick” effect, suggesting regeneration of spontaneous connections, and a “lymphatic pump” effect, proposing an intrinsic lympho-venous shunt within the transferred nodes. This theory is supported by an earlier rat model study by Cheng et al., who demonstrated the rapid diffusion of dye towards the vascularized lymph nodes (34). In contrast, a canine model study by Suami et al. appears to support the alternative theory of “bridging” by using VLNT to encourage the generation of new lymphatic channels in the implanted area (35). Interestingly, Saaristo et al. found that transferred lymph nodes express high levels of endogenous lymphatic vessel growth factors, which may induce regrowth of the lymphatic network. Their study suggests that these growth factors may have contributed to the growth of the new lymphatic channels in VLNT (22).

Moreover, on a cellular level, Viitanen et al. compared the production of cytokines in patients undergoing combined DIEP and VLNT procedures against those undergoing VLNT-only procedures or DIEP-only procedures. Not only did they discover that VLNT increased the production of prolymphangiogenic growth factor vascular endothelial growth factor-C, but they also observed that anti-inflammatory and antifibrotic cytokine interleukin-10 was up-regulated in the combined group. They concluded that the transfer of healthy tissue inhibits the proinflammatory response after surgery (36). This finding was also observed in the study by Montag et al., where patients who underwent combined procedures were more likely to experience a reduction in recurrent BRCL-related cellulitis (17).

Variability in outcomes

Outcomes following VLNT can vary among patients and across different studies, as reflected in our results. While most studies report improvements in arm volumes, others fail to show significant improvements in their measurements (11,12,17,19,21). Factors such as the stage of lymphedema, surgical technique, choice of donor and recipient sites, and postoperative management can influence the results. It is essential to note that while surgery may be proposed as the future of treatment for BRCL, conservative complex decongestive therapy, including manual lymphatic drainage, compression therapy, skin care and exercise, has been demonstrated to improve outcomes (6). While many studies reported promising early and mid-term outcomes, longer-term data are still required to fully understand the sustainability of the benefits and potential late complications of VLNT.

Our findings align with prior reviews, such as that conducted by Gasteratos et al., which included lymphaticovenous anastomosis (LVA) for lymphedema prophylaxis. However, the present review provides a more focused and in-depth evaluation of VLNT specifically as a therapeutic intervention for BCRL, thereby offering greater clarity on its clinical efficacy and role in reconstructive practice (37).

Limitations

A key limitation of this review is the reliance on the NOS for assessing study quality. While the NOS is widely used for evaluating observational studies, its domains are relatively narrow and do not fully capture all potential sources of bias relevant to surgical research, such as reporting bias or technical variability between centres. Moreover, many of its criteria require subjective interpretation, which may introduce variability between reviewers despite efforts to standardise scoring. The lack of established thresholds to categorise studies as “high” or “low” quality further complicates interpretation, and the equal weighting of all items does not reflect the differing impact of specific biases on study validity. Finally, compared with more recent tools such as ROBINS-I, the NOS provides a less nuanced assessment of bias, which may limit the robustness of quality appraisal in this context.

The included studies are also highly heterogeneous and mostly retrospective in nature. Differences in outcome reporting and varying sample sizes would have increased the risk of bias when consolidating the findings into a meta-analysis. Furthermore, the variability in follow-up in our included articles—25 months (range 6–70 months)—may result in under-reporting of long-term outcomes (>3 years) related to BRCL.

Conclusions

This systematic review represents the most comprehensive and up-to-date synthesis of evidence regarding the integration of VLNT with DIEP flap breast reconstruction. Our systematic review also highlights that combining VLNT abdominal-based flap breast reconstruction, such as the DIEP, offers a unique opportunity to address both aesthetic and functional challenges in patients with BCRL. Evidence suggests that this combined approach not only restores breast mould but also improves lymphatic function, reduces the risk of cellulitis, and enhances QOL, particularly in patients with moderate to advanced disease, by reducing their reliance on compression therapy. Moreover, donor-site selection, surgical technique, and adjunctive measures such as reverse lymphatic mapping remain critical to optimising outcomes and minimising complications.

Nevertheless, current evidence is limited by small, retrospective cohorts and variable follow-up, underscoring the need for larger prospective studies with standardised outcome measures and long-term evaluation. Future research should also focus on refining patient selection criteria, improving donor-site safety, and further elucidating the biological mechanisms underlying VLNT. Until such data become available, VLNT combined with DIEP flap reconstruction should be considered a promising but evolving option in the multidisciplinary management of BCRL.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://abs.amegroups.com/article/view/10.21037/abs-25-25/rc

Peer Review File: Available at https://abs.amegroups.com/article/view/10.21037/abs-25-25/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://abs.amegroups.com/article/view/10.21037/abs-25-25/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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