Abstract
Background:
Lymphedema may develop when axillary lymph node dissection (ALND) injures and obstructs the lymph ducts in the upper limb. In patients with breast cancer, lymphedema is difficult to treat and can cause arm swelling, heaviness, and restricted movement. We aimed to identify the prevalence and risk factors for lymphedema after ALND in patients with breast cancer.
Methods and Results:
This retrospective study included 175 patients with breast cancer who underwent ALND in the Nagasaki University Hospital, Japan, between 2005 and 2018. Lymphedema was defined as symptomatic arm swelling with a >2-cm difference in the arm circumference between the affected and contralateral arms. Patients were divided into two groups according to the presence or absence of lymphedema. Surgical and pathological findings were compared between the two groups. Univariate and multivariate analyses were performed, including the chi-square test, Student's t-test, and logistic regression analysis. Lymphedema was prevalent in 20% of the study participants, and the mean time interval from surgery to development of lymphedema was 479 days. In the univariate analysis, a body mass index of >26 kg/m2, smoking, radiotherapy (RT), and dissection of >18 axillary lymph nodes (ALNs) significantly increased the risk of lymphedema. In the multivariate analysis, smoking, RT, and dissection of >18 ALNs significantly increased the risk of lymphedema.
Conclusions:
The prevalence of lymphedema in our study was 20%. Our findings suggest that smoking, RT, and dissection of >18 ALNs are risk factors for lymphedema. Aggressive and empiric ALND might be associated with axillary lymph duct damage.
Keywords: axillary lymph node dissection, axillary reverse mapping, breast cancer, lymphedema
Introduction
Breast cancer is the most common malignancy in women, with approximately 2.1 million new cases reported worldwide in 2018. Moreover, it is the fifth leading cause of cancer-related mortality, with approximately 620,000 deaths in both men and women in 2018.1 The interval from diagnosis to death in patients with breast cancer is generally long, and the age-standardized 5-year net survival rate is approximately 90% worldwide.2,3
Surgery, endocrine therapy, anti-human epidermal growth factor receptor 2 (HER2) therapy, chemotherapy, and radiotherapy (RT) are all effective treatment options to improve the survival of patients with breast cancer.4–8 However, they are associated with frequent adverse events and complications.9 Therefore, in addition to effective treatment, the prevention of adverse events and complications in patients with breast cancer has become increasingly important.
Lymphedema is one of the major complications of breast cancer; it causes arm swelling and heaviness, impaired limb mobility, and decreased quality of life. It is difficult to treat lymphedema once it occurs. Axillary lymph node dissection (ALND), RT to the regional lymph nodes (LNs), chemotherapy, obesity, and infection have been reported as risk factors for lymphedema in patients with breast cancer.10 The extent of axillary surgery and the number of dissected LNs also appear to have a direct correlation with the risk of lymphedema.11,12 In previous studies, the estimated incidences of lymphedema were 19.3%–24.6% in patients who underwent ALND and 2.2%–8.3% in patients who underwent sentinel lymph node biopsy (SLNB).13–15
Considering the findings of the ACOSOG Z0011,16 AMAROS,17 and IBCSG 23-0118 trials, the use of ALND as a treatment option in patients with breast cancer has been decreasing. However, all patients with clinical axillary LN (ALN) metastasis and some patients with sentinel LN metastasis require ALND. Although ALND increases the risk of lymphedema and decreases the quality of life,19 the surgical procedure for ALND has not changed in several decades.
In our institute, the empiric upper border for ALND is the lower edge of the axillary vein. This surgical procedure may cause injury and lymph duct obstruction in the upper limb, leading to lymphedema. Therefore, it is necessary to improve this surgical technique to prevent lymphedema. Lymphedema in patients with breast cancer has not been studied in our institute. Therefore, this study aimed to identify the prevalence and risk factors for lymphedema after ALND in patients with breast cancer.
Materials and Methods
Patients
This retrospective study was approved by the institutional review board of our hospital (approved number 20101911), and the requirement for informed consent was waived. We retrospectively reviewed the charts and collected the data of 1182 patients with breast cancer who underwent surgery at the Nagasaki University Hospital, Japan, between January 2005 and December 2018. The exclusion criteria were as follows: patients who underwent mastectomy alone or with SLNB (n = 967) and patients who were lost to follow-up, including those who were followed up in other hospitals (n = 37). After exclusion, the study comprised 178 ALNDs in 175 patients with breast cancer (Fig. 1). Patients were divided into two groups: patients with and without lymphedema.
FIG. 1.
Flowchart of the selection process of the study participants. ALND, axillary lymph node dissection; SLNB, sentinel lymph node biopsy.
Clinicopathological assessments and molecular subtypes
Patient-related variables in this study included age, body mass index (BMI), and smoking. Breast cancer related variables included estrogen receptor (ER), progesterone receptor (PgR), HER2 expression, pathological tumor-node-metastasis (TNM) staging, and lymphovascular invasion. Pathological staging was reclassified and graded according to the TNM classification system (8th edition).20
Breast cancer treatment
Treatment-related variables included the type of breast and axillary surgery, timing of chemotherapy and RT, number of dissected ALNs, number of metastatic LNs, and local recurrence of ALNs. For breast surgery, either partial mastectomy (Bp) or total mastectomy (Bt) was performed based on the tumor extension and surgeon's recommendations. For axillary surgery, patients clinically diagnosed with LN metastasis, and sentinel LN metastasis on SLNB, underwent ALND. In this study, SLNB was performed using the combined method (dye with a radioisotope) or indocyanine green (ICG) dye method. For ALND, level I (lateral to the pectoralis minor) and level II (under the pectoralis minor) LNs were dissected; for the dissection, the axillary vein was considered the upper border, whereas branches of the thoracodorsal vessels were considered the lower border.
In patients with HER2-positive or triple-negative breast cancer, neoadjuvant chemotherapy (NAC) or adjuvant chemotherapy (AC) was administered. In patients with ER-positive breast cancer, AC was administered in those at high risk of recurrence secondary to LN metastasis and with pathological T3 or T4 stage and/or lymphovascular invasion. In addition, patients with locally advanced breast cancer, who preferred to undergo Bp, despite a large tumor size, received NAC. In general, NAC and AC regimens were a combination of an anthracycline-containing regimen and taxane (such as four cycles of doxorubicin and cyclophosphamide, fluorouracil, epirubicin, and cyclophosphamide or epirubicin and cyclophosphamide, followed by four cycles of docetaxel).
The NAC regimen plus trastuzumab was administered in patients with HER2-positive breast cancer. Chemotherapy was not administered to patients with an advanced age, a low-performance status, and who refused to undergo chemotherapy.
In almost all patients who underwent Bp, the residual breast was irradiated, which included a certain amount of irradiation to the axillary region. Moreover, in patients with four or more LN metastases, the regional LNs (axillary, supraclavicular, and internal mammary nodes, if necessary) were irradiated; the chest wall and regional LNs were irradiated in patients who underwent Bt. Furthermore, irradiation was delivered to patients with three or fewer LN metastases, provided they did not receive chemotherapy and/or had a high risk of recurrence. RT was performed at a dose of 2 Gy per fraction (50 Gy/25Fr). If the surgical margins were positive, the patients received boosted irradiation (10 Gy/5Fr) to the tumor bed or underwent an additional excision to prevent local recurrence.
Evaluation of lymphedema
The diagnostic criteria for lymphedema included symptomatic arm swelling and a >2-cm difference in the arm circumference compared with that of the contralateral arm at a 5-cm distal or 10-cm proximal distance from the elbow fossa line. Patients who met both criteria were considered as having lymphedema. The time interval from surgery to the development of lymphedema was calculated from the date of surgery to the date of diagnosis of lymphedema.
Statistical analyses
Univariate and multivariate analyses were performed to evaluate the risk factors for lymphedema using the chi-square test, Student's t-test, and logistic regression analysis. Continuous data were expressed as mean (standard deviation [SD]) [median]. The level of significance was set at p ≤ 0.1 for the univariate analysis; all significant variables from the univariate analysis were assessed in a multivariate analysis. Risk factors with p < 0.05 in the multivariate analysis were considered statistically significant. In addition, we calculated the odds ratios (ORs) and 95% confidence intervals (CIs) in the multivariate analysis. All statistical analyses were performed using JMP Pro software version 15 (Statistical Analysis System Institute, Inc., Cary, NC, USA).
Results
The characteristics of the patients with and without lymphedema are shown in Table 1. The results of the assessed variables expressed as mean (SD) [median] were as follows: the observation period in all patients was 2052 (959) [2080] days, the age was 56 (13.2) [55] years, the BMI was 23.3 (4.07) [22.5] kg/m2, the number of ALNs was 18.0 (7.29) [16], and the number of metastatic LNs was 3.75 (5.83) [2]. Eleven patients (6.2%) had a history of smoking. One hundred two patients (57%) received RT to the regional LNs. One hundred fifty-seven patients (88%) received chemotherapy, of whom 57 (32%) received NAC and 100 (56%) received AC. Forty-four patients (25%) underwent Bp, and 134 patients (75%) underwent Bt.
Table 1.
Characteristics of Patients with Breast Cancer (N = 178) With and Without Lymphedema
| Characteristic | Without lymphedema (n = 142) | With lymphedema (n = 36) | Univariate, p-value |
|---|---|---|---|
| Observation period (days) | 2008 (960) [2077] | 2225 (948) [2151] | 0.23 |
| Age (years) | 57 (13.3) [55] | 55 (12.7) [52.5] | 0.41 |
| BMI (kg/m2) | 23.2 (4.13) [22.4] | 23.8 (3.84) [22.8] | 0.43 |
| ≤26 | 114 (80) | 24 (67) | 0.08 |
| >26 | 28 (20) | 12 (33) | |
| Smoking | 6 (4.2) | 5 (14) | 0.04 |
| Expression status | |||
| ER+ | 111 (78) | 28 (78) | 0.96 |
| PgR+ | 100 (70) | 23 (64) | 0.45 |
| HER2+ | 23 (16) | 9 (25) | 0.22 |
| Lymphovascular invasion | |||
| ly (+) | 96 (68) | 20 (56) | 0.37 |
| v (+) | 82 (58) | 23 (64) | 0.22 |
| Stage | 0.44 | ||
| I | 8 (5.6) | 3 (8.3) | |
| IIA | 34 (24) | 12 (33) | |
| IIB | 25 (18) | 8 (22) | |
| IIIA | 37 (26) | 9 (25) | |
| IIIB | 13 (9.2) | 2 (5.6) | |
| IIIC | 10 (7.0) | 1 (2.8) | |
| IV | 3 (2.1) | 1 (2.8) | |
| RT to the regional LNs | 77 (54) | 25 (69) | 0.09 |
| Chemotherapy | |||
| None | 15 (11) | 1 (2.8) | 0.14 |
| NAC | 43 (30) | 14 (39) | 0.50 |
| AC | 80 (56) | 20 (56) | |
| Surgery | |||
| Bp | 36 (25) | 8 (22)28 (78) | 0.70 |
| Bt | 106 (75) | 28 (78) | |
| SLNB → ALND | 57 (40) | 18 (50) | |
| ALND | 85 (60) | 18 (50) | 0.28 |
| No. of ALNs | 17 (7.28) [16] | 19 (7.27) [18] | 0.18 |
| ≤18 | 96 (68) | 18 (50) | 0.05 |
| >18 | 46 (32) | 18 (50) | |
| No. of metastatic LNs | 3.6 (5.58) [2] | 3.9 (6.82) [2] | 0.86 |
Continuous data are expressed as mean (SD) [median]. Categorical data are expressed as n (%).
AC, adjuvant chemotherapy; ALN, axillary lymph node; ALND, axillary lymph node dissection; BMI, body mass index; Bp, partial mastectomy; Bt, total mastectomy; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; LN, lymph node; ly, lymphatic invasion; NAC, neoadjuvant chemotherapy; PgR, progesterone receptor; RT, radiotherapy; SD, standard deviation; SLNB, sentinel lymph node biopsy; v, vascular invasion.
One hundred thirty-nine patients (78%) had ER-positive tumors, 123 (69%) had PgR-positive tumors, and 32 (18%) had HER2-positive tumors. Eleven (6.2%), 46 (26%), 33 (19%), 46 (26%), 15 (8.4%), 11 (6.2%), and 4 (2.2%) patients had stage I, IIA, IIB, IIIA, IIIB, IIIC, and IV tumors, respectively. Lymphedema occurred in 36 patients (20%), and 142 patients did not develop lymphedema. The mean (SD) [median] time interval from surgery to the development of lymphedema was 479 (502) [330] days. Two patients (1.1%) had local ALN recurrence. A BMI >26 kg/m2 and >18 ALNs were set as the cutoff values because these represented the maximum area under the curve in the receiver operating characteristic curve analysis.
In the univariate analysis, the significant variables were smoking (p = 0.04), RT to the regional LNs (p = 0.095), BMI >26 kg/m2 (p = 0.08), and dissection of >18 ALNs (p = 0.05). Of these, smoking (p = 0.025; OR, 4.79; 95% CI: 1.23–18.47), RT (p = 0.032; OR, 2.42, 95% CI: 1.07–5.88), and dissection of >18 ALNs (p = 0.047, OR: 2.20, 95% CI: 1.01–4.84) remained significant in the multivariate analysis, whereas BMI >26 kg/m2 (p = 0.160, OR: 1.85, 95% CI: 0.78–4.26) was no longer significant (Table 2). The prevalence of lymphedema in patients with ≤18 dissected ALNs was 15.8%. In patients with >18 dissected ALNs, the prevalence of lymphedema was 28.1%.
Table 2.
Multivariate Analysis of Variables Significant in the Univariate Analysis
| Variable | Multivariate analysis |
|
|---|---|---|
| OR (95% CI) | p | |
| BMI (kg/m2) (≤26/>26) | 1.85 (0.78–4.26) | 0.160 |
| Smoking | 4.79 (1.23–18.47) | 0.025 |
| RT | 2.42 (1.07–5.88) | 0.032 |
| No. of ALNs (≤18/>18) | 2.20 (1.01–4.84) | 0.047 |
CI, confidence interval; OR, odds ratio.
Discussion
In this study, we showed that smoking, RT to the regional LNs, and dissection of >18 ALNs were associated with an increased risk of lymphedema. These results are consistent with those of previous studies that have shown that axillary surgery and RT increase the risk of lymphedema.10,13,19,21 The prevalence of lymphedema in our study was within the estimated range of 19.3%–24.6% that has been previously reported in patients who underwent ALND.13–15
One study reported that the risk of lymphedema was highest during the first 6–12 months postoperatively in patients who underwent ALND and the first 18–24 months postoperatively in patients who underwent ALND, followed by post-mastectomy RT within 12–30 months.13 These findings were similar to the findings of this study, in which the mean time intervals from surgery to the development of lymphedema were 351 days in patients who underwent ALND and 526 days in patients who underwent ALND and RT.
Previous studies suggest that the prevalence of lymphedema is associated with the number of dissected ALNs. Kilbreath et al.11 reported that the prevalence of lymphedema was 3.3% in patients with ≤5 dissected ALNs; however, it was 18.2% in patients with >5 dissected ALNs. Similarly, Kim et al.12 reported that the prevalence of lymphedema was 6.0% in patients with ≤10 dissected ALNs but 27% in patients with >10 dissected ALNs. In our study, dissection of >18 ALNs was a significant risk factor for lymphedema.
An accurate diagnosis of the ALN status requires the resection of ≥10 ALNs. However, the definition of an adequate ALND is controversial. The age of the patient and surgeon-related factors are associated with the number of dissected ALNs. In particular, younger patients and academic-affiliated surgeons were more likely to be associated with a higher number of dissected ALNs.22,23 In addition, several studies have shown that a high BMI is a risk factor for lymphedema in patients with breast cancer.24–26 However, in this study, a high BMI did not significantly increase the risk of lymphedema, although the patients with a BMI >26 kg/m2 tended to develop lymphedema.
Whether NAC and AC are risk factors for lymphedema remain unclear. Some studies have shown that chemotherapy, especially taxane-based chemotherapy, significantly increases the risk of lymphedema,14,27 whereas other studies have revealed that chemotherapy is not a risk factor for the development of lymphedema.28,29 In our study, NAC and AC did not increase the risk of lymphedema.
Our findings suggest that extensive ALND might increase the risk of lymphedema. Axillary surgery, especially ALND, may damage the lymphatic system of the upper limb. Recently, new surgical techniques have been developed to prevent lymphedema. The Lymphatic Microsurgical Preventive Healing Approach (LYMPHA) technique is a prophylactic surgical procedure that creates lymphatic venous anastomoses between the lymphatics of the arm and the branch of the axillary vein.30,31 Boccardo et al.31 reported that the LYMPHA technique reduced the incidence of lymphedema and that lymphedema developed in only 4.05% of patients who underwent ALND using the LYMPHA technique. However, it is difficult for breast surgeons to perform ALND with LYMPHA alone as it requires the involvement of plastic surgeons with microsurgical techniques.
Axillary reverse mapping (ARM) has also been developed to preserve axillary lymphatic drainage.32,33 ARM is based on the theory that the upper limb and breasts have separate lymphatic drainage pathways. The resection of visualized LNs and lymph ducts can be avoided by injecting a dye (blue dye or ICG) into the upper limb while performing ALND.21,34,35 We have started clinical trials on ARM using ICG, to reduce the risk of lymphedema in patients with breast cancer undergoing ALND.
Although smoking was a risk factor for lymphedema in this study, similar results have not been reported previously. The mechanism by which smoking causes lymphedema is unknown, and data on ex-smokers were not available for this study. Further studies are required to determine whether smoking cessation reduces lymphedema and whether smoking definitely increases the risk of lymphedema.
This study had several limitations. First, this study was limited by its retrospective design. We were unable to remove the selection bias and collect data for all objectives because of inadequate medical records or untraceable patients. For example, we may not have picked up asymptomatic patients who had a >2-cm difference in arm circumference. Second, we did not analyze the range of ALND, the number of ALNs present, specimen handling, and pathologist- and surgeon-related factors affecting the range of ALND. However, the number of dissected ALNs has previously been used as a surrogate measurement owing to its association with the range of ALND.22
Conclusions
In conclusion, in our study, the prevalence of lymphedema among patients who underwent ALND was 20%. Our findings suggest that smoking, RT to the regional LNs, and dissection of >18 ALNs are risk factors for lymphedema. Aggressive and empiric ALND might be associated with axillary lymph duct damage. Therefore, we have started clinical trials on ARM using ICG to reduce the risk of lymphedema in patients with breast cancer undergoing ALND.
Acknowledgment
The authors thank Editage for their English language editing support.
Authors' Contributions
Y.H. and R.O. contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Y.H., R.O., and S.S. The first draft of the article was prepared by Y.H. and R.O. All authors commented on the previous versions of the article. All authors read and approved the final article.
Statement of Ethics
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The study was approved by the Ethics Committee of Nagasaki University Hospital, Nagasaki, Japan (No. 20101911). The need for informed consent was waived due to the retrospective nature of the study.
Author Disclosure Statement
No competing financial interests exist.
Funding Information
No funding was received for this article.
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