Risk factors for the development of severe breast cancer-related lymphedema: a retrospective cohort study

Lymphedema is a condition caused by impairment of the lymphatic system, which usually results in progressive swelling due to an abnormal accumulation of lymph fluid [1, 2]. Sufferers can experience negative physical, psychological, and emotional effects, and incur additional financial burdens [3]. Breast cancer-related lymphedema (BCRL) can be a painful, potential debilitating complication after axillary dissection and regional nodal irradiation for breast cancer, having a rate ranging from 9 to 65% [4‐6]. But due to the wider use of sentinel lymph node biopsy, the incidence of BCRL has decreased significantly, estimated to be 1–7% [7].

Although secondary lymphedema symptoms are usually mild and temporary, this group is three times more likely to suffer from moderate or severe edema compared to those with no symptoms[8]. The treatment of mild to moderate secondary lymphedema symptoms involves manual lymphatic drainage, massage, compression garments, and physical therapy [9]. However, for patients with advanced lymphedema, few treatments, including surgery, can halt the progress of the condition. Despite being the standard treatment for breast cancer, axillary lymph node dissection (ALND) may result in lymphedema in 20–50% of patients [10]. Other factors influencing include modified radical mastectomy (MRM), radiotherapy, body mass index (BMI), cellulitis, hypertension, education level, and chemotherapy[5, 11‐18].

To date, no systematic evaluation of severe lymphedema risk factors has been conducted. In this study, we conducted a retrospective clinical analysis of BCRL patients who underwent either conservative breast cancer surgery or mastectomy, with the ami of pinpointing the risk factors that are likely to lead to severe lymphedema. A nomogram was further developed to facilitate the prediction of severe lymphedema risk in future patients.

Breast cancer-related lymphedema is one of the most feared complications of post-surgery breast cancer survivors. Patients suffering from lymphedema frequently report a lower quality of life, poorer mobility, reduced self-esteem, coupled with an increased a higher risk of infection [16, 17]. Severe lymphedema is challenging to manage, has a higher risk of recurrence and progression, and requires long-term follow-up and monitoring. Identifying risk factors is crucial, as it aids physicians in recognizing high-risk patients and offering early interventions to prevent disease progression. A deeper understanding of risk factors can also lead to more effective treatment options. Despite the considerable evidence that has been collected regarding the risk factors for the development of lymphedema, the predictive indicators for severe lymphedema remain poorly understood. Therefore, this study examined, both individually and in combination, intraoperative or preoperative characteristics in BCRL patients in order to identify factors related to severe lymphedema and to develop a nomogram for assessing the severity of the lymphedema within 3 years of surgery. The results of this study revealed that advanced age, IPNs dissection, positive lymph nodes, and low education level were associated with an increased risk of developing severe lymphedema. IPNs dissection, in particular, had a greater influence on the development of severe lymphedema than the other risk factors. The nomogram, which integrated age, IPNs dissection, positive lymph nodes, and education level, showed a moderate performance in predicting the severity of lymphedema three years following surgery. Thus, this nomogram can be considered a useful tool for risk assessment and triage of the severity of lymphedema within 3 years of surgery.

Recent research highlighted a series of risk factors associated with lymphedema, including ALND, BMI, radiotherapy, age, chemotherapy, and the number of cycles of chemotherapy [15, 24, 25]. Chemotherapy may influence the inflammatory response and immunological status of cancer survivors, resulting in negative impacts on the normal operation of the lymphatic system [26]. It was suggetsed that BMI at BCRL diagnosis was the major risk factor associated with severe lymphedema [27]. However, findings from this study showed no significant association between BMI, chemotherapy, the number of cycles of chemotherapy and the severity of lymphedema. We hypothesize that sustained risk factors may determine the risk of developing severe lymph edema, since the negative impacts of BMI, radiotherapy, and chemotherapy can be reversed in subsequent in-hospital treatments, whereas age, educational level, and impaired lymphatic system are irreversible. A meta-analysis of 7 studies depicted that older patients were prone to suffer from severe forms of BCRL, yet the exact cause and effect relationship remains unclear [28]. In has been suggested that impaired contractility, increased permeability and immune cell dysfunction related to aging may explain the faster deterioration seen in older women [29]. Furthermore, this study also highlighted the importance of exploring a patient’s understanding of their disease and treatment options, as lower education levels have been linked to higher risk of severe lymphedema. Previously, Fu et al. demonstrated that BCRL patients with a lower education level were more likely to develop severe symptoms at 12 months post-surgery [30, 31].

It has been demonstrated that the incidence of lymphedema was highest in patients with thirty or more lymph nodes removed and increased with the number of positive nodes [21, 24, 32]. However, the association between the number of positive lymph nodes and the development of severe lymphedema remains unclear. Our study revealed that a larger number of positive nodes contribute to a higher risk of severe lymphedema, even though we did not find an association between total lymph node dissection and severe lymphedema. Generally, the more lymph nodes that are dissected, the more severely impaired lymph flow is. Nevertheless, it appears to be related to the location of the lymph nodes, as evidenced by the contribution of IPN to lymphedema. Thus, further investigations are necessary to delineate the exact role that the number of lymph nodes plays in the development of severe lymphedema. It is possible that lymphatic blockage from tumoral infiltration of the lymph node may be responsible for the slight increase in the risk of severe lymphedema by positive lymph nodes.

Notably, our data revealed that IPNs dissection had a considerable influence on the severity of lymphedema, which had not been addressed by previous studies focusing on BCRL risk factors. These findings suggest that IPNs dissection may be a crucial independent risk factor for the onset of lymphedema, which warrants further validation. IPNs, also referred to as Rotter’s nodes, located between pectoralis major and minor, are one of the lymphatic drainage pathways in breast cancer with a metastatic rate of only 4-9.9% [33]. At present, there is an ongoing discussion regarding whether routinely conducting IPNs dissection has any prospective prognostic or therapeutic benefits despite the recommendation from National Comprehensive Cancer Network (NCCN) in their guidelines [34]. Removal of interpectoral lymphatic tissue can lead to injury of the pectoral nerves and vessels, resulting in muscle atrophy and shoulder pain [35]. Our data further showed the contribution of IPNs removal to the development of severe lymphedema. Therefore, these data suggest that greater importance should be placed on IPN dissection and its inclusion in postoperative lymphatic management. For patients with pN0/N1 breast cancer, IPN clearance can be safely omitted even when modified radical mastectomy (MRM) breast conservation surgery is performed [36].

Our study has several limitations that should be considered. Firstly, our identification of risk factors of severe lymphedema was based on an limited regional retrospective database, which may not take into account potential ethnic or regional differences. Secondly, the internal validation of the results, which was conducted using bootstrapping, was limited by the small number of cases in the retrospective cohort. It would be preferable to validate the findings in external cohorts or prospective cohorts. Thirdly, our study only looked into the contribution of intraoperative clinical and laboratory indicators to severe lymphedema, while postoperative prevention and intervention are essential to the occurrence and development of the condition. Finally, due to the retrospective nature of our study, some risk factors associated with lymphedema were likely not included due to incomplete/unavailable data, which could limit the applicability of the nomogram. Thus, further research is required to combine the intraoperative and postoperative indicators to predict the development of severe lymphedema. Despite these limitations, we believe that the findings of this study are usable in terms of severe lymphedema prevention and further intervention globally.

In summary, we determined that age, IPNs dissection, positive lymph nodes, and education level were independent risk factors of severe lymphedema, with IPNs dissection having the most significant effect on the development of severe BCRL. These findings could be of use for the formulation of lymphedema surveillance strategies and the instruction of patients in clinical practice. Additionally, a nomogram incorporating age, IPNs dissection, positive lymph nodes, and education level was devised, which may be applied to conveniently evaluate the risk of severe lymphedema in patients undergoing surgery with ALND. Notwithstanding, further investigations in larger, multi-center, and prospective cohorts are necessary to validate these findings.