Abstract
Background
Accurate characterization of the breast cancer-related lymphedema (BCLR) population is essential to understand its pathophysiology and develop predictive models for identifying at-risk patients and implementing tailored preventive microsurgical strategies. Key factors influencing BCRL severity and progression remain unclear. This study characterizes patients with BCRL seeking microsurgical treatment and evaluates the impact of oncological treatment intensity on lymphedema severity and progression.
Methods
This cohort study was conducted at an outpatient tertiary lymphedema clinic between 2017 and 2023. BCRL severity was assessed at intake by a lymphedema-specialized plastic surgeon using International Society of Lymphology staging and indocyanine green lymphography with near-infrared fluorescence imaging (ICG-NIFI). Data were collected during scheduled medical evaluations and analyzed retrospectively. Exploratory analysis investigated associations between oncological treatment intensity and BCRL severity and progression.
Results
A total of 163 consecutive female patients with BCRL were included. Lymphedema severity varied significantly, with no consistent link between severity and time since onset. A significant association was found between axillary lymph node dissection (ALND) and ICG-NIFI stages (p<0.001). However, no significant associations were found between oncological treatment intensity—surgery, radiotherapy, systemic treatment—and BCRL severity and progression. Analyses further revealed associations between lymphedema severity, body mass index, postmenopausal status, and clinical course.
Conclusion
This study provides a comprehensive profile of patients with BCRL seeking microsurgical treatment, revealing variable lymphedema progression patterns. Oncological treatment intensity did not appear to influence BCRL severity or progression, suggesting that these may depend more on biological predisposition. These findings enhance BCRL understanding and highlight the importance of precise patient characterization, laying the foundation for targeted, individually tailored preventive microsurgical interventions.
Supplementary Information
The online version contains supplementary material available at 10.1245/s10434-025-18694-8.
Keywords: Breast cancer, Breast cancer-related lymphedema, Microsurgery, Oncology, Secondary lymphedema
Breast cancer is the most common cancer among women worldwide, recording 2.3 million new cases in 2020 and projections indicating a rise to over 3 million annually by 2040.1 Despite advancements in cancer care and personalized medicine, long-term complications from the disease and its treatments persist. One of these complications is breast cancer-related lymphedema (BCRL), which affects 20–41% of patients after treatment.2
This chronic and progressive condition results from disruption of the lymphatic system, after which fluid accumulation, inflammation, and swelling lead to hardening of the skin, fibrosis, and deformation of the affected body part, resulting in reduced mobility and loss of function.3–5These structural disruptions are believed to arise after procedures such as axillary lymph node dissection (ALND), axilla-preserving surgeries such as sentinel lymph node biopsy (SLNB) and targeted axillary dissection, radiotherapy, or surgery and radiotherapy combined.6 Documented patient-related risk factors include high body mass index (BMI), subclinical edema, and cellulitis of the affected limb.7 BCRL causes symptoms such as swelling, pain, impaired arm function, and infections, in turn significantly degrading quality of life (QoL),8,9 often forcing patients to reduce working hours or stop working, affecting their economic stability.9,10
BCRL is typically managed through decongestive therapy, involving conservative techniques such as compression therapy, manual lymphatic drainage, bandaging, taping, massage, and exercise. When conservative methods prove to be insufficient, (micro)surgical interventions such as lymphaticovenous anastomosis (LVA) and vascularized lymph node transfer (VLNT) may be considered. These microsurgical techniques have demonstrated potential in alleviating symptoms and improving QoL, but complete restoration of lymphatic function has not yet been achieved and treatment remains focused on symptom management.11,12
Accurate characterization of the BCRL population is crucial for enhancing knowledge of its pathophysiology and epidemiology and for developing predictive models to identify at-risk patients. This understanding is crucial for implementing preventive strategies such as immediate lymphatic reconstruction in a healthcare field challenged by economic and expertise constraints, while still aiming to reduce the healthcare burden and improve patient QoL.13
This study aims to establish a comprehensive characterization of the BCRL population seeking microsurgical treatment and investigate associations between breast cancer treatment intensity and lymphedema progression and severity.
Methods
A prospective database was created of patients with BCRL seeking microsurgical treatment at a university medical center’s outpatient clinic in the Netherlands. Data from 2017 to 2023 were collected during scheduled medical evaluations and extracted from electronic health records.
Clinical Assessment
BCRL severity was assessed by a lymphedema-specialized plastic surgeon using International Society of Lymphology (ISL) staging, incorporating limb circumference measurements and clinical symptoms.14 Indocyanine green lymphography with near-infrared fluorescence imaging (ICG-NIFI) was performed at intake and classified per MD Anderson BCRL staging.15 ICG-NIFI staging (I–V) evaluates lymphatic patency and dermal backflow, with stage I indicating numerous patent lymphatics and minimal backflow, whereas higher stages reflect progressive decline in lymphatic patency and increased dermal backflow.15 Stage IV is characterized by dermal backflow involving the hand, and stage V represents complete absence of ICG movement past the ICG injection site.15 Microsurgical recommendations were based on staging, progression, and symptoms. LVA was typically indicated for ICG-NIFI stages II–III, whereas patients at stage IV were recommended VLNT. Lymphedema progression was assessed through patient self-report, tracking onset from initial breast cancer treatment to microsurgery consultation, based on changes in limb diameter, pain, heaviness, and fatigue.
Data Collection
At intake, patients completed patient-reported outcome measure questionnaires, including the Lymphoedema functioning, disability and health questionnaire (Lymph-ICF),16 the EQ5D-5L,17 the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire,18 and the Michigan Hand Outcomes Questionnaire (MHQ).19 Reviewed data included patient characteristics, lymphedema-specific information, and oncological history. Patient characteristics covered demographics, comorbidities, intoxications, and referral information. Lymphedema characteristics included affected regions, triggers, clinical progression, prior conservative and microsurgical treatments, infections, severity according to ISL staging,14 and ICG-NIFI staging categorized per MD Anderson staging.15 Oncological history covered tumor pathology, TNM staging, DNA mutations, surgical outcomes, and details of radiation and systemic therapies. Data usage was approved under an opt-out consent model.
Statistical Analysis
A power analysis determined a sample size of 163 to detect effect sizes over 0.35 (α = 0.05, β = 0.8). Data analysis was performed with Rstudio version 4.3.1, and missing data were addressed through multivariate imputation by chained equations using the “mice” package.20 Descriptive statistics were used for data summarization, presenting nominal and ordinal variables in frequencies and percentages, and continuous variables as means with standard deviation (SD) or medians with interquartile range (IQR). Exploratory analyses evaluated associations between breast cancer treatment modalities and BCRL severity and progression. Shapiro–Wilk tests were used to assess normality; non-normal distributions were described using medians and IQRs. Kruskal–Wallis and analysis of variance tests were used to analyze variable distributions, with Dunn and Tukey post hoc tests for significant findings. Associations between categorical variables were investigated using chi-squared tests. Bonferroni correction adjusted for multiple testing, setting significance thresholds at p<0.00119 for primary analyses and p<0.05 for secondary analyses.
Results
Patient Characteristics
Baseline characteristics are displayed in Table 1. This cohort study included 163 female patients with an average ± SD age of 59.4 ± 11.6 years and a mean ± SD BMI of 28.3 ± 5.03 kg/m2. Most patients (89%) were referred by specialists; 11% were referred by general practitioners.
Table 1.
Baseline characteristics
| Characteristic | Overall (N=163) |
|---|---|
| Age | 60.0 (51.0–66.0) |
| Sex, female | 163 (100) |
| BMI (kg/m2) | 27.8 (24.7–31.2) |
| Menopausal status | |
| Premenopausal | 15 (9.2) |
| Perimenopausal | 24 (14.7) |
| Postmenopausal | 124 (76.1) |
| Dominance | |
| Right | 137 (84.0) |
| Left | 23 (14.1) |
| Ambidextrous | 3 (1.8) |
| Smoking | |
| No | 107 (65.6) |
| Stopped smoking | 48 (29.4) |
| Yes, actively | 8 (4.9) |
| Alcohol (yes) | 55 (33.7) |
| Comorbidities (yes) | |
| Hypertension | 44 (27) |
| Cardiovascular disease | 18 (11) |
| Diabetes mellitus | 14 (8.6) |
Data are presented as median (interquartile range) or n (%) unless otherwise indicated
BMI, body mass index
Breast Cancer Treatment
Oncological characteristics are summarized in Fig 1 (full data in Supplementary Table 1). The upper outer quadrant was the most common primary tumor location (65.6%), followed by the upper medial quadrant (14.7%). Nearly all patients (98.8%) underwent surgical removal of oncological tissue, with mastectomies representing 60.2% and breast-conserving surgery 39.8% of procedures. Reconstructive surgery was performed in 50.3% of mastectomies. Axillary surgery was performed in 99.4% of patients, with 55.2% undergoing ALND, 34.4% both ALND and SLNB, and 9.8% only SLNB.
Fig. 1.
Multi-layered pie charts illustrating a tumor characteristics, b surgical treatment, and c systemic and radiation treatments in patient breast cancer histories. Adj, adjuvant; ALND, axillary lymph node dissection; ER, estrogen receptor; SLNB, sentinel lymph node biopsy
In this study, 147 of 163 patients (90.2%) underwent chemotherapy; 34.7% received neoadjuvant, 64.6% adjuvant, and 0.7% both. The most common chemotherapy regimens were a combination of anthracycline and taxane-based regimens (63.2%), followed by solely anthracycline-based (23.9%) regimens and solely taxane-based regimens (3.1%). Taxane-based chemotherapy was used in 66.3% of cases, whereas platinum-based chemotherapy was used in 4.9%. Antihormonal therapy, primarily tamoxifen, was administered in 67.5% of cases. HER2-targeted therapy, specifically monoclonal antibodies, was administered to 19 patients (11.7%), all of whom received trastuzumab, with two also receiving pertuzumab.
Radiotherapy was administered to 87.7% of patients, targeting the breast or chest wall, axilla, and associated lymphatic regions. The median number of sessions was 25 (range 0–33), with a median radiation dose of 50 Gy (range 0–70), and 27.6% of patients receiving an additional radiation boost.
Lymphedema Characteristics
Lymphedema characteristics are presented in Table 2. BCRL affected the right side in 50.3% of patients and the left side in 49.1%, with bilateral involvement in only one patient (0.6%). The years since lymphedema onset ranged from 1 to 25 years (median 7). The median time from breast cancer diagnosis to lymphedema onset was 1 year (IQR 0–2).
Table 2.
Lymphedema characteristics
| Characteristics | Overall (N=163) |
|---|---|
| Years since BCRL onset | 7 (5–11) |
| Time between breast cancer diagnosis and lymphedema onset | 1 (0–2) |
| Affected side | |
| Right | 82 (50.3) |
| Left | 80 (49.1) |
| Bilateral | 1 (0.6) |
| ISL – stage | |
| Stage I | 16 (9.8) |
| Stage IIa | 41 (25.2) |
| Stage IIb | 76 (46.6) |
| Stage III | 30 (18.4) |
| ICG result | |
| Stage 1 | 17 (10.4) |
| Stage 2 | 59 (36.2) |
| Stage 3 | 50 (30.7) |
| Stage 4 | 37 (22.7) |
| Affected locations | |
| Hand | 81 (49.7) |
| Lower arm | 148 (90.8) |
| Upper arm | 151 (92.6) |
| Shoulder | 5 (3.1) |
| Supraclavicular region | 3 (1.8) |
| Breast | 22 (13.5) |
| Flank | 19 (11.7) |
| Multiple affected locations (yes) | 150 (92.0) |
| Pitting edema (yes) | 106 (65.0) |
| Infections in the affected limb (yes) | 55 (33.7) |
| Clinical coursea | |
| Decrease | 3 (1.8) |
| Stable | 78 (47.9) |
| Gradual increase | 75 (46) |
| Rapid increase | 7 (4.3) |
Data are presented as median (interquartile range) or n (%) unless otherwise indicated
BCRL, breast cancer-related lymphedema; ICG, indocyanine green lymphography; ISL, International Society of Lymphology
aChanges in clinical symptoms since intake, categorized as decrease, stable, gradual increase, or rapid increase
BCRL severity, assessed by ISL and ICG-NIFI staging, varied regardless of time since onset Fig 2. Patient-reported events correlating with lymphedema onset included radiotherapy (22.7%), breast surgery (13.5%), and ALND (7.4%). Among the patients attributing it to radiotherapy (n = 37), 32.4% had received additional radiation boosts. Of those linking it to surgery (n= 22), 68.2% (n = 15) underwent mastectomy and 31.8% (n = 7) had lumpectomy. In 37.4% (n = 61), the onset of lymphedema could not be correlated to a specific event.
Fig. 2.
Years since breast cancer-related lymphedema (BCRL) onset in relation to BCRL severity across a International Society of Lymphology (ISL) and b indocyanine green lymphography with near-infrared fluorescence imaging (ICG-NIFI) stages
Fig 3 illustrates lymphedema distribution across various body parts, organized by ISL and ICG-NIFI staging. The most commonly affected areas were the lower and upper arm, observed in 148 (90.8%) and 151 patients (92.6%), respectively. The majority of patients (92%) reported BCRL affecting multiple body parts. A pattern of increasing lymphedema involvement with severity was evident: in the lower stages, lymphedema primarily affected the lower and upper arms, with less involvement of the hand, breast, and flank areas. By ISL stage III, lymphedema prevalence in the upper and lower arm increased to 90.0% and 96.7%, respectively. Hand involvement increased from 23.5% in ICG-NIFI stage I to 59.5% in stage IV. Breast and flank involvement remained lower throughout advancing stages. The shoulder and supraclavicular region were minimally affected across all stages.
Fig. 3.
The gradient illustrates the distribution pattern of breast cancer-related lymphedema (BCRL) across body parts in relation to International Society of Lymphology (ISL) and indocyanine green lymphography with near-infrared fluorescence imaging (ICG-NIFI) stages. The left arm of each torso depicts the clinically observable changes in the affected body parts with increasing severity
Changes in limb diameter, pain, heaviness, and tiredness were recorded as changes in clinical course or progression. Most patients reported either a stable course (47.9%) or a gradual increase (46.0%) in symptoms, and few experienced a decrease (1.8%) or a rapid increase (4.3%).
Regarding lymphedema management, 93.9% had received conservative treatments before considering microsurgery. The most common conservative treatment modalities consisted of compression sleeves and manual lymphatic drainage, with 63.8% of patients using a combination of techniques, including wrapping, pneumatic compression, hyperbaric oxygen therapy, and alternative medicine.
Microsurgical Treatment Recommendation
Microsurgical treatment recommendations are described in Table 3. The majority of the patients (80.4%) were advised to receive microsurgical treatment. LVA was the most frequently recommended procedure, suggested for 100 patients (76.3%). Additionally, 23 patients (17.6%) were recommended free VLNT, and eight (6%) were advised to have a combination of deep inferior epigastric perforator flap with either LVA or VLNT.
Table 3.
Microsurgical treatment recommendation
| Recommendation | Overall (N=163) |
|---|---|
| Microsurgical intervention (yes) | 131 (80.4) |
| Microsurgical treatment recommendation | |
| LVA | 100 (76.3) |
| VLNT | 23 (17.5) |
| DIEP + LVA | 4 (3.1) |
| DIEP + VLNT | 4 (3.1) |
Data are presented as n (%)
DIEP, deep inferior epigastric perforator; LVA, lymphaticovenous anastomosis; VLNT, vascularized lymph node transfer
Patient-Reported Outcome Measures at Intake
The mean ± SD Lymph-ICF score was 38.9 ± 17.3, categorized by severity: one patient (0.6%) had “no problem”, 34 patients (20.9%) had “small problem”, 80 (49.1%) “moderate problem”, and 48 patients (29.4%) had “severe problem” (Supplementary Figure 1). EQ5D-5L index scores, which are measured on a fixed scale from −0.59 to 1, ranged from −0.158 to 1 within this cohort, with a median of 0.739 (IQR 0.6–0.8). DASH scores ranged from 2.5 to 83.3 with a median score of 34.2 (IQR 18.8–45.8). MHQ total scores ranged from 8.75 to 100, with a median score of 62.4 (IQR 47.9–78.8).
Exploratory Statistical Analysis
Primary univariate exploratory analyses Table 4 investigated associations between breast cancer treatment modalities and BCRL severity and progression. No significant associations were found between breast surgery type and BCRL severity across ISL (p = 0.89) and ICG-NIFI (p = 0.35) stages or clinical progression (p = 0.83). ALND was significantly associated with higher ICG-NIFI stages (p<0.001), with significant differences persisting between stage I and II and stages I and III after Bonferroni correction (αcorrected = 0.00119). SLNB showed no significant association with ISL stages (p = 0.06). An initially significant association between regional nodal irradiation and ISL stages (p = 0.01) did not remain significant after Bonferroni correction. Similarly, although the total number of lymph nodes removed was associated with ICG-NIFI stages (p = 0.04), this significance did not hold after applying the Bonferroni correction.
Table 4.
Exploratory statistical analyses evaluating associations between breast cancer treatment intensity, breast cancer-related lymphedema (BCRL) severity and progression
| Variable | ISL stage | ICG-NIFI stage | Clinical coursea | |||
|---|---|---|---|---|---|---|
| χ2 or H | p | χ2 or H | p | χ2 or H | p | |
| Primary analyses | ||||||
| Breast surgery b | 1.286 | 0.733 | 2.743 | 0.433 | 0.547 | 0.908 |
| Axillary lymph node dissection | 6.215 | 0.102 | 17.222 | <0.001c | 2.507 | 0.474 |
| Sentinel lymph node biopsy | 5.744 | 0.125 | 8.672 | 0.039 | 4.985 | 0.056 |
| Lymph nodes removed (total) | 1.926 | 0.588 | 8.379 | 0.038 | 0.179 | 0.981 |
| Radiotherapy | 2.045 | 0.563 | 0.438 | 0.932 | 0.473 | 0.925 |
| Regional nodal irradiation | 11.063 | 0.011 | 0.127 | 0.988 | 0.806 | 0.848 |
| Radiotherapy boost | 3.005 | 0.808 | 8.104 | 0.231 | 0.727 | 0.994 |
| High radiation dosage (>60 Gy) | 2.267 | 0.519 | 2.656 | 0.448 | 4.025 | 0.259 |
| Chemotherapy | 0.464 | 0.927 | 8.137 | 0.202 | 3.134 | 0.371 |
| Neoadjuvant or adjuvant | 4.839 | 0.848 | 8.070 | 0.527 | 25.882 | 0.002 |
| Number of chemotherapy sessions | 1.918 | 0.590 | 2.718 | 0.437 | 2.183 | 0.535 |
| Taxane-based chemotherapy | 1.863 | 0.601 | 1.615 | 0.656 | 0.116 | 0.989 |
| Breast reconstructive surgery | 2.729 | 0.435 | 1.639 | 0.651 | 1.585 | 0.663 |
| Monoclonal antibodies (anti-HER2) | 1.980 | 0.577 | 6.433 | 0.092 | 4.191 | 0.242 |
| Secondary analyses | ||||||
| Body mass index | 9.497 | 0.023 | 4.827 | 0.185 | 9.282 | 0.026 |
| Postmenopausal status | 16.533 | <0.001 | 3.098 | 0.377 | 3.409 | 0.333 |
| Clinical course | 6.611 | 0.678 | 25.347 | 0.003 | NA | NA |
aDecline, stable, gradual increase, rapid increase in clinical symptoms
bMastectomy or lumpectomy
cStatistically significant association after Bonferroni correction
HER2, human epidermal growth factor receptor 2; ICG-NIFI, indocyanine green lymphography with near-infrared fluorescence imaging; ISL, International Society of Lymphology
No significant associations were found between radiotherapy and ISL (p = 0.56) or ICG-NIFI stages (p = 0.93) and clinical progression (p = 0.93). Similarly, the application of radiation boosts, as well as radiation dosages exceeding 60 Gy, revealed no significant associations with ISL (p = 0.81; p = 0.52), ICG-NIFI stages (p = 0.23; p = 0.45), and clinical progression (p = 0.99; p = 0.26). Chemotherapy, regardless of timing or the number of sessions, demonstrated no significant association with ISL (p = 0.93; p = 0.85; p = 0.59) and ICG-NIFI stages (p = 0.20; p = 0.53; p = 0.44). Initial findings linking chemotherapy timing (adjuvant or neoadjuvant) and clinical course (p = 0.002) did not hold after Bonferroni correction. Taxane-based chemotherapy showed no significant effects on ISL (p = 0.60) and ICG-NIFI stages (p = 0.66) or clinical progression (p = 0.99). Breast reconstructive surgery also showed no significant effects on ISL (p = 0.44) and ICG-NIFI stages (p = 0.65) or clinical progression (p = 0.66). Secondary exploratory analyses Table 3 revealed significant associations between BMI and both ISL stages and clinical course (p = 0.023; p = 0.026), postmenopausal status and ISL stages (p<0.001), and clinical course and ICG-NIFI stages (p = 0.003).
Patient-Reported Outcome Measures
MHQ total scores varied significantly across ISL stages, with stage III scoring notably lower than stage I (mean difference −18.28; 95% confidence interval [CI] −34.99 to −1.57) and stage IIa (mean difference −13.38; 95% CI −26.35 to −0.41). Analysis of variance tests showed significant variations in Lymph-ICF, DASH, and EQ5D-5L scores with clinical progression. Post-hoc analysis highlighted significant differences in Lymph-ICF scores between “stable” and “gradual increase” groups (p = 0.004), in EQ5D-5L scores between “stable” and both “gradual increase” (p = 0.02) and “rapid increase” groups (p = 0.045), and in DASH between “stable” and “gradual increase” groups (p = 0.01). No associations were found between radiation dosage, chemotherapy sessions, and patient-reported QoL.
Discussion
This study provides a comprehensive characterization of patients with BCRL seeking microsurgical treatment at a tertiary care center. Although this cohort represents a selective, high-risk population, its characterization holds considerable clinical relevance because these are precisely the patient profiles that need to be identified earlier in the course of treatment to enable timely implementation of preventive strategies. As interest in LYMPHA and other preventive interventions continues to grow, a significant gap remains in the understanding of the patient population at risk. This study helps lessen the gap by outlining the lymphedema characteristics and treatment profiles of a population already referred for microsurgical treatment.
Compared with the general Dutch breast cancer population, patients in this cohort underwent more intensive oncological treatment.21 National trends over the past 25 years have shown a shift toward SLNB as the standard surgical axillary approach, with ALND rates decreasing from 70% in 2000 to 4% in 2023, and SLNB rates increasing from 33% to 84% in the same period.21 Despite this national trend, 89.6% of patients in this cohort underwent ALND. Additionally, 90.2% underwent chemotherapy, whereas the national average in 2023 was 30%.21 Similarly, 88.3% of patients in this cohort received radiotherapy, with the national average being approximately 64%.21 These findings highlight the high-risk nature of this cohort.
Interestingly, despite this cohort’s intensive oncologic treatment profile, BCRL severity and progression varied considerably. ALND was significantly associated with higher ICG-NIFI stages, supporting existing evidence identifying ALND as a major risk factor for BCRL.7,22,23 Radiotherapy, an equally recognized risk factor for BCRL as well as (taxane-based) chemotherapy, were anticipated to be associated with BCRL severity and progression based on treatment intensity.7,23–27 However, no significant associations were found between treatment modalities, such as radiotherapy, chemotherapy (including taxane-based regimens), or hormone therapy, and BCRL severity or progression. These findings suggest that, although breast cancer treatment may trigger the onset of BCRL, its intensity may not directly influence the condition’s progression, indicating that individual predisposition or susceptibility may play a larger role.26 Identifying the extent of this individual predisposition is crucial as these treatments continue to be a key component of breast cancer treatment.
Moreover, lymphedema staging did not consistently align with the years since onset, suggesting that BCRL progression is variable and not solely dependent on the time since onset. Distinct patterns were observed in the distribution of affected body parts relative to lymphedema severity. Earlier stages more commonly involved the breast and flank, whereas higher stages showed pronounced involvement of the hand, lower arm, and upper arm, suggesting a trend in lymphatic dysfunction from proximal to distal regions.
Clinical progression of BCRL, defined by changes in symptoms over time, showed that lower ICG-NIFI stages were often associated with stable or gradually worsening symptoms, whereas higher stages exhibited more variable symptom patterns. Patients with stable lymphedema reported better functional outcomes and QoL, emphasizing the importance of symptom stability. Most patients were classified as moderate to severe on the Lymph-ICF questionnaires, emphasizing the significant impact of lymphedema on QoL and the need for targeted interventions for symptom stability.
Finally, notable differences were observed between the two staging systems being used to classify BCRL severity, ISL and ICG-NIFI. Although both aim to quantify BCRL severity, different aspects of lymphedema are being scored. ISL staging reports clinical signs of lymphedema, which can vary within a single limb, complicating interpretation and classification.16 In contrast, ICG-NIFI provides a real-time view of the lymphatic system, allowing for a more objective assessment of lymphatic dysfunction and subsequently classification of severity.17 These differences underscore the need for a unified classification system to ensure consistency in evaluating BCRL severity.
Limitations and Suggestions for Future Research
This study’s findings are based on a highly selected patient population, limiting their generalizability. The study’s retrospective design and inherent data limitations necessitated the use of multivariate imputation by chained equations, whereas the small sample size also restricted subgroup analyses. Larger, prospective studies with more robust correction models are needed to validate these results and further explore variable interactions. Given the increasing influence of genetic makeup, future studies should consider expanding the scope of the data collected.
Conclusions
This study offers a comprehensive profiling of patients with BCRL seeking microsurgical treatment, revealing patterns in its development not previously described. Patients presented with various stages of lymphedema, irrespective of time since onset or prior treatments, suggesting a variable progression timeline. Contrary to expectations, oncological treatment intensity did not appear to influence lymphedema severity or progression within this cohort. These findings challenge existing theories and suggest that BCRL severity and progression may depend more on biological predisposition than oncological treatment intensity. Although the highly selective nature of this patient population warrants cautious interpretation, these findings contribute to the growing understanding of BCRL and lay the groundwork for future studies to identify at-risk patients, allowing for implementation of targeted, individually tailored preventive strategies.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgment
The authors extend their gratitude to Dr. JM Simons for the valuable insights into radiation therapy and to K. van Gemert for artistic contributions to the visual abstract.
Author contributions
D. van Gemert and Drs. Beelen had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. D. van Gemert and Drs. Beelen contributed equally as co-first authors.
Funding
This project received no financial support for the research, authorship, and/or publication of this article.
Data availability
The datasets generated and/or analyzed during the current study are not publicly available because of privacy or ethical restrictions but are available from the corresponding author on reasonable request.
Disclosure
The authors declare no conflicts of interest.
Ethical Approval
A non-WMO declaration was provided by the Medical Ethics Review Committee of the Erasmus Medical Center (MEC-2022-0569).
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated and/or analyzed during the current study are not publicly available because of privacy or ethical restrictions but are available from the corresponding author on reasonable request.