Indocyanine Green Lymphography Screening of Breast Cancer-Related Lymphedema: A Two-Year Prospective Cohort Study after Axillary Lymph Node Dissection

1. Introduction

Breast cancer-related lymphedema (BCRL) is one of the significant morbidity in breast cancer patients, with a cumulative incidence of 10-50% [1,2,3]. Axillary lymph node dissection (ALND) is considered the major contributing treatment risk factor besides radiotherapy and chemotherapy [4,5,6]. Indonesia's breast cancer population is centered at a locally advanced stage [7]. Therefore, ALND is still commonly performed, which increases the risk of BCRL [5,8]. We believe that prioritizing screening and early detection is essential to preventive care [9,10,11].

Several studies show methods for BCRL diagnosis, such as clinical symptoms, relative arm volume increase (RAVI), water volumetry, lymphoscintigraphy, bioimpedance spectroscopy (BIS), and perometry [8,12,13]. Among those methods, the most commonly used are 1) clinical symptoms such as swelling and heaviness, 2) RAVI of 10%, and 3) BIS, which is frequently used for screening (48%) [14,15,16]. However, BIS has a false negative rate of 25% compared to volume displacement measurement. Moreover, bioimpedance spectroscopy is related to a lower positive predictive value (34%) than perometry (54%) [13,16]. Therefore, a more sensitive measurement is needed for BCRL screening.

Indocyanine green lymphography (ICG-L) is currently considered the most sensitive diagnostic tool for lymphedema as it has high sensitivity compared to lymphoscintigraphy or BIS [17,18]. Therefore, ICG-L has previously been used for BCRL diagnosis in several studies [19,20]. One of the advantages of ICG-L is the ability to show in real-time the normal (linear pattern) and abnormal (dermal backflow pattern) lymphatic function. The dermal backflow (DB) pattern consists of splash, stardust, and diffuse pattern [21]. Splash pattern is the earliest ICG-L finding in asymptomatic patients and becomes the hallmark of lymphedema early signs [22].

In Indonesia, diagnostic modalities for BCRL are not widely provided. For example, lymphoscintigraphy is unavailable in every hospital, and no BIS technology exists in Indonesia. Currently, we use clinical symptoms, upper extremity lymphedema (UEL) index, and ICG-L for diagnostic modalities [23]. To our knowledge, only a few studies investigating BCRL incidence using ICG-L [19]. Therefore, our study aims to analyze BCRL cumulative incidence and ICG-L stage among breast cancer patients with ALND.

2. Materials and Methods

2.1. Study Design and Subjects

This prospective cohort study was conducted among breast cancer patients with ALND at Dharmais Cancer Hospital from October 2022 to October 2024. The institutional review board approved the study. The inclusion criteria were breast cancer patients aged >18 years old with ECOG score >1, clinically node-positive, and with or without neoadjuvant systemic therapy. We excluded patients with previous breast and axillary surgeries, radiotherapy, preoperative abnormal lymphatic drainage detected by ICG-L, and patients with iodine allergy, asthma, decreased kidney function, pregnancy, and lactation.

2.2. Surgical Technique

Breast cancer surgery was performed with standard mastectomy or lumpectomy technique. The ALND was done at level I and II, if necessary level III axillary region. During surgery, we collected lymphatic speciments for histopathological assessment which was described previously in our study [24].

2.3. ICG Lymphography Examination

The ICG-L procedure was carried out before and after the surgery as per the scheduled time. We used ICG dye (Premix Indocyanine Green USP 0.5%) that was injected subcutaneously (@0.1 ml) at the second and fourth web spaces of the hand and the ulnar border of the palmaris longus tendon at the wrist joint level. Superficial lymphatic circulation was assessed at 5 minutes (transient phase) and 2 hours (plateau phase).

At this point, we determined the ICG-L stages that is classified as follows: stage 0, the linear pattern only; stage I, linear and splash patterns; stage II, linear and stardust/diffuse pattern in one region; stage III, linear and stardust/diffuse pattern in two regions; stage IV, linear and stardust/diffuse pattern in three regions; stage V, stardust and/or diffuse pattern [25].

BCRL was defined by the presence of minimum ICG-L stage II in area of at least 30% in each arm region, with or without clinical symptoms and UEL index >10%.

2.4. Follow-up and Outcomes

We evaluated the patients’ clinical symptoms, UEL index, and ICG-L every two months in the first year and three months in the second year. The study outcome were 2-years BCRL cumulative incidence and ICG-L stage proportion.

2.5. Statistical Analysis

Numerical data was presented in mean ± SD if normally distributed or median (IQR) if not normally distributed, while categorical data was shown as n (%). Two years-BCRL cumulative incidence were analyzed using Kaplan-Meier survival analysis. Data analysis was performed using the Statistical Package for the Social Sciences (SPSS) version 27.0.

3. Results

In two years, 69 patients were included in this study. The median (IQR) age was 47 (40-54) years, and the mean±SD BMI was 26.3±5.1 kg/m2. There were 46 patients (66.7%) in the locally advanced stage with mastectomy as the common surgery type in 53 patients (76.8%). ALND was performed most frequently on lymph node level I-II in 51 patients (73.9%), although 18 patients (26.1%) underwent ALND level I-III. Radiotherapy was given to 42 patients (60.9%), chemotherapy to 64 patients (93.8%), and hormonal therapy to 49 patients (71%).

The median (IQR) dissected lymph node was 18 (14-21), with the number of lymph node metastases 2 (0-10). There were 16 patients (23.2%) with lymph vessel obstruction, which already occurred during surgery. A total of 66 patients (95.7%) were presented with no special type (NST) histopathology, with luminal B as the most frequent subtype in 26 patients (37.7%). Demographic data of the study subjects are summarized in Table 1.

BCRL occurred in 35 (50.7%) patients with a 2-year cumulative incidence of 58.0% (45.2-71.4) and a median (95% CI) cumulative incidence 16.0 (11.2-20.8) months as shown in Figure 1. Table 2 shows that 25 BCRL patients experienced symptoms (71.4%). The most common signs were heaviness in 15 (60%) and swelling in 12 patients (48%). The UEL index increment > 10 % was only discovered in 11 patients (31.4%). Most BCRL patients had ICG-L stage II, as shown in 18 (51.4%) subjects. The ICG-L stage distribution and clinical features are presented in Table 2 and Figure 2, respectively. In those without lymphedema, ICG-L Stage I or splash pattern occurred in 24 subjects (71%).

4. Discussion

The subjects in our study had a high risk of developing BCRL because they had high BMI, received radiotherapy, greater number of dissected lymph nodes, and had a high frequency of lymph node metastasis. Based on theoretical understanding, obesity is a systemic condition that impacts the lymphatic system. Fat deposition in the organs of obese patients leads to structural, metabolic, and inflammatory changes, which contribute to lymphatic system dysfunction [26,27].

Since most of our patients were in a locally advanced stage, they needed adjuvant radiotherapy. Radiotherapy causes lymphatic vessel fibrosis, which increases the risk of lymphedema after ALND [28]. Radiation exposure upregulates the endothelial nitric oxide synthase expression, which leads to the production of nitric oxide and decreases lymphatic vessel contractility. In addition, radiation induces the release of pro-inflammatory cytokines such as TGF-β, which give rise to fibrosis of the lymphatic vessels that leads to BCRL [6,29,30,31].

The majority of our patients also had a high number of dissected lymph nodes. Furhtermore, around 30% of our subjects experienced ALND level I-III. Extensive axillary lymph node removal may damage the lymphatic system of the upper limb [32]. As a result, a series of inflammation can occur that will cause fibrosis and BCRL [5,33]. Therefore, the risk of lymphedema directly correlates with the number of lymph nodes removed [32]. Kilbreath et al. study revealed that retrieval of more than five lymph nodes accounted for a higher incidence of lymphedema (18.2%) compared to less than five lymph nodes (3.3%) [34]. A study by Di Sipio et al. also showed that a high number of lymph nodes dissected is also a risk factor [8].

Histopathological examination of the lymphatic vessel exhibited that 23% of them experienced hypertrophy and fibrosis of the tunica media as well as narrowing of the lumen. This finding can be associated with lymph node metastasis and extracapsular extension, leading to lymphatic flow obstruction. As a result, it increases intraluminal pressure, thickens the lumen wall, and obstructs the lymphatic vessels [35,36]. Our data shows that early-stage lymphatic vessel obstruction can occur before ALND without signs of lymphatic system abnormalities or lymphedema symptoms. If this condition is not treated immediately, BCRL will eventually occur.

The BCRL cumulative incidence is commonly reported to be between 20-30% [8], but with variation between 10-50% [1,2,3]. Differences in measurement methods, length of follow-up, and types of study design could explain the variability of the incidence. The 2-year BCRL cumulative incidence in our study was 58%. It exhibited a higher BCRL proportion that is commonly reported (20-30%) [8]. The difference can be explained by the fact that the previous studies commonly defined lymphedema by symptoms and arm volume measurement [8], which is a less sensitive method [16]. Since ICG-L is more sensitive to diagnosing lymphedema, therefore, the 2-year BCRL cumulative incidence in our study is relatively high.

Since curing lymphedema is difficult once it progresses [9,37], choosing the most sensitive tool to detect early-stage lymphedema is the key to effective BCRL prevention. ICG-L screening in our study provides evidence that BCRL can be diagnosed in an early stage. This was indicated by the following findings: 1) BCRL was detected before the symptoms occurred in 30% of patients; 2) The UEL index increased by more than 10% was only found in 30% of patients; and 3). Fifty-one percent of the participants were diagnosed with ICG-L stage II. Moreover, 71% of patients without lymphedema had ICG-L stage I or splash pattern, which showed early signs of lymphatic abnormalities [22]. Therefore, in accordance with other studies, we recommend ICG-L for BCRL screening since it is sensitive to diagnose lymphedema before the onset of clinical symptoms and arm volume changes.

Our study supports BCRL preventive management through screening and early detection so that early intervention can be initiated. There are several methods for lymphedema prevention; the first one is conservative treatment using compression therapy [38,39]. Recent randomized controlled trials verify the efficacy of compression sleeves after ALND to prevent BCRL. However, it requires long-term usage, which causes low adherence in some patients [40,41,42]. Hence, compression therapy adherence poses a challenge that may limit the risk-reduction strategy of BCRL [43]. This opinion may correspond with the situation in Indonesia; moreover, compression sleeve garments are not covered by public insurance.

The second preventive intention is to utilize immediate lymphatic reconstruction (ILR), which has emerged as the primary prevention for BCRL [2,44,45]. The concept of ILR using lymphaticovenous anastomosis (LVA) has also been used for secondary prevention of lymphedema [46,47]. Yamamoto et al. utilized efferent lymphatic vessel anastomosis when lymphedema was still in the subclinical stage (splash pattern). The technique prevented lymphedema progression, as shown by the reduction from splash to linear pattern [47]. Our previous study also showed that LVA could prevent BCRL progression when detected in the early stage, even before the surgery was performed [48]. Hence, based on those studies, our findings support BCRL screening with ICG-L since it can detect lymphedema in the early stage. Therefore, immediate intervention such as compression therapy or LVA can be deployed to prevent lymphedema progression.

We are aware that our study has limitations. Transient and subclinical lymphedema could be counted in our BCRL definition. But, the key to prevention is to find lymphedema as early as possible. This can only be performed by ICG-L since it detects early changes in lymphatic circulation. Another limitation is our short follow-up time; therefore, the long-term delayed onset of BCRL cannot yet be evaluated. Longer follow-up time is needed. Despite this, we found that ICG-L is a sensitive diagnostic tool for BCRL screening and early detection.

5. Conclusions

Based on ICG-L analysis, BCRL can be detected more frequently and at an early stage. This highlights the high sensitivity of ICG-L as a screening diagnostic tool. Such findings emphasize its value in initiating timely interventions to prevent the progression of lymphedema. Therefore, we recommend ICG-L for BCRL screening and early detection in breast cancer patients with ALND.