Outcome Analysis of Combined Surgical Approaches in Advanced-stage Upper Extremity Breast Cancer-related Lymphedema

Abstract

Background:

This study aimed to discuss several surgical approaches for advanced-stage breast cancer-related lymphedema and compared their treatment outcomes.

Methods:

The patients who underwent surgery with International Society of Lymphology stage III lymphedema were included in this study. The three surgical methods used here were (1) suction-assisted lipectomy with lymphovenous anastomosis, (2) autologous breast reconstruction with muscle-sparing transverse rectus abdominis muscle flap combined with inguinal lymph node transfer, and (3) vascularized lymph node transfer with free omental flap. Analysis of the postoperative outcomes in the patients was based on the difference in volume between patients pre- and postoperatively, LYMPH-Q questionnaire, and bioelectrical impedance analysis.

Results:

Eighty-seven patients with stage IIb or higher disease underwent surgery. 38 patients underwent suction-assisted lipectomy + lymphovenous anastomosis, 23 underwent autologous breast reconstruction with vascularized lymph node transfer + lymphovenous anastomosis, and 26 underwent right gastroepiploic omental vascularized lymph node transfer with lymphovenous anastomosis. The LYMPH-Q questionnaire, which evaluates patients’ subjective satisfaction, showed that the autologous breast reconstruction group showed the greatest improvement, whereas in bioimpedance analysis, the omental flap group demonstrated the greatest postoperative improvement compared with preoperative values. However, suction-assisted lipectomy was considered the most effective surgical method for reducing limb volume in patients with high-stage lymphedema accompanied by fibrosis and volume increase.

Conclusions:

We observed slightly different clinical effects for each surgical method; however, all surgical methods demonstrated a reduction in the degree of edema and an increase in patient satisfaction.

Takeaways

Question: We compared the treatment outcomes of surgical approaches for advanced-stage breast cancer-related lymphedema.

Findings: The LYMPH-Q questionnaire, which evaluates patients’ subjective satisfaction, showed that the autologous breast reconstruction group showed the greatest improvement, whereas in bioimpedance analysis, the omental flap group demonstrated the greatest postoperative improvement compared with preoperative values. However, suction-assisted lipectomy was considered the most effective surgical method for reducing limb volume in patients with high-stage lymphedema accompanied by fibrosis and volume increase.

Meaning: We observed slightly different clinical effects for each surgical method; however, all surgical methods demonstrated a reduction in the degree of edema and an increase in patient satisfaction.

INTRODUCTION

Breast cancer-related lymphedema is one of the recognized reasons for the greatly reduced quality of life of survivors of breast cancer treatment.¹ Although many advances have been made in preventing, diagnosing, and treating lymphedema, its cure remains a clinical challenge.² However, microsurgery technology has greatly advanced since the 1990s, and since then, surgical treatment of breast cancer-related lymphedema has also greatly evolved. Furthermore, after the efficacy of lymphovenous anastomosis (or lymphovenous bypass) was recognized by Koshima,³ many subsequent studies have consistently demonstrated the effectiveness of lymphovenous anastomosis for breast cancer-related lymphedema treatment.^4,5

As lymphedema progresses, lymphatic vessels undergo a deterioration process, which leads to the narrowing of the lumen and a decrease in contractility due to repeated inflammation and fibrosis.^2,6–8 Moreover, since lymphovenous anastomosis is a procedure that effectively bypasses functional lymphatic vessels with veins, effective lymphovenous anastomosis implementation is difficult in advanced-stage lymphedema due to advanced lymphatic deterioration.^9,10 Consequently, in such cases, vascularized lymph node transfer (VLNT) through the free flap technique, in which lymph nodes collected from other parts of the body are transplanted to the edematous limb where lymphedema is occurring, has recently gained popularity, with various studies demonstrating its clinical usefulness.^11,12 Moreover, the physiological background of lymph node transfer has been elucidated through recent basic research.^13,14 Although several donor sites have been introduced and results have been reported, similar clinical outcomes and surgical risks have been reported for lymph node transfer from each donor site.^15–17

Liposuction is the most common debulking surgery performed in patients with advanced-stage lymphedema and is a safe and effective option for advanced disease. It can reduce the fatty and fibrous tissue that cannot be removed otherwise. However, there are concerns that liposuction may damage the remaining normal lymphatic structures. In addition, it is difficult to evaluate the procedure’s surgical outcomes because they may vary depending on postoperative care.

Among the several surgical approaches for advanced-stage breast cancer-related lymphedema, our institution currently selects surgical methods based on decision-making algorithms in accordance with a patient’s situation or need. The types of operative methods available are (1) suction-assisted lipectomy with lymphovenous anastomosis, (2) autologous breast reconstruction with deep inferior epigastric perforator, or muscle-sparing transverse rectus abdominis muscle flap combined with inguinal lymph node transfer, and (3) VLNT with free omental flap. This study aimed to discuss these methods and compare the treatment outcomes of these three combined surgical approaches.

METHODS

From April 2020 to April 2022, patients who underwent surgery at the lymphedema clinic of the Department of Plastic and Reconstructive Surgery at Seoul National University Bundang Hospital diagnosed with International Society of Lymphology stage IIb and III lymphedema were included in this retrospective outcomes study. All patients exhibited grade 3 lymphedema on preoperative lymphoscintigraphy and stage III or higher arm dermal backflow stage on ICG lymphography.^18–20 Additionally, dermal thickening and subcutaneous infiltration over a 50% circumference on noncontrast magnetic resonance imaging examination also accompanied magnetic resonance imaging stage III lymphedema.¹⁸ Furthermore, patient information such as sex, age, preoperative risk factors, and cellulitis history was collected through electronic medical records and analyzed.

SURGICAL OPTIONS

Patients could select from three surgical methods according to their clinical situation and personal needs through adequate preoperative consultation (Fig. 1). Based on the surgical options, the patients were grouped as follows:

Fig. 1.

Diagram of operative method selection for advanced-stage breast cancer-related lymphedema.

1. Patients who did not want to undergo general anesthesia and free flap surgery with mild contractures of the axilla and desired volume reduction through lipectomy of the involved limb: Combined suction-assisted lipectomy + lymphovenous anastomosis (SAL+LVA group, Fig. 2). Lymphovenous anastomosis was primarily performed on the forearm distal to the elbow after indocyanine green lymphography mapping and ultrasound examination, whereas liposuction was mostly performed on the upper arm. When liposuction of forearm was needed, Great care was taken to ensure that the scope of the two procedures did not overlap. Two to four end-to-end anastomoses were performed at various locations distal to the elbow.

2. Patients who were actively seeking delayed breast reconstruction simultaneously with surgery for lymphedema: autologous breast reconstruction using deep inferior epigastric perforator/transverse rectus abdominis muscle flap with simultaneous VLNT with superior circumflex iliac artery perforator or superficial inferior epigastric artery flap with combined lymphovenous anastomosis (MSTRAM+VLNT group, Fig. 3.). One or two sites of end-to-end lymphovenous anastomosis were done separately at the forearm before the free flap surgery.

3. Patients who did not want breast reconstruction but required VLNT due to severe axillary contracture from previous lymphadenectomy and radiation: VLNT with right gastroepiploic artery-based omental flap with combined lymphovenous anastomosis (omental VLNT group, Fig. 4). Lymphovenous anastomosis was also done at the forearm separately.

Fig. 2.

Combined suction-assisted lipectomy with lymphovenous anastomosis. A, Preoperative patient photograph with indications for suction-assisted lipectomy with lymphovenous anastomosis. B, Postoperative photograph 3 months later.

Fig. 3.

Combined suction-assisted lipectomy with lymphovenous anastomosis. A, Preoperative patient photograph with indications for suction-assisted lipectomy with lymphovenous anastomosis. B, Postoperative photograph 3 months later.

Fig. 4.

Patient photograph with indications for omental VLNT. The patient had symptoms from axillary fibrosis due to previous lymphatic dissection and radiotherapy sessions. A, Preoperative patient photograph with indications for for omental VLNT. B, Intraoperative photograph after vessel anastomosis. C. Immediate postoperative photograph. The wound is closed without tension.

POSTOPERATIVE OUTCOME EVALUATION

Analysis of the postoperative outcomes in the patients was based on three factors.

1. The difference in volume between patients pre- and postoperatively: The circumference of the affected/unaffected arm of the patients was measured at 10 cm above the elbow, at the elbow, at the bottom 10 cm and 20 cm, and at the back of the hand using a standardized measuring tape. The segmented volume was measured using the truncated cone method.¹⁹ After measuring both sides in the same manner, the change in the percentage difference was analyzed based on the unaffected side. Volumes measured preoperatively, at 6 months, and at 1 year postoperatively were compared based on the measured volumes.

2. LYMPH-Q questionnaire administered at 6 months and at 1 year postoperatively: The results of patient-related outcome measured preoperatively, at 6 months, and at 1 year postoperatively in patients with lymphedema were collected and analyzed. The Lymphedema Functioning, Disability, and Health Questionnaire for Upper Limb Lymphedema, which has been validated²¹ and underwent cross-cultural validation,²² was translated into Korean in our department, and the patients’ responses to the questionnaire were recorded. The Lymphedema Functioning, Disability, and Health Questionnaire for Upper Limb Lymphedema consists of five sections (physical symptoms, physical strength, mental health, daily activity, and social activity), including 29 questions and scores from 0 to 10. The total score is calculated as [(sum of scores on all questions/29 – number of questions not answered) × 10] for each question. The total scores were individually measured, compared, and analyzed.

3. Bioelectrical impedance analysis: The ratio of extracellular fluid was measured using a bioelectrical impedance analyzer (Inbody S10 Biospace device, Inbody Co. Ltd., Seoul, South Korea), and was analyzed at each regular outpatient visit. Bioelectrical impedance analysis is used to analyze the ratio of extracellular water in various parts of the human body. The amount and ratio of water in each limb are measured as relative values to the total amount of water in the body. The impedance ratio between the arm affected with lymphedema and the contralateral normal arm was obtained through single-frequency bioimpedance analysis measurements at 1 and 5 kHz. This ratio indicates an increase in impedance in the affected arm with lymphedema compared with that in the normal side, which is proportional to the increase in extracellular water in the edematous arm.^23,24

STATISTICAL ANALYSIS

For descriptive variables, each statistic was reported as mean ± SD or frequency for each group. To compare categorical variables between the groups, the values of each group were analyzed using Fisher exact test. One-way analysis of variance was used between each group for each time frame to compare continuous variables between the three groups for the primary outcomes (volume, bioimpedance, and the LYMPH-Q questionnaire). Repeated-measure one-way analysis of variance was used to compare the preoperative, 6-month, and 12-month postoperative variables within each group. The D-Agostino and Pearson test was used to determine whether the variables in each group were normally distributed. Statistical significance was set at a P value less than 0.05, and statistical analyses were performed using the Prism software (GraphPad Software, LLC, San Diego, Calif.).

RESULTS

During the study, 87 patients with stage III or higher disease underwent surgery at our department (Table 1). Thirty-eight patients underwent suction-assisted lipectomy + lymphovenous anastomosis, 23 underwent autologous breast reconstruction with VLNT + lymphovenous anastomosis, and 26 underwent right gastroepiploic omental VLNT with lymphovenous anastomosis. There were no perioperative complications in any patient, including surgical site infection, postoperative hematoma, or seroma.

Table 1.

Demographics and Patient Characteristics

			Total	SAL + LVA	MSTRAM + VLNT	Omental VLNT	P
Patients, n (%)			87	38	23	26
Age (y, mean ± SD)			52.3 ± 9.1	51.1 ± 12.3	53.3 ± 10.1	52.1 ± 11.9	0.768
BMI (kg/m², Mean ± SD)			26.8 ± 4.2	27.9 ± 5.9	26.6 ± 6.1	27.1 ± 9.2	0.429
Length of follow-up (mo, mean ± SD)			29.2 ± 6.5	28.9 ± 7.1	31.8 ± 9.9	22.3 ± 10.2	0.538
Duration of lymphedema (y, mean ± SD)			8.1 ± 7.7	7.1 ± 6.2	8.3 ± 10.9	7.3 ± 9.1	0.31
Comorbidity	Hypertension		30	18	7	5
	Diabetes mellitus		11	7	2	2
Surgical history	Total mastectomy		48	24	21	3
	Breast-conserving surgery		21	12	0	9
	Nipple-sparing mastectomy + reconstruction		18	11	2	5
Lymph node dissection history	Axillary lymphadenectomy	Level I	49	21	13	15
		Level II	17	7	5	5
		Level III	9	5	2	2
	Sentinel lymph node biopsy		12	5	3	4
Adjuvant treatment	Radiation		70	25	20	25
	Neoadjuvant chemotherapy		20	7	7	6
	Adjuvant chemotherapy		51	15	12	15
ISL lymphedema stage	IIb		11	6	3	2
	III		76	32	20	24
Arm dermal backflow stage	I		0	0	0	0
	II		0	0	0	0
	III		38	15	10	13
	IV		44	21	11	12
	V		5	2	2	1
Upper limb cellulitis history	Single episode		14	5	3	6
	Recurrent episode		5	2	2	1
No. LVAs performed (average)			2.0	2.8	1.3	1.4

LVA, Lymphovenous anastomosis; MSTRAM, muscle-sparing transversus rectus abdominis muscle flap; SAL, Suction-assisted liposuction; ISL, International Society of Lymphology.

The postoperative outcomes were as follows (Fig. 5 and Table 2). In all three groups, the volume of the affected limb compared with the contralateral limb was significantly reduced postoperatively. Among them, the SAL + LVA group had the largest volume reduction, decreasing from a preoperative average of 1.35 times larger than the contralateral limb to 1.06 times (P = 0.03) at 12 months postoperatively. Consequently, we observed that the average volume difference in the SAL + LVA group at 12 months postsurgery was significantly smaller than that in the other two groups. However, the MSTRAM + VLNT and omental VLNT groups also experienced a significant volume decrease postoperatively compared with their preoperative values (MSTRAM + VLNT: 1.26 ± 0.27 preoperatively to 1.19 ± 0.11, 12 months postoperatively; omental VLNT:1.31 ± 0.19 to 1.20 ± 0.11).

Fig. 5.

Graphs showing the results of three different operative patient groups. A, The MSTRA M + VLNT group shows the highest subjective improvement. B, The omental VLNT group has the highest improved bioimpedance analysis results. C, The SAL + LVA group shows the highest volume reduction.

Table 2.

Outcomes of the Three Operative Groups

			Total	SAL + LVA	MSTRAM + VLNT	Omental VLNT	P (Intergroup Comparison)
Patients, n (%)			87	38	23	26
Volume compared with contralateral limb		Preoperative		1.35 ± 0.15	1.26 ± 0.27	1.31 ± 0.19	0.242
		6 months		1.19 ± 0.31	1.22 ± 0.39	1.22 ± 0.22	0.518
		12 months		1.06 ± 0.28*	1.19 ± 0.11	1.20 ± 0.11	0.102
Bioimpedance analysis	Interlimb impedence ratio (1 kHz)	preoperative		1.60 ± 0.19	1.61 ± 0.38	1.61 ± 0.21	0.739
		6 months		1.57 ± 0.24	1.42 ± 0.19	1.41 ± 0.19	0.311
		12 months		1.44 ± 0.28	1.39 ± 0.19	1.24 ± 0.28	0.191
	Interlimb impedence ratio (5 kHz)	Preoperative		1.59 ± 0.19	1.61 ± 0.31	1.62 ± 0.19	0.615
		6 months		1.56 ± 0.21	1.44 ± 0.27	1.42 ± 0.2	0.483
		12 months		1.44 ± 0.25	1.4 ± 0.20	1.24 ± 0.27*	0.02
LYMPH-Q questionnaire	Total score	Preoperative		67	68	70	0.301
		6 months		46	41	55	0.294
		12 months		43	22*	50	0.01

LVA, lymphovenous anastomosis; MSTRAM, muscle-sparing transversus rectus abdominis muscle flap; SAL, suction-assisted liposuction.

Values in boldface indicate statistical significance (P < 0.05) in intergroup comparison.

^*Statistically significant (P < 0.05) in preoperative and 12 months average comparison.

From the LYMPH-Q questionnaire scores, we observed in all three groups that the discomfort felt by the patients due to lymphedema postoperatively was significantly reduced compared with that preoperatively. The MSTRAM + VLNT group showed the greatest degree of improvement; their preoperative LYMPH-Q scores decreased from an average of 68 points to 22 points at 12 months postsurgery (P < 0.01). In the other two groups, the LYMPH-Q score significantly decreased (67–43 and 70–50, respectively).

In the bioimpedance analysis, postoperative improvement levels were also statistically significant compared with preoperative values in all three groups. Among the three groups, the omental VLNT group showed the largest improvement in the impedance ratio at both 1 kHz and 5 kHz compared with the contralateral normal limb (1.61 ± 0.21 and 1.24 ± 0.28 versus 1.62 ± 0.19 and 1.24 ± 0.27, respectively).

DISCUSSION

Lymphedema after breast cancer is currently a very challenging disease to cure. Treatment options are even more limited in advanced-stage patients with repeated cellulitis and severe soft tissue fibrosis due to failure to prevent lymphedema progression. In addition, the therapeutic effect of complete decongestive therapy and manual lymphatic drainage can be less effective in patients with advanced-stage lymphedema than in those with early-stage lymphedema.^25,26 Furthermore, patients with advanced-stage lymphedema have lower compliance with treatment.

Ongoing research on the various surgical methods for treating advanced lymphedema continues to overcome these limitations. Research on combinations of different surgical approaches is also underway. For example, in a 2015 study by Nguyen et al,²⁷ 29 patients underwent simultaneous VLNT with microvascular breast reconstruction, using a deep inferior epigastric perforator/transverse rectus abdominis muscle-free flap. They reported that 79% of the patients experienced symptomatic improvements and significant improvement in limb volume. Furthermore, this study showed that simultaneously applying a lymph node flap during breast reconstruction in patients with breast cancer-related lymphedema can positively impact lymphedema improvement and patient satisfaction. In addition, a 2021 study by Schaverien et al¹⁶ involved patients who underwent VLNT, including mesenteric or omental flap surgery. They reported that these patients showed decreased limb volume, improved bioimpedance spectroscopy results, satisfactory subjective patient-reported outcomes, and reduced cellulitis episodes compared with those who received only conservative therapy without surgery.

Di Taranto et al²⁸ summarized the surgical outcomes in patients with stage II–III lower-limb lymphedema, through a protocol that combined gastroepiploic VLNT, lymphovenous anastomosis, and suction lipectomy in an article published in 2020. In this study, the authors compared and reported the outcomes of a case series in which VLNT, liposuction, and lymphovenous anastomosis were administered simultaneously; both groups experienced a significant decrease in limb volume, skin tonicity, and cellulitis episodes. In 2022, Deptula et al²⁹ reported outcomes using nanofibrillar collagen scaffolds combined with lymphovenous anastomosis and VLNT in lymphedema surgery. The surgical method was selected using an algorithm designed by the authors. They reported that 14 patients with stage II–III lymphedema experienced an effective reduction in limb volume.

When considering surgical treatments for advanced-stage breast cancer-related lymphedema, surgeons preferentially use imaging modalities such as lymphoscintigraphy and indocyanine green lymphangiography to assess whether functional lymphatics³⁰ and lymphovenous anastomosis are feasible in the patient’s affected limb. Recently, lymphovenous anastomosis has been effectively attempted, even for advanced-stage breast cancer-related lymphedema, through a more precise preoperative mapping technique using ultrasound,^31,32 with good outcomes. However, it has been reported that in advanced-stage lymphedema, suction-assisted lipectomy or VLNT combinations provide better results than lymphovenous anastomosis alone.¹² In addition, the absence of the breast in patients with breast cancer-related lymphedema is also a problem directly related to quality of life. Hence, the surgical method for lymphedema may also vary slightly depending on the patient’s need for delayed breast reconstruction.

In the present study, the authors presented three different surgical options and decision-making algorithms for patients diagnosed with International Society of Lymphology stage III breast cancer-related lymphedema: (1) lymphovenous anastomosis + liposuction, (2) autologous breast reconstruction with VLNT + lymphovenous anastomosis, and (3) gastroepiploic VLNT + lymphovenous anastomosis. In the present study, the group that underwent only lymphovenous anastomosis (LVA) was excluded. The authors deliberated on including this patient group in the study; however, considering the current practice at our clinic for advanced-stage lymphedema, which primarily involves simultaneous performance of liposuction and LVA from the initial surgical procedure, we opted to analyze the results by categorizing them into three groups to reflect this approach.

Consequently, by analyzing the surgical effect in patients grouped through the aforementioned surgical methods, it was found that all groups experienced surgical effects above a certain threshold. Slight differences in the detailed indicators for each group were also observed. The LYMPH-Q questionnaire, which evaluates patients’ subjective satisfaction, showed that the MSTRAM + VLNT group showed the greatest improvement. Furthermore, in the bioimpedance analysis of the limbs with lymphedema, the omental VLNT group showed the greatest postoperative improvement compared with preoperative values. The degree of volume reduction differed from the previous two items, and the patient group who received SAL + LVA had the largest volume reduction compared with the preoperative volume.

For patients who underwent breast reconstruction, the satisfaction and convenience of having new breasts were found to restore their psychological confidence and increase their physical activity. This can be attributed to the fact that delayed breast reconstruction has been proven to have several beneficial psychological and physical effects in numerous studies.^33,34 Furthermore, based on previous studies, bioimpedance analysis can be considered the most objective measurement of the degree of lymphatic clearance in patients with lymphedema, and the omental VLNT group showed the most significant improvement.^23,24,35 We hold the belief that the omental flap offers numerous advantages due to its rich lymphatic network and abundant lymph nodes.^13,36,37 Additionally, the extended length and greater surface area of coverage provided by the omentum facilitate the rapid restoration of lymphatic drainage from the upper arm through the site of flap implantation, specifically the axilla. although the groin flap can also serve as a viable VLNT option, we place greater emphasis on achieving physiological restoration of lymphatic drainage, wherein the omentum surpasses other available VLNT flap options in terms of strength and efficacy. Finally, effective liposuction has been demonstrated to have various therapeutic effects in patients with lymphedema.^38,39 Based on the results of this study, suction-assisted lipectomy is considered the most effective surgical method for reducing limb volume in patients with high-stage lymphedema accompanied by fibrosis and volume increase.

If the surgical method is decided after sufficient discussions based on the patient’s clinical needs, the patient’s compliance will improve, and postoperative satisfaction may increase. Furthermore, since lymphovenous anastomosis, liposuction, omental VLNT, and autologous breast reconstruction vary according to surgical technique and postoperative recovery or appearance, it is reasonable for patients and doctors to decide on a surgical method based on sufficient information on these methods. This study showed that the expected outcomes for each surgical method are distinct; hence, these combined surgical approaches provide more options for patients with advanced lymphedema in stages II and III who do not have a unique treatment method for each situation and indication. Consequently, this study is expected to be a helpful tool for patients and physicians in the selection of effective surgical methods for treatment.

This study had several limitations. First, this study did not involve a prospective analysis for randomizing patients from the preoperative stage. Hence, there was the possibility of a bias depending on the treatment process and individual circumstances due to the retrospective nature of the study. Second, although the study population is similar to the number of patients in previously published articles, the relatively small number of patients included in this study was also a limitation. However, despite these practical limitations, this study is significant because it is the first to systematically analyze surgical outcomes and determine various options for surgically treating advanced-stage lymphedema from the patient’s perspective. Moreover, the continuous surge in surgical cases and data accumulation after this report can provide an opportunity to continuously produce more accurate and objective clinical outcome analysis studies.

CONCLUSIONS

Based on patients’ clinical needs, we applied three different surgical methods for patients with stage III breast cancer-related lymphedema who did not have many effective treatment options. We observed slightly different clinical effects for each surgical method; however, all surgical methods demonstrated a reduction in the degree of edema and an increase in patient satisfaction. Consequently, this study can serve as a rationale for physicians in determining optimal surgical methods for patients with advanced-stage breast cancer-related lymphedema in the future.

DISCLOSURE

The authors have no financial interest to declare in relation to the content of this article.

ACKNOWLEDGMENTS

Samples were collected after obtaining informed consent and the study protocols were approved by the Seoul National University Hospital institutional review board (No. H-1108-098-374). This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (grant no.: HR22C1363).