Vascularized Lymph Node Transfer for Patients with Breast Cancer-Related Lymphedema Can Potentially Reduce the Burden of Ongoing Conservative Management

Abstract

Background:

Vascularized lymph node transfer (VLNT) microsurgery is conducted in selected specialist lymphatic programs as a surgical treatment option for breast cancer-related lymphedema (BCRL) with variation in treatment outcomes.

Methods and Results:

Ten patients with BCRL underwent VLNT from 2012 to 2015. Donor sites were the inguinal (n = 6) or supraclavicular fossa/neck (n = 4) regions and recipient sites were the axilla (n = 6) or elbow regions (n = 4). Outcomes included changes in limb volume and extracellular fluid ratios, postoperative garment use, number of cellulitis episodes, and self-reported symptom improvement. At a mean follow-up of 46 months from surgery (range: 28–66 months), the excess volume in the affected arm had reduced (n = 4) or remained stable (n = 1) for 5 of 10 patients (50%) (mean change: −106.4 mL, range: −515.5 to +69.6 mL). Four of these five patients had also reduced (n = 3) or discontinued (n = 1) wearing compression garments and three reported a reduction in episodes of cellulitis. The remaining five patients had an increase of over 100 mL in postoperative excess volume (mean change: 295.8 mL, range: 142.1–382.8 mL). Three of these five patients reported noncompliance with compression garments. Despite the increase in limb volume, some patients reported softness in swelling (n = 3) and better response to conservative treatment (n = 1).

Conclusion:

Our results warrant continuation of VLNT as a surgical treatment option for patients with BCRL and show that the burden of conservative management such as wearing garments can be reduced over time for some patients. Longer term follow-up with standardized measures across all centers is required to further investigate VLNT.

Introduction

Breast Cancer-Related Lymphedema (BCRL) resulting from removal of, or damage to, axillary lymph nodes during dissection and/or radiation is a devastating complication impacting function and quality of life.^1–3 Surgery is sometimes pursued to slow or halt progression of the disease with the aim of improving lymphatic flow, reducing the burden of conservative treatment modalities, and decreasing the incidence of cellulitis.^4,5

Surgical options, including physiological procedures for early-moderate lymphedema or debulking procedures for advanced lymphedema, are being increasingly used for patients with BCRL, but with varying results.^6–10 Vascularized lymph node transfer (VLNT) surgery involves microsurgical transfer of healthy lymph nodes with anastomoses of source vessels to the affected limb.¹¹ VLNT aims to improve lymph transport and drainage, delay the formation of fibrotic and adipose tissue, and reduce infection and compression garment use.^12,13 Nodal tissue can be harvested from the inguinal,^13,14 supraclavicular,¹⁵ submental,¹⁶ thoracic, or omental regions.¹⁷ For treatment of arm lymphedema, the lymph node flap is transferred to the wrist, elbow, or axilla.^{13,14,16–18}

Most publications measure improvement after VLNT as a reduction in circumference in centimeters (cm) or as a reduction in excess volume in milliliters (mLs), between the affected and unaffected arm. However, there is variation in measurement points on the limb, formulae used, and values reported. A systematic review of more than 300 patients who had undergone VLNT reported that over 85% had some improvement in outcome. Mean circumferential reduction rates reported ranged from 24% to 64%.¹⁹

This study reviews our medium- to long-term experience of the first 10 patients with BCRL, who underwent VLNT surgery at Macquarie University Hospital in Sydney with a minimum follow-up period of 24 months that included physical examination, volume measurement, bioimpedance spectroscopy (BIS), imaging, and self-report. To date, this is the only study that has attempted to follow all patients closely with multimodality surveillance, multiple parameters, and close observation intervals (up to 5 years).

Materials and Methods

Participants and assessments

The study comprised 10 consecutive patients with BCRL who underwent VLNT at Macquarie University Hospital between August 2012 and June 2015 by a single surgeon (Q.D.N.). Eligible female patients had early to moderate stage I-II lymphedema²⁰ and had completed maximal conservative therapy. Medical/lymphedema history, cellulitis details, height and weight, excess limb volume, and BIS values were recorded using the U400^® device (ImpediMed, Brisbane, Australia).^21,22

Excess volume (absolute volume difference between the affected and unaffected arm) was the primary outcome measure derived from 4-cm-circumference measurements as recommended by the International Society of Lymphology.^23,24 The U400 device produces a lymphedema-index (L-Dex^®) value that represents the difference in impedance between the affected and the unaffected upper limb. Clinically, L-Dex values recorded at regular time intervals to observe trend line variation may indicate a change in extracellular fluid or tissue composition of the affected limb. A postoperative change in L-Dex of <10 points or excess volume of <100 mL was considered stable.²⁵

All patients had preoperative radionuclide lymphoscintigraphy at 6–12 months postsurgery to evaluate lymphatic drainage patterns and tracer uptake in lymph node basins.²⁶ Although subjective, demonstrated tracer uptake in the recipient nodal basin, reduced dermal backflow, or reduction in transit time to the axilla, compared with the preoperative scan, were considered an improvement. Patients also underwent ultrasound assessments at 6–12 months postsurgery to evaluate the viability of lymph nodes at the recipient sites.

Decisions about eligibility for surgery were made at our multidisciplinary team meetings following detailed evaluation of assessments. Information about their previous radiation treatment details was limited as patients came from all across Australia to our clinic. Patients who received radiation knew the extent to the breast or chest-wall but usually not the extent of regional node irradiation. The multidisciplinary team included representatives from rehabilitation medicine, oncology, plastic surgery, physiotherapy, and occupational therapy. Patients were informed that the lymphatic surgery could not guarantee improvement, and that the aim would be to control the lymphedema rather than to reverse or cure the disease process.

Discussions were held with patients to manage their expectations of realistic surgical outcomes, especially regarding the need for ongoing conservative management following surgery. The risk of donor-site lymphedema and the possibility of postoperative infection were also discussed.

Surgical protocol

Initially, only inguinal node harvests were offered. However, after the first year, patients were considered for a supraclavicular fossa (SCF) node harvest due to reported concerns of donor-site lymphedema in the groin.^27,28 Groin nodes were harvested either in isolation (with and without attached skin monitoring paddle) (n = 5) or as an extension of the abdominal skin flap used for breast reconstruction for one patient.²⁹ The nodal tissue harvest was taken below the inguinal ligament, at or above the inguinal crease and lateral to the femoral vessels as previously described.¹³

Supraclavicular VLNT involved the harvest of level Vb nodal flap through a 5 cm incision along the base of the neck, based on either transverse cervical or supraclavicular vessels (n = 4).^30,31 No monitoring skin paddle was attached. Initially, there was a preference for harvesting the flap from the right side to avoid any iatrogenic injury to the thoracic duct, but with increased experience, nodal harvest was done on the opposite SCF to the patient's treated breast cancer, with care taken to avoid the thoracic duct when harvesting on the left neck. Research suggests that there is a relatively low risk of donor-site lymphedema in this region.³⁰

Follow-up assessment and care after surgery

Hospital stays were 4–7 days with priority given to wound care and healing. Prophylactic antibiotics were given perioperatively and continued for 3 days. The practice of harvesting a monitoring skin paddle was abandoned as it was found to be unreliable. Instead, a Cook–Swartz implantable Doppler probe was routinely used for the subsequent five patients to monitor flow across the flap artery using a transducer attached to a silicone cuff wrapped around the vessel that gave an audible signal with active flow.³²

Surgical drains were routine for both donor and recipient sites. A compression garment was avoided for a minimum of 2 weeks and both limb elevation and rest were advised, although gentle movement was allowed. Upon discharge, gentle lymphatic massage was permitted in the direction of lymphatic drainage toward the axilla and SCF, with care taken to avoid direct pressure on the lymph node flap during the first 4 weeks. After 4 weeks, lymphatic drainage massage could also be directed toward the transferred lymph nodes. The patient was advised to continue wearing garments for at least 12 months after surgery, with new garments every 6 months starting with their preoperative garment provided it was in good condition.

Patients were followed up with volume and BIS measurements at 1, 3, 6, and 12 months after surgery and biannually thereafter. After 12 months, patients with a stable condition could reduce the frequency of garment wear on a trial basis and potentially wean off the garment if limb volume did not increase. However, they were encouraged to continue with their other preoperative treatment modalities such as lymphatic drainage massage, exercises, and pneumatic compression pump as required.

Volume and BIS measurements taken at 1 year after surgery (with a window of 8 to 13 months) and at last available follow-up have been reported here. Subjective reports on changes in symptoms and conservative management regimen were obtained with open- and close-ended questions and via e-mailed/online surveys and from patient medical records. This included the Patient Specific Functional Scale, a self-reported patient outcome measure designed to assess patients' functional ability across three specific activities identified by the patient (results not reported due to small sample size). Changes in conservative management were recorded, including frequency and intensity of compression garment wear and number of cellulitis episodes.

Results

Ten female patients with a mean age of 51 years (range: 43–59) with BCRL underwent VLNT surgery. Two patients had undergone breast conservation surgery and eight had undergone a total mastectomy. All 10 patients underwent axillary lymph node dissection and chemotherapy and 8 had adjuvant radiation treatment (Table 1).

Table 1.

Changes in Limb Volume, Bioimpedance Spectroscopy, Lymphoscintigraphy, and Self-Reported Outcomes Compared with Preoperative Assessment (Sorted by Absolute Change in Excess Volume at Last Follow-Up Assessment)

Patient information				Excess volume			BIS (L-Dex value)			Use of compression garment compared with presurgery ≠	Improvement in LSG findings compared with presurgery	Subjective report by patients
Patient ID	Age (years)	LE duration (months)	FU time (months)	Presurgery affected limb^b	Last FU affected limb^b	Absolute change (% change)	Presurgery	Last FU	Absolute change (% change)	Use of compression garment compared with presurgery ≠	Improvement in LSG findings compared with presurgery	Softer arm	Swelling resolves more quickly	Swelling responds better to conservative treatment
10	51	24	30	815.3	299.8	−515.5 (−63)	48.7	8.2	−40.5 (−83)	Reduced from daily class 2 to weekend only and class 1	Yes	Yes
4	52	48	67	721.9	579.3	−142.6 (−20)	48.7	58.1	9.4 (19)	Reduced from day time 7 to 5 days a week/4 hours a day	Yes		Yes
5	49	72	40.8	309.7	257.8	−51.9 (−17)	23	14.5	−8.5 (−37)	Reduced from wearing garment sometimes plus bandaging to no garment	Yes	Yes
7	50	48	57.6	598.1	555.3	−42.8 (−7)	14.6	9.0	−5.6 (−38)	Reduced from 24/7 compression to 12/7	Yes	Yes		Yes
3	43	54	34.8	618.4	688	69.6 (11)	43	41.5	−1.5 (−3)	No change	Yes
1	58	9	66	542.8	684.9	142.1 (26)	39.7	33.3	−6.4 (−16)	Reduced from daily garment to no garment	Yes	Yes	Yes
2	44	17	27.6	225.7	483.1	257.4 (114)	16	26.2	10.2 (64)	No change	No
8	59	12	37.2	455.3	761.7	306.4 (67)	28	26.3	−1.7 (−6)	Reduced from daily class 2 to class 1 some days per week	N/A	Yes
9	61	4	50.4	311.2	648.9	337.7 (109)	58.4	4.0	−54.4 (−93)	Reduced from daily class 2 sleeve to occasional sleeve	Yes	Yes
6	47	42	52.8	383.7	766.5	382.8 (100)	44.7	53.5	8.8 (20)	Reduced from 16 hours a day to no garment	No	Yes	Yes	Yes

Patient ID: chronological order by date of surgery (1 = first patient, 10 = last patient). Patients 1, 2, 3, 4: VLNT from inguinal region to axilla; Patients 5, 7, 10: VLNT from supraclavicular region to cubital region; Patient 6: VLNT from supraclavicular region to axilla; Patient 8: VLNT transfer from inguinal region (+DIEP flap) to axilla; Patient 9: VLNT from inguinal region to cubital region.

BIS, bioimpedance spectroscopy; DIEP, deep inferior epigastric perforator; FU, follow-up; LE, lymphedema; LSG, lymphoscintigraphy; N/A, not applicable; VLNT, vascularized lymph node transfer.

Lymphedema affected the dominant arm in nine patients. The duration of BCRL ranged from 9 to 72 months (mean, 33 months) and all patients had stage II lymphedema. All patients were using one or more conservative modalities that included a combination of compression garments, skin care, exercise, manual lymphatic drainage, pneumatic compression pump, and/or bandaging sessions. Four patients (40%) reported having one or more cellulitis episodes before surgery.

At a mean follow-up time from surgery of 46 months (range: 28–66 months), the excess volume in the affected arm had reduced or remained stable for 5 of the 10 patients (50%) (mean change: −106.4 mL, range: −515.5 to +69.6 mL) (Table 1). Four of these five patients had also reduced (n = 3) or discontinued (n = 2) garment use and three reported a reduction in the number of cellulitis episodes. Most of these respondents (n = 4) also reported that their arm was softer and that any transient swelling tended to be “less severe.” Two patients indicated that they no longer felt the “aching feeling” that was noted preoperatively and one noted that the arm responded better to conservative treatment modalities such as pneumatic compression pump and manual lymphatic drainage.

The remaining five patients had an increase in excess volume of over 100 mL at their last follow-up compared with preoperative measures (mean change: +295.8 mL, range: +142.1 to +382.8 mL). Three of these five patients reported reduced garment use but continued with other treatment modalities such as lymphatic massage and/or pneumatic compression pump. Despite the increase in limb volume, 7 of the 10 patients (70%) reported that their arm was softer, 3 reported quicker resolution of swelling, and 2 patients reported they had better response to conservative treatment (Table 1).

Changes in L-Dex values corresponded well with changes in volume measures for the five respondents whose volume measures improved or remained stable, but less so for the remaining patients. Seven patients had a reduced L-Dex value at last follow-up and six of these patients had reduced (n = 4) or no garment use (n = 2) (Table 1).

There were minimal postoperative complications. One patient had a postoperative infection that resolved with antibiotics and two patients had temporary proximal thigh edema that resolved by 12 months. Patients who had an SCF nodal flap generally had a small area of numbness due to division of the cutaneous branches of the cervical nerves that improved with time.

Ultrasound imaging was conducted to assess the number of viable lymph nodes in the recipient site at 6 months (and repeated in some patients at about 12 months) after surgery. Two or more lymph node nodes were detected in flaps harvested from the supraclavicular region, compared with one or none detected in flaps harvested from the groin area. Ultrasound was able to detect lymph nodes in seven of the nine patients evaluated. Of note, detection of nodes on ultrasound is difficult and dependent on operator experience, and so, the absence of nodal visualization is not necessarily indicative of node absence.

Follow-up nuclear lymphoscintigraphy assessments conducted at ∼6–12 months postsurgery reported some improvement in the scan findings of all five patients with stable or improved volume measures and for two patients with increased volume (Table 1).

Discussion

This report details our medium- to long-term experience of treating 10 consecutive patients with BCRL with VLNT, followed for a mean follow-up time of almost 4 years. For carefully selected patients, this surgical treatment has the potential to reduce lymphedema progression, symptom severity, cellulitis frequency, and garment use.

The two key theories hypothesized to explain the mechanism of action after VLNT are “lymphangiogenesis” and the “lymph pump” theory.³³ Lymphangiogenesis is the process of forming of new lymph vessels between the transferred tissue and the recipient area, a process that is thought to be stimulated by growth factors and cytokines produced from the transplanted lymph nodes and inflammatory cells.^18,34–36 The other hypothesis is that the transferred lymph nodes act as a pump and suction pathway for lymphatic clearance.^14,37 In addition, the release of scar tissue at the recipient site is thought to assist lymph flow and drainage.³⁸

The results of VLNT are variable and this is, at least in part, due to differences in patient selection, preoperative, intraoperative, and postoperative techniques, and methods of evaluation. Institutions vary in how lymphedema is measured; some report mean reduction in circumference, while others report mean reduction in limb volume. In addition, reduction in the number of cellulitis episodes, improvement in lymphoscintigraphy findings, subjective improvement of symptoms, and reduced need for lymphedema therapy and compression garments are sometimes reported (Table 2). We have found this group of patients to be highly motivated to find a solution that does not involve continuous use of a compression garment. Our surgical assessment and imaging protocol are reported elsewhere.³⁹

Table 2.

Studies of Vascularized Lymph Node Transfer for Patients with Breast Cancer-Related Lymphedema

Location	Year	Case series study design	No.	Time period	Donor site (No.)	Recipient site (No. of patients)	Mean FU time (months)	Outcome measure	Presentation of results	Proportion of patients who showed improvement as per study assessment criteria
France¹³	2006	Retros	24	1991–1997	Groin	Axilla (17); Axilla + elbow (7)	100	Circ (four points)	Percent decrease in upper limb perimeter	More than 50% improvement in 66.7% of patients
Taiwan¹⁴	2009	Retros	13	1997–2005	Groin	Wrist	56	Circ (10 cm proximal to elbow joint)	Mean circumference reduction: 50.6%	Some circumference reduction in 92.3% patients; two patients had additional surgery^b
Finland¹⁸	2012	Retros	9	2008–2010	Groin (DIEP^b)	Axilla	6	Circ (two points on arm)	Reduction in any measurement point ≥1 cm considered “improvement”	“Improvement” in 77.8% of patients
Taiwan¹⁶	2013	Prosp Case/ control	10	2009–2011	Groin	Wrist (8); elbow (2)	39	Circ (two points on arm)	Mean circumferential reduction rate: 40.4%	Reduction in upper arm circumference in 80% of patients
China⁴⁹	2014	Retros	10	2008–2011	Groin	Axilla	12	Mid-upper arm circ	Mean circumference reduction: 2.12 ± 2.33 cm	Reduced circumference in 88.9% of patients
USA⁵⁰	2015	Retros	29	2011–2013	Groin (DIEP^a)	Axilla	11	Mean differential volume change	Mean reduction of differential volume: 21% to 11%	“Sustained improvement” in 79% of patients
USA⁴⁰	2017	Prosp	24	2013–2015	Groin	Axilla	12	Volume from circ (4-cm intervals)	Mean reduction rate in differential volume of 42.7%	N/A
Australia (this study)	2019	Retros	10	2012–2015	Groin (6) Neck (4)	Axilla (6); elbow (4)	47	Volume from circ (4-cm intervals)	Decrease in absolute excess volume or <100 mL increase considered “stable”	Improved/stable condition in 50% of patients
								BIS	≤10-point increase in L-Dex value considered stable	Improved/stable condition in 90% of patients

Donor-site groin and combined with DIEP flap breast reconstruction surgery.

Suction lipectomy/wedge excision.

Circ, circumference; No., number of patients; Prosp, prospective case series; Retros, retrospective case series.

In our study, we chose to examine absolute volume measures using a truncated cone volume calculation and considered stability to be no more than an increase of 100 mL in excess volume between the affected and unaffected side over baseline. Five of the 10 patients (50%) had stable or reduced lymphedema after a mean follow-up period of 46 months. Furthermore, most patients also had reduced or stable L-Dex values (no more than 10 units of increase from baseline). Reduced L-Dex values indicate that there is relatively less extracellular fluid in the affected arm. Of note, however, is that as lymphedema progresses and the amount of fat and fibrotic tissue increases, it is likely (as for patients 6, 8, and 9) that arm volume may increase without a parallel increase in the L-Dex value.⁴⁰

As well as volume measurements, there is increasing recognition of the importance of subjective measures and patient-reported outcomes, as well as imaging assessments, when evaluating surgical treatment outcomes.^13,19,41,42 Regardless of change in limb size, the majority of patients in this series reported subjective improvement such as softness in their limb. Some also noted increased responsiveness to conservative management and faster reduction of swelling. More than half the patients in this series reported that they had either reduced their use of compression garments or no longer felt the need to wear garments to control their swelling.

The heterogeneity of donor and recipient sites in this series did not allow for detailed evaluation of any one site. Two of our patients developed temporary thigh edema, which eventually settled. For this pilot study, the technique of reverse lymphatic mapping to minimize risk of donor-site lymphedema, which is our current practice, had not been instituted. While the vascular anatomy of the supraclavicular flap is fairly constant, considerable fluctuations in lymph node count were noted by Steinbacher et al.⁴³

Other donor-site options have been suggested, including the submental region and the omentum.^16,44,45 In our practice, we have become increasingly inclined toward using the supraclavicular region as the donor site because of the dual benefits of a minimal risk of donor-site lymphedema and a relatively inconspicuous scar owing to the anatomical location (Fig. 1). A recent study explored the correlation between the quantity of transferred lymph nodes and outcomes in patients undergoing submental VLNT for lower limb lymphedema.⁴⁶ Their findings suggested a significantly greater improvement in circumferential difference in flaps with three or more lymph nodes. Some animal studies have also suggested this correlation.⁴⁷ From the surgeon's personal experience in neck dissection and anatomical studies,⁴⁸ level Vb of the neck (supraclavicular region) has higher nodal yield than level 1 (submental region). Other benefits include a more discrete scar compared with other donor sites and a longer vascular pedicle length compared with the submental flap.

FIG. 1.

VLNT from supraclavicular fossa (donor site) to cubital fossa (recipient site). (a) Location of recipient site in medial right elbow region. (b) Harvesting VLNT from right lower neck. (c) Donor-site scar 3 years after VLNT. (d) Right hand and forearm edema before VLNT. (e) Right hand and forearm edema 3 years after VLNT. VLNT, vascularized lymph node transfer. Color images are available online.

The actual donor site is less relevant to the discussion. Rather it is the nodal count that is more pertinent in a discussion of lymph node transfer and its efficacy. There is no actual boundary to the groin or neck regional node, and so, the number of nodes harvested may vary from case to case even within the same anatomical region. For this reason, we attempted to quantify the nodal harvest with postoperative ultrasound. This was not always successful due to a number of reasons ranging from sonographer experience to postoperative scarring, edema, size variation of nodes, and so on.

Initially, we placed the nodal flaps in the ipsilateral axilla and, for later cases, nodal flaps were placed more distally in the limb just proximal or distal to the elbow joint on the medial side, being closer to the area of maximal edema. The different practices are due to two theoretical explanations of the mechanism of action: (1) the lymph node flap reduces scarring and repairs local lymphatic damage and (2) the lymph node flap acts as a lymphatic pump by collecting nearby lymphatic fluid/osmotically active particles and passing them into the venous system within the nodes explained above.³⁸ Our personal experience from the study cohort and subsequent cases suggests that distal node placement is more effective except where there is extensive proximal scarring at the axilla, in which case scar release/excision is performed and the lymph node flap is placed within the area of scar release to reduce recurrence of scar contracture.

Ultrasound imaging was performed postoperatively with the aim of detecting the number of functioning lymph nodes at the recipient site. In this series, it was difficult to establish whether the number of lymph nodes detected by ultrasound correlated with relatively better surgical outcomes. A recent cadaver study highlighted the limitation of ultrasound imaging in detecting very small lymph nodes due to the confusion of similar-looking fat lobules and indicated that the actual detection rate can be as low as 26%.⁴⁹

Potential complications of this surgery include development of lymphedema in the donor site, flap loss, infection, and bulkiness at the recipient site,⁵ but complications are rare.²⁷ In our case series, two patients who had a transfer from the groin area reported mild donor-site lymphedema that resolved in time and another patient had a postoperative infection that resolved promptly with antibiotics.

There are some limitations to this study apart from the small sample size. Although there were improvements reported on lymphoscintigraphy in many patients in our study, these results should be interpreted with caution. Comments were made concerning the changing presence of dermal backflow in some areas and the speed of migration of the contrast, but there was no standardized or precise way of recording such changes. Second, as the reporting radiologist could not be blinded to the presurgery scan, an inherent bias toward reporting an improvement is possible. However, we had the benefit of evaluating follow-up data, including volume measures, BIS, and self-management reports over a mean of 4 years (minimum 24 months).

Positive self-reports from patients in relation to symptom relief, reduction in the incidence of cellulitis, reduced garment use, and more responsive and less frequent conservative management required to manage this chronic condition provide an impetus to conduct further investigation into VLNT surgery as a carefully selected treatment option within a multidisciplinary setting.

Ethical Statement

The procedures followed were in accordance with the Ethical Standards of the Responsible Committee on Human Experimentation (Institutional and National) and with the Helsinki Declaration of 1975, as revised in 2008. The research was approved by the Macquarie University Human Research and Ethics Committee (Reference No. 5201300315).

Footnotes

Acknowledgments

The authors thank Philippa Sutton for editorial assistance with the preparation of this article and all our clinical and therapy staff at the ALERT clinic.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received.

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